NovoSeven®1 mg, 2 mg and 5 mgpowder and solvent for solution for injection

Qualitative and quantitative compositioneptacog alfa (activated) 1 mg/vial (corresponds to50 KIU/vial), 1 mg/ml after reconstitutioneptacog alfa (activated) 2 mg/vial (corresponds to100 KIU/vial), 1 mg/ml after reconstitutioneptacog alfa (activated) 5 mg/vial (corresponds to250 KIU/vial), 1 mg/ml after reconstitution1 KIU equals 1000 IU (International Units)eptacog alfa (activated) is recombinant coagulationfactor VIIa (rFVIIa) with a molecular mass ofapproximately 50,000 Dalton produced in babyhamster kidney cells (BHK Cells) by recombinantDNA technology.

Excipients:After reconstitution 1 ml solution contains 10 mgsucrose.For a full list of excipients, see List of excipients.

Pharmaceutical formPowder and solvent for solution for injection.White lyophilised powder. Solvent: clear colourlesssolution. The reconstituted solution has a pH ofapproximately 6.0.

Clinical particularsTherapeutic indicationsNovoSeven® is indicated for the treatment ofbleeding episodes and for the prevention ofbleeding in those undergoing surgery or invasiveprocedures in the following patient groups:• in patients with congenital haemophilia with

inhibitors to coagulation factors VIII or IX > 5 BU• in patients with congenital haemophilia who

are expected to have a high anamnesticresponse to factor VIII or factor IXadministration

• 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, andwith past or present refractoriness to platelettransfusions.

Posology and method of administrationTreatment should be initiated under the supervisionof a physician experienced in the treatment ofhaemophilia and/or bleeding disorders.

DosageHaemophilia A or B with inhibitors orexpected to have a high anamnestic responseDoseNovoSeven® should be given as early as possibleafter the start of a bleeding episode. Therecommended initial dose, administered byintravenous bolus injection, is 90 µg per kg bodyweight.Following the initial dose of NovoSeven® furtherinjections may be repeated. The duration oftreatment and the interval between injections willvary with the severity of the haemorrhage, theinvasive procedures or surgery being performed.

Dosing in childrenCurrent clinical experience does not warrant ageneral differentiation in dosing between childrenand adults, although children have faster clearance

than adults. Therefore, higher doses of rFVIIa maybe needed in paediatric patients to achieve similarplasma concentrations as in adult patients, seePharmacokinetic properties.

Dose intervalInitially 2-3 hours to obtain haemostasis.If continued therapy is needed, the dose intervalcan be increased successively once effectivehaemostasis is achieved to every 4, 6, 8 or12 hours for as long as treatment is judged asbeing indicated.

Mild to moderate bleeding episodes(including home therapy)Early intervention has been shown to be efficaciousin the treatment of mild to moderate joint, muscleand mucocutaneous bleeds. Two dosing regimenscan 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 additionaldose of 90 µg per kg body weight can beadministered.

2) One single injection of 270 µg per kg bodyweight.

The duration of the home therapy should notexceed 24 hours.There is no clinical experience with administrationof a single dose of 270 µg per kg body weight inelderly patients.

Serious bleeding episodesAn initial dose of 90 µg per kg body weight isrecommended and could be administered on theway to the hospital where the patient is usuallytreated. The following dose varies according to thetype and severity of the haemorrhage. Dosingfrequency should initially be every second houruntil clinical improvement is observed. If continuedtherapy is indicated, the dose interval can then beincreased to 3 hours for 1-2 days. Thereafter, thedose interval can be increased successively to every4, 6, 8 or 12 hours for as long as treatment isjudged as being indicated. A major bleedingepisode may be treated for 2-3 weeks but can beextended beyond this if clinically warranted.

Invasive procedure/surgeryAn initial dose of 90 µg per kg body weight shouldbe given immediately before the intervention. Thedose should be repeated after 2 hours and then at2-3 hour intervals for the first 24-48 hoursdepending on the intervention performed and theclinical status of the patient. In major surgery, thedose should be continued at 2-4 hour intervals for6-7 days. The dose interval may then be increasedto 6-8 hours for another 2 weeks of treatment.Patients undergoing major surgery may be treatedfor up to 2-3 weeks until healing has occurred.

