Antihemophilic Factor (Human)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Kit, Intravenous:

Monoclate-P: ~1000 units [DSC], ~1500 units [DSC] [contains mouse (murine) and/or hamster protein]

Solution Reconstituted, Intravenous:

Koate: ~250 units (1 ea); ~500 units (1 ea); ~1000 units (1 ea) [contains albumin human, polyethylene glycol, polysorbate 80]

Solution Reconstituted, Intravenous [preservative free]:

Hemofil M: ~250 units (1 ea); ~500 units (1 ea); ~1000 units (1 ea); ~1700 units (1 ea) [contains albumin human, polyethylene glycol]

Koate-DVI: ~250 units (1 ea); ~500 units (1 ea); ~1000 units (1 ea) [contains albumin human, polyethylene glycol, polysorbate 80]

Pharmacology

Mechanism of Action

Protein (factor VIII) in normal plasma which is necessary for clot formation and maintenance of hemostasis; activates factor X in conjunction with activated factor IX; activated factor X converts prothrombin to thrombin, which converts fibrinogen to fibrin, and with factor XIII forms a stable clot

Pharmacokinetics/Pharmacodynamics

Distribution

Does not readily cross the placenta

Half-Life Elimination

Mean: 14.8 to 17.5 hours

Use: Labeled Indications

Hemophilia A: Control and prevention of bleeding episodes in patients with hemophilia A (classic hemophilia); perioperative management of hemophilia A.

Limitations of use: Not indicated for the treatment of von Willebrand disease.

Contraindications

Hypersensitivity (eg, anaphylaxis) to antihemophilic factor (human) or any component of the formulation; hypersensitivity to mouse proteins (Hemofil M and Monoclate-P only).

Dosage and Administration

Dosing: Adult

Hemophilia A: IV: Individualize dosage based on coagulation studies performed prior to treatment and at regular intervals during treatment. In general, administration of factor VIII 1 unit/kg will increase circulating factor VIII levels by ~2 units/dL. Refer to product information for specific manufacturer recommended dosing. Alternatively, the World Federation of Hemophilia (WFH) has recommended general dosing for factor VIII products.

Dosage based on desired factor VIII increase (%):

To calculate dosage needed based on desired factor VIII increase (%):

Body weight (kg) x 0.5 units/kg x desired factor VIII increase (%) = units factor VIII required

For example:

50 kg x 0.5 units/kg x 30 (% increase) = 750 units factor VIII

Dosage based on expected factor VIII increase (%):

It is also possible to calculate the expected % factor VIII increase:

(# units administered x 2%/units/kg) divided by body weight (kg) = expected % factor VIII increase

For example:

(1400 units x 2%/units/kg) divided by 70 kg = 40%

World Federation of Hemophilia (WFH) treatment recommendations when no significant resource constraint exists (WFH [Srivastava 2013]):

World Federation of Hemophilia (WFH) treatment recommendations when no significant resource constraint exists (Srivastava 2013):

Desired Factor VIII Level to Maintain and Duration Based on Site of Hemorrhage/Clinical Situation:

Joint: 40 to 60 units/dL for 1 to 2 days, may be longer if response is inadequate

Superficial muscle (no neurovascular compromise): 40 to 60 units/dL for 2 to 3 days, sometimes longer if response is inadequate

Iliopsoas and deep muscle with neurovascular injury, or substantial blood loss: Initial: 80 to 100 units/dL for 1 to 2 days; Maintenance: 30 to 60 units/dL for 3 to 5 days, sometimes longer as secondary prophylaxis during physiotherapy

CNS/head: Initial: 80 to 100 units/dL for 1 to 7 days; Maintenance: 50 units/dL for 8 to 21 days

Throat and neck: Initial: 80 to 100 units/dL for 1 to 7 days; Maintenance: 50 units/dL for 8 to 14 days

Gastrointestinal: Initial: 80 to 100 units/dL for 7 to 14 days; Maintenance: 50 units/dL (duration not specified)

Renal: 50 units/dL for 3 to 5 days

Deep laceration: 50 units/dL for 5 to 7 days

Surgery (major): Preop: 80 to 100 units/dL; Postop: 60 to 80 units/dL for 1 to 3 days; then 40 to 60 units/dL for 4 to 6 days; then 30 to 50 units/dL for 7 to 14 days

Surgery (minor): Preop: 50 to 80 units/dL; Postop: 30 to 80 units/dL for 1 to 5 days depending on procedure type

Note: Factor VIII level may either be expressed as units/dL or as %. Dosing frequency most commonly corresponds to the half-life of factor VIII but should be determined based on an assessment of factor VIII levels before the next dose.

