NOVOSEVEN 1mg (50KUI) powder + solvent for injection medication leaflet

NovoSeven 1 mg (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 1 mg (50 KIU)

NovoSeven is presented as powder and solvent for solution for injection containing 1 mg eptacog alfa(activated) per vial (corresponds to 50 KIU/vial).

NovoSeven 2 mg (100 KIU)

NovoSeven is presented as powder and solvent for solution for injection containing 2 mg eptacog alfa(activated) per vial (corresponds to 100 KIU/vial).

NovoSeven 5 mg (250 KIU)

NovoSeven is presented as powder and solvent for solution for injection containing 5 mg eptacog alfa(activated) per vial (corresponds to 250 KIU/vial).

NovoSeven 8 mg (400 KIU)

NovoSeven is presented as powder and solvent for solution for injection containing 8 mg eptacog alfa(activated) per vial (corresponds to 400 KIU/vial).

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

eptacog alfa (activated) is recombinant coagulation factor VIIa (rFVIIa) with a molecular mass ofapproximately 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) when reconstituted withsolvent.

For the full list of excipients, see section 6.1.

Powder and solvent for solution for injection.

White lyophilised powder. Solvent: clear colourless solution. The reconstituted solution has a pH ofapproximately 6.0.

NovoSeven is indicated for the treatment of bleeding episodes and for the prevention of bleeding inthose 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 tofactor VIII or factor IX administration

* in patients with acquired haemophilia

* in patients with congenital FVII deficiency

* in patients with Glanzmann’s thrombasthenia with past or present refractoriness to platelettransfusions, or where platelets are not readily available.

Severe postpartum haemorrhage

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

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

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

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. Therecommended 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 treatmentand the interval between injections will vary with the severity of the haemorrhage, the invasiveprocedures or surgery being performed.

Current clinical experience does not warrant a general differentiation in dosing between children andadults, although children have faster clearance than adults. Therefore, higher doses of rFVIIa may beneeded in paediatric patients to achieve similar plasma concentrations as in adult patients (see section5.2).

Dose interval

Initially 2 - 3 hours to obtain haemostasis.

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

Mild to moderate bleeding episodes (including home therapy)

Early intervention has been shown to be efficacious in the treatment of mild to moderate joint, muscleand 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 beadministered.

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

The duration of home therapy should not exceed 24 hours. Only after consultation with thehaemophilia treatment centre can continued home treatment be considered.

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

Serious bleeding episodes

An initial dose of 90 µg per kg body weight is recommended and could be administered on the way tothe hospital where the patient is usually treated. The following dose varies according to the type andseverity of the haemorrhage. Dosing frequency should initially be every second hour until clinicalimprovement is observed. If continued therapy is indicated, the dose interval can then be increased to3 hours for 1 - 2 days. Thereafter, the dose interval can be increased successively to every 4, 6, 8 or12 hours for as long as treatment is judged as being indicated. A major bleeding episode may betreated 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. Thedose should be repeated after 2 hours and then at 2 - 3 hour intervals for the first 24 - 48 hoursdepending on the intervention performed and the clinical status of the patient. In major surgery, thedose should be continued at 2 - 4 hour intervals for 6 - 7 days. The dose interval may then beincreased 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. Therecommended 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 oftreatment and the interval between injections will vary with the severity of the haemorrhage, theinvasive procedures or the surgery being performed.

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

Factor VII deficiency

Dose, dose range and dose interval

The recommended dose range in adults and children for treatment of bleeding episodes and for theprevention of bleeding in patients undergoing surgery or invasive procedures is 15 - 30 μg per kgbody weight every 4 - 6 hours until haemostasis is achieved. Dose and frequency of injections shouldbe adapted to each individual.

Limited clinical experience in long term prophylaxis has been gathered in the paediatric populationbelow 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 toeach individual.

Glanzmann’s thrombasthenia

Dose, dose range and dose interval

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

For those patients who are not refractory, platelets is the first line treatment for Glanzmann’sthrombasthenia.

Severe postpartum haemorrhage

Dose range and dose interval

The recommended dose range for the treatment of bleeding is 60 - 90 µg per kg body weightadministered by intravenous bolus injection. Peak coagulant activity can be expected at 10 minutes. Asecond 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 administeredafter 30 minutes.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

Administer the solution 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 andclinical 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 andaPTT and clinical efficacy of rFVIIa.

