qanastek/EMEA-V3 huggingface dataset:
Severe cases of skin rash, including erythema multiforme and Stevens-Johnson Syndrome (both rare) have been reported in ongoing clinical trials with PREZISTA co-administered with 100 mg ritonavir.
Każijiet serji ta ’ raxx fil- ġilda, inkluż eritema multiforme u s- sindrome ta ’ Stevens- Johnson (it- tnejn li huma rari), ġew irrapputatati fi provi kliniċi li għadhom sejrin bi PREZISTA amministrat flimkien ma ’ 100 mg ritonavir.
The safety assessment in antiretroviral treatment-naïve adult patients (n=343) is based on all safety data from the Phase III trial ARTEMIS comparing PREZISTA/rtv 800/100 mg q.d. versus lopinavir/ritonavir 800/200 mg per day.
L- istima ta ’ sigurtà f’ pazjenti adulti li qatt ma ħadu kura antiretrovirali qabel (n=343) hija bbażata fuq id- dejta kollha ta ’ sigurtà mill- prova tal- Fażi III ARTEMIS li tqabbel PREZISTA/ rtv 800/ 100 mg q. d. versus lopinavir/ ritonavir 800/ 200 mg kuljum.
Median exposure in the PREZISTA/ritonavir group was 56.3 weeks.
Esponiment medjan fil- grupp ta ’ PREZISTA/ ritonavir kien 56. 3 ġimgħat.
0.6% of the patients discontinued treatment due to adverse drug reactions.
0. 6% tal- pazjenti waqqfu l- kura minħabba reazzjonijiet aversi għall- mediċina.
In these treatment naïve-patients, the following adverse drug reactions were identified:
F’ dawn il- pazjenti li qatt ma ħadu kura, ir- reazzjonijiet avversi għall- mediċina li ġejjin ġew identifikati:
ADRs of at least moderate intensity and reported in more than one patient Common: hypertriglyceridaemia, hypercholesterolaemia, headache, diarrhoea, nausea, increased alanine aminotransferase.
ADRs li kienu tal- anqas ta ’ qawwa moderata u kienu rrappurtati f’ aktar minn pazjent wieħed Komuni: ipertrigliċeridimja, iperkolesterolimja, uġigħ ta ’ ras, dijarea, tqalligħ, żieda fl- alanine aminotransferase.
Uncommon: hyperlipidaemia, vomiting, abdominal pain, increased aspartate aminotransferase, rash (including maculopapular rash), allergic dermatitis, pruritus.
15 Mhux komuni: iperlipidimja, rimettar, uġigħ fl- addome, żieda fl- aspartate aminotransferase, raxx (inkluż raxx makulopapulari), dermatite allerġika, ħakk.
ADRs of all severity grades and reported in more than one patient Very common: diarrhoea, nausea.
ADRs ta ’ kull grad ta ’ qawwa u rrappurtati f’ aktar minn pazjent wieħed Komuni ħafna: dijarea, tqalligħ.
Common: hypertriglyceridaemia, hypercholesterolaemia, anorexia, insomnia, headache, dizziness, dysgeusia, vomiting, abdominal pain, abdominal discomfort, abdominal distension, flatulence, increased alanine aminotransferase, rash (including maculopapular, papular rash), alopecia, dry skin, pruritus, fatigue.
Komuni: ipertrigliċeridimja, iperkolesterolimja, anoreksja, insomnja, uġigħ ta ’ ras, sturdament, disgewżja, rimettar, uġigħ fl- addome, skonfort fl- addome, nefħa fl- addome, gass, żieda fl- alanine aminotransferase, raxx (inkluż makulopapulari, raxx papulari) alopeċja, ġilda xotta, ħakk, għejja.
Uncommon: upper respiratory tract infection, diabetes mellitus, hyperlipidaemia, abnormal dreams, hypoaesthesia, disturbance in attention, somnolence, dyspepsia, eructation, increased aspartate aminotransferase, allergic dermatitis, urticaria, dermatitis, night sweats, myalgia, muscle spasms, asthenia.
Mhux komuni: infezzjoni fin- naħa ta ’ fuq tal- apparat tan- nifs, dijabete mellitus, iperlipidimja, ħolm mhux normali, ipoestesija, disturb fl- attenzjoni, ħeddla tan- ngħas, dispepsja, tifwieq, żieda fl- aspartate aminotransferase, dermatite allerġika, urtikarja, dermatite, għaraq bil- lejl, majalġja, spażmi fil - muskoli, astenja.
Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients, including loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump) (see section 4.4).
Terapija b’ taħlita ta ’ għadd ta ’ mediċini antiretrovirali kienet assoċjata ma ’ ridistribuzzjoni tax- xaħam tal- ġisem (lipodistrofija) fil- pazjent ta ’ l- HIV, inkluż telf ta ’ xaħam ta ’ taħt il- ġilda, periferali u fil - wiċċ, żieda fix- xaħam intra- addominali u tal- vixxri, ipertrofija tas- sider u akkumulazzjoni ta ’ xaħam dorsoċervikali (ħotba tal- buflu) (ara sezzjoni 4. 4).
14 Combination antiretroviral therapy has also been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (see section 4.4).
Terapija b’ taħlita ta ’ għadd ta ’ mediċini antiretrovirali kienet ukoll assoċjata ma ’ anormalitajiet metaboliċi bħal ipertrigliserajdimja, iperkolesterolimja, reżistenza għall- insulina, iperġliċemija u iperlaktatemija (ara sezzjoni 4. 4).
Increased CPK, myalgia, myositis and rarely, rhabdomyolysis have been reported with the use of protease inhibitors, particularly in combination with NRTIs.
