qanastek/EMEA-V3 huggingface dataset:
John's wort is expected to substantially decrease maraviroc concentrations and may result in suboptimal levels and lead to loss of virologic response and possible resistance to maraviroc.
Dan jista jirriżulta f’ livelli sub- ottimali ta ’ maraviroc, u hekk jwassal għal telf fir- rispons viroloġiku u possibilment reżistenza għal maraviroc.
Concomitant use of maraviroc and St.
Użu fl- istess żmien ta ’ maraviroc u St.
John's wort (Hypericum Perforatum) or products containing St.
John' s wort (Hypericum Perforatum) jew prodotti li jkun fihom St.
John's wort is not recommended.
John' s wort mhux rakkomandat.
No meaningful clinical data on exposure during pregnancy are available.
Għal CELSENTRI m’ hemmx tagħrif kliniku dwar l- użu waqt it- tqala.
Studies in rats and rabbits showed reproductive toxicity at high exposures.
Studji fil- firien u fil- fniek urew tossiċita ’ riproduttiva f’ espożizzjonijiet għolja.
Primary pharmacological activity (CCR5 receptor affinity) was limited in these species (see section 5.3).
Attivita farmakoloġika primarja (affinita għal reċettur CCR5) kienet limitata f’ dawn l- ispeċi (ara sezzjoni 5. 3).
CELSENTRI should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
CELSENTRI għandu jintuża biss waqt it - tqala jekk il- benefiċċju potenzjali jiġġustifika r- riskju potenzjali għall- fetu.
Studies in lactating rats indicate that maraviroc is extensively secreted into rat milk.
Studji fuq firien jreddgħu jindikaw li maraviroc jitneħħa b’ mod estensiv fil- ħalib tal- firien.
Primary pharmacological activity (CCR5 receptor affinity) was limited in these species.
L- attività farmakoloġika primarja (affinità tar- riċettur CCR5) kienet limitata f’ dawn l- ispeċi.
It is not known whether maraviroc is secreted into human milk.
Mhux magħruf jekk maraviroc jitneħħiex fil- ħalib tal- bniedem.
Mothers should be instructed not to breast-feed if they are receiving CELSENTRI because of the potential for HIV transmission as well as any possible undesirable effects in breast-fed infants.
L- ommijiet għandhom jingħataw struzzjonijiet biex ma jreddgħux jekk ikunu qegħdin jirċievu CELSENTRI minħabba l- potenzjal ta ’ trasmissjoni ta ’ l - HIV kif ukoll kwalunkwe effett mhux mixtieq li jista ’ jkun hemm fi trabi li jkunu qegħdin jiġu mreddgħa.
CELSENTRI may cause dizziness.
CELSENTRI jista ’ jikkawża sturdament.
Patients should be instructed that if they experience dizziness they should avoid potentially hazardous tasks such as driving or operating machinery.
Il- pazjenti għandhom jiġu avżati li jekk iħossu sturdament huma għandhom jevitaw attivitajiet li jistgħu jkunu perikolużi bħal sewqan jew tħaddim ta ’ makkinarju.
8 4.8 Undesirable effects
4. 8 Effetti mhux mixtieqa
The safety profile of CELSENTRI is based on 1349 HIV-1 infected patients who received at least one dose of CELSENTRI during clinical studies.
Il- profil tas- sigurtà ta ’ CELSENTRI huwa bbażat fuq 1349 pazjent infettati bl- HIV- 1 li rċevew mill - anqas doża waħda ta ’ CELSENTRI waqt studji kliniċi.
This includes 427 patients who received the recommended dose 300 mg twice daily and a further 401 patients who received 300 mg once daily for at least 24 weeks.
Dan jinkludi 427 pazjent li rċevew id- doża rakkomandata ta ’ 300 mg darbtejn kuljum u 401 pazjent ieħor li rċevew 300 mg darba kuljum għal mill- anqas 24 ġimgħa.
Assessment of treatment related adverse reactions is based on pooled data at the recommended dose from two Phase 3 studies (MOTIVATE 1 and MOTIVATE 2) in CCR5-tropic HIV-1 infected patients.
L- evalwazzjoni tar- reazzjonijiet avversi b’ rabta mal- kura hija bbażata fuq informazzjoni miġbura bid- doża rakkomandata minn żewġ studji ta ’ Fażi 3 (MOTIVATE 1 and MOTIVATE 2) fuq pazjenti infettati bl- HIV- 1 CCR5- tropiku.
The most frequently reported adverse reactions occurring in the Phase 3 studies at the recommended dose regardless of the incidence compared to OBT alone were diarrhoea, nausea and headache.
10 L- aktar reazzjonijiet avversi rrapportati ta ’ sikwit li seħħew fl- istudji ta ’ Fażi 3 bid- doża rakkomandata irrispittivament mill inċidenza meta mqabbla ma OBT waħdu kienu dijarea, dardir u wġigħ ta ’ ras.
The reported frequencies for these events as well as the rates of discontinuation due to any adverse reactions were similar in patients receiving CELSENTRI 300 mg twice daily + OBT (Optimised Background Therapy) compared to those receiving OBT alone.
Dawn ir- reazzjonijiet avversi kienu komuni (≥1/ 100 sa < 1/ 10) Il- frekwenzi rrapportati għal dawn l - avvenimenti kif ukoll ir- rati ta ’ twaqqif minħabba kwalunkwe reazzjoni avversa kienu simili f’ pazjenti jirċievu CELSENTRI 300 mg darbtejn kuljum + OBT (Optimised Background Therapy) meta mqabbla ma ’ dawk jirċievu OBT waħedha.
The adverse reactions are listed by system organ class (SOC) and frequency.
Ir- reazzjonijiet avversi huma elenkati skond is- sistema tal- klassifika tal- organi fid- database MedDRA.
Frequencies are defined as very common (≥ 1/ 10), common (≥ 1/ 100 to < 1/ 10) and uncommon (≥ 1/ 1000 to < 1/ 100).
Il- frekwenzi huma definiti bħala komuni ħafna (≥ 1/ 10), komuni (≥ 1/ 100 sa < 1/ 10) u mhux komuni (≥1/ 1000 sa < 1/ 100).
The adverse reactions and laboratory abnormalities presented below are not exposure adjusted.
Ir- reazzjonijiet avversi u anormalitajiet tal- laboratorju li huma murija hawn taħt m’ humiex aġġustati skond l- esposizzjoni.
The following table presents adverse reactions occurring at a numerically higher rate among patients receiving CELSENTRI 300 mg twice daily + OBT than patients on OBT alone with an incidence of ≥ 1%.
It- tabella li ġejja tippreżenta reazzjonijiet avversi li jseħħu b’ rata numerika ogħla fost pazjenti li jirċievu CELSENTRI 300 mg darbtejn kuljum + OBT milli f’ pazjenti fuq OBT waħedha b’ inċidenza ta ’ ≥1%.