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

In pathological conditions in which tissue factor may be expressed more extensively than considerednormal, there may be a 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, septicaemiaor DIC. Because of the risk of thromboembolic complications, caution should be exercised whenadministering NovoSeven to patients with a history of coronary heart disease, to patients with liverdisease, to post-operative patients, to pregnant or peripartum women, to neonates, or to patients at riskof thromboembolic events or DIC. 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, severehaemorrhage, transfusion, DIC, surgery/invasive procedures and coagulopathy) are knowncontributing factors to the thromboembolic risk; and in particular venous thromboembolic riskassociated with the administration of NovoSeven (see section 4.8).

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 possibilityexists that patients treated with the product may develop hypersensitivity to these proteins. In suchcases treatment with antihistamines i.v. should be considered.

If allergic or anaphylactic-type reactions occur, the administration should be discontinuedimmediately. In case of shock, standard medical treatment for shock should be implemented. Patientsshould be informed of the early signs of hypersensitivity reactions. If such symptoms occur, thepatient 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 specialised intreatment of haemophilia patients with coagulation factor VIII or IX inhibitors, or if not possible, inclose collaboration with a physician specialised in haemophilia treatment.

If bleeding is not kept under control hospital care is mandatory. Patients/carers should inform thephysician/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 coagulantactivity before and after administration of NovoSeven. In case the factor VIIa activity fails to reach theexpected level or bleeding is not controlled after treatment with the recommended doses, antibodyformation may be suspected and analysis for antibodies should be performed. Thrombosis has beenreported in FVII deficient patients receiving NovoSeven during surgery but the risk of thrombosis infactor VII deficient patients treated with NovoSeven is unknown (see section 5.1).

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

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

The risk of a potential interaction between NovoSeven and coagulation factor concentrates isunknown. Simultaneous use of prothrombin complex concentrates, activated or not, should beavoided.

Antifibrinolytics have been reported to reduce blood loss in association with surgery in haemophiliapatients, especially in orthopaedic surgery and surgery in regions rich in fibrinolytic activity, such asthe oral cavity. Antifibrinolytics are also used to reduce blood loss in women with postpartumhaemorrhage. Experience with concomitant administration of antifibrinolytics and rFVIIa treatment is,however, limited.

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.

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

It is unknown whether rFVIIa is excreted in human breast milk. The excretion of rFVIIa in milk hasnot been studied in animals. A decision on whether to continue/discontinue breast-feeding or tocontinue/discontinue therapy with NovoSeven should be made taking into account the benefit ofbreast-feeding to the child and the benefit of NovoSeven therapy to the woman.

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

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

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).

Table 1 lists adverse reactions reported during clinical trials and from spontaneous (post-marketing)reports. Within each frequency grouping, undesirable effects are presented in order of decreasingseriousness. Adverse drug reactions reported post-marketing only (i.e. not in clinical trials) arepresented with a frequency of ‘not known’.

Clinical trials conducted in 484 patients (including 4297 treatment episodes) with haemophilia A and

B, acquired haemophilia, factor VII deficiency or Glanzmann’s thrombasthenia have shown thatadverse drug reactions are common (≥ 1/100 to < 1/10). As the total number of treatment episodes inclinical trials is below 10,000, the lowest possible frequency of adverse drug reactions that can beassigned is rare (≥ 1/10,000 to < 1/1,000).

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

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

Table 1 Adverse reactions from clinical trials and spontaneous (post-marketing) reports

MedDRA system Uncommon (≥1/1,000 to Rare (≥1/10,000 to <1/1,000) Frequency Not Knownorgan class <1/100)

Blood and - Disseminatedlymphatic system intravascular coagulationdisorders (see section 4.4)

- Related laboratoryfindings, includingelevated levels of D-dimer and decreasedlevels of AT (see section4.4)

- Coagulopathy

Gastrointestinal - Nauseadisorders

General disorders - Therapeutic response - Injection site reactionand decreased* including injection siteadministration painsite conditions - Pyrexia

Immune system - Hypersensitivity (see - Anaphylactic reactiondisorders sections 4.3 and 4.4)

