Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism Of Action Patients with hemophilia B are deficient in coagulation factor IX, which is required for effective hemostasis. Treatment with RIXUBIS temporarily replaces the missing coagulation factor IX. Pharmacodynamics The administration of RIXUBIS increases plasma levels of factor IX, and can temporarily correct the coagulation defect in these patients by decreasing the aPTT. Pharmacokinetics PTPs ≥ 12 Years of Age A randomized, blinded, controlled pharmacokinetic trial of RIXUBIS was conducted in non-bleeding subjects ( ≥ 15 years of age). The subjects received RIXUBIS as an intravenous infusion. The infusion rate for the first administration during the trial was not to exceed 4 mL/minute with a maximum infusion rate of 10 mL/minute. The dose range of RIXUBIS was from 71.3 to 79.4 international units/kg (mean dose = 74.7 international units/kg). Blood samples for factor IX activity measurements were obtained up to 72 hours and a non-compartmental analysis was used to estimate pharmacokinetic parameters. The pharmacokinetic evaluation was repeated for RIXUBIS in a prospective, open-label, uncontrolled trial with RIXUBIS in subjects who participated in the initial trial and had then received RIXUBIS for 26 ± 1 (mean ± SD) weeks for routine prophylaxis, and accumulated at least 30 exposure days to RIXUBIS. The dose range of RIXUBIS in this repeat pharmacokinetic trial was 64.5 to 79.2 international units/kg (mean dose = 74.6 international units/kg). Table 4 presents the pharmacokinetic parameters for all evaluable subjects (per protocol analysis). Table 4 : Pharmacokinetic Parameters for RIXUBIS Following Single and Repeat Dosing ( ≥ 12 years of age) Parameter First Dose (N=25) Repeat Dose (N=23) AUC0-inf (IUhrs/dL)a Mean (SD) 1207 (242) 1305 (300) Min; Max 850; 1710 838; 1864 Incremental recovery at Cmax (IU/dL:IU/kg)b Mean (SD) 0.87 (0.22) 0.95 (0.25) Min; Max 0.53; 1.35 0.52; 1.38 Half-life (hrs) Mean (SD) 26.7 (9.6) 25.4 (6.9) Min; Max 15.8; 52.3 16.2; 42.2 Cmax (IU/dL) Mean (SD) 66.2 (15.8) 72.7 (19.7) Min; Max 41.7; 100.3 38.5; 106.3 Mean Residence Time (hrs) Mean (SD) 30.8 (7.3) 29.9 (4.2) Min; Max 22.3; 47.8 21.3; 37.5 Vssc (mL/kg) Mean (SD) 201.9 (77.4) 178.6 (45.2) Min; Max 110.0; 394.0 112.0; 272.0 Clearance [mL/(kghr)] Mean (SD) 6.4 (1.3) 6.0 (1.5) Min; Max 4.3; 9.1 4.1; 9.5 a Area under the plasma concentration-time curve from time 0 to infinity hours post-infusion. b Calculated as (Cmax – baseline factor IX) divided by the dose in IU/kg, where Cmax is the maximum post-infusion factor IX measurement. c Volume of distribution at steady state. Data from PTPs who underwent repeat in vivo recovery testing for up to 26 weeks demonstrated that the incremental factor IX recovery was consistent over time (Table 5). Table 5 : Incremental Recovery for RIXUBIS 30 Minutes After Infusion ( ≥ 12 years of age) Incremental recovery 30 min after infusion (IU/dL:IU/kg)a Day 1 (N=73) Week 5 (N=71) Week 13 (N=68) Week 26 (N=55) At trial completion/ terminationb (N=23) Mean ± SD 0.79 ± 0.20 0.83 ± 0.21 0.85 ± 0.25 0.89 ± 0.12 0.87 ± 0.20 Median (range) 0.78 (0.26-1.35) 0.79 (0.46-1.48) 0.83 (0.14-1.47) 0.88 (0.52-1.29) 0.89 (0.52-1.32) a Calculated as (C30min – baseline factor IX) divided by the dose in IU/kg, where C30min is the factor IX measurement 30 minutes after infusion. b If not coinciding with week 26 visit. PTPs < 12 Years of Age Twenty-three male subjects underwent a pharmacokinetic evaluation of RIXUBIS as part of the combined pediatric trial ( < 6 years and 6 - < 12 years). The mean (± SD) and median dose were 75.5 ± 3.0 and 75.3 international units/kg, respectively, with a range of 70.0 to 83.6 international units/kg. Non-linear mixed model (population PK) was used to estimate the pharmacokinetic parameters from factor IX activity measurements in blood samples obtained up to 60 hours following the infusion. Pharmacokinetic parameters for all subjects are presented in Table 6. Table 6 : Pharmacokinetic Parameters for PTPs Parameter ≥ 12 yearsa (N=25) 6 - < 12 years (N=12) < 6 years (N=11) AUC0-inf (IUhr/dL)a Mean ± SD 1185±273 886 ± 134 864 724±119 Median (range) 1197 (783-1780) (730-1138) 717 (488-947) Half-life (hr) Mean ± SD 25.7 ± 1.5 23.2 ± 1.6 27.7 ± 2.7 Median (range) 25.6 (22.8-29.0) 22.6 (21.8-27.4) 27.3 (24.0-32.2) Mean residence time (hr) Mean ± SD 30.2 ± 2.2 25.3 ± 1.8 30.6 ± 3.3 Median (range) 30.3 (25.9-33.9) 24.7 (23.7-30.3) 30.1 (26.2-36.2) Vssb (mL/kg) Mean ± SD 201.5 ± 47.2 220.9 ± 31.7 322.5 ± 52.3 Median (range) 190.2 (138-300) 218.5 (169.9-270.1) 315.7 (264.7-441.5) Clearance (mL/[kghr]) Mean ± SD 6.7 ± 1.5 8.7 ± 1.2 10.6 ± 1.7 Median (range) 6.43 (4.1-9.9) 8.6 (6.9-10.8) 10.5 (8.1-14.4) a Non-linear mixed model (population PK) was applied on the reduced 4 blood samples (30min, 6hr, 24hr, and 60hr). Incremental recovery 30 minutes after infusion was determined for all subjects in the combined trial during the pharmacokinetic evaluation (exposure day 1), at week 5, 13, and 26 visits, and at the time of trial completion or termination, if it did not coincide with the week 26 visit. The data demonstrate that the incremental recovery is consistent over time across all pediatric age groups. (see Tables 7 and 8) Table 7 : Incremental Recovery for RIXUBIS 30 Minutes After Infusion Ages < 6 Years Incremental recovery 30 min after infusion (IU/dL-IU/kg)a PK (ED 1) (N=10) Week 5 (N=11) Week 13 (N=10) Week 26 (N=10) Mean ± SD 0.59 ± 0.13 0.63 ± 0.10 0.68 ± 0.12 0.65 ± 0.13 Median (range) 0.59 (0.31-0.75) 0.6 (0.49-0.80) 0.66 (0.51-0.84) 0.61 (0.51-0.84) a Calculated as (C30min–baseline factor IX) divided by the dose in IU/kg, where C30min is the factor IX measurement 30 minutes after infusion. Table 8 : Incremental Recovery for RIXUBIS 30 Minutes After Infusion Ages 6 to < 12 Years Incremental recovery 30 min after infusion PK (ED 1) N=12) Week 5 (N=12) Week 13 (N=11) Week 26 (N=11) (IU/dL-IU/kg)a Mean ± SD 0.73 ± 0.16 0.73 ± 0.13 0.73 ± 0.14 0.8 ± 0.14 Median (range) 0.71 (0.51 - 1.00) 0.70 (0.48-0.92) 0.70 (0.54-1.00) 0.78 (0.56-1.01) a Calculated as (C30min–baseline factor IX) divided by the dose in IU/kg, where C30min is the factor IX measurement 30 minutes after infusion. Clinical Studies Prophylaxis and Control of Bleeding in PTPs ≥ 12 Years of Age The efficacy of RIXUBIS has been evaluated in a prospective, open-label, uncontrolled multicenter trial, in which a total of 73 male PTPs between 12 and 65 years of age received RIXUBIS either for routine prophylaxis or on-demand treatment. In addition, there is an ongoing prospective, open-label, uncontrolled, multicenter trial where 14 PTPs underwent minor or major surgeries receiving RIXUBIS for perioperative management. PTPs were defined as subjects who were exposed to a factor IX containing product for ≥ 150 days. All subjects had severe (factor IX level < 1%) or moderately severe (factor IX level ≤ 2%) hemophilia B. The majority of subjects (88%) had arthropathy and/or target joints (66%) at screening. Subjects with history of a detectable factor IX inhibitor ≥ 0.6 BU, history of severe allergic reactions following exposure to factor IX containing products, evidence of severe chronic liver disease (INR > 1.4), impaired renal function, CD4 count < 200 cells/mm³, or any hemostatic defect other than hemophilia B, were excluded from the trial. Of 59 subjects who received RIXUBIS for routine prophylaxis, 56 subjects received the product for a minimum of 3 months and were included in the efficacy evaluation. The prophylactic regimen consisted of 40 to 60 international units/kg RIXUBIS twice weekly. An additional 14 subjects received RIXUBIS on-demand for treatment of bleeding episodes only. These subjects had to have at least 12 documented bleeding episodes requiring treatment within 12 months prior to enrollment. In the on-demand arm, the mean treatment duration was 3.5 ± 1 months (median 3.4, ranging from 1.2 to 5.1 months) and the mean total annualized bleeding rate (ABR was 33.9 ± 17.37 with a median of 27 ranging from 12.9 to 73.1. In the prophylaxis arm the mean ABR was 4.3 for all bleeds, 1.7 for spontaneous bleeds, and 2.9 for joint bleeds (Table 9). Table 9 : Efficacy of Prophylaxis with RIXUBIS (N = 56) ≥ 12 Years of Age Total ABR Mean ± SD 4.3 ± 5.80 Median (range) 2.0 (0.0-23.4) ABR for joint bleeds Mean ± SD 2.9 ± 4.25 Median (range) 0.0 (0.0-21.5) ABR for spontaneous bleeds Mean ± SD 1.7 ± 3.26 Median (range) 0.0 (0.0-15.6) Subjects with zero bleeding episodes % (n) 42.9% (24) * The prophylactic regimen consisted of 40 to 60 international units/kg RIXUBIS twice weekly. Treatment of Bleeding Episodes in PTPs ≥ 12 Years of Age A total of 249 bleeding episodes were treated with RIXUBIS, of which 115 bleeds were recorded for subjects treated on prophylaxis and 134 bleeds for those with the on-demand regimen. There were 197 joint bleeds and 52 non-joint bleeds (soft tissue, muscle, body cavity and other). Of the 249 bleeding episodes, 15 were major, 163 were moderate, and 71 were minor (see Table 1 for definitions of major, moderate and minor). Treatment was individualized based on the severity, cause, and site of bleed. The majority (211; 84.7%) were treated with 1 to 2 infusions. Of these, 153 (61.4%) were treated with 1 infusion and 58 (23.3%) were treated with 2 infusions. No non-responders were reported. Hemostatic efficacy at resolution of a bleed was rated excellent or good in 96% of all treated bleeding episodes (Excellent is defined as full relief of pain and cessation of objective signs of bleeding after a single infusion; no additional infusion is required for the control of bleeding; Good is defined as definite pain relief and/or improvement in signs of bleeding after a single infusion; possibly requires more than one infusion for complete resolution). Prophylaxis and Control of Bleeding in PTPs < 12 Years of Age The efficacy of RIXUBIS has been evaluated in a clinical trial, in which a total of 23 male, (PTPs) between 1.8 and 11.8 years (median age 7.10 years) with 11 subjects < 6 years, received RIXUBIS for prophylaxis and control of bleeding episodes. PTPs were defined as subjects who were exposed to a factor IX-containing product on ≥ 150 days for subjects aged 6 to < 12 years and on ≥ 50 days for subjects aged < 6 years. All subjects had severe (factor IX level < 1%) or moderately severe (factor IX level ≤ 2%) hemophilia B. Subjects with a history of or a detectable FIX inhibitor ≥ 0.6 BU, a history of severe allergic reactions following exposure to FIX, evidence of severe chronic liver disease (INR > 1.4), impaired renal function, a CD4 count < 200 cells/mm³ or any hemostatic effect other than hemophilia B were excluded from participation. All 23 subjects received prophylactic treatment with RIXUBIS for a minimum of 3 months and were included in the efficacy evaluation for prophylaxis (see Table 10). Table 10 : Efficacy of Prophylaxis of RIXUBIS in 23 PTPs < 12 Years of Age Total annualized bleeding rate (ABR) Mean ± SD 2.7 ± 3.14 Median (range) 2.0 (0.0-10.8) ABR for joint bleeds Mean ± SD 0.8 ± 1.76 Median (range) 0.0 (0.0-7.2) ABR for spontaneous bleeds Mean ± SD 0.2 ± 0.66 Median (range) 0.0 (0.0-2.0) Subjects with zero bleeds % (n) 39.1.% (9) * The prophylactic regimen consisted of 40 to 80 international units/kg RIXUBIS twice weekly. Treatment of Bleeding Episodes in PTPs < 12 Years of Age A total of 26 bleeding episodes were treated with RIXUBIS, of which 23 bleeds were due to injury, 2 spontaneous and 1 of unknown origin; 19 bleeds were non-joint (soft tissue, muscle, body cavity, intracranial and other) and 7 were joint bleeds of which 1 was a bleed into a target joint. Of the 26 bleeding episodes, 15 were minor, 9 moderate, and 2 major (Minor: little or no pain; little or no change in the range of motion of affected joint (if joint bleeding event); mild restriction of mobility and activity; Moderate: mild to moderate pain; some decrease in range of motion of affected joint (if joint bleeding event); moderate decrease in mobility and activity; Major/ life threatening: significant pain; substantial decrease in range of motion of affected joint (if joint bleeding event); incapacity; life threatening). Treatment was individualized based on the severity, cause and site of bleed. The majority (23; 88.5%) were treated with 1 to 2 infusions. Of the treated bleeding episodes 15 (57.7%) received 1 infusion, 8 (30.8%) received 2 infusions, and 3 (11.5%) were treated with 3 infusions. Hemostatic efficacy at resolution of a bleed was rated excellent or good in 96.2% of all treated bleeding episodes. Perioperative Management The efficacy analysis of RIXUBIS in perioperative management included 14 surgeries performed in 14 PTPs between 19 and 54 years of age undergoing major or minor surgical (see Table 2 for definitions of major and minor), dental or other surgical invasive procedures. Eleven procedures (including 7 orthopedic and 1 dental surgeries) were major, 3 procedures (including 2 dental extractions) were minor. Subjects undergoing major surgeries also underwent a pharmacokinetic evaluation. All subjects were dosed based on their most recent individual incremental recovery. The recommended initial loading dose of RIXUBIS was used to ensure that during surgery factor IX activity levels of 80-100% for major surgeries and 30-60% for minor surgeries were maintained. RIXUBIS was administered by intravenous bolus infusions. Hemostasis was maintained throughout the trial duration. The following are the surgical procedures and results of the assessment of the hemostatic response at various points. Fourteen surgeries (11 major; 3 minor), included in the intraoperative assessment had a rating of 'excellent'. At discharge from hospital 11/14 surgeries (8 major) had a rating of 'excellent' and 3/14 (3 major) had a rating of 'good'. The rating of excellent, good, fair and none at 72 hours post-surgery was based on the hemostasis achieved as compared to that expected in hemostatically normal subjects. REFERENCES 1. Roberts HR, Eberst ME. Current management of hemophilia B. Hematol Oncol Clin North Am. 1993;7(6):1269-1280.

