natgillin/translations-raw huggingface dataset:
Hos mennesker blev effekten af både daglig og intermitterende administration af ibandronsyre med et dosisfrit interval på 9 - 10 uger bekræftet i et klinisk studie (MF 4411) i hvilket, der blev påvist antifraktur effekt af ibandronsyre.
In humans, the efficacy of both daily and intermittent administration with a dose-free interval of 9 - 10 weeks of ibandronic acid was confirmed in a clinical trial (MF 4411), in which ibandronic acid demonstrated anti-fracture efficacy.
I dyreforsøg resulterede ibandronsyre i biokemiske ændringer, som indikerer en dosisafhængig hæmning af knogleresorptionen, herunder suppression af biokemiske urinmarkører for nedbrydning af knogle- kollagen (som f. eks deoxypyridinolin og kollagen type 1krydsbundne N- telopeptider (NTX).
In animal models ibandronic acid produced biochemical changes indicative of dose-dependent inhibition of bone resorption, including suppression of urinary biochemical markers of bone collagen degradation (such as deoxypyridinoline, and cross-linked N-telopeptides of type I collagen (NTX)).
Både daglige og intermitterende (med et dosisfrit interval på 9 - 10 uger pr. kvartal) orale doser og intravenøse doser af ibandronsyre til postmenopausale kvinder medførte biokemiske ændringer, som tyder på dosisafhængig hæmning af knogleresorptionen.
Both daily, intermittent (with a dose-free interval of 9 - 10 weeks per quarter) oral doses as well as intravenous doses of ibandronic acid in postmenopausal women produced biochemical changes indicative of dose-dependent inhibition of bone resorption.
Intravenøse injektioner med Bondenza nedsatte koncentrationen af serum- C- telopeptid af alfakæden af type I kollagen (CTX) indenfor 3 - 7 dage efter påbegyndelsen af behandlingen og af osteocalcin indenfor 3 måneder.
Bondenza intravenous injection decreased levels of serum C-telopeptide of the alpha chain of Type I collagen (CTX) within 3 - 7 days of starting treatment and decreased levels of osteocalcin within 3 months.
Den histologiske analyse af knoglebiopsier efter to og tre års behandling af postmenopausale kvinder med orale ibandronsyre - doser på 2, 5 mg daglig og intermitterende intravenøse doser på op til 1 mg hver 3. måned, viste knogler af normal kvalitet og ingen tegn på mineraliseringsdefekt.
The histological analysis of bone biopsies after two and three years of treatment of postmenopausal women with doses of oral ibandronic acid 2.5 mg daily and intermittent intravenous doses of up to 1 mg every 3 months showed bone of normal quality and no indication of a mineralisation defect.
Der blev også set et forventet fald i knogleomsætning, normal knoglekvalitet og fravær af mineraliseringsdefekt efter 2 års behandling med i. v behandling med Bondenza 3 mg.
An expected decrease in bone turnover, normal quality of bone and absence of defects in mineralization were also seen after two years of treatment with Bondenza 3 mg injection.
I et 2- års, randomiseret, dobbeltblindt, non- inferiority, multicenterstudie (BM 16550) var intravenøs injektion af Bondenza 3 mg hver 3. måned mindst ligeså effektivt som oral ibandronsyre 2, 5 mg daglig hos postmenopausale kvinder (1386 kvinder i alderen 55- 80 år) med osteoporose (lumbal BMD T- score under – 2, 5 SD ved baseline).
Bondenza 3 mg intravenous injection, administered every 3 months, was shown to be at least as effective as oral ibandronic acid 2.5 mg daily in a 2-year, randomised, double-blind, multicentre, non- inferiority study (BM16550) of postmenopausal women (1386 women aged 55 - 80) with osteoporosis (lumbar spine BMD T-score below -2.5 SD at baseline).
Det blev dokumenteret både i den primære analyse efter et år og i den bekræftende analyse af toårs endpoint (tabel 3).
This was demonstrated in both the primary analysis at one year and in the confirmatory analysis at two years endpoint (Table 3).
Den primære analyse af data fra studie BM 16550 efter et år og den bekræftende analyse efter 2 år dokumenterede non- inferiority af injektionsregimet med 3 mg hver 3. måned sammenlignet med 2, 5 mg oralt daglig med hensyn til stigning i BMD af lumbal columna, total hofte, lårbenshals og trochanter (tabel 3).
