VA Class:BL500

AHFS Class:

• Hemostatics 20:28.16

Generic Name(s):

• Antihemophilic Factor (Human)

• Antihemophilic Factor (Human)/von Willebrand Factor Complex

Chemical Name:

• blood-coagulation factor VIII (human), glycoform α

Antihemophilic factor (human) is a preparation of antihemophilic factor (blood coagulation factor VIII) prepared from pooled human plasma.153,158,167 Antihemophilic factor/von Willebrand factor complex (human) is a preparation of antihemophilic factor and von Willebrand factor prepared from pooled human plasma.122,133

Hemophilia A

Overview

Antihemophilic factor (human) and antihemophilic factor/von Willebrand factor complex (human) are used for the prevention and control of bleeding episodes in individuals with hemophilia A (congenital factor VIII deficiency; classic hemophilia).122,133,153,158,167 Antihemophilic factor concentrates provide a means of temporarily replacing missing or dysfunctional factor VIII in patients with hemophilia A in order to prevent or control bleeding episodes153,155,158,160,175,178,180 or to perform emergency or elective surgery.158,167

Antihemophilic factor (human) also may be effective for the prevention or treatment of bleeding episodes in certain patients with hemophilia A who have low levels of neutralizing antibodies (alloantibodies; inhibitors) to factor VIII.153,154,160,176,179,180,215,255 However, administration to such patients may result in anamnestic responses and increased inhibitor levels,160,176,179,180,182,194 and management of bleeding in patients with inhibitors may be difficult.122,164,165,166,169 (See Cautions: Neutralizing Antibodies to Factor VIII.)

Antihemophilic factor (human) has been used in certain patients with acquired hemophilia A† who have low levels of spontaneously acquired inhibitors to antihemophilic factor (autoantibodies).251,253

Antihemophilic factor/von Willebrand factor complex (human) is used in the management of von Willebrand disease when use of desmopressin is known or suspected to be inadequate.122,133 While safety and efficacy of antihemophilic factor (human) have not been established for the treatment of von Willebrand disease†,153,158,167 it has been suggested that certain preparations that have a high content of von Willebrand factor (i.e., Koate^®-DVI) also may be used for the management of this condition.161,200,246

Prevention and Control of Bleeding Episodes

Antihemophilic factor (human) and antihemophilic factor/von Willebrand factor complex (human) are used for the prevention and control of bleeding episodes in patients with hemophilia A.122,133,153,158,167 Antihemophilic factor concentrates are among several treatment options that can be used in the management of patients with hemophilia A.110,134,154,175,176,177,183,215,246 Desmopressin may be effective for the short-term control or prevention of bleeding in patients with mild to moderate hemophilia A who have plasma antihemophilic factor levels that are at least 5% of normal,134,154,160,175,177,183,215,246 and the Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation and other clinicians consider desmopressin the treatment of choice for these patients.134,154,160,175,177,183,246 Patients with mild to moderate hemophilia A who do not respond adequately to desmopressin and patients who have moderate to severe hemophilia A and plasma factor VIII levels less than 5% of normal generally require replacement therapy with an antihemophilic factor preparation.154,160,175,177,183,215,246

Several antihemophilic factor concentrates currently are available in the US for the treatment of hemophilia A; these include a variety of plasma-derived and recombinant preparations (e.g., antihemophilic factor [recombinant]; antihemophilic factor [human]; antihemophilic factor [recombinant], Fc fusion protein).246,248 Because these preparations vary based on characteristics such as purity, half-life, recovery, method of manufacture, viral removal and inactivation processes, potential immunogenicity, and other attributes, they are not pharmacologically or therapeutically equivalent.243 Among the commercially available antihemophilic factor concentrates, MASAC recommends preferential use of recombinant preparations because of their potentially superior safety profile with respect to pathogen transmission.218,246,247 Although improved viral depleting and donor screening practices have greatly reduced the risk of transmission of human immunodeficiency virus (HIV), hepatitis A virus (HAV), hepatitis B virus (HBV), and hepatitis C virus (HCV) with currently available plasma-derived antihemophilic factor preparations, these preparations are potentially capable of transmitting other disease agents such as nonenveloped viruses (e.g., parvovirus B19) and prions (e.g., causative agent for Creutzfeldt-Jakob disease [CJD] and variant CJD [vCJD]).215,247 (See Risk of Transmissible Agents in Plasma-derived Preparations under Cautions: Precautions and Contraindications.) In other hemophilia management guidelines (e.g., World Federation of Hemophilia), no preference is given for recombinant over plasma-derived factor concentrates; rather, these experts state that choice of preparation should be determined based on local criteria.215 When selecting an appropriate antihemophilic factor preparation for patients with hemophilia A, clinicians should consider the characteristics of each clotting factor concentrate in addition to individual patient variables, patient/provider preference, and emerging data.215,243,246,247 In all patients, the risk of pathogen transmission must be weighed against the benefits of therapy.247

Routine Prophylaxis of Bleeding Episodes

Antihemophilic factor concentrates also have been used for routine prophylaxis (i.e., administration at regular intervals on an ongoing basis) to prevent or reduce joint bleeding in individuals with severe hemophilia A.158,215,224,225,226,231 Such prophylaxis is considered the current standard of care for patients with hemophilia A.215,218 Routine administration of coagulation factor concentrates has been shown to decrease the frequency of spontaneous musculoskeletal bleeding, preserve joint function, and improve quality of life.215,231 Up to 25 years of experience with prophylactic treatment of patients with hemophilia A or B was documented in a study conducted in Sweden; the study showed that boys with severe hemophilia who were initiated on a prophylactic regimen at a young age (1-2 years of age) and given large doses of factor concentrates (2000-9000 units/kg annually) experienced virtually no bleeding, maintained normal joint structure, and were able to lead normal lives.224,231 Because of the observed benefits of prophylaxis, MASAC recommends that regular administration of clotting factor concentrates be considered in all individuals with severe hemophilia A (factor VIII activity less than 1%).218 Prophylaxis should be instituted at an early age (e.g., 1-2 years) prior to the onset of frequent bleeding; however, there are no clear guidelines as to when prophylaxis should be discontinued.218 Once prophylaxis is initiated, it may need to be continued indefinitely, unless the patient develops neutralizing antibodies (inhibitors) to factor VIII and/or there is a lack of response to the drug.218 When making treatment decisions regarding initiation of long-term prophylaxis, the risks and benefits of such a strategy should be evaluated and thoroughly discussed with the patient and/or their caregivers.218

For information on overall principles for treatment of hemophilia A and overall expert recommendations for such disease, see Choice of Antihemophilic Factor Preparations under Uses: Hemophilia A, in Antihemophilic Factor (Recombinant) 20:28.16.

Acquired Hemophilia A

Although antihemophilic factor (human) therapy in high doses may be effective in some patients with acquired hemophilia A† who have low levels of acquired factor VIII inhibitors,153,160,184,185,251 current evidence indicates that bypassing agents (e.g., anti-inhibitor coagulant complex, factor VIIa [recombinant]) are substantially more effective in achieving hemostatic control and are considered the treatment of choice in patients with this condition.179,184,213,214,251,253 Acquired hemophilia A is a rare disorder characterized by the spontaneous development of antibodies to factor VIII (autoantibodies) in patients who do not have congenital hemophilia A and who previously had normal plasma levels of antihemophilic factor.160,176,179,180,185,214 For further information on acquired hemophilia A, see Uses: Acquired Hemophilia A, in Antihemophilic Factor [Recombinant] 20:28.16.

von Willebrand Disease

Antihemophilic factor/von Willebrand factor complex (human) preparations are used when necessary to prevent or control bleeding in patients with von Willebrand disease.122,133,161,201,244,246,250 These factor concentrates are used for the treatment of spontaneous or trauma-induced bleeding episodes and for the prevention of excessive bleeding during and after surgery in patients with severe von Willebrand disease or when use of desmopressin is inadequate or contraindicated.122,133 Antihemophilic factor/von Willebrand factor complex (human) is designated an orphan drug by FDA for use in the treatment of von Willebrand disease.169

Although certain preparations of antihemophilic factor (human) (e.g., Koate^®-DVI) that contain naturally occurring von Willebrand factor as part of the manufacturing process have been used in selected patients with von Willebrand disease†,161,201,244,246 antihemophilic factor preparations containing little or no von Willebrand factor generally are not useful in the treatment of this disease.250

