Brand name: Vesanoid
Drug class: Antineoplastic Agents
VA class: AN900
Chemical name: Retinoic Acid
Molecular formula: C₂₀H₂₈O₂
CAS number: 302-79-4

Medically reviewed by Drugs.com on Mar 22, 2024. Written by ASHP.

Introduction

Antineoplastic agent; retinoid.

Uses for Tretinoin

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 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.

Cautions for Tretinoin

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.

Drug Interactions

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

Tretinoin Pharmacokinetics

Absorption

Bioavailability

About 50%; marked interpatient variation.

Food

Effect of food on tretinoin absorption not evaluated; generally, retinoid absorption is enhanced by food. Tretinoin is fat soluble; fat-restricted diet may cause reduced bioavailability.

Plasma Concentrations

Decreased over time by tretinoin's apparent induction of its own metabolism. After 1 week of continuous therapy, concentrations decrease to about one-third of those on the first day. In pediatric patients, mean AUC on day 28 was about one-fifth that determined on day 1.

Distribution

Extent

Not fully characterized.

Crosses the placenta in animals; not known whether tretinoin distributes into milk.

Plasma Protein Binding

>95% (mainly albumin).

Elimination

Metabolism

Evidence that tretinoin induces its own metabolism.

Precise metabolic pathway not fully elucidated. In the liver, stereoisomerization followed by oxidation occurs; CYP isoenzymes (e.g., CYP3A4, CYP2C8, CYP2E) are implicated in oxidation.

Various metabolites identified, but activity mainly results from the parent drug.

Elimination Route

>90% in urine and feces; 63% in urine within 72 hours, and 31% in feces within 6 days. Metabolites (glucuronide conjugates) excreted in urine and bile.

Half-life

0.5–2 hours after initial dose.

Special Populations

The effect of renal or hepatic impairment not established.

Stability

Storage

Oral

Capsules

15–30°C. Protect from light.

Actions

• Not a cytolytic agent; precise mechanism(s) of action not fully elucidated.

• PML/RAR-α fusion protein resulting from 15;17 chromosomal translocation apparently blocks myeloid differentiation at the promyelocyte stage; induces cellular differentiation and decreases proliferation of APL cells.

• Causes initial maturation of primitive promyelocytes (derived from the cellular leukemic clone) followed by normal, polyclonal hematopoietic cell repopulation of bone marrow and peripheral blood.

• Apoptosis (programmed cell death) may be a mechanism for eliminating malignant cells.

• Tretinoin alone does not eradicate the leukemic clone because PML/RAR-α fusion protein usually can be detected following induction.

• High initial complete response rate, but remissions induced and maintained by tretinoin alone are short (median: 3.5 months).

• Clinical resistance occurs with prolonged administration; increased tretinoin metabolism and clearance with resultant, reduction in plasma concentrations, may contribute to resistance.

Advice to Patients

• Importance of advising patients of adverse effects and associated manifestations.

• Importance of advising patients that their ability to drive or operate machinery might be impaired, especially if experiencing dizziness or severe headache.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of women using effective contraception (i.e., 2 reliable forms of contraception simultaneously unless abstinence is the chosen method) during tretinoin therapy and for 1 month following discontinuance, unless a hysterectomy has been performed. Importance of informing women that progestin-only preparations (i.e., minipill) may be an inadequate method of contraception during tretinoin therapy and for 1 month following discontinuance.

• Importance of fully informing women of high risk of fetal harm and risks of contraceptive failure, discussing desirability of continuing or terminating pregnancy when administered during pregnancy or when woman becomes pregnant while receiving the drug.

• Importance of performing pregnancy testing before initiation of tretinoin, and repeating pregnancy testing and contraception counseling monthly during tretinoin therapy.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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