NovoSeven RT

Blood Coagulation Factors

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. The solution should be clear and colorless.
Coagulation parameters do not necessarily correlate with or predict the effectiveness of treatment. These parameters can be used to adjust treatment schedules, if necessary.[30132] [65187]

Reconstitution
NovoSeven RT (powder and histidine diluent vial)
Bring the powder and diluent to room temperature, but not above 37 degrees C (98.6 degrees F).
Use syringe needles with a gauge size of 20 to 26.
Inject air into the histidine diluent vial and withdraw the quantity required.
For a final concentration of 1 mg/mL, use the following volume to reconstitute:
1 mg vial = 1.1 mL diluent
2 mg vial = 2.1 mL diluent
5 mg vial = 5.2 mL diluent
8 mg vial = 8.1 mL diluent
Insert the syringe needle containing the diluent into the powder vial, aiming the needle against the side of the vial so that the stream of liquid runs down the side of the vial. Do not inject the diluent directly onto the powder.
Gently swirl the vial until all the material is dissolved.
Inject air into the vial of reconstituted solution using a sterile syringe and withdraw the appropriate dose.
Storage: Store the reconstituted solution at room temperature or refrigerated for up to 3 hours. Do not freeze or store in syringes.[30132]
 
NovoSeven RT (powder and pre-filled histidine diluent syringe)
Bring the powder and diluent to room temperature, but not above 37 degrees C (98.6 degrees F).
For a final concentration of 1 mg/mL, use the following volume to reconstitute:
1 mg vial = 1 mL diluent
2 mg vial = 2 mL diluent
5 mg vial = 5 mL diluent
8 mg vial = 8 mL diluent
Place the vial adapter onto the powder vial.
Insert the plunger rod into the syringe, then screw a few turns until resistance is felt.
Screw the prefilled syringe onto the vial adapter.
Slowly inject the diluent into the vial. Keep the plunger rod pressed down and swirl the vial gently until the powder is dissolved.
Invert the vial and allow the solution to fill the syringe. Pull the plunger rod downward to draw the mixed solution into the syringe.
Tap the syringe to remove air bubbles and withdraw the required dose.
Storage: Store the reconstituted solution at room temperature or refrigerated for up to 3 hours. Do not freeze or store in syringes.[30132]
 
Sevenfact
Inspect contents of the kit(s). Make sure each vial has a matching colored syringe.
Bring the powder and diluent to room temperature.
For a final concentration of 1 mg/mL, use the following volume to reconstitute:
1 mg vial = 1.1 mL diluent
5 mg vial = 5.2 mL diluent
Place the vial adapter onto the powder vial.
Screw the prefilled syringe onto the vial adapter.
Insert the plunger rod into the syringe, then screw a few turns, so the plunger rod is attached to the gray rubber stopper in the syringe.
Slowly inject the diluent into the vial. Keep the plunger rod pressed down and swirl the vial gently until the powder is dissolved.
Without withdrawing drug back into the syringe, unscrew the syringe from the vial.
Withdraw the reconstituted solution using an infusion syringe large enough to hold the dose.
Storage: Store the reconstituted solution at room temperature or between 36 to 86 degrees F (2 to 30 degrees C) for up to 4 hours. Do not freeze or store in syringes.[65187]
 
Intermittent IV Infusion
NovoSeven RT
Administer as a slow IV bolus over 2 to 5 minutes, depending upon the dose administered.
Use 0.9% Sodium Chloride Injection if the line needs to be flushed before or after administration.
Do not mix with other infusion solutions.
Caution: The prefilled diluent syringe is made of glass with an internal tip diameter of 0.037 inches, and is compatible with a standard Luer-lock connector. Some needleless connectors are incompatible with the glass diluent syringes; use can damage the connector and affect administration. To administer the product through incompatible needleless connectors, withdraw the reconstituted product into a standard 10 mL sterile Luer-lock plastic syringe.[30132]
 
Sevenfact
Administer as a slow IV bolus over 2 minutes.
Do not mix with other infusion solutions.[65187]
 
