Bexarotene

FDA Drug Information • Also known as: Bexarotene, Targretin

Brand Names: Bexarotene, Targretin
Dosage Form: CAPSULE, LIQUID FILLED
Product Type: DRUG FOR FURTHER PROCESSING

⚠ Boxed Warning (Black Box)

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 ) WARNING: BIRTH DEFECTS See full prescribing information for complete boxed warning. 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 )

Description

11 DESCRIPTION Bexarotene capsules are a member of a subclass of retinoids that selectively activate retinoid X receptors (RXRs). These retinoid receptors have biologic activity distinct from that of retinoic acid receptors (RARs). The chemical name of bexarotene is 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) ethenyl] benzoic acid, and the structural formula is as follows: Bexarotene is an off-white to white powder with a molecular weight of 348.48 and a molecular formula of C 24 H 28 O 2 . It is insoluble in water and slightly soluble in vegetable oils and ethanol, USP. Each bexarotene capsule contains 75 mg of bexarotene for oral administration. It also contains the following inactive ingredients: butylated hydroxyanisole, polyethylene glycol, polysorbate and povidone. The capsule shell contains gelatin, glycerin, sorbitol, titanium dioxide and water. Chemical Structure

What Is Bexarotene Used For?

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. Bexarotene capsules are a retinoid indicated for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma in patients who are refractory to at least one prior systemic therapy. ( 1 )

Dosage and Administration

2 DOSAGE AND ADMINISTRATION The recommended initial dose of bexarotene is 300 mg/m 2 /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 Initial Dose Calculation According to Body Surface Area Initial Dose Level (300 mg/m 2 /day) Number of 75 mg Bexarotene Capsules Body Surface Area (m 2 ) Total Daily Dose (mg/day) 0.88 – 1.12 300 4 1.13 – 1.37 375 5 1.38 – 1.62 450 6 1.63 – 1.87 525 7 1.88 – 2.12 600 8 2.13 – 2.37 675 9 2.38 – 2.62 750 10 Recommended initial dose is 300 mg/m 2 /day. ( 2 ) Take bexarotene capsules as a single oral daily dose with a meal. ( 2 ) Dose adjustment: may be adjusted to 200 mg/m 2 /day then to 100 mg/m 2 /day. ( 2 ) Dose Modification Guidelines: The 300 mg/m 2 /day dose level of bexarotene may be adjusted to 200 mg/m 2 /day then to 100 mg/m 2 /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/m 2 /day is well tolerated, the dose may be escalated to 400 mg/m 2 /day with careful monitoring. Duration of Therapy: In clinical trials in CTCL, bexarotene was administered for up to 97 weeks. Bexarotene capsules should be continued as long as the patient is deriving benefit.

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information: Hyperlipidemia [ see Warnings and Precautions (5.1) ] Pancreatitis [ see Warnings and Precautions (5.2) ] Hepatotoxicity, cholestasis, and hepatic failure [ see Warnings and Precautions (5.3) ] Hypothyroidism [ see Warnings and Precautions (5.4) ] Neutropenia [ see Warnings and Precautions (5.5) ] Cataracts [ see Warnings and Precautions (5.6) ] Vitamin A Supplementation Hazard [ see Warnings and Precautions (5.7) ] Hypoglycemia Risk in Patients with Diabetes Mellitus [ see Warnings and Precautions (5.8) ] Photosensitivity [ see Warnings and Precautions (5.9) ] Laboratory Tests [ see Warnings and Precautions (5.10) ] Drug/Laboratory Test Interactions [ see Warnings and Precautions (5.11) ] The most common adverse reactions (greater than 10%) include: hyperlipidemia, hypercholesteremia, headache, hypothyroidism, asthenia, leukopenia, rash, nausea, infection, peripheral edema, abdominal pain, and dry skin. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Upsher-Smith Laboratories, LLC at 1-855-899-9180 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of bexarotene has been evaluated in two clinical trials of 152 patients with CTCL who received bexarotene for up to 97 weeks and in 352 patients in other trials. The mean duration of therapy for the 152 patients with CTCL was 166 days. The most common adverse events reported with an incidence of at least 10% in patients with CTCL treated at an initial dose of 300 mg/m 2 /day of bexarotene are shown in Table 2. The events at least possibly related to treatment are lipid abnormalities (elevated triglycerides, elevated total and LDL cholesterol and decreased HDL cholesterol), hypothyroidism, headache, asthenia, rash, leukopenia, anemia, nausea, infection, peripheral edema, abdominal pain, and dry skin. Most adverse events occurred at a greater incidence in patients treated at starting doses of greater than 300 mg/m 2 /day (see Table 2 ). Adverse reactions leading to bexarotene dose reduction or discontinuation in at least two patients were hyperlipemia, neutropenia/leukopenia, diarrhea, fatigue/lethargy, hypothyroidism, headache, liver function test abnormalities, rash, pancreatitis, nausea, anemia, allergic reaction, muscle spasm, pneumonia, and confusion. The NCI Grade 3 and NCI Grade 4 adverse reactions reported in two or more patients with CTCL treated at an initial dose of 300 mg/m 2 /day of bexarotene (see Table 3 ) were hypertriglyceridemia, pruritus, headache, peripheral edema, leukopenia, rash, and hypercholesteremia. Most of these moderately severe or severe adverse events occurred at a higher rate in patients treated at starting doses of greater than 300 mg/m 2 /day than in patients treated at a starting dose of 300 mg/m 2 /day. In patients with CTCL receiving an initial dose of 300 mg/m 2 /day, the incidence of NCI Grade 3 or 4 elevations in triglycerides and total cholesterol was 28% and 25%, respectively (Table 4). In contrast, in patients with CTCL receiving greater than 300 mg/m 2 /day, the incidence of NCI Grade 3 or 4 elevated triglycerides and total cholesterol was 45% and 45%, respectively. Other Grade 3 and 4 laboratory abnormalities are shown in Table 3. In addition to the 152 patients enrolled in the two CTCL trials, 352 patients received bexarotene as monotherapy for various advanced malignancies at doses from 5 mg/m 2 /day to 1000 mg/m 2 /day. The common adverse reactions (incidence greater than 10%) were similar to those seen in patients with CTCL. In the 504 patients (CTCL and non-CTCL) who received bexarotene...

