Antihemophilic Factor (Recombinant)

Dosage Forms

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

Kogenate FS Bio-Set: 250 units [DSC], 500 units [DSC], 1000 units [DSC], 2000 units [DSC], 3000 units [DSC]

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: 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, polysorbate 80]

Pharmacology

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/Pharmacodynamics

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 and Adolescents: 6.9 to 8.3 hours; Adults: 11 to 17 hours

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.

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.

Dosage and Administration

Dosing: Adult

Hemophilia A: IV: 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.

Control and prevention of bleeding episodes or perioperative management:

Dosage based on desired factor VIII increase (%) (WFH [Srivastava 2013]):

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

[Body weight (kg) x desired factor VIII increase (%)] divided by 2 (%/units/kg) = units factor VIII required

For example:

50 kg x 30 (% increase) divided by 2 = 750 units factor VIII

Administration frequency should be determined based on product half-life, factor VIII activity, and clinical response.

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

Table has been converted to the following text.

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

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

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

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

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

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

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

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

Renal: 50% for 3 to 5 days

Deep laceration: 50% for 5 to 7 days

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

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

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

Continuous infusion (off-label; for patients who require prolonged periods of treatment [eg, intracranial hemorrhage or surgery] to avoid peaks and troughs associated with intermittent infusions, increase target factor VIII achievement, and reduce cost) (Batorova 2000; Batorova 2002; Batorova 2012; Martinowitz 1992; Poon 2012; Rickard 1995; WFH [Srivastava 2013]): Following initial bolus to achieve the desired factor VIII peak activity, initiate factor VIII infusion at a rate of 2 to 4 units/kg/hour. An empiric factor VIII infusion rate can be calculated using the infusion rate equation below, where factor VIII clearance is typically 3 to 4 mL/kg/hour initially (based on population pharmacokinetics). Adjust factor VIII infusion rates based on frequent evaluation of factor VIII activity, which should be used to recalculate factor VIII clearance at steady-state and the new infusion rate using the equations below. If factor VIII levels are below target, consider factor VIII bolus administration in addition to increasing the factor VIII continuous infusion rate. The decision to administer an additional bolus should be based on the severity of the bleeding event or bleeding risk of the surgery/procedure, the patient's clinical condition, and the degree below target of the factor VIII level.

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

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

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

Manufacturer’s labeling: Refer to manufacturer's labeling for specific recommendations; varies by product.

Routine prophylaxis to prevent or reduce the frequency of bleeding episodes: Note: Maintain factor VIII trough levels between 1% and 5% as clinically indicated (Collins 2011; Rossbach 2010).

Advate: 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: 20 to 50 units/kg 2 to 3 times weekly

Helixate FS: 25 units/kg 3 times weekly

Kogenate FS: 25 units/kg 3 times weekly

Kovaltry: 20 to 40 units/kg 2 or 3 times weekly

Novoeight: 20 to 50 units/kg 3 times weekly or 20 to 40 units/kg every other day

Nuwiq: 30 to 40 units/kg every other day

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Individualize dosage based on coagulation studies performed prior to treatment and at regular intervals during treatment; for every 1 international unit per kg body weight of rAHF administered, factor VIII level should increase by 2% (or 2 units/dL); calculated dosage should be adjusted to the actual vial size

Control or prevention of bleeding in patients with factor VIII deficiency (hemophilia A): IV: Infants, Children, and Adolescents: Dosage is expressed in units of factor VIII activity (ie, international units) and must be individualized based on formulation, severity of factor VIII deficiency, extent and location of bleed, and clinical situation of patient.

Formula for units required to raise blood level:

Number of Factor VIII Units required = body weight (in kg) x 0.5 units/kg per units/dL x desired 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 80% x 0.5 units/kg per units/dL = 1000 units

Manufacturer's labeling: Advate, Helixate FS, Kogenate FS, Recombinate, Xyntha: Desired factor VIII level, dosing interval, and duration based on hemorrhage type: IV:

Minor hemorrhage (early joint hemorrhage, mild muscle or oral bleed): 10-20 units/kg/dose

Desired factor VIII levels (% or units/dL): 20-40

Frequency of dosing: Every 8-24 hours (Advate: <6 years old) or every 12-24 hours (Advate: ≥6 years old; Helixate FS; Kogentae FS; Xyntha)

Duration of treatment: 1-3 days until bleeding is resolved or healing achieved; mild, superficial, or early hemorrhages may respond to a single dose

Moderate hemorrhage (intramuscular bleed, hematoma, moderate bleeding into oral cavity, definite joint bleed, and known trauma): 15-30 units/kg/dose

Desired factor VIII levels (% or units/dL): 30-60

Frequency of dosing: Every 8-24 hours (Advate: <6 years old) or every 12-24 hours (Advate: ≥6 years old; Helixate FS; Kogenate FS; Xyntha)

Duration of treatment: ≥3 days until bleeding, pain, and disability are resolved or healing is achieved

