(an tee hee moe FIL ik FAK tor ree KOM be nant)
Hemophilia A:
Control and prevention of bleeding episodes: For the prevention and control of bleeding episodes in adults and children with hemophilia A.
Perioperative management: For surgical prophylaxis in adults and children with hemophilia A.
Routine prophylaxis to prevent or reduce the frequency of bleeding: For 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): For 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.
Hypersensitivity (eg, anaphylaxis) to antihemophilic factor, mouse or hamster protein (Advate, Afstyla, Helixate FS, Kogenate FS, Kovaltry, Novoeight, Recombinate, Xyntha), bovine protein (Recombinate only), or any component of the formulation.
Hemophilia A: IV: Individualize dosage based on coagulation studies performed prior to treatment and at regular intervals during treatment. In general, administration of factor VIII 1 unit/kg will increase circulating factor VIII levels by ~2 units/dL.
Control and prevention of bleeding episodes or perioperative management:
Manufacturer 's labeling: Refer to manufacturer 's labeling for specific recommendations; varies by product.
Alternate recommendations (WFH [Srivastava 2013]):
Dosage based on desired factor VIII increase (%):
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
Dosage based on expected factor VIII increase (%):
It is also possible to calculate the expected % factor VIII increase:
[# units administered x 2 (%/units/kg)] divided by body weight (kg) = expected % factor VIII increase
For example:
[1,400 units x 2] divided by 70 kg = 40%
World Federation of Hemophilia (WFH) treatment recommendations when no significant resource constraint exists (WFH [Srivastava 2013]):
2013 World Federation of Hemophilia Treatment Recommendations (When No Significant Resource Constraint Exists)Site of Hemorrhage/Clinical Situation
Desired Factor VIII Level to Maintain
Duration
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 to 60 units/dL
1 to 2 days, may be longer if response is inadequate
Superficial muscle/no neurovascular compromise
40 to 60 units/dL
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 units/dL
Initial: 1 to 2 days
Maintenance: 30 to 60 units/dL
Maintenance: 3 to 5 days, sometimes longer as secondary prophylaxis during physiotherapy
CNS/Head
Initial: 80 to 100 units/dL
Initial: 1 to 7 days
Maintenance: 50 units/dL
Maintenance: 8 to 21 days
Throat and neck
Initial: 80 to 100 units/dL
Initial: 1 to 7 days
Maintenance: 50 units/dL
Maintenance: 8 to 14 days
Gastrointestinal
Initial: 80 to 100 units/dL
Initial: 7 to 14 days
Maintenance: 50 units/dL
Maintenance: 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
Postop: 60 to 80 units/dL
Postop: 1 to 3 days
Postop: 40 to 60 units/dL
Postop: 4 to 6 days
Postop: 30 to 50 units/dL
Postop: 7 to 14 days
Surgery (minor)
Preop: 50 to 80 units/dL
Postop: 30 to 80 units/dL
Postop: 1 to 5 days depending on procedure type
World Federation of Hemophilia (WFH) treatment recommendations when no significant resource constraint exists (Srivastava 2013):
Desired Factor VIII Level to Maintain and Duration Based on Site of Hemorrhage/Clinical Situation:
Joint: 40 to 60 units/dL for 1 to 2 days, may be longer if response is inadequate
Superficial muscle (no neurovascular compromise): 40 to 60 units/dL 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 units/dL for 1 to 2 days; Maintenance: 30 to 60 units/dL for 3 to 5 days, sometimes longer as secondary prophylaxis during physiotherapy
CNS/head: Initial: 80 to 100 units/dL for 1 to 7 days; Maintenance: 50 units/dL for 8 to 21 days
Throat and neck: Initial: 80 to 100 units/dL for 1 to 7 days; Maintenance: 50 units/dL for 8 to 14 days
Gastrointestinal: Initial: 80 to 100 units/dL for 7 to 14 days; Maintenance: 50 units/dL (duration not specified)
Renal: 50 units/dL for 3 to 5 days
Deep laceration: 50 units/dL for 5 to 7 days
Surgery (major): Preop: 80 to 100 units/dL; Postop: 60 to 80 units/dL for 1 to 3 days; then 40 to 60 units/dL for 4 to 6 days; then 30 to 50 units/dL for 7 to 14 days
Surgery (minor): Preop: 50 to 80 units/dL; Postop: 30 to 80 units/dL for 1 to 5 days depending on procedure type
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.
