natgillin/translations-raw huggingface dataset:
Det Europæiske Lægemiddelagentur (EMEA) vurderer hvert år ny information vedrørende produktet, og produktresuméet vil om nødvendigt blive opdateret.
The European Medicines Agency (EMEA) will review any new information which may become available every year and this SPC will be updated as necessary.
Virkningsmekanisme Bortezomib er en proteasom- hæmmer.
Mechanism of action Bortezomib is a proteasome inhibitor.
Den er specifikt designet til at hæmme chymotrypsinlignende aktivitet ved 26S- proteasom i pattedyrceller.
It is specifically designed to inhibit the chymotrypsin-like activity of the 26S proteasome in mammalian cells.
26S- proteasom er et stort proteinkompleks, som nedbryder ubiquitinerede proteiner.
The 26S proteasome is a large protein complex that degrades ubiquitinated proteins.
Ubiquitin- proteasom- pathway’ en spiller en vigtig rolle i reguleringen af omsætningen af specifikke proteiner, som derved opretholder homeostasen i cellerne.
The ubiquitin-proteasome pathway plays an essential role in regulating the turnover of specific proteins, thereby maintaining homeostasis within cells.
Hæmning af 26S- proteasom forhindrer denne målretteede proteolyse og påvirker multiple signalleringskaskader i cellen, hvilket til sidst resulterer i cancer- celle- død.
Inhibition of the 26S proteasome prevents this targeted proteolysis and affects multiple signalling cascades within the cell, ultimately resulting in cancer cell death.
I koncentrationer på 10 µM hæmmer bortezomib ikke nogen af en lang række screenede receptorer og proteaser og er mere end 1500 gange så selektivt for proteasom end for det næste foretrukne enzym.
At 10 μ M concentrations, bortezomib does not inhibit any of a wide variety of receptors and proteases screened and is more than 1500-fold more selective for the proteasome than for its next preferable enzyme.
Bortezomib- medieret proteasomhæmning påvirker cancerceller på flere måder, inklusive – men ikke begrænset til – ændring af regulatorproteiner, som styrer cellecyklusprogression og aktiveringen af nuklear faktor kappa B (NF- κB).
Bortezomib mediated proteasome inhibition affects cancer cells in a number of ways, including, but not limited to, altering regulatory proteins, which control cell cycle progression and nuclear factor kappa B (NF-kB) activation.
NF - κB er en transkriptionsfaktor, hvis aktivering kræves til mange aspekter af tumorgenese, inklusive cellevækst og – overlevelse, angiogenese, celle- celle- interaktioner og metastase.
13 including cell growth and survival, angiogenesis, cell-cell interactions, and metastasis.
Forsøg har påvist, at bortezomib er cytotoksisk over for en række cancercelletyper, og at cancerceller er mere følsomme over for proapoptotiske virkninger af proteasom- hæmning end normale celler.
Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types and that cancer cells are more sensitive to the pro-apoptotic effects of proteasome inhibition than normal cells.
Et prospektivt, internationalt, randomiseret (1: 1), åbent klinisk fase III- forsøg (VISTA) med 682 patienter blev gennemført for at bestemme, om VELCADE (1, 3 mg/ m2) i kombination med melphalan (9 mg/ m2) og prednison (60 mg/ m2) medførte en forbedring i tid til progression (TTP) ved sammenligning med melphalan (9 mg/ m2) og prednison (60 mg/ m2) til patienter med tidligere ubehandlet myelomatose.
Clinical efficacy in previously untreated multiple myeloma A prospective Phase III, international, randomised (1:1), open-label clinical study (VISTA) of 682 patients was conducted to determine whether VELCADE (1.3 mg/ m2) in combination with melphalan (9 mg/ m2) and prednisone (60 mg/ m2) resulted in improvement in time to progression (TTP) when compared to melphalan (9 mg/ m2) and prednisone (60 mg/ m2) in patients with previously untreated multiple myeloma.
Baselinedemografi og patientkarakteristika er opsummeret i tabel 7.
Baseline demographics and patient characteristics are summarized in Table 7.
