Ecallantide

12.1 Mechanism of Action Hereditary angioedema (HAE) is a rare genetic disorder caused by mutations to C1-esterase-inhibitor (C1-INH) located on Chromosome 11q and inherited as an autosomal dominant trait. HAE is characterized by low levels of C1-INH activity and low levels of C4. C1-INH functions to regulate the activation of the complement and intrinsic coagulation (contact system pathway) and is a major endogenous inhibitor of plasma kallikrein. The kallikrein-kinin system is a complex proteolytic cascade involved in the initiation of both inflammatory and coagulation pathways. One critical aspect of this pathway is the conversion of High Molecular Weight (HMW) kininogen to bradykinin by the protease plasma kallikrein. In HAE, normal regulation of plasma kallikrein activity and the classical complement cascade is therefore not present. During attacks, unregulated activity of plasma kallikrein results in excessive bradykinin generation. Bradykinin is a vasodilator which is thought by some to be responsible for the characteristic HAE symptoms of localized swelling, inflammation, and pain. KALBITOR is a potent (Ki = 25 pM), selective, reversible inhibitor of plasma kallikrein. KALBITOR binds to plasma kallikrein and blocks its binding site, inhibiting the conversion of HMW kininogen to bradykinin. By directly inhibiting plasma kallikrein, KALBITOR reduces the conversion of HMW kininogen to bradykinin and thereby treats symptoms of the disease during acute episodic attacks of HAE.

1 INDICATIONS AND USAGE KALBITOR ® (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. ( 1 )

2 DOSAGE AND ADMINISTRATION 30 mg (3 mL), administered subcutaneously in three 10 mg (1 mL) injections. If an attack persists, an additional dose of 30 mg may be administered within a 24 hour period. ( 2.1 ) KALBITOR should only be administered by a healthcare professional with appropriate medical support to manage anaphylaxis and hereditary angioedema. ( 2.2 ). 2.1 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. 2.2 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.

6 ADVERSE REACTIONS Hypersensitivity reactions, including anaphylaxis, have occurred in patients treated with KALBITOR [ see Contraindications (4) and Warnings and Precautions (5.1) ]. The most common adverse reactions occurring in ≥3% of KALBITOR-treated patients and greater than placebo are headache, nausea, diarrhea, pyrexia, injection site reactions, and nasopharyngitis. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals U.S.A., Inc. at 1-877-TAKEDA-7 (1-877-825-3327) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. 6.2 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. 6.3 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.

7 DRUG INTERACTIONS No formal drug interactions studies were performed. No in vitro metabolism studies were performed.