Annex 1 Letters supporting the application (separate document) Annex 2 Pivotal clinical trials (and extension studies) evaluating for treatment of acute HAE attacks Reference Study type Patients Treatment regimens Primary end points Craig et al. J Allergy Clin Immunol 2009 (I.M.P.A.C.T.1) Pivotal trial (Berinert ) Prospective, multinational, parallelgroup, randomised, placebo controlled, 3 arm, double blind, phase II/III study to compare the efficacy of (Berinert ) with placebo in the treatment of acute HAE attacks Randomised =125 ITT=124 Placebo, n=42; 10 U/kg, n=39; 20 U/kg, n=43 Single IV infusion of pdc1 INH at a dose of 10 or 20 U/kg, or placebo, for a single abdominal or facial attack (not laryngeal) Median time to onset of symptom relief was significantly shorter with 20 U/kg (0.5 h) than with placebo (1.5 h; p=0.0025). The median time to onset of symptom relief with 10 U/kg (1.2 h) was only slightly shorter than with placebo (1.5 h; p=0.2731). The reduction in median time to onset of symptom relief was more pronounced for severe attacks (0.5 h with 20 U/kg vs 13.5 h with placebo) than for moderate attacks (0.8 h with 20 U/kg vs 1.3 h with placebo) The recommended dose of in the treatment of acute HAE attacks is therefore 20 U/kg Craig et al. Allergy 2011 (I.M.P.A.C.T.2) Prospective, openlabel, uncontrolled, multicentre extension study of I.M.P.A.C.T.1 ITT=57 (Total of 1085 HAE attacks in 57 patients were treated with ) Single IV infusion of 20 U/kg for each attack (including laryngeal) Median duration of treatment = 24 months (range 0 51) Patients received for median of 7 attacks (range 1 184) Median time to onset of symptom relief was 0.46 h (28 min, 95% CI=0.39 0.53; range=0.17 497.0). Individual average time to onset of symptom relief was <1 hr in 51/57 (89.5%) patients. Median time to complete resolution of HAE symptoms was 15.48 h (95% CI=11.64 21.59; range=0.64 497.0) and was shortest for laryngeal attacks (5.79 h, 95% CI=2.05 25.90; range=0.63 48.25) Individual average time to compete resolution of HAE symptoms was <24 h in 41/57 (71.9%) patients. 20 U/kg was sufficient in 1073 of 1085 attacks (99%). In 12 cases (1%) additional doses, up to a total of 60 U/kg per attack, were administered. Zuraw et al. NEJM 2009 Pivotal trial (Cinryze ) Double blind, placebo 207 subjects participated in the trial, 1,000 U (in 10 ml sterile water) or Time from administration of the study drug to unequivocal relief of symptoms at the defining site was 2.41; 95% CI 1.17 4.95; p = 0.02. Page 1
Reference Study type Patients Treatment regimens Primary end points Phase 3 LEVP2005 1/Part A controlled clinical study comparing (Cinryze ) with placebo for treatment of an acute attack of HAE 71 presented with attacks and were randomized. 36 subjects received and 35 subjects received placebo. placebo (10 ml saline) administered IV If there was no response to treatment 60 min after the first dose, a second 1,000 U dose could be administered. Subjects with laryngeal attacks were treated openlabel The onset of unequivocal relief within 4 hours after treatment: 60% vs 42%, respectively (p = 0.06). Time to the complete resolution of the attack: 12.3 hours vs 25.0 hours in the placebo group (p = 0.004). Riedl et al. AAA1 2012 Phase 3 LEVP2006 1 (CHANGE 2) Open label extension study of LEVP2005 1/Part A. The study population comprised 113 subjects (aged 2 80 years); 101 received for an acute attack 1,000 U for attacks of angioedema at any anatomic location. Median time to the onset of relief during the first attack was 45 min. None of the 84 laryngeal attacks required intubation. The number of attacks with unequivocal relief of the defining symptom within 1 and 4 hours after the first dose was 412 (68%) and 529 (87%), respectively. Of the 101 patients treated for an attack during the study period; 80 achieved unequivocal relief of their first attacks within 4 hours after dosing with the study medication (response rate: 79%). The efficacy of did not decline in the subjects treated for >1 attacks. In the 15 subjects who had 10 attacks, median time to the onset of relief of their 10th attack was 30 min. Page 2