Adverse reactions occurring at a numerically higher rate among patients receiving CELSENTRI 300 mg twice daily + OBT than patients on OBT alone with an incidence of ≥ 1%
Reazzjonijiet avversi li jseħħu f’ rata numerikament ogħla fost pazjenti li jirċievu CELSENTRI 300 mg darbtejn kuljum + OBT milli f’ pazjenti fuq OBT waħedha b’ inċidenza ta ’ ≥1% Sistema ta ’ klassifika ta ’ l - Organi
System Organ Class Investigations
Investigazzjonijiet
Adverse Reaction alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyltransferase increased, weight decreased
żieda fl- alanine aminotransferase increased, żieda fl- aspartate aminotransferase, żieda tal- gamma - glutamyltransferase, tnaqqis fil- piż
Frequency common
komuni
dizziness, paraesthesia, dysgeusia, somnolence
sturdament, parasteżja, togħma ħażina, ngħas
common
komuni
Respiratory, thoracic and mediastinal disorders
Disturbi respiratorji, toraċiċi u medjastinali
Cough
sogħla
nausea
dardir
very common
komuni ħafna
vomiting, abdominal pain, abdominal distension, dyspepsia, constipation
rimettar, uġigħ addominali, nefħa addominali, dispepsja, stitikezza
rash, pruritus
raxx, prurite
Musculoskeletal and connective tissue disorders
Disturbi muskolu- skeltrali u tal - connective tissue
muscle spasms, back pain
spażmi fil- muskoli, uġigħ fid- dahar
General disorders and administration site conditions
Disturbi ġenerali u kondizzjonijiet ta 'mnejn jingħata
Insomnia
nuqqas ta ’ rqad
Clinically important adverse reactions occurring in less than 1% of adult patients receiving CELSENTRI in Phase 3 studies are presented below.
Reazzjonijiet avversi klinikament importanti li jseħħu f’ inqas minn 1% ta ’ pazjenti adulti li jirċievu CELSENTRI fi studji ta ’ Fażi 3 huma ppreżentati hawn taħt.
Clinically important adverse reactions occurring in less than 1% of adult patients receiving CELSENTRI in Phase 3 studies
Reazzjonijiet avversi klinikament importanti li jseħħu f’ inqas minn 1% ta ’ pazjenti adulti li jirċievu CELSENTRI fi studji ta ’ Fażi 3 Sistema ta ’ klassifika ta ’ l - Organi
System Organ Class Cardiac disorders
mhux komuni
Adverse Reaction myocardial infarction, myocardial
panċitopenija, newtropenija, limfadenopatija
Frequency uncommon
mhux komuni
9 ischaemia
mhux komuni
Blood and lymphatic system disorders
Disturbi respiratorji, toraċiċi u medjastinali
pancytopenia, neutropenia, lymphadenopathy
diqa respiratorja, bronkospażmu
uncommon
mhux komuni
Nervous system disorders
Disturbi gastro- intestinali
loss of consciousness, epilepsy, petit mal epilepsy, convulsion, facial palsy, polyneuropathy, areflexia
pankreatite, emorraġija mir- rektum
Respiratory, thoracic and Mediastinal disorders
Disturbi fil- kliewi u fis- sistema urinarja
respiratory distress, bronchospasm
insuffiċjenza tal- kliewi, poliurja
Gastrointestinal disorders Renal and urinary disorders Musculoskeletal and connective tissue disorders
Disturbi muskolu- skeltrali u tal - connective tissue
pancreatitis, rectal haemorrhage renal failure, polyuria Myositis
Infezzjonijiet u infestazzjonijiet Disturbi fil- fwied u fil- marrara
uncommon uncommon uncommon
mhux komuni mhux komuni:
Infections and infestations Hepatobiliary disorders Psychiatric disorders
Disturbi psikjatriċi
Pneumonia hepatic cirrhosis Hallucination
alluċinazzjonijiet
uncommon uncommon uncommon
mhux komuni
In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise (see section 4.4).
F’ pazjenti infettati bl- HIV li jkollhom defiċjenza immuni severa fil- mument tal- bidu ta ’ terapija antiretrovirali kkombinata (CART), tista ’ tiżviluppa reazzjoni infjammatorja għal infezzjonijiet opportunistiċi bla sintomi jew residwi (ara sezzjoni 4. 4).
Laboratory abnormalities Table 5 shows the incidence ≥ 1% of Grade 3-4 Abnormalities (ACTG Criteria) based on the maximum shift in laboratory test values without regard to baseline values.
Anormalitajiet tal- laboratorju Tabella 5 turi l- inċidenza ≥1% ta ’ Anormalitajiet ta ’ Grad 3- 4 (Kriterji ACTG) ibbażata fuq iċ- ċaqliq massimu fil- valuri tat- test fil- laboratorju mingħajr ma jitqiesu l- valuri bażiċi.
Incidence ≥ 1% of grade 3-4 abnormalities (ACTG criteria) based on maximum shift in laboratory test values without regard to baseline studies MOTIVATE 1 and MOTIVATE 2 (pooled analysis, up to 48 weeks)
Inċidenza ≥1% ta ’ anormalitajiet ta ’ grad 3- 4 (Kriterji ACTG) ibbażata fuq iċ- ċaqliq massimu fil- valuri tat- test fil- laboratorju mingħajr ma jitqiesu l- istudji tal- linja bażi (MOTIVATE 1 u MOTIVATE 2 (analiżi miġbura, sa 48 ġimgħa)
Laboratory parameter
Parametru tal- laboratorju
Limit
Limitu
twice daily + OBT
darbtejn kuljum + OBT
alone
waħedha
Upper Limit of Normal
Aspartate aminotransferase Alanine aminotransferase Bilirubin Totali Amylase Lipase
> 5.0x ULN > 5.0x ULN > 5.0x ULN > 2.0x ULN > 2.0x ULN < 750/ mm3
> 5. 0x ULN > 5. 0x ULN > 5. 0x ULN > 2. 0x ULN > 2. 0x ULN < 750/ mm3
* Percentages based on total patients evaluated for each laboratory parameter
Limitu ta ’ Fuq tan- Normal * Perċentwali bbażati fuq il- pazjenti totali evalwati għal kull parametru tal- laboratorju
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART).
Ġew irrapportati każijiet ta ’ osteonekrożi, b’ mod partikolari f’ pazjenti b’ fatturi ta ’ riskju rikonoxxuti b’ mod ġenerali, mard tal- HIV avvanzat jew espożizzjoni fuq perjodu ta ’ żmien twil għal terapija ta ’ kombinazzjoni antiretrovirali (CART).
The frequency of this is unknown (see section 4.4).
Il- frekwenza ta ’ dan għadha mhux magħrufa (ara sezzjoni 4. 4).
The highest dose administered in clinical studies was 1200 mg.
L- ogħla doża mogħtija fl- istudji kliniċi kienet 1200 mg.
The dose limiting adverse reaction was postural hypotension.
Ir- reazzjoni avversa li jillimita d- doża kien pressjoni baxxa relatata mal- pożizzjoni tal- ġisem.
Prolongation of the QT interval was seen in dogs and monkeys at plasma concentrations 6 and 12 times, respectively, those expected in humans at the maximum recommended dose of 300 mg twice daily.
Titwil ta ’ l- intervall QT ġie muri fil- klieb u x- xadini b’ konċentrazzjonijiet fil- plasma ta ’ 6 u 12- il darba aktar, rispettivament, minn dawk mistennija fil- bniedem bid- doża massima rakkomandata ta ’ 300 mg darbtejn kuljum.
However, no clinically significant QT prolongation compared to OBT alone was seen in the Phase 3 clinical studies using the recommended dose of maraviroc or in a specific pharmacokinetic study to evaluate the potential of CELSENTRI to prolong the QT interval.
