NovoSeven 1 mg (50 KIU), NovoSeven 2 mg (100 KIU), NovoSeven 5 mg (250 KIU)

Remove UK from reporting side effects section. Update to revision of text date.

Update regarding in-line filter size range for procedure for pooling of vials for hospital use only:

"Compatibility with the product was demonstrated for the system consisting of a 50 ml syringe (polypropylene), a 2 m infusion tube (polyethylene) and an in-line filters within a the range of 0.2 to 5 micrometer pore size."

"An in-line filter within a the range of 0.2 to 5 micrometer pore size must be ensured for administration."

1.      What NovoSeven® is and what it is used for

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NovoSeven® can also be given to you by a doctor to treat heavy bleeding after delivery of your baby, even if you do not have a bleeding disorder.

4.      Possible side effects

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If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via

United Kingdom (Northern Ireland):

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

6.      Contents of the pack and other information

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This leaflet was last revised in 10/2020 05/2022

4.1    Therapeutic indications

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Severe postpartum haemorrhage

NovoSeven is indicated for the treatment of severe postpartum haemorrhage when uterotonics are insufficient to achieve haemostasis.

4.2    Posology and method of administration

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In the management of severe postpartum haemorrhage, appropriate multidisciplinary expertise should be consulted. In addition to obstetricians, this includes anaesthesiologists, critical care specialists and/or haematologists. Standard management practices should remain implemented, based on the individual patient’s requirements. Maintenance of adequate fibrinogen concentration and platelet count is recommended in order to optimise the benefit of NovoSeven treatment.

...

Severe postpartum haemorrhage

Dose range and dose interval

The recommended dose range for the treatment of bleeding is 60 – 90 µg per kg body weight administered by intravenous bolus injection. Peak coagulant activity can be expected at 10 minutes. A second dose can be administered based on clinical response of the individual patient.

It is recommended that in case of insufficient haemostatic response, a second dose can be administered after 30 minutes.

4.4    Special warnings and precautions for use

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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 exercised when administering NovoSeven to patients with a history of coronary heart disease, to patients with liver disease, to post-operative patients post-operatively, to pregnant or peripartum women, to neonates, or to patients at risk of thromboembolic events phenomena or DICdisseminated intravascular coagulation. In each of these situations, the potential benefit of treatment with NovoSeven should be weighed against the risk of these complications.

In severe postpartum haemorrhage and pregnancy, the clinical conditions (delivery, severe haemorrhage, transfusion, DIC, surgery/invasive procedures and coagulopathy) are known contributing factors to the thromboembolic risk; and in particular venous thromboembolic risk associated with the administration of NovoSeven (see section 4.8).

4.5    Interaction with other medicinal products and other forms of interaction

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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. Antifibrinolytics are also used to reduce blood loss in women with postpartum haemorrhage. Experience with concomitant administration of anti-fibrinolytics and rFVIIa treatment is, however, limited.

4.8    Undesirable effects

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The most frequent adverse drug reactions are pyrexia and rash (uncommon: ≥ 1/1,000 to < 1/100), and the most serious adverse drug reactions include venous thromboembolic events (uncommon: ≥ 1/1,000 to < 1/100) and arterial are thromboembolic events (rare: ≥ 1/10,000 to < 1/1,000).

...

Women with severe postpartum haemorrhage

In an open-label randomised clinical trial, venous thromboembolic events were reported in 2 of 51 patients treated with a single dose of NovoSeven (median dose 58 μg/kg) and none of 33 patients not treated with NovoSeven; no arterial thromboembolic events were reported in either group.

In 4 non-interventional studies, venous thromboembolic events were reported in 3 of 358 (0.8%) patients treated with NovoSeven (median dose range 63-105 µg/kg) and arterial thromboembolic events were reported in 1 (0.3%) patient treated with NovoSeven.

For known contributing factors to thromboembolic risk associated with pregnancy and severe postpartum haemorrhage, see section 4.4.

5.1    Pharmacodynamic properties

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Pharmacotherapeutic group: Blood coagulation factors, ATC code: B02BD08

Mechanism of action

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.

Pharmacodynamic effects

The pharmacodynamic effect of factor VIIa gives rise to an increased local formation of factor Xa, thrombin and fibrin.

The time to peak coagulant activity after administration of NovoSeven was approximately 10 minutes in healthy subjects and patients with haemophilia.

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.

