JIVI 500UI 200UI / ml powder + solvent for injection medication leaflet

Jivi 250 IU powder and solvent for solution for injection

Jivi 500 IU powder and solvent for solution for injection

Jivi 1000 IU powder and solvent for solution for injection

Jivi 2000 IU powder and solvent for solution for injection

Jivi 3000 IU powder and solvent for solution for injection

Jivi 250 IU powder and solvent for solution for injection

After reconstitution with the solvent provided, one mL of solution contains approximately 100 IU(250 IU/2.5 mL) of human coagulation factor VIII, damoctocog alfa pegol.

Jivi 500 IU powder and solvent for solution for injection

After reconstitution with the solvent provided, one mL of solution contains approximately 200 IU(500 IU/2.5 mL) of human coagulation factor VIII, damoctocog alfa pegol.

Jivi 1000 IU powder and solvent for solution for injection

After reconstitution with the solvent provided, one mL of solution contains approximately 400 IU(1 000 IU/2.5 mL) of human coagulation factor VIII, damoctocog alfa pegol.

Jivi 2000 IU powder and solvent for solution for injection

After reconstitution with the solvent provided, one mL of solution contains approximately 800 IU(2 000 IU/2.5 mL) of human coagulation factor VIII, damoctocog alfa pegol.

Jivi 3000 IU powder and solvent for solution for injection

After reconstitution with the solvent provided, one mL of solution contains approximately 1 200 IU(3 000 IU/2.5 mL) of human coagulation factor VIII, damoctocog alfa pegol.

The potency International Unit (IU) is determined using the European Pharmacopoeia chromogenicassay. The specific activity of Jivi is approximately 10 000 IU/mg protein.

The active substance, damoctocog alfa pegol, is a site specifically PEGylated B-domain deletedrecombinant human coagulation factor VIII, produced in baby hamster kidney cells (BHK), with a60 kDa branched polyethylene-glycol (two 30 kDa PEG) moiety. The molecular weight of the proteinis approximately 234 kDa.

Jivi is produced without the addition of any human or animal derived protein in the cell cultureprocess, purification, PEGylation or final formulation.

For the full list of excipients, see section 6.1.

Powder and solvent for solution for injection.

Powder: solid, white to slightly yellow.

Solvent: clear solution.

Treatment and prophylaxis of bleeding in previously treated patients ≥ 12 years of age withhaemophilia A (congenital factor VIII deficiency).

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

During the course of treatment, appropriate determination of factor VIII levels is advised to confirmthat adequate FVIII levels have been achieved. Individual patients may vary in their response tofactor VIII, demonstrating different half-lives and recoveries. Dose based on bodyweight may requireadjustment in overweight patients. In the case of major surgical interventions in particular, precisemonitoring of the substitution therapy by means of coagulation analysis (plasma factor VIII activity) isindispensable.

When using an in vitro activated partial thromboplastin time (aPTT)-based one stage clotting assay fordetermining factor VIII activity in patients’ blood samples, plasma factor VIII activity results can besignificantly affected by both the type of aPTT reagent and the reference standard used in the assay,which can result in over- or under-estimation of factor VIII activity. It should be noted that there canbe significant discrepancies between assay results obtained by specific reagents used in the aPTT-based one stage clotting assay and the chromogenic assay. This is of importance when monitoring thefactor VIII activity of Jivi, and when changing laboratory and/or reagents used in the assay. Thisapplies also for modified long-acting factor VIII products.

Laboratories intending to measure Jivi activity should check their procedures for accuracy. A fieldstudy has indicated that the factor VIII activity of Jivi can be accurately measured in plasma usingeither a validated chromogenic substrate (CS) assay or a one-stage (OS) clotting assay using specificreagents. For Jivi some silica-based one-stage assays (e.g., APTT-SP, STA-PTT) may underestimatethe factor VIII activity of Jivi in plasma samples; some reagents, e.g. with kaolin-based activators,have the potential for overestimation.

The clinical effect of factor VIII is the most important element in evaluating the effectiveness oftreatment. It may be necessary to adjust the individual dosing at patient level in order to attainsatisfactory clinical results. If the calculated dose fails to attain the expected factor VIII levels or ifbleeding is not controlled after administration of the calculated dose, the presence of a circulatingfactor VIII-inhibitor or anti-PEG antibodies in the patient should be suspected (see section 4.4).