Investigations - Increased fibrindegradation products

- Increase of alanineaminotransferase,alkaline phosphatase,lactate dehydrogenaseand prothrombin

Nervous system - Headachedisorders

Skin and - Rash (including - Flushingsubcutaneous allergic dermatitis andtissue disorders rash erythematous) - Angioedema

- Pruritus and urticaria

Vascular - Venous - Arterial thromboembolic - Intracardiac thrombusdisorders thromboembolic events (myocardialevents (deep vein infarction, cerebralthrombosis, infarction, cerebralthrombosis at i.v. site, ischaemia, cerebralpulmonary embolism, artery occlusion,thromboembolic cerebrovascular accident,events of the liver renal artery thrombosis,including portal vein peripheral ischaemia,thrombosis, renal vein peripheral arterialthrombosis, thrombosis and intestinalthrombophlebitis, ischaemia)superficialthrombophlebitis and - Angina pectorisintestinal ischaemia)

* Lack of efficacy (therapeutic response decreased) has been reported. It is important that the dosageregimen of NovoSeven is compliant with the recommended dosage as stated in section 4.2.

Inhibitory antibody formation

In post-marketing experience, there have been no reports of inhibitory antibodies against NovoSevenor FVII in patients with haemophilia A or B. Development of inhibitory antibodies to NovoSeven hasbeen 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 somecases, the antibodies showed inhibitory effect in vitro. Risk factors that may have contributed toantibody 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 VIIdeficiency treated with NovoSeven should be monitored for factor VII antibodies (see section 4.4).

Thromboembolic events - arterial and venous

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

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

Thromboembolic events may lead to cardiac arrest.

Patients with acquired haemophilia

Clinical trials conducted in 61 patients with acquired haemophilia with a total of 100 treatmentepisodes, showed that certain adverse drug reactions were reported more frequently (1% based ontreatment episodes): Arterial thromboembolic events (cerebral artery occlusion, cerebrovascularaccident), venous thromboembolic events (pulmonary embolism and deep vein thrombosis), anginapectoris, nausea, pyrexia, erythematous rash and investigation of increased levels of fibrin degradationproducts.

Women with severe postpartum haemorrhage

In an open-label randomised clinical trial, venous thromboembolic events were reported in 2 of 51patients treated with a single dose of NovoSeven (median dose 58 μg/kg) and none of 33 patients nottreated 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 thromboembolicevents were reported in 1 (0.3%) patient treated with NovoSeven.

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

Four cases of overdose have been reported in patients with haemophilia in 16 years. The onlycomplication reported in connection with an overdose was a slight transient increase in blood pressurein 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’sthrombasthenia.

In patients with factor VII deficiency, where the recommended dose is 15 - 30 µg/kg rFVIIa, oneepisode 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, thedevelopment of antibodies against NovoSeven and FVII has been associated with overdose in onepatient with factor VII deficiency.

The dose schedule should not be intentionally increased above the recommended doses due to theabsence 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 includesthe binding of factor VIIa to exposed tissue factor. This complex activates factor IX into factor IXaand factor X into factor Xa, leading to the initial conversion of small amounts of prothrombin intothrombin. Thrombin leads to the activation of platelets and factors V and VIII at the site of injury andto the formation of the haemostatic plug by converting fibrinogen into fibrin. Pharmacological dosesof NovoSeven activate factor X directly on the surface of activated platelets, localized to the site ofinjury, independently of tissue factor. This results in the conversion of prothrombin into large amountsof thrombin independently of tissue factor.

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 minutesin healthy subjects and patients with haemophilia.

A theoretical risk for the development of systemic activation of the coagulation system in patientssuffering from underlying diseases predisposing them to DIC cannot be totally excluded.

