(antihemophilic factor [Recombinant])
Three completed multicenter, open-label studies support the analysis of safety and efficacy of XYNTHA in on-demand treatment and control of bleeding episodes and perioperative management, and routine prophylaxis in PTPs with hemophilia A. These completed clinical studies for XYNTHA examined 174 PTP subjects, 94 from the first study, and 50 from a second study, for on-demand treatment and routine prophylaxis and 30 from a third study for surgical prophylaxis. Subjects with severe to moderately severe hemophilia A (FVIII:C ≤2%) and no history of FVIII inhibitors were eligible for the trials.
On-demand Treatment and Control of Bleeding Episodes
On-demand treatment in adolescents and adults
Ninety-four (94) subjects, 12 years of age and older 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. Eighty-nine (89) subjects accrued ≥50 EDs. Median age for the 94 treated subjects was 24 years (mean 28 and min-max: 12–60 years).
Of these 94 subjects, 30 evaluable subjects participated in a randomized crossover pharmacokinetics substudy. 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)].16
Fifty-three subjects (53/94) received XYNTHA on-demand treatment for a total of 187 bleeding episodes. 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%) occurred ≤48 hours after the last dose and 39% (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%). 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 31 IU/kg (min-max: 6–74 IU/kg) and the median exposure per subject was 3 days (min-max: 1–26).
The majority of bleeding episodes (173/187 or 93%) resolved with 1 or 2 infusions (Table 5). One hundred thirty-two of 187 bleeding episodes (132/187 or 71%) treated with XYNTHA were rated excellent or good in their response to initial treatment, 45 (24%) were rated moderate. Five (3%) were rated no response, and 5 (3%) were not rated.
| Response to 1st Infusion | Number of Infusions (%) 1 | Number of Infusions (%) 2 | Number of Infusions (%) 3 | Number of Infusions (%) 4 | Number of Infusions (%) >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) | 5¶ |
| Total | 139 (74.3) | 34 (18.2) | 7 (3.7) | 3 (1.6) | 4 (2.1) | 187 |
Of the 94 subjects described above, in the first completed open-label safety and efficacy study of XYNTHA, 18 were adolescent subjects 12 to <17 years of age with severe to moderately severe hemophilia A (FVIII:C ≤2%). Ten (10) of these adolescent subjects, received XYNTHA for the on-demand treatment of 66 bleeding episodes, with the majority of the bleeding episodes (63/66 or 95%) resolving with 1 or 2 infusions. The response to infusion was rated on a pre-specified 4 point hemostatic efficacy scale. Thirty-eight (38) of 66 bleeding episodes (58%) were rated excellent or good in their response to initial treatment, 24 (36%) were rated as moderate, and 4 (6%) were not rated. The median dose per on demand infusion was 47 IU/kg (min-max: 24–74).
On-demand treatment in children
Additional data for 50 subjects are available from a second safety and efficacy study of XYNTHA in children (≤12 years of age) with severe to moderately severe hemophilia A (FVIII:C ≤2%). Of the 50 subjects, 38 subjects received XYNTHA for on-demand and follow-up treatment of 562 bleeding episodes with the majority of the bleeding episodes (518/562 or 92%) resolving with 1 or 2 infusions. Of 559 bleeding episodes treated with XYNTHA with response assessments to the first infusion, 526 (94%) were rated excellent or good in their response to initial treatment and 27 (5%) were rated as moderate. The median dose per on-demand infusion was 28 IU/kg (min-max: 10–92).
Perioperative Management
In a study (n=30) for surgical prophylaxis in subjects with hemophilia A, XYNTHA was administered to 25 efficacy-evaluable PTPs undergoing major surgical procedures (11 total knee replacements, 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 the knee after a total knee replacement, 1 hip arthroplasty revision, 1 stapes replacement, 1 ankle 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 initial postoperative period were excellent or good for all assessments. Intraoperative blood loss was reported as "normal" or "absent" for all subjects. Thirteen of the subjects (13/25 or 52%) had blood loss in the postoperative period. The postoperative blood loss was rated as "normal" for ten of these cases while three cases were rated "abnormal" (1 due to hemorrhage following surgical trauma to the epigastric artery, 1 due to an 800 mL blood loss after hip replacement surgery, and 1 after an elbow synovectomy where the blood loss could not be measured by the investigator).
| Time of Hemostatic Efficacy Assessment | Excellent* | Good† | Number of subjects |
|---|---|---|---|
| |||
| End of surgery | 18 (72%) | 7 (28%) | 25 |
| End of initial postoperative period‡ | 23 (92%) | 2 (8%) | 25 |
Routine Prophylaxis
One hundred and two (102) subjects (94 subjects ≥12 years of age and 8 subjects <12 years of age) received XYNTHA for routine prophylaxis, for comparison of annualized bleeding rate (ABR) to on-demand treatment alone as a part of 2 completed studies. XYNTHA was administered for routine prophylaxis at a dose of 25 ± 5 IU/kg every other day (in subjects <12 years of age) or 30 ± 5 IU/kg administered 3 times weekly (in subjects 12 years of age or older), with provisions for dose escalation based on pre-specified criteria (over a 4-week period, 2 spontaneous bleeds into a major joint and/or target joint, or 3 or more spontaneous bleeding episodes in any location). Among these 102 subjects, 7 dose escalations were prescribed for 6 subjects.
