Bexarotene

Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: 4-[1-(5,6,7,8-Tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)ethenyl]benzoic acid
Molecular Formula: C₂₄H₂₈O₂
CAS Number: 153559-49-0
Brands: Targretin

May cause birth defects in humans; teratogenicity and embryolethality demonstrated in animals.^{1 2} Contraindicated in pregnant women.^{1 2} See Fetal/Neonatal Morbidity and Mortality under Cautions.

Introduction

Antineoplastic agent; synthetic retinoid analog.¹

Uses for Bexarotene

Cutaneous T-cell Lymphoma

Treatment of skin manifestations of cutaneous T-cell lymphoma (CTCL) in patients who are refractory to at least one prior systemic therapy.^{1 8 9}

Bexarotene Dosage and Administration

Administration

Oral Administration

Administer orally once daily with a meal.^{1 2 3}

Dosage

Adults

CTCL

Oral

Initially, 300 mg/m² daily.^{1 2 3}

If intolerable adverse effects occur, decrease dosage to 200 mg/m² daily, then 100 mg/m² daily, or temporarily discontinue.^{1 2} When toxicity is controlled, carefully readjust dosage upward.^{1 2}

If no tumor response is observed after 8 weeks and the 300-mg/m² daily dosage is well tolerated, increase to 400 mg/m² daily with careful monitoring.^{1 2 3}

Continue as long as benefit is derived from therapy.^{1 2} Optimum duration is not known.¹

Cautions for Bexarotene

Contraindications

• 
  

  Known or suspected pregnancy.^{1 2 3}

  
  


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  Known hypersensitivity to bexarotene or any ingredient in the formulation.^{1 2}

  
  

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryolethality demonstrated in animals.^{1 2 2}

Exclude pregnancy 1 week prior to initiation of therapy.¹ Initiate therapy on second or third day of normal menstrual period.¹ Repeat pregnancy tests monthly during therapy.¹ To facilitate pregnancy test assessment and counseling, dispense no more than 1 month supply.^{1 2}

Use contraception (2 reliable forms, including at least 1 nonhormonal method) for 1 month before, during, and for 1 month after administration.^{1 2} Male patients should use condoms during sexual intercourse with women who are or may become pregnant.^{1 2}

If pregnancy occurs, immediately discontinue and apprise of potential fetal hazard.^{1 2}

Effects on Lipoproteins

Lipid abnormalities (e.g., hyperlipidemia, elevated fasting triglycerides and cholesterol, decreased HDL-cholesterol) occur in most patients; usually develop within 2–4 weeks and are reversible with cessation of therapy.¹

If fasting triglycerides are or become elevated, institute antilipemic therapy and reduce bexarotene dosage or suspend therapy.¹ Gemfibrozil is not recommended.¹ (See Specific Drugs and Foods under Interactions.) Monitor fasting blood lipid levels weekly until lipid response is established, then at 8 week intervals.¹

Pancreatitis

Possible acute pancreatitis; possibly fatal.^{1 2} Patients with risk factors for pancreatitis (e.g., prior pancreatitis, uncontrolled hyperlipidemia or diabetes mellitus, excessive alcohol consumption, biliary tract disease, or therapy with drugs associated with pancreatic toxicity or known to increase triglyceride concentrations) generally should not receive bexarotene.^{1 2}

Hepatic Effects

Possible elevations in AST and ALT; usually resolve within 1 month following decrease in dosage or discontinuance.^{1 2}

Monitor liver function tests at baseline; after 1, 2, and 4 weeks of treatment; and at least every 8 weeks thereafter.¹ Consider discontinuance if transaminases or bilirubin increase to 3 times ULN.^{1 2}

Thyroid Effects

Possible hypothyroidism.^{1 2} Consider thyroid supplementation in patients with laboratory evidence of hypothyroidism.¹ Monitoring of thyroid function tests recommended.¹

Hematologic Effects

Leukopenia (generally neutropenia) possible, rarely associated with serious adverse events;^{1 2} time to onset usually 4–8 weeks, with resolution occurring within 30 days of dosage reduction or discontinuance of the drug in most patients.^{1 2} Obtain WBC with differential at baseline and periodically during therapy.¹

Ocular Effects

New cataracts or worsening of existing cataracts possible.^{1 2} Ophthalmologic evaluation recommended if visual difficulties occur.^{1 2}

Sensitivity Reactions

Hypersensitivity

Use with caution in patients with known hypersensitivity to retinoids.^{1 2}

Photosensitivity Reactions

Sunburn and skin sensitivity to sunlight possible in patients exposed to direct sunlight.^{1 2} Minimize exposure to sunlight and artificial UV light.^{1 2}

Specific Populations

Pregnancy

Category X.^{1 2} (See Fetal/Neonatal Morbidity and Mortality and also Contraindications under Cautions.)

Lactation

Not known whether bexarotene is distributed into milk.^{1 2} Discontinue nursing or the drug.^{1 2}

Pediatric Use

Safety and efficacy not established in children <18 years of age.^{1 2}

Geriatric Use

No substantial differences in safety relative to younger adults, but increased sensitivity cannot be ruled out.^{1 2}

Hepatic Impairment

Use only with great caution.¹ (See Hepatic Effects under Cautions and also Elimination: Special Populations under Pharmacokinetics.)