CLINICAL PHARMACOLOGY Action And Clinical Pharmacology Mechanism Of Action IDELVION, Coagulation Factor IX (Recombinant), Albumin Fusion Protein (rIX-FP), is a recombinant fusion protein linking recombinant coagulation FIX with recombinant albumin that effectively replaces the missing coagulation FIX needed for hemostasis and provides for longer dose regimens. The prolongation of the half-life of IDELVION and the enhanced systemic exposure are achieved by fusion with recombinant albumin, which has a long intrinsic half-life. IDELVION remains intact in the circulation until FIX is activated, whereupon albumin is cleaved, releasing activated FIX (FIXa) when it is needed for coagulation. Albumin is a natural, inert carrier protein in plasma with a long half-life of approximately 20 days that is not involved in immune defense or immune response. Genetic fusion of recombinant coagulation FIX with albumin extends the half-life of FIX (See Sub-Section Pharmacokinetics). Pharmacodynamics Haemophilia B is a sex linked hereditary disorder of blood coagulation due to decreased levels of FIX and results in profuse bleeding into joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma. By replacement therapy the plasma levels of FIX is increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies. FIX is activated by factor VII/tissue factor complex in the extrinsic pathway as well as factor XIa in the intrinsic coagulation pathway. Activated FIX, in combination with activated factor VIII, activates factor X. This results ultimately in the conversion of prothrombin to thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed. FIX activity is absent or greatly reduced in patients with haemophilia B and substitution therapy may be required. The administration of IDELVION increases plasma levels of FIX, and can temporarily correct the coagulation defect in these patients. Pharmacokinetics Adults ( ≥ 18 years) The pharmacokinetics of IDELVION were evaluated following an intravenous injection of a single dose of 25, 50 and 75 IU/kg. The PK parameters were based on plasma FIX activity measured by the one-stage clotting assay. Blood samples for PK analysis were collected prior to dosing and up to 336 hours (14 days) after dosing. The PK data demonstrate that rIX-FP has an improved PK profile in comparison to plasma-derived FIX (pdFIX) and rFIX products. Table 5 provides the pharmacokinetic parameters following a single injection of 50 IU/kg of IDELVION. Table 5: Pharmacokinetic Parameters (Arithmetic Mean, CV%) Following a Single Injection of 50 IU/kg of IDELVION PK Parameters rIX-FP 50 IU/kg (N=47) IR (IU/dL)/(IU/kg) 1.30 (23.8) Cmax (IU/dL) 66.6 (26.7) AUCo-inf (h*IU/dL) 7482 (28.4) t-½ (h) 104.2 (25.4) MRT (h) 142.8 (22.7) CL (mL/h/kg) 0.731 (26.8) Vss (dL/kg) 1.020 (27.9) Time to 1% FIX Activity (d)a 21.0 Time to 3% FIX Activity (d)a 15.5 Time to 5% FIX Activity (d)a 12.0 a = Estimated time to median FIX activity maintained above the pre-specified % IR = incremental recovery recorded 30 minutes after injection; AUC = area under the FIX activity time curve; t½ = half-life; MRT = mean residence time; CL = body weight adjusted clearance; Vss = body weight adjusted volume of distribution at steady-state. In the pivotal trial, after a single dose of 50 IU/kg IDELVION has a prolonged circulating half-life, enlarged area under the FIX activity time curve, lower clearance and an increased incremental recovery. The mean (CV%) incremental recovery of IDELVION was 1.30 (23.8%) which is higher than that of the previous FIX product [pdFIX or rFIX; 1.00 (25.7%)]. Therefore, one IU/kg IDELVION provides a mean increase of 1.30 IU/dL in the circulating level of FIX. Repeat PK assessment for up to 30 weeks demonstrated a stable pharmacokinetic profile and that incremental recovery was consistent over time. The PK after a single dose of 75 IU/kg IDELVION was derived from 8 evaluable subjects. The mean FIX activity at Day 14 was 6.65%. The estimated time to 1% FIX activity is approximately 27 days after a single dose of 75 IU/kg IDELVION, based on population PK modeling simulations. The PK after a single dose of 25 IU/kg IDELVION was derived from 7 evaluable subjects. The mean FIX activity at Day 14 was 2.97%. The estimated time to 1% FIX activity is approximately 16.5 days after a single dose of 25 IU/kg IDELVION, based on population PK modeling simulations. PTPs ( < 18 years) Pharmacokinetics parameters of rIX-FP were evaluated in 8 adolescents (12 to < 18 years of age) and 27 children (1 to < 12 years of age) in open-label, multi-center studies following a 50 IU/kg intravenous injection of IDELVION. The PK samples were collected prior to dosing and at multiple time points up to 336 hours (14 days) after dosing. Table 6 summarizes the PK parameters calculated from the pediatric data of 35 subjects 1 to < 18 years of age. These parameters were estimated based on the plasma FIX activity over time profile. Compared to adults, incremental recovery appeared to be slightly lower and body weight-adjusted clearance appeared to be higher in children. Table 6: Comparison of Pharmacokinetic Parameters by Age Category (Arithmetic Mean, CV%) Following a Single Injection of 50 IU/kg of IDELVION PK Parameters 1 to < 12 years (N=27) 12 to < 18 years (N=8) IR (IU/dL)/(IU/kg) 1.01 (22.5) 1.11 (27.7) Cmax (IU/dL) 50.9 (21.8) 55.3 (28.1) AUC0-inf (h*IU/dL) 4788 (31.3) 5347 (48.2) 1-½ (h) 91.0 (17.7) 87.3 (35.7) MRT (h) 125.8 (17.4) 119 (31.2) CL (mL/h/kg) 1.13 (27.1) 1.08 (39.3) Vss (dL/kg) 1.38 (21.0) 1.16 (14.0) IR = incremental recovery recorded 30 minutes after injection; AUC = area under the FIX activity time curve; t½ = half-life; MRT = mean residence time; CL = body weight adjusted clearance; Vss = body weight adjusted volume of distribution at steady-state. Clinical Trials Study Demographics And Trial Design The efficacy, PK and safety of IDELVION, Coagulation Factor IX (Recombinant), Albumin Fusion Protein (rIX-FP), has been evaluated in a prospective, open-label, multicenter clinical study that compared episodic (on-demand) treatment to weekly routine prophylaxis; compared weekly routine prophylaxis to every 10 or 14 day routine prophylaxis; determined hemostatic efficacy in the treatment of bleeding episodes; and determined hemostatic efficacy during perioperative management of subjects undergoing surgical procedures. PK of IDELVION was evaluated in all subjects in the pivotal study, except those who completed a PK assessment in a prior study. A total of 63 male PTPs with severe hemophilia B ( ≤ 2% endogenous FIX activity), between 12 and 61 years of age (median 30 years) received IDELVION for up to 27 months. Forty subjects in the prophylaxis arm received weekly routine prophylaxis at an initial dose of 35-50 IU/kg, with median dose of 40 IU/kg of IDELVION at the end of the weekly prophylaxis period. Twenty-six out of 40 subjects in the prophylaxis arm subsequently crossed-over to every 10 or 14 day routine prophylaxis and received 50-75 IU/kg of IDELVION after approximately 26 weeks of weekly prophylaxis. Twenty-three subjects in the on-demand arm received IDELVION as needed for the treatment of bleeding episodes, 19 subjects subsequently crossed-over to weekly prophylaxis after approximately 26 weeks of episodic treatment. If a subject required a surgical procedure during the study, the subject could be enrolled in the surgical substudy. Routine Prophylaxis Based on a matched pairs design, the median percent reduction in the number of spontaneous bleeds per year (annualized spontaneous bleeding rate, (AsBR)) with IDELVION prophylaxis compared to on-demand was 100% (IQR 90.5%, 100%). A comparison of the AsBRs and Annualized Bleeding Rates (ABRs) in 19 subjects evaluable for efficacy is summarized in Table 9. Table 9: Comparison of Annualized Bleeding Rates (ABR) Bleeding episode etiology On-demand (n=19)* Weekly Prophylaxis (n=19)* Percent Reduction in ABR with prophylaxis (n=19)* Spontaneous Mean (SD) 14.57 (8.421) 0.73 (1.171) 95.96 (5.539) Median 15.43 0 100 IQR 7.98, 17.96 0, 0.96 90.5, 100 Range 2.0, 39.5 0, 4.2 82.8, 100 Total Mean (SD) 20.78 (9.194) 2.87 (4.814) 88.80 (17.762) Median 19.22 1.58 90.94 IQR 16.70, 25.84 0, 4.06 81.19, 100 Range 2.0, 46.1 0, 21.1 54.3, 100 * Based on matched pairs design IQR = interquartile range, defined for 25th percentile and 75th percentile; SD = standard deviation; Subjects evaluable for efficacy are subjects who received at least one dose of on-demand treatment, and one dose of prophylaxis treatment. Based on matched pairs design for spontaneous ABRs, both 7 day prophylaxis and 14 day prophylaxis regimens with IDELVION were demonstrated to be effective. The spontaneous ABRs in subjects on weekly and 14-day prophylaxis are summarized in Table 10. Table 10: Comparison of Annualized Bleeding Rate by Prophylaxis Regimen Bleeding Episode Etiology Weekly Routine Prophylaxis (n=21)* 14-day Prophylaxis (n=21)* Spontaneous Mean (SD) 0.28 (1.010) 1.07 (2.114) Median 0 0 IQR 0, 0 0, 1.00 Range 0, 4.5 0, 7.3 * Based on a matched pairs design IQR = interquartile range; SD = Standard deviation Treatment Of Bleeding Episodes A total of 358 bleeding events were treated with IDELVION; 93.6% of bleeds were resolved with one injection and 98.6% with no more than two injections. Assessment of response to each injection was recorded in an eDiary by subjects at 24 hours after treatment. Overall treatment efficacy was assessment for each bleeding episode by the investigator based on a 4-point scale. Efficacy in control of bleeding episodes is summarized in Table 11. Table 11: Efficacy* in Control of Bleeding Number of Bleeding Episodes Requiring Treatment (n = 358) Number of injections to treat bleeding episodes 1 injection, n (%) 335 (93.6) 2 injections, n (%) 18 (5.0) 1 or 2 injections, n (%) 353 (98.6) > 2 injections, n (%) 5 (1.4) Assessment of Efficacy* Excellent or Good efficacy, n (%) 337 (94.1) Moderate efficacy, n (%) 9 (2.5) Poor/no response, n (%) 1 (0.3) * Excellent: Pain relief and/or unequivocal improvement in objective signs of bleeding and no additional infusion required in order to achieve hemostasis; Good: Definite pain relief and/or improvement in signs of bleeding at approximately 8 hours after the first infusion, but may require a second infusion; Moderate: Probable or slight beneficial effect, and requires more than two infusions to achieve hemostasis; Poor/no response: No improvement at all or condition worsens, additional hemostatic intervention is required. Responses evaluated at approximately 24 hours after treatment. Perioperative Management In three clinical studies, 7 subjects received IDELVION for perioperative management in 9 surgical procedures. Dose was individualized based on subject's PK and clinical response to treatment at the investigator's discretion. The efficacy analysis of IDELVION in perioperative management included 7 surgeries in 5 PTPs between 12 and 61 years of age undergoing major or minor surgical procedure, including dental surgeries. The nine surgical procedures included a double mastectomy, 2 knee replacements, a hemorrhoidectomy, a rhinoplasty and 3 complicated and 1 uncomplicated dental surgeries. Two of the 4 dental surgeries were performed in children < 12 years. Perioperative FIX replacement with IDELVION was by intravenous bolus injection only. The safety of continuous infusion was not evaluated. Hemostasis was assessed by the investigator/surgeon at wound closure (intraoperative assessment), 72 hours after surgery or at hospital discharge and at the end of the surgical substudy using a 4 point-scale of excellent, good, fair and none. The nine surgeries included in the intraoperative assessment of hemostatic response was rated as excellent (n = 8). One patient was not rated post-dental extraction. At 72 hours or hospital discharge 7/9 had a rating of “excellent” and 2/9 had a rating of “good”. There was no clinical evidence of thrombotic complications in any of the subjects. Detailed Pharmacology See Section ACTION AND CLINICAL PHARMACOLOGY. Microbiology Not applicable. Toxicology The toxicological program included studies after single or repeated bolus dosing in rodent and non-rodent species. Rats and monkeys were selected as they represent the standard animals for these types of toxicological investigations and rIX-FP was shown to be pharmacologically active in these species. A single intravenous bolus injection of rIX-FP at doses up to 500 IU/kg was well tolerated in cynomolgus monkeys and rats with no toxicologically significant changes. The No Observed Adverse Effect Level (NOAEL) was considered to be 500 IU/kg for both species. The repeat-dose studies (28 days) reflect the clinical practice of multiple treatments for hemophilia B patients. Due to the expected immune response against the heterologous human protein, an interim sacrifice was carried out at Day 6. Overall, administration of rIX-FP by intravenous injections on 28 consecutive days at doses up to 500 IU/kg/day was well tolerated in the rat with no findings indicative of adverse toxicity and a NOAEL of 500 IU/kg was considered under the conditions of this study. The same was observed following repeated dosing in cynomolgus monkeys leading to a NOAEL of 500 IU/kg. To evaluate the potential genotoxicity risk, two in vitro studies were performed with rIX-FP, i.e. the bacterial reverse mutation test (Ames test) and the chromosome aberration test in human lymphocytes. Both assays showed no evidence of mutagenic activity. Local tolerance investigations were included in the single-dose and repeat-dose toxicity studies in rats and monkeys. Furthermore, a separate local tolerance study was performed in rabbits with no local or systemic signs of reaction to treatment leading to the overall conclusion that rIX-FP was locally well tolerated following repeated intravenous bolus injections in the rat and cynomolgus monkey and following a single intravenous, intra-arterial and perivenous administration to rabbits. The thrombogenic potential of rIX-FP was evaluated using a modified Wessler stasis model in rabbits, a standard model to investigate thrombogenicity. There was no indication of thrombogenic activity at the three doses of rIX-FP tested, i.e. 75 IU/kg, 150 IU/kg and 500 IU/kg. Nonclinical studies evaluating the carcinogenic potential of rIX-FP have not been conducted. Animal reproductive and developmental toxicity studies were also not conducted with rIX-FP. However, no adverse effects on reproductive organs were observed by macroscopic and microscopic pathological investigations in repeated dose toxicity studies. REFERENCES 1. Santagostino E, Negrier C, Klamroth R, Tiede A, Pabinger-Fasching I, Voigt C, Jacobs I, Morfini M. Safety and pharmacokinetics of a novel recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in hemophilia B patients. Blood. 2012 Sep 20; 120(12):2405-11.

CLINICAL PHARMACOLOGY Mechanism Of Action Patients with hemophilia B are deficient in coagulation Factor IX, which is required for effective hemostasis. Treatment with REBINYN temporarily replaces the missing coagulation Factor IX. The Factor IX in REBINYN is conjugated to a 40-kDa polyethylene glycol molecule, which slows down its removal from the blood circulation. Pharmacodynamics The administration of REBINYN increases plasma levels of Factor IX and can temporarily correct the coagulation defect in hemophilia B patients, as reflected by a decrease in aPTT. Pharmacokinetics Pharmacokinetic (PK) parameters of REBINYN were evaluated in previously treated subjects, including a subset of subjects in the adult/adolescent trial and all subjects in the main phase of the pediatric trial [see Clinical Studies]. PK samples were collected prior to dosing and at multiple time points up to 168 hours after dosing. The analysis of plasma samples was conducted using the one-stage clotting assay. Steady state pharmacokinetic parameters for adolescents and adults following once-weekly prophylactic treatment of REBINYN 40 IU/kg are shown in Table 5. Table 5: Steady-state pharmacokinetic parameters of REBINYN (40 IU/kg) in adolescents and adults (geometric mean (CV)) PK Parameter 13-17 years N=3 ≥ 18 years N=6 Half-life (hours) 103.1 (14.2) 114.9 (9.7) Incremental Recovery30min (IU/dL per IU/kg) 1.82 (28.2) 1.92 (19.6) AUC0-168 (IU*hours/dL) 9072 (22) 9280 (15) Clearance (mL/hour/kg) 0.4 (16.7) 0.4 (11.4) Mean residence time (hours) 144.4 (15.3) 158.1 (9.6) Vss (mL/kg) 60.5 (31.1) 65.8 (11.9) Factor IX activity 168 h after dosing (%) 28.9 (18.6) 32.4 (17.1) Abbreviations: AUC = area under plasma concentration-time curve; Vss= volume of distribution at steady state; CV=coefficient of variation. The mean steady state pre-dose trough levels and post-dose peak levels across the clinical trials for all previously treated subjects are shown in Table 6. Table 6: Factor IX peak and trough levels of REBINYN (40 IU/kg) by age at steady state ≤ 6 years N=12 7-12 years N=13 13-17 years N=9 ≥ 18years N=20 Mean Factor IX peak level (%) (95% CI) 65.5 (60.6; 70.7) 71.4 (66.3; 77.0) 82.8 (70.7; 96.9) 97.9 (87.7; 109.3) Mean Factor IX trough level* (%) (95% CI) 15.4 (13.2; 17.9) 18.7 (16.2; 21.6) 23.7 (19.9; 28.2) 29.3 (26.0; 33.0) Min, Max** 9.2; 24.5 8.3; 28.3 18.6; 34.6 21.3; 42.2 * Factor IX activity from samples collected at clinical site visits just prior to administration of next weekly dose **Individual geometric mean trough values Single-dose pharmacokinetic parameters of REBINYN in children, adolescents and adults are listed in Table 7. Table 7: Single Dose Pharmacokinetic Parameters of REBINYN (40 IU/kg) in children, adolescents and adults (geometric mean (CV)) PK Parameter ≤ 6 years N=12 7-12 years N=13 13-17 years N=3 ≥ 18 years N=6 Half-life (hours) 69.6 (15.8) 76.3 (25.5) 89.4 (24.1) 83.0 (22.5) Incremental Recovery30min (IU/dL per IU/kg) 1.51 (7.31) 1.59 (16.2) 1.96 (14.7) 2.34 (11.3) AUCinf (IU*h/dL) 4617 (14) 5618 (19) 7986 (35) 9063 (16) Clearance (mL/hour/kg) 0.8 (13.0) 0.6 (21.9) 0.5 (30.4) 0.4 (14.7) Mean residence time (hours) 95.4 (15.3) 105.1 (24.2) 124.2 (24.4) 115.5 (21.8) Vss (mL/kg) 72.3 (14.8) 68.3 (21.7) 58.6 (7.8) 47.0 (15.9) Factor IX activity 168 h after dosing (%) 8.4 (16.3) 10.9 (18.9) 14.6 (59.6) 16.8 (30.6) Abbreviations: AUC = area under plasma concentration-time curve; Vss = volume of distribution at steady state; CV = coefficient of variation. Pharmacokinetics were investigated in 9 subjects in the adult/adolescent trial, of which 5 were normal weight (body mass index (BMI) 18.5 to 24.9 kg/m²) and 4 were overweight (BMI 25 to < 29.9 kg/m²). The pharmacokinetic parameters were not affected by BMI. The Factor IX activity following 80 IU/kg infusion in major surgery is shown in Table 8. Table 8: Factor IX activity following 80 IU/kg bolus for major surgery 30 minutes N=13 8 hours1 N=12 24 hours1 N=12 48 hours2 N=7 Factor IX activity (%) Median (Range) 143 (123-224) 138 (101-175) 112 (62-146) 73(40-110) 1 Excludes one subject with no Factor IX activity measurement obtained. 2 Excludes two subjects with no Factor IX activity measurement obtained and additionally 4 subjects re-dosed prior to second day after surgery for whom the Factor IX activity at 24 hours were 84%, 112%, 131% and 134%. The 48 hours measurement reflects a measurement on the 2nd day after surgery (range 47-57 hours). Animal Toxicology And/Or Pharmacology REBINYN was intraveneously administered in repeat-dose toxicity studies in immune-deficient rats (40-1200 IU/kg/week for 26 weeks) and immune-competent monkeys (350-3750 IU/kg/week for four weeks). Accumulation of the 40-kDa polyethylene-glycol (PEG) was detected by immunohistochemical staining in epithelial cells of the choroid plexus in the brain of the majority of animals. This finding was not associated with morphological changes or abnormal clinical signs. Clinical Studies Four multicenter, non-controlled trials were conducted to evaluate the safety and efficacy of REBINYN in routine treatment, on-demand treatment and control of bleeding episodes, and perioperative management in previously treated male patients with hemophilia B (Factor IX activity ≤ 2%). Previously treated patients were defined as patients receiving treatment with other Factor IX products for ≥ 150 exposure days for adolescents and adults, and ≥ 50 exposure days for pediatric patients. The key exclusion criteria across trials included known or suspected hypersensitivity to trial or related products, known history of Factor IX inhibitors or current inhibitor ≥ 0.6 BU, HIV-positive with a viral load ≥ 400,000 copies/mL or CD4+ lymphocyte count ≤ 200/μL, additional congenital or acquired coagulation disorders, previous arterial thrombotic events, and recipients of immune modulating or chemotherapeutic medication. The efficacy evaluation included 105 subjects: 62 adults (18 to 65 years old), 18 adolescents (13 to 17 years old), and 25 children (1 to 12 years old). Adult/adolescent trial: The trial included 74 adolescent and adult previously treated patients. There were two routine treatment arms, with single-blind randomization to either 10 IU/kg or 40 IU/kg once-weekly for approximately 52 weeks, and an open-label on-demand treatment arm for approximately 28 weeks. Surgery trial: The surgery trial included 13 previously treated adolescent and adult patients who received one infusion of REBINYN 80 IU/kg on the day of surgery, and post-operatively received infusions of 40 IU/kg, at the investigator's discretion, for up to 3 weeks after surgery. Adult/adolescent extension trial: There were 71 subjects from the adult/adolescent trial and surgery trial who continued routine treatment or on-demand treatment with REBINYN in an open-label extension trial, with the possibility to switch regimens during the trial. Pediatric trial: The main phase of the pediatric trial included 25 pediatric previously treated patients (1-12 years old) in which subjects received routine treatment with REBINYN 40 IU/kg once-weekly for approximately 52 weeks. Treatment Of Bleeding Episodes A total of 597 bleeding episodes were reported in 79 out of 105 subjects in the clinical program in previously treated patients. Bleeding episodes were treated with REBINYN at 40 IU/kg for minor or moderate bleeds or 80 IU/kg for major bleeds, with additional doses of 40 IU/kg as needed. The median dose to treat a bleeding episode was 42.3 IU/kg. An overall assessment of efficacy was performed by the subject (for home treatment) or the study site investigator (for treatment under medical supervision) using a 4-point scale of excellent, good, moderate, or poor. The overall success rate (defined as excellent or good) for treatment of bleeding episodes was 93.2% as shown in Table 9. The success rate and dose needed for treatment of bleeding episodes were independent of the location of the bleeding. The success rate for treatment of bleeding episodes was also independent of whether the bleed was traumatic or spontaneous. Table 9: Efficacy in treatment of bleeding episodes in previously treated patients New Bleeding Episodes n = 597 Efficacy assessment* Excellent or Good 551 (93%) Moderate or Poor 40 (7%) Number of injections to treat a bleeding episode 1 injection 521 (87%) 2 injections 60 (10%) > 2 injections 16 (3%) *Efficacy assessment was based on 591 evaluated bleeding episodes (data missing for six bleeding episodes). Efficacy was assessed according to a four-point scale using: Excellent: Abrupt pain relief and/or clear improvement in objective signs of bleeding within 8 hours after a single injection; Good: Noticeable pain relief and/or improvement in signs of bleeding within 8 hours after a single injection; Moderate: Probable or slight beneficial effect within the first 8 hours after the first injection but requiring more than one injection within 8 hours; Poor: No improvement, or worsening of symptoms within 8 hours after the second of two injections. In the on-demand arm there were 143 bleeding episodes in 14 of 15 subjects. The overall success rate was 95.1% (135 of 142 evaluated bleeds). A total of 120 bleeds (83.9%) of the 143 bleeding episodes were treated with one injection, and 20 (14.0%) were treated with two injections. Perioperative Management In the surgery trial, the efficacy analysis of REBINYN in perioperative management included 13 surgical procedures of which 9 were major and performed in 13 previously treated adolescent and adult patients. The procedures included 9 orthopedic, 1 gastrointestinal and 3 in the oral cavity. The hemostatic effect during surgery was evaluated on a four-point scale of excellent, good, moderate, or poor. The intraoperative hemostatic effect was rated as excellent or good for the 13 surgeries, for a success rate of 100%. A pre-operative dose of 80 IU/kg REBINYN was effective, and no subjects required additional doses on the day of surgery. The median number of additional 40 IU/kg doses in the post-operative period was 2.0 for Days 1 to 6, 1.5 for Days 7-13, and 3.0 for Days 1 to 13. The mean total consumption of REBINYN in the pre- and post-operative period was 241 IU/kg (range: 81 to 460 IU/kg). There was no unexpected postoperative bleeding. Three additional major surgeries and 18 minor surgery procedures were evaluated in the extension trial for REBINYN in previously treated patients. The hemostatic effect during major and minor surgery was confirmed with a success rate of 100%.

