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 reactions that have been reported in greater than 4% of the subjects who received Berinert in clinical studies were subsequent HAE attack, headache, abdominal pain, nausea, muscle spasms, pain, diarrhea and vomiting. 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) (see Clinical Studies), 124 subjects experiencing an acute moderate to severe abdominal or facial HAE attack were treated with Berinert (either a 10 unit per kg body weight or a 20 unit 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 attack with laryngeal edema, swelling (shoulder and chest), exacerbation of hereditary angioedema, and laryngospasm. Table 1: Adverse Reactions* Occurring up to 4 hours After Initial Infusion in More Than 4% of Subjects, Irrespective of Causality†
Adverse Reactions Number (%) of Subjects Reporting Adverse Reactions Berinert 20 units/kg
(n = 43) Number (%) of Subjects Reporting Adverse Reactions Placebo Group
(n = 42) Nausea† 3 (7%) 5 (11.9%) Dysgeusia 2 (4.7%) 0 (0) Abdominal Pain† 2 (4.7%) 3 (7.1%) Vomiting† 1 (2.3%) 3 (7.1%) Diarrhea† 0 (0) 4 (9.5%) Headache 0 (0) 2 (4.8%) * The study protocol specified that adverse events that began within 72 hours of blinded study medication administration were to be classified as at least possibly related to study medication (ie, adverse reactions).
† The following abdominal symptoms were identified in the protocol as associated with HAE abdominal attacks: abdominal pain, bloating, cramps, nausea, vomiting, and diarrhea. Table 2: Adverse Reactions* Occurring in More Than 4% of Subjects up to 72 hours After Infusion of Initial or Rescue Medication† by Intent-to- Treat, Irrespective of Causality
Adverse Reactions Number (%) of Subjects Reporting Adverse Reactions†‡ Berinert 20 units/kg
(n = 43) Number (%) of Subjects Reporting Adverse Reactions†‡ Placebo Group
( n = 42) Nausea 3 (7%) 11 (26.2%) Headache 3 (7%) 5 (11.9%) Abdominal Pain 3 (7%) 5 (11.9%) Dysgeusia 2 (4.7%) 1 (2.4%) Vomiting 1 (2.3%) 7 (16.7%) Pain 1 (2.3%) 4 (9.5%) Muscle spasms 1 (2.3%) 4 (9.5%) Diarrhea 0 (0) 8 (19%) Back pain 0 (0) 2 (4.8%) Facial pain 0 (0) 2 (4.8%) * The study protocol specified that adverse events that began within 72 hours of blinded study medication administration were to be classified as at least possibly related to study medication (ie, adverse reactions).
† If a subject experienced no relief or insufficient relief of symptoms within 4 hours after infusion, investigators had the option to administer a blinded second infusion (“rescue” treatment) of Berinert (20 units/kg for the placebo group or 10 units/kg for the 10 units/kg group), or placebo (for the 20 units/kg group).
‡ Adverse reactions following either initial treatment and/or blinded “rescue” treatment. Because more subjects in the placebo randomization group than in the Berinert randomization 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. Table 3 lists the adverse events that occurred in more than 4% of the subjects 7 to 9 days after the end of a Berinert infusion, irrespective of causality. Table 3: Adverse Events Occurring in More Than 4% of Subjects* Receiving Berinert at Either 10 Units/kg or 20 units/kg 7 to 9 Days after Infusion, Irrespective of Causality
Adverse Events Number (%) of Subjects Reporting Adverse Events
(n=108) Hereditary angioedema 12 (11.1%) Headache 12 (11.1%) Abdominal pain† 7 (6.5%) Nausea† 7 (6.5%) Muscle spasms 6 (5.6%) Pain 6 (5.6%) Diarrhea† 5 (4.6%) Vomiting† 5 (4.6%) * Includes subjects in the placebo group who received Berinert 20 units/kg as rescue study medication.
† These symptoms were identified in the protocol as related to the underlying disease. Any increase in intensity or new occurrence of these symptoms after study medication administration was considered to be an adverse event. 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. Extension Study In an interim safety analysis, of the ongoing open-label extension study, 56 subjects with 559 acute moderate to severe abdominal, facial, peripheral and/or laryngeal attacks received a 20 unit/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 4 lists the adverse events that occurred in this interim safety analysis of the ongoing open-label extension study in more than 4% of subjects up to 72 hours or 9 days after the end of a Berinert infusion, irrespective of causality. Table 4: Incidence of Adverse Events by Descending Frequency Occurring in More Than 4% of Subjects Receiving Berinert up to 72 Hours or 9 Days After Infusion, Irrespective of Causality
Adverse Events Number (%) of Subjects Reporting Adverse Events up to 72 hours
(n=56) Number (%) of Subjects Reporting Adverse Events up to 9 Days
(n=56) Headache 3 (5.4%) 4 (7.1%) Abdominal pain 3 (5.4%) 3 (5.4%) Hereditary angioedema 2 (3.6%) 4 (7.1%) Nasopharyngitis 2 (3.6%) 3 (5.4%) 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, a few suspected cases of viral transmission, including cases of acute hepatitis C, injection-site pain, injection-site redness, chills, and fever. 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
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