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CONTRAINDICATIONS
• Patients who have or have had PML
• Patients who have had a hypersensitivity reaction to natalizumab products or any of the ingredients in TYRUKO
WARNINGS AND PRECAUTIONS
Progressive Multifocal Leukoencephalopathy (PML)
• Infection by the JC Virus (JCV) is required for the development of PML
• 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 test result should be retested periodically
• There are no known interventions that can reliably prevent PML or that can adequately treat PML if it occurs
• Postmarketing data suggest that the risk of developing PML may be associated with relative levels of serum anti-JCV antibody compared to a calibrator as measured by ELISA (often described as an anti-JCV antibody index value)
• MRI findings may be apparent before clinical signs or symptoms suggestive of PML. Monitoring with MRI for signs that may be consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present. Consider monitoring patients at high risk for PML more frequently. Lower PML-related mortality and morbidity have been reported following natalizumab products discontinuation in patients with PML who were initially asymptomatic compared to patients with PML who had characteristic clinical signs and symptoms at diagnosis
• PML has been reported after discontinuation of natalizumab products in patients who did not have findings suggestive of PML at the time of discontinuation. Patients should continue to be monitored for any new signs or symptoms that may be suggestive of PML for at least 6 months after discontinuation of TYRUKO
• Adverse events that may occur during plasma exchange (PLEX) include clearance of other medications and volume shifts, which have the potential to lead to hypotension or pulmonary edema. Although PLEX has not been prospectively studied in natalizumab-treated patients with PML, it has been used in such patients in the postmarketing setting to remove natalizumab more quickly from the circulation. There is no evidence that PLEX has any benefit in the treatment of opportunistic infections such as PML
• JCV infection of granule cell neurons in the cerebellum, i.e., JCV granule cell neuronopathy (GCN), with symptoms similar to PML, has been reported in patients treated with natalizumab products. JCV GCN can occur with or without concomitant PML and can cause cerebellar dysfunction. Diagnosis and management of JCV GCN should follow guidance provided for PML
• Immune reconstitution inflammatory syndrome (IRIS) has been reported in the majority of natalizumab product-treated patients who developed PML and subsequently discontinued natalizumab products. In almost all cases, IRIS occurred after PLEX was used to eliminate circulating natalizumab products. It presents as a clinical decline in the patient’s condition after natalizumab product 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. Natalizumab products have not been associated with IRIS in patients discontinuing treatment with natalizumab products for reasons unrelated to PML. In natalizumab product-treated patients with PML, IRIS has been reported within days to several weeks after PLEX. Monitoring for development of IRIS and appropriate treatment of the associated inflammation should be undertaken
TYRUKO REMS Program
• Because of the risk of PML, TYRUKO is available only through a restricted distribution program under a REMS called the TYRUKO REMS Program
• Patients must be enrolled in the TYRUKO REMS Program, read the Medication Guide, understand the risks associated with TYRUKO, and complete and sign the Patient Enrollment Form for each patient
Herpes Infections – Encephalitis, Meningitis, and Acute Retinal Necrosis (ARN)
• Natalizumab products increase the risk of developing encephalitis and meningitis caused by herpes simplex and varicella zoster viruses
• Serious, life-threatening, and sometimes fatal cases have been reported in the postmarketing setting in multiple sclerosis patients receiving natalizumab products
• The duration of treatment with natalizumab products prior to onset ranged from a few months to several years
• Monitor patients receiving TYRUKO for signs and symptoms of meningitis and encephalitis. If herpes encephalitis or meningitis occurs, TYRUKO should be discontinued, and appropriate treatment for herpes encephalitis/meningitis should be administered
• Patients being administered natalizumab products are at a higher risk of ARN, a fulminant viral infection of the retina caused by the family of herpes viruses. Patients with eye symptoms such as decreased visual acuity, redness, or eye pain should be referred for retinal screening as serious cases of ARN can lead to blindness of 1 or both eyes
• Following clinical diagnosis of ARN, consider discontinuation of TYRUKO
Hepatotoxicity
• Clinically significant liver injury, including acute liver failure requiring transplant, has been reported in patients treated with natalizumab products in the postmarketing setting
