natgillin/translations-raw huggingface dataset:
I den længerevarende 26- ugers vedligeholdelsesfase i et placebokontrolleret forsøg, var forekomsten af EPS 18, 2% for aripiprazol- behandlede patienter og 15, 7% for placebo - behandlede patienter.
In the long term 26-week maintenance phase of a placebo-controlled trial, the incidence of EPS was 18.2% for aripiprazole-treated patients and 15.7% for placebo-treated patients.
I placebokontrollerede forsøg var forekomsten af akathisia hos bipolære patienter 12, 1% med aripiprazol og 3, 2% med placebo.
In placebo-controlled trials, the incidence of akathisia in bipolar patients was 12.1% with aripiprazole and 3.2% with placebo.
Hos skizofrene patienter var forekomsten af akathisia 6, 2% med aripiprazol og 3, 0% med placebo.
In schizophrenia patients the incidence of akathisia was 6.2% with aripiprazole and 3.0% with placebo.
Sammenligning af aripiprazol og placebo hos den gruppe af patienter, der oplevede potentielt klinisk signifikante ændringer i rutinemæssige laboratorieprøver viste ingen medicinsk vigtige forskelle.
Comparisons between aripiprazole and placebo in the proportions of patients experiencing potentially clinically significant changes in routine laboratory parameters revealed no medically important differences.
Der sås forhøjelser i CPK (kreatinfosfokinase), almindeligvis forbigående og asymptomatiske, hos 3, 5% af de aripiprazol- behandlede patienter sammenlignet med 2, 0% af de placebo- behandlede.
Elevations of CPK (Creatine Phosphokinase), generally transient and asymptomatic, were observed in 3.5% of aripiprazole treated patients as compared to 2.0% of patients who received placebo.
Andre fund:
Other findings:
4. 4).
Undesirable effects known to be associated with antipsychotic therapy and also reported during treatment with aripiprazole include neuroleptic malignant syndrome, tardive dyskinesia, seizure, cerebrovascular adverse events and increased mortality in elderly demented patients, hyperglycaemia and diabetes mellitus (see section 4.4).
Efter markedsføring:
Post-Marketing:
Følgende bivirkninger er rapporteret efter markedsføring.
The following adverse events have been reported during post-marketing surveillance.
Hyppigheden af disse bivirkninger betragtes som ukendt (kan ikke estimeres ud fra foreliggende data).
The frequency of these events is considered not known (cannot be estimated from the available data).
forhøjet kreatinfosfokinase, forhøjet blodsukker, skiftende blodsukker, forhøjet glykosyleret hæmoglobin
increased Creatine Phosphokinase, blood glucose increased, blood glucose fluctuation, glycosylated haemoglobin increased
QT- forlængelse, ventrikulære arytmier, pludselig uforklaret død, hjertestop, torsades de pointes, bradykardi
QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia
Blod - og lymfesystemet:
Blood and the lymphatic system disorders:
leukopeni, neutropeni, thrombocytopeni
leukopenia, neutropenia, thrombocytopenia
taleforstyrrelser, NMS (Neuroleptic Malignant Syndrome), grand mal krampeanfald
speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion
Mave- tarmkanalen:
Gastrointestinal disorders:
udslæt, fotosensitivitetsreaktion, alopeci, kraftig sveddannelse
rash, photosensitivity reaction, alopecia, hyperhidrosis
rhabdomyolyse, myalgi, stivhed
rhabdomyolysis, myalgia, stiffness
vægtøgning, vægttab, anoreksi, hyponatræmi
weight gain, weight decreased, anorexia, hyponatremia
synkope, hypertension, tromboemboliske hændelser
syncope, hypertension, thromboembolic events
ubalance i temperaturregulering (fx hypotermi, pyrexi), brystsmerter, perifert ødem
temperature regulation disorder (e. g. hypothermia, pyrexia), chest pain, peripheral oedema
allergisk reaktion (fx anafylaktisk reaktion, angioødem inklusive hævelse af tunge, tungeødem, ansigtsødem, pruritus og urticaria
allergic reaction (e. g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria)
gulsot, hepatitis, forhøjet alanin- aminotransferase (ALAT), forhøjet aspartat- aminotransferase (ASAT), forhøjet gammaglutamyltransferase (GGT), forhøjet alkalinfosfatase
jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase
4. 4)
agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4)
4. 9 Overdosering
4.9 Overdose
Der er hos voksne patienter i kliniske forsøg og efter markedsføring konstateret utilsigtet eller tilsigtet overdosering med aripiprazol alene i estimerede doser på op til 1260 mg uden dødsfald.