Żieda f’ CPK, uġigħ fil- muskoli, mijosite u rarament rabdomajalożi ġew irrappurtati bl- użu ta ’ l - Impedituri ta ’ Protease, partikolarment meta jittieħdu flimkien ma ’ l- NRTIs.
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).
Każijiet ta’ osteonekrożi ġew irrappurtati partikolarment f’ pazjenti b’ fatturi ta ’ riskju ġeneralment magħrufa, marda ta ’ l- HIV avvanzata jew esponiment fit- tul għal terapija b’ taħlita ta ’ għadd ta ’ mediċini antiretrovirali (CART).
The frequency of this is unknown (see section 4.4).
Il- frekwenza m’ hijiex magħrufa (ara sezzjoni 4. 4).
In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise (see section 4.4).
Fil- pazjenti infettati bl- HIV u b’ immunodefiċjenza serja fil- bidu tat- trattement b’ taħlita ta ’ għadd ta ’ mediċini antiretrovirali, tista ’ sseħħ reazzjoni infjammatorja għall- infezzjonijiet li ma ’ jurux sintomi jew għal infezzjonijiet opportunistiċi li jkun għad- fadal (ara sezzjni 4. 4).
There have been reports of increased spontaneous bleeding in haemophiliac patients receiving antiretroviral protease inhibitors (see section 4.4).
Kien hemm rapporti ta ’ żieda fil- fsada spontanja fil- pazjenti morda bl- emofilja li qed jirċievu Impedituri ta ’ Protease (ara sezzjoni 4. 4).
Patients co-infected with hepatitis B and/or hepatitis C virus Among 1,968 treatment-experienced patients receiving PREZISTA co-administered with ritonavir 600/100 mg b.i.d., 236 patients were co-infected with hepatitis B or C.
Pazjenti ko- infettati bil- virus ta ’ l- epatite B u/ jew l- epatite Ċ Fost 1, 968 pazjent li kienu ħadu kura qabel u li kienu qed jirċievu PREZISTA flimkien ma ’ ritonavir 600 mg/ 100 mg b. i. d., 236 pazjent kienu co- infettati bl- epatite B jew Ċ.
Co-infected patients were more likely to have baseline and treatment emergent hepatic transaminase elevations than those without chronic viral hepatitis (see section 4.4).
Pazjenti ko- infettati kellhom aktar probabbiltà li jkollhom żieda tal- linja bażi u li tfaċċat minħabba t- trattament fit- transaminase epatiku milli dawk li ma kellhomx epatite virali kronika (ara sezzjoni 4. 4).
Human experience of acute overdose with PREZISTA co-administered with 100 mg ritonavir is limited.
Esperjenza fil- bnedmin ta ’ doża eċċessiva akuta bi PREZISTA flimkien ma 100 mg ritonavir hija limitata.
Single doses up to 3,200 mg of darunavir as oral solution alone and up to 1,600 mg of the tablet formulation of darunavir in combination with ritonavir have been administered to healthy volunteers without untoward symptomatic effects.
Dożi uniċi sa ’ 3, 200 mg darunavir bħala mistura waħedha u sa ’ 1, 600 mg ta ’ pilloli ta ’ darunavir ma ’ ritonavir ġew amministrati lil voluntiera b’ saħħithom mingħajr l- ebda effetti sintomatiċi ħżiena.
There is no specific antidote for overdose with PREZISTA.
Ma hemm l- ebda antidot speċifiku għall- doża eċċessiva.
Treatment of overdose with PREZISTA consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.
It- trattament ta ’ doża eċċessiva ta ’ PREZISTA jikkonsisti f’ miżuri ġenerali ta ’ għajnuna inkluż monitoraġġ tas- sinjali vitali u osservazzjoni ta ’ l- istat kliniku tal- pazjent.
If indicated, elimination of unabsorbed active substance is to be achieved by emesis or gastric lavage.
Jekk ikun indikat, l- eliminazzjoni tas- sustanza attiva li tkun għada ma ġietx assorbita għandha ssir permezz ta ’ induzzjoni tal- vomtu jew tindif ta ’ l- istonku.
Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance.
L - amministrazzjoni tal- faħam attivat tista ’ wkoll tgħin fit- tneħħija tas- sustanza attiva li tkun għadha ma ġietx assorbita.
Since darunavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.
Minħabba li darunavir jeħel ħafna mal- proteini tad- demm, huwa improbabbli li d - dijalisi tkun ta ’ benefiċċju fit- tneħħija tas- sustanza attiva.
Antiviral for systemic use, ATC code:
Antivirali għall- użu sistemiku, Kodiċi ATC:
Mechanism of action Darunavir is an inhibitor of the dimerisation and of the catalytic activity of the HIV-1 protease (KD of 4.5 x 10-12M).
Mod ta ’ kif jaħdem Darunavir huwa impeditur tad- dimerizzazzjoni u l- attività katalittika ta ’ l - HIV- 1 protease (KD ta ’ 4. 5 x 10- 12M).
It selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in virus infected cells, thereby preventing the formation of mature infectious virus particles.
Huwa selettivament jimpedixxi l- qasma ta ’ poliproteini Gag- Pol li fihom il - kowd ta ’ l- HIV fiċ- ċelluli infettati bil- virus, u permezz t’ hekk ifixkel il- formazzjoni ta ’ biċċiet infettivi maturi tal- virus.
Antiviral activity in vitro Darunavir exhibits activity against laboratory strains and clinical isolates of HIV-1 and laboratory strains of HIV-2 in acutely infected T-cell lines, human peripheral blood mononuclear cells and human monocytes/macrophages with median EC50 values ranging from 1.2 to 8.5 nM (0.7 to 5.0 ng/ml).
