XYNTHA (antihemophilic Factor (Recombinant))

• Xyntha may be contraindicated in patients with a known hypersensitivity to any of the constituents of the preparation (see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING). 

• Xyntha has not been studied in patients with a known history of hypersensitivity to hamster proteins and may be contraindicated in these patients.

4.1 Dosing Considerations

• Treatment with Xyntha should be initiated under the supervision of a health professional experienced in the treatment of hemophilia A.
• Xyntha is appropriate for use in adults and children including newborns.
• 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. Individual patients may vary in their response to factor VIII, achieving different levels of in vivo recovery and demonstrating different half-lives.  Doses administered should be titrated to the patient’s clinical response.  In the presence of an inhibitor, higher doses or appropriate alternative treatment may be required.  Dosage adjustment for patients with renal or hepatic impairment has not been studied in clinical trials.
• The number of units of factor VIII administered is expressed in International Units (IU), which are related to the current World Health Organization (WHO) international standard for factor VIII activity. Factor VIII activity in plasma is expressed either as a percentage (relative to normal human plasma) or in IU (relative to an International Standard for factor VIII in plasma).
• One IU of factor VIII activity corresponds approximately to the quantity of factor VIII in one mL 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 2 IU/dL.  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) 

• Clinical data support the use of the one-stage clotting assay for monitoring Xyntha therapy.
• The labeled potency of Xyntha is based on the European Pharmacopoeia chromogenic substrate assay in which the Pfizer In-House Recombinant Factor VIII Potency Reference 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.
• Precise monitoring of the replacement therapy by means of plasma factor VIII activity assay should be considered, particularly for surgical intervention.

4.2 Recommended Dose and Dosage Adjustment

Dosing for Bleeding and Surgery:

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

Dosage for Prophylaxis

Xyntha has been administered prophylactically in a pivotal clinical trial in adolescent and adult previously treated patients at a dose of 30 + 5 IU/kg given 3 times weekly.

Inhibitors

Patients using factor VIII replacement therapy 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.  In patients with factor VIII inhibitors, factor VIII therapy may not be effective and other therapeutic options should be considered.  Management of such patients should be directed by health professionals with experience in the care of patients with hemophilia.

4.3 Reconstitution

Always wash your hands before performing the following procedures.  Use germ-free methods during the preparation procedures. 

All components used in the mixing and injection of Xyntha should be used as soon as possible after opening their sterile containers to minimize unnecessary exposure to room air. 

Xyntha Vial Kit:

Use only the materials provided in the Xyntha kit for dissolving the Xyntha powder with the sodium chloride diluent. 

Xyntha is administered by intravenous injection after dissolving with the supplied diluent (0.9% sodium chloride) in the pre-filled syringe. 

Note: If you use more than one vial of Xyntha per injection, each vial should be dissolved according to the following instructions.  The empty syringe should be removed leaving the vial adapter in place, and a separate large luer lock syringe may be used to draw back the dissolved 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. 

Xyntha Solofuse:

Note: If you use 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.

4.4 Administration

Patients should follow the specific reconstitution and administration procedures provided by their health professionals.  For instructions, patients should follow the recommendations in the below Administration and Reconstitution sections.  The procedures below are provided as general guidelines for the reconstitution and administration of Xyntha. 

Additional instructions are provided after Infusion section that detail the use of a Xyntha vial and a Xyntha Solofuse or multiple Xyntha Solofuse [see Combined Use of a Xyntha Vial Kit and a Xyntha Solofuse, and Multiple Xyntha Solofuse Reconstitution to a 10 cc or Larger Luer Lock Syringe]. 

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 

Xyntha Vial Kit:

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

Xyntha Solofuse:

Xyntha Solofuse is administered by IV infusion after reconstitution of the freeze-dried powder with the diluent (0.9% Sodium Chloride).  Both the Xyntha powder and the diluent are supplied within the prefilled dual-chamber syringe.  

Xyntha Vial Kit:

Xyntha should be infused within 3 hours after dissolving.  The dissolved solution may be stored at room temperature prior to infusion. 

Xyntha Solofuse:

The reconstituted solution may be stored at room temperature prior to administration, but should be administered within 3 hours after reconstitution or removal of the grey rubber tip cap.

