Factor VIII, recombinant human: Pediatric drug information

For additional information see "Factor VIII, recombinant human: Drug information" and "Factor VIII, recombinant human: Patient drug information"

For abbreviations, symbols, and age group definitions show table

Brand Names: US

Advate;
Afstyla;
Kogenate FS;
Kovaltry;
Novoeight;
Nuwiq;
Recombinate;
Xyntha;
Xyntha Solofuse

Brand Names: Canada

Advate [DSC];
Kovaltry;
Nuwiq;
Xyntha;
Xyntha Solofuse;
Zonovate

Therapeutic Category

Antihemophilic Agent

Dosing: Neonatal

Hemophilia A

Hemophilia A: Individualize dosage based on clinical response and factor VIII activity evaluated at baseline and at regular intervals during treatment. Patients with inhibitory antibodies to factor VIII may require higher doses, more frequent administration, and/or selection of alternative therapy.

Treatment and control 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. Ages vary by product; see product-specific labeling for approved ages.

Neonates: IV:

Intermittent IV bolus dosing: IV: Utilize steps 1 through 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. These 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 (Ref).

**WFH Treatment Recommendations^a**
Site of hemorrhage/Clinical situation	Desired factor VIII peak level	Duration^b
^aWFH = World Federation of Hemophilia (Ref).
^bDepending on procedure; the number of doses would depend on the half-life of the clotting factor concentrate used.
^c May be longer if response is inadequate.
^d A single dose may be sufficient for some joint bleeds; determine need for additional doses based on clinical response.
^e Sometimes longer as secondary prophylaxis during physical therapy.
Joint	40 to 60 units/dL	1 to 2 days^c,d
Superficial muscle/no neurovascular compromise	40 to 60 units/dL	2 to 3 days^c
Iliopsoas or deep muscle with neurovascular injury, or substantial blood loss	Initial: 80 to 100 units/dL	1 to 2 days
	Maintenance: 30 to 60 units/dL	3 to 5 days^e
CNS/Head	Initial: 80 to 100 units/dL	1 to 7 days
CNS/Head	Maintenance: 50 units/dL	8 to 21 days
Throat and neck	Initial: 80 to 100 units/dL	1 to 7 days
Throat and neck	Maintenance: 50 units/dL	8 to 14 days
Gastrointestinal	Initial: 80 to 100 units/dL	7 to 14 days
Gastrointestinal	Maintenance: 50 units/dL	Not specified
Renal	50 units/dL	3 to 5 days
Deep laceration	50 units/dL	5 to 7 days
Surgery (major)	Preop: 80 to 100 units/dL	Single dose
	Postop: 60 to 80 units/dL	1 to 3 days
	Postop: 40 to 60 units/dL	4 to 6 days
	Postop: 30 to 50 units/dL	7 to 14 days
Surgery (minor)	Preop: 50 to 80 units/dL	Single dose
Surgery (minor)	Postop: 30 to 80 units/dL	1 to 5 days

Step 2: Calculate dose using desired peak factor VIII level from step 1 and the following equation:

Formula for units required to raise blood level:

Factor VIII units required = [(desired peak factor VIII level − baseline factor VIII level) × body weight (kg)]/2

Example for 25 kg patient with a 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) × 25 kg]/2 = 375 units of factor VIII

Step 3: Determine the frequency of repeat dosing based on half-life of product used (see product-specific labeling for details), type of bleed or surgery, and patient response. If subsequent factor VIII levels are available for individual patients, these should be taken into consideration when determining the frequency of repeat dose.

**Antihemophilic Factor (Recombinant) Administration Frequency According to Clinical Scenario**
Product	Type of bleeding event			Type of surgery
Product	Minor severity^a	Moderate severity^b	Major severity^c	Minor bleeding risk^d	Major bleeding risk^e
^a Minor bleeds include early hemarthrosis, mild muscle bleeding, or mild oral bleeding episode.
^b Moderate bleeds include muscle bleeding, moderate bleeding into the oral cavity, definite hemarthroses, and known trauma.
^c Major bleeds include significant GI bleeding; intracranial, intra-abdominal, or intrathoracic bleeding; CNS bleeding; bleeding in the retropharyngeal or retroperitoneal spaces or iliopsoas sheath; fractures; head trauma.
^d Including tooth extraction.
^e For example: Intracranial, intra-abdominal, or intrathoracic surgery; joint replacement surgery.
Advate	Every 8 to 24 hours	Every 8 to 24 hours	Every 6 to 12 hours	Every 12 to 24 hours	Every 6 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 is 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

Routine prophylaxis to prevent or reduce the frequency of bleeding episodes:

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 (Ref).

