DISCLAIMER FDA INDICATIONS INITIAL COVERAGE CRITERIA POSITION STATEMENT. Subject: Aubagio (teriflunomide) Original Effective Date: 10/30/2013

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1 Subject: Aubagio (teriflunomide) Original Effective Date: 10/30/2013 Policy Number: MCP-146 Revision Date(s): Review Date(s): 12/16/15; 6/15/2016; 3/21/2017 DISCLAIMER This Molina Clinical Policy (MCP) is intended to facilitate the Utilization Management process. It expresses Molina's determination as to whether certain services or supplies are medically necessary, experimental, investigational, or cosmetic for purposes of determining appropriateness of payment. The conclusion that a particular service or supply is medically necessary does not constitute a representation or warranty that this service or supply is covered (i.e., will be paid for by Molina) for a particular member. The member's benefit plan determines coverage. Each benefit plan defines which services are covered, which are excluded, and which are subject to dollar caps or other limits. Members and their providers will need to consult the member's benefit plan to determine if there are any exclusion(s) or other benefit limitations applicable to this service or supply. If there is a discrepancy between this policy and a member's plan of benefits, the benefits plan will govern. In addition, coverage may be mandated by applicable legal requirements of a State, the Federal government or CMS for Medicare and Medicaid members. CMS's Coverage Database can be found on the CMS website. The coverage directive(s) and criteria from an existing National Coverage Determination (NCD) or Local Coverage Determination (LCD) will supersede the contents of this MCP document and provide the directive for all Medicare members. FDA INDICATIONS For the treatment of patients with relapsing forms of MS (relapsing-remitting MS, progressive-relapsing MS, and secondary progressive MS with relapse). Available as: Tablets: 7mg, 14mg Approved by the FDA: September 12, 2012 INITIAL COVERAGE CRITERIA POSITION STATEMENT SCOPE OF POLICY This policy addresses the use of Aubagio (teriflunomide) for the treatment of relapsing forms of MS (relapsingremitting MS, progressive-relapsing MS, and secondary progressive MS with relapse). The covered FDA-approved indications are conditions that are considered medically necessary; however it is not inclusive of all conditions which may be approved by the Medical Reviewer. At the discretion of the Medical Director and on a case-by-case basis, Molina Healthcare may consider authorization of the biologic therapies addressed in this Policy for members with exceptional circumstances and for members with severe disease who may fall outside of the defined criteria. Molina Healthcare reserves the right to update this Policy and revise coverage criteria to include or omit any off-label condition(s) as necessary based on medical literature and clinical studies that may become available. Page 1 of 24

2 Currently the published studies supporting concomitant therapy of any two disease modifying agents in MS have been limited, and due to the risk for developing serious adverse effects may be higher with combination therapy, Molina Healthcare will authorize coverage of only one disease modifying agent (DMA) at a time. The long-term safety and effectiveness of teriflunomide when used in combination with other disease-modifying multiple sclerosis (MS) agents has not been established. Therefore, Molina Healthcare will not authorize concomitant use with other disease-modifying multiple sclerosis therapies. There are numerous safety concerns including hepatotoxicity and teratogenicity, considerable monitoring, and an accelerated elimination procedure involved with teriflunomide. Therefore this agent should be reserved as an option for members who are unable to self-administer injections or who have conditions precluding them from repeated injections or have contraindications to other well-established therapeutic agents for MS. As with any novel pharmacological agent, post-marketing surveillance will be essential in more definitively characterizing the long-term safety and efficacy of teriflunomide in the treatment of MS. The safety and efficacy of glatiramer acetate (Copaxone ) and interferon (IFNβ) products are well-established. Recent clinical trials have not produced clinically different results compared to trials published previously. However, currently, there is no high quality evidence that establishes teriflunomide as safer as or more effective than other disease-modifying medications used in the treatment of MS. Published clinical trials have only directly compared teriflunomide to placebo. No head-to-head trials for teriflunomide have been published and therefore insufficient evidence to make comparative conclusions. There are no head-to-head trials that provide evidence that Aubagio is either safer or more efficacious than Avonex, Extavia, Betaseron, Copaxone, or Rebif. [AMR Neurologist, August 2013 Review #421782] The TENERE trial is an active comparator trial and not a head-to-head study, where both active arms were compared to placebo. The trial compared teriflunomide to subcutaneous interferon β-1a (Rebif) three times a week and did not treat all subjects for a fixed time period. Instead, its primary outcome measure was treatment failure, defined as either relapse or permanent drug discontinuation. Aubagio (teriflunomide) Initiation of therapy with Aubagio (teriflunomide) may be authorized for members who meet ALL of the following criteria [ALL] 1. Prescriber specialty [ONE] Board-certified Neurologist Board-certified Multiple Sclerosis physician specialist Consult with a Board-certified neurologist or physician specialist with experience in prescribing multiple sclerosis therapy (submit consultation notes) 2. Diagnosis/Indication [ALL] A definitive diagnosis of a relapsing form of multiple sclerosis as defined by the McDonald criteria. L Relapsing forms of MS including: [ONE] Relapsing-remitting multiple sclerosis [RRMS] Secondary-progressive multiple sclerosis [SPMS] with relapses Progressive-relapsing multiple sclerosis [PRMS] NOTE: Refer to Appendix 2 for a summary of the 2010 McDonald Criteria of MS. Page 2 of 24