The primary analysis of data from study BM16550 at one year and the confirmatory analysis at 2 years demonstrated the non-inferiority of 3 mg every 3 months injection dosing regimen compared to 2.5 mg oral daily dosing regimen, in terms of mean increases in BMD at lumbar spine, total hip, femoral neck and trochanter (Table 3).
22 Tabel 3:
21 Table 3:
Gennemsnitlig relativ ændring i BMD fra baseline af lumbal columna, total hofte, lårbenshals og trochanter efter et års (primær analyse) og to års behandling (per protokol population) i studie BM 16550
Mean relative change from baseline of lumbar spine, total hip, femoral neck and trochanter BMD after one year (primary analysis) and two years of treatment (Per-Protocol Population) in study BM 16550.
Et års data fra studie BM 16550
One year data in study BM 16550
To års data fra studie BM 16550
Two year data in study BM 16550
Gennemsnitlig relativ ændring fra baseline,% [95%] konfidensinterval]
from baseline% [95% CI]
ibandronsyre Bondenza 3 2, 5 mg daglig mg injektion hver 3. måned (N=377) (N=365)
3 mg injection every 3 months (N=365)
ibandronsyre Bondenza 3 mg 2, 5 mg daglig injektion hver 3. måned (N=334) (N=334)
3 mg injection every 3 months (N=334)
Lumbal columna
Lumbar spine L2-L4 BMD
Trochanter BMD
Trochanter BMD
Desuden blev det i en prospektiv planlagt analyse blev vist, at injektion med Bondenza 3 mg hver 3. måned var bedre end oral ibandronsyre 2, 5 mg daglig efter et år (p < 0, 001) og efter to år (p < 0, 001).
Furthermore, Bondenza 3 mg injection every 3 months was proven superior to oral ibandronic acid 2.5 mg daily for increases in lumbar spine BMD in a prospectively planned analysis at one year, p < 0.001, and at two years, p < 0.001.
Efter et års behandling havde 92, 1% af patienterne, som fik en 3 mg injektion hver 3. måned øget eller fastholdt den lumbale columna BMD (dvs. de var respondenter), sammenlignet med 84, 9% af patienterne som fik 2, 5 mg dagligt oralt (p = 0, 002).
For lumbar spine BMD, 92.1% of patients receiving 3 mg injection every 3 months increased or maintained their BMD after 1 year of treatment (i. e. were responders) compared with 84.9% of patients receiving oral 2.5 mg daily (p=0.002).
Efter 2 års behandling havde 92, 8% af patienterne som fik injektion med 3 mg, og 84, 7% af patienterne som fik oral behandling med 2, 5 mg, øget eller fastholdt den lumbale BMD (p = 0, 001).
After 2 years of treatment, 92.8% of patients receiving 3 mg injections and 84.7% of patient receiving 2.5 mg oral therapy had increased or maintained lumbar spine BMD (p=0.001).
Med hensyn til hofte BMD var 82, 3 af patienterne, som fik en 3 mg injektion hver 3. måned, respondenter efter et år sammenlignet med 75, 1% af patienterne som fik 2, 5 mg dagligt oralt (p = 0, 02).
For total hip BMD, 82.3% of patients receiving 3 mg injection every 3 months were responders at one year, compared with 75.1% of patients receiving 2.5 mg daily orally (p=0.02).
Efter 2 års behandling havde 85, 6% af patienterne, som fik injektion med 3 mg og 77, 0% af patienterne som fik 2, 5 mg oralt, øget eller fastholdt hofte BMD (p = 0, 004).
After 2 years of treatment, 85.6% of patients receiving 3 mg injections and 77.0% of patient receiving 2.5 mg oral therapy had increased or maintained total hip BMD (p=0.004).
Efter et år var andelen af patienter som øgede eller fastholdt deres BMD for både lumbal og hofte, 76, 2% i behandlingsarmen med 3 mg injektion hver 3. måned og 67, 2% i armen med 2, 5 mg daglig oralt (p = 0, 007).
The proportion of patients who increased or maintained their BMD at one year at both lumbar spine and total hip was 76.2% in the 3 mg injection every 3 months arm and 67.2% in the 2.5 mg daily orally arm (p=0.007).