Attività antivirali in vitro Darunavir juri attività kontra razez tal- laboratorju u ċelluli puri ta ’ virusis iżolati klinikament ta ’ HIV- 1 u razez tal- laboratorju ta ’ HIV- 2 f’ linji ta ’ ċelluli T infettati b’ mod akut, ċelluli mononukleari periferali tad- demm umani u makrofaġi/ monoċiti umani b’ medjan ta ’ valuri EC50 minn 1. 2 sa 8. 5 nM (0. 7 sa 5. 0 ng/ ml).
Darunavir demonstrates antiviral activity in vitro against a broad panel of HIV-1 group M (A, B, C, D, E, F, G) and group O primary isolates with EC50 values ranging from < 0.1 to 4.3 nM.
Darunavir juri attività antivirali in vitro kontra sezzjoni wiesa ’ ta ’ ċelluli puri tal - virusis iżolati primarjament ta ’ HIV- 1 grupp M (A, B, C, D, E, F, G) u grupp O b’ valuri EC50 minn < 0. 1 to 4. 3 nM.
These EC50 values are well below the 50% cellular toxicity concentration range of 87 µM to > 100 µM.
Dawn il- valuri huma ħafna anqas minn 50% tal- limiti minn 87 µM sa > 100 µM ta ’ tossiċità ċellulari.
15 The EC50 value of darunavir increases by a median factor of 5.4 in the presence of human serum.
Il- valur EC50 ta ’ darunavir jiżdied b’ fattur medjan ta ’ 5. 4 fil- preżenza tas- serum uman.
Darunavir showed synergistic antiviral activity when studied in combination with the protease inhibitors ritonavir, nelfinavir, or amprenavir and additive antiviral activity when studied in combination with the protease inhibitors indinavir, saquinavir, lopinavir, atazanavir, or tipranavir, the N(t)RTIs zidovudine, lamivudine, zalcitabine, didanosine, stavudine, abacavir, emtricitabine, or tenofovir, the NNRTIs nevirapine, delavirdine, or efavirenz and the fusion inhibitor enfuvirtide.
Darunavir wera attività antivirali sinerġistika meta ġie studjat flimkien ma ’ Impedituri ta ’ Protease ritonavir, nelfinavir, jew amprenavir u attività antivirali addittiva meta ġie studjat flimkien ma ’ l - Impedituri ta ’ Protease indinavir, saquinavir, lopinavir, atazanavir, jew tipranavir, in- N( t) RTIs zidovudine, lamivudine, zalcitabine, didanosine, stavudine, abacavir, emtricitabine, jew tenofovir, in - NNRTIs nevirapine, delavirdine, jew efavirenz u l- Imepditur tal- Fużjoni enfuvirtide.
No antagonism was observed between darunavir and any of those antiretrovirals.
L- ebda antagoniżmu ma ġie osservat bejn darunavir u kwalunwe wieħed minn dawn l- antiretrovirali.
Resistance In vitro selection of darunavir-resistant virus from wild type HIV-1 was lengthy (> 3 years).
Reżistenza L- għażla in vitro tal- virus reżistenti għal darunavir minn tip ta ’ HIV- 1 li jeżisti fin- natura ħadet fit- tul (> 3 snin).
The selected viruses were unable to grow in the presence of darunavir concentrations above 400 nM.
Il- virusis magħżula ma setgħux jikbru fil- preżenza ta ’ konċentrazzjonijiet ta ’ aktar minn 400 nM darunavir.
Viruses selected in these conditions and showing decreased susceptibility to darunavir (range:
Virusis magħżula f’ dawn il- kundizzjonijiet u li urew suxxettibilità mnaqqsa għal darunavir (medda:
23-50-fold) harboured 2 to 4 amino acid substitutions in the protease gene.
23- 50 darba) kellhom fihom bejn 2 u 4 sostituzzjonijiet tal- aċidu amminiku fil- ġene protease.
Identification of determinants of decreased susceptibility to darunavir in those viruses is under investigation.
L- identifikazzjoni tad- determinanti ta ’ suxxettibilità mnaqqsa għal darunavir f’ dawk il - virusis qed tiġi investigata.
In vitro selection of darunavir resistant HIV-1 (range:
L- għażla in vitro ta ’ HIV- 1 reżistenti għal darunavir (medda:
53-641-fold change in EC50 values [FC]) from 9 HIV-1 strains harbouring multiple PI Resistance-Associated Mutations (RAMs) showed that a minimum of 8 darunavir in vitro selected mutations were required in the HIV-1 protease to render a virus resistant (FC > 10) to darunavir.
53- 641 drabi ta ’ bidla fil- valuri EC50 [FC]) minn 9 razez tal- virus HIV- 1 li kellhom fihom għadd ta ’ Tibdiliet Ġenetiċi Assoċjati mar - Reżistenza (RAMs) tal - PI urew li fil- protease HIV- 1 hemm bżonn ta ’ minimu ta ’ 8 tibdiliet ġenetiċi magħżula in vitro għal darunavir biex jagħmlu l- virus reżistenti (FC > 10) għal darunavir.
In a pooled analysis of the POWER 1, 2 and 3 (see Clinical experience subsection) and DUET 1 and 2 (TMC125-C206 and TMC125-C216) trials the amino acid substitutions identified that developed on PREZISTA co-administered with ritonavir (600/100 mg b.i.d.) in ≥ 20% of the isolates from subjects who experienced virologic failure by rebound were V32I, I54L and L89V.
F’ analiżi pooled tal- provi POWER 1, 2 u 3 (ara s- sottosezzjoni Esperjenza klinika) u DUET 1 u 2 (TMC125- C206 u TMC125- C216) is- sostituzzjonijiet ta ’ l- aċidu amminiku identifikati li żviluppaw bi PREZISTA amministrat flimkien ma ’ ritonavir (600/ 100 mg b. i. d) f’ ≥ 20% taċ- ċelluli tal- virus iżolati minn individwi li esperjenzaw falliment viroloġiku permezz ta ’ reazzjoni opposta kienu V32I, I54L u L89V.
