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Bexarotene

Pronunciation: bex-AIR-oh-teen
Class: Rexinoid

Trade Names

Targretin
- Gelatin capsules for oral use 75 mg

Pharmacology

Bexarotene selectively binds and activates retinoid X receptor subtypes (RXRα, RXRβ, RXRΥ). Once activated, these receptors function as transcription factors that regulate the expression of genes that control cellular differentiation and proliferation. Inhibits the growth in vitro of some tumor cell lines of hematopoietic and squamous cell origin and induces tumor regression in vivo in some animal models.

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Pharmacokinetics

Absorption

Oral

T max is about 2 h. High-fat meal increased AUC 35% and C max 48%.

Topical

Plasma concentrations generally are less than 5 ng/mL and do not exceed 55 ng/mL.

Distribution

Greater than 99% protein bound.

Metabolism

CYP3A4 may be responsible for the oxidative metabolites (active).

Elimination

The t ½ is about 7 h. Less than 1% is excreted in urine. Eliminated primarily through hepatobiliary system.

Indications and Usage

Refractory cutaneous T-cell lymphoma (CTCL).

Contraindications

Pregnancy; hypersensitivity to bexarotene or other product components.

Dosage and Administration

Refractory CTCL
Adults

PO

Initial dose

300 mg/m 2 /day as a single daily dose. An initial dose of 150 to 225 mg also has been used.

Maintenance dose

Increase dose to 400 mg/m 2 /day if no tumor response after 8 wk. A target maintenance dose of 450 to 525 mg also has been used. Continue therapy as response is favorable. See manufacturer product information for specific body surface area dosing.

Adults

Topical Apply topical gel to cutaneous lesions every other day initially. Increase application at weekly intervals (eg, every day, twice daily, 3 times daily) up to target dose of 4 times daily as tolerated. Onset of response ranges from 4 to 56 wk. Continue therapy as long as response is favorable. Consider reducing frequency or discontinuing application if severe skin irritation occurs. Resume therapy after several days.

Dosage Adjustment (Oral Therapy)
Adults

PO Adverse reactions requiring dosage adjustment include AST, ALT, or bilirubin greater than 3 times the ULN, leukopenia or neutropenia, or hypertriglyceridemia unresponsive to therapy. Reduce dose to 200 mg/m 2 /day. If reaction does not resolve, decrease to 100 mg/m 2 /day or temporarily discontinue. Bexarotene is metabolized extensively by hepatic CYP-450 3A4 isoenzymes. Dosage adjustment in hepatic insufficiency is warranted; however, there are not specific guidelines.

General Advice

  • In women of childbearing potential, initiate therapy on the second or third day of a normal menstrual period.
  • Give with food. There are no data about administration on an empty stomach.
  • Gently apply gel to lesions without rubbing. Spread gel in an even, generous layer. Allow gel to dry for 5 to 10 min before covering with loose clothing. Do not cover with occlusive dressings. Keep treated lesions dry for 3 h after applying gel.
  • To minimize irritation and redness of healthy skin, apply bexarotene gel only to CTCL lesions. Avoid applying gel to surrounding healthy skin.
  • Wipe hands and fingers with a disposable tissue immediately after applying bexarotene gel. Wash hands thoroughly with soap and water. Although systemic absorption of bexarotene is minimal with topical use, gloves may be worn at the health care provider's discretion.
  • Avoid contact with eyes, mucous membranes, and unaffected skin.

Storage/Stability

Store capsule at 36° to 77°F. Store gel at controlled room temperature (59° to 86°F). Avoid exposing to high temperatures and humidity after the bottle is opened. Protect from light.

Drug Interactions

Antidiabetic agents (eg, insulin sulfonylureas, insulin-sensitizers)

May enhance antidiabetic agents, resulting in hypoglycemia.

Contraceptives, oral

Potentially can induce metabolic enzymes and thereby theoretically reduce plasma concentrations of hormonal contraceptives. It is strongly recommended that 2 reliable forms of contraception be used concurrently, 1 of which should be nonhormonal.

CYP-450 inducers (eg, rifampin, phenytoin, phenobarbital, primidone)

May reduce plasma bexarotene concentrations.

CYP-450 inhibitors (eg, ketoconazole, itraconazole, erythromycin, grapefruit juice)

May increase plasma bexarotene concentrations.

DEET

For topical use, the absorption of DEET increases when used concomitantly with bexarotene gel, resulting in increased toxicity of DEET.

Gemfibrozil

Resulted in substantial increases in plasma concentrations of bexarotene.

Tamoxifen

Coadministration of bexarotene capsules and tamoxifen resulted in a modest decrease in plasma tamoxifen concentrations, possibly through an induction of CYP-450 3A4.

