The most frequently reported serious adverse events in Study 1 (see CLINICAL STUDIES) with TYSABRI^Ò were infections (3.2% versus 2.6% in placebo, including urinary tract infection [0.8% versus 0.3%] and pneumonia [0.6% versus 0%]), acute hypersensitivity reactions (1.1% versus 0.3%, including anaphylaxis/anaphylactoid reaction [0.8% versus 0%]), depression (1.0% versus 1.0%, including suicidal ideation or attempt [0.6% versus 0.3%]), and cholelithiasis (1.0% versus 0.3%). In Study 2, serious adverse events of appendicitis were also more common in patients who received TYSABRI^Ò (0.8% versus 0.2% in placebo) (see WARNINGS, Hypersensitivity and ADVERSE REACTIONS, Infections).

The most frequently reported adverse reactions resulting in clinical intervention (i.e., discontinuation of TYSABRI^Ò), were urticaria (1%) and other hypersensitivity reactions (1%) (see WARNINGS, Hypersensitivity).

Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of TYSABRI^Ò cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice. The adverse reaction information does, however, provide a basis for identifying the adverse events that appear to be related to drug use and a basis for approximating rates.

A total of 1617 multiple sclerosis patients in controlled studies received TYSABRI^Ò, with a median duration of exposure of 28 months.

Table 3 enumerates adverse events and selected laboratory abnormalities that occurred in Study 1 at an incidence of at least 1 percentage point higher in TYSABRI^Ò-treated patients than was observed in placebo-treated patients.

In Study 2, peripheral edema was more common in patients who received TYSABRI^Ò (5% versus 1% in placebo).

Progressive Multifocal Leukoencephalopathy (PML) has occurred in 3 patients who received TYSABRI^Ò in clinical trials (see BOXED WARNING and WARNINGS, Progressive Multifocal Leukoencephalopathy). Two cases of PML were observed in the 1869 patients with multiple sclerosis who were treated for a median of 120 weeks. These 2 patients had received TYSABRI in addition to interferon beta-1a (see BOXED WARNING and WARNINGS, Progressive Multifocal Leukoencephalopathy). The third case occurred after 8 doses in one of the 1043 patients with Crohns disease who were evaluated for PML.

In Studies 1 and 2, the rate of any type of infection was approximately 1.5 per patient-year in bothTYSABRI ^Ò-treated patients and placebo-treated patients. The infections were predominately upper respiratory tract infections, influenza, and urinary tract infections.

In Study 1, the incidence of serious infection was approximately 3% in TYSABRI^Ò-treated patients and placebo-treated patients. Most patients did not interrupt treatment with TYSABRI^Ò during infections.

The only opportunistic infection in the multiple sclerosis clinical trials was a case of cryptosporidial gastroenteritis with a prolonged course.

In clinical studies for indications other than multiple sclerosis, opportunistic infections (e.g., pneumocystis carinii pneumonia, pulmonary mycobacterium avium intracellulare, bronchopulmonary aspergillosis, and burkholderia cepacia) have been uncommonly observed in TYSABRI^Ò-treated patients; some of these patients were receiving concurrent immunosuppressants (see WARNINGS, Immunosuppression). Two serious non-bacterial meningitides occurred in TYSABRI^Ò-treated patients compared to none in placebo-treated patients.

In post-marketing experience, one patient who received TYSABRI^Ò developed herpes encephalitis and died; a second patient developed herpes meningitis and recovered with appropriate treatment.

An infusion-related reaction was defined in clinical trials as any adverse event occurring within 2 hours of the start of an infusion. Approximately 24% of TYSABRI^Ò-treated multiple sclerosis patients experienced an infusion-related reaction, compared to 18% of placebo-treated patients. Events more common in the TYSABRI^Ò-treated patients included headache, dizziness, fatigue, urticaria, pruritus, and rigors. Acute urticaria was observed in approximately 2% of patients. Other hypersensitivity reactions were observed in 1% of patients receiving TYSABRI^Ò. Serious systemic hypersensitivity infusion reactions occurred in <1% of patients. All patients recovered with treatment and/or discontinuation of the infusion.

Patients who became persistently positive for antibodies to TYSABRI^Ò were more likely to have an infusion-related reaction than those who were antibody-negative (see ADVERSE REACTIONS, Immunogenicity).

Patients in Study 1 were tested for antibodies to natalizumab every 12 weeks. The assays used were unable to detect low to moderate levels of antibodies to natalizumab. Approximately 9% of patients receiving TYSABRI^Ò developed detectable antibodies at least once during treatment. Approximately 6% of patients had positive antibodies on more than one occasion. Approximately 82% of patients who became persistently antibody-positive developed detectable antibodies by 12 weeks. Anti-natalizumab antibodies were neutralizing in vitro.

The presence of anti-natalizumab antibodies was correlated with a reduction in serum natalizumab levels. In Study 1, the Week 12 pre-infusion mean natalizumab serum concentration in antibody-negative patients was 14.9 mcg/mL compared to 1.3 mcg/mL in antibody-positive patients. Persistent antibody-positivity was associated with a substantial decrease in the effectiveness of TYSABRI^Ò. The risk of increased disability and the annualized relapse rate were similar in persistently antibody-positive TYSABRI^Ò-treated patients and patients who received placebo. A similar phenomenon was also observed in Study 2.

Infusion-related reactions most often associated with persistent antibody-positivity included urticaria, rigors, nausea, vomiting, headache, flushing, dizziness, pruritus, tremor, feeling cold, and pyrexia. Additional adverse events more common in persistently antibody-positive patients included myalgia, hypertension, dyspnea, anxiety, and tachycardia.

If the presence of persistent antibodies is suspected, antibody testing should be performed. Antibodies may be detected and confirmed with sequential serum antibody tests. Antibodies detected early in the treatment course (e.g., within the first 6 months) may be transient and disappear with continued dosing. Repeat testing at 3 months after the initial positive result is recommended in patients in whom antibodies are detected to confirm that antibodies are persistent. Prescribers should consider the overall benefits and risks of TYSABRI^Ò in a patient with persistent antibodies.

The long-term immunogenicity of TYSABRI^Ò and the effects of low to moderate levels of antibody to natalizumab are unknown. Experience with other monoclonal antibodies suggests that patients who receive therapeutic antibodies after an extended period without treatment may be at higher risk of hypersensitivity reactions than patients who received regularly scheduled treatment. It is not known if this will occur with TYSABRI^Ò(see WARNINGS, Hypersensitivity and ADVERSE REACTIONS, Infusion-related Reactions) .

Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody-positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to TYSABRI^Ò with the incidence of antibodies to other products may be misleading.

See BOXED WARNING and WARNINGS, Immunosuppression.

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