Antihemophilic Factor

Pronunciation: (AN-tee-HEE-moe-FIL-ik FAK-tor)
Class: Antihemophilic agent

Trade Names

Advate
- Injection, powder for solution antihemophilic factor (AHF) (recombinant) 250 units
- Injection, powder for solution AHF (recombinant) 500 units
- Injection, powder for solution AHF (recombinant) 1,000 units
- Injection, powder for solution AHF (recombinant) 1,500 units
- Injection, powder for solution AHF (recombinant) 2,000 units
- Injection, powder for solution AHF (recombinant) 3,000 units

Alphanate
- Injection, lyophilized powder for solution AHF (human) ≥ 5 units/mg of total protein

Helixate FS
- Injection, lyophilized powder for solution AHF (recombinant) 250 units
- Injection, lyophilized powder for solution AHF (recombinant) 500 units
- Injection, lyophilized powder for solution AHF (recombinant) 1,000 units
- Injection, lyophilized powder for solution AHF (recombinant) 2,000 units

Hemofil M
- Injection, powder for solution AHF (human) 2 to 20 units/mg of total protein

Koate-DVI
- Injection, lyophilized powder for solution AHF (human) 250 units
- Injection, lyophilized powder for solution AHF (human) 500 units
- Injection, lyophilized powder for solution AHF (human) 1,000 units

Kogenate FS
- Injection, lyophilized powder for solution AHF (recombinant) 250 units
- Injection, lyophilized powder for solution AHF (recombinant) 500 units
- Injection, lyophilized powder for solution AHF (recombinant) 1,000 units
- Injection, lyophilized powder for solution AHF (recombinant) 2,000 units

Monoclate-P
- Injection, lyophilized powder for solution AHF (human) 250 units
- Injection, lyophilized powder for solution AHF (human) 500 units
- Injection, lyophilized powder for solution AHF (human) 1,000 units
- Injection, lyophilized powder for solution AHF (human) 1,500 units

Recombinate
- Injection, lyophilized powder for solution AHF (recombinant) 250 units
- Injection, lyophilized powder for solution AHF (recombinant) 500 units
- Injection, lyophilized powder for solution AHF (recombinant) 1,000 units

ReFacto
- Injection, lyophilized powder for solution AHF (recombinant) 250 units
- Injection, lyophilized powder for solution AHF (recombinant) 500 units
- Injection, lyophilized powder for solution AHF (recombinant) 1,000 units
- Injection, lyophilized powder for solution AHF (recombinant) 2,000 units

Xyntha
- Injection, lyophilized powder for solution AHF (recombinant) 250 units
- Injection, lyophilized powder for solution AHF (recombinant) 500 units
- Injection, lyophilized powder for solution AHF (recombinant) 1,000 units
- Injection, lyophilized powder for solution AHF (recombinant) 2,000 units
- Injection, lyophilized powder for solution AHF (recombinant) 3,000 units

Pharmacology

Increases factor VIII plasma levels, temporarily correcting the coagulation defect caused by factor VIII deficiency in patients with hemophilia A.

Pharmacokinetics

Absorption

Advate

Mean C _max is 120 units/dL.

Kogenate FS

Mean C _max at 24 wk is 109 units/dL.

ReFacto

Mean C _max at 12 mo is 2.21 units/mL.

Xyntha

C _max at 6 mo is 1.24 units/mL.

Distribution

Advate

Mean steady-state Vd is 0.47 dL/kg.

Elimination

Advate , Xyntha

Mean half-life is approximately 12 h.

Kogenate FS

Mean half-life at 24 wk is 14 h.

Monoclate-P

Mean half-life is 18 h.

ReFacto

Mean half-life is 11.4 h.

Indications and Usage

Control and prevention of bleeding episodes in patients with hemophilia A; surgical prophylaxis of bleeding in patients with hemophilia A. May be of therapeutic value in patients with factor VIII inhibitors not exceeding 10 Bethesda units (BU)/mL.

