natgillin/translations-raw huggingface dataset:
MikroCT- analysen (μCT) påviste øget trabekulær knoglevolumen og bevarelse af trabekulær knoglearkitektur hos patienter behandlet med Aclasta sammenlignet med placebo.
8 tomography (μ CT) analysis demonstrated increased trabecular bone volume and preservation of trabecular bone architecture in patients treated with Aclasta compared to placebo.
8 Knogleomsætningsmarkører Knoglespecifik basisk fosfatase( bone- specific alkaline phosphatase – BSAP), serum N- terminal propeptid af type I- collagen (P1NP) og serum beta- C- telopeptider (b- CTx) blev evalueret i subsæt fra 517 til 1. 246 patienter med jævne mellemrum under hele studiet.
Bone turnover markers Bone specific alkaline phosphatase (BSAP), serum N-terminal propeptide of type I collagen (P1NP) and serum beta-C-telopeptides (b-CTx) were evaluated in subsets ranging from 517 to 1,246 patients at periodic intervals throughout the study.
Behandling med en årlig Aclasta - dosis på 5 mg reducerede BSAP signifikant med 30% i forhold til baseline ved 12 måneder, hvilket blev opretholdt med 28% under baselineniveau ved 36 måneder.
Treatment with a 5 mg annual dose of Aclasta significantly reduced BSAP by 30% relative to baseline at 12 months which was sustained at 28% below baseline levels at 36 months.
P1NP var signifikant reduceret med 61% under baselineniveau ved 12 måneder, og dette blev opretholdt med 52% under baseline ved 36 måneder.
P1NP was significantly reduced by 61% below baseline levels at 12 months and was sustained at 52% below baseline levels at 36 months.
B- CTx var signifikant reduceret med 61% under baselineniveau ved 12 måneder, og det blev opretholdt med 55% under baseline ved 36 måneder.
B-CTx was significantly reduced by 61% below baseline levels at 12 months and was sustained at 55% below baseline levels at 36 months.
Effekt på højde I det treårige osteoporosestudie blev den stående højde målt årligt med et stadiometer.
Effect on height In the three-year osteoporosis study standing height was measured annually using a stadiometer.
2, 5 mm mindre højdetab sammenlignet med placebo (95% CI:
The Aclasta group revealed approximately 2.5 mm less height loss compared to placebo (95% CI:
Dage med nedsat funktionsevne Aclasta reducerede signifikant det gennemsnitlige antal dage med begrænset aktivitet og antal dage med sengeleje på grund af rygsmerter med henholdsvis 17, 9 dage og 11, 3 dage sammenlignet med placebo og reducerede signifikant det gennemsnitlige antal dage med begrænset aktivitet og dage med sengeleje på grund af frakturer med henholdsvis 2, 9 dage og 0, 5 dage sammenlignet med placebo (alle p < 0, 01).
Days of disability Aclasta significantly reduced the mean days of limited activity and the days of bed rest due to back pain by 17.9 days and 11.3 days respectively compared to placebo and significantly reduced the mean days of limited activity and the days of bed rest due to fractures by 2.9 days and 0.5 days respectively compared to placebo (all p < 0.01).
Klinisk effekt i behandlingen af osteoporose hos patienter med øget frakturrisiko efter nylig hoftefraktur (RTF) Incidensen af kliniske frakturer, herunder vertebrale og non- vertebrale frakturer samt hoftefrakturer, blev bedømt i 2. 127 mænd og kvinder i alderen 50- 59 år (gennemsnitsalder 74, 5 år) med en nylig (inden for 90 dage) lavenergi hoftefraktur, som blev fulgt i gennemsnitligt 2 år på studiemedicin.
Clinical efficacy in the treatment of osteoporosis in patients at increased risk of fracture after a recent hip fracture (RFT) The incidence of clinical fractures, including vertebral, non-vertebral and hip fractures, was evaluated in 2,127 men and women aged 50-95 years (mean age 74.5 years) with a recent (within 90 days) low- trauma hip fracture who were followed for an average of 2 years on study medication.
Omkring 42% af patienterne havde en lårbenshals BMD T- score lavere end - 2, 5 og omkring 45% af patienterne havde en lårbenshals BMD T- score over - 2, 5.
