BERINERT SIDE EFFECTS
- Generic Name: [c1 esterase inhibitor (human)] freeze-dried powder
- Brand Name: Berinert
- Drug Class: Immunomodulators
SIDE EFFECTS
The most serious adverse reaction reported in subjects enrolled in clinical studies who received BERINERT was an increase in the severity of pain associated with HAE.
The most common adverse reaction reported in greater than 4% of the subjects and greater than placebo among subjects who received BERINERT in the placebo-controlled clinical trial was dysgeusia.
Clinical Trials Experience
Because clinical studies 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.
Placebo-Controlled Clinical Study
In the placebo-controlled clinical study, referred to as the randomized clinical trial (RCT), 124 subjects experiencing an acute moderate to severe abdominal or facial HAE attack were treated with BERINERT (either a 10 IU per kg body weight or a 20 IU per kg body weight dose), or placebo (physiological saline solution).
The treatment-emergent serious adverse reactions/events that occurred in 5 subjects in the RCT were laryngeal edema, facial HAE attacks with laryngeal edema, swelling (shoulder and chest), exacerbation of hereditary angioedema, and laryngospasm.
After initial infusion or rescue Medication treatment with BERINERT versus placebo, in the intent-to-treat population only one adverse reaction was reported in greater than one subject in either treatment group, at a frequency higher than placebo: dysgeusia was reported within 4 hours of infusion of BERINERT versus placebo (2/43, 4.7% vs. 0/42, 0%) and up to 72 hours (2/43, 4.7% vs. 1/42, 2.4%). Because more subjects in the placebo group than in the BERINERT group received rescue treatment, the median observation period in this analysis for subjects randomized to placebo was slightly longer than for subjects randomized to receive BERINERT.
Subjects were tested at baseline and after 3 months for possible exposure to Parvovirus B19, hepatitis B, hepatitis C, and HIV-1 and HIV-2. No subject who underwent testing evidenced seroconversion or treatment-emergent positive polymerase chain reaction testing for these pathogens.
Open-Label Extension Study
In the safety analysis of the open-label extension study, 57 subjects with 1085 acute moderate to severe abdominal, facial, peripheral, and laryngeal HAE attacks received a 20 IU/kg body weight dose of BERINERT [see Clinical Studies]. This study provides additional safety data in subjects who received multiple infusions of the product for sequential HAE attacks (one infusion per attack).
Table 1 lists the adverse reactions that occurred in the safety analysis of the open-label extension study in ≥2 subjects or associated with ≥5 HAE attacks during infusion or within 24 hours or 72 hours after the end of a BERINERT infusion.
Table 1: Incidence of subjects and HAE Attacks with Adverse Reactions (ARs) Starting during Infusion or Within 24 hours or 72 hours after End of an Infusion (Experienced by ≥2 subjects or Associated with ≥5 HAE Attacks Overall) by Preferred Term (Safety subject and HAE Attack Populations) – Open-Label Extension Study
| Preferred term | Number (%) of subjects (n=57) |
Number (%) of Attacks (n=1085) |
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| ARs within 24 hours | ARs within 72 hours | ARs within 24 hours | ARs within 72 hours | |
| Any preferred term | 13 (22.8%) | 20 (35.1%) | 27 (2.5%) | 41 (3.8%) |
| Headache | 2 (3.5%) | 4 (7.0%) | 3 (0.3%) | 6 (0.6%) |
| Nasopharyngitis | 1 (1.8%) | 2 (3.5%) | 1 (<0.1%) | 2 (0.2%) |
| Abdominal pain or discomfort | 1 (1.8%) | 3 (5.3%) | 2 (0.2%) | 6 (0.6%) |
| Upper respiratory tract infection | 0 (0) | 1 (1.8%) | 0 (0) | 1 (<0.1%) |
| Hereditary angioedema attack† | 1 (1.8%) | 1 (1.8%) | 1 (<0.1%) | 1 (<0.1%) |
| Influenza like illness | 1 (1.8%) | 2 (3.5%) | 1 (<0.1%) | 2 (0.2%) |
| Rash | 2 (3.5%) | 2 (3.5%) | 2 (0.2%) | 2 (0.2%) |
| Vulvovaginal mycotic infection | 0 (0) | 2 (3.5%) | 0 (0) | 2 (0.2%) |
| Nausea | 1 (1.8%) | 1 (1.8%) | 4 (0.4%) | 5 (0.5%) |
| N = total number of subjects/HAE attacks Data are sorted by decreasing frequency by number of subjects. *Because of the allowance of rescue medication in both study arms, all listed adverse events were considered to be at least potentially related to study medication (e.g., adverse reactions), regardless of the investigator’s opinion concerning causality. †Hereditary angioedema attacks were only to be reported as adverse reaction if it was a worsening of symptoms during a treated HAE attack. New HAE attacks were not to be reported as adverse reactions. Although the adverse reaction of hereditary angioedema in subject 22301 was a new HAE attack that started after the previous HAE attack had completely resolved, this HAE attack was reported as an adverse reaction, because the HAE attack was not included in the study and treated outside study site with medication other than the study medication. |
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The incidence and type of adverse reactions with BERINERT when administered for treatment of multiple consecutive acute HAE attacks of any type was similar to those previously observed. As in the placebo-controlled study, no proven cases of infections due to HIV-1/2, HAV, HBV, HCV or Parvovirus B19 were observed during the study.
Immunogenicity
In a post-marketing study forty-six subjects with Type I or Type II HAE were monitored for inhibitory or non-inhibitory antibodies to C1-INH. Blood samples for antibody assessment were taken at Day 1 (First HAE attack requiring administration of a dose of 20 IU/kg IV, baseline value), and at 3, 6 and 9 months. No subjects developed inhibitory antibodies to C1-INH at any of the time points following infusion of BERINERT. Thirteen subjects (28.2%), however, had detectable levels of non-inhibitory Abs at some point during the study, including 9 subjects (19.6%) who had detectable non-inhibitory Abs at baseline. The presence of non-inhibitory anti-C1-INH Abs did not induce apparent immunologically-associated clinical events.
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, it may be misleading to compare the incidence of antibodies to BERINERT in the studies described above with the incidence of antibodies in other studies or to other products.
Postmarketing Experience
Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure.
Adverse reactions reported in Europe since 1979 in patients receiving BERINERT for treatment of HAE include hypersensitivity/anaphylactic reactions, injection-site pain, injection-site redness, chills, and fever.
TE Events Associated With HAE Treatment
TE events including basilar artery thrombosis, multiple pulmonary microemboli, and thrombosis have been reported with the use of BERINERT at the recommended dose following treatment of HAE.
TE Events Associated With Use In Unapproved Indications
TE events have also been reported with the use of BERINERT in patients receiving higher than recommended doses during cardiac surgery (unapproved indication) include carotid artery thrombosis, cerebral thrombosis, myocardial infarction, pulmonary embolism, renal vein thrombosis, sagittal sinus thrombosis, inferior vena cava thrombosis, superior vena cava thrombosis, internal jugular vein thrombosis, and peripheral venous thrombosis.
The following adverse reactions, identified by system organ class, have been attributed to BERINERT during post-approval use outside the US.
- Immune System Disorder: Hypersensitivity/anaphylactic reactions, and shock
- General/Body as a Whole: Pain on injection, redness at injection site, chills, and fever.
SRC: NLM .