Continuous infusion (for patients who require prolonged periods of treatment [eg, intracranial hemorrhage or surgery] to avoid peaks and troughs associated with intermittent infusions) (Batorova 2002; Batorova 2012; Poon 2012; Rickard 1995; WFH [Srivastava 2013]): Following initial bolus to achieve the desired factor VIII level, initiate 2 to 4 units/kg/hour; adjust dose based on frequent factor assays and calculation of factor VIII clearance at steady-state using the following equations:

Factor VIII clearance (mL/kg/hour) = (current infusion rate in units/kg/hour) divided by (plasma level in units/mL)

New infusion rate (units/kg/hour) = (factor VIII clearance in mL/kg/hour) x (desired plasma level in units/mL)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Individualize dosage based on coagulation studies performed prior to and during treatment at regular intervals:

Hemophilia A: Children and Adolescents: IV: For every 1 international unit per kg body weight of AHF (human) administered, factor VIII level should increase by 2%; calculated dosage should be adjusted to the actual vial size

Formula to calculate dosage required, based on desired increase in factor VIII (% of normal) (Note: This formula assumes that the patient's baseline AHF level is <1%): Units required = Body weight (kg) x 0.5 x desired increase in factor VIII (units/dL or % of normal)

Hospitalized patients: 20-50 units/kg/dose; may be higher for special circumstances. Dose can be given every 12-24 hours and more frequently in special circumstances.

Hemophilia A with high titer of inhibitor antibody: 50-75 units/kg/hour has been given

General dosing guidelines (consult individual product labeling for specific dosage recommendations): Children and Adolescents: IV:

Minor hemorrhage (required peak postinfusion AHF level: 20% to 40%): 10-20 units/kg; repeat every 12-24 hours for 1-3 days until bleeding is resolved or healing achieved; mild superficial or early hemorrhages may respond to a single dose

Moderate hemorrhage (required peak postinfusion AHF level: 30% to 60%): 15-30 units/kg; repeat every 12-24 hours for ≥3 days until pain and disability are resolved

Alternatively (to achieve peak postinfusion AHF level: 50%) Initial: 25 units/kg; maintenance: 10-15 units/kg every 8-12 hours

Severe/life-threatening hemorrhage (required peak postinfusion AHF level: 60% to 100%): 30-50 units/kg; repeat every 8-24 hours until threat is resolved

Alternatively (to achieve peak postinfusion AHF level: 80% to 100%): 40-50 units/kg; maintenance: 20-25 units/kg every 8-12 hours

Minor surgery (required peak postinfusion AHF level: Range 30% to 80%): 15-40 units/kg; dose is highly dependent upon procedure and specific product recommendations; for some procedures, a single dose plus oral antifibrinolytic therapy within 1 hour is sufficient; in other procedures, may repeat dose every 12-24 hours as needed

Major surgery (required peak pre- and postsurgery AHF level: 80% to 100%): 40-50 units/kg; repeat every 8-24 hours depending on state of healing

Prophylaxis: May also be given on a regular schedule to prevent bleeding

Reconstitution

If refrigerated, the dried concentrate and diluent should be warmed to room temperature before reconstitution. Gently swirl or rotate vial after adding diluent; do not shake vigorously.

Continuous infusion (off-label method of administration): Further dilution after initial reconstitution is unnecessary (Batorova 2012).

Administration

IV:

Hemofil M, Koate: Administer at a rate comfortable to the patient (≤10 mL/minute).

Monoclate-P: Administer at a rate comfortable to the patient (~2 mL/minute).

According to the World Federation of Hemophilia (WFH), infuse by slow IV injection at a rate not to exceed 3 mL/minute; may also administer as a continuous infusion in select patients (WFH [Srivastava 2013]). When administering as a continuous infusion, may use a portable mini-pump or syringe pump (Batorova 2012).

Storage

Store under refrigeration, 2°C to 8°C (36°F to 46°F); do not freeze. Use within 3 hours of reconstitution. Do not refrigerate after reconstitution, precipitation may occur.

Hemofil M: May also be stored at room temperature not to exceed 30°C (86°F).

Koate; Monoclate-P: May also be stored at 25°C (77°F) for ≤6 months. Store in original package to protect from light.

