Print

Date Printed: December 18, 2017: 11:34 AM

Private Property of Blue Cross and Blue Shield of Florida.
This medical policy (medical coverage guideline) is Copyright 2017, Blue Cross and Blue Shield of Florida (BCBSF). All Rights Reserved. You may not copy or use this document or disclose its contents without the express written permission of BCBSF. The medical codes referenced in this document may be proprietary and owned by others. BCBSF makes no claim of ownership of such codes. Our use of such codes in this document is for explanation and guidance and should not be construed as a license for their use by you. Before utilizing the codes, please be sure that to the extent required, you have secured any appropriate licenses for such use. Current Procedural Terminology (CPT) is copyright 2017 American Medical Association. All Rights Reserved. No fee schedules, basic units, relative values, or related listings are included in CPT. The AMA assumes no liability for the data contained herein. Applicable FARS/DFARS restrictions apply to government use. CPT® is a trademark of the American Medical Association. The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

09-J1000-41

Original Effective Date: 01/01/12

Reviewed: 04/10/13

Revised: 12/15/16

Subject: Bexarotene (Targretin®) Capsules and Gel

THIS MEDICAL COVERAGE GUIDELINE IS NOT AN AUTHORIZATION, CERTIFICATION, EXPLANATION OF BENEFITS, OR A GUARANTEE OF PAYMENT, NOR DOES IT SUBSTITUTE FOR OR CONSTITUTE MEDICAL ADVICE. ALL MEDICAL DECISIONS ARE SOLELY THE RESPONSIBILITY OF THE PATIENT AND PHYSICIAN. BENEFITS ARE DETERMINED BY THE GROUP CONTRACT, MEMBER BENEFIT BOOKLET, AND/OR INDIVIDUAL SUBSCRIBER CERTIFICATE IN EFFECT AT THE TIME SERVICES WERE RENDERED. THIS MEDICAL COVERAGE GUIDELINE APPLIES TO ALL LINES OF BUSINESS UNLESS OTHERWISE NOTED IN THE PROGRAM EXCEPTIONS SECTION.

           
Position Statement Dosage/ Administration Billing/Coding Reimbursement Program Exceptions Definitions
           
Related Guidelines Other References Updates  
           

DESCRIPTION:

Bexarotene (Targertin®) is a synthetic retinoid, also called a rexinoid due to its selectivity for the retinoid X-receptor. It has been primarily studied in persons with cutaneous T-cell lymphoma (CTCL). The CTCLs represent a heterogeneous group of non-Hodgkin lymphomas (NHL) characterized by an initial inflammation of the skin with clonally-derived malignant T lymphocytes. Mycosis fungoides (MF) is an extranodal NHL of mature T-cell with primary cutaneous involvement, and it is the most common type of CTCL accounting for 50 to 70% of CTCL cases. Sézary syndrome (SS) is an erythrodermic, leukemic variant of CTCL characterized by significant blood involvement and lymphadenopathy, and only accounts for 1 to 3% of cases. Oral bexarotene was approved by the US Food and Drug Administration (FDA) in 1999 for the treatment of CTCL in persons who are refractory to at least one prior systemic therapy. The following year, the FDA approved bexarotene 1% gel for the treatment of CTCL in patients with early stage disease who have not tolerated other therapies or who have refractory or persistent disease.

The NCCN guidelines for NHL list bexarotene gel as a category 2A topical treatment option for chronic or smoldering adult T-Cell leukemia/lymphoma (ATLL), primary cutaneous marginal zone or follicle center lymphoma, and mycosis fungoides (MF). For ATLL and MF treatment, numerous localized skin-directed therapies are recommended (e.g., corticosteroids, imiquimod, mechlorethamine) with no preference given to a particular agent. The guidelines list bexarotene oral capsules as a category 2A treatment option for primary cutaneous anaplastic large cell lymphoma (ALCL) with multifocal lesions, symptomatic lymphomatoid papulosis (LyP) or LyP with extensive lesions, MF, and Sézary syndrome (SS).