Annex 3 Selected studies of for treatment of acute HAE attacks in various clinical settings Reference Study type No. of patients Inclusion criteria Treatment regimens Outcomes Acute laryngeal attacks Bork and Barnstedt. Arch Intern Med 2001 Retrospective study 42 Patients monitored over a 29 year period 18 patients experiencing laryngeal attacks treated with (500 1000 U) All 193 acute episodes in 18 patients effectively treated with Duration of laryngeal oedema (mean ± SD) Treated: 15.3 ± 9.3 h (193 attacks) Untreated: 100.8 ± 26.2 h (324 attacks); p<0.001 Craig et al. J Clin Immunol 2010 Data from 39 laryngeal attacks in 16 patients with HAE that were treated with (Berinert ) 20 U/kg in the prospective, openlabel I.M.P.A.C.T.2 study 16 (39 laryngeal attacks) Patients 6 years and treated for laryngeal attack in I.M.P.A.C.T.2 Single IV infusion of 20 U/kg (range 18 20 U/kg) The number of laryngeal attacks/patient ranged from 1 8, 7 patients were treated for more than one laryngeal attack. Median time between start of treatment and onset of symptom relief was 0.25 h (15 min, 95% CI 0.25 0.50 h; range 0.1 1.3 h). All attacks were treated successfully. Onset of relief was reported within 1 h of start of treatment, in 95% of all attacks, and time to onset of relief was <0.75 h (45 min) in 85% of patients. Median time to complete symptom resolution was 8.25 hours (95% CI 4.1 21.5 h; range 0.6 48.9 h) when analysed by attack, and 5.87 h (95% CI 2.05 18.26 h; range 0.6 48.3 h) when analysed per patient. Riedl et al. Am J Rhinol Allergy, 2013 A post hoc analysis of an open label treatment study evaluating the effectiveness of pdc1 INH (Cinryze ) in the treatment of laryngeal attacks in patients with HAE. 37 patients (84 laryngeal attacks). Treated for laryngeal attack in LEVP 2006 1 (Riedl et al. 2012) 1000 U was administered IV, with a second 1000 U dose given after 60 min if indicated. 60 (50/84) and 77% (65/84) of attacks achieved unequivocal relief within 1 and 4 hours, respectively, after treatment. When was administered within 4 hours of symptom onset, clinical relief was achieved in 94% (45/48) of attacks within 4 hours after treatment. Page 3
Reference Study type No. of patients Inclusion criteria Treatment regimens Outcomes Paediatric population Farkas et al. J Allergy Clin Immunol 2012 Prospective study 50 Patients <18 years with type I or type II HAE, and diagnosed at the Hungarian HAE Center between 1992 and 2010 152 of 1392 attacks (upper airway, abdominal and subcutaneous) 27 patients treated with 500 IU Time to initial symptom relief ranged from 15 to 60 min in almost all attacks. Time to complete resolution ranged from less than 12 hours (in all attacks of upper airway) to 48 hours. Schneider et al. Pediatr Allergy Immunol 2013 Post hoc analysis of a placebo controlled and open label extension study 16 Paediatric patients 10 18 years of age from the I.M.P.A.C.T.1 and I.M.P.A.C.T.2 studies. 116 attacks in total treated with 10/20 U/kg b.w. In the I.M.P.A.C.T.2 study, the median time to onset of symptom relief in paediatric patients was similar to that for adults (0.49 h vs 0.45 h), as was the median time to complete resolution of symptoms (14.1 h in the paediatric group vs 15.9 h in adult patients). Lumry et al. J Pediatr 2013 Post hoc analysis of 2 placebo controlled and 2 open label extension studies. 