6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction 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 practice.
Clinical Trials of ELELYSO as Initial Therapy
- Clinical Trial in Patients 19 Years and Older
The safety of ELELYSO at dosages of either 30 units/kg (n=16) or 60 units/kg (n=16) every other week was assessed in 32 adult treatment-naïve patients (aged 19 to 74 years) with Type 1 Gaucher disease in a 9-month double-blind, randomized clinical trial.
|Preferred Term||Treatment-Naïve Adults (N=32)|
|Abdominal pain||2 (6)|
- Clinical Trial in Patients 16 Years and Younger
The safety of ELELYSO at dosages of either 30 units/kg (n=4) or 60 units/kg (n=5) every other week was assessed in 9 pediatric treatment-naïve patients (aged 2 to 13 years) with Type 1 Gaucher disease in a 12-month randomized clinical trial.
The most common adverse reaction (≥10%) was vomiting, which occurred in 4 of 9 patients. Two patients developed hypersensitivity reactions; one patient experienced severe vomiting and gastrointestinal inflammation, and 1 experienced mild throat irritation and chest discomfort. Both patients responded to treatment with antihistamines and continued ELELYSO treatment.
Clinical Trial in Patients Switching from Imiglucerase Treatment to ELELYSO
The safety of ELELYSO was assessed in 31 patients (26 adult and 5 pediatric patients), ages 6 to 66 years old, with Type 1 Gaucher disease who had previously been receiving treatment with imiglucerase for a minimum of 2 years. ELELYSO was administered for 9 months at the same number of units as each patient's previous imiglucerase dose.
|Preferred Term||Patients Switched from Imiglucerase|
(N=31; 26 adults and 5 children)
|Pain in extremity||3 (10)|
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 medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other taliglucerase alfa products may be misleading.
Anti-Drug Antibodies (ADA)
In a clinical trial of treatment-naïve adults, 17 (53%) of 32 patients developed ADA during treatment with ELELYSO, and 2 (6%) of 32 patients tested positive for ADA at baseline prior to ELELYSO treatment. Of the 17 patients who developed ADA during ELELYSO treatment, 6 patients (35%) developed hypersensitivity reactions, 2 of whom met criteria for anaphylaxis. Two of the 17 patients who developed ADA during ELELYSO treatment discontinued treatment due to hypersensitivity reactions, one of whom had met criteria for anaphylaxis. Of the 2 patients who tested positive for ADA prior to initiation of ELELYSO treatment, one patient developed a hypersensitivity reaction during the first dose of ELELYSO and withdrew from the study. The second patient did not experience a hypersensitivity reaction.
In a clinical trial of treatment-naïve pediatric patients, 2 (22%) of 9 patients developed ADA during treatment with ELELYSO, and one of 9 patients was ADA-positive prior to initiation of ELELYSO. Two of these 3 patients experienced hypersensitivity reactions (1 who developed ADA during treatment and became negative after Week 12 and 1 who was ADA-positive at baseline and became ADA negative after Week 8) and continued treatment with ELELYSO. The third patient who developed ADA during treatment and continued to be ADA-positive until study completion at Week 52 did not experience a hypersensitivity reaction.
In clinical trials of 31 patients (26 adult and 5 pediatric patients) who switched from imiglucerase to ELELYSO treatment, 5 adults (16% of patients) developed ADA during treatment with ELELYSO. Four additional patients (13%, 2 adults and 2 children) tested positive for ADA at baseline but became ADA-negative after the switch to ELELYSO; one of these adult patients subsequently developed ADA to ELELYSO. Two adult patients (1 patient who developed ADA after the switch and 1 who was ADA positive at baseline) experienced hypersensitivity reactions. Both patients continued treatment with ELELYSO.
The relationship between ADA and hypersensitivity reactions is not fully understood. Monitoring for ADA to ELELYSO may be useful in ADA positive patients or in patients who have experienced hypersensitivity reactions to ELELYSO or other enzyme replacement therapies.
Thirty (30) of the 31 adult and pediatric patients who developed ADA to ELELYSO during treatment or tested positive for ADA at baseline were evaluated for neutralizing activity of the ADA in the mannose receptor binding and enzyme activity assays. Nineteen (63%) of the 30 patients had neutralizing antibodies capable of inhibiting mannose receptor binding of ELELYSO. Eight of these 19 patients had neutralizing antibodies capable of inhibiting the enzymatic activity of ELELYSO. Available data do not indicate a clear relationship between the presence of mannose receptor binding neutralizing antibodies or neutralizing antibodies capable of inhibiting the enzymatic activity of ELELYSO and the therapeutic response to ELELYSO.
6.3 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of ELELYSO in countries where it is marketed. Because these reactions include those reported voluntarily from a population of uncertain size in addition to those from postmarketing studies, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Gastrointestinal disorders: Vomiting, diarrhea
General disorders and administration site conditions: Fatigue
Immune system disorders: Anaphylaxis [see Warning and Precautions (5.1)], Type III immune-mediated fixed drug eruption
Musculoskeletal and connective tissue disorders: Back pain