Manufactured by:
CSL Behring GmbH
35041 Marburg, Germany
US License No. 1765

Distributed by:
CSL Behring LLC
Kankakee, IL 60901 USA

Rx only

DESCRIPTION

Antihemophilic Factor/von Willebrand Factor Complex (Human), Dried, Pasteurized, Humate-P®, is a stable, purified, sterile, lyophilized concentrate of Antihemophilic Factor (Human) and von Willebrand Factor (VWF) (Human) to be administered by the intravenous route in the treatment of patients with classical hemophilia (hemophilia A) and von Willebrand disease (VWD) (see CLINICAL PHARMACOLOGY).

Humate-P® is purified from the cold insoluble fraction of pooled human fresh-frozen plasma and contains highly purified and concentrated Antihemophilic Factor/von Willebrand Factor Complex (Human). Humate-P® has a high degree of purity with a low amount of non-factor proteins. Fibrinogen is less than or equal to 0.2 mg/mL. Humate-P® has a higher Factor potency than cryoprecipitate preparations. Each vial of Humate-P® contains the labeled amount of Factor VIII activity in international units (IU). Additionally, each vial of Humate-P® also contains the labeled amount of von Willebrand Factor:Ristocetin Cofactor (VWF:RCo) activity expressed in IU (see DOSAGE AND ADMINISTRATION). An IU is defined by the current international standard established by the World Health Organization. One IU Factor VIII or 1 IU VWF:RCo is approximately equal to the level of Factor VIII or VWF:RCo found in 1.0 mL of fresh-pooled human plasma.

Upon reconstitution with the volume of diluent provided (Sterile Diluent for Humate-P®), each mL of Humate-P® contains 40 to 80 IU Factor VIII activity, 72 to 224 IU VWF:RCo activity1, 15 to 33 mg of glycine, 3.5 to 9.3 mg of sodium citrate, 2 to 5.3 mg of sodium chloride, 8 to 16 mg of Albumin (Human), 2 to 14 mg of other proteins and 10 to 20 mg of total proteins.

Humate-P® has been demonstrated in several studies to contain the high molecular weight multimers of VWF. This component is considered to be important for correcting the coagulation defect in patients with VWD.1-5 When administered to patients with VWD (types 1, 2, or 3)6, bleeding time decreased.2,5,7-9 This effect was correlated with the presence of a multimeric composition of VWF similar to that found in normal plasma.2,4,5,7,9

Humate-P® contains anti-A and anti-B blood group isoagglutinins (see PRECAUTIONS, Laboratory Tests).

This product is prepared from pooled human plasma collected from U.S. licensed facilities in the U.S.

All Source Plasma used in the manufacture of this product was tested by FDA-licensed Nucleic Acid Tests (NAT) for HCV and HIV-1 and found to be nonreactive (negative).

An investigational NAT for HBV was also performed on all Source Plasma used in the manufacture of this product and found to be nonreactive (negative). The aim of the HBV test is to detect low levels of viral material, however, the significance of a nonreactive (negative) result has not been established.

This correlates to a VWF:RCo to Factor VIII activity average ratio of 2.4 which is used to calculate the nominal values of VWF:RCo activity and is the average VWF:RCo activity.

1

Virus Reduction Capacity

The manufacturing procedure for Humate-P® includes multiple processing steps that reduce the risk of virus transmission. The virus reduction capacity of the manufacturing process was eva luated in a series of in vitro spiking experiments; the steps were: 1) cryoprecipitation; 2) Al(OH)3 adsorption, glycine precipitation and NaCl precipitation, studied in combination; and 3) pasteurization in aqueous solution at 60°C for 10 hours. Total mean cumulative virus reductions ranged from 6.0 to ≥ 11.3 log10 as shown in Table 1.

CLINICAL PHARMACOLOGY

General

The Antihemophilic Factor/von Willebrand Factor Complex consists of two different noncovalently bound proteins (Factor VIII and von Willebrand factor). Factor VIII is an essential cofactor in activation of Factor X leading ultimately to formation of thrombin and fibrin. The VWF promotes platelet aggregation and platelet adhesion on damaged vascular endothelium; it also serves as a stabilizing carrier protein for the procoagulant protein Factor VIII.10,11 The activity of VWF is measured as VWF:RCo.

Pharmacokinetics in Hemophilia A

After intravenous injection of Antihemophilic Factor/von Willebrand Factor Complex (Human), Dried, Pasteurized, Humate-P®, in humans, there is a rapid increase of plasma Factor VIII activity (FVIII:C) followed by a rapid decrease in activity and a subsequent slower rate of decrease in activity. Studies with Humate-P® in hemophilic subjects have demonstrated a mean half-life of 12.2 hours (range: 8.4 to 17.4 hours).

