Factor VIII, recombinant human: Drug information

(For additional information see "Factor VIII, recombinant human: Patient drug information" and see "Factor VIII, recombinant human: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)

Brand Names: US

Advate;
Afstyla;
Helixate FS [DSC];
Kogenate FS;
Kovaltry;
Novoeight;
Nuwiq;
Recombinate;
Xyntha;
Xyntha Solofuse

Brand Names: Canada

Advate;
Kovaltry;
Nuwiq;
Xyntha;
Xyntha Solofuse;
Zonovate

Pharmacologic Category

Antihemophilic Agent

Dosing: Adult

Hemophilia A, without inhibitors

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 (WFH [Srivastava 2020]).

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.

**Antihemophilic Factor (Recombinant) WFH Treatment Recommendations^d**
Type of hemorrhage or surgery	Lower-dose practice pattern		Higher-dose practice pattern
Type of hemorrhage or surgery	Desired peak factor VIII level (units/dL)	Treatment duration (days)	Desired peak factor VIII level (units/dL)	Treatment duration (days)
^aMay be longer if response is inadequate. ^bSometimes longer as secondary prophylaxis during physical therapy. ^cA single dose may be sufficient for some joint bleeds; determine need for additional doses based on clinical response. ^dWFH [Srivastava 2020].
Joint	10 to 20	1 to 2^a,c	40 to 60	1 to 2^a,c
Superficial muscle/no neurovascular compromise (except iliopsoas)	10 to 20	2 to 3^a	40 to 60	2 to 3^a
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 5^b	30 to 60	3 to 5^b
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
Maintenance	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.

**Antihemophilic Factor (Recombinant) Administration Frequency According to Clinical Scenario**
Product	Bleeding event			Surgery
Product	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
Helixate 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
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 (Batorova 2002; Batorova 2012; Holme 2018; Martinowitz 1992; Poon 2012; Rickard 1995; WFH [Srivastava 2020] ):

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 (WFH [Srivastava 2020]).

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.

Helixate FS: IV: 25 units/kg 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.

Dosing: Kidney Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Pediatric

(For additional information see "Factor VIII, recombinant human: Pediatric drug information")

Hemophilia A

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 (WFH [Srivastava 2020]): 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	Frequency^A	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
CNS/Head	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
Throat and neck	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
Gastrointestinal	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
Surgery (minor)	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 (Prelog 2016).

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 (Batorova 2002; Poon 2012; Prelog 2016; WFH [Srivastava 2020]):

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 (Batorova 2012; Dingli 2002).

Routine prophylaxis: Note: Maintain factor VIII trough levels >3% to 5% or higher as clinically indicated (WFH [Srivastava 2020]).

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 (WFH [Srivastava 2020]): 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.

Dosing: Kidney Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Hepatic Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Older Adult

Refer to adult dosing.

Dosing: Obesity: Adult

There are insufficient data to recommend the best dosing weight to use in patients with obesity. Dose adjustments should ultimately be made based on individual patient response to therapy. Due to the paucity of data, refer to institutional protocols. Refer to adult dosing for indication-specific dosing.

Dosage Forms: US

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

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]

Helixate FS: 250 units [DSC], 500 units [DSC], 1000 units [DSC], 2000 units [DSC], 3000 units [DSC] [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]

Generic Equivalent Available: US

Dosage Forms Considerations

Strengths expressed with approximate values. Consult individual vial labels for exact potency within each vial.

Dosage Forms: Canada

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]

Administration: Adult

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

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 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 (Batorova 2002; Batorova 2012; Holme 2018; Poon 2012; Rickard 1995; Suzuki 2017; WFH [Srivastava 2020]).

Administration: Pediatric

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 (Batorova 2012; Prelog 2016).

Use: Labeled Indications

Hemophilia A:

Control and prevention of bleeding episodes: Prevention and control of bleeding episodes in adults and children with hemophilia A.

Perioperative management: Surgical prophylaxis in adults and children with hemophilia A.

Routine prophylaxis to prevent or reduce the frequency of bleeding: Routine prophylactic treatment to prevent or reduce the frequency of bleeding episodes in adults and children with hemophilia A.

Routine prophylaxis to prevent bleeding episodes and joint damage (Helixate FS, Kogenate FS): Routine prophylactic treatment to reduce the frequency of bleeding episodes and the risk of joint damage in children without preexisting joint damage.

