Download TARGRETIN (bexarotene)

PHARMACY COVERAGE GUIDELINES
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01/01/16
09/15/16
08/29/16
TARGRETIN® (bexarotene) oral capsule & external gel
Coverage for services, procedures, medical devices and drugs are dependent upon benefit eligibility as
outlined in the member's specific benefit plan. This Pharmacy Coverage Guideline must be read in its
entirety to determine coverage eligibility, if any.
This Pharmacy Coverage Guideline provides information related to coverage determinations only and does
not imply that a service or treatment is clinically appropriate or inappropriate. The provider and the member
are responsible for all decisions regarding the appropriateness of care. Providers should provide BCBSAZ
complete medical rationale when requesting any exceptions to these guidelines.
The section identified as “Description” defines or describes a service, procedure, medical device or drug
and is in no way intended as a statement of medical necessity and/or coverage.
The section identified as “Criteria” defines criteria to determine whether a service, procedure, medical
device or drug is considered medically necessary or experimental or investigational.
State or federal mandates, e.g., FEP program, may dictate that any drug, device or biological product
approved by the U.S. Food and Drug Administration (FDA) may not be considered experimental or
investigational and thus the drug, device or biological product may be assessed only on the basis of
medical necessity.
Pharmacy Coverage Guidelines are subject to change as new information becomes available.
For purposes of this Pharmacy Coverage Guideline, the terms "experimental" and "investigational" are
considered to be interchangeable.
BLUE CROSS®, BLUE SHIELD® and the Cross and Shield Symbols are registered service marks of the
Blue Cross and Blue Shield Association, an association of independent Blue Cross and Blue Shield Plans.
All other trademarks and service marks contained in this guideline are the property of their respective
owners, which are not affiliated with BCBSAZ.
Description:
Targretin (bexarotene) capsules are indicated for the treatment of cutaneous manifestations of cutaneous T-cell
lymphoma (CTCL) in patients who are refractory to at least one prior systemic therapy. Targretin (bexarotene) 1%
gel is 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.
Lymphoma is a common blood cancer. There are two main forms of lymphoma: Hodgkin lymphoma (HL) and
non-Hodgkin lymphoma (NHL). Lymphoma occurs when lymphocytes grow and multiply uncontrollably, and travel
to other parts of the body, such as lymph nodes, spleen, bone marrow, blood, or other organs. Two types of
lymphocytes can develop into lymphomas: B-lymphocytes (B-cells) and T-lymphocytes (T-cells). T-cell
lymphomas account for approximately 15 percent of all NHLs in the United States.
One of the most common forms of T-cell lymphoma is cutaneous T-cell lymphoma (CTCL), a general term for Tcell lymphomas that involve the skin. CTCL also can involve the blood, the lymph nodes, and other internal
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PHARMACY COVERAGE GUIDELINES
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TARGRETIN® (bexarotene) oral capsule & external gel (cont.)
organs. Most patients with CTCL experience only skin symptoms, without serious complications; however,
approximately 10 percent of those who progress to later stages develop serious complications. Early stage CTCL
is typically indolent; some patients with early-stage CTCL might not progress to later stages at all, while others
might progress rapidly, with the cancer spreading to lymph nodes and/or internal organs.
Mycosis fungoides (MF) and Sezary syndrome (SS) are two types of CTCL. MF (also known as Alibert-Bazin
syndrome or granuloma fungoides) is the most common form of CTCL that generally affects the skin. In MF,
malignant T-cells migrate and accumulate in the skin, initially resulting in dry skin and red rash that may or may
not itch, eventually other skin lesions form. The malignant T-cells may also involve lymph nodes and spread to
other areas such as liver, spleen, and lungs. SS is a more aggressive form of CTCL with widespread skin
involvement, enlarged lymph nodes and malignant lymphocytes (Sezary cells) in the skin, lymph nodes, and
blood. The disease is classified into various stages depending upon skin (T), node (N), viscera (M), and blood (B)
involvement.
In Stage IA, less than 10% of the skin is covered with patches, papules, and/or plaques, lymph nodes are not
enlarged, there is no visceral involvement, and the blood may or may not contain circulating sezary cells, defined
as < 5% of peripheral blood. With Stage IB, 10% or more of the skin is covered with patches, papules, and/or
plaques. The lymph nodes are not enlarged, there is no visceral involvement, and the blood may or may not
contain circulating sezary cells, defined as < 5% of peripheral blood.
