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MP 5.01.97 Tysabri (natalizumab)

Medical Policy

Section
Prescription Drug

Original Policy Date
07/06/2006

Last Review Status/Date
Local Policy/05:2010

Issue
5:2010
Return to Medical Policy Index

Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.


Description

Multiple Sclerosis

Tysabri is indicated as monotherapy for the treatment of patients with relapsing forms of multiple sclerosis (MS) to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations. Because Tysabri increases the risk of progressive leukoencephaly (PML), it is generally recommended for patients who have had an inadequate response to, or unable to tolerate alternate MS therapies. This product is the first humanized monoclonal antibody approved for the treatment of MS. Tysabri acts by preventing the movement of possibly harmful cells from the bloodstream into the central nervous system. The most commonly reported adverse events with Tysabri were infections, hypersensitivity reactions, depression, and gallstones. Tysabri is available as a 300 mg single-use vial and is given intravenously every 4 weeks. The drug will only be prescribed, distributed and infused by prescribers, pharmacies and infusion centers registered with the TOUCH program.  (See Appendix for further details of the TOUCH program.)

Multiple Sclerosis (MS) is a demyelinating disease accompanied by a lymphocytic infiltration in lesions. Evidence relating to pathogenesis suggests genetic, infective, and/or immune mechanisms. Tysabri has been investigated in patients with relapsing/remitting MS, where the treatment goals are to decrease the frequency and severity of future attacks and, if possible, to improve the functional deficit to some extent in those same patients.  Tysabri was initially FDA approved in November 2004, and was withdrawn by the manufacturer in February 2005 after three patients in the drug’s clinical trials developed progressive leukoencephalopathy (PML), a serious and often fatal viral infection of the brain.  In addition, the FDA put clinical trials of the drug on hold in February 2005, based on this information.  FDA allowed clinical trials of Tysabri to resume in February 2006, and in March 2006 FDA approved Tysabri to be distributed strictly through a risk management program called the TOUCH program.  The safety of Tysabri beyond an infusion period of longer than two years has not been established.  Also, Tysabri has not been studied in patients with chronic progressive multiple sclerosis, in children, or in pregnant females with MS.  It is not known if patients older than 65 have a different response to Tysabri.  Tysabri does not cure MS.  

Crohn`s Disease

There is no cure for Crohn`s disease, and treatment regimens are directed towardincluding remission, maintaining remission and addressing complications. The 5-ASA agents (e.g., mesalamine), antibiotics (e.g., metronidazole), corticosteroids, asathioprine, 6-mercaptopurine, and methotrexate are among several options used in treating Crohn`s disease. The choice of a specific treatment depends on severity, response, and location of the disease.

Biologic-response modifiers may also be used in the treatment of Crohn`s disease. Current biologic-response modifiers approved for use in the treatmen tof Crohn`s disease include:

  • Adalimumab (Humira® )
  • Certolizumab (Cimzia® )
  • Infliximab (Remicade® )
  • Natalizumab &Tysabri® )

Ancillary disease or care management interventions that are intended to accompany natalizumab (Tysabri® ) [27]

The following clinical assessments are performed at three and six months after the first infusion and every six months thereafter to evaluate patients for the presence of adverse effects:

  • Liver function tests (including total bilirubin in patients with signs and symptoms of hepatotoxicity)
  • Complete blood count (CBC)
  • Evaluate for signs and symptoms of progressive multifocal leukoencephalopathy (PML)
  • Evaluate for signs and symptoms of infection

The effectiveness of natalizumab (Tysabri® ) in Crohn`s disease is primarily determined by evaluation for signs of clinical response, such as decreased symptoms, decreasing frequency of bowel movements, and the decrease of corticosteroids.


Policy

Multiple Sclerosis

Tysabri requires preauthorization in all cases and the following criteria will require strict adherence.

