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Indication
XYNTHA™ Antihemophilic Factor (Recombinant), Plasma/Albumin-Free is indicated for the control and prevention of bleeding episodes in patients with hemophilia A and for surgical prophylaxis 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 von Willebrand’s disease.

Important Safety Information

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. Patients should be advised to discontinue use of the product and contact their physicians if these symptoms occur.
Inhibitors have been detected in patients receiving factor VIII containing products. In a pivotal phase 3 study, two of 89 patients (2.2 percent) who completed > 50 exposure days developed factor VIII inhibitor. These results were consistent with the pre-specified endpoint of the study. 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.
XYNTHA contains trace amounts of hamster proteins. Patients treated with this product could develop hypersensitivity to these nonhuman mammalian proteins.
When clinically indicated, patients should have plasma factor VIII activity levels monitored by the one-stage clotting assay to confirm that adequate factor VIII levels have been achieved and are maintained.
The most frequently reported adverse reactions in clinical studies were headache and fever.

DOSAGE AND ADMINISTRATION

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 onestage

clotting assay. This method of potency assignment is intended to harmonize XYNTHA

with clinical monitoring using a one-stage clotting assay.

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.	60–100	Repeat infusion every 8-24 hours until bleeding is resolved.

CLINICAL PHARMACOLOGY

1. 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.

2. Pharmacodynamics

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

3. 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%.

原廠資訊連結：http://www.wyeth.com/hcp/xyntha