Adverse reactions : תופעות לוואי

8. ADVERSE REACTIONS
The following adverse reactions are described elsewhere in the labeling: •   Infections [see Warnings and Precautions; Infections (6)]
•   Infusion-Related Reactions [see Warnings and Precautions; Infusion-Related Reactions (6)]

Clinical Trial 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.
The safety data described in this section reflect exposure to GAMIFANT in which 34 patients with untreated primary HLH and previously treated patients with primary HLH received GAMIFANT at a starting dose of 1 mg/kg every 3 days with dose increases up to 10 mg/kg [see Dosage and Administration; Recommended Dosing (3) and Clinical Studies (13)]. The median duration of treatment with GAMIFANT was 59 days (range: 4 to 245 days) and the median cumulative dose was 25 mg/kg (range: 4 to 254 mg/kg).
The median age of study population was 1 year (range: 0.1 to 13 years), 53% were female, and 65% were Caucasian.
Serious adverse reactions were reported in 53% of patients. The most common serious adverse reactions (≥ 3%) included infections, gastrointestinal hemorrhage, and multiple organ dysfunction. Fatal adverse reactions occurred in two (6%) of patients and included septic shock and gastrointestinal hemorrhage.
Disseminated histoplasmosis led to drug discontinuation in one patient. The most commonly reported adverse reactions (≥ 20%) were infections, hypertension, infusion-related reactions, and pyrexia. Adverse reactions reported in ≥ 10% of patients during treatment with GAMIFANT are presented in Table 2.
Table 2:       Adverse Reactions Reported in ≥ 10% of Patients with Primary HLH Adverse Reactions                                                    GAMIFANT (%)
(N = 34)
Infectionsa                                                              56 
Hypertensionb                                                              41 
Infusion-related reactionsc                                                27 

Adverse Reactions                                                             GAMIFANT (%)
(N = 34)
Pyrexia                                                                           24 
Hypokalemia                                                                           15 
Constipation                                                                          15 
Rash                                                                                  12 
Abdominal pain                                                                        12 
Cytomegalovirus infection                                                             12 
Diarrhea                                                                              12 
Lymphocytosis                                                                         12 
Cough                                                                                 12 
Irritability                                                                          12 
Tachycardia                                                                           12 
Tachypnea                                                                             12 a
Includes viral, bacterial, fungal, and infections in which no pathogen was identified b
Includes secondary hypertension c
Includes events of drug eruption, pyrexia, rash, erythema, and hyperhidrosis Additional selected adverse reactions (all grades) that were reported in less than 10% of patients treated with GAMIFANT included: vomiting, acute kidney injury, asthenia, bradycardia, dyspnea, gastro-intestinal hemorrhage, epistaxis, and peripheral edema.

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 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 emapalumab products may be misleading.
The immunogenicity of emapalumab has been evaluated using an electrochemiluminescence- based immunoassay (ECLIA). A total of 64 subjects were evaluated for anti-therapeutic antibodies (ATAs) to emapalumab after treatment with GAMIFANT. ATAs were detected in 3/64 subjects (5%) who received GAMIFANT.


Treatment-emergent ATAs were detected in 1/33 (3%) of patients in the primary HLH clinical trial. The ATAs in this patient were found to have neutralizing ability. One patient receiving GAMIFANT through compassionate use developed transient non-neutralizing treatment- emergent ATAs. In both of these patients, ATAs occurred within the first 9 weeks following the initiation of GAMIFANT treatment. In addition, one healthy subject tested positive for ATAs following a single dose of GAMIFANT. No evidence of an altered safety or efficacy profile was identified in the primary HLH patients who developed antibodies to emapalumab.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization of the medicinal product is important.
It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il