46 Children and adolescents who participated in the 4 studies In the acute attack treatment studies, 1000 U of was given (with an additional 1000 U given 1 hour later if needed). The median time to the start of unequivocal relief in the acuteattack treatment study (n = 12) was 30 min with, compared with 2 hours for placebo. In the open label extension (n = 22), clinical relief began within 4 hours of therapy in 89% of attacks. Pregnant and nursing women Martinez Saguer et al. Am J Obstet Gynecol 2010 Observational study investigating the course of HAE before, during and after pregnancy and assessment of the efficacy and safety of (Berinert ) ITT=22 (22 women with 35 pregnancies) Women with type I HAE undergoing pregnancy between 1995 and 2007 500 or 1000 U either on demand or as IRT In 29/35 (83%) of pregnancies, attack rates increased during pregnancy The mean number of attacks was 9.4 (SD=10.5) in the nine months before pregnancy and 44.0 (SD=38.0) during pregnancy. Attacks rates were highest during the second and third trimesters. was used to treat attacks in 29/35 (82.9%) of Page 4
Reference Study type No. of patients Inclusion criteria Treatment regimens Outcomes for treatment of HAE attacks pregnancies HAE attacks were well controlled with. Czaller et al. Eur J Obstet Gynecol Reprod Biol 2010 Retrospective analysis of the natural course of HAE during pregnancy and impact of (Berinert ) treatment ITT=41 (41 women with 118 pregnancies) Data extracted from Hungarian National HAE Registry, medical charts and patients diaries 13 patients received 91 vials of for relief of acute attacks and for short or longterm prophylaxis during 118 pregnancies. HAE attack frequency increased in 39/82 (47.6%) full term pregnancies, clinical signs decreased in 27/82 (32.9%) and 16/82 (19.5%) pregnancies had no influence on HAE. was effective in all instances and no adverse effects were observed. Symptomatic improvement of all types of attack consistently occurred within 15 60 min of administration. Worsening of symptoms did not occur. Every woman treated with delivered a healthy neonate (disregarding inheritance of HAE). Baker et al. Allergy Asthma Proc 2013 Retrospective analysis of clinical trial and compassionate use data 16 Pregnant patients enrolled in either open label extensions of two randomized, double blind, placebo controlled trials of (Cinryze ) or in a compassionate use program was administered as acute treatment, preprocedural prophylaxis, or routine prophylaxis. For acute treatment, Cinryze at 1000 U was administered IV followed by a second 1000 U dose 60 min later, if necessary. Of the 16 unique subjects, 13 subjects delivered 14 healthy neonates (including 1 set of twins), 2 subjects had adverse foetal outcomes deemed unrelated to by investigators, and 1 subject s outcome was unknown. Home therapy and self administration Kreuz et al. Transfusion 2012 (Home therapy in adolescents) Retrospective, observational study 20 paediatric patients Median age Paediatric patients eligible for home therapy and with data from previous physician based 500 or 1000 U depending on patient s body weight and clinical history. Median duration of all 20 patients on home therapy was Median time from initial signs of an attack (or oedema symptoms) to start of treatment was significantly shorter with home therapy (15 min) than with previous physician based therapy (67.5 min). Median time from start of treatment to initial symptom relief was significantly shorter with home therapy (40 min) than with Page 5