While desmopressin generally is the treatment of choice for the management of type 1 von Willebrand disease, many experts recommend the use of von Willebrand factor-containing concentrates in patients with type 1 disease who are unresponsive to or cannot take (e.g., because of a contraindication) desmopressin.133,161,201,244,246,250 von Willebrand-containing factor concentrates also are recommended in individuals with type 2A, 2M, or 2N von Willebrand disease who do not respond to desmopressin.161,201,246 In addition, since desmopressin usually is not used in patients with type 2B disease (because of the risk for thromboembolic events) and is not indicated in patients with type 3 disease (because the drug has not been shown to be effective), a von Willebrand-containing factor concentrate should be used if prevention or control of bleeding is necessary in such patients.161,201,244,246,250 However, the manufacturer of antihemophilic factor/von Willebrand factor complex (human) (Alphanate^®) states that this preparation should not be used in patients with severe type 3 von Willebrand disease undergoing major surgery because of a lack of demonstrated efficacy in such patients.122,232 von Willebrand factor-containing concentrates also may be particularly useful in the management of von Willebrand disease in children younger than 2 years of age who generally do not respond as well to desmopressin as older pediatric patients.246,250 Cryoprecipitate should not be used in the management of patients with von Willebrand disease except in emergency, life- or limb-threatening situations when von Willebrand factor concentrates are not available.161,246

Reconstitution and Administration

Antihemophilic factor (human) and antihemophilic factor/von Willebrand factor complex (human) are administered by slow IV injection or by IV infusion over several minutes.122,133,153,158,167 (See Rate of Administration under Dosage and Administration: Reconstitution and Administration.) Coagulation factor concentrates also have been given by continuous IV infusion†.228,229,230

Antihemophilic factor (human) and antihemophilic factor/von Willebrand factor complex (human) should be filtered before administration; filter needles or filter transfer sets are provided with all commercially available preparations.122,133,153,158,167,215 Only plastic syringes should be used to prepare and administer the drugs since the solutions tend to stick to ground surfaces of glass syringes.122,133,153,167

Antihemophilic factor concentrates may be self-administered in medically supervised home treatment programs for hemophilia A after appropriate training is provided.215

Instructions on reconstitution, dilution, and administration of antihemophilic factor (human) and antihemophilic factor/von Willebrand factor complex (human) vary according to the specific preparation; the manufacturer's labeling should be consulted for detailed information on individual preparations.122,133,153,158,167 Prior to reconstitution, the lyophilized powder for injection and diluent supplied by the manufacturer should be warmed to room temperature (not exceeding 37°C).122,133,153,158,167 After addition of the diluent, the vial should be gently swirled or rotated until the concentrate is completely dissolved; the vial should not be shaken.122,133,153,167 Some preparations (e.g., Monoclate-P^®) easily reconstitute within 1 minute,167 while complete dissolution of other preparations may require up to 5 minutes.122

Reconstituted solutions of antihemophilic factor (human) or antihemophilic factor/von Willebrand factor complex (human) should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.122,153,158,167 The drug should be administered within 3 hours after reconstitution to ensure sterility of the preparation.122,133,153,158,167 The reconstituted preparations should not be refrigerated, and the solution should not be at a temperature less than room temperature during infusion because precipitation of the active ingredients may occur.122,133,153,158

Rate of Administration

The rate of administration of antihemophilic factor (human) and antihemophilic factor/von Willebrand factor complex (human) should be individualized according to the patient's response.122,158,167 One manufacturer states that the pulse rate should be determined before and during IV administration; if there is a substantial increase in pulse rate, the rate of administration should be reduced or administration should be temporarily stopped.153

Alphanate^® and Hemofil^® M should be administered at a rate not exceeding 10 mL/minute.122,153 High rates of administration may result in vasomotor reactions.122

Humate-P^® should be administered at a rate not exceeding 4 mL/minute.133

Koate^®-DVI generally is well tolerated when the entire dose of the drug is given over 5-10 minutes.158

Monoclate-P^® should be administered at a rate that is comfortable for the patient, approximately 2 mL/minute.167

Dosage

Dosage of antihemophilic factor (human) and antihemophilic factor/von Willebrand factor complex (human) is expressed in terms of international units (IU, units);122,133,153,158,167 1 unit of antihemophilic factor is approximately equivalent to the amount of factor VIII in 1 mL of fresh pooled human plasma.122,133,158,167 In general, administration of 1 unit/kg of these antihemophilic factor preparations will increase the circulating factor VIII level by approximately 2 units/dL (2%).122,133,153,167

Prevention and Control of Bleeding Episodes in Hemophilia A

Dosage and duration of antihemophilic factor (human) or antihemophilic factor/von Willebrand factor complex (human) therapy should be individualized based on the degree of deficiency of antihemophilic factor (coagulation factor VIII), desired factor VIII level, weight of the patient, type and severity of bleeding, presence of factor VIII inhibitors, and the patient's clinical and pharmacokinetic (e.g., half-life, in vivo recovery) response.122,133,158,167,215 The dosage required to establish hemostasis will vary with each patient and circumstance since there is considerable variability among patients and their clinical conditions.122,133,158,167,215 Dosage should be carefully individualized based on coagulation studies performed prior to therapy and at regular intervals during treatment.122,133,153,158

The following formulas may be used to calculate the approximate percentage increase in plasma factor VIII levels expected from a given dose, or the dose required to achieve a particular percentage increase in the plasma factor VIII level:122,153,158,167

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

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

The desired factor VIII level is determined by the clinical situation and severity of bleeding.122,133,153,158 For recommendations on target factor VIII levels, see the individual preparation-specific dosage sections below. These calculations and the suggested dosage regimens that follow are only approximations and should not preclude appropriate clinical monitoring and laboratory determinations of factor VIII levels.122,133,153,158 It is strongly recommended that serial assays of factor VIII be performed at suitable intervals to ensure that adequate factor VIII levels have been attained and maintained.122,133,153,158,167 The patient's factor VIII activity should be measured after a dose is given to verify calculated doses.215 (See Cautions: Neutralizing Antibodies to Factor VIII.)

Careful control of the dose is especially important in cases of life-threatening bleeding or major surgery.122,153 If the calculated dosage is ineffective in achieving adequate factor VIII levels or if bleeding is not controlled, the presence of inhibitors to antihemophilic factor should be suspected.122,153,215 (See Neutralizing Antibodies to Factor VIII under Cautions: Systemic Effects, in Antihemophilic Factor [Recombinant] 20:28.16) Higher than recommended dosages of antihemophilic factor concentrates may be required to achieve hemostasis in patients with inhibitors.122,153,158

Alphanate®

For the treatment of minor bleeding (e.g., large bruises, substantial cuts or scrapes, uncomplicated joint bleeding) in adults and adolescents older than 16 years of age, the manufacturer of Alphanate^® recommends a dosage of 15 units/kg twice daily to achieve plasma factor VIII levels of 30% of normal.122 Treatment should be continued until bleeding stops and healing has been achieved (1-2 days).122

For the treatment of moderate bleeding (e.g., epistaxis, mouth and gum bleeding, tooth extraction, hematuria) in adults and adolescents older than 16 years of age, the manufacturer of Alphanate^® suggests a dosage of 25 units/kg twice daily to achieve plasma factor VIII levels of 50% of normal.122 Treatment should be continued until healing has been achieved (average 2-7 days).122

For the treatment of major bleeding (e.g., joint or muscle bleeding, major trauma, hematuria, intracranial and intraperitoneal bleeding) in adults and adolescents older than 16 years of age, an Alphanate^® dosage of 40-50 units/kg twice daily for at least 3-5 days is recommended to achieve plasma factor VIII levels of 80-100% of normal.122 Additional doses of 25 units/kg twice daily should be given to maintain plasma factor VIII levels at 50% of normal until healing is achieved; up to 10 days of treatment may be required for major bleeding events.122 An even longer duration of therapy (up to 6 months) may be required for the treatment of intracranial hemorrhage to prevent recurrence of bleeding.122

For surgical procedures in adults and adolescents older than 16 years of age, plasma factor VIII levels should be increased to approximately 80-100% of normal by administering a preoperative Alphanate^® dose of 40-50 units/kg.122 Additional doses of 30-50 units/kg should be given twice daily for 7-10 days (or until healing is complete) to maintain plasma factor VIII levels of 60-100% of normal.122

