VA Class:BL500

AHFS Class:

• Hemostatics 20:28.16

Generic Name(s):

• Antihemophilic Factor (Recombinant)

Antihemophilic factor (recombinant) is a biosynthetic (recombinant DNA origin) preparation of antihemophilic factor (blood coagulation factor VIII).1,2,7,8,10,11,40,120,121,122,151,153 The drug is structurally similar to endogenous human factor VIII and produces the same biologic effects as plasma-derived antihemophilic factor (human).1,2,3,4,7,8,9,10,40,49,50,69,77,120,121,122,151,153

Hemophilia A

Overview

Antihemophilic factor (recombinant) is used in patients with hemophilia A (congenital factor VIII deficiency; classic hemophilia) for the prevention and control of bleeding episodes, perioperative management (i.e., surgical prophylaxis), and routine prophylaxis (i.e., administration at regular intervals on an ongoing basis) to prevent or reduce the frequency of bleeding events.1,2,3,4,5,9,23,24,40,41,47,48,55,56,68,69,73,74,76,120,121,122,151,153,215,246 Antihemophilic factor (recombinant) provides a means of temporarily replacing missing or dysfunctional factor VIII in such patients1,2,5,9,40,47,55,68,69,73,120,121,122,151,153 and is designated an orphan drug by FDA for use in the treatment of hemophilia A.114

Antihemophilic factor (recombinant) 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.1,2,27,55,67,85,95,120,121,122 However, administration to such patients may result in anamnestic responses and increased inhibitor levels,1,120,121 and management of bleeding in patients with inhibitors may be difficult.1,60,95 (See Neutralizing Antibodies to Factor VIII under Cautions: Systemic Effects.)

Antihemophilic factor (recombinant) has been used in certain patients with acquired hemophilia A† who have low levels of spontaneously acquired inhibitors (autoantibodies) to antihemophilic factor.85,93

Antihemophilic factor (recombinant) does not contain appreciable amounts of von Willebrand factor and should not be used in the treatment of von Willebrand disease.1,2,119,120,121,122,151,153

Prevention and Control of Bleeding Episodes

Antihemophilic factor (recombinant) is one of several treatment options that can be used in the management of bleeding in patients with hemophilia A.1,2,3,4,5,41,48,55,56,68,69,73,76,95,96,120,121,122,151,153,215,246 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,56,68,73,74,95,96,215,246 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.56,68,73,74,95,96,246 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.56,68,74,95,96,215,246

Antihemophilic factor (recombinant) has been used effectively in infants, children, and adults for prevention and treatment of bleeding episodes in patients with moderate or severe hemophilia A and has been used as part of medically supervised home treatment programs for these patients.3,4,5,23,24,40,47,48,55,56,74,76 The drug has been effective in the management of spontaneous or traumatic bleeding episodes including hemarthrosis, intramuscular hematoma, and soft tissue bleeding and also has been effective in major acute bleeding episodes such as GI, retroperitoneal, tonsillar, and ocular bleeding.1,3,5,47,48,76 In several studies in patients with moderately severe or severe hemophilia A (plasma factor VIII activity of 2% or less of normal) who used antihemophilic factor (recombinant) for the control of spontaneous or traumatic bleeding principally as part of home treatment programs, 80-93% of bleeding episodes were controlled with 1 or 2 infusions of the drug.4,47,76 Most of these patients averaged one bleeding episode every 14.6 days and self-administered antihemophilic factor (recombinant) once weekly.4 Major acute bleeding episodes may require hospitalization and more prolonged therapy with antihemophilic factor (recombinant).47,106 Antihemophilic factor (recombinant) has been used effectively in hemophilia A patients who have been previously treated with antihemophilic factor concentrates as well as in patients who have had no prior antihemophilic factor therapy; safety and efficacy of some commercially available preparations (e.g., Novoeight^®, Xyntha^®) have been evaluated only in previously treated patients.1,5,40,47,76,151,153 Antihemophilic factor (recombinant) has been used effectively to maintain hemostasis perioperatively and postoperatively in patients undergoing minor surgery (e.g., tooth extraction, elective circumcision) as well as major surgery (e.g., bilateral osteotomies, thoracotomy, liver transplant, joint replacement, laparotomy, prostatectomy, lumbar puncture, bilateral inguinal herniorrhaphy).1,2,76,120,121,122,151,153

Routine Prophylaxis of Bleeding Episodes

Antihemophilic factor (recombinant) also is used for routine prophylaxis (i.e., administration at regular intervals on an ongoing basis) to prevent or reduce the frequency of bleeding episodes in patients with hemophilia A.2,120,121,122,135,136,143,151,153,215,224,231 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.215,224,231 Up to 25 years of experience with prophylactic treatment of 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) 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 In a multicenter, randomized, open-label study comparing prophylactic infusions of antihemophilic factor (recombinant) with episodic treatment (i.e., administration of drug at the time of joint damage) in boys younger than 30 months of age with severe hemophilia, joint structure was preserved in 93% of patients who received the prophylactic regimen compared with 55% of those in the episodic-therapy group.136 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% of normal).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

MASAC Recommendations

Pending further accumulation of data, MASAC makes the following observations and recommendations concerning the treatment of hemophilia A and other bleeding disorders:218,243,246,247

• Individuals with hemophilia A may be treated with one of several antihemophilic factor concentrates; these include a variety of plasma-derived and recombinant preparations (e.g., antihemophilic factor [recombinant]; antihemophilic factor [human]; antihemophilic factor [recombinant], Fc fusion protein).246,249 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.243,247
• 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 methods of viral inactivation (e.g., heat treatment in aqueous solution [pasteurization], solvent/detergent treatment, immunoaffinity purification) and improved donor screening practices have resulted in antihemophilic factor (human) preparations with greatly reduced risk for transmission of human immunodeficiency virus (HIV), hepatitis A virus (HAV), hepatitis B virus (HBV), and hepatitis C virus (HCV),3,4,5,8,15,16,17,18,20,21,22,25,40,53,54,55,56,68,70,74,96,246 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]).246,247 (See Risk of Transmissible Agents in Plasma-derived Preparations under Cautions: Precautions and Contraindications, in Antihemophilic Factor [Human] 20:28.16.) There have been a few probable cases of vCJD acquired through transfusion of human red blood cells (RBCs).247,248 Parvovirus B19 and prions may be markers for other blood-borne infectious agents that have not yet been discovered or recognized.247 Transmission of nonenveloped viruses, including HAV and parvovirus B19, has been documented following administration of plasma-derived clotting factors, but risk has been reduced with additional viral attenuation methods such as filtration.246
• For the treatment of mild hemophilia A, desmopressin should be used whenever possible.246 However, desmopressin should not be used in certain patients (e.g., children younger than 2 years of age).246
• Cryoprecipitate should not be used as a treatment alternative for the management of hemophilia A.246 Despite donor screening for HIV-1, HBV, and HCV, cryoprecipitate may still be infectious.246 While the current estimate for the risk of HIV transmission from a single unit of blood is 1 in every 1 million donations, the risk of HCV transmission is somewhat higher, being approximately 1 in 900,000.246
• Hepatitis B vaccination is recommended by the American Academy of Pediatrics (AAP) for all children.246 Vaccination against HBV is particularly important in individuals with hemophilia and other congenital bleeding disorders and should be initiated at birth or at the time of diagnosis.246 In addition, hepatitis A virus vaccine is recommended for all unvaccinated individuals older than 1 year of age with hemophilia or other congenital bleeding disorders who are HAV seronegative.246
• When choosing the appropriate antihemophilic factor preparations for patients with hemophilia, clinicians should exercise their best judgment based on their assessment of emerging data.246
• Decisions about the selection of preparations for the treatment of hemophilia are complicated for patients, families, and treating clinicians.246 Patient education, psychosocial support, and financial counseling are critical components of comprehensive care.246

Choice of Antihemophilic Factor Preparations

Antihemophilic factor (recombinant) appears to produce the same pharmacologic effects as plasma-derived antihemophilic factor (human) and the drugs appear to have similar immunogenic effects.3,4,7,8,9,10,14,40,49,50,68,69,76,77,89 Therefore, the major difference between antihemophilic factor (recombinant) and plasma-derived antihemophilic factor (human) appears to be the relative risk of transmission of human viral infection.3,4,8,9,14,40,41,49,52,55,69,73,76,110,246 MASAC considers recombinant antihemophilic factor preparations the treatment of choice for individuals with hemophilia A because of their potentially superior safety profile with respect to pathogen transmission.218,246,247 (See MASAC Recommendations under Uses: Hemophilia A.)

