Coagulation Factor Ix (Recombinant)

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 )

IXINITY is available as a lyophilized white or almost white powder, in single-dose glass vials containing nominally 250, 500, 1000, 1500, 2000, or 3000 IU per vial. IXINITY is available as a lyophilized white or almost white powder, in single-dose glass vials containing nominally 250, 500, 1000, 1500, 2000, or 3000 international units (IU) per vial (3)

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 )

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).

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.

Pediatric Use: The safety and effectiveness of IXINITY have been established in pediatric patients. Lower recovery, shorter half-life, and higher clearance (based on kg body weight) have been observed in children (< 12 years). Dose adjustment may be needed. ( 8.4 , 12.3 )

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.

8.2 Lactation Risk Summary There is no information regarding the presence of IXINITY in human milk, the effect on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for IXINITY and any potential adverse effects on the breastfed infant from IXINITY or from the underlying maternal condition.

8.4 Pediatric Use The safety, efficacy, and pharmacokinetics of IXINITY have been evaluated in previously treated pediatric patients (PTP). Subjects received twice or once weekly prophylaxis treatment (four subjects were prescribed once a week treatment, 17 were prescribed twice a week treatment) with IXINITY for a mean of 158.7 exposure days [see Clinical Studies ( 14 ) ]. Compared to adolescents and adults (≥ 12 years old), children (< 12 years old) showed higher Factor IX body weight-adjusted clearance, shorter half-life, and lower recovery. Adjustment in dose or dosing frequency may be needed [see Dosage and Administration ( 2.1 ) and Clinical Pharmacology ( 12.3 ) ]. There were no inhibitors detected [see Clinical Pharmacology ( 12.6 ) ]. One patient in the pediatric study had an adverse reaction of hypersensitivity resulting in withdrawal from the study. No new safety concerns were identified in the pediatric trial [see Adverse Reactions ( 6.1 ) ].

8.5 Geriatric Use Clinical studies of IXINITY did not include subjects aged 65 and over. It is not known whether elderly patients respond differently than younger patients. Individualize dose selection for elderly patients [see Dosage and Administration (2.1) ].

Hemophilia B is a sex-linked hereditary disorder of blood coagulation caused by a deficiency in factor IX and results in bleeding into joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma. Treatment with IXINITY replaces factor IX, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.