Approximately 42% of patients had a femoral neck BMD T-score below -2.5 and approximately 45% of the patients had a femoral neck BMD T-score above -2.5.
D- vitamin niveauerne blev ikke målt rutinemæssigt, men en støddosis D- vitamin (50. 000 til 125. 000 IE oralt eller intramuskulært) blev givet til flertallet af patienterne 2 uger før infusionen.
Vitamin D levels were not routinely measured but a loading dose of vitamin D (50,000 to 125,000 IU orally or via the intramuscular route) was given to the majority of patients 2 weeks prior to infusion.
Alle deltagerne modtog dagligt 1. 000 til 1. 500 mg usammensat calcium plus 800 til 1. 200 IE D- vitaminsupplement.
All participants received 1,000 to 1,500 mg of elemental calcium plus 800 to 1,200 IU of vitamin D supplementation per day.
6 uger efter hoftefrakturhelingen.
Ninety-five percent of the patients received their infusion two or more weeks after the hip fracture repair and the median timing of infusion was approximately six weeks after the hip fracture repair.
Tabel 4
9 Table 4
Sammenligninger mellem behandlinger af incidensen af vigtige kliniske frakturvariabler
Between treatment comparisons of the incidence of key clinical fracture variables
Aclasta Placebo Absolut reduktion i
Aclasta Placebo Absolute reduction (N=1,065) (N=1,062) in fracture event
(N=1, 065) hændelses - rate (%)
Relative risk reduction in
(N=1, 062) hændelses - rate (%)
event rate event rate (%) (%)
frakturhændelses - rate% (CI)
rate% (CI)
risikoreduktion i frakturincidens% (CI)
fracture incidence% (CI)
Alle kliniske frakturer (1) Klinisk vertebral fraktur (2) Ikke- vertebral fraktur (1) * p- værdi < 0, 05, ** p- værdi < 0, 01
Any clinical fracture (1) Clinical vertebral fracture (2) Non-vertebral fracture (1) *p-value < 0.05, **p-value < 0.01
8, 6 1, 7 7, 6
8.6 13.9 1.7 3.8 7.6 10.7
13, 9 3, 8 10, 7
5.3 2.1 3.1
5, 3 (2, 3, 8, 3) 2, 1 (0, 5, 3, 7) 3, 1 (0, 3, 5, 9)
(2.3, 8.3) (0.5, 3.7) (0.3, 5.9)
35 (26, 50) ** 46 (8, 68) * 27 (2, 45) *
35 (16, 50)** 46 (8, 68)* 27 (2, 45)*
(1) Ekskl. frakturer på fingre, tæer og ansigt (2) Inkl. kliniske frakturer på torakale og lumbale ryghvirvler
(1) Excluding finger, toe and facial fractures (2) Including clinical thoracic and clinical lumbar vertebral fractures
9 Studiet var ikke designet til at måle signifikante forskelle i hoftefraktur, men der ses en tendens mod reduktion i nye hoftefakturer.
The study was not designed to measure significant differences in hip fracture, but a trend was seen towards reduction in new hip fractures.
All cause mortaliteten var 10% (101 patienter) i gruppen behandlet med Aclasta sammenlignet med 13% (141 patienter) i placebogruppen.
All cause mortality was 10% (101 patients) in the Aclasta-treated group compared to 13% (141 patients) in the placebo group.
Det svarer til en reduktion på 28% i risikoen for all cause mortalitet (p=0, 01).
This corresponds to a 28% reduction in the risk of all cause mortality (p=0.01).
Incidensen af forsinket heling af hoftefrakturer var sammenlignelig mellem Aclasta (34 [3, 2%]) og placebo (29 [2, 7%]).
The incidence of delayed hip fracture healing was comparable between Aclasta (34 [3.2%]) and placebo (29 [2.7%]).
Effekt på knoglemineraldensitet (BMD) I HORIZON- RFT- studiet forøgede Aclastabehandling signifikant BMD i forhold til placebo ved hofteledet og lårbenshalsen ved alle tidspunkter (12, 24 og 36 måneder).
Effect on bone mineral density (BMD) In the HORIZON-RFT study Aclasta treatment significantly increased BMD at the total hip and femoral neck relative to treatment with placebo at all timepoints.
