NOVOEIGHT 500UI powder + solvent for injection medication leaflet

NovoEight 250 IU powder and solvent for solution for injection

NovoEight 500 IU powder and solvent for solution for injection

NovoEight 1000 IU powder and solvent for solution for injection

NovoEight 1500 IU powder and solvent for solution for injection

NovoEight 2000 IU powder and solvent for solution for injection

NovoEight 3000 IU powder and solvent for solution for injection

NovoEight 250 IU powder and solvent for solution for injection.

Each powder vial contains nominally 250 IU human coagulation factor VIII (rDNA), turoctocog alfa.

After reconstitution NovoEight contains approximately 62.5 IU/ml of human coagulation factor VIII(rDNA), turoctocog alfa.

NovoEight 500 IU powder and solvent for solution for injection.

Each powder vial contains nominally 500 IU human coagulation factor VIII (rDNA), turoctocog alfa.

After reconstitution NovoEight contains approximately 125 IU/ml of human coagulation factor VIII(rDNA), turoctocog alfa.

NovoEight 1000 IU powder and solvent for solution for injection.

Each powder vial contains nominally 1000 IU human coagulation factor VIII (rDNA), turoctocog alfa.

After reconstitution NovoEight contains approximately 250 IU/ml of human coagulation factor VIII(rDNA), turoctocog alfa.

NovoEight 1500 IU powder and solvent for solution for injection.

Each powder vial contains nominally 1500 IU human coagulation factor VIII (rDNA), turoctocog alfa.

After reconstitution NovoEight contains approximately 375 IU/ml of human coagulation factor VIII(rDNA), turoctocog alfa.

NovoEight 2000 IU powder and solvent for solution for injection.

Each powder vial contains nominally 2000 IU human coagulation factor VIII (rDNA), turoctocog alfa.

After reconstitution NovoEight contains approximately 500 IU/ml of human coagulation factor VIII(rDNA), turoctocog alfa.

NovoEight 3000 IU powder and solvent for solution for injection.

Each powder vial contains nominally 3000 IU human coagulation factor VIII (rDNA), turoctocog alfa.

After reconstitution NovoEight contains approximately 750 IU/ml of human coagulation factor VIII(rDNA), turoctocog alfa.

The potency (IU) is determined using the European Pharmacopoeia (Ph. Eur) chromogenic assay. Thespecific activity of NovoEight is approximately 8,300 IU/mg protein.

Turoctocog alfa (human coagulation factor VIII (rDNA)) is a purified protein that has 1,445 aminoacids with an approximate molecular mass of 166 kDA. It is produced by recombinant DNAtechnology in Chinese hamster ovary (CHO) cells, and prepared without the addition of any human oranimal derived protein in the cell culture process, purification or final formulation.

Turoctocog alfa is a B-domain truncated recombinant human coagulation factor VIII (B-domainconsists of 21 amino acids of the wild type B-domain) without any other modifications in the aminoacid sequence.

The medicinal product contains 30.5 mg sodium per reconstituted vial.

For the full list of excipients, see section 6.1.

Powder and solvent for solution for injection.

White or slightly yellow powder or friable mass.

Clear and colourless solution for injection.

Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIIIdeficiency).

NovoEight can be used for all age groups.

Treatment should be under the supervision of a doctor experienced in the treatment of haemophilia.

During the course of treatment, appropriate determination of factor VIII levels is advised to guide thedose to be administered and the frequency of repeated injections. Individual patients may vary in theirresponse to factor VIII, demonstrating different half-lives and recoveries. Dose based on bodyweightmay require adjustment in underweight or overweight patients. In a single dose pharmacokinetic studyin adult patients the maximum exposure (Cmax) and the total exposure (AUC) increased with increasingbody mass index (BMI) indicating that dose adjustments may be required. An increase in dose may berequired for underweight patients (BMI <18.5 kg/m2) and a decrease in dose may be required for obesepatients (BMI ≥30 kg/m2), but there is insufficient data to recommend specific dose adjustments, seesection 5.2.

