Introduction

Antineoplastic agent; retinoid.

Uses for Tretinoin (Systemic)

Acute Promyelocytic Leukemia

Used to induce remission in acute promyelocytic leukemia (APL), French-American-British classification M3 including the M3 variant, characterized by the presence of certain genetic markers (i.e., 15;17 chromosomal translocation and/or PML/RAR-α gene) in patients with relapsed or refractory disease following anthracycline-based chemotherapy or in patients for whom anthracycline therapy is contraindicated.

Most clinicians recommend addition of tretinoin to induction combination chemotherapy (anthracycline-based) as initial^{† [off-label]} treatment for APL in patients with previously untreated disease.

May initiate tretinoin therapy based on the morphologic diagnosis of APL, but perform cytogenetic evaluation to confirm presence of the 15;17 translocation, and if absent, perform molecular diagnostic testing for the PML/RAR-α fusion protein.

May be ineffective when these genetic markers are absent; consider alternative therapy.

Tretinoin (Systemic) Dosage and Administration

General

• Tretinoin apparently induces its own metabolism; clinical failure may be related to a lack of sustained effective concentrations during prolonged treatment. (See Plasma Concentrations under Pharmacokinetics.) Increasing dosage to compensate does not increase response.

Administration

Oral Administration

Administer orally in 2-equally divided doses.

Manufacturer makes no specific recommendations regarding administration with meals; however, food has enhanced absorption of other retinoids. (See Absorption under Pharmacokinetics.)

Dosage

Discontinue tretinoin and consider alternative treatment if the presence of 15;17 chromosomal translocation and/or PML/RAR-α gene is not confirmed and the disease is not responding.

Unless contraindicated, administer consolidation and/or maintenance chemotherapy to all patients following tretinoin induction therapy.

Consider temporary discontinuance if serum transaminase concentrations >5 times the ULN. (See Hepatic Effects under Cautions.)

Consider temporary discontinuance in patients with moderate or severe retinoic acid-APL syndrome. (See RA-APL Syndrome under Cautions.)

Pediatric Patients

Acute Promyelocytic Leukemia

Oral

45 mg/m² daily administered in 2 evenly divided doses.

Continue until 30 days after complete remission is achieved, or for a total of 90 days, whichever occurs first. Some clinicians recommend continuing until complete remission is achieved, or for a total of 90 days (whichever occurs first).

Consider dosage reduction if serious or intolerable drug toxicity; however, safety and efficacy of dosages <45 mg/m² daily have not been established.

Adults

Acute Promyelocytic Leukemia

Oral

45 mg/m² daily administered in 2 evenly divided doses.

Continue until 30 days after complete remission is achieved, or for a total of 90 days, whichever occurs first. Some clinicians recommend continuing until complete remission is achieved, or for a total of 90 days (whichever occurs first).

Prescribing Limits

Pediatric Patients

Acute Promyelocytic Leukemia

Oral

Safety and efficacy of dosages <45 mg/m² daily have not been established.

Maximum duration: 30 days after complete remission, up to 90 days of therapy.

Adults

Acute Promyelocytic Leukemia

Oral

Maximum duration: 30 days after complete remission, up to 90 days of therapy.

Contraindications

• Known hypersensitivity to tretinoin or other retinoids, parabens, or any other ingredient in the formulation.

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryotoxicity demonstrated in animals.

Limited experience in pregnant women, but other retinoids are associated with increased spontaneous abortions and major and sometimes fatal fetal abnormalities (e.g., abnormalities of the CNS, musculoskeletal system, external ear, eye, thymus, and great vessels; facial dysmorphia; cleft palate; parathyroid hormone deficiency; low IQ scores (i.e., <85), with or without obvious CNS abnormalities).

High risk of severely deformed infants in pregnant women; use during pregnancy only in life-threatening situations, or for severe disease for which safer drugs cannot be used or are ineffective. Currently there is no antepartum method for determining whether a fetus is affected.

Exclude pregnancy using a reliable blood or urine pregnancy test with a sensitivity of ≥50 mIU/mL within 1 week before initiating tretinoin; delay tretinoin initiation (whenever possible) until pregnancy test is negative; if delay is not feasible, place on 2 reliable forms of contraception. Repeat pregnancy tests and contraception counseling monthly during therapy.

