NovoSeven 1mg (50 KIU) powder and solvent for solution for injection

NovoSeven 2 mg (100 KIU) powder and solvent for solution for injection

NovoSeven 5 mg (250 KIU) powder and solvent for solution for injection

NovoSeven 8 mg (400 KIU) powder and solvent for solution for injection

NovoSeven is presented as powder and solvent for solution for injection containing

1 mg eptacog alfa (activated) per vial (corresponds to 50 KIU/vial).

2 mg eptacog alfa (activated) per vial (corresponds to 100 KIU/vial).

5 mg eptacog alfa (activated) per vial (corresponds to 250 KIU/vial).

8 mg eptacog alfa (activated) per vial (corresponds to 400 KIU/vial).

1 KIU equals 1000 IU (International Units).

eptacog alfa (activated) is recombinant coagulation factor VIIa (rFVIIa) with a molecular mass of approximately 50,000 Dalton produced in baby hamster kidney cells (BHK Cells) by recombinant DNA technology.

After reconstitution, the product contains 1 mg/ml eptacog alfa (activated) and 10 mg/ml sucrose when reconstituted with solvent.

For a full list of excipients, see Section 6.1.

Powder and solvent for solution for injection.

White lyophilized powder. Solvent: clear colourless solution. The reconstituted solution has a pH of approximately 6.0.

NovoSeven is indicated for the treatment of bleeding episodes and for the prevention of bleeding in those undergoing surgery or invasive procedures in the following patient groups:

• in patients with congenital haemophilia with inhibitors to coagulation factors VIII or IX > 5 Bethesda Units (BU)

• in patients with congenital haemophilia who are expected to have a high anamnestic response to factor VIII or factor IX administration

• in patients with acquired haemophilia

• in patients with congenital FVII deficiency

• in patients with Glanzmann's thrombasthenia with antibodies to GP IIb - IIIa and/or HLA, and with past or present refractoriness to platelet transfusions.

Treatment should be initiated under the supervision of a physician experienced in the treatment of haemophilia and/or bleeding disorders.

Posology

Haemophilia A or B with inhibitors or expected to have a high anamnestic response

Dose

NovoSeven should be given as early as possible after the start of a bleeding episode. The recommended initial dose, administered by intravenous bolus injection, is 90 μg per kg body weight.

Following the initial dose of NovoSeven further injections may be repeated. The duration of treatment and the interval between injections will vary with the severity of the haemorrhage, the invasive procedures or surgery being performed.

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. Therefore, higher doses of rFVIIa may be needed in paediatric patients to achieve similar plasma concentrations as in adult patients (see Section 5.2).

Dose interval

Initially 2 - 3 hours to obtain haemostasis.

If continued therapy is needed, the dose interval can be increased successively once effective haemostasis is achieved to every 4, 6, 8 or 12 hours for as long as treatment is judged as being indicated.

Mild to moderate bleeding episodes (including home therapy)

Early intervention has been shown to be efficacious in the treatment of mild to moderate joint, muscle and mucocutaneous bleeds. Two dosing regimens can be recommended:

1) Two to three injections of 90 µg per kg body weight administered at three-hour intervals

If further treatment is required, one additional dose of 90 µg per kg body weight can be administered

2) One single injection of 270 µg per kg body weight

The duration of the home therapy should not exceed 24 hours.

There is no clinical experience with administration of a single dose of 270 µg per kg body weight in elderly patients.

Serious bleeding episodes

An initial dose of 90 µg per kg body weight is recommended and could be administered on the way to the hospital where the patient is usually treated. The following dose varies according to the type and severity of the haemorrhage. Dosing frequency should initially be every second hour until clinical improvement is observed. If continued therapy is indicated, the dose interval can then be increased to 3 hours for 1 - 2 days. Thereafter, the dose interval can be increased successively to every 4, 6, 8 or 12 hours for as long as treatment is judged as being indicated. A major bleeding episode may be treated for 2 - 3 weeks but can be extended beyond this if clinically warranted.