The dose and duration of substitution therapy depends on the severity of the factor VIII deficiency, thelocation and extent of the bleeding and on 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 concentrate standard for factor VIII products. Factor VIII activity inplasma is expressed either as a percentage (relative to normal human plasma) or preferably in IU(relative to an International Standard for factor VIII in plasma).

One IU of factor VIII activity is equivalent to that quantity of factor VIII in one mL of normal humanplasma.

The calculation of the required dose of factor VIII is based on the empirical finding that 1 IUfactor VIII per kg body weight raises the plasma factor VIII activity by 1.5-2.5 % of normal activity.

The required dose of Jivi is determined using the following formula:

Required units = body weight (kg) x desired factor VIII rise (% or IU/dL) x reciprocal of observedrecovery (i.e. 0.5 for recovery of 2.0%).

The amount to be administered and the frequency of administration should always be oriented to theclinical effectiveness required 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) in the corresponding period. The following table can beused to guide dosing in bleeding episodes and surgery:

Table 1: Guide for dosing in bleeding episodes and surgery for adolescents and adults

Degree of haemorrhage/Type Factor VIII level Frequency of doses (hours)/Duration ofof surgical procedure required (%) therapy (days)(IU/dL)

Early haemarthrosis, muscle Repeat injection every 24-48 hours.bleeding or oral bleeding 20-40 At least 1 day, until bleeding episode asindicated by pain is resolved or healing isachieved

More extensive Repeat injection every 24-48 hours forhaemarthrosis, muscle 30-60 3 to 4 days or more until pain and acutebleeding or haematoma disability are resolved.

Life-threatening

Haemorrhages 60-100 Repeat injection every 8 to 24 hours untilthreat is resolved.

Minor surgery 30-60 Every 24 hours, at least 1 day, until healing isincluding tooth extraction achieved.

Major surgery Repeat dose every12-24 hours until adequate wound healing,80-100 (pre- and then therapy for at least another 7 days topost-operative) maintain factor VIII activity of 30-60%(IU/dL).

All treatment decisions for identifying appropriate prophylactic treatment regimens should be guidedby clinical judgement based on individual patient characteristics and treatment response.

For prophylaxis the dose is 45-60 IU/kg every 5 days. Based on patient clinical characteristics the dosecan also be 60 IU/kg every 7 days or 30-40 IU/kg two times per week (see sections 5.1 and 5.2).

For overweight patients, the maximum dose per injection for prophylaxis should not be higher thanapproximately 6 000 IU.

Jivi is not indicated in previously untreated patients and in patients less than 12 years of age.

Adolescent population

On demand and prophylactic treatment dosing in adolescent patients is the same as for adult patients.

There is limited experience in patients ≥ 65 years.

Jivi is for intravenous use.

Jivi should be injected intravenously over a period of 2 to 5 minutes depending on the total volume.

The rate of administration should be determined by the patient’s comfort level (maximal rate ofinjection: 2.5 mL/min).

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

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

Known allergic reactions to mouse or hamster proteins.

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

Allergic type hypersensitivity reactions are possible with Jivi. The medicinal product may containtraces of mouse and hamster proteins. Hypersensitivity reactions could also be related to antibodiesagainst PEG (see paragraph Immune response to polyethylene glycol (PEG)). If symptoms ofhypersensitivity occur, patients should be advised to discontinue the use of the medicinal productimmediately and contact their physician. Patients should be informed of the early signs ofhypersensitivity reactions including hives, generalized urticaria, tightness of the chest, wheezing,hypotension, and anaphylaxis. Symptomatic treatment for hypersensitivity should be instituted asappropriate. In case of anaphylaxis or shock, the current medical standards for treatment should beimplemented.

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)per mL of plasma using the modified Bethesda assay. The risk of developing inhibitors is correlated tothe severity of the disease as well as the exposure to factor VIII, this risk being highest within the first50 exposure days (ED) but continues throughout life although the risk is uncommon. Rarely, inhibitorsmay develop after the first 50 exposure days.

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 observations and laboratory tests.

If the expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled withan appropriate dose, testing for factor VIII inhibitor presence should be performed. In patients withhigh levels of inhibitor, factor VIII therapy may not be effective and other therapeutic options shouldbe considered. Management of such patients should be directed by physicians with experience in thecare of haemophilia and factor VIII inhibitors.

Immune response to polyethylene glycol (PEG)

A clinical immune response associated with anti-PEG antibodies, manifested as symptoms of acutehypersensitivity and/or loss of drug effect has been observed primarily within the first 4 exposuredays. Low post-injection factor VIII levels in the absence of detectable factor VIII inhibitors indicatethat loss of drug effect is likely due to anti-PEG antibodies; in such cases Jivi should be discontinuedand patients switched to a previously effective factor VIII product.

A significant decrease in the risk of an immune response to PEG was observed with an increase in age.

This effect may be related to a developmental change in immunity, and although it is difficult to definea clear cut-off age for the change in risk, this phenomenon predominantly occurs in young childrenwith haemophilia.

The implications of any potential risk to affected patients with a hypersensitivity reaction to pegylatedproteins are unknown. Data show that in the affected subjects, following discontinuation of Jivi, theanti-PEG IgM antibodies decreased in titre and became undetectable over time. No cross-reactivity ofanti-PEG IgM antibodies with other unmodified factor VIII products was observed. All patients couldbe successfully treated with their previous factor VIII products.

In patients with existing cardiovascular risk factors, substitution therapy with factor VIII may increasethe cardiovascular 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.

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

Jivi is not indicated in patients < 12 years of age and in previously untreated patients.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially‘sodium-free’.

Interactions of human coagulation factor VIII (rDNA) products with other medicinal products havenot been reported.

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

In the repeat dose systemic toxicity studies in rats and rabbits with Jivi, treatment related effects onmale reproductive organs were not seen (see section 5.3). The effect on fertility in humans isunknown.

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

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

Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treatedwith factor VIII, including with Jivi (see section 5.1). If such inhibitors occur, the condition willmanifest itself as an insufficient clinical response. In such cases, it is recommended that a specializedhaemophilia centre be contacted.

The most frequently reported adverse reactions in clinical studies in PTPs were headache, cough andpyrexia.

A total of 221 patients constituted the safety population from three pivotal Phase I and III studies[PROTECT VIII], 148 adolescents/adults and 73 paediatric patients < 12 years. In PROTECT VIII,121 patients continued in the extension study with a median total treatment duration of 3.9 years[range: 0.8-7.0].

In the paediatric study, 59/73 patients < 12 years continued in the extension study. Median (range)total time in study (main study + extension) was 5.8 (1.0-6.6) years with a median of 430 (range 98-671) ED per subject, 39 subjects were treated for =/> 5 years.

The median number of exposure days to Jivi per subject was 237 (min-max: 1-698) for all subjects inthe clinical studies.

Overall, in both studies 75 patients were observed for a treatment duration of more than 5 years.

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: verycommon (≥ 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).

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

Table 2: Frequency of adverse drug reactions in clinical studies

MedDRA Standard Adverse reactions Frequency

System Organ Class

Blood and lymphatic system disorders FVIII inhibition Uncommon (PTPs)a

Immune system disorders Hypersensitivity common

Psychiatric disorders Insomnia common

Nervous system disorders Headache very common

Dizziness common

Dysgeusia uncommon

Vascular disorders Flushing uncommon

Respiratory, thoracic and mediastinal Cough commondisorders

Gastrointestinal disorders Abdominal pain, Nausea, common

Skin and subcutaneous tissue disorders Erythemac, Rashd common

Pruritus uncommon

General disorders and administration Injection site reactions b, commonsite conditions Pyrexiaa Frequency is based on studies with all factor VIII products which included patients with severehaemophilia A. PTPs = previously-treated patients”b includes injection site pruritus, injection site rash and vessel puncture site pruritusc includes erythema and erythema multiformed includes rash and rash papular

There was no change in the safety profile during the PROTECT VIII and the paediatric extensionstudies.

Immunogenicity was evaluated during clinical studies with Jivi in 159 (including surgery patients)previously treated adolescents (≥ 12 years of age) and adults diagnosed with severe haemophilia A(FVIII:C < 1%), and ≥ 150 previous exposure days.

FVIII inhibitors

No de novo or confirmed cases of inhibitor against factor VIII occurred. A single unconfirmed positiveresult of a low titre of factor VIII inhibitor (1.7 BU/mL) was reported in one adult patient undergoingsurgery.

Anti¬PEG antibodies

Immunogenicity against PEG with development of specific IgM anti-PEG antibodies was observed inone patient. The immune response was accompanied by a clinical hypersensitivity reaction after4 injections of Jivi. Antibodies to PEG disappeared after discontinuation of Jivi.

No clinical immune response to PEG resulting in loss of drug efficacy or hypersensitivity wasobserved from the 5th ED through the end of the extension studies.

In completed clinical studies with 73 paediatric PTPs < 12 years (44 PTPs < 6 years, 29 PTPs6¬< 12 years), adverse reactions due to immune response to PEG were observed in children less than6 years of age. In 10 of 44 patients (23%) in the age group of younger than 6 years of age loss of drugeffect due to neutralising anti-PEG antibodies during the first 4 exposure days was observed. In3 of 44 patients (7%), loss of drug effect was combined with hypersensitivity reactions (seesection 4.4). No triggers or predictors of the immune response to PEG could be identified.

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.

There was one case of overdose in the clinical studies. No adverse events were reported.

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

The factor VIII/von Willebrand factor complex consists of two molecules (factor VIII and von

Willebrand factor) with different physiological functions. When infused into a patient withhaemophilia, factor VIII binds to patient’s von Willebrand factor. Activated factor VIII acts as acofactor for 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 fibrinand a clot can be formed. Haemophilia A is a sex-linked hereditary disorder of blood coagulation dueto decreased levels or absence of factor VIII:C that results in bleeding into joints, muscles or internalorgans, either spontaneously or as a result of accidental or surgical trauma. By replacement therapy theplasma levels of factor VIII are increased, thereby enabling a temporary correction of the factordeficiency and correction of the bleeding tendencies.

Damoctocog alfa pegol is a PEGylated form of rFVIII. Site-specific PEGylation reduces clearance offactor VIII resulting in an extended half-life while maintaining the normal functions of the B-domaindeleted rFVIII molecule (see section 5.2). Damoctocog alfa pegol does not contain von Willebrandfactor.

Clinical studies

A total of 232 previously treated patients with severe haemophilia A have been exposed in the clinicalstudy program which included one phase I study and two phase II/III studies. One-hundred and fifty-nine (159) subjects were ≥ 12 years of age,

Phase II/III(PROTECT VIII):The pharmacokinetics, safety and efficacy of Jivi for on demand treatment,prophylaxis with three regimens (two times per week 30-40 IU/kg, every 5-days 45-60 IU/kg andevery 7-days 60 IU/kg) and haemostasis during major surgeries were evaluated in a multi-national,open-label, uncontrolled, partially randomized study which was performed in compliance with theagreed Paediatric Investigation Plan. An extension study included patients completing the main study.

The primary efficacy variable was annualized bleed rate (ABR).

One hundred and thirty-four male PTPs received at least one injection of Jivi (including 13 subjectsaged 12 to 17 years of age) for prophylaxis (n=114) or on-demand treatment (n=20) for a period of36 weeks. A total of 121 subjects received treatment during the extension study, 107 subjects receivedprophylaxis and 14 subjects on-demand treatment. Thirty-six subjects received prophylaxis treatmentfor > 5 years up to 7.0 years. Total median (range) time in study was 3.9 years (0.8 - 7.0 years) in all121 patients. Haemostasis during 20 major surgeries in 17 patients was evaluated in the surgery part.

Phase III(Paediatric): Pharmacokinetics, safety, and efficacy of Jivi for three prophylaxis regimens (twiceweekly, every 5 and every 7 days) and treatment of breakthrough bleeds were evaluated in a multi-national, uncontrolled, open-label study in 73 paediatric patients (< 12 years of age) during a period of50 EDs and at least 6 months. This study has been performed in compliance with the agreed Paediatric

Investigation Plan. Sixty-one subjects (83.6%) completed the main study and 59 patients continued inthe optional extension study with a total median time in study of 5.8 years (range 1.0-6.6 years).

Prophylactic treatment in subjects ≥ 12 years

During the main study period subjects were assigned to prophylaxis 2x/week (n=24) or randomized toevery 5 days (n=43) or every 7 days (n=43) or received on-demand treatment (n=20) with Jivi. Ninetynine of 110 patients (90%) remained on the assigned regimen. Eleven patients in the every 7 days armincreased frequency. The median dose for all prophylaxis regimens was 46.9 IU/kg/injection. Themedian (Q1; Q3) ABR during prophylaxis was 2.09 (0.0; 6.1) for all bleeds and 0.0 (0;0 4.2) forspontaneous bleeds as compared to 23.4 (18; 37) total bleeds in the on-demand group. Forty-two outof 110 in the prophylaxis arms (38.2%) experienced no bleeding episode.

During the extension study (median duration of 3.2 years, range 0.1-6.3 years), 23 patients weretreated 2x/week, 33 patients every 5-days, 23 patients every 7 days during total time in the extensionstudy and 28 patients changed treatment regimen. The median dose for prophylaxis was 47.8 IU/kg.

The overall median (Q1; Q3) total ABR was 1.49 (0.4; 4.8) and 0.75 (0.0: 2.9) for spontaneous bleedsin the combined prophylaxis groups and total ABR was 34.1 in the on-demand group.

Of note, ABR is not comparable between different factor concentrates and between different clinicalstudies.

Treatment of bleeding

Of the 702 bleeding events treated with Jivi during the main study, 636 (90.6%) were treated with 1 or2 injections, thereof 81.1% with 1 injection. The median (range) dose per injection was 31.7 (14;62) IU/kg. During the extension 1902 bleeds were treated with Jivi and 94.0% were controlled with 1or 2 injections, thereof 84.9% with 1 injection. The median (range) dose was 37.9 (15;64) IU/kg/injection.

Perioperative management

A total of 20 major surgical procedures were performed and assessed in 17 patients. The median totaldose for major surgeries was 219 IU/kg (range: 50-1500 IU/kg, including postoperative period up to3 weeks). Perioperative haemostatic efficacy was rated as good or excellent during all major surgeries.

Additional 34 minor surgeries were performed in 19 patients. Haemostasis was assessed as good orexcellent in all available cases.

Paediatric population < 12 years of age

The use of Jivi in children below 12 years is not indicated (see section 4.2, for information onpaediatric use).

A total of 73 previously treated paediatric patients (44 subjects < 6 years and 29 subjects6 to < 12 years) received prophylaxis treatment twice weekly, every 5 days or every 7 days in thephase III study. For 53 patients who completed the main study, the median (Q1; Q3) annualisedbleeding rate was 2.87 (1.1; 6.1) and the spontaneous ABR was 0.0 (0.0; 2.6). For treatment of bleeds,84.4 % of the bleeds were resolved with 1 injection, and 91.9% of the bleeds were resolved with1 or 2 injections.

11 patients in the age group < 6 years dropped out due to an immune response to PEG associated withloss of efficacy and/or hypersensitivity reaction during the first four ED.

For 59 patients who continued in the extension study the overall median (Q1; Q3) ABR during theextension period was 1.64 (0.5; 3.1). For 30 patients ≥ 12 years at the end of the extension study, themedian (Q1; Q3) ABR was 1.76 (0.5; 3.3).

The pharmacokinetics (PK) of Jivi was compared to that of factor VIII in a crossover Phase I study.

PK was also evaluated in 22 subjects (≥12 years) and in 16 of these subjects after 6 months ofprophylaxis treatment in the Phase II/III study.

The PK data (based on chromogenic assay) indicated that Jivi has a reduced clearance (CL), resultingin a terminal half-life that is 1.4-fold longer and a dose normalized AUC which is 1.4-fold higher, ascompared to the comparative factor VIII product. Dose proportional increases were observed betweenthe doses of 25 and 60 IU/kg indicating dose linearity between 25 IU/kg and 60 IU/kg.

Table 3 summarizes the PK parameters after single dose of 60 IU/kg from the Phase II/III study where

PK was evaluated in 22 subjects. Repeated PK measurements did not indicate any relevant changes in

PK characteristics after long-term treatment.

Table 3: Pharmacokinetic parameters (geometric mean (%CV) and arithmetic mean (SD)) for

Jivi following a single 60 IU/kg dose based on chromogenic assay.

Parameters (units) Jivi

Patients ≥12 yearsn=22

AUC (IU*h/dL) 3710 (33.8)3900 ± 1280

AUC, norm (h*kg/dL) 62.5 (33.7)65.7 ± 21.4

Cmax (IU/dL) 163 (14.7)164 ± 23.8t½ (h) 17.1 (27.1)17.6 ± 4.26

MRTIV (h) 24.4 (27.5)25.2 ± 6.19

Vss (dL/kg) 0.391 (16.3)0.396 ± 0.0631

CL (dL/h/kg) 0.0160 (33.7)0.0168 ± 0.00553

AUC: area under the curve; AUC, norm: dose normalized AUC Cmax: maximum drug concentration; ,t½: terminal half¬life; MRT IV : mean residence time after an intravenous administration; VSS: apparent volumedistribution at steady¬state; CL: clearance

Incremental recovery was determined in 131 patients at several time points. The median (Q1; Q3)recovery was 2.6 (2.3; 3.0) by chromogenic assay.

A population PK model was developed based on all available factor VIII measurements (from dense

PK sampling and all recovery samples) throughout the 3 clinical studies allowing calculation of PKparameters for subjects in the various studies. The table 4 below provides PK parameters based on thepopulation PK model.

Table 4: PK parameters (geometric mean [%CV]) based on population PK model, usingchromogenic assay.

PK parameter (unit) 12 ≤ 18 years ≥ 18 years Total (≥ 12 years)

N=12 N=133 N=145

AUC (IU.h/dL)* 3341 (34.2) 4052 (31.1) 3997 (31.6)

AUCnorm (kg.h/dL) 57.4 (32.6) 67.5 (30.6) 66.6 (31.0)t1/2 (h) 16.8 (25.2) 17.4 (28.8) 17.4 (28.4)

Vss (dL/kg) 0.423 (15.5) 0.373 (15.6) 0.376 (15.9)

CL (dL/h/kg) 0.0174 (34.2) 0.0148 (31.1) 0.0150 (31.6)

*AUC calculated for a dose of 60 IU/kg

Jivi was evaluated in pharmacology, single and repeated dose as well as juvenile toxicity studies inrats and rabbits. In a long-term, 6-months chronic toxicity study no indication of PEG accumulation orother effects related to administration of Jivi were seen. In addition, 4 weeks toxicity studies with the

PEG moiety of Jivi were conducted in two species. The PEG-linker moiety was also tested in astandard set of in vivo and in vitro genotoxicity studies, and they did not indicate a potential forgenotoxicity. These studies did not reveal any safety concerns for humans.

Single dose studies in rats with the radio-labelled PEG moiety showed that there was no indication ofretention or irreversible binding of radioactivity in the animal body. Specifically, no residualradioactivity was detected in the brain, indicating that the radio-labelled compound did not cross theblood brain barrier. In distribution and excretion studies in rats, the 60 kDa PEG moiety of Jivi wasshown to be widely distributed to and eliminated from organs and tissues and excreted in urine (68.4%up to day 231 after administration) and faeces (13.8% up to day 168 after administration).

No long-term studies in animals to evaluate the carcinogenic potential of Jivi, or studies to determinethe effects of Jivi on reproduction have been conducted.

Sucrose

Histidine

Glycine (E 640)

Sodium chloride

Calcium chloride dihydrate (E 509)

Polysorbate 80 (E 433)

Acetic acid, glacial (for pH adjustment) (E 260)

Water for injections

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

Only the components provided in the package should be used for reconstitution and injection becausetreatment failure can occur as a consequence of factor VIII adsorption to the internal surfaces of someinjection equipment.

Unopened vial2 years.

The chemical and physical in-use stability after reconstitution has been demonstrated for 3 hours atroom temperature. Do not refrigerate after reconstitution.

From a microbiological point of view the product should be used immediately after reconstitution. Ifnot used immediately, the in-use storage times and conditions prior to use are the responsibility of theuser.

Store in a refrigerator (2 °C ¬ 8 °C).

Do not freeze.

Keep the vial and the pre-filled syringe in the outer carton in order to protect from light.

Within its overall shelf life of 2 years, the product (when kept in its outer carton) may be stored at upto 25 °C for a limited period of 6-months. The end date of the 6 month storage period at a temperatureup to 25 °C should be recorded on the product carton. This date should never exceed the expiry dateprinted on the outer carton. At the end of this period the product should not be put back in therefrigerator but should be used or discarded.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

Each single package of Jivi contains:

* one vial with powder (10 mL clear type 1 glass vial with grey bromobutyl rubber blend stopperand aluminium seal)

* one pre-filled syringe with 2.5 mL solvent (clear type 1 glass cylinder syringe with greybromobutyl rubber blend stopper)

* one syringe plunger rod

* one vial adapter (with integrated filter)

* one venipuncture set

Pack sizes− 1 single pack.− 1 multipack with 30 single packs.

Not all pack sizes may be marketed.

Jivi powder should only be reconstituted with the supplied solvent (2.5 mL water for injections) in theprefilled-syringe and the vial adapter. The medicinal product must be prepared for injection underaseptic conditions. If any component of the package is opened or damaged, do not use this component.

After reconstitution the solution is clear and colourless and then drawn back into the syringe.

Parenteral medicinal products should be inspected visually for particulate matter and discolourationprior to administration.

The reconstituted product must be filtered prior to administration to remove potential particulatematter in the solution. Filtering is achieved by using the vial adapter.

Detailed instructions for reconstitution and administration of Jivi

You will need alcohol swabs, gauze pads, plasters and tourniquet. These items are not included in the

Jivi package.

1. Wash your hands thoroughly using soap and warm water.

2. Hold an unopened vial and also a syringe in your hands to warm it to a comfortabletemperature (do not exceed 37 °C).

3. Remove the protective cap from the vial (A). Wipe the rubber stopper onthe vial with an alcohol swab and allow the stopper to air dry before use.

4. Place the powder vial on a firm, non-slip surface. Peel off the paper coveron the plastic housing of the vial adapter. Do not remove the adapter fromthe plastic housing. Holding the adapter housing, place over the powdervial and firmly press down (B). The adapter will snap over the vial cap. Donot remove the adapter housing at this point.

5. Hold the pre-filled syringe with solvent upright. Grasp the plunger rod asper the picture and attach the rod by turning it firmly clockwise into thethreaded stopper (C).

6. Holding the syringe by the barrel, snap the syringe cap off the tip (D). Donot touch the syringe tip with your hand or any surface. Set the syringeaside for further use.

7. Now remove and discard the adapter housing (E).

8. Attach the pre-filled syringe to the threaded vial adapter by turningclockwise (F).

9. Inject the solvent by slowly pushing down on the plunger rod (G).

10. Swirl vial gently until all the powder is dissolved (H). Do not shake thevial. Be sure that the powder is completely dissolved. Look to check thereare no particles or discoloration before you use the solution. Do not usesolutions containing visible particles or that are cloudy.

11. Hold the vial on the end above the vial adapter and syringe (I). Fill thesyringe by drawing the plunger out slowly and smoothly. Ensure that thefull content of the vial is drawn into the syringe. Hold the syringe uprightand push the plunger until no air is left in the syringe.

12. Apply a tourniquet to your arm.

13. Determine the point of injection and clean the skin.

14. Puncture the vein and secure the venipuncture set with a plaster.

15. Holding the vial adapter in place, remove the syringe from the vial adapter(the adapter should remain attached to the vial). Attach the syringe to thevenipuncture set (J). Ensure that no blood enters the syringe16. Remove tourniquet.

17. Inject the solution into a vein over 2 to 5 minutes, keeping an eye on the position of theneedle. The speed of injection should be based on your comfort, but should not be faster than2.5 mL per minute.

18. If a further dose is needed, use a new syringe with the powder reconstituted as describedabove.

19. If no further dose is required, remove the venipuncture set and syringe. Hold a pad firmlyover the injection site on your outstretched arm for about 2 minutes. Finally, apply a smallpressure dressing to the injection site and consider if a plaster is necessary.

20. It is recommended that every time you use Jivi, you note down the name and the batchnumber of the product.

21. Do not throw away any medicines via wastewater or household waste. Ask your pharmacistor physician how to throw away medicines you no longer use. These measures will helpprotect the environment

Jivi is for single use only.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Bayer AG51368 Leverkusen

Germany

EU/1/18/1324/001 - 1 x (Jivi 250 IU)

EU/1/18/1324/002 - 1 x (Jivi 500 IU)

EU/1/18/1324/003 - 1 x (Jivi 1000 IU)

EU/1/18/1324/004 - 1 x (Jivi 2000 IU)

EU/1/18/1324/005 - 1 x (Jivi 3000 IU)

EU/1/18/1324/006 - 30 x (Jivi 250 IU)

EU/1/18/1324/007 - 30 x (Jivi 500 IU)

EU/1/18/1324/008 - 30 x (Jivi 1000 IU)

EU/1/18/1324/009 - 30 x (Jivi 2000 IU)

EU/1/18/1324/010 - 30 x (Jivi 3000 IU)

Date of first authorisation: 22 November 2018

Date of latest renewal:

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

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