3 3. Age/Gender/Other restrictions [ONE] 18 years of age or older The safety and efficacy of Aubagio (teriflunomide) in children have not been established. a,b Expanded Disability Status Scale (EDSS) score of 5.5 or lower 1,4,5 (disability severe enough to impair full daily activities) OR documentation supporting the disability within this range NOTE: Appendix 3 for a summary of the Expanded Disability Status Scale (EDSS) 4. Step/Conservative Therapy/Other condition Requirements [ALL] Documented inadequate response (to at least 6 months of therapy), intolerance, FDA labeled contraindication, or hypersensitivity to an interferon beta product (Avonex, Rebif, Betaseron, or Extavia ) AND a noninterferon, glatiramer acetate (Copaxone ). NOTE: Needle phobia is not considered an intolerance or contraindication to the first-line diseasemodifying therapies (DMT's) Inadequate response is defined as meeting TWO of the following three criteria during treatment with one of these agents: Increase in frequency (at least two clinical relapses within the past 12 months), severity and/or sequelae of relapses Changes in MRI: continues to have CNS lesion progression as measured by MRI (increased number or volume of gadolinium-enhancing lesions, T2 hyperintense lesions and/or T1 hypointense lesions) Increase in disability progression: Sustained worsening of EDSS score, routine neurological observation, mobility, or ability to perform activities of daily living For use as monotherapy therapy only: Prescriber intends to use Aubagio (teriflunomide) as a single agent; no other disease-modifying multiple sclerosis medications are being administered concomitantly, including but not limited to: interferon beta-1a (Avonex, Rebif ), interferon beta-1b (Betaseron, Extavia ), glatiramer acetate (Copaxone ), mitoxantrone (Novantrone ), natalizumab (Tysabri ), fingolimod (Gilenya ), Tecfidera (dimethyl fumarate) The safety of teriflunomide when used in combination with other disease-modifying MS medications has not been established. NOTE: Members who are approved for coverage of Aubagio (teriflunomide) will be excluded from coverage of other disease-modifying multiple sclerosis medications, including but not limited to:, interferon beta-1a (Avonex, Rebif ), interferon beta-1b (Betaseron, Extavia ), glatiramer (Copaxone ), mitoxantrone (Novantrone ), natalizumab (Tysabri ), fingolimod (Gilenya ), dimethyl fumarate (Tecfidera ) Aubagio (teriflunomide) will not be used concomitantly with leflunomide (Arava) Concomitant administration of Aubagio with leflunomide (Arava) is contraindicated. Teriflunomide is an active metabolite of leflunomide (Arava). Therefore, these medications should not be administered concomitantly. Page 3 of 24

4 Tuberculin skin test indicates no evidence of active, latent or inadequately treated tuberculosis infection within the recent 3 months Prior to initiating teriflunomide, screen patients for latent tuberculosis infection with a tuberculin skin test. Teriflunomide has not been studied in patients with a positive tuberculosis screen, and the safety of teriflunomide in individuals with latent tuberculosis infection is unknown No clinically significant infection or a history of chronic or recurrent infections 5. Contraindications/Exclusions to Aubagio (teriflunomide) therapy [ANY] Authorization will not be granted if ANY of the following conditions apply [ANY] Non-FDA approved indications Hypersensitivity to Aubagio (teriflunomide) or any ingredient in the formulation a,b Severe hepatic impairment Pregnancy, breastfeeding, individuals wishing to parent children during the course of the treatment, and women of childbearing potential not using reliable contraception Concurrent with leflunomide Member has a non-relapsing form of MS (e.g., primary progressive MS). The efficacy of Aubagio has not been established in patients with MS with non-relapsing forms of MS. a Concurrent use of Aubagio with other disease-modifying agents used for MS (i.e., Avonex, Rebif, Betaseron, Extavia, Copaxone, Tysabri, Gilenya, and Tecfidera). These agents are not indicated for use in combination. a The long-term safety of these combinations in the treatment of MS has not been established. Secondary progressive MS with no clinical or MRI evidence of relapses Member is currently responsive to and tolerating another immune system modifying drugs for MS Total bilirubin, ALT, or AST greater than 2 times the upper limit of normal Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) greater than two times the upper limit of normal (ULN) before initiating treatment, should not normally be treated with teriflunomide. a Significantly impaired bone marrow function or, significant anemia, leukopenia or thrombocytopenia 9 Persistent significant or severe infection 9 Known history of active tuberculosis not adequately treated Liver function impairment or known history of hepatitis 9 Human immunodeficiency virus [HIV] positive a,c,13 Teriflunomide may cause immunosuppression, and is therefore not recommended for use in patients with severe immunodeficiency, bone marrow dysplasia, or uncontrolled infection. Patients taking teriflunomide may be more susceptible to infections, including opportunistic infections. c The normal adult CD4 count for most laboratories falls in a range of 800 to 1050 cells/mm 3 ; furthermore, when considering laboratory variations of two standard deviations, the normal CD4 cell count range falls within 500 to 1400 cells/mm 3. Opportunistic illnesses typically occur when the CD4 cell count has decreased <200 cells/microl, although they can less commonly occur at higher CD4 cell counts. Page 4 of 24

5 6. Labs/Reports/Documentation required [ALL] Documented of diagnosis of Relapsing forms of Multiple Sclerosis supported by recent MRI within the recent 6 months: [ONE] Relapsing-remitting multiple sclerosis [RRMS] Secondary-progressive multiple sclerosis [SPMS] with relapses Progressive-relapsing multiple sclerosis [PRMS] Documented inadequate response (to at least 6 months of therapy), intolerance, FDA labeled contraindication, or hypersensitivity to an interferon beta product (Avonex, Rebif, Betaseron, or Extavia ) AND glatiramer acetate (Copaxone ). Documentation of TWO of the following three criteria during treatment with one of these agents: [TWO] Increase in frequency (at least two clinical relapses within the past 12 months), severity and/or sequelae of relapses Changes in MRI: continues to have CNS lesion progression as measured by MRI (increased number or volume of gadolinium-enhancing lesions, T2 hyperintense lesions and/or T1 hypointense lesions) Increase in disability progression: Sustained worsening of EDSS score or routine neurological observation [such as decreased mobility or decreased ability to perform activities of daily living due to disease progression] Confirmation of ONE of the following from the Prescriber AND by verifying in member s prescription profile [ONE] Member is not currently being treated with another disease-modifying agent for MS Member is currently being treated with another disease-modifying agent for MS AND the diseasemodifying agent will be discontinued before starting the requested agent Tuberculin skin test indicates no evidence of active, latent or inadequately treated tuberculosis infection within the recent 3 months Prior to initiating teriflunomide, screen patients for latent tuberculosis infection with a tuberculin skin test. Teriflunomide has not been studied in patients with a positive tuberculosis screen, and the safety of teriflunomide in individuals with latent tuberculosis infection is unknown Documentation of the following BASELINE lab reports/exams [ALL] Baseline MRI [utilized to identify lesion progression (response to treatment) while on Aubagio therapy] Normal CBC (complete blood count) within 6 months prior to initiation of Aubagio NOTE: Further CBC monitoring should be based on signs and symptoms of infection. Transaminase and bilirubin levels obtained within 6 months prior to initiation of Aubagio NOTE: Patients with pre-existing acute or chronic liver disease, or those with ALT levels greater than 2 times ULN before initiating treatment, should not be started on Aubagio. a,b,c NOTE: ALT levels should continue to be monitored at least monthly for 6 months after the start of therapy If member is female: A documented negative pregnancy test prior to initiating therapy is required. Page 5 of 24