Clinical efficacy and safety

Congenital FVII deficiency

In an observational registry (F7HAEM-3578) covering subjects with congenital FVII deficiency, the median dose for long term prophylaxis against bleeding in 22 paediatric patients (below 12 years of age) with Factor VII deficiency and a severe clinical phenotype was 30 µg/kg (range 17 µg/kg to 200 µg/kg; the dose most often used was 30 µg/kg in 10 patients) with a median dose frequency of 3 doses per week (range 1 to 7; the dose frequency most often reported was 3 per week in 13 patients).

In the same registry 3 out of 91 surgical patients experienced thromboembolic events.

Glanzmann’s thrombasthenia

An observational registry (F7HAEM-3521) covered 133 subjects with Glanzmann’s thrombasthenia treated with NovoSeven. The median dose per infusion for treatment of 333 bleeding episodes was 90 µg/kg (range 28 to 450 µg/kg). NovoSeven was used in 157 surgical procedures, at a median dose of 92 µg/kg (up to 270 µg/kg). Treatment with NovoSeven, alone or in combination with antifibrinolytics and/or platelets, was defined as effective when bleeding was stopped for at least 6 hours. The efficacy rates were 81% and 82%, respectively, in patients with positive or negative refractoriness to platelet transfusions, and 77% and 85%, respectively, in patients testing positive or negative for antibodies to platelets. Positive status indicates at least one positive test at any admission.

Severe postpartum haemorrhage

The efficacy and safety of NovoSeven was assessed in 84 women with severe postpartum haemorrhage in a multicentre, open-label clinical trial. Patients were randomised either to treatment with a single dose of 60 µg/kg of NovoSeven (in addition to standard of care; N=42) or to reference therapy (standard of care alone; N=42), following failure of uterotonics (sulprostone). The treatment groups were well balanced in terms of demographic characteristics and postpartum haemorrhage treatment prior to randomisation. Fibrinogen and tranexamic acid were part of standard of care. Information on fibrinogen/tranexamic acid use was available from approximately 57% of patients in the NovoSeven group and 43% of patients in the reference group. Of these, about 40% of the patients in both groups received fibrinogen and/or tranexamic acid. Bleeding was considered to have stopped (i.e. treatment success) if the estimated blood flow decreased to less than 50 ml per 10 minutes within the 30 minutes following randomisation. If the bleeding was uncontrolled or intractable, invasive procedures were considered.

In the primary analysis, fewer women in the NovoSeven group (21 vs 35) had at least one embolisation and/or ligation procedure compared to the reference group, corresponding to a statistically significant 40% relative reduction in risk for the NovoSeven group compared to the reference group (relative risk = 0.60 (95% confidence interval: 0.43 – 0.84, p=0.0012)).

In the reference group, 8 of the 42 patients received late NovoSeven as a compassionate treatment in an attempt to avoid salvage hysterectomy, which succeeded in 2 cases.

5.2    Pharmacokinetic properties 

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Severe postpartum haemorrhage

Pharmacokinetics of NovoSeven in patients with severe postpartum haemorrhage have not been investigated.

9.    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

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Date of first authorisation: 23 February 1996

Date of latest renewal: 23 09 February 2006

10.     DATE OF REVISION OF THE TEXT

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06/2021 05/2022

Section 6.5

Reference to vial-vial presentation removed (deregistered in EU)

Section 6.6

Reference to vial-vial presentation removed (deregistered in EU)

Section 8

EU numbers for vial-vial presentation removed (deregistered in EU)

Section 10

Date of revision updated to: 06/2021

Section 4.4

New text added:

"Sodium content

The medicinal product contains less than 1 mmol sodium (23 mg) per injection, indicating that it is essentially ‘sodium free’.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded."

Addition of joint SmPC covering all presentations

Additional 8 mg presentation added as per the authorised EMA-approved SmPC. This presentation is added to the local SmPC only, i.e. no change to marketing status. 

Section 6.3 updated as follows:

"The shelf life for the product packed for sale is 3 years when the product is stored below 25°C.

 In vial

After reconstitution, chemical and physical stability has 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. The reconstituted solution should be stored in the vial.

 In syringe (50 ml polypropylene) in hospital settings only

Reconstitution must take place in controlled and validated aseptic conditions by adequately trained staff. Under these conditions, chemical and physical stability has been demonstrated for 24 hours at 25°C when stored in a 50 ml syringe (polypropylene). If not used immediately, the conditions prior to use are the responsibility of the user and the in-use storage time must not be longer than as stated above.