In clinical trials and post-marketing experience, accidental or intentional acute overdosage of aripiprazole alone was identified in adult patients with reported estimated doses up to 1,260 mg with no fatalities.
De observerede, potentielt vigtige medicinske tegn og symptomer omfatter lethargi, blodtryksstigning, somnolens, takykardi, kvalme, opkastninger og diarré.
The potentially medically important signs and symptoms observed included lethargy, increased blood pressure, somnolence, tachycardia, nausea, vomiting and diarrhoea.
De potentielt alvorlige medicinske symptomer rapporteret er somnolens, forbigående bevidstløshed og ekstrapyramidale symptomer.
The potentially medically serious signs and symptoms reported included somnolence, transient loss of consciousness and extrapyramidal symptoms.
Medicinsk kul (50 g) administreret en time efter aripiprazol nedsatte aripiprazol Cmax med omkring 41% og AUC med omkring 51%; dette viser, at kul kan være effektivt i behandlingen af overdosering.
Activated charcoal (50 g), administered one hour after aripiprazole, decreased aripiprazole Cmax by about 41% and AUC by about 51%, suggesting that charcoal may be effective in the treatment of overdose.
5. 1 Farmakodynamiske egenskaber
5.1 Pharmacodynamic properties
Farmakoterapeutisk klassifikation: antipsykotika, ATC- kode:
Pharmacotherapeutic group: antipsychotics, ATC code:
Det er foreslået, at aripiprazols virkning på skizofreni og bipolar lidelse type 1 medieres gennem en kombination af partiel agonisme på dopamin D2 - og serotonin 5- HT1a- receptorer samt antagonisme på serotonin 5- HT2a- receptorer.
8 It has been proposed that aripiprazole’ s efficacy in schizophrenia and Bipolar I Disorder is mediated through a combination of partial agonism at dopamine D2 and serotonin 5HT1a receptors and antagonism of serotonin 5HT2a receptors.
Aripiprazol har høj bindingsaffinitet in vitro for dopamin D2 - og D3 -, serotonin 5- HT1a - og 5- HT2a -
Aripiprazole exhibited high binding affinity in vitro for dopamine D2 and D3, serotonin 5HT1a and 5HT2a receptors and moderate affinity for dopamine D4, serotonin 5HT2c and 5HT7, alpha-1 adrenergic and histamine H1 receptors.
Aripiprazol viser også moderat bindingsaffinitet for serotonin- reuptake site og ingen væsentlig affinitet for muscarine receptorer.
Aripiprazole also exhibited moderate binding affinity for the serotonin reuptake site and no appreciable affinity for muscarinic receptors.
Interaktion med andre receptorer end dopamin - og serotonin- subtyper kan forklare nogle af de andre kliniske virkninger af aripiprazol.
Interaction with receptors other than dopamine and serotonin subtypes may explain some of the other clinical effects of aripiprazole.
Ved administration af aripiprazoldoser i intervallet 0, 5- 30 mg, én gang dagligt til raske personer i 2 uger, sås dosisafhængig reduktion i bindingen af 11C- racloprid, en D2/ D3- receptorligand til caudatus og putamen påvist ved positronemissionstomografi.
Aripiprazole doses ranging from 0.5 to 30 mg administered once a day to healthy subjects for 2 weeks produced a dose-dependent reduction in the binding of 11C-raclopride, a D2/ D3 receptor ligand, to the caudate and putamen detected by positron emission tomography.
Yderligere information om kliniske forsøg:
Further information on clinical trials:
I tre kortere varende (4- 6 uger), placebokontrollerede undersøgelser med 1228 skizofrene patienter med positive eller negative symptomer var aripiprazol forbundet med statistisk signifikant, større forbedring i psykotiske symptomer sammenlignet med placebo.