6 ADMINISTRATION, QUANTITY LIMITATIONS, AND AUTHORIZATION PERIOD 7. Recommended Dosing Regimen [ALL] Dosage prescribed is within the FDA-approved labeling: The recommended dose of Aubagio is 7mg or 14 mg once daily. Higher doses have not been shown to be safe and effective. 8. Authorization Limit [ALL] May authorize up to 6 months of initial therapy for quantity limitation sufficient for a 30-day supply per fill based on FDA-approved dosages. Quantity limit: 1 tablet per day (30 tablets per 30 days) Duration: There are no recommended limits to the duration of treatment with teriflunomide at this time. a,b,c 9. Route of Administration [ALL] Medication is considered to be self-administered until information from the manufacturer, scientific literature, practice standards, or governing State or Federal agency indicates otherwise. If member meets all criteria and approval for therapy is granted, medication will be dispensed by a specialty pharmacy vendor at the discretion of Molina Healthcare. Self-administered medications may not be dispensed for self-administration and billed through the medical benefit by a provider; they must be dispensed through a participating pharmacy. Page 6 of 24

7 CONTINUATION OF THERAPY Continuation of therapy with Aubagio (teriflunomide) may be authorized for members who meet ALL of the following criteria [ALL] 1. Initial Coverage Criteria Member currently meets ALL initial coverage criteria 2. Compliance Member compliance with therapy as verified by Prescriber and member s medication fill history (review Rx history for compliance) NOTE: Therapy may be discontinued due to compliance issues or poor adherence upon agreement among treating physician, member, and Medical Director. Prescriber compliance with current FDA safety-monitoring guidelines for teriflunomide: [ALL] Monthly liver function tests for 6 months after initiation of therapy CBC (if there are any signs or symptoms of hematologic toxicity) Blood pressure (periodically) NOTE: Subsequent liver-function testing after 6 months should be performed at the discretion of the prescribing physician. 3. Labs/Reports/Documentation required [ALL] Stabilization or positive response to Aubagio (teriflunomide) treatment. Demonstrated efficacy evidenced by ANY of the following but not limited to: [ALL APPLICABLE] Relapses: A decrease in frequency, severity, sequelae relapses from baseline 1 Radiologic evidence of disease activity: Beneficial effect on MRI measures of disease severity 1 (decrease in number or volume of gadolinium-enhancing lesions, T2 hyperintense lesions and/or T1 hypointense lesions) Disability progression: EDSS score remains less than or equal to 5.5 or stabilization/improvement routine neurological observation, mobility, or ability to perform activities of daily living Validated patient reported outcome measure [i.e. Fatigue Impact Scale (FIS), Medical Outcome Study SF-36, etc] Fatigue Impact Scale (FIS) is a validated patient reported outcome measure that evaluates the effect of fatigue on the lives of people with MS. The Medical Outcome Study SF-36 is a self-administered health-reported quality of life outcome measure that is validated for several indications and patient populations. 4. Discontinuation of Treatment [ANY] Authorization will not be granted if ANY of the following conditions apply [ANY] Steady progression of disability Drug toxicity or serious adverse reaction Non-FDA approved indications Contraindications/Exclusions to Tecfidera (dimethyl fumarate) therapy [ANY] Hypersensitivity to Aubagio (teriflunomide) or any ingredient in the formulation a,b Page 7 of 24

8 Severe hepatic impairment Pregnancy, breastfeeding, individuals wishing to parent children during the course of the treatment, and women of childbearing potential not using reliable contraception Concurrent therapy with leflunomide Concurrent use of Aubagio with other disease-modifying agents used for MS (i.e., Avonex, Rebif, Betaseron, Extavia, Copaxone, Tysabri, Gilenya, and Tecfidera) These agents are not indicated for use in combination. a The long-term safety of these combinations in the treatment of MS has not been established. Diagnosis of primary progressive multiple sclerosis Secondary progressive MS with no clinical or MRI evidence of relapses Total bilirubin, ALT, or AST greater than 3 times the upper limit of normal Significantly impaired bone marrow function or, significant anemia, leukopenia or thrombocytopenia 9 Persistent significant or severe infection 9 Known history of active tuberculosis not adequately treated Liver function impairment or known history of hepatitis 9 Human immunodeficiency virus [HIV] positive 9 NOTE: In patients who need to discontinue therapy, an accelerated elimination protocol has been developed by the manufacturer (refer to Coverage Exclusions section labeled Accelerated Elimination Procedure ). In the absence of this accelerated elimination, clearance of the drug takes an average of about 8 months and in some individuals may take as long as 2 years. ADMINISTRATION, QUANTITY LIMITATIONS, AND AUTHORIZATION PERIOD 5. Recommended Dosing Regimen [ALL] Dosage prescribed is within the FDA-approved labeling: The recommended dose of Aubagio is 7 mg or 14 mg once daily. Higher doses have not been shown to be safe and effective. 6. Authorization Limit [ALL] May authorize up to 12 months of continuation of treatment for quantity limitation sufficient for a 30-day supply per fill based on FDA-approved dosages. Quantity limit: 1 tablet per day (30 tablets per 30 days) Duration: There are no recommended limits to the duration of treatment with teriflunomide at this time. a,b,c 7. Route of Administration [ALL] Medication is considered to be self-administered until information from the manufacturer, scientific literature, practice standards, or governing State or Federal agency indicates self-administration is not safe or acceptable. If member meets all criteria and approval for therapy is granted, medication will be dispensed by a specialty pharmacy vendor at the discretion of Molina Healthcare. Self-administered medications may not be dispensed for self-administration and billed through the medical benefit by a provider; they must be dispensed through a participating pharmacy. Page 8 of 24

