Bddrfviii (Moroctocog Alfa [AF-CC]) for Surgical Haemostasis in Patients with Haemophilia A: Results of a Pivotal Study

Haemophilia (2010), 1–9 DOI: 10.1111/j.1365-2516.2010.02239.x

ORIGINAL ARTICLE BDDrFVIII (Moroctocog alfa [AF-CC]) for surgical haemostasis in patients with haemophilia A: results of a pivotal study

J. WINDYGA,* L. RUSEN, R. GRUPPO,à A. C. O’BRIEN,§ P. KELLY,§ D. A ROTH§ andS. ARKIN§ *Center for Haemophilia Treatment, Institute of Haematology and Transfusion Medicine, Warsaw, Poland; National Institute for Transfusional Haematology, Bucharest, Romania; àCincinnati Children’s Hospital Medical Center, Cincinnati, OH; and §Pﬁzer Inc, Cambridge, MA, USA

Summary. Moroctocog alfa (AF-CC) (XynthaÔ, Haemostasis ratings following the initial postoper- BDDrFVIII) is manufactured by a process designed ative period were excellent for 92% (23/25) and to enhance the theoretical viral safety profile good for 8% (2/25) of patients. Intra-operative relative to ReFactoÒ, its predecessor, and to blood loss was rated as normal in all patients. provide alignment with clinical monitoring by the Thirteen patients had postoperative blood loss; in one-stage clotting assay. To evaluate the efficacy 10, this was rated as normal. A low frequency of and safety of B-domain-deleted recombinant factor transfusion was reported in both the intra-opera- VIII (BDDrFVIII) was given as bolus injection (BI) tive and postoperative settings. Adverse events or continuous infusion (CI) in haemophilia patients (AEs) were consistent with surgery; three were undergoing major surgery. BDDrFVIII was admin- considered related to BDDrFVIII. One patient had istered by BI or CI per investigator discretion peri- a related AE of postoperative haemorrhage. A clin- operatively for at least 6 days. Thirty patients ically silent low-titre inhibitor was detected in one enrolled and were treated with at least one dose patient, and one patient had a false-positive inhib- of BDDrFVIII. Twenty-five patients were evaluable itor titre. This study demonstrates that BDDrFVIII for efficacy. Outcomes were favourable against a is safe and efficacious for surgical prophylaxis in background of multiple major surgical procedures. haemophilia A patients undergoing major surgery. All haemostatic efficacy ratings were ‘excellent’ or ‘good’. End-of-surgery haemostasis ratings, the Keywords: B-domain-deleted factor VIII, bolus injec- primary efficacy endpoint, were excellent for 72% tion, continuous infusion, factor VIII inhibitors, (18/25) and good for 28% (7/25) of patients. haemophilia A, surgical haemostasis

factor VIII (BDDrFVIII) manufactured by a process Introduction that has been modiﬁed to enhance the theoretical Improvements in the manufacture of recombinant viral safety proﬁle relative to predecessor product, factor VIII (rFVIII) have been intended to reduce the ReFactoÒ [1]. risk of transmitting viral infection and to increase In addition, the method for assignment of potency ease of use. Moroctocog alfa (AF-CC) (XynthaÔ, for this preparation of BDDrFVIII has been aligned BDDrFVIII) is a B-domain-deleted recombinant with the one-stage clotting assay, thereby harmoniz- ing the labelled potency of the drug with routine clinical monitoring using the one-stage clotting assay Correspondence: Jerzy Windyga, MD, PhD, Head, Department of [2]. Previous studies have demonstrated that Disorders of Haemostasis and Internal Medicine, Institute of Haematology and Transfusion Medicine, 14 I. Gandhi Str., 02-776 BDDrFVIII is safe and effective in the prevention Warsaw, Poland. and treatment of haemorrhages and has pharmaco- Tel.: +48 22 3496 158; fax: +48 22 3496 159; kinetic (PK) equivalence to full-length rFVIII [2]. e-mail: [email protected] Factor VIII (FVIII) replacement therapy is critical Accepted after revision 10 February 2010 in maintaining haemostasis in patients with haemo-

Ó 2010 Blackwell Publishing Ltd 1 2 J. WINDYGA et al. philia A undergoing surgery. This is usually limit of normal or international normalized ratio achieved by administering FVIII concentrate during £1.5 and an absolute CD4 count >200 cells lL)1. the surgical and postsurgical periods, until wound Patients being treated for human immunodeficiency healing has been completed. Typically, replacement virus (HIV) had to be on a stable antiviral regimen. therapy is administered by bolus injections (BI); Exclusion criteria included a bleeding disorder in however, reports suggest that administration by addition to haemophilia A, regular use of antifibrin- continuous infusion (CI) may be associated with olytic agents or other agents known to influence reduced requirements for FVIII concentrate and less platelet function and concomitant therapy with fluctuation in FVIII activity plasma levels [3–8]. immunosuppressive drugs. This open-label study was conducted to assess the safety and efficacy of BDDrFVIII administered by Study design and treatment either BI or CI for the management of surgical haemostasis in patients with severe and moderately Patients were designated to receive BDDrFVIII by severe haemophilia A undergoing elective major either BI or CI by the investigator at screening based surgery. on investigator preference and local treatment practices. At baseline (approximately 4 weeks before surgery), following a 3-day washout of all FVIII Materials and methods products, a 50 IU kg)1 infusion of BDDrFVIII was This was a phase 3, open-label, multicentre, administered for a recovery assessment in BI patients prospective study performed at a total of 13 study and for PK assessment in CI patients to estimate sites in seven countries, including the United States, recovery and clearance rate, respectively. Investiga- New Zealand, Russia, Sweden, Austria, Poland and tors reported their target FVIII activity level for Romania. surgery and used results from the baseline assess- The study was designed in accordance with the ments to plan the initial BDDrFVIII dose and suggestions provided by the Committee for Medic- injection frequency (BI) or infusion rate (CI). Patients inal Products for Human Use (CHMP) of the returned to their usual FVIII replacement therapy European Medicines Agency (EMEA) and conducted regimen after this assessment until the day of surgery. in accordance with the International Conference on On the day of surgery, all patients received a bolus Harmonisation Guideline for Good Clinical Practice loading dose of BDDrFVIII to achieve the previously (GCP) and the ethical principles that have their planned target plasma level of FVIII:C. Blood sam- origins in the Declaration of Helsinki. All patients ples were obtained before and after the loading dose provided written informed consent/assent prior to to determine levels of FVIII:C. Patients treated by CI surgery. began a BDDrFVIII infusion approximately 30 min after the start of the loading dose. Supplemental bolus doses (BI and CI) or rate adjustments (CI) Patients could be made during the intra-operative period to At least 25 patients were to be enrolled, including 12 account for possible variation in recovery and/or to to be treated by CI. All patients were to be men account for individual variation from the expected ‡12 years of age with severe or moderately severe clearance if needed, based on subsequent determina- haemophilia A undergoing elective major surgery tions of FVIII:C. that was anticipated to require rFVIII infusions with For administration by CI, BDDrFVIII was pre- monitoring for at least 6 days after surgery. Major pared based upon the results from Neidhardt et al. surgery was defined as surgery involving open [9]. Large volume preparations were prepared with a abdominal, intracranial, orthopaedic, retroperito- final BDDrFVIII concentration of ‡10 IU mL)1 neal, thoracic, pharyngeal, or retropharyngeal resuspended in either 5% dextrose solution or procedures, or invasive dental procedures involving normal saline, with minimum flow rates of 6 or complicated extractions. 20 mL h)1 respectively. Small doses of heparin Inclusion criteria included FVIII concentration (2–6 IU heparin mL)1 of infusate) could be added (FVIII:C) £2%, negative assays for FVIII inhibitor to the solution to assist the administration of CI. at both local and central laboratories at screening, a Patients received BDDrFVIII for ‡6 consecutive negative history of a FVIII inhibitor and ‡150 prior postoperative days (initial postoperative period) by exposure days to treatment with any FVIII product. BI or CI depending on the investigator-assigned Patients were to have adequate liver and kidney treatment. Inpatient postoperative care had to be function, prothrombin time £1.25 times the upper ‡2 days for BI patients and ‡6 days for CI patients;

Haemophilia (2010), 1–9 Ó 2010 Blackwell Publishing Ltd BDDRFVIII FOR SURGICAL HAEMOSTASIS IN HAEMOPHILIA A 3 daily assessments at the study site were required Secondary efficacy endpoints were the four-point during the first 6 days after surgery for all patients. Surgical Hemostasis Efficacy Scale rating as assessed During the initial postoperative period, preinfu- on postoperative day 7 for previously discharged BI sion blood samples for FVIII:C were obtained patients or the day of hospital discharge for other approximately 15 min before BI at least once daily. patients; the total consumption of BDDrFVIII and For CI patients, FVIII:C was measured and recorded consumption per bleeding event; the number of each day during infusion. If FVIII:C did not bleeding episodes and the efficacy of BDDrFVIII in sufficiently approximate the target level, additional treating the episode using a previously described BI could be administered for BI patients, or for four-point scale [2]; the comparison of the predicted CI patients, the infusion rate could be adjusted and actual blood loss and transfusions and the PK of accordingly. For CI patients, supplemental BIs BDDrFVIII in the patient population. Investigators could be used in conjunction with CI at the predicted and recorded estimates of intra-operative investigator’s discretion to acutely correct the blood loss and intra-operative transfusion needs FVIII:C to the predetermined target level. Any preoperatively based on the assumption that surgery bleeding episodes occurring during either the initial would be completed without major complications; (first 6 postoperative days or period until discharge, blood loss was rated as ‘normal’ or ‘abnormal’. whichever occurred later) or final postoperative Information about infusions of study drug, bleeding period (remainder of treatment period up to a total episodes (categorized as spontaneous or traumatic; of 6 weeks) were to be treated with an on-demand expected surgical blood loss was not included in infusion(s) of BDDrFVIII. characterizing bleeding episodes), blood loss and During the final postoperative period, patients transfusions was recorded intra-operatively and could continue postsurgical treatment with throughout the trial in medical records and patient BDDrFVIII administered by BI on an outpatient diaries. basis for a total of up to 6 weeks. The final study visit The incidence of less-than-expected therapeutic was conducted at the end of this period, after which effect (LETE) was also evaluated in the prophylactic, the patients could return to their respective pre- on-demand and low recovery settings. Definitions of surgical regimens of commercially available FVIII LETE in these specific circumstances have been replacement therapy. Approximately 4 weeks after previously described [2]. the final visit, the patient completed the study Assessment of FVIII:C for preoperative planning activities with a final study contact. and to monitor intra-operative and postoperative dosing was performed using assays for FVIII:C activity performed at the local institution. Specimens Endpoints and assessments for central laboratory measurements of FVIII:C, The primary endpoint was haemostatic efficacy using the one-stage clotting assay, were collected in during the surgical procedure through 1 h after parallel, analysed and used for analysis of PK surgery completion (referred to as end of surgery), parameters. For BI patients, the FVIII recovery study as assessed by the investigator or surgeon. The was performed with blood samples for FVIII activity assessment was based on comparison to experience taken within 2 h before and 15 min, 30 min and 1 h with similar patients undergoing similar procedures, after infusion of a dose of approximately 50 IU kg)1 using the four-point Surgical Hemostasis Efficacy of BDDrFVIII. For CI patients, PK parameters were Rating Scale (Table 1). calculated to determine FVIII recovery and clearance via blood samples drawn within 2 h before and Table 1. Surgical haemostasis efficacy rating scale. 15 min, 30 min, and 1, 3, 6, 9, 24, 28, 32 and 48 h after infusion of a dose of approximately 50 IU kg)1 Rating Criteria of BDDrFVIII. Excellent Achieved haemostasis comparable to that expected Safety evaluations included recording of adverse after similar surgery in a patient without events (AEs) [AEs and haemophilia events (AEs haemophilia Good Prolonged time to haemostasis, with somewhat uniquely related to the condition of haemophilia or increased bleeding compared with that expected the direct consequence of a bleeding episode)] and after similar surgery in a patient without concomitant treatments, physical examinations with haemophilia measurements of vital signs and laboratory evalua- Moderate Obviously delayed haemostasis, but manageable tions. Immunogenicity testing was performed by a with additional infusions central laboratory (Covance Laboratories, Chantilly, None No haemostatic response VA, USA) on samples obtained at screening, baseline,

Ó 2010 Blackwell Publishing Ltd Haemophilia (2010), 1–9 4 J. WINDYGA et al. day of surgery and final postoperative visits. Assess- Table 2. Baseline demographics and clinical characteristics, all ment of the presence of activity-neutralizing anti- patients. bodies against FVIII (inhibitors) was performed using Bolus injection, Continuous Total, the Nijmegen modification of the Bethesda inhibitor n = 22 infusion, n =8 n = 30 assay and a normal plasma test base and reported in Age, mean years 35.05 38.13 35.87 Bethesda Units (BU); a patient was considered to Male, n (%) 22 (100.0) 8 (100.0) 30 (100.0) have developed a positive FVIII inhibitor if he had a White race, n (%) 22 (100.0) 8 (100.0) 30 (100.0) titre of ‡0.6 BU mL)1 in a sample assayed at the Weight, mean kg 76.68 75.99 76.50 central laboratory using the Nijmegen assay after Previous exposure 22 (100.0) 8 (100.0) 30 (100.0) days 150, n (%) receiving study drug. Specimens testing positive for ‡ Haemophilia severity, n (%) inhibitor by Nijmegen assay were then tested by £1% 17 (77.3) 3 (37.5) 20 (66.7) Bethesda assay against a plasma-derived FVIII test >1% to £2% 5 (22.7) 5 (62.5) 10 (33.3) base and against a BDDrFVIII test base. Serum Target joints, n (%) samples were also tested for the development of No 3 (13.6) 0 3 (10.0) antibodies to BDDrFVIII; TN8.2, the affinity ligand Yes 19 (86.4) 8 (100) 27 (90.0) used in purification of BDDrFVIII and CHO cell HIV status, n (%) Negative 19 (86.4) 7 (87.5) 26 (86.7) proteins derived from the cell line used in the Reactive 3 (13.6) 1 (12.5) 4 (13.3) manufacture of BDDrFVIII, using a validated HCV status, n (%) enzyme-linked immunosorbent assay (ELISA). Negative 3 (13.6) 1 (12.5) 4 (13.3) Reactive 19 (86.4) 7 (87.5) 26 (86.7) Statistical analysis HIV, human immunodeficiency virus; HCV, hepatitis C virus. All safety analyses were performed on the intent- to-treat (ITT) population, which included all en- patient withdrew for personal reasons before surgery rolled patients who received ‡1 dose of study drug. but had baseline PK determinations. Twenty-five The efficacy evaluable population, which was used patients met the criteria for inclusion in the efficacy for analyses of the primary and secondary efficacy evaluable population. Reasons for exclusion from endpoints, was the subset of ITT patients that met this population were inhibitor development before eligibility criteria, had a major surgical procedure, surgery in one patient, protocol violations in three had study drug administered over a period of ‡6 days patients (administration of autologous fresh frozen after surgery, had an efficacy assessment of study plasma during the surgical procedure) and termina- drug use in support of surgery and did not have a tion from the study prior to surgery in one patient. major protocol violation. Efficacy data on and Median patient age was 34.5 years (range, 18–53). subsequent to the date of inhibitor development Demographical and baseline illness characteristics were not included in efficacy analyses. were generally similar between treatment groups, All efficacy and safety endpoints were summarized except for a greater proportional representation of with descriptive statistics as appropriate. For contin- severe disease (FVIII:C £ 1%) in the BI patient uous variables, number, mean, standard deviation population (Table 2). (SD), median, minimum and maximum were pro- Most surgical procedures were orthopaedic; for vided. For categorical variables, frequency and per- the efficacy evaluable population, the most common centage are presented for each category. Missing data was the total joint replacements in 12 (48%) patients were not imputed. The sample size was based on (11 total knee replacements and one hip replace- clinical rather than statistical considerations and is ment) and knee/elbow synovectomies in five (20%) consistent with a sample size suggested by regulatory patients. authorities. Concomitant treatment Results During the study, 29 of 30 (96.7%) patients used concomitant medications; most were those Patients commonly used in the surgical setting. Non-study Thirty patients enrolled (22 BI, 8 CI) were treated drug FVIII concentrates were used by 14 patients with ‡1 dose of BDDrFVIII and were included in the (46.7%). This largely reflects FVIII replacement ITT population. A total of 29 patients underwent therapy during the screening period and subsequent surgery and completed the study; the remaining to the final visit, when patients used commercial

Haemophilia (2010), 1–9 Ó 2010 Blackwell Publishing Ltd BDDRFVIII FOR SURGICAL HAEMOSTASIS IN HAEMOPHILIA A 5

FVIII concentrate of their choice. At variance similar for the 25 patients who were evaluable for with protocol-specified procedures, one patient efficacy; the median total dose was 90 841 IU (range administered on-demand infusions of commercially 36 500–231 044 IU) for the BI patients and available rFVIII on two occasions during the final 68 621 IU (range 50 854–96 251 IU) for the CI postoperative period, once for the treatment of a patients. Owing to the non-random designation of haemorrhage, and once for physiotherapy. Antifibri- patients to respective treatment groups and the nolytics were used by two patients (aminocaproic limited patient numbers in the CI group, no formal acid for 4 days and cyclokapron for 1 day; n =1 comparison of consumption is possible. patient each). Pharmacotherapy for systemic throm- Two BI patients had a supplemental intra-opera- boprophylaxis was not administered to study tive dose of BDDrFVIII prompted by local laboratory patients. Heparin flush was used for two BI patients FVIII:C measurements below the predetermined at one study site (surgical procedures: arthroscopic target FVIII:C level. For each CI patient, the initial synovectomy of the elbow) to establish and maintain rate of CI was informed by the respective study site patency of peripherally inserted central catheter standard of care rather than the clearance calculated lines. from the patient’s baseline PK assessment. All CI of BDDrFVIII were administered by large volume preparation, for six patients (all at one study site) FVIII consumption using normal saline and for one patient (at another Extent of exposure to BDDrFVIII for the ITT study site) using 5% dextrose in water (D5W) for population is described in Table 3. Among the ITT BDDrFVIII resuspension. For each CI patient, there patients, the median total dose was 83 002 IU (range was at least one occasion in which the infusion 36 500–231 044 IU) for the BI patients and concentration of BDDrFVIII was lower than the 74 311 IU (range 4405–96 251 IU) for the CI protocol-specified limit (10 IU mL)1). For five CI patients. BI patients received a median dose of patients (all administered normal saline solution), the 25.5 IU kg)1 (range 8.4–72.9 IU kg)1) per infusion infusion rate was less than the protocol-specified over a median of 43 (range 16–72) infusions. CI limit (20 mL h)1) on at least one occasion. patients received a mean ± SD rate of 3.7 ± 0.9 IU kg)1 h)1 during the intra-operative period Efficacy and 2.8 ± 0.9 IU kg)1 h)1 in the initial postoperative period. In addition, during the final postoperative Target FVIII:C levels in support of the surgical period, all CI patients received a median BI dose of procedure ranged from 1.0 to 1.5 IU mL)1, reflecting 13 IU kg)1 (range 5.6–47.2 IU kg)1) over a median the varying local treatment practices of the respective of 17 (range 13–29) infusions. Exposure data were study sites. The median presurgical BDDrFVIII dose was 50.6 IU kg)1 (range: 22.9–77.7 IU kg)1). The resultant median postinfusion FVIII:C was Table 3. BDDrFVIII exposure, all patients. 0.97 IU mL)1 (range: 0.592–1.574 IU mL)1), with BI, n = 22 CI, n = 8* five of 25 patients having preinfusion FVIII:C values Total units (IU per patient) of ‡0.03 IU mL)1. These data are consistent with the Mean 92 608 66 247 results predicted by the baseline K-values. Median 83 002 74 311 All haemostatic efficacy ratings were reported as Range 36 500–231 044 4405*–96 251 excellent or good during the intra-operative period, Surgical dose, IU kg)1 per infusion)1 – median (range) Preoperative 49.3 (21.3–72.9) 49.8 (22.9–52.2) and similar results were reported for efficacy ratings Intra-operative 25.8 (23.6–27.9) N/A at the end of the initial postoperative period (Fig. 1). Initial postoperative 30.4 (8.4–70.5) N/A The percentage of evaluable (BI and CI combined) Final postoperative 23.4 (8.4–58.3) 13.0 (5.6–47.2) patients with a rating of excellent was 72% in the Continuous infusion rate, IU kg )1h)1 per patient – mean ± SD intra-operative period and 92% at day 7/day of Intra-operative N/A 3.7 ± 0.9 discharge. Initial postoperative N/A 2.8 ± 0.9 Intra-operative blood loss was reported in 24 of Exposure days/patient Mean ± SD 31.0 ± 7.2 25.5 ± 11.4 the 25 efficacy evaluable patients; for all patients, Median 33 29 blood loss was rated as normal (Fig. 2). In 20 of 25 Range 15–40 1*–37 patients, intra-operative blood loss was less than or BI, bolus injection; CI, continuous infusion; N/A, not applicable. equal to the volume predicted preoperatively. Thir- *Includes one patient who only underwent a PK assessment and teen patients had postoperative blood loss; in 10 did not undergo a surgical procedure. cases, the blood loss was rated as normal. Of those