Oversigt over patient - og sygdomskarakteristika ved baseline i VISTA- forsøget
Summary of baseline patient and disease characteristics in the VISTA study
Median alder i år (interval) Køn: mand/ kvinde
Median age in years (range) Gender: male/ female
Race: kaukasisk/ asiatisk/ sort/ andet Karnofsky performance statusscore ≤ 70 Hæmoglobin < 100 g/ l 9
Race: caucasian/ asian/ black/ other Karnofsky performance status score ≤ 70 Hemoglobin < 100 g/ l Platelet count < 75 x 109/ l Disease Characteristics
1%
88% / 10% / 1% / 1% 35% 37% < 1%
Sygdomskarakteristika
87% / 11% / 2% / 0% 33% 36% 1%
Myelomatype (%):
Type of myeloma (%):
IgG/ IgA/ Let kæde Median β2- mikroglobulin (mg/ l) Median albumin (g/ l) Kreatininclearance ≤ 30 ml/ min [n (%)]
IgG/ IgA/ Light chain Median β 2-microglobulin (mg/ l) Median albumin (g/ l) Creatinine clearance ≤ 30 ml/ min [n (%)]
64% / 24% / 8% 4, 2 33, 0 20 (6%)
64% / 24% / 8% 4.2 33.0 20 (6%)
62% / 26% / 8% 4, 3 33, 0 16 (5%)
62% / 26% / 8% 4.3 33.0 16 (5%)
På tidspunktet for en forudspecificeret interimanalyse var det primære effektmål, tid til progression, opnået, og patienterne i M+P- gruppen blev tilbudt Vc+M+P- behandling.
At the time of a pre-specified interim analysis, the primary endpoint, time to progression, was met and patients in the M+P arm were offered Vc+M+P treatment.
Efter interimanalysen blev overlevelsen fortsat fulgt.
Survival continued to be followed after the interim analysis.
Median opfølgning var 16, 3 måneder.
Median follow-up was 16.3 months.
Effektresultaterne fremgår af tabel 8:
Efficacy results are presented in Table 7:
Tabel 8:
14 Table 7:
Oversigt over effektanalyserne i VISTA- forsøget Effektmål Tid til progression –
Summary of efficacy analyses in the VISTA study Efficacy endpoint Time to progression –
Hændelser n (%)
Events n (%) Mediana (95% CI)
Hazard ratiob
Hazard ratiob
(95% CI) p- værdi c Progressionsfri overlevelse
(95% CI) p-value c Progression-free survival
(95% CI) p- værdi c Samlet overlevelse
(95% CI) p-value c Overall survival
(0, 49, 0, 76) 0, 00001
(0.49, 0.76) 0.00001
Hændelser (dødsfald) n (%) Hazard ratiob (95% CI) p- værdi c
Events (deaths) n (%) Hazard ratiob (95% CI) c
Responsrate populatione n = 668
Response rate populatione n = 668
PRf n (%) nCR n (%) CR + PRf n (%) p- værdid
PRf n (%) nCR n (%)
Reduktion i serum M- protein populationg n=667
Reduction in serum M-protein populationg n=667
> =90% n (%) Tid til første respons i CR + PR
> =90% n (%) Time to first response in CR + PR
Median Mediana responsvarighed
Median a Median response duration
1, 4 md.
1.4 mo
4, 2 md.
4.2 mo
CRf CR + PRf Tid til næste behandling
CRf CR + PRf Time to next therapy
19, 9 md.
24.0 mo 19.9 mo
13, 1 md.
12.8 mo 13.1 mo
Hændelser n (%) Mediana (95% CI)
Events n (%) Mediana
127 (38) 20, 8 md
127 (38) 20.8 mo
Hazard ratiob
(95% CI) Hazard ratiob
(95% CI) p- værdi c a Kaplan- Meier- estimat b
(95% CI)
Estimatet af Hazard ratio er baseret på Cox 'proportionelle risikomodel justeret for opdelingsfaktorer: β2- mikroglobulin, albumin og region.
