Hemophilia A: Individualize dosage based on clinical response and factor VIII activity evaluated at baseline and at regular intervals during treatment. In general, administration of factor VIII 1 unit/kg will increase circulating factor VIII levels by ~2% of normal. Patients with inhibitory antibodies to factor VIII may require higher doses, more frequent administration, and/or selection of alternative therapy.
General dosing for control and prevention of bleeding episodes or perioperative management: IV: Note: Dosage is expressed in units of factor VIII activity and must be individualized based on formulation, severity of factor VIII deficiency, extent and location of bleed, individualized incremental recovery using factor VIII activity assays, and clinical situation of patient.
Formula for units required to raise blood level:
Number of Factor VIII Units required = body weight (in kg) x 0.5 units/kg per units/dL x desired factor VIII level increase (units/dL or %)
For example, for a desired 100% level in a 3 kg patient who has an actual level of 20%: Number of Factor VIII Units needed = 3 kg x 0.5 units/kg per units/dL x 80% = 120 units
Treatment recommendations (Ref): Note: Factor VIII level may either be expressed as % or as units/dL.
Intermittent IV: The following recommendations reflect WFH guidelines for higher-dose practice patterns; this dosing is typically used in areas where no significant resource constraints exist; recommendations may vary from those found within prescribing information or practitioner preference. Frequency is based on type of bleed or surgery and varies by product; see specific product labeling for details. If Factor VIII levels are available, subsequent doses should be based on the half-life of factor VIII and on the recovery in an individual patient for a particular product.
Site of Hemorrhage/Clinical Situation |
Desired Factor VIII Peak Level |
FrequencyA |
Duration |
---|---|---|---|
AFrequency is based on type of bleed or surgery and varies by product; see specific product labeling for details. | |||
Joint |
40% to 60% |
Every 12 to 24 hours; some products recommend more frequent (every 8 to 24 hours) for patients <6 years |
1 to 2 days, may be longer if response is inadequate |
Superficial muscle/no neurovascular compromise |
40% to 60% |
Every 12 to 24 hours; some products recommend more frequent (every 8 to 24 hours) for patients <6 years |
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% |
Every 8 to 24 hours; some products recommend more frequent (every 6 to 12 hours) for patients <6 years |
Initial: 1 to 2 days |
Maintenance: 30% to 60% |
Maintenance: 3 to 5 days, sometimes longer as secondary prophylaxis during physiotherapy | ||
CNS/Head |
Initial: 80% to 100% |
Every 8 to 24 hours; some products recommend more frequent (every 6 to 12 hours) for patients <6 years |
Initial: 1 to 7 days |
Maintenance: 50% |
Maintenance: 8 to 21 days | ||
Throat and neck |
Initial: 80% to 100% |
Every 8 to 24 hours; some products recommend more frequent (every 6 to 12 hours) for patients <6 years |
Initial: 1 to 7 days |
Maintenance: 50% |
Maintenance: 8 to 14 days | ||
Gastrointestinal |
Initial: 80% to 100% |
Every 8 to 24 hours; some products recommend more frequent (every 6 to 12 hours) for patients <6 years |
Initial: 7 to 14 days |
Maintenance: 50% |
Maintenance: Not specified | ||
Renal |
50% |
Every 12 to 24 hours; some products recommend more frequent (every 8 to 24 hours) for patients <6 years |
3 to 5 days |
Deep laceration |
50% |
Every 12 to 24 hours; some products recommend more frequent (every 8 to 24 hours) for patients <6 years |
5 to 7 days |
Surgery (major) |
Preop: 80% to 100% |
Single dose |
|
Postop: 60% to 80% |
Every 8 to 24 hours; some products recommend more frequent (every 6 to 24 hours) dosing for patients <6 years |
Postop: 1 to 3 days | |
Postop: 40% to 60% |
Postop: 4 to 6 days | ||
Postop: 30% to 50% |
Postop: 7 to 14 days | ||
Surgery (minor) |
Preop: 50% to 80% |
Single dose |
|
Postop: 30% to 80% |
Every 12 to 24 hours |
Postop: 1 to 5 days depending on procedure type |
Routine prophylaxis: Note: Maintain factor VIII trough levels >3% to 5% or higher as clinically indicated (Ref).
Advate: IV: 20 to 40 units/kg/dose every other day (3 to 4 times weekly). Alternatively, an every-third-day dosing regimen may be used to target factor VIII trough levels of ≥1%.
Afstyla: IV: 30 to 50 units/kg/dose 2 to 3 times weekly; more frequent or higher doses may be needed due to higher clearance in this age.
Helixate FS, Kogenate FS: IV: 25 units/kg/dose given every other day.
Kolvatry: IV: 20 to 50 units/kg/dose 2 to 3 times weekly; alternatively, may administer every other day.
Novoeight: IV: 25 to 60 units/kg/dose 3 times weekly or 25 to 50 units/kg/dose every other day.
Hemophilia A: Individualize dosage based on clinical response and factor VIII activity evaluated at baseline and at regular intervals during treatment. In general, administration of factor VIII 1 unit/kg will increase circulating factor VIII levels by ~2% of normal. Patients with inhibitory antibodies to factor VIII may require higher doses, more frequent administration, and/or selection of alternative therapy.
