Clinical Policy: Multiple Sclerosis Reference Number: CP.CPA.206 Effective Date: Last Review Date: Line of Business: Commercial

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1 Clinical Policy: Reference Number: CP.CPA.206 Effective Date: Last Review Date: Line of Business: Commercial Revision Log See Important Reminder at the end of this policy for important regulatory and legal information. Description The following are disease modifying agents requiring prior authorization: interferon beta-1a ( Avonex, Rebif ), interferon beta-1b (Extavia, Betaseron ), glatiramer acetate (Copaxone, Glatopa), mitoxantrone, fingolimod (Gilenya ), teriflunomide (Aubagio ), dimethyl fumarate (Tecfidera ), peginterferon beta-1a (Plegridy ), alemtuzumab (Lemtrada ), natalizumab (Tysabri ), daclizumab (Zinbryta ). FDA approved indication Avonex: Treatment of patients with relapsing forms of multiple sclerosis to decrease the frequency of clinical exacerbations and delay the accumulation of physical disability, including patients who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis. Rebif: Treatment of patients with relapsing forms of multiple sclerosis to decrease the frequency of clinical exacerbations and delay the accumulation of physical disability. Extavia, Betaseron: Treatment of patients with relapsing forms of multiple sclerosis to decrease the frequency of clinical exacerbations, including patients who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis. Copaxone, Glatopa: For the treatment of patients with relapsing-forms of multiple sclerosis. Mitoxantrone: Reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis (i.e., patients whose neurologic status is significantly abnormal between relapses). In combination with corticosteroids as initial chemotherapy for the treatment of patients with pain related to advanced hormone-refractory prostate cancer. In combination with corticosteroids as initial therapy of acute nonlymphocytic leukemia in adults. This category includes myelogenous, promyelocytic, monocytic, and erythroid acute leukemias. Aubagio: Treatment of patients with relapsing forms of multiple sclerosis. Tecfidera: Treatment of patients with relapsing forms of multiple sclerosis. Page 1 of 11

2 Gilenya: Treatment of patients with relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability. Plegridy: Treatment of patients with relapsing forms of multiple sclerosis. Lemtrada: Treatment of patients with relapsing forms of multiple sclerosis (MS). Because of its safety profile, the use of Lemtrada should be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS. Tysabri: As monotherapy for the treatment of patients with relapsing forms of multiple sclerosis. Tysabri increases the risk of progressive multifocal leukoencephalopathy (PML). When initiating and continuing treatment with Tysabri, physicians should consider whether the expected benefit of Tysabri is sufficient to offset this risk. Inducing and maintaining clinical response and remission in adult patients with moderately to severely active Crohn s disease (CD) with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional CD therapies and inhibitors of tumor necrosis factor (TNF)-alpha. Zinbryta: For the treatment of adult patients with relapsing forms of multiple sclerosis (MS). Because of its safety profile, the use of Zinbryta should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS. Policy/Criteria Provider must submit documentation (which may include office chart notes and lab results) supporting that member has met all approval criteria It is the policy of health plans affiliated with Centene Corporation that Aubagio, Avonex, Rebif, Extavia, Betaseron, Copaxone, Glatopa, mitoxantrone, Gilenya, Tecfidera, Plegridy, Lemtrada, Tysabri, and Zinbryta are medically necessary when the following criteria are met: I. Initial Approval Criteria A. Relapsing Remitting (RRMS) (must meet all): 1. Diagnosis of RRMS; 2. Prescribed by or in consultation with a neurologist; 3. For Tysabri, Zinbryta, Extavia or Lemtrada: Failure to two of the following unless contraindicated or clinically significant adverse effects are experienced: Aubagio, Tecfidera, Gilenya, Avonex, Betaseron, Plegridy, Copaxone, Glatopa or Rebif; 4. Mitoxantrone can be approved in patients with frequent relapses or severe disease despite therapy with one of the other agents; 5. Dose does not exceed the FDA recommended maximum dose (see Section V). Approval duration: Aubagio, Gilenya, Lemtrada, Mitoxantrone, Tecfidera, Tysabri: Length of benefit All others: 6 months or to renewal date, whichever is longer B. Secondary Progressive (SPMS) (must meet all): Page 2 of 11

