REBINYN

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 ).

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.