INFORMATION FOR HEALTH PROFESSIONALS

Home  |  Consumers  |  Health Professionals  |  Regulatory  |  Other  |  Hot Topics  |  Search

Data Sheet

NovoSeven

Recombinant Coagulation Factor VIIa (eptacog alpha) powder for injection

Name of Medicine

NOVOSEVEN NOVO NORDISK

Recombinant Coagulation Factor VIIa (eptacog alpha)

Presentation

Recombinant Coagulation Factor VIIa is supplied as a powder for injections. Each vial contains 1.2 mg (60 KIU), 2.4 mg (120 KIU) or 4.8 mg (240 KIU) Recombinant Coagulation Factor VIIa (rFVIIa) per vial for reconstitution with Water for Injections, Ph.Eur.

After reconstitution with the supplied diluent (Water for Injections, Ph.Eur. 2.2 ml, 4.3 ml or 8.5 ml) each vial contains 0.6 mg/ml. NovoSeven is administered intravenously as a bolus injection.

Uses

Pharmacotherapeutic group: Coagulation factors, ATC code: B02B D08.

NovoSeven contains activated recombinant coagulation factor VII. The mechanism of action includes the binding of factor VIIa to exposed tissue factor. This complex activates factor IX into factor IXa and factor X into factor Xa, leading to the initial conversion of small amounts of prothrombin into thrombin. Thrombin leads to the activation of platelets and factors V and VIII at the site of injury and to the formation of the haemostatic plug by converting fibrinogen into fibrin. Pharmacological doses of NovoSeven activate factor X directly on the surface of activated platelets, localized to the site of injury, independently of tissue factor. This results in the conversion of prothrombin into large amounts of thrombin independently of tissue factor. Accordingly, the pharmacodynamic effect of factor VIIa gives rise to an increased local formation of factor Xa, thrombin and fibrin.

A theoretical risk for the development of systemic activation of the coagulation system in patients suffering from under-lying diseases predisposing for DIC cannot be totally excluded although clinical post marketing experience to date has not resulted in reporting of this as a significant adverse drug reaction.

Pharmacokinetics

Healthy subjects

The pharmacokinetics of NovoSeven was investigated in 35 healthy Caucasian and Japanese subjects in a dose-escalation study. Subjects were stratified according to gender and ethnic group and dosed with 40, 80 and 160µg NovoSeven per kg bodyweight and/or placebo (3 doses each). The pharmacokinetic profiles indicated dose proportionality. Pharmacokinetics were similar across gender and across ethnic groups. Mean steady state volume of distribution ranged from 130 to 165 ml/kg, mean values of clearance ranged from 33.3 to 37.2 ml/h x kg, and mean terminal half-life ranged from 3.9 to 6.0 hours, which considering the variability is similar to values obtained in patients with haemophilia A or B.

Haemophilia A and B with inhibitors

Using the FVIIa assay, the pharmacokinetic properties of NovoSeven were studied in 12 paediatric and 5 adult patients. Dose proportionality was established in children for the investigated doses of 90 and 180 µg per kg body weight, which is in accordance with previous findings at lower doses (17.5 - 70 μg/kg rFVIIa). Mean clearance was approximately 50% higher in paediatric patients relative to adults (78 versus 53 ml/kg x hr), whereas the mean terminal half life was determined to 2.3 hours in both groups. Mean volume of distribution at steady state was 196 ml/kg in paediatric patients versus 159 ml/kg in adults.

Factor VII Deficiency

Single dose pharmacokinetics of NovoSeven 15 and 30μg/kg, showed no significant difference between the two doses with regard to dose-independent parameters: total body clearance (70.8-79.1 mL/h x kg), volume of distribution at steady state (280-290 mL/kg), mean residence time (3.75-3.80 h), and half-life (2.82-3.11 h). The mean in vivo plasma recovery was approximately 20%.

Glanzmann's Thrombasthenia

Pharmacokinetics of NovoSeven in patients with Glanzmann's Thrombasthenia have not been investigated, but is expected to be similar to the pharmacokinetics in haemophilia A and B patients.

