BDDrFVIII (Moroctocog alfa [AF-CC]) for surgical ...either BI or CI for the management of surgical haemostasis in patients with severe and moderately severe haemophilia A undergoing

ORIGINAL ARTICLE

BDDrFVIII (Moroctocog alfa [AF-CC]) for surgicalhaemostasis in patients with haemophilia A: results of apivotal study

J. WINDYGA,* L. RUSEN,! R. GRUPPO," A. C. O’BRIEN,§ P. KELLY,§ D. A ROTH§ and S. ARKIN§

*Center for Haemophilia Treatment, Institute of Haematology and Transfusion Medicine, Warsaw, Poland; !NationalInstitute for Transfusional Haematology, Bucharest, Romania; "Cincinnati Children’s Hospital Medical Center,Cincinnati, OH; and §Pfizer Inc, Cambridge, MA, USA

Summary. Moroctocog alfa (AF-CC) (Xyntha!,BDDrFVIII) is manufactured by a process designedto enhance the theoretical viral safety profilerelative to ReFacto", its predecessor, and toprovide alignment with clinical monitoring by theone-stage clotting assay. To evaluate the efficacyand safety of B-domain-deleted recombinant factorVIII (BDDrFVIII) was given as bolus injection (BI)or continuous infusion (CI) in haemophilia patientsundergoing major surgery. BDDrFVIII was admin-istered by BI or CI per investigator discretion peri-operatively for at least 6 days. Thirty patientsenrolled and were treated with at least one doseof BDDrFVIII. Twenty-five patients were evaluablefor efficacy. Outcomes were favourable against abackground of multiple major surgical procedures.All haemostatic efficacy ratings were ‘excellent’ or‘good’. End-of-surgery haemostasis ratings, theprimary efficacy endpoint, were excellent for 72%(18/25) and good for 28% (7/25) of patients.

Haemostasis ratings following the initial postoper-ative period were excellent for 92% (23/25) andgood for 8% (2/25) of patients. Intra-operativeblood loss was rated as normal in all patients.Thirteen patients had postoperative blood loss; in10, this was rated as normal. A low frequency oftransfusion was reported in both the intra-opera-tive and postoperative settings. Adverse events(AEs) were consistent with surgery; three wereconsidered related to BDDrFVIII. One patient hada related AE of postoperative haemorrhage. A clin-ically silent low-titre inhibitor was detected in onepatient, and one patient had a false-positive inhib-itor titre. This study demonstrates that BDDrFVIIIis safe and efficacious for surgical prophylaxis inhaemophilia A patients undergoing major surgery.

Keywords: B-domain-deleted factor VIII, bolus injec-tion, continuous infusion, factor VIII inhibitors,haemophilia A, surgical haemostasis

Introduction

Improvements in the manufacture of recombinantfactor VIII (rFVIII) have been intended to reduce therisk of transmitting viral infection and to increaseease of use. Moroctocog alfa (AF-CC) (Xyntha!,BDDrFVIII) is a B-domain-deleted recombinant

factor VIII (BDDrFVIII) manufactured by a processthat has been modified to enhance the theoreticalviral safety profile relative to predecessor product,ReFacto" [1].In addition, the method for assignment of potency

for this preparation of BDDrFVIII has been alignedwith the one-stage clotting assay, thereby harmoniz-ing the labelled potency of the drug with routineclinical monitoring using the one-stage clotting assay[2]. Previous studies have demonstrated thatBDDrFVIII is safe and effective in the preventionand treatment of haemorrhages and has pharmaco-kinetic (PK) equivalence to full-length rFVIII [2].Factor VIII (FVIII) replacement therapy is critical

in maintaining haemostasis in patients with haemo-

Correspondence: Jerzy Windyga, MD, PhD, Head, Department ofDisorders of Haemostasis and Internal Medicine, Institute ofHaematology and Transfusion Medicine, 14 I. Gandhi Str., 02-776Warsaw, Poland.Tel.: +48 22 3496 158; fax: +48 22 3496 159;e-mail: [email protected]

Accepted after revision 10 February 2010

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

# 2010 Blackwell Publishing Ltd 1

philia A undergoing surgery. This is usuallyachieved by administering FVIII concentrate duringthe surgical and postsurgical periods, until woundhealing has been completed. Typically, replacementtherapy is administered by bolus injections (BI);however, reports suggest that administration bycontinuous infusion (CI) may be associated withreduced requirements for FVIII concentrate and lessfluctuation in FVIII activity plasma levels [3–8].This open-label study was conducted to assess thesafety and efficacy of BDDrFVIII administered byeither BI or CI for the management of surgicalhaemostasis in patients with severe and moderatelysevere haemophilia A undergoing elective majorsurgery.

Materials and methods

This was a phase 3, open-label, multicentre,prospective study performed at a total of 13 studysites in seven countries, including the United States,New Zealand, Russia, Sweden, Austria, Poland andRomania.The study was designed in accordance with the

suggestions provided by the Committee for Medic-inal Products for Human Use (CHMP) of theEuropean Medicines Agency (EMEA) and conductedin accordance with the International Conference onHarmonisation Guideline for Good Clinical Practice(GCP) and the ethical principles that have theirorigins in the Declaration of Helsinki. All patientsprovided written informed consent/assent prior tosurgery.

Patients

At least 25 patients were to be enrolled, including 12to be treated by CI. All patients were to be men‡12 years of age with severe or moderately severehaemophilia A undergoing elective major surgerythat was anticipated to require rFVIII infusions withmonitoring for at least 6 days after surgery. Majorsurgery was defined as surgery involving openabdominal, intracranial, orthopaedic, retroperito-neal, thoracic, pharyngeal, or retropharyngealprocedures, or invasive dental procedures involvingcomplicated extractions.Inclusion criteria included FVIII concentration

(FVIII:C) £2%, negative assays for FVIII inhibitorat both local and central laboratories at screening, anegative history of a FVIII inhibitor and ‡150 priorexposure days to treatment with any FVIII product.Patients were to have adequate liver and kidneyfunction, prothrombin time £1.25 times the upper

limit of normal or international normalized ratio£1.5 and an absolute CD4 count >200 cells lL)1.Patients being treated for human immunodeficiencyvirus (HIV) had to be on a stable antiviral regimen.Exclusion criteria included a bleeding disorder inaddition to haemophilia A, regular use of antifibrin-olytic agents or other agents known to influenceplatelet function and concomitant therapy withimmunosuppressive drugs.

Study design and treatment

Patients were designated to receive BDDrFVIII byeither BI or CI by the investigator at screening basedon investigator preference and local treatment prac-tices. At baseline (approximately 4 weeks beforesurgery), following a 3-day washout of all FVIIIproducts, a 50 IU kg)1 infusion of BDDrFVIII wasadministered for a recovery assessment in BI patientsand for PK assessment in CI patients to estimaterecovery and clearance rate, respectively. Investiga-tors reported their target FVIII activity level forsurgery and used results from the baseline assess-ments to plan the initial BDDrFVIII dose andinjection frequency (BI) or infusion rate (CI). Patientsreturned to their usual FVIII replacement therapyregimen after this assessment until the day of surgery.On the day of surgery, all patients received a bolus

loading dose of BDDrFVIII to achieve the previouslyplanned target plasma level of FVIII:C. Blood sam-ples were obtained before and after the loading doseto determine levels of FVIII:C. Patients treated by CIbegan a BDDrFVIII infusion approximately 30 minafter the start of the loading dose. Supplementalbolus doses (BI and CI) or rate adjustments (CI)could be made during the intra-operative period toaccount for possible variation in recovery and/or toaccount for individual variation from the expectedclearance if needed, based on subsequent determina-tions of FVIII:C.For administration by CI, BDDrFVIII was pre-

pared based upon the results from Neidhardt et al.[9]. Large volume preparations were prepared with afinal BDDrFVIII concentration of ‡10 IU mL)1

resuspended in either 5% dextrose solution ornormal saline, with minimum flow rates of 6 or20 mL h)1 respectively. Small doses of heparin(2–6 IU heparin mL)1 of infusate) could be addedto the solution to assist the administration of CI.Patients received BDDrFVIII for ‡6 consecutive

postoperative days (initial postoperative period) byBI or CI depending on the investigator-assignedtreatment. Inpatient postoperative care had to be‡2 days for BI patients and ‡6 days for CI patients;

2 J. WINDYGA et al.

Haemophilia (2010), 1–9 # 2010 Blackwell Publishing Ltd

daily assessments at the study site were requiredduring the first 6 days after surgery for all patients.During the initial postoperative period, preinfu-

sion blood samples for FVIII:C were obtainedapproximately 15 min before BI at least once daily.For CI patients, FVIII:C was measured and recordedeach day during infusion. If FVIII:C did notsufficiently approximate the target level, additionalBI could be administered for BI patients, or forCI patients, the infusion rate could be adjustedaccordingly. For CI patients, supplemental BIscould be used in conjunction with CI at theinvestigator’s discretion to acutely correct theFVIII:C to the predetermined target level. Anybleeding episodes occurring during either the initial(first 6 postoperative days or period until discharge,whichever occurred later) or final postoperativeperiod (remainder of treatment period up to a totalof 6 weeks) were to be treated with an on-demandinfusion(s) of BDDrFVIII.During the final postoperative period, patients

could continue postsurgical treatment withBDDrFVIII administered by BI on an outpatientbasis for a total of up to 6 weeks. The final study visitwas conducted at the end of this period, after whichthe patients could return to their respective pre-surgical regimens of commercially available FVIIIreplacement therapy. Approximately 4 weeks afterthe final visit, the patient completed the studyactivities with a final study contact.

Endpoints and assessments

The primary endpoint was haemostatic efficacyduring the surgical procedure through 1 h aftersurgery completion (referred to as end of surgery),as assessed by the investigator or surgeon. Theassessment was based on comparison to experiencewith similar patients undergoing similar procedures,using the four-point Surgical Hemostasis EfficacyRating Scale (Table 1).

Secondary efficacy endpoints were the four-pointSurgical Hemostasis Efficacy Scale rating as assessedon postoperative day 7 for previously discharged BIpatients or the day of hospital discharge for otherpatients; the total consumption of BDDrFVIII andconsumption per bleeding event; the number ofbleeding episodes and the efficacy of BDDrFVIII intreating the episode using a previously describedfour-point scale [2]; the comparison of the predictedand actual blood loss and transfusions and the PK ofBDDrFVIII in the patient population. Investigatorspredicted and recorded estimates of intra-operativeblood loss and intra-operative transfusion needspreoperatively based on the assumption that surgerywould be completed without major complications;blood loss was rated as ‘normal’ or ‘abnormal’.Information about infusions of study drug, bleedingepisodes (categorized as spontaneous or traumatic;expected surgical blood loss was not included incharacterizing bleeding episodes), blood loss andtransfusions was recorded intra-operatively andthroughout the trial in medical records and patientdiaries.The incidence of less-than-expected therapeutic

effect (LETE) was also evaluated in the prophylactic,on-demand and low recovery settings. Definitions ofLETE in these specific circumstances have beenpreviously described [2].Assessment of FVIII:C for preoperative planning

and to monitor intra-operative and postoperativedosing was performed using assays for FVIII:Cactivity performed at the local institution. Specimensfor central laboratory measurements of FVIII:C,using the one-stage clotting assay, were collected inparallel, analysed and used for analysis of PKparameters. For BI patients, the FVIII recovery studywas performed with blood samples for FVIII activitytaken within 2 h before and 15 min, 30 min and 1 hafter infusion of a dose of approximately 50 IU kg)1

of BDDrFVIII. For CI patients, PK parameters werecalculated to determine FVIII recovery and clearancevia blood samples drawn within 2 h before and15 min, 30 min, and 1, 3, 6, 9, 24, 28, 32 and 48 hafter infusion of a dose of approximately 50 IU kg)1

of BDDrFVIII.Safety evaluations included recording of adverse

events (AEs) [AEs and haemophilia events (AEsuniquely related to the condition of haemophilia orthe direct consequence of a bleeding episode)] andconcomitant treatments, physical examinations withmeasurements of vital signs and laboratory evalua-tions. Immunogenicity testing was performed by acentral laboratory (Covance Laboratories, Chantilly,VA, USA) on samples obtained at screening, baseline,

Table 1. Surgical haemostasis efficacy rating scale.

Rating Criteria

Excellent Achieved haemostasis comparable to that expectedafter similar surgery in a patient withouthaemophilia

Good Prolonged time to haemostasis, with somewhatincreased bleeding compared with that expectedafter similar surgery in a patient withouthaemophilia

Moderate Obviously delayed haemostasis, but manageablewith additional infusions

None No haemostatic response

BDDRFVIII FOR SURGICAL HAEMOSTASIS IN HAEMOPHILIA A 3

# 2010 Blackwell Publishing Ltd Haemophilia (2010), 1–9

day of surgery and final postoperative visits. Assess-ment of the presence of activity-neutralizing anti-bodies against FVIII (inhibitors) was performed usingthe Nijmegen modification of the Bethesda inhibitorassay and a normal plasma test base and reported inBethesda Units (BU); a patient was considered tohave developed a positive FVIII inhibitor if he had atitre of ‡0.6 BU mL)1 in a sample assayed at thecentral laboratory using the Nijmegen assay afterreceiving study drug. Specimens testing positive forinhibitor by Nijmegen assay were then tested byBethesda assay against a plasma-derived FVIII testbase and against a BDDrFVIII test base. Serumsamples were also tested for the development ofantibodies to BDDrFVIII; TN8.2, the affinity ligandused in purification of BDDrFVIII and CHO cellproteins derived from the cell line used in themanufacture of BDDrFVIII, using a validatedenzyme-linked immunosorbent assay (ELISA).

Statistical analysis

All safety analyses were performed on the intent-to-treat (ITT) population, which included all en-rolled patients who received ‡1 dose of study drug.The efficacy evaluable population, which was usedfor analyses of the primary and secondary efficacyendpoints, was the subset of ITT patients that meteligibility criteria, had a major surgical procedure,had study drug administered over a period of ‡6 daysafter surgery, had an efficacy assessment of studydrug use in support of surgery and did not have amajor protocol violation. Efficacy data on andsubsequent to the date of inhibitor developmentwere not included in efficacy analyses.All efficacy and safety endpoints were summarized

with descriptive statistics as appropriate. For contin-uous variables, number, mean, standard deviation(SD), median, minimum and maximum were pro-vided. For categorical variables, frequency and per-centage are presented for each category. Missing datawere not imputed. The sample size was based onclinical rather than statistical considerations and isconsistent with a sample size suggested by regulatoryauthorities.

Results

Patients

Thirty patients enrolled (22 BI, 8 CI) were treatedwith ‡1 dose of BDDrFVIII and were included in theITT population. A total of 29 patients underwentsurgery and completed the study; the remaining

patient withdrew for personal reasons before surgerybut had baseline PK determinations. Twenty-fivepatients met the criteria for inclusion in the efficacyevaluable population. Reasons for exclusion fromthis population were inhibitor development beforesurgery in one patient, protocol violations in threepatients (administration of autologous fresh frozenplasma during the surgical procedure) and termina-tion from the study prior to surgery in one patient.Median patient age was 34.5 years (range, 18–53).

Demographical and baseline illness characteristicswere generally similar between treatment groups,except for a greater proportional representation ofsevere disease (FVIII:C £ 1%) in the BI patientpopulation (Table 2).Most surgical procedures were orthopaedic; for

the efficacy evaluable population, the most commonwas the total joint replacements in 12 (48%) patients(11 total knee replacements and one hip replace-ment) and knee/elbow synovectomies in five (20%)patients.

Concomitant treatment

During the study, 29 of 30 (96.7%) patients usedconcomitant medications; most were thosecommonly used in the surgical setting. Non-studydrug FVIII concentrates were used by 14 patients(46.7%). This largely reflects FVIII replacementtherapy during the screening period and subsequentto the final visit, when patients used commercial

Table 2. Baseline demographics and clinical characteristics, allpatients.

Bolus injection,n = 22

Continuousinfusion, n = 8

Total,n = 30

Age, mean years 35.05 38.13 35.87Male, n (%) 22 (100.0) 8 (100.0) 30 (100.0)White race, n (%) 22 (100.0) 8 (100.0) 30 (100.0)Weight, mean kg 76.68 75.99 76.50Previous exposuredays ‡150, n (%)

22 (100.0) 8 (100.0) 30 (100.0)

Haemophilia severity, n (%)£1% 17 (77.3) 3 (37.5) 20 (66.7)>1% to £2% 5 (22.7) 5 (62.5) 10 (33.3)

Target joints, n (%)No 3 (13.6) 0 3 (10.0)Yes 19 (86.4) 8 (100) 27 (90.0)

HIV status, n (%)Negative 19 (86.4) 7 (87.5) 26 (86.7)Reactive 3 (13.6) 1 (12.5) 4 (13.3)

HCV status, n (%)Negative 3 (13.6) 1 (12.5) 4 (13.3)Reactive 19 (86.4) 7 (87.5) 26 (86.7)

HIV, human immunodeficiency virus; HCV, hepatitis C virus.

4 J. WINDYGA et al.


FVIII concentrate of their choice. At variancewith protocol-specified procedures, one patientadministered on-demand infusions of commerciallyavailable rFVIII on two occasions during the finalpostoperative period, once for the treatment of ahaemorrhage, and once for physiotherapy. Antifibri-nolytics were used by two patients (aminocaproicacid for 4 days and cyclokapron for 1 day; n = 1patient each). Pharmacotherapy for systemic throm-boprophylaxis was not administered to studypatients. Heparin flush was used for two BI patientsat one study site (surgical procedures: arthroscopicsynovectomy of the elbow) to establish and maintainpatency of peripherally inserted central catheterlines.