Madankollu, ma deher l- ebda titwil klinikament sinifikanti fil- QT meta mqabbel ma ’ OBT waħedha fl- istudji kliniċi ta ’ Fażi 3 bl- użu tad- doża rakkomandata ta ’ maraviroc
10 There is no specific antidote for overdose with CELSENTRI.
12 jew fi studju farmakokinetiku speċifku biex jiġi evalwat il- potenzjal ta ’ CELSENTRI li jtawwal l - intervall QT.
Treatment of overdose should consist of general supportive measures including keeping the patient in a supine position, careful assessment of patient vital signs, blood pressure and ECG.
It- trattament ta ’ doża eċċessiva għandu jikkonsisti f’ miżuri ġenerali ta ’ sostenn fosthom iż- żamma tal- pazjent f’ pożizzjoni wiċċu ’ l fuq, valutazzjoni bir- reqqa tas- sinjali vitali tal- pazjent, il- pressjoni tad- demm u ECG.
If indicated, elimination of unabsorbed active maraviroc should be achieved by emesis or gastric lavage.
Jekk tkun indikata, l- eliminazzjoni ta ’ maraviroc attiv mhux assorbit għandha tinkiseb permezz ta ’ emesi jew ħasil ta ’ l- istonku.
Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance.
Jista ’ jiġi amministrat ukoll faħam attivat biex jgħin fit- tneħħija tas - sustanza attiva mhux assorbita.
Since maraviroc is moderately protein bound, dialysis may be beneficial in removal of this medicine.
Billi maraviroc jeħel moderatament mal- proteini tad- demm, dijalisi tista ’ tkun utli fit- tneħħija ta ’ din il- mediċina.
Antivirals for systemic use, Other Antivirals ATC code:
Antivirali għal użu sistemiku, Antivirali Oħra Kodiċi ATC:
Mechanism of action:
Mekkaniżmu ta ’ azzjoni:
Maraviroc is a member of a therapeutic class called CCR5 antagonists.
Maraviroc jifforma parti minn klassi terapewtika msejħa antagonisti CCR5.
Maraviroc selectively binds to the human chemokine receptor CCR5, preventing CCR5-tropic HIV-1 from entering cells.
Maraviroc jeħel b’ mod selettiv mar- riċettur tal- chemokine uman CCR5, u hekk jimpedixxi lill- HIV- 1 CCR5- tropiku milli jidħol fiċ- ċelloli.
Antiviral activity in vitro:
Attività antivirali in vitro:
Maraviroc has no antiviral activity in vitro against viruses which can use CXCR4 as their entry co- receptor (dual-tropic or CXCR4-tropic viruses, collectively termed ‘ CXCR4-using’ virus below).
Maraviroc ma għandu ebda attività antivirali in vitro kontra virus li jistgħu jużaw CXCR4 bħala l- ko - riċettur tad- dħul tagħhom (virus dual- tropic jew CXCR4- tropiku, flimkien issir referenza għalihom bħala virus ‘ li juża CXCR4 ’ hawn taħt).
The serum adjusted EC90 value in 43 primary HIV-1 clinical isolates was 0.57 (0.06 – 10.7) ng/ mL without significant changes between different subtypes tested.
L- EC90 aġġustat skond is- serum, fi 43 isolati kliniċi primarji, kien 0. 57 (0. 06 – 10. 7) ng/ mL mingħajr ebda bdil sinifikanti bejn is- sub- tipi studjati.
The antiviral activity of maraviroc against HIV-2 has not been evaluated.
L- attività antivirali ta ’ maraviroc kontra l- HIV- 2 għadha ma ġietx evalwata.
For details please refer to http: / /www. emea. europa. eu/ htms/ human/ epar/ eparintro.
Għal aktar dettallji jekk jogħġbok irreferi għal http: // www. emea. europa. eu/ htms/ human/ epar/ eparintro.
When used with other antiretroviral medicinal products in cell culture, the combination of maraviroc was not antagonistic with a range of NRTIs, NNRTIs, PIs or the HIV fusion inhibitor enfuvirtide.
Meta ntuża ma ’ prodotti mediċinali antiretrovirali oħra f’ kultura ta ’ ċelluli it- taħlita ta ’ maraviroc ma kienetx antagonista għal NRTIs, PIs u l- inibitur tal- fużjoni ta ’ l- HIV enfuvirtide.
Resistance:
Reżistenza:
Viral escape from maraviroc can occur via 2 routes: the selection of virus which can use CXCR4 as its entry co-receptor (CXCR4-using virus) or the selection of virus that continues to use exclusively CCR5 (CCR5-tropic virus).
Il- ħruġ tal- virus minn maraviroc jista ’ jseħħ permezz ta ’ 2 rotot: l- għażla tal- virus li jista ’ juża CXCR4 bħala l- ko- riċettur ta ’ dħul tiegħu (virus li juża CXCR4) jew l- għażla ta ’ virus li jibqa ’ juża biss CCR5 (virus tropiku CCR5).
HIV-1 variants with reduced susceptibility to maraviroc have been selected in vitro, following serial passage of two CCR5-tropic viruses (0 laboratory strains, 2 clinical isolates).
Il- varjanti ta ’ HIV- 1 b’ suxxettibilità mnaqqsa għal maraviroc ġew magħżula in vitro, wara passaġġ serjali ta ’ żewġ virus CCR5- tropiċi (0 razza tal- laboratorju, 2 iżolati kliniċi).
The maraviroc-resistant viruses remained CCR5-tropic and there was no conversion from a CCR5-tropic virus to a CXCR4- using virus.
Il- virus reżistenti għal maraviroc baqgħu CCR5- tropiċi u ma kien hemm l- ebda qalba minn virus CCR5- tropiku għal virus li juża CXCR5.
Phenotypic resistance: concentration response curves for the maraviroc-resistant viruses were characterized phenotypically by curves that did not reach 100% inhibition in assays using serial dilutions of maraviroc.
Il- kurvi tar- rispons mal- konċentrazzjoni għall- virus reżistenti għal maraviroc kienu kkaratterizzati finotipikament minn kurvi li ma laħqux 100% inibizzjoni f’ analiżi tal- mediċina fejn intużaw diluzzjonijiet serjali ta ’ maraviroc.
Traditional IC50/ IC90 fold-change was not a useful parameter to measure phenotypic resistance, as those values were sometimes unchanged despite significantly reduced sensitivity.
Bidla tradizzjonali fl- IC50/ IC90 ma kinitx parametru utli biex titkejjel ir- reżistenza fenotipika, minħabba li xi kultant, dawk il- valuri ma nbidlux minkejja li s- senittività tnaqqset b’ mod sinjifikanti.
Genotypic resistance: mutations were found to accumulate in the gp120 envelope glycoprotein (the viral protein that binds to the CCR5 co-receptor).
Instab li l- mutazzjonijiet jakkumulaw fil- gp120 envelope glycoprotein (il - proteina virali li tingħaqad mal- ko- riċettur CCR5).
The position of these mutations was not consistent between different isolates.
Il- pożizzjoni ta ’ dawn il- mutazzjonijiet ma kinitx konsistenti bejn iżolati differenti.
Hence, the relevance of these mutations to maraviroc susceptibility in other viruses is not known.
Għaldaqstant, ir- relevanza ta ’ dawn il- mutazzjonijiet għas - suxxettibilità ta ’ maraviroc f’ virusijiet oħra m’ hijiex magħrufa.
