Human plasma-derived von Willebrand factor (contains factor VIII): Drug information

(For additional information see "Human plasma-derived von Willebrand factor (contains factor VIII): Patient drug information" and see "Human plasma-derived von Willebrand factor (contains factor VIII): Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)

Brand Names: US

Alphanate;
Alphanate/VWF Complex/Human [DSC];
Humate-P;
Wilate

Brand Names: Canada

Humate-P;
Wilate

Pharmacologic Category

Antihemophilic Agent;
Blood Product Derivative

Dosing: Adult

Hemophilia A, without inhibitors

Hemophilia A, without inhibitors:

Treatment and control of bleeding episodes or perioperative management:

Intermittent IV bolus dosing: IV: Utilize steps 1 to 3 to determine intermittent bolus dosing strategy. Individualize dosage based on coagulation studies performed prior to treatment and at regular intervals during treatment. In general, administration of factor VIII 1 unit/kg will increase circulating factor VIII levels by ~2 units/dL (Ref).

Step 1: Determine desired factor VIII peak level and anticipated duration of therapy based on the World Federation of Hemophilia (WFH) treatment recommendations; see table. Selection of the lower-dose practice pattern requires closer observation with the potential for requiring escalation to higher doses based on clinical response.

Note: For patients without inhibitors and receiving emicizumab who experience breakthrough bleeding, antihemophilic factor should be dosed to target the desired peak factor VIII levels outlined in the table as emicizumab is not indicated for treatment of bleeding episodes.

**Antihemophilic Factor/von Willebrand Factor Complex (Human) WFH Treatment Recommendations^d**
Type of hemorrhage or surgery	Lower-dose practice pattern		Higher-dose practice pattern
Type of hemorrhage or surgery	Desired peak factor VIII level (units/dL)	Treatment duration (days)	Desired peak factor VIII level (units/dL)	Treatment duration (days)
^aMay be longer if response is inadequate. ^bSometimes longer as secondary prophylaxis during physical therapy. ^cA single dose may be sufficient for some joint bleeds; determine need for additional doses based on clinical response. ^dWFH [Srivastava 2020].
Joint	10 to 20	1 to 2^a,c	40 to 60	1 to 2^a,c
Superficial muscle/no neurovascular compromise (except iliopsoas)	10 to 20	2 to 3^a	40 to 60	2 to 3^a
Iliopsoas or deep muscle with neurovascular injury or substantial blood loss:
Initial	20 to 40	1 to 2	80 to 100	1 to 2
Maintenance	10 to 20	3 to 5^b	30 to 60	3 to 5^b
Intracranial:
Initial	50 to 80	1 to 3	80 to 100	1 to 7
Maintenance	30 to 50	4 to 7	50	8 to 21
Maintenance	20 to 40	8 to 14	-	-
Throat and Neck:
Initial	30 to 50	1 to 3	80 to 100	1 to 7
Maintenance	10 to 20	4 to 7	50	8 to 14
Gastrointestinal:
Initial	30 to 50	1 to 3	80 to 100	7 to 14
Maintenance	10 to 20	4 to 7	50	-
Renal	20 to 40	3 to 5	50	3 to 5
Deep laceration	20 to 40	5 to 7	50	5 to 7
Surgery (major):
Preop	60 to 80	-	80 to 100	-
Postop	30 to 40	1 to 3	60 to 80	1 to 3
	20 to 30	4 to 6	40 to 60	4 to 6
	10 to 20	7 to 14	30 to 50	7 to 14
Surgery (minor):
Preop	40 to 80	-	50 to 80	-
Postop	20 to 50	1 to 5	30 to 80	1 to 5

Step 2: Calculate dose using desired peak factor VIII level from step 1 and the following equation:

Factor VIII units required = [(desired peak factor VIII level − patient's baseline factor VIII level) × body weight (kg)]/2

Note: Factor VIII level units are units/dL.

Example for 50 kg patient with desired peak factor VIII level of 35 units/dL and baseline factor VIII level of 5 units/dL:

Factor VIII units required = [(35 units/dL − 5 units/dL) × 50 kg]/2 = 750 units of factor VIII

Step 3: Determine need for repeat dosing based on manufacturer's recommended frequency of repeat dosing. Note: Frequency of administration must also take into consideration subsequent factor VIII activity measurements and the clinical response.

**Antihemophilic Factor/von Willebrand Factor Complex (Human) Administration Frequency According to Clinical Scenario**
Product	Bleeding event			Surgery
Product	Minor severity	Moderate severity	Major severity	Minor bleeding risk	Major bleeding risk
Alphanate	Every 12 hours	Every 12 hours	Every 12 hours	Every 12 hours	Every 12 hours
Humate-P	Every 12 to 24 hours	Every 8 to 12 hours	Every 8 hours	No recommendation in product labeling	No recommendation in product labeling
Wilate	Every 12 to 24 hours	Every 12 to 24 hours	Every 12 to 24 hours	Every 12 to 24 hours	Every 12 to 24 hours

Continuous infusion dosing(Ref):

Note: Continuous infusion administration is preferred over intermittent bolus administration for patients requiring prolonged treatment courses (eg, postoperative management after surgery with major bleeding risk). To ensure safe and effective use, only products with extended stability information should be used. Extended stability information may not be available for all products; contact product manufacturer to obtain current recommendations. Use of a smart infusion pump with small volume infusion capability is also necessary.