3 1. Diagnosis of SPMS; 2. Prescribed by or in consultation with a neurologist; 3. Request is for mitoxantrone, Betaseron, or Rebif; 4. For Betaseron and Rebif, member has active relapsing disease; 5. Dose does not exceed the FDA recommended maximum dose (see Section V). Approval duration: Mitoxantrone: Length of benefit All others: 6 months or to renewal date, whichever is longer C. Progressive relapsing multiple sclerosis (PRMS), Hormone-refractory prostate cancer, Acute nonlymphocytic leukemia (ANLL), Hodgkin s lymphoma or non- Hodgkin s lymphoma (must meet all): 1. Diagnosis of one of the following: a. PRMS confirmed by a neurologist; b. Hormone-refractory prostate cancer; c. ANLL in adults (including myelogenous, (i.e. acute myelogenous leukemia), promyelocytic, monocytic, and erythroid acute leukemias); d. Hodgkin s lymphoma or non-hodgkin s lymphoma which has relapsed following treatment with other chemotherapy; 2. Request is for mitoxantrone; 3. Cumulative dose does not exceed 140 mg/m 2. Approval duration: Length of benefit D. Crohn s Disease (must meet all): 1. Request is for Tysabri; 2. Refer to policy CP.CPA.194 Biologic DMARDs. E. Other diagnoses/indications 1. Refer to CP.CPA.09 if diagnosis is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized). II. Continued Therapy A. All Indications in Section I (must meet all): 1. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving the requested therapy for indications listed in Section I and has received this medication for at least 30 days; 2. Member is responding positively to therapy (e.g., improved or maintained disease control evidenced by decreased or stabilized Expanded Disability Status Scale (EDSS) score or reduction in relapses or lesions on MRI); 3. If request is for a dose increase, new dose does not exceed the FDA recommended maximum dose (see Section V). Approval duration: Aubagio, Gilenya, Lemtrada, Mitoxantrone, Tecfidera, Tysabri: Length of benefit All others: 6 months or to renewal date, whichever is longer B. Other diagnoses/indications(must meet 1 or 2): Page 3 of 11

4 1. Currently receiving medication via Centene benefit and documentation supports positive response to therapy. Approval duration: Duration of request or 12 months (whichever is less); or 2. Refer to CP.CPA.09 if diagnosis is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized). III. Diagnoses/Indications for which coverage is NOT authorized: A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off-label use policy CP.CPA.09 or evidence of coverage documents; B. Primary progressive multiple sclerosis. IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key MS: multiple sclerosis PML: progressive multifocal leukoencephalopathy CD: crohn s disease TNF: tumor necrosis factor RRMS: relapsing remitting multiple sclerosis SPMS: secondary progressive multiple sclerosis PRMS: progressive relapsing multiple sclerosis ANLL: acute nonlymphocytic leukemia DMARD: disease-modifying antirheumatic drugs Appendix B: General Information Serono has discontinued the marketing of Novantrone the branded product of mitoxantrone. Generic equivalents are available. Criteria for evaluation of continuous therapy have not been firmly established. The following are efficacy endpoints used in clinical trials: o Number of courses of ACTH or corticosteroids per 24 months o Number of hospitalizations per 24 months o Number of exacerbations per 24 months o Repeat evaluation of EDSS o Repeat MRI or other imaging The following criteria should be considered for cessation of current treatment: o Steady progression of disability over two years o Treatment with at least three (3) courses of ACTH or corticosteroids during a 2 year period required despite therapy o Consistent non-compliance in taking the medication as prescribed by the physician o Severe drug toxicity Mitoxantrone should be reserved for patients who have failed or who have had a clinically significant adverse reaction to other disease-modifying agents or for those patients who have developed SPMS or PRMS. Four clinical subtypes of MS include: 1) Relapsing remitting (RR) MS - acute relapses with full recovery, 2) Secondary progressive (SP) MS - progression of disease with relapsing course, 3) Primary progressive (PP) MS - progression of disability from onset, Page 4 of 11