Invasive procedure/surgery

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

Acquired Haemophilia

Dose and dose interval

NovoSeven should be given as early as possible after the start of a bleeding episode. The recommended initial dose, administered by intravenous bolus injection, is 90 µg per kg body weight. Following the initial dose of NovoSeven further injections may be given if required. The duration of treatment and the interval between injections will vary with the severity of the haemorrhage, the invasive procedures or the surgery being performed.

The initial dose interval should be 2 - 3 hours. Once haemostasis has been achieved, the dose interval can be increased successively to every 4, 6, 8 or 12 hours for as long as treatment is judged to be indicated.

Factor VII deficiency

Dose, dose range and dose interval

The recommended dose range for treatment of bleeding episodes and for the prevention of bleeding in patients undergoing surgery or invasive procedures is 15 - 30 μg per kg body weight every 4 - 6 hours until haemostasis is achieved. Dose and frequency of injections should be adapted to each individual.

Glanzmann's thrombasthenia

Dose, dose range and dose interval

The recommended dose for treatment of bleeding episodes and for the prevention of bleeding in patients undergoing surgery or invasive procedures is 90 µg (range 80 - 120 µg) per kg body weight at intervals of two hours (1.5 - 2.5 hours). At least three doses should be administered to secure effective haemostasis. The recommended route of administration is bolus injection as lack of efficacy may appear in connection with continuous infusion.

For those patients who are not refractory, platelets are the first line treatment for Glanzmann's thrombasthenia.

Method of administration

Reconstitute the solution as described under section 6.6 and administer as an intravenous bolus injection over 2 - 5 minutes.

Monitoring of treatment – laboratory tests

There is no requirement for monitoring of NovoSeven therapy. Severity of bleeding condition and clinical response to NovoSeven administration must guide dosing requirements.

After administration of rFVIIa, prothrombin time (PT) and activated partial thromboplastin time (aPTT) have been shown to shorten, however no correlation has been demonstrated between PT and aPTT and clinical efficacy of rFVIIa.

Hypersensitivity to the active substance, or to any of the excipients, or to mouse, hamster or bovine protein.

In pathological conditions in which tissue factor may be expressed more extensively than considered normal, there may be a potential risk of development of thrombotic events or induction of Disseminated Intravascular Coagulation (DIC) in association with NovoSeven treatment.

Such situations may include patients with advanced atherosclerotic disease, crush injury, septicaemia or DIC. Because of the risk of thromboembolic complications, caution should be excercised when administering NovoSeven to patients with a history of coronary heart disease, to patients with liver disease, to patients post-operatively, to neonates, or to patients at risk of thromboembolic phenomena or disseminated intravascular coagulation. In each of these situations, the potential benefit of treatment with NovoSeven should be weighed against the risk of these complications.

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 such cases treatment with antihistamines i.v. should be considered.

If allergic or anaphylactic-type reactions occur, the administration should be discontinued immediately. In case of shock, standard medical treatment for shock should be implemented. Patients should be informed of the early signs of hypersensitivity reactions. If such symptoms occur, the patient should be advised to discontinue use of the product immediately and contact their physician.

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.

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.

Patients with rare hereditary problems of fructose intolerance, glucose malabsorption or sucrose-isomaltase insufficiency should not take this medicine

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 orthopaedic surgery and surgery in regions rich in fibrinolytic activity, such as the oral cavity. Experience with concomitant administration of anti-fibrinolytics and rFVIIa treatment is however limited.

Pregnancy

As a precautionary measure, it is preferable to avoid use of NovoSeven during pregnancy. Data on a limited number of exposed pregnancies within approved indications indicate no adverse effects of rFVIIa on pregnancy or on the health of the foetus/new-born child. To date, no other relevant epidemiological data are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see Section 5.3).

Lactation

It is unknown whether rFVIIa is excreted in human breast milk. The excretion of rFVIIa in milk has not been studied in animals. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with NovoSeven should be made taking into account the benefit of breast-feeding to the child and the benefit of NovoSeven therapy to the woman.

No studies on the effect on the ability to drive and use machines have been performed.

The frequencies of both serious and non-serious adverse drug reactions are listed by system organ classes in the table below.

* 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 stated in Section 4.2.