IV: Administer an initial bolus to achieve the desired factor VIII level (see steps 1 and 2 under intermittent bolus dosing), then initiate continuous infusion at 2 to 4 units/kg/hour. Adjust dose based on frequent factor assays (at least daily) and calculation of factor VIII clearance at steady-state using the below equations.

Factor VIII clearance (mL/kg/hour) = (current infusion rate in units/kg/hour) divided by (measured factor VIII level in units/mL)

New infusion rate (units/kg/hour) = (factor VIII clearance in mL/kg/hour) x (desired factor VIII level in units/mL)

Note: With infusion dose increases, re-bolus should be considered to achieve target factor VIII level more quickly. See steps 1 and 2 under intermittent bolus dosing to determine re-bolus dose.

Routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with moderate/severe hemophilia A, without inhibitors: IV: 25 to 40 units/kg of factor VIII concentrate every 2 to 3 days. Preferably, dosing should be tailored to ensure trough factor VIII levels of at least 1% and ideally ≥3% to 5% are achieved, but prophylaxis targets should be tailored to individual level of activity, lifestyle, and pharmacokinetics. Dose escalation should be considered for patients adherent to prescribed prophylaxis but still experiencing breakthrough bleeding events (Ref).

von Willebrand disease

von Willebrand disease (VWD):

Note: Dosage is expressed in von Willebrand factor:Ristocetin cofactor (VWF:RCo) units. Products are not identical and should not be used interchangeably (Ref). Refer to product-specific information regarding in vivo recovery and VWF:RCo to FVIII ratios.

Treatment and control of bleeding episodes or perioperative management:

Intermittent IV bolus dosing:

**Antihemophilic Factor-von Willebrand Factor Complex (Human) Dose According to Clinical Scenario^a**
Indication	Loading dose^b	Maintenance dose^b	Monitoring	Therapeutic goal (efficacy)	Therapeutic goal (safety)	Treatment duration^c
^aNHLBI 2007. ^bIf known, utilize prior patient-specific dosing information to tailor initial dosing. ^cThe duration of therapy can vary for specific types of surgery. Therapy should be individualized based on the patient, type of procedure, and bleeding history.
Minor bleeding or minor surgery	30 to 60 VWF:RCo units/kg	20 to 40 VWF:RCo units/kg every 12 to 48 hours	VWF:RCo and FVIII peak and trough levels at least once	Trough levels: VWF:RCo and FVIII >50 units/dL	Peak levels: Do not exceed VWF:RCo >200 units/dL or FVIII >250 to 300 units/dL	3 to 5 days
Major bleeding or major surgery	40 to 60 VWF:RCo units/kg	20 to 40 VWF:RCo units/kg every 8 to 24 hours	VWF:RCo and FVIII peak and trough levels at least daily	Trough levels: VWF:RCo and FVIII >50 units/dL	Peak levels: Do not exceed VWF:RCo >200 units/dL or FVIII > 250 to 300 units/dL	7 to 14 days

Continuous IV infusion dosing:

Note: Use only products with extended stability information; extended stability information may not be available for all products; contact product manufacturer to obtain current recommendations. Use of a smart infusion pump with small volume infusion capability is also necessary.

IV: Administer an initial bolus to achieve the desired factor VWF:RCo and FVIII levels (see table under "Intermittent IV Bolus Dosing"), then initiate continuous infusion at 1 to 2 units/kg/hour (Ref); initial dose is not well established and may differ based on previously known patient-specific response, history of bleeding, and/or type of procedure; refer to institutional protocols. Adjust dose based on frequent VWF:RCo and FVIII levels (at least daily) and calculation of VWF:RCo clearance at steady state using the equations below (Ref).

VWF:RCo clearance (mL/kg/hour) = (current infusion rate in units/kg/hour) divided by (measured factor VWF:RCo level in units/mL)

New infusion rate (VWF:RCo units/kg/hour) = (VWF:RCo clearance in mL/kg/hour) × (desired factor VWF:RCo level in units/mL)

Note: With infusion dose increases, re-bolus should be considered to achieve target factor VWF:RCo level more quickly. See table under "Intermittent IV Bolus Dosing" for bolus dosing recommendations.

Routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with frequent bleeding episodes:

IV:

Product-specific dosing: Wilate: 20 to 40 VWF:RCo units/kg 2 to 3 times per week depending on bleeding severity and clinical response.

Off-label dosing: 40 to 60 VWF:RCo units/kg once per week, 2 times per week, 3 times per week, or every other day, depending on bleeding severity and clinical response (Ref).

Dosing: Kidney Impairment: Adult

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Obesity: Adult

There are insufficient data to recommend the best dosing weight to use in patients with obesity. Due to a paucity of data, dose adjustments should be determined based on individual patient response to therapy. Refer to adult dosing for indication-specific dosing and institutional protocols.

Dosing: Older Adult

Refer to adult dosing.

Dosing: Pediatric

(For additional information see "Human plasma-derived von Willebrand factor (contains factor VIII): Pediatric drug information")

Note: Antihemophilic factor/von Willebrand factor complex (human) is a combination product that contains both factor VIII and von Willebrand factor. Dosing should be calculated based on the units of factor VIII for hemophilia A and calculated based on units of von Willebrand factor present for von Willebrand disease. Products are not identical and should not be used interchangeably.

