Dosing & Uses
Dosage Forms & Strengths
capsule
- 10mg
Acute Promyelocytic Leukemia
For use in patients with APL classification M3, which is characterized by the presence of t(15;17) translocation and/or the presence of the PML/RAR-alpha gene, who are refractory to, or have relapsed from, anthracycline chemotherapy, as well as for use in patients for whom anthracycline-based chemotherapy is contraindicated
Remission Induction
- 45 mg/m²/day PO divided q12hr
- Discontinue 30 days after complete remission or 90 days after start of treatment (whichever comes first)
Remission Induction In Combination with an Anthracycline
- 45 mg/m²/day PO divided q12hr
- Discontinue 30 days after complete remission or 90 days after start of treatment (whichever comes first)
Consolidation Therapy (Off-label)
- Intermediate and high risk patients: 45 mg/m² PO divided q12hr for 15 days/month for 3 months
Maintenance of Remission (Off-label)
- 45 mg/m²/day PO divided q12hr for 15 days every 3 months for 2 years
Dosing Adjustment (Toxicity)
APL differentiation syndrome: 10 mg dexamethasone IV q12hr for 3-5 days; consider interrupting tretinoin until resolution of hypoxia
Liver function tests >5 times upper limit of normal: Consider withholding treatment temporarily
Patient Monitoring
Monitor CBC, coagulation, liver function tests, serum lipids
Dosage Forms & Strengths
capsule
- 10mg
Acute promyelocytic leukemia
For use in patients with APL classification M3, which is characterized by the presence of t(15;17) translocation and/or the presence of the PML/RAR-alpha gene, who are refractory to, or have relapsed from, anthracycline chemotherapy, as well as in patients in whom anthracycline-based chemotherapy is contraindicated
Remission Induction
- 45 mg/m²/day PO divided q12hr
- Discontinue 30 days after remission or 90 days after start of treatment (whichever comes first)
Remission Induction with an Anthracycline
- 25 mg/m²/day PO divided q12hr until complete remission or 90 days
Consolidation Therapy (Off-label)
- Intermediate and high risk patients: 25 mg/m² PO divided q12hr for 15 days/month for 3 months
Maintenance of Remission (Off-label)
- 25 mg/m²/day PO divided q12hr for 15 days every 3 months for 2 years
Dosing Adjustment (Toxicity)
APL differentiation syndrome: 10 mg dexamethasone IV q12hr for 3-5 days; consider interrupting tretinoin until resolution of hypoxia
Liver function tests >5 times upper limit of normal: Consider withholding treatment temporarily
Patient Monitoring
Monitor CBC, coagulation, liver function tests, serum lipids
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
>10%
Headache (86%)
Fever (83%)
Bone pain (77%)
Dry mucous membranes (77%)
Malaise (67%)
URI (63%)
Shivering (60%)
Dyspnea (60%)
Hemorrhage (60%)
Elevated liver function tests (50-60%)
Hyperlipidemia (60%)
Infections (58%)
Nausea and vomiting (57%)
Rash (54%)
Peripheral edema (52%)
Leukocytosis (40%)
Pain (37%)
Abdominal pain (31%)
DIC (26%)
Respiratory insufficiency (26%)
Mucositis (26%)
GI disorder (26%)
Retinoic acid-APL syndrome (25%)
Ear ache (23%)
Diarrhea (23%)
Pleural effusion (20%)
Dizziness (20%)
Pruritus (20%)
Sweating (20%)
Anxiety (17%)
Paresthesia (17%)
Constipation (17%)
Vision changes (17%)
Dyspepsia (14%)
Rales (14%)
Depression (14%)
Insomnia (14%)
Alopecia (14%)
Skin changes (14%)
Confusion (11%)
Abdominal distention (11%)
Renal insufficiency (11%)
1-10% (selected)
Cardiac failure (6%)
Pallor (6%)
Cardiac arrest (3%)
Cardiomyopathy (3%)
Myocarditis (3%)
Stroke (3%)
Heart murmur (3%)
Hemmorrhage (9%)
Facial edema (6%)
Intracranial hypertension (9%)
Hypotaxia (3%)
Seizure (3%)
Somnolence (3%)
Facial paralysis (3%)
Spinal cord disorder (3%)
Light reflex absent (3%)
Ulcer (3%)
Cellulitis (8%)
Hepatosplenomegaly (9%)
Dysuria (9%)
Enlarged prostate (3%)
Ascites (3%)
Hepatitis (3%)
Tremor (3%)
Bone inflammation (3%)