Neonates:

High dose: IV: 25 to 40 units/kg/dose every 2 days.

Intermediate dose: IV: 15 to 25 units/kg/dose 3 times weekly.

Low dose: IV: 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 improve adherence; close monitoring is required since patients are at a higher risk for bleeding until escalation occurs.

Dosing: Pediatric

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.

Treatment and control 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. Ages vary by product; see product-specific labeling for approved ages.

Infants, Children, and Adolescents: IV:

Intermittent IV bolus dosing: Utilize steps 1 through 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).

**WFH Treatment Recommendations^a**
Site of hemorrhage/Clinical situation	Desired factor VIII peak level	Duration^b
^aWFH = World Federation of Hemophilia (Ref).
^bDepending on procedure; the number of doses would depend on the half-life of the clotting factor concentrate used.
^c May be longer if response is inadequate.
^d A single dose may be sufficient for some joint bleeds; determine need for additional doses based on clinical response.
^e Sometimes longer as secondary prophylaxis during physical therapy.
Joint	40 to 60 units/dL	1 to 2 days^c,d
Superficial muscle/no neurovascular compromise	40 to 60 units/dL	2 to 3 days^c
Iliopsoas or deep muscle with neurovascular injury, or substantial blood loss	Initial: 80 to 100 units/dL	1 to 2 days
	Maintenance: 30 to 60 units/dL	3 to 5 days^e
CNS/Head	Initial: 80 to 100 units/dL	1 to 7 days
CNS/Head	Maintenance: 50 units/dL	8 to 21 days
Throat and neck	Initial: 80 to 100 units/dL	1 to 7 days
Throat and neck	Maintenance: 50 units/dL	8 to 14 days
Gastrointestinal	Initial: 80 to 100 units/dL	7 to 14 days
Gastrointestinal	Maintenance: 50 units/dL	Not specified
Renal	50 units/dL	3 to 5 days
Deep laceration	50 units/dL	5 to 7 days
Surgery (major)	Preop: 80 to 100 units/dL	Single dose
	Postop: 60 to 80 units/dL	1 to 3 days
	Postop: 40 to 60 units/dL	4 to 6 days
	Postop: 30 to 50 units/dL	7 to 14 days
Surgery (minor)	Preop: 50 to 80 units/dL	Single dose
Surgery (minor)	Postop: 30 to 80 units/dL	1 to 5 days

Step 2: Calculate dose using desired peak factor VIII level from step 1 and the following equation:

Formula for units required to raise blood level:

Factor VIII units required = [(desired peak factor VIII level − baseline factor VIII level) × body weight (kg)]/2

Example for 25 kg patient with a 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) × 25 kg]/2 = 375 units of factor VIII

**Antihemophilic Factor (Recombinant) Administration Frequency According to Clinical Scenario**
Product	Type of bleeding event			Type of surgery
Product	Minor severity^a	Moderate severity^b	Major severity^c	Minor bleeding risk^d	Major bleeding risk^e
^a Minor bleeds include early hemarthrosis, mild muscle bleeding, or mild oral bleeding episode.
^b Moderate bleeds include muscle bleeding, moderate bleeding into the oral cavity, definite hemarthroses, and known trauma.
^c Major bleeds include significant GI bleeding; intracranial, intra-abdominal, or intrathoracic bleeding; CNS bleeding; bleeding in the retropharyngeal or retroperitoneal spaces or iliopsoas sheath; fractures; head trauma.
^d Including tooth extraction.
^e For example: Intracranial, intra-abdominal, or intrathoracic surgery; joint replacement surgery.
Advate	Infants and Children <6 years: Every 8 to 24 hours	Infants and Children <6 years: Every 8 to 24 hours	Infants and Children <6 years: Every 6 to 12 hours	Infants, Children, and Adolescents: Every 12 to 24 hours	Infants and Children <6 years: Every 6 to 24 hours
Advate	Children ≥6 years and Adolescents: Every 12 to 24 hours	Children ≥6 years and Adolescents: Every 12 to 24 hours	Children ≥6 years and Adolescents: Every 8 to 24 hours	Infants, Children, and Adolescents: Every 12 to 24 hours	Children ≥6 years and Adolescents: 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 is 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

Continuous IV infusion dosing: Limited data available (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 avoid peaks and troughs associated with intermittent infusions. 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. In general, administration of factor VIII 4 units/kg/hour will increase circulating factor VIII levels by 1 unit/mL.