FVIII consumption

Extent of exposure to BDDrFVIII for the ITTpopulation is described in Table 3. Among the ITTpatients, the median total dose was 83 002 IU (range36 500–231 044 IU) for the BI patients and74 311 IU (range 4405–96 251 IU) for the CIpatients. BI patients received a median dose of25.5 IU kg)1 (range 8.4–72.9 IU kg)1) per infusionover a median of 43 (range 16–72) infusions. CIpatients received a mean ± SD rate of 3.7 ±0.9 IU kg)1 h)1 during the intra-operative periodand 2.8 ± 0.9 IU kg)1 h)1 in the initial postoperativeperiod. In addition, during the final postoperativeperiod, all CI patients received a median BI dose of13 IU kg)1 (range 5.6–47.2 IU kg)1) over a medianof 17 (range 13–29) infusions. Exposure data were

similar for the 25 patients who were evaluable forefficacy; the median total dose was 90 841 IU (range36 500–231 044 IU) for the BI patients and68 621 IU (range 50 854–96 251 IU) for the CIpatients. Owing to the non-random designation ofpatients to respective treatment groups and thelimited patient numbers in the CI group, no formalcomparison of consumption is possible.Two BI patients had a supplemental intra-opera-

tive dose of BDDrFVIII prompted by local laboratoryFVIII:C measurements below the predeterminedtarget FVIII:C level. For each CI patient, the initialrate of CI was informed by the respective study sitestandard of care rather than the clearance calculatedfrom the patient’s baseline PK assessment. All CI ofBDDrFVIII were administered by large volumepreparation, for six patients (all at one study site)using normal saline and for one patient (at anotherstudy site) using 5% dextrose in water (D5W) forBDDrFVIII resuspension. For each CI patient, therewas at least one occasion in which the infusionconcentration of BDDrFVIII was lower than theprotocol-specified limit (10 IU mL)1). For five CIpatients (all administered normal saline solution), theinfusion rate was less than the protocol-specifiedlimit (20 mL h)1) on at least one occasion.

Efficacy

Target FVIII:C levels in support of the surgicalprocedure ranged from 1.0 to 1.5 IU mL)1, reflectingthe varying local treatment practices of the respectivestudy sites. The median presurgical BDDrFVIII dosewas 50.6 IU kg)1 (range: 22.9–77.7 IU kg)1). Theresultant median postinfusion FVIII:C was0.97 IU mL)1 (range: 0.592–1.574 IU mL)1), withfive of 25 patients having preinfusion FVIII:C valuesof ‡0.03 IU mL)1. These data are consistent with theresults predicted by the baseline K-values.All haemostatic efficacy ratings were reported as

excellent or good during the intra-operative period,and similar results were reported for efficacy ratingsat the end of the initial postoperative period (Fig. 1).The percentage of evaluable (BI and CI combined)patients with a rating of excellent was 72% in theintra-operative period and 92% at day 7/day ofdischarge.Intra-operative blood loss was reported in 24 of

the 25 efficacy evaluable patients; for all patients,blood loss was rated as normal (Fig. 2). In 20 of 25patients, intra-operative blood loss was less than orequal to the volume predicted preoperatively. Thir-teen patients had postoperative blood loss; in 10cases, the blood loss was rated as normal. Of those

Table 3. BDDrFVIII exposure, all patients.

BI, n = 22 CI, n = 8*

Total units (IU per patient)Mean 92 608 66 247Median 83 002 74 311Range 36 500–231 044 4405*–96 251

Surgical dose, IU kg)1 per infusion)1 – median (range)Preoperative 49.3 (21.3–72.9) 49.8 (22.9–52.2)Intra-operative 25.8 (23.6–27.9) N/AInitial postoperative 30.4 (8.4–70.5) N/AFinal postoperative 23.4 (8.4–58.3) 13.0 (5.6–47.2)

Continuous infusion rate, IU kg )1h)1 per patient – mean ± SDIntra-operative N/A 3.7 ± 0.9Initial postoperative N/A 2.8 ± 0.9

Exposure days/patientMean ± SD 31.0 ± 7.2 25.5 ± 11.4Median 33 29Range 15–40 1*–37

BI, bolus injection; CI, continuous infusion; N/A, not applicable.*Includes one patient who only underwent a PK assessment anddid not undergo a surgical procedure.



rated as abnormal, one followed surgical trauma tothe epigastric artery, one was because of an 800 mLblood loss after hip replacement surgery and oneoccurred after an elbow synovectomy in which thelost blood was absorbed into the surgical dressingand could not be quantified by the investigator.Of the nine patients predicted to require red blood

cell (RBC) transfusions during the intra-operativeperiod, only one received a transfusion. Two patientspredicted not to require intra-operative RBC trans-fusion received transfusions with packed RBCs; forboth, blood loss was reported as normal. During the

postoperative period, three patients received RBCtransfusions, including the patient who had surgicaltrauma to the epigastric artery, and one patientreceived fresh frozen plasma.A total of 10 bleeding episodes in seven patients

were reported in the postoperative setting andrequired 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 of24.4 IU kg)1 and a median dose among CI patientsof 19.7 IU kg)1. Seven cases were due to injury, inthree instances affecting the joint that had undergonesurgery, and three cases were spontaneous. Nineepisodes were treated and resolved with a singleinfusion of study drug, and one bleeding episode oftraumatic origin required a second infusion. All butone of these episodes occurred during the finaloutpatient postoperative period. Response ratingsto the initial BDDrFVIII infusion to treat the episodewere excellent or good for all haemorrhages.There were two true events of LETE (i.e., in the

absence of confounding factors), both in theprophylactic setting with spontaneous bleeding with-in 48 h of a prophylactic dose of BDDrFVIII. In onepatient, the investigator reported at the final postop-erative visit that there had been a spontaneous soft

Fig. 1. Surgical haemostasis efficacy ratings, efficacy evaluablepopulation.

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

6 J. WINDYGA et al.


tissue bleeding episode 33.9 h after a prophylaticinfusion of BDDrFVIII. The second patient had aspontaneous bleeding episode of the right hip 1 dayafter total knee replacement while receiving treat-ment by CI. Steady-state FVIII:C was 100% and104% by the local and central laboratories respec-tively. The bleeding episode was not treated with anyBI of study drug. The patient required no additionaltransfusions. Haemostatic efficacy assessment at theconclusion of the initial postoperative period hadbeen reported as excellent.

Pharmacokinetics

PK data were available for all 30 patients. For bothBI and CI patients, the mean ± SD K-value was2.11 ± 0.43 IU dL)1 per IU kg)1, and themean ± SD in vivo recovery value was 101 ± 20%.For CI patients undergoing full PK assessments, themean plasma FVIII:C-vs.-time profiles increasedsharply after intravenous infusion of BDDrFVIII.After the end of the infusion, the decline of FVIII:Cexhibited biphasic disposition characteristics withrelatively rapid but limited distribution into anextravascular space followed by a slow eliminationphase with a mean ± SD t! of 16.7 ± 5.4 h.

Safety

Adverse events. There were no reported AEs ofallergic reaction or thrombosis. AEs occurring in>10% (>3 patients) of the study population werefever in 13 (43.3%), local reaction to procedure(postoperative pain in the operative wound) in 11(36.7%), anaemia in nine (30%), infection in five(16.7%) and headache and nausea in four patientseach (13.3%). AEs considered to be related toBDDrFVIII were one event of haemorrhage and oneevent of a false-positive inhibitor, both in the samepatient, and one event of FVIII inhibitor develop-ment in a second patient. Both events were reportedby the respective investigators as FVIII inhibition.Seven serious AEs (fever, postoperative haemor-rhage, accidental injury, cough increased, cellulitisand both events of FVIII inhibition) were reported infive patients. All except FVIII inhibition were con-sidered unrelated to BDDrFVIII and resolved. Thetwo reported instances of FVIII inhibition arediscussed below. There were no changes in labora-tory values that were considered to be related toBDDrFVIII. Unexpected bleeding in the postopera-tive period was reported as an AE for two patients.Both events (abnormal bleeding following surgicaltrauma to the epigastric artery and unquantifiable

blood loss into the surgical dressing after an arthro-scopic synovectomy of the elbow) were discussedabove.

Immunogenicity. Positive inhibitor results byNijmegen assay were reported (by the central labora-tory) for two patients, one of which had a trueinhibitor under complex clinical circumstances andthe other a false positive without clinical sequelae.The true inhibitor was detected in a patient whotested negative for inhibitors at screening and base-line, but subsequently had a low-titre inhibitor(0.9 BU mL)1) detected preoperatively by the centrallaboratory. Prior to inhibitor onset, he had onedose of BDDrFVIII for the PK study dose at the timeof his baseline assessment. Between the baselineassessment and the time of his surgery when theinitial positive preoperative inhibitor was detected,the patient had 3 days of treatment with commer-cially available plasma-derived FVIII to successfullycontrol a haemorrhage. As central laboratory resultsof the preoperative blood draw were not availableuntil after surgery, the patient underwent a surgicalknee synovectomy as planned. The patient wasadministered BDDrFVIII by BI for a total con-sumption of 66 920 IU. The patient’s preinhibitorbaseline K-value was 1.96 IU dL)1 per IU kg)1.Postinhibitor (prior to surgery), the patient’s K-valuewas 1.25 IU dL)1 per IU kg)1. Efficacy ratingswere excellent at end of surgery and at postoperativeday 7/day of discharge, blood loss was rated normaland the patient had no transfusion or bleedingepisode. At the final postoperative visit, the FVIIIinhibitor titre was 1.51 BU mL)1 as determined bythe central laboratory, and 1 BU mL)1 at final contactas determined by the local laboratory.The second patient had a false-positive low-titre

result (by central laboratory Nijmegen assay) at thefinal study visit. This low-titre FVIII inhibitor of0.63 BU mL)1 was reported by the central labora-tory (Nijmegen result), while the same specimentested negative in the central laboratory againstplasma-derived FVIII test base and againstBDDrFVIII test base, indicating that the positiveNijmegen assay result was spurious. In addition, thepaired local laboratory FVIII inhibitor result fromthis visit was also negative. At 2-month follow-up,the local laboratory reported a titre of 0.47 BU mL)1

(defined as a negative result) and the central labora-tory reported a titre of 0.0 BU mL)1. The ELISAresult from the final visit, when the isolated spuriouslow-titre inhibitor was noted, was negative for animmune response to BDDrFVIII, confirming thefalse-positive designation of this result.



One patient developed anti-BDDrFVIII antibodiesthat were considered a positive immune response byELISA at the final postoperative visit; there was noinhibitor development reported in this patient. Onepatient developed anti-CHO antibodies that wereconsidered a positive immune response by ELISA atthe final postoperative visit, with no reported asso-ciated allergic reaction. One patient had anti-TN8.2antibodies at study entry but did not have an immuneresponse following treatment with BDDrFVIII. Thesefindings in the absence of symptoms or otherevidence of FVIII neutralizing antibodies are ofunknown clinical significance.

Discussion

In this prospective clinical trial of patients undergo-ing elective major surgery, BDDrFVIII given by eitherBI or CI resulted in excellent haemostasis in mostpatients and good haemostasis in the remainder.Blood loss was rated as normal during the intra-operative period in all patients, and in the postop-erative period, abnormal bleeding was rare. Fewpatients required transfusions either intra-operativelyor postoperatively. Median total BDDrFVIII con-sumption per patient (by ITT analysis) was83 002 IU for BI and 74 311 IU for CI. BDDrFVIIIwas safe and well-tolerated, with a persistent low-titre inhibitor detected in one patient and a transientfalse-positive inhibitor detected in another patient.The central laboratory mean ± SD K-value ofBDDrFVIII (2.11 ± 0.43 IU dL)1 per IU kg)1)aligned with prior experience (2.35 ± 0.47 IU dL)1

per IU kg)1) [2].Findings in this study expand the published

evidence that BDDrFVIII is safe and effective in themanagement of patients with haemophilia. Resultsfrom this study are consistent with published expe-rience using the predecessor BDDrFVIII ReFactoproduct. In a prospective, multinational study of 38previously treated or untreated patients undergoing48 major or minor surgical procedures, patients weretreated preoperatively with ReFacto to attain atarget level of 0.5–1.0 IU mL)1 for major and0.2–0.5 IU mL)1 for minor surgery [10]. Duringthe peri-operative period, the mean dose per surgicalprocedure was 62 IU kg)1, and a total of 1759infusions were given over a median period of20 days. Surgical procedures were major in 31 cases.Haemostasis was rated excellent or good by thesurgeon for 99.6% of infusions given either intra-operatively or postoperatively. Blood loss and trans-fusion requirements were not greater than would beexpected for patients without haemophilia.

In a retrospective study of 16 patients withhaemophilia who had major surgical proceduresand were treated with ReFacto, all patients weretreated with preoperative BI followed by CI for aperiod of 5–21 days [11]. Intra-operative haemo-stasis was rated excellent or good in 12 (75%) ofpatients, and moderate in the remainder; there wasno evidence of insufficient FVIII levels in patientswith moderate ratings. Intra-operative blood losswas considered normal. Transfusions were requiredfor bleeding episodes in 20% of patients. Reasons forthe increased transfusion frequency and a greaterproportion of moderate ratings in that report oftreatment with predecessor product are unclear.Administration of BDDrFVIII by BI is most com-

monly used to manage haemophilia patients under-going surgical procedures and is considered thestandard of care. However, adjusted-dose CI hasbeen proposed to offer advantages over BI bypreventing both wasteful high FVIII peaks andsub-therapeutic FVIII concentrations [3–8]. Datafrom non-randomized studies suggest a lower inci-dence of decreases in haemoglobin and fewer trans-fusions in patients treated by CI [3]. BDDrFVIII hasbeen demonstrated to be stable in vitro in simulatedCI conditions [9]. This study provides initial, albeitlimited, data regarding administration of BDDrFVIIIby CI. Although BDDrFVIII was successfully admin-istered by CI in large volume preparations, therequisite 20 mL h)1 minimum infusion rate whenresuspended in normal saline was not easily main-tained; however, this had no apparent impact onclinical efficacy outcomes. Preparing BDDrFVIII forCI in D5W permits a minimum flow rate of 6 mL h)1

without excessive adsorption loss to tubing surfaces[9] and therefore provides greater flexibility.Although efficacy results were encouraging, addi-tional experience would be required to support anydefinitive conclusions regarding administration by CI.A high incidence of thromboembolic disease is

known to be associated with knee and hip jointreplacement surgery in non-haemophilic patients[12,13]. Despite the high proportion of joint replace-ment procedures in this study and the absence ofpharmacological systemic thrombophrophylaxis, noinstances of symptomatic thrombosis were observed.Potential explanations include the use of non-phar-macological/mechanical measures in a subset ofpatients (e.g., antiembolic stockings) and a youngerpatient population than might usually experiencereplacement surgery. An incidence of transfusions injoint replacement surgery as high as 67% has beenreported in general patient populations [14]. In thecurrent study, 4 of 12 (33%) patients who under-

8 J. WINDYGA et al.


went joint replacement surgery required transfusionsin the intra-operative or postoperative period; pro-viding additional evidence for the clinical efficacy ofFVIII replacement with BDDrFVIII in the surgicalsetting.The development of FVIII inhibitors is a serious

complication of treatment with FVIII. Treatment-related risk factors for inhibitor development includesurgery and a period of intensive treatment, which arehypothesized to increase risk by creating an inflam-matory state [15–17]. It has been suggested thattreatment using CI may increase this risk [18]. In thecurrent study, one patient treated by BI developed alow-titre inhibitor after exposure to a single dose ofstudy drug preoperatively followed by his usualreplacement therapy over 3 days; the low-titre inhib-itor was present at final follow-up in this patient. In asecond patient treated by BI, a transient false-positiveinhibitor was reported at the final study visit.In conclusion, the findings of this study provide

additional evidence that BDDrFVIII is efficacious forsurgical prophylaxis in haemophilia A patientsundergoing major surgery when administered eitherby intravenous bolus or CI. BDDrFVIII is associatedwith a favourable safety profile and low frequency ofimmune response.

Acknowledgements

Research funding was provided by Wyeth Pharma-ceuticals, Collegeville, PA, which was acquired byPfizer Inc in October, 2009. Professional medicalwriting assistance was provided by Naomi Pliskow,MD and funded by Wyeth Pharmaceuticals,which was acquired by Pfizer Inc in October, 2009.The authors would like to thank the followinginvestigators: Alice Ma, Elaine Eyster, Ingrid Pabin-ger, Vladimir Zorenko, Erik Berntorp, Mark Smithand Paul Harper.

Disclosures

L. Rusen has acted as a speaker for Wyeth Romaniaand have received a small fee for this contribution.R. Gruppo has acted as a paid consultant and as amedical advisory board member to Wyeth Pharma-ceuticals. A. C O’Brien, P. Kelly, D. Roth andS. Arkin are employees of Pfizer Inc.

References

1 Kelley BD, Booth J, Tannatt M et al. Isolation of a peptide ligandfor affinity purification of factor VIII using phage display.J Chromatogr A 2004; 1038: 121–30.

2 Recht M, Nemes L, Matysiak M et al. Clinical evaluation ofmoroctocog alfa (AF-CC), a new generation of B-domain deletedrecombinant factor VIII (BDDrFVIII) for treatment of haemo-philia A: demonstration of safety, efficacy, and pharmacokineticequivalence to full-length recombinant factor VIII. Haemophilia2009; 15: 869–80.