Inhibitors to coagulation Factors VIII or IX

The kinetics of single intravenous doses of eptacog alfa (activated) were studied using a Factor VII clot assay in 15 male haemophiliacs aged 15 to 63 years. The patient population included ten patients with inhibitors (9 haemophilia A) and 5 without inhibitors with ten of the patients incurring joint or muscle bleeds during the study. There were 23 bleeding episodes. Three doses of eptacog alfa (activated) were studied; 17.5, 35 and 70μg/kg, escalating from 17.5μg/kg, with a maximum of two doses at each level and an interval of 2-24 hours between doses.

The kinetics were linear in the dose range studied. Clearance was slightly higher (median 32.6 versus 31.0mL/h.kg) and elimination half-life slightly lower (median 2.30 versus 2.89h) in bleeding compared with non-bleeding patients, which was consistent with the consumption of eptacog alfa (activated) to repair tissue damage. The presence of inhibitors did not appear to affect the kinetics; however, the number of subjects studied was low.

After a single intravenous injection of eptacog alfa (activated) 35-70μg/kg to haemophiliac A and B patients with inhibitors (n=13), mean peak coagulant activity occurred at 10 minutes and returned to normal at 8-12 hours. The mean Factor VII coagulant half-life was 2.6±0.5 hours. Activated partial thromboplastin time shortened from 122 seconds to 83 seconds and prothrombin time from 12.3 seconds to 8.8 seconds at 20 minutes and returned to normal by 24 hours.

Indications

NovoSeven is indicated for the treatment of bleeding episodes and surgery in patients with inhibitors to coagulation factors (FVIII or FIX) > 10 BU or in patients with antibody titre < 10 BU who are expected to have a high anamnestic response to Factor VIII or Factor IX.

NovoSeven is indicated for the prevention and treatment of bleeding episodes in patients with congenital Factor VII deficiency or Glanzmann's Thrombasthenia.

Dosage & Administration

Dosage

Dose range:

Serious bleeding episodes and surgery

From 60 to 120 μg (3 to 6 KIU) per kg bodyweight per single dose given by intravenous bolus injection. Administration time is 2 to 5 minutes.

Dosing in children

Current clinical experience does not warrant a general differentiation in dosing between children and adults, although children have faster clearance than adults.

Dose intervals:

2 to 3 hours initially, then 4 to 12 hours.

Serious bleeding episodes

The dosage varies according to the type and severity of the haemorrhages. As a guideline, an initial dose of 90 μg (4.5 KIU) per kg bodyweight is recommended. Dosing frequency should initially be every second hour until clinical improvement is observed. If continued therapy is indicated, the dosage interval can then be increased to 3 hours for 1 to 2 days. Hereafter, the dosage interval can be increased successively to every 4, 6, 8 or 12 hours for the period of time treatment is judged as being indicated. A major bleed may be treated for 2 to 3 weeks but can be extended beyond this if clinically warranted.

Surgery

An initial dose of 90 μg (4.5 KIU) per kg bodyweight should be given immediately before the procedure. The dose should be repeated after 2 hours and then at 2 to 3 hour intervals for the first 24 to 48 hours depending on the surgery performed and the clinical status of the patient. In major surgery, the dosage should be continued at 2 to 4 hour intervals for 6 to 7 days. The dosage interval may then be increased to 6 to 8 hours for another 2 weeks of treatment. Patients undergoing major surgery should be treated for up to 2 to 3 weeks until healing has occurred.

Anti-fibrinolytics have been reported to reduce blood loss in association with surgery in haemophilia patients, especially in regions rich in fibrinolytic activity, such as the oral cavity.

Preliminary experience indicates that concomitant use of anti-fibrinolytic therapy in minor and major surgery is clinically safe.

For patients with Factor IX inhibitors or acquired antibodies to Factor VIII, only experience of use of NovoSeven in minor surgery exists.

Mild to moderate bleeding episodes

In the home-treatment setting early intervention doses of 4.5 KIU/kg b.w. (90 μg/kg b.w.) have been efficacious to treat mild to moderate joint, muscle and mucocutaneous bleeds. Based on clinical data two dosing regimens can be recommended:

1. Two to three injections of 90 μg/kg body weight administered at three-hour intervals.
2. One single injection of 270 μg/kg body weight.
   If further treatment is required, a dose of 90 μg/kg body weight should be administered at three hourly intervals. The duration of the home treatment should not exceed 24 hours.