Because biosynthetic preparations of antihemophilic factor (recombinant) are not prepared using pooled human plasma, they are associated with a decreased risk of transmission of human viruses (e.g., HIV, HAV, HBV, HCV) compared with that associated with plasma-derived antihemophilic factor (human).3,4,8,9,14,40,49,52,55,69,73,76,110,246 In addition, while some antihemophilic factor (recombinant) preparations contain albumin human (Recombinate^®, ReFacto^®),1,2 other preparations are formulated without albumin human (Advate^®, Helixate^® FS, Kogenate^® FS, Novoeight^®, Xyntha^®), which further reduces the risk of transmission of viruses.120,121,122,151,153 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.215,247

Acquired Hemophilia A

Antihemophilic factor (recombinant) has been used in the management of bleeding episodes in some patients with acquired hemophilia A† who have low levels of inhibitors.85,93,106,251,253 Although antihemophilic factor therapy may be effective in some patients with low levels of acquired antihemophilic factor inhibitors when given in high doses,85,93,106,251 current evidence indicates that bypassing agents are substantially more effective in achieving hemostatic control and are considered the treatment of choice in patients with this condition.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.27,28,33,55,61,86,87,88,92,93,95,125,251 Spontaneously acquired factor VIII inhibitors have been reported most frequently in postpartum women; geriatric adults; patients with autoimmune disorders such as rheumatoid arthritis or systemic lupus erythematosus; patients with malignant diseases such as plasma cell dyscrasias or lymphoproliferative disorders; and patients with other conditions such as diabetes, inflammatory bowel disease, dermatologic disorders (e.g., erythema multiforme, dermatitis herpetiformis), or prior anti-infective agent therapy (e.g., penicillin, chloramphenicol, sulfonamides).27,28,30,31,33,55,61,87,93,95 Occasionally, inhibitors to factor VIII arise spontaneously in some patients, including young children and geriatric adults, with no apparent condition that would predispose them to inhibitor formation.30,55,61,93

Factor VIII antibodies that develop in patients with acquired hemophilia A are predominantly IgG immunoglobulins that are similar to, but more heterogeneous than, those that develop in patients with congenital hemophilia A.28,31,55,61,67,88,90,93,95 Inhibitors isolated from patients with acquired hemophilia A differ from those in patients with congenital hemophilia A with regard to their inactivation kinetics.27,28,61,62,67,90,95,251 Inhibitors in patients with congenital hemophilia A, if present in high concentrations, can completely inactivate antihemophilic factor; however, the interaction between inhibitors in patients with acquired hemophilia A and antihemophilic factor generally involves an initial rapid neutralization phase followed by a slower secondary phase, and high concentrations of these inhibitors may only partially inactivate antihemophilic factor.28,61,62,67,90,95,251 Patients with acquired hemophilia A may have measurable levels of factor VIII, despite the fact that the inhibitor may be present in moderately high concentrations; this measured level of factor VIII may be misleading and result in underestimation of antibody activity and the need for antihemophilic factor therapy.28,61,62,67,90,93,95 Factor VIII inhibitor levels in patients with acquired hemophilia A can fluctuate greatly over time86,87 and, in about one-third of patients (especially postpartum or young patients), acquired factor VIII inhibitors disappear within 12-18 months without treatment.27,55,61,67,88,95 In other cases, acquired factor VIII antibodies persist for 48 months or longer and may persist for as long as 20 years.55

Acquired hemophilia A generally is suspected when there is an unexplained prolongation of the activated partial thromboplastin time (aPTT) in a patient with a normal prothrombin time or when there is a spontaneous bleeding episode (e.g., ecchymoses, soft tissue hematomas, intractable epistaxis) in a patient who does not have hemophilia A.27,28,31,33,55,61,67,86,87,88,95 Patients with acquired hemophilia A frequently develop hematomas in muscles or have soft tissue ecchymoses, mucosal bleeding, or GI bleeding; hemarthroses occur less frequently in patients with acquired hemophilia A than in patients with congenital hemophilia A.31,33,67,87,88,95 Because of the unpredictable nature of bleeding that can occur in patients with acquired hemophilia A, these patients may be at increased risk of major bleeding episodes and fatal bleeding.27,31,33,61,67,92,106

Management of patients with acquired hemophilia A consists of treating the acute bleeding episode, followed by long-term suppression of inhibitor formation.214,251 To control acute bleeding episodes, a bypassing agent such as anti-inhibitor coagulant complex (activated prothrombin complex concentrate [APCC])27,61,67,77,85,86,93 or factor VIIa (recombinant)124,125 should be administered.214,251,253 Immunosuppressive therapy that includes use of corticosteroids (e.g., prednisone) with or without other agents (e.g., cyclophosphamide) also should be initiated upon diagnosis to suppress formation of the autoantibodies.27,31,33,55,62,85,88,92,93,94,95,125,254 Some patients with acquired hemophilia A who have very low levels of inhibitors and mild to moderate bleeding may respond to therapy with desmopressin.27,67,85,95,106,27,251 However, many patients with acquired hemophilia A, especially those with higher levels of inhibitor and more severe bleeding, generally are managed with other alternatives, and desmopressin no longer is recommended in current hemophilia management guidelines.27,30,61,67,85,86,88,93,95,106,214

Reconstitution and Administration

Antihemophilic factor (recombinant) is administered by slow IV injection or by IV infusion over several minutes.1,2,3,4,120,121,122,151,153 (See Rate of Administration under Dosage and Administration: Reconstitution and Administration.) The drug also has been given by continuous IV infusion†.144,145,146

Antihemophilic factor (recombinant) therapy should be initiated under the supervision of a clinician experienced in the treatment of hemophilia A.1,2,120,122,151 The drug may be self-administered in medically supervised home treatment programs for patients with hemophilia A after appropriate training is provided by a clinician.4,23,24,55,56,74,96,106

Instructions on reconstitution, dilution, and administration of antihemophilic factor (recombinant) vary according to the specific preparation; the manufacturer's labeling should be consulted for detailed information on individual preparations.1,2,120,121,122,151,152,153 Prior to reconstitution, the lyophilized powders and diluents supplied by the manufacturers should be allowed to reach room temperature.1,2,108,120,121,122,151,153 After addition of the diluent, the solution should be gently swirled until the powder is completely dissolved; the vial should not be shaken.1,2,120,121,122,151,153

Reconstituted solutions of antihemophilic factor (recombinant) should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.1,2,120,121,122,151,153 Reconstituted solutions should be kept at room temperature1,2,121,122,151,153 and should be administered within 3 hours (for most preparations) after reconstitution; reconstituted solutions of Novoeight^® can be stored at room temperature (up to 30°C) for up to 4 hours according to the storage conditions specified by the manufacturer.1,2,121,122,151,153 It is recommended that antihemophilic factor (recombinant) be reconstituted and administered using supplies (e.g., tubing, administration sets, vial adapters, filter needles) provided by the manufacturer.1,2,120,121,122,151,153 Because protein solutions tend to stick to ground surfaces of glass syringes, some manufacturers suggest that only plastic syringes should be used to reconstitute and administer the drugs.1,122 The prefilled diluent syringe provided with Novoeight^® is made of glass and is designed to be compatible with standard Luer-lock connectors; other needleless connectors may be incompatible with the glass syringe and may affect administration.153 The manufacturer's labeling should be consulted for instructions on how to administer Novoeight^® through incompatible needleless connectors.153

Reconstituted solutions of antihemophilic factor (recombinant) should not be administered in the same tubing or container with other drugs.2,151,153

Rate of Administration

The rate of administration of antihemophilic factor (recombinant) should be individualized according to the patient's response.1,2,120,121,122,151 Some manufacturers recommend that the patient's pulse rate be determined before and during administration and, if there is a substantial increase in pulse rate, the rate of administration should be reduced or administration stopped temporarily.1,120,121,122

Advate^® should be administered over a period of 5 minutes or less (maximum rate of 10 mL/minute).122

The manufacturers of Helixate^® FS and Kogenate^® FS state that the drugs may be administered over a period of 1-15 minutes.120,121

Novoeight^® should be administered over a period of 2-5 minutes.153

The manufacturer of Recombinate^® states that the drug generally can be administered over a period of up to 1 minute (i.e., up to 10 mL/minute when reconstituted with 10 mL of sterile water for injection1 or up to 5 mL/minute when reconstituted with 5 mL of sterile water for injection)152 without substantial adverse effects; however the rate of administration should be determined by the patient's comfort level.1,152

The manufacturer of ReFacto^® and Xyntha^® states that the drugs should be given IV over several minutes; the rate of administration should be determined by the patient's comfort level.2,151

Dosage

Dosage of antihemophilic factor (recombinant) is expressed in terms of international units (IU, units) of antihemophilic factor activity;1,2,120,121,122,151,153 1 unit is approximately equal to the quantity of antihemophilic factor present in 1 mL of fresh pooled human plasma.72,120,121,122,151,153 In general, administration of 1 unit/kg of antihemophilic factor (recombinant) will increase the circulating factor VIII level by approximately 2 units/dL (2%).2,48,55,74,151,153