In three short-term (4 to 6 weeks) placebo-controlled trials involving 1,228 schizophrenic patients, presenting with positive or negative symptoms, aripiprazole was associated with statistically significantly greater improvements in psychotic symptoms compared to placebo.
ABILIFY er effektivt til at opretholde klinisk forbedring under fortsættelsesbehandling hos patienter med respons på den indledende behandling.
ABILIFY is effective in maintaining the clinical improvement during continuation therapy in patients who have shown an initial treatment response.
I et kontrolleret forsøg med haloperidol var andelen af responderende patienter, der opretholdt respons på lægemidlet efter 52 uger, den samme i begge grupper (aripiprazol 77% og haloperidol 73%).
In a haloperidol-controlled trial, the proportion of responder patients maintaining response to medicinal product at 52-weeks was similar in both groups (aripiprazole 77% and haloperidol 73%).
Andelen af patienter, der gennemførte forsøget, var signifikant højere for patienter i behandling med aripiprazol (43%) end med halperidol (30%).
The overall completion rate was significantly higher for patients on aripiprazole (43%) than for haloperidol (30%).
Faktiske scorer på bedømmelsesskalaer anvendt som sekundære endpoint, inklusive PANSS og Montgomery- Asberg Depression Rating Scale, viste en signifikant forbedring i forhold til haloperidol.
Actual scores in rating scales used as secondary endpoints, including PANSS and the Montgomery-Asberg Depression Rating Scale showed a significant improvement over haloperidol.
I et 26- ugers, placebokontrolleret forsøg med stabiliserede patienter med kronisk skizofreni var aripiprazol forbundet med en signifikant større reduktion i tilbagefaldsraten; 34% i aripiprazolgruppen og 57% i placebo.
In a 26-week, placebo-controlled trial in stabilised patients with chronic schizophrenia, aripiprazole had significantly greater reduction in relapse rate, 34% in aripiprazole group and 57% in placebo.
Vægtændring: aripiprazol er i kliniske forsøg ikke vist at forårsage klinisk relevante vægtstigninger.
Weight gain: in clinical trials aripiprazole has not been shown to induce clinically relevant weight gain.
I et 26- ugers, kontrolleret, dobbeltblindt, multinationalt forsøg med olanzapin til behandling af skizofreni, som inkluderede 314 patienter, og hvor det primære endpoint var vægtstigning, fandtes signifikant færre patienter at have 7% eller yderligere vægtstigning i forhold til baseline (dvs en stigning på mindst 5, 6 kg for en middel- baselinevægt på ∼80, 5 kg) med aripripazol (N= 18 eller 13% af de evaluérbare patienter) sammenlignet med olanzapin (N= 45 eller 33% af de evaluérbare patienter).
In a 26-week, olanzapine-controlled, double-blind, multi-national study of schizophrenia which included 314 patients and where the primary end-point was weight gain, significantly less patients had at least 7% weight gain over baseline (i. e. a gain of at least 5.6 kg for a mean baseline weight of ~80.5 kg) on aripiprazole (N= 18, or 13% of evaluable patients), compared to olanzapine (N= 45, or 33% of evaluable patients).
Maniske episoder ved bipolar lidelse type 1:
Manic episodes in Bipolar I Disorder:
I to, 3- ugers placebokontrollerede enkeltstofforsøg med fleksible doser til patienter med manisk eller blandet episode af bipolar lidelse type 1, viste aripiprazol bedre effekt end placebo til reduktion af de maniske symptomer over 3 uger.
In two 3-week, flexible-dose, placebo-controlled monotherapy trials involving patients with a manic or mixed episode of Bipolar I Disorder, aripiprazole demonstrated superior efficacy to placebo in reduction of manic symptoms over 3 weeks.
I et 3- ugers, placebokontrolleret enkeltstofforsøg med fast dosis til patienter med manisk eller blandet episode med bipolar lidelse type 1, havde aripiprazol ikke bedre effekt end placebo.
In one 3-week, fixed-dose, placebo-controlled monotherapy trial involving patients with a manic or mixed episode of Bipolar I Disorder, aripiprazole failed to demonstrate superior efficacy to placebo.
