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Antihemophilic Factor/von Willebrand Factor Complex (Human)

Pronunciation

(an tee hee moe FIL ik FAK tor von WILL le brand FAK tor KOM plex HYU man)

Index Terms

  • AHF (Human)
  • Factor VIII (Human)/von Willebrand Factor
  • Factor VIII Concentrate
  • FVIII/vWF
  • von Willebrand Factor/Factor VIII Complex
  • VWF/FVIII Concentrate
  • VWF:RCo
  • vWF:RCof

Dosage Forms

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

Injection, powder for reconstitution [human derived]:

Alphanate:

250 units [Factor VIII and VWF:RCo ratio varies by lot; contains albumin and polysorbate 80; packaged with diluent]

500 units [Factor VIII and VWF:RCo ratio varies by lot; contains albumin and polysorbate 80; packaged with diluent]

1000 units [Factor VIII and VWF:RCo ratio varies by lot; contains albumin and polysorbate 80; packaged with diluent]

1500 units [Factor VIII and VWF:RCo ratio varies by lot; contains albumin and polysorbate 80; packaged with diluent]

2000 units [Factor VIII and VWF:RCo ratio varies by lot; contains albumin and polysorbate 80; packaged with diluent]

Humate-P:

FVIII 250 units and VWF:RCo 600 units [contains albumin; packaged with diluent]

FVIII 500 units and VWF:RCo 1200 units [contains albumin; packaged with diluent]

FVIII 1000 units and VWF:RCo 2400 units [contains albumin; packaged with diluent]

Wilate:

FVIII 450 units and VWF:RCo 450 units [contains polysorbate 80 (in diluent); packaged with diluent] [DSC]

FVIII 500 units and VWF:RCo 500 units [contains polysorbate 80 (in diluent); packaged with diluent]

FVIII 900 units and VWF:RCo 900 units [contains polysorbate 80 (in diluent); packaged with diluent] [DSC]

FVIII 1000 units and VWF:RCo 1000 units [contains polysorbate 80 (in diluent); packaged with diluent]

Brand Names: U.S.

  • Alphanate
  • Humate-P
  • Wilate

Pharmacologic Category

  • Antihemophilic Agent
  • Blood Product Derivative

Pharmacology

Factor VIII and von Willebrand factor (VWF), obtained from pooled human plasma, are used to replace endogenous factor VIII and VWF in patients with hemophilia or VWD. Factor VIII in conjunction with activated factor IX, activates factor X which converts prothrombin to thrombin and fibrinogen to fibrin. VWF promotes platelet aggregation and adhesion to damaged vascular endothelium and acts as a stabilizing carrier protein for factor VIII. (Circulating levels of functional VWF are measured as ristocetin cofactor activity [VWF:RCo].)

Distribution

Vdss: VWF:RCo: 53 to 72 mL/kg

Onset of Action

Shortening of bleeding time: Immediate; maximum effect: 1 to 2 hours

Duration of Action

VWD: Shortening of bleeding time: <6 hours postinfusion; presence of VWF multimers detected in the plasma: ≥24 hours

Half-Life Elimination

Factor VIII coagulant activity (FVIII:C): Range: 8-28 hours in patients with hemophilia A

VWF:RCo: Range: 3-34 hours in patients with VWD

Special Populations: Gender

Does not appear to affect the pharmacokinetics after administration of Humate-P. Women had a higher clearance of vWF:RCo than men when given Wilate. Clinical significance is not known.

