Antihemophilic Factor (Human) (Monograph)

Brand names: Alphanate, Hemofil-M, Humate-P, Koate-DVI, Monoclate-P
Drug class: Hemostatics
VA class: BL500
CAS number: 9001-27-8

Medically reviewed by Drugs.com on Feb 14, 2024. Written by ASHP.

Introduction

Antihemophilic factor (human): Antihemophilic factor (blood coagulation factor VIII) prepared from pooled human plasma.

Antihemophilic factor/von Willebrand factor complex (human): Antihemophilic factor and von Willebrand factor prepared from pooled human plasma.

Uses for Antihemophilic Factor (Human)

Hemophilia A

Prevention and control of bleeding episodes in patients with hemophilia A (congenital factor VIII deficiency; classic hemophilia).

Maintenance of hemostasis in patients with hemophilia A undergoing surgery (i.e., perioperative management).

Antihemophilic factor replacement therapy generally is required in patients with mild to moderate hemophilia A who do not respond adequately to desmopressin or those with moderate to severe hemophilia A and factor VIII levels <5% of normal.

Also used for routine prophylaxis (i.e., administration at regular intervals) to prevent or reduce frequency of bleeding events. Such prophylaxis considered the current standard of care for patients with hemophilia A. Decreases frequency of spontaneous musculoskeletal bleeding, preserves joint function, and improves quality of life.

Several antihemophilic factor concentrates are currently available in the US, including a variety of recombinant and plasma-derived preparations; the Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation recommends preferential use of recombinant antihemophilic factor preparations because of their potentially superior safety profile with respect to pathogen transmission. Other experts (e.g., World Federation of Hemophilia) state that choice of preparation should be determined by local criteria. When selecting an appropriate antihemophilic factor preparation, consider characteristics of each clotting factor concentrate, individual patient variables, patient/provider preference, and emerging data.

Has been used for treatment of bleeding in patients with hemophilia A who have developed relatively low levels of neutralizing antibodies (alloantibodies; inhibitors) to factor VIII. (See Neutralizing Antibodies to Factor VIII under Cautions.)

Acquired Hemophilia A

Although antihemophilic factor (human) therapy may be effective in some patients with low levels of acquired factor VIII inhibitors when given in high dosages, bypassing agents are substantially more effective and are considered treatment of choice.

von Willebrand Disease

Antihemophilic factor/von Willebrand factor complex (human) is used to prevent or control bleeding (e.g., spontaneous or trauma-induced bleeding or for prevention of bleeding during surgery) in patients with von Willebrand disease. Generally used in patients with severe (e.g., type 3) von Willebrand disease or when use of desmopressin is inadequate or contraindicated.

Designated an orphan drug by FDA for treatment of von Willebrand disease.

Certain preparations (i.e., Alphanate) should not be used in patients with type 3 von Willebrand disease undergoing major surgery because of a lack of demonstrated efficacy.

Certain antihemophilic factor (human) preparations that contain naturally occurring von Willebrand factor as part of the manufacturing process (i.e., Koate-DVI) may be effective in the management of von Willebrand disease^{† [off-label]}. However, preparations containing antihemophilic factor but little or no von Willebrand factor generally not useful in the treatment of von Willebrand disease.

Related/similar drugs

tranexamic acid, desmopressin, Cyklokapron, DDAVP, Hemlibra, antihemophilic factor

Antihemophilic Factor (Human) Dosage and Administration

General

• Individualize dosage and duration of therapy based on severity of factor VIII or von Willebrand factor deficiency, location and extent of bleeding, and patient's clinical and pharmacokinetic (e.g., in vivo recovery, half-life) response.

• Monitor factor VIII or von Willebrand factor: Ristocetin cofactor (vWF:RCo) levels periodically during treatment to individualize dosage and assess response to therapy. Careful control is especially important in cases of life-threatening bleeding or major surgery. (See Laboratory Monitoring under Cautions.)

Administration

IV Administration

Administer by slow IV injection or by IV infusion over several minutes.

Has been given as a continuous IV infusion^{† [off-label]}.

Reconstitute and administer using plastic syringes only.

Instructions on reconstitution, dilution, and administration vary according to preparation; consult manufacturer’s labeling for specific information on each antihemophilic factor (human) or antihemophilic factor/von Willebrand factor complex (human) product.

Reconstitution

Prior to reconstitution, allow lyophilized drug and diluent to warm to room temperature; do not exceed 37°C.

Reconstitute using diluent provided by manufacturer.

Following addition of diluent, gently swirl solution to dissolve powder completely; do not shake.

Rate of Administration

Individualize infusion rates according to patient response. Monitor pulse before and during infusion. Slow infusion rate or temporarily discontinue therapy if there is a substantial increase in pulse rate.

Alphanate, Hemofil-M: Administer at a rate ≤10 mL/minute.

Humate-P: Administer at a rate ≤4 mL/minute.

Koate-DVI: Generally well-tolerated when given over 5–10 minutes.

Monoclate-P: Administer at a rate of approximately 2 mL/minute.

Dosage

Dosage (potency) expressed in terms of international units (IU, units). One unit is approximately equivalent to amount of factor VIII or vWF:RCo in 1 mL of fresh pooled human plasma.

Administration of 1 unit/kg antihemophilic factor (human) generally increases factor VIII level by approximately 2% and vWF:Co by approximately 5%.

