Coverage Policies

Effective Date:

a)    This policy will apply to all services performed on or after the above revision date which will become the new effective date.

b)    For all services referred to in this policy that were performed before the revision date, contact customer service for the rules that would apply.

1)    Tysabri is covered subject the Medical Policy Statement below and is subject to retrospective review to ensure compliance with this statement.

2)    Tysabri is a recombinant humanized monoclonal antibody that is used to treat relapsing remitting multiple sclerosis or moderate-to-severe Crohn’s disease.

3)    Because Tysabri increases the risk of progressive multifocal leukoencephalopathy (PML), a severe and often fatal degenerative neurological disease, it can only be prescribed through a risk minimization plan called Tysabri Outreach Unified Commitment to Health, which registers prescribers, infusion centers, and pharmacies.

1)    Tysabri is covered subject to this Medical Policy Statement and is subject to retrospective review to ensure compliance.

2)    QualChoice considers Natalizumab (Tysabri) medically necessary for the treatment of individuals with relapsing, remitting multiple sclerosis (but not for the treatment of chronic progressive multiple sclerosis) for persons with a contraindication, allergy, intolerance, or failure of a one-month trial of an alternate disease-modifying multiple sclerosis therapy, such as fingolimod, glatiramer, or interferon.

3)    QualChoice considers Natalizumab medically necessary for the treatment of adults with moderate-to-severely active Crohn`s disease with evidence of inflammation, and who have had an inadequate response to, or are unable to tolerate, conventional Crohn`s disease therapies including anti-inflammatory drugs (e.g., sulfasalazine), corticosteroids, immunosuppressive agents (e.g., 6-mercaptopurine or azathioprine), and inhibitors of tumor necrosis factor-alpha (e.g., adalimumab or infliximab). 

4)    Tysabri should not be used in combination with TNF-alpha inhibitors or immunosuppressants such as 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate.

5)    Patients being treated with natalizumab should be reevaluated every 6 months to determine if continued therapy is medically necessary. QualChoice considers Natalizumab experimental and investigational for all other indications.

6)    QualChoice considers testing for anti-natalizumab antibodies medically necessary for individuals with a suboptimal clinical response. Repeat testing at 3 months after the initial positive result is recommended in individuals in whom antibodies are detected to confirm that antibodies are persistent. Prescribers should consider the overall benefits and risks of natalizumab in persons with persistent antibodies.

7)    QualChoice considers diagnostic tests, including polymerase chain reaction (PCR) testing of cerebrospinal fluid for John Cunningham (JC) polyomavirus, for diagnosis of progressive multifocal leukoencephalopathy in persons before initiating natalizumab treatment not medically necessary.

Codes Used In This BI:

J2323   Natalizumab (Tysabri) Injection, 1 mg

Tysabri is available only through a risk minimization plan called Tysabri Outreach Unified Commitment to Health (the TOUCH™ Prescribing Program) which registers prescribers, infusion centers, and pharmacies associated with infusion centers.  Additionally, Tysabri can only be prescribed to patients who are enrolled in and meet all the requirements of the program.

Multiple Sclerosis

In the AFFIRM study (n=942), patients were randomly assigned to receive either 300 mg natalizumab (n=627) or placebo (n=315). The primary endpoints were the rate of clinical relapse at one year and the rate of sustained progression of disability. The results showed that natalizumab reduced the rate of clinical relapse at one year by 68% (p<0.001) and led to an 83% reduction in the accumulation of new or enlarging hyperintense lesions, as detected by T2-weighted magnetic resonance imaging (MRI), over two years (mean numbers of lesions, 1.9 with natalizumab and 11.0 with placebo; p<0.001). Natalizumab reduced the risk of sustained progression of disability by 42% over two years (hazard ratio, 0.58; 95% confidence interval, 0.43 to 0.77; p<0.001). The cumulative probability of progression was 17% in the natalizumab group and 29% in the placebo group. There were 92% fewer lesions (as detected by gadolinium enhanced

MRI) in the natalizumab group than in the placebo group at both one and two years

(p<0.001). The adverse events that were significantly more frequent in the natalizumab group than in the placebo group were fatigue (27% vs. 21%, p=0.048) and allergic reaction (9% vs. 4%, p=0.012). Hypersensitivity reactions of any kind occurred in 25 patients receiving natalizumab (4%), and serious hypersensitivity reactions occurred in 8 patients (1%). In conclusion, natalizumab reduced the risk of the sustained progression of disability and the rate of clinical relapse in patients with relapsing multiple sclerosis.