Use: Labeled Indications

Factor VIII deficiency: Alphanate, Humate-P: Prevention and treatment of hemorrhagic episodes in patients with hemophilia A (classical hemophilia); Note: Wilate is not approved for use in patients with hemophilia A or acquired factor VIII deficiency

von Willebrand disease (VWD):

Alphanate: Prophylaxis with surgical and/or invasive procedures in patients with VWD when desmopressin is either ineffective or contraindicated; Note: Not indicated for patients with severe VWD (type 3) undergoing major surgery

Humate-P: Treatment of spontaneous or trauma-induced bleeding, as well as prevention of excessive bleeding during and after surgery in patients with severe VWD, including mild or moderate disease where use of desmopressin is known or suspected to be inadequate; Note: Not indicated for the prophylaxis of spontaneous bleeding episodes

Wilate: Treatment of spontaneous and trauma-induced bleeding in patients with severe VWD, including mild or moderate disease where use of desmopressin is known or suspected to be inadequate or contraindicated; Note: Not indicated for prophylaxis of spontaneous bleeding or prevention of excessive bleeding during and after surgery

Contraindications

History of anaphylactic or severe systemic response to antihemophilic factor or von Willebrand factor formulations; hypersensitivity to any component of the formulation

Dosage

Factor VIII deficiency: General guidelines (consult specific product labeling for Alphanate or Humate-P): Children and Adults: 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.

Minor hemorrhage: Loading dose: FVIII:C 15 units/kg to achieve FVIII:C plasma level ~30% of normal. If second infusion is needed, half the loading dose may be given once or twice daily for 1 to 2 days.

Moderate hemorrhage: Loading dose: FVIII:C 25 units/kg to achieve FVIII:C plasma level ~50% of normal; Maintenance: FVIII:C 15 units/kg every 8 to 12 hours for 1 to 2 days in order to maintain FVIII:C plasma levels at 30% of normal. Repeat the same dose once or twice daily for up to 7 days or until adequate wound healing.

Life-threatening hemorrhage/major surgery: Loading dose: FVIII:C 40 to 50 units/kg; Maintenance: FVIII:C 20 to 25 units/kg every 8 to 12 hours to maintain FVIII:C plasma levels at 80% to 100% of normal for 7 days. Continue same dose once or twice daily for another 7 days in order to maintain FVIII:C levels at 30% to 50% of normal.

von Willebrand disease (VWD): Treatment:

Humate-P: Children and Adults: 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 would be expected to raise circulating VWF:RCo ~5 units/dL

Type 1, mild VWD: Minor hemorrhage (if desmopressin is not appropriate) or major hemorrhage:

Loading dose: VWF:RCo 40 to 60 units/kg

Maintenance dose: VWF:RCo 40 to 50 units/kg every 8 to 12 hours for 3 days, keeping VWF:RCo nadir >50%; follow with 40 to 50 units/kg daily for up to 7 days

Type 1, moderate or severe VWD:

Minor hemorrhage: VWF:RCo 40 to 50 units/kg for 1 to 2 doses

Major hemorrhage:

Loading dose: VWF:RCo 50 to 75 units/kg

Maintenance dose: VWF:RCo 40 to 60 units/kg every 8 to 12 hours for 3 days to keep the VWF:RCo nadir >50%, then 40 to 60 units/kg daily for a total of up to 7 days

Types 2 and 3 VWD:

Minor hemorrhage: VWF:RCo 40 to 50 units/kg for 1 to 2 doses

Major hemorrhage:

Loading dose: VWF:RCo 60 to 80 units/kg

Maintenance dose: VWF:RCo 40 to 60 units/kg every 8 to 12 hours for 3 days, keeping the VWF:RCo nadir >50%; follow with 40 to 60 units/kg daily for a total of up to 7 days

Wilate: Children and Adults: IV:

Minor hemorrhage:

Loading dose: VWF:RCo: 20 to 40 units/kg

Maintenance dose: 20 to 30 units/kg every 12 to 24 hours for ≤3 days, keeping the VWF:RCo nadir >30%

Major hemorrhage:

Loading dose: VWF:RCo: 40 to 60 units/kg

Maintenance dose: 20 to 40 units/kg every 12 to 24 hours for 5 to 7 days, keeping the VWF:RCo nadir >50%

von Willebrand disease (VWD): Prophylaxis:

Alphanate: Surgery/invasive procedure prophylaxis (except patients with type 3 undergoing major surgery):

Children: IV:

Preoperative dose: VWF:RCo: 75 units/kg 1 hour prior to surgery

Maintenance dose: VWF:RCo: 50 to 75 units/kg every 8 to 12 hours as clinically needed. For minor procedures, maintain FVIII:C activity level of 40 to 50 units/dL during postoperative days 1 to 3; for major procedures, maintain FVIII:C activity level of 100 units/dL for 3 to 7 days. Do not exceed FVIII:C activity level of 150 units/dL.

