Natalizumab Dosage

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Usual Adult Dose for:

Additional dosage information:

Usual Adult Dose for Multiple Sclerosis

300 mg IV, infused over approximately 1 hour, every 4 weeks

Usual Adult Dose for Crohn's Disease - Maintenance

300 mg IV, infused over approximately 1 hour, every 4 weeks

If the patient with Crohn's disease (CD) has not experienced therapeutic benefit by 12 weeks of induction therapy, natalizumab should be discontinued. For patients with CD that start natalizumab while on chronic oral corticosteroids, steroid tapering should commence as soon as a therapeutic benefit of natalizumab has occurred; if the patient cannot be tapered off of oral corticosteroids within 6 months of starting natalizumab, natalizumab should be discontinued. Other than the initial 6-month taper, prescribers should consider discontinuing natalizumab for patients who require additional steroid use that exceeds 3 months in a calendar year to control their CD.

Renal Dose Adjustments

Data not available

Liver Dose Adjustments

Data not available

Precautions

Natalizumab is contraindicated in patients who have or have had progressive multifocal leukoencephalopathy (PML). PML is caused by the JC virus (JCV) and normally only occurs in immunocompromised patients.

Natalizumab increases the risk of PML, an opportunistic viral infection of the brain that usually leads to death or severe disability. The risk of developing PML increases with the number of natalizumab infusions received. PML has been reported with natalizumab in patients who were recently or concomitantly treated with immunomodulators or immunosuppressants, as well as with natalizumab monotherapy. Patients should be monitored and natalizumab should be withheld 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. If initial evaluations for PML are negative but clinical suspicion remains, natalizumab should continue to be withheld and evaluations should be repeated. There are no known interventions that can reliably prevent PML or adequately treat PML if it is observed. It is unknown if early detection of PML and natalizumab discontinuation will mitigate the disease.

Because of the risk of PML, natalizumab is available only through a special restricted distribution program called the TOUCH (R) Prescribing Program. Prescribers, infusion centers, and pharmacies associated with infusion centers registered with the program will be able to prescribe, distribute, or infuse the product. For physicians and patients, the TOUCH (R) Prescribing Program has two components: MS TOUCH (R) (for patients with multiple sclerosis) and CD TOUCH (R) (for patients with Crohn's disease). In addition, natalizumab must be administered only to patients who are enrolled in and meet all the conditions of the MS or CD TOUCH (R) Prescribing Program. The TOUCH (R) Prescribing Program may be contacted at 1-800-456-2255. The patient should be evaluated 3 months after the first infusion, 6 months after the first infusion, and every 6 months thereafter. Every 6 months, physicians should determine whether patients should continue on treatment and if so treatment should be reauthorized at that time. The Patient Status Report and Reauthorization Questionnaire should be submitted to Biogen Idec 6 months after initiating treatment with natalizumab and every 6 months thereafter.

Three factors known to increase the risk of PML in natalizumab-treated patients have been identified: longer treatment duration (especially beyond 2 years), prior immunosuppressant therapy, and the presence of anti-JCV antibodies. The risks and benefits of continuing natalizumab therapy should be carefully considered in patients who are found to be anti-JCV antibody positive and have at least one additional risk factor.

Since patients who are anti-JCV antibody positive have a higher risk for developing PML, testing for anti-JCV antibody status prior to therapy (or during therapy if antibody status is unknown) should be considered. Although JCV infection is required for the development of PML, anti-JCV antibody testing should not be used to diagnose PML. Anti-JCV antibody negative status indicates exposure to the JC virus has not been detected. Patients who test negative are still at risk for PML development due to the potential for a new JCV infection or a false negative test result; therefore, such patients should be retested periodically. A patient with a positive anti-JCV antibody test at any time should be considered anti-JCV antibody positive regardless of any prior or subsequent anti-JCV antibody testing. Anti-JCV antibody status should be determined using an analytically and clinically validated immunoassay. Anti-JCV antibody testing should not be performed during or for at least 2 weeks following plasma exchange due to the removal of antibodies from the serum.

In general, patients receiving chronic immunosuppressant or immunomodulatory therapy, or who have systemic medical conditions resulting in significantly compromised immune system function should not be treated with natalizumab.

In multiple sclerosis patients, an MRI scan should be obtained prior to initiating natalizumab. The MRI may be helpful in differentiating subsequent multiple sclerosis symptoms from PML. In Crohn's disease patients, a baseline brain MRI may also be helpful to distinguish preexistent lesions from newly formed lesions, but brain lesions at baseline that could cause diagnostic difficulty while on natalizumab are uncommon. Patients on natalizumab should be monitored for any sign or symptom suggestive of PML. Natalizumab should be withheld at once at the first sign or symptom suggestive of PML.