Reference Study type No. of patients Inclusion criteria Treatment regimens Outcomes 14.0 years (range 7.0 17.7) therapy 3.0 years (range 1.1 6.7). Cumulatively the 20 patients had received home therapy for 74.1 patient years, during which approximately 2,400 treatments were administered previous physician based therapy (60 min). Mean number of days in hospital was significantly shorter with home therapy than with previous physician based therapy (0.11 days/year vs 3.8 days/year, respectively; p=0.008). The occurrence of laryngeal attacks decreased on home therapy (only 2 patients had laryngeal attacks). All attacks were treated successfully with administered as home therapy. Bygum et al Eur J Dermatol. 2009 (Self admin and QoL) QoL study ITT=7 All patients registered at Odense Hospital with HAE attacks requiring emergency department administration of (Berinert ) more than once a month were offered to be taught selfadministration. Patients were trained to selfadminister IV on demand After training, all patients were able to treat severe angioedema attacks. Mean DLQI scores decreased from 12.6 (standard deviation [SD]=4.65) before home therapy to 2.7 (SD=1.38) after therapy (p<0.001), a clinically significant 9.9 unit (79%) reduction. Mean SF 36 scores increased significantly for all parameters after home therapy; increases ranged from 13.6% for 'physical function' (p=0.0153) to 96.4% for 'role physical' (p<0.0001). Home therapy resulted in significantly improved QoL and reduced use of emergency services. Kreuz et al. Transfusion 2009 (HAE patients refractory to danazol prophylaxis and QoL) data on efficacy, safety and QoL data associated with pdc1 INH (Berinert ) use prospectively collected and compared with retrospective data on danazol ITT=22 PK data in 15/22 (68.2%) Aged >18 years, with HAE who discontinued longterm prophylaxis with danazol due to lack of efficacy, intolerability and/or severe side effects Based on documented attack intervals and consumption per attack, an individual treatment regimen was prepared for each patient. Usual dose of was 500 to 1000 U up to twice a week. All patients trained on selfinfusion. The change from danazol treatment to IRT with resulted in a median decrease of 43 attacks per year (p<0.001) and decrease of laryngeal attacks from 24 per year to 0. Total QOL score increased from 12.5 (95% CI, 10 18) with danazol to 48.5 (95% CI, 45 57; p<0.001) with IRT. Page 6
Annex 4 Selected studies demonstrating the safety of in various patient populations Reference Study description patients Intervention Outcome measures Bork Korger 2012 Post marketing surveillance study spontaneous reports of adverse drug reactions (ADRs) received by CSL Behring for its human pasteurized C1 INH concentrate (Berinert ), covering the 26 year period from 1985 until 30 June 2011. Craig et al. J Allergy Clin Immunol 2009 (I.M.P.A.C.T.1) Pivotal trial (Berinert ) Prospective, multinational, parallel group, randomised, placebo controlled, 3 arm, double blind, phase II/III study Randomised =126 ITT=124 Placebo, n=42; 10 U/kg, n=39; 20 U/kg, n=43 Approximately 374 million units of were administered worldwide in the 26 year observation period, encompassing more than 600,000 treatments in the approved indication Single IV infusion of pdc1 INH at a dose of 10 or 20 U/kg, or placebo, for a single abdominal or facial attack (not laryngeal) A total of 95 cases of suspected ADRs were reported worldwide, with 61 cases covered by the product s known safety profile: allergic or anaphylactic type reactions (9; in very rare cases involving shock), chills and fever (5), lack of effect (26), suspected virus transmission (5; not attributed to the product), and