Bexarotene

BEXAROTENE- bexarotene capsule
Amneal Pharmaceuticals NY LLC

WARNING: BIRTH DEFECTS

Bexarotene is a member of the retinoid class of drugs that is associated with birth defects in humans. Bexarotene also caused birth defects when administered orally to pregnant rats. Bexarotene must not be administered to a pregnant woman. (8.1)

1 INDICATIONS AND USAGE

Bexarotene capsules are indicated for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma in patients who are refractory to at least one prior systemic therapy.

2 DOSAGE AND ADMINISTRATION

The recommended initial dose of bexarotene capsules is 300 mg/m2 /day (see Table 1). Bexarotene capsules should be taken as a single oral daily dose with a meal. For precautions to prevent pregnancy and birth defects in women of child-bearing potential [see Use in Specific Populations (8.1)].

Table 1: Bexarotene Capsules Initial Dose Calculation According to Body Surface Area

Initial Dose Level (300 mg/m2 /day)

Number of 75 mg Bexarotene Capsules

Body Surface Area (m2)

Total Daily Dose (mg/day)

0.88 to 1.12

300

4

1.13 to 1.37

375

5

1.38 to 1.62

450

6

1.63 to 1.87

525

7

1.88 to 2.12

600

8

2.13 to 2.37

675

9

2.38 to 2.62

750

10

Dose Modification Guidelines: The 300 mg/m2 /day dose level of bexarotene capsules may be adjusted to 200 mg/m2 /day then to 100 mg/m2 /day, or temporarily suspended, if necessitated by toxicity. When toxicity is controlled, doses may be carefully readjusted upward. If there is no tumor response after eight weeks of treatment and if the initial dose of 300 mg/m2 /day is well tolerated, the dose may be escalated to 400 mg/m2 /day with careful monitoring.

Duration of Therapy: In clinical trials in CTCL, bexarotene capsules was administered for up to 97 weeks.

Bexarotene capsules should be continued as long as the patient is deriving benefit.

3 DOSAGE FORMS AND STRENGTHS

Capsules: 75 mg, white, oblong soft gelatin capsules imprinted “A125” with black ink.

4 CONTRAINDICATIONS

4.1 Pregnancy

Bexarotene can cause fetal harm when administered to a pregnant female. Bexarotene is a member of the retinoid class of drugs that is associated with birth defects in humans and is contraindicated in females who are pregnant. Bexarotene was also teratogenic and caused developmental mortality when administered orally to pregnant rats. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be advised of the potential risk to a fetus.

4.2 Hypersensitivity

Bexarotene capsules are contraindicated in patients with a known serious hypersensitivity to bexarotene or other components of the product.

5 WARNINGS AND PRECAUTIONS

5.1 Hyperlipidemia

Bexarotene induces substantial elevations in lipids in most patients. About 70% of patients with CTCL who received an initial dose of ≥300 mg/m2 /day of bexarotene had fasting triglyceride levels greater than 2.5 times the upper limit of normal. About 55% had values over 800 mg/dL with a median of about 1200 mg/dL in those patients. Cholesterol elevations above 300 mg/dL occurred in approximately 60% and 75% of patients with CTCL who received an initial dose of 300 mg/m2 /day or greater than 300 mg/m2 /day, respectively. Decreases in high density lipoprotein (HDL) cholesterol to less than 25 mg/dL were seen in about 55% and 90% of patients receiving an initial dose of 300 mg/m2 /day or greater than 300 mg/m2 /day, respectively, of bexarotene. Monitor lipid changes and treat abnormalities during therapy. The effects on triglycerides, HDL cholesterol, and total cholesterol were reversible with cessation of therapy, and could generally be mitigated by dose reduction and/or concomitant antilipemic therapy.

Perform fasting blood lipid determinations before bexarotene therapy is initiated and weekly until the lipid response to bexarotene is established, which usually occurs within two to four weeks, and monitor at eight week intervals thereafter. Fasting triglycerides should be normal or normalized with appropriate intervention prior to initiating bexarotene therapy. Maintain triglyceride levels below 400 mg/dL to reduce the risk of clinical sequelae [see Warnings and Precautions (5.2)]. If fasting triglycerides are elevated or become elevated during treatment, institute antilipemic therapy, and if necessary, reduce or interrupt the dose of bexarotene. In the 300 mg/m2 /day initial dose group, 60% of patients were given lipid lowering drugs. Atorvastatin was used in 48% (73/152) of patients with CTCL. Because of a potential drug-drug interaction, avoid gemfibrozil use with bexarotene [see Drug Interactions (7)].

5.2 Pancreatitis

Acute pancreatitis, including a fatal case, has been reported in four patients with CTCL and in six patients with non-CTCL cancers treated with bexarotene; the cases were associated with marked elevations of fasting serum triglycerides, the lowest being 770 mg/dL in one patient. One patient with advanced non-CTCL cancer died of pancreatitis. Interrupt bexarotene and evaluate if pancreatitis is suspected. Patients with CTCL who have risk factors for pancreatitis (e.g., prior pancreatitis, uncontrolled hyperlipidemia, excessive alcohol consumption, uncontrolled diabetes mellitus, biliary tract disease, and medications known to increase triglyceride levels or to be associated with pancreatic toxicity) may be at greater risk for pancreatitis associated with bexarotene [see Warnings and Precautions (5.1)].

5.3 Hepatotoxicity, cholestasis, and hepatic failure

Bexarotene caused elevations in liver chemistry tests (LFTs) in 5% (AST), 2% (ALT), and 0% (bilirubin) in patients with CTCL receiving an initial dose of 300 mg/m2 /day. In contrast, with an initial dose greater than 300 mg/m2 /day of bexarotene, the incidence of LFT elevations was higher at 7% (SGOT/AST), 9% (SGPT/ALT), and 6% (bilirubin). Two patients developed cholestasis, including one patient who died of liver failure. In clinical trials, elevated LFTs resolved within one month in 80% of patients following a decrease in dose or discontinuation of therapy. Obtain baseline LFTs and monitor LFTs after one, two and four weeks of treatment initiation, and if stable, at least every eight weeks thereafter during treatment. Interrupt or discontinue bexarotene if test results exceed three times the upper limit of normal values for AST, ALT, or bilirubin.

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