Ó 2010 Blackwell Publishing Ltd Haemophilia (2010), 1–9 6 J. WINDYGA et al.

postoperative period, three patients received RBC transfusions, including the patient who had surgical trauma to the epigastric artery, and one patient received fresh frozen plasma. A total of 10 bleeding episodes in seven patients were reported in the postoperative setting and required on-demand treatment with BDDrFVIII. The range of infusion doses was 12.2–49.9 IU kg)1 with a median dose among BI patients of 24.4 IU kg)1 and a median dose among CI patients of 19.7 IU kg)1. Seven cases were due to injury, in Fig. 1. Surgical haemostasis efficacy ratings, efficacy evaluable three instances affecting the joint that had undergone population. surgery, and three cases were spontaneous. Nine episodes were treated and resolved with a single rated as abnormal, one followed surgical trauma to infusion of study drug, and one bleeding episode of the epigastric artery, one was because of an 800 mL traumatic origin required a second infusion. All but blood loss after hip replacement surgery and one one of these episodes occurred during the final occurred after an elbow synovectomy in which the outpatient postoperative period. Response ratings lost blood was absorbed into the surgical dressing to the initial BDDrFVIII infusion to treat the episode and could not be quantified by the investigator. were excellent or good for all haemorrhages. Of the nine patients predicted to require red blood There were two true events of LETE (i.e., in the cell (RBC) transfusions during the intra-operative absence of confounding factors), both in the period, only one received a transfusion. Two patients prophylactic setting with spontaneous bleeding with- predicted not to require intra-operative RBC trans- in 48 h of a prophylactic dose of BDDrFVIII. In one fusion received transfusions with packed RBCs; for patient, the investigator reported at the final postop- both, blood loss was reported as normal. During the erative visit that there had been a spontaneous soft

Fig. 2. Blood loss, efﬁcacy evaluable population. All blood loss rated as normal unless otherwise indicated. *Postoperative blood loss rated abnormal but volume could not be quantiﬁed. **Occured during the intraoperative period. Postoperative blood loss rated abnormal due to hemorrhage following surgical trauma to epigastric artery. àPostoperative blood loss rated abnormal.

Haemophilia (2010), 1–9 Ó 2010 Blackwell Publishing Ltd BDDRFVIII FOR SURGICAL HAEMOSTASIS IN HAEMOPHILIA A 7 tissue bleeding episode 33.9 h after a prophylatic blood loss into the surgical dressing after an arthro- infusion of BDDrFVIII. The second patient had a scopic synovectomy of the elbow) were discussed spontaneous bleeding episode of the right hip 1 day above. after total knee replacement while receiving treatment by CI. Steady-state FVIII:C was 100% and Immunogenicity. Positive inhibitor results by 104% by the local and central laboratories respec- Nijmegen assay were reported (by the central labora- tively. The bleeding episode was not treated with any tory) for two patients, one of which had a true BI of study drug. The patient required no additional inhibitor under complex clinical circumstances and transfusions. Haemostatic efficacy assessment at the the other a false positive without clinical sequelae. conclusion of the initial postoperative period had The true inhibitor was detected in a patient who been reported as excellent. tested negative for inhibitors at screening and baseline, but subsequently had a low-titre inhibitor (0.9 BU mL)1) detected preoperatively by the central Pharmacokinetics laboratory. Prior to inhibitor onset, he had one PK data were available for all 30 patients. For both dose of BDDrFVIII for the PK study dose at the time BI and CI patients, the mean ± SD K-value was of his baseline assessment. Between the baseline 2.11 ± 0.43 IU dL)1 per IU kg)1, and the assessment and the time of his surgery when the mean ± SD in vivo recovery value was 101 ± 20%. initial positive preoperative inhibitor was detected, For CI patients undergoing full PK assessments, the the patient had 3 days of treatment with commer- mean plasma FVIII:C-vs.-time profiles increased cially available plasma-derived FVIII to successfully sharply after intravenous infusion of BDDrFVIII. control a haemorrhage. As central laboratory results After the end of the infusion, the decline of FVIII:C of the preoperative blood draw were not available exhibited biphasic disposition characteristics with until after surgery, the patient underwent a surgical relatively rapid but limited distribution into an knee synovectomy as planned. The patient was extravascular space followed by a slow elimination administered BDDrFVIII by BI for a total con- phase with a mean ± SD t½of 16.7 ± 5.4 h. sumption of 66 920 IU. The patient’s preinhibitor baseline K-value was 1.96 IU dL)1 per IU kg)1. Postinhibitor (prior to surgery), the patient’s K-value Safety was 1.25 IU dL)1 per IU kg)1. Efficacy ratings Adverse events. There were no reported AEs of were excellent at end of surgery and at postoperative allergic reaction or thrombosis. AEs occurring in day 7/day of discharge, blood loss was rated normal >10% (>3 patients) of the study population were and the patient had no transfusion or bleeding fever in 13 (43.3%), local reaction to procedure episode. At the final postoperative visit, the FVIII (postoperative pain in the operative wound) in 11 inhibitor titre was 1.51 BU mL)1 as determined by (36.7%), anaemia in nine (30%), infection in five the central laboratory, and 1 BU mL)1 at final contact (16.7%) and headache and nausea in four patients as determined by the local laboratory. each (13.3%). AEs considered to be related to The second patient had a false-positive low-titre BDDrFVIII were one event of haemorrhage and one result (by central laboratory Nijmegen assay) at the event of a false-positive inhibitor, both in the same final study visit. This low-titre FVIII inhibitor of patient, and one event of FVIII inhibitor develop- 0.63 BU mL)1 was reported by the central labora- ment in a second patient. Both events were reported tory (Nijmegen result), while the same specimen by the respective investigators as FVIII inhibition. tested negative in the central laboratory against Seven serious AEs (fever, postoperative haemor- plasma-derived FVIII test base and against rhage, accidental injury, cough increased, cellulitis BDDrFVIII test base, indicating that the positive and both events of FVIII inhibition) were reported in Nijmegen assay result was spurious. In addition, the five patients. All except FVIII inhibition were con- paired local laboratory FVIII inhibitor result from sidered unrelated to BDDrFVIII and resolved. The this visit was also negative. At 2-month follow-up, two reported instances of FVIII inhibition are the local laboratory reported a titre of 0.47 BU mL)1 discussed below. There were no changes in labora- (defined as a negative result) and the central laboratory values that were considered to be related to tory reported a titre of 0.0 BU mL)1. The ELISA BDDrFVIII. Unexpected bleeding in the postopera- result from the final visit, when the isolated spurious tive period was reported as an AE for two patients. low-titre inhibitor was noted, was negative for an Both events (abnormal bleeding following surgical immune response to BDDrFVIII, confirming the trauma to the epigastric artery and unquantifiable false-positive designation of this result.

Ó 2010 Blackwell Publishing Ltd Haemophilia (2010), 1–9 8 J. WINDYGA et al.

One patient developed anti-BDDrFVIII antibodies In a retrospective study of 16 patients with that were considered a positive immune response by haemophilia who had major surgical procedures ELISA at the final postoperative visit; there was no and were treated with ReFacto, all patients were inhibitor development reported in this patient. One treated with preoperative BI followed by CI for a patient developed anti-CHO antibodies that were period of 5–21 days [11]. Intra-operative haemo- considered a positive immune response by ELISA at stasis was rated excellent or good in 12 (75%) of the final postoperative visit, with no reported asso- patients, and moderate in the remainder; there was ciated allergic reaction. One patient had anti-TN8.2 no evidence of insufficient FVIII levels in patients antibodies at study entry but did not have an immune with moderate ratings. Intra-operative blood loss response following treatment with BDDrFVIII. These was considered normal. Transfusions were required findings in the absence of symptoms or other for bleeding episodes in 20% of patients. Reasons for evidence of FVIII neutralizing antibodies are of the increased transfusion frequency and a greater unknown clinical significance. proportion of moderate ratings in that report of treatment with predecessor product are unclear. Administration of BDDrFVIII by BI is most com- Discussion monly used to manage haemophilia patients under- In this prospective clinical trial of patients undergo- going surgical procedures and is considered the ing elective major surgery, BDDrFVIII given by either standard of care. However, adjusted-dose CI has BI or CI resulted in excellent haemostasis in most been proposed to offer advantages over BI by patients and good haemostasis in the remainder. preventing both wasteful high FVIII peaks and Blood loss was rated as normal during the intra- sub-therapeutic FVIII concentrations [3–8]. Data operative period in all patients, and in the postop- from non-randomized studies suggest a lower inci- erative period, abnormal bleeding was rare. Few dence of decreases in haemoglobin and fewer trans- patients required transfusions either intra-operatively fusions in patients treated by CI [3]. BDDrFVIII has or postoperatively. Median total BDDrFVIII con- been demonstrated to be stable in vitro in simulated sumption per patient (by ITT analysis) was CI conditions [9]. This study provides initial, albeit 83 002 IU for BI and 74 311 IU for CI. BDDrFVIII limited, data regarding administration of BDDrFVIII was safe and well-tolerated, with a persistent low- by CI. Although BDDrFVIII was successfully admin- titre inhibitor detected in one patient and a transient istered by CI in large volume preparations, the false-positive inhibitor detected in another patient. requisite 20 mL h)1 minimum infusion rate when The central laboratory mean ± SD K-value of resuspended in normal saline was not easily main- BDDrFVIII (2.11 ± 0.43 IU dL)1 per IU kg)1) tained; however, this had no apparent impact on aligned with prior experience (2.35 ± 0.47 IU dL)1 clinical efficacy outcomes. Preparing BDDrFVIII for )1 )1 per IU kg ) [2]. CI in D5W permits a minimum flow rate of 6 mL h Findings in this study expand the published without excessive adsorption loss to tubing surfaces evidence that BDDrFVIII is safe and effective in the [9] and therefore provides greater flexibility. management of patients with haemophilia. Results Although efficacy results were encouraging, addi- from this study are consistent with published expe- tional experience would be required to support any rience using the predecessor BDDrFVIII ReFacto definitive conclusions regarding administration by CI. product. In a prospective, multinational study of 38 A high incidence of thromboembolic disease is previously treated or untreated patients undergoing known to be associated with knee and hip joint 48 major or minor surgical procedures, patients were replacement surgery in non-haemophilic patients treated preoperatively with ReFacto to attain a [12,13]. Despite the high proportion of joint replace- target level of 0.5–1.0 IU mL)1 for major and ment procedures in this study and the absence of 0.2–0.5 IU mL)1 for minor surgery [10]. During pharmacological systemic thrombophrophylaxis, no the peri-operative period, the mean dose per surgical instances of symptomatic thrombosis were observed. procedure was 62 IU kg)1, and a total of 1759 Potential explanations include the use of non-phar- infusions were given over a median period of macological/mechanical measures in a subset of 20 days. Surgical procedures were major in 31 cases. patients (e.g., antiembolic stockings) and a younger Haemostasis was rated excellent or good by the patient population than might usually experience surgeon for 99.6% of infusions given either intra- replacement surgery. An incidence of transfusions in operatively or postoperatively. Blood loss and trans- joint replacement surgery as high as 67% has been fusion requirements were not greater than would be reported in general patient populations [14]. In the expected for patients without haemophilia. current study, 4 of 12 (33%) patients who under-

Haemophilia (2010), 1–9 Ó 2010 Blackwell Publishing Ltd BDDRFVIII FOR SURGICAL HAEMOSTASIS IN HAEMOPHILIA A 9 went joint replacement surgery required transfusions 2 Recht M, Nemes L, Matysiak M et al. Clinical evaluation of in the intra-operative or postoperative period; pro- moroctocog alfa (AF-CC), a new generation of B-domain deleted recombinant factor VIII (BDDrFVIII) for treatment of haemo- viding additional evidence for the clinical efficacy of philia A: demonstration of safety, efficacy, and pharmacokinetic FVIII replacement with BDDrFVIII in the surgical equivalence to full-length recombinant factor VIII. Haemophilia setting. 2009; 15: 869–80. The development of FVIII inhibitors is a serious 3 Batorova A, Martinowitz U. Intermittent injections vs. continuous infusion of factor VIII in haemophilia patients undergoing major complication of treatment with FVIII. Treatment- surgery. Br J Haematol 2000; 110: 715–20. related risk factors for inhibitor development include 4 Batorova A, Martinowitz U. Continuous infusion of coagulation surgery and a period of intensive treatment, which are factors. Haemophilia 2002; 8: 170–7. hypothesized to increase risk by creating an inflam- 5 Dingli D, Gastineau DA, Gilchrist GS, Nichols WL, Wilke JL. Continuous factor VIII infusion therapy in patients with haemo- matory state [15–17]. It has been suggested that philia A undergoing surgical procedures with plasma-derived or treatment using CI may increase this risk [18]. In the recombinant factor VIII concentrates. Haemophilia 2002; 8: current study, one patient treated by BI developed a 629–34. 6 Stachnik JM, Gabay MP. Continuous infusion of coagulation low-titre inhibitor after exposure to a single dose of factor products. Ann Pharmacother 2002; 36: 882–91. study drug preoperatively followed by his usual 7 Martinowitz U, Schulman S, Gitel S, Horozowski H, Heim M, replacement therapy over 3 days; the low-titre inhib- Varon D. Adjusted dose continuous infusion of factor VIII itor was present at final follow-up in this patient. In a in patients with haemophilia. Br J Haematol 1992; 82: 729– 34. second patient treated by BI, a transient false-positive 8 Martinowitz U, Luboshitz J, Bashari D et al. Stability, efficacy, inhibitor was reported at the final study visit. and safety of continuously infused sucrose-formulated In conclusion, the findings of this study provide recombinant factor VIII (rFVIII-FS) during surgery in patients additional evidence that BDDrFVIII is efficacious for with severe haemophilia. Haemophilia 2009; 15: 676–85. 9 Neidhart E, Koval R, Burke E, Warne N. In vitro evaluation of surgical prophylaxis in haemophilia A patients B-domain deleted recombinant factor VIII (ReFacto) stability undergoing major surgery when administered either during simulated continuous infusion administration. Haemo- by intravenous bolus or CI. BDDrFVIII is associated philia 2005; 11: 319–25. with a favourable safety profile and low frequency of 10 Lusher JM, Lee CA, Kessler CM, Bedrossians CL, for the ReFacto Phase III Study Group. The safety and efficacy of B-domain immune response. deleted recombinant actor VIII concentrate in patients with severe haemophilia A. Haemophilia 2003; 9: 38–49. 11 Stieltjes N, Altisent C, Auerswald G et al. Continuous infusion of Acknowledgements B-domain deleted recombinant factor VIII (ReFacto) in patients with haemophilia A undergoing surgery: clinical experience. Research funding was provided by Wyeth Pharma- Haemophilia 2004; 10: 452–8. ceuticals, Collegeville, PA, which was acquired by 12 Geerts WH, Pineo GF, Heit JA et al. Prevention of venous Pfizer Inc in October, 2009. Professional medical thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126 writing assistance was provided by Naomi Pliskow, (3 Suppl.): 338S–400S. MD and funded by Wyeth Pharmaceuticals, 13 Nicolaides AN, Fareed J, Kakkar AK et al. Prevention and treat- which was acquired by Pfizer Inc in October, 2009. ment of venous thromboembolism. InternationalConsensus The authors would like to thank the following Statement (guidelines according to scientific evidence). Int Angiol 2006; 25: 101–61. investigators: Alice Ma, Elaine Eyster, Ingrid Pabin- 14 Rosencher N, Kerkkamp HE, Macheras G et al. Orthopedic ger, Vladimir Zorenko, Erik Berntorp, Mark Smith Surgery Transfusion Hemoglobin European Overview (OSTHEO) and Paul Harper. study: blood management in elective knee and hip arthroplasty in Europe. Transfusion 2003; 43: 459–69. 15 Ghosh K, Shetty S. Immune response to FVIII in hemophilia A: an Disclosures overview of risk factors. Clinic Rev Allerg Immunol 2009; 37: 58– 66. L. Rusen has acted as a speaker for Wyeth Romania 16 Ghosh K, Jijina F, Shetty S, Madkaikar M, Mohanty D. First-time and have received a small fee for this contribution. development of FVIII inhibitor in haemophilia patients during the postoperative period. Haemophilia 2002; 8: 776–80. R. Gruppo has acted as a paid consultant and as a 17 Gouw C, Van Den Berg HM, Le Cessie S, Van Der Bom JG. medical advisory board member to Wyeth Pharma- Treatment characteristics and the risk of inhibitor development: ceuticals. A. C O’Brien, P. Kelly, D. Roth and a multicenter cohort study among previously untreated S. Arkin are employees of Pfizer Inc. patients with severe hemophilia A. J Thromb Haemost, 2007; 5: 1383–90. 18 Eckhardt CL, Menke LA, van Ommen CH et al. Intensive perioperative use of factor VIII and the Arg593 fi Cys mutation are References risk factors for inhibitor development in mild/moderate hemophilia A. J Thromb Haemost 2009; 7: 930–7. 1 Kelley BD, Booth J, Tannatt M et al. Isolation of a peptide ligand for affinity purification of factor VIII using phage display. J Chromatogr A 2004; 1038: 121–30.