Continuous infusion (for patients who require prolonged periods of treatment [eg, intracranial hemorrhage or surgery] to avoid peaks and troughs associated with intermittent infusions) (Batorova 2002; Batorova 2012; Poon 2012; Rickard 1995; WFH [Srivastava 2013]): Following initial bolus to achieve the desired factor VIII level, initiate 2 to 4 units/kg/hour; adjust dose based on frequent factor 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) 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)
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
Xyntha (Canadian labeling; not in US labeling): Treatment experienced patients: 25 to 35 units/kg 3 times weekly
Refer to adult dosing.
Hemophilia A: Children and Adolescents: IV: Individualize dosage based on coagulation studies performed prior to treatment and at regular intervals during treatment. In general, administration of factor VIII 1 unit/kg will increase circulating factor VIII levels by ~2 units/dL. Children <6 years may require higher doses and/or more frequent administration.
Control and prevention of bleeding episodes or perioperative management: Refer to adult dosing.
Routine prophylaxis to prevent bleeding episodes: Note: Maintain factor VIII trough levels between 1% and 5% as clinically indicated (Collins 2011; Rossbach 2010).
Advate: Refer to adult dosing.
Afstyla:
Children <12 years: 30 to 50 units/kg 2 to 3 times weekly
Children ≥12 years and Adolescents: Refer to adult dosing.
Kovaltry:
Children ≤12 years: 25 to 50 units/kg twice weekly, 3 times weekly, or every other day according to individual requirements.
Children >12 years and Adolescents: Refer to adult dosing.
Novoeight:
Children <12 years: 25 to 60 units per kg 3 times weekly or 25 to 50 units/kg every other day
Children ≥12 years and Adolescents: Refer to adult dosing.
Nuwiq:
Children 2 to 11 years: 30 to 50 units/kg every other day or 3 times weekly
Children ≥12 years and Adolescents: Refer to adult dosing.
Xyntha (Canadian labeling; not in US labeling): Adolescents (treatment experienced): Refer to adult dosing.
Routine prophylaxis to prevent bleeding episodes and joint damage (in patients without preexisting joint damage):
Helixate FS, Kogenate FS: Children ≤12 years and Adolescents: 25 units/kg every other day.
There are no dosage adjustments provided in the manufacturer 's labeling.
There are no dosage adjustments provided in the manufacturer 's labeling.
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).
IV: Use administration sets/tubing provided by manufacturer (if provided). 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 reconstituted with 5 mL of SWFI: Infuse up to a maximum rate of 5 mL/minute
Recombinate reconstituted with 10 mL of SWFI: Infuse up to a maximum rate of 10 mL/minute
Xyntha, Xyntha Solufuse: Infuse over several minutes. Do not admix or administer in same tubing as other medications.
According to the World Federation of Hemophilia (WFH), infuse by slow IV injection at a rate not to exceed 3 mL/minute (adults) or 100 units/minute (young children); may also administer as a continuous infusion in select patients (WFH [Srivastava 2013]). When administering as a continuous infusion, may use a portable mini-pump or syringe pump (Batorova 2012).
Some products may contain sodium.
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: May also be stored at room temperature (not to exceed 30 ‚ °C [86 ‚ °F]) up to 12 months; do not return to refrigerator; after 12 months at room temperature, use immediately or discard. Store in original package to protect from light. Use within 4 hours of reconstitution.