In the SENTINEL study (n=1,171), natalizumab 300 mg IV (589 patients) or placebo (582 patients) every 4 weeks was added to interferon beta-1a (Avonex®).8 The primary end points were the rate of clinical relapse at 1 year and the cumulative probability of disability progression sustained for 12 weeks, as measured by the Expanded Disability Status Scale, at 2 years. Combination therapy was associated with a lower annualized rate of relapse over a two-year period than was interferon beta-1a alone (0.34 vs. 0.75, p<0.001) and with fewer new or enlarging lesions on T (2)-weighted magnetic resonance imaging (0.9 vs. 5.4, p<0.001). The results showed that combination therapy resulted in a 24% reduction in the relative risk of sustained disability progression (hazard ratio, 0.76; 95% confidence interval, 0.61 to 0.96; p=0.02). Kaplan-Meier estimates of the cumulative probability of progression at two years were 23% with combination therapy and 29% with interferon beta-1a alone. Adverse events associated with combination therapy were anxiety, pharyngitis, sinus congestion, and peripheral edema. Two cases of progressive multifocal leukoencephalopathy, one of which was fatal, were diagnosed in natalizumab-treated patients. In conclusion, natalizumab added to interferon beta-1a was significantly more effective than interferon beta-1a alone in patients with relapsing multiple sclerosis. It is not known how long Natalizumab continues to be effective.  It does appear that longer usage increases the risk of PML.

Crohn’s Disease

A Cochrane systemic review of four studies suggested that natalizumab (300 mg or 3 to 4 mg/kg) was effective for induction of clinical response and remission in patients with moderately to severely active Crohn`s disease. This benefit was statistically significant for one, two, and three infusion treatments. There was a trend toward increased benefit with additional infusions of natalizumab. Natalizumab appears to provide greater benefit for patient subgroups characterized by objective confirmation of active inflammation or chronically active disease despite conventional therapies. These subgroup analyses demonstrated significantly greater clinical response and remission rates for natalizumab compared with placebo in patients with elevated C-reactive protein levels, active disease despite the use of immunosuppressants, or prior anti-tumor necrosis factor therapy. These benefits were apparent for both short term (one infusion) and longer term treatment (two or three infusions). Natalizumab was generally well tolerated and the safety profile observed in the four included studies was similar. Adverse events occurred infrequently and were experienced by a similar proportion of natalizumab and placebo treated patients. There were no statistically significant differences between natalizumab and placebo treated patients in the proportions of patients who withdrew due to adverse events or those who experienced serious adverse events. The included trials lacked adequate power to detect serious adverse events that occur infrequently.

Safety Concerns

The FDA issued a Drug Safety Communication dated February 5, 2010 to communicate that the risk of developing progressive multifocal leukoencephalopathy (PML), a rare but serious brain infection associated with the use of Tysabri (natalizumab), increases with the number of Tysabri infusions received. This safety information, based on reports of 31 confirmed cases of PML received by the FDA as of January 21, 2010, is included in the Tysabri drug label and patient Medication Guide.

The FDA issued a second Drug Safety Communication dated April 22, 2011 to provide a safety update on PML associated with natalizumab. The Tysabri label has been revised to include new information about the risk of PML. The updated drug label includes a table summarizing rates of PML with natalizumab use according to the number of infusions (duration of exposure). The new label also includes information on a newly identified PML risk factor. Patients who took an immune system suppressing medication (e.g., mitoxantrone, azathioprine, methotrexate, cyclophosphamide, and mycophenolate) prior to taking Tysabri have been shown to be at an increased risk for developing PML.

The FDA-approved labeling for natalizumab (Tysabri) states that 300 mg of

Natalizumab (Tysabri) should be infused intravenously over approximately 1 hour every 4 weeks. In Crohn’s patients, natalizumab should be discontinued in patients that have not experienced therapeutic benefit by 12 weeks of induction therapy, and in patients that cannot discontinue chronic concomitant steroids within 6 months of starting therapy.

Calabresi PA, Giovannoni G, Confavreux C, et al; AFFIRM and SENTINEL Investigators. The incidence and significance of anti-natalizumab antibodies: Results from AFFIRM and SENTINEL. Neurology. 2007; 69(14):1391-1403.

2. MacDonald JK, McDonald JWD.Natalizumab for induction of remission in Crohn’s disease. Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No.: CD006097. DOI:10.1002/14651858.CD006097.pub2.

3. National Institute for Health and Clinical Excellence (NICE). Natalizumab for the treatment of adults with highly active relapsing-remitting multiple sclerosis. NICE Technology Appraisal Guidance 127. London, UK: NICE; August 2007.

4. Polman CH, O`Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of Natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006 Mar 2; 354(9):899-910.

5. Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. 2006 Mar 2; 354(9):911-23.

6. U.S. Food and Drug Administration Drug Safety Communication: Risk of Progressive Multifocal Encephalopathy (PML) with the use of Tysabri (natalizumab). http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm199872.htm. Accessed May 25, 2010.

7. U.S. Food and Drug Administration Drug Safety Communication: Safety Update on Progressive Multifocal Encephalopathy (PML) associated with Tysabri (Natalizumab).http://www.fda.gov/Drugs/DrugSafety/ucm252045.htm. Accessed April 26, 2011.

This policy applies to all health plans and products administered by QualChoice, both those insured by QualChoice and those that are self-funded by the sponsoring employer, unless there is indication in this policy otherwise or a stated exclusion in your medical plan booklet.  Consult the individual plan sponsor Summary Plan Description (SPD) for self-insured plans or the specific Evidence of Coverage (EOC) or Certificate of Coverage (COC) for those plans or products insured by QualChoice.  In the event of a discrepancy between this policy and a self-insured customer’s SPD or the specific QualChoice EOC or COC, the SPD, EOC, or COC, as applicable, will prevail.  State and federal mandates will be followed as they apply.