All women (including those with a history of infertility or menopause) must use 2 reliable forms of contraception simultaneously during therapy and for 1 month following discontinuance, unless a hysterectomy has been performed. Progestin-only preparations (i.e., minipill) may be an inadequate method of contraception during tretinoin therapy.

Cytogenetic Confirmation of Diagnosis

May initiate therapy based on the morphologic diagnosis of APL. However, confirm diagnosis by performing cytogenetic evaluation to confirm presence of the 15;17 translocation; if absent, perform molecular diagnostic testing for the PML/RAR-α fusion protein.

Consider alternative therapy when these genetic markers are absent; efficacy not established in acute myelogenous leukemia (AML) subtypes other than APL.

RA-APL Syndrome

Possible RA-APL syndrome (APL differentiation syndrome), characterized by fever, dyspnea, acute respiratory distress, weight gain, pulmonary infiltrates, pleural and pericardial effusions, edema, and hepatic, renal, and multiorgan failure occasionally accompanied by impaired myocardial contractility and episodic hypotension; can occur with or without concomitant leukocytosis. Onset generally occurs within the first month of treatment, but can occur after the first dose. (See Retinoic Acid-APL [RA-APL] Syndrome in Boxed Warning.)

Progressive hypoxemia requiring endotracheal intubation and mechanical ventilation may occur in severe cases; deaths reported secondary to progressive hypoxemia and multiorgan failure.

If signs or symptoms of the syndrome (e.g., fever, dyspnea, weight gain, abnormal chest auscultatory findings, radiographic abnormalities) occur, immediately institute high-dose corticosteroid treatment (e.g., dexamethasone 10 mg IV every 12 hours for at least 3 days or until resolution of symptoms), regardless of leukocyte count; may reduce morbidity and mortality. If syndrome recurs, initiate another course of corticosteroid treatment.

Tretinoin discontinuance not required in most patients during RA-APL syndrome treatment; however, consider temporary interruption of therapy in moderate and severe cases.

Leukocytosis

Possible rapidly evolving leukocytosis; may be associated with an increased risk of life-threatening complications.

The optimal management of leukocytosis not established, but initiate high-dose corticosteroid treatment immediately if leukocytosis and signs or symptoms of RA-APL syndrome develop together.

Lower incidence of the RA-APL syndrome reported with routine addition of chemotherapy agents to tretinoin when baseline leukocyte count >5000/mm³, or when initial leukopenia exists and subsequent rapid increase in leukocyte count develops.

Consider adding full-dose chemotherapy (including anthracycline, unless contraindicated) to tretinoin therapy on day 1 or 2 if baseline leukocyte count is >5000/mm³.

Immediately initiate chemotherapy if baseline leukocyte count of <5000/mm³ subsequently increases to >6000/mm³ by day 5, 10,000/mm³ by day 10, or 15,000/mm³ by day 28.

Pseudotumor Cerebri

Possible pseudotumor cerebri (benign intracranial hypertension), especially in pediatric patients. Increased risk possible with concomitant use of other agents known to cause pseudotumor cerebri or intracranial hypertension. (See Specific Drugs under Interactions.)

Evaluate for pseudotumor cerebri if signs or symptoms (e.g., papilledema, headache, nausea, vomiting, visual disturbances) occur; if present, treat appropriately (including neurological assessment). Opiate analgesics, corticosteroids, and lumbar puncture may be required.

Lipids

Possible reversible hypercholesterolemia and/or hypertriglyceridemia.

Clinical importance of transient lipid elevations unknown, but venous thrombosis and MI reported in otherwise low-risk patients.

Hepatic Effects

Possible elevated liver function tests; test abnormalities usually resolve during or after treatment.

Consider temporary discontinuance if serum transaminase concentrations are >5 times the ULN.

General Precautions

Laboratory Tests

Frequently monitor hematologic profile, coagulation profile, liver function tests, and serum cholesterol and triglyceride concentrations, and clinically assess cardiac status during tretinoin therapy.

Thrombosis

Venous or arterial thrombosis involving any organ system (e.g., cerebrovascular accident, MI, renal infarct) reported during first month of treatment. Use caution if used concomitantly with antifibrinolytic agents. (See Specific Drugs under Interactions.)