CLINICAL PHARMACOLOGY Hemophilia B, or Christmas disease, is an X-linked recessively inherited disorder of blood coagulation characterized by insufficient or abnormal synthesis of the clotting protein Factor IX. Factor IX is a vitamin K-dependent coagulation factor which is synthesized in the liver. Factor IX is activated by Factor XIa in the intrinsic coagulation pathway. Activated Factor IX (IXa), in combination with Factor VIII: C, activates Factor X to Xa, resulting ultimately in the conversion of prothrombin to thrombin and the formation of a fibrin clot. The infusion of exogenous Factor IX to replace the deficiency present in Hemophilia B temporarily restores hemostasis. Depending upon the subject's level of biologically active Factor IX, clinical symptoms range from moderate skin bruising or excessive hemorrhage after trauma or surgery to spontaneous hemorrhage into joints, muscles or internal organs including the brain. Severe or recurring hemorrhages can produce death, organ dysfunction or orthopedic deformity. Infusion of Factor IX Complex concentrates that contain varying but significant amounts of the other liver-dependent blood coagulation proteins (Factors II, VII and X) into subjects with Hemophilia B, results in Factor IX recoveries ranging from approximately 0. 57-1. 1 IU/dL rise per IU/kg body weight infused with plasma half-lives for Factor IX ranging from approximately 23 hours to 31 hours.1,2 Infusion of Mononine® (coagulation factor ix (human)) into ten subjects with severe or moderate Hemophilia B has shown a mean recovery of 0. 67 IU/dL rise per IU/kg body weight infused and a mean half-life of 22.6 hours.3 After six months of experience with repeated infusions performed on the nine subjects who remained in the study, it was shown that the half-life and recovery was maintained at a level comparable to that found with the initial infusion. The six-month data showed a mean recovery of 0. 68 IU/dL rise per IU/kg body weight infused and a mean half-life of 25.3 hours.3 The data show no statistically significant differences between the initial and six-month values. Two studies were conducted to provide Mononine® (coagulation factor ix (human)) for treatment of hemophilia B subjects who required extensive Factor IX replacement for surgery, trauma, or spontaneous bleeding (73 unique subjects and eight subjects enrolled twice for a total of 81 subjects), as well as to evaluate the safety and efficacy of Mononine® (coagulation factor ix (human)) . The overall mean recovery during treatment was determined to be 1.23 ± 0.42 IU/dL rise/IU/kg (K) (range = 0.59 to 2.92 K) among the 55 subjects included in recovery analyses in the one study and to be 1. 12 ± 0.52 K (range = 0.61 to 2.08 K) among 10 subjects included in these analyses in the second study. Five (5/81,6%) subjects reported adverse events attributed to Mononine® (coagulation factor ix (human)) across the two studies. In these stud-ies, 100 doses of Mononine® (coagulation factor ix (human)) were administered at what are considered high doses for a Factor IX concen-trate, a range of 71 to 161 IU/kg to a total of 36 subjects. Sixty-seven (67) of these infusions were the subject of recovery analyses. Mean recovery tended to decrease as the dose of Mononine® (coagulation factor ix (human)) increased:1.09 ± 0.52 K at doses > 75-95 IU/kg (n=38), 0.98 ± 0.45 K at doses > 95-115 IU/kg (n=21), 0.70 ± 0.38 K at doses > 115-135 IU/kg (n=2), 0.67 K at doses > 135-155 IU/kg (n=1), and 0. 73 ± 0. 34 K at doses > 155 IU/kg (n=5). Among the 36 subjects who received these high doses, only one (2. 8%) reported an adverse experience with a possible relationship to Mononine® (coagulation factor ix (human)) (“difficulty in concentrating”; subject recovered). In no subjects were thrombogenic complications observed or reported.4 The manufacturing procedure for Mononine® (coagulation factor ix (human)) includes multiple processing steps that have been designed to reduce the risk of virus transmission. Validation studies of the monoclonal antibody (MAb) immunoaffinity chromatography/chemical treatment step and two sequential ultrafiltration steps used in the production of Mononine® (coagulation factor ix (human)) document the virus reduction capacity of the processes employed. These studies were conducted using the relevant viruses Human Immunodeficiency Virus (HIV) and Hepatitis AVirus (HAV), the specific model viruses Bovine Viral Diarrhea Virus (BVDV) for Hepatitis C Virus (HCV) and Canine Parvovirus (CPV) for Human Parvovirus B19, and the non-specific model virus Pseudorabies Virus (PRV). The results of these virus validation studies utilizing a wide range of viruses with different physicochemical properties are summarized in Table 1 below: Table1 in vitroVirus Reduction Studies Virus Cumulative Virus Reduction Capacity (Log10 Reduction) HIV ≥ 11.7 BVDV ≥ 12.2 PRV ≥ 15.5 HAV ≥ 5.1 CPV ≥ 12.0 Clinical Studies The virus safety of Coagulation Factor IX (Human), Mononine® (coagulation factor ix (human)) , has been studied in clinical trials of two cohorts of hemophilia B subjects previously unexposed to blood or blood products.5 One cohort of subjects included those with moderate to severe factor IX deficiency requiring chronic replacement therapy (41 subjects were dosed); the second cohort included subjects with a mild deficiency requiring factor IX replacement for surgical procedures (10 subjects were dosed). These subjects were followed for serum alanine aminotransferase (ALT) elevations, as well as for a range of viral serologies. Thirty-seven (37) subjects (30 with moderate to severe deficiency and seven with a mild deficiency) were evaluable for assessment of virus hepatitis safety by the International Society on Thrombosis and Haemostasis-Scientific and Standardization Committee criteria. None of these subjects showed evidence of transmission of hepatitis A, B, C, or HIV. Mononine® (coagulation factor ix (human)) contains trace amounts of the murine monoclonal antibody (MAb) used in its purification ( ≤ 50 ng mouse protein/100 IU). While the levels of mouse protein are extremely low, infusion of such proteins might theoretically induce human anti-mouse antibody (HAMA) responses. To test this possibility, human IgG, IgM, and IgE antibodies to mouse IgG were assessed by immunoradiometric assay (IRMA) in 11 hemophilia B subjects who received Mononine® (coagulation factor ix (human)) and were previously untreated with other blood products. HAMAs were evaluated prior to the first infusion and at 2 to 42 months after initial treatment. Human IgE antibodies to mouse IgG were below the level of detectability at all time points for all subjects, and there were no statistically significant increases in either human IgG antibodies or human IgM antibodies to mouse protein. 6 In clinical studies of Mononine® (coagulation factor ix (human)) , subjects were monitored for evidence of disseminated intravascular coagulation. In six subjects evaluated after infusion, fibrinogen levels and platelet counts were unchanged, and fibrin degradation products did not appear.3 In further clinical evaluations of Mononine® (coagulation factor ix (human)) , in a crossover study with a Factor IX Complex concentrate, Mononine® (coagulation factor ix (human)) was not associated with the formation of prothrombin activation fragment (F1+2) whereas the Factor IX Complex was associated with the formation of prothrombin activation fragment (F1+2).3,7 Prothrombin activation fragment (F1+2) is indicative of activation of prothrombin. During the period from 1992 to 1996, five subjects showed transient ALTelevations that were greater than twice the upper normal limit. These subjects were investigated thoroughly and none of the ALTelevations was associated with seroconversion. In three of the five subjects, a single ALTelevation greater than 2 times the upper limit of normal was recorded during the course of the study. No concomitant symptoms occurred and the virus hepatitis serology tests did not reveal any abnormalities. In addition, in one of these three subjects with single ALTelevations, a relationship to Mononine® (coagulation factor ix (human)) could be excluded due to a span of 18 months between the infusion of Mononine® (coagulation factor ix (human)) and occurrence of the elevated ALTlevel. In one of the two remaining subjects, the ALTlevel had been elevated prior to the first infusion of Mononine® (coagulation factor ix (human)) and normalized thereafter. Subsequently, this subject's ALTlevels were elevated intermittently over a period of 24 months, which appeared to be temporally related to the administration of concomitant medications: acetaminophen, amoxicillin, cephalosporins, and halothane. These medications are known to cause liver enzyme elevations. Further, there were no clinical signs of viral hepatitis, nor any other viral disease in these four subjects. The remaining subject of the five was found to have recurring ALTelevations that persisted for a period of five months, gradually decreasing to normal levels. Approximately three days after his first Mononine® (coagulation factor ix (human)) infusion this subject received hepatitis Bimmune globulin and his first injection of hepatitis Bvaccine. At that time, the subject's ALTlevel was slightly above the upper limit of normal (55 IU/L, upper limit of normal:35). Five days later, the subject experienced flu-like symptoms, nausea and vomiting, which were treated with ampicillin and promethazine. The ALT value recorded eight days thereafter (approximately 13 days after the Mononine® (coagulation factor ix (human)) infusion) was found to be clearly elevated at 629 IU/L. ALTlevels subsequently decreased again and were in the range of 160 to 220 IU/Lfor the next four to five months, with mildly elevated aspartate aminotransferase and creatinine phosphokinase values. Serology for hepatits A, B, and C remained negative (except for the expected positive serology of anti-HBs due to the vaccination against hepatitis B). As a result, there was no serological evidence of hepatitis A, B, or C. This subject's idiosyncratic spikes in aminotrans-ferase values and gastrointestinal symptoms were not considered to be of viral origin. However, a causal relationship between prior administration of Mononine® (coagulation factor ix (human)) and these aminotransferase elevations and mild symptoms could not be ruled out. REFERENCES 1. Zauber NP, Levin J. Factor IX levels in patients with hemophilia B (Christmas disease) following transfusion with concentrates of Factor IX orfresh frozen plasma (FFP). Medicine (Baltimore) 56(3): 213-24, 1977. 2. Smith KJ, Thompson AR. Labeled Factor IX Kinetics in Patients withHemophilia-B. Blood 58(3): 625-629, 1981. 3. Kim HC, McMillan CW, White GC, Bergman GE, Horton MW, Saidi P. Purified Factor IX Using Monoclonal Immunoaffinity Technique: ClinicalTrials in Hemophilia B and Comparison to Prothrombin ComplexConcentrates. Blood 79(3): 568-575, 1992. 4. Warrier I, Kasper CK, White II GC, Shapiro AD, Bergman GE, theMononine® (coagulation factor ix (human)) Study Group. Safety of high doses of a monoclonal antibody-purified factor IX concentrate. Am J Hematol 49:92-94, 1995. 5. Shapiro AD, Ragni MV, Lusher JM, Culbert S, Koerper MA, Bergman GE, Hannan MM. Safety and Efficacy of Monoclonal Antibody Purified FactorIX Concentrate in Previously Untreated Patients with Hemophilia B. Thrombosis and Haemostasis 75:30-35, 1996. 6. Davis HM, Nash DW, Clymer MD, Frigo ML, Bergman GE. Lack of immune response to mouse IgG in previously untreated haemophilia A andhaemophilia B patients treated with monoclonal antibody purified factor VIIIand factor IX preparations. Haemophilia 3(2): 102-107, April 1997. 7. Kim HC, Matts L, Eisele J, Czachur M, Saidi P. Monoclonal AntibodyPurified Factor IX - Comparative Thrombogenicity to ProthrombinComplex Concentrate. Seminars in Hematology 28 (Suppl. 6tono. 3): 15-20, July 1991.

Find Lowest Prices on RIXUBIS [Coagulation Factor IX (Recombinant)] for Intravenous Injection DESCRIPTION RIXUBIS [Coagulation Factor IX (Recombinant)] is a purified protein produced by recombinant DNA technology. Its amino acid sequence is identical to that of the Ala-148 allelic form of plasma derived factor IX, and its structural and functional characteristics are similar to those of plasma derived factor IX. RIXUBIS is produced by a genetically engineered CHO cell line. No human or animal proteins are added during any stage of manufacturing or formulation of RIXUBIS. The CHO cell line secretes recombinant factor IX into a defined cell culture medium that does not contain hormones, and the recombinant factor IX is purified by a chromatography purification process that does not require a monoclonal antibody step. The process includes validated virus inactivation/removal steps, namely solvent/detergent treatment and 15 nm nanofiltration. RIXUBIS is predominantly a single component by sodium dodecyl sulfate-polyacrylamide gel electrophoresis evaluation. The specific activity of RIXUBIS is ≥ 200 international units per milligram of protein. Factor IX preactivation, the percent of Factor IXa/Factor IX as measured by activity assays, is ≤ 0.03%. The potency in international units is determined using an in vitro thromboplastin time (aPTT)-based one-stage clotting assay calibrated against the World Health Organization (WHO) International Standard for Factor IX concentrate. Factor IX potency results can be affected by the type of aPTT reagent and reference standard used in the assay; differences of up to 40% have been observed. RIXUBIS is formulated as a sterile, nonpyrogenic lyophilized powder to be reconstituted with Sterile Water for Injection for intravenous administration. It does not contain any preservatives and is available in single-use vials containing the labeled amount of factor IX activity, expressed in international units. Each vial contains nominally 250, 500, 1000, 2000 or 3000 international units of recombinant coagulation factor IX. After reconstitution of the lyophilized powder, all dosage strengths yield a clear, colorless solution. The concentrations of excipients are: Excipient Concentration L-histidine 20 mM sodium chloride 60 mM calcium chloride 4 mM Mannitol 110 mM Sucrose 35 mM polysorbate 80 0.005%

Find Lowest Prices on IDELVION™ [Coagulation Factor IX (Recombinant), Albumin Fusion Protein (rIX-FP)] Lyophilized Powder Reconstituted for Intravenous Injection Summary Product Information Route of Administration Dosage Form / Strength Clinically Relevant Non-medicinal Ingredients Intravenous Injection Lyophilized powder in following nominal strengths: 250 IU1/vial, 500 IU/vial, 1000 IU/vial, 2000 IU/vial Mannitol, Polysorbate 80, Sucrose, Trisodium citrate. For a complete listing see Dosage Forms, Composition and Packaging. The number of units of FIX administered is expressed in International Units (IU), which are related to the current WHO standard for FIX products. One IU of FIX activity in plasma is equivalent to that quantity of FIX in one mL of normal human plasma. FIX activity in plasma is expressed either as a percentage (relative to normal human plasma) or in IU (relative to an International Standard for FIX in plasma). DESCRIPTION IDELVION, Coagulation Factor IX (Recombinant), Albumin Fusion Protein (rIX-FP), is a long acting purified protein produced by recombinant DNA technology, generated by the genetic fusion of recombinant albumin to recombinant coagulation Factor IX (rFIX). IDELVION is a preservative free, sterile, non-pyrogenic, lyophilized powder to be reconstituted with Sterile Water for Injection (SWFI) for intravenous injection. It is available in single-use vials in the following presentations: 250 IU, 500 IU, 1000 IU, and 2000 IU of the active substance rIX-FP. Pharmaceutical Information Drug Substance Proper name: Coagulation Factor IX (Recombinant), Albumin Fusion Protein (rIX-FP) Chemical name: Albutrepenonacog Alfa Molecular formula and molecular mass: Full length rIX-FP is expressed as a single chain glycopeptide of 1018 amino acids with a molecular weight of ~125 kDa. Structural formula: The primary amino acid sequence is comparable to the most prevalent Thr148 allelic form of native FIX. rIX-FP was generated by the genetic fusion of recombinant human albumin to recombinant FIX. FIX complementary DNA (cDNA) was joined to human albumin cDNA by a FIX-derived cleavable linker sequence extended by an N-terminal proline residue. Physicochemical properties: The purified drug substance is a yellow to colorless solution that is visibly free of particulates. It is produced to have a minimum concentration of 8 mg/mL protein with a specific activity no less than 53 IU/mg. Product Characteristics IDELVION, Coagulation Factor IX (Recombinant), Albumin Fusion Protein (rIX-FP), is a long acting purified protein produced by recombinant DNA technology, generated by the genetic fusion of recombinant albumin to recombinant coagulation Factor IX (rFIX). The genetic fusion of the cDNA of human albumin to the cDNA of human coagulation Factor IX (FIX) enables the protein to be produced as a single recombinant protein and assures product homogeneity by avoiding chemical conjugation. The rFIX portion is identical to the Thr148 allelic form of plasma-derived FIX. The cleavable linker between the rFIX and albumin molecules is derived from the endogenous activation peptide in native FIX. rIX-FP remains intact in the circulation until FIX is activated, whereupon albumin is cleaved off, releasing activated FIX (FIXa) only when it is needed for coagulation. No human or animal proteins are added during any stage of manufacturing or formulation of IDELVION. IDELVION is a glycoprotein consisting of 1018 amino acids secreted by a genetically engineered Chinese Hamster ovary (CHO) cell line. The CHO cell line secretes rIX-FP into a chemically defined, cell culture medium that does not contain hormones with the exception of recombinant human insulin, and the rIX-FP is purified by a chromatography purification process that does not require a monoclonal antibody step. The linker is derived from the actual activation peptide in native FIX. rIX-FP remains intact in the circulation until initiation of the coagulation cascade. The normal activation mechanism cleaves the albumin moiety simultaneously releasing albumin and activating FIX to facilitate coagulation. The manufacturing process includes two validated virus inactivation/removal steps, namely solvent/detergent treatment and nanofiltration. The potency in International Units (IU) is determined using an in vitro activated partial thromboplastin time (aPTT)-based one-stage clotting assay calibrated against the World Health Organization (WHO) International Standard for FIX concentrate. Viral Inactivation The manufacturing process has two dedicated, orthogonal virus reduction steps including nanofiltration.