Infants, Children, and Adolescents: Continuous IV infusion: Note: Use with caution and consider risk vs benefit in patients with <20 exposure days or mild hemophilia due to increased risk of inhibitor development (Ref).

Following initial bolus to achieve the desired factor VIII level (see steps 1 and 2 under intermittent bolus dosing): 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 (Ref):

Factor VIII clearance (mL/kg/hour) = (current infusion rate in units/kg/hour) / (measured factor VIII level in units/mL)

New infusion rate (units/kg/hour) = (factor VIII clearance in mL/kg/hour) × (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:

Infants, Children, and Adolescents:

High dose: IV: 25 to 40 units/kg/dose every 2 days.

Intermediate dose: IV: 15 to 25 units/kg/dose 3 times weekly.

Breakthrough bleeding, treatment in patients with hemophilia A receiving fitusiran

Breakthrough bleeding, treatment in patients with hemophilia A receiving fitusiran:

Note: Antihemophilic factor (recombinant) doses provided below are recommended for breakthrough bleeding in patients who are receiving fitusiran; higher doses may be associated with increased risk of thrombotic events (Ref).

Children ≥12 years and Adolescents:

During the first 7 days of fitusiran initiation: IV: Manage bleeding with patient's previously established antihemophilic factor (recombinant) regimen (Ref).

More than 7 days from first fitusiran dose: IV: Initial: 10 units/kg/dose; repeat dose may be considered after 24 hours if indicated. Higher doses or more frequent administration may be considered based on clinical judgment (weigh risks of thrombosis vs benefits); maximum dose: 20 units/kg (Ref).

Dosing: Kidney Impairment: Pediatric

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

Dosing: Liver Impairment: Pediatric

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

Dosing: Adult

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

Hemophilia A, treatment and control of bleeding episodes in patients receiving fitusiran

Hemophilia A, treatment and control of bleeding episodes in patients receiving fitusiran:

During first 7 days of fitusiran initiation:

IV: Manage bleeding with patient’s previously established regimen of clotting factor concentrate or bypassing agent (Ref).

After 7 days from first fitusiran dose:

IV: Initial: 10 to 20 units/kg; reassess clinical status and need for repeat doses; in general, dose should not be repeated within 24 hours. Higher doses or more frequent administration may be considered based on clinical judgment (Ref).

Hemophilia A, without inhibitors

Hemophilia A, without inhibitors:

Treatment and control of bleeding episodes or perioperative management (when baseline factor VIII level is known):

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.

**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	Treatment duration	Desired peak factor VIII level	Treatment duration
^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 units/dL	1 to 2 days^a,c	40 to 60 units/dL	1 to 2 days^a,c
Superficial muscle/no neurovascular compromise (except iliopsoas)	10 to 20 units/dL	2 to 3 days^a	40 to 60 units/dL	2 to 3 days^a
Iliopsoas or deep muscle with neurovascular injury or substantial blood loss:
Initial	20 to 40 units/dL	1 to 2 days	80 to 100 units/dL	1 to 2 days
Maintenance	10 to 20 units/dL	3 to 5 days^b	30 to 60 units/dL	3 to 5 days^b
Intracranial:
Initial	50 to 80 units/dL	1 to 3 days	80 to 100 units/dL	1 to 7 days
Maintenance	30 to 50 units/dL	4 to 7 days	50 units/dL	8 to 21 days
Maintenance	20 to 40 units/dL	8 to 14 days	-	-
Throat and neck:
Initial	30 to 50 units/dL	1 to 3 days	80 to 100 units/dL	1 to 7 days
Maintenance	10 to 20 units/dL	4 to 7 days	50 units/dL	8 to 14 days
Gastrointestinal:
Initial	30 to 50 units/dL	1 to 3 days	80 to 100 units/dL	7 to 14 days
Maintenance	10 to 20 units/dL	4 to 7 days	50 units/dL	-
Renal	20 to 40 units/dL	3 to 5 days	50 units/dL	3 to 5 days
Deep laceration	20 to 40 units/dL	5 to 7 days	50 units/dL	5 to 7 days
Surgery (major):
Preop	60 to 80 units/dL	-	80 to 100 units/dL	-
Postop	30 to 40 units/dL	1 to 3 days	60 to 80 units/dL	1 to 3 days
	20 to 30 units/dL	4 to 6 days	40 to 60 units/dL	4 to 6 days
	10 to 20 units/dL	7 to 14 days	30 to 50 units/dL	7 to 14 days
Surgery (minor):
Preop	40 to 80 units/dL	-	50 to 80 units/dL	-
Postop	20 to 50 units/dL	1 to 5 days	30 to 80 units/dL	1 to 5 days