5 and 4) Progressive relapsing (PR) MS - progression of disease from onset, with clear acute relapses. Patients with some preexisting conditions (e.g., ischemic heart disease, history of myocardial infarction, congestive heart failure, history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, history of symptomatic bradycardia, history of recurrent syncope, severe untreated sleep apnea, AV block, sinoatrial heart block) may poorly tolerate the Gilenya -induced bradycardia, or experience serious rhythm disturbances after the first dose of Gilenya. Prior to treatment with Gilenya, these patients should have a cardiac evaluation by a physician appropriately trained to conduct such evaluation, and, if treated with Gilenya, should be monitored overnight with continuous ECG in a medical facility after the first dose. Gilenya is contraindicated in patients who in the last 6 months experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization or Class III/IV heart failure). Gilenya has been designated an orphan drug by the US Food and Drug Administration (FDA) for use in the treatment of chronic inflammatory demyelinating polyneuropathy; however, this use is not in the FDA-approved labeling for the drug. Mitoxantrone has IIa recommendations from Drugdex for use in anthracycline resistant breast cancer, liver cancer and ovarian cancer, however these indications are not listed by the National Comprehensive Cancer Network (NCCN) guidelines. Prescribing information for Lemtrada includes a boxed warning about the potential for serious, sometimes fatal, autoimmune conditions such as immune thrombocytopenia and anti-glomerular basement membrane disease. It also warns about serious and lifethreatening infusion reactions, increased risk of malignancies (including thyroid cancer, melanoma, and blood cancers). Lemtrada will only be available from certified prescribers, and patients will be enrolled in a Risk Evaluation and Mitigation Strategy (REMS) program to ensure that ongoing periodic monitoring will be maintained to detect potential problems. Tysabri has a boxed warning for the increased risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability. Treatment duration, prior immunosuppressant use, and presence of anti-jc virus (JCV) antibodies are risk factors associated with increased risk of PML in Tysabri-treated patients. The risks and benefits of continuing treatment with Tysabri should be carefully considered in patients who are found to be anti-jcv antibody positive and have one or more additional risk factors. Patients with all three known risk factors have an estimated risk of PML of 11/1,000. Zinbryta has black box warnings for hepatic Injury including autoimmune hepatitis Zinbryta can cause severe liver injury including life-threatening events, liver failure, and autoimmune hepatitis. Obtain transaminase and bilirubin levels before initiation of Zinbryta. Monitor and evaluate transaminase and bilirubin levels monthly and up to 6 months after the last dose Zinbryta is contraindicated in patients with pre-existing hepatic disease or hepatic impairment Appendix C: Therapeutic Alternatives: N/A Page 5 of 11

6 V. Dosage and Administration Drug Dosing Regimen Dose Limit/ Maximum Dose Avonex 30 mcg IM Q Wk. 30 mcg IM once a week Betaseron Copaxone Glatopa Plegridy Avonex may be titrated to reduce the incidence of flu-like symptoms, starting with 7.5 mcg for the first week and increasing the dose by 7.5 mcg each week for the next 3 weeks until the recommended dose of 30 mcg weekly is obtained. 250 mcg SC QOD Generally, start at mg (0.25 ml) SC QOD, and increase over a six week period to 0.25 mg (1 ml) QOD. 20 mg SC QD or 40 mg SC TIW For SC injection only, doses are not interchangeable 20 mg SC QD, dose is not interchangeable with glatiramer acetate 40 mg/ml 125 mcg SC every 14 days Dose should be titrated, starting with 63 mcg on day 1, 94 mcg on day 15, and 125 mcg (full dose) on day mcg every other day Once daily dose schedule: 20 mg/day Three times weekly dose schedule: 40 mg/dose Once daily dose schedule: 20 mg/day Three times weekly dose schedule: 40 mg/dose 125 mcg SC every 14 days Rebif 22 mcg or 44 mcg SC TIW titrated over a 4 week period. 44 mcg subcutaneously every 48 hours Aubagio 7 mg or 14 mg PO QD 14mg per day Gilenya 0.5 mg PO QD 0.5mg per day Tecfidera 120 mg PO BID for 7 days followed by 240 mg PO BID. 480mg per day Extavia (interferon beta- 1b) Administration with food may reduce the incidence of flushing. 250 mcg SC QOD 250 mcg every other day Page 6 of 11

