Xyntha

X

ihemophilic factor (recombinant, plasma/albumin-free)
Dosage Form: injection
FULL PRESCRIBING INFORMATION Indications and Usage for Xyntha Control and Prevention of Bleeding Episodes in Hemophilia A

Xyntha Antihemophilic Factor (Recombinant), Plasma/Albumin-Free is indicated for the control and prevention of bleeding episodes in patients with hemophilia A (congenital factor VIII deficiency or classic hemophilia).

Xyntha does not contain von Willebrand factor, and therefore is not indicated in patients with von Willebrand's disease.

Surgical Prophylaxis in Patients with Hemophilia A

Xyntha Antihemophilic Factor (Recombinant), Plasma/Albumin-Free is indicated for surgical prophylaxis in patients with hemophilia A.

Xyntha Dosage and Administration

For Intravenous Use After Reconstitution

Treatment with Xyntha Antihemophilic Factor (Recombinant), Plasma/Albumin-Free should be initiated 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. Doses administered should be titrated to the patient's clinical response. In the presence of an inhibitor, higher doses may be required.1

One International Unit (IU) of factor VIII activity corresponds approximately to the quantity of factor VIII in one milliliter of normal human plasma. The calculation of the required 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 by approximately 2 IU/dL.2 The required dosage 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)

The labeled potency of Xyntha is based on the European Pharmacopoeia chromogenic substrate assay, in which the Wyeth manufacturing standard has been calibrated using a one-stage clotting assay. This method of potency assignment is intended to harmonize Xyntha with clinical monitoring using a one-stage clotting assay [see Clinical Pharmacology (12.3)].

Control and Prevention of Bleeding Episodes

In the case of the following bleeding events, consideration should be given to maintaining the factor VIII activity at or above the plasma levels (in % of normal or in IU/dL) outlined below for the indicated period.

The following chart can be used to guide dosing in bleeding episodes:

Type of Bleeding Episode Factor VIII Level Required (IU/dL or % of normal) Frequency of Doses / Duration of Therapy Minor Early hemarthrosis, minor
muscle or oral bleeds. 20–40 Repeat every 12-24 hours
as necessary until resolved.
At least 1 day, depending
upon the severity of the bleeding episode. Moderate Bleeding into muscles.
Mild head trauma.
Bleeding into the oral cavity. 30–60 Repeat infusion every
12-24 hours for 3-4 days or
until adequate local
hemostasis is achieved. Major Gastrointestinal bleeding.
Intracranial, intra-abdominal
or intrathoracic bleeding.
Fractures. 60–100 Repeat infusion every 8-24
hours until bleeding is
resolved. Surgical Prophylaxis in Patients with Hemophilia A

In the case of the following bleeding events, consideration should be given to maintaining the factor VIII activity at or above the plasma levels (in % of normal or in IU/dL) outlined below for the indicated period. Monitoring of replacement therapy by means of plasma factor VIII activity is recommended, particularly for surgical intervention.

The following chart can be used to guide dosing in surgery:

Type of Surgery Factor VIII Level Required (IU/dL or % of normal) Frequency of Doses / Duration of Therapy Minor Minor operations, including tooth extraction. 30–60 Repeat infusion every
12-24 hours for 3-4 days or
until adequate local
hemostasis is achieved.
For tooth extraction, a
single infusion plus oral
antifibrinolytic therapy within 1 hour may be sufficient. Major Major operations. 60–100 Repeat infusion every 8-24
hours until threat is
resolved, or in the case of
surgery, until adequate
local hemostasis and wound healing are achieved. Instructions for Use

Xyntha is administered by intravenous (IV) infusion after reconstitution of the freeze-dried powder with the supplied pre-filled diluent (0.9% Sodium Chloride solution) syringe.

Patients should follow the specific reconstitution and administration procedures provided by their physicians. For instructions, patients should follow the recommendations in the FDA-Approved Patient Labeling (17). The procedures below are provided as general guidelines for the reconstitution and administration of Xyntha.

Additional instructions are provided after Administration 2.5 that detail the use of a Xyntha vial and Prefilled Dual-Chamber Syringe [see Use of a Xyntha Vial Kit and a Xyntha Prefilled Dual-Chamber Syringe Kit (2.6)].