Specific Populations

Pregnancy

Category D. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether tretinoin is distributed into milk. Discontinue nursing because of potential for serious adverse effects in nursing infants.

Pediatric Use

Use with increased caution in pediatric patients; limited clinical data for use in children.

Safety and efficacy not established in infants <1 year of age.

Increase risk of severe headache and pseudotumor cerebri, requiring treatment with analgesics and lumbar puncture. (See Pseudotumor Cerebri under Cautions.)

Dosage reduction may be appropriate if severe adverse effects occur, but safety and efficacy of dosages <45 mg/m² daily have not been established.

Geriatric Use

Safety and efficacy in those ≥60 years of age similar to those in younger adults, but increased sensitivity cannot be ruled out.

Common Adverse Effects

Respiratory effects (upper respiratory tract disorders, dyspnea, respiratory insufficiency), headache, dizziness, paresthesias, anxiety, insomnia, depression, confusion, skin/mucous membrane dryness, rash, pruritus, increased sweating, alopecia, skin changes, GI effects (nausea and vomiting, GI hemorrhage, mucositis, abdominal pain, diarrhea, constipation), bone pain, myalgia, peripheral edema, chest discomfort, edema, arrhythmias, flushing, hypotension, hypertension, phlebitis, renal insufficiency, earache, feeling of fullness in the ears, visual disturbances, fever, malaise, shivering.

General

• Tretinoin apparently induces its own metabolism; clinical failure may be related to a lack of sustained effective concentrations during prolonged treatment. (See Plasma Concentrations under Pharmacokinetics.) Increasing dosage to compensate does not increase response.

Administration

Oral Administration

Administer orally in 2-equally divided doses.

Manufacturer makes no specific recommendations regarding administration with meals; however, food has enhanced absorption of other retinoids. (See Absorption under Pharmacokinetics.)

Dosage

Discontinue tretinoin and consider alternative treatment if the presence of 15;17 chromosomal translocation and/or PML/RAR-α gene is not confirmed and the disease is not responding.

Unless contraindicated, administer consolidation and/or maintenance chemotherapy to all patients following tretinoin induction therapy.

Consider temporary discontinuance if serum transaminase concentrations >5 times the ULN. (See Hepatic Effects under Cautions.)

Consider temporary discontinuance in patients with moderate or severe retinoic acid-APL syndrome. (See RA-APL Syndrome under Cautions.)

Pediatric Patients

Acute Promyelocytic Leukemia

Oral

45 mg/m² daily administered in 2 evenly divided doses.

Continue until 30 days after complete remission is achieved, or for a total of 90 days, whichever occurs first. Some clinicians recommend continuing until complete remission is achieved, or for a total of 90 days (whichever occurs first).

Consider dosage reduction if serious or intolerable drug toxicity; however, safety and efficacy of dosages <45 mg/m² daily have not been established.

Adults

Acute Promyelocytic Leukemia

Oral

45 mg/m² daily administered in 2 evenly divided doses.

Continue until 30 days after complete remission is achieved, or for a total of 90 days, whichever occurs first. Some clinicians recommend continuing until complete remission is achieved, or for a total of 90 days (whichever occurs first).

Prescribing Limits

Pediatric Patients

Acute Promyelocytic Leukemia

Oral

Safety and efficacy of dosages <45 mg/m² daily have not been established.

Maximum duration: 30 days after complete remission, up to 90 days of therapy.

Adults

Acute Promyelocytic Leukemia

Oral

Maximum duration: 30 days after complete remission, up to 90 days of therapy.

Metabolized by CYP isoenzymes.

Drugs Affecting Hepatic Microsomal Enzymes

Concomitant use of drugs that affect CYP isoenzymes (e.g., CYP3A4, CYP2C8, CYP2E) may alter metabolism of tretinoin; not known whether concomitant use of drugs affecting the CYP enzyme system alters the efficacy or toxicity of tretinoin.

Inducers of CYP isoenzymes: Potential pharmacokinetic interaction (decreased plasma tretinoin concentrations).

Inhibitors of CYP isoenzymes: Potential pharmacokinetic interaction (increased plasma tretinoin concentrations).

Specific Drugs