THE FOLLOWING ARE INFORMATION FROM PDR FOR TRETINOIN, MNINOXIDIL. FINASTERIDE, HYDROCORTISONE AND FLUOCINOLONE. THESE ARE THE ACTIVE INGREDIENTS IN OUR TOPICAL FORMULA.  PLEASE READ BELOW. BY USING THE PRODUCT, YOU AGREE AND CONSENT THAT YOU HAVE READ, AND UNDERSTOOD THE SIDE EFFECTS OF THESE MEDICATIONS.

 

TRETINOIN PDR  

  • CLASSES

    Antineoplastic Retinoids
    Anti-wrinkle Agents, Rx
    Topical Retinoids for use for Acne

    BOXED WARNING

    Requires a specialized care setting, requires an experienced clinician, respiratory insufficiency

    Oral tretinoin therapy requires an experienced clinician and requires a specialized care setting. Only clinicians experienced in the management of patients with acute leukemia should use oral tretinoin; patients who have acute promyelocytic leukemia are at high risk in general and may experience severe adverse reactions to tretinoin. Patients receiving oral tretinoin should be managed in facilities equipped and staffed with adequate laboratory and supportive medical services to monitor for drug toxicity and to care for patients compromised by these toxicities, including respiratory insufficiency.

    Acute promyelocytic leukemia differentiation syndrome

    Approximately 25% of patients who receive tretinoin for the treatment of acute promyelocytic leukemia have experienced acute promyelocytic leukemia differentiation syndrome. When seen in association with the use of tretinoin, this syndrome is also known as retinoic acid-acute promyelocytic leukemia (RA-APL) syndrome (see Adverse Reactions for more detailed description of RA-APL syndrome). Patients must be carefully monitored for any signs or symptoms of this syndrome.

    Leukocytosis

    In the treatment of acute promyelocytic leukemia, approximately 40% of patients will develop rapidly evolving leukocytosis, and these patients have a higher risk of life-threatening complications. High initial leukocyte counts or rapidly increasing leukocyte counts during treatment may be predictive of retinoic acid-acute promyelocytic leukemia (RA-APL) syndrome (see Adverse Reactions). However, RA-APL syndrome has been observed with or without concomitant leukocytosis. The manufacturer recommends the immediate initiation of high-dose steroids if signs and symptoms of RA-APL are present together with leukocytosis. Some clinicians routinely add chemotherapy to oral tretinoin therapy when patients present with a WBC count > 5000/mm3 or in the case of a rapid increase in WBC count in leukopenic patients at the start of treatment. Consideration could be given to adding chemotherapy (usually cytarabine and an anthracycline, if not contraindicated) to tretinoin therapy on day 1 or 2 for patients presenting with a WBC count > 5000/mm3 or immediately, for patients presenting with a WBC count of < 5000/mm3, if the WBC count reaches >= 6000/mm3 by day 5, >= 10,000/mm3 by day 10, or >= 15,000/mm3 by day 28. The majority of patients do not require discontinuation of tretinoin therapy during RA-APL syndrome.

    Contraception requirements, pregnancy, pregnancy testing, reproductive risk

    Teratogenic and embryotoxic effects have been demonstrated in animals receiving oral tretinoin or large doses (i.e., many times greater than the normal human dose) of topical tretinoin. Adequate and well-controlled trials have not been performed in humans, but increased spontaneous abortions and major human fetal abnormalities have occurred when pregnant women received other retinoids. There have been 30 case reports of temporally-associated, congenital malformations during 25 years of clinical use of Retin-A. The significance of these spontaneous reports in terms of risk to the fetus is not known. Avoid use of topical tretinoin over large areas of skin or for prolonged periods. The benefit-risk profile should be considered before prescribing. Reproductive risk should be discussed. There is a high risk of birth defects if oral tretinoin is administered during pregnancy. Females of childbearing potential must use two reliable forms of contraception simultaneously during oral tretinoin therapy and for one month following discontinuation of therapy, unless abstinence is the chosen method. Contraception requirements must be followed even when there is a history of infertility or menopause, unless a hysterectomy has been performed. Within one week of beginning tretinoin oral therapy, the patient should have a negative pregnancy test; if possible, treatment with tretinoin should be delayed until pregnancy testing results are known. Pregnancy testing and counseling should occur monthly during oral tretinoin therapy.[48166] [48167] [63467]

    DEA CLASS

    Rx

    DESCRIPTION

    Naturally occurring retinoid analog; also known as all-trans-retinoic acid (aTRA)
    Oral form used in acute promyelocytic leukemia; topical form used for cutaneous disorders like acne and photoaging
    Treatment with oral form may cause acute promyelocytic leukemia differentiation syndrome

    COMMON BRAND NAMES

    Altinac, Altreno, Atralin, AVITA, Refissa, Renova, Retin-A, Retin-A Micro, Tretin-X, Vesanoid

    HOW SUPPLIED

    Altinac/AVITA/Refissa/Renova/Retin-A/Tretinoin/Tretin-X Topical Cream: 0.02%, 0.025%, 0.0375%, 0.05%, 0.075%, 0.1%
    Altreno Topical Lotion: 0.05%
    Atralin/AVITA/Retin-A/Retin-A Micro/Tretinoin/Tretin-X Topical Gel: 0.01%, 0.025%, 0.04%, 0.05%, 0.06%, 0.08%, 0.1%
    Tretinoin/Vesanoid Oral Cap: 10mg

    DOSAGE & INDICATIONS

    For the treatment of acne vulgaris.
    Topical dosage
    Adults

    Apply a thin layer of topical tretinoin to the affected area(s) once daily at bedtime. Temporary discontinuation or reduction in application frequency may be necessary until the patient is able to tolerate the treatment. Frequency of application should be closely monitored by careful observation of the clinical response and skin tolerance; efficacy has not been established for less than once daily application frequency. Application of excessive amounts may result in ‘caking’ or ‘pilling’ and will not provide incremental efficacy. During the early weeks of treatment, an apparent exacerbation of inflammatory lesions may occur. If tolerated, this should not be considered a reason to discontinue therapy. Up to 7 weeks of therapy may be required before improvement is evident. This may be followed by a reduced dosage schedule. 

    Children and Adolescents 12 years and older

    Apply a thin layer of topical tretinoin to the affected area(s) once daily at bedtime. Temporary discontinuation or reduction in application frequency may be necessary until the patient is able to tolerate the treatment. Frequency of application should be closely monitored by careful observation of the clinical response and skin tolerance; efficacy has not been established for less than once daily application frequency. Application of excessive amounts may result in ‘caking’ or ‘pilling’ and will not provide incremental efficacy. During the early weeks of treatment, an apparent exacerbation of inflammatory lesions may occur. If tolerated, this should not be considered a reason to discontinue therapy. Up to 7 weeks of therapy may be required before improvement is evident. This may be followed by a reduced dosage schedule.[48167] [55916]

    Topical dosage (Atralin 0.05% gel)
    Adults

    Apply a thin layer to the affected area(s) once daily at bedtime. Temporary discontinuation or reduction in application frequency may be necessary until the patient is able to tolerate the treatment. Frequency of application should be closely monitored by careful observation of the clinical response and skin tolerance; efficacy has not been established for less than once daily application frequency. Application of excessive amounts may result in ‘caking’ or ‘pilling’ and will not provide incremental efficacy. During the early weeks of treatment, an apparent exacerbation of inflammatory lesions may occur. If tolerated, this should not be considered a reason to discontinue therapy. Up to 6 weeks of therapy may be required before improvement is evident. This may be followed by a reduced dosage schedule.

    Children and Adolescents 10 years and older

    Apply a thin layer to the affected area(s) once daily at bedtime. Temporary discontinuation or reduction in application frequency may be necessary until the patient is able to tolerate the treatment. Frequency of application should be closely monitored by careful observation of the clinical response and skin tolerance; efficacy has not been established for less than once daily application frequency. Application of excessive amounts may result in ‘caking’ or ‘pilling’ and will not provide incremental efficacy. During the early weeks of treatment, an apparent exacerbation of inflammatory lesions may occur. If tolerated, this should not be considered a reason to discontinue therapy. Up to 6 weeks of therapy may be required before improvement is evident. This may be followed by a reduced dosage schedule.[55917]

    Topical dosage (Altreno 0.05% lotion)
    Adults

    Apply a thin layer to the affected area(s) once daily. Temporary discontinuation or reduction in application frequency may be necessary until the patient is able to tolerate the treatment.

    Children and Adolescents 9 years and older

    Apply a thin layer to the affected area(s) once daily. Temporary discontinuation or reduction in application frequency may be necessary until the patient is able to tolerate the treatment.

    For adjunctive treatment of photoaging including palliation of fine facial wrinkles, facial mottled hyperpigmentation (i.e., ‘liver spots’), and facial skin roughness.
    Topical dosage (Renova 0.02% and 0.05%; Refissa 0.05%)
    Adults

    Apply a pea-sized amount to cover the entire affected area once daily before bedtime for 24 to 48 weeks. Most improvement is noted during the first 24 weeks of treatment. Use in combination with comprehensive skin care and sun avoidance programs. Brown spots begin to fade at around 6—8 weeks and there is a decrease in fine lines and wrinkles around 3 to 6 months. Discontinuation of treatment usually results in a loss of effect. The safety and efficacy of tretinoin therapy beyond 48 weeks has not been established.

    For the treatment of acute promyelocytic leukemia (APL). 
    NOTE: Retinoic acid-APL (RA-APL) syndrome characterized by fever, dyspnea, acute respiratory distress, weight gain, radiographic pulmonary infiltrates, pleural and pericardial effusions, edema, and hepatic, renal, and multi-organ failure requires prompt treatment with high-dose steroids (e.g., dexamethasone 10 mg IV every 12 hours for 3 days or until the resolution of symptoms). RA-APL syndrome may occur with or without leukocytosis.
    For remission induction treatment in patients with APL who are refractory to or who have relapsed from anthracycline chemotherapy or who have a contraindication to anthracycline-based therapy.
    Oral dosage
    Adults

    45 mg/m2/day PO in 2 equally divided doses until complete remission is documented. Therapy should be discontinued 30 days after remission or after 90 days of treatment, whichever occurs first. After induction therapy with tretinoin, all patients should receive standard consolidation and/or maintenance therapy for APL unless otherwise contraindicated.

    Adolescents and Children >= 1 year

    45 mg/m2/day PO in 2 divided doses after meals until complete remission is documented. Therapy should be discontinued 30 days after remission or after 90 days of treatment, whichever occurs first. A decrease in the recommended dosage may be considered for patients who experience serious or intolerable toxicity. However, the safety and efficacy of lower doses have not been established. After induction therapy with tretinoin, all patients should receive standard consolidation and/or maintenance therapy for APL unless otherwise contraindicated.

    For maintenance therapy following induction and consolidation therapy†.
    Oral dosage
    Adults, Adolescents, and Children

    45 mg/m2/day PO once daily or divided every 12 hours alone or with regimens containing 6-mercaptopurine and methotrexate for 1 to 2 years following induction and consolidation therapy has been studied in randomized clinical trials. Tretinoin was given daily for 1 year or for 15 days every 3 months alone or with 6-MP 90 mg/m2 PO daily plus methotrexate 15 mg/m2 PO once weekly for 2 years, or alternating every 3 months with 6-MP/methotrexate for 2 years. In one 4-arm trial, the 12-year disease-free survival (DFS) rates were not significantly different in patients who received 2 years of chemotherapy compared with no chemotherapy (68.9% vs 69%) or in patients who received 2 years of tretinoin compared with no tretinoin (68.3% vs 69.7%) in 318 patients who were (PCR)-negative for the PML-RARA fusion gene following induction therapy with tretinoin and idarubicin and 3 cycles of intensive consolidation therapy.The 10-year cumulative incidence of relapse was significantly decreased with 2 years of chemotherapy- and tretinoin-containing maintenance therapy in patients with a hematologic complete remission (CR) following either tretinoin or chemotherapy induction therapy and 2 cycles of consolidation therapy in another 4-arm trial; however, the 10-year overall survival rate was significantly improved with chemotherapy compared with no chemotherapy maintenance therapy (85.2% vs 79.2%; p = 0.02) but not with tretinoin compared with no tretinoin maintenance therapy (82.7% vs 79.4%). The 5-year DFS rate was significantly improved with 1 year of tretinoin maintenance therapy compared with observation only (61% vs 36%; p < 0.0001) in patients who achieved a CR following either tretinoin or chemotherapy induction therapy and 2 cycles of consolidation therapy in another randomized study.

    For remission induction and consolidation treatment in patients with newly diagnosed, low-risk APL in combination with arsenic trioxide†.
    Oral dosage
    Adults

    22.5 mg/m2 orally twice daily (dose rounded to the nearest 10-mg increment) in combination with arsenic 0.15 mg/kg IV over 2 hours once daily until bone marrow remission or for up to a maximum of 60 days as induction therapy followed by consolidation therapy with tretinoin 22.5 mg/m2 orally twice daily (dose rounded to the nearest 10-mg increment) as continuous therapy during weeks 1 and 2 (on all 4 cycles) and during weeks 5 and 6 (on cycles 1, 2, and 3 only) in combination with arsenic trioxide 0.15 mg/kg IV daily given 5 days per week for 4 consecutive weeks (total of 20 doses/cycle). Consolidation therapy is repeated every 8 weeks for 4 cycles. During induction therapy, all patients should receive differentiation syndrome prophylaxis with prednisone 0.5 mg/kg orally once daily.

    For remission induction treatment in patients with newly diagnosed APL, in combination with idarubicin†.
    Oral dosage
    Adults <= 61 years

    45 mg/m2/day PO in 2 divided doses until complete remission (CR) to a maximum of 45 or 90 days plus idarubicin 12 mg/m2/dose IV on days 2, 4, 6, and 8 has been evaluated in 2 clinical trials (AIDA 0493 study; AIDA 2000 study). Adults less than 20 years of age received tretinoin 25 mg/m2/day PO in the AIDA 0493 study. Patients who achieved a hematologic CR received 3 anthracycline-containing consolidation therapy courses. Additionally, most patients in these studies who achieved a molecular CR after consolidation received up to 2 years of tretinoin-containing maintenance therapy. Prophylactic use of corticosteroids was recommended during induction therapy to help prevent differentiation (retinoic acid) syndrome.

    Children and Adolescents

    25 mg/m2/day PO in 2 divided doses until complete remission (CR) or a maximum of 90 days plus idarubicin 12 mg/m2/dose IV on days 2, 4, 6, and 8 has been evaluated in a clinical trial (AIDA 0493 study). Patients who achieved a hematologic CR received 3 multi-agent chemotherapy consolidation courses containing anthracyclines and cytarabine. Additionally, most patients who achieved a molecular CR after consolidation received up to 2 years of tretinoin-containing maintenance therapy. In a subgroup analysis of the AIDA 0493 study, induction therapy with tretinoin plus idarubicin resulted in a post-induction hematologic CR rate of 96% in 107 evaluable pediatric patients (median age, 11.6 years; range, 1.4—17.9 years). Tretinoin was administered for a median of 32 days (range, 1—56 days) during induction therapy. The 10-year event-free survival and overall survival rates were 76% and 89%, respectively. Retinoic acid syndrome was reported in 8 patients (definitely present, n = 2; indeterminate, n = 6) and pseudotumor cerebri developed in 10 patients. There were 4 deaths during induction therapy.

    For consolidation treatment following tretinoin and idarubicin induction therapy in patients with newly diagnosed APL, in combination with idarubicin-containing chemotherapy†.
    Oral dosage
    Adults <= 61 years

    Following induction therapy with tretinoin (45 mg/m2/day PO in 2 divided daily doses until complete remission (CR) or a maximum of 45 days) plus idarubicin (12 mg/m2/dose IV on days 2, 4, 6, and 8), patients who achieved a hematologic CR received 3 risk-adapted tretinoin- and anthracycline-based consolidation therapy courses in a clinical study (AIDA 2000 study). All patients in this study received tretinoin 45 mg/m2/day PO for 15 days starting on day 1 of each consolidation cycle. Patients with low- or intermediate–risk APL (defined as an initial white blood cell count < 10 X 109/L) received: idarubicin 5 mg/m2/dose IV on days 1—4 (course 1), mitoxantrone 10 mg/m2/dose IV on days 1—5 (course 2); and idarubicin 12 mg/m2/dose on day 1 (course 3). Patients with high–risk APL received: idarubicin 5 mg/m2/dose IV on days 1—4 and cytarabine 1000 mg/m2/day IV on days 1—4 (course 1); mitoxantrone 10 mg/m2/dose IV on days 1—5 and etoposide 100 mg/m2/dose IV on days 1—5 (course 2); and idarubicin 12 mg/m2/dose IV on day 1, cytarabine 150 mg/m2 subcutaneously every 8 hours on days 1—5, and 6-thioguanine 70 mg/m2 PO every 8 hours on days 1—5 (course 3). Intrathecal methotrexate 12 mg and methylprednisone 40 mg were administered prior to each consolidation course in patients with high-risk disease. Additionally, patients who achieved a molecular CR after consolidation received up to 2 years of tretinoin-containing maintenance therapy.

    For the treatment of melasma†.
    Topical dosage
    Adults

    Topical tretinoin 0.05% to 0.1% applied once daily to affected areas in combination with hydroquinone with or without hydrocortisone has been effective. Treatment should also include avoidance of sun exposure and use of sunscreens. To decrease side effects, some studies have applied tretinoin twice weekly instead of daily.

    For the treatment of diseases of keratinization† (e.g., actinic keratosis†, ichthyosis†, keloids†, keratosis follicularis†); acne rosacea†; skin hyperpigmentation†.
    Topical dosage
    Adults

    Topical tretinoin 0.025% to 0.1% applied once daily to affected areas has been used in the treatment of various diseases of keratinization, often in combination with other agents.

    For the treatment of AIDS-related Kaposi’s sarcoma†.
    Oral dosage
    Adults

    Dose is not established; however, 45 mg/m2/day PO divided in 2 daily doses x12 weeks was studied in one phase II study; escalating doses up to 150 mg/m2/day divided in 3 daily doses have also been studied. Tretinoin resulted in a partial response (PR) rate of 42% in 19 patients with low-risk AIDS-related Kaposi sarcoma in a multicenter, phase II study; additionally, 37% of patients had stable disease (SD). Six patients also received concurrent antiretroviral therapy, although no patients received a protease inhibitor. Responding patients continued tretinoin therapy beyond 12 weeks (mean duration, 27 +/- 7 weeks; range, 16 to 36 weeks) and the median time to response and time to disease progression in these patients were 56 and 332 days, respectively. Treatment with escalating doses of tretinoin (initial dosage of 45 mg/m2/day in 2 daily doses given every 12 hours on week 1 titrated weekly to a target dosage of 150 mg/m2/day in 3 daily doses given every 8 hours by week 5; median dosage of 90 mg/m2/day; range, 70-300 mg/day) led to a PR rate of 17% in 24 evaluable patients with mucocutaneous, nonvisceral AIDS-related Kaposi’s sarcoma in another phase II trial; additionally, 13% of patients achieved a minor response and 29% of patients had SD. Most patients (74%) in this study had not received prior treatment for AIDS-related Kaposi sarcoma and 89% of patients were receiving concurrent antiretroviral therapy. The median time to response was 22 weeks (range, 12 to 28 weeks). At a median follow-up of 5 months (range, 1 to 17 months), the median disease-free survival time was 5 months and the median overall survival time was 27.3 months.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    The maximum tolerated oral dose in patients with myelodysplastic syndromes or solid tumors was 195 mg/m2 PO.

    Elderly

    The maximum tolerated oral dose in patients with myelodysplastic syndromes or solid tumors was 195 mg/m2 PO.

    Adolescents

    The maximum oral dose in pediatric patients is 60 mg/m2 PO.

    Children

    The maximum oral dose in pediatric patients is 60 mg/m2 PO.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    The clearance of systemic tretinoin would be expected to be greatly decreased in patients with hepatic impairment; however, no specific dosage adjustment guidelines are available. It has been recommended if hepatic enzymes increase to > 5-times the upper limit of normal consideration should be given to temporarily discontinuing oral tretinoin therapy.

    Renal Impairment

    Specific guidelines for dosage adjustments of systemic tretinoin therapy in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration

    The effects of food on tretinoin bioavailability are unknown. The manufacturer makes no specific recommendations on oral administration, however, the absorption of retinoids as a class is enhanced by food.
    Females of childbearing potential must use two reliable forms of contraception simultaneously during oral tretinoin therapy and for one month following discontinuation of therapy, unless abstinence is the chosen method. Within one week of beginning tretinoin oral therapy, the patient should have a negative pregnancy test; if possible, treatment with tretinoin should be delayed until the results of the pregnancy test are known. Pregnancy testing and counseling should occur monthly during oral tretinoin therapy.
    Acute promyelocytic leukemia (APL) patients are considered high risk and administration of oral tretinoin may result in severe adverse reactions. Administration of tretinoin to these patients should be done only under the supervision of physicians experienced in the treatment of acute leukemia, and at a facility equipped to manage such adverse reactions, including respiratory compromise. It should be determined prior to the initiation of treatment that the benefit of therapy outweighs the risks to the patient.

    Topical Administration

    Topical tretinoin is a dermal irritant; the dermatologic response to greater than 48 weeks of chronic therapy is not known.
    Before applying topical formulations of tretinoin, clean affected area with a mild soap, pat skin dry and wait 20—30 minutes before applying the product. The microsphere gel may be applied immediately after washing the face.

    Cream/Ointment/Lotion Formulations

    Cream: Rub cream gently into the affected area. Avoid over-application. Wash hands immediately after applying.
    Lotion: Apply thin layer to cover affected areas. Wash hands immediately after applying.[63467]

    Other Topical Formulations

    Solution: Apply using clean fingertips, a gauze pad, or cotton swabs to the cleansed affected area. Avoid over-saturation of gauze or cotton to prevent the solution from running onto unaffected areas. Wash hands immediately after applying.
    Gel: Apply lightly to the affected area. Excessive application results in pilling of the gel. Wash hands immediately after applying.
    Microsphere gel: Apply lightly to the affected area. Excessive application results in caking of the gel. Wash hands immediately after applying.

    STORAGE

    Altinac:
    – Store below 80 degrees F
    Altreno:
    – Protect from freezing
    – Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Atralin:
    – Protect from freezing
    – Store at controlled room temperature (between 68 and 77 degrees F)
    AVITA:
    – Store below 80 degrees F
    Refissa:
    – Store below 80 degrees F
    Renova:
    – Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Retin-A:
    – Store below 80 degrees F
    Retin-A Micro:
    – Flammable, keep away from heat and flame
    – Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Tretin-X:
    – Store below 80 degrees F
    Vesanoid:
    – Protect from light
    – Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Requires a specialized care setting, requires an experienced clinician, respiratory insufficiency

    Oral tretinoin therapy requires an experienced clinician and requires a specialized care setting. Only clinicians experienced in the management of patients with acute leukemia should use oral tretinoin; patients who have acute promyelocytic leukemia are at high risk in general and may experience severe adverse reactions to tretinoin. Patients receiving oral tretinoin should be managed in facilities equipped and staffed with adequate laboratory and supportive medical services to monitor for drug toxicity and to care for patients compromised by these toxicities, including respiratory insufficiency.

    Retinoid hypersensitivity

    Tretinoin is contraindicated in patients who experience retinoid hypersensitivity reactions to vitamin A or other retinoids because cross-sensitivity between agents is possible. True contact allergy to tretinoin is rare.

    Paraben hypersensitivity

    Oral tretinoin should not be administered to patients who have paraben hypersensitivity. Paraben is used as a preservative in the gelatin capsule.

    Fish hypersensitivity

    The Atralin brand of tretinoin gel and Altreno brand of tretinoin lotion contain soluble fish proteins and should be used with caution in patients with known fish hypersensitivity. Patients should be instructed to contact their health care provider if they develop pruritus or urticaria following application.[63467]

    Acute promyelocytic leukemia differentiation syndrome

    Approximately 25% of patients who receive tretinoin for the treatment of acute promyelocytic leukemia have experienced acute promyelocytic leukemia differentiation syndrome. When seen in association with the use of tretinoin, this syndrome is also known as retinoic acid-acute promyelocytic leukemia (RA-APL) syndrome (see Adverse Reactions for more detailed description of RA-APL syndrome). Patients must be carefully monitored for any signs or symptoms of this syndrome.

    Leukocytosis

    In the treatment of acute promyelocytic leukemia, approximately 40% of patients will develop rapidly evolving leukocytosis, and these patients have a higher risk of life-threatening complications. High initial leukocyte counts or rapidly increasing leukocyte counts during treatment may be predictive of retinoic acid-acute promyelocytic leukemia (RA-APL) syndrome (see Adverse Reactions). However, RA-APL syndrome has been observed with or without concomitant leukocytosis. The manufacturer recommends the immediate initiation of high-dose steroids if signs and symptoms of RA-APL are present together with leukocytosis. Some clinicians routinely add chemotherapy to oral tretinoin therapy when patients present with a WBC count > 5000/mm3 or in the case of a rapid increase in WBC count in leukopenic patients at the start of treatment. Consideration could be given to adding chemotherapy (usually cytarabine and an anthracycline, if not contraindicated) to tretinoin therapy on day 1 or 2 for patients presenting with a WBC count > 5000/mm3 or immediately, for patients presenting with a WBC count of < 5000/mm3, if the WBC count reaches >= 6000/mm3 by day 5, >= 10,000/mm3 by day 10, or >= 15,000/mm3 by day 28. The majority of patients do not require discontinuation of tretinoin therapy during RA-APL syndrome.

    Skin photosensitivity disorder, sunburn, sunlight (UV) exposure

    Retinoids may cause photosensitivity.[30713] Treatment with topical tretinoin should be postponed until sunburn has resolved to avoid exacerbation of the irritation, inflammation, and dryness associated with sunburned skin. Patients with a skin photosensitivity disorder should be closely evaluated prior to receiving tretinoin therapy. If sun exposure cannot be avoided during topical tretinoin therapy, sunscreen products and physical sun blocks (protective clothing, hats) are recommended for protection of treated areas. Sunlight (UV) exposure potentiates the inflammatory effects of tretinoin. Patients who may have considerable sun exposure due to their occupation and those patients with inherent sensitivity to sunlight should exercise particular caution when using topical tretinoin. Weather extremes, such as wind or cold, also may be irritating to patients receiving tretinoin.

    Eczema

    Topical tretinoin should be avoided, if possible, in patients with eczema because severe irritation of eczematous skin is likely.

    Hepatic disease

    Elevated hepatic enzymes has been reported in patients receiving oral tretinoin. Patients with hepatic disease could be more prone to developing this condition. It is recommended that if the serum hepatic enzyme levels are greater than 5-times the upper limit of normal, consideration should be given to temporarily discontinuing oral tretinoin therapy.

    Contraception requirements, pregnancy, pregnancy testing, reproductive risk

    Teratogenic and embryotoxic effects have been demonstrated in animals receiving oral tretinoin or large doses (i.e., many times greater than the normal human dose) of topical tretinoin. Adequate and well-controlled trials have not been performed in humans, but increased spontaneous abortions and major human fetal abnormalities have occurred when pregnant women received other retinoids. There have been 30 case reports of temporally-associated, congenital malformations during 25 years of clinical use of Retin-A. The significance of these spontaneous reports in terms of risk to the fetus is not known. Avoid use of topical tretinoin over large areas of skin or for prolonged periods. The benefit-risk profile should be considered before prescribing. Reproductive risk should be discussed. There is a high risk of birth defects if oral tretinoin is administered during pregnancy. Females of childbearing potential must use two reliable forms of contraception simultaneously during oral tretinoin therapy and for one month following discontinuation of therapy, unless abstinence is the chosen method. Contraception requirements must be followed even when there is a history of infertility or menopause, unless a hysterectomy has been performed. Within one week of beginning tretinoin oral therapy, the patient should have a negative pregnancy test; if possible, treatment with tretinoin should be delayed until pregnancy testing results are known. Pregnancy testing and counseling should occur monthly during oral tretinoin therapy.[48166] [48167] [63467]

    Breast-feeding

    According to the manufacturers, breast-feeding should be discontinued prior to receiving oral tretinoin and caution should be used with topical tretinoin. It is unknown whether oral or topical tretinoin is distributed into breast milk. Systemic absorption of tretinoin after topical application is low , and therefore it is unlikely that a significant amount of the drug is excreted into breast-milk. However, consideration for the use of an alternative topical agent (e.g., azelaic acid, benzoyl peroxide, clindamycin, erythromycin) may be appropriate for some patients. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants, neonates

    With the exception of the 0.05% lotion (approved for use in children 9 years and older) and 0.05% gel (approved for use in children 10 years and older) formulations, safety and efficacy of topical tretinoin have not been established in neonates, infants and children under 12 years of age. Children are prone to developing severe headache and pseudotumor cerebri while receiving oral tretinoin. For relief, some patients may require treatment with analgesics or lumbar puncture. The safety and efficacy of oral tretinoin in infants have not been established.[63467]

    Hypercholesterolemia, hyperlipidemia, hypertriglyceridemia

    Oral tretinoin should be used cautiously in patients with hyperlipidemia. Hypercholesterolemia and/or hypertriglyceridemia occurs in as many as 60% of patients receiving oral tretinoin. Monitor the lipid profile while patients are receiving oral tretinoin.

    Accidental exposure, ocular exposure

    Tretinoin cream, gel, lotion, and liquid are for external use only. Avoid ocular exposure, including eyelids, and contact with the mouth, angles of the nose, and mucous membranes. If eye contact occurs, rinse thoroughly with large amounts of water. Apply only to affected areas; accidental exposure to unaffected skin may cause irritation. Topical tretinoin is flammable; do not use near heat, open flame, or while smoking.

    ADVERSE REACTIONS

    Severe

    GI bleeding / Delayed / 34.0-34.0
    disseminated intravascular coagulation (DIC) / Delayed / 26.0-26.0
    arrhythmia exacerbation / Early / 23.0-23.0
    pleural effusion / Delayed / 20.0-20.0
    visual impairment / Early / 17.0-17.0
    increased intracranial pressure / Early / 9.0-9.0
    intracranial bleeding / Delayed / 9.0-9.0
    heart failure / Delayed / 6.0-6.0
    hearing loss / Delayed / 6.0-6.0
    pulmonary edema / Early / 3.0-3.0
    laryngeal edema / Rapid / 3.0-3.0
    peptic ulcer / Delayed / 3.0-3.0
    cardiomyopathy / Delayed / 3.0-3.0
    pericarditis / Delayed / 3.0-3.0
    pulmonary hypertension / Delayed / 3.0-3.0
    myocarditis / Delayed / 3.0-3.0
    myocardial infarction / Delayed / 3.0-3.0
    cardiac arrest / Early / 3.0-3.0
    stroke / Early / 3.0-3.0
    agnosia / Delayed / 3.0-3.0
    seizures / Delayed / 3.0-3.0
    coma / Early / 3.0-3.0
    renal failure (unspecified) / Delayed / 3.0-3.0
    renal tubular necrosis / Delayed / 3.0-3.0
    erythema nodosum / Delayed / Incidence not known
    differentiation syndrome / Delayed / Incidence not known
    pericardial effusion / Delayed / Incidence not known
    hypervitaminosis A / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    papilledema / Delayed / Incidence not known
    spontaneous fetal abortion / Delayed / Incidence not known
    teratogenesis / Delayed / Incidence not known

    Moderate

    bone pain / Delayed / 77.0-77.0
    dyspnea / Early / 60.0-60.0
    elevated hepatic enzymes / Delayed / 50.0-60.0
    hyperlipidemia / Delayed / 0-60.0
    bleeding / Early / 60.0-60.0
    fluid retention / Delayed / 29.0-52.0
    peripheral edema / Delayed / 52.0-52.0
    stomatitis / Delayed / 26.0-26.0
    constipation / Delayed / 17.0-17.0
    wheezing / Rapid / 14.0-14.0
    hypotension / Rapid / 14.0-14.0
    depression / Delayed / 14.0-14.0
    phlebitis / Rapid / 11.0-11.0
    hypertension / Early / 11.0-11.0
    confusion / Early / 11.0-11.0
    flank pain / Delayed / 9.0-9.0
    hepatomegaly / Delayed / 9.0-9.0
    splenomegaly / Delayed / 9.0-9.0
    dysuria / Early / 9.0-9.0
    edema / Delayed / 6.0-6.0
    hallucinations / Early / 6.0-6.0
    ascites / Delayed / 3.0-3.0
    hepatitis / Delayed / 3.0-3.0
    impaired cognition / Early / 3.0-3.0
    ataxia / Delayed / 3.0-3.0
    dysarthria / Delayed / 3.0-3.0
    aphasia / Delayed / 3.0-3.0
    encephalopathy / Delayed / 3.0-3.0
    thrombocytosis / Delayed / 0-1.0
    erythema / Early / 10.0
    hypoxia / Early / Incidence not known
    respiratory depression / Rapid / Incidence not known
    pseudotumor cerebri / Delayed / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known
    hypercholesterolemia / Delayed / Incidence not known
    hypercalcemia / Delayed / Incidence not known