thrombosis (16). In 2 cases of thrombosis causality was assessed as unlikely. The other 14 cases of thrombosis occurred during off label use of the product, in cardiac surgery involving substantially higher doses than indicated in the label. The most commonly reported AEs in patients receiving 20 U/kg were nausea, abdominal pain, dysgeusia, peripheral oedema, vomiting, pain, and muscle spasms. was well tolerated. No seroconversions were observed for HIV, hepatitis virus, or human B19 virus. Craig et al. Allergy 2011 (I.M.P.A.C.T.2) Zuraw et al. NEJM 2009 Phase 3 LEVP2005 1/Part A Pivotal trial extension study Prospective, open label, uncontrolled, multicentre extension study of I.M.P.A.C.T.1 Pivotal trial (Cinryze ) Double blind, placebo controlled clinical study. ITT=57 (Total of 1085 HAE attacks in 57 patients were treated with pdc1 INH) 207 subjects participated in the trial, 71 presented with attacks and Single IV infusion of 20 U/kg for each attack (including laryngeal) Median duration of treatment = 24 months (range 0 51) Patients received for median of 7 attacks (range 1 184) 1,000 U (in 10 ml sterile water) or placebo (10 ml saline) administered IV If there was no response to was well tolerated during repeat administrations, with no drug related SAEs reported Only 3/13 AEs were classified as possibly related to the study drug (in the placebo group, tetany [carpal tunnel spasm] in 1 subject and contact dermatitis in 1 subject; in the group, rash at the injection site in 1 subject). Page 7
Riedl et al. AAA1 2012 Phase 3 LEVP2006 1 (CHANGE 2) Bork Steffensen 2013 Cinryze epar 2011 Open label extension study of LEVP2005 1. Systematic literature survey of the efficacy and safety of (Berinert ) in patients with HAE (up to Dec 2011). Evidence was synthesized from 89 studies (one RCT, 16 observational and 72 descriptive studies) Summary of results assessed across the Cinryze clinical trial programme (total of >14,500 Cinryze infusions administered across two randomised trials, three openlabel studies and three compassionate use studies) were randomized. 36 subjects received and 35 subjects received placebo. The study population comprised 113 subjects (aged 2 80 years); 101 received for an acute attack ~2000 patients with HAE (~1100 patientstreated with ) 385 patients with HAE Farkas Jakab 2007 Retrospective survey 61 patients who experienced 468 acute oedematous attacks (94 attacks in 22 children and 6 attacks in 4 pregnant women). treatment 60 min after the first dose, a second 1,000 U dose could be administered. Subjects with laryngeal attacks were treated openlabel 1,000 U for attacks of angioedema at any anatomic location. Dose from 500 U or 10/20 U/kg b.w. Treatment emergent adverse events (TEAEs) were reported by 46 of 113 patients (41%). Of the 129 TEAEs, most (87%, 112) were of mild or moderate intensity. Three patients reported 4 TEAEs considered related to. Of these, 2 events were possibly related (injection site pain and rash) and 2 (sinusitis and joint swelling) were of unknown relationship to. Thirteen serious TEAEs were experienced by 6 patients (5%), but all were considered unrelated to the study drug. There was no evidence of human immunodeficiency virus or viral hepatitis transmission or detection of clinically relevant anti C1 INH antibodies Treatment with was generally well tolerated in all patient groups (including children and pregnant/nursing women). Administration of C1 INH was not associated with transmission of viruses or development of autoantibodies irrespective of treatment duration. Intravenous was well tolerated when used to treat HAE episodes. Rash was the only common (frequency 1 to <10 %) adverse event with a suspected (possibly, probably or definitely) relationship to treatment with intravenous 500 U No adverse reactions, viral infections, and antibody formation against the purified protein were reported. Farkas Harmat Retrospective survey 26 children/ 500 U No treatment related AEs were reported in patients receiving pdc1 Page 8