3 Batorova A, Martinowitz U. Intermittent injections vs. continuousinfusion of factor VIII in haemophilia patients undergoing majorsurgery. Br J Haematol 2000; 110: 715–20.

4 Batorova A, Martinowitz U. Continuous infusion of coagulationfactors. Haemophilia 2002; 8: 170–7.

5 Dingli D, Gastineau DA, Gilchrist GS, Nichols WL, Wilke JL.Continuous factor VIII infusion therapy in patients with haemo-philia A undergoing surgical procedures with plasma-derived orrecombinant factor VIII concentrates. Haemophilia 2002; 8:629–34.

6 Stachnik JM, Gabay MP. Continuous infusion of coagulationfactor products. Ann Pharmacother 2002; 36: 882–91.

7 Martinowitz U, Schulman S, Gitel S, Horozowski H, Heim M,Varon D. Adjusted dose continuous infusion of factor VIIIin patients with haemophilia. Br J Haematol 1992; 82: 729–34.

8 Martinowitz U, Luboshitz J, Bashari D et al. Stability, efficacy,and safety of continuously infused sucrose-formulatedrecombinant factor VIII (rFVIII-FS) during surgery in patientswith severe haemophilia. Haemophilia 2009; 15: 676–85.

9 Neidhart E, Koval R, Burke E, Warne N. In vitro evaluation ofB-domain deleted recombinant factor VIII (ReFacto) stabilityduring simulated continuous infusion administration. Haemo-philia 2005; 11: 319–25.

10 Lusher JM, Lee CA, Kessler CM, Bedrossians CL, for the ReFactoPhase III Study Group. The safety and efficacy of B-domaindeleted recombinant actor VIII concentrate in patients with severehaemophilia A. Haemophilia 2003; 9: 38–49.

11 Stieltjes N, Altisent C, Auerswald G et al. Continuous infusion ofB-domain deleted recombinant factor VIII (ReFacto) in patientswith haemophilia A undergoing surgery: clinical experience.Haemophilia 2004; 10: 452–8.

12 Geerts WH, Pineo GF, Heit JA et al. Prevention of venousthromboembolism: the Seventh ACCP Conference onAntithrombotic and Thrombolytic Therapy. Chest 2004; 126(3 Suppl.): 338S–400S.

13 Nicolaides AN, Fareed J, Kakkar AK et al. Prevention and treat-ment of venous thromboembolism. InternationalConsensusStatement (guidelines according to scientific evidence). Int Angiol2006; 25: 101–61.

14 Rosencher N, Kerkkamp HE, Macheras G et al. OrthopedicSurgery Transfusion Hemoglobin European Overview (OSTHEO)study: blood management in elective knee and hip arthroplasty inEurope. Transfusion 2003; 43: 459–69.

15 Ghosh K, Shetty S. Immune response to FVIII in hemophilia A: anoverview of risk factors. Clinic Rev Allerg Immunol 2009; 37: 58–66.

16 Ghosh K, Jijina F, Shetty S, Madkaikar M, Mohanty D. First-timedevelopment of FVIII inhibitor in haemophilia patients during thepostoperative period. Haemophilia 2002; 8: 776–80.

17 Gouw C, Van Den Berg HM, Le Cessie S, Van Der Bom JG.Treatment characteristics and the risk of inhibitor development:a multicenter cohort study among previously untreatedpatients with severe hemophilia A. J Thromb Haemost, 2007; 5:1383–90.

18 Eckhardt CL, Menke LA, van Ommen CH et al. Intensive peri-operative use of factor VIII and the Arg593 fi Cys mutation arerisk factors for inhibitor development in mild/moderate hemo-philia A. J Thromb Haemost 2009; 7: 930–7.



FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

XYNTHA, Antihemophilic Factor (Recombinant), is indicated for use in adults andchildren with hemophilia A (congenital factor VIII deficiency) for:• Control and prevention of bleeding episodes• Perioperative managementXYNTHA does not contain von Willebrand factor, and therefore is not indicated inpatients with von Willebrand’s disease.

2 DOSAGE AND ADMINISTRATIONFor intravenous use after reconstitution only.

2.1 Dose• Initiate treatment with XYNTHA under the supervision of a physician experienced in

the treatment of hemophilia A. • Dosage and duration of treatment depend on the severity of the factor VIII deficiency,

the location and extent of bleeding, and the patient’s clinical condition. Titrate theadministered doses to the patient’s clinical response.

• One International Unit (IU) of factor VIII activity corresponds approximately to thequantity of factor VIII in one milliliter of normal human plasma. The calculation of therequired dosage of factor VIII is based upon the empirical finding that, on average, 1 IU of factor VIII per kg body weight raises the plasma factor VIII activity byapproximately 2 IU/dL.2

The expected in vivo peak increase in factor VIII level expressed as IU/dL (or % normal)can be estimated using the following formulas:Dosage (International Units) = body weight (kg) x desired factor VIII rise (IU/dL or % ofnormal) x 0.5 (IU/kg per IU/dL)orIU/dL (or % normal) = Total Dose (IU)/body weight (kg) x 2 [IU/dL]/[IU/kg]

Control and Prevention of Bleeding Episodes

A guide for dosing XYNTHA for the control and prevention of bleeding episodes isprovided in Table 1. Maintain the plasma factor VIII activity at or above the levels (in %of normal or in IU/dL) outlined in Table 1 for the indicated period.

Table 1: Dosing for Control and Prevention of Bleeding Episodes

Type of Factor VIII Level Frequency DurationBleeding Required (IU/dL or of Doses ofEpisode % of normal) (hours) Therapy

MinorEarly hemarthrosis, 20–40 12-24 At least 1 day,minor muscle depending uponor oral bleeds. the severity of the

bleeding episode.ModerateBleeding into muscles. 30–60 12-24 3-4 days or untilMild head trauma. adequate localBleeding into the hemostasis oral cavity. is achieved.MajorGastrointestinal bleeding. 60–100 8-24 Until bleeding isIntracranial, intra-abdominal resolved.or intrathoracic bleeding. Fractures.

Perioperative Management

A guide for dosing XYNTHA during surgery (perioperative management) is provided inTable 2. Maintain the plasma factor VIII activity level at or above the level (in % ofnormal or in IU/dL) outlined in Table 2 for the indicated period. Monitor the replacementtherapy by means of plasma factor VIII activity.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use XYNTHA® safely andeffectively. See full prescribing information for XYNTHA®.XYNTHA® (antihemophilic factor [recombinant]) lyophilized powder for solution, forintravenous injectionInitial U.S. Approval: 2008------------------------------------ RECENT MAJOR CHANGES ----------------------------------- Indications and Usage (1) 10/2014------------------------------------ INDICATIONS AND USAGE ------------------------------------ • XYNTHA is a recombinant antihemophilic factor indicated in adults and children withhemophilia A for control and prevention of bleeding episodes and for perioperativemanagement. (1)

• XYNTHA is not indicated in patients with von Willebrand’s disease. (1)-------------------------------- DOSAGE AND ADMINISTRATION --------------------------------For intravenous use after reconstitution only (2)• The required dose is determined using the following formula: Required units = body weight (kg) x desired factor VIII rise (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL), where IU = International Unit.

• Frequency of XYNTHA administration is determined by the type of bleeding episode andthe recommendation of the treating physician. (2.1, 2.2)

------------------------------- DOSAGE FORMS AND STRENGTHS-------------------------------XYNTHA is available as lyophilized powder in single-use vials containing nominally 250,500, 1000, or 2000 IU. (3)

--------------------------------------- CONTRAINDICATIONS --------------------------------------Do not use in patients who have manifested life-threatening immediate hypersensitivityreactions, including anaphylaxis, to the product or its components, including hamsterproteins. (4)--------------------------------- WARNINGS AND PRECAUTIONS --------------------------------• Anaphylaxis and severe hypersensitivity reactions are possible. Patients may develophypersensitivity to hamster protein, which is present in trace amounts in XYNTHA. Shouldsuch reactions occur, discontinue treatment with the product and administer appropriatetreatment. (5.1)

• Development of activity-neutralizing antibodies has been detected in patients receivingfactor VIII-containing products, including XYNTHA. If expected plasma factor VIII activitylevels are not attained, or if bleeding is not controlled with an appropriate dose, performan assay that measures factor VIII inhibitor concentration. (5.2, 5.3, 6.2)

--------------------------------------- ADVERSE REACTIONS --------------------------------------• The most common adverse reactions (≥ 10%) with XYNTHA in adult and pediatric PTPswere headache, arthralgia, pyrexia, and cough. (6)

• Across all studies, 3 subjects developed factor VIII inhibitors (2.1%). (6.2)To report SUSPECTED ADVERSE REACTIONS, contact Wyeth Pharmaceuticals Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch-------------------------------- USE IN SPECIFIC POPULATIONS --------------------------------• Pregnancy: No human or animal data. Use only if clearly needed. (8.1)• Pediatrics: Half-lives are shorter, volumes of distribution are larger, and recovery is lowerafter XYNTHA administration in children. Higher or more frequent dosing may beneeded. (8.4)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labelingRevised: 10/2014

FULL PRESCRIBING INFORMATION: CONTENTS*1 INDICATIONS AND USAGE2 DOSAGE AND ADMINISTRATION 2.1 Dosing 2.2 Preparation and Reconstitution 2.3 Administration 2.4 Use of a XYNTHA Vial Kit and a XYNTHA SOLOFUSE™ Kit3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions 5.2 Neutralizing Antibodies 5.3 Monitoring Laboratory Tests6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Immunogenicity 6.3 Postmarketing Experience

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Labor and Delivery 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use11 DESCRIPTION12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology14 CLINICAL STUDIES15 REFERENCES16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION*Sections or subsections omitted from the full prescribing information are not listed

Table 2: Dosing for Perioperative ManagementType Factor VIII Level Frequency Durationof Required (IU/dL or of Doses of

Surgery % of normal) (hours) Therapy

MinorMinor operations, 30–60 12-24 3-4 days or untilincluding tooth adequate localextraction. hemostasis is

achieved. For tooth extraction, a single infusion plus oral antifibrinolytic therapy within 1 hour may be sufficient.

MajorMajor operations. 60-100 8-24 Until threat is

resolved, or in the case of surgery, until adequate local hemostasis and wound healing are achieved.

2.2 Preparation and ReconstitutionPreparation1. 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 tothe atmosphere.

Note:• 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 vialadapter in place. Use a separate 10 milliliter or larger luer lock syringe (not includedin this kit) to draw back the reconstituted contents of each vial. Do not detach thediluent syringe or the large luer lock syringe until ready to attach the large luer locksyringe to the next vial adapter.

• If the patient uses one vial of XYNTHA with one XYNTHA SOLOFUSE™ for theinfusion, reconstitute the vial and the syringe according to the instructions for eachrespective product kit. Use a separate 10 milliliter or larger luer lock syringe (notincluded in this kit) to draw back the reconstituted contents of the vial and thesyringe. [see Dosage and Administration (2.4)]

Reconstitution1. Allow the XYNTHA vial and the prefilled diluent syringe to reach room temperature. 2. Remove the plastic flip-top cap from the XYNTHA vial to expose the central portions

of the rubber stopper.

3. Wipe the top of the vial with the alcohol swab provided, or use another antisepticsolution, and allow to dry. After cleaning, do not touch the rubber stopper or allow itto touch any surface.

4. Peel back the cover from the clear plastic vial adapter package. Do not remove theadapter from the package.

5. Place the XYNTHA vial on a flat surface. While holding the adapter package, place thevial adapter over the XYNTHA vial and press down firmly on the package until theadapter spike penetrates the vial stopper.

6. Grasp the plunger rod as shown in the diagram. Avoid contact with the shaft of theplunger rod. Attach the threaded end of the plunger rod to the diluent syringe plungerby pushing and turning firmly.

7. Break off the tamper-resistant plastic tip cap from the diluent syringe by snapping theperforation of the cap. Do not touch the inside of the cap or the syringe tip. Thediluent syringe may need to be recapped (if not administering reconstituted XYNTHAimmediately), so place the cap on its top on a clean surface in a spot where it wouldbe least likely to become environmentally contaminated.

8. Lift the package away from the adapter and discard the package.

9. Place the XYNTHA vial, with the adapter attached, on a flat surface. Connect thediluent syringe to the vial adapter by inserting the tip into the adapter opening whilefirmly pushing and turning the syringe clockwise until secured.

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

11. Without removing the syringe, gently swirl the contents of the XYNTHA vial until thepowder is dissolved.

Note: The final solution should be inspected visually for particulate matter beforeadministration. The solution should be clear to slightly opalescent and colorless. If itis not, discard the solution and use a new kit.

12. Invert the XYNTHA vial and slowly draw the solution into the syringe.

13. Detach the syringe from the vial adapter by gently pulling and turning the syringecounterclockwise. Discard the empty XYNTHA vial with the adapter attached.

Note:• If the solution is not used immediately, carefully replace the syringe cap. Do not touch the syringe tip or the inside of the cap.• Store the reconstituted solution at room temperature prior to administration, but use within 3 hours after reconstitution.• 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 ofXYNTHA, 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 AdministrationFor intravenous infusion after reconstitution only.Inspect the final XYNTHA solution visually for particulate matter and discoloration priorto administration, whenever solution and container permit. The solution should be clearto 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 steriledisposable plastic syringe. Do not administer XYNTHA in the same tubing or containerwith 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.

3. Remove the protective needle cover and perform venipuncture. Insert the needle onthe infusion set tubing into the vein, and remove the tourniquet. Verify proper needleplacement.

4. Inject the reconstituted XYNTHA product intravenously over several minutes. The rateof administration should be determined by the patient’s comfort level.

5. After infusing XYNTHA, remove and discard the infusion set. The amount of drugproduct left in the infusion set will not affect treatment.

Note: Dispose of all unused solution, the empty vial(s), and other used medicalsupplies in an appropriate container.

2.4 Use of a XYNTHA Vial Kit with a XYNTHA SOLOFUSE™ KitThese instructions are for the use of only one XYNTHA Vial Kit with one XYNTHASOLOFUSE™ Kit. For further information, please contact the Medical InformationDepartment at Wyeth Pharmaceuticals, 1-800-438-1985.1. 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 vial and the vial adapter inplace.

3. Reconstitute the XYNTHA SOLOFUSE™ using the instructions included with theproduct kit, remembering to remove most, but not all, of the air from the drugproduct chamber.

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

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. 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.

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

8. Invert the vial and slowly draw the solution into the large luer lock syringe.

9. Detach the syringe from the vial adapter by gently turning and pulling the syringecounterclockwise. Discard the vial with the adapter attached.

10. Attach the infusion set to the large luer lock syringe as directed [see Dosage andAdministration (2.3)].

3 DOSAGE FORMS AND STRENGTHS XYNTHA is available as a white to off-white lyophilized powder in the following nominaldosages: • 250 International Units • 500 International Units • 1000 International Units • 2000 International UnitsEach XYNTHA vial has the actual recombinant factor VIII (rFVIII) potency in InternationalUnits stated on the label.

4 CONTRAINDICATIONS XYNTHA is contraindicated in patients who have manifested life-threatening immediatehypersensitivity reactions, including anaphylaxis, to the product or its components,including hamster proteins.

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions Allergic-type hypersensitivity reactions, including anaphylaxis, are possible withXYNTHA. Inform patients of the early signs or symptoms of hypersensitivity reactions(including hives [rash with itching], generalized urticaria, chest tightness, wheezing, andhypotension) and anaphylaxis. Discontinue XYNTHA if hypersensitivity symptoms occurand administer appropriate emergency treatment.XYNTHA contains trace amounts of hamster proteins. Patients treated with this productmay develop hypersensitivity to these non-human mammalian proteins.

5.2 Neutralizing Antibodies Inhibitors have been reported following administration of XYNTHA. Monitor patients forthe development of factor VIII inhibitors by appropriate clinical observations andlaboratory tests. If expected factor VIII activity plasma levels are not attained, or ifbleeding is not controlled with an appropriate dose, perform an assay that measuresfactor VIII inhibitor concentration to determine if a factor VIII inhibitor is present [seeWarnings and Precautions (5.3)].4,5,6,7,8,9,10,11,12

5.3 Monitoring Laboratory Tests • Use individual factor VIII values for recovery and, if clinically indicated, other

pharmacokinetic characteristics to guide dosing and administration. • 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, whenclinically indicated [see Dosage and Administration (2)].

• Monitor for development of factor VIII inhibitors. Perform assay to determine iffactor VIII inhibitor is present when expected factor VIII activity plasma levels arenot attained, or when bleeding is not controlled with the expected dose of XYNTHA.Use Bethesda Units (BU) to titer inhibitors.

6 ADVERSE REACTIONSThe most common adverse reactions (≥ 10%) with XYNTHA in adult and pediatric PTPswere headache, arthralgia, pyrexia, and cough.