Hemofil M®

For the treatment of early hemarthrosis or muscle bleeding or oral bleeding, the manufacturer of Hemofil M^® recommends that doses be given to achieve peak postinfusion levels of factor VIII that are 20-40% of normal.153 To maintain adequate levels, doses should be given every 12-24 hours for 1-3 days until the bleeding episode resolves (indicated by relief of pain) or healing is achieved.153

For more extensive hemarthrosis, muscle bleeding, or hematoma, the manufacturer recommends that doses of Hemofil M^® be given to achieve peak postinfusion levels of factor VIII that are 30-60% of normal.153 Doses should be given every 12-24 hours for 3 days or longer until pain and disability resolve.153

For life-threatening bleeding (e.g., head injury, throat bleeding, severe abdominal pain), the manufacturer recommends that doses of Hemofil M^® be given to achieve peak postinfusion levels of factor VIII that are 60-100% of normal.153 Doses should be given every 8-24 hours until the threat is resolved.153

For minor surgery, including tooth extraction, the manufacturer recommends that doses of Hemofil M^® be given to achieve peak postinfusion levels of factor VIII that are 60-80% of normal.153 In approximately 70% of cases, this level is achieved with a single dose of Hemofil M^® given in conjunction with oral antifibrinolytic therapy administered within 1 hour of the procedure.153

For major surgery, the manufacturer recommends that doses of Hemofil M^® be given to achieve pre- and postoperative levels of factor VIII that are 80-100% of normal.153 Doses should be repeated every 8-24 hours depending on the patient's state of healing.153

Humate-P®

For the treatment of minor bleeding (early joint or muscle bleed, severe epistaxis), the manufacturer recommends a loading dose of 15 units/kg of Humate-P^® to achieve plasma factor VIII levels of approximately 30% of normal.133 A single dose may be sufficient; if necessary, doses equal to 50% of the loading dose may be given once or twice daily for 1-2 days.133

For the treatment of moderate bleeding (advanced joint or muscle bleed; neck, tongue, or pharyngeal hematoma without airway compromise; tooth extraction; severe abdominal pain), the manufacturer of Humate-P^® recommends a loading dose of 25 units/kg to achieve plasma factor VIII levels of approximately 50% of normal, followed by 15 units/kg every 8-12 hours for the first 1-2 days to maintain plasma levels at 30% of normal.133 Thereafter, the same dose may be given once or twice daily for a total of up to 7 days or until adequate wound healing.133

For the treatment of life-threatening bleeding (major surgery; GI bleeding; neck, tongue, or pharyngeal hematoma with potential for airway compromise; intracranial, intra-abdominal, or intrathoracic bleeding; fractures), the manufacturer of Humate-P^® recommends an initial dose of 40-50 units/kg followed by 20-25 units/kg every 8 hours to maintain plasma factor VIII levels at 80-100% of normal for 7 days.133 Thereafter, the same dose may be given once or twice daily for another 7 days to maintain plasma levels at 30-50% of normal.133

Adequate and well-controlled studies evaluating use of Humate-P^® in pediatric patients are not available; when immediate control of bleeding is necessary in a pediatric patient, the manufacturer recommends that the general recommendations for dosage and administration in adults be considered.133

Koate®-DVI

The manufacturer of Koate^®-DVI makes the following general dosage recommendations.158

Mild superficial or early bleeding may respond to a single Koate^®-DVI dose of 10 units/kg, which should result in an in vivo increase in plasma factor VIII levels of approximately 20%.158 Additional doses are not necessary unless there is evidence of further bleeding.158

For more serious bleeding episodes (e.g., definite hemarthroses, known trauma), a Koate^®-DVI dose of approximately 15-25 units/kg should result in a 30-50% increase in plasma factor VIII levels.158 If additional therapy is required, additional doses of 10-15 units/kg may be given every 8-12 hours.158

In patients with life-threatening bleeding or possible hemorrhage involving vital structures (e.g., CNS, retropharyngeal and retroperitoneal spaces, iliopsoas sheath), plasma factor VIII levels should be increased to 80-100% of normal.158 This usually can be achieved with an initial dose of Koate^®-DVI of 40-50 units/kg and a maintenance dosage of 20-25 units/kg every 8-12 hours.158

For major surgical procedures, plasma factor VIII levels should be increased to approximately 100% of normal by administering a preoperative Koate^®-DVI dose of 50 units/kg.158 Factor VIII levels should be checked to verify that the expected level is achieved prior to surgery and additional levels measured throughout the perioperative period of major procedures to ensure adequate replacement therapy.158 Additional doses may be necessary every 6-12 hours initially, and for a total of 10-14 days until healing is complete.158 The 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.158

Monoclate-P®

The manufacturer states that a single infusion of Monoclate-P^® may be sufficient to achieve plasma factor VIII levels of at least 30% of normal for minor bleeding episodes.167 For the treatment of moderate bleeding and for minor surgical procedures, the manufacturer states that an initial dose of 15-25 units/kg may be adequate to achieve a plasma factor VIII level of 30-50% of normal and, if further treatment is required, a maintenance dosage of 10-15 units/kg may be given every 8-12 hours.167 For severe bleeding (e.g., bleeding near vital organs such as the neck, throat, and subperitoneal region), the manufacturer recommends an initial dose of 40-50 units/kg and a maintenance dosage of 20-25 units/kg given every 8-12 hours to achieve plasma factor VIII levels of 80-100% of normal.167

For major surgical procedures, the manufacturer suggests that an initial dose of antihemophilic factor (human) sufficient to achieve a plasma factor VIII level of 80-100% of normal be given 1 hour before surgery and that a second dose equal to one-half the initial dose be given 5 hours later.167 The plasma level of factor VIII should be maintained at a daily minimum of at least 30% of normal for 10-14 days postoperatively.167

Routine Prophylaxis of Bleeding Episodes in Hemophilia A

Various dosing protocols have been recommended for routine prophylaxis with antihemophilic factor concentrates; the optimal regimen remains to be established.215,218,225,231 A dosage of 25-40 units/kg every other day (minimum 3 times a week) usually is recommended for prophylaxis.215,218,231 The Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation 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 above 1% of normal between infusions.218 Prophylaxis should be instituted at a young age (e.g., 1-2 years) prior to the onset of frequent bleeding; however, the optimum duration of prophylaxis is not known.218 Patients should be reevaluated periodically to determine the need for continued therapy; some patients may require life-long prophylaxis.218

von Willebrand Disease

Dosage and duration of antihemophilic factor/von Willebrand factor complex (human) therapy for the treatment of patients with von Willebrand disease should be individualized based on the degree of deficiency of von Willebrand factor, the location and extent of bleeding, and the patient's clinical and pharmacokinetic (e.g., in vivo recovery) response.122,133 Dosage of antihemophilic factor/von Willebrand factor complex (human) for the treatment of von Willebrand disease is expressed in terms of international units (IU, units) of von Willebrand factor: Ristocetin cofactor (vWF:RCo).122,133 One unit of vWF:RCo is approximately equivalent to the amount of vWF:RCo in 1 mL of fresh pooled human plasma.122,133 The amount of vWF:RCo activity contained in each vial of antihemophilic factor/von Willebrand factor complex (human) is indicated on the label.122,133

Alphanate®

The manufacturer states that the ratio of vWF:RCo to factor VIII varies depending on the manufacturing lot.122 Therefore, dosage of Alphanate^® for management of von Willebrand disease should be reevaluated whenever a different manufacturing lot is indicated on the vial.122

When Alphanate^® is used in adults with von Willebrand disease who are undergoing a minor surgical or invasive procedure, the manufacturer recommends a preoperative dose of 60 units/kg of vWF:RCo followed by additional doses of 40-60 units/kg of vWR:RCo every 8-12 hours as clinically needed for 1-3 days to achieve a target factor VIII level of 40-50%.122 In adults with type 1 or type 2 von Willebrand disease undergoing a major surgical or invasive procedure, a preoperative dose of Alphanate^® 60 units/kg of vWF:RCo is recommended to achieve a target factor VIII level of 100%; subsequent doses of 40-60 units/kg of vWR:RCo should be administered every 8-12 hours as clinically needed for at least 3-7 days to maintain factor VIII levels at 100%.122 Alphanate^® is not recommended in patients with type 3 von Willebrand disease undergoing major surgery.122 (See Uses: von Willebrand Disease.)

