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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.

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.

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

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.

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.