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warnings and cautions
5 WARNINGS AND PRECAUTIONS Hypersensitivity reactions, including anaphylaxis, may occur. 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 ). The use of factor IX-containing products has been associated with the development of thromboembolism ( 5.4 ). 5.1 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, may occur with IXINITY, and have been reported with factor IX containing products. Signs of allergic reactions, which can progress to anaphylaxis, may include angioedema, chest tightness, hypotension, lethargy, nausea, vomiting, 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 Inhibitors 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 ) ]. 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 may occur with using IXINITY (e.g., pulmonary embolism, venous thrombosis, and arterial thrombosis), and has been associated with the use of factor IX containing products. 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).
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 Cangene Corporation at 1-800-768-2304 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 14 adverse reactions were reported following IXINITY administration among 6 of the 77 subjects who received at least one dose of IXINITY in trials of previously treated patients (PTPs), which included 11 subjects < 18 years of age. A total of 9641 infusions of IXINITY were administered to the 77 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 Patients (n = 77) (%) Congenital, familial and genetic disorders Hemophilia (i.e. lack of efficacy) 1 1 (1.3%) General disorders and administration site conditions Asthenia 1 1 (1.3%) Injection site discomfort 1 1 (1.3%) Infections and infestations Influenza 1 1 (1.3%) Nervous system disorders Headache 5 2 (2.6%) Dysgeusia 1 1 (1.3%) Lethargy 1 1 (1.3%) Psychiatric disorders Apathy 1 1 (1.3%) Depression 1 1 (1.3%) Skin and subcutaneous tissue disorders Rash pruritic 1 1 (1.3%) 6.2 Immunogenicity All subjects participating in the clinical trial were monitored for inhibitory and non-inhibitory antibodies to factor IX and antibodies for CHO proteins at the following time points; pre-infusion, after the first 5 exposure days, and then every 3 months thereafter. No subjects in IXINITY clinical trials developed inhibitors to factor IX, including 55 subjects with more than 50 exposure days and 45 of those subjects with more than 100 exposure days. Non-inhibitory factor IX binding antibodies were detected in 30% (23/77) of subjects, including 5 subjects positive at baseline. In three of the subjects, the non-inhibitory factor IX antibodies were persistent, while in the remainder the antibodies were sporadic and non-persistent. No clinical adverse findings related to non-inhibitory factor IX antibody formation were identified. Detection of non-inhibitory antibodies against factor IX has been reported following administration of other factor IX products. The clinical significance of this finding is unknown. In IXINITY clinical trials, 29% (20/68) of subjects tested positive for antibodies against CHO cell proteins. No clinical adverse findings were associated with these antibodies. Reports have been published of sporadic detection of antibodies against CHO cell proteins in subjects treated with other recombinant coagulation factor products produced in CHO cells, as well as in non-hemophilic subjects (). The clinical significance of this is unknown. The manufacturing process for IXINITY was modified to include an additional step to ensure increased clearance of CHO proteins to address the anti-CHO protein response seen in clinical trials. The anti-CHO protein response status of the clinical trial subjects who transitioned to the modified product (n = 17) remained negative (n = 10), stable/nonspecific assay binding (n = 5), or declined (n = 2) after the transition to modified IXINITY for at least 3 months. The detection of antibody formation is dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection and concomitant medications. For these reasons, comparisons of the incidence of antibodies to IXINITY with the incidence of antibodies to other products may be misleading.