CLINICAL POLICY Department: Medical Management Document Name: MS Treatments

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1 Page: 1 of 21 IMPORTANT REMINDER This Clinical Policy has been developed by appropriately experienced and licensed health care professionals based on a thorough review and consideration of generally accepted standards of medical practice, peer-reviewed medical literature, government agency/program approval status, and other indicia of medical necessity. The purpose of this Clinical Policy is to provide a guide to medical necessity. Benefit determinations should be based in all cases on the applicable contract provisions governing plan benefits ( Benefit Plan Contract ) and applicable state and federal requirements, as well as applicable plan-level administrative policies and procedures. To the extent there are any conflicts between this Clinical Policy and the Benefit Plan Contract provisions, the Benefit Plan Contract provisions will control. Clinical policies are intended to be reflective of current scientific research and clinical thinking. This Clinical Policy is not intended to dictate to providers how to practice medicine, nor does it constitute a contract or guarantee regarding payment or results. 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. Subject The intent of the criteria is to ensure that patients follow selection elements for targeted therapies for the treatment of multiple sclerosis (MS) established by Centene medical policy. Table 1. Targeted Therapies for the Treatment of MS 1-11 Medication Generic Name FDA-approved Indication Ampyra dalfampridine To improve walking in patients with multiple sclerosis. Aubagio teriflunomide Relapsing forms of MS Avonex Betaseron Extavia interferon beta-1a (IFNβ-1a) interferon beta-1b (IFNβ-1b) Relapsing forms of MS, including patients who have experienced a first clinical episode and have MRI features consistent with MS Relapsing forms of MS, including patients who have experienced a first clinical episode and have MRI features consistent with MS Copaxone glatiramer acetate Relapsing-remitting MS (RRMS), including patients who have experienced a first clinical episode and have MRI features consistent with MS Gilenya fingolimod Relapsing forms of MS mitoxantrone mitoxantrone Relapsing forms of MS, secondary progressive MS (SPMS) Rebif interferon beta-1a (IFNβ-1a) Relapsing forms of MS

2 Page: 2 of 21 Medication Generic Name FDA-approved Indication Tecfidera dimethyl fumarate Relapsing forms of MS Tysabri natalizumab Relapsing forms of MS This includes patients with RRMS, progressive-relapsing MS (PRMS) and SPMS with relapse. Management Challenge Multiple sclerosis (MS) is a chronic, recurring neurologic disorder often diagnosed in early adulthood. 12,13 MS can manifest in various forms with unpredictable clinical courses. 13 Some patients have mild disease and long periods of remission; others are completely disabled as communications between the brain and body break down. 13 In the United States, approximately 400,000 people have MS and nearly 200 new cases are diagnosed each week Early diagnosis and treatment are essential to improve the quality of life of patients with MS and to limit the lifelong personal and economic burdens of the condition. 15 Disease-modifying therapies may limit relapses and slow disease progression. 12 Policy/Criteria It is the policy of Health Plans affiliated with Centene Corporation that the treatment of MS is medically necessary when meeting the following algorithm criteria: Figure 1: IFN-β Algorithm Figure 2: Copaxone Algorithm Figure 3: Gilenya Algorithm Figure 4: Tysabri Algorithm Figure 5: Ampyra Algorithm Figure 6: Mitoxantrone Algorithm Figure 7: Aubagio Algorithm Figure 8: Tecfidera Algorithm

3 Page: 3 of 21 Figure 1: IFN-β Algorithm Referral for Avonex, Betaseron, Extavia, Rebif Will prescribed agent be used as monotherapy? Has the patient previously experienced anaphylaxis with interferon therapy? no PPMS What is the diagnosis? 1 st clinical episode SPMS Does the patient have MRI features consistent with MS? RRMS PRMS Approve 12 months Does the patient experience relapses? Approve 1 month