In the case of major surgical interventions in particular, precise monitoring of the substitution therapyby means of coagulation analysis (plasma factor VIII activity) is indispensable.

When using an in vitro thromboplastin time (aPTT)-based one stage clotting assay for determiningfactor VIII activity in patients’ blood samples, plasma factor VIII activity results can be significantlyaffected by both the type of aPTT reagent and the reference standard used in the assay. Also there canbe significant discrepancies between assay results obtained by aPTT-based one stage clotting assayand the chromogenic assay according to Ph. Eur. This is of importance particularly when changing thelaboratory and/or reagents used in the assay.

The dose and duration of the substitution therapy depend on the severity of the factor VIII deficiency,on the location and extent of the bleeding and the patient’s clinical condition.

The number of units of factor VIII administered is expressed in International Units (IU), which arerelated to the current WHO standard for factor VIII products. The activity of factor VIII in plasma isexpressed either as percentage (relative to normal level human plasma) or in International Units(relative to an International Standard for factor VIII in plasma).

One International Unit (IU) of factor VIII activity is equivalent to that quantity of factor VIII in one mlnormal human plasma.

On-demand treatment

The calculation of the required dose of factor VIII is based on the empirical finding that 1

International Unit (IU) factor VIII per kg body weight raises the plasma factor VIII activity by 2 IU/dl.

The required dose is determined using the following formula:

Required units = body weight (kg) x desired factor VIII rise (%) (IU/dl) x 0.5 (IU/kg per IU/dl).

The amount to be administered and the frequency of administration should always be oriented to theclinical effectiveness in the individual case.

In the case of the following haemorrhagic events, the factor VIII activity should not fall below thegiven plasma activity level (in % of normal or IU/dl) in the corresponding period. The following tablecan be used to guide dosing in bleeding episodes and surgery:

Table 1 Guide for dosing in bleeding episodes and surgery

Degree of haemorrhage/Type of FVIII level required (%) Frequency of dosessurgical procedure (IU/dl) (hours)/Duration of therapy (days)

Early haemarthrosis, muscle bleeding 20-40 Repeat every 12 to 24 hours, ator oral bleeding least 1 day, until the bleedingepisode as indicated by pain isresolved or healing achieved

More extensive haemarthrosis, 30-60 Repeat infusion every 12-24 hoursmuscle bleeding or haematoma for 3-4 days or more until pain andacute disability are resolved

Life threatening haemorrhages 60-100 Repeat infusion every 8 to 24 hoursuntil threat is resolved

Minor surgery including tooth 30-60 Every 24 hours, at least 1 day, untilextraction healing is achieved

Major surgery 80-100 Repeat infusion every 8-24 hours(pre- and postoperative) until adequate wound healing, thentherapy for at least another 7 daysto maintain a factor VIII activity of30% to 60% (IU/dl)

For long term prophylaxis against bleeding in patients with severe haemophilia A. The usualrecommended doses are 20-40 IU of factor VIII per kg body weight every second day or 20-50 IU offactor VIII per kg body weight 3 times weekly. In adults and adolesents (>12 years) a less frequentregimen (40-60 IU/kg every third day or twice weekly) may be applicable. In some cases, especially inyounger patients, shorter dosage intervals or higher doses may be necessary.

There is limited experience of surgery in paediatric patients.

There is no experience in patients >65 years.

For long term prophylaxis against bleeding in patients below the age of 12, doses of 25-50 IU offactor VIII per kg body weight every second day or 25-60 IU of factor VIII per kg body weight3 times weekly are recommended. For paediatric patients above the age of 12 the doserecommendations are the same as for adults.

The recommended infusion rate for NovoEight is 1-2 ml/min. The rate should be determined by thepatient’s comfort level.

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

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Known allergic reaction to hamster proteins.