If the solution is not used immediately, the syringe should be stored upright and the protective blue vent cap should remain on the Xyntha Solofuse until ready to infuse. 

Infusion (Intravenous Injection)

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 4 DOSAGE AND ADMINISTRATION section be followed closely.  

Note: The tubing of the infusion set included with Xyntha vial kit and Xyntha Solofuse kit does not contain DEHP. 

Xyntha Vial kit: 

You should inject Xyntha as instructed by your hemophilia doctor or nurse.  Once you learn how to self-infuse, you can follow the instructions in this insert. 

Always wash your hands before doing the following procedures.  Germ-free methods should be used during injection. 

Xyntha should be administered using the pre-filled diluent syringe provided or a single sterile disposable plastic luer-lock syringe.  In addition, the solution should be withdrawn from the vial using the vial adapter.

You should record the lot number of the product every time you use Xyntha.  The lot number can be found on the vial label.  The peel-off label on the vial may be used to record the lot number.

In the absence of incompatibility studies, reconstituted Xyntha should not be administered in the same tubing or container with other medicinal products.  Infusion kit components supplied in this carton are compatible with Xyntha for administration. 

The reconstituted Xyntha solution does not contain a preservative and should be used within 3 hours of reconstitution. 

Xyntha Solofuse: 

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

Xyntha, as provided in the prefilled dual-chamber syringe, should routinely be administered using the infusion set included in the kit. 

Combined Use of a Xyntha Vial Kit and a Xyntha Solofuse Kit 

These instructions are for the combined use of only one Xyntha vial kit and one Xyntha Solofuse Kit.

Multiple Xyntha Solofuse Reconstitution to a 10 cc or Larger Luer Lock Syringe 

The instructions below are for the use of multiple Xyntha Solofuse kits with a 10 cc or larger luer lock syringe. 

Note: Luer-to-luer syringe connectors are not provided in these kits.  Instruct patients to contact Pfizer for information on how to obtain the luer-to-luer syringe connectors.

4.5 Missed Dose

Proceed with your next dose immediately and continue at regular intervals as advised by your health professionals. Do not take a double dose to make up for a forgotten dose.

Xyntha Vial Kit:

Xyntha, Antihemophilic Factor (Recombinant) freeze-dried is supplied in kits that include single-use vials that contain nominally 250, 500, 1000, or 2000 IU per vial.  Actual factor VIII activity in IU is stated on the label of each Xyntha Antihemophilic Factor (Recombinant) vial. 

In addition, each Xyntha Antihemophilic Factor (Recombinant) kit contains: one pre-filled diluent syringe containing 4 mL 0.9% Sodium Chloride with plunger rod for assembly, one vial adapter, one sterile infusion set, two alcohol swabs, one bandage, one gauze, and one package insert. 

Xyntha Solofuse:

Xyntha Antihemophilic Factor (Recombinant), is supplied in a kit that includes the Xyntha freeze-dried powder that contain nominally 250, 500, 1000, 2000, or 3000 IU and 4 mL 0.9 % Sodium Chloride solution for reconstitution in a prefilled dual-chamber syringe.  Actual factor VIII activity in IU is stated on the label of each Xyntha Antihemophilic Factor (Recombinant) pre-filled dual-chamber syringe.

8.1 Adverse Reaction Overview

The most frequently reported treatment-emergent adverse reaction, on a per infusion basis, was vomiting. Most adverse reactions reported were considered mild or moderate in severity. 

In addition, as with any intravenous protein product, allergic type hypersensitivity reactions are possible.  Manifestations of hypersensitivity reactions may include hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. 

Patients with hemophilia A may develop neutralizing antibodies (inhibitors) to factor VIII.  As with all coagulation factor VIII products, patients are to be monitored for the development of inhibitors that are quantified in Bethesda Units (BUs) using either the Bethesda assay or Bethesda assay with the Nijmegen modification. If such inhibitors occur, the condition may manifest itself as an insufficient clinical response or an unexpectedly low yield of plasma factor VIII activity.  In such cases, it is recommended that a specialized hemophilia center be contacted. 

