These highlights do not include all the information needed to use Berinert safely and effectively. See full prescribing information for Berinert. Berinert [C1 Esterase Inhibitor (Human)]For intravenous use. Freeze-Dried Powder for Reconstitution.Initial

Berinert [C1 Esterase Inhibitor (Human)]Freeze-dried powder

Berinert is a plasma-derived concentrate of C1 Esterase Inhibitor (Human) indicated for the treatment of acute abdominal or facial attacks of hereditary angioedema (HAE) in adult and adolescent patients.

The safety and efficacy of Berinert for prophylactic therapy have not been established.

For Intravenous Use Only.

Administer Berinert at a dose of 20 units per kg body weight by intravenous injection.

Berinert is provided as a freeze-dried powder for reconstitution with the diluent (sterile water) provided. Store the vial in the original carton in order to protect from light. Do not freeze.

Each Berinert kit consists of one carton containing one single-use vial of Berinert, one 10 mL vial of diluent (sterile water), one Mix2Vial transfer set, and one alcohol swab.

Use either the Mix2Vial transfer set provided with Berinert (see How Supplied [16.1] ) or a commercially available double-ended needle and vented filter spike.

Reconstitution

The procedures below are provided as general guidelines for the reconstitution and administration of Berinert.

Administration

Do not mix Berinert with other medicinal products and administer by a separate infusion line.

Use aseptic technique when administering Berinert.

Administer Berinert by slow intravenous injection at a rate of approximately 4 mL per minute.

Berinert is contraindicated in individuals who have experienced life-threatening hypersensitivity reactions, including anaphylaxis, to C1 esterase inhibitor preparations.

Severe hypersensitivity reactions may occur. Epinephrine should be immediately available for treatment of acute severe hypersensitivity reaction (see Patient Counseling Information [17]). The signs and symptoms of hypersensitivity reactions may include hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and/or anaphylaxis during or after injection of Berinert.

Because hypersensitivity reactions may have symptoms similar to HAE attacks, treatment methods should be carefully considered. In case of suspected hypersensitivity, immediately discontinue administration of Berinert and institute appropriate treatment.

Thrombotic events have been reported in association with Berinert when used off-label and at higher than labeled doses. Animal studies have confirmed the risk of thrombosis from intravenous administration of C1 esterase inhibitor products (see Overdosage [10] and Animal Toxicology and/or Pharmacology [13.2]).

Because Berinert is made from human blood, it may contain infectious agents (eg, viruses and, theoretically, the Creutzfeldt-Jakob disease [CJD] agent) that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by processes demonstrated to inactivate and/or remove certain viruses during manufacturing (see Description [11] and Patient Counseling Information [17] ).

Despite these measures, such products may still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products.

Since 1979, a few suspected cases of viral transmission have been reported with the use of Berinert outside the US, including cases of acute hepatitis C. From the incomplete information available from these cases, it was not possible to determine with certainty if the infections were or were not related to prior administration of Berinert.

The physician should discuss the risks and benefits of this product with the patient before prescribing or administering it to the patient. (See Patient Counseling Information [17.1]).

All infections thought by a physician possibly to have been transmitted by Berinert should be reported by lot number, by the physician, or other healthcare provider to the CSL Behring Pharmacovigilance Department at 1-866-915-6958.

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 spasm, pain, diarrhea and vomiting.

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 [14] ), 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 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.

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 [14] ). 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.

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.

No drug interaction studies have been conducted.

Pregnancy Category C. Animal reproduction studies have not been conducted with Berinert. It is not known whether Berinert can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Berinert should be given to a pregnant woman only if clearly needed. In a retrospective case collection study, 20 pregnant women ranging in age from 20 to 35 years received Berinert with repeated doses up to 3,500 units per attack; these women reported no complications during delivery and no harmful effects on their 34 neonates.

The safety and effectiveness of Berinert administration prior to or during labor and delivery have not been established. Use only if clearly needed.

It is not known whether Berinert is excreted in human milk. Because many drugs are excreted in human milk, use only if clearly needed when treating a nursing woman.