Drug Interactions

There are no known significant interactions.

Adverse Reactions

1% to 10%:

Hematologic & oncologic: Increased Factor VIII inhibitors (6%)

Local: Inflammation at injection site (2%)

<1%: Chest tightness, dizziness, dysgeusia, fever, headache

Frequency not defined: Hypersensitivity: Hypersensitivity reaction

Postmarketing: Abdominal pain, anaphylaxis, bradycardia, bronchospasm, chest pain, chills, cough, cyanosis, diarrhea, dyspnea, edema, facial edema, fatigue, flushing, hyperhidrosis, hyperventilation, hypotension, irritability, musculoskeletal pain, nausea, ocular hyperemia, pruritus, skin rash, tachycardia, urticaria, visual impairment, vomiting

Warnings/Precautions

Concerns related to adverse effects:

• Antibody formation: The development of factor VIII antibodies has been reported with antihemophilic factors; monitor for signs of formation of antibodies to factor VIII. Suspect factor VIII antibodies if the plasma factor VIII level does not increase as expected or if bleeding is not controlled after administration.
• Hypersensitivity reactions: Hypersensitivity reactions (including anaphylaxis) may occur; discontinue immediately if hypersensitivity symptoms occur and administer appropriate treatment.

Special populations:

• Blood types A, B, and AB: Contains trace amounts of blood groups A and B isohemagglutinins; use caution when large or frequently repeated doses are given to individuals with blood groups A, B, and AB. Monitor patients for signs of intravascular hemolysis and falling hematocrit; discontinue therapy and consider administration of serologically compatible type O red blood cells if progressive hemolytic anemia occurs.

Dosage form specific issues:

• Albumin: Products vary by preparation method; final formulations contain human albumin.
• Human plasma: Product of human plasma; may potentially contain infectious agents which could transmit disease. Screening of donors, as well as testing and/or inactivation or removal of certain viruses, reduces the risk. Infections thought to be transmitted by this product should be reported to the manufacturer. Hepatitis A and B vaccination is recommended for all patients receiving plasma derivatives.
• Mouse protein: Hemofil M and Monoclate-P contain trace amounts of mouse protein; use is contraindicated in patients with hypersensitivity to mouse protein.
• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.
• von Willebrand factor: Some products may contain naturally occurring von Willebrand factor for stabilization; however, efficacy has not been established for the treatment of von Willebrand disease.

Other warnings/precautions:

• Appropriate use: Dosage requirements will vary in patients with factor VIII inhibitors; optimal treatment should be determined by clinical response. Frequency of use is determined by the severity of the disorder or bleeding pattern.

Monitoring Parameters

Heart rate and blood pressure (before and during IV administration); AHF levels prior to and during treatment; in patients with circulating inhibitors, the inhibitor level should be monitored; hematocrit; monitor for signs and symptoms of intravascular hemolysis; bleeding

When administering as a continuous infusion, monitor frequently for pump failure (WFH [Srivastava 2013]).

Pregnancy

Pregnancy Considerations

Pregnant hemophilia A carriers may have an increased bleeding risk following abortion, invasive procedures, miscarriage, and delivery; close surveillance is recommended. Factor VIII levels should be monitored at the first antenatal visit, once or twice during the third trimester, prior to surgical or invasive procedures, and at delivery. Although factor VIII concentrations increase in pregnant patients, factor VIII replacement is recommended if concentrations are <0.5 IU/mL and any of the following occur: need for invasive procedures (including delivery), spontaneous miscarriage, insertion and removal of epidural catheters, or active bleeding. Hemostatic factor VIII concentrations should be maintained for at least 3 to 5 days following invasive procedures or postpartum. If a replacement product is indicated, a recombinant product is preferred (NHF 2017; RCOG [Pavord 2017]; WFH [Srivastava 2013]).

Patient Education

What is this drug used for?

• It is used to treat hemophilia.
• It is used to treat or prevent bleeding.

Frequently reported side effects of this drug

• Anxiety
• Headache
• Abdominal pain
• Nausea

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Parvovirus B19 or hepatitis A infection like chills, severe fatigue, runny nose, rash, joint pain, lack of appetite, nausea, vomiting, abdominal pain, or yellow skin or eyes
• Shortness of breath
• Severe dizziness
• Passing out
• Burning or numbness feeling
• Restlessness
• Blurred vision
• Flushing
• Severe loss of strength and energy
• Fast heartbeat
• Chest pain
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.