Kogenate FS

For routine prophylactic treatment to reduce the frequency of bleeding episodes and the risk of joint damage in children with no preexisting joint damage.

ReFacto

Short-term prophylaxis to reduce the frequency of spontaneous bleeding episodes.

Contraindications

Hypersensitivity to any component of the product.

Advate , Helixate FS , Kogenate FS , ReFacto

Known hypersensitivity to hamster or mouse proteins.

Advate , Kogenate FS

Patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis.

Hemofil M , Monoclate-P

Known hypersensitivity to mouse proteins.

Recombinate

Known hypersensitivity to bovine, hamster, or mouse proteins.

Xyntha

Known hypersensitivity to hamster proteins.

Dosage and Administration

Classical hemophilia
Bleeding prophylaxis Alphanate

Administer prophylactically daily or every other day to raise factor VIII level to approximately 15%.

Helixate FS , Koate-DVI , Kogenate FS

May administer on a regular schedule for prophylaxis of bleeding.

ReFacto

Administer 2 times/wk for short-term prophylaxis. In children, shorter dosage intervals or higher doses may be necessary.

Mild hemorrhage

For hemarthrosis, muscle bleeding episode, or mild oral bleeding episodes.

Advate , Recombinate Adults and Children 6 y of age and older

A dose to achieve a level of 20% to 40% of normal. Infuse every 12 to 24 h for 1 to 3 days until the bleeding episode is resolved or healing is achieved.

Alphanate

A dose sufficient to raise the plasma factor VIII level to 20%.

Helixate FS , Kogenate FS

10 to 20 units/kg to achieve a level of 20% to 40% of normal. Repeat dose if evidence of further bleeding.

Hemofil M

A dose to achieve a level of 20% to 40% of normal. Infuse every 12 to 24 h for 1 to 3 days until the bleeding episode as indicated by pain is resolved or healing is achieved.

Koate-DVI

A single dose of 10 units/kg to raise the factor VIII level approximately 20%.

Monoclate-P

A single infusion to raise the factor VIII level to 30% or more.

ReFacto , Xyntha Adults and Children 6 y of age and older

A dose sufficient to achieve a level of 20% to 40% of normal. Infuse every 12 to 24 h as necessary until resolved for at least 1 day, depending upon the severity of the hemorrhage.

Moderate hemorrhage

For more extensive hemarthrosis, muscle bleeding, or hematoma; known trauma; minor operations, including tooth extraction; hemorrhages into the oral cavity; mild trauma capitis.

Advate , Recombinate Adults and Children 6 y of age and older

A dose sufficient to achieve a level of 30% to 60% of normal. Infuse every 12 to 24 h for 3 days or longer until pain and disability are resolved.

Alphanate

A dose to raise the factor VIII level to 30%.

Helixate FS , Kogenate FS

15 to 30 units/kg to achieve a level of 30% to 60% of normal. Repeat 1 dose at 12 to 24 h if needed.

Hemofil M

A dose to achieve a level of 30% to 60% of normal. Infuse every 12 to 24 h for 3 days or longer.

Koate-DVI , Monoclate

15 to 25 units/kg to raise the factor VIII level to 30% to 50%. If required, repeat dose of 10 to 15 units/kg every 8 to 12 h.

ReFacto , Xyntha Adults and Children 6 y of age and older

A dose to achieve a level of 30% to 60% of normal. Infuse every 12 to 24 h for 3 to 4 days or until adequate local hemostasis is achieved.

Major hemorrhage

For life-threatening bleeding episodes, such as intracranial, intra-abdominal, or intrathoracic hemorrhages; GI bleeding; CNS bleeding; bleeding in the retropharyngeal or retroperitoneal spaces, or iliopsoas sheath.

Advate , Recombinate Adults and Children 6 y of age and older

A dose to achieve a level of 60% to 100% of normal. Infuse every 8 to 24 h until resolution of the bleeding episode has occurred.

Alphanate

Administer 2 times/day over several days to raise the factor VIII level to 30% to 50%.