Note: If the patient uses more than one vial and/or prefilled dual-chamber syringe of Xyntha per infusion, each vial and/or syringe should be reconstituted according to the instructions for that respective product kit. A separate 10 cc or larger luer lock syringe (not included in this kit) may be used to draw back the reconstituted contents of each vial or syringe.

Preparation and Reconstitution Preparation Always wash your hands before performing the following procedures. Aseptic technique (meaning clean and germ-free) should be used during the reconstitution procedure. All components used in the reconstitution and administration of this product should be used as soon as possible after opening their sterile containers to minimize unnecessary exposure to the atmosphere.

Note: If you use more than one vial of Xyntha per infusion, each vial should be reconstituted according to the following instructions. The diluent syringe should be removed, leaving the vial adapter in place, and a separate large luer lock syringe may be used to draw back the reconstituted contents of each vial. Do not detach the diluent syringes or the large luer lock syringe until you are ready to attach the large luer lock syringe to the next vial adapter.

Reconstitution Allow the vials of freeze-dried Xyntha and the pre-filled diluent syringe to reach room temperature. Remove the plastic flip-top cap from the Xyntha vial to expose the central portions of the rubber stopper. Wipe the top of the vial with the alcohol swab provided, or use another antiseptic solution, and allow to dry. After cleaning, do not touch the rubber stopper with your hand or allow it to touch any surface. Peel back the cover from the clear plastic vial adapter package. Do not remove the adapter from the package. Place the vial on a flat surface. While holding the adapter package, place the vial adapter over the vial and press down firmly on the package until the adapter spike penetrates the vial stopper. Grasp the plunger rod as shown in the diagram. Avoid contact with the shaft of the plunger rod. Attach the threaded end of the plunger rod to the diluent syringe plunger by pushing and turning firmly. Break off the tamper-resistant plastic tip cap from the diluent syringe by snapping the perforation of the cap. Do not touch the inside of the cap or the syringe tip. The diluent syringe may need to be recapped (if not administering reconstituted Xyntha immediately), so place the cap on its top on a clean surface in a spot where it would be least likely to become environmentally contaminated. Lift the package away from the adapter and discard the package. Place the vial on a flat surface. Connect the diluent syringe to the vial adapter by inserting the tip into the adapter opening while firmly pushing and turning the syringe clockwise until secured. Slowly depress the plunger rod to inject all the diluent into the Xyntha vial. Without removing the syringe, gently swirl the contents of the vial until the powder is dissolved.

Note: The final solution should be inspected visually for particulate matter before administration. The solution should be clear to slightly opalescent and colorless. If it is not, the solution should be discarded and a new kit should be used.

Invert the vial and slowly draw the solution into the syringe. Detach the syringe from the vial adapter by gently pulling and turning the syringe counter?clockwise. Discard the vial with the adapter attached.

Note: If the solution is not to be used immediately, the syringe cap should be carefully replaced. Do not touch the syringe tip or the inside of the cap.

The reconstituted solution may be stored at room temperature prior to administration, but should be administered within 3 hours.

Xyntha, when reconstituted, contains polysorbate 80, which is known to increase the rate of di-(2-ethylhexyl)phthalate (DEHP) extraction from polyvinyl chloride (PVC). This should be considered during the preparation and administration of Xyntha, including storage time elapsed in a PVC container following reconstitution. It is important that the recommendations in Dosage and Administration (2) be followed closely.

Administration

Xyntha is administered by intravenous (IV) infusion after reconstitution of the freeze-dried powder with the diluent (0.9% Sodium Chloride) syringe. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Xyntha should be administered using the tubing provided in this kit and the pre?filled diluent syringe provided, or a single sterile disposable plastic syringe. In addition, the solution should be withdrawn from the vial using the vial adapter.

Attach the syringe to the luer end of the infusion set tubing provided. Apply a tourniquet and prepare the injections site by wiping the skin well with an alcohol swab provided in the kit. Remove the protective needle cover and perform venipuncture. Insert the needle on the infusion set tubing into the vein, and remove the tourniquet. The reconstituted Xyntha product should be injected intravenously over several minutes. The rate of administration should be determined by the patient's comfort level. As with any intravenous administration, always verify proper needle placement.

Reconstituted Xyntha should not be administered in the same tubing or container with other medicinal products.3

After infusing Xyntha, remove the infusion set and discard. The amount of drug product left in the infusion set will not affect treatment.

