Introduction

Biosynthetic preparation (recombinant DNA origin) of blood coagulation factor VIIa.

Uses for Factor VIIa (Recombinant)

Hemophilia A or B with Inhibitors

Treatment and prevention of hemorrhagic episodes in patients with hemophilia A (antihemophilic factor [factor VIII] deficiency; classic hemophilia) or hemophilia B (factor IX deficiency; Christmas disease) who have developed inhibitors (alloantibodies) to factor VIII or factor IX, respectively; designated an orphan drug by FDA for this use.

Prevention of bleeding in patients with hemophilia A or B with inhibitors to factor VIII or factor IX, respectively, undergoing surgery or invasive procedures; designated an orphan drug by FDA for this use.

Management of hemophilia in patients with inhibitors may be difficult and consultation with a hemophilia treatment center is strongly recommended.

The Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation and other experts state that factor VIIa (recombinant) is one of several therapeutic options for the management of hemophilic patients with inhibitors. Treatment of choice depends on several factors (e.g., severity and location of bleeding, type [low- or high-responding] and titer of inhibitor, history of anamnestic response, previous response to these preparations).

Patients with low titers (e.g., <5–10 Bethesda units/mL) of inhibitors may be effectively treated with high dosages of coagulation factor concentrates (factor VIII or factor IX). Bypassing agents (e.g., factor VIIa [recombinant]) generally are used when a response to specific factor replacement therapy has not been obtained or is unlikely. MASAC recommends use of a bypassing agent in hemophilia A or hemophilia B patients with inhibitors in settings where clotting factor preparations would otherwise be used, including before and after surgery and physical therapy.

Acquired Hemophilia

Treatment and prevention of bleeding in patients with acquired hemophilia (i.e., those with acquired inhibitor antibodies [autoantibodies] to factor VIII); designated an orphan drug by FDA for this use.

Prevention of bleeding in patients with acquired hemophilia undergoing surgery or invasive procedures; designated an orphan drug by FDA for this use.

One of several options used to control bleeding in patients with acquired hemophilia.

Factor VII Deficiency

Management of hemorrhagic episodes in patients with congenital factor VII deficiency; designated an orphan drug by FDA for this use.

Prevention of bleeding in patients with congenital factor VII deficiency undergoing surgery or invasive procedures; designated an orphan drug by FDA for this use.

MASAC recommends use of factor VIIa (recombinant) for management of bleeding in patients with congenital factor VII deficiency.

Nonhemophilic Hemorrhage

Has been used in nonhemophilic patients^{† [off-label]} in a variety of clinical settings (e.g., intracranial hemorrhage [ICH], advanced liver disease, liver surgery, trauma, cardiac surgery, spinal surgery, GI bleeding, reversal of warfarin anticoagulation) to control or prevent excessive or life-threatening hemorrhage. However, efficacy and safety of the drug in these settings not established. Additional randomized controlled studies are needed to establish the role of factor VIIa (recombinant) as a general hemostatic agent in patients without hemophilia.

Factor VIIa (Recombinant) Dosage and Administration

General

• Administer only under direct supervision of a clinician experienced in the management of bleeding disorders.

• Adjust dose and dosing interval based on severity of bleeding and hemostatic response.

• Coagulation parameters (e.g., PT/INR, aPTT, plasma factor VII clotting activity [FVII:C]) have not been shown to directly correlate with hemostatic response. (See Adequate Patient Evaluation and Monitoring under Cautions.)

Administration

IV Administration

Administer by slow (over 2–5 minutes) IV injection.

Has been given as a continuous IV infusion^{† [off-label]}; however, manufacturer states that the drug should not be admixed with any IV infusion solutions. If flushing of the line is necessary prior to and following drug administration, use 0.9% sodium chloride injection.

Reconstitution

Select appropriate vial size and diluent based on indicated dosage. Prior to reconstitution, allow lyophilized powder and diluent supplied by manufacturer (histidine diluent) to warm to room temperature (≤37°C).

Reconstitute vials containing 1, 2, or 5 mg of lyophilized factor VIIa (recombinant) with 1.1, 2.1, or 5.2 mL of histidine diluent, respectively, to provide a solution containing approximately 1 mg/mL (1000 mcg/mL). Reconstitute only with the histidine diluent provided by manufacturer; do not use sterile water for injection or any other diluent.