Hemophilia A

Hemophilia A (Factor VIII deficiency): Individualize dosage based on clinical response and factor VIII activity evaluated at baseline and at regular intervals during treatment. In general, administration of factor VIII 1 unit/kg will increase circulating factor VIII levels by ~2% of normal. Patients with inhibitory antibodies to factor VIII may require higher doses, more frequent administration, and/or selection of alternative therapy.

General dosing for control and prevention of bleeding episodes or perioperative management: Note: Dosage is expressed in units of factor VIII activity and must be individualized based on formulation, severity of factor VIII deficiency, extent and location of bleed, individualized incremental recovery using factor VIII activity assays, and clinical situation of patient. Guidelines do not specify a preferred agent; see product-specific labeling for approved ages and indications.

Infants, Children, and Adolescents: IV:

Formula for units required to raise blood level:

Number of Factor VIII Units required = body weight (in kg) x 0.5 units/kg per units/dL x desired factor VIII level increase (units/dL or %)

For example, for a desired 100% level in a 25 kg patient who has an actual level of 20%: Number of Factor VIII Units needed = 25 kg x 0.5 units/kg per units/dL x 80% = 1,000 units

Treatment recommendations (Ref): Note: Factor VIII level may either be expressed as % or as units/dL.

Intermittent IV: Infants, Children, and Adolescents: The following recommendations reflect World Federation of Hemophilia (WFH) guidelines for higher dose practice patterns; this dosing is typically used in areas where no significant resource constraints exist; recommendations may vary from those found within prescribing information or practitioner preference. Frequency is based on type of bleed or surgery and varies by product; see specific product labeling for details. Dosing frequency most commonly corresponds to the half-life of factor VIII but should be determined based on an assessment of factor VIII levels (if available) before the next dose.

Site of Hemorrhage/Clinical Situation	Desired Factor VIII Peak Level	Frequency^a	Duration
^aFrequency is based on type of bleed or surgery and varies by product; see specific product labeling for details. Life-threatening hemorrhages may require every-8-hour dosing.
Joint	40% to 60%	Every 12 to 24 hours	1 to 2 days, may be longer if response is inadequate
Superficial muscle/no neurovascular compromise	40% to 60%	Every 12 to 24 hours	2 to 3 days, sometimes longer if response is inadequate
Iliopsoas and deep muscle with neurovascular injury, or substantial blood loss	Initial: 80% to 100%	Every 8 to 24 hours	Initial: 1 to 2 days
	Maintenance: 30% to 60%	Every 8 to 24 hours	Maintenance: 3 to 5 days, sometimes longer as secondary prophylaxis during physiotherapy
CNS/Head	Initial: 80% to 100%	Every 8 to 24 hours	Initial: 1 to 7 days
CNS/Head	Maintenance: 50%	Every 8 to 24 hours	Maintenance: 8 to 21 days
Throat and neck	Initial: 80% to 100%	Every 12 to 24 hours; more frequent doses (every 8 hours) may be needed for life-threatening bleeding	Initial: 1 to 7 days
Throat and neck	Maintenance: 50%		Maintenance: 8 to 14 days
Gastrointestinal	Initial: 80% to 100%	Every 12 to 24 hours; more frequent doses (every 8 hours) may be needed for life-threatening bleeding	Initial: 7 to 14 days
Gastrointestinal	Maintenance: 50%		Maintenance: Not specified
Renal	50%	Every 12 to 24 hours	3 to 5 days
Deep laceration	50%	Every 12 to 24 hours	5 to 7 days
Surgery (major)	Preop: 80% to 100%	Single dose
	Postop: 60% to 80%	Every 8 to 24 hours	Postop: 1 to 3 days
	Postop: 40% to 60%		Postop: 4 to 6 days
	Postop: 30% to 50%		Postop: 7 to 14 days
Surgery (minor)	Preop: 50% to 80%	Single dose
Surgery (minor)	Postop: 30% to 80%	Every 12 to 24 hours	Postop: 1 to 5 days depending on procedure type

Routine prophylaxis: Note: Maintain factor VIII trough levels >3% to 5% or higher as clinically indicated (Ref).

Product-specific dosing:

Wilate: Children ≥12 years and Adolescents: IV: 20 to 40 units/kg/dose every 2 to 3 days.

Guideline dosing (Ref) : Note: Dose should be individualized; dose intensity should take into account disease severity, patient's activity and lifestyle and pharmacokinetic properties of product and should be adjusted if breakthrough bleeding occurs. See guidelines for in-depth discussion of risks and benefits of each approach. Guidelines do not specify a preferred agent; see product specific labeling for approved ages and indications.

Infants, Children, and Adolescents: IV:

High dose: 25 to 40 units/kg/dose every 2 days.

Intermediate dose: 15 to 25 units/kg/dose 3 times weekly.

Low dose: 10 to 15 units/kg/dose 2 to 3 times weekly. Note: Low dose prophylaxis may be used in young patients as initial therapy to allow patients and families to gradually adjust to prophylaxis and improve adherence; close monitoring is required since patients are at a higher risk for bleeding until escalation occurs.

von Willebrand disease, treatment

von Willebrand disease (VWD), treatment: Dosage is expressed in international units of von Willebrand factor: Ristocetin cofactor (VWF:RCo): Dose must be individualized based on type of VWD, extent and location of bleeding, clinical status of patient, and coagulation studies performed prior to and at regular intervals during treatment. For major bleeds where repeated dosing is required, monitor and maintain the FVIII plasma concentration as described for the treatment of hemophilia A. Products are not identical and should not be used interchangeably (Ref).