Kaplan-Meier estimate. b Hazard ratio estimate is based on a Cox proportional-hazard model adjusted for stratification factors: β 2-microglobulin, albumin, and region.
Ikke- estimerbar
A hazard ratio less than 1 indicates an advantage for VMP c p-value based on the stratified log-rank test adjusted for stratification factors: beta2-microglobulin, albumin, and region d p-value for Response Rate (CR + PR) from the Cochran-Mantel-Haenszel chi-square test adjusted for the stratification factors e Response population includes patients who had measurable disease at baseline f EBMT criteria g All randomized patients with secretory disease
Klinisk effekt ved recidiverende eller refraktær myelomatose
Not estimable
Sikkerheden og effekten ved VELCADE blev vurderet i to forsøg med den anbefalede dosis på 1, 3 mg/ m2: et randomiseret, komparativt fase III- forsøg versus dexametason (Dex) med 669 patienter med recidiverende eller refraktær multipelt myelom, som havde fået 1- 3 tidligere behandlinger og et fase II- forsøg med en enkelt gruppe med 202 patienter med recidiverende eller refraktær myelomatose, som havde fået mindst 2 tidligere behandlinger, og som i deres seneste behandlingsregime havde oplevet progression (se tabel 9, 10 og 11).
(see Tables 9, 10 and 11).
Dosering i fase II - og fase III- forsøg Fase II
Dosing regimens in Phase II and Phase III studies Phase
Dag 1, 4, 8, 11 (resten dag 12- 21)
Treatment schedule
III
Dose
1, 3 mg/ m2 (intravenøs bolus)
Regimen
III
II III III
Dex a) dag 1- 4, 9- 12, 17- 20 b) dag 1- 4
Day 1,4,8,11, (rest Day 12-21) 1.3 mg/ m2 (intravenous bolus) Vc* 1.3 mg/ m2 a) Days 1,4,8,11, (Rest Day 12-21) (intravenous bolus) b) Days 1,8,15,22 Dex 40 mg (oral) a) Days 1– 4, 9 – 12, 17– 20Days 1– 4
a) hver 5. uge x 4 b) hver 4. uge x 5
Q3 weeks x 8cycles (extension**) a) Q3weeks x 8, then b) Q5 weeks x 3 a) Q5 week x 4 b) Q4 week x 5
20 mg (oralt) (dag 1, 2, 4, 5, 8, 9, 11, 12)
Add Dex*** 20 mg (oral) (Days 1,2,4,5,8,9, 11,12)
hver 3. uge
Q3 weeks
* a) indledende behandling, a) og b) repræsenterer et helt behandlingsforløb ** Forlængelsesforsøg gav patienterne mulighed for at fortsætte med VELCADE, hvis de havde haft gavn af behandlingen *** Hvis de efter 2 eller 4 cyklusser med VELCADE oplevede henholdsvis progression eller stabil sygdom, kunne de få dexamethanson
*a) is the initial treatment, a) and b) represent a full course of treatment **An extension study authorised patients benefiting from treatment to continue receiving VELCADE ***If after 2 or 4 cycles of VELCADE, the patients had progressive disease or stable disease, respectively, they could receive dexamethasone
Patientkarakteristika i fase II - og fase III- forsøg
Patient characteristics in Phase II and Phase III studies
Fase II Vc
Phase II Vc
Fase III Vc
Phase III Vc
Fase III Dex
Phase III Dex
Patientantal, Mænd i%
Patient number, ITT analysis Male% Median age, yrs (range) Caucasian Karnofsky PS > 80% Platelets < 75,000/μ l Hemoglobin < 100g/ l Median Creatinine Clearance, ml/ min (range) 74
202 60
202 60 59 (34-84) 81% 80 21% 44% (14-221)
333 56
333 56 61 (33-84) 90% 87% 6% 32% 73.3 (15.6-170.7)
336 60
336 60 61 (27-86) 88% 84% 4% 28% 73.3 (15.3-261.1)
Medianalder i Kaukasisk
Myeloma IgG Myeloma IgA Myeloma light chain Median duration since diagnosis (yrs) Chromosome 13 abnormalities Median β 2-microglobulin (mg/ l) Median number prior treatment lines* (range)
59 (34- 84) 81%