Adults: IV:

Preoperative dose: VWF:RCo: 60 units/kg 1 hour prior to surgery

Maintenance dose: VWF:RCo: 40 to 60 units/kg every 8 to 12 hours as clinically needed. For minor procedures, maintain FVIII:C activity level of 40 to 50 units/dL during postoperative days 1 to 3; for major procedures, maintain VFIII:C activity level of 100 units/dL for 3 to 7 days. Do not exceed FVIII:C activity level of 150 units/dL.

Humate-P: Surgery/procedure prevention of bleeding: Children and Adults: IV:

Emergency surgery: Administer VWF:RCo 50 to 60 units/kg; monitor trough coagulation factor levels for subsequent doses

Surgical management (nonemergency):

Loading dose calculation based on baseline target VWF:RCo: (Target peak VWF:RCo - Baseline VWF:RCo) x weight (in kg) / IVR = units VWF:RCo required. Administer loading dose 1 to 2 hours prior to surgery. Note: If in vivo recovery (IVR) not available, assume 2 units/dL per units/kg of VWF:RCo product administered.

Target concentrations for VWF:RCo following loading dose:

Major surgery: 100 units/dL

Minor surgery: 50 to 60 units/dL

Maintenance dose: Initial: One-half loading dose, followed by subsequent dosing determined by target trough concentrations, generally every 8-12 hours. Patients with shorter half-lives may require dosing every 6 hours.

Target maintenance trough VWF:RCo concentrations:

Major surgery: >50 units/dL for up to 3 days, followed by >30 units/dL for a minimum total treatment of 72 hours

Minor surgery: ≥30 units/dL for a minimum duration of 48 hours

Oral surgery: ≥30 units/dL for a minimum duration of 8 to 12 hours

Elderly: Response in the elderly is not expected to differ from that of younger patients; dosage should be individualized

Dosage adjustment in renal impairment: There are no dosage adjustments provided in the manufacturer’s labeling.

Dosage adjustment in hepatic impairment: There are no dosage adjustments provided in the manufacturer’s labeling.

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. Use provided filter transfer set to withdraw solution from vial of Alphanate or Humate-P; remove filter spike prior to administration. Use provided transfer device to reconstitute Wilate. Refer to product labeling for specific details.

Administration

Alphanate: Infuse slowly (maximum rate: 10 mL/minute)

Humate-P: Infuse slowly (maximum rate: 4 mL/minute)

Wilate: Infuse slowly at a rate of 2 to 4 mL/minute

Storage

Alphanate: Store intact vials at ≤25°C (77°F); do not freeze. May store reconstituted solution at room temperature (≤30°C). Use within 3 hours of reconstitution; do not refrigerate after reconstitution.

Humate-P®: Store unopened vials at ≤25°C (≤77°F) until expiration date on label; avoid freezing. Use within 3 hours of reconstitution. Do not refrigerate after reconstitution, precipitation may occur.

Wilate: Store intact vials for ≤36 months under refrigeration at 2°C to 8°C (36°F to 46°F); do not freeze. Protect from light. Intact vials may also be stored at room temperature (not to exceed 25˚C/77˚F) for ≤6 months. Once stored at room temperature, do not return to the refrigerator. Following reconstitution, use solution immediately.

Drug Interactions

There are no known significant interactions.

Adverse Reactions

Frequency not always defined.