General dosing for control and prevention of bleeding episodes or perioperative management: Note: Dosage is expressed in units of factor VIII activity and must be individualized based on formulation, severity of factor VIII deficiency, extent and location of bleed, individualized incremental recovery using factor VIII activity assays, and clinical situation of patient.
Infants, Children, and Adolescents: IV:
Formula for units required to raise blood level:
Number of Factor VIII Units required = body weight (in kg) x 0.5 units/kg per units/dL x desired factor VIII level increase (units/dL or %)
For example, for a desired 100% level in a 25 kg patient who has an actual level of 20%: Number of Factor VIII Units needed = 25 kg x 0.5 units/kg per units/dL x 80% = 1,000 units
Treatment recommendations (Ref): Note: Factor VIII level may either be expressed as % or as units/dL.
Intermittent IV: Infants, Children, and Adolescents: The following recommendations reflect WFH guidelines for higher-dose practice patterns; this dosing is typically used in areas where no significant resource constraints exist; recommendations may vary from those found within prescribing information or practitioner preference. Frequency is based on type of bleed or surgery and varies by product; see specific product labeling for details. Dosing frequency most commonly corresponds to the half-life of factor VIII but should be determined based on an assessment of factor VIII levels (if available) before the next dose.
Site of Hemorrhage/Clinical Situation |
Desired Factor VIII Peak Level |
FrequencyA |
Duration |
---|---|---|---|
AFrequency is based on type of bleed or surgery and varies by product; see specific product labeling for details. | |||
Joint |
40% to 60% |
Every 12 to 24 hours; some products recommend more frequent (every 8 to 24 hours) for patients <6 years |
1 to 2 days, may be longer if response is inadequate |
Superficial muscle/no neurovascular compromise |
40% to 60% |
Every 12 to 24 hours; some products recommend more frequent (every 8 to 24 hours) for patients <6 years |
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% |
Every 8 to 24 hours; some products recommend more frequent (every 6 to 12 hours) for patients <6 years |
Initial: 1 to 2 days |
Maintenance: 30% to 60% |
Maintenance: 3 to 5 days, sometimes longer as secondary prophylaxis during physiotherapy | ||
CNS/Head |
Initial: 80% to 100% |
Every 8 to 24 hours; some products recommend more frequent (every 6 to 12 hours) for patients <6 years |
Initial: 1 to 7 days |
Maintenance: 50% |
Maintenance: 8 to 21 days | ||
Throat and neck |
Initial: 80% to 100% |
Every 8 to 24 hours; some products recommend more frequent (every 6 to 12 hours) for patients <6 years |
Initial: 1 to 7 days |
Maintenance: 50% |
Maintenance: 8 to 14 days | ||
Gastrointestinal |
Initial: 80% to 100% |
Every 8 to 24 hours; some products recommend more frequent (every 6 to 12 hours) for patients <6 years |
Initial: 7 to 14 days |
Maintenance: 50% |
Maintenance: Not specified | ||
Renal |
50% |
Every 12 to 24 hours; some products recommend more frequent (every 8 to 24 hours) for patients <6 years |
3 to 5 days |
Deep laceration |
50% |
Every 12 to 24 hours; some products recommend more frequent (every 8 to 24 hours) for patients <6 years |
5 to 7 days |
Surgery (major) |
Preop: 80% to 100% |
Single dose |
|
Postop: 60% to 80% |
Every 8 to 24 hours; some products recommend more frequent (every 6 to 24 hours) dosing for patients <6 years |
Postop: 1 to 3 days | |
Postop: 40% to 60% |
Postop: 4 to 6 days | ||
Postop: 30% to 50% |
Postop: 7 to 14 days | ||
Surgery (minor) |
Preop: 50% to 80% |
Single dose |
|
Postop: 30% to 80% |
Every 12 to 24 hours |
Postop: 1 to 5 days depending on procedure type |
Continuous IV infusion: Infants, Children, and Adolescents: Note: In general, administration of factor VIII 4 units/kg/hour will increase circulating factor VIII levels by 1 unit/mL (Ref).
Control and prevention of bleeding episodes: Limited data available: Note: For patients who require prolonged periods of treatment (eg, intracranial hemorrhage or surgery) to avoid peaks and troughs associated with intermittent infusions (Ref):
Following initial bolus to achieve the desired factor VIII level: Initial dosing: 2 to 4 units/kg/hour; adjust dose based on frequent factor VIII 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) / (plasma Factor level in units/mL)
New infusion rate (units/kg/hour) = (factor VIII clearance in mL/kg/hour) x (desired plasma level in units/mL)
Perioperative management: Limited data available: Initial: 25 to 50 units/kg prior to surgery, followed by continuous infusion at a rate of 3 to 5 units/kg/hour; regimen based on 2 studies evaluating use in pediatric surgery patients (age range: 0.9 to 17 years); rate was adjusted and additional boluses given as needed to maintain desired factor VIII level (Ref).
Routine prophylaxis: Note: Maintain factor VIII trough levels >3% to 5% or higher as clinically indicated (Ref).
Product-specific dosing:
Advate: Infants, Children, and Adolescents: IV: 20 to 40 units/kg/dose every other day (3 to 4 times weekly). Alternatively, an every-third-day dosing regimen may be used to target factor VIII trough levels of ≥1%.
Afstyla:
Infants and Children <12 years: IV: 30 to 50 units/kg/dose 2 to 3 times weekly; more frequent or higher doses may be required due to higher drug clearance.