Immune reconstitution inflammatory syndrome (IRIS) has been reported in the majority of patients who discontinued natalizumab as a result of developing PML, but not in patients who discontinued natalizumab for other reasons. In most cases, IRIS occurred within days to several weeks after plasma exchange was used to remove circulating natalizumab. It presents as a clinical decline in the patient's condition after natalizumab removal (and in some cases after apparent clinical improvement) that may be rapid, can lead to serious neurological complications or death, and is often associated with characteristic changes in the MRI. Monitoring for IRIS development and appropriate treatment of associated inflammation are recommended.

The immune system effects of natalizumab may increase the risk of infections. Similarly, concurrent use of antineoplastic, immunosuppressant, or immunomodulating agents may further increase the risk of infections, including PML and other opportunistic infections, over the risk observed with the use of natalizumab alone. The safety and efficacy of natalizumab therapy in combination with antineoplastic, immunosuppressant, or immunomodulating agents have not been established. Patients receiving chronic immunosuppressant or immunomodulatory therapy or who have systemic medical conditions resulting in significantly compromised immune system function should not ordinarily be treated with natalizumab. The risk of PML is also increased in patients who were treated with an immunosuppressant prior to natalizumab. For patients with Crohn's disease who start natalizumab therapy while on chronic corticosteroids, steroid withdrawal should be commenced as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within six months, natalizumab should be discontinued.

Hypersensitivity reactions, including serious systemic reactions, (e.g., anaphylaxis) have been reported. These reactions are associated with antibodies to natalizumab and usually occur within 2 hours of the start of the infusion. Patients should be instructed to report immediately to their physicians any signs or symptoms consistent with a hypersensitivity reaction during or following an intravenous infusion of natalizumab. Patient should be closely monitored during the infusion and for 1 hour after the infusion is complete. If a hypersensitivity reaction is seen, administration of natalizumab should be discontinued and appropriate therapy initiated. Patients who experience a hypersensitivity reaction should not be retreated with natalizumab therapy. Hypersensitivity reactions were more frequent in patients with antibodies to natalizumab compared to patients who did not develop antibodies to natalizumab in both MS and CD trials. Therefore, the possibility of antibodies to natalizumab therapy should be considered in patients who have hypersensitivity reactions. If the presence of persistent antibodies is suspected, antibody testing should be conducted. Antibodies may be detected and confirmed with sequential serum antibody tests. Antibodies detected early in the course of therapy (e.g., within the first 6 months) may be transient and disappear with continued dosing. Testing should be repeated at 3 months after the initial positive result is recommended in patients in whom antibodies are detected to confirm that antibodies are persistent. Physicians should consider the overall benefits and risks of natalizumab in a patient with persistent antibodies. Experience with monoclonal antibodies, including natalizumab, suggests that patients who receive therapeutic monoclonal antibodies after an extended period without therapy may be at higher risk of hypersensitivity reactions than patients who received regularly scheduled therapy. Given that patients with persistent antibodies to natalizumab experience reduced efficacy, and that hypersensitivity reactions are more common in such patients, consideration should be given to testing for the presence of antibodies in patients who wish to recommence treatment following a dose interruption. Following a period of dose interruption, patients testing negative for antibodies prior to re-dosing have a risk of antibody formation.

Clinically significant liver injury has been observed in patients treated with natalizumab during postmarketing experience. Signs of liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, occurred early as six days after the first dose; signs of liver injury recurred upon rechallenge, providing evidence that natalizumab caused the effect. The combination of transaminase elevations and elevated bilirubin without evidence of obstruction is generally recognized as an important predictor of severe liver injury that may lead to death or the need for a liver transplant in some individuals. Natalizumab therapy should be discontinued in patients with jaundice or other evidence of significant liver injury (e.g., laboratory evidence).

Natalizumab therapy induces increases in circulating lymphocytes, monocytes, eosinophils, basophils, and nucleated red blood cells. Observed changes persist during natalizumab exposure, but are reversible, returning to baseline levels usually within 16 weeks after the last administration. Elevations of neutrophils have not been reported. Natalizumab therapy induces mild decreases in hemoglobin levels that are frequently transient.

There are no data on the effects of vaccinations or secondary transmission of infection by live vaccines in patients receiving natalizumab.

The safety and efficacy have not been established in pediatric patients (less than 18 years of age).

Dialysis

Data not available

Other Comments

The US FDA requires a Risk Evaluation and Mitigation Strategy (REMS) for natalizumab. It includes a Medication Guide, elements to assure safe use, and an implementation system. Additional information is available at www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm.

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