Helixate FS , Kogenate FS

40 to 50 units/kg to achieve a level of 80% to 100% of normal. Repeat a dose of 20 to 25 units/kg every 8 to 12 h.

Hemofil M

A dose to achieve a level of 60% to 100% of normal. Infuse every 8 to 24 h until threat is resolved.

Koate-DVI , Monoclate

Initial dose of 40 to 50 units/kg to raise the factor VIII level to 80% to 100% of normal. Maintenance dosage of 20 to 25 units/kg every 8 to 12 h.

ReFacto , Xyntha Adults and Children 6 y of age and older

A dose sufficient to achieve a level of 60% to 100% of normal. Infuse every 8 to 24 h until threat is resolved.

Surgery
Advate Adults and Children 6 y of age and older Minor

A dose to achieve a level of 60% to 100% of normal for minor surgery, including tooth extraction. Give a single bolus infusion beginning within 1 h of the operation, with optional additional dosing every 12 to 24 h as needed to control bleeding.

Major

A dose sufficient to achieve a level of 80% to 120% pre- and postoperatively. For bolus infusion replacement, repeat infusions every 8 to 24 h, depending on the desired level of factor VIII and state of wound healing.

Alphanate

Raise the factor VIII level postoperatively to 50% to 80% and maintain at or above 30% for about 2 wk.

Helixate FS , Kogenate FS Major

50 units/kg preoperatively to raise factor VIII level to 100% activity before surgery begins. May repeat after 6 to 12 h initially and for a total of 10 to 14 days until healing is complete.

Hemofil M Minor

A dose to achieve a level of 60% to 80%. A single infusion plus oral antifibrinolytic therapy within 1 h.

Major

A dose to achieve a level of 80% to 100% of normal pre- and postoperatively. Infuse every 8 to 24 h depending on state of healing.

Koate-DVI Major

Preoperative dose of 50 units/kg to raise factor VIII level to 100%. Repeat dose every 6 to 12 h, initially, and for up to 10 to 14 days.

Monoclate Major

1 h preoperatively at a dose sufficient to raise factor VIII levels to achieve 80% to 100% of normal. Give a second dose, half the size of the first dose, 5 h after. Maintain factor VIII levels at least 30% of normal for 10 to 14 days postoperatively.

Recombinate Minor

Infuse to achieve a peak postinfusion factor VIII activity of 60% to 80% of normal in combination with oral antifibrinolytic therapy for minor surgery. Infuse within 1 h of the procedure.

Major

Infuse to achieve a peak postinfusion factor VIII activity of 80% to 100% pre- and postoperatively. Infuse every 8 to 24 h depending on state of healing.

ReFacto Major

A dose to achieve a level of 60% to 100% of normal. Infuse every 8 to 24 h until adequate local hemostasis is achieved.

Xyntha Adults and Children 6 y of age and older Minor

Infuse to achieve a peak postinfusion factor VIII activity of 30% to 60% of normal for minor operations. Infuse every 12 to 24 h for 3 to 4 days or until adequate local hemostasis is achieved. For tooth extraction, a single infusion plus oral antifibrinolytic therapy within one hour may be sufficient.

Major

Infuse to achieve a peak postinfusion factor VIII activity of 60% to 100% of normal. Infuse every 8 to 24 h until adequate local hemostasis and wound healing are achieved.

General Advice

Administer at room temperature.
Administer Kogenate FS , Koate-DVI , Hemofil M , Recombinate , or Xyntha within 3 h after reconstitution.

Storage/Stability

Advate , Alphanate

Store in refrigerator at 36° to 46°F. May be stored at temperatures not exceeding 86°F for 6 mo. Avoid freezing.

Helixate FS , Kogenate FS , ReFacto

Store in refrigerator at 36° to 46°F. Alternatively, may be stored at temperatures not exceeding 77°F for up to 3 mo. Do not freeze. Protect from extreme exposure to light.

