UTAH MEDICAID DUR REPORT JANUARY 2015 MULTIPLE SCLEROSIS (MS): INFUSION DRUGS

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1 UTAH MEDICAID DUR REPORT JANUARY 2015 MULTIPLE SCLEROSIS (MS): INFUSION DRUGS Mitoxantrone (Novantrone ) Natalizumab (Tysabri ) Drug Regimen Review Center Joanita Lake B.Pharm, MSc EBHC (Oxon), Clinical Pharmacist Melissa Archer Pharm D, Clinical Pharmacist Gary M. Oderda Pharm D, M.P.H, Professor Ekaterina Efimova Pharm D student Chelsea Elise Williams Pharm D student Halee R. Namanny Pharm D student University of Utah College of Pharmacy Copyright 2014 by University of Utah College of Pharmacy Salt Lake City, Utah. All rights reserved

2 Contents Introduction... 3 Indications... 4 Methodology... 4 Clinical Guidelines... 4 Clinical Efficacy... 8 Safety... 9 Place in therapy and potential criteria to be reviewed Utah Medicaid Utilization Data Conclusions Appendix 1 Drug information Appendix 2 Systematic reviews Appendix 3 Drug Class Review(s) Appendix 4 Additional evidence References

3 Introduction Demyelinating diseases are neurological disorders defined by the destruction of central nervous system (CNS) tissue and are typically immune-mediated conditions. 2,3 Multiple sclerosis (MS) is the most common demyelinating disorder and is characterized by inflammation, demyelination, scarring, and neuronal loss. 2,3 Patients with MS can exhibit benign illness to a debilitating disease resulting in significant changes to one s lifestyle. 2,3 Multiple sclerosis affects nearly 400,000 individuals in the United States and 2.5 million individuals worldwide. 4-6 The average estimated lifetime cost of illness from MS is estimated to be $1.2 million. 4-7 Prevalence is higher in women than men and the disease is usually diagnosed between the ages of 20 and 50 years. 4,5,7 The cause of multiple sclerosis is not known. 2,3 Both genetic (race and gender) and environmental factors (geographical location, exposure to the sun, birth month) are linked to the disease Immunology also plays a role; MS is thought to be an auto-immune disease mediated by T-cells that compromise the blood brain barrier and allow inflammatory mediators to enter and attack the CNS. Diagnosis of MS is based on clinical symptoms in combination with evidence of lesions on magnetic resonance imaging (MRI). Symptoms vary depending on the location and severity of the CNS lesions and may include sensory loss, optic neuritis, weakness, parasthesias, ataxia, tremor, fatigue, cognitive changes, and bladder dysfunction. 2,3 Multiple sclerosis (MS) is a chronic disease that can progress intermittently or continuously and is divided into four disease courses: relapsing-remitting multiple sclerosis (RRMS), primary-progressive multiple sclerosis (PPMS), secondary-progressive multiple sclerosis (SPMS), and progressive-relapsing multiple sclerosis (PRMS). 2,3 Relapsing-remitting multiple sclerosis is the most common form of MS and is characterized by exacerbations of neurological dysfunction followed by remissions. 12 RRMS may eventually develop into secondary progressive multiple sclerosis which is characterized by a neurologic deterioration with or without relapses. Primary progressive multiple sclerosis occurs in 10-15% of patients with MS and is characterized by disease progression with some minor improvements and without any exacerbations. 10,13 Progressive relapsing multiple sclerosis affects less than 5% of patients and is characterized by disease progression with acute relapses. Most medications used in the treatment of MS are indicated in the treatment of RRMS or SPMS; there are currently no medications labeled for use in PPMS. 2,3 Treatment of MS varies depending on the clinical subset of MS present and individual patient characteristics. 2,3,5,7 In general, treatment may include disease modifying agents in combination with symptomatic treatment. 2,3 Symptomatic treatments include glucocorticoid therapy, benzodiazepines, muscle relaxers, anticonvulsants, antidepressants, and medications used to treat urinary disorders. 2,3 Currently, no curative medication therapies are available in the treatment of MS. 5,7 Disease-modifying agents provide symptomatic relief and reduced disease progression. Several self-injectable disease modifying agents are available for the treatment of MS including glatiramer (Copaxone ), interferon beta-1a (Avonex, Rebif ), interferon beta-1b (Betaseron, Extavia ), and a new Peginterferon beta-1a agent (Plegridy). MS treatment options also include infusion agents; mitoxantrone (Novantrone ), and natalizumab (Tysabri ); and oral agents; teriflunomide (Aubagio ), fingolimod (Gilenya ), and dimethyl fumarate (Tecfidera ). Mitoxantrone is an intravenous synthetic antineoplastic anthracenedione (given every three months) that was approved in 2000, and Natalizumab is an intravenous recombinant monoclonal antibody (given every 4 weeks) that was approved in ,15 Natalizumab is usually prescribed once other drugs have failed or when the disease is rapidly worsening. 16 3