    Mild

    headache / Early / 86.0-86.0
    fever / Early / 83.0-83.0
    fatigue / Early / 66.0-66.0
    malaise / Early / 66.0-66.0
    shivering / Rapid / 63.0-63.0
    vomiting / Early / 57.0-57.0
    nausea / Early / 57.0-57.0
    rash / Early / 54.0-54.0
    leukocytosis / Delayed / 40.0-40.0
    abdominal pain / Early / 31.0-31.0
    weight gain / Delayed / 23.0-23.0
    diarrhea / Early / 23.0-23.0
    flushing / Rapid / 23.0-23.0
    otalgia / Early / 23.0-23.0
    dizziness / Early / 20.0-20.0
    diaphoresis / Early / 20.0-20.0
    anorexia / Delayed / 17.0-17.0
    weight loss / Delayed / 17.0-17.0
    anxiety / Delayed / 17.0-17.0
    paresthesias / Delayed / 17.0-17.0
    alopecia / Delayed / 14.0-14.0
    myalgia / Early / 14.0-14.0
    dyspepsia / Early / 14.0-14.0
    insomnia / Early / 14.0-14.0
    agitation / Early / 9.0-9.0
    pallor / Early / 6.0-6.0
    asterixis / Delayed / 3.0-3.0
    weakness / Early / 3.0-3.0
    tremor / Early / 3.0-3.0
    hyporeflexia / Delayed / 3.0-3.0
    drowsiness / Early / 3.0-3.0
    hypothermia / Delayed / 3.0-3.0
    increased urinary frequency / Early / 3.0-3.0
    skin hyperpigmentation / Delayed / 2.0-2.0
    skin hypopigmentation / Delayed / 2.0-2.0
    skin irritation / Early / 10.0
    pruritus / Rapid / 20.0
    xerosis / Delayed / 10.0
    photosensitivity / Delayed / Incidence not known
    vesicular rash / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abciximab: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as tretinoin. 
    Acetohexamide: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as sulfonylureas, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Adapalene; Benzoyl Peroxide: (Moderate) Benzoyl peroxide can potentiate the skin irritation caused by topical tretinoin. Concurrent application of these agents on areas treated with tretinoin should be avoided. 
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Alpha interferons: (Moderate) Use of alpha interferons are associated with myelosuppression; additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives. 
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Aminocaproic Acid: (Major) Rare cases of fatal thrombotic complications have been reported in patients treated with systemic tretinoin, and antifibrinolytic agents. This is thought to be due to the persistent procoagulant tendency often associated with systemic tretinoin, ATRA therapy. Monitor patients closely and avoid if possible. 
    Amiodarone: (Moderate) The concomitant use of systemic tretinoin, ATRA and amiodarone should be done cautiously due to the potential for increased cranial pressure and an increased risk of pseudotumor cerebri. Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea, vomiting, and visual disturbances. 
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Anagrelide: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as tretinoin. 
    Anticoagulants: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Antithrombin III: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Antithymocyte Globulin: (Moderate) Because antithymocyte globulin is an immunosuppressant, additive affects may be seen with other immunosuppressives or antineoplastic agents. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk of infection or other side effects. 
    Apixaban: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Aprotinin: (Major) Rare cases of fatal thrombotic complications have been reported in patients treated with systemic tretinoin and antifibrinolytic agents. This is thought to be due to the persistent procoagulant tendency often associated with systemic tretinoin therapy. Monitor patients closely and avoid if possible. 
    Argatroban: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Aspirin, ASA; Dipyridamole: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as tretinoin. 
    Atenolol; Chlorthalidone: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Azelastine; Fluticasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Azilsartan; Chlorthalidone: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Barbiturates: (Moderate) Barbiturates may increase the CYP450 metabolism of tretinoin, ATRA, potentially resulting in decreased plasma concentrations of tretinoin, ATRA. Monitor for decreased clinical effects of tretinoin, ATRA while receiving concomitant therapy. 
    Beclomethasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Bendroflumethiazide; Nadolol: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Benzoyl Peroxide: (Moderate) Benzoyl peroxide can potentiate the skin irritation caused by topical tretinoin. Concurrent application of these agents on areas treated with tretinoin should be avoided. 
    Benzoyl Peroxide; Clindamycin: (Moderate) Benzoyl peroxide can potentiate the skin irritation caused by topical tretinoin. Concurrent application of these agents on areas treated with tretinoin should be avoided. 
    Benzoyl Peroxide; Erythromycin: (Moderate) Benzoyl peroxide can potentiate the skin irritation caused by topical tretinoin. Concurrent application of these agents on areas treated with tretinoin should be avoided. 
    Benzoyl Peroxide; Sulfur: (Moderate) Benzoyl peroxide can potentiate the skin irritation caused by topical tretinoin. Concurrent application of these agents on areas treated with tretinoin should be avoided. 
    Betamethasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Betrixaban: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Bivalirudin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Budesonide: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Budesonide; Formoterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Carbamazepine: (Moderate) Concurrent use of hepatic cytochrome P450 inducers, such as carbamazepine, with oral tretinoin therapy may result in significant decreases in serum tretinoin levels. Patients should be closely monitored for decreased clinical effects of tretinoin while receiving concomitant therapy. Also monitor for potential additive side effects, such as risk of infection. 
    Chlorothiazide: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Chlorpromazine: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Chlorpropamide: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as sulfonylureas, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Chlorthalidone: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Chlorthalidone; Clonidine: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Cholestyramine: (Moderate) Cholestyramine can bind with and possibly decrease the oral absorption of tretinoin. To minimize drug interactions, administer other drugs at least 1 hour before or at least 4 to 6 hours after the administration of cholestyramine. 
    Ciclesonide: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Cilostazol: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as tretinoin. 
    Cimetidine: (Moderate) Cimetidine may decrease the CYP450 metabolism of systemic tretinoin, ATRA, potentially resulting in increased plasma concentrations of tretinoin, ATRA. 
    Ciprofloxacin: (Moderate) Use tretinoin with caution in patients who are also taking drugs known to be photosensitizers, such as ciprofloxacin, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Clopidogrel: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as tretinoin. 
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist. 
    Cod Liver Oil: (Severe) Patients should avoid or limit supplementation with vitamin A during treatment with retinoids to avoid potential additive toxic effects. 
    Colestipol: (Moderate) The bile-acid sequesterant colestipol is well-known to cause drug interactions by binding and decreasing the oral administration of many drugs, which may include interaction with oral tretinoin; to minimize drug interactions, administer other drugs at least 1 hour before or at least 4 to 6 hours after the administration of cholestyramine or colestipol. 
    Corticosteroids: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Corticotropin, ACTH: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Cortisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Cyclosporine: (Moderate) Cyclosporine may decrease the CYP450 metabolism of tretinoin, ATRA, potentially resulting in increased plasma concentrations of tretinoin, ATRA. No specific studies have been done with oral tretinoin and cyclosporine, however, patients should be closely monitored for tretinoin toxicity while receiving concomitant therapy. 
    Dabigatran: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Dalteparin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Danaparoid: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Danazol: (Moderate) The concomitant use of systemic tretinoin, ATRA and danazol should be done cautiously due to the potential for increased intracranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea, vomiting, and visual disturbances. 
    Deflazacort: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Desirudin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Dexamethasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Diclofenac: (Minor) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Diclofenac; Misoprostol: (Minor) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy. 
    Diltiazem: (Moderate) Diltiazem may decrease the CYP450 metabolism of tretinoin, ATRA, potentially resulting in increased plasma concentrations of tretinoin, ATRA. 
    Diphenhydramine; Ibuprofen: (Moderate) The concomitant use of systemic tretinoin, ATRA and ibuprofen should be done cautiously due to the potential for increased intracranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea, vomiting, and visual disturbances. 
    Diphenhydramine; Naproxen: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Dipyridamole: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as tretinoin. 
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to drugs that alter immune system activity like antineoplastic drugs. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources. 
    Edoxaban: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Enoxaparin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Eptifibatide: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as tretinoin. 
    Eravacycline: (Major) Avoid the concomitant use of systemic tretinoin and eravacycline due to the potential for increased cranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Early signs and symptoms include papilledema, headache, nausea, vomiting, and visual disturbances. In addition, a manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking photosensitizers, such as eravacycline, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Erythromycin: (Moderate) Erythromycin may decrease the CYP450 metabolism of tretinoin, ATRA, potentially resulting in increased plasma concentrations of tretinoin, ATRA. No specific studies have been done with oral tretinoin and erythromycin, however, patients should be closely monitored for tretinoin toxicity while receiving concomitant therapy. 
    Erythromycin; Sulfisoxazole: (Moderate) Erythromycin may decrease the CYP450 metabolism of tretinoin, ATRA, potentially resulting in increased plasma concentrations of tretinoin, ATRA. No specific studies have been done with oral tretinoin and erythromycin, however, patients should be closely monitored for tretinoin toxicity while receiving concomitant therapy. 
    Esomeprazole; Naproxen: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Etodolac: (Minor) An increased risk of bleeding may occur when NSAIDs, such as etodolac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Famotidine; Ibuprofen: (Moderate) The concomitant use of systemic tretinoin, ATRA and ibuprofen should be done cautiously due to the potential for increased intracranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea, vomiting, and visual disturbances. 
    Felbamate: (Moderate) Felbamate may increase the CYP450 metabolism of tretinoin, ATRA, potentially resulting in decreased plasma concentrations of tretinoin, ATRA. Monitor for decreased clinical effects of tretinoin, ATRA while receiving concomitant therapy. 
    Fenoprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as fenoprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Filgrastim, G-CSF: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy. 
    Fludrocortisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Flunisolide: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Fluphenazine: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Flurbiprofen: (Minor) An increased risk of bleeding may occur when NSAIDs, such as flurbiprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Fluticasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Fluticasone; Salmeterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Fluticasone; Umeclidinium; Vilanterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Fluticasone; Vilanterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Fondaparinux: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Formoterol; Mometasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Gemifloxacin: (Moderate) Use tretinoin with caution in patients who are also taking drugs known to be photosensitizers, such as gemifloxacin, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Gentamicin: (Moderate) The concomitant use of systemic tretinoin, ATRA and systemic gentamicin should be done cautiously due to the potential for increased intracranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea, vomiting, and visual disturbances. 
    Glimepiride: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as sulfonylureas, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Glimepiride; Pioglitazone: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as sulfonylureas, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Glimepiride; Rosiglitazone: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as sulfonylureas, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Glipizide: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as sulfonylureas, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Glipizide; Metformin: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as sulfonylureas, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Glyburide: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as sulfonylureas, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Glyburide; Metformin: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as sulfonylureas, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Griseofulvin: (Moderate) Griseofulvin may increase the CYP450 metabolism of tretinoin, ATRA, potentially resulting in decreased plasma concentrations of tretinoin, ATRA. No specific studies have been done with oral tretinoin and griseofulvin, however, patients should be closely monitored for decreased clinical effects of tretinoin, ATRA while receiving concomitant therapy. Additionally, a manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as griseofulvin, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Heparin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Hydantoins: (Moderate) Concurrent oral tretinoin therapy with drugs that are inducers of the hepatic cytochrome P450 enzyme system like the hydantoin anticonvulsants can result in significant decreases in serum tretinoin levels, a CYP450 substrate. Monitor for decreased clinical effects while receiving concomitant therapy. 
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Hydrochlorothiazide, HCTZ; Irbesartan: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Hydrochlorothiazide, HCTZ; Losartan: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Hydrochlorothiazide, HCTZ; Spironolactone: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Hydrochlorothiazide, HCTZ; Telmisartan: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Hydrochlorothiazide, HCTZ; Triamterene: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Hydrocodone; Ibuprofen: (Moderate) The concomitant use of systemic tretinoin, ATRA and ibuprofen should be done cautiously due to the potential for increased intracranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea, vomiting, and visual disturbances. 
    Hydrocortisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Ibuprofen: (Moderate) The concomitant use of systemic tretinoin, ATRA and ibuprofen should be done cautiously due to the potential for increased intracranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea, vomiting, and visual disturbances. 
    Ibuprofen; Oxycodone: (Moderate) The concomitant use of systemic tretinoin, ATRA and ibuprofen should be done cautiously due to the potential for increased intracranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea, vomiting, and visual disturbances. 
    Ibuprofen; Pseudoephedrine: (Moderate) The concomitant use of systemic tretinoin, ATRA and ibuprofen should be done cautiously due to the potential for increased intracranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea, vomiting, and visual disturbances. 
    Indapamide: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Indomethacin: (Major) An increased risk of bleeding may occur when NSAIDs, such as indomethacin, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Interferon Alfa-2a: (Moderate) Use of alpha interferons are associated with myelosuppression; additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives. 
    Interferon Alfa-2b: (Moderate) Use of alpha interferons are associated with myelosuppression; additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives. 
    Interferon Alfa-2b; Ribavirin: (Moderate) Use of alpha interferons are associated with myelosuppression; additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives. 
    Interferon Alfacon-1: (Moderate) Use of alpha interferons are associated with myelosuppression; additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives. 
    Interferon Alfa-n3: (Moderate) Use of alpha interferons are associated with myelosuppression; additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives. 
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Rifampin may increase the CYP450 metabolism of tretinoin, ATRA, potentially resulting in decreased plasma concentrations of tretinoin, ATRA. No specific studies have been done with oral tretinoin and rifampin, however, patients should be closely monitored for decreased clinical effects of tretinoin, ATRA while receiving concomitant therapy. 
    Isoniazid, INH; Rifampin: (Moderate) Rifampin may increase the CYP450 metabolism of tretinoin, ATRA, potentially resulting in decreased plasma concentrations of tretinoin, ATRA. No specific studies have been done with oral tretinoin and rifampin, however, patients should be closely monitored for decreased clinical effects of tretinoin, ATRA while receiving concomitant therapy. 
    Ketoconazole: (Major) Concurrent oral tretinoin therapy with drugs that inhibit the hepatic cytochrome (CYP) P450 enzyme system can result in significant increases in serum tretinoin levels. In 13 patients who had received oral tretinoin daily for 4 consecutive weeks, a 72% increase in mean tretinoin plasma AUC was observed when ketoconazole (400 mg to 1200 mg PO) was given 1 hour before the tretinoin dose. This interaction may be due to inhibition of tretinoin metabolism by the azole antifungal; the precise CYP enzymes involved have not been identified, but CYP3A, 2C8 and 2E have been implicated in preliminary data. Similar interactions may occur with other systemic azole antifungals, such as voriconazole. No specific studies have been done with oral tretinoin and other inhibitors of CYP450 isoenzymes (such as cimetidine, cyclosporine, diltiazem, erythromycin, and verapamil), however, patients should be closely monitored for tretinoin toxicity while receiving concomitant therapy. 
    Ketorolac: (Major) An increased risk of bleeding may occur when NSAIDs, such as ketorolac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Lansoprazole; Naproxen: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Lepirudin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Levofloxacin: (Moderate) Use tretinoin with caution in patients who are also taking drugs known to be photosensitizers, such as levofloxacin, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Lithium: (Moderate) The concomitant use of systemic tretinoin, ATRA and lithium should be done cautiously due to the potential for increased intracranial pressure and an increased risk of pseudotumor cerebri. Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea, vomiting, and visual disturbances. 
    Meclofenamate Sodium: (Major) An increased risk of bleeding may occur when NSAIDs, such as meclofenamate sodium, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Mefenamic Acid: (Major) An increased risk of bleeding may occur when NSAIDs, such as mefenamic acid, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Meloxicam: (Minor) An increased risk of bleeding may occur when NSAIDs, such as meloxicam, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Mesoridazine: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Methotrexate: (Major) Concomitant use of systemic retinoids, such as tretinoin, and methotrexate could increase risk of liver-related side effects of methotrexate and such patients should be monitored closely during methotrexate therapy. Topical retinoid products do not appear to pose this increased risk for liver problems. 
    Methoxsalen: (Moderate) Use methoxsalen and retinoids together with caution; the risk of severe burns/phototoxicity may be additive. If concurrent use is necessary, closely monitor patients for signs or symptoms of skin toxicity. 
    Methyclothiazide: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Methylprednisolone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Metolazone: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Mometasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Moxifloxacin: (Moderate) Use tretinoin with caution in patients who are also taking drugs known to be photosensitizers, such as moxifloxacin, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Nabumetone: (Minor) An increased risk of bleeding may occur when NSAIDs, such as nabumetone, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Naproxen: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Naproxen; Pseudoephedrine: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Naproxen; Sumatriptan: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Norfloxacin: (Moderate) Use tretinoin with caution in patients who are also taking drugs known to be photosensitizers, such as norfloxacin, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Ofloxacin: (Moderate) Use tretinoin with caution in patients who are also taking drugs known to be photosensitizers, such as ofloxacin, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Orlistat: (Moderate) The bioavailability of orally administered retinoids may be decreased if coadministered with orlistat. In patients receiving orally-administered retinoids along with orlistat, close monitoring is recommended. In addition, the manufacturer recommends that fat-soluble vitamin analogues be administered at least 2 hours before or after the administration of orlistat to limit effects on oral absorption. 
    Oxaprozin: (Minor) An increased risk of bleeding may occur when NSAIDs, such as oxaprozin, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents. 
    Pegfilgrastim: (Major) Pegfilgrastim induces the proliferation of neutrophil-progenitor cells, and because antineoplastic agents exert toxic effects against rapidly growing cells, pegfilgrastim should not be given 14 days before or for 24 hours after cytotoxic chemotherapy. 
    Peginterferon Alfa-2a: (Moderate) Use of alpha interferons are associated with myelosuppression; additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives. 
    Peginterferon Alfa-2b: (Moderate) Use of alpha interferons are associated with myelosuppression; additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives. 
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity. 
    Pentosan: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Perphenazine: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Perphenazine; Amitriptyline: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Phenothiazines: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Phentermine; Topiramate: (Moderate) Topiramate may increase the CYP450 metabolism of tretinoin, ATRA, potentially resulting in decreased plasma concentrations of tretinoin, ATRA. Monitor for decreased clinical effects of tretinoin, ATRA while receiving concomitant therapy. 
    Photosensitizing agents: (Moderate) Use photosensitizing agents and retinoids together with caution; the risk of severe burns/phototoxicity may be additive. If concurrent use is necessary, closely monitor patients for signs or symptoms of skin toxicity. 
    Piroxicam: (Minor) An increased risk of bleeding may occur when NSAIDs, such as piroxicam, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Platelet Inhibitors: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as tretinoin. 
    Porfimer: (Moderate) Use photosensitizing agents and retinoids together with caution; the risk of severe burns/phototoxicity may be additive. If concurrent use is necessary, closely monitor patients for signs or symptoms of skin toxicity. 
    Prasugrel: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as tretinoin. 
    Prednisolone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Prednisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Prochlorperazine: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Rifabutin: (Moderate) Rifabutin may increase the CYP450 metabolism of tretinoin, ATRA, potentially resulting in decreased plasma concentrations of tretinoin, ATRA. No specific studies have been done with oral tretinoin and rifabutin, however, patients should be closely monitored for decreased clinical effects of tretinoin, ATRA while receiving concomitant therapy. 
    Rifampin: (Moderate) Rifampin may increase the CYP450 metabolism of tretinoin, ATRA, potentially resulting in decreased plasma concentrations of tretinoin, ATRA. No specific studies have been done with oral tretinoin and rifampin, however, patients should be closely monitored for decreased clinical effects of tretinoin, ATRA while receiving concomitant therapy. 
    Rifapentine: (Moderate) Rifapentine may increase the CYP450 metabolism of tretinoin, ATRA, potentially resulting in decreased plasma concentrations of tretinoin, ATRA. No specific studies have been done with oral tretinoin and rifapentine, however, patients should be closely monitored for decreased clinical effects of tretinoin, ATRA while receiving concomitant therapy. 
    Rivaroxaban: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Salicylic Acid: (Moderate) Dryness of the skin and mucus membranes are common side effects of retinoid therapy. Simultaneous use of retinoids and topical drying agents, such as salicylic acid, can potentiate the drying effects of retinoids on the skin. Be alert for signs of skin irritation, the offending topical agents may need to be used less often or discontinued during retinoid therapy. 
    Sodium Thiosulfate; Salicylic Acid: (Moderate) Dryness of the skin and mucus membranes are common side effects of retinoid therapy. Simultaneous use of retinoids and topical drying agents, such as salicylic acid, can potentiate the drying effects of retinoids on the skin. Be alert for signs of skin irritation, the offending topical agents may need to be used less often or discontinued during retinoid therapy. 
    St. John’s Wort, Hypericum perforatum: (Moderate) In theory it is possible that additive photosensitizing effects may result from the concomitant use of St. John’s wort with other photosensitizing drugs such as retinoids. 
    Sulfonylureas: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as sulfonylureas, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Sulindac: (Minor) An increased risk of bleeding may occur when NSAIDs, such as sulindac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Tbo-Filgrastim: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy. 
    Tetracyclines: (Major) The concomitant use of systemic tretinoin, ATRA and systemic tetracyclines should be avoided due to the potential for increased intracranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Pseudotumor cerebri has been reported with systemic retinoid use alone and early signs and symptoms include papilledema, headache, nausea, vomiting and visual disturbances. In addition, a manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as tetracyclines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Thiazide diuretics: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Thiethylperazine: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Thioridazine: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Thrombolytic Agents: (Moderate) Patients with thrombocytopenia are at increased risk of bleeding complications. An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents. 
    Thyroid hormones: (Moderate) The concomitant use of systemic tretinoin, ATRA and thyroid hormones should be done cautiously due to the potential for increased intracranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea, vomiting, and visual disturbances. 
    Ticagrelor: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as tretinoin. 
    Ticlopidine: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as tretinoin. 
    Tinzaparin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Tirofiban: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as tretinoin. 
    Tolazamide: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as sulfonylureas, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Tolbutamide: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as sulfonylureas, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Tolmetin: (Minor) An increased risk of bleeding may occur when NSAIDs, such as tolmetin, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Topiramate: (Moderate) Topiramate may increase the CYP450 metabolism of tretinoin, ATRA, potentially resulting in decreased plasma concentrations of tretinoin, ATRA. Monitor for decreased clinical effects of tretinoin, ATRA while receiving concomitant therapy. 
    Trandolapril; Verapamil: (Moderate) Verapamil may decrease the CYP450 metabolism of tretinoin, ATRA, potentially resulting in increased plasma concentrations of tretinoin, ATRA. Monitor for tretinoin toxicity while receiving concomitant therapy. 
    Tranexamic Acid: (Major) Rare cases of fatal thrombotic complications have been reported in patients treated with systemic all-trans retinoic acid (ATRA) or tretinoin and the use of antifibrinolytic agents, like tranexamic acid. This is thought to be due to the persistent procoagulant tendency often associated with systemic tretinoin therapy. 
    Triamcinolone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Trifluoperazine: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy. 
    Verapamil: (Moderate) Verapamil may decrease the CYP450 metabolism of tretinoin, ATRA, potentially resulting in increased plasma concentrations of tretinoin, ATRA. Monitor for tretinoin toxicity while receiving concomitant therapy. 
    Verteporfin: (Moderate) Use photosensitizing agents and retinoids together with caution; the risk of severe burns/phototoxicity may be additive. If concurrent use is necessary, closely monitor patients for signs or symptoms of skin toxicity. 
    Vorapaxar: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as tretinoin. 
    Voriconazole: (Major) Voriconazole is an inhibitor of CYP3A4 isoenzyme. Drugs that are substrates for CYP3A4, such as tretinoin, when combined with voriconazole, may theoretically have reduced metabolism, and therefore higher serum concentrations resulting in toxicity. 
    Warfarin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 

    PREGNANCY AND LACTATION

    Pregnancy

    Teratogenic and embryotoxic effects have been demonstrated in animals receiving oral tretinoin or large doses (i.e., many times greater than the normal human dose) of topical tretinoin. Adequate and well-controlled trials have not been performed in humans, but increased spontaneous abortions and major human fetal abnormalities have occurred when pregnant women received other retinoids. There have been 30 case reports of temporally-associated, congenital malformations during 25 years of clinical use of Retin-A. The significance of these spontaneous reports in terms of risk to the fetus is not known. Avoid use of topical tretinoin over large areas of skin or for prolonged periods. The benefit-risk profile should be considered before prescribing. Reproductive risk should be discussed. There is a high risk of birth defects if oral tretinoin is administered during pregnancy. Females of childbearing potential must use two reliable forms of contraception simultaneously during oral tretinoin therapy and for one month following discontinuation of therapy, unless abstinence is the chosen method. Contraception requirements must be followed even when there is a history of infertility or menopause, unless a hysterectomy has been performed. Within one week of beginning tretinoin oral therapy, the patient should have a negative pregnancy test; if possible, treatment with tretinoin should be delayed until pregnancy testing results are known. Pregnancy testing and counseling should occur monthly during oral tretinoin therapy.[48166] [48167] [63467]

    MECHANISM OF ACTION

    Mechanism of Action: Retinoids are intracrine and paracrine mediators of cell differentiation and proliferation, apoptosis (programmed cell death), and reproduction. Cells regulate the formation of specific retinoid isomers depending upon the cellular action required. The numerous effects of retinoids reflect the complex biology of the nuclear receptors that mediate retinoid activity. Retinoid receptors are divided into retinoid X receptors (RXRs) and retinoic acid receptors (RARs); both types can be further divided into 3 subtypes: Alpha, beta, and gamma. These receptor subtypes are further divided into many isoforms. Retinoid receptors are structurally similar but have different affinities for different types of retinoids and distribution varies throughout the body resulting in a wide range of actions. Tretinoin binds to all three RARs, but does not bind to RXRs except at very high concentrations. RAR-alpha and RAR-beta have been associated with the development of acute promyelocytic leukemia and squamous cell cancers, respectively. RAR-gamma is associated with retinoid effects on mucocutaneous tissues and bone.•Skin Disorders: By binding to RARs, tretinoin modifies gene expression, subsequent protein synthesis, and epithelial cell growth and differentiation. It has not been established whether the clinical effects of tretinoin are mediated through activation of RARs, other mechanisms such as irritation, or both. Tretinoin appears to prevent horny cell cohesion and to increase epidermal cell turnover and mitotic activity. Subsequently, in patients with acne, expulsion of existing comedones occurs, and formation of new comedones is prevented through sloughing and expulsion of horny cells from the follicle. Tretinoin reduces the cell layers of the stratum corneum. The bacterium involved in acne, Propionibacterium acnes, and sebum production are unaffected. An additional action of tretinoin may involve keratinization inhibition, which would explain its effectiveness in treating keratinization disorders.•Photodamage: Topical tretinoin is effective in reducing fine wrinkling, mottled hyperpigmentation, roughness, and laxity associated with photodamaged skin. Ultraviolet irradiation induces three metalloproteinases in human skin: collagenase, 92-kd gelatinase, and stromelysin-1. The combined actions of these enzymes can fully degrade skin collagen. Pretreatment of skin with tretinoin inhibits the induction of these skin matrix metalloproteinase proteins and activity by 70—80% in both connective tissue and outer layers of irradiated skin.•Acute Promyelocytic Leukemia: Similar to other retinoids, tretinoin induces cellular differentiation in malignant cells. Acute promyelocytic leukemia (APL) is caused by a genetic lesion that disrupts the alpha retinoic acid receptor (RAR-alpha) gene found on the long arm of chromosome 17 and the PML gene found on chromosome 15. The fusion protein that is formed, PML-RAR-alpha, inhibits apoptotic pathways and blocks myeloid differentiation when present in levels greater than those of the normal RAR-alpha protein. The presence of this gene translocation [t(15;17)] is used for diagnosis of APL and as a marker of response following treatment with either cytotoxic agents or tretinoin. During tretinoin treatment, cells expressing PML/RAR-alpha undergo cellular differentiation at a rate higher than normal cells. At therapeutic doses of tretinoin, the activity of the fusion protein on differentiation converts from inhibitory to stimulatory. Terminal differentiation of APL cells as the mechanism of tretinoin therapy is supported by 1) the absence of bone marrow aplasia during treatment; 2) the appearance of cells during treatment with the morphologic characteristics of maturation stages intermediate between promyelocytes and neutrophils; 3) the presence, during treatment, of PML and RAR-alpha rearrangements in peripheral blood neutrophils that disappear after treatment. Treatment with tretinoin reverses the bleeding diathesis seen in APL, before any morphologic response is noted. A retinoic acid syndrome, similar to capillary leak syndrome, may be seen in some patients (see Adverse Reactions). The etiology of this syndrome is unknown, but may be due to decreases in leukocyte adhesion protein activity. Resistance to tretinoin may develop due to pharmacokinetic reasons (decreased bioavailability) and/or changes in proteins involved in the cellular activity of tretinoin.

    PHARMACOKINETICS

    Tretinoin is administered topically and orally; an intravenous formulation is under investigation. 
     
    Systemic tretinoin is greater than 95% bound to plasma proteins, primarily albumin. The distribution of tretinoin has not been determined. Tretinoin is metabolized by the cytochrome P450 hepatic enzyme system. The metabolites include 13-cis retinoic acid, 4-oxo trans retinoic acid, 4-oxo cis retinoic acid, and 4-oxo trans retinoic acid glucuronide. Tretinoin appears to induce its own metabolism. An approximately 10-fold increase in the urinary excretion of 4-oxo trans retinoic acid glucuronide is observed after 2—6 weeks of continuous dosing when compared with baseline.

    Oral Route

    After administration of a single oral dose, tretinoin is well absorbed, with peak plasma concentrations showing considerable interpatient variability. Mean peak plasma concentrations are 347 +/- 266 ng/ml and occur between 1 and 3 hours after dosing.
     
    About 90% of an oral dose is excreted in the urine and feces within 72 hours and 6 days, respectively.

    Intravenous Route

    One of the proposed benefits of the liposomal injection form of tretinoin, is the ability to overcome excessively rapid hepatic clearance and subsequent drug resistance associated with oral administration.

    Topical Route

    Following topical application, a minimal amount of drug is absorbed systemically. There is no expected difference in the systemic absorption of tretinoin from the microsphere formulation. Prolonged treatment or application to large body surface areas can enhance systemic absorption.
     
    Approximately 1—5% of a topically applied dose is excreted in the urine within 24 hours.

  •  

 

TRETINOIN 

  • CLASSES

    Antineoplastic Retinoids
    Anti-wrinkle Agents, Rx
    Topical Retinoids for use for Acne

    BOXED WARNING

    Requires a specialized care setting, requires an experienced clinician, respiratory insufficiency

    Oral tretinoin therapy requires an experienced clinician and requires a specialized care setting. Only clinicians experienced in the management of patients with acute leukemia should use oral tretinoin; patients who have acute promyelocytic leukemia are at high risk in general and may experience severe adverse reactions to tretinoin. Patients receiving oral tretinoin should be managed in facilities equipped and staffed with adequate laboratory and supportive medical services to monitor for drug toxicity and to care for patients compromised by these toxicities, including respiratory insufficiency.

    Acute promyelocytic leukemia differentiation syndrome

    Approximately 25% of patients who receive tretinoin for the treatment of acute promyelocytic leukemia have experienced acute promyelocytic leukemia differentiation syndrome. When seen in association with the use of tretinoin, this syndrome is also known as retinoic acid-acute promyelocytic leukemia (RA-APL) syndrome (see Adverse Reactions for more detailed description of RA-APL syndrome). Patients must be carefully monitored for any signs or symptoms of this syndrome.

    Leukocytosis

    In the treatment of acute promyelocytic leukemia, approximately 40% of patients will develop rapidly evolving leukocytosis, and these patients have a higher risk of life-threatening complications. High initial leukocyte counts or rapidly increasing leukocyte counts during treatment may be predictive of retinoic acid-acute promyelocytic leukemia (RA-APL) syndrome (see Adverse Reactions). However, RA-APL syndrome has been observed with or without concomitant leukocytosis. The manufacturer recommends the immediate initiation of high-dose steroids if signs and symptoms of RA-APL are present together with leukocytosis. Some clinicians routinely add chemotherapy to oral tretinoin therapy when patients present with a WBC count > 5000/mm3 or in the case of a rapid increase in WBC count in leukopenic patients at the start of treatment. Consideration could be given to adding chemotherapy (usually cytarabine and an anthracycline, if not contraindicated) to tretinoin therapy on day 1 or 2 for patients presenting with a WBC count > 5000/mm3 or immediately, for patients presenting with a WBC count of < 5000/mm3, if the WBC count reaches >= 6000/mm3 by day 5, >= 10,000/mm3 by day 10, or >= 15,000/mm3 by day 28. The majority of patients do not require discontinuation of tretinoin therapy during RA-APL syndrome.

    Contraception requirements, pregnancy, pregnancy testing, reproductive risk

    Teratogenic and embryotoxic effects have been demonstrated in animals receiving oral tretinoin or large doses (i.e., many times greater than the normal human dose) of topical tretinoin. Adequate and well-controlled trials have not been performed in humans, but increased spontaneous abortions and major human fetal abnormalities have occurred when pregnant women received other retinoids. There have been 30 case reports of temporally-associated, congenital malformations during 25 years of clinical use of Retin-A. The significance of these spontaneous reports in terms of risk to the fetus is not known. Avoid use of topical tretinoin over large areas of skin or for prolonged periods. The benefit-risk profile should be considered before prescribing. Reproductive risk should be discussed. There is a high risk of birth defects if oral tretinoin is administered during pregnancy. Females of childbearing potential must use two reliable forms of contraception simultaneously during oral tretinoin therapy and for one month following discontinuation of therapy, unless abstinence is the chosen method. Contraception requirements must be followed even when there is a history of infertility or menopause, unless a hysterectomy has been performed. Within one week of beginning tretinoin oral therapy, the patient should have a negative pregnancy test; if possible, treatment with tretinoin should be delayed until pregnancy testing results are known. Pregnancy testing and counseling should occur monthly during oral tretinoin therapy.[48166] [48167] [63467]

    DEA CLASS

    Rx

    DESCRIPTION

    Naturally occurring retinoid analog; also known as all-trans-retinoic acid (aTRA)
    Oral form used in acute promyelocytic leukemia; topical form used for cutaneous disorders like acne and photoaging
    Treatment with oral form may cause acute promyelocytic leukemia differentiation syndrome

    COMMON BRAND NAMES

    Altinac, Altreno, Atralin, AVITA, Refissa, Renova, Retin-A, Retin-A Micro, Tretin-X, Vesanoid

    HOW SUPPLIED

    Altinac/AVITA/Refissa/Renova/Retin-A/Tretinoin/Tretin-X Topical Cream: 0.02%, 0.025%, 0.0375%, 0.05%, 0.075%, 0.1%
    Altreno Topical Lotion: 0.05%
    Atralin/AVITA/Retin-A/Retin-A Micro/Tretinoin/Tretin-X Topical Gel: 0.01%, 0.025%, 0.04%, 0.05%, 0.06%, 0.08%, 0.1%
    Tretinoin/Vesanoid Oral Cap: 10mg

    DOSAGE & INDICATIONS

    For the treatment of acne vulgaris.
    Topical dosage
    Adults

    Apply a thin layer of topical tretinoin to the affected area(s) once daily at bedtime. Temporary discontinuation or reduction in application frequency may be necessary until the patient is able to tolerate the treatment. Frequency of application should be closely monitored by careful observation of the clinical response and skin tolerance; efficacy has not been established for less than once daily application frequency. Application of excessive amounts may result in ‘caking’ or ‘pilling’ and will not provide incremental efficacy. During the early weeks of treatment, an apparent exacerbation of inflammatory lesions may occur. If tolerated, this should not be considered a reason to discontinue therapy. Up to 7 weeks of therapy may be required before improvement is evident. This may be followed by a reduced dosage schedule. 

    Children and Adolescents 12 years and older

    Apply a thin layer of topical tretinoin to the affected area(s) once daily at bedtime. Temporary discontinuation or reduction in application frequency may be necessary until the patient is able to tolerate the treatment. Frequency of application should be closely monitored by careful observation of the clinical response and skin tolerance; efficacy has not been established for less than once daily application frequency. Application of excessive amounts may result in ‘caking’ or ‘pilling’ and will not provide incremental efficacy. During the early weeks of treatment, an apparent exacerbation of inflammatory lesions may occur. If tolerated, this should not be considered a reason to discontinue therapy. Up to 7 weeks of therapy may be required before improvement is evident. This may be followed by a reduced dosage schedule.[48167] [55916]

    Topical dosage (Atralin 0.05% gel)
    Adults

    Apply a thin layer to the affected area(s) once daily at bedtime. Temporary discontinuation or reduction in application frequency may be necessary until the patient is able to tolerate the treatment. Frequency of application should be closely monitored by careful observation of the clinical response and skin tolerance; efficacy has not been established for less than once daily application frequency. Application of excessive amounts may result in ‘caking’ or ‘pilling’ and will not provide incremental efficacy. During the early weeks of treatment, an apparent exacerbation of inflammatory lesions may occur. If tolerated, this should not be considered a reason to discontinue therapy. Up to 6 weeks of therapy may be required before improvement is evident. This may be followed by a reduced dosage schedule.

    Children and Adolescents 10 years and older

    Apply a thin layer to the affected area(s) once daily at bedtime. Temporary discontinuation or reduction in application frequency may be necessary until the patient is able to tolerate the treatment. Frequency of application should be closely monitored by careful observation of the clinical response and skin tolerance; efficacy has not been established for less than once daily application frequency. Application of excessive amounts may result in ‘caking’ or ‘pilling’ and will not provide incremental efficacy. During the early weeks of treatment, an apparent exacerbation of inflammatory lesions may occur. If tolerated, this should not be considered a reason to discontinue therapy. Up to 6 weeks of therapy may be required before improvement is evident. This may be followed by a reduced dosage schedule.[55917]

    Topical dosage (Altreno 0.05% lotion)
    Adults

    Apply a thin layer to the affected area(s) once daily. Temporary discontinuation or reduction in application frequency may be necessary until the patient is able to tolerate the treatment.

    Children and Adolescents 9 years and older

    Apply a thin layer to the affected area(s) once daily. Temporary discontinuation or reduction in application frequency may be necessary until the patient is able to tolerate the treatment.

    For adjunctive treatment of photoaging including palliation of fine facial wrinkles, facial mottled hyperpigmentation (i.e., ‘liver spots’), and facial skin roughness.
    Topical dosage (Renova 0.02% and 0.05%; Refissa 0.05%)
    Adults

    Apply a pea-sized amount to cover the entire affected area once daily before bedtime for 24 to 48 weeks. Most improvement is noted during the first 24 weeks of treatment. Use in combination with comprehensive skin care and sun avoidance programs. Brown spots begin to fade at around 6—8 weeks and there is a decrease in fine lines and wrinkles around 3 to 6 months. Discontinuation of treatment usually results in a loss of effect. The safety and efficacy of tretinoin therapy beyond 48 weeks has not been established.

    For the treatment of acute promyelocytic leukemia (APL). 
    NOTE: Retinoic acid-APL (RA-APL) syndrome characterized by fever, dyspnea, acute respiratory distress, weight gain, radiographic pulmonary infiltrates, pleural and pericardial effusions, edema, and hepatic, renal, and multi-organ failure requires prompt treatment with high-dose steroids (e.g., dexamethasone 10 mg IV every 12 hours for 3 days or until the resolution of symptoms). RA-APL syndrome may occur with or without leukocytosis.
    For remission induction treatment in patients with APL who are refractory to or who have relapsed from anthracycline chemotherapy or who have a contraindication to anthracycline-based therapy.
    Oral dosage
    Adults

    45 mg/m2/day PO in 2 equally divided doses until complete remission is documented. Therapy should be discontinued 30 days after remission or after 90 days of treatment, whichever occurs first. After induction therapy with tretinoin, all patients should receive standard consolidation and/or maintenance therapy for APL unless otherwise contraindicated.

    Adolescents and Children >= 1 year

    45 mg/m2/day PO in 2 divided doses after meals until complete remission is documented. Therapy should be discontinued 30 days after remission or after 90 days of treatment, whichever occurs first. A decrease in the recommended dosage may be considered for patients who experience serious or intolerable toxicity. However, the safety and efficacy of lower doses have not been established. After induction therapy with tretinoin, all patients should receive standard consolidation and/or maintenance therapy for APL unless otherwise contraindicated.

    For maintenance therapy following induction and consolidation therapy†.
    Oral dosage
    Adults, Adolescents, and Children

    45 mg/m2/day PO once daily or divided every 12 hours alone or with regimens containing 6-mercaptopurine and methotrexate for 1 to 2 years following induction and consolidation therapy has been studied in randomized clinical trials. Tretinoin was given daily for 1 year or for 15 days every 3 months alone or with 6-MP 90 mg/m2 PO daily plus methotrexate 15 mg/m2 PO once weekly for 2 years, or alternating every 3 months with 6-MP/methotrexate for 2 years. In one 4-arm trial, the 12-year disease-free survival (DFS) rates were not significantly different in patients who received 2 years of chemotherapy compared with no chemotherapy (68.9% vs 69%) or in patients who received 2 years of tretinoin compared with no tretinoin (68.3% vs 69.7%) in 318 patients who were (PCR)-negative for the PML-RARA fusion gene following induction therapy with tretinoin and idarubicin and 3 cycles of intensive consolidation therapy.The 10-year cumulative incidence of relapse was significantly decreased with 2 years of chemotherapy- and tretinoin-containing maintenance therapy in patients with a hematologic complete remission (CR) following either tretinoin or chemotherapy induction therapy and 2 cycles of consolidation therapy in another 4-arm trial; however, the 10-year overall survival rate was significantly improved with chemotherapy compared with no chemotherapy maintenance therapy (85.2% vs 79.2%; p = 0.02) but not with tretinoin compared with no tretinoin maintenance therapy (82.7% vs 79.4%). The 5-year DFS rate was significantly improved with 1 year of tretinoin maintenance therapy compared with observation only (61% vs 36%; p < 0.0001) in patients who achieved a CR following either tretinoin or chemotherapy induction therapy and 2 cycles of consolidation therapy in another randomized study.

    For remission induction and consolidation treatment in patients with newly diagnosed, low-risk APL in combination with arsenic trioxide†.
    Oral dosage
    Adults

    22.5 mg/m2 orally twice daily (dose rounded to the nearest 10-mg increment) in combination with arsenic 0.15 mg/kg IV over 2 hours once daily until bone marrow remission or for up to a maximum of 60 days as induction therapy followed by consolidation therapy with tretinoin 22.5 mg/m2 orally twice daily (dose rounded to the nearest 10-mg increment) as continuous therapy during weeks 1 and 2 (on all 4 cycles) and during weeks 5 and 6 (on cycles 1, 2, and 3 only) in combination with arsenic trioxide 0.15 mg/kg IV daily given 5 days per week for 4 consecutive weeks (total of 20 doses/cycle). Consolidation therapy is repeated every 8 weeks for 4 cycles. During induction therapy, all patients should receive differentiation syndrome prophylaxis with prednisone 0.5 mg/kg orally once daily.

    For remission induction treatment in patients with newly diagnosed APL, in combination with idarubicin†.
    Oral dosage
    Adults <= 61 years

    45 mg/m2/day PO in 2 divided doses until complete remission (CR) to a maximum of 45 or 90 days plus idarubicin 12 mg/m2/dose IV on days 2, 4, 6, and 8 has been evaluated in 2 clinical trials (AIDA 0493 study; AIDA 2000 study). Adults less than 20 years of age received tretinoin 25 mg/m2/day PO in the AIDA 0493 study. Patients who achieved a hematologic CR received 3 anthracycline-containing consolidation therapy courses. Additionally, most patients in these studies who achieved a molecular CR after consolidation received up to 2 years of tretinoin-containing maintenance therapy. Prophylactic use of corticosteroids was recommended during induction therapy to help prevent differentiation (retinoic acid) syndrome.

    Children and Adolescents

    25 mg/m2/day PO in 2 divided doses until complete remission (CR) or a maximum of 90 days plus idarubicin 12 mg/m2/dose IV on days 2, 4, 6, and 8 has been evaluated in a clinical trial (AIDA 0493 study). Patients who achieved a hematologic CR received 3 multi-agent chemotherapy consolidation courses containing anthracyclines and cytarabine. Additionally, most patients who achieved a molecular CR after consolidation received up to 2 years of tretinoin-containing maintenance therapy. In a subgroup analysis of the AIDA 0493 study, induction therapy with tretinoin plus idarubicin resulted in a post-induction hematologic CR rate of 96% in 107 evaluable pediatric patients (median age, 11.6 years; range, 1.4—17.9 years). Tretinoin was administered for a median of 32 days (range, 1—56 days) during induction therapy. The 10-year event-free survival and overall survival rates were 76% and 89%, respectively. Retinoic acid syndrome was reported in 8 patients (definitely present, n = 2; indeterminate, n = 6) and pseudotumor cerebri developed in 10 patients. There were 4 deaths during induction therapy.

    For consolidation treatment following tretinoin and idarubicin induction therapy in patients with newly diagnosed APL, in combination with idarubicin-containing chemotherapy†.
    Oral dosage
    Adults <= 61 years

    Following induction therapy with tretinoin (45 mg/m2/day PO in 2 divided daily doses until complete remission (CR) or a maximum of 45 days) plus idarubicin (12 mg/m2/dose IV on days 2, 4, 6, and 8), patients who achieved a hematologic CR received 3 risk-adapted tretinoin- and anthracycline-based consolidation therapy courses in a clinical study (AIDA 2000 study). All patients in this study received tretinoin 45 mg/m2/day PO for 15 days starting on day 1 of each consolidation cycle. Patients with low- or intermediate–risk APL (defined as an initial white blood cell count < 10 X 109/L) received: idarubicin 5 mg/m2/dose IV on days 1—4 (course 1), mitoxantrone 10 mg/m2/dose IV on days 1—5 (course 2); and idarubicin 12 mg/m2/dose on day 1 (course 3). Patients with high–risk APL received: idarubicin 5 mg/m2/dose IV on days 1—4 and cytarabine 1000 mg/m2/day IV on days 1—4 (course 1); mitoxantrone 10 mg/m2/dose IV on days 1—5 and etoposide 100 mg/m2/dose IV on days 1—5 (course 2); and idarubicin 12 mg/m2/dose IV on day 1, cytarabine 150 mg/m2 subcutaneously every 8 hours on days 1—5, and 6-thioguanine 70 mg/m2 PO every 8 hours on days 1—5 (course 3). Intrathecal methotrexate 12 mg and methylprednisone 40 mg were administered prior to each consolidation course in patients with high-risk disease. Additionally, patients who achieved a molecular CR after consolidation received up to 2 years of tretinoin-containing maintenance therapy.

    For the treatment of melasma†.
    Topical dosage
    Adults

    Topical tretinoin 0.05% to 0.1% applied once daily to affected areas in combination with hydroquinone with or without hydrocortisone has been effective. Treatment should also include avoidance of sun exposure and use of sunscreens. To decrease side effects, some studies have applied tretinoin twice weekly instead of daily.

    For the treatment of diseases of keratinization† (e.g., actinic keratosis†, ichthyosis†, keloids†, keratosis follicularis†); acne rosacea†; skin hyperpigmentation†.
    Topical dosage
    Adults

    Topical tretinoin 0.025% to 0.1% applied once daily to affected areas has been used in the treatment of various diseases of keratinization, often in combination with other agents.

    For the treatment of AIDS-related Kaposi’s sarcoma†.
    Oral dosage
    Adults

    Dose is not established; however, 45 mg/m2/day PO divided in 2 daily doses x12 weeks was studied in one phase II study; escalating doses up to 150 mg/m2/day divided in 3 daily doses have also been studied. Tretinoin resulted in a partial response (PR) rate of 42% in 19 patients with low-risk AIDS-related Kaposi sarcoma in a multicenter, phase II study; additionally, 37% of patients had stable disease (SD). Six patients also received concurrent antiretroviral therapy, although no patients received a protease inhibitor. Responding patients continued tretinoin therapy beyond 12 weeks (mean duration, 27 +/- 7 weeks; range, 16 to 36 weeks) and the median time to response and time to disease progression in these patients were 56 and 332 days, respectively. Treatment with escalating doses of tretinoin (initial dosage of 45 mg/m2/day in 2 daily doses given every 12 hours on week 1 titrated weekly to a target dosage of 150 mg/m2/day in 3 daily doses given every 8 hours by week 5; median dosage of 90 mg/m2/day; range, 70-300 mg/day) led to a PR rate of 17% in 24 evaluable patients with mucocutaneous, nonvisceral AIDS-related Kaposi’s sarcoma in another phase II trial; additionally, 13% of patients achieved a minor response and 29% of patients had SD. Most patients (74%) in this study had not received prior treatment for AIDS-related Kaposi sarcoma and 89% of patients were receiving concurrent antiretroviral therapy. The median time to response was 22 weeks (range, 12 to 28 weeks). At a median follow-up of 5 months (range, 1 to 17 months), the median disease-free survival time was 5 months and the median overall survival time was 27.3 months.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    The maximum tolerated oral dose in patients with myelodysplastic syndromes or solid tumors was 195 mg/m2 PO.

    Elderly

    The maximum tolerated oral dose in patients with myelodysplastic syndromes or solid tumors was 195 mg/m2 PO.

    Adolescents

    The maximum oral dose in pediatric patients is 60 mg/m2 PO.

    Children

    The maximum oral dose in pediatric patients is 60 mg/m2 PO.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    The clearance of systemic tretinoin would be expected to be greatly decreased in patients with hepatic impairment; however, no specific dosage adjustment guidelines are available. It has been recommended if hepatic enzymes increase to > 5-times the upper limit of normal consideration should be given to temporarily discontinuing oral tretinoin therapy.

    Renal Impairment

    Specific guidelines for dosage adjustments of systemic tretinoin therapy in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration

    The effects of food on tretinoin bioavailability are unknown. The manufacturer makes no specific recommendations on oral administration, however, the absorption of retinoids as a class is enhanced by food.
    Females of childbearing potential must use two reliable forms of contraception simultaneously during oral tretinoin therapy and for one month following discontinuation of therapy, unless abstinence is the chosen method. Within one week of beginning tretinoin oral therapy, the patient should have a negative pregnancy test; if possible, treatment with tretinoin should be delayed until the results of the pregnancy test are known. Pregnancy testing and counseling should occur monthly during oral tretinoin therapy.
    Acute promyelocytic leukemia (APL) patients are considered high risk and administration of oral tretinoin may result in severe adverse reactions. Administration of tretinoin to these patients should be done only under the supervision of physicians experienced in the treatment of acute leukemia, and at a facility equipped to manage such adverse reactions, including respiratory compromise. It should be determined prior to the initiation of treatment that the benefit of therapy outweighs the risks to the patient.