Drug Interactions

7 DRUG INTERACTIONS Effect of Other Drugs on Bexarotene Gemfibrozil: Concomitant administration of bexarotene and gemfibrozil resulted in increases in plasma concentrations of bexarotene. Concomitant administration of gemfibrozil with bexarotene is not recommended. Effect of Bexarotene on Other Drugs Bexarotene may be an inducer for the CYP3A4 enzymes, and may reduce plasma concentrations of other substrates metabolized by CYP3A4. Drug products which may be affected include oral or other systemic hormonal contraceptives. Thus, if treatment with bexarotene is intended for a female with reproductive potential, it is strongly recommended that a non-hormonal contraception be considered [ see Use in Specific Populations (8.3) , Clinical Pharmacology (12.3) ]. Laboratory Test Interference CA125 assay values in patients with ovarian cancer may be increased by bexarotene therapy.

Contraindications

4 CONTRAINDICATIONS Pregnancy ( Boxed Warning , 4.1 ) Known hypersensitivity to bexarotene ( 4.2 ) 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.

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary Bexarotene, a retinoid, can cause fetal harm based on findings from animal studies when administered to a pregnant female and is contraindicated during pregnancy. Bexarotene was teratogenic and caused developmental mortality in rats following oral administration during organogenesis [ see Data ]. Bexarotene must not be given to a pregnant female or a female who intends to become pregnant. If pregnancy does occur during treatment with bexarotene, immediately discontinue the drug and advise the pregnant female of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. Data Animal Data Bexarotene caused malformations when administered orally to pregnant rats during days 7 to 17 of gestation. Developmental abnormalities included incomplete ossification at 4 mg/kg/day and cleft palate, depressed eye bulge/microphthalmia, and small ears at 16 mg/kg/day. The plasma AUC of bexarotene in rats at 4 mg/kg/day is approximately one third the AUC in humans at the recommended daily dose. At doses greater than 10 mg/kg/day, bexarotene caused developmental mortality. The no effect dose for fetal effects in rats was 1 mg/kg/day (producing an AUC approximately one sixth of the AUC at the recommended human daily dose).

Overdosage

10 OVERDOSAGE Doses up to 1000 mg/m 2 /day of bexarotene have been administered in short-term trials in patients with advanced cancer without acute toxic effects. Single doses of 1500 mg/kg and 720 mg/kg were tolerated without significant toxicity in rats and dogs, respectively. These doses are approximately 30 and 50 times, respectively, the recommended human dose on a mg/m 2 basis.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Bexarotene Capsules are supplied as 75 mg off-white, oblong soft gelatin capsules, imprinted "US285" in black ink. They are supplied as follows: Bottles of 100 capsules: NDC 0832-0285-00 Store at 2° to 25°C (36° to 77°F). Avoid exposing to high temperatures and humidity after the bottle is opened. Protect from light.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.