Efter to år opfyldte henholdsvis 80, 1% og 68, 8% af patienterne dette kriterium i behandlingsarmenene som fik henholdsvis injektion med 3 mg hver 3. måned og 2, 5 mg daglig (p = 0, 001).
At two years, 80.1% and 68.8% of patients met this criterion in the 3 mg every 3 months injection arm and the 2.5 mg daily arm (p=0.001).
Der blev set klinisk betydende reduktioner i serum- CTX koncentrationer på alle målte tidspunkter.
Clinically meaningful reductions in serum CTX levels were observed at all time points measured.
Efter 12 måneder var de mediane, relative ændringer fra baseline – 58, 6% for regimet med intravenøs injektion af 3 mg hver 3. måned og – 62, 6% for det orale regime med 2, 5 mg daglig.
At 12 months median relative changes from baseline were – 58.6% for the intravenous injection of 3 mg every 3 months regimen and – 62.6% for oral 2.5 mg daily regimen.
Desuden var 64, 8% af patienterne som fik injektion med 3 mg hver 3. måned respondenter (defineret som et fald på ≥50% fra baseline), sammenlignet med 64, 9% af patienterne som fik 2, 5 mg daglig oralt.
In addition, 64.8% of patients receiving 3 mg every 3 months injection were identified as responders (defined as a decrease ≥ 50% from baseline), compared with 64.9% of patients receiving 2.5 mg daily orally.
Reduktion i serum- CTX blev fastholdt i de 2 år, med over halvdelen af patienterne klassificeret som respondenter i begge behandlingsgrupper.
Serum CTX reduction was maintained over the 2 years, with more than half of the patients identified as responders in both treatment groups.
Baseret på resultaterne fra studie BM 16550 forventes intravenøs injektion med Bondenza 3 mg hver 3. måned at være mindst ligeså effektivt som ibandronsyre 2, 5 mg oralt daglig med hensyn til at forebygge frakturer.
Based on the results of study BM 16550, Bondenza 3 mg intravenous injection, administered every 3 months is expected to be at least as effective in preventing fractures as the oral regimen of ibandronic acid 2.5 mg daily.
23 Ibandronsyre tabletter, 2, 5 mg daglig
22 Ibandronic acid 2.5 mg daily tablets
I det første tre- års, randomiserede, dobbeltblinde, placebokontrollerede frakturstudie (MF 4411) påvistes et statistisk signifikant og medicinsk relevant fald i hyppigheden af nye røntgen - morfometriske og kliniske vertebrale frakturer (tabel 4).
In the initial three-year, randomised, double-blind, placebo-controlled, fracture study (MF 4411), a statistically significant and medically relevant decrease in the incidence of new radiographic morphometric and clinical vertebral fractures was demonstrated (table 4).
I denne undersøgelse blev ibandronsyre undersøgt ved doser på 2, 5 mg daglig og 20 mg intermitterende som et eksploratorisk regime. ibandronsyre blev indtaget 60 minutter før første indtagelse af mad eller drikkevarer (post- dosis fasteperiode).
Ibandronic acid was taken 60 minutes before the first food or drink of the day (post-dose fasting period).
Undersøgelsen omfattede kvinder i alderen 55 til 80 år, som var mindst 5 år postmenopausale, havde lumbal BMD på - 2 til - 5 SD under den præmenopausale middelværdi (T - score) i mindst én ryghvirvel [L1- L4], og som havde haft 1- 4 tidligere vertebrale frakturer.
The study enrolled women aged 55 to 80 years, who were at least 5 years postmenopausal, who had a BMD at the lumbar spine of -2 to -5 SD below the premenopausal mean (T-score) in at least one vertebra [L1-L4], and who had one to four prevalent vertebral fractures.
Effekten evalueredes hos 2. 928 patienter.
Efficacy was evaluated in 2,928 patients.
Ibandronsyre 2, 5 mg administreret dagligt resulterede i en statistisk signifikant og medicinsk relevant reduktion i forekomsten af nye vertebrale frakturer.
Ibandronic acid 2.5 mg administered daily, showed a statistically significant and medically relevant reduction in the incidence of new vertebral fractures.
Hyppigheden af kliniske vertebrale frakturer blev desuden signifikant reduceret med 49% (p=0, 011).
The incidence of clinical vertebral fractures was also significantly reduced by 49% after 3 years (p=0.011).
