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Factor VIIa (Recombinant)

Medically reviewed by Drugs.com. Last updated on Nov 12, 2020.

Pronunciation

(FAK ter SEV en aye ree KOM be nant)

Index Terms

  • Coagulation Factor VIIa
  • Eptacog Alfa (Activated)
  • rFVIIa
  • Sevenfact

Dosage Forms

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

Solution Reconstituted, Intravenous:

Sevenfact: Factor VIIa, recombinant-jncw 1 mg (1 ea); Factor VIIa, recombinant-jncw 5 mg (1 ea) [contains polysorbate 80]

Solution Reconstituted, Intravenous [preservative free]:

NovoSeven RT: 1 mg (1 ea); 2 mg (1 ea); 5 mg (1 ea); 8 mg (1 ea) [contains polysorbate 80]

Brand Names: U.S.

  • NovoSeven RT
  • Sevenfact

Pharmacologic Category

  • Antihemophilic Agent

Pharmacology

Recombinant factor VIIa, a vitamin K-dependent glycoprotein, promotes hemostasis by activating the extrinsic pathway of the coagulation cascade. It replaces deficient activated coagulation factor VII, which complexes with tissue factor and may activate coagulation factor X to Xa and factor IX to IXa. When complexed with other factors, coagulation factor Xa converts prothrombin to thrombin, a key step in the formation of a fibrin-platelet hemostatic plug.

Distribution

Hemophilia:

Vss:

NovoSeven RT: Hemophilia A with inhibitors:

Children:

≤5 years: 145 ± 1 mL/kg.

6 to 12 years: 149 ± 22 mL/kg.

Adults: 130 ± 37 mL/kg.

SevenFact: 11.9 to 19.9 L.

Factor VII deficiency: NovoSeven RT: Vss: 230 ± 70 mL/kg.

Excretion

Hemophilia:

Clearance:

NovoSeven RT: Hemophilia A with inhibitors:

Children:

≤5 years: 61 ± 9 mL/hour/kg.

6 to 12 years: 52 ± 12 mL/hour/kg.

Adults: 43 ± 15 mL/hour/kg.

SevenFact: 5.8 to 8 L/hour.

Factor VII deficiency: NovoSeven RT:

Clearance: 67.7 ± 17.9 mL/kg/hour.

Half-Life Elimination

Hemophilia:

Half-life, terminal:

NovoSeven RT: Hemophilia A with inhibitors:

Children:

≤5 years: 1.9 ± 0.6 hours.

6 to 12 years: 3 ± 0.5 hours.

Adults: 3.2 ± 0.3 hours.

SevenFact: 1.4 to 1.7 hours.

Factor VII deficiency: NovoSeven RT: Half-life, terminal: 2.62 ± 0.63 hours.

Use: Labeled Indications

Bleeding episodes and perioperative management (NovoSeven RT): Treatment of bleeding episodes and perioperative management in adults and children with hemophilia A or B with inhibitors, congenital factor VII deficiency, and Glanzmann thrombasthenia with refractoriness to platelet transfusions, with or without antibodies to platelets; treatment of bleeding episodes and perioperative management in adults with acquired hemophilia.

Bleeding episodes (SevenFact): Treatment and control of bleeding episodes in adults and adolescents ≥12 years of age with hemophilia A or B with inhibitors.

Limitation of use: SevenFact is not indicated for the treatment of patients with congenital factor VII deficiency.

Off Label Uses

Intracranial hemorrhage associated with danaparoid

Based on the Neurocritical Care Society and the Society of Critical Care Medicine guideline for reversal of antithrombotics in intracranial hemorrhage, factor VIIa (recombinant) may be used to reverse the anticoagulant effect following intracranial hemorrhage associated with danaparoid.

Intracranial hemorrhage associated with low molecular weight heparin (if protamine is contraindicated)

Based on the Neurocritical Care Society and the Society of Critical Care Medicine guideline for reversal of antithrombotics in intracranial hemorrhage, factor VIIa (recombinant) may be considered to reverse the anticoagulant effect following intracranial hemorrhage associated with therapeutic dosing of low molecular weight heparins if protamine is contraindicated.

Refractory bleeding after cardiac surgery in nonhemophiliac patients

Data from case series and retrospective studies suggests that factor VIIa (recombinant) may be beneficial for the management of refractory bleeding following cardiac surgery in patients without hemophilia [Chapman 2011], [Gelsomino 2008], [Karkouti 2008], [Romagnoli 2006].

Based on Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists Blood Conservation Clinical Practice Guidelines, factor VIIa (recombinant) may be considered for the treatment of refractory bleeding after cardiac surgery in nonhemophiliac patients.