4 Page: 4 of 21 Figure 2: Copaxone Algorithm Will Copaxone be used as monotherapy? What is the diagnosis? 1 st clinical episode RRMS PPMS PRMS SPMS Does the patient have MRI features consistent with MS? Approve 12 months

5 Page: 5 of 21 Figure 3: Gilenya Algorithm Diagnosis of a relapsing form of MS (See Appendix B) with MRI features of MS? Will Gilenya be used as monotherapy? Experienced any of the following within the last 6 months? MI, Unstable angina Stroke, TIA Decompensated heart failure requiring hospitalization Class III or IV heart failure History or presence of Mobitz Type II 2 nd degree AV block, 3 rd degree AV block, or Sick sinus syndrome? Does the patient have a functioning pacemaker? History or presence of any other indication in Appendix G? Does the patient have a baseline QTc interval 500ms? / unknown Currently receiving treatment with Class Ia or Class III antiarrhythmic drugs? (See Appendix D) Approve 12 months

6 Page: 6 of 21 Figure 4: Tysabri Algorithm Will Tysabri be used as monotherapy? What is the diagnosis? CD Refer to Centene IBD Treatment criteria MS Relapsing form of MS (See Appendix B) or rapidly progressing form of MS? yes yes Does patient have a history of PML? no, relapsing form of MS Tried and had insufficient response to other biologics for MS? (See Appendix C) MRI features consistent with MS?, progressing form of MS Approve 6 months Currently receiving Tysabri through the Centene benefit? no Has the patient developed any condition listed in Appendix F? yes

7 Page: 7 of 21 Figure 5: Ampyra Algorithm Diagnosis and MRI features of MS? History of seizures? CrCl 50 ml/ minute? Is the prescribed dose >10 mg twice daily? Currently receiving Ampyra through the Centene benefit? Prior to initiating therapy, does/did the patient have sustained walking impairment? Received at least 2 months of treatment? Approve to 2 months total Is/was the patient able to walk 25 feet (with or without assistance)? Currently on Ampyra treatment? Improvement in walking speed since starting Ampyra therapy? Improvement in an objective measure of walking ability since starting Ampyra? Approve 6 months Approve for 2 months

8 Page: 8 of 21 Figure 6: Mitoxantrone Algorithm MRI features consistent with MS? Collect baseline or current LVEF, CBC with diff, and lifetime mitoxantrone dose LVEF < 50%? ANC <1500 cell/mm 3? Is the lifetime dose >140 mg/ m 2? Will mitoxantrone be used as monotherapy? What is the diagnosis? Other MS Relapsing form of MS (See Appendix B) or secondary progressive MS? Approve one dose

9 Page: 9 of 21 Figure 7: Aubagio Algorithm Relapsing form of MS (See Appendix B) with MRI features of MS? Will Aubagio be used as monotherapy? Currently receiving treatment with leflunomide? Approve 12 months

10 Page: 10 of 21 Figure 8: Tecfidera Algorithm Will Tecfidera be used as monotherapy? Relapsing form of MS (See Appendix B) with MRI features of MS? Collect CBC results performed in past 6 months 0-6 months How long has patient been on treatment? 12+ months Collect CBC results performed in past 12 months 6-12 months Approve 6 months Collect CBC results performed in past 6 months Approve 12 months Background: Multiple Sclerosis Clinical Course During an MS attack, inflammation and plaques form in the white matter of the central nervous system (CNS). 13 Patients with MS have one of four clinical courses defined by the American Academy of Neurology: 12,17 Relapsing-Remitting MS (RRMS): Self-limited attacks of neurologic function followed by a variable degree of recovery. This is the most common initial diagnosis. Secondary Progressive MS (SPMS): Begins as RRMS, but the attack rate is reduced and the patient experiences a steady decline in neurologic function unrelated to acute attacks. Most patients with RRMS will eventually develop SPMS as a natural progression of the disorder. It may occur with or without relapse.

