Bexarotene topical

Class: Skin and Mucous Membrane Agents, Miscellaneous
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

Introduction

Antineoplastic agent; synthetic retinoid analog.^{1 2 3 4 5 6 7 8 9 10 11 12}

Uses for Bexarotene

Cutaneous T-cell Lymphoma

Treatment of skin lesions in patients with early (stage IA and IB) cutaneous T-cell lymphoma (CTCL) who have refractory or persistent disease after other therapies or who are unable to tolerate other therapies (designated an orphan drug by US FDA for this use).^{1 2 5 12 13 14}

Not studied in combination with other CTCL therapies.¹

Bexarotene Dosage and Administration

Administration

Topical Administration

Topically apply a sufficient amount for a generous coating and rub gently into affected areas of skin.¹

Wait at least 20 minutes after bathing before application.^{1 2 5} Avoid use of occlusive dressings or wrappings.^{1 2 5}

Avoid contact with healthy skin or mucous membranes (e.g., eyes, mouth, vagina).^{1 2 5}

Allow gel to dry 5–10 minutes before covering a treated area with clothing.^{1 2 5}

Dosage

Adults

CTCL

Topical

Initially, once daily, every other day, for the first week.^{1 2 5}

Increase application frequency at weekly intervals to once, then twice daily, then 3 times daily, and finally 4 times daily, according to individual lesion tolerance.^{1 2 5}

If application site toxicity occurs, reduce application frequency; temporarily discontinue if severe irritation occurs.¹

Most responses occurred when applied ≥2 times daily in clinical studies.^{1 5} Therapeutic response may be observed as early as 4 weeks, but usually occurred later.^{1 5}

Continue as long as benefit is derived.^{1 5} Although continued for up to 172 weeks in clinical studies, optimum duration is not known.^{1 5 6 7 8 13}

Cautions for Bexarotene

Contraindications

• 
  

  Known or suspected pregnancy.^{1 2 5}

  
  


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  Known hypersensitivity to bexarotene or any ingredient in the formulation.^{1 2 5}

  
  

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryolethality demonstrated in animals receiving oral bexarotene.^{1 2 5}

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) for 1 month before, during, and for 1 month after discontinuance.^{1 2 5} Male patients should use condoms during sexual intercourse with women who are or may become pregnant during and for at least 1 month after discontinuance.^{1 2 5}

If pregnancy occurs, immediately discontinue and apprise of potential fetal hazard.^{1 5}

Sensitivity Reactions

Hypersensitivity

Use with caution in patients with known hypersensitivity to retinoids.^{1 2 5}

Photosensitivity

Minimize exposure to sunlight and artificial UV light.^{1 2 5} Sunburn and skin sensitivity to sunlight observed in patients receiving oral bexarotene.¹¹

Specific Populations

Pregnancy

Category X.^{1 5} (See Fetal/Neonatal Morbidity and Mortality and also Contraindications under Cautions.)

Lactation

Not known whether bexarotene is distributed into milk.^{1 5} Discontinue nursing or the drug.^{1 2 5}

Pediatric Use

Safety and efficacy not established in children <18 years of age.^{1 5 13}

Geriatric Use

No substantial differences in safety relative to younger adults, but increased sensitivity cannot be ruled out.^{1 5}

Common Adverse Effects

Rash, pruritus, skin disorders (e.g., inflammation, excoriation, sticky or tacky skin sensation), pain, contact dermatitis.^{1 2 3 5 6 7 8 9 12 13}

Interactions for Bexarotene

Orally administered bexarotene is metabolized by CYP3A4.^{1 5 11 12}

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors or inducers of CYP3A4: pharmacokinetic interaction unlikely with topical bexarotene because of low systemic exposure.^{1 5}

Protein-bound Drugs

Pharmacokinetic interaction unlikely with topicalbexarotene.^{1 13}

Specific Drugs

Drug	Interaction	Comments
Diethyltoluamide (DEET)	Increased DEET toxicity observed in animals1 2 5	Avoid concomitant use1 2 5
Gemfibrozil	Pharmacokinetic interaction unlikely with topicalbexarotene1 5 13
Vitamin A	Possible increased toxicity1 2 5

Bexarotene Pharmacokinetics

Absorption

Bioavailability

Plasma concentrations generally were low or undetectable following single or multiple daily topical application of low to moderate dosage intensity and increased as surface area treated or amount applied increased.^{1 5 12}

Distribution

Extent

Distribution of bexarotene into organs or tissues has not been evaluated.¹ Not known whether bexarotene is distributed into milk.^{1 5}