Prevention and Control of Bleeding Episodes in Hemophilia A

Dosage and duration of antihemophilic factor (recombinant) therapy should be individualized based on the degree of deficiency of coagulation factor VIII (antihemophilic factor), desired factor VIII level, weight of the patient, location and severity of bleeding, presence of inhibitors to antihemophilic factor, and the patient's clinical and pharmacokinetic (e.g., half-life, in vivo recovery) response.1,2,55,120,121,122,151,153 The dosage required to establish hemostasis will vary with each patient and circumstance since there is considerable variability between patients and their clinical conditions.1,2,120,121,122,151,153

The manufacturers of antihemophilic factor (recombinant) have suggested the following calculations and dosage guidelines for the prevention and control of bleeding in patients with hemophilia A based on the degree of bleeding or type of surgery.1,2,120,121,122,151,153

To calculate the approximate percentage increase in plasma factor VIII levels expected from a given dose of antihemophilic factor (recombinant) or the dose of the drug required to achieve a particular percentage increase in the plasma factor VIII level, the following formulas may be used.1,2,120,121,122,151,153 These formulas generally apply only to patients without antihemophilic factor inhibitors.106

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.1,2,120,121,122,151,153 For recommendations on target factor VIII levels, see the individual product-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.1,2,55,120,121,122,151,153Serial assays of factor VIII should be performed (usually with the one-stage clotting assay) when clinically indicated to ensure that adequate levels have been achieved and maintained.1,2,120,121,122,151,153

Careful control of the dose of antihemophilic factor is especially important in cases of life-threatening bleeding or major surgery.1,120,121,122,153 If the calculated dose is ineffective in attaining the expected levels of factor VIII or if bleeding is not controlled after administration of the calculated dose, the presence of inhibitors to antihemophilic factor should be suspected.1,120,121,122,153 Higher than recommended doses of antihemophilic factor (recombinant) may be required to achieve hemostasis in patients with low-titer inhibitors.1,2,120,121,122,151 (See Neutralizing Antibodies to Factor VIII under Cautions: Systemic Effects.)

Advate®

For the treatment of minor bleeding (e.g., early hemarthrosis, mild muscle bleeding, mild oral bleeding) in adults and children with hemophilia A, the manufacturer of Advate^® recommends that levels of factor VIII be maintained at 20-40% or more of normal.122 This may be achieved by administering 10-20 units/kg every 12-24 hours (8-24 hours for patients younger than 6 years of age) for approximately 1-3 days until the bleeding episode resolves (indicated by relief of pain) or healing is achieved.122

In patients with moderate bleeding (e.g., moderate bleeding into muscles, bleeding into the oral cavity, definite hemarthrosis, known trauma), factor VIII levels should be maintained at 30-60% or more of normal.122 This may be achieved by administering 15-30 units/kg of Advate^® every 12-24 hours (8-24 hours for patients younger than 6 years of age) for approximately 3 days or longer until the bleeding episode resolves (indicated by relief of pain) or healing is achieved.122

In patients with major bleeding (e.g., substantial GI bleeding; intracranial, intra-abdominal, or intrathoracic bleeding; CNS bleeding; bleeding in the retropharyngeal or retroperitoneal spaces or iliopsoas sheath; fractures; head trauma), levels of factor VIII should be maintained at 60-100% or more of normal.122 This may be achieved by administering 30-50 units/kg of Advate^® every 8-24 hours (6-12 hours for patients younger than 6 years of age) until the bleeding episode is resolved.122

For patients undergoing minor surgery (e.g., tooth extraction), the manufacturer recommends that doses of Advate^® be given to maintain a factor VIII level of 60-100% or more of normal.122 A single dose (30-50 units/kg) administered within 1 hour of the procedure is recommended; additional doses should be given every 12-24 hours as needed to control bleeding.122 Adjunctive therapy may be considered for dental procedures.122

For patients undergoing major surgery (e.g., intracranial, intra-abdominal, intrathoracic, joint replacement), pre- and postoperative levels of factor VIII should be maintained at 80-120% or more of normal.122 A preoperative dose of Advate^® 40-60 units/kg to achieve 100% factor VIII activity is recommended; doses should be repeated every 8-24 hours (6-24 hours for patients younger than 6 years of age) depending on the desired level of factor VIII and state of wound healing.122

Helixate® FS and Kogenate® FS

For the treatment of minor bleeding (e.g., early hemarthrosis, minor muscle or oral bleeding) in adults and children with hemophilia A, the manufacturer of Helixate^® FS and Kogenate^® FS recommends that levels of factor VIII be maintained at 20-40% or more of normal.120,121 This may be achieved by administering 10-20 units/kg of Helixate^® FS or Kogenate^® FS; doses should be repeated until bleeding is resolved.120,121

For the treatment of moderate bleeding (e.g., bleeding into muscles or the oral cavity, definite hemarthroses, known trauma), levels of factor VIII should be maintained at 30-60% or more of normal.120,121 This can be achieved by administering 15-30 units/kg of Helixate^® FS or Kogenate^® FS every 12-24 hours until bleeding is resolved.120,121

For the treatment of major bleeding (e.g., GI, intracranial, intra-abdominal, intrathoracic, or CNS bleeding; bleeding in the retropharyngeal or retroperitoneal spaces or iliopsoas sheath; fractures or head trauma), levels of factor VIII should be maintained at 80-100% or more of normal.120,121 This can be achieved by administering an initial dose of Helixate^® FS or Kogenate^® FS 40-50 units/kg; additional doses of 20-25 units/kg should be given every 8-12 hours until bleeding is resolved.120,121

For patients undergoing minor surgery (e.g., tooth extraction), levels of factor VIII should be maintained at 30-60% or more of normal.120,121 This can be achieved by administering 15-30 units/kg of Helixate^® FS or Kogenate^® FS every 12-24 hours until bleeding is resolved.120,121

For patients undergoing major surgery (e.g., tonsillectomy, inguinal herniotomy, synovectomy, total knee replacement, craniotomy, osteosynthesis, trauma), plasma levels of factor VIII activity should be maintained at 100% of normal by administering a preoperative dose of Helixate^® FS or Kogenate^® FS 50 units/kg.120,121 Additional doses should be given as necessary every 6-12 hours to maintain factor VIII levels in the desired range until healing is complete.120,121

Novoeight®

For the management of minor bleeding (e.g., early hemarthrosis, minor muscle or oral bleeding) in adults and children with hemophilia A, the manufacturer recommends that an appropriate dose of Novoeight^® be given to maintain factor VIII levels of at least 20-40% of normal.153 Doses should be repeated every 12-24 hours for at least 1 day until the bleeding episode resolves.153

In patients with moderate bleeding (e.g., muscle bleeding, mild head trauma, bleeding into the oral cavity), the manufacturer recommends that an appropriate dose of Novoeight^® be given to maintain factor VIII levels of at least 30-60% of normal.153 Doses should be repeated every 12-24 hours for approximately 3-4 days until pain and acute disability resolve.153

In patients with major bleeding (e.g., life- or limb-threatening; GI, intracranial, intra-abdominal, or intrathoracic bleeding; fractures), the manufacturer recommends that an appropriate dose of Novoeight^® be given to maintain factor VIII levels of at least 60-100% of normal.153 Doses should be repeated every 8-24 hours for approximately 7-10 days until bleeding resolves.153

In patients undergoing minor surgery (e.g., tooth extraction), the manufacturer recommends that an appropriate dose of Novoeight^® be given to maintain factor VIII levels of at least 30-60% of normal.153 Doses should be repeated every 24 hours until healing is achieved; at least 1 day of treatment is recommended.153

In patients undergoing major surgery (e.g., intracranial, intra-abdominal, intrathoracic, joint replacement surgery), the manufacturer recommends that doses of Novoeight^® be given to maintain preoperative and postoperative factor VIII levels of at least 80-100% of normal.153 Doses should be repeated every 8-24 hours until adequate wound healing occurs; treatment should then be continued for at least 7 days to maintain factor VIII levels of 30-60% of normal.153

Recombinate®

For the treatment of early hemarthrosis, muscle bleeding, or oral bleeding in adults and children with hemophilia A, the manufacturer recommends that doses of Recombinate^® be given to achieve peak postinfusion levels of factor VIII that are 20-40% of normal.1 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.1

For more extensive hemarthrosis, muscle bleeding, or hematoma, the manufacturer recommends that doses of Recombinate^® be given to achieve peak postinfusion levels of factor VIII that are 30-60% of normal.1 Doses should be given every 12-24 hours for 3 days or longer until pain and disability resolve.1