Intervention in frequently bleeding patients

Patients with Haemophilia A or B with inhibitors and a high bleeding frequency defined as 4 or more bleeding episodes per month can be treated with NovoSeven administered as a once daily dose of 90 μg/kg body weight for three months to reduce the frequency of bleeding.

Factor VII deficiency

15-30 μg/ per kg body weight every 4-6 hours until haemostasis is achieved. Dose and frequency of injections should be individually titrated.

Glanzmann's Thrombasthenia

90-120 μg/ per kg body weight at maximum intervals of 2.5 hours. At least three doses are recommended to secure effective haemostasis. The prophylaxis of invasive/surgical procedures may require a more prolonged use of NovoSeven depending on the extent of the procedures.

Administration

Dissolve the preparation as described under Reconstitution (below) and administer as an intravenous bolus injection:

NovoSeven should not be mixed with infusion solutions or be given in a drip.

Reconstitution

Always Use Aseptic Technique

1. Bring NovoSeven (powder) and Water for Injections, Ph. Eur. (diluent) to room temperature (but not above 37°C).
2. Remove protective caps from powder and diluent bottles to expose central portion of rubber stoppers. If the caps are loose or missing do not use the vials.
3. Cleanse stoppers with alcohol swab and allow to dry prior to use.
4. Take the transfer needle out of the package. Take the syringe out of its package. Attach the disposable syringe supplied in the package and remove protective covering from the needle.
5. Draw back the plunger (to the same volume as in the solvent vial) to admit air into the syringe.
6. Insert the transfer needle through the diluent bottle stopper at its centre and inject air into the bottle. Hold the bottle upside down, then withdraw the total content of the bottle into the syringe.
7. Inject the diluent from the syringe into the bottle containing the powder through the centre of the stopper (the powder does not contain vacuum).
8. Gently swirl until all material is dissolved.

The enclosed disposable syringe should be used for reconstitution and administration of the preparation.

NovoSeven is for intravenous bolus injection only and should not be mixed with infusion solutions or be given in a drip.

Administration should preferably take place immediately or at least within 3 hours after reconstitution.

The enclosed disposable syringe is compatible with the reconstituted preparation, but do not store reconstituted NovoSeven in plastic syringes.

Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration whenever solution and container permit. Do not use if the reconstituted NovoSeven is not clear and colourless.

ADMINISTRATION

1. Draw back the plunger (to the same volume as you are going to inject) to admit air into the syringe.
2. Insert transfer needle into the vial containing reconstituted NovoSeven.
3. Inject air into the vial and then withdraw the reconstituted NovoSeven into the syringe.
4. Remove and discard the transfer needle.
5. Take the infusion set out of its package. Attach the infusion set to the syringe. Remove the needle covering and administer NovoSeven intravenously over a period of 2-5 minutes.
6. Discard the syringe and the infusion set

Remember to discard the used needles in a safe way (e.g. use the needle disposal can).

Contraindications

NovoSeven should not be administered to patients with known hypersensitivity to any of the components of NovoSeven. NovoSeven is contraindicated in patients with known hypersensitivity to mouse, hamster or bovine protein.

Warnings & Precautions

In pathological conditions in which tissue factor can be expected in circulating blood, there is a potential risk of thrombotic events or induction of DIC in association with NovoSeven treatment. Such situations may include patients with advanced atherosclerotic disease, crush injury, septicemia or DIC.

Patients in such conditions receiving NovoSeven should be kept under close observation for signs and symptoms of untoward activation of the coagulation system or thrombosis.

As recombinant coagulation factor VIIa NovoSeven may contain trace amounts of mouse IgG, bovine IgG and other residual culture proteins (hamster and bovine serum proteins), the remote possibility exists that patients treated with the product may develop hypersensitivity to these proteins.

In case of severe bleeds the product should be administered in hospitals preferably specialized in treatment of haemophilia patients with coagulation Factor VIII or IX inhibitors, or if not possible in close collaboration with a physician specialized in haemophilia treatment.

The duration of the ambulatory treatment should not exceed 24 hours. If bleeding is not kept under control hospital care is mandatory. Patients/carers should inform the physician/supervising hospital at the earliest possible opportunity about all usages of NovoSeven.