Resultater fra 3- års frakturstudiet MF 4411 (%, 95% Konfidensinterval)
Results from 3 years fracture study MF 4411 (%, 95% CI)
Relativ risiko reduktion
Relative risk reduction New morphometric vertebral fractures
Relativ risiko reduktion af kliniske
Relative risk reduction of clinical
(14, 03; 69, 49) Hyppighed af kliniske vertebrale
vertebral fracture
2, 75%
(14.03, 69.49)
frakturer Lumbal BMD – gennemsnitlig
Incidence of clinical vertebral fracture
(3, 73; 6, 92)
5.33% (3.73, 6.92)
(1, 61; 3, 89)
2.75% (1.61, 3.89)
ændring i forhold til baseline - efter 3 år Hofte BMD – gennemsnitlig ændring
BMD – mean change relative to baseline lumbar spine at year 3
1, 26% (0, 8; 1, 7)
1.26% (0.8, 1.7)
6, 54% (6, 1; 7, 0)
6.54% (6.1, 7.0)
i forhold til baseline - efter 3 år
BMD – mean change relative to baseline total hip at year 3
- 0, 69% (- 1, 0; - 0, 4)
-0.69% (-1.0, -0.4)
3, 36% (3, 0; 3, 7)
3.36% (3.0, 3.7)
Effekten af behandlingen med ibandronsyre blev yderligere vurderet i en analyse af subpopulationen af patienter, som ved baseline havde en lumbal BMD T- score under - 2, 5 (tabel 5).
The treatment effect of ibandronic acid was further assessed in an analysis of the subpopulation of patients who, at baseline, had a lumbar spine BMD T-score below – 2.5 (table 5).
Resultater fra 3- års frakturundersøgelsen MF 4411 (%, 95% Konfidensinterval) for patienter med lumbal BMD T- score under - 2, 5 ved baseline.
Results from 3 years fracture study MF 4411 (%, 95% CI) for patients with lumbar spine BMD T-score below – 2.5 at baseline
Nye morfometriske vertebrale frakturer
Relative Risk Reduction New morphometric vertebral fractures
vertebrale frakturer
Incidence of new morphometric vertebral fractures
(9, 53; 15, 55)
(9.53, 15.55)
(3, 31; 7, 41)
5.36% (3.31, 7.41)
vertebrale frakturer
Relative risk reduction of clinical vertebral fracture
(9, 49; 71, 91) Hyppighed af kliniske vertebrale
ibandronic acid 2.5 mg daily
6, 97%
(N=587)
3, 57%
(N=575)
(4, 67; 9, 27)
6.97% (4.67, 9.27)
Daglig oral behandling med 2, 5 mg ibandronsyre - tabletter resulterede i en tiltagende øgning af BMD både vertebralt og non- vertebralt.
Daily oral treatment with ibandronic acid 2.5 mg tablets resulted in progressive increases in BMD at vertebral and nonvertebral sites of the skeleton.
Stigningen i hofte BMD i forhold til baseline var 2, 8% i lårbenshalsen, 3, 4% i hele hoften og 5, 5% i trochanter.
Increases at the hip compared to baseline were 2.8% at the femoral neck, 3.4% at the total hip, and 5.5% at the trochanter.
Biokemiske markører for knogleomsætning (som f. eks urin CTX og serum osteocalcin) viste det forventede suppressionsmønster til præmenopausale værdier og maksimal suppression opnåedes indenfor 3- 6 måneder ved anvendelse af 2, 5 mg ibandronsyre daglig.
Biochemical markers of bone turnover (such as urinary CTX and serum Osteocalcin) showed the expected pattern of suppression to premenopausal levels and reached maximum suppression within a period of 3 - 6 months of using 2.5 mg ibandronic acid daily.
En klinisk relevant reduktion på 50% i biokemiske markører for knogleresorption blev observeret allerede en måned efter start på behandling med ibandronsyre 2, 5 mg.
A clinically meaningful reduction of 50% of biochemical markers of bone resorption was observed as early as one month after starting treatment with ibandronic acid 2.5 mg.
Plasmakoncentrationen af ibandronsyre øges dosisproportionalt efter intravenøs administration af 0, 5 – 6 mg.
Plasma concentrations of ibandronic acid increase in a dose-proportional manner after intravenous administration of 0.5 mg to 6 mg.