Secondary prophylaxis of bleeding events in congenital hemophilia A or B with inhibitors

Data from a small multicenter, randomized, double-blind trial supports the use of factor VIIa (recombinant) as secondary prophylaxis of bleeding events in male patients with congenital hemophilia A or B with inhibitors and who have frequent bleeds requiring hemostatic therapy [Konkle 2007].

Contraindications

NovoSeven RT: There are no contraindications listed in the manufacturer's labeling.

SevenFact: Severe hypersensitivity to factor VIIa (recombinant)-jncw or any component of the formulation; known allergy to rabbits or rabbit proteins.

Canadian labeling: Additional contraindications (not in the US labeling): Known hypersensitivity to eptacog alfa (activated), any component of the formulation, or to mouse, hamster, or bovine protein.

Dosing: Adult

Acquired hemophilia: IV:

NovoSeven RT:

Bleeding episodes: 70 to 90 mcg/kg/dose every 2 to 3 hours until hemostasis is achieved.

Perioperative management: 70 to 90 mcg/kg/dose immediately before surgery; repeat every 2 to 3 hours for the duration of surgery and until hemostasis achieved.

Congenital factor VII deficiency: IV:

NovoSeven RT:

Bleeding episodes: 15 to 30 mcg/kg/dose every 4 to 6 hours until hemostasis is achieved. Doses as low as 10 mcg/kg have been effective.

Perioperative management: 15 to 30 mcg/kg/dose immediately before surgery; repeat every 4 to 6 hours for the duration of surgery and until hemostasis achieved. Doses as low as 10 mcg/kg have been effective.

Congenital hemophilia A or B with inhibitors: IV:

NovoSeven RT:

Bleeding episodes: 90 mcg/kg/dose every 2 hours until hemostasis is achieved or until the treatment is judged ineffective. Doses between 35 and 90 mcg/kg/dose have been used successfully in clinical trials. The dose, interval, and duration of therapy may be adjusted based upon the severity of bleeding and the degree of hemostasis achieved. For patients experiencing severe bleeds, dosing should be continued at 3- to 6-hour intervals post-hemostasis. The duration of any post-hemostatic dosing should be minimized.

Perioperative management: 90 mcg/kg/dose immediately before surgery (additional bolus doses may be administered for major surgery if required); repeat at 2-hour intervals for the duration of surgery. For minor surgery, continue 90 mcg/kg/dose postoperatively every 2 hours for 48 hours, then every 2 to 6 hours until healed. For major surgery, continue 90 mcg/kg/dose postoperatively every 2 hours for 5 days, then every 4 hours or by continuous infusion at 50 mcg/kg/hour until healed.

Secondary prophylaxis of bleeding events (off-label use): 90 mcg/kg once daily. In a clinical trial, male patients with frequent bleeds (mean ≥4 bleeding events per month requiring hemostatic therapy) received prophylaxis for a duration of 3 months (Konkle 2007).

SevenFact:

Note: Maximum dosage has not been established; cumulative daily dosages >900 mcg/kg, which may be associated with a greater risk of thromboembolic complications, have not been studied.

Mild to moderate bleeding (eg, joint, superficial muscle, soft tissue and mucous membranes): 75 mcg/kg every 3 hours until hemostasis is achieved OR initial dose of 225 mcg/kg and if hemostasis is not achieved within 9 hours, administer 75 mcg/kg every 3 hours as needed to achieve hemostasis. If successful control of bleeding does not occur within 24 hours of initial administration, consider alternative treatments. Continue therapy to support healing and prevent recurrent hemorrhage after hemostasis to maintain the hemostatic plug.

Severe bleeding (eg, life- or limb-threatening hemorrhage, iliopsoas and deep muscle with neurovascular injury, retroperitoneum, intracranial, or GI): Initial: 225 mcg/kg, then 6 hours later (if needed) administer 75 mcg/kg every 2 hours until hemostasis is achieved; continue therapy to support healing and prevent recurrent hemorrhage.

Glanzmann thrombasthenia: IV:

NovoSeven RT:

Bleeding episodes (severe, refractory to platelet transfusions): 90 mcg/kg/dose every 2 to 6 hours until hemostasis is achieved.

Perioperative management: 90 mcg/kg/dose immediately before surgery; repeat at 2-hour intervals for the duration of surgery. Continue 90 mcg/kg/dose every 2 to 6 hours to prevent postoperative bleeding. Note: Higher doses (100 to 140 mcg/kg) may be used for surgical patients who have clinical refractoriness with or without platelet-specific antibodies compared to those with neither.