Hemorrhage, treatment: Product-specific dosing:

Humate P: Infants, Children, and Adolescents: Note: In general, administration of 1 unit/kg of factor VIII would be expected to raise circulating VWF:RCo ~5 units/dL.

General dosing: IV: VWF:RCo 40 to 80 units/kg/dose every 8 to 12 hours; adjust based on extent and location of hemorrhage.

Dosing based on Von Willebrand type and hemorrhage severity:

Type 1, mild VWD (baseline VWF:RCo activity typically >30%): Minor hemorrhage (if desmopressin is known or suspected to be inadequate) or major hemorrhage (eg, severe or refractory epistaxis, GI bleeding, CNS trauma, traumatic hemorrhage): IV:

Loading dose: VWF:RCo 40 to 60 units/kg.

Maintenance dose: VWF:RCo 40 to 50 units/kg/dose every 8 to 12 hours for 3 days to maintain VWF:RCo nadir >50%; follow with VWF:RCo 40 to 50 units/kg/dose once daily for up to 7 days.

Type 1, moderate or severe VWD (baseline VWF:RCo activity typically <30%): IV:

Minor hemorrhage (eg, epistaxis, oral bleeding, menorrhagia): VWF:RCo 40 to 50 units/kg/dose for 1 to 2 doses.

Major hemorrhage (eg, severe or refractory epistaxis, GI bleeding, CNS trauma, hemarthrosis, traumatic hemorrhage):

Loading dose: VWF:RCo 50 to 75 units/kg.

Maintenance dose: VWF:RCo 40 to 60 units/kg/dose every 8 to 12 hours for 3 days to maintain VWF:RCo nadir >50%; follow with VWF:RCo 40 to 60 units/kg/dose once daily for up to 7 days.

Types 2 (all variants) and 3 VWD: IV:

Minor hemorrhage (eg, epistaxis, oral bleeding, menorrhagia): VWF:RCo 40 to 50 units/kg/dose for 1 to 2 doses.

Major hemorrhage (eg, severe or refractory epistaxis, GI bleeding, CNS trauma, hemarthrosis, traumatic hemorrhage):

Loading dose: VWF:RCo 60 to 80 units/kg.

Maintenance dose: VWF:RCo 40 to 60 units/kg/dose every 8 to 12 hours for 3 days to maintain VWF:RCo nadir >50%; follow with 40 to 60 units/kg/dose once daily for up to 7 days.

Wilate: Children ≥5 years and Adolescents: IV: Note: Patients with Type 3 VWD and those with GI bleeding may require higher doses. In general, administration of VWF:RCo 1 unit/kg will increase the plasma VWF activity by ~2 units/dL (or 2% of normal), as demonstrated by the following formulas:

Dosage (units) based on desired factor VWF:RCo increase (units/dL or % normal)

Dosage (units) = Body weight (kg) x 0.5 (units/kg per units/dL) x desired VWF:RCo increase (units/dL or % normal)

Minor hemorrhage: IV:

Loading dose: VWF:RCo 20 to 40 units/kg.

Maintenance dose: VWF:RCo 20 to 30 units/kg/dose every 12 to 24 hours for ≤3 days, keeping the nadir of VWF:RCo and FVIII activity >30%.

Major hemorrhage: IV:

Loading dose: VWF:RCo 40 to 60 units/kg.

Maintenance dose: VWF:RCo 20 to 40 units/kg/dose every 12 to 24 hours for 5 to 7 days, keeping the nadir of VWF:RCo and FVIII activity >50%.

Prophylaxis, surgical/procedural:

Alphanate: Children ≥7 years and Adolescents:

Minor surgery/bleeding: IV:

Preoperative/preprocedure dose: VWF:RCo 75 units/kg as a single dose 1 hour prior to surgery to achieve a target FVIII:C activity level of 40 to 50 units/dL.

Maintenance dose: VWF:RCo 50 to 75 units/kg/dose every 8 to 12 hours as clinically needed to maintain FVIII:C activity level of 40 to 50 units/dL for 1 to 3 days; do not exceed FVIII:C activity level of 150 units/dL.

Major surgery/bleeding (excluding Type 3 VWD): IV:

Preoperative/preprocedure dose: VWF:RCo 75 units/kg as a single dose 1 hour prior to surgery to achieve a target FVIII:C activity level of 100 units/dL.

Maintenance dose: VWF:RCo 50 to 75 units/kg/dose every 8 to 12 hours as clinically needed to maintain FVIII:C activity level of 100 units/dL for at least 3 to 7 days; do not exceed FVIII:C activity level of 150 units/dL.

Humate-P: Infants, Children, and Adolescents:

General dosing recommendations: Whenever possible, the in vivo recovery (IVR) should be calculated and baseline plasma VWF:RCo and FVIII activity should be assessed in all patients prior to surgery. The loading dose may then be calculated using the IVR.

Note: If the calculated IVR is not available, assume IVR to be 2 unit/dL per units/kg of VWF:RCo administered.

Procedure-specific target VWF:RCo and FVIII:C plasma concentrations and minimum durations:

Oral surgery (extraction of ≤2 nonmolar teeth with no bony involvement): IV:

Loading dose: Calculate the loading dose to achieve a target peak plasma VWF:RCo concentration of 50 to 60 units/dL and target peak plasma FVIII:C concentration of 40 to 50 units/dL; administer 1 to 2 hours prior to surgery. Repeat doses may be required to attain target concentrations.

