Factor VIII, recombinant human pegylated: Pediatric drug information

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

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)

Brand Names: US

Adynovate;
Esperoct;
Jivi

Brand Names: Canada

Adynovate;
Esperoct;
Jivi

Therapeutic Category

Antihemophilic Agent

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. Patients with inhibitory antibodies to factor VIII may require higher doses, more frequent administration, and/or selection of alternative therapy.

General dosing for control and prevention 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. Product selection is age dependent.

Children and Adolescents (Adynovate, Esperoct) or Children ≥12 years and Adolescents (Jivi): 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; (WFH [Srivastava 2020]).
^b Depending on procedure; the number of doses would depend on the half-life of the clotting factor concentrate (CFC) 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.
^eSometimes 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 − patient's 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

Note: Factor VIII level units are units/dL.

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 [Pegylated]) 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.
Adynovate	Every 12 to 24 hours	Every 12 to 24 hours	Every 8 to 24 hours	Single dose typically adequate; re-dose at 24 hours if needed	Every 8 to 24 hours; patients <12 years may require more frequent dosing every 6 to 24 hours
Esperoct	Single dose typically adequate	An additional dose may be administered after 24 hours	Every 24 hours	Every 24 hours if needed	Every 24 hours; after the first week extend to every 48 hours until wound healing has occurred
Jivi	Every 24 to 48 hours	Every 24 to 48 hours	Every 8 to 24 hours	Every 24 hours	Every 12 to 24 hours

Routine prophylaxis to reduce the frequency of bleeding episodes: Note: Maintain trough factor VIII levels >3% to 5% or higher as clinically indicated based on level of activity, lifestyle, and pharmacokinetics. Dose escalation should be considered for patients adherent to prescribed prophylaxis but still experiencing breakthrough bleeding events (Ref).

Product-specific dosing:

Adynovate:

Children <12 years: IV: 55 units/kg/dose twice weekly; adjust dose and dosing interval based on clinical response; maximum dose: 70 units/kg/dose.

Children ≥12 years and Adolescents: IV: 40 to 50 units/kg/dose twice weekly; adjust dose based on clinical response.

Esperoct:

Children <12 years: IV: 65 units/kg/dose twice weekly; adjust dose and dosing interval based on clinical response.

Children ≥12 years and Adolescents: IV: 50 units/kg/dose every 4 days; adjust dose and dosing interval based on clinical response.

Jivi: Children ≥12 years and Adolescents: IV: 30 to 40 units/kg/dose twice weekly; based on bleeding episodes, the dose may be adjusted to 45 to 60 units/kg/dose every 5 days, then may be further adjusted to less or more frequent dosing based on clinical response.

Dosing: Kidney Impairment: Pediatric

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

Dosing: Hepatic Impairment: Pediatric

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

Dosing: Adult

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

Hemophilia A, without inhibitors

Hemophilia A, without inhibitors:

Treatment and control of bleeding episodes or perioperative management:

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

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 [Pegylated]) Administration Frequency According to Clinical Scenario**
Product	Bleeding event			Surgery
Product	Minor severity	Moderate severity	Major severity	Minor bleeding risk	Major bleeding risk
Adynovate	Every 12 to 24 hours	Every 12 to 24 hours	Every 8 to 24 hours	Single dose typically adequate; re-dose at 24 hours if needed	Every 8 to 24 hours
Esperoct	Single dose typically adequate	Every 24 hours	Every 24 hours	Every 24 hours	Every 24 hours
Jivi	Every 24 to 48 hours	Every 24 to 48 hours	Every 8 to 24 hours	Every 24 hours	Every 12 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) × (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 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).

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

Esperoct: IV: 50 units/kg/dose every 4 days; adjust dose based on clinical response.

Jivi: IV: 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: Kidney Impairment: Adult

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

Dosing: Hepatic 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.

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

1% to 10%:

Cardiovascular: Flushing (≤1%)

Dermatologic: Erythema of skin (2%), pruritus (2%), skin rash (≤5%), urticaria (2%)

Gastrointestinal: Abdominal pain (3% to 4%), diarrhea (7%), dysgeusia (1%), nausea (≤5%), vomiting (3% to 5%)

Hypersensitivity: Hypersensitivity reaction (≤4%, including severe hypersensitivity reaction)

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

Nervous system: Dizziness (1% to 2%), insomnia (2% to 3%)

Respiratory: Cough (7% to 8%)

Miscellaneous: Fever (5% to 9%)

<1%:

Dermatologic: Pruritic rash

Gastrointestinal: Acute pancreatitis

Hematologic & oncologic: Eosinophilia

Hypersensitivity: Infusion-related reaction

Immunologic: Antibody development

Ophthalmic: Ocular hyperemia

Postmarketing: Hypersensitivity: Anaphylaxis

Contraindications

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

Warnings/Precautions

Concerns related to adverse effects:

• Antibody formation: Formation of antibodies (inhibitors) to factor VIII 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: Hypersensitivity reactions, including anaphylaxis, have occurred. Angioedema, chest tightness, dyspnea, nausea, pruritus, urticaria, vomiting, and wheezing may progress to anaphylaxis. Discontinue immediately and institute appropriate treatment if hypersensitivity 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 or Esperoct.