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

Allergic type hypersensitivity reactions are possible with NovoEight. The product contains traces ofhamster proteins, which in some patients may cause allergic reactions. If symptoms of hypersensitivityoccur, patients should be advised to discontinue use of the medicinal product immediately and contacttheir physician. Patients should be informed of the early signs of hypersensitivity reactions includinghives, generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis.

In case of shock, standard medical treatment for shock should be implemented.

The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in themanagement of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulinsdirected against the factor VIII procoagulant activity, which are quantified in Bethesda Units (BU) perml of plasma using the modified assay. The risk of developing inhibitors is correlated to the severity ofthe disease as well as the exposure to factor VIII, this risk being highest within the first 50 exposuredays but continues throughout life although the risk is uncommon.

The clinical relevance of inhibitor development will depend on the titre of the inhibitor, with low titreposing less of a risk of insufficient clinical response than high titre inhibitors.

In general, all patients treated with coagulation factor VIII products should be carefully monitored forthe development of inhibitors by appropriate clinical observation and laboratory test. If the expectedfactor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriatedose, testing for factor VIII inhibitor presence should be performed. In patients with high levels ofinhibitor, factor VIII therapy may not be effective and other therapeutic options should be considered.

Management of such patients should be directed by physicians with experience in the care ofhaemophilia and factor VIII inhibitors.

Cardiovascular event

In patients with existing cardiovascular risk factors, substitiution therapy with FVIII may increase thecardiovascular risk.

If a central venous access device (CVAD) is required, risk of CVAD-related complications includinglocal infections, bacteraemia and catheter site thrombosis should be considered.

It is strongly recommended that every time that NovoEight is administered to a patient, the name andbatch number of the product are recorded in order to maintain a link between the patient and the batchof the medicinal product.

The listed warnings and precautions apply both to adults and children.

Excipient related considerations

The medicinal product contains 30.5 mg sodium per reconstituted vial, equivalent to 1.5% of the

WHO recommended maximum daily intake of 2 g sodium for an adult.

No interactions of human coagulation factor VIII (rDNA) products with other medicinal products havebeen reported.

Animal reproduction studies have not been conducted with NovoEight. Based on the rare occurrenceof haemophilia A in women, experience regarding the use of factor VIII during pregnancy andbreastfeeding is not available. Therefore, factor VIII should be used during pregnancy and lactationonly if clearly indicated.

NovoEight has no influence on the ability to drive and use machines.

Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at theinfusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea,restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observedrarely and may in some cases progress to severe anaphylaxis (including shock).

Very rarely development of antibodies to hamster protein with related hypersensitivity reactions hasbeen observed.

Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treatedwith factor VIII, including with NovoEight. If such inhibitors occur, the condition will manifest itselfas an insufficient clinical response. In such cases, it is recommended that a specialised haemophiliacentre is contacted.

The table presented below is according to the MedDRA system organ classification (SOC and

Preferred Term Level).

Frequencies have been evaluated according to the following convention: very common (≥1/10),common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare(<1/10,000), and not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2 Frequency of adverse drug reactions in clinical trials

System Organ Class Frequencya in Frequencya in Adverse reaction

PTPs PUPs

Blood and lymphatic Uncommonb Very commonb FVIII inhibitionsystem disorders

Psychiatric disorders Uncommon Insomnia

Nervous system Uncommon Headache, dizziness, burningdisorders sensation

Cardiac disorders Uncommon Sinus tachycardia, acutemyocardial infarction

Vascular disorders Uncommon Hypertension, lymphoedema,hyperaemia

Common Flushing, Thrombophlebitissuperficial

Skin and subcutaneous Common Rash, rash erythematoustissue disorders Uncommon Rash, lichenoid keratosis, skinburning sensation

Musculoskeletal and Uncommon Musculoskeletal stiffness,connective tissue arthropathy, pain in extremity,disorders musculoskeletal pain