2002 adolescents INH for treatment of an acute oedematous attack (n=9) Kreuz Rusicke 2012 Lumry, Manning et al. 2013 Czaller, Visy et al. 2010 Martinez Saguer, Rusicke et al. 2010 Retrospective, observational study to assess the efficacy and safety of home therapy with in paediatric patients with HAE who had previously been treated with physician based therapy. To evaluate the use of (Cinryze ) for the acute management and prevention of HAE attacks in the subgroup of children and adolescents who participated in 2 placebocontrolled and 2 open label extension studies. Retrospective analysis of clinical data on treatment of HAE attacks in pregnant women extracted from the National HAE Registry, medical charts and patient diaries. Observational study to characterize the rate and location of acute HAE attacks associated with pregnancy and, as appropriate, assess the efficacy and safety of treating these attacks with. 20 children (median age 14.0 years [range 7.0 17.7 years]) 46 children/ adolescents who received 2237 infusions 41 female patients (118 pregnancies [82 full term and 36 abortions]) 22 patients (35 pregnancies) 500 or 1000 U No side effects were reported retrospectively by any of the patients or their carers (including injection site related events) 500 IU (36 instances of acute attacks in 9 patients before labour, 12 instances in 3 post partum/nursing patients) 500 or 1000 U ondemand therapy in 11 pregnancies was shown to be well tolerated. No serious or severe adverse events were considered by the investigator to be related to, and no adverse events led to discontinuation of treatment. There was no evidence of HIV or viral hepatitis transmission or development of clinically relevant anti C1 INH antibodies in these studies. No treatment related AEs were reported before, during or after pregnancy. No still births or spontaneous abortions or drug related abnormalities of children were reported. Viral transmission did not occur either in mothers or in neonates. No adverse events were associated with treatment, no stillbirths or spontaneous abortions were reported; no confirmed conversions of viral titers for hepatitis A, B, C, or G or HIV occurred in any of the mothers or newborn children. Page 9
Annex 5 List of AEs reported in pivotal trials of AE category I.M.P.A.C.T.1 (Craig, Levy et al. 2009) (Berinert ) As long as 4 hours after treatment a Placebo (N=41) 10 U/kg (N=39) 20 U/kg (N=46) Any time a All doses b (N=108) I.M.P.A.C.T.2 (Craig, Bewtra et al. 2011) (Berinert ) All doses (N=57) LEV2005 1/Part A NCT00289211 (Cinryze ) Placebo (N=12) (N=71) LEV2005 1/Part B NCT01005888 (Cinryze ) Placebo (N=23) (N=25) CHANGE 2 (Riedl, Hurewitz et al. 2012) (Cinryze ) b (N=113) Hereditary angioedema 0 0 0 14 (13.0) 2 (3.5) 4 (3.5) CHANGE 3 NCT00462709 (Cinryze ) Headache 2 (4.9) 1 (2.6) 0 13 (12.0) 5 (8.8 3 (2.1) Abdominal pain 3 (7.3) 1 (2.6) 2 (4.3) 7 (6.5) 2 (3.5) Nausea 5 (12.2) 1 (2.6) 3 (6.5) 7 (6.5) 1 (1.8) 2 (1.4) Muscle spasms 2 (4.9) 4 (10.3) 1 (2.2) 6 (5.6) Pain 1 (2.4) 4 (10.3) 1 (2.2) 6 (5.6) Diarrhoea 4 (9.8) 1 (2.6) 0 5 (4.6) Vomiting 3 (7.3) 1 (2.6) 1 (2.2) 5 (4.6) Back pain 1 (2.4) 0 0 4 (3.7) Dysgeusia 0 1 (2.6) 2 (4.3) 4 (3.7) Oedema peripheral 0 1 (2.6) 1 (2.2) 4 (3.7) Abdominal distension 0 1 (2.6) 0 2 (1.9) (N=146) Upper respiratory tract infection 0 0 0 2 (1.9) 2 (3.5) Face oedema 1 (2.4) 1 (2.6) 0 1 (0.9) Lip swelling 1 (2.4) 1 (2.6) 0 1 (0.9) Page 10