POSITION STATEMENT:

Comparative Effectiveness

The Food and Drug Administration has deemed the drug(s) or biological product(s) in this coverage policy to be appropriate for self-administration or administration by a caregiver (i.e., not a healthcare professional). Therefore, coverage (i.e., administration) in a provider-administered setting such as an outpatient hospital, ambulatory surgical suite, physician office, or emergency facility is not considered medically necessary.

Initiation of bexarotene (Targretin®) oral capsule meets the definition of medical necessity when ALL of the following are met:

1. The member has ANY of the following conditions AND all associated criteria are met:

a. Mycosis Fungoides (MF)/Sézary Syndrome (SS)

i. Will be used as either a single-agent therapy, OR in combination an interferon, phototherapy, or photopheresis (with or without an interferon)

b. Primary cutaneous anaplastic large cell lymphoma (ALCL)

i. Member has multifocal lesions (as opposed to solitary or grouped lesions)

ii. Bexarotene will be used as a single-agent therapy

c. Lymphomatoid papulosis (LyP)

i. Member has extensive lesions or is symptomatic (as opposed to limited lesions or is asymptomatic)

ii. Bexarotene will be used as a single-agent therapy

2. The dosage of bexarotene does not exceed 400 mg/m2/day

Approval duration: 6 months

Initiation of bexarotene (Targretin®) topical gel meets the definition of medical necessity when ALL of the following are met:

1. The member has ANY of the following conditions AND all associated criteria are met:

a. Mycosis Fungoides (MF)

i. Member has limited or localized skin involvement (as opposed to generalized skin involvement)

ii. Member is refractory to, has contraindication(s) to, or has persistent adverse effect(s) to at least two other recommended topical drug therapies (i.e., corticosteroid, imiquimod, or mechlorethamine) [the specific adverse effect(s) or contraindication(s) must be specified]

b. Primary cutaneous marginal zone or follicle center lymphoma

i. Member does NOT have extracutaneous disease

ii. Bexarotene will be used as a single-agent therapy

c. Adult T-Cell Leukemia/Lymphoma (ATLL)

i. Member has the chronic/smoldering disease subtype (as opposed to the acute or lymphoma subtypes)

ii. Member has limited or localized skin involvement (as opposed to generalized skin involvement)

iii. Member is refractory to, has contraindications to, or has persistent adverse effects to at least two other recommended topical drug therapies (i.e., corticosteroid, imiquimod, or mechlorethamine) [the specific adverse effect(s) or contraindication(s) must be specified]

2. The applied quantity of bexarotene gel does not exceed 4 grams/day (two 60g tubes/month)

Approval duration: 6 months

Continuation of bexarotene oral capsule or topical gel meets the definition of medical necessity when ALL of the following are met:

1. Authorization/reauthorization for bexarotene has been previously approved by Florida Blue or another health plan in the past 2 years for the treatment of a Florida Blue approved indication, OR the member previously met ALL indication-specific initiation criteria

2. The member has not experienced disease progression while receiving treatment with bexarotene

3. The member’s dosage does not exceed:

a. Oral capsules – 400 mg/m2/day

b. Topical gel 4 grams/day (two 60g tubes/month)

Approval duration: 1 year

DOSAGE/ADMINISTRATION:

THIS INFORMATION IS PROVIDED FOR INFORMATIONAL PURPOSES ONLY AND SHOULD NOT BE USED AS A SOURCE FOR MAKING PRESCRIBING OR OTHER MEDICAL DETERMINATIONS. PROVIDERS SHOULD REFER TO THE MANUFACTURER’S FULL PRESCRIBING INFORMATION FOR DOSAGE GUIDELINES AND OTHER INFORMATION RELATED TO THIS MEDICATION BEFORE MAKING ANY CLINICAL DECISIONS REGARDING ITS USAGE.

Oral Capsule:

FDA-Approved

Indicated for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma in patients who are refractory to at least one prior systemic therapy

• Initial dosage: 300 mg/m²/day (see TABLE 1 below), as a single oral daily dose with a meal.

• Maintenance dosage: Increase to 400 mg/m²/day if no tumor response after 8 weeks. In clinical trials in CTCL, bexarotene capsules were administered for up to 97 weeks. Bexarotene capsules should be continued as long as the member is deriving benefit.