Children ≥12 years and Adolescents: IV: 20 to 50 units/kg/dose 2 to 3 times weekly.
Helixate FS, Kogenate FS:
Infants, Children, and Adolescents ≤16 years: IV: 25 units/kg/dose given every other day.
Adolescents >16 years: IV: 25 units/kg/dose 3 times a week.
Kovaltry:
Infants and Children: IV: 20 to 50 units/kg/dose every other day, twice weekly or 3 times weekly, dependent on patient response.
Adolescents: IV: 20 to 40 units/kg/dose 2 to 3 times weekly.
Novoeight:
Infants and Children <12 years: IV: 25 to 60 units/kg/dose 3 times weekly or 25 to 50 units/kg/dose every other day.
Children ≥12 years and Adolescents: IV: 20 to 50 units/kg/dose 3 times weekly or 20 to 40 units/kg/dose every other day.
Nuwiq:
Children 2 to 11 years: IV: 30 to 50 units/kg/dose every other day or 3 times weekly.
Children ≥12 years and Adolescents: IV: 30 to 40 units/kg/dose every other day.
Xyntha, Xyntha Solofuse:
Children <12 years: IV: 25 units/kg/dose every other day; more frequent or higher doses may be required due to higher drug clearance.
Children ≥12 years and Adolescents: IV: 30 units/kg/dose 3 times weekly.
Guideline dosing (Ref): Note: Dose should be individualized; dose intensity should take into account disease severity, patient's activity and lifestyle, and pharmacokinetic properties of product, and should be adjusted if breakthrough bleeding occurs. See guidelines for in-depth discussion of risks and benefits of each approach.
Infants, Children, and Adolescents: IV:
High dose: 25 to 40 units/kg/dose every 2 days.
Intermediate dose: 15 to 25 units/kg/dose 3 times weekly.
Low dose: 10 to 15 units/kg/dose 2 to 3 times weekly. Note: Low dose prophylaxis may be used in young patients as initial therapy to allow patients and families to gradually adjust to prophylaxis and improves adherence; close monitoring is required since patients are at a higher risk for bleeding until escalation occurs.
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling.
(For additional information see "Factor VIII, recombinant human: Drug information")
Hemophilia A, without inhibitors:
Treatment and control of bleeding episodes or perioperative management:
Intermittent IV bolus dosing: IV: Utilize steps 1 to 3 to determine intermittent bolus dosing strategy. 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 (Ref).
Step 1: Determine desired factor VIII peak level and anticipated duration of therapy based on the World Federation of Hemophilia (WFH) treatment recommendations; see table. Selection of the lower-dose practice pattern requires closer observation with the potential for requiring escalation to higher doses based on clinical response.
Note: For patients without inhibitors and receiving emicizumab who experience breakthrough bleeding, antihemophilic factor should be dosed to target the desired peak factor VIII levels outlined in the table as emicizumab is not indicated for treatment of bleeding episodes.
Type of hemorrhage or surgery |
Lower-dose practice pattern |
Higher-dose practice pattern | ||||||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Desired peak factor VIII level (units/dL) |
Treatment duration (days) |
Desired peak factor VIII level (units/dL) |
Treatment duration (days) | |||||||||||||||||||||||||||||||||||||||||||||||||||
a May be longer if response is inadequate. b Sometimes longer as secondary prophylaxis during physical therapy. c A single dose may be sufficient for some joint bleeds; determine need for additional doses based on clinical response. d WFH [Srivastava 2020]. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Joint |
10 to 20 |
1 to 2a,c |
40 to 60 |
1 to 2a,c | ||||||||||||||||||||||||||||||||||||||||||||||||||
Superficial muscle/no neurovascular compromise (except iliopsoas) |
10 to 20 |
2 to 3a |
40 to 60 |
2 to 3a | ||||||||||||||||||||||||||||||||||||||||||||||||||
Iliopsoas or deep muscle with neurovascular injury or substantial blood loss: | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Initial |
20 to 40 |
1 to 2 |
80 to 100 |
1 to 2 | ||||||||||||||||||||||||||||||||||||||||||||||||||
Maintenance |
10 to 20 |
3 to 5b |
30 to 60 |
3 to 5b | ||||||||||||||||||||||||||||||||||||||||||||||||||
Intracranial: | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Initial |
50 to 80 |
1 to 3 |
80 to 100 |
1 to 7 | ||||||||||||||||||||||||||||||||||||||||||||||||||
Maintenance |
30 to 50 |
4 to 7 |
50 |
8 to 21 | ||||||||||||||||||||||||||||||||||||||||||||||||||
20 to 40 |
8 to 14 |
- |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||
Throat and Neck: | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Initial |
30 to 50 |
1 to 3 |
80 to 100 |
1 to 7 | ||||||||||||||||||||||||||||||||||||||||||||||||||
Maintenance |
10 to 20 |
4 to 7 |
50 |
8 to 14 | ||||||||||||||||||||||||||||||||||||||||||||||||||
Gastrointestinal: | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Initial |
30 to 50 |
1 to 3 |
80 to 100 |
7 to 14 | ||||||||||||||||||||||||||||||||||||||||||||||||||
Maintenance |
10 to 20 |
4 to 7 |
50 |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||
Renal |
20 to 40 |
3 to 5 |
50 |
3 to 5 | ||||||||||||||||||||||||||||||||||||||||||||||||||
Deep laceration |
20 to 40 |
5 to 7 |
50 |
5 to 7 | ||||||||||||||||||||||||||||||||||||||||||||||||||
Surgery (major): | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Preop |
60 to 80 |
- |
80 to 100 |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||
Postop |
30 to 40 |
1 to 3 |
60 to 80 |
1 to 3 | ||||||||||||||||||||||||||||||||||||||||||||||||||
20 to 30 |
4 to 6 |
40 to 60 |
4 to 6 | |||||||||||||||||||||||||||||||||||||||||||||||||||
10 to 20 |
7 to 14 |
30 to 50 |
7 to 14 | |||||||||||||||||||||||||||||||||||||||||||||||||||
Surgery (minor): | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Preop |
40 to 80 |
- |
50 to 80 |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||
Postop |
20 to 50 |
1 to 5 |
30 to 80 |
1 to 5 |
Step 2: Calculate dose using desired peak factor VIII level from step 1 and the following equation:
Factor VIII units required = [(desired peak factor VIII level − patient's baseline factor VIII level) × body weight (kg)]/2
Note: Factor VIII level units are units/dL.