Continuous IV Infusion
NovoSeven RT
Administer at a rate of 50 mcg/kg/hour using an infusion pump.
Use 0.9% Sodium Chloride Injection if the line needs to be flushed before or after administration.[30132]
Previous recommendations (i.e., to add heparin or low molecular weight heparin to the factor VII concentrate) are no longer commonly used. Heparin leads to a 20% to 30% loss of factor VIIa activity, and low molecular weight heparin causes aggregation, although a loss in activity is not apparent.[32320] [32809]
When administered via a WalkMed infusion pump system at a rate of 0.3 mL/hour at 25 degrees C, factor VIIa concentrates were stable after 3 days. Similarly, when administered via a WalkMed 350, Meddex 2001 syringe, or a CADD-Plus minipump at a rate of 0.1 mL/hour, factor VIIa concentrates were stable after 3 days when protected from light and kept at room temperature.[32808]

thrombosis / Delayed / 0.2-4.0
thromboembolism / Delayed / 0.2-4.0
increased intracranial pressure / Early / 1.5-1.5
disseminated intravascular coagulation (DIC) / Delayed / 0-1.0
stroke / Early / Incidence not known
pulmonary embolism / Delayed / Incidence not known
myocardial infarction / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
anaphylactic shock / Rapid / Incidence not known

hypertension / Early / 2.0-2.0
phlebitis / Rapid / 1.3-1.3
dyspnea / Early / 0.7-0.7
antibody formation / Delayed / Incidence not known
angina / Early / Incidence not known
infusion-related reactions / Rapid / Incidence not known
wheezing / Rapid / Incidence not known

dizziness / Early / 13.0-13.0
headache / Early / 0-6.5
fever / Early / 0-4.0
nausea / Early / 0-1.0
rash / Early / Incidence not known
pruritus / Rapid / Incidence not known
arthralgia / Delayed / Incidence not known

Serious arterial and venous thrombotic events may occur with recombinant factor VIIa (rFVIIa) administration. Monitor patients for signs and symptoms of activation of the coagulation system and for thrombosis. Discontinue or dose reduce rFVII, depending on the patient's condition, when there is laboratory confirmation of intravascular coagulation or the presence of clinical thrombosis. Patients with a history of congenital or acquired hemophilia receiving concomitant treatment with activated or non-activated prothrombin complex (aPCC/PCC) or other hemostatic agents, arteriosclerosis, coronary artery disease, cerebrovascular disease, crush injury (trauma), sepsis, or thromboembolism may have an increased risk of thromboembolic events. There is limited information about the safety of rFVIIa in patients with a history of arterial or venous thromboembolic disease because these patients were excluded from clinical trials.[30132] [65187] Two meta-analyses of pooled data collected in patients receiving rFVIIa for intracerebral hemorrhage, advanced hepatic disease, trauma, cardiac surgery, spinal surgery, and other therapeutic areas showed a higher risk of thrombotic events in patients receiving rFVIIa compared to placebo (10% vs. 7.5%). Arterial thromboembolic events, including myocardial infarction, myocardial ischemia, cerebral infarction, and cerebral ischemia, were significantly increased in patients receiving rFVIIa compared to placebo (5.3% to 5.6% vs. 2.8% to 3%). Venous thromboembolic events did not occur more frequently than placebo in patients receiving rFVIIa (4.8% vs. 4.7%). One clinical study in elderly non-hemophilia intracerebral hemorrhage patients also reported an increased risk of arterial thromboembolic events, including myocardial ischemia, myocardial infarction, and cerebral ischemia and/or infarction.[31727] In addition, since the approval of rFVIIa, 220 reports describing 246 thromboembolic events (arterial, venous, and those involving devices) have been reported to the FDA in patients receiving rFVIIa (data collected through November 1, 2005). It should be noted that approximately 87% of these reports have been in patients receiving rFVIIa for off-label indications.[32139]

NovoSeven RT, SevenFACT

Rx

Glycoprotein similar to human plasma-derived factor VII, a vitamin K-dependent factor
Used for the treatment of acute bleeding and perioperative management of patients with hemophilia A or B with inhibitors, congenital factor VII deficiency, Glanzmann's thrombasthenia with refractoriness to platelet transfusions, and acquired hemophilia
Potential for thrombotic events

90 mcg/kg/dose IV every 2 hours until hemostasis is achieved or the treatment has been deemed inadequate. Adjust dose and interval based on the severity of bleeding. For joint or muscle bleeds, a decision on outcome was reached for most patients within 8 doses, although more doses were required for severe bleeds. For severe bleeds, continue 90 mcg/kg/dose IV every 3 to 6 hours thereafter to maintain the hemostatic plug; monitor and minimize the duration of any post-hemostatic dosing.[30132]

