factor IX

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 ).

12.1 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.

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 ru

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 cl

5 WARNINGS AND PRECAUTIONS • Hypersensitivity reactions, including anaphylaxis, have occurred. Should hypersensitivity reactions occur, discontinue REBINYN and administer appropriate treatment ( 5.1 ). • Neutralizing antibodies (inhibitors) to Factor IX have occurred following administration of REBINYN. Perform an assay that measures Factor IX inhibitor concentration if bleeding is not controlled with the recommended dose of REBINYN or if plasma Factor IX activity level fails to increase as expected (5.2 , 5.5 ). • The use of Factor IX- products has been associated with the development of thromboembolic complications ( 5.3 ). • Nephrotic syndrome has been reported following immune tolerance induction with Factor IX-containing products in hemophilia B patients with Factor IX inhibitors and a history of allergic reactions to Factor IX. ( 5.4 ) • Factor IX activity assay results may vary with the type of activated partial thromboplastin time reagent used ( 5.5 ). 5.1 Hypersensitivity Reactions Allergic-type hypersensitivity reactions, including anaphylaxis, have occurred with REBINYN. The product may contain traces of hamster proteins which in some patients may cause allergic reactions. 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. 5.2 Inhibitors The formation of inhibitors (neutralizing antibodies) to Factor IX has occurred following REBINYN. If expected plasma factor IX activity levels are not attained, or if bleeding is not controlled as expected with the administered dose, perform an assay that measures Factor IX inhibitor concentration. Monitor all patients using clinical observations and laboratory tests for the development of inhibitors [ see Warnings and Precautions (5.5) ]. 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. 5.3 Thrombotic Events The use of Factor IX-containing products has been associated with thromboembolic complications. Due to the potential risk of thromboembolic 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. 5.4 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. 5.5 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 ( 2 ) ]. 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 recommen

4 CONTRAINDICATIONS REBINYN is contraindicated in patients who have known hypersensitivity to REBINYN or its components (including hamster proteins) [ see Warnings and Precautions ( 5.1 ) and Description ( 11 ) ] Do not use in patients who have known hypersensitivity to REBINYN or its components, including hamster proteins ( 4 ).