Ixinity

1 INDICATIONS AND USAGE IXINITY, Coagulation Factor IX (Recombinant), is a human blood coagulation factor indicated in adults and children with hemophilia B for: On-demand treatment and control of bleeding episodes Perioperative management Routine prophylaxis to reduce the frequency of bleeding episodes IXINITY is not indicated for induction of immune tolerance in patients with hemophilia B [see Warnings and Precautions ( 5.3 ) ]. IXINITY, Coagulation Factor IX (Recombinant), is a human blood coagulation factor indicated in adults and children with hemophilia B for: On-demand treatment and control of bleeding episodes ( 1 ) Perioperative management ( 1 ) Routine prophylaxis to reduce the frequency of bleeding episodes ( 1 ) IXINITY is not indicated for induction of immune tolerance in patients with hemophilia B. ( 1 )

2 DOSAGE AND ADMINISTRATION For intravenous use after reconstitution only. For intravenous use after reconstitution only. On-demand treatment and control of bleeding episodes and perioperative management of bleeding: Adolescents/Adults (≥ 12 years of age): One international unit (IU) of IXINITY per kg body weight increases the circulating activity of factor IX by 0.98 IU/dL. ( 2.1 ) Children (< 12 years of age): One international (IU) of IXINITY per kg body weight increases the circulating activity of factor IX by 0.79 IU/dL. ( 2.1 ) Initial dose: Required factor IX units (IU) = body weight (kg) x desired factor IX increase (% of normal or IU/dL) x reciprocal of observed recovery (IU/kg per IU/dL). ( 2.1 ) The maintenance dose depends on the type of bleed or surgery, the intensity of the hemostatic challenge, and number of days until adequate wound healing is achieved. ( 2.1 ) Routine prophylaxis: Adolescents/Adults (≥ 12 years of age): 40 to 70 IU/kg twice weekly. ( 2.1 ) Children (< 12 years of age): 35 to 75 IU/kg twice weekly. Adjust the dosing regimen (dose or frequency) based on the patient’s clinical response. ( 2.1 ) 2.1 Dose Each vial of IXINITY has the recombinant factor IX (rFIX) potency in international units (IU) stated on the vial. Dosage and duration of treatment for factor IX products depend on the severity of the factor IX deficiency, the location and extent of bleeding, the patient’s clinical condition, age, and pharmacokinetic parameters of factor IX, such as incremental recovery and half-life. Initial Dose Adolescents/Adults ≥ 12 years of age): Calculate the initial dose of IXINITY based on the empirical finding that one international unit (IU) of IXINITY per kg body weight increases the circulating level of factor IX by 0.98 international units/dL (IU/dL) of plasma in adults and children ≥ 12 years of age. Children (< 12 years of age): Calculate the initial dose of IXINITY based on the empirical finding that one international unit (IU) of IXINITY per kg body weight increases the circulating level of factor IX by 0.79 international units/dL (IU/dL) of plasma in children < 12 years of age. Initial Dose = body weight (kg) x desired factor IX increase (% of normal or IU/dL) × reciprocal of observed recovery (IU/kg per IU/dL) Incremental Recovery in Previously Treated Patients (PTPs) Base calculation of the dose on the patient’s individual incremental recovery using serial factor IX activity assays, to account for the wide range of inter-individual differences in incremental recovery and the type of aPTT reagent used for the assay. Titrate the dose based on the patient’s clinical response and individual pharmacokinetics, in particular incremental recovery and half-life. Adolescents/Adults (≥ 12 years of age): For an incremental recovery of 0.98 IU/dL per IU/kg (0.98% of normal), calculate the dose as follows: Dose (IU) = body weight (kg) x desired factor IX increase (% of normal or IU/dL) × 1.02 dL/kg Examples (assuming patient’s baseline factor IX level is < 1% of normal): A peak of 70% is required in a 60 kg patient. The appropriate dose would be (60 kg × 70 IU/dL)/(0.98 IU/dL per IU/kg) = 4286 IU A dose of 4550 international units (IUs) of IXINITY administered to a 70 kg patient should be expected to result in a peak post-infusion factor IX increase of 4550 IU x (0.98 IU/dL per IU/kg)/(70 kg) = 64 IU/dL (approximately 64% of normal) Children (< 12 years of age): A lower recovery has been observed in pediatric patients (< 12 years, n=20). For an incremental recovery of 0.79 IU/dL per IU/kg (0.79% of normal), calculate the dose as follows: Dose (IU) = body weight (kg) x desired factor IX increase (% of normal or IU/dL) × 1.27 dL/kg Examples (assuming patient’s baseline factor IX level is < 1% of normal): A peak of 60% is required in a 20 kg patient. The appropriate dose would be (20 kg x 60 IU/dL)/(0.79 IU/dL per IU/kg) = 1519 IU A dose of 500 international units (IUs) of IXINITY administered to a 7 kg patient…

