ANTIHEMOPHILIC FACTOR (HUMAN
■ RECOMBINANT
■ RECOMBINANT [Fc FUSION PROTEIN]
■ RECOMBINANT [PEGYLATED]
■ RECOMBINANT [PEGYLATED-aucl]
■ RECOMBINANT [SINGLE CHAIN]
■ RECOMBINANT [PORCINE SEQUENCE]a)
Pronounciation
Trade Name(s)
a Recombinant (Porcine Sequence [Obizur]) is indicated for use only in acquired hemophilia. Not indicated for use in congenital hemophilia A.
USUAL DOSE (International units [IU])
Pretesting and baseline studies required; see Monitor.
Adults and pediatric patients:
Dosing is completely individualized. Dose, frequency, and duration of treatment are based on severity of the factor VIII deficiency, location and extent of bleeding, clinical condition of the patient, desired antihemophilic factor level, body weight, and presence of factor VIII inhibitors. Measure factor VIII level before administration; see Monitor. In general, a dose of 1 IU/kg will raise the plasma factor VIII activity by 2 IU/dL. On average, a plasma antihemophilic factor level of 20% to 40% of normal is required to control minor hemorrhage. A level of 30% to 60% of normal may be required to control moderate bleeding; greater percentages are required for major bleeding or surgical procedures.
All products except Obizur use a variation of the following formula.
To calculate the dose needed based on a desired factor VIII increase (%):
Dose (IU) = Body weight (kg) × Desired factor VIII increase (IU/dL or % of normal) × 0.5
To calculate the expected % factor VIII increase for a given dose:
Expected % factor VIII increase = (# Units administered × 2) ÷ Body weight (kg)
The following charts outline AHF dosing recommendations for the various AHF products. Consult individual product labeling for more detailed information.
aJivi: Total recommended maximum dose per infusion is approximately 6,000 IU (rounded to vial size). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
aJivi: Total recommended maximum dose per infusion is approximately 6,000 IU (rounded to vial size). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Obizur does not use a formula. Indicated for use only in acquired hemophilia. Not indicated for use in congenital hemophilia A. The recommended dose of Obizur for minor, moderate, and/or major bleeding is 200 IU/kg as an initial dose. Subsequent doses may be given every 4 to 12 hours and should be titrated to individual clinical response and to maintain recommended factor VIII trough levels (50% to 100% of normal for minor or moderate bleeding and 100% to 200% of normal for an acute bleed, decreasing to 50% to 100% of normal after acute bleed is controlled, if required). Maintain the factor VIII activity within the target range. Plasma levels of factor VIII should not exceed 200% of normal or 200 IU/dL.
Routine prophylaxis to prevent or reduce the frequency of bleeding
(e.g., severe factor VIII deficiency with frequent hemorrhages):
20 to 40 IU/kg every other day (3 to 4 times per week). Alternately, an every-third-day dosing regimen targeted to maintain factor VIII trough levels greater than or equal to 1% may be used. Adjust dose based on patient response.
Adults and adolescents (12 years of age or older):
Administer 40 to 50 IU/kg 2 times per week. Pediatric patients (under 12 years of age): 55 IU/kg 2 times per week with a maximum of 70 IU/kg/dose. Adjust dose based on patient’s clinical response.
Adults and adolescents (12 years of age or older):
Recommended starting regimen is 20 to 50 IU/kg administered 2 to 3 times weekly. Pediatric patients (under 12 years of age): Recommended starting regimen is 30 to 50 IU/kg administered 2 to 3 times weekly. More frequent or higher doses may be required in pediatric patients under 12 years of age to account for the higher clearance in this age-group. Adjust dose based on patient’s response.
Initiate therapy with a dose of 50 IU/kg every 4 days. Adjust dose based on patient response (range 25 to 65 IU/kg at 3- to 5-day intervals). More frequent or higher doses up to 80 IU/kg may be required in pediatric patients under 6 years of age.
Initiate therapy at 30 to 40 IU/kg twice weekly. Based on bleeding episodes, the regimen may be adjusted to 45 to 60 IU/kg every 5 days. Regimen may be further individually adjusted to less or more frequent dosing. Total recommended maximum dose per infusion is approximately 6,000 IU (rounded to vial size).
25 IU/kg 3 times a week. Pediatric patients: 25 IU/kg every other day.
20 to 40 IU/kg 2 or 3 times a week. Pediatric patients 12 years of age or younger: 25 to 50 IU/kg twice weekly, 3 times weekly, or every other day according to individual requirements.
Adults and adolescents (12 years of age or older):
20 to 50 IU/kg 3 times a week or 20 to 40 IU/kg every other day. Pediatric patients (under 12 years of age): 25 to 60 IU/kg 3 times a week or 25 to 50 IU/kg every other day.