11 Page: 11 of 21 Progressive-Relapsing MS (PRMS): Steady decline in neurologic function from onset with occasional acute attacks. Primary Progressive MS (PPMS): Steady decline in neurologic function from onset without superimposed attacks. Disease-Modifying Therapies for Multiple Sclerosis Disease modifying therapy should be considered once a diagnosis of a relapsing form of MS is confirmed. 15,16 According to the Medical Advisory Board of the National Multiple Sclerosis Society, treatment with disease-modifying agents should continue indefinitely, as indicated, unless there is a clear lack of benefit, intolerable side effects, or an emergence of new data or therapies. 16 Although an exact mechanism for therapeutic effect has not been fully elucidated for all currently approved MS therapies, disease-modifying agents generally target the immune system dysfunction in patients with relapsing MS. 1-13,15 Immunomodulators, such as the beta interferons (IFNβ) and glatiramer acetate, reduce the MS attack rate and severity, improve MRI disease activity, and may slow sustained disability progression. 10 Interferon beta1-a is a natural cytokine produced in the body. There are several interferon beta1-a products such as Avonex and Rebif that are approved for the treatment of multiple sclerosis to slow down the progression and exacerbation of the disease. Interferon beta1-a exerts its action by increasing the number of anti-inflammatory agents while decreasing the number of pro-inflammatory cytokines. 3,9 They may also reduce the cross of inflammatory agents into the blood brain barrier and increase nerve growth factor production which is essential for the neuronal reparation process. Currently, Avonex has three different formulations delivered via the intramuscular route; the pen, prefilled syringe and powdered form are the three formulations. 3 They are all approved for once-a-week administration and is given intramuscularly which results in less frequent dosing for the patient. The most common side effect associated with the initial treatment with Avonex is flu-like symptoms which can be minimized by pre-medicating with analgesics such as NSAIDS or APAP. Some other less common side effects include depression, suicidal thoughts, seizures, cardiac problems, liver and blood problems and may be considered for discontinuation of the drug. Rebif is currently available in the prefilled syringe form and is delivered via the subcutaneous route. Rebif is approved for three times a week dosage. Similarly to Avonex, the common side effect of Rebif is flulike symptoms. Rebif can also cause injection site reactions. Depression, seizures, allergic reaction, abdominal pain, liver, thyroid and blood problems can also occur during the use of Rebif. 9 Interferon beta-1b has the same indication and a similar mode of action to that of interferon beta-1a There are currently two FDA approved products available for the treatment of multiple sclerosis; Betaseron and Extavia. Both are delivered via subcutaneous route and are administered every other day. The common side effects are flulike symptoms and injection site reactions such as swelling, pain and discoloration. Flulike symptoms can be managed with analgesics and injection site