Cardiovascular: Facial edema (>5%), peripheral edema (1%), vasodilatation (1%), chest pain, orthostatic hypotension, phlebitis, pulmonary embolism (large doses), subdural hematoma, thrombophlebitis

Central nervous system: Chills (>5%), fatigue (>5%), pain (>5%), paresthesia (3% to >5%), dizziness (1%), cerebral hemorrhage, drowsiness, headache, insomnia

Dermatologic: Skin rash (>5%), pruritus (1% to >5%), urticaria (1% to >5%), diaphoresis

Endocrine & metabolic: Hypermenorrhea

Gastrointestinal: Nausea (24%; postoperative), constipation, gastrointestinal hemorrhage, sore throat, vomiting

Genitourinary: Urinary retention, urinary tract infection

Hematologic & oncologic: Hemorrhage (30%; postoperative), pseudothrombocytopenia (1%; severe), anemia, decreased hematocrit (moderate), increased factor VIII inhibitors, von Willebrand factor inhibitor formation

Hepatic: Increased serum ALT

Hypersensitivity: Anaphylaxis, hypersensitivity reaction (2%)

Infection: Parvovirus B19 seroconversion (3%; not accompanied by clinical signs of disease), infection, sepsis

Local: Pain at injection site

Neuromuscular & skeletal: Arthralgia (>5%), limb pain (1%), back pain

Renal: Pyelonephritis

Respiratory: Respiratory distress (>5%), cough, pharyngitis

Miscellaneous: Postoperative pain (17%), fever (>5%)

Postmarketing and/or case reports (Limited to important or life-threatening): Antibody development (neutralizing), cardiorespiratory arrest, hemolysis, hypervolemia, parotid gland enlargement, seizure, shock, tachycardia, thromboembolic complications, venous thrombosis (femoral)

Warnings/Precautions

Concerns related to adverse effects:

• Antibody formation: Neutralizing antibodies (inhibitors) may develop to factor VIII or von Willebrand factor, particularly in patients with type 3 (severe) von Willebrand disease. Patients who develop antibodies against von Willebrand factor will not have an effective clinical response to therapy and infusions may result in anaphylactic reactions; these patients should be managed by an experienced physician and alternatives to therapy should be considered. Any patient who has an inadequate response to therapy or a severe adverse reaction should be evaluated for the presence of inhibitors.

• Hypersensitivity reactions: Allergic reactions, including anaphylaxis, have been observed; monitor patients closely during infusion; patients experiencing anaphylactic reactions should be evaluated for the presence of inhibitors.

• Thrombotic events: Risk of thromboembolic events may be increased with ongoing use; monitor concentrations of von Willebrand factor and factor VIII closely; use with caution when treating VWD patients with risk factors for thrombosis; avoid excessive increases in factor VIII activity. Incidence of thrombosis may be increased in females.

Special populations:

• Blood types A, B, and AB: Alphanate and Humate-P contain 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; the patient should be monitored for signs of progressive anemia and the possibility of intravascular hemolysis should be considered.

• Hemophilia A: The dosage requirement will vary in patients with factor VIII inhibitors; optimal treatment should be determined by clinical response.

Dosage form specific issues:

• 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. Strongly consider hepatitis A and B vaccination.

• 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.

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; VWF activity (circulating levels of functional VWF are measured as ristocetin cofactor activity [VWF:RCo]). In surgical patients, monitor VWF:RCo at baseline and after surgery, trough VWF:RCo and FVIII:C at least daily.

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal reproduction studies have not been conducted. Parvovirus B19 or hepatitis A, which may be present in plasma-derived products, may affect a pregnant woman more seriously than nonpregnant women.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dyspepsia. Have patient report immediately to prescriber signs of hemorrhaging, signs of infection, flushing, severe dizziness, syncope, significant headache, paresthesia, edema, considerable nausea, intolerable asthenia, akathisia, urine discoloration, jaundice, angina, dyspnea, hemoptysis, edema of extremities, tachycardia, mouth discoloration, strength differences from one side to another, difficulty speaking or thinking, change in balance, or blurred vision (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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