4 Indications Mitoxantrone is approved for use in both relapsing-remitting and progressive forms of MS. 17 NOVANTRONE is indicated for reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis (i.e., patients whose neurologic status is significantly abnormal between relapses). NOVANTRONE is not indicated in the treatment of patients with primary progressive multiple sclerosis. 18 It is also indicated in Acute nonlymphocytic leukemias (ANLL), and Prostate cancer (advanced, hormone-refractory). 11 Natalizumab is indicated as monotherapy for the treatment of patients with relapsing forms of multiple sclerosis (MS). 1 It is also indicated in Crohn's Disease in adult patients with moderately to severely active Crohn s disease with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional Crohn s disease therapies and inhibitors of tumor necrosis factor-alpha (TNF-alpha). 1 Methodology A Cochrane Library literature search for systematic reviews was conducted. Medline (PubMed), Up to Date, the Agency for Healthcare Research and Quality (AHRQ), the American Academy of Neurology (AAN) website, the FDA website (including product labeled information), Micromedex and Lexicomp were searched for safety information, systematic reviews, clinical trials, and guidelines. As per the hierarchy of evidence, high quality systematic reviews and evidence based guidelines were searched for first. After review of the sources, the following were examined: (a) 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 (2002), (b) National Institute for Health and Care Excellence (NICE) Guidance 32, (c) NHS England Clinical commissioning policy (d) Recommendations from the Canadian Agency for Drugs and Technologies in Health 19, (e) Recommendations from the Croatian Society of Neurology of Croatian Medical Association 20 (f) Recommendations from the National Multiple Sclerosis Society 21 (g) product labels, (h) Immunization and MS: A summary of published evidence and recommendations (2002) 22, (i) Oregon Health & Science University Drug Class Review: Disease-modifying Drugs for Multiple Sclerosis 23 (j) Drug Class Review: Disease Modifying Agents for Multiple Sclerosis from Oregon State University, 24 and (k) Three Systematic Reviews from the Cochrane Library (Appendix 2). Clinical Guidelines The US guideline for Multiple Sclerosis has not been updated recently. The following guidance documents applicable to the agents included in this review were listed amongst guideline documents for MS on the American Academy of Neurology website (A and B below). Additional guidance documents were also identified and have been included after these summaries. (A) Evidence Report: The Efficacy and Safety of Mitoxantrone (Novantrone) in the Treatment of Multiple Sclerosis (May 2010 Current guideline. Reaffirmed on July 13, 2013.) 25 The objective of this review was to examine the available literature on the efficacy and safety of mitoxantrone (MX) (approved in 2000) use in patients with MS since the initial report of the Therapeutics and Technology Assessment Subcommittee in It is stated that according to the original report mitoxantrone probably reduced clinical attack rates, MRI activity, and disease progression. Subsequent reports of decreased systolic function, heart failure, and leukemia prompted the US Food and Drug Administration to institute a black box warning in This more recent review concluded that the risk of systolic 4

5 dysfunction and leukemia in patients treated with mitoxantrone is higher than suggested at the time of the previous report, but that comprehensive postmarketing surveillance data are lacking. This information is put into clinical context: Recommendations on MX use reflecting the potential for harm would require a risk-benefit analysis and are beyond the scope of an evidence-based guideline. In the absence of such an analysis, it is reasonable for clinicians to follow the recommendations outlined in the product monograph and include ejection fraction assessments before initiating treatment and administering each dose of MX and yearly after discontinuation of treatment. It is not known whether patients treated with MX with asymptomatic decreased LVEF will experience long-term sequelae. The long-term sequelae of asymptomatic cardiotoxicity is not clear. It is reasonable for clinicians to monitor patients for treatment-related acute leukemia (TRAL) after MX therapy with periodic complete blood cell counts, although the optimal timing of such monitoring is not known. Clinicians contemplating MX administration for an individual patient with MS must weigh the potential for benefit against the potential for harm given the 12% risk of systolic dysfunction and 0.8% risk of TRAL and the availability of alternative therapies with less severe toxicities (e.g., interferon-β and glatiramer acetate) for patients with RRMS. RECOMMENDATIONS FOR FUTURE RESEARCH The best evidence for MX use in MS remains the MIMS trial. The first report of the TTA in 2003 recommended that the results of this trial be replicated, and this has not occurred to date. No Class I evidence exists to support the use of MX in the MS population. Future trials using MX induction followed by standard disease-modifying agents should be considered. Any future trial should include a prospective, long-term safety analysis. While the rate of symptomatic cardiotoxicity and TRAL appears low, more reports are arising to suggest that these risks are higher than indicated by the initial evidence. It is imperative that longterm, prospective postmarketing data be compiled to better quantify the risks of MX therapy. 25 (B) The use of mitoxantrone (Novantrone) for the treatment of multiple sclerosis. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (November 2003, Current guideline. Reaffirmed on July 13, 2013) 26 Practice recommendations 1. On the basis of evidence from a single Class I study and a few Class II or III studies, it appears that mitoxantrone may have a beneficial effect on disease progression in patients with MS whose clinical condition is deteriorating (Type B recommendation). In general, however, this agent is of limited use and of potentially great toxicity. Therefore, it should be reserved for patients with rapidly advancing disease who have failed other therapies. 2. On the basis of several consistent Class II and III studies, mitoxantrone probably reduces the clinical attack rate and reduces attack-related MRI outcomes in patients with relapsing MS (Type B recommendation). The potential toxicity of mitoxantrone, however, considerably limits its use in patients with relapsing forms of MS. 3. Because of the potential toxicity of mitoxantrone, it should be administered under the supervision of a physician experienced in the use of cytotoxic chemotherapeutic agents (Type A Recommendation). In addition, patients being treated with mitoxantrone should be monitored routinely for cardiac, liver, and kidney function abnormalities (Type A Recommendation). Recommendations for future research 1. A large, multicenter trial of mitoxantrone is essential to confirm the apparent benefit in the treatment of SPMS. This need is especially acute for patients who fail immunomodulatory therapy or in whom combination therapy with immunomodulatory agents is being contemplated. Also, because of potential difficulties with the use of methylene blue as a placebo, other means of observer blinding should be employed and both clinical and MRI outcomes need to be assessed. 5

