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Factor VIIa (Systemic)



INN:

Eptacog alfa

VA CLASSIFICATION
Primary: BL116

Commonly used brand name(s): NovoSeven.

Other commonly used names are:
Coagulation factor VIIa (recombinant), factor 7, proconvertin, recombinant activated factor VII, recombinant coagulation factor VIIa, recombinant factor VIIa, and rFVIIa. Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Antihemorrhagic—

Indications

General considerations
Factor VIIa (rFVIIa) is only indicated for use in hemophilia A and B patients who have developed inhibitor antibodies to factor VIII (antihemophilic factor) or factor IX{01}.


Accepted

Hemophilia A, hemorrhagic complications of (treatment)—Factor VIIa is indicated for the control of bleeding events in hemophilia A patients with inhibitor antibodies to factor VIII or factor IX{01}.

Hemophilia B, hemorrhagic complications of (treatment)—Factor VIIa is indicated for the control of bleeding events in hemophilia B patients with inhibitor antibodies to factor VIII or factor IX{01}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Factor VIIa (rFVIIa) is cloned in baby hamster kidney cells (BHK cells) and secreted in its single-chain form into the culture medium (containing newborn calf serum){01}. It is then proteolitically converted by autocatalysis to the active two-chain form (rFVIIa) in a chromatographic purification process{01}. The purification process removes exogenous viruses, such as MuLV, SV40, Pox Virus, Reovirus, BEV, IBR virus{01}. The production and formulation of factor VIIa does not use any human serum or proteins{01}.
Molecular weight—
    50K Dalton {01}

Mechanism of action/Effect:

Factor VIIa is a vitamin K-dependent glycoprotein made up of 406 amino acid residues, and is structurally similar to human plasma-derived factor VIIa{01}. It promotes hemostasis by complexing with tissue factor and activating coagulation factors in the intrinsic pathway: factor X to factor Xa, and factor IX to factor IXa{01}. Activated factor X (factor Xa), complexed with other factors, converts prothrombin to thrombin and fibrinogen to fibrin to form a hemostatic plug {01}.

Absorption:

44% (median plasma recovery){01}.


Distribution:


VolD:

103 mL/kg (apparent, median at steady state) {01}.


Half-life:

Elimination: 2.3 hours (median){01}.


Duration of action:

3 hours (median residence time){01}.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients with a history of allergies, especially those who are allergic to or have known hypersensitivity to mouse, hamster, or bovine proteins{01}.

Carcinogenicity

No evidence of carcinogenicity was found in two mutagenicity studies; no chronic carcinogenicity studies have been performed with factor VIIa{01}.

Mutagenicity

No chromosomal aberrations were found in either in vitro studies (cultured human lymphocytes) or in vivo studies (mouse micronucleus test). Other mutagenicity studies such as the Ames test have not been conducted with factor VIIa{01}.

Pregnancy/Reproduction
Fertility—
Doses up to 3 mg/kg/day of factor VIIa had no effect on mating performance, fertility, or litter characteristics in male and female rats{01}.

Pregnancy—
Studies have not been done in humans{01}. Studies in rats and rabbits showed mortality was associated with doses up to 6 and 5 mg/kg, respectively{01}. In rabbits given doses of 5 mg/kg, an abortion rate of 2 of 25 litters was reported{01}. In rats given doses of 6 mg/kg, the abortion rate was 0 of 25 litters, but only 23 of the 25 rats gave birth successfully as 2 of those 25 litters died during the early period of lactation{01}. No evidence of teratogenicity was detected in the studies with rats or rabbits{01}.

FDA Pregnancy Category C{01}.


Labor and delivery—

Factor VIIa was given to a female patient with endogenous factor VII deficiency during vaginal delivery (36 mcg/kg) and during tubal ligation (90 mcg/kg){01}. No adverse reactions were reported during labor, delivery, or the tubal ligation{01}.

Breast-feeding

It is not known whether factor VIIa is distributed into human breast milk{01}. Because of the potential for serious adverse effects in nursing infants, a decision should be made to either stop breast-feeding or discontinue using factor VIIa{01}.