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
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.

Treatment and control of bleeding episodes (when baseline factor VIII level is not known):

Note: After the loading dose, if possible, it is preferred to obtain a factor VIII level to determine subsequent doses based on patient needs rather than continuing an empiric dosing regimen. In general, administration of factor VIII 1 unit/kg will increase circulating factor VIII levels by ~2 units/dL (Ref). Consider transfer of care to comprehensive hemophilia treatment center with capacity to perform clotting factor assays and inhibitor testing. For patients without inhibitors and receiving emicizumab who experience breakthrough bleeding, antihemophilic factor should be dosed to target the desired peak factor VIII level as emicizumab is not indicated for treatment of bleeding episodes (Ref).

**Antihemophilic Factor (Recombinant) D** **ose and** **Frequency According to Clinical Scenario^a**
Product and bleeding severity	Loading dose, IV	Desired peak factor VIII level^b	Maintenance dose^b, IV	Frequency of maintenance dose^b	Treatment duration^c
^aManufacturer’s labeling.
^bDesired peak factor VIII level, dose, and frequency of maintenance dose administration may change as bleeding becomes more controlled. Individualize dosing to patient-specific needs by evaluating circulating factor VIII levels.
^c Dosing continues until bleeding resolves and may extend beyond what is indicated in this table. It is preferable to individualize dosing based on patient-specific needs by evaluating circulating factor VIII levels.
^dNational Bleeding Disorders Foundation, Medical and Scientific Advisory Council of the National Hemophilia Foundation, document #257.
^eApproximate dose based on estimated incremental recovery of 2 units/dL (manufacturer’s labeling).
Advate
Minor bleeding	10 to 20 units/kg	20 to 40 units/dL	10 to 20 units/kg	Every 12 to 24 hours	1 to 3 days
Moderate bleeding	15 to 30 units/kg	30 to 60 units/dL	15 to 30 units/kg	Every 12 to 24 hours	≥3 days
Major bleeding	50 units/kg^d	80 to 100 units/dL^d	30 to 50 units/kg	Every 8 to 24 hours	Not specified
Afstyla
Minor bleeding	10 to 20 units/kg^e	20 to 40 units/dL	10 to 20 units/kg^e	Every 12 to 24 hours	Not specified
Moderate bleeding	15 to 30 units/kg^e	30 to 60 units/dL	15 to 30 units/kg^e	Every 12 to 24 hours	Not specified
Major bleeding	50 units/kg^d	80 to 100 units/dL^d	30 to 50 units/kg^e	Every 8 to 24 hours	Not specified
Kogenate FS
Minor bleeding	10 to 20 units/kg	20 to 40 units/dL	10 to 20 units/kg	Repeat if evidence of bleeding	Not specified
Moderate bleeding	15 to 30 units/kg	30 to 60 units/dL	15 to 30 units/kg	Every 12 to 24 hours	Not specified
Major bleeding	50 units/kg^d	80 to 100 units/dL^d	20 to 25 units/kg	Every 8 to 12 hours	Not specified
Kovaltry
Minor bleeding	10 to 20 units/kg^e	20 to 40 units/dL	10 to 20 units/kg^e	Every 12 to 24 hours	At least 1 day
Moderate bleeding	15 to 30 units/kg^e	30 to 60 units/dL	15 to 30 units/kg^e	Every 12 to 24 hours	3 to 4 days
Major bleeding	50 units/kg^d	80 to 100 units/dL^d	30 to 50 units/kg^e	Every 8 to 24 hours	Not specified
Novoeight
Minor bleeding	10 to 20 units/kg^e	20 to 40 units/dL	10 to 20 units/kg^e	Every 12 to 24 hours	At least 1 day
Moderate bleeding	15 to 30 units/kg^e	30 to 60 units/dL	15 to 30 units/kg^e	Every 12 to 24 hours	3 to 4 days
Major bleeding	50 units/kg^d	80 to 100 units/dL^d	30 to 50 units/kg^e	Every 8 to 24 hours	7 to 10 days
Nuwiq
Minor bleeding	10 to 20 units/kg^e	20 to 40 units/dL	10 to 20 units/kg^e	Every 12 to 24 hours	At least 1 day
Moderate bleeding	15 to 30 units/kg^e	30 to 60 units/dL	15 to 30 units/kg^e	Every 12 to 24 hours	3 to 4 days
Major bleeding	50 units/kg^d	80 to 100 units/dL^d	30 to 50 units/kg^e	Every 8 to 24 hours	Not specified
Recombinate
Minor bleeding	10 to 20 units/kg^e	20 to 40 units/dL	10 to 20 units/kg^e	Every 12 to 24 hours	1 to 3 days
Moderate bleeding	15 to 30 units/kg^e	30 to 60 units/dL	15 to 30 units/kg^e	Every 12 to 24 hours	≥3 days
Major bleeding	50 units/kg^d	80 to 100 units/dL^d	30 to 50 units/kg^e	Every 8 to 24 hours	Not specified
Xyntha/Xyntha Solofuse
Minor bleeding	10 to 20 units/kg^e	20 to 40 units/dL	10 to 20 units/kg^e	Every 12 to 24 hours	At least 1 day
Moderate bleeding	15 to 30 units/kg^e	30 to 60 units/dL	15 to 30 units/kg^e	Every 12 to 24 hours	3 to 4 days
Major bleeding	50 units/kg^d	80 to 100 units/dL^d	30 to 50 units/kg^e	Every 8 to 24 hours	Not specified
Zonovate (Canadian product)
Minor bleeding	10 to 20 units/kg^e	20 to 40 units/dL	10 to 20 units/kg^e	Every 12 to 24 hours	At least 1 day
Moderate bleeding	15 to 30 units/kg^e	30 to 60 units/dL	15 to 30 units/kg^e	Every 12 to 24 hours	3 to 4 days
Major bleeding	50 units/kg^d	80 to 100 units/dL^d	30 to 50 units/kg^e	Every 8 to 24 hours	Not specified