60% 24% 14% 4.0 15% 3.5 6 (2-15)
61 (33- 84) 90%
60% 23% 12% 3.5 25.7% 3.7 2 (1-7)
61 (27- 86) 88%
59% 24% 13% 3.1 25.0% 3.6 2 (1-8)
Hæmoglobin < 100g/ l Median kreatinin- clearance, ml/ min (interval) Myelom- IgG Myelom- IgA Letkædet myelom Median varighed siden diagnosen (år) Kromosom 13- abnormiteter Median β2 mikroglobulin (mg/ l) Median antal tidligere behandlinger (interval) * 1 tidligere behandling > 1 tidligere behandling
1 prior line > 1 prior line
32% 73, 3 (15, 6- 170, 7) 60% 23% 12% 3, 5 25, 7% 3, 7 2 (1- 7) n=132( 40%) n= 186 (60%)
n =132 (40%) n = 186 (60%) n =
28% 73, 3 (15, 3- 261, 1) 59% 24% 13% 3, 1 25, 0% 3, 6 2 (1- 8) n= 119 (35%) n= 194 (65%)
n = 119 (35%) 194 (65%)
* Inklusive steroider, alkylerende midler, antracykliner, thalidomid og stamcelletransplantationer
*Including steroids, alkylating agents, anthracyclines, thalidomide and stem cell transplants
Tabel 11:
16 Table 11:
Patienter i behandling med VELCADE i fase II - og III- forsøg
Patient exposure to treatment with VELCADE during Phase II and III studies
fase II Vc
Phase II Vc
Fået mindst 1 dosis Gennemført 4 cyklusser
Received at least 1 dose Completed 4 cycles
a) alle indl. cyklusser (antal) b) hele behandlingen (antal)
a) all initial cycles (number) b) full course (number) c) extension *
27% (8 cyklusser) ikke relevant
27% (8 cycles) NA N= 63 pts (median 7 cycles) or total median 14 cycles (range 7-32)
29% (8 cyklusser) 9% (11 cyklusser)
29% (8 cycles) 9% (11 cycles) NA
36% (4 cyklusser) 5% (9 cyklusser)
36% (4 cycles) 5% (9 cycles) NA
* Patienterne kan fortsætte med behandlingen efter at have gennemført 8 cyklusser, hvis de har gavn af behandlingen.
*Patients could continue on treatment after completing 8 cycles, in case of benefit NA = not applicable
I fase III- forsøget førte behandlingen med VELCADE til signifikant længere tid indtil progression, en signifikant længere overlevelse og en signifikant højere responsrate sammenlignet med behandling med dexametason (se tabel 12) hos alle patienter samt hos patienter, som tidligere havde fået én behandling.
In the Phase III study, treatment with VELCADE led to a significantly longer time to progression, a significantly prolonged survival and a significantly higher response rate, compared to treatment with dexamethasone (see Table 12), in all patients as well as in patients who have received 1 prior line of therapy.
Som et resultat af den forud planlagte interimanalyse blev dexametason- gruppen standset på anbefaling fra datamonitoreringskomiteen og fik derefter tilbudt VELCADE uanset sygdommens status.
As a result of a preplanned interim analysis, the Dexamethasone arm was halted at the recommendation of the data monitoring committee and all patients randomised to dexamethasone were then offered VELCADE, regardless of disease status.
På grund af det tidlige cross- over er den mediane varighed af opfølgningen for de overlevende patienter 8, 3 måneder.
Due to this early crossover, the median duration of follow-up for surviving patients is 8.3 months.
Både hos de patienter, som var refraktære over for den seneste behandling, og de, der ikke var refraktære, var den samlede overlevelse signifikant længere og responsraten var signifikant højere i VELCADE- gruppen.
Both in patients who were refractory to their last prior therapy and those who were not refractory, overall survival was significantly longer and response rate was significantly higher on the VELCADE arm.