    Topical Administration

    Topical tretinoin is a dermal irritant; the dermatologic response to greater than 48 weeks of chronic therapy is not known.
    Before applying topical formulations of tretinoin, clean affected area with a mild soap, pat skin dry and wait 20—30 minutes before applying the product. The microsphere gel may be applied immediately after washing the face.

    Cream/Ointment/Lotion Formulations

    Cream: Rub cream gently into the affected area. Avoid over-application. Wash hands immediately after applying.
    Lotion: Apply thin layer to cover affected areas. Wash hands immediately after applying.[63467]

    Other Topical Formulations

    Solution: Apply using clean fingertips, a gauze pad, or cotton swabs to the cleansed affected area. Avoid over-saturation of gauze or cotton to prevent the solution from running onto unaffected areas. Wash hands immediately after applying.
    Gel: Apply lightly to the affected area. Excessive application results in pilling of the gel. Wash hands immediately after applying.
    Microsphere gel: Apply lightly to the affected area. Excessive application results in caking of the gel. Wash hands immediately after applying.

    STORAGE

    Altinac:
    – Store below 80 degrees F
    Altreno:
    – Protect from freezing
    – Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Atralin:
    – Protect from freezing
    – Store at controlled room temperature (between 68 and 77 degrees F)
    AVITA:
    – Store below 80 degrees F
    Refissa:
    – Store below 80 degrees F
    Renova:
    – Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Retin-A:
    – Store below 80 degrees F
    Retin-A Micro:
    – Flammable, keep away from heat and flame
    – Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Tretin-X:
    – Store below 80 degrees F
    Vesanoid:
    – Protect from light
    – Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Requires a specialized care setting, requires an experienced clinician, respiratory insufficiency

    Oral tretinoin therapy requires an experienced clinician and requires a specialized care setting. Only clinicians experienced in the management of patients with acute leukemia should use oral tretinoin; patients who have acute promyelocytic leukemia are at high risk in general and may experience severe adverse reactions to tretinoin. Patients receiving oral tretinoin should be managed in facilities equipped and staffed with adequate laboratory and supportive medical services to monitor for drug toxicity and to care for patients compromised by these toxicities, including respiratory insufficiency.

    Retinoid hypersensitivity

    Tretinoin is contraindicated in patients who experience retinoid hypersensitivity reactions to vitamin A or other retinoids because cross-sensitivity between agents is possible. True contact allergy to tretinoin is rare.

    Paraben hypersensitivity

    Oral tretinoin should not be administered to patients who have paraben hypersensitivity. Paraben is used as a preservative in the gelatin capsule.

    Fish hypersensitivity

    The Atralin brand of tretinoin gel and Altreno brand of tretinoin lotion contain soluble fish proteins and should be used with caution in patients with known fish hypersensitivity. Patients should be instructed to contact their health care provider if they develop pruritus or urticaria following application.[63467]

    Acute promyelocytic leukemia differentiation syndrome

    Approximately 25% of patients who receive tretinoin for the treatment of acute promyelocytic leukemia have experienced acute promyelocytic leukemia differentiation syndrome. When seen in association with the use of tretinoin, this syndrome is also known as retinoic acid-acute promyelocytic leukemia (RA-APL) syndrome (see Adverse Reactions for more detailed description of RA-APL syndrome). Patients must be carefully monitored for any signs or symptoms of this syndrome.

    Leukocytosis

    In the treatment of acute promyelocytic leukemia, approximately 40% of patients will develop rapidly evolving leukocytosis, and these patients have a higher risk of life-threatening complications. High initial leukocyte counts or rapidly increasing leukocyte counts during treatment may be predictive of retinoic acid-acute promyelocytic leukemia (RA-APL) syndrome (see Adverse Reactions). However, RA-APL syndrome has been observed with or without concomitant leukocytosis. The manufacturer recommends the immediate initiation of high-dose steroids if signs and symptoms of RA-APL are present together with leukocytosis. Some clinicians routinely add chemotherapy to oral tretinoin therapy when patients present with a WBC count > 5000/mm3 or in the case of a rapid increase in WBC count in leukopenic patients at the start of treatment. Consideration could be given to adding chemotherapy (usually cytarabine and an anthracycline, if not contraindicated) to tretinoin therapy on day 1 or 2 for patients presenting with a WBC count > 5000/mm3 or immediately, for patients presenting with a WBC count of < 5000/mm3, if the WBC count reaches >= 6000/mm3 by day 5, >= 10,000/mm3 by day 10, or >= 15,000/mm3 by day 28. The majority of patients do not require discontinuation of tretinoin therapy during RA-APL syndrome.

    Skin photosensitivity disorder, sunburn, sunlight (UV) exposure

    Retinoids may cause photosensitivity.[30713] Treatment with topical tretinoin should be postponed until sunburn has resolved to avoid exacerbation of the irritation, inflammation, and dryness associated with sunburned skin. Patients with a skin photosensitivity disorder should be closely evaluated prior to receiving tretinoin therapy. If sun exposure cannot be avoided during topical tretinoin therapy, sunscreen products and physical sun blocks (protective clothing, hats) are recommended for protection of treated areas. Sunlight (UV) exposure potentiates the inflammatory effects of tretinoin. Patients who may have considerable sun exposure due to their occupation and those patients with inherent sensitivity to sunlight should exercise particular caution when using topical tretinoin. Weather extremes, such as wind or cold, also may be irritating to patients receiving tretinoin.

    Eczema

    Topical tretinoin should be avoided, if possible, in patients with eczema because severe irritation of eczematous skin is likely.

    Hepatic disease

    Elevated hepatic enzymes has been reported in patients receiving oral tretinoin. Patients with hepatic disease could be more prone to developing this condition. It is recommended that if the serum hepatic enzyme levels are greater than 5-times the upper limit of normal, consideration should be given to temporarily discontinuing oral tretinoin therapy.

    Contraception requirements, pregnancy, pregnancy testing, reproductive risk

    Teratogenic and embryotoxic effects have been demonstrated in animals receiving oral tretinoin or large doses (i.e., many times greater than the normal human dose) of topical tretinoin. Adequate and well-controlled trials have not been performed in humans, but increased spontaneous abortions and major human fetal abnormalities have occurred when pregnant women received other retinoids. There have been 30 case reports of temporally-associated, congenital malformations during 25 years of clinical use of Retin-A. The significance of these spontaneous reports in terms of risk to the fetus is not known. Avoid use of topical tretinoin over large areas of skin or for prolonged periods. The benefit-risk profile should be considered before prescribing. Reproductive risk should be discussed. There is a high risk of birth defects if oral tretinoin is administered during pregnancy. Females of childbearing potential must use two reliable forms of contraception simultaneously during oral tretinoin therapy and for one month following discontinuation of therapy, unless abstinence is the chosen method. Contraception requirements must be followed even when there is a history of infertility or menopause, unless a hysterectomy has been performed. Within one week of beginning tretinoin oral therapy, the patient should have a negative pregnancy test; if possible, treatment with tretinoin should be delayed until pregnancy testing results are known. Pregnancy testing and counseling should occur monthly during oral tretinoin therapy.[48166] [48167] [63467]

    Breast-feeding

    According to the manufacturers, breast-feeding should be discontinued prior to receiving oral tretinoin and caution should be used with topical tretinoin. It is unknown whether oral or topical tretinoin is distributed into breast milk. Systemic absorption of tretinoin after topical application is low , and therefore it is unlikely that a significant amount of the drug is excreted into breast-milk. However, consideration for the use of an alternative topical agent (e.g., azelaic acid, benzoyl peroxide, clindamycin, erythromycin) may be appropriate for some patients. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants, neonates

    With the exception of the 0.05% lotion (approved for use in children 9 years and older) and 0.05% gel (approved for use in children 10 years and older) formulations, safety and efficacy of topical tretinoin have not been established in neonates, infants and children under 12 years of age. Children are prone to developing severe headache and pseudotumor cerebri while receiving oral tretinoin. For relief, some patients may require treatment with analgesics or lumbar puncture. The safety and efficacy of oral tretinoin in infants have not been established.[63467]

    Hypercholesterolemia, hyperlipidemia, hypertriglyceridemia

    Oral tretinoin should be used cautiously in patients with hyperlipidemia. Hypercholesterolemia and/or hypertriglyceridemia occurs in as many as 60% of patients receiving oral tretinoin. Monitor the lipid profile while patients are receiving oral tretinoin.

    Accidental exposure, ocular exposure

    Tretinoin cream, gel, lotion, and liquid are for external use only. Avoid ocular exposure, including eyelids, and contact with the mouth, angles of the nose, and mucous membranes. If eye contact occurs, rinse thoroughly with large amounts of water. Apply only to affected areas; accidental exposure to unaffected skin may cause irritation. Topical tretinoin is flammable; do not use near heat, open flame, or while smoking.

    ADVERSE REACTIONS

    Severe

    GI bleeding / Delayed / 34.0-34.0
    disseminated intravascular coagulation (DIC) / Delayed / 26.0-26.0
    arrhythmia exacerbation / Early / 23.0-23.0
    pleural effusion / Delayed / 20.0-20.0
    visual impairment / Early / 17.0-17.0
    increased intracranial pressure / Early / 9.0-9.0
    intracranial bleeding / Delayed / 9.0-9.0
    heart failure / Delayed / 6.0-6.0
    hearing loss / Delayed / 6.0-6.0
    pulmonary edema / Early / 3.0-3.0
    laryngeal edema / Rapid / 3.0-3.0
    peptic ulcer / Delayed / 3.0-3.0
    cardiomyopathy / Delayed / 3.0-3.0
    pericarditis / Delayed / 3.0-3.0
    pulmonary hypertension / Delayed / 3.0-3.0
    myocarditis / Delayed / 3.0-3.0
    myocardial infarction / Delayed / 3.0-3.0
    cardiac arrest / Early / 3.0-3.0
    stroke / Early / 3.0-3.0
    agnosia / Delayed / 3.0-3.0
    seizures / Delayed / 3.0-3.0
    coma / Early / 3.0-3.0
    renal failure (unspecified) / Delayed / 3.0-3.0
    renal tubular necrosis / Delayed / 3.0-3.0
    erythema nodosum / Delayed / Incidence not known
    differentiation syndrome / Delayed / Incidence not known
    pericardial effusion / Delayed / Incidence not known
    hypervitaminosis A / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    papilledema / Delayed / Incidence not known
    spontaneous fetal abortion / Delayed / Incidence not known
    teratogenesis / Delayed / Incidence not known

    Moderate

    bone pain / Delayed / 77.0-77.0
    dyspnea / Early / 60.0-60.0
    elevated hepatic enzymes / Delayed / 50.0-60.0
    hyperlipidemia / Delayed / 0-60.0
    bleeding / Early / 60.0-60.0
    fluid retention / Delayed / 29.0-52.0
    peripheral edema / Delayed / 52.0-52.0
    stomatitis / Delayed / 26.0-26.0
    constipation / Delayed / 17.0-17.0
    wheezing / Rapid / 14.0-14.0
    hypotension / Rapid / 14.0-14.0
    depression / Delayed / 14.0-14.0
    phlebitis / Rapid / 11.0-11.0
    hypertension / Early / 11.0-11.0
    confusion / Early / 11.0-11.0
    flank pain / Delayed / 9.0-9.0
    hepatomegaly / Delayed / 9.0-9.0
    splenomegaly / Delayed / 9.0-9.0
    dysuria / Early / 9.0-9.0
    edema / Delayed / 6.0-6.0
    hallucinations / Early / 6.0-6.0
    ascites / Delayed / 3.0-3.0
    hepatitis / Delayed / 3.0-3.0
    impaired cognition / Early / 3.0-3.0
    ataxia / Delayed / 3.0-3.0
    dysarthria / Delayed / 3.0-3.0
    aphasia / Delayed / 3.0-3.0
    encephalopathy / Delayed / 3.0-3.0
    thrombocytosis / Delayed / 0-1.0
    erythema / Early / 10.0
    hypoxia / Early / Incidence not known
    respiratory depression / Rapid / Incidence not known
    pseudotumor cerebri / Delayed / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known
    hypercholesterolemia / Delayed / Incidence not known
    hypercalcemia / Delayed / Incidence not known

    Mild

    headache / Early / 86.0-86.0
    fever / Early / 83.0-83.0
    fatigue / Early / 66.0-66.0
    malaise / Early / 66.0-66.0
    shivering / Rapid / 63.0-63.0
    vomiting / Early / 57.0-57.0
    nausea / Early / 57.0-57.0
    rash / Early / 54.0-54.0
    leukocytosis / Delayed / 40.0-40.0
    abdominal pain / Early / 31.0-31.0
    weight gain / Delayed / 23.0-23.0
    diarrhea / Early / 23.0-23.0
    flushing / Rapid / 23.0-23.0
    otalgia / Early / 23.0-23.0
    dizziness / Early / 20.0-20.0
    diaphoresis / Early / 20.0-20.0
    anorexia / Delayed / 17.0-17.0
    weight loss / Delayed / 17.0-17.0
    anxiety / Delayed / 17.0-17.0
    paresthesias / Delayed / 17.0-17.0
    alopecia / Delayed / 14.0-14.0
    myalgia / Early / 14.0-14.0
    dyspepsia / Early / 14.0-14.0
    insomnia / Early / 14.0-14.0
    agitation / Early / 9.0-9.0
    pallor / Early / 6.0-6.0
    asterixis / Delayed / 3.0-3.0
    weakness / Early / 3.0-3.0
    tremor / Early / 3.0-3.0
    hyporeflexia / Delayed / 3.0-3.0
    drowsiness / Early / 3.0-3.0
    hypothermia / Delayed / 3.0-3.0
    increased urinary frequency / Early / 3.0-3.0
    skin hyperpigmentation / Delayed / 2.0-2.0
    skin hypopigmentation / Delayed / 2.0-2.0
    skin irritation / Early / 10.0
    pruritus / Rapid / 20.0
    xerosis / Delayed / 10.0
    photosensitivity / Delayed / Incidence not known
    vesicular rash / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abciximab: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as tretinoin. 
    Acetohexamide: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as sulfonylureas, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Adapalene; Benzoyl Peroxide: (Moderate) Benzoyl peroxide can potentiate the skin irritation caused by topical tretinoin. Concurrent application of these agents on areas treated with tretinoin should be avoided. 
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Alpha interferons: (Moderate) Use of alpha interferons are associated with myelosuppression; additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives. 
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Aminocaproic Acid: (Major) Rare cases of fatal thrombotic complications have been reported in patients treated with systemic tretinoin, and antifibrinolytic agents. This is thought to be due to the persistent procoagulant tendency often associated with systemic tretinoin, ATRA therapy. Monitor patients closely and avoid if possible. 
    Amiodarone: (Moderate) The concomitant use of systemic tretinoin, ATRA and amiodarone should be done cautiously due to the potential for increased cranial pressure and an increased risk of pseudotumor cerebri. Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea, vomiting, and visual disturbances. 
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Anagrelide: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as tretinoin. 
    Anticoagulants: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Antithrombin III: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Antithymocyte Globulin: (Moderate) Because antithymocyte globulin is an immunosuppressant, additive affects may be seen with other immunosuppressives or antineoplastic agents. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk of infection or other side effects. 
    Apixaban: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Aprotinin: (Major) Rare cases of fatal thrombotic complications have been reported in patients treated with systemic tretinoin and antifibrinolytic agents. This is thought to be due to the persistent procoagulant tendency often associated with systemic tretinoin therapy. Monitor patients closely and avoid if possible. 
    Argatroban: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Aspirin, ASA; Dipyridamole: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as tretinoin. 
    Atenolol; Chlorthalidone: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Azelastine; Fluticasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Azilsartan; Chlorthalidone: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Barbiturates: (Moderate) Barbiturates may increase the CYP450 metabolism of tretinoin, ATRA, potentially resulting in decreased plasma concentrations of tretinoin, ATRA. Monitor for decreased clinical effects of tretinoin, ATRA while receiving concomitant therapy. 
    Beclomethasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Bendroflumethiazide; Nadolol: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Benzoyl Peroxide: (Moderate) Benzoyl peroxide can potentiate the skin irritation caused by topical tretinoin. Concurrent application of these agents on areas treated with tretinoin should be avoided. 
    Benzoyl Peroxide; Clindamycin: (Moderate) Benzoyl peroxide can potentiate the skin irritation caused by topical tretinoin. Concurrent application of these agents on areas treated with tretinoin should be avoided. 
    Benzoyl Peroxide; Erythromycin: (Moderate) Benzoyl peroxide can potentiate the skin irritation caused by topical tretinoin. Concurrent application of these agents on areas treated with tretinoin should be avoided. 
    Benzoyl Peroxide; Sulfur: (Moderate) Benzoyl peroxide can potentiate the skin irritation caused by topical tretinoin. Concurrent application of these agents on areas treated with tretinoin should be avoided. 
    Betamethasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Betrixaban: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Bivalirudin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Budesonide: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Budesonide; Formoterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Carbamazepine: (Moderate) Concurrent use of hepatic cytochrome P450 inducers, such as carbamazepine, with oral tretinoin therapy may result in significant decreases in serum tretinoin levels. Patients should be closely monitored for decreased clinical effects of tretinoin while receiving concomitant therapy. Also monitor for potential additive side effects, such as risk of infection. 
    Chlorothiazide: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Chlorpromazine: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Chlorpropamide: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as sulfonylureas, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Chlorthalidone: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Chlorthalidone; Clonidine: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Cholestyramine: (Moderate) Cholestyramine can bind with and possibly decrease the oral absorption of tretinoin. To minimize drug interactions, administer other drugs at least 1 hour before or at least 4 to 6 hours after the administration of cholestyramine. 
    Ciclesonide: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Cilostazol: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as tretinoin. 
    Cimetidine: (Moderate) Cimetidine may decrease the CYP450 metabolism of systemic tretinoin, ATRA, potentially resulting in increased plasma concentrations of tretinoin, ATRA. 
    Ciprofloxacin: (Moderate) Use tretinoin with caution in patients who are also taking drugs known to be photosensitizers, such as ciprofloxacin, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Clopidogrel: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as tretinoin. 
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist. 
    Cod Liver Oil: (Severe) Patients should avoid or limit supplementation with vitamin A during treatment with retinoids to avoid potential additive toxic effects. 
    Colestipol: (Moderate) The bile-acid sequesterant colestipol is well-known to cause drug interactions by binding and decreasing the oral administration of many drugs, which may include interaction with oral tretinoin; to minimize drug interactions, administer other drugs at least 1 hour before or at least 4 to 6 hours after the administration of cholestyramine or colestipol. 
    Corticosteroids: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Corticotropin, ACTH: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Cortisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Cyclosporine: (Moderate) Cyclosporine may decrease the CYP450 metabolism of tretinoin, ATRA, potentially resulting in increased plasma concentrations of tretinoin, ATRA. No specific studies have been done with oral tretinoin and cyclosporine, however, patients should be closely monitored for tretinoin toxicity while receiving concomitant therapy. 
    Dabigatran: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Dalteparin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Danaparoid: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Danazol: (Moderate) The concomitant use of systemic tretinoin, ATRA and danazol should be done cautiously due to the potential for increased intracranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea, vomiting, and visual disturbances. 
    Deflazacort: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Desirudin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Dexamethasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Diclofenac: (Minor) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Diclofenac; Misoprostol: (Minor) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy. 
    Diltiazem: (Moderate) Diltiazem may decrease the CYP450 metabolism of tretinoin, ATRA, potentially resulting in increased plasma concentrations of tretinoin, ATRA. 
    Diphenhydramine; Ibuprofen: (Moderate) The concomitant use of systemic tretinoin, ATRA and ibuprofen should be done cautiously due to the potential for increased intracranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea, vomiting, and visual disturbances. 
    Diphenhydramine; Naproxen: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Dipyridamole: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as tretinoin. 
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to drugs that alter immune system activity like antineoplastic drugs. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources. 
    Edoxaban: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Enoxaparin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Eptifibatide: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as tretinoin. 
    Eravacycline: (Major) Avoid the concomitant use of systemic tretinoin and eravacycline due to the potential for increased cranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Early signs and symptoms include papilledema, headache, nausea, vomiting, and visual disturbances. In addition, a manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking photosensitizers, such as eravacycline, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Erythromycin: (Moderate) Erythromycin may decrease the CYP450 metabolism of tretinoin, ATRA, potentially resulting in increased plasma concentrations of tretinoin, ATRA. No specific studies have been done with oral tretinoin and erythromycin, however, patients should be closely monitored for tretinoin toxicity while receiving concomitant therapy. 
    Erythromycin; Sulfisoxazole: (Moderate) Erythromycin may decrease the CYP450 metabolism of tretinoin, ATRA, potentially resulting in increased plasma concentrations of tretinoin, ATRA. No specific studies have been done with oral tretinoin and erythromycin, however, patients should be closely monitored for tretinoin toxicity while receiving concomitant therapy. 
    Esomeprazole; Naproxen: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Etodolac: (Minor) An increased risk of bleeding may occur when NSAIDs, such as etodolac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Famotidine; Ibuprofen: (Moderate) The concomitant use of systemic tretinoin, ATRA and ibuprofen should be done cautiously due to the potential for increased intracranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea, vomiting, and visual disturbances. 
    Felbamate: (Moderate) Felbamate may increase the CYP450 metabolism of tretinoin, ATRA, potentially resulting in decreased plasma concentrations of tretinoin, ATRA. Monitor for decreased clinical effects of tretinoin, ATRA while receiving concomitant therapy. 
    Fenoprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as fenoprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Filgrastim, G-CSF: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy. 
    Fludrocortisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Flunisolide: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Fluphenazine: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Flurbiprofen: (Minor) An increased risk of bleeding may occur when NSAIDs, such as flurbiprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Fluticasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Fluticasone; Salmeterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Fluticasone; Umeclidinium; Vilanterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Fluticasone; Vilanterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Fondaparinux: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Formoterol; Mometasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Gemifloxacin: (Moderate) Use tretinoin with caution in patients who are also taking drugs known to be photosensitizers, such as gemifloxacin, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Gentamicin: (Moderate) The concomitant use of systemic tretinoin, ATRA and systemic gentamicin should be done cautiously due to the potential for increased intracranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea, vomiting, and visual disturbances. 
    Glimepiride: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as sulfonylureas, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Glimepiride; Pioglitazone: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as sulfonylureas, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Glimepiride; Rosiglitazone: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as sulfonylureas, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Glipizide: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as sulfonylureas, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Glipizide; Metformin: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as sulfonylureas, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Glyburide: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as sulfonylureas, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Glyburide; Metformin: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as sulfonylureas, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Griseofulvin: (Moderate) Griseofulvin may increase the CYP450 metabolism of tretinoin, ATRA, potentially resulting in decreased plasma concentrations of tretinoin, ATRA. No specific studies have been done with oral tretinoin and griseofulvin, however, patients should be closely monitored for decreased clinical effects of tretinoin, ATRA while receiving concomitant therapy. Additionally, a manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as griseofulvin, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Heparin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Hydantoins: (Moderate) Concurrent oral tretinoin therapy with drugs that are inducers of the hepatic cytochrome P450 enzyme system like the hydantoin anticonvulsants can result in significant decreases in serum tretinoin levels, a CYP450 substrate. Monitor for decreased clinical effects while receiving concomitant therapy. 
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Hydrochlorothiazide, HCTZ; Irbesartan: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Hydrochlorothiazide, HCTZ; Losartan: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Hydrochlorothiazide, HCTZ; Spironolactone: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Hydrochlorothiazide, HCTZ; Telmisartan: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Hydrochlorothiazide, HCTZ; Triamterene: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Hydrocodone; Ibuprofen: (Moderate) The concomitant use of systemic tretinoin, ATRA and ibuprofen should be done cautiously due to the potential for increased intracranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea, vomiting, and visual disturbances. 
    Hydrocortisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Ibuprofen: (Moderate) The concomitant use of systemic tretinoin, ATRA and ibuprofen should be done cautiously due to the potential for increased intracranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea, vomiting, and visual disturbances. 
    Ibuprofen; Oxycodone: (Moderate) The concomitant use of systemic tretinoin, ATRA and ibuprofen should be done cautiously due to the potential for increased intracranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea, vomiting, and visual disturbances. 
    Ibuprofen; Pseudoephedrine: (Moderate) The concomitant use of systemic tretinoin, ATRA and ibuprofen should be done cautiously due to the potential for increased intracranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea, vomiting, and visual disturbances. 
    Indapamide: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Indomethacin: (Major) An increased risk of bleeding may occur when NSAIDs, such as indomethacin, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Interferon Alfa-2a: (Moderate) Use of alpha interferons are associated with myelosuppression; additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives. 
    Interferon Alfa-2b: (Moderate) Use of alpha interferons are associated with myelosuppression; additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives. 
    Interferon Alfa-2b; Ribavirin: (Moderate) Use of alpha interferons are associated with myelosuppression; additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives. 
    Interferon Alfacon-1: (Moderate) Use of alpha interferons are associated with myelosuppression; additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives. 
    Interferon Alfa-n3: (Moderate) Use of alpha interferons are associated with myelosuppression; additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives. 
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Rifampin may increase the CYP450 metabolism of tretinoin, ATRA, potentially resulting in decreased plasma concentrations of tretinoin, ATRA. No specific studies have been done with oral tretinoin and rifampin, however, patients should be closely monitored for decreased clinical effects of tretinoin, ATRA while receiving concomitant therapy. 
    Isoniazid, INH; Rifampin: (Moderate) Rifampin may increase the CYP450 metabolism of tretinoin, ATRA, potentially resulting in decreased plasma concentrations of tretinoin, ATRA. No specific studies have been done with oral tretinoin and rifampin, however, patients should be closely monitored for decreased clinical effects of tretinoin, ATRA while receiving concomitant therapy. 
    Ketoconazole: (Major) Concurrent oral tretinoin therapy with drugs that inhibit the hepatic cytochrome (CYP) P450 enzyme system can result in significant increases in serum tretinoin levels. In 13 patients who had received oral tretinoin daily for 4 consecutive weeks, a 72% increase in mean tretinoin plasma AUC was observed when ketoconazole (400 mg to 1200 mg PO) was given 1 hour before the tretinoin dose. This interaction may be due to inhibition of tretinoin metabolism by the azole antifungal; the precise CYP enzymes involved have not been identified, but CYP3A, 2C8 and 2E have been implicated in preliminary data. Similar interactions may occur with other systemic azole antifungals, such as voriconazole. No specific studies have been done with oral tretinoin and other inhibitors of CYP450 isoenzymes (such as cimetidine, cyclosporine, diltiazem, erythromycin, and verapamil), however, patients should be closely monitored for tretinoin toxicity while receiving concomitant therapy. 
    Ketorolac: (Major) An increased risk of bleeding may occur when NSAIDs, such as ketorolac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Lansoprazole; Naproxen: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Lepirudin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Levofloxacin: (Moderate) Use tretinoin with caution in patients who are also taking drugs known to be photosensitizers, such as levofloxacin, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Lithium: (Moderate) The concomitant use of systemic tretinoin, ATRA and lithium should be done cautiously due to the potential for increased intracranial pressure and an increased risk of pseudotumor cerebri. Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea, vomiting, and visual disturbances. 
    Meclofenamate Sodium: (Major) An increased risk of bleeding may occur when NSAIDs, such as meclofenamate sodium, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Mefenamic Acid: (Major) An increased risk of bleeding may occur when NSAIDs, such as mefenamic acid, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Meloxicam: (Minor) An increased risk of bleeding may occur when NSAIDs, such as meloxicam, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Mesoridazine: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Methotrexate: (Major) Concomitant use of systemic retinoids, such as tretinoin, and methotrexate could increase risk of liver-related side effects of methotrexate and such patients should be monitored closely during methotrexate therapy. Topical retinoid products do not appear to pose this increased risk for liver problems. 
    Methoxsalen: (Moderate) Use methoxsalen and retinoids together with caution; the risk of severe burns/phototoxicity may be additive. If concurrent use is necessary, closely monitor patients for signs or symptoms of skin toxicity. 
    Methyclothiazide: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Methylprednisolone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Metolazone: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Mometasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Moxifloxacin: (Moderate) Use tretinoin with caution in patients who are also taking drugs known to be photosensitizers, such as moxifloxacin, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Nabumetone: (Minor) An increased risk of bleeding may occur when NSAIDs, such as nabumetone, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Naproxen: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Naproxen; Pseudoephedrine: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Naproxen; Sumatriptan: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Norfloxacin: (Moderate) Use tretinoin with caution in patients who are also taking drugs known to be photosensitizers, such as norfloxacin, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Ofloxacin: (Moderate) Use tretinoin with caution in patients who are also taking drugs known to be photosensitizers, such as ofloxacin, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Orlistat: (Moderate) The bioavailability of orally administered retinoids may be decreased if coadministered with orlistat. In patients receiving orally-administered retinoids along with orlistat, close monitoring is recommended. In addition, the manufacturer recommends that fat-soluble vitamin analogues be administered at least 2 hours before or after the administration of orlistat to limit effects on oral absorption. 
    Oxaprozin: (Minor) An increased risk of bleeding may occur when NSAIDs, such as oxaprozin, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents. 
    Pegfilgrastim: (Major) Pegfilgrastim induces the proliferation of neutrophil-progenitor cells, and because antineoplastic agents exert toxic effects against rapidly growing cells, pegfilgrastim should not be given 14 days before or for 24 hours after cytotoxic chemotherapy. 
    Peginterferon Alfa-2a: (Moderate) Use of alpha interferons are associated with myelosuppression; additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives. 
    Peginterferon Alfa-2b: (Moderate) Use of alpha interferons are associated with myelosuppression; additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives. 
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity. 
    Pentosan: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Perphenazine: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Perphenazine; Amitriptyline: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Phenothiazines: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Phentermine; Topiramate: (Moderate) Topiramate may increase the CYP450 metabolism of tretinoin, ATRA, potentially resulting in decreased plasma concentrations of tretinoin, ATRA. Monitor for decreased clinical effects of tretinoin, ATRA while receiving concomitant therapy. 
    Photosensitizing agents: (Moderate) Use photosensitizing agents and retinoids together with caution; the risk of severe burns/phototoxicity may be additive. If concurrent use is necessary, closely monitor patients for signs or symptoms of skin toxicity. 
    Piroxicam: (Minor) An increased risk of bleeding may occur when NSAIDs, such as piroxicam, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Platelet Inhibitors: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as tretinoin. 
    Porfimer: (Moderate) Use photosensitizing agents and retinoids together with caution; the risk of severe burns/phototoxicity may be additive. If concurrent use is necessary, closely monitor patients for signs or symptoms of skin toxicity. 
    Prasugrel: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as tretinoin. 
    Prednisolone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Prednisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Prochlorperazine: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Rifabutin: (Moderate) Rifabutin may increase the CYP450 metabolism of tretinoin, ATRA, potentially resulting in decreased plasma concentrations of tretinoin, ATRA. No specific studies have been done with oral tretinoin and rifabutin, however, patients should be closely monitored for decreased clinical effects of tretinoin, ATRA while receiving concomitant therapy. 
    Rifampin: (Moderate) Rifampin may increase the CYP450 metabolism of tretinoin, ATRA, potentially resulting in decreased plasma concentrations of tretinoin, ATRA. No specific studies have been done with oral tretinoin and rifampin, however, patients should be closely monitored for decreased clinical effects of tretinoin, ATRA while receiving concomitant therapy. 
    Rifapentine: (Moderate) Rifapentine may increase the CYP450 metabolism of tretinoin, ATRA, potentially resulting in decreased plasma concentrations of tretinoin, ATRA. No specific studies have been done with oral tretinoin and rifapentine, however, patients should be closely monitored for decreased clinical effects of tretinoin, ATRA while receiving concomitant therapy. 
    Rivaroxaban: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Salicylic Acid: (Moderate) Dryness of the skin and mucus membranes are common side effects of retinoid therapy. Simultaneous use of retinoids and topical drying agents, such as salicylic acid, can potentiate the drying effects of retinoids on the skin. Be alert for signs of skin irritation, the offending topical agents may need to be used less often or discontinued during retinoid therapy. 
    Sodium Thiosulfate; Salicylic Acid: (Moderate) Dryness of the skin and mucus membranes are common side effects of retinoid therapy. Simultaneous use of retinoids and topical drying agents, such as salicylic acid, can potentiate the drying effects of retinoids on the skin. Be alert for signs of skin irritation, the offending topical agents may need to be used less often or discontinued during retinoid therapy. 
    St. John’s Wort, Hypericum perforatum: (Moderate) In theory it is possible that additive photosensitizing effects may result from the concomitant use of St. John’s wort with other photosensitizing drugs such as retinoids. 
    Sulfonylureas: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as sulfonylureas, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Sulindac: (Minor) An increased risk of bleeding may occur when NSAIDs, such as sulindac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Tbo-Filgrastim: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy. 
    Tetracyclines: (Major) The concomitant use of systemic tretinoin, ATRA and systemic tetracyclines should be avoided due to the potential for increased intracranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Pseudotumor cerebri has been reported with systemic retinoid use alone and early signs and symptoms include papilledema, headache, nausea, vomiting and visual disturbances. In addition, a manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as tetracyclines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Thiazide diuretics: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Thiethylperazine: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Thioridazine: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Thrombolytic Agents: (Moderate) Patients with thrombocytopenia are at increased risk of bleeding complications. An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents. 
    Thyroid hormones: (Moderate) The concomitant use of systemic tretinoin, ATRA and thyroid hormones should be done cautiously due to the potential for increased intracranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea, vomiting, and visual disturbances. 
    Ticagrelor: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as tretinoin. 
    Ticlopidine: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as tretinoin. 
    Tinzaparin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 
    Tirofiban: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as tretinoin. 
    Tolazamide: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as sulfonylureas, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Tolbutamide: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as sulfonylureas, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Tolmetin: (Minor) An increased risk of bleeding may occur when NSAIDs, such as tolmetin, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. 
    Topiramate: (Moderate) Topiramate may increase the CYP450 metabolism of tretinoin, ATRA, potentially resulting in decreased plasma concentrations of tretinoin, ATRA. Monitor for decreased clinical effects of tretinoin, ATRA while receiving concomitant therapy. 
    Trandolapril; Verapamil: (Moderate) Verapamil may decrease the CYP450 metabolism of tretinoin, ATRA, potentially resulting in increased plasma concentrations of tretinoin, ATRA. Monitor for tretinoin toxicity while receiving concomitant therapy. 
    Tranexamic Acid: (Major) Rare cases of fatal thrombotic complications have been reported in patients treated with systemic all-trans retinoic acid (ATRA) or tretinoin and the use of antifibrinolytic agents, like tranexamic acid. This is thought to be due to the persistent procoagulant tendency often associated with systemic tretinoin therapy. 
    Triamcinolone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
    Trifluoperazine: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas. 
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy. 
    Verapamil: (Moderate) Verapamil may decrease the CYP450 metabolism of tretinoin, ATRA, potentially resulting in increased plasma concentrations of tretinoin, ATRA. Monitor for tretinoin toxicity while receiving concomitant therapy. 
    Verteporfin: (Moderate) Use photosensitizing agents and retinoids together with caution; the risk of severe burns/phototoxicity may be additive. If concurrent use is necessary, closely monitor patients for signs or symptoms of skin toxicity. 
    Vorapaxar: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as tretinoin. 
    Voriconazole: (Major) Voriconazole is an inhibitor of CYP3A4 isoenzyme. Drugs that are substrates for CYP3A4, such as tretinoin, when combined with voriconazole, may theoretically have reduced metabolism, and therefore higher serum concentrations resulting in toxicity. 
    Warfarin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. 

    PREGNANCY AND LACTATION

    Pregnancy

    Teratogenic and embryotoxic effects have been demonstrated in animals receiving oral tretinoin or large doses (i.e., many times greater than the normal human dose) of topical tretinoin. Adequate and well-controlled trials have not been performed in humans, but increased spontaneous abortions and major human fetal abnormalities have occurred when pregnant women received other retinoids. There have been 30 case reports of temporally-associated, congenital malformations during 25 years of clinical use of Retin-A. The significance of these spontaneous reports in terms of risk to the fetus is not known. Avoid use of topical tretinoin over large areas of skin or for prolonged periods. The benefit-risk profile should be considered before prescribing. Reproductive risk should be discussed. There is a high risk of birth defects if oral tretinoin is administered during pregnancy. Females of childbearing potential must use two reliable forms of contraception simultaneously during oral tretinoin therapy and for one month following discontinuation of therapy, unless abstinence is the chosen method. Contraception requirements must be followed even when there is a history of infertility or menopause, unless a hysterectomy has been performed. Within one week of beginning tretinoin oral therapy, the patient should have a negative pregnancy test; if possible, treatment with tretinoin should be delayed until pregnancy testing results are known. Pregnancy testing and counseling should occur monthly during oral tretinoin therapy.[48166] [48167] [63467]

    MECHANISM OF ACTION

    Mechanism of Action: Retinoids are intracrine and paracrine mediators of cell differentiation and proliferation, apoptosis (programmed cell death), and reproduction. Cells regulate the formation of specific retinoid isomers depending upon the cellular action required. The numerous effects of retinoids reflect the complex biology of the nuclear receptors that mediate retinoid activity. Retinoid receptors are divided into retinoid X receptors (RXRs) and retinoic acid receptors (RARs); both types can be further divided into 3 subtypes: Alpha, beta, and gamma. These receptor subtypes are further divided into many isoforms. Retinoid receptors are structurally similar but have different affinities for different types of retinoids and distribution varies throughout the body resulting in a wide range of actions. Tretinoin binds to all three RARs, but does not bind to RXRs except at very high concentrations. RAR-alpha and RAR-beta have been associated with the development of acute promyelocytic leukemia and squamous cell cancers, respectively. RAR-gamma is associated with retinoid effects on mucocutaneous tissues and bone.•Skin Disorders: By binding to RARs, tretinoin modifies gene expression, subsequent protein synthesis, and epithelial cell growth and differentiation. It has not been established whether the clinical effects of tretinoin are mediated through activation of RARs, other mechanisms such as irritation, or both. Tretinoin appears to prevent horny cell cohesion and to increase epidermal cell turnover and mitotic activity. Subsequently, in patients with acne, expulsion of existing comedones occurs, and formation of new comedones is prevented through sloughing and expulsion of horny cells from the follicle. Tretinoin reduces the cell layers of the stratum corneum. The bacterium involved in acne, Propionibacterium acnes, and sebum production are unaffected. An additional action of tretinoin may involve keratinization inhibition, which would explain its effectiveness in treating keratinization disorders.•Photodamage: Topical tretinoin is effective in reducing fine wrinkling, mottled hyperpigmentation, roughness, and laxity associated with photodamaged skin. Ultraviolet irradiation induces three metalloproteinases in human skin: collagenase, 92-kd gelatinase, and stromelysin-1. The combined actions of these enzymes can fully degrade skin collagen. Pretreatment of skin with tretinoin inhibits the induction of these skin matrix metalloproteinase proteins and activity by 70—80% in both connective tissue and outer layers of irradiated skin.•Acute Promyelocytic Leukemia: Similar to other retinoids, tretinoin induces cellular differentiation in malignant cells. Acute promyelocytic leukemia (APL) is caused by a genetic lesion that disrupts the alpha retinoic acid receptor (RAR-alpha) gene found on the long arm of chromosome 17 and the PML gene found on chromosome 15. The fusion protein that is formed, PML-RAR-alpha, inhibits apoptotic pathways and blocks myeloid differentiation when present in levels greater than those of the normal RAR-alpha protein. The presence of this gene translocation [t(15;17)] is used for diagnosis of APL and as a marker of response following treatment with either cytotoxic agents or tretinoin. During tretinoin treatment, cells expressing PML/RAR-alpha undergo cellular differentiation at a rate higher than normal cells. At therapeutic doses of tretinoin, the activity of the fusion protein on differentiation converts from inhibitory to stimulatory. Terminal differentiation of APL cells as the mechanism of tretinoin therapy is supported by 1) the absence of bone marrow aplasia during treatment; 2) the appearance of cells during treatment with the morphologic characteristics of maturation stages intermediate between promyelocytes and neutrophils; 3) the presence, during treatment, of PML and RAR-alpha rearrangements in peripheral blood neutrophils that disappear after treatment. Treatment with tretinoin reverses the bleeding diathesis seen in APL, before any morphologic response is noted. A retinoic acid syndrome, similar to capillary leak syndrome, may be seen in some patients (see Adverse Reactions). The etiology of this syndrome is unknown, but may be due to decreases in leukocyte adhesion protein activity. Resistance to tretinoin may develop due to pharmacokinetic reasons (decreased bioavailability) and/or changes in proteins involved in the cellular activity of tretinoin.

    PHARMACOKINETICS

    Tretinoin is administered topically and orally; an intravenous formulation is under investigation. 
     
    Systemic tretinoin is greater than 95% bound to plasma proteins, primarily albumin. The distribution of tretinoin has not been determined. Tretinoin is metabolized by the cytochrome P450 hepatic enzyme system. The metabolites include 13-cis retinoic acid, 4-oxo trans retinoic acid, 4-oxo cis retinoic acid, and 4-oxo trans retinoic acid glucuronide. Tretinoin appears to induce its own metabolism. An approximately 10-fold increase in the urinary excretion of 4-oxo trans retinoic acid glucuronide is observed after 2—6 weeks of continuous dosing when compared with baseline.

    Oral Route

    After administration of a single oral dose, tretinoin is well absorbed, with peak plasma concentrations showing considerable interpatient variability. Mean peak plasma concentrations are 347 +/- 266 ng/ml and occur between 1 and 3 hours after dosing.
     
    About 90% of an oral dose is excreted in the urine and feces within 72 hours and 6 days, respectively.

    Intravenous Route

    One of the proposed benefits of the liposomal injection form of tretinoin, is the ability to overcome excessively rapid hepatic clearance and subsequent drug resistance associated with oral administration.

