Antihemophilic Factor/von Willebrand Factor Complex (Human)

Dosage Forms

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

Kit, Intravenous:

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

Solution Reconstituted, Intravenous:

Alphanate/VWF Complex/Human: 2000 units (1 ea) [contains albumin human, polyethylene glycol, polysorbate 80]

Solution Reconstituted, Intravenous [preservative free]:

Alphanate/VWF Complex/Human: 250 units (1 ea) [contains albumin human, polyethylene glycol, polysorbate 80]

Alphanate/VWF Complex/Human: 250 units (1 ea) [contains albumin human, polysorbate 80]

Alphanate/VWF Complex/Human: 250 units (1 ea) [contains polyethylene glycol, polysorbate 80]

Alphanate/VWF Complex/Human: 500 units (1 ea) [contains albumin human, polyethylene glycol, polysorbate 80]

Alphanate/VWF Complex/Human: 500 units (1 ea) [contains albumin human, polysorbate 80]

Alphanate/VWF Complex/Human: 500 units (1 ea) [contains polyethylene glycol, polysorbate 80]

Alphanate/VWF Complex/Human: 1000 units (1 ea) [contains albumin human, polyethylene glycol, polysorbate 80]

Alphanate/VWF Complex/Human: 1000 units (1 ea) [contains albumin human, polysorbate 80]

Alphanate/VWF Complex/Human: 1000 units (1 ea) [contains polyethylene glycol, polysorbate 80]

Alphanate/VWF Complex/Human: 1500 units (1 ea) [contains albumin human, polyethylene glycol, polysorbate 80]

Alphanate/VWF Complex/Human: 1500 units (1 ea) [contains albumin human, polysorbate 80]

Alphanate/VWF Complex/Human: 1500 units (1 ea) [contains polyethylene glycol, polysorbate 80]

Alphanate/VWF Complex/Human: 2000 units (1 ea) [contains albumin human, polyethylene glycol, polysorbate 80]

Alphanate/VWF Complex/Human: 2000 units (1 ea) [contains albumin human, polysorbate 80]

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) [contains albumin human]

Wilate: FVIII 500 units and VWF:RCo 500 units (1 ea [DSC]); FVIII 1000 units and VWF:RCo 1000 units (1 ea [DSC]) [contains polysorbate 80]

Pharmacology

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/Pharmacodynamics

Distribution

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

Onset of Action

Shortening of bleeding time: Immediate; maximum effect: 1 to 2 hours.

Duration of Action

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

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 to 15 hours; pediatric: 9 to 15 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.

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.

Limitations of use: Safety and efficacy of prophylactic dosing to prevent spontaneous bleeding have not been conducted in patients with von Willebrand disease.

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

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).

Dosage and Administration

Dosing: Adult

Hemophilia A (Factor VIII deficiency): IV: Note: Dosage and duration of treatment must be individualized based on the severity of factor VIII deficiency, extent and location of bleeding, presence of inhibitors and clinical status of patient. Titrate the dose as needed based on clinical response; whenever possible, perform serial FVIII activity assays to assess clinical response.

Hemorrhage, treatment: Note: Factor VIII concentrations may either be expressed as units/dL or as %. Dosing frequency most commonly corresponds to the half-life of factor VIII but should be determined based on an assessment of factor VIII levels before the next dose. Guidelines do not specify a preferred agent; see product specific information for approved ages and uses.

General dosing recommendations: The following recommendations reflect general dosing requirements; may vary from those found within prescribing information or practitioner preference (WFH [Srivastav 2013]).

In general, administration of 1 unit/kg of factor VIII will increase plasma factor VIII concentrations by ~2 units/dL (or 2%); calculated dosage should be adjusted to the actual vial size.

Formula to calculate dosage required is based on desired increase in factor VIII (% of normal); Note: This formula assumes that the patient's baseline AHF level is <1%:

Dose (units) = Body weight (kg) x 0.5 x desired factor VIII increase (units/dL or % of normal)

World Federation of Hemophilia (WFH) treatment recommendations when no significant resource constraint exists (WFH [Srivastava 2013]):

Table has been converted to the following text.