Direct diluent toward side of vial; do not inject directly onto powder.

Gently swirl solution until all the powder is dissolved.

May store reconstituted solutions under refrigeration or at room temperature, but administer within 3 hours after reconstitution; discard any unused solution after 3 hours.

Dosage

Pediatric Patients

Hemophilia A or B with Inhibitors

Hemorrhagic Episodes

90 mcg/kg every 2 hours until hemostasis achieved or response to drug is inadequate; doses of 35–120 mcg/kg have been used successfully in clinical studies.

For severe bleeding episodes, continue treatment every 3–6 hours after hemostasis is achieved to prevent recurrence of bleeding. Optimum duration of therapy not established; minimize duration of posthemostatic dosing. (See Posthemostatic Dosing under Cautions.)

Surgical Prophylaxis

Minor surgery: 90 mcg/kg immediately prior to procedure; repeat every 2 hours during procedure. Continue every 2 hours postoperatively for 48 hours, then every 2–6 hours until healing achieved.

Major surgery: 90 mcg/kg immediately prior to procedure; repeat every 2 hours during procedure. Continue every 2 hours postoperatively for 5 days, then every 4 hours until healing achieved. Administer additional doses, if required.

Acquired Hemophilia

IV

70–90 mcg/kg every 2–3 hours until hemostasis achieved.

Factor VII Deficiency

Hemorrhagic Episodes and Surgical Prophylaxis

15–30 mcg/kg every 4–6 hours until hemostasis achieved. Although minimum effective dose not established, manufacturer states that doses as low as 10 mcg/kg have been effective.

Individualize dose and dosing frequency. Monitor PT and plasma factor VII clotting activity (FVII:C) prior to and following administration. Consider possibility that antibodies to factor VII may have developed if therapeutic response or expected factor VII levels are not achieved with calculated dosages. (See Development of Antibodies to Factor VII under Cautions.)

Adults

Hemophilia A or B with Inhibitors

Hemorrhagic Episodes

90 mcg/kg every 2 hours until hemostasis achieved or response to drug is inadequate; doses of 35–120 mcg/kg have been used successfully in clinical studies.

For severe bleeding episodes, continue treatment every 3–6 hours after hemostasis is achieved to prevent recurrence of bleeding. Optimum duration of therapy not established; minimize duration of posthemostatic dosing. (See Posthemostatic Dosing under Cautions.)

Surgical Prophylaxis

Minor surgery: 90 mcg/kg immediately prior to procedure; repeat every 2 hours during procedure. Continue every 2 hours for 48 hours postoperatively, then every 2–6 hours until healing achieved.

Major surgery: 90 mcg/kg immediately prior to procedure; repeat every 2 hours during procedure. Continue every 2 hours postoperatively for 5 days, then every 4 hours until healing achieved. Administer additional doses, if required.

Acquired Hemophilia

IV

70–90 mcg/kg every 2–3 hours until hemostasis achieved.

Factor VII Deficiency

Hemorrhagic Episodes and Surgical Prophylaxis

15–30 mcg/kg every 4–6 hours until hemostasis achieved. Although minimum effective dose not established, manufacturer states that doses as low as 10 mcg/kg have been effective.

Individualize dose and dosing frequency. Consider possibility that antibodies to factor VII may have developed if therapeutic response or expected factor VII levels are not achieved with calculated dosages. (See Development of Antibodies to Factor VII under Cautions.)

Contraindications

• Manufacturer states no known contraindications.

Warnings/Precautions

Warnings

Thromboembolic Events

Risk of serious thromboembolic events. Adverse arterial and venous thromboembolic events reported in clinical studies and during postmarketing experience. Risk of thrombosis, particularly arterial thromboembolic events (e.g., myocardial ischemia, MI, cerebral ischemia and/or infarction), may be further increased in nonhemophilic patients who receive factor VIIa (recombinant) for non-FDA-labeled indications.

Potentially greater risk in patients with disseminated intravascular coagulation (DIC), advanced atherosclerotic disease, crush injuries, septicemia, or concomitant treatment with activated or nonactivated prothrombin complex concentrates (APCCs or PCCs) due to circulating tissue factor (TF) or predisposing coagulopathy.