Use following formulas to calculate dose or expected increase in factor VIII levels from a given dose in patients with hemophilia A:

Dose required to achieve desired factor VIII levels:

Dose (units) = body weight (in kg) × 0.5 × desired factor VIII increase (in % of normal)

Approximate % increase in factor VIII levels expected from a given dose:

Expected factor VIII increase (in % of normal) = [dose (units)/body weight (in kg)] × 2

Determine desired factor VIII level by the clinical situation and severity of bleeding. (For recommendations on target factor VIII levels, see the individual preparation-specific dosage sections below.) These calculations and suggested dosage regimens are only approximations and should not preclude appropriate clinical monitoring and laboratory determinations of factor VIII levels. Perform serial assays of factor VIII at suitable intervals to ensure that adequate levels have been attained and maintained.

If calculated dosage is ineffective in achieving adequate factor VIII levels or if bleeding is not controlled, consider possibility of inhibitor development. (See Neutralizing Antibodies to Factor VIII under Cautions.) Some patients with inhibitors may require higher or more frequent doses.

Consult manufacturers’ prescribing information for specific dosage recommendations for each antihemophilic factor (human) preparation.

Pediatric Patients

Prevention and Control of Bleeding Episodes in Hemophilia A

Alphanate

IV

Pediatric patients >16 years of age with minor bleeding (e.g., large bruises, substantial cuts or scrapes, uncomplicated joint bleeding): 15 units/kg twice daily to achieve a plasma factor VIII level of 30% of normal; usually for 1–2 days (until bleeding stops and healing achieved).

Pediatric patients >16 years of age with moderate bleeding (e.g., epistaxis, mouth and gum bleeding, tooth extraction, hematuria): 25 units/kg twice daily to achieve a plasma factor VIII level of 50% of normal; usually for 2–7 days (until healing achieved).

Pediatric patients >16 years of age with major bleeding (e.g., joint or muscle bleeding, major trauma, hematuria, intracranial or intraperitoneal hemorrhage): Initially, 40–50 units/kg twice daily to achieve a plasma factor VIII level of 80–100% of normal for at least 3–5 days; give additional doses of 25 units/kg twice daily for up to 10 days (until healing is achieved) to maintain a plasma factor VIII level of 50% of normal. Intracranial hemorrhage may require treatment for up to 6 months.

Pediatric patients >16 years of age undergoing surgery: Initially, 40–50 units/kg to achieve a plasma factor VIII level of 80–100% of normal prior to surgery. Give additional doses of 30–50 units/kg twice daily for 7–10 days (or until healing achieved) to maintain a plasma factor VIII level of 60–100% of normal.

Hemofil-M

IV

Early hemarthrosis, muscle bleeding or oral bleeding: Administer appropriate dose to achieve a peak plasma factor VIII postinfusion level of 20–40% of normal. To maintain adequate levels, administer doses every 12–24 hours for 1–3 days until bleeding resolves (indicated by relief of pain) or healing achieved.

More extensive hemarthrosis, muscle bleeding, or hematoma: Administer appropriate dose to achieve peak plasma factor VIII postinfusion level of 30–60% of normal. Give doses every 12–24 hours for 3 days or longer until pain and disability resolve.

Life-threatening bleeding (e.g., head injury, throat bleeding, severe abdominal pain): Administer appropriate dose to achieve a peak plasma factor VIII postinfusion level of 60–100% of normal. Give doses every 8–24 hours until bleeding resolves.

Minor surgery (e.g., tooth extraction): Administer appropriate dose to achieve a peak plasma factor VIII postinfusion level of 60–80% of normal. A single infusion given in conjunction with an oral antifibrinolytic agent usually is sufficient in about 70% of patients.

Major surgery: Administer appropriate dose to achieve peak plasma factor VIII pre- and postoperative levels of 80–100% of normal. Repeat doses every 8–24 hours depending on state of healing.

Monoclate-P

IV

Mild bleeding: A single infusion may be sufficient to achieve a plasma factor VIII level of ≥30% of normal.

Moderate bleeding: Initially, 15–25 units/kg to achieve a plasma factor VIII level of 30–50% of normal. If needed, give additional doses of 10–15 units/kg every 8–12 hours.

Severe bleeding (e.g., neck, throat, subperitoneal bleeding): Initially, 40–50 units/kg and a maintenance dosage of 20–25 units/kg given every 8–12 hours to achieve a plasma factor VIII level of 80–100% of normal.

Minor surgery: Initially, 15–25 units/kg to achieve a plasma factor VIII level of 30–50% of normal. If needed, give additional doses of 10–15 units/kg every 8–12 hours.

Major surgery: Administer an appropriate dose to achieve a plasma factor VIII level of 80–100% of normal 1 hour before surgery; administer a second dose equal to 50% of the initial dose 5 hours later. Maintain a plasma factor VIII level of ≥30% of normal for 10–14 days after surgery.

Routine Prophylaxis of Bleeding Episodes in Hemophilia A

IV

Various dosing regimens have been recommended. MASAC states that an antihemophilic factor dosage of 25–50 units/kg 3 times a week or every other day usually is sufficient to maintain trough factor VIII concentrations >1% between infusions.

MASAC states that prophylaxis should be instituted at an early age (e.g., 1–2 years) prior to the onset of frequent bleeding; however, optimum duration of prophylaxis not known.

Individualize prophylactic regimens; evaluate patients periodically to determine continued need for prophylaxis.

von Willebrand Disease (Alphanate)

Amount of vWF:RCo and factor VIII contained in each vial of Alphanate is indicated on the label. Ratio of vWF:RCo to factor VIII varies depending on the manufacturing lot; therefore, reevaluate dosage of Alphanate for management of von Willebrand disease whenever a different manufacturing lot is indicated on the vial.