Behandling med Aclasta resulterede i 5, 4% stigning i BMD på hele hoften og 4, 3% ved lårbenshalsen over 24 måneder sammenlignet med placebo.
Treatment with Aclasta resulted in an increase in BMD of 5.4% at the total hip and 4.3% at the femoral neck over 24 months as compared to placebo.
Klinisk effekt hos mænd I HORIZON- RTF studiet blev 508 mænd randomiseret og 185 patienter fik BMD bedømt ved 24 måneder.
Clinical efficacy in men In the HORIZON-RFT study 508 men were randomised into the study and 185 patients had BMD assessed at 24 months.
Ved 24 måneder blev der observeret en signifikant øgning på 3, 6% i BMD over hele hoften hos patienter, som blev behandlet med Aclasta, svarende til effekten observeret hos post - menopausale kvinder i HORIZON- PFT studiet.
At 24 months a similar significant increase of 3.6% in total hip BMD was observed for patients treated with Aclasta as compared to the effects observed in post-menopausal women in the HORIZON-PFT study.
Studiet var ikke dimensioneret til at vise en reduktion i kliniske frakturer hos mænd; incidensen af kliniske frakturer var 7, 5% hos mænd behandlet med Aclasta i forhold til 8, 7% for placebo.
The study was not powered to show a reduction in clinical fractures in men; the incidence of clinical fractures was 7.5% in men treated with Aclasta versus 8.7% for placebo.
I et andet studie, som omfattede mænd, (studie CZOL446M2308) var en årlig infusion af Aclasta non - inferiør i forhold til ugentlig alendronat for den procentuelle ændring i lænderyg- BMD ved måned 24 i forhold til baseline.
In another study in men (study CZOL446M2308) an annual infusion of Aclasta was non-inferior to weekly alendronate for the percentage change in lumbar spine BMD at month 24 relative to baseline.
Klinisk effekt ved behandling af Pagets sygdom af knoglerne Aclasta blev undersøgt hos mænd og kvinder i alderen over 30 år med primært mild til moderat Pagets sygdom af knoglerne (gennemsnitlig serum alkalisk fosfatase niveau på 2, 6- 3, 0 gange den øvre grænseværdi for det normale aldersspecifikke referenceområde ved inklusion i studiet) bekræftet ved radiografisk påvisning.
Clinical efficacy in the treatment of Paget’ s disease of the bone Aclasta was studied in male and female patients aged above 30 years with primarily mild to moderate Paget’ s disease of the bone (median serum alkaline phosphatase level 2.6– 3.0 times the upper limit of the age-specific normal reference range at the time of study entry) confirmed by radiographic evidence.
Efter 6 måneder viste Aclasta respons hos 96% (169/ 176) og en serum alkalisk phosphatase (SAP) normaliseringsrate hos 89% (156/ 176) sammenlignet med 74% (127/ 171) og 58% (99/ 171) for risedronat (alle p < 0, 001).
After 6 months, Aclasta showed 96% (169/ 176) and 89% (156/ 176) response and serum alkaline phosphatase (SAP) normalisation rates compared to 74% (127/ 171) and 58% (99/ 171) for risedronate (all p < 0.001).
Patienter, som blev klassificeret som respondere efter 6 måneders hovedstudie, var egnet til at deltage i et udvidet opfølgningsstudie.
10 Patients who were classified as responders at the end of the 6 month core study were eligible to enter an extended follow-up period.
Af de 143 patienter behandlet med Aclasta og 107 patienter behandlet med risedronat, som deltog i et udvidet observationsstudie med en gennemsnitlig opfølgningsvarighed på 18 måneder efter dosis, vedligeholdt 141 patienter behandlet med Aclasta deres terapeutiske respons sammenlignet med 71 patienter behandlet med risedronat.
Of the 143 Aclasta-treated patients and 107 risedronate-treated patients who entered an extended observation study, after a median duration of follow-up of 18 months from time of dosing, 141 Aclasta-treated patients maintained their therapeutic response compared to 71 risedronate-treated patients.
Dette svarer til en reduktion på 96% i risikoen for tilbagefald hos patienter behandlet med Aclasta i forhold til risedronat.
This corresponds to a 96% reduction of risk of relapse in Aclasta versus risedronate-treated patients.