90 mcg/kg/dose IV every 2 hours until hemostasis is achieved or the treatment has been deemed inadequate. Adjust dose and interval based on the severity of bleeding. For joint or muscle bleeds, a decision on outcome was reached for most patients within 8 doses, although more doses were required for severe bleeds. For severe bleeds, continue 90 mcg/kg/dose IV every 3 to 6 hours thereafter to maintain the hemostatic plug; monitor and minimize the duration of any post-hemostatic dosing.[30132]

Dose, frequency, and duration of treatment depend on the location and severity of bleeding, need for urgent hemostasis, known patient responsiveness to FVIIa-containing bypassing agents, clinical response, and hemostasis evaluation. For mild to moderate bleeding, give 75 mcg/kg/dose IV every 3 hours until hemostasis is achieved or 225 mcg/kg/dose IV initially followed by 75 mg/kg/dose IV every 3 hours if hemostasis is not achieved within 9 hours of the initial dose. Consider alternative treatments if control of bleeding does not occur within 24 hours. For severe bleeding, give 225 mcg/kg/dose IV initially followed by 75 mcg/kg/dose IV every 2 hours if hemostasis is not achieved 6 hours after the initial dose. Continue treatment to support healing and prevent recurrent bleeding.[65187]

Dose, frequency, and duration of treatment depend on the location and severity of bleeding, need for urgent hemostasis, known patient responsiveness to FVIIa-containing bypassing agents, clinical response, and hemostasis evaluation. For mild to moderate bleeding, give 75 mcg/kg/dose IV every 3 hours until hemostasis is achieved or 225 mcg/kg/dose IV initially followed by 75 mg/kg/dose IV every 3 hours if hemostasis is not achieved within 9 hours of the initial dose. Continue treatment to support healing and maintain the hemostatic plug. Consider alternative treatments if control of bleeding does not occur within 24 hours. For severe bleeding, give 225 mcg/kg/dose IV initially followed by 75 mcg/kg/dose IV every 2 hours if hemostasis is not achieved 6 hours after the initial dose. Continue treatment to support healing and prevent recurrent bleeding.[65187]

For minor surgery, 90 mcg/kg/dose IV immediately before surgery, then every 2 hours during surgery and for 48 hours postoperatively, then every 2 to 6 hours until healing occurs. For major surgery, 90 mcg/kg/dose IV immediately before surgery, then every 2 hours during surgery and for 5 days postoperatively, then every 4 hours or by continuous infusion at 50 mcg/kg/hour until healing occurs.[30132]

For minor surgery, 90 mcg/kg/dose IV immediately before surgery, then every 2 hours during surgery and for 48 hours postoperatively, then every 2 to 6 hours until healing occurs. For major surgery, 90 mcg/kg/dose IV immediately before surgery, then every 2 hours during surgery and for 5 days postoperatively, then every 4 hours or by continuous infusion at 50 mcg/kg/hour until healing occurs.[30132]

For minor surgery, 90 to 120 mcg/kg/dose IV preoperatively, then every 2 hours for up to 4 doses. For intermediate surgery, 120 mcg/kg/dose IV preoperatively and every 2 hours through surgery, followed by 90 to 120 mcg/kg/dose IV every 2 hours thru day 1, every 3 hours on day 2, every 4 hours on days 3 thru 5, and every 6 hours on days 6 thru 14. For major surgery, follow intermediate surgery intermittent infusion dosing or give 15 to 50 mcg/kg/hour continuous IV infusion through postoperative day 14.[32800]

For minor surgery, 120 to 150 mcg/kg/dose IV preoperatively, then every 3 to 6 hours for 24 hours. For intermediate surgery, 150 mcg/kg/dose IV preoperatively and every 2 hours through surgery, followed by 90 to 120 mcg/kg/dose IV every 2 hours thru day 1, every 3 hours on day 2, every 4 hours on days 3 thru 5, and every 6 hours on days 6 thru 14. For major surgery, follow intermediate surgery intermittent infusion dosing or give 15 to 50 mcg/kg/hour continuous IV infusion through postoperative day 14.[32800]

15 to 30 mcg/kg/dose IV every 4 to 6 hours until hemostasis is achieved; adjust dose and frequency to each individual patient. Doses as low as 10 mcg/kg have been effective.[30132]

