Kalbitor

WARNING: ANAPHYLAXIS Anaphylaxis has been reported after administration of KALBITOR. Because of the risk of anaphylaxis, KALBITOR should only be administered by a healthcare professional with appropriate medical support to manage anaphylaxis and hereditary angioedema. Healthcare professionals should be aware of the similarity of symptoms between hypersensitivity reactions and hereditary angioedema and patients should be monitored closely. Do not administer KALBITOR to patients with known clinical hypersensitivity to KALBITOR. [ see Contraindications (4) , Warnings and Precautions (5.1) , and Adverse Reactions (6) ] WARNING: ANAPHYLAXIS See full prescribing information for complete boxed warning Anaphylaxis has been reported after administration of KALBITOR ® . Because of the risk of anaphylaxis, KALBITOR should only be administered by a healthcare professional with appropriate medical support to manage anaphylaxis and hereditary angioedema. Healthcare professionals should be aware of the similarity of symptoms between hypersensitivity reactions and hereditary angioedema and patients should be monitored closely. Do not administer KALBITOR to patients with known clinical hypersensitivity to KALBITOR [ see Contraindications (4) , Warnings and Precautions (5.1) , and Adverse Reactions (6) ].

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions Including Anaphylaxis: Anaphylaxis has occurred in 4% of treated patients. Administer KALBITOR in a setting equipped to manage anaphylaxis and hereditary angioedema. Given the similarity in hypersensitivity symptoms and acute HAE symptoms, monitor patients closely for hypersensitivity reactions ( 5 ). 5.1 Hypersensitivity Reactions, Including Anaphylaxis Potentially serious hypersensitivity reactions, including anaphylaxis, have occurred in patients treated with KALBITOR. In 255 HAE patients treated with intravenous or subcutaneous KALBITOR in clinical studies, 10 patients (4%) experienced anaphylaxis. For the subgroup of 187 patients treated with subcutaneous KALBITOR, 5 patients (3%) experienced anaphylaxis. Symptoms associated with these reactions have included chest discomfort, flushing, pharyngeal edema, pruritus, rhinorrhea, sneezing, nasal congestion, throat irritation, urticaria, wheezing, and hypotension. These reactions occurred within the first hour after dosing. Other adverse reactions indicative of hypersensitivity reactions included the following: pruritus (5%), rash (3%), and urticaria (2%). Patients should be observed for an appropriate period of time after administration of KALBITOR, taking into account the time to onset of anaphylaxis seen in clinical trials. Given the similarity in hypersensitivity symptoms and acute HAE symptoms, patients should be monitored closely in the event of a hypersensitivity reaction. KALBITOR should not be administered to any patients with known clinical hypersensitivity to KALBITOR [ see Contraindications (4) ] .

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.

<table width="85%" ID="table1"><caption>Table 1: Adverse Reactions Occurring at &#x2265;3% and Higher than Placebo in 2 Placebo Controlled Clinical Trials in Patients with HAE Treated with KALBITOR</caption><col width="34%" align="left" valign="top"/><col width="33%" align="center" valign="top"/><col width="33%" align="center" valign="top"/><thead><tr><th/><th styleCode="Botrule">KALBITOR N=100</th><th styleCode="Botrule">Placebo N=81</th></tr><tr><th>Adverse Reactions </th><th>n (%) <footnote ID="ft1_a">Patients experiencing more than 1 event with the same preferred term are counted only once for that preferred term.</footnote></th><th>n (%)<footnoteRef IDREF="ft1_a"/></th></tr></thead><tbody><tr><td>Headache</td><td>8 (8%)</td><td>6 (7%)</td></tr><tr><td>Nausea</td><td>5 (5%)</td><td>1 (1%)</td></tr><tr><td>Diarrhea</td><td>4 (4%)</td><td>3 (4%)</td></tr><tr><td>Pyrexia</td><td>4 (4%)</td><td>0</td></tr><tr><td>Injection site reactions </td><td>3 (3%)</td><td>1 (1%)</td></tr><tr><td>Nasopharyngitis</td><td>3 (3%)</td><td>0</td></tr></tbody></table>