• 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.

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 antihemophilic factor) may occur at any time; in general, formation of inhibitors are 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 (WFH [Srivastava 2020]).

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.

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]

Generic Equivalent Available: US

Yes

Pricing: US

Solution (reconstituted) (Esperoct Intravenous)

500 unit (Price provided is per AHF Unit): $3.06

1000 unit (Price provided is per AHF Unit): $3.06

1500 unit (Price provided is per AHF Unit): $3.06

2000 unit (Price provided is per AHF Unit): $3.06

3000 unit (Price provided is per AHF Unit): $3.06

Solution (reconstituted) (Jivi Intravenous)

500 unit (Price provided is per AHF Unit): $3.31

1000 unit (Price provided is per AHF Unit): $3.31

2000 unit (Price provided is per AHF Unit): $3.31

3000 unit (Price provided is per AHF Unit): $3.31

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.

Solution Reconstituted, Intravenous:

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

Esperoct: 500 units (1 ea); 3000 units (1 ea) [contains polysorbate 80]

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

Administration: Pediatric

Parenteral: IV:

Adynovate: Children and Adolescents: Infuse IV over ≤5 minutes; maximum infusion rate: 10 mL/minute.

Esperoct: Children and Adolescents: Infuse IV over approximately 2 minutes. Note: Some needleless connectors may be incompatible with the Esperoct syringe; refer to the manufacturer's labeling for administration instructions if using an incompatible needleless connector.

Jivi: Children ≥12 years and Adolescents: Infuse IV over 1 to 15 minutes; adjust rate to individual patient response not to exceed a maximum infusion rate: 2.5 mL/minute.

Administration: Adult

IV:

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

Esperoct: Infuse over ~2 minutes. Note: Some needleless connectors may be incompatible with the Esperoct syringe; refer to the manufacturer's labeling for administration instructions if using an incompatible needleless connector.

Jivi: Infuse over 1 to 15 minutes (maximum infusion rate: 2.5 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

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.

Esperoct: Store intact vials at 2°C to 8°C (36°F to 46°F) in original package to protect from light. Do not freeze. May also store up to 30°C (86°F) for ≤12 months or up to 40°C (104°F) for ≤3 months. After storage at room temperature, do not return to refrigerator. Following reconstitution, use immediately or may store solution in vial with vial adaptor and syringe attached at room temperature (≤30°C [≤86°F]) for ≤4 hours or refrigerated (2°C to 8°C [36°F to 46°F]) for ≤24 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.

Use

Adynovate, Esperoct: Treatment of hemophilia A (congenital factor VIII deficiency) in any of the following: On-demand treatment and control of bleeding episodes; perioperative management; routine prophylaxis to reduce the frequency of bleeding episodes (All indications: FDA approved in ages ≥1 year and adults).

Jivi: Treatment of previously treated patients with hemophilia A in any of the following: On-demand treatment and control of bleeding episodes; perioperative management; routine prophylaxis to reduce the frequency of bleeding episodes (All indications: FDA approved in ages ≥12 years and adults).

Note: Antihemophilic factor (recombinant [pegylated]) is not indicated for the treatment of von Willebrand disease.

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

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

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 (NHF 2017; RCOG [Pavord 2017]; WFH [Srivastava 2020]). Initial reports using the recombinant pegylated product have been limited to use in males (Brand 2016; Dunn 2018; Konkle 2015).

Monitoring Parameters

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 as peaks 15 to 30 minutes after infusion to assess target level achievement (WFH [Srivastava 2020]). Note: The World Federation of Hemophilia (WFH) recommends use of a chromogenic factor VIII activity assay or one-stage aPTT-based assay with a validated reagent, calibrated with a plasma standard traceable to a WHO international standard for monitoring Esperoct and Jivi; for Adynovate, WFH advises that more laboratory assay studies are required to inform recommendations about laboratory monitoring (WFH [Srivastava 2020]).