Knoglehistologi blev evalueret hos 7 patienter med Pagets sygdom 6 måneder efter behandling med 5 mg zoledronsyre.
Bone histology was evaluated in 7 patients with Paget’ s disease 6 months after treatment with 5 mg zoledronic acid.
10 5. 2 Farmakokinetiske egenskaber
5.2 Pharmacokinetic properties
Efter påbegyndelse af infusion med zoledronsyre, øges plasmakoncentrationen af den aktive substans hurtigt, og maksimal koncentration nås ved slutningen af infusionsperioden, efterfulgt af et hurtigt fald til < 10% af maksimalkoncentrationen efter 4 timer og < 1% af maksimalkoncentrationen efter 24 timer, med en efterfølgende forlænget periode med meget lave koncentrationer der ikke overstiger 0, 1% af den maksimale koncentration.
After initiation of the zoledronic acid infusion, plasma concentrations of the active substance increased rapidly, achieving their peak at the end of the infusion period, followed by a rapid decline to < 10% of peak after 4 hours and < 1% of peak after 24 hours, with a subsequent prolonged period of very low concentrations not exceeding 0.1% of peak levels.
Intravenøst administreret zoledronsyre elimineres i en trifasisk proces: hurtig bifasisk elimination fra det systemiske kredsløb med halveringstider på t½α 0, 24 og t½β 1, 87 timer efterfulgt af en lang elimineringsfase med en terminal eliminationshalveringstid på t½γ 146 timer.
Intravenously administered zoledronic acid is eliminated by a triphasic process: rapid biphasic disappearance from the systemic circulation, with half-lives of t½α 0.24 and t½β 1.87 hours, followed by a long elimination phase with a terminal elimination half-life of t½γ 146 hours.
De tidlige dispositionsfaser (α og β med ovenstående t½- værdier) repræsenterer formodentlig hurtigt optag i knogle og udskillelse via nyrerne.
The early disposition phases (α and β, with t½ values above) presumably represent rapid uptake into bone and excretion via the kidneys.
Total legemsclearance er 5, 04±2, 5 l/ h uafhængigt af dosis og uanset køn, alder, race og legemsvægt.
The total body clearance is 5.04 ± 2.5 l/ h, independent of dose, and unaffected by gender, age, race or body weight.
Inter - og intraindividuel variation i clearance for zoledronsyre i plasma er vist at være henholdsvis 36% og 34%.
The inter- and intra-subject variation for plasma clearance of zoledronic acid was shown to be 36% and 34%, respectively.
Forøgelse af infusionstiden fra 5 til 15 minutter forårsagede en 30% nedgang i zoledronsyre koncentrationen ved afslutningen af infusionen, men havde ingen effekt på arealet under plasma koncentration mod tid kurven.
Increasing the infusion time from 5 to 15 minutes caused a 30% decrease in zoledronic acid concentration at the end of the infusion, but had no effect on the area under the plasma concentration versus time curve.
Der er ikke udført specifikke lægemiddelinteraktionsstudier med zoledronsyre.
No specific drug-drug interaction studies have been conducted with zoledronic acid.
Siden zoledronsyre ikke metaboliseres i mennesker og stoffet havde lille eller ingen effekt som direkte virkende og/ eller irreversibel metabolismeafhængig hæmmer af P450 enzymer, er det usandsynligt, at zoledronsyre reducerer den metaboliske udskillelse af stoffer, som metaboliseres af cytokrom P450 enzymsystemet.
Since zoledronic acid is not metabolised in humans and the substance was found to have little or no capacity as a direct- acting and/ or irreversible metabolism-dependent inhibitor of P450 enzymes, zoledronic acid is unlikely to reduce the metabolic clearance of substances which are metabolised via the cytochrome P450 enzyme systems.
Zoledronsyre bindes ikke mærkbart til plasmaproteiner (cirka 43- 55% bundet), og bindingen er uafhængig af koncentrationen.
Zoledronic acid is not highly bound to plasma proteins (approximately 43-55% bound) and binding is concentration independent.
4. 2) Den renale clearance af zoledronsyre korrelerer tydeligt med creatininclearance, idet den renale clearance udgjorde 75±33% af creatininclearance, hvilket viste en median på 84±29 ml/ min (varierende fra 22 til 143 ml/ min) hos de 64 undersøgte patienter.