Note: Dispose of all unused solution, the empty vial(s) and other used medical supplies in an appropriate container for throwing away medical waste that might hurt others if not handled properly.

Use of a Xyntha Vial Kit and a Xyntha Prefilled Dual-Chamber Syringe Kit

These instructions are for the use of only one Xyntha vial kit and one Xyntha Pre-filled Dual-Chamber Syringe Kit. For further information, please contact the Medical Information Department at Wyeth Pharmaceuticals, 1-800-934-5556.

Reconstitute the Xyntha vial using the instructions included with this kit. 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 in place. Reconstitute the Xyntha Prefilled Dual-Chamber Syringe using the instructions included with the kit, remembering to remove most, but not all, of the air from the drug product chamber. After removing the protective blue vented cap, connect the Xyntha Prefilled Dual?Chamber Syringe to the vial adapter by inserting the tip into the adapter opening while firmly pushing and turning the syringe clockwise until secured. Slowly depress the plunger rod of the Xyntha Prefilled Dual-Chamber Syringe until the contents empty into the Xyntha vial. The plunger rod may move back slightly after release. Detach and discard the empty Xyntha Prefilled Dual-Chamber Syringe from the vial adapter.

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

Connect a sterile 10 cc or larger luer lock syringe to the vial adapter. You may want to inject some air into the vial to make withdrawing the vial contents easier. Invert the vial and slowly draw the solution into the 10 cc or larger luer lock syringe. Detach the syringe from the vial adapter by gently turning and pulling the syringe counterclockwise. Discard the vial with the adapter attached. Attach the infusion set to the 10 cc or larger luer lock syringe as directed [see Dosage and Administration (2.5)].

Note: Dispose of all unused solution, the empty Xyntha Prefilled Dual-Chamber Syringe, and other used medical supplies in an appropriate container for throwing away medical waste that might hurt others if not handled properly.

Dosage Forms and Strengths

Xyntha is supplied as a white to off-white powder in the following dosages:

250 IU 500 IU 1000 IU 2000 IU Contraindications

None.

Warnings and Precautions Anaphylaxis and Severe Hypersensitivity Reactions

Allergic type hypersensitivity reactions are possible. Patients should be informed of the early signs or symptoms of hypersensitivity reactions [including hives (rash with itching), generalized urticaria, tightness of the chest, wheezing, and hypotension] and anaphylaxis [see Patient Counseling Information (17)]. Patients should be advised to discontinue use of the product and contact their physicians if these symptoms occur.

Neutralizing Antibodies

The occurrence of neutralizing antibodies (inhibitors) is well known in the treatment of patients with hemophilia A. Inhibitors have been detected in patients receiving factor VIII-containing products. Inhibitors are common in previously untreated patients 4,5,6 and have been observed in previously treated patients on factor VIII products.7,8,9,10,11,12 Patients using coagulation factor VIII products, including Xyntha, should be monitored for the development of factor VIII inhibitors. If expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, an assay should be performed to determine if a factor VIII inhibitor is present [see Warnings and Precautions (5.4)]. If detected, inhibitors should be titered in Bethesda Units (BU).

Formation of Antibodies to Hamster Protein

Xyntha contains trace amounts of hamster proteins. Patients treated with this product could develop hypersensitivity to these non-human mammalian proteins.

Monitoring: Laboratory Tests Monitor plasma factor VIII activity levels by the one-stage clotting assay to confirm that adequate factor VIII levels have been achieved and are maintained [see Dosage and Administration (2)]. It is recommended that individual factor VIII values for recovery and, if clinically indicated, other pharmacokinetic characteristics be used to guide dosing and administration. Monitor for development of factor VIII inhibitors. Perform assay to determine if factor VIII inhibitor is present when expected factor VIII activity plasma levels are not attained, or when bleeding is not controlled with the expected dose of Xyntha. Use Bethesda Units (BU) to titer inhibitors. Adverse Reactions

The most common adverse reaction in study 1 is headache (24% of subjects) and in study 2 is pyrexia (41% of subjects).