Heart rate and blood pressure before and during IV administration; signs and symptoms of bleeding, hemoglobin and hematocrit, and signs and symptoms of 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 (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, 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)

Note: Pharmacokinetic data for Adynovate are based on a single dose of 45 units/kg and plasma factor VIII activity measured by one-stage assay. Pharmacokinetic data for Esperoct are based on a single dose of 50 units/kg and plasma factor VIII activity measured by one-stage assay. Pharmacokinetic data for Jivi are based on combined data for single doses of 25 units/kg and 60 units/kg and plasma factor VIII activity measured by one-stage assay.

Distribution: V_ss:

Adynovate: Children <6 years of age: 0.56 ± 0.12 dL/kg; Children 6 to <12 years of age: 0.54 ± 0.09 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.

Esperoct: Children <6 years of age: 44.2 mL/kg; Children 6 to <12 years of age: 47.3 mL/kg; Children and Adolescents 12 to <18 years of age: 36.4 mL/kg; Adults ≥18 years of age: 37.3 mL/kg.

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

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.

Esperoct: Children <6 years of age: 14.7 hours; Children 6 to <12 years of age: 13.8 hours; Children and Adolescents 12 to <18 years of age: 17.4 hours; Adults ≥18 years of age: 21.7 hours.

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

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

Pharmacokinetics: Additional Considerations (Adult Data Unless Noted)

Obesity: Esperoct: Incremental recovery increased by ~17% and 41%, AUC increased by ~10% and 27%, and clearance decreased by ~8% and 23% in adult patients with a BMI of 25 to <30 kg/m² and 30 to <35 kg/m², respectively, in comparison to subjects with a BMI <25 kg/m².

Brand Names: International

International Brand Names by Country

For country code abbreviations (show table)

(AE) United Arab Emirates: Adynovate;
(AR) Argentina: Adynovate;
(AT) Austria: Adynovi;
(BE) Belgium: Adynovi;
(BG) Bulgaria: Adynovi;
(BR) Brazil: Adynovate;
(CH) Switzerland: Adynovi;
(CO) Colombia: Adynovate;
(CZ) Czech Republic: Adynovi;
(DE) Germany: Adynovi;
(EE) Estonia: Adynovi;
(ES) Spain: Adynovi;
(FI) Finland: Adynovi;
(GB) United Kingdom: Adynovi;
(GR) Greece: Adynovi;
(HU) Hungary: Adynovi;
(IT) Italy: Adynovi;
(JP) Japan: Adynovate;
(KR) Korea, Republic of: Adynovate;
(LT) Lithuania: Adynovi;
(LU) Luxembourg: Adynovi;
(LV) Latvia: Adynovi;
(MX) Mexico: Adynovate;
(NL) Netherlands: Adynovi;
(NO) Norway: Adynovi;
(PL) Poland: Adynovi;
(PR) Puerto Rico: Adynovate;
(PT) Portugal: Adynovi;
(QA) Qatar: Adynovate | Jivi;
(RO) Romania: Adynovi;
(SA) Saudi Arabia: Adynovate;
(SE) Sweden: Adynovi;
(SI) Slovenia: Adynovi;
(TW) Taiwan: Adynovate

