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Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Approximately 1500 patients with RMS received BONSPRI in clinical studies. In Study 1 and Study 2, 1882 patients with RMS were randomized, 946 of whom were treated with BONSPRI for a median duration of 85 weeks; 33% of patients receiving BONSPRI were treated for up to 120 weeks [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. The most common adverse reactions occurring in greater than 10% of patients treated with BONSPRI and more frequently than in patients treated with teriflunomide were upper respiratory tract infections, injection-related reactions (systemic), headache, and injection- site reactions (local). The most common cause of discontinuation in patients treated with BONSPRI was low immunoglobulin M (3.3%), defined in trial protocols as IgM at 10% below the lower limit of normal (LLN).
Table 2 summarizes the adverse drug reactions that occurred in Study 1 and Study 2. (See Table 2.)
Click on icon to see table/diagram/imageInjection-Related Reactions and Injection-Site Reactions: The incidence of injection-related reactions (systemic) was highest with the first injection (14.4%), decreasing with subsequent injections (4.4% with second, less than 3% with third injection). Injection-related reactions were mostly (99.8%) mild to moderate in severity. Two (0.2%) patients treated with BONSPRI reported serious injection-related reactions. There were no life-threatening injection-related reactions. Most frequently reported symptoms (2% or greater) included fever, headache, myalgia, chills, and fatigue.
In addition to systemic injection-related reactions, local reactions at the administration site were very common. Local injection-site reactions were all mild to moderate in severity. The most frequently reported symptoms (2% or greater) included erythema, pain, itching, and swelling [see Injection-Related Reactions under Precautions].
Laboratory Abnormalities: Immunoglobulins: In Study 1 and Study 2, a decrease in the mean level of IgM was observed in BONSPRI-treated patients but was not associated with an increased risk of infections [see Reduction in Immunoglobulins under Precautions]. In 14.3% of patients in Study 1 and Study 2, treatment with BONSPRI resulted in a decrease in a serum IgM that reached a value below 0.34 g/dL. BONSPRI was associated with a decrease of 4.3% in mean IgG levels after 48 weeks of treatment and an increase of 2.2% after 96 weeks.
Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay.
Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medication, and the underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described as follows with the incidence of antibodies in other studies or to other ofatumumab products may be misleading.
Treatment induced anti-drug antibodies (ADAs) were detected in 2 of 914 (0.2%) BONSPRI-treated patients; no patients with treatment enhancing or neutralizing ADAs were identified.
There was no impact of positive ADA titers on PK, safety profile or B-cell kinetics in any patient; however, these data are not adequate to assess the impact of ADAs on the safety and efficacy of BONSPRI.
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