Example for 50 kg patient with desired peak factor VIII level of 35 units/dL and baseline factor VIII level of 5 units/dL:
Factor VIII units required = [(35 units/dL − 5 units/dL) × 50 kg]/2 = 750 units of factor VIII
Step 3: Determine need for repeat dosing based on manufacturer's recommended frequency of repeat dosing. Note: Frequency of administration must also take into consideration subsequent factor VIII activity measurements and the clinical response.
Product |
Bleeding event |
Surgery | |||
---|---|---|---|---|---|
Minor severity |
Moderate severity |
Major severity |
Minor bleeding risk |
Major bleeding risk | |
Advate |
Every 12 to 24 hours |
Every 12 to 24 hours |
Every 8 to 24 hours |
Every 12 to 24 hours |
Every 8 to 24 hours |
Afstyla |
Every 12 to 24 hours |
Every 12 to 24 hours |
Every 8 to 24 hours |
Every 24 hours |
Every 8 to 24 hours |
Kogenate FS |
Repeat × 1 if evidence of further bleeding |
Every 12 to 24 hours |
Every 8 to 12 hours |
Every 12 to 24 hours |
Every 6 to 12 hours |
Kovaltry |
Every 12 to 24 hours |
Every 12 to 24 hours |
Every 8 to 24 hours |
Every 24 hours |
Every 8 to 24 hours |
Novoeight |
Every 12 to 24 hours |
Every 12 to 24 hours |
Every 8 to 24 hours |
Every 24 hours |
Every 8 to 24 hours |
Nuwiq |
Every 12 to 24 hours |
Every 12 to 24 hours |
Every 8 to 24 hours |
Every 24 hours |
Every 8 to 24 hours |
Recombinate |
Every 12 to 24 hours |
Every 12 to 24 hours |
Every 8 to 24 hours |
A single dose typically adequate |
Every 8 to 24 hours |
Xyntha/Xyntha Solofuse |
Every 12 to 24 hours |
Every 12 to 24 hours |
Every 8 to 24 hours |
Every 12 to 24 hours |
Every 8 to 24 hours |
Zonovate (Canadian product) |
Every 12 to 24 hours |
Every 12 to 24 hours |
Every 8 to 24 hours |
Every 24 hours |
Every 8 to 24 hours |
Continuous infusion dosing (Ref):
Note: Continuous infusion administration is preferred over intermittent bolus administration for patients requiring prolonged treatment courses (eg, postoperative management after surgery with major bleeding risk). To ensure safe and effective use, only products with extended stability information should be used. Extended stability information may not be available for all products; contact product manufacturer to obtain current recommendations. Use of a smart infusion pump with small volume infusion capability is also necessary.
IV: Administer an initial bolus to achieve the desired factor VIII level (see steps 1 and 2 under intermittent bolus dosing), then initiate continuous infusion at 2 to 4 units/kg/hour. Adjust dose based on frequent factor assays (at least daily) and calculation of factor VIII clearance at steady-state using the below equations.
Factor VIII clearance (mL/kg/hour) = (current infusion rate in units/kg/hour) divided by (measured factor VIII level in units/mL)
New infusion rate (units/kg/hour) = (factor VIII clearance in mL/kg/hour) x (desired factor VIII level in units/mL)
Note: With infusion dose increases, re-bolus should be considered to achieve target factor VIII level more quickly. See steps 1 and 2 under intermittent bolus dosing to determine re-bolus dose.
Routine prophylaxis to prevent or reduce the frequency of bleeding episodes:
Note: Preferably, dosing should be tailored to ensure trough factor VIII levels of at least 1% and ideally ≥3 to 5% are achieved, but prophylaxis targets should be tailored to individual level of activity, lifestyle, and pharmacokinetics. Dose escalation should be considered for patients adherent to prescribed prophylaxis but still experiencing breakthrough bleeding events (Ref).
Advate: IV: 20 to 40 units/kg every other day (3 to 4 times weekly). Alternatively, an every-third-day dosing regimen may be used to target factor VIII trough levels of ≥1%.
Afstyla: IV: 20 to 50 units/kg 2 to 3 times weekly.
Kogenate FS: IV: 25 units/kg 3 times weekly.
Kovaltry: IV: 20 to 40 units/kg 2 or 3 times weekly.