Acquired haemophiliaDose and dose intervalNovoSeven® should be given as early as possibleafter the start of a bleeding episode. Therecommended initial dose, administered byintravenous bolus injection, is 90 µg per kg bodyweight. Following the initial dose of NovoSeven®further injections may be given if required. Theduration of treatment and the interval betweeninjections will vary with the severity of thehaemorrhage, the invasive procedures or thesurgery being performed.The initial dose interval should be 2-3 hours. Oncehaemostasis has been achieved, the dose intervalcan be increased successively to every 4, 6, 8 or12 hours for as long as treatment is judged to beindicated.

Factor VII deficiencyDose, dose range and dose intervalThe recommended dose range for treatment ofbleeding episodes and for the prevention ofbleeding in patients undergoing surgery or invasiveprocedures is 15-30 μg per kg body weight every4-6 hours until haemostasis is achieved. Dose andfrequency of injections should be adapted to eachindividual.

Glanzmann’s thrombastheniaDose, dose range and dose intervalThe recommended dose for treatment of bleedingepisodes and for the prevention of bleeding inpatients undergoing surgery or invasive proceduresis 90 µg (range 80-120 µg) per kg body weight atintervals of two hours (1.5-2.5 hours). At leastthree doses should be administered to secureeffective haemostasis. The recommended route ofadministration is bolus injection as lack of efficacymay appear in connection with continuousinfusion.For those patients who are not refractory, plateletsare the first line treatment for Glanzmann’sthrombasthenia.

Method of administrationReconstitute the solution as described underNovoSeven® user instructions and administer asan intravenous bolus injection over 2-5 minutes.

Monitoring of treatment – laboratory testsThere is no requirement for monitoring ofNovoSeven® therapy. Severity of bleeding condition

the mean terminal half-life was determined to2.3 hours in both groups. Mean volume ofdistribution at steady state was 196 mL/kg inpaediatric patients versus 159 mL/kg in adults.Clearance appears related with age, therefore inyounger patients clearance may be increased bymore than 50%.

Factor VII deficiencySingle dose pharmacokinetics of rFVIIa, 15 and30 μg per kg body weight, showed no significantdifference between the two doses used withregard to dose-independent parameters: total bodyclearance (70.8-79.1 ml/h×kg), volume ofdistribution at steady state (280-290 ml/kg), meanresidence time (3.75-3.80 h), and half-life(2.82-3.11 h). The mean in vivo plasma recoverywas approximately 20%.

Glanzmann’s thrombastheniaPharmacokinetics of NovoSeven® in patients withGlanzmann’s thrombasthenia have not beeninvestigated, but are expected to be similar to thepharmacokinetics in haemophilia A and B patients.

Preclinical safety dataAll findings in the preclinical safety programmewere related to the pharmacological effect ofrFVIIa.

Pharmaceutical particularsList of excipientsPowderSodium chloride, calcium chloride dihydrate,glycylglycine, polysorbate 80, mannitol, sucrose,methionine, hydrochloric acid (for pH-adjustment)and sodium hydroxide (for pH-adjustment).

SolventHistidine, hydrochloric acid (for pH-adjustment),sodium hydroxide (for pH-adjustment) and waterfor injections.

IncompatibilitiesNovoSeven® must not be mixed with infusionsolutions or be given in a drip.

Shelf lifeAfter reconstitution, chemical and physical stabilityhave been demonstrated for 6 hours at 25°C and24 hours at 5°C.From a microbiological point of view, the productshould be used immediately. If not usedimmediately, storage time and storage conditionsprior 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.

Special precautions for storage– 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 Shelf life.

Nature and contents of containerEach NovoSeven® package contains:– 1 vial with white powder for solution for

injection– 1 vial with solvent for reconstitution.The NovoSeven® package contains Type I glass vialsclosed with a chlorobutyl rubber stopper, coveredwith an aluminium cap.The closed vials are equipped with atamper-evident snap-off cap which is made ofpolypropylene.Not all pack sizes may be marketed.

