February 13, 2016
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"The U.S. Food and Drug Administration today approved Tretten, Coagulation Factor XIII A-Subunit (Recombinant), the first recombinant product for use in the routine prevention of bleeding in adults and children who have a rare clotting disorder, k"...




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 (antihemophilic factor) increases plasma levels of factor VIII activity and can temporarily correct the coagulation defect in these patients.


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


In a pivotal crossover clinical study, 30 evaluable previously treated patients [PTP] ( ≥ 12 years) received a single infusion of 50 IU/kg of XYNTHA (antihemophilic factor) followed by a full-length recombinant FVIII (FLrFVIII, Advate®) or a single infusion of FLrFVIII followed by XYNTHA (antihemophilic factor) in a randomized crossover design. The one-stage clotting assay method was used to determine the concentrations of these two products in blood. XYNTHA (antihemophilic factor) was shown to be pharmacokinetically equivalent to FLrFVIII as the 90% confidence intervals for XYNTHA (antihemophilic factor) -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 (antihemophilic factor) 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 (antihemophilic factor) 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 (antihemophilic factor) ; the 90% confidence intervals for XYNTHA (antihemophilic factor) 6 month-to-baseline ratios of the mean values of Cmax and AUC∞ were within pre-established limits of 80% to 125%.

Table 2: Pharmacokinetic Parameter Estimates for XYNTHA (antihemophilic factor) at Baseline (Cross-over phase) and Month 6 (Follow-up phase) in Previously Treated Patients with Hemophilia A

Parameter Parameters at Initial Visit
(Crossover phase, n = 30)
Mean ± SD
Parameters at Month 6
(Follow-up phase, n = 25)
Mean ± SD
Cmax (IU/mL) 1.08 ± 0.22 1.24 ± 0.42
AUC (IU·hr/mL) 13.5 ± 5.6 15.0 ± 7.5
t1/2 (hr) 11.2 ± 5.0 11.8 ± 6.2*
CL (mL/hr/kg) 4.51 ± 2.23 4.04 ± 1.87
(IU/dL per IU/kg) In vivo Recovery (%) 2.15 0.44 103 ± 21 2.47 0.84 116 ± 40
Abbreviations: AUC = area under the plasma concentration-time curve from time zero to infinity; Cmax = peak concentration; K-value = incremental recovery; t1/2 = plasma elimination half-life; CL = clearance; n = number of subjects; SD = standard deviation.
* One subject was excluded from the calculation due to lack of a well-defined terminal phase.

Animal Toxicology and/or Pharmacology

Preclinical studies evaluating XYNTHA (antihemophilic factor) in hemophilia A dogs without inhibitors demonstrated safe and effective restoration of hemostasis. XYNTHA (antihemophilic factor) demonstrated a toxicological profile that was similar to the toxicological profile observed with the predecessor product. Toxicity associated with XYNTHA (antihemophilic factor) 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.

Clinical Studies

The efficacy of XYNTHA (antihemophilic factor) was evaluated in Study 1, in which subjects received XYNTHA (antihemophilic factor) on a prophylaxis treatment regimen, with on-demand treatment administered as clinically indicated. Ninety-four (94) subjects were enrolled and treated with at least one dose and all are included in the intent-to-treat (ITT) population. Eighty-nine (89) subjects accrued ≥ 50 exposure days. From the 94 subjects enrolled, thirty (30) evaluable subjects participated in the PK study and received at least 1 PK dose. Twenty-five (25) evaluable subjects with FVIII:C ≤ 1% completed both the first (PK1) and the second (PK2) assessments [see CLINICAL PHARMACOLOGY]. 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%.

In the open-label safety and efficacy period, all 94 subjects received XYNTHA (antihemophilic factor) for routine prophylaxis at the dose of 30 ± 5 IU/kg 3 times a week with provisions for dose escalation based on pre-specified criteria. Seven (7) dose escalations were prescribed for 6 subjects during the course of the study. Forty-three (43) of ninety-four (94), i.e. 45.7%, subjects 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 to 42.1).

Fifty-three (53) of 94 subjects received XYNTHA (antihemophilic factor) for on-demand treatment for a total of 187 bleeding episodes (Table 3). Seven of these bleeding episodes occurred in subjects prior to switching to a prophylaxis treatment regimen. One hundred ten of one hundred eighty (110/180) bleeds (61.1%) occurred ≤ 48 hours after the last dose and 38.9% (70 of 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 of 110 bleeds; 58.2%). Forty-two (42) of 70 bleeds (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).

Table 3: Time Interval Between Last Prophylaxis Dose of XYNTHA (antihemophilic factor) and Start of Bleed

≤ 24 hrs > 24 ≤ 48 hrs > 48 ≤ 72 hrs > 72 hrs Unknowna Total
Spon Traum Spon Traum Spon Traum Spon Traum Spon Traum  
13 20 33 44 24 12 18 16 3 4 187
a Bleeds with unknown start time or bleeds in which previous prophylaxis dose was before the start of the safety and efficacy period of the study. Abbreviations: Spon = spontaneous new bleed; Traum = new bleed due to trauma; hrs = hours.

The majority of bleeding episodes (173/187; 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 (132) of 187 bleeding episodes (70.6%) treated with XYNTHA (antihemophilic factor) were rated excellent or good in their response to initial treatment, 45 (24.1%) were rated moderate. Five [5] (2.7%) were rated no response and 5 (2.7%) were not rated.

Table 4: Summary of Response to Infusions to Treat New Bleeding Episode by Number of Infusions Needed for Resolution

Response to 1st Infusion Number of Infusions (%) Total Number
of Bleeds
1 2 3 4 > 4
Excellent 42 (95.5) 2
Good 69 (78.4) 16 (18.2) 3
Moderate 24 (53.3) 16 (35.6) 2
No Response 0 (0.0) 0
2 (40.0) 2 (40.0) 1 (20.0) 5
Not Assessed 4 (80.0) 0 (0.0) 0
1 (20.0) 0
Total 139 (74.3) 34 (18.2) 7
a Includes 1 infusion with commercial FVIII that occurred before routine prophylaxis began.

In an ongoing, open-label study of XYNTHA (antihemophilic factor) in surgical prophylaxis, 21 of at least 25 evaluable PTPs with severe or moderately severe (FVIII:C ≤ 2%) hemophilia A undergoing major surgical procedures received XYNTHA (antihemophilic factor) . One (1) subject received XYNTHA (antihemophilic factor) for a pre-surgery pharmacokinetic assessment only and had not undergone surgery.

The results of an interim analysis on 21 of the 25 planned evaluable subjects who had undergone major surgical procedures (13 total knee replacements, 1 hip replacement, 3 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) are presented in Table 5. For the 21 surgical subjects, 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. All reported blood loss during the intra-operative and postoperative periods was rated normal with the exception of one subject who experienced iatrogenic bleeding.

Table 5: Summary of Hemostatic Efficacy

Time of Hemostatic Efficacy Assessment Excellent Good Number of subjects
End of surgery 14 (67%) 7 (33%) 21
End of initial postoperative perioda 16 (84%) 3 (16%) 19
a Conclusion of initial postoperative period is date of discharge or postoperative Day 6, whichever occurs later.


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.

Last reviewed on RxList: 3/18/2008
This monograph has been modified to include the generic and brand name in many instances.

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