Uanset β2- mikroglobulintal ved baseline var alle effektparametre (tiden indtil progression og samlet overlevelse samt responsrate) signifikant forbedrede i VELCADE- gruppen.
Regardless of β 2- microglobulin levels at baseline, all efficacy parameters (time to progression and overall survival, as well as response rate) were significantly improved on the VELCADE arm.
I den refraktære population i fase II- forsøget blev responsen fastlagt af en uafhængig review- komite, og responskriterierne fra The European Bone Marrow Transplant Group blev brugt.
In the refractory population of the Phase II study, responses were determined by an independent review committee and the response criteria were those of the European Bone Marrow Transplant Group.
Denne overlevelse var større end den mediane 6- 9 måneders overlevelse, der blev forventet af rådgivende kliniske investigatorer for en lignende patientpopulation.
This survival was greater than the six-to-nine month median survival anticipated by consultant clinical investigators for a similar patient population.
Ved multivarians analyse var responsraten uafhængig af myelomtype, performance status, kromosom 13 deletion- status, eller antallet eller typen af tidligere behandling; patienter, som havde fået 2 eller 3 tidligere behandlinger, havde en responsrate på 32% (10/ 32) og patienter, som havde fået mere end 7 tidligere behandlinger, havde en responsrate på 31% (21/ 67).
Patients who had received 2 to 3 prior therapeutic regimens had a response rate of 32% (10/ 32) and patients who received greater than 7 prior therapeutic regimens had a response rate of 31% (21/ 67).
Tabel 12:
Table 12:
Fase III
Summary of
1 tidligere
disease outcomes from the Phase III and Phase II Phase III Phase III All patients 1 Prior line of therapy
> 1 tidligere
studies Phase III > 1 Prior line of
≥2
≥ 2
Alle patienter
Phase II prior
behandling
therapy
behandling Dex
lines
Tidsrelaterede
Time related
Dex Vc
Dex Vc Dex
Vc Dex n=119
Vc Dex
hændelser
events TTP, days
n=336a n=132a b
n=132a 212d
a n=200a n=217a
n=200a 148b
n=202a
n=202a 210
TTP, dage [95% CI]
[95% CI]
189b [148, 211]
[148, 211]
106 212d [86, [188, 267] 128]
[188, 267]
169d 148b 87b [105, [129, [84, 191] 192] 107]
[129, 192]
210 [154, 281]
[154, 281]
1 års
1 year survival,%
66d 89d
89d
72d 73 62
62
overlevelse,%
[95% CI]
[74, 85]
[59,72]
[59, 72] [82, 95]
[82,95]
[62, 83 [64, 82] [53, 71]
[62,83]
16 [95% CI]
[64,82]
]
[53,71]
Vc n=193
Vc
CR CR + nCR
CR + nCR
20 (6) b 41 (13) b
41 (13) b
2 (< 1) b 5 (2) b 56 (18)
5 (2) b
8 (6) 16 (13)
16 (13)
2 (2) 4 (4) 29
4 (4)
12 (6) 25 (13)
25 (13)
0 (0) 1 (< 1) 27 (13)
1 (< 1)
(4) ** (10) **
(10)**
b
56 (18) b
(26) d
29 (26) d
b
27 (13) b
CR + nCR+
146 (46)
108
108 (35)
(41)
45 (41)
63 (31) (35) **
63 (31)
Median varighed dage (måneder) Tiden indtil
Median duration
126 385 * (4. 1)
126 (4.1)
respons CR + PR (dage) a
Days (months) Time to response
27 38 *
27
Intent to Treat (ITT) population b p- værdi fra den stratificerede log- rank test; analyse ud fra behandling udelukker opdeling på tidligere behandling; p < 0, 0001 c Responspopulation omfatter patienter, som havde målbar sygdom ved baseline og fik mindst 1 dosis forsøgsmedicin. d p- værdi fra Cochran- Mantel- Haenszel chi- square- testen justeret for opdelingsfaktorer; analyse ud fra behandling udelukker opdeling på tidligere behandling * CR+PR+MR ** CR=CR, (IF -); nCR=CR (IF+)
Intent to Treat (ITT) population b p-value from the stratified log-rank test; analysis by line of therapy excludes stratification for therapeutic history; p < 0.0001 c Response population includes patients who had measurable disease at baseline and received at least 1 dose of study drug. d p-value from the Cochran-Mantel-Haenszel chi-square test adjusted for the stratification factors; analysis by line of therapy excludes stratification for therapeutic history *CR+PR+MR **CR=CR, (IF-); nCR=CR (IF+) NA = not applicable, NE = not estimated
I fase II- forsøget kunne de patienter, som ikke havde en optimal respons på behandlingen med VELCADE alene, få højdosis dexamethason sammen med VELCADE (se tabel 9).