6 2. Mitoxantrone treatment for 2 to 3 years must be demonstrated to impact favorably long-term outcome in order to justify its potential risk to patients. 3. It would be of value to measure the relative effectiveness of mitoxantrone compared to other immunosuppressive agents (e.g., booster cyclophosphamide treatments) with similar biologic effects, but that can be administered for prolonged periods without the cardiac toxicity that limits prolonged use of mitoxantrone. 4. It would be useful to explore the possible benefit of a very brief course of mitoxantrone in patients who are deteriorating rapidly despite optimal disease modifying therapy and thereby potentially halt the clinical decline. In this way, the cumulative dose of mitoxantrone could be limited and the same therapeutic strategy could be employed subsequently if the patient deteriorated again. The clinical utility of such a therapeutic approach should be studied. 5. Strategies employing potential cardioprotective agents, to be used in conjunction with mitoxantrone, should be explored. Such strategies might allow mitoxantrone to be used over a longer period of time. The long-term cardiac toxicity of short-term treatment also needs to be explored, as does the possibility that there may be individual variation in the susceptibility to such toxicity. 6. Different dosing regimens of mitoxantrone need to be explored in order to possibly prolong the duration of potential therapy. 26 (C) Natalizumab: The AAN website lists The Use of Natalizumab (Tysabri) for the Treatment of Multiple Sclerosis (September 2008), but states that this guideline is retired. 27 The web page include information regarding the FDA drug safety communication (issued on January 20, 2012) regarding a new risk factor for progressive multifocal leukoencephalopathy (PML) associated with natalizumab. The 2008 (retired) guideline states: RECOMMENDATIONS 1. Because of the possibility that natalizumab therapy may be responsible for the increased risk of PML, it is recommended that natalizumab be reserved for use in selected patients with relapsing remitting disease who have failed other therapies either through continued disease activity or medication intolerance, or who have a particularly aggressive initial disease course. This recommendation is very similar to that of the FDA. 2. Similarly, because combination therapy with IFNβ and natalizumab may increase the risk of PML, it should not be used. There are also no data to support the use of natalizumab combined with other disease-modifying agents as compared to natalizumab alone. The use of natalizumab in combination with agents not inducing immune suppression should be reserved for properly controlled and monitored clinical trials. 27 (D) Guideline on disease modifying therapies (February 2002; Current guideline. Reaffirmed October 17, 2003 and July 19, 2008.) 28 : Treatment with glucocorticoids has been shown to have a short-term benefit in acute MS attacks treatment. Long-term benefits of glucocorticoids for MS have not been validated. Evidence suggests interferon beta is effective in reducing acute relapses in patients with MS and those, who have clinically isolated syndrome and are at high risk of developing MS. In addition, patients that have RRMS or SPMS with continuing relapses can benefit from interferon beta treatment. Those patients that are at high risk of developing clinically definite MS (CDMS) have the development of the disease delayed when treated with interferon beta-1a. Some clinical trials showed interferon beta is associated with dose-response curve. It is also important to consider neutralizing antibody (Nab) production when treated with interferon beta, since it is associated with a reduction in clinical effectiveness of agents in this class. Evidence suggests that the rate of Nab production is lower in patients treated with interferon beta-1a than with interferon beta-1b. 6

7 Glatiramer acetate has been shown to be an effective agent in reducing rates of relapses in patients with RRMS. Both glatiramer and interferon beta have a potential of slowing down the disease disability progression and benefit disease severity (T2 burden) in patients with MS. Based on evidence from a single trial, methotrexate has a potential benefit in course of the disease in progressive MS. Azathioprine can reduce MS relapse rates, however the evidence is conflicting. Cladribine does not improve disease progression, but reduces Gd enhancement in patients with relapsing and progressive MS. Cyclosporine might show benefit in progressive MS and mitoxantrone in relapsing forms of MS, however frequent adverse reactions outweigh the benefits. There was little or no benefit in disease progression when treating MS patients with sulfasalazine, plasma exchange, intravenous immunoglobulin, and cyclophosphamide; however, plasma exchange showed a potential benefit for treatment of severe acute demyelination in non-disabled MS patients. (E) Immunization and MS: A summary of published evidence and recommendations (December 2002; Update in progress. Reaffirmed on December 9, 2006.) 22 The Immunization Panel of the MS Council for Clinical Practice Guidelines recommends that patients with MS should follow Centers for Disease Control (CDC) indications for immunizations. It is expert opinion to delay vaccinations during clinically significant relapses until patients have stabilized or have begun to improve from the relapse (approximately 4 to 6 weeks after the start of the relapse). Tetanus vaccination (for wounds) should be administered regardless of presence of the relapses. It is also expert opinion that Pneumococcal vaccine should be considered for patients with compromised pulmonary function, such as wheelchairdependant or bed-bound patients. The benefits versus risk of administering influenza vaccination should be discussed with each patient individually. 22 Additional Guidance documents: National Multiple Sclerosis Society released a Clinical Bulletin in 2012 The National Multiple Sclerosis Society released a Clinical Bulletin in 2012 providing recommendations for treatment strategies, symptom management, and a ranking for the disease modifying treatments. Based on these recommendations, the differentiation was made between first- and second-line therapies. Appropriate first-line therapies included interferon-β medications, Copaxone, and Fingolimod while the others (Tysabri, Novantrone) were considered additional or second-line options. The bulletin was released in 2012 and therefore did not include the newer medications for the treatment of multiple sclerosis. 21 Canadian Drug Expert Committee (CDEC) Recommendation for drug therapies for relapsing-remitting multiple sclerosis (2013). 19 Glatiramer acetate or IFN-β 1b is recommended as initial therapy for patients with relapsing-remitting multiple sclerosis (RRMS). Both of these medications should be tried before initiating a different therapy. If failure occurs or patients have contraindications to both of these medications, initiation of dimethyl fumarate, fingolimod, or natalizumab is recommended. It is advised that these selections should be based on cost and safety concerns. National Institute for Health and Care Excellence (NICE) & The National Health Service (NHS) According to the NICE pathway for managing MS, based on a NICE technology appraisal (NICE technology appraisals [TA127] Published date: August 2007: Natalizumab for the treatment of adults with highly active relapsing remitting multiple sclerosis): 7

