All-trans retinoic acid

U.S. BRAND NAMES — Vesanoid®
PHARMACOLOGIC CATEGORY Antineoplastic Agent, Miscellaneous
DOSING: ADULTS Acute promyelocytic leukemia (APL): Oral: Remission induction: 45 mg/m2/day in 2-3 divided doses for up to 30 days after complete remission (maximum duration of treatment: 90 days) Remission maintenance: 45-200 mg/m2/day in 2-3 divided doses for up to 12 months.
DOSING: PEDIATRIC — APL induction of remission, remission maintenance: Oral: Refer to adult dosing.
DOSING: ELDERLY — Refer to adult dosing.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule: 10 mg [contains soybean oil and parabens]
DOSAGE FORMS: CONCISE Capsule: Vesanoid®: 10 mg
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — Administer with meals; do not crush capsules
USE — Induction of remission in patients with acute promyelocytic leukemia (APL), French American British (FAB) classification M3 (including the M3 variant)
ADVERSE REACTIONS SIGNIFICANT — Virtually all patients experience some drug-related toxicity, especially headache, fever, weakness and fatigue. These adverse effects are seldom permanent or irreversible nor do they usually require therapy interruption.
>10%: Cardiovascular: Peripheral edema (52%), chest discomfort (32%), edema (29%), arrhythmias (23%), flushing (23%), hypotension (14%), hypertension (11%) Central nervous system: Headache (86%), fever (83%), malaise (66%), pain (37%), dizziness (20%), anxiety (17%), insomnia (14%), depression (14%), confusion (11%) Dermatologic: Skin/mucous membrane dryness (77%), pruritus (20%), rash (54%), alopecia (14%) Endocrine & metabolic: Hypercholesterolemia and/or hypertriglyceridemia (60%) Gastrointestinal: Nausea/vomiting (57%), liver function tests increased (50% to 60%), GI hemorrhage (34%), abdominal pain (31%), mucositis (26%), diarrhea (23%), constipation (17%), dyspepsia (14%), abdominal distention (11%), weight gain (23%), weight loss (17%), xerostomia, anorexia (17%) Hematologic: Hemorrhage (60%), leukocytosis (40%), disseminated intravascular coagulation (DIC) (26%) Local: Phlebitis (11%), injection site reactions (17%) Neuromuscular & skeletal: Bone pain (77%), myalgia (14%), paresthesia (17%) Ocular: Visual disturbances (17%) Otic: Earache/ear fullness (23%) Renal: Renal insufficiency (11%) Respiratory: Upper respiratory tract disorders (63%), dyspnea (60%), respiratory insufficiency (26%), pleural effusion (20%), pneumonia (14%), rales (14%), expiratory wheezing (14%), dry nose Miscellaneous: Infection (58%), shivering (63%), retinoic acid-acute promyelocytic leukemia syndrome (25%), diaphoresis increased (20%)
1% to 10%: Cardiovascular: Cerebral hemorrhage (9%), pallor (6%), cardiac failure (6%), cardiac arrest (3%), enlarged heart (3%), heart murmur (3%), ischemia, stroke (3%), MI (93%), myocarditis (3%), pericarditis (3%), pulmonary hypertension (3%), secondary cardiomyopathy (3%) Central nervous system: Intracranial hypertension (9%), agitation (9%), hallucination (6%), agnosia (3%), aphasia (3%), cerebellar edema (3%), cerebral hemorrhage (9%), seizure (3%), coma (3%), CNS depression (3%), dysarthria (3%), encephalopathy (3%), hypotaxia (3%), light reflex absent (3%), spinal cord disorder (3%), unconsciousness (3%), dementia (3%), forgetfulness (3%), somnolence (3%), slow speech (3%), hypothermia (3%) Dermatologic: Cellulitis (8%), photosensitivity Endocrine & metabolic: Acidosis (3%) Gastrointestinal: Hepatosplenomegaly (9%), hepatitis (3%), ulcer (3%) Genitourinary: Dysuria (9%), acute renal failure (3%), micturition frequency (3%), renal tubular necrosis (3%), enlarged prostate (3%) Hepatic: Ascites (3%), hepatitis Neuromuscular & skeletal: Tremor (3%), leg weakness (3%), hyporeflexia, dysarthria, facial paralysis, hemiplegia, flank pain, asterixis, abnormal gait (3%), bone inflammation (3%) Ocular: Dry eyes, visual acuity change (6%), visual field deficit (3%) Otic: Hearing loss Renal: Acute renal failure, renal tubular necrosis Respiratory: Lower respiratory tract disorders (9%), pulmonary infiltration (6%), bronchial asthma (3%), pulmonary/larynx edema Miscellaneous: Face edema
