"The European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) has started a review of factor VIII-containing products to evaluate the risk of neutralizing antifactor VIII alloantibodies (inhibitors) developing in patients"...
Mechanism Of Action
XYNTHA temporarily replaces the missing clotting factor VIII that is needed for effective hemostasis.
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.
The pharmacokinetic parameters of XYNTHA in 30 previously treated adult patients (PTP) 12 to 60 years old, who received a single infusion of 50 IU/kg XYNTHA are summarized in Table 3.
In addition, 25 of the same subjects later received a single infusion of 50 IU/kg of XYNTHA for a 6-month follow-up pharmacokinetic study. The parameters were comparable between baseline and 6 months, indicating no time-dependent changes in the pharmacokinetics of XYNTHA.
In a separate study, 8 of 30 subjects at least 12 years old with hemophilia A undergoing elective major surgery received a single 50 IU/kg infusion of XYNTHA. The pharmacokinetic parameters in these subjects are also summarized in Table 3.
Table 3: Mean ± SD XYNTHA Pharmacokinetic Parameters
in Previously Treated Patients with Hemophilia A after Single 50 IU/kg Dose
(n = 30)
(n = 25)
|Cmax (IU/mL)||1.08 ± 0.22||1.24 ± 0.42||1.08 ± 0.24|
|AUC∞ (IU-hr/mL)||13.5 ± 5.6||15.0 ± 7.5||16.0 ± 5.2|
|t½ (hr)||11.2 ± 5.0||11.8 ± 6.2*||16.7 ± 5.4|
|CL (mL/hr/kg)||4.51 ± 2.23||4.04 ± 1.87||3.48 ± 1.25|
|Vss (mL/kg)||66.1 ± 33.0||67.4 ± 32.6||69.0 ± 20.1|
|Recovery (IU/dL per IU/kg)||2.15 ± 0.44||2.47 ± 0.84||2.17 ± 0.47|
|Abbreviations: AUC = area under the plasma
concentration-time curve from zero to infinity; C = peak concentration; t =
plasma elimination half-life; CL = clearance; n = number of subjects; SD =
standard deviation; Vss = volume of distribution at steady-state.
* One subject was excluded from the calculation due to lack of a well-defined terminal phase.
Table 4 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 3.7–5.8 years after single 50 IU/kg doses of XYNTHA. Compared to adults, the half-life of XYNTHA is shorter in children and the clearance (based on per kg body weight) is approximately 40% higher in children.
Table 4: Mean ± SD XYNTHA Pharmacokinetic Parameters
in Previously Treated Pediatric Patients with Hemophilia A after Single 50
|Age (min - max, yr))||3.7 - 5.8||14 - 15|
|Cmax (IU/mL)||0.78 ± 0.34||0.97 ± 0.21|
|AUC∞ (IU-hr/mL)||12.2 ± 6.50||8.5 ± 4.0|
|t½ (hr)||8.3 ± 2.7||6.9 ± 2.4|
|CL (mL/hr/kg)||6.29 ± 4.87||6.62 ± 2.16|
|Vss (mL/kg)||66.9 ± 55.6||67.1 ± 13.6|
|Recovery (IU/dL per IU/kg)||1.52 ± 0.69||1.95 ± 0.41|
|Abbreviations: AUC∞ = area under the plasma concentration-time curve from zero to infinity; Cmax = peak concentration; t½ = plasma elimination half-life; CL = clearance; n = number of subjects; SD = standard deviation; Vss = volume of distribution at steady-state.|
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.
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 (EDs). 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%.
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].16
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. 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 (Table 5). 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.
Table 5: Summary of Response to Infusions to Treat New
Bleeding Episode by Number of Infusions Needed for Resolution
|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)||5¶|
|Total||139 (74.3)||34 (18.2)||7 (3.7)||3 (1.6)||4 (2.1)||187|
|Excellent: Definite pain relief and/or improvement in
signs of bleeding starting within 8 hours after an infusion, with no additional
†Good: Definite pain relief and/or improvement in signs of bleeding starting within 8 hours after an infusion, with at least one additional infusion administered for complete resolution of the bleeding episode.
‡Moderate Probable or slight improvement starting after 8 hours following the infusion, with at least one additional infusion administered for complete resolution of the bleeding episode.
§No Response: No improvement at all between infusions or during the 24 hour interval following an infusion, or condition worsens.
ÂIncludes one infusion with commercial FVIII that occurred before routine prophylaxis began.
Perioperative Management Study
In an open-label study (n=30) for surgical prophylaxis in subjects with hemophilia A, XYNTHA was administered to 25 efficacy-evaluable PTPs with severe or moderately severe (FVIII:C ≤ 2%) hemophilia A 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).
Table 6: Summary of Hemostatic Efficacy
|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|
|Excellent : Achieved hemostasis comparable to that
expected after similar surgery in a patient without hemophilia.
†Good: Prolonged time to hemostasis, with somewhat increased bleeding compared with that expected after similar surgery in a patient without hemophilia.
‡End of initial postoperative period is date of discharge or postoperative Day 6, whichever occurs later.
1. Nilsson IM, Berntorp EE and Freiburghaus C. Treatment of patients with factor VIII and IX inhibitors. Thromb Haemost. 1993;70(1):56–59.
3. Juhlin F. Stability and Compatibility of Reconstituted Recombinant Factor VIII SQ, 250 IU/ml, in a System for Continuous Infusion. Pharmacia Document 9610224, 1996.
15. Mann KG and Ziedens KB. Overview of Hemostasis. In: Lee CA, Berntorp EE and Hoots WK, eds. Textbook of Hemophilia. USA, Blackwell Publishing; 2005:1–4.
16. Recht M, Nemes L, Matysiak M et al. Clinical Evaluation of Moroctocog Alfa (AF-CC), a New Generation of B-Domain Deleted Recombinant Factor VIII (BDDrFVIII) for Treatment of Haemophilia A: Demonstration of Safety, Efficacy and Pharmacokinetic Equivalence to Full-length Recombinant Factor VIII. Haemophilia 2009; 1–12.
17. Windyga J, Rusen L, Gruppo R, et al. BDDrFVIII (Moroctocog alfa [AF-CC]) for surgical haemostasis in patients with haemophilia A: results of a pivotal study. Haemophilia. 2010 Sep 1;16(5):731-9.
Last reviewed on RxList: 3/7/2016
This monograph has been modified to include the generic and brand name in many instances.
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