Amino acid substitutions that developed in 10 to 20% of the isolates were V11I, I13V, L33F, I50V and F53L.
Sostituzzjonijiet ta ’ l- aċidu amminiku li żviluppaw f’ min 10 sa 20% tal- virusis iżolati kienu V11I, I13V, L33F, I50V u F53L.
Amino acid substitutions that developed in 5 to 10% of isolates were L10F, I15V, M36L, K43T, M46I, I47V, A71I, G73S, T74P, L76V, V82I and I84V.
Sostituzzjonijiet ta ’ l- aċidu amminiku li żviluppaw f’ bejn 5 u 10% tal - virusis l- iżolati kienu L10F, I15V, M36L, K43T, M46I, I47V, A71I, G73S, T74P, L76V, V82I u I84V.
Of the viruses isolated from patients experiencing virologic failure by rebound from the PREZISTA/ rtv 600/ 100 mg b. i. d. group of the POWER and DUET trials, 85% of those susceptible to darunavir at baseline developed decreased susceptibility to darunavir during treatment.
Mill- virusis iżolati minn pazjenti li kienu qed jesperjenzaw falliment viroloġiku permezz ta ’ rebound mill- grupp PREZISTA/ rtv 600/ 100 mg b. i. d. tal- provi POWER u DUET, 85% ta ’ dawk suxxettibbli għal darunavir fil- linja bażi żviluppaw suxxettibilità mnaqqsa għal darunavir waqt il- kura.
In the same group of patients, 71% of viruses that were susceptible to tipranavir at baseline remained susceptible after treatment.
Fl- istess grupp ta ’ pazjenti, 71% tal- virusis li kienu suxxettibbli għal tipranavir baqgħu suxxettibbli wara l- kura.
Cross-resistance Darunavir has a < 10-fold decreased susceptibility against 90% of 3,309 clinical isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and/or tipranavir showing that viruses resistant to most PIs remain susceptible to darunavir.
17 saquinavir u/ jew tipranavir li juri li l- virusis reżistenti għall- maġġoranza tal- PIs jibqgħu suxxettibbli għal darunavir.
Clinical experience Efficacy of PREZISTA co-administered with 100 mg ritonavir in treatment-naïve patients There are no data on the efficacy of darunavir co-administered with 100 mg ritonavir in treatment-naïve HIV-1 infected patients.
Esperjenza klinika Effikaċja ta ’ PREZISTA amministrat flimkien ma ’ 100 mg ritonavir f’ pazjenti li ma ħadu l- ebda trattament qabel M’ hemm l- ebda tagħrif dwar l- effikaċja ta ’ darunavir amministrat flimkien ma ’ 100 mg ritonavir f’ pazjenti infettati bl- HIV- 1 li ma ħadu l- ebda trattament qabel.
Efficacy of PREZISTA co-administered with 100 mg ritonavir in treatment-experienced patients The evidence of efficacy of PREZISTA co-administered with ritonavir (600/100 mg b.i.d.) in treatment-experienced patients is based on the 48 weeks analysis of the Phase III trial TITAN in treatment-experienced lopinavir naïve patients and on the analyses of 96 weeks data from the Phase IIb trials POWER 1, 2 and 3 in patients with high level of PI resistance.
Effikaċja ta ’ PREZISTA amministrat flimkien ma ’ 100 mg ritonavir f’ pazjenti li ġieli ħadu trattament L- evidenza tal- effikaċja tat- trattment bi PREZISTA amministrat flimkien ma ’ ritonavir (600/ 100 mg b. i. d.) f’ pazjenti li ġieli ħadu trattament qabel huwa bbażat fuq l- analiżi ta ’ 48 ġimgħa tal- prova TITAN tal- Fażi III f’ pazjenti li ġieli ħadu trattament qabel iżda qatt ma ħadu lopinavir u fuq l- analiżi ta ’ data ta ’ 96 ġimgħa mill- provi POWER 1, 2 u 3 tal- Fażi IIb f’ pazjenti b’ livell għoli ta ’ reżistenza għall- PI.
TITAN is an ongoing randomised, controlled, open-label Phase III trial comparing PREZISTA co-administered with ritonavir (600/100 mg b.i.d.) versus lopinavir/ritonavir (400/100 mg b.i.d) in treatment-experienced, lopinavir naïve HIV-1 infected adult patients.
TITAN hija prova tal- Fażi III randomised, ikkontrollata, open- label li għadha sejra, li tqabbel PREZISTA mogħti flimkien ma ’ ritonavir (600/ 100 mg b. i. d.) versus lopinavir/ ritonavir (400/ 100 mg b. i. d) f’ pazjenti adulti infettati bl- HIV- 1 li ġieli ħadu trattament qabel iżda qatt ma ħadu lopinavir.
Both arms used an Optimised Background Regimen (OBR) consisting of at least 2 antiretrovirals (NRTIs with or without NNRTIs).
Iż- żewġ fergħat użaw Sfond bl- Aħjar Użu tat- Teħid tal- Kura (OBR) li jikkonsisti f’ mill - anqas 2 antiretrovirali (NRTIs flimkien ma l- NNRTIs jew mingħajrhom).
The mean baseline plasma HIV-1 RNA was 4.33 log10 copies/ml and the median baseline CD4+ cell count was 235 x 106 cells/l (range 3 – 831 x 106 cells/l) in the PREZISTA/ritonavir arm.