Cross-resistance in vitro:
13 Cross- resistance in vitro:
HIV-1 clinical isolates resistant to nucleoside analogue reverse transcriptase inhibitors (NRTI), non- nucleoside analogue reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI) and enfuvirtide
Iżolati kliniċi tal- HIV- 1 li kienu reżistenti għal inibituri tan- nucleoside analogue reverse transcriptase (NRTI), tan- non- nucleoside analogue reverse transcriptase inhibitors (NNRTI), tal- inibituri tal - protease (PI) u enfuvirtide kienu kollha suxxettibli għal maraviroc f’ kulturi taċ- ċelluli.
Maraviroc-resistant viruses that emerged in vitro remained sensitive to the fusion inhibitor enfuvirtide and the protease inhibitor saquinavir.
Virus reżistenti għall- Maraviroc li ħarġu in vitro baqgħu sensittivi għal inibitur tal- fużjoni enfuvirtide u tal- inibitur tal - protease saquinavir.
Treatment naïve patients The resistance profile in treatment-naïve patients has not been characterized.
Pazjenti li qatt ma ħadu t- trattament qabel Il- profil ta ’ reżistenza f’ pazjenti li qatt ma ħadu t- trattament qabel għadu ma ġiex ikkaratterizzat
Treatment experienced patients In the pivotal studies (MOTIVATE 1 and MOTIVATE 2), 7.6% of patients had a change in tropism result from CCR5-tropic to CXCR4-tropic or dual/ mixed-tropic between screening and baseline (a period of 4-6 weeks).
Pazjenti li ħadu t- trattament qabel Fl- istudji ewlenin (MOTIVATE 1 and MOTIVATE 2), 7. 6% tal- pazjenti kellhom bidla fir- riżultat tat - tropiżmu minn CCR5- tropic għal CXCR4- tropic jew dual/ imħallat- tropic bejn skrining u linja bażi (f’ perjodu ta ’ 4- 6 ġimgħat).
Failure with CXCR4-using virus:
Falliment ma virus li juża CXCR4:
CXCR4-using virus was detected at failure in approximately 60% of subjects who failed treatment on CELSENTRI, as compared to 6% of subjects who experienced treatment failure in the OBT alone arm.
Virus li juża CXCR4 kien misjub fil- punt meta t- terapija ma ħadmitx, f’ 60% tas- suġġetti li fihom falla t- trattament b’ CELSENTRI, mqabbel ma ’ 6% of subjects li fihom ma ħadimx it- trattament fil- grupp trattat b’ OBT biss.
To investigate the likely origin of the on-treatment CXCR4-using virus, a detailed clonal analysis was conducted on virus from 20 representative subjects (16 subjects from the CELSENTRI arms and 4 subjects from the OBT alone arm) in whom CXCR4-using virus was detected at treatment failure.
Sabiex ikun investigat l- oriġini tal- virus li juża CXCR4 li ħareġ waqt it- trattament, analiżi klonali saret fuq virus minn 20 rappreżentant (16 il- suġġett mill- grupp trattat b’ CELSENTRI u 4 suġġetti mill- grupp trattat b’ OBT biss) li fihom dan il- virus ħareġ fil- punt meta t- terapija ma ħadmitx.
This analysis indicated that CXCR4-virus emerged from a pre-existing CXCR4-using reservoir not detected at baseline, rather than from mutation of CCR5-tropic virus present at baseline.
Dan l- analiżi indika li l- virus CXCR4 ħareġ minn virus li juża CXCR4 pre- eżistenti, li ma kienx nstab fuq livell bażi iktar milli minħabba mutazzjoni ta ’ virus tropiku CCR5 li kien preżenti fuq livell bażi.
An analysis of tropism following failure of CELSENTRI therapy with CXCR4 -using virus, demonstrated that the virus population reverted back to CCR5 tropism in the majority of patients during follow up after discontinuation of CELSENTRI.
Barra minn hekk, analiżi ta ’ tropiżmu wara li terapija ta ’ CELSENTRI b’ virus li juża CXCR4 ma ħadmitx, uriet li l- popolazzjoni tal- virus marret lura għal tropiżmu CCR5 fil- maġġoranza tal- pazjent waqt follow up wara t- twaqif ta ’ CELSENTRI.
Out of 44 patients studied, the virus population in 30 reverted back to exclusively CCR5-tropism during a median follow-up of 203 days; 14 patients continued to have detectable CXCR4 -using virus.
Fi 30 minn 44 pazjent studjat, il - popolazzjoni tal- virus marret lura għal tropiżmu CCR5 waqt follow up medjan ta ’ 203 ġurnata; 14 il - pazjent baqgħu jidhru b’ virus li juża CXCR4.
However, the follow-up period in these patients were shorter (median 16 days).
Madanakollu, il- perjodu ta ’ follow up f’ dawn il- pazjenti kien iqsar (medjan 16 il- ġurnata).
At time of failure with CXCR4-using virus, the resistance pattern to other antiretrovirals appears similar to that of the CCR5-tropic population at baseline, based on available data.
Ibbażat fuq tagħrif disponibbli, fil- punt meta t- terapija b’ virus li juża CXCR4 ma ħadmitx, ir - reżistenza għal mediċini antiretrovirali oħra tidher simili għal dik ta ’ CCR5- tropic tal- popolazzjoni tal - linja bażi.
Hence, in the selection of a treatment regimen, it should be assumed that viruses forming part of the previously undetected CXCR4 -using population (i. e. minor viral population) harbours the same resistance pattern as the CCR5-tropic population.
Għalekk meta jintgħażel it- tip ta ’ trattament irid jiġi assumat li il- viruses li jagħmlu parti minn dik il- poplazzjoni ta ’ virus li jużaw CXCR4 – li ma kienux ġew misjuba qabel (i. e. il - popolazzjoni virali minuri) għandha l- istess reżistenza bħal dik il- popolazzjoni ta ’ CCR5- tropic.
Failure with CCR5-tropic virus:
Reżistenza fenotipika:
Phenotypic resistance: in patients with CCR5-tropic virus at time of treatment failure with CELSENTRI, 22 out of 58 patients had virus with reduced sensitivity to maraviroc.
F’ pazjenti b’ virus tat- tip CCR5- tropiku fil- punt meta t- trattament b’ CELSENTRI ma jkunx ħadem, 22 il- pazjent minn 58, wrew virus b’ sensittività mnaqqsa għal maraviroc.
In the remaining 36 patients, there was no evidence of virus with reduced sensitivity as identified by exploratory virology analyses on a representative group.
Fil- bqija tal- pazjenti, 36, ma kienx hemm evidenza ta ’ virus b’ inqas sensittivita ’, kif identifikat b’ analiżi viroloġika esploratorja fuq grupp rappreżentattiv ta ’ pazjenti.
The latter group had markers correlating to low compliance (low and variable drug levels and often a calculated high residual sensitivity score of the OBT).
Il- grupp ta ’ l- aħħar kellu marki li jikkorrelataw ma ’ nuqqas ta ’ kif tkun segwita t- terapija (livelli baxxi u varjabbli ta ’ mediċina u spiss, valur għoli kkalkulat ta ’ sensitivita ’ residwa ta ’ OBT).
In patients failing therapy with R5-virus only, maraviroc might be considered still active if the maximal percentage inhibition (MPI) value is ≥ 95% (Phenosense Entry assay).
F’ pazjenti li fallew it - trattament b’ virus R5 biss, maraviroc jista ’ jkun xorta waħda ikkunsidrat attiv jekk il- persentaġġ massimu ta ’ inibizzjoni (MPI) huwa ≥95% (Phenosense Entry assay).