8 Natalizumab is recommended as an option for the treatment only of rapidly evolving severe relapsing remitting multiple sclerosis (RES). RES is defined by two or more disabling relapses in 1 year, and one or more gadolinium-enhancing lesions on brain magnetic resonance imaging (MRI) or a significant increase in T2 lesion load compared with a previous MRI. 29 In 2002, the Department of Health agreed a risk-sharing scheme with manufacturers to ensure that the disease-modifying treatments be made cost effective for the NHS to provide to patients (DH Health Service Circular HSC 2002/004). 29 In April 2013 NHS England published a clinical commissioning policy outlining use of these treatments, including criteria for commencement and stopping of these disease-modifying therapies. 29 It is stated that the criteria for starting and stopping these treatments are based upon the Association of British Neurologists (ABN) Guidelines. 30 Please refer to the complete document as this is a brief abstract from the policy and it states that the criteria must be used in conjunction with definitions in the original document. 30 Natalizumab for rapidly evolving severe (RES) relapsing-remitting MS Starting Criteria All of the following criteria* must be met. The patient: has had two or more disabling relapses in the past year has one or more gadolinium-enhancing lesions on MRI or increase in T2 lesion load compared with previous MRI unless comparator MRI is unavailable or assessment of gadolinium-enhancement is unreliable as the patient is treated with steroids at around the time of scan. has had no previous disease modifying therapy OR is receiving treatment with beta interferon and does not meet the agreed stopping criteria. *As per NICE Technology Appraisal Guidance 127 patients with high disease activity taking beta interferon or glatiramer acetate but do not fulfil the RES criteria will not be routinely funded for natalizumab. Stopping Criteria One or more of the following criteria are met: No reduction in frequency or severity of relapses compared with pre-treatment phase following a minimum 3 month period of natalizumab treatment Unacceptable adverse effects of the drug The patient is pregnant, breast feeding or attempting conception Development of secondary progressive disease causing inability to walk for more than 6 months Stopping criteria should be made known to patients and agreed before treatment is begun. 30 Clinical Efficacy Please refer to Appendix 2 for information from Cochrane Systematic Reviews regarding these agents. An Oregon Drug Class review (Appendix 3) compared the effectiveness and safety of disease-modifying drugs for the treatment of multiple sclerosis: Glatiramer acetate (Copaxone ), interferon beta-1a (Avonex, Rebif ), interferon beta-1b (Betaseron, Extavia ), mitoxantrone (Novantrone ), and natalizumab (Tysabri ). 23 The authors concluded that there was fair evidence that interferon beta-1a IM (Avonex ) is less effective than interferon beta-1a SC (Rebif ) and interferon beta-1b (Betaseron ) for preventing relapse in patients with relapsing remitting multiple sclerosis. 23 They stated that on other outcomes and in other populations, direct evidence is either lacking or shows few differences in effectiveness or safety among the disease-modifying drugs used to treat multiple sclerosis. 23 8

9 Safety In addition to the information provided in this section, please also refer to the Systematic review section and appendix 1. According to the Oregon Drug Class review, significant long-term concerns associated with natalizumab and mitoxantrone included progressive multifocal leukoencephalopathy (in patients receiving natalizumab >12 months), and permanent amenorrhea in older women receiving higher total dose of mitoxantrone. 23 Tysabri In 2004, Tysabri was temporarily withdrawn from the market due to four cases of progressive multifocal leukoencephalopathy (PML). However, due to the relatively low incidence of PML and the significant benefits provided by Tysabri, it was reintroduced. Recently, it has been found that infection with John Cunningham Virus (JCV) can cause PML. It has been suggested that this serious complication has a 23% mortality rate and can cause incapacitating disability in many of the survivors. Development of PML has been associated with treatment duration of Tysabri for more than 2 years and prior use of immunosuppressant drugs (e.g., Novantrone, azathioprine, methotrexate). 31 Currently, a two-step antibody test is available to determine exposure and likely latent infection with JCV. Essentially a zero-risk is conferred with a negative antibody test. In patients that are JCV-positive, a magnetic resonance imaging (MRI) scan is performed every 4 months while taking Tysabri to identify early signs of PML; JCV-negative patients have an MRI performed every 6-12 months and are rechecked for JCV antibodies every six months. 31 Due to the risk of PML, Tysabri is only available through the Tysabri Outreach Unified Commitment to Health (TOUCH) prescribing program. TOUCH is a restricted distribution program that focuses on warning patients about use of antineoplastic, immunosuppressant, and immunomodulating agents as well as promotes early diagnosis of PML and timely discontinuation of Tysabri. Patients, prescribers, pharmacies, and infusion sites must be enrolled or authorized in order to receive, prescribe, dispense, or infuse Tysabri. 32 Novantrone Novantrone has a maximum lifetime dose of 140 mg/m 2 (because the risk of cardiotoxicity increases with increasing cumulative doses). 33 This maximum lifetime dose was added in an effort to mitigate the cardiotoxic effects when the indication for use of mitoxantrone was expanded to include the treatment of patients with secondary (chronic) progressive, progressive relapsing or worsening relapsing-remitting multiple sclerosis (MS) in In 2005, a black box warning was added by the FDA to Novantrone product labeling. Postmarketing surveillance reported cardiotoxicity at doses < 100mg/m 2 and treatment-related acute leukemia (TRAL). New recommendations for monitoring included left ventricular ejection fraction (LVEF) prior to initiating therapy and before each dose. In 2008, the FDA recommended further changes in monitoring parameters with the inclusion of annual cardiac function testing after completing treatment due to the potential for delayed cardiotoxicity (decreased LVEF and/or congestive heart failure). 34 9

