WARNINGS

1. Experienced Physician and Institution

Patients with acute promyelocytic leukemia (APL) are at high risk in general and can have severe adverse reactions to VESANOID (tretinoin). VESANOID should therefore be administered only to patients with APL under the strict supervision of a physician who is experienced in the management of patients with acute leukemia and in a facility with laboratory and supportive services sufficient to monitor drug tolerance and protect and maintain a patient compromised by drug toxicity, including respiratory compromise. Use of VESANOID requires that the physician concludes that the possible benefit to the patient outweighs the following known adverse effects of the therapy.

2. Retinoic Acid-APL Syndrome

About 25% of patients with APL treated with VESANOID have experienced a syndrome called the retinoic acid-APL (RA-APL) syndrome characterized by 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 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 multi-organ failure. The syndrome generally occurs during the first month of treatment, with some cases reported following the first dose of VESANOID.

The management of the syndrome 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. At the first signs suggestive of the syndrome (unexplained fever, dyspnea and/or weight gain, abnormal chest auscultatory findings or radiographic abnormalities), high-dose steroids (dexamethasone 10 mg intravenously administered every 12 hours for 3 days or until the resolution of symptoms) should be immediately initiated, irrespective of the leukocyte count. The majority of patients do not require termination of VESANOID therapy during treatment of the RA-APL syndrome. However, in cases of moderate and severe RA-APL syndrome, temporary interruption of VESANOID therapy should be considered.

3. Leukocytosis at Presentation and Rapidly Evolving Leukocytosis During VESANOID Treatment

During VESANOID treatment about 40% of patients will develop rapidly evolving leukocytosis. Patients who present with high WBC at diagnosis (>5x109/L) have an increased risk of a further rapid increase in WBC counts. 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, treatment with high-dose steroids should be initiated immediately. Some investigators routinely add chemotherapy to VESANOID treatment in the case of patients presenting with a WBC count of >5x10⁹/L or in the case of a rapid increase in WBC count for patients leukopenic at start of treatment, and have reported a lower incidence of the RA-APL syndrome. Consideration could be given to adding full-dose chemotherapy (including an anthracycline if not contraindicated) to the VESANOID therapy on day 1 or 2 for patients presenting with a WBC count of >5x10⁹/L, or immediately, for patients presenting with a WBC count of <5x10⁹/L, if the WBC count reaches ≥ 6x10⁹/L by day 5, or ≥ 10x10⁹/L by day 10, or ≥ 15x10⁹/L by day 28.

4. Teratogenic Effects. Pregnancy Category D - see WARNINGS

There is a high risk that a severely deformed infant will result if VESANOID is administered during pregnancy. If, nonetheless, it is determined that VESANOID represents the best available treatment for a pregnant woman or a woman of childbearing potential, it must be assured that the patient has received full information and warnings of the risk to the fetus if she were to be pregnant and of the risk of possible contraception failure and has been instructed in the need to use two reliable forms of contraception simultaneously during therapy and for 1 month following discontinuation of therapy, and has acknowledged her understanding of the need for using dual contraception, unless abstinence is the chosen method

Within 1 week prior to the institution of VESANOID therapy, the patient should have blood or urine collected for a serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL. When possible, VESANOID therapy should be delayed until a negative result from this test is obtained. When a delay is not possible, the patient should be placed on two reliable forms of contraception. Pregnancy testing and contraception counseling should be repeated monthly throughout the period of VESANOID treatment.