Residual activity in vivo for viruses with MPI-values < 95% has not been determined.
Attivita ’ residwa ta ’ viruses in vivo b’ valuri MPI < 95% ma ġietx stabbilita.
Genotypic resistance:
Reżistenza ġenotipika:
Key mutations (V3-loop) can presently not be suggested due to the high variability of the V3-sequence, and the low number of samples analysed.
Mutazzjonijiet speċifiċi (V3- loop) bħalissa ma jistgħux ikunu suġġeriti minħabba varjabilita ’ għolja tas- sekwenza V3, u n- numru żgħir ta ’ ezemplari analizzati..
Clinical Results
Riżultati kliniċi
Studies in CCR5-tropic Treatment-Experienced Patients:
Studji fuq Pazjenti CCR5- tropiċi li Diġà ħadu l- Kura Qabel:
The clinical efficacy of CELSENTRI (in combination with other antiretroviral medicinal products) on plasma HIV RNA levels and CD4+ cell counts have been investigated in two pivotal ongoing, randomized, double blind, multicentre studies (MOTIVATE 1 and MOTIVATE 2, n=1076) in patients infected with CCR5 tropic HIV-1 as determined by the Monogram Trofile Assay.
14 double blind, multicentre, kontinwi magħmula b’ għażla każwali (MOTIVATE 1 u MOTIVATE 2, n=1076) f’ pazjenti infettati bil- virus ta ’ l- HIV- 1 CCR5 tropiku kif stabbilit bil- Monogram Trofile Assay..
Patients who were eligible for these studies had prior exposure to at least 3 antiretroviral medicinal product classes [≥ 1 nucleoside reverse transcriptase inhibitors (NRTI), ≥ 1 non-nucleoside reverse transcriptase inhibitors (NNRTI), ≥ 2 protease inhibitors (PI), and/ or enfurvirtide] or documented
Il- pazjenti li kienu eleġibbli għal dawn l- istudji kellhom espożizzjoni preċedenti għal mill- inqas 3 klassijiet antiretrovirali tal- prodott mediċinali [≥1 nucleoside reverse transcriptase inhibitors (NRTI), ≥1 non- nucleoside reverse transcriptase inhibitors (NNRTI), ≥2 inibituri tal- protease (PI), u/ jew enfurvirtide] jew reżistenza jew intolleranza dokumentata għal mill- anqas membru wieħed ta ’ kull klassi.
Patients were randomised in a 2:2:1 ratio to CELSENTRI 300 mg (dose equivalence) once daily, twice daily or placebo in combination with an optimized background consisting of 3 to 6 antiretroviral medicinal products (excluding low-dose ritonavir).
Il- pazjenti ġew magħżula fi proporzjon ta ’ 2: 2: 1 għal CELSENTRI 300 mg darba kuljum (ekwivalenza tad- doża) darba kuljum, darbtejn kuljum jew plaċebo f’ kombinazzjoni ma ’ sfond ottimizzat magħmul minn sa 6 prodotti mediċinali antiretrovirali (eskluża doża baxxa ta ’ ritonavir).
The OBT was selected on the basis of the subject’ s prior treatment history and baseline genotypic and phenotypic viral resistance measurements.
L - OBT intagħżlet fuq il- bażi ta ’ fuq il- bażi ta ’ l- istorja ta ’ kura preċedenti tal- pazjent u kejl bażiċi ta ’ reżistenza virali ġenotipika u finotipika.
Demographic and baseline characteristics of patients in studies MOTIVATE 1 and MOTIVATE 2 (Pooled Analysis)
Karatteristiċi Demografiċi u ta ’ bażi tal- pazjenti fl- istudji MOTIVATE 1 u MOTIVATE 2 (Analiżi Miġbura)
Demographic and Baseline Characteristics
Karatteristiċi Demografiċi u tal- linja Bażi
Age (years)
darbtejn kuljum + OBT N = 209 N = 426 Età (snin)
N
45. 7
= 426 46.3
(Medda, snin)
N
21- 73
(Range, years) Male Sex
Sess maskil
21-73 89.7%
89. 7%
29-72 88.5%
88. 5%
Race (White/ Black/ Other) Mean Baseline HIV-1 RNA (log10 copies/ mL) Median Baseline CD4+ Cell Count (cells/ mm3)
Razza (Bajda/ Sewda/ Oħra) HIV- 1 RNA Bażiku Medju (log10 kopji/ mL)
85.2% /
85. 2% /
12% / 2.8% 4.85 166.8
12% / 2. 8% 4. 85
12.4% / 2.4% 4.86 171.3
85. 2% / 12. 4% / 2. 4% 4. 86
(range, cells/ mm3)
Medjan Bażiku ta ’ l- Għadd taċ- ċelloli CD4 +( ċelloli/ mm3)
(2.0-820.0)
166. 8
(1.0-675.0)
171. 3
Screening Viral Load > 100,000 copies/ mL
(medda, ċelloli/ mm3) Screening tat- Tagħbija Virali > 100, 000 kopja/ mL
179 (42.0%)
(2. 0- 820. 0) 179 (42. 0%)
84 (40.2%)
(1. 0- 675. 0) 84 (40. 2%)
Baseline CD4+ Cell Count ≤ 200 cells/ mm3 Number (Percentage) of patients with GSS score:
Linja Bażi ta ’ l- Għadd taċ- Ċelloli CD4+ ≤200 ċellola/ mm3 Numru (Perċentwal) ta ’ pazjenti bi skor GSS:
250 (58.7%)
250 (58. 7%)
118 (56.5%)
118 (56. 5%)
0 1 2 ≥ 3
0 1 2 ≥3 Assaġġ ta ’ reżistenza ta ’ GeneSeq
102 (23.9%) 138 (32.4%) 80 (18.8%) 104 (24.4%)
102 (23. 9%) 138 (32. 4%) 80 (18. 8%) 104 (24. 4%)
51 (24.4%) 53 (25.4%) 41 (19.6%) 59 (28.2%)
51 (24. 4%) 53 (25. 4%) 41 (19. 6%) 59 (28. 2%)
Limited numbers of patients from ethnicities other than Caucasian were included in the pivotal clinical studies, therefore very limited data are available in these patient populations.
Numru limitat ta ’ pazjenti ta ’ etniċita ’ oħra differenti minn Caucasian kienu inklużi fl- istudji kliniċi ewlenin, għalekk it- tagħrif disponibbli għal dawn il- popolazzjonijiet ta ’ pazjenti huwa limitat.
The mean increase in CD4+ cell count from baseline in patients who failed with a change in tropism result to dual/ mixed tropic or CXCR4, in the CELSENTRI 300 mg twice daily + OBT (+56 cells/ mm3) group was greater than that seen in patients failing OBT alone (+13.8 cells/ mm3) regardless of tropism.
Iż- żieda medja fl- għadd taċ- ċelloli CD4+ mil- linja bażi f’ pazjenti li ma marrux tajjeb b’ bidla fir - riżultat tat- tropiżmu għal tropiku dual/ imħallat jew CXCR4, fil- grupp ta ’ CELSENTRI 300 mg darbtejn kuljum + OBT (+56 ċelloli/ mm3) kienet ikbar minn dik li rriżultat f’ pazjenti li ma marrux tajjeb b’ OBT waħdu (+13. 8 cells/ mm3) minkejja t- tropiżmu.