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Study 1 is a pivotal phase 3 (safety and efficacy) study in which previously treated patients (PTPs) with hemophilia A received Xyntha for routine prophylaxis and on-demand treatment, 94 subjects received at least one dose of Xyntha, resulting in a total of 6,775 infusions [see Clinical Studies (14)]. In Study 1, the most frequently reported treatment-emergent adverse reaction was headache (24% of subjects). Other adverse reactions reported in ? 5% of subjects were: nausea (6%), diarrhea (5%), asthenia (5%) and pyrexia (5%). No subject developed anti-CHO or anti-TN8.2 antibodies.

Study 2 (surgery) is an on-going open-label, single-arm study of at least 25 evaluable PTPs with severe or moderately severe hemophilia A (factor VIII activity in plasma [FVIII:C] ? 2%) who required elective major surgery and were planned to receive Xyntha replacement therapy for at least 6 days post-surgery. Twenty-two subjects received at least one dose of Xyntha, resulting in 766 infusions [see Clinical Studies (14)].

In Study 2, the most frequently reported treatment-emergent adverse reaction was pyrexia (41% of subjects). Other adverse reactions reported in ? 5% of subjects were: headache (9%), nausea (9%), diarrhea (5%), vomiting (5%) and asthenia (5%). The adverse reactions reported in either study were considered mild or moderate in severity.

Immunogenicity

In Study 1, the incidence of FVIII inhibitors to Xyntha was the primary safety endpoint. Two subjects with inhibitors were observed in 89 subjects (2.2%) who completed ? 50 exposure days. These results were consistent with the pre-specified endpoint that no more than 2 inhibitors may be observed in at least 81 subjects.

In a Bayesian statistical analysis, results from this study were used to update PTP results from a prior supporting study using Xyntha manufactured at the initial facility, where one de novo and two recurrent inhibitors were observed in 110 subjects, and the experience with predecessor product (1 inhibitor in 113 subjects). This Bayesian analysis indicates that the population (true) inhibitor rate for Xyntha, the estimate of the 95% upper limit of the true inhibitor rate, was 4.17% (see Table 1).

Table 1: Bayesian Posterior Distribution of Inhibitor Rate a Prior alpha of 2.5 plus the number of observed inhibitors.

b Prior beta of 110 plus the number of subjects analyzed minus the number of observed inhibitors.

c Posterior probability is the probability that the true inhibitor rate is less than the upper acceptable limit of 4.4%. A posterior probability greater than 0.95 is deemed acceptable.

d The 95% upper limit of the true inhibitor rate (the maximum rate calculated with at least 95% probability) based on the posterior distribution. An inhibitor rate less than 4.4% is deemed acceptable.

---Posterior Beta Distribution
Characteristics--- FVIII Inhibitor
Nijmegen Result
(BU/mL) Number of
Inhibitors Number of
Subjects
Analyzed Observed
Inhibitor
Rate (%) Alphaa Betab Posterior
Probabilityc 95% Upper Limit
of Inhibitor
Rate (%)d ?0.6 2 89 2.25 4.5 197 0.9613 4.17 Drug Interactions

None known.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C

Animal reproduction studies have not been conducted with Xyntha Antihemophilic Factor (Recombinant), Plasma/Albumin-Free. It is also not known whether Xyntha can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Xyntha should be given to a pregnant woman only if clinically indicated.

Labor and Delivery

There is no information available on the effect of factor VIII replacement therapy on labor and delivery. Xyntha should be used only if clinically indicated.

Nursing Mothers

It is not known whether this drug is excreted into human milk. Because many drugs are excreted into human milk, caution should be exercised if Xyntha is administered to nursing mothers. Xyntha should be given to nursing mothers only if clinically indicated.

Pediatric Use

A study of Xyntha in previously treated patients less than 6 years of age is currently ongoing.

Pharmacokinetics of Xyntha was studied in 7 previously treated patients 12-16 years of age. Pharmacokinetic parameters in these patients were similar to those obtained for adults after a dose of 50 IU/kg. For these 7 patients, the mean (± SD) Cmax and AUC? were 1.09 ± 0.21 IU/mL and 11.5 ± 5.2 IU?h/mL, respectively. The mean clearance and plasma half?life values were 5.23 ± 2.36 mL/h/kg and 8.03 ± 2.44 hours (range 3.52 – 10.6 hours), respectively. The mean K?value and in vivo recoveries were 2.18 ± 0.41 IU/dL per IU/kg and 112 ± 23%, respectively.

Geriatric Use

Clinical studies of Xyntha did not include subjects aged 65 and over. In general, dose selection for an elderly patient should be individualized.