6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reactionrates observed in the clinical trials of a drug cannot be directly compared to rates in theclinical trials of another drug and may not reflect the rates observed in clinical practice.XYNTHA was evaluated in five clinical studies (N=155), four completed studies withadult and pediatric PTPs and one ongoing study in pediatric PTPs < 6 years of age.The safety and efficacy of XYNTHA was evaluated in two completed pivotal studies. Inthe first study (n=94), safety and efficacy were examined in previously treated patients(PTPs) with hemophilia A (factor VIII activity in plasma [FVIII:C] ≤ 2%) who receivedXYNTHA for routine prophylaxis and on-demand treatment. Ninety-four subjectsreceived at least one dose of XYNTHA, resulting in a total of 6,775 infusions [seeClinical Studies (14)]. The second study (n=30) examined the use of XYNTHA forsurgical prophylaxis in previously treated patients with severe or moderately severe

hemophilia A (FVIII:C ≤ 2%) who required elective major surgery and were expected to receive XYNTHA replacement therapy for at least 6 days post-surgery. All subjectsreceived at least one dose of XYNTHA, resulting in 1161 infusions. One subject receivedXYNTHA for a pre-surgery pharmacokinetic assessment only and did not undergosurgery. [see Clinical Studies (14)]Across all studies, safety was evaluated in 48 previously treated pediatric patients <16 years of age (28 children, < 6 years of age and 20 adolescents, 12 to <16 years ofage). A total of 7,150 infusions of XYNTHA were administered with a median dose perinfusion of 29 IU/kg (min, max: 9,108 IU/kg).Across all studies, the most common adverse reactions (≥ 10%) with XYNTHA in adultand pediatric PTPs were headache (26% of subjects), arthralgia (25%), pyrexia (21%),cough (11%). Other adverse reactions reported in ≥ 5% of subjects were: diarrhea(8%), vomiting (7%), asthenia (7%), and nausea (6%).

6.2 ImmunogenicityThere is a potential for immunogenicity with therapeutic proteins. The development offactor VIII inhibitors with XYNTHA was evaluated in 144 adult and pediatric PTPs with at least 50 EDs. Laboratory-based assessments for FVIII inhibitor (partial Nijmegenmodification of the Bethesda inhibitor assay) were conducted in the clinical studies. The criterion for a positive FVIII result test result was ≥ 0.6 BU/mL. Across all studies, 3 subjects developed factor VIII inhibitors (2.1%).The clinical studies for XYNTHA examined 124 subjects (94 for bleeding and 30 forsurgery) who had previously been treated with factor VIII (PTPs). In the safety andefficacy study, two subjects with inhibitors were observed in 89 subjects (2.2%) whocompleted ≥ 50 exposure days. In a Bayesian statistical analysis, results from this studywere used to update PTP results from a prior supporting study using XYNTHAmanufactured at the initial facility (with one de novo and two recurrent inhibitorsobserved in 110 subjects) and the experience with predecessor product (with oneinhibitor observed in 113 subjects). The Bayesian analysis indicated that the populationinhibitor rate for XYNTHA, an estimate of the 95% upper limit of the true inhibitor rate,was 4.17%.None of the PTPs developed anti-CHO (Chinese hamster ovary) or anti-TN8.2 antibodies.One PTP developed anti-FVIII antibodies; but, this subject did not develop an inhibitor.In the surgery study, one low titer persistent inhibitor and one transient false-positiveinhibitor were reported. In this study, one surgical subject developed anti-CHO cellantibodies with no associated allergic reaction. One subject developed anti-FVIIIantibodies; but, this subject did not develop an inhibitor.Across all studies, safety was evaluated in 40 previously treated pediatric patients <16 years of age with at least 50 EDs (25 children, <6 years of age and 15 adolescents,12 to <16 years of age). Of these, one pediatric subject developed an inhibitor. The detection of antibody formation is highly dependent on the sensitivity and specificityof the assay. Additionally, the observed incidence of antibody, including neutralizingantibody, positivity in an assay may be influenced by several factors, including assaymethodology, sample handling, timing of sample collection, concomitant medications,and underlying disease. For these reasons, comparisons of the incidence of antibodiesto XYNTHA with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing ExperienceBecause these reactions are reported voluntarily from a population of uncertain size, it isnot always possible to reliably estimate their frequency or establish a causal relationshipto drug exposure.

The following postmarketing adverse reactions have been reported for XYNTHA: AnaphylaxisInadequate therapeutic response

8 USE IN SPECIFIC POPULATIONS

8.1 PregnancyPregnancy Category C. Animal reproduction studies have not been conducted withXYNTHA. It is not known whether XYNTHA can cause fetal harm when administered to apregnant woman or can affect reproduction capacity. XYNTHA should be given to apregnant woman only if clinically indicated.

8.2 Labor and DeliveryThere is no information available on the effect of factor VIII replacement therapy onlabor and delivery. XYNTHA should be used only if clinically indicated.

8.3 Nursing MothersIt is not known whether this drug is excreted into human milk. Because many drugs areexcreted into human milk, caution should be exercised if XYNTHA is administered tonursing mothers. XYNTHA should be given to nursing mothers only if clinicallyindicated.

8.4 Pediatric UseIn the completed open label safety and efficacy study of XYNTHA (n=94), 17 adolescent subjects 12 to <16 years of age with severe or moderately severe hemophilia A (FVIII:C ≤ 2%), who were previously treated with at least 150 EDs to FVIII products, received XYNTHA for on-demand and follow-up treatment. Themedian dose per infusion was 47 IU/kg (min-max: 24-74) and the median exposure per subject was 6 days (min-max: 1-26).

Of the 17 subjects < 16 yrs of age who received at least 1 dose of XYNTHA, 10 subjectshad bleeding episodes during the study. Among the 10 subjects with responseassessments, a total of 66 bleeding episodes were treated with on-demand infusions ofXYNTHA. The majority of the bleeding episodes (63/66 or 95.5%) resolved with 1 or 2infusions. Thirty-eight (38) of 66 bleeding episodes (57.6%) were rated excellent orgood in their response to initial treatment, 24 (36.4%) were rated as moderate and 4(6.1%) were not rated.Additional data are available from a safety and efficacy study of XYNTHA in children < 6 years of age with moderately severe or severe hemophilia A (FVIII:C ≤ 2%) and withat least 20 prior EDs to FVIII products. In this study subjects received XYNTHA for on-demand and follow-up treatment of bleeding episodes. The median dose per infusionwas 28 IU/kg and the median exposure per subject was 16 days.Of the 27 subjects < 6 years of age who received at least 1 dose of XYNTHA, 25 hadbleeding episodes during the study. Among the 24 subjects with response assessmentsthere were 493 bleeds. The majority of the bleeding episodes (462/493 or 93.7%)resolved with 1 or 2 infusions. Subjects rated the outcomes of infusions on a pre-specified four (4) point hemostatic efficacy scale. Of 493 bleeding episodes treated withXYNTHA, 468 (94.9%) were rated excellent or good in their response to initial treatmentand 22 (4.5%) were rated as moderate.In comparison to the pharmacokinetic parameters reported in adults, children haveshorter half-lives, larger volumes of distribution and lower recovery of factor VIII after XYNTHA administration. The clearance (based on per kg body weight) isapproximately 40% higher in children. Higher or more frequent doses may be requiredto account for the observed differences in pharmacokinetic parameters. [see ClinicalPharmacology (12.3)]

8.5 Geriatric UseClinical studies of XYNTHA did not include subjects aged 65 and over. In general, doseselection for an elderly patient should be individualized.

11 DESCRIPTIONThe active ingredient in XYNTHA, Antihemophilic Factor (Recombinant), is arecombinant antihemophilic factor (rAHF), also called coagulation factor VIII, which isproduced by recombinant DNA technology. It is secreted by a genetically engineeredChinese hamster ovary (CHO) cell line. The cell line is grown in a chemically defined cellculture medium that contains recombinant insulin, but does not contain any materialsderived from human or animal sources.The rAHF in XYNTHA is a purified glycoprotein, with an approximate molecular mass of170 kDa consisting of 1,438 amino acids, which does not contain the B-domain.13 Theamino acid sequence of the rAHF is comparable to the 90 + 80 kDa form of humancoagulation factor VIII. The purification process uses a series of chromatography steps, one of which is basedon affinity chromatography using a patented synthetic peptide affinity ligand.14 Theprocess also includes a solvent-detergent viral inactivation step and a virus-retainingnanofiltration step. The potency expressed in International Units (IU) is determined using the chromogenicassay of the European Pharmacopoeia. The Wyeth manufacturing reference standard forpotency has been calibrated against the World Health Organization (WHO) InternationalStandard for factor VIII activity using the one-stage clotting assay. The specific activityof XYNTHA is 5,500 to 9,900 IU per milligram of protein. XYNTHA is formulated as a sterile, nonpyrogenic, no preservative, lyophilized powderpreparation for intravenous injection. Each single-use vial contains nominally 250, 500,1000, or 2000 IU of XYNTHA. Upon reconstitution, the product is a clear to slightlyopalescent, colorless solution that contains sodium chloride, sucrose, L-histidine,calcium chloride, and polysorbate 80.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

XYNTHA temporarily replaces the missing clotting factor VIII that is needed for effectivehemostasis.

12.2 PharmacodynamicsThe activated partial thromboplastin time (aPTT) is prolonged in patients withhemophilia. Determination of aPTT is a conventional in vitro assay for biological activityof factor VIII. Treatment with XYNTHA normalizes the aPTT over the effective dosingperiod.

12.3 PharmacokineticsThe pharmacokinetic parameters of XYNTHA in 30 previously treated adult patients(PTP) 12 to 60 years old, who received a single infusion of 50 IU/kg XYNTHA aresummarized in Table 3.In addition, 25 of the same subjects later received a single infusion of 50 IU/kg ofXYNTHA for a 6-month follow-up pharmacokinetic study. The parameters werecomparable between baseline and 6 months, indicating no time-dependent changes inthe pharmacokinetics of XYNTHA.In a separate study, 8 of 30 subjects at least 12 years old with hemophilia A undergoingelective major surgery received a single 50 IU/kg infusion of XYNTHA. Thepharmacokinetic parameters in these subjects are also summarized in Table 3.

Table 3: Mean ± SD XYNTHA Pharmacokinetic Parameters in Previously Treated Patients with Hemophilia A after Single 50 IU/kg Dose

Initial Visit Pre-surgeryParameter (n=30) Month 6 (n=25) (n=8)

Cmax (IU/mL) 1.08 ± 0.22 1.24 ± 0.42 1.08 ± 0.24AUC

∞(IU·hr/mL) 13.5 ± 5.6 15.0 ± 7.5 16.0 ± 5.2

t1/2 (hr) 11.2 ± 5.0 11.8 ± 6.2* 16.7 ± 5.4CL (mL/hr/kg) 4.51 ± 2.23 4.04 ± 1.87 3.48 ± 1.25Vss (mL/kg) 66.1 ± 33.0 67.4 ± 32.6 69.0 ± 20.1Recovery 2.15 ± 0.44 2.47 ± 0.84 2.17 ± 0.47(IU/dL per IU/kg)

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 ofsubjects; SD = standard deviation; Vss = volume of distribution at steady-state.*One subject was excluded from the calculation due to lack of a well-defined terminalphase.

Table 4 shows the pharmacokinetic parameters of nine children; four aged 14 or 15years of age, who are also included in the summary for the adults above, along with fivechildren aged 3.7-5.8 years after single 50 IU/kg doses of XYNTHA. Compared to adults,the half-life of XYNTHA is shorter in children and the clearance (based on per kg bodyweight) is approximately 40% higher in children.

Table 4: Mean ± SD XYNTHA Pharmacokinetic Parameters in Previously TreatedPediatric Patients with Hemophilia A after Single 50 IU/kg Dose

Parameter Young Children (n=5) Adolescents (n=4)Age (min - max, yr)) 3.7 - 5.8 14 - 15Cmax (IU/mL) 0.78 ± 0.34 0.97 ± 0.21AUC

∞(IU·hr/mL) 12.2 ± 6.50 8.5 ± 4.0

t1/2 (hr) 8.3 ± 2.7 6.9 ± 2.4CL (mL/hr/kg) 6.29 ± 4.87 6.62 ± 2.16Vss (mL/kg) 66.9 ± 55.6 67.1 ± 13.6Recovery 1.52 ± 0.69 1.95 ± 0.41(IU/dL per IU/kg)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 ofsubjects; SD = standard deviation; Vss = volume of distribution at steady-state.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No studies have been conducted with XYNTHA to assess its mutagenic or carcinogenicpotential. XYNTHA has been shown to be comparable to the predecessor product withrespect to its biochemical and physicochemical properties, as well as its nonclinical invivo pharmacology and toxicology. By inference, predecessor product and XYNTHAwould be expected to have equivalent mutagenic and carcinogenic potential. Thepredecessor product has been shown to be nongenotoxic in the mouse micronucleusassay. No studies have been conducted in animals to assess impairment of fertility orfetal development.

13.2 Animal Toxicology and/or PharmacologyPreclinical studies evaluating XYNTHA in hemophilia A dogs without inhibitorsdemonstrated safe and effective restoration of hemostasis. XYNTHA demonstrated atoxicological profile that was similar to the toxicological profile observed with thepredecessor product. Toxicity associated with XYNTHA was primarily associated withanti-FVIII neutralizing antibody generation first detectable at 15 days of repeat dosing inhigh (approximately 735 IU/kg/day) level-dosed, non-human primates.

14 CLINICAL STUDIES Safety and Efficacy StudyIn an open label safety and efficacy study (n=94), subjects received XYNTHA in a routineprophylaxis treatment regimen with on-demand treatment administered as clinicallyindicated. All 94 subjects were treated with at least one dose and all are included in theintent-to-treat (ITT) population. All subjects had been previously treated (previously treatedpatients or PTPs) with factor VIII. Eighty-nine (89) subjects accrued ≥ 50 exposure days(EDs). Median age for the 94 treated subjects was 24 years (mean 27.7 and range 12-60years). All subjects had ≥ 150 previous exposure days with baseline FVIII activity level of ≤ 2%. Of the 94 subjects enrolled in this study, 30 evaluable subjects participated in a randomizedcrossover pharmacokinetics study. Twenty-five (25/30) of these subjects with FVIII:C ≤ 1%completed both the first (PK1) and the second (PK2) pharmacokinetic assessments [seeClinical Pharmacology (12.3)].16

For routine prophylaxis, XYNTHA was administered at a dose of 30 ± 5 IU/kg 3 times a weekwith provisions for dose escalation based on pre-specified criteria. Seven dose escalationswere prescribed for 6 subjects during the course of the study. Forty-three subjects (43/94 or45.7%) reported no bleeding while on routine prophylaxis. The median annualized bleedingrate (ABR) for all bleeding episodes was 1.9 (mean 3.9, range 0-42.1).Fifty-three subjects (53/94) received XYNTHA on-demand treatment for a total of 187bleeding episodes. Seven of these bleeding episodes occurred in subjects prior to switchingto a prophylaxis treatment regimen. One hundred ten of 180 bleeds (110/180 or 61.1%)occurred ≤ 48 hours after the last dose and 38.9% (70/180 bleeds) occurred > 48 hours afterthe last dose. The majority of bleeds reported to occur ≤ 48 hours after the last prophylaxisdose were traumatic (64/110 bleeds or 58.2%). Forty-two bleeds (42/70 or 60%) reported tooccur > 48 hours after the last prophylaxis dose were spontaneous. The on-demand

treatment dosing regimen was determined by the investigator. The median dose for on-demand treatment was 30.6 IU/kg (range 6.4 to 74.4 IU/kg). The majority of bleeding episodes (173/187 or 92.5%) resolved with 1 or 2 infusions (Table5). Subjects rated the outcomes of infusions on a pre-specified four (4) point hemostaticefficacy scale. One hundred thirty-two of 187 bleeding episodes (132/187 or 70.6%) treatedwith XYNTHA were rated excellent or good in their response to initial treatment, 45 (24.1%)were rated moderate. Five (2.7%) were rated no response, and 5 (2.7%) were not rated.

Table 5: Summary of Response to Infusions to Treat New Bleeding Episode byNumber of Infusions Needed for Resolution

Number of Infusions (%) Response Total Numberto 1st Infusion 1 2 3 4 > 4 of Bleeds

Excellenta 42 (95.5) 2 (4.5) 0 (0.0) 0 (0.0) 0 (0.0) 44Goodb 69 (78.4) 16 (18.2) 3 (3.4) 0 (0.0) 0 (0.0) 88Moderatec 24 (53.3) 16 (35.6) 2 (4.4) 0 (0.0) 3 (6.7) 45No Responsed 0 (0.0) 0 (0.0) 2 (40.0) 2 (40.0) 1 (20.0) 5Not Assessed 4 (80.0) 0 (0.0) 0 (0.0) 1 (20.0) 0 (0.0) 5e

Total 139 (74.3) 34 (18.2) 7 (3.7) 3 (1.6) 4 (2.1) 187a Excellent: Definite pain relief and/or improvement in signs of bleeding starting within 8 hoursafter an infusion, with no additional infusion administered.b Good: Definite pain relief and/or improvement in signs of bleeding starting within 8 hoursafter an infusion, with at least one additional infusion administered for complete resolution ofthe bleeding episode.c Moderate: Probable or slight improvement starting after 8 hours following the infusion, withat 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 intervalfollowing an infusion, or condition worsens.e Includes one infusion with commercial FVIII that occurred before routine prophylaxis began.

Perioperative Management StudyIn an open-label study (n=30) for surgical prophylaxis in subjects with hemophilia A,XYNTHA was administered to 25 efficacy-evaluable PTPs with severe or moderately severe(FVIII:C ≤ 2%) hemophilia A undergoing major surgical procedures (11 total kneereplacements, 1 hip replacement, 5 synovectomies, 1 left ulnar nerve transposition release,1 ventral hernia repair/scar revision, 1 knee arthroscopy, 1 revision and debridement of theknee after a total knee replacement, 1 hip arthroplasty revision, 1 stapes replacement, 1ankle arthrodesis, and 1 pseudotumor excision).17

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 initialpostoperative period were “excellent” or “good” for all assessments. Intraoperative bloodloss was reported as “normal” or “absent” for all subjects. Thirteen of the subjects (13/25or 52%) had blood loss in the postoperative period. The postoperative blood loss was ratedas “normal” for ten of these cases while three cases were rated “abnormal” (1 due tohemorrhage following surgical trauma to the epigastric artery, 1 due to an 800 mL bloodloss after hip replacement surgery, and 1 after an elbow synovectomy where the blood losscould not be measured by the investigator).