5 WARNINGS AND PRECAUTIONS Hypersensitivity reactions, including anaphylaxis has occurred. Should symptoms occur, discontinue IXINITY and administer appropriate treatment. Patients may also develop hypersensitivity to hamster (CHO) protein, which is present in trace amounts in the product ( 5.1 ) Development of neutralizing antibodies (inhibitors) to IXINITY may occur. If expected factor IX activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, perform an assay that measures factor IX inhibitor concentration ( 5.2 ) Nephrotic syndrome has been reported following immune tolerance induction with factor IX products in hemophilia B patients with factor IX inhibitors ( 5.3 ) Thromboembolism has occurred with IXINITY use ( 5.4 ) 5.1 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, has occurred with IXINITY. Signs of allergic reactions, which can progress to anaphylaxis, include urticaria, angioedema, chest or throat tightness, hypotension, lethargy, nausea, vomiting, dysphagia, paresthesia, restlessness, wheezing and dyspnea. Immediately discontinue administration and initiate appropriate treatment if allergic or anaphylactic-type reactions occur. In case of severe allergic reactions, consider alternative hemostatic measures. There are literature reports of allergic reactions occurring in close temporal association with the development of factor IX inhibitors. IXINITY contains trace amounts of Chinese hamster ovary (CHO) proteins. Patients treated with this product may develop hypersensitivity to CHO proteins. 5.2 Neutralizing Antibodies Development of neutralizing antibodies (inhibitors) to IXINITY may occur. If expected factor IX activity plasma levels are not attained, or if bleeding is not controlled as expected with the calculated dose, perform an assay that measures factor IX inhibitor concentration [see Warnings and Precautions (5.5) ]. Patients with factor IX inhibitors are at an increased risk of severe hypersensitivity reactions or anaphylaxis if re-exposed to IXINITY. 5.3 Nephrotic Syndrome Nephrotic syndrome may occur with IXINITY. Nephrotic syndrome has been reported following attempted immune tolerance induction in hemophilia B patients with factor IX inhibitors and a history of allergic reactions. 5.4 Thromboembolism Thromboembolism has occurred with IXINITY use. One thrombotic event of deep vein thrombosis was reported in an adult female over 45 years of age from post-marketing experience. Because of the potential risk for thromboembolism with the use of factor IX products, monitor for early signs of thromboembolism and consumptive coagulopathy when administering IXINITY to patients with liver disease, fibrinolysis, peri-operative status, or risk for thromboembolic events or disseminated intravascular coagulation. 5.5 Monitoring Laboratory Tests Monitor patients for factor IX activity levels with the one-stage clotting assay to confirm that adequate factor IX levels have been achieved and maintained, when clinically indicated. Factor IX results can be affected by the type of aPTT reagent used [see Dosage and Administration (2.1) ]. Monitor patients for the development of inhibitors if expected factor IX activity plasma levels are not attained, or if bleeding is not controlled with the recommended dose of IXINITY. Assays used to determine if factor IX inhibitor is present should be titered in Bethesda Units (BUs).

4 CONTRAINDICATIONS IXINITY is contraindicated in patients who have known hypersensitivity to IXINITY or its excipients, including hamster protein [see Warnings and Precautions (5.1) ]. Do not use in patients with known hypersensitivity to IXINITY or its excipients, including hamster protein ( 4 )

8.1 Pregnancy Risk Summary There are no data with IXINITY use in pregnant women to inform a drug-associated risk. Animal reproduction studies have not been conducted with IXINITY. 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.

6 ADVERSE REACTIONS The most common adverse reaction (> 2%) reported in clinical trials was headache. The most common adverse reaction observed in > 2% of patients in clinical trials was headache ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Medexus Pharma, Inc. at 1-844-859-6675 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 the clinical trials of another drug and may not reflect the rates observed in clinical practice. A total of 15 adverse reactions were reported following IXINITY administration among 7 of the 98 subjects who received at least one dose of IXINITY in trials of previously treated patients (PTPs), which included 11 subjects 12 - 18 years of age and 21 subjects < 12 years of age. A total of 12,952 infusions of IXINITY were administered to the 98 subjects. The adverse reactions that were assessed as probably or possibly related to study drug are provided in the table below. Table 3 Summary of Adverse Reactions MedDRA Standard System Organ Class Adverse Reaction Number of Events Number of Subjects (n = 98) (%) Congenital, familial and genetic disorders Hemophilia (i.e., lack of efficacy) 1 1 (1.0%) General disorders and administration site conditions Asthenia 1 1 (1.0%) Injection site discomfort 1 1 (1.0%) Immune System Disorders Hypersensitivity 1 1 (1.0%) Infections and infestations Influenza 1 1 (1.0%) Nervous system disorders Headache 5 2 (2.0%) Dysgeusia 1 1 (1.0%) Lethargy 1 1 (1.0%) Psychiatric disorders Apathy 1 1 (1.0%) Depression 1 1 (1.0%) Skin and subcutaneous tissue disorders Rash pruritic 1 1 (1.0%) 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of IXINITY. 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. Immune System Disorders: Anaphylaxis Vascular Disorders: Deep vein thrombosis The following class adverse reactions have been seen with another recombinant factor IX: inadequate factor IX recovery, inhibitor development, angioedema, hypotension, and thrombosis.