Ó 2010 Blackwell Publishing Ltd Haemophilia (2010), 1–9 HIGHLIGHTS OF PRESCRIBING INFORMATION ------DOSAGE FORMS AND STRENGTHS ------These highlights do not include all the information needed to use XYNTHA safely and XYNTHA is available as lyophilized powder in single-use vials containing nominally 250, effectively. See full prescribing information for XYNTHA. 500, 1000, or 2000 IU. (3) XYNTHA® (antihemophilic factor [recombinant]) lyophilized powder ------CONTRAINDICATIONS ------for solution, for intravenous injection Do not use in patients who have manifested life-threatening immediate hypersensitivity Initial U.S. Approval: 2008 reactions, including anaphylaxis, to the product or its components, including hamster proteins. (4) ------RECENT MAJOR CHANGES ------Indications and Usage (1) 8/2020 ------WARNINGS AND PRECAUTIONS ------Dosage and Administration (2.1) 8/2020 • Anaphylaxis and severe hypersensitivity reactions are possible. Patients may develop hypersensitivity to hamster protein, which is present in trace amounts in XYNTHA. ------INDICATIONS AND USAGE ------Should such reactions occur, discontinue treatment with the product and administer • XYNTHA is a recombinant antihemophilic factor indicated in adults and children with appropriate treatment. (5.1) hemophilia A for on-demand treatment and control of bleeding episodes, for perioperative • Development of neutralizing antibodies has been reported in patients using XYNTHA. If management, and for routine prophylaxis to reduce the frequency of bleeding episodes. (1) expected plasma factor VIII activity levels are not attained, or if bleeding is not controlled • XYNTHA is not indicated in patients with von Willebrand’s disease. (1) with an appropriate dose, perform an assay that measures factor VIII inhibitor ------DOSAGE AND ADMINISTRATION ------concentration. (5.2, 5.3, 6.2) For intravenous use after reconstitution only (2) ------ADVERSE REACTIONS ------• The required dose is determined using the following formula: • The most common adverse reactions (≥10%) with XYNTHA in adult and pediatric Required units = body weight (kg) x desired factor VIII rise (IU/dL or % of normal) x previously treated patients (PTPs) were headache, arthralgia, pyrexia, and cough. (6) 0.5 (IU/kg per IU/dL), where IU = International Unit. (2.1) • Across all studies, 4 subjects developed factor VIII inhibitors (2.4%). (6.2) Routine prophylaxis (2.1) • Adults and adolescents (≥12 years): The recommended starting regimen is 30 IU/kg of To report SUSPECTED ADVERSE REACTIONS, contact Wyeth Pharmaceuticals LLC. at XYNTHA administered 3 times weekly. 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch • Children (<12 years): The recommended starting regimen is 25 IU/kg of XYNTHA ------USE IN SPECIFIC POPULATIONS ------administered every other day. More frequent or higher doses may be required in children Pediatrics: Half-lives are shorter, volumes of distribution are larger, and recovery is <12 years of age to account for the higher clearance in this age group. lower after XYNTHA administration in children. Higher or more frequent dosing may be • Adjust the dosing regimen (dose or frequency) based on the patient’s clinical response. needed. (8.4) • Frequency of XYNTHA administration is determined by the type of bleeding episode and the recommendation of the treating physician. (2.1, 2.2) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 8/2020

FULL PRESCRIBING INFORMATION: CONTENTS* 8 USE IN SPECIFIC POPULATIONS 1 INDICATIONS AND USAGE 8.1 Pregnancy 2 DOSAGE AND ADMINISTRATION 8.2 Lactation 2.1 Dose 8.4 Pediatric Use 2.2 Preparation and Reconstitution 8.5 Geriatric Use 2.3 Administration 11 DESCRIPTION 2.4 Use of a XYNTHA Vial Kit and a XYNTHA SOLOFUSE Kit 12 CLINICAL PHARMACOLOGY 3 DOSAGE FORMS AND STRENGTHS 12.1 Mechanism of Action 4 CONTRAINDICATIONS 12.2 Pharmacodynamics 5 WARNINGS AND PRECAUTIONS 12.3 Pharmacokinetics 5.1 Hypersensitivity Reactions 13 NONCLINICAL TOXICOLOGY 5.2 Neutralizing Antibodies 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.3 Monitoring Laboratory Tests 13.2 Animal Toxicology and/or Pharmacology 6 ADVERSE REACTIONS 14 CLINICAL STUDIES 6.1 Clinical Trials Experience 15 REFERENCES 6.2 Immunogenicity 16 HOW SUPPLIED/STORAGE AND HANDLING 6.3 Postmarketing Experience 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed

FULL PRESCRIBING INFORMATION On-demand treatment and Control of Bleeding Episodes 1 INDICATIONS AND USAGE A guide for dosing XYNTHA for on-demand treatment and control of bleeding episodes is provided in Table 1. Maintain the plasma factor VIII activity at or above the levels (in % of XYNTHA, Antihemophilic Factor (Recombinant), is indicated for use in adults and children normal or in IU/dL) outlined in Table 1 for the indicated period. with hemophilia A (congenital factor VIII deficiency) for: • On-demand treatment and control of bleeding episodes Table 1: Dosing for On-demand treatment and Control of Bleeding Episodes • Perioperative management Type of Bleeding Episode Factor VIII Level Frequency of Duration of • Routine prophylaxis to reduce the frequency of bleeding episodes Required (IU/dL or Doses (hours) Therapy XYNTHA does not contain von Willebrand factor, and therefore is not indicated in patients % of normal) with von Willebrand’s disease. Minor 2 DOSAGE AND ADMINISTRATION Early hemarthrosis, minor 20-40 12-24 At least 1 day, For intravenous use after reconstitution only. muscle or oral bleeds. depending 2.1 Dose upon the severity • Dosage and duration of treatment depend on the severity of the factor VIII deficiency, of the bleeding the location and extent of bleeding, and the patient’s clinical condition. Titrate the episode. administered doses to the patient’s clinical response. Moderate • One International Unit (IU) of factor VIII activity corresponds approximately to the Bleeding into muscles. 30-60 12-24 3-4 days or quantity of factor VIII in one milliliter of normal human plasma. The calculation Mild head trauma. until adequate of the required dosage of factor VIII is based upon the empirical finding that, on Bleeding into the oral cavity. local average, 1 IU of factor VIII per kg body weight raises the plasma factor VIII activity hemostasis by approximately 2 IU/dL.2 is achieved. The expected in vivo peak increase in factor VIII level expressed as IU/dL (or % of normal) Major can be estimated using the following formulas: Dosage (International Units) = body weight (kg) x desired factor VIII rise (IU/dL or % of Gastrointestinal bleeding. 60-100 8-24 Until bleeding normal) x 0.5 (IU/kg per IU/dL) Intracranial, intra-abdominal, is resolved. or intrathoracic bleeding. or Fractures. IU/dL (or % of normal) = Total Dose (IU)/body weight (kg) x 2 [IU/dL]/[IU/kg] Perioperative Management A guide for dosing XYNTHA during surgery (perioperative management) is provided in Table 2. Maintain the plasma factor VIII activity level at or above the level (in % of normal or in IU/dL) outlined in Table 2 for the indicated period. Monitor the replacement therapy by means of plasma factor VIII activity. Table 2: Dosing for Perioperative Management Type of Surgery Factor VIII Level Frequency of Duration of Required Doses Therapy 7. Break off the tamper-resistant plastic tip cap from the diluent syringe by snapping (IU/dL or % of (hours) (days) the perforation of the cap. Do not touch the inside of the cap or the syringe tip. normal) The diluent syringe may need to be recapped (if not administering reconstituted Minor XYNTHA immediately), so place the cap on its top on a clean surface in a spot where it would be least likely to become environmentally contaminated. Minor operations, 30-60 12-24 3-4 days or until adequate including tooth local hemostasis is achieved. extraction. For tooth extraction, a single infusion plus oral antifibrinolytic therapy within 1 hour may be sufficient. Major Major operations. 60-100 8-24 Until threat is resolved, or in the case of surgery, until 8. Lift the package away from the adapter and discard the package. adequate local hemostasis and wound healing are achieved. Routine Prophylaxis • Adults and adolescents (≥12 years): The recommended starting regimen is 30 IU/kg of XYNTHA administered 3 times weekly. • Children (<12 years): The recommended starting regimen is 25 IU/kg of XYNTHA administered every other day. More frequent or higher doses may be required in children <12 years of age to account for the higher clearance in this age group [see Clinical Pharmacology (12.3)]. 9. Place the XYNTHA vial, with the adapter attached, on a flat surface. Connect the • Adjust the dosing regimen (dose or frequency) based on the patient’s clinical diluent syringe to the vial adapter by inserting the tip into the adapter opening while response. firmly pushing and turning the syringe clockwise until secured. 2.2 Preparation and Reconstitution Preparation 1. Always wash hands before performing the following procedures. 2. Use aseptic technique during the reconstitution procedures. 3. Use all components in the reconstitution and administration of this product as soon as possible after opening their sterile containers to minimize unnecessary exposure to the atmosphere. Note: 10. Slowly depress the plunger rod to inject all the diluent into the XYNTHA vial. • If the patient uses more than one vial of XYNTHA per infusion, reconstitute each vial according to the following instructions. Remove the diluent syringe, leaving the vial adapter in place. Use a separate 10 milliliter or larger luer lock syringe (not included in this kit) to draw back the reconstituted contents of each vial. Do not detach the diluent syringe or the large luer lock syringe until ready to attach the large luer lock syringe to the next vial adapter. • If the patient uses one vial of XYNTHA with one XYNTHA SOLOFUSE® for the infusion, reconstitute the vial and the syringe according to the instructions for each respective product kit. Use a separate 10 milliliter or larger luer lock syringe (not included 11. Without removing the syringe, gently swirl the contents of the XYNTHA vial until the in this kit) to draw back the reconstituted contents of the vial and the syringe. powder is dissolved. [see Dosage and Administration (2.4)] Note: The final solution should be inspected visually for particulate matter before Reconstitution administration. The solution should be clear to slightly opalescent and colorless. 1. Allow the XYNTHA vial and the prefilled diluent syringe to reach room temperature. If it is not, discard the solution and use a new kit. 2. Remove the plastic flip-top cap from the XYNTHA vial to expose the central portions 12. Invert the XYNTHA vial and slowly draw the solution into the syringe. of the rubber stopper.

3. Wipe the top of the vial with the alcohol swab provided, or use another antiseptic 13. Detach the syringe from the vial adapter by gently pulling and turning the syringe solution, and allow to dry. After cleaning, do not touch the rubber stopper or allow counterclockwise. Discard the empty XYNTHA vial with the adapter attached. it to touch any surface. Note: 4. Peel back the cover from the clear plastic vial adapter package. Do not remove the • If the solution is not used immediately, carefully replace the syringe cap. Do not adapter from the package. touch the syringe tip or the inside of the cap. 5. Place the XYNTHA vial on a flat surface. While holding the adapter package, place • Store the reconstituted solution at room temperature prior to administration, but the vial adapter over the XYNTHA vial and press down firmly on the package until use within 3 hours after reconstitution. the adapter spike penetrates the vial stopper. • XYNTHA, when reconstituted, contains polysorbate 80, which is known to increase the rate of di-(2-ethylhexyl) phthalate (DEHP) extraction from polyvinyl chloride (PVC). This should be considered during the preparation and administration of XYNTHA, including storage time elapsed in a PVC container following reconstitution. The tubing of the infusion set included with this kit does not contain DEHP. 2.3 Administration For intravenous infusion after reconstitution only. 6. Grasp the plunger rod as shown in the diagram. Avoid contact with the shaft of Inspect the final XYNTHA solution visually for particulate matter and discoloration prior to the plunger rod. Attach the threaded end of the plunger rod to the diluent syringe administration, whenever solution and container permit. The solution should be clear to plunger by pushing and turning firmly. slightly opalescent and colorless. If it is not, discard the solution and use a new kit. Use the tubing and the prefilled diluent syringe provided in this kit or a single sterile disposable plastic syringe. Do not administer XYNTHA in the same tubing or container with other medicinal products. 1. Attach the syringe to the luer end of the infusion set tubing provided. 2. Apply a tourniquet and prepare the injection site by wiping the skin well with an alcohol swab provided in the kit.

6. Detach and discard the empty XYNTHA SOLOFUSE from the vial adapter. Note: If the syringe turns without detaching from the vial adapter, grasp the white collar and turn.

3. Remove the protective needle cover and perform venipuncture. Insert the needle on the infusion set tubing into the vein, and remove the tourniquet. Verify proper needle placement. 4. Inject the reconstituted XYNTHA product intravenously over several minutes. The rate of administration should be determined by the patient’s comfort level.

7. Connect a sterile 10 milliliter or larger luer lock syringe to the vial adapter. Inject some air into the vial to make withdrawing the vial contents easier.