IV

Patients undergoing a minor surgical or invasive procedure: Initially, 75 units/kg of vWF:RCo prior to procedure to achieve factor VIII levels of 40–50%; follow with additional doses of 50–75 units/kg of vWF:RCo every 8–12 hours as clinically needed for 1–3 days to maintain factor VIII levels at 40–50%.

Type 1 or type 2 patients undergoing a major surgical or invasive procedure: Initially, 75 units/kg of vWF:RCo prior to procedure to achieve factor VIII levels of 100%; follow with additional doses of 50–75 units/kg of vWF:RCo every 8–12 hours as clinically needed for at least 3–7 days to maintain factor VIII levels at 100%.

Therapeutic goal is to achieve trough factor VIII and vWF:RCo levels >50%; do not exceed 150%.

von Willebrand Disease (Humate-P)

IV

Adjust dosage according to extent and location of bleeding. Usually administer doses of 40–80 units/kg of vWF:RCo (corresponding to 17–33 units/kg of antihemophilic factor) every 8–12 hours; repeat doses for as long as needed based on repeated monitoring of appropriate clinical and laboratory measures.

Expected levels of vWF:RCo based on expected in vivo recovery of 2% increase per unit/kg of vWF:RCo administered. Administration of 1 unit/kg of antihemophilic factor can be expected to result in an increase in circulating vWF:RCo of approximately 5%.

In all patients with major bleeding, monitor and maintain factor VIII levels according to the usual guidelines for patients with hemophilia A.

Type 1 (Mild) von Willebrand Disease (Baseline vWF:RCo Activity Typically >30%)

IV

Pediatric patients (excluding neonates) with major bleeding (e.g., severe or refractory epistaxis, GI bleeding, CNS trauma, traumatic bleeding) or minor bleeding when use of desmopressin is inadequate or contraindicated: Initially, 40–60 units/kg of vWF:RCo, followed by 40–50 units/kg of vWF:RCo every 8–12 hours for 3 days to maintain a trough vWF:RCo level of >50%. Continue with 40–50 units/kg vWF:RCo daily for up to 7 days.

Type 1 (Moderate or Severe) von Willebrand Disease (Baseline vWF:RCo Activity Typically <30%)

IV

Pediatric patients (excluding neonates) with minor bleeding (e.g., epistaxis, oral bleeding, menorrhagia): 40–50 units/kg of vWF:RCo given as 1 or 2 doses.

Pediatric patients (excluding neonates) with major bleeding (e.g., severe or refractory epistaxis, GI bleeding, CNS trauma, hemarthrosis, traumatic bleeding): Initially, 50–75 units/kg of vWF:RCo, followed by 40–60 units/kg of vWF:RCo every 8–12 hours for 3 days to maintain a vWF:RCo trough level of >50%. Continue with 40–60 units/kg of vWF:RCo daily for up to 7 days.

Type 2 (All Variants) and Type 3 von Willebrand Disease

IV

Pediatric patients (excluding neonates) with minor bleeding (e.g., epistaxis, oral bleeding, menorrhagia): 40–50 units/kg of vWF:RCo given as 1 or 2 doses.

Pediatric patients (excluding neonates) with major bleeding (e.g., severe or refractory epistaxis, GI bleeding, CNS trauma, hemarthrosis, traumatic bleeding): Initially, 60–80 units/kg of vWF:RCo, followed by 40–60 units/kg of vWF:RCo every 8–12 hours for 3 days to maintain a vWF:RCo trough level >50%. Continue with 40–60 units/kg of vWF:RCo daily for up to 7 days.

Prevention of Excessive Perioperative Bleeding in von Willebrand Disease

Whenever possible, calculate dosages for surgical prophylaxis based on incremental in vivo recovery (IVR) values. If individual IVR values not available, assume IVR of 2% per unit/kg of vWF:RCo. In case of emergency surgery, administer a loading dose of 50–60 units/kg of vWF:RCo and closely monitor trough coagulation factor levels.

To calculate IVR, use the following formula. Measure plasma vWF:RCo level at baseline and 30 minutes following a calculated dose.

IVR = (plasma vWF:RCo_{time + 30 minutes} - plasma vWF:RCo_baseline) / calculated dose (in units/kg)

Calculate loading dose (administered 1–2 hours prior to surgery) using the following formula:

Dose required (units of vWF:RCo) = [(target peak plasma vWF:RCo - baseline plasma vWF:RCo) x body weight (in kg)]/IVR

Administer loading doses to achieve specific target peak vWF:RCo and factor VIII levels. Additional doses may be necessary to achieve recommended factor VIII levels; because of a higher ratio of vWF:RCo to factor VIII (2.4 to 1), vWF:RCo will increase proportionally more than factor VIII with increasing doses.

Administer initial maintenance dose equal to one-half the loading dose (irrespective of any additional loading doses given to meet target factor VIII goals); follow with additional maintenance doses based on trough plasma vWF:RCo and factor VIII levels. Frequency of administration depends on individual pharmacokinetic parameters; in the absence of such data, administer every 8 hours initially.

Monitor trough vWF:RCo and factor VIII levels at least once daily, and during and after surgery. Modify dose and/or frequency of antihemophilic factor administration if hemostasis is insufficient or measured trough coagulation factor levels are not within recommended range. Because factor VIII is the main predictor of surgical hemostasis, some clinicians recommend monitoring factor VIII levels every 12 hours on the day a dose is administered, then every 24 hours thereafter. Determine duration of therapy based on hemostatic response.

