Leaflet NUWIQ 2000UI powder+solvent for injection

Nuwiq 250 IU powder and solvent for solution for injection

Nuwiq 500 IU powder and solvent for solution for injection

Nuwiq 1000 IU powder and solvent for solution for injection

Nuwiq 1500 IU powder and solvent for solution for injection

Nuwiq 2000 IU powder and solvent for solution for injection

Nuwiq 2500 IU powder and solvent for solution for injection

Nuwiq 3000 IU powder and solvent for solution for injection

Nuwiq 4000 IU powder and solvent for solution for injection

Nuwiq 250 IU powder and solvent for solution for injection

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

Nuwiq 250 IU contains approximately 100 IU/mL of human coagulation factor VIII (rDNA),simoctocog alfa after reconstitution.

Nuwiq 500 IU powder and solvent for solution for injection

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

Nuwiq 500 IU contains approximately 200 IU/mL of human coagulation factor VIII (rDNA),simoctocog alfa after reconstitution.

Nuwiq 1000 IU powder and solvent for solution for injection

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

Nuwiq 1000 IU contains approximately 400 IU/mL of human coagulation factor VIII (rDNA),simoctocog alfa after reconstitution.

Nuwiq 1500 IU powder and solvent for solution for injection

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

Nuwiq 1500 IU contains approximately 600 IU/mL of human coagulation factor VIII (rDNA),simoctocog alfa after reconstitution.

Nuwiq 2000 IU powder and solvent for solution for injection

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

Nuwiq 2000 IU contains approximately 800 IU/mL of human coagulation factor VIII (rDNA),simoctocog alfa after reconstitution.

Nuwiq 2500 IU powder and solvent for solution for injection

Each vial contains nominally 2500 IU human coagulation factor VIII (rDNA), simoctocog alfa.

Nuwiq 2500 IU contains approximately 1000 IU/mL of human coagulation factor VIII (rDNA),simoctocog alfa after reconstitution.

Nuwiq 3000 IU powder and solvent for solution for injection

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

Nuwiq 3000 IU contains approximately 1200 IU/mL of human coagulation factor VIII (rDNA),simoctocog alfa after reconstitution.

Nuwiq 4000 IU powder and solvent for solution for injection

Each vial contains nominally 4000 IU human coagulation factor VIII (rDNA), simoctocog alfa.

Nuwiq 4000 IU contains approximately 1600 IU/mL of human coagulation factor VIII (rDNA),simoctocog alfa after reconstitution.

The potency (IU) is determined using the European Pharmacopoeia chromogenic assay. The specificactivity of Nuwiq is approximately 9500 IU/mg protein.

Simoctocog alfa (human coagulation factor VIII (rDNA)) is a purified protein that has 1440 aminoacids. The amino acid sequence is comparable to the 90 + 80 kDa form of human plasma factor VIII(i.e. B-domain deleted). Nuwiq is produced by recombinant DNA technology in genetically modifiedhuman embryonic kidney (HEK) 293F cells. No animal or human derived materials are added duringthe manufacturing process or to the final medicinal product.

One mL of reconstituted solution contains 7.35 mg sodium (18.4 mg sodium per vial).

For the full list of excipients, see section 6.1.

Powder and solvent for solution for injection.

Powder: white to off-white friable powder.

Solvent: a clear, colourless liquid.

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

Nuwiq can be used for all age groups.

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 guide thedose to be administered and the frequency of repeated infusions. 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 the case of major surgicalinterventions in particular, precise monitoring of the substitution therapy by means of coagulationanalysis (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 on the patient’s clinical condition.

The number of units of factor VIII administered is expressed in International Units (IU), which isrelated 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

International Units (relative to an International Standard for factor VIII in plasma).

One International Unit (IU) of factor VIII activity is equivalent to the quantity of factor VIII in onemL of normal human plasma.

On-demand treatment

The calculation of the required dose of factor VIII is based on the empirical finding that1 International Unit (IU) factor VIII per kg body weight raises the plasma factor VIII activity byapproximately 2% of normal activity or 2 IU/dL. The required dose is determined using the followingformula:

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

Expected factor VIII rise (% of normal) = 2 x administered IUbody weight (kg)

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, factor VIII activity should not fall below the givenplasma activity level (in % of normal or IU/dL) in the corresponding period. The following table canbe used to guide dosing in bleeding episodes and surgery.

Degree of haemorrhage/ Factor VIII level Frequency of doses (hours)/

Type of surgical procedure required (%) (IU/dL) Duration of therapy (days)

Early haemarthrosis, muscle 20-40 Repeat every 12 to 24 hours. At leastbleeding or oral bleeding 1 day, until the bleeding episode asindicated by pain is resolved or healingis achieved.

More extensive haemarthrosis, 30-60 Repeat infusion every 12 to 24 hoursmuscle bleeding or haematoma for 3 to 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 30-60 Every 24 hours, at least 1 day, untilincluding tooth extraction healing is achieved.

Major surgery 80-100 Repeat infusion every 8-24 hours until(pre- and adequate wound healing, then therapypostoperative) for at least another 7 days to maintain afactor VIII activity of 30% to60% (IU/dL).

For long-term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses are20 to 40 IU of factor VIII per kg body weight at intervals of 2 to 3 days. The regimen may be adjustedbased on patient response.

In some cases, especially in younger patients, shorter dose intervals or higher doses may be necessary.

The posology is the same in adults and children and adolescents, however, shorter dose intervals orhigher doses may be necessary for children and adolescents. Currently available data are described insections 4.8, 5.1 and 5.2.

Nuwiq is for intravenous use.

It is recommended that not more than 4 mL per minute be administered.

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.

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

As with any intravenous protein product, allergic type hypersensitivity reactions are possible. Nuwiqcontains traces of human host cell proteins other than factor VIII. 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)per mL of plasma using the modified assay. The risk of developing inhibitors is correlated to theseverity of the disease as well as the exposure to factor VIII, this risk being highest within the first 50exposure days but continues throughout life although the risk is uncommon.

Cases of recurrent inhibitor (low titre) have been observed after switching from one factor VIIIproduct to another in previously treated patients with more than 100 exposure days who have aprevious history of inhibitor development. Therefore, it is recommended to monitor all patientscarefully for inhibitor occurrence following any product switch.

The clinical relevance of inhibitor development will depend on the titre of the inhibitor, with low titreinhibitors which are transiently present or remain consistently low titre posing less of a risk ofinsufficient 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 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.

In patients with existing cardiovascular risk factors, substitution 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.

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

Excipient related considerations (sodium content)

This medicinal product contains 18.4 mg sodium per vial, equivalent to 0.92 % of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

No interaction studies have been performed with Nuwiq.

Animal reproduction studies have not been conducted with factor VIII.

Based on the rare occurrence of haemophilia A in women, experience regarding the use of factor VIIIduring pregnancy and breast feeding is not available. Therefore, factor VIII should be used duringpregnancy and breast-feeding only if clearly indicated. There are no fertility data available.

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

Hypersensitivity or allergic reactions (which may include angiooedema, burning and stinging at theinfusion site, chills, flushing, headache, hives, hypotension, lethargy, nausea, rash, restlessness,tachycardia, tightness of the chest, tingling, urticaria, including generalised urticaria, vomiting,wheezing) have rarely been observed with FVIII preparations and may in some cases progress tosevere anaphylaxis (including shock).

Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treatedwith factor VIII, including with Nuwiq. If such inhibitors occur, the condition will manifest itself as aninsufficient clinical response. In such cases, it is recommended that a specialised haemophilia centrebe contacted.

Table 1 presented below is according to the MedDRA system organ classification (SOC and Preferred

Term Level). Frequencies are based on reports from clinical trials with a total of 355 unique subjectswith severe haemophilia A, of which 247 were previously treated patients (PTPs) and 108 werepreviously untreated patients (PUPs).

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), not known (cannot be estimated from the available data).

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

Table 1. Frequency of adverse reactions in clinical studies

MedDRA Standard System Adverse reactions Frequency

Organ Class

Blood and lymphatic system Anaemia Uncommon*disorders Factor VIII inhibition Uncommon (PTPs) #

Very common (PUPs)#

Haemorrhagic anaemia U ncommon*

Immune system disorders Hypersensitivity Common*

Nervous system disorders Dizziness Uncommon*

Headache Uncommon*

Paraesthesia Uncommon*

Ear and labyrinth disorders Vertigo Uncommon*

Respiratory, thoracic and Dyspnoea Uncommon*mediastinal disorders

Gastrointestinal disorders Dry mouth Uncommon*

Musculoskeletal and connective Back pain Uncommon*tissue disorders

General disorders and Pyrexia Common*administration site conditions Chest pain Uncommon*

Injection site inflammation Uncommon*

Injection site pain Uncommon*

Malaise Uncommon*

Investigations Non-neutralising antibody Uncommon*positive (in PTPs)

* Calculated as patients with adverse reactions per total number of 355 study patients, of which 247 previouslytreated patients (PTPs) and 108 previously untreated patients (PUPs).# Frequency is based on studies with all FVIII products which included patients with severe haemophilia A. PTPs= previously-treated patients, PUPs = previously-untreated patients

A non-neutralizing anti-factor VIII antibody was detected in one adult patient (see Table 1). Thesample was tested by the central laboratory at eight dilutions. The result was positive only at dilutionfactor 1 and the antibody titre was very low. Inhibitory activity, as measured by the modified Bethesdaassay, was not detected in this patient. Clinical efficacy and in vivo recovery of Nuwiq was notaffected in this patient.

Frequency, type and severity of adverse reactions in children and adolescents are assumed to be thesame as in adults.

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 cases of overdose have been 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 haemophiliac patient,factor VIII binds to von Willebrand factor in the patient’s circulation. 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 of factor VIII:C and results in profuse bleeding into joints, muscles or internalorgans, either spontaneously or as results of accidental or surgical trauma. By replacement therapy theplasma levels of factor VIII are increased, thereby temporarily enabling a correction of the factor VIIIdeficiency and correction of the bleeding tendencies.

Adult and adolescent population 12 - 65 years of age

In a clinical study in 32 adult patients with severe haemophilia A, the median consumption of Nuwiqfor prophylaxis was 468.7 IU/kg/month.

Treatment of bleeding

The median dose to treat break-through bleeding episodes was 33.0 IU/kg in these patients who wereon prophylaxis. In another clinical study, 22 adult patients were treated on demand. In total 986bleeding episodes were treated with a median dose of 30.9 IU/kg. In general, minor bleeds requiredslightly lower, and more severe bleeds required up to three-fold higher median doses.

Individualised prophylaxis

Individualised PK-based prophylaxis was evaluated in 66 adult PTPs with severe haemophilia A.

Following a 1-3 month standard prophylaxis phase (every other day or 3 times weekly dosing), 44(67%) patients were switched to a dosing regimen based on their PK assessment, and 40 completed the6 months of prophylaxis according to the assigned dosing and treatment scheme. Of these patients, 34(85%) were treated twice weekly or less. 33 (82.5%) patients did not experience any bleeds and 36(90.0%) patients had no spontaneous bleeds. The mean ± SD annualised bleeding rate was 1.2 ± 3.9and the mean ± SD dose were 52.2 ± 12.2 IU/kg per injection and 99.7 ± 25.6 IU/kg per week.

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

Data were obtained in 29 previously treated children between 2 and 5 years of age, 31 childrenbetween 6 and 12 years of age and one adolescent of 14 years. The median dose per prophylacticinfusion was 37.8 IU/kg. Twenty patients used median doses of more than 45 IU/kg. The medianconsumption of Nuwiq for prophylaxis per month was 521.9 IU/kg. A higher median dose of Nuwiqwas required to treat bleedings in children (43.9 IU/kg) than in adults (33.0 IU/kg), and a highermedian dose was required to treat moderate to major than minor bleedings (78.2 IU/kg vs. 41.7 IU/kg).

Younger children in general required higher median doses (6-12 years: 43.9 IU/kg; 2-5 years:52.6 IU/kg). These data were corroborated by a long-term follow-up of 49 of these children who weretreated for an additional median period of approximately 30 months (range from 9.5 to 52 months);during this period 45% of children had no spontaneous bleeds.

Data from 108 previously untreated patients with severe haemophilia A (<1% FVIII:C) were obtainedin a prospective open-label clinical study. In the majority of patients prophylactic treatment wasinitiated after the occurrence of the first bleeding episode requiring treatment.

Adult population

Table 2. PK parameters for Nuwiq (Dose: 50 IU/kg) in adult previously treated patients (age 18-65 years) with severe haemophilia A (n = 20)

PK parameter Chromogenic assay

Mean ± SD Median (range)

AUC (hr*IU/mL) 22.6 ± 8.0 22.3 (8.4 - 38.1)

T1/2 (hr) 14.7 ± 10.4 12.5 (5.4 - 55.6)

IVR (%/IU/kg) 2.5 ± 0.4 2.5 (1.7 - 3.2)

CL (mL/hr/kg) 3.0 ± 1.2 2.7 (1.5-6.4)

AUC = Area under the curve (FVIII:C), T1/2 = Terminal half-life,

IVR = Incremental in vivo recovery, CL = Clearance, SD = Standard deviation

Table 3. PK parameters for Nuwiq (Dose: 50 IU/kg) in previously treated children aged 6 to 12years with severe haemophilia A (n = 12)

PK parameter Chromogenic assay

Mean ± SD Median (range)

AUC (hr*IU/mL) 13.2 ± 3.4 12.8 (7.8 - 19.1)

T1/2 (hr) 10.0 ± 1.9 9.9 (7.6 - 14.1)

IVR (%/IU/kg) 1.9 ± 0.4 1.9 (1.2 - 2.6)

CL (mL/hr/kg) 4.3 ± 1.2 4.2 (2.8 - 6.9)

AUC = Area under the curve (FVIII:C), T1/2 = Terminal half-life,

IVR = Incremental in vivo recovery, CL = Clearance, SD = Standard deviation

Table 4. PK parameters for Nuwiq (Dose: 50 IU/kg) in previously treated children aged 2 to 5years with severe haemophilia A (n = 13)

PK parameter Chromogenic assay

Mean ± SD Median (range)

AUC (hr*IU/mL) 11.7 ± 5.3 10.5 (4.9 - 23.8)

T1/2 (hr) 9.5 ± 3.3 8.2 (4.3 - 17.3)

IVR (%/IU/kg) 1.9 ± 0.3 1.8 (1.5 - 2.4)

PK parameter Chromogenic assay

Mean ± SD Median (range)

CL (mL/hr/kg) 5.4 ± 2.4 5.1 ( 2.3 - 10.9)

AUC = Area under the curve (FVIII:C), T1/2 = Terminal half-life,

IVR = Incremental in vivo recovery, CL = Clearance, SD = Standard deviation

As known from the literature, recovery and half-life was lower in young children than in adults andclearance higher, which may be due in part to the known higher plasma volume per kilogram bodyweight in younger patients.

Weight adjusted subgroups

Table 5. Weight-adjusted PK parameters for Nuwiq (Dose: 50 IU/kg) in adult previously treatedpatients (age 18-65 years) with severe haemophilia A (n = 20)

PK parameter All Normal weight Pre-adipose Adipose(n=20) (n=14) (n=4) (n=2)

Chromogenic assay Mean ± SD

AUC (hr*IU/mL) 22.6 ± 8.0 20.4 ± 6.9 24.9 ± 8.9 33.5 ± 6.5

T1/2 (hr) 14.7 ± 10.4 14.7 ± 12.1 13.4 ± 5.9 17.2 ± 4.8

IVR (%/IU/kg) 2.5 ± 0.4 2.4 ± 0.4 2.7 ± 0.4 2.8 ± 0.3

CL (mL/hr/kg) 3.0 ± 1.2 3.2 ± 1.3 2.6 ± 1.0 1.8 ± 0.4

Chromogenic assay Median (range)

AUC (hr*IU/mL) 22.3 (8.4 - 38.1) 21.2 (8.4 - 32.6) 23.3 (17.4 - 35.5) 33.5 (28.9 - 38.1)

T1/2 (hr) 12.5 (5.4 - 55.6) 12.3 (5.4 - 55.6) 11.2 (9.3 - 22.0) 17.2 (13.8 - 20.6)

IVR (%/IU/kg) 2.5 (1.7 - 3.2) 2.4 (1.7 - 3.1) 2.8 (2.3 - 3.2) 2.8 (2.6 - 3.0)

CL (mL/hr/kg) 2.7 (1.5 - 6.4) 2.8 (1.7 - 6.4) 2.5 (1.6 - 3.7) 1.8 (1.5 - 2.0)

Normal weight: BMI 18.5-25 kg/m2, Pre-adipose: BMI 25-30 kg/m2, Adipose: BMI > 30 kg/m2, SD =

Standard deviation

In pre-clinical studies, Nuwiq was used to safely and effectively restore haemostasis in dogs withhaemophilia. Toxicology studies showed that local intravenous administration and systemic exposurewere well tolerated in laboratory animals (rats and cynomolgus monkeys).

Specific studies with long-term repeated administration such as reproduction toxicity, chronic toxicity,and carcinogenicity were not performed with Nuwiq due to the immune response to heterologousproteins in all non-human mammalian species.

No studies were performed on the mutagenic potential of Nuwiq.

Ex vivo evaluations using a commercial assay kit to quantify T cell response to protein therapeuticsindicate a low risk of immunogenicity.

Sucrose

Sodium chloride

Calcium chloride dihydrate

Arginine hydrochloride

Sodium citrate dihydrate

Poloxamer 188

Water for injections

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

Only the provided injection sets should be used because treatment failure can occur as a consequenceof human coagulation factor VIII adsorption to the internal surfaces of some injection equipment.

Unopened vial2 years

During the shelf-life, the product may be kept at room temperature (up to 25 °C) for a single periodnot exceeding 1 month. Once the medicinal product has been taken out of the refrigerator, it must notbe returned to the refrigerator. Please record the beginning of storage at room temperature on theproduct carton.

After reconstitution, chemical and physical in-use stability has been demonstrated for 24 hours whenstored at room temperature.

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

Keep the reconstituted solution at room temperature. Do not refrigerate after reconstitution.

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

Do not freeze.

Store vial in the original package in order to protect from light.

For storage at room temperature and storage conditions after reconstitution of the medicinal product,see section 6.3.

Nuwiq with solvent supplied in a pre-filled syringe

Each pack contains:

- 1 powder vial with 250, 500, 1000, 1500, 2000, 2500, 3000 or 4000 IU simoctocog alfa in atype 1 glass vial, closed with coated bromobutyl stopper and sealed with aluminium flip-off cap

- Solvent: 1 borosilicate pre-filled glass syringe containing 2.5 mL water for injections

- 1 sterile vial adapter for reconstitution with 1 butterfly needle and 2 alcohol swabs

Nuwiq with solvent supplied in a vial

Each pack contains:

- 1 powder vial with 250, 500, 1000, 1500, 2000, 2500, 3000 or 4000 IU simoctocog alfa in atype 1 glass vial, closed with coated bromobutyl stopper and sealed with aluminium flip-off cap

- Solvent: 1 type 1 glass vial containing 2.5 mL water for injections

- 1 transfer device for reconstitution, 1 disposable syringe, 1 butterfly needle (infusion set) and 2alcohol swabs

Nuwiq with solvent supplied in a pre-filled syringe

The powder should only be reconstituted with the supplied solvent (2.5 mL water for injections) usingthe supplied injection set. The vial should be gently rotated until all powder is dissolved. Afterreconstitution, the solution should be drawn back into the syringe.

The reconstituted medicinal product should be inspected visually for particulate matter anddiscoloration prior to administration. The reconstituted medicinal product is a clear, colourlesssolution, free from foreign particles and has a pH of 6.5 to 7.5. Do not use solutions that are cloudy orhave deposits.

Instructions for preparation and administration1. Allow the solvent syringe (water for injections) and the powder in the closed vial to reachroom temperature. You can do this by holding them in your hands until they feel as warm asyour hands. Do not use any other way to heat the vial and pre-filled syringe. This temperatureshould be maintained during reconstitution.

2. Remove the plastic flip-off cap from the powder vial to expose the central portions of therubber stopper. Do not remove the gray stopper or metal ring around the top of the vial.

3. Wipe the top of the vial with an alcohol swab. Allow the alcohol to dry.

4. Peel back the paper cover from the vial adapter package. Do not remove the adapter from thepackage.

5. Place the powder vial on an even surface and hold it. Take the adapter package and place thevial adapter over the centre of the rubber stopper of the powder vial. Press down firmly theadapter package until the adapter spike penetrates the rubber stopper. The adapter snaps to thevial when done.

6. Peel back the paper cover from the pre-filled syringe package. Hold the plunger rod at the endand do not touch the shaft. Attach the threaded end of the plunger rod to the solvent syringeplunger. Turn the plunger rod clockwise until a slight resistance is felt.

7. Break off the tamper-proof plastic tip from the solvent syringe by snapping the perforation ofthe cap. Do not touch the inside of the cap or the syringe tip. In case the solution is not usedimmediately close the filled syringe with the tamper-proof plastic tip for storage.

8. Remove the adapter packaging and discard.

9. Firmly connect the solvent syringe to the vial adapter by turning clockwise until resistance isfelt.

10. Slowly inject all solvent into the powder vial by pressing down the plunger rod.

11. Without removing the syringe, gently move or swirl the vial in circles a few times to dissolvethe powder. Do not shake. Wait until all the powder dissolves completely.

12. Visually inspect the final solution for particles before administration. The solution should beclear and colourless, practically free from visible particles. Do not use solutions that arecloudy or have deposits.

13. Turn the vial attached to the syringe upside down, and slowly draw the final solution into thesyringe. Make sure that the entire content of the vial is transferred to the syringe.

14. Detach the filled syringe from the vial adapter by turning counter clockwise and discard theempty vial.

15. The solution is now prepared for immediate use. Do not refrigerate.

16. Clean the chosen injection site with one of the provided alcohol swabs.

17. Attach the provided infusion set to the syringe.

Insert the needle of the infusion set into the chosen vein. If you have used a tourniquet to makethe vein easier to see, this tourniquet should be released before you start injecting the solution.

No blood must flow into the syringe due to the risk of formation of fibrin clots.

18. Inject the solution into the vein at a slow speed, not faster than 4 mL per minute.

If you use more than one vial of powder for one treatment, you may use the same injection needleagain. The vial adapter and the syringe are for single use only.

Nuwiq with solvent supplied in a vial

The powder should only be reconstituted with the supplied solvent (2.5 mL water for injections) usingthe supplied transfer device. The transfer device must be attached first to the solvent vial and then tothe powder vial. Otherwise a loss of vacuum occurs and the transfer of the solvent into the powder vialdoes not take place. If solvent is not completely transferred to the powder vial during this process,please contact the marketing authorisation holder.

The vial should be gently rotated until all powder is dissolved. After reconstitution, the solution shouldbe drawn into the supplied disposable syringe. The reconstituted medicinal product should beinspected visually for particulate matter and discoloration prior to administration. The reconstitutedmedicinal product is a clear, colourless solution, free from foreign particles and has a pH of 6.5 to 7.5.

Do not use solutions that are cloudy or have deposits.

Instructions for preparation and administration1. Allow the solvent (water for injections) in the closed vial and the powder in the closed vial toreach room temperature. You can do this by holding them in your hands until they feel aswarm as your hands. Do not use any other way to heat the two vials. This temperature shouldbe maintained during reconstitution.

2. Remove the plastic flip-off caps from the powder vial and the solvent vial to expose thecentral portions of the rubber stopper. Do not remove the gray stopper or metal ring around thetop of the vial.

3. Wipe the top of both vials with an alcohol swab. Allow the alcohol to dry. Do not touch therubber stoppers after you wipped them with the alcohol swab.

4. Peel back the lid from the transfer device blister package. Do not remove the transfer devicefrom its package.

5. Place the solvent vial on an even surface and hold it firmly. Without removing the blisterpackage, place the blue part of the transfer device on top of the solvent vial and press straightand firmly down until it snaps into place. Do not twist while attaching.

6. Hold the solvent vial, remove the outer package from the transfer device, while leaving thetransfer device firmly attached to the solvent vial.

7. Place the powder vial on an even surface and hold it. Quickly invert the solvent vial with theattached transfer device. Place the white part of the transfer device on top of the powder vialand press firmly down until it snaps into place . Do not twist while attaching. The solvent willflow automatically into the powder vial.

8. Without removing the transfer device with the solvent vial attached, gently move or swirl thevial in circles a few times to dissolve the powder. Do not shake. Wait until all the powderdissolves completely.

9. Unscrew the transfer device into two parts and discard the empty solvent vial with the bluepart of the transfer device.

10. Visually inspect the final solution for particles before administration. The solution should beclear and colourless, practically free from visible particles. Do not use solutions that arecloudy or have deposits.

11. Attach the disposable syringe to the white plastic part of the transfer device by turningclockwise.

12.

Turn the vial attached to the syringe upside down, and slowly draw the final solution into thesyringe. Make sure that the entire content of the vial is transferred to the syringe.

13. Detach the filled syringe from the white part of the transfer device by turning clockwise anddiscard the empty vial with the white part of the transfer device.

14. The solution is now prepared for immediate use. Do not refrigerate.

15. Clean the chosen injection site with one of the provided alcohol swabs.

16. Attachthe provided infusion set (butterfly needle) to the syringe.

Insert the needle of the infusion set into the chosen vein. If you have used a tourniquet to makethe vein easier to see, this tourniquet should be released before you start injecting the solution.

No blood must flow into the syringe due to the risk of formation of fibrin clots.

17. Inject the solution into the vein at a slow speed, not faster than 4 mL per minute.

If you use more than one vial of powder for one treatment, you may use the same injection needleagain. The transfer device and the syringe are for single use only.

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

Octapharma AB

Lars Forssells gata 23112 75 Stockholm

Sweden

Nuwiq with solvent supplied in a pre-filled syringe

EU/1/14/936/001-008

Nuwiq with solvent supplied in a vial

EU/1/14/936/009-016

Date of first authorisation: 22 July 2014

Date of latest renewal: 26 April 2019

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

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