Antihemophilic Factor (Recombinant [Pegylated])

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous [preservative free]:

Adynovate: ~250 units (1 ea); ~3000 units (1 ea); ~2000 units (1 ea); ~1500 units (1 ea); ~1000 units (1 ea); ~750 units (1 ea); ~500 units (1 ea) [contains polysorbate 80]

Esperoct: antihemophilic factor (recombinant) glycopegylated-exei ~500 units (1 ea); antihemophilic factor (recombinant) glycopegylated-exei ~3000 units (1 ea); antihemophilic factor (recombinant) glycopegylated-exei ~2000 units (1 ea); antihemophilic factor (recombinant) glycopegylated-exei ~1500 units (1 ea); antihemophilic factor (recombinant) glycopegylated-exei ~1000 units (1 ea) [contains polysorbate 80]

Jivi: ~500 units (1 ea); ~1000 units (1 ea); ~2000 units (1 ea); ~3000 units (1 ea) [latex free; contains polysorbate 80]

Pharmacology

Mechanism of Action

Factor VIII replacement, necessary for clot formation and maintenance of hemostasis, 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:

Adynovate: Children <6 years of age: 0.97 ± 0.23 dL/kg; Children 6 to <12 years of age: 1.59 ± 0.34 dL/kg; Children and Adolescents 12 to <18 years of age: 0.56 ± 0.18 dL/kg; Adults ≥18 years of age: 0.43 ± 0.11 dL/kg

Jivi: Children ≥12 years of age, Adolescents, and Adults: 36 ± 6.5 to 44.7 ± 5.4 mL/kg

Time to Peak

Adynovate: Children and Adolescents 12 to <18 years of age: 0.26 ± 0.1 hours; Adults ≥18 years: 0.46 ± 0.29 hours

Half-Life Elimination

Adynovate: Children <6 years of age: 11.8 ± 2.43 hours; Children 6 to <12 years of age: 12.4 ± 1.67 hours; Children and Adolescents 12 to <18 years of age: 13.43 ± 4.05 hours; Adults ≥18 years of age: 14.69 ± 3.79 hours

Jivi: Children ≥12 years of age, Adolescents, and Adults: 17.4 ± 3.8 to 21.4 ± 13.1 hours

Use: Labeled Indications

Hemophilia A:

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

Treatment and control of bleeding episodes: On-demand treatment and control of bleeding episodes in adults and children with hemophilia A.

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

Limitations of use: Not indicated for the treatment of von Willebrand disease. Jivi is not indicated for previously untreated patients.

Contraindications

Hypersensitivity (eg, anaphylactic reaction) to antihemophilic factor (recombinant [pegylated]), antihemophilic factor (recombinant), mouse or hamster protein, or any component of the formulation

Dosage and Administration

Dosing: Adult

Hemophilia A: IV: Dose, dosing frequency, and duration based on location and severity of bleeding, target factor VIII levels, and clinical condition of the patient. 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.

Treatment and control of bleeding episodes:

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%

Table has been converted to the following text.

General Antihemophilic Factor Dosing for On-demand Treatment and Control of Bleeding Episodes:

Minor (eg, early hemarthrosis, mild muscle bleeding, or mild oral bleeding episode):

Adynovate: 20 to 40 units/dL (or % of normal) as the target factor VIII level with a dose of 10 to 20 units/kg/dose every 12 to 24 hours until bleeding is resolved.

Jivi: 20 to 40 units/dL (or % of normal) as the target factor VIII level with a dose of 10 to 20 units/kg/dose every 24 to 48 hours until bleeding is resolved; maximum dose per infusion (according to Jivi manufacturer): ~6,000 units (rounded to vial size).

Moderate (eg, muscle bleeding, moderate bleeding into the oral cavity, definite hemarthroses, and known trauma):

Adynovate: 30 to 60 units/dL (or % of normal) as the target factor VIII level with a dose of 15 to 30 units/kg/dose every 12 to 24 hours until bleeding is resolved.