Marketing authorisation holderNovo Nordisk A/SNovo AlléDK-2880 BagsværdDenmark

breast-feeding to the child and the benefit ofNovoSeven® therapy to the woman.

Effects on ability to drive and use machinesNo studies on the effect on the ability to drive anduse machines have been performed.

Undesirable effectsClinical trials conducted in 484 patients (including4297 treatment episodes) with haemophilia A andB, acquired haemophilia, factor VII deficiency orGlanzmann’s thrombasthenia have shown thatadverse drug reactions are common (≥ 1/100 to< 1/10). As the total number of treatment episodesis below 10,000, the lowest possible frequency ofadverse drug reactions that can be assigned is rare(> 1/10,000, < 1/1,000).The most frequent adverse drug reactions arepyrexia and rash (uncommon: > 1/1,000, < 1/100),and the most serious adverse drug reactions arethromboembolic events.The frequencies of both serious and non-seriousadverse drug reactions are listed by system organclasses below.

Blood and lymphatic system disordersRare (> 1/10,000, < 1/1,000)Disseminated intravascular coagulation and relatedlaboratory findings including elevated levels ofD-dimer and AT-III, see Special warnings andprecautions for useCoagulopathy

Immune system disordersRare (> 1/10,000,< 1/1,000)Hypersensitivity, see Contraindications and Specialwarnings and precautions for useNot knownAnaphylactic reaction

Nervous system disordersRare (> 1/10,000, < 1/1,000)Headache

Vascular disordersRare (> 1/10,000, < 1/1,000)Arterial thromboembolic events: (myocardialinfarction, cerebral infarction, cerebral ischaemia,cerebral artery occlusion, cerebrovascular accident,renal artery thrombosis, peripheral ischaemia,peripheral arterial thrombosis and intestinalischaemia)Uncommon (> 1/1,000, < 1/100)Venous thromboembolic events: (deep veinthrombosis, thrombosis at i.v. site, pulmonaryembolism, thromboembolic events of the liverincluding portal vein thrombosis, renal veinthrombosis, thrombophlebitis, superficialthrombophlebitis and intestinal ischaemia)Rare (> 1/10,000, < 1/1,000)Angina pectoris

Gastrointestinal disordersRare (> 1/10,000, < 1/1,000)Nausea

Skin and subcutaneous disordersUncommon (> 1/1,000, < 1/100)Rash (including allergic dermatitis and rasherythematous)Pruritus and urticaria

Not knownFlushingAngioedema

General disorders and administration siteconditionsUncommon (> 1/1,000, < 1/100)Therapeutic response decreased*Pyrexia

Rare (> 1/10,000, < 1/1,000)Injection site reaction

Not knownInjection site pain

InvestigationsRare (> 1/10,000, < 1/1,000)Increase of alanine aminotransferase, alkalinephosphatase, lactate dehydrogenase andprothrombin.

Within each frequency grouping, undesirableeffects are presented in order of decreasingseriousness. Adverse drug reaction reportedpost-marketing only (i.e. not in clinical trials) arepresented with a frequency of not known.*Lack of efficacy (therapeutic response decreased)has been reported. It is important that the dosageregimen of NovoSeven® is compliant with therecommended dosage as stated in Dosage.Arterial thromboembolic events in patients withacquired haemophilia have a frequency ofcommon (≥ 1/100 to < 1/10).When NovoSeven® is administered to patientsoutside approved indications, arterialthromboembolic events are common(≥ 1/100 to < 1/10). A higher risk of arterialthromboembolic adverse events (5.6% in patientstreated with NovoSeven® versus 3.0% inplacebo-treated patients) has been shown in ameta-analysis of pooled data fromplacebo-controlled trials conducted outside current

approved indications in various clinical settings,each of these having distinct patient characteristicsand hence different underlying risk profiles.Safety and efficacy of NovoSeven® have not beenestablished outside the approved indications andtherefore NovoSeven® is not recommended.Thromboembolic events may lead to cardiac arrest.There have been no confirmed reports ofantibodies against NovoSeven® or FVII in patientswith haemophilia A or B.