Il- linja bażi medja ta ’ RNA HIV- 1 fil- plażma kienet 4. 33 log10 kopja/ ml u l- linja bażi medjana tal- għadd ta ’ ċelluli CD4+ kienet 235 x 106 ċelluli/ l (medda minn 3 – 831 x 106 ċelluli/ l) fil- fergħa ta ’ PREZISTA/ ritonavir.
The table below shows the efficacy data of the 48 week analysis from the TITAN trial.
It- tabella hawn taħt turi d- data tal- effikaċja tal- analiżi ta ’ 48 ġimgħa mill- prova TITAN.
TITAN
TITAN Effetti
Treatment difference (95% CI of difference)
Differenza fil- kura (95% CI tad- differenza)
HIV-1 RNA < 400 copies/mla
HIV- 1 RNA < 400 kopja/ mla
228 (76.5%)
228 (76. 5%)
199 (67.0%)
199 (67. 0%)
9.5% (2.3; 16.7)b
9. 5% (2. 3; 16. 7) b
HIV-1 RNA < 50 copies/mla
HIV- 1 RNA < 50 kopja/ mla
211 (70.8%)
211 (70. 8%)
179 (60.3%)
179 (60. 3%)
10.5% (2.9; 18.1)b
10. 5% (2. 9; 18. 1) b - 0. 23d
mean HIV-1 RNA log change from baseline (log10 copies/ml)c
medja ta ’ tibdil log fl- HIV- 1 RNA mill- linja bażi (log10 kopja/ ml) c
-1.95
- 1. 95
-1.72
- 1. 72
-0.23d (-0.44; -0.02)b
(- 0. 44; - 0. 02) b
median CD4+ cell count change from baseline (x 106/l)c a
il- medjan ta ’ tibdil fl- għadd ta ’ ċelluli CD4+ mill- linja bażi (x 106/ l) c a Imputazzjonijiet skont l- algoriżmu TLOVR b
Imputations according to the TLOVR algorithm b Based on a normal approximation of the difference in% response c NC=F d Difference in means
Ibbażat fuq l- approssimazzjoni normali tad- diferenza fil -% tar- rispons c NC=F d Differenza fil- medji
Non-inferiority in virologic response, defined as the percentage of subjects with plasma HIV-1 RNA level < 400 copies/ml, was demonstrated (at the chosen 12% non-inferiority margin) for both Intent-To-Treat and On Protocol populations.
Il- fatt li l- kura mhijiex inferjuri għall- kura standard f’ termini ta ’ rispons viroloġiku, definita bħala l - perċentwal ta ’ individwi b’ livell ta ’ < 400 kopja/ ml ta ’ HIV- 1 RNA fil- plażma, intwera (fil- marġini magħżula ta ’ 12% għall- fatt li l- kura mhijiex inferjuri għall- kura standard) kemm għal popolazzjonijiet li kien hemm l- intenzjoni li jiġu kkurati kif ukoll dawk li kienu kkurati skont protokoll.
POWER 1 and POWER 2 are randomised, controlled trials consisting of an initial dose-finding part and a second long-term part in which all patients randomised to PREZISTA co-administered with 100 mg ritonavir received the recommended dose of 600/100 mg b.i.d.
POWER 1 u POWER 2 huma provi kkontrollati randomised li jikkonsistu f’ parti tal- bidu biex tinstab id- doża u t- tieni parti li tieħu tul ta ’ żmien li fiha l- pazjenti kollha randomised għal PREZISTA amministrat flimkien ma 100 mg ritonavir rċievew id- doża rrakkomandata ta ’ 600 mg/ 100 mg b. i. d.
HIV-1 infected patients who were eligible for these trials had previously failed more than 1 PI containing regimen.PREZISTA co-administered with 100 mg ritonavir plus an optimised background regimen (OBR) was compared to a control group receiving an investigator-selected PI(s) regimen plus an OBR.
Pazjenti infettati bl- HIV- 1 li kienu eliġibli għal dawn il- provi, kienu qabel fallew aktar minn kors ta ’ trattament wieħed li kien fih PI. PREZISTA amministrat flimkien ma ’ 100 mg ritonavir flimkien ma ’ kors ta ’ trattament ottimali fl- isfond (OBR) kien imqabbel ma grupp ta ’ kontroll li kien qed jieħu kors
The OBR consisted of at least 2 NRTIs with or without enfuvirtide (ENF).
L- OBR kien jikkonsisti f’ min ta ’ lanqas 2 NRTIs bil jew mingħajr enfuvirtide (ENF).
POWER 3: additional data on the efficacy of PREZISTA co-administered with ritonavir 600/100 mg b.i.d. with OBR have been obtained in similar treatment-experienced patients participating in the non-randomised trial TMC114-C215.
POWER 3: tagħrif addizzjonali dwar l- effikaċja ta ’ PREZISTA amministrat flimkien ma ’ ritonavir 600 mg/ 100 mg b. i. d. ma ’ OBR inkisbu minn pazjenti li ġieli ħadu trattament u li ħadu sehem fi provi oħra mhux randomised TMC114- C215.
Entry criteria were the same as and baseline characteristics were comparable to those of POWER 1 and POWER 2.
Il- kriterji għad- dħul kienu l- istess bħal u l- karatteristici tal - linja bażi kienu kumparabbli ma ’ dawk ta ’ POWER- 1 u POWER- 2.
The table below shows the efficacy data of the 48-week analyses on the recommended 600 mg dose of PREZISTA co-administered with 100 mg ritonavir b.i.d. from the pooled POWER 1 and POWER 2 trials as well as from the POWER 3 trial.
