Tretinoin - Warnings and Precautions

5 WARNINGS AND PRECAUTIONS • Patients Without t(15;17) Translocation or PML/RARα Fusion : Tretinoin capsules may be initiated based on morphological diagnosis of APL.

Confirm diagnosis by detection of the t(15;17) translocation or PML/RARα fusion. • Leukocytosis : Consider administering cytoreductive chemotherapy (including an anthracycline if not contraindicated or hydroxyurea) with tretinoin capsules in the setting of leukocytosis, as clinically indicated. • Intracranial Hypertension : Tretinoin capsules have been associated with benign intracranial hypertension, especially in pediatric patients.

Consider interruption, dose reduction, or discontinuation of tretinoin capsules as appropriate. • Lipid Abnormalities : Patients experienced hypercholesterolemia and/or hypertriglyceridemia, which may be reversible upon completion of treatment.

Monitor fasting triglycerides and cholesterol at baseline and periodically during treatment. • Hepatotoxicity : Monitor liver function test results at baseline and during treatment as clinically indicated. • Thromboembolic Events : Venous and arterial events have been reported; these events may occur during the first month of treatment with tretinoin capsules. ( 5.8 , 7.4 ) 5.1 Embryo-Fetal Toxicity Tretinoin capsules can cause embryo-fetal loss and malformations when administered to a pregnant woman.

Tretinoin capsules are a retinoid and there is an increased risk of major congenital malformations, spontaneous abortions and premature births following exposure to retinoids during pregnancy in humans.

Tretinoin has teratogenic and embryotoxic effects in mice, rats, hamsters, rabbits and pigtail monkeys at doses less than the human dose on a mg/m 2 basis.

Advise pregnant women of the potential risk to a fetus.

Advise females of reproductive potential to use 2 effective methods of contraception during treatment with tretinoin capsules and for 1 month following the last dose.

Advise males with female partners of reproductive potential to use effective contraception during treatment with tretinoin capsules and for 1 week following the last dose [see Use in Specific Populations ( 8.1 , 8.3 )] .

5.2 Differentiation Syndrome Differentiation Syndrome, which may be life-threatening or fatal, occurred in about 26% of patients with APL who received tretinoin capsules [see Adverse Reactions ] .

Symptoms include fever, dyspnea, acute respiratory distress, weight gain, radiographic pulmonary infiltrates, pleural and pericardial effusions, edema, and hepatic, renal, and multi-organ failure.

This syndrome has been accompanied by impaired myocardial contractility and episodic hypotension and it has been observed with or without concomitant leukocytosis.

This syndrome generally occurs during the first month of treatment, as early as following the first dose.

Endotracheal intubation and mechanical ventilation were required in some cases due to progressive hypoxemia and several patients have died with multi-organ failure.

At the first signs or symptoms of this syndrome, immediately administer dexamethasone 10 mg intravenously every 12 hours until signs and symptoms have abated for at least 3 days and initiate hemodynamic monitoring until resolution of signs and symptoms.

Consider withholding tretinoin capsules for moderate and severe differentiation syndrome until resolution [see Adverse Reactions ] .

5.3 Patients Without t(15;17) Translocation or PML/RARα Fusion Tretinoin capsules may be initiated based on the morphological diagnosis of acute promyelocytic leukemia (APL).

Confirm the diagnosis of APL by detection of the t(15;17) translocation using cytogenetic studies or PML/RARα fusion using molecular diagnostic techniques.

Tretinoin capsules are not recommended for use in patients without these genetic markers [see Indications and Usage ] .

5.4 Leukocytosis Rapidly evolving leukocytosis, which can be life-threatening, occurred in about 40% of patients with APL who received tretinoin capsules [see Adverse Reactions ] .

Patients who present with a baseline white blood cell count (WBC) > 5 × 10 9 /L have an increased risk.

Patients who receive chemotherapy with tretinoin capsules may be at a reduced risk.

Rapidly evolving leukocytosis is associated with a higher risk of life-threatening complications.

Consider administering cytoreductive chemotherapy (including an anthracycline if not contraindicated or hydroxyurea) with tretinoin capsules in the setting of leukocytosis, as clinically indicated.

5.5 Intracranial Hypertension Retinoids, including tretinoin capsules, have been associated with intracranial hypertension, especially in pediatric patients.