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

Medication Safety Issues

Sound-alike/look-alike issues:

Factor VIII may be confused with Factor XIII

Other safety concerns:

Confusion may occur due to the omitting of “Factor VIII” from some product labeling. Review product contents carefully prior to dispensing any antihemophilic factor.

Adverse Reactions

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: 55%; previously treated patients: <1%; may include neutralizing antibodies)

Local: Catheter infection (18% to 19%)

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: Chills (≤7%), dizziness (≤2%), insomnia (1% to 2%), malaise (1%), procedural pain (5%)

Neuromuscular & skeletal: Asthenia (6%), back pain (4%), 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%)

Miscellaneous: Limb injury (6%)

<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

Neuromuscular & skeletal: Neurological deterioration, paresthesia, tremor

Renal: Renal neoplasm (benign)

Respiratory: Epistaxis

Frequency not defined: Endocrine & metabolic: Hot flash

Postmarketing:

Cardiovascular: Chest pain, facial edema, tachycardia

Hypersensitivity: Anaphylaxis, angioedema

Nervous system: Loss of consciousness, restlessness

Respiratory: Cyanosis, laryngeal edema

Contraindications

Hypersensitivity (eg, anaphylaxis) to antihemophilic factor, mouse or hamster protein (Advate, Afstyla, Helixate FS, Kogenate FS, Kovaltry, Novoeight, Recombinate, Xyntha, Zonovate [Canadian product]), bovine protein (Recombinate only), or any component of the formulation.

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; 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.

Warnings: Additional Pediatric Considerations

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.

Metabolism/Transport Effects

None known.

Drug Interactions

There are no known significant interactions.

Pregnancy Considerations

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]).

Breastfeeding Considerations

It is not known if antihemophilic factor (recombinant) is present in breast milk.

According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.

Dietary Considerations

Some products may contain sodium.

Monitoring Parameters

Monitoring assay selection: For Advate, Afstyla, Kogenate FS, and Kovaltry, the World Federation of Hemophilia (WFH) recommends use of a one-stage or chromogenic factor VIII activity assay calibrated with a plasma standard traceable to a WHO international standard. For all other products, refer to the manufacturer's labeling for assay recommendations. Note: For patients receiving concomitant emicizumab therapy, emicizumab interferes with chromogenic factor VIII assays which use human factor IXa and factor X; use of chromogenic assays with bovine factor IXa and X is required to obtain reliable factor VIII activity when emicizumab is present (WFH [Srivastava 2020]).

Monitoring frequency: During treatment of an acute bleeding event or in the perioperative setting using intermittent bolus administration, factor VIII levels should be measured at baseline, and as peaks 15 to 30 minutes after infusion to assess target level achievement. Measurement of FVIII trough levels may aid in calculation of subsequent doses. Subsequent doses should ideally be based on the FVIII half-life and on the factor recovery of the individual patients. The frequency of peak factor VIII activity monitoring during active treatment depends on the indication, clinical response, and treatment day (WFH [Srivastava 2020]).

When administered as a continuous infusion, monitor factor VIII activity at baseline, peak factor VIII activity 15 to 30 minutes after initial bolus administration, and at least daily while on continuous infusion therapy. Frequently assess proper functioning of vascular access devices and infusion pumps for pump failure (WFH [Srivastava 2020]).

For long-term bleeding prophylaxis, trough factor VIII measurements should be obtained to tailor prophylaxis regimens, with the goal of achieving factor VIII troughs >3 to 5 units/dL; prophylaxis targets should be tailored to individual level of activity, lifestyle, and pharmacokinetics.

Patients with low-titer inhibitors receiving factor VIII concentrate products should undergo frequent assessment of factor VIII levels and inhibitor titers to ensure response is maintained.

Additional monitoring considerations:

Heart rate and BP before and during IV administration, signs of hypersensitivity reactions, hemoglobin/hematocrit, and signs and symptoms of intravascular hemolysis.

For both intermittent bolus and continuous infusion administration, lower than expected factor VIII recovery or reduced half-life are early signs of inhibitor formation.

Reference Range

Classification of hemophilia; normal is defined as 100% 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

Mechanism of Action

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.

Pharmacokinetics

Distribution: V_ss: ~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.

