Coagulation Factor Ix Recombinant, Glycopegylated

1 INDICATIONS AND USAGE 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 (congenital Factor IX deficiency) for: • On-demand treatment and control of bleeding episodes • Perioperative management of bleeding • Routine prophylaxis to reduce the frequency of bleeding episodes Limitations of Use : REBINYN is not indicated for immune tolerance induction in patients with hemophilia B. 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 (congenital Factor IX deficiency) for: • On-demand treatment and control of bleeding episodes • Perioperative management of bleeding • Routine prophylaxis to reduce the frequency of bleeding episodes Limitations of Use : REBINYN is not indicated for immune tolerance induction in patients with hemophilia B ( 1 ).

2 DOSAGE AND ADMINISTRATION For intravenous infusion after reconstitution only. For intravenous infusion after reconstitution only ( 2 ). • Each carton and vial label for REBINYN states the actual Factor IX potency in international units (IU) ( 2.1 ). On-demand treatment and control of bleeding episodes: • 40 IU/kg body weight for minor and moderate bleeds, and 80 IU/kg body weight for major bleeds. Additional doses of 40 IU/kg can be given ( 2.1 ). Perioperative management: • Pre-operative dose of 40 IU/kg body weight for minor surgery, and 80 IU/kg body weight for major surgery. As clinically needed for the perioperative management of bleeding, repeated doses of 40 IU/kg (in 1-3 day intervals) within the first week after major surgery may be administered. • Frequency may be extended to once weekly after the first week until bleeding stops and healing is achieved ( 2.1 ). Routine prophylaxis : • 40 IU/kg body weight once weekly ( 2.1 ). 2.1 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 ( 5.5 ) ]. • 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 (in 1-3 day intervals) within the first week after major surgery may be administered.* Due to the long half-life of REBINYN, the frequency of dosing in the post-surgical setting may be extended to once weekly after the first week until bleeding stops and healing is achieved. *See 12.3 Pharmacokinetics, Table 8 Routine Prophylaxis For prophylaxis use, the recommended dose is 40 IU/kg body weight once weekly. Adjust dosing regimen based on individual patient’s bleeding pattern, and physical activity. 2.2 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 ( 2.3 )]. 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. Overview of REBINYN Package Fig. A Fig. B Fig. C Fig. D Fig. E Fig. F FIg. G Fig. H Fig. I Fig. J 2.3 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 ( 11 ) ]. 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 Clave ® /MicroClave ® , InVision-Plus ® , InVision-Plus CS ® , Invision-Plus Junior ® , Bionector ® ), and their use can damage the connector and affect administration. To administer REBINYN through incompatible needleless connectors, withdraw the reconstituted product into a standard 10 mL sterile Luer-lock plastic syringe. 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. Fig. K