Adults and adolescents (12 to 17 years of age):
30 to 40 IU/kg every other day. Pediatric patients (2 to 11 years of age): 30 to 50 IU/kg every other day or 3 times per week.
Titrate the dose and frequency to the patient’s clinical response.
■ If factor VIII level fails to increase as expected or if bleeding is not controlled after administration of the calculated dose, factor VIII antibodies (inhibitors) are probable; may respond to an increased dose, especially if titer is less than 10 Bethesda units/mL. Frequent determinations of circulating AHF levels indicated.
■ Higher or more frequent dosing may be required in pediatric patients.
Products are available in multiple strengths. Actual number of AHF units is shown on each vial. Consult package insert of product to obtain product-specific information on dilution. All preparations provide diluent, and most provide administration equipment that may include transfer devices, needles (single- or double-ended), filters or filter needles, syringes, vial adapters, and/or administration sets for each vial. Use only the diluent provided, and maintain strict aseptic technique. Warm to room temperature (25° C [77° F]) before dilution and maintain throughout administration to avoid precipitation of active ingredients. If more than one vial is required to achieve the desired dose, multiple vials may be drawn into the same container (e.g., syringe). Follow manufacturer’s instructions. Products do not contain a preservative, and all products must be used within 3 hours of reconstitution (4 hours for Afstyla and Novoeight).
Supplied by manufacturer if required.
Consult package insert of product to obtain product-specific information on storage requirements after reconstitution. Before reconstitution, store all formulations in original packages to protect from light at 2° to 8° C (35° to 46° F). (Recombinate may be stored at RT or under refrigeration.) Do not freeze. All formulations except Adynovate and Obizur can be stored at RT for 2 months or longer before reconstitution. Adynovate can be stored at RT for up to 1 month. Do not return to the refrigerator after storage at RT. Afstyla can be stored at RT, not to exceed 25° C (77° F), for a single period of up to 3 months (within the expiration date on carton and vial labels). Do not return product to the refrigerator. Jivi can be stored at RT for up to 6 months. Do not return to the refrigerator after storage at RT. Obizur should be refrigerated until use. Do not use beyond expiration dates on vials (or revised expiration date if stored at RT, whichever is earlier).
Administration through a separate line without mixing with other IV fluids or medications is recommended.
Use administration set supplied by manufacturer, if provided. Rate of administration is based on patient comfort. Reduce rate of infusion or temporarily discontinue if there is a significant increase in heart rate or if S/S of hypersensitivity occur.
A single dose over 5 minutes or less. Do not exceed a rate of 10 mL/min.
A single dose administered at a rate not to exceed 10 mL/min.
A single dose administered over 1 to 15 minutes. Maximum infusion rate is 2.5 mL/min.
Helixate FS, Kogenate FS, Kogenate FS Bio-Set, Kovaltry, Kovaltry Bio-Set:
A single dose over 1 to 15 minutes is usually well tolerated.
A single dose over 5 to 10 minutes.
A single dose over 2 to 5 minutes.
A single dose at a maximum rate of 4 mL/min.
A single dose at a rate of 1 to 2 mL/min.
Recombinate (reconstituted with 5 mL of SWFI):
Do not exceed a rate of 5 mL/min.
Recombinate (reconstituted with 10 mL SWFI):
Do not exceed a rate of 10 mL/min.
A single dose over several minutes, based on patient comfort.
AHF is one of nine major factors in the blood that must act in sequence to produce coagulation, or clotting. It is the specific clotting factor deficient in patients with hemophilia A (classic hemophilia). Administration of AHF can temporarily correct the coagulation defect in these patients. One international unit (IU) of AHF is approximately equal to the level of factor VIII activity in 1 mL of fresh pooled human plasma. Adynovate and Jivi exhibit an extended terminal half-life through pegylation, which reduces binding to the physiologic factor VIII clearance receptor (LRP1). Afstyla is expressed as a single-chain factor VIII molecule with covalent linkage between heavy and light chains, keeping the molecule in the single-chain form and resulting in increased stability and increased von Willebrand factor (vWF) affinity. vWF stabilizes factor VIII and protects it from degradation.
Recombinant porcine sequence AHF (Obizur):
Patients with acquired hemophilia have normal factor VIII genes but develop autoantibodies against their own factor VIII (i.e., inhibitors). These autoantibodies neutralize circulating human factor VIII and create a functional deficiency of factor VIII. Obizur temporarily replaces the inhibited endogenous factor VIII that is needed for effective hemostasis in patients with acquired hemophilia A.