Patients with acquired haemophilia

Clinical trials conducted in 61 patients with acquired haemophilia with a total of 100 treatment episodes, showed that certain adverse drug reactions were reported more frequent (1% based on treatment episodes): Arterial thromboembolic events (cerebral artery occlusion, cerebrovascular accident), venous thromboembolic events (pulmonary embolism and deep vein thrombosis), angina pectoris, nausea, pyrexia, erythematous rash and investigation of increased levels of fibrin degradation products.

Inhibitory antibody formation

In post-marketing experience, there have been no reports of antibodies against NovoSeven or FVII in patients with haemophilia A or B.

In clinical trials of patients with factor VII deficiency, formation of antibodies against NovoSeven and FVII is the only adverse drug reaction reported (frequency: common ( 1/100 to < 1/10)). In some cases, the antibodies showed inhibitory effect in vitro. Risk factors that may have contributed to antibody development including previous treatment with human plasma and/or plasma-derived factor VII, severe mutation of FVII gene, and overdose of NovoSeven, were present. Patients with factor VII deficiency treated with NovoSeven should be monitored for factor VII antibodies, (see Section 4.4).

Thromboembolic events

When NovoSeven is administered to patients outside approved indications, arterial thromboembolic events are common ( 1/100 to < 1/10). A higher risk of arterial thromboembolic adverse events (see table: Vascular disorders) (5.6% in patients treated with NovoSeven versus 3.0% in placebo-treated patients) has been shown in a meta-analysis of pooled data from placebo-controlled trials conducted outside current approved indications in various clinical settings, each of these having distinct patient characteristics and hence different underlying risk profiles.

Safety and efficacy of NovoSeven have not been established outside the approved indications and therefore NovoSeven should not be used.

Thromboembolic events may lead to cardiac arrest.

Dose limiting toxicities of NovoSeven have not been investigated in clinical trials.

Three cases of overdose have been reported in patients with haemophilia in 13 years. The only complication reported in connection with an overdose was a slight transient increase in blood pressure in a 16 year-old patient receiving 24 mg rFVIIa instead of 5.5 mg.

No cases of overdose have been reported in patients with acquired haemophilia or Glanzmann's thrombasthenia.

In patients with factor VII deficiency, where the recommended dose is 15 – 30 µg/kg rFVIIa, one episode of overdose has been associated with a thrombotic event (occipital stroke) in an elderly (> 80 year) male patient treated with 10 – 20 times the recommended dose. In addition, the development of antibodies against NovoSeven and FVII has been associated with overdose in one patient with factor VII deficiency.

The dose schedule should not be intentionally increased above the recommended doses due to the absence of information on the additional risk that may be incurred.

Pharmacotherapeutic group: Blood coagulation factors, ATC code: B02BD08

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 underlying diseases predisposing them to DIC cannot be totally excluded.

Healthy subjects

Using the FVII clotting assay, the pharmacokinetics of rFVIIa were investigated in 35 healthy Caucasian and Japanese subjects in a dose-escalation study. Subjects were stratified according to sex and ethnic group and dosed with 40, 80 and 160 µg rFVIIa per kg body weight and/or placebo (3 doses each). The pharmacokinetic profiles indicated dose proportionality. The pharmacokinetics were similar across sex and ethnic groups. The mean steady state volume of distribution ranged from 130 to 165 ml/kg, the mean values of clearance ranged from 33.3 to 37.2 ml/h×kg, and the mean terminal half-life ranged from 3.9 to 6.0 hours.

Haemophilia A and B with inhibitors

Using the FVIIa assay, the pharmacokinetic properties of rFVIIa were studied in 12 paediatric (2 - 12 years) and 5 adult patients in non bleeding state. 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/h×kg), 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. Clearance appears related with age, therefore in younger patients clearance may be increased by more than 50%.

Factor VII deficiency

Single dose pharmacokinetics of rFVIIa, 15 and 30 μg per kg body weight, showed no significant difference between the two doses used with regard to dose-independent parameters: total body clearance (70.8 - 79.1 ml/h×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 are expected to be similar to the pharmacokinetics in haemophilia A and B patients.

All findings in the preclinical safety programme were related to the pharmacological effect of rFVIIa.