TABLE 1:

Initial dose level 300 mg/m2 day

Body Surface Area (m2)

Total Daily Dose (mg/day)

Number of 75 mg Targretin Capsules

0.88 - 1.12

300

4

1.13 - 1.37

375

5

1.38 - 1.62

450

6

1.63 - 1.87

525

7

1.88 - 2.12

600

8

2.13 - 2.37

675

9

2.38 - 2.62

750

10

Dosage Adjustments

If necessitated by toxicity reduce dose to 200 mg/m²/day. If reaction does not resolve, decrease to 100 mg/m²/day or temporarily discontinue. When toxicity is controlled, doses may be carefully readjusted upward.

Drug Availability:

• 75 mg capsule

Topical 1% Gel:

FDA-Approved

Indicated for the topical treatment of cutaneous lesions in patients with CTCL (Stage IA and IB) who have refractory or persistent disease after other therapies or who have not tolerated other therapies

Initially the gel should be applied once every other day for the first week. The application frequency should be increased at weekly intervals to once daily, then twice daily, then three times daily and finally four times daily according to individual lesion tolerance. Most patients are able to maintain a dosing frequency of two to four times per day, and most responses are seen at dosing frequencies of two times per day and higher. Treatment should be continued as long as the patient is deriving benefit. If application site toxicity occurs, the application frequency can be reduced. Should severe irritation occur, application of drug can be temporarily discontinued for a few days until the symptoms subside. Sufficient gel should be applied to cover the lesion with a generous coating. The gel should be allowed to dry before covering with clothing. Because unaffected skin may become irritated, application of the gel to normal skin surrounding the lesions should be avoided. Occlusive dressings should not be used with the gel,

Dosage Adjustments

No specific dosage recommendations are given in the package insert for hepatic or renal impairment because no formal studies have been conducted. However, because renal insufficiency can result in significant protein binding changes, and bexarotene is >99% protein bound, pharmacokinetics may be altered in patients with renal insufficiency. Also, because less than 1% of the dose of oral bexarotene is excreted in the urine unchanged and there is in vitro evidence of extensive hepatic contribution to bexarotene elimination, hepatic impairment would be expected to lead to greatly decreased clearance.

Drug Availability:

Tube containing 60 g of 1% gel (600 mg active bexarotene)

PRECAUTIONS:

Oral Capsule:

Boxed Warning

Bexarotene is a member of the retinoid class of drugs that is associated with birth defects in humans. Bexarotene also caused birth defects when administered orally to pregnant rats. Bexarotene must not be administered to a pregnant woman.

Contraindications

A known hypersensitivity to bexarotene or other components of the product

Can cause fetal harm when administered to a pregnant woman, and must not be given to a pregnant woman or a woman who intends to become pregnant. If a woman becomes pregnant while taking bexarotene capsules, the capsules must be stopped immediately and the woman must be given appropriate counseling.

Precautions/Warnings

Lipid abnormalities: Bexarotene capsules induce major lipid abnormalities in most individuals. These must be monitored and treated during long-term therapy. Fasting blood lipid determinations should be performed before bexarotene capsules therapy is initiated and weekly until the lipid response to bexarotene capsules is established, which usually occurs within 2 to 4 weeks and at 8 week intervals thereafter. Fasting triglycerides should be normal or normalized with appropriate intervention prior to initiating bexarotene capsules therapy. Attempts should be made to maintain triglyceride levels below 400 mg/dL to reduce the risk of clinical sequelae. If fasting triglycerides are elevated or become elevated during treatment, antilipemic therapy should be instituted, and if necessary, the dose of bexarotene capsules reduced or suspended. Because of a potential drug-drug interaction, gemfibrozil is not recommended for use with bexarotene capsules.

Pancreatitis: Acute pancreatitis has been reported in persons with non-CTCL cancers treated with bexarotene capsules; the cases were associated with marked elevations of fasting serum triglycerides, the lowest being 770 mg/dL in 1 individual. Members with CTCL who have risk factors for pancreatitis (eg, prior pancreatitis, uncontrolled hyperlipidemia, excessive alcohol consumption, uncontrolled diabetes mellitus, biliary tract disease, and medications known to increase triglyceride levels or to be associated with pancreatic toxicity) should generally not be treated with bexarotene capsules.