It- tabella t’ hawn taħt turi t- tagħrif ta ’ l- analiżi tat- 48 ġimgħa ta ’ l- effikaċja fuq id- doża rrakkomadata ta ’ 600 mg PREZISTA amministrat flimkien ma ’ 100 mg ritonavir b. i. d. mill- provi ta ’ POWER 1 u POWER 2 miġbura flimkien kif ukoll mill- prova POWER 3.
POWER 1 and POWER 2 pooled data Outcomes at 48 weeks
POWER 1 u POWER 2 tagħrif miġbur flimkien Effetti fit- 48 ġimgħa
Mean plasma HIV-1 RNA
HIV- 1 RNA medju
4.61 log10 copies/ml (PREZISTA/ritonavir) 4.49 log10 copies/ml (control)
4. 61 log10 kopji/ ml (PREZISTA/ ritonavir)
4.58 log10 copies/ml
4. 58 log10 kopji/ ml
Median CD4+ cell count
tal- plażma Għadd medjan taċ -
153 x 106 cells/l (PREZISTA/ritonavir) 163 x 106 cells/l (control)
4. 49 log10 kopji/ ml (kontroll) 153 x 106 ċelluli/ l (PREZISTA/ ritonavir)
120 x 106 cells/l
120 x 106 ċelluli/ l
Outcomes
Effetti
PREZISTA/ritonavir Control Treatment 600/100 mg b.i.d. n=124 difference n=131
PREZISTA/ ritonavir Kontroll Differenza fit - 600/ 100 mg b. i. d. n=124 trattament n=131
HIV-1 RNA log10 mean change from baseline (log10 copies/ml)a
HIV- 1 RNA log10 medja tal- bidla mil- linja bażi (log10 kopji/ ml) a
-1.69 -0.37 1.32 (1.58; 1.05)d
- 1. 69 - 0. 37 1. 32 (1. 58; 1. 05) d
-1.62
- 1. 62
CD4+ cell count mean change from baseline (x 106/l)b
Għadd taċ- ċelluli CD4+ medja tal- bidla mil- linja bażi (x 106/ l) b
HIV RNA > 1 log10 below baselinec
HIV RNA > 1 log10 taħt il- linja bażic
81 (61.8%) 20 (16.1%) 45.7% (35.0%; 56.4%)d 17
81 (61. 8%) 20 (16. 1%) 45. 7% (35. 0%; 56. 4%) d
196 (58.7%)
196 (58. 7%)
HIV RNA
HIV RNA < 400 kopja/ mlc
72 (55.0%) 18 (14.5%) 40.4%
72 (55. 0%) 18 (14. 5%) 40. 4% (29. 8%; 51. 1%) d
183 (54.8%)
183 (54. 8%)
HIV RNA < 50 copies/mlc a
HIV RNA < 50 kopja/ mlc a
14 (11.3%)
59 (45. 0%) 14 (11. 3%) 33. 7% (23. 4%; 44. 1%) d
155 (46.4%)
155 (46. 4%)
Non-completer is failure imputation: patients who discontinued prematurely are imputed with a change equal to 0 b Last Observation Carried Forward imputation c Imputations according to the TLOVR algorithm d 95% confidence intervals.
Min ma kompliex hija imputazzjoni ta ’ falliment: pazjenti li waqfu qabel mit- trattament huma attribwiti b’ bidla ugwali għal 0 b Imputazzjoni ta ’ Last Observation Carried Forward c Imputazzjonijiet skont l- algoriiżmu TLOVR d 95% confidence intervals.
Analyses of data through 96 weeks of treatment in the three POWER trials demonstrated sustained antiretroviral efficacy and immunological benefit.
Analiżi tad- dejta matul is- 96 ġimgħa ta ’ kura fit- tliet provi POWER uriet effikaċja antiretrovirali u benefiċċju immunoloġiku.
Treatment with PREZISTA co-administered with ritonavir (600/100 mg b.i.d.) resulted in 56.5% (POWER 1 and 2) and 52.2% (POWER 3) of responders with a decrease of at least 1 log10 in HIV RNA from baseline, 38.9% (POWER 1 and 2) and 42.1% (POWER 3) of subjects with an HIV RNA level < 50 copies/ml and 49.6% (POWER 1 and 2) and 50.0% (POWER 3) respectively of subjects with an HIV RNA level less than 400 copies/ml.
Kura bi PREZISTA amministrat flimkien ma ’ ritonavir (600/ 100 mg b. i. d.) irriżulta f ’ 56. 5% (POWER 1 u POWER 2) u 52. 2% (POWER 3) ta ’ dawk li rrispondew ikollhom tnaqqis ta ’ lanqas ta ’ log10 wieħed ta ’ HIV RNA mil- linja bażi, 38. 9% (POWER 1 u POWER 2) u 42. 1% (POWER 3) ta ’ l- individwi b’ livell ta ’ HIV RNA < 50 kopja/ ml u 49. 6% (POWER 1 u POWER 2) u 50. 0% (POWER 3) rispettivament ta ’ l- individwi b’ livell ta ’ HIV RNA anqas minn 400 kopja/ ml.
The mean decrease in HIV RNA level compared to baseline was 1.58 (POWER 1 and 2) and 1.43 (POWER 3) log10 copies/ml and a mean increase in CD4+ cell count of 133 x 106 cells/l (POWER 1 and 2) and 103 x 106 cells/l (POWER 3) was observed.
It- tnaqqis medju fil- livell HIV RNA imqabbel mal- linja bażi kien 1. 58 (POWER 1 u POWER 2) u 1. 43 (POWER 3) log10 kopja/ ml u kienet osservata żieda medja fl- għadd taċ- ċelluli CD4+ ta ’ 133 x 106 ċelluli/ l (POWER 1 u 2) u 103 x 106 ċelluli/ l (POWER 3).
Out of the 206 subjects who responded with complete viral suppression (< 50 copies/ml) at week 48, 177 subjects (86% of the responders at week 48) remained responders at week 96.