Safety and efficacy of Berinert in children (ages 0 through 12) have not been established. The clinical studies included an insufficient number of subjects in this age group to determine whether they respond differently from older subjects. The safety and efficacy of Berinert were eva luated in 5 children (ages 3 through 12) and in 8 adolescent subjects (ages 13 through 16) (see Pharmacokinetics [12.3] ).

Safety and efficacy of Berinert in the geriatric population have not been established. Clinical studies with Berinert included four subjects older than 65 years. The clinical studies included an insufficient number of subjects in this age group to determine whether they respond differently from younger subjects.

The development of thrombosis has been reported after doses exceeding 20 units/kg body weight of Berinert when used off-label in newborns and young children with congenital heart anomalies during or after cardiac surgery under extracorporeal circulation.

The maximum dose administered in clinical studies in hereditary angioedema was 20 units/kg body weight. Overdosage did not occur in connection with treatment of HAE.

Berinert is a human plasma-derived, purified, pasteurized, lyophilized concentrate of C1 esterase inhibitor to be reconstituted for intravenous administration. Berinert is prepared from large pools of human plasma from US donors. One standard unit of C1 esterase inhibitor concentrate is equal to the amount of C1 esterase inhibitor in 1 mL of fresh citrated human plasma, which is equivalent to 270 mg/L or 2.5 µM/L. No international laboratory standard for quantifying C1 esterase inhibitor. An in-house standard is used to assure lot-to-lot consistency in product potency.

C1 esterase inhibitor is a soluble, single-chain glycoprotein containing 478 amino acid residues organized into three beta-sheets and eight or nine alpha-helices. The heavily glycosylated molecule has an apparent molecular weight of 105 kD, of which the carbohydrate chains comprise 26% to 35%.

Each vial of Berinert contains 500 units C1 esterase inhibitor, 50 to 80 mg total protein, 85 to 115 mg glycine, 70 to 100 mg sodium chloride, and 25 to 35 mg sodium citrate.

All plasma used in the manufacture of Berinert is obtained from US donors and is tested using serological assays for hepatitis B surface antigen and antibodies to HIV-1/2 and HCV. Additionally, the plasma is tested with Nucleic Acid Testing (NAT) for HCV and HIV-1 and found to be non-reactive (negative). In addition, the plasma is tested by NAT for HAV and Human Parvovirus B19. Only plasma that has passed virus screening is used for production, and the limit for Parvovirus B19 in the fractionation pool is set not to exceed 10 IU of Parvovirus B19 DNA per mL.

The manufacturing process for Berinert includes multiple steps that reduce the risk of virus transmission. The virus inactivation/reduction capacity of three steps (pasteurization in aqueous solution at 60°C for 10 hours, hydrophobic interaction chromatography, and the combination of ion exchange chromatographies and ammonium sulphate precipitation) was eva luated in a series of in vitro spiking experiments. The total mean cumulative virus inactivation/reduction is shown in Table 5.

C1 esterase inhibitor is a normal constituent of human plasma and belongs to the group of serine protease inhibitors (serpins) that includes antithrombin III, alpha-protease inhibitor, alpha-antiplasmin, and heparin cofactor II. As with the other inhibitors in this group, C1 esterase inhibitor has an important inhibiting potential on several of the major cascade systems of the human body, including the complement system, the intrinsic coagulation (contact) system, the fibrinolytic system, and the coagulation cascade. Regulation of these systems is performed through the formation of complexes between the proteinase and the inhibitor, resulting in inactivation of both and consumption of the C1 esterase inhibitor.

C1 esterase inhibitor, which is usually activated during the inflammatory process, inactivates its substrate by covalently binding to the reactive site. C1 esterase inhibitor is the only known inhibitor for the subcomponent of the complement component 1 (C1r), C1s, coagulation factor XIIa, and kallikrein. Additionally, C1 esterase inhibitor is the main inhibitor for coagulation factor XIa of the intrinsic coagulation cascade.