Common Haemarthrosis, Musclehaemorrhage

Respiratory, thoracic Common Coughand mediastinaldisorders

General disorders and Common Injection site reactionscadministration site Common Pyrexia, catheter site erythemaconditions Uncommon Fatigue, feeling hot, oedemaperipheral, pyrexia

Investigations Common Hepatic enzymes increasedd

Common Anti factor VIII antibodypositive

Uncommon Heart rate increased

Gastrointestinal Common Vomitingdisorders

Injury, poisoning and Common Incorrect dose administeredprocedural Common Infusion related reactioncomplications Uncommon Contusion

Product issues Common Thrombosis in devicea Calculated based on total number of unique patients in all clinical trials (301), of which 242were previously treated patients (PTPs) and 60 were previously untreated patients (PUPs).b Frequency is based on studies with all FVIII products which included patients with severehaemophilia A.c Injection site reactions include injection site erythema, injection site extravasation and injectionsite pruritus.d Hepatic enzymes increased include alanine aminotransferase, aspartate aminotransferase,gamma-glutamyltransferase and bilirubin.

During all clinical studies with NovoEight in previously treated patients, a total of 35 adversereactions were reported in 23 of 242 patients exposed to NovoEight. The most frequently reportedadverse reactions were injection site reactions, incorrect dose administered and hepatic enzymesincreased. Of the 35 adverse reactions, 2 were reported in 1 out of 31 patients below 6 years of age,none in patients from 6 to ≤12 years of age, 1 event in 1 out of 24 patients (12 to <18 years of age) and32 were reported in 21 out of 155 adults (≥18 years).

In clinical trials involving 63 previously treated paediatric patients between 0 and 12 years of age and24 adolescents between 12 and 18 years of age with severe haemophilia A no difference in the safetyprofile of NovoEight was observed between paediatric patients and adults.

In the trial with previously untreated patients, between 0 and 6 years of age, a total of 46 adversereactions were reported in 33 of 60 patients exposed to NovoEight. The most frequently reportedadverse reaction was Factor VIII inhibition, see section 4.4. High risk genetic mutations wereidentified in 92.3% of the overall and 93.8% of the high titre confirmed inhibitors. No other factorswere significantly associated with inhibitor development.

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.

No symptoms of overdose with recombinant coagulation factor VIII have been reported.

Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factor VIII, ATC code: B02BD02.

NovoEight contains turoctocog alfa, a human coagulation factor VIII (rDNA), with a truncated B-domain. This glycoprotein has the same structure as human factor VIII when activated, and post-translational modifications that are similar to those of the plasma-derived molecule. The tyrosinesulphation site present at Tyr1680 (native full length), which is important for the binding to von

Willebrand factor, has been found to be fully sulphated in the turoctocog alfa molecule. When infusedinto a haemophilia patient, factor VIII binds to endogenous von Willebrand Factor in the patient’scirculation. The factor VIII/von Willebrand factor complex consists of two molecules (factor VIII andvon Willebrand factor) with different physiological functions. Activated factor VIII acts as a co-factorfor activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor

X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can beformed. Haemophilia A is a sex-linked hereditary disorder of blood coagulation due to decreasedlevels of factor VIII:C and results in profuse bleeding into joints, muscles or internal organs, eitherspontaneously or as a result of accidental or surgical trauma. By replacement therapy the plasma levelsof factor VIII are increased, thereby enabling a temporary correction of the factor deficiency andcorrection of bleeding tendencies.

Of note, annualised bleeding rate (ABR) is not comparable between different factor concentrates andbetween different clinical studies.