9 COVERAGE EXCLUSIONS All other uses of the mentioned drugs that are not an FDA-approved indication or included in Coverage Criteria section above are considered experimental/investigational and is not a covered benefit. The following list may not be all-inclusive and is subject to change based on research and medical literature: For all other conditions, including but not limited to primary progressive (PPMS) and progressive relapsing (PRMS) MS. Teriflunomide has not been studied in progressive forms of MS (primary progressive MS and progressiverelapsing MS). Concomitant use with other disease-modifying multiple sclerosis therapies The safety and effectiveness of teriflunomide when used in combination with other disease-modifying MS medications has not been established. WARNINGS/ PRECAUTIONS A. Adverse Reactions Black Box Warnings Teriflunomide is an active metabolite of leflunomide. As such it bears the same warnings; pregnancy category X and a black box warning concerning hepatotoxicity. There is no evidence that teriflunomide is less or more toxic than leflunomide, its parent drug. Hepatotoxicity Teriflunomide carries an FDA black box warning for hepatotoxicity. Elevations in transaminases were observed more frequently in patients on teriflunomide than in those on placebo. Severe liver injury including fatal liver failure has been reported in patients treated with leflunomide, which is indicated for rheumatoid arthritis. A similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide. Most elevations occurred at 3 to 4 months of treatment and returned to baseline if treatment was discontinued and the elimination procedure was followed. It is recommended that transaminase and bilirubin determinations be obtained prior to starting treatment (up to 6 months) and monthly for the first 6 months of treatment. Subsequent testing should be repeated if symptoms suggestive of hepatic dysfunction occur or if the patient is started on other potentially hepatotoxic medications. Patients with preexisting liver disease should be treated with caution. If drug induced liver injury is suspected, discontinue Aubagio and start accelerated elimination procedure. Risk of Teratogenicity Teriflunomide carries an FDA black box warning for teratogenicity. Animal studies suggest that teriflunomide may cause fetal harm, including fetal death and fetal malformations. Pregnancy must be avoided during Aubagio treatment. Pregnancy must be excluded prior to initiating treatment.effective contraception should be used during teriflunomide treatment in women of childbearing potential. Women who wish to become pregnant, or men taking teriflunomide who wish to father a child, should discontinue teriflunomide treatment and be treated with the rapid elimination protocol. Pursuit of pregnancy should be deferred until blood tests demonstrate that teriflunomide levels below 0.02 MCP/ ml have been attained. Contraindications a,b Severe hepatic impairment Pregnant women or women of childbearing potential not using reliable contraception Co-administration with leflunomide Page 9 of 24

10 Common Adverse Effects: The most common adverse reactions for teriflunomide in the 14-mg and 7-mg groups, respectively, during the clinical trials were headache (19% and 22%), ALT increase (14% and 12%), alopecia (13% and 10%), diarrhea (18% and 15%), influenza (12% and 9%), nausea (14% and 9%), and paresthesia (10% and 9%). Alopecia was the most common cause of discontinuation because of adverse events in controlled clinical studies compared with placebo (0.5% and 1.4% of patients on teriflunomide 7 and 14 mg, respectively, and 0% on placebo). Reports followed a dose response with the 14mg teriflunomide reporting higher rates of the ADE. Adverse events resulted in discontinuation rates of 8.1%, 9.8% and 10.9% for placebo, 7 mg and 14 mg of teriflunomide respectively. Hypophosphatemia: In clinical trials, 18% of teriflunomide-treated subjects had mild hypophosphatemia (at least 0.6 mmol/l and less than lower limit of normal) compared with 9% of placebo-treated subjects; 5% of teriflunomide-treated subjects had moderate hypophosphatemia (at least 0.3 and less than 0.6 mmol/l) compared with 1% of placebo-treated subjects. No subject in either treatment group had serum phosphorus less than 0.3 mmol/l. Accelerated Drug Elimination Procedure An accelerated elimination protocol for teriflunomide is recommended for those individuals discontinuing the drug (due to suspected liver injury, cases of pregnancy, women of childbearing age, significant overdose or toxicity, or other circumstances that require rapid lowering of teriflunomide plasma concentrations) since it takes an average of 8 months, and in some cases as long as 2 years, to achieve plasma concentrations of <0.02 MCP/ml. The protocol advises either: Administration of 8 grams of cholesytramine every 8 hours for 11 days (4 grams can be used if the larger dose is not tolerated) or 50 grams of activated charcoal powder every 12 hours for 11 days Effective elimination of teriflunomide should be confirmed with plasma concentration measurements. B. Special Populations a,b Pregnancy: Category X. Teriflunomide is contraindicated in women who are pregnant or women of childbearing potential not using reliable contraception. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. If pregnancy does occur during treatment, immediately discontinue the drug and initiate an accelerated elimination procedure; this may decrease the risk to the fetus. Lactation: It is not known whether this drug is excreted in human milk. Teriflunomide is highly bound (more than 99.3%) to plasma albumin; its low molecular weight (about 270) and long elimination half-life (about 2 weeks) suggest it will be excreted into breast milk.2 Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in breast-feeding infants, make a decision whether to discontinue breast-feeding or the drug, taking into account the importance of the drug to the mother. Pediatric: Safety and efficacy have not been established in children. Geriatric: Clinical studies of teriflunomide did not include patients older than 65 years. Page 10 of 24