Table 6: Summary of Hemostatic Efficacy

Time of Hemostatic Efficacy Assessment Excellenta Goodb Number of subjects

End of surgery 18 (72%) 7 (28%) 25 End of initial postoperative periodc 23 (92%) 2 (8%) 25a Excellent : Achieved hemostasis comparable to that expected after similar surgery in a patientwithout hemophilia.b Good: Prolonged time to hemostasis, with somewhat increased bleeding compared with thatexpected after similar surgery in a patient without hemophiliac End of initial postoperative period is date of discharge or postoperative Day 6, whicheveroccurs later.

15 REFERENCES1. Nilsson IM, Berntorp EE and Freiburghaus C. Treatment of patients with factor VIII

and IX inhibitors. Thromb Haemost. 1993;70(1):56-59.2. Hoyer LW. Hemophilia A. N Engl J Med. 1994;330:38-47.3. Juhlin F. Stability and Compatibility of Reconstituted Recombinant Factor VIII SQ,

250 IU/ml, in a System for Continuous Infusion. Pharmacia Document 9610224,1996.

4. Ehrenforth S, Kreuz W, Scharrer I, et al. Incidence of development of factor VIII andfactor IX inhibitors in hemophiliacs. Lancet. 1992;339:594-598.

5. Lusher J, Arkin S, Abildgaard CF, Schwartz RS, the Kogenate PUP Study Group.Recombinant factor VIII for the treatment of previously untreated patients withhemophilia A. N Engl J Med. 1993;328:453-459.

6. Bray GL, Gomperts ED, Courter S, et al. A multicenter study of recombinant factorVIII (Recombinate): safety, efficacy, and inhibitor risk in previously untreatedpatients with hemophilia A. Blood. 1994;83(9):2428-2435.

7. Kessler C, Sachse K. Factor VIII:C inhibitor associated with monoclonal-antibodypurified FVIII concentrate. Lancet. 1990;335:1403.

8. Schwartz RS, Abildgaard CF, Aledort LM, et al. Human recombinant DNA-derivedantihemophilic factor (factor VIII) in the treatment of hemophilia A. N Engl J Med.1990;323:1800-1805.

9. White GC II, Courter S, Bray GL, et al. A multicenter study of recombinant factor VIII(Recombinate™) in previously treated patients with hemophilia A. Thromb Haemost.1997;77(4):660-667.

10. Gruppo R, Chen H, Schroth P, et al. Safety and immunogenicity of recombinantfactor VIII (Recombinate™) in previously untreated patients: A 7.3 year update.Haemophilia. 1998;4:228 (Abstract No. 291, XXIII Congress of the WFH, TheHague).

11. Scharrer I, Bray GL, Neutzling O. Incidence of inhibitors in haemophilia A patients - areview of recent studies of recombinant and plasma-derived factor VIII concentrates.Haemophilia. 1999;5:145-154.

12. Abshire TC, Brackmann HH, Scharrer I, et al. Sucrose formulated recombinanthuman antihemophilic Factor VIII is safe and efficacious for treatment of hemophiliaA in home therapy: Results of a multicenter, international, clinical investigation.Thromb Haemost. 2000;83(6):811-816.

13. Sandberg H, Almstedt A, Brandt J, Castro VM, Gray E, Holmquist L, et al. Structuraland Functional Characterization of B-Domain Deleted Recombinant Factor VIII. SemHematol. 2001;38 (Suppl. 4):4-12.

14. Kelley BD, Tannatt M, Magnusson R, Hagelberg S. Development and Validation of anAffinity Chromatography Step Using a Peptide Ligand for cGMP Production of FactorVIII. Biotechnol Bioeng. 2004;87(3):400-412.

15. Mann KG and Ziedens KB. Overview of Hemostasis. In: Lee CA, Berntorp EE andHoots WK, eds. Textbook of Hemophilia. USA, Blackwell Publishing; 2005:1-4.

16. Recht M, Nemes L, Matysiak M et al. Clinical Evaluation of Moroctocog Alfa (AF-CC),a New Generation of B-Domain Deleted Recombinant Factor VIII (BDDrFVIII) forTreatment of Haemophilia A: Demonstration of Safety, Efficacy and PharmacokineticEquivalence to Full-length Recombinant Factor VIII. Haemophilia 2009; 1-12.

17. Windyga J, Rusen L, Gruppo R, et al. BDDrFVIII (Moroctocog alfa [AF-CC]) forsurgical haemostasis in patients with haemophilia A: results of a pivotal study.Haemophilia. 2010 Sep 1;16(5):731-9.

16 HOW SUPPLIED/STORAGE AND HANDLING

How SuppliedXYNTHA® is supplied in kits that include single-use vials containing nominally 250, 500,1000, or 2000 International Units lyophilized powder per vial:250 International Units Kit: NDC 58394-012-01500 International Units Kit: NDC 58394-013-011000 International Units Kit: NDC 58394-014-012000 International Units Kit: NDC 58394-015-01Each XYNTHA Vial Kit contains: one prefilled diluent syringe containing 4 mL 0.9%Sodium Chloride with plunger rod for assembly, one vial adapter, one sterile infusionset, two alcohol swabs, one bandage, one gauze pad, and one package insert.Actual factor VIII activity in International Units is stated on the label of each XYNTHAvial.

Storage and Handling• 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 the label.

• Within the expiration date, XYNTHA also may be stored at room temperature not toexceed 25°C (77°F) for up to 3 months.

• 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 refrigerator more than once.• 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 return the product to refrigerated storage. The diluent syringe may be stored at 2° to 25°C (36° to 77°F).• Do not use XYNTHA after the expiration date.• Do not freeze. (Freezing may damage the prefilled diluent syringe.)• During storage, avoid prolonged exposure of XYNTHA vial to light.• Store the reconstituted solution at room temperature prior to administration. Administer XYNTHA within 3 hours after reconstitution.

17 PATIENT COUNSELING INFORMATION• Advise patients to read the FDA-approved patient labeling (Patient Information and

Instructions for Use).• Advise patients to report any adverse reactions or problems that concern them when

taking XYNTHA to their healthcare provider.• Allergic-type hypersensitivity reactions are possible. Discuss the early signs of

hypersensitivity reactions (including hives [rash with itching]), generalized urticaria,tightness of the chest, wheezing, hypotension) and anaphylaxis. Advise patients todiscontinue use of the product, call their healthcare provider, and go to theemergency department if these symptoms occur.

• Advise patients to contact their healthcare provider if they experience a lack of aclinical response to factor VIII replacement therapy, as this may be a manifestation ofan inhibitor.

• Advise patients to notify their healthcare provider if they become pregnant or intendto become pregnant during therapy, or if they are breastfeeding.

• Advise patients to consult their healthcare provider prior to travel and to bring anadequate supply of XYNTHA, based on their current regimen, for anticipatedtreatment when traveling.

FDA-Approved Patient LabelingPatient InformationXYNTHA® /ZIN-tha/[Antihemophilic Factor (Recombinant)]Please read this patient information carefully before using XYNTHAand each time you get a refill. There may be new information. Thisleaflet does not take the place of talking with your healthcare providerabout your medical problems or your treatment. What is XYNTHA?XYNTHA is an injectable medicine that is used to help control andprevent bleeding in people with hemophilia A. Hemophilia A is alsocalled classic hemophilia. Your healthcare provider may give youXYNTHA 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 ifXYNTHA may harm your unborn baby.

• are breastfeeding. It is not known if XYNTHA passes into your milkand 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 asover-the-counter medicines, supplements, or herbal remedies. How should I infuse XYNTHA?Step-by-step instructions for infusing with XYNTHA are provided atthe 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 healthcareprovider before using. Call your healthcare provider right away if bleeding is not controlledafter using XYNTHA.Your body can make antibodies against XYNTHA (called “inhibitors”)that may stop XYNTHA from working properly. Your healthcareprovider may need to take blood tests from time to time to monitor forinhibitors.Call your healthcare provider right away if you take more than the doseyou should take. Talk to your healthcare provider before traveling. Plan to bring enoughXYNTHA for your treatment during this time. What are the possible side effects of XYNTHA?Call your healthcare provider or go to the emergency department rightaway if you have any of the following symptoms because these maybe 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• hivesCommon side effects of XYNTHA are• headache• fever• nausea• vomiting• diarrhea• weakness

Talk to your healthcare provider about any side effect that bothers you or that does not go away. You may report side effects to FDA at 1-800-FDA-1088.How should I store XYNTHA?Store XYNTHA in the refrigerator at 36° to 46°F (2° to 8°C). Store thediluent syringe at 36° to 77°F (2° to 25°C).Do not freeze.Protect from light.XYNTHA can last at room temperature (below 77°F) for up to 3months. If you store XYNTHA at room temperature, carefully writedown the date you put XYNTHA at room temperature, so you willknow when to either put it back in the refrigerator, use it immediately,or throw it away. There is a space on the carton for you to write thedate.If stored at room temperature, XYNTHA can be returned one time tothe refrigerator until the expiration date. Do not store at roomtemperature and return it to the refrigerator more than once. Throwaway any unused XYNTHA after the expiration date.Infuse XYNTHA within 3 hours of reconstitution. You can keep thereconstituted 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 slightlyopalescent and colorless.Dispose of all materials, whether reconstituted or not, in anappropriate medical waste container.What else should I know about XYNTHA?Medicines are sometimes prescribed for purposes other than thoselisted here. Talk to your healthcare provider if you have any concerns.You can ask your healthcare provider for information about XYNTHAthat was written for healthcare professionals.Do not share XYNTHA with other people, even if they have the samesymptoms that you have. Instructions for UseXYNTHA® /ZIN-tha/[Antihemophilic Factor (Recombinant)]XYNTHA is supplied as a lyophilized powder. Before you can infuse it(intravenous injection), you must reconstitute the powder by mixing itwith the liquid diluent supplied. The liquid diluent is 0.9% sodiumchloride.Reconstitute and infuse XYNTHA using the infusion set, diluent,syringe, and adapter provided in this kit. Please follow the directionsbelow for the proper use of this product.PREPARATION AND RECONSTITUTION OF XYNTHA®

Preparation1. 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.4. For additional instructions on the use of a XYNTHA Vial Kit and a

XYNTHA SOLOFUSE™ kit, see detailed information provided afterthe INFUSION OF XYNTHA section.

ReconstitutionNote: If you use more than one vial of XYNTHA for each infusion,reconstitute each vial according to steps 1 through 11.1. Let the XYNTHA vial and the prefilled diluent syringe reach room temperature.2. Remove the plastic flip-top cap from the XYNTHA vial to show the

center part of the rubber stopper.

3. Wipe the top of the vial with the alcohol swab provided, or useanother antiseptic solution, and allow to dry. After cleaning, do nottouch the rubber stopper with your hand or allow it to touch anysurface.

4. Peel back the cover from the clear plastic vial adapter package. Donot remove the adapter from the package.

5. Place the XYNTHA vial on a flat surface. While holding the adapter in the package, place the vial adapter over the XYNTHA vial. Press down firmly on the package until the adapter snaps into place on top of the vial, with the adapter spike going into the vial stopper.

6. Grasp the plunger rod as shown in the picture below. Do not touchthe shaft of the plunger rod. Attach the threaded end of the plungerrod to the diluent syringe plunger by pushing and turning firmly.

7. Break off the tamper-resistant, plastic tip cap from the diluentsyringe by snapping the perforation of the cap. Do not touch theinside of the cap or the syringe tip. The diluent syringe may need tobe recapped (if reconstituted XYNTHA is not used immediately), soplace the cap on its top on a clean surface in a spot where it willstay clean.

8. Lift the package cover away from the adapter and throw thepackage away.

9. Place the XYNTHA vial on a flat surface. Connect the diluent syringeto the vial adapter by inserting the tip of the syringe into the adapteropening while firmly pushing and turning the syringe clockwiseuntil the connection is secured.

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

11. With the syringe still connected to the adapter, gently swirl thecontents of the vial until the powder is dissolved.

Look carefully at the final solution. The solution should be clearto slightly opalescent and colorless. If it is not, throw away thesolution and use a new kit.

12. Make sure the syringe plunger rod is still fully pressed down, thenturn over the XYNTHA vial. Slowly pull the solution into thesyringe. Turn the syringe upward again and remove any airbubbles by gently tapping the syringe with your finger and slowlypushing air out of the syringe.

If you reconstituted more than one vial of XYNTHA, remove thediluent syringe from the vial adapter and leave the vial adapter attached to the XYNTHA vial. Quickly attach a separate large luerlock syringe and pull the reconstituted solution as instructedabove. Repeat this procedure with each vial in turn. Do not detachthe diluent syringe or the large luer lock syringe until you areready to attach the large luer lock syringe to the next vial adapter.

13. Remove the syringe from the vial adapter by gently pulling andturning the syringe counterclockwise. Throw away the emptyXYNTHA vial with the adapter attached.

Note:• If you are not using the solution right away, carefully replace thesyringe cap. Do not touch the syringe tip or the inside of the cap.

• Infuse XYNTHA solution within 3 hours after reconstitution. 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.INFUSION OF XYNTHA Your healthcare provider will teach you how to infuse XYNTHAyourself. Once you learn how to do this, you can follow theinstructions in this insert.Before XYNTHA can be infused, you must reconstitute it as instructedabove in the PREPARATION AND RECONSTITUTION OF XYNTHAsection. After reconstitution, be sure to look carefully at the XYNTHA solution.The solution should be clear to slightly opalescent and colorless. If itis not, throw away the solution and use a new kit.Use the infusion set included in the kit to infuse XYNTHA. Do notinfuse 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.

3. Remove the protective needle cover and insert the butterfly needle of the infusion set tubing into your vein as instructed by yourhealthcare provider. Remove the tourniquet. Verify proper needleplacement.

4. Infuse the reconstituted XYNTHA product over several minutes. Your comfort level should determine the rate of infusion.

5. After infusing XYNTHA, remove the infusion set and throw it away.The amount of liquid left in the infusion set will not affect yourtreatment.

Note:• Throw away all unused solution, the empty vial(s), and other usedmedical supplies in an appropriate container.

• It is a good idea to record the lot number from the XYNTHA viallabel every time you use XYNTHA. You can use the peel-off labelfound on the vial to record the lot number.

ADDITIONAL INSTRUCTIONSXYNTHA is also supplied in kits that have both the XYNTHA powderand the diluent within single-use prefilled dual-chamber syringes,called XYNTHA SOLOFUSE™.If you use one XYNTHA vial and one of XYNTHA SOLOFUSE™ for theinfusion, reconstitute the XYNTHA vial and the XYNTHA SOLOFUSE™according to the specific directions for that respective product kit. Usea separate 10 milliliter or larger luer lock syringe (not included in thiskit) to draw back the reconstituted contents of the XYNTHA vial andXYNTHA SOLOFUSE™.Use of a XYNTHA Vial Kit with a XYNTHA SOLOFUSE™ KitThese instructions are for the use of only one XYNTHA vial kit and oneXYNTHA SOLOFUSE™ Kit. For further information, please contact yourhealthcare provider or call the Medical Information Department atWyeth Pharmaceuticals, 1-800-438-1985.1. Reconstitute the XYNTHA vial using the instructions described in

PREPARATION AND RECONSTITUTION OF XYNTHA section. Detachthe empty diluent syringe from the vial adapter by gently turningand pulling the syringe counterclockwise, leaving the contents in theXYNTHA vial with the vial adapter in place.

2. Reconstitute the XYNTHA SOLOFUSE™ using the instructionsincluded with the product kit, remembering to remove most, but notall, of the air from the syringe.

3. After removing the protective blue vented cap, connect the XYNTHASOLOFUSE™ to the vial adapter by inserting the tip into the adapteropening while firmly pushing and turning the syringe clockwise untilsecured.

4. Slowly depress the plunger rod of the XYNTHA SOLOFUSE™ untilthe contents empty into the XYNTHA vial. The plunger rod maymove back slightly after release.

5. Detach the empty XYNTHA SOLOFUSE™ from the vial adapter andthrow it away.

If the syringe turns without detaching from the vial adapter, grasp the white collar and turn.

6. Connect a sterile 10 milliliter or larger luer lock syringe to the vialadapter. You may want to inject some air into the XYNTHA vial tomake withdrawing the vial contents easier.

7. Invert the XYNTHA vial and slowly draw the solution into the largeluer lock syringe.

8. Detach the large luer lock syringe from the vial adapter by gentlyturning and pulling the syringe counterclockwise. Throw away theempty XYNTHA vial with the adapter attached.

9. Attach the infusion set to the large luer lock syringe as directed inthe INFUSION OF XYNTHA section.

Note: Dispose of all unused solution and other used medical suppliesin an appropriate container.

License no: 3LAB-0516-5.0

Manufactured by

Wyeth Pharmaceuticals IncA subsidiary of Pfizer Inc, Philadelphia, PA 19101

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

XYNTHA, Antihemophilic Factor (Recombinant), is indicated for use in adults andchildren with hemophilia A (congenital factor VIII deficiency) for:• Control and prevention of bleeding episodes• Perioperative managementXYNTHA does not contain von Willebrand factor, and therefore is not indicated inpatients with von Willebrand’s disease.

