Antineoplastic Agent, Miscellaneous

Treatment of cutaneous manifestations of cutaneous T-cell lymphoma in patients who are refractory to at least one prior systemic therapy

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Bexarotene caused birth defects when administered orally to pregnant rats. It must not be given to a pregnant woman or a woman who intends to become pregnant. If a woman becomes pregnant while taking the drug, it must be stopped immediately and appropriate counseling be given. It is not known whether bexarotene is excreted in human milk. Contraindicated in breast-feeding.

Hypersensitivity to bexarotene or any component, pregnancy, breast-feeding

Pregnancy test needed 1 week before initiation and every month thereafter. Effective contraception must be in place one month before initiation, during therapy, and for at least 1 month after discontinuation. Male patients with sexual partners who are pregnant, possibly pregnant, or who could become pregnant, must use condoms during sexual intercourse during treatment and for 1 month after last dose. In a majority of patients, it induces major lipid abnormalities in triglyceride, total cholesterol, and HDL, and is reversible on discontinuation. Use extreme caution in patients with underlying hypertriglyceridemia. Pancreatitis secondary to hypertriglyceridemia has been reported. Monitor for liver function test abnormalities and discontinue drug if tests are three times the upper limit of normal values for AST (SGOT), ALT (SGPT) or bilirubin. Hypothyroidism occurs in about a third of patients. Monitor for signs and symptoms of infection about 4-8 weeks after initiation (leukopenia may occur). Any new visual abnormalities experienced by the patient should be evaluated by an ophthalmologist (cataracts can form, or worsen, especially in the geriatric population). May cause photosensitization. Safety and efficacy are not established in the pediatric population. Avoid use in hepatically impaired patients. Limit additional vitamin A intake to <15,000 int. units/day. Use caution with diabetic patients: monitor for hypoglycemia.

First percentage is at a dose of 300 mg/m²/day; the second percentage is at a dose >300 mg/m²/day. Grade 3 and grade 4 events that occurred more frequently in patients at both doses were hyperlipidemia, hypertriglyceridemia, pruritus, headache, peripheral edema, leukopenia, rash, and hypercholesterolemia. Frequency of events was dose-related.

Central nervous system: Headache (30% to 42%), chills (10% to 13%)

Cardiovascular: Peripheral edema (13% to 11%)

Dermatologic: Rash (17% to 23%), exfoliative dermatitis (10% to 28%)

Endocrine & metabolic: Hyperlipidemia (about 79% in both dosing ranges), hypercholesteremia (32% to 62%), hypothyroidism (29% to 53%)

Hematologic: Leukopenia (17% to 47%)

Neuromuscular & skeletal: Weakness (20% to 45%)

Miscellaneous: Infection (13% to 23%)

<10%:

Central nervous system: Fever (5% to 17%), insomnia (5% to 11%), subdural hematoma, syncope, depression, agitation, ataxia, confusion, dizziness, hyperesthesia

Cardiovascular: Hemorrhage, hypertension, angina pectoris, right heart failure, tachycardia, cerebrovascular accident

Dermatologic: Dry skin (about 10% for both dosing ranges), alopecia (4% to 11%), skin ulceration, acne, skin nodule, maculopapular rash, serous drainage, vesicular bullous rash, cheilitis

Endocrine & metabolic: Hypoproteinemia, hyperglycemia, weight loss, weight gain, serum amylase (elevated), breast pain

Gastrointestinal: Abdominal pain (10.7% to 3.8%), nausea (15.5% to 7.5%), diarrhea (7.1% to 41.5%), vomiting (3.6% to 13.2%), anorexia (2.4% to 22.6%), constipation, xerostomia, flatulence, colitis, dyspepsia, gastroenteritis, gingivitis, melena, pancreatitis,

Genitourinary: Albuminuria, hematuria, urinary incontinence, urinary tract infection, urinary urgency, dysuria, kidney function abnormality

Hematologic: Hypochromic anemia (4% to 13%), anemia (6% - 24.5%), eosinophilia, thrombocythemia, coagulation time increased, lymphocytosis, thrombocytopenia