Maintenance: One-half loading dose every 8 hours as needed to maintain trough VWF:RCo concentration ≥30 units/dL up to 3 days postsurgery and trough FVIII:C concentration >30 units/dL after day 3. Patients with shorter half-lives may require dosing every 6 hours; may lengthen the dosing interval to every 12 hours as appropriate based on pharmacokinetic data. Administer at least one maintenance dose. Do not exceed VWF:RCo or FVIII:C trough concentration of 100 units/dL.

Minor surgery: IV:

Maintenance: One-half loading dose every 8 hours for at least 48 hours to maintain trough VWF:RCo concentration ≥30 units/dL up to 3 days postsurgery and trough FVIII:C concentration >30 units/dL after day 3. Patients with shorter half-lives may require dosing every 6 hours; may lengthen the dosing interval to every 12 hours as appropriate based on pharmacokinetic data. Do not exceed VWF:RCo or FVIII:C trough concentration of 100 units/dL.

Major surgery/Oral surgery (extraction of >2 teeth or >1 impacted wisdom tooth): IV:

Loading dose: Calculate the loading dose to achieve a target peak plasma VWF:RCo concentration of 100 units/dL and target peak plasma FVIII:C concentration of 80 to 100 units/dL; administer 1 to 2 hours prior to surgery. Repeat doses may be required to attain target concentrations.

Maintenance: One-half loading dose every 8 hours for at least 72 hours to maintain both trough VWF:RCo and FVIII:C concentrations >50 units/dL for up to 3 days postsurgery and >30 units/dL after day 3. Patients with shorter half-lives may require dosing every 6 hours; may lengthen the dosing interval to every 12 hours as appropriate based on pharmacokinetic data. Do not exceed VWF:RCo or FVIII:C trough concentration of 100 units/dL.

Emergency surgery: IV: VWF:RCo 50 to 60 units/kg prior to surgery to achieve a target VWF:RCo peak plasma concentration of 100 units/dL; monitor trough coagulation factor levels and administer subsequent doses as needed to maintain FVIII:C activity level of 80 to 100 units/dL.

Wilate: Infants, Children, and Adolescents:

General dosing recommendations: The in vivo recovery (IVR) should be calculated and baseline plasma VWF:RCo activity should be assessed in all patients prior to surgery. The loading dose may then be calculated using the IVR. The formula to calculate the loading dose is as follows:

Loading dose (units) = [(Target peak VWF:RCo [units/dL] – Baseline VWF:RCo [units/dL]) x weight (kg)] divided by IVR (units/dL per units/kg)

Note: If the calculated IVR is not available, assume IVR to be 2 units/dL per unit/kg of VWF:RCo administered. If the calculated IVR is >2.5, assume IVR to be 2.5 units/dL per units/kg of VWF:RCo administered.

Procedure-specific dosing and target VWF:RCo concentrations:

Minor surgery (including tooth extraction): IV:

Loading dose: VWF:RCo 30 to 60 units/kg administered within 3 hours prior to surgery to achieve VWF:RCo peak concentration 50% of normal.

Maintenance: VWF:RCo 15 to 30 units/kg/dose (or one-half the loading dose) every 12 to 24 hours to maintain VWF:RCo trough concentrations >30% of normal until wound healing is achieved, for up to 3 days. Do not exceed FVIII:C activity concentrations of 250%.

Major surgery: IV:

Loading dose: VWF:RCo 40 to 60 units/kg administered within 3 hours prior to surgery to achieve VWF:RCo peak concentration 100% of normal.

Maintenance: VWF:RCo 20 to 40 units/kg/dose (or one-half the loading dose) every 12 hours for the first 24 hours after the start of surgery to maintain VWF:RCo trough concentrations >50% of normal; then may adjust to every 12 to 24 hours to maintain VWF:RCo trough concentrations > 50% of normal and continue until wound healing is achieved, up to 6 days or more. Do not exceed FVIII:C activity concentration of 250%.

Dosing: Kidney Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Hepatic Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%:

Gastrointestinal: Nausea (24%; postoperative)

Hematologic & oncologic: Hemorrhage (30%; postoperative)

Miscellaneous: Postoperative pain (17%)

1% to 10%:

Cardiovascular: Chest tightness (>5%), edema (>5%), facial edema (>1%), peripheral edema (1%), vasodilation (1%)

Central nervous system: Chills (>1%), headache (>1%), pain (>1%), paresthesia (>1%), dizziness (≥1%)

Dermatologic: Pruritus (>1%), skin rash (>1%), urticaria (>1%)

Hematologic & oncologic: Thrombocythemia (4%; exacerbation)

Hypersensitivity: Hypersensitivity reaction (2%)

Infection: Parvovirus B19 seroconversion (3%; not accompanied by clinical signs of disease)

Neuromuscular & skeletal: Back pain (>1%), limb pain (1%)

Respiratory: Respiratory distress (>1%)

Miscellaneous: Fever (≥1%)

Frequency not defined:

Cardiovascular: Orthostatic hypotension, phlebitis, pulmonary embolism, subdural hematoma, thrombophlebitis

Central nervous system: Cerebral hemorrhage

Endocrine & metabolic: Heavy menstrual bleeding

Gastrointestinal: Gastrointestinal hemorrhage, vomiting

Hematologic & oncologic: Decreased hematocrit (moderate), increased factor VIII inhibitors

Hepatic: Increased serum alanine aminotransferase

Hypersensitivity: Anaphylaxis, angioedema

Infection: Infection, sepsis

Renal: Pyelonephritis

Postmarketing and/or case reports: Abdominal pain, antibody development (neutralizing), arthralgia, bleeding tendency disorder, chest discomfort, cough, dyspnea, fatigue, hemolysis, hemolytic anemia, hypertension, hypervolemia, infusion-site pain, lethargy, shock, sleep disorder, thromboembolic complications

Contraindications

Hypersensitivity reaction, including anaphylactic or severe systemic reaction to antihemophilic factor or von Willebrand factor or any component of the formulation; hypersensitivity to human plasma derived products (Wilate only).