Common Adverse Effects

Lipid abnormalities, hypothyroidism, headache, asthenia, rash, leukopenia, anemia, nausea, infection, peripheral edema, abdominal pain, dry skin.^{1 2}

Interactions for Bexarotene

Metabolized by CYP3A4.¹ Possibly also an inducer of CYP3A4.¹

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors or inducers of CYP3A4: potential pharmacokinetic interaction (altered bexarotene metabolism).^{1 2 3}

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4: potential pharmacokinetic interaction (decreased plasma substrate concentrations).¹

Protein-bound Drugs

Potential pharmacokinetic interaction (bexarotene displacement by, or bexarotene displacement of, other protein-bound drugs).¹

Specific Drugs and Foods

Drug or Food	Interaction	Comments
Antidiabetic agents (e.g., insulin, sulfonylureas, other oral antidiabetic agents)	Potential increased incidence of hypoglycemia1 2 3	Use concomitantly with caution1
Antifungals (e.g., itraconazole, ketoconazole)	Possible increased plasma bexarotene concentrations1 2 3
Atorvastatin	Pharmacokinetic interaction unlikely1
Erythromycin	Possible increased plasma bexarotene concentrations 1 2 3
Gemfibrozil	Increased plasma bexarotene concentrations1 2 3	Concomitant use not recommended1 2
Grapefruit juice	Possible increased plasma bexarotene concentrations1 2 3
Hormonal contraceptives	Decreased plasma concentrations of hormonal contraceptives1
Phenobarbital	Possible decreased plasma bexarotene concentrations1 2 3
Phenytoin	Possible decreased plasma bexarotene concentrations1 2 3
Rifampin	Possible decreased plasma bexarotene concentrations1 2 3
Tamoxifen	Decreased plasma tamoxifen concentrations1
Vitamin A	Possible increased toxicity1 2

Bexarotene Pharmacokinetics

Absorption

Bioavailability

Absorbed following oral administration, with peak plasma concentrations attained within approximately 2 hours.¹

Food

Peak plasma concentrations and AUC (after 75–300 mg doses) increased by approximately 48 and 35%, respectively, after a meal containing fat compared with glucose solution.¹

Distribution

Extent

Distribution into body tissues and fluids has not been evaluated.¹

It is not known whether bexarotene is distributed into milk.¹

Plasma Protein Binding

>99%.¹

Special Populations

In patients with renal impairment, possible altered protein binding and pharmacokinetics.¹

Elimination

Metabolism

Metabolized extensively in the liver; in vitro, metabolized principally via CYP3A4 oxidation.¹ Oxidative metabolites active in vitro; relative contributions of parent drug or metabolites to safety and efficacy unknown.¹

Elimination Route

Bexarotene and its metabolites eliminated principally via biliary excretion; not excreted in urine in appreciable amounts.^{1 2 3}

Half-life

Approximately 7 hours.¹

Special Populations

In patients with hepatic impairment, greatly decreased clearance expected.¹

Stability

Storage

Oral

Capsules

2–25°C.¹ Avoid exposure to high temperatures and humidity after bottle is opened; protect from light.¹

ActionsActions

• 
  

  Selectively binds with and activates retinoid X receptor (RXR) subtypes (RXR_α, RXR_β, and RXR_γ).^{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

  
  

Advice to Patients

• 
  

  Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed.¹

  
  


• 
  

  Importance of women and men taking measures to avoid pregnancy because of risk to fetus.^{1 2}

  
  


• 
  

  Importance of men using condoms during sexual intercourse while receiving the drug and for at least 1 month after discontinuing the drug.^{1 2}

  
  


• 
  

  Importance of monthly pregnancy tests.^{1 2}

  
  


• 
  

  Importance of patients informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.^{1 2}

  
  


• 
  

  Importance of taking bexarotene with, or immediately following, a meal.^{1 2}

  
  


• 
  

  Risk of photosensitivity reactions.^{1 2}

  
  


• 
  

  Risk of hypoglycemia in patients being treated for diabetes mellitus.^{1 2}

  
  


• 
  

  Importance of adhering to laboratory appointment schedules.^{1 2}

  
  


• 
  

  Importance of informing patients of other important precautionary information. (See Cautions.)

  
  

Preparations

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

Bexarotene

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	75 mg	Targretin (with povidone)	Ligand

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Targretin 75MG Capsules (EISAI): 30/$1079.99 or 90/$3179.96

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions May 2006. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Ligand Pharmaceuticals. Targretin (bexarotene) capsules prescribing information. San Diego, CA; 2003 Apr.

2. Ligand Pharmaceuticals. Targretin capsules (bexarotene) product monograph. San Diego, CA; 2000 Feb.

3. Anon. Bexarotene (Targretin) for cutaneous T-cell lymphoma. Med Lett Drugs Ther. 2000; 42:31-2. [PubMed 10788961]

4. Duvic M, Martin AG, Kim Y et al. Phase 2 and 3 clinical trial of oral bexarotene (Targretin capsules) for the treatment of refractory or persistent early-stage cutaneous T-cell lymphoma. Arch Dermatol. 2001; 137:581-93. [IDIS 464564] [PubMed 11346336]

5. Duvic M, Hymes K, Heald P et al. Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II-III trial results. J Clin Oncol. 2001; 19:2456-71. [IDIS 465867] [PubMed 11331325]

6. Ligand Pharmaceuticals. Targretin (bexarotene) gel 1% prescribing information. San Diego, CA; 2001 Jan. From Ligand web site

7. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD; 2000 Aug 3. From FDA web site From FDA web site.

8. Anon. Drugs of choice for cancer. Treat Guidel Med Lett. 2003; 1:41-52. [PubMed 15529105]

9. Mycosis fungoides and the Sezary syndrome. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2003 Dec 12.

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