Tretinoin (Systemic)

Brand names: Vesanoid
Drug class: Antineoplastic Agents

Usage of 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.

Relate drugs

How to use Tretinoin (Systemic)

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.

    Warnings

    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.

    What other drugs will affect Tretinoin (Systemic)

    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

    Drug

    Interaction

    Comments

    Antifibrinolytic agents (e.g., tranexamic acid, aminocaproic acid, aprotinin)

    Fatal thrombotic complications reported with concomitant use

    Use concomitantly with caution

    Cimetidine

    Possible increased plasma tretinoin concentrations

    Corticosteroids

    Possible decreased plasma tretinoin concentrations

    Cyclosporine

    Possible increased plasma tretinoin concentrations

    Diltiazem

    Possible increased plasma tretinoin concentrations

    Erythromycin

    Possible increased plasma tretinoin concentrations

    Hydroxyurea

    Concurrent use may cause a synergistic effect leading to massive cell lysis

    Bone marrow necrosis, sometimes fatal, has been reported

    Use concomitantly with caution

    Ketoconazole

    Possible increased plasma tretinoin concentrations; administration of ketoconazole 1 hour prior to day 29 tretinoin dose associated with 72% increase in mean tretinoin AUC

    Pentobarbital

    Possible decreased plasma tretinoin concentrations

    Phenobarbital

    Possible decreased plasma tretinoin concentrations

    Rifampin

    Possible decreased plasma tretinoin concentrations

    Tetracyclines

    Increased risk of pseudotumor cerebri or intracranial hypertension

    Verapamil

    Possible increased plasma tretinoin concentrations

    Vitamin A

    Concurrent use may aggravate symptoms of hypervitaminosis A

    Avoid concomitant use

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