Novoeight: IV: 20 to 50 units/kg 3 times weekly or 20 to 40 units/kg every other day.
Nuwiq: IV: 30 to 40 units/kg every other day.
Xyntha/Xyntha Solofuse: IV: 30 units/kg 3 times weekly.
Zonovate [Canadian product]: IV: 20 to 50 units/kg 3 times weekly or 20 to 40 units/kg every other day.
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Actual frequency may vary by product and population. Reported adverse reactions are for adults and pediatrics.
>10%:
Dermatologic: Pruritus (≤16%), skin rash (≤16%), urticaria (≤16%)
Hematologic & oncologic: Increased factor VIII inhibitors (previously untreated patients/minimally treated patients: 50% to 55%; previously treated patients: <1%; may include neutralizing antibodies)
Nervous system: Headache (9% to 24%)
Neuromuscular & skeletal: Arthralgia (5% to 23%)
Respiratory: Cough (10% to 13%), nasopharyngitis (12%), upper respiratory tract infection (7% to 22%)
Miscellaneous: Fever (9%; previously untreated patients/minimally treated patients: 30%; previously treated patents: 4%)
1% to 10%:
Gastrointestinal: Abdominal distress (1%), abdominal pain (4%), diarrhea (5% to 8%), dyspepsia (2%), vomiting (3% to 8%)
Hypersensitivity: Hypersensitivity reaction (≤2%)
Infection: Varicella zoster infection (4%)
Local: Infusion-site reaction (4% to 7%), injection-site reaction (1% to 3%)
Nervous system: Asthenia (6%), chills (≤7%), dizziness (≤2%), insomnia (1% to 2%), malaise (1%), procedural pain (5%)
Neuromuscular & skeletal: Back pain (4%), limb injury (6%), limb pain (≤4%)
Otic:Otic infection (≤5%)
Respiratory: Dyspnea (1%), lower respiratory tract infection (8%), nasal congestion (6%), pharyngitis (5%), pharyngolaryngeal pain (5%), rhinitis (8%)
<1%:
Cardiovascular: Chest discomfort, cold extremity, flushing, hypotension, palpitations, sinus tachycardia, syncope
Dermatologic: Allergic dermatitis, erythema of skin, hyperhidrosis, maculopapular rash, pallor
Gastrointestinal: Dysgeusia, nausea
Hematologic & oncologic: Hematoma, lymphadenopathy
Local: Inflammation at injection site, pain at injection site
Nervous system: Fatigue, feeling hot, neurological deterioration, paresthesia, tremor
Renal: Renal neoplasm (benign)
Respiratory: Epistaxis
Frequency not defined: Endocrine & metabolic: Hot flash
Postmarketing:
Cardiovascular: Chest pain, tachycardia
Hypersensitivity: Anaphylaxis, angioedema, facial edema
Nervous system: Loss of consciousness, restlessness
Respiratory: Cyanosis, laryngeal edema
Hypersensitivity (eg, anaphylaxis) to antihemophilic factor, mouse or hamster protein (Advate, Afstyla, Kogenate FS, Kovaltry, Novoeight, Recombinate, Xyntha, Zonovate [Canadian product]), bovine protein (Recombinate only), or any component of the formulation.
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; may occur at any time but more common in young children with severe hemophilia and previously untreated patients. 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: Allergic hypersensitivity reactions (including anaphylaxis) may occur; discontinue if hypersensitivity symptoms occur and administer appropriate treatment.
Dosage form specific issues:
• Albumin: Recombinate is stabilized using human albumin.
• Bovine: Recombinate may contain bovine protein.
• Mouse/hamster protein: Some products may contain trace amounts of mouse or hamster 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.
• Sucrose: Some products are stabilized with or may contain sucrose.
• von Willebrand factor: Some products contain naturally-occurring von Willebrand factor for stabilization; however, efficacy has not been established for the treatment of von Willebrand disease.
Other warnings/precautions:
• Dose requirements: The dosage requirement will vary in patients with factor VIII inhibitors; optimal treatment should be determined by clinical response.
Allergic-type hypersensitivity reactions including anaphylaxis may occur; discontinue therapy immediately if urticaria, hives, hypotension, tightness of the chest, wheezing, or anaphylaxis develop; emergency treatment and resuscitative measures (eg, epinephrine, oxygen) may be needed. Clinical response to antihemophilic factor administration may vary; dosage must be individualized based on coagulation studies (performed prior to treatment and at regular intervals during treatment) and clinical response. If bleeding is not controlled with the recommended dose, determine plasma level of factor VIII and follow with a sufficient dose to achieve satisfactory clinical response. If plasma levels of factor VIII fail to increase as expected or bleeding continues, suspect the presence of an inhibitor; test as appropriate. Formation of factor VIII inhibitors (neutralizing antibodies to AHF recombinant) may occur at any time, but is more common in young children with severe hemophilia during the first years of therapy, or in patients at any age who received little prior therapy with factor VIII; monitor patients appropriately.