Desired Factor VIII Concentration to Maintain and Duration Based on Site of Hemorrhage/Clinical Situation (when no significant resource constraints exist) (WFH [Srivastava 2013]):

Joint: 40 to 60 units/dL for 1 to 2 days, may be longer if response is inadequate

Superficial muscle (no neurovascular compromise): 40 to 60 units/dL for 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 units/dL for 1 to 2 days; Maintenance: 30 to 60 units/dL for 3 to 5 days, sometimes longer as secondary prophylaxis during physiotherapy

CNS/head: Initial: 80 to 100 units/dL for 1 to 7 days; Maintenance: 50 units/dL for 8 to 21 days

Throat and neck: Initial: 80 to 100 units/dL for 1 to 7 days; Maintenance: 50 units/dL for 8 to 14 days

Gastrointestinal: Initial: 80 to 100 units/dL for 7 to 14 days; Maintenance: 50 units/dL (duration not specified)

Renal: 50 units/dL for 3 to 5 days

Deep laceration: 50 units/dL for 5 to 7 days

Surgery (major):

Preoperative: 80 to 100 units/dL

Postoperative: 60 to 80 units/dL for postop days 1 to 3, then 40 to 60 units/dL for postop days 4 to 6, then 30 to 50 units/dL for postop days 7 to 14

Surgery (minor):

Preoperative: 50 to 80 units/dL

Postoperative: 30 to 80 units/dL for 1 to 5 days depending on procedure type

Product-specific dosing:

Alphanate: Note: In general, administration of Alphanate FVIII:C 1 unit/kg will increase the plasma FVIII:C activity by ~2 units/dL (or 2% of normal), as demonstrated by the following formulas:

Dosage (units) based on desired increase in factor VIII (units/dL or % normal)

Dosage (units) = Body Weight (kg) x 0.5 (units/kg per units/dL) x desired factor VIII increase (units/dL or % normal)

Minor hemorrhage (large bruises; significant cuts or scrapes; uncomplicated joint hemorrhage): FVIII:C 15 units/kg every 12 hours to achieve FVIII:C plasma concentration 30% of normal. Continue until hemorrhage stops and healing has been achieved (1 to 2 days).

Moderate hemorrhage (nose, mouth, and gum bleeds; dental extractions; hematuria): FVIII:C 25 units/kg every 12 hours to achieve FVIII:C plasma concentration 50% of normal. Continue treatment until healing has been achieved (2 to 7 days, on average).

Major hemorrhage (joint hemorrhage; muscle hemorrhage; major trauma; hematuria; intracranial and intraperitoneal bleeding): FVIII:C 40 to 50 units/kg every 12 hours to achieve FVIII:C plasma concentrations 80% to 100% of normal for at least 3 to 5 days. Continue with FVIII:C 25 units/kg every 12 hours to maintain FVIII:C plasma concentrations at 80% to 10% of normal until healing has been achieved for up to 10 days. Intracranial hemorrhage may require prophylactic treatment for up to 6 months.

Surgery:

Preoperative: FVIII:C 40 to 50 units/kg to achieve FVIII:C concentrations 80% to 100% of normal

Postoperative: FVIII:C 30 to 50 units/kg/dose every 12 hours to maintain FVIII:C concentrations at 60% to 100% of normal for the next 7 to 10 days or until healing has been achieved

Humate-P:

Minor hemorrhage (early joint or muscle bleed; severe epistaxis):

Loading dose: FVIII:C 15 units/kg to achieve FVIII:C plasma concentration ~30% of normal.

Maintenance dose: One loading dose infusion may be sufficient. If second infusion is needed, administer half the loading dose once or twice daily for 1 to 2 days.

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

Loading dose: FVIII:C 25 units/kg to achieve FVIII:C plasma level ~50% of normal

Maintenance dose: FVIII:C 15 units/kg every 8 to 12 hours for 1 to 2 days in order to maintain FVIII:C plasma concentrations at 30% of normal. Repeat dose once or twice daily for up to 7 days or until adequate wound healing is achieved.