Xyntha Description

Antihemophilic Factor (Recombinant), Plasma/Albumin-Free, the active ingredient in Xyntha, is a recombinant coagulation factor VIII produced by recombinant DNA technology for use in therapy of factor VIII deficiency. The Antihemophilic Factor (Recombinant), Plasma/Albumin?Free in Xyntha is a purified glycoprotein, with an approximate molecular mass of 170 kDa consisting of 1,438 amino acids, which does not contain the B-domain.13 The amino acid sequence of Antihemophilic Factor (Recombinant), Plasma/Albumin-Free in Xyntha is comparable to the 90 + 80 kDa form of human factor VIII.

The Antihemophilic Factor (Recombinant), Plasma/Albumin?Free in Xyntha is secreted by a genetically engineered Chinese hamster ovary (CHO) cell line. The cell line is grown in a chemically defined cell culture medium that contains recombinant insulin, but does not contain any materials derived from human or animal sources. The Antihemophilic Factor (Recombinant), Plasma/Albumin?Free in Xyntha is purified by a process that uses a series of chromatography steps, one of which is based on affinity chromatography using a patented synthetic peptide affinity ligand.14 The process also includes a solvent-detergent viral inactivation step and a virus?retaining nanofiltration step.

The potency expressed in International Units (IU) is determined using the chromogenic assay of the European Pharmacopoeia. The Wyeth manufacturing reference standard for potency has been calibrated against the World Health Organization (WHO) International Standard for factor VIII activity using the one-stage clotting assay. The specific activity of Xyntha is 5,500 to 9,900 IU per milligram of protein.

Xyntha is formulated as a sterile, nonpyrogenic, preservative-free, freeze-dried powder preparation for intravenous (IV) injection. Each single-use vial contains nominally 250, 500, 1000 or 2000 IU of Xyntha. Upon reconstitution, the product is a clear to slightly opalescent, colorless solution that contains sodium chloride, sucrose, L-histidine, calcium chloride and polysorbate 80.

Xyntha - Clinical Pharmacology Mechanism of Action

Factor VIII is the specific clotting factor deficient in patients with hemophilia A (classical hemophilia).15 Activated factor VIII acts as a cofactor for activated factor IX, accelerating the conversion of factor X to activated factor X.15 Activated factor X converts prothrombin into thrombin.15 Thrombin then converts fibrinogen into fibrin, and a clot is formed.15 Factor VIII activity is greatly reduced in patients with hemophilia A, and, therefore, replacement therapy is necessary. The administration of Xyntha increases plasma levels of factor VIII activity and can temporarily correct the coagulation defect in these patients.

Pharmacodynamics

The administration of Xyntha increases plasma levels of factor VIII activity and can temporarily correct the coagulation defect in hemophilia A patients.

Pharmacokinetics

In a pivotal crossover clinical study, 30 evaluable previously treated patients [PTP] (? 12 years) received a single infusion of 50 IU/kg of Xyntha followed by a full-length recombinant FVIII (FLrFVIII, Advate®) or a single infusion of FLrFVIII followed by Xyntha in a randomized crossover design. The one-stage clotting assay method was used to determine the concentrations of these two products in blood. Xyntha was shown to be pharmacokinetically equivalent to FLrFVIII as the 90% confidence intervals for Xyntha-to-FLrFVIII ratios of the mean values of Cmax and AUC? were within pre-established limits of 80% to 125%. The pharmacokinetic parameters of Xyntha in the above group of patients are summarized in Table 2.

In addition, 25 PTPs received a single infusion of 50 IU/kg of Xyntha for a 6-month follow-up PK study. The pharmacokinetic parameters were comparable between baseline and month 6, indicating no time-dependent changes in the pharmacokinetic properties of Xyntha; the 90% confidence intervals for Xyntha 6 month-to-baseline ratios of the mean values of Cmax and AUC? were within pre-established limits of 80% to 125%.

Table 2: Pharmacokinetic Parameter Estimates for Xyntha at Baseline (Cross-over phase) and Month 6 (Follow-up phase) in Previously Treated Patients with Hemophilia A Parameter Parameters at Initial Visit (Crossover phase, n = 30) Mean ± SD Parameters at Month 6 (Follow-up phase, n = 25) Mean ± SD Abbreviations: AUC? = area under the plasma concentration-time curve from zero to infinity; Cmax = peak concentration; K?value = incremental recovery; t1/2 = plasma elimination half-life; CL = clearance; n = number of subjects; SD = standard deviation.