Strengths expressed with approximate values. Consult individual vial labels for exact potency within each vial.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Kit, Intravenous:
Kogenate FS: 250 units, 500 units, 1000 units
Kit, Intravenous [preservative free]:
Afstyla: 250 units, 500 units, 1000 units, 1500 units, 2000 units, 2500 units, 3000 units [contains polysorbate 80]
Kogenate FS: 2000 units, 3000 units
Nuwiq: 250 units, 500 units, 1000 units, 2000 units, 2500 units, 3000 units, 4000 units
Xyntha: 250 units, 500 units, 1000 units, 2000 units [albumin free; contains polysorbate 80]
Xyntha Solofuse: 250 units, 500 units, 1000 units, 2000 units, 3000 units [albumin free; contains polysorbate 80]
Solution Reconstituted, Intravenous:
Kovaltry: 250 units (1 ea); 500 units (1 ea); 1000 units (1 ea); 2000 units (1 ea); 3000 units (1 ea) [contains polysorbate 80]
Solution Reconstituted, Intravenous [preservative free]:
Advate: 250 units (1 ea); 500 units (1 ea); 1000 units (1 ea); 1500 units (1 ea); 2000 units (1 ea); 3000 units (1 ea); 4000 units (1 ea) [albumin free; contains polysorbate 80]
Novoeight: 250 units (1 ea); 500 units (1 ea); 1000 units (1 ea); 1500 units (1 ea); 2000 units (1 ea); 3000 units (1 ea) [contains polysorbate 80]
Nuwiq: 1500 units (1 ea) [latex free]
Nuwiq: 250 units (1 ea); 500 units (1 ea); 1000 units (1 ea); 2000 units (1 ea); 2500 units (1 ea); 3000 units (1 ea); 4000 units (1 ea)
Recombinate: 220-400 units (1 ea); 401-800 units (1 ea); 801-1240 units (1 ea); 1241-1800 units (1 ea); 1801-2400 units (1 ea) [contains albumin human, polyethylene glycol (macrogol), polysorbate 80]
No
Kit (Afstyla Intravenous)
250 unit (Price provided is per AHF Unit): $2.21
500 unit (Price provided is per AHF Unit): $2.21
1000 unit (Price provided is per AHF Unit): $2.21
1500 unit (Price provided is per AHF Unit): $2.21
2000 unit (Price provided is per AHF Unit): $2.21
2500 unit (Price provided is per AHF Unit): $2.21
3000 unit (Price provided is per AHF Unit): $2.21
Kit (Kogenate FS Intravenous)
250 unit (Price provided is per AHF Unit): $2.42
500 unit (Price provided is per AHF Unit): $2.42
1000 unit (Price provided is per AHF Unit): $2.42
2000 unit (Price provided is per AHF Unit): $2.42
3000 unit (Price provided is per AHF Unit): $2.42
Kit (Nuwiq Intravenous)
250 unit (Price provided is per AHF Unit): $2.28
500 unit (Price provided is per AHF Unit): $2.28
1000 unit (Price provided is per AHF Unit): $2.28
2000 unit (Price provided is per AHF Unit): $2.28
2500 unit (Price provided is per AHF Unit): $2.28
3000 unit (Price provided is per AHF Unit): $2.28
4000 unit (Price provided is per AHF Unit): $2.28
Kit (Xyntha Intravenous)
250 unit (Price provided is per AHF Unit): $2.18
500 unit (Price provided is per AHF Unit): $2.18
1000 unit (Price provided is per AHF Unit): $2.18
2000 unit (Price provided is per AHF Unit): $2.18
Kit (Xyntha Solofuse Intravenous)
250 unit (Price provided is per AHF Unit): $2.18
500 unit (Price provided is per AHF Unit): $2.18
1000 unit (Price provided is per AHF Unit): $2.18
2000 unit (Price provided is per AHF Unit): $2.18
3000 unit (Price provided is per AHF Unit): $2.18
Solution (reconstituted) (Advate Intravenous)
250 unit (Price provided is per AHF Unit): $2.28
500 unit (Price provided is per AHF Unit): $2.28
1000 unit (Price provided is per AHF Unit): $2.28
1500 unit (Price provided is per AHF Unit): $2.28
2000 unit (Price provided is per AHF Unit): $2.28
3000 unit (Price provided is per AHF Unit): $2.28
4000 unit (Price provided is per AHF Unit): $2.28
Solution (reconstituted) (Kovaltry Intravenous)
250 unit (per each): $2.64
500 unit (Price provided is per AHF Unit): $2.64
500 unit (per each): $2.64
1000 unit (per each): $2.64
2000 unit (per each): $2.64
3000 unit (per each): $2.64
Solution (reconstituted) (Novoeight Intravenous)
250 unit (Price provided is per AHF Unit): $2.59
500 unit (Price provided is per AHF Unit): $2.59
1000 unit (Price provided is per AHF Unit): $2.59
1500 unit (Price provided is per AHF Unit): $2.59
2000 unit (Price provided is per AHF Unit): $2.59
3000 unit (Price provided is per AHF Unit): $2.59
Solution (reconstituted) (Nuwiq Intravenous)
250 unit (Price provided is per AHF Unit): $2.28
500 unit (Price provided is per AHF Unit): $2.28
1000 unit (Price provided is per AHF Unit): $2.28
1500 unit (Price provided is per AHF Unit): $2.28
2000 unit (Price provided is per AHF Unit): $2.28
2500 unit (Price provided is per AHF Unit): $2.28
3000 unit (Price provided is per AHF Unit): $2.28
4000 unit (Price provided is per AHF Unit): $2.28
Solution (reconstituted) (Recombinate Intravenous)
220-400 unit (Price provided is per AHF Unit): $2.28
401-800 unit (Price provided is per AHF Unit): $2.28
801-1240 unit (Price provided is per AHF Unit): $2.28
1241-1800 unit (Price provided is per AHF Unit): $2.28
