FDA label 2c0e32e8-0f04-4519-4ecb-cbedee69419d

5 WARNINGS AND PRECAUTIONS Anaphylaxis and severe hypersensitivity reactions are possible. Should such reactions occur, treatment with the product should be discontinued, and appropriate treatment should be administered. ( 5.1 ) Development of activity-neutralizing antibodies has been detected in patients receiving factor VIII-containing products. If expected plasma factor VIII activity levels are not attained, or if bleeding is not controlled with an appropriate dose, an assay that measures factor VIII inhibitor concentration should be performed. ( 5.2 , 5.4 ) Patients may develop hypersensitivity to hamster protein, which is present in trace amounts in the product. ( 5.3 ) 5.1 Anaphylaxis and Severe Hypersensitivity Reactions Allergic type hypersensitivity reactions are possible. Patients should be informed of the early signs or symptoms of hypersensitivity reactions [including hives (rash with itching), generalized urticaria, tightness of the chest, wheezing, and hypotension] and anaphylaxis [ see Patient Counseling Information ( 17 ) ]. Patients should be advised to discontinue use of the product and contact their physicians if these symptoms occur. 5.2 Neutralizing Antibodies The occurrence of neutralizing antibodies (inhibitors) is well known in the treatment of patients with hemophilia A. Inhibitors have been detected in patients receiving factor VIII-containing products. Inhibitors are common in previously untreated patients 4,5,6 and have been observed in previously treated patients on factor VIII products. 7,8,9,10,11,12 Patients using coagulation factor VIII products, including XYNTHA, should be monitored for the development of factor VIII inhibitors. If expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, an assay should be performed to determine if a factor VIII inhibitor is present [ see Warnings and Precautions ( 5.4 ) ]. If detected, inhibitors should be titered in Bethesda Units (BU). 5.3 Formation of Antibodies to Hamster Protein XYNTHA contains trace amounts of hamster proteins. Patients treated with this product could develop hypersensitivity to these non-human mammalian proteins. 5.4 Monitoring: Laboratory Tests Monitor plasma factor VIII activity levels by the one-stage clotting assay to confirm that adequate factor VIII levels have been achieved and are maintained, when clinically indicated [ see Dosage and Administration ( 2 ) ]. It is recommended that individual factor VIII values for recovery and, if clinically indicated, other pharmacokinetic characteristics be used to guide dosing and administration. Monitor for development of factor VIII inhibitors. Perform assay to determine if factor VIII inhibitor is present when expected factor VIII activity plasma levels are not attained, or when bleeding is not controlled with the expected dose of XYNTHA. Use Bethesda Units (BU) to titer inhibitors.

6 ADVERSE REACTIONS The most common adverse reaction in study 1 is headache (24% of subjects) and in study 2 is pyrexia (41% of subjects). The most common adverse reaction in Study 1 is headache (24% of subjects) and in Study 2 is pyrexia (41% of subjects). ( 6.1 ) Two out of 89 subjects (who completed ≥ 50 exposure days) developed an inhibitor during the course of the study. The observation of 2 inhibitors in 89 subjects who completed ≥ 50 exposure days was consistent with a 95% probability that the inhibitor formation rate with XYNTHA is less than 4.17% using a Bayesian analysis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Wyeth Pharmaceuticals, Inc. at 1-800-934-5556 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. Study 1 is a pivotal phase 3 (safety and efficacy) study in which previously treated patients (PTPs) with hemophilia A received XYNTHA for routine prophylaxis and on-demand treatment, 94 subjects received at least one dose of XYNTHA, resulting in a total of 6,775 infusions [ see Clinical Studies ( 14 ) ]. In Study 1, the most frequently reported treatment-emergent adverse reaction was headache (24% of subjects). Other adverse reactions reported in ≥ 5% of subjects were: nausea (6%), diarrhea (5%), asthenia (5%) and pyrexia (5%). No subject developed anti-CHO or anti-TN8.2 antibodies. Study 2 (surgery) is an on-going, open-label, single-arm study of at least 25 evaluable PTPs with severe or moderately severe hemophilia A (factor VIII activity in plasma [FVIII:C] ≤ 2%) who required elective major surgery and were planned to receive XYNTHA replacement therapy for at least 6 days post-surgery. Twenty-two subjects received at least one dose of XYNTHA, resulting in 766 infusions [ see Clinical Studies ( 14 ) ]. In Study 2, the most frequently reported treatment-emergent adverse reaction was pyrexia (41% of subjects). Other adverse reactions reported in ≥ 5% of subjects were: headache (9%), nausea (9%), diarrhea (5%), vomiting (5%) and asthenia (5%). The adverse reactions reported in either study were considered mild or moderate in severity. Immunogenicity In Study 1, the incidence of FVIII inhibitors to XYNTHA was the primary safety endpoint. Two subjects with inhibitors were observed in 89 subjects (2.2%) who completed ≥ 50 exposure days. These results were consistent with the pre-specified endpoint that no more than 2 inhibitors may be observed in at least 81 subjects. In a Bayesian statistical analysis, results from this study were used to update PTP results from a prior supporting study using XYNTHA manufactured at the initial facility, where one de novo and two recurrent inhibitors were observed in 110 subjects, and the experience with predecessor product (1 inhibitor in 113 subjects). This Bayesian analysis indicates that the population (true) inhibitor rate for XYNTHA, the estimate of the 95% upper limit of the true inhibitor rate, was 4.17% (see Table 1 ). Table 1: Bayesian Posterior Distribution of Inhibitor Rate ---Posterior Beta Distribution Characteristics--- a Prior alpha of 2.5 plus the number of observed inhibitors. b Prior beta of 110 plus the number of subjects analyzed minus the number of observed inhibitors. c Posterior probability is the probability that the true inhibitor rate is less than the upper acceptable limit of 4.4%. A posterior probability greater than 0.95 is deemed acceptable. d The 95% upper limit of the true inhibitor rate (the maximum rate calculated with at least 95% probability) based on the posterior distribution. An inhibitor rate less than 4.4% is deemed acceptable. FVIII Inhibitor Nijmegen Result (BU/mL) Number of Inhibitors Number of Subjects Analyzed Observed Inhibitor Rate (%) Alpha a Beta b Posterior Probability c 95% Upper Limit of Inhibitor Rate (%) d ≥0.6 2 89 2.25 4.5 197 0.9613 4.17