Life-threatening hemorrhage (major surgery; GI bleeding; neck, tongue, or pharyngeal hematoma [with potential for airway compromise]; intracranial, intraabdominal, or intrathoracic bleeding; fractures):

Loading dose: FVIII:C 40 to 50 units/kg

Maintenance dose: FVIII:C 20 to 25 units/kg every 8 hours to maintain FVIII:C plasma concentrations at 80% to 100% of normal for 7 days. Repeat dose once or twice daily for another 7 days in order to maintain FVIII:C concentrations at 30% to 50% of normal.

Wilate: Note: In general, administration of Wilate 1 unit/kg will increase the plasma FVIII level by ~2 units/dL (2% of normal) as demonstrated by the following formula:

Dosage (units) based on desired increase in factor VIII (units/dL or % normal).

Dosage (units) = Body Weight (kg) × 0.5 (units/kg per units/dL) × desired factor VIII increase (units/dL or % normal).

Titrate dose and frequency based on the patient's clinical response and condition, individual needs, severity of deficiency, severity of hemorrhage, desired FVIII level, and presence of inhibitor.

Prophylaxis, routine: 20 to 40 units/kg every 2 to 3 days. Exact dosing should be defined by patient's clinical status and response.

Moderate hemorrhage: FVIII:C 30 to 40 units/kg every 12 to 24 hours to achieve plasma FVIII:C level 60% to 80% of normal. Continue treatment at least 3 to 4 days and until hemorrhage stops.

Major hemorrhage: FVIII:C 35 to 50 units/kg every 12 to 24 hours to achieve plasma FVIII:C level 70% to 100% of normal. Continue treatment at least 3 to 4 days and until hemorrhage stops.

Life-threatening hemorrhage: FVIII:C 35 to 50 units/kg every 8 to 24 hours to achieve plasma FVIII:C level 70% to 100% of normal. Continue treatment until threat has resolved.

von Willebrand disease (VWD):

General guidelines: Dosage is expressed in units of von Willebrand factor:Ristocetin cofactor (VWF:RCo): Dose must be individualized based on type of von Willebrand disease, 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 (NHLBI 2007).

Treatment of bleeding episodes: IV:

Product specific dosing:

Humate-P: Note: In general, administration of factor VIII 1 unit/kg would be expected to raise circulating VWF:RCo ~5 units/dL. Dosing is based on Von Willebrand type and hemorrhage severity.

Type 1, mild von Willebrand disease (baseline VWF:RCo activity typically >30%):

Minor hemorrhage (eg, epistaxis, oral bleeding, menorrhagia): Typically treatable with desmopressin.

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):

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

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

Type 1, moderate or severe von Willebrand disease (baseline VWF:RCo activity typically <30%):

Minor hemorrhage (eg, epistaxis, oral bleeding, menorrhagia): VWF:RCo 40 to 50 units/kg 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 every 8 to 12 hours for 3 days to keep trough level of VWF:RCo >50%, follow with VWF:RCo 40 to 60 units/kg once daily for up to 7 days

Types 2 (all variants) and Type 3 von Willebrand disease:

Minor hemorrhage (eg, epistaxis, oral bleeding, menorrhagia): VWF:RCo 40 to 50 units/kg 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 every 8 to 12 hours for 3 days to keep trough level of VWF:RCo >50%; follow with 40 to 60 units/kg once daily for up to 7 days

Wilate: 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:

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

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

Major hemorrhage:

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

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

Prophylaxis, surgical/procedural: IV:

Product-specific dosing:

Alphanate:

Minor surgery/bleeding:

Preoperative/preprocedure dose: VWF:RCo: 60 units/kg 1 hour prior to surgery to achieve a target FVIII:C activity level of 40 to 50 units/dL.