6 ADVERSE REACTIONS Common adverse reactions (incidence ≥ 1%) in PTPs reported in clinical trials for REBINYN were itching and injection site reactions. Common adverse reactions (incidence ≥ 1%) in PUPs reported in clinical trials for REBINYN were rash, FIX inhibitors, hypersensitivity, itching, injection site reaction, and anaphylactic reaction. The most frequently reported adverse reactions (≥ 1%) in previously treated patients (PTPs) and previously untreated patients (PUPs) were itching and injection site reactions ( 6 ). Additional frequently reported adverse reactions (≥ 1%) in PUPs included rash, Factor IX inhibition, hypersensitivity, and anaphylactic reaction ( 6 ). In animals administered repeat doses of REBINYN, accumulation of polyethylene-glycol (PEG) was observed in the choroid plexus, pituitary, circumventricular organs, and cranial motor neurons ( 8.4 and 13.2 ). The potential clinical implications of these animal findings are unknown ( 6.3 ). To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc. at 1-877-668-6777 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice. Previously Treated Patients (PTPs) In five multicenter, prospective, non-controlled, open-label clinical trials, 115 PTPs [0 to 6 years old: 12 subjects (10%); 7 to 12 years old: 13 subjects (11%); 13 to 17 years old: 18 subjects (16%); ≥18 years old: 72 subjects (63%)] received at least one dose of REBINYN as part of routine prophylaxis, on-demand treatment of bleeding episodes, perioperative management of major and minor surgery, or pharmacokinetic evaluation [ see Clinical Studies (14) ]. A PTP 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. A total of 15,167 injections were administered over a median of 733 days (range: 29- 2951 days), equivalent to 15,137 exposure days and 292 patient-years. Adverse reactions in PTPs are listed in Table 3. Table 3: Summary of Adverse Reactions in Previously Treated Patients System Organ Class Adverse Reaction Number of subjects (%) N=115 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) Previously Untreated Patients (PUPs) In one multicenter, prospective, non-controlled, open-label clinical trial conducted in PUPs, 50 subjects (≤6 years of age) received at least one dose of REBINYN [see Clinical Studies (14) ]. A PUP was defined as a subject previously untreated or exposed to FIX-containing products less than or equal to 3 exposure days (5 previous exposures to blood components was acceptable). A total of 6,737 injections were administered over a median of 996 days (range: 61- 2,233 days), equivalent to 6,709 exposure days and 142 patient-years. Adverse reactions in PUPs are listed in Table 4. Table 4: Summary of Adverse Reactions in Previously Untreated Patients System Organ Class Adverse Reaction Number of subjects (%) N=50 Blood and lymphatic system disorders Factor IX inhibition 4 (8) General disorders and administration site conditions Injection site reaction 1 (2) Immune system disorders Anaphylactic reaction Hypersensitivty 1 (2) 3 (6) Skin and subcutaneous tissue disorders Rash Itching 9 (18) 2 (4) 6.2 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, one anaphylactic reaction 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 ( 5.1 , 5.2 ) ]. 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. 6.3 Neurologic Considerations Animals administered repeat doses of REBINYN showed accumulation of PEG in the choroid plexus, pituitary, circumventricular organs, and cranial motor neurons [ see Use in Specific Populations ( 8.4 ) and Animal Toxicology and/or Pharmacology ( 13.2 ) ]. The potential clinical implications of these animal findings are unknown. In the pediatric studies, 47 PUPs and 25 PTPs receiving routine prophylaxis with REBINYN at a weekly dose of 40 IU/kg were followed for central nervous system (CNS)-related ADRs for 6 and 8 years, respectively. The median duration of follow up of ADRs in the PUP and PTP studies were 2 and 7 years, respectively. Furthermore, neurological examinations were prospectively conducted in 44 PUPs and 17 PTPs with a median follow up of 2 years, and neurocognitive assessments were prospectively performed in 38 PUPs and 16 PTPs with a median follow up of 1 year. Although no clear clinical implications of the animal findings are known and no clear clinical neurologic or neurocognitive safety signal has emerged, the physician should consider whether the patient is vulnerable to cognitive impairment, such as infants and children who have developing brains, and patients who are cognitively impaired. Factors such as duration of use, cumulative dose, age of the patient and co-morbidities that may increase risk of adverse neurologic and/or neurocognitive events should be considered when prescribing REBINYN. Report adverse neurocognitive and neurologic reactions. 6.4 Postmarketing Experience The following adverse reactions have been identified during post-approval use of REBINYN. Because these 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. Blood and lymphatic system disorders: Factor IX inhibitor development.

12.3 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 (14) ]. 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 Recovery 30min (IU/dL per IU/kg) 1.82 (28.2) 1.92 (19.6) AUC 0-168 (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) Min, Max** 15.4 (13.2; 17.9) 9.2; 24.5 18.7 (16.2; 21.6) 8.3; 28.3 23.7 (19.9; 28.2) 18.6; 34.6 29.3 (26.0; 33.0) 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 Recovery 30min (IU/dL per IU/kg) 1.51 (7.31) 1.59 (16.2) 1.96 (14.7) 2.34 (11.3) AUC inf (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/m 2 ) and 4 were overweight (BMI 25 to <29.9 kg/m 2 ). 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 8 hours 1 24 hours 1 48 hours 2 N=13 N=12 N=12 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).