Four multi-centre, open-labelled, non-controlled trials have been conducted to evaluate the safety andefficacy of NovoEight in the prevention and treatment of bleeds and during surgery in patients withsevere haemophilia A (FVIII activity ≤1%). Three of these trials were performed in previously treatedpatients and the fourth in previously untreated patients. The trials included 298 exposed patients; 175adolescents or adult patients without inhibitors from the age of 12 years (≥150 exposure days), 63previously treated paediatric patients without inhibitors below 12 years of age (≥50 exposure days)and 60 previously untreated patients below 6 years of age.188 out of 238 previously treated patients continued into the safety extension trial. Treatment with

NovoEight was shown to be safe and had the intended haemostatic and preventive effect.

Of the 3,293 reported bleeds observed in 298 of the patients, 2,902 (88.1%) of the bleeds wereresolved with 1-2 infusions of NovoEight.

Table 3 Consumption of NovoEight and haemostatic success rates in previously untreatedpatients (PUP) and previously treated patients (PTP)

Younger Younger Older Adolescents Adults Totalchildren children children (12 - (≥18 years)(0 - (0 - (6 - <18 years) PTP<6 years) <6 years) <12 years) PTP

PUP PTP PTP

Number of 60 31 32 24 151 298patients

Dose used forpreventionper patient(IU/kg BW)

Mean (SD) 45.2 (14.4) 41.5 (8.1) 38.4 (9.4) 28.5 (9.3) 28.5 (8.3) 32.8 (10.9)

Min ; Max 4.5 ; 363.8 3.4 ; 196.3. 3.2 ; 62.5 17.4 ; 73.9 12.0 ; 97.4 3.2 ; 363.8

Dose used fortreatment ofbleed (IU/kg

BW) 43.6 (15.2) 44.0 (12.6) 40.4 (10.5) 29.3 (10.3) 35.0 (12.3) 37.5 (13.4)

Mean (SD) 11.9 ; 118.9 21.4 ; 193.8 24.0 ; 71.4 12.4 ; 76.8 6.4 ; 104.0 6.4 ; 193.8

Min ; Max

Success ratea 87.0% 92.2% 88.4% 85.1% 89.6% 88.9%%

BW: Body weight, SD: Standard deviationa Success is defined as either 'Excellent' or 'Good'.

Pre-authorisation clinical data were corroborated by a non-interventional, post-authorisation safetystudy conducted in order to provide additional documentation of the immunogenicity, and efficacy andsafety of NovoEight in routine clinical practice. In total 68 previously treated patients (>150 EDs), ofwhich 14 patients were <12 years and 54 patients were ≥12 years, received either on-demand (N=5) orprophylactic (N=63) treatment for a total of 87.8 patient years and 8967 EDs.

A total of 30 surgeries were performed in 25 patients of which 26 were major surgeries and 4 wereminor. Haemostasis was successful in all surgeries and no treatment failures were reported.

Data on Immune Tolerance Induction (ITI) has been collected in patients with haemophilia A who haddeveloped inhibitors to factor VIII. During clinical trial in PUPs, 21 patients were treated with ITI and18 (86%) patients completed ITI with a negative inhibitor test result.

All pharmacokinetic (PK) studies with NovoEight were conducted after i.v. administration of 50 IU/kg

NovoEight in previously treated patients with severe haemophilia A (FVIII ≤1%). The analysis ofplasma samples was conducted using both the one-stage clotting assay and the chromogenic assay.

The assay performance of NovoEight in FVIII:C assays was evaluated and compared to a marketedfull length recombinant FVIII product. The study showed that comparable and consistent results wereobtained for both products and that NovoEight can be reliably measured in plasma without the need ofa separate NovoEight standard.

The single dose pharmacokinetic parameters of NovoEight are listed in Table 4 for the one-stageclotting assay and in Table 5 for the chromogenic assay.