Maintenance dose: VWF:RCo: 40 to 60 units/kg 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):

Preoperative/preprocedure dose: VWF:RCo: 60 units/kg 1 hour prior to surgery to achieve a target FVIII:C activity level of 100 units/dL.

Maintenance dose: VWF:RCo: 40 to 60 units/kg every 8 to 12 hours as clinically needed to maintain FVIII:C activity level of 100 units/dL for 3 to 7 days. Do not exceed FVIII:C activity level of 150 units/dL.

Humate-P:

General guidelines: 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. The formulas to calculate the IVR and loading dose are as follows:

in vivo Recovery (IVR) (units/dL per units/kg of VWF:RCo administered) based on VWF:RCo increase (units/dL) and dose (units/kg):

IVR (units/dL per units/kg of VWF:RCo administered) = [Plasma VWF:RCo 30 minutes after infusion (units/dL)] – [Plasma VWF:RCo at baseline (units/dL)] / Dose (units/kg)

Loading dose (units) based on baseline and target peak plasma VWF:RCo concentration (units/dL) and IVR (units/dL per units/kg of VWF:RCo administered):

Loading dose (units) = ([Target Peak Plasma VWF:RCo Concentration (units/dL)] – [Baseline Plasma VWF:RCo Concentration (units/dL)]) x Body Weight (kg) \ IVR (units/dL per units/kg of VWF:RCo administered)

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

Oral surgery (extraction of ≤2 non-molar teeth with no bony involvement):

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 dose: One-half loading dose every 8 hours for at least 8 to 12 hours as needed to keep trough VWF:RCo concentration ≥30 units/dL up to 3 days postsurgery and trough FVIII:C concentration >30 units/dL after day 3. Administer at least one maintenance dose following surgery. Subsequent therapy with an antifibrinolytic agent is usually administered until adequate healing is achieved. Do not exceed VWF:RCo or FVIII:C trough concentration of 100 units/dL.

Minor surgery:

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 dose: One-half loading dose every 8 hours for at least 48 hours to keep 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 teeth):

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 dose: One-half loading dose every 8 hours for at least 72 hours to keep trough VWF:RCo and FVIII:C concentrations >50 units/dL up to 3 days post-surgery 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:

Loading dose: VWF:RCo 50 to 60 units/kg administered 1 to 2 hours prior to surgery to achieve a target VWF:RCo peak plasma concentration of 100 units/dL. Monitor trough coagulation factor concentrations and administer subsequent doses as needed to maintain FVIII:C activity level of 80 to 100 units/dL.

Wilate: IV:

General guidelines: 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 formulas to calculate the IVR and loading dose are as follows:

in vivo Recovery (IVR) (units/dL per units/kg of VWF:RCo administered) based on VWF:RCo increase (units/dL) and a dose of 60 units/kg:

IVR (units/dL per units/kg of VWF:RCo administered) = [Plasma VWF:RCo 30 minutes after infusion (units/dL)] – [Plasma VWF:RCo at baseline (units/dL)] / 60 (units/kg)

Loading dose (units) based on baseline and target peak plasma VWF:RCo concentration (units/dL) and IVR (units/dL per units/kg of VWF:RCo administered):

Loading dose (units) = ([Target Peak Plasma VWF:RCo Concentration (units/dL)] – [Baseline Plasma VWF:RCo Concentration (units/dL)]) x Body Weight (kg) \ IVR (units/dL per units/kg of VWF:RCo administered)

Note: If the calculated IVR is not available, assume IVR to be 2 units/dL per units/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.

Minor surgery (including tooth extraction):

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

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

Major surgery:

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

Maintenance dose: VWF:RCo 20 to 40 units/kg (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 levels of 250%.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Hemophilia A (Factor VIII deficiency): Note: Dosage and duration of treatment must be individualized based on the severity of factor VIII deficiency, extent and location of bleeding, presence of inhibitors and clinical status of patient. Titrate the dose as needed based on clinical response; whenever possible, perform serial FVIII activity assays to assess clinical response.