Liver function test abnormalities: Baseline LFTs should be obtained, and LFTs should be carefully monitored after 1, 2, and 4 weeks of treatment initiation, and if stable, at least every 8 weeks thereafter during treatment. Consideration should be given to a suspension or discontinuation of bexarotene capsules if test results reach greater than 3 times the upper limit of normal values for AST, ALT, or bilirubin.

Thyroid axis alterations: Treatment with thyroid hormone supplements should be considered in members with laboratory evidence of hypothyroidism. Baseline thyroid function tests should be obtained and members should be monitored during treatment.

Leukopenia: Determination of WBC with differential should be obtained at baseline and periodically during treatment.

Cataracts: Posterior subcapsular cataracts were observed in preclinical toxicity studies in rats and dogs administered bexarotene daily for 6 months. Members treated with bexarotene capsules who experience visual difficulties should have an appropriate ophthalmologic evaluation.

Vitamin A supplementation: In clinical studies, subjects were advised to limit vitamin A intake to less than or equal to 15,000 IU/day. Because of the relationship of bexarotene to vitamin A, members should be advised to limit vitamin A supplements to avoid potential additive toxic effects.

Hypersensitivity reactions: Bexarotene capsules should be used with caution in members with a known hypersensitivity to retinoids. Clinical instances of cross-reactivity have not been noted.

Renal function impairment: No formal studies have been conducted with bexarotene capsules in persons with renal insufficiency. Urinary elimination of bexarotene and its known metabolites is a minor excretory pathway for bexarotene (less than 1% of administered dose), but because renal insufficiency can result in significant protein binding changes, and bexarotene is greater than 99% protein bound, pharmacokinetics may be altered in members with renal insufficiency.

Hepatic function impairment: No specific studies have been conducted with bexarotene capsules in persons with hepatic insufficiency. Because less than 1% of the dose is excreted in the urine unchanged and there is in vitro evidence of extensive hepatic contribution to bexarotene elimination, hepatic impairment would be expected to lead to greatly decreased clearance. Bexarotene capsules should be used only with caution in this population.

Diabetes mellitus: Caution should be used when administering bexarotene capsules in members using insulin, agents enhancing insulin secretion (eg, sulfonylureas), or insulin-sensitizers (eg, troglitazone). Based on the mechanism of action, bexarotene capsules could enhance the action of these agents, resulting in hypoglycemia. Hypoglycemia has not been associated with the use of bexarotene capsules as monotherapy.

Photosensitivity: Retinoids as a class have been associated with photosensitivity.

Children: Safety and effectiveness in pediatric members have not been established.

Topical 1% Gel:

Boxed Warnings

None

Contraindications

A known hypersensitivity to bexarotene or other components of the product

Pregnancy Category X. May cause fetal harm when administered to a pregnant woman, and must not be given to a pregnant woman or a woman who intends to become pregnant.

Precautions/Warnings

Vitamin A Supplementation: In clinical studies, patients were advised to limit vitamin A intake to ≤15,000 IU/day. Because of the relationship of bexarotene to vitamin A, patients should be advised to limit vitamin A supplements to avoid potential additive toxic effects.

Photosensitivity: Retinoids as a class have been associated with photosensitivity. In vitro assays indicate that bexarotene is a potential photosensitizing agent. There were no reports of photosensitivity in patients in the clinical studies. Patients should be advised to minimize exposure to sunlight and artificial ultraviolet light during treatment.

Drug-Drug Interactions: Patients who are applying bexarotene gel should not concurrently use products that contain DEET, a common component of insect repellent products. An animal toxicology study showed increased DEET toxicity when DEET was included as part of the formulation.

