Currently Viewing:
Supplements Best Practices for Natalizumab Utilization in the Treatment of Multiple Sclerosis
Currently Reading
Recommendations for the Selection, Treatment, and Management of Patients Utilizing Natalizumab Therapy for Multiple Sclerosis
John Foley, MD
Quantifying the Role of Natalizumab in Health and Economic Outcomes in Multiple Sclerosis
David W. Brandes, MS, MD, FAAN; Fadia T. Shaya, PhD, MPH; and Michael W. Pill, PharmD
Participating Faculty

Recommendations for the Selection, Treatment, and Management of Patients Utilizing Natalizumab Therapy for Multiple Sclerosis

John Foley, MD
Some patients show hypersensitivity to natalizumab infusions, which may be the result of the patient developing antibodies to natalizumab. If persistent antibody positivity is suspected (ie, reduced treatment efficacy and an increased incidence of infusion reactions such as pruritus, nausea, flushing, dyspnea), antibody testing should be performed. It should be noted that antibodies detected within the first 6 months of treatment may be transient and disappear with continued dosing. Repeat testing at 3 months after the initial positive result is recommended to confirm that antibodies are persistent. If persistent antibody positivity is confirmed, clinicians should discontinue natalizumab therapy.1,9 Patients developing antibodies after 6 months of initial treatment most likely have persistent antibody positivity.9





Managing Adverse Events

Short-Term Events

Two short-term adverse events associated with natalizumab are hypersensitivity reactions and infusion-related reactions. Hypersensitivity reactions are allergic reactions that usually occur within 2 hours of the start of the infusion; typical symptoms manifest as urticaria with or without systemic signs and symptoms (eg, changes in airway, breathing, circulation, and vital signs). If a patient shows any symptoms indicative of a hypersensitivity reaction, natalizumab should be discontinued.1,9





In contrast, an infusion-related reaction generally does not warrant discontinuation. An infusion-related reaction is defined as any adverse event that occurs within 2 hours of infusion1 but is not considered to be immunoglobulin E-mediated. Common infusion-reaction symptoms include headache, dizziness, fatigue, nausea, sweats, and rigors.1 These symptoms can be treated symptomatically, and patients with a history of infusion reactions can be pretreated with H1 and/or H2 blockers and/or acetaminophen.9





Progressive Multifocal Leukoencephalopathy

As discussed earlier, the most serious long-term adverse event associated with natalizumab is the development of PML. Although PML is rare, it is a very serious condition without an effective treatment.





While symptoms of PML are dependent on the location of the lesion, the 3 most common presenting symptoms associated with PML are motor weakness, visual disturbance, and altered mental status.10 Aphasias, cerebellar signs, seizures, headaches, and vertigo have also been associated with PML.11 Because PML is rare and can affect different brain areas and pathways, it is unfortunately difficult to diagnose. Generally, if a patient shows the above-listed symptoms, or if other non-MS-related symptoms appear, it is advised that natalizumab therapy be discontinued until PML can be ruled out (Figure).12 While most non-MS symptoms are unlikely related to PML, it is important to distinguish PML from relapsing MS.12





Patients at Risk for PML

As discussed, immunosuppression from any cause is associated with development of PML, and could predispose patients receiving natalizumab to the condition. Aside from this and treatment duration, there are no other known patient characteristics that make one more susceptible to PML. Since the risk of PML increases with longer duration of natalizumab treatment and is something that can be managed directly, some physicians believe that a natalizumab "holiday" may be beneficial; however, currently there are no data to indicate that a drug holiday reduces the risk of PML.





Patients With PML

If any new signs or symptoms suggestive of PML are observed, natalizumab dosing should be immediately withheld. If PML is confirmed, natalizumab should not be reinstated. Furthermore, natalizumab can be removed more quickly by plasma exchange therapy. Khatri et al13 showed that 3 sessions of plasma exchange therapy over a period of 1 week reduced plasma concentrations of natalizumab by 92%. Immune reconstitution inflammatory syndrome (IRIS) has been reported in the majority of patients using natalizumab who developed PML and subsequently discontinued natalizumab. In almost all cases, IRIS occurred after plasma exchange was used to eliminate circulating natalizumab.1





The use of antiviral agents to treat patients with PML has been investigated. To date, however, all evidence is anecdotal, and until properly performed trials have been developed, there are no available treatment options for PML.





The TOUCH Prescribing Program

At present, the most effective method to monitor for PML is clinical vigilance. To help physicians monitor for PML, a restricted distribution plan is in place for natalizumab. Natalizumab is available in the United States only through a restricted distribution program called the Tysabri Outreach: Unified Commitment to Health, or TOUCH, Prescribing Program.1 Only prescribers and patients enrolled in the TOUCH Prescribing Program can prescribe and receive natalizumab, and only pharmacies and infusion centers authorized by the TOUCH Prescribing Program can dispense and infuse natalizumab. All prescribers, pharmacists, infusion center staff, and patients must be educated about the TOUCH program and the risks associated with natalizumab therapy, including PML and other opportunistic infections.





