Subject:
Intravenous Drug Therapy for Multiple Sclerosis
Description:
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IMPORTANT NOTE:
The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.
Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.
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Multiple Sclerosis (MS) is an incurable, degenerative, immune-mediated demyelinating disease of the central nervous system, which affects approximately 400,000 people in the US.
The American Academy of Neurology classifies MS into four different categories:
- Relapsing-remitting MS (RRMS), which is classified as self-limiting attacks of neurological dysfunction. The attacks develop acutely and evolve over days to weeks. The recovery of function is not always complete and is seen over the next several weeks to months. Between attacks, patients are usually symptomatically and neurologically stable.
- Secondary-progressive MS (SPMS) usually begins as RRMS; however, the attack rate is reduced and the course continues as steady deterioration.
- Primary progressive MS (PPMS) is a steady decline in function from the beginning without acute attacks.
- Progressive-relapsing MS (PRMS) begins with a progressive course; however, patients experience occasional attacks.
MS is diagnosed from lesions seen on MRI or after a second demyelinating event, and symptoms can include spasticity, fatigue, pain, cognitive dysfunction, depression, and weakness. There is no cure for MS, but national practice guidelines advocate early and lifelong immunomodulatory treatment to slow disease progression and help prevent irreversible neurological damage. Mitoxantrone (Novantrone) is effective in MS, but due to its potential for serious toxicities, it is only indicated for rapidly advancing disease in patients who have failed other therapies. Injectable corticosteroids are used for acute exacerbations of multiple sclerosis. Cytoxan (cyclophosphamide) is used for the treatment of multiple sclerosis.
Novantrone (mitoxantrone) intercalates DNA causing crosslinks and strand breaks, inhibits topoisomerase II, and interferes with RNA production leading to cytocidal effects. Common side-effects include nausea, alopecia, amenorrhea, and infection. The use of Novantrone resulted in a mean change of the Expanded Disability Status Scale (EDSS), decreased the number of relapses, and decreased the number of brain lesions on an MRI.
Currently the manufacturer, EMD Serono, has chosen to discontinue distributing Novantrone. This was not due to safety concerns. The drug is still available under the generic name mitoxantrone hydrochloride.
This policy only applies to intravenous drug therapies for multiple sclerosis. For natalizumab (Tysabri) - Please refer to policy 050 Multiple Sclerosis: Natalizumab (Tysabri). For alemtuzumab (Lemtrada) - Please refer to policy 127 Lemtrada (Alemtuzumab). For ocrelizumab (Ocrevus) – Please refer to policy 150 Ocrelizumab (Ocrevus).
[INFORMATIONAL NOTE: Novantrone packaging includes the following BLACK BOX WARNINGS:
- Mitoxantrone should be administered under the supervision of a health care provider experienced in the use of cytotoxic chemotherapy agents. It should be given slowly into a freely flowing intravenous (IV) infusion, never subcutaneously, intramuscularly (IM), intra-arterially, or intrathecally. Severe local tissue damage may occur if there is extravasation during administration. Severe local tissue damage may occur if there is extravasation during administration.
- Except for the treatment of acute nonlymphocytic leukemia, mitoxantrone therapy generally should not be given to patients with baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving mitoxantrone.
- Cardiotoxicity: Congestive heart failure (CHF), potentially fatal, may occur during therapy with mitoxantrone or months to years after termination of therapy. Cardiotoxicity risk increases with cumulative mitoxantrone dose and may occur whether or not cardiac risk factors are present. Presence or history of cardiovascular disease, radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or use of other cardiotoxic drugs may increase this risk. In cancer patients, the risk of symptomatic CHF was estimated to be 2.6% for patients receiving up to a cumulative dose of 140 mg/m2. To mitigate the cardiotoxicity risk with mitoxantrone, consider the following:
- All patients should be assessed for cardiac signs and symptoms by history, physical examination, and electrocardiogram (ECG) prior to start of mitoxantrone therapy.