7 Zinbryta 150 mg SC once monthly 150 mg/month subcutaneously for multiple sclerosis Mitoxantrone Lemtrada Tysabri 12 mg/m 2 IV infusion every three months with a cumulative lifetime maximum dose of 140 mg/m 2. Hormone-Refractory Prostate Cancer 12 to 14 mg/m 2 IV infusion every 21 days Acute Nonlymphocytic Leukemia 12 mg/m 2 IV infusion on days 1-3 with 100 mg/m 2 of cytarabine days 1-7 First year: 12 mg/day IV infusion for 5 consecutive days (60 mg total dose) Second year: 12 mg/day for 3 consecutive days (36 mg total dose) 300 mg IV Q 4 Wks Maximum cumulative lifetime dose of mitoxantrone is 140 mg/m 2 IV. 12 mg/dose IV 300 mg IV Q 4 Wks Therapeutic alternatives are listed as Brand name (generic) when the drug is available by brand name only and generic (Brand name ) when the drug is available by both brand and generic. *Requires Prior Authorization VI. Product Availability Drug Avonex Availability 30 mcg (6.6 MIU) powder for injection single-use vial; 30 mcg/0.5ml (6.6 MIU) single-use pre-filled syringe; 30 mcg/0.5ml (6.6 MIU) single use pre-filled autoinjector Rebif Pre-filled Syringes (single-use): Titration Pack contains six 8.8 mcg/0.2ml and six 22 mcg/0.5ml; 22mcg/0.5ml; 44mcg/0.5ml Rebif Rebidose Autoinjectors (single-use): Titration Pack contains six 8.8 mcg/0.2ml and six 22 mcg/0.5ml; 22mcg/0.5ml; 44mcg/0.5ml Betaseron Extavia Copaxone 0.3 mg lyophilized powder for injection in a singleuse vial kit 0.3 mg lyophilized powder for injection in a single use glass vial kit 20 mg/ml single use pre-filled syringe kit (30-count cartons) 40 mg/ml single use pre-filled syringe kit (12-count cartons) Page 7 of 11

8 Glatopa Lemtrada mitoxantrone Aubagio Gilenya Tecfidera Plegridy Tysabri Zinbryta 20 mg/ml single-dose prefilled syringe 12 mg/1.2 ml single use vial multi-dose vials of 20mg/10ml, 25mg/12.5ml, 30mg/15ml solution for injection 7 mg, 14 mg tablets 0.5 mg capsules Tecfidera: 30-day Starter Pack: 7-day bottle 120 mg capsules, quantity 14 and 23-day bottle 240 mg capsules, quantity 46; 120 mg, 240 mg capsules 125 mcg per 0.5 ml of solution in a single-dose prefilled pen, Starter Pack containing 63 mcg per 0.5 ml of solution in a single-dose prefilled pen and 94 mcg per 0.5 ml solution in a single-dose prefilled pen, 125 mcg per 0.5 ml of solution in a single-dose prefilled syringe, Starter Pack containing 63 mcg per 0.5 ml of solution in a single-dose prefilled syringe and 94 mcg per 0.5 ml of solution in a single-dose prefilled syringe Single-use vial: 300 mg/15 ml in solution 150 mg/ml solution in a single-dose prefilled syringe VII. References 1. Avonex Prescribing information Cambridge, MA: Biogen, Inc. March Rebif Prescribing information Rockland, MA: Serono, Inc. November Betaseron Prescribing information Montville, NJ: Berlex Laboratories. April Extavia Prescribing Information Montville, NJ: Novartis. December Copaxone Prescribing information North Wales, PA: Teva-Neuroscience, Inc. January Plegridy Prescribing information Cambridge, MA: Biogen Idec Inc. October Mitoxantrone Prescribing information North Wales, PA: Teva, June Aubagio Prescribing Information Cambridge, MA: Sanofi Company. October Gilenya Prescribing Information East Hanover, NJ: Novartis Pharmaceuticals; February Lemtrada Prescribing information Cambridge, MA: Genzyme, Inc. November Tecfidera Prescribing Information Cambridge, MA: Biogen Idec Inc. February Glatopa Prescribing information Princeton, NJ: Sandoz Inc., January Tysabri Prescribing Information. Cambridge, MA: Biogen Idec Inc; December Zinbryta Prescribing information North Chicago, IL: AbbVie Inc., May Goodin DS, et al. Disease modifying therapies in multiple sclerosis. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology 2002; 58: Changing therapy in relapsing multiple sclerosis: considerations and recommendations of a task force of the national multiple sclerosis society. Expert Opinion Paper (Accessed June 4, 2016 at Fernandez O. Combination therapy in multiple sclerosis. J Neurologic Sci. 2007;259: Page 8 of 11