Infusion personnel are mandated to ask patients questions regarding their health status prior to every natalizumab infusion as part of the TOUCH Prescribing Program. These questions screen for new neurologic problems, medical conditions that can weaken the immune system, and use of medicines that can weaken the immune system. Some physicians add more specific questions to the mandatory list to enhance long-term management and surveillance of health-related issues. Prescribers must (1) ensure that the patient receives the medication guide; (2) review the TOUCH Prescriber/Patient Enrollment form with the patient and answer all questions; and (3) obtain consent from the patient as part of the initial prescription process.1 Also, prescribers must (1) report any serious opportunistic and atypical infections in patients given natalizumab to Biogen Idec or Elan; (2) evaluate patients at 3 months and 6 months following the first infusion, and every 6 months thereafter; and (3) determine every 6 months whether patients should continue on treatment and, if so, reauthorize treatment every 6 months.





Patients are instructed to promptly contact their physician if they develop any new or worsening symptoms that persist over several days, particularly neurologic symptoms.14 Symptoms that may indicate PML include behavioral and neuropsychological alterations, homonymous hemianopsia, cortical blindness, hemiparesis, acute or subacute cognitive dysfunction, aphasia, seizures, ataxia, and tremor.9





To ensure implementation of the TOUCH Prescribing Program is appropriate and effective, the manufacturer regularly evaluates the effectiveness of the program and reports health outcomes data (eg, PML rate, overall safety) and systems/ process data and quality and compliance metrics to the US Food and Drug Administration.15





Conclusion

MS is a serious, debilitating disease and, as the disease progresses, treatment decisions must balance the inherent risks of the disease with the risks of more aggressive treatment. One such treatment option is natalizumab, which has shown powerful efficacy in patients with MS. However, the risk of developing PML following natalizumab therapy outweighs the benefits for some patients. Proper clinical vigilance is the best method to help reduce the risk of PML, and adherence of the TOUCH Prescribing Program can reduce the risk of serious adverse events in patients treated with natalizumab.

 

Acknowledgment: Editorial support for this manuscript was provided by James Radke.

Author Affiliation: From the Rocky Mountain Multiple Sclerosis Clinic, Salt Lake City, UT.

Funding Source: Financial support for this work, including honoraria, was provided by Biogen Idec.

Author Disclosures: Dr Foley reports advisory board membership and receipt of honoraria and lectureship fees from Biogen Idec. He has also received honoraria from Genentech and Teva.

Authorship Information: Concept and design; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; supervision; and approval of final version of manuscript.

Address correspondence to: John Foley, MD, Rocky Mountain Multiple Sclerosis Clinic, 370 E 9th Ave, Ste 106, Salt Lake City, UT 84103. E- mail: ldjfoley@gmail.com.

 

 

1. Tysabri [prescribing information]. Cambridge, MA: Biogen Idec Inc; 2009.

2. Rice GP, Hartung HP, Calabresi PA. Anti-alpha4 integrin therapy for multiple sclerosis: mechanisms and rationale. Neurology. 2005;64(8):1336-1342.

3. Polman CH, O'Connor PW, Havrdova E, et al; AFFIRM Investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):899-910.

4. Hutchinson M, Kappos L, Calabresi PA, et al. The efficacy of natalizumab in patients with relapsing multiple sclerosis: subgroup analyses of AFFIRM and SENTINEL. J Neurol. 2009;256(3):405-415.

5. Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):911-923.

6. PML incidence in patients receiving Tysabri. https://medinfo.biogenidec.com/  [registration required]. Accessed May 10, 2010.

7. Munschauer FE, Benedict RHB, Granger CV, Niewczyk PM. Introduction to best practice recommendations for the selection and management of patients with MS on natalizumab. Mult Scler. 2009;15(4 suppl):S1-S6.

8. Coyle PK, Jeffrey DR. Clinical efficacy and benefit of natalizumab. Mult Scler. 2009;15(4 suppl):S7-S15.

9. Coyle PK, Foley JF, Fox EJ, et al. Best practice recommendations for the selection and management of patients with multiple sclerosis receiving natalizumab therapy. Mult Scler. 2009;15(4 suppl):S26-S36.

10. Tornatore C, Clifford DB. Clinical vigilance for progressive multifocal leukoencephalopathy in the context of natalizumab use. Mult Scler. 2009;15(4 suppl):S16-S25.

11. Weber T. Progressive multifocal leukoencephalopathy. Neurol Clin. 2008;26(3):833-854.

12. Kappos L, Bates D, Hartung HP, et al. Natalizumab treatment for multiple sclerosis: recommendations for patient selection and monitoring. Lancet Neurol. 2007;6(5):431-441.

13. Khatri BO, Man S, Giovannoni G, et al. Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function. Neurology. 2009;72(5):402-409.

14. Tysabri (natalizumab) Medication Guide. http://www.fda.gov/downloads/Drugs/DrugSafety/UCM089809.pdf. Accessed April 23, 2010.

15. Tysabri risk minimization action plan: summary of TOUCH. http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM107197.pdf. Accessed April 23, 2010.

 

PDF
 
Copyright AJMC 2006-2018 Clinical Care Targeted Communications Group, LLC. All Rights Reserved.
x
Welcome the the new and improved AJMC.com, the premier managed market network. Tell us about yourself so that we can serve you better.
Sign Up