In Stage IIA, any amount of skin may be covered with patches, papules and/or plaques, lymph nodes are
enlarged and may or may not have abnormal cells, there is still no visceral involvement, and the blood may or
may not contain circulating sezary cells. Stage IIB has the same characteristics except now there are one or more
tumorous skin lesions.
With Stage III, there is erythrodermic skin (greater than 80% of body surface with red patches, papules, or
plaques), the lymph nodes may or may not be enlarged, when enlarged the nodes may or may not contain
abnormal cells, and there is no visceral involvement. With Stage IIIA there are no circulating seazry cells in the
blood, with Stage IIIB there are circulating sezary cells.
In Stages IVA and IVB, patches, papules, plaques or tumors involve any amount of the skin surface. The lymph
nodes tend to be enlarged and contain atypical cells and there is a significant level of Seazry cells in the blood.
Patients with visceral involvement classified as Stage IVB.
Sezary syndrome is a leukemic form of CTCL in which there is significant blood involvement with sezary cells,
lymphadenopathy, and erythrodermic skin.
Stages IA, IIB, and IIA are considered early stage MF. Prognosis and survival depends on the stage at diagnosis.
In the management of early-stage MF, skin-directed therapies may be categorized in two ways: “skin-limited
therapies” for limited or localized disease and “skin-generalized therapies” for generalized skin involvement. Skin
directed therapies include: topical corticosteroids, topical chemotherapy (such as Nitrogen Mustard and
Carmustine), local superficial radiation, topical retinoids (such as Bexarotene and Tazarotene), phototherapy
(such as PUVA and UVB), topical imiquimod, and total skin electron beam radiation. With generalized skin
involvement therapies include: topical corticosteroids, topical chemotherapy (such as Nitrogen Mustard and
Carmustine), phototherapy (such as PUVA and UVB), and total skin electron beam radiation.
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PHARMACY COVERAGE GUIDELINES
SECTION:
DRUGS
ORIGINAL EFFECTIVE DATE:
LAST REVIEW DATE:
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ARCHIVE DATE:
01/01/16
09/15/16
08/29/16
TARGRETIN® (bexarotene) oral capsule & external gel (cont.)
Systemic therapies include: oral retinoids (Acitretin, Bexarotene, Isotretinoin), alpha-interferon, Vorinostat,
Istodax, Methotrexate, Cyclophosphamide, Chlorambucil, Cladribine, Fludarabine, Pentostatin, and others.
Targretin (bexarotene) is a member of a subclass of retinoids that selectively activate retinoid X receptors (RXRs).
These retinoid receptors have biologic activity distinct from that of retinoic acid receptors (RARs).
Bexarotene selectively binds and activates retinoid X receptor subtypes (RXRα, RXRβ, RXRγ). RXRs can form
heterodimers with various receptor partners such as retinoic acid receptors (RARs), vitamin D receptor, thyroid
receptor, and peroxisome proliferator activator receptors (PPARs). Once activated, these receptors function as
transcription factors that regulate the expression of genes that control cellular differentiation and proliferation.
Bexarotene inhibits the growth in vitro of some tumor cell lines of hematopoietic and squamous cell origin. It also
induces tumor regression in vivo in some animal models. The exact mechanism of action of bexarotene in the
treatment of CTCL is unknown.
Definitions:
Drug related events:
Ineffective / failure
Use of a drug employing optimal doses (FDA-recommended doses) for optimal duration; where the condition
being treated has not improved or worsened
A request for branded agent due to generic drug failure or ineffectiveness will be assessed for potential
approval with documentation of use of optimal dose / duration of the generic product and meeting other
criteria within the coverage guideline. When the drug in question is a combination product, there must be
documentation of failure / ineffectiveness of concurrent use (each ingredient used at the same time) of
individual generic components. When the drug in question is a low dose formulation, there must be
documentation of failure / ineffectiveness of low dose generic formulation.
Adverse Drug Event: Allergic reaction / Hypersensitivity / Intolerance
Use of a drug produced a significant reaction where continued use of the drug places the individual at risk for
either lack of improvement or worsening of the condition being treated or at risk for harm and the concern is
documented in medical record. A significant adverse drug event is when an individual’s outcome is death,
life-threatening, hospitalization (initial or prolonged), disability resulting in a significant, persistent, or
permanent change, impairment, damage or disruption in the individuals’ body function/structure, physical
activities or quality of life, or requires intervention to prevent permanent impairment or damage.
Allergic reaction / hypersensitivity – may or may not involve the active ingredient. When the active
ingredient is involved, use of same or a chemically similar agent places the individual at risk for harm
when the same or chemically similar agent is used. The subsequent reaction may be the same as the
original reaction or a more exaggerated response may be seen, potentially placing the individual at even
greater risk for harm.