1801-2400 unit (Price provided is per AHF Unit): $2.28
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Kit, Intravenous:
Xyntha: 250 units, 500 units [contains polysorbate 80]
Xyntha Solofuse: 500 units, 1000 units, 2000 units, 3000 units [contains polysorbate 80]
Solution Reconstituted, Intravenous:
Advate: 250 units (1 ea); 500 units (1 ea); 1000 units (1 ea); 1500 units (1 ea); 2000 units (1 ea); 3000 units (1 ea) [contains polysorbate 80]
Kovaltry: 250 units (1 ea); 500 units (1 ea); 1000 units (1 ea); 2000 units (1 ea); 3000 units (1 ea) [contains polysorbate 80]
Nuwiq: 250 units (1 ea); 500 units (1 ea); 1000 units (1 ea); 2000 units (1 ea); 3000 units (1 ea); 4000 units (1 ea)
Zonovate: 250 units (1 ea); 500 units (1 ea); 1000 units (1 ea); 1500 units (1 ea); 2000 units (1 ea); 3000 units (1 ea) [contains polysorbate 80]
One unit of rAHF is equal to the factor VIII activity present in 1 mL of fresh pooled human plasma. If bleeding is not controlled with adequate dose, test for the presence of factor VIII inhibitor; larger doses of rAHF may be therapeutic with inhibitor titers <10 Bethesda units/mL; it may not be possible or practical to control bleeding if inhibitor titers >10 Bethesda units/mL (due to the very large rAHF doses required); other treatments (eg, antihemophilic factor [porcine], factor IX complex concentrates, recombinant factor VIIa, or anti-inhibitor coagulant complex) may be needed in patients with inhibitor titers >10 Bethesda units/mL.
Parenteral: IV administration only; use administration sets/tubing provided by manufacturer (if provided). Adjust administration rate based on patient response.
Intermittent IV: Rate of administration should be determined by patient tolerability (maximum rates vary by product).
Advate: Infuse over ≤5 minutes; maximum infusion rate: 10 mL/minute.
Afstyla: Infuse up to a maximum infusion rate of 10 mL/minute.
Helixate FS, Kogenate FS, Kovaltry: Infuse over 1 to 15 minutes.
Novoeight: Infuse slowly over 2 to 5 minutes.
Nuwiq: Infuse up to a maximum infusion rate of 4 mL/minute.
Recombinate: Infuse at a maximum rate of 5 mL/minute when reconstituted with 5 mL of SWFI.
Xyntha, Xyntha Solofuse: Infuse over several minutes. Do not admix or administer in same tubing as other medications.
Continuous IV infusion: Further dilution after initial reconstitution is unnecessary (Ref).
IV: Rate of administration should be determined by patient tolerability (maximum rates vary by product).
Advate: Infuse over ≤5 minutes (maximum: 10 mL/minute)
Afstyla: Infuse up to a maximum rate of 10 mL/minute
Kogenate FS, Kovaltry: Infuse over 1 to 15 minutes
Novoeight: Infuse slowly over 2 to 5 minutes
Nuwiq: Infuse up to a maximum rate of 4 mL/minute
Recombinate: Infuse up to a maximum rate of 5 mL/minute
Xyntha, Xyntha Solofuse: Infuse over several minutes. Do not admix or administer in same tubing as other medications.
Zonovate [Canadian product]: Infuse at a rate of 1 to 2 mL/minute.
Continuous infusion (off-label rate): Has also been administered as a continuous infusion to avoid peaks and troughs associated with intermittent infusions in patients who require prolonged treatment periods. Use a smart infusion pump with small volume infusion capability. Refer to protocols for product selection and preparation details (Ref).
Prior to reconstitution, store refrigerated at 2°C to 8°C (36°F to 46°F); do not freeze. Do not refrigerate after reconstitution (unless otherwise noted).
Additional product-specific storage information:
Advate: May also be stored at room temperature (not to exceed 30°C [86°F]) up to 6 months; do not return to refrigerator. Use within 3 hours of reconstitution.
Afstyla: May also be stored at room temperature (not to exceed 25°C [77°F]) up to 3 months; do not return to refrigerator. Store in original package to protect from light. Use within 4 hours of reconstitution.
Kogenate FS, Kovaltry: May also be stored at room temperature (not to exceed 25°C [77°F]) up to 12 months; do not return to refrigerator. Protect from extreme exposure to light during storage. Use within 3 hours of reconstitution.
Novoeight: Store in original package to protect from light. May also be stored at room temperature:
≤30°C (86°F) for up to 12 months; do not return to refrigerator; must be used within 4 hours of reconstitution if stored at this temperature
>30°C to ≤40°C (>86°F to 104°F) for up to 3 months; do not return to refrigerator; must be used within 2 hours of reconstitution if stored at this temperature
Nuwiq: May also be stored at room temperature (not to exceed 25°C [77°F]) up to 3 months; do not return to refrigerator. Store in original package to protect from light. Use within 3 hours of reconstitution.
Recombinate: May also be stored at room temperature, not to exceed 30°C (86°F). Use within 3 hours of reconstitution.