11 Hepatic Impairment: Teriflunomide is a metabolite of leflunomide. As such, it has the same precautions as leflunomide regarding hepatic impairment and use. Teriflunomide can be used without dose adjustment in patients with mild to moderate hepatic impairment. It is contraindicated in patients with severe hepatic impairment. Patients with preexisting liver disease may be at an increased risk of developing elevated serum transaminases when taking teriflunomide. Renal Impairment: Teriflunomide can be used in patients with mild, moderate or severe renal failure without dosage adjustments. C. Drug Interactions a,b Concomitant drugs that are metabolized by CYP2C8. Teriflunomide is an inhibitor of CYP2C8 (could increase serum levels of CYP2C8 substrates) and an inducer CYP1A2 (thus could decrease serum levels of CYP1A2 substrates). Therefore, it is recommended that patients be monitored if on concomitant drugs that are metabolized by CYP2C8 (such as repaglinide, paclitaxel, pioglitazone, and rosiglitazone) or if on concomitant drugs that are metabolized by CYP1A2 (such as duloxetine, alosetron, theophylline, and tizanidine). Warfarin. There was a 25% decrease in INR when teriflunomide was given concomitantly with warfarin as compared with warfarin alone. It is thus recommended to perform thorough monitoring of INR if using concomitantly with warfarin. Ethinyl estradiol and levonorgestrel. An increase in ethinyl estradiol and levonorgestrel was seen when these oral contraceptives were given concomitantly with repeated doses of teriflunomide. The type or dose of oral contraception should be considered if used concomitantly with teriflunomide. Leflunomide. Concurrent use of teriflunomide with leflunomide is contraindicated. Vaccination with live vaccines is not recommended. DESCRIPTION OF PROCEDURE/SERVICE/PHARMACEUTICAL Aubagio (teriflunomide) is the second oral disease-modifying multiple sclerosis (MS) treatment option approved by the FDA to for the treatment of relapsing forms of multiple sclerosis. Teriflunomide is the active metabolite of leflunomide, which was approved by the FDA in 1998 for treatment of rheumatoid arthritis. Teriflunomide possesses both anti-proliferative and anti-inflammatory properties. The exact mechanism by which teriflunomide exerts its therapeutic effect in MS is not fully understood, but it is known to reduce the proliferation of lymphocytes by blocking the mitochondrial enzyme dihydroorotate dehydrogenase (DHO-DH) which is involved in de novo pyrimidines. This inhibition results in anti-proliferative effects among peripheral T-and B-lymphocytes, leading to a reduced concentration of activated lymphocytes in the CNS. Additionally, teriflunomide inhibits protein tyrosine kinase activity which results in reducing T cell proliferation and activation with a resultant decrease in the production of cytokines. a,b,c Teriflunomide is rapidly absorbed after a single dose with peak absorption occurring between 1-2 hours post dose. The bioavailability approaches 100%. The plasma concentrations of teriflunomide were dose proportional, thus demonstrating linear pharmacokinetics. The drug is highly protein bound with a low volume of distribution. Teriflunomide demonstrates a very long elimination half-life which can range from days. The manufacturer suggests the use of a rapid elimination protocol with cholestyramine or activated charcoal when patients discontinue therapy. Page 11 of 24

12 GENERAL INFORMATION Multiple sclerosis (MS) is an autoimmune, neurodegenerative disorder characterized by repeated episodes of inflammation within the nervous tissue of the brain and spinal cord, resulting in injury to the myelin sheaths and subsequently the nerve cell axons. 6,7 The course of MS is highly varied and unpredictable. In most patients, the disease is characterized initially by episodes of reversible neurological deficits, which is often followed by progressive neurological deterioration over time. 6,7 MS affects approximately 400,000 people in the United States, with 200 people newly diagnosed every week. 8 It is one of the major causes of neurologic disability in young and middle-aged adults; the mean age of onset is approximately 30 years. 8 Women are affected two to three times as often as men. 9 Disease Characteristics Clinically, MS presents with four relatively distinguishable patterns based on the course of disease. Of the four clinical subtypes of MS (primary progressive, progressive relapsing, RRMS and secondary progressive), RRMS is the most common and is characterized by acute relapses followed by partial or full recovery. A,M,N (1) Relapsing remitting MS: the most common form, affecting about 85% of MS patients. It is marked by flare-ups (relapses or exacerbations) of symptoms followed by periods of remission, when symptoms improve or disappear. (2) Secondary progressive MS: may develop in some patients with relapsing remitting disease. For many patients, treatment with disease-modifying agents helps delay such progression. The disease course continues to worsen with or without periods of remission or leveling off of symptom severity (plateaus). (3) Primary progressive MS: affects approximately 10% of MS patients. Symptoms continue to worsen gradually from the beginning. There are no relapses or remissions, but there may be occasional plateaus. This form of MS is more resistant to the drugs typically used to treat the disease. (4) Progressive-relapsing MS: PRMS affects about 5% of patients. It is characterized by continuous neurologic decline from the time of diagnosis, accompanied by distinct attacks. It is progressive from the start, with intermittent flare-ups of worsening symptoms along the way. There are no periods of remission. Diagnosis Currently, there are no specific set of symptoms or physical findings and no one laboratory test that can, alone, confirm a diagnosis of MS. 6 The diagnosis is based on evidence of: (1) At least two different lesions (plaques or scars) in the white matter of the CNS (the space dissemination criterion); (2) At least two different episodes in the disease course (the time dissemination criterion); and (3) Chronic inflammation of the CNS, as determined by analysis of the CSF (the inflammatory criterion). The presence of one or more of these criteria allows a general diagnosis of MS, which may be refined according to the subsequent course of the disease. UpToDate notes MRI is the test of choice to support the clinical diagnosis of MS. The McDonald diagnostic criteria include specific clinical and MRI findings needed for the demonstration of lesion dissemination in time and space, the core requirement of the diagnosis. L -Refer to Appendix 2 for a summary of diagnostic criteria for MS. Page 12 of 24

