Bexarotene

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

Lipid abnormalities: Targretin® (bexarotene) capsules induce major lipid abnormalities in most patients. These must be monitored and treated during long term therapy. About 70% of patients with CTCL who received an initial dose of ≥ 300 mg/m2/day of Targretin® (bexarotene) capsules 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 Targretin® (bexarotene) capsules. The effects on triglycerides, HDL cholesterol, and total cholesterol were reversible with cessation of therapy, and could generally be mitigated by dose reduction or concomitant antilipemic therapy.

Fasting blood lipid determinations should be performed before Targretin® (bexarotene) capsules therapy is initiated and weekly until the lipid response to Targretin® (bexarotene) capsules is established, which usually occurs within two to four weeks, and at eight week intervals thereafter. Fasting triglycerides should be normal or normalized with appropriate intervention prior to initiating Targretin® (bexarotene) capsules therapy. Attempts should be made to maintain triglyceride levels below 400 mg/dL to reduce the risk of clinical sequelae (see WARNINGS: Pancreatitis). If fasting triglycerides are elevated or become elevated during treatment, antilipemic therapy should be instituted, and if necessary, the dose of Targretin® (bexarotene) capsules reduced or suspended. 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 (see PRECAUTIONS: Drug-Drug Interactions), gemfibrozil is not recommended for use with Targretin® (bexarotene) capsules.

Pancreatitis: Acute pancreatitis has been reported in four patients with CTCL and in six patients with non-CTCL cancers treated with Targretin® (bexarotene) capsules; 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. 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) should generally not be treated with Targretin® (bexarotene) capsules (see WARNINGS: Lipids abnormalities and PRECAUTIONS: Laboratory Tests).

Liver function test abnormalities: For patients with CTCL receiving an initial dose level of 300 mg/m2/day of Targretin® (bexarotene) capsules, elevations in liver function tests (LFTs) have been observed in 5% (SGOT/AST), 2% (SGPT/ALT), and 0% (bilirubin). In contrast, with an initial dose greater than 300 mg/m2/day of Targretin® (bexarotene) capsules, 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, elevation of LFTs resolved within one month in 80% of patients following a decrease in dose or discontinuation of therapy. Baseline LFTs should be obtained, and LFTs should be carefully monitored after one, two and four weeks of treatment initiation, and if stable, at least every eight weeks thereafter during treatment. Consideration should be given to a suspension or discontinuation of Targretin® (bexarotene) capsules if test results reach greater than three times the upper limit of normal values for SGOT/AST, SGPT/ALT, or bilirubin.

Hepatic Insufficiency: No specific studies have been conducted with Targretin® (bexarotene) capsules in patients with hepatic insufficiency. Because less than 1% of the dose is excreted in the urine unchanged and there is in vitro evidence of extensive hepatic contribution to bexarotene elimination, hepatic impairment would be expected to lead to greatly decreased clearance. Targretin® (bexarotene) capsules should be used only with great caution in this population.

Thyroid axis alterations: Targretin® (bexarotene) capsules induce biochemical evidence of or clinical hypothyroidism in about half of all patients treated, causing a reversible reduction in thyroid hormone (total thyroxine [total T4]) and thyroid-stimulating hormone (TSH) levels. The incidence of decreases in TSH and total T4 about 60% and 45%, respectively, in patients with CTCL receiving an initial dose of 300 mg/m2/day. Hypothyroidism was reported as an adverse event in 29% of patients. Treatment with thyroid hormone supplements should be considered in patients with laboratory evidence of hypothyroidism. In the 300 mg/m2/day initial dose group, 37% of patients were treated with thyroid hormone replacement. Baseline thyroid function tests should be obtained and patients monitored during treatment.

