Coagulation Factor Ix Recombinant, Glycopegylated

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 ).

REBINYN is available as a white to off-white lyophilized powder in single-dose vials containing nominally 500, 1000, 2000, or 3000 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, 500, or 750 IU per mL of REBINYN respectively. REBINYN is available as a lyophilized powder in single-dose vials of 500, 1000, 2000, and 3000 IU ( 3 ).

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 ).

• 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 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.

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.

Pediatric Use: No dose adjustment is needed ( 8.4 ).

8.1 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. 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.

8.2 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.

8.4 Pediatric Use Safety and efficacy of REBINYN were evaluated in four clinical trials that included 43 PTPs and in one clinical trial that included 50 pediatric PUPs [ see Adverse Reactions ( 6 ) and Clinical Studies ( 14 ) ]. Twelve of these subjects were ≤ 6 years of age; 13 subjects were 7 to 12 years of age; and 18 subjects were 13 to 17 years of age. Pharmacokinetic parameters were evaluated for 28 of the pediatric PTPs who were treated with REBINYN 40 IU/kg [ see Clinical Pharmacology ( 12.3 ) ]. Body weight-adjusted clearance was observed to be higher for pediatric subjects than for adult subjects. However, in clinical trials, no dose adjustment was needed in pediatric subjects who received a fixed dose of 40 IU/kg every week for routine prophylaxis. Juvenile Animal Toxicity Data A juvenile animal neurotoxicity study was conducted to evaluate the potential neurotoxicity of REBINYN when intravenously administered 120-1200 IU/kg/twice weekly in immature male rats from 3 to 13 weeks of age, followed by a 13-week treatment-free period. Accumulation of PEG was observed in the choroid plexus, pituitary, circumventricular organs, and the cranial motor neurons. PEG levels in these tissues increased with dose and dose duration (10 weeks) and remained detectable after the 13-week treatment-free period. Treatment-related PEG-positive vacuolated macrophages were observed in the pituitary. The accumulation of PEG was not associated with neurobehavioral changes, fertility, or functional effects.

8.5 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, 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. 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 Neurologic Considerations ( 6.3 ) ].

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.