June 30, 2016
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Alphanate

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Alphanate




CLINICAL PHARMACOLOGY

Mechanism Of Action

ALPHANATE contains antihemophilic factor (FVIII) and von Willebrand factor (VWF), constituents of normal plasma. FVIII is an essential cofactor in activation of factor X leading to formation of thrombin and fibrin. VWF promotes platelet aggregation and platelet adhesion on damaged vascular endothelium; it also serves as a stabilizing carrier protein for the procoagulant protein FVIII.12, 13

After administration, ALPHANATE temporarily replaces the missing coagulation factor VIII and von Willebrand factor needed for effective hemostasis.

Pharmacokinetics

Pharmacokinetics In Hemophilia A

Following the administration of ALPHANATE during clinical trials, the mean in vivo half-life of FVIII observed in 12 adult subjects with severe hemophilia A was 17.9 ± 9.6 hours. In this same study, the in vivo recovery was 96.7 ± 14.5% at 10 minutes postinfusion. Recovery at 10 minutes post-infusion was also determined as 2.4 ± 0.4 IU FVIII rise/dL plasma per IU FVIII infused/kg body weight.

Pharmacokinetics In Von Willebrand Disease (VWD)

A pharmacokinetic crossover study was conducted in 14 non-bleeding subjects with VWD (1 type 1, 2 type 2A, and 11 type 3) comparing the pharmacokinetics of ALPHANATE (A-SD/HT) and an earlier formulation, ALPHANATE (A-SD). Subjects received, in random order at least seven days apart, a single intravenous dose of each product, 60 IU VWF:RCo/kg (75 IU VWF:RCo/kg in subjects younger than 18 years of age). Pharmacokinetic parameters were similar for the two products and indicated that they were biochemically equivalent. Pharmacokinetic analysis of ALPHANATE (A-SD/HT) in the 14 subjects revealed the following results: the median plasma levels (% normal) of VWF:RCo rose from 10 IU/dL (range: 10 to 27 IU/dL) at baseline to 206 IU/ dL (range: 87 to 440 IU/dL) 15 minutes post-infusion; median plasma levels of FVIII:C rose from 5 IU/dL (range: 2 to 114 IU/dL) to 206 IU/dL (range: 110 to 421 IU/dL). The median bleeding time (BT) prior to infusion was 30 minutes (mean, 28.8 ± 4.41 minutes; range: 13.5 to 30 minutes), which shortened to 10.38 minutes (mean, 10.4 ± 3.2 minutes; range: 6 to 16 minutes) 1 hour post-infusion.

Following infusion of ALPHANATE (A-SD/HT), the median half-lives for VWF:RCo, FVIII:C and VWF:Ag were 6.91 hours (range: 3.8 to 16.22 hours), 20.92 hours (range: 7.19 to 32.2 hours), and 12.8 hours (range: 10.34 to 17.45 hours), respectively. The median incremental in vivo recoveries of VWF:RCo and FVIII:C were 3.12 (IU/dL)/(IU/kg) [range: 1.28 to 5.73 (IU/dL)/(IU/kg)] for VWF:RCo and 1.95 (IU/dL)/(IU/kg) [range: 1.33 to 3.32 (IU/dL)/(IU/kg)] for FVIII:C. The pharmacokinetic data in VWD are summarized in Table 4.

Table 4: Pharmacokinetic data in VWD

Parameter Plasma VWF:RCo (Mean ± SD) Plasma FVIII:C (Mean ± SD) Plasma VWF:Ag (Mean ± SD)
Number of subjects 14 14 14
Mean plasma levels (IU/dL)
  Baseline 11.86 ± 4.97 21.00 ± 33.83 -
  15 minutes post infusion 215.50 ± 101.70 215.29 ± 94.26 -
T½ (Half-life in hours) 7.67 ± 3.32 21.58 ± 7.79 13.06 ± 2.20
Incremental in vivo recovery in (IU/dL)/(IU/kg) 3.29 ± 1.46 2.13 ± 0.58 -