Warnings/Precautions

Concerns related to adverse effects:

• Antibody formation: Neutralizing antibodies (inhibitors) may develop to factor VIII or von Willebrand factor, particularly in patients with type 3 (severe) von Willebrand disease. Patients who develop antibodies against von Willebrand factor will not have an effective clinical response to therapy and infusions may result in anaphylactic reactions; these patients should be managed by an experienced physician and alternatives to therapy should be considered. Patients with hemophilia should have an appropriate laboratory assessment if expected factor VIII plasma levels are not attained or if bleeding is not controlled following an adequate dose. Any patient who has an inadequate response to therapy or a severe adverse reaction should be evaluated for the presence of inhibitors.

• Hypersensitivity reactions: Hypersensitivity or allergic reactions have been observed, including anaphylaxis and shock (with or without fever). Monitor patients closely during infusion; if allergic symptoms occur, discontinue administration and initiate treatment immediately. Patients experiencing anaphylactic reactions should be evaluated for the presence of inhibitors.

• Thrombotic events: Thromboembolic events have been reported; especially in patients with known risk factors for thrombosis. Risk of thromboembolic events may be increased in female patients, patients with endogenous high concentrations of factor VIII, and in patients who receive continued treatment resulting in an excessive rise in factor VIII activity; monitor concentrations of von Willebrand factor and factor VIII closely. Use with caution and consider antithrombotic measures when treating patients with von Willebrand disease that are at an increased risk for thrombosis.

• Vasomotor reactions: Rapid administration may result in vasomotor reactions; do not exceed administration rate recommendations.

Dosage form specific issues:

• Albumin: Products vary by preparation method; some final formulations may contain human albumin.

• Blood types A, B, and AB: Alphanate and Humate-P contain trace amounts of blood groups A and B isohemagglutinins; use caution when large or frequently repeated doses are given to individuals with blood groups A, B, and AB. Monitor patients for signs of intravascular hemolysis and falling hematocrit; discontinue therapy and consider administration of serologically compatible type O red blood cells if progressive hemolytic anemia occurs.

• Human plasma: Product of human plasma; may potentially contain infectious agents (eg, viruses, the variant Creutzfeldt-Jakob disease [vCJD], theoretically the Creutzfeldt-Jakob disease [CJD]) that could transmit disease. Screening of donors, as well as testing and/or inactivation or removal of certain viruses, reduces the risk. Infections thought to be transmitted by this product should be reported to the manufacturer. Hepatitis A and B vaccination is recommended for all patients receiving plasma derivatives.

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.

Other warnings/precautions:

• Appropriate use: Dosage requirements will vary in patients with factor VIII inhibitors; optimal treatment should be determined by the extent of bleeding, presence of inhibitors, and clinical response. Frequency of use is determined by the severity of the disorder or bleeding pattern.

Warnings: Additional Pediatric Considerations

Formation of factor VIII inhibitors (neutralizing antibodies to AHF human) may occur, particularly in patients with Type 3 (severe) von Willebrand disease; reported overall incidence is 3% to 52%; an increase of inhibitor antibody concentration is seen at 2 to 7 days, with peak concentrations at 1 to 3 weeks after therapy; children <5 years of age may also be at greatest risk. Patients who develop antibodies (usually antibody concentration >10 Bethesda units/mL) against von Willebrand factor will not have an effective clinical response to therapy and infusions may result in anaphylactic reactions; these patients should be managed by an experienced physician and alternatives to therapy should be considered. Any patient who has an inadequate response to therapy or a severe adverse reaction should be evaluated for the presence of inhibitors.

Dosage Forms Considerations

Strengths expressed with approximate values. Consult individual vial labels for exact potency within each vial.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Kit, Intravenous [preservative free]:

Wilate: FVIII 500 units and VWF:RCo 500 units, FVIII 1000 units and VWF:RCo 1000 units [contains polysorbate 80]

Solution Reconstituted, Intravenous [preservative free]:

Alphanate: 250 units (1 ea); 500 units (1 ea); 1000 units (1 ea); 1500 units (1 ea); 2000 units (1 ea) [contains albumin human, polysorbate 80]

Alphanate/VWF Complex/Human: 250 units (1 ea [DSC]); 500 units (1 ea [DSC]); 1000 units (1 ea [DSC]); 1500 units (1 ea [DSC]); 2000 units (1 ea [DSC]) [contains albumin human, polyethylene glycol (macrogol), polysorbate 80]

Humate-P: FVIII 250 units and VWF:RCo 600 units (1 ea); FVIII 500 units and VWF:RCo 1200 units (1 ea); FVIII 1000 units and VWF:RCo 2400 units (1 ea) [contains albumin human]

Generic Equivalent Available: US

Pricing: US

Kit (Wilate Intravenous)