Weigh risk of thromboembolism against benefits of factor VIIa (recombinant) therapy. Use with caution, especially in patients with known risk factors for thromboembolism (e.g., elderly patients, neonates, those with a history of CHD, liver disease, DIC, or who require postoperative immobilization).

Closely monitor for thrombosis or other signs of an activated coagulation system. Reduce dosage or discontinue therapy if thrombosis occurs or laboratory tests confirm presence of intravascular coagulation.

Report thrombotic complications and other adverse effects associated with factor VIIa (recombinant) to the Hemophilia and Thrombosis Research Society (HTRS) Registry at 877-362-7355.

Posthemostatic Dosing

Safety and efficacy of prolonged elevations of factor VIIa have not been evaluated, and most appropriate duration of posthemostatic therapy with factor VIIa (recombinant) is not known; exercise caution if factor VIIa (recombinant) used for extended periods to maintain hemostasis. Minimize duration of posthemostatic therapy and closely monitor patients (preferably by a clinician experienced in the posthemostatic management of hemophilia).

Development of Antibodies to Factor VII

Development of antibodies to factor VII reported rarely in patients with congenital factor VII deficiency receiving factor VIIa (recombinant). In some cases, inhibitory effects were demonstrated in vitro; clinical importance not established.

Monitor PT and factor VII coagulant activity prior to and following drug administration in patients with factor VII deficiency. Suspect antibody formation if factor VIIa activity fails to reach the expected level, PT is not corrected, or bleeding is not controlled after treatment with recommended dosages of factor VIIa (recombinant) and perform appropriate screening tests. (See Adequate Patient Evaluation and Monitoring under Cautions.)

Adequate Patient Evaluation and Monitoring

Monitor patients with congenital factor VII deficiency receiving factor VIIa (recombinant) for evidence of antibody development. (See Development of Antibodies to Factor VII under Cautions.)

Evaluate hemostasis to determine effectiveness of factor VIIa (recombinant) and need for dosage adjustments. Laboratory parameters (e.g., PT/INR, aPTT, plasma factor VII clotting activity) have not been shown to correlate directly with hemostasis; furthermore, coagulation assays may produce different results depending on the specific reagent used.

Administration of factor VIIa (recombinant) generally shortens PT and aPTT and has been shown to rapidly normalize INR; however, clinical importance not known.

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., including anaphylactic shock, flushing, urticaria, rash, angioedema) reported. Administer with caution in patients with known hypersensitivity to factor VIIa (recombinant) or any ingredient in the formulation.

Factor VIIa (recombinant) contains trace amounts of animal protein which may stimulate antibody production and cause hypersensitivity reactions. Use with caution in patients with known hypersensitivity to murine, hamster, or bovine proteins.

If severe hypersensitivity or anaphylaxis occurs, discontinue drug immediately and initiate appropriate therapy.

Specific Populations

Pregnancy

Category C.

Thrombotic events have been reported in women without a bleeding disorder receiving factor VIIa (recombinant) for uncontrolled postpartum hemorrhage. (See Thromboembolic Events under Cautions.)

Lactation

Not known whether factor VIIa (recombinant) is distributed into human milk. Discontinue nursing or the drug.

Pediatric Use

NovoSeven RT has not been evaluated in patients ≤16 years of age to determine if there are differences in safety and efficacy among various pediatric age groups. The predecessor product (NovoSeven) has been used in pediatric patients 0–16 years of age; no substantial differences in safety and efficacy relative to adults.

In clinical trials, dosing in pediatric patients was determined according to body weight and not age.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients. Potential risk of adverse thromboembolic events in geriatric patients; use with caution. (See Thromboembolic Events under Cautions.)

Common Adverse Effects

Fever, hemorrhage, injection site reaction, arthralgia, headache, BP changes (hypotension or hypertension), nausea, vomiting, pain, edema, rash.

General

• Administer only under direct supervision of a clinician experienced in the management of bleeding disorders.

• Adjust dose and dosing interval based on severity of bleeding and hemostatic response.

• Coagulation parameters (e.g., PT/INR, aPTT, plasma factor VII clotting activity [FVII:C]) have not been shown to directly correlate with hemostatic response. (See Adequate Patient Evaluation and Monitoring under Cautions.)