Patients with Factor VII deficiencyFormation of antibodies against NovoSeven® andFVII is the only adverse drug reaction reported inthese clinical trials of patients with factor VIIdeficiency exposed to NovoSeven® (frequency:common (≥ 1/100 to < 1/10)). In two out of fivepatients with reported antibody formation againstNovoSeven® and FVII, reported in clinical trials andpost-marketing, the antibodies showed inhibitoryeffect in vitro. Risk factors that may havecontributed to antibody development includingprevious treatment with human plasma and/orplasma-derived factor VII, severe mutation of FVIIgene, and overdose of NovoSeven®, were present.Patients with factor VII deficiency treated withNovoSeven® should be monitored for factor VIIantibodies, see Special warnings and precautionsfor use.

OverdoseDose limiting toxicities of NovoSeven® have notbeen investigated in clinical trials.A few cases of overdose have been reported inpatients with haemophilia. The only complicationreported in connection with an overdose was aslight transient increase in blood pressure in a16 year-old patient receiving 24 mg rFVIIa insteadof 5.5 mg.No cases of overdose have been reported inpatients with acquired haemophilia or Glanzmann’sthrombasthenia.In patients with factor VII deficiency, where therecommended dose is 15-30 µg/kg rFVIIa, oneepisode of overdose has been associated with athrombotic event (occipital stroke) in an elderly(> 80 year) male patient treated with 10-20 timesthe 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 intentionallyincreased above the recommended doses due tothe absence of information on the additional riskthat may be incurred.

Pharmacological propertiesPharmacodynamic propertiesPharmacotherapeutic group: Blood Coagulationfactors, ATC code: B02BD08NovoSeven® contains activated recombinantcoagulation factor VII. The mechanism of actionincludes the binding of factor VIIa to exposedtissue factor. This complex activates factor IX intofactor IXa and factor X into factor Xa, leading tothe initial conversion of small amounts ofprothrombin into thrombin. Thrombin leads to theactivation of platelets and factors V and VIII at thesite of injury and to the formation of thehaemostatic plug by converting fibrinogen intofibrin. Pharmacological doses of NovoSeven®activate factor X directly on the surface ofactivated platelets, localised to the site of injury,independently of tissue factor. This results in theconversion of prothrombin into large amounts ofthrombin independently of tissue factor.Accordingly, the pharmacodynamic effect of factorVIIa gives rise to an increased local formation offactor Xa, thrombin and fibrin.A theoretical risk for the development of systemicactivation of the coagulation system in patientssuffering from underlying diseases predisposingthem to DIC cannot be totally excluded.

Pharmacokinetic propertiesHealthy subjectsUsing the FVII clotting assay, the pharmacokineticsof NovoSeven® were investigated in 35 healthyCaucasian and Japanese subjects in a dose-escalation study. Subjects were stratified accordingto sex and ethnic group and dosed with 40, 80and 160 µg NovoSeven® per kg body weightand/or placebo (3 doses each). Thepharmacokinetic profiles indicated doseproportionality. The pharmacokinetics were similaracross sex and ethnic groups. The mean steadystate volume of distribution ranged from 130 to165 mL/kg, the mean values of clearance rangedfrom 33.3 to 37.2 ml/h×kg, and the meanterminal half-life ranged from 3.9 to 6.0 hours.

Haemophilia A and B with inhibitorsUsing the FVIIa assay, the pharmacokineticproperties of NovoSeven® were studied in12 paediatric (2-12 years) and five adult patients innon-bleeding state. Dose proportionality wasestablished in children for the investigated doses of90 and 180 µg per kg body weight, which is inaccordance with previous findings at lower doses(17.5-70 µg/kg rFVIIa). The mean clearance wasapproximately 50% higher in paediatric patientsrelative to adults (78 versus 53 ml/h×kg), whereas

and clinical response to NovoSeven® administrationmust guide dosing requirements.After administration of rFVIIa, prothrombin time(PT) and activated partial thromboplastin time(aPTT) have been shown to shorten, however, nocorrelation has been demonstrated between PTand aPTT and clinical efficacy of rFVIIa.

ContraindicationsHypersensitivity to the active substance, or to anyof the excipients, or to mouse, hamster or bovineprotein.