Table 4 Single-dose pharmacokinetic parameters of NovoEight (50 IU/kg) by age - one stageclotting assay - Mean (SD)

P arameter 0 − <6 years 6 − <12 years ≥12 yearsn=14 n=14 n=33

Incremental recovery 1.8 (0.7) 2.0 (0.4) 2.2 (0.4)(IU/dl)/(IU/kg)

AUC ((IU*h)/dl) 992 (411) 1109(374) 1526 (577)

CL (ml/h/kg) 6.21 (3.66) 5.02 (1.68) 3.63 (1.09)t½ (h) 7.65 (1.84) 8.02 (1.89) 11.00 (4.65)

Vss (ml/kg) 56.68 (26.43) 46.82 (10.63) 47.40 (9.21)

Cmax (IU/dl) 100 (58) 107 (35) 123 (41)

Mean residence time 9.63 (2.50) 9.91 (2.57) 14.19 (5.08)(h)

Abbreviations: AUC = area under the factor VIII activity time profile; CL = clearance; t1/2 = terminalhalf-life; Vss = volume of distribution at steady-state; Cmax = maximum factor VIII activity.

Table 5 Single-dose pharmacokinetic parameters of NovoEight (50 IU/kg) by age - chromogenicassay - Mean (SD)

Parameter 0 − <6 years 6 − <12 years ≥12 yearsn=14 n=14 n=33

Incremental recovery 2.2 (0.6) 2.5 (0.6) 2.9 (0.6)(IU/dl)/(IU/kg)

AUC ((IU*h)/dl) 1223 (436) 1437 (348) 1963 (773)

CL (ml/h/kg) 4.59 (1.73) 3.70 (1.00) 2.86 (0.94)t½ (h) 9.99 (1.71) 9.42 (1.52) 11.22 (6.86)

Vss (ml/kg) 55.46 (23.53) 41.23 (6.00) 38.18 (10.24)

Cmax (IU/dl) 112 (31) 125 (27) 163 (50)

Mean residence time 12.06 (1.90) 11.61 (2.32) 14.54 (5.77)(h)

Abbreviations: AUC = area under the factor VIII activity time profile; CL = clearance; t1/2 = terminalhalf-life; Vss = volume of distribution at steady-state; Cmax = maximum factor VIII activity.

The pharmacokinetic parameters were comparable between paediatric patients below 6 years of ageand the paediatric patients from 6 to below 12 years of age. Some variation was observed in thepharmacokinetic parameters of NovoEight between paediatric and adult patients. The higher CL andthe shorter t½ seen in paediatric patients compared to adult patients with haemophilia A may be due inpart to the known higher plasma volume per kilogram body weight in younger patients.

A single dose pharmacokinetic trial (50 IU/kg) was performed in 35 haemophilia patients (≥18 yearsof age) in different BMI categories. The maximum exposure (Cmax) and the total exposure (AUC)increase with increasing BMI indicating that dose adjustments may be required for underweight (BMI<18.5 kg/m2) and obese patients (BMI ≥30 kg/m2), see section 4.2.

Table 6 Single-dose pharmacokinetic parameters of NovoEight (50 IU/kg) by BMI classesa -

One-stage clotting assay - Mean (SD)

PK parameter Underweight Normal weight Overweight Obese class I Obese class II/III

N=5 N=7 N=8 N=7 N=7

Incrementalrecovery 1.7 (0.2) 2.0 (0.2) 2.4 (0.4) 2.3 (0.3)b 2.6 (0.3)(IU/dl)/(IU/kg)

AUC ((IU*h)/dl) 1510 (360) 1920 (610) 1730 (610) 2030 (840) 2350 (590)

CL (ml/h/kg) 3.91 (0.94) 3.20 (1.00) 3.63 (1.24) 3.37 (1.79) 2.51 (0.63)t½ (h) 11.3 (2.0) 11.7 (3.5) 9.4 (2.9) 11.2 (3.5) 11.1 (2.7)

Vss (ml/kg) 56.8 (5.4) 44.8 (6.5) 39.6 (6.0) 42.0 (9.0) 35.0 (4.6)

Cmax (IU/dl) 100 (11) 121 (10) 144 (26) 140 (21) 161 (32)

Mean residence 15.1 (3.0) 15.3 (4.8) 11.9 (3.7) 14.4 (4.6) 14.6 (3.7)time (h)a BMI groups: Underweight: BMI <18.5 kg/m2, Normal weight: BMI 18.5-24.9 kg/m2, Overweight:

BMI 25-29.9 kg/m2, Obese class I: BMI 30-34.9 kg/m2, Obese class II/III: BMI ≥35 kg/m2.b Based on 6 patients only.