I to, 12- ugers, placebo - og aktivt kontrollerede enkeltstofforsøg med patienter med en manisk eller blandet episode af bipolar lidelse type 1, med eller uden psykotiske træk, havde aripiprazol bedre effekt end placebo ved uge 3 og en vedligeholdelse af effekt sammenlignelig med lithium eller haloperidol ved uge 12.
In two 12-week, placebo- and active-controlled monotherapy trials in patients with a manic or mixed episode of Bipolar I Disorder, with or without psychotic features, aripiprazole demonstrated superior efficacy to placebo at week 3 and a maintenance of effect comparable to lithium or haloperidol at week 12.
Andel af patienter i symptomatisk remission fra mani var sammenlignelig mellem aripiprazol og lithium eller haloperidol ved uge 12.
Aripiprazole also demonstrated a comparable proportion of patients in symptomatic remission from mania as lithium or haloperidol at week 12.
I et 6- ugers, placebokontrolleret forsøg med patienter med manisk eller blandet episode af bipolar lidelse type 1, med eller uden psykotiske træk, som havde delvist manglende respons på enkeltstofbehandling med lithium eller valproat efter 2 uger med terapeutiske serumniveauer, forbedrede tillæg af aripiprazol reduktionen af de maniske symptomer i forhold til enkeltstofbehandling med lithium eller valproat.
In a 6-week, placebo-controlled trial involving patients with a manic or mixed episode of Bipolar I Disorder, with or without psychotic features, who were partially non-responsive to lithium or valproate monotherapy for 2 weeks at therapeutic serum levels, the addition of aripiprazole as adjunctive therapy resulted in superior efficacy in reduction of manic symptoms than lithium or valproate monotherapy.
I et 26- ugers, placebokontrolleret forsøg, efterfulgt af en 74- ugers forlængelse, med maniske patienter, som oplevede remission med aripiprazol under en stabiliseringsfase inden randomisering, havde aripiprazol bedre effekt end placebo ved forebyggelse af bipolært recidiv, primært ved at forebygge recidiv af mani, men havde ikke bedre effekt end placebo ved forebyggelse af recidiv af depression.
9 In a 26-week, placebo-controlled trial, followed by a 74-week extension, in manic patients who achieved remission on aripiprazole during a stabilization phase prior to randomization, aripiprazole demonstrated superiority over placebo in preventing bipolar recurrence, primarily in preventing recurrence into mania but failed to demonstrate superiority over placebo in preventing recurrence into depression.
9 5. 2 Farmakokinetiske egenskaber
5.2 Pharmacokinetic properties
Absorption:
Absorption:
Aripiprazol absorberes godt, med maksimal plasmakoncentration inden for 3- 5 timer efter administration.
Aripiprazole is well absorbed, with peak plasma concentrations occurring within 3-5 hours after dosing.
Aripiprazol gennemgår minimal præ- systemisk metabolisme.
Aripiprazole undergoes minimal pre-systemic metabolism.
Den absolutte orale biotilgængelighed af tabletformuleringen er 87%.
The absolute oral bioavailability of the tablet formulation is 87%.
Aripiprazol fordeles i stor udstrækning, med et faktisk fordelingsvolumen på 4, 9 l/ kg, indikerende omfattende ekstravaskulær fordeling.
Aripiprazole is widely distributed throughout the body with an apparent volume of distribution of 4.9 l/ kg, indicating extensive extravascular distribution.
Ved terapeutiske koncentrationer bindes aripiprazol og dehydro - aripiprazol mere end 99% til serumproteiner, primært til albumin.
At therapeutic concentrations, aripiprazole and dehydro-aripiprazole are greater than 99% bound to serum proteins, binding primarily to albumin.
Aripiprazol metaboliseres hovedsageligt i leveren via tre biotransformationsveje: dehydrogenering, hydroxylering og N- dealkylering.
Aripiprazole is extensively metabolised by the liver primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation.
Baseret på in vitro- forsøg er CYP3A4 og CYP2D6 ansvarlige for dehydrogenering og hydroxylering af aripiprazol, og N- dealkylering katalyseres ved CYP3A4.
Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalysed by CYP3A4.
Ved steady- state repræsenterer dehydro- aripiprazol, den aktive metabolit, omkring 40% af aripiprazol AUC i plasma.
At steady state, dehydro-aripiprazole, the active metabolite, represents about 40% of aripiprazole AUC in plasma.
Elimination:
Elimination:
Middel- eliminationshalveringstiden for aripiprazol er cirka 75 timer hos ekstensive omdannere via CYP2D6 og cirka 146 timer hos dårlige omdannere.
The mean elimination half-lives for aripiprazole are approximately 75 hours in extensive metabolisers of CYP2D6 and approximately 146 hours in poor metabolisers of CYP2D6.
Total- clearance af aripiprazol er 0, 7 ml/ min/ kg, primært hepatisk.
The total body clearance of aripiprazole is 0.7 ml/ min/ kg, which is primarily hepatic.
27% af den administrerede radioaktivitet genfundet i urinen og cirka 60% i fæces.
Following a single oral dose of [14C]-labelled aripiprazole, approximately 27% of the administered radioactivity was recovered in the urine and approximately 60% in the faeces.
18% blev genfundet uomdannet i fæces.
Less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% was recovered unchanged in the faeces.
Rygning og race:
Smoking and Race:
Befolkningsfarmakokinetisk evaluering har ikke vist tegn på klinisk signifikante racerelaterede forskelle eller at rygning skulle påvirke farmakokinetik for aripiprazol.
Population pharmacokinetic evaluation has revealed no evidence of clinically significant race-related differences or effects from smoking upon the pharmacokinetics of aripiprazole.
Nyrelidelse:
Renal Disease:
Farmakokinetiske karakteristika ved aripiprazol og dehydro- aripiprazol er fundet at være ens hos patienter med svær nyrelidelse og unge, raske forsøgspersoner.
The pharmacokinetic characteristics of aripiprazole and dehydro-aripiprazole were found to be similar in patients with severe renal disease compared to young healthy subjects.
Leverlidelse:
10 Hepatic Disease:
Et enkeltdosis- forsøg med patienter med varierende grad af levercirrhose (Child- Pugh- klasse A, B og C) har ikke vist, at hepatisk svækkelse skulle have signifikant betydning for farmakokinetik for aripiprazol og dehydro- aripiprazol, men undersøgelsen omfattede kun 3 patienter med klasse C levercirrhose, hvilket er utilstrækkelig basis for en konklusion vedrørende metabolisk kapacitet.
A single-dose study in subjects with varying degrees of liver cirrhosis (Child-Pugh Classes A, B, and C) did not reveal a significant effect of hepatic impairment on the pharmacokinetics of aripiprazole and dehydro-aripiprazole, but the study included only 3 patients with Class C liver cirrhosis, which is insufficient to draw conclusions on their metabolic capacity.
10 5. 3 Prækliniske sikkerhedsdata
5.3 Preclinical safety data
De prækliniske data viser ingen særlig risiko for mennesker vurderet ud fra konventionelle undersøgelser af sikkerhedsfarmakologi, toksicitet efter gentagne doser, genotoksicitet, karcinogenicitet og reproduktionstoksicitet.
Non-clinical safety data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeat-dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction.
Disse virkninger vurderes derfor til at være af ringe relevans ved klinisk brug.
Toxicologically significant effects were observed only at doses or exposures that were sufficiently in excess of the maximum human dose or exposure, indicating that these effects were limited or of no relevance to clinical use.
Dette indbefattede: dosisafhængig binyretoksicitet (lipofuscin pigmentakkumulering og/ eller parenkymalt celletab) hos rotter efter 104 uger med 20- 60 mg/ kg/ dag (3- 10 gange middel- steady- state AUC ved den maksimale, anbefalede humane dosis) samt øget forekomst af binyrekarcinomer og kombinerede binyreadenomer/ karcinomer hos hunrotter ved 60 mg/ kg/ dag (10 gange middel- steady- state AUC ved den maksimale, anbefalede humane dosis).