For life-threatening bleeding (e.g., head injury, throat bleeding, severe abdominal pain), the manufacturer recommends that doses of Recombinate^® be given to achieve peak postinfusion levels of factor VIII that are 60-100% of normal.1 Doses should be given every 8-24 hours until the threat is resolved.1

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

For major surgery, the manufacturer recommends that doses of Recombinate^® be given to achieve a pre- and postoperative level of factor VIII of 80-100% of normal.1 Doses should be repeated every 8-24 hours depending on the patient's state of healing.1

ReFacto® and Xyntha®

For the management of minor bleeding (e.g., early hemarthrosis, minor muscle or oral bleeding) in adults and children with hemophilia A, the manufacturer recommends that doses of ReFacto^® or Xyntha^® be given to achieve levels of factor VIII that are at least 20-40% of normal.2,151 To maintain adequate levels, doses should be given every 12-24 hours as necessary until the bleeding episode resolves.2,151 At least 1 day of therapy usually is required depending on the severity of bleeding.2,151

For the management of moderate bleeding (e.g., muscle bleeding, mild head trauma, bleeding into the oral cavity), the manufacturer recommends that doses of ReFacto^®or Xyntha^® be given to achieve factor VIII levels of at least 30-60% of normal.2,151 Doses should be given every 12-24 hours for 3-4 days or until adequate local hemostasis is achieved.2,151

For major bleeding (e.g., GI, intracranial, intra-abdominal, or intrathoracic bleeding; fractures), the manufacturer recommends that doses of ReFacto^® or Xyntha^® be given to achieve factor VIII levels of at least 60-100% of normal.2,151 Doses should be given every 8-24 hours until bleeding is resolved2,151

In patients undergoing minor surgery (e.g., tooth extraction), the manufacturer recommends that doses of ReFacto^® or Xyntha^® be given to achieve factor VIII levels of at least 30-60% of normal.2,151 Doses should be given every 12-24 hours for 3-4 days or until adequate local hemostasis is achieved.2,151 For tooth extraction, a single dose in conjunction with oral antifibrinolytic therapy within 1 hour may be sufficient.2,151

In patients undergoing major surgery, the manufacturer recommends that doses of ReFacto^® or Xyntha^® be given to achieve factor VIII levels of at least 60-100% of normal.2,151 Doses should be repeated every 8-24 hours until adequate local hemostasis is achieved.2,151

Routine Prophylaxis of Bleeding Episodes in Hemophilia A

Various dosing protocols have been recommended for routine prophylaxis of bleeding with antihemophilic factor concentrates in patients with hemophilia A.120,121,136,215,218 A dosage of 25-40 units/kg every other day (minimum 3 times a week) usually is recommended for prophylaxis.120,121,136,151,215 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.136,218 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 prophylaxis.218

Advate®

For routine prophylaxis with Advate^® to prevent or reduce the frequency of bleeding episodes in adults and children with hemophilia A, the manufacturer recommends a dosage of 20-40 units/kg every other day (3-4 times a week); alternatively, a dose may be given every third day to achieve factor VIII levels of at least 1% of normal.122 Dosage should be adjusted based on individual clinical response.122

Helixate® FS and Kogenate® FS

When Helixate^® FS or Kogenate^® FS is used for routine prophylaxis in adults and children with hemophilia A, the recommended dosage is 25 units/kg 3 times a week in adults and 25 units/kg every other day in children.120,121

Novoeight®

For routine prophylaxis with Novoeight^® in adults and children with hemophilia A, the manufacturer recommends dosage regimens based on the patient's age.153 In adults and adolescents 12 years of age or older, a prophylactic dosage of 20-50 units/kg 3 times a week or 20-40 units/kg every other day is recommended.153 In children younger than 12 years of age, a prophylactic dosage of 25-60 units/kg 3 times a week or 25-50 units/kg every other day is recommended.153

ReFacto®

For short-term routine prophylaxis to prevent or reduce the frequency of spontaneous musculoskeletal bleeding in individuals with hemophilia A, the manufacturer of ReFacto^® states that the drug should be given at least twice weekly; in some patients, especially pediatric patients, shorter dosage intervals or higher dosages may be necessary.2 There is some evidence from pharmacokinetic and pharmacodynamic modeling studies that routine prophylactic dosing 3 times weekly may be associated with a lower bleeding risk than twice-weekly dosing; however, randomized comparisons evaluating different dosage regimens for routine prophylaxis currently are lacking.2 In clinical studies, the mean dose of ReFacto^® administered for routine prophylaxis was 29 units/kg in previously treated individuals 8-73 years of age and 53 units/kg in previously untreated pediatric patients up to 52 months of age.2

Xyntha®

The manufacturer of Xyntha^® does not provide specific dosage recommendations for routine prophylaxis in patients with hemophilia A; in clinical studies, prophylactic regimens of 25-35 units/kg 3 times a week were administered.151

Antihemophilic factor (recombinant) generally is well tolerated, and adverse reactions have been reported in 1% or less of patients receiving the drug.1,4,5,9,44,47,69,76 Adverse effects reported with antihemophilic factor (recombinant) usually are self-limited and mild to moderate in severity.4,5,44,47,69

Further study is needed to determine whether there are differences in adverse effects related to the different types of antihemophilic factor (recombinant) preparations currently available in the US (Advate^®, Helixate^® FS, Kogenate^® FS, Novoeight^®, Recombinate^®, ReFacto^®, Xyntha^®).106,108

Although Helixate^® FS and Kogenate^® FS 250-, 500-, and 1000-unit vials contain 28 mg of sucrose per vial, and Helixate^® FS and Kogenate^® FS 2000- and 3000-unit vials contain 52 mg of sucrose, the manufacturers state that IV administration of these preparations will not affect blood glucose concentrations.120,121

Local Effects

Adverse local effects, including burning, pruritus, rash, and erythema, have been reported following IV administration of antihemophilic factor (recombinant).2,4,5,44,47,108,122 Injection-site reactions have been reported as one of the most frequent adverse effects with Novoeight^®.153

Systemic Effects

Sensitivity Reactions

Systemic hypersensitivity reactions, including anaphylaxis, have been reported with antihemophilic factor (recombinant) preparations.1,120,121,122,122,151,153 All these preparations contain trace amounts of animal proteins that may theoretically cause hypersensitivity reactions in sensitive individuals.1,2,120,121,122,151,153 Such reactions have included urticaria, rash with pruritus, generalized urticaria, chest tightness, dyspnea, wheezing, hypotension, anaphylaxis, dizziness, paresthesias, flushing, facial swelling, pruritus, nausea, vomiting, edema, shortness of breath, and tachycardia.1,2,120,121,122,151,153 (See Sensitivity Reactions under Cautions: Precautions and Contraindications.) Erythematous rash has been reported rarely in patients receiving Recombinate^®; however, a causal relationship to the drug has not been definitely established.76

The principal protein contained in Recombinate^® and ReFacto^® is albumin human.1,2,152 Adverse reactions associated with IV administration of albumin are rare; however, nausea, fever, chills, and urticaria have been reported in patients receiving the protein.1,152

Neutralizing Antibodies to Factor VIII

Patients with hemophilia A have developed neutralizing antibodies (inhibitors) to factor VIII following treatment with antihemophilic factor-containing preparations.1,2,4,5,13,29,39,46,69,76,89,120,121,122,151,153,215,250,255 While antihemophilic factor (recombinant) may be effective for the management of bleeding in some of these patients with relatively low levels (e.g., less than 5-10 Bethesda units/mL) of inhibitor antibodies to antihemophilic factor when given in high doses,1,2,27,55,67,85,95,120,121,122,215,255 administration of the drug to such patients may result in anamnestic responses and increased levels of inhibitor.1,120,121 Patients with hemophilia A and inhibitors may not respond to treatment with antihemophilic factor (recombinant) or the response may be much less than would otherwise be expected.1 Although the presence of antihemophilic factor inhibitors generally does not increase the frequency or severity of bleeding in patients with hemophilia A, patients with such inhibitors generally have a higher risk of hemophilia A-associated mortality than patients who do not have inhibitors.26,27,55,56,59,61,62,63,66,74

Management of bleeding in patients with antihemophilic factor inhibitors may be difficult and requires careful monitoring, especially if surgical procedures are indicated.1,60,95 There are several therapeutic alternatives that can be used for the prevention and control of bleeding in hemophilia A patients who have inhibitors.27,55,61,62,65,67,73,74,77,78,85,95,97,127,128,215,246 MASAC recommends the use of a bypassing agent (e.g., anti-inhibitor coagulant complex [activated prothrombin complex concentrate, APCC], factor VIIa [recombinant]) in hemophilia A patients with inhibitors to prevent or control bleeding in settings in which antihemophilic factor preparations would otherwise be used, including before and after surgery and physical therapy.131