Section 6.6 updated as follows:

...

Do not store reconstituted NovoSeven in plastic syringes, unless as described in section 6.3. 

It is recommended to use NovoSeven immediately after reconstitution, unless as described in section 6.3.

...

Procedure for pooling of vials for hospital use only:  

During in vitro studies, the chemical and physical in-use stability has been demonstrated for 24 hours at 25°C in a 50 ml syringe (polypropylene). Compatibility with the product was demonstrated for the system consisting of a 50 ml syringe (polypropylene), a 2 m infusion tube (polyethylene) and an in-line filter with a 5 micrometer pore size. 

Pooling of vials (hospital use only): 

•        All steps should be completed under controlled and validated aseptic conditions by adequately trained staff.

•        If not reconstituted, pooled or used as recommended the in-use times and conditions prior to use are the responsibility of the user.

•        Ensure that a vial adapter is used irrespective of presentation.

•        Reconstitute the product as described above under Reconstitution for relevant product presentation. Unscrew the empty syringe from the vial adapter and for both presentations ensure that a vial adapter is attached to the vial containing reconstituted product.

•        Repeat the procedure with the appropriate number of additional vials, solvent vials/pre-filled syringes and vial adapters.

•        Draw approximately 5 ml of sterile air into the 50 ml syringe (polypropylene). Screw the syringe securely onto the vial adapter until resistance is felt. Hold the syringe slightly tilted with the vial pointing downwards. Push the plunger rod gently to inject a little air into the vial. Turn the syringe with the vial upside down and withdraw the contents of the vial into the syringe.

•        Repeat the above procedure with the remaining vials with reconstituted product, to obtain the desired volume in the syringe.

•        An in-line filter with a 5 micrometer pore size must be ensured for administration. Ensure that the syringe, the infusion tube and the in-line filter are primed and free of air before administration.

•        The syringe with adequately reconstituted product is now ready for administration in a CE-marked infusion pump (accepting a 50 ml syringe).

•        The infusion pump must only be operated by trained hospital personnel.

10.     date of revision of the text

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

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).

1 KIU equals 1,000 IU (International Units).

Eeptacog alfa (activated) is recombinant coagulation factor VIIa (rFVIIa) with a molecular mass of approximately 50,000 Daltons 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 thea full list of excipients, see sSection 6.1.

3.         PHARMACEUTICAL FORM

Powder and solvent for solution for injection.

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

4.         CLINICAL PARTICULARS

…

4.2      Posology and method of administration

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 mg 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.

Paediatric populationDosing 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 sSection 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. Only after consultation with the haemophilia treatment centre can continued home treatment be considered.

…

Factor VII deficiency

Dose, dose range and dose interval

The recommended dose range in adults and children 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.

Paediatric population

Limited clinical experience in long term prophylaxis has been gathered in the paediatric population below 12 years of age, with a severe clinical phenotype (see section 5.1).

Dose and frequency of injections for prophylaxis should be based on clinical response and 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 isare the first line treatment for Glanzmann’s thrombasthenia.

Method of administration

For instructions on Rreconstitution of the medicinal product before administration, see section 6.6. e the solution as described under section 6.6 and aAdminister the solution as an intravenous bolus injection over 2 – 5 minutes.

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4.3      Contraindications

Hypersensitivity to the active substance, or to any of the excipients listed in section 6.1, or to mouse, hamster or bovine protein.

4.4      Special warnings and precautions for use

…

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.

…

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

…

4.6      Fertility, Ppregnancy and lactation

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 sSection 5.3).

Breast-feedingLactation

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.

Fertility

Data from non-clinical studies as well as post-marketing data show no indication that rFVIIa has a harmful effect on male or female fertility.

4.7      Effects on ability to drive and use machines

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

4.8      Undesirable effects

Summary of the safety profile

The most frequently reported adverse drug reactions are decreased therapeutic response, pyrexia, rash, venous thromboembolic events, pruritus and urticaria. These reactions are reported as uncommon (≥ 1/1,000, < 1/100).

Tabulated summary of adverse reactions

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 sSection 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.

Description of selected adverse reactions.

Inhibitory antibody formation

In post-marketing experience, there have been no reports of inhibitory antibodies against NovoSeven or FVII in patients with haemophilia A or B. Development of inhibitory antibodies to NovoSeven has been reported in a post-marketing observational registry of patients with congenital FVII deficiency.

