Antihemophilic Factor / von Willebrand Factor Complex (Human)

Pronunciation: AN-tee-HEE-moe-FIL-ik FAK-tor/von WILL-a-brand FAK-tor
Class: Antihemophilic factor combination

Trade Names

Humate-P
- Injection, lyophilized, powder for solution antihemophilic factor (AHF) 250 units and von Willebrand factor:ristocetin cofactor (vWF:RCo) 600 units per vial
- Injection, lyophilized, powder for solution AHF 500 units and vWF:RCo 1,200 units per vial
- Injection, lyophilized, powder for solution AHF 1,000 units and vWF:RCo 2,400 units per vial

Wilate
- Injection, lyophilized, powder for solution vWF:RCo 450 units and AHF 450 units per vial
- Injection, lyophilized, powder for solution vWF:RCo 900 units and AHF 900 units per vial

Pharmacology

The AHF (factor VIII) component is an essential cofactor in activation of factor X leading to formation of thrombin and fibrin. The vWF promotes platelet aggregation and platelet adhesion on damaged vascular endothelium; in addition, this factor serves as a stabilizing carrier protein for the procoagulant protein factor VIII.

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Pharmacokinetics

Absorption

In hemophilia A, after IV injection, there is a rapid increase of plasma factor VIII activity followed by a rapid decrease in activity and a subsequent slower rate of decrease in activity.

In von Willebrand disease (vWD), there is wide intersubject variability in pharmacokinetic values.

Distribution

In vWD, the Vd ranges from 29 to 290 mL/kg.

Elimination

Mean half-life in hemophilic patients is 12.2 h. In vWD, the Cl ranges from 1 to 53 mL/h/kg.

Special Populations

Gender

Does not appear to affect the pharmacokinetics after administration of Humate-P . Women had a higher Cl of vWF:RCo than men when given Wilate . Clinical significance is not known.

Age

Does not appear to affect the pharmacokinetics.

Type of von Willebrand disease

Does not appear to affect the pharmacokinetics.

Indications and Usage

Treatment and prevention of bleeding in adults with hemophilia A ( Humate-P only); treatment of spontaneous and trauma-induced bleeding episodes, as well as patients with mild or moderate vWD in whom the use of desmopressin is known or suspected to be effective ( Humate-P and Wilate ); prevention of excessive bleeding during and after surgery in adults and children with vWD ( Humate-P only).

Contraindications

History of anaphylactic or severe systemic response to AHF or vWF preparations; known hypersensitivity to any component of the product.

Dosage and Administration

Hemophilia A ( Humate-P )
Adults

IV In general, 1 unit of factor VIII activity/kg body weight will increase circulating factor VIII levels by approximately 2 units/dL. Dosage may vary with individual cases and must be individualized according to needs of the patient (eg, presence of inhibitors, severity of hemorrhage, weight). The following are dosage recommendations (VIII:C equals plasma factor VIII activity):

Minor hemorrhage (eg, early joint or muscle bleed, severe epistaxis)

Loading dose of FVIII:C 15 units/kg to achieve FVIII:C plasma level of approximately 30% of normal; 1 infusion may be sufficient. If needed, half of the loading dose may be given once or twice daily for 1 to 2 days.

Moderate hemorrhage (eg, advanced joint or muscle bleed; neck, tongue, or pharyngeal hematoma without airway compromise; tooth extraction; severe abdominal pain)

Loading dose of FVIII:C 25 units/kg to achieve FVIII:C plasma level of approximately 50% of normal, followed by 15 units of FVIII:C/kg every 8 to 12 h for the first 1 to 2 days to maintain FVIII:C plasma level at 30% of normal, and then the same dose once or twice daily for up to 7 days or until adequate wound healing.

Life-threatening hemorrhage (eg, major operations; GI bleeding; neck, tongue, or pharyngeal hematoma with potential for airway compromise; intracranial, intra-abdominal, or intrathoracic bleeding; fractures)

Start with 40 to 50 units of FVIII:C/kg, followed by 20 to 25 units of FVIII:C/kg every 8 h to maintain FVIII:C plasma level at 80% to 100% of normal for 7 days, then continue the same dose once or twice a day for another 7 days in order to maintain the FVIII:C level at 30% to 50% of normal.

von Willebrand Disease
Adults and Children

( Humate-P ) IV Adjust the dosage based on the extent and location of bleeding.