Outcomes of randomised treatment at week 48 (pooled studies MOTIVATE 1 and MOTIVATE 2)
Riżultati tat- Trattament randomizzat f’ ġimgħa 48 (Studji miġbura MOTIVATE 1 u MOTIVATE 2) Differenza fil- Kura1
HIV-1 RNA
Riżultati
OBT alone N=209
kunfidenza 2) darbtejn kuljum + OBT HIV- 1 RNA
Treatment Difference1 (Confidence Interval2)
N=209
Change from baseline
Bidla fil- Linja Bażi
-1.84
- 1. 84
-0.78
- 0. 78
(log10 copies/ mL)
(log10 kopji/ mL)
(-1.33, -0.78)
(- 1. 33, - 0. 78)
Proportion of patients with HIV RNA < 400 copies/ ml
15 Perċentwali ta ’ pazjenti b’ HIV RNA < 400 kopji/ ml Perċentwali ta ’ pazjenti b’ HIV
56.1%
56. 1%
22.5%
22. 5%
4.76 (3.24, 7.00)
4. 76 (3. 24, 7. 00)
Proportion of patients with HIV RNA < 50 copies/ ml CD4+ cell count
RNA < 50 kopji/ ml
45.5%
45. 5%
16.7%
16. 7%)
4.49 (2.96, 6.83)
4. 49 (2. 96, 6. 83)
Change from baseline (cells/ mm3) 1 p-values < 0.0001
ċelloli CD4+ (ċelloli/ mm3) 1 valur p < 0. 0001 2
124.07
124. 07
60.93
60. 93
63.13 (44.28, 81.99)
63. 13 (44. 28, 81. 99)
13 2 For all efficacy endpoints the confidence intervals were 95%, except for HIV-1 RNA Change from baseline which was 97.5%
Għall- endpoints kollha ta ’ l- effikaċja l- intervalli ta ’ kunfidenza kienu 95%, ħlief għall- Bidla fl- HIV - 1 RNA mil- linja bażi li kienet 97. 5%
CELSENTRI 300 mg twice daily + OBT was superior to OBT alone across all subgroups of patients analysed (see Table 8).
CELSENTRI 300 mg darbtejn kuljum + OBT kien aqwa minn OBT waħidha fil- gruppi ta ’ pazjenti kollha analizzati (ara Tabella 8).
Patients with very low CD4+ count at baseline (i. e. < 50 cells/ uL) had a less favourable outcome.
Pazjenti b’ livell baxx ta ’ CD4+ fil- linja bażi (i. e. < 50ċelluli/ uL) kellhom riżultat inqas favorevoli.
This subgroup had a high degree of bad prognostic markers, i. e. extensive resistance and high baseline viral loads.
Dan is- sottogrupp għandu livelli għoljin ta ’ markaturi pronjostici ħżiena, i. e. reżistenza estensiva u linja bażi virali għolja.
Proportion of patients achieving < 50 copies/ ml at Week 48 by subgroup (pooled Studies MOTIVATE 1 and MOTIVATE 2, ITT)
Madanakollu, benefiċċju sinifikattiv tat - trattament b’ CELSENTRI meta mqabbel ma OBT waħdu kien għadu ippruvat (ara Tabella 8).
HIV-1 RNA < 50 copies/ ml
Tabella 8 Proporzjon ta ’ pazjenti li kisbu < 50 kopja/ ml f’ Ġimgħa 48 skond is- sottogrupp (Studji miġbura MOTIVATE 1 u MOTIVATE 2, ITT) HIV- 1 RNA < 50 kopja/ ml
twice daily + OBT
darbtejn kuljum + OBT N=426
N=426
waħedha N=209
N=209
Linja bażi
Baseline HIV-1 RNA:
HIV- 1 RNA
< 5.0 log10 copies/ ml ≥ 5.0 log10 copies/ ml
< 5. 0 log10 kopji/ ml ≥5. 0 log10 kopji/ ml CD4+( ċelluli/ uL):
58.4% 34.7%
58. 4% 34. 7%
26.0% 9.5%
26. 0% 9. 5%
16.5
16. 5
36.4 56.7 57.8 72.9
36. 4 56. 7 57. 8 72. 9
12.0 21.8 21.0 38.5
12. 0 21. 8 21. 0 38. 5
Number of active ARVs in OBT1,2:
Numru ta ’ ARV attivi f’ OBT1, 2:
0 1 2
2. 0%
32.7% 44.5% 58.2%
44. 5%
2.0% 7.4% 31.7%
7. 4%
62%
58. 2% 62%
38.6%
31. 7% 38. 6%
Discontinuations or virological failures considered as failures.
Twaqqif jew fallimenti viroloġiċi meqjusa bħala fallimenti.
2 Based on GSS.
2 Ibbażati fuq punteġġ GSS.
Studies in Non-CCR5-tropic Treatment-Experienced Patients:
Studji fuq Pazjenti Mhux CCR5- tropiċi Esperjenzati bil- Kura:
Study A4001029 was an exploratory study in patients infected with dual/ mixed or CXCR4 tropic HIV-1 with a similar design as the studies MOTIVATE 1 and MOTIVATE 2.
Studju A4001029 kien eżami esploratorju magħmul b’ għażla każwali f’ pazjenti infettati bi dual/ mixed jew CXCR4 tropic HIV- 1 b’ disinn simili għall- istudji MOTIVATE 1 u MOTIVATE 2.
In this study, neither superiority nor non-inferiority to OBT alone were demonstrated although there was no adverse outcome on viral load or CD4+ cell count
F’ dan l - istudju, la s- superjorità u lanqas n- nuqqas ta ’ inferjorità għal OBT weħidha ma ntwerew għalkemm ma kien hemm ebda riżultat avers fuq it- tagħbija virali jew l- għadd taċ- ċelloli CD4+.
Absorption: the absorption of maraviroc is variable with multiple peaks.
Assorbiment: l- assorbiment ta ’ maraviroc huwa varjabbli b’ aktar minn quċċata waħda.
Median peak maraviroc plasma concentrations is attained at 2 hours (range 0.5-4 hours) following single oral doses of 300 mg commercial tablet administered to healthy volunteers.
L- ogħla konċentrazzjoni medja ta ’ maraviroc fil- plasma tintlaħaq sagħtejn (medda 0. 5- 4 sigħat) wara l -
The pharmacokinetics of oral maraviroc are not dose proportional over the dose range.
Il- farmakokinetiċi ta ’ maraviroc orali mhumiex proporzjonali mad- doża fuq il- medda tad- dożi.
The absolute bioavailability of a 100 mg dose is 23% and is predicted to be 33% at 300 mg.
Il- bijodisponibilità assoluta ta ’ doża ta ’ 100 mg hi 23% u hija mistennija li tkun 33% bi 300 mg.
Maraviroc is a substrate for the efflux transporter P-glycoprotein.
Maraviroc hu sottostrat għat- trasportatur effluss P- glikoproteina.
Coadministration of a 300 mg tablet with a high fat breakfast reduced maraviroc Cmax and AUC by 33% in healthy volunteers.
L- amministrazzjoni ta ’ pillola ta ’ 300 mg ma ’ kolazzjon b’ kontenut għoli ta ’ xaħam naqqas il- Cmax u l - AUC ta ’ maraviroc bi 33% f’ voluntiera b’ saħħithom.
There were no food restrictions in the studies that demonstrated the efficacy and safety of CELSENTRI (see section 5.1).