15 to 30 mcg/kg/dose IV every 4 to 6 hours until hemostasis is achieved; adjust dose and frequency to each individual patient. Doses as low as 10 mcg/kg have been effective.[30132]

15 to 30 mcg/kg/dose IV immediately before surgery, then every 4 to 6 hours during surgery and until hemostasis is achieved; adjust dose and duration to each individual patient. Doses as low as 10 mcg/kg have been effective.[30132]

15 to 30 mcg/kg/dose IV immediately before surgery, then every 4 to 6 hours during surgery and until hemostasis is achieved; adjust dose and duration to each individual patient. Doses as low as 10 mcg/kg have been effective.[30132]

90 mcg/kg/dose IV every 2 to 6 hours until hemostasis is achieved.[30132]

90 mcg/kg/dose IV every 2 to 6 hours until hemostasis is achieved.[30132]

90 mcg/kg/dose IV immediately before surgery, then every 2 hours during surgery, then every 2 to 6 hours postoperatively to prevent bleeding. Higher doses of 100 to 140 mcg/kg can be used in patients who have clinical refractoriness with or without platelet-specific antibodies.[30132]

90 mcg/kg/dose IV immediately before surgery, then every 2 hours during surgery, then every 2 to 6 hours postoperatively to prevent bleeding. Higher doses of 100 to 140 mcg/kg can be used in patients who have clinical refractoriness with or without platelet-specific antibodies.[30132]

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

70 to 90 mcg/kg/dose IV immediately before surgery, then every 2 to 3 hours during surgery and until hemostasis is achieved.[30132]

Experience with factor VIIa in von Willebrand's patients is limited. Two patients were treated with tranexamic acid and factor VIIa 150 to 200 mcg/kg IV initially followed by 90 mcg/kg IV every 2 hours for 48 hours during and after extensive dental surgery. This treatment provided effective hemostasis in these patients.[25757]

Dosage not established. 100 mcg/kg IV every 2 to 6 hours for 8 doses or 200 mcg/kg IV once followed by 100 mcg/kg IV every 2 to 6 hours up to a total dose of 300 mcg/kg or 600 mcg/kg has been used.[59394]  Guidelines do not recommend.[64335]

35 to 90 mcg/kg IV as a single dose. Use is controversial and rare. Guidelines suggest consideration of use only for life-threatening hemorrhage when all other medical and surgical interventions have been exhausted.

†Indicates off-label use

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

Anti-inhibitor Coagulant Complex: (Major) Avoid concomitant use of recombinant factor VIIa and activated prothrombin complex concentrates (aPCCs) due to the increased risk for thrombotic events.
Factor XIII A-Subunit, Recombinant: (Major) Concomitant use of recombinant factor XIII A-subunit with factor VIIa, recombinant may result in thrombosis. However, no clinical or nonclinical human studies have been performed with recombinant factor XIII A-subunit and recombinant factor VIIa at recommended human doses. Simultaneous use of factor VIIa, recombinant and recombinant factor XIII A-subunit should be avoided due to the potential for thrombosis.
Factor XIII Concentrate: (Major) The risk of potential interaction between factor VIIa, recombinant and coagulation factor concentrates has not been adequately evaluated. Simultaneous use of factor VIIa, recombinant and factor XIII concentrate should be avoided due to the potential for thrombosis.

Coagulation Factor VIIA Recombinant Human/SevenFACT Intravenous Inj Pwd: 1mg, 5mg
NovoSeven RT Intravenous Inj Pwd F/Sol: 1000mcg, 2000mcg, 5000mcg, 8000mcg

Specific maximum dosage information is not available. Individualize dosage based on the indication, location and extent of bleeding, need for urgent hemostasis, and known patient responsiveness to factor VIIa-containing bypassing agents during prior bleeding events. Cumulative daily doses more than 900 mcg/kg, which may be associated with a greater risk of thromboembolic complications, have not been studied.