Powder

Sodium chloride

Calcium chloride dihydrate

Glycylglycine

Polysorbate 80

Mannitol

Sucrose

Methionine

Hydrochloric acid (for pH-adjustment)

Sodium hydroxide (for pH-adjustment)

Solvent

Histidine

Hydrochloric acid (for pH-adjustment)

Sodium hydroxide (for pH-adjustment)

Water for injections

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

The shelf life for the product packed for sale is:

3 years when the product is stored below 25°C

After reconstitution, chemical and physical stability have been demonstrated for 6 hours at 25°C and 24 hours at 5°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, storage time and storage conditions prior to use are the responsibility of the user, and should not be longer than 24 hours at 2°C - 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

– Store powder and solvent below 25°C.

– Store powder and solvent protected from light.

– Do not freeze to prevent damage to the solvent vial.

– For storage conditions of the reconstituted medicinal product, see Section 6.3.

The NovoSeven package contains Type I glass vials closed with a chlorobutyl rubber stopper, covered with an aluminium cap.The closed vials are equipped with a tamper-evident snap-off cap which is made of polypropylene.

Each NovoSeven package contains:

1 mg & 2 mg

– 1 vial (2 ml) with white powder for solution for injection

– 1 vial (2 ml) with solvent for reconstitution

5 mg & 8 mg

– 1 vial (12 ml) with white powder for solution for injection

– 1 vial (12 ml) with solvent for reconstitution

Always use an aseptic technique

Reconstitution

• NovoSeven powder and solvent vials should be at room temperature at reconstitution. Remove the plastic caps from the two vials. If the caps are loose or missing, do not use the vials. Clean the rubber stoppers on the vials with alcohol swabs and allow them to dry before use. Use a disposable syringe of an appropriate size and a vial adapter, transfer needle (20 - 26G) or other suitable device.

• Attach the vial adapter to the solvent vial. If using a transfer needle, screw the transfer needle tightly onto the syringe.

• Pull the plunger to draw in a volume of air that is equal to the amount of solvent in the solvent vial (ml equals cc on the syringe).

• Screw the syringe tightly onto the vial adapter on the solvent vial. If using a transfer needle, insert the transfer needle into the rubber stopper of the solvent vial. Inject air into the vial by pushing the plunger until you feel a clear resistance.

• Hold the syringe with the solvent vial upside down. If using a transfer needle, make sure the transfer needle tip is in the solvent. Pull the plunger to draw the solvent into the syringe.

• Remove the empty solvent vial. If using a vial adapter, tip the syringe to remove it from the vial.

• Attach the syringe with the vial adapter or transfer needle to the powder vial. If using a transfer needle, make sure to penetrate the centre of the rubber stopper. Hold the syringe slightly tilted with the vial facing downwards. Push the plunger slowly to inject the solvent into the powder vial. Make sure not to aim the stream of solvent directly at the NovoSeven powder as this will cause foaming.

• Gently swirl the vial until all the powder is dissolved. Do not shake the vial as this will cause foaming.

NovoSeven reconstituted solution is colourless and should be inspected visually for particulate matter and discolouration prior to administration.

Do not store reconstituted NovoSeven in plastic syringes.

It is recommended to use NovoSeven immediately after reconstitution.

Administration

• Ensure that the plunger is pushed all the way in before turning the syringe upside down (it may have been pushed out by the pressure in the syringe). If using a transfer needle, make sure the transfer needle tip is in the solution. Hold the syringe with the vial upside down and pull the plunger to draw all the solution into the syringe.

• If using a vial adapter, unscrew the vial adapter with the empty vial. If using a transfer needle, remove the transfer needle from the vial, replace the transfer needle cap, and twist the transfer needle off the syringe.

• NovoSeven is now ready for injection. Locate a suitable site, and slowly inject NovoSeven into a vein over a period of 2 - 5 minutes without removing the needle from the injection site.

Safely dispose of the syringe, vials and any unused product. Any unused product or waste material should be disposed of in accordance with local requirements.

Novo Nordisk A/S

Novo Allé

DK-2880 Bagsværd

Denmark

Date of first authorisation: 23 February 1996

Date of latest renewal: 23 February 2006

01/2012

Detailed information on this product is available on the website of the European Medicines Agency (EMA) http://www.ema.europa.eu/