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Date Printed: June 23, 2017: 06:25 PM

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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-J1000-61

Original Effective Date: 01/01/12

Reviewed: 04/10/13

Revised: 11/01/15

Subject: Tretinoin Oral Capsules

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:

Tretinoin, also known as all-trans-retinoic acid (ATRA), is a naturally occurring derivative of vitamin A. As vitamin A (retinol) derivatives, retinoids are important regulators of cell reproduction, and cell proliferation and differentiation; however, unlike vitamin A, retinoids are not converted into rhodopsin, which is needed for night vision. Topical tretinoin is indicated in the treatment of mild to moderate acne (e.g., grades I-III) and photo-damaged skin. Topical tretinoin has also been used in the symptomatic management of keratinization disorders such as ichthyosis and keratosis follicularis. Tretinoin represents a new class of anticancer drugs, differentiating agents. Oral tretinoin is used in the treatment of acute promyelocytic leukemia (APL) and is undergoing phase III investigation in the treatment of Kaposi's sarcoma. In the treatment of APL, tretinoin offers a less toxic means to induce complete remission than conventional chemotherapy.

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.

Tretinoin capsules meet the definition of medical necessity when used to treat the following conditions:

Acute Promyelocytic Leukemia (APL) as either induction or consolidation therapy

Non Hodgkin Lymphoma (NHL) – Mycosis Fungoides/Sézary Syndrome (ANY of the following):

• As a single agent.

• In combination with interferon therapy, phototherapies or photopheresis.

• As adjuvant systemic biologic therapy after total skin electron beam therapy.

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.

Acute Promyelocytic Leukemia (APL)

The recommended dose is 45 mg/m2/day administered as two evenly divided doses until complete remission is documented. Therapy should be discontinued 30 days after achievement of complete remission or after 90 days of treatment, whichever occurs first.

If after initiation of treatment of tretinoin the presence of the t(15;17) translocation is not confirmed by cytogenetics and/or by polymerase chain reaction studies and the member has not responded to tretinoin, alternative therapy appropriate for acute myelogenous leukemia should be considered.

Tretinoin is for the induction of remission only. Optimal consolidation or maintenance regimens have not been determined. All members should, therefore, receive a standard consolidation and/or maintenance chemotherapy regimen for APL after induction therapy with tretinoin, unless otherwise contraindicated.

PRECAUTIONS:

Contraindications: Tretinoin is contraindicated in members with a known hypersensitivity to tretinoin, any of its components, or other retinoids.

Warnings

WARNINGS

1. Experienced Physician and Institution

Members with acute promyelocytic leukemia (APL) are at high risk in general and can have severe adverse reactions to tretinoin. Tretinoin should therefore be administered only to members with APL under the strict supervision of a physician who is experienced in the management of members with acute leukemia and in a facility with laboratory and supportive services sufficient to monitor drug tolerance and protect and maintain a member compromised by drug toxicity, including respiratory compromise. Use of tretinoin requires that the physician concludes that the possible benefit to the member outweighs the following known adverse effects of the therapy.

2. Retinoic Acid-APL Syndrome

About 25% of members with APL treated with tretinoin have experienced a syndrome called the retinoic-acid-APL (RA-APL) syndrome characterized by fever, dyspnea, acute respiratory distress, weight gain, radiographic pulmonary infiltrates, pleural and pericardial effusions, edema, and hepatic, renal, and multi-organ failure. This syndrome has occasionally been accompanied by impaired myocardial contractility and episodic hypotension. It has been observed with or without concomitant leukocytosis. Endotracheal intubation and mechanical ventilation have been required in some cases due to progressive hypoxemia, and several members have expired with multi-organ failure. The syndrome generally occurs during the first month of treatment, with some cases reported following the first dose of tretinoin.

The management of the syndrome has not been defined rigorously, but high dose steroids given at the first suspicion of the RA-APL syndrome appear to reduce morbidity and mortality. At the first signs suggestive of the syndrome (unexplained fever, dyspnea and/or weight gain, abnormal chest auscultatory findings or radiographic abnormalities), high dose steroids (dexamethasone 10 mg intravenously administered every 12 hours for 3 days or until the resolution of symptoms) should be immediately initiated, irrespective of the leukocyte count. The majority of members do not require termination of tretinoin therapy during treatment of the RA-APL syndrome. However, in cases of moderate and severe RA-APL syndrome, temporary interruption of tretinoin therapy should be considered. 1

3. Leukocytosis at Presentation and Rapidly Evolving Leukocytosis During Tretinoin Treatment

During tretinoin treatment about 40% of members will develop rapidly evolving leukocytosis. Members who present with high WBC at diagnosis (> 5x109/L) have an increased risk of a further rapid increase in WBC counts. Rapidly evolving leukocytosis is associated with a higher risk of life threatening complications.

If signs and symptoms of the RA-APL syndrome are present together with leukocytosis, treatment with high dose steroids should be initiated immediately. Some investigators routinely add chemotherapy to tretinoin treatment in the case of members presenting with a WBC count of > 5x109/L or in the case of a rapid increase in WBC count for members leukopenic at start of treatment, and have reported a lower incidence of the RA-APL syndrome. Consideration could be given to adding full dose chemotherapy (including an anthracycline if not contraindicated) to the tretinoin therapy on day 1 or 2 for members presenting with a WBC count of > 5x109/L, or immediately, for members presenting with a WBC count of < 5x109/L, if the WBC count reaches ≥ 6x109/L by day 5, or ≥ 10x109/L by day 10, or ≥ 15x109/L by day 28.