5. After infusing XYNTHA, remove and discard the infusion set. The amount of drug product left in the infusion set will not affect treatment. Note: Dispose of all unused solution, the empty vial(s), and other used medical supplies in an appropriate container. 2.4 Use of a XYNTHA Vial Kit with a XYNTHA SOLOFUSE Kit 8. Invert the vial and slowly draw the solution into the large luer lock syringe. These instructions are for the use of only one XYNTHA Vial Kit with one XYNTHA SOLOFUSE Kit. 1. Reconstitute the XYNTHA vial using the instructions described in Preparation and Reconstitution [see Dosage and Administration (2.2)]. 2. Detach the empty diluent syringe from the vial adapter by gently turning and pulling the syringe counterclockwise, leaving the contents in the XYNTHA vial with the vial adapter in place. 9. Detach the syringe from the vial adapter by gently turning and pulling the syringe counterclockwise. Discard the vial with the adapter attached. 10. Attach the infusion set to the large luer lock syringe as directed [see Dosage and Administration (2.3)]. 3 DOSAGE FORMS AND STRENGTHS XYNTHA is available as a white to off-white lyophilized powder in the following nominal dosages: 3. Reconstitute the XYNTHA SOLOFUSE using the instructions included with the • 250 International Units product kit, remembering to remove most, but not all, of the air from the drug product chamber. • 500 International Units • 1000 International Units • 2000 International Units Each XYNTHA vial has the actual recombinant factor VIII (rFVIII) potency in International Units stated on the label. 4 CONTRAINDICATIONS XYNTHA is contraindicated in patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis, to the product or its components, including 4. After removing the protective blue vented cap, connect the XYNTHA SOLOFUSE to hamster proteins. the vial adapter by inserting the tip into the adapter opening while firmly pushing and turning the syringe clockwise until secured. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Allergic-type hypersensitivity reactions, including anaphylaxis, are possible with XYNTHA. Inform patients of the early signs or symptoms of hypersensitivity reactions (including hives [rash with itching], generalized urticaria, chest tightness, wheezing, and hypotension) and anaphylaxis. Discontinue XYNTHA if hypersensitivity symptoms occur and administer appropriate emergency treatment. XYNTHA contains trace amounts of hamster proteins. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins. 5. Slowly depress the plunger rod of the XYNTHA SOLOFUSE until the contents empty into the XYNTHA vial. The plunger rod may move back slightly after release. 5.2 Neutralizing Antibodies Inhibitors have been reported following administration of XYNTHA. Monitor patients for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests. If expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, perform an assay that measures factor VIII inhibitor concentration to determine if a factor VIII inhibitor is present [see Warnings and Precautions (5.3)].4,5,6,7,8,9,10,11,12 5.3 Monitoring Laboratory Tests 8 USE IN SPECIFIC POPULATIONS • Use individual factor VIII values for recovery and, if clinically indicated, other 8.1 Pregnancy pharmacokinetic characteristics to guide dosing and administration. Risk Summary • 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 It is not known whether XYNTHA can cause fetal harm when administered to a pregnant clinically indicated [see Dosage and Administration (2)]. woman or can affect reproduction capacity. Animal reproduction studies have not been conducted with XYNTHA. • 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 There is no information available on the effect of factor VIII replacement therapy on labor not attained, or when bleeding is not controlled with the expected dose of XYNTHA. and delivery. XYNTHA should be used only if clinically indicated. Use Bethesda Units (BU) to titer inhibitors. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. 6 ADVERSE REACTIONS 8.2 Lactation The most common adverse reactions (≥10%) with XYNTHA in adult and pediatric previously treated patients (PTPs) were headache, arthralgia, pyrexia, and cough. Risk Summary 6.1 Clinical Trials Experience There is no information regarding the presence of XYNTHA in human milk, the effect on the breastfed infant, or the effects on milk production. The developmental and health benefits Because clinical trials are conducted under widely varying conditions, adverse reaction of breastfeeding should be considered along with the mother’s clinical need for XYNTHA rates observed in the clinical trials of a drug cannot be directly compared to rates in the and any potential adverse effects on the breastfed child from XYNTHA or from the clinical trials of another drug and may not reflect the rates observed in clinical practice. underlying maternal condition. XYNTHA was evaluated in five completed clinical studies (N=178), comprising four studies with adult and pediatric PTPs. 8.4 Pediatric Use The safety and efficacy of XYNTHA was evaluated in two completed pivotal studies. In the Safety and efficacy with XYNTHA were evaluated in clinical studies in 68 pediatric subjects ≤ first study (n=94), safety and efficacy were examined in PTPs with severe to moderately <17 years of age (18 subjects aged 12 to <17 years, 50 subjects aged 12 years). There severe hemophilia A (factor VIII activity in plasma [FVIII:C] ≤2%) who received XYNTHA were no apparent differences in the efficacy and safety in pediatric subjects as compared for routine prophylaxis and on-demand treatment. Ninety-four subjects received at least to adults [see Adverse Reactions (6.1) and Clinical Studies (14)]. one dose of XYNTHA, resulting in a total of 6,775 infusions [see Clinical Studies (14)]. In comparison to the pharmacokinetic parameters reported in adults, children have shorter The second study (n=30) examined the use of XYNTHA for surgical prophylaxis in PTPs half-lives, larger volumes of distribution and lower recovery of factor VIII after XYNTHA with severe to moderately severe hemophilia A (FVIII:C ≤2%) who required elective major administration. The clearance (based on per kg body weight) is approximately 40% higher surgery and were expected to receive XYNTHA replacement therapy for at least 6 days in children. Higher or more frequent doses may be required to account for the observed post-surgery. All subjects received at least one dose of XYNTHA, resulting in 1,161 infusions. differences in pharmacokinetic parameters [see Clinical Pharmacology (12.3)]. One subject received XYNTHA for a pre-surgery pharmacokinetic assessment only and did 8.5 Geriatric Use not undergo surgery [see Clinical Studies (14)]. Clinical studies of XYNTHA did not include sufficient numbers of subjects aged 65 and Across all studies, safety was evaluated in 72 pediatric PTPs <17 years of age (46 subjects over to determine whether they respond differently from younger subjects. Other reported <6 years of age (4 subjects were 0 to <2 years of age), 4 subjects 6 to <12 years of age, clinical experience has not identified differences in responses between the elderly and and 22 adolescents, 12 to <17 years of age). A total of 13,109 infusions of XYNTHA were younger patients. In general, dose selection for an elderly patient should be cautious, administered with a median dose per infusion of 28 IU/kg (min-max: 6-108 IU/kg). usually starting at the low end of the dosing range, reflecting the greater frequency Across all studies, the most common adverse reactions (≥10%) with XYNTHA in adult and of decreased hepatic, renal, or cardiac function and of concomitant disease or other pediatric PTPs were headache (24%), arthralgia (23%), pyrexia (23%), and cough (12%). drug therapy. Other adverse reactions reported in ≥5% of subjects were: diarrhea (8%), vomiting (8%), 11 DESCRIPTION and asthenia (6%). The active ingredient in XYNTHA, Antihemophilic Factor (Recombinant), is a recombinant 6.2 Immunogenicity antihemophilic factor (rAHF), also called coagulation factor VIII, which is produced by There is a potential for immunogenicity with therapeutic proteins. The development of recombinant DNA technology. It is secreted by a genetically engineered Chinese hamster factor VIII inhibitors with XYNTHA was evaluated in 167 adult and pediatric PTPs with at ovary (CHO) cell line. The cell line is grown in a chemically defined cell culture medium least 50 exposure days (EDs). Laboratory-based assessments for FVIII inhibitor (partial that contains recombinant insulin, but does not contain any materials derived from human Nijmegen modification of the Bethesda inhibitor assay) were conducted in the clinical or animal sources. studies. The criterion for a positive FVIII result test result was ≥0.6 BU/mL. Across all The rAHF in XYNTHA is a purified glycoprotein, with an approximate molecular mass studies, 4 subjects developed factor VIII inhibitors (2.4%). of 170 kDa consisting of 1,438 amino acids, which does not contain the B-domain.13 The completed clinical studies for XYNTHA examined 178 subjects (30 for surgical The amino acid sequence of the rAHF is comparable to the 90 + 80 kDa form of human prophylaxis) who had previously been treated with factor VIII (PTPs). In the first safety coagulation factor VIII. and efficacy study, factor VIII inhibitors were detected in two of 89 subjects (2.2%) who The purification process uses a series of chromatography steps, one of which is based completed ≥50 EDs. In a Bayesian statistical analysis, results from this study were used on affinity chromatography using a patented synthetic peptide affinity ligand.14 The to update PTP results from a prior supporting study using XYNTHA manufactured at the process also includes a solvent-detergent viral inactivation step and a virus-retaining initial facility (with one de novo and two recurrent inhibitors observed in 110 subjects) and nanofiltration step. the experience with predecessor product (with one inhibitor observed in 113 subjects). The potency expressed in International Units (IU) is determined using the chromogenic The Bayesian analysis indicated that the population inhibitor rate for XYNTHA, an estimate assay of the European Pharmacopoeia. The Wyeth manufacturing reference standard for of the 95% upper limit of the true inhibitor rate, was 4.17%. potency has been calibrated against the World Health Organization (WHO) International None of the PTPs developed anti-CHO (Chinese hamster ovary) or anti-TN8.2 antibodies. Standard for factor VIII activity using the one-stage clotting assay. The specific activity of One PTP developed anti-FVIII antibodies; but, this subject did not develop an inhibitor. XYNTHA is 5,500 to 9,900 IU per milligram of protein. In the surgery study, one low titer persistent inhibitor and one transient false-positive XYNTHA is formulated as a sterile, nonpyrogenic, no preservative, lyophilized powder inhibitor were reported. In this study, one surgical subject developed anti-CHO cell preparation for intravenous injection. Each single-use vial contains nominally 250, 500, antibodies with no associated allergic reaction. One subject developed anti-FVIII antibodies; 1000, or 2000 IU of XYNTHA. Upon reconstitution, the product is a clear to slightly but, this subject did not develop an inhibitor. opalescent, colorless solution that contains sodium chloride, sucrose, L-histidine, calcium Across all studies, immunogenicity was evaluated in 64 pediatric PTPs <17 years chloride, and polysorbate 80. of age with at least 50 EDs (43 children <6 years of age, 4 subjects 6 to <12 years of age, 12 CLINICAL PHARMACOLOGY and 17 adolescents, 12 to <17 years of age). Of these, 2 pediatric subjects developed an inhibitor. 12.1 Mechanism of Action The detection of antibody formation is highly dependent on the sensitivity and specificity of XYNTHA temporarily replaces the missing clotting factor VIII that is needed for effective the assay. Additionally, the observed incidence of antibody, including neutralizing antibody, hemostasis. positivity in an assay may be influenced by several factors, including assay methodology, 12.2 Pharmacodynamics sample handling, timing of sample collection, concomitant medications, and underlying The activated partial thromboplastin time (aPTT) is prolonged in patients with hemophilia. disease. For these reasons, comparisons of the incidence of antibodies to XYNTHA with Determination of aPTT is a conventional in vitro assay for biological activity of factor VIII. the incidence of antibodies to other products may be misleading. Treatment with XYNTHA normalizes the aPTT over the effective dosing period. 6.3 Postmarketing Experience 12.3 Pharmacokinetics Because these reactions are reported voluntarily from a population of uncertain size, it is The pharmacokinetic parameters of XYNTHA in 30 PTPs 12 to 60 years old, who received not always possible to reliably estimate their frequency or establish a causal relationship a single infusion of 50 IU/kg XYNTHA are summarized in Table 3. to drug exposure. In addition, 25 of the same subjects later received a single infusion of 50 IU/kg of XYNTHA The following postmarketing adverse reaction has been reported for XYNTHA: for a 6-month follow-up pharmacokinetic study. The parameters were comparable between Inadequate therapeutic response baseline and 6 months, indicating no time-dependent changes in the pharmacokinetics of XYNTHA. In a separate study, 8 of 30 subjects at least 12 years old with hemophilia A undergoing Of these 94 subjects, 30 evaluable subjects participated in a randomized crossover elective major surgery received a single 50 IU/kg infusion of XYNTHA. The pharmacokinetic pharmacokinetics substudy. Twenty-five (25/30) of these subjects with FVIII:C≤ 1% parameters in these subjects are also summarized in Table 3. completed both the first (PK1) and the second (PK2) pharmacokinetic assessments see[ Clinical Pharmacology (12.3)].16 Table 3: Mean ± SD XYNTHA Pharmacokinetic Parameters in Previously Treated Fifty-three subjects (53/94) received XYNTHA on-demand treatment for a total of Patients with Hemophilia A after Single 50 IU/kg Dose 187 bleeding episodes. Seven of these bleeding episodes occurred in subjects prior to Parameter Initial Visit Month 6 Pre-surgery switching to a prophylaxis treatment regimen. One hundred ten of 180 bleeds (110/180 or (n = 30) (n = 25) (n=8) 61%) occurred ≤48 hours after the last dose and 39% (70/180 bleeds) occurred >48 hours