    Topical Route

    Following topical application, a minimal amount of drug is absorbed systemically. There is no expected difference in the systemic absorption of tretinoin from the microsphere formulation. Prolonged treatment or application to large body surface areas can enhance systemic absorption.
     
    Approximately 1—5% of a topically applied dose is excreted in the urine within 24 hours.

  •  

 

 

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MINOXIDIL UPDATE 

FDA Date: 06/09/2011

FDA Drug Safety Communication for 5-alpha Reductase Inhibitors

5-alpha Reductase Inhibitors (5-ARIs) May Increase the Risk of a More Serious Form of Prostate Cancer

This information reflects FDA’s current analysis of data available to FDA concerning this drug. FDA intends to update this sheet when additional information or analyses become available.

FDA is informing healthcare professionals that the Warnings and Precautions section of the labels for the 5-alpha reductase inhibitor (5-ARI) class of drugs has been revised to include new safety information about the increased risk of being diagnosed with a more serious form of prostate cancer (high-grade prostate cancer). This risk appears to be low, but healthcare professionals should be aware of this safety information, and weigh the known benefits against the potential risks when deciding to start or continue treatment with 5-ARIs in men.

The new safety information is based on FDA’s review of two large, randomized controlled trials the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, which evaluated daily use of finasteride 5 mg versus placebo for 7 years and daily use of dutasteride 0.5 mg versus placebo for 4 years, respectively, for the reduction in the risk of prostate cancer in men at least 50 years of age. The trials demonstrated an overall reduction in prostate cancer diagnoses with finasteride 5 mg and dutasteride treatment. This overall reduction was due to a decreased incidence of lower-risk forms of prostate cancer. However, both trials showed an increased incidence of high-grade prostate cancer with finasteride and dutasteride treatment

Healthcare professionals should:

– be aware that 5-ARIs may increase the risk of high-grade prostate cancer.

– prior to initiating therapy with 5-ARIs, perform appropriate evaluation to rule out other urological conditions, including prostate cancer, that might mimic benign prostatic hyperplasia (BPH).

– be aware that treatment with 5-ARIs causes an approximate 50% reduction in prostate-specific antigen (PSA) values by 6 months; however, individual patients receiving 5-ARIs may experience varying decreases in PSA values. Therefore, any confirmed increase in PSA while on a 5-ARI may signal the presence of prostate cancer and should be evaluated, even if that PSA is in the normal range of men not taking a 5-ARI.

– know that 5-ARIs are not approved for the prevention of prostate cancer.

View the full FDA Drug Safety Communication on FDA.gov

 

 

 

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MINOXIDIL 

CLASSES

5-Alpha Reductase Inhibitors
Alopecia Agents

DEA CLASS

Rx

DESCRIPTION

5-alpha reductase inhibitor
Used for symptomatic treatment of BPH and male pattern baldness (i.e., androgenetic alopecia)
May decrease risk of low-grade prostate cancer; but, may increase risk of more serious high-grade prostate cancer

COMMON BRAND NAMES

Propecia, Proscar

HOW SUPPLIED

Finasteride/Propecia/Proscar Oral Tab: 1mg, 5mg

DOSAGE & INDICATIONS

For the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to improve symptoms, to reduce the risk of acute urinary retention, and to reduce the risk of the need for surgery including transurethral resection of the prostate (TURP) and prostatectomy.
Oral dosage (Proscar)
Adult males

5 mg PO once daily. A minimum of 6 months therapy may be necessary to assess response, with up to 12 months necessary in some patients. In a double-blind, randomized, placebo-controlled study, 3040 men with moderate to severe urinary symptoms and enlarged prostate were treated with finasteride 5 mg PO once daily or placebo for 4 years. Finasteride reduced BPH symptoms and prostate volume, increased the urinary flow rate, and reduced the probability of surgery and acute urinary retention. In a long-term, double-blind clinical trial of 3047 men with BPH, combination therapy of doxazosin (4—8 mg PO once daily) and finasteride (5 mg PO once daily) was shown to significantly reduce the risk of overall clinical progression of BPH than either drug alone. However, further study is required.

For the treatment of male pattern hair loss (i.e., androgenetic alopecia), in patients with mild to moderate hair loss of the vertex and anterior mid-scalp area.
Oral dosage(Propecia)
Adult males, including Geriatric males

1 mg PO once daily. Daily use for >= 3 months is necessary before benefit is observed. Continued use is recommended to sustain benefit. Withdrawal of treatment leads to reversal of effect within 12 months.

For the second-line treatment of hirsutism†.
Oral dosage
Adult, non-pregnant women

5 mg PO once daily either alone or in combination with oral contraceptives was shown to reduce hirsutism in women with mild hirsutism. Women with moderate to severe hirsutism either do not respond or only respond initially. Adverse effects from finasteride were minimal compared to other antiandrogens such as cyproterone, flutamide, and spironolactone. 

For prostate cancer prophylaxis†.
Oral dosage
Adults

The risks of finasteride for prostate cancer prevention outweigh the benefits. In a 7-year placebo-controlled study, finasteride 5 mg PO once daily was shown to prevent or delay the development of prostate cancer in healthy men (>= 55 years of age) with a low risk of prostate cancer (PSA <= 3 ng/mL). Prostate specific antigen (PSA) levels, digital rectal exams, and biopsies were used to aid in the diagnosis of prostate cancer. Results showed that men receiving finasteride had a 26% decreased risk of being diagnosed with prostate cancer compared to placebo (p < 0.0001); however, the risk reduction was limited to Gleason score (GS) <= 6 cancers. There was an increased incidence of high-grade prostate cancer (GS 7—10) with finasteride compared to placebo (6.4% vs. 5.2%, respectively, p = 0.005). Finasteride was also associated with a higher incidence of sexual side effects versus placebo.

†Indicates off-label use

MAXIMUM DOSAGE

Adults

Males: 5 mg/day PO for benign prostatic hyperplasia (BPH); the manufacturer literature states that patients have received up to 80 mg/day PO for three months without adverse effects; however, it is not clear if the dose was used therapeutically or provided additional benefit over the usual dose range. Maximum dose-response is 1 mg/day PO for alopecia.

Elderly

Males: 5 mg/day PO for benign prostatic hyperplasia (BPH); the manufacturer literature states that patients have received up to 80 mg/day PO for three months without adverse effects; however, it is not clear if the dose was used therapeutically or provided additional benefit over the usual dose range. Maximum dose-response is 1 mg/day PO for alopecia.

Adolescents

Not indicated.

Children

Not indicated.

DOSING CONSIDERATIONS

Hepatic Impairment

Finasteride should be initiated with caution in patients with hepatic disease. Since finasteride is metabolized extensively in the liver, reduced metabolism is possible. The effect of hepatic impairment on finasteride pharmacokinetics has not been studied.

Renal Impairment

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

ADMINISTRATION

Oral Administration

Finasteride may be administered without regard to meals.
Women who are pregnant or may get pregnant must not handle/administer broken or crushed finasteride tablets; the active ingredient could harm the unborn baby. Exposure to whole tablets is not expected to cause harm as long as they are not swallowed.

STORAGE

Propecia:
– Protect from moisture
– Store at controlled room temperature (between 68 and 77 degrees F)
Proscar:
– Protect from light
– Store at controlled room temperature (between 68 and 77 degrees F)

CONTRAINDICATIONS / PRECAUTIONS

Females, pregnancy

Finasteride is not FDA-approved for use in females of childbearing potential and is contraindicated during pregnancy. Finasteride may cause fetal harm. Finasteride and other 5-alpha-reductase inhibitors, by inhibiting the conversion of testosterone to DHT, have the ability to cause abnormalities in the external genitalia of the male fetus. Pregnant women or females trying to conceive should not handle crushed or broken finasteride tablets. The distribution of finasteride into human semen has been assessed and appears to be well below the threshold concentration associated with fetal anomalies in animals. 

Breast-feeding

Finasteride is not FDA-approved for use in females of childbearing potential and is recommended to be avoided during breast-feeding. It is not known whether finasteride is excreted in human milk. Therefore, the effects of finasteride on breast-feeding or a nursing infant cannot be determined. 

Children, infants

Finasteride is not indicated for use in adolescents, children, or infants. Safety and effectiveness have not been established in pediatric patients under 18 years of age. 

Hepatic disease

Finasteride should be used with caution in patients with hepatic disease, since finasteride is metabolized extensively in the liver. Data are lacking regarding the incidence of adverse effects or drug accumulation in patients with hepatic impairment.

Prostate cancer, urinary tract obstruction

Finasteride reduces total serum prostate specific antigen (PSA). In a typical patient undergoing treatment for BPH with finasteride (>= 6 months), a 50% decrease in serum PSA concentrations can be expected; however, individual patients may experience varying decreases in PSA values. During treatment, serum PSA concentrations may decrease even in the presence of prostate cancer. If clinicians use serum PSA concentrations as an aid in the detection of prostate cancer in men receiving finasteride, values should be doubled for comparison with normal ranges in untreated men. Any increase from baseline, even if the value is within the normal range for untreated men, may signal the presence of prostate cancer. If clinicians elect to use percent free PSA (free to total PSA ratio) as a marker, no adjustment in PSA values appear to be necessary as the value is not significantly decreased by finasteride. In June 2011, a review of two large, randomized controlled trials, the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial prompted the FDA to alert healthcare professionals of the potential risk of an increased incidence of high-grade prostate cancer in patients receiving finasteride or dutasteride treatment. Results from the PCPT trial showed that men receiving finasteride had a 26% decreased risk of being diagnosed with prostate cancer when compared to placebo (p < 0.0001); however, the risk reduction was limited to Gleason score (GS) <= 6 cancers. There was an increased incidence of GS 8—10 prostate cancers with finasteride compared to placebo (1.8% vs. 1.1%, respectively). Therefore, in initiating or continuing treatment with finasteride, clinicians should weigh the known benefits of treatment against the potential risk and be aware that finasteride may increase the risk of high-grade prostate cancer. Further, lower urinary tract symptoms of BPH can be indicative of other urological diseases, including prostate cancer. Patients should be assessed to rule out other urological diseases prior to treatment with finasteride. Patients with a large residual urinary volume and/or severely diminished urinary flow may not be good candidates for 5-alpha-reductase inhibitor therapy and should be carefully monitored for urinary tract obstruction.

Blood donation

Men treated with finasteride should refrain from blood donation while taking finasteride. The purpose of this is to prevent administration of finasteride to a pregnant female transfusion recipient.

Geriatric

Clinical efficacy studies of finasteride for hair loss did not include subjects aged 65 and over. Based on the pharmacokinetics of finasteride 5 mg, no dosage adjustment is necessary in the geriatric patient. However, the efficacy of finasteride for hair loss in the elderly has not been established.

Infertility

The clinical significance of finasteride’s effect on semen characteristics for an individual male patient’s fertility is not known; consider the potential effects on semen when assessing a male with infertility. Finasteride may cause spermatogenesis inhibition or oligospermia, decreased sperm motility, or decreased semen volume. In a 52-week, randomized, double-blind, placebo-controlled study in healthy men, finasteride (5 mg PO once daily) significantly decreased total sperm count (-34.3%) compared to baseline at 26 weeks but not at 52 weeks or at the 24-week follow-up. Semen volume was decreased at 52 weeks for finasteride (-14.5%), but the effect was not statistically significant. Sperm concentration was decreased by finasteride (-7.4%) but was not significant for either drug. Significant reductions of 6 to 12% in sperm motility were observed during treatment. Sperm morphology was not affected. One subject taking finasteride had decreases in sperm count of more than 90% of baseline values at 52 weeks; partial recovery was noted at the 24-week follow-up. During post marketing surveillance, male infertility and/or poor seminal quality following treatment discontinuation have been reported. It should be noted that normalization or improvement of seminal quality has also been reported after discontinuation of finasteride. 

ADVERSE REACTIONS

Severe

angioedema / Rapid / Incidence not known
new primary malignancy / Delayed / Incidence not known
teratogenesis / Delayed / Incidence not known

Moderate

impotence (erectile dysfunction) / Delayed / Incidence not known
ejaculation dysfunction / Delayed / Incidence not known
depression / Delayed / Incidence not known
infertility / Delayed / Incidence not known

Mild

libido decrease / Delayed / 1.8-1.8
gynecomastia / Delayed / 10.0
breast enlargement / Delayed / 10.0
testicular pain / Early / Incidence not known
decreased ejaculate volume / Delayed / Incidence not known
pruritus / Rapid / Incidence not known
orgasm dysfunction / Delayed / Incidence not known
mastalgia / Delayed / Incidence not known
rash / Early / Incidence not known
urticaria / Rapid / Incidence not known
oligospermia / Delayed / Incidence not known
spermatogenesis inhibition / Delayed / Incidence not known

DRUG INTERACTIONS

Saw Palmetto, Serenoa repens: (Moderate) Saw palmetto may inhibit 5 alpha-reductase, preventing the conversion of testosterone to dihydrotestosterone. This action is similar to the action of 5-alpha reductase inhibitors, such as dutasteride and finasteride. Co-use is likely to be common by patients, but the effects of co-use are not known. In theory, the effects could be additive, but it is not known if the added effects would be beneficial or harmful. Clinicians should be alert for any unusual effects if patients ingest saw palmetto supplements while taking 5-alpha reductase inhibitors. 
Soy Isoflavones: (Minor) Theoretically, because the soy isoflavones appear to inhibit type II 5-alpha-reductase, the soy isoflavones may have additive effects with other 5-alpha reductase inhibitors. 
Terazosin: (Minor) Terazosin has been reported to increase peak concentrations of finasteride by 16% and AUC by 31% when the two agents are coadministered. The interaction is of minor importance. 

PREGNANCY AND LACTATION

Pregnancy

Finasteride is not FDA-approved for use in females of childbearing potential and is contraindicated during pregnancy. Finasteride may cause fetal harm. Finasteride and other 5-alpha-reductase inhibitors, by inhibiting the conversion of testosterone to DHT, have the ability to cause abnormalities in the external genitalia of the male fetus. Pregnant women or females trying to conceive should not handle crushed or broken finasteride tablets. The distribution of finasteride into human semen has been assessed and appears to be well below the threshold concentration associated with fetal anomalies in animals. 

MECHANISM OF ACTION

Finasteride is a synthetic 4-aza analog of testosterone that acts as a competitive, specific inhibitor of type II 5-alpha-reductase, an intracellular enzyme that converts testosterone to the potent androgen 5-alpha-dihydrotestosterone (DHT). The type II 5alpha-reductase isozyme is primarily found in prostate, seminal vesicles, epididymides, and hair follicles, as well as liver. The type II isozyme is responsible for two-thirds of circulating DHT. DHT is the primary androgen that stimulates the development of prostate tissue. When used for the treatment of benign prostatic hyperplasia, as the enzymatic conversion from testosterone to DHT is inhibited, a desirable reduction in prostate hypertrophy is achieved, and urine flow should be improved. In male pattern hair loss, the balding scalp contains miniaturized hair follicles and increased amounts of DHT compared with hairy scalp. Finasteride decreases scalp and serum DHT concentrations, thus interrupting a key factor in the development of androgenetic alopecia in those patients genetically predisposed. Finasteride does not appear to affect circulating concentrations of cortisol, estradiol, prolactin, thyroid-stimulating hormone, thyroxine or cholesterol. Research to date also suggests that finasteride does not affect the hypothalamic-pituitary-testicular-axis.

PHARMACOKINETICS

Finasteride is administered orally in the treatment of either BPH or male pattern baldness. Approximately 90% is bound to plasma proteins; yet the drug has been found to cross the blood-brain barrier. This is not problematic, since finasteride generally does not affect other hormones. Daily dosing causes accumulation to occur, with plasma concentrations increasing by 50% over those observed from a single dose. The mean plasma elimination half-life of finasteride is 4.8 to 6 hours (range, 3 to 16 hours); however, the turnover rate for the type II 5-alpha-reductase enzyme complex is slow, with a turnover half-life of approximately 30 days. After oral dosing, about half of the unchanged drug is excreted in the feces, and one-third is metabolized in the liver to the 17-carboxylic acid, which is then excreted in the urine (39%) and the feces (57%).
 
A single 5 mg oral dose rapidly reduces serum DHT concentrations by as much as 70%, with the maximum reduction occurring at about 8 hours. The effect lasts for at least 24 hours, so once daily dosing is appropriate. Actual clinical effects, however, are not realized for 3 to 6 months after beginning therapy.
 
Affected cytochrome P450(CYP450) isoenzymes and drug transporters: CYP3A4, UGT1A4
While finasteride is metabolized by hepatic CYP3A4 isoenzymes, no drug interactions of clinical importance have been identified, likely due to the hormonal mechanisms of action and relatively large therapeutic window of effect. Finasteride does not appear to affect the CYP450-linked drug metabolizing enzyme system. Compounds that have been tested in man have included antipyrine, digoxin, propranolol, theophylline, and warfarin and no clinically meaningful interactions were found. Finasteride has not been associated with clinically important drug interactions during clinical trials, including a 4-year safety trial of 3,040 males aged 45 to 78 years. while finasteride markedly inhibited UGT1A4 activity in vitro in a drug transporter study; the data strongly suggested that finasteride is unlikely to cause clinically significant drug-drug interactions mediated via inhibition of the hepatic UGT enzymes involved in drug metabolism in vivo.

Oral Route

The mean bioavailability following a single dose of finasteride is about 63—65%; however, bioavailability is highly variable.

 

—————————

FINASTERIDE UPDATE BY FDA

 

FDA Drug Safety Communication for 5-alpha Reductase Inhibitors

5-alpha Reductase Inhibitors (5-ARIs) May Increase the Risk of a More Serious Form of Prostate Cancer

This information reflects FDA’s current analysis of data available to FDA concerning this drug. FDA intends to update this sheet when additional information or analyses become available.

FDA is informing healthcare professionals that the Warnings and Precautions section of the labels for the 5-alpha reductase inhibitor (5-ARI) class of drugs has been revised to include new safety information about the increased risk of being diagnosed with a more serious form of prostate cancer (high-grade prostate cancer). This risk appears to be low, but healthcare professionals should be aware of this safety information, and weigh the known benefits against the potential risks when deciding to start or continue treatment with 5-ARIs in men.

The new safety information is based on FDA’s review of two large, randomized controlled trials the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, which evaluated daily use of finasteride 5 mg versus placebo for 7 years and daily use of dutasteride 0.5 mg versus placebo for 4 years, respectively, for the reduction in the risk of prostate cancer in men at least 50 years of age. The trials demonstrated an overall reduction in prostate cancer diagnoses with finasteride 5 mg and dutasteride treatment. This overall reduction was due to a decreased incidence of lower-risk forms of prostate cancer. However, both trials showed an increased incidence of high-grade prostate cancer with finasteride and dutasteride treatment

Healthcare professionals should:

– be aware that 5-ARIs may increase the risk of high-grade prostate cancer.

– prior to initiating therapy with 5-ARIs, perform appropriate evaluation to rule out other urological conditions, including prostate cancer, that might mimic benign prostatic hyperplasia (BPH).

– be aware that treatment with 5-ARIs causes an approximate 50% reduction in prostate-specific antigen (PSA) values by 6 months; however, individual patients receiving 5-ARIs may experience varying decreases in PSA values. Therefore, any confirmed increase in PSA while on a 5-ARI may signal the presence of prostate cancer and should be evaluated, even if that PSA is in the normal range of men not taking a 5-ARI.

– know that 5-ARIs are not approved for the prevention of prostate cancer.

View the full FDA Drug Safety Communication on FDA.gov

 

 

 

————————————-

FINASTERIDE 

CLASSES

5-Alpha Reductase Inhibitors
Alopecia Agents

DEA CLASS

Rx

DESCRIPTION

5-alpha reductase inhibitor
Used for symptomatic treatment of BPH and male pattern baldness (i.e., androgenetic alopecia)
May decrease risk of low-grade prostate cancer; but, may increase risk of more serious high-grade prostate cancer

COMMON BRAND NAMES

Propecia, Proscar

HOW SUPPLIED

Finasteride/Propecia/Proscar Oral Tab: 1mg, 5mg

DOSAGE & INDICATIONS

For the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to improve symptoms, to reduce the risk of acute urinary retention, and to reduce the risk of the need for surgery including transurethral resection of the prostate (TURP) and prostatectomy.
Oral dosage (Proscar)
Adult males

5 mg PO once daily. A minimum of 6 months therapy may be necessary to assess response, with up to 12 months necessary in some patients. In a double-blind, randomized, placebo-controlled study, 3040 men with moderate to severe urinary symptoms and enlarged prostate were treated with finasteride 5 mg PO once daily or placebo for 4 years. Finasteride reduced BPH symptoms and prostate volume, increased the urinary flow rate, and reduced the probability of surgery and acute urinary retention. In a long-term, double-blind clinical trial of 3047 men with BPH, combination therapy of doxazosin (4—8 mg PO once daily) and finasteride (5 mg PO once daily) was shown to significantly reduce the risk of overall clinical progression of BPH than either drug alone. However, further study is required.

For the treatment of male pattern hair loss (i.e., androgenetic alopecia), in patients with mild to moderate hair loss of the vertex and anterior mid-scalp area.
Oral dosage(Propecia)
Adult males, including Geriatric males

1 mg PO once daily. Daily use for >= 3 months is necessary before benefit is observed. Continued use is recommended to sustain benefit. Withdrawal of treatment leads to reversal of effect within 12 months.

For the second-line treatment of hirsutism†.
Oral dosage
Adult, non-pregnant women

5 mg PO once daily either alone or in combination with oral contraceptives was shown to reduce hirsutism in women with mild hirsutism. Women with moderate to severe hirsutism either do not respond or only respond initially. Adverse effects from finasteride were minimal compared to other antiandrogens such as cyproterone, flutamide, and spironolactone. 

For prostate cancer prophylaxis†.
Oral dosage
Adults

The risks of finasteride for prostate cancer prevention outweigh the benefits. In a 7-year placebo-controlled study, finasteride 5 mg PO once daily was shown to prevent or delay the development of prostate cancer in healthy men (>= 55 years of age) with a low risk of prostate cancer (PSA <= 3 ng/mL). Prostate specific antigen (PSA) levels, digital rectal exams, and biopsies were used to aid in the diagnosis of prostate cancer. Results showed that men receiving finasteride had a 26% decreased risk of being diagnosed with prostate cancer compared to placebo (p < 0.0001); however, the risk reduction was limited to Gleason score (GS) <= 6 cancers. There was an increased incidence of high-grade prostate cancer (GS 7—10) with finasteride compared to placebo (6.4% vs. 5.2%, respectively, p = 0.005). Finasteride was also associated with a higher incidence of sexual side effects versus placebo.

†Indicates off-label use

MAXIMUM DOSAGE

Adults

Males: 5 mg/day PO for benign prostatic hyperplasia (BPH); the manufacturer literature states that patients have received up to 80 mg/day PO for three months without adverse effects; however, it is not clear if the dose was used therapeutically or provided additional benefit over the usual dose range. Maximum dose-response is 1 mg/day PO for alopecia.

Elderly

Males: 5 mg/day PO for benign prostatic hyperplasia (BPH); the manufacturer literature states that patients have received up to 80 mg/day PO for three months without adverse effects; however, it is not clear if the dose was used therapeutically or provided additional benefit over the usual dose range. Maximum dose-response is 1 mg/day PO for alopecia.

Adolescents

Not indicated.

Children

Not indicated.

DOSING CONSIDERATIONS

Hepatic Impairment

Finasteride should be initiated with caution in patients with hepatic disease. Since finasteride is metabolized extensively in the liver, reduced metabolism is possible. The effect of hepatic impairment on finasteride pharmacokinetics has not been studied.

Renal Impairment

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

ADMINISTRATION

Oral Administration

Finasteride may be administered without regard to meals.
Women who are pregnant or may get pregnant must not handle/administer broken or crushed finasteride tablets; the active ingredient could harm the unborn baby. Exposure to whole tablets is not expected to cause harm as long as they are not swallowed.

STORAGE

Propecia:
– Protect from moisture
– Store at controlled room temperature (between 68 and 77 degrees F)
Proscar:
– Protect from light
– Store at controlled room temperature (between 68 and 77 degrees F)

CONTRAINDICATIONS / PRECAUTIONS

Females, pregnancy

Finasteride is not FDA-approved for use in females of childbearing potential and is contraindicated during pregnancy. Finasteride may cause fetal harm. Finasteride and other 5-alpha-reductase inhibitors, by inhibiting the conversion of testosterone to DHT, have the ability to cause abnormalities in the external genitalia of the male fetus. Pregnant women or females trying to conceive should not handle crushed or broken finasteride tablets. The distribution of finasteride into human semen has been assessed and appears to be well below the threshold concentration associated with fetal anomalies in animals. 

Breast-feeding

Finasteride is not FDA-approved for use in females of childbearing potential and is recommended to be avoided during breast-feeding. It is not known whether finasteride is excreted in human milk. Therefore, the effects of finasteride on breast-feeding or a nursing infant cannot be determined. 

Children, infants

Finasteride is not indicated for use in adolescents, children, or infants. Safety and effectiveness have not been established in pediatric patients under 18 years of age. 

Hepatic disease

Finasteride should be used with caution in patients with hepatic disease, since finasteride is metabolized extensively in the liver. Data are lacking regarding the incidence of adverse effects or drug accumulation in patients with hepatic impairment.

Prostate cancer, urinary tract obstruction

Finasteride reduces total serum prostate specific antigen (PSA). In a typical patient undergoing treatment for BPH with finasteride (>= 6 months), a 50% decrease in serum PSA concentrations can be expected; however, individual patients may experience varying decreases in PSA values. During treatment, serum PSA concentrations may decrease even in the presence of prostate cancer. If clinicians use serum PSA concentrations as an aid in the detection of prostate cancer in men receiving finasteride, values should be doubled for comparison with normal ranges in untreated men. Any increase from baseline, even if the value is within the normal range for untreated men, may signal the presence of prostate cancer. If clinicians elect to use percent free PSA (free to total PSA ratio) as a marker, no adjustment in PSA values appear to be necessary as the value is not significantly decreased by finasteride. In June 2011, a review of two large, randomized controlled trials, the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial prompted the FDA to alert healthcare professionals of the potential risk of an increased incidence of high-grade prostate cancer in patients receiving finasteride or dutasteride treatment. Results from the PCPT trial showed that men receiving finasteride had a 26% decreased risk of being diagnosed with prostate cancer when compared to placebo (p < 0.0001); however, the risk reduction was limited to Gleason score (GS) <= 6 cancers. There was an increased incidence of GS 8—10 prostate cancers with finasteride compared to placebo (1.8% vs. 1.1%, respectively). Therefore, in initiating or continuing treatment with finasteride, clinicians should weigh the known benefits of treatment against the potential risk and be aware that finasteride may increase the risk of high-grade prostate cancer. Further, lower urinary tract symptoms of BPH can be indicative of other urological diseases, including prostate cancer. Patients should be assessed to rule out other urological diseases prior to treatment with finasteride. Patients with a large residual urinary volume and/or severely diminished urinary flow may not be good candidates for 5-alpha-reductase inhibitor therapy and should be carefully monitored for urinary tract obstruction.

Blood donation

Men treated with finasteride should refrain from blood donation while taking finasteride. The purpose of this is to prevent administration of finasteride to a pregnant female transfusion recipient.

Geriatric

Clinical efficacy studies of finasteride for hair loss did not include subjects aged 65 and over. Based on the pharmacokinetics of finasteride 5 mg, no dosage adjustment is necessary in the geriatric patient. However, the efficacy of finasteride for hair loss in the elderly has not been established.

Infertility

The clinical significance of finasteride’s effect on semen characteristics for an individual male patient’s fertility is not known; consider the potential effects on semen when assessing a male with infertility. Finasteride may cause spermatogenesis inhibition or oligospermia, decreased sperm motility, or decreased semen volume. In a 52-week, randomized, double-blind, placebo-controlled study in healthy men, finasteride (5 mg PO once daily) significantly decreased total sperm count (-34.3%) compared to baseline at 26 weeks but not at 52 weeks or at the 24-week follow-up. Semen volume was decreased at 52 weeks for finasteride (-14.5%), but the effect was not statistically significant. Sperm concentration was decreased by finasteride (-7.4%) but was not significant for either drug. Significant reductions of 6 to 12% in sperm motility were observed during treatment. Sperm morphology was not affected. One subject taking finasteride had decreases in sperm count of more than 90% of baseline values at 52 weeks; partial recovery was noted at the 24-week follow-up. During post marketing surveillance, male infertility and/or poor seminal quality following treatment discontinuation have been reported. It should be noted that normalization or improvement of seminal quality has also been reported after discontinuation of finasteride. 

ADVERSE REACTIONS

Severe

angioedema / Rapid / Incidence not known
new primary malignancy / Delayed / Incidence not known
teratogenesis / Delayed / Incidence not known

Moderate

impotence (erectile dysfunction) / Delayed / Incidence not known
ejaculation dysfunction / Delayed / Incidence not known
depression / Delayed / Incidence not known
infertility / Delayed / Incidence not known

Mild

libido decrease / Delayed / 1.8-1.8
gynecomastia / Delayed / 10.0
breast enlargement / Delayed / 10.0
testicular pain / Early / Incidence not known
decreased ejaculate volume / Delayed / Incidence not known
pruritus / Rapid / Incidence not known
orgasm dysfunction / Delayed / Incidence not known
mastalgia / Delayed / Incidence not known
rash / Early / Incidence not known
urticaria / Rapid / Incidence not known
oligospermia / Delayed / Incidence not known
spermatogenesis inhibition / Delayed / Incidence not known

DRUG INTERACTIONS

Saw Palmetto, Serenoa repens: (Moderate) Saw palmetto may inhibit 5 alpha-reductase, preventing the conversion of testosterone to dihydrotestosterone. This action is similar to the action of 5-alpha reductase inhibitors, such as dutasteride and finasteride. Co-use is likely to be common by patients, but the effects of co-use are not known. In theory, the effects could be additive, but it is not known if the added effects would be beneficial or harmful. Clinicians should be alert for any unusual effects if patients ingest saw palmetto supplements while taking 5-alpha reductase inhibitors. 
Soy Isoflavones: (Minor) Theoretically, because the soy isoflavones appear to inhibit type II 5-alpha-reductase, the soy isoflavones may have additive effects with other 5-alpha reductase inhibitors. 
Terazosin: (Minor) Terazosin has been reported to increase peak concentrations of finasteride by 16% and AUC by 31% when the two agents are coadministered. The interaction is of minor importance. 

PREGNANCY AND LACTATION

Pregnancy

Finasteride is not FDA-approved for use in females of childbearing potential and is contraindicated during pregnancy. Finasteride may cause fetal harm. Finasteride and other 5-alpha-reductase inhibitors, by inhibiting the conversion of testosterone to DHT, have the ability to cause abnormalities in the external genitalia of the male fetus. Pregnant women or females trying to conceive should not handle crushed or broken finasteride tablets. The distribution of finasteride into human semen has been assessed and appears to be well below the threshold concentration associated with fetal anomalies in animals. 

MECHANISM OF ACTION

Finasteride is a synthetic 4-aza analog of testosterone that acts as a competitive, specific inhibitor of type II 5-alpha-reductase, an intracellular enzyme that converts testosterone to the potent androgen 5-alpha-dihydrotestosterone (DHT). The type II 5alpha-reductase isozyme is primarily found in prostate, seminal vesicles, epididymides, and hair follicles, as well as liver. The type II isozyme is responsible for two-thirds of circulating DHT. DHT is the primary androgen that stimulates the development of prostate tissue. When used for the treatment of benign prostatic hyperplasia, as the enzymatic conversion from testosterone to DHT is inhibited, a desirable reduction in prostate hypertrophy is achieved, and urine flow should be improved. In male pattern hair loss, the balding scalp contains miniaturized hair follicles and increased amounts of DHT compared with hairy scalp. Finasteride decreases scalp and serum DHT concentrations, thus interrupting a key factor in the development of androgenetic alopecia in those patients genetically predisposed. Finasteride does not appear to affect circulating concentrations of cortisol, estradiol, prolactin, thyroid-stimulating hormone, thyroxine or cholesterol. Research to date also suggests that finasteride does not affect the hypothalamic-pituitary-testicular-axis.

PHARMACOKINETICS

Finasteride is administered orally in the treatment of either BPH or male pattern baldness. Approximately 90% is bound to plasma proteins; yet the drug has been found to cross the blood-brain barrier. This is not problematic, since finasteride generally does not affect other hormones. Daily dosing causes accumulation to occur, with plasma concentrations increasing by 50% over those observed from a single dose. The mean plasma elimination half-life of finasteride is 4.8 to 6 hours (range, 3 to 16 hours); however, the turnover rate for the type II 5-alpha-reductase enzyme complex is slow, with a turnover half-life of approximately 30 days. After oral dosing, about half of the unchanged drug is excreted in the feces, and one-third is metabolized in the liver to the 17-carboxylic acid, which is then excreted in the urine (39%) and the feces (57%).
 
A single 5 mg oral dose rapidly reduces serum DHT concentrations by as much as 70%, with the maximum reduction occurring at about 8 hours. The effect lasts for at least 24 hours, so once daily dosing is appropriate. Actual clinical effects, however, are not realized for 3 to 6 months after beginning therapy.
 
Affected cytochrome P450(CYP450) isoenzymes and drug transporters: CYP3A4, UGT1A4
While finasteride is metabolized by hepatic CYP3A4 isoenzymes, no drug interactions of clinical importance have been identified, likely due to the hormonal mechanisms of action and relatively large therapeutic window of effect. Finasteride does not appear to affect the CYP450-linked drug metabolizing enzyme system. Compounds that have been tested in man have included antipyrine, digoxin, propranolol, theophylline, and warfarin and no clinically meaningful interactions were found. Finasteride has not been associated with clinically important drug interactions during clinical trials, including a 4-year safety trial of 3,040 males aged 45 to 78 years. while finasteride markedly inhibited UGT1A4 activity in vitro in a drug transporter study; the data strongly suggested that finasteride is unlikely to cause clinically significant drug-drug interactions mediated via inhibition of the hepatic UGT enzymes involved in drug metabolism in vivo.

Oral Route

The mean bioavailability following a single dose of finasteride is about 63—65%; however, bioavailability is highly variable.

 

FLUOCINOLONE

CLASSES

Ophthalmological Corticosteroids
Otic Corticosteroids
Plain Topical Corticosteroids
Topical Scalp Anti-inflammatories, with Corticosteroids

DEA CLASS

Rx

DESCRIPTION

Synthetic fluorinated corticosteroid of medium- to high-potency
Used topically for inflammatory corticosteroid-responsive dermatoses and psoriasis in adult and pediatric patients; an otic oil-based solution is used for chronic eczematous external otitis
Intravitreal implants are available that treat chronic non-infectious uveitis or diabetic macular edema

COMMON BRAND NAMES

Capex, Derma-Smoothe/FS, DermOtic Oil, Flac, Fluonid, Iluvien, Retisert, Synalar, YUTIQ

HOW SUPPLIED

Capex Topical Shampoo: 12mg
Capex/Fluocinolone/Fluocinolone Acetonide/Fluonid/Synalar Topical Sol: 0.01%, 12mg
Derma-Smoothe/FS/Fluocinolone/Fluocinolone Acetonide Topical Oil: 0.01%
DermOtic Oil/Flac/Fluocinolone/Fluocinolone Acetonide Auricular (Otic) Oil: 0.01%
Fluocinolone/Fluocinolone Acetonide/Synalar Topical Cream: 0.01%, 0.025%
Fluocinolone/Fluocinolone Acetonide/Synalar Topical Ointment: 0.025%
Iluvien/YUTIQ Intravitreal Insert: 0.18mg, 0.19mg
Retisert Intravitreal Imp: 0.59mg

DOSAGE & INDICATIONS

For the treatment of mild to moderate inflammatory manifestations of corticosteroid-responsive dermatitis such as alopecia areata, atopic dermatitis, contact dermatitis, exfoliative dermatitis, Rhus dermatitis due to plants like poison ivy, or seborrheic dermatitis (facial and intertriginous areas), discoid lupus erythematosus (facial and intertriginous areas), eczema, granuloma annulare, intertrigo, cutaneous lichen planus, lichen simplex chronicus, polymorphous light eruption, pompholyx (dyshidrosis), nodular prurigo, anogenital or senilis pruritus, psoriasis (facial and intertriginous areas), or xerosis (inflammatory phase).
For atopic dermatitis.
Topical dosage (topical oil)
Adults

Apply topically as a thin film to the affected area 3 times per day.

Adolescents, Children, and Infants 3 months and older

Moisten skin and apply topically as a thin film to the affected areas twice daily. Do not treat longer than 4 weeks continuously. The FDA-approved use of Derma-Smoothe/FS oil in pediatric patients 3 months and older is limited to patients with moderate to severe atopic dermatitis. Do not apply to the face or diaper area. Avoid application to intertriginous areas.

For psoriasis of the scalp.
Topical dosage (topical oil)
Adults

Wet or dampen hair and scalp thoroughly prior to use. Apply a thin film of oil once daily, massage well and cover the scalp with the supplied shower cap. Leave on overnight or for a minimum of 4 hours before washing off. Wash hair with regular shampoo and rinse thoroughly. In a vehicle-controlled study, after 21 days of treatment 60% of patients receiving fluocinolone topical oil and 21% of patients receiving drug vehicle achieved a good to excellent clinical response.

For seborrheic dermatitis of the scalp.
Topical dosage (shampoo)
Adults

No more than one (1) ounce of shampoo should be applied to the scalp area once daily, worked into a lather and allowed to remain on the scalp for approximately 5 minutes. Rinse the hair and scalp completely twice. In vehicle-controlled studies, after 14 days of treatment, 84% of patients on fluocinolone and 29% of patients on drug vehicle had cleared or markedly improved.

Topical dosage (cream, ointment, or topical solution)
Adults

Apply sparingly to the affected area 2 to 4 times per day, depending on the severity of the condition. In hairy sites, the hair should be parted to allow direct contact with the lesion. Occlusive dressings may be used for the management of recalcitrant conditions.

Children and Adolescents

Apply sparingly to the affected area 2 to 4 times per day, depending on the severity of the condition. In hairy sites, the hair should be parted to allow direct contact with the lesion. Occlusive dressings may be used for the management of recalcitrant conditions.

For the treatment of chronic non-infectious uveitis affecting the posterior segment of the eye.
Intravitreal implant dosage (Retisert)
Adults

Surgically insert 1 implant tablet (containing 0.59 mg fluocinolone acetonide) into the posterior segment of the affected eye. The implant releases fluocinolone acetonide at an initial rate of 0.6 mcg/day, decreasing over the first month to 0.3 to 0.4 mcg/day at steady state, and lasting approximately 30 months. If there is a recurrence of uveitis after the implant is depleted, the implant may be replaced.

Intravitreal implant dosage (Yutiq)
Adults

Inject 1 implant (containing 0.18 mg fluocinolone acetonide) intravitreally. Monitor the patient for elevated intraocular pressure and endophthalmitis. The implant is designed to release fluocinolone acetonide at an initial rate of 0.25 mcg/day, and lasting 36 months.

For the treatment of diabetic macular edema in patients who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure.
Intravitreal implant dosage (Iluvien)
Adults

Inject 1 implant (containing 0.19 mg fluocinolone acetonide) intravitreally. Monitor the patient for elevated intraocular pressure and endophthalmitis. The implant is designed to release fluocinolone acetonide at an initial rate of 0.25 mcg/day, and lasting 36 months. According to the American Diabetes Association (ADA), intravitreous steroids are considered second-line alternative treatment options for central-involved diabetic macular edema (CIDME). These drugs are rarely used as first-line treatment options, because when compared against intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents, steroid therapies are associated with inferior visual acuity outcomes and increased rate of cataracts and glaucoma.

For the treatment of chronic eczematous otitis externa.
Otic topical dosage (Otic oil, e.g., DermOtic Oil 0.01%)
Adults

5 drops instilled into the affected ear(s) twice daily for 7 to 14 days; not to exceed 14 consecutive days of treatment.

Children and Adolescents 2 years and older

5 drops instilled into the affected ear(s) twice daily for 7 to 14 days; not to exceed 14 consecutive days of treatment.

MAXIMUM DOSAGE

NOTE: In general, corticosteroid dosage must be individualized and is highly variable depending on the nature and severity of the disease, dosage form selected, and patient age and response.

Adults

Topical: 4 applications/day cream, ointment, or topical solution; 3 applications/day topical oil; 1 ounce (30 mL)/day shampoo.
Ophthalmic inserts: 1 Retisert implant approximately every 30 months; 1 Iluvien implant or Yutiq implant approximately every 36 months.

Geriatric

Topical: 4 applications/day cream, ointment, or topical solution; 3 applications/day topical oil; 1 ounce (30 mL)/day shampoo.
Ophthalmic inserts: 1 Retisert implant approximately every 30 months; 1 Iluvien implant or Yutiq implant approximately every 36 months.

Adolescents

4 applications/day cream, ointment, or topical solution; 2 applications/day topical oil. Safety and efficacy have not been established for other dosage forms.

Children

2 years and older: 4 applications/day cream, ointment or topical solution; 2 applications/day topical oil. Safety and efficacy have not been established for other dosage forms.
Less than 2 years: 2 applications/day topical oil. Safety and efficacy have not been established for other dosage forms.

Infants

3 months and older: 2 applications/day topical oil. Safety and efficacy have not been established for other dosage forms.
Less than 3 months: Safety and efficacy have not been established.

DOSING CONSIDERATIONS

Hepatic Impairment

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no topical dosage adjustments are needed.