Reports of lack of effect, mainly in prophylaxis patients, have been received during the clinical trials and post-marketing setting.  The lack of effect and/or low factor VIII recovery has been reported in patients with inhibitors but also in patients who had no evidence of inhibitors.  The lack of effect has been described as bleeding into target joints, bleeding into new joints, other bleeding, or a subjective feeling by the patient of a new onset bleeding.  In order to ensure an adequate therapeutic response, it is important TO INDIVIDUALLY TITRATE AND MONITOR each patient’s dose of Xyntha, particularly when initiating treatment with Xyntha (see 7 WARNINGS AND PRECAUTIONS and 4 DOSAGE AND ADMINISTRATION). 

If any reaction takes place that is thought to be related to the administration of Xyntha, the rate of infusion should be decreased or the infusion stopped, as dictated by the response of the patient.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions.  The adverse reaction rates observed in the clinical trials therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Adverse reaction frequencies are calculated on an event per infusion basis.

(*) = These adverse reactions were totaled from adverse events and hemophilia events across all studies regardless of relatedness to study drug.

All other adverse reactions were totaled across all studies from study drug-related adverse events and hemophilia events ONLY

For the adverse reaction frequencies, surgical patients receiving continuous infusion (CI), any day CI is administered is considered one infusion.

(†) = Frequency for the Adverse Reaction Factor VIII inhibition is expressed on a per patient basis 

In a clinical trial (Study 301), 32 out of 101 (32%) previously untreated patients treated with Xyntha manufactured by the previous process developed inhibitors: 16 out of 101 (16%) with a titre >5 Bethesda Units (BU/mL) and 16 out of 101 (16%) with a titre ≤5 BU/mL.  The median number of exposure days prior to inhibitor development in these patients was 12 days (range 3 - 49 days).  Of the 16 high responder patients, 15 received immune tolerance (IT) treatment.  Eleven (11) of the high responders had a titre of <0.6 BU/mL at their latest available test after IT.  In addition, IT treatment was started in 10 of the 16 low titre (≤5 BU/mL) patients, 9 of whom had titres <0.6 BU/mL for their latest value.  Therefore, IT had an overall efficacy of 80% (20/25), 73% for high responders and 90% for low responders.  Five (5) of the 6 remaining low responder patients who did not receive IT also had a titre <0.6 BU/mL for their latest value. 

In a clinical trial of Xyntha manufactured by the previous process, one (1) of 113 (0.9%) previously heavily treated patients who were evaluated for efficacy in bleeding episodes  developed a high titre inhibitor.  Inhibitor development in this patient occurred in the same time frame as the development of monoclonal gammopathy of uncertain significance.  The patient was noted initially at a local laboratory to have a treatment-emergent low titre inhibitor at 98 exposure days, which was confirmed at 2 BU/mL at the central laboratory at 113 exposure days.  After 18 months on continued treatment with Xyntha, the inhibitor level rose to nearly 13 BU/mL and a bleeding episode failed to respond to Xyntha treatment. 

In a pivotal phase 3 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 6775 infusions.  In this study, the incidence of FVIII inhibitors to Xyntha was the primary safety endpoint.  Two patients with low titre, transient inhibitors were observed in these 94 patients (2.1%).  In a Bayesian statistical analysis, results from this study (two out of 94 subjects developed an inhibitor, 89 had 50 or more exposure days to XYNTHA) were used to update PTP results from prior supporting studies of Xyntha.  This Bayesian analysis indicates that the population (true) inhibitor rate for Xyntha was below a predefined acceptable value of 4.4%; the estimate of the 95% upper limit of the true inhibitor rate was 4.07%. 

In a pivotal phase 3 study for surgical prophylaxis in patients with hemophilia A (study 311), one low titre persistent inhibitor and one transient, false-positive inhibitor were reported. 

Laboratory increases in anti-FVIII antibody titres, in the absence of inhibitor development, have been observed in clinical trials.  In a study of PTPs receiving XYNTHA for routine treatment and prevention of bleeding episodes (study 310) and in a study of PTPs for surgical prophylaxis (study 311), 1 of 94 (1%) patients, and 1 of 30 (3%) patients, respectively, developed anti-FVIII antibodies; these patients did not develop an inhibitor.  The clinical significance of these antibodies, in the absence of an inhibitor, is unclear. 