IV

Pediatric patients (excluding neonates) undergoing major surgery: Administer appropriate loading dose to achieve a target peak plasma vWF:RCo level of 100% and a peak plasma factor VIII level of 80–100%. Give initial maintenance dose equal to one-half the loading dose and subsequent doses to achieve target trough vWF:RCo levels of >50% (>50% of factor VIII activity) for up to 3 days following surgery and target trough vWF:RCo levels of >30% (>30% of factor VIII activity) after day 3. Minimum duration of treatment is 72 hours.

Pediatric patients (excluding neonates) undergoing minor surgery: Administer appropriate loading dose to achieve a target peak plasma vWF:RCo level of 50–60% and a peak plasma factor VIII level of 40–50%. Give initial maintenance dose equal to one-half the loading dose and subsequent doses to achieve target trough plasma vWF:RCo levels of ≥30% for up to 3 days following surgery and target trough factor VIII levels >30% after day 3. Minimum duration of treatment is 48 hours.

Pediatric patients (excluding neonates) undergoing oral surgery: Administer appropriate loading dose to achieve a target peak vWF:RCo level of 50–60% and a peak plasma factor VIII level of 40–50%. Give initial maintenance dose equal to one-half the loading dose and subsequent doses to achieve target trough vWF:RCo levels of ≥30% for up to 3 days following surgery and target trough factor VIII levels >30% after day 3. Minimum duration of treatment is 8–12 hours.

Adults

Prevention and Control of Bleeding Episodes in Hemophilia A

Alphanate

IV

Minor bleeding (e.g., large bruises, cuts or scrapes, uncomplicated joint bleeding): 15 units/kg twice daily to achieve a plasma factor VIII level of 30% of normal; usually for 1–2 days (until bleeding stops and healing achieved).

Moderate bleeding (e.g., epistaxis, mouth and gum bleeding, tooth extraction, hematuria): 25 units/kg twice daily to achieve a plasma factor VIII level of 50% of normal; usually for 2–7 days, until healing achieved.

Major bleeding (e.g., joint or muscle bleeding, major trauma, hematuria, intracranial and intraperitoneal bleeding): Initially, 40–50 units/kg twice daily to achieve a plasma factor VIII level of 80–100% of normal for at least 3–5 days. Give additional doses of 25 units/kg twice daily for up to 10 days (until healing is achieved) to maintain a plasma factor VIII level of 50% of normal. Intracranial hemorrhage may require treatment for up to 6 months.

Surgery: Initially, 40–50 units/kg to achieve a plasma factor VIII level of 80–100% of normal prior to surgery. Give additional doses of 25–50 units/kg twice daily for 7–10 days (or until healing achieved) to maintain a plasma factor VIII level of 60–100% of normal.

Humate-P

IV

Minor bleeding (e.g., early joint or muscle bleeding, severe epistaxis): Initially, 15 units/kg to achieve a plasma factor VIII level of approximately 30% of normal. A single dose may be sufficient; if necessary, administer additional doses equal to 50% of the loading dose once or twice daily for 1–2 days.

Moderate bleeding (e.g., advanced joint or muscle bleeding; neck, tongue, or pharyngeal hematoma without airway compromise; severe abdominal pain; tooth extraction): Initially, 25 units/kg to achieve a plasma factor VIII level of approximately 50% of normal, followed by 15 units/kg every 8–12 hours for the first 1–2 days to maintain a plasma factor VIII level of 30% of normal. Thereafter, the same dose may be given once or twice daily for up to 7 days or until adequate wound healing.

Life-threatening bleeding (e.g., major surgery, GI bleeding; neck, tongue, or pharyngeal hematoma with potential for airway compromise; intracranial, intra-abdominal, or intrathoracic bleeding; fractures): Initially, 40–50 units/kg followed by 20–25 units/kg every 8 hours to maintain a plasma factor VIII level of 80–100% of normal for 7 days. Thereafter, the same dose may be given once or twice daily for another 7 days to maintain a plasma factor VIII level of 30–50% of normal.

Hemofil-M

IV

Early hemarthrosis, muscle bleeding or oral bleeding: Administer appropriate dosage to achieve a peak plasma factor VIII postinfusion level of 20–40% of normal. To maintain adequate levels, administer doses every 12–24 hours for 1–3 days until bleeding resolves (indicated by relief of pain) or healing achieved.

More extensive hemarthrosis, muscle bleeding, or hematoma: Administer appropriate dose to achieve peak plasma factor VIII postinfusion level of 30–60% of normal. Give doses every 12–24 hours for 3 days or longer until pain and disability resolve.

Life-threatening bleeding (e.g., head injury, throat bleeding, severe abdominal pain): Administer appropriate dose to achieve a peak plasma factor VIII postinfusion level of 60–100% of normal. Give doses every 8–24 hours until bleeding resolves.

Minor surgery (e.g., tooth extraction): Administer appropriate dose to achieve a peak plasma factor VIII postinfusion level of 60–80% of normal. A single infusion given in conjunction with an oral antifibrinolytic agent usually is sufficient in about 70% of patients.

Major surgery: Administer appropriate dose to achieve peak plasma factor VIII pre- and postoperative levels of 80–100% of normal. Repeat doses every 8–24 hours depending on state of healing.

Koate-DVI

IV

Mild bleeding (superficial or early bleeding): A single 10-unit/kg dose may be sufficient to achieve an in vivo factor VIII level of approximately 20% of normal. Repeat only if evidence of further bleeding.

Moderate bleeding (more serious bleeding episodes including definite hemarthroses, known trauma): Initially, 15–25 units/kg to achieve a plasma factor VIII level of 30–50% of normal. If additional therapy is required, give additional doses of 10–15 units/kg every 8–12 hours.