REBINYN® (Coagulation Factor IX (Recombinant) for Reconstitution DESCRIPTION REBINYN is a sterile, non-pyrogenic, white to off-white lyophilized powder for reconstitution with the provided histidine diluent for intravenous infusion. After reconstitution, the solution appears as a clear and colorless liquid, free from visible particles and contains the following excipients per mL: sodium chloride, 2.34 mg; histidine, 3.10 mg; sucrose, 10 mg; mannitol, 25 mg; polysorbate 80, 0.05 mg. REBINYN is available in single-use vials containing the labeled amount of Factor IX activity, expressed in IU. Each vial contains nominally 500 IU, 1000 IU or 2000 IU. REBINYN potency is assigned using an in vitro, activated partial thromboplastin time (aPTT)-based, one-stage clotting assay calibrated against the World Health Organization (WHO) international standard for Factor IX concentrates. REBINYN contains no preservatives. REBINYN is a purified recombinant human Factor IX (rFIX) with a 40 kilodalton (kDa) polyethylene-glycol (PEG) conjugated to the protein. The 40 kDa PEG group is selectively attached to specific -N-linked glycans in the rFIX activation peptide, with mono-PEGylated rFIX as the predominant form of REBINYN. The rFIX protein in REBINYN consists of a gamma-carboxylated (Gla) domain, two EGF-like (epidermal growth factor) domains, an activation peptide (which is cleaved off upon activation), and a protease domain. Once activated, the resulting rFIX has structural and functional properties similar to those of endogenous activated Factor IX. The primary amino acid sequence in REBINYN is identical to the Thr148 allelic form of human plasma-derived Factor IX and consists of 415 amino acids. The average molecular weight of REBINYN is approximately 98 kDa and the molecular weight of the protein moiety alone is 56 kDa. The nominal specific activity of REBINYN is 152 IU/mg protein. REBINYN is produced by recombinant DNA technology in Chinese Hamster Ovary (CHO) cells. No additives of human or animal origin are used in the cell culture, purification, conjugation, or formulation of REBINYN. The rFIX protein is purified by a series of chromatographic steps, including an affinity chromatography step using a monoclonal antibody (produced in CHO cells), to selectively isolate rFIX from the cell culture medium. The production process includes two dedicated viral clearance steps, namely a detergent treatment step for inactivation and a 20 nm filtration step for removal of viruses. The conjugation of the PEG-group is done by an enzymatic reaction during the purification process, followed by final purification of REBINYN.

Find Lowest Prices on Mononine® Coagulation Factor IX (Human) Monoclonal Antibody Purified DESCRIPTION Coagulation Factor IX (Human), Mononine® (coagulation factor ix human) , is a sterile, stable, lyophilized concentrate of Factor IX prepared from pooled human plasma and is intended for use in therapy of Factor IX deficiency, known as Hemophilia B or Christmas disease. Mononine® (coagulation factor ix human) is purified of extraneous plasma-derived proteins, including Factors II, VII and X, by use of immunoaffinity chromatography. A murine monoclonal antibody to Factor IX is used as an affinity ligand to isolate Factor IX from the source material. Factor IX is then dissociated from the mon-oclonal antibody, recovered, purified further, formulated and provided as a sterile, lyophilized powder. The immunoaffinity protocol utilized results in a highly pure Factor IX preparation. It shows predominantly a single component by SDS polyacrylamide electrophoretic evaluation and has a specific activity of not less than 190 Factor IX units per mg total protein. All Source Plasma used in the manufacture of this product was tested by FDA-licensed Nucleic Acid Tests (NAT) for HCV and HIV-1 and found to be nonreactive (negative). An investigational NAT for HBV was also performed on all Source Plasma used in the manufacture of this product and found to be nonreactive (negative). The aim of the HBV test is to detect low levels of viral mate-rial, however, the significance of a nonreactive (negative) result has not been established. This concentrate has been processed by monoclonal antibody immunoaffinity chromatography during its manufacture, which has been shown to be capable of reducing the risk of viral transmission. Additionally, a chemical treatment protocol and two sequential ultrafiltration steps used in its manufacture have also been shown to be capable of significant virus reductions. However, no procedure has been shown to be totally effective in removing the risk of viral infectivity from coagulation factor concentrates (see CLINICAL PHARMACOLOGY and WARNINGS). Mononine® (coagulation factor ix human) is a highly purified preparation of Factor IX. When stored as directed, it will maintain its labeled potency for the period indicated on the container label. Each vial contains the labeled amount of Factor IX activity expressed in International Units (IU). One IU represents the activity of Factor IX present in 1 mL of normal, pooled plasma. When reconstituted as recommended, the resulting solution is a clear, colorless, isotonic preparation of neutral pH, containing approximately 100 times the Factor IX potency found in an equal volume of plasma. Each mL of the reconstituted concentrate contains approximately 100 IU of Factor IX and non-detectable levels of Factors II, VII and X ( < 0.0025 IU per Factor IX unit using standard coagulation assays). Each vial also contains histidine (approx. 10mM), sodium chloride (approx. 0.066M), mannitol (approx. 3%) and polysorbate 80 (approx. 0.0075%). Hydrochloric acid and/or sodium hydroxide may have been used to adjust pH. Mononine® (coagulation factor ix human) also contains trace amounts ( ≤ 50 ng mouse protein/100 Factor IX activity units) of the murine monoclonal antibody used in its purification (see CLINICAL PHARMACOLOGY). Mononine (coagulation factor ix human) ® is to be administered only intravenously.

INDICATIONS RIXUBIS (Coagulation Factor IX [Recombinant]) is an antihemophilic factor indicated in adults and children with hemophilia B for: Control and prevention of bleeding episodes, perioperative management, and routine prophylaxis. RIXUBIS is not indicated for induction of immune tolerance in patients with hemophilia B [see WARNINGS AND PRECAUTIONS]. DOSAGE AND ADMINISTRATION For intravenous use after reconstitution only. Each vial of RIXUBIS has the recombinant Factor IX (rFIX) potency in international units stated on the vial. Initiate treatment under the supervision of a physician experienced in the treatment of hemophilia. Dosage and duration of treatment with RIXUBIS depend on the severity of factor IX deficiency, the location and extent of bleeding, the patient's clinical condition, age, and pharmacokinetic parameters of factor IX, such as incremental recovery and half-life. Dosing of RIXUBIS may differ from that of plasma-derived factor IX products [see CLINICAL PHARMACOLOGY]. Subjects at the low end of the observed factor IX recovery range may require dose adjustment of RIXUBIS. Monitor patients using a factor IX activity assay to ensure that the desired factor IX activity plasma level has been attained. If necessary, adjust the dose and the frequency of repeated infusions as appropriate. Evaluate the patient for the development of factor IX inhibitors if the expected factor IX activity plasma levels are not attained or if bleeding is not controlled with an appropriate dose [see WARNINGS AND PRECAUTIONS]. Dosing Guidelines Calculating Initial Dose The initial dose of RIXUBIS is calculated based on the empirical finding that one international unit of RIXUBIS per kg body weight is expected to increase the circulating level of factor IX by 0.7 international units/dL of plasma (0.7% of normal) for patients < 12 years of age and by 0.9 international units/dL of plasma (0.9% of normal) in patients ≥ 12 years of age. A guide for calculating the initial dose of RIXUBIS for treatment of bleeding episodes is as follows: Initial Dose = body weight (kg) x desired factor IX increase (% of normal or IU/dL) x reciprocal of observed recovery (IU/kg per IU/dL) Incremental Recovery in Previously Treated Patients (PTPs) Base the calculation of the dose on the patient's individual incremental recovery using serial factor IX activity assays, due to the wide range of inter-individual differences in incremental recovery. Titrate the dose based on the patient's clinical response and individual pharmacokinetics, in particular incremental recovery and half-life. Patients < 12 Years of Age On average, a 22% lower recovery has been observed in pediatric patients ( < 12 years, n=23). For an incremental recovery of 0.7 international units/dL of plasma (0.7% of normal), the dose is calculated as follows: Dose (international units) = body weight (kg) x desired factor IX increase (% of normal or IU/dL) x 1.4 dL/kg Example (assuming patient's baseline factor IX level is < 1% of normal) 1. A dose of 1500 international units of RIXUBIS, administered to a 20 kg patient should be expect to result in a peak post-infusion factor IX increase of 1500 international units x {[0.7 IU/dL]/[IU/kg}/[20 kg] = 53.6 international units/dL (53.6% of normal). Patients ≥ 12 Years of Age For an incremental recovery of 0.9 international units/dL of plasma (0.9% of normal), the dose is calculated as follows: Dose (international units) = body weight (kg) x desired factor IX increase (% of normal or IU/dL) x 1.1 dL/kg Examples (assuming patient's baseline factor IX level is < 1% of normal): A dose of 4550 international units of RIXUBIS, administered to a 70 kg patient, should be expected to result in a peak post-infusion factor IX increase of 4550 international units x {[0.9 IU/dL]/[IU/kg]}/[70 kg] = 58.5 international units/dL (58.5 % of normal). A peak level of 70% is required in a 60 kg patient. The appropriate dose would be 60 kg x 70 international units/dL/{[0.9 IU/dL]/[IU/kg]} = 4667 international units. Control And Prevention Of Bleeding Episodes And Perioperative Management A guide for dosing RIXUBIS in the control and prevention of bleeding episodes and perioperative management is provided in Table 1 and Table 2, respectively. Ensure the factor IX activity level is achieved and maintained in the corresponding period. Table 1 : Dosing for Control and Prevention of Bleeding Episodes Type of Bleeding Episodes Circulating Factor IX Level Required (% or IU/dL) Dosing Interval (hours) Duration of Therapy (days) Minor Uncomplicated hemarthrosis, superficial muscular or soft tissue 20-30 12-24 At least 1 day, until healing is achieved Moderate Intramuscular or soft tissue with dissection, mucous membranes, hematuria 25-50 12-24 2-7 days, until bleeding stops and healing is achieved Major Pharyngeal, retropharyngeal, retroperitoneal, CNS 50-100 12-24 7-10 days, until bleeding stops and healing is achieved Adapted from Roberts and Eberst1 Table 2 : Dosing for Perioperative Management Type of Surgery Circulating Factor IX Level Required (% or IU/dL) Dosing Interval (hours) Duration of Therapy (days) Minor e.g., tooth extraction 30-60 24 At least 1 day, until healing is achieved Major e.g., intracranial, intraabdominal, intrathoracic, joint replacement 80-100 8-24 7-10 days, until bleeding stops and healing is achieved Routine Prophylaxis The dose for previously treated patients (PTPs) is 60 to 80 international units per kg twice weekly for patients < 12 years of age and is 40 to 60 international units per kg twice weekly for patients ≥ 12 years of age. Adjust the dose based on the individual patient's age, bleeding pattern, and physical activity. Preparation And Reconstitution The procedures below are provided as general guidelines for the preparation and reconstitution of RIXUBIS. Always work on a clean surface and wash hands before performing the following procedures: Use aseptic technique during reconstitution procedure. Allow the RIXUBIS vial (dry factor concentrate) and Sterile Water for Injection, USP vial (diluent) to reach room temperature. Remove caps from the factor concentrate and diluent vials. Cleanse stoppers with germicidal solution and allow to dry prior to use. Place the vials on a flat surface. Open the BAXJECT II device package by peeling away the lid, without touching the inside (Figure A). Do not remove the device from the package. Note that the BAXJECT II device is intended for use with a single vial of RIXUBIS and Sterile Water for Injection, USP only; therefore, reconstituting and withdrawing a second vial into the syringe requires a second BAXJECT II device. Turn the package over. Press straight down to fully insert the clear plastic spike through the diluent vial stopper (Figure B). Grip the BAXJECT II package at its edge and pull the package off the device (Figure C). Do not remove the blue cap from the BAXJECT II device. Do not touch the exposed white plastic spike. Turn the system over so that the diluent vial is on top. Quickly insert the white plastic spike fully into the RIXUBIS vial stopper by pushing straight down (Figure D). The vacuum will draw the diluent into the RIXUBIS vial. Swirl gently until the powder is completely dissolved. Do not refrigerate after reconstitution. Use within 3 hours of reconstitution. Administration For intravenous bolus infusion only. The safety and efficacy of RIXUBIS administration by continuous infusion has not been established. Inspect parenteral drug products for particulate matter and discoloration prior to administration. The solution should be clear and colorless in appearance. Do not use RIXUBIS if you notice any particulates or turbidity in the solution and notify Baxter. Perform product administration and handling of the administration set and needles with caution. Percutaneous puncture with a needle contaminated with blood can transmit infectious viruses including HIV (AIDS) and hepatitis. Obtain immediate medical attention if injury occurs. Place needles in a sharps container after single-use. Administer RIXUBIS at room temperature and within 3 hours of reconstitution. Discard any unused product. Use a plastic syringe with this product. Remove the blue cap from the BAXJECT II device. Connect the syringe to the BAXJECT II device by screwing it clockwise until the syringe is secured (Figure E). Do not over tighten. Do not inject air. Turn the system upside down (factor concentrate vial now on top). Draw the factor concentrate into the syringe by pulling the plunger back slowly (Figure F). Disconnect the syringe by unscrewing it counter clockwise; attach a suitable needle to the syringe and inject intravenously by bolus infusion. If a patient is to receive more than one vial of RIXUBIS, the contents of multiple vials may be drawn into the same syringe. Maximum infusion rate of 10 mL/min. HOW SUPPLIED Dosage Forms And Strengths RIXUBIS is a white or almost white lyophilized powder in single-use vials containing nominally 250, 500, 1000, 2000 or 3000 international units. RIXUBIS is available as single-use vials containing the following product strengths: Color Code Nominal Strength (international units) Kit NDC Light Blue 250 0944-3026-02 Pink 500 0944-3028-02 Green 1000 0944-3030-02 Orange 2000 0944-3032-02 Silver 3000 0944-3034-02 Actual factor IX activity in international units is stated on the unit carton and vial label. Each kit also contains 5 mL of Sterile Water for Injection and a BAXJECT II transfer device. Storage And Handling Store at refrigerated temperature; 2° to 8°C (36° to 46°F) for up to 24 months. Do not freeze. May store at room temperature not to exceed 30°C (86°F) for up to 12 months within the 24 month time period. Write on the carton the date RIXUBIS was removed from refrigeration. After storage at room temperature, do not return the product to the refrigerator. Do not use beyond the expiration date printed on the carton or vial. Baxter Healthcare Corporation, Westlake Village, CA 91362 USA. Revised: Sep 2014