500-500 unit (Price provided is per AHF Unit): $2.00

1000-1000 unit (Price provided is per AHF Unit): $2.00

Solution (reconstituted) (Alphanate Intravenous)

250 unit (Price provided is per AHF Unit): $1.61

500 unit (Price provided is per AHF Unit): $1.61

1000 unit (Price provided is per AHF Unit): $1.61

1500 unit (Price provided is per AHF Unit): $1.61

2000 unit (Price provided is per AHF Unit): $1.61

Solution (reconstituted) (Humate-P Intravenous)

250-600 unit (Price provided is per AHF Unit): $1.86

500-1200 unit (Price provided is per AHF Unit): $1.86

1000-2400 unit (Price provided is per AHF Unit): $1.86

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous:

Humate-P: FVIII 250 units and VWF:RCo 600 units (1 ea); FVIII 1000 units and VWF:RCo 2400 units (1 ea); FVIII 500 units and VWF:RCo 1200 units (1 ea)

Wilate: FVIII 500 units and VWF:RCo 500 units (1 ea); FVIII 1000 units and VWF:RCo 1000 units (1 ea)

Administration: Adult

IV:

Alphanate: Infuse slowly (maximum rate: 10 mL/minute).

Humate-P: Infuse slowly (maximum rate: 4 mL/minute).

Wilate: Infuse slowly at a rate of 2 to 4 mL/minute; reduce the rate of or interrupt administration in patients who experience a marked increase in the pulse rate.

Continuous infusion (off-label rate): Has also been administered as a continuous infusion to avoid peaks and troughs associated with intermittent infusions in patients who require prolonged treatment periods. Use a smart infusion pump with small volume infusion capability. Refer to institutional protocols for product selection and preparation details (Ref).

Administration: Pediatric

Parenteral: IV: Administer through a separate line, do not mix with drugs or other IV fluids. Vasomotor reactions may result from rapid administration.

Alphanate: Infuse slowly; maximum rate: 10 mL/minute

Humate-P: Infuse slowly; maximum rate: 4 mL/minute

Wilate: Infuse slowly at a rate of 2 to 4 mL/minute; reduce the rate or interrupt administration in patients who experience a marked increase in pulse rate.

Use: Labeled Indications

Hemophilia A:

Alphanate: Treatment and prevention of bleeding in adult and pediatric patients with factor VIII deficiency due to hemophilia A (classical hemophilia).

Humate-P: Treatment and prevention of bleeding in adults with hemophilia A (classical hemophilia).

Wilate: Treatment and prevention of bleeding in adults and pediatric patients ≥12 years of age with hemophilia A (classical hemophilia).

von Willebrand disease:

Alphanate: Surgical and/or invasive procedures in adult and pediatric patients with von Willebrand disease when desmopressin is either ineffective or contraindicated

Limitations of use: Not indicated for patients with severe von Willebrand disease (type 3) undergoing major surgery.

Humate-P: Treatment of spontaneous or trauma-induced bleeding, as well as prevention of excessive bleeding during and after surgery in adult and pediatric patients with severe von Willebrand disease, including mild or moderate von Willebrand disease where use of desmopressin is known or suspected to be inadequate.

Wilate: On demand treatment and control of bleeding episodes, perioperative management of bleeding, and prophylaxis to reduce the frequency of bleeding episodes in adult and pediatric patients with von Willebrand disease.

Medication Safety Issues

Sound-alike/look-alike issues:

Factor VIII may be confused with Factor XIII

Metabolism/Transport Effects

None known.

Drug Interactions

There are no known significant interactions.

Pregnancy Considerations

Pregnant carriers of hemophilia A and those with von Willebrand disease may have an increased bleeding risk following invasive procedures, spontaneous miscarriage, termination of pregnancy, and delivery; close surveillance is recommended. Factor VIII concentrations may increase in pregnant patients; changes in von Willebrand factor levels may vary during pregnancy depending on type. Patients should be monitored at the first antenatal visit, once or twice during the third trimester, prior to surgical or invasive procedures, and at delivery. Replacement is recommended if concentrations are <50 units/dL and any of the following occur: need for invasive procedures (including delivery), spontaneous miscarriage, insertion and removal of epidural catheters, or active bleeding. Hemostatic concentrations should be maintained for at least 3 to 5 days following invasive procedures or postpartum. When VWF replacement therapy is needed, a recombinant product or a product made from a safe plasma source with viral testing that contains both factor VIII and von Willebrand factor is recommended. A recombinant product is one of the preferred agents if prophylaxis or treatment is needed for hemophilia A during pregnancy (NHF 2017; RCOG [Pavord 2017]; WFH [Srivastava 2020]).

Breastfeeding Considerations

It is not known if antihemophilic factor/von Willebrand factor (human) is present in breast milk.

According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.

Monitoring Parameters

Heart rate and blood pressure (before and during administration); AHF concentrations prior to and during treatment; in patients with circulating inhibitors, the inhibitor concentration should be monitored; hematocrit; monitor for signs and symptoms of intravascular hemolysis; bleeding; VWF activity (circulating levels of functional VWF are measured as ristocetin cofactor activity [VWF:RCo]). In surgical patients, monitor VWF:RCo at baseline and after surgery, trough VWF:RCo and FVIII:C at least daily; hypersensitivity reactions during infusion.