<table ID="Gf5487dd3-b292-4915-89d2-27d38c4c1bd3" frame="border" border="1"> <caption ID="G86595782-528e-4390-9ef1-7e404ac4a5f2">Table 1: Bayesian Posterior Distribution of Inhibitor Rate</caption> <colgroup> <col width="100px"/> <col width="72px"/> <col width="100px"/> <col width="84px"/> <col width="44px"/> <col width="32px"/> <col width="68px"/> <col width="40px"/> </colgroup> <thead valign="bottom"> <tr valign="bottom"> <th colspan="2" valign="bottom"> </th> <th colspan="2" valign="bottom"> </th> <th colspan="4" valign="bottom">---Posterior Beta Distribution Characteristics---</th> </tr> </thead> <tfoot> <tr> <td colspan="8"> ^a Prior alpha of 2.5 plus the number of observed inhibitors.<paragraph ID="G23e8d5a7-9d29-4f2e-8c16-deb0be2e9949"> ^b Prior beta of 110 plus the number of subjects analyzed minus the number of observed inhibitors.</paragraph> <paragraph ID="Ga3fec071-19d6-4208-907b-2fa6c312cba6"> ^c Posterior probability is the probability that the true inhibitor rate is less than the upper acceptable limit of 4.4%. A posterior probability greater than 0.95 is deemed acceptable.</paragraph> <paragraph ID="G060236a1-48e8-40a9-8e34-c56d2b937bd1"> ^d The 95% upper limit of the true inhibitor rate (the maximum rate calculated with at least 95% probability) based on the posterior distribution. An inhibitor rate less than 4.4% is deemed acceptable.</paragraph> </td> </tr> </tfoot> <tbody> <tr> <td align="center" valign="bottom">FVIII Inhibitor Nijmegen Result (BU/mL)</td> <td align="center" valign="bottom">Number of Inhibitors</td> <td align="center" valign="bottom">Number of Subjects Analyzed</td> <td align="center" valign="bottom">Observed Inhibitor Rate (%)</td> <td align="center" valign="bottom">Alpha^a </td> <td align="center" valign="bottom">Beta^b </td> <td align="center" valign="bottom">Posterior Probability^c </td> <td align="center" valign="bottom">95% Upper Limit of Inhibitor Rate (%)^d </td> </tr> <tr> <td align="center" valign="bottom">&#x2265;0.6</td> <td align="center" valign="bottom">2</td> <td align="center" valign="bottom">89</td> <td align="center" valign="bottom">2.25</td> <td align="center" valign="bottom">4.5</td> <td align="center" valign="bottom">197</td> <td align="center" valign="bottom">0.9613</td> <td align="center" valign="bottom">4.17</td> </tr> </tbody> </table>