Cmax (IU/mL) 1.08 ± 0.22 1.24 ± 0.42 1.08 ± 0.24 after the last dose. The majority of bleeds reported to occur ≤48 hours after the last AUC (IU•hr/mL) 13.5 ± 5.6 15.0 ± 7.5 16.0 ± 5.2 prophylaxis dose were traumatic (64/110 bleeds or 58%). Forty-two bleeds (42/70 or ∞ 60%) reported to occur >48 hours after the last prophylaxis dose were spontaneous. The t1/2 (hr) 11.2 ± 5.0 11.8 ± 6.2* 16.7 ± 5.4 on-demand treatment dosing regimen was determined by the investigator. The median CL (mL/hr/kg) 4.51 ± 2.23 4.04 ± 1.87 3.48 ± 1.25 dose for on-demand treatment was 31 IU/kg (min-max: 6-74 IU/kg) and the median exposure per subject was 3 days (min-max: 1-26). Vss (mL/kg) 66.1 ± 33.0 67.4 ± 32.6 69.0 ± 20.1 The majority of bleeding episodes (173/187 or 93%) resolved with 1 or 2 infusions Recovery 2.15 ± 0.44 2.47 ± 0.84 2.17 ± 0.47 (Table 5). One hundred thirty-two of 187 bleeding episodes (132/187 or 71%) treated with (IU/dL per IU/kg) XYNTHA were rated excellent or good in their response to initial treatment, 45 (24%) were Abbreviations: AUC∞ = area under the plasma concentration-time curve from zero to infinity; rated moderate. Five (3%) were rated no response, and 5 (3%) were not rated. Cmax = peak concentration; t1/2 = plasma elimination half-life; CL = clearance; n = number of subjects; SD = standard deviation; Vss = volume of distribution at steady-state. Table 5: Summary of Response to Infusions to Treat New Bleeding Episode by *One subject was excluded from the calculation due to lack of a well-defined terminal phase. Number of Infusions Needed for Resolution Number of Infusions (%) Table 4 shows the pharmacokinetic parameters of nine children; four aged 14 or 15 years Response 1 2 3 4 >4 Total of age, who are also included in the summary for the adults above, along with five children to 1st Infusion Number aged 3.7-5.8 years after single 50 IU/kg doses of XYNTHA. Compared to adults, the half-life of of XYNTHA is shorter in children and the clearance (based on per kg body weight) is Bleeds approximately 40% higher in children. Excellenta 42 (95.5) 2 (4.5) 0 (0.0) 0 (0.0) 0 (0.0) 44 16 Table 4: Mean ± SD XYNTHA Pharmacokinetic Parameters in Previously Treated Goodb 69 (78.4) 3 (3.4) 0 (0.0) 0 (0.0) 88 Pediatric Patients with Hemophilia A after Single 50 IU/kg Dose (18.2) 16 Parameter Young Children (n=5) Adolescents (n=4) Moderatec 24 (53.3) 2 (4.4) 0 (0.0) 3 (6.7) 45 (35.6) Age (min - max, yr)) 3.7 - 5.8 14 - 15 No Responsed 0 (0.0) 0 (0.0) 2 (40.0) 2 (40.0) 1 (20.0) 5 C (IU/mL) 0.78 ± 0.34 0.97 ± 0.21 max Not Assessed 4 (80.0) 0 (0.0) 0 (0.0) 1 (20.0) 0 (0.0) 5e AUC∞ (IU∙hr/mL) 12.2 ± 6.50 8.5 ± 4.0 34 t (hr) 8.3 ± 2.7 6.9 ± 2.4 Total 139 (74.3) 7 (3.7) 3 (1.6) 4 (2.1) 187 1/2 (18.2) CL (mL/hr/kg) 6.29 ± 4.87 6.62 ± 2.16 a Excellent: Definite pain relief and/or improvement in signs of bleeding starting within 8 hours after Vss (mL/kg) 66.9 ± 55.6 67.1 ± 13.6 an infusion, with no additional infusion administered. b Good: Definite pain relief and/or improvement in signs of bleeding starting within 8 hours after an Recovery 1.52 ± 0.69 1.95 ± 0.41 infusion, with at least one additional infusion administered for complete resolution of the bleeding (IU/dL per IU/kg) episode. c Moderate: Probable or slight improvement starting after 8 hours following the infusion, with at Abbreviations: AUC∞ = area under the plasma concentration-time curve from zero to infinity; least one additional infusion administered for complete resolution of the bleeding episode. Cmax = peak concentration; t1/2 = plasma elimination half-life; CL = clearance; n = number of subjects; d No Response: No improvement at all between infusions or during the 24 hour interval following an SD = standard deviation; Vss = volume of distribution at steady-state. infusion, or condition worsens. e Includes one infusion with commercial FVIII that occurred before routine prophylaxis began. 13 NONCLINICAL TOXICOLOGY Of the 94 subjects described above, in the first completed open-label safety and efficacy 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility study of XYNTHA, 18 were adolescent subjects 12 to <17 years of age with severe to No studies have been conducted with XYNTHA to assess its mutagenic or carcinogenic moderately severe hemophilia A (FVIII:C ≤2%). Ten (10) of these adolescent subjects, potential. XYNTHA has been shown to be comparable to the predecessor product with received XYNTHA for the on-demand treatment of 66 bleeding episodes, with the majority respect to its biochemical and physicochemical properties, as well as its nonclinical of the bleeding episodes (63/66 or 95%) resolving with 1 or 2 infusions. The response to in vivo pharmacology and toxicology. By inference, predecessor product and XYNTHA infusion was rated on a pre-specified 4 point hemostatic efficacy scale. Thirty-eight (38) would be expected to have equivalent mutagenic and carcinogenic potential. The of 66 bleeding episodes (58%) were rated excellent or good in their response to initial predecessor product has been shown to be nongenotoxic in the mouse micronucleus treatment, 24 (36%) were rated as moderate, and 4 (6%) were not rated. The median dose assay. No studies have been conducted in animals to assess impairment of fertility or per on demand infusion was 47 IU/kg (min-max: 24-74). fetal development. On-demand treatment in children 13.2 Animal Toxicology and/or Pharmacology Additional data for 50 subjects are available from a second safety and efficacy study of Preclinical studies evaluating XYNTHA in hemophilia A dogs without inhibitors XYNTHA in children (≤12 years of age) with severe to moderately severe hemophilia A demonstrated safe and effective restoration of hemostasis. XYNTHA demonstrated a (FVIII:C ≤2%). Of the 50 subjects, 38 subjects received XYNTHA for on-demand and toxicological profile that was similar to the toxicological profile observed with the follow-up treatment of 562 bleeding episodes with the majority of the bleeding episodes predecessor product. Toxicity associated with XYNTHA was primarily associated with (518/562 or 92%) resolving with 1 or 2 infusions. Of 559 bleeding episodes treated with anti-FVIII neutralizing antibody generation first detectable at 15 days of repeat dosing in XYNTHA with response assessments to the first infusion, 526 (94%) were rated excellent high (approximately 735 IU/kg/day) level-dosed, non-human primates. or good in their response to initial treatment and 27 (5%) were rated as moderate. The median dose per on-demand infusion was 28 IU/kg (min-max: 10-92). 14 CLINICAL STUDIES Three completed multicenter, open-label studies support the analysis of safety and efficacy Perioperative Management of XYNTHA in on-demand treatment and control of bleeding episodes and perioperative In a study (n=30) for surgical prophylaxis in subjects with hemophilia A, XYNTHA was management, and routine prophylaxis in PTPs with hemophilia A. These completed clinical administered to 25 efficacy-evaluable PTPs undergoing major surgical procedures (11 total studies for XYNTHA examined 174 PTP subjects, 94 from the first study, and 50 from knee replacements, 1 hip replacement, 5 synovectomies, 1 left ulnar nerve transposition a second study, for on-demand treatment and routine prophylaxis and 30 from a third release, 1 ventral hernia repair/scar revision, 1 knee arthroscopy, 1 revision and study for surgical prophylaxis. Subjects with severe to moderately severe hemophilia A debridement of the knee after a total knee replacement, 1 hip arthroplasty revision, 1 stapes (FVIII:C ≤2%) and no history of FVIII inhibitors were eligible for the trials. replacement, 1 ankle arthrodesis, and 1 pseudotumor excision).17 On-demand Treatment and Control of Bleeding Episodes The results of the hemostatic efficacy ratings for these subjects are presented in Table 6. Investigator’s ratings of efficacy at the end of surgery and at the end of the initial On-demand treatment in adolescents and adults postoperative period were excellent or good for all assessments. Intraoperative blood loss Ninety-four (94) subjects, 12 years of age and older received XYNTHA in a routine was reported as “normal” or “absent” for all subjects. Thirteen of the subjects (13/25 or prophylaxis treatment regimen with on-demand treatment administered as clinically 52%) had blood loss in the postoperative period. The postoperative blood loss was rated indicated. All 94 subjects were treated with at least one dose and all are included in the as “normal” for ten of these cases while three cases were rated “abnormal” (1 due to intent-to-treat (ITT) population. Eighty-nine (89) subjects accrued ≥50 EDs. Median age for hemorrhage following surgical trauma to the epigastric artery, 1 due to an 800 mL blood the 94 treated subjects was 24 years (mean 28 and min-max: 12-60 years). loss after hip replacement surgery, and 1 after an elbow synovectomy where the blood loss could not be measured by the investigator). Table 6: Summary of Hemostatic Efficacy 7. Kessler C, Sachse K. Factor VIII:C inhibitor associated with monoclonal-antibody purified FVIII concentrate.Lancet . 1990;335:1403. Time of Hemostatic Efficacy Excellenta Goodb Number of subjects Assessment 8. Schwartz RS, Abildgaard CF, Aledort LM, et al. Human recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia A. N Engl J Med. End of surgery 18 (72%) 7 (28%) 25 1990;323:1800-1805. End of initial postoperative periodc 23 (92%) 2 (8%) 25 9. White GC II, Courter S, Bray GL, et al. A multicenter study of recombinant factor a Excellent: Achieved hemostasis comparable to that expected after similar surgery in a patient VIII (Recombinate™) in previously treated patients with hemophilia A. Thromb without hemophilia. Haemost. 1997;77(4):660-667. b Good: Prolonged time to hemostasis, with somewhat increased bleeding compared with that expected after similar surgery in a patient without hemophilia. 10. Gruppo R, Chen H, Schroth P, et al. Safety and immunogenicity of recombinant c End of initial postoperative period is date of discharge or postoperative Day 6, whichever factor VIII (Recombinate™) in previously untreated patients: A 7.3 year update. occurs later. Haemophilia. 1998;4:228 (Abstract No. 291, XXIII Congress of the WFH, The Hague). Routine Prophylaxis 11. Scharrer I, Bray GL, Neutzling O. Incidence of inhibitors in haemophilia A One hundred and two (102) subjects (94 subjects ≥12 years of age and 8 subjects patients - a review of recent studies of recombinant and plasma-derived factor VIII <12 years of age) received XYNTHA for routine prophylaxis, for comparison of annualized concentrates. Haemophilia. 1999;5:145-154. bleeding rate (ABR) to on-demand treatment alone as a part of 2 completed studies. 12. Abshire TC, Brackmann HH, Scharrer I, et al. Sucrose formulated recombinant XYNTHA was administered for routine prophylaxis at a dose of 25 ± 5 IU/kg every other human antihemophilic Factor VIII is safe and efficacious for treatment of hemophilia A day (in subjects <12 years of age) or 30 ± 5 IU/kg administered 3 times weekly (in subjects in home therapy: Results of a multicenter, international, clinical investigation. 12 years of age or older), with provisions for dose escalation based on pre-specified Thromb Haemost. 2000;83(6):811-816. criteria (over a 4-week period, 2 spontaneous bleeds into a major joint and/or target joint, or 3 or more spontaneous bleeding episodes in any location). Among these 102 subjects, 13. Sandberg H, Almstedt A, Brandt J, Castro VM, Gray E, Holmquist L, et al. Structural 7 dose escalations were prescribed for 6 subjects. and Functional Characterization of B-Domain Deleted Recombinant Factor VIII. Sem In subjects ≥12 years, 42 subjects (42/94 or 45%) reported no bleeding while on routine Hematol. 2001;38 (Suppl. 4):4-12. prophylaxis. The mean±SD total ABR during routine prophylaxis was 4.0±6.64 with median 14. Kelley BD, Tannatt M, Magnusson R, Hagelberg S. Development and Validation of (min-max) of 1.9 (0.0-44.2). The mean ABR for subjects during routine prophylaxis was an Affinity Chromatography Step Using a Peptide Ligand for cGMP Production of 88% lower than the mean ABR for subjects during on-demand treatment (Table 7). Factor VIII. Biotechnol Bioeng. 2004;87(3):400-412. In subjects <12 years, 4 subjects (4/8 or 50%) reported no bleeding while on routine 15. Mann KG and Ziedens KB. Overview of Hemostasis. In: Lee CA, Berntorp EE and prophylaxis. The mean±SD total ABR during routine prophylaxis was 1.5±2.2 with median Hoots WK, eds. Textbook of Hemophilia. USA, Blackwell Publishing; 2005:1-4. (min-max) of 0.6 (0.0-6.2). The mean ABR for subjects during routine prophylaxis was 16. Recht M, Nemes L, Matysiak M et al. Clinical Evaluation of Moroctocog Alfa 97% lower than the mean ABR for subjects during on-demand treatment (Table 7). (AF-CC), a New Generation of B-Domain Deleted Recombinant Factor VIII (BDDrFVIII) for Treatment of Haemophilia A: Demonstration of Safety, Efficacy and Table 7: Summary of Annualized Bleeding Rate During Routine Pharmacokinetic Equivalence to Full-length Recombinant Factor VIII. Haemophilia Prophylaxis Treatment with XYNTHA 2009; 1-12. Age Number % Statistic Treated Treated Treated 17. Windyga J, Rusen L, Gruppo R, et al. BDDrFVIII (Moroctocog alfa [AF-CC]) Category of Reduction Total Spontaneous Traumatic for surgical haemostasis in patients with haemophilia A: results of a pivotal study. (years) Subjects from OD Routine Routine Routine Haemophilia. 2010 Sep 1;16(5):731-9. Prophylaxis Prophylaxis Prophylaxis 16 HOW SUPPLIED/STORAGE AND HANDLING ABR ABR ABR How Supplied 0 to <12 8 97% Mean±SD 1.5±2.20 0.6±1.31 0.9±1.30 Each XYNTHA Vial Kit contains: one prefilled diluent syringe containing 4 mL 0.9% Median 0.6 0.0 0.0 Sodium Chloride with plunger rod for assembly, one vial adapter, one sterile infusion (Min-Max) (0.0-6.2) (0.0-3.7) (0.0-3.2) set, two alcohol swabs, one bandage, one gauze pad, and one package insert. The drug product, diluents for injection and the rest of components included within the XYNTHA ≥12 94a 88% Mean±SD 4.0±6.64 2.0±4.25 2.0±4.10 250, 500, 1000, or 2000 International Units kit are free from natural rubber and natural rubber latex. Median 1.9 0.0 0.0 (Min-Max) (0.0-44.2) (0.0-32.1) (0.0-23.3) XYNTHA is supplied in kits that include single-use vials containing nominally 250, 500, 1000, or 2000 International Units lyophilized powder per vial: 12 to <17 18b 84% Mean±SD 7.3±11.37 3.3±7.73 4.0±5.94 XYNTHA Vial Kit Median 3.0 0.0 1.9 (Min-Max) (0.0-44.2) (0.0-32.1) (0.0-19.6) Nominal Strength Fill Size Color Indicator Vial Kit NDC # ≥17 76 89% Mean±SD 3.2±4.70 1.6±2.88 1.6±3.42 250 International Units Yellow 58394-012-01 Median 1.9 0.0 0.0 500 International Units Blue 58394-013-01 (Min-Max) (0.0-23.3) (0.0-13.7) (0.0-23.3) 1000 International Units Green 58394-014-01 OD = on demand; ABR = annualized bleeding rate; SD = standard deviation, Min = minimum, Max = maximum. 2000 International Units Red 58394-015-01 aThe treated total ABR mean±SD during prophylaxis for the 93 subjects aged ≥12 years (outlier removed), was 3.6±5.18 with median (min-max) of 1.9 (0.0-23.3). The spontaneous treated ABR mean±SD was 1.6±2.87 with median (min-max) of 0.0 (0.0-13.7). The traumatic ABR mean±SD was 1.9±3.99 with median (min-max) of 0.0 (0.0-23.3). Actual factor VIII activity in International Units is stated on the label of each XYNTHA vial. bThe treated total ABR mean±SD during prophylaxis for the 17 adolescents (outlier removed), was 5.2±6.90 with median Storage and Handling (min-max) of 2.0 (0.0-21.4). The spontaneous ABR mean±SD was 1.6±2.94 with median (min-max) of 0.0 (0.0-11.6). The traumatic ABR mean±SD was 3.5±5.77 with median (min-max) of 1.9 (0.0-19.6). • Store XYNTHA under refrigeration at a temperature of 2° to 8°C (36° to 46°F) for up to 36 months from the date of manufacture until the expiration date stated on 15 REFERENCES the label. 1. Nilsson IM, Berntorp EE and Freiburghaus C. Treatment of patients with factor VIII • Within the expiration date, XYNTHA also may be stored at room temperature not to and IX inhibitors. Thromb Haemost. 1993;70(1):56-59. exceed 25°C (77°F) for up to 3 months. 2. Hoyer LW. Hemophilia A. N Engl J Med. 1994;330:38-47. • After room temperature storage, XYNTHA can be returned to the refrigerator until the expiration date. Do not store XYNTHA at room temperature and return it to the 3. Juhlin F. Stability and Compatibility of Reconstituted Recombinant Factor VIII SQ, refrigerator more than once. 250 IU/ml, in a System for Continuous Infusion. Pharmacia Document 9610224, 1996. • Clearly record the starting date at room temperature storage in the space provided on the outer carton. At the end of the 3-month period, immediately use, discard, or 4. Ehrenforth S, Kreuz W, Scharrer I, et al. Incidence of development of factor VIII and return the product to refrigerated storage. The diluent syringe may be stored at 2° factor IX inhibitors in hemophiliacs. Lancet. 1992;339:594-598. to 25°C (36° to 77°F). 5. Lusher J, Arkin S, Abildgaard CF, Schwartz RS, the Kogenate PUP Study Group. • Do not use XYNTHA after the expiration date. Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. N Engl J Med. 1993;328:453-459. • Do not freeze. (Freezing may damage the prefilled diluent syringe.) 6. Bray GL, Gomperts ED, Courter S, et al. A multicenter study of recombinant factor • During storage, avoid prolonged exposure of XYNTHA vial to light. VIII (Recombinate): safety, efficacy, and inhibitor risk in previously untreated • Store the reconstituted solution at room temperature prior to administration. patients with hemophilia A. Blood. 1994;83(9):2428-2435. Administer XYNTHA within 3 hours after reconstitution. 17 PATIENT COUNSELING INFORMATION FDA-Approved Patient Labeling Advise patients to: Patient Information • read the FDA-approved patient labeling (Patient Information and Instructions for Use). • report any adverse reactions or problems that concern them when taking XYNTHA XYNTHA® /ZIN-tha/ to their healthcare provider. [Antihemophilic Factor (Recombinant)] • discontinue use of the product, call their healthcare provider, and go to the emergency department if any allergic-type hypersensitivity reactions occur. Inform Please read this patient information carefully before using XYNTHA and patients of the early signs of hypersensitivity reactions (including hives [rash with each time you get a refill. There may be new information. This leaflet itching]), generalized urticaria, tightness of the chest, wheezing, hypotension) and does not take the place of talking with your healthcare provider about anaphylaxis. your medical problems or your treatment. • contact their healthcare provider if they experience a lack of a clinical response to factor VIII replacement therapy, as this may be a manifestation of an inhibitor. What is XYNTHA? • notify their healthcare provider if they become pregnant or intend to become pregnant during therapy, or if they are breastfeeding. XYNTHA is an injectable medicine that is used to help control and reduce bleeding in people with hemophilia A. Hemophilia A is also called classic hemophilia. Your healthcare provider may give you XYNTHA when you have surgery. XYNTHA is not used to treat von Willebrand’s disease. What should I tell my healthcare provider before using XYNTHA? Tell your healthcare provider about all of your medical conditions, including if you: • have any allergies, including allergies to hamsters. • are pregnant or planning to become pregnant. It is not known if XYNTHA may harm your unborn baby. • are breastfeeding. It is not known if XYNTHA passes into your milk and if it can harm your baby. Tell your healthcare provider about all of the medicines you take, including all prescription and non-prescription medicines, such as over-the-counter medicines, supplements, or herbal remedies. How should I infuse XYNTHA? Step-by-step instructions for infusing with XYNTHA are provided at the end of this leaflet. The steps listed below are general guidelines for using XYNTHA. Always follow any specific instructions from your healthcare provider. If you are unsure of the procedures, please call your healthcare provider before using. Call your healthcare provider right away if bleeding is not controlled after using XYNTHA. Call your healthcare provider right away if you take more than the dose you should take. Talk to your healthcare provider before traveling. Plan to bring enough XYNTHA for your treatment during this time. What are the possible side effects of XYNTHA? Call your healthcare provider or go to the emergency department right away if you have any of the following symptoms because these may be signs of a serious allergic reaction: • wheezing • difficulty breathing • chest tightness • turning blue (look at lips and gums) • fast heartbeat • swelling of the face • faintness • rash • hives Common side effects of XYNTHA are • headache • joint pain • fever • cough 4. For additional instructions on the use of a XYNTHA Vial Kit and a • vomiting XYNTHA SOLOFUSE kit, see detailed information provided after the INFUSION OF XYNTHA section. • diarrhea • weakness Reconstitution Note: If you use more than one vial of XYNTHA for each infusion, Your body can make antibodies against XYNTHA (called “inhibitors”) reconstitute each vial according to steps 1 through 11. that may stop XYNTHA from working properly. Your healthcare provider may need to take blood tests from time to time to monitor for inhibitors. 1. Let the XYNTHA vial and the prefilled diluent syringe reach room temperature. Talk to your healthcare provider about any side effect that bothers 2. Remove the plastic flip-top cap from the XYNTHA vial to show you or that does not go away. You may report side effects to FDA at the center part of the rubber stopper. 1-800-FDA-1088. How should I store XYNTHA? Store XYNTHA in the refrigerator at 36° to 46°F (2° to 8°C). Store the diluent syringe at 36° to 77°F (2° to 25°C). Do not freeze. Protect from light. 3. Wipe the top of the vial with the alcohol swab provided, or use XYNTHA can last at room temperature (below 77°F) for up to 3 months. another antiseptic solution, and allow to dry. After cleaning, do If you store XYNTHA at room temperature, carefully write down the date not touch the rubber stopper with your hand or allow it to touch you put XYNTHA at room temperature, so you will know when to either any surface. put it back in the refrigerator, use it immediately, or throw it away. There 4. Peel back the cover from the clear plastic vial adapter package. is a space on the carton for you to write the date. Do not remove the adapter from the package. If stored at room temperature, XYNTHA can be returned one time to the 5. Place the XYNTHA vial on a flat surface. While holding the adapter refrigerator until the expiration date. Do not store at room temperature in the package, place the vial adapter over the XYNTHA vial. Press and return it to the refrigerator more than once. Throw away any unused down firmly on the package until the adapter snaps into place on XYNTHA after the expiration date. top of the vial, with the adapter spike going into the vial stopper. Infuse XYNTHA within 3 hours of reconstitution. You can keep the reconstituted solution at room temperature before infusion for up to 3 hours. If you have not used it in 3 hours, throw it away. Do not use reconstituted XYNTHA if it is not clear to slightly opalescent and colorless. Dispose of all materials, whether reconstituted or not, in an appropriate medical waste container. 6. Grasp the plunger rod as shown in the picture below. Do not touch the shaft of the plunger rod. Attach the threaded end of What else should I know about XYNTHA? the plunger rod to the diluent syringe plunger by pushing and Medicines are sometimes prescribed for purposes other than those listed turning firmly. here. Talk to your healthcare provider if you have any concerns. You can ask your healthcare provider for information about XYNTHA that was written for healthcare professionals. Do not share XYNTHA with other people, even if they have the same symptoms that you have.

Instructions for Use 7. Break off the tamper-resistant, plastic tip cap from the diluent ® XYNTHA /ZIN-tha/ syringe by snapping the perforation of the cap. Do not touch the [Antihemophilic Factor (Recombinant)] inside of the cap or the syringe tip. The diluent syringe may need XYNTHA is supplied as a lyophilized powder. Before you can infuse it to be recapped (if reconstituted XYNTHA is not used immediately), (intravenous injection), you must reconstitute the powder by mixing it so place the cap on its top on a clean surface in a spot where it with the liquid diluent supplied. The liquid diluent is 0.9% sodium chloride. will stay clean. Reconstitute and infuse XYNTHA using the infusion set, diluent, syringe, and adapter provided in this kit. Please follow the directions below for the proper use of this product. PREPARATION AND RECONSTITUTION OF XYNTHA Preparation 1. Always wash your hands before doing the following steps. 2. Keep everything clean and germ-free while you are reconstituting XYNTHA. 3. Once the vials are open, finish reconstituting XYNTHA as soon as possible. This will help to keep them germ-free. 8. Lift the package cover away from the adapter and throw the INFUSION OF XYNTHA package away. Your healthcare provider will teach you how to infuse XYNTHA yourself. Once you learn how to do this, you can follow the instructions in this insert. Before XYNTHA can be infused, you must reconstitute it as instructed above in the PREPARATION AND RECONSTITUTION OF XYNTHA section. After reconstitution, be sure to look carefully at the XYNTHA solution. The solution should be clear to slightly opalescent and colorless. If it is 9. Place the XYNTHA vial on a flat surface. Connect the diluent not, throw away the solution and use a new kit. syringe to the vial adapter by inserting the tip of the syringe into the adapter opening while firmly pushing and turning the syringe Use the infusion set included in the kit to infuse XYNTHA. Do not infuse clockwise until the connection is secured. XYNTHA in the same tubing or container with other medicines. 1. Attach the syringe to the luer end of the provided infusion set tubing. 2. Apply a tourniquet and prepare the injection site by wiping the skin well with an alcohol swab provided in the kit.

10. Slowly push the plunger rod to inject all the diluent into the XYNTHA vial.

3. Remove the protective needle cover and insert the butterfly needle of the infusion set tubing into your vein as instructed by your healthcare provider. Remove the tourniquet. Verify proper needle placement. 11. With the syringe still connected to the adapter, gently swirl the 4. Infuse the reconstituted XYNTHA product over several minutes. contents of the vial until the powder is dissolved. Your comfort level should determine the rate of infusion. Look carefully at the final solution. The solution should be clear to slightly opalescent and colorless. If it is not, throw away the solution and use a new kit. 12. Make sure the syringe plunger rod is still fully pressed down, then turn over the XYNTHA vial. Slowly pull the solution into the syringe. Turn the syringe upward again and remove any air bubbles by gently tapping the syringe with your finger and slowly 5. After infusing XYNTHA, remove the infusion set and throw it away. pushing air out of the syringe. The amount of liquid left in the infusion set will not affect your If you reconstituted more than one vial of XYNTHA, remove the treatment. diluent syringe from the vial adapter and leave the vial adapter attached to the XYNTHA vial. Quickly attach a separate large Note: luer lock syringe and pull the reconstituted solution as instructed • Dispose of all unused solution, the empty vial(s), and other used above. Repeat this procedure with each vial in turn. Do not detach medical supplies in an appropriate container. the diluent syringe or the large luer lock syringe until you are ready to attach the large luer lock syringe to the next vial adapter.

• It is a good idea to record the lot number from the XYNTHA vial label every time you use XYNTHA. You can use the peel-off label found on the vial to record the lot number. 13. Remove the syringe from the vial adapter by gently pulling and ADDITIONAL INSTRUCTIONS turning the syringe counterclockwise. Throw away the empty XYNTHA is also supplied in kits that have both the XYNTHA powder and XYNTHA vial with the adapter attached. the diluent within single-use prefilled dual-chamber syringes, called Note: XYNTHA SOLOFUSE. • If you are not using the solution right away, carefully replace the If you use one XYNTHA vial and one of XYNTHA SOLOFUSE for the syringe cap. Do not touch the syringe tip or the inside of the cap. infusion, reconstitute the XYNTHA vial and the XYNTHA SOLOFUSE • Infuse XYNTHA solution within 3 hours after reconstitution. The according to the specific directions for that respective product kit. Use reconstituted solution may be kept at room temperature for up to a separate 10 milliliter or larger luer lock syringe (not included in this 3 hours prior to infusion. If you have not used it in 3 hours, throw kit) to draw back the reconstituted contents of the XYNTHA vial and it away. XYNTHA SOLOFUSE. Use of a XYNTHA Vial Kit with a XYNTHA SOLOFUSE Kit 6. Connect a sterile 10 milliliter or larger luer lock syringe to the vial These instructions are for the use of only one XYNTHA vial kit and adapter. You may want to inject some air into the XYNTHA vial to one XYNTHA SOLOFUSE Kit. For further information, please contact make withdrawing the vial contents easier. your healthcare provider or call the Medical Information Department at Wyeth Pharmaceuticals, 1-800-438-1985. 1. Reconstitute the XYNTHA vial using the instructions described in PREPARATION AND RECONSTITUTION OF XYNTHA section. Detach the empty diluent syringe from the vial adapter by gently turning and pulling the syringe counterclockwise, leaving the contents in the XYNTHA vial with the vial adapter in place. 7. Invert the XYNTHA vial and slowly draw the solution into the large luer lock syringe.

2. Reconstitute the XYNTHA SOLOFUSE using the instructions included with the kit, remembering to remove most, but not all, of the air from the syringe. 8. Detach the large luer lock syringe from the vial adapter by gently turning and pulling the syringe counterclockwise. Throw away the empty XYNTHA vial with the adapter attached. 9. Attach the infusion set to the large luer lock syringe as directed in the INFUSION OF XYNTHA section. Note: Dispose of all unused solution and other used medical supplies in an appropriate container.

This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com.

