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).

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

2 DOSAGE AND ADMINISTRATION

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:

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:

Administer XYNTHA by intravenous infusion after reconstitution of the lyophilized powder with the supplied prefilled diluent (0.9% Sodium Chloride solution) syringe.

Patients should follow the specific reconstitution and administration procedures provided by their physician. Instructions are provided in the FDA-approved patient labeling [see Patient Counseling Information (17)]. The procedures below are general guidelines for the preparation, reconstitution and administration of XYNTHA.

For additional instructions on the use of a XYNTHA vial and a XYNTHA SOLOFUSE, see Use of a XYNTHA Vial Kit and a XYNTHA SOLOFUSE™ Kit section below [see Dosage and Administration (2.6)].

2.4 Preparation and Reconstitution

Reconstitution

1. 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 antiseptic solution, and allow to dry. After cleaning, do not touch the rubber stopper or allow it to touch any surface.
4. Peel back the cover from the clear plastic vial adapter package. Do not remove the adapter from the package.
5. Place the XYNTHA vial on a flat surface. While holding the adapter package, place the vial adapter over the XYNTHA vial and press down firmly on the package until the adapter spike penetrates the vial stopper.
    
6. 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.
    
7. 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.
    
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 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.
    
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 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, 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 syringe counterclockwise. 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 of XYNTHA, including storage time elapsed in a PVC container following reconstitution. The tubing of the infusion set included with this kit does not contain DEHP.

2.5 Administration

Administer XYNTHA by intravenous infusion after reconstitution only.

Inspect the final XYNTHA solution visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The solution should be clear to slightly opalescent and colorless. If it is not, discard the solution and use a new kit.

Use the tubing and the prefilled diluent syringe provided in this kit or a single sterile disposable plastic syringe. Do not administer XYNTHA in the same tubing or container with other medicinal products.

1. Attach the syringe to the luer end of the infusion set tubing provided.
2. Apply a tourniquet and prepare the injection site by wiping the skin well with an alcohol swab provided in the kit.
    
3. Remove the protective needle cover and perform venipuncture. Insert the needle on the infusion set tubing into the vein, and remove the tourniquet. Verify proper needle placement.
4. Inject the reconstituted XYNTHA product intravenously over several minutes. The rate of administration should be determined by the patient's comfort level.
    
5. After infusing XYNTHA, remove and discard the infusion set. The amount of drug product left in the infusion set will not affect treatment.

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

2.6 Use of a XYNTHA Vial Kit with a XYNTHA SOLOFUSE™ Kit

Allergic type hypersensitivity reactions are possible. Inform patients of the early signs or symptoms of hypersensitivity reactions (including hives [rash with itching], generalized urticaria, chest tightness, wheezing, and hypotension) and anaphylaxis. Advise patients to discontinue use of the product and to contact their physician if these symptoms occur. [See Patient Counseling Information (17)]

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

5.2 Neutralizing Antibodies

Patients using coagulation factor VIII products, including XYNTHA, should be monitored for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests. Inhibitors have been reported following administration of XYNTHA. 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 (5.3)].4,5,6,7,8,9,10,11,12

5.3 Monitoring: Laboratory Tests

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.

XYNTHA was evaluated in two clinical studies (N=124). In the 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 received XYNTHA for routine prophylaxis and on-demand treatment. Ninety-four patients received at least one dose of XYNTHA, resulting in a total of 6,775 infusions [see Clinical Studies (14)]. The second study (n=30) examined the use of XYNTHA for surgical 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 patients received at least one dose of XYNTHA, resulting in 1161 infusions. One patient received XYNTHA for a pre-surgery pharmacokinetic assessment only and did not undergo surgery. [see Clinical Studies (14)].

The most frequently reported adverse reaction in PTP patients was headache (24% of subjects). Other adverse reactions reported in ≥ 5% of patients were: nausea (6%), diarrhea (5%), asthenia (5%), and pyrexia (5%).