Special populations (see section 4.2) The renal clearance of zoledronic acid was correlated with creatinine clearance, renal clearance representing 75 ± 33% of the creatinine clearance, which showed a mean of 84 ± 29 ml/ min (range 22 to 143 ml/ min) in the 64 patients studied.
Manglende akkumulering af stof givet som flere doser uanset nyrefunktionen, indikerer, at dosisjustering af zoledronsyre ved mild (Clkr = 50– 80 ml/ min) og moderat nedsat nyrefunktion ned til en kreatininclearance på 35 ml/ min ikke er nødvendig.
Small observed increases in AUC(0-24hr), by about 30% to 40% in mild to moderate renal impairment, compared to a patient with normal renal function, and lack of accumulation of drug with multiple doses irrespective of renal function, suggest that dose adjustments of zoledronic acid in mild (Clcr = 50– 80 ml/ min) and moderate renal impairment down to a creatinine clearance of 35 ml/ min are not necessary.
Der er kun begrænsede data tilgængelig ved svær nedsat nyrefunktion (kreatininclearance < 30 ml/ min), det er derfor ikke muligt at give nogle dosisanbefalinger for denne population.
As only limited data are available in severe renal impairment (creatinine clearance < 30 ml/ min), no dosing recommendations are possible for this population.
5. 3 Prækliniske sikkerhedsdata
11 5.3 Preclinical safety data
Akut toksicitet Den højeste ikke- letale intravenøse enkeltdosis var 10 mg/ kg legemsvægt hos mus og 0, 6 mg/ kg hos rotter.
Acute toxicity The highest non-lethal single intravenous dose was 10 mg/ kg body weight in mice and 0.6 mg/ kg in rats.
I enkelt- dosis infusions hundestudier, administreret over 15 minutter, var 1, 0 mg/ kg (6 gange den anbefalede humane terapeutiske eksponering baseret på AUC) fint tolereret uden nyreproblemer.
In the single-dose dog infusion studies, 1.0 mg/ kg (6 fold the recommended human therapeutic exposure based on AUC) administered over 15 minutes was well tolerated with no renal effects.
Subkronisk og kronisk toksicitet I intravenøse infusionsstudier blev renal tolerabilitet overfor zoledronsyre bestemt hos rotter, som fik 0, 6 mg/ kg givet som 15 minutters infusion i alt seks gange med 3 dages interval (for en kumulativ dosis svarende til AUC niveau cirka 6 gange højere den humane terapeutiske eksponering), mens fem
Subchronic and chronic toxicity In the intravenous infusion studies, renal tolerability of zoledronic acid was established in rats when given 0.6 mg/ kg as 15-minute infusions at 3-day intervals, six times in total (for a cumulative dose that corresponded to AUC levels about 6 times the human therapeutic exposure) while five 15-minute infusions of 0.25 mg/ kg administered at 2– 3-week intervals (a cumulative dose that corresponded to 7 times the human therapeutic exposure) were well tolerated in dogs.
I intravenøse bolusstudier faldt dosis, som var fint tolereret med stigende studievarighed:
In the intravenous bolus studies, the doses that were well-tolerated decreased with increasing study duration:
0, 2 og 0, 02 mg/ kg dagligt var fint tolereret i 4 uger hos henholdsvis rotter og hunde, men kun 0, 01 mg/ kg og 0, 005 mg/ kg hos henholdsvis rotter og hunde, når det indgives i 52 uger.
0.2 and 0.02 mg/ kg daily was well tolerated for 4 weeks in rats and dogs, respectively but only 0.01 mg/ kg and 0.005 mg/ kg in rats and dogs, respectively, when given for 52 weeks.
Dette resultat afspejler stoffets farmakologiske antiresorptive aktivitet.
The most frequent finding in the repeat-dose studies consisted of increased primary spongiosa in the metaphyses of long bones in growing animals at nearly all doses, a finding that reflected the compound’ s pharmacological antiresorptive activity.
Reproduktionstoksicitet Teratogenstudier blev udført på to arter, begge via subkutan administration.
Reproduction toxicity Teratology studies were performed in two species, both via subcutaneous administration.
