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Factor VIIa (Recombinant)

Pronunciation

(FAK ter SEV en aye ree KOM be nant)

Index Terms

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

Dosage Forms

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

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

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 A or B: Vss: Children 2 to 12 years: 164 mL/kg; Adults: 107 to 128 mL/kg

Factor VII deficiency: Vss: 280 to 290 mL/kg

Excretion

Hemophilia A or B: Clearance: Children 2 to 12 years: 58 mL/hour/kg; Adults: 31 to 39 mL/hour/kg

Factor VII deficiency: Clearance: 71 to 79 mL/kg/hour

Half-Life Elimination

Hemophilia A or B: Half-life, terminal: Children 2 to 12 years: 2.6 hours; Adults: 2.9 to 3.1 hours

Factor VII deficiency: Half-life, terminal: 2.8 to 3.1 hours

Use: Labeled Indications

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

Use: Unlabeled

Warfarin-related intracerebral hemorrhage; treatment of refractory bleeding after cardiac surgery in nonhemophiliac patients

Contraindications

There are no contraindications listed in the manufacturer’s labeling.

Dosing: Adult

IV:

Congenital hemophilia A or B with inhibitors:

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 until healed.

Congenital factor VII deficiency:

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.

Acquired hemophilia:

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.

Glanzmann’s thrombasthenia:

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 average infused doses (median 100 mcg/kg) were noted for surgical patients who had clinical refractoriness with or without platelet-specific antibodies compared to those with neither.

Intracerebral hemorrhage (ICH) (warfarin-related) (off-label use; Freeman 2004; Ilyas 2008): 10 to 100 mcg/kg/dose (see "Note" below) administered concurrently with IV vitamin K (to correct the nonfactor VII coagulation factors).

Note: Lower doses (10 to 20 mcg/kg) are generally preferred given the higher risk of thromboembolic complications with higher doses; response is highly variable; monitor INR frequently after administration since rebound increases in INR occur quickly given the short half-life of rFVIIa; duration of INR correction is dose dependent. Routine use as a sole agent is not recommended for warfarin-related ICH (Morgenstern 2010).

Treatment of refractory bleeding after cardiac surgery in nonhemophiliac patients: Dosing not established; doses in the range of 35 to 70 mcg/kg/dose have been recommended based on low-quality evidence (case series, observational studies) (Chapman 2011; Ferraris 2011; Karkouti 2007); in patients with a left ventricular assist device, lower doses (ie, 10 to 20 mcg/kg) may be preferred to reduce thromboembolic events (Bruckner 2009).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Congenital factor VII deficiency: Children and Adolescents: Refer to adult dosing.

Glanzmann’s thrombasthenia: Children and Adolescents: Refer to adult dosing.

Congenital hemophilia A or B with inhibitors: Children and Adolescents: Refer to adult dosing.

Dosing: Renal Impairment

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

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

Reconstitution

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.

NovoSeven RT: 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

Administration

IV: For IV administration only as a bolus over 2 to 5 minutes (depending on the dose administered). Use NS to flush line (if necessary) before and after administration. Administer within 3 hours after reconstitution.

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.

Drug Interactions

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

Adverse Reactions

1% to 10%:

Cardiovascular: Thrombosis (4%), hypertension (2%), bradycardia (1%), edema (1%), hypotension (1%)

Central nervous system: Cerebrovascular disease (<2%), headache (1%), pain (1%)

Dermatologic: Pruritus (1%), skin rash (1%)

Endocrine & metabolic: Decreased serum fibrinogen (2%)

Gastrointestinal: Vomiting (1%)

Hematologic & oncologic: Decreased prothrombin time (1%), disseminated intravascular coagulation (1%), increased fibrinolysis (1%), purpura (1%)

Hepatic: Abnormal hepatic function tests (<2%)

Hypersensitivity: Hypersensitivity reaction (1%)

Local: Injection site reaction (1%)

Neuromuscular & skeletal: Osteoarthrosis (1%)

Renal: Renal function abnormality (1%)

Respiratory: Pneumonia (1%)

Miscellaneous: Fever (4%), decreased therapeutic response (<2%)

<1% (Limited to important or life-threatening): Anaphylactic shock, anaphylaxis, angina pectoris, angioedema, antibody development, arterial embolism (retinal), arterial thrombosis, arterial thrombosis (limb, retinal), bowel infarction, cerebral infarction, cerebral ischemia, cerebrovascular accident, deep vein thrombosis, hepatic artery thrombosis, hypersensitivity, immunogenicity, increased fibrin degradation products (including D-dimer elevation), intracardiac thrombus, local phlebitis, myocardial infarction, myocardial ischemia, nausea, occlusion of cerebral arteries, peripheral ischemia, portal vein thrombosis, pulmonary embolism, renal artery thrombosis, thrombophlebitis, venous thrombosis at injection site

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: In patients with factor VII deficiency, 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. Use with caution in patients with known hypersensitivity to mouse, hamster, or bovine proteins, or factor VIIa, or any components of the product. If hypersensitivity reaction occurs, discontinue use and administer appropriate treatment; carefully consider the benefits versus the risk of continued treatment with factor VIIa.

• 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 due to circulating tissue factor or predisposing coagulopathy in patients with disseminated intravascular coagulation (DIC), advanced atherosclerotic disease, septicemia, crush injury, concomitant treatment with activated or nonactivated prothrombin complex concentrates, or uncontrolled postpartum hemorrhage. Use with caution in patients with an increased risk of thromboembolic complications (eg, coronary heart disease, liver disease, DIC, postoperative immobilization, elderly patients, and neonates). 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; 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, monitor for factor VII antibodies.

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Factor VII concentrations may vary significantly in pregnant women with coagulation disorders. Pregnant women with hemophilia should have clotting factors monitored, particularly at 28 and 34 weeks gestation and prior to invasive procedures. Recombinant factor VIIa is recommended for the management of bleeding disorders in pregnant women with factor VII deficiency. Prophylaxis at delivery may be needed if factor VII concentrations are <10 to 20 units /dL or in women with a significant bleeding history and treatment should continue for 3 to 5 days postpartum depending on route of delivery. The neonate may also be at an increased risk of bleeding following delivery and should be tested for the coagulation disorder (Kadir 2009; Lee 2006).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Have patient report immediately to prescriber signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), angina, shortness of breath, coughing up blood, jaw pain, neck pain, back pain, arm pain, severe dizziness, passing out, abdominal pain, or abdominal edema (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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