Kalbitor Drug Information

® (ecallantide) is indicated for treatment of acute attacks of hereditary angioedema (HAE) in patients 12 years of age and older. KALBITOR is a plasma kallikrein inhibitor indicated for treatment of acute attacks of hereditary angioedema (HAE) in patients 12 years of age and older.

Recommended Dosing

The recommended dose of KALBITOR is 30 mg (3 mL), administered subcutaneously in three 10 mg (1 mL) injections. If the attack persists, an additional dose of 30 mg may be administered within a 24 hour period.

Administration Instructions

KALBITOR should only be administered by a healthcare professional with appropriate medical support to manage anaphylaxis and hereditary angioedema. KALBITOR should be refrigerated and protected from the light. KALBITOR is a clear, colorless liquid; visually inspect each vial for particulate matter and discoloration prior to administration.

If there is particulate matter or discoloration, the vial should not be used. Using aseptic technique, withdraw 1 mL (10 mg) of KALBITOR from the vial using a large bore needle. Change the needle on the syringe to a needle suitable for subcutaneous injection.

The recommended needle size is 27 gauge. Inject KALBITOR into the skin of the abdomen, thigh, or upper arm. Repeat the procedure for each of the 3 vials comprising the KALBITOR dose.

The injection site for each of the injections may be in the same or in different anatomic locations (abdomen, thigh, upper arm). There is no need for site rotation. Injection sites should be separated by at least 2 inches (5 cm) and away from the anatomical site of attack. The same instructions apply to an additional dose administered within 24 hours.

Different injection sites or the same anatomical location (as used for the first administration) may be used.

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. The safety data described below reflect exposure to KALBITOR in 255 patients with HAE treated with either intravenous or subcutaneous KALBITOR. Of the 255 patients, 66% of patients were female and 86% were Caucasian. Patients treated with KALBITOR were between the ages of 10 and 78 years.

Overall, the most common adverse reactions in 255 patients with HAE were headache (16%), nausea (13%), fatigue (12%), diarrhea (11%), upper respiratory tract infection (8%), injection site reactions (7%), nasopharyngitis (6%), vomiting (6%), pruritus (5%), upper abdominal pain (5%), and pyrexia (5%). Anaphylaxis was reported in 4% of patients with HAE. Injection site reactions were characterized by local pruritus, erythema, pain, irritation, urticaria, and/or bruising. The incidence of adverse reactions below is based upon 2 placebo-controlled, clinical trials (EDEMA3 ® and EDEMA4) in a total of 143 unique patients with HAE. Patients were treated with KALBITOR 30 mg subcutaneous or placebo. Patients were permitted to participate sequentially in both placebo-controlled trials; safety data collected during exposure to KALBITOR was attributed to treatment with KALBITOR, and safety data collected during exposure to placebo was attributed to treatment with placebo.

Table 1 shows adverse reactions occurring in ≥3% of KALBITOR-treated patients that also occurred at a higher rate than in the placebo-treated patients in the two controlled trials (EDEMA3 and EDEMA4) of the 30 mg subcutaneous dose. Table 1: Adverse Reactions Occurring at ≥3% and Higher than Placebo in 2 Placebo Controlled Clinical Trials in Patients with HAE Treated with KALBITOR KALBITOR N=100 Placebo N=81 Adverse Reactions n (%) Patients experiencing more than 1 event with the same preferred term are counted only once for that preferred term. n (%) Headache 8 (8%) 6 (7%) Nausea 5 (5%) 1 (1%) Diarrhea 4 (4%) 3 (4%) Pyrexia 4 (4%) 0 Injection site reactions 3 (3%) 1 (1%) Nasopharyngitis 3 (3%) 0 Some patients in EDEMA3 and EDEMA4 received a second, open-label 30 mg subcutaneous dose of KALBITOR within 24 hours following the initial dose. Adverse reactions reported by these patients who received the additional 30 mg subcutaneous dose of KALBITOR were consistent with those reported in the patients receiving a single dose.