Jivi: 30 to 60 units/dL (or % of normal) as the target factor VIII level with a dose of 15 to 30 units/kg/dose every 24 to 48 hours until bleeding is resolved; maximum dose per infusion (according to Jivi manufacturer): ~6,000 units (rounded to vial size).

Major (eg, significant gastrointestinal bleeding, intracranial, intra-abdominal or intrathoracic bleeding, central nervous system bleeding, bleeding in the retropharyngeal or retroperitoneal spaces or iliopsoas sheath, fractures, head trauma): Adynovate and Jivi: 60 to 100 units/dL (or % of normal) as the target factor VIII level with a dose of 30 to 50 units/kg/dose every 8 to 24 hours until bleeding is resolved; maximum dose per infusion (according to Jivi manufacturer): ~6,000 units (rounded to vial size).

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.

Perioperative management:

Minor (eg, tooth extraction): Initial:

Adynovate: 30 to 50 units/kg/dose beginning 1 hour before surgery to achieve factor VIII level of 60% to 100% of normal; repeat after 24 hours if necessary until bleeding is resolved.

Jivi: 15 to 30 units/kg/dose to achieve factor VIII level of 30% to 60% of normal pre- and postoperatively; repeat every 24 hours and continue for at least 1 day until healing is achieved. Maximum dose per infusion (according to Jivi manufacturer): ~6,000 units (rounded to vial size).

Major (eg, intracranial, intra-abdominal, or intrathoracic surgery, joint replacement surgery): Initial:

Adynovate: 40 to 60 units/kg/dose beginning 1 hour before surgery to achieve factor VIII level of 80% to 120% of normal pre- and postoperatively. Verify 100% activity has been achieved prior to surgery. Maintenance: 40 to 60 units/kg/dose every 8 to 24 hours until adequate wound healing.

Jivi: 40 to 50 units/kg/dose to achieve factor VIII level of 80% to 100% of normal pre- and postoperatively. Repeat every 12 to 24 hours until adequate wound healing is complete, then continue for at least another 7 days to maintain factor VIII activity of 30% to 60% of normal. Maximum dose per infusion (according to Jivi manufacturer): ~6,000 units (rounded to vial size).

Routine prophylaxis to reduce the frequency of bleeding episodes: Initial:

Adynovate: 40 to 50 units/kg/dose twice weekly; adjust dose based on clinical response.

Jivi: 30 to 40 units/kg/dose twice weekly; adjust dose to 45 to 60 units/kg every 5 days, then may be further adjusted to less or more frequent dosing based on clinical response. Maximum dose per infusion (according to Jivi manufacturer): ~6,000 units (rounded to vial size).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Hemophilia A:

Perioperative management:

Adynovate:

Children 1 to <12 years of age: IV:

Minor (eg, tooth extraction): Refer to adult dosing.

Major (eg, intracranial, intra-abdominal, or intrathoracic surgery, joint replacement surgery): Initial: 40 to 60 units/kg/dose beginning 1 hour before surgery to achieve factor VIII level of 80% to 120% of normal pre- and postoperatively. Verify 100% activity has been achieved prior to surgery. Maintenance: 40 to 60 units/kg/dose every 6 to 24 hours until adequate wound healing.

Children ≥12 years of age and Adolescents: IV: Refer to adult dosing.

Jivi: Children ≥12 years of age and Adolescents: IV: Refer to adult dosing.

Treatment and control of bleeding episodes:

Adynovate: Children ≥1 year of age and Adolescents: IV: Refer to adult dosing.

Jivi: Children ≥12 years of age and Adolescents: IV: Refer to adult dosing.

Routine prophylaxis to reduce the frequency of bleeding episodes:

Adynovate:

Children 1 to <12 years of age: IV: 55 units/kg/dose twice weekly (maximum dose: 70 units/kg/dose); adjust dose based on clinical response.

Children ≥12 years of age and Adolescents: IV: Refer to adult dosing.

Jivi: Children ≥12 years of age and Adolescents: IV: Refer to adult dosing.