INDICATIONS IDELVION, Coagulation Factor IX (Recombinant), Albumin Fusion Protein (rIX-FP), is an antihemophilic factor indicated in patients with hemophilia B (congenital FIX deficiency) or Christmas disease for: Routine prophylaxis to prevent or reduce the frequency of bleeding episodes Control and prevention of bleeding episodes Control and prevention of bleeding in the perioperative setting Studies described in this monograph have been performed only in previously treated patients (PTPs). Geriatrics ( > 65 Years of Age) See subsection Special Population, under Section WARNINGS AND PRECAUTIONS. Pediatrics ( < 18 Years of Age) See subsection Special Population, under Section WARNINGS AND PRECAUTIONS. DOSAGE AND ADMINISTRATION Dosing Considerations Treatment with IDELVION should be initiated under the supervision of a healthcare professional experienced in the treatment of hemophilia B (factor IX deficiency). The decision on the use of home treatment of bleeding and prophylaxis of bleeding in patients with haemophilia B should be made by the treating physician. The physician should ensure that appropriate training is provided and the use is reviewed at intervals. For intravenous use after reconstitution only. Each vial of IDELVION has the recombinant FIX (rFIX) potency in International Units (IU) stated on the carton and vial label. Dosage and duration of treatment with IDELVION depends on the severity of FIX deficiency, the location and extent of bleeding and the patient's clinical condition and response. Recommended Dose And Dosage Adjustment Routine Prophylaxis The recommended dose is 25 to 40 IU of IDELVION per kg body weight every 7 days, or 50 to 75 IU of IDELVION per kg every 14 days. Adjust the dosing regimen based upon the individual patient's clinical condition and response. The recommended dose regimen for pediatric patients is the same as for adults (See Section ACTION AND CLINICAL PHARMACOLOGY). Calculating Required Dose The calculation of the required dose of IDELVION is based on the empirical finding that one IU of IDELVION per kg body weight is expected to increase the circulating level of FIX by an average of 1.3 IU/dL (1.3% of normal) in patients ≥ 12 years of age and by 1.0 IU/dL (1.0% of normal) in patients < 12 years of age. The required dose of IDELVION for treatment of bleeding episodes is determined using the following formula: Required Units (IU) = body weight (kg) x desired FIX rise (% of normal or IU/dL) x (reciprocal of recovery (IU/kg per IU/dL) OR Increase in FIX IU/dL (or % of normal) = Dose (IU) x Recovery (IU/dL per IU/kg)/body weight (kg) Adjust the dose based on the individual patient's clinical condition and response. Patients < 12 years of Age For an incremental recovery of 1 IU/dL per 1 IU/kg, the dose is calculated as follows: Dose (IU) = body weight (kg) x desired FIX increase (IU/dL) x 1 dL/kg Example A peak level of 50 % of normal is required in a 20 kg patient with severe haemophilia B. The appropriate dose would be 20 kg x 50 IU/dL x 1 dL/kg = 1000 IUs. A dose of 1000 IUs of IDELVION, administered to a 25 kg patient, should be expected to result in a peak post-injection FIX increase of 1000 IUs/25 kg x 1.0 (IU/dL per IU/kg) = 40 IU/dL (40 % of normal). Patients ≥ 12 years of Age For an incremental recovery of 1.3 IU/dL per 1 IU/kg, the dose is calculated as follows: Dose (IU) = body weight (kg) x desired FIX increase (IU/dL) x 0.77 dL/kg Example 3. A peak level of 50 % of normal is required in an 80 kg patient with severe haemophilia B. The appropriate dose would be 80 kg x 50 IU/dL x 0.77 dL/kg = 3080 IUs. 4. A dose of 2000 IUs of IDELVION, administered to a 80 kg patient, should be expected to result in a peak post-injection FIX increase of 2000 IUs x 1.3 (IU/dL per IU/kg) /80 kg = 32.5 IU/dL (32.5 % of normal). Control And Prevention Of Bleeding Episodes And Perioperative Management A guide for dosing IDELVION in the control and prevention of bleeding episodes and perioperative management is provided in Table 2 and Table 3, respectively. Ensure that the FIX activity level is achieved and maintained in the corresponding period. The recommended circulating FIX level requirement for pediatric patients is the same as for adults (See Section ACTION AND CLINICAL PHARMACOLOGY). Table 2: Dosing for Control and Prevention of Bleeding Episodes Type of Bleeding Episode Circulating FIX Level Required (%) (IU/dL) Frequency of Dose (hours) / Duration of Therapy (Days) Minor or Moderate Hemarthrosis, muscle bleeding (except iliopsoas) or oral bleeding 30-60 Single dose of 25-50 IU/kg should be sufficient for majority of bleeds. Maintenance dose after 48-72 hours, if there is further evidence of bleeding. Major Life threatening hemorrhages, deep muscle bleeding, including iliopsoas 60-100 50-80 IU/kg Repeat every 48-72 hours for the first week. Maintenance dose weekly until bleeding stops and healing is achieved. Table 3: Dosing for Perioperative Management Type of Surgery Circulating FIX Required (% or IU/dL) Dosing Interval (hours) Duration of Therapy (days) Minor (including uncomplicated tooth extraction) 50-80 (initial level) Single dose of 40-60 IU/kg should be sufficient for a majority of minor surgeries. If needed, maintenance dose after 48-72 hours until bleeding stops and healing is achieved. Major 60-100 (initial level) 50-80 IU/kg Repeat dose every 48-72 hours for the first week. Maintenance dose 1-2 times per week until bleeding stops and healing is achieved. Administration Do not mix IDELVION with other medicinal products. Administer by intravenous injection. The rate of administration should be determined by the patient's comfort level. Use aseptic technique when administering IDELVION. Administer IDELVION at room temperature. For injection of IDELVION, the provided administration sets are recommended to be used because treatment failure can occur as a consequence of factor IX adsorption to the internal surface of some injection equipment. As with any coagulation product, care should be taken that no blood should enter the syringe, as there is the possibility of fibrin clot formation. IDELVION is for single use only. Following administration, discard any unused solution and all administration equipment in an appropriate manner as per local requirements. It is strongly recommended that every time that IDELVION is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the medicinal product. Reconstitution Reconstitute IDELVION using aseptic technique with diluent provided in the kit. Do not use IDELVION beyond the expiration date on the vial label and carton. Visually inspect the reconstituted solution for particulate matter and discoloration prior to administration. The solution should be a yellow to colorless clear liquid and free from visible particles. Do not use if discoloration or particulate matter is observed. The procedures provided in Table 4 are general guidelines for the preparation and reconstitution of IDELVION. Table 4: IDELVION Reconstitution Instructions Follow the steps below and use aseptic techniques to administer IDELVION. A. PREPARATION Prepare the vials/Mix2Vial® and infusion supplies. Ensure that the diluent and IDELVION vials are at room temperature. Prepare syringes, infusion sets and other supplies for the administration. B. RECONSTITUTION: follow these steps to reconstitute IDELVION 1. Clean Stoppers: Remove the flip caps from both vials (IDELVION and diluent). Wipe the rubber stoppers with an antiseptic and allow the rubber stopper to dry. 2. Open the Mix2Vial® package by peeling away the lid. To maintain sterility, leave the Mix2Vial® set in its clear outer package. 3. Prepare Diluent Vial: Place the diluent vial on an even flat surface and hold the vial tightly. Grip the Mix2Vial® keeping it in the package. Push the plastic spike at the blue end of the Mix2Vial® set firmly through the center of the diluent vial stopper. 4.Remove the Mix2Vial® packaging: While holding the diluent vial, carefully remove the outer package from the Mix2Vial® set. Make sure that you pull off only the package, not the Mix2Vial® set. 5.Transfer Diluent into IDELVION Vial: Place the product vial on an even flat surface and hold the vial tight. Invert the diluent vial with the Mix2Vial® set attached to it and push the plastic spike of the clear end of the Mix2Vial® end firmly through the stopper of the IDELVION vial. The diluent will transfer into the IDELVION vial automatically. 6. Dissolve IDELVION: With the diluent and IDELVION vial still attached to the Mix2Vial® set, gently swirl the IDELVION vial to ensure the product is fully dissolved. Do not shake the vial. 7. Unscrew empty diluent (Blue) vial: With one hand, grip the clear end of the Mix2Vial® set and with the other hand grip the blue end of the Mix2Vial® set and unscrew the set into two pieces. 8. Load the syringe: Draw air into an empty, sterile syringe. Use the syringe provided with the product. With the IDELVION vial upright, screw the syringe to the Mix2Vial® set. Inject air into the product vial. While keeping the syringe plunger pressed, invert the IDELVION vial and draw the solution into the syringe by pulling the plunger back slowly. 9. Prepare the administration set equipped with microbore tubing: Once the solution has been transferred into the syringe, firmly grip the barrel of the syringe (keeping the plunger facing down) and unscrew the syringe from the Mix2Vial® set. Attach the syringe to the provided infusion set or another suitable administration set. 10. After reconstitution, administration should begin promptly or within 3 hours. 11.Use a separate, unused Mix2Vial® transfer set for each product vial. C. Administer IDELVION using aseptic technique: Thoroughly wash and dry hands. Locate vein. Clean the injection site using an antiseptic skin preparation. Allow each site to dry before proceeding. Insert the needle into the vein. Check for proper placement of the needle. Inject IDELVION into the vein using a slow intravenous injection. HOW SUPPLIED Dosage Forms, Composition And Packaging IDELVION, Coagulation Factor IX (Recombinant), Albumin Fusion Protein (rIX-FP), is a preservative free, sterile, non-pyrogenic, lyophilized powder to be reconstituted with Sterile Water for Injection (SWFI) for intravenous injection. IDELVION is available in single-use vials containing actual FIX activity printed on the vial label and product carton, expressed in International Units (IU). Each vial contains nominally 250 IU, 500 IU, 1000 IU, or 2000 IU of IDELVION and must be reconstituted with the respective supplied volume of SWFI (diluent) listed in Table 7: Table 7: Reconstitution Diluent Volume Lyophilized rIX-FP Format Diluent Volume for Reconstitution Concentration of product once reconstituted 250 IU 2.5 mL 100 IU/mL 500 IU 2.5 mL 200 IU/mL 1000IU 2.5 mL 400 IU/mL 2000IU 5 mL 400 IU/mL The IDELVION package consists of 2 boxes. The “Product box” contains one single-use product vial containing lyophilized Coagulation Factor IX (Recombinant), Albumin Fusion Protein (rIX-FP) and one vial of Sterile Water for Injection (Diluent). The “Device box” contains one Mix2Vial® filter transfer set, one syringe, one infusion set and a plaster (non-sterile). After reconstitution of the lyophilized powder, all dosage strengths yield a clear, yellow to colorless solution. The concentrations of excipients based on the presentation are summarized in Table 8. Table 8: Excipients within each nominal composition of IDELVION following reconstitution with WFI Excipient Nominal Composition after Reconstitution with WFI 250 IU vial 500 IU vial 1000 IU vial 2000 IU vial Tri-sodium citrate 6.5 mg/mL 6.5 mg/mL 6.5 mg/mL 6.5 mg/mL Polysorbate 80 0.06 mg/mL 0.12 mg/mL 0.24 mg/mL 0.24 mg/mL Mannitol 18 mg/mL 29 mg/mL 29 mg/mL 29 mg/mL Sucrose 7 mg/mL 12 mg/mL 12 mg/mL 12 mg/mL Storage And Stability Store at +2 °C to +25° C. Do not freeze. The shelf life of IDELVION is up to 24 months for 250 IU and 500 IU or 36 months for 1000 IU and 2000 IU. Do not use beyond the expiration date on the IDELVION carton and vial labels. Store vial in original carton to protect from light. Product after reconstitution: the product administration should begin promptly or within 3 hours. CSL Behring Canada, Inc. Revised: Jan 2016

INDICATIONS REBINYN, Coagulation Factor IX (Recombinant), GlycoPEGylated, is a recombinant DNA-derived coagulation Factor IX concentrate indicated for use in adults and children with hemophilia B for: On-demand treatment and control of bleeding episodes Perioperative management of bleeding Limitations Of Use REBINYN is not indicated for routine prophylaxis in the treatment of patients with hemophilia B. REBINYN is not indicated for immune tolerance induction in patients with hemophilia B. DOSAGE AND ADMINISTRATION For intravenous infusion after reconstitution only. Dosing Guidelines Dose and duration of treatment depend on the location and extent of bleeding, and the patient's clinical condition. If monitoring of Factor IX activity is performed, use a chromogenic assay or selected one-stage clotting assay validated for use with REBINYN [see WARNINGS AND PRECAUTIONS]. Each carton and vial label for REBINYN states the actual Factor IX potency in IU. On-demand Treatment And Control Of Bleeding Episodes REBINYN dosing for on-demand treatment and control of bleeding episodes is provided in Table 1. Table 1: Dosing for On-demand Treatment and Control of Bleeding Episodes Type of bleeding Recommended dose IU/kg body weight Additional information Minor and moderate For example: Uncomplicated joint bleeds, minor muscular bleeds, mucosal or subcutaneous bleeds 40 A single dose should be sufficient for minor and moderate bleeds. Additional doses of 40 IU/kg can be given. Major For example: Intracranial, retroperitoneal, iliopsoas and neck bleeds, muscle bleeds with compartment syndrome and bleeds associated with a significant decrease in the hemoglobin level 80 Additional doses of 40 IU/kg can be given. Perioperative Management REBINYN dosing for perioperative management is provided in Table 2. Table 2: Dosing for Perioperative Management Type of surgical procedure Recommended dose IU/kg body weight Additional Information Minor For example: Implanting pumps in subcutaneous tissue, skin biopsies or simple dental procedures 40 A single pre-operative dose should be sufficient. Additional doses can be given if needed. Major For example: Body cavity is entered, mesenchymal barrier is crossed, fascial plane is opened, organ is removed, normal anatomy is operatively altered 80 Pre-operative dose 40 As clinically needed for the perioperative management of bleeding, repeated doses of 40 IU/kg *See Pharmacokinetics, Table 8 Reconstitution Always wash hands and ensure that the area is clean before performing the reconstitution procedures. Use aseptic technique during the reconstitution procedures. If the patient uses more than one vial of REBINYN per infusion, reconstitute each vial according to the following instructions. Overview Of REBINYN Package The instructions below serve as a general guideline for reconstitution of REBINYN. For full instructions, refer to the FDA-approved patient information and Instructions for Use. Reconstitution 1. Bring the REBINYN vial and the pre-filled diluent syringe to room temperature. 2. Remove the plastic cap from the REBINYN vial. 3. Wipe the rubber stopper on the vial with a sterile alcohol swab and allow it to dry prior to use. 4. Remove the protective paper from the vial adapter. Do not remove the vial adapter from the protective cap. 5. Place the vial on a flat and solid surface. While holding the protective cap, place the vial adapter over the REBINYN vial and press down firmly on the protective cap until the vial adapter spike penetrates the rubber stopper. 6. Remove the protective cap from the vial adapter. 7. Grasp the plunger rod as shown in the diagram. Attach the plunger rod to the syringe by holding the plunger rod by the wide top end. Turn the plunger rod clockwise into the rubber plunger inside the pre-filled diluent syringe until resistance is felt. 8. Break off the syringe cap from the pre-filled diluent syringe by snapping the perforation of the cap. 9. Connect the pre-filled diluent syringe to the vial adapter by turning it clockwise until it is secured. 10. Push the plunger rod to slowly inject all the diluent into the vial. 11. Without removing the syringe, gently swirl the REBINYN vial until all of the powder is dissolved. 12. Administer the REBINYN solution immediately [see Administration]. If not used immediately after reconstitution, store the solution in the vial with the vial adapter and the syringe attached, at room temperature ≤ 86°F (30°C). Do not store for longer than 4 hours. Administration For intravenous infusion only. Accidental needle stick with a needle contaminated with blood can transmit infectious viruses including HIV (AIDS) and hepatitis. If a needle stick occurs, obtain immediate medical attention. Place needles in a sharps container after single use. Inspect the reconstituted REBINYN solution visually prior to administration [see DESCRIPTION]. The solution should be clear and have no particles. Do not use if particulate matter or discoloration is observed. Do not administer REBINYN in the same tubing or container with other medicinal products. 1. Invert the REBINYN vial and slowly draw the solution into the syringe. 2. Detach the syringe from the vial adapter by turning the syringe counterclockwise. 3. Attach the syringe to the luer end of an infusion needle set. 4. Infuse the reconstituted REBINYN intravenously slowly over 1 to 4 minutes. 5. After infusion, safely dispose of the syringe with the infusion set, the vial with the vial adapter, any unused REBINYN, and other waste materials. Caution: The pre-filled diluent syringe is made of glass with an internal tip diameter of 0.037 inches, and is compatible with a standard Luer-lock connector. Some needleless connectors for intravenous catheters are incompatible with the glass diluent syringes (for example, certain connectors with an internal spike, such as ClaveREBINYN through incompatible needleless connectors, withdraw the reconstituted product into a standard 10 mL sterile Luer-lock plastic syringe. ® /MicroClave®, InVision-Plus®, InVision-Plus CS®, Invision-Plus Junior®, Bionector®), and their use can damage the connector and affect administration. To administer If you encounter any problems with attaching the pre-filled histidine-diluent syringe to any Luer-lock compatible device, please contact Novo Nordisk at (844) 303-4448. HOW SUPPLIED Dosage Forms And Strengths REBINYN is available as a white to off-white lyophilized powder in single-use vials containing nominally 500, 1000, or 2000 IU per vial. Each carton and vial label for REBINYN states the actual Factor IX potency in IU. After reconstitution with 4 mL of histidine diluent, the reconstituted solution contains approximately 125, 250 or 500 IU per mL of REBINYN respectively. REBINYN is supplied in packages comprised of a single-use vial containing nominally 500, 1000, or 2000 IU of Factor IX potency; a MixPro® pre-filled diluent syringe containing 10 mM histidine solution (1.6 mg/mL), and a sterile vial adapter with 25 micrometer filter, which serves as a needleless reconstitution device. The actual Factor IX potency in IU is stated on each REBINYN carton and vial. Table 10: REBINYN Presentations Presentation (Nominal Product Strength; IU) Cap Color Indicator Carton NDC Number Components 500 Red NDC 0169 7905 01 REBINYN in single-use vial [NDC 0169 7955 11] Pre-filled histidine diluent in syringe, 4 mL [NDC 0169 7009 98] Vial adapter 1000 Green NDC 0169 7901 01 REBINYN in single-use vial [NDC 0169 7911 11] Pre-filled histidine diluent in syringe, 4 mL [NDC 0169 7009 98] Vial adapter 2000 Yellow NDC 0169 7902 01 REBINYN in single-use vial [NDC 0169 7922 11] Pre-filled histidine diluent in syringe, 4 mL [NDC 0169 7009 98] The REBINYN vials are made of glass, closed with a chlorobutyl rubber stopper (not made with natural rubber latex), and sealed with an aluminum cap. The pre-filled diluent syringes are made of glass, with a siliconised bromobutyl rubber plunger (not made with rubber latex). The closed vials and pre-filled diluent syringes are equipped with a tamper-evident snap-off cap which is made of polypropylene. Storage And Handling Store REBINYN in the original package in order to protect from light. Store REBINYN under refrigeration at a temperature of 36°F-46°F (2°C - 8°C) for up to 24 months from the date of manufacture until the expiration date stated on the label. REBINYN may be stored at room temperature not to exceed 86°F (30°C) for up to 6 months within the 24-month time period. Record the date when the product was removed from the refrigerator in the space provided on the outer carton. The total time of storage at room temperature should not exceed 6 months. Do not return the product to the refrigerator. Do not use REBINYN after the end of the 6-month period at room temperature storage, or after the expiration date stated on the vial, whichever occurs earlier. Do not freeze REBINYN. Use REBINYN within 4 hours after reconstitution when stored at room temperature. Store the reconstituted product in the vial. Discard any unused reconstituted product stored at room temperature for more than 4 hours. Novo Nordisk Inc. 800 Scudders Mill Road, Plainsboro, NJ 08536, USA. 1-844-REB-INYN. Manufactured by: Novo Nordisk A/S , Novo Allé, DK-2880 Bagsvaerd. Revised: May 2017