Tysabri infusions may be considered medically necessary when the following criteria are met:

 

Patients meeting ALL of the following criteria will be considered for Tysabri infusions:

  • Diagnosis of relapsing/remitting MS
  • At least 18 years of age and less than 65 years of age
  • Neurologist documenting the diagnosis
  • Functional status is ambulatory
  • Not currently receiving any interferon-beta (Rebif, Avonex, Betaseron) or glatiramer acetate (Copaxone) treatment; but must have tried and failed Avonex or Rebif in the previous 180 days.
  • Diagnosis of at least two focal neurological deficits (i.e., loss of vision, diplopia, localized numbness or weakness, etc) where the first resolved and the second followed after a period of at least 6 months                            
  • MRI suggestive of MS
  • Proof of enrollment in the TOUCH program by prescribing physician, member and location of service (i.e., infusion center)
  • Adherence to all rules governing the TOUCH program, including specifically but not limited to:
    • MRI prior to beginning Tysabri to differentiate potential future MS from PML
    • MD evaluation at 3 and 6 mos after first infusion, then every 6 months thereafter
  • If requesting ongoing Tysabri infusions, a statement from a neurologist indicating that Tysabri has been effective in decreasing relapses as evidenced by objective data is required.

Tysabri is considered not medically necessary as a treatment of MS in patients who have not tried other therapies previously; or who have been helped by, or would be able to tolerate other therapies for MS.
 

Other applications of Tysabri infusions are considered investigational, including but not limited to the following conditions:

  • Chronic progressive multiple sclerosis
  • Having a medical condition that could weaken the immune system such as leukemia, lymphoma, organ transplant, HIV, AIDS, etc.

Crohn`s Disease

Tysabri may be considered medically necessary for patients with active Crohn's disease when the following criteria have been met:

  • elevated baseline C-reactive protein (CRP) levels of ≥6mg/dL.
  • Other disease-modifying treatment options are not effective, not tolerated or are contraindicated
  • Tysabri use is non-concomitant with tumor necrosis factor-alpha inhibitors (such as infliximab (Remicade® ), adalimumab (Humira® ), and certolizumab pegol (Cimzia® ).


Policy Guidelines

The fact that a Covered Provider may prescribe, order or recommend Tysabri does not, in and of itself, necessarily establish that such service is Medically Necessary.

The term Medically Necessary as defined and used in the policy is strictly limited to the application and interpretation of this policy, and any determination of whether a service is Medically Necessary hereunder is made solely for the purpose of determining whether services rendered are covered services.


Benefit Application

Tysabri is only available as a major medical benefit, and is not to be administered through the pharmacy benefit.

May not apply to Medicare Advantage, Medicare Supplement, or Federal Employee Program (FEP) policies, depending on policy and benefit requirements.

May not apply to National or ASC Accounts, please check contract specific language. 


Rationale

Effectiveness in Crohn`s Disease

There is good quality evidence supporting the use of natalizumab (Tysabri) in the management of Crohn`s disease, that is supplemented by a Cochrane review.

An elevated C-reactive protein (CRP) level (> 6mg/dL) at initiation of treatment with natalizumab appears to be an indicator of positive response to natalizumab based on a post hoc analysis of an initial trial and a follow up trial that used elevated CRP as an entry criterion.

  • The initial pivotal trial (Sanborn et al. 2005 [33]), an enrichment design, that studied natalizumab in the treatment of CD failed to reach its primary endpoint in its first phase (ENACT-I). In a post hoc analysis of trial data, it was determined that there was an association between elevated CRP levels at baseline and response to natalizumab.
  • The second pivotal trial (Tragan et al. 2007 [31]) used elevated CRP as an entry criterion. In this follow up trial, there was a statistical difference reported between natalizumab and placebo.