Renal Impairment

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

ADMINISTRATION

Topical Administration
Cream/Ointment/Lotion Formulations

Cream, Ointment, or Topical Solution:
For external use only.
Apply sparingly in a thin film to the affected area and rub gently. Do not apply to areas of broken skin. Avoid contact with the eyes.
When applying to hairy areas, part the hair and apply a small amount to the affected area or lesion; rub in gently.
Until the medication has dried, protect from washing, clothing, or rubbing. Hair may be washed as usual but not immediately after application.
Occlusive dressing may be used for the management of psoriasis or recalcitrant conditions; follow the orders of the prescriber. 

Other Topical Formulations

Shampoo:
For external use only.
Prior to dispensing: Empty the contents of the enclosed capsule into the shampoo base prior to dispensing. Shake well. The extemporaneously prepared shampoo is stable for 2 months from the time of preparation.
Shake shampoo well prior to each use.
Apply to the scalp area and work into a lather. Let stand for 5 minutes, then rinse thoroughly.
In case of eye contact, rinse liberally with water.
 
Topical Body Oil:
For external use only. Shake well before each use.
Moisten the affected skin area; apply a thin film of oil to the affected area and rub in gently.
Do not apply to the face, axillae, groin, or diaper area unless specifically directed by the prescriber. Avoid application to intertriginous areas.
Do not use with occlusive dressing unless under the specific order of the prescriber.
 
Scalp Topical Oil:
For external use only. For use on the scalp only.
Wet or dampen hair and scalp before using.
Apply a thin film of oil, massage well, and cover the scalp with the supplied shower cap.
Leave on overnight or for a minimum of 4 hours before washing off.
Wash hair with regular shampoo and rinse thoroughly.

Otic Administration

Otic Oil:
For external ear use only.
The patient should tilt their head so the affected ear is facing up. Pull the earlobe backward and upward and use the supplied ear-dropper to apply the drops. The patient should keep their head tilted for approximately 1 minute and use a clean cotton ball to remove any excess medication dripping form the ear.
Administration may be repeated, if necessary, for the opposite ear.
Do not use occlusive dressings.
Avoid contact with the eyes. In case of contact, rinse eyes liberally with water.

Other Administration Route(s)

Intravitreal Administration
Intravitreal administration procedures should be carried out under aseptic conditions as directed for the specific product.
 
Retisert implant tablet for surgical implantation:
Fluocinolone intravitreal implants (Retisert) are surgically implanted into the posterior segment of the affected eye.
Implants should only be handled by the suture tab, as damage to the implant can result in an increased rate of drug release.
During implantation, care should be taken avoid sheer forces on the implant that could disengage the silicone cup reservoir (which contains a fluocinolone acetonide tablet) from the suture tab.
Prolonged hydration may reduce the strength of the adhesive bond between the silicone cup reservoir and the suture tab, indicating a potential for the separation of these components. Monitor the integrity of the implant during ophthalmologic examinations.
Do not resterilize fluocinolone intravitreal implant tablets by any method.
 
Iluvien implant for intravitreal injection:
Intravitreal administration should be carried out under aseptic conditions, which include use of sterile gloves, a sterile drape, a sterile caliper, and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a broad-spectrum microbicide should be given prior to insertion.
Optimal placement of the implant is inferior to the optic disc and posterior to the equator of the eye. Measure 4 millimeters inferotemporal from the limbus with the aid of calipers for point of entry into the sclera.
The exterior of the tray should not be considered sterile. Do not use unit if there are signs of damage to the tray or lid. Do not touch the interior surface when peeling the lid from the tray. Visually check through the viewing window of the preloaded applicator to ensure that there is a drug implant inside.
With sterile, gloved hands, remove the applicator from the tray touching only the sterile interior tray surface and applicator. The applicator tip must be kept above the horizontal plane prior to injection to ensure that the implant is properly positioned within the applicator.
Just before inserting the needle into the eye, remove the protective cap and gently push the applicator button down and slide it to the first stop (at the curved black marks alongside the button track). At the first stop, release the button and it should move to the UP position. Do not use the unit if it does not move to the UP position.
Inspect the tip of the needle to ensure it is not bent.
Gently displace the conjunctiva so that after withdrawing the needle, the conjunctival and scleral needle entry sites will not align. Avoid contact between the needle and the lid margin or lashes. Insert the needle through the conjunctiva and sclera. To release the implant, while the button is in the UP position, advance the button by sliding it forward to the end of the button track and remove the needle. Do not remove the needle until the button reaches the end of the track.
Remove the lid speculum and perform indirect ophthalmoscopy to verify placement of the implant, adequate central retinal artery perfusion and absence of any other complications.
Immediately after the intravitreal injection, monitor the patient for elevation in intraocular pressure (IOP) and endophthalmitis. Appropriate monitoring may consist of a check for perfusion of the optic nerve head immediately after the injection, tonometry within 30 minutes following the injection, and biomicroscopy 2 to 7 days following the injection.
Instruct patients to promptly report any symptoms suggestive of endophthalmitis.
 
Yutiq implant for intravitreal injection:
Intravitreal administration should be carried out under aseptic conditions, which include use of sterile gloves, a sterile drape, a sterile caliper, and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a broad-spectrum microbicide should be given prior to insertion.
Just prior to injection, administer topical and/or subconjunctival anesthesia at the injection site (inferotemporal quadrant recommended).
Administer 2 to 3 drops of a broad-spectrum microbicide into the lower fornix. The lids may be scrubbed with cotton-tipped applicators soaked with a broad-spectrum microbicide. Place a sterile lid speculum. Have the patient look up and apply additional microbicide solution to the injection site. Allow 30 to 60 seconds for the topical antiseptic to dry prior to injection.
Optimal placement is inferior to the optic disc and posterior to the equator of the eye. Measure 4 millimeters inferotemporal from the limbus with the aid of callipers for point of entry into the sclera.
Using sterile procedure, open the sterile foil pouch.
Remove the applicator from the sterile pouch by grasping the barrel of the applicator; do not grasp the plunger.
Remove the black plunger stop from the plunger.
Carefully remove the protective cap from the needle and inspect the needle tip to ensure it is not bent.
Remove the trombone wire from the distal end of the needle. Prior to injection, keep the applicator tip above the horizontal plane to ensure that the implant does not fall out of the applicator.
Gently displace the conjunctiva so that after withdrawing the needle, the conjunctival and scleral needle entry sites will not align. Care should be taken to avoid contact between the needle and the lid margin or lashes.
Insert the needle through the conjunctiva and sclera up to the positive stop of the applicator.
Depress the plunger at the back of the applicator fully to deliver the implant into the back of the eye.
Remove the applicator from the eye and discard in biohazard sharps container.
Remove the lid speculum and perform indirect ophthalmoscopy to verify adequate central retinal artery perfusion, absence of any other complications, and to verify the placement of the implant. Scleral depression may enhance visualisation of the implant. Immediate measurement of intraocular pressure (IOP) may be performed at the discretion of the ophthalmologist.
Immediately after the intravitreal injection, monitor the patient for elevation in intraocular pressure (IOP) and endophthalmitis. Appropriate monitoring may consist of a check for perfusion of the optic nerve head immediately after the injection, tonometry within 30 minutes following the injection, and biomicroscopy 2 to 7 days following the injection. Instruct patients to promptly report any symptoms suggestive of endophthalmitis.

STORAGE

Generic:
– Avoid excessive heat (above 104 degrees F)
– Protect from freezing
– Store between 59 to 77 degrees F
Capex:
– Product should be used within 2 months after opening
– Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
Derma-Smoothe/FS:
– Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
DermOtic Oil :
– Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
Flac:
– Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
Fluonid :
– Avoid excessive heat (above 104 degrees F)
– Protect from freezing
– Store between 59 to 77 degrees F
Iluvien:
– Store at room temperature (between 59 to 86 degrees F)
Retisert:
– Protect from freezing
– Store between 59 to 77 degrees F
– Store in original container
Synalar:
– Avoid excessive heat (above 104 degrees F)
– Protect from freezing
– Store between 59 to 77 degrees F
YUTIQ:
– Store at room temperature (between 59 to 86 degrees F)

CONTRAINDICATIONS / PRECAUTIONS

Cushing’s syndrome, hypothalamic-pituitary-adrenal (HPA) suppression, occlusive dressing, skin abrasion

Systemic absorption of topical corticosteroids such as fluocinolone can produce reversible hypothalamic-pituitary-adrenal (HPA) suppression, manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria in some patients. To minimize risk of HPA axis suppression, patients should be treated for no more than 2 weeks at a time and only small areas should be treated. Conditions that increase systemic absorption include use over large surface areas, prolonged use, use in areas where the epidermal barrier is disrupted (i.e., skin abrasion), and the use of occlusive dressings. Fluocinolone and other fluorinated topical corticosteroids should be used cautiously on areas of the body that have a thin layer of skin. Absorption of topical steroids is markedly increased when these agents are applied to areas such as the axilla, eyelids, face, scalp, or scrotum. Patients applying fluocinolone to a large surface area or to areas under an occlusive dressing should be evaluated periodically for evidence of HPA axis suppression. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent corticosteroid.

Ocular exposure, ophthalmic administration

Care should be taken to avoid ocular exposure to topical fluocinolone products; ophthalmic administration of topical fluocinolone creams, ointments, topical solutions and topical or otic oils should be avoided.

Children, growth inhibition, increased intracranial pressure, infants, neonates

Children, infants, and neonates may demonstrate a greater susceptibility to topical corticosteroid induced hypothalamic-pituitary-adrenal (HPA) axis suppression and Cushing’s syndrome compared to adult patients because of larger skin surface area to body weight ratio. HPA axis suppression, Cushing’s syndrome, and increased intracranial pressure have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include growth inhibition (linear growth retardation and delayed weight gain), low plasma cortisol levels, and absence of response in ACTH stimulation. Manifestations of intracranial hypertension including bulging fontanelles, headaches, and bilateral papilledema. Administration of topical corticosteroids to children should be limited to the least amount compatible with an effective therapeutic regimen. Chronic use may interfere with growth and development. Use topical products with caution in young children; if children are being treated topically in the diaper area, tight-fitting diapers or plastic pants should be avoided as these garments may act as an occlusive dressing and increase systemic absorption of the drug. The safety and efficacy of fluocinolone otic drops have not been established in pediatric patients under 2 years of age. Safety and effectiveness of Retisert fluocinolone intravitreal implant tablets have not been established in pediatric patients below the age of 12 years ; the Iluvien and Yutiq intravitreal implants have not been studied in pediatric patients. 
 

Fungal infection, herpes infection, herpes simplex keratitis (dendritic keratitis), infection, measles, ocular infection, varicella, viral infection

Topical corticosteroids should be used with caution in individuals with dermatological infections; the normal inflammatory response to local infections can be masked by corticosteroids such as fluocinolone. Application of topical corticosteroids to areas of infection, including tuberculosis of the skin, dermatologic fungal infection, and cutaneous or systemic viral infection (e.g., herpes infection, measles, varicella), should be initiated or continued only if the appropriate antiinfective treatment is instituted. If a favorable response does not occur promptly, the corticosteroid should be discontinued until the infection has been adequately controlled. Fluocinolone intravitreal implants (Retisert, Iluvien, and Yutiq) are contraindicated for use in ocular infection, including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, or varicella, as well as ophthalmic bacterial, mycobacterial, viral, and fungal infections. Corticosteroid implants are not recommended to be used in patients with a history of ocular herpes simplex because of the potential for reactivation of the viral infection. Corticosteroids reduce resistance to infections; do not perform simultaneous bilateral intravitreal implantation in order to limit the possibility of post-operative bilateral ophthalmic infection or other adverse effects. 

Acne rosacea, acne vulgaris, perioral dermatitis

High-potency topical corticosteroids should not be used to treat acne vulgaris, acne rosacea, or perioral dermatitis. Fluocinolone may aggravate these conditions. Topical corticosteroids may delay the healing of non-infected wounds, such as venous stasis ulcers.

Diabetes mellitus

Topical corticosteroids, like fluocinolone, should be used with caution in patients with diabetes mellitus. Exacerbation of diabetes may occur with systemic absorption of the topical corticosteroid. Use of topical corticosteroids may further delay healing of skin ulcers in diabetic patients.

Geriatric, skin atrophy

Topical corticosteroids, like fluocinolone, should be used for brief periods, or under close medical supervision in patients with evidence of pre-existing skin atrophy. Geriatric patients may be more likely to have preexisting skin atrophy secondary to aging. Purpura and skin lacerations that may raise the skin and subcutaneous tissue from deep fascia may be more likely to occur with the use of topical corticosteroids in geriatric patients. Use of lower potency topical corticosteroids also may be necessary in some patients.

Pregnancy

There are no adequate and well-controlled studies of topical application or intravitreal insertion of fluocinolone during pregnancy. Use during pregnancy only when clearly needed. Topical corticosteroids, including fluocinolone, should not be used in large amounts, on large areas, or for prolonged periods of time in pregnant women. Guidelines recommend mild to moderate potency topical agents over potent corticosteroids, which should be used in short durations. Fetal growth restriction and a significantly increased risk of low birthweight has been reported with use of potent or very potent topical corticosteroids during the third trimester, particularly when using more than 300 grams. Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. 

Breast-feeding

It is not known whether topical or intravitreal administration of fluocinolone could result in sufficient systemic absorption to produce detectable quantities in breast milk.   However, most dermatologists stress that topical corticosteroids can be safely used during lactation and breast-feeding. If applied topically, care should be used to ensure the infant will not come into direct contact with the area of application, such as the breast. Increased blood pressure has been reported in an infant whose mother applied a high potency topical corticosteroid ointment directly to the nipples. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Peanut hypersensitivity

Fluocinolone body, scalp, and otic topical oils contain refined peanut oil, USP. Avoid using these products in patients with peanut hypersensitivity as hypersensitivity reactions have been reported. If wheal and flare type reactions, which may be limited to pruritus, or other manifestations of hypersensitivity develop, the products should be discontinued immediately. In one study, topical fluocinolone 0.01% in peanut oil was well tolerated even in patients with peanut allergic sensitivity. Another article concurred.

Corticosteroid hypersensitivity

Although true corticosteroid hypersensitivity is rare, patients who have demonstrated a prior hypersensitivity reaction to fluocinolone should not receive the drug. It is possible, though also rare, that such patients will display cross-hypersensitivity to other corticosteroids. It is advisable that patients who have a hypersensitivity reaction to any corticosteroid undergo skin testing, which, although not a conclusive predictor, may help to determine if hypersensitivity to another corticosteroid exists. Such patients should be carefully monitored during and following the administration of any corticosteroid.

Glaucoma, implant insertion and removal complications, increased intraocular pressure

Use of corticosteroids including the fluocinolone intravitreal implants may produce posterior subcapsular cataracts, increased intraocular pressure, and glaucoma. The Iluvien fluocinolone intravitreal implant is contraindicated for use in patients with glaucoma who have a cup to disc ratio greater than 0.8. Intravitreal implant insertion and removal complications have been reported, and may vary with the implant and the technique used for insertion. For example, patients with an absent or torn posterior capsule of the lens are at increased risk of migration of an intravitreal implant into the anterior chamber. 

ADVERSE REACTIONS

Severe

ocular hypertension / Delayed / 22.0-90.0
visual impairment / Early / 10.0-40.0
macular edema / Delayed / 10.0-40.0
ocular hemorrhage / Delayed / 10.0-40.0
retinal detachment / Delayed / 5.0-9.0
retinal hemorrhage / Delayed / 5.0-9.0
optic atrophy / Delayed / 2.0-2.0
skin atrophy / Delayed / Incidence not known
papilledema / Delayed / Incidence not known
increased intracranial pressure / Early / Incidence not known
wound dehiscence / Delayed / Incidence not known
endophthalmitis / Delayed / Incidence not known

Moderate

cataracts / Delayed / 50.0-90.0
hypotonia / Delayed / 7.0-40.0
blurred vision / Early / 10.0-40.0
conjunctival hyperemia / Early / 2.0-40.0
erythema / Early / 1.0-10.0
hyphema / Delayed / 5.0-9.0
blepharitis / Early / 5.0-9.0
conjunctivitis / Delayed / 4.0-9.0
photopsia / Delayed / 5.0-9.0
ocular inflammation / Early / 1.0-9.0
photophobia / Early / 2.0-9.0
corneal edema / Early / 4.0-9.0
withdrawal / Early / Incidence not known
growth inhibition / Delayed / Incidence not known
hypothalamic-pituitary-adrenal (HPA) suppression / Delayed / Incidence not known
Cushing’s syndrome / Delayed / Incidence not known
hypertension / Early / Incidence not known
hyperglycemia / Delayed / Incidence not known
glycosuria / Early / Incidence not known
pseudotumor cerebri / Delayed / Incidence not known
adrenocortical insufficiency / Delayed / Incidence not known
ocular infection / Delayed / Incidence not known
skin ulcer / Delayed / Incidence not known
impaired wound healing / Delayed / Incidence not known
tolerance / Delayed / Incidence not known
contact dermatitis / Delayed / Incidence not known

Mild

ocular pain / Early / 8.0-90.0
foreign body sensation / Rapid / 3.0-40.0
ocular pruritus / Rapid / 3.0-40.0
ocular irritation / Rapid / 1.0-40.0
xerophthalmia / Early / 10.0-40.0
blepharedema / Early / 10.0-40.0
ptosis / Delayed / 10.0-40.0
headache / Early / 9.0-33.0
pharyngitis / Delayed / 5.0-20.0
xerosis / Delayed / 1.0-10.0
maculopapular rash / Early / 1.0-10.0
pruritus / Rapid / 1.0-10.0
skin irritation / Early / 1.0-10.0
diplopia / Early / 5.0-9.0
lacrimation / Early / 1.0-9.0
ocular discharge / Delayed / 2.0-9.0
arthralgia / Delayed / 2.0-5.0
miliaria / Delayed / Incidence not known
purpura / Delayed / Incidence not known
folliculitis / Delayed / Incidence not known
telangiectasia / Delayed / Incidence not known
striae / Delayed / Incidence not known
acneiform rash / Delayed / Incidence not known
infection / Delayed / Incidence not known
hypertrichosis / Delayed / Incidence not known
skin hypopigmentation / Delayed / Incidence not known
sinusitis / Delayed / Incidence not known

DRUG INTERACTIONS

Benzalkonium Chloride: (Moderate) The use of topical aluminum products (aluminum acetate, Burow’s solution or aluminum chloride) with benzalkonium chloride aqueous solutions may be incompatible. 
Metyrapone: (Major) Medications which affect pituitary or adrenocortical function, including all corticosteroid therapy, should be discontinued prior to and during testing with metyrapone. Patients taking inadvertent doses of corticosteroids on the test day may exhibit abnormally high basal plasma cortisol levels and a decreased response to the test. Although systemic absorption of topical corticosteroids is minimal, temporary discontinuation of these products should be considered if possible to reduce the potential for interference with the test results. 

PREGNANCY AND LACTATION

Pregnancy

There are no adequate and well-controlled studies of topical application or intravitreal insertion of fluocinolone during pregnancy. Use during pregnancy only when clearly needed. Topical corticosteroids, including fluocinolone, should not be used in large amounts, on large areas, or for prolonged periods of time in pregnant women. Guidelines recommend mild to moderate potency topical agents over potent corticosteroids, which should be used in short durations. Fetal growth restriction and a significantly increased risk of low birthweight has been reported with use of potent or very potent topical corticosteroids during the third trimester, particularly when using more than 300 grams. Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. 

It is not known whether topical or intravitreal administration of fluocinolone could result in sufficient systemic absorption to produce detectable quantities in breast milk.   However, most dermatologists stress that topical corticosteroids can be safely used during lactation and breast-feeding. If applied topically, care should be used to ensure the infant will not come into direct contact with the area of application, such as the breast. Increased blood pressure has been reported in an infant whose mother applied a high potency topical corticosteroid ointment directly to the nipples. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

MECHANISM OF ACTION

Corticosteroids inhibit inflammatory responses to a variety of inciting agents including multiple inflammatory cytokines. They inhibit edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. Corticosteroids are thought to act by inhibition of phospholipase A2 via induction of inhibitory proteins collectively called lipocortins. It is postulated that these proteins control biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting release of the common precursor, arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2. Topical corticosteroids exhibit anti-inflammatory, antipruritic, and vasoconstrictive properties. These actions correspond to decreased edema, erythema, pruritus, plaque formation and scaling of the affected skin.

PHARMACOKINETICS

Fluocinolone is applied topically as a cream, ointment, solution, shampoo or topical oil and can be for ophthalmic use as an intravitreal implant. Anti-inflammatory effects are usually not seen for hours after fluocinolone application, since the mechanism of action requires alterations in synthesis of proteins. Because fluocinolone is fluorinated and also contains a substituted 17-hydroxyl group, it is not metabolized in the skin. Repeated application results in a cumulative depot effect in the skin, which may lead to a prolonged duration of action and increased systemic absorption. Fluocinolone is metabolized primarily in the liver and excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile.

Topical Route

The extent of percutaneous absorption of the topical corticosteroids is dependent on many factors, including the pharmaceutical vehicle and the integrity of the epidermis. Absorption after topical application of fluocinolone is increased in areas that have skin damage, inflammation, or occlusion, or in areas where the stratum corneum is thin such as the eyelids, genitalia, axillae, and face. The use of occlusive dressings with the application of fluocinolone enhances penetration into the skin, and may increase the chance of systemic absorption. Ointments have a hydrating effect, are lipophilic, and enhance the penetration of clobetasol into the skin. Fluocinolone solutions also have enhanced topical penetration versus cream preparations.

Other Route(s)

Ophthalmic Route
There appears to be minimal systemic absorption following ophthalmic administration. Following intravitreal implantation of one 0.59 mg fluocinolone acetonide tablet (Retisert), fluocinolone acetonide is released at a rate of approximately 0.6 mcg/day, decreasing over the first month to a steady state of 0.3—0.4 mcg/day over approximately 30 months. In this time period, aqueous and vitreous humor concentrations are highly variable. In clinical trials, throughout an observational period of up to 34 months, aqueous and vitreous humor concentrations ranged from below the limit of detection (0.2 ng/mL) to 589 ng/mL. Following intravitreal implantation of a 0.2 mcg/day or 0.5 mcg/day fluocinolone acetonide insert, plasma concentrations of fluocinolone acetonide were below the lower limit of quantitation at all post-administration time points from day 7 through month 36 in a human pharmacokinetic study. 

 

HYDROCORTINE PDR

 

CLASSES

Compounding Kits Miscellaneous
Plain Topical Corticosteroids
Systemic Corticosteroids, Plain
Topical Anti-hemorrhoidals with Corticosteroids

DEA CLASS

OTC, Rx

DESCRIPTION

Naturally occurring adrenal steroid hormone with glucocorticoid and mineralocorticoid activity
A preferred corticosteroid for adrenal insufficiency states; also used for a variety of inflammatory diseases systemically and rectally
Topical dosage forms are considered low-potency; used for mild to moderate corticosteroid responsive dermatoses

COMMON BRAND NAMES

A-Hydrocort, Ala-Cort, Ala-Scalp, Anucort-HC, Anumed-HC, Anusol HC, Caldecort, Cetacort, Colocort, Cortaid, Cortaid Advanced, Cortaid Intensive Therapy, Cortef, Cortenema, Corticaine, Corticool, Cortifoam, Cortizone, Cortizone-10, Cortizone-10 Cooling Relief, Cortizone-10 Intensive Healing, Cortizone-10 Plus, Dermarest Dricort, Dermarest Eczema, Encort, First – Hydrocortisone, Gly-Cort, GRx HiCort, Hemmorex-HC, Hemorrhoidal-HC, Hemril, Hycort, Hydro Skin, Hydrocortisone in Absorbase, Hydrocortone, Hydroskin, Hytone, Instacort, Lacticare HC, Locoid, Locoid Lipocream, MiCort-HC, Monistat Complete Care Instant Itch Relief Cream, Neosporin Eczema, NuCort, Nutracort, NuZon, Pandel, Penecort, Preparation H Hydrocortisone, Procto-Kit, Procto-Med HC, Procto-Pak, Proctocort, Proctocream-HC, Proctosert HC, Proctosol-HC, Proctozone-HC, Rectacort HC, Rectasol-HC, Rederm, Sarnol-HC, Scalacort, Scalpicin Anti-Itch, Solu-Cortef, Texacort, Tucks HC, Walgreens Intensive Healing, Westcort

HOW SUPPLIED

A-Hydrocort/Hydrocortisone/Hydrocortisone Sodium Succinate/Solu-Cortef Intramuscular Inj Pwd F/Sol: 100mg, 250mg, 500mg, 1000mg
A-Hydrocort/Hydrocortisone/Hydrocortisone Sodium Succinate/Solu-Cortef Intravenous Inj Pwd F/Sol: 100mg, 250mg, 500mg, 1000mg
Ala-Cort/Ala-Scalp/Cetacort/Cortaid/Cortizone-10 Intensive Healing/Dermarest Eczema/Gly-Cort/Hydro Skin/Hydrocortisone/Hydrocortisone Butyrate/Hydroskin/Hytone/Lacticare HC/Locoid/NuCort/Nutracort/Rederm/Sarnol-HC Topical Lotion: 0.1%, 1%, 2%, 2.5%
Ala-Cort/Anusol HC/Caldecort/Cortaid/Cortaid Advanced/Cortaid Intensive Therapy/Corticaine/Cortizone/Cortizone-10/Cortizone-10 Plus/Dermarest Dricort/Hycort/Hydrocortisone/Hydrocortisone Butyrate/Hydrocortisone Valerate/Hydroskin/Hytone/Instacort/Locoid/Locoid Lipocream/MiCort-HC/Monistat Complete Care Instant Itch Relief Cream/Neosporin Eczema/Nutracort/Pandel/Penecort/Preparation H Hydrocortisone/Proctocort/Proctocream-HC/Procto-Kit/Procto-Med HC/Procto-Pak/Proctosol-HC/Proctozone-HC/Walgreens Intensive Healing/Westcort Topical Cream: 0.1%, 0.2%, 0.5%, 1%, 2.5%
Anucort-HC/Anumed-HC/Anusol HC/Encort/GRx HiCort/Hemmorex-HC/Hemorrhoidal-HC/Hemril/Hydrocortisone/Hydrocortisone Acetate/Proctocort/Proctosert HC/Proctosol-HC/Rectacort HC/Rectasol-HC Rectal Supp: 25mg, 30mg
Colocort/Cortenema/Hydrocortisone Rectal Enema: 60mL, 100mg
Cortaid Intensive Therapy Topical Spray: 1%
Cortaid/Cortizone/Cortizone-10/Hydrocortisone/Hydrocortisone Acetate/Hydrocortisone Butyrate/Hydrocortisone in Absorbase/Hydrocortisone Valerate/Hytone/Locoid/Tucks HC/Westcort Topical Ointment: 0.1%, 0.2%, 0.5%, 1%, 2.5%
Cortef/Hydrocortisone/Hydrocortone Oral Tab: 5mg, 10mg, 20mg
Corticool/Cortizone-10 Cooling Relief/Hydrocortisone/Instacort/NuZon Topical Gel: 1%, 2%
Cortifoam Topical Foam: 10%
Hydrocortisone/Hydrocortisone Butyrate/Locoid/Scalpicin Anti-Itch/Texacort Topical Sol: 0.1%, 1%, 2.5%

DOSAGE & INDICATIONS

For the treatment of primary adrenocortical insufficiency (e.g., Addison’s Disease, congenital adrenal hyperplasia or CAH) or secondary adrenocortical insufficiency.
For adrenal crisis prophylaxis in adult patients with known or suspected adrenal insufficiency undergoing minor surgery or with a minor illness (e.g., inguinal hernia repair, colonoscopy, mild febrile illness, gastroenteritis).
Intravenous or Intramuscular dosage (hydrocortisone sodium succinate injection)
Adults

Although the manufacturer recommends 200 to 500 mg IV or IM every 2 to 6 hours starting at the beginning of the surgical procedure or the onset of the acute physiologic stressor , recommendations developed from the literature and expert opinion suggest lower doses are effective and decrease the risk of adverse effects (e.g., hyperglycemia, immunosuppression). A single dose of 25 mg IV/IM is recommended by one author , and 50 to 100 mg IV/IM is recommended by another. In the case of surgeries, the dose should be administered before the procedure. Although hydrocortisone has historically been the preferred agent, some experts recommend longer acting steroids such as methylprednisolone or dexamethasone. In addition to the supplementation doses, patients who are treated with chronic steroids should also be given their usual dose or equivalent for the acute period; patients receiving the equivalent to prednisone 5 mg/day (i.e., hydrocortisone 20 mg/day) or less do not require additional supplementation.

For adrenal crisis prophylaxis in adult patients with known or suspected adrenal insufficiency undergoing moderate surgery or with a moderate illness (e.g., open cholecystectomy, hemicolectomy, significant febrile illness, pneumonia, severe gastroenteritis).
Intravenous or Intramuscular dosage (hydrocortisone sodium succinate injection)
Adults

Although the manufacturer recommends 200 to 500 mg IV or IM every 2 to 6 hours starting at the beginning of the surgical procedure or the onset of the acute physiologic stressor , recommendations developed from the literature and expert opinion suggest lower doses are effective and decrease the risk of adverse effects (e.g., hyperglycemia, immunosuppression). One author recommends 50 to 75 mg IV/IM on the day of the procedure; then, taper to the usual dose over the next 1 to 2 days. Another author recommends 50 mg IV/IM every 6 hours during the medical or surgical stress; then, taper the dose by 50% every day until the usual dose is reached. Although hydrocortisone has historically been the preferred agent, some experts recommend longer acting steroids such as methylprednisolone or dexamethasone. In addition to the supplementation doses, patients who are treated with chronic steroids should also be given their usual dose or equivalent for the acute period; patients receiving the equivalent to prednisone 5 mg/day (i.e., hydrocortisone 20 mg/day) or less do not require additional supplementation.

For adrenal crisis prophylaxis in adult patients with known or suspected adrenal insufficiency undergoing major surgery, or with other acute stressors (e.g., major cardiothoracic surgery, Whipple procedure, liver resection, pancreatitis, acute systemic infection, shock).
Intravenous or Intramuscular dosage (hydrocortisone sodium succinate injection)
Adults

Although the manufacturer recommends 200 to 500 mg IV or IM every 2 to 6 hours starting at the beginning of surgical procedure or the onset of the acute physiologic stressor , recommendations developed from the literature and expert opinion suggest lower doses are effective and decrease the risk of adverse effects (e.g., hyperglycemia, immunosuppression). In severe illnesses or major surgeries, one author recommends 100 to 150 mg IV/IM on the day of the procedure; taper to the usual dose over the next 1 to 2 days. Another author recommends 50 mg IV/IM every 6 hours during the medical or surgical stress; then, taper the dose by 50% every day until the usual dose is reached. Although hydrocortisone has historically been the preferred agent, some experts recommend longer acting steroids such as methylprednisolone or dexamethasone. In addition to the supplementation doses, patients who are treated with chronic steroids should also be given their usual dose or equivalent for the acute period; patients receiving the equivalent to prednisone 5 mg/day (i.e., hydrocortisone 20 mg/day) or less do not require additional supplementation.

For adrenal crisis prophylaxis in adult patients with known or suspected adrenal insufficiency and a critical illness (e.g., shock).
Intravenous or Intramuscular dosage (hydrocortisone sodium succinate injection)
Adults

Although the manufacturer recommends 200 to 500 mg IV or IM every 2 to 6 hours starting at the beginning the acute physiologic stressor , recommendations developed from the literature and expert opinion suggest lower doses are effective. In critically ill patients, 50 to 100 mg IV every 6 to 8 hours or 0.18 mg/kg/hour as a continuous IV infusion until the shock is resolved has been recommended; 50 mcg/day of fludrocortisone is also recommended in this situation. Once the shock is resolved, the hydrocortisone can be gradually tapered; follow vital signs and serum sodium concentrations closely. Although, hydrocortisone has historically been the preferred agent, some experts recommend longer acting steroids such as methylprednisolone or dexamethasone. In addition to the supplementation doses, patients who are treated with chronic steroids should also be given their usual dose or equivalent for the acute period; patients receiving the equivalent to prednisone 5 mg/day (i.e., hydrocortisone 20 mg/day) or less do not require additional supplementation.

For the treatment of acute adrenocortical insufficiency.
Intramuscular or Intravenous dosage (hydrocortisone sodium succinate injection)
Adults

100 to 500 mg IM or IV. May repeat every 2 to 6 hours depending upon patient condition and response.

Adolescents and Children

Initially, 50 to 75 mg/m2/dose or 2 to 3 mg/kg/dose IM or IV (Max: 100 mg), followed by 50 to 75 mg/m2/day IM or IV divided every 6 hours. 

Infants and Neonates

Initially, 50 to 75 mg/m2/dose or 2 to 3 mg/kg/dose IM or IV (Max: 100 mg), followed by 50 to 75 mg/m2/day or 4 to 20 mg/kg/day IM or IV divided every 6 hours. 

For adrenal crisis prophylaxis in pediatric patients with known or suspected adrenal insufficiency with other acute stressors (e.g., febrile illness with a temperature more than 38.5 degrees Celsius, gastroenteritis with dehydration, major trauma):.
Intramuscular or Intravenous dosage (hydrocortisone sodium succinate injection)
Adolescents and Children 6 years and older

An initial dose of 50 mg/m2 IM will provide 6 to 8 hours of coverage. If the patient’s condition does not improve or worsens during this time, IV stress dosing (3 to 4 times the daily maintenance dose divided every 6 hours) may need to be initiated. Alternatively, an initial dose of 100 mg IM has been recommended for patients with CAH. 

Children 1 to 5 years

An initial dose of 50 mg/m2 IM will provide 6 to 8 hours of coverage. If the patient’s condition does not improve or worsens during this time, IV stress dosing (3 to 4 times the daily maintenance dose divided every 6 hours) may need to be initiated. Alternatively, an initial dose of 50 mg IM has been recommended for patients with CAH. 

Infants and Neonates

An initial dose of 50 mg/m2 IM will provide 6 to 8 hours of coverage. If the patient’s condition does not improve or worsens during this time, IV stress dosing (3 to 4 times the daily maintenance dose divided every 6 hours) may need to be initiated. Alternatively, an initial dose of 25 mg IM has been recommended for patients with CAH. 

Oral dosage
Adolescents, Children, Infants, and Neonates

30 to 50 mg/m2/day PO given in 3 to 4 divided doses (approximately triple the daily maintenance dose) is commonly recommended. Varying recommendations of increases in the daily maintenance dose anywhere from 2 to 10 times have been made depending on the level of stress and the patient’s individual needs. 

Rectal dosage†
Adolescents, Children, and Infants

100 mg/m2/dose PR every 8 hours has been recommended as an alternative to parenteral administration in patients who cannot tolerate oral administration due to illness. Due to large interindividual differences in bioavailability, higher doses (150 to 200 mg/m2/dose PR) may be required in patients who do not show an adequate response (serum cortisol concentration more than 1,000 nmol/L 3 hours after administration). It is recommended that patients response to rectal hydrocortisone be tested prior to use during illness. In a study of patients with adrenal insufficiency (n = 57, age 1 month to 17 years), 43 patients responded adequately to a dose of 100 mg/m2 rectally. Risk factors for failed response included younger age and obesity. Suppositories used in this study were compounded in a Witepsol W45 base.

For adrenal crisis prophylaxis in pediatric patients with known or suspected adrenal insufficiency undergoing surgery accompanied by general anesthesia.
Intramuscular or Intravenous dosage (hydrocortisone sodium succinate injection)
Adolescents and Children 6 years and older

50 mg/m2 IV 30 to 60 minutes prior to induction of anesthesia,with repeat doses of 50 mg/m2/dose IV every 6 hours or as a continuous infusion until the patient has recovered, has been recommended. For patients with congenital adrenal hyperplasia (CAH), 2 mg/kg/dose IV at induction of anesthesia with repeat doses every 4 hours or as a continuous IV infusion for prolonged procedures or recovery times has also been recommended. Alternatively, an initial stress dose of 100 mg IM followed by IV doses equivalent to 3 to 4 times the daily maintenance dose divided every 6 hours has been recommended. 

Children 1 to 5 years

50 mg/m2 IV 30 to 60 minutes prior to induction of anesthesia, with repeat doses of 50 mg/m2/dose IV every 6 hours or as a continuous infusion until the patient has recovered, has been recommended. For patients with congenital adrenal hyperplasia (CAH), 2 mg/kg/dose IV at induction of anesthesia with repeat doses every 4 hours or as a continuous IV infusion for prolonged procedures or recovery times has also been recommended. Alternatively, an initial stress dose of 50 mg IM followed by IV doses equivalent to 3 to 4 times the daily maintenance dose divided every 6 hours has been recommended. 

Infants and Neonates

50 mg/m2 IV 30 to 60 minutes prior to induction of anesthesia, with repeat doses of 50 mg/m2/dose IV every 6 hours or as a continuous infusion until the patient has recovered, has been recommended. For patients with congenital adrenal hyperplasia (CAH), 2 mg/kg/dose IV at induction of anesthesia with repeat doses every 4 hours or as a continuous IV infusion for prolonged procedures or recovery times has also been recommended. Alternatively, an initial stress dose of 25 mg IM followed by IV doses equivalent to 3 to 4 times the daily maintenance dose divided every 6 hours has been recommended. 

Oral dosage
Adults

20 to 240 mg/day PO given in 2 to 4 divided doses.

Adolescents and Children

Initially, 8 to 20 mg/m2/day PO given in 3 divided doses; individualize doses to minimize symptoms of adrenal insufficiency while avoiding growth retardation and Cushingoid symptoms that occur with overdosage. A usual dose of 5 to 10 mg/day PO 3 times daily has been recommended by the American Academy of Pediatrics. Doses more than 17 mg/m2/day in adolescents have been associated with loss of height and shorter adult height. Patients with primary adrenal insufficiency may require higher initial doses then those with secondary adrenal insufficiency. Patients with classic CAH also require treatment with fludrocortisone (0.05 to 0.3 mg/day PO given in 1 to 2 divided doses). 

Infants and Neonates

Initially, 8 to 20 mg/m2/day PO given in 3 divided doses; individualize doses to minimize symptoms of adrenal insufficiency while avoiding growth retardation and Cushingoid symptoms that occur with overdosage. A usual dose of 2.5 to 5 mg/day PO 3 times daily has been recommended by the American Academy of Pediatrics (AAP). Doses more than 20 mg/m2/day PO have been associated with loss of height and shorter adult height. Patients with primary adrenal insufficiency may require higher initial doses then those with secondary adrenal insufficiency. Neonates and infants with classic CAH also require treatment with fludrocortisone (0.05 to 0.3 mg/day PO given in 1 to 2 divided doses) and sodium chloride supplementation (1 to 2 grams/day or 17 to 34 mEq/day PO divided and given with several feedings). 

Intramuscular or Intravenous dosage (hydrocortisone sodium succinate injection)
Adults

100 to 500 mg IM or IV. Repeat doses at 2, 4, or 6 hour intervals.

For use in nonspecific proctitis, postirradiation (factitial) proctitis, cryptitis, or for other non-specific inflammatory conditions of the anorectum.
Rectal dosage (rectal suppositories)
Adults

For nonspecific proctitis, insert 1 suppository PR twice per day, morning and evening, for 2 weeks. May give 1 suppository PR 3 times per day, or 2 suppositories PR twice per day, if needed. For factitial proctitis, the recommended duration of therapy is 6 to 8 weeks or less, depending on response.

For the treatment of inflammatory bowel disease (Crohn’s disease or ulcerative colitis).
For adjunctive treatment of Crohn’s disease or ulcerative colitis using oral or parenteral therapy.
Oral dosage
Adults

20 to 240 mg (base)/day PO, given in 2 to 4 divided doses.

Infants, Children, and Adolescents

A general dose range of 0.56 to 8 mg/kg/day or 16 to 240 mg/m2/day PO given in 3 to 4 divided doses has been recommended. Adjust according to patient response.

Intramuscular or Intravenous dosage (hydrocortisone sodium succinate injection)
Adults

100 to 500 mg IM or IV. Repeat doses at 2, 4, or 6 hour intervals.

Infants, Children, and Adolescents

0.56 to 8 mg/kg/day or 20 to 240 mg/m2/day IM or IV given in 3 to 4 divided dose is the FDA-approved general dosage range. Adjust according to patient response.

For adjunctive rectal treatment of chronic ulcerative colitis, particularly if disease limited to the distal portion of the rectum.
Rectal dosage (rectal retention enema suspension)
Adults

100 mg PR, as a retention enema, nightly for 21 nights or until clinical and proctological remission are achieved. Clinical symptoms usually subside promptly within 3 to 5 days. However, improvement in the appearance of the mucosa, as seen by sigmoidoscopic examination, may lag somewhat behind clinical improvement. If clinical or proctologic improvement fails to occur within 2 or 3 weeks, discontinue. Difficult but responding cases may require as long as 2 or 3 months of treatment. If treatment is continued for longer than 21 nights, therapy should be withdrawn gradually by giving the product every other night for 2 to 3 weeks, then discontinuing it.

Rectal foam dosage (hydrocortisone acetate rectal foam)
Adults

One applicatorful (90 mg of hydrocortisone acetate) PR once daily or twice per day for 2 to 3 weeks, and every second day thereafter. Rectal foam formulation usually reserved for treatment of ulcerative proctitis in patients who cannot retain corticosteroid enemas.

Rectal dosage (hydrocortisone acetate rectal suppositories)
Adults

Insert 1 suppository PR 2 to 3 times per day, for 2 weeks. For more severe cases may use 2 suppositories PR twice per day.

For the relief of inflammation, pruritus ani, and swelling associated with hemorrhoids.
External topical dosage (hydrocortisone cream)
Adults

Apply to the external affected area (skin outside the anus) as a thin film from 2 to 4 times daily depending on the severity of the condition. Not for rectal use.

Rectal dosage (hydrocortisone acetate rectal suppositories)
Adults

Insert 1 suppository PR twice daily, morning and night, for 2 weeks.