BILLING/CODING INFORMATION:

The following codes may be used to describe:

HCPCS Coding:

J3490

Unclassified drugs (for topical formulation)

J8999

Prescription drug, oral, chemotherapeutic, NOS (for oral formulation)

ICD-10 Diagnoses Codes That Support Medical Necessity: Bexarotene % topical gel (Effective 10/01/15)

C82.60 C82.69

Cutaneous follicle center lymphoma

C83.80 C83.89

Other non-follicular lymphoma

C84.00 – C84.09

Mycosis fungoides

C88.4

Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue [MALT-lymphoma]

C91.50 – C91.52

Adult T-cell lymphoma/leukemia (HTLV-1-associated)

ICD-10 Diagnoses Codes That Support Medical Necessity: Bexarotene oral capsules (Effective 10/01/15)

C84.00 – C84.09

Mycosis fungoides

C84.10 – C84.19

Sézary disease

C86.6

Primary cutaneous CD30-positive T-cell proliferations

REIMBURSEMENT INFORMATION:

Refer to section entitled POSITION STATEMENT.

PROGRAM EXCEPTIONS:

Federal Employee Program (FEP): Follow FEP guidelines.

State Account Organization (SAO): Follow SAO guidelines.

Medicare Advantage Products: No National Coverage Determination (NCD) and/or Local Coverage Determination (LCD) were found at the time of the last guideline review date.

DEFINITIONS:

No guideline specific definitions apply.

RELATED GUIDELINES:

Bendamustine HCl (Bendeka®, Treanda®) Injection, 09-J2000-40
Brentuximab (Adcetris®) Injection, 09-J1000-53

Doxorubicin HCl Liposome (Doxil®) IV, 09-J0000-91

Gemcitabine (Gemzar®), 09-J0000-96

Oxaliplatin (Eloxatin®) IV, 09-J1000-00

Pralatrexate (Folotyn™) IV, 09-J1000-18

Psoralens with Ultraviolet A (PUVA), Psoralens with Ultraviolet A (PUVA)

Temozolomide (Temodar®) Capsule and Injection, 09-J1000-52

Tretinoin Oral Capsules, 09-J1000-61

Vorinostat (Zolinza®) Capsules, 09-J1000-54

OTHER:

None.

REFERENCES:

  1. Breneman D, Duvic M, Kuzel T,et al. Phase 1 and 2 trial of bexarotene gel for skin-directed treatment of patients with cutaneous T-cell lymphoma. Arch Dermatol. 2002 Mar;138(3):325-32.
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. URL www.clinicalpharmacilogy-ip.com. Accessed 10/21/16. .
  3. 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 May;137(5):581-93.
  4. Heald P, Mehlmauer M, Martin AG, et al. Topical bexarotene therapy for patients with refractory or persistent early-stage cutaneous T-cell lymphoma: results of the phase III clinical trial. J Am Acad Dermatol. 2003 Nov;49(5):801-15.
  5. Micromedex® Healthcare Series [Internet Database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Accessed 10/21/16.
  6. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Version 3.2016. Non-Hodgkin’s Lymphomas. Available at http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf. Accessed10/21/16.
  7. NCCN Drugs & Biologics Compendium [Internet]. Fort Washington (PA): National Comprehensive Cancer Network; 2016 [cited 2016 Oct 21]. Available from: http://www.nccn.org/professionals/drug_compendium/content/contents.asp/
  8. Targretin (bexarotene capsule, liquid filled) [package insert]. Valeant Pharmaceuticals. Bridgewater, NJ: June 2016.
  9. Targretin (bexarotene gel) [package insert]. Valeant Pharmaceuticals. Bridgewater, NJ: February 2014.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Policy Committee on 11/09/16.

GUIDELINE UPDATE INFORMATION:

01/01/12

New Medical Coverage Guideline.

11/15/12

Review and revision to guideline; consisting of updating dosing, coding and references.

05/15/13

Revision to guideline; consisting of revising position statement to remove quantity limit, description, dosage/administration, and precautions sections, updating references. No Longer Review

11/01/15

Revision: ICD-9 Codes deleted.

12/15/16

Revision to guideline consisting of adding the topical gel formulation and updating the position statement of the oral formulation with the current NCCN recommendations.

Date Printed: December 18, 2017: 11:34 AM