Ma kienx hemm restrizzjonijiet ta ’ l- ikel fl - istudji li wrew l- effikaċja u s- sigurtà ta ’ maraviroc (ara sezzjoni 5. 1).
Therefore, CELSENTRI can be taken with or without food at the recommended doses (see section 4.2).
Għalhekk, CELSENTRI jista ’ jittieħed ma ’ l- ikel jew waħdu fid- dożi rakkomandati (ara sezzjoni 4. 2).
Distribution: maraviroc is bound (approximately 76%) to human plasma proteins, and shows moderate affinity for albumin and alpha-1 acid glycoprotein.
Distribuzzjoni: maraviroc jeħel (madwar 76%) mal- proteini tal- plasma umana, u juri affinità moderata għall- albumin u l- glikoproteina ta ’ l- aċidu alpha- 1.
The volume of distribution of maraviroc is approximately 194 L.
Il- volum tad- distribuzzjoni ta ’ maraviroc hu madwar 194 L.
14 Metabolism: studies in humans and in vitro studies using human liver microsomes and expressed enzymes have demonstrated that maraviroc is principally metabolized by the cytochrome P450 system to metabolites that are essentially inactive against HIV-1.
Metaboliżmu: studji fil- bniedem u studji in vitro li użaw mikrosomi tal- fwied uman u enzimi espressi wrew li maraviroc jiġi metabolizzat prinċipalment mis- sistema taċ- ċitokromu P450 għal metaboliti li huma essenzjalment inattivi kontra l- HIV- 1.
In vitro studies indicate that CYP3A4 is the major enzyme responsible for maraviroc metabolism.
L- istudji in vitro jindikaw li CYP3A4 hija l- enzima prinċipali responsabbli għall- metaboliżmu ta ’ maraviroc.
In vitro studies also indicate that polymorphic enzymes CYP2C9, CYP2D6 and CYP2C19 do not contribute significantly to the metabolism of maraviroc.
L- istudji in vitro jindikaw ukoll li l- enzimi polimorfiċi CYP2C9, CYP2D6 u CYP2C19 ma jikkontribwixxux b’ mod sinifikanti għall - metaboliżmu ta ’ maraviroc.
Maraviroc is the major circulating component (approximately 42% radioactivity) following a single oral dose of 300 mg.
Maraviroc hu l- akbar komponent ta ’ ċirkolazzjoni (madwar 42% radjuattività) wara doża orali waħda ta ’ 300 mg.
The most significant circulating metabolite in humans is a secondary amine (approximately 22% radioactivity) formed by N-dealkylation.
L- aktar metabolit ta ’ ċirkolazzjoni importanti fil- bniedem hu ammina sekondarja (madwar 22% radjuattività) iffurmata b’ N- dealkylation.
This polar metabolite has no significant pharmacological activity.
Dan il- metabolit polari m’ għandux attività farmakoloġika sinifikanti.
Other metabolites are products of mono-oxidation and are only minor components of plasma radioactivity.
Metaboliti oħrajn huma prodotti ta ’ mono- ossidazzjoni u huma biss komponenti minuri tar- radjuattività fil- plasma.
Elimination: a mass balance/ excretion study was conducted using a single 300 mg dose of 14C-labeled maraviroc.
Eliminazzjoni: ġie mwettaq studju dwar il- bilanċ tal- massa/ eskrezzjoni billi ntużat doża waħda ta ’ 300 mg ta ’ maraviroc 14C- tikkettat.
Approximately 20% of the radiolabel was recovered in the urine and 76% was recovered in the faeces over 168 hours.
Madwar 20% tar- radjutikketta kien irkuprat fl- awrina u 76% kien irkuprat fl- ippurgar fuq perjodu ta ’ 168 siegħa.
Maraviroc was the major component present in urine (mean of 8% dose) and faeces (mean of 25% dose).
Maraviroc kien il- komponent prinċipali preżenti fl - awrina (medja ta ’ 8% tad- doża) u fl- ippurgar (medja ta ’ 25% tad- doża).
The remainder was excreted as metabolites.
Il- bqija tneħħa bħala metaboliti.
After intravenous administration (30 mg), the half-life of maraviroc was 13.2 h, 22% of the dose was excreted unchanged in the urine and the values of total clearance and renal clearance were 44.0 L/ h and 10.17 L/ h respectively.
Wara għoti ġol- vini (30mg), il- half- life ta ’ maraviroc kien 13. 2 h, 22% tad- doża inħarġet mhux mibdula fl- awrina u l- valuri tat- tneħħija totali u tat- tneħħija mill- kliewi kienu 44. 0 L/ h u 10. 17 L/ h rispettivament.
Children: the pharmacokinetics of maraviroc in paediatric patients have not been established (see section 4.2).
Tfal: il- farmakokinetiċi ta ’ maraviroc f’ pazjenti pedjatriċi ma ġewx stabbiliti (ara sezzjoni 4. 2).
Elderly: population analysis of the Phase 1/ 2a and Phase 3 studies (16-65 years of age) has been conducted and no effect of age has been observed (see section 4.2).
Anzjani: l- analiżi tal- popolazzjoni ta ’ l- istudji ta ’ Fażi 1/ 2a u Fażi 3 (16- 65 sena t’ età) saret u ma ġie osservat ebda effett ta ’ l- età (ara sezzjoni 4. 2).
Renal impairment: the pharmacokinetics of maraviroc have not been studied in patients with renal impairment.
Indeboliment tal- kliewi: il- farmakokinetiċi ta ’ maraviroc ma ġewx studjati f’ pazjenti b’ indeboliment tal- kliewi.
However, renal clearance contributes less than 25% of maraviroc total clearance in the absence of CYP3A4 inhibitors, therefore the impact of renal impairment on maraviroc elimination should be minimal.
Madankollu, il- clearance mill- kliewi tikkontribwixxi anqas minn 25% tal- clearance totali ta ’ maraviroc, fin- nuqqas ta ’ inibituri ta ’ CYP3A4, għalhekk l- impatt ta ’ indeboliment tal- kliewi fuq l - eliminazzjoni ta ’ maraviroc għandu jkun minimu.
In the presence of metabolic inhibitors, renal clearance may account for up to 70% of total clearance of maraviroc and hence renal impairment may result in increased maraviroc exposures in this case (see sections 4.2 and 4.4).
Fil- preżenza ta ’ inibituri metaboliċi, it- tneħħija mill - kliewi tista ’ tammonta għal 70% tat- tneħħija totali ta ’ maraviroc u għalhekk, l- indeboliment tal- kliewi jista ’ jirriżulta f’ espożizzjonijiet miżjuda ta ’ maraviroc f’ dan il- każ (ara sezzjonijiet 4. 2 u 4. 4).
Hepatic impairment: maraviroc is primarily metabolized and eliminated by the liver.
Indeboliment tal- fwied: maraviroc huwa metabolizzat primarjament u eliminat mill- fwied.
A study compared the pharmacokinetics of a single 300 mg dose of CELSENTRI in patients with mild (Child- Pugh Class A, n=8), and moderate (Child-Pugh Class B, n=8) hepatic impairment compared to healthy subjects (n=8).
Studju qabbel il- farmakokinetiċi ta ’ doża waħdanija ta ’ 300mg ta ’ CELSENTRI f’ pazjenti b’ indeboliment tal- fwied ħafif (Child- Pugh Klassi A, n=8), u moderat (Child- Pugh Klassi B, n=8) meta mqaabbel ma ’ suġġetti b’ saħħithom (n=8).