Plasma Protein Binding

>99%.¹

Special Populations

In patients with renal impairment, pharmacokinetics may be altered because of substantial protein binding changes.¹

Elimination

Special Populations

In patients with hepatic impairment, greatly decreased clearance would be expected.^{1 11}

In patients with renal impairment, pharmacokinetics may be altered because of substantial protein binding changes.¹

Stability

Storage

Topical

Gel

25°C (may be exposed to 15–30°C); protect from light.¹

Avoid exposure to high temperatures and humidity after tube is opened.¹

ActionsActions

• 
  

  Selectively binds with and activates retinoid X receptor (RXR) subtypes (RXR_α, RXR_β, and RXR_γ).^{1 2 3 4 5 6 7 8 9 10 11 12} Activated RXRs function as transcription factors that regulate the expression of genes controlling cellular differentiation, apoptosis, and proliferation.^{1 3 4 5 10 11 12}

  
  


• 
  

  Exact mechanism(s) of action not determined.^{1 11}

  
  

Advice to Patients

• 
  

  Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed.^{1 2 5}

  
  


• 
  

  Importance of women and men taking measures to avoid pregnancy during therapy because of risk to fetus.^{1 2 5}

  
  


• 
  

  Importance of men using condoms during sexual intercourse while receiving the drug and for at least 1 month after discontinuance.^{1 5}

  
  


• 
  

  Importance of monthly pregnancy tests.¹

  
  


• 
  

  Risk of photosensitivity reactions.^{1 2 5}

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, dietary supplements, and herbal products as well as any concomitant illnesses.^{1 5}

  
  


• 
  

  Provide copy of manufacturer’s patient instructions.²

  
  


• 
  

  Importance of informing patients of other important precautionary information.¹ (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
Topical	Gel	1%	Targretin (with butylated hydroxytoluene and polyethylene glycol)	Ligand

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 February 01, 2005. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Ligand Pharmaceuticals, Inc. Targretin (bexarotene) gel 1% prescribing information. San Diego, CA; 2000 July.

2. Ligand Pharmaceuticals, Inc. Targretin (bexarotene) gel 1% patient instructions for use.

3. Breneman D. Investigators present interim phase I/II data on Targretin. Paper presented at 38th annual meeting and exposition of the American Society of Hematology. San Diego, CA; 1996 Dec 9.

4. Anon. Ligand updates market on Targretin (LGD 1069) topical. Paper presented at 14th annual Hambrecht and Quist Life Sciences Conference. San Diego, CA: 1996 Jan.

5. Ligand Pharmaceuticals. Product information summary on Targretin. San Diego, CA; 2000 July.

6. Heald P, Mehlmauer M, Martin A et al. The benefits of topical bexarotene (Targretin) in patients with refractory or persistent early stage CTCL. J Invest Dermatol. 2000; 114:840.

7. Kuzel T, Breneman D, Duvic M et al. Phase I-II trial of Targretin(gel in the topical treatment of patients with cutaneous T-cell lymphoma. J Invest Dermatol. 2000; 114:839.

8. Breneman D, Duvic M, Kuzel T et al. Phase 1-2 clinical trial demonstrates the safety and efficacy of bexarotene (LGD1069) topical gel for the treatment of cutaneous t-cell lymphoma. Paper presented at the 57th Annual Meeting of the American Academy of Dermatology. New Orleans, LA: 1999 Mar 19-24.

9. Whaley KL, Cather J, Walker D et al. Topical retinoids improve stage 1 cutaneous t cell lymphoma lesions. Paper presented at the meeting of the Society for Investigative Dermatology. Washington, DC: 1997 Apr.

10. Vu-Dac N, Schoonjans K, Kosykh V et al. Retinoids increase human apolipoprotein A-11 expression through activation of the retinoid X receptor but not the retinoic acid receptor. Mol Cell Biol. 1996; 16:3350-60. [PubMed 8668150]

11. Ligand Pharmaceuticals, Inc. Targretin (bexarotene) capsules prescribing information. San Diego, CA; 1999 December.

12. Lowe MN, Plosker GL. Bexarotene. Am J Clin Dermatol. 2000; 1:245-50. [PubMed 11702369]

13. Ligand Pharmaceuticals, San Diego, CA; Personal communication.

14. Food and Drug Administration. 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 [Dec 8, 2000]. From FDA web site.

a. Ligand Pharmaceuticals, Inc. Targretin (bexarotene) gel 1% prescribing information. San Diego, CA; 2001 Jan.

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