In clinical trials of PTPs receiving Xyntha for routine treatment and prevention of bleeding episodes, 0 of 94 (0%) patients in study 310, and 3 of 110 (3%) patients in study 306/307, developed a lab increase in anti-CHO (Chinese hamster ovary, the cell line which is the source of factor VIII for Xyntha) antibody titre, without any apparent clinical effect.  In a study of Xyntha for surgical prophylaxis (study 311) 1 of 30 (3%) patients developed a lab increase for antibody to CHO.  Twenty of 113 (18%) previously treated patients (PTPs) receiving Xyntha manufactured by the previous process (study 300) had an increase in anti-CHO (Chinese hamster ovary, the cell line which is the source of factor VIII for Xyntha) antibody titre, without any apparent clinical effect. 

Trace amounts of hamster protein may be present in Xyntha. Development of antibodies to hamster protein has been observed in clinical studies, but there were no associated clinical sequelae.

8.2.1 Clinical Trial Adverse Reactions – Pediatrics

In a clinical study (study 313) in pediatric (6 months to <16 years) PTPs (≥20 ED) with hemophilia A (FVIII:C ≤2%), 2 low-titre, clinically silent inhibitor were observed in 49 patients at risk in the study for developing an inhibitor.

8.5 Post-Market Adverse Reactions

There have been spontaneous post-marketing reports of high titre inhibitors developing in previously treated patients.

10.1 Mechanism of Action

Xyntha, recombinant coagulation factor VIII, is a glycoprotein with an approximate molecular mass of 170,000 Da, consisting of 1,438 amino acids, which does not contain the non-functional B-domain.  Xyntha is a recombinant DNA-based substance which has functional characteristics comparable to those of endogenous factor VIII. Activated factor VIII acts as a cofactor for activated factor IX accelerating the conversion of factor X to activated factor X.  Activated factor X converts prothrombin into thrombin.  Thrombin then converts fibrinogen into fibrin which forms an insoluble clot.

The factor VIII/von Willebrand factor complex consists of two molecules (factor VIII and von Willebrand factor) with different physiological functions. When infused into a patient with hemophilia, factor VIII binds to von Willebrand factor in the patient’s circulation.

Hemophilia A is an X chromosome-linked hereditary disorder of blood coagulation due to decreased levels of factor VIII:C and results in bleeding into joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma. Factor VIII activity is greatly reduced in patients with hemophilia A. The administration of Xyntha increases plasma levels of factor VIII activity and can temporarily correct the coagulation defect in these patients.

10.2 Pharmacodynamics

Factor VIII is the specific clotting factor deficient in patients with hemophilia A (classical hemophilia).  The administration of Xyntha, Antihemophilic Factor (Recombinant)[BDDrFVIII] increases plasma levels of factor VIII and can temporarily correct the coagulation defect in these patients. 

10.3 Pharmacokinetics

One Stage Assay

In a pivotal cross-over pharmacokinetic study, Xyntha was shown to be bioequivalent to another recombinant factor VIII product (rFVIII, Advate^®) in 30 previously treated patients (PTPs) (≥ 12 years) using the one-stage clotting assay.  The ratios of geometric least square means of Xyntha-to-Advate^® were 100%, 89.8% and 88.0% for K-value, AUC_t and AUC_∞, respectively.  The corresponding 90% confidence intervals about the ratios of Xyntha to Advate^® geometric means were within the bioequivalence window of 80% to 125%, demonstrating bioequivalence of Xyntha to Advate^®. 

Figure -1: Xyntha vs. Advate

In the same study, the pharmacokinetic parameters for Xyntha were determined at baseline and followed-up in 25 PTPs (≥12 years) after repeated administration of Xyntha for six months.  At baseline, following a single 2-minute intravenous infusion of 50 IU/kg dose of Xyntha, plasma FVIII:C increased sharply with a mean (±SD) C_max of 1.12 (±0.19) IU/mL.  Thereafter, the decline of FVIII:C exhibited biphasic disposition characteristics.  In the initial phase, the activity dropped at a rate consistent with relatively rapid but limited distribution into extravascular space.  The mean (±SD) steady-state volume of distribution was 65.1 (± 35.1) mL/kg.  During the terminal phase, the rate of decline in FVIII:C was slower than the initial phase with a mean (±SD) terminal elimination half-life of 11.8 (± 5.1) hours.  A comparable pharmacokinetic profile was obtained after repeated use for six months.  The ratios of geometric least square means of month 6-to-baseline pharmacokinetic were 107%, 100% and 104% for recovery, AUC_T and AUC_∞, respectively. No time-dependent changes in the pharmacokinetic properties of Xyntha were observed (Table 3).