12 Page: 12 of 21 reactions can be managed by rotating the injection site. Other less common side effects such as depression, allergic reaction, seizure and liver problems are also reported. 4,6 Copaxone (glatiramer acetate) is an FDA approved product indicated for the treatment of relapsing-remitting MS (RRMS), including patients who have experienced a first clinical episode and have MRI features consistent with MS. The mechanism for therapeutic effect is not fully understood, however it is thought to mimic myelin basic protein and induces and activates suppressor T-cells specific for myelin antigen. It is contraindicated in patients with a hypersensitivity to glatiramer acetate or mannitol. Lipoatrophy and skin necrosis may occur therefore it is vital to instruct patients in proper injection technique and to rotate injection sites. Immediate Post-Injection Reaction (flushing, chest pain, dyspnea, etc.) may occur with the use of this drug as well. Copaxone is relatively safe in pregnancy. The pregnancy category is B and is not associated with lower mean birth weight, congenital anomaly, preterm birth (<37 weeks), or spontaneous abortion. 5 Mitoxantrone is indicated in the management of several forms of worsening MS, including secondary progressive MS, progressive relapsing MS, and advanced relapsing-remitting MS and effectively reduces the frequency of relapses. The use of mitoxantrone is limited by its adverse effect profile however. Use of mitoxantrone may cause serious and fatal heart damage and other cardio-toxicities including heart failure. It also can cause leukemia. Frequent tests, including a heart scan (EKG), are recommended before each injection of this medicine. In order to reduce the risk of heart damage associated with Mitoxantrone, the FDA has limited number of doses a patient can receive. The FDA recommends up to 12 total doses, or no more than 140 mg/m^2 total cumulative dose. Typically, the medicine is injected once every 3 months at a dose of 12mg/m^2 for 2 to 3 years. Because Mitoxantrone is an immunosuppressant agent, it leads to reduction of lymphocyte as well. In summary, interferon therapy remains the first choice for patients unless the therapy is ineffective or if a patient is intolerant to or has contraindications with interferon therapy. 17 Gilenya (fingolimod) is the first FDA-approved oral disease-modifying therapy. It is a sphingosine 1-phosphate receptor modulator. 7 The mechanism for therapeutic effect in treating MS may involve a reduction of lymphocyte migration into the central nervous system. Gilenya can reduce the frequency of clinical exacerbations and delay the accumulation of physical disability. Gilenya may result in decreases in heart rate and thus monitoring heart rate is essential at least during the first 6 hours after the initial dose. Gilenya may also cause atrioventricular conduction delay upon initiation of therapy, macular edema, reduction in lymphocyte count, and an elevation of liver enzymes, all of which may increase in patients with diabetes and other conditions that were barred from the pivotal trial. In the event of severe liver injury, Gilenya must be discontinued as well. Gilenya may also increase the risk of infections and a CBC count must be done prior to initiating treatment; It is also imperative to monitor for infection throughout the duration of treatment and 2 months post

13 Page: 13 of 21 discontinuation of the drug. In addition, this drug should not be initiated in patients with an active infection. A recent FDA safety review following reports of a patient death after the first dose of Gilenya resulted in a labeling revision that contraindicates use of Gilenya in patients with cardiac conditions. Such contraindications are listed in appendix E. Additionally, a post-marketing report of progressive multifocal leukoencephalopathy (PML) in a patient who had received Tysabri therapy prior to initiating Gilenya has raised concerns regarding washout periods following Tysabri discontinuation. Although the patient had received Tysabri therapy for over three years and had positive antibodies to the JC virus which causes PML, a contribution from Gilenya therapy could not 18 12,19,20 be ruled out. If posterior reversible encephalopathy syndrome (PRES) is also suspected in a patient, Gilenya should be discontinued. Women of childbearing age should also use contraception while on Gilenya and for 2 months after the discontinuation of Gilenya due to its potential to induce fetal harm. Tecfidera (dimethyl fumarate) is an oral treatment FDA-approved for relapsing forms of MS. 10 The efficacy and safety of Tecfidera were demonstrated in two placebo-controlled phase 3 studies involving 1234 patients (DEFINE Study) and 1417 patients (CONFIRM Study). Both studies included two dosing regimens, 240 mg two or three times daily and the CONFIRM Study included an additional comparator group receiving glatiramer acetate. 36,37 The primary endpoint was the proportion of patients who experience a relapse in the DEFINE study and the annualized relapse rate in the CONFIRM Study. 36,37 Both Tecfidera twice-daily and Tecfidera thrice-daily groups were significantly lower in the proportion of patients whose disease relapsed compared to the placebo group in the DEFINE study. 36 In both of the studies, annualized relapse rates, disability progression, and new or enlarging T2-weighted of the Tecfidera groups were significantly reduced compared to the placebo group placebo. 36 Flushing was the most common adverse reactions followed by abdominal pain, diarrhea, and nausea. 10 However, Tecfidera may decrease lymphocyte counts and so a recent blood test must be available before initiating therapy to identify patients with pre-existing low lymphocyte counts (i.e. within 6 months). Patients should also inform their physician if they plan for pregnancy soon. It is also recommended to enroll in the TECFIDERA pregnancy registry for patients contemplating pregnancy. Overall though, Tecfidera has a favorable safety profile which makes it an attractive oral therapy option for patients with relapsing forms of MS. Tysabri (natalizumab) is a selective adhesion-molecule inhibitor that blocks immune cell movement into the CNS and suppresses the inflammation characteristic of MS. 11,27 Tysabri is effective in reducing the rate of relapse and in slowing the accumulation of physical disability. 11,27 However, Tysabri carries a boxed warning regarding the risk of PML, a rare viral infection of the brain that is often fatal. 11 There is no cure for PML or any way to predict who will develop the disease. Patients who developed PML in the pivotal trial were on concomitant therapy with interferon beta-1a or were immunocompromised due to past treatment with immunosuppressants. In the post-marketing setting, additional cases of PML have been reported in MS patients who were