The most frequently reported adverse reaction in surgical patients was pyrexia (43%). Other adverse reactions reported in ≥ 5% of patients were: headache (13%), nausea (13%), and vomiting (7%).

6.2 Immunogenicity Information

There is a potential for immunogenicity with therapeutic proteins. The clinical studies for XYNTHA examined 94 patients who had previously been treated with factor VIII (PTPs) and 30 surgical patients. In the safety and efficacy study, two subjects with inhibitors were observed in 89 subjects (2.2%) who completed ≥ 50 exposure days. 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 (with one de novo and two recurrent inhibitors observed in 110 patients) and the experience with predecessor product (with one inhibitor observed in 113 subjects). The Bayesian analysis indicated that the population inhibitor 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 patient did not develop an inhibitor.

In the surgery study, one low titer persistent inhibitor and one transient false-positive inhibitor were reported. In this study, one surgical patient developed anti-CHO cell antibodies with no associated allergic reaction. One patient developed anti-FVIII antibodies; but, this patient did not develop an inhibitor.

Overall, no allergic manifestation to any immune response was observed during the study.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody, including neutralizing antibody, positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparisons of the incidence of antibodies to XYNTHA with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following postmarketing adverse reactions have been reported for XYNTHA:

Hypersensitivity Reactions

Anaphylaxis

Inhibitor Development

Inadequate therapeutic response

7 DRUG INTERACTIONS

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.

8.3 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.

8.4 Pediatric Use

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.

8.5 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.

11 DESCRIPTION

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

12.2 Pharmacodynamics

The activated partial thromboplastin time (aPTT) is prolonged in patients with hemophilia. Determination of aPTT is a conventional in vitro assay for biological activity of factor VIII. Treatment with XYNTHA normalizes the aPTT over the effective dosing period.

12.3 Pharmacokinetics

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 nonclinical 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.

13.2 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.

14 CLINICAL STUDIES

Safety and Efficacy Study

In an open label safety and efficacy study (n=94), subjects received XYNTHA in a routine prophylaxis treatment regimen with on-demand treatment administered as clinically indicated. All 94 subjects were treated with at least one dose and all are included in the intent-to-treat (ITT) population. All subjects had been previously treated (previously treated patients or PTPs) with factor VIII. Eighty-nine (89) subjects accrued ≥ 50 exposure days. 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%.

For routine prophylaxis, XYNTHA was administered at a dose of 30 ± 5 IU/kg 3 times a week with provisions for dose escalation based on pre-specified criteria. Seven dose escalations were prescribed for 6 subjects during the course of the study. Forty-three subjects (43/94 or 45.7%) reported no bleeding while on routine prophylaxis. The median annualized bleeding rate (ABR) for all bleeding episodes was 1.9 (mean 3.9, range 0–42.1).

Fifty-three subjects (53/94) received XYNTHA on-demand treatment for a total of 187 bleeding episodes (see Table 2). Seven of these bleeding episodes occurred in subjects prior to switching to 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 after the last dose. The majority of bleeds reported to occur ≤ 48 hours after the last prophylaxis dose 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-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. Subjects rated the outcomes of infusions on a pre-specified four (4) point hemostatic efficacy scale. One hundred thirty-two of 187 bleeding episodes (132/187 or 70.6%) treated with 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.

Of the 94 subjects enrolled in this study, 30 evaluable subjects participated in a randomized crossover pharmacokinetics study. Twenty-five (25/30) of these subjects with FVIII:C ≤ 1% completed both the first (PK1) and the second (PK2) pharmacokinetic assessments [see Clinical Pharmacology (12.3)].

XYNTHA® 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 58394-012-01

500 International Units Kit: NDC 58394-013-01

1000 International Units Kit: NDC 58394-014-01

2000 International Units Kit: NDC 58394-015-01

Each 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 infusion set, 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 XYNTHA vial.

16.2 Storage and Handling

Product After Reconstitution:

• Store the reconstituted solution at room temperature prior to administration. Remember to administer XYNTHA within 3 hours after reconstitution.

17 PATIENT COUNSELING INFORMATION