*One subject was excluded from the calculation due to lack of a well-defined terminal phase.

Cmax (IU/mL) 1.08 ± 0.22 1.24 ± 0.42 AUC? (IU?hr/mL) 13.5 ± 5.6 15.0 ± 7.5 t1/2 (hr) 11.2 ± 5.0 11.8 ± 6.2* CL (mL/hr/kg) 4.51 ± 2.23 4.04 ± 1.87 K-value
(IU/dL per IU/kg) 2.15 ± 0.44 2.47 ± 0.84 In vivo Recovery (%) 103 ± 21 116 ± 40 Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been conducted with Xyntha to assess its mutagenic or carcinogenic potential. Xyntha has been shown to be comparable to the predecessor product with respect to its biochemical and physicochemical properties, as well as its non-clinical in vivo pharmacology and toxicology. By inference, predecessor product and Xyntha would be expected to have equivalent mutagenic and carcinogenic potential. The predecessor product has been shown to be nongenotoxic in the mouse micronucleus assay. No studies have been conducted in animals to assess impairment of fertility or fetal development.

Animal Toxicology and/or Pharmacology

Preclinical studies evaluating Xyntha in hemophilia A dogs without inhibitors demonstrated safe and effective restoration of hemostasis. Xyntha demonstrated a toxicological profile that was similar to the toxicological profile observed with the predecessor product. Toxicity associated with Xyntha was primarily associated with anti-FVIII neutralizing antibody generation first detectable at 15 days of repeat dosing in high (approximately 735 IU/kg/day) level-dosed, non-human primates.

Clinical Studies

The efficacy of Xyntha was evaluated in Study 1, in which subjects received Xyntha on a prophylaxis treatment regimen, with on-demand treatment administered as clinically indicated. Ninety-four (94) subjects were enrolled and treated with at least one dose, and all are included in the intent-to-treat (ITT) population. Eighty-nine (89) subjects accrued ? 50 exposure days. From the 94 subjects enrolled, thirty (30) evaluable subjects participated in the PK study and received at least 1 PK dose. Twenty-five (25) evaluable subjects with FVIII:C ? 1% completed both the first (PK1) and the second (PK2) assessments [see Clinical Pharmacology (12.3)]. Median age for the 94 treated subjects was 24 years (mean 27.7 and range 12-60 years). All subjects had ? 150 previous exposure days with baseline FVIII activity level of ? 2%.

In the open-label safety and efficacy period, all 94 subjects received Xyntha for routine prophylaxis at the dose of 30 ± 5 IU/kg 3 times a week with provisions for dose escalation based on pre-specified criteria. Seven (7) dose escalations were prescribed for 6 subjects during the course of the study. Forty-three (43) of ninety-four (94), i.e. 45.7%, subjects reported no bleeding while on routine prophylaxis. The median annualized bleeding rate (ABR) for all bleeding episodes was 1.9 (mean 3.9, range 0 to 42.1).

Fifty-three (53) of 94 subjects received Xyntha for on-demand treatment for a total of 187 bleeding episodes (Table 3). Seven of these bleeding episodes occurred in subjects prior to switching to a prophylaxis treatment regimen. One hundred ten of one hundred eighty (110/180) bleeds (61.1%) occurred ? 48 hours after the last dose and 38.9% (70 of 180 bleeds) occurred > 48 hours after the last dose. The majority of bleeds reported to occur ? 48 hours after the last prophylaxis dose were traumatic (64 of 110 bleeds; 58.2%). Forty-two (42) of 70 bleeds (60%) reported to occur > 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).

Table 3: Time Interval Between Last Prophylaxis Dose of Xyntha and Start of Bleed a Bleeds with unknown start time or bleeds in which previous prophylaxis dose was before the start of the safety and efficacy period of the study. Abbreviations: Spon = spontaneous new bleed; Traum = new bleed due to trauma; hrs = hours. ? 24 hrs > 24 ? 48 hrs > 48 ? 72 hrs > 72 hrs Unknowna Total Bleeding Episodes Spon Traum Spon Traum Spon Traum Spon Traum Spon Traum   13 20 33 44 24 12 18 16 3 4 187

The majority of bleeding episodes (173/187; 92.5%) resolved with 1 or 2 infusions. Subjects rated the outcomes of infusions on a pre-specified four (4) point hemostatic efficacy scale. One hundred thirty-two (132) of 187 bleeding episodes (70.6%) treated with Xyntha were rated excellent or good in their response to initial treatment, 45 (24.1%) were rated moderate. Five [5] (2.7%) were rated no response, and 5 (2.7%) were not rated.