INDICATIONS Mononine® (coagulation factor ix (human)) , is indicated for the prevention and control of bleeding in Factor IX deficiency, also known as Hemophilia B or Christmas disease. Mononine® (coagulation factor ix (human)) is not indicated in the treatment or prophylaxis of Hemophilia A patients with inhibitors to Factor VIII. Mononine® (coagulation factor ix (human)) , contains non-detectable levels of Factors II, VII and X ( < 0. 0025 IU per Factor IX unit using standard coagulation assays) and is, therefore, not indicated for replacement therapy of these clotting factors. Mononine® (coagulation factor ix (human)) is also not indicated in the treatment or reversal of coumarin-induced anticoagulation or in a hemorrhagic state caused by hepatitis-induced lack of production of liver dependent coagulation factors. DOSAGE AND ADMINISTRATION Mononine® (coagulation factor ix (human)) is intended for intravenous administration only. It should be reconstituted with the volume of Sterile Water for Injection, USP supplied with the lot, and administered within three hours of reconstitution. Do not refrigerate after reconstitution. After administration, any unused solution and the administration equipment should be discarded. As a general rule, 1 IU of Factor IX activity per kg can be expected to increase the circulating level of Factor IX by 1% [IU/dL] of normal. The following formula provides a guide to dosage calculations: Number of Factor IX required (IU) = Body Weight (in kg) x desired Factor IX increase (% or IU/dL normal) x 1.0 IU/kg IU [per IU/dL] The amount of Mononine® (coagulation factor ix (human)) to be infused, as well as the frequency of infusions, will vary with each patient and with the clinical situation. 11,12 As a general rule, the level of Factor IX required for treatment of different conditions is as follows: Minor Spontaneous Hemorrhage, Prophylaxis Major Trauma or Surgery Desired levels of Factor IX for Hemostasis 15-25% [or IU/dL] 25-50% [or IU/dL] Initial loading dose to achieve desired level up to 20-30 IU/kg up to 75 IU/kg Frequency of dosing once; repeated in 24 hours if necessary every 18-30 hours, depending on T½ and measured Factor IX levels Duration of treatment once; repeated if necessary up to ten days,depending upon nature of insult Recovery of the loading dose varies from patient to patient. Doses administered should be titrated to the patient's response. Mononine® (coagulation factor ix (human)) administered in doses of ≥ 75 IU/kg were well tolerated (see CLINICAL PHARMACOLOGY). In the presence of an inhibitor to Factor IX, higher doses of Mononine® (coagulation factor ix (human)) might be necessary to overcome the inhibitor (see PRECAUTIONS). No data on the treatment of patients with inhibitors to Factor IX with Mononine® (coagulation factor ix (human)) are available. For information on rate of administration, see Rate of Administration, below. Reconstitution Warm both the diluent and Coagulation Factor IX (Human), Mononine® (coagulation factor ix (human)) , in unopened vials to room temperature [not above 37°C (98°F)]. Remove the caps from both vials to expose the central portions of the rubber stoppers. Treat the surface of the rubber stoppers with antiseptic solution and allow them to dry. Using aseptic technique, insert one end of the double-end needle into the rubber stopper of the dilu-ent vial. Invert the diluent vial and insert the other end of the double-end needle into the rubber stopper of the Mononine® (coagulation factor ix (human)) vial. Direct the diluent, which will be drawn in by vacuum, over the entire surface of the Mononine® (coagulation factor ix (human)) cake. (In order to assure transfer of all the diluent, adjust the position of the tip of the needle in the diluent vial to the inside edge of the diluent stopper.) Rotate the vial to ensure complete wetting of the cake during the transfer process. Remove the diluent vial to release the vacuum, then remove the double-end needle from the Mononine® (coagulation factor ix (human)) vial. Gently swirl the vial until the powder is dissolved and the solution is ready for administration. The concentrate routinely and easily reconstitutes within one minute. To assure sterility, Mononine® (coagulation factor ix (human)) should be administered within three hours after reconstitution. Product should be filtered prior to use as described under Administration. Parenteral drug preparations should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Administration Intravenous Injection Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Plastic disposable syringes are recommended with Mononine® (coagulation factor ix (human)) solution. The ground glass surfaces of all-glass syringes tend to stick with solutions of this type. Please note, this concentrate is supplied with a SELF-VENTING filter spike. Using aseptic technique, attach the vented filter spike to a sterile diposable syringe. CAUTION: The use of other, non-vented filter needles or spikes without the proper procedure may result in an air lock and prevent the complete transfer of the concentrate. CAUTION: DO NOT INJECT AIR INTO THE MONONINE® (coagulation factor ix (human)) VIAL. The self-venting feature of the vented filter spike precludes the need to inject air in order to facilitate withdrawal of the reconstituted solution. The injection of air could cause partial product loss through the vent filter. Insert the vented filter spike into the stopper of the Mononine® (coagulation factor ix (human)) vial, invert the vial, and position the filter spike so that the orifice is at the inside edge of the stopper. Withdraw the reconstituted solution into the syringe. Discard the filter spike. Perform venipuncture using the enclosed winged needle with microbore tubing. Attach the syringe to the luer end of the tubing. CAUTION: Use of other winged needles without microbore tubing, although compatible with the concentrate, will result in a larger retention of solution within the winged infusion set. Rate of Administration The rate of administration should be determined by the response and comfort of the patient; intravenous dosage administration rates of up to 225 IU/minute have been regularly tolerated without incident. When reconstituted as directed, i. e. , to approximately 100 IU/mL, Mononine® (coagulation factor ix (human)) should be administered at a rate of approximately 2. 0 mL per minute. Storage When stored at refrigerator temperature, 2-8°C (36-46°F), Mononine® (coagulation factor ix (human)) is stable for the period indicated by the expiration date on its label. Within this period, Mononine® (coagulation factor ix (human)) may be stored at room temperature not to exceed 25°C (77°F), for up to one month. Avoid freezing, which may damage container for the diluent. HOW SUPPLIED Mononine® (coagulation factor ix (human)) is supplied in a single dose vial with Sterile Water for Injection, USP, double-ended needle for reconstitution, vented filter spike for withdrawal, winged infusion set and alcohol swabs. Factor IX activity in IU is stated on the label of each vial. The following strengths are available: NDC 0053-7668-02 in 10 mL vials containing approximately 500 IU (Dosage-MID) NDC 0053-7668-04 in 20 mL vials containing approximately 1,000 IU (Dosage-HIGH) REFERENCES 11. Kasper CK, Dietrich SL. Comprehensive Management of Hemophilia. ClinHaematol 14(2):489-512, 1985. 12. JohnsonAJ, AronsonDL, WilliamsWJ. Preparationandclinicaluseofplasma and plasma fractions. Chap 167 in Hematology3rdEdition, WilliamsWJ, BeutlerE, Erslev AJ, Lichtman MA (Eds.), McGraw Hill Book Co. New York: pp 1563-1583, 1983. Manufactured by: CSL Behring LLC, Kankakee, IL 60901 USA. Revised January, 2007.

PATIENT INFORMATION RIXUBIS [Coagulation Factor IX (Recombinant)] This leaflet summarizes important information about RIXUBIS. Please read it carefully before using this medicine. This information does not take the place of talking with your healthcare provider, and it does not include all of the important information about RIXUBIS. If you have any questions after reading this, ask your healthcare provider. What is RIXUBIS? RIXUBIS is a medicine used to replace clotting factor (Factor IX) that is missing in people with hemophilia B. Hemophilia B is also called congenital factor IX deficiency or Christmas disease. Hemophilia B is an inherited bleeding disorder that prevents blood from clotting normally. RIXUBIS is used to prevent and control bleeding in people with hemophilia B. Your healthcare provider may give you RIXUBIS when you have surgery. RIXUBIS can reduce the number of bleeding episodes when used regularly (prophylaxis). Who should not use RIXUBIS? You should not use RIXUBIS if you are allergic to hamsters are allergic to any ingredients in RIXUBIS. Tell your healthcare provider if you are pregnant or breastfeeding because RIXUBIS may not be right for you. What should I tell my healthcare provider before using RIXUBIS? You should tell your healthcare provider if you have or have had any medical problems take any medicines, including prescription and non-prescription medicines, such as over-the-counter medicines, supplements or herbal remedies have any allergies, including allergies to hamsters are breastfeeding. It is not known if RIXUBIS passes into your milk and if it can harm your baby are pregnant or planning to become pregnant. It is not known if RIXUBIS may harm your unborn baby have been told that you have inhibitors to factor IX (because RIXUBIS may not work for you). How should I infuse RIXUBIS? RIXUBIS is given directly into the bloodstream. RIXUBIS should be administered as ordered by your healthcare provider. You should be trained on how to do infusions by your healthcare provider or hemophilia treatment center. Many people with hemophilia B learn to infuse their RIXUBIS by themselves or with the help of a family member. Your healthcare provider will tell you how much RIXUBIS to use based on your weight, the severity of your hemophilia B, and where you are bleeding. You may have to have blood tests done after getting RIXUBIS to be sure that your blood level of factor IX is high enough to clot your blood. Call your healthcare provider right away if your bleeding does not stop after taking RIXUBIS. What are the possible side effects of RIXUBIS? Allergic reactions may occur with RIXUBIS. Call your healthcare provider or get emergency treatment right away if you get a rash or hives, itching, tightness of the throat, chest pain or tightness, difficulty breathing, lightheadedness, dizziness, nausea or fainting. Some common side effects of RIXUBIS were unusual taste in the mouth and limb pain. Tell your healthcare provider about any side effects that bother you or do not go away. These are not all the side effects possible with RIXUBIS. You can ask your healthcare provider for information that is written for healthcare professionals. What are the RIXUBIS dosage strengths? RIXUBIS comes in five different dosage strengths: 250, 500, 1000, 2000 and 3000 international units. The actual strength will be imprinted on the label and on the box. The five different strengths are color coded, as follows: Dosage strength of approximately 250 international units per vial Dosage strength of approximately 500 international units per vial Dosage strength of approximately 1000 international units per vial Dosage strength of approximately 2000 international units per vial Dosage strength of approximately 3000 international units per vial Always check the actual dosage strength printed on the label to make sure you are using the strength prescribed by your healthcare provider. How should I store RIXUBIS? Store at refrigerated temperature 2° to 8°C (36° to 46°F) for up to 24 months. Do not freeze. May store at room temperature not to exceed 30°C (86°F) for up to 12 months within the 24 month time period. Write on the carton the date RIXUBIS is removed from refrigeration. After storage at room temperature, do not return the product to the refrigerator. Do not use after the expiration date printed on the carton or vial. Reconstituted product (after mixing dry product with wet diluent) must be used within 3 hours and cannot be stored or refrigerated. Discard any RIXUBIS left in the vial at the end of your infusion. What else should I know about RIXUBIS? Your body may form inhibitors to factor IX. An inhibitor is part of the body's defense system. If you form inhibitors, it may stop RIXUBIS from working properly. Consult with your healthcare provider to make sure you are carefully monitored with blood tests for the development of inhibitors to factor IX. Medicines are sometimes prescribed for purposes other than those listed here. Do not use RIXUBIS for a condition for which it is not prescribed. Do not share RIXUBIS with other people, even if they have the same symptoms that you have. Recredits at Baxter available to patients For information on patient assistance programs that are available to you, including the Baxter CARE Program, please contact the Baxter Insurance Assistance Helpline at 1-888-229-8379. INSTRUCTIONS FOR USE RIXUBIS [Coagulation Factor IX (Recombinant)] For intravenous use only Do not attempt to do an infusion to yourself unless you have been taught how by your healthcare provider or hemophilia center. Always follow the specific instructions given by your healthcare provider. The steps listed below are general guidelines for using RIXUBIS. If you are unsure of the procedures, please call your healthcare provider before using RIXUBIS. Call your healthcare provider right away if bleeding is not controlled after using RIXUBIS. Your healthcare provider will prescribe the dose that you should take. Your healthcare provider may need to take blood tests from time to time. Talk to your healthcare provider before traveling. Plan to bring enough RIXUBIS for your treatment during this time. Dispose of all materials, including any leftover reconstituted RIXUBIS product, in an appropriate container. 1. Prepare a clean flat surface and gather all the materials you will need for the infusion. Check the expiration date, and let the vial with the RIXUBIS concentrate and the Sterile Water for Injection, USP (diluent) warm up to room temperature. Wash your hands and put on clean exam gloves. If infusing yourself at home, the use of gloves is optional. 2. Remove caps from the RIXUBIS concentrate and diluent vials to expose the centers of the rubber stoppers. 3. Disinfect the stoppers with an alcohol swab (or other suitable solution suggested by your healthcare provider or hemophilia center) by rubbing the stoppers firmly for several seconds and allow them to dry prior to use. Place the vials on a flat surface. 4. Open the BAXJECT II device package by peeling away the lid, without touching the inside of the package. Do not remove the BAXJECT II device from the package. 5. Turn the package with the BAXJECT II device upside down and place it over the top of the diluent vial. Fully insert the clear plastic spike of the device into the center of the diluent vial stopper by pushing straight down. Grip the package at its edge and lift it off the device. Be careful not to touch the white plastic spike. Do not remove the blue cap from the BAXJECT II device. The diluent vial now has the BAXJECT II device connected to it and is ready to be connected to the RIXUBIS vial. 6. To connect the diluent vial to the RIXUBIS vial, turn the diluent vial over and place it on top of the vial containing RIXUBIS concentrate. Fully insert the white plastic spike into the RIXUBIS vial stopper by pushing straight down. Diluent will flow into the RIXUBIS vial. This should be done right away to keep the liquid free of germs. 7. Swirl the connected vials gently and continuously until the powder is completely dissolved. Do not shake. The RIXUBIS solution should look clear and colorless. If not, do not use it and notify Baxter immediately. 8. Take off the blue cap from the BAXJECT II device and connect the syringe by screwing it clockwise until the syringe is secured. Do not over tighten. Be careful to not inject air. 9. Turn over the connected vials so that the RIXUBIS vial is on top. Draw the RIXUBIS solution into the syringe by pulling back the plunger slowly. Disconnect the syringe from the BAXJECT II unscrewing it counterclockwise. 10. If you are using more than one vial of RIXUBIS, the contents of more than one vial may be drawn into the same syringe. Make sure you mix each vial of RIXUBIS with the Sterile Water for Injection, USP that is provided in the box (following Steps 1-9). You will need a separate BAXJECT II device to mix each additional vial of RIXUBIS. 11. Attach the infusion needle to the syringe using a winged (butterfly) infusion set, if available. Point the needle up and remove any air bubbles by gently tapping the syringe with your finger and slowly and carefully pushing air out of the syringe and needle. 12. Apply a tourniquet and get the infusion site ready by wiping the skin well with an alcohol swab (or other suitable solution suggested by your healthcare provider or hemophilia center). 13. Insert the needle into the vein and remove the tourniquet. Slowly infuse the RIXUBIS. Do not infuse any faster than 10 mL per minute. 14. Take the needle out of the vein and use sterile gauze to put pressure on the infusion site for several minutes. Do not recap the needle. Place it with the used syringe in a hard-walled sharps container for proper disposal. 15. Dispose of the used vials and BAXJECT II system in your hard-walled sharps container without taking them apart. Do not dispose of these supplies in ordinary household trash. 16. Remove the peel-off label from the RIXUBIS vial and place it in your logbook. Clean any spilled blood with a freshly prepared mixture of 1 part bleach and 9 parts water, soap and water, or any household disinfecting solution. Important: Contact your healthcare provider or local hemophilia treatment center if you experience any problems.