- All patients should have baseline quantitative evaluation of left ventricular ejection fraction (LVEF) using appropriate methodology (eg, echocardiogram, multigated radionuclide angiography [MUGA], or magnetic resonance imaging [MRI])
- Multiple sclerosis (MS) patients with a baseline LVEF below the lower limit of normal should not be treated with mitoxantrone.
- MS patients should be assessed for cardiac signs and symptoms by history, physical examination, and ECG prior to each dose.
- MS patients should undergo quantitative reevaluation of LVEF prior to each dose using the same methodology that was used to assess baseline LVEF. Additional doses of mitoxantrone should not be administered to MS patients who have experienced either a drop in LVEF to below the lower limit of normal or a clinically significant reduction in LVEF during mitoxantrone therapy.
- MS patients should not receive a cumulative mitoxantrone dose higher than 140 mg/m2.
- MS patients should undergo yearly quantitative LVEF evaluation after stopping mitoxantrone to monitor for late-occurring cardiotoxicity.
- Mitoxantrone therapy in patients with MS and in patients with cancer increases the risk of developing secondary acute myeloid leukemia.
Policy:
Note: For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance.
1. The prescriber is a specialist in the area of the patient’s diagnosis (e.g. neurologist) or has consulted with a specialist in the area of the patient’s diagnosis.
2. The following drugs are considered medically necessary for the following conditions:
- Novantrone (mitoxantrone) – for the treatment of secondary (chronic), progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis
- [INFORMATIONAL NOTE: Mitoxantrone is not indicated for the treatment of primary progressive multiple sclerosis.]
- Corticosteroids (e.g., methylprednisolone, sodium succinate) – for the treatment of members with acute exacerbations/relapses of MS.
3. When medically necessary, initial and continued therapy will be eligible for a period of 1 year at the following FDA recommended dose:
- Novantrone (mitoxantrone): 12 mg/m2 IV infusion every 3 months.
- Note: The FDA approved package insert indicates that mitoxantrone should not be administered to patients who have received a cumulative dose of 140 mg/m2 or greater
4. Other non-oncology uses of Novantrone (mitoxantrone), are considered investigational, including but not limited to, neuromyleitis optica.
Medicare Coverage
Per Local Coverage Determination (LCD): Immunosuppressive Drugs (L33824), coverage of methylprednisolone (J2920, J2930) is limited to those situations in which the medication cannot be tolerated or absorbed if taken orally and is self-administered by the beneficiary.
Per Local Coverage Determination (LCD): Intravenous Immune Globulin (IVIG) (L35093), the current evidence is inadequate to assess the value of IVIG in the treatment of multiple sclerosis. IVIG may be useful in persons as a second-line therapy in acute relapses of Relapsing Remitting Multiple Sclerosis (MS), but is generally not considered effective for maintenance therapy of MS or in slowing disease progression. Individual Consideration may be given when IVIG is used in the treatment of an acute relapse of Relapsing Remitting MS.
Medicaid Coverage
For Horizon NJ Health members, please follow this link for the corresponding HNJH drug policy https://services3.horizon-bcbsnj.com/ddn/NJhealthWeb.nsf
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Horizon BCBSNJ Medical Policy Development Process:
This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.
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Index:
Intravenous Drug Therapy for Multiple Sclerosis
Drug Therapy for Multiple Sclerosis
Injectable Drugs for Multiple Sclerosis
Corticosteroids
Cyclophosphamide (Cytoxan)
Cytoxan (Cyclophosphamide)
Mitoxantrone (Novantrone)
Multiple Sclerosis, Injectable Drugs for
Novantrone (Mitoxantrone)
References:
1. Avonex prescribing information. Biogen Idec Inc. Cambridge, MA. 7/2019.
2. Betaseron prescribing information. Bayer HealthCare Pharmaceuticals Inc. Whippany, NJ. 8/2019.
3. Copaxone prescribing information. Teva Pharmaceuticals. Parsippany, NJ. 1/2014 12/2019.
4. Rebif prescribing information. EMD Serono Inc. Rockland, MA. 7/2019.
5. Novantrone prescribing information. Serono Inc. Rockland, MA. 5/2018.
6. Goodin DS, et al. The use of mitoxantrone (Novatrone) for the treatment of multiple sclerosis: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2003;61: 1332-8.