Congenital FVII deficiency

In an observational registry (F7HAEM-3578) covering subjects with congenital FVII deficiency, themedian dose for long term prophylaxis against bleeding in 22 paediatric patients (below 12 years ofage) with Factor VII deficiency and a severe clinical phenotype was 30 µg/kg (range 17 µg/kg to200 µg/kg; the dose most often used was 30 µg/kg in 10 patients) with a median dose frequency of 3doses 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 thrombastheniatreated with NovoSeven. The median dose per infusion for treatment of 333 bleeding episodes was90 µg/kg (range 28 to 450 µg/kg). NovoSeven was used in 157 surgical procedures, at a median doseof 92 µg/kg (up to 270 µg/kg). Treatment with NovoSeven, alone or in combination withantifibrinolytics and/or platelets, was defined as effective when bleeding was stopped for at least 6hours. The efficacy rates were 81% and 82%, respectively, in patients with positive or negativerefractoriness to platelet transfusions, and 77% and 85%, respectively, in patients testing positive ornegative 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 postpartumhaemorrhage in a multicentre, open-label clinical trial. Patients were randomised either to treatmentwith a single dose of 60 µg/kg of NovoSeven (in addition to standard of care; N=42) or to referencetherapy (standard of care alone; N=42), following failure of uterotonics (sulprostone). The treatmentgroups were well balanced in terms of demographic characteristics and postpartum haemorrhagetreatment 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 inthe NovoSeven group and 43% of patients in the reference group. Of these, about 40% of the patientsin 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 withinthe 30 minutes following randomisation. If the bleeding was uncontrolled or intractable, invasiveprocedures were considered.

In the primary analysis, fewer women in the NovoSeven group (21 vs 35) had at least oneembolisation and/or ligation procedure compared to the reference group, corresponding to astatistically significant 40% relative reduction in risk for the NovoSeven group compared to thereference 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 inan attempt to avoid salvage hysterectomy, which succeeded in 2 cases.

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 sexand ethnic group and dosed with 40, 80 and 160 µg rFVIIa per kg body weight (3 doses each) and/orplacebo. 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 ofclearance ranged from 33.3 to 37.2 ml/h×kg.

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 inadults.

Mean clearance was approximately 50% higher in paediatric patients relative to adults (78 versus53 ml/h×kg), whereas the mean terminal half-life was determined to 2.3 hours in both groups.

Clearance appears related with age, therefore in younger patients clearance may be increased by morethan 50%.

Dose proportionality was established in children for the investigated doses of 90 and 180 µg per kgbody 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 significantdifference between the two doses used with regard to dose-independent parameters:

Volume of distribution at steady state (280 - 290 ml/kg), 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 beeninvestigated, but are expected to be similar to the pharmacokinetics in haemophilia A and B patients.

Severe postpartum haemorrhage

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

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

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

Sodium chloride

Calcium chloride dihydrate

Glycylglycine

Polysorbate 80

Mannitol

Sucrose

Methionine

Hydrochloric acid (for pH-adjustment)

Sodium hydroxide (for pH-adjustment)

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.

In vial

After reconstitution, chemical and physical stability has been demonstrated for 6 hours at 25°C and24 hours at 5°C.

From a microbiological point of view, the product should be used immediately. If not usedimmediately, storage time and storage conditions prior to use are the responsibility of the user, andshould not be longer than 24 hours at 2°C - 8°C, unless reconstitution has taken place in controlledand 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 trainedstaff. Under these conditions, chemical and physical stability has been demonstrated for 24 hours at25°C when stored in a 50 ml syringe (polypropylene). If not used immediately, the conditions prior touse are the responsibility of the user and the in-use storage time must not be longer than as statedabove.

- Store powder and solvent below 25°C.- Store powder and solvent protected from light.- Do not freeze.- For storage conditions of the reconstituted medicinal product, see section 6.3.

The solvent of NovoSeven is provided in a pre-filled syringe. Not all presentations may be marketed.

The NovoSeven 1 mg (50 KIU)/NovoSeven 2 mg (100 KIU) package contains- 1 vial (2 ml) with white powder for solution for injection- 1 pre-filled syringe (3 ml) with solvent for reconstitution- 1 plunger rod- 1 vial adapter, with an integrated particle filter with a pore size of 25 micrometer.

The NovoSeven 5 mg (250 KIU)/NovoSeven 8 mg (400 KIU) package contains- 1 vial (12 ml) with white powder for solution for injection- 1 pre-filled syringe (10 ml) with solvent for reconstitution- 1 plunger rod- 1 vial adapter, with an integrated particle filter with a pore size of 25 micrometer.

Vial: Type I glass vial closed with a chlorobutyl rubber stopper, covered with an aluminium cap. Theclosed vial is equipped with a polypropylene tamper-evident snap-off cap.

Pre-filled syringe: Type I glass barrel with a polypropylene backstop and bromobutyl rubber plunger.