In subjects ≥12 years, 42 subjects (42/94 or 45%) reported no bleeding while on routine prophylaxis. The mean±SD total ABR during routine prophylaxis was 4.0±6.64 with median (min-max) of 1.9 (0.0–44.2). The mean ABR for subjects during routine prophylaxis was 88% lower than the mean ABR for subjects during on-demand treatment (Table 7).
In subjects <12 years, 4 subjects (4/8 or 50%) reported no bleeding while on routine prophylaxis. The mean±SD total ABR during routine prophylaxis was 1.5±2.2 with median (min-max) of 0.6 (0.0–6.2). The mean ABR for subjects during routine prophylaxis was 97% lower than the mean ABR for subjects during on-demand treatment (Table 7).
| Age Category (years) | Number of Subjects | % Reduction from OD | Treated Total Routine Prophylaxis ABR Mean ± SD Median (Min-Max) | Treated Spontaneous Routine Prophylaxis ABR Mean ± SD Median (Min-Max) | Treated Traumatic Routine Prophylaxis ABR Mean ± SD Median (Min-Max) |
|---|---|---|---|---|---|
| OD = on demand; ABR = annualized bleeding rate; SD = standard deviation, Min = minimum, Max = maximum. | |||||
| |||||
| 0 to <12 | 8 | 97% | 1.5 ± 2.20 0.6 (0.0–6.2) | 0.6 ± 1.31 0.0 (0.0–3.7) | 0.9 ± 1.30 0.0 (0.0–3.2) |
| ≥12 | 94* | 88% | 4.0 ± 6.64 1.9 (0.0–44.2) | 2.0 ± 4.25 0.0 (0.0–32.1) | 2.0 ± 4.10 0.0 (0.0–23.3) |
| 12 to <17 | 18† | 84% | 7.3 ± 11.37 3.0 (0.0–44.2) | 3.3 ± 7.73 0.0 (0.0–32.1) | 4.0 ± 5.94 1.9 (0.0–19.6) |
| ≥17 | 76 | 89% | 3.2 ± 4.70 1.9 (0.0–23.3) | 1.6 ± 2.88 0.0 (0.0–13.7) | 1.6 ± 3.42 0.0 (0.0–23.3) |
Patient Information
XYNTHA® SOLOFUSE® /ZIN-tha/
[Antihemophilic Factor (Recombinant)]
Please read this patient information carefully before using XYNTHA and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical problems or your treatment.
What is XYNTHA?
XYNTHA is an injectable medicine that is used to help control and reduce bleeding in people with hemophilia A. Hemophilia A is also called classic hemophilia. Your healthcare provider may give you XYNTHA 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:
Tell your healthcare provider about all of the medicines you take, including all prescription and non-prescription medicines, such as over-the-counter medicines, supplements, or herbal remedies.
How should I infuse XYNTHA?
Step-by-step instructions for infusing with XYNTHA SOLOFUSE are provided at the end of this leaflet.
The steps listed below are general guidelines for using XYNTHA SOLOFUSE. Always follow any specific instructions from your healthcare provider. If you are unsure of the procedures, please call your healthcare provider before using.
Call your healthcare provider right away if bleeding is not controlled after using XYNTHA.
Call your healthcare provider right away if you take more than the dose you should take.
Talk to your healthcare provider before traveling. Plan to bring enough XYNTHA 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 right away if you have any of the following symptoms because these may be signs of a serious allergic reaction:
Common side effects of XYNTHA are
Your body can make antibodies against XYNTHA (called "inhibitors") that may stop XYNTHA from working properly. Your healthcare provider may need to take blood tests from time to time to monitor for inhibitors.
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) for up to 3 months. If you store XYNTHA SOLOFUSE at room temperature, carefully write down the date you put XYNTHA SOLOFUSE at room temperature, so you will know when to throw it away. 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 grey rubber tip cap from the prefilled dual-chamber syringe. You can keep the reconstituted solution at room temperature before infusion for up to 3 hours. If it is not used in 3 hours, throw it away.
Do not use reconstituted XYNTHA if it is not clear to slightly opalescent and colorless.
Dispose of all materials, whether reconstituted or not, in an appropriate medical waste container.
What else should I know about XYNTHA?
Medicines are sometimes prescribed for purposes other than those listed here. Talk to your healthcare provider if you have any concerns. You can ask your healthcare provider for information about XYNTHA SOLOFUSE that was written for healthcare professionals.
Do not share XYNTHA SOLOFUSE with other people, even if they have the same symptoms that you have.
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