7. Goodin DS, et al. Disease modifying therapies in multiple sclerosis: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2002;58:169-78.
8. Frohman EM, et al. The utility of MRI in suspected MS: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2003;61:602-11.
9. Stuart WH. Clinical Management of Multiple Sclerosis: The Treatment Paradigm and Issues of Patient Management. J Manag Care Pharm 2004;10(3) (suppl S-b): S19-S25.
10. Rich SJ, et al. Stepped-Care Approach to Treating MS: A Managed Care Treatment Algorithm. J Manag Care Pharm 2004;10(3)(suppl S-b):S26-S32.
11. Berlex Completes Recruitment for Betaseron BEYOND Study: Largest Ever Clinical Study in Multiple Sclerosis. Berlex Press Release: July 20, 2005.
12. Leary SM, et al. Interferon beta-1a in primary progressive MS: an exploratory, randomized, controlled trial. Neurology 2003 Jan 14;60(1):44-51.
13. Montalban X. Overview of European pilot study of interferon beta-1b in primary progressive multiple sclerosis. Mult Scler 2004;10 Suppl 1:S662.
14. Wolinsky JS. The PROMiSe trial: baseline data review and progress report. Mult Scler 2004 Jun;10 Suppl 1:S65-71; discussion S71-2.
15. Leary SM, et al. Primary Progressive Multiple Sclerosis: Current and Future Treatment Options. CNS Drugs 2005;19(5):369-76.
16. Wolinsky JS. The diagnosis of primary progressive multiple sclerosis. J Neurol Sci 206:145-52.
17. Kita M, et al. A Phase II trial of mitoxantrone in patients with primary progressive multiple sclerosis. Neurology 2004;62 suppl. 5:A99.
18. Clanet M, Kappos L, Hartung HP, Hohlfeld R; European IFNbeta-1a Dose-Comparison Study Investigators. Interferon beta-1a in relapsing multiple sclerosis: four-year extension of the European IFNbeta-1a Dose-Comparison Study. Mult Scler 2004 Apr;10(2):139-44.
19. Micromedex Health Series. Thomson Gateway. [Available at: http://www.thomsonhc.com/hcs/librarian/PFPUI/AH1fgpoxqU9YR]
20. AHFS Drug Information. American Society of Health-System Pharmacists, Inc. 2005.
21. Cohen JA, Calabresi PA, Chakraborty S. et al. Avonex Combination Trial in relapsing_remitting MS: rationale, design and baseline data. Multiple Sclerosis 2008;14:370–382.
22. Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis (MS) Combi Rx. Available at http://clinicaltrials.gov/ct2/show/NCT00211887?term=CombiRx&rank=1. (Accessed May 15 2008).
23. May, T. REGARD: Glatiramer Acetate, Inteferon-Beta Equally Effective for MS. Medscape Medical News 2007. Available at http://www.medscape.com/viewarticle/564944. (Accessed on May 15 2008).
24. Bayer Healthcare Pharmaceuticals. BEYOND (Betaseron Efficacy Yielding Outcomes of New Dose): Study Results [letter]:2007.
25. Vollmer T, Panitch H, Bar-Or A, et al. Glatiramer acetate after induction therapy with mitoxantrone in relapsing multiple sclerosis. Multiple Sclerosis 2008;00:1-8.
26. Cross, AH et al. Ritiximab reduces B cells and T cells in cerebrospinal fluid of multiple sclerosis patients. J Neuroimmunol 2006;180:63-70.
27. Cree B, Lamb S, Chin A, et al. Tolerability and effects of rituximab (anti-CD20 antibody) in neuromyelitis optica (NMO) and rapidly worsening multiple sclerosis (MS). Neurology 2004;62(suppl 5):A492. Abstract.
28.. Hauser, SL, Waubant E, et al. B-cell depletion wtih rituximab in relapsing-remitting multiple sclerosis. N Engl J Med February 2008;358:676-88.
