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TYSABRI (natalizumab) injection
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use TYSABRI safely and effectively. See full prescribing information for TYSABRI.
TYSABRI (natalizumab) injection, for intravenous use
Initial U.S. Approval: 2004
WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY
See full prescribing information for complete boxed warning
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TYSABRI increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability (5.1)
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Monitor patients, and withhold TYSABRI immediately at the first sign or symptom suggestive of PML (4, 5.1)
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TYSABRI is available only through a special restricted distribution program called the TOUCH® Prescribing Program and must be administered only to patients enrolled in this program (5.1, 5.2)
RECENT MAJOR CHANGES
Warnings and Precautions
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Progressive Multifocal Leukoencephalopathy ( 5.1) 12/2012
INDICATIONS AND USAGE
TYSABRI is an integrin receptor antagonist indicated for treatment of:
Multiple Sclerosis (MS) (1.1)
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As monotherapy for the treatment of patients with relapsing forms of multiple sclerosis to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations. TYSABRI is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate MS therapy.
Crohn's Disease (CD) (1.2)
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Inducing and maintaining clinical response and remission 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 CD therapies and inhibitors of TNF-α.
Important Limitations:
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In CD, TYSABRI should not be used in combination with immunosuppressants or inhibitors of TNF-α.
DOSAGE AND ADMINISTRATION
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300 mg infused intravenously over approximately one hour, every four weeks. Do not give as an intravenous push or bolus (2.1, 2.2).
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TYSABRI solution must be administered within 8 hours of preparation (2.3).
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Observe patients during the infusion and for one hour after the infusion is complete (2.4).
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In CD, discontinue in patients that have not experienced therapeutic benefit by 12 weeks of induction therapy, and in patients that cannot discontinue chronic concomitant steroids within six months of starting therapy (2.2).
DOSAGE FORMS AND STRENGTHS
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Solution [300 mg per 15 mL vial] for dilution prior to infusion (3).
CONTRAINDICATIONS
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Patients who have or have had PML (4).
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Patients who have had a hypersensitivity reaction to TYSABRI (4).
WARNINGS AND PRECAUTIONS
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Progressive Multifocal Leukoencephalopathy (PML): Has occurred in patients who received TYSABRI. Patients who have significantly compromised immune system function should not ordinarily be treated with TYSABRI. Obtain an MRI scan in MS patients prior to initiating TYSABRI. Monitor MS and CD patients and withhold TYSABRI at the first sign or symptom suggestive of PML. Treatment duration, prior immunosuppressant use, and presence of anti-JC virus antibodies are associated with increased risk of PML in TYSABRI-treated patients (5.1).
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Hypersensitivity reactions: Serious hypersensitivity reactions (e.g., anaphylaxis) have occurred. Permanently discontinue TYSABRI if such a reaction occurs (5.3).
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Immunosuppression/Infections: TYSABRI may increase the risk for certain infections. Monitor patients for development of infections due to increased risk with use of TYSABRI (5.4).
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Hepatotoxicity: Clinically significant liver injury has occurred. Discontinue TYSABRI in patients with jaundice or evidence of liver injury (5.5).
ADVERSE REACTIONS
The most common adverse reactions (incidence ≥ 10%) in MS were headache, fatigue, arthralgia, urinary tract infection, lower respiratory tract infection, gastroenteritis, vaginitis, depression, pain in extremity, abdominal discomfort, diarrhea NOS, and rash; and in CD were headache, upper respiratory tract infections, nausea, and fatigue (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Biogen Idec or Elan at 1-800-456-2255 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
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Pregnancy: Based on animal data, may cause fetal harm. (8.1)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 1/2012
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 Multiple Sclerosis (MS)
TYSABRI is indicated as monotherapy for the treatment of patients with relapsing forms of multiple sclerosis to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations. The efficacy of TYSABRI beyond two years is unknown.
Because TYSABRI increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability, TYSABRI is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate multiple sclerosis therapy [see Boxed Warning, Warnings and Precautions (5.1)].
Safety and efficacy in patients with chronic progressive multiple sclerosis have not been studied.