HAE patients have low levels of endogenous or functional C1 esterase inhibitor. Although the events that induce attacks of angioedema in HAE patients are not well defined, it has been postulated that increased vascular permeability and the clinical manifestation of HAE attacks may be primarily mediated through contact system activation. Suppression of contact system activation by C1 esterase inhibitor through the inactivation of plasma kallikrein and factor XIIa is thought to modulate this vascular permeability by preventing the generation of bradykinin.

Administration of Berinert to patients with C1 esterase inhibitor deficiency replaces the missing or malfunctioning protein in patients. The plasma concentration of C1 esterase inhibitor in healthy volunteers is approximately 270 mg/L.

The pharmacokinetics of Berinert were eva luated in an open-label, uncontrolled, single-center study in 40 subjects (35 adults and 5 children under 16 years of age) with either mild or severe HAE. All subjects received a single intravenous injection of Berinert ranging from 500 units to 1500 units. Blood samples were taken during an attack-free period at baseline and for up to 72 hours after drug administration. Pharmacokinetic parameters were estimated using non-compartmental analysis (with or without baseline adjustment). Table 6 summarizes the pharmacokinetic parameters in 35 adult subjects with HAE.

Table 7 summarizes the pharmacokinetic parameters in 5 pediatric subjects (ages 6 through 13) with HAE. Based on adjusted baseline, compared to adults, the half-life of Berinert was shorter and clearance was faster in this limited cohort of children. However, the clinical implication of this difference is not known.

Studies have not been conducted to eva luate the pharmacokinetics of Berinert in special patient populations identified by gender, race, geriatric age, or the presence of renal or hepatic impairment.

No animal studies have been completed to eva luate the effects of Berinert on carcinogenesis, mutagenesis, and impairment of fertility.

Acute intravenous toxicity of Berinert was performed in mice at 1500, 3000, and 6000 units/kg and in rats at 1000, 2000, and 3000 units/kg. Berinert was well tolerated and no signs of toxicity were observed up to the highest dose administered.

Repeat intravenous dose toxicity was studied in a 14-day repeat dose study in rats at doses of 20, 60, and 200 units/kg/day. Berinert was well tolerated and no toxicity was observed up to the highest dose administered. No antibody response against C1 esterase inhibitor could be demonstrated in this study after multiple dosing with Berinert.

In a safety pharmacology study, Berinert was administered to beagle dogs intravenously at a cumulative dose of 3500 units/kg. No adverse effects were seen on the cardiovascular and respiratory system. There was a drop in body temperature, reduced coagulation time, and a decrease in thrombocyte aggregation.

Local intravenous tolerance of Berinert was eva luated in rabbits at 1500 units. No pathological changes were noted at the time of injection or during the following 24 hours. No pathological signs were noted during necropsy.

Thrombotic events have been reported in association with C1 esterase inhibitor products when used off-label and at higher than labeled doses (see Overdosage [10]). Animal studies have confirmed the risk of thrombosis from intravenous administration of C1 esterase inhibitor products.

The safety and efficacy of Berinert in the treatment of acute abdominal or facial attacks in subjects with hereditary angioedema were demonstrated in a placebo-controlled, double-blind, prospective, multinational, randomized, parallel-group, dose-finding, three-arm, clinical study, referred to as the randomized clinical trial (RCT). The RCT assessed the efficacy and safety of Berinert in 124 adult and pediatric subjects with C1 esterase inhibitor deficiency who were experiencing an acute moderate to severe attack of abdominal or facial HAE. Subjects ranged in age from six to 72 years of age; 67.7% were female and 32.3% were male; and approximately 90% were Caucasian.

The study objectives were to eva luate whether Berinert shortens the time to onset of relief of symptoms of an abdominal or facial attack compared to placebo and to compare the efficacy of two different doses of Berinert. The time to onset of relief of symptoms was determined by the subject's response to a standard question posed at appropriate time intervals for as long as 24 hours after start of treatment, taking into account all single HAE symptoms. In addition the severity of the single HAE symptoms was assessed over time.