<1% (Limited to important or life-threatening): Arterial thrombosis, basophilia, cataracts, conjunctivitis, erythema nodosum, hypercalcemia, hyperuricemia, inflammatory bowel syndrome, irreversible hearing loss, pancreatitis, pseudomotor cerebri, renal infarct, Sweet's syndrome, vasculitis, venous thrombosis
CONTRAINDICATIONS — Sensitivity to parabens, vitamin A, other retinoids, or any component of the formulation; pregnancy
WARNINGS / PRECAUTIONS Box warnings: Acute promyelocytic leukemia (APL): See "Disease-related concerns" below. Experienced physician: See "Other warnings/precautions" below. Leukocytosis: See "Concerns related to adverse effects" below. Pregnancy: See "Special populations" below.
Special handling: Hazardous agent: Use appropriate precautions for handling and disposal.
Concerns related to adverse effects: Leukocytosis: [U.S. Boxed Warning]: During treatment, ~40% of patients will develop rapidly evolving leukocytosis; may be associated with a higher risk of life-threatening complications. Lipid effects: Up to 60% of patients experienced hypercholesterolemia or hypertriglyceridemia, which were reversible upon completion of treatment. Liver function test abnormalities: Elevated liver function test results occur in 50% to 60% of patients during treatment. Carefully monitor liver function test results during treatment and give consideration to a temporary withdrawal of tretinoin if test results reach >5 times the upper limit of normal. Pseudotumor cerebri: Retinoids have been associated with pseudotumor cerebri (benign intracranial hypertension), especially in children. Concurrent use of other drugs associated with this effect (eg, tetracyclines) may increase risk. Early signs and symptoms include papilledema, headache, nausea, vomiting and visual disturbances.
Disease-related concerns: Acute promyelocytic leukemia (APL): [U.S. Boxed Warning]: Patients with APL are at high risk and can have severe adverse reactions to tretinoin. About 25% of patients with APL and treated with tretinoin, have experienced retinoic acid-APL (RA-APL) syndrome, characterized by fever, dyspnea, acute respiratory distress, weight gain, radiographic pulmonary infiltrates and 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. It has been observed with or without concomitant leukocytosis. Endotracheal intubation and mechanical ventilation have been required in some cases due to progressive hypoxemia, and several patients have expired with multiorgan failure. The syndrome usually occurs during the first month of treatment, with some cases reported following the first dose. Management of the syndrome has not been defined, but high-dose steroids given at the first suspicion of RA-APL syndrome appear to reduce morbidity and mortality. At the first signs suggestive of the syndrome, immediately initiate high-dose steroids (dexamethasone 10 mg I.V.) every 12 hours for 3 days or until resolution of symptoms, regardless of the leukocyte count. The majority of patients do not require termination of tretinoin therapy during treatment of the RA-APL syndrome. If signs and symptoms of the RA-APL syndrome are present together with leukocytosis, initiate treatment with high-dose steroids immediately. Consider adding full-dose chemotherapy (including an anthracycline, if not contraindicated) to the tretinoin therapy on day 1 or 2 for patients presenting with a WBC count of >5 x 109/L or immediately, for patients presenting with a WBC count of <5 x 109/L, if the WBC count reaches 6 x 109/L by day 5, or 10 x 109/L by day 10 or 15 x 109/L by day 28.
