ASH Clinical News February 2016 | Page 32

ADYNOVATE [Antihemophilic Factor (Recombinant), PEGylated] Lyophilized Powder for Solution For Intravenous Injection Brief Summary of Prescribing Information: Please see package insert for full Prescribing Information. INDICATIONS AND USAGE ADYNOVATE, Antihemophilic Factor (Recombinant), PEGylated, is a human antihemophilic factor indicated in adolescent and adult patients (12 years and older) with hemophilia A (congenital factor VIII deficiency) for: • On-demand treatment and control of bleeding episodes Table 2: Adverse Reactions Reported for ADYNOVATE MedDRA Preferred Term Number of Subjects n (%) (N=169) Percent per Infusion (N = 13579) Diarrhea 1 (0.6%) 0.01% Nausea 2 (1.2%) 0.01% Nervous System Disorders Headache 5 (3.0%) 0.06% Vascular Disorders Flushing 1 (0.6%) 0.01% MedDRA System Organ Class Gastrointestinal Disorders • Routine prophylaxis to reduce the frequency of bleeding episodes ADYNOVATE is not indicated for the treatment of von Willebrand disease. CONTRAINDICATIONS ADYNOVAT E is contraindicated in patients who have had prior anaphylactic reaction to ADYNOVATE, to the parent molecule (ADVATE), mouse or hamster protein, or excipients of ADYNOVATE (e.g. Tris, mannitol, trehalose, glutathione, and/or polysorbate 80). WARNINGS AND PRECAUTIONS Hypersensitivity Reactions Hypersensitivity reactions are possible with ADYNOVATE. Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with other recombinant antihemophilic factor VIII products, including the parent molecule, ADVATE. Early signs of hypersensitivity reactions that can progress to anaphylaxis may include angioedema, chest tightness, dyspnea, wheezing, urticaria, and pruritus. Immediately discontinue administration and initiate appropriate treatment if hypersensitivity reactions occur. Neutralizing Antibodies Formation of neutralizing antibodies (inhibitors) to factor VIII can occur following administration of ADYNOVATE. Monitor patients regularly for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests. Perform an assay that measures factor VIII inhibitor concentration if the plasma factor VIII level fails to increase as expected, or if bleeding is not controlled with expected dose. Monitoring Laboratory Tests • Monitor plasma factor VIII activity by performing a validated onestage clotting assay to confirm the adequate factor VIII levels have been achieved and maintained [see Dosage and Administration (2)]. • Monitor for the development of factor VIII inhibitors. Perform the Bethesda inhibitor assay to determine if factor VIII inhibitor is present. If expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with the expected dose of ADYNOVATE, use Bethesda Units (BU) to determine inhibitor levels. ADVERSE REACTIONS Common adverse reactions (≥1% of subjects) reported in the clinical studies were headache and nausea. No events of hypersensitivity were reported. Immunogenicity The risk of the development of factor VIII inhibitors with the use of ADYNOVATE was evaluated in 2 completed and 3 ongoing clinical trials. Study subjects consisted of adult (n=143 with ≥ prior 150 EDs) and pediatric PTPs [(< 6 years of age with ≥50 prior EDs (n= 3), ≥6 years of age with ≥150 prior EDs (n= 23)]. In 120 adult and pediatric PTPs who were treated for at least 50 exposure days with ADYNOVATE, the factor VIII inhibitor frequency was 0 (95% CI of 0 to 0.03) for the risk of any factor VIII inhibitor. None of the 169 individual subjects who received at least one infusion of ADYNOVATE developed neutralizing antibodies to factor VIII. Immunogenicity also was evaluated by measuring the development of binding IgG and IgM antibodies against factor VIII, PEGylated (PEG)-factor VIII, PEG and Chinese hamster ovary (CHO) protein using validated ELISA assays. None of the 169 treated subjects with at least one infusion of ADYNOVATE developed a persistent binding antibody response to any of these antigens. Thirteen subjects in total showed pre-existing antibodies to factor VIII (n=1), PEG-factor VIII (n=12) and/or PEG (n=3) prior to the first exposure to ADYNOVATE. Eight subjects who tested negative at screening developed transient IgG antibodies against factor VIII (n=5), or PEG-FVIII (n=3) at one or two consecutive study visits. Binding antibodies that were detected prior to exposure to ADYNOVATE or that transiently developed during the study could not be correlated to an impaired treatment efficacy, altered PK parameters or adverse reactions. No subject had pre-existing or treatment-emergent antibodies to CHO protein. The detection of antibodies that are reactive to factor VIII is highly dependent on many factors, including: the sensitivity and specificity of the assay, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to ADYNOVATE with the incidence of antibodies to other products may be misleading. 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 practice. The safety of ADYNOVATE was evaluated in 169 previously treated patients (PTPs) with severe hemophilia A (factor VIII less than 1% of normal), who received at least one dose of ADYNOVATE in 2 multi-center, prospective, open label clinical studies and 3 ongoing clinical studies. The median duration of participation per subject was 333 (min-max: 1-593) days and the median number of exposure days to ADYNOVATE per subject was 96 (min-max: 1-170). Table 2 lists the adverse reactions reported during clinical studies. Baxalta, Advate, Adynovate, and Baxject are trademarks of Baxalta US Inc. Patented: see www.baxalta.com/productpatents/. Baxalta US Inc. Westlake Village, CA 91362 USA U.S. License No. 2020 Issued 11/2015 15E001-ADY-US