Pediatrics

No differences in safety or efficacy were identified in any age group from infants to adolescents (0 to 16 years of age){01}. Dosing in clinical trials was determined according to body weight and not according to age{01}.


Geriatrics


Factor VIIa was not studied in geriatric patients{01}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

» Activated prothrombin complex concentrates or
» Prothrombin complex concentrates    (concurrent use is not recommended with factor VIIa{01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Hypersensitivity to recombinant factor VIIa or other product components{01}
» Hypersensitivity to mouse, hamster, or bovine proteins{01}
Risk-benefit should be considered when the following medical problems exist
Advanced atherosclerotic disease or
Crush injury or
Disseminated intravascular coagulation (DIC) or
Septicemia or
Signs or symptoms of coagulation system activation or
Thrombosis    (increased risk of thrombotic events{01})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Activated partial thromboplastin time (aPTT)
Plasma factor VII clotting activity (FVII:C)
Prothrombin time (PT)    (Laboratory coagulation parameters have shown no direct correlation to the achievement of hemostasis, but they may be used as an adjunct in monitoring the effectiveness and dosing schedule of factor VIIa{01}. Different assay reagents may yield different results for these assays{01}. If patients develop signs or symptoms of activation of the coagulation system or thrombosis, they should be monitored{01}. When there is laboratory confirmation of intravascular coagulation or presence of clinical thrombosis, factor VIIa dosage should be reduced or the treatment stopped, depending on the patients symptoms.{01} )




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent—³2%
    
Fever{01}
    
fibrinogen plasma decreased {01}or
hemorrhage (not otherwise specified){01} (bleeding problems)
    
hemarthrosis{01} (joint pain and/or stiffness)
    
hypertension{01} (high blood pressure )

{01}Incidence less frequent or rare—1%
    
Anaphylaxis or other allergic reaction to factor VIIa, or to mouse, hamster, or bovine protein{01} (changes in facial color; fast or irregular breathing; puffiness or swelling of eyelids or around the eyes; shortness of breath; tightness in chest; wheezing; skin rash ; hives; itching)
    
bradycardia{01} (slow or irregular heartbeat [less than 50 beats per minute])
    
coagulation disorders, including decreased prothrombin or increased fibrinolysis{01} (bleeding problems), disseminated intravascular coagulation{01} (cyanosis [bluish color], especially of the hands and feet; ecchymoses at injection sites [large, nonelevated blue or purplish patches on the skin]; excessive sweating ; persistent bleeding or oozing from puncture sites or mucous membranes [bowel, mouth, nose, or urinary bladder])
    
edema{01} (bloating or swelling of face, hands, lower legs, and/or feet)
    
hypotension{01} (faintness; dizziness; lightheadedness when getting up from a lying or sitting position; chills ; cold sweats; confusion; fast heartbeat; shakiness; slurred speech ; blurred vision; unusual tiredness or weakness )
    
pneumonia{01} ( chest pain; cough; fever or chills; sneezing; shortness of breath; sore throat; troubled breathing; tightness in chest ; wheezing)
    
pruritus{01} (itchy skin)
    
renal dysfunction{01} (high blood pressure; shortness of breath, troubled breathing, tightness in chest, and/or wheezing; sudden decrease in the amount of urine; swelling of face, fingers, feet, and/or lower legs; continuing thirst ; unusual tiredness or weakness; weight gain)
{01}
{01}

Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent or rare—1%
    
Arthrosis{01} (pain or stiffness in muscles or joints)
    
headache{01}
    
injection site reaction (burning or stinging at injection site; changes in blood pressure or pulse rate; chills; drowsiness ; fever; flushing [rednesss of face]; headache; nausea or vomiting; shortness of breath)
    
purpura{01} (pinpoint red or purple spots on skin)
    
skin rash{01}
    
vomiting{01}
{01}
{01}



Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose
No complications from overdose were observed in two cases of accidental overdose by bolus administration {01}. However, because there is a lack of information on dose-limiting toxicities, the recommended dosing schedule should not be exceeded intentionally {01}.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Factor VIIa (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to factor VIIa or to mouse, hamster, or bovine protein{01}
Other medications, especially activated prothrombin complex concentrates or prothrombin complex concentrates.