For the treatment of allergic disorders including anaphylaxis, anaphylactic shock, or anaphylactoid reactions, angioedema, acute noninfectious laryngeal edema, drug hypersensitivity reactions, transfusion-related reactions, serum sickness, severe perennial or seasonal allergic rhinitis, or urticaria.
For the non-emergent treatment of hypersensitivity or allergic conditions.
Oral dosage
Adults

20 to 240 mg/day PO, given in 2 to 4 divided doses.

Adolescents, Children, and Infants

A general dose range of 0.56 to 8 mg/kg/day or 16 to 240 mg/m2/day PO given in 3 to 4 divided doses has been recommended. Adjust according to patient response.

For the urgent treatment of severe conditions such as anaphylaxis, angioedema, acute noninfectious laryngeal edema, or urticarial transfusion-related reactions.
Intravenous dosage (hydrocortisone sodium succinate injection)
Adults

The FDA-approved general dosage range is 100 to 500 mg IV; repeat doses at 2, 4, or 6 hour intervals as indicated. However, in certain acute, life-threatening situations, higher doses (e.g., 5 to 10 mg/kg/dose IV [Max: 625 mg/dose]) may be justified according to practice parameters.

Adolescents, Children, and Infants

The FDA-approved general dosage range is 0.56 to 8 mg/kg/day or 20 to 240 mg/m2/day IV given in 3 to 4 divided doses. However, in certain acute, life-threatening situations, higher doses may be justified.

For the treatment of corticosteroid-responsive dermatologic disorders (e.g., alopecia areata, atopic dermatitis, bullous dermatitis herpetiformis, contact dermatitis including Rhus dermatitis due to poison ivy, poison oak, poison sumac, discoid lupus erythematosus, eczema, exfoliative dermatitis, insect bites or stings, granuloma annulare, keloids, lichen striatus, lichen planus, lichen simplex, necrobiosis lipoidica diabeticorum, pemphigus, pityriasis rosea, polymorphous light eruption, pompholyx (dyshidrosis), pruritus, psoriasis, sarcoidosis, seborrheic dermatitis, urticaria, xerosis).
For mild-to-moderate corticosteroid responsive dermatoses.
Topical dosage (hydrocortisone or hydrocortisone acetate)
Adults, Adolescents, Children 2 years and older

Apply topically and sparingly to affected areas 2 to 4 times per day. Follow the directions on the specific product labeling. Occlusive dressings may be used for the management of psoriasis or refractory conditions; however, occlusive dressings can increase absorption as much as 10 to 100 times which may increase the risk of systemic adverse reactions. Avoid the use of tight-fitting diapers or plastic pants in patients being treated in the diaper area as these may act as an occlusive dressing. For self-medication, apply a 0.5% or 1% non-prescription topical product to affected areas not more than 3 to 4 times per day. If condition worsens, or if symptoms persist for more than 7 days or clear up and occur again within a few days, discontinue therapy.

Infants and Children up to 2 years

Only for use with a prescriber’s prescription. Apply topically and sparingly to affected areas 2 to 4 times per day. Follow the directions on the specific product labeling. Occlusive dressings may be used for the management of psoriasis or refractory conditions; however, occlusive dressings can increase absorption as much as 10 to 100 times which may increase the risk of systemic adverse reactions. Avoid the use of tight-fitting diapers or plastic pants in patients being treated in the diaper area as these may act as an occlusive dressing. 

Topical dosage (hydrocortisone valerate)
Adults

Apply a thin film to the affected areas 2 or 3 times daily, depending on severity of the condition. If no improvement observed after 2 weeks, reassess diagnosis.

Topical dosage (hydrocortisone butyrate cream, ointment, and topical solution)
Adults, Adolescents, Children, and Infants

Apply sparingly to affected areas 2 to 3 times per day. Follow the directions on the specific product labeling. Occlusive dressings may be used for the management of psoriasis or refractory conditions; however, occlusive dressings can increase absorption as much as 10 to 100 times which may increase the risk of systemic adverse reactions. When used in small children, advise caregivers to avoid the use of tight-fitting diapers or plastic pants in patients being treated in the diaper area as these may act as an occlusive dressing. 

Topical dosage (hydrocortisone butyrate lipocream)
Adults

 Apply a thin film to the affected areas 2 or 3 times daily, depending on severity of the condition.

Topical dosage (hydrocortisone probutate cream)
Adults

Apply thin film to affected areas 1 or 2 times daily; if no improvement after 2 weeks, reassess diagnosis.

For mild to moderate atopic dermatitis.
Topical dosage (hydrocortisone butyrate lotion)
Adults

Apply sparingly to affected areas twice daily; if no improvement after 2 weeks, reassess diagnosis. Safety and efficacy have not been established beyond 4 weeks of therapy.

Infants 3 months and older, Children, and Adolscents

Apply sparingly to affected areas twice daily; if no improvement after 2 weeks, reassess diagnosis. Safety and efficacy have not been established beyond 4 weeks of therapy.

Topical dosage (hydrocortisone butyrate lipocream)
Adults

Apply sparingly to affected areas twice daily; if no improvement after 2 weeks, reassess diagnosis. Safety and efficacy have not been established beyond 4 weeks of therapy.

Infants 3 months and older, Children, and Adolescents

Apply sparingly to affected areas twice daily; if no improvement after 2 weeks, reassess diagnosis. Safety and efficacy have not been established beyond 4 weeks of therapy.

For the systemic treatment of severe inflammatory dermatoses, like severe exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, or psoriasis unresponsive to topical treatment.
Oral dosage
Adults

20 to 240 mg/day PO, given in 2 to 4 divided doses.

Adolescents, Children, and Infants

A general dose range of 0.56 to 8 mg/kg/day or 16 to 240 mg/m2/day PO given in 3 to 4 divided doses has been recommended. Adjust according to patient response.

Intramuscular or Intravenous dosage (hydrocortisone sodium succinate injection)
Adults

100 to 500 mg IM or IV. Repeat doses at 2, 4, or 6 hour intervals.

Adolescents, Children, and Infants

0.56 to 8 mg/kg/day or 20 to 240 mg/m2/day IM or IV given in 3 to 4 divided dose is the FDA-approved general dosage range. Adjust according to patient response.

For adjunctive therapy in the treatment of rheumatic disorders including acute gouty arthritis, ankylosing spondylitis, rheumatoid arthritis, juvenile rheumatoid arthritis (JRA)/juvenile idiopathic arthritis (JIA), post-traumatic osteoarthritis, pseudogout†, or psoriatic arthritis.
Oral dosage
Adults

20 to 240 mg/day PO, given in 2 to 4 divided doses.

Adolescents, Children, and Infants

A general dose range of 0.56 to 8 mg/kg/day or 16 to 240 mg/m2/day PO given in 3 to 4 divided doses has been recommended. Adjust according to patient response.

Intramuscular or Intravenous dosage (hydrocortisone sodium succinate injection)
Adults

100 to 500 mg IM or IV. Repeat doses at 2, 4, or 6 hour intervals.

Adolescents, Children, and Infants

0.56 to 8 mg/kg/day or 20 to 240 mg/m2/day IM or IV given in 3 to 4 divided dose is the FDA-approved general dosage range. Adjust according to patient response.

For the treatment of acute episodes or exacerbation of non-rheumatic inflammation including acute and subacute bursitis, epicondylitis, and acute non-specific tenosynovitis.
Oral dosage
Adults

20 to 240 mg/day PO, given in 2 to 4 divided doses.

Adolescents, Children, and Infants

A general dose range of 0.56 to 8 mg/kg/day or 16 to 240 mg/m2/day PO given in 3 to 4 divided doses has been recommended. Adjust according to patient response.

For the short-term treatment of hypercalcemia associated with neoplastic disease.
Intravenous or Intramuscular dosage (hydrocortisone sodium succinate injection)
Adults

200 to 300 mg IV once per day for 3 to 5 days has been recommended.

Adolescents, Children, and Infants

0.56 to 8 mg/kg/day or 20 to 240 mg/m2/day IM or IV given in 3 to 4 divided dose is the FDA-approved general dosage range. Adjust according to patient response.

For the treatment of complicated or disseminated pulmonary tuberculosis infection (i.e., tuberculous meningitis and pericarditis) as adjunctive therapy in combination with antituberculous therapy.
Oral dosage
Adults

The FDA-labeled dose is 20 to 240 mg/day PO, depending upon the disease being treated. Adjunctive corticosteroid therapy has been shown to improve survival for patients with tuberculosis involving the CNS and pericardium, but has not been universally recommended by guidelines for all forms of tuberculosis. Initial doses in clinical trials for tuberculosis in general have used IV doses of either 4 mg/kg IV every 24 hours or 150 to 250 mg IV daily; many trials were prior to the use of rifampin, which may decrease bioavailability and increase plasma clearance of corticosteroids. A meta-analysis suggests that steroid use may reduce mortality in all forms of tuberculosis which may be influenced by genetic variation at the LTA4H gene.

Adolescents, Children, and Infants

A general dose range of 0.56 to 8 mg/kg/day or 16 to 240 mg/m2/day PO given in 3 to 4 divided doses has been recommended. Adjust according to patient response.

Intramuscular or Intravenous dosage (hydrocortisone sodium succinate injection)
Adults

100 to 500 mg IM or IV; doses may be repeated at 2, 4, or 6 hour intervals. Adjunctive corticosteroid therapy has been shown to improve survival for patients with tuberculosis involving the CNS and pericardium, but has not been universally recommended by guidelines for all forms of tuberculosis. Clinical trials for tuberculosis in general have used IV doses of either 4 mg/kg IV every 24 hours or 150 to 250 mg IV daily; many trials were prior to the use of rifampin, which may decrease bioavailability and increase plasma clearance of corticosteroids. A meta-analysis suggests that steroid use may reduce mortality in all forms of tuberculosis which may be influenced by genetic variation at the LTA4H gene.

Adolescents, Children, and Infants

0.56 to 8 mg/kg/day or 20 to 240 mg/m2/day IM or IV given in 3 to 4 divided dose is the FDA-approved general dosage range. Adjust according to patient response.

For the management of nephrotic syndrome to induce diuresis or decrease proteinuria.
Oral dosage
Adults

20 to 240 mg/day PO, given in 2 to 4 divided doses.

Infants, Children, and Adolescents

A general dose range of 0.56 to 8 mg/kg/day or 16 to 240 mg/m2/day PO given in 3 to 4 divided doses has been recommended. Adjust according to patient response.

Intramuscular or Intravenous dosage (hydrocortisone sodium succinate injection)
Adults

100 mg to 500 mg IM or IV. Repeat doses at 2, 4, or 6 hour intervals.

Infants, Children, and Adolescents

0.56 to 8 mg/kg/day or 20 to 240 mg/m2/day IM or IV given in 3 to 4 divided dose is the FDA-approved general dosage range. Adjust according to patient response.

For the treatment of neurologic or myocardial involvement associated with trichinosis.
Oral dosage
Adults

20 to 240 mg (base)/day PO, given in 2 to 4 divided doses.

Adolescents, Children, and Infants

A general dose range of 0.56 to 8 mg/kg/day or 16 to 240 mg/m2/day PO given in 3 to 4 divided doses has been recommended. Adjust according to patient response.

Intramuscular or Intravenous dosage (hydrocortisone sodium succinate injection)
Adults

100 mg to 500 mg IM or IV. Repeat doses at 2, 4, or 6 hour intervals.

Adolescents, Children, and Infants

0.56 to 8 mg/kg/day or 20 to 240 mg/m2/day IM or IV given in 3 to 4 divided dose is the FDA-approved general dosage range. Adjust according to patient response.

For the treatment of nonsuppurative thyroiditis.
Oral dosage
Adults

20 to 240 mg (base)/day PO, given in 2 to 4 divided doses.

Adolescents, Children, and Infants

A general dose range of 0.56 to 8 mg/kg/day or 16 to 240 mg/m2/day PO given in 3 to 4 divided doses has been recommended. Adjust according to patient response.

Intramuscular or Intravenous dosage (hydrocortisone sodium succinate injection)
Adults

100 to 500 mg IM or IV. Repeat doses at 2, 4, or 6 hour intervals.

Adolescents, Children, and Infants

0.56 to 8 mg/kg/day or 20 to 240 mg/m2/day IM or IV given in 3 to 4 divided dose is the FDA-approved general dosage range. Adjust according to patient response.

For rheumatic and related disorders such as acute rheumatic carditis, systemic dermatomyositis (polymyositis), systemic lupus erythematosus (SLE), temporal arteritis, Churg-Strauss syndrome†, mixed connective tissue disease†, polyarteritis nodosa†, relapsing polychondritis†, polymyalgia rheumatica†, symptomatic sarcoidosis, vasculitis†, or Wegener’s granulomatosis†.
Oral dosage
Adults

20 to 240 mg/day PO, given in 2 to 4 divided doses.

Adolescents, Children, and Infants

A general dose range of 0.56 to 8 mg/kg/day or 16 to 240 mg/m2/day PO given in 3 to 4 divided doses has been recommended. Adjust according to patient response.

Intramuscular or Intravenous dosage (hydrocortisone sodium succinate injection)
Adults

100 to 500 mg IM or IV. Repeat doses at 2, 4, or 6 hour intervals.

Infants, Children, and Adolescents

0.56 to 8 mg/kg/day or 20 to 240 mg/m2/day IM or IV given in 3 to 4 divided dose is the FDA-approved general dosage range. Adjust according to patient response.

For the treatment of corticosteroid-responsive hematologic disorders, like immune thrombocytopenic purpura (ITP), secondary thrombocytopenia in adults, acquired (autoimmune) hemolytic anemia, erythroblastopenia, and congenital hypoplastic anemia; OR for the palliative treatment of neoplastic disease in adults and acute leukemias of childhood including acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, non-Hodgkin’s lymphoma (NHL), cutaneous T-cell lymphoma (CTCL) (aka mycosis fungoides), or multiple myeloma†.
Oral dosage
Adults

20 to 240 mg/day PO, given in 2 to 4 divided doses.

Adolescents, Children, and Infants

A general dose range of 0.56 to 8 mg/kg/day or 16 to 240 mg/m2/day PO given in 3 to 4 divided doses has been recommended. Adjust according to patient response.

Intramuscular or Intravenous dosage (hydrocortisone sodium succinate injection)
Adults

100 to 500 mg IM or IV. Repeat doses at 2, 4, or 6 hour intervals.

Adolescents, Children, and Infants

0.56 to 8 mg/kg/day or 20 to 240 mg/m2/day IM or IV given in 3 to 4 divided dose is the FDA-approved general dosage range. Adjust according to patient response.

For the treatment of respiratory inflammatory conditions including bronchial asthma, aspiration pneumonitis, berylliosis, chronic obstructive pulmonary disease (COPD), Loeffler’s syndrome, or noncardiogenic pulmonary edema†.
Oral dosage
Adults

20 to 240 mg/day PO, given in 2 to 4 divided doses. Although the National Asthma Education and Prevention Program guidelines recommend prednisone, prednisolone, or methylprednisolone as the systemic corticosteroids of choice for the management of moderate to severe asthma exacerbations, they state that other corticosteroids, such as hydrocortisone, given in equipotent daily doses are likely to be as effective. Administer hydrocortisone IV or IM initially for the treatment of severe respiratory conditions or those compromising the airway.

Adolescents, Children, and Infants

A general dose range of 0.56 to 8 mg/kg/day or 16 to 240 mg/m2/day PO given in 3 to 4 divided doses has been recommended. Adjust according to patient response. Although the National Asthma Education and Prevention Program guidelines recommend prednisone, prednisolone, or methylprednisolone as the systemic corticosteroids of choice for the management of moderate to severe asthma exacerbations, they state that other corticosteroids, such as hydrocortisone, given in equipotent daily doses are likely to be as effective. Administer hydrocortisone IV or IM initially for the treatment of severe respiratory conditions or those compromising the airway.

Intramuscular or Intravenous dosage (hydrocortisone sodium succinate injection)
Adults

100 to 500 mg IM or IV. Repeat doses at 2, 4, or 6 hour intervals. Although the National Asthma Education and Prevention Program guidelines recommend prednisone, prednisolone, or methylprednisolone as the systemic corticosteroids of choice for the management of moderate to severe asthma exacerbations, they state that other corticosteroids, such as hydrocortisone, given in equipotent daily doses are likely to be as effective.

Adolescents, Children, and Infants

0.56 to 8 mg/kg/day or 20 to 240 mg/m2/day IM or IV given in 3 to 4 divided dose is the FDA-approved general dosage range. Adjust according to patient response. An initial dose of 6 mg/kg IV followed by 8 to 10 mg/kg/day IV given in 4 divided doses for 1 to 2 days was used in 2 studies (combined n = 85, age 2 months to 11 years) of patients with acute asthma. Although 1 study found improvements in patients receiving hydrocortisone compared to placebo, another study comparing hydrocortisone to dexamethasone found a significantly shorter duration of hospital stay in patients receiving dexamethasone. The National Asthma Education and Prevention Program guidelines recommend prednisone, prednisolone, or methylprednisolone as the systemic corticosteroids of choice for the management of moderate to severe asthma exacerbations; however, the guidelines state that other corticosteroids, such as hydrocortisone, given in equipotent daily doses are likely to be as effective.

For the treatment of septic shock† and/or hypotension† in patients whose blood pressure is poorly responsive to adequate fluid resuscitation and vasopressor therapy.
Intravenous dosage (hydrocortisone sodium succinate injection)
Adults

200 mg/day IV continuous infusion if adequate fluid resuscitation and vasopressor therapy are unable to restore hemodynamic stability. Taper dose once vasopressors are no longer required. Hydrocortisone should not be administered in sepsis in the absence of shock. The adrenocorticotropic hormone stimulation test is not recommended to identify patients with septic shock who should receive hydrocortisone.

Infants, Children, and Adolescents

An initial dose of 2 mg/kg/day IV or 50 mg/m2/day IV given in divided doses or as a continuous infusion and titrated to resolution of shock to doses as high as 50 mg/kg/day IV is recommended by the Society of Critical Care Medicine for patients with suspected or proven absolute adrenal insufficiency (peak cortisol concentration after corticotropin stimulation less than 18 mcg/dL) or adrenal-pituitary axis failure and catecholamine resistant shock. An initial dose of 100 mg/m2 IV (Max: 200 mg) followed by 25 mg/m2/dose IV every 6 hours (Max: 50 mg/dose) was used in a study of patients with systemic inflammatory response syndrome with hypotension requiring fluid resuscitation and vasopressors (n = 97, age 0.5 months to 24 years). A portion of patients (n = 60) also received fludrocortisone (50 mcg/day PO for patients weighing less than 35 kg and 100 mcg/day PO for patients weighing 35 kg or more).

Neonates

1 mg/kg IV every 8 to 12 hours for 1 to 5 days has been studied in premature and term neonates (combined n from 3 studies = 89, gestational age 23 to 40 weeks). An initial loading dose of 2 mg/kg IV was used in 1 retrospective study and another prospective, observational study used a higher maintenance dose of 3 to 6 mg/kg/day IV divided 2 to 4 times daily in a small number of patients (n = 5) with severe capillary leak syndrome and/or previous steroid treatment. In the largest prospective, randomized, placebo controlled study (n = 48, gestational age 25.2 to 29.9 weeks), patients receiving hydrocortisone 1 mg/kg IV every 8 hours for 5 days required significantly less vasopressor support (lower doses of dopamine and dobutamine, shorter duration of vasopressor therapy, and fewer patients requiring more than 1 vasopressor) compared to patients receiving placebo. The trend of the average mean arterial blood pressure (MAP) was also significantly higher in patients receiving hydrocortisone compared to patients receiving placebo.

For the prevention of chronic lung disease (CLD)† in mechanically ventilated patients.
Intravenous dosage (hydrocortisone sodium succinate injection)
Premature neonates

0.5 mg/kg/dose IV every 12 hours for 9 to 12 days followed by 0.25 mg/kg/day IV every 12 hours for 3 days, started within the first 48 hours of life, has been studied (combined n from 3 studies = 450, birth weight 500 to 1,249 grams). The rate of survival without chronic lung disease (CLD) was significantly increased in 2 studies in patients receiving hydrocortisone compared to those receiving placebo. Although the largest study (n = 360) did not find a significantly increased rate of survival without CLD in the overall study group, the rate of survival without CLD was significantly improved in a subset of patients receiving hydrocortisone who were exposed to chorioamnionitis. This study was terminated early due to a higher incidence of intestinal perforation in patients receiving hydrocortisone and indomethacin (vs. indomethacin plus placebo). The American Academy of Pediatrics states that hydrocortisone at a dose of 1 mg/kg/day IV given for the first 2 weeks of life may increase the rate of survival without CLD, especially in neonates delivered in a setting of prenatal inflammation, without adverse effects on neurodevelopment.

For the treatment of refractory neonatal hypoglycemia†.
Intravenous dosage (hydrocortisone sodium succinate injection)
Neonates

5 mg/kg/day IV given in 2 divided doses has been recommended in neonates not responding to glucose infusions of 12 to 15 mg/kg/minute. 

Oral dosage
Neonates

5 mg/kg/day PO given in 2 divided doses has been recommended in neonates not responding to glucose infusions of 12 to 15 mg/kg/minute. 

For the treatment of corticosteroid-responsive ophthalmic disorders, including allergic conjunctivitis (not controlled topically), allergic marginal corneal ulcer, anterior segment inflammation, chorioretinitis, endophthalmitis†, Graves’ ophthalmopathy, herpes zoster ocular infection (herpes zoster ophthalmicus), iritis, keratitis, postoperative ocular inflammation, optic neuritis, diffuse posterior uveitis, or vernal keratoconjunctivitis.
Oral dosage
Adults

20 to 240 mg/day PO, given in 2 to 4 divided doses.

Adolescents, Children, and Infants

A general dose range of 0.56 to 8 mg/kg/day or 16 to 240 mg/m2/day PO given in 3 to 4 divided doses has been recommended. Adjust according to patient response.

Intramuscular or Intravenous dosage (hydrocortisone sodium succinate injection)
Adults

100 to 500 mg IM or IV. Repeat doses at 2, 4, or 6 hour intervals.

Adolescents, Children, and Infants

0.56 to 8 mg/kg/day or 20 to 240 mg/m2/day IM or IV given in 3 to 4 divided dose is the FDA-approved general dosage range. Adjust according to patient response.

For adjunctive therapy in the treatment of carpal tunnel syndrome†.
Local injection (hydrocortisone acetate suspension for injection)
Adults

25 mg as a single injection adjacent to the carpal tunnel has been effective for conservative therapy. Reassess at 6 to 8 weeks. To avoid median-nerve injury, use specialized administration techniques. Use of more than 2 or 3 repeat injections is not advised; local tendon damage may occur. The definitive treatment for median-nerve entrapment is surgery. Corticosteroids are temporary measures; patients who have intermittent pain and paresthesias without any fixed motor-sensory deficits may respond to conservative therapy.

†Indicates off-label use

MAXIMUM DOSAGE

Corticosteroid dosage must be individualized and is highly variable depending on the nature and severity of the disease, and on patient response. There is no absolute maximum dosage.

DOSING CONSIDERATIONS

Hepatic Impairment

Systemic dosage may need adjustment depending on the degree of hepatic insufficiency, but quantitative recommendations are not available.

Renal Impairment

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

ADMINISTRATION

Oral Administration

Administer with meals to minimize indigestion or GI irritation. If given once daily, administer in the morning to coincide with the body’s normal cortisol secretion.

Oral Solid Formulations

Tablets may be crushed and mixed with a small amount of liquid just prior to administration for patient’s unable to swallow tablets. Crushed tablets are recommended over oral suspension in patients with congenital adrenal hyperplasia (CAH) due to results of a study showing hydrocortisone cypionate suspension (Cortef suspension) was not bioequivalent to the tablets. 

Oral Liquid Formulations

Oral Suspension
Shake well before administering. Measure dosage with calibrated measuring device.

Extemporaneous Compounding-Oral

Extemporaneous Compounding-Oral Suspension
Extemporaneous 2.5 mg/ml Hydrocortisone Oral Suspension Preparation
Dissolve 0.02 gram of methyl hydroxybenzoate, 0.08 gram of propyl hydroxybenzoate, 0.6 gram of citric acid monohydrate, and 10 mL of syrup BP in hot water to make the vehicle.
Triturate the cooled vehicle with 1 gram of sodium carboxymethylcellulose and allow solution to stand overnight.
Weigh out 250 mg of hydrocortisone powder or grind twelve and one-half (12.5) 20 mg hydrocortisone tablets into a fine powder in a glass mortar.
Combine the ground tablets or the 250 mg of hydrocortisone powder with 0.5 mL of polysorbate 80 and triturate.
Add the vehicle to the hydrocortisone powder mixture and transfer to amber plastic bottles.
Add enough water to bring the total volume to 100 mL.
Storage: The resulting suspension is chemically stable at 5 and 25 degrees Celsius for 90 days; however, a 30 day expiration is suggested due to the lack of antimicrobial preservative.

Injectable Administration

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Use solution only if it is clear.

Intravenous Administration

Reconstitution and Preparation:
100 mg vial: For IV injection, add 2 mL or less of Bacteriostatic Water for Injection or Bacteriostatic Sodium Chloride Injection to the contents of one vial.
Further dilution is not necessary for direct IV injection.
For intravenous infusion, add 2 mL or less of Bacteriostatic Water for Injection to the vial; this solution may then be added to 100 to 1000 mL of 5% Dextrose, 0.9% Sodium Chloride, or 5% Dextrose with 0.9% Sodium Chloride injection.
ACT-O-VIAL presentations: Press down on plastic activator to force diluent into the lower compartment. Gently agitate to effect solution. Remove plastic tab covering center of stopper, and sterilize the stopper top. Insert needle squarely through center of stopper until tip is just visible. Invert vial and withdraw dose.
 Further dilution is not necessary for direct IV injection.
For intravenous infusion, add the 100 mg solution to 100 to 1000 mL of 5% Dextrose, 0.9% Sodium Chloride, or 5% Dextrose with 0.9% Sodium Chloride injection. The 250 mg solution may be added to 250 to 1000 mL, the 500 mg solution may be added to 500 to 1000 mL, and the 1000 mg solution may be added to 1000 mL of the same diluents. Alternatively, 100 to 3000 mg may be added to 50 mL of the above diluents. Do not dilute or mix with other solutions because of possible incompatibilities. The resulting solutions are stable for at least 4 hours.
 
Direct IV injection administration:
Inject the reconstituted solution over a period of 30 seconds (e.g., 100 mg) to 10 minutes (e.g., 500 mg or more).
 
Continuous IV infusion administration:
Reconstituted isolutions may be administered by IV piggyback, but do not dilute or mix with solutions other than 5% Dextrose, 0.9% Sodium Chloride, or 5% Dextrose and 0.9% Sodium Chloride because of possible incompatibilities.

Intramuscular Administration

Reconstitution and Administration
100 mg vial: Add 2 mL or less of Bacteriostatic Water for Injection or Bacteriostatic 0.9% Sodium Chloride Injection to the contents of 1 vial.
ACT-O-VIAL (100mg, 250 mg, 500 mg, 1000 mg): Press down on plastic activator to force diluent into the lower compartment. Gently agitate to effect solution. Remove plastic tab covering center of stopper. Sterilize top of stopper with a suitable germicide. Insert needle squarely through center of stopper until tip is just visible. Invert vial and withdraw dose. Further dilution is not necessary for IM injection.
Do NOT administer hydrocortisone IM into the deltoid muscle as subcutaneous atrophy occurs with high frequency after such use.

Topical Administration
Cream/Ointment/Lotion Formulations

Cream, lotion, or ointment: Apply sparingly in a thin film and rub gently into the cleansed affected area. Occlusive dressings may be necessary for severe conditions.

Other Topical Formulations

Solution or gel: Apply sparingly in a thin film and rub gently into the cleansed affected area. Occlusive dressings may be necessary for severe conditions.
Aerosol spray: Shake container gently once or twice each time before using. Spray each four square inch area for about 1 to 2 seconds from a distance of about 15 cm.

Rectal Administration

Aerosol Rectal Foam:
Wash hands before and after application.
Place cap on top of container and shake the container vigorously for 5 to 10 seconds before each use; cap should not be removed during use.
Hold container upright on a level surface and gently place the tip of the applicator onto the nose of the container cap. Container must be held upright to obtain proper flow of medication.
Pull applicator plunger past the fill line on the applicator barrel.
To fill the applicator barrel, press down firmly on cap flanges, hold for 1 to 2 seconds, and release. Allow 5 to 10 seconds for foam to expand in the applicator barrel. Repeat until the foam reaches the fill line. Remove applicator from container cap. A burst of air may be released from container with the first pump.
Hold applicator firmly by barrel, making sure thumb and middle finger are positioned securely underneath and resting against barrel wings. Place index finger over the plunger. Gently insert tip into anus. Once in place, push plunger to expel foam, then withdraw applicator. Apply to anus only with the applicator provided with the foam. Do not insert any part of the applicator past the anus into the rectum. Fingers or any other mechanical device should not be used to administer the aerosol foam. Do not insert any part of the aerosol container directly into the anus.
The container and cap should be disassembled and rinsed with warm water after each use. The applicator parts should be pulled apart for thorough cleaning with warm water after each use.
 
Rectal Retention Enema:
Instruct patient to lie down on left side during administration and for 30 minutes afterwards to allow the medication to distribute throughout the colon. Encourage patient to retain enema for at least 1 hour or, preferably, all night before expelling.
 
Rectal Suppository:
Instruct patient on proper use of suppository. Unwrap the suppository prior to insertion. Moisten the suppository with water prior to insertion. If suppository is too soft because of storage in a warm place, chill in the refrigerator for 30 minutes or run cold water over it before removing wrapper.
 
Topical Cream for hemorrhoids:
Apply as a thin film to the cleansed affected area around the anus. Do not insert rectally.

STORAGE

Generic:
– Store at room temperature (between 59 to 86 degrees F)
A-Hydrocort:
– Discard product if it contains particulate matter, is cloudy, or discolored
– Discard reconstituted product if not used within 3 days
– Protect from light
– Reconstituted product may be stored at controlled room temperature (68 to 77 degrees F)
– Store unreconstituted product at 68 to 77 degrees F
Ala-Cort:
– Store at controlled room temperature (between 68 and 77 degrees F)
Ala-Scalp:
– Avoid exposure to heat
– Protect from light
– Protect from moisture
– Store at room temperature (between 59 to 86 degrees F)
Anucort-HC:
– Avoid exposure to heat
– Protect from freezing
– Store at controlled room temperature (between 68 and 77 degrees F)
Anumed-HC:
– Avoid exposure to heat
– Protect from freezing
– Store at controlled room temperature (between 68 and 77 degrees F)
Anusol HC:
– Avoid exposure to heat
– Protect from freezing
– Store at controlled room temperature (between 68 and 77 degrees F)
Balneol for Her:
– Protect from moisture
– Store at controlled room temperature (between 68 and 77 degrees F)
Caldecort :
– Store at controlled room temperature (between 68 and 77 degrees F)
Cetacort:
– Storage information not available
Colocort :
– Store at controlled room temperature (between 68 and 77 degrees F)
Cortaid:
– Store at controlled room temperature (between 68 and 77 degrees F)
Cortaid Advanced:
– Store at controlled room temperature (between 68 and 77 degrees F)
Cortaid Intensive Therapy:
– Store at controlled room temperature (between 68 and 77 degrees F)
CortAlo:
– Store at room temperature (between 59 to 86 degrees F)
Cortef:
– Store at controlled room temperature (between 68 and 77 degrees F)
Cortenema:
– Store at controlled room temperature (between 68 and 77 degrees F)
Corticaine:
– Store between 68 to 77 degrees F
Corticool:
– Storage information not available
Cortifoam:
– Do not refrigerate
– Do Not Store at Temperatures Above 120 degrees F (49 degrees C)
– Store at controlled room temperature (between 68 and 77 degrees F)
Cortizone:
– Store at controlled room temperature (between 68 and 77 degrees F)
Cortizone-10:
– Store at controlled room temperature (between 68 and 77 degrees F)
Cortizone-10 Cooling Relief:
– Storage information not available
Cortizone-10 Intensive Healing:
– Storage information not available
Cortizone-10 Plus:
– Store at controlled room temperature (between 68 and 77 degrees F)
Dermarest Dricort:
– Store at controlled room temperature (between 68 and 77 degrees F)
Dermarest Eczema:
– Storage information not available
Encort:
– Avoid exposure to heat
– Protect from freezing
– Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
First – Hydrocortisone:
– Store at room temperature (between 59 to 86 degrees F)
Gly-Cort :
– Storage information not available
GRx HiCort:
– Avoid exposure to heat
– Protect from freezing
– Store at controlled room temperature (between 68 and 77 degrees F)
Hemmorex-HC:
– Avoid exposure to heat
– Protect from freezing
– Store at controlled room temperature (between 68 and 77 degrees F)
Hemorrhoidal-HC:
– Avoid exposure to heat
– Protect from freezing
– Store at controlled room temperature (between 68 and 77 degrees F)
Hemril :
– Avoid exposure to heat
– Protect from freezing
– Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
Hycort:
– Store at controlled room temperature (between 68 and 77 degrees F)
Hydro Skin:
– Storage information not available
Hydrocortisone in Absorbase:
– Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
Hydrocortone:
– Store at controlled room temperature (between 68 and 77 degrees F)
Hydroskin :
– Store at controlled room temperature (between 68 and 77 degrees F)
Hytone:
– Store at controlled room temperature (between 68 and 77 degrees F)
Instacort:
– Store at controlled room temperature (between 68 and 77 degrees F)
Lacticare HC:
– Storage information not available
Locoid:
– Protect from freezing
– Store at 77 degrees F; excursions permitted to 59-86 degrees F
Locoid Lipocream:
– Protect from freezing
– Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
MiCort-HC :
– Protect from freezing
– Store at 77 degrees F; excursions permitted to 59-86 degrees F
Monistat Complete Care Instant Itch Relief Cream:
– Store at controlled room temperature (between 68 and 77 degrees F)
Neosporin Eczema:
– Store at controlled room temperature (between 68 and 77 degrees F)
NuCort :
– Store at room temperature (between 59 to 86 degrees F)
Nutracort:
– Store at controlled room temperature (between 68 and 77 degrees F)
NuZon:
– Store at room temperature (between 59 to 86 degrees F)
Pandel:
– Store at controlled room temperature (between 68 and 77 degrees F)
Penecort:
– Store at controlled room temperature (between 68 and 77 degrees F)
Preparation H Hydrocortisone:
– Store at controlled room temperature (between 68 and 77 degrees F)
Proctocort:
– Avoid exposure to heat
– Protect from freezing
– Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
Proctocream-HC:
– Store at controlled room temperature (between 68 and 77 degrees F)
Procto-Kit:
– Store at controlled room temperature (between 68 and 77 degrees F)
Procto-Med HC :
– Store at controlled room temperature (between 68 and 77 degrees F)
Procto-Pak:
– Protect from freezing
– Store at room temperature (between 59 to 86 degrees F)
Proctosert HC :
– Avoid exposure to heat
– Protect from freezing
– Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
Proctosol-HC:
– Avoid exposure to heat
– Protect from freezing
– Store at controlled room temperature (between 68 and 77 degrees F)
Proctozone-HC:
– Store at controlled room temperature (between 68 and 77 degrees F)
Rectacort HC:
– Avoid exposure to heat
– Protect from freezing
– Store at controlled room temperature (between 68 and 77 degrees F)
Rectasol-HC:
– Avoid exposure to heat
– Protect from freezing
– Store at controlled room temperature (between 68 and 77 degrees F)
Rederm:
– Storage information not available
Sarnol-HC:
– Storage information not available
Scalacort:
– Avoid exposure to heat
– Protect from freezing
– Store at room temperature (between 59 to 86 degrees F)
Scalpicin Anti-Itch:
– Avoid excessive humidity
– Store between 68 to 77 degrees F
Solu-Cortef:
– Discard reconstituted product if not used within 3 days
– Protect from light
– Store at controlled room temperature (between 68 and 77 degrees F)
Texacort:
– Store at room temperature (between 59 to 86 degrees F)
Tucks HC:
– Store at room temperature (between 59 to 86 degrees F)
Walgreens Intensive Healing:
– Store at controlled room temperature (between 68 and 77 degrees F)
Westcort:
– Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

CONTRAINDICATIONS / PRECAUTIONS

Abrupt discontinuation, Cushing’s syndrome, skin abrasion

Systemic corticosteroids can aggravate Cushing’s syndrome and should be avoided in patients with Cushing’s syndrome. Prolonged administration of pharmacological doses of systemic corticosteroids or topical preparations (resulting in systemic absorption) may result in hypothalamic-pituitary-adrenal (HPA) suppression and/or manifestations of Cushing’s syndrome in some patients. Acute adrenal insufficiency and even death may occur following abrupt discontinuation of prolonged systemic therapy. In addition, a withdrawal syndrome unrelated to adrenocortical insufficiency may occur following sudden discontinuation of corticosteroid therapy. These effects are thought to be due to the sudden change in glucocorticoid concentration rather than to low corticosteroid levels. Withdrawal from prolonged systemic corticosteroid therapy should be gradual. HPA suppression can last for up to 12 months following cessation of systemic therapy. Recovery of HPA axis function is generally prompt and complete upon discontinuation of the topical corticosteroid. HPA-suppressed patients may need supplemental corticosteroid treatment during periods of physiologic stress, such as surgical procedures, acute blood loss, or infection, even after the corticosteroid has been discontinued. Conditions that increase systemic absorption of topical corticosteroids include use over large surface areas, prolonged use, use in areas where the epidermal barrier is disrupted (i.e., skin abrasion), and the use of an occlusive dressing. Patients receiving large doses of hydrocortisone applied to a large surface area should be evaluated periodically for evidence of HPA axis suppression and/or manifestations of Cushing’s syndrome. If these effects are noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent corticosteroid.

Growth inhibition, increased intracranial pressure

Chronic corticosteroid therapy in pediatric patients may interfere with growth and development. Chronic use of systemic or topical corticosteroids may cause growth inhibition (including linear growth retardation and delayed weight gain) in pediatric patients. Children and infants may absorb proportionally larger amounts of topical corticosteroids due to a larger skin surface area to body weight ratio, and therefore are more susceptible to developing systemic toxicity, especially with very-high-potency topical products. Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing’s syndrome, and increased intracranial pressure have been reported in children receiving corticosteroids. Administration of corticosteroids to pediatric patients should be limited to the least amount compatible with an effective therapeutic regimen. If children are being treated topically in the diaper area, tight-fitting diapers or plastic pants should be avoided as these garments may act as an occlusive dressing and increase systemic absorption of the drug. 

Immunosuppression

Patients receiving high-dose (e.g., equivalent to 1 mg/kg or more of prednisone daily) systemic corticosteroid therapy, such as hydrocortisone, for any period of time, particularly in conjunction with corticosteroid sparing drugs (e.g., troleandomycin) are at risk to develop immunosuppression; patients receiving moderate doses of systemic corticosteroids, such as hydrocortisone, for short periods or low doses for prolonged periods may also be at risk. When given in combination with other immunosuppressive agents, there is a risk of over-immunosuppression. 

Fungal infection, infection

Systemic corticosteroid therapy, such as hydrocortisone, can mask the symptoms of infection and should not be used in patients with fungal infection or bacterial infection that are not adequately controlled with antiinfective agents. Although the manufacturers state that systemic hydrocortisone is contraindicated in patients with systemic fungal infections, in clinical use systemic corticosteroids can be administered to these patients as long as appropriate antiinfective therapy is administered simultaneously. 

Acne rosacea, acne vulgaris, herpes infection, measles, perioral dermatitis, peripheral vascular disease, tuberculosis, varicella, viral infection

Reactivation of tuberculosis may occur in patients with latent tuberculosis or tuberculin reactivity; close observation for disease reactivation is needed if corticosteroids are indicated in such patients. Further, chemoprophylaxis is advised if prolonged corticosteroid therapy is needed. Patients receiving immunosuppressive doses of systemic corticosteroids should be advised to avoid exposure to viral infections (i.e., measles or varicella) because these diseases may be more serious or even fatal in immunosuppressed patients. If exposed to chicken pox, prophylaxis with varicella zoster immune globulin may be indicated. Pediatric patients dependent on systemic corticosteroids should undergo anti-varicella-zoster virus antibody testing. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin may be indicated. Instruct patients to avoid exposure to chicken pox and measles and to get immediate medical advice if exposure occurs. Application of topical corticosteroids to areas of infection, including tuberculosis of the skin, dermatologic fungal infection, and cutaneous or systemic viral infection (e.g., herpes infection, measles, varicella), should be initiated or continued only if the appropriate antiinfective treatment is instituted. If the infection does not respond to the antimicrobial therapy, the concurrent use of the topical corticosteroid should be discontinued until the infection is controlled. Topical corticosteroids should not be used to treat acne vulgaris, acne rosacea, or perioral dermatitis as they may exacerbate these conditions. Topical corticosteroids may delay the healing of non-infected wounds, such as venous stasis ulcers. Use topical hydrocortisone preparations with caution in patients with markedly impaired circulation or peripheral vascular disease; skin ulceration has been reported in these patients following topical corticosteroid use.

Surgery

If surgery is required, physicians should inquire if the patient has received systemic corticosteroid therapy, such as hydrocortisone, within the last 12 months and discuss the disease for which they were being treated. In such cases, patients should be encouraged to always carry identification cards that include disease state, type, and dose of corticosteroid that was used.

Myocardial infarction

Corticosteroid therapy, such as hydrocortisone, has been associated with left ventricular free-wall rupture in patients with recent myocardial infarction, and should therefore be used cautiously in these patients.

Heart failure, hypertension

Systemic corticosteroids, such as hydrocortisone, can cause edema and weight gain. Use with caution in patients with congestive heart failure or hypertension as this can cause an exacerbation of their condition.

