Tretinoin Capsules

General

Tretinoin has potentially significant toxic side effects in APL patients. Patients undergoing therapy should be closely observed for signs of respiratory compromise and/or leukocytosis (see boxed WARNINGS). Supportive care appropriate for APL patients, eg, prophylaxis for bleeding, prompt therapy for infection, should be maintained during therapy with tretinoin.

There is a risk of thrombosis (both venous and arterial) which may involve any organ system, during the first month of treatment (see ADVERSE REACTIONS). Therefore, caution should be exercised when treating patients with the combination of tretinoin and anti-fibrinolytic agents, such as tranexamic acid, aminocaproic acid or aprotinin (see Drug Interactions). [3,4]

The ability to drive or operate machinery might be impaired in patients treated with tretinoin, particularly if they are experiencing dizziness or severe headache.

Microdosed progesterone preparations (“minipill”) may be an inadequate method of contraception during treatment with tretinoin. [5]

Laboratory Tests

The patient’s hematologic profile, coagulation profile, liver function test results, and triglyceride and cholesterol levels should be monitored frequently.

Drug Interactions

Limited clinical data on potential drug interactions are available.

As tretinoin is metabolized by the hepatic P450 system, there is a potential for alteration of pharmacokinetics parameters in patients administered concomitant medications that are also inducers or inhibitors of this system. Medications that generally induce hepatic P450 enzymes include rifampicin, glucocorticoids, phenobarbital and pentobarbital. Medications that generally inhibit hepatic P450 enzymes include ketoconazole, cimetidine, erythromycin, verapamil, diltiazem and cyclosporine. To date there are no data to suggest that co-use with these medications increases or decreases either efficacy or toxicity of tretinoin.

Tretinoin may cause pseudotumor cerebri/intracranial hypertension. Concomitant administration of tretinoin and agents known to cause pseudotumor cerebri/intracranial hypertension as well might increase the risk of this condition (see WARNINGS).

As with other retinoids, tretinoin must not be administered in combination with vitamin A because symptoms of hypervitaminosis A could be aggravated.

Cases of fatal thrombotic complications have been reported rarely in patients concomitantly treated with tretinoin and anti-fibrinolytic agents. Therefore, caution should be exercised when administering tretinoin concomitantly with these agents (see PRECAUTIONS: General).

Effect of Food

No data on the effect of food on the absorption of tretinoin are available. The absorption of retinoids as a class has been shown to be enhanced when taken together with food.

Carcinogenesis, Mutagenesis and Impairment of Fertility

No long-term carcinogenicity studies with tretinoin have been conducted. In short-term carcinogenicity studies, tretinoin at a dose of 30 mg/kg/day (about 2 times the human dose on a mg/m2 basis) was shown to increase the rate of diethylnitrosamine (DEN)-induced mouse liver adenomas and carcinomas. Tretinoin was negative when tested in the Ames and Chinese hamster V79 cell HGPRT assays for mutagenicity. A twofold increase in the sister chromatid exchange (SCE) has been demonstrated in human diploid fibroblasts, but other chromosome aberration assays, including an in vitro assay in human peripheral lymphocytes and an in vivo mouse micronucleus assay, did not show a clastogenic or aneuploidogenic effect. Adverse effects on fertility and reproductive performance were not observed in studies conducted in rats at doses up to 5 mg/kg/day (about 2/3 the human dose on a mg/m2 basis). In a 6-week toxicology study in dogs, minimal to marked testicular degeneration, with increased numbers of immature spermatozoa, were observed at 10 mg/kg/day (about 4 times the equivalent human dose in mg/m 2).

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions from tretinoin in nursing infants, mothers should discontinue nursing prior to taking this drug.

Pediatric Use

There are limited clinical data on the pediatric use of tretinoin. Of 15 pediatric patients (age range: 1 to 16 years) treated with tretinoin, the incidence of complete remission was 67%. Safety and effectiveness in pediatric patients below the age of 1 year have not been established. Some pediatric patients experience severe headache and pseudotumor cerebri, requiring analgesic treatment and lumbar puncture for relief. Increased caution is recommended in the treatment of pediatric patients. Dose reduction may be considered for pediatric patients experiencing serious and/or intolerable toxicity; however, the efficacy and safety of tretinoin at doses lower than 45 mg/m2/day have not been evaluated in the pediatric population.

Geriatric Use

Of the total number of subjects in clinical studies of tretinoin, 21.4% were 60 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

68462-792-01

Tretinoin Capsules
10 mg

CAUSES BIRTH DEFECTS. DO NOT GET PREGNANT.