Table 7 Single-dose pharmacokinetic parameters of NovoEight (50 IU/kg) by BMI classesa -

Chromogenic assay - Mean (SD)

PK parameter Underweight Normal weight Overweight Obese class I Obese class

N=5 N=7 N=9 N=7 II/III N=7

Incrementalrecovery 2.2 (0.4) 2.9 (0.3) 3.0 (0.5) 3.2 (0.5) 3.5 (0.5)(IU/dl)/(IU/kg)

AUC ((IU*h)/dl) 1860 (700) 2730 (860) 2310 (1020) 2780 (1210) 3050 (730)

CL (ml/h/kg) 3.28 (0.87) 2.25 (0.73) 2.84 (1.09) 2.58 (1.56) 1.94 (0.52)t½ (h) 11.7 (2.4) 11.5 (3.6) 9.7 (3.4) 10.4 (3.2) 10.5 (2.5)

Vss (ml/kg) 49.1 (10.4) 31.2 (4.5) 31.6 (5.8) 28.9 (5.1) 25.7 (4.0)

Cmax (IU/dl) 138 (29) 185 (24) 194 (31) 200 (33) 227 (32)

Mean residence 15.5 (3.2) 15.2 (4.9) 12.6 (4.8) 13.5 (4.6) 13.9 (3.7)time (h)a BMI groups: Underweight: BMI <18.5 kg/m2, Normal weight: BMI 18.5-24.9 kg/m2, Overweight:

BMI 25-29.9 kg/m2, Obese class I: BMI 30-34.9 kg/m2, Obese class II/III: BMI ≥35 kg/m2.

Non-clinical data reveal no special concern for humans based on conventional studies of safetypharmacology and repeated dose toxicity.

Sodium chloride

L-histidine

Sucrose

Polysorbate 80

L-methionine

Calcium chloride dihydrate

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

Sodium chloride

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

Unopened vial30 months when stored in a refrigerator (2°C - 8°C).

During the shelf life, the product may be kept at:

* room temperature (≤ 30°C) for a single period no longer than 9 monthsor

* above room temperature (30°C up to 40°C) for a single period no longer than 3 months.

Once the product has been taken out of the refrigerator, the product must not be returned to therefrigerator.

Please record the beginning of storage and the storage temperature on the product carton.

Chemical and physical in-use stability have been demonstrated for:

* 24 hours stored at 2°C - 8°C

* 4 hours stored at 30°C, for product which has been kept for a single period no longer than9 months at room temperature (≤30°C)

* 4 hours stored up to 40°C, for product which has been kept for a single period no longer than3 months at above room temperature (30°C up to 40°C).

From a microbiological point of view, the medicinal product should be used immediately afterreconstitution. If not used immediately, in-use storage times and conditions prior to use are theresponsibility of the user and would normally not be longer than as stated above, unless reconstitutionhas taken place in controlled and validated aseptic conditions.

Any unused reconstituted product stored at room temperature (≤30°C) or up to 40°C for more than4 hours should be discarded.

Store in refrigerator (2°C - 8°C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

For storage at room temperature (≤30°C) or up to 40°C and storage conditions after reconstitution ofthe medicinal product, see section 6.3.

Each pack of NovoEight 250 IU, 500 IU, 1000 IU, 1500 IU, 2000 IU and 3000 IU powder and solventfor solution for injection contains:

- 1 glass vial (type I) with powder and chlorobutyl rubber stopper- 1 sterile vial adapter for reconstitution- 1 pre-filled syringe of 4 ml solvent with backstop (polypropylene), a rubber plunger(bromobutyl) and a syringe cap with a stopper (bromobutyl)- 1 plunger rod (polypropylene).