Reconstitution

Allow vial and diluent (SWFI) to warm to room temperature before reconstitution. Gently swirl vial in a circular motion after adding diluent until dissolved; do not shake. The solution should be clear and colorless. See product information for additional details.

Administration

IV:

Adynovate: Infuse over ≤5 minutes (maximum infusion rate: 10 mL/minute)

Jivi: Infuse over 1 to 15 minutes (maximum infusion rate: 2.5 mL/minute)

Storage

Adynovate: Store intact vials at 2°C to 8°C (36°F to 46°F) in original package to protect from extreme exposure to light. Do not freeze. May also store up to 30°C (86°F) for ≤3 months. After storage at room temperature, do not return to refrigerator. Following reconstitution, use immediately or may store at room temperature ≤3 hours before administration.

Jivi: Store intact vials at 2°C to 8°C (36°F to 46°F) in original package to protect from extreme exposure to light. Do not freeze. May also store up to 25°C (77°F) for ≤6 months. After storage at room temperature, do not return to refrigerator. Following reconstitution, use immediately or may store at room temperature for ≤3 hours before administration.

Drug Interactions

Pegloticase: May diminish the therapeutic effect of PEGylated Drug Products. Monitor therapy

Pegvaliase: PEGylated Drug Products may enhance the adverse/toxic effect of Pegvaliase. Specifically, the risk of anaphylaxis or hypersensitivity reactions may be increased. Monitor therapy

Adverse Reactions

>10%: Nervous system: Headache (2% to 14%)

1% to 10%:

Cardiovascular: Flushing (≤1%)

Dermatologic: Skin rash (≤5%), erythema of skin (2%), pruritus (2%)

Gastrointestinal: Vomiting (3% to 5%), nausea (≤5%), abdominal pain (3% to 4%), dysgeusia (1%)

Hypersensitivity: Hypersensitivity reaction (≤4%)

Local: Injection site reaction (1% to 3%)

Nervous system: Insomnia (2% to 3%), dizziness (1% to 2%)

Respiratory: Cough (7% to 8%)

Miscellaneous: Fever (5% to 9%)

<1%: Acute pancreatitis, antibody development, diarrhea

Frequency not defined: Hypersensitivity: Anaphylaxis, severe hypersensitivity reaction

Warnings/Precautions

Concerns related to adverse effects:

• Antibody formation: Formation of antibodies (inhibitors) to factor VIII antibodies may occur; monitor patients for the development of antibodies by clinical observation and laboratory tests. 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: May occur, including severe reactions. Monitor patients for hypersensitivity reactions; discontinue immediately if allergic or anaphylactic-type reactions occur.

Dosage form specific issues:

• Mouse/hamster protein: Products may contain trace amounts of mouse or hamster protein.
• Polyethylene glycol: Products contain polyethylene glycol (PEG). 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 <6 years of age) with Jivi. In case of clinical suspicion of loss of drug effect, test for factor VIII inhibitors and factor VIII recovery. A low postinfusion factor VIII level in the absence of detectable factor VIII inhibitors likely indicates anti-PEG antibodies; discontinue Jivi and switch patients to a previously effective factor VIII product. A similar clinical immune response has not been observed with Adynovate.
• Polysorbate 80: 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.

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

Hypersensitivity reactions, heart rate and blood pressure (before and during IV administration); plasma factor VIII activity prior to and during treatment (to confirm adequate factor VIII levels have been achieved and maintained); development of factor VIII inhibitors using the Bethesda inhibitor assay; signs of bleeding; hemoglobin, hematocrit.

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]). Initial reports using the recombinant pegylated product have been limited to use in males (Brand 2016; Dunn 2018; Konkle 2015).

Patient Education

What is this drug used for?

• It is used to treat hemophilia.
• It is used to treat or prevent bleeding.

Frequently reported side effects of this drug

• Headache
• Mild fever
• Cough

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Shortness of breath
• Wheezing
• Chest pain
• Dizziness
• Passing out
• Severe nausea
• Severe vomiting
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.