Severe/life-threatening hemorrhage (GI, intracranial, intra-abdominal, intrathoracic bleeding, retroperitoneal, retropharyngeal, illiopsoas, CNS bleeding or head trauma, fractures):

Helixate FS, Kogenate FS: Initial: 40-50 units/kg; maintenance: 20-25 units/kg/dose

Desired factor VIII levels (% or units/dL): 80-100

Frequency of dosing: Every 8-12 hours

Duration of treatment: Until bleeding is resolved (duration not specified)

Advate, Recombinate, Xyntha: 30-50 units/kg/dose

Desired factor VIII levels (% or units/dL): 60-100

Frequency of dosing: Every 6-12 hours (Advate: <6 years old) or 8-24 hours (Advate: ≥6 years old; Recombinate; Xyntha)

Duration of treatment: Until bleeding is resolved (duration not specified)

Alternative dosing: Note: The following recommendations reflect guideline recommendations for general dosing requirements; may vary from those found within prescribing information or practitioner preference:

IV: Infants, Children, and Adolescents: Desired factor VIII level to maintain and duration based on site of hemorrhage/clinical situation (when no significant resource constraints exist) [WFH guidelines (Srivastava, 2013)]. Note: Factor VIII level may either be expressed as units/dL or as %. Dosing frequency most commonly corresponds to the half-life of factor VIII but should be determined based on an assessment of factor VIII levels before the next dose.

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

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

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

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

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

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

Renal: 50 units/dL for 3-5 days

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

Continuous IV infusion: Infants, Children, and Adolescents: 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; WFH guidelines (Srivastava, 2013)]:

Following initial bolus to achieve the desired factor VIII level: Initial dosing: 2-4 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: IV: Infants, Children, and Adolescents:

Manufacturer's labeling: Desired factor VIII level, dosing interval, and duration based on surgery type:

Minor surgery (including dental extractions):

Advate: 30-50 units/kg as bolus infusion beginning within 1 hour prior to surgery; for dental procedures, adjunctive therapy may be considered

Desired factor VIII levels (% or units/dL): 60-100

Frequency of dosing: Every 12-24 hours as needed to control bleeding

Duration of treatment: Until bleeding is resolved (duration not specified)

Helixate FS, Kogenate FS, Xyntha: 15-30 units/kg/dose; for dental procedures, a single dose plus oral antifibrinolytic therapy within 1 hour may be sufficient

Desired factor VIII levels (% or units/dL): 30-60

Frequency of dosing: Every 12-24 hours

Duration of treatment: 3-4 days or until bleeding is resolved

Recombinate:

Desired factor VIII levels (% or units/dL): 60-80

Frequency of dosing: Single dose plus oral antifibrinolytic therapy within 1 hour is sufficient for most cases

Major surgery (tonsillectomy, hernia repair, intracranial, intra-abdominal or intrahtoracic surgery; joint replacement, trauma):

Advate: 40-60 units/kg/dose

Desired factor VIII levels (% or units/dL): Pre- and postoperative levels: 80-120; verify 100% activity has been achieved prior to surgery

Frequency of dosing: Every 6-24 hours (<6 years old) or every 8-24 hours (≥6 years old) as needed

Duration of treatment: Based on desired level and state of healing

Helixate FS, Kogenate FS: 50 units/kg/dose

Desired factor VIII levels (% or units/dL): Pre- and postoperative levels: 100; verify 100% activity has been achieved prior to surgery

Frequency of dosing: Every 6-12 hours as needed

Duration of treatment: Until healing is complete (~10-14 days)

Recombinate: 40-50 units/kg/dose

Desired factor VIII levels (% or units/dL): Pre- and postoperative: 80-100

Frequency of dosing: Every 8-24 hours

Duration of treatment: Based on state of healing

Xyntha: Children ≥12 years and Adolescents:

Desired factor VIII levels (% or units/dL): 60-100

Frequency of dosing: Every 8-24 hours

Duration of treatment: Until bleeding is resolved and wound healing is achieved

Alternative dosing: Note: The following recommendations reflect guideline recommendations for general dosing requirements; may vary from those found within prescribing information or practitioner preference:

IV: Desired factor VIII level to maintain and duration based on site of hemorrhage/clinical situation (when no significant resource constraints exist) [WFH guidelines (Srivastava, 2013)]. Note: Factor VIII level may either be expressed as units/dL or as %. Dosing frequency most commonly corresponds to the half-life of factor VIII but should be determined based on an assessment of factor VIII levels before the next dose.