13 TREATMENT OPTIONS The approach to treating MS includes the management of symptoms, treatment of acute relapses and utilization of disease-modifying therapies to reduce the frequency and severity of relapses and delay disease and disability progression. To date, a cure remains elusive and current therapies fail to reverse degenerative processes and deficits. Current diseasemodifying drugs are most effective for the relapsing-remitting form of MS and less effective for secondary progressive decline. Treatment of multiple sclerosis (MS) has 2 aspects: immunomodulatory therapy for the underlying immune disorder and therapies to relieve or modify symptoms. Immunomodulatory therapy is directed toward reducing the frequency of relapses and slowing progression. No curative, FDA-approved therapies for MS are currently available. A-M The ultimate goal in the long-term management of MS is to prevent or delay the progression of axonal damage that leads to permanent neurological disability. Diseasemodifying therapies (DMTs) are partly effective in achieving this goal. DMTs can reduce the number of exacerbations, reduce the duration and severity, slow disease progression, and reduce the relapse rate. As of this writing in July 2013, the DMTs approved for use in relapsing forms of MS in the United States include the following: interferon beta-1a (Avonex ; Biogen Idec): intramuscularly once a week interferon beta-1a (Rebif): subcutaneously 3 times a week interferon beta-1b (Betaseron ; Bayer HealthCare): subcutaneously every other day interferon beta-1b (Extavia ; Novartis Pharmaceuticals Corporation): subcutaneously every other day glatiramer acetate (Copaxone ; Teva Pharmaceuticals): subcutaneously daily fingolimod (Gilenya ; Novartis Pharmaceuticals Corporation): oral daily teriflunomide (Aubagio, Sanofi): oral daily dimethyl fumarate (Tecfidera, Biogen): oral daily mitoxantrone (Novantrone ; Wyeth-Ayerst) (intravenously every 3 months); and natalizumab (Tysabri ; Biogen Idec and Elan Pharmaceuticals, Inc.): intravenously every 4 weeks Dimethyl fumarate (Tecfidera ), fingolimod (Gilenya ) and teriflunomide (Aubagio) are currently the only oral agents available to treat multiple sclerosis. Disease-modifying agents such as the β-interferon products (Betaseron/Extavia [interferon β-1b] and Avonex/Rebif [interferon β-1a]), Aubagio (teriflunomide), Gilenya (fingolimod), Novantrone (mitoxantrone), and Tysabri (natalizumab) are all indicated for relapsing forms of MS (RRMS, PRMS, and SPMS with relapse) while Copaxone (glatiramer) is indicated for RRMS. In addition, the β-interferon products and Copaxone are indicated in clinically isolated syndrome (CIS). The β-interferons have the potential to produce flu-like symptoms, fatigue, and/or depression, whereas Copaxone (glatiramer) has better tolerability and is categorized as Pregnancy Category B. Tysabri (natalizumab) should be reserved for patients who have failed other therapies or who have a particularly aggressive initial disease course since there is risk of potentially fatal progressive multifocal encephalopathy (PML). Novantrone (mitoxantrone) is the only agent indicated for SPMS; however, its use in MS has fallen out of favor due to significant safety concerns and availability of safer agents with demonstrated efficacy. Gilenya (fingolimod) and Aubagio (teriflunomide) offer novel oral treatment options but are limited by lack of longterm data. Page 13 of 24

