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Pronunciation:

(beks AIR oh teen)

U.S. Brand Names:

Targretin®

Generic Available:

Canadian Brand Names:

Targretin®

Use:

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

Topical: Treatment of cutaneous lesions in patients with refractory cutaneous T-cell lymphoma (stage 1A and 1B) or who have not tolerated other therapies

Pregnancy Risk Factor:

Pregnancy Implications:

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. Women of childbearing potential should use two forms of reliable contraception, one should be nonhormonal.

Lactation:

Excretion in breast milk unknown/contraindicated

Contraindications:

Hypersensitivity to bexarotene or any component of the formulation; pregnancy

Warnings/Precautions:

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. Induces significant lipid abnormalities in a majority of patients (triglyceride, total cholesterol, and HDL); 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.

Adverse Reactions:

First percentage is at a dose of 300 mg/m²/day; the second percentage is at a dose >300 mg/m²/day.

>10%:

Cardiovascular: Peripheral edema (13% to 11%)

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

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%:

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

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

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/gain, serum amylase (elevated), breast pain

Gastrointestinal: Abdominal pain (11% to 4%), nausea (16% to 8%), diarrhea (7% to 42%), vomiting (4% to 13%), anorexia (2% to 23%), 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% to 25%), eosinophilia, thrombocythemia, coagulation time increased, lymphocytosis, thrombocytopenia

Hepatic: LDH increase (7% to 13%), hepatic failure

Neuromuscular & skeletal: Back pain (2% 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 (4% to 13%), bacterial infection (1% to 13%)

Topical:

Cardiovascular: Edema (10%)

Central nervous system: Headache (14%), weakness (6%), pain (30%)

Dermatologic: Rash (14% to 72%), pruritus (6% to 40%), contact dermatitis (14%), exfoliative dermatitis (6%)

Hematologic: Leukopenia (6%), lymphadenopathy (6%)

Neuromuscular & skeletal: Paresthesia (6%)

Respiratory: Cough (6%), pharyngitis (6%)

Miscellaneous: Diaphoresis (6%), infection (18%)

Overdosage/Toxicology:

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.

Drug Interactions:

Substrate of CYP3A4 (minor); Induces CYP3A4 (weak)

DEET (a common component of insect repellents) should not be used concomitantly with the gel formulation; increased DEET toxicity may occur.

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

Hormonal contraceptives: Bexarotene may increase the metabolism and decrease the serum levels of hormonal contraceptives. Two reliable forms of contraception are recommended. At least one nonhormonal form of contraception is recommended for women of childbearing potential.

Tamoxifen: Bexarotene may decrease the serum levels of tamoxifen by ~35%.

Ethanol/Nutrition/Herb Interactions:

Food: Take with a fat-containing meal. Bexarotene serum levels may be increased by grapefruit juice; avoid concurrent use.

Herb/Nutraceutical: Avoid dong quai, St John's wort (may also cause photosensitization). St John's wort may decrease bexarotene levels. Additional vitamin A supplements may lead to vitamin A toxicity (dry skin, irritation, arthralgias, myalgias, abdominal pain, hepatic changes).

Stability:

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

Mechanism of Action:

The exact mechanism is unknown. Binds and activates retinoid X receptor subtypes. 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.

Pharmacodynamics/Kinetics:

Absorption: Significantly improved by a fat-containing meal

Protein binding: >99%

Metabolism: Hepatic via CYP3A4 isoenzyme; four metabolites identified; further metabolized by glucuronidation

Half-life elimination: 7 hours

Time to peak: 2 hours

Excretion: Primarily feces; urine (<1% as unchanged drug and metabolites)

Dosage:

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

Topical: Apply once every other day for first week, then increase on a weekly basis to once daily, 2 times/day, 3 times/day, and finally 4 times/day, according to tolerance

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

Administration:

Oral: Administer capsule following a fat-containing meal.

Topical: Allow gel to dry before covering with clothing. Avoid application to normal skin. Use of occlusive dressings is not recommended.

Monitoring Parameters:

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

Dietary Considerations:

It is preferable to take the oral capsule following a fat-containing meal.

Patient Education:

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Use exactly as directed. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. Avoid grapefruit juice, St John's wort, or additional vitamin A supplements while using this medication. You may be more susceptible to infection (avoid crowds and exposure to infection and do not have any vaccinations without consulting prescriber). May cause nausea, vomiting, anorexia, flatulence (frequent, small meals, good mouth care, chewing gum, or sucking lozenges may help); constipation (increased exercise, fluid, fruit, or fiber may help); diarrhea (buttermilk, boiled milk, or yogurt may help); headache, back or muscle pain (consult prescriber for mild analgesic); or photosensitivity (avoid direct sunlight, wear protective clothing and hat, use sunblock, and protective eyewear). Report chest pain, rapid heartbeat; unresolved GI effects; headache, back or muscle pain; skin dryness, skin rash or peeling; mucous membrane lesions; altered urinary patterns; flu syndrome or opportunistic infection (eg, weakness, fatigue, white plaques or sores in mouth, vaginal discharge, chills, fever); CNS disturbances (insomnia, dizziness, agitation, confusion, depression); vision or hearing changes; or any other adverse effects. Pregnancy/breast-feeding precautions: Pregnancy test is needed 1 week before initiation of therapy and every month during therapy. Consult prescriber for appropriate barrier contraceptives. Effective contraception must be in place 1 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 when having sexual intercourse while using this medication and for 1 month after last dose. Do not breast-feed.

Oral: Take exactly as directed, at the same time each day with a fat-containing meal. If you miss a dose, take as soon as possible. If it is almost time for next dose, skip the missed dose and continue on regular schedule. Do not double doses.

Topical: Apply as directed. Allow gel to dry before covering. Avoid applying to normal skin or mucous membranes. Do not use occlusive dressings.

Nursing Implications:

Educate patient about medicine and frequency of laboratory monitoring

Dental Health: Effects on Dental Treatment:

Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation) and gingivitis.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

No information available to require special precautions

Mental Health: Effects on Mental Status:

May cause insomnia, agitation, confusion, and depression

Mental Health: Effects on Psychiatric Treatment:

Leukopenia is common; use caution with clozapine and carbamazepine; effects of psychotropics may be altered secondary to the insomnia, confusion, agitation, and depression seen with bexarotene

Oncology: Emetic Potential:

Low (10% to 30%)

Dosage Forms:

Capsule: 75 mg

Gel: 1% (60 g)

International Brand Names:

Targretin® (AT, CA, DE, ES, FR, GB)

References

Duvic M, "Bexarotene and DAB(389)IL-2 (denileukin diftitox, ONTAK) in Treatment of Cutaneous T-cell Lymphomas: Algorithms,"Clin Lymphoma, 2000, 1(Suppl 1):51-5.

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