Manufactured by 4. Slowly depress the plunger rod of the XYNTHA SOLOFUSE until Wyeth Pharmaceuticals LLC the contents empty into the XYNTHA vial. The plunger rod may A subsidiary of Pfizer Inc, Philadelphia, PA 19101 move back slightly after release. License no: 3 LAB-0516-8.0

5. Detach the empty XYNTHA SOLOFUSE from the vial adapter and throw it away. If the syringe turns without detaching from the vial adapter, grasp the white collar and turn. HIGHLIGHTS OF PRESCRIBING INFORMATION ------DOSAGE FORMS AND STRENGTHS ------These highlights do not include all the information needed to use XYNTHA safely XYNTHA SOLOFUSE is available as lyophilized powder in single-use prefilled dual-chamber and effectively. See full prescribing information for XYNTHA. syringes containing nominally 250, 500, 1000, 2000, or 3000 IU. (3) XYNTHA® SOLOFUSE® (antihemophilic factor [recombinant]) ------CONTRAINDICATIONS ------lyophilized powder for solution in prefilled dual-chamber syringe, Do not use in patients who have manifested life-threatening immediate hypersensitivity for intravenous injection reactions, including anaphylaxis, to the product or its components, including hamster Initial U.S. Approval: 2008 proteins. (4)

------RECENT MAJOR CHANGES ------WARNINGS AND PRECAUTIONS ------Indications and Usage (1) 8/2020 • Anaphylaxis and severe hypersensitivity reactions are possible. Patients may develop Dosage and Administration (2.1) 8/2020 hypersensitivity to hamster protein, which is present in trace amounts in XYNTHA. Should such reactions occur, discontinue treatment with the product, and administer ------INDICATIONS AND USAGE ------appropriate treatment. (5.1) • XYNTHA is a recombinant antihemophilic factor indicated in adults and children • Development of neutralizing antibodies has been reported in patients using XYNTHA. with hemophilia A for on-demand treatment and control of bleeding episodes for If expected plasma factor VIII activity levels are not attained, or if bleeding is not perioperative management and for routine prophylaxis to reduce the frequency of controlled with an appropriate dose, perform an assay that measures factor VIII inhibitor bleeding episodes. (1) concentration. (5.2, 5.3, 6.2) XYNTHA is not indicated in patients with von Willebrand’s disease. (1) • ------ADVERSE REACTIONS ------DOSAGE AND ADMINISTRATION ------• The most common adverse reactions (≥10%) with XYNTHA in adult and pediatric For intravenous use after reconstitution only (2) previously treated patients (PTPs) were headache, arthralgia, pyrexia, and cough. (6) • The required dose is determined using the following formula: • Across all studies, 4 subjects developed factor VIII inhibitors (2.4%). (6.2) Required units = body weight (kg) x desired factor VIII rise (IU/dL or % of normal) To report SUSPECTED ADVERSE REACTIONS, contact Wyeth Pharmaceuticals LLC. at x 0.5 (IU/kg per IU/dL), where IU = International Unit. (2.1) 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch Routine prophylaxis (2.1) ------USE IN SPECIFIC POPULATIONS ------• Adults and adolescents (≥12 years): The recommended starting regimen is 30 IU/kg of XYNTHA administered 3 times weekly. Pediatrics: Half-lives are shorter, volumes of distribution are larger, and recovery is lower after XYNTHA administration in children. Higher or more frequent dosing may be • Children (<12 years): The recommended starting regimen is 25 IU/kg of XYNTHA needed. (8.4) administered every other day. More frequent or higher doses may be required in children <12 years of age to account for the higher clearance in this age group. See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. • Adjust the dosing regimen (dose or frequency) based on the patient’s clinical response. Revised: 8/2020 • Frequency of XYNTHA administration is determined by the type of bleeding episode and the recommendation of the treating physician. (2.1, 2.2)

FULL PRESCRIBING INFORMATION: CONTENTS * 8 USE IN SPECIFIC POPULATIONS 1 INDICATIONS AND USAGE 8.1 Pregnancy 2 DOSAGE AND ADMINISTRATION 8.2 Lactation 2.1 Dose 8.4 Pediatric Use 2.2 Preparation and Reconstitution 8.5 Geriatric Use 2.3 Administration 11 DESCRIPTION 2.4 Use of a XYNTHA Vial Kit and a XYNTHA SOLOFUSE Kit 12 CLINICAL PHARMACOLOGY 2.5 Use of Multiple XYNTHA SOLOFUSE Kits 12.1 Mechanism of Action 3 DOSAGE FORMS AND STRENGTHS 12.2 Pharmacodynamics 4 CONTRAINDICATIONS 12.3 Pharmacokinetics 5 WARNINGS AND PRECAUTIONS 13 NONCLINICAL TOXICOLOGY 5.1 Hypersensitivity Reactions 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.2 Neutralizing Antibodies 13.2 Animal Toxicology and/or Pharmacology 5.3 Monitoring Laboratory Tests 14 CLINICAL STUDIES 6 ADVERSE REACTIONS 15 REFERENCES 6.1 Clinical Trials Experience 16 HOW SUPPLIED/STORAGE AND HANDLING 6.2 Immunogenicity 17 PATIENT COUNSELING INFORMATION 6.3 Postmarketing Experience * Sections or subsections omitted from the full prescribing information are not listed

Table 2: Dosing for Perioperative Management Type of Surgery Factor VIII Level Frequency of Duration of Required Doses Therapy (IU/dL or % of (hours) (days) normal) Minor Minor operations, 30-60 12-24 3-4 days or until adequate 6. Gently and slowly advance the plunger rod by pushing until the two stoppers inside including tooth local hemostasis is achieved. the XYNTHA SOLOFUSE meet, and all of the diluent is transferred to the chamber extraction. For tooth extraction, a single infusion plus oral containing the XYNTHA powder. antifibrinolytic therapy within Note: To prevent the escape of fluid from the tip of the syringe, the plunger rod 1 hour may be sufficient. should not be pushed with excessive force. Major Major operations. 60-100 8-24 Until threat is resolved, or in the case of surgery, until adequate local hemostasis and wound healing are achieved. Routine Prophylaxis • Adults and adolescents (≥12 years): The recommended starting regimen is 30 IU/kg of XYNTHA administered 3 times weekly. 7. With the XYNTHA SOLOFUSE remaining upright, swirl gently several times until the • Children (<12 years): The recommended starting regimen is 25 IU/kg of XYNTHA powder is dissolved. administered every other day. More frequent or higher doses may be required in children <12 years of age to account for the higher clearance in this age group [see Clinical Pharmacology (12.3)]. • Adjust the dosing regimen (dose or frequency) based on the patient’s clinical response. 2.2 Preparation and Reconstitution Preparation 1. Always wash hands before performing the following procedures. Note: The final solution should be inspected visually for particulate matter before 2. Use aseptic technique during the reconstitution procedures. administration. The solution should be clear to slightly opalescent and colorless. If it is 3. Use all components for the reconstitution and administration of this product as not, discard the solution and use a new kit. soon as possible after opening their sterile containers to minimize unnecessary 8. Holding the XYNTHA SOLOFUSE in an upright position, slowly advance the plunger exposure to the atmosphere. rod until most, but not all, of the air is removed from the drug product chamber. Note: • If the patient uses one vial of XYNTHA with one XYNTHA SOLOFUSE for the infusion, reconstitute the vial and the syringe according to the instructions for that respective product kit. Use a separate 10 milliliter or larger luer lock syringe (not included in this kit) to draw back the reconstituted contents of the vial and the syringe. [see Dosage and Administration (2.4)] • If the patient uses multiple XYNTHA SOLOFUSE syringes for the infusion, reconstitute each syringe according to the instructions below. Use a separate 10 milliliter or larger luer lock syringe (not included in this kit) to draw back the reconstituted contents of Note: each syringe. [see Dosage and Administration (2.5)] • If the solution is not to be used immediately, store the syringe upright, leaving the Reconstitution protective blue vent cap on the XYNTHA SOLOFUSE until ready to infuse. 1. Allow the XYNTHA SOLOFUSE Kit to reach room temperature. • Store the reconstituted solution at room temperature prior to administration, but 2. Remove the contents of the XYNTHA SOLOFUSE Kit and place on a clean surface, use within 3 hours after reconstitution or after removal of the grey rubber tip cap. making sure you have all the supplies you will need. • XYNTHA, when reconstituted, contains polysorbate 80, which is known to increase 3. Grasp the plunger rod as shown in the following diagram. Avoid contact with the the rate of di-(2-ethylhexyl) phthalate (DEHP) extraction from polyvinyl chloride shaft of the plunger rod. Screw the plunger rod firmly into the opening in the finger (PVC). This should be considered during the preparation and administration of rest of the XYNTHA SOLOFUSE by pushing and turning firmly until resistance is felt XYNTHA, including storage time elapsed in a PVC container following reconstitution. (approximately 2 turns). The tubing of the infusion set included with this kit does not contain DEHP. 2.3 Administration For intravenous infusion after reconstitution only. Inspect the final XYNTHA solution visually for particulate matter and discoloration prior to administration. The solution should be clear to slightly opalescent and colorless. If it is not, discard the solution and use a new kit. Administer XYNTHA solution using the infusion set included in the kit. Do not administer reconstituted XYNTHA in the same tubing or container with other medicinal products. Note: Once the white tamper-evident seal is removed it is important to keep the 1. After removing the protective blue vented cap, firmly attach the intravenous infusion XYNTHA SOLOFUSE in the upright position throughout the reconstitution process set provided in the kit onto the XYNTHA SOLOFUSE. to prevent possible leakage. 4. Holding the XYNTHA SOLOFUSE upright, remove the white tamper-evident seal by bending the seal right to left (or a gentle rocking motion) to break the perforation of the cap and expose the grey rubber tip cap of the XYNTHA SOLOFUSE.

2. Apply a tourniquet and prepare the injection site by wiping the skin well with an alcohol swab provided in the kit. 3. Remove the protective needle cover and perform venipuncture. Insert the needle on the infusion set tubing into the vein, and remove the tourniquet. Verify proper needle placement. 4. Inject the reconstituted XYNTHA intravenously over several minutes. The rate of 8. Invert the vial and slowly draw the solution into the large luer lock syringe. administration should be determined by the patient’s comfort level.

9. Detach the syringe from the vial adapter by gently turning and pulling the syringe 5. After infusing XYNTHA, remove and discard the infusion set. The amount of drug counterclockwise. Discard the empty XYNTHA vial with the adapter attached. product left in the infusion set will not affect treatment. 10 Attach the infusion set to the large luer lock syringe as directed [see Dosage and Note: Dispose of all unused solution, the empty XYNTHA SOLOFUSE, and other used Administration (2.3)]. medical supplies in an appropriate container. 2.5 Use of Multiple XYNTHA SOLOFUSE Kits 2.4 Use of a XYNTHA Vial Kit with a XYNTHA SOLOFUSE Kit The instructions below are for the use of multiple XYNTHA SOLOFUSE kits with a 10 milliliter These instructions are for the use of only one XYNTHA vial kit with one XYNTHA SOLOFUSE or larger luer lock syringe. For further information, please contact the Medical Information Kit. Department at Wyeth Pharmaceuticals, 1-800-438-1985. 1. Reconstitute the XYNTHA vial using the instructions included with the product kit. Note: Luer-to-luer syringe connectors are not provided in these kits. Instruct patients to 2. Detach the empty diluent syringe from the vial adapter by gently turning and pulling contact their XYNTHA supplier to order. the syringe counterclockwise, leaving the contents in the vial and the vial adapter 1. Reconstitute all XYNTHA SOLOFUSE according to instructions described in in place. Preparation and Reconstitution [see Dosage and Administration (2.2)]. 2. Holding the XYNTHA SOLOFUSE in an upright position, slowly advance the plunger rod until most, but not all, of the air is removed from the drug product chamber.

3. Reconstitute the XYNTHA SOLOFUSE using the instructions described in Preparation and Reconstitution [see Dosage and Administration (2.2)]. Remember to remove most, but not all, of the air from the drug product chamber. 3. Remove the luer-to-luer syringe connector from its package. 4. After removing the protective blue vented cap, connect a sterile 10 milliliter or larger luer lock syringe to one opening (port) in the syringe connector and the XYNTHA SOLOFUSE to the remaining open port on the opposite end.

4. After removing the protective blue vented cap, connect the XYNTHA SOLOFUSE to the vial adapter by inserting the tip into the adapter opening while firmly pushing and turning the syringe clockwise until secured.

5. With the XYNTHA SOLOFUSE on top, slowly depress the plunger rod until the contents empty into the large luer lock syringe.

5. Slowly depress the plunger rod of the XYNTHA SOLOFUSE until the contents empty into the XYNTHA vial. The plunger rod may move back slightly after release. 6. Remove the empty XYNTHA SOLOFUSE and repeat procedures 3 and 4 above for any additional reconstituted XYNTHA SOLOFUSE. 7. Remove the luer-to-luer syringe connector from the large luer lock syringe and attach the infusion set as directed [see Dosage and Administration (2.3)]. 3 DOSAGE FORMS AND STRENGTHS XYNTHA SOLOFUSE is available as a white to off-white lyophilized powder in the following 6. Detach and discard the empty XYNTHA SOLOFUSE from the vial adapter. nominal dosages: Note: If the syringe turns without detaching from the vial adapter, grasp the white • 250 International Units collar and turn. • 500 International Units • 1000 International Units • 2000 International Units • 3000 International Units Each XYNTHA SOLOFUSE has the actual recombinant factor VIII (rFVIII) potency in International Units stated on the label. 4 CONTRAINDICATIONS XYNTHA is contraindicated in patients who have manifested life-threatening immediate 7. Connect a sterile 10 milliliter or larger luer lock syringe to the vial adapter. Inject hypersensitivity reactions, including anaphylaxis, to the product or its components, some air into the vial to make withdrawing the vial contents easier. including hamster proteins. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Allergic type hypersensitivity reactions, including anaphylaxis, are possible with XYNTHA. Inform patients of the early signs or symptoms of hypersensitivity reactions (including hives [rash with itching], generalized urticaria, chest tightness, wheezing, and hypotension) and anaphylaxis. Discontinue XYNTHA if hypersensitivity symptoms occur and administer appropriate emergency treatment. XYNTHA contains trace amounts of hamster proteins. Patients treated with this product 6.3 Postmarketing Experience may develop hypersensitivity to these non-human mammalian proteins. Because these reactions are reported voluntarily from a population of uncertain size, it is 5.2 Neutralizing Antibodies not always possible to reliably estimate their frequency or establish a causal relationship Inhibitors have been reported following administration of XYNTHA. Monitor patients to drug exposure. for the development of factor VIII inhibitors by appropriate clinical observations and The following postmarketing adverse reaction has been reported for XYNTHA: laboratory tests. If expected factor VIII activity plasma levels are not attained, or if bleeding Inadequate therapeutic response is not controlled with an appropriate dose, perform an assay that measures factor VIII inhibitor concentration to determine if a factor VIII inhibitor is present [see Warnings and 8 USE IN SPECIFIC POPULATIONS Precautions (5.3)].4,5,6,7,8,9,10,11,12 8.1 Pregnancy 5.3 Monitoring Laboratory Tests Risk Summary • Use individual factor VIII values for recovery and, if clinically indicated, other It is not known whether XYNTHA can cause fetal harm when administered to a pregnant pharmacokinetic characteristics to guide dosing and administration. woman or can affect reproduction capacity. Animal reproduction studies have not been • Monitor plasma factor VIII activity levels by the one-stage clotting assay to confirm conducted with XYNTHA. that adequate factor VIII levels have been achieved and are maintained, when There is no information available on the effect of factor VIII replacement therapy on labor clinically indicated [see Dosage and Administration (2)]. and delivery. XYNTHA should be used only if clinically indicated. • Monitor for development of factor VIII inhibitors. Perform assay to determine if In the U.S. general population, the estimated background risk of major birth defects and factor VIII inhibitor is present when expected factor VIII activity plasma levels are miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. not attained, or when bleeding is not controlled with the expected dose of XYNTHA. 8.2 Lactation Use Bethesda Units (BU) to titer inhibitors. Risk Summary 6 ADVERSE REACTIONS There is no information regarding the presence of XYNTHA in human milk, the effect on the The most common adverse reactions (≥10%) with XYNTHA in adult and pediatric breastfed infant, or the effects on milk production. The developmental and health benefits previously treated patients (PTPs) were headache, arthralgia, pyrexia, and cough. of breastfeeding should be considered along with the mother’s clinical need for XYNTHA 6.1 Clinical Trials Experience and any potential adverse effects on the breastfed child from XYNTHA or from the Because clinical trials are conducted under widely varying conditions, adverse reaction underlying maternal condition. rates observed in the clinical trials of a drug cannot be directly compared to rates in the 8.4 Pediatric Use clinical trials of another drug and may not reflect the rates observed in clinical practice. Safety and efficacy with XYNTHA were evaluated in clinical studies in 68 pediatric subjects XYNTHA was evaluated in five completed clinical studies (N=178), comprising four studies <17 years of age (18 subjects aged 12 to <17 years, 50 subjects aged ≤12 years). There with adult and pediatric PTPs. were no apparent differences in the efficacy and safety in pediatric subjects as compared The safety and efficacy of XYNTHA was evaluated in two completed pivotal studies. In the to adults [see Adverse Reactions (6.1) and Clinical Studies (14)]. first study (n=94), safety and efficacy were examined in PTPs with severe to moderately In comparison to the pharmacokinetic parameters reported in adults, children have shorter severe hemophilia A (factor VIII activity in plasma [FVIII:C] ≤2%) who received XYNTHA half-lives, larger volumes of distribution and lower recovery of factor VIII after XYNTHA for routine prophylaxis and on-demand treatment. Ninety-four subjects received at least administration. The clearance (based on per kg body weight) is approximately 40% higher one dose of XYNTHA, resulting in a total of 6,775 infusions [see Clinical Studies (14)]. in children. Higher or more frequent doses may be required to account for the observed The second study (n=30) examined the use of XYNTHA for surgical prophylaxis in PTPs differences in pharmacokinetic parameters [see Clinical Pharmacology (12.3)]. with severe to moderately severe hemophilia A (FVIII:C ≤2%) who required elective major 8.5 Geriatric Use surgery and were expected to receive XYNTHA replacement therapy for at least 6 days post-surgery. All subjects received at least one dose of XYNTHA, resulting in 1,161 Clinical studies of XYNTHA did not include sufficient numbers of subjects aged 65 and infusions. One subject received XYNTHA for a pre-surgery pharmacokinetic assessment over to determine whether they respond differently from younger subjects. Other reported only and did not undergo surgery [see Clinical Studies (14)]. clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, Across all studies, safety was evaluated in 72 pediatric PTPs <17 years of age (46 subjects, usually starting at the low end of the dosing range, reflecting the greater frequency <6 years of age (4 subjects were 0 to <2 years of age), 4 subjects 6 to <12 years of age, of decreased hepatic, renal, or cardiac function and of concomitant disease or other and 22 adolescents, 12 to <17 years of age). A total of 13,109 infusions of XYNTHA were drug therapy. administered with a median dose per infusion of 28 IU/kg (min-max: 6-108 IU/kg). Across all studies, the most common adverse reactions (≥10%) with XYNTHA in adult and 11 DESCRIPTION pediatric PTPs were headache (24%), arthralgia (23%), pyrexia (23%), and cough (12%). The active ingredient in XYNTHA, Antihemophilic Factor (Recombinant), is a recombinant Other adverse reactions reported in ≥5% of subjects were: diarrhea (8%), vomiting (8%), antihemophilic factor (rAHF), also called coagulation factor VIII, which is produced by and asthenia (6%). recombinant DNA technology. It is secreted by a genetically engineered Chinese hamster ovary (CHO) cell line. The cell line is grown in a chemically defined cell culture medium 6.2 Immunogenicity that contains recombinant insulin, but does not contain any materials derived from human There is a potential for immunogenicity with therapeutic proteins. The development of or animal sources. factor VIII inhibitors with XYNTHA was evaluated in 167 adult and pediatric PTPs with at The rAHF in XYNTHA is a purified glycoprotein, with an approximate molecular mass least 50 exposure days (EDs). Laboratory-based assessments for FVIII inhibitor (partial of 170 kDa consisting of 1,438 amino acids, which does not contain the B-domain.13 Nijmegen modification of the Bethesda inhibitor assay) were conducted in the clinical The amino acid sequence of the rAHF is comparable to the 90 + 80 kDa form of human studies. The criterion for a positive FVIII result test result was ≥0.6 BU/mL. Across all coagulation factor VIII. studies, 4 subjects developed factor VIII inhibitors (2.4%). The purification process uses a series of chromatography steps, one of which is based The completed clinical studies for XYNTHA examined 178 subjects (30 for surgical on affinity chromatography using a patented synthetic peptide affinity ligand.14 The prophylaxis) who had previously been treated with factor VIII (PTPs). In the first safety process also includes a solvent-detergent viral inactivation step and a virus-retaining and efficacy study, factor VIII inhibitors were detected in two of 89 subjects (2.2%) who nanofiltration step. completed ≥50 EDs. 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 The potency expressed in International Units (IU) is determined using the chromogenic initial facility (with one de novo and two recurrent inhibitors observed in 110 subjects) and assay of the European Pharmacopoeia. The Wyeth manufacturing reference standard for the experience with predecessor product (with one inhibitor observed in 113 subjects). potency has been calibrated against the World Health Organization (WHO) International The Bayesian analysis indicated that the population inhibitor rate for XYNTHA, an estimate Standard for factor VIII activity using the one-stage clotting assay. The specific activity of of the 95% upper limit of the true inhibitor rate, was 4.17%. XYNTHA is 5,500 to 9,900 IU per milligram of protein. None of the PTPs developed anti-CHO (Chinese hamster ovary) or anti-TN8.2 antibodies. XYNTHA is formulated as a sterile, nonpyrogenic, no preservative, lyophilized powder One PTP developed anti-FVIII antibodies; but, this subject did not develop an inhibitor. preparation for intravenous injection. Each single-use prefilled dual-chamber syringe (named XYNTHA SOLOFUSE) contains nominally 250, 500, 1000, 2000, or 3000 IU of In the surgery study, one low titer persistent inhibitor and one transient false-positive XYNTHA. Upon reconstitution, the product is a clear to slightly opalescent, colorless inhibitor were reported. In this study, one surgical subject developed anti-CHO cell solution that contains sodium chloride, sucrose, L-histidine, calcium chloride and antibodies with no associated allergic reaction. One subject developed anti-FVIII antibodies; polysorbate 80. but, this subject did not develop an inhibitor. Across all studies, immunogenicity was evaluated in 64 pediatric PTPs <17 years of age 12 CLINICAL PHARMACOLOGY with at least 50 EDs (43 children <6 years of age, 4 subjects 6 to <12 years of age, and 12.1 Mechanism of Action 17 adolescents, 12 to <17 years of age). Of these, 2 pediatric subjects developed an inhibitor. XYNTHA temporarily replaces the missing clotting factor VIII that is needed for effective The detection of antibody formation is highly dependent on the sensitivity and specificity of hemostasis. the assay. Additionally, the observed incidence of antibody, including neutralizing antibody, positivity in an assay may be influenced by several factors, including assay methodology, 12.2 Pharmacodynamics sample handling, timing of sample collection, concomitant medications, and underlying The activated partial thromboplastin time (aPTT) is prolonged in patients with hemophilia. disease. For these reasons, comparisons of the incidence of antibodies to XYNTHA with Determination of aPTT is a conventional in vitro assay for biological activity of factor VIII. the incidence of antibodies to other products may be misleading. Treatment with XYNTHA normalizes the aPTT over the effective dosing period. 12.3 Pharmacokinetics indicated. All 94 subjects were treated with at least one dose and all are included in the The pharmacokinetic parameters of XYNTHA in 30 PTPs 12 to 60 years old, who received intent-to-treat (ITT) population. Eighty-nine (89) subjects accrued ≥50 EDs. Median age for a single infusion of 50 IU/kg XYNTHA are summarized in Table 3. the 94 treated subjects was 24 years (mean 28 and min-max: 12-60 years). In addition, 25 of the same subjects later received a single infusion of 50 IU/kg of XYNTHA Of these 94 subjects, 30 evaluable subjects participated in a randomized crossover for a 6-month follow-up pharmacokinetic study. The parameters were comparable between pharmacokinetics substudy. Twenty-five (25/30) of these subjects with FVIII:C≤ 1% baseline and 6 months, indicating no time-dependent changes in the pharmacokinetics completed both the first (PK1) and the second (PK2) pharmacokinetic assessments [see of XYNTHA. Clinical Pharmacology (12.3)].16 In a separate study, 8 of 30 subjects at least 12 years old with hemophilia A undergoing Fifty-three subjects (53/94) received XYNTHA on-demand treatment for a total of elective major surgery received a single 50 IU/kg infusion of XYNTHA. The pharmacokinetic 187 bleeding episodes. Seven of these bleeding episodes occurred in subjects prior to parameters in these subjects are also summarized in Table 3. switching to a prophylaxis treatment regimen. One hundred ten of 180 bleeds (110/180 or 61%) occurred ≤48 hours after the last dose and 39% (70/180 bleeds) occurred >48 hours Table 3: Mean ± SD XYNTHA Pharmacokinetic Parameters in Previously Treated after the last dose. The majority of bleeds reported to occur ≤48 hours after the last Patients with Hemophilia A after Single 50 IU/kg Dose prophylaxis dose were traumatic (64/110 bleeds or 58%). Forty-two bleeds (42/70 or Parameter Initial Visit Month 6 Pre-surgery 60%) reported to occur >48 hours after the last prophylaxis dose were spontaneous. The (n = 30) (n = 25) (n=8) on-demand treatment dosing regimen was determined by the investigator. The median dose for on-demand treatment was 31 IU/kg (min-max: 6-74 IU/kg) and the median C (IU/mL) 1.08 ± 0.22 1.24 ± 0.42 1.08 ± 0.24 max exposure per subject was 3 days (min-max: 1-26). AUC∞ (IU•hr/mL) 13.5 ± 5.6 15.0 ± 7.5 16.0 ± 5.2 The majority of bleeding episodes (173/187 or 93%) resolved with 1 or 2 infusions