Severe bleeding (life-threatening bleeding or possible hemorrhage involving vital structures [e.g., CNS, retropharyngeal and retroperitoneal spaces, iliopsoas sheath]): Increase plasma factor VIII level to 80–100% of normal with an initial dose of 40–50 units/kg and a maintenance dosage of 20–25 units/kg every 8–12 hours.

Major surgery: Increase plasma factor VIII level to approximately 100% with a preoperative 50-unit/kg dose. Check plasma factor VIII levels to verify that the expected level is achieved prior to surgery. Give additional doses if necessary, every 6–12 hours initially, and for a total of 10–14 days until healing complete.

Intensity of antihemophilic factor therapy required depends on the type of surgery and postoperative regimen employed; less intensive treatment schedules may provide adequate hemostasis for minor surgical procedures.

Monoclate-P

IV

Mild bleeding: A single infusion may be sufficient to achieve a plasma factor VIII level of ≥30% of normal.

Moderate bleeding: Initially, 15–25 units/kg to achieve a plasma factor VIII level of 30–50% of normal. If needed, give additional doses of 10–15 units/kg every 8–12 hours.

Severe bleeding (e.g., neck, throat, subperitoneal bleeding): Initially, 40–50 units/kg and a maintenance dosage of 20–25 units/kg given every 8–12 hours may be sufficient to achieve a plasma factor VIII level of 80–100% of normal.

Minor surgery: Initially, 15–25 units/kg to achieve a plasma factor VIII level of 30–50% of normal; maintenance doses of 10–15 units/kg may be given every 8–12 hours if needed.

Major surgery: Administer appropriate dosage to achieve plasma factor VIII level of 80–100% of normal 1 hour before surgery; administer a second dose equal to 50% of the initial dose 5 hours later. Maintain a plasma factor VIII level of ≥30% of normal for 10–14 days after surgery.

Routine Prophylaxis of Bleeding Episodes in Hemophilia A

IV

Various dosing regimens have been recommended. MASAC states that an antihemophilic factor dosage of 25–50 units/kg 3 times a week or every other day usually is sufficient to maintain trough factor VIII concentrations >1% between infusions.

Individualize prophylactic regimens; evaluate patients periodically to determine continued need for prophylaxis.

von Willebrand Disease (Alphanate)

Amount of vWF:RCo and factor VIII contained in each vial of Alphanate is indicated on the label. Ratio of vWF:RCo to factor VIII varies depending on the manufacturing lot; therefore, reevaluate dosage of Alphanate for management of von Willebrand disease whenever a different manufacturing lot is indicated on the vial.

IV

Patients undergoing a minor surgical or invasive procedure: Initially, 60 units/kg of vWF:RCo prior to procedure to achieve a target factor VIII level of 40–50% of normal; follow with additional doses of 40–60 units/kg of vWF:RCo every 8–12 hours as clinically needed for 1–3 days to maintain factor VIII levels at 40–50% of normal.

Type 1 or type 2 patients undergoing a major surgical or invasive procedure: Initially, 60 units/kg of vWF:RCo prior to procedure to achieve a factor VIII level of 100% of normal; follow with additional dosages of 40–60 units/kg of vWF:RCo every 8–12 hours as clinically needed for 3–7 days to maintain factor VIII levels at 100%.

Therapeutic goal is to achieve trough factor VIII and vWF:RCo levels >50%; do not exceed 150%.

von Willebrand Disease (Humate-P)

IV

Adjust dosage according to extent and location of bleeding. Usually administer dosage of 40–80 units/kg of vWF:RCo (corresponding to 17–33 units/kg of antihemophilic factor) every 8–12 hours; repeat doses for as long as needed based on monitoring of appropriate clinical and laboratory measures.

Expected levels of vWF:RCo based on expected in vivo recovery of 2% increase per unit/kg of vWF:RCo administered. Administration of 1 unit/kg of antihemophilic factor can be expected to result in an increase in circulating vWF:RCo of approximately 5%.

In all patients with major bleeding, monitor and maintain factor VIII levels according to the usual guidelines for patients with hemophilia A.

Type 1 (Mild) von Willebrand Disease (Baseline vWF:RCo Activity Typically >30%)

IV

Major bleeding (e.g., severe or refractory epistaxis, GI bleeding, CNS trauma, traumatic bleeding) or minor bleeding when use of desmopressin is inadequate or contraindicated: Initially, 40–60 units/kg of vWF:RCo, followed by 40–50 units/kg of vWF:RCo every 8–12 hours for 3 days to maintain a trough vWF:RCo level of >50%. Continue with 40–50 units/kg of vWF:RCo daily for up to 7 days.

Type 1 (Moderate or Severe) von Willebrand Disease (Baseline vWF:RCo Activity Typically <30%)

IV

Minor bleeding (e.g., epistaxis, oral bleeding, menorrhagia): 40–50 units/kg of vWF:RCo given as 1 or 2 doses.

Major bleeding (e.g., severe or refractory epistaxis, GI bleeding, CNS trauma, hemarthrosis, traumatic bleeding): Initially, 50–75 units/kg of vWF:RCo, followed by 40–60 units/kg of vWF:RCo every 8–12 hours for 3 days to maintain a vWF:RCo trough level of >50%. Continue with 40–60 units/kg of vWF:RCo daily for up to 7 days.

Type 2 (All Variants) and Type 3 von Willebrand Disease

IV

Minor bleeding (e.g., epistaxis, oral bleeding, menorrhagia): 40–50 units/kg of vWF:RCo given as 1 or 2 doses.