NovoEight is to be administered intravenously after reconstitution of the powder with the solventsupplied in the syringe. After reconstitution the solution appears as a clear or slightly opalescentsolution. Do not use solutions that are cloudy or have deposits.

You will also need an infusion set (tubing and butterfly needle), sterile alcohol swabs, gauze pads andplasters. These devices are not included in the NovoEight package.

Always use an aseptic technique.

A)

Take the vial, the vial adapter and the pre-filled Asyringe out of the carton. Leave the plunger roduntouched in the carton. Bring the vial and thepre-filled syringe to room temperature. You cando this by holding them in your hands until theyfeel as warm as your hands. Do not use anyother way to heat the vial and pre-filled syringe.

B)

Remove the plastic cap from the vial. If the Bplastic cap is loose or missing, do not use thevial. Wipe the rubber stopper on the vial with asterile alcohol swab and allow it to air dry for afew seconds before use.

C)

Remove the protective paper from the vial Cadapter. If the protective paper is not fullysealed or if it is broken, do not use the vialadapter.

Do not take the vial adapter out of the protectivecap with your fingers.

D)

Turn over the protective cap and snap the vial Dadapter onto the vial. Once attached do notremove the vial adapter from the vial.

E)

Lightly squeeze the protective cap with your Ethumb and index finger as shown. Remove theprotective cap from the vial adapter.

F)

Grasp the plunger rod by the wide top and Fimmediately connect the plunger rod to thesyringe by turning it clockwise into the plungerinside the pre-filled syringe until resistance isfelt.

G)

Remove the syringe cap from the pre-filled Gsyringe by bending it down until the perforationbreaks. Do not touch the syringe tip under thesyringe cap.

H)

Screw the pre-filled syringe securely onto the Hvial adapter until resistance is felt.

I)

Hold the pre-filled syringe slightly tilted with Ithe vial pointing downwards. Push the plungerrod to inject all the solvent into the vial.

J)

Keep the plunger rod pressed down and swirl Jthe vial gently until all the powder is dissolved.

Do not shake the vial as this will cause foaming.

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

If a larger dose is needed, repeat steps A to J with additional vials, vial adapters and pre-filledsyringes.

Administration of the reconstituted solution

K)

Keep the plunger rod pushed completely in. K

Turn the syringe with the vial upside down. Stoppushing the plunger rod and let it move back onits own while the reconstituted solution fills thesyringe. Pull the plunger rod slightly downwardsto draw the reconstituted solution into thesyringe.

In case you only need part of the entire vial, usethe scale on the syringe to see how muchreconstituted solution you withdraw, asinstructed by your doctor or nurse.

While holding the vial upside down, tap thesyringe gently to let any air bubbles rise to thetop. Push the plunger rod slowly until all airbubbles are gone.

L)

Unscrew the vial adapter with the vial. L

NovoEight is now ready for injection. Locate asuitable site and slowly inject NovoEight intothe vein over a period of 2-5 minutes.

After injection, safely dispose of all unused NovoEight solution, the syringe with the infusion set, thevial with the vial adapter and other waste materials as instructed by your pharmacist.

Do not throw it out with the ordinary household waste.

Novo Nordisk A/S

Novo Allé

DK-2880 Bagsværd

Denmark

NovoEight 250 IU

EU/1/13/888/001

NovoEight 500 IU

EU/1/13/888/002

NovoEight 1000 IU

EU/1/13/888/003

NovoEight 1500 IU

EU/1/13/888/004

NovoEight 2000 IU

EU/1/13/888/005

NovoEight 3000 IU

EU/1/13/888/006

Date of first authorisation: 13 November 2013

Date of latest renewal: 30 July 2018

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

Agency http://www.ema.europa.eu.