Adynovate (antihemophilic factor [recombinant (pegylated)]) [prescribing information]. Lexington, MA: Takeda Pharmaceuticals USA Inc; August 2023.
Alade SL, Brown RE, Paquet A Jr. Polysorbate 80 and E-Ferol toxicity. Pediatrics. 1986;77(4):593-597. [PubMed 3960626]
Batorova A, Martinowitz U. Continuous infusion of coagulation factors. Haemophilia. 2002;8(3):170-177. doi:10.1046/j.1365-2516.2002.00635.x [PubMed 12010406]
Batorova A, Holme P, Gringeri A, et al; European Haemophilia Treatment Standardisation Board. Continuous infusion in haemophilia: current practice in Europe. Haemophilia. 2012;18(5):753-759. doi:10.1111/j.1365-2516.2012.02810.x [PubMed 22530687]
Brand B, Gruppo R, Wynn TT. Efficacy and safety of pegylated full-length recombinant factor VIII with extended half-life for perioperative haemostasis in haemophilia A patients. Haemophilia. 2016;22(4):e251-e258. doi: 10.1111/hae.12963. [PubMed 27328112]
Centers for Disease Control and Prevention (CDC). Unusual syndrome with fatalities among premature infants: association with a new intravenous vitamin E product. MMWR Morb Mortal Wkly Rep. 1984;33(14):198-199. http://www.cdc.gov/mmwr/preview/mmwrhtml/00000319.htm. [PubMed 6423951]
Dunn AL, Ahuja SP, Mullins ES. Real-world experience with use of Antihemophilic Factor (Recombinant), PEGylated for prophylaxis in severe haemophilia A. Haemophilia. 2018;24(3):e84-e92. doi: 10.1111/hae.13403. [PubMed 29359417]
Esperoct (antihemophilic factor [recombinant (pegylated)]) [prescribing information]. Plainsboro, NJ: Novo Nordisk Inc; October 2019.
Esperoct (antihemophilic factor [recombinant (pegylated)]) [prescribing information]. Plainsboro, NJ: Novo Nordisk Inc; August 2022.
Henrard S, Speybroeck N, Hermans C. Impact of being underweight or overweight on factor VIII dosing in hemophilia A patients. Haematologica. 2013;98(9):1481-1486. doi: 10.3324/haematol.2013.084038. [PubMed 23645693]
Holme PA, Tjønnfjord GE, Batorova A. Continuous infusion of coagulation factor concentrates during intensive treatment. Haemophilia. 2018;24(1):24-32. doi:10.1111/hae.13331 [PubMed 28873263]
Isaksson M, Jansson L. Contact allergy to Tween 80 in an inhalation suspension. Contact Dermatitis. 2002;47(5):312-313. [PubMed 12534540]
Jivi (antihemophilic factor [recombinant {pegylated}]) [prescribing information]. Whippany, NJ: Bayer HealthCare LLC; August 2018.
Konkle BA, Stasyshyn O, Chowdary P, et al. Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A. Blood. 2015;126(9):1078-1085. [PubMed 26157075]
Lucente P, Iorizzo M, Pazzaglia M. Contact sensitivity to Tween 80 in a child. Contact Dermatitis. 2000;43(3):172. [PubMed 10985636]
Martinowitz U, Schulman S, Gitel S, Horozowski H, Heim M, Varon D. Adjusted dose continuous infusion of factor VIII in patients with haemophilia A. Br J Haematol. 1992;82(4):729-734. doi:10.1111/j.1365-2141.1992.tb06951.x [PubMed 1482660]
McEneny-King A, Chelle P, Henrard S, Hermans C, Iorio A, Edginton AN. Modeling of body weight metrics for effective and cost-efficient conventional factor VIII dosing in hemophilia A prophylaxis. Pharmaceutics. 2017;9(4):47. doi: 10.3390/pharmaceutics9040047. [PubMed 29039750]
National Hemophilia Foundation (NHF). Medical and Scientific Advisory Council (MASAC) guidelines for perinatal management of women with bleeding disorders and carriers of hemophilia A and B (MASAC document 251). https://www.hemophilia.org/node/3660. Published September 17, 2017. Accessed June 7, 2018.
Pavord S, Rayment R, Madan B, et al; for the Royal College of Obstetricians and Gynaecologists. Management of inherited bleeding disorders in pregnancy: Green-top Guideline No. 71 (joint with UKHCDO). BJOG. 2017;124(8):e193–e263. doi: 10.1111/1471-0528.14592. [PubMed 28447403]
Poon MC, Card R. Hemophilia management in transfusion medicine. Transfus Apher Sci. 2012;46(3):299-307. doi:10.1016/j.transci.2012.03.020 [PubMed 22503305]
Rickard KA. Guidelines for therapy and optimal dosages of coagulation factors for treatment of bleeding and surgery in haemophilia. Haemophilia. 1995;1(suppl 1):8-13. doi:10.1111/j.1365-2516.1995.tb00104.x [PubMed 27214734]
Shelley WB, Talanin N, Shelley ED. Polysorbate 80 hypersensitivity. Lancet. 1995;345(8960):1312-1313. [PubMed 7746084]
Srivastava A, Santagostino E, Dougall A, et al; WFH Guidelines for the Management of Hemophilia panelists and co-authors. WFH guidelines for the management of hemophilia, 3rd edition. Haemophilia. 2020;26(suppl 6):1-158. doi:10.1111/hae.14046 [PubMed 32744769]
Suzuki N, Hirakawa A, Kishimoto M, et al. Retrospective analysis of in vivo recovery and clearance during continuous infusion of recombinant factor VIII products: a single-institution study. Haemophilia. 2017;23(2):215-221. doi:10.1111/hae.13082 [PubMed 27704637]
Tiede A, Cid AR, Goldmann G, et al. Body mass index best predicts recovery of recombinant factor VIII in underweight to obese patients with severe haemophilia A. Thromb Haemost. 2020;120(2):277-288. doi: 10.1055/s-0039-3400745. [PubMed 31887776]

Topic 141008 Version 13.0

خرید پکیج

Factor VIII, recombinant human pegylated: Pediatric drug information