1.2 Crohn's Disease (CD)
TYSABRI is indicated for inducing and maintaining clinical response and remission 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 CD therapies and inhibitors of TNF-α. TYSABRI should not be used in combination with immunosuppressants (e.g., 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate) or inhibitors of TNF-α [see Boxed Warning, Warnings and Precautions (5.1)].
2 DOSAGE AND ADMINISTRATION
2.1 Multiple Sclerosis (MS)
Only prescribers registered in the MS TOUCH® Prescribing Program may prescribe TYSABRI for multiple sclerosis [see Boxed Warning, Warnings and Precautions (5.2)]. The recommended dose of TYSABRI for multiple sclerosis is 300 mg intravenous infusion over one hour every four weeks.
2.2 Crohn's Disease (CD)
Only prescribers registered in the CD TOUCH® Prescribing Program may prescribe TYSABRI for Crohn's disease [see Boxed Warning, Warnings and Precautions (5.1)].
The recommended dose of TYSABRI for Crohn's disease is 300 mg intravenous infusion over one hour every four weeks. TYSABRI should not be used with concomitant immunosuppressants (e.g., 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate) or concomitant inhibitors of TNF-α. Aminosalicylates may be continued during treatment with TYSABRI.
If the patient with Crohn's disease has not experienced therapeutic benefit by 12 weeks of induction therapy, discontinue TYSABRI. For patients with Crohn's disease that start TYSABRI while on chronic oral corticosteroids, commence steroid tapering as soon as a therapeutic benefit of TYSABRI has occurred; if the patient with Crohn's disease cannot be tapered off of oral corticosteroids within six months of starting TYSABRI, discontinue TYSABRI. Other than the initial six-month taper, prescribers should consider discontinuing TYSABRI for patients who require additional steroid use that exceeds three months in a calendar year to control their Crohn's disease.
2.3 Dilution Instructions
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Use aseptic technique when preparing TYSABRI solution for intravenous infusion. Each vial is intended for single use only.
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TYSABRI is a colorless, clear to slightly opalescent concentrate. Inspect the TYSABRI vial for particulate material and discoloration prior to dilution and administration. If visible particulates are observed and/or the liquid in the vial is discolored, the vial must not be used.
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To prepare the solution, withdraw 15 mL of TYSABRI concentrate from the vial using a sterile needle and syringe. Inject the concentrate into 100 mL 0.9% Sodium Chloride Injection, USP. No other IV diluents may be used to prepare the TYSABRI solution.
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Gently invert the TYSABRI solution to mix completely. Do not shake. Inspect the solution visually for particulate material prior to administration.
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The final dosage solution has a concentration of 2.6 mg/mL.
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Following dilution, infuse TYSABRI solution immediately, or refrigerate solution at 2 to 8°C, and use within 8 hours. If stored at 2 to 8°C, allow the solution to warm to room temperature prior to infusion. DO NOT FREEZE.
2.4 Administration Instructions
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Infuse TYSABRI 300 mg in 100 mL 0.9% Sodium Chloride Injection, USP, over approximately one hour (infusion rate approximately 5 mg per minute). Do not administer TYSABRI as an intravenous push or bolus injection. After the infusion is complete, flush with 0.9% Sodium Chloride Injection, USP.
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Observe patients during the infusion and for one hour after the infusion is complete. Promptly discontinue the infusion upon the first observation of any signs or symptoms consistent with a hypersensitivity-type reaction [see Warnings and Precautions (5.3)].
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Use of filtration devices during administration has not been eva luated. Other medications should not be injected into infusion set side ports or mixed with TYSABRI.
3 DOSAGE FORMS AND STRENGTHS
TYSABRI is a concentrated solution that must be diluted prior to intravenous infusion. TYSABRI injection is supplied as 300 mg natalizumab in 15 mL (20 mg/mL) in a sterile, single-use vial free of preservatives.
4 CONTRAINDICATIONS
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TYSABRI is contraindicated in patients who have or have had progressive multifocal leukoencephalopathy (PML) [see Boxed Warning, Warnings and Precautions (5.1)].
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TYSABRI should not be administered to a patient who has had a hypersensitivity reaction to TYSABRI. Observed reactions range from urticaria to anaphylaxis [see Warnings and Precautions (5.3)].