Hemofil M , Recombinate

Store in refrigerator at 36° to 46°F or at temperatures not exceeding 86°F. Avoid freezing. Administer within 3 h of reconstitution. Do not freeze.

Koate-DVI

Store in refrigerator at 36° to 46°F. Store lyophilized powder at temperatures of up to 77°F for up to 6 mo. Avoid freezing. Administer within 3 h of reconstitution.

Monoclate-P

Store in refrigerator at 36° to 46°F. Alternatively, may be stored at a temperature not exceeding 77°F for up to 6 mo. Avoid freezing.

Xyntha

Store in refrigerator at 36° to 46°F. Alternatively, may be stored at temperatures not exceeding 77°F for up to 3 mo. The diluent syringe may be stored at 36° to 77°F. Avoid freezing. Avoid prolonged exposure of vial to light.

Drug Interactions

None well documented.

Adverse Reactions

Cardiovascular

Advate

Hot flushes (2%).

Helixate FS , Kogenate FS

Increased blood pressure (1%); hypotension (postmarketing).

Recombinate

Flushing.

ReFacto

Hypotension, vasodilation (1%).

Xyntha

Headache (24%); asthenia (5%).

CNS

Advate

Headache (29%); dizziness (2%).

Helixate FS , Kogenate FS

Dizziness (2%); depersonalization (1%).

Koate-DVI

Headache, jittery feeling, tingling in the arm, ear, and face.

Recombinate

Fatigue.

ReFacto

Dizziness, headache (4%); asthenia, chills (2%); somnolence (1%).

Dermatologic

Advate

Increased sweating, pruritus (1%).

Helixate FS , Kogenate FS

Rash (2%); pruritus (1%); urticaria (postmarketing).

Hemofil M

Urticaria (rare).

ReFacto

Pruritus (23%), rash, urticaria (1%).

EENT

Advate

Nasopharyngitis (15%); pharyngolaryngeal pain (11%); dysgeusia (1%).

Helixate FS , Kogenate FS , ReFacto

Rhinitis (1%).

Koate-DVI

Blurred vision.

Recombinate

Nosebleeds.

GI

Advate

Abdominal pain upper, diarrhea, nausea (1%).

Helixate FS , Kogenate FS

Nausea, unusual taste (1%).

Hemofil M

Nausea (rare).

Koate-DVI

Nausea, stomachache.

Monoclate-P , Recombinate

Nausea.

ReFacto

Nausea (17%); taste perversion (3%); abdominal pain, anorexia, diarrhea, GI hemorrhage (1%).

Xyntha

Nausea (9%); diarrhea, vomiting (5%).

Hematologic-Lymphatic

Advate

Bleeding tendency, decreased coagulation factor VIII, decreased hematocrit, hematoma (1%).

Alphanate

Acute hemolytic anemia, hyperfibrinogenemia (rare), increased bleeding tendency.

ReFacto

Factor VIII inhibitor (32%); factor VIII AB lab increase (26%); Chinese hamster ovary AB lab increase (17%); mouse IgG AB increase (13%); hemorrhage (2%).

Local

Advate

Catheter-related infection (1%).

Helixate FS , Kogenate FS

Local injection-site reactions (1%).

Monoclate-P

Stinging at infusion site.

ReFacto

Injection-site pain (3%); catheter infection, catheter miscellaneous, catheter thrombosis (1%).

Metabolic-Nutritional

ReFacto

Edema (1%).

Musculoskeletal

Advate

Arthralgia (23%).

ReFacto

Arthralgia (1%).

Respiratory

Advate

Cough (15%); dyspnea (1%).

ReFacto

Dyspnea (4%).

Miscellaneous

Advate

Limb injury (35%); accident, pyrexia (17%); fall (13%).

Hemofil M

Chills, fever (rare).

Monoclate-P

Allergic reactions, mild chills.

ReFacto

Fever (6%); pain, UTI (2%); anaphylactic reaction, AST increased, infection (1%).

Xyntha

Pyrexia (41%).