10 Mitoxantrone black box warning: ALERT: U.S. Boxed Warning Experienced physician: Mitoxantrone should be administered under the supervision of a health care provider experienced in the use of cytotoxic chemotherapy agents. Bone marrow suppression: 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/mm 3. 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 patients with cancer, the risk of symptomatic CHF was estimated to be 2.6% for patients receiving up to a cumulative dose of 140 mg/m 2. To mitigate the cardiotoxicity risk with mitoxantrone, consider the following: o All patients should be assessed for cardiac signs and symptoms by history, physical examination, and electrocardiogram (ECG) prior to start of mitoxantrone therapy. o All patients should have baseline quantitative evaluation of left ventricular ejection fraction (LVEF) using appropriate methodology (eg, echocardiogram, multigated radionuclide angiogram [MUGA], magnetic resonance imaging [MRI]). o Patients with multiple sclerosis (MS) with a baseline LVEF below the lower limit of normal should not be treated with mitoxantrone. o Patients with MS should be assessed for cardiac signs and symptoms by history, physical examination, and ECG prior to each dose. o Patients with MS 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 a drop in LVEF to below the lower limit of normal or a clinically significant reduction in LVEF during mitoxantrone therapy. o Patients with MS should not receive a cumulative mitoxantrone dose higher than 140 mg/m 2. o Patients with MS should undergo yearly quantitative LVEF evaluation after stopping mitoxantrone to monitor for late-occurring cardiotoxicity. Secondary leukemia: Mitoxantrone therapy in MS patients and in patients with cancer increases the risk of developing secondary acute myeloid leukemia (AML). Appropriate administration: Mitoxantrone should be given slowly into a freely flowing intravenous (IV) infusion. It must never be given subcutaneously, intramuscularly (IM), or intra-arterially. Severe local tissue damage may occur if there is extravasation during administration. Not for intrathecal use. Severe injury with permanent sequelae can result from intrathecal administration

11 Natalizumab black box warning: Progressive multifocal leukoencephalopathy: Natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability. Risk factors for the development of PML include duration of therapy, prior use of immunosuppressants, and presence of anti JC virus (JCV) antibodies. These factors should be considered in the context of expected benefit when initiating and continuing treatment with natalizumab. Because of the risk of PML, natalizumab is available only through a restricted program under a risk evaluation and mitigation strategy (REMS) called the TOUCH prescribing program. Monitor patients on natalizumab for any new sign or symptom that may be suggestive of PML. Withhold natalizumab dosing immediately at the first sign or symptom suggestive of PML. For diagnosis, an evaluation that includes a gadolinium-enhanced magnetic resonance imaging (MRI) scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA are recommended. 1 A FDA alert was issued in 2012 regarding the risk factor for PML: Special Alerts Risk Factor Identified for Progressive Multifocal Leukoencephalopathy Associated with natalizumab January 2012 The U.S. Food and Drug Administration (FDA) is alerting clinicians and the public to a newly identified risk factor for the development of progressive multifocal leukoencephalopathy (PML) associated with natalizumab (Tysabri ). A positive test result for anti-jc virus (JCV) antibodies is a risk factor for the development of PML. Additional risk factors include a longer duration of treatment (especially >2 years) and a history of immunosuppressant medication use (eg, mitoxantrone, azathioprine, methotrexate, cyclophosphamide or mycophenolate mofetil). Patients demonstrating all three risk factors have an estimated PML risk of 11/1000. As of January 4, 2012, the FDA is aware of 201 confirmed worldwide cases of PML among ~96,582 patients related to the use of natalizumab. Anti-JCV antibody status is determined by performing an anti-jcv antibody detection test (eg, Stratify JCV Antibody ELISA test); a positive result indicates prior exposure to JCV. Consider testing prior to natalizumab treatment (or during treatment if status is unknown). When assessing the risk for PML using anti-jcv antibody status, a positive test at any time is considered a risk factor regardless of prior or future test results. The risks and benefits of continued natalizumab treatment should be weighed in a patient with a history of a positive anti- JCV antibody test. Patients with a negative result may still be at risk for PML as new JCV infection or false negative result are possible; periodic retesting may be warranted. Natalizumab treatment should be discontinued immediately at the first sign or symptom of PML (eg, progressive weakness on one side of the body, limb clumsiness, visual disturbance, changes in thinking, memory, personality or orientation). Patients should be counseled to contact their prescriber if symptoms occur. Adverse events should be reported to the FDA through the MedWatch program. 1 11