Precautions while using this medication
Notifying physicians if early signs of hypersensitivity reactions occur, including hives, urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis


Side/adverse effects
Signs of potential side effects, especially fever, fibrinogen plasma decreased, hemorrhage, hemarthrosis, hypertension, anaphylaxis or other allergic reactions, bradycardia, coagulation disorders, including decreased prothrombin or increased fibrinolysis, or disseminated intravascular coagulation, edema, hypotension, pneumonia, pruritus, or renal dysfunction,


Parenteral Dosage Forms

FACTOR VIIa (RECOMBINANT)

Usual Adult and Adolescent Dose

Usual adult dose

Note: Factor VIIa is indicated for hemophilia A or B patients with inhibitor antibodies to Factor VIII or Factor IX {01}.

Treatment of hemorrhage
Intravenous, 90 mcg/kg administered as a slow (over 2 to 5 minutes) bolus every two hours until hemostasis is achieved or until the treatment is deemed to be inadequate {01}.


Note: Doses between 35 and 120 mcg/kg have been used in clinical trials, and both the dose and interval may be adjusted based on the severity of the bleeding and degree of hemostasis desired {01}.
The minimal effective dose has not been established {01}. The majority of adverse effects were reported in patients who received more than twelve doses {01}.
Post-Hemostatic Dosing: The appropriate duration of post-hemostatic dosing has not been studied{01}. For severe bleeds, dosing should continue at 3-6 hour intervals after hemostasis is achieved, to maintain the hemostatic plug{01}. The biological and clinical effects of prolonged elevated levels of factor VIIa have not been studied; therefore, the duration of post-hemostatic dosing should be minimized, and patients should be appropriately monitored by a physician experienced in the treatment of hemophilia during this time period{01}.


Usual Pediatric Dose
See Usual adult dose.{01}

Strength(s) usually available
U.S.—


1.2 mg vial (Rx) [NovoSeven ( sodium chloride 3 mg per mL) (calcium chloride dihydrate 1.5 mg per mL) (mouse protein £1.2 nanogram (ng) per mg) (bovine protein £30 ng per mg) (BHK-cells £19 ng per mg)]{01}


4.8 mg vial (Rx) [NovoSeven ( sodium chloride 3 mg per mL) (calcium chloride dihydrate 1.5 mg per mL) (mouse protein £1.2 nanogram (ng) per mg) (bovine protein £30 ng per mg) (BHK-cells £19 ng per mg)]{01}

Canada—
Not commercially available.

Packaging and storage:
Store unreconstituted lyophilized powder under refrigeration 2 to 8° C (36 to 46° F) and protected from direct sunlight. Do not use after the expiration date{01}.

Store reconstituted solution at room temperature or under refrigeration for up to 3 hours. Do not freeze the reconstituted solution or store it in syringes{01}.

Preparation of dosage form:
The diluent of Sterile Water for Injection, USP, and dry concentrate should be brought to room temperature, approximately 25° C (77° F), prior to reconstitution. Reconstitute the 1.2 mg vial with 2.2 mL of Sterile Water for Injection, USP, and the 4.8 mg vial with 8.5 mL of Sterile Water for Injection, USP. After reconstitution, each vial contains approximately 0.6 mg per mL (600 mcg/mL) of factor VIIa {01}.

Note: The diluent should NOT be injected directly onto the lyophilized powder, but should be injected onto the side of the vial so that a stream of liquid runs down the side of the vial{01}.


Dissolve the powder by gently swirling the vial. The solution should be clear and colorless{01}.

Stability:
Reconstituted factor VII may be stored at room temperature or under refrigeration, but should be used within 3 hours after reconstitution{01}.

The reconstituted solution should not be frozen or stored in syringes{01}.

Additional information:
Factor VIIa should not be mixed with infusion solutions. It is intended for bolus injection only{01}.



Developed: 05/09/2000



References
  1. Product Information: NovoSeven®, Factor VIIa for injection. Novo Nordisk, Princeton, NJ, (PI revised 3/1999) reviewed 3/2000.
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