14 Page: 14 of 21 receiving no concomitant immunomodulatory therapy. Importantly, half of the cases appear in patients who are not on concomitant therapy and who never were exposed to chemotherapy. The risk of developing PML appears to increase with longer Tysabri treatment duration. Ordinarily, patients receiving chronic immunosuppressant or immunomodulatory therapy or who have systemic medical conditions resulting in significantly compromised immune system function should not be treated with Tysabri. It is essential to have an MRI done to differentiate subsequent MS symptoms from PML before initiating therapy. Other contraindications include patients who have had a history of PML and those who have had a hypersensitivity reaction to Tysabri. Fatal occurrences of Herpes encephalitis and meningitis have been seen and discontinuation of the drug and treatment of these disease states must take into effect immediately. Other reasons to discontinue the drug are listed in appendix F. Tysabri is only available through a restricted access program and is generally considered as a second-line therapy in the management of relapsing MS. Aubagio (teriflunomide)is a pyrimidine synthesis inhibitor indicated for the treatment of patients with relapsing forms of multiple sclerosis. 2 Aubagio reduces T- and B-cell activation and exhibits antiproliferative properties. 34 A reduction in the number of activated lymphocytes in the central nervous system is thought to be a factor in the mechanism by which Aubagio exerts its therapeutic effect in multiple sclerosis. 34 FDA approval of Aubagio was based on the results of a randomized, double-blind, placebo-controlled, parallel-group trial of 1088 patients with relapsing forms of multiple sclerosis. 34 Aubagio was associated with a significant reduction in annualized relapse rate compared to placebo (31% relative risk reduction for both 7mg and 14mg doses, P<0.001). Additionally, fewer patients in the higher dose Aubagio group experienced sustained disability progression compared to placebo (P=0.03), but there was no significant difference in the proportion of patients with disability progression between the lower dose Aubagio group and placebo. The most common adverse reactions with Aubagio were elevated alanine aminotransferase (ALT) levels, diarrhea, nausea, alopecia, influenza, and paresthesia. Aubagio is contraindicated in patients with severe hepatic impairment and pregnancy. 34 Female patients of childbearing potential should use reliable contraception throughout treatment with Aubagio. Aubagio may increase exposure to ethinylestradiol and levonorgesterel, therefore considerable attention should be given in choosing an appropriate contraception agent. Aubagio is the active metabolite of leflunomide and is contraindicated in patients currently receiving treatment with leflunomide as well. Transaminase and bilirubin levels should be obtained within 6 months prior to initiating therapy with Aubagio, and ALT levels should be monitored at least monthly for six months thereafter. Aubagio may also decrease WBC and therefore a recent CBC should be available before initiating therapy with Aubagio. If signs and symptoms of infection or of peripheral neuropathy develop, or if severe skin reactions occur, discontinue the drug and and undergo elimination procedures by administering cholestyramine or activated charcoal. Aubagio may decrease INR as well so appropriate monitoring of INR needs to take place.