Administration

IV Administration

Administer by slow (over 2–5 minutes) IV injection.

Has been given as a continuous IV infusion^{† [off-label]}; however, manufacturer states that the drug should not be admixed with any IV infusion solutions. If flushing of the line is necessary prior to and following drug administration, use 0.9% sodium chloride injection.

Reconstitution

Select appropriate vial size and diluent based on indicated dosage. Prior to reconstitution, allow lyophilized powder and diluent supplied by manufacturer (histidine diluent) to warm to room temperature (≤37°C).

Reconstitute vials containing 1, 2, or 5 mg of lyophilized factor VIIa (recombinant) with 1.1, 2.1, or 5.2 mL of histidine diluent, respectively, to provide a solution containing approximately 1 mg/mL (1000 mcg/mL). Reconstitute only with the histidine diluent provided by manufacturer; do not use sterile water for injection or any other diluent.

Direct diluent toward side of vial; do not inject directly onto powder.

Gently swirl solution until all the powder is dissolved.

May store reconstituted solutions under refrigeration or at room temperature, but administer within 3 hours after reconstitution; discard any unused solution after 3 hours.

Dosage

Pediatric Patients

Hemophilia A or B with Inhibitors

Hemorrhagic Episodes

90 mcg/kg every 2 hours until hemostasis achieved or response to drug is inadequate; doses of 35–120 mcg/kg have been used successfully in clinical studies.

For severe bleeding episodes, continue treatment every 3–6 hours after hemostasis is achieved to prevent recurrence of bleeding. Optimum duration of therapy not established; minimize duration of posthemostatic dosing. (See Posthemostatic Dosing under Cautions.)

Surgical Prophylaxis

Minor surgery: 90 mcg/kg immediately prior to procedure; repeat every 2 hours during procedure. Continue every 2 hours postoperatively for 48 hours, then every 2–6 hours until healing achieved.

Major surgery: 90 mcg/kg immediately prior to procedure; repeat every 2 hours during procedure. Continue every 2 hours postoperatively for 5 days, then every 4 hours until healing achieved. Administer additional doses, if required.

Acquired Hemophilia

IV

70–90 mcg/kg every 2–3 hours until hemostasis achieved.

Factor VII Deficiency

Hemorrhagic Episodes and Surgical Prophylaxis

15–30 mcg/kg every 4–6 hours until hemostasis achieved. Although minimum effective dose not established, manufacturer states that doses as low as 10 mcg/kg have been effective.

Individualize dose and dosing frequency. Monitor PT and plasma factor VII clotting activity (FVII:C) prior to and following administration. Consider possibility that antibodies to factor VII may have developed if therapeutic response or expected factor VII levels are not achieved with calculated dosages. (See Development of Antibodies to Factor VII under Cautions.)

Adults

Hemophilia A or B with Inhibitors

Hemorrhagic Episodes

90 mcg/kg every 2 hours until hemostasis achieved or response to drug is inadequate; doses of 35–120 mcg/kg have been used successfully in clinical studies.

For severe bleeding episodes, continue treatment every 3–6 hours after hemostasis is achieved to prevent recurrence of bleeding. Optimum duration of therapy not established; minimize duration of posthemostatic dosing. (See Posthemostatic Dosing under Cautions.)

Surgical Prophylaxis

Minor surgery: 90 mcg/kg immediately prior to procedure; repeat every 2 hours during procedure. Continue every 2 hours for 48 hours postoperatively, then every 2–6 hours until healing achieved.

Major surgery: 90 mcg/kg immediately prior to procedure; repeat every 2 hours during procedure. Continue every 2 hours postoperatively for 5 days, then every 4 hours until healing achieved. Administer additional doses, if required.

Acquired Hemophilia

IV

70–90 mcg/kg every 2–3 hours until hemostasis achieved.

Factor VII Deficiency

Hemorrhagic Episodes and Surgical Prophylaxis

15–30 mcg/kg every 4–6 hours until hemostasis achieved. Although minimum effective dose not established, manufacturer states that doses as low as 10 mcg/kg have been effective.

Individualize dose and dosing frequency. Consider possibility that antibodies to factor VII may have developed if therapeutic response or expected factor VII levels are not achieved with calculated dosages. (See Development of Antibodies to Factor VII under Cautions.)

Specific Drugs