On-demand treatment and control of bleeding episodes in adults and pediatric patients with hemophilia A (congenital factor VIII deficiency) (all products except Jivi and Obizur).
■ Perioperative management (surgical prophylaxis) in adults and pediatric patients with hemophilia A (all products except Jivi and Obizur).
■ Routine prophylaxis to prevent or reduce the frequency of bleeding in adults and pediatric patients with hemophilia A (Advate, Adynovate, Afstyla, Eloctate, Helixate FS, Kogenate FS, Kovaltry, Kovaltry Bio-Set, Novoeight, Nuwiq).
■ Routine prophylaxis to prevent bleeding episodes and risk of joint damage in pediatric patients without pre-existing joint damage (Helixate FS, Kogenate FS).
■ On-demand treatment and control of bleeding episodes, perioperative management of bleeding, and routine prophylaxis to reduce the frequency of bleeding episodes in adolescent and adult patients (12 years and older) with hemophilia A (Jivi).
■ Treatment of bleeding episodes in adults with acquired hemophilia A (Obizur).
Not indicated for treatment of von Willebrand disease.
Jivi is not indicated for use in pediatric patients under 12 years of age due to greater risk for hypersensitivity reactions.
■ Jivi is not indicated for use in previously untreated patients.
Safety and efficacy of Obizur have not been established in patients with a baseline anti-porcine factor VIII inhibitor titer of greater than 20 Bethesda units.
■ Obizur is not indicated for treatment of congenital hemophilia A.
Hypersensitivity to the specific product or to any component of a product (e.g., mouse, hamster, or bovine protein [monoclonal antibody–derived factor VIII, porcine sequence]; various stabilizers; polysorbate 80; polyethylene glycol [PEG]).
Should be administered under the direction of a physician specialist.
■ Hypersensitivity reactions (including anaphylaxis) are possible.
■ Formation of neutralizing antibodies (inhibitors) to factor VIII can occur; see Monitor.
■ In patients receiving Jivi, a clinical immune response associated with IgM anti-PEG antibodies (manifested as symptoms of acute hypersensitivity and/or loss of drug effect) has been observed, primarily in patients under 6 years of age. Symptoms of the clinical immune response were transient, and anti-PEG IgM titers decreased over time to undetectable levels. In cases of clinical suspicion of loss of drug effect, conduct testing for Factor VIII inhibitors. A low post-infusion Factor VIII level in the absence of detectable Factor VIII inhibitors indicates that loss of drug effect is likely due to anti-PEG antibodies. Discontinue Jivi and switch patient to a previously effective Factor VIII product.
■ Plasma-derived products may contain infectious agents that can cause disease (e.g., viruses and, theoretically, the Creutzfeldt-Jakob disease agent). The risk that these products will transmit an infectious agent has been reduced by screening plasma donors, testing for the presence of viruses, and inactivating and/or removing certain viruses during manufacturing. Hepatitis A and parvovirus 19 have been reported infrequently with plasma-based products, usually in immunocompromised patients or pregnant females.
■ Intravascular hemolysis can occur when large volumes of plasma-derived products are given to individuals with blood groups A, B, or AB. Monitor for progressive anemia.
■ Components of some products may contain latex; use caution to avoid a hypersensitivity reaction.
■ Hemophilic patients with cardiovascular risk factors or diseases may be at the same risk as nonhemophilic patients for developing cardiovascular events when clotting has been normalized by treatment with factor VIII.
■ Treatment of choice when volume or RBC replacement is not needed; avoids hypervolemia and hyperproteinemia.
■ Not useful to treat other coagulation factor deficiencies.
■ Catheter-related infections may occur if antihemophilic factor is administered via central venous access devices (CVADs). These infections have not been associated with the actual AHF product.
■ Desmopressin may be the preferred treatment for mild to moderate hemophilia A (AHF levels that are at least 5%).
Identification of factor VIII deficiency with determination of circulating AHF levels should be obtained before administration. Monitor plasma factor VIII activity by the one-stage clotting assay (except Afstyla and Jivi [see below]) to confirm that adequate factor VIII levels have been achieved and maintained. Adjust dose as indicated.
■ Monitor heart rate and blood pressure before and during treatment.
■ Monitor for the development of factor VIII inhibitors. Should be suspected if factor VIII plasma levels are not obtained or if bleeding is not controlled with an appropriate dose. The Bethesda inhibitor assay determines if factor VIII inhibitors are present. Bethesda Units (BU) are used to report inhibitor levels.
■ Monitor patients with a known or suspected inhibitor to factor VIII more frequently.
■ Monitor for S/S of a hypersensitivity reaction (e.g., anaphylaxis, angioedema, chest or throat tightness, dizziness, dyspnea, face swelling, fever, flushing, hypotension, laryngeal edema, nausea, paresthesia, pruritus, rash, tachycardia, urticaria, vomiting, wheezing).