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 sSection 4.4).

Thromboembolic events- arterial and venous

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.

Other special populations

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 frequently (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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the online reporting option (preferred method) accessible from the IMB homepage (www.imb.ie). A downloadable report form is also accessible from the IMB website, which may be completed manually and submitted to the IMB via ‘freepost’ (see details below). Alternatively, the traditional post-paid ‘yellow card’ option may also be used.

FREEPOST

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

email: imbpharmacovigilance@imb.ie

4.9      Overdose

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

FourThree cases of overdose have been reported in patients with haemophilia in 163 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.

…

5.         PHARMACOLOGICAL PROPERTIES

5.1      Pharmacodynamic properties

Pharmacotherapeutic group: Blood coagulation factors, ATC code: B02BD08

Mechanism of action

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.

Pharmacodynamic effects

TAccordingly, 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.

In an observational registry (F7HAEM-3578) covering subjects with congenital FVII deficiency, the median dose for long term prophylaxis against bleeding in 22 paediatric patients (below 12 years of age) with Factor VII deficiency and a severe clinical phenotype was 30 µg/kg (range 17 µg/kg to 200 µg/kg; the dose most often used was 30 µg/kg in 10 patients) with a median dose frequency of 3 doses per week (range 1 to 7; the dose frequency most often reported was 3 per week in 13 patients).

In the same registry 3 out of 91 surgical patients experienced thromboembolic events.

5.2      Pharmacokinetic properties

Healthy subjects

Distribution, elimination and linearity

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 (3 doses each) 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.

, Tand the mean terminal half-life ranged from 3.9 to 6.0 hours.

The pharmacokinetic profiles indicated dose proportionality.

Haemophilia A and B with inhibitors

Distribution, elimination and linearity

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.

Mean volume of distribution at steady state was 196 ml/kg in paediatric patients versus 159 ml/kg in adults.

 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%.

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).

Factor VII deficiency

Distribution and elimination

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), Vvolume 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), total body clearance (70.8 –- 79.1 ml/h×kg) and mean residence time (3.75 – -3.80 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.

…

6.3      Shelf life

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 hasve been demonstrated for 6 hours at 25°C and 24 hours at 5°C.

…

6.6      Special precautions for disposal and other handling

…

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

…

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

…

Safely dispose of the used materials. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

…

10.     date of revision of the text

1204/2013

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

The exact changes to the SmPC can be seen as follows (new text shown in blue):

4.5      Interaction with other medicinal products and other forms of interaction

Based on a non-clinical study (see section 5.3) it is not recommended to combine rFVIIa and rFXIII. There are no clinical data available on interaction between rFVIIa and rFXIII.

4.8      Undesirable effects

Inhibitory antibody formation

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

5.3      Preclinical safety data

A potential synergistic effect of combined treatment with rFXIII and rFVIIa in an advanced cardiovascular model in cynomolgus monkey resulted in exaggerated pharmacology (thrombosis and death) at a lower dose level than when administering the individual compounds.

 
Section 8 - MA numbers
Powder in vial and solvent in pre-filled syringe:
NovoSeven® 1 mg EU/1/96/006/008
NovoSeven® 2 mg EU/1/96/006/009
NovoSeven® 5 mg EU/1/96/006/010

Disseminated intravascular coagulation and related laboratory findings including elevated levels of D-dimer and decreased levels of AT-III, (see Section 4.4)

6.3 Shelf Life

Shelf life has been increased from 2 years to 3 years

10.date of revision of the text

10/2010

4.6     Pregnancy and lactation

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

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:

* 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):

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 (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.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

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 in section 4.4.

–        Venous thrombotic events such as thrombophlebitis, deep vein thrombosis and hereto 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.

–        Thrombotic events of the liver. In the vast majority of cases the patients were predisposed due to liver disease or liver surgery.

Isolated cases of hypersensitivity reactions including anaphylactic reactions have been reported post-marketing. 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 rFVIIa. 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 treated with NovoSeven 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 rFVIIa.

4.9     Overdose

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.

A thrombotic event has been reported in an elderly (> 80 year) male patient with factor VII deficiency treated with 10 - 20 times the recommended dose.

 No other thrombotic complications from overdose have been reported, not even after treatment of a 6 year old boy with haemophilia A with inhibitors with 8 - 10 times the recommended dose.

10.     date of revision of the text

 Deleted and Added:

08/2008 05/2009

 Added:

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