t1/2 (hr) 11.2 ± 5.0 11.8 ± 6.2* 16.7 ± 5.4 (Table 5). One hundred thirty-two of 187 bleeding episodes (132/187 or 71%) treated with CL (mL/hr/kg) 4.51 ± 2.23 4.04 ± 1.87 3.48 ± 1.25 XYNTHA were rated excellent or good in their response to initial treatment, 45 (24%) were rated moderate. Five (3%) were rated no response, and 5 (3%) were not rated. Vss (mL/kg) 66.1 ± 33.0 67.4 ± 32.6 69.0 ± 20.1 Recovery 2.15 ± 0.44 2.47 ± 0.84 2.17 ± 0.47 Table 5: Summary of Response to Infusions to Treat New Bleeding Episode by (IU/dL per IU/kg) Number of Infusions Needed for Resolution Number of Infusions (%) Abbreviations: AUC∞ = area under the plasma concentration-time curve from zero to infinity; Cmax = peak concentration; t1/2 = plasma elimination half-life; CL = clearance; n = number of subjects; Total SD = standard deviation; Vss = volume of distribution at steady-state. Number *One subject was excluded from the calculation due to lack of a well-defined terminal phase. Response of to 1st Infusion 1 2 3 4 >4 Bleeds Table 4 shows the pharmacokinetic parameters of nine children; four aged 14 or 15 years Excellenta 42 (95.5) 2 (4.5) 0 (0.0) 0 (0.0) 0 (0.0) 44 of age, who are also included in the summary for the adults above, along with five children 16 aged 3.7-5.8 years after single 50 IU/kg doses of XYNTHA. Compared to adults, the Goodb 69 (78.4) 3 (3.4) 0 (0.0) 0 (0.0) 88 half-life of XYNTHA is shorter in children and the clearance (based on per kg body weight) (18.2) 16 is approximately 40% higher in children. Moderatec 24 (53.3) 2 (4.4) 0 (0.0) 3 (6.7) 45 (35.6) Table 4: Mean ± SD XYNTHA Pharmacokinetic Parameters in Previously Treated No Responsed 0 (0.0) 0 (0.0) 2 (40.0) 2 (40.0) 1 (20.0) 5 Pediatric Patients with Hemophilia A after Single 50 IU/kg Dose Not Assessed 4 (80.0) 0 (0.0) 0 (0.0) 1 (20.0) 0 (0.0) 5e Parameter Young Children (n=5) Adolescents (n=4) 34 Age (min - max, yr)) 3.7 - 5.8 14 - 15 Total 139 (74.3) 7 (3.7) 3 (1.6) 4 (2.1) 187 (18.2) C (IU/mL) 0.78 ± 0.34 0.97 ± 0.21 max a Excellent: Definite pain relief and/or improvement in signs of bleeding starting within 8 hours after AUC∞ (IU∙hr/mL) 12.2 ± 6.50 8.5 ± 4.0 an infusion, with no additional infusion administered. b Good: Definite pain relief and/or improvement in signs of bleeding starting within 8 hours after an t1/2 (hr) 8.3 ± 2.7 6.9 ± 2.4 infusion, with at least one additional infusion administered for complete resolution of the bleeding CL (mL/hr/kg) 6.29 ± 4.87 6.62 ± 2.16 episode. c Moderate: Probable or slight improvement starting after 8 hours following the infusion, with at Vss (mL/kg) 66.9 ± 55.6 67.1 ± 13.6 least one additional infusion administered for complete resolution of the bleeding episode. d No Response: No improvement at all between infusions or during the 24 hour interval following an Recovery 1.52 ± 0.69 1.95 ± 0.41 infusion, or condition worsens. (IU/dL per IU/kg) e Includes one infusion with commercial FVIII that occurred before routine prophylaxis began.

Abbreviations: AUC∞ = area under the plasma concentration-time curve from zero to infinity; Cmax = peak concentration; t1/2 = plasma elimination half-life; CL = clearance; n = number of subjects; Of the 94 subjects described above, in the first completed open-label safety and efficacy SD = standard deviation; Vss = volume of distribution at steady-state. study of XYNTHA, 18 were adolescent subjects 12 to <17 years of age with severe to moderately severe hemophilia A (FVIII:C ≤2%). Ten (10) of these adolescent subjects, 13 NONCLINICAL TOXICOLOGY received XYNTHA for the on-demand treatment of 66 bleeding episodes, with the majority of the bleeding episodes (63/66 or 95%) resolving with 1 or 2 infusions. The response to 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility infusion was rated on a pre-specified 4 point hemostatic efficacy scale. Thirty-eight (38) No studies have been conducted with XYNTHA to assess its mutagenic or carcinogenic of 66 bleeding episodes (58%) were rated excellent or good in their response to initial potential. XYNTHA has been shown to be comparable to the predecessor product with treatment, 24 (36%) were rated as moderate, and 4 (6%) were not rated. The median dose respect to its biochemical and physicochemical properties, as well as its nonclinical per on demand infusion was 47 IU/kg (min-max: 24-74). in vivo pharmacology and toxicology. By inference, predecessor product and XYNTHA would be expected to have equivalent mutagenic and carcinogenic potential. The predecessor On-demand treatment in children product has been shown to be nongenotoxic in the mouse micronucleus assay. No studies Additional data for 50 subjects are available from a second safety and efficacy study of have been conducted in animals to assess impairment of fertility or fetal development. XYNTHA in children (≤12 years of age) with severe to moderately severe hemophilia A 13.2 Animal Toxicology and/or Pharmacology (FVIII:C ≤2%). Of the 50 subjects, 38 subjects received XYNTHA for on-demand and follow-up treatment of 562 bleeding episodes with the majority of the bleeding episodes Preclinical studies evaluating XYNTHA in hemophilia A dogs without inhibitors (518/562 or 92%) resolving with 1 or 2 infusions. Of 559 bleeding episodes treated with demonstrated safe and effective restoration of hemostasis. XYNTHA demonstrated a XYNTHA with response assessments to the first infusion, 526 (94%) were rated excellent toxicological profile that was similar to the toxicological profile observed with the or good in their response to initial treatment and 27 (5%) were rated as moderate. The predecessor product. Toxicity associated with XYNTHA was primarily associated with median dose per on-demand infusion was 28 IU/kg (min-max: 10-92). anti-FVIII neutralizing antibody generation first detectable at 15 days of repeat dosing in high (approximately 735 IU/kg/day) level-dosed, non-human primates. Perioperative Management In a study (n=30) for surgical prophylaxis in subjects with hemophilia A, XYNTHA was 14 CLINICAL STUDIES administered to 25 efficacy-evaluable PTPs undergoing major surgical procedures Three completed multicenter, open-label studies support the analysis of safety and efficacy (11 total knee replacements, 1 hip replacement, 5 synovectomies, 1 left ulnar nerve of XYNTHA in on-demand treatment and control of bleeding episodes and perioperative transposition release, 1 ventral hernia repair/scar revision, 1 knee arthroscopy, 1 revision management, and routine prophylaxis in PTPs with hemophilia A. These completed clinical and debridement of the knee after a total knee replacement, 1 hip arthroplasty revision, studies for XYNTHA examined 174 PTP subjects, 94 from the first study, and 50 from a 1 stapes replacement, 1 ankle arthrodesis, and 1 pseudotumor excision).17 second study, for on-demand treatment and routine prophylaxis and 30 from a third study The results of the hemostatic efficacy ratings for these subjects are presented in Table 6. for surgical prophylaxis. Subjects with severe to moderately severe hemophilia A (FVIII:C Investigator’s ratings of efficacy at the end of surgery and at the end of the initial post- ≤2%) and no history of FVIII inhibitors were eligible for the trials. operative period were excellent or good for all assessments. Intraoperative blood loss was On-demand Treatment and Control of Bleeding Episodes reported as “normal” or “absent” for all subjects. Thirteen of the subjects (13/25 or 52%) On-demand treatment in adolescents and adults had blood loss in the postoperative period. The postoperative blood loss was rated as Ninety-four (94) subjects, 12 years of age and older received XYNTHA in a routine “normal” for ten of these cases while three cases were rated “abnormal” (1 due to prophylaxis treatment regimen with on-demand treatment administered as clinically hemorrhage following surgical trauma to the epigastric artery, 1 due to an 800 mL blood loss after hip replacement surgery, and 1 after an elbow synovectomy where the blood loss 7. Kessler C, Sachse K. Factor VIII:C inhibitor associated with monoclonal-antibody could not be measured by the investigator). purified FVIII concentrate. Lancet. 1990;335:1403. 8. Schwartz RS, Abildgaard CF, Aledort LM, et al. Human recombinant DNA-derived Table 6: Summary of Hemostatic Efficacy antihemophilic factor (factor VIII) in the treatment of hemophilia A. N Engl J Med. Time of Hemostatic Efficacy Excellenta Goodb Number of subjects 1990;323:1800-1805. Assessment 9. White GC II, Courter S, Bray GL, et al. A multicenter study of recombinant End of surgery 18 (72%) 7 (28%) 25 factor VIII (Recombinate™) in previously treated patients with hemophilia A. End of initial postoperative periodc 23 (92%) 2 (8%) 25 Thromb Haemost. 1997;77(4):660-667. a Excellent: Achieved hemostasis comparable to that expected after similar surgery in a patient 10. Gruppo R, Chen H, Schroth P, et al. Safety and immunogenicity of recombinant without hemophilia. factor VIII (Recombinate™) in previously untreated patients: A 7.3 year update. b Good: Prolonged time to hemostasis, with somewhat increased bleeding compared with that Haemophilia. 1998;4:228 (Abstract No. 291, XXIII Congress of the WFH, The Hague). expected after similar surgery in a patient without hemophilia. c End of initial postoperative period is date of discharge or postoperative Day 6, whichever 11. Scharrer I, Bray GL, Neutzling O. Incidence of inhibitors in haemophilia A occurs later. patients - a review of recent studies of recombinant and plasma-derived factor VIII concentrates. Haemophilia. 1999;5:145-154. Routine Prophylaxis 12. Abshire TC, Brackmann HH, Scharrer I, et al. Sucrose formulated recombinant One hundred and two (102) subjects (94 subjects ≥12 years of age and 8 subjects human antihemophilic Factor VIII is safe and efficacious for treatment of <12 years of age) received XYNTHA for routine prophylaxis, for comparison of annualized hemophilia A in home therapy: Results of a multicenter, international, clinical bleeding rate (ABR) to on-demand treatment alone as a part of 2 completed studies. investigation. Thromb Haemost. 2000;83(6):811-816. XYNTHA was administered for routine prophylaxis at a dose of 25 ± 5 IU/kg every other 13. Sandberg H, Almstedt A, Brandt J, Castro VM, Gray E, Holmquist L, et al. Structural day (in subjects <12 years of age) or 30 ± 5 IU/kg administered 3 times weekly (in subjects and Functional Characterization of B-Domain Deleted Recombinant Factor VIII. 12 years of age or older), with provisions for dose escalation based on pre-specified Sem Hematol. 2001;38 (Suppl. 4):4-12. criteria (over a 4-week period, 2 spontaneous bleeds into a major joint and/or target joint, or 3 or more spontaneous bleeding episodes in any location). Among these 102 subjects, 14. Kelley BD, Tannatt M, Magnusson R, Hagelberg S. Development and Validation of 7 dose escalations were prescribed for 6 subjects. an Affinity Chromatography Step Using a Peptide Ligand for cGMP Production of Factor VIII. Biotechnol Bioeng. 2004;87(3):400-412. In subjects ≥12 years, 42 subjects (42/94 or 45%) reported no bleeding while on routine prophylaxis. The mean±SD total ABR during routine prophylaxis was 4.0±6.64 with median 15. Mann KG and Ziedens KB. Overview of Hemostasis. In: Lee CA, Berntorp EE and (min-max) of 1.9 (0.0-44.2). The mean ABR for subjects during routine prophylaxis was Hoots WK, eds. Textbook of Hemophilia. USA, Blackwell Publishing; 2005:1-4. 88% lower than the mean ABR for subjects during on-demand treatment (Table 7). 16. Recht M, Nemes L, Matysiak M et al. Clinical Evaluation of Moroctocog Alfa In subjects <12 years, 4 subjects (4/8 or 50%) reported no bleeding while on routine (AF-CC), a New Generation of B-Domain Deleted Recombinant Factor VIII prophylaxis. The mean±SD total ABR during routine prophylaxis was 1.5±2.2 with median (BDDrFVIII) for Treatment of Haemophilia A: Demonstration of Safety, Efficacy and (min-max) of 0.6 (0.0-6.2). The mean ABR for subjects during routine prophylaxis was Pharmacokinetic Equivalence to Full-length Recombinant Factor VIII. Haemophilia 97% lower than the mean ABR for subjects during on-demand treatment (Table 7). 2009; 1-12. 17. Windyga J, Rusen L, Gruppo R, et al. BDDrFVIII (Moroctocog alfa [AF-CC]) for Table 7: Summary of Annualized Bleeding Rate During Routine surgical haemostasis in patients with haemophilia A: results of a pivotal study. Prophylaxis Treatment with XYNTHA Haemophilia. 2010 Sep 1;16(5):731-9. Age Number % Statistic Treated Treated Treated 16 HOW SUPPLIED/STORAGE AND HANDLING Category of Reduction Total Spontaneous Traumatic (years) Subjects from OD Routine Routine Routine How Supplied Prophylaxis Prophylaxis Prophylaxis Each XYNTHA SOLOFUSE Kit contains: one plunger rod for assembly, one sterile infusion ABR ABR ABR set, two alcohol swabs, one bandage, one gauze pad, one vented sterile cap, and one package insert. The drug product, diluents for injection and the rest of components included within 0 to <12 8 97% Mean±SD 1.5±2.20 0.6±1.31 0.9±1.30 the XYNTHA 250, 500, 1000, 2000, or 3000 International Units kit are free from natural Median 0.6 0.0 0.0 rubber and natural rubber latex. (Min-Max) (0.0-6.2) (0.0-3.7) (0.0-3.2) XYNTHA SOLOFUSE is supplied in a kit that includes the XYNTHA lyophilized powder containing nominally 250, 500, 1000, 2000 or 3000 IU and 4 mL 0.9 % Sodium Chloride ≥12 94a 88% Mean±SD 4.0±6.64 2.0±4.25 2.0±4.10 solution for reconstitution in a prefilled dual-chamber syringe: Median 1.9 0.0 0.0 (Min-Max) (0.0-44.2) (0.0-32.1) (0.0-23.3) XYNTHA SOLOFUSE Kit Nominal Strength Fill Size Color Indicator Kit NDC # 12 to <17 18b 84% Mean±SD 7.3±11.37 3.3±7.73 4.0±5.94 250 International Units Yellow 58394-022-03 Median 3.0 0.0 1.9 500 International Units Blue 58394-023-03 (Min-Max) (0.0-44.2) (0.0-32.1) (0.0-19.6) 1000 International Units Green 58394-024-03 ≥17 76 89% Mean±SD 3.2±4.70 1.6±2.88 1.6±3.42 2000 International Units Red 58394-025-03 Median 1.9 0.0 0.0 3000 International Units Gray 58394-016-03 (Min-Max) (0.0-23.3) (0.0-13.7) (0.0-23.3)