Major bleeding (e.g., severe or refractory epistaxis, GI bleeding, CNS trauma, hemarthrosis, traumatic bleeding): Initially, 60–80 units/kg of vWF:RCo, followed by 40–60 units/kg of vWF:RCo every 8–12 hours for 3 days to maintain a vWF:RCo trough level of >50%. Continue with 40–60 units/kg of vWF:RCo daily for up to 7 days.

Prevention of Excessive Perioperative Bleeding in von Willebrand Disease

Whenever possible, calculate dosages for surgical prophylaxis based on IVR values. If individual IVR values not available, assume IVR of 2% per unit/kg. In case of emergency surgery, administer loading dose of 50–60 units/kg of vWF:RCo and closely monitor trough coagulation factor levels.

To calculate IVR, use the following formula. Measure plasma vWF:RCo level at baseline and 30 minutes following a calculated dose.

IVR = (plasma vWF:RCo_{time + 30 minutes} - plasma vWF:RCo_baseline) / calculated dose (in units/kg)

Calculate loading dose (administered 1–2 hours prior to surgery) using the following formula:

Dose required (units vWF:RCo) = [(target peak plasma vWF:RCo - baseline plasma vWF:RCo) x body weight (in kg)]/IVR

Administer loading doses to achieve specific target peak vWF:RCo and factor VIII levels. Additional doses may be necessary to achieve recommended factor VIII levels; because of a higher ratio of vWF:RCo to factor VIII (2.4 to 1), vWF:RCo will increase proportionally more than factor VIII with increasing doses.

Administer initial maintenance dose equal to one-half the loading dose (irrespective of any additional loading doses given to meet target factor VIII goals); follow with additional maintenance doses based on trough plasma vWF:RCo and factor VIII levels. Frequency of administration depends on individual pharmacokinetic parameters; in the absence of such data, administer every 8 hours initially.

Monitor trough vWF:RCo and factor VIII levels at least once daily, and during and after surgery. Modify dose and/or frequency of antihemophilic factor administration if hemostasis is insufficient or measured trough coagulation factor levels are not within recommended range. Because factor VIII is the main predictor of surgical hemostasis, some clinicians recommend monitoring factor VIII levels every 12 hours on the day a dose is administered, then every 24 hours thereafter. Determine duration of therapy based on hemostatic response.

IV

Major surgery: Administer appropriate loading dose to achieve a target peak plasma vWF:RCo level of 100% and a peak plasma factor VIII level of 80–100%. Give initial maintenance dose equal to one-half the loading dose and subsequent doses to achieve target trough vWF:RCo levels of >50% (>50% of factor VIII activity) for up to 3 days following surgery and target trough vWF:RCo levels of >30% (>30% of factor VIII activity) after day 3. Minimum duration of treatment is 72 hours.

Minor surgery: Administer appropriate loading dose to achieve a target peak plasma vWF:RCo level of 50–60% and a peak plasma factor VIII level of 40–50%. Give initial maintenance dose equal to one-half the loading dose and subsequent doses to achieve target trough plasma vWF:RCo levels of ≥30% for up to 3 days following surgery and target trough factor VIII levels >30% after day 3. Minimum duration of treatment is 48 hours.

Oral surgery: Administer appropriate loading dose to achieve a target peak vWF:RCo level of 50–60% and a peak plasma factor VIII level of 40–50%. Give initial maintenance dose equal to one-half the loading dose and subsequent doses to achieve target trough vWF:RCo levels of ≥30% for up to 3 days following surgery and target trough factor VIII levels >30% after day 3. Minimum duration of treatment is 8–12 hours.

Prescribing Limits

Pediatric Patients

Hemophilia A

IV

Hemofil-M: Maximum infusion rate 10 mL/minute.

von Willebrand Disease

IV

Alphanate: Maximum infusion rate 10 mL/minute.

Humate-P: Maximum infusion rate 4 mL/minute.

Adults

Hemophilia A

IV

Alphanate, Hemofil-M: Maximum infusion rate 10 mL/minute. Higher rates may result in vasomotor reactions.

Humate-P: Maximum infusion rate 4 mL/minute.

von Willebrand Disease

IV

Alphanate: Maximum infusion rate 10 mL/minute.

Humate-P: Maximum infusion rate 4 mL/minute.

Cautions for Antihemophilic Factor (Human)

Contraindications

• Hypersensitivity or severe systemic reaction to antihemophilic factor or von Willebrand factor preparations or any ingredient in the formulations.

• Known hypersensitivity to murine protein (Hemofil-M, Monoclate-P).

• The manufacturer states that there are no known contraindications to the use of Koate-DVI.

Warnings/Precautions

Warnings

Risk of Transmissible Agents in Plasma-derived Preparations

Improved donor screening, viral-inactivating procedures (e.g., solvent/detergent, heat treatment), and/or immunoaffinity chromatography procedures have reduced but not completely eliminated risk of pathogen transmission with plasma-derived antihemophilic factor preparations.

Possibility still exists for transmission of human viruses (e.g., HIV, hepatitis A virus [HAV], HBV, HCV) and other infectious agents (e.g., other unknown viruses, causative agents for Creutzfeldt-Jakob disease [CJD] or variant CJD [vCJD]).

Although transmission of nonenveloped viruses, including HAV and parvovirus B19, has been documented following administration of plasma-derived coagulation factors, risk has been reduced with additional viral attenuation methods such as nanofiltration.

Carefully weigh risk of pathogen transmission versus benefits of therapy. Report any suspected infections associated with the drug to the manufacturer, FDA, and CDC.

Risk of Hepatitis

Risk of hepatitis A or hepatitis B infection.