Safety

  • Nataluzimab (Tysabri®) is associated with an increased risk of progressive multifocal leukoencephalopathy (PML), a serious brain infection. This was observed in randomized controlled trials with natalizumab (Tysabri® ) and was confirmed in an FDA postmarketing safety anaylsis. Other disease-modifying medications used in the treatment of Crohn`s disease are not associated with an increased risk of PML. Because of this safety concern, nataluzimab (Tysabri®) is not recommended as a first-line therapy for Crohn`s disease.
  • The risk of PML increases with exposure to nataluzimab. The mean duration of treatment was 17.9 doses before onset of PML. Doses higher than 300 mg or frequency more often than every 28 days have not been adequately evaluated. [36]
  • Concomitant administration of nataluzimab (Tysabri®) with other disease-modifying agents is not recommended because if may increase the risk of serious infections, including PML.
    • Avoid concomitant administration with immunosuppressive agents (6-mercaptopurine, asathiopurine, cyclosporine, and methotrexate), TNF-alpha inhibitors (adalimumab [Humira® ], infliximab [Remicade® ]), or certolizumab pegol (Cimzia® ).

Nataluzimab (Tysabri®) may be utilized in quantities up to 300mg every 28 days. The safety and efficacy of higher doses in Crohn`s disease has not been established.

 

 

References:

  • Tysabri [package insert]. Biogen Idec and Elan Pharmaceuticals, June 2006.
  • National Multiple Sclerosis Society: Just the Facts, 2005-2006 brochure.
  • Company Press Release, “Biogen Idec and Elan Announce Voluntary Suspension of Tysabri”, February 28, 2005.
  • Dow Jones Press Release, “FDA Clears MS Drug Tysabri for Return to the Market in July”, June 5, 2006
  • Department of Health & Human Services Public Health Service, “Tysabri Risk Minimization Action Plan: Summary of TOUCH”, BL 125104/15

 

Codes

Number

Description

CPT

 90760 Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hours (new code effective 01/01/06)
ICD-9 Procedure J2323 Injection, natalizumab, per 1 mg
ICD-9 Diagnosis 340

Multiple sclerosis

  555 Crohn's disease


Index

Tysabri
natalizumab
MS therapy
biologics

 


Policy History

Date

Action

Reason

07/06/2006 Add to Prescription Drug Section New policy
01/17/08 Replace Policy Deleted code Q4079
10/06/09 Updated policy number only Policy re-numbered to 5.01.97
12/01/09 Replace policy Avonex and Rebif must have been tried and failed was added to criteria


Appendix

TOUCH program information:

Tysabri is only available through a Risk Management Plan called the TOUCH Prescribing Program.  Biogen Idec, Inc, the Tysabri manufacturer, and Elan Pharmaceuticals, the Tysabri distributor, will manage the program.  In order to receive Tysabri, members must converse with their physician and understand the risks and benefits of Tysabri and agree to all of the instructions within the TOUCH program.  

Prescribing Program

 

Biogen Idec, Inc. will ensure that its Risk Minimization Action Plan, TOUCH, addresses the following requirements:

  • Tysabri will only be available under a special restricted distribution program called TOUCH.
  • Only prescribers registered with TOUCH and who agree to comply with the TOUCH program will be able to prescribe Tysabri.
  • Only infusion centers registered and authorized under TOUCH will be able to administer Tysabri.
  • Only pharmacies registered with TOUCH will be able to dispense Tysabrito affiliated authorized infusion centers.
  • Only patients enrolled in TOUCH and who agree to comply with the TOUCH program will be able to receive Tysabri.
  • All TOUCH prescribers, pharmacies, infusion centers, and patients will be educated about the TOUCH program and the risks of Tysabri treatment.
  • Safety surveillance, including monitoring and reporting of PML infections, other serious opportunistic infections, and deaths and systematic tracking of patients and drug disposition will be conducted. 

Pharmacy and Infusion Center Requirements
Biogen Idec, Inc. will limit the distribution of Tysabri through specialty and central pharmacies to authorized infusion centers. The agreements between Biogen Idec and the specialty and central pharmacies and infusion centers require the following:

  • All pharmacies and infusion sites will be registered with the TOUCH program, and agree to comply with the TOUCH program.
  • Infusion sites and central pharmacies will obtain Tysabri  directly from a single contract distributor or specialty pharmacy.
  • All appropriate pharmacy and infusion center staff will be trained by Biogen Idec and/or Elan Pharmaceuticals about the TOUCH program and about the known risks, potential benefits, and appropriate use of Tysabri.
  • All appropriate pharmacy and infusion center staff will be trained by Biogen Idec and/or Elan Pharmaceuticals in adverse experience reporting procedures, including 15 day reporting of PML infection, other serious opportunistic infections, and deaths.
  • Infusion center staff are to follow the infusion guidelines outlined below:
    • Accept only prescriptions from prescribers in the TOUCH program.
    • Only infuse patients who are enrolled in the TOUCH program.
    • Prior to infusing a patient, the infusion site will verify in the patient's medical record that the patient is authorized to receive Tysabri.
    • Prior to infusing a patient, the infusion site will, confirm that there is a current Notice of Patient Authorization on file, and confirm that there is not a Notice of Discontinuation on file.
    • Prior to infusing a patient, the infusion site will provide the patient the Medication Guide and give the patient time to read it.
    • Prior to infusing a patient, the infusion site will complete the Pre-Infusion Patient Checklist and confirm prescriber clearance if needed.
    • Within one day of completing the Pre-Infusion Patient Checklist, the infusion site will fax the form to Biogen Idec.
    • The infusion site will not dispense Tysabri if it is determined that the patient (or their prescriber) is not in conformance with the TOUCH program.
    • Keep a record of the Tysabri prescription, Notice of Patient Authorization, and the Pre-infusion Patient Checklist, with each Tysabri prescription for each corresponding patient.
  • Central pharmacies are to follow the dispensing guidelines outlined below:
    • Fill valid prescriptions for Tysabriin accordance with all applicable laws and regulations
    • Dispense Tysbari only to affiliated authorized infusion sites.
    • Complete the Tysabri Inventory Tracking Log for every dose/vial of Tysabri dispensed to authorized infusion sites. The Inventory Tracking Log will be kept for at least 5 years from the date of the final log entry. 

Prescriber Requirements

  • Biogen Idec will accept registration of prescribers who agree to the following:
  • To comply with the TOUCH program.
  • To determine that a patient has a relapsing form of MS based on clinical and radiological evidence before prescribing Tysabri.
  • That he/she is capable of diagnosing and managing opportunistic infections and PML, or prepared to refer to specialists with those abilities.
  • To counsel all patients on the benefits and risks of Tysabri  therapy, including the risks of PML, and to provide each patient with the Tysabri Medication Guide.
  • To not prescribe Tysabri  to any patient who is inappropriate for receiving the drug under the TOUCH program.
  • To sign and complete the Prescriber/Patient Enrollment form for each patient, and to fax it to Biogen Idec before the patient can begin to receive infusions.
  • To report to Biogen Idec, as soon as possible, any case of PML, any hospitalization due to opportunistic infection, and any death.
  • To evaluate the patient 3 months after the first infusion, 6 months after the first infusion, every 6 months thereafter as long as the patient receives Tysabri, and 6 months after Tysabrihas been discontinued.
  • To determine every 6 months whether each patient should continue on Tysabri therapy and fill out the Patient Status Report and Reauthorization Questionnaire. 

Patient Requirements

 

Biogen Idec will accept registration for patients who meet the following conditions:

  • Must be registered in the TOUCH program.
  • Must understand the risks and benefits of Tysabri treatment, including that taking the drug increases the risk of getting PML.
  • Must complete and sign the Prescriber/Patient Enrollment Form indicating the patient’s understanding of the potential risks associated with Tysabri treatment.
  • Must agree to contact their prescriber if new or worsening symptoms, especially nervous system symptoms develop.
  • Must read the Tysabri Medication Guide.
  • Must agree to notify the TOUCH program if they switch infusion sites and/or prescribers
  • Must provide information about other medicines and treatments at each Tysabri infusion.
     

Educational Program

Biogen Idec, Inc. will provide prescribers, infusion site staff, pharmacists and patients with educational materials on the benefits and risks associated with Tysabri therapy, the increased risk of PML, and the requirements of the TOUCH program.  

Healthcare Provider and Patient Educational Materials

 

Educational information about the drug will be distributed to prescribers, pharmacies, infusion sites, and patients.  

