qanastek/EMEA-V3 huggingface dataset:
CR+ nCR + PR CR + nCR+
nCR + PR
121 (38) b
b
64 (34) b
27 (13) b
80 (43)
80 (43) 238
Median duration
Tul medju
242 (8.0)
Jiem (xhur)
169 (5.6)
242 (8. 0)
246 (8.1)
169 (5. 6)
189 (6.2)
246 (8. 1) 189 (6. 2)
238 (7.8)
(7. 8)
126 (4.1)
126 (4. 1)
Days (months) Time to response
Żmien għal
CR + PR (days) a
rispons
38*
CR +
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
Popolazzjoni bl- Intenzjoni biex tikkura (ITT) b valur- p mit- test log- rank stratifikat, analiżi skond il- linja ta ’ terapija teskludi l- istratifikazzjoni għall - istrja terapewtika; p < 0. 0001 c Il- popolazzjoni tar- rispons tinkludi pazjenti li kellhom mard li seta ’ jitkejjel mil- linja bażi u rċevew mill- inqas doża waħda tal- mediċina fl- istudju. d valur- p mit- test chi- square Cochran- Mantel- Haenszel aġġustata għal fatturi stratifikati; analiżi skond il- linja tat- terapija teskludi stratifikazzjoni għall- istorja terapewtika * CR+PR+MR ** CR=CR, (IF -); nCR=CR (IF+) MA = Mhux Applikabbli, MS = Ma saritx stima
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).
Fl- istudju ta ’ Fażi II, il- pazjenti li ma kellhomx l- aħjar rispons għat- terapija b’ VELCADE biss setgħu jieħdu doża għolja ta ’ dexamethasone flimkien ma ’ VELCADE (ara Tabella 9).
The protocol allowed patients to receive dexamethasone if they had had a less than optimal response to VELCADE alone.
Il- protokoll ħalla lill - pazjenti jieħdu dexamethasone jekk kellhom rispons b’ VELCADE biss li kienet inqas minn ottimali.
A total of 74 evaluable patients were administered dexamethasone in combination with VELCADE.
Total ta ’ 74 pazjent li setgħu ikunu evalwati ħadu dexamethasone flimkien ma ’ VELCADE.
Eighteen percent of patients achieved, or had an improved response (MR (11%) or PR (7%)) with combination treatment.
18% tal - pazjenti laħqu jew kellhom rispons imtejjeb (MR (11%) jew PR (7%)) b’ terapija kombinata.
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.
Wara li ngħataw dożi b’ daqqa fil- vina ta ’ 1. 0 mg/ m2 u 1. 3 mg/ m2 lil 11- il pazjent b’ majloma multipla u valuri ta ’ tneħħija tal- kreatinina ikbar minn 50ml/ min, il- medja ta ’ konċentrazzjonijiet massimi ta ’ bortezomib fil- plażma wara l- ewwel doża kienu 57 u 112 ng/ ml, rispettivament.
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.
Fid- dożi ta ’ wara, il - medja ta ’ konċentrazzjonijiet massimi fil- plażma kienu fuq medda minn 67 sa 106 ng/ ml għal doża ta ’ 1. 0 mg / m2 u minn 89 sa 120 ng/ ml għal doża ta ’ 1. 3 mg/ m2.
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.
Distribuzzjoni Il- volum medju ta ’ distribuzzjoni (Vd) ta ’ bortezomib kien mifrux minn 1659 l sa 3294 l wara li ngħatat doża waħda jew doża ripetuta ta ’ 1. 0 mg/ m2 jew 1. 3 mg/ m2 lil pazjenti b’ majloma multipla.
This suggests that bortezomib distributes widely to peripheral tissues.
Dan jissuġġerixxi li bortezomib jiġi distribwit b’ mod wiesa ’ fit- tessuti periferali.
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.
Fuq medda ta ’ konċentrazzjoni ta 'Bortezomib ta' bejn 0. 01 u 1. 0 μg/ ml, l- irbit mal- proteina in vitro kien medja ta '82. 9% fi plażma tal- bniedem.
The fraction of bortezomib bound to plasma proteins was not concentration- dependent.
Il- porzjon ta 'bortezomib li ntrabat mal- proteini tal- plażma ma kienx jiddependi mill- konċentrazzjoni.
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.
Metaboliżmu Studji in vitro bi kromożomi ta ’ fwied uman u isożimi P450 ċitokromiċi espressi mid- DNA uman jindikaw li bortezomib huwa primarjament metabolizzat bl- ossiġnu permezz ta ’ isożimi P450 ċitokromiċi, 3A4, 2ċ19, u 1A2.
The major metabolic pathway is deboronation to form two deboronated metabolites that subsequently undergo hydroxylation to several metabolites.
Il- mogħdija metabolika maġġuri hija d- deboronazzjoni biex jiġu ffurmati żewġ metaboliti deboronizzati li wara jgħaddu minn proċess ta ’ idrossilazzjoni għal għadd ta ’ metaboliti.
Deboronated-bortezomib metabolites are inactive as 26S proteasome inhibitors.
Metaboliti deboronati permezz ta ’ bortezomib mhumiex attivi bħala inibituri proteasome 26S.
Elimination The mean elimination half-life (t1/ 2) of bortezomib upon multiple dosing ranged from 40-193 hours.
Eliminazzjoni Il- half- life medja ta ’ eliminazzjoni (t1/ 2) ta ’ bortezomib wara li ngħataw ħafna dożi kienet fuq medda minn 40- 193 siegħa.
Bortezomib is eliminated more rapidly following the first dose compared to subsequent doses.
Bortezomib huwa eliminat b’ mod aktar mgħaġġel wara l- ewwel doża meta mqabbel mad- dożi sussegwenti.
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.
Tneħħijiet totali medji mill- ġisem kienu 102 u 112 l/ s wara l- ewwel doża għad- dożi ta ’ 1. 0 mg/ m2 u 1. 3 mg/ m2, rispettivament, u fuq medda minn 15 sa 32 l/ s u 18 sa 32 l/ s għad- dożi sussegwenti ta ’ 1. 0 mg/ m2 u 1. 3 mg/ m2, rispettivament.
Special populations Hepatic impairment Formal studies in patients with severely impaired hepatic function have not been conducted to date (see section 4.4).
18 Popolazzjonijiet speċjali Indeboliment tal- fwied Sa llum ma sarux studji formali f' pazjenti b’ indeboliment qawwi tal- funzjoni tal- fwied. (ara sezzjoni 4. 4).
In the absence of data VELCADE is contraindicated in patients with severe liver impairment (see section 4.3).
Fin- nuqqas ta 'tagħrif VELCADE m' għandux jingħata lil pazjenti b’ indeboliment qawwi tal - fwied.
Renal impairment
(ara sezzjoni 4. 3).
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:
Indeboliment tal- kliewi Studju farmakokinetiku sar f’ pazjenti bi gradi varji ta ’ indeboliment tal- kliewi li kienu kklassifikati skond il- valuri tat- tneħħija tal- kreatinina (CrCL) tagħhom fil- gruppi li ġejjin:
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).