Hepatic: LDH increase (7.1% to 13%), hepatic failure

Neuromuscular & skeletal: Back pain (2.4% to 11%), arthralgia, myalgia, bone pain, myasthenia, arthrosis, neuropathy

Ocular: Dry eyes, conjunctivitis, blepharitis, corneal lesion, visual field defects, keratitis

Otic: Ear pain, otitis externa

Renal: Creatinine (elevated)

Respiratory: Pharyngitis, rhinitis, dyspnea, pleural effusion, bronchitis, increased cough, lung edema, hemoptysis, hypoxia

Miscellaneous: Flu-like syndrome (3.6% to 13.2%), bacterial infection (1.2% to 13.2%)

Doses up to 1000 mg/m²/day have been used in humans without acute toxic effects. Any overdose should be treated with supportive care focused on the symptoms exhibited.

CYP3A3/4 substrate

Decreased effect: Inducers of CYP3A3/4 (rifampin, phenytoin, phenobarbital, nafcillin) may cause a reduction in bexarotene concentration

Gemfibrozil caused a significant increase in bexarotene serum concentration; avoid concurrent use; consider atorvastatin as an alternative to gemfibrozil

Store at 2°C to 25°C (36°F to 77°F); protect from light

The exact mechanism in the treatment of cutaneous T-cell lymphoma is unknown. Binds and activates retinoid X receptor subtypes. Retinoid receptor subtypes can form heterodimers with various receptor partners such as retinoic acid receptors, vitamin D receptor, thyroid receptor and peroxisome proliferator activator receptors. Once activated, these receptors function as transcription factors that regulate the expression of genes which control cellular differentiation and proliferation. Bexarotene inhibits the growth in vitro of some tumor cell lines of hematopoietic and squamous cell origin.

Absorption: Significantly improved by a fat-containing meal

Protein binding: >99%

Metabolism: CYP3A3/4 enzyme system involved in metabolism. Four metabolites have been identified. Oxidative metabolites are further metabolized by glucuronidation.

Half-life: 7 hours

Time to peak: 2 hours

Elimination: Primarily through the hepatobiliary system. Only a very small amount (<1%) of bexarotene and its metabolites are excreted in the urine.

Adults: Oral: 300 mg/m²/day taken as a single daily dose. If there is no tumor response after 8 weeks and the initial dose was well tolerated, then an increase to 400 mg/m²/day can be made with careful monitoring. Maintain as long as the patient is deriving benefit.

If the initial dose is not tolerated, then it may be adjusted to 200 mg/m²/day, then to 100 mg/m²/day or temporarily suspended if necessary to manage toxicity

Dosing adjustment in renal impairment: No studies have been conducted; however, renal insufficiency may result in significant protein binding changes and alter pharmacokinetics of bexarotene

Dosing adjustment in hepatic impairment: No studies have been conducted; however, hepatic impairment would be expected to result in decreased clearance of bexarotene due to the extensive hepatic contribution to elimination

Take with a fat-containing meal

If female, pregnancy test 1 week before initiation then monthly while on bexarotene; lipid panel before initiation, then weekly until lipid response established and then at 8-week intervals thereafter; baseline LFTs, repeat at 1, 2, and 4 weeks after initiation then at 8-week intervals thereafter if stable; baseline and periodic thyroid function tests; baseline CBC with periodic monitoring

No information available to require special precautions

No effects or complications reported

Take with a fat-containing meal. Get pregnancy test before starting therapy and then every month thereafter while on the medicine. Do not get pregnant while taking this medicine. Use 2 forms of birth control 1 month before, during, and for at least a month after completion of therapy. For male patients, protect your partner against pregnancy by wearing a condom. Continue using protection for 1 month after last dose. Take at a similar time daily. Call your healthcare provider if you have a fever, chills, or any signs of infection. You are at risk of infections: stay away from crowds and people with viruses. Wash your hands frequently. Check vitamin A intake with your healthcare provider. You should avoid large amounts of vitamin A.

Educate patient about medicine and frequency of laboratory monitoring

Capsule: 75 mg