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.

Dosing: Kidney Impairment: Adult

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

Dosing: Liver Impairment: Adult

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

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: 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

Contraindications

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.

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.

Dosage Forms Considerations

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

Dosage Forms: US

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]

Generic Equivalent Available: US

Pricing: US

Kit (Afstyla Intravenous)

250 unit (Price provided is per AHF Unit): $2.35

500 unit (Price provided is per AHF Unit): $2.35

1000 unit (Price provided is per AHF Unit): $2.35

1500 unit (Price provided is per AHF Unit): $2.35

2000 unit (Price provided is per AHF Unit): $2.35

2500 unit (Price provided is per AHF Unit): $2.35

3000 unit (Price provided is per AHF Unit): $2.35

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): $2.29

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

1000 unit (Price provided is per AHF Unit): $2.29

2000 unit (Price provided is per AHF Unit): $2.29

Kit (Xyntha Solofuse Intravenous)

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

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

1000 unit (Price provided is per AHF Unit): $2.29

2000 unit (Price provided is per AHF Unit): $2.29

3000 unit (Price provided is per AHF Unit): $2.29

Solution (reconstituted) (Advate Intravenous)

250 unit (Price provided is per AHF Unit): $2.35

500 unit (Price provided is per AHF Unit): $2.35

1000 unit (Price provided is per AHF Unit): $2.35

1500 unit (Price provided is per AHF Unit): $2.35

2000 unit (Price provided is per AHF Unit): $2.35

3000 unit (Price provided is per AHF Unit): $2.35

4000 unit (Price provided is per AHF Unit): $2.35

Solution (reconstituted) (Kovaltry Intravenous)