In a pivotal phase III study (Study 311) for surgical prophylaxis, Xyntha pharmacokinetics were evaluated during the perioperative management of patients with hemophilia A who were undergoing major surgery.  At the baseline visit, all patients received a single dose of Xyntha of approximately 50 IU/kg. Plasma samples were analyzed for FVIII activity using a validated one-stage (OS) clotting method.   Recovery data are available for a total of 30 patients; the mean (± standard deviation [SD]) K-value was 2.11(± 0.43) IU/dL per IU/kg, and the mean (±SD) in vivo recovery value was 101.0% (± 20%). 

Chromogenic Assay

The labeled potency of Xyntha manufactured by the previous process is based on the European Pharmacopoeia chromogenic substrate assay in which the Pfizer In-House Recombinant Factor VIII Potency Reference Standard has been calibrated to the WHO International Standard using the chromogenic substrate assay.

In a crossover pharmacokinetic study of eighteen (18) previously treated patients using the chromogenic assay, the circulating mean half-life for Xyntha manufactured by the previous process was 14.8 ± 5.6 hours (ranged from 7.6 - 28.5 hours), which was not statistically significantly different from plasma-derived Antihemophilic Factor (Human), (pdAHF), which had a mean half-life of 13.7 ± 3.7 hours  (ranged from 8.8 - 25.1 hours).  Mean incremental recovery (K-value) of Xyntha manufactured by the previous process in plasma was 2.4 ± 0.4 IU/dL per IU/kg (ranged from 1.9 - 3.3 IU/dL per IU/kg).  This was comparable to the mean incremental recovery observed in plasma for pdAHF which was 2.3 ± 0.3 IU/dL per IU/kg (ranged from 1.7 - 2.9 IU/dL per IU/kg).

In additional clinical studies using Xyntha manufactured by the previous process, pharmacokinetic parameters measured using the chromogenic assay were determined for previously treated patients (PTPs) and previously untreated patients (PUPs).  In PTPs (n=101; median age 26 ± 12 years), Xyntha manufactured by the previous process had a recovery at Week 0 of 2.4 ± 0.4 IU/dL per IU/kg (range 1.1 to 3.8 IU/dL per IU/kg).  In measurements over 4 years of use (Month 3 [n=90], Month 6 [n=87], Month 12 [n=88], Month 24 [n=70], Month 36 [n=64] and Month 48 [n=52]), the mean incremental recovery was reproducible and ranged from 2.3 to 2.5 IU/dL per IU/kg.  A subset of 37 study subjects had evaluable pharmacokinetic profiles at both baseline and Month 12.  The 90% confidence intervals for the ratios of the mean values of Month 12-to-baseline AUC_T, AUC_∞, and K-value were well within the bioequivalence window of 80% to 125%, demonstrating the stability of these pharmacokinetic parameters over 1 year.  In PUPs (n=59; median age 10 ± 8.3 months), Xyntha manufactured by the previous process had a mean recovery at Week 0 of 1.5 ± 0.6 IU/dL per IU/kg (range 0.2 to 2.8 IU/dL per IU/kg).  The mean incremental recovery for PUPs was stable over time (5 visits during a 2-year period) and ranged from 1.5 to 1.8 IU/dL per IU/kg of Xyntha manufactured by the previous process.  Population pharmacokinetic modeling using data from 44 PUPs led to a mean estimated half-life of Xyntha manufactured by the previous process in PUPs of 8.0 ± 2.2 hours.

Abbreviations: AUC_∞=area under the plasma concentration-time curve from time zero to infinity; AUC_T=area under the plasma concentration-time curve from zero to the last measurable concentration; C_max=peak concentration; SD=standard deviation; V_ss=volume of distribution at steady-state. 

Special Populations and Conditions - Pediatrics

Table 5 shows the pharmacokinetic parameters of nine children, four aged 14 or 15 years of age, who are also included in the summary for the adults above, along with five children aged 3.7 to 5.8 years after Xyntha administration. Compared with adults, the half-life of factor VIII after Xyntha is shorter in children and clearance (based on body weight) is approximately 40% higher in children.