14 CLINICAL EFFICACY Only clinical studies published in their entirety in reputable peer-reviewed journals will be evaluated. Three large clinical trials of Aubagio have been completed (discussed below), and at least two more are ongoing (TOPIC and TERACLES). The TOPIC trial in early MS or clinically isolated syndrome, and TERACLES, investigating teriflunomide as an adjunct to therapy with interferon. In the phase 3 TERACLES trial, teriflunomide is being compared with placebo in 1,455 patients previously treated with interferon beta. This is the first phase 3 study of an oral drug as an add-on to standard therapy in relapsing MS. The trial is expected to finish in April Another ongoing phase 3 trial, TOPIC, is comparing teriflunomide (7 mg or 14 mg) with placebo in 780 patients who presented with their first clinical symptom of MS. The primary objective is to see whether teriflunomide can prevent or delay conversion to clinically definite MS. The trial s estimated completion date is November Two large clinical trials were conducted to test the effectiveness and safety of Aubagio : TEMSO and TOWER. TEriflunomide Multiple Sclerosis Oral (TEMSO) 1 FDA approval for teriflunomide was based on the data from the TEriflunomide Multiple Sclerosis Oral (TEMSO) trial, 1 a phase III study that enrolled 1,088 patients with relapsing forms of MS in a double blind, placebo controlled study that assessed the safety and efficacy of teriflunomide 7mg and 14mg in adults with relapsing forms of MS. Patients were followed for 108 weeks. All included in the trial had experienced at least 1 relapse in the preceding year and had not used interferon beta for at least 4 months. The primary endpoint was the annualized relapse rate (ARR). Both teriflunomide doses were significantly more effective than placebo for the outcome of ARR. Both doses significantly reduced the annualized relapse rate by approximately 31%. The 14-mg dose also reduced the risk of sustained disability progression by 29.8% relative to placebo. Aubagio (7-mg dose) resulted in a 39.4% reduction in brain lesion volume on MRI compared with placebo; the 14-mg dose resulted in a 67.4% reduction. The number of gadolinium-enhancing lesions were also reduced with both doses compared with placebo, and a trend toward a greater effect was observed with the higher dose. Notably, no difference in the rate of serious infection, opportunistic infection, or malignancy was found between patients taking Aubagio and those on placebo. The most commonly reported adverse events (ADE) were diarrhea, nausea, hair thinning and elevated alanine transferase levels. These reports followed a dose response with the 14mg teriflunomide reporting higher rates of the ADE. Discontinuation rates due to ADRs were approximately 11% in the teriflunomide arm compared to 8.1% in the placebo group in TEMSO trial. Adverse events resulted in discontinuation rates of 8.1%, 9.8% and 10.9% for placebo, 7 mg and 14 mg of teriflunomide respectively. Summary: Results of the TEMSO (TEriflunomide Multiple Sclerosis) trial 1 showed a significant reduction in annualized relapse rate and sustained accumulation of disability with both the 7- and the 14-mg daily doses versus placebo. Inclusion criteria included a definite diagnosis of MS and at least 1 relapse over the year preceding the trial or 2 relapses over the 2 years preceding the trial. MRI was performed at screening and at various time points thereafter. Upon entry to the trial, the patient s Expanded Disability Status Scale (EDSS) score was 5.5. Patients were randomized to one of two doses for teriflunomide (7 and 14 mg) or placebo. Neurological examinations were performed every 12 weeks until 108 weeks and at unscheduled visits for suspected relapse. MRI was also performed at screening and at weeks 24, 48, 72, and 108. Teriflunomide in the 2 year TEMSO trial reduced annualized MS relapse rates by 54% versus placebo 37% and confirmed disability progression was 21.7% in the active treatment group versus 27.3% in the placebo group. There was also a statistically significant reduction in the time to disability progression, sustained for 12 weeks, by 30% in the 14-mg dose group compared to placebo. MRI outcomes demonstrated a significantly lower change in total lesion volume from baseline in the 7-mg and 14-mg groups compared with the placebo group. Reference: O Connor et al. N Engl J Med. 2011;365: Page 14 of 24

15 Teriflunomide Oral in People With Relapsing Remitting Multiple Sclerosis (TOWER) 4,5 The Teriflunomide Oral in People with Relapsing Remitting Multiple Sclerosis (TOWER) study is the second large, multicenter, randomized, placebo-controlled, double-blind, phase III clinical trial that evaluated the efficacy and safety of teriflunomide in patients with relapsing MS. The TOWER trial compared 2 doses of teriflunomide (Aubagio, Genzyme/Sanofi), 14 mg/d and 7 mg/d, versus placebo in patients with relapsing multiple sclerosis (MS). A total of 1169 patients with relapsing MS were randomly assigned to treatment with 7 or 14 mg of teriflunomide or placebo. The subjects were randomized from 189 centers across the United States and Europe. Trial Design: In a 108-week study, two doses of teriflunomide (7 mg and 14 mg) were compared with placebo in 1088 individuals aged 18 to 55 years with relapsing MS, an Expanded Disability Status Scale (EDSS) score of 0 to 5.5, and at least one relapse in the year prior to entry or two relapses in the 2 years prior to entry in a randomized, double-blind trial. Primary Endpoint: Annualized relapse rate (ARR), the number of confirmed relapses per patient-year. Secondary Endpoints: Confirmed progression of disability by Expanded Disability Status Scale (EDSS) for at least 12 weeks MRI disease measures Safety and tolerability measure Results: Annualized relapse rate (primary outcome) was reduced in both active treatment groups as compared with the placebo group (0.37 for both doses versus 0.54 for placebo, p < 0.001) with a relative risk reduction of 31% for both doses. The higher dose of teriflunomide reduced relapse rates by 37% compared to placebo and reduced the risk of disability progression (sustained for 12 weeks) by 31.5%. In both treatment groups the time to first relapse was longer and more patients remained free of relapse. This was a significant result in comparison to placebo. Confirmed disability progression was reduced in both active treatment groups as compared with the placebo group; however, the reduction was statistically significant only for the 14mg dose (27.3% placebo, 21.7% 7 mg [p=0.08] and 20.2% 14 mg [p = 0.03]. There was a significant decrease in ARR in both the 7 mg and 14 mg teriflunomide treatment arms in comparison to placebo (22.3% [P = 0.02] and 36.3% [P < ], respectively). In the 14 mg treatment arm, there was a 31.5% reduction in the risk of 12-week sustained disability accumulation in comparison to placebo (P = 0.04), while there was no statistically significant difference in the 7 mg treatment arm MRI measures of disease activity favored both doses as compared with placebo, including the key MRI secondary outcome of change in total lesion volume from baseline (p=0.03 for the 7-mg dose; p<0.001 for the 14-mg dose). Subjects in both treatment groups had significantly fewer Gd-enhancing lesions and unique active lesions per scan than subjects in the placebo group. No significant differences in brain atrophy from baseline were observed among the three groups. Teriflunomide was well-tolerated with 13% of patients receiving 7mg and 15.6% of those on 14mg discontinuing the trial due to adverse events (placebo had a 6.2% discontinuation rate. Page 15 of 24

