Factor VIIa (Recombinant)

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]

Pharmacology

Mechanism of Action

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.

Pharmacokinetics/Pharmacodynamics

Distribution

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

Factor VII deficiency: V_ss: 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 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.

Use: Off Label

Intracranial hemorrhage associated with danaparoidyes

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)yes

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 patientscyes

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 inhibitorsb

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

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

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

Dosage and Administration

Dosing: Adult

Acquired hemophilia: IV:

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:

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:

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).

Glanzmann thrombasthenia: 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/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: Infants, Children, and Adolescents: IV:

Bleeding episodes: 90 mcg/kg 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, interval, and duration of therapy may be adjusted based on severity of bleeding and the degree of hemostasis achieved. For patients treated for joint or muscle bleeds, a decision on the outcome of treatment was reached within 8 doses in the majority of patients, although more doses were required for severe bleeds; adverse effects were reported most commonly in patients treated with 12 or more doses. For patients experiencing severe bleeds to maintain the hemostatic plug, dosing should be continued at 3- to 6-hour intervals; the duration of posthemostatic dosing should be minimized.

Perioperative management: 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 every 2 hours for 48 hours, then every 2 to 6 hours until healed. For major surgery, continue 90 mcg/kg every 2 hours for 5 days, then every 4 hours until healed.

Congenital factor VII deficiency: Infants, Children, and Adolescents: IV:

Bleeding episodes: 15 to 30 mcg/kg 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 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.

Glanzmann's thrombasthenia: 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 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.

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. Administer within 3 hours after reconstitution.

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 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.

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%, postmarketing, and/or case reports: Anaphylactic shock, anaphylaxis, angina pectoris, angioedema, antibody development, arterial embolism (retinal), arterial thrombosis, arterial thrombosis (limb, retinal), arthralgia bowel infarction, cerebral infarction, cerebral ischemia, cerebrovascular accident, deep vein thrombosis, flushing, 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, pain at injection site, peripheral ischemia, portal vein thrombosis, pulmonary embolism, renal artery thrombosis, shock, thrombophlebitis, urticaria, venous thrombosis at injection site

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. Patients with known hypersensitivity to mouse, hamster, or bovine proteins 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 congenital hemophilia receiving concomitant treatment with activated prothrombin complex concentrates, older patients with acquired hemophilia receiving other hemostatic agents, or patients with a history of cardiac or vascular disease or otherwise predisposed to thrombotic events. 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

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.

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

• Severe cerebrovascular disease like change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or vision changes,
• 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 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.