Monitor closely for signs and symptoms of hepatitis A during therapy. (See Advice to Patients.)

Experts recommend administration of hepatitis B vaccine to all individuals with bleeding disorders who are seronegative and have not already been vaccinated; vaccination is recommended at birth or at time of diagnosis.

Immunization with hepatitis A vaccine is recommended for all individuals ≥12 months of age with hemophilia A or other congenital bleeding disorders who are HAV seronegative.

Risk of HIV Infection

Potential vehicle for transmission of HIV. HIV seroconversion reported in the past in patients who received blood or blood products from donors not screened for HIV and/or prepared using suboptimal viral-inactivating procedures. (See Risk of Transmissible Agents in Plasma-derived Preparations under Cautions.)

No reports to date of HIV seroconversion with currently available antihemophilic factor (human) preparations.

Risk of Creutzfeldt-Jakob Disease

Theoretical possibility of transmitting causative agent of CJD or vCJD. Several probable cases of vCJD transmission reported from transfusion of human RBCs. However, no cases of CJD or vCJD from antihemophilic factor preparations reported to date. For further information on CJD and vCJD precautions related to blood and blood products, consult the FDA’s guidance for industry ().

Risk of West Nile Virus

Evidence of West Nile virus (WNV) transmission through transplanted organs (e.g., heart, liver, kidney) and blood products. However, WNV transmission through commercially available factor VIII preparations unlikely due to current viral-inactivating procedures.

For further information on WNV precautions related to blood and blood products, consult the FDA’s guidance for industry ().

Thromboembolism

Thromboembolic events reported in patients with von Willebrand disease receiving antihemophilic factor/von Willebrand factor complex (human), usually occurring in setting of known thrombotic risk factors.

Although a causal relationship not established, high levels of endogenous factor VIII have been associated with thrombosis.

Exercise caution when using coagulation factor replacement therapy in all von Willebrand disease patients with high thrombotic risk. Consider use of antithrombotic measures.

Neutralizing Antibodies to Factor VIII

Risk of development of neutralizing antibodies (inhibitors) to factor VIII following treatment with any antihemophilic factor preparation. Reported to occur in approximately 20–30% of patients with severe hemophilia A and 5–10% of those with mild to moderate disease.

Inhibitors may diminish or neutralize response to therapy. Anamnestic responses and increased levels of inhibitor possible with continued administration of drug.

Monitor for development of inhibitors during treatment with clinical observation and appropriate laboratory tests. Consider possibility of inhibitors in patients who fail to respond to adequate dosages of antihemophilic factor (human) or antihemophilic factor/von Willebrand factor complex (human), particularly in those who previously achieved a response.

Some reports suggest possible development of alloantibodies to von Willebrand factor following replacement therapy in patients with type 3 von Willebrand disease.

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., hives, generalized urticaria, tightness of the chest, wheezing, hypotension, anaphylaxis) reported. (See Contraindications under Cautions.)

The principal protein in Hemofil M is albumin human. Adverse reactions associated with IV administration of albumin are rare; however, nausea, fever, chills, and urticaria have been reported in patients receiving the protein.

If hypersensitivity reaction occurs, discontinue drug immediately and initiate appropriate therapy.

Antibody Formation to Nonhuman Mammalian Proteins

Some preparations of antihemophilic factor (human) contain trace amounts of animal proteins (Hemofil-M, Monoclate-P) which may stimulate antibody production and cause hypersensitivity reactions.

Latex Sensitivity

Packaging components for some preparations (e.g., Hemofil-M, Koate-DVI) may contain natural latex proteins; take appropriate precautions if injection is handled by or administered to individuals with a history of natural latex sensitivity.

General Precautions

Hematologic Effects

Some preparations of antihemophilic factor (human) contain trace amounts of blood groups A and B isohemagglutins; intravascular hemolysis and anemia possible, especially when large or frequently repeated doses are given to individuals with blood groups A, B, or AB.

Monitor for signs of intravascular hemolysis and progressive anemia (performing hematocrit and direct antiglobulin [Coombs test]) in such individuals. If hemolysis or hemolytic anemia occurs, discontinue therapy and initiate appropriate treatment; consider administration of serologically compatible RBCs from blood group O.

Laboratory Monitoring

To ensure adequate therapeutic response, monitor factor VIII and vWF:RCo (if used in patients with von Willebrand disease) levels at regular intervals during therapy, especially in patients with major bleeding or who require surgery.

Monitor for development of inhibitors during treatment. (See Neutralizing Antibodies to Factor VIII under Cautions.)

Specific Populations

Pregnancy

Category C.

Lactation

Not known whether antihemophilic factor (human) or antihemophilic factor/von Willebrand factor (human) is distributed into human milk. Use with caution and only if clearly indicated.

Pediatric Use

Alphanate: Safety and efficacy not established in children ≤16 years of age with hemophilia A. Evaluated in a limited number of pediatric patients ≤18 years of age with von Willebrand disease; no clinically important differences observed between pediatric patients and adults.

Humate-P: No adequate and well-controlled studies in pediatric patients with hemophilia A. Long-term evaluation of joint damage not available for pediatric patients; joint damage may result from suboptimal treatment of hemarthroses. Safety and efficacy established in infants, children, and adolescents with von Willebrand disease, but not in neonates.

Koate-DVI: Not studied in pediatric patients; manufacturer states that the predecessor product (Koate-HP, solvent/detergent-treated antihemophilic factor [human]) has been used extensively in pediatric patients. Adverse effects reported in pediatric patients generally have been similar to those reported in adults.