Mill- 206 individwu li rrispondew b’ suppressjoni virali kompleta (< 50 kopja/ ml) fit- 48 ġimgħa, 177 ta ’ l- individwi (86% ta ’ dawk li rrispondew fit- 48 ġimgħa) baqgħu jirrispondu fis- 96 ġimgħa.
Baseline genotype or phenotype and virologic outcome In a pooled analysis of the 600/100 mg b.i.d. groups of the POWER and DUET trials, the presence at baseline of 3 or more of mutations V11I, V32I, L33F, I47V, I50V, I54L or M, T74P, L76V, I84V or L89V was associated with a decreased virologic response to PREZISTA co-administered with 100 mg ritonavir.
Linja bażi ġenotipika jew fenotipika u l- effetti viroloġiċi F’ analizi pooled tal- gruppi 600/ 100 mg b. i. d. tal- provi POWER u DUET, il- preżenza fil- linja bażi ta ’ 3 tibdiliet ġenetiċi jew aktar V11I, V32I, L33F, I47V, I50V, I54L jew M, T74P, L76V, I84V jew L89V kienet assoċjata ma ’ tnaqqis fir- rispons viroloġiku għal PREZISTA amministrat flimkien ma ’
The presence of these individual mutations was associated with a median of 13 to 15 PI resistance associated mutations of the IAS-USA list of mutations.
Il- preżenza ta ’ dawn it- tibdiliet ġenetiċi individwali kienet assoċjata ma ’ medjan ta ’ minn 13- 15- il tibdila ġenetika assoċjata ma ’ reżistenza għall- PI mill- lista ta ’ IAS- USA ta ’ tibdiliet ġenetiċi.
In early treatment-experienced patients (TITAN) three or more of these mutations were only found in 4% of the patients at baseline.
Fil- pazjenti tal- bidu li ġieli kienu ħadu kura (TITAN) tlieta minn dawn il- mutazzjonijiet jew aktar instabu biss f’ 4% tal- pazjenti fil- linja bażi.
Response (HIV-1 RNA < 50 copies/ml at week 24) to PREZISTA co-administered with ritonavir (600/100 mg b.i.d.) by baseline genotype* and by use of enfuvirtide (ENF):
Rispons (HIV- 1 RNA < 50 kopja/ ml fl- 24 ġimgħa) għal PREZISTA amministrat flimkien ma ’ ritonavir (600 mg/ 100 mg b. i. d) skond il- ġenotip tal- linja bażi * u permezz ta ’ l- użu ta ’ enfuvirtide (ENF):
As treated analysis of the POWER and DUET trials.
Bħala analizi trattata tal- provi POWER u DUET.
Number of mutations at baseline*
Numru ta ’ tibdiliet ġenetiċi fil- linja bażi *
All subjects% n/N
L- indvidwi kollha
Subjects with no/non-naïve use of ENF% n/N
Individwi mingħajr l - użu/ bl- użu mhux inġenwu ta ’ ENF
Subjects with naïve use of ENF% n/N
Individwi bl- użu inġenwu ta ’ ENF
All ranges
Il- meddiet kollha
45% 455/1,014
45% 455/ 1, 014
* Number of mutations from the list of mutations associated with a diminished response to PREZISTA/ritonavir (V11I, V32I, L33F, I47V, I50V, I54L or M, T74P, L76V, I84V or L89V)
* Numru ta ’ tibdiliet ġenetiċi mill- lista ta ’ tibdiliet ġenetiċi assoċjati ma ’ nuqqas ta ’ rispons għall- PREZISTA/ ritonavir (V11I, V32I, L33F, I47V, I50V, I54L jew M, T74P, L76V, I84V jew L89V)
Baseline darunavir phenotype (shift in susceptibility relative to reference) was shown to be a predictive factor of virologic outcome.
Il- fenotip tal- linja bażi ta ’ darunavir (bidla żgħira fis- suxxettibbilità fejn għandha x’ taqsam mar - riferenza) intwera li kienet fattur li juri l- effett viroloġiku minn qabel.
Response (HIV-1 RNA < 50 copies/ml at week 24) to PREZISTA co-administered with ritonavir (600/100 mg b.i.d.) by baseline darunavir phenotype and by use of enfuvirtide:
Rispons (HIV- 1 RNA < 50 kopja/ ml fl- 24 ġimgħa) għal PREZISTA flimkien ma ’ ritonavir (600/ 100 mg b. i. d.) skond il- fenotip tal- linja bażi ta ’ darunavir u bl- użu ta ’ enfuvirtide:
As treated analysis of the POWER and DUET trials.
Bħala analiżi trattata tal- provi POWER u DUET.
18 Baseline darunavir phenotype
Il- fenotip tal- linja bażi ta ’ darunavir
The pharmacokinetic properties of darunavir, co-administered with ritonavir, have been evaluated in healthy adult volunteers and in HIV-1 infected patients.
Il- tagħrif farmakokinetiċi ta ’ darunavir amministrat flimkien ma ’ ritonavir, ġie evalwati f’ voluntiera adulti b’ saħħithom u f’ pazjenti infettati bl- HIV- 1.
Exposure to darunavir was higher in HIV-1 infected patients than in healthy subjects.
Esponiment għal darunavir kien ogħla fil- pazjenti infettati bl- HIV- 1 milli f’ pazjenti b’ saħħithom.
The increased exposure to darunavir in HIV-1 infected patients compared to healthy subjects may be explained by the higher concentrations of alpha-1-acid glycoprotein (AAG) in HIV-1 infected patients, resulting in higher darunavir binding to plasma AAG and, therefore, higher plasma concentrations.