Helixate FS, 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.

Pricing: US

Kit (Afstyla Intravenous)

250 unit (Price provided is per AHF Unit): $2.15

500 unit (Price provided is per AHF Unit): $2.15

1000 unit (Price provided is per AHF Unit): $2.15

1500 unit (Price provided is per AHF Unit): $2.15

2000 unit (Price provided is per AHF Unit): $2.15

2500 unit (Price provided is per AHF Unit): $2.15

3000 unit (Price provided is per AHF Unit): $2.15

Kit (Kogenate FS Intravenous)

250 unit (Price provided is per AHF Unit): $2.30

500 unit (Price provided is per AHF Unit): $2.30

1000 unit (Price provided is per AHF Unit): $2.30

2000 unit (Price provided is per AHF Unit): $2.30

3000 unit (Price provided is per AHF Unit): $2.30

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): $1.91

500 unit (Price provided is per AHF Unit): $1.91

1000 unit (Price provided is per AHF Unit): $1.91

2000 unit (Price provided is per AHF Unit): $1.91

Kit (Xyntha Solofuse Intravenous)

250 unit (Price provided is per AHF Unit): $1.91

500 unit (Price provided is per AHF Unit): $1.91

1000 unit (Price provided is per AHF Unit): $1.91

2000 unit (Price provided is per AHF Unit): $1.91

3000 unit (Price provided is per AHF Unit): $1.91

Solution (reconstituted) (Advate Intravenous)

250 unit (Price provided is per AHF Unit): $2.15

500 unit (Price provided is per AHF Unit): $2.15

1000 unit (Price provided is per AHF Unit): $2.15

1500 unit (Price provided is per AHF Unit): $2.15

2000 unit (Price provided is per AHF Unit): $2.15

3000 unit (Price provided is per AHF Unit): $2.15

4000 unit (Price provided is per AHF Unit): $2.15

Solution (reconstituted) (Kovaltry Intravenous)

250 unit (per each): $2.29

500 unit (Price provided is per AHF Unit): $2.29

500 unit (per each): $2.29

1000 unit (per each): $2.29

2000 unit (per each): $2.29

3000 unit (per each): $2.29

Solution (reconstituted) (Novoeight Intravenous)

250 unit (Price provided is per AHF Unit): $2.40

500 unit (Price provided is per AHF Unit): $2.40

1000 unit (Price provided is per AHF Unit): $2.40

1500 unit (Price provided is per AHF Unit): $2.40

2000 unit (Price provided is per AHF Unit): $2.40

3000 unit (Price provided is per AHF Unit): $2.40

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): $2.15

401-800 unit (Price provided is per AHF Unit): $2.15

801-1240 unit (Price provided is per AHF Unit): $2.15

1241-1800 unit (Price provided is per AHF Unit): $2.15

1801-2400 unit (Price provided is per AHF Unit): $2.15

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.

Brand Names: International

Advate (AR, AT, AU, BE, CH, CY, CZ, DE, DK, EE, ES, FR, GB, GR, HR, HU, IE, IS, IT, JP, KR, LT, MT, MY, NL, NO, NZ, PT, RO, SE, SG, SI, SK);
Afstyla (AT, AU, CZ, DE, DK, EE, HR, LT, LV, NO, PT, SK);
Green Eight (KR);
Green VIII (LK);
Greenmono (KR);
Helixate (AT, GR, HU, IT, NL, PL);
Helixate Nexgen (AU, BE, CZ, DE, DK, EE, ES, FR, NO, SE);
Helixate NexGen (GB, IE);
Kogenate (AT, BE, CH, CL, CY, CZ, DE, DK, EE, ES, FR, GB, GR, HR, HU, IE, IT, JO, LT, LU, MT, NL, NO, NZ, PL, PT, RO, SE, SI, TW);
Kogenate FS (AE, AR, AU, BH, CN, CO, EC, ID, IL, LB, MY, QA, SA, SG, TH, ZA);
Kryobulin TIM 3 (HN);
Octanate (ID, MY);
Profilate SD (HK);
Recombinate (AR, AT, AU, BE, BG, BR, CH, CZ, DE, DK, EE, ES, FI, FR, GB, IE, IL, IT, LT, NL, NZ, SE, TH);
Refacto (AT, CY, CZ, GR, HU, IT, NL, PL);
Refacto AF (BE, CH, DE, DK, EE, FR, GB, NO, SE);
Xyntha (AR, AU, CL, KR, LB, MY, NZ, SA, SG, TW)