PATIENT INFORMATION REBINYN (reh-be-NINE) Coagulation Factor IX (Recombinant), GlycoPEGylated Read the Patient Product Information and the Instructions For Use that come with REBINYN before you start taking this medicine and each time you get a refill. There may be new information. This Patient Product Information does not take the place of talking with your healthcare provider about your medical condition or treatment. If you have questions about REBINYN after reading this information, ask your healthcare provider. What is the most important information I need to know about REBINYN? Do not attempt to do an infusion yourself unless you have been taught how by your healthcare provider or hemophilia treatment center. You must carefully follow your healthcare provider's instructions regarding the dose and schedule for infusing REBINYN so that your treatment will work best for you. What is REBINYN? REBINYN is an injectable medicine used to replace clotting Factor IX that is missing in patients with hemophilia B. Hemophilia B is an inherited bleeding disorder in all age groups that prevents blood from clotting normally. REBINYN is used to treat and control bleeding in people with hemophilia B. Your healthcare provider may give you REBINYN when you have surgery. Who should not use REBINYN? You should not use REBINYN if you are allergic to Factor IX or any of the other ingredients of REBINYN if you are allergic to hamster proteins If you are not sure, talk to your healthcare provider before using this medicine. Tell your healthcare provider if you are pregnant or nursing because REBINYN might not be right for you. What should I tell my healthcare provider before I use REBINYN? You should tell your healthcare provider if you Have or have had any medical conditions. Take any medicines, including non-prescription medicines and dietary supplements. Are nursing. Are pregnant or planning to become pregnant. Have been told that you have inhibitors to Factor IX. How should I use REBINYN? Treatment with REBINYN should be started by a healthcare provider who is experienced in the care of patients with hemophilia B. REBINYN is given as an infusion into the vein. You may infuse REBINYN at a hemophilia treatment center, at your healthcare provider's office or in your home. You should be trained on how to do infusions by your hemophilia treatment center or healthcare provider. Many people with hemophilia B learn to infuse the medicine by themselves or with the help of a family member. Your healthcare provider will tell you how much REBINYN to use based on your weight, the severity of your hemophilia B, and where you are bleeding. Your dose will be calculated in international units, IU. Call your healthcare provider right away if your bleeding does not stop after taking REBINYN. If your bleeding is not adequately controlled, it could be due to the development of Factor IX inhibitors. This should be checked by your healthcare provider. You might need a higher dose of REBINYN or even a different product to control bleeding. Do not increase the total dose of REBINYN to control your bleeding without consulting your healthcare provider. Use in children REBINYN can be used in children. Your healthcare provider will decide the dose of REBINYN you will receive. If you forget to use REBINYN If you forget a dose, infuse the missed dose when you discover the mistake. Do not infuse a double dose to make up for a forgotten dose. Proceed with the next infusions as scheduled and continue as advised by your healthcare provider. If you stop using REBINYN Do not stop using REBINYN without consulting your healthcare provider. If you have any further questions on the use of this product, ask your healthcare provider. What if I take too much REBINYN? Always take REBINYN exactly as your healthcare provider has told you. You should check with your healthcare provider if you are not sure. If you infuse more REBINYN than recommended, tell your healthcare provider as soon as possible. What are the possible side effects of REBINYN? Common Side Effects Include: swelling, pain, rash or redness at the location of infusion itching Other Possible Side Effects: You could have an allergic reaction to coagulation Factor IX products. Call your healthcare provider right away or get emergency treatment right away if you get any of the following signs of an allergic reaction: hives, chest tightness, wheezing, difficulty breathing, and/or swelling of the face. Your body can also make antibodies called “inhibitors” against REBINYN, which may stop REBINYN from working properly. Your healthcare provider may need to test your blood for inhibitors from time to time. You may be at an increased risk of forming blood clots in your body, especially if you have risk factors for developing blood clots. Call your healthcare provider if you have chest pain, difficulty breathing, leg tenderness or swelling. These are not all of the possible side effects from REBINYN. Ask your healthcare provider for more information. You are encouraged to report side effects to FDA at 1-800-FDA-1088. Tell your healthcare provider about any side effect that bothers you or that does not go away. What are the REBINYN dosage strengths? REBINYN comes in three different dosage strengths. The actual number of international units (IU) of Factor IX in the vial will be imprinted on the label and on the box. The three different strengths are as follows: Cap Color Indicator Nominal Strength Red 500 IU per vial Green 1000 IU per vial Yellow 2000 IU per vial Always check the actual dosage strength printed on the label to make sure you are using the strength prescribed by your healthcare provider. How should I store REBINYN? Prior to Reconstitution (mixing the dry powder in the vial with the diluent): Store in original package in order to protect from light. Do not freeze REBINYN. REBINYN vials can be stored in the refrigerator (36-46°F [2°C - 8°C]) for up to 24 months until the expiration date, or at room temperature (up to 86°F [30°C]) for a single period not more than 6 months. If you choose to store REBINYN at room temperature: Note the date that the product is removed from refrigeration on the box. The total time of storage at room temperature should not be more than 6 months. Do not return the product to the refrigerator. Do not use after 6 months from this date or the expiration date listed on the vial, whichever is earlier. Do not use this medicine after the expiration date which is on the outer carton and the vial. The expiration date refers to the last day of that month. After Reconstitution: The reconstituted (the final product once the powder is mixed with the diluent) REBINYN should appear clear without visible particles. The reconstituted REBINYN should be used immediately. If you cannot use the reconstituted REBINYN immediately, it should be used within 4 hours when stored at or below 86°F (30°C). Store the reconstituted product in the vial. Keep this medicine out of the sight and out of reach of children. What else should I know about REBINYN and hemophilia B? Medicines are sometimes prescribed for purposes other than those listed here. Do not use REBINYN for a condition for which it is not prescribed. Do not share REBINYN with other people, even if they have the same symptoms that you have. For more information about REBINYN, please call Novo Nordisk at 1-844-REB-INYN. Instructions on how to use REBINYN® MixPro® READ THESE INSTRUCTIONS CAREFULLY BEFORE USING REBINYN. REBINYN is supplied as a powder. Before infusion (administration) it must be mixed (reconstituted) with the liquid diluent supplied in the syringe. The liquid diluent is a histidine solution. The mixed REBINYN must be infused into your vein (intravenous infusion). The equipment in this package is designed to mix and infuse REBINYN. You will also need an infusion set (tubing and butterfly needle), sterile alcohol swabs, gauze pads, and bandages. Don't use the equipment without proper training from your doctor or nurse. Always wash your hands and ensure that the area around you is clean. When you prepare and infuse medication directly into the veins, it is important to use a clean and germ free (aseptic) technique. Improper technique can introduce germs that can infect the blood. Don't open the equipment until you are ready to use it. Don't use the equipment if it has been dropped, or if it is damaged. Use a new package instead. Don't use the equipment if it is expired. Use a new package instead. The expiration date is printed on the outer carton and on the vial, the vial adapter and the pre-filled syringe. Don't use the equipment if you suspect it is contaminated. Use a new package instead. Don't dispose of any of the items until after you have infused the mixed solution. The equipment is for single use only. Content The package contains: Vial with REBINYN powder Vial adapter Pre-filled syringe with diluent Plunger rod (placed under the syringe) 1. Prepare the vial and the syringe Take out the number of REBINYN® packages you need. Check the expiry date. Check the name, strength and color of the package, to make sure it contains the correct product. Wash your hands and dry them properly using a clean towel or air dry. Take the vial, the vial adapter and the pre-filled syringe out of the carton. Leave the plunger rod untouched in the carton. Bring the vial and the pre-filled syringe to room temperature. You can do this by holding them in your hands until they feel as warm as your hands. Remove the plastic cap from the vial. If the plastic cap is loose or missing, don't use the vial. Wipe the rubber stopper with a sterile alcohol swab and allow it to air dry for a few seconds before use to ensure that it is as germ free as possible. Don't touch the rubber stopper with your fingers as this can transfer germs. 2. Attach the vial adapter Remove the protective paper from the vial adapter. Don't take the vial adapter out of the protective cap with your fingers. If you touch the spike on the vial adapter germs from your fingers can be transferred. If the protective paper is not fully sealed or if it is broken, don't use the vial adapter. Place the vial on a flat and solid surface. Turn over the protective cap, and snap the vial adapter onto the vial. Once attached, don't remove the vial adapter from the vial. Lightly squeeze the protective cap with your thumb and index finger as shown. Remove the protective cap from the vial adapter. Don't lift the vial adapter from the vial when removing the protective cap. 3. Attach the plunger rod and the syringe Grasp the plunger rod by the wide top end and take it out of the carton. Don't touch the sides or the thread of the plunger rod. If you touch the sides or the thread germs from your fingers can be transferred. Immediately connect the plunger rod to the syringe by turning it clockwise into the rubber plunger inside the pre-filled syringe until resistance is felt. Remove the syringe cap from the pre-filled syringe by bending it down until the perforation breaks. Don't touch the syringe tip under the syringe cap. If you touch the syringe tip germs from your fingers can be transferred. If the syringe cap is loose or missing, don't use the pre-filled syringe. Screw the pre-filled syringe securely onto the vial adapter until resistance is felt. 4. Mix the powder with the diluent Hold the pre-filled syringe slightly tilted with the vial pointing downwards. Push the plunger rod to inject all the diluent into the vial. Keep the plunger rod pressed down and swirl the vial gently until all the powder is dissolved. Don't shake the vial as this will cause foaming. Check the mixed solution. It must be clear and colorless. If you notice visible particles or discoloration, don't use it. Use a new package instead. REBINYN is recommended to be used immediately after it is mixed. If you cannot use the mixed REBINYN solution immediately, it should be used within 4 hours when stored at room temperature at or below 86°F (30°C). Store the reconstituted product in the vial. Do not freeze mixed REBINYN solution or store it in syringes. Keep mixed REBINYN solution out of direct light. If your dose requires more than one vial, repeat step A to J with additional vials, vial adapters and pre-filled syringes until you have reached your required dose. Keep the plunger rod pushed completely in. Turn the syringe with the vial upside down. Stop pushing the plunger rod and let it move back on its own while the mixed solution fills the syringe. Pull the plunger rod slightly downwards to draw the mixed solution into the syringe. In case you only need part of the entire vial, use the scale on the syringe to see how much mixed solution you withdraw, as instructed by your doctor or nurse. While holding the vial upside down, tap the syringe gently to let any air bubbles rise to the top. Push the plunger rod slowly until all air bubbles are gone. Unscrew the vial adapter with the vial. Don't touch the syringe tip. If you touch the syringe tip germs from your fingers can be transferred. Caution: The pre-filled diluent syringe is made of glass with an internal tip diameter of 0.037 inches, and is compatible with a standard Luer-lock connector. Some needleless connectors for intravenous catheters are incompatible with the glass diluent syringes (for example, certain connectors with an internal spike, such as Clave®/MicroClave®, InVision-Plus®, InVision-Plus CS®, Invision-PlusJunior®, Bionector®). The use of these needleless connectors can damage the connector and affect administration. To administer REBINYN through incompatible needleless connectors, withdraw reconstituted product into a standard 10 mL sterile Luer-lock plastic syringe. If you have encountered any problems with attaching the pre-filled histidine diluent syringe to any Luer-lock compatible device, please contact Novo Nordisk at (844) 303-4448. 5. Infuse the mixed solution REBINYN is now ready to infuse into your vein. Do not mix REBINYN with any other intravenous infusions or medications. Infuse the mixed solution slowly over 1 to 4 minutes as instructed by your doctor or nurse. Infusing the solution via a central venous access device (CVAD) such as a central venous catheter or subcutaneous port: Use a clean and germ free (aseptic) technique. Follow the instructions for proper use for your connector and central venous access device in consultation with your doctor or nurse. Infusing into a CVAD may require using a sterile 10 mL plastic syringe for withdrawal of the mixed solution and infusion. If necessary, use 0.9% Sodium Chloride Injection, USP to flush the CVAD line before or after REBINYN infusion. The peel-off label found on the REBINYN vial can be used to record the lot number. Disposal After infusion, safely dispose of all unused REBINYN solution, the syringe with the infusion set, the vial with the vial adapter, and other waste materials in an appropriate container for throwing away medical waste. Don't throw it out with the ordinary household trash. Don't disassemble the vial and vial adapter before disposal. Don't reuse the equipment. Important information Contact your healthcare provider or local hemophilia treatment center if you experience any problems.

PATIENT INFORMATION Patients should be informed of the early symptoms and signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, dyspnea, wheezing, faintness, hypotension, and anaphylaxis. Patients should be advised to discontinue use of the product and contact their physician and/or seek immediate emergency care, depending on the severity of the reaction, if these symptoms occur. Some viruses such as hepatitis A are particularly difficult to remove or inactivate at this time. Although the overwhelming number of hepatitis A cases are community acquired, there have been reports of these infections associated with the use of such plasma-derived products. Therefore, physicians should be alert to the potential symptoms of hepatitis A infections and inform patients under their supervision receiving plasma-derived products to report potential symptoms promptly. Evidence of hepatitis A may include several days to weeks of poor appetite, tiredness, and low-grade fever followed by nausea, vomiting and pain in the belly. Dark urine and a yellowed complexion are also common symptoms. Patients should be encouraged to consult their physicians if such symptoms occur.

OVERDOSE No symptoms of overdose with IDELVION have been reported. For management of a suspected drug overdose, contact your regional Poison Control Centre. CONTRAINDICATIONS IDELVION, Coagulation Factor IX (Recombinant), Albumin Fusion Protein (rIX-FP), is contraindicated in patients who have a known hypersensitivity to IDELVION, any of its components, excipients or hamster protein. For a complete listing, see Dosage Forms, Composition And Packaging.

OVERDOSE No information provided. CONTRAINDICATIONS REBINYN is contraindicated in patients who have known hypersensitivity to REBINYN or its components (including hamster proteins) [see WARNINGS AND PRECAUTIONS and DESCRIPTION]

OVERDOSE No information provided. CONTRAINDICATIONS Known hypersensitivity to mouse protein is a contraindication to Mononine® (coagulation factor ix (human)) .

SIDE EFFECTS Common adverse reactions observed in > 1% of subjects in clinical studies were dysgeusia, pain in extremity, and positive furin antibody test. 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 clinical practice. During clinical development, in a combined trial, 99 male previously treated patients (PTPs; exposed to a factor IX-containing product for ≥ 150 days) received at least one infusion of RIXUBIS as part of either on-demand treatment of bleeding episodes, perioperative management of major and minor surgical, dental, or other invasive procedures, routine prophylaxis, or pharmacokinetic evaluation of RIXUBIS. Eleven subjects (11.1%) were < 6 years of age, 12 (12.1%) were 6 to < 12 years of age, 3 (3%) were adolescents (12 to < 16 years of age), and 73 (73.7%) were adults (16 years of age and older). The subjects received a total of 14,018 infusions with a median of 163 infusions of RIXUBIS (range 8 to 327 infusions), for a median of 156 exposure days (range 8 to 316 days). A total of 337 adverse events were reported in 80 (80.8%) of the 99 subjects. Adverse reactions that occurred in > 1% of subjects are shown in Table 3. Table 3 : Summary of Adverse Reactions System Organ Class Adverse Reactions (AR) Number of ARs (N) Number of Subjects (N=99) n (%) Percent per Infusion (N=14,018) Nervous System Disorders Dysgeusia 2 1 (1.01%) 0.014% Musculoskeletal and Connective Tissue Disorders Pain in extremity 1 1 (1.01%) 0.007% Investigations Positive furin antibody testa 2 2 (2.02%) 0.014% a See Immunogenicity. Immunogenicity All 99 subjects were monitored for inhibitory and binding antibodies to factor IX, and binding antibodies to CHO protein and furin, at the following time points: at screening, at 72 hours following the first infusion of RIXUBIS and the commercial recombinant factor IX product in the crossover portion of the pharmacokinetic trial, after 5 and 13 weeks following first exposure to RIXUBIS, and thereafter every 3 months. Antibodies against furin were tested by an in-house enzyme-linked immunosorbent assay (ELISA). A titer of 1:20 or 1:40 was considered to be indeterminate for the above validated assay, as these titers were too low to be verified by the confirmatory assay. No subjects developed neutralizing antibodies to factor IX. Low-titer, non-neutralizing antibodies against factor IX were observed in 21 (21.2%) subjects at one or more time points. Three of these 21 subjects were found to have these antibodies at screening, prior to receiving RIXUBIS. Six of the 21 subjects were pediatric (2 subjects in < 6 years of age cohort, 4 subjects in 6 to < 12 years age cohort). No clinical adverse findings were observed in any of these 21 subjects. Nineteen subjects (19.2%) had signals for antibodies against furin (indeterminate specificity). Five of these 19 subjects expressed signals for antibodies at screening, prior to RIXUBIS treatment. One subject had an antibody signal after treatment with the comparator product and prior to RIXUBIS treatment. Two additional subjects had a positive titer of 1:80 that was not present when checked at a later time point and therefore considered transient. Two of the 19 subjects were pediatric (6 to < 12 years age cohort). All post-treatment antibody titer increases in these two pediatric subjects were < 2 dilution steps and therefore considered unrelated to treatment. No clinical adverse findings were observed in any of these 19 subjects. In a trial of 500 normal volunteers, using the same assay as in the clinical trial, 7% had titers of 1:20 or 1:40 and 1.2% had higher titers ranging from 1:80 to 1:320. These antibodies are thought to be part of a natural immune system response. To date, these antibodies have not been associated with any clinical adverse findings. The detection of antibody formation is 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. Thrombogenicity There was no clinical evidence of thromboembolic complications in any of the subjects. Out-of-range values for thrombogenicity markers (thrombin-antithrombin III, prothrombin fragment 1.2, and D-dimer), determined during the pharmacokinetic portion of the combined trial, did not reveal any pattern indicative of clinically relevant thrombogenicity with either RIXUBIS or a comparator factor IX-containing product. Post-marketing Experience Because the following reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders Hypersensitivity (including symptoms such as dyspnea, pruritus) Skin and Subcutaneous Tissue Disorders Urticaria, rash The following class adverse reactions have been seen with another recombinant factor IX: inadequate factor IX recovery, inhibitor development, anaphylaxis, angioedema, hypotension, and thrombosis. DRUG INTERACTIONS No information provided.

SIDE EFFECTS Adverse Drug Reaction Overview The most common adverse reaction (incidence ≥ 1%) reported in clinical trials was headache. Clinical Trial Adverse Drug Reactions Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. Completed Clinical Trials In 4 multicenter, prospective, open-label clinical trials with IDELVION, 107 previously treated patients (PTPs, exposed to a FIX-containing product for ≥ 100 exposure days) were evaluated. A total of 6,384 injections were administered over a median of 469 days (range: 25 to 986 days), with a median 3000 IU per injection (range: (138.9-10,570.0 IU). The median total amount of rIX-FP administered was 127,110.0 IU (range: 1900.0-999,051.4). Two subjects withdrew from the study due to an adverse reaction (headache, infusion related reaction). No neutralizing antibodies (inhibitors) to FIX or antibodies to CHO host cell protein have been detected with the use of IDELVION. No events of anaphylaxis or thrombosis were reported. Related Adverse Events were reported in 8 of 107 (7.5%) subjects. Out of these 8 cases, 5 cases were considered to be Adverse Reactions (ARs) and are listed in Table 1. Table 1: Summary of Adverse Reactions MedDRA Standard System Organ Class MedDRA Preferred Term (Adverse Reaction) Number of subjects n (%), (N=107) Frequency Category Nervous system disorders Headache 2 (1.9) Uncommon Dizziness 1 (0.9) Rare Skin and subcutaneous tissue disorders Rash 1 (0.9) Uncommon Immune system disorders Infusion related reaction* 1 (0.9) Rare * One patient reported a non-serious hypersensitivity reaction with atypical symptoms. This was later considered to be an infusion related reaction. On-going Clinical Trials One previously untreated patient from the ongoing clinical trial reported low-titer inhibitor against factor IX. There are insufficient data to provide information on inhibitor incidence in PUPs. DRUG INTERACTIONS Drug-Drug Interactions There are no known drug interactions reported with IDELVION. No drug interactions studies have been performed.

SIDE EFFECTS Common adverse reactions (incidence ≥ 1%) reported in clinical trials for REBINYN were itching and injection site reactions. 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 clinical trials of another drug and may not reflect the rates observed in clinical practice. During the clinical development program, 115 previously treated male patients received at least one dose of REBINYN [see Clinical Studies]. A previously treated patient was defined as a subject with a history of at least 150 exposure days to other Factor IX products (adolescent/adult subjects) or 50 exposure days to other Factor IX products (pediatric subjects), and no history of inhibitors. There were a total of 8801 exposure days, equivalent to 170 patient-years. A total of 40 patients (35%) were treated for more than 2 years. Adverse reactions are shown in Table 3. Table 3: Summary of Adverse Reactions in Previously Treated Patients System Organ Class Adverse Reaction Number of subjects (%) General disorders and administration site conditions Injection site reactions 4 (4) Immune system disorders Hypersensitivity 1 (1) Skin and subcutaneous tissue disorders Itching 3 (3) Immunogenicity Subjects were monitored for inhibitory antibodies to factor IX prior to dosing, on a monthly basis for the first three months, every two months up to one year, every three months for an additional year, and then every 6 months until end of trial. No inhibitors were reported in the clinical trials in previously treated patients. In an ongoing trial in previously untreated patients, anaphylaxis has occurred with development of a factor IX inhibitor following treatment with REBINYN. Inhibitor development and anaphylactic reactions are more likely to occur during the early phases of factor IX replacement therapy [see WARNINGS AND PRECAUTIONS]. The detection 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. Neurologic Considerations Animals administered repeat doses of REBINYN showed accumulation of PEG in the choroid plexus [see Animal Toxicology and/or Pharmacology]. The potential clinical implications of these animal findings are unknown. The physician should consider whether the patient may be vulnerable, such as infants and children who have developing brains and patients who are cognitively impaired. Physician's discretion is advised with regard to neurocognitive assessments, taking into consideration factors such as duration of use, cumulative dose, age of the patient and related comorbidities that are likely to increase the risks to patients. Adverse neurologic reactions should be reported. DRUG INTERACTIONS No information provided.

