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.
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 (Astermark 2007; manufacturer’s labeling). 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 (manufacturer’s labeling).
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).
There are no dosage adjustments provided the in manufacturer’s labeling.
There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.
(For additional information see "Factor VIIa (activated), recombinant human: Pediatric drug information")
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.
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling; use with caution.
Refer to adult dosing.
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]
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous:
NiaStase RT: 1 mg (1 ea); 2 mg (1 ea); 5 mg (1 ea) [contains polysorbate 80]
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.
Parenteral: IV administration only:
NovoSeven RT: Use NS to flush line (if necessary) before and after administration.
Intermittent IV: Administer as a slow bolus over 2 to 5 minutes. Do not mix with other infusion solutions.
Continuous 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: Intermittent IV: Administer over ≤2 minutes Do not mix with other infusion solutions.
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.
Intracranial hemorrhage associated with danaparoid; Intracranial hemorrhage associated with low molecular weight heparin (if protamine is contraindicated); Refractory bleeding after cardiac surgery in nonhemophiliac patients; Secondary prophylaxis of bleeding events in congenital hemophilia A or B with inhibitors
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
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.
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).
None known.
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. Risk D: Consider therapy modification
Factor XIII A-Subunit (Recombinant): May enhance the thrombogenic effect of Factor VIIa (Recombinant). Risk C: Monitor therapy
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).
It is not known if factor VIIa (recombinant) is present in breast milk. According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.
Some products may contain sodium.
Hemoglobin and hematocrit; evidence of hemostasis; blood loss; signs/symptoms of thrombosis. Note: There are no reliable laboratory tests to measure recombinant factor VIIa efficacy. Tests used to monitor hemostatic efficacy, such as PT/INR, aPTT, factor activity assays, and thromboelastography, are not useful. In factor VII deficient patients, monitor for factor VII antibodies if the expected clinical response is not achieved with recommended doses.
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.
Hemophilia:
Distribution: 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.
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.
Excretion: 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:
Distribution: Vss: 230 ± 70 mL/kg.
Half-life, terminal: 2.62 ± 0.63 hours.
Excretion: Clearance: 67.7 ± 17.9 mL/kg/hour.
Solution (reconstituted) (NovoSeven RT Intravenous)
1 mg (0 Price provided is per microgram): $2.98
2 mg (0 Price provided is per microgram): $2.98
5 mg (0 Price provided is per microgram): $2.98
8 mg (0 Price provided is per microgram): $2.98
Solution (reconstituted) (Sevenfact Intravenous)
1 mg (per each): $2,748.00
5 mg (per each): $13,740.00
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.