Special warnings and precautions for useIn pathological conditions in which tissue factormay be expressed more extensively thanconsidered normal, there may be a potential risk ofdevelopment of thrombotic events or induction ofDisseminated Intravascular Coagulation (DIC) inassociation with NovoSeven® treatment.Such situations may include patients withadvanced atherosclerotic disease, crush injury,septicaemia or DIC. Because the risk ofthromboembolic complications, caution should beexercised when administering NovoSeven® topatients with a history of coronary heart disease, topatients with liver disease, to patients followingmajor surgery, to neonates, or to patients at risk ofthromboembolic phenomena or disseminatedintravascular coagulation. In each of thesesituations, the potential benefit of treatment withNovoSeven® should be weighed against the risk ofthese complications.As recombinant coagulation factor VIIaNovoSeven® may contain trace amounts of mouseIgG, bovine IgG and other residual culture proteins(hamster and bovine serum proteins), the remotepossibility exists that patients treated with theproduct may develop hypersensitivity to theseproteins. In such cases treatment withantihistamines i.v. should be considered.If allergic or anaphylactic-type reactions occur, theadministration should be discontinuedimmediately. In case of shock, standard medicaltreatment for shock should be implemented.Patients should be informed of the early signs ofhypersensitivity reactions. If such symptoms occur,the patient should be advised to discontinue use ofthe product immediately and contact theirphysician.In case of severe bleeds, the product should beadministered in hospitals preferably specialised intreatment of haemophilia patients withcoagulation factor VIII or IX inhibitors, or if notpossible, in close collaboration with a physicianspecialised in haemophilia treatment.If bleeding is not kept under control, hospital careis mandatory. Patients/carers should inform thephysician/supervising hospital at the earliestpossible opportunity about all usages ofNovoSeven®.Factor VII deficient patients should be monitoredfor prothrombin time and factor VII coagulantactivity before and after administration ofNovoSeven®. In case the factor VIIa activity fails toreach the expected level or bleeding is notcontrolled after treatment with the recommendeddoses, antibody formation may be suspected andanalysis for antibodies should be performed. Therisk of thrombosis in factor VII deficient patientstreated with NovoSeven® is unknown.Patients with rare hereditary problems of fructoseintolerance, glucose malabsorption or sucrose-isomaltase insufficiency should not take thismedicine.

Interaction with other medicinal products andother forms of interactionThe risk of a potential interaction betweenNovoSeven® and coagulation factor concentrates isunknown. Simultaneous use of prothrombincomplex concentrates, activated or not, should beavoided.Anti-fibrinolytics have been reported to reduceblood loss in association with surgery inhaemophilia patients, especially in orthopaedicsurgery and surgery in regions rich in fibrinolyticactivity, such as the oral cavity. Experience withconcomitant administration of anti-fibrinolytics andrFVIIa treatment is, however, limited.

Pregnancy and lactationPregnancyAs a precautionary measure it is preferable to avoidthe use of NovoSeven® during pregnancy. Data ona limited number of exposed pregnancies withinapproved indications indicate no adverse effects ofrFVIIa on pregnancy or on the health of thefoetus/new-born child. To date, no other relevantepidemiological data are available. Animal studiesdo not indicate direct or indirect harmful effectswith respect to pregnancy, embryonal/foetaldevelopment, parturition or postnataldevelopment, see Preclinical safety data.

LactationIt is unknown whether rFVIIa is excreted in humanbreast milk. The excretion of rFVIIa in milk has notbeen studied in animals. A decision on whether tocontinue/discontinue breast-feeding or tocontinue/discontinue therapy with NovoSeven®should be made taking into account the benefit of

8-90

22-0

0-00

3-1

NovoSeven®1 mg, 2 mg and 5 mgpowder and solvent for solution forinjection

Code: 100% directionLength: Max 25 mm (100%)

Code centre line

RA Labelling & IT

Insert: 420x342-011Current 1.01 languageProf

Colour: PMS 280C

8-9022-00-003-1_v1-7:layout 1 2010-02-17 9:53 AM Page 1

Solvent vial Powder vial

Plastic cap

Rubber stopperRubber stopper

Plastic cap

Remove the protective paperfrom the vial adapter withouttaking it out of the protectivecap. Attach the vial adapter tothe solvent vial. Onceattached, remove theprotective cap. Take care notto touch the spike on the vialadapter. If using a needle,remove needle from thepackaging without taking itout of the protective cap.Screw the needle tightly ontothe syringe.