Intracranial hemorrhage associated with danaparoid (off-label use): IV: 90 mcg/kg once (NCS/SCCM [Frontera 2016]).

Intracranial hemorrhage associated with low molecular weight heparin (if protamine is contraindicated) (alternative agent) (off-label use): Note: Not for use in patients with intracranial hemorrhage receiving prophylactic low molecular weight heparin.

IV: 90 mcg/kg once (NCS/SCCM [Frontera 2016]).

Refractory bleeding after cardiac surgery in nonhemophiliac patients (off-label use): Note: Dosing not established; recommendations based on low-quality evidence (case series, observational studies).

IV: Initial range of ~11 to 22 mcg/kg/dose (median ~17 mcg/kg) has been used (Gelsomino 2008; Romagnoli 2006); others have used a range of ~35 to 72 mcg/kg/dose (median ~49 mcg/kg) (Karkouti 2008). For persistent bleeding, 1 or 2 additional doses may be required in some patients (Chapman 2011; Gelsomino 2008; Karkouti 2008; Romagnoli 2006). In patients with a left ventricular assist device, a single lower dose of 10 to 20 mcg/kg may be preferred to reduce thromboembolic events (Bruckner 2009).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Hemophilia A or B (congenital) with inhibitors: Note: Dose, frequency and duration of therapy should be individualized based on severity of the bleeding, need for urgent hemostasis, and prior patient response to factor VIIa bypassing agents in previous bleeding events.

NovoSeven RT:

Bleeding episodes: Infants, Children, and Adolescents: IV: 90 mcg/kg/dose every 2 hours until hemostasis is achieved or until the treatment is judged ineffective. Doses between 35 to 90 mcg/kg have been used successfully in clinical trials. The dose, frequency, and duration of therapy should be adjusted based on severity of bleeding and the degree of hemostasis achieved. For patients experiencing severe bleeds to maintain the hemostatic plug, dosing should be continued at 3- to 6-hour intervals; the duration of post-hemostatic dosing has not been studied. Monitor and minimize the duration of post-hemostatic dosing.

Perioperative management: Infants, Children, and Adolescents: IV: 90 mcg/kg immediately before surgery (additional bolus doses may be administered for major surgery if required); repeat at 2-hour intervals for the duration of surgery. For minor surgery, continue 90 mcg/kg/dose every 2 hours for 48 hours, then every 2 to 6 hours until healing achieved. For major surgery, continue 90 mcg/kg/dose every 2 hours for 5 days, then every 4 hours or by continuous infusion at 50 mcg/kg/hour until healing achieved.

Secondary prophylaxis of bleeding events: Very limited data available: Children ≥5 years and Adolescents: IV: 90 mcg/kg/dose OR 270 mcg/kg/dose once daily (Konkle 2007; Meeks 2016). Dosing based on a trial which enrolled 22 male patients, including 16 pediatric patients (age: 5 to <18 years), with severe congenital hemophilia with high inhibitor titers, a need for treatment with bypassing agents, and who had experienced at least 4 bleeds requiring hemostatic therapy the previous month. Patients were randomized to receive either 90 mcg/kg/dose or 270 mcg/kg/dose IV daily as prophylaxis for 3 months. The overall bleeding frequency was reduced by 45% and 59% in the 90 mcg/kg group and the 270 mcg/kg group, respectively, with the most significant decrease was seen in joint bleeds. No thromboembolic events were reported (Konkle 2007).

SevenFact: Note: Maximum dosage has not been established; cumulative daily dosages >900 mcg/kg, which may be associated with a greater risk of thromboembolic complications, have not been studied. The dose, frequency, and duration of therapy should be adjusted based on patient's response to therapy and the degree of hemostasis achieved.

Children ≥12 years and Adolescents:

Mild to moderate bleeding (eg, joint, superficial muscle, soft tissue and mucous membranes): IV: 75 mcg/kg/dose every 3 hours until hemostasis is achieved OR initial dose of 225 mcg/kg and if hemostasis is not achieved within 9 hours, administer 75 mcg/kg/dose every 3 hours as needed to achieve hemostasis. If successful control of bleeding does not occur within 24 hours of initial administration, consider alternative treatments. Continue therapy to support healing and prevent recurrent hemorrhage after hemostasis to maintain the hemostatic plug. Duration of therapy should be individualized by site and severity of bleeding.

Severe bleeding (eg, life- or limb-threatening hemorrhage, iliopsoas and deep muscle with neurovascular injury, retroperitoneum, intracranial, or GI): IV: Initial: 225 mcg/kg/dose, then 6 hours later (if needed) administer 75 mcg/kg/dose every 2 hours until hemostasis is achieved; continue therapy to support healing and prevent recurrent hemorrhage. Duration of therapy should be individualized based on site and severity of bleeding and use of other procoagulant therapies. Consider the risk of thrombosis with subsequent dosing after hemostasis achieved.