Type 1 (mild, if desmopressin is inappropriate [baseline vWF:RCo activity typically more than 30%]) with major hemorrhage (eg, severe or refractory epistaxis, GI bleeding, CNS trauma, traumatic hemorrhage)

Loading dose 40 to 60 units/kg, then 40 to 50 units/kg every 8 to 12 h for 3 days to keep the trough level of vWF:RCo more than 50%; then 40 to 50 units/kg daily for a total of up to 7 days of treatment.

Type 1 (moderate or severe [baseline vWF:RCo activity typically less than 30%]) with minor hemorrhage (eg, epistaxis, oral bleeding, menorrhagia)

40 to 50 units/kg for 1 or 2 doses.

Type 1 (moderate or severe [baseline vWF:RCo activity typically less than 30%]) with major hemorrhage (eg, severe or refractory epistaxis, GI bleeding, CNS trauma, hemarthrosis or traumatic hemorrhage)

Loading dose 50 to 75 units/kg, then 40 to 60 units/kg every 8 to 12 h for 3 days to keep the trough level of vWF:RCo more than 50%; then 40 to 60 units/kg daily for a total of up to 7 days of treatment. Factor VIII:C levels should be monitored and maintained according to the guidelines for hemophilia A therapy.

Type 2 (all variants) and type 3 with minor hemorrhage (eg, epistaxis, oral bleeding, menorrhagia)

40 to 50 units/kg for 1 or 2 doses.

Type 2 (all variants) and type 3 with major hemorrhage (eg, severe or refractory epistaxis, GI bleeding, CNS trauma, hemarthrosis, traumatic hemorrhage)

Loading dose of 60 to 80 units/kg, then 40 to 60 units/kg every 8 to 12 h for 3 days to keep trough level of vWF:RCo more than 50%; then 40 to 60 units/kg daily for up to 7 days of treatment. Factor VIII:C levels should be monitored and maintained according to guidelines for hemophilia A therapy.

Wilate

IV Adjust the dosage based on the extent and location of bleeding.

Minor hemorrhage

Loading dose of 20 to 40 units/kg, then 20 to 30 units/kg every 12 to 24 h for 3 days to keep the trough level of vWF:RCo and FVIII activity more than 30%.

Major hemorrhage

Loading dose of 40 to 60 units/kg, then 20 to 40 units/kg every 12 to 24 h for 5 to 7 days to keep the trough level of vWF:RCo and FVIII activity more than 50%.

Prevention of Excessive Bleeding During and After Surgery in von Willebrand Disease ( Humate-P )
Adults and Children

IV In case of emergency surgery, administer a loading dose of 50 to 60 units/kg and closely monitor the patient's trough coagulation factor levels. When possible, it is recommended that the incremental in vivo recovery be measured and that baseline plasma vWF:RCo and FVIII:C be assessed in all patients prior to surgery. The in vivo recovery is measured as follows: in vivo recovery equals the plasma vWF:RCo at time plus 30 minutes minus the plasma vWF:RCo at baseline. This value is divided by 60 units/kg.

• Loading dose: Guidelines for calculating the loading dose for adults and children are provided in the product information.
• Maintenance dose: The initial maintenance dose for the prevention of excessive bleeding during and after surgery should be half of the loading dose, irrespective of additional dosing required to meet FVIII:C targets.

The following are recommendations for target trough plasma levels (based on type of surgery and number of days following surgery) and minimum duration of treatment for subsequent maintenance doses.

vWF:RCo target trough plasma levels Major surgery

Up to 3 days following surgery, the target trough plasma levels is more than 50 units/dL; after 3 days, the target trough plasma levels is more than 30 units/dL. The minimum duration of treatment is 72 h.

Minor surgery

Up to 3 days following surgery, the target trough plasma levels is 30 units/dL or more and the minimum duration of treatment is 48 h.

Oral surgery

After 3 days following oral surgery, the target trough plasma levels is 30 units/dL or more and the minimum duration of treatment is 8 to 12 h.

FVIII:C target trough plasma levels Major surgery

Up to 3 days following surgery, the target trough plasma levels is more than 50 units/dL; after 3 days, the target trough plasma levels is more than 30 units/dL. The minimum duration of treatment is 72 h.

Minor surgery

After 3 days following surgery, the target trough plasma levels is more than 30 units/dL and the minimum duration of treatment is 48 h.

Oral surgery

After 3 days following oral surgery, the target trough plasma levels is more than 30 units/dL and the minimum duration of treatment is 8 to 12 h.