15 Aubagio Avonex Betaseron Extavia Copaxone Gilenya mitoxantrone Rebif Tecfidera Tysabri CLINICAL POLICY Page: 15 of 21 Preliminary data from a head-to-head trial of Aubagio versus Rebif failed to demonstrate that treatment with Aubagio was superior to Rebif with regard to time to failure, defined as a confirmed relapse or permanent treatment discontinuation. 35 Fewer patients in the teriflunomide group permanently discontinued treatment compared to the group receiving treatment with Rebif, but there was no significant difference in adjusted annualized relapse rates between all patient groups. Ampyra (dalfampridine) is indicated for improving walking ability in patients with MS. 1 Ampyra is a broad spectrum potassium channel blocker that improves conduction of action potentials in demyelinated axons. Myelin destruction is considered a pathologic hallmark of multiple sclerosis. 29,30 Demyelination exposes potassium channels, impairing the conduction and generation of action potential through the neuronal axons. As this is correlated with the appearance of clinically significant symptoms, restored conduction should enhance the quality of life for an MS patient. Ampyra is contraindicated in patients who have a history of seizures, moderate or severe renal impairment (CrCl <50 ml/min). Patients with a CrCl ml/min may be at an increased risk of seizures. Therefore, the benefits of Ampyra must be considered against the risk of seizures. Other contraindications include those who have a history of hypersensitivity to Ampyra or 4-amino pyridine. Ampyra can cause anaphylaxis and as a result needs to be discontinued and not re-started. Safety The algorithms provide detail how all pertinent safety concerns are addressed within the program. Table 2. Safety Concerns with Multiple Sclerosis Disease-Modifying Therapies 2-11,19,26 Safety Concern AML X Bradyarrhythmia and atrioventricular block X Compromised immune system/infection risk X X X X Concomitant biologic use X X X X X Depression/suicidal ideation X X X Injection site necrosis X X X Lipoatrophy X LVEF <50%, cumulative lifetime dose >140 mg/m 2 X

16 Aubagio Avonex Betaseron Extavia Copaxone Gilenya mitoxantrone Rebif Tecfidera Tysabri CLINICAL POLICY Page: 16 of 21 Safety Concern Macular edema X Monitoring for hematologic adverse events X X X X X Monitoring for hepatic injury X X X X X X X Neutropenia (<1500 cells/mm 3 ) X Peripheral neuropathy X PML (any sign or history of) X Respiratory effects X Risk of teratogenicity X LVEF = left ventricular ejection fraction; AML = acute myelogenous leukemia; PML = progressive multifocal leukoencephalopathy Table 3. Safety Concerns with Ampyra 1 Safety Concern History of seizure Renal impairment (CrCl 50 ml/minute) CrCl = creatinine clearance Appendices Appendix A: Abbreviations ANC: Absolute neutrophil count AV: Atrioventricular CBC: Complete blood count CD: Crohn s disease CIS: Clinically-isolated syndrome CrCl: Creatinine clearance IFN-β: Interferon beta LVEF: Left ventricular ejection fraction MI: Myocardial infarction MS: Multiple sclerosis PPMS: Primary progressive multiple sclerosis PRMS: Progressive-relapsing multiple sclerosis RRMS: Relapsing-remitting multiple sclerosis SPMS: Secondary progressive multiple sclerosis T25FW: Timed 25-foot walk TIA: Transient ischemic attack Appendix B: Relapsing forms of MS Relapsing-remitting MS (RRMS) Secondary progressive MS (SPMS) with relapses Progressive-relapsing MS (PRMS)