Normali (CrCL ≥60 ml/ min/ 1. 73 m2, n=12), Ħafif (CrCL=40- 59 ml/ min/ 1. 73 m2, n=10), Moderat (CrCL=20 - 39 ml/ min/ 1. 73 m2, n=9), u Qawwi (CrCL < 20 ml/ min/ 1. 73 m2, n=3).
A group of dialysis patients who were dosed after dialysis was also included in the study (n=8).
Grupp ta ’ pazjenti fuq id - dijalisi li ngħataw id- doża wara d- dijalisi kienu wkoll inklużi fl- istudju (n=8).
Patients were administered intravenous doses of 0.7 to 1.3 mg/ m2 of VELCADE twice weekly.
Il- pazjenti ngħataw dożi minn 0. 7 sa 1. 3 mg/ m2 ta ’ VELCADE ġol- vina darbtejn fil- ġimgħa.
Exposure of VELCADE (dose-normalized AUC and Cmax) was comparable among all the groups (see section 4.2).
Esponiment għall- VELCADE (AUC u Cmax normalizzati għad- doża) kien kumparabbli fost il- gruppi kollha (ara sezzjoni 4. 2).
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 kellu attività klastoġenika (aberrazzjonijiet fl- istruttura tal- kromożomi) f' eżami in vitro għal aberrazzjonijiet kromosomali b' ċelluli ta 'l- ovarji tal- ħamster Ċiniż (CHO) anke b' konċentrazzjonijiet ta' 3. 125 μg/ ml, li kienet l- iċken konċentrazzjoni li kienet evalwata.
Bortezomib was not genotoxic when tested in the in vitro mutagenicity assay (Ames assay) and in vivo micronucleus assay in mice.
Bortezomib ma kienx ġenotossiku meta kien ittestjat in vitro għal bidliet ġenetiċi (assay ta 'Ames) u in vivo f' eżami mikronukleu fil- ġrieden.
Developmental toxicity studies in the rat and rabbit have shown embryo-fetal lethality at maternally toxic dosages, but no direct embryo-foetal toxicity below maternally toxic dosages.
Studji dwar it- tossiċità għall- iżvilupp fil- firien u l- fniek urew li d- dożi li kienu tossiċi għall- omm kienu letali għall- embriju u l- fetu, imma ma kienx hemm tossiċità diretta għall- embriju u l- fetu meta d- dożi kienu taħt il- livell tossiku għall- omm.
Fertility studies were not performed but evaluation of reproductive tissues has been performed in the general toxicity studies.
Ma sarux studju dwar il- fertilità imma fl- istudju ġenerali dwar it- tossiċità saret evalwazzjoni tat- tessuti riproduttivi.
In the 6-month rat study, degenerative effects in both the testes and the ovary have been observed.
Fl- istudju ta '6 xhur tal- firien, kienu osservati effetti deġenerattivi kemm fit- testikoli kif ukoll fl- ovarji.
It is, therefore, likely that bortezomib could have a potential effect on either male or female fertility.
Għalhekk, aktarx li Bortezomib għandu effett potenzjali fuq il- fertilità tar- raġel jew tal- mara.
Peri- and postnatal development studies were not conducted.
Ma sarux studji ta 'l- iżvilupp madwar u wara l- ħlas.
In multi-cycle general toxicity studies conducted in the rat and monkey, the principal target organs included the gastrointestinal tract, resulting in vomiting and/ or diarrhoea; haematopoietic and lymphatic tissues, resulting in peripheral blood cytopenias, lymphoid tissue atrophy and haematopoietic bone marrow hypocellularity; peripheral neuropathy (observed in monkeys, mice and dogs) involving sensory nerve axons; and mild changes in the kidneys.
Fi studji ta 'tossiċità ġenerali ta' iktar minn ċiklu wieħed, li saru fuq il- firien u x- xadini, l- organi li ntlaqtu prinċipalment kienu l- passaġġ gastro- intestinali, li wassal għal rimettar u/ jew dijarrea: tessuti ħematopojetiċi u limfatiċi, li wassal għal ċitopenji fid- demm periferali, atrofija tat- tessuti limfojdi u ipoċellularità ħematopojetika tal- mudullun; newropatija periferali (osservat f' xadini, ġrieden u klieb) li tinkludi l- axons tan- nervituri sensorjali; u bidliet ħfief fil- kliewi.
All these target organs have shown partial to full recovery following discontinuation of treatment.
Dawn l- organi milquta kollha rpiljaw parzjalment jew għal kollox wara li twaqqaf tat- trattament.
Based on animal studies, the penetration of bortezomib through the blood-brain barrier appears to be limited, if any and the relevance to humans is unknown.
Fuq il- bażi ta 'l- istudju fuq l- annimali, jidher li bortezomib jippenetra l- barriera bejn id- demm u l - moħħ b' mod limitat jew xejn, u mhux magħruf x' relevanza ghandu dan għall- bniedem.
Cardiovascular safety pharmacology studies in monkeys and dogs show that intravenous doses approximately two to three times the recommended clinical dose on a mg/ m2 basis are associated with increases in heart rate, decreases in contractility, hypotension and death.
Studji dwar is- sigurtà farmakoloġika kardjovaskulari f’ xadini u klieb juru li dożi għal ġol- vini li huma bejn wieħed u ieħor minn 2 sa 3 darbiet id- doża klinika rakkomandata fuq bażi ta ’ mg/ m2 huma marbuta ma ’ żidiet fit- taħbit tal- qalb, tnaqqis fil- kapiċità ta ’ kontrazzjoni, ipotensjoni u mewt.
In dogs, the decreased cardiac contractility and hypotension responded to acute intervention with positive inotropic or pressor agents.
Fi klieb it- tnaqqis fil- kapiċità kardijaka ta ’ kontrazzjoni u ipotensjoni irrispondew għall- intervent akut b’ aġenti inotropiċi pożittivi jew pressor.
Moreover, in dog studies, a slight increase in the corrected QT interval was observed.
Ukoll, fi studji bil- klieb ġiet osservata żieda żgħira fl- intervall QT korrett.
Mannitol (E 421) Nitrogen.
Mannitol (E 421) Nitroġenu.
19 The reconstituted solution should be used immediately after preparation.
Is- soluzzjoni rikostitwita għandha tintuża malli tiġi ppreparata.
If the reconstituted solution is not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.
Jekk is- soluzzjoni ma tintużax minnufih, iż- żmien u l- kondizzjonijiet tal- ħażna qabel l- użu huma r- responsabbilta` ta 'min jagħmel użu minnha.
However, the chemical and physical in-use stability of the reconstituted solution has been demonstrated for 8 hours at 25 °C stored in the original vial and/ or a syringe prior to administration, with a maximum of 8 hours in the syringe.
Madankollu, intwera li l- istabilità kimika u fiżika waqt l- użu tas- soluzzjoni rrikostitwita hija ta '8 sigħat f' temperatura ta' 25 °C maħżuna fil- fjala oriġinali u/ jew ġo siringa qabel ma tingħata, b' massimu ta '8 sigħat ġos- siringa.
Do not store above 30°C.
Taħżinx f' temperatura ogħla minn 30°C.
Keep the vial in the outer carton in order to protect from light.
Żomm il- fjala fil- kaxxa ta 'barra biex tipproteġi mid- dawl.
For storage conditions of the reconstituted medicinal product, see section 6.3.
Għall- kundizzjonijiet ta ’ ħażna tal- prodott mediċinali rikonstitwit, ara sezzjoni 6. 3..
Type 1 glass 5 ml-vial with a grey bromobutyl stopper and an aluminium seal, with a green cap.
Ħġieg tat- tip 1, fjala ta ’ 5 ml, b' tapp griż tal- bromobutyl u siġill ta 'l- aluminju b’ għatu aħdar.
The vial is contained in a transparent blister pack consisting of a tray with a lid.
Il- fjala qegħda ġo pakkett trasparenti li jikkonsisti fi trej b’ għatu.
Pack containing 1 single-use vial.
Pakkett li fih fjala waħda li tintuża darba biss.
General precautions Bortezomib is a cytotoxic agent.
Prekawzjonijiet ġenerali Bortezomib huwa sustanza ċitotossika.
Therefore, caution should be used during handling and preparation of VELCADE.
Għalhekk, għandha ssir attenzjoni waqt l- immaniġġjar u l - preparazzjoni ta ’ VELCADE.
Use of gloves and other protective clothing to prevent skin contact is recommended.
Huwa rakkomandat l- użu ta 'l- ingwanti u ħwejjeġ oħra protettivi biex ma jkunx hemm kuntatt mal- ġilda.
Aseptic technique must be strictly observed throughout handling of VELCADE, since it contains no preservative.
It- teknika asettika għandha tiġi osservata b' mod strett waqt l- immaniġġar ta 'VELCADE billi ma fihx preservanti.
Instructions for reconstitution Each vial must be reconstituted with 1 ml of sodium chloride 9 mg/ ml (0.9%) for injection.
Istruzzjonijiet għar- rikostituzzjoni Kull fjala ta 'VELCADE trid tkun rikostitwita b' 1 ml ta' sodium chloride 9 mg/ ml (0. 9%) għall - injezzjoni.
Dissolution of the lyophilised powder is completed in less than 2 minutes.
It- trab lajofilizzat idub f' inqas minn 2 minuti.
After reconstitution, each ml solution contains 1 mg bortezomib.
Wara r- rikostituzzjoni, kull ml ta ’ soluzzjoni jkun fih1mg bortezomib.
The reconstituted solution is clear and colourless, with a final pH of 4 to 7.
Is- soluzzjoni hija transparenti u bla kulur, b' pH finali ta 'bejn 4 u 7.
The reconstituted solution must be inspected visually for particulate matter and discolouration prior to administration.
Is- soluzzjoni rikostitwita trid tiġi miflija għal xi frak jew għal bidla fil- kulur qabel ma tingħata.
If any discolouration or particulate matter is observed, the reconstituted solution must be discarded.
Jekk ikun hemm bdil fil- kulur jew xi frak, is- soluzzjoni rrikostitwita għandha tintrema.
Disposal For single use only.
Rimi Għal użu darba biss.
JANSSEN-CILAG INTERNATIONAL NV Turnhoutseweg 30 B-2340 Beerse Belgium
JANSSEN- CILAG INTERNATIONAL NV Turnhoutseweg 30 B- 2340 Beerse
26/ 04/ 2004 Date of latest renewal:
26/ 4/ 2004 Data tal- aħħar tiġdid:
VELCADE 3.5 mg powder for solution for injection
VELCADE 3. 5 mg trab għal soluzzjoni għall- injezzjoni
Each vial contains 3.5 mg bortezomib (as a mannitol boronic ester).
Kull fjala fiha 3. 58 mg bortezomib (bħala mannitol boronic ester).
22 Dose adjustments during treatment and re-initiation of treatment for monotherapy VELCADE treatment must be withheld at the onset of any Grade 3 non-haematological or any Grade 4 haematological toxicities, excluding neuropathy as discussed below (see also section 4.4).
Bidliet fid- doża waqt il- kura u meta l- kura terġa 'tinbeda bħala monoterapija Il- kura b’ VELCADE trid tieqaf mill- bidu jekk ikun hemm xi tossiċitajiet mhux ematoloġiċi ta' Grad 3 jew ematoloġiċi ta 'Grad 4, ħlief għan- newropatija kif imfisser hawn taħt (ara wkoll sezzjoni 4. 4).
Patients who experience bortezomib-related neuropathic pain and/ or peripheral neuropathy are to be managed as presented in Table 1 (see section 4.4).
22 Pazjenti li jkollhom uġigħ newropatiku u/ jew newropatija periferali relatati ma 'bortezomib għandhom ikunu trattati skond Tabella 1 (ara sezzjoni 4. 4).
Posology modification of dose and regimen No action
Bidla fil- pożoloġija tad- doża u tat- teħid tagħha Ma titteħidx azzjoni Naqqas għal 1. 0 mg/ m2
Elderly patients There is no evidence to suggest that dose adjustments are necessary in patients over 65 years of age (see section 4.8).
Pazjenti anzjani M' hemmx evidenza li tindika li hemm bżonn ta 'bidliet fid- doża għall- pazjenti li għandhom aktar minn 65 sena (ara sezzjoni 4. 8).
Renal impairment The pharmacokinetics of bortezomib are not influenced in patients with mild to moderate renal impairment (CCl > 20 ml/ min/ 1.73 m2); therefore, dose adjustments are not necessary for these patients.
Indeboliment tal- kliewi Il- farmakokinetika ta ’ bortezomib m’ hijiex influwenzata f’ pazjenti b’ indeboliment tal- kliewi ħafif sa moderat (CrCl > 20 ml/ min/ 1. 73 m2); għalhekk aġġustamenti tad- doża m’ humiex meħtieġa għal dawn il- pazjenti.
It is unknown if the pharmacokinetics of bortezomib are influenced in patients with severe renal impairment not undergoing dialysis (CCl < 20 ml/ min/ 1.73 m2).
M’ huwiex magħruf jekk il- farmakokinetika ta ’ bortezomib hijiex influwenzata f’ pazjenti b’ indeboliment qawwi tal- kliewi li mhumiex qegħdin fuq id- dijalisi (CrCl < 20 ml/ min/ 1. 73 m2).
Posology combination therapy VELCADE (bortezomib) is administered in combination with oral melphalan and oral prednisone for nine 6-week treatment cycles as shown in Table 2.
Pożoloġija għal terapija mħallta VELCADE (bortezomib) jingħata flimkien ma ’ melphalan mill- ħalq u prednisone mill- ħalq għal disa ’ ċikli ta ’ kura ta ’ 6 ġimgħat ’ il wieħed kif muri f’ Tabella 2.
23 (days 1, 8, 22 and 29).
Fiċ- Ċikli 5- 9, VELCADE jingħata darba fil- ġimgħa (jiem 1, 8, 22 u 29).
Table 2: Recommended Posology for VELCADE in combination with melphalan and prednisone for patients with previously untreated multiple myeloma Twice weekly VELCADE (cycles 1-4)
23 Tabella 2: Pożologija rrakkommandata għal VELCADE flimkien ma ’ melphalan u prednisone għall - pazjenti b’ majloma multipla li qatt ma kienet ikkurata qabel VELCADE Darbtejn fil- Ġimgħa (Ċikli 1- 4)
11
Jum Jum Jum Perjod 4 8 11
25
mistrie ħ
29
mistrieħ
32
-- --
period
Perjod -- -- -- --
M P
Perjodu
(9 mg/ m) (60 mg/ m2)
M (9 mg/ m
Day Day Day Day 1 2
2)
--
u ta ’
--
ta ’
--
mistrie ħ
Once weekly VELCADE (cycles 5-9)
VELCADE Darba fil- Ġimgħa (Ċikli 5- 9)
1.3 mg/ m2)
Jum Jum Jum Jum
period
Perjo -- --
M P
Perjodu ta ’
(9 mg/ m2) (60 mg/ m2)
M (9 mg/ m
Day Day Day 1 2
2)
rest -- period
P (60 mg/ m2)
rest period
mistri eħ
Vc = VELCADE; M = melphalan, P=prednisone
VELCADE; M = melphalan, P=prednisone
Dose adjustments for combination therapy Dose modification and re-initiation of therapy when VELCADE is administered in combination with melphalan and prednisone
Modifikazzjoni fid- doża u bidu mill- ġdid tat- terapija meta VELCADE jiġi amministrat flimkien ma ’ melphalan u prednisone
Table3: Posology modifications during subsequent cycles Toxicity Haematological toxicity during a cycle
Tossiċità Tossiċità ematoloġika waqt ċiklu
• If prolonged Grade 4 neutropenia or thrombocytopenia, or thrombocytopenia with bleeding is observed in the previous cycle
• Jekk tiġi osservata newtropenja jew
• If platelet counts ≤ 30 × 109/ l or ANC ≤ 0.75 x 109/ l on a VELCADE dosing day (other than Day 1)
tromboċitopenja tal- ġrad 4 li tieħu fit- tul, jew tiġi osservata tromboċitopenja bil- fsada fiċ - ċiklu ta ’ qabel Jekk l- għadd tal- plejtlits ikun ≤30 × 109/ l jew • Il- kura b’ VELCADE m’ għandiex tingħata l- ANC ikun ≤0. 75 x 109/ l fil- jum meta jmiss doża ta ’ VELCADE (sakemm ma jkunx l- 1 Jum) • Id- doża ta ’ VELCADE għandha titnaqqas b’ livell Jekk ħafna mid- dożi ta ’ VELCADE f’ ċiklu 1 ta ’ doża (minn 1. 3 mg/ m2 sa 1 mg/ m2, jew minn ma jingħatawx (≥ 3 dożi waqt l- għoti ta ’ 1 mg/ m2 sa 0. 7 mg/ m2) darbtejn fil- ġimgħa jew ≥ 2 dożi waqt l- għoti ta ’ darba fil- ġimgħa)
VELCADE therapy should be withheld
24 Tossiċità
VELCADE dose should be reduced by 1 dose level (from 1.3 mg/ m2 to 1 mg/ m2, or from 1 mg/ m2 to 0.7 mg/ m2) VELCADE therapy should be withheld until
Modifikazzjoni fil- pożoloġija jew dewmien
Grade ≥ 3 non-haematological toxicities
Terapija b’ VELCADE għandha titwaqqaf sakemm is- sintomi tat- tossiċità jkunu rrisolvew għal Grad 1 Tossiċitajiet mhux ematoloġiċi tal- grad ≥ 3 jew għal- linja bażi.
24 Method of administration The reconstituted solution is administered as a 3-5 second bolus intravenous injection through a peripheral or central intravenous catheter followed by a flush with sodium chloride 9 mg/ ml (0.9%) solution for injection.
Metodu ta ’ kif jingħata Is- soluzzjoni rikostitwita tingħata bħala injezzjoni f’ daqqa ġol- vina fi 3- 5 sekondi minn kateter periferali jew ċentrali ġol- vina segwit minn tlaħliħa b’ soluzzjoni għall- injezzjoni ta ’ sodium chloride 9 mg/ ml (0. 9%).
Cases of ileus have been uncommonly reported (see section 4.8), therefore patients who experience constipation should be closely monitored.
Ġew rappurtati każijiet b’ mod mux komuni ta 'sadd fil- musrana (ara sezzjoni 4. 8) għalhekk pazjenti li jkollhom stitikezza għandhom jiġu mmonitorjati bir- reqqa.
However, cases of severe motor neuropathy with or without sensory peripheral neuropathy have been reported.
Madankollu, ġew rappurati każijiet ta 'newropatija motorja severa b’ newropatija sensorjali periferali jew mingħajrha.
It is recommended that patients be carefully monitored for symptoms of neuropathy such as a burning sensation, hyperesthesia, hypoesthesia, paraesthesia, discomfort, neuropathic pain or weakness.
25 Huwa rakkomandat li l- pazjenti jiġu mmonitorjati b' reqqa għal sintomi ta 'newropatija bħal sensazzjoni ta' ħruq, iperestesija, ipoestesija, parestesija, skumdità u uġigħ newropatiku jew dgħjufija.
25 Seizures Seizures have been uncommonly reported in patients without previous history of seizures or epilepsy.
Attakki ta ’ puplesija Attakki ta 'puplesija ma tantx ġew rappurtati f' pazjenti li ma kellhomx diġa` storja ta' attakki ta 'puplesija jew epilessija.
In a single-agent Phase III randomised, comparative study the incidence of heart failure in the VELCADE group was similar to that in the dexamethasone group.
Fi studju randomised komparattiv ta ’ Fażi III b’ sustanza waħda l- inċidenza ta ’ insuffiċjenza tal- qalb fil- grupp li kien qed jieħu VELCADE huwa simili għall- grupp li kien qed jieħu dexamethasone.
Pulmonary disorders There have been rare reports of acute diffuse infiltrative pulmonary disease of unknown aetiology such as pneumonitis, interstitial pneumonia, lung infiltration, and acute respiratory distress syndrome (ARDS) in patients receiving VELCADE (see section 4.8).
26 Distubi fil- pulmun Kien hemm rapporti rari ta ’ mard pulmonari akut infiltrat b’ mod diffuż b’ etjoloġija mhix magħrufa bħal pulmonite, pulmonija interstitjali, infiltrazzjoni tal- pulmun, sindromue ta ’ għeja respiratorja akuta (ARDS) f’ pazjenti li kienu qed jieħdu VELCADE (ara sezzjoni 4. 8).
A pre-treatment chest radiograph is recommended to determine if any additional diagnostic measures are necessary and to serve as a baseline for potential post-treatment pulmonary changes.
Huwa rrakkomandat illi qabel it- trattament isir radjograf tas- sider sabiex jiġi stabbilit jekk hemmx bżonn li jittieħdu miżuri dijanjostiċi addizzjonali kif ukoll sabiex iservu bħala linja bażi għall - possibilita` ta ’ tibdil pulmunari wara t- trattament.
Therefore, this specific regimen with concomitant administration with high-dose cytarabine (2g/ m2 per day) by continuous infusion over 24 hours is not recommended.
Għalhekk, din il - kura partikolari li tingħata flimkien ma ’ doża qawwija ta ’ cytarabine (2 g/ m2 kuljum) b’ infużjoni kontinwa matul 24 siegħa mhix rakkomandata.
Such patients should be monitored closely.
Dawn il- pazjenti għandhom jiġu mmonitorjati bir- reqqa (ara sezzjonijiet 4. 2 u 5. 2).
26 Rare cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions.
Reazzjonjiet epatiċi Ġew irrapurtati każijiet rari ta ’ insuffiċjenza akuta tal- fwied f’ pazjenti li kienu qed jieħdu medikazzjoni multipla fl- istess ħin u b’ kondizzjonijiet mediċi serji sottostanti.
Based on the limited contribution (7%) of CYP2D6 to the metabolism of bortezomib, the CYP2D6 poor metabolizer phenotype is not expected to affect the overall disposition of bortezomib.
Billi CYP2D6 ftit (7%) jikkontribwixxi għall- metaboliżmu ta 'bortezomib, CYP2D6 fenotip metabolizzatur dgħajjef mhux mistenni li jaffettwa d- dispożizzjoni ġenerali ta' bortezomib.
Patients should be closely monitored when given bortezomib in combination with CYP2C19- inhibitors (e. g. fluoxetine).
Il- pazjenti għandhom jiġu monitorjati bir- reqqa meta jingħataw bortezomib flimkien ma ’ inibituri potenti CYP2C19 (ngħidu aħna fluoxetine).
Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetics.
Pazjenti li qed jieħdu sustanzi orali għal kontra d - dijabete u li qed jingħataw il- kura b' VELCADE għandhom bżonn monitoraġġ bir- reqqa tal- livell tal - glukosju fid- demm, u bdil fid- doża tal- mediċina għal kontra d- dijabete.
27 4.6 Pregnancy and lactation
4. 6 Tqala u treddigħ
In non-clinical studies, bortezomib had no effects on embryonal/ foetal development in rats and rabbits at the highest maternally tolerated doses.
Ma sarux studji fl- annimali dwar l- effetti ta ’ bortezomib fuq il- ħlas u l- iżvilupp wara l- ħlas (ara sezzjoni 5. 3).
It is not known whether bortezomib is excreted in human milk.
Mhux magħruf jekk bortezomib joħroġx mal- ħalib tas- sider.
Therefore, patients must be cautious when operating machinery, or when driving (see section 4.8).
VELCADE jista 'jkollu x' jaqsam b’ mod komuni ħafna ma' għeja, b’ mod komuni ma ’ sturdament, b’ mod mhux komuni ma ’ telf mis- sensi, b’ mod komuni ma ’ ipotensjoni ortostatika/ tal- qagħda jew vista mċajpra.
4.8 Undesirable effects
Għalhekk, il - pazjenti għandhom joqogħdu attenti meta jħaddmu l- magni jew meta jsuqu (ara sezzjoni 4. 8).
The following undesirable effects were considered by the investigators to have at least a possible or probable causal relationship to VELCADE during the conduct of 5 non-comparative Phase II studies and 1 comparative Phase III trial VELCADE vs dexamethasone in 663 patients with relapsed or refractory multiple myeloma, of whom 331 received VELCADE as single agent.
L- effetti mhux mixtieqa li ġejjin tqiesu mill- investigaturi li kienu possibilment jew probabbilment kawżati minn VELCADE waqt 5 studji mhux komparattivi ta 'Fażi II u prova waħda komparattiva ta ’ Fażi III ta ’ VELCADE kontra dexamethasone f’ 663 pazjent b' majloma multipla refrattorja jew b’ episodju ġdid tal- marda, li minnhom 331 ħadu VELCADE waħdu.
The safety database comprises data from patients with multiple myeloma or B-cell lymphocytic leukemia (CLL).
Il- bażidata dwar sigurtà tinkludi tagħrif mill- pazjenti b’ majloma multipla jew lewċemija limfoċitika taċ- ċelluli- B (CLL).
Adverse reactions in patients with relapsed/ refractory multiple myeloma Infections and infestations Very common: herpes zoster (including disseminated).
L- effetti mhux mixtieqa huma mniżżla skond is- serjetà tagħhom bl - aktar serji jitniżżlu l- ewwel Tabella 4:
Common: pneumonia, bronchitis, sinusitis, nasopharyngitis, herpes simplex.
Reazzjonijiet avversi f’ pazjenti b’ majloma multipla b’ episodju ġdid/ refrattorja għall- kura Infezzjonijiet u infestazzjonijiet Komuni ħafna: herpes zoster (inkluż dak disseminat).
28 Blood and lymphatic system disorders (see section 4.4) Very common:
Disturbi tad- demm u tas- sistema limfatika (ara sezzjoni 4. 4) Komuni ħafna: tromboċitopenja, newtropinja, anemija.
thrombocytopenia, neutropenia, anaemia.
panċitopinja, newtropinja bid- deni, anemija emolitika, purpura trombosajtipenika,
Common: leukopenia, lymphopenia.
Disturbi fis- sistema immuni Mhux komuni:
Immune system disorders Uncommon: hypersensitivity, immunocomplex mediated hypersensitivity, potentially immunocomplex-mediated reactions, such as serum-sickness-type reaction, polyarthritis with rash and proliferative glomerulonephritis (see section 4.4).
potenzjalment huma marbuta ma ’ l- immunokompless, bħal’ mhi reazzjoni tat- tip tal- marda tas- serum, polijartrite b’ raxx u glomerulonefrite proliferattiva (ara sezzjoni 4. 4) Disturbi fis- sistema endokrinarja Mhux komuni: sekrezzjoni ta ’ l- ormon antidijuretiku (ADH) mhux f’ waqtha.
Endocrine disorders Uncommon: inappropriate antidiuretic hormone (ADH) secretion.
Mhux komuni:
Metabolism and nutrition disorders Very common:
diżidratazzjoni, ipokalimja, ipergliċemja iperkalemija, kakeksja, iperkalċimja, ipokalċimja, ipernatremija, iponatremija,
appetite decreased.
Disturbi psikjatriċi Komuni:
Common: dehydration, hypokalaemia, hyperglycaemia.
konfużjoni, depressjoni, insomnja, ansjetà.
Uncommon: hyperkalaemia, cachexia, hypercalcaemia, hypocalcaemia, hypernatraemia, hyponatraemia, hypoglycaemia, hyperuricaemia, vitamin B12 deficiency, appetite increased, hypomagnesaemia, hypophosphataemia.
Uncommon: aġitazzjoni, delirju, alliċunazzjonijiet, nuqqas ta 'kwiet, bdil fil- burdata, bdil fl- istat mentali, disturbi fl- irqad, irritabilità, ħolm mhux normali.
Psychiatric disorders Common: confusion, depression, insomnia, anxiety.
Disturbi fis- sistema nervuża (ara sezzjonijiet 4. 4 u 4. 7) Komuni ħafna: uġigħ ta 'ras.
Nervous system disorders(see sections 4.4 and 4.7) Very common:
newropatija periferali, newropatija sensorja periferali, (ara sezzjoni 4. 4), paresteżja,
peripheral neuropathy, peripheral sensory neuropathy (see section 4.4),
polinewropatija, newropatija periferali aggravata, sturdament (ħlief il- vertigo), disgewsja,
Uncommon: paraplegia, intracranial haemorrhage, subarachnoid haemorrhage convulsions (see section 4.4), peripheral motor neuropathy, syncope, paresis, disturbance in attention, increased activity, ageusia, somnolence, migraine, cognitive disorder, jerky movements, dizziness postural, sciatica, mononeuropathy, speech disorder, restless leg syndrome.
29 agewsija, tħeddil, emikranja, disturbi konjittivi, muvimenti f’ daqqa, sturdament tal- qagħda, xjatika, mononewropatija, disturbi fit- taħdit, sindromu taċ- ċaqlieq tar- riġel.
Eye disorders Common: vision blurred (see section 4.7), eye pain.
Mhux komuni: iħammġu, fotofobja, għajnejn.
Uncommon: eye haemorrhage, vision abnormal, dry eye, conjunctivitis, eye discharge, photophobia, eye irritation, lacrimation increased, conjunctival hyperaemia, eye swelling.
vista mċajpra (ara sezzjoni 4. 7) uġiegħ fl- għajnejn. fsada fl- għajnejn, vista mhux normali, għajnejn niexfa, konġunktivite, għajnejn irritazzjoni fl- għajnejn, żieda fid- dmugħ, iperemija tal- konġanktivite, nefħa fl -
Ear and labyrinth disorders Common: vertigo.
vertigo
Uncommon: deafness, tinnitus, hypoacusis, hearing impaired.
Mhux komuni: truxija, tinnitus, ipoakużi, indeboliment fis- smiegħ Disturbi fil- qalb Mhux komuni:
Rare: new onset of decreased left ventricular ejection fraction.
Rari: insuffiċjenza mill- ġdid tat- tfigħ ‘ il barra ventrikolari tax- xellug Disturbi vaskulari Komuni:
29 Respiratory, thoracic and mediastinal disorders Very Common:
Disturbi respiratorji, toraċiċi u medjastinali Komuni ħafna: dispneja Komuni:
Skin and subcutaneous tissue disorders Very common:
edema periorbitali, urtikarja, raxx bil- ħakk, ħakk, eritema, żieda fl- għaraq,, ġilda niexfa,
rash.
Mhux komuni: ġeneralizzat,
Common: periorbital oedema, urticaria, rash pruritic, pruritus, erythema, sweating increased, dry skin, eczema.
raxx vaskulitiku, raxx eritematoniku, reazzjoni fotosensittiva, tbenġila, raxx raxx makulari, raxx papulari, psorijażi, raxx ġeneralizzat, edema tal- kappell ta ’ l- għajn,
Uncommon: vasculitic rash, rash erythematous, photosensitivity reaction, contusion, pruritus generalised, rash macular, rash papular, psoriasis, rash generalized, eyelid oedema, face oedema, dermatitis, alopecia, nail disorder, skin discolouration, dermatitis atopic, hair texture abnormal, heat rash, night sweats, pressure sore, ichthyosis, skin nodule.
edema tal- wiċċ, dermatite, waqgħa tax- xahar, mard tad- dwiefer, bidla fil- kulur tal- ġilda, dermatite atopika, għamla tax- xahar mhux normali, raxx tas- sħana, għaraq bil- lejl, ferita tas- sodda, iktjosi, għoqda fil- ġilda.
Musculoskeletal and, connective tissue bone disorders Very Common:
Komuni:
myalgia.
telqa tal- muskoli, uġigħ muskoloskeletali, uġigħ fid- driegħ jew ir- riġel, bugħawwieġ,
Common: muscle weakness, musculoskeletal pain, pain in limb, muscle cramps, arthralgia, bone pain, back pain, peripheral swelling.
Mhux komuni: muskoli, ġogi ibsin,
Renal and urinary disorders Common: renal impairment, dysuria.
Mhux komuni: proteinurja, iżżomm
Uncommon: renal failure acute, renal failure, oliguria, renal colic, haematuria, proteinuria, urinary retention, urinary frequency, difficulty in micturition, loin pain, urinary incontinence, micturition urgency.
u fis- sistema urinarja indeboliment tal- kliewi, dajsurja. insuffiċjenza renali akuta, insuffiċjenza renali, aligurija, kolik renali, ħematurja, lura milli tagħmel l- urina, tagħmel l- urina b' mod frekwenti, diffikulta` biex
Reproductive system and breast disorders Uncommon: testicular pain, erectile dysfunction.
tagħmel l- urina, uġigħ fil- ġenbejn, inkontinenza fl- urina, urgenza biex tagħmel l- urina.
General disorders and administration site conditions Very Common:
Komuni:
Uncommon: fall, mucosal haemorrhage, mucosal inflammation, neuralgia, injection site phlebitis, extravasation inflammation tenderness, injection site erythema, feeling cold, chest pressure sensation, chest discomfort, groin pain, chest tightness.
Mhux komuni: bilirubina tad- demm,
Uncommon: alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, blood alkaline phosphatase increased, blood creatinine increased, blood urea increased, gamma-glutamyltransferase increased, blood amylase increased, liver function tests abnormal, red blood cell count decreased, white blood cell count decreased, blood bicarbonate decreased, heart rate irregular, C-reactive protein increased, blood phosphate decreased, weight increased.
Korriment u avvelenament Mhux komuni: proċedura, ħarqiet.
30 Summary of safety data in patients with previously untreated multiple myeloma:
Sommarju ta ’ tagħrif ta ’ sigurtà f’ pazjenti b’ majloma multipla li qatt ma kienet ikkurata qabel:
Total Toxicity Grade, n
Total Grad ta ’ tossiċità, n (%) Total Grad ta ’ tossiċità, n (%) Klassifikazzjoni tas- Sistema ta ’ l - Organi MedDRA Terminu Ppreferut Infezzjonijiet u infestazzjonijiet
Thrombocytopenia Neutropenia Anaemia Leukopenia Lymphopenia Metabolism and nutrition disorders
Newtropenja Anemija Lewkopenja Limfopenja Disturbi fil- metaboliżmu u n - nutrizzjoni
164 (48) 60 (18) 160 (47) 101 (30) 33 109 (32) 41 (12) 108 (32) 64 (19) 78 (23) 46 (14)
160 (47) 101 (30) 33 (109 (32) 41 (12) 108 (32) 64 (19) 78 (23) 46 (14)
57 (17) 140 (42) 48 (14) (10) 143 (42) 77 (23) 4 (1) 156 (46) 61 (18) 8 (2) 93 (28) 53 (16) 17 (5) 51 (15) 26 (8)
10) 143 (42) 77 (23) 4 (1) 156 (46) 61 (18) 8 (2) 93 (28) 53 (16) 17 (5) 51 (15) 26 (8)
Anorexia Psychiatric disorders
Anoreksja
64 (19) 6 (2)
64 (19) 6 (2) 31
0 21 (6) 0
0)
Peripheral Neuropathy Neuralgia Paraesthesia Gastrointestinal disorders
Nevralġija Paresteżija Disturbi gastro- intestinali
Nausea Diarrhoea Vomiting Constipation Abdominal Pain Upper Skin and subcutaneous tissue disorders
Dijarea Rimettar Stitikezza Uġigħ fin- naħa ta ’ fuq ta ’ l- addome Disturbi fil- ġilda u fit- tessuti ta ’ taħt il- ġilda
Fatigue Asthenia Pyrexia
Għeja kbira Astenja
Three (3%)
F’ dan l- istudju, riattivazzjoni tal - virus erpete zoster kienet aktar komuni f’ pazjenti kkurati b’ Vc+M+P meta mqabbel ma ’ M+P (11% vs 3% rispettivament).
31 of the 91 patients in the Vc+M+P treatment group who received prophylactic anti-virals developed herpes zoster reactivation.
Tlieta (3%) mill- 91 pazjent fil- grupp ta ’ kura b’ Vc+M+P li rċievew mediċini kontra l- virus bħala profilassi żviluppaw riattivazzjoni ta ’ l- erpete zoster.
Clinically significant adverse reactions are listed in Table 6, if they have been reported during post approval use of VELCADE and may or may not have been reported in clinical trials.
Esperjenza ta ’ wara t- Tqegħid tal- Prodott fis- Suq F’ Tabella 6 jitniżżlu reazzjonijiet mhux mixtieqa li huma klinikament sinifikanti jekk ġew irrapurtati waqt l- użu wara l- approvazzjoni ta ’ VELCADE u setgħu ġew jew ma ġewx irrapurati fi provi kliniċi.
Encephalopathy, autonomic neuropathy
Enċefalopatija, newropatija awtonomika Herpes fl- għajnejn Imblukkar kardijaku, perikardite, waqfien kardijaku jew
Cardiac tamponade, pericarditis, cardiac and cardiopulmonary arrest, Not known:
kardjopulmonari, arritmiji ventrikulari, imblukkkar totali atriju - ventrikulari, fibrillazzjoni atrijali, takikardija, takikardija tas- sinus u
ventricular arrhythmias, atrio-ventricular block complete, atrial fibrillation, tachycardia, sinus and ventricular tachycardia
32
Gastrointestinal disorders
ventrikulari.
For preclinical cardiovascular safety pharmacology studies, see section 5.3.
Fil- pazjenti, doża eċċessiva iktar minn darbtejn mid- doża rakkomandata ġiet marbuta ma ’ episodju akut ta ’ ipotensjoni sintomatika u trombositapenija b’ riżultati fatali (Għal studji prekliniċi kardjovaskulari ta ’ sigurtà farmakoloġika, ara sezzjoni 5. 3).
Other antineoplastic agent, ATC code:
Sustanzi antineoplastiċi oħra, Kodiċi ATC:
Mechanism of action Bortezomib is a proteasome inhibitor.
Mekkaniżmu kif jaħdem Bortezomib huwa inibitur tal- proteasome.
Inhibition of the proteasome results in cell cycle arrest and apoptosis.
L- inibizzjoni tal- proteasome iwassal għall- waqfien taċ- ċiklu taċ- ċellula u għall- apoptożi.
NF-kB is a transcription factor whose activation is required for many aspects of tumourigenesis, including cell growth and survival, angiogenesis, cell-cell interactions, and metastasis.
NF- kB huwa fattur ta 'traskrizzjoni li l - attivazzjoni tiegħu hemm bżonnha għal ħafna aspetti tal- ġenesi tat- tumur, inkluż l- iżvilupp u l -
In myeloma, bortezomib affects the ability of myeloma cells to interact with the bone marrow microenvironment.
33 għajxien taċ- ċellula, l- anġjoġenesi, interazzjonijiet bejn iċ- ċelluli u l- metastażi.
Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types and that cancer cells are more sensitive to the proapoptotic effects of proteasome inhibition than normal cells.
Esperimenti wrew li bortezomib huwa ċitotossiku għal varjetà ta 'tipi ta' ċelluli tal- kanċer, u li ċ- ċelluli tal- kanċer huma iktar sentittivi għall- effetti preventivi ta 'l- inibizzjoni ta ’ proteasome milli ċelluli normali.
Clinical efficacy in previously untreated multiple myeloma A prospective Phase III, international, randomized (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.
Effikaċja klinika f’ majloma multipla li qatt ma kienet ikkurata qabel Studju kliniku prospettiv tal- Fazi III randomised (1: 1), open- label, internazzjonali (VISTA) ta ’ 682 pazjent kien magħmul biex jiġi dderminat jekk VELCADE (1. 3 mg/ m2) flimkien ma ’ melphalan (9 mg/ m2) u prednisone (60 mg/ m2) jirriżultawx f’ titjib fiż- żmien ta ’ progressjoni (TTP) meta mqabbel ma ’ melphalan (9 mg/ m2) u prednisone (60 mg/ m2) f’ pazjenti b’ majloma multipla li qatt ma kienet ikkurata qabel.
Patient Characteristics
Karatteristiċi tal- pazjent
Caucasian/ asian/ black/ other Karnofsky performance status score ≤ 70 Hemoglobin < 100 g/ l Platelet count < 75 x 109/ l
Razza: kawkasu/ a/ asjatiku/ a/ iswed/ sewda/ oħra Punteġġ tal- performance status Karnofsky ≤70 Emoglobina < 100 g/ l Għadd tal- plejtlits < 75 x 109/ l Karatteristiċi tal- Marda
33 Disease Characteristics Type of myeloma (%):
Tip ta ’ majloma (%):
IgG/ IgA/ Light chain Median β 2-microglobulin (mg/ l)
IgG/ IgA/ Sekwenza ta ’ katina ħafifa
64% /
64% / 24% / 8%
26% / 8% 4.3
26% / 8%
Median albumin (g/ l)
Albumina medjana (g/ l)
Creatinine clearance ≤ 30 ml/ min [n (%)]
Tneħħija tal- kreatinina ≤30 mL/ min [n (%)]
Efficacy results are presented in Table 8:
Riżultati ta ’ effikaċja huma ppreżentati f’ Tabella 8:
Summary of Efficacy Analyses in the VISTA study Efficacy endpoint Time to progression
Tabella 8 - Sommarju tal- analiżi tal- effikaċja fl- istudju VISTA Il- punt aħħari tal- effikaċja Żmien għall- progressjoni –
101 (29) 20.7 mo
101 (29) 20. 7 mo
152 (45) 15.0 mo
152 (45) 15. 0 mo
Hazard ratiob
(95% CI) c
(17.6, 24,7)
(0. 42, 0. 70)
0.54
Valur- p Sopravivenza mingħajr progressjoni
(14.1, 17.9)
0. 000002
(95% CI) p-value c Progression-free survival
Każijiet n (%) Medjana (95% CI)
(0.42, 0.70) 0.000002
135 (39) 18. 3 mo
Events n (%) Mediana (95% CI)
190 (56) 14. 0 mo
135 (39) 18.3 mo
(16. 6, 21. 7)
190 (56) 14.0 mo
(11. 1, 15. 0)
Hazard ratiob
(95% CI) Valur- p c
(16.6, 21.7)
(0. 49, 0. 76) 0. 00001
0.61
34 Il- punt aħħari tal- effikaċja Sopravivenza totali
(11.1, 15.0)
Vc+M+P n=344
(0.49, 0.76) 0.00001
M+P n=338
Events (deaths) n (%) Hazard ratiob (95% CI) p-value c
Każijiet (imwiet) n (%) b
Response rate populatione n = 668
(95% CI) Valur- p c Rata ta ’ rispons e popolazzjoni n = 668
Reduction in serum M-protein populationg n=667
Tnaqqis tal- proteina M fis- serum popolazzjonig n=667
Median Mediana response duration
Medjan Medjana ta ’ tul ta ’ żmien tar- rispons
24.0 mo 19.9 mo
19. 9 mo
12.8 mo 13.1 mo
13. 1 mo
Events n (%) Mediana (95% CI)
Żmien għall- kura li jmiss Każijiet n (%) Medjana
Hazard ratiob
(95% CI) Proporzjon ta ’ periklub
(95% CI) p-value c
(95% CI) Valur- pc a Stima Kaplan- Meier. b
(0.39, 0.70) 0.000009
(0. 39, 0. 70) 0. 000009
Hazard ratio estimate is based on a Cox proportional-hazard model adjusted for stratification factors: beta2-microglobulin, albumin, and region.
L- Istima tal- proporzjon tar- riskju hija bbażata fuq il- mudell Cox ta ’ riskju proporzjonali aġġustat għal fatturi ta ’ stratifikazzjoni: β2- mikroglobulina, albumina, u reġjun.
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: β 2-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 NE:
Proporzjon ta ’ riskju anqas minn 1 jindika vantaġġ għall- VMP c Valur- p ibbażat fuq it- test log- rank stratifikat aġġustat għal fatturi ta ’ stratifikazzjoni: β2 - mikroglobulina, albumina, u reġjun. d Valur- p għar- Rata ta ’ Rispons (CR + PR) mit- test chi- square Cochran- Mantel- Haenszel aġġustat għal fatturi ta ’ stratifikazzjoni e Rispons tal- popolazzjoni jinkludi pazjenti li kellhom marda li titkejjel fil- linja bażi f Kriterji EBMT g Il- pazjenti randomized kollha b’ mard ta ’ sekrezzjoni NE:
Clinical efficacy in relapsed or refractory multiple myeloma The safety and efficacy of VELCADE were evaluated in 2 studies at the recommended dose of 1.3 mg/ m2: a Phase III randomized, comparative study, versus dexamethasone (Dex), of 669 patients with relapsed or refractory multiple myeloma who had received 1-3 prior lines of therapy, and a Phase II single-arm study of 202 patients with relapsed and refractory multiple myeloma, who had received at least 2 prior lines of treatment and who were progressing on their most recent treatment.
Studji kliniċi f’ majloma multipla b’ episodju ġdid tagħha jew refrattorja Is- sigurtà u l- effikaċja ta ’ VELCADE kienu evalwati f’ 2 studji bid- doża rakkomandata ta ’ 1. 3 mg/ m2: studju random komparattiv ta ’ Fażi III kontra dexamethasone (Dex), ta ’ 669 pazjent b’ majloma multipla refrattorja jew b’ episodju ġdid tagħha li ħadu bejn 1 u 3 linji ta ’ terapija minn qabel, u studju ta ’ Fażi II b’ taqsima waħda b’ 202 pazjenti b’ majloma multipla refrattorja jew b’ episodju ġdid tagħha, li kienu ħadu mill- inqas 2 linji ta ’ terapija minn qabel u li kienu għaddejjin fuq l- iktar terapija reċenti.
Dosing regimens in Phase II and Phase III studies Phase/ arm Treatment schedule
Kuri ta ’ dożaġġ fl- istudji ta ’ Fażi II u Fażi III Fażi/ fergħa Skeda ta ’ kura
Dose
Kura
Regimen
II Vc:
II III III
mistrieħ 12- 21) III Vc *
Vc:
35
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) c) Days 1– 4, 9 – 12, 17– 20Days 1– 4
mistrieħ 12- 21) b) Jiem 1, 8, 15, 22 III Dex c) Jiem 1– 4, 9– 12, 17– 20 d) Jiem 1– 4
Q3 weeks x 8 cycles (extension**) a) Q3weeks x 8, then b) Q5 weeks x 3 a) Q5 week x 4 b) Q4 week x 5
wara b) Q5 ġimgħat x 3 a) Q5 ġimgħa x 4 b) Q4 ġimgħa x 5
II
II Żid Dex ***
Myeloma IgG Myeloma IgA Myeloma light chain Median duration since diagnosis (yrs) Chromosome 13 abnormalities
Emoglobina < 100g/ l Clearance medja tal- Kreatitina, ml/ min 74
60% 24% 14% 4.0 15%
44%
60% 23% 12% 3.5 25.7%
32% 73. 3
59% 24% 13% 3.1 25.0%
28% 73. 3
35 Median β 2 microglobulin (mg/ l) Median number prior treatment lines* (range)
(medda) Majloma IgG Majloma IgA Katina ħafifa tal- majloma Tul medju mid- djanjożi (snin) Anormalitajiet fil- Kromożomi 13 Medjan β2- mikroglobulina (mg/ l) Numru medju qabel il- linja ta ’ kura * (medda)
3.5 6 (2-15)
(14- 221) 60% 24% 14% 4. 0 15% 3. 5 6 (2- 15)
3.7 2 (1-7)
(15. 6- 170. 7) 60% 23% 12% 3. 5 25. 7% 3. 7 2 (1- 7)
3.6 2 (1-8)
(15. 3- 261. 1) 59% 24% 13% 3. 1 25. 0% 3. 6 2 (1- 8)
Patient exposure to treatment with VELCADE during Phase II Vc
Fażi II Vc
Phase II and III studies Phase III Phase III Vc Dex
Fażi III Dex
27% (8 cycles) NA n = 63 pts (median 7 cycles) or total median 14 cycles (range 7-32)
27% (8 ċikli) MA n = 63 punti (medja MA ta ’ 7 ċikli) jew total ta ’ medja ta ’ 14- il ċiklu (medda 7- 32)
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.
Fl- istudju ta ’ Fażi III, il- kura b’ VELCADE wassal għal titwil sinifikanti tal- progressjoni, titwil sinifikanti ta ’ sopravivenza, u rata ogħla ta ’ rispons b’ mod sinifikanti, meta mqabbel mal- kura