Antihemophilic factor concentrates also have been used to induce immune tolerance as a long-term strategy aimed at preventing anamnesis and suppressing further antibody production in patients with hemophilia A and a history of inhibitors.95,99,100,101,102,106,141,215,255 While some experts state that there is insufficient evidence to recommend use of immune tolerance therapy in patients with antihemophilic factor inhibitors,141 others state that such therapy may be useful for eradicating inhibitors in patients with severe hemophilia A.215

Characterization of Antihemophilic Factor Inhibitors

Antihemophilic factor inhibitors are IgG immunoglobulins and circulating antibodies that neutralize the procoagulant activity of antihemophilic factor.23,27,28,29,55,61,62,65,67,73,74,95,255 Such alloantibodies have been identified in patients with hemophilia A who have received antihemophilic factor preparations.3,4,5,23,24,55,56,57,58,61,62,63,64,65,67,73,74,76,95,98,99,100,101,102,103,104,151 The risk of developing inhibitors is dependent on a variety of factors, including genetic predisposition and the extent of exposure to antihemophilic factor concentrates, with risk highest within the first 20 days of exposure.1,26,27,46,55,58,59,61,62,95,106,215 Although the development of inhibitors is more common in patients who have not been previously treated with a factor VIII preparation, inhibitors also have been observed in previously treated patients.120,121,122,151,250 In addition, spontaneously acquired autoantibodies to endogenous factor VIII have been identified in nonhemophilic patients who have acquired hemophilia A.27,28,30,31,33,55,61,62,86,87,88 (See Uses: Acquired Hemophilia A.) Autoantibodies are similar to, but more heterogeneous than, the alloantibodies that develop in patients with congenital hemophilia A.28,31,55,61,67,88,90,93

Antihemophilic factor antibodies bind to and react with the factor VIII molecule interfering with the coagulant activity of the factor.29,55,61,62,255 In some instances, the antibodies appear to prevent interaction of exogenous antihemophilic factor or endogenous (native) factor VIII with phospholipid that is necessary for activation of factor X by activated factor IX.29,55 Results of in vitro and in vivo neutralization and immunoblotting studies indicate that alloantibodies appear to bind predominantly to the A2 and C2 domains of the factor VIII molecule.90 These antibodies appear to be specific and react only with factor VIII and not with other coagulation factors;55,61,95 however, the affinity of the antibodies for factor VIII may show considerable interindividual variation.55

Prevalence of Antihemophilic Factor Inhibitors in Patients with Hemophilia A

Antihemophilic factor 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.215,255 Retrospective and prospective studies evaluating the prevalence of antihemophilic factor inhibitors in patients with moderate or severe hemophilia A indicate that 3-52% of patients who have received plasma-derived antihemophilic factor (human) have had inhibitors to antihemophilic factor.3,4,5,23,24,55,56,57,58,61,63,64,65,67,73,74,76,89,95,98,101,102,104

In one prospective study in previously untreated neonates and children 50 months of age or younger with severe hemophilia A (plasma factor VIII activity 2% or less of normal) who received Recombinate^® antihemophilic factor (recombinant) for prophylaxis and treatment of bleeding episodes, 24% of patients developed antihemophilic factor inhibitors.76 These patients received 3-45 total days of exposure to antihemophilic factor (recombinant) and those who developed inhibitors generally did so within the first 10 days.76 Although a few of these children developed levels of antihemophilic factor inhibitors sufficient to necessitate use of an alternative drug for the control of bleeding, most children who developed inhibitors had only low levels and the recombinant preparation continued to be effective.76

In clinical studies in previously untreated or minimally treated pediatric patients receiving Helixate^® FS or Kogenate^® FS, inhibitor development was observed in 15% of the patients; inhibitors were detected after a median of 7 exposure days (range 2-16 days) and found to be present in low and high concentrations.120,121

In clinical studies in previously untreated patients receiving Advate^®, approximately 20% of patients developed inhibitors to factor VIII, some of which were present in high titers; inhibitors were detected at a median of 11 exposure days.122 The incidence of antibody development was substantially lower in previously treated patients receiving Advate^® (reported in only 1 adult among 198 total adults and pediatric patients who received the drug).122

No confirmed inhibitors were reported in clinical studies of Novoeight^® in which previously treated patients received the drug; previously untreated patients were not evaluated.153

Among previously untreated patients evaluated in clinical studies of ReFacto^®, inhibitors were detected in 31.7% of patients; at least 1 case of a high-titer inhibitor also was reported in the population of previously treated patients in these studies.2 In clinical studies with Xyntha^®, inhibitor development occurred in approximately 2% of previously treated patients, including at least 1 pediatric patient; previously untreated patients were not included in these studies.151

Patients with Hemophilia A at Risk for Development of Antihemophilic Factor Inhibitors

Although it has been difficult to clearly identify what elements predispose patients to develop antihemophilic factor inhibitors,62,89,90,95 many patients with hemophilia A appear to be genetically predisposed to develop inhibitors following exposure to preparations containing antihemophilic factor.26,27,46,55,58,59,61,62,95 Studies using antihemophilic factor (human) indicate that the risk of inhibitor development appears to correlate with the severity of hemophilia A and also may correlate with the extent of exposure to the drug.1,27,57,59,61,62,89,95,98,101,102,104 Antihemophilic factor inhibitors have been reported most frequently in patients with severe or moderately severe hemophilia A (plasma factor VIII activity of 2% of normal or lower)23,24,27,56,57,59,61,62,89,95,98,101,102,104 but also have been reported occasionally in patients with mild hemophilia A.23,24,56,95,98,104

Studies using antihemophilic factor (human) indicate that inhibitors to antihemophilic factor generally are identified in patients with hemophilia A during the first 50-90 days of antihemophilic factor therapy,58,59,63,106 and the probability of developing inhibitors is highest during the first 20 exposures to the drug.1,106 These antibodies usually are identified in patients when they are younger than 20 years of a patients younger than 10 years of age appear to be at the greatest risk of developing inhibitors.27,57,58,59,62,63,95,98,104,106 Development of inhibitors in patients who previously have received long-term antihemophilic factor therapy without inhibitor development is rare (8 per 1000 patient-years of observation).58,60

Identifying and Quantifying Inhibitors to Antihemophilic Factor

Various methods, including the Bethesda assay, New Oxford assay, immunodiffusion techniques, and enzyme-linked immunosorbent assays (ELISA), have been used to identify and quantify antihemophilic factor inhibitor concentrations in patient plasma.27,28,55,65,95 In the US, the in vitro method most frequently used to detect and quantify antihemophilic factor inhibitors is the Bethesda assay.27,28,55,65,67,91,95,255 In the Bethesda assay, the patient's plasma is incubated with factor VIII obtained from normal pooled plasma and the amount of inactivation of factor VIII is measured and expressed in terms of Bethesda units/mL of plasma or serum.1,27,28,55,65,67,91 One Bethesda unit is defined as the amount of patient plasma that inactivates half the factor VIII present in a 50:50 mixture (with normal patient plasma) incubated at 37°C for 2 hours.28,55,65,67,95

Using the Bethesda assay, patients with antihemophilic factor inhibitors are subdivided into those with low antibody titers (less than 5 Bethesda units/mL) and those with high titers (5 Bethesda units/mL or greater). 150,215 Following administration of antihemophilic factor preparations to patients with hemophilia A, the antibody response usually is characterized as a low response or a high response.27,55,62,67,95,98,101 About 10-33% of hemophilia A patients are low responders who have low initial levels of inhibitors that tend to remain low even following repeated doses of antihemophilic factor.23,26,27,55,57,61,62,63,67,98 In some low responders, especially children or patients who have not previously received antihemophilic factor therapy, the presence of low levels of antihemophilic factor inhibitors is transient;27,57,59,61 inhibitors may be detected on a single occasion or may persist for a varying length of time and then disappear despite continued therapy with antihemophilic factor.27,57,59,61 The clinical importance of transient, low levels of antihemophilic factor inhibitors is unclear.57 Most hemophilia A patients are high responders who develop high titers of antihemophilic factor antibody and exhibit a typical anamnestic response each time they receive a preparation containing antihemophilic factor.23,26,27,55,57,61,62,63,67,95,98 In a typical anamnestic response, levels of antihemophilic factor inhibitor increase substantially with each dose of antihemophilic factor beginning 2-7 days after the dose and peaking within 1-3 weeks.27,55,67,95 The antibody titer may decrease slowly if no additional doses of preparations containing antihemophilic factor are given; however, these patients will usually have an anamnestic response each time they receive antihemophilic factor.67,95 Low responders may convert to high responders after prolonged, intensive antihemophilic factor therapy.55,61,67

Antibodies to Nonhuman Mammalian Proteins

Recombinate^® contains trace amounts of mouse protein (maximum concentration 0.1 ng/unit), hamster protein (maximum concentration 1 ng CHO protein per unit), and bovine protein (maximum concentration 1 ng/unit).1 Advate^®, Helixate^® FS, and Kogenate^® FS contain trace amounts of mouse immunoglobulin G and hamster proteins.120,121,122 Xyntha^® contains trace amounts of hamster proteins and Refacto^® contains trace amounts of murine proteins.151 Antibodies against some of these nonhuman mammalian proteins have been identified in a few patients,45 but there is no evidence that administration of antihemophilic factor (recombinant) results in development of significant antibody titers against nonhuman mammalian proteins.4,5,9 However, there is a remote possibility that patients who receive the drugs, particularly those who receive long-term therapy, could develop hypersensitivity to the nonhuman mammalian proteins contained in these preparations.1,2,40,120,121 (See Antibodies to Nonhuman Mammalian Proteins under Cautions: Precautions and Contraindications.)