250 unit (Price provided is per AHF Unit): $2.89

250 unit (per each): $2.89

500 unit (Price provided is per AHF Unit): $2.89

500 unit (per each): $2.89

1000 unit (per each): $2.89

2000 unit (per each): $2.89

3000 unit (per each): $2.89

Solution (reconstituted) (Novoeight Intravenous)

250 unit (Price provided is per AHF Unit): $2.71

500 unit (Price provided is per AHF Unit): $2.71

1000 unit (Price provided is per AHF Unit): $2.71

1500 unit (Price provided is per AHF Unit): $2.71

2000 unit (Price provided is per AHF Unit): $2.71

3000 unit (Price provided is per AHF Unit): $2.71

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): $2.35

401-800 unit (Price provided is per AHF Unit): $2.35

801-1240 unit (Price provided is per AHF Unit): $2.35

1241-1800 unit (Price provided is per AHF Unit): $2.35

1801-2400 unit (Price provided is per AHF Unit): $2.35

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.

Dosage Forms: Canada

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

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 ([DSC]); 500 units ([DSC]); 1000 units ([DSC]); 1500 units ([DSC]); 2000 units ([DSC]); 3000 units ([DSC]) [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]

Additional Information

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.

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.

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). Use a smart infusion pump with small volume infusion capability (Ref).

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

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).

Storage/Stability

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.

Use

Advate, Afstyla, Kovaltry, Novoeight, 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 all ages).

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).

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.

Note: Products are 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.

Metabolism/Transport Effects

None known.

Drug Interactions

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 by clicking on the “Launch drug interactions program” link above.

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

Fitusiran: May increase thrombogenic effects of Clotting Factor Concentrates (CFCs) and Bypassing Agents (BPAs). Management: Stop CFC/BPA prophylaxis no later than 7 days after starting fitusiran. If bleeding occurs during the first 7 days of fitusiran, manage with the prior dosing regimen of CFC/BPA. If bleeding occurs after 7 days, use reduced CFC/BPA doses and frequencies. Risk D: Consider Therapy Modification

Dietary Considerations

Some products may contain sodium.

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 (NBDF 2017; RCOG [Pavord 2017]; WFH [Srivastava 2020]).

Monitoring Parameters

Note: 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 monitoring (WFH [Srivastava 2020]).

Monitor factor VIII levels prior to and during treatment, typically during treatment of an acute bleeding event or in the perioperative setting; factor VIII levels should be measured at baseline, as peaks 15 to 30 minutes after infusion to assess target level achievement and troughs to aid in calculation of subsequent doses. The frequency of monitoring 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 (WFH [Srivastava 2020]).

Monitor 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).

Reference Range

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.

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 (Adult Data Unless Noted)

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.

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.

Brand Names: International

International Brand Names by Country

For country code abbreviations (show table)