When Alphanate^® is used in pediatric patients with von Willebrand disease undergoing a minor surgical or invasive procedure, the manufacturer recommends a preoperative dose of 75 units/kg of vWF:RCo followed by additional doses of 50-75 units/kg of vWR:RCo every 8-12 hours as clinically needed for 1-3 days to achieve target factor VIII levels of 40-50%.122 In pediatric patients with von Willebrand disease (except type 3) undergoing a major surgical or invasive procedure, the manufacturer recommends a preoperative dose of 75 units/kg of vWF:RCo to achieve a target factor VIII level of 100%; additional doses of 50-75 units/kg of vWR:RCo every 8-12 hours should be given as clinically needed for at least 3-7 days to maintain factor VIII levels at 100%.122

In all patients receiving Alphanate^® for surgical hemostasis, the manufacturer recommends that peak and trough factor VIII and vWR:RCo levels be monitored at least once daily, with the therapeutic goal of maintaining trough levels higher than 50%; levels should not exceed 150%.122

Humate-P®

When Humate-P^® is used for the treatment of von Willebrand disease, dosage should be adjusted according to the extent and location of bleeding.133 In general, Humate-P^® is given in a dosage of 40-80 units/kg of vWF:RCo (corresponding to 17-33 units/kg of antihemophilic factor) every 8-12 hours; repeat doses are administered for as long as needed based on monitoring of appropriate clinical and laboratory measures.133 Expected levels of vWF:RCo are based on an expected in vivo recovery of 2 units/dL increase per unit/kg of vWF:RCo administered.133 Administration of 1 unit/kg of antihemophilic factor can be expected to result in an increase in circulating vWF:RCo of approximately 5 units/dL.133 The manufacturer of Humate-P^® makes the following general dosage recommendations for the treatment of patients with von Willebrand disease based on the type of disease (type 1, 2, or 3) and severity of bleeding.133 In all patients with major bleeding in whom repeated dosing is required, factor VIII levels should be monitored and maintained according to the usual guidelines for patients with hemophilia A.133

For patients with mild type 1 von Willebrand disease (baseline vWF:RCo activity typically exceeding 30%) who have major bleeding (e.g., severe or refractory epistaxis, GI bleeding, CNS trauma, traumatic bleeding) or minor bleeding in whom desmopressin is known or suspected to be inadequate, a loading dose of Humate-P^® of 40-60 units/kg of vWF:RCo is recommended followed by 40-50 units/kg of vWF:RCo every 8-12 hours for 3 days to keep the trough level of vWF:RCo exceeding 50%.133 Then, 40-50 units/kg of vWF:RCo can be given daily for a total of up to 7 days of treatment.133

For patients with moderate or severe type 1 von Willebrand disease (baseline vWF:RCo activity typically less than 30%) who have minor bleeding (e.g., epistaxis, oral bleeding, menorrhagia), the recommended dosage of Humate-P^® is 40-50 units/kg of vWF:RCo (1 or 2 doses).133 If these patients have major bleeding (e.g., severe or refractory epistaxis, GI bleeding, CNS trauma, hemarthrosis or traumatic bleeding), a loading dose of Humate-P^® of 50-75 units/kg of vWF:RCo is recommended, followed by 40-60 units/kg of vWF:RCo every 8-12 hours for 3 days to keep the trough level of vWF:RCo exceeding 50%.133 Then, 40-60 units/kg of vWF:RCo can be given daily for a total of up to 7 days of treatment.133

For patients with type 2 (all variants) or type 3 von Willebrand disease who have minor bleeding, the recommended dosage of Humate-P^® is 40-50 units/kg of vWF:RCo (1 or 2 doses).133 If these patients have major bleeding, a loading dose of Humate-P^® of 60-80 units/kg of vWF:RCo is recommended, followed by 40-60 units/kg of vWF:RCo every 8-12 hours for 3 days to keep the trough level of vWF:RCo exceeding 50%.133 Then, 40-60 units/kg can be given daily for a total of up to 7 days of treatment.133

For prevention of excessive bleeding during and after surgery in patients with von Willebrand disease, dosages of Humate-P^® should be calculated based on incremental in vivo recovery (IVR) values whenever possible.133 However, in cases of emergency surgery, a loading dose of 50-60 units/kg of vWF:RCo is recommended followed by close monitoring of the patient's trough coagulation factor levels.133 Determination of IVR requires measurement of the baseline plasma vWF:RCo level and the plasma vWF:RCo level 30 minutes following a calculated dose.133 The following formulas are used to calculate IVR and loading doses of Humate-P^®.133 If individual IVR values are not available, a loading dose can be calculated based on an assumed IVR of 2% per unit/kg of vWF:RCo.133

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

Loading dose (units of vWF:RCo) = [(Target peak plasma vWF:RCo - baseline plasma vWF:RCo) x body weight (in kg)]/IVR

The manufacturer recommends that Humate-P^® be dosed to achieve specific target peak and trough plasma levels of vWF:RCo and factor VIII to maintain adequate hemostasis during and after surgery.133 Trough levels of vWF:RCo and factor VIII should be monitored at least once daily and during and after surgery to avoid excessive accumulation of such clotting factors.133 Because factor VIII is the main predictor of surgical hemostasis, some clinicians recommend that factor VIII levels be monitored every 12 hours on the day an antihemophilic factor dose is given, then every 24 hours thereafter.244 Dose and/or frequency of Humate-P^® administration should be adjusted if hemostasis is insufficient or measured trough coagulation factor levels are outside the recommended range.133

When Humate-P^® is used in patients with von Willebrand disease who are undergoing major surgery, a loading dose should be administered (1-2 hours before surgery) to achieve a target peak plasma vWF:RCo level of 100% and a target peak plasma factor VIII level of 80-100%.133 Additional doses may be required to achieve recommended target peak factor VIII levels; because of a higher ratio of vWF:RCo to factor VIII activity (2.4 to 1), vWF:RCo will increase proportionally more than factor VIII with increasing doses.133 The initial maintenance dose should be one-half the loading dose (irrespective of any additional loading doses that may have been required to meet factor VIII target goals).133 Subsequent maintenance doses should be given to achieve target trough vWF:RCo levels exceeding 50% (exceeding 50% factor VIII activity) for up to 3 days following major surgery and target trough vWF:RCo levels exceeding 30% (exceeding 30% factor VIII activity) after day 3.133

For patients with von Willebrand disease undergoing minor surgery (including oral surgery), a loading dose of Humate-P^® should be administered (1-2 hours before surgery) to achieve a target peak plasma vWF:RCo level of 50-60% and a target peak plasma factor VIII level of 40-50%.133 The initial maintenance dose should be one-half the loading dose (irrespective of any additional loading doses that may have been required to meet factor VIII target goals).133 Subsequent maintenance doses should be given to achieve target trough plasma vWF:RCo levels of at least 30% for up to 3 days following minor surgery and target trough factor VIII levels exceeding 30% after day 3.133

The frequency of Humate-P^® administration for treatment of von Willebrand disease in patients undergoing surgery is dependent on individual pharmacokinetic parameters (e.g., half-life of vWF:RCo); in the absence of pharmacokinetic data, the manufacturer recommends a dosing frequency of every 8 hours initially with further adjustments based on trough coagulation factor levels.133 Duration of therapy generally depends on the type of surgery performed, but should be determined individually for each patient based on hemostatic response.133 The manufacturer recommends a minimum duration of therapy of 72 hours for major surgery, 48 hours for minor surgery, and 8-12 hours for oral surgery.133

Sensitivity Reactions

The most common adverse effects of antihemophilic factor (human) and antihemophilic factor/von Willebrand factor complex (human) are allergic or anaphylactic reactions including urticaria, chest tightness, rash, pruritus, edema, anaphylaxis, and shock.122,133,153,158,167

Neutralizing Antibodies to Factor VIII

Patients with hemophilia A have developed neutralizing antibodies (inhibitors) to factor VIII following treatment with antihemophilic factor-containing preparations.110,122,134,160,179,180,181,182,194,215,255 Antihemophilic factor inhibitors are IgG immunoglobulins and circulating antibodies that neutralize the procoagulant activity of antihemophilic factor.110,122,134,160,176,179,180,181,182 Such inhibitors have been reported to occur in about 20-30% of patients with severe hemophilia A and about 5-10% of those with mild or moderate disease.215 The risk of developing inhibitors is dependent on a variety of factors, including genetic predisposition and the extent of exposure to factor VIII, with risk highest within the first 20 days of exposure.153,215 Administration of antihemophilic factor (human) to patients who already have antihemophilic factor antibodies may result in anamnestic responses and increased levels of inhibitor following infusion of the drug.160,176,179,180,182,194 (See Neutralizing Antibodies to Factor VIII under Cautions: Precautions and Contraindications.)