12 Place in therapy and potential criteria to be reviewed Factors and limitations to consider when considering the mitoxantrone and natalizumab s place in therapy: Neurologist involvement and coordination of care: It is recommended to refer people suspected of having MS to a consultant neurologist. 35 Also, it is recommended to involve professionals who can best meet the needs of the person with MS and who have expertise in managing MS. 35 Healthcare professionals could include consultant neurologists, MS nurses, physiotherapists and occupational therapists, speech and language therapists, psychologists, dieticians, social care and continence specialists, and GPs. 35 Treatment options: Evidence exist that the self-injectable disease-modifying drugs are effective in the treatment of RRMS. Because of concerns about cardiotoxicity and acute leukaemias, it is recommended by the authors of a recently updated Cochrane review that mitoxantrone (MX) treatment should be limited to patients with worsening RRMS and SPMS after a careful assessment of the individual patients risk and benefit profiles, also considering the present availability of alternative therapies with less severe adverse events. Moreover, MX-treated patients need to be followed-up after the end of treatment to control the risk of serious adverse events. 36 Also due to safety concerns (PML risk), the authors of a recent Cochrane review concluded that natalizumab (NTZ ) should be used only by skilled neurologists in MS centres under surveillance programs. 16 Cost is another important consideration. It is not possible to recommend the same strategy for all patients because of the variation in the course of the disease as well as the variety of patient disabilities. 17 Modifiable risk factors for relapse or progression of MS: Apart from pharmacological treatment options, it is important to ensure other measures are implemented as well. NICE recommend (1) encouraging people with MS to exercise (regular exercise may have beneficial effects on their MS and does not have any harmful effects on their MS) (2) advising people with MS not to smoke (explain that it may increase the progression of disability) Pregnancy: According to NICE, relapse rates may reduce during pregnancy and may increase 3 6 months after childbirth before returning to pre-pregnancy rates. 35 Pregnancy does not increase the risk of progression of disease. Natalizumab is pregnancy category C and Mitoxantrone is Category D. 37 Pediatric patients: Safety and effectiveness of mitoxantrone and natalizumab have not been established in pediatric patients. 37 Comorbidities/Disease-related concerns: Refer to Appendix 2. Mitoxantrone: Hepatic impairment (clearance is reduced) - use with caution (Canadian labeling contraindicates in severe impairment) and dosage adjustment is recommended. Multiple sclerosis: Not for treatment of multiple sclerosis in patients with concurrent hepatic impairment. Not for treatment of primary progressive multiple sclerosis. Natalizumab: Use with caution in patients with a history of depression (closely monitor) 1 Efficacy: Refer to guideline and efficacy sections Vaccinations: It is important to note that live vaccinations may be contraindicated in people with MS who are being treated with disease-modifying therapies i.e for Mitoxantrone: Contraindicated: Rotavirus Vaccine, Live (established) Major Drug Interaction: Adenovirus Vaccine Type 4, Live (established) Adenovirus Vaccine Type 7, Live (established) Bacillus of Calmette and Guerin Vaccine, Live (established) Cobicistat (theoretical) Influenza Virus Vaccine, Live (established) Measles Virus Vaccine, Live (established) Mumps Virus Vaccine, Live (established) Rubella Virus Vaccine, Live (established) Smallpox Vaccine (established) 12

13 Topotecan (theoretical) Typhoid Vaccine (established) Valspodar (probable) Varicella Virus Vaccine (established) Yellow Fever Vaccine (established). 35,37 NICE also recommend to discuss with the MS patient the possible benefits of flu vaccination and the possible risk of relapse after flu vaccination if they have relapsing remitting MS. 35 Administration: Treatment options include self-injectable, infusion, and oral agents. Adverse effects: Refer to Appendix 2 and the black box warnings. As with many therapies, the riskbenefit balance may be unfavorable for certain MS treatments i.e. natalizumab (can induce progressive multifocal leukoencephalopathy, especially with more than two years of treatment); and mitoxantrone (March 2005 FDA warning: cardiotoxicity and therapy-related acute leukaemia). 38 The risks and benefits should be weighed prior to treating each patient. The authors of a recent meta-analysis (2013) report that it is important to consider that the efficacy and the risk-benefit of all these treatments beyond two years are uncertain, and this is a very relevant point for a lifetime disease such as MS. Thus, studies on the long-term efficacy and safety of immunotherapies for MS are urgently needed. Mitoxantrone and natalizumab both carry black box warnings. Natalizumab has a REMS (including a medication guide). Duplication of therapy: Natalizumab should be used as monotherapy only (combining it with other DMDs increases risk of PML); Patients are generally treated with one DMD at a time; Worsening disease is sometimes treated with combination DMD therapy, but the decision to escalate immunotherapy is based on limited evidence 39 Monitoring: Refer to appendix 2 13

14 Utah Medicaid Utilization Data ALL CLAIMS GENERIC DESCRIPTION CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS Mitoxantrone HCl Mitoxantrone Intravenous 2 MG Natalizumab Tysabri Intravenous 300 MG PHARMACY CLAIMS GENERIC DESCRIPTION CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS Mitoxantrone HCl Mitoxantrone Intravenous 2 MG Natalizumab Tysabri Intravenous 300 MG MEDICAL CLAIMS GENERIC DESCRIPTION CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS Mitoxantrone HCl Mitoxantrone Intravenous 2 MG Natalizumab Tysabri Intravenous 300 MG