Monoclate-P: Safety and efficacy established in children with hemophilia A; manufacturer recommends following adult dosage guidelines.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients. Use with caution due to greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly. Individualize dosage.

Common Adverse Effects

Hemophilia A: Urticaria, fever, chills, nausea, chest tightness, stinging at infusion site, paresthesia, headache, rash, pruritus, edema, vasodilation, postoperative bleeding, vomiting, pain, somnolence, lethargy, jitteriness, abdominal pain, blurred vision.

Von Willebrand disease: Urticaria, chest tightness, rash, pruritus, chills, paresthesia, edema, phlebitis, pharyngitis, headache, fever, pseudothrombocytopenia, extremity pain, vasodilation, hypervolemia, constipation, urinary retention, dizziness, postoperative complications (e.g., bleeding, nausea, pain ).

Drug Interactions

No formal drug interaction studies to date.

Antihemophilic Factor (Human) Pharmacokinetics

Absorption

Bioavailability

Following IV administration, peak plasma concentrations of factor VIII generally occur 10–15 minutes after end of infusion; may occur up to 1–2 hours later.

Plasma Concentrations

Following IV infusion over 5–15 minutes, plasma concentrations of factor VIII increase by approximately 0.02–0.025 unit/mL per units/kg administered.

Duration

Von Willebrand disease: Decreased bleeding time generally persists for <6 hours.

Distribution

Extent

Circulates in plasma; minimally distributed (about 14%) outside vascular system.

Does not readily cross placenta.

Not known whether antihemophilic factor (human) is distributed into human milk.

Plasma Binding

Binds noncovalently to von Willebrand factor.

Elimination

Elimination Route

Rapidly cleared from plasma following IV administration. Possibly eliminated partly via reticuloendothelial system.

Half-life

Factor VIII: About 12 hours (range: 8–18 hours).

Von Willebrand factor: Approximately 7–11 hours.

Special Populations

Possible increased clearance of factor VIII in patients with severe von Willebrand disease.

Stability

Storage

Parenteral

Powder for Infusion

Alphanate: ≤25°C (avoid freezing). Store reconstituted solution at room temperature (≤30°C); use within 3 hours of reconstitution.

Hemofil-M: 2–8°C (avoid freezing to prevent damage to the diluent vial) or at room temperature ≤30°C up to expiration date. Do not refrigerate after reconstitution; use solution within 3 hours of reconstitution.

Humate-P: ≤25°C up to expiration date; avoid freezing. Do not refrigerate after reconstitution; use solution within 3 hours of reconstitution.

Koate DVI: 2–8°C (avoid freezing to prevent damage to the diluent vial); may store at room temperature ≤25°C up to 6 months. Do not refrigerate after reconstitution; use solution within 3 hours of reconstitution.

Monoclate-P: 2–8°C (avoid freezing to prevent damage to the diluent vial) up to expiration date or store at room temperature ≤25°C for up to 6 months. Use solution within 3 hours of reconstitution.

Actions

• Antihemophilic factor (human) preparations are concentrates of factor VIII derived from pooled human plasma. Antihemophilic factor/von Willebrand factor complex (human) preparations are concentrates of factor VIII and von Willebrand factor prepared from pooled human plasma.

• Factor VIII is essential for blood clotting and maintenance of hemostasis.

• Patients with hemophilia A (classic hemophilia) have decreased levels of endogenous factor VIII or dysfunctional factor VIII, resulting in a bleeding tendency and clinical manifestations such as bleeding into soft tissues, muscles, and weight-bearing joints.

• Decreased levels of endogenous factor VIII also may occur in patients with von Willebrand disease who have levels of vWF that are insufficient for in vivo stabilization of factor VIII.

• Clinical severity and frequency of bleeding in patients with hemophilia A correlate with the degree of deficiency in factor VIII activity. Patients with mild hemophilia A generally have >5% of normal activity, those with moderate disease generally have 1–5% of normal activity, and those with severe disease have <1% of normal activity.

• Administration of antihemophilic factor (human) or antihemophilic factor/von Willebrand factor complex (human) increases plasma levels of factor VIII and temporarily corrects the coagulation defect in patients with hemophilia A.

• Provides exogenous source of von Willebrand factor (Alphanate, Humate-P); decreases bleeding time and temporarily corrects coagulation defect in patients with von Willebrand disease. Von Willebrand factor promotes platelet adhesion and aggregation on damaged vascular endothelium; binds noncovalently to factor VIII, and stabilizes and protects factor VIII from degradation.

• Prepared using different methods (e.g., precipitation, gel filtration, chromatography, nanofiltration) to isolate and purify factor VIII and von Willebrand factor (for Alphanate and Humate-P).

• Undergoes viral inactivation processes (solvent/detergent, heat treatment [pasteurization, dry heat]) to reduce risk of viral transmission.

Advice to Patients

• Risk of developing neutralizing antibodies (inhibitors) to factor VIII; importance of informing clinician if usual dosages of factor VIII not able to control bleeding.

• Risk of transmission of parvovirus B19 and/or hepatitis A from plasma-derived factor concentrates. Importance of informing clinician if symptoms of potential parvovirus B19 infection (e.g., low grade fever, drowsiness, chills, runny nose, rash, arthralgias, arthritis, joint pain) or hepatitis A infection (e.g., low grade fever, anorexia, nausea, vomiting, fatigue, jaundice, dark urine, abdominal pain) occur.

• Importance of discontinuing therapy and immediately informing clinician if hives, urticaria, chest tightness, dyspnea, faintness, hypotension, wheezing, or other manifestations of hypersensitivity reaction or anaphylaxis occur.

• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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