Antibodies to Nonmammalian Proteins

The principal protein contained in Hemofil^® M is albumin human.153 Adverse reactions associated with IV administration of albumin are rare; however, nausea, fever, chills, and urticaria have been reported in patients receiving the protein.153 Hemofil^® M and Monoclate-P^® also contain trace amounts of murine (mouse) protein, which may stimulate antibody formation in some patients.153,167 Limited experience to date suggests that the frequency of antibody formation during therapy with these preparations is low and may not be associated with clinically evident effects.153,167 Some patients may have evidence of antibody to murine protein prior to initiation of therapy, and the possibility of false-positive results secondary to cross-reactive proteins (e.g., rheumatoid factor) should be considered.153,167 Although hypersensitivity reactions to these murine proteins have not been reported to date, the possibility that such reactions could occur during therapy with Hemofil^® M or Monoclate-P^® should be considered.153,167

Other Adverse Effects

Other adverse effects that have occurred in patients receiving these factor concentrates include headache,122,158 paresthesia,122,133,158 nausea,122,153,158,167 vomiting,122 abdominal pain,158 jittery feeling,158 pain,122 somnolence,122 lethargy,122 disturbance of vision,158 mild vasodilation,122 joint pain,122 fatigue,122 respiratory distress,122 fever,122,153 chills,122,153 pharyngitis,122 and stinging at the infusion site.122,167

Massive doses of antihemophilic factor (human) (Alphanate^®) have rarely resulted in acute hemolytic anemia, increased bleeding tendency, or hyperfibrinogenemia.122 Thromboembolic events have occurred in patients with von Willebrand disease and other thrombotic risk factors receiving coagulation factor replacement therapy; early reports suggest that the risk of thromboembolism may be higher in females.122,133

The most common adverse events occurring in patients receiving Humate-P^® for prevention of excessive bleeding during and after surgery include postoperative bleeding and epistaxis.133

Precautions and Contraindications

Antihemophilic factor (human) preparations should only be administered to patients in whom a deficiency in the specific clotting factor has been demonstrated, and such deficiencies should be confirmed prior to initiating therapy.153,158 Antihemophilic factor/von Willebrand factor complex (human) therapy should be initiated under the supervision of a clinician experienced in the treatment of hemophilia A or von Willebrand disease.122

Risk of Transmissible Agents in Plasma-derived Preparations

Various heat-treatment processes, chemical (solvent/detergent) inactivation procedures, and/or immunoaffinity chromatography procedures are used during the manufacture of currently available antihemophilic factor (human) preparations in an attempt to reduce the viral infectious potential of these plasma-derived preparations.122,133,153,158,167 The safety provided by the various heat-treatment processes depends on the heating temperature, duration of heating, and the moisture content of the product during heating.150,156,159,170,173 Other factors unique to the manufacturing processes (e.g., use and nature of stabilizers, other proteins present) may also affect the margin of safety provided by the manufacturing process used for each product.150,159 Viral attenuation methods used in the production of currently available antihemophilic factor (human) preparations that appear to be effective in reducing the risk for transmission of viral infections are heat in aqueous solution (pasteurization), solvent/detergent treatment, and/or immunoaffinity purification.246

Although improved viral depleting and donor screening practices have greatly reduced the risk of transmission of human immunodeficiency virus (HIV), hepatitis A virus (HAV), hepatitis B virus (HBV), and hepatitis C virus (HCV) with currently available plasma-derived antihemophilic factor preparations, no method has been shown to be totally effective in removing the risk of viral infectivity from coagulation factor preparations derived from pooled human plasma and there is still a possibility of human viral transmission from these preparations.122,133,153,154,158,167,183,246,247

Although transmission of viruses that do not have a lipid envelope, such as parvovirus B19 and HAV, have occurred with commercially available plasma-derived clotting factor concentrates, the risk has been reduced with additional viral attenuation methods such as nanofiltration.133,167,195,153,246,247 Nevertheless, patients receiving clotting factor concentrates should be informed of the potential for transmission of viral infections such as parvovirus B19 or hepatitis A infection and immediately report any manifestations of 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) to a clinician.122,133,153,158,167

Although there has been no evidence to date of such transmission, it has been suggested that plasma-derived preparations are potentially capable of transmitting unknown viruses or other disease agents, such as prions (e.g., causative agents for Creutzfeldt-Jakob disease [CJD] or variant CJD [vCJD]).174,196,199,200,202,246,247 Parvovirus B19 and prions also may be markers for other blood-borne infectious agents that have not yet been discovered or recognized.247

Clinicians should carefully weigh the risk of pathogen transmission versus benefits of antihemophilic factor (human) therapy prior to use of the drug.122,153,158,247 Any suspected infections associated with antihemophilic factor (human) therapy should be reported to the manufacturer, FDA, and to the Centers for Disease Control and Prevention (CDC).122,133,153,158,167,246

Risk of Hepatitis

Because antihemophilic factor (human) is prepared from pooled plasma, it may contain the causative agents of viral hepatitis.122,133,153,158,167 Although plasma used in preparation of antihemophilic factor (human) has been tested and shown to be negative for HBV and HCV and all currently available antihemophilic factor (human) preparations undergo heat-treatment and/or chemical (solvent/detergent) procedures during manufacturing in an attempt to reduce viral infectious potential, no method has been shown to be totally effective in removing hepatitis infectivity.116,117,121,132,133,143,148,150,153,156,158,159,167,170,246 There is evidence of transmission of hepatitis A from chemical-inactivated (solvent/detergent) preparations of antihemophilic factor (human) prepared and distributed outside the US.195,198 Seroconversion for antibody to hepatitis A virus also was reported in a few recipients of a similar preparation marketed in the US and in at least one patient who received a factor IX (human) preparation inactivated by a chemical (solvent/detergent) process.151,198

Active immunization against HBV using hepatitis B vaccine is recommended by the American Academy of Pediatrics (AAP) and other experts for all children, and is particularly important for patients with hemophilia and other congenital bleeding disorders.197,246 It is recommended that hepatitis B vaccination be initiated at birth or at the time of diagnosis.122,133,150,158,174,246 (See Hepatitis B Vaccine 80:12.)

Immunization against HAV with hepatitis A virus vaccine inactivated is recommended for all individuals 1 year of age or older with hemophilia or other congenital bleeding disorders who are HAV seronegative.133,233,235,246 (See Hepatitis A Virus Vaccine Inactivated 80:12.)

Risk of HIV Infection

Antihemophilic factor (human) is a potential vehicle for transmission of HIV.246 Although HIV seroconversion occurred in some hemophilia patients in the past who have received blood transfusions and/or coagulation factor concentrates, including antihemophilic factor (human), that were obtained from donors who had not been screened for HIV and/or were prepared using a suboptimal viral-inactivating procedure (e.g., heat-treatment only),100,101,102,107,127,136,142,147,148,149 there now is considerable evidence that improved viral-depleting processes and improved donor screening practices used in the manufacture of currently available preparations of antihemophilic factor (human) have resulted in products with greatly reduced risk for transmission of HIV.246