9 18. Costello F, Stuve O, Weber MS, Zamvil SS, Froham E. Combination therapies for multiple sclerosis: scientific rationale, clinical trials, and clinical practice. Curr Opin Neurol. 2007; 20: Goodin DS, Frohman EM, Hurwitz B, et al. Neutralizing antibodies to interferon beta: assessment of their clinical and radiographic impact: an evidence report. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2007; 68: Montalban X. MS treatment: postmarketing studies. J Neurologic Sci. 2007; 259: Federal Register. Determination That Novantrone (Mitoxantrone Hydrochloride) Injection, Equivalent to 25 Milligrams Base/12.5 Milliliter and Equivalent to 30 Milligrams Base/15 Milliliter, Was Not Withdrawn From Sale for Reasons of Safety or Effectiveness / Vol. 76, No. 71 / Wednesday, April 13, 2011Accessed at 13/pdf/ pdf on June 4, Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367(12): Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367(12): Kappos L, Radue EW, O Connor P, et al. FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010;362(5): O Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Eng J Med. 2011;365: O Connor P, Li D, Freedman MS, et al. A Phase II study of the safety and efficacy of teriflunomide in the multiple sclerosis with relapses. Neurology. 2006;66; Freedman MS, Wolinsky JS, Wamil B, et al. Teriflunomide added to interferon-beta in relapsing multiple sclerosis: A randomized phase II trial. Neurology. 2012; 78: Ransohoff RM. Natalizumab for multiple sclerosis. N Engl J Med 2007;356: Keeley KA. Rivey MP. Allington DR. Natalizumab for the treatment of multiple sclerosis and Crohn's disease. Ann Pharmacother 2005; 39(11): DRUGDEX System [Internet database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Accessed June 4, McEvoy GK, ed. AHFS: Drug Information. Bethesda, MD: American Society of Health- System Pharmacists; 2007: , , American Hospital Formulary Service Drug Information. Available at: Accessed June Reviews, Revisions, and Approvals Date P&T Approval Date Converted to new template. Minor changes to verbiage and grammar. References updated Important Reminder This clinical policy has been developed by appropriately experienced and licensed health care professionals based on a review and consideration of currently available generally accepted standards of medical practice; peer-reviewed medical literature; government agency/program approval status; evidence-based guidelines and positions of leading national health professional organizations; views of physicians practicing in relevant clinical areas affected by this clinical Page 9 of 11

10 policy; and other available clinical information. The Health Plan makes no representations and accepts no liability with respect to the content of any external information used or relied upon in developing this clinical policy. This clinical policy is consistent with standards of medical practice current at the time that this clinical policy was approved. Health Plan means a health plan that has adopted this clinical policy and that is operated or administered, in whole or in part, by Centene Management Company, LLC, or any of such health plan s affiliates, as applicable. The purpose of this clinical policy is to provide a guide to medical necessity, which is a component of the guidelines used to assist in making coverage decisions and administering benefits. It does not constitute a contract or guarantee regarding payment or results. Coverage decisions and the administration of benefits are subject to all terms, conditions, exclusions and limitations of the coverage documents (e.g., evidence of coverage, certificate of coverage, policy, contract of insurance, etc.), as well as to state and federal requirements and applicable Health Plan-level administrative policies and procedures. This clinical policy is effective as of the date determined by the Health Plan. The date of posting may not be the effective date of this clinical policy. This clinical policy may be subject to applicable legal and regulatory requirements relating to provider notification. If there is a discrepancy between the effective date of this clinical policy and any applicable legal or regulatory requirement, the requirements of law and regulation shall govern. The Health Plan retains the right to change, amend or withdraw this clinical policy, and additional clinical policies may be developed and adopted as needed, at any time. This clinical policy does not constitute medical advice, medical treatment or medical care. It is not intended to dictate to providers how to practice medicine. Providers are expected to exercise professional medical judgment in providing the most appropriate care, and are solely responsible for the medical advice and treatment of members. This clinical policy is not intended to recommend treatment for members. Members should consult with their treating physician in connection with diagnosis and treatment decisions. Providers referred to in this clinical policy are independent contractors who exercise independent judgment and over whom the Health Plan has no control or right of control. Providers are not agents or employees of the Health Plan. This clinical policy is the property of the Health Plan. Unauthorized copying, use, and distribution of this clinical policy or any information contained herein are strictly prohibited. Providers, members and their representatives are bound to the terms and conditions expressed herein through the terms of their contracts. Where no such contract exists, providers, members and their representatives agree to be bound by such terms and conditions by providing services to members and/or submitting claims for payment for such services Centene Corporation. All rights reserved. All materials are exclusively owned by Centene Corporation and are protected by United States copyright law and international copyright law. No part of this publication may be reproduced, copied, modified, distributed, displayed, stored in a retrieval system, transmitted in any form or by any means, or otherwise published without the prior written permission of Centene Corporation. You may not alter or remove any trademark, copyright Page 10 of 11

11 or other notice contained herein. Centene and Centene Corporation are registered trademarks exclusively owned by Centene Corporation. Page 11 of 11