Xyntha: May also be stored at room temperature (not to exceed 25°C [77°F]) up to 3 months; after room temperature storage, product may be returned to the refrigerator until the expiration date; however, do not store at room temperature and return to refrigerator temperature more than once. Avoid prolonged exposure to light during storage. Use within 3 hours of reconstitution.
Xyntha Solofuse: May also be stored at room temperature not to exceed 25°C [77°F]) up to 3 months; do not return to refrigerator; after 3 months at room temperature, must use immediately or discard. Use within 3 hours of reconstitution.
Zonovate (Canadian product): Store intact vial in original package to protect from light. Following reconstitution, use immediately or may store at 2°C to 8°C (36°F to 46°F) but must be used within 24 hours. Store reconstituted product in the vial, with vial adapter and syringe still attached and out of direct light; discard any unused reconstituted product. May also be stored at room temperature:
≤30°C (86°F) for up to 12 months; do not return to refrigerator; must be used within 4 hours of reconstitution if stored at this temperature.
>30°C to ≤40°C (>86°F to 104°F) for up to 3 months; do not return to refrigerator; must be used within 2 hours of reconstitution if stored at this temperature.
Note: Antihemophilic Factor (Recombinant) is not indicated for the treatment of von Willebrand disease.
Advate, Afstyla, Novoeight: On-demand treatment and control of bleeding episodes in patients with hemophilia A; perioperative management of patients with hemophilia A; routine prophylaxis to reduce the frequency of bleeding episodes in patients with hemophilia A (All indications: FDA approved in all ages).
Helixate FS, Kogenate FS: On-demand treatment and control of bleeding episodes in patients with hemophilia A (FDA approved in all ages); perioperative management of patients with hemophilia A (FDA approved in all ages); routine prophylaxis to reduce the frequency of bleeding episodes and reduce the risk of joint damage in children with hemophilia A with no preexisting joint damage (FDA approved in ages 0 to 16 years); routine prophylaxis to reduce the frequency of bleeding episodes (FDA approved in adults).
Kovaltry: Prevention and control of bleeding episodes in patients with hemophilia A; perioperative management of patients with hemophilia A; routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with hemophilia A (All indications: FDA approved in all ages).
Nuwiq: On-demand treatment and control of bleeding episodes in patients with hemophilia A; perioperative management of patients with hemophilia A; routine prophylaxis to reduce the frequency of bleeding episodes in patients with hemophilia A (All indications: FDA approved in ages >2 and adults).
Recombinate: Prevention and control of bleeding episodes in patients with hemophilia A; perioperative management of patients with hemophilia A (All indications: FDA approved in all ages).
Xyntha, Xyntha Solofuse: On-demand treatment and control of bleeding episodes in patients with hemophilia A; perioperative management of patients with hemophilia A; routine prophylaxis to reduce the frequency of bleeding episodes in patients with hemophilia A (All indications: FDA approved in pediatric patients [age not specified] and adults).
Has also been used in patients with acquired factor VIII inhibitors <10 Bethesda units/mL.
Factor VIII may be confused with Factor XIII
Confusion may occur due to the omitting of “Factor VIII” from some product labeling. Review product contents carefully prior to dispensing any antihemophilic factor.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program
There are no known significant interactions.
Some products may contain sodium.
Pregnant carriers of hemophilia A may have an increased bleeding risk following invasive procedures, spontaneous miscarriage, termination of pregnancy, 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 <50 units/dL 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 2020]).
Monitor factor VIII levels prior to and during treatment, heart rate and blood pressure (before and during IV administration). Monitor for signs and symptoms of bleeding, hemoglobin and hematocrit, and for hypersensitivity reactions; monitor for the development of inhibitor antibodies by clinical observations (eg, inadequate control of bleeding with adequate doses) and laboratory tests (eg, inhibitor level, Bethesda assay).
Classification of hemophilia; normal is defined as 1 unit/mL of factor VIII (WFH [Srivastava 2020]).
Severe: Factor level <1% of normal.
Moderate: Factor level 1% to 5% of normal.
Mild: Factor level 5% to <40% of normal.
Factor VIII replacement, necessary for clot formation and maintenance of hemostasis. It 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.
Distribution: Vss: ~0.4 to 0.85 dL/kg.
Half-life elimination:
Advate: Children <12 years: 8.7 to 11.2 hours; Adolescents and Adults: 12 hours.
Afstyla: Children <12 years: 10.2 to 10.4 hours; Children ≥12 years and Adolescents: 14.3 hours; Adults: 14.2 hours.
Kogenate FS: Children: 10.7 hours; Adults: 13.7 to 14.6 hours.
Kovaltry: Children <12 years: ~12 hours; Children ≥12 years, Adolescents, and Adults: ~14 hours.
Novoeight: Children <12 years: 7.7 to 10 hours; Adolescents and Adults: 11 to 12 hours.
Nuwiq: Children ≤12 years: 11.9 to 13.1 hours; Adolescents and Adults: 17.1 hours.
Recombinate: Adults: 14.6 ± 4.9 hours.
Xyntha, Xyntha Solofuse: Children 3.7 to 5.8 years: 8.3 ± 2.7 hours; Adolescents 14 to 15 years: 6.9 ± 2.4 hours; Adults: 11 to 17 hours.
Zonovate [Canadian product]: Children ≤12 years: ~7.5 to 10 hours; Adolescents and Adults: ~11 to 12 hours.
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