2 DOSAGE AND ADMINISTRATIONFor intravenous use after reconstitution only.

2.1 Dose• Initiate treatment with XYNTHA under the supervision of a physician experienced in

the treatment of hemophilia A. • Dosage and duration of treatment depend on the severity of the factor VIII deficiency,

the location and extent of bleeding, and the patient’s clinical condition. Titrate theadministered doses to the patient’s clinical response.

• One International Unit (IU) of factor VIII activity corresponds approximately to thequantity of factor VIII in one milliliter of normal human plasma. The calculation of therequired dosage of factor VIII is based upon the empirical finding that, on average, 1 IU of factor VIII per kg body weight raises the plasma factor VIII activity byapproximately 2 IU/dL.2

The expected in vivo peak increase in factor VIII level expressed as IU/dL (or % normal)can be estimated using the following formulas:Dosage (International Units) = body weight (kg) x desired factor VIII rise (IU/dL or % ofnormal) x 0.5 (IU/kg per IU/dL)orIU/dL (or % normal) = Total Dose (IU)/body weight (kg) x 2 [IU/dL]/[IU/kg]

Control and Prevention of Bleeding Episodes

A guide for dosing XYNTHA for the control and prevention of bleeding episodes isprovided in Table 1. Maintain the plasma factor VIII activity at or above the levels (in %of normal or in IU/dL) outlined in Table 1 for the indicated period.

Table 1: Dosing for Control and Prevention of Bleeding Episodes

Type of Factor VIII Level Frequency DurationBleeding Required (IU/dL or of Doses ofEpisode % of normal) (hours) Therapy

MinorEarly hemarthrosis, 20–40 12-24 At least 1 day,minor muscle depending uponor oral bleeds. the severity of the

bleeding episode.ModerateBleeding into muscles. 30–60 12-24 3-4 days or untilMild head trauma. adequate localBleeding into the hemostasis oral cavity. is achieved.MajorGastrointestinal bleeding. 60–100 8-24 Until bleeding isIntracranial, intraabdominal resolved.or intrathoracic bleeding. Fractures.

Perioperative Management

A guide for dosing XYNTHA during surgery (perioperative management) is provided inTable 2. Maintain the plasma factor VIII activity level at or above the level (in % ofnormal or in IU/dL) outlined in Table 2 for the indicated period. Monitor the replacementtherapy by means of plasma factor VIII activity.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use XYNTHA safely andeffectively. See full prescribing information for XYNTHA.XYNTHA® SOLOFUSE™ (antihemophilic factor [recombinant]) lyophilized powder forsolution in prefilled dual-chamber syringe, for intravenous injectionInitial U.S. Approval: 2008------------------------------------ RECENT MAJOR CHANGES ----------------------------------- Indications and Usage (1) 10/2014------------------------------------ INDICATIONS AND USAGE ------------------------------------ • XYNTHA is a recombinant antihemophilic factor indicated in adults and children withhemophilia A for control and prevention of bleeding episodes and for perioperativemanagement. (1)

• XYNTHA is not indicated in patients with von Willebrand’s disease. (1)-------------------------------- DOSAGE AND ADMINISTRATION --------------------------------For intravenous use after reconstitution only (2)• The required dose is determined using the following formula: Required units = body weight (kg) x desired factor VIII rise (IU/dL or % of normal) x 0.5(IU/kg per IU/dL), where IU = International Unit.

• Frequency of XYNTHA administration is determined by the type of bleeding episode andthe recommendation of the treating physician. (2.1, 2.2)

------------------------------- DOSAGE FORMS AND STRENGTHS-------------------------------XYNTHA SOLOFUSE is available as lyophilized powder in single-use prefilled dual-chamber syringes containing nominally 250, 500, 1000, 2000, or 3000 IU. (3)

--------------------------------------- CONTRAINDICATIONS --------------------------------------Do not use in patients who have manifested life-threatening immediate hypersensitivityreactions, including anaphylaxis, to the product or its components, including hamsterproteins. (4)--------------------------------- WARNINGS AND PRECAUTIONS --------------------------------• Anaphylaxis and severe hypersensitivity reactions are possible. Patients may develophypersensitivity to hamster protein, which is present in trace amounts in XYNTHA. Shouldsuch reactions occur, discontinue treatment with the product, and administer appropriatetreatment. (5.1)

• Development of activity-neutralizing antibodies has been detected in patients receivingfactor VIII-containing products, including XYNTHA. If expected plasma factor VIII activitylevels are not attained, or if bleeding is not controlled with an appropriate dose, performan assay that measures factor VIII inhibitor concentration. (5.2, 5.3, 6.2)

--------------------------------------- ADVERSE REACTIONS --------------------------------------• The most common adverse reactions (≥ 10%) with XYNTHA in adult and pediatric PTPswere headache, arthralgia, pyrexia, and cough. (6)

• Across all studies, 3 subjects developed factor VIII inhibitors (2.1%). (6.2)To report SUSPECTED ADVERSE REACTIONS, contact Wyeth Pharmaceuticals Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch-------------------------------- USE IN SPECIFIC POPULATIONS --------------------------------• Pregnancy: No human or animal data. Use only if clearly needed. (8.1)• Pediatrics: Half-lives are shorter, volumes of distribution are larger, and recovery is lowerafter XYNTHA administration in children. Higher or more frequent dosing may beneeded. (8.4)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labelingRevised: 10/2014

FULL PRESCRIBING INFORMATION: CONTENTS*1 INDICATIONS AND USAGE2 DOSAGE AND ADMINISTRATION 2.1 Dosing 2.2 Preparation and Reconstitution 2.3 Administration 2.4 Use of a XYNTHA Vial Kit and a XYNTHA® SOLOFUSE™ Kit 2.5 Use of Multiple XYNTHA® SOLOFUSE™ 3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions 5.2 Neutralizing Antibodies 5.3 Monitoring Laboratory Tests6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Immunogenicity 6.3 Postmarketing Experience

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Labor and Delivery 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use11 DESCRIPTION12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology14 CLINICAL STUDIES15 REFERENCES16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION*Sections or subsections omitted from the full prescribing information are not listed

Table 2: Dosing for Perioperative Management

Type Factor VIII Level Frequency Durationof Required (IU/dL or of Doses of

Surgery % of normal) (hours) Therapy

MinorMinor operations, 30–60 12-24 3-4 days or untilincluding tooth adequate localextraction. hemostasis is

achieved. For tooth extraction, a single infusion plus oral antifibrinolytic therapy within 1 hour may be sufficient.

MajorMajor operations. 60-100 8-24 Until threat is

resolved, or in the case of surgery, until adequate local hemostasis and wound healing are achieved.

2.2 Preparation and ReconstitutionPreparation1. Always wash hands before performing the following procedures.2. Use aseptic technique during the reconstitution procedures.3. Use all components for the reconstitution and administration of this product as soon

as possible after opening their sterile containers to minimize unnecessary exposure tothe atmosphere.

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 thatrespective product kit. Use a separate 10 milliliter or larger luer lock syringe (notincluded in this kit) to draw back the reconstituted contents of the vial and thesyringe. [see Dosage and Administration (2.4)]

• If the patient uses multiple XYNTHA SOLOFUSE syringes for the infusion, reconstituteeach syringe according to the instructions below. Use a separate 10 milliliter or largerluer lock syringe (not included in this kit) to draw back the reconstituted contents ofeach syringe. [see Dosage and Administration (2.5)]

Reconstitution1. Allow the XYNTHA SOLOFUSE Kit to reach room temperature. 2. Remove the contents of the XYNTHA® SOLOFUSE™ Kit and place on a clean surface,

making sure you have all the supplies you will need.3. Grasp the plunger rod as shown in the following diagram. Avoid contact with the

shaft of the plunger rod. Screw the plunger rod firmly into the opening in the fingerrest of the XYNTHA® SOLOFUSE™ by pushing and turning firmly until resistance isfelt (approximately 2 turns).

Note: Once the white tamper-evident seal is removed it is important to keep the XYNTHA® SOLOFUSE™ in the upright position throughout the reconstitution processto prevent possible leakage.

4. Holding the XYNTHA® SOLOFUSE™ upright, remove the white tamper-evident seal bybending the seal right to left (or a gentle rocking motion) to break the perforation ofthe cap and expose the grey rubber tip cap of the XYNTHA® SOLOFUSE™.

5. Remove the protective blue vented sterile cap from its package. While holding the XYNTHA® SOLOFUSE™ upright, remove the grey rubber tip cap and replace it withthe protective blue vented cap (prevents pressure build-up). Avoid touching the openend of both the syringe and the protective blue vented cap.

6. Gently and slowly advance the plunger rod by pushing until the two stoppers insidethe XYNTHA® SOLOFUSE™ meet, and all of the diluent is transferred to the chambercontaining the XYNTHA powder.

Note: To prevent the escape of fluid from the tip of the syringe, the plunger rodshould not be pushed with excessive force.

7. With the XYNTHA® SOLOFUSE™ remaining upright, swirl gently several times untilthe powder is dissolved.

Note: The final solution should be inspected visually for particulate matter beforeadministration. The solution should be clear to slightly opalescent and colorless. If itis not, discard the solution and use a new kit.

8. Holding the XYNTHA® SOLOFUSE™ in an upright position, slowly advance the plungerrod until most, but not all, of the air is removed from the drug product chamber.

Note:• If the solution is not to be used immediately, store the syringe upright, leaving the

protective blue vent cap on the XYNTHA® SOLOFUSE™ until ready to infuse.• Store the reconstituted solution at room temperature prior to administration, but use

within 3 hours after reconstitution or after removal of the grey rubber tip cap. • 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 ofXYNTHA, 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 AdministrationFor intravenous infusion after reconstitution only.Inspect the final XYNTHA solution visually for particulate matter and discoloration priorto administration. The solution should be clear to slightly opalescent and colorless. If itis not, discard the solution and use a new kit.Administer XYNTHA solution using the infusion set included in the kit. Do not administerreconstituted XYNTHA in the same tubing or container with other medicinal products.1. After removing the protective blue vented cap, firmly attach the intravenous infusion

set provided in the kit onto the XYNTHA® SOLOFUSE™.

2. Apply a tourniquet and prepare the injection site by wiping the skin well with analcohol swab provided in the kit.

3. Remove the protective needle cover and perform venipuncture. Insert the needle onthe infusion set tubing into the vein, and remove the tourniquet. Verify proper needleplacement.

4. Inject the reconstituted XYNTHA intravenously over several minutes. The rate ofadministration should be determined by the patient’s comfort level.

5. After infusing XYNTHA, remove and discard the infusion set. The amount of drugproduct left in the infusion set will not affect treatment.

Note: Dispose of all unused solution, the empty XYNTHA® SOLOFUSE™, and otherused medical supplies in an appropriate container.

2.4 Use of a XYNTHA Vial Kit with a XYNTHA® SOLOFUSE™ KitThese instructions are for the use of only one XYNTHA vial kit with one XYNTHA®

SOLOFUSE™ Kit. For further information, please contact the Medical InformationDepartment at Wyeth Pharmaceuticals, 1-800-438-1985.1. Reconstitute the XYNTHA vial using the instructions included with the product kit.2. Detach the empty diluent syringe from the vial adapter by gently turning and pulling

the syringe counterclockwise, leaving the contents in the vial and the vial adapter inplace.

3. Reconstitute the XYNTHA® SOLOFUSE™ using the instructions described inPreparation and Reconstitution [see Dosage and Administration (2.2)]. Remember toremove most, but not all, of the air from the drug product chamber.

4. After removing the protective blue vented cap, connect the XYNTHA® SOLOFUSE™ tothe vial adapter by inserting the tip into the adapter opening while firmly pushing andturning the syringe clockwise until secured.

5. Slowly depress the plunger rod of the XYNTHA® SOLOFUSE™ until the contentsempty into the XYNTHA vial. The plunger rod may move back slightly after release.

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.

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.

8. Invert the vial and slowly draw the solution into the large luer lock syringe.

9. Detach the syringe from the vial adapter by gently turning and pulling the syringe counterclockwise. Discard the empty XYNTHA vial with the adapter attached.

10. Attach the infusion set to the large luer lock syringe as directed [see Dosage andAdministration (2.3)].

2.5 Use of Multiple XYNTHA® SOLOFUSE™ KitsThe 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 theMedical Information Department at Wyeth Pharmaceuticals, 1-800-438-1985.Note: Luer-to-luer syringe connectors are not provided in these kits. Instruct patients tocontact their XYNTHA supplier to order.1. Reconstitute all XYNTHA® SOLOFUSE™ according to instructions described in

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. 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.

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

6. Remove the empty XYNTHA® SOLOFUSE™ and repeat procedures 3 and 4 above forany additional reconstituted XYNTHA SOLOFUSE.

7. Remove the luer-to-luer syringe connector from the large luer lock syringe and attachthe 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 thefollowing nominal dosages: • 250 International Units • 500 International Units • 1000 International Units • 2000 International Units • 3000 International UnitsEach XYNTHA SOLOFUSE has the actual recombinant factor VIII (rFVIII) potency inInternational Units stated on the label.

4 CONTRAINDICATIONS XYNTHA is contraindicated in patients who have manifested life-threatening immediatehypersensitivity reactions, including anaphylaxis, to the product or its components,including hamster proteins.

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions Allergic type hypersensitivity reactions, including anaphylaxis, are possible withXYNTHA. Inform patients of the early signs or symptoms of hypersensitivity reactions(including hives [rash with itching], generalized urticaria, chest tightness, wheezing, andhypotension) and anaphylaxis. Discontinue XYNTHA if hypersensitivity symptoms occurand administer appropriate emergency treatment.XYNTHA contains trace amounts of hamster proteins. Patients treated with this productmay develop hypersensitivity to these non-human mammalian proteins.

5.2 Neutralizing Antibodies Inhibitors have been reported following administration of XYNTHA. Monitor patients forthe development of factor VIII inhibitors by appropriate clinical observations andlaboratory tests. If expected factor VIII activity plasma levels are not attained, or ifbleeding is not controlled with an appropriate dose, perform an assay that measuresfactor VIII inhibitor concentration to determine if a factor VIII inhibitor is present [seeWarnings and Precautions (5.3)].4,5,6,7,8,9,10,11,12

5.3 Monitoring Laboratory Tests • Use individual factor VIII values for recovery and, if clinically indicated, other

pharmacokinetic characteristics to guide dosing and administration. • 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, whenclinically indicated [see Dosage and Administration (2)].

• Monitor for development of factor VIII inhibitors. Perform assay to determine iffactor VIII inhibitor is present when expected factor VIII activity plasma levels arenot attained, or when bleeding is not controlled with the expected dose of XYNTHA.Use Bethesda Units (BU) to titer inhibitors.

6 ADVERSE REACTIONSThe most common adverse reactions (≥ 10%) with XYNTHA in adult and pediatric PTPswere headache, arthralgia, pyrexia, and cough.

6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reactionrates observed in the clinical trials of a drug cannot be directly compared to rates in theclinical trials of another drug and may not reflect the rates observed in clinical practice.XYNTHA was evaluated in five clinical studies (N=155), four completed studies withadult and pediatric PTPs and one ongoing study in pediatric PTPs < 6 years of age.The safety and efficacy of XYNTHA was evaluated in two completed pivotal studies. Inthe first study (n=94), safety and efficacy were examined in previously treated patients(PTPs) with hemophilia A (factor VIII activity in plasma [FVIII: C] ≤ 2%) who receivedXYNTHA for routine prophylaxis and on-demand treatment. Ninety-four subjectsreceived at least one dose of XYNTHA, resulting in a total of 6,775 infusions [seeClinical Studies (14)]. The second study (n=30) examined the use of XYNTHA forsurgical prophylaxis in previously treated patients with severe or moderately severehemophilia A (FVIII: C ≤ 2%) who required elective major surgery and were expected to receive XYNTHA replacement therapy for at least 6 days post-surgery. All subjectsreceived at least one dose of XYNTHA, resulting in 1161 infusions. One subject receivedXYNTHA for a pre-surgery pharmacokinetic assessment only and did not undergosurgery [see Clinical Studies (14)].Across all studies, safety was evaluated in 48 previously treated pediatric patients <16 years of age (28 children, < 6 years of age and 20 adolescents, 12 to <16 years ofage). A total of 7,150 infusions of XYNTHA were administered with a median dose perinfusion of 29 IU/kg (min, max: 9,108 IU/kg).Across all studies, the most common adverse reactions (≥ 10%) with XYNTHA in adultand pediatric PTPs were headache (26% of subjects), arthralgia (25%), pyrexia (21%),cough (11%). Other adverse reactions reported in ≥ 5% of subjects were: diarrhea(8%), vomiting (7%), asthenia (7%), and nausea (6%).

