curred 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) ] .

r 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.

ts 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.

imes 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. 8.2 lactation risk summary there are no data on the presence of ecallantide in human milk, the effects on the breastfed infant, or the effects on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for kalbitor and any potential adverse effects on the breastfed child from kalbitor or from the underlying maternal condition. 8.4 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 [see clinical pharmacology (12.3) and clinical studies (14) ] . 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 [see adverse reactions (6.1) ] . safety and effectiveness of kalbitor in patients less than 12 years of age have not been established. 8.5 geriatric use clinical trials of kalbitor did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. in general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

ackground 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.

lator 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. 12.2 pharmacodynamics no exposure-response relationships for kalbitor to components of the complement or kallikrein-kinin pathways have been established. the effect of kalbitor on activated partial thromboplastin time (aptt) was measured because of potential effect on the intrinsic coagulation pathway. prolongation of aptt has been observed following intravenous dosing of kalbitor at doses ≥20 mg/m 2 . at 80 mg administered intravenously in healthy subjects, aptt values were prolonged approximately two-fold over baseline values and returned to normal by 4 hours post-dose. for patients taking kalbitor, no significant qt prolongation has been seen. in a randomized, placebo-controlled trial (edema4) studying the 30 mg subcutaneous dose versus placebo, 12-lead ecgs were obtained at baseline, 2 hours and 4 hours post-dose (covering the time of expected c max ), and at follow-up (day 7). ecgs were evaluated for pr interval, qrs complex, and qtc interval. kalbitor had no significant effect on the qtc interval, heart rate, or any other components of the ecg. 12.3 pharmacokinetics following the administration of a single 30 mg subcutaneous dose of kalbitor to healthy subjects, a mean (± standard deviation) maximum plasma concentration of 586 ± 106 ng/ml was observed approximately 2 to 3 hours post-dose. the mean area under the concentration-time curve was 3017 ± 402 ng*hr/ml. following administration, plasma concentration declined with a mean elimination half-life of 2.0 ± 0.5 hours. plasma clearance was 153 ± 20 ml/min and the volume of distribution was 26.4 ± 7.8 l. based on a population pharmacokinetic analysis, body weight, age, and gender were not found to affect kalbitor exposure significantly. ecallantide is a small protein (7054 da) and renal elimination in the urine of treated subjects has been demonstrated. no pharmacokinetic data are available in patients or subjects with hepatic or renal impairment.

ore is a point-in-time measure of symptom severity. at baseline, and post-dosing at 4 hours and 24 hours, patients rated the severity of each affected symptom on a categorical scale (0 = normal, 1 = mild, 2 = moderate, 3 = severe). patient-reported severity was based on each patient's assessment of symptom impact on their ability to perform routine activities. ratings were averaged to obtain the mscs score. the endpoint was reported as the change in mscs score from baseline. a decrease in mscs score reflected an improvement in symptom severity; the maximum possible change toward improvement was -3. tos is a measure of symptom response to treatment. at 4 hours and 24 hours post-dosing, patient assessment of response for each anatomic site of attack involvement was recorded on a categorical scale (significant improvement [100], improvement [50], same [0], worsening [-50], significant worsening [-100]). the response at each anatomic site was weighted by baseline severity and then the weighted scores across all involved sites were averaged to calculate the tos. a tos value >0 reflected an improvement in symptoms from baseline. the maximum possible score was +100. edema4 edema4 was a randomized, double-blind, placebo-controlled trial in which 96 patients were randomized 1:1 to receive kalbitor 30 mg subcutaneous or placebo for acute attacks of hae. the primary endpoint was the change from baseline in mscs score at 4 hours, and the tos at 4 hours was a key secondary endpoint. patients treated with kalbitor demonstrated a greater decrease from baseline in the mscs than placebo and a greater tos than patients with placebo and the results were statistically significant (table 2). at 24 hours, patients treated with kalbitor also demonstrated a greater decrease from baseline in the mscs than placebo (-1.5 vs. -1.1; p = 0.04) and a greater tos (89 vs. 55, p = 0.03). table 2: change in mscs score and tos at 4 hours edema4 edema3 kalbitor (n=48) placebo (n=48) kalbitor (n=36) placebo (n=36) mscs: mean symptom complex severity tos: treatment outcome score ci: confidence interval change in mscs score at 4 hours n 47 42 34 35 mean -0.8 -0.4 -1.1 -0.6 95% ci -1.0, -0.6 -0.6, -0.1 -1.4, -0.8 -0.8, -0.4 p-value 0.010 0.041 tos at 4 hours n 47 42 34 35 mean 53 8 63 36 95% ci 39, 68 -12, 28 49, 76 17, 54 p-value 0.003 0.045 more patients in the placebo group (24/48, 50%) required medical intervention to treat unresolved symptoms within 24 hours compared to the kalbitor-treated group (16/48, 33%). some patients reported improvement following a second 30 mg subcutaneous dose of kalbitor, administered within 24 hours following the initial dose for symptom persistence or relapse, but efficacy was not systematically assessed for the second dose. edema3 edema3 was a randomized, double-blind, placebo-controlled trial in which 72 patients were randomized 1:1 to receive kalbitor or placebo for acute attacks of hae. edema3 was similar in design to edema4 with the exception of the order of the prespecified efficacy endpoints. in edema3, the primary endpoint was the tos at 4 hours, and the key secondary efficacy endpoint was the change from baseline in mscs at 4 hours. as in edema4, patients treated with kalbitor demonstrated a greater decrease from baseline in the mscs than placebo and a greater tos than patients treated with placebo and the results were statistically significant (table 2). in addition, more patients in the placebo group (13/36, 36%) required medical intervention to treat unresolved symptoms within 24 hours compared to the kalbitor-treated group (5/36, 14%).