Cardiovascular Risk

When their clotting abnormalities have been normalized by treatment with antihemophilic factor, patients with hemophilia who have cardiovascular risk factors or diseases may be at the same risk for development of cardiovascular events as nonhemophilic patients.120,121

Other Systemic Effects

Dizziness,2,4,44,47,120,121 lightheadedness,4 nausea,1,2,120,121,122,151 headache,2,122,151 diarrhea,2,122,151 constipation,122 vomiting,122,151 asthenia,2,151 generalized discomfort,120,121 joint pain and swelling,122 fatigue/malaise,120,121,122 pain,2,122 extremity pain,122 earache,122 ear infection,122 facial flushing,1,5,120,121 facial swelling,120,121 rash,1,2,120,121 pruritus,2,120,121 urticaria,2,5,120,121 rhinitis,2,120,121 nasopharyngitis,122 influenza-like symptoms,122 somnolence,2 falling,122 restlessness,120,121 depersonalization,120,121 chest discomfort,4,120,121,122 chest tightness,4,47 dyspnea,2,4,47 cough,120,121,122 sore throat,122 nasal congestion,122 wheezing,120,121 chills,1,2 fever,2,122,153 epistaxis,1 mouth dryness,4,47 cold feet,47 unpleasant/unusual/metallic taste in the mouth,2,4,44,120,121 and a slight increase or decrease in blood pressure2,47,120,121 have been reported in patients receiving antihemophilic factor (recombinant). Hepatic enzyme elevations were reported as one of the most frequent adverse effects of Novoeight^®.153

Precautions and Contraindications

Antihemophilic factor (recombinant) is indicated only for the treatment of bleeding disorders that result from a deficiency in blood coagulation factor VIII (antihemophilic factor).1,120,121,122 Therefore, prior to initiation of antihemophilic factor (recombinant) therapy, appropriate laboratory tests should be performed to confirm that a deficiency in factor VIII exists.1,120,121

Sensitivity Reactions

Patients receiving antihemophilic factor (recombinant) should be warned of the possibility of hypersensitivity reactions and informed of the manifestations of such reactions.1,2,120,121,122,151,153 (See Sensitivity Reactions under Cautions: Systemic Effects.) Patients should be advised to discontinue antihemophilic factor (recombinant) therapy and seek immediate treatment if a hypersensitivity reaction occurs.1,2,121,122,151,153 All commercially available preparations of antihemophilic factor (recombinant) are contraindicated in patients who have had life-threatening, immediate hypersensitivity reactions (including anaphylaxis) to any ingredient in the preparations.1,120,121,122,151,153

Some packaging components of Recombinate^® contain natural latex proteins in the form of natural rubber latex.1,147,148 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.147,148 Therefore, healthcare professionals should take appropriate precautions when administration of Recombinate^® is considered in individuals with a history of natural latex sensitivity.147,148

Neutralizing Antibodies to Factor VIII

Patients receiving antihemophilic factor (recombinant) should be monitored for the development of neutralizing antibodies (inhibitors) to factor VIII with appropriate clinical observations and laboratory tests (e.g., Bethesda assay).1,2,60,66,74,95,120,121,122,151,153 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,215 and in patients who have unexpectedly prolonged activated partial thromboplastin times (aPTT).27,61,65,74,95 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 Consultation with a hemophilia treatment center is strongly recommended for the management of bleeding in patients with inhibitors.215

Antibodies to Nonhuman Mammalian Proteins

Because Recombinate^® contains trace amounts of murine, bovine, and hamster proteins and Advate^®, Helixate^® FS, Kogenate^® FS, and ReFacto^® contain trace amounts of murine and hamster proteins, these preparations are contraindicated in individuals with known hypersensitivity to these nonhuman mammalian proteins.1,2,120,121,122 Patients receiving Novoeight^® or Xyntha^®, which contain trace amounts of hamster proteins, may develop hypersensitivity to these nonhuman mammalian proteins; therefore, these preparations are contraindicated in patients with known hypersensitivity to hamster proteins.151,153

Potential Risk of Transmissible Agents

Because antihemophilic factor (recombinant) preparations are not prepared using pooled human plasma, they are associated with a decreased risk of transmission of human viruses (e.g., human immunodeficiency virus [HIV], hepatitis A virus [HAV], hepatitis B virus [HBV], hepatitis C virus [HCV]) compared with the risk associated with plasma-derived antihemophilic factor (human).3,4,8,9,14,40,49,52,55,69,73,76,110,246 There is, however, a theoretic but remote risk that other viruses (e.g., those associated with the mammalian cell cultures employed in manufacturing) could be transmitted by recombinant preparations.40,49,106,108,110,246 To date, there have been no known cases of mammalian virus transmission involving any therapeutic recombinant product.110,246

Pediatric Precautions

Antihemophilic factor (recombinant) has been used in pediatric patients of all ages for the management of hemophilia A; adverse effects reported in pediatric patients generally have been similar to those reported in adults.1,2,4,5,47,120,121,153 Safety and efficacy of antihemophilic factor (recombinant) have been evaluated in previously treated children as well as in those who have had no previous exposure to antihemophilic factor therapy.1,2,4,5,47,120,121,151,153

Helixate^® FS and Kogenate^® FS are FDA-labeled for routine prophylactic treatment in pediatric patients with no preexisting joint damage.120,121 Such use is based on data from a multicenter randomized open-label study in children younger than 30 months with severe hemophilia and normal baseline joint structure; results of the study indicate that regular administration of antihemophilic factor (recombinant) in this pediatric population reduces the frequency of spontaneous joint bleeding and risk of joint damage.120,121 The manufacturers state that these findings can be extrapolated and applied to older pediatric patients 2.5-16 years of age who do not have preexisting joint damage.120,121

In neonates and children who previously had not received therapy with any antihemophilic factor preparation, urticaria, flushing, and erythema at the infusion site have occurred rarely following administration of antihemophilic factor (recombinant).5,106,108 In one study in neonates and children, about 20% of children who were evaluated for the presence of antihemophilic factor inhibitors had developed inhibitors within 1-15 months after initiation of therapy with a preparation of antihemophilic factor (recombinant) that is no longer commercially available in the US.5 (See Pharmacology: Immunogenic Effects.)

Compared with adults, children have higher clearance, lower incremental in vivo factor VIII recovery, and a shorter factor VIII half-life, which should be taken into account in dosage selection and during monitoring of factor VIII levels in pediatric patients.1,120,121,122,151,153 More frequent or larger doses may be necessary to adjust for these pharmacokinetic differences.1,120,121,122,151,153

Geriatric Precautions

Clinical studies with antihemophilic factor (recombinant) either did not include any patients 65 years of age or older or did not include sufficient numbers of such patients to determine whether geriatric patients respond differently than younger patients.2,120,121,122,151,153 As with any patient receiving antihemophilic factor (recombinant), dosage should be individualized in geriatric patients.2,120,121,122,151

Mutagenicity and Carcinogenicity

Recombinate^®, at doses up to 10 times the maximum human dose, was not mutagenic in vitro or in vivo in studies evaluating reverse mutations, chromosomal aberrations, and increases in micronuclei in bone marrow polychromatic erythrocytes.1 In vitro and in vivo studies using other antihemophilic factor (recombinant) preparations have not revealed mutagenic effects.2,120,121

Long-term studies have not been performed to date to evaluate the carcinogenic potential of antihemophilic factor (recombinant).1,2,120,121,151

Pregnancy, Fertility, and Lactation

Pregnancy

Animal reproduction studies have not been performed to date with antihemophilic factor (recombinant).1,2,120,121,122,151,153 It is not known whether antihemophilic factor (recombinant) can cause fetal harm when administered to pregnant women, and the drug should be used during pregnancy only when clearly needed.1,2,120,121,122,151,153

Fertility

It is not known whether antihemophilic factor (recombinant) can affect reproductive capacity.1,2,120,121,122,151