Hemorrhage, treatment: Infants, Children, and Adolescents: IV: Note: Factor VIII concentrations may either be expressed as units/dL or as %. Dosing frequency most commonly corresponds to the half-life of factor VIII but should be determined based on an assessment of factor VIII levels before the next dose. Guidelines do not specify a preferred agent; see product specific information for approved ages and uses.

General dosing recommendations: The following recommendations reflect general dosing requirements; may vary from those found within prescribing information or practitioner preference (WFH [Srivastav 2013]).

In general, administration of 1 unit/kg of factor VIII will increase circulating factor VIII concentrations by ~2 units/dL (or 2%); calculated dosage should be adjusted to the actual vial size.

Formula to calculate dosage required is based on desired increase in factor VIII (% of normal); Note: This formula assumes that the patient's baseline AHF level is <1%:

Dose (units) = Body weight (kg) x 0.5 x desired factor VIII increase (units/dL or % of normal)

Table has been converted to the following text.

Desired Factor VIII Concentration to Maintain and Duration Based on Site of Hemorrhage/Clinical Situation (when no significant resource constraints exist) (WFH [Srivastava 2013]):

Joint: 40 to 60 units/dL for 1 to 2 days, may be longer if response is inadequate

Superficial muscle (no neurovascular compromise): 40 to 60 units/dL for 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 units/dL for 1 to 2 days; Maintenance: 30 to 60 units/dL for 3 to 5 days, sometimes longer as secondary prophylaxis during physiotherapy

CNS/head: Initial: 80 to 100 units/dL for 1 to 7 days; Maintenance: 50 units/dL for 8 to 21 days

Throat and neck: Initial: 80 to 100 units/dL for 1 to 7 days; Maintenance: 50 units/dL for 8 to 14 days

Gastrointestinal: Initial: 80 to 100 units/dL for 7 to 14 days; Maintenance: 50 units/dL (duration not specified)

Renal: 50 units/dL for 3 to 5 days

Deep laceration: 50 units/dL for 5 to 7 days

Surgery (major):

Preoperative: 80 to 100 units/dL

Postoperative: 60 to 80 units/dL for postop days 1 to 3, then 40 to 60 units/dL for postop days 4 to 6, then 30 to 50 units/dL for postop days 7 to 14

Surgery (minor):

Preoperative: 50 to 80 units/dL

Postoperative: 30 to 80 units/dL for 1 to 5 days depending on procedure type

Product-specific dosing: Alphanate: Children ≥7 years and Adolescents: IV: Note: In general, administration of Alphanate FVIII:C 1 unit/kg will increase the plasma FVIII:C activity by ~2 units/dL (or 2% of normal), as demonstrated by the following formulas:

Dosage (units) based on desired increase in factor VIII (units/dL or % normal):

Dosage (units) = Body Weight (kg) x 0.5 (units/kg per units/dL) x desired factor VIII increase (units/dL or % normal)

Minor hemorrhage (large bruises; significant cuts or scrapes; uncomplicated joint hemorrhage): FVIII:C 15 units/kg/dose twice daily to achieve FVIII:C concentration 30% of normal. Continue until hemorrhage stops and healing has been achieved (1 to 2 days).

Moderate hemorrhage (nose, mouth, and gum bleeds; dental extractions; hematuria): FVIII:C 25 units/kg/dose twice daily to achieve FVIII:C concentration 50% of normal. Continue treatment until healing has been achieved (2 to 7 days, on average).

Major hemorrhage (joint hemorrhage; muscle hemorrhage; major trauma; hematuria; intracranial and intraperitoneal bleeding): FVIII:C 40 to 50 units/kg/dose twice daily to achieve FVIII:C concentrations 80% to 100% of normal for at least 3 to 5 days; followed by FVIII:C 25 units/kg/dose twice daily to maintain FVIII:C concentrations at 50% of normal until healing has been achieved. Major hemorrhages may require treatment for up to 10 days. Intracranial hemorrhage may require prophylactic therapy for up to 6 months.