Geometric mean ratios for Cmax and AUClast were 11% and 25% higher respectively for subjects with mild hepatic impairment, and 32% and 46% higher respectively for subjects with moderate hepatic impairment compared to subjects with normal hepatic function.
Il- proporzjonijiet ġeometriċi medji għal Cmax u AUClast kienu 11% u 25% ogħal rispettivament għal suġġetti b’ indeboliment tal- fwied ħafif, u 32% u 46% ogħla rispettivament għal suġġetti b’ indeboliment tal- fwied moderat meta mqabbel ma ’ suġġetti b’ funzjoni tal- fwied normali.
The effects of moderate hepatic impairment may be underestimated due to limited data in patients with decreased metabolic capacity and higher renal clearance in these subjects.
L- effetti ta ’ indeboliment moderat tal- fwied jista ma jkunx meqjus biżżejjed minħabba informazzjoni limitata fuq pazjenti b’ kapaċita ’ metabolika mnaqqsa u clearance renali għolja aktar.
The results should therefore be interpreted with caution.
Għaldaqstant dawn ir- riżultati għandhom jiġu interpretati b’ kawtela.
The pharmacokinetics of maraviroc have not been studied in subjects with severe hepatic impairment (see sections 4.2 and 4.4).
Il- farmakokinetiċi ta ’ maraviroc ma ġewx studjati f’ suġġetti b’ indeboliment tal- fwied sever (ara sezzjoni 4. 2 u 4. 4).
Race: no relevant difference between Caucasian, Asian and Black subjects has been observed.
Ma ġiet osservata ebda differenza relevanti bejn suġġetti mill- Kawkasu, Asjatiċi u Suwed.
The pharmacokinetics in other races has not been evaluated.
Il - farmakokinetiċi f’ razez oħrajn ma ġietx evalwata.
Gender: no relevant differences in pharmacokinetics have been observed.
Ma ġew osservati ebda differenzi relevanti fil- farmakokinetiċi.
Primary pharmacological activity (CCR5 receptor affinity) was present in the monkey (100% receptor occupancy) and limited in the mouse, rat, rabbit and dog.
L- attività farmakoloġika primarja (l- affinità tar- riċettur ta ’ CCR5) kienet preżenti fix- xadini (okkupazzjoni ta ’ 100% tar- riċettur) u limitata fil- ġrieden, firien, fniek u klieb.
In mice and human beings that lack CCR5 receptors through genetic deletion, no significant adverse consequences have been reported.
Fil- ġrieden u fil - bnedmin li ma għandhomx riċetturi ta ’ CCR5 permezz ta ’ tneħħija ġenetika, ma ġew irrapportati ebda konsegwenzi avversi sinjifikanti.
15 In vitro and in vivo studies showed that maraviroc has a potential to increase QTc interval at supratherapeutic doses with no evidence of arrhythmia.
Studji in vitro u in vivo studies urew li maraviroc għandu l- potenzjali li jżid l- intervall ta ’ QTc f’ dożi supraterapewtiċi mingħajr evidenza ta ’ arrhythmia.
Repeated dose toxicity studies in rats identified the liver as the primary target organ for toxicity (increases in transaminases, bile duct hyperplasia, necrosis).
Studji ripetuti tal- ħsara tad- doża fil- firien, identifikaw il- fwied bħala l- organu fil- mira ewlieni li ssirlu l- aktar ħsara (żieda fit- transaminases,, iperplażja tal- bile duct, nekrożi).
Maraviroc was evaluated for carcinogenic potential by a 6 month transgenic mouse study and a 24 month study in rats.
Maraviroc ġie evalwat għall- potenzjal karċinoġeniku bi studju ta ’ 6 xhur fuq ġrieden transġeniċi u studju ta ’ 24 xahar fuq il- firien.
In mice, no statistically significant increase in the incidence of tumors was reported at systemic exposures from 7 to 39-times the human exposure (unbound AUC 0-24h measurement) at a dose of 300 mg twice daily.
Fil- ġrieden, ebda żieda statistikament sinjifikanti fl- inċidenza ta ’ xi tip ta ’ tumur ma ġiet irrapportata b’ espożizzjoni sistemika fil- medda ta ’ 7 sa 39 darba l- espożizzjoni umana (ibbażat fuq kejl ta ’ l- AUC mhux marbuta minn 0- 24 siegħa) bid- doża massima rakkomandata ta ’ 300 mg darbtejn kuljum.
In rats, administration of maraviroc at a systemic exposure 21-times the expected human exposure produced thyroid adenomas associated with adaptive liver changes.
Fil- firien, l- amministrazzjoni ta ’ maraviroc b’ esponiment sistemiku ta ’ 21 darba aktar mill- espożizzjoni fuq il- bniedem ipproduċiet adenoma fit- tirojde, assoċjati ma ’ bidliet adattivi tal- fwied,.
These findings are considered of low human relevance.
Dawn ir- riżultati huma meqjusa ta ’ relevanza baxxa għall- bniedem.
In addition, cholangiocarcinomas (2/ 60 males at 900 mg/ kg) and cholangioma (1/ 60 females at 500 mg/ kg) were reported in the rat study at a systemic exposure at least 15-times the expected free human exposure.
Barra minn hekk, cholangiocarcinomas (2/ 60 irġiel bi 900 mg/ kg) u cholangioma (1/ 60 nisa bi 500 mg/ kg) kienu rappurtati fl- istudju tal- ġrieden b’ esposizzjoni sistemika mill- anqas 15- il darba l- esposizzjoni ħielsa mistennija fil- bniedem.
Maraviroc was not mutagenic or genotoxic in a battery of in vitro and in vivo assays including bacterial reverse mutation, chromosome aberrations in human lymphocytes and rat bone marrow micronucleus.
Maraviroc ma kienx mutaġeniku jew ġenotossiku f’ batterija ta ’ assaġġi in vitro u in vivo li kienu jinkludu tibdil batteriku b’ lura, aberrazzjoni ta ’ kromosomi f’ limfoċiti umani u mikronukleu tal - mudullun tal- firien.
Maraviroc did not impair mating or fertility of male or female rats, and did not affect sperm of treated male rats up to 1000 mg/ kg.
Maraviroc ma indebolixxiex it- tgħammir jew il- fertilità tal- firien irġiel jew nisa, u ma affettwax l - isperma ta ’ firien irġiel ittrattati b’ sa 1000 mg/ kg.
The exposure at this dose level corresponded to 39-fold the estimated free clinical AUC for a 300 mg twice daily dose.
L- esponiment b’ din id- doża kien jikkorrispondi għal 39 darba l- AUC klinika libera stmata għal doża ta ’ 300 mg darbtejn kuljum.
Embryofoetal development studies were conducted in rats and rabbits at doses up to 39- and 34-fold the estimated free clinical AUC for a 300 mg twice daily dose.
Saru studji fuq il- firien u l- fniek dwar l- iżvilupp ta ’ l- embriju u l- fetu b’ dożi sa 39 u 34 darba l- AUC klinika libera stmata għal doża ta ’ 300 mg darbtejn kuljum.
In rabbit, ,7 foetuses had external anomalies at maternally toxic doses and 1 foetus at the mid dose of 75 mg/ kg.
Fil- fniek, f’ dożi tossiċi għall- omm, 7 feti kellhom anomalijiet esterni u fetu minnhom b’ doża ta’ 75 mg/ kg.