Hearing loss (6%)
<1%
Arterial thrombosis
Hypercalcemia
Myositis
Pancreatitis
Thrombocytosis
Venous thrombosis
Irreversible hearing loss
Genital ulceration
Warnings
Black Box Warnings
Administration: Administered under the supervision of an experienced cancer chemotherapy physician in a facility equipped to diagnose and manage complications
Teratogenic effects: High risk of severe infant deformity if administered during pregnancy; if treatment with tretinoin is required in women of childbearing potential, 2 reliable forms of contraception should be used during, and for 1 month after, therapy; if it is determined that tretinoin represents the best available treatment for a pregnant woman, patients should be informed of the risk to the fetus
Retinoic acide-APL syndrome: About 25% of patients with APL treated with tretinoin experience a syndrome called the retinoic acid-APL syndrome, which can be fatal and is characterized by fever, dyspnea, acute respiratory distress, weight gain, radiographic pulmonary infiltrates, pleural or pericardial effusions, edema, and hepatic, renal, and/or multiorgan failure; this syndrome has occasionally been accompanied by impaired myocardial contractility and episodic hypotension; management has not been defined rigorously, but high-dose steroids given at the first suspicion of the RA-APL syndrome appear to reduce morbidity and mortality
Rapidly evolving leukocytosis: About 40% of patients will develop rapidly evolving leukocytosis; those who present with high WBC at diagnosis (ie, >5 x10^9/L) have an increased risk; if signs and symptoms of the RA-APL syndrome are present together with leukocytosis, treatment with high-dose steroids should be initiated immediately
Contraindications
Hypersensitivity to retinoids, parabens, or formulation components
Cautions
Teratogenic and embryotoxic in animal studies and is expected to cause fetal harm in pregnant women; effective contraception must be used by all females of childbearing potential during and for 1 month after discontinuation (see Black Box Warnings)
Microdosed progesterone oral contraception (“minipill”) may not be adequate for contraception during tretinoin therapy
Patients without the t(15;17) translocation genetic marker should be considered for alternative treatment
Retinoic acid-APL syndrome, which can be fatal, has been reported (see Black Box Warnings)
Leukocytosis may occur (see Black Box Warnings)
Pseudotumor cerebri associated with retinoids, especially in pediatric patients; dizziness or severe headache may be symptoms
Up to 60% incidence of hypercholesterolemia and/or hypertriglyceridemia; reversible upon completion of treatment
Elevated liver function tests may occur in 50-60% of patients during treatment
Increased risk of thrombosis during first month of treatment
Do not coadminister with other retinoids or in combination with vitamin A because symptoms of hypervitaminosis A
Pregnancy & Lactation
Pregnancy category: D (systemic)
Lactation: Unknown if excreted in breast milk; do not breast-feed, because of potential for serious adverse reactions in infant
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Retinoid, induces differentiation and decreased proliferation of APL cells; produces an initial maturation of promyelocytes, followed by a repopulation of the bone marrow and peripheral blood by normal polyclonal hematopoietic cells in patients achieving complete remission
Absorption
Peak plasma time: 1-2 hours
Peak plasma concentration: 347 ng/mL
Distribution
Protein bound: 95%
Metabolism
Metabolized by hepatic cytochrome 450
Metabolites: 13-cis retinoic acid, 4-oxo trans retinoic acid, 4-oxo cis retinoic acid, 4-oxo trans retinoic acid glucuronide
Elimination
Half-life: 0.5-2 hours
Excretion: urine 63%; feces 30%
Images
Patient Handout
Formulary
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