The syringe cap consists of bromobutyl rubber and polypropylene tamper evident seal.

Plunger rod: made of polypropylene.

The solvent of NovoSeven is provided in a pre-filled syringe. Not all presentations may be marketed.

Handling procedures are described below.

Powder in vial and solvent in pre-filled syringe:

Always use an aseptic technique.

* The NovoSeven powder vial and pre-filled syringe with solvent should be at room temperatureat reconstitution. Remove the plastic cap from the vial. If the cap is loose or missing, do not usethe vial. Wipe the rubber stopper on the vial with a sterile alcohol swab and allow it to dry for afew seconds before use. Do not touch the rubber stopper after wiping it.

* Remove the protective paper from the vial adapter. Do not take the vial adapter out of theprotective cap. If the protective paper is not fully sealed or it is broken do not use the vialadapter. Turn over the protective cap, and snap the vial adapter onto the vial. Lightly squeezethe protective cap with the thumb and index finger. Remove the protective cap from the vialadapter.

* Screw the plunger rod clockwise into the plunger inside the pre-filled syringe until resistance isfelt. Remove the syringe cap from the pre-filled syringe by bending it down until the perforationbreaks. Do not touch the syringe tip under the syringe cap. If the syringe cap is loose or missing,do not use the pre-filled syringe.

* Screw the pre-filled syringe securely onto the vial adapter until resistance is felt. Hold the pre-filled syringe slightly tilted with the vial pointing downwards. Push the plunger rod to inject allthe solvent into the vial. Keep the plunger rod pressed down and swirl the vial gently until allthe powder is dissolved. Do not shake the vial as this will cause foaming.

If a larger dose is needed, repeat the procedure with additional vials, pre-filled syringes and vialadapters.

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

It is recommended to use NovoSeven immediately after reconstitution. For storage conditions of thereconstituted medicinal product, see section 6.3.

* Keep the plunger rod pushed completely in. Turn the syringe with the vial upside down. Stoppushing the plunger rod and let it move back on its own while the reconstituted solution fills thesyringe. Pull the plunger rod slightly downwards to draw the mixed solution into the syringe.

* While holding the vial upside down, tap the syringe gently to let any air bubbles rise to the top.

Push the plunger rod slowly until all air bubbles are gone.

If the entire dose is not required, use the scale on the syringe to see how much mixed solution iswithdrawn.

* Unscrew the vial adapter with the vial.

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

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

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 hoursat 25°C in a 50 ml syringe (polypropylene). Compatibility with the product was demonstrated for thesystem consisting of a 50 ml syringe (polypropylene), a 2 m infusion tube (polyethylene) and in-linefilters within the range of 0.2 to 5 micrometer pore size.

Pooling of vials (hospital use only):

* All steps should be completed under controlled and validated aseptic conditions by adequatelytrained staff.

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

* Ensure that a vial adapter is used.

* Reconstitute the product as described above under Reconstitution. Unscrew the empty syringefrom the vial adapter and ensure that a vial adapter is attached to the vial containingreconstituted product.

* Repeat the procedure with the appropriate number of additional vials, pre-filled syringes andvial adapters.

* Draw approximately 5 ml of sterile air into the 50 ml syringe (polypropylene). Screw thesyringe securely onto the vial adapter until resistance is felt. Hold the syringe slightly tilted withthe vial pointing downwards. Push the plunger rod gently to inject a little air into the vial. Turnthe 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 thedesired volume in the syringe.

* An in-line filter within the range of 0.2 to 5 micrometer pore size must be ensured foradministration. Ensure that the syringe, the infusion tube and the in-line filter are primed andfree 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.

Novo Nordisk A/S

Novo Allé

DK-2880 Bagsværd

Denmark

NovoSeven 1 mg (50 KIU)

EU/1/96/006/008

NovoSeven 2 mg (100 KIU)

EU/1/96/006/009

NovoSeven 5 mg (250 KIU)

EU/1/96/006/010

NovoSeven 8 mg (400 KIU)

EU/1/96/006/011

Date of first authorisation: 23 February 1996

Date of latest renewal: 09 February 2006

Detailed information on this medicinal product is available on the website of the European Medicines

Agency (EMA) http://www.ema.europa.eu.