Pull the plunger to draw in avolume of air that is equal tothe amount of solvent in thesolvent vial (ml equals cc onthe syringe).

Screw the syringe tightly ontothe vial adapter on the solventvial. If using a needle, removethe protective cap and insertthe needle into the rubberstopper of the solvent vial.Take care not to touch the endof the needle. Inject air intothe vial by pushing the plungeruntil you feel a clearresistance.

Preparing the solutionWash your hands. NovoSeven® powder and solvent vials should be atroom temperature at reconstitution. Remove the plastic caps from the twovials. If the caps are loose or missing, do not use the vials. Clean therubber stoppers on the vials with alcohol swabs and allow them to drybefore use. Use a disposable syringe of an appropriate size and a vialadapter, transfer needle (20-26G) or other suitable device.

A

B

C

NOVOSEVEN® USER INSTRUCTIONS

Remove the empty solvent vial.If you use a vial adapter, tipthe syringe to remove it fromthe vial.

Attach the syringe with vialadapter or transfer needle tothe powder vial. If you use atransfer needle, make sure topenetrate the centre of therubber stopper. Hold thesyringe slightly tilted with thevial facing downwards. Pushthe plunger slowly to inject thesolvent into the powder vial.Make sure not to aim thestream of solvent directly atthe NovoSeven® powder asthis will cause foaming.

Gently swirl the vial until allthe powder is dissolved. Donot shake the vial as this willcause foaming. Check thesolution for bits anddiscolouration. If you noticeeither, do not use it.NovoSeven® reconstitutedproduct is a clear, colourlesssolution. Keep the vial adapteror needle attached to the vial.

E

F

G

Although NovoSeven® will be stable for 24 hours after it has beenmixed, you should use it at once to avoid infection. If you do not use itimmediately after mixing, you should store the vial with the syringe stillattached in a refrigerator at 2°C-8°C for no longer than 24 hours. Do notstore the solution without your doctor’s advice.

Hold the syringe with thesolvent vial upside down. Ifyou are using a transferneedle, make sure that theneedle tip is in the solvent.Pull the plunger to draw thesolvent into the syringe.

D

Ensure that the plunger ispushed all the way in beforeturning the syringe upsidedown (it may have beenpushed out by the pressure inthe syringe). If you use atransfer needle, make surethat the transfer needle tip isin the solution. Hold thesyringe with the vial upsidedown and pull the plunger todraw all the solution into thesyringe.

If you use a vial adapter,unscrew the vial adapter withthe empty vial. If you use atransfer needle, remove thetransfer needle from the vial,replace the needle cap, andtwist the needle off thesyringe.NovoSeven® is now ready forinjection. Follow the injectionprocedure as instructed byyour healthcare professional.

Injecting the solution

H

I

J Safely dispose of the syringe,vials, any unused product andother waste materials asinstructed by your healthcareprofessional.

A

B

C

D

E

F

G

H

I

J

NovoSeven® is a trademark owned byNovo Nordisk Health Care AG,Switzerland

© 2010Novo Nordisk A/S

8-9022-00-003-1_v1-7:layout 1 2010-02-17 9:53 AM Page 2

Novo Nordisk A/S Electronic Signature Page

Commodity no.: Version:

Documentum ObjectID : This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. Document signed by: Initials Full Name Capacity Reason Date and Time of

Signature (Server Time)

Time Zone(Signer)

22 Feb 2010 09:35:43

8-9022-00-003-1

1.7

0911b6048031badc

weis Karin WeiserRegulatory 2nd Proof reader 2010-02-18 15:30:35 GMT+1

anli Annelise MeldgaardAffiliate 1st Proof reader 2010-02-22 09:23:50 GMT+1

jklo Jeannet KlosGraphics 1st Approver 2010-02-22 10:12:51 GMT+1

sqes Søssan EspersenQuality Assurance 1st Approver 2010-02-22 10:41:06 GMT+1