15 Number of patients (A) Diagnosis MS INFUSION THERAPY AND DIAGNOSIS* ICD TOTAL PATIENTS PERCENT Multiple Sclerosis (MS) % TOTAL UNIQUE PATIENTS ON MS INFUSION DRUGS % TOTAL UNIQUE PATIENTS ON ANY MS THERAPY 485 * Diagnosis date within 60 days before or 60 days after receiving MS infusion drug. Including self-injectable, infusion, and oral MS drugs Self-injectables: Interferon beta-1a (Avonex and Rebif), Peginterferon beta-1a (Plegridy), Interferon beta-1b (Betaseron and Extavia), or Glatiramer acetate (Copaxone) Infusion: Mitoxantrone (Novantrone), or Natalizumab (Tysabri) Oral: Teriflunomide (Aubagio), Fingolimod (Gilenya), or Dimethyl fumarate (Tecfidera) (B) Age and Sex Age and Sex < >64 Age M F TOTAL PATIENTS AGE* M F Total < > TOTAL * Age at first fill.

16 (C) Prescribers Prescribers Psychiatrist Neurologist Nurse Practitioner PRESCRIBER TYPE* TOTAL CLAIMS Nurse Practitioner % Neurologist % Psychiatrist % TOTAL CLAIMS 13 * Prescribers of medications dispensed at a pharmacy. The 11 claims for Tysabri were all prescribed by a single psychiatrist and were all for a single patient (a midthirties female), filled between January and November of This patient had 26 different diagnosis codes for MS (ICD 340) submitted during the past 3 years, including 7 during the time she was receiving Tysabri. Several psychiatric diagnoses were also submitted for this patient including depression, major depressive affective disorder recurrent episode moderate degree, bipolar disorder, insomnia, and drug-induced psychotic disorder w/delusions. Depression is common during the course of MS. 40 Depression and MS have many of the same symptoms (e.g., sleep disturbance, fatigue) and there is a complicated relationship/link that is not fully understood. 40 Important safety considerations: Diagnosis of depression in patients with MS is difficult since the clinical picture may be related to the underlying MS or to coexisting depression. It is therefore important to have a neurologist involved when treating patients for MS. Potential off-label use by other prescribers It is important to consider that depression is listed on the natalizumab product label as one of the most common adverse reactions (incidence 10%) seen in MS patients that received natalizumab. 14 However, as mentioned before, depression is common during the course of the disease itself. Also, there is some evidence (some conflicting too) that the interferon medications may trigger or worsen depression in susceptible individuals

17 Conclusions Both natalizumab and mitoxantrone are associated with serious safety concerns, and safety measures and surveillance are therefore important with the use of these products. These products should only be used by skilled neurologists in patients with MS after assessing the risk versus benefit and after considering other available treatment options. It is important to ensure that patients are appropriately monitored. Mitoxantrone should be administered under the supervision of a health care provider experienced in the use of cytotoxic chemotherapy agents, and natalizumab is only available through the TOUCH restricted distribution program. Mitoxantrone utilization in the Utah Medicaid population has been very low since 2011 (no patients so far in 2014), and the TOUCH program for natalizumab should ensure appropriate use (24-46 patients per year; ). Currently it does not appear to be necessary to implement prior authorizations for mitoxantrone or natalizumab in the Utah Medicaid population. However, Tysabri was prescribed by a psychiatrist to one patient so you may wish to consider requiring a neurologist consult within 60 days. 17

18 Appendix 1 Drug information Name Class Labeled indication Mitoxantrone Topoisomerase Acute (Novantrone ) 11,18 II inhibitor nonlymphocytic leukemia Antineoplastic (ANLL) Natalizumab (Tysabri ) 1,14 Monoclonal antibody Immune suppressant Advances hormonerefractory prostate cancer Secondary progressive (SPMS) or relapsingremitting MS (RRMS) Crohn disease Relapsing forms of MS Infusion agents MS Dose Adverse reactions Warnings/precautions Special considerations 12 mg/m 2 IV every 3 months. Maximum lifetime dose : 140 mg/m mg IV over 1 hour every 4 weeks Edema, arrhythmia, ECG and cardiac function changes, fever, pain, fatigue, headache, alopecia, menstrual disorder, amenorrhea, hyperglycemia, GI effects, UTI, abnormal urine, pancytopenia, anemia, increase in ALT, GGT, serum creatinine and BUN, muscular weakness, infections, sepsis Headache, fatigue, depression, rash, nausea, GI discomfort, UTI, arthralgia, back and extremities pain, upper/lower respiratory infection, infusion-related reactions [US Boxed Warning]: risk of severe myelosuppression, extravasation, myocardial toxicity, acute myelogenous leukemia (AML). Hyperuricemia **Do NOT administer intrathecally risk of permanent neurological damage [US Boxed Warning]: progressive multifocal leukoencephalopathy (PML) Hepatotoxicity, herpes infection, infusion reactions, immune reconstitution inflammatory syndrome (IRIS), infections, patients undergoing treatment for Crohn s Disease or have depression. ** Discontinue if LVEF < 50% Do NOT use for treatment of primary progressive multiple sclerosis Pregnancy risk factor D ** Contraindicated in patients with history of PML Note: The marketing status of the branded product, Novantrone, on the FDA website states discontinued, but the generic mitoxantrone states prescription (in marketing status). 18