Precautions

Monitor

Identification of clotting defect as factor VIII deficiency is essential before administering AHF. When indicated, monitor plasma factor VIII activity levels by one-stage clotting assay to confirm that adequate factor VIII levels have been achieved and are maintained.

Determine pulse rate before and during administration. If a sufficient increase occurs, reducing the rate of administration or temporarily halting the injection usually allows the symptoms to disappear promptly.

Monitor patients for development of factor VIII inhibitors.

Pregnancy

Category C .

Lactation

Undetermined.

Children

Advate , Xyntha

Studies in previously treated patients younger than 6 y of age are currently ongoing. A least 54 subjects younger than 16 y of age have been treated with Advate in phase 2/3 studies.

Alphanate

Safety and efficacy not established in children younger than 16 y of age.

Helixate FS , Kogenate FS , Recombinate , ReFacto

Appropriate for use in children of all ages, including neonates.

Koate-DVI

Safety and efficacy not established in children.

Monoclate-P

Safety and efficacy have been demonstrated in 33 children; as in adults, base dosing upon weight.

Elderly

Helixate FS , Kogenate FS , Monoclate-P , ReFacto , Xyntha

Studies did not include subjects 65 y of age and older. Use with caution; individualize dose selection.

Hypersensitivity

Kogenate FS , ReFacto , Xyntha

Allergic-type hypersensitivity reactions, including anaphylaxis, may occur.

Bovine/Hamster/Mouse protein antibodies

Hemofil M and Monoclate-P contain trace amounts of mouse proteins; therefore, patients may develop hypersensitivity to these proteins. Advate , Helixate FS , Kogenate FS , and ReFacto contain trace amounts of mouse and hamster proteins; therefore, patients may develop hypersensitivity to these proteins. Xyntha contains trace amounts of hamster proteins; therefore, patients may develop hypersensitivity to these proteins. Recombinate contains trace amounts of bovine, hamster, and mouse proteins; therefore, patients may develop hypersensitivity to these proteins.

Hemolysis

When large or frequently repeated doses are needed in patients of blood group A, B, or AB, intravascular hemolysis may occur; monitor the hematocrit and direct Coombs tests.

Infections

Alphanate , Hemofil M , Koate-DVI , and Monoclate-P are made from human blood, which may contain infectious agents, such as viruses, that can cause disease.

Latex sensitivity

Hemofil M , Recombinate

Certain components used in packaging contain dry natural latex rubber that may cause allergic reactions in latex-sensitive individuals.

Neutralizing antibodies

Neutralizing antibodies (inhibitors) of factor VIII may occur in patients with hemophilia A. Inhibitor titers above 10 BU/mL are likely to make control of hemostasis with AHF concentrates impossible or impractical because of the large doses required. Alternative means of treating or preventing bleeding may be required.

Viruses

Some viruses, such as parvovirus B19 or hepatitis A, are particularly difficult to remove or inactivate at this time and may seriously affect seronegative pregnant women or immunocompromised individuals.

von Willebrand disease

Not effective in controlling the bleeding of patients with von Willebrand disease.

Overdosage

Symptoms

Alphanate

Massive doses have rarely resulted in acute hemolytic anemia, hyperfibrinogenemia, or increased bleeding tendency.

Xyntha

No symptoms of overdose have been reported.

Patient Information

Instruct patients to discontinue use and contact health care provider if early signs or symptoms of hypersensitivity or anaphylaxis, including generalized urticaria, hypotension, rash with itching, tightness of the chest, and wheezing, occur.
Advise patients that some viruses, such as parvovirus B19 or hepatitis A, are particularly difficult to remove or inactivate at this time and may seriously affect seronegative pregnant women or immunocompromised individuals.
Advise patients to contact health care provider if they experience a lack of clinical response to factor VIII replacement therapy because this may be a manifestation of an inhibitor.
Advise patients to bring an adequate supply of agent for anticipated treatment when traveling and to consult health care provider before traveling.

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