Subjects were randomized to receive a single 10 unit/kg body weight dose of Berinert (39 subjects), a single 20 unit/kg dose of Berinert (43 subjects), or a single dose of placebo (42 subjects) by slow intravenous infusion (recommended to be given at a rate of approximately 4 mL per minute) within 5 hours of an HAE attack. At least 70% of the subjects in each treatment group were required to be experiencing an abdominal attack.

If a subject experienced no relief or insufficient relief of symptoms by 4 hours after infusion, investigators had the option to administer a second infusion of Berinert (20 units/kg for the placebo group, 10 units/kg for the 10 units/kg group), or placebo (for the 20 units/kg group). This masked (blinded) "rescue study medication" was administered to subjects and they were then followed until complete resolution of symptoms was achieved. Adverse events were collected for up to 7 to 9 days following the initial administration of Berinert or placebo.

In the rare case that a subject developed life-threatening laryngeal edema after inclusion into the study, immediate start of open-label treatment with a 20 unit/kg body weight dose of Berinert was allowed.

All subjects who received confounding medication (rescue medication) before symptom relief were regarded as "non-responders." Therefore, time to onset of symptom relief was set at 24 hours if a subject received any rescue medication (ie, rescue study medication, narcotic analgesics, non-narcotic analgesics, anti-emetics, open-label C1 inhibitor, androgens at increased dose, or fresh frozen plasma) between 5 hours before administration of blinded study medication until time to onset of relief.

For the trial to be considered successful, the study protocol specified the following criteria for the differences between the Berinert 20 units/kg and the placebo group:

Subjects treated with 20 units/kg body weight of Berinert experienced a significant reduction (p=0.0016; “Wilcoxon Rank Sum test”) in time to onset of relief from symptoms of an HAE attack as compared to placebo (median of 48 minutes for Berinert 20 units/kg body weight, as compared to a median of >4 hours for placebo). The time to onset of relief from symptoms of an HAE attack for subjects in the 10 unit/kg dose of Berinert was not statistically significantly different from that of subjects in the placebo group.

Figure 9 is a Kaplan-Meier curve showing the percentage of subjects reporting onset of relief of HAE attack symptoms as a function of time. Individual time points beyond 4 hours are not presented on the graph, because the protocol permitted blinded rescue medication, analgesics, and/or anti-emetics to be administered starting 4 hours after randomized blinded study medication had been administered.

In addition, the efficacy of Berinert 20 units/kg body weight could be confirmed by observing a reduction in the intensity of single HAE symptoms at an earlier time compared to placebo. For abdominal attacks Figure 10a shows the time to start of relief of the last symptom to improve that was already present at baseline. Pre-defined abdominal HAE symptoms included pain, nausea, vomiting, cramps and diarrhea. Figure 10b shows the respective time to start of relief of the first symptom to improve that was already present at baseline.

For facial attacks, single HAE symptoms were recorded. In addition, photos were taken at pre-determined time points and assessed by the members of an independent Data Safety Monitoring Board (DSMB), who were blinded as to treatment, center and other outcome measures. The change in the severity of the edema when compared to baseline was assessed on a scale with outcomes "no change", "better", "worse" and "resolved". Figure 11 shows the time to start of relief from serial facial photographs by DSMB assessment.

Table 8 compares additional endpoints, including changes in HAE symptoms and use of rescue medication in subjects receiving Berinert at 20 units/kg body weight and placebo.

Both the proportion of subjects with increased intensity of clinical HAE symptoms between 2 and 4 hours after start of treatment compared to baseline, and the number of vomiting episodes within 4 hours after start of study treatment demonstrated trends in favor of Berinert in comparison to placebo (p-values <0.1). Tables 9 through 12 present additional information regarding responses to treatment.

No subjects treated with Berinert at 20 units/kg body weight reported worsening of symptoms at 4 hours after administration of study medication compared to baseline.

The study demonstrated that the Berinert 20 unit/kg body weight dose was significantly more efficacious than the Berinert 10 unit/kg body weight dose or placebo.