Pharmacokinetics in von Willebrand disease

Pharmacokinetic studies of Humate-P® have been performed with cohorts of subjects in the nonbleeding state. Wide inter-subject variability was observed in pharmacokinetic values obtained from these studies.

The pharmacokinetics of Humate-P® were eva luated in 41 subjects in a prospective US study in the nonbleeding state prior to a surgical procedure. Subjects received 60 IU VWF:RCo/kg body weight of Humate-P®. Sixteen subjects had type 1 VWD, two had type 2A, four had type 2B, six had type 2M, and 13 had type 3. The median terminal half-life of VWF:RCo was 11 hours (range: 3.5 to 33.6 hours), excluding five subjects with a half-life exceeding the blood sampling time of 24 or 48 hours. The median clearance and volume of distribution at steady state were 3.1 mL/hr/kg (range: 1 to 16.6 mL/hr/kg) and 53 mL/kg (range: 29 to 141 mL/kg), respectively. The median in vivo recovery for VWF:RCo activity was 2.4 IU/dL per IU/kg (range: 1.1 to 4.2). High molecular weight multimers were measured in 13 subjects with type 3 VWD; 11 had absent or barely detectable multimers at baseline. Of those 11 subjects, all had some high molecular weight multimers present 24 hours after infusion of Humate-P®.

Pharmacokinetics were also eva luated in 28 subjects in a European study in the nonbleeding state prior to a surgical procedure. Subjects received 80 IU VWF:RCo/kg body weight of Humate-P®. Ten subjects had type 1 VWD, 10 had type 2A, one had type 2M, and seven had type 3. The median terminal half-life of VWF:RCo was 10 hours (range: 2.8 to 28.3 hours), excluding one subject with a half-life exceeding the blood sampling time of 48 hours. The median clearance and volume of distribution at steady state were 4.8 mL/hr/kg (range: 2.1 to 53 mL/hr/kg) and 59 mL/kg (range: 32 to 290 mL/kg), respectively. The median in vivo recovery for VWF:RCo activity was 1.9 IU/dL per IU/kg (range: 0.6 to 4.5). Infusion of Humate-P® corrected the defect of the multimer pattern in subjects with types 2A and 3 VWD. High molecular weight multimers were detectable until at least 8 hours after infusion.

Based on the small sample size eva luation, it appears that age, sex, and types of VWD have no impact on the pharmacokinetics of VWF:RCo.

CLINICAL STUDIES

Clinical efficacy of Humate-P® in the control of bleeding in subjects with VWD was determined by a retrospective review of clinical safety and efficacy data obtained from 97 Canadian VWD subjects who were provided with product under an Emergency Drug Release Program. Dosage schedule and duration of therapy were determined by the judgment of the medical practitioner.

There were 514 requests for product use for surgery, bleeding or prophylaxis in the 97 Canadian subjects. Of these, product was not used in 151 cases, and follow-up safety and/or efficacy information was available for 303 (83%) of the remaining 363 requests. In many cases, product from one request was used for several treatment courses in one subject. Therefore, there are more reported treatment courses than requests.

Humate-P® was administered to 97 subjects, in 530 treatment courses: 73 for surgery, 344 for treatment of bleeding and 20 for prophylaxis of bleeding. For 93 "other" uses, the majority involved dental procedures, diagnostic procedures, prophylaxis prior to a procedure, or a test dose.

A summary of the number of subjects and bleeding episodes treated, by VWD type, and corresponding efficacy rating is provided in Table 2. The efficacy rating was excellent/good in 100% of bleeding episodes treated in type 1, 2A and 2B subjects. In type 3 subjects, 95% of the bleeding episodes were rated as excellent/good and a poor (or no) response was observed in the remaining 5% of bleeding episodes treated.

For pediatric subjects a summary of the number of subjects and bleeding episodes treated, by VWD type, and corresponding efficacy rating is provided in Table 3. The efficacy rating was excellent/good in 100% of bleeding episodes treated in infants (types 2A, 3), children (types 1, 2A, 2B) and adolescents (types 1, 2B). In type 3 children and adolescents, 90% and 96% of the bleeding episodes were rated as excellent/good and a poor/none response was observed in the remaining 10% and 4% of the bleeding episodes, respectively.

The dosing information (all subjects) for bleeding events is summarized in Table 4.

Two clinical studies, one in the US and one in Europe, investigated the safety and hemostatic efficacy of Humate-P® in subjects with VWD undergoing surgery.

The US clinical study investigated the safety and hemostatic efficacy of Humate-P® in 35 subjects (21 females and 14 males) with VWD undergoing surgery. Subjects ranged from 3 to 75 years old (mean 32.9); seven were 15 years old or younger, and two were 65 years old or older. Twelve had type 1 VWD, two had type 2A, three had type 2B, five had type 2M, and 13 had type 3. Twenty-eight of the surgical procedures were classified as major (e.g., orthoped