17 Page: 17 of 21 Appendix C: Biologic therapies for MS treatment Avonex (interferon beta 1a) Betaseron (interferon beta 1b) Copaxone (glatiramer acetate) Extavia (interferon beta 1b) Gilenya (fingolimod) mitoxantrone Rebif (interferon beta 1a) Appendix D: Class Ia and Class III antiarrhythmic agents 31,32 Class Ia agents: Disopyramide (rpace ) Procainamide Quinidine Class III agents: Amiodarone (Cordarone, Pacerone ) Dofetilide (Tikosyn ) Dronedarone (Multaq ) Ibutilide (Corvert ) Sotalol (Betapace, Sorine ) Appendix E: Cardiac conditions that are contraindicated with Gilenya 7 Arrhythmia Prolonged QT level On medications that can alter heart rate. History or presence of Mobitz Type 2 second degree or third degree atrioventricular block Sick sinus syndrome (unless patient has a functioning pacemaker), Baseline QTc interval >/= 500 msec, Being treated with a class 1A or 3 anti-arrhythmic drugs If a patient has experienced the following conditions in the last 6 months such as a: o Heart attack o TIA o Unstable angina o Decompensated heart failure requiring o Stroke hospitalization Appendix F: Conditions for the Discontinuation of Tysabri 11 ) If herpes encephalitis and meningitis occur Severe hepatotoxicity Anaphylaxis JC Virus + in patients with 24 months of therapy Appendix G: Conditions for the Discontinuation of Gilenya 7

18 Page: 18 of 21 History or presence of any of the following: Mobitz Type II 2nd degree AV block 2nd or 3rd AV degree AV block Sick sinus syndrome Severe liver injury Significant reduction in heart rate Active Infection Posterior Reversible Encephalopathy Syndrome (PRES) Bibliography 1. Ampyra [package insert]. Hawthorne, NY: Acorda Therapeutics, Inc.; January Aubagio [package insert].cambridge, MA: Genzyme Corporation, A Sanofi Company, September Avonex [package insert]. Cambridge, MA: Biogen Idec Inc.; March Betaseron [package insert]. Montville, NJ: Bayer HealthCare Pharmaceuticals Inc.; January Copaxone [package insert]. Kansas City, MO: Teva Neuroscience, Inc.; February Extavia [package insert]. East Hanover, NJ: vartis Pharmaceutical Corporation; March Gilenya [package insert]. East Hanover, NJ: vartis Pharmaceuticals Corporation; May Mitoxantrone [package insert]. Bedford, OH: Bedford Laboratories; vember Rebif [package insert]. Rockland, MA; EMD Serono Inc.; February Tecfidera [package insert]. Cambridge, MA : Biogen Idec Inc., : March Tysabri [package insert]. Cambridge, MA: Biogen Idec Inc.; January Goodin DS, Frohman EM, Garmany GP, 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: Multiple Sclerosis: Hope Through Research. Bethesda, MD: National Institutes of Health, National Institute of Neurological Disorders and Stroke; April NIH Publication Available at: Accessed May 23, Frohman EM, Goodin DS, Calabresi PA, 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: Fox RJ, Sweeney PJ. Multiple Sclerosis. Cleveland, OH: The Cleveland Clinic Foundation; Available at: s.htm. Accessed May 23, 2013.