■ Monitor for signs of bleeding.
■ Monitor hemoglobin and hematocrit.
■ Monitor patients with CVADs for S/S of infection.
■ See Precautions.
Monitoring of plasma factor VIII levels by a chromogenic assay is preferred over the one-stage clotting assay routinely used in U.S. clinical laboratories (most accurately reflects the clinical hemostatic potential of Afstyla). The one-stage clotting assay result underestimates the factor VIII activity level compared with the chromogenic assay result by approximately one-half. If the one-stage clotting assay is used, multiply the result by a conversion factor of 2 to determine the patient’s factor VIII activity level.
Monitor the Factor VIII activity of Jivi in plasma using either a validated chromogenic substrate assay or a validated one-stage clotting assay. Validation required to prevent underestimation or overestimation of Factor VIII activity; see manufacturer’s prescribing information.
Monitor factor VIII activity 30 minutes and 3 hours after initial dose and 30 minutes after subsequent doses. Use of the Nijmegen-Bethesda inhibitor assay is recommended.
Read manufacturer-supplied patient product information.
■ Instruction for self-administration and proper storage and preparation may be appropriate.
■ Discontinue antihemophilic factor and immediately report S/S of a hypersensitivity reaction (e.g., hives, hypotension, itching, rash, tightness of the chest, wheezing).
■ Review prescription and nonprescription medications with a healthcare provider.
■ Contact provider for lack of clinical response. May indicate development of inhibitors.
■ Consult with healthcare provider before travel. Bring an adequate supply of AHF based on current treatment regimen.
Report S/S of hepatitis A (e.g., persistent poor appetite and tiredness, fever, dark urine, yellowing of the skin, nausea, vomiting, and abdominal pain).
■ Report S/S of parvovirus B19 (e.g., chills, drowsiness, fever, and runny nose followed 2 weeks later by a rash and joint pain).
Use during pregnancy only if clearly needed.
■ Use caution during breast-feeding.
■ Advate, Afstyla, Helixate FS, Kogenate FS, Kovaltry, Kovaltry Bio-Set, and Recombinate have been used in pediatric patients of all ages, including infants. Other formulations are indicated for use in pediatric patients but did not include newborns in clinical trials.
■ All products: Clearance (based on kg body weight) is higher in the pediatric population. Half-life is shorter; see Dose Adjustments.
■ Jivi: Safety and effectiveness in pediatric patients under 12 years of age has not been established. Jivi is not indicated in this age-group. Adverse reactions due to immune response to PEG, including hypersensitivity reactions and/or loss of drug effect, have been observed; see Precautions.
■ Obizur: Safety and efficacy for use in pediatric patients not established.
Numbers in clinical studies insufficient to determine whether the elderly respond differently from younger subjects.
May respond to reduced rate of administration. Serious adverse reactions include hypersensitivity reactions and factor VIII inhibitors.
Abdominal pain, blurred vision, bradycardia, chills, clouding or loss of consciousness, diarrhea, dizziness, dysgeusia, factor VIII inhibition, fever, flushing, headache, hemolytic anemia, hyperfibrinogenemia, hypersensitivity reactions (anaphylaxis, backache, chills, erythema, fever, hives, hypotension, nausea, pruritus, rash, tightness of chest, urticaria, wheezing), lethargy, paresthesias, somnolence, stinging at infusion site, tachycardia, tingling, or vomiting may occur.
The most commonly reported side effects included arthralgia, back pain, central venous access device–associated infections, chills, cough, dizziness, dry mouth, epistaxis, fever, flushing, headache, increased hepatic enzymes, infusion site reactions (e.g., inflammation, pain), inhibitor formation in previously untreated or minimally treated patients, limb injury, malaise, nasopharyngitis, nausea, nonneutralizing anti–factor VIII antibody formation, paresthesia, skin-associated hypersensitivity reactions (e.g., erythema, pruritus, rash, urticaria), and generalized hypersensitivity reactions, including anaphylaxis.
In clinical trials, development of inhibitors to porcine factor VIII occurred in more than 5% of patients.
Anti-PEG antibodies.
Most side effects usually subside spontaneously in 15 to 20 minutes and are generally related to the rate of infusion. Keep the physician informed. Slow or discontinue infusion temporarily if heart rate increases or beginning S/S of a hypersensitivity reaction occur. Discontinue immediately and treat hypersensitivity reactions (antihistamines, epinephrine, corticosteroids). Premedication with antihistamines (e.g., diphenhydramine) may be considered for patients with previous hypersensitivity reactions. Resuscitate as necessary.