Osteoporosis

Prolonged systemic corticosteroid therapy, such as hydrocortisone, can lead to osteoporosis, vertebral compression fractures, aseptic necrosis of femoral and humoral heads, and pathologic fractures of long bones secondary to protein catabolism. Use cautiously in older (>= 65 years), debilitated, or postmenopausal patients because they are especially susceptible to these adverse effects. A high-protein diet may alleviate or prevent the adverse effects associated with protein catabolism.

Diabetes mellitus

Systemic corticosteroids, such as hydrocortisone, may decrease glucose tolerance, produce hyperglycemia, and aggravate or precipitate diabetes mellitus. This may especially occur in patients predisposed to diabetes mellitus. When corticosteroid therapy is necessary in patients with diabetes mellitus, changes in insulin, oral antidiabetic agent dosage, and/or diet may be required. Topical corticosteroids should be used with caution in patients with diabetes mellitus. Exacerbation of diabetes may occur with systemic absorption of the topical corticosteroid. Use of topical corticosteroids may further delay healing of skin ulcers in diabetic patients.

Diverticulitis, GI disease, GI perforation, inflammatory bowel disease, peptic ulcer disease, ulcerative colitis

Oral corticosteroids, such as hydrocortisone, can cause gastrointestinal irritation. The drugs should be used with caution in patients with GI disease, diverticulitis, nonspecific ulcerative colitis, or intestinal anastomosis (because of the possibility of perforation). While used for the short-term treatment of acute exacerbations of chronic inflammatory bowel disease such as ulcerative colitis and Crohn’s disease, corticosteroids should not be used in patients where there is a possibility of impending GI perforation, abscess, or pyogenic infection. Some patients may require long-term corticosteroid therapy to suppress disease activity, but generally this practice is not recommended. Corticosteroids should not be used in patients with peptic ulcer disease except under life-threatening circumstances.

Hepatic disease, hypothyroidism, psychosis, renal disease, seizure disorder

Systemic corticosteroids should be used with extreme caution in patients with psychosis, emotional instability, renal disease, and seizure disorder because the drugs can exacerbate these conditions. Patients with hepatic disease, such as cirrhosis, or hypothyroidism can have an exaggerated response to systemic corticosteroids. Use systemic corticosteroids, such as hydrocortisone, with caution in these patients.

Myasthenia gravis

Systemic glucocorticoids, such as hydrocortisone, should be used with caution in patients with myasthenia gravis who are being treated with anticholinesterase agents (see Drug Interactions).

Coagulopathy, hemophilia, thromboembolic disease

Systemic corticosteroids rarely may increase blood coagulability, causing intravascular thrombosis, thrombophlebitis, and thromboembolism. Therefore, systemic corticosteroids, such as hydrocortisone, should be used with caution in patients with preexisting coagulopathy (e.g., hemophilia) or thromboembolic disease.

Pregnancy

Systemic and rectal preparations of hydrocortisone must be used with caution during human pregnancy. Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Complications, including cleft palate, stillbirth, and premature abortion, have been reported during animal studies. If hydrocortisone must be used during pregnancy, the potential risks should be discussed with the patient. However, insufficient treatment of an underlying condition (e.g., Addison’s disease) during pregnancy is also associated with fetal and maternal risks and the mother may require additional monitoring to ensure adequate replacement during pregnancy and in the post-partum period as requirements return to pre-pregnancy levels. Infants born to mothers who have taken substantial doses of corticosteroids during pregnancy should be monitored for signs of hypoadrenalism. Topical application of hydrocortisone warrants caution during pregnancy as there are no adequate and well-controlled studies. Topical corticosteroids should not be used in large amounts, on large areas, or for prolonged periods of time in pregnant women. Guidelines recommend mild to moderate potency agents, such as topical hydrocortisone, over potent topical corticosteroids, which should be used in short durations. Fetal growth restriction and a significantly increased risk of low birthweight has been reported with use of potent or very potent topical corticosteroids during the third trimester, particularly when using more than 300 grams. Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. Systemic corticosteroids have been shown to impair fertility in male rats; the impact to human male fertility is not certain. 

Breast-feeding

The use of systemic and rectal hydrocortisone has not been studied during breast-feeding; however cortisol is a normal component of breast milk. Other corticosteroids (prednisone and prednisolone) are usually considered compatible with breast-feeding. It is not known whether topical administration of desonide could result in sufficient systemic absorption to produce detectable quantities in breast milk. However, most dermatologists stress that topical corticosteroids can be safely used during lactation and breast-feeding. If applied topically, care should be used to ensure the infant will not come into direct contact with the area of application, such as the breast. Increased blood pressure has been reported in an infant whose mother applied a high potency topical corticosteroid ointment directly to the nipples. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Vaccination

Corticosteroid therapy, such as hydrocortisone, usually does not contraindicate vaccination with live-virus vaccines when such therapy is of short-term (< 2 weeks); low to moderate dose; long-term alternate day treatment with short-acting preparations; maintenance physiologic doses (replacement therapy); or administration topically (skin or eye), by aerosol, or by intra-articular, bursal or tendon injection. The immunosuppressive effects of steroid treatment differ, but many clinicians consider a dose equivalent to either 2 mg/kg/day or 20 mg/day of prednisone as sufficiently immunosuppressive to raise concern about the safety of immunization with live-virus vaccines. In general, patients with severe immunosuppression due to large doses of corticosteroids should not receive vaccination with live-virus vaccines. When cancer chemotherapy or immunosuppressive therapy is being considered (e.g., for patients with Hodgkin’s disease or organ transplantation), vaccination should precede the initiation of chemotherapy or immunotherapy by >= 2 weeks. Patients vaccinated while on immunosuppressive therapy or in the 2 weeks prior to starting therapy should be considered unimmunized and should be revaccinated at least 3 months after discontinuation of therapy. In patients who have received high-dose, systemic corticosteroids for >= 2 weeks, it is recommended to wait at least 3 months after discontinuation of therapy before administering a live-virus vaccine.

Asthma, sulfite hypersensitivity

Some commercially available formulations of hydrocortisone may contain sulfites. Sulfites may cause allergic reactions in some people. They should be used with caution in patients with known sulfite hypersensitivity. Patients with asthma are more likely to experience this sensitivity reaction than non-asthmatic patients.

Neonates, premature neonates

Several commercial formulations of hydrocortisone injection are contraindicated in premature neonates because these products contain benzyl alcohol. Use these formulations of hydrocortisone with caution in neonates. Administration of benzyl alcohol to neonates can result in a ‘gasping syndrome’, which is a potentially fatal condition characterized by metabolic acidosis and CNS, respiratory, circulatory, and renal dysfunction; it is also characterized by high concentrations of benzyl alcohol and its metabolites in the blood and urine. While the minimum amount of benzyl alcohol at which toxicity may occur is not known, ‘gasping syndrome’ has been associated with benzyl alcohol dosages more than 99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic failure, renal failure, hypotension, bradycardia, and cardiovascular collapse. Rare cases of death, primarily in premature neonates, have been reported. Further, an increased incidence of kernicterus, especially in small, premature neonates has been reported. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. Premature neonates, neonates with a low birth weight, and patients who receive a high dose may be more likely to develop toxicity.

Benzyl alcohol hypersensitivity, corticosteroid hypersensitivity

True corticosteroid hypersensitivity reactions are rare. While a hypersensitivity reaction could be to a specific salt of the corticosteroid (i.e., hydrocortisone sodium succinate), patients who have demonstrated a prior hypersensitivity reaction to hydrocortisone should receive any form of hydrocortisone with extreme caution. It is possible, though also rare, that such patients will display cross-hypersensitivity to other corticosteroids; there have been reports that a cross-sensitivity between hydrocortisone and methylprednisolone may exist. Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy. It is advisable that patients who have a hypersensitivity reaction to any corticosteroid undergo skin testing, which, although not a conclusive predictor, may help to determine if hypersensitivity to another corticosteroid exists. Such patients should be carefully monitored during and following the administration of any corticosteroid. Some injectable formulations of hydrocortisone contain benzyl alcohol and should be used with caution in those patients with benzyl alcohol hypersensitivity. 

Cataracts, glaucoma, ocular exposure, ocular infection, ophthalmic administration, visual disturbance

Corticosteroids should be used cautiously in patients with glaucoma or any other visual disturbance. Corticosteroids are well known to cause cataracts and can exacerbate glaucoma during long-term administration. Patients receiving corticosteroids chronically should be periodically assessed for cataract formation. There is also an increase in the propensity for secondary ocular infection caused by fungal or viral infections. Care should be taken to avoid ocular exposure; ophthalmic administration of topical hydrocortisone preparations should be avoided. Visual impairment, ocular hypertension and worsened cataracts have been reported with ocular exposure to other high potency topical corticosteroids. Preexisting glaucoma may be aggravated if hydrocortisone is applied in the periorbital area.

Skin atrophy

Injection of hydrocortisone may result in dermal and/or subdermal changes forming depressions in the skin at the injection site. In order to minimize the incidence of subdermal and dermal atrophy, care must be exercised not to exceed recommended doses in injections. Injection into the deltoid muscle should be avoided because of a high incidence of subcutaneous atrophy. Topical corticosteroids, such as hydrocortisone, should be used for brief periods, or under close medical supervision in patients with evidence of pre-existing skin atrophy. Use of lower potency topical corticosteroids may be necessary in some patients, such as the elderly adult. Prolonged use of a topical corticosteroid, and the application of the steroid to thin areas of skin appear to increase the risk for atrophy.

Geriatric

Use systemic corticosteroids with caution in the geriatric patient; the risks and benefits of therapy should be considered for any individual patient. Reported clinical experience has not identified differences in responses between geriatric and younger adult patients. In general, dose selection for an elderly patient should be cautious; start at the lower end of the dosing range due to potential decreased hepatic, renal, cardiac function, or concomitant disease in geriatric patients. Prolonged systemic corticosteroid therapy, such as hydrocortisone, can lead to osteoporosis, vertebral compression fractures, aseptic necrosis of femoral and humoral heads, and pathologic fractures of long bones secondary to protein catabolism. Use cautiously in elderly or postmenopausal patients because they are especially susceptible to these adverse effects. A high-protein diet may alleviate or prevent the adverse effects associated with protein catabolism. Additionally, topical corticosteroids, such as hydrocortisone, should be used for brief periods, or under close medical supervision in patients with evidence of pre-existing skin atrophy. Elderly patients may be more likely to have preexisting skin atrophy secondary to aging. According to the Beers Criteria, systemic corticosteroids are considered potentially inappropriate medications (PIMs) for use in geriatric patients with delirium or at high risk for delirium and should be avoided in these patient populations due to the possibility of new-onset delirium or exacerbation of the current condition. The Beers expert panel notes that oral and parenteral corticosteroids may be required for conditions such as exacerbation of chronic obstructive pulmonary disease (COPD) but should be prescribed in the lowest effective dose and for the shortest possible duration. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities. According to the OBRA guidelines, the need for continued use of a glucocorticoid, with the exception of topical or inhaled formulations, should be documented, along with monitoring for and management of adverse consequences. Intermediate or longer-term use may cause hyperglycemia, psychosis, edema, insomnia, hypertension, osteoporosis, mood lability, or depression.

Epidural administration, intrathecal administration


Intrathecal administration of hydrocortisone sodium succinate injection is contraindicated. Severe medical events, including arachnoiditis, meningitis, paraparesis, paraplegia, and sensory disturbances, have been reported after intrathecal administration. Epidural lipomatosis has been reported with hydrocortisone sodium succinate injection. Epidural administration of corticosteroids should be used with great caution. Rare, but serious adverse reactions, including cortical blindness, stroke, spinal cord infarction, paralysis, seizures, nerve injury, brain edema, and death have been associated with epidural administration of injectable corticosteroids. These events have been reported with and without the use of fluoroscopy. Many cases were temporally associated with the corticosteroid injection; reactions occurred within minutes to 48 hours after injection. Some cases of neurologic events were confirmed through magnetic resonance imaging (MRI) or computed tomography (CT) scan. Many patients did not recover from the reported adverse effects. Discuss the benefits and risks of epidural corticosteroid injections with the patient before treatment. If a decision is made to proceed with corticosteroid epidural administration, counsel patients to seek emergency medical attention if they experience symptoms after injection such as vision changes, tingling in the arms or legs, dizziness, severe headache, seizures, or sudden weakness or numbness of face, arm, or leg.

Pheochromocytoma

Use hydrocortisone with caution in patients with diagnosed or suspected pheochromocytoma. Pheochromocytoma crisis, which can be fatal, has been reported after administration of systemic corticosteroids. Consider the risk of pheochromocytoma crisis prior to administering corticosteroids in any patients with suspected pheochromocytoma.

ADVERSE REACTIONS

Severe

exfoliative dermatitis / Delayed / Incidence not known
increased intracranial pressure / Early / Incidence not known
papilledema / Delayed / Incidence not known
tendon rupture / Delayed / Incidence not known
bone fractures / Delayed / Incidence not known
avascular necrosis / Delayed / Incidence not known
esophageal ulceration / Delayed / Incidence not known
GI perforation / Delayed / Incidence not known
pancreatitis / Delayed / Incidence not known
GI bleeding / Delayed / Incidence not known
peptic ulcer / Delayed / Incidence not known
skin atrophy / Delayed / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
lupus-like symptoms / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
heart failure / Delayed / Incidence not known
seizures / Delayed / Incidence not known
optic neuritis / Delayed / Incidence not known
retinopathy / Delayed / Incidence not known
visual impairment / Early / Incidence not known
ocular hypertension / Delayed / Incidence not known
cardiac arrest / Early / Incidence not known
thrombosis / Delayed / Incidence not known
pulmonary edema / Early / Incidence not known
stroke / Early / Incidence not known
bradycardia / Rapid / Incidence not known
vasculitis / Delayed / Incidence not known
cardiomyopathy / Delayed / Incidence not known
myocardial infarction / Delayed / Incidence not known
arrhythmia exacerbation / Early / Incidence not known
thromboembolism / Delayed / Incidence not known

Moderate

erythema / Early / 1.0-10.0
hypothalamic-pituitary-adrenal (HPA) suppression / Delayed / Incidence not known
hypotension / Rapid / Incidence not known
physiological dependence / Delayed / Incidence not known
pseudotumor cerebri / Delayed / Incidence not known
withdrawal / Early / Incidence not known
adrenocortical insufficiency / Delayed / Incidence not known
hypothyroidism / Delayed / Incidence not known
Cushing’s syndrome / Delayed / Incidence not known
hyperthyroidism / Delayed / Incidence not known
postmenopausal bleeding / Delayed / Incidence not known
osteopenia / Delayed / Incidence not known
myopathy / Delayed / Incidence not known
osteoporosis / Delayed / Incidence not known
constipation / Delayed / Incidence not known
gastritis / Delayed / Incidence not known
impaired wound healing / Delayed / Incidence not known
skin ulcer / Delayed / Incidence not known
candidiasis / Delayed / Incidence not known
neutropenia / Delayed / Incidence not known
immunosuppression / Delayed / Incidence not known
hypertension / Early / Incidence not known
hypokalemia / Delayed / Incidence not known
hypernatremia / Delayed / Incidence not known
hypocalcemia / Delayed / Incidence not known
metabolic alkalosis / Delayed / Incidence not known
edema / Delayed / Incidence not known
fluid retention / Delayed / Incidence not known
sodium retention / Delayed / Incidence not known
neuritis / Delayed / Incidence not known
psychosis / Early / Incidence not known
memory impairment / Delayed / Incidence not known
peripheral neuropathy / Delayed / Incidence not known
euphoria / Early / Incidence not known
mania / Early / Incidence not known
delirium / Early / Incidence not known
hallucinations / Early / Incidence not known
EEG changes / Delayed / Incidence not known
amnesia / Delayed / Incidence not known
depression / Delayed / Incidence not known
impaired cognition / Early / Incidence not known
exophthalmos / Delayed / Incidence not known
blurred vision / Early / Incidence not known
ocular infection / Delayed / Incidence not known
cataracts / Delayed / Incidence not known
glycosuria / Early / Incidence not known
hyperglycemia / Delayed / Incidence not known
diabetes mellitus / Delayed / Incidence not known
phlebitis / Rapid / Incidence not known
hypercholesterolemia / Delayed / Incidence not known
sinus tachycardia / Rapid / Incidence not known
palpitations / Early / Incidence not known
angina / Early / Incidence not known
tolerance / Delayed / Incidence not known
growth inhibition / Delayed / Incidence not known
hepatomegaly / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
contact dermatitis / Delayed / Incidence not known
anemia / Delayed / Incidence not known
glossitis / Early / Incidence not known

Mild

pruritus / Rapid / 1.0-10.0
maculopapular rash / Early / 1.0-10.0
xerosis / Delayed / 1.0-10.0
skin irritation / Early / 1.0-10.0
lethargy / Early / Incidence not known
fever / Early / Incidence not known
dysmenorrhea / Delayed / Incidence not known
amenorrhea / Delayed / Incidence not known
menstrual irregularity / Delayed / Incidence not known
arthralgia / Delayed / Incidence not known
myalgia / Early / Incidence not known
arthropathy / Delayed / Incidence not known
weakness / Early / Incidence not known
abdominal pain / Early / Incidence not known
appetite stimulation / Delayed / Incidence not known
nausea / Early / Incidence not known
weight gain / Delayed / Incidence not known
vomiting / Early / Incidence not known
hiccups / Early / Incidence not known
anorexia / Delayed / Incidence not known
weight loss / Delayed / Incidence not known
diarrhea / Early / Incidence not known
petechiae / Delayed / Incidence not known
urticaria / Rapid / Incidence not known
acne vulgaris / Delayed / Incidence not known
telangiectasia / Delayed / Incidence not known
folliculitis / Delayed / Incidence not known
alopecia / Delayed / Incidence not known
skin hyperpigmentation / Delayed / Incidence not known
acneiform rash / Delayed / Incidence not known
hypertrichosis / Delayed / Incidence not known
rash / Early / Incidence not known
miliaria / Delayed / Incidence not known
perineal pain / Early / Incidence not known
diaphoresis / Early / Incidence not known
striae / Delayed / Incidence not known
purpura / Delayed / Incidence not known
ecchymosis / Delayed / Incidence not known
hirsutism / Delayed / Incidence not known
injection site reaction / Rapid / Incidence not known
skin hypopigmentation / Delayed / Incidence not known
leukocytosis / Delayed / Incidence not known
infection / Delayed / Incidence not known
vertigo / Early / Incidence not known
restlessness / Early / Incidence not known
malaise / Early / Incidence not known
irritability / Delayed / Incidence not known
anxiety / Delayed / Incidence not known
headache / Early / Incidence not known
emotional lability / Early / Incidence not known
paresthesias / Delayed / Incidence not known
insomnia / Early / Incidence not known
syncope / Early / Incidence not known
dizziness / Early / Incidence not known