Surgery (major):

Preop: 80-100 units/dL

Postop: 60-80 units/dL for 1-3 days; then 40-60 units/dL for 4-6 days; then 30-50 units/dL for 7-14 days

Surgery (minor):

Preop: 50-80 units/dL

Postop: 30-80 units/dL for 1-5 days depending on procedure type

Continuous IV infusion: Infants, Children, and Adolescents: Limited data available: Initial: 25-50 units/kg prior to surgery, followed by continuous infusion at a rate of 3-5 units/kg/hour; regimen based on two studies evaluating use in pediatric surgery patients (age range: 0.9-17 years); rate was adjusted and additional boluses given as needed to maintain desired factor VIII level (Batorova, 2012; Dingli, 2002)

Routine prophylaxis: IV: Infants, Children, and Adolescents:

Manufacturer's labeling:

Advate: 20-40 units/kg/dose every other day (3-4 times weekly). Alternatively, an every-third-day dosing regimen may be used to target factor VIII trough levels of ≥1%

Helixate FS, Kogenate FS: Note: For use in patients with no pre-existing joint damage: 25 units/kg/dose given every other day

Alternative dosing: 15-30 units/kg/dose 3 times weekly (WFH guidelines [Srivastava, 2013] [Utrecht protocol]) or 25-40 units/kg/dose 3 times weekly (WFH guidelines [Srivastava, 2013] [Malmö protocol]) or 25-50 units/kg/dose administered 3 times weekly or every other day (National Hemophilia Foundation, MASAC recommendation, 2007); optimum regimen has yet to be defined.

Dosing: Obesity

Novoeight: There are no specific dosage adjustments provided in the manufacturer's labeling. AUC is higher and clearance lower in adults with BMI ≥30 kg/m²; adjust dose as necessary in these patients.

Reconstitution

If refrigerated, the dried concentrate and diluent should be warmed to room temperature before reconstitution. Gently agitate or rotate vial after adding diluent, do not shake vigorously. Refer to product specific labeling for reconstitution instructions and for detailed information regarding compatibility with administration sets; recommendations vary by product.

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

Administration

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.

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. Refer to protocols for product selection and preparation details.

Dietary Considerations

Some products may contain sodium.

Storage

Prior to reconstitution, store refrigerated at 2°C to 8°C (36°F to 46°F); do not freeze. Do not refrigerate after reconstitution.

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.

Helixate FS, 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.

Drug Interactions

There are no known significant interactions.

Adverse Reactions

Actual frequency may vary by product.

>10%:

Central nervous system: Headache (7% to 24%)

Dermatologic: Pruritus (≤16%), skin rash (≤16%), urticaria (≤16%)

Hematologic & oncologic: Increased factor VIII inhibitors (≤43%)

Local: Catheter infection (18% to 19%)

Neuromuscular & skeletal: Arthralgia (8% to 23%)

Respiratory: Cough (12% to 19%), nasopharyngitis (17%)

Miscellaneous: Fever (≤43%; in patients previously exposed to factor VIII products: <1%)

1% to 10%:

Cardiovascular: Chest discomfort (1%), palpitations (1%), sinus tachycardia (1%)

Central nervous system: Pain (8%), procedural pain (5%), insomnia (3%), chills (≤1%), dizziness (≤1%)

Dermatologic: Allergic dermatitis (1%)

Gastrointestinal: Vomiting (7% to 8%), diarrhea (5% to 8%), abdominal distress (2%), abdominal pain (2%), dyspepsia (2%)

Hematologic & oncologic: Lymphadenopathy (1%)

Hepatic: Increased liver enzymes (in patients previously exposed to factor VIII products: 1%)

Hypersensitivity: Hypersensitivity reaction (2%)

Local: Injection site reaction (1% to 7%)

Neuromuscular & skeletal: Asthenia (6%), back pain (≤3%; more common in children)

Otic: Otic infection (≤5%)

Respiratory: Pharyngolaryngeal pain (9%), upper respiratory tract infection (9%), nasal congestion (8%), rhinorrhea (5%)

Miscellaneous: Limb injury (10%)

<1%, postmarketing, and/or case reports: Anaphylaxis, angioedema, cold extremity, cyanosis, dysgeusia, edema, epistaxis, erythema of skin, facial edema, facial flushing, fatigue, feeling hot, flushing, hematoma, hot flash, hyperhidrosis, hypotension, inflammation at injection site, joint swelling, laryngeal edema, limb pain, loss of consciousness, maculopapular rash, malaise, myalgia, nausea, pain at injection site, pallor, paresthesia, restlessness, tachycardia, tremor, vertigo, xerostomia

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.

Monitoring Parameters

Monitor plasma factor VIII activity (prior to and during IV administration); monitor hemoglobin/hematocrit; monitor for development of factor VIII inhibitors. Monitor heart rate and blood pressure (before and during IV administration); monitor for signs/symptoms of bleeding; hypersensitivity reactions.

Pregnancy

Pregnancy Considerations

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

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience injection site irritation, headache, common cold symptoms, runny nose, loss of strength and energy, cough, stuffy nose, sore throat, back pain, dry mouth, joint swelling, joint pain, or diarrhea. Have patient report immediately to prescriber dizziness, passing out, sensation of cold, shortness of breath, flushing, nausea, vomiting, agitation, fast heartbeat, chills, pale skin, mouth discoloration, chest pain, or burning or numbness feeling (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

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