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.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Kit, Intravenous:
Kogenate FS: 250 units, 500 units, 1000 units [contains mouse (murine) and/or hamster protein]
Kit, Intravenous [preservative free]:
Afstyla: 250 units, 500 units, 1000 units, 2000 units, 3000 units [contains polysorbate 80]
Helixate FS: 250 units, 500 units, 1000 units, 2000 units, 3000 units [contains polysorbate 80]
Kogenate FS: 2000 units, 3000 units [contains mouse (murine) and/or hamster protein]
Kogenate FS Bio-Set: 250 units, 500 units, 1000 units, 2000 units, 3000 units [contains mouse (murine) and/or hamster protein]
Nuwiq: 250 units, 500 units, 1000 units, 2000 units
Xyntha: 250 units, 500 units, 1000 units, 2000 units [albumin free; contains mouse (murine) and/or hamster protein, polysorbate 80]
Xyntha Solofuse: 250 units, 500 units, 1000 units, 2000 units, 3000 units [albumin free; contains mouse (murine) and/or hamster protein, 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 mouse (murine) and/or hamster protein, 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]
Eloctate: 250 units (1 ea); 500 units (1 ea); 750 units (1 ea); 1000 units (1 ea); 1500 units (1 ea); 2000 units (1 ea); 3000 units (1 ea)
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 mouse (murine) and/or hamster protein, polysorbate 80]
Nuwiq: 250 units (1 ea); 500 units (1 ea); 1000 units (1 ea); 2000 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]
There are no known significant interactions.
Heart rate and blood pressure (before and during IV administration); plasma factor VIII activity prior to and during treatment; development of factor VIII inhibitors; signs of bleeding; hemoglobin, hematocrit; hypersensitivity reactions
When administering as a continuous infusion, monitor frequently for pump failure (WFH [Srivastava 2013]).
Actual frequency may vary by product.
>10%:
Central nervous system: Headache (7% to 26%)
Dermatologic: Pruritus ( ≤16%), skin rash ( ≤16%), urticaria ( ≤16%)
Gastrointestinal: Nausea (6% to 13%), vomiting (7% to 12%)
Hematologic & oncologic: Increased factor VIII inhibitors ( ≤20%)
Local: Catheter infection (18% to 19%)
Neuromuscular & skeletal: Arthralgia (8% to 25%)
Respiratory: Cough (11% 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: 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 (3% to 7%)
Neuromuscular & skeletal: Weakness (5% to 7%), 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% (Limited to important or life-threatening): Anorexia, catheter complication (venous catheter access), cold extremities, cyanosis, epistaxis, facial flushing, feeling hot, hematoma, hypotension, limb pain, loss of consciousness, maculopapular rash, malaise, myalgia, paresthesia, tachycardia, tremor, vasodilatation
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. 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.
C
Animal reproduction studies have not been conducted. Factor VIII concentrations may increase in pregnant women with coagulation disorders. Pregnant women should have clotting factors monitored, particularly at 28 and 34 weeks gestation and prior to invasive procedures. Prophylaxis may be needed if concentrations are <50 units/mL at term and treatment should continue for 3 to 5 days postpartum depending on route of delivery. Because parvovirus infection may cause hydrops fetalis or fetal death, a recombinant product is preferred if prophylaxis or treatment is needed. The neonate may also be at an increased risk of bleeding following delivery and should be tested for the coagulation disorder (Kadir 2009; Lee 2006).
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.
Vss: ~0.4 to 0.85 dL/kg
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 hours
Xyntha, Xyntha Solofuse: Children and Adolescents: 6.9 to 8.3 hours; Adults: 11 to 17 hours
- 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 headache, loss of strength and energy, cough, rhinitis, pharyngitis, injection site pain, back pain, dry mouth, muscle pain, joint pain, or diarrhea. Have patient report immediately to prescriber dizziness, passing out, sensation of cold, shortness of breath, dysphagia, flushing, nausea, vomiting, agitation, tachycardia, chills, pale skin, mouth discoloration, angina, wheezing, 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.