Congenital factor VII deficiency:

NovoSeven RT: Infants, Children, and Adolescents: IV:

Bleeding episodes: 15 to 30 mcg/kg/dose every 4 to 6 hours until hemostasis is achieved. Doses as low as 10 mcg/kg/dose have been effective. Adjust dose and frequency to each individual patient.

Perioperative management: 15 to 30 mcg/kg immediately before surgery; repeat every 4 to 6 hours for the duration of surgery and until hemostasis achieved. Doses as low as 10 mcg/kg/dose have been effective. Adjust dose and frequency to each individual patient.

Glanzmann thrombasthenia:

NovoSeven RT: Infants, Children, and Adolescents: IV:

Bleeding episodes, severe (refractory to platelet transfusions): 90 mcg/kg/dose every 2 to 6 hours until hemostasis is achieved.

Perioperative management: 90 mcg/kg immediately before surgery; repeat at 2-hour intervals for the duration of surgery. Continue 90 mcg/kg/dose every 2 to 6 hours to prevent postoperative bleeding. Note: Higher doses of 100 to 140 mcg/kg can be used for surgical patients who have clinical refractoriness with or without platelet-specific antibodies.

Reconstitution

NovoSeven RT:

Prior to reconstitution, bring vials to a temperature not above 37°C (98.6°F). Add recommended diluent along wall of vial; do not inject directly onto powder. Gently swirl until dissolved. Do not mix with other infusion solutions. Administer within 3 hours after reconstitution.

Reconstitute each vial to a final concentration of 1 mg/mL using the provided histidine diluent as follows:

1 mg vial: 1.1 mL histidine diluent vial or 1 mL prefilled histidine diluent syringe.

2 mg vial: 2.1 mL histidine diluent vial or 2 mL prefilled histidine diluent syringe.

5 mg vial: 5.2 mL histidine diluent vial or 5 mL prefilled histidine diluent syringe.

8 mg vial: 8.1 mL histidine diluent vial or 8 mL prefilled histidine diluent syringe.

SevenFact:

Prior to reconstitution, bring vial and prefilled syringe (diluent) to room temperature. Add recommended diluent slowly into vial (refer to manufacturer's labeling for further information); gently swirl powder until dissolved. Do not mix with other infusion solutions. Administer within 4 hours after reconstitution.

Reconstitute each vial to a final concentration of 1 mg/mL using the provided SWFI diluent as follows:

1 mg vial: 1.1 mL prefilled SWFI diluent syringe.

5 mg vial: 5.2 mL prefilled SWFI diluent syringe.

Administration

NovoSeven RT:

IV bolus: Administer over 2 to 5 minutes (depending on the dose). Use NS to flush line (if necessary) before and after administration.

IV infusion: May be infused as a continuous IV infusion for perioperative management of major bleeding in patients with congenital hemophilia A or B. Continuous infusions should be infused via an infusion pump.

SevenFact:

IV bolus: Administer over ≤2 minutes.

Dietary Considerations

Some products may contain sodium.

Storage

NovoSeven RT: Prior to reconstitution, store between 2°C to 25°C (36°F to 77°F); do not freeze. Protect from light. Reconstituted solutions may be stored at room temperature or under refrigeration but must be infused within 3 hours of reconstitution. Do not freeze reconstituted solutions. Do not store reconstituted solutions in syringes.

SevenFact: Prior to reconstitution, store between 2°C to 30°C (36°F to 86°F); do not freeze. Protect from light. Reconstituted solutions should be stored at room temperature but may be stored between 2°C to 30°C (36°F to 86°F) for up to 4 hours. Do not freeze reconstituted solution or store in syringes.

Drug Interactions

Anti-inhibitor Coagulant Complex (Human): May enhance the thrombogenic effect of Factor VIIa (Recombinant). Management: Consider avoiding concomitant use of factor VIIa (recombinant) and activated prothrombin concentrates, such as anti-inhibitor coagulant complex (human), due to an increased risk of developing thrombotic events. Consider therapy modification

Factor XIII A-Subunit (Recombinant): May enhance the thrombogenic effect of Factor VIIa (Recombinant). Monitor therapy

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

1% to 10%:

Cardiovascular: Hypertension (2%), thrombosis (≤4%; including internal jugular thrombosis)

Endocrine & metabolic: Decreased serum fibrinogen (2%)