4. Teratogenic Effects. Pregnancy Category D

There is a high risk that a severely deformed infant will result if tretinoin is administered during pregnancy. If, nonetheless, it is determined that tretinoin represents the best available treatment for a pregnant woman or a woman of childbearing potential, it must be assured that the member has received full information and warnings of the risk to the fetus if she were to be pregnant and of the risk of possible contraception failure and has been instructed in the need to use two reliable forms of contraception simultaneously during therapy and for 1 month following discontinuation of therapy, and has acknowledged her understanding of the need for using dual contraception, unless abstinence is the chosen method.

Within 1 week prior to the institution of tretinoin therapy, the member should have blood or urine collected for a serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL. When possible, tretinoin therapy should be delayed until a negative result from this test is obtained. When a delay is not possible, the member should be placed on two reliable forms of contraception. Pregnancy testing and contraception counseling should be repeated monthly throughout the period of tretinoin treatment.

Members Without the t(15;17) Translocation: Initiation of therapy with tretinoin may be based on the morphological diagnosis of acute promyelocytic leukemia. Confirmation of the diagnosis of APL should be sought by detection of the t(15;17) genetic marker by cytogenetic studies. If these are negative, PML/RARα fusion should be sought using molecular diagnostic techniques. The response rate of other AML subtypes to tretinoin has not been demonstrated; therefore, members who lack the genetic marker should be considered for alternative treatment.

Pseudotumor Cerebri: Retinoids, including tretinoin, have been associated with pseudotumor cerebri (benign intracranial hypertension), especially in pediatric members. The concomitant use of other agents known to cause pseudotumor cerebri/intracranial hypertension, such as tetracyclines, might increase the risk of this condition. Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea and vomiting, and visual disturbances. Members with these symptoms should be evaluated for pseudotumor cerebri, and, if present, appropriate care should be instituted in concert with neurological assessment.

Lipids: Up to 60% of members experienced hypercholesterolemia and/or hypertriglyceridemia, which were reversible upon completion of treatment. The clinical consequences of temporary elevation of triglycerides and cholesterol are unknown, but venous thrombosis and myocardial infarction have been reported in members who ordinarily are at low risk for such complications.

Elevated Liver Function Test Results: Elevated liver function test results occur in 50% to 60% of members during treatment. Liver function test results should be carefully monitored during treatment and consideration be given to a temporary withdrawal of tretinoin if test results reach > 5 times the upper limit of normal values. However, the majority of these abnormalities resolve without interruption of tretinoin or after completion of treatment.

BILLING/CODING INFORMATION:

HCPCS Coding

J8999

Prescription drug, oral, chemotherapeutic, NOS

ICD-10 Diagnoses Codes That Support Medical Necessity (Effective 10/01/15)

C84.00 – C84.09

Mycosis fungoides

C84.10 – C84.19

Sezary’s disease

C92.00 – C92.02

Acute myeloblastic leukemia

C92.40 – C92.42

Acute promyelocytic leukemia

C92.50 – C92.52

Acute myelomonocytic leukemia

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 Part D: BCBSF has delegated to Prime Therapeutics authority to make coverage determinations for the Medicare Part D services referenced in this guideline.

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

DEFINITIONS:

Adjuvant: a pharmacological or immunological agent that modifies the effect of other agents, such as a drug or vaccine.

Consolidation Therapy: treatment that is given after cancer has disappeared following the initial therapy. Consolidation therapy is used to kill any cancer cells that may be left in the body. It may include radiation therapy, a stem cell transplant, or treatment with drugs that kill cancer cells. Also called intensification therapy and postremission therapy.

Induction Therapy: Initial treatment used to reduce a cancer. Induction therapy is followed by other treatments, such as chemotherapy, radiation therapy, and hormone therapy to get rid of cancer that remains. Also called first-line therapy, primary therapy, and primary treatment.

RELATED GUIDELINES:

Allogeneic Bone Marrow and Stem Cell Transplantation, 02-38240-01
Autologous Bone Marrow and Stem Cell Transplantation, 02-38241-01

Azacitidine (Vidaza®) Injection, 09-J0000-84

Bortezomib (Velcade®) IV, 09-J0000-92

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

Erythropoiesis Stimulating Agents, 09-J0000-31

Gemcitabine (Gemzar®), 09-J0000-96

Granulocyte Colony Stimulating Factors, 09-J0000-62

H.P. Acthar® Gel, 09-J1000-15

Immune Globulin Therapy, 09-J0000-06

Interferon alfa-n3 (Alferon N Injection®), 09-J0000-33

Interferons for Oncology Use, 09-J1000-37

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

Paclitaxel and Paclitaxel (protein-bound) IV, 09-J1000-05

Vinorelbine Tartrate (Navelbine®) IV, 09-J1000-03

OTHER:

None

REFERENCES:

  1. Clinical Pharmacology. Copyright® 2011 Elsevier. Accessed 10/30/12.
  2. DRUGDEX®. Accessed 10/30/12.
  3. Facts & Comparisons® E Answers. Accessed 10/30/12.
  4. Ingenix HCPCS Level II, Expert 2012.
  5. Ingenix ICD-9-CM for Physicians-Volumes 1 & 2, Expert 2012.
  6. NCCN Drugs & Biologics Compendium™. Accessed 10/30/12.
  7. Tretinoin Prescribing Information (Barr Laboratories Inc.). Revised 11/2010.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Policy Committee on 04/10/13.

GUIDELINE UPDATE INFORMATION:

01/01/12

New Medical Coverage Guideline.

01/15/13

Review and revision to guideline; consisting of reformatting position statement, updating dosage and administration, precautions and references.

05/15/13

Revision to guideline; consisting of removing the quantity limit and adding duration of approval. No Longer Review.

11/01/15

Revision: ICD-9 Codes deleted.

Date Printed: June 23, 2017: 06:25 PM