Pronunciation:

(TRET i noyn, oral)

U.S. Brand Names:

Synonyms:

Generic Available:

Canadian Brand Names:

Use:

Pregnancy Risk Factor:

Pregnancy Implications:

Lactation:

Contraindications:

Warnings/Precautions:

About 25% of patients with APL, who have been treated with tretinoin, have experienced a syndrome called the retinoic acid-APL (RA-APL) syndrome which is characterized by fever, dyspnea, weight gain, radiographic pulmonary infiltrates and pleural or pericardial effusions. 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.

During treatment, ~40% of patients will develop rapidly evolving leukocytosis. Rapidly evolving leukocytosis is associated with a higher risk of life-threatening complications.

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.

Not to be used in women of childbearing potential unless the woman is capable of complying with effective contraceptive measures; therapy is normally begun on the second or third day of next normal menstrual period; two reliable methods of effective contraception must be used during therapy and for 1 month after discontinuation of therapy, unless abstinence is the chosen method. Within one week prior to the institution of tretinoin therapy, the patient should have blood or urine collected for a serum or urine pregnancy test with a sensitivity of at least 50 mIU/L. When possible, delay tretinoin therapy until a negative result from this test is obtained. When a delay is not possible, place the patient on two reliable forms of contraception. Repeat pregnancy testing and contraception counseling monthly throughout the period of treatment.

Initiation of therapy with tretinoin may be based on the morphological diagnosis of APL. Confirm the diagnosis of APL by detection of the t(15;17) genetic marker by cytogenetic studies. If these are negative, PML/RAR fusion should be sought using molecular diagnostic techniques. The response rate of other AML subtypes to tretinoin has not been demonstrated.

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.

Up to 60% of patients experienced hypercholesterolemia or hypertriglyceridemia, which were reversible upon completion of treatment. 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.

Adverse Reactions:

>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 (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: Infections (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%), MI (3%), enlarged heart (3%), heart murmur (3%), ischemia, stroke (3%), 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%), seizures(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%: Arterial thrombosis, basophilia, cataracts, conjunctivitis, corneal opacities, erythema nodosum, erythrocyte sedimentation rate increased, gum bleeding, hematocrit decreased, hemoglobin decreased, hypercalcemia, hyperhistaminemia, hyperuricemia, inflammatory bowel syndrome, irreversible hearing loss, mood changes, myositis, optic neuritis, pancreatitis, pseudomotor cerebri, renal infarct, Sweet's syndrome, vasculitis, venous thrombosis

Overdosage/Toxicology:

Drug Interactions:

Antifibrinolytic agents (eg, aminocaproic acid, aprotinin, tranexamic acid): Concurrent use may increase risk of thrombosis.

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.

Stability:

Mechanism of Action:

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%)

Dosage:

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. Note: Optimal consolidation or maintenance regimens have not been determined. All patients should therefore receive a standard consolidation or maintenance chemotherapy regimen for APL after induction therapy with tretinoin unless otherwise contraindicated.

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Dental Health: Effects on Dental Treatment:

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