(AE) United Arab Emirates: Advate | Recombinate;
(AR) Argentina: Advate | Kogenate fs | Kovaltry;
(AT) Austria: Advate | Iblias | Kogenate | Kovaltry | Recombinate;
(AU) Australia: Advate | Kogenate | Recombinate;
(BE) Belgium: Advate | Helixate nexgen | Kogenate | Kovaltry | Recombinate;
(BG) Bulgaria: Advate | Kogenate | Kovaltry;
(BR) Brazil: Advate | Kovaltry;
(CH) Switzerland: Helixate M2V | Helixate nexgen | Kogenate SF | Kovaltry | Recombinate;
(CL) Chile: Kogenate;
(CO) Colombia: Advate | Kovaltry | Recombinate;
(CZ) Czech Republic: Advate | Helixate nexgen | Kovaltry | Recombinate;
(DE) Germany: Advate | Iblias | Kogenate | Kovaltry | Recombinate;
(EC) Ecuador: Kovaltry;
(EE) Estonia: Advate | Recombinate;
(EG) Egypt: Kogenate fs;
(ES) Spain: Advate | Helixate nexgen | Iblias | Kogenate | Kovaltry | Recombinate;
(FI) Finland: Advate | Helixate nexgen | Kogenate | Kovaltry | Recombinate;
(FR) France: Advate | Helixate nexgen | Kogenate | Kovaltry;
(GB) United Kingdom: Advate | Helixate nexgen | Kogenate | Recombinate;
(GR) Greece: Advate | Helixate nexgen | Kogenate | Kovaltry;
(HK) Hong Kong: Advate | Kogenate fs;
(HU) Hungary: Helixate nexgen | Kogenate | Kovaltry;
(ID) Indonesia: Kogenate;
(IE) Ireland: Advate | Helixate nexgen;
(IN) India: Recombinate;
(IS) Iceland: Helixate nexgen;
(IT) Italy: Advate | Kogenate | Kovaltry;
(JO) Jordan: Kogenate;
(JP) Japan: Advate | Kogenate | Kogenate fs | Recombinate;
(KR) Korea, Republic of: Advate | Kogenate fs | Recombinate;
(KW) Kuwait: Kogenate;
(LB) Lebanon: Kogenate | Recombinate;
(LT) Lithuania: Advate | Kogenate bayer | Kovaltry;
(LU) Luxembourg: Kogenate | Kovaltry;
(LV) Latvia: Advate | Kogenate | Recombinate;
(MA) Morocco: Kogenate;
(MX) Mexico: Advate | Kovaltry | Recombinate;
(MY) Malaysia: Advate | Kogenate fs;
(NL) Netherlands: Advate | Helixate nexgen | Iblias | Kogenate | Kovaltry | Recombinate;
(NO) Norway: Advate | Helixate nexgen | Kovaltry;
(NZ) New Zealand: Advate | Kogenate SF | Recombinate;
(PA) Panama: Kovaltry;
(PL) Poland: Kogenate bayer;
(PR) Puerto Rico: Advate | Kogenate fs | Kovaltry;
(PT) Portugal: Advate | Helixate nexgen | Kogenate | Recombinate;
(PY) Paraguay: Kovaltry;
(QA) Qatar: Advate | Afstyla | Kogenate FS | Kovaltry | NovoEight | Xyntha | Xyntha Solofuse;
(RO) Romania: Advate | Kogenate bayer | Kovaltry | Recombinate;
(RU) Russian Federation: Advate | Kogenate fs;
(SA) Saudi Arabia: Advate | Kogenate | Recombinate;
(SE) Sweden: Advate | Helixate nexgen | Kogenate bayer | Kovaltry | Recombinate;
(SG) Singapore: Advate | Kogenate fs;
(SI) Slovenia: Advate | Kovaltry;
(SK) Slovakia: Advate | Kogenate;
(SR) Suriname: Advate;
(TH) Thailand: Advate | Kogenate fs | Recombinate;
(TN) Tunisia: Advate | Kogenate fs;
(TR) Turkey: Advate | Kovaltry | Recombinate;
(TW) Taiwan: Advate | Kogenate | Kogenate fs | Kovaltry;
(UA) Ukraine: Advate | Kogenate fs | Recombinate;
(ZA) South Africa: Kogenate | Kovaltry

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Kogenate FS (antihemophilic factor [recombinant]) [prescribing information]. Whippany, NJ: Bayer HealthCare LLC; December 2019.
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; December 2022.
Kovaltry (antihemophilic factor [recombinant]) [product monograph]. Mississauga, Ontario, Canada: Bayer Inc; March 2023.
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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; December 2024.
Nuwiq (antihemophilic factor [recombinant]) [prescribing information]. Paramus, NJ: Octapharma USA Inc; September 2020.
Nuwiq (antihemophilic factor [recombinant]) [prescribing information]. Hoboken, NJ: Octapharma; July 2017.
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Qfitlia (fitusiran) [prescribing information]. Cambridge, MA: Genzyme Corporation; March 2025.
Recombinate (antihemophilic factor [recombinant]) [prescribing information]. Lexington, MA: Takeda Pharmaceuticals USA Inc; March 2023.
Refer to manufacturer’s labeling.
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Xyntha (antihemophilic factor [recombinant]) [prescribing information]. Philadelphia, PA: Wyeth Pharmaceuticals LLC; July 2022.
Xyntha Solofuse (antihemophilic factor [recombinant]) [prescribing information]. Philadelphia, PA: Wyeth Pharmaceuticals LLC; July 2022.
Zonovate (antihemophilic factor [recombinant]) [product monograph]. Mississauga, Ontario, Canada: Novo Nordisk Canada Inc; April 2021.

Topic 12757 Version 357.0

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Factor VIII, recombinant human: Pediatric drug information