If the reaction occurred from the active/main generic ingredient; request for branded agent with same
active ingredient will not be considered unless it is proven (documented) that active ingredient did not
cause reaction and the request meets other criteria within the coverage guideline
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PHARMACY COVERAGE GUIDELINES
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LAST REVIEW DATE:
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01/01/16
09/15/16
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TARGRETIN® (bexarotene) oral capsule & external gel (cont.)
Intolerance – these events represent circumstance(s) where use of a drug produced a significant reaction
and continued use may result in non-adherence to proposed therapy and this concern is documented in
medical record
Contraindication
Use of a drug that is not recommended by the manufacturer or FDA labelling
Use of any drug in the face of a contraindication is outside of the FDA and manufacturer’s labelled
recommendation and is considered investigational or experimental
Non-adherence
Individual does not follow prescribe regimen that places the individual at risk for lack of improvement or
worsening of the condition being treated and this concern is documented in medical record
Precertification:
Precertification (Prior Authorization) is required for members with a Blue Cross Blue Shield of Arizona (BCBSAZ)
pharmacy benefit for medication(s) or product(s) indicated in this guideline.
This Pharmacy Coverage Guideline does not apply to FEP or other states’ Blues Plans.
Information about medications that require precertification is available at www.azblue.com/pharmacy.
Some large (100+) benefit plan groups may customize certain benefits, including adding or deleting precertification
requirements.
All applicable benefit plan provisions apply, e.g., waiting periods, limitations, exclusions, waivers and benefit
maximums.
Criteria:
See “Resources” section for FDA-approved dosage.

Precertification for Targretin (bexarotene) oral capsule & external gel requires completion of the specific
request form in its entirety. All requested data must be provided. Once completed the form must be signed by
the prescribing provider and faxed back to BCBSAZ Pharmacy Management at (602) 864-3126 or emailed to
[email protected]. Incomplete forms will be returned.

FDA-approved product labeling (indication, age, dosage, testing, contraindications, exclusions, etc.) of
Targretin (bexarotene) oral capsule & external gel is considered medically necessary when ALL of the
following criteria are met:
1. Individual is 18 years of age or older
2. Individual has medical record documentation of a confirmed diagnosis of ONE of the following:
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PHARMACY COVERAGE GUIDELINES
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ORIGINAL EFFECTIVE DATE:
LAST REVIEW DATE:
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ARCHIVE DATE:
01/01/16
09/15/16
08/29/16
TARGRETIN® (bexarotene) oral capsule & external gel (cont.)


Cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) and are refractory to at least
one prior systemic therapy
Cutaneous lesions with early stage CTCL (Stage IA and IB) who have refractory or persistent
disease after other therapies or who have not tolerated other therapies
3. ALL of the following baseline tests have been completed before initiation of treatment:
 For Targretin capsules only:
 Fasting lipid profile, including triglycerides
 Liver function tests
 Thyroid function
 Complete blood count with differential
 Negative pregnancy test in a woman of child bearing potential, unless using two reliable forms of
contraception, one of which is non-hormonal
4. Absence of ALL of the following contraindications:
 Pregnancy in a woman of child bearing potential, unless using two reliable forms of contraception,
one of which is non-hormonal
5. Absence of ALL of the following exclusions:
 Woman who is breast feeding an infant or child
 Male on Targretin who has a female partner of child bearing potential not using condoms
 Simultaneous use with vitamin A > 15,000 IU/day
 For Targretin capsules only:
 Simultaneous use with Gemfibrozil
 Liver tests that exceed three times the upper limit of normal for AST,ALT, or bilirubin
 For Targretin gel only:
 Simultaneous use with products that contain DEET (N,N-diethyl-m-toluamide) as a
component of insect repellent product
OR

A non-FDA approved use for the treatment of cancer of Targretin is considered medically necessary
when ONE of the following criteria are met:
1. A non-FDA approved use for the treatment of cancer is recognized as safe and effective for the
requested type of cancer, that is listed and supported by in ONE of the nationally recognized compendia
or guidelines:
 American Hospital Formulary Service
 National Comprehensive Cancer Network (NCCN) Drugs & Biologics Compendium
 Thomson Micromedex compendium DrugDex
 Elsevier Gold Standard’s Clinical Pharmacology compendium
 American Society of Clinical Oncologist (ASCO) treatment guidelines
 Other authoritative reference as identified by the Secretary of the United States Department of
Human Health Services
2. A non-FDA approved use for the treatment of cancer that is established from clinical trial(s) that have
been published in peer reviewed professional medical journal(s) that has been submitted by the
prescriber if ALL of the following apply:
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PHARMACY COVERAGE GUIDELINES
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ORIGINAL EFFECTIVE DATE:
LAST REVIEW DATE:
LAST CRITERIA REVISION DATE:
ARCHIVE DATE:
01/01/16
09/15/16
08/29/16
TARGRETIN® (bexarotene) oral capsule & external gel (cont.)




