Professional Information

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

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

Trade Names:
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

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

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

Trade Names:
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

Trade Names:
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

Trade Names:
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

Trade Names:
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

Trade Names:
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

Pharmacology

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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 weeks 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 weeks 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

Dosage and duration of treatment depend on the severity of the factor VIII deficiency, the location and extent of bleeding, and the patient's clinical condition. Titrate administered doses to the patient's response. The required dosage can be determined using the following formula:

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

Advate , Hemofil-M

A peak level of 70% is required in a 40 kg child. See individual product information for dosing guidelines for treatment of hemorrhages and surgical procedures.

Short-Term Routine Prophylaxis ( ReFacto )
Adults and Children (all ages including neonates)

IV Administer at least 2 times/wk. In some cases, especially in children, shorter dosage intervals or higher doses may be necessary. In clinical studies, the mean dose/infusion for previously treated patients and previously untreated patients was 29 and 53 units/kg, respectively.

Routine Prophylaxis in Children With No Preexisting Joint Damage ( Kogenate FS )
Children

IV 25 units/kg of body weight every other day.

General Advice

Dosing and duration of treatment varies based on severity of bleeding and types of surgery. See individual product labeling for more information.
AHF concentrates may be administered on a regular schedule for prophylaxis of bleeding.
Administer at room temperature.
As a general rule, 1 unit of AHF activity per kg will increase the circulating AHF level by 2%.
Administer at a rate that is comfortable to the patient.
May administer at a rate of up to 10 mL/min with no significant reactions.

Kogenate FS
Kogenate FS is administered by IV injection after reconstitution of lyophilized powder with supplied diluent.
Administer Kogenate FS within 3 h after reconstitution.
A dose of Kogenate FS may be administered over a period of 1 to 15 min.

ReFacto
ReFacto is administered by IV infusion after reconstitution of the lyophilized powder.
1 unit of factor VIII activity corresponds approximately to the quantity of factor VIII in 1 mL of normal human plasma.

Xyntha
Xyntha is administered by IV infusion after reconstitution of the freeze-dried powder with supplied pre-filled diluent syringe.
Do not administer reconstituted Xyntha in the same tubing or container with other medicinal products.
When reconstituted, contains polysorbate 80, which is known to increase the rate of di-(2-ethylhexy)phthalate (DEHP) extraction from polyvinyl chloride (PVC). Consider this during the preparation and administration of Xyntha , including storage time elapsed in a PVC container following reconstitution.

Storage/Stability

Advate

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

Alphanate

Store in refrigerator at 36° to 46°F. Do not freeze. May be stored at temperatures not exceeding 86°F for up to 2 mo.

Helixate FS , Kogenate FS

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.

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.

ReFacto

Store in refrigerator at 36° to 46°F. Alternatively, may be stored at temperatures not exceeding 77°F for up to 3 mo. At the end of 3 mo, the product should be used immediately or discarded. Avoid freezing. Avoid prolonged exposure of vial to light. Reconstituted product may be stored at room temperature prior to administration. Use within 3 h after reconstitution.

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.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Helixate FS

Slight increase in BP (1%); hypotension (postmarketing).

ReFacto

Hemorrhage (2%); hypotension, vasodilatation (1%); thrombophlebitis of upper arm (postmarketing).

CNS

Advate

Headache (29%).

Alphanate

Headache, lethargy, somnolence.

Helixate FS

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

Koate-DVI

Headache.

ReFacto

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

Xyntha

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

Dermatologic

Alphanate , Hemofil M

Urticaria.

Helixate FS

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

Kogenate FS

Pruritus, rash, urticaria (16%).

ReFacto

Pruritus (2%); rash, urticaria (1%).

EENT

Advate

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

Helixate FS

Rhinitis (1%).

Koate-DVI

Blurred vision.

ReFacto

Taste perversion (3%).

GI

Alphanate

Nausea, vomiting.

Helixate FS

Nausea, unusual taste (1%).

Hemofil M , Monoclate-P

Nausea.

Koate-DVI

Nausea, stomachache.

ReFacto

Nausea (4%); anorexia, diarrhea, GI hemorrhage (1%).

Xyntha

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

Genitourinary

ReFacto

UTI (1%).

Hematologic-Lymphatic

Advate

Decreased coagulation factor VIII, hematoma.

Kogenate FS

Factor VIII inhibition (15%).

ReFacto

Factor VIII inhibitor (32%); factor VIII AB lab increase (26%); Chinese hamster ovary AB lab increase (17%); mouse immunoglobulin G AB lab increase (12%).

Hypersensitivity

Alphanate , Koate-DVI , Monoclate-P

Allergic reaction.

Helixate FS , Kogenate FS

Allergic reactions, anaphylactic reactions (postmarketing).

ReFacto

Anaphylactoid reaction (1%).

Lab Tests

ReFacto

Increased AST (1%).

Local

Alphanate , Monoclate-P

Stinging at infusion site.

Helixate FS

Injection-site reactions (2%).

Kogenate FS

Catheter removal (59%); infusion-site reactions (7%).

ReFacto

Injection-site pain (2%); injection-site reaction (1%).

Musculoskeletal

Advate

Arthralgia (23%).

ReFacto

Arthralgia (1%).

Respiratory

Advate

Cough (15%).

Helixate FS

Dyspnea (postmarketing).

ReFacto

Dyspnea (2%); rhinitis (1%).

Miscellaneous

Advate

Limb injury (35%); pyrexia (17%); accident (15%); fall (13%).

Alphanate , Hemofil M

Chills, fever.

Koate-DVI

Jittery feeling; tingling in the arm, ear, and face.

Kogenate FS

Central line infection (19%); pyrexia (3%).

Monoclate-P

Factor VIII inhibitors, mild chills.

ReFacto

Fever (6%); catheter thrombosis, chills, pain (2%); abdominal pain, catheter infection, edema, infection (1%); arm weakness (postmarketing).

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.

Hemofil M

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.

ReFacto , Xyntha

Monitor patients for development of factor VIII inhibitors.

Pregnancy

Category C .

Lactation

Undetermined.

Children

Advate , Xyntha

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

Alphanate

Safety and efficacy not established in children younger than 16 yr 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 yr of age and older. Use with caution. Individualize dose selection.

Hypersensitivity

Kogenate FS , ReFacto , Xyntha

Allergic-type hypersensitivity (including anaphylaxis) reactions 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

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 either 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.