Leukopenia: A total of 18% of patients with CTCL receiving an initial dose of 300 mg/m2/day of Targretin® (bexarotene) capsules had reversible leukopenia in the range of 1000 to <3000 WBC/mm3. Patients receiving an initial dose greater than 300 mg/m2/day of Targretin® (bexarotene) capsules had an incidence of leukopenia of 43%. No patient with CTCL treated with Targretin® (bexarotene) capsules developed leukopenia of less than 1000 WBC/mm3. The time to onset of leukopenia was generally four to eight weeks. The leukopenia observed in most patients was explained by neutropenia. In the 300 mg/m2/day initial dose group, the incidence of NCI Grade 3 and Grade 4 neutropenia, respectively, was 12% and 4%. The leukopenia and neutropenia experienced during Targretin® (bexarotene) capsules therapy resolved after dose reduction or discontinuation of treatment, on average within 30 days in 93% of the patients with CTCL and 82% of patients with non-CTCL cancers. Leukopenia and neutropenia were rarely associated with severe sequelae or serious adverse events. Determination of WBC with differential should be obtained at baseline and periodically during treatment.

Cataracts:Posterior subcapsular cataracts were observed in preclinical toxicity studies in rats and dogs administered bexarotene daily for 6 months. In 15 of 79 patients who had serial slit lamp examinations, new cataracts or worsening of previous cataracts were found. Because of the high prevalence and rate of cataract formation in older patient populations, the relationship of Targretin® (bexarotene) capsules and cataracts cannot be determined in the absence of an appropriate control group. Patients treated with Targretin® (bexarotene) capsules who experience visual difficulties should have an appropriate ophthalmologic evaluation.

Oral:

Common side effects of bexarotene capsules include the following:

• decreased thyroid activity
• headache
• weakness
• rash
• low white blood cell counts
• anemia
• nausea
• infection
• swelling
• stomach pain
• dry skin

Topical:

Common side effects of bexarotene gel include the following:

• itching
• redness, burning, irritation, or scaling of the skin
• rash
• pain
• sweating
• weakness
• headache
• swelling of the arms, hands, feet, ankles, or lower legs

This is not a complete list of this medication’s side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Grapefruit and grapefruit juice may interact with this medication and can lead to potentially dangerous effects. Discuss the use of grapefruit products with your doctor.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

This medication falls into category X.

• For female patients:
  • If you can become pregnant, you will need to avoid becoming pregnant during your treatment with bexarotene. You must use two acceptable forms of birth control for 1 month before you begin to take bexarotene, at all times during your treatment, and for 1 month after your treatment. Your doctor will tell you which forms of birth control are acceptable. Bexarotene may decrease the effectiveness of hormonal contraceptives (birth control pills, patches, rings, implants, and injections), so it is especially important to use a second form of birth control along with this type of contraceptive.
  • You will begin to take bexarotene on the second or third day of your menstrual period. You must have a negative pregnancy test within 1 week of the start of your treatment and every month during your treatment. After each negative pregnancy test, you will be given only 1 month's supply of bexarotene.
  • Stop taking bexarotene and call your doctor right away if you think you are pregnant, you miss a menstrual period, or you have sex without using two forms of birth control.
• For male patients:
  • You must use a condom every time you have sexual contact with a female who is pregnant or able to become pregnant while you are taking bexarotene and for 1 month after your treatment. Call your doctor if your partner becomes pregnant during this time.

Oral:

• Store capsules at room temperature.
• Avoid exposing capsules to high temperatures and humidity after the bottle is opened.
• Protect capsules from light.
• Keep this and all medications out of the reach of children.

Topical:

• This product contains alcohol an should be kept away from open flame.
• Bexarotene gel takes time to work. In clinical trials, some patients began to respond as early as 4 weeks, but most patients did not experience their best response until 48 to 62 weeks of treatment. Do not stop treatment at the first sign of improvement. Continue to use bexarotene gel as instructed by your health care provider.
• The opening of the bexarotene gel tube is covered by a metal safety seal. If this seal has been punctured or is not visible when you first open the package, DO NOT USE this tube and promptly return the product to your pharmacy or place of purchase.
• To open, use the pointed portion of the cap to puncture the metal safety seal.
• Always use the cap to close the tube tightly after each use.
• Store at room temperature. Keep away from heat or flame.
• The gel should not be used after the expiration date printed on the tube.
• Keep this and all medications out of the reach of children.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Usual Adult Dose for Cutaneous T-cell Lymphoma:

300 mg/m2/day orally once a day with a meal

Duration of Therapy: This drug should be continued as long as the patient is deriving benefit. In clinical trials with CTCL patients, this drug was administered for up to 118 weeks.

