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  • 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

    Oral tretinoin is classified as FDA pregnancy risk category D and topical tretinoin is classified as FDA pregnancy risk category C . 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. 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.

    DEA CLASS

    Rx

    DESCRIPTION

    Naturally occurring retinoid analog; also known as all-trans-retinoic acid (aTRA); oral and intravenous forms used in acute promyelocytic leukemia; topical form used for cutaneous disorders like acne and photoaging.

    COMMON BRAND NAMES

    Altinac, 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%
    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, Adolescents, and Children 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.

    Topical dosage (Atralin 0.05% gel)
    Adults, Adolescents, and Children 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.

    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-to-intermediate risk APL in combination with arsenic trioxide†.
    Oral dosage
    Adults and geriatric patients <= 71 years

    45 mg/m2 per day orally (in 2 divided doses) starting day 1 plus arsenic trioxide 0.15 mg/kg per day IV over 2 hours starting day 1 until complete hematological remission (or a maximum of 60 days) followed by consolidation therapy with tretinoin 45 mg/m2 per day (in 2 divided doses) for 2 weeks on and 2 weeks off for 7 cycles on weeks 1—2, 5—6, 9—10, 13—14, 17—18, 21—22, and 25—26 plus arsenic trioxide 0.15 mg/kg per day given 5 days/week (Monday-Friday) for 4 weeks on and 4 weeks off for 4 cycles on weeks 1—4, 9—12, 17—20, and 25—28 was evaluated in a multinational, randomized, phase III noninferiority study. The tretinoin dose was rounded to the nearest 10-mg increment. Hydroxyurea use was permitted if leukocytosis developed during induction therapy. Prednisone 0.5 mg/kg per day was started on day 1 until the end of induction therapy as differentiation syndrome prophylaxis.

    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—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%—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.

    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
    Atralin:
    - Protect from freezing
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 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:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store upright
    Tretin-X:
    - Store below 80 degrees F
    Vesanoid:
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 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 contains 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.

    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. 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

    Oral tretinoin is classified as FDA pregnancy risk category D and topical tretinoin is classified as FDA pregnancy risk category C . 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. 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.

    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

    The safety and efficacy of topical tretinoin have not been established in neonates, infants and children < 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.

    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, 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
    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
    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
    respiratory depression / Rapid / Incidence not known
    hypoxia / Early / 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 (unspecified) / 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
    pruritus / Rapid / 20.0
    xerosis / Delayed / 10.0
    skin irritation / Early / 10.0
    vesicular rash / Delayed / Incidence not known
    photosensitivity / 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.
    Bacillus Calmette-Guerin Vaccine, BCG: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus 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.
    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.
    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.
    Ethanol: (Moderate) Products that contain ethanol can further dry and irritate the skin and should not be used with tretinoin; it is advisable to allow the effects of such preparations to subside before initiating topical tretinoin treatment.
    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.
    Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
    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.
    Intranasal Influenza Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus 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.
    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.
    Live Vaccines: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus 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.
    Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus 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.
    Measles/Mumps/Rubella Vaccines, MMR: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus 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.
    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.
    Rotavirus Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus 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.
    Rubella Virus Vaccine Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus 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.
    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.
    Sargramostim, GM-CSF: (Major) Sargramostim, GM-CSF, induces proliferation of hematopoietic progenitor cells, and because antineoplastic agents exert their toxic effects against rapidly growing cells, sargramostim is contraindicated during the 24 hours before or after cytotoxic chemotherapy.
    Sipuleucel-T: (Major) Concomitant use of sipuleucel-T and antineoplastic agents should be avoided. Concurrent administration of antineoplastic agents with the leukapheresis procedure that occurs prior to sipuleucel-T infusion has not been studied. Sipuleucel-T stimulates the immune system and patients receiving antineoplastic agents may have a diminished response to sipuleucel-T. When appropriate, consider discontinuing or reducing the dose of antineoplastic agents prior to initiating therapy with sipuleucel-T.
    Smallpox Vaccine, Vaccinia Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus 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.
    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.
    Typhoid Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus 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.
    Varicella-Zoster Virus Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus 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.
    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.
    Yellow Fever Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus 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.

    PREGNANCY AND LACTATION

    Pregnancy

    Oral tretinoin is classified as FDA pregnancy risk category D and topical tretinoin is classified as FDA pregnancy risk category C . 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. 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.

    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.