Immunogenicity

In the KALBITOR HAE program, patients developed antibodies to KALBITOR. Rates of seroconversion increased with exposure to KALBITOR over time. Overall, 20.2% of patients seroconverted to anti-ecallantide antibodies. Neutralizing antibodies to ecallantide were determined in vitro to be present in 8.8% of patients and were not associated with loss of efficacy.

Anti-ecallantide IgE antibodies were detected at a rate of 4.7% for tested patients, and anti- P. pastoris IgE antibodies were also detected at a rate of 20.2%. Patients who seroconvert may be at a higher risk of a hypersensitivity reaction. The long-term effects of antibodies to KALBITOR are not known. The test results for the ecallantide program were determined using one of two assay formats: ELISA and bridging electrochemiluminescence (ECL). As with all therapeutic proteins, there is a potential for immunogenicity with the use of KALBITOR. The incidence 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 to KALBITOR with the incidence of antibodies to other products may be misleading.

Postmarketing Experience Similar adverse reactions have been observed postmarketing as described for

clinical trial experience. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency or to establish a causal relationship with drug exposure.

No formal drug interactions studies were performed. No in vitro metabolism studies were performed.

Pregnancy Risk Summary The available data from the pharmacovigilance database for KALBITOR have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In an animal reproduction study, increased early fetal deaths resulting in decreased live fetuses were observed in rats following treatment during the period of organogenesis at an intravenous dose approximately 1.6 times the maximum recommended human dose (MRHD) in the presence of maternal toxicity. There were no effects on embryofetal survival or structural abnormalities in rats and rabbits following treatment during the period of organogenesis with intravenous doses up to approximately 1.1 and 6 times the MRHD, respectively, or rats treated with subcutaneous doses up to 2.4 times the MRHD. In a pre- and post-natal development study with rats, there were no effects on pup survival and development with subcutaneous doses up to approximately 2.7 times the MRHD. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an embryofetal development study with rats, ecallantide administered by the intravenous route during the period of organogenesis from gestation days 7 to 17 at a dose approximately 1.6 times the MRHD (on a mg/m 2 basis at a maternal intravenous dose of 15 mg/kg/day) caused increased numbers of early resorptions and percentages of resorbed conceptuses per litter resulting in decreased numbers of live fetuses in the presence of mild maternal toxicity.

No effects on embryofetal survival or structural abnormalities were observed in rats with intravenous doses up to approximately 1.1 times the MRHD (on a mg/m 2 basis with maternal intravenous dose of 10 mg/kg/day). In an embryofetal development study with rats, ecallantide administered by the subcutaneous route during the period of organogenesis from gestation days 7 to 17 at doses up to approximately 2.4 times the MRHD (on an AUC basis with maternal subcutaneous doses up to 20 mg/kg/day) had no effects on embryofetal survival or structural abnormalities. In an embryofetal development study with rabbits, ecallantide administered by the intravenous route during the period of organogenesis from gestation days 7 to 19 at doses up to approximately 6 times the MRHD (on an AUC basis with maternal intravenous doses up to 5 mg/kg/day in rabbits) had no effects on embryofetal survival or structural abnormalities. In a pre- and post-natal development study with rats, ecallantide administered by the subcutaneous route from gestation day 7 through lactation day 20 at doses up to approximately 2.7 times the MRHD (on a mg/m 2 basis with maternal subcutaneous doses up to 25 mg/kg/day) had no effects on pup survival and behavioral or physical development.

Pediatric Use The safety and effectiveness of KALBITOR have been established in patients 12 to 17 years of age. The efficacy of KALBITOR in the 12-15 year age group is extrapolated from efficacy in patients 16 years of age and older with support from population pharmacokinetic analyses showing similar drug exposure levels in adults and adolescents . The safety profile observed in pediatric patients 12-17 years of age was similar to the adverse reactions observed in the overall clinical trial population . Safety and effectiveness of KALBITOR in patients less than 12 years of age have not been established.

Do not administer KALBITOR to a patient who has known clinical hypersensitivity to KALBITOR.. Do not administer KALBITOR to a patient who has known clinical hypersensitivity to KALBITOR.

There have been no reports of overdose with KALBITOR. HAE patients have received single doses up to 90 mg intravenously without evidence of dose-related toxicity.