Lactation

It is not known whether antihemophilic factor (recombinant) is distributed into human milk.120,121,122,151,153 Because many drugs are distributed into milk, caution should be exercised when antihemophilic factor (recombinant) is used in nursing women.1,120,121,122,151,153 Some manufacturers state that the drug should be used in nursing women only if clinically indicated.2,120,121,151,153

Pharmacology

Antihemophilic factor (recombinant) is structurally similar to and appears to produce the same pharmacologic effects as endogenous human blood coagulation factor VIII.1,3,4,7,8,9,10,12,40,49,50,69,77 Factor VIII is essential for blood clotting and the maintenance of effective hemostasis.12,23,24,73,74,82,95,96 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.7,12,23,24,69,74,82,95,96 Factor Xa then acts in the presence of activated factor V, negatively charged phospholipids, and calcium to convert prothrombin to thrombin.12,24,69,74,82,95,96

While biosynthesis of endogenous factor VIII previously was thought to occur principally in liver parenchymal (hepatic) cells,7,11,12,23,95,96 evidence of normal or elevated levels of this factor in patients with severe hepatocellular disease suggests that other sites (e.g., reticuloendothelial [mononuclear phagocyte] system, sinusoidal endothelial cells, other liver cells) also may be responsible for its synthesis; other sites (e.g., spleen, kidneys, lymphocytes) also may be involved but to a lesser extent.12,95,96 Although endogenous factor VIII is synthesized as a single-chain polypeptide, it apparently circulates in plasma as a 2-chain, metal-ion stabilized complex consisting of a light chain with a molecular weight of 80,000 daltons and a heavy chain with a molecular weight of 90,000-210,000 daltons.7,12,29,69,95,96 The presence of both a light- and heavy-chain subunit is necessary for pharmacologic activity of factor VIII.7,12,82,96

The amino acid sequence contained in the endogenous human factor VIII molecule is composed of 3 distinct structural domains called A, B, and C.7,11,12,29,69,95,96 The carbohydrate-rich B domain does not appear to be necessary for pharmacologic activity and is proteolytically released when factor VIII is activated by thrombin or activated factor X;11,29,95,106 variable cleavage within the B domain results in the varying molecular weights of the heavy-chain subunit.7,11,69,95

In vivo, endogenous human 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.7,11,12,23,29,74,95,96 The binding site for vWF appears to occur within the light-chain subunit of factor VIII.7,12,95,96,106 When factor VIII is activated by thrombin or activated factor X, cleavage occurs within both the heavy and light chains of the molecule and factor VIII is dissociated from vWF.74,106

Patients with hemophilia A 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.1,4,12,23,24,41,69,73,95,96 Hemophilia A is an X-linked recessively inherited coagulation disorder expressed in males and carried by females.4,12,19,23,24,41,73,74,95,96 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.12,24,55,56,73

The average plasma factor VIII activity in healthy individuals is designated as 100% (range: 70-140%).23,24,73,95 Normal hemostasis in the absence of trauma or surgery generally requires at least 25-30% plasma factor VIII activity.23,74,96,106 The clinical severity and frequency of bleeding in patients with hemophilia A correlate with the degree of deficiency in factor VIII activity.23,24,41,73,74 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.23,24,95 Administration of antihemophilic factor (recombinant) to patients with hemophilia A results in increased plasma levels of factor VIII and temporarily corrects the coagulation defect in these patients.1 When antihemophilic factor (recombinant) is used for replacement therapy, administration of 1 unit/kg generally increases plasma factor VIII activity by approximately 2% (0.02 units/mL).1,48,55,74 Treatment with antihemophilic factor (recombinant) normalizes the activated partial thromboplastin time (aPTT), which is prolonged in patients with hemophilia.120,121,122

Studies evaluating the pharmacologic effects of antihemophilic factor (recombinant) compared with plasma-derived antihemophilic factor (human) indicate that the drugs are similar.1,3,4,7,8,9,10,40,49,50,69,77 Results of in vitro studies indicate that recombinant and plasma-derived preparations of antihemophilic factor exhibit similar dose-response curves and activity in one- and two-stage clotting assays as well as identical kinetics of factor X activation, inactivation by activated protein C, and binding to vWF.7,50 In addition, Western blot analysis, amino acid analysis, N -terminal sequence analysis, C -terminal sequence analysis, peptide mapping, and sodium dodecyl sulfate-polyacrylamine gel electrophoresis (SDS-PAGE) have not revealed clinically important differences in the structures of antihemophilic factor (recombinant) and antihemophilic factor (human); differences between the preparations appear to be principally quantitative.7,10,50

Immunogenic Effects

Results of limited preliminary studies indicate that the immunogenicity of antihemophilic factor (recombinant) and antihemophilic factor (human) appear to be similar, and use of antihemophilic factor (recombinant) does not appear to be associated with an increased risk of development of inhibitor antibodies to antihemophilic factor (alloantibodies) compared with that reported for plasma-derived preparations of antihemophilic factor.40,76,83 However, further long-term follow-up of patients receiving antihemophilic factor (recombinant) is necessary before valid conclusions can be made concerning the relative antigenicity of the preparations.4,5,8,40,83,89 (For further information on antihemophilic factor antibodies, see Neutralizing Antibodies to Factor VIII under Cautions: Systemic Effects.)

Antibodies directed against some of the nonhuman mammalian proteins contained in antihemophilic factor (recombinant) have been reported in a few patients,45 but further study is needed to determine whether long-term therapy with antihemophilic factor (recombinant) will result in the development of clinically important antibody titers against these animal proteins.40

Results of studies using various preparations of plasma-derived antihemophilic factor (human) in patients with human immunodeficiency virus (HIV) infection indicate that highly purified preparations may be less immunosuppressive than less purified antihemophilic factor preparations.3,40,75,83,84,107 In one prospective study in HIV-seropositive or -seronegative hemophilia A patients, use of antihemophilic factor (recombinant) for up to 3.5 years in the HIV-seronegative patients did not result in any clinically important alterations in absolute helper/inducer (CD4⁺, T4⁺) T-cell counts, suppressor/cytotoxic (CD8⁺, T8⁺) T-cell counts, or β₂-microglobulin levels.75 In the HIV-seropositive patients, there was a small but statistically significant decrease in the absolute CD4⁺ T-cell count over the 3.5-year study; however, there were no clinically important differences in the percentage of CD4⁺ T-cells or β₂-microglobulin levels.75

Pharmacokinetics

The pharmacokinetics and metabolic fate of antihemophilic factor (recombinant) after parenteral administration have not been fully determined.43,48 The pharmacokinetics of the recombinant preparations appears to be similar to that of plasma-derived antihemophilic factor (human),1,3,4,9,43,48,49,109,120,121 and there is a linear correlation between the dose of antihemophilic factor (recombinant) and plasma levels of factor VIII achieved.43 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.132 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.132 Factor VIII circulates in plasma bound to von Willebrand factor; extravascular distribution is minimal (about 14%).132 Plasma levels of antihemophilic factor (recombinant) reportedly decline in a multiphasic manner in most patients, but also may decline in a monophasic manner.43

The half-life of antihemophilic factor (recombinant) ranges from about 7-17 hours depending on patient age, sampling time, specific assay used, and other factors.1,2,120,121,122,151,153

In pharmacokinetic studies in adults and adolescents with hemophilia A, mean in vivo recovery following administration of antihemophilic factor (recombinant) concentrates have ranged from 1.8-2.8% per unit/kg infused, with lower recovery values observed in pediatric patients.2,120,121,122,151 Incremental recovery values generally remained consistent over time.120,121,122

Chemistry and Stability

Chemistry

Antihemophilic factor (recombinant) is a sterile, lyophilized powder containing biosynthetic blood coagulation factor VIII prepared using recombinant DNA technology.1,7,8,10,11,40,120,121,122 Antihemophilic factor (recombinant) is structurally similar to endogenous human factor VIII and produces the same biologic effects as plasma-derived antihemophilic factor (human).1,3,4,7,8,9,10,40,49,50,69,77,120,121,122 The most important difference between antihemophilic factor (recombinant) and antihemophilic factor (human) is that the biosynthetic preparation is associated with a substantially reduced risk of contamination with blood-borne human viruses compared with that associated with preparations prepared from pooled human plasma.3,4,8,9,14,40,49,50,68,69,73,76,110,122,246