Data obtained during the period prior to the availability of effective viral-inactivating procedures and specific HIV donor screening procedures indicate that the prevalence of HIV seropositivity in patients with coagulation disorders requiring plasma-derived coagulation factor concentrates varied according to type and severity of the disorder, with an overall prevalence of about 70%137 (reported range: 33-92%)142 in hemophilia A patients and about 35%137 (reported range: 14-52%)142 in hemophilia B patients. In antihemophilic factor (human) recipients, seropositivity appeared to be associated with more severe hemophilia,114,144 greater antihemophilic factor dosage received,114,127,144 elevated immunoglobulin and immune complex levels,114 and lower CD4⁺ T-cell counts.114,127,131,136 The total number of hemophiliacs who developed clinical manifestations of acquired immunodeficiency syndrome (AIDS) during that period was relatively small compared with other high-risk groups,128,129 but the incidence rates were high (a cumulative incidence estimated at 3% for patients with hemophilia A and 1% for those with hemophilia B in the US as of September 1987)142 and continued surveillance is important.100,129,136,138,143,144,149 In addition, the cumulative AIDS incidence for seropositive hemophiliacs varies regionally, being calculated to be as high as 18% six years after seroconversion in one US hemophilia treatment center.136,142 In addition, the incidence rate of AIDS in patients with hemophilia A was approximately 3-6 times greater than the incidence rate in patients with hemophilia B,100,129,142 and the incidence rate among patients with hemophilia A increased with the severity of factor VIII deficiency.129

Although HIV seroconversion has occurred in several patients receiving previously available heat-treated coagulation factor concentrates138,139,140,146,148,149,150 (including concentrates manufactured from plasma that had undergone serologic testing for HIV141,149 as well as those that had not),138,140 and has occurred in a few patients who had been treated exclusively with heat-treated concentrates,138,149 there have been no reports to date of HIV seroconversion associated with any of the currently available antihemophilic factor (human) preparations. 246 However, the possibility of transmission of HIV-1 or HIV-2 with use of currently available viral-inactivated plasma-derived products still remains.246

Risk of Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease

Because antihemophilic factor (human) is prepared from human blood, it theoretically may carry a risk of transmitting the causative agent of Creutzfeldt-Jakob disease (CJD) or variant CJD (vCJD).122,174,202,247 There have been 3 probable cases of vCJD acquired through transfusion of human red blood cells (RBCs) identified by an ongoing epidemiologic review being conducted in the United Kingdom.174,219 One of these patients developed symptoms of vCJD 6.5 and 7.8 years, respectively, after receiving non-leukodepleted RBCs from 2 different donors; the donors developed clinical symptoms approximately 40 and 21 months after donating.219 The third probable case of transfusion-associated vCJD had no clinical symptoms of the disease prior to death, but abnormal prion protein was found in postmortem lymphoid tissue (5 years after RBC transfusion); the donor involved in this case had made the RBC donation 18 months before the onset of their clinical symptoms.219 Although attempts to transmit CJD to nonhuman primates via blood transfusion have failed, bovine spongiform encephalopathy (BSE) has been transmitted to at least one sheep through blood transfusion.202,203

There is no evidence to date that CJD or vCJD has been transmitted by plasma-derived preparations such as antihemophilic factor (human); however, MASAC states that every effort should be made to make recombinant clotting factors available to all who would benefit from them and that all barriers to conversion from human plasma-derived concentrates to recombinant clotting factors should be removed.247

Tests are being developed to detect CJD and vCJD infection in blood and plasma donors.202 Until such donor screening tests are available for these diseases, the FDA has recommended interim preventive measures that include specific guidelines for deferral of blood and plasma donors with possible exposure to CJD and vCJD that are based on geographic considerations and guidelines for product retrieval, quarantine, and disposition that are based on consideration of risk in the donor and product and the effect that withdrawals and deferrals might have on the supply of blood, blood components, and plasma derivatives.202 For further information on CJD and vCJD precautions related to blood and blood products, the FDA's guidance for industry should be consulted ([Web]).202

Risk of West Nile Virus Infection

There is evidence that West Nile Virus (WNV) can be transmitted in transplanted organs (e.g., heart, liver, kidney) and blood products (e.g., whole blood, packed red blood cells, fresh frozen plasma).205,208,209,211,237 WNV has been isolated from frozen plasma obtained from a blood donor subsequently found to have WNV, indicating that the virus can survive in frozen blood components.237 It is unlikely that WNV would be transmitted through commercially available plasma-derived preparations of clotting factors since WNV is an enveloped virus, like HCV, which is known to be inactivated by the heat and solvent/detergent viral inactivation procedures used in the manufacture of these preparations.207,237

Since 2005, several FDA-approved nucleic acid tests have become available to screen donated blood for WNV; when potential donors test positive for WNV infection using one of these licensed donor screening tests, blood donation should be deferred for 120 days.211,237 The FDA also recommends additional measures to assess donor suitability to help screen out potential blood donors who have past or present manifestations that suggest WNV illness.237 When potential donors have a medical diagnosis of WNV infection or there is suspicion of WNV infection (including diagnosis based on symptoms and/or laboratory results), blood donation should be deferred for 120 days after diagnosis or onset of illness with headache, whichever occurs later.237 In addition, when donors report an otherwise unexplained febrile illness with headache or other symptoms suggestive of WNV infection (i.e., flu-like symptoms that include fever with headache, eye pain, body aches, generalized weakness, new skin rash or swollen lymph nodes or other evidence of WNV infection) within 2 weeks after donation during the typical WNV season (or at other times if there is evidence of local WNV activity), deferment for 120 days following onset of illness is recommended.237 Deferment also is recommended for individuals whose blood or blood components were potentially associated with a transfusion-related WNV transmission.237 These recommendations apply to whole blood and blood components intended for transfusion and blood components, including recovered plasma, source leukocytes, and source plasma, intended for use in further manufacturing into injectable or noninjectable products.237

Because of the possible transmission of WNV through organ transplants and blood transfusions, any case of WNV that occurs in a patient who received organs, blood, or blood products within the 4 weeks preceding onset of the illness should be reported to CDC through state and local health authorities and serum or tissue samples should be retained for later studies.205,237 In addition, cases of WNV infection occurring in blood or organ donors within 2 weeks after their donation should be reported to CDC.205,237 Prompt reporting of such individuals will facilitate withdrawal of potentially infected products.

For further information on WNV precautions related to blood and blood products, the FDA's guidance for industry should be consulted ([Web]).237

Neutralizing Antibodies to Factor VIII

Patients with neutralizing antibodies (inhibitors) to factor VIII may not respond to treatment with the drug, or the response may be much less than would otherwise be expected.122,164,165,166,169 Management of bleeding in patients with antihemophilic factor inhibitors may be difficult and requires careful monitoring, especially if surgical procedures are indicated.122,164,165,166,169 Patients receiving antihemophilic factor (human) should be carefully monitored for the development of inhibitors with appropriate clinical observation and laboratory tests.122,215,222 The presence of inhibitors should be suspected in any patient with hemophilia A who fails to respond to adequate dosages of antihemophilic factor, particularly in those who had previously achieved a response.122,153,158,215,222 Patients who receive intensive clotting factor therapy, such as those in whom repeated treatments are administered, also should be monitored for the development of inhibitors.215 Treatment of patients with inhibitors should be guided by the patient's clinical response and frequent assessment of factor VIII levels.153,158 Consultation with a hemophilia treatment center is strongly recommended for the management of bleeding in patients with inhibitors.215 For further information on the development, characterization, and prevalence of inhibitors to antihemophilic factor and information on patients at risk for and identification and quantification of these inhibitors, see Neutralizing Antibodies to Factor VIII under Cautions: Systemic Effects, in Antihemophilic Factor (Recombinant) 20:28.16.

Patients with type 3 von Willebrand disease also have occasionally developed inhibitors to von Willebrand factor following replacement therapy.122

Other Precautions and Contraindications

Serious hypersensitivity reactions, including anaphylaxis, have occurred with the use of antihemophilic factor (human) and antihemophilic factor/von Willebrand factor complex (human) preparations.122,133,153 Patients should be advised to discontinue therapy and contact their clinician if manifestations of a hypersensitivity reaction (e.g., urticaria, pruritus, wheezing, chest tightness, hypotension, anaphylaxis) occur.122,153,167

Some preparations of antihemophilic factor (human) contain trace amounts of blood groups A and B isohemagglutinins and when large or frequently repeated doses are given to individuals with blood groups A, B, or AB, the patient should be monitored for signs of progressive anemia and the possibility of intravascular hemolysis should be considered; the hematocrit and direct antiglobulin (Coombs) test should be monitored.122,133,153,167 If hemolysis or hemolytic anemia occurs, antihemophilic factor (human) should be discontinued and appropriate treatment initiated; administration of serologically compatible red blood cells from blood group O should be considered.122,133 Although purification procedures employed during the manufacture of Hemofil^® M and Monoclate-P^® (see Chemistry and Stability: Chemistry) substantially reduce the presence of blood group-specific antibodies, this precaution still applies to these antihemophilic factor preparations.153,167

Thromboembolic events have been reported in patients with von Willebrand disease receiving antihemophilic factor/von Willebrand factor complex (human) for replacement therapy.122,133 This usually has occurred in the setting of known risk factors for thrombosis and has been historically reported more frequently in females than in males.122,133 Although a causal relationship has not been established, high levels of endogenous factor VIII also have been associated with thrombosis.122,133 Coagulation factor replacement therapy should be used with caution and antithrombotic measures should be considered in all von Willebrand patients in situations of high thrombotic risk.122,133

Hemofil^® M and Monoclate-P^® are contraindicated in patients with known hypersensitivity to murine (mouse) protein.153,167 (See Cautions: Antibodies to Nonmammalian Proteins.)