16 Active comparator trial with IFNB1a (Rebif): TENERE 9 TENERE (Comparing the Effectiveness and Safety of Teriflunomide and Interferon Beta-1a in Patients with Relapsing Multiple Sclerosis) compared two oral doses of Aubagio (7 mg and 14 mg once daily) to standard-dose treatment with Rebif (interferon beta-1a). This phase III trial randomized 324 individuals with relapsing MS to receive Aubagio 7mg or 14mg, or Rebif (interferon beta-1a, EMD Serono Inc. and Pfizer) 44MCP three times per week subcutaneously for 48 weeks. The primary endpoint was risk of failure, meaning the first occurrence of a relapse, or permanent study treatment discontinuation for any cause. Secondary outcome measures included: ARR, fatigue (measured by the fatigue impact scale), and subject satisfaction (assessed by the treatment satisfaction questionnaire for medication). No statistical superiority was observed between the Rebif and teriflunomide arms (7mg and 14mg) on risk of treatment failure, the primary composite endpoint of the study. Risk of treatment failure was defined as the occurrence of a confirmed relapse or permanent treatment discontinuation for any cause, whichever came first. There was no statistical difference between the three groups for this measure. In the study, 48.6% of patients receiving 7mg of oral teriflunomide (n=109) and 37.8% of patients receiving 14mg of oral teriflunomide (n=111) reached the primary endpoint, versus 42.3% of patients receiving interferon beta 1-a (n=104). However, the rate of permanent treatment discontinuation was lower with Aubagio (18.3 and 19.8%) than in the Rebif group (28.8%). Summary: An active comparator trial with IFNB1a (Rebif) demonstrated no statistical superiority between the treatment arms for the risk of treatment failure, the primary composite endpoint of the study. Additionally, the treatment arms were not distinguishable on the endpoint of estimated annual relapse rate. It is noted that the evidence from this trial was unreliable because the primary endpoint was reduction of MRI lesions. This radiographic endpoint has not been correlated with clinically relevant endpoints, such as exacerbations or decrease in disability. COCHRANE DATABASE OF SYSTEMATIC REVIEWS A Cochrane review was not available for Aubagio (teriflunomide) at the time of this writing in June 2013; however there is an Intervention Review. O The authors evaluated two studies involving 1204 people evaluated the efficacy and safety of teriflunomide 7 mg and 14 mg, alone or with add-on IFN-β, versus placebo for adult patients with relapsing forms of MS [relapsing-remitting (RRMS), secondary progressive (SPMS) with relapse, and progressive relapsing MS (PRMS)] and an entry Expanded Disability Status Scale (EDSS) score of 5.5. Both studies had high attrition bias (26.8% and 36.4% attrition respectively). Teriflunomide 7 or 14 mg alone had potential benefits on reducing relapse rates, and alone or with add-on IFN-β was safe for patients with relapsing forms of MS in the short term. The most common adverse events included nasopharyngitis, headache, diarrhea, fatigue, elevated alanine aminotransferase levels, nausea, hair thinning or decreased hair density, influenza, back pain, urinary tract infection, and pain in the arms or legs. Four ongoing trials were identified. The review did not provide any clear recommendations for the use of teriflunomide as a DMT for MS because the studies had limited quality, were of short duration and were funded by a pharmaceutical company. The authors noted that only low-level evidence for the use of teriflunomide as a disease-modifying therapy for MS were available. This was due to the limited quality of the available RCTs and did not conduct meta-analysis because of the clinical and methodological diversity of the included studies. Short-term teriflunomide, 7 or 14 mg alone or with add-on IFN-β, was safe for patients with relapsing MS. Both teriflunomide 7 and 14 mg alone had potential benefits for patients with relapsing forms of MS. We are waiting for the publication of ongoing RCTs with higher methodological quality, a better evaluation of the adverse events, and longer periods of observation are needed to assess safety, disability progression, neuroprotection and quality of life. Page 16 of 24

17 HAYES DIRECTORY A Hayes Directory report addressing Aubagio (teriflunomide) in the treatment of multiple sclerosis was not available at the time of this writing in June 2013; however there is Prognosis Overview which monitors emerging health technologies as these go through clinical trial development and the regulatory approval process. UPTODATE UpToDate confirms that there are no consensus guidelines, with the exception that mitoxantrone, which should be reserved for patients with rapidly advancing disease who have failed other therapies. H UpToDate recommends the following based upon clinical experience, the available clinical data, neutralizing antibody formation, side effect profile, route of administration, and MRI data: Avonex or glatiramer acetate as agents of first choice for patients with RRMS, depending upon the patient's lifestyle and laboratory data. These agents are generally continued indefinitely unless side effects are intolerable or the patient begins to fail in terms of response, after which use of another agent can be considered. For patients with highly active RRMS who have a poor response to both beta interferons and glatiramer acetate, or intolerance of these immunomodulators, the recommendation is to add intravenous methylprednisolone monthly bolus or treatment with natalizumab. GUIDELINES At the time of this writing in June 2013, there are currently no guidelines which address the use of teriflunomide in multiple sclerosis (MS). There are no current evidence-based guidelines in the United States for disease-modifying drugs (DMDs) in multiple sclerosis. Clinical practice guidelines from the American Academy of Neurology (AAN) were published in 2002, A prior to the availability of natalizumab and the oral MS agents. The American Academy of Neurology A does not recommend one agent over another; however glucocorticoids, interferon beta and glatiramer acetate have the strongest recommendations for use in relapsing forms of multiple sclerosis (MS). National Institute for Health and Clinical Excellence (NICE), I and European Federation of Neurological Societies (EFNS) J have not been updated since the introduction of teriflunomide (Aubagio) and fingolimod (Gilenya ), and dimethyl fumarate (Tecfidera ). The American Academy of Neurology, A the National MS Society C,D and the National Institute for Clinical Excellence (NICE) E recommend treatment with glatiramer acetate or IFNβ in MS patients NOTE: To date, these organizations have not updated its guidelines to reflect the use of the oral agents]. National Institute for Clinical Excellence (NICE) NICE recommends that due to its adverse effect profile, fingolimod be reserved as an option for highly active RRMS in adults, only if patients have an unchanged or increased relapse rate or ongoing severe relapses compared with the precious year despite treatment with beta interferon. F NICE recommends natalizumab as an option for the treatment only of rapidly evolving severe relapseremitting multiple sclerosis (RRMS), defined as two or more disabling relapses in one year, and one or more gadolinium-enhancing lesions on brain magnetic resonance imaging (MRI) or a significant increase in T2 lesion load compared to a previous MRI. K Page 17 of 24