For country code abbreviations (show table)

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Advate (antihemophilic factor [recombinant]) [prescribing information]. Lexington, MA: Baxalta US Inc; December 2018.
Afstyla (antihemophilic factor [recombinant]) [prescribing information]. Kankakee, IL: CSL Behring LLC; April 2020.
Afstyla (antihemophilic factor [recombinant]) [prescribing information]. Kankakee, IL: CSL Behring LLC; December 2019.
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Helixate FS (antihemophilic factor [recombinant]) [prescribing information]. Kankakee, IL: CSL Behring LLC; June 2016.
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Kogenate FS (antihemophilic factor [recombinant]) [prescribing information]. Whippany, NJ: Bayer HealthCare LLC; May 2016.
Kogenate FS with Bio-Set (antihemophilic factor [recombinant]) [prescribing information]. Whippany, NJ: Bayer HealthCare LLC; May 2016.
Kogenate FS with Vial Adapter (antihemophilic factor [recombinant]) [prescribing information]. Whippany, NJ: Bayer HealthCare LLC; May 2016.
Kovaltry (antihemophilic factor [recombinant]) [prescribing information]. Whippany, NJ: Bayer HealthCare LLC; October 2021.
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Lucente P, Iorizzo M, Pazzaglia M. Contact sensitivity to Tween 80 in a child. Contact Dermatitis. 2000;43(3):172. [PubMed 10985636]
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National Hemophilia Foundation (NHF). MASAC recommendations concerning prophylaxis (regular administration of clotting factor concentrate to prevent bleeding). 2007. Available at http://www.hemophilia.org/NHFWeb/Resource/StaticPages/menu0/menu5/menu57/masac179.pdf
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Novoeight (antihemophilic factor [recombinant]) [prescribing information]. Plainsboro, NJ: Novo Nordisk Inc; July 2020.
Nuwiq (antihemophilic factor [recombinant]) [prescribing information]. Paramus, NJ: Octapharma USA Inc; September 2020.
Nuwiq (antihemophilic factor [recombinant]) [prescribing information]. Hoboken, NJ: Octapharma; July 2017.
Pavord S, Rayment R, Madan B, et al; for the Royal College of Obstetricians and Gynaecologists. Management of inherited bleeding disorders in pregnancy: Green-top Guideline No. 71 (joint with UKHCDO). BJOG. 2017;124(8):e193–e263. doi: 10.1111/1471-0528.14592. [PubMed 28447403]
Poon MC, Card R. Hemophilia management in transfusion medicine. Transfus Apher Sci. 2012;46(3):299-307. doi:10.1016/j.transci.2012.03.020 [PubMed 22503305]
Prelog T, Dolničar MB, Kitanovski L. Low-dose continuous infusion of factor VIII in patients with haemophilia A. Blood Transfus. 2016;14(5):474-480. [PubMed 26674820]
Recombinate (antihemophilic factor [recombinant]) [prescribing information]. Lexington, MA: Baxalta US Inc; June 2018.
Rickard KA. Guidelines for therapy and optimal dosages of coagulation factors for treatment of bleeding and surgery in haemophilia. Haemophilia. 1995;1(suppl 1):8-13. doi:10.1111/j.1365-2516.1995.tb00104.x
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Srivastava A, Santagostino E, Dougall A, et al; WFH Guidelines for the Management of Hemophilia panelists and co-authors. WFH guidelines for the management of hemophilia, 3rd edition. Haemophilia. 2020;26(suppl 6):1-158. doi:10.1111/hae.14046 [PubMed 32744769]
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Xyntha (antihemophilic factor [recombinant]) [prescribing information]. Philadelphia, PA: Wyeth Pharmaceuticals Inc; August 2020.
Xyntha Solofuse (antihemophilic factor [recombinant]) [prescribing information]. Philadelphia, PA: Wyeth Pharmaceuticals LLC; August 2020.
Zonovate (antihemophilic factor [recombinant]) [product monograph]. Mississauga, Ontario, Canada: Novo Nordisk Canada Inc; April 2021.

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