Recombinant factor VIIa (rFVIIa) functions as native activated factor VII (FVIIa) in the plasma. Recombinant factor VIIa may exert its effects through tissue factor (TF) dependent or independent mechanisms or, most likely, a combination of these mechanisms. TF is normally located in the deeper layers of the vessel wall without any direct contact with the circulation. Low concentrations of FVIIa are constitutively present in serum accounting for about 1% (4 mg/mL) of the total amount of factor VII protein. At the site of tissue injury, TF and FVIIa form complexes and initiate the extrinsic coagulation cascade by activating factor IX and factor X. Factor Xa, in combination with other factors, then converts prothrombin to thrombin leading to the formation of a hemostatic plug and local hemostasis by conversion of fibrinogen into fibrin. At concentrations obtained therapeutically, rFVIIa activates enough factor IX and X on the surface of activated platelets to restore the formation of thrombin by platelets. This would allow each platelet to produce more thrombin leading to a stable fibrin network even in the absence of an optimal initial platelet plug. Localization of rFVIIa on activated platelets would tend to restrict the activity of rFVIIa to the sites of injury. In addition, the platelet surface activity of rFVIIa could explain its effect in patients with thrombocytopenia and platelet function defects.[25749]
 
Administration of rFVIIa reduces the prothrombin time (PT) and activated partial thromboplastin time (aPTT) in patients with factor VII deficiency and hemophilia patients. In patients with hemophilia A/B with inhibitors, the PT shortened to about a 7-second plateau at a FVII:C concentration of approximately 5 Units/mL. For FVII:C concentrations more than 5 Units/mL, there is not further change in PT. Administration of rFVIIa shortens the prolonged aPTT in hemophilia A/B patients with inhibitors; however, normalization is usually not observed in doses shown to induce clinical improvement. These changes do not result in a hypercoagulable state or thrombotic events since the activity of rFVIIa seems to be restricted to the site of injury. The amount of thrombin and factor Xa generated in the presence of rFVIIa is not higher than that in normal plasma. The onset of generation of factor Xa and thrombin is earlier in the presence of rFVIIa than without rFVIIa.[25750]

Recombinant factor VIIa (rFVIIa) is administered intravenously. Half-life is approximately 1.5 to 3 hours.[30132] [65187]
 
Affected cytochrome P450 isoenzymes and drug transporters: none

NovoSeven RT
Hemophilia A or B
Pharmacokinetic parameters after a single 17.5, 35, or 70 mcg/kg IV dose (n = 15) were as follows: Vd = 108.86 mL/kg; AUC = 53.31 units/mL x hour; CL = 33.84 mL/kg/hour; half-life = 2.72 hours; mean residence time (MRT) = 3.33 hours. Pharmacokinetic parameters after a single 90 mcg/kg IV dose (n = 6) were as follows: Vd = 121 mL/kg; AUC = 2.45 units/mL x hour; CL = 37.6 mL/kg/hour; half-life = 3.2 hours; MRT = 3.31 hours; incremental recovery (IR) = 0.94 units/dL per units/kg.[30132]
 
FVII deficiency
Pharmacokinetic parameters after a single 30 mcg/kg IV dose (n = 5) were as follows: Vd = 230 mL/kg; AUC = 23.7 units/mL x hour; CL = 67.7 mL/kg/hour; half-life = 2.62 hours; MRT = 3.46 hours; IR = 0.53 units/dL per units/kg.[30132]
 
Sevenfact
Cmax occurred 5 minutes after infusion. Observed plasma concentration-time profiles show a biexponential decay from Cmax to return to baseline approximately 8 hours after dosing. Pharmacokinetic parameters for the 75 mcg/kg dose group (n = 6) were as follows: Vd = 19.9 L; Cmax = 566.2 ng/mL; AUC = 589.1 ng/mL x hour; CL = 8 L/hour; half-life = 1.7 hours. Pharmacokinetic parameters for the 225 mcg/kg dose group (n = 5) were as follows: Vd = 11.9 L; Cmax = 2,440.6 ng/mL; AUC = 2,841.2 ng/mL x hour; CL = 5.8 L/hour; half-life = 1.4 hours.[65187]

There are no adequate and well-controlled studies of recombinant factor VIIa (rFVIIa) in pregnant women to determine if there is a drug-related risk. It is unknown whether rFVIIa can cause fetal harm during human pregnancy.[30132] [65187] Treatment of rats and rabbits has been associated with mortality at doses up to 5 to 6 mg/kg; no evidence of teratogenicity was observed.[30132] Factor VII concentrates have been given to pregnant women with factor VII deficiency during the peripartum and postpartum periods to minimize bleeding.[25758]

There is no information regarding the presence of recombinant factor VIIa (rFVIIa) in human milk, the effect on the breast-fed infant, or the effects on milk production. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition.[30132] [65187] If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.