Following infusion of both ALPHANATE (A-SD) and ALPHANATE (A-SD/HT), an increase in the size of VWF multimers was seen and persisted for at least 24 hours. The shortening of the BT was transient, lasting less than 6 hours following treatment and did not correlate with the presence of large and intermediate size VWF multimers.14

Clinical Studies

In a prospective, multi-center clinical study, 37 subjects with VWD (6 Type 1, 19 Type 2, 12 Type 3) underwent 59 surgical procedures for which ALPHANATE (A-SD) or ALPHANATE (A-SD/HT) was administered [21 subjects received ALPHANATE (A-SD), 18 received ALPHANATE (A-SD/HT), and 2 received both products] for bleeding prophylaxis (see Table 5). An initial pre-operative infusion of 60 IU VWF:RCo/kg (75 IU VWF:RCo/kg for subjects less than 18 years of age), was administered one hour before surgery. A blood sample was obtained 15 minutes after the initial infusion for the determination of the plasma FVIII:C level. The level had to equal or exceed 100% of normal for an operation to proceed. No cryoprecipitate or alternative FVIII product was administered during these surgical procedures. Platelets were required in two subjects. The protocol permitted intraoperative infusions of ALPHANATE (A-SD) and ALPHANATE (A-SD/HT) at 60 IU VWF:RCo/kg (75 IU VWF:RCo/kg for subjects less than 18 years of age) to be administered as required according to the judgment of the investigator.

Table 5: Number of and Types of Surgical Procedures

Parameter Treatment with ALPHANATE Total
Type of Surgical Procedure A-SD A-SD/HT
Number of Subjects 21 18 37^
Dental 14 6 20
Dermatologic 1 1 2
Gastrointestinal 4 4 8
Gastrointestinal (diagnostic) 6 0 6
Genitourinary 0 2 2
Gynecologic 2 1 3
Head and neck 1 1 2
Orthopedic 4 3 7
Vascular 3 6 9
Total number of procedures 35 24 59
^ Two subjects received both preparations; the total number of subjects is therefore less than the sum of the columns.

Post-operative infusions at doses of 40 to 60 IU VWF:RCo/kg (50 to 75 IU VWF:RCo/kg for pediatric subjects) were administered at 8 to 12-hour intervals until healing had occurred. For maintenance of secondary hemostasis (after primary hemostasis was achieved), the dose was reduced after the third post-operative day. [see DOSAGE AND ADMINISTRATION].

Overall, in the surgical procedures using either product, the BT at 30 minutes post-infusion was fully corrected in 18 (32.7%) cases, partially corrected in 24 (43.6%) cases, not corrected in 12 (21.8%) cases, and was not done in one case (1.8%). Overall, the mean blood loss was lower than predicted prospectively. Surgical infusion summary data are included in Table 6.

Table 6: Prophylaxis with ALPHANATE (A-SD) and/or ALPHANATE (A-SD/HT) in Surgery

Parameter A-SD A-SD/HT Total
Number of subjects 21 18 37*
Number of surgical procedures 35 24 59
Median number of infusions per surgical procedure (range) 3
(1-13)
4
(1-18)
4
(1-18)
Median dosage IU VWF:RCo/kg
  Infusion #1 (range) 59.8
(19.8-75.1)
59.9
(40.6-75.0)
59.9
(19.8-75.1)
  Infusion ≥ #2 combined (range) 40.0
(4.5-75.1)
40.0
(10.0-63.1)
40.0
(4.5-75.1)
* Two subjects received both products.

Additionally, surgical procedures using ALPHANATE SD/HT only were categorized as major, minor or invasive procedures according to definitions used in the study. The outcome of each surgery was evaluated according to a clinical rating scale (excellent, good, poor or none) and was considered successful if the outcome was excellent or good.