Comments: If there is no tumor response after 8 weeks of treatment and the initial dose was well-tolerated, the dose may be escalated to 400 mg/m2/day with careful monitoring.

Use: Treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients refractory to at least one prior systemic therapy.

• Selectively binds with and activates retinoid X receptor (RXR) subtypes (RXRα, RXRβ, and RXRγ).1 2 3 Activated RXRs function as transcription factors that regulate the expression of genes controlling cellular differentiation and proliferation.1 2 3

• Exact mechanism(s) of action not determined, but bexarotene is active in all clinical stages of CTCL.2

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Avoid prolonged exposure to sunlight or artificial ultraviolet light (e.g. sunlamps). Bexarotene may increase the sensitivity of your skin to sunlight. Use a sunscreen and wear protective clothing when exposure to the sun is unavoidable.

Do not take bexarotene if you are pregnant or if you could become pregnant. Bexarotene is in the FDA pregnancy category X. This means that bexarotene will cause birth defects in an unborn baby. You must take a pregnancy test and have negative results within one week before starting treatment with bexarotene, and a pregnancy test should be repeated monthly during treatment. Bexarotene should be started on the second or third day of a normal menstrual period. Also, you will need to use two reliable forms of birth control at the same time for one month before starting treatment with bexarotene, during treatment with bexarotene, and for at least 1 month following the end of your treatment. If you become pregnant, stop using birth control, or miss your menstrual period, immediately stop taking bexarotene and notify your doctor. Men taking bexarotene with sexual partners who are pregnant, possibly pregnant, or who could become pregnant, must use condoms during sexual intercourse while using bexarotene and for at least one month after the last dose of bexarotene.

Swallow each capsule whole. Do not chew them, dissolve them in liquid, or allow them to dissolve in your mouth.

Your doctor will want to monitor the levels of lipids (triglycerides and cholesterol) and thyroid hormones in your blood periodically during treatment with bexarotene. Treatment may be necessary if your cholesterol or triglyceride levels become elevated, or if your thyroid hormone levels are low.

Grapefruit and grapefruit juice may interact with bexarotene. The interaction could have potentially dangerous effects. Discuss the use of grapefruit and grapefruit juice with your doctor. Do not increase or decrease the amount of grapefruit products in your diet without first talking to your doctor.

Data not available

This drug is a retinoid, a drug class associated with birth defects in humans. Additionally, animal studies have revealed evidence of developmental mortality, teratogenicity (e.g., cleft palate, incomplete ossification, depressed eye bulge/microphthalmia, small ears), testicular degeneration, and reversible aspermatogenesis. US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D and X are being phased out.

UK: Use is contraindicated during pregnancy and in women of childbearing potential without effective birth control measures. US: Use is contraindicated during pregnancy. US FDA pregnancy category: Not Assigned Comments: -Negative pregnancy tests (e.g., serum beta-human chorionic gonadotropin [beta-HCG]) with sensitivity of at least 50 mIU/L should be obtained within one week prior to therapy and at monthly intervals during treatment. -Female patients of reproductive potential should use effective contraception for one month prior to therapy initiation, during therapy, and for at least one month following treatment discontinuation. -Two reliable forms of contraception should be used simultaneously; one form should be non-hormonal as this drug may reduce the efficacy of oral and other systemic hormonal contraceptives. -Male patients should use condoms during treatment and for at least one month after the last dose if they have sexual partners who are pregnant or of childbearing potential.