SIDE EFFECTS As with the intravenous administration of other plasma-derived products, the following reactions may be observed following administration: headache, fever, chills, flushing, nausea, vomiting, tingling, lethargy, hives, stinging or burning at the infusion site or manifestations of allergic reactions. In a clinical study with Mononine® (coagulation factor ix (human)) in previously untreated hemophilia Bpatients, five patients experienced ALTelevations. Serologic tests for hepatitis A, hepatitis B, hepatitis C, Cytomegalovirus, and Epstein-Barr virus were negative. The following adverse reactions have been spontaneously reported during post-marketing use of Mononine® (coagulation factor ix (human)) as well as other Factor IX products:anaphylaxis, angioedema, cyanosis, dyspnea, hypotension, thrombosis, inadequate therapeutic response, and inhibitor development. There is a potential risk of thromboembolic episodes following the administration of Mononine® (see WARNINGS and PRECAUTIONS). The patient should be monitored closely during the infusion of Mononine® (coagulation factor ix (human)) to observe for the development of any reaction. If any reaction takes place that is thought to be related to the administration of Mononine® (coagulation factor ix (human)) , the rate of infusion should be decreased or the infusion stopped, as dictated by the response of the patient. Should evidence of an acute hypersensitivity reaction be observed, the infusion should be stopped promptly and appropriate countermeasures and supportive therapy should be administered. DRUG INTERACTIONS No information provided.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Hypersensitivity Reactions Hypersensitivity reactions have been reported with RIXUBIS. Anaphylaxis and other hypersensitivity reactions are possible. The risk is highest during the early phases of initial exposure in previously untreated patients (PUPs), in particular in patients with high-risk gene mutations. Early signs of allergic reactions, which can progress to anaphylaxis, include angioedema, chest tightness, hypotension, lethargy, nausea, vomiting, paresthesia, restlessness, wheezing, and dyspnea. Immediately discontinue administration and initiate appropriate treatment if allergic- or anaphylactic-type reactions occur. In case of severe allergic reactions, alternative hemostatic measures should be considered. There have been reports in the literature showing an association between the occurrence of a factor IX inhibitor and allergic reactions. Evaluate patients experiencing allergic reactions for the presence of an inhibitor. RIXUBIS contains trace amounts of Chinese hamster ovary (CHO) proteins. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins. Inhibitors Evaluate patients regularly for the development of factor IX inhibitors by appropriate clinical observations and laboratory tests. Perform an assay that measures factor IX inhibitor concentration if expected factor IX activity plasma levels are not attained, or if bleeding is not controlled with an expected dose. Contact a specialized hemophilia treatment center if a patient develops an inhibitor. Patients with factor IX inhibitors are at an increased risk of severe hypersensitivity reactions or anaphylaxis if re-exposed to RIXUBIS. RIXUBIS may not be effective in patients with high titer factor IX inhibitors and other therapeutic options should be considered. Nephrotic Syndrome Nephrotic syndrome has been reported following attempted immune tolerance induction in hemophilia B patients with factor IX inhibitors. The safety and efficacy of using RIXUBIS for immune tolerance induction have not been established. Thromboembolic Complications The use of factor IX containing products has been associated with the development of thromboembolic complications (e.g., pulmonary embolism, venous thrombosis, and arterial thrombosis). Due to the potential risk for thromboembolic complications, monitor patients for early signs of thromboembolic and consumptive coagulopathy, when administering RIXUBIS to patients with liver disease, with signs of fibrinolysis, peri- and post-operatively, or at risk for thromboembolic events or DIC. The benefit of treatment with RIXUBIS should be weighed against the risk of these complications in patients with DIC or those at risk for DIC or thromboembolic events. Monitoring Laboratory Tests Monitor factor IX activity plasma levels by the one-stage clotting assay to confirm that adequate factor IX levels have been achieved and maintained [see DOSAGE AND ADMINISTRATION]. Monitor for the development of inhibitors if expected factor IX activity plasma levels are not attained, or if bleeding is not controlled with the recommended dose of RIXUBIS. Assays used to determine if factor IX inhibitor is present should be titered in Bethesda Units (BUs). Patient Counseling Information See FDA-approved Patient Labeling (Patient Information and Instructions for Use) Advise patients to report any adverse reactions or problems following RIXUBIS administration to their physician or healthcare provider. Inform patients of the early signs of hypersensitivity reactions (including hives, generalized urticaria, chest tightness, wheezing, and hypotension) and anaphylaxis. Instruct patients to discontinue use of the product and contact their physician if these symptoms occur. Advise patients to contact their physician or treatment facility for further treatment and/or assessment if they experience a lack of a clinical response to factor IX replacement therapy, as in some cases this may be a manifestation of an inhibitor. Ask patients to follow the specific preparation and administration procedures provided by their physician. Inform patients to follow the recommendations in the FDA-approved patient labeling. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Nonclinical studies evaluating the carcinogenic and mutagenic potential of RIXUBIS have not been conducted. No adverse effects on reproductive organs were observed by macroscopic and microscopic pathological investigations in repeated dose toxicity studies. No investigations on impairment of fertility have been conducted. Use In Specific Populations Pregnancy Pregnancy Category C Animal reproduction studies have not been conducted with RIXUBIS. It is also not known whether RIXUBIS can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. RIXUBIS should be given to a pregnant woman only if clearly needed. Nursing Mothers It is not known whether RIXUBIS is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when this product is administered to a nursing woman. Pediatric Use Safety, efficacy and pharmacokinetics of RIXUBIS have been evaluated in 23 previously treated pediatric patients. Twelve (52.2%) were 6 to < 12 years of age and 11 subjects (47.8%) were < 6 years of age. Previously treated pediatric subjects 6 to < 12 years of age were previously treated with plasma-derived and/or recombinant factor IX concentrate(s) for a minimum of 150 exposure days (based on the subject's medical records). Subjects < 6 years of age were previously treated with plasma-derived and/or recombinant factor IX concentrate(s) for > 50 exposure days (based on the subject's medical records). Incremental recovery was observed to be 22% lower in pediatric patients ( < 12 years) and dose adjustment is needed [see DOSAGE AND ADMINISTRATIONand CLINICAL PHARMACOLOGY]. The mean incremental recovery (in ([IU/dL]/[IU/kg]) at the initial pharmacokinetics evaluation was 0.67 (± 0.16) in subjects of both age cohorts, with lower values in the younger age cohort (0.59 ± 0.13) and higher values in the older age group (0.73 ± 0.16). Clearance was higher in the younger age cohort, with a mean clearance of 10.6 ± 1.7 mL/(kg.hr) (median: 10.5; range: 8.1-14.4) in the < 6 years age cohort compared to a mean clearance of 8.7 ± 1.2 mL/(kg.hr) (median: 8.6; range: 6.9-10.8) in the 6 to < 12 years age cohort. In a prospective, open-label, uncontrolled multicenter trial with patients < 12 years of age, a total of 41 infusions were given for the treatment of 26 bleeding episodes (7 joint, 19 muscle and soft tissue). Bleeding was controlled in all episodes. In 23 of 26 (88.5%) of the episodes, hemostasis was achieved with one or two infusions. The mean annualized bleeding episode rate (ABR) for children < 12 years of age was 2.7 bleeds per patient per year ± 3.14 with a median of 2 ranging from 0 to 10.8. See Clinical Studies for patients 12 to < 16 years of age. The median ABR during prophylaxis was comparable among children, adolescents and adults. Geriatric Use Clinical studies of RIXUBIS did not include subjects aged 65 and over. It is not known whether elderly patients respond differently than younger patients. Dose selection for an elderly patient should be individualized [see DOSAGE AND ADMINISTRATION].

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Hypersensitivity Reactions Allergic-type hypersensitivity reactions, including anaphylaxis, are possible with REBINYN. The product may contain traces of hamster proteins which in some patients may cause allergic reactions. Early signs of allergic reactions, which can progress to anaphylaxis, may include angioedema, chest tightness, difficulty breathing, wheezing, urticaria, and itching. Observe patients for signs and symptoms of acute hypersensitivity reactions, particularly during the early phases of exposure to the product. Discontinue use of REBINYN if allergic- or anaphylactic - type reactions occur, and initiate appropriate treatment. Inhibitors The formation of inhibitors (neutralizing antibodies) to Factor IX may occur during Factor replacement therapy in the treatment of hemophilia B. Monitor all patients using clinical observations and laboratory tests for the development of inhibitors [see Monitoring Laboratory Tests]. An association between the development of Factor IX inhibitors and allergic reactions has been reported. Evaluate patients experiencing allergic reactions for the presence of an inhibitor. Patients with Factor IX inhibitors may be at an increased risk of severe allergic reactions with subsequent exposure to Factor IX. Thrombotic Events The use of Factor IX-containing products has been associated with thrombotic complications. Due to the potential risk of thrombotic complications, monitor patients for early signs of thrombotic and consumptive coagulopathy when administering this product to patients with liver disease, post-operatively, to newborn infants, or to patients at risk of thrombosis or disseminated intravascular coagulation (DIC). In each of these situations, the benefit of treatment with REBINYN should be weighed against the risk of these complications. Nephrotic Syndrome Nephrotic syndrome has been reported following immune tolerance induction therapy with Factor IX products in hemophilia B patients with Factor IX inhibitors, often with a history of allergic reactions to Factor IX. The safety and efficacy of using REBINYN for immune tolerance induction have not been established. Monitoring Laboratory Tests If monitoring of Factor IX activity is performed, use a chromogenic assay or selected one-stage clotting assay validated for use with REBINYN [see DOSAGE AND ADMINISTRATION]. The one-stage clotting assay results can be significantly affected by the type of activated partial thromboplastin time (aPTT) reagent used, which can result in over- or under-estimation of Factor IX activity. Avoid the use of silica-based reagents, as some may overestimate the activity of REBINYN. If a validated one-stage clotting or chromogenic assay is not available locally, then use of a reference laboratory is recommended. If bleeding is not controlled with the recommended dose of REBINYN, or if the expected Factor IX activity levels in plasma are not attained, then perform a Bethesda assay to determine if Factor IX inhibitors are present. Patient Counseling Information Advise patients to read the FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use). Inform patients of the early signs of hypersensitivity reactions including rash, hives, itching, facial swelling, tightness of the chest and wheezing. Advise patients to discontinue use of the product and contact their healthcare provider if these symptoms occur. Advise patients to contact their healthcare provider for further treatment and/or assessment if they experience a lack of a clinical response to Factor IX therapy, as in some cases this may be a manifestation of an inhibitor. Advise patients to contact their healthcare provider if they experience any thrombotic complications. Advise patients to follow the recommendations regarding proper sharps disposal provided in the FDA-approved Instructions for Use. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Studies in animals to evaluate the carcinogenic or genotoxic potential of REBINYN, or studies to determine the effects of REBINYN on fertility, have not been performed. Use In Specific Populations Pregnancy Risk Summary There are no data with REBINYN use in pregnant women to determine whether there is a drug-associated risk. Animal reproduction studies have not been conducted with REBINYN. It is unknown whether REBINYN can cause fetal harm when administered to a pregnant woman or can affect fertility. REBINYN should be given to a pregnant woman only if clearly needed. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Lactation Risk Summary There is no information regarding the presence of REBINYN in human milk, the effect on the breastfed infant, and the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for REBINYN and any potential adverse effects on the breastfed infant from REBINYN or from the underlying maternal condition. Pediatric Use Safety and efficacy of REBINYN were evaluated in 43 previously treated pediatric patients [see Clinical Studies]. Twelve of these subjects (28%) were 1 to 6 years of age; 13 subjects (30%) were 7 to 12 years of age; and 18 subjects (42%) were 13 to 17 years of age. Pharmacokinetic parameters were evaluated for 28 of these subjects who were treated with REBINYN 40 IU/kg [see CLINICAL PHARMACOLOGY]. No difference in the safety profile of REBINYN was observed between previously treated pediatric subjects and adult subjects. Body weight-adjusted clearance was higher for pediatric subjects than for adult subjects. Fixed doses were studied in the clinical trials and no dose adjustment was required for pediatric subjects. Twenty-eight of the forty-three previously treated pediatric subjects (1 to 17 years old) were treated with REBINYN for 137 bleeding episodes. Results are provided in Table 4. Table 4: Efficacy in treatment of bleeding episodes in pediatric subjects by age New bleeding episodes ≤ 6 years n=11 7-12 years n=31 13-17 years n=95* Efficacy assessment** Excellent or good 10 (91%) 29 (94%) 91 (97%) Moderate or poor 1 (9%) 2 (6%) 3 (3%) Number of injections to treat a bleeding episode 1 injection 9 (82%) 27 (87%) 78 (82%) 2 injections 1 (9%) 4 (13%) 12 (13%) > 2 injections 1 (9%) - 5 (5%) *Efficacy assessment was missing for one bleeding episode. **Efficacy assessment [Response] was assessed according to a four-point scale using: Excellent: Abrupt pain relief and/or clear improvement in objective signs of bleeding within 8 hours after a single injection; Good: Noticeable pain relief and/or improvement in signs of bleeding within 8 hours after a single injection; Moderate: Probable or slight beneficial effect within the first 8 hours after the first injection but requiring more than one injection within 8 hours; Poor: No improvement, or worsening of symptoms within 8 hours after the second of two injections. Animals administered repeat doses of REBINYN showed accumulation of PEG in the choroid plexus [see Animal Toxicology and/or Pharmacology]. The potential clinical implications of these animal findings are unknown. No adverse neurologic effects of PEG have been reported in infants, children, and adolescents exposed to REBINYN during clinical trials. The potential consequences of long term exposure have not been fully evaluated [see Section 6.3]. Geriatric Use Clinical studies of REBINYN did not include sufficient numbers of subjects age 65 and over to determine whether or not they respond differently than younger subjects. Animals administered repeat doses of REBINYN showed accumulation of PEG in the choroid plexus [see Animal Toxicology and/or Pharmacology]. The potential clinical implications of these animal findings are unknown. No adverse neurologic effects of PEG have been reported in adults exposed to REBINYN during clinical trials, however use in older adults with baseline cognitive dysfunction has not been fully evaluated [see ADVERSE REACTIONS].

WARNINGS Mononine® is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. Because Mononine® is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current viral infections and by inactivating and/or removing certain viruses during manufacture (see DESCRIPTION section for virus reduction measures). The manufacturing procedure for Mononine® (coagulation factor ix (human)) includes processing steps designed to reduce further the risk of virus transmission. Stringent procedures, utilized at plasma collection centers, plasma testing laboratories, and fractionation facilities are designed to reduce the risk of virus transmission. The primary virus reduction step of the Mononine® (coagulation factor ix (human)) manufacturing process is the use of two sequential virus retentive ultrafilter membranes designed to separate viruses from Factor IX. In addition, the purification procedure (several chromatography steps) used in the manufacture of Mononine® (coagulation factor ix (human)) also provides virus reduction capacity. Despite these measures, such products may still potentially contain human pathogenic agents, including those not yet known or identified. Thus the risk of transmission of infectious agents cannot be totally eliminated. Any infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to ZLBBehring at 800-504-5434 (in the U. S. and Canada). The physician should discuss the risks and benefits of this product with the patient. Individuals who receive infusions of blood or plasma products may develop signs and/or symptoms of some viral infections, particularly nonA, nonB hepatitis. (See INFORMATION FOR PATIENTS.) Since the use of Factor IX Complex concentrates has historically been associated with the development of thromboembolic complications, the use of Factor IX-containing products may be potentially hazardous in patients with signs of fibrinolysis and in patients with disseminated intravascular coagulation (DIC). Hypersensitivity and allergic type hypersensitivity reactions, including anaphylaxis, have been reported for all factor IX products. Frequently, these events have occurred in close temporal association with the development of factor IX inhibitors. Patients should be informed of the early symptoms and signs of hypersensitivity reactions, including hives, generalized urticaria, angioedema, chest tightness, dyspnea, wheezing, faint-ness, hypotension, tachycardia, and anaphylaxis. Patients should be advised to discontinue use of product and contact their physician and/or seek immediate emergency care, depending on the severity of the reac-tion, if any of these symptoms occur. Preliminary information suggests a relationship may exist between the presence of major deletion mutations in the factor IX gene and an increased risk of inhibitor formation and of acute hypersensitivity reactions. Patients known to have major deletion mutations of the factor IX gene should be observed closely for signs and symptoms of acute hypersensitivity reactions, particularly during the early phases of initial exposure to product. Nephrotic syndrome has been reported following attempted immune tolerance induction with factor IX products in Hemophilia B patients with factor IX inhibitors and a history of severe allergic reactions to factor IX. The safety and efficacy of using Mononine® (coagulation factor ix (human)) in attempted immune tolerance induction has not been established. PRECAUTIONS Extensive clinical experience suggests that there is a lower risk of thromboembolic complications with the use of Mononine® (coagulation factor ix (human)) than with prothrombin complex concentrates. However, as with all products containing Factor IX, caution should be exercised when administering Mononine® (coagulation factor ix (human)) to patients with liver disease, to patients post-operatively, to neonates, or to patients at risk of thromboembolic phenomena or DIC. 8, 9 In each of these situations, the potential benefit of treatment with Mononine® (coagulation factor ix (human)) should be weighed against the potential risk of these complications. Coagulation Factor IX (Human), Mononine® (coagulation factor ix (human)) , should be administered intravenously at a rate that will permit observation of the patient for any immediate reaction. Rates of infusion of up to 225 IU per minute have been regularly tolerated with no adverse reactions. If any reaction takes place that is thought to be related to the administration of Mononine® (coagulation factor ix (human)) , the rate of infusion should be decreased or the infusion stopped, as dictated by the response of the patient. The infusion should be stopped promptly and appropriate countermeasures and supportive therapy should be administered should evidence of an acute hypersensitivity reaction be observed. Patients known to have major deletion mutations of the factor IXgene may be at increased risk for inhibitor formation and acute hypersensitivity reactions. (See WARNINGS.) During the course of treatment, determination of daily Factor IX levels is advised to guide the dose to be administered and the frequency of repeated infusions. Individual patients may vary in their response to Mononine® (coagulation factor ix (human)) , achieving different levels of in vivo recovery and demonstrating different half-lives. The use of high doses of Factor IX Complex concentrates has been reported to be associated with instances of myocardial infarction, disseminated intravascular coagulation, venous thrombosis and pulmonary embolism. Generally a Factor IX level of 25-50% [IU/dL] is considered adequate for hemostasis, including major hemorrhages and surgery. Attempting to maintain Factor IX levels of > 75-100% [IU/dL] during treatment is not routinely recommended nor required. To achieve Factor IX levels that will remain above 25% [IU/dL] between once a day administrations, each daily dose should attempt to raise the 30-minute post-infusion Factor IX level to 50-60% [IU/dL] (see DOSAGE AND ADMINISTRATION). No controlled studies have been available regarding the use of ε-amino caproic acid or other antifibrinolyt-ic agents following an initial infusion of Mononine® (coagulation factor ix (human)) for the prevention or treatment of oral bleeding following trauma or dental procedures such as extractions. Pregnancy Category C Animal reproduction studies have not been conducted with Mononine® (coagulation factor ix (human)) . It is also not known whether Mononine® (coagulation factor ix (human)) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Mononine® (coagulation factor ix (human)) should be given to a pregnant woman only if clearly needed. Pediatric Use Evaluation of the safety and effectiveness of Mononine® (coagulation factor ix (human)) treatment in 51 pediatric patients between the ages of 1 day and 20 years, as a part of virus safety trials and trials for surgery, trauma or spontaneous bleeding, showed that excellent hemostasis was achieved with no thrombotic complications. 10 Included in the experience with patients aged birth to 20 years are two long-term virus safety studies demonstrating lack of virus transmission. Dosing in children is based on body weight and is generally based on the same guidelines as for adults (see DOSAGE AND ADMINISTRATION). Geriatric Use Clinical studies of Mononine® (coagulation factor ix (human)) did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. As for all patients, dosing for geriatric patients should be appropriate to their overall situation. REFERENCES 8. Aledort LM: Factor IX and Thrombosis. Scand J Haematology Suppl. 30:40, 1977. 9. Cederbaum AI, Blatt PM, Roberts HR. Intravascular coagulation with useof human prothrombin complex concentrates. Ann Intern Med 84:683-687, 1976. 10. Kurczynski E, Lusher JM, Pitel P, Shapiro AD, Bergman GE, the Mononine® (coagulation factor ix (human)) StudyGroup. Safetyand efficacyofmonoclonal antibody-purified factor IX concentrate for management of bleeding and surgical prophylaxis in previously treated children with hemophilia B. Int J Ped Hemat/Oncol 2:211-216, 1995.