Vitamin A

Bexarotene is a member of the retinoids. Limit vitamin A supplements to avoid potential additive toxic effects (up to 15,000 units/day).

Laboratory Test Interactions

CA125 assay values in patients with ovarian cancer may be increased by bexarotene therapy.

Adverse Reactions

Cardiovascular

Peripheral edema (oral).

CNS

Headache, asthenia (oral).

Dermatologic

Photosensitivity; rash, dry skin, exfoliative dermatitis, alopecia (oral); pruritus, pain, skin disorder (topical).

Endocrine

Hypothyroidism (oral).

GI

Nausea, vomiting, diarrhea, anorexia, hyperbilirubinemia, elevated LFTs (oral).

Genitourinary

Fetal malformation; developmental abnormality; developmental mortality.

Hematologic

Leukopenia, anemia (oral).

Metabolic-Nutritional

Hyperlipidemia, hypercholesteremia (oral).

Other

Infection, flu-like symptom, fever, chills (oral).

Precautions

Warnings

Contraindication in pregnancy.

Teratogenicity has been reported when administered orally to pregnant rats.


Monitor

Monitor fasting lipid panels at baseline, weekly for 2 to 4 wk, and every 8 wk during therapy. Reduce triglyceride concentrations to less than 400 mg/dL before starting bexarotene. Lipid-lowering medications, such as the statins, may be helpful; do not use gemfibrozil.

Monitor LFTs (eg, bilirubin, AST, ALT) at baseline and 1, 2, and 4 wk after starting bexarotene. If results are stable, monitor every 8 wk throughout treatment.


Pregnancy

Category X . Perform a pregnancy test 1 wk before initiating bexarotene therapy in women. In all women of childbearing age, initiate 2 methods of contraception 1 mo before starting bexarotene therapy, during therapy, and for 1 mo after bexarotene discontinuation. Repeat pregnancy test monthly and reinforce contraceptive counseling; dispense up to a 1 mo supply to facilitate these efforts. For men with partners of childbearing potential, recommend condom use during therapy and for 1 mo after discontinuation.

Lactation

Undetermined. Because of the potential for serious adverse reactions in breast-feeding infants from bexarotene, decide whether to discontinue breast-feeding or to discontinue the drug, taking into account the importance of the drug to the mother.

Children

Safety and efficacy not established.

Hepatic Function

There is in vitro evidence of extensive hepatic contribution to bexarotene elimination.

Fertility

Caused testicular degeneration when oral doses of 1.5 mg/kg/day were given to dogs for 91 days.

Photosensitivity

Retinoids as a class have been associated with photosensitivity.

Cataracts

Posterior subcapsular cataracts were observed in preclinical toxicity studies in rats and dogs administered bexarotene daily for 6 mo.

Diabetes mellitus

Use caution when administering in patients using insulin, agents enhancing insulin secretion (eg, sulfonlyureas), or insulin-sensitizers. Bexarotene could enhance the action of these agents, resulting in hypoglycemia.

Leukopenia

A total of 18% of patients with CTCL receiving an initial dose of 300 mg/m 2 /day of bexarotene had reversible leukopenia in the range of 1,000 to less than 3,000 WBC/mm 3 .

Lipid abnormalities

Induces major lipid abnormalities in most patients that must be monitored and treated during long-term therapy. Triglyceride levels greater than 2.5 times the ULN and cholesterol elevations greater than 300 mg/dL occurred in about 60% and 75% of patients with CTCL who received an initial dose of 300 mg/m 2 /day, respectively. Decreases in HDL also were seen.

LFT abnormalities

Elevations in LFTs have been observed in 5% (AST), 2% (ALT) for those patients receiving initial doses.

Pancreatitis

Acute pancreatitis has been reported in 4 patients with CTCL and in 6 patients with non-CTCL cancers treated with bexarotene.

Thyroid abnormalities

Bexarotene induces biochemical evidence of clinical hypothyroidism in about 50% of all patients treated, causing a reversible reduction in thyroid hormone (total thyroxine [total T 4 ]) and TSH levels.

Vitamin A supplementation

Advise patients to limit vitamin A intake to up to 15,000 units/day to avoid potential additive toxic effects.

Patient Information

  • Advise women of childbearing potential to avoid becoming pregnant when taking bexarotene. Effective contraception must be used for 1 mo prior to the initiation of therapy, during therapy, and for at least 1 mo following discontinuation of therapy; it is recommended that 2 reliable forms of contraception be used simultaneously unless abstinence is the chosen method.
  • Advise patients to limit vitamin A supplements to avoid potential additive effects.
  • Advise patients to minimize exposure to sunlight and artificial UV light.
  • Instruct patients to avoid using insect repellents that contain DEET.

Copyright © 2009 Wolters Kluwer Health.

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