Distribution Efter initial systemisk eksponering, bindes ibandronsyre hurtigt til knogler eller udskilles med urinen.
Distribution After initial systemic exposure, ibandronic acid rapidly binds to bone or is excreted into urine.
Hos mennesker er det tilsyneladende terminale fordelingsvolumen mindst 90 liter og det estimeres, at 40 - 50% af den cirkulerende dosis bindes til knoglerne.
In humans, the apparent terminal volume of distribution is at least 90 l and the amount of dose reaching the bone is estimated to be 40 – 50% of the circulating dose.
Sandsynligheden for interaktioner med andre lægemidler på grund af displacering er derfor ringe.
Protein binding in human plasma is approximately 85% - 87% (determined in vitro at therapeutic ibandronic acid concentrations), and thus there is a low potential for interaction with other medicinal products due to displacement.
25 Elimination Ibandronsyre fjernes fra cirkulationen via knogleabsorption (estimeret til 40 - 50% hos postmenopausale kvinder), og resten udskilles uændret gennem nyrerne.
Elimination Ibandronic acid is removed from the circulation via bone absorption (estimated to be 40 – 50% in postmenopausal women) and the remainder is eliminated unchanged by the kidney.
Måleområdet for de tilsyneladende halveringstider er bredt, den tilsyneladende terminale halveringstid er generelt i området 10 - 72 timer.
The range of observed apparent half-lives is broad, the apparent terminal half-life is generally in the range of 10 - 72 hours.
De tidlige plasma - værdier falder hurtigt, og når 10% af peakværdien indenfor 3 og 8 timer efter henholdsvis intravenøs og oral administration.
Early plasma levels fall quickly, reaching 10% of the peak values within 3 and 8 hours after intravenous or oral administration, respectively.
Den totale clearance af ibandronsyre er lav med middelværdier i området 84 - 160 ml/ min.
24 Total clearance of ibandronic acid is low with average values in the range 84 - 160 ml/ min.
60 ml/ min hos raske postmenopausale kvinder) udgør 50 - 60% af den totale clearance og er relateret til kreatininclearance.
Renal clearance (about 60 ml/ min in healthy postmenopausal females) accounts for 50 – 60% of total clearance, and is related to creatinine clearance.
Patienter med nedsat nyrefunktion Den renale clearance for ibandronsyre hos patienter med forskellige grader af nedsat nyrefunktion er lineært relateret til kreatininclearance (CLcr).
Patients with renal impairment Renal clearance of ibandronic acid in patients with various degrees of renal impairment is linearly related to creatinine clearance (CLcr).
Dosisjustering er ikke nødvendig for patienter med mild eller moderat nyrefunktionsnedsættelse (CLcr ≥ 30 ml/ min).
No dose adjustment is necessary for patients with mild or moderate renal impairment (CLcr equal or above 30 ml/ min).
Patienter med svært nedsat nyrefunktion (CLcr < 30 ml/ min) som fik 10 mg oral ibandronsyre dagligt i 21 dage, havde 2 - 3 gange højere plasmakoncentrationer end personer med normal nyrefunktion og den totale ibandronsyre clearance var 44 ml/ min.
Subjects with severe renal impairment (CLcr less than 30 ml/ min) receiving daily oral administration of 10 mg ibandronic acid for 21 days, had 2 - 3 fold higher plasma concentrations than subjects with normal renal function and total clearance of ibandronic acid was 44 ml/ min.
Efter intravenøs administration af 0, 5 mg ibandronsyre faldt den totale, renale og ikke- renale clearance hos patienter med svær nyrefunktions - nedsættelse, med henholdsvis 67%, 77% og 50%, men der fandtes ikke nedsat tolerabilitet i forbindelse med den øgede eksponering.
After intravenous administration of 0.5 mg of ibandronic acid, total, renal, and non-renal clearances decreased by 67%, 77% and 50%, respectively, in subjects with severe renal failure, but there was no reduction in tolerability associated with the increase in exposure.
4. 2 og pkt.
Due to the limited clinical experience, Bondenza is not recommended in patients with severe renal impairment (see section 4.2 and section 4.4).
Ældre population I en multivariant analyse kunne alder ikke påvises som en uafhængig faktor for nogen af de undersøgte farmakokinetiske parametre.
Elderly Population In a multivariate analysis, age was not found to be an independent factor of any of the pharmacokinetic parameters studied.