6.2 ImmunogenicityThere is a potential for immunogenicity with therapeutic proteins. The development offactor VIII inhibitors with XYNTHA was evaluated in 144 adult and pediatric PTPs with atleast 50 EDs. Laboratory-based assessments for FVIII inhibitor (partial Nijmegenmodification of the Bethesda inhibitor assay) were conducted in the clinical studies. The criterion for a positive FVIII result test result was ≥ 0.6 BU/mL. Across all studies, 3 subjects developed factor VIII inhibitors (2.1%).The clinical studies for XYNTHA examined 124 subjects (94 for bleeding and 30 forsurgery) who had previously been treated with factor VIII (PTPs). In the safety andefficacy study, two subjects with inhibitors were observed in 89 subjects (2.2%) whocompleted ≥ 50 exposure days.In a Bayesian statistical analysis, results from this study were used to update PTPresults from a prior supporting study using XYNTHA manufactured at the initial facility(with one de novo and two recurrent inhibitors observed in 110 subjects) and theexperience with predecessor product (with one inhibitor observed in 113 subjects). TheBayesian analysis indicated that the population inhibitor rate for XYNTHA, an estimate ofthe 95% upper limit of the true inhibitor rate, was 4.17%.None of the PTPs developed anti-CHO (Chinese hamster ovary) or anti-TN8.2 antibodies.One PTP developed anti-FVIII antibodies; but, this subject did not develop an inhibitor.In the surgery study, one low titer persistent inhibitor and one transient false-positiveinhibitor were reported. In this study, one surgical subject developed anti-CHO cellantibodies with no associated allergic reaction. One subject developed anti-FVIIIantibodies; but, this subject did not develop an inhibitor.Across all studies, safety was evaluated in 40 previously treated pediatric patients <16 years of age with at least 50 EDs (25 children, <6 years of age and 15 adolescents,12 to <16 years of age). Of these, one pediatric subject developed an inhibitor. The detection of antibody formation is highly dependent on the sensitivity and specificityof the assay. Additionally, the observed incidence of antibody, including neutralizingantibody, positivity in an assay may be influenced by several factors, including assaymethodology, sample handling, timing of sample collection, concomitant medications,and underlying disease. For these reasons, comparisons of the incidence of antibodiesto XYNTHA with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing ExperienceBecause these reactions are reported voluntarily from a population of uncertain size, it isnot always possible to reliably estimate their frequency or establish a causal relationshipto drug exposure.

The following postmarketing adverse reactions have been reported for XYNTHA: AnaphylaxisInadequate therapeutic response

8 USE IN SPECIFIC POPULATIONS

8.1 PregnancyPregnancy Category C. Animal reproduction studies have not been conducted withXYNTHA. It is not known whether XYNTHA can cause fetal harm when administered to apregnant woman or can affect reproduction capacity. XYNTHA should be given to apregnant woman only if clinically indicated.

8.2 Labor and DeliveryThere is no information available on the effect of factor VIII replacement therapy onlabor and delivery. XYNTHA should be used only if clinically indicated.

8.3 Nursing MothersIt is not known whether this drug is excreted into human milk. Because many drugs areexcreted into human milk, caution should be exercised if XYNTHA is administered tonursing mothers. XYNTHA should be given to nursing mothers only if clinicallyindicated.

8.4 Pediatric UseIn the completed open label safety and efficacy study of XYNTHA (n=94), 17 adolescent subjects 12 to <16 years of age with severe or moderately severe hemophilia A (FVIII:C ≤ 2%), who were previously treated with at least 150 EDs to FVIII products, received XYNTHA for on-demand and follow-up treatment. Themedian dose per infusion was 47 IU/kg (min-max: 24-74) and the median exposure per subject was 6 days (min-max: 1-26).Of the 17 subjects < 16 yrs of age who received at least 1 dose of XYNTHA, 10 subjectshad bleeding episodes during the study. Among the 10 subjects with responseassessments, a total of 66 bleeding episodes were treated with on-demand infusions ofXYNTHA. The majority of the bleeding episodes (63/66 or 95.5%) resolved with 1 or 2infusions. Thirty-eight (38) of 66 bleeding episodes (57.6%) were rated excellent orgood in their response to initial treatment, 24 (36.4%) were rated as moderate and 4(6.1%) were not rated.Additional data are available from a safety and efficacy study of XYNTHA in children < 6 years of age with moderately severe or severe hemophilia A (FVIII:C ≤ 2%) and with at least 20 prior EDs to FVIII products. In this study subjects received XYNTHA for on-demand and follow-up treatment of bleeding episodes. The median dose perinfusion was 28 IU/kg and the median exposure per subject was 16 days.Of the 27 subjects < 6 years of age who received at least 1 dose of XYNTHA, 25 hadbleeding episodes during the study. Among the 24 subjects with response assessmentsthere were 493 bleeds. The majority of the bleeding episodes (462/493 or 93.7%)resolved with 1 or 2 infusions. Subjects rated the outcomes of infusions on a pre-specified four (4) point hemostatic efficacy scale. Of 493 bleeding episodes treated withXYNTHA, 468 (94.9%) were rated excellent or good in their response to initial treatmentand 22 (4.5%) were rated as moderate.In comparison to the pharmacokinetic parameters reported in adults, children haveshorter half-lives, larger volumes of distribution and lower recovery of factor VIII after XYNTHA administration. The clearance (based on per kg body weight) isapproximately 40% higher in children. Higher or more frequent doses may be requiredto account for the observed differences in pharmacokinetic parameters. [see ClinicalPharmacology (12.3)]

8.5 Geriatric UseClinical studies of XYNTHA did not include subjects aged 65 and over. In general, doseselection for an elderly patient should be individualized.

11 DESCRIPTIONThe active ingredient in XYNTHA, Antihemophilic Factor (Recombinant), is arecombinant antihemophilic factor (rAHF), also called coagulation factor VIII, which isproduced by recombinant DNA technology. It is secreted by a genetically engineeredChinese hamster ovary (CHO) cell line. The cell line is grown in a chemically defined cellculture medium that contains recombinant insulin, but does not contain any materialsderived from human or animal sources.The rAHF in XYNTHA is a purified glycoprotein, with an approximate molecular mass of170 kDa consisting of 1,438 amino acids, which does not contain the B-domain.13 Theamino acid sequence of the rAHF is comparable to the 90 + 80 kDa form of humancoagulation factor VIII. The purification process uses a series of chromatography steps, one of which is basedon affinity chromatography using a patented synthetic peptide affinity ligand.14 Theprocess also includes a solvent-detergent viral inactivation step and a virus-retainingnanofiltration step. The potency expressed in International Units (IU) is determined using the chromogenicassay of the European Pharmacopoeia. The Wyeth manufacturing reference standard forpotency has been calibrated against the World Health Organization (WHO) InternationalStandard for factor VIII activity using the one-stage clotting assay. The specific activityof XYNTHA is 5,500 to 9,900 IU per milligram of protein. XYNTHA is formulated as a sterile, nonpyrogenic, no preservative, lyophilized powderpreparation for intravenous injection. Each single-use prefilled dual-chamber syringe

(named XYNTHA SOLOFUSE) contains nominally 250, 500, 1000, 2000, or 3000 IU ofXYNTHA. Upon reconstitution, the product is a clear to slightly opalescent, colorlesssolution that contains sodium chloride, sucrose, L-histidine, calcium chloride andpolysorbate 80.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

XYNTHA temporarily replaces the missing clotting factor VIII that is needed for effectivehemostasis.

12.2 PharmacodynamicsThe activated partial thromboplastin time (aPTT) is prolonged in patients withhemophilia. Determination of aPTT is a conventional in vitro assay for biological activityof factor VIII. Treatment with XYNTHA normalizes the aPTT over the effective dosingperiod.

12.3 PharmacokineticsThe pharmacokinetic parameters of XYNTHA in 30 previously treated adult patients(PTP) 12 to 60 years old, who received a single infusion of 50 IU/kg XYNTHA aresummarized in Table 3.In addition, 25 of the same subjects later received a single infusion of 50 IU/kg ofXYNTHA for a 6-month follow-up pharmacokinetic study. The parameters werecomparable between baseline and 6 months, indicating no time-dependent changes inthe pharmacokinetics of XYNTHA.In a separate study, 8 of 30 subjects at least 12 years old with hemophilia A undergoingelective major surgery received a single 50 IU/kg infusion of XYNTHA. Thepharmacokinetic parameters in these subjects are also summarized in Table 3.

Table 3: Mean ± SD XYNTHA Pharmacokinetic Parameters in Previously Treated Patients with Hemophilia A after Single 50 IU/kg Dose

Initial Visit Month 6 Pre-surgeryParameter (n=30) (n=25) (n=8)

Cmax (IU/mL) 1.08 ± 0.22 1.24 ± 0.42 1.08 ± 0.24AUC

∞(IU·hr/mL) 13.5 ± 5.6 15.0 ± 7.5 16.0 ± 5.2

t1/2 (hr) 11.2 ± 5.0 11.8 ± 6.2* 16.7 ± 5.4CL (mL/hr/kg) 4.51 ± 2.23 4.04 ± 1.87 3.48 ± 1.25Vss (mL/kg) 66.1 ± 33.0 67.4 ± 32.6 69.0 ± 20.1Recovery 2.15 ± 0.44 2.47 ± 0.84 2.17 ± 0.47(IU/dL per IU/kg)

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 ofsubjects; SD = standard deviation; Vss = volume of distribution at steady-state.*One subject was excluded from the calculation due to lack of a well-defined terminalphase.

Table 4 shows the pharmacokinetic parameters of nine children; four aged 14 or 15years of age, who are also included in the summary for the adults above, along with fivechildren aged 3.7-5.8 years after single 50 IU/kg doses of XYNTHA. Compared to adults,the half-life of XYNTHA is shorter in children and the clearance (based on per kg bodyweight) is approximately 40% higher in children.

Table 4: Mean ± SD XYNTHA Pharmacokinetic Parameters in Previously TreatedPediatric Patients with Hemophilia A after Single 50 IU/kg Dose

Parameter Young Children (n=5) Adolescents (n=4)Age (min - max, yr) 3.7 - 5.8 14 - 15Cmax (IU/mL) 0.78 ± 0.34 0.97 ± 0.21AUC

∞(IU·hr/mL) 12.2 ± 6.50 8.5 ± 4.0

t1/2 (hr) 8.3 ± 2.7 6.9 ± 2.4CL (mL/hr/kg) 6.29 ± 4.87 6.62 ± 2.16Vss (mL/kg) 66.9 ± 55.6 67.1 ± 13.6Recovery 1.52 ± 0.69 1.95 ± 0.41(IU/dL per IU/kg)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 ofsubjects; SD = standard deviation; Vss = volume of distribution at steady-state.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No studies have been conducted with XYNTHA to assess its mutagenic or carcinogenicpotential. XYNTHA has been shown to be comparable to the predecessor product withrespect to its biochemical and physicochemical properties, as well as its nonclinical in vivo pharmacology and toxicology. By inference, predecessor product and XYNTHAwould be expected to have equivalent mutagenic and carcinogenic potential. Thepredecessor product has been shown to be nongenotoxic in the mouse micronucleusassay. No studies have been conducted in animals to assess impairment of fertility orfetal development.

13.2 Animal Toxicology and/or PharmacologyPreclinical studies evaluating XYNTHA in hemophilia A dogs without inhibitorsdemonstrated safe and effective restoration of hemostasis. XYNTHA demonstrated atoxicological profile that was similar to the toxicological profile observed with thepredecessor product. Toxicity associated with XYNTHA was primarily associated withanti-FVIII neutralizing antibody generation first detectable at 15 days of repeat dosing inhigh (approximately 735 IU/kg/day) level-dosed, non-human primates.

14 CLINICAL STUDIES Safety and Efficacy StudyIn an open label safety and efficacy study (n=94), subjects received XYNTHA in a routineprophylaxis treatment regimen with on-demand treatment administered as clinicallyindicated. All 94 subjects were treated with at least one dose and all are included in theintent-to-treat (ITT) population. All subjects had been previously treated (previously treatedpatients or PTPs) with factor VIII. Eighty-nine (89) subjects accrued ≥ 50 exposure days(EDs). Median age for the 94 treated subjects was 24 years (mean 27.7 and range 12-60years). All subjects had ≥ 150 previous exposure days with baseline FVIII activity level of ≤ 2%. Of the 94 subjects enrolled in this study, 30 evaluable subjects participated in arandomized crossover pharmacokinetics study. Twenty-five (25/30) of these subjects withFVIII:C ≤ 1% completed both the first (PK1) and the second (PK2) pharmacokineticassessments [see Clinical Pharmacology (12.3)].16

For routine prophylaxis, XYNTHA was administered at a dose of 30 ± 5 IU/kg 3 times a weekwith provisions for dose escalation based on pre-specified criteria. Seven dose escalationswere prescribed for 6 subjects during the course of the study. Forty-three subjects (43/94 or45.7%) reported no bleeding while on routine prophylaxis. The median annualized bleedingrate (ABR) for all bleeding episodes was 1.9 (mean 3.9, range 0-42.1).Fifty-three subjects (53/94) received XYNTHA on-demand treatment for a total of 187bleeding episodes. Seven of these bleeding episodes occurred in subjects prior to switchingto a prophylaxis treatment regimen. One hundred ten of 180 bleeds (110/180 or 61.1%)occurred ≤ 48 hours after the last dose and 38.9% (70/180 bleeds) occurred > 48 hours afterthe last dose. The majority of bleeds reported to occur ≤ 48 hours after the last prophylaxisdose were traumatic (64/110 bleeds or 58.2%). Forty-two bleeds (42/70 or 60%) reported to occur > 48 hours after the last prophylaxis dose were spontaneous. The on-demandtreatment dosing regimen was determined by the investigator. The median dose for on-demand treatment was 30.6 IU/kg (range, 6.4 to 74.4 IU/kg). The majority of bleeding episodes (173/187 or 92.5%) resolved with 1 or 2 infusions (Table5). Subjects rated the outcomes of infusions on a pre-specified four (4) point hemostaticefficacy scale. One hundred thirty-two of 187 bleeding episodes (132/187 or 70.6%) treatedwith XYNTHA were rated excellent or good in their response to initial treatment, 45 (24.1%)were rated moderate. Five (2.7%) were rated no response, and 5 (2.7%) were not rated.

Table 5: Summary of Response to Infusions to Treat New Bleeding Episode byNumber of Infusions Needed for Resolution

Number of Infusions (%) Response Total Numberto 1st Infusion 1 2 3 4 > 4 of Bleeds

Excellenta 42 (95.5) 2 (4.5) 0 (0.0) 0 (0.0) 0 (0.0) 44Goodb 69 (78.4) 16 (18.2) 3 (3.4) 0 (0.0) 0 (0.0) 88Moderatec 24 (53.3) 16 (35.6) 2 (4.4) 0 (0.0) 3 (6.7) 45No Responsed 0 (0.0) 0 (0.0) 2 (40.0) 2 (40.0) 1 (20.0) 5Not Assessed 4 (80.0) 0 (0.0) 0 (0.0) 1 (20.0) 0 (0.0) 5e

Total 139 (74.3) 34 (18.2) 7 (3.7) 3 (1.6) 4 (2.1) 187a Excellent: Definite pain relief and/or improvement in signs of bleeding starting within 8 hoursafter an infusion, with no additional infusion administered.b Good: Definite pain relief and/or improvement in signs of bleeding starting within 8 hoursafter an infusion, with at least one additional infusion administered for complete resolution ofthe bleeding episode.c Moderate: Probable or slight improvement starting after 8 hours following the infusion, withat 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 intervalfollowing an infusion, or condition worsens.e Includes one infusion with commercial FVIII that occurred before routine prophylaxis began.

Perioperative Management StudyIn an open-label study (n=30) for surgical prophylaxis in subjects with hemophilia A,XYNTHA was administered to 25 efficacy-evaluable PTPs with severe or moderately severe(FVIII:C ≤ 2%) hemophilia A undergoing major surgical procedures (11 total kneereplacements, 1 hip replacement, 5 synovectomies, 1 left ulnar nerve transposition release,1 ventral hernia repair/scar revision, 1 knee arthroscopy, 1 revision and debridement of theknee after a total knee replacement, 1 hip arthroplasty revision, 1 stapes replacement, 1ankle arthrodesis, and 1 pseudotumor excision).17

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 initialpostoperative period were “excellent” or “good” for all assessments. Intraoperative bloodloss was reported as “normal” or “absent” for all subjects. Thirteen of the subjects (13/25or 52%) had blood loss in the postoperative period. The postoperative blood loss was ratedas “normal” for ten of these cases while three cases were rated “abnormal” (1 due tohemorrhage following surgical trauma to the epigastric artery, 1 due to an 800 mL bloodloss after hip replacement surgery, and 1 after an elbow synovectomy where the blood losscould not be measured by the investigator).

Table 6: Summary of Hemostatic Efficacy

Time of Hemostatic Efficacy Assessment Excellenta Goodb Number of subjects

End of surgery 18 (72%) 7 (28%) 25 End of initial postoperative periodc 23 (92%) 2 (8%) 25a Excellent: Achieved hemostasis comparable to that expected after similar surgery in a patientwithout hemophilia.b Good: Prolonged time to hemostasis, with somewhat increased bleeding compared with thatexpected after similar surgery in a patient without hemophilia.c End of initial postoperative period is date of discharge or postoperative Day 6, whicheveroccurs later.

15 REFERENCES1. Nilsson IM, Berntorp EE and Freiburghaus C. Treatment of patients with factor VIII

and IX inhibitors. Thromb Haemost. 1993;70(1):56-59.2. Hoyer LW. Hemophilia A. N Engl J Med. 1994;330:38-47.3. Juhlin F. Stability and Compatibility of Reconstituted Recombinant Factor VIII SQ,

250 IU/ml, in a System for Continuous Infusion. Pharmacia Document 9610224,1996.

4. Ehrenforth S, Kreuz W, Scharrer I, et al. Incidence of development of factor VIII andfactor IX inhibitors in hemophiliacs. Lancet. 1992;339:594-598.