Immunologic: Antibody development

Local: Discomfort at injection site, hematoma at injection site, infusion site reaction

Nervous system: Dizziness, headache (1%), intracranial hypertension (1%)

Neuromuscular & skeletal: Hemarthrosis (acute, postoperative: 2%)

Miscellaneous: Fever (1% to 4%)

<1%:

Cardiovascular: Acute myocardial infarction, angina pectoris, cerebral ischemia, cerebrovascular accident, deep vein thrombosis, localized phlebitis, occlusion of cerebral arteries, pulmonary embolism, shock

Gastrointestinal: Nausea

Respiratory: Dyspnea

Frequency not defined:

Cardiovascular: Arterial thrombosis, deep vein thrombophlebitis, venous thrombosis

Hematologic & oncologic: Disseminated intravascular coagulation

Hepatic: Abnormal liver function

Hypersensitivity: Anaphylactic shock

Nervous system: Cerebrovascular disease, pain

ALERT: U.S. Boxed Warning

Thrombosis:

Serious arterial and venous thrombotic events following administration of Factor VIIa (recombinant) have been reported. Discuss the risks and explain the signs and symptoms of thrombotic and thromboembolic events to patients who will receive Factor VIIa (recombinant). Monitor patients for signs and symptoms of activation of the coagulation system and for thrombosis.

Warnings/Precautions

Concerns related to adverse effects:

• Antibody formation: If factor VIIa activity does not reach the expected level, prothrombin time is not corrected, or bleeding is uncontrolled (with recommended doses), suspect antibody formation and perform antibody analysis. Prothrombin time and factor VII coagulant activity should be measured before and after administration in patients with factor VII deficiency.

• Hypersensitivity reactions: Hypersensitivity reactions, including anaphylaxis, have been reported with use. Patients with known hypersensitivity to rabbit, mouse, hamster, or bovine proteins, or IgE-based hypersensitivity to casein may be at higher risk. If hypersensitivity reaction occurs, discontinue use and administer appropriate treatment.

• Thromboembolic events: [US Boxed Warning]: Serious arterial and venous thrombotic events following administration of Factor VIIa (recombinant) have been reported. Discuss the risks and explain the signs and symptoms of thrombotic and thromboembolic events to patients who will receive factor VIIa (recombinant). Monitor patients for signs and symptoms of activation of the coagulation system and for thrombosis. All patients receiving factor VIIa should be monitored for signs and symptoms of activation of the coagulation system or thrombosis; thrombotic events may be increased in patients with history of congenital or acquired hemophilia receiving concomitant treatment with activated or nonactivated prothrombin complex or other hemostatic agents, older patients with acquired hemophilia receiving other hemostatic agents, or patients with a history of atherosclerotic or coronary artery disease, cerebrovascular disease, crush injury, septicemia, or thromboembolism. Decreased dosage or discontinuation is warranted with confirmed intravascular coagulation or presence of clinical thrombosis.

Dosage form specific issues:

• 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.

Other warnings/precautions:

• Reduced efficacy: A number of factors influence the efficacy of factor VIIa, including hypothermia, thrombocytopenia, acidosis, and the amount of blood products transfused prior to administration (Dunkley 2008).

Monitoring Parameters

Monitor for evidence of hemostasis and thrombosis (including laboratory confirmation of intravascular coagulation, if appropriate). Although the prothrombin time (PT)/INR, aPTT, and factor VII clotting activity have shown no direct correlation with achieving hemostasis, these parameters may be useful as adjunct tests to evaluate efficacy and guide dose or interval adjustments. In factor VII – deficient patients, monitor PT and factor VII clotting activity before and after administration. Monitor for factor VII antibodies if the factor VIIa activity fails to reach the expected level, if PT is not corrected, or if bleeding is not controlled after treatment with recommended doses.

Pregnancy Considerations

Pregnant patients with inherited bleeding disorders, including factor VII deficiency and Glanzmann’s thrombasthenia, may have an increased risk of bleeding following abortion, antenatal procedures, delivery, and miscarriage; close surveillance is recommended. Patients with factor VII deficiency and severe or abnormal bleeding should be treated with recombinant factor VIIa. Patients with Glanzmann’s thrombasthenia and a history of bleeding can be treated prophylactically with recombinant factor VIIa at delivery (RCOG [Pavord 2017).

Patient Education

What is this drug used for?

• It is used to treat or prevent bleeding.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight

• Blood clots like numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; fast heartbeat; or coughing up blood.

• Severe headache

• Vision changes

• Severe dizziness

• Passing out

• Abdominal pain

• Abdominal swelling

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, 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 limited summary of general information about the medicine’s uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.