General Advice

• IV use only.
• Administer immediately ( Wilate ) or within 3 h after reconstitution ( Humate-P ).
• Before infusion, ensure that the vial and diluent are at room temperature.
• Administer injection solution slowly, max of 4 mL/min IV with a venipuncture set of another suitable injection set.
• Adjust dose individually by clinical judgment of the potential for compromise of a vital structure and by frequent monitoring of factor VIII activity in the patient's plasma.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
• Do not mix with other medicinal products or administer simultaneously with other IV preparations in the same infusion set.
• Discard the administration equipment and any unused solution after use.

Storage/Stability

Humate-P

When stored up to 77°F, the product is stable for the period indicated by the expiration date on the label. Avoid freezing. Do not refrigerate after reconstitution.

Wilate

Store vials for up to 36 mo from the date of manufacture at 36° to 46°F and protected from light. Within this period, the vials may be stored for a period of up to 6 mo at room temperature (maximum 77°F). Once stored at room temperature, the product must not be returned to the refrigerator. The shelf-life expires after the storage at room temperature or the expiration date on the product vial, whichever is earliest. Do not freeze.

Drug Interactions

None well documented.

Adverse Reactions

Cardiovascular

Chest pain, pulmonary embolism, thromboembolic complications, thrombophlebitis, vasodilation.

CNS

Cerebral hemorrhage/subdural hematoma, dizziness, headache, insomnia, paresthesia.

Dermatologic

Increased sweating, pruritus, rash, urticaria.

EENT

Ear bleeding, epistaxis, sore throat.

GI

Abdominal pain, constipation, GI bleeding, nausea, vomiting.

Genitourinary

Groin bleeding, hematuria, menorrhagia, pyelonephritis, urinary retention, UTI.

Hematologic-Lymphatic

Anemia/decreased hemoglobin, pseudothrombocytopenia; hemolysis (postmarketing).

Lab Tests

Increased ALT.

Local

Injection-site bleeding.

Musculoskeletal

Back pain, shoulder bleeding.

Respiratory

Hemoptysis; cough, dyspnea (postmarketing).

Miscellaneous

Serious life- or limb-threatening bleeding (10%); allergic symptoms, including allergic/anaphylactic reaction, chest tightness, edema, pruritus, rash, and urticaria (6%); chills, development of inhibitors to factor VIII, facial edema, fever, hypervolemia, infection, pain, peripheral edema, sepsis; hypervolemia (postmarketing).

Precautions

Monitor Frequently monitor factor VIII activity in the plasma. When very large or frequently repeated doses are administered, monitor patients of blood groups A, B, and AB for signs of intravascular hemolysis and decreasing hematocrit values, and treat appropriately. Monitor factor VIII levels of vWD patients using standard coagulation tests, especially in cases of surgery. Give strong consideration to monitoring vWF:RCo levels in vWD patients for the prevention of excessive bleeding during surgery. It is advisable to monitor trough vWF:RCo and FVIII:C levels at least once daily in order to adjust the dose as needed to avoid excessive coagulation factors.

Pregnancy

Category C .

Lactation

Undetermined.

Children

Hemophilia A

Safety and efficacy not established.

von Willebrand disease

Safety and efficacy not established in neonates. Dose children based upon weight (kg) in accordance with information in the Administration and Dosage section.

Elderly

Studies did not include sufficient numbers of subjects 65 yr of age and older to determine if they respond differently from younger individuals.

Hypersensitivity

Allergic reactions (eg, angioedema, flushing, hives, hypotension, tachycardia, urticaria, wheezing) have been observed and in some cases may progress to severe anaphylaxis.

Infections

Because AHF/vWF is prepared from human plasma, there is a risk of transmitting infectious agents (eg, viruses), including Creutzfeldt-Jakob disease.

Inhibitor formation

Patients with vWD, especially type 3, may develop neutralizing antibodies (inhibitors) to vWD.

Thromboembolic events

Have been reported, especially in the setting of known risk factors for thrombosis. Reports may indicate a higher incidence in women.

Overdosage

Symptoms

No information available.

Patient Information

• Advise patients that this medication comes from human blood and that, rarely, patients receiving this drug have developed certain viral infections (eg, parovirus B19, hepatitis A). Advise patients to contact health care provider if they develop symptoms such as fever, joint aches or pain, loss of appetite, nausea, rash, unusual tiredness, or vomiting.
• Inform patients that undergoing multiple treatments with AHF/vWF may increase the risk of thrombotic events.
• Advise patients that there is a potential of developing inhibitors to vWF, leading to an inadequate response.
• Inform patients of the early signs of hypersensitivity reactions, including anaphylaxis, generalized urticaria, hives, hypotension, tightness of chest, and wheezing.

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