These included: dose-dependent adrenocortical toxicity (lipofuscin pigment accumulation and/ or parenchymal cell loss) in rats after 104 weeks at 20 to 60 mg/ kg/ day (3 to 10 times the mean steady-state AUC at the maximum recommended human dose) and increased adrenocortical carcinomas and combined adrenocortical adenomas/ carcinomas in female rats at 60 mg/ kg/ day (10 times the mean steady-state AUC at the maximum recommended human dose).
Den højeste ikke- tumorfremkaldende eksponering hos hunrotter var 7 gange den anbefalede humane dosis.
The highest nontumorigenic exposure in female rats was 7 times the human exposure at the recommended dose.
Derudover sås cholelithiasis som følge af udfældning af sulfatkonjugater af hydroxymetabolitter af aripiprazol i galden hos aber efter gentagne orale doser på 25- 125 mg/ kg/ dag (1- 3 gange middel - steady- state AUC ved den maksimale, anbefalede kliniske dosis eller 16- 81 gange den anbefalede, humane dosis baseret på mg/ m2).
An additional finding was cholelithiasis as a consequence of precipitation of sulphate conjugates of hydroxy metabolites of aripiprazole in the bile of monkeys after repeated oral dosing at 25 to 125 mg/ kg/ day (1 to 3 times the mean steady-state AUC at the maximum recommended clinical dose or 16 to 81 times the maximum recommended human dose based on mg/ m2).
Koncentrationerne af sulfatkonjugat af hydroxyaripiprazol i den humane galdeblære ved den højeste foreslåede dosis (30 mg/ dag) var dog ikke mere end 6% af de galdekoncentrationer, der sås hos aber i 39- ugersforsøget og lå godt under (6%) grænserne for in vitro opløselighed.
However, the concentrations of the sulphate conjugates of hydroxy aripiprazole in human bile at the highest dose proposed, 30 mg per day, were no more than 6% of the bile concentrations found in the monkeys in the 39-week study and are well below (6%) their limits of in vitro solubility.
Aripiprazol er, baseret på resultater fra en fuld skala af standard- genotoksicitetstest, ikke fundet at være genotoksisk.
Based on results of a full range of standard genotoxicity tests, aripiprazole was considered non-genotoxic.
Der er hos rotter observeret udviklingsmæssig toksicitet, inklusive dosisafhængig, forsinket føtal ossifikation og mulig teratogen effekt ved doser som resulterede i sub- terapeutisk optagelse (baseret på AUC), og hos kaniner ved doser, der resulterede i optagelser henholdsvis 3 og 11 gange middel- steady- state AUC ved maksimal, anbefalet klinisk dosis.
Developmental toxicity, including dose-dependent delayed foetal ossification and possible teratogenic effects, were observed in rats at doses resulting in subtherapeutic exposures (based on AUC) and in rabbits at doses resulting in exposures 3 and 11 times the mean steady-state AUC at the maximum recommended clinical dose.
6. 1 Hjælpestoffer
6.1 List of excipients
Indigotin (E132) aluminiumlak
Indigo carmine aluminium lake (E132)
6. 2 Uforligeligheder
6.2 Incompatibilities
6. 3 Opbevaringstid
6.3 Shelf life
6. 4 Særlige opbevaringsforhold
11 6.4 Special precautions for storage
11 6. 5 Emballagetype og pakningsstørrelser
6.5 Nature and contents of container
Aluminium- blisterstrips i æsker med 14 x 1, 28 x 1, 49 x 1, 56 x 1, 98 x 1 tabletter.
Aluminium perforated unit dose blisters in cartons of 14 x 1, 28 x 1, 49 x 1, 56 x 1, 98 x 1 tablets.
6. 6 Regler for destruktion og anden håndtering
6.6 Special precautions for disposal and other handling
Hunton House Highbridge Business Park, Oxford Road Uxbridge - Middlesex UB8 1HU - Storbritannien
Hunton House Highbridge Business Park, Oxford Road Uxbridge - Middlesex UB8 1HU - United Kingdom
DATO FOR FØRSTE TILLADELSE/ FORNYELSE AF TILLADELSEN
DATE OF FIRST AUTHORISATION/ RENEWAL OF THE AUTHORISATION
4. juni 2004
4 June 2004