There currently are 2 types of antihemophilic factor (recombinant) preparations commercially available in the US.1,8,120,121,122,151,153 Both types of antihemophilic factor (recombinant) are produced using mammalian cells that have been genetically altered to express human factor VIII and are termed mammalian-derived antihemophilic factor (recombinant);1,8,40 however, different methods are used to express, isolate, harvest, and purify the factor VIII contained in the preparations.1,8,40 Helixate^® FS and Kogenate^® FS are produced using baby hamster kidney (BHK-21) cells.120,121 Advate^®, Novoeight^®, Recombinate^®, ReFacto^®, and Xyntha^® are produced using Chinese hamster ovary (CHO) cells.1,2,122,151,153 Both types of mammalian-derived antihemophilic factor (recombinant) are highly purified glycoproteins containing multiple peptides, including the intact light-chain subunit of factor VIII (molecular weight 80,000 daltons), various extensions of the heavy-chain subunit of the factor (molecular weight 90,000 daltons), and trace amounts of mammalian proteins.1,10,40 Because the preparations are mammalian derived, they are glycosylated.11,109 The carbohydrate side chains of antihemophilic factor (recombinant) are similar, but not identical, to those of endogenous human factor VIII.3,40,109

Potency of antihemophilic factor (recombinant) is expressed in terms of international units (IU, units) of antihemophilic factor activity.1,2,120,121,122,151,153 One unit as defined by the World Health Organization (WHO) International Standard for Antihemophilic Factor is approximately equal to the quantity of factor VIII present in 1 mL of fresh, pooled, normal human plasma.1,72,95,120,121,122,151,153 Potency of Xyntha^® is determined using an assay referenced to the European Pharmacopoeia, but calibrated against the WHO International Standard for factor VIII.151

Advate® and Recombinate®

Advate^® and Recombinate^® antihemophilic factor (recombinant) are produced by introducing human blood coagulation factor VIII genes into CHO cells.1,122

The manufacturing process for Advate^® and Recombinate^® involves coexpression of factor VIII with von Willebrand factor (vWF).1,7,40,108,122 The presence of vWF in the culture helps stabilize the factor VIII molecule and results in a higher yield of antihemophilic factor (recombinant); the vWF is removed substantially during the purification process.1,7,10,11,40,122 Advate^® and Recombinate^® are harvested and purified using column chromatography and monoclonal antibody immunoaffinity chromatography.1,10,122 The principal difference between these preparations is that Recombinate^® contains albumin human,1 but the manufacturing process for Advate^® employs no additives of human or animal origin.122

Advate^® occurs as a white to off-white powder; reconstituted solutions are clear and colorless.122 Reconstituted solutions contain the following stabilizers and excipients: mannitol, trehalose, sodium chloride, histidine, Tris, calcium chloride, polysorbate 80, and glutathione.122 The drug contains not more than 2 ng of vWF per unit of antihemophilic factor (recombinant).122 Advate^® contains no preservatives.122

Recombinate^® occurs as off-white to faint yellow, lyophilized powder; reconstituted solutions are colorless or faint yellow.1 Each mL of reconstituted Recombinate^® contains not more than 12.5 mg of albumin human, 1.5 mg of polyethylene glycol (3350), 0.18 mEq (4 mg) of sodium, and 0.2 mg of calcium.1 Recombinate^® also contain 55 mM of histidine and each unit contains 1.5 mcg of polysorbate 80.1 The drug contains not more than 2 ng of vWF per unit of antihemophilic factor (recombinant).1 Following reconstitution, Recombinate^® solution should be colorless to faint yellow and substantially free from foreign particles.1

Helixate® FS and Kogenate® FS

Helixate^® FS and Kogenate^® FS antihemophilic factor (recombinant) are produced by introducing human factor VIII genes into baby hamster kidney cells.120,121 The cell culture medium contains human plasma protein solution (HPPS) and recombinant insulin, but does not contain any proteins derived from animal sources.120,121 Helixate^® FS and Kogenate^® FS are manufactured using a purification process that includes a solvent/detergent virus inactivation step in addition to use of ion exchange chromatography, monoclonal antibody immunoaffinity chromatography, and other chromatographic steps designed to purify antihemophilic factor (recombinant) and remove contaminating substances.120,121

Helixate^® FS and Kogenate^® FS are stabilized with sucrose (0.9-1.3%), glycine (21-25 mg/mL), and histidine (18-23 mM) rather than with albumin human.120,121 These preparations also contain calcium (2-3 mM), sodium (26-36 mEq/L), chloride (31-40 mEq/L), and polysorbate 80 (64-96 mcg/mL) and trace amounts of imidazole, tributyl phosphate, and copper.120,121 Helixate^® FS and Kogenate^® FS contain no preservatives.120,121

Novoeight®

Novoeight^® antihemophilic factor (recombinant) is produced by introducing human blood coagulation factor VIII genes into CHO cells.153

Novoeight^® is purified using a series of chromatography steps, including immunoaffinity with a monoclonal antibody specific for factor VIII.153 The CHO cell line used to produce Novoeight^® secretes recombinant factor VIII into a cell culture medium that does not contain any human or animal additives.153 The manufacturing process also includes 2 dedicated viral inactivation/clearance steps (detergent treatment and nanofiltration).153

Novoeight^® is commercially available as a white lyophilized powder; reconstituted solutions of the drug contain sodium chloride, histidine, sucrose, polysorbate 80, L-methionine, and calcium chloride dihydrate.153 Novoeight^® contains no preservatives.153

ReFacto®

ReFacto^® antihemophilic factor (recombinant) is produced by introducing human blood coagulation factor VIII genes into CHO cells.2

The CHO cell line used to produce ReFacto^® secretes B-domain deleted recombinant factor VIII into a defined cell culture medium that contains albumin human and recombinant insulin, but does not contain any proteins derived from animal sources.2 ReFacto^® is purified using chromatography.2 Following reconstitution, ReFacto^® occurs as a clear, colorless solution and contains sodium chloride, sucrose, L-histidine, calcium chloride, and polysorbate 80; the drug contains no preservatives.2

Xyntha®

Xyntha^® antihemophilic factor (recombinant) is produced by introducing human blood coagulation factor VIII genes into CHO cells.151 The CHO cell line used to produce Xyntha^® is grown in a chemically defined cell culture medium that contains recombinant insulin, but does not contain any materials derived from human or animal sources.151 Xyntha^® is purified using a series of chromatography steps, including affinity chromatography using a synthetic peptide affinity ligand.151 The process also includes a solvent-detergent viral inactivation step and a virus-retaining nanofiltration step.151

Following reconstitution, Xyntha^® occurs as a clear to slightly opalescent colorless solution that contains sodium chloride, sucrose, l-histidine, calcium chloride, and polysorbate 80; the drug contains no preservatives.151 The surfactant (polysorbate 80) contained in the reconstituted solution is known to increase the rate of extraction of diethylhexylphthalate (DEHP) from PVC containers and administration sets.151 The manufacturer states that this should be considered during preparation and administration of Xyntha^®, including storage time elapsed in a PVC container following reconstitution.151 The tubing of the manufacturer-provided infusion set does not contain DEHP.151

Stability

Commercially available Advate^®, Helixate^® FS, Kogenate^® FS, Novoeight^®, Recombinate^®, ReFacto^®, and Xyntha^® antihemophilic factor (recombinant) lyophilized powders should be stored at 2-8°C (freezing should be avoided).1,2,120,121,122,151,153 Room temperature storage is permitted with all preparations; however, specific recommendations regarding temperature and duration of such storage vary depending on the preparation.1,2,120,121,122,151,153 Recombinate^® lyophilized powder may be stored at room temperature (up to 30°C).1 Helixate^® FS and Kogenate^® FS may be stored for a period of up to 12 months at room temperature (up to 25°C).120,121 ReFacto^® and Xyntha^® lyophilized powders may be stored at room temperature (up to 25°C) for up to 3 months (not to exceed the expiration date).2,151 Advate^® lyophilized powder may be stored at room temperature (up to 30°C) for up to 6 months (not to exceed the expiration date), and Novoeight^® lyophilized powder may be stored at room temperature (up to 30°C) for up to 12 months.122,153 Once stored at room temperature, antihemophilic factor (recombinant) lyophilized powders generally should not be returned to refrigeration.2,120,121,122,153 Vials or prefilled syringes containing diluent provided by the manufacturers should not be frozen since damage could occur.1,2,122,151

The manufacturers of some antihemophilic factor (recombinant) preparations state that prolonged or extreme exposure to light should be avoided.2,120,121,151

Commercially available preparations of antihemophilic factor (recombinant) do not contain preservatives, and solutions of the drugs should be administered within 3 hours (when using Advate^®, Helixate^® FS, Kogenate^® FS, Recombinate^®, ReFacto^®, or Xyntha^®) or 4 hours (when using Novoeight^®) following reconstitution.1,2,120,121,122,151,153 Reconstituted solutions should be stored at room temperature prior to administration.1,2,120,121,122,151,153

1. Baxter Healthcare Corporation. Recombinate^® antihemophilic factor (recombinant) (with 10 mL sterile water for injection) prescribing information. Westlake Village, CA; 2010 Dec.

2. Wyeth. ReFacto^® antihemophilic factor (recombinant) prescribing information. Philadelphia, PA; 2007 Dec.

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