Study results also were evaluated independently by two referees with clinical experience in this field in the same way (surgery categorization and outcome of each surgery according to a clinical rating scale). There was a high level of agreement between the referee evaluations and the analyzed outcome data, with a decrease of only a single success in achieving hemostasis (21/24 [referees evaluation] vs. 22/24 [investigators evaluation]).

A retrospective, multi-center study was performed to assess the efficacy of ALPHANATE (A-SD/ HT) as replacement therapy in preventing excessive bleeding in subjects with congenital VWD undergoing surgical or invasive procedures, for whom DDAVP was ineffective or inadequate. A total of 61 surgeries/procedures in 39 subjects were evaluated.15

Of the 39 subjects, 18 had Type 1 VWD (46.2%); 12 subjects (30.8%) had Type 2 VWD, and 9 subjects (23.1%) had Type 3 VWD. Median age was 40 years; approximately one-half of the subjects were male.

The primary efficacy variable was the overall treatment outcome for each surgical or invasive procedure, as rated by the investigator using a 4-point verbal rating scale (VRS): “excellent,” “good,” “poor,” or “none (no indication of efficacy).” The categorization of the replacement treatment outcome was based upon the investigator's clinical experience and defined in Table 7.

Table 7: Rating Scale and Clinical Efficacy of ALPHANATE Therapy

Rating Clinical Efficacy*
Hemostasis Dosing
Excellent Hemostasis not different from that expected for subjects without known bleeding disorders. No upward dosage adjustment for ALPHANATE replacement therapy.
Good Hemostasis slightly inferior from that expected for subjects without known bleeding disorders but judged as not clinically relevant. Minor upward dosage adjustment for ALPHANATE replacement therapy.
Poor Less hemostasis than expected for subjects without known bleeding disorders attributed to vWD despite ALPHANATE replacement therapy. Relevant upward dosage adjustment for ALPHANATE replacement therapy. No need for alternative therapy.
None Severe bleeding attributed to vWD despite ALPHANATE replacement therapy. Relevant upward dosage adjustment for ALPHANATE replacement therapy and/or need for alternative unexpected therapy.
* The efficacy assessment period included the entire perioperative period.

In addition, an independent referee committee was convened to evaluate the efficacy outcomes. More than 90% of the surgical outcomes received an investigator and referee's overall and daily rating of “effective” (“excellent” or “good”) in achieving hemostasis/preventing bleeding. The majority of ratings were considered “excellent” ( ≥ 81.3% in each VWD type). Nine Type 3 subjects underwent 1 major and 15 minor procedures. Two procedures (1 major and 1 minor) in 1 subject with Type 3 VWD received an overall efficacy rating of “none,” and one minor procedure in a subject with Type 2 VWD received an overall efficacy rating of “poor.”

REFERENCES

12. Hoyer, L.W. The Factor VIII Complex: Structure and Function. Blood 1981; 58:1-13.

13. Meyer, D., Girma, J-P. von Willebrand Factor: Structure and Function. Thrombosis and Haemostasis 1993; 70:99-104.

14. Mannucci, P.M., Chediak, J., Hanna, W. Byrnes, J.J., Kessler, C.M., Ledford, M., Retzios, A.D., Kapelan, B.A., Gallagher, P., Schwartz, R.S., and the Alphanate Study Group. Treatment of von Willebrand's Disease (VWD) with a high purity factor VIII concentrate: Dissociation between correction of the bleeding time (BT), VWF multimer pattern, and treatment efficacy. Blood 1999; 94 (Suppl 1, Part 2 of 2):98b.

15. Rivard, G.E., Aledort, L., et al. Efficacy of factor VIII/von Willebrand factor concentrate Alphanate in preventing excessive bleeding during surgery in subjects with von Willebrand disease. Haemophilia 2008; 14, 271-275.

Last reviewed on RxList: 5/2/2016
This monograph has been modified to include the generic and brand name in many instances.

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