5. Lusher J, Arkin S, Abildgaard CF, Schwartz RS, the Kogenate PUP Study Group.Recombinant factor VIII for the treatment of previously untreated patients withhemophilia A. N Engl J Med. 1993;328:453-459.

6. Bray GL, Gomperts ED, Courter S, et al. A multicenter study of recombinant factorVIII (Recombinate): safety, efficacy, and inhibitor risk in previously untreatedpatients with hemophilia A. Blood. 1994;83(9):2428-2435.

7. Kessler C, Sachse K. Factor VIII:C inhibitor associated with monoclonal-antibodypurified FVIII concentrate. Lancet. 1990;335:1403.

8. Schwartz RS, Abildgaard CF, Aledort LM, et al. Human recombinant DNA-derivedantihemophilic factor (factor VIII) in the treatment of hemophilia A. N Engl J Med.1990;323:1800-1805.

9. White GC II, Courter S, Bray GL, et al. A multicenter study of recombinant factor VIII(Recombinate™) in previously treated patients with hemophilia A. Thromb Haemost.1997;77(4):660-667.

10. Gruppo R, Chen H, Schroth P, et al. Safety and immunogenicity of recombinantfactor VIII (Recombinate™) in previously untreated patients: A 7.3 year update.Haemophilia. 1998;4:228 (Abstract No. 291, XXIII Congress of the WFH, TheHague).

11. Scharrer I, Bray GL, Neutzling O. Incidence of inhibitors in haemophilia A patients - areview of recent studies of recombinant and plasma-derived factor VIII concentrates.Haemophilia. 1999;5:145-154.

12. Abshire TC, Brackmann HH, Scharrer I, et al. Sucrose formulated recombinanthuman antihemophilic Factor VIII is safe and efficacious for treatment of hemophiliaA in home therapy: Results of a multicenter, international, clinical investigation.Thromb Haemost. 2000;83(6):811-816.

13. Sandberg H, Almstedt A, Brandt J, Castro VM, Gray E, Holmquist L, et al. Structuraland Functional Characterization of B-Domain Deleted Recombinant Factor VIII. SemHematol. 2001;38 (Suppl. 4):4-12.

14. Kelley BD, Tannatt M, Magnusson R, Hagelberg S. Development and Validation of anAffinity Chromatography Step Using a Peptide Ligand for cGMP Production of FactorVIII. Biotechnol Bioeng. 2004;87(3):400-412.

15. Mann KG and Ziedens KB. Overview of Hemostasis. In: Lee CA, Berntorp EE andHoots WK, eds. Textbook of Hemophilia. USA, Blackwell Publishing; 2005:1-4.

16. Recht M, Nemes L, Matysiak M et al. Clinical Evaluation of Moroctocog Alfa (AF-CC),a New Generation of B-Domain Deleted Recombinant Factor VIII (BDDrFVIII) forTreatment of Haemophilia A: Demonstration of Safety, Efficacy and PharmacokineticEquivalence to Full-length Recombinant Factor VIII. Haemophilia 2009; 1-12.

17. Windyga J, Rusen L, Gruppo R, et al. BDDrFVIII (Moroctocog alfa [AF-CC]) forsurgical haemostasis in patients with haemophilia A: results of a pivotal study.Haemophilia. 2010 Sep 1;16(5):731-9.

16 HOW SUPPLIED/STORAGE AND HANDLING

How SuppliedXYNTHA® SOLOFUSE™ is supplied in a kit that includes the XYNTHA lyophilized powdercontaining nominally 250, 500, 1000, 2000 or 3000 IU and 4 mL 0.9% Sodium Chloridesolution for reconstitution in a prefilled dual-chamber syringe: 250 International Units Kit: NDC 58394-022-03500 International Units Kit: NDC 58394-023-031000 International Units Kit: NDC 58394-024-032000 International Units Kit: NDC 58394-025-033000 International Units Kit: NDC 58394-016-03Each XYNTHA® SOLOFUSE™ Kit contains: one plunger rod for assembly, one sterileinfusion set, two alcohol swabs, one bandage, one gauze pad, one vented sterile cap, andone package insert.Actual factor VIII activity in International Units is stated on the label of each XYNTHA® SOLOFUSE™.

Storage and HandlingProduct as Packaged for Sale:• Store XYNTHA® SOLOFUSE™ 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 datestated on the label.

• Within the expiration date, XYNTHA® SOLOFUSE™ also may be stored at roomtemperature not to exceed 25°C (77°F) for up to 3 months.

• Clearly record the starting date at room temperature storage in the space provided onthe outer carton. At the end of the 3-month period, immediately use or discard theproduct. Do not put the product back into the refrigerator.

• Do not use XYNTHA® SOLOFUSE™ after the expiration date stated on the label orafter 3 months when stored at room temperature, whichever is earlier.

• Do not freeze. (Freezing may damage the XYNTHA® SOLOFUSE™.)• During storage, avoid prolonged exposure of XYNTHA® SOLOFUSE™ to light.• Store the reconstituted solution at room temperature prior to administration.

Remember to Administer XYNTHA® SOLOFUSE™ within 3 hours after reconstitutionor after removal of the grey rubber tip cap from the product.

17 PATIENT COUNSELING INFORMATION• Advise patients to read the FDA-approved patient labeling (Patient Information and

Instructions for Use).• Advise patients to report any adverse reactions or problems that concern them when

taking XYNTHA to their healthcare provider.• Allergic-type hypersensitivity reactions are possible. Discuss the early signs of

hypersensitivity reactions (including hives [rash with itching], generalized urticaria,tightness of the chest, wheezing, hypotension) and anaphylaxis. Advise patients todiscontinue use of the product, call their healthcare provider, and go to theemergency department if these symptoms occur.

• Advise patients to contact their healthcare provider if they experience a lack of aclinical response to factor VIII replacement therapy, as this may be a manifestation ofan inhibitor.

• Advise patients to notify their healthcare provider if they become pregnant or intendto become pregnant during therapy, or if they are breastfeeding.

• Local irritation may occur when infusing XYNTHA SOLOFUSE.• Advise patients to consult their healthcare provider prior to travel and to bring an

adequate supply of XYNTHA SOLOFUSE, based on their current regimen, foranticipated treatment when traveling.

FDA-Approved Patient LabelingPatient InformationXYNTHA® SOLOFUSE™ /ZIN-tha/[Antihemophilic Factor (Recombinant)]Please read this patient information carefully before using XYNTHAand each time you get a refill. There may be new information. Thisleaflet does not take the place of talking with your healthcare providerabout your medical problems or your treatment. What is XYNTHA?XYNTHA is an injectable medicine that is used to help control andprevent bleeding in people with hemophilia A. Hemophilia A is alsocalled classic hemophilia. Your healthcare provider may give youXYNTHA 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 ifXYNTHA may harm your unborn baby.

• are breastfeeding. It is not known if XYNTHA passes into your milkand 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 asover-the-counter medicines, supplements, or herbal remedies. How should I infuse XYNTHA?Step-by-step instructions for infusing with XYNTHA SOLOFUSE areprovided at the end of this leaflet.The steps listed below are general guidelines for using XYNTHASOLOFUSE. Always follow any specific instructions from yourhealthcare provider. If you are unsure of the procedures, please callyour healthcare provider before using. Call your healthcare provider right away if bleeding is not controlledafter using XYNTHA.Your body can make antibodies against XYNTHA (called “inhibitors”)that may stop XYNTHA from working properly. Your healthcareprovider may need to take blood tests from time to time to monitor forinhibitors.Call your healthcare provider right away if you take more than the doseyou should take. Talk to your healthcare provider before traveling. Plan to bring enoughXYNTHA 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 rightaway if you have any of the following symptoms because these maybe 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• hivesCommon side effects of XYNTHA are• headache• fever• nausea• vomiting• diarrhea• weakness

Talk to your healthcare provider about any side effect that bothers you or that does not go away. You may report side effects to FDA at 1-800-FDA-1088.How should I store XYNTHA SOLOFUSE?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) forup to 3 months. If you store XYNTHA® SOLOFUSE™ at roomtemperature, carefully write down the date you put XYNTHA®

SOLOFUSE™ at room temperature, so you will know when to throw itaway. There is a space on the carton for you to write the date. Throw away any unused XYNTHA SOLOFUSE after the expiration date. Infuse within 3 hours after reconstitution or after removal of the greyrubber tip cap from the prefilled dual-chamber syringe. You can keepthe reconstituted solution at room temperature before infusion for upto 3 hours. If it is not used in 3 hours, throw it away. Do not use reconstituted XYNTHA if it is not clear to slightlyopalescent and colorless. Dispose of all materials, whether reconstituted or not, in anappropriate medical waste container. What else should I know about XYNTHA?Medicines are sometimes prescribed for purposes other than thoselisted here. Talk to your healthcare provider if you have any concerns.You can ask your healthcare provider for information about XYNTHASOLOFUSE that was written for healthcare professionals. Do not share XYNTHA SOLOFUSE with other people, even if they havethe same symptoms that you have.

Instructions for UseXYNTHA® SOLOFUSE™ /ZIN-tha/[Antihemophilic Factor (Recombinant)]XYNTHA SOLOFUSE is supplied as a pre-filled dual-chamber syringewith lyophilized XYNTHA powder in one chamber and 0.9% sodiumchloride solution in the other chamber. Before you can infuse it(intravenous injection), you must reconstitute the powder by mixing itwith the sodium chloride solution. Reconstitute and infuse XYNTHA® SOLOFUSE™ using the infusion setprovided in this kit. Please follow the directions below for the properuse of this product.PREPARATION AND RECONSTITUTION OF XYNTHA® SOLOFUSE™Preparation1. 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 thedetailed information provided after INFUSION OF XYNTHA section.

Reconstitution1. Allow the XYNTHA SOLOFUSE to reach room temperature.2. Remove the contents of the XYNTHA® SOLOFUSE™ Kit and place

on a clean surface, making sure you have all the supplies you willneed.

3. Grasp the plunger rod as shown in the following diagram. Do nottouch the shaft of the plunger rod. Screw the plunger rod firmly intothe opening in the finger rest of the XYNTHA® SOLOFUSE™ bypushing and turning firmly until resistance is felt (approximately 2turns).

Throughout the reconstitution process, it is important to keep theXYNTHA® SOLOFUSE™ upright to prevent possible leakage.

4. Holding the XYNTHA® SOLOFUSE™ upright, remove the whitetamper-evident seal by bending the seal right to left (or a gentlerocking motion) to break the perforation of the cap and expose thegrey rubber tip cap of the XYNTHA® SOLOFUSE™.

5. Remove the protective blue vented sterile cap from its package. While holding the XYNTHA® SOLOFUSE™ upright, remove the grey

rubber tip cap and replace it with the protective blue vented cap(prevents pressure build-up). Avoid touching the open end of boththe syringe and the protective blue vented cap.

6. Gently and slowly push the plunger rod until the two stoppersinside the XYNTHA® SOLOFUSE™ meet, and all of the diluent istransferred to the chamber containing the XYNTHA powder.

Note: To prevent the escape of fluid from the tip of the syringe, donot push the plunger rod with excessive force.

7. With the XYNTHA® SOLOFUSE™ remaining upright, swirl gentlyseveral times until the powder is dissolved.

Look carefully at the solution in the XYNTHA® SOLOFUSE™. Thesolution should be clear to slightly opalescent and colorless. If itis not, throw away the solution and use a new kit.

8. Holding the XYNTHA® SOLOFUSE™ in an upright position, slowlyadvance the plunger rod until most, but not all, of the air isremoved from the drug product chamber.

Note:• If you are not using the solution immediately, store the syringeupright and keep the protective blue vent cap on the XYNTHA®

SOLOFUSE™ until ready to infuse.• Infuse XYNTHA solution within 3 hours after reconstitution orremoval of the grey tip cap from the XYNTHA SOLOFUSE. Thereconstituted 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 eachinfusion, a luer-to-luer syringe connector can be used (not includedin this kit). Please contact your doctor or healthcare provider, or callthe Wyeth Medical Information Department at 1-800-438-1985, foradditional information.

INFUSION OF XYNTHA Your healthcare provider will teach you how to infuse XYNTHAyourself. Once you learn how to do this, you can follow theinstructions in this insert.Before XYNTHA can be infused, you must reconstitute it as instructedabove in the PREPARATION AND RECONSTITUTION OF XYNTHASOLOFUSE section. After reconstitution, be sure to look carefully at the XYNTHA solution.The solution should be clear to slightly opalescent and colorless. If itis not, throw away the solution and use a new kit.Use the infusion set included in the kit to infuse XYNTHA. Do notinfuse XYNTHA in the same tubing or container with other medicines.1. After removing the protective blue vented cap, firmly attach the

intravenous infusion set provided in the kit onto the XYNTHA®

SOLOFUSE™.

2. Apply a tourniquet and prepare the injection site by wiping the skinwell with an alcohol swab provided in the kit.

3. Remove the protective needle cover and insert the butterfly needleof the infusion set tubing into your vein as instructed by yourhealthcare provider. Remove the tourniquet. Verify proper needleplacement.

4. Infuse the reconstituted XYNTHA product over several minutes.Your comfort level should determine the rate of infusion.

5. After infusing XYNTHA, remove the infusion set and throw it away.The amount of liquid left in the infusion set will not affect yourtreatment.

Note:• Throw away all unused solution, the empty XYNTHA® SOLOFUSE™,and other used medical supplies in an appropriate container.

• It is a good idea to record the lot number from the XYNTHA®

SOLOFUSE™ label every time you use XYNTHA. You can use thepeel-off label found on the XYNTHA® SOLOFUSE™ to record the lotnumber.

ADDITIONAL INSTRUCTIONSXYNTHA is also supplied in kits that include single-use vials withlyophilized powder and prefilled diluent syringes.If you use one XYNTHA vial and one XYNTHA® SOLOFUSE™ for theinfusion, reconstitute the XYNTHA vial and the XYNTHA® SOLOFUSE™according to the specific directions for that respective product kit. Usea separate, 10 milliliter or larger luer lock syringe (not included in thiskit) to draw back the reconstituted contents of the XYNTHA vial andthe XYNTHA® SOLOFUSE™.If you use multiple XYNTHA® SOLOFUSE™ kits for the infusion,reconstitute each XYNTHA® SOLOFUSE™ according to the directionsabove. Use a separate, 10 milliliter or larger luer lock syringe (notincluded in this kit) to draw back the reconstituted contents of anyadditional XYNTHA® SOLOFUSE™.Use of a XYNTHA Vial Kit with a XYNTHA® SOLOFUSE™ KitThese instructions are for the use of only one XYNTHA vial kit withone XYNTHA® SOLOFUSE™ Kit. For further information, please contactyour healthcare provider or call the Medical Information Department atWyeth Pharmaceuticals, 1-800-438-1985.1. Reconstitute the XYNTHA vial using the instructions included with

the kit. Detach the empty diluent syringe from the vial adapter bygently turning and pulling the syringe counterclockwise, leaving thecontents in the XYNTHA vial with the vial adapter in place.

2. Reconstitute the XYNTHA® SOLOFUSE™ using the instructionsincluded with the product kit, remembering to remove most, but notall, of the air from the syringe.

3. After removing the protective blue vented cap, connect theXYNTHA® SOLOFUSE™ to the vial adapter by inserting the tip intothe adapter opening while firmly pushing and turning the syringeclockwise until secured.

4. Slowly push the plunger rod of the XYNTHA® SOLOFUSE™ to emptythe contents into the XYNTHA vial. The plunger rod may move backslightly after release.

5. Detach the empty XYNTHA® SOLOFUSE™ from the vial adapter andthrow it away.

If the syringe turns without detaching from the vial adapter, grasp the white collar and turn.

6. Connect a sterile 10 milliliter or larger luer lock syringe to the vialadapter. You may want to inject some air into the vial to makewithdrawing the vial contents easier.

7. Invert the XYNTHA vial and slowly draw the solution into the largeluer lock syringe.

8. Detach the large luer lock syringe from the vial adapter by gentlyturning and pulling the syringe counterclockwise. Throw away theempty XYNTHA vial with the adapter attached.

9. Attach the infusion set to the large luer lock syringe as directed inthe INFUSION OF XYNTHA section.

Note: Dispose of all unused solution, the empty XYNTHA®

SOLOFUSE™, and other used medical supplies in an appropriatecontainer.

Use of Multiple XYNTHA® SOLOFUSE™ KitsThe 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.1. Reconstitute all XYNTHA® SOLOFUSE™ according to instructions

described in PREPARATION AND RECONSTITUTION OF XYNTHA®

SOLOFUSE™ section. Holding the XYNTHA® SOLOFUSE™ in anupright position, slowly push the plunger rod until most, but not all,of the air is removed from the syringe.

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 thesyringe connector and the XYNTHA® SOLOFUSE™ to the remainingopen port on the opposite end.

4. With the XYNTHA® SOLOFUSE™ on top, slowly push the plungerrod to empty all the XYNTHA SOLOFUSE content into the large luerlock 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 locksyringe and attach the infusion set as directed in the INFUSION OFXYNTHA section.

Note: Dispose of all unused solution, the empty XYNTHA®

SOLOFUSE™, and other used medical supplies in an appropriatecontainer.

License no: 3LAB-0500-9.0

Manufactured by

Wyeth Pharmaceuticals IncA subsidiary of Pfizer Inc, Philadelphia, PA 19101

Documents

BDDrFVIII (Moroctocog alfa [AF-CC]) for surgical ...either BI or CI for the management of surgical haemostasis in patients with severe and moderately severe haemophilia A undergoing