Surgery:

Preoperative: FVIII:C 40 to 50 units/kg to achieve FVIII:C concentrations 80% to 100% of normal

Postoperative: FVIII:C 30 to 50 units/kg/dose twice daily to maintain FVIII:C concentrations at 60% to 100% of normal for the next 7 to 10 days or until healing has been achieved.

Prophylaxis, primary: Limited data available; multiple protocols exist; optimum regimen has yet to be defined: Infants, Children, and Adolescents: IV:

Utrecht protocol: 15 to 30 units/kg/dose 3 times weekly (WFH [Srivastava 2013])

Malmö protocol: 25 to 40 units/kg/dose 3 times weekly (WFH [Srivastava 2013])

MASAC recommendations: 25 to 50 units/kg/dose 3 times weekly or every other day (National Hemophilia Foundation, MASAC recommendation 2007)

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 (NHLBI 2007).

Hemorrhage, treatment: Product-specific dosing:

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

General dosing: 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 not appropriate) or major hemorrhage (eg, severe or refractory epistaxis, GI bleeding, CNS trauma, traumatic hemorrhage):

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, 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%):

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; 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:

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, 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:

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:

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: IV:

Minor surgery/bleeding:

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):

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 3 to 7 days; do not exceed FVIII:C activity level of 150 units/dL

Humate-P: Infants, Children, and Adolescents: IV:

Emergency surgery: VWF:RCo 50 to 60 units/kg to achieve a target VWF:RCo peak plasma concentration of 100 units/dL; monitor trough coagulation factor levels for subsequent doses

Nonemergent surgical management:

Loading dose: Calculate based on patient's baseline and target VWF:RCo and IVR. The IVR (in vivo recovery) ideally should be assessed prior to surgery (eg, previous course of Humate P). If the calculated IVR is not available, assume IVR to be 2 units/dL per unit/kg of VWF:RCo administered.

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

Note: Target peak VWF:RCo plasma concentrations are dependent on surgery type (see below).

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

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

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:

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 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):

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 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.

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. 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. The formulas 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)] / IVR (units/dL per units/kg)

Procedure specific dosing and target VWF:RCo concentrations:

Minor surgery (including tooth extraction):

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:

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%.

Reconstitution

If refrigerated, the dried concentrate and diluent should be warmed to room temperature before reconstitution. Gently swirl or rotate vial after adding diluent; do not shake vigorously. For Alphanate or Humate-P, use provided filter transfer set to withdraw solution from vial; remove filter spike prior to administration. For Wilate, use provided transfer device. Refer to product labeling for specific details.

Administration

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.

Storage

Products are stable for three years, up to the expiration date printed on the label. For single use; discard any unused contents in vial.

Alphanate: Store intact vials at ≤25°C (≤77°F); do not freeze. May store reconstituted solution at room temperature (≤30°C). Use within 3 hours of reconstitution; do not refrigerate after reconstitution.

Humate-P: Store intact vials at ≤25°C (≤77°F); do not freeze. Once reconstituted, do not refrigerate and use within 3 hours.

Wilate: Store intact vials under refrigeration at 2°C to 8°C (36°F to 46°F); do not freeze. Store in original container to protect from light. Intact vials may also be stored at room temperature (not to exceed 25°C [77°F]) for ≤6 months. Once stored at room temperature, do not return to the refrigerator. Following reconstitution, use solution immediately.

Drug Interactions

There are no known significant interactions.

Adverse Reactions

>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

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.

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.

Pregnancy

Pregnancy Considerations

Pregnant hemophilia A carriers and those with von Willebrand disease may have an increased bleeding risk following abortion, invasive procedures, miscarriage, 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 <0.5 IU/mL 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 2013]).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience constipation or back pain. Have patient report immediately to prescriber signs of infection, signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), signs of blood clots (numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; fast heartbeat; or coughing up blood), flushing, severe dizziness, passing out, severe headache, burning or numbness feeling, stinging, edema, severe nausea, severe vomiting, severe loss of strength and energy, agitation, dark urine, yellow skin, fast heartbeat, or mouth discoloration (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.