Mechanism of Action

Factor VIII and von Willebrand factor (VWF), obtained from pooled human plasma, are used to replace endogenous factor VIII and VWF in patients with hemophilia or von Willebrand disease. Factor VIII in conjunction with activated factor IX, activates factor X which converts prothrombin to thrombin and fibrinogen to fibrin. VWF promotes platelet aggregation and adhesion to damaged vascular endothelium and acts as a stabilizing carrier protein for factor VIII. (Circulating levels of functional VWF are measured as ristocetin cofactor activity [VWF:RCo]).

Pharmacokinetics (Adult Data Unless Noted)

Onset: Shortening of bleeding time: Immediate.

Maximum effect: 1 to 2 hours.

Duration: von Willebrand disease: Shortening of bleeding time: <6 hours postinfusion; presence of VWF multimers detected in the plasma: ≥24 hours (Alphanate).

Distribution:

V_d: Factor VIII activity (in patients with hemophilia A): Wilate: Adult: 0.36 to 0.82 dL/kg; pediatric patients ≥12 years: 0.53 to 0.85 dL/kg.

V_dss: VWF:RCo (in patients with von Willebrand disease): Humate: 29 to 290 mL/kg; Wilate: 15 to 160 mL/kg.

Half-life elimination:

Factor VIII coagulant activity (FVIII:C): Range (in patients with hemophilia A): Alphanate: 8 to 28 hours; Humate: 8 to 17 hours; Wilate: Adult: 6.3 to 15.43 hours; pediatric patients ≥12 years: 9.37 to 14.57 hours.

VWF:RCo: Range (in patients with von Willebrand disease): Alphanate: 4 to 16 hours; Humate: 3 to 34 hours; Wilate: 6 to 49 hours.

Brand Names: International

International Brand Names by Country

For country code abbreviations (show table)

(AE) United Arab Emirates: Haemate p;
(AR) Argentina: 8y | Haemate p | Immunate | Wilate;
(AT) Austria: Haemate p | Immunate | Wilate;
(AU) Australia: Biostate;
(BE) Belgium: Haemate p | Wilate;
(BG) Bulgaria: Immunate | Wilate;
(BR) Brazil: Alphanate | Biostate | Haemate p | Immunate | Immunate s/d | Voncento | Wilate;
(CH) Switzerland: Haemate HS | Immunate | Immunate Stim Plus | Voncento | Wilate;
(CL) Chile: Alphanate;
(CO) Colombia: Dried factor viii fraction + factor de von willebrand | Haemate p | Immunate | Voncento | Wilate;
(CZ) Czech Republic: Haemate p | Immunate Stim Plus | Wilate;
(DE) Germany: Haemate | Haemate HS | Immunate | Voncento;
(EE) Estonia: Immunate | Wilate;
(EG) Egypt: Dried factor viii fraction, type 8Y;
(ES) Spain: Wilate;
(FI) Finland: Haemate | Immunate;
(FR) France: Eqwilate | Voncento | Wilstart;
(GB) United Kingdom: 8y | Alphanate | Dried factor viii fraction, type 8Y | Haemate | Haemate p | Voncento | Wilate;
(GR) Greece: Haemate p;
(HK) Hong Kong: Aleviate | Alphanate | Biostate;
(HU) Hungary: Haemate p | Immunate s/d | Immunate Stim Plus | Wilate;
(ID) Indonesia: 8y | Haemate;
(IE) Ireland: Wilate;
(IN) India: Immunate;
(IT) Italy: Alphanate | Haemate p | Immunate Stim Plus | Wilate;
(JP) Japan: Confact f | Haemate p;
(KR) Korea, Republic of: Immunate;
(KW) Kuwait: Haemate | Immunate;
(LB) Lebanon: Wilate;
(LT) Lithuania: Haemate p | Immunate | Wilate;
(LU) Luxembourg: Haemate p | Wilate;
(LV) Latvia: Haemate p | Immunate;
(MX) Mexico: Haemate p | Immunate | Wilate;
(MY) Malaysia: Alphanate | Immunate | Wilate;
(NL) Netherlands: Haemate p | Immunate | Wilate;
(NO) Norway: Haemate | Immunate | Wilate;
(PE) Peru: Concentrado de factor VIII | Haemate p;
(PL) Poland: Haemate p | Immunate | Immunate Stim Plus;
(PR) Puerto Rico: Wilate;
(PT) Portugal: Haemate | Haemate p | Wilate;
(PY) Paraguay: Immunate | Wilate;
(QA) Qatar: Haemate P;
(RO) Romania: Immunate | Wilate;
(RU) Russian Federation: Haemate p | Immunate | Wilate;
(SA) Saudi Arabia: Haemate | Immunate | Wilate;
(SE) Sweden: Haemate | Immunate | Wilate;
(SG) Singapore: Alphanate;
(SI) Slovenia: Haemate p | Wilate;
(SK) Slovakia: Wilate;
(TH) Thailand: Alphanate | Immunate;
(TN) Tunisia: Haemate | Immunate;
(TR) Turkey: Haemate p | Immunate Stim Plus;
(TW) Taiwan: Alphanate | Haemate p;
(UA) Ukraine: Immunate;
(UY) Uruguay: Haemate p | Immunate | Immunate Stim Plus;
(ZA) South Africa: Haemate p | Haemosolvate factor viii

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Wilate (antihemophilic factor/von Willebrand factor complex [human]) [prescribing information]. Paramus, NJ: Octapharma USA Inc; December 2023.

Topic 8782 Version 216.0

خرید پکیج

Human plasma-derived von Willebrand factor (contains factor VIII): Drug information