The TOUCH Educational Materials and forms include:

  • The Patient Medication Guide and Package Insert (for patients and prescribers)
  • TOUCH Prescribing Education Slide Set
  • Tysabriand TOUCH Prescribing Program Slide Set (for prescribers and patients)
  • TOUCH Prescribing Program Overview (general description)
    Prescriber/Patient Enrollment Form (signed by patients and prescribers)
  • Infusion Site Enrollment Form (for infusion site enrollment)
  • Central Pharmacy Enrollment Form (for central pharmacy enrollment into TOUCH)
  • Tysabri Inventory Tracking Log (central pharmacies use to document dispensing of Tysabri to affiliated authorized infusion sites)
  • Patient Status Report and Reauthorization Questionnaire (filled out ever 6 months by prescribers)
  • Tysabri Patient Discontinuation Notification Form (for prescribers to de-enroll a patient from the program)
  • Tysabri Patient Discontinuation Questionnaire (for prescribers to complete at discontinuation and 6 months after the patient discontinues Tysabri)
  • TOUCH Enrollment Kit (for prospective prescribers -- contains above information and describes program)
  • Dear Doctor and Dear Patient Letters
  • Patient Getting Started Brochure (information for patients about TOUCH and Tysabri)
  • Healthcare Professional Infusion Guide (for infusion sites)
  • Guidance for Evaluation of New Neurologic Symptoms in Patients Receiving Tysabri (for healthcare professionals) 

Additional Information Sources

  • www.TYSABRI.com
  • Biogen Idec's Call Center: a call center designed to respond to healthcare provider, pharmacist, infusion center, and patient questions and requests for information. 

Reporting: Biogen Idec, Inc. will implement a reporting and collection system for safety information as follows:

  • All spontaneous and solicited adverse event reports from any post-marketing source will be reported as per 21 CFR 600.80.
  • Within 15 calendar days a report for all confirmed cases of PML will be sent to FDA. Summary numbers for possible cases as flagged by the pre-infusion checklist will be reported in the periodic report.
  • Within 15 calendar days a report of any other serious opportunistic infections or deaths of any cause will be reported to FDA.
     

Biogen Idec, Inc. will also establish a Pregnancy Registry in the US to determine the safety of Tysabriin pregnant patients. The primary objective will be to evaluate any pattern or increase in birth defects in children of women with MS who were exposed to Tysabriat any time within 3 months prior to conception, or at any time during pregnancy, where the outcome of the pregnancy is unknown at the time of enrollment.  

TOUCH Safety Surveillance

 

Biogen Idec, through the TOUCH prescribing program will systematically follow and actively solicit information regarding the occurrence of PML and other serious opportunistic infections through a variety of mechanisms on every Tysabri-treated patient in the U.S. The various mechanisms include: through collection and assessment of Pre-Infusion Patient Checklists and the Prescriber/Patient Enrollment form; through serious adverse event reporting; and through contact with prescribers every 6 months in the form of a Patient Status Report and Reauthorization Questionnaire. In addition, attempts will be made to find and follow for 6 months patients who discontinue TYSABRIÒ  treatment. Biogen Idec and Elan Pharmaceuticals are also creating a joint Tysabri Safety Review Committee to review safety data and determine any appropriate corrective actions, if needed.  

TOUCH Program Evaluation

 

Biogen Idec, Inc. will evaluate the effectiveness of the Tysabri RiskMAP and will report the results quarterly for the first year, then every 6 months for 2 years, and annually thereafter to FDA. Each submission to FDA will include analyses of two major datasets:

  • Health Outcomes Data (e.g. PML rate, overall safety)
  • Systems/Process Data, Quality and Compliance Metrics
     

Biogen Idec, Inc. is also establishing a multi-disciplinary Tysabri  Risk Management Review Committee to evaluate the effectiveness of the risk management plan. The decisions and outcomes of the Committee will be included in the Tysabri RiskMAP reports to FDA. In addition, Biogen Idec, Inc. and Elan Pharmaceuticals will create a joint Tysabri Compliance Review Committee to facilitate RiskMAP compliance.


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