Special populations: Pregnancy: [U.S. Boxed Warning]: High risk of teratogenicity; not to be used in women of childbearing potential unless the woman is capable of complying with effective contraceptive measures. Repeat pregnancy testing and contraception counseling monthly throughout the period of treatment.
Other warnings/precautions: Experienced physician: [U.S. Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.
DRUG INTERACTIONS — Substrate of CYP2A6 (minor), 2B6 (minor), 2C8 (major), 2C9 (minor); Inhibits CYP2C9 (weak); Induces CYP2E1 (weak)
Antifibrinolytic agents (eg, aminocaproic acid, aprotinin, tranexamic acid): Concurrent use may increase risk of thrombosis.
CYP2C8 Inhibitors may increase the levels/effects of tretinoin. Example inhibitors include atazanavir, gemfibrozil, and ritonavir.
Ketoconazole: Increases the mean plasma AUC of tretinoin.
Tetracyclines: Concurrent use may increase risk of pseudotumor cerebri.
ETHANOL / NUTRITION / HERB INTERACTIONS Ethanol: Avoid ethanol (may increase CNS depression).
Food: Absorption of retinoids has been shown to be enhanced when taken with food.
Herb/Nutraceutical: St John's wort may decrease tretinoin levels. Avoid dong quai, St John's wort (may also cause photosensitization). Avoid additional vitamin A supplementation. May lead to vitamin A toxicity.
PREGNANCY RISK FACTOR — D (show table)
PREGNANCY IMPLICATIONS — Oral tretinoin is teratogenic and fetotoxic in rats at doses 1000 and 500 times the topical human dose, respectively.
LACTATION — Enters breast milk/not recommended
DIETARY CONSIDERATIONS — To enhance absorption, some clinicians recommend giving with a fatty meal. Capsule contains soybean oil.
PRICING — (data from drugstore.com)Capsules (Vesanoid) 10 mg (30): $554.88
MONITORING PARAMETERS — Monitor the patient's hematologic profile, coagulation profile, liver function test results and triglyceride and cholesterol levels frequently
TOXICOLOGY / OVERDOSE COMPREHENSIVE — The maximum tolerated dose in adult patients with myelodysplastic syndrome in solid tumors was 195 mg/m2/day; the maximum tolerated dose in pediatric patients was lower at 60 mg/m2/day. Overdosage with other retinoids has been associated with transient headache, facial flushing, cheilosis, abdominal pain, dizziness, and ataxia. These symptoms resolved quickly without residual effects.
CANADIAN BRAND NAMES — Vesanoid®
INTERNATIONAL BRAND NAMES — Vesanoid (CA. PL)
MECHANISM OF ACTION — Tretinoin appears to bind one or more nuclear receptors and inhibits clonal proliferation and/or granulocyte differentiation
PHARMACODYNAMICS / KINETICS Protein binding: >95%
Metabolism: Hepatic via CYP; primary metabolite: 4-oxo-all-trans-retinoic acid
Half-life elimination: Terminal: Parent drug: 0.5-2 hours
Time to peak, serum: 1-2 hours
Excretion: Urine (63%); feces (30%)
PATIENT INFORMATION — Take with food; do not crush, chew, or dissolve capsules. You will need frequent blood tests while taking this medication. Maintain adequate hydration (2-3 L/day of fluids unless instructed to restrict fluid intake), avoid alcohol and foods containing vitamin A, and foods with high fat content. You may experience lethargy, dizziness, visual changes, confusion, anxiety (avoid driving or engaging in tasks requiring alertness until response to drug is known). For nausea/vomiting, loss of appetite, or dry mouth, small frequent meals, chewing gum, or sucking lozenges may help. You may experience photosensitivity (use sunscreen, wear protective clothing and eyewear, and avoid direct sunlight). You may experience dry, itchy, skin, and dry or irritated eyes (avoid contact lenses). Report persistent vomiting or diarrhea, difficulty breathing, unusual bleeding or bruising, acute GI pain, bone pain, or vision changes immediately.