19 MONITORING (from Micromedex Drug Comparisons) 37 Mitoxantrone multiple sclerosis: clinical improvement is indicative of efficacy prostate cancer and leukemia: evidence of cancer response is indicative of efficacy CBC (including platelets); prior to each course, if signs and symptoms of infection develop, and frequently during therapy ; include differential chemical laboratory parameters; closely and frequently during therapy hepatic function tests; prior to each course of therapy serum uric acid levels; before initiating mitoxantrone in the treatment of leukemia signs and symptoms of tumor lysis syndrome, especially in patients at risk of tumor lysis syndrome or with large tumor burden pregnancy test; before each dose of mitoxantrone in women with multiple sclerosis who are biologically capable of becoming pregnant, even if birth control is being used cardiac function; by physical exam, history, and ECG prior to initiation of therapy in all patients, regularly thereafter in patients with risk factors (eg, prior anthracycline therapy, prior mediastinal radiotherapy, preexisting cardiovascular disease), and prior to each dose in patients with multiple sclerosis left ventricular ejection fraction (LVEF); prior to initiation of therapy in all patients; regularly in patients with risk factors (eg, prior anthracycline therapy, prior mediastinal radiotherapy, preexisting cardiovascular disease); prior to each dose in patients with multiple sclerosis (MS) (using the same method as used for baseline evaluation); in any patient if signs or symptoms of congestive heart failure develop; annually in patients with MS after completion of mitoxantrone therapy Natalizumab evaluate, as required by the TOUCH (R) Prescribing Program, 3 and 6 months after the first infusion, every 6 months during therapy, and for at least 6 months after discontinuation Crohn's disease: decrease in the Crohn's Disease Activity Index (CDAI) score is indicative of efficacy multiple sclerosis: longer time to onset of sustained increase in disability and reduction in annualized relapse rate is indicative of efficacy anti-jc virus antibodies; prior to treatment or during treatment if status is unknown; retest periodically if initial result negative; wait at least 2 weeks after plasma exchange to perform test serum antibodies to natalizumab in select patients, particularly if suspected; repeat 3 months after initial positive result to confirm; consider antibody testing in patients who wish to recommence therapy following a dose interruption development of infection MRI scan in patients with multiple sclerosis prior to initiating therapy; baseline MRI may also be helpful in patients with Crohn's Disease signs/symptoms of hypersensitivity during the infusion and for 1 hour after infusion signs/symptoms of meningitis and encephalitis signs/symptoms suggestive of progressive multifocal leukoencephalopathy; during treatment and for 6 months following discontinuation 19

20 Appendix 2 Systematic reviews Cochrane reviews Author/Date Title Objective Main results Author s Conclusion Filippini G, et al Immunomodulators and immunosuppressants for multiple sclerosis: a network metaanalysis To estimate the relative efficacy and acceptability of interferon ß-1b (IFNß- 1b) (Betaseron), interferon ß-1a (IFNß-1a) (Rebif and Avonex), glatiramer acetate, natalizumab, mitoxantrone, methotrexate, cyclophosphamide, azathioprine, intravenous immunoglobulins, and long-term corticosteroids versus placebo or another active agent in participants with MS and to provide a ranking of the treatments according to their effectiveness and riskbenefit balance. Forty-four trials were included in this review, in which 17,401 participants had been randomised. Twenty-three trials included relapsing-remitting MS (RRMS) (9096 participants, 52%), 18 trials included progressive MS (7726, 44%), and three trials included both RRMS and progressive MS (579, 3%). The majority of the included trials were short-term studies, with the median duration being 24 months. The results originated mostly from 33 trials on IFNß, glatiramer acetate, and natalizumab that overall contributed outcome data for 9881 participants (66%). From the pairwise meta-analysis, there was high quality evidence that natalizumab and IFNß-1a (Rebif) were effective against recurrence of relapses in RRMS during the first 24 months of treatment compared to placebo (odds ratio (OR) 0.32, 95% confidence interval (CI) 0.24 to 0.43; OR 0.45, 95% CI 0.28 to 0.71, respectively); they were more effective than IFNß- 1a (Avonex) (OR 0.28, 95% CI 0.22 to 0.36; OR 0.19, 95% CI 0.06 to 0.60, respectively). IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having clinical relapses compared to placebo (OR 0.55, 95% CI 0.31 to 0.99; OR 0.15, 95% CI 0.04 to 0.54, respectively) but the quality of evidence for these treatments was graded as moderate. From the network meta-analysis, the most effective drug appeared to be natalizumab (median OR versus placebo 0.29, 95% credible intervals (CrI) 0.17 to 0.51), followed by IFNß-1a (Rebif) (median OR versus placebo 0.44, 95% CrI 0.24 to 0.70), mitoxantrone (median OR versus placebo 0.43, 95% CrI 0.20 to 0.87), glatiramer acetate (median OR versus placebo 0.48, 95% CrI 0.38 to 0.75), IFNß-1b (Betaseron) (median OR versus placebo 0.48, 95% CrI 0.29 to 0.78). However, our confidence was moderate for direct comparison of mitoxantrone and IFNB-1b vs placebo and very low for direct comparison of glatiramer vs placebo. The relapse outcome for RRMS at three years follow-up was not reported by any of the included trials. Disability progression was based on surrogate markers in the Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefitrisk balance might be unfavourable. IFNß- 1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß- 1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond