BENEFIX 250UI powder + solvent for injection medication leaflet

BeneFIX 250 IU powder and solvent for solution for injection

BeneFIX 500 IU powder and solvent for solution for injection

BeneFIX 1000 IU powder and solvent for solution for injection

BeneFIX 1500 IU powder and solvent for solution for injection

BeneFIX 2000 IU powder and solvent for solution for injection

BeneFIX 3000 IU powder and solvent for solution for injection

BeneFIX 250 IU powder and solvent for solution for injection

Each vial contains nominally 250 IU nonacog alfa (recombinant coagulation factor IX). Afterreconstitution with the accompanying 5 mL (0.234%) sodium chloride solution for injection, each mLof the solution contains approximately 50 IU nonacog alfa.

BeneFIX 500 IU powder and solvent for solution for injection

Each vial contains nominally 500 IU nonacog alfa (recombinant coagulation factor IX). Afterreconstitution with the accompanying 5 mL (0.234%) sodium chloride solution for injection, each mLof the solution contains approximately 100 IU nonacog alfa.

BeneFIX 1000 IU powder and solvent for solution for injection

Each vial contains nominally 1000 IU nonacog alfa (recombinant coagulation factor IX). Afterreconstitution with the accompanying 5 mL (0.234%) sodium chloride solution for injection, each mLof the solution contains approximately 200 IU nonacog alfa.

BeneFIX 1500 IU powder and solvent for solution for injection

Each vial contains nominally 1500 IU nonacog alfa (recombinant coagulation factor IX). Afterreconstitution with the accompanying 5 mL (0.234%) sodium chloride solution for injection, each mLof the solution contains approximately 300 IU nonacog alfa.

BeneFIX 2000 IU powder and solvent for solution for injection

Each vial contains nominally 2000 IU nonacog alfa (recombinant coagulation factor IX). Afterreconstitution with the accompanying 5 mL (0.234%) sodium chloride solution for injection, each mLof the solution contains approximately 400 IU nonacog alfa.

BeneFIX 3000 IU powder and solvent for solution for injection

Each vial contains nominally 3000 IU nonacog alfa (recombinant coagulation factor IX). Afterreconstitution with the accompanying 5 mL (0.234%) sodium chloride solution for injection, each mLof the solution contains approximately 600 IU nonacog alfa.

The potency (IU) is determined using the European Pharmacopoeia one-stage clotting assay. Thespecific activity of BeneFIX is not less than 200 IU/mg protein.

BeneFIX contains recombinant coagulation factor IX, (INN = nonacog alfa). Nonacog alfa is apurified protein that has 415 amino acids in a single chain. It has a primary amino acid sequence that iscomparable to the Ala148 allelic form of plasma-derived factor IX, and some post-translationalmodifications of the recombinant molecule are different from those of the plasma-derived molecule.

Recombinant coagulation factor IX is a glycoprotein that is secreted by genetically engineeredmammalian cells derived from a Chinese hamster ovary (CHO) cell line.

For the full list of excipients, see section 6.1.

BeneFIX 250 IU, 500 IU, 1000 IU, 1500 IU, 2000 IU, 3000 IU powder and solvent for solution forinjection

Powder and solvent for solution for injection

White/almost white powder and clear and colourless solvent.

Treatment and prophylaxis of bleeding in patients with haemophilia B (congenital factor IXdeficiency).

BeneFIX 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 IX levels is advised to guide thedose to be administered and the frequency of repeated infusions. Individual patients may vary in theirresponse to factor IX, 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 IX activity) is indispensable.

When using an in vitro thromboplastin time (aPTT)-based one stage clotting assay for determiningfactor IX activity in patients’ blood samples, plasma factor IX activity results can be significantlyaffected by both the type of aPTT reagent and the reference standard used in the assay. This is ofimportance particularly when changing the laboratory and/or reagents used in the assay.

Dose and duration of the substitution therapy depend on the severity of the factor IX deficiency, on thelocation and extent of bleeding, and on the patient's clinical condition.

The number of units of factor IX administered is expressed in International Units (IU), which isrelated to the current WHO standard for factor IX products. Factor IX activity in plasma is expressedeither as a percentage (relative to normal human plasma) or in International Units (relative to aninternational standard for factor IX in plasma).

One International Unit (IU) of factor IX activity is equivalent to that quantity of factor IX in one mLof normal human plasma.

The calculation of the required dose of BeneFIX can be based on the finding that one unit of factor IXactivity per kg body weight is expected to increase the circulating level of factor IX, an average of0.8 IU/dL (range from 0.4 to 1.4 IU/dL) in patients ≥ 12 years (further information in section 5.2).

The required dose is determined using the following formula:

Number of = body weight (in kg) X desired factor IX X reciprocal offactor IX IU increase (%) or (IU/dL) observed recoveryrequired

Example: For a recovery of 0.8 IU/dL, the formula reads:

Number of = body weight (in kg) X desired factor IX X 1.3 IU/kgfactor IX IU increase (%) or (IU/dL)required

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 IX activity should not fall below the givenplasma activity levels (in % of normal or in IU/dL) in the corresponding period. The following tablecan be used to guide dosing in bleeding episodes and surgery:

Degree of Factor IX level Frequency of doses (hours)/Duration ofhaemorrhage/Type of required (%) or Therapy (days)surgical procedure (IU/dL)

Early haemarthrosis, muscle 20-40 Repeat every 24 hours. At least 1 day, untilbleeding or oral bleeding the bleeding episode as indicated by pain isresolved or healing is achieved.

More extensive 30-60 Repeat infusion every 24 hours for 3-4 dayshaemarthrosis, muscle or more until pain and acute disability arebleeding or haematoma resolved.

Life-threatening 60-100 Repeat infusion every 8 to 24 hours untilhaemorrhages threat is resolved.

Minor: 30-60 Every 24 hours, at least

Including tooth extraction 1 day, until healing is achieved.

Major 80-100 Repeat infusion every 8-24 hours until(pre- and adequate wound healing, then therapy for atpostoperative) least another 7 days to maintain a factor IXactivity of 30% to 60% (IU/dL)

BeneFIX may be administered for long term prophylaxis against bleeding in patients withhaemophilia B. In a clinical study for routine secondary prophylaxis the average dose for previouslytreated patients (PTP) was 40 IU/kg (range 13 to 78 IU/kg) at intervals of 3 to 4 days.

In some cases, especially in younger patients, shorter dosage intervals or higher doses may benecessary.

There is limited documentation of on-demand treatment and surgery in paediatric patients less than6 years of age treated with BeneFIX.

Mean dosage (± standard deviation) for prophylaxis was 63.7 (± 19.1) IU/kg at intervals of 3 to 7 days.

In younger patients, shorter dosage intervals or higher doses may be necessary. FIX consumption forroutine prophylaxis in 22 evaluable patients was 4607 (± 1849) IU/kg per year and 378 (± 152) IU/kgper month.

Close monitoring of factor IX plasma activity should be performed as clinically indicated, as well ascalculation of pharmacokinetic parameters such as recovery and half-life, in order to adjust doses asappropriate.

Clinical studies of BeneFIX did not include sufficient numbers of subjects aged 65 and over todetermine whether they respond differently from younger subjects. As with any patient receiving

BeneFIX, dose selection for an elderly patient should be individualised.

BeneFIX is administered by intravenous infusion after reconstitution of the lyophilised powder forsolution for injection with sterile 0.234% sodium chloride solution (see section 6.6).

BeneFIX should be administered at a slow infusion rate. In most of the cases, an infusion rate of up to4 mL per minute has been used. The rate of administration should be determined by the patient’scomfort level.

If any suspected hypersensitivity reaction takes place that is thought to be related to the administrationof BeneFIX, the rate of infusion should be decreased or the infusion stopped (see sections 4.4 and 4.8).

Agglutination of red blood cells in the tube/syringe

There have been reports of agglutination of red blood cells in the tube/syringe with the administrationof BeneFIX. No adverse events have been reported in association with this observation. To minimizethe possibility of agglutination, it is important to limit the amount of blood entering the tubing. Bloodshould not enter the syringe. If agglutination of red blood cells in the tubing/syringe is observed,discard all this material (tubing, syringe and BeneFIX solution) and resume administration with a newpackage.

Continuous infusion

Administration by continuous infusion has not been approved and is not recommended (see alsosections 4.4 and 6.6).

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

Patients can affix one of the peel-off labels found on the vial to document the batch number in theirdiary or for reporting any side effects.

Allergic-type hypersensitivity reactions are possible with BeneFIX. The product contains traces ofhamster proteins. Potentially life-threatening anaphylactic/anaphylactoid reactions have occurred withfactor IX products, including BeneFIX. If symptoms of hypersensitivity occur, patients should beadvised to discontinue use of the medicinal product immediately and contact their physician. Patientsshould be informed of early signs of hypersensitivity reactions including difficult breathing, shortnessof breath, swelling, hives, generalised urticaria, itching, tightness of the chest, bronchospasm,laryngospasm, wheezing, hypotension, blurred vision, and anaphylaxis.

In some cases, these reactions have progressed to severe anaphylaxis. In the case of shock, the currentmedical standards for treatment of shock should be observed. In case of severe allergic reactions,alternative haemostatic measures should be considered.

Inhibitors are an uncommon event in previously treated patients (PTPs) receiving factor IX-containingproducts. As one PTP treated with BeneFIX developed a clinically relevant low responding inhibitorduring clinical studies and experience on antigenicity with recombinant factor IX is still limited,patients treated with BeneFIX should be carefully monitored for the development of factor IXinhibitors that should be titrated in Bethesda Units using appropriate biological testing.

There have been reports in the literature showing a correlation between the occurrence of a factor IXinhibitor and allergic reactions. Therefore, patients experiencing allergic reactions should be evaluatedfor the presence of an inhibitor. It should be noted that patients with factor IX inhibitors may be at anincreased risk of anaphylaxis with subsequent challenge with factor IX. Preliminary informationsuggests a relationship may exist between the presence of major deletion mutations in a patient's factor

IX gene and an increased risk of inhibitor formation and of acute hypersensitivity reactions. Patientsknown to have major deletion mutations of the factor IX gene should be observed closely for signs andsymptoms of acute hypersensitivity reactions, particularly during the early phases of initial exposure toproduct.

Because of the risk of allergic reactions with factor IX concentrates, the initial administrations offactor IX should, according to the treating physician’s judgement, be performed under medicalobservation where proper medical care for allergic reactions could be provided.

Thrombosis

Although BeneFIX contains only factor IX, the risk of thrombosis and disseminated intravascularcoagulation (DIC) should be recognised. Since the use of factor IX complex concentrates hashistorically been associated with the development of thromboembolic complications, the use of factor

IX-containing products may be potentially hazardous in patients with signs of fibrinolysis and inpatients with disseminated intravascular coagulation (DIC). Because of the potential risk ofthrombotic complications, clinical surveillance for early signs of thrombotic and consumptivecoagulopathy should be initiated with appropriate biological testing when administering this productto patients with liver disease, to patients post-operatively, to new-born infants, or to patients at risk ofthrombotic phenomena or DIC. In each of these situations, the benefit of treatment with BeneFIXshould be weighed against the risk of these complications.

The safety and efficacy of BeneFIX administration by continuous infusion have not been established(see also sections 4.2 and 4.8). There have been post-marketing reports of thrombotic events, includinglife-threatening superior vena cava (SVC) syndrome in critically ill neonates, while receivingcontinuous-infusion BeneFIX through a central venous catheter (see also section 4.8).

In patients with existing cardiovascular risk factors, substitution therapy with FIX may increase thecardiovascular risk.

Nephrotic syndrome

Nephrotic syndrome has been reported following attempted immune tolerance induction inhaemophilia B patients with factor IX inhibitors and a history of allergic reaction. The safety andefficacy of using BeneFIX for immune tolerance induction has not been established.

Sufficient data have not been obtained from clinical studies on the treatment of previously untreatedpatients (PUPs) with BeneFIX.

After reconstitution, BeneFIX contains 0.2 mmol sodium (4.6 mg) per vial, that is to say essentially‘sodium-free’. Depending on body weight of the patient and posology of BeneFIX, patients couldreceive multiple vials. This should be taken into consideration if the patient is on a low salt diet.

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

Animal reproduction studies have not been conducted with factor IX. Based on the rare occurrence ofhaemophilia B in women, experience regarding the use of factor IX during pregnancy andbreastfeeding is not available. Therefore, factor IX should be used during pregnancy andbreast-feeding only if clearly indicated.

The effect of BeneFIX on fertility has not been established.

BeneFIX has no influence on the ability to drive or 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 observed andmay in some cases progress to severe anaphylaxis (including shock). In some cases, these reactionshave progressed to severe anaphylaxis, and they have occurred in close temporal association withdevelopment of factor IX inhibitors (see also section 4.4). Nephrotic syndrome has been reportedfollowing attempted immune tolerance induction in haemophilia B patients with factor IX inhibitorsand a history of allergic reaction.

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

Patients with haemophilia B may develop neutralising antibodies (inhibitors) to factor IX. If suchinhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, itis recommended that a specialised haemophilia centre be contacted.

There is a potential risk of thromboembolic episodes following the administration of factor IXproducts, see section 4.4.

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), not known (cannotbe estimated from the available data). The table lists adverse reactions reported in the clinical trials ofpreviously treated patients and identified in postmarketing use. The frequencies are based on allcausality treatment emergent adverse events in pooled clinical trials with 224 subjects.

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

System organ class Very Common Uncommon Frequencycommon ≥ 1/100 ≥ 1/1,000 to not known≥ 1/10 to < 1/10 < 1/100 (cannot beestimated fromthe available data)

Infections and Infusion-siteinfestations cellulitisa

Blood and lymphatic Factor IXsystem disorders inhibitionb

Immune system Hypersensitivityc Anaphylacticdisorders reaction*

Nervous system Headached Dizziness; Somnolence;disorders Dysgeusia tremor

Eye disorders Visualimpairmente

Cardiac disorders Tachycardiaf

Vascular disorders Phlebitis; Hypotensionh Superior vena cavaflushingg syndromei,* ;deep veinthrombosis*;thrombosis*;thrombophlebitis*

Respiratory, thoracic Coughjand mediastinaldisorders

Gastrointestinal Vomiting; nauseadisorders

Skin and subcutaneous Rashk; urticariatissue disorders

Renal and urinary Renal infarctldisorders

General disorders and Pyrexia Chest discomforto; Inadequate therapeuticadministration site infusion-site response*conditions reactionn;infusion-site painm

Investigations Inadequate factor IXrecovery p, *

* ADR identified post-marketinga including cellulitisb low-titer transient inhibitor formationc including drug hypersensitivity, angioedema, bronchospasm, wheezing, dyspnoea, and laryngospasmd including migraine, sinus headachee including scintillating scotoma and blurred visionf including heart rate increased, sinus tachycardiag including hot flush, feeling hot, skin warmh including blood pressure decreasedi superior vena cava (SVC) syndrome in critically ill neonates, while receiving continuous-infusion of BeneFIXthrough a central venous catheterj including productive coughk including rash macular, rash papular, rash maculopapularl developed in a hepatitis C antibody-positive patient 12 days after a dose of BeneFIX for a bleeding episode.m including injection site pain, infusion-site discomfortn including infusion-site pruritus, infusion-site erythemao including chest pain and chest tightnessp This is a verbatim term. No MedDRA 17.1 PT was retrieved.

Hypersensitivity/allergic reactions

If any suspected hypersensitivity reaction takes place that is thought to be related to the administrationof BeneFIX see sections 4.2 and 4.4.

Inhibitor development

A clinically relevant, low responding inhibitor was detected in 1 out of 65 BeneFIX patients(including 9 patients participating only in the surgery study) who had previously received plasma-derived products. This patient was able to continue treatment with BeneFIX with no anamnestic rise ininhibitor or anaphylaxis (see section 4.4).

Allergic reactions might be experienced more frequently in children than in adults.

There are insufficient data to provide information on inhibitor incidence in PUPs (see alsosection 5.1).

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 have been reported with recombinant coagulation factor IX products.

Pharmacotherapeutic group: Antihaemorrhagics, blood coagulation factor IX; ATC code: B02BD04

BeneFIX contains recombinant coagulation factor IX, (nonacog alfa). Recombinant coagulationfactor IX is a single chain glycoprotein with an approximate molecular mass of 55,000 Daltons that isa member of the serine protease family of vitamin K-dependent coagulation factors. Recombinantcoagulation factor IX is a recombinant DNA-based protein therapeutic which has structural andfunctional characteristics comparable to endogenous factor IX. Factor IX is activated byfactor VII/tissue factor complex in the extrinsic pathway as well as factor XIa in the intrinsiccoagulation pathway. Activated factor IX, in combination with activated factor VIII, activatesfactor X. This results ultimately in the conversion of prothrombin to thrombin. Thrombin thenconverts fibrinogen into fibrin and a clot can be formed. Factor IX activity is absent or greatly reducedin patients with haemophilia B and substitution therapy may be required.

Haemophilia B is a sex-linked hereditary disorder of blood coagulation due to decreased levels offactor IX and results in profuse bleeding into joints, muscles or internal organs, either spontaneouslyor as a result of accidental or surgical trauma. By replacement therapy the plasma levels of factor IX isincreased, thereby enabling a temporary correction of the factor deficiency and correction of thebleeding tendencies.

Efficacy analysis in study 3090A1-301-WW was based on 22 evaluable paediatric subjects onprophylaxis regimen including 4 on-demand patients who shortly changed to prophylaxis. Twopatients underwent surgical procedures (circumcision and port-a-catheter insertion). Safety analysis of25 evaluable patients reflected a safety profile as expected. The only documented serious adverseevent related with BeneFIX was reported from the only included PUP, who experiencedhypersensitivity and inhibitor development.

In two open-label studies BeneFIX was found to be safely administered at 100 IU/kg once-weekly.

However, the half-life of the product (see section 5.2) and the limited pharmacokinetic study data forthe once-weekly regimen do not allow recommending this regimen in general for long-termprophylaxis in severe haemophilia B patients.

In a randomized, cross-over pharmacokinetic study, BeneFIX reconstituted in 0.234% sodium chloridediluent was shown to be pharmacokinetically equivalent to the previously marketed BeneFIX(reconstituted with sterile water) in 24 previously treated patients (≥12 years) at a dose of 75 IU/kg. Inaddition, pharmacokinetic parameters were followed up in 23 of the same patients after repeatedadministration of BeneFIX for six months and found to be unchanged compared with those obtained atthe initial evaluation. A summary of pharmacokinetic data is presented in Table 1.

Table 1. Pharmacokinetic Parameter Estimates for BeneFIX (75 IU/kg) at Baseline and

Month 6 in Previously Treated Patients with Haemophilia B

Parameter Baseline n = 24 Month 6 n = 23

Mean ± SD Mean ± SD

Cmax (IU/dL) 54.5 ± 15.0 57.3 ± 13.2

AUC∞ (IU∙hr/dL) 940 ± 237 923 ± 205t1/2 (hr) 22.4 ± 5.3 23.8 ± 6.5

CL (mL/hr/kg) 8.47 ± 2.12 8.54 ± 2.04

Recovery(IU/dL per IU/kg) 0.73 ± 0.20 0.76 ± 0.18

Abbreviations: AUC∞ = area under the plasma concentration-time curve from time zero to infinity; Cmax =peak concentration; t1/2 = plasma elimination half-life; CL = clearance; SD = standard deviation.

A population pharmacokinetic model was developed using data collected in 73 patients aged 7 monthsto 60 years. The parameters estimated using the final 2-compartment model are shown in Table 2.

Infants and children had higher clearance, larger volume of distribution, shorter half-life and lowerrecovery than adolescents and adults. The terminal phase has not been covered unambiguously due tolack of data beyond 24 hours in paediatric subjects < 6 years of age.

Table 2. Mean ± SD Pharmacokinetic Parameters Based on Individual Bayes Estimates from

Population Pharmacokinetic Analysis

Age Group Infants Children Children Adolescents Adults(years) <2 2 to < 6 6 to < 12 12 to < 18 18 to 60

Number ofsubjects 7 16 1 19 30

Clearance(mL/h/kg) 13.1 ± 2.1 13.1 ± 2.9 15.5 9.2 ± 2.3 8.0 ± 0.6

Vss (mL/kg) 252 ± 35 257 ± 25 303 234 ± 49 225 ± 59

Eliminationhalf-life (h) 15.6 ± 1.2 16.7 ± 1.9 16.3 21.5 ± 5.0 23.9 ± 4.5

Recovery(IU/dL per 0.61 ± 0.10 0.60 ± 0.08 0.47 0.69 ± 0.16 0.74 ± 0.20

IU/kg)

Non-clinical data reveal no special hazard for humans based on conventional studies of genotoxicity.

No investigations on carcinogenicity, fertility impairment and foetal development have beenconducted.

Sucrose

Glycine

L-Histidine

Polysorbate 80

Sodium chloride solution

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts. Only the provided infusion set should be used. Treatment failure can occur as a consequenceof human coagulation factor IX adsorption to the internal surfaces of some infusion equipment.

2 years

The reconstituted product does not contain a preservative and should be used immediately, but nolonger than 3 hours after reconstitution. Chemical and physical in-use stability has been demonstratedfor 3 hours at temperatures up to 25°C.

Store below 30°C. Do not freeze.

BeneFIX 250 IU, 500 IU, 1000 IU, 1500 IU, 2000 IU, 3000 IU powder and solvent for solution forinjection

BeneFIX 250 IU, 500 IU, 1000 IU, 1500 IU, 2000 IU, 3000 IU of powder in a 10 mL vial (type 1glass) with a stopper (chlorobutyl) and a flip-off seal (aluminium) and 5 mL of clear, colourlesssolvent in a prefilled syringe (type 1 glass) with a plunger stopper (bromobutyl), a tip-cap(bromobutyl) and a sterile vial adapter reconstitution device, a sterile infusion set, two alcohol swabs,a plaster, and a gauze pad.

BeneFIX is administered by intravenous infusion after reconstitution of the lyophilised powder forinjection with the supplied solvent (0.234% w/v sodium chloride solution) in the pre-filled syringe(see also section 3 of the package leaflet for reconstitution instructions).

BeneFIX, when reconstituted, contains polysorbate-80, which is known to increase the rate ofdi-(2-ethylhexyl)phthalate (DEHP) extraction from polyvinyl chloride (PVC). This should beconsidered during the preparation and administration of BeneFIX. It is important that therecommendations in section 4.2 be followed closely.

Any unused product or waste material should be disposed of in accordance with local requirements.

Because the use of BeneFIX by continuous infusion has not been evaluated, BeneFIX should not bemixed with infusion solutions or be given in a drip.

Pfizer Europe MA EEIG

Boulevard de la Plaine 171050 Bruxelles

Belgium

EU/1/97/047/004

EU/1/97/047/005

EU/1/97/047/006

EU/1/97/047/009

EU/1/97/047/007

EU/1/97/047/008

Date of first authorisation: 27 August 1997

Date of latest renewal: 20 July 2012

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

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