26 Pædiatrisk population Der findes ikke data vedrørende brugen af Bondenza til disse aldersgrupper.
Paediatric Population There are no data on the use of Bondenza in these age groups.
Hos hunde blev der kun iagttaget toksiske virkninger f. eks tegn på renal skade ved eksponering, som anses for i tilstrækkelig grad at overstige maksimal eksponering for mennesker, og disse er derfor kun af ringe relevans for klinisk brug.
Toxic effects, e. g. signs of renal damage, were observed in dogs only at exposures considered sufficiently in excess of the maximum human exposure, indicating little relevance to clinical use.
Reproduktionstoksicitet:
25 Reproductive toxicity:
Der er ikke udført specifikke studier for 3- måneders regimet.
Specific studies for the 3-monthly dosing regimen have not been performed.
I studier med daglig intravenøs administration fandtes der ikke tegn på direkte føtal toksisk eller teratogen effekt af ibandronsyre hos rotter og kaniner.
In studies with daily i. v. dosing regimen, there was no evidence for a direct foetal toxic or teratogenic effect of ibandronic acid in rats and rabbits.
Legemsvægten var reduceret hos F1- afkommet hos rotter.
Body weight gain was decreased in F1 offspring in rats.
Andre bivirkninger af ibandronsyre hos rotter i reproduktionstoksicitets- undersøgelserne var de samme som for øvrige bisphosphonater.
Other adverse reactions to ibandronic acid in reproductive toxicity studies in the rat were those observed with bisphosphonates as a class.
Natriumchlorid Iseddikesyre Natriumacetattrihydrat Vand til injektionsvæsker
Sodium chloride Glacial acetic acid Sodium acetate trihydrate Water for injections
Bondenza- injektionsvæske, opløsning må ikke blandes med calciumholdige opløsninger eller andre intravenøst administrerede lægemidler.
Bondenza solution for injection must not be mixed with calcium-containing solutions or other intravenously administered medicinal products.
27 6. 6 Regler for destruktion
6.6 Special precautions for disposal
Hvis præparatet administreres i en eksisterende intravenøs infusionsslange, skal infusionsvæsken begrænses til enten isotonisk saltvand eller 50 mg/ ml (5%) glucoseopløsning.
Where the product is administered into an existing intravenous infusion line, the infusate should be restricted to either isotonic saline or 50 mg/ ml (5%) glucose solution.
Ubrugt injektionsvæske, opløsning, sprøjter og injektionskanyler skal bortskaffes i overensstemmelse med lokale krav.
Any unused solution for injection, syringe and injection needle should be disposed of in accordance with local requirements.
Yderligere informationer om dette lægemiddel er tilgængelig på Det europæiske Lægemiddelagenturs (EMEAs) hjemmeside http: // www. emea. europa. eu /
Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http: / /www. emea. europa. eu/
28 BILAG II
27 ANNEX II
INDEHAVER AF VIRKSOMHEDSGODKENDELSE ANSVARLIG FOR BATCHFRIGIVELSE
28 A MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE
Roche Pharma AG Emil- Barell- Strasse 1 D- 79639 Grenzach- Wyhlen Tyskland
Roche Pharma AG Emil-Barell-Strasse 1 D-79639 Grenzach-Wyhlen Germany
Injektionsvæske, opløsning i fyldt sprøjte:
Solution for injection in pre-filled syringe:
Roche Diagnostics GmbH Sandhoferstrasse 116 D- 68305 Mannheim Tyskland
Roche Diagnostics GmbH Sandhoferstrasse 116 D-68305 Mannheim Germany
Indehaveren for markedsføringstilladelsen skal forsætte med at indsende årlige PSURs, hvis ikke andet specificeres af CHMP.
The MAH will continue to submit yearly PSURs, unless otherwise specified by the CHMP.
Indehaveren af markedsføringstilladelsen skal sikre, at pharmacovigilancesystemet, som er beskrevet i dokumentet ” Beskrivelse af pharmacovigilancesystemet ” indsendt den 16. november 2005, samt enhver efterfølgende opdatering, er implementeret og virker, før og mens produktet er på markedet.
The MAH must ensure that the system of pharmacovigilance, as described in the document “ Description of the PharmacoVigilance system” submitted on 16 November 2005, and any subsequent updates, is in place and functioning before and whilst the product is on the market.