DRUG INTERACTIONS

Abatacept: (Moderate) Concomitant use of immunosuppressives, as well as long-term corticosteroids, may potentially increase the risk of serious infection in abatacept treated patients. Advise patients taking abatacept to seek immediate medical advice if they develop signs and symptoms suggestive of infection. 
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Salicylates or NSAIDs should be used cautiously in patients receiving corticosteroids. While there is controversy regarding the ulcerogenic potential of corticosteroids alone, concomitant administration of corticosteroids with aspirin may increase the GI toxicity of aspirin and other non-acetylated salicylates. Withdrawal of corticosteroids can result in increased plasma concentrations of salicylate and possible toxicity. Concomitant use of corticosteroids may increase the risk of adverse GI events due to NSAIDs. Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged coadministration should be avoided. 
Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Salicylates or NSAIDs should be used cautiously in patients receiving corticosteroids. While there is controversy regarding the ulcerogenic potential of corticosteroids alone, concomitant administration of corticosteroids with aspirin may increase the GI toxicity of aspirin and other non-acetylated salicylates. Withdrawal of corticosteroids can result in increased plasma concentrations of salicylate and possible toxicity. Concomitant use of corticosteroids may increase the risk of adverse GI events due to NSAIDs. Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged coadministration should be avoided. 
Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Salicylates or NSAIDs should be used cautiously in patients receiving corticosteroids. While there is controversy regarding the ulcerogenic potential of corticosteroids alone, concomitant administration of corticosteroids with aspirin may increase the GI toxicity of aspirin and other non-acetylated salicylates. Withdrawal of corticosteroids can result in increased plasma concentrations of salicylate and possible toxicity. Concomitant use of corticosteroids may increase the risk of adverse GI events due to NSAIDs. Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged coadministration should be avoided. 
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly. 
Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly. 
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly. 
Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly. 
Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly. 
Acetazolamide: (Moderate) Corticosteroids may increase the risk of hypokalemia if used concurrently with acetazolamide. Hypokalemia may be especially severe with prolonged use of corticotropin, ACTH. Monitor serum potassium levels to determine the need for potassium supplementation and/or alteration in drug therapy. 
Acetohexamide: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Adalimumab: (Moderate) Closely monitor for the development of signs and symptoms of infection if coadministration of a corticosteroid with adalimumab is necessary. Adalimumab treatment increases the risk for serious infections that may lead to hospitalization or death. Patients taking concomitant immunosuppressants including corticosteroids may be at greater risk of infection. 
Albiglutide: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Aldesleukin, IL-2: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
Alemtuzumab: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Alogliptin; Metformin: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Alpha-glucosidase Inhibitors: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Altretamine: (Minor) Concurrent use of altretamine with other agents which cause bone marrow or immune suppression such as corticosteroids may result in additive effects. 
Ambenonium Chloride: (Minor) Corticosteroids may interact with cholinesterase inhibitors including ambenonium, neostigmine, and pyridostigmine, occasionally causing severe muscle weakness in patients with myasthenia gravis. Glucocorticoids are occasionally used therapeutically, however, in the treatment of some patients with myasthenia gravis. In such patients, it is recommended that corticosteroid therapy be initiated at low dosages and with close clinical monitoring. The dosage should be increased gradually as tolerated, with continued careful monitoring of the patient’s clinical status. 
Amifampridine: (Moderate) Carefully consider the need for concomitant treatment with systemic corticosteroids and amifampridine, as coadministration may increase the risk of seizures. If coadministration occurs, closely monitor patients for seizure activity. Seizures have been observed in patients without a history of seizures taking amifampridine at recommended doses. Systemic corticosteroids may increase the risk of seizures in some patients. 
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Aminosalicylate sodium, Aminosalicylic acid: (Moderate) Salicylates or NSAIDs should be used cautiously in patients receiving corticosteroids. While there is controversy regarding the ulcerogenic potential of corticosteroids alone, concomitant administration of corticosteroids with aspirin may increase the GI toxicity of aspirin and other non-acetylated salicylates. Withdrawal of corticosteroids can result in increased plasma concentrations of salicylate and possible toxicity. Concomitant use of corticosteroids may increase the risk of adverse GI events due to NSAIDs. Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged coadministration should be avoided. 
Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Amoxicillin; Clarithromycin; Lansoprazole: (Moderate) Clarithromycin inhibits CYP3A4 and has the potential to result in increased plasma concentrations of corticosteroids. Therefore, the dose of corticosteroid should be titrated to avoid steroid toxicity. 
Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Clarithromycin inhibits CYP3A4 and has the potential to result in increased plasma concentrations of corticosteroids. Therefore, the dose of corticosteroid should be titrated to avoid steroid toxicity. 
Amphotericin B cholesteryl sulfate complex (ABCD): (Moderate) The potassium-wasting effects of corticosteroid therapy can be exacerbated by concomitant administration of other potassium-depleting drugs including amphotericin B. Serum potassium levels should be monitored in patients receiving these drugs concomitantly. 
Amphotericin B lipid complex (ABLC): (Moderate) The potassium-wasting effects of corticosteroid therapy can be exacerbated by concomitant administration of other potassium-depleting drugs including amphotericin B. Serum potassium levels should be monitored in patients receiving these drugs concomitantly. 
Amphotericin B liposomal (LAmB): (Moderate) The potassium-wasting effects of corticosteroid therapy can be exacerbated by concomitant administration of other potassium-depleting drugs including amphotericin B. Serum potassium levels should be monitored in patients receiving these drugs concomitantly. 
Amphotericin B: (Moderate) The potassium-wasting effects of corticosteroid therapy can be exacerbated by concomitant administration of other potassium-depleting drugs including amphotericin B. Serum potassium levels should be monitored in patients receiving these drugs concomitantly. 
Antithymocyte Globulin: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
Antitumor antibiotics: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
Argatroban: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together. 
Arsenic Trioxide: (Major) Because electrolyte abnormalities increase the risk of QT interval prolongation and serious arrhythmias, avoid the concomitant use of arsenic trioxide with drugs that may cause electrolyte abnormalities, particularly hypokalemia and hypomagnesemia. Examples of drugs that may cause electrolyte abnormalities include corticosteroids. If concomitant drug use is unavoidable, frequently monitor serum electrolytes (and replace as necessary) and electrocardiograms. 
Asparaginase Erwinia chrysanthemi: (Moderate) Concomitant use of L-asparaginase with corticosteroids can result in additive hyperglycemia. L-Asparaginase transiently inhibits insulin production contributing to hyperglycemia seen during concurrent corticosteroid therapy. Insulin therapy may be required in some cases. Administration of L-asparaginase after rather than before corticosteroids reportedly has produced fewer hypersensitivity reactions. 
Aspirin, ASA: (Moderate) Salicylates or NSAIDs should be used cautiously in patients receiving corticosteroids. While there is controversy regarding the ulcerogenic potential of corticosteroids alone, concomitant administration of corticosteroids with aspirin may increase the GI toxicity of aspirin and other non-acetylated salicylates. Withdrawal of corticosteroids can result in increased plasma concentrations of salicylate and possible toxicity. Concomitant use of corticosteroids may increase the risk of adverse GI events due to NSAIDs. Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged coadministration should be avoided. 
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Salicylates or NSAIDs should be used cautiously in patients receiving corticosteroids. While there is controversy regarding the ulcerogenic potential of corticosteroids alone, concomitant administration of corticosteroids with aspirin may increase the GI toxicity of aspirin and other non-acetylated salicylates. Withdrawal of corticosteroids can result in increased plasma concentrations of salicylate and possible toxicity. Concomitant use of corticosteroids may increase the risk of adverse GI events due to NSAIDs. Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged coadministration should be avoided. 
Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Salicylates or NSAIDs should be used cautiously in patients receiving corticosteroids. While there is controversy regarding the ulcerogenic potential of corticosteroids alone, concomitant administration of corticosteroids with aspirin may increase the GI toxicity of aspirin and other non-acetylated salicylates. Withdrawal of corticosteroids can result in increased plasma concentrations of salicylate and possible toxicity. Concomitant use of corticosteroids may increase the risk of adverse GI events due to NSAIDs. Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged coadministration should be avoided. 
Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Salicylates or NSAIDs should be used cautiously in patients receiving corticosteroids. While there is controversy regarding the ulcerogenic potential of corticosteroids alone, concomitant administration of corticosteroids with aspirin may increase the GI toxicity of aspirin and other non-acetylated salicylates. Withdrawal of corticosteroids can result in increased plasma concentrations of salicylate and possible toxicity. Concomitant use of corticosteroids may increase the risk of adverse GI events due to NSAIDs. Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged coadministration should be avoided. 
Aspirin, ASA; Carisoprodol: (Moderate) Salicylates or NSAIDs should be used cautiously in patients receiving corticosteroids. While there is controversy regarding the ulcerogenic potential of corticosteroids alone, concomitant administration of corticosteroids with aspirin may increase the GI toxicity of aspirin and other non-acetylated salicylates. Withdrawal of corticosteroids can result in increased plasma concentrations of salicylate and possible toxicity. Concomitant use of corticosteroids may increase the risk of adverse GI events due to NSAIDs. Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged coadministration should be avoided. 
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Salicylates or NSAIDs should be used cautiously in patients receiving corticosteroids. While there is controversy regarding the ulcerogenic potential of corticosteroids alone, concomitant administration of corticosteroids with aspirin may increase the GI toxicity of aspirin and other non-acetylated salicylates. Withdrawal of corticosteroids can result in increased plasma concentrations of salicylate and possible toxicity. Concomitant use of corticosteroids may increase the risk of adverse GI events due to NSAIDs. Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged coadministration should be avoided. 
Aspirin, ASA; Dipyridamole: (Moderate) Salicylates or NSAIDs should be used cautiously in patients receiving corticosteroids. While there is controversy regarding the ulcerogenic potential of corticosteroids alone, concomitant administration of corticosteroids with aspirin may increase the GI toxicity of aspirin and other non-acetylated salicylates. Withdrawal of corticosteroids can result in increased plasma concentrations of salicylate and possible toxicity. Concomitant use of corticosteroids may increase the risk of adverse GI events due to NSAIDs. Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged coadministration should be avoided. 
Aspirin, ASA; Omeprazole: (Moderate) Salicylates or NSAIDs should be used cautiously in patients receiving corticosteroids. While there is controversy regarding the ulcerogenic potential of corticosteroids alone, concomitant administration of corticosteroids with aspirin may increase the GI toxicity of aspirin and other non-acetylated salicylates. Withdrawal of corticosteroids can result in increased plasma concentrations of salicylate and possible toxicity. Concomitant use of corticosteroids may increase the risk of adverse GI events due to NSAIDs. Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged coadministration should be avoided. 
Aspirin, ASA; Oxycodone: (Moderate) Salicylates or NSAIDs should be used cautiously in patients receiving corticosteroids. While there is controversy regarding the ulcerogenic potential of corticosteroids alone, concomitant administration of corticosteroids with aspirin may increase the GI toxicity of aspirin and other non-acetylated salicylates. Withdrawal of corticosteroids can result in increased plasma concentrations of salicylate and possible toxicity. Concomitant use of corticosteroids may increase the risk of adverse GI events due to NSAIDs. Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged coadministration should be avoided. 
Aspirin, ASA; Pravastatin: (Moderate) Salicylates or NSAIDs should be used cautiously in patients receiving corticosteroids. While there is controversy regarding the ulcerogenic potential of corticosteroids alone, concomitant administration of corticosteroids with aspirin may increase the GI toxicity of aspirin and other non-acetylated salicylates. Withdrawal of corticosteroids can result in increased plasma concentrations of salicylate and possible toxicity. Concomitant use of corticosteroids may increase the risk of adverse GI events due to NSAIDs. Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged coadministration should be avoided. 
Atenolol; Chlorthalidone: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Atracurium: (Moderate) Caution and close monitoring are advised if corticosteroids and neuromuscular blockers are used together, particularly for long periods, due to enhanced neuromuscular blocking effects. In such patients, a peripheral nerve stimulator may be of value in monitoring the response. Concurrent use may increase the risk of acute myopathy. This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years. 
Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Salicylates or NSAIDs should be used cautiously in patients receiving corticosteroids. While there is controversy regarding the ulcerogenic potential of corticosteroids alone, concomitant administration of corticosteroids with aspirin may increase the GI toxicity of aspirin and other non-acetylated salicylates. Withdrawal of corticosteroids can result in increased plasma concentrations of salicylate and possible toxicity. Concomitant use of corticosteroids may increase the risk of adverse GI events due to NSAIDs. Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged coadministration should be avoided. 
Azathioprine: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
Azilsartan; Chlorthalidone: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Basiliximab: (Minor) Because systemically administered corticosteroids have immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives. 
Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Bendroflumethiazide; Nadolol: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Salicylates or NSAIDs should be used cautiously in patients receiving corticosteroids. While there is controversy regarding the ulcerogenic potential of corticosteroids alone, concomitant administration of corticosteroids with aspirin may increase the GI toxicity of aspirin and other non-acetylated salicylates. Withdrawal of corticosteroids can result in increased plasma concentrations of salicylate and possible toxicity. Concomitant use of corticosteroids may increase the risk of adverse GI events due to NSAIDs. Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged coadministration should be avoided. 
Bepridil: (Moderate) Hypokalemia-producing agents, including corticosteroids, may increase the risk of bepridil-induced arrhythmias and should therefore be administered cautiously in patients receiving bepridil therapy. 
Bevacizumab: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
Bismuth Subsalicylate: (Moderate) Salicylates or NSAIDs should be used cautiously in patients receiving corticosteroids. While there is controversy regarding the ulcerogenic potential of corticosteroids alone, concomitant administration of corticosteroids with aspirin may increase the GI toxicity of aspirin and other non-acetylated salicylates. Withdrawal of corticosteroids can result in increased plasma concentrations of salicylate and possible toxicity. Concomitant use of corticosteroids may increase the risk of adverse GI events due to NSAIDs. Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged coadministration should be avoided. 
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Salicylates or NSAIDs should be used cautiously in patients receiving corticosteroids. While there is controversy regarding the ulcerogenic potential of corticosteroids alone, concomitant administration of corticosteroids with aspirin may increase the GI toxicity of aspirin and other non-acetylated salicylates. Withdrawal of corticosteroids can result in increased plasma concentrations of salicylate and possible toxicity. Concomitant use of corticosteroids may increase the risk of adverse GI events due to NSAIDs. Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged coadministration should be avoided. 
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Bivalirudin: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together. 
Bortezomib: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly. 
Bupropion: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as systemic corticosteroids. The manufacturer recommends low initial dosing and slow dosage titration if these combinations must be used; the patient should be closely monitored. 
Bupropion; Naltrexone: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as systemic corticosteroids. The manufacturer recommends low initial dosing and slow dosage titration if these combinations must be used; the patient should be closely monitored. 
Calcium Carbonate: (Moderate) Calcium absorption is reduced when calcium carbonate is taken concomitantly with systemic corticosteroids. Systemic corticosteroids induce a negative calcium balance by inhibiting intestinal calcium absorption as well as by increasing renal calcium losses. The mechanism by which these drugs inhibit calcium absorption in the intestine is likely to involve a direct inhibition of absorptive cell function. 
Calcium Carbonate; Magnesium Hydroxide: (Moderate) Calcium absorption is reduced when calcium carbonate is taken concomitantly with systemic corticosteroids. Systemic corticosteroids induce a negative calcium balance by inhibiting intestinal calcium absorption as well as by increasing renal calcium losses. The mechanism by which these drugs inhibit calcium absorption in the intestine is likely to involve a direct inhibition of absorptive cell function. 
Calcium Carbonate; Risedronate: (Moderate) Calcium absorption is reduced when calcium carbonate is taken concomitantly with systemic corticosteroids. Systemic corticosteroids induce a negative calcium balance by inhibiting intestinal calcium absorption as well as by increasing renal calcium losses. The mechanism by which these drugs inhibit calcium absorption in the intestine is likely to involve a direct inhibition of absorptive cell function. 
Calcium Carbonate; Simethicone: (Moderate) Calcium absorption is reduced when calcium carbonate is taken concomitantly with systemic corticosteroids. Systemic corticosteroids induce a negative calcium balance by inhibiting intestinal calcium absorption as well as by increasing renal calcium losses. The mechanism by which these drugs inhibit calcium absorption in the intestine is likely to involve a direct inhibition of absorptive cell function. 
Canagliflozin: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Canagliflozin; Metformin: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly. 
Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly. 
Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly. 
Carbetapentane; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly. 
Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly. 
Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly. 
Carbinoxamine; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly. 
Carmustine, BCNU: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
Chlophedianol; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly. 
Chlorambucil: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
Chlorothiazide: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly. 
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly. 
Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly. 
Chlorpheniramine; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly. 
Chlorpropamide: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Chlorthalidone: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Chlorthalidone; Clonidine: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Cholestyramine: (Moderate) Cholestyramine has been shown to bind to hydrocortisone. To minimize drug interactions, the manufacturer recommends to administer other drugs at least 1 hour before or at least 4 to 6 hours after the administration of cholestyramine. 
Choline Salicylate; Magnesium Salicylate: (Moderate) Salicylates or NSAIDs should be used cautiously in patients receiving corticosteroids. While there is controversy regarding the ulcerogenic potential of corticosteroids alone, concomitant administration of corticosteroids with aspirin may increase the GI toxicity of aspirin and other non-acetylated salicylates. Withdrawal of corticosteroids can result in increased plasma concentrations of salicylate and possible toxicity. Concomitant use of corticosteroids may increase the risk of adverse GI events due to NSAIDs. Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged coadministration should be avoided. 
Cimetidine: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together. 
Cisatracurium: (Moderate) Caution and close monitoring are advised if corticosteroids and neuromuscular blockers are used together, particularly for long periods, due to enhanced neuromuscular blocking effects. In such patients, a peripheral nerve stimulator may be of value in monitoring the response. Concurrent use may increase the risk of acute myopathy. This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years. 
Citalopram: (Major) Citalopram causes dose-dependent QT interval prolongation. Concurrent use of citalopram and medications known to cause electrolyte imbalance may increase the risk of developing QT prolongation. Therefore, caution is advisable during concurrent use of citalopram and corticosteroids. It should be noted that CYP3A4 is one of the isoenzymes involved in the metabolism of citalopram, and dexamethasone is an inducer of this isoenzyme. In theory, decreased efficacy of citalopram is possible during combined use with dexamethasone; however, because citalopram is metabolized by multiple enzyme systems, induction of one pathway may not appreciably increase citalopram clearance. 
Clarithromycin: (Moderate) Clarithromycin inhibits CYP3A4 and has the potential to result in increased plasma concentrations of corticosteroids. Therefore, the dose of corticosteroid should be titrated to avoid steroid toxicity. 
Clindamycin: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together. 
Clofarabine: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
Cod Liver Oil: (Minor) A relationship of functional antagonism exists between vitamin D analogs, which promote calcium absorption, and corticosteroids, which inhibit calcium absorption. Therapeutic effect of cod liver oil should be monitored when used concomitantly with corticosteroids. 
Codeine; Phenylephrine; Promethazine: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly. 
Colestipol: (Moderate) The bile-acid sequestrant colestipol is well-known to cause drug interactions by binding and decreasing the oral administration of many drugs. Colestipol can bind with and possibly decrease the oral absorption of hydrocortisone. According to the manufacturer, administer other drugs at least 1 hour before or at least 4 to 6 hours after the administration of colestipol. 
Conivaptan: (Moderate) Conivaptan has been associated with hypokalemia (9.8%). Although not studied, consider the potential for additive hypokalemic effects if conivaptan is coadministered with drugs known to induce hypokalemia, such as corticosteroids. 
Cosyntropin: (Major) Patients receiving hydrocortisone should omit their pre-test doses on the day selected for testing. Patients taking inadvertent doses of hydrocortisone may exhibit abnormally high basal plasma cortisol concentrations and a decreased response to the test. A paradoxical decrease in plasma cortisol concentrations may be seen in patients receiving hydrocortisone following a stimulating dose of cosyntropin injection. 
Dapagliflozin: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Dapagliflozin; Metformin: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Dapagliflozin; Saxagliptin: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Denileukin Diftitox: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
Denosumab: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection. 
Desmopressin: (Major) Desmopressin, when used in the treatment of nocturia is contraindicated with corticosteroids because of the risk of severe hyponatremia. Desmopressin can be started or resumed 3 days or 5 half-lives after the corticosteroid is discontinued, whichever is longer. 
Dextran: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together. 
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly. 
Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly. 
Digoxin: (Moderate) Hypokalemia, hypomagnesemia, or hypercalcemia increase digoxin’s effect. Corticosteroids can precipitate digoxin toxicity via their effect on electrolyte balance. It is recommended that serum potassium, magnesium, and calcium be monitored regularly in patients receiving digoxin. 
Dipeptidyl Peptidase-4 Inhibitors: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly. 
Diphenhydramine; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly. 
Dofetilide: (Major) Corticosteroids can cause increases in blood pressure, sodium and water retention, and hypokalemia, predisposing patients to interactions with certain other medications. Corticosteroid-induced hypokalemia could also enhance the proarrhythmic effects of dofetilide. 
Doxacurium: (Moderate) Caution and close monitoring are advised if corticosteroids and neuromuscular blockers are used together, particularly for long periods, due to enhanced neuromuscular blocking effects. In such patients, a peripheral nerve stimulator may be of value in monitoring the response. Concurrent use may increase the risk of acute myopathy. This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years. 
Droperidol: (Moderate) Caution is advised when using droperidol in combination with corticosteroids which may lead to electrolyte abnormalities, especially hypokalemia or hypomagnesemia, as such abnormalities may increase the risk for QT prolongation or cardiac arrhythmias. 
Dulaglutide: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Echinacea: (Moderate) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to immunosuppressant drugs like corticosteroids. For some patients who are using corticosteroids for serious illness, such as cancer or organ transplant, this potential interaction may result in the preferable avoidance of Echinacea. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources. 
Econazole: (Minor) In vitro studies indicate that corticosteroids inhibit the antifungal activity of econazole against C. albicans in a concentration-dependent manner. When the concentration of the corticosteroid was equal to or greater than that of econazole on a weight basis, the antifungal activity of econazole was substantially inhibited. When the corticosteroid concentration was one-tenth that of econazole, no inhibition of antifungal activity was observed. 
Efalizumab: (Major) Patients receiving immunosuppressives should not receive concurrent therapy with efalizumab because of the possibility of increased infections and malignancies. 
Empagliflozin: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Empagliflozin; Linagliptin: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Empagliflozin; Metformin: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Ephedrine: (Moderate) Ephedrine may enhance the metabolic clearance of corticosteroids. Decreased blood concentrations and lessened physiologic activity may necessitate an increase in corticosteroid dosage. 
Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Erlotinib: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with hydrocortisone is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases; patients receiving concomitant hydrocortisone may be at increased risk. 
Ertugliflozin: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Ertugliflozin; Metformin: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Ertugliflozin; Sitagliptin: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Erythromycin: (Moderate) Erythromycin inhibits CYP3A4 and has the potential to result in increased plasma concentrations of corticosteroids. Therefore, the dose of corticosteroid should be titrated to avoid steroid toxicity.
Erythromycin; Sulfisoxazole: (Moderate) Erythromycin inhibits CYP3A4 and has the potential to result in increased plasma concentrations of corticosteroids. Therefore, the dose of corticosteroid should be titrated to avoid steroid toxicity. 
Eslicarbazepine: (Moderate) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Hydrocodone is metabolized by CYP3A4. Coadministration may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with eslicarbazepine. 
Estramustine: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
Estrogens: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together. 
Exenatide: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Fluconazole: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together. 
Fluoxymesterone: (Moderate) Coadministration of corticosteroids and fluoxymesterone may increase the risk of edema, especially in patients with underlying cardiac or hepatic disease. Corticosteroids with greater mineralocorticoid activity, such as fludrocortisone, may be more likely to cause edema. Administer these drugs in combination with caution. 
Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Gallium Ga 68 Dotatate: (Moderate) Corticosteroids may accentuate the electrolyte loss associated with diuretic therapy resulting in hypokalemia. Also, corticotropin may cause calcium loss and sodium and fluid retention. Mannitol itself can cause hypernatremia. Close monitoring of electrolytes should occur in patients receiving these drugs concomitantly. 
Gentamicin: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together. 
Glimepiride: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Glimepiride; Pioglitazone: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Glimepiride; Rosiglitazone: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Glipizide: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Glipizide; Metformin: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Glyburide: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Glyburide; Metformin: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Glycerol Phenylbutyrate: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely. 
Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly. 
Halofantrine: (Major) Due to the risks of cardiac toxicity of halofantrine in patients with hypokalemia and/or hypomagnesemia, the use of halofantrine should be avoided in combination with agents that may lead to electrolyte losses, such as corticosteroids. 
Haloperidol: (Major) QT prolongation has been observed during haloperidol treatment. Use of haloperidol and medications known to cause electrolyte imbalance may increase the risk of QT prolongation. Therefore, caution is advisable during concurrent use of haloperidol and corticosteroids. Topical corticosteroids are less likely to interact. 
Hemin: (Moderate) Hemin works by inhibiting aminolevulinic acid synthetase. Corticosteroids increase the activity of this enzyme should not be used with hemin. 
Heparin: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together. 
Hetastarch: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together. 
Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Hydrochlorothiazide, HCTZ: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Hydrochlorothiazide, HCTZ; Irbesartan: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Hydrochlorothiazide, HCTZ; Losartan: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. (Moderate) Patients receiving corticosteroids during propranolol therapy may be at increased risk of hypoglycemia due to the loss of counter-regulatory cortisol response. This effect may be more pronounced in infants and young children. If concurrent use is necessary, carefully monitor vital signs and blood glucose concentrations as clinically indicated. 
Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Hydrochlorothiazide, HCTZ; Spironolactone: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Hydrochlorothiazide, HCTZ; Telmisartan: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Hydrochlorothiazide, HCTZ; Triamterene: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Hydrocodone; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly. 
Hydroxyurea: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
Hylan G-F 20: (Major) The safety and efficacy of hylan G-F 20 given concomitantly with other intra-articular injectables have not been established. Other intra-articular injections may include intra-articular steroids (betamethasone, dexamethasone, hydrocortisone, prednisolone, methylprednisolone, and triamcinolone). 
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Salicylates or NSAIDs should be used cautiously in patients receiving corticosteroids. While there is controversy regarding the ulcerogenic potential of corticosteroids alone, concomitant administration of corticosteroids with aspirin may increase the GI toxicity of aspirin and other non-acetylated salicylates. Withdrawal of corticosteroids can result in increased plasma concentrations of salicylate and possible toxicity. Concomitant use of corticosteroids may increase the risk of adverse GI events due to NSAIDs. Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged coadministration should be avoided. (Moderate) Use sodium phosphate cautiously with corticosteroids, especially mineralocorticoids or corticotropin, ACTH, as concurrent use can cause hypernatremia. 
Ibritumomab Tiuxetan: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together. (Moderate) Use sodium phosphate cautiously with corticosteroids, especially mineralocorticoids or corticotropin, ACTH, as concurrent use can cause hypernatremia. (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
Incretin Mimetics: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Indapamide: (Moderate) Additive hypokalemia may occur when indapamide is coadministered with other drugs with a significant risk of hypokalemia such as systemic corticosteroids. Coadminister with caution and careful monitoring. 
Insulin Degludec; Liraglutide: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Insulin Glargine; Lixisenatide: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Insulins: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Interferon Alfa-2a: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
Interferon Alfa-2b: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
Interferon Alfa-2b; Ribavirin: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
Iohexol: (Major) Serious adverse events, including death, have been observed during intrathecal administration of both corticosteroids (i.e., hydrocortisone) and radiopaque contrast agents (i.e., iohexol); therefore, concurrent use of these medications via the intrathecal route is contraindicated. Cases of cortical blindness, stroke, spinal cord infarction, paralysis, seizures, nerve injury, brain edema, and death have been temporally associated (i.e., within minutes to 48 hours after injection) with epidural administration of injectable corticosteroids. In addition, patients inadvertently administered iohexol formulations not indicated for intrathecal use have experienced seizures, convulsions, cerebral hemorrhages, brain edema, and death. Administering these medications together via the intrathecal route may increase the risk for serious adverse events. 
Iopamidol: (Severe) Because both intrathecal corticosteroids (i.e., hydrocortisone) and intrathecal radiopaque contrast agents (i.e., iopamidoll) can increase the risk of seizures, the intrathecal administration of corticosteroids with intrathecal radiopaque contrast agents is contraindicated. 
Isoproterenol: (Moderate) The risk of cardiac toxicity with isoproterenol in asthma patients appears to be increased with the coadministration of corticosteroids. Intravenous infusions of isoproterenol in refractory asthmatic children at rates of 0.05 to 2.7 mcg/kg/min have caused clinical deterioration, myocardial infarction (necrosis), congestive heart failure and death. 
Isotretinoin: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution. 
L-Asparaginase Escherichia coli: (Moderate) Concomitant use of L-asparaginase with corticosteroids can result in additive hyperglycemia. L-Asparaginase transiently inhibits insulin production contributing to hyperglycemia seen during concurrent corticosteroid therapy. Insulin therapy may be required in some cases. Administration of L-asparaginase after rather than before corticosteroids reportedly has produced fewer hypersensitivity reactions. 
Levetiracetam: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together. 
Levomethadyl: (Major) Caution is advised when using levomethadyl in combination with other agents, such as corticosteroids, that may lead to electrolyte abnormalities, especially hypokalemia or hypomagnesemia. 
Linagliptin; Metformin: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Liraglutide: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Live Vaccines: (Severe) Live vaccines should generally not be administered to an immunosuppressed patient. Live vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system. The immunosuppressive effects of steroid treatment differ, but many clinicians consider a dose equivalent to either 2 mg/kg/day or 20 mg/day of prednisone as sufficiently immunosuppressive to raise concern about the safety of immunization with live vaccines. Patients on corticosteroid treatment for 2 weeks or more may be vaccinated after steroid therapy has been discontinued for at least 3 months in accordance with general recommendations for the use of live vaccines. The CDC has stated that discontinuation of steroids for 1 month prior to live vaccine administration may be sufficient. Live vaccines should not be given to individuals who are considered to be immunocompromised until more information is available. 
Lixisenatide: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Lomustine, CCNU: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
Loop diuretics: (Moderate) Corticosteroids may accentuate the electrolyte loss associated with diuretic therapy resulting in hypokalemia and/or hypomagnesemia. While glucocorticoids with mineralocorticoid activity (e.g., cortisone, hydrocortisone) can cause sodium and fluid retention. Close monitoring of electrolytes should occur in patients receiving these drugs concomitantly. 
Macimorelin: (Major) Avoid use of macimorelin with drugs that directly affect pituitary growth hormone secretion, such as corticosteroids. Healthcare providers are advised to discontinue corticosteroid therapy and observe a sufficient washout period before administering macimorelin. Use of these medications together may impact the accuracy of the macimorelin growth hormone test. 
Magnesium Salicylate: (Moderate) Salicylates or NSAIDs should be used cautiously in patients receiving corticosteroids. While there is controversy regarding the ulcerogenic potential of corticosteroids alone, concomitant administration of corticosteroids with aspirin may increase the GI toxicity of aspirin and other non-acetylated salicylates. Withdrawal of corticosteroids can result in increased plasma concentrations of salicylate and possible toxicity. Concomitant use of corticosteroids may increase the risk of adverse GI events due to NSAIDs. Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged coadministration should be avoided. 
Mannitol: (Moderate) Corticosteroids may accentuate the electrolyte loss associated with diuretic therapy resulting in hypokalemia. Also, corticotropin may cause calcium loss and sodium and fluid retention. Mannitol itself can cause hypernatremia. Close monitoring of electrolytes should occur in patients receiving these drugs concomitantly. 
Mecasermin rinfabate: (Moderate) Additional monitoring may be required when coadministering systemic or inhaled corticosteroids and mecasermin, recombinant, rh-IGF-1. In animal studies, corticosteroids impair the growth-stimulating effects of growth hormone (GH) through interference with the physiological stimulation of epiphyseal chondrocyte proliferation exerted by GH and IGF-1. Dexamethasone administration on long bone tissue in vitro resulted in a decrease of local synthesis of IGF-1. Similar counteractive effects are expected in humans. If systemic or inhaled glucocorticoid therapy is required, the steroid dose should be carefully adjusted and growth rate monitored. 
Mecasermin, Recombinant, rh-IGF-1: (Moderate) Additional monitoring may be required when coadministering systemic or inhaled corticosteroids and mecasermin, recombinant, rh-IGF-1. In animal studies, corticosteroids impair the growth-stimulating effects of growth hormone (GH) through interference with the physiological stimulation of epiphyseal chondrocyte proliferation exerted by GH and IGF-1. Dexamethasone administration on long bone tissue in vitro resulted in a decrease of local synthesis of IGF-1. Similar counteractive effects are expected in humans. If systemic or inhaled glucocorticoid therapy is required, the steroid dose should be carefully adjusted and growth rate monitored. 
Meglitinides: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Melphalan: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
Mepenzolate: (Minor) Anticholinergics, such as mepenzolate, antagonize the effects of antiglaucoma agents. Mepenzolate is contraindicated in patients with glaucoma and therefore should not be coadministered with medications being prescribed for the treatment of glaucoma. In addition, anticholinergic drugs taken concurrently with corticosteroids in the presence of increased intraocular pressure may be hazardous. 
Metformin: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Metformin; Pioglitazone: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Metformin; Repaglinide: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Metformin; Rosiglitazone: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Metformin; Saxagliptin: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Metformin; Sitagliptin: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Methazolamide: (Moderate) Corticosteroids may increase the risk of hypokalemia if used concurrently with methazolamide. Hypokalemia may be especially severe with prolonged use of corticotropin, ACTH. Monitor serum potassium levels to determine the need for potassium supplementation and/or alteration in drug therapy. The chronic use of corticosteroids may augment calcium excretion with methazolamide leading to increased risk for hypocalcemia and/or osteoporosis. 
Methenamine; Sodium Acid Phosphate: (Moderate) Use sodium phosphate cautiously with corticosteroids, especially mineralocorticoids or corticotropin, ACTH, as concurrent use can cause hypernatremia. 
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Moderate) Use sodium phosphate cautiously with corticosteroids, especially mineralocorticoids or corticotropin, ACTH, as concurrent use can cause hypernatremia. 
Methoxsalen: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
Methyclothiazide: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Metolazone: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Metyrapone: (Severe) Medications which affect pituitary or adrenocortical function, including all corticosteroid therapy, should be discontinued prior to and during testing with metyrapone. Patients taking inadvertent doses of corticosteroids on the test day may exhibit abnormally high basal plasma cortisol levels and a decreased response to the test. Although systemic absorption of topical corticosteroids is minimal, temporary discontinuation of these products should be considered if possible to reduce the potential for interference with the test results. 
Micafungin: (Moderate) Leukopenia, neutropenia, anemia, and thrombocytopenia have been associated with micafungin. Patients who are taking immunosuppressives such as the corticosteroids with micafungin concomitantly may have additive risks for infection or other side effects. In a pharmacokinetic trial, micafungin had no effect on the pharmacokinetics of prednisolone. Acute intravascular hemolysis and hemoglobinuria was seen in a healthy volunteer during infusion of micafungin (200 mg) and oral prednisolone (20 mg). This reaction was transient, and the subject did not develop significant anemia. 
Mifepristone: (Major) Mifepristone for termination of pregnancy is contraindicated in patients on long-term corticosteroid therapy and mifepristone for Cushing’s disease or other chronic conditions is contraindicated in patients who require concomitant treatment with systemic corticosteroids for life-saving purposes, such as serious medical conditions or illnesses (e.g., immunosuppression after organ transplantation). For other situations where corticosteroids are used for treating non-life threatening conditions, mifepristone may lead to reduced corticosteroid efficacy and exacerbation or deterioration of such conditions. This is because mifepristone exhibits antiglucocorticoid activity that may antagonize corticosteroid therapy and the stabilization of the underlying corticosteroid-treated illness. Mifepristone may also cause adrenal insufficiency, so patients receiving corticosteroids for non life-threatening illness require close monitoring. Because serum cortisol levels remain elevated and may even increase during treatment with mifepristone, serum cortisol levels do not provide an accurate assessment of hypoadrenalism. Patients should be closely monitored for signs and symptoms of adrenal insufficiency, If adrenal insufficiency occurs, stop mifepristone treatment and administer systemic glucocorticoids without delay; high doses may be needed to treat these events. Factors considered in deciding on the duration of glucocorticoid treatment should include the long half-life of mifepristone (85 hours). 
Mitotane: (Major) Because of increased glucocorticoid clearance, a higher dose of hydrocortisone (50 mg/day or more) may be needed for the treatment of adrenal insufficiency in patients treated with mitotane; some may require additional fludrocortisone. 
Mitoxantrone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
Mivacurium: (Moderate) Caution and close monitoring are advised if corticosteroids and neuromuscular blockers are used together, particularly for long periods, due to enhanced neuromuscular blocking effects. In such patients, a peripheral nerve stimulator may be of value in monitoring the response. Concurrent use may increase the risk of acute myopathy. This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years. 
Moxifloxacin: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together. 
Muromonab-CD3: (Major) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk for the development of severe infections. Close clinical monitoring is advised with concurrent use; in the presence of serious infections, continuation of the corticosteroid or immunosuppressive agent may be necessary but should be accompanied by appropriate antimicrobial therapies as indicated. 
Natalizumab: (Major) Ordinarily, patients receiving chronic immunosuppressant therapy should not be treated with natalizumab. Treatment recommendations for combined corticosteroid therapy are dependent on the underlying indication for natalizumab therapy. Corticosteroids should be tapered in those patients with Crohn’s disease who are on chronic corticosteroids when they start natalizumab therapy, as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within 6 months, discontinue natalizumab. The concomitant use of natalizumab and corticosteroids may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy, over the risk observed with use of natalizumab alone. In multiple sclerosis (MS) clinical trials, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in natalizumab-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids. Short courses of steroid use during natalizumab, such as when they are needed for MS relapse treatment, appear to be acceptable for use concurrently. 
Nateglinide: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Nelarabine: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
Neostigmine: (Minor) Corticosteroids may interact with cholinesterase inhibitors including ambenonium, neostigmine, and pyridostigmine, occasionally causing severe muscle weakness in patients with myasthenia gravis. Glucocorticoids are occasionally used therapeutically, however, in the treatment of some patients with myasthenia gravis. In such patients, it is recommended that corticosteroid therapy be initiated at low dosages and with close clinical monitoring. The dosage should be increased gradually as tolerated, with continued careful monitoring of the patient’s clinical status. 
Neuromuscular blockers: (Moderate) Caution and close monitoring are advised if corticosteroids and neuromuscular blockers are used together, particularly for long periods, due to enhanced neuromuscular blocking effects. In such patients, a peripheral nerve stimulator may be of value in monitoring the response. Concurrent use may increase the risk of acute myopathy. This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years. 
Nonsteroidal antiinflammatory drugs: (Moderate) Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged concomitant administration should be avoided. Concomitant use of corticosteroids appears to increase the risk of adverse GI events due to NSAIDs. Corticosteroids can have profound effects on sodium-potassium balance; NSAIDs also can affect sodium and fluid balance. Monitor serum potassium concentrations; potassium supplementation may be necessary. In addition, NSAIDs may mask fever, pain, swelling and other signs and symptoms of an infection; use NSAIDs with caution in patients receiving immunosuppressant dosages of corticosteroids. The Beers criteria recommends that this drug combination be avoided in older adults; if coadministration cannot be avoided, provide gastrointestinal protection. 
Ocrelizumab: (Moderate) Ocrelizumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids. Concomitant use of ocrelizumab with any of these therapies may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection. 
Ondansetron: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together. 
Oxymetholone: (Moderate) Concomitant use of oxymetholone with corticosteroids or corticotropin, ACTH may cause increased edema. Manage edema with diuretic and/or digitalis therapy. 
Pancuronium: (Moderate) Caution and close monitoring are advised if corticosteroids and neuromuscular blockers are used together, particularly for long periods, due to enhanced neuromuscular blocking effects. In such patients, a peripheral nerve stimulator may be of value in monitoring the response. Concurrent use may increase the risk of acute myopathy. This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years. 
Pegaspargase: (Moderate) Concomitant use of pegaspargase with corticosteroids can result in additive hyperglycemia. Insulin therapy may be required in some cases. 
Penicillamine: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity. 
Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly. 
Phenylephrine; Promethazine: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly. 
Photosensitizing agents: (Minor) Corticosteroids administered systemically prior to or concomitantly with photosensitizing agents may decrease the efficacy of photodynamic therapy. 
Physostigmine: (Minor) Corticosteroids may interact with cholinesterase inhibitors, occasionally causing severe muscle weakness in patients with myasthenia gravis. Glucocorticoids are occasionally used therapeutically, however, in the treatment of some patients with myasthenia gravis. In such patients, it is recommended that corticosteroid therapy be initiated at low dosages and with close clinical monitoring. The dosage should be increased gradually as tolerated, with continued careful monitoring of the patient’s clinical status. 
Pimozide: (Moderate) According to the manufacturer of pimozide, the drug should not be coadministered with drugs known to cause electrolyte imbalances, such as high-dose, systemic corticosteroid therapy. Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP), and electrolyte imbalances (e.g., hypokalemia, hypocalcemia, hypomagnesemia) may increase the risk of life-threatening arrhythmias. Pimozide is contraindicated in patients with known hypokalemia or hypomagnesemia. Topical corticosteroids are less likely to interact. 
Potassium Chloride: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together. 
Potassium Phosphate; Sodium Phosphate: (Moderate) Use sodium phosphate cautiously with corticosteroids, especially mineralocorticoids or corticotropin, ACTH, as concurrent use can cause hypernatremia. 
Potassium: (Moderate) Corticotropin can cause alterations in serum potassium levels. The use of potassium salts or supplements would be expected to alter the effects of corticotropin on serum potassium levels. Also, there have been reports of generalized tonic-clonic seizures and/or loss of consciousness associated with use of bowel preparation products in patients with no prior history of seizure disorder. Therefore, magnesium sulfate; potassium sulfate; sodium sulfate should be administered with caution during concurrent use of medications that lower the seizure threshold such as systemic corticosteroids. 
Potassium-sparing diuretics: (Minor) The manufacturer of spironolactone lists corticosteroids as a potential drug that interacts with spironolactone. Intensified electrolyte depletion, particularly hypokalemia, may occur. However, potassium-sparing diuretics such as spironolactone do not induce hypokalemia. In fact, hypokalemia is one of the indications for potassium-sparing diuretic therapy. Therefore, drugs that induce potassium loss, such as corticosteroids, could counter the hyperkalemic effects of potassium-sparing diuretics. 
Pramlintide: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Moderate) Corticosteroids blunt the adrenal secretion of endogenous DHEA and DHEAS, resulting in reduced DHEA and DHEAS serum concentrations. 
Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Moderate) Corticosteroids blunt the adrenal secretion of endogenous DHEA and DHEAS, resulting in reduced DHEA and DHEAS serum concentrations. 
Propranolol: (Moderate) Patients receiving corticosteroids during propranolol therapy may be at increased risk of hypoglycemia due to the loss of counter-regulatory cortisol response. This effect may be more pronounced in infants and young children. If concurrent use is necessary, carefully monitor vital signs and blood glucose concentrations as clinically indicated. 
Purine analogs: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects. 
Pyridostigmine: (Minor) Corticosteroids may interact with cholinesterase inhibitors including ambenonium, neostigmine, and pyridostigmine, occasionally causing severe muscle weakness in patients with myasthenia gravis. Glucocorticoids are occasionally used therapeutically, however, in the treatment of some patients with myasthenia gravis. In such patients, it is recommended that corticosteroid therapy be initiated at low dosages and with close clinical monitoring. The dosage should be increased gradually as tolerated, with continued careful monitoring of the patient’s clinical status. 
Quetiapine: (Major) QT prolongation has occurred during concurrent use of quetiapine and medications known to cause electrolyte imbalance. Therefore, caution is advisable during concurrent use of quetiapine and corticosteroids. 
Rapacuronium: (Moderate) Caution and close monitoring are advised if corticosteroids and neuromuscular blockers are used together, particularly for long periods, due to enhanced neuromuscular blocking effects. In such patients, a peripheral nerve stimulator may be of value in monitoring the response. Concurrent use may increase the risk of acute myopathy. This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years. 
Repaglinide: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Ritodrine: (Major) Ritodrine has caused maternal pulmonary edema, which appears more often in patients treated concomitantly with corticosteroids. Patients so treated should be closely monitored in the hospital. 
Rituximab: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy. 
Rituximab; Hyaluronidase: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy. 
Rocuronium: (Moderate) Caution and close monitoring are advised if corticosteroids and neuromuscular blockers are used together, particularly for long periods, due to enhanced neuromuscular blocking effects. In such patients, a peripheral nerve stimulator may be of value in monitoring the response. Concurrent use may increase the risk of acute myopathy. This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years. 
Salicylates: (Moderate) Salicylates or NSAIDs should be used cautiously in patients receiving corticosteroids. While there is controversy regarding the ulcerogenic potential of corticosteroids alone, concomitant administration of corticosteroids with aspirin may increase the GI toxicity of aspirin and other non-acetylated salicylates. Withdrawal of corticosteroids can result in increased plasma concentrations of salicylate and possible toxicity. Concomitant use of corticosteroids may increase the risk of adverse GI events due to NSAIDs. Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged coadministration should be avoided. 
Salsalate: (Moderate) Salicylates or NSAIDs should be used cautiously in patients receiving corticosteroids. While there is controversy regarding the ulcerogenic potential of corticosteroids alone, concomitant administration of corticosteroids with aspirin may increase the GI toxicity of aspirin and other non-acetylated salicylates. Withdrawal of corticosteroids can result in increased plasma concentrations of salicylate and possible toxicity. Concomitant use of corticosteroids may increase the risk of adverse GI events due to NSAIDs. Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged coadministration should be avoided. 
Sargramostim, GM-CSF: (Major) Avoid the concomitant use of sargramostim and systemic corticosteroid agents due to the risk of additive myeloproliferative effects. If coadministration of these drugs is required, frequently monitor patients for clinical and laboratory signs of excess myeloproliferative effects (e.g., leukocytosis). Sargramostim is a recombinant human granulocyte-macrophage colony-stimulating factor that works by promoting proliferation and differentiation of hematopoietic progenitor cells. 
Semaglutide: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
SGLT2 Inhibitors: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Sodium Benzoate; Sodium Phenylacetate: (Moderate) Corticosteroids may cause protein breakdown, which could lead to elevated blood ammonia concentrations, especially in patients with an impaired ability to form urea. Corticosteroids should be used with caution in patients receiving treatment for hyperammonemia. 
Sodium Chloride: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together. 
Sodium Phenylbutyrate: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids. 
Sodium Phosphate Monobasic Monohydrate; Sodium Phosphate Dibasic Anhydrous: (Moderate) Use sodium phosphate cautiously with corticosteroids, especially mineralocorticoids or corticotropin, ACTH, as concurrent use can cause hypernatremia. 
Somatropin, rh-GH: (Moderate) Corticosteroids can retard bone growth and therefore, can inhibit the growth-promoting effects of somatropin. If corticosteroid therapy is required, the corticosteroid dose should be carefully adjusted. 
Succinylcholine: (Moderate) Caution and close monitoring are advised if corticosteroids and neuromuscular blockers are used together, particularly for long periods, due to enhanced neuromuscular blocking effects. In such patients, a peripheral nerve stimulator may be of value in monitoring the response. Concurrent use may increase the risk of acute myopathy. This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years. 
Sulfonylureas: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Telbivudine: (Moderate) The risk of myopathy may be increased if corticosteroids are coadministered with telbivudine. Monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration. 
Testosterone: (Moderate) Coadministration of corticosteroids and testosterone may increase the risk of edema, especially in patients with underlying cardiac or hepatic disease. Corticosteroids with greater mineralocorticoid activity, such as fludrocortisone, may be more likely to cause edema. Administer these drugs in combination with caution. 
Thiazide diuretics: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required. 
Thiazolidinediones: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Thyroid hormones: (Moderate) The metabolism of corticosteroids is increased in hyperthyroidism and decreased in hypothyroidism. Dosage adjustments may be necessary when initiating, changing or discontinuing thyroid hormones or antithyroid agents. 
Tobramycin: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together. 
Tocilizumab: (Moderate) Closely observe patients for signs of infection. Most patients taking tocilizumab who developed serious infections were taking concomitant immunosuppressives such as systemic corticosteroids. 
Tolazamide: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Tolbutamide: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. 
Tositumomab: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
Tretinoin, ATRA: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. 
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy. 
Tubocurarine: (Moderate) Caution and close monitoring are advised if corticosteroids and neuromuscular blockers are used together, particularly for long periods, due to enhanced neuromuscular blocking effects. In such patients, a peripheral nerve stimulator may be of value in monitoring the response. Concurrent use may increase the risk of acute myopathy. This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years. 
Vancomycin: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together. 
Vecuronium: (Moderate) Caution and close monitoring are advised if corticosteroids and neuromuscular blockers are used together, particularly for long periods, due to enhanced neuromuscular blocking effects. In such patients, a peripheral nerve stimulator may be of value in monitoring the response. Concurrent use may increase the risk of acute myopathy. This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years. 
Vigabatrin: (Major) Vigabatrin should not be used with corticosteroids, which are associated with serious ophthalmic effects (e.g., retinopathy or glaucoma) unless the benefit of treatment clearly outweighs the risks. 
Vinblastine: (Minor) Use caution when administering vinblastine concurrently with a CYP3A4 inducer such as dexamethasone. Vinblastine is metabolized by CYP3A4 and dexamethasone may decrease vinblastine plasma concentrations. In addition, because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with antineoplastic agents. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk for the development of severe infections. Close clinical monitoring is advised with concurrent use; in the presence of serious infections, continuation of the corticosteroid or immunosuppressive agent may be necessary but should be accompanied by appropriate antimicrobial therapies as indicated. 
Vincristine Liposomal: (Moderate) Use sodium phosphate cautiously with corticosteroids, especially mineralocorticoids or corticotropin, ACTH, as concurrent use can cause hypernatremia. 
Voriconazole: (Minor) Voriconazole is an inhibitor of the hepatic CYP3A4 isoenzyme and hydrocortisone is a substrate for CYP3A4. Theoretically, reduced metabolism of hydrocortisone might occur when voriconazole is co-administered. The clinical impact of this potential interaction is not certain. 
Vorinostat: (Moderate) Use vorinostat and corticosteroids together with caution; the risk of QT prolongation and arrhythmias may be increased if electrolyte abnormalities occur. Corticosteroids may cause electrolyte imbalances; hypomagnesemia, hypokalemia, or hypocalcemia and may increase the risk of QT prolongation with vorinostat. Frequently monitor serum electrolytes if concomitant use of these drugs is necessary. 
Warfarin: (Moderate) The effect of corticosteroids on oral anticoagulants (e.g., warfarin) is variable. There are reports of enhanced as well as diminished effects of anticoagulants when given concurrently with corticosteroids; however, limited published data exist, and the mechanism of the interaction is not well described. High-dose corticosteroids appear to pose a greater risk for increased anticoagulant effect. In addition, corticosteroids have been associated with a risk of peptic ulcer and gastrointestinal bleeding. Thus corticosteroids should be used cautiously and with appropriate clinical monitoring in patients receiving oral anticoagulants; coagulation indices (e.g., INR, etc.) should be monitored to maintain the desired anticoagulant effect. During high-dose corticosteroid administration, daily laboratory monitoring may be desirable. 
Zafirlukast: (Minor) Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as corticosteroids. 
Zileuton: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Although administration of zileuton with other drugs metabolized by CYP3A4 has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates. 

PREGNANCY AND LACTATION

Pregnancy

Systemic and rectal preparations of hydrocortisone must be used with caution during human pregnancy. Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Complications, including cleft palate, stillbirth, and premature abortion, have been reported during animal studies. If hydrocortisone must be used during pregnancy, the potential risks should be discussed with the patient. However, insufficient treatment of an underlying condition (e.g., Addison’s disease) during pregnancy is also associated with fetal and maternal risks and the mother may require additional monitoring to ensure adequate replacement during pregnancy and in the post-partum period as requirements return to pre-pregnancy levels. Infants born to mothers who have taken substantial doses of corticosteroids during pregnancy should be monitored for signs of hypoadrenalism. Topical application of hydrocortisone warrants caution during pregnancy as there are no adequate and well-controlled studies. Topical corticosteroids should not be used in large amounts, on large areas, or for prolonged periods of time in pregnant women. Guidelines recommend mild to moderate potency agents, such as topical hydrocortisone, over potent topical corticosteroids, which should be used in short durations. Fetal growth restriction and a significantly increased risk of low birthweight has been reported with use of potent or very potent topical corticosteroids during the third trimester, particularly when using more than 300 grams. Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. Systemic corticosteroids have been shown to impair fertility in male rats; the impact to human male fertility is not certain. 

The use of systemic and rectal hydrocortisone has not been studied during breast-feeding; however cortisol is a normal component of breast milk. Other corticosteroids (prednisone and prednisolone) are usually considered compatible with breast-feeding. It is not known whether topical administration of desonide could result in sufficient systemic absorption to produce detectable quantities in breast milk. However, most dermatologists stress that topical corticosteroids can be safely used during lactation and breast-feeding. If applied topically, care should be used to ensure the infant will not come into direct contact with the area of application, such as the breast. Increased blood pressure has been reported in an infant whose mother applied a high potency topical corticosteroid ointment directly to the nipples. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

MECHANISM OF ACTION

Endogenous corticosteroids are secreted by the adrenal cortex, and their effects are believed to be due to enzyme modification rather than to a direct hormone-induced action. Corticosteroids are loosely classified into two categories, mineralocorticoids and glucocorticoids, depending on their primary pharmacological activity. Mineralocorticoids alter electrolyte and fluid balance by facilitating sodium resorption and hydrogen and potassium excretion at the level of the distal renal tubule, resulting in edema and hypertension. Glucocorticoids exert some mineralocorticoid effects but are also involved in a number of other metabolic pathways including gluconeogenesis, fat redistribution, protein metabolism, and calcium balance. Hydrocortisone possesses both mineralocorticoid actions and glucocorticoid actions.
 
Corticosteroids exhibit anti-inflammatory, antipruritic, and vasoconstrictive properties. At the cellular level, corticosteroids induce peptides called lipocortins. Lipocortins antagonize phospholipase A2, an enzyme which causes the breakdown of leukocyte lysosomal membranes to release arachidonic acid. This action decreases the subsequent formation and release of endogenous inflammatory mediators including prostaglandins, kinins, histamine, liposomal enzymes and the complement system.
 
Early anti-inflammatory effects of topical corticosteroids include the inhibition of macrophage and leukocyte movement and activity in the inflamed area by reversing vascular dilation and permeability. Later inflammatory processes such as capillary production, collagen deposition, keloid (scar) formation also are inhibited by corticosteroids. Clinically, these actions correspond to decreased edema, erythema, pruritus, plaque formation and scaling of the affected skin.
 
In the treatment of asthma, corticosteroids block the late phase allergic response to allergens. Mediators involved in the pathogenesis of asthma include histamine, leukotrienes (slow releasing substance of anaphylaxis, SRS-A), eosinophil chemotactic factor of anaphylaxis (ECF-A), neutrophil chemotactic factor (NCF), cytokines, hydroxyeicosatetraenoic acids, prostaglandin-generating factor of anaphylaxis (PGF-A), prostaglandins, major basic protein, bradykinin, adenosine, peroxides, and superoxide anions. Different cell types are responsible for release of these mediators including airway epithelium, eosinophils, basophils, lung parenchyma, lymphocytes, macrophages, mast cells, neutrophils, and platelets. Corticosteroids inhibit the release of these mediators as well as inhibit IgE synthesis, attenuate mucous secretion and eicosanoid generation, up-regulate beta-receptors, promote vasoconstriction, and suppress inflammatory cell influx and inflammatory processes. Clinical effects in asthma include a reduction in bronchial hyperresponsiveness to allergens, a decreased number of asthma exacerbations, and an improvement in FEV1, peak-flow rate, and respiratory symptoms. Since corticosteroid effects take several hours to days to become clinically noticeable, they are ineffective for primary treatment of severe acute bronchospastic attacks or for status asthmaticus. Inhaled corticosteroids have no bronchodilatory properties.

PHARMACOKINETICS

Hydrocortisone is administered via oral, parenteral, topical, and rectal routes. Circulating drug binds extensively to plasma proteins, and only the unbound portion of a dose is active. Systemic hydrocortisone is quickly distributed into the kidneys, intestines, skin, liver, and muscle. Corticosteroids distribute into breast milk and cross the placenta. Systemic hydrocortisone is metabolized by the liver to inactive metabolites. These inactive metabolites, as well as a small portion of unchanged drug, are excreted in the urine. The biological half-life of hydrocortisone is 8 to 12 hours.
 
Affected cytochrome P450 (CYP450)isoenzymes and drug transporters: None

Oral Route

Hydrocortisone is rapidly absorbed after an oral dose; peak effects occur within 1 to 2 hours.

Intravenous Route

Peak effects of hydrocortisone after intravenous administration occur within 1 to 2 hours.

Intramuscular Route

After intramuscular administration of hydrocortisone, the onset and duration of action depend on the type of injection and the extent of the local blood supply.

Topical Route

Systemic absorption after topical application of hydrocortisone is dependant on the vehicle, the state of the skin at the application site, the use of occlusive dressings, and the age of the patient. Absorption is increased in areas that have skin damage, inflammation, or occlusion, or where the stratum corneum is thin such as the eyelids, genitalia, and face. Factors that can increase systemic absorption of topical hydrocortisone include occlusive dressings, large surface area, frequent application, longer duration of treatment, increased humidity or temperature, and younger age. Topical preparations distribute throughout the area of application but are only minimally absorbed into the circulation. Topical preparations of hydrocortisone are metabolized in the skin.

Other Route(s)

Rectal Route
When a suppository containing hydrocortisone acetate is administered rectally, about 26% of a dose is absorbed in normal subjects; absorption may vary across abraded or inflamed surfaces. Hydrocortisone rectal suspension is partially absorbed after rectal administration. In patients with ulcerative colitis, up to 50% of hydrocortisone was absorbed when administered as the rectal suspension.
 
Intra-articular Route
The onset and duration of action depend on type of hydrocortisone injection and the extent of the local blood supply.

SUMMARY OF FINASTERIDE SIDE EFFECS:

FINASTERIDE
All se dw pt including but not limited to hypersensitivity reaction (allergic reaction), angioedema, prostate cancer (high-grade), breast cancer, male infertility, Impotence, loss in sexual ability, desire, drive, or performance, decrease libido, hypotension, abnormal ejaculation, sexual dysfunction, loss of interest in sex, or trouble having an orgasm, erectile dysfunction, decrease volume of ejaculate, tenderness in genital organs, testicular pain, infertility, poor seminal quality, poor sperm mobility, gynecomastia (enlarge breast tissue), swelling in your face, throat hands or feet, swelling or tenderness in your breasts, lump under the arms or in the breast area, change in shape of penis, dizziness, weakness, feeling like you might pass out, headache, confusion, runny nose, sleepiness or unusual drowsiness, sneezing, stuffy nose, abdominal/stomach pain, back pain, decreased amount of semen, diarrhea, hives or welts, itchy skin, rapid weight gain, redness of the skin, skin rash, swelling of the lips and face, tingling of the hands or feet, unusual weight gain or loss, breast cancer in males and females, depression, lower testosterone, and shrinkage of sexual organs. All sexual side effects may be long-term (permanent). Patient can not share the medication with any female. Females of childbearing age can not take this medication, as it is a Category X. Impotence, loss in sexual ability, desire, drive, or performance, decrease libido, hypotension, abnormal ejaculation, sexual dysfunction, loss of interest in sex, or trouble having an orgasm, erectile dysfunction, decrease volume of ejaculate, tenderness in genital organs, testicular pain, infertility, poor seminal quality, poor sperm mobility, gynecomastia (enlarge breast tissue), swelling in your face, throat hands or feet, swelling or tenderness in your breasts, lump under the arms or in the breast area, change in shape of penis, dizziness, weakness, feeling like you might pass out, headache, confusion, brain fog, fogginess of the head, short-term and long-term memory loss, terrible fatigue, trouble concentrating, increasingly moody, depression, runny nose, sleepiness or unusual drowsiness, sneezing, stuffy nose, abdominal/stomach pain, back pain, decreased amount of semen, diarrhea, hives or welts, itchy skin, rapid weight gain, redness of the skin, skin rash, swelling of the lips and face, tingling of the hands or feet, unusual weight gain or loss, , depression, lower testosterone, complete loss of testosterone, breast cancer, post-finasteride syndrome (www.pfsfoundation.org/about-pfs-post-finasteride-syndrome/), and shrinkage of sexual organs. All sexual side effects may be long-term (permanent). There may also be other side effects that may occur that have not been listed. 

FEMALE PATIENTS: If you are female and take this medication, you understand all the risks and are aware that this is an off label use of the drug. You take the medication at your own risk and you understand not to get pregnant. You must use two forms of contraception, both birth control and condoms. There is an increased risk of breast cancer (see below). 

How common are sexual dysfunctions? Summary of clinical trials
Meta-Analysis Study of sexual side effects
Trial Name # Men In the Study: Decrease Libido | Erectile Dysfunction | Sexual Dysfunction
Meta Analysis * 10 trials, 6,779 | 1.16 | 0.66 |1.21
* Meta Analysis study Effect of 5 Alpha-Reductase Inhibitors on Sexual Dysfunction: A Meta Analysis

Drug-Related Adverse Experiences for PROPECIA (finasteride 1 mg) in Year 1 (%) MALE PATTERN HAIR LOSS** 
Decrease Libido | Erectile Dysfunction | Ejaculation Disorder
Propecia Group (n=945) 1.8 | 1.3 | 1.2
Placebo Group (n=934) 1.3 | 0.7 | 0.7
**Source: (Table 1, http://www.rxlist.com/propecia-drug.htm)

Risk breast cancer: Summary of clinical Trials
TRIAL NAME # MEN IN THE STUDY| PROSCAR GROUP | PLACEBO GROUP
PCPT 18,882 | 1 | 1
MTOPS 3,047 | 4 | 0
PLESS 3,040 | 0 | 2


Changes to Finasteride Labeling by the FDA (April 2012)
-April 2012, the FDA changed the professional label for Propecia, Finasteride and Proscar.
-New labeling states “Reproductive System: Sexual dysfunction that continued after discontinuation of treatment has been reported after discontinuation of finasteride. ” Labeling change was “based on a review of 421 post-marketing cases from 19998-2011, or about 7 million patient years of drug exposure, of which 59 reported persistent sexual dysfunction.” Dr Epstein, past chairman of International Society of Hair Restoration Surgery states “it is not fully understood yet if finasteride leads to permanent sexual side effects.

This is written for full transparency about the possibility of the side effects of propecia (finasteride, Proscar), some of which may be long term, and that you are fully informed about the above side effects. Our goal is to empower our patients to make educated decisions about their treatment choices. The above is not a complete list of all side effects or studies conducted.

——————————–PLEASE NOTE BELOW ——————————————————–

TOPICAL FINASTERIDE IS A COMPOUNDED FORMULA. FINASTERIDE IS AN FDA APPROVED DRUG HOWEVER THE TOPICAL VERSION IS AN OFF LABEL USE OF AN FDA APPROVED MEDICATION. YOU UNDERSTAND AND AGREE THAT THE TOPICAL VERSION OF FINASTERIDE IS OFF LABEL USE AND THE SAFETY AND EFFICACY OF TOPICAL FINASTERIDE HAS NOT BEEN TESTED IN ANY CLINICAL TRIALS OR VALIDATED BY THE FDA. YOU ARE USING THE TOPICAL FINASTERIDE AT YOUR OWN RISK. IN ADDITION, THE COMBINATION OF TOPICAL FINASTERIDE MIXED WITH TOPICAL MINOXIDIL AND TOPICAL RETINOINC ACID HAS NOT BEEN TESTED IN ANY CLINICAL TRIALS OR VALIDATED OR APPROVED BY THE FDA. THESE ARE ALL FDA APPROVED MEDICATIONS AND ARE BEING COMPOUNDED FOR YOU AND THE COMBINATIONS OF THESE FDA APPROVED MEDICATIONS IS AN OFF LABEL USE OF THESE DRUGS. YOU TAKE ALL AND FULL RESPONSIBILITY AND USE THIS COMPOUNDED FORMULA AT YOUR OWN RISK. In no case shall Dr. Ben Behnam or Dr. Sean Behnam or any of the employees of Dermatology and Hair Restoration Specialists Inc. be liable for any direct or indirect damages, including but not limited to physical (including death), psychological, financial, emotional, monetary or otherwise, that may arise from the use of the above mentioned drugs either individually or combined together orally or topically.