Some antihemophilic factor-containing preparations are contraindicated in patients with known hypersensitivity to the products or their components.122,133,153 Some packaging components of Hemofil-M^® and Koate^®-DVI contain natural latex proteins in the form of natural rubber latex.153,158 Some individuals may be hypersensitive to natural latex proteins found in a wide range of medical devices, including such packaging components, and the level of sensitivity may vary depending on the form of natural rubber present; rarely, hypersensitivity reactions to natural latex proteins have been fatal.238,241 Therefore, healthcare professionals should take appropriate precautions when administering such preparations in individuals with a history of natural latex sensitivity.153,238,241

Pediatric Precautions

Antihemophilic factor (human) has been used in pediatric patients for the treatment of hemophilia A;121,158,167 however, safety and efficacy of some commercially available preparations of the drug have not been established in clinical studies in children.133,153,158 Adverse effects reported in pediatric patients generally have been similar to those reported in adult patients.122,158

Safety and efficacy of Alphanate^® have not been established in children 16 years of age or younger with hemophilia A.122 Alphanate^® has been studied in a limited number of pediatric patients younger than 18 years of age with von Willebrand disease; no clinically importance differences were observed between pediatric patients and adults.122

The manufacturer of Humate-P^® states that adequate and well-controlled studies with long-term evaluation of joint damage have not been performed in pediatric patients with hemophilia A; joint damage may result from suboptimal treatment of hemarthroses.133 Safety and efficacy of Humate-P^® for the treatment of von Willebrand disease have been established in infants, children, and adolescents, but have not yet been evaluated in neonates.133

Although Koate^®-DVI has not been studied in pediatric patients, the manufacturer states that the predecessor product (Koate^®-HP, solvent/detergent treated antihemophilic factor [human]) has been used extensively in pediatric patients.158 Adverse effects reported in pediatric patients generally were similar to those reported in adults.158

Safety and efficacy of Monoclate-P^® have been established in pediatric patients with hemophilia A.167

Geriatric Precautions

Clinical studies using Humate-P^® or Monoclate-P^® did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently from younger patients.133,167 As with any patient receiving antihemophilic factor (human) or antihemophilic factor/von Willebrand factor complex (human) therapy, dosage should be individualized in geriatric patients.133,167 Cautious dosage selection is recommended.167

Pregnancy and Lactation

Animal reproduction studies have not been performed with antihemophilic factor (human).122,133,153,158,167 It is not known whether antihemophilic factor (human) can affect reproduction capacity or can cause fetal harm when administered to pregnant women.122,133,153,158,167,169 Antihemophilic factor (human) should be used during pregnancy only when clearly needed.122,133,153,158,167

Since it is not known if antihemophilic factor (human) or antihemophilic factor/von Willebrand factor complex (human) is distributed into milk, the drugs should be used with caution in nursing women and only if clearly indicated.122,133,153

Pharmacology

Factor VIII is essential for blood clotting and the maintenance of effective hemostasis.110,123,134,154,155,160,175,194 In the intrinsic blood coagulation pathway, activated factor VIII acts as a cofactor with activated factor IX (Christmas factor) in the activation of factor X (Stuart-Prower factor) to factor Xa.110,123,154,155,160,175,194 Factor Xa then acts in the presence of activated factor V, negatively charged phospholipids, and calcium to convert prothrombin to thrombin.123,154,155,160,175,194 In vivo, endogenous factor VIII is noncovalently bound to von Willebrand factor (vWF); vWF helps to stabilize factor VIII, promoting the association of the light and heavy chains of the factor with resultant protection from biologic degradation and accumulation of stable factor VIII.110,154,160,175,194 For further information on the pharmacology of endogenous factor VIII, see Pharmacology in Antihemophilic Factor (Recombinant) 20:28.16.

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.110,123,134,160,175,194 Hemophilia A is an X-linked recessively inherited coagulation disorder expressed in males and carried by females.110,123,134,160,175,194

The average plasma factor VIII activity in healthy individuals is designated as 100% range: 70-140%).110,123,134,160 Normal hemostasis in the absence of trauma or surgery generally requires at least 25-30% plasma factor VIII activity.110,154,175 The clinical severity and frequency of bleeding in patients with hemophilia A correlates with the degree of deficiency in factor VIII activity.110,123,134,154,194 Patients with mild hemophilia A generally have more than 5% of normal activity, those with moderate disease generally have 1-5% of normal activity, and those with severe disease have less than 1% of normal activity.110,123,160,194 Administration of antihemophilic factor (human) to patients with hemophilia A results in increased plasma levels of factor VIII and temporarily corrects the coagulation defect in these patients.122,160,194 When antihemophilic factor (human) is used for replacement therapy, administration of 1 unit/kg generally increases plasma factor VIII activity by approximately 2% (0.02 units/mL).154,160,176,194

Von Willebrand disease is characterized by a quantitative or qualitative deficiency of von Willebrand factor (vWF).244 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.123,134,176,177 Von Willebrand factor plays an essential role in hemostasis by protecting factor VIII from inactivation and clearance and by promoting platelet aggregation and adhesion at sites of vascular injury.122,133,244 Patients with type 1 von Willebrand disease (accounts for 60-80% of cases) have mild to moderately decreased levels of von Willebrand factor and factor VIII (5-30% of normal plasma levels).244 Type 2 disease (accounts for 10-30% of cases) is characterized by a functional abnormality of von Willebrand factor and is further divided into subtypes (2A, 2B, 2M, 2N) based on the specific defect.244 Patients with type 3 disease (accounts for 1-5% of cases) have very low or undetectable levels of von Willebrand factor (less than 1% of normal plasma levels) and moderately low levels of factor VIII (1-10% of normal plasma levels).244 Clinical manifestations of von Willebrand disease include excessive and prolonged bleeding after surgery, mucosal tract bleeding, and spontaneous soft-tissue bleeding in severely affected patients.161,244 Antihemophilic factor (human) preparations containing high molecular weight multimers of von Willebrand factor (e.g., Alphanate^®, Humate-P^®) provide an exogenous source of von Willebrand factor and can temporarily correct the coagulation defect in patients with von Willebrand disease.122,133 When administered to patients with type 1, 2, or 3 disease, such preparations were effective in decreasing bleeding time.122,133

Pharmacokinetics

Following IV infusion of antihemophilic factor concentrates over 5-15 minutes, plasma concentrations of factor VIII increase by approximately 0.02-0.025 units/mL per unit/kg administered.223 Peak plasma concentrations of factor VIII generally occur within 10-15 minutes after the end of an infusion, but may occur up to 1-2 hours later.223 Factor VIII circulates in plasma bound to von Willebrand factor; extravascular distribution is minimal (about 14%).223 Antihemophilic factor (human) is rapidly cleared from plasma following IV administration in both hemophilic and healthy individuals. The half-life of antihemophilic factor (human) or antihemophilic factor/von Willebrand factor complex (human) has been reported to range from 8-28 hours, with an average of approximately 12 hours.122,133,153,158,167 Generally, disappearance curves appear biphasic. It has been theorized that the first phase represents an equilibration between intravascular and extravascular compartments and the second phase represents the true rate of utilization. Antihemophilic factor does not readily cross the placenta. Elimination of factor VIII may occur partly through the reticuloendothelial system.223 It is not known whether antihemophilic factor (human) or antihemophilic factor/von Willebrand factor complex (human) is distributed into human milk.133,234,236