5 WARNINGS AND PRECAUTIONS
5.1 Progressive Multifocal Leukoencephalopathy (PML)
Progressive multifocal leukoencephalopathy, an opportunistic infection caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, developed in three patients who received TYSABRI in clinical trials [see Boxed Warning]. Two cases of PML were observed among 1869 patients with multiple sclerosis treated for a median of 120 weeks. The third case occurred among 1043 patients with Crohn's disease after the patient received eight doses. Both multiple sclerosis patients were receiving concomitant immunomodulatory therapy and the Crohn's disease patient had been treated in the past with immunosuppressive therapy.
In the postmarketing setting, additional cases of PML have been reported in multiple sclerosis and Crohn's disease patients who were receiving no concomitant immunomodulatory therapy. Three factors that are known to increase the risk of PML in TYSABRI-treated patients have been identified:
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Longer treatment duration, especially beyond 2 years. There is limited experience in patients who have received more than 4 years of TYSABRI treatment.
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Prior treatment with an immunosuppressant (e.g., mitoxantrone, azathioprine, methotrexate, cyclophosphamide, mycophenolate mofetil).
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The presence of anti-JCV antibodies. Patients who are anti-JCV antibody positive have a higher risk for developing PML.
The risks and benefits of continuing treatment with Tysabri should be carefully considered in patients who are found to be anti-JCV antibody positive and have one or more additional risk factors. Patients with all three known risk factors have an estimated risk of PML of 11/1,000.
Consideration should be given to testing patients for anti-JCV antibody status prior to treatment or during treatment if antibody status is unknown. Infection by the JC virus is required for the development of PML. Anti-JCV antibody negative status indicates that exposure to the JC virus has not been detected. Patients who are anti-JCV antibody negative are still at risk for the development of PML due to the potential for a new JCV infection or a false negative test result. Therefore, patients with a negative anti-JCV antibody test result should be retested every 6 months. For purposes of risk assessment, a patient with a positive anti-JCV antibody test at any time is considered anti-JCV antibody positive regardless of the results of any prior or subsequent anti-JCV antibody testing. When assessed, anti-JCV antibody status should be determined using an analytically and clinically validated immunoassay.
Anti-JCV antibody testing should not be used to diagnose PML. Anti-JCV antibody testing should not be performed for at least two weeks following plasma exchange due to the removal of antibodies from the serum.
There are no known interventions that can reliably prevent PML or adequately treat PML if it occurs. It is not known whether early detection of PML and discontinuation of TYSABRI will mitigate the disease.
Ordinarily, 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 TYSABRI.
Because of the risk of PML, TYSABRI is available only under a special restricted distribution program, the TOUCH® Prescribing Program.
In multiple sclerosis patients, an MRI scan should be obtained prior to initiating therapy with TYSABRI. This 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 pre-existent lesions from newly developed lesions, but brain lesions at baseline that could cause diagnostic difficulty while on TYSABRI therapy are uncommon.
Healthcare professionals should monitor patients on TYSABRI for any new sign or symptom suggestive of PML. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. The progression of deficits usually leads to death or severe disability over weeks or months. Withhold TYSABRI dosing immediately at the first sign or symptom suggestive of PML.
For diagnosis of PML, an eva luation including a gadolinium-enhanced MRI scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA are recommended. If the initial eva luations for PML are negative but clinical suspicion for PML remains, continue to withhold TYSABRI dosing and repeat the eva luations.
There are no known interventions that can adequately treat PML if it occurs. Three sessions of plasma exchange over 5 to 8 days were shown to accelerate TYSABRI clearance in a study of 12 patients with MS who did not have PML, although in the majority of patients alpha-4 integrin receptor binding remained high. Adverse events which may occur during plasma exchange include clearance of other medications and volume shifts, which have the potential to lead to hypotension or pulmonary edema. Although plasma exchange has not been studied in TYSABRI treated patients with PML, it has been used in such patients in the postmarketing setting to remove TYSABRI more quickly from the circulation. Anti-JCV antibody testing should not be performed during or for at least two weeks following plasma exchange due to the removal of antibodies from the serum.
Immune reconstitution inflammatory syndrome (IRIS) has been rep |
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