Der blev observeret teratogenicitet hos rotter ved doser på ≥ 0, 2 mg/ kg og sås tydeligt i form af ydre og viscerale misdannelser samt misdannelser i skelettet.
Teratogenicity was observed in rats at doses ≥ 0.2 mg/ kg and was manifested by external, visceral and skeletal malformations.
Dystoki blev observeret ved den laveste dosis (0, 01 mg/ kg kropsvægt), der blev afprøvet i rotter.
Dystocia was observed at the lowest dose (0.01 mg/ kg body weight) tested in rats.
Der blev ikke observeret teratogene eller embyo/ føtal effekter hos kaniner, selvom maternal toksicitet blev bemærket ved 0, 1 mg/ kg på grund af nedsat niveau af serum calcium.
No teratological or embryo/ foetal effects were observed in rabbits, although maternal toxicity was marked at 0.1 mg/ kg due to decreased serum calcium levels.
Mutagenicitet og cancerogent potentiale Zoledronsyre var ikke mutagen i de udførte mutagenicitetsprøver, og undersøgelse af carcinogenicitet kunne ikke påvise carcinogent potentiale.
Mutagenicity and carcinogenic potential Zoledronic acid was not mutagenic in the mutagenicity tests performed and carcinogenicity testing did not provide any evidence of carcinogenic potential.
Mannitol Natriumcitrat Vand til injektionsvæsker
Mannitol Sodium citrate Water for injections
Aclasta må ikke komme i kontakt med calcium- holdige opløsninger.
Aclasta must not be allowed to come into contact with any calcium-containing solutions.
Uåbnet flaske:
Unopened bottle:
24 timer ved 2°C - 8°C
24 hours at 2°C - 8°C
Ud fra et mikrobiologisk synspunkt skal produktet anvendes straks.
12 From a microbiological point of view, the product should be used immediately.
Hvis produktet ikke anvendes med det samme, er brugeren ansvarlig for opbevaringstid og – betingelser, og vil normalt ikke være længere end 24 timer ved 2°C - 8°C.
If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C - 8°C.
6. 5 Emballagetyper og pakningsstørrelser
6.5 Nature and contents of container
100 ml farveløs plastic (cykloolefinik polymer) flaske lukket med fluoro- polymer dækket bromobutyl gummiprop og et aluminium/ polypropylen fliplåg.
100 ml transparent plastic (cycloolefinic polymer) bottle closed with a fluoro-polymer coated bromobutyl rubber stopper and an aluminium/ polypropylene cap with a flip component.
12 Aclasta leveres i pakninger, der indeholder 1 flaske som enkeltstykspakning eller i multipakninger, bestående af 5 pakninger, der hver indeholder 1 flaske.
Aclasta is supplied in packs containing one bottle as unit pack or in multi-packs comprising 5 packs, each containing 1 bottle.
Novartis Europharm Limited Wimblehurst Road Horsham West Sussex, RH12 5AB Storbritannien
Novartis Europharm Limited Wimblehurst Road Horsham West Sussex, RH12 5AB United Kingdom
13 BILAG II
13 ANNEX II
Novartis Pharma GmbH Roonstraße 25 D- 90429 Nürnberg Tyskland
Novartis Pharma GmbH Roonstraße 25 D-90429 Nuremberg Germany
Lægemidlet må kun udleveres efter begrænset recept (jf. bilag I:
(See Annex I:
Indehaveren af markedsføringstilladelsen (MAH) skal sikre at uddannelsesprogrammet, der er implementeret til den godkendte indikation, behandling af postmenopausal osteoporose, er udvidet til læger, der forventes at udskrive recepter til den nye indikation: behandling af osteoporose hos postmenopausale kvinder og mænd med øget risiko for fraktur, inklusive personer med en nylig lavenergi hoftefraktur.
The Marketing Authorisation Holder (MAH) shall ensure that the educational programme implemented for the authorised indication of treatment of post-menopausal osteoporosis, is extended to the potential prescribers concerned by the new indication: treatment of osteoporosis in post- menopausal women and men at increased risk of fracture, including those with a recent low-trauma hip fracture.
Uddannelsesprogrammet indeholder følgende: • Lægeundervisningsmateriale • Patientinformationspakke
The educational programme contains the following: • Physician educational material • Patient information pack