Factor VII deficient patients should be monitored for prothrombin time and factor VII coagulant activity before and after administration of NovoSeven. In case the factor VIIa activity fails to reach the expected level or bleeding is not controlled after treatment with the recommended doses, antibody formation may be suspected and analysis for antibodies should be performed. The risk of thrombosis in factor VII deficient patients treated with NovoSeven is unknown.

Treatment of Factor VII deficient patients with Factor VII/Factor VIIa is associated with the potential risk of development of Factor VII/Factor VIIa antibodies.

Patients with a history of allergic reactions should be carefully monitored.

Use in the Elderly

Clinical experience with administration of a single dose of 270μg/kg body weight in elderly patients is limited.

Pregnancy

From an animal reproduction study it was concluded that intravenous administration of NovoSeven to male and female rats at dose levels up to 3.0 mg/kg b.w./day (150 KIU/kg b.w./day) had no effect upon mating performance, fertility and litter responses. It is not known whether NovoSeven can cause foetal harm when administered to a pregnant woman or can affect reproduction capacity. NovoSeven should only be given to a pregnant women if clearly needed.

Lactation

It is not known whether this drug is excreted in human milk, but since many drugs are, caution should be exercised when NovoSeven is administered to nursing women.

Effects on ability to drive and use machines

None known

Adverse Effects

Based on post-marketing experience adverse drug reactions are rare (< 1 per 1,000 standard doses). When analysed by system organ classes, the reporting rates of adverse drug reactions during the post-marketing period, including both serious and non-serious reactions, are as indicated in the table below:

Blood and lymphatic disorders
Very rare < 1/10,000)	Few cases of coagulopathic disorders, such as increased D-dimer and consumptive coagulopathy, have been reported. Patients at increased risk of disseminated intravascular coagulation, as described under 'Warnings and Precautions' should be carefully monitored.
Cardiac disorders
Very rare (< /10,000)	Myocardial infarction: refer to 'serious thrombotic adverse reactions during the post-marketing period' below.
Gastrointestinal disorders
Very rare (< 1/10,000)	Few cases of nausea have been reported.
General disorders and administration site conditions
Rare (> 1/10,000, < 1/1,000)	Lack of efficacy (therapeutic response decreased) has been reported. It is important that the dosage regimen of NovoSeven is compliant with the recommended dosage as described under 'Dosage &amp; Administration'.
Very rare (< 1/10,000)	Fever may occur. Pain, especially at injection site may also occur on rare occasions.
Investigations
Very rare (< 1/10,000)	Increase of alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase and prothrombin levels have been reported.
Nervous system disorders
Very rare (< 1/10,000)	Cerebrovascular disorders including cerebral infarction and cerebral ischaemia have been reported: refer to 'serious thrombotic adverse reactions during the post-marketing period' below.
Skin and subcutaneous tissue disorders
Very rare (<1/10,000)	Skin rashes may occur.
Vascular disorders
Very rare (<1/10,000)	Venous thrombotic events have been reported: refer to 'serious thrombotic adverse reactions during the post-marketing period' below. Incidents of haemorrhage have been reported. NovoSeven is not expected to precipitate haemorrhage, but pre-existing haemorrhage may continue in case of insufficient efficacy or sub-optimal dosage regimen.

Serious adverse reactions reported during the post-marketing period include:

• Arterial thrombotic events such as myocardial infarctions or ischaemia, cerebrovascular disorders and bowel infarction. In the vast majority of cases the patients were predisposed to arterial thrombotic disorders either due to underlying disease, age, atherosclerotic or current medical conditions as described under 'Warnings and Precautions'.
• Venous thrombotic events such as thrombophlebitis, deep vein thrombosis and related pulmonary embolism. In the vast majority of cases the patients were predisposed to venous thrombotic events due to concurrent risk factors. Patients at increased risk of venous thrombotic disorders either due to concurrent conditions, previous history of thrombotic events, post surgery immobilisation or venous catheterisation should be carefully monitored.

Anaphylactic reactions have not been reported spontaneously during the post-marketing period, but patients with a history of allergic reactions should be carefully monitored.

There have been no reports of antibodies against factor VII in haemophilia A or B patients.