• Signs of liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, occurred as early as 6 days after the first dose; signs of liver injury have also been reported for the first time after multiple doses
• TYRUKO should be discontinued in patients with jaundice or other evidence of significant liver injury (e.g., laboratory evidence)
Hypersensitivity/Antibody Formation
• Hypersensitivity reactions have occurred in patients receiving natalizumab products, including serious systemic reactions (e.g., anaphylaxis) which occurred at an incidence of <1%
• Reactions usually occur within 2 hours of the start of the infusion. Symptoms associated with these reactions can include urticaria, dizziness, fever, rash, rigors, pruritus, nausea, flushing, hypotension, dyspnea, and chest pain
• If a hypersensitivity reaction occurs, discontinue administration of TYRUKO and initiate appropriate therapy. Patients who experience a hypersensitivity reaction should not be re-treated with TYRUKO
• Hypersensitivity reactions were more frequent in patients with antibodies to natalizumab compared with patients who did not develop antibodies to natalizumab in both MS and Crohn’s disease (CD) studies
• Patients who receive natalizumab products for a short exposure (1 to 2 infusions) followed by an extended period without treatment are at higher risk of developing anti-drug antibodies and/or hypersensitivity reactions on re-exposure, compared to patients who received regularly scheduled treatment
Immunosuppression/Infections
• The immune system effects of natalizumab products may increase the risk for infections
• Concurrent use of antineoplastic, immunosuppressant, or immunomodulating agents may further increase the risk of infections over the risk observed with use of natalizumab alone
• In Study MS1, certain types of infections—including pneumonias and urinary tract infections (including serious cases), gastroenteritis, vaginal infections, tooth infections, tonsillitis, and herpes infections—occurred more often in natalizumab-treated patients than in placebo-treated patients. One opportunistic infection, a cryptosporidial gastroenteritis with a prolonged course, was observed in a patient who received natalizumab in Study MS1
• In Studies MS1 and MS2, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in natalizumab-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids
• In a long-term safety study of patients, opportunistic infections (pulmonary mycobacterium avium intracellulare, aspergilloma, cryptococcal fungemia and meningitis, and Candida pneumonia) have been observed in <1% of natalizumab-treated patients
Laboratory Test Abnormalities
• In clinical trials, natalizumab was observed to induce increases in circulating lymphocytes, monocytes, eosinophils, basophils, and nucleated red blood cells. Observed changes persisted during natalizumab exposure, but were reversible, returning to baseline levels usually within 16 weeks after the last dose. Elevations of neutrophils were not observed. Natalizumab induces mild decreases in hemoglobin levels (mean decrease of 0.6 g/dL) that are frequently transient
Thrombocytopenia
• Cases of thrombocytopenia, including immune thrombocytopenic purpura (ITP), have been reported with the use of natalizumab products in the postmarketing setting. Symptoms of thrombocytopenia may include easy bruising, abnormal bleeding, and petechiae. Delay in the diagnosis and treatment of thrombocytopenia may lead to serious and life-threatening sequelae. If thrombocytopenia is suspected, TYRUKO should be discontinued
• Cases of neonatal thrombocytopenia, at times associated with anemia, have been reported in newborns with in utero exposure to natalizumab products. A complete blood count (CBC) should be obtained in neonates with in utero exposure to TYRUKO
ADVERSE REACTIONS
The most common adverse reactions reported at an incidence of ≥10% with natalizumab and ≥2% difference with placebo were headache (38% vs 33%), fatigue (27% vs 21%), infusion reactions (24% vs 18%), urinary tract infections (21% vs 17%), arthralgia (19% vs 14%), depression (19% vs 16%), pain in extremity (16% vs 14%), rash (12% vs 9%), gastroenteritis (11% vs 9%), and vaginitis (10% vs 6%)
The most frequently reported serious adverse reactions in Study MS1 were infections (3.2% vs 2.6% in placebo, including urinary tract infection [0.8% vs 0.3%] and pneumonia [0.6% vs 0%]), acute hypersensitivity reactions (1.1% vs 0.3%, including anaphylaxis/anaphylactoid reaction [0.8% vs 0%]), depression (1.0% vs 1.0%, including suicidal ideation or attempt [0.6% vs 0.3%]), and cholelithiasis (1.0% vs 0.3%). In Study MS2, serious adverse reactions of appendicitis were also more common in patients who received natalizumab (0.8% vs 0.2% in placebo)
USE IN SPECIFIC POPULATIONS
Based on animal data, natalizumab may cause fetal harm. TYRUKO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus
Please see full Prescribing Information.
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