Nasopharyngitis 3 (5.3) 5 (4.4) Abdominal discomfort 2 (3.5) Influenza like illness 2 (3.5) Rash 2 (3.5) 1 (1.4) 1 (4.0) 3 (2.7) 3 (2.1) Vulvovaginal mycotic infection 2 (3.5) Tetany 1 (8.3) Dermatitis contact 1 (1.4) Chest discomfort 1 (4.0) Pyrexia 1 (4.0) Dizziness 1 (4.0) Cough 1 (4.0) 3 (2.7) Pruritus 1 (4.0) Erythema 1 (4.0) Sinusitis 6 (5.3) Pharyngitis streptococcal 4 (3.5) Bronchitis 3 (2.7) Constipation 3 (2.7) Phlebitis 2 (1.4) a Most common AEs (>1 patient overall) b Patients treated with Berinert at any time during the study, including use of Berinert as rescue medication in the placebo and Berinert 10 U/kg groups c Treatment emergent AEs reported in 2% of patients in the ITT Safety population Page 11
Annex 6 Summary of reported AEs with and comparators (Berinert ) (Cinryze ) Icatibant (Firazyr ) Conestat alfa (Ruconest ) I.M.P.A.C.T.1 a I.M.P.A.C.T.2 b Acute attacks c FAST 1 d FAST 2 d Acute attacks e Acute attacks e 20 U/kg (n=46) 20 U/kg (n=57) 1000 U (n=36) 30 mg (n=27) 30 mg (n=36) 100 U/kg (n=29) 50 U/kg (n=12) Patients with AEs 9 (19.6%) 25 (43.9%) 6 (17%) 12 (44%) 19 (53%) 7 (24%) 4 (33%) Patients with at least possibly related AEs 5 (10.9%) 8 (14.0%) 1 (3%) 4 (15%) 5 (14%) 1 (3%) 0 Patients with SAE 0 1 (1.8%) 0 0 4 (11%) 1 (3%) 0 Patients with AEs leading to discontinuation of treatment 0 1 (1.8) 0 0 0 0 0 Most common treatment related AEs Gastrointestinal disorders 3 (6.5%) 2 (3.5%) 1 (3%) Nervous system disorders 2 (4.3%) 2 (3.5%) 1 (4%) 1 (3%) Infections and infestations 1 (1.8%) General disorders and administration site conditions 2 (4.3%) 3 (5.3%) 1 (3%) 1 (4%) 3 (8%) Investigations 1 (4%) Skin and subcutaneous tissue disorders 1 (1.8%) 1 (3%) Musculoskeletal and connective tissue disorders 1 (2.2%) Respiratory, thoracic, and mediastinal disorders 1 (4%) Congenital, familial, and genetic disorders 1 (3%) AEs occurring within 4 hours; * AEs occurring at any time during follow up in patients treated with Berinert at any time during the study (10 U/kg or 20 U/kg), including use of Berinert as rescue medication in the placebo and Berinert 10 U/kg groups; One patient (retrospectively found not to have HAE) had two SAEs that were unrelated to study medication; Infusion related reaction 2 min after the start of infusion for the second attack of the patient in this study; the event resolved after 4.6 h and could not be clearly defined as allergic or anaphylactic a (Craig, Levy et al. 2009), b (Craig, Bewtra et al. 2011), c (Zuraw, Busse et al. 2010), d (Cicardi, Banerji et al. 2010), e (Zuraw, Cicardi et al. 2010) Page 12
Cicardi, M., A. Banerji, et al. (2010). "Icatibant, a new bradykinin receptor antagonist, in hereditary angioedema." N Engl J Med 363(6): 532 541. Craig, T. J., A. K. Bewtra, et al. (2011). "C1 esterase inhibitor concentrate in 1085 Hereditary Angioedema attacks final results of the I.M.P.A.C.T.2 study." Allergy 66(12): 1604 1611. Craig, T. J., R. J. Levy, et al. (2009). "Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks." J Allergy Clin Immunol 124(4): 801 808. Riedl, M. A., D. S. Hurewitz, et al. (2012). "Nanofiltered C1 esterase inhibitor (human) for the treatment of acute attacks of hereditary angioedema: an open label trial." Ann Allergy Asthma Immunol 108(1): 49 53. Zuraw, B., M. Cicardi, et al. (2010). "Recombinant human C1 inhibitor for the treatment of acute angioedema attacks in patients with hereditary angioedema." J Allergy Clin Immunol 126(4): 821 827 e814. Zuraw, B. L., P. J. Busse, et al. (2010). "Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema." N Engl J Med 363(6): 513 522. Page 13