29. Bar-Or, A, Calabresi AJ, et al. Rituximab in relapsing-remitting multiple sclerosis: A 72-week, open-label,, phase I trial. Ann Neurol 2008;63(3):395-400.
30. Cree B, Lamb S, Chin A, et al. Tolerability and effects of rituximab (anti-CD20 antibody) in neuromyelitis optica (NMO) and rapidly worsening multiple sclerosis (MS). Neurology 2004;62(suppl 5):A492. Abstract.
31. Rizvi, SA, Bashir K, et al. Other therapy options and future strategies for treating patients with multiple sclerosis. Neurology 2004;63(suppl 6):S47-S54.
32. Pilz, G, Wipfler, P, Ladurner G, et al. Modern Multiple Sclerosis Treatment: What is Approved, What is on the Horizon. Drug Discovery Today December 2008; 13(23/24):1013-1025.
33. Linker, Ra, Kieseier, BC, Gold, R, et al. Identification and development of new therapeutics for multiple sclerosis. Trends in Pharmacological Sciences September 17, 2008; 29(11): 558-565.
34. Extavia prescribing information. Novartis Pharmaceutical Corp. East Hanover, NJ. August 2019.
35. Ampyra (dalfampridine) Prescribing Information. Hawthorne, NY. Acorda Therapeutics, Inc. December 2019.
36. Goodman AD, Brown TR, Krupp LB, et al. Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial. Lancet. 2009;373(9665):732-8.
37. Gilenya prescribing information. Novartis Pharmaceuticals Corp. East Hanover, NJ. December 2019.
38. U.S. Food and Drug Administration. Gilenya (fingolimod): Drug Safety Communication - Safety Review of a Reported Death After the First Dose. December 20, 2011. [Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm284355.htm]
39. Aubagio prescribing information. Genzyme Corporation. Cambridge, MA. September 2019.
40. Tecfidera (dimethyl fumarate) Prescribing Information. Biogen Idec Inc. Cambridge, MA. December 2019.
41. Van Oosten BW, Killestein J, Barkhof F, et al. PML in a patient treated with dimethyl fumarate form a compounding pharmacy. N Engl J Med. 2013 Apr 25;368(17):1658-9.
42. Ermis U, Weis J, Schulz JB. PML in a patient treated with fumaric acid. N Engl J Med. 2013 Apr 25;368(17):1657-8.
43. Boneschi FM, Vacchi L, Rovaris M, et al. Mitoxantrone for multiple sclerosis. The Cochrane Library. 2013.
44. Le Page E, Deburghgraeve V, Lester MA, et al. Alemtuzumab as rescue therapy in a cohort of 16 aggressive multiple sclerosis patients previously treated by Mitoxantrone: an observational study. J Neuro. 2015;1-11.
45. Mitoxantrone. Clinicaltrial.gov. Accessed on 1/29/2020. Available at: https://clinicaltrials.gov/ct2/results?cond=&term=Novantrone&cntry=&state=&city=&dist=
46. Mitoxantrone [prescribing information]. Lake Forest, IL: Hospira, Inc; May 2018.
Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)
CPT*
HCPCS
J1825
J1826
J1830
J2323
J2920
J2930
J7509
J8499
J9293
Q3028
* CPT copyright 2020 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.
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Medical policies can be highly technical and are designed for use by the Horizon BCBSNJ professional staff in making coverage determinations. Members referring to this policy should discuss it with their treating physician, and should refer to their specific benefit plan for the terms, conditions, limitations and exclusions of their coverage.
The Horizon BCBSNJ Medical Policy Manual is proprietary. It is to be used only as authorized by Horizon BCBSNJ and its affiliates. The contents of this Medical Policy are not to be copied, reproduced or circulated to other parties without the express written consent of Horizon BCBSNJ. The contents of this Medical Policy may be updated or changed without notice, unless otherwise required by law and/or regulation. However, benefit determinations are made in the context of medical policies existing at the time of the decision and are not subject to later revision as the result of a change in medical policy
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