In the Phase II study, patients who did not obtain an optimal response to therapy with VELCADE alone were able to receive high-dose dexamethasone in conjunction with VELCADE (see Table 9).
18% af patienterne nåede eller havde en forbedret respons (MR (11%) eller PR (7%)) med kombinationsbehandlingen.
Eighteen percent of patients achieved, or had an improved response (MR (11%) or PR (7%)) with combination treatment.
Efter intravenøs bolusindgift af en dosis på 1, 0 mg/ m2 og 1, 3 mg/ m2 til 11 patienter med myelomatose og kreatinin- clearance- værdier på mere end 50 ml/ min., var de gennemsnitlige maksimale plasmakoncentrationer efter første dosis af bortezomib henholdsvis 57 og 112 mg/ ml.
Following intravenous bolus administration of a 1.0 mg/ m2 and 1.3 mg/ m2 dose to 11 patients with multiple myeloma and creatinine clearance values greater than 50 ml/ min, the mean first-dose maximum plasma concentrations of bortezomib were 57 and 112 ng/ ml, respectively.
Ved efterfølgende doser lå de gennemsnitlige maksimale observerede plasmakoncentrationer på 67- 106 ng/ ml for en dosis på 1, 0 mg/ m2 og på 89- 120 ng/ ml for en dosis på 1, 3 mg/ m2.
In subsequent doses, mean maximum observed plasma concentrations ranged from 67 to 106 ng/ ml for the 1.0 mg/ m2 dose and 89 to 120 ng/ ml for the 1.3 mg/ m2 dose.
Fordeling Den gennemsnitlige distributionsvolumen (Vd) for bortezomib var 1659- 3294 l efter indgift af enkeltdoser eller gentagne doser på 1, 0 mg/ m2 eller 1, 3 mg/ m2 til patienter med myelomatose.
Distribution The mean distribution volume (Vd) of bortezomib ranged from 1659 l to 3294 l following single- or repeated-dose administration of 1.0 mg/ m2 or 1.3 mg/ m2 to patients with multiple myeloma.
I bortezomibs koncentrationsinterval på 0, 01- 1, 0 µg/ ml var in vitro proteinbindingen gennemsnitligt 82, 9% i humant plasma.
Over a bortezomib concentration range of 0.01 to 1.0 μ g/ ml, the in vitro protein binding averaged 82.9% in human plasma.
Fraktionen af bortezomib bundet til plasmaproteiner var ikke koncentrationsafhængig.
The fraction of bortezomib bound to plasma proteins was not concentration- dependent.
Metabolisme In vitro- forsøg med humane levermikrosomer og cDNA- udtrykte cytokrom P450- isozymer indikerer, at bortezomib hovedsageligt metaboliseres ved oxydering via cytokrom P450- enzymer, 3A4, 2C19 og 1A2.
Metabolism In vitro studies with human liver microsomes and human cDNA-expressed cytochrome P450 isozymes indicate that bortezomib is primarily oxidatively metabolized via cytochrome P450 enzymes, 3A4, 2C19, and 1A2.
Den primære metabolisme er deborering, hvorved der dannes to deborerede metabolitter, som efterfølgende undergår hydroksylering til flere metabolitter.
The major metabolic pathway is deboronation to form two deboronated metabolites that subsequently undergo hydroxylation to several metabolites.
Deboronerede bortezomibmetabolitter er inaktive som 26S- proteasomhæmmere.
Deboronated-bortezomib metabolites are inactive as 26S proteasome inhibitors.
Elimination Den gennemsnitlige eliminationshalveringstid (t 1/ 2) for bortezomib efter gentagne doser var mellem 40- 193 timer.
Elimination The mean elimination half-life (t1/ 2) of bortezomib upon multiple dosing ranged from 40-193 hours.
Den gennemsnitlige totale clearance var 102 og 112 l/ t. efter første dosis på henholdsvis 1, 0 mg/ m2 og 1, 3
Mean total body clearances were 102 and 112 l/ h following the first dose for doses of 1.0 mg/ m2 and 1.3 mg/ m2, respectively, and ranged from 15 to 32 l/ h and 18 to 32 l/ h following subsequent doses for doses of 1.0 mg/ m2 and 1.3 mg/ m2, respectively.
Særlige populationer Nedsat leverfunktion Officielle forsøg med patienter med svært nedsat leverfunktion er ikke gennemført på nuværende tidspunkt (se pkt.
Special populations Hepatic impairment Formal studies in patients with severely impaired hepatic function have not been conducted to date (see section 4.4).
Ved manglende data er VELCADE kontraindiceret til patienter med stærkt nedsat leverfunktion (se pkt.
In the absence of data VELCADE is contraindicated in patients with severe liver impairment (see section 4.3).
4. 3).
Renal impairment
Nedsat nyrefunktion Et farmakokinetisk forsøg er foretaget hos patienter med varierende grad af nedsat nyrefunktion, som blev klassificeret i følgende grupper i henhold til deres kreatinin- clearance (CrCL):
18 A pharmacokinetic study was conducted in patients with various degrees of renal impairment who were classified according to their creatinine clearance values (CrCL) into the following groups:
Normal (CrCL ≥60ml/ min/ 1, 73 m2, n=12), Mild (CrCL=40- 59 ml/ min/ 1, 73m2, n=10), Moderat (CrCL=20- 39 ml/ min/ 1, 73 m2, n=9) og Alvorlig (CrCL < 20ml/ min/ 1, 73 m2, n=3).
Normal (CrCL ≥ 60 ml/ min/ 1.73 m2, n=12), Mild (CrCL=40-59 ml/ min/ 1.73 m2, n=10), Moderate (CrCL=20-39 ml/ min/ 1.73 m2, n=9), and Severe (CrCL < 20 ml/ min/ 1.73 m2, n=3).
En gruppe dialysepatienter, som fik VELCADE efter dialyse, blev også inkluderet i forsøget (n=8).
A group of dialysis patients who were dosed after dialysis was also included in the study (n=8).
Patienterne fik administreret intravenøse doser VELCADE på 0, 7 til 1, 3 mg/ m2 to gange ugentlig.
Patients were administered intravenous doses of 0.7 to 1.3 mg/ m2 of VELCADE twice weekly.
4. 2).
Exposure of VELCADE (dose-normalized AUC and Cmax) was comparable among all the groups (see section 4.2).
Bortezomib var positivt for klastogen aktivitet (strukturelle kromosomafvigelser) i in vitro- analysen af kromosomafvigelser ved hjælp af ovarieceller fra kinesiske hamstre (CHO) i koncentrationer så lave som 3, 125 µg/ ml, som var den lavest vurderede koncentration.
Bortezomib was positive for clastogenic activity (structural chromosomal aberrations) in the in vitro chromosomal aberration assay using Chinese hamster ovary (CHO) cells at concentrations as low as 3.125 μ g/ ml, which was the lowest concentration evaluated.
Bortezomib var ikke genotoksisk i in vitro- analyser af mutagenicitet (Ames ’ test) og in vivo- analyser af mikronukleus hos mus.
Bortezomib was not genotoxic when tested in the in vitro mutagenicity assay (Ames assay) and in vivo micronucleus assay in mice.