19 Page: 19 of National Multiple Sclerosis Society. Disease Management Consensus Statement. New York, NY: National Multiple Sclerosis Society; Available at: Accessed May 23, National Multiple Sclerosis Society. What is Multiple Sclerosis? New York, NY: National Multiple Sclerosis Society; Available at: Accessed June 13, vartis statement: Gilenya (fingolimod) safety information update. Available at: Accessed May 7, Marriott JJ, Miyasaki JM, Gronseth G, O Connor PW. The efficacy and safety of mitoxantrone in the treatment of multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2010;74: Smith B, Carson S, Fu R, et al. Drug class review: disease-modifying drugs for multiple sclerosis. Final update 1 report; August Available at: Accessed April 11, Stuart WH, Cohan S, Richert JR, Achiron A. Selecting a disease-modifying agent as platform therapy in the long-term management of multiple sclerosis. Neurology 2004;63(Suppl 5):S19- S Goodin DG, Li D, Traboulsee A. The interferon beta-1b 16-year long-term follow-up study: Predictive clinical and magnetic resonance imaging markers. 60 th Annual Meeting of the American Academy of Neurology (AAN), Chicago, IL, April 15, Neurology. 2008; 70 (11, Suppl 1): A Abstract [P02.142]. 23. Goodin D, Ebers G, Reder AT. Early treatment with interferon beta-1b associated with improved long-term outcome in multiple sclerosis. 24 th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), ACTRIMS, and LACTRIMS. Montréal, Canada, September 18, Multiple Sclerosis. 2008; 14 (Suppl 1): S44. Abstract P Goodin D, Ebers G, Reder AT. Higher exposure to interferon beta-1b is associated with improved long-term outcomes, but the effect is substantially reduced by delaying treatment. European Neurologic Society (ENS), Nice France, June J Neurol. 2008; 255 (Suppl 2):177. Abstract P Goodin DS, Frohman EM, Hurwitz B, et al. Neutralizing Antibodies to Interferon beta: Assessment of their Clinical and Radiographic Impact: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2007;68: Stuart WH, Vermersch P. Concomitant therapy for multiple sclerosis. Neurology. 2004;63(Suppl 5):S28-S34.

20 Page: 20 of Polman CH, O Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. New Eng J Med. 2006;354: Yousry TA, Habil M, Major EO, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Eng J Med. 2006;354: Korenke AR, Rivey MP, Allington DR. Sustained-release fampridine for symptomatic treatment of multiple sclerosis. Ann Pharmacother. 2008;42: Feret B. Fampridine-SR: a potassium-channel blocker for the improvement of walking ability in patients with MS. Formulary. 2009;44: Fuster V, Ryden LE, Cannom DS et al ACCF/AHA/HRS Focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation. J Am Coll Cardiol. 2011;57:e101-e Multaq [package insert]. Bridgewater, NJ: Sanofi Aventis U.S. LLC; January Coates TD, Baehner RL. Laboratory Evaluation of Neutropenia and Neutrophil Dysfunction. Up to date Patient Information. Available at: Accessed April 5, O Connor P, Wolinsky JS, Confavreux C et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365: Vermersch PV, Czlonkowska A, Grimaldi LM et al. A multicenter, randomized, parallel-group, rater-blinded study comparing the effectiveness and safety of teriflunomide and subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis [abstract]. CMSC-ACTRIMS 2012 Annual Meeting; San Diego, CA. 36. Gold R, Kappos L, Arnald DL et al. Placebo-Controlled Phase 3 Study of Oral BG-12 for Relapsing Multiple Sclerosis. N Engl J Med 2012;367: Fox RJ, Miller DH, Phillips T et al. Placebo-Controlled Phase 3 Study of Oral BG-12 or Glatiramer in Multiple Sclerosis. N Engl J Med 2012;367: Revision Log Date Adopting SGM criteria for treatment of MS 12/10 Added decision criteria: Has patient been assessed for cardiac signs and 12/11 symptoms? (Figure 5) Removed Appendix C rmal Lab Values for LFT and CBC and Thyroid Function Tests. Removed question regarding efficacy of treatment. 11/12 In vantrone algorithm, removed questions regarding monitoring AML and cardiac signs/symptoms these questions do not drive to denial. Added the step requirements for Gilenya and added a monotherapy statement to 05/13 Tecfidera. All approval durations incorporated into the algorithms. 05/13 MRI diagnostic piece for initial prescribing added to algorithms 05/13

21 Page: 21 of 21 Removed pregnancy question and CBC monitoring question from Figure 7 and requirement to fail other drugs before approving Gilenya. Added additional indications in Appendix G for indications to discontinue Gilenya 06/ 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. 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 or other notice contained herein. Centene and Centene Corporation are registered trademarks exclusively owned by Centene Corporation.