Isolated cases of factor VII deficient patients developing antibodies against factor VII have been reported after treatment with NovoSeven. These patients have previously been treated with human plasma and/or plasma-derived factor VII. In two patients the antibodies showed inhibitory effect in vitro. Patients with factor VII deficiency should be monitored for factor VII antibodies.

One case of angioneurotic oedema has been reported spontaneously in a patient with Glanzmann's thrombasthenia after administration of NovoSeven.

Interactions

The risk of a potential interaction between NovoSeven and coagulation factor concentrates is unknown. Simultaneous use of prothrombin complex concentrates, activated or not should be avoided.

Anti-fibrinolytics have been reported to reduce blood loss in association with surgery in haemophilia patients, especially in regions rich in fibrinolytic activity, such as the oral cavity. Experience with concomitant administration of anti-fibrinolytics and NovoSeven treatment is however limited.

Overdosage

From human use no thrombotic complications to overdose have been reported, even after accidental administration of 800 μg/kg b.w. (40 KIU/kg b.w.)

Pharmaceutical Precautions

NovoSeven should be stored under refrigeration (2° to 8°C). Do not use after the expiry date.

Freezing should be avoided to prevent damage to the diluent vial.

Avoid exposure to direct sunlight.

Medicine Classification

Prescription Medicine.

Package Quantities

1.2 mg/vial Recombinant Coagulation Factor VIIa
2.2 ml Water for Injections, Ph. Eur.
Sterile disposable syringe size 3 ml

2.4 mg/vial Recombinant Coagulation Factor VIIa
4.3 ml Water for Injections, Ph. Eur.
Disposable syringe 6 ml

4.8 mg/vial Recombinant Coagulation Factor VIIa
8.5 ml Water for Injections, Ph. Eur.
Disposable syringe 12 ml

Each pack contains one vial of freeze dried Recombinant Coagulation Factor VIIa, one vial of Water for Injections Ph. Eur., one sterile disposable syringe for reconstitution and administration, one sterile vial adapter for reconstitution, one sterile infusion set for administration, two alcohol swabs for cleansing the rubber stoppers on the vials, and a package insert with instructions for use.

Further Information

Qualitative Composition:

Recombinant Coagulation Factor VIIa. Human Factor VII was cloned and expressed in baby hamster kidney cells (BHK cells). Recombinant Factor VII is secreted from the BHK cells and is activated during the purification procedure. NovoSeven Recombinant Coagulation Factor VIIa is structurally very similar to plasma-derived activated Factor VII (Human).

Quantitative Composition:

Recombinant Coagulation Factor VIIa (rFVIIa) 1.2 mg/bottle (corresponds to 60 KIU/bottle)

Recombinant Coagulation Factor VIIa (rFVIIa) 2.4 mg/bottle (corresponds to 120 KIU/bottle)

Recombinant Coagulation Factor VIIa (rFVIIa) 4.8 mg/bottle (corresponds to 240 KIU/bottle)

Please note that the above units are international units, measured with reference to the first international standard of FVIIa 89/688. Thus, these units should not be mistaken for units of other coagulation factors including FVII. 1 KIU equals 1000 IU (International Units). After reconstitution with the appropriate volume of diluent each vial contains 0.6 mg/ml (30 KIU/ml).

List of excipients:

Sodium chloride
Calcium chloride dehydrate
Glycylglycine
Polysorbate 80
Mannitol

After reconstitution with the appropriate volume of diluent (Water for Injections, Ph. Eur.), each bottle contains NovoSeven 0.6 mg/ml (30 KIU/ml). Sodium chloride 3 mg/ml, calcium chloride dihydrate 1.5 mg/ml, glycylglycine 1.3 mg/ml, polysorbate 80 0.1 mg/ml and mannitol 30 mg/ml are present in the preparation.

Shelf Life:

The reconstituted product should preferably be administered immediately.

Name and Address

Novo Nordisk Pharmaceuticals Ltd
PO Box 51-268
Pakuranga
Auckland
Telephone: (09) 916 5590
Fax: (09) 916 5595

Date of Preparation

16 April 2007

NovoSeven is a trademark owned by Novo Nordisk Healthcare AG, Switzerland.