Chemistry and Stability

Chemistry

Antihemophilic factor (human) is a sterile, lyophilized powder containing the blood coagulation factor VIII fraction prepared from pooled human plasma.153,158,167 Antihemophilic factor/von Willebrand factor complex (human) is a sterile, lyophilized powder containing blood coagulation factor VIII and von Willebrand factor prepared from pooled human plasma.122,133 Commercially available antihemophilic factor (human) powder for injection meets standards established by the Center for Biologics Evaluation and Research of the FDA.245

A variety of preparations of antihemophilic factor (human) or antihemophilic factor/von Willebrand factor complex (human) currently are available.122,133,153,158,167,170,246 Some preparations use precipitation and chemical procedures to isolate antihemophilic factor (human) from plasma (e.g., Humate-P^®); others use a more specific immunoaffinity chromatography procedure (e.g., Hemofil^® M, Monoclate-P^®) or gel filtration (permeation), heparin agarose, or other chromatography procedure (e.g., Alphanate^®, Koate^®-DVI).122,153,158,159,167,170 All currently available preparations of antihemophilic factor (human) concentrates undergo viral inactivation processes during manufacture using chemical (solvent/detergent) and/or heat-treatment procedures to reduce the risk of transmission of viral infection.122,133,153,156,158,159,167,246 Heat-treatment procedures currently used include wet heat in aqueous solution (pasteurization) (e.g., Humate-P^®, Monoclate-P^®) or dry heat at 80°C for 72 hours (Alphanate^®, Koate^®-DVI).122,133,150,167,158,170 In addition, immunoaffinity purification steps used in preparation of some antihemophilic factor (human) products (e.g., Hemofil^® M, Monoclate-P^®) also help to decrease viral contamination of the products.167,246 However, no method has been shown to be totally effective in removing the risk of viral infectivity from plasma-derived coagulation factor preparations.122,133,153,158,167,246,247 (See Cautions: Precautions and Contraindications.)

Potency of antihemophilic factor (human) and antihemophilic factor/von Willebrand factor complex (human) is expressed in terms of international units (IU, units).122,133,153,158,167 One unit as defined by the World Health Organization Standard for Blood Coagulation Factor VIII, human, is approximately equal to the quantity of antihemophilic factor or von Willebrand factor: Ristocetin cofactor (vWF:RCo) present in 1 mL of fresh pooled human plasma.122,133,158,167 Each vial of antihemophilic factor (human) or antihemophilic factor/von Willebrand factor complex (human) is labeled with the specific amount of factor VIII activity and vWF:RCo (when applicable).122,133,153,158,167

Alphanate®

Alphanate^® is a sterile lyophilized concentrate of highly purified factor VIII and von Willebrand factor.122 Alphanate^® is prepared from pooled human venous plasma using cryoprecipitation and fractional solubilization and is purified using heparin agarose chromatography purification.122 Heparin agarose chromatography involves use of a heparin ligand coupled to a cross-linked agarose matrix; the heparin ligand has an affinity for the heparin binding domain of the von Willebrand factor/factor VIII:C complex.122 Alphanate^® undergoes a chemical viral inactivation procedure using an organic solvent (tributyl phosphate) and detergent (polysorbate [Tween^®] 80) and undergoes a heat treatment step (80°C heat treatment for 72 hours) to reduce the risk of transmission of viruses.122 The drug is stabilized with albumin human and has a potency of at least 500 units per g of protein after stabilization.122

Hemofil® M

Antihemophilic factor (human), method M, monoclonal purified (Hemofil^® M) is a sterile, concentrate of antihemophilic factor.153 Hemofil^® M is isolated from pooled human plasma by immunoaffinity chromatography using a murine monoclonal antibody that binds specifically to factor VIII.153 The preparation is further purified by ion exchange chromatography and undergoes a chemical viral inactivation procedure using an organic solvent (tri- N -butyl phosphate) and a detergent (octoxynol 9) to reduce the risk of viral transmission; an additional nanofiltration step is incorporated to further enhance the viral safety of the product.153 No more than 12.5 mg/mL of albumin human is contained in the preparation; additional stabilizing agents include polyethylene glycol, histidine, and glycine.153 The preparation also contains trace amounts (not more than 10 ng per 100 units) of murine (mouse) protein.153 In the absence of the albumin stabilizer, Hemofil^® M has a specific activity of approximately 2 million units per g of protein.153

Humate-P®

Humate-P^® is a sterile, lyophilized concentrate of purified factor VIII and von Willebrand factor (vWF) complex prepared from pooled human plasma.133 Humate-P^® contains only low amounts of nonfactor proteins and 0.2 mg/mL or less of fibrinogen.133 Humate-P^® undergoes multiple processing steps to reduce the risk of viral transmission, including cryoprecipitation, adsorption, and heat treatment to 60°C for 10 hours in aqueous solution.133 When Humate-P^® is reconstituted as directed, each mL contains 40-80 units of antihemophilic factor activity, 72-224 units of vWR:RCo activity, 15-33 mg of glycine, 3.5-9.3 mg of sodium citrate, 2-5.3 mg of sodium chloride, 8-16 mg of albumin human, 2-14 mg of other proteins, and 10-20 mg of total proteins.133

Koate®-DVI

Koate^®-DVI is a sterile, lyophilized concentrate of factor VIII prepared from pooled human plasma.158 Koate^®-DVI is purified from the cold insoluble fraction of pooled fresh-frozen plasma and undergoes treatment with tributyl phosphate and polysorbate 80 as well as dry heat treatment at 80°C for 72 hours to reduce the risk of transmission of viruses.158 When reconstituted as directed, Koate^®-DVI contains approximately 50-150 times as much factor VIII as an equal volume of fresh plasma.158 The specific activity after addition of albumin human is in the range of 9-22 units/mg protein.158 Koate^®-DVI contains not more than 1500 mcg/mL of polyethylene glycol, 0.05 M glycine, 25 mcg/mL polysorbate 80, 5 mcg/g tributyl phosphate, 3 m M calcium, 1 mcg/mL aluminum, 0.06 M histidine, and 10 mg/mL albumin human.158

Monoclate-P®

Monoclate-P^® is a sterile, lyophilized powder of highly purified factor VIII prepared from pooled human venous plasma via murine monoclonal antibody and affinity chromatography purification procedures.167 Factor VIII complex in Monoclate-P^® is initially isolated via a murine monoclonal antibody against von Willebrand factor antigen (vWF:AG).167 Factor VIII:C is dissociated from vWF:AG and then recovered and formulated to provide a sterile, lyophilized powder of factor VIII.167 During manufacturing, Monoclate-P^® undergoes a wet-heat treatment procedure (pasteurization by heating at 60°C for 10 hours in aqueous solution) to reduce the risk of transmission of viruses.167 Monoclate-P^® 250-, 500-, and 1000-unit concentrates contain approximately 50-150 times as much factor VIII as an equal volume of fresh plasma, and the 1500- unit concentrate contains approximately 120-180 times as much factor VIII as an equal volume of fresh plasma.167 Because the product is highly purified, Monoclate-P^® is a concentrated preparation with an antihemophilic factor potency of 4000-10,000 units per g of protein following stabilization with albumin human.167 In the absence of the albumin stabilizer, the preparation has a potency exceeding 3 million units per gram of protein.167 Monoclate-P^® also contains trace amounts (not more than 50 ng per 100 units) of murine (mouse) protein.167 (See Cautions: Adverse Effects.)

Following reconstitution with the manufacturer-supplied diluent, Monoclate-P^® antihemophilic factor (human) solution is a clear, colorless solution.167

Stability

Antihemophilic factor (human) powder for injection should be stored at 2-8°C;153,158,167 freezing of the diluent should be avoided to prevent breakage of the diluent container.153,158,167 Some commercially available powders for injection may also be stored at room temperature (up to 25-30°C) for periods of up to 2-6 months or up to the expiration date, depending on the specific preparation;153,158,167 the manufacturers' storage recommendations for specific preparations should be consulted.153,158,167

Antihemophilic factor/von Willebrand factor complex (human) powder for injection should be stored at temperatures less than 25°C (freezing should be avoided); when stored as directed, these preparations are stable for 3 years up to the expiration date stated on the label.122,133

Reconstituted solutions of antihemophilic factor (human) and antihemophilic factor/von Willebrand factor complex (human) should be administered within 3 hours of reconstitution.122,133,158,167 Solutions of antihemophilic factor (human) should not be refrigerated.122,133,153,158

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