Table 4: Summary of Response to Infusions to Treat New Bleeding Episode by Number of Infusions Needed for Resolution a Includes 1 infusion with commercial FVIII that occurred before routine prophylaxis began.   --------Number of Infusions (%)------   Response to 1st Infusion 1 2 3 4 >4 Total Number of Bleeds Excellent 42 (95.5) 2 (4.5) 0 (0.0) 0 (0.0) 0 (0.0) 44 Good 69 (78.4) 16 (18.2) 3 (3.4) 0 (0.0) 0 (0.0) 88 Moderate 24 (53.3) 16 (35.6) 2 (4.4) 0 (0.0) 3 (6.7) 45 No Response 0 (0.0) 0 (0.0) 2 (40.0) 2 (40.0) 1 (20.0) 5 Not Assessed 4 (80.0) 0 (0.0) 0 (0.0) 1 (20.0) 0 (0.0) 5a Total 139 (74.3) 34 (18.2) 7 (3.7) 3 (1.6) 4 (2.1) 187

In an ongoing, open-label study of Xyntha in surgical prophylaxis, 21 of at least 25 evaluable PTPs with severe or moderately severe (FVIII:C ? 2%) hemophilia A undergoing major surgical procedures received Xyntha. One (1) subject received Xyntha for a pre-surgery pharmacokinetic assessment only and had not undergone surgery.

The results of an interim analysis on 21 of the 25 planned evaluable subjects who had undergone major surgical procedures (13 total knee replacements, 1 hip replacement, 3 synovectomies, 1 left ulnar nerve transposition release, 1 ventral hernia repair/scar revision, 1 knee arthroscopy, 1 revision and debridement of the knee after a total knee replacement) are presented in Table 5. For the 21 surgical subjects, investigator's ratings of efficacy at the end of surgery and at the end of the initial postoperative period were excellent or good for all assessments. All reported blood loss during the intra-operative and postoperative periods was rated normal with the exception of one subject who experienced iatrogenic bleeding.

Table 5: Summary of Hemostatic Efficacy a Conclusion of initial postoperative period is date of discharge or postoperative Day 6, whichever occurs later. Time of Hemostatic Efficacy Assessment Excellent Good Number of subjects End of surgery 14 (67%) 7 (33%) 21 End of initial postoperative perioda 16 (84%) 3 (16%) 19 REFERENCES Nilsson IM, Berntorp EE and Freiburghaus C. Treatment of patients with factor VIII and IX inhibitors. Thromb Haemost. 1993;70(1):56-59. Hoyer LW. Hemophilia A. N Engl J Med. 1994;330:38-47. Juhlin F. Stability and Compatibility of Reconstituted Recombinant Factor VIII SQ, 250 IU/ml, in a System for Continuous Infusion. Pharmacia Document 9610224, 1996. Ehrenforth S, Kreuz W, Scharrer I, et al. Incidence of development of factor VIII and factor IX inhibitors in hemophiliacs. Lancet. 1992;339:594-598. Lusher J, Arkin S, Abildgaard CF, Schwartz RS, the Kogenate PUP Study Group. Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. N Engl J Med. 1993;328:453-459. Bray GL, Gomperts ED, Courter S, et al. A multicenter study of recombinant factor VIII (Recombinate): safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. Blood. 1994;83(9):2428-2435. Kessler C, Sachse K. Factor VIII:C inhibitor associated with monoclonal-antibody purified FVIII concentrate. Lancet. 1990;335:1403. Schwartz RS, Abildgaard CF, Aledort LM, et al. Human recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia A. N Engl J Med. 1990;323:1800-1805. 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. Gruppo R, Chen H, Schroth P, et al. Safety and immunogenicity of recombinant factor VIII (Recombinate™) in previously untreated patients: A 7.3 year update. Haemophilia. 1998;4:228 (Abstract

Xyntha

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