At least two articles from major peer reviewed professional medical journals have recognized,
based on scientific or medical criteria, the drug's safety and effectiveness for treatment of the
indication for which the drug has been prescribed
No article from a major peer reviewed professional medical journal has concluded, based on
scientific or medical criteria, that the drug is unsafe or ineffective or that the drug's safety and
effectiveness cannot be determined for the treatment of the indication for which the drug has
been prescribed
The literature meets the uniform requirements for manuscripts submitted to biomedical journals
established by the international committee of medical journal editors or is published in a journal
specified by the United States department of health and human services as acceptable peer
reviewed medical literature pursuant to section 186(t)(2)(B) of the social security act (42 United
States Code section 1395x(t)(2)(B))
Oncology medications for all other indications not previously listed is considered experimental or
investigational based upon:
1.
2.
3.
4.
Lack of final approval from the Food and Drug Administration, and
Insufficient scientific evidence to permit conclusions concerning the effect on health outcomes, and
Insufficient evidence to support improvement of the net health outcome, and
Insufficient evidence to support improvement of the net health outcome as much as, or more than,
established alternatives, and
5. Insufficient evidence to support improvement outside the investigational setting.
Resources:
Targretin Capsule. Package Insert. Revised by manufacturer 5/2013. Accessed 08-04-2015, 07-22-2016.
Targretin Gel. Package Insert. Revised by manufacturer 7/2013. Accessed 08-04-2015, 07-22-2016.
FDA-approved indication and dosage:
Indication
Recommended Dose
TARGRETIN (bexarotene)
capsules are indicated for the
treatment of cutaneous
manifestations of cutaneous Tcell lymphoma in patients who
are refractory to at least one
prior systemic therapy.
The recommended initial dose of Targretin capsule is 300 mg/m 2/day. Targretin
capsule should be taken as a single oral daily dose with a meal.
Targretin Capsule Initial Dose Calculation According to Body Surface Area
Initial Dose Level (300 mg/m2/day)
Body Surface Area (m2)
Total Daily Dose (mg/day)
0.88 – 1.12
300
1.13 – 1.37
375
1.38 – 1.62
450
1.63 – 1.87
525
1.88 – 2.12
600
2.13 – 2.37
875
2.38 – 2.62
750
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Number of 75 mg
Targretin Capsules
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PHARMACY COVERAGE GUIDELINES
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LAST REVIEW DATE:
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ARCHIVE DATE:
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09/15/16
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TARGRETIN® (bexarotene) oral capsule & external gel (cont.)
Dose Modification Guidelines: The 300 mg/m2/day dose level of Targretin capsules
may be adjusted to 200 mg/m2/day then to 100 mg/m2/day, or temporarily suspended,
if necessitated by toxicity. When toxicity is controlled, dose may be carefully
readjusted upward. If there is no tumor response after eight weeks of treatment and if
the initial dose of 300 mg/m2/day is well tolerated, the dose may be escalated to 400
mg/m2/day with careful monitoring.
Duration of Therapy: In clinical trials in CTCL, Targretin capsules were administered
for up to 97 weeks.
Targretin capsules should be continued as long as the patient is deriving benefit.
TARGRETIN (bexarotene) gel
1% is 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.
TARGRETIN (bexarotene) gel 1% should be initially 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. Generally, patients were able to maintain a
dosing frequency of two to four times per day. Most responses were seen at dosing
frequencies of two times per day and higher. 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. In addition, do not apply the gel near mucosal surfaces of the body.
A response may be seen as soon as four weeks after initiation of therapy but most
patients require longer application. With continued application, further benefit may be
attained. The longest onset time for the first response among the responders was 392
days based on the Composite Assessment of Index Lesion Severity in the multicenter
study. In clinical trials, Targretin gel was applied for up to 172 weeks.
Targretin gel should be continued as long as the patient is deriving benefit.
Occlusive dressings should not be used with Targretin gel.
Targretin gel is a topical therapy and is not intended for systemic use. Targretin gel
has not been studied in combination with other CTCL therapies.
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