OD = on demand; ABR = annualized bleeding rate; SD = standard deviation, Min = minimum, Max = maximum. Actual factor VIII activity in International Units is stated on the label of each XYNTHA SOLOFUSE. aThe treated total ABR mean±SD during prophylaxis for the 93 subjects aged ≥12 years (outlier removed), was 3.6±5.18 with median (min-max) of 1.9 (0.0-23.3). The spontaneous treated ABR mean±SD was 1.6±2.87 with median (min-max) Storage and Handling of 0.0 (0.0-13.7). The traumatic ABR mean±SD was 1.9±3.99 with median (min-max) of 0.0 (0.0-23.3). Product as Packaged for Sale: bThe treated total ABR mean±SD during prophylaxis for the 17 adolescents (outlier removed), was 5.2±6.90 with median (min-max) of 2.0 (0.0-21.4). The spontaneous ABR mean±SD was 1.6±2.94 with median (min-max) of 0.0 (0.0-11.6). • Store XYNTHA SOLOFUSE under refrigeration at a temperature of 2° to 8°C The traumatic ABR mean±SD was 3.5±5.77 with median (min-max) of 1.9 (0.0-19.6). (36° to 46°F) for up to 36 months from the date of manufacture until the expiration date stated on the label. 15 REFERENCES • Within the expiration date, XYNTHA SOLOFUSE also may be stored at room 1. Nilsson IM, Berntorp EE and Freiburghaus C. Treatment of patients with factor VIII temperature not to exceed 25°C (77°F) for up to 3 months. and IX inhibitors. Thromb Haemost. 1993;70(1):56-59. • Clearly record the starting date at room temperature storage in the space provided 2. Hoyer LW. Hemophilia A. N Engl J Med. 1994;330:38-47. on the outer carton. At the end of the 3-month period, immediately use or discard 3. Juhlin F. Stability and Compatibility of Reconstituted Recombinant Factor VIII SQ, the product. Do not put the product back into the refrigerator. 250 IU/ml, in a System for Continuous Infusion. Pharmacia Document 9610224, • Do not use XYNTHA SOLOFUSE after the expiration date stated on the label or after 1996. 3 months when stored at room temperature, whichever is earlier. 4. Ehrenforth S, Kreuz W, Scharrer I, et al. Incidence of development of factor VIII and • Do not freeze. (Freezing may damage the XYNTHA SOLOFUSE.) factor IX inhibitors in hemophiliacs. Lancet. 1992;339:594-598. • During storage, avoid prolonged exposure of XYNTHA SOLOFUSE to light. 5. Lusher J, Arkin S, Abildgaard CF, Schwartz RS, the Kogenate PUP Study Group. • Store the reconstituted solution at room temperature prior to administration. Recombinant factor VIII for the treatment of previously untreated patients with Administer XYNTHA SOLOFUSE within 3 hours after reconstitution or after removal hemophilia A. N Engl J Med. 1993;328:453-459. of the grey rubber tip cap from the product. 6. Bray GL, Gomperts ED, Courter S, et al. A multicenter study of recombinant factor VIII (Recombinate): safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. Blood. 1994;83(9):2428-2435. 17 PATIENT COUNSELING INFORMATION FDA-Approved Patient Labeling Advise patients to: Patient Information • read the FDA-approved patient labeling (Patient Information and Instructions for Use). XYNTHA® SOLOFUSE® /ZIN-tha/ • report any adverse reactions or problems that concern them when taking XYNTHA [Antihemophilic Factor (Recombinant)] to their healthcare provider. • discontinue use of the product, call their healthcare provider, and go to the Please read this patient information carefully before using XYNTHA and emergency department if any allergic-type hypersensitivity reactions occur. Inform each time you get a refill. There may be new information. This leaflet patients of the early signs of hypersensitivity reactions (including hives [rash with does not take the place of talking with your healthcare provider about itching]), generalized urticaria, tightness of the chest, wheezing, hypotension) and anaphylaxis. your medical problems or your treatment. • contact their healthcare provider if they experience a lack of a clinical response to What is XYNTHA? factor VIII replacement therapy, as this may be a manifestation of an inhibitor. • notify their healthcare provider if they become pregnant or intend to become XYNTHA is an injectable medicine that is used to help control and pregnant during therapy, or if they are breastfeeding. reduce bleeding in people with hemophilia A. Hemophilia A is also called • Local irritation may occur when infusing XYNTHA SOLOFUSE. classic hemophilia. Your healthcare provider may give you XYNTHA when you have surgery. XYNTHA is not used to treat von Willebrand’s disease. What should I tell my healthcare provider before using XYNTHA? Tell your healthcare provider about all of your medical conditions, including if you: • have any allergies, including allergies to hamsters. • are pregnant or planning to become pregnant. It is not known if XYNTHA may harm your unborn baby. • are breastfeeding. It is not known if XYNTHA passes into your milk and if it can harm your baby. Tell your healthcare provider about all of the medicines you take, including all prescription and non-prescription medicines, such as over-the-counter medicines, supplements, or herbal remedies. How should I infuse XYNTHA? Step-by-step instructions for infusing with XYNTHA SOLOFUSE are provided at the end of this leaflet. The steps listed below are general guidelines for using XYNTHA SOLOFUSE. Always follow any specific instructions from your healthcare provider. If you are unsure of the procedures, please call your healthcare provider before using. Call your healthcare provider right away if bleeding is not controlled after using XYNTHA. Call your healthcare provider right away if you take more than the dose you should take. Talk to your healthcare provider before traveling. Plan to bring enough XYNTHA SOLOFUSE for your treatment during this time. What are the possible side effects of XYNTHA? Call your healthcare provider or go to the emergency department right away if you have any of the following symptoms because these may be signs of a serious allergic reaction: • wheezing • difficulty breathing • chest tightness • turning blue (look at lips and gums) • fast heartbeat • swelling of the face • faintness • rash • hives Common side effects of XYNTHA are • headache • joint pain • fever • cough Reconstitution • vomiting 1. Allow the XYNTHA SOLOFUSE to reach room temperature. • diarrhea 2. Remove the contents of the XYNTHA SOLOFUSE Kit and place • weakness on a clean surface, making sure you have all the supplies you will need. Your body can make antibodies against XYNTHA (called “inhibitors”) that may stop XYNTHA from working properly. Your healthcare provider 3. Grasp the plunger rod as shown in the following diagram. Do not touch the shaft of the plunger rod. Screw the plunger rod firmly may need to take blood tests from time to time to monitor for inhibitors. into the opening in the finger rest of the XYNTHA SOLOFUSE by Talk to your healthcare provider about any side effect that bothers pushing and turning firmly until resistance is felt (approximately you or that does not go away. You may report side effects to FDA at 2 turns). 1-800-FDA-1088. Throughout the reconstitution process, it is important to keep the How should I store XYNTHA SOLOFUSE? XYNTHA SOLOFUSE upright to prevent possible leakage. Store in the refrigerator at 36° to 46°F (2° to 8°C). Do not freeze. Protect from light. XYNTHA SOLOFUSE can last at room temperature (below 77°F) for up to 3 months. If you store XYNTHA SOLOFUSE at room temperature, carefully write down the date you put XYNTHA SOLOFUSE at room temperature, so you will know when to throw it away. There is a space 4. Holding the XYNTHA SOLOFUSE upright, remove the white tamper-evident seal by bending the seal right to left (or a gentle on the carton for you to write the date. rocking motion) to break the perforation of the cap and expose Throw away any unused XYNTHA SOLOFUSE after the expiration date. the grey rubber tip cap of the XYNTHA SOLOFUSE. Infuse within 3 hours after reconstitution or after removal of the grey rubber tip cap from the prefilled dual-chamber syringe. You can keep the reconstituted solution at room temperature before infusion for up to 3 hours. If it is not used in 3 hours, throw it away. Do not use reconstituted XYNTHA if it is not clear to slightly opalescent and colorless. Dispose of all materials, whether reconstituted or not, in an appropriate 5. Remove the protective blue vented sterile cap from its package. medical waste container. While holding the XYNTHA SOLOFUSE upright, remove the grey What else should I know about XYNTHA? rubber tip cap and replace it with the protective blue vented cap (prevents pressure build-up). Avoid touching the open end of Medicines are sometimes prescribed for purposes other than those both the syringe and the protective blue vented cap. listed here. Talk to your healthcare provider if you have any concerns. You can ask your healthcare provider for information about XYNTHA SOLOFUSE that was written for healthcare professionals. Do not share XYNTHA SOLOFUSE with other people, even if they have the same symptoms that you have.

Instructions for Use ® ® XYNTHA SOLOFUSE /ZIN-tha/ 6. Gently and slowly push the plunger rod until the two stoppers [Antihemophilic Factor (Recombinant)] inside the XYNTHA SOLOFUSE meet, and all of the diluent is XYNTHA SOLOFUSE is supplied as a pre-filled dual-chamber syringe transferred to the chamber containing the XYNTHA powder. with lyophilized XYNTHA powder in one chamber and 0.9% sodium Note: To prevent the escape of fluid from the tip of the syringe, chloride solution in the other chamber. Before you can infuse it do not push the plunger rod with excessive force. (intravenous injection), you must reconstitute the powder by mixing it with the sodium chloride solution. Reconstitute and infuse XYNTHA SOLOFUSE using the infusion set provided in this kit. Please follow the directions below for the proper use of this product. PREPARATION AND RECONSTITUTION OF XYNTHA SOLOFUSE Preparation 1. Always wash your hands before doing the following steps. 2. Keep everything clean and germ-free while you are reconstituting XYNTHA SOLOFUSE. 3. Once the syringes are open, finish reconstituting XYNTHA SOLOFUSE as soon as possible. This will help to keep them germ-free. 4. For additional instructions on the use of a XYNTHA SOLOFUSE and a XYNTHA vial or multiple XYNTHA SOLOFUSE, see the detailed information provided after INFUSION OF XYNTHA section. 7. With the XYNTHA SOLOFUSE remaining upright, swirl gently 2. Apply a tourniquet and prepare the injection site by wiping the several times until the powder is dissolved. skin well with an alcohol swab provided in the kit.

Look carefully at the solution in the XYNTHA SOLOFUSE. The 3. Remove the protective needle cover and insert the butterfly solution should be clear to slightly opalescent and colorless. If needle of the infusion set tubing into your vein as instructed by it is not, throw away the solution and use a new kit. your healthcare provider. Remove the tourniquet. Verify proper needle placement. 8. Holding the XYNTHA SOLOFUSE in an upright position, slowly advance the plunger rod until most, but not all, of the air is 4. Infuse the reconstituted XYNTHA product over several minutes. Your comfort level should determine the rate of infusion. removed from the drug product chamber.

5. After infusing XYNTHA, remove the infusion set and throw it Note: away. The amount of liquid left in the infusion set will not affect • If you are not using the solution immediately, store the your treatment. syringe upright and keep the protective blue vent cap on the Note: XYNTHA SOLOFUSE until ready to infuse. • Dispose of all unused solution, the empty XYNTHA SOLOFUSE, • Infuse XYNTHA solution within 3 hours after reconstitution or and other used medical supplies in an appropriate container. removal of the grey tip cap from the XYNTHA SOLOFUSE. The reconstituted solution may be kept at room temperature for up to 3 hours prior to infusion. If you have not used it in 3 hours, throw it away. • If more than one XYNTHA SOLOFUSE is needed for each infusion, a luer-to-luer syringe connector can be used (not included in this kit). Please contact your doctor or healthcare provider, or call the Wyeth Medical Information Department at • It is a good idea to record the lot number from the 1-800-438-1985, for additional information. XYNTHA SOLOFUSE label every time you use XYNTHA. You can use the peel-off label found on the XYNTHA SOLOFUSE to record INFUSION OF XYNTHA the lot number. Your healthcare provider will teach you how to infuse XYNTHA ADDITIONAL INSTRUCTIONS yourself. Once you learn how to do this, you can follow the instructions in this insert. XYNTHA is also supplied in kits that include single-use vials with lyophilized powder and prefilled diluent syringes. Before XYNTHA can be infused, you must reconstitute it as If you use one XYNTHA vial and one XYNTHA SOLOFUSE for the instructed above in the PREPARATION AND RECONSTITUTION OF infusion, reconstitute the XYNTHA vial and the XYNTHA SOLOFUSE XYNTHA SOLOFUSE section. according to the specific directions for that respective product kit. Use After reconstitution, be sure to look carefully at the XYNTHA solution. a separate, 10 milliliter or larger luer lock syringe (not included in this The solution should be clear to slightly opalescent and colorless. If it is kit) to draw back the reconstituted contents of the XYNTHA vial and the not, throw away the solution and use a new kit. XYNTHA SOLOFUSE. Use the infusion set included in the kit to infuse XYNTHA. Do not infuse If you use multiple XYNTHA SOLOFUSE kits for the infusion, XYNTHA in the same tubing or container with other medicines. reconstitute each XYNTHA SOLOFUSE according to the directions above. 1. After removing the protective blue vented cap, firmly attach Use a separate, 10 milliliter or larger luer lock syringe (not included the intravenous infusion set provided in the kit onto the in this kit) to draw back the reconstituted contents of any additional XYNTHA SOLOFUSE. XYNTHA SOLOFUSE. Use of a XYNTHA Vial Kit with a XYNTHA SOLOFUSE Kit These instructions are for the use of only one XYNTHA vial kit with one XYNTHA SOLOFUSE Kit. For further information, please contact your healthcare provider or call the Medical Information Department at Wyeth Pharmaceuticals, 1-800-438-1985. 1. Reconstitute the XYNTHA vial using the instructions included 7. Invert the XYNTHA vial and slowly draw the solution into the with the kit. Detach the empty diluent syringe from the vial adapter large luer lock syringe. by gently turning and pulling the syringe counterclockwise, leaving the contents in the XYNTHA vial with the vial adapter in place.

8. Detach the large luer lock syringe from the vial adapter by gently turning and pulling the syringe counterclockwise. Throw away 2. Reconstitute the XYNTHA SOLOFUSE using the instructions the empty XYNTHA vial with the adapter attached. included with the product kit, remembering to remove most, but 9. Attach the infusion set to the large luer lock syringe as directed in not all, of the air from the syringe. the INFUSION OF XYNTHA section. Note: Dispose of all unused solution, the empty XYNTHA SOLOFUSE, and other used medical supplies in an appropriate container.

3. After removing the protective blue vented cap, connect the XYNTHA SOLOFUSE to the vial adapter by inserting the tip into the adapter opening while firmly pushing and turning the syringe clockwise until secured. Use of Multiple XYNTHA SOLOFUSE Kits The instructions below are for the use of multiple XYNTHA SOLOFUSE kits with a 10 milliliter or larger luer lock syringe. For further information, please contact your healthcare provider or call the Medical Information Department at Wyeth Pharmaceuticals, 1-800-438-1985. Note: Luer-to-luer syringe connectors are not provided in the kits. Contact your XYNTHA supplier to order. 4. Slowly push the plunger rod of the XYNTHA SOLOFUSE to empty 1. Reconstitute all XYNTHA SOLOFUSE according to instructions the contents into the XYNTHA vial. The plunger rod may move described in PREPARATION AND RECONSTITUTION OF back slightly after release. XYNTHA SOLOFUSE section. Holding the XYNTHA SOLOFUSE in an upright position, slowly push the plunger rod until most, but not all, of the air is removed from the syringe.

5. Detach the empty XYNTHA SOLOFUSE from the vial adapter and throw it away. If the syringe turns without detaching from the vial adapter, grasp the white collar and turn. 2. Remove the luer-to-luer syringe connector from its package. 3. After removing the protective blue vented cap, connect a sterile 10 milliliter or larger luer lock syringe to one opening (port) in the syringe connector and the XYNTHA SOLOFUSE to the remaining open port on the opposite end.

6. Connect a sterile 10 milliliter or larger luer lock syringe to the vial adapter. You may want to inject some air into the vial to make withdrawing the vial contents easier. 4. With the XYNTHA SOLOFUSE on top, slowly push the plunger rod to empty all the XYNTHA SOLOFUSE content into the large luer lock syringe.

5. Remove the empty XYNTHA SOLOFUSE and repeat procedures 3 and 4 above for any additional XYNTHA SOLOFUSE. 6. Remove the luer-to-luer syringe connector from the large luer lock syringe and attach the infusion set as directed in the INFUSION OF XYNTHA section. Note: Dispose of all unused solution, the empty XYNTHA SOLOFUSE, and other used medical supplies in an appropriate container.

This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com.

Manufactured by

Wyeth Pharmaceuticals LLC A subsidiary of Pfizer Inc, Philadelphia, PA 19101

License no: 3 LAB-0500-12.0