Iż- żieda fl- esponiment għal darunavir fil- pazjenti infettati bl- HIV- 1 meta mqabbla ma ’ pazjenti b’ saħħithom tista ’ tiġi spjegata permezz tal - konċentrazzjonijiet ogħla tal- glikoproteina alpha- 1- acid (AAG) fil- pazjenti infettati bl- HIV- 1, li twassal għal aktar twaħħil ta ’ darunavir ma ’ l- AAG fil- plażma u, għalhekk konċentrazzjonijiet ogħla fil- plażma.
Darunavir is primarily metabolised by CYP3A.
20 Darunavir huwa mmetabolizzat primarjament mis- CYP3A.
Ritonavir inhibits CYP3A, thereby increasing the plasma concentrations of darunavir considerably.
Ritonavir jimpedixxi CYP3A u permezz ta ’ hekk iżid il- konċentrazzjonijiet ta ’ darunavir fil- plażma b’ mod konsiderevoli.
Absorption Darunavir was rapidly absorbed following oral administration.
Assorbiment Darunavir kien assorbit malajr wara amministrazzjoni mill- ħalq.
Maximum plasma concentration of darunavir in the presence of low dose ritonavir is generally achieved within 2.5-4.0 hours.
L- ogħla konċentrazzjoni ta ’ darunavir fil- plażma fil- preżenza ta ’ doża baxxa ta ’ ritonavir ġeneralment tintlaħaq fi żmien 2. 5 – 4. 0 sigħat.
The absolute oral bioavailability of a single 600 mg dose of darunavir alone was approximately 37% and increased to approximately 82% in the presence of 100 mg b.i.d. ritonavir.
Il- biodisponibiltà orali assoluta ta ’ doża waħda ta ’ 600 mg darunavir waħdu kienet ta ’ bejn wieħed u ieħor 37% u żdiedet għal madwar 82% fil- preżenza ta ’ 100 mg b. i. d. ritonavir.
The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in the systemic exposure of darunavir when a single dose of 600 mg darunavir was given orally in combination with ritonavir at 100 mg b.i.d.
L- effett ta ’ titjib farmakokinetiku totali ta ’ ritonavir kien ta ’ żieda ta ’ bejn wieħed u ieħor 14- il darba fl- esponiment sistemiku ta ’ darunavir meta doża waħda ta ’ darunavir 600 mg ingħatat mill- ħalq flimkien ma ’ ritonavir f’ doża ta ’ 100 mg b. i. d.
(see section 4.4).
(ara sezzjoni 4. 4).
When administered without food, the relative bioavailability of darunavir in the presence of low dose ritonavir is 30% lower as compared to intake with food.
Meta amministrat mingħajr ikel, il- biodisponibiltà ta ’ darunavir fil- preżenza ta ’ doża baxxa ta ’ ritonavir hija 30% anqas meta mqabbla ma ’ teħid ma ’ l- ikel.
Therefore, PREZISTA tablets should be taken with ritonavir and with food.
Għalhekk il- pilloli PREZISTA għandhom jittieħdu ma ’ ritonavir u ma ’ l- ikel.
The type of food does not affect exposure to darunavir.
It- tip ta ’ ikel ma jaffetwax l- esponiment għal darunavir.
Darunavir binds primarily to plasma alpha-1-acid glycoprotein.
Darunavir jeħel primarjament mal- glikoproteina alpha- 1- acid fil- plażma.
Following intravenous administration, the volume of distribution of darunavir alone was 88.1 ± 59.0 l (Mean ± SD) and increased to 131 ± 49.9 l (Mean ± SD) in the presence of 100 mg twice-daily ritonavir.
Wara amministrazjoni fil- vini, il- volum ta’ distribuzzjoni ta ’ darunavir waħdu kien ta ’ 88. 1 ± 59. 0 l (Medja ± SD) u żdied għal 131 ± 49. 9 l (Medja ± SD) fil- preżenza ta’ 100 mg ritonavir darbtejn kuljum.
Metabolism In vitro experiments with human liver microsomes (HLMs) indicate that darunavir primarily undergoes oxidative metabolism.
Metaboliżmu Esperimenti in vitro b’ mikrosomi tal- fwied uman (HLMs) juru li darunavir jgħaddi primarjament minn metaboliżmu ossidattiv.
Darunavir is extensively metabolised by the hepatic CYP system and almost exclusively by isozyme CYP3A4.
Darunavir jiġi metabolizzat estensivament mis- sistema epatika CYP u kważi esklusivament mill- isożima CYP3A4.
A 14C-darunavir trial in healthy volunteers showed that a majority of the radioactivity in plasma after a single 400/100 mg darunavir with ritonavir dose was due to the parent active substance.
Prova ta ’ 14C- darunavir f’ voluntiera b’ saħħithom uriet li l - maġġoranza ta ’ radjuattività fil- plażma wara doża waħda ta ’ 400/ 100 mg darunavir ma ’ ritonavir kienet minħabba s- sustanza attiva oriġinali.
At least 3 oxidative metabolites of darunavir have been identified in humans; all showed activity that was at least 10-fold less than the activity of darunavir against wild type HIV.
Ta ’ lanqas 3 sustanzi ossidattivi iffurmati mill - metaboliżmu ta ’ darunavir kienu identifikati fil- bnedmin; kollha wrew attività li kienet ta ’ lanqas 10 darbiet anqas mill- attività ta ’ darunavir kontra l- HIV li jinstab fin- natura.
Elimination After a 400/100 mg 14C-darunavir with ritonavir dose, approximately 79.5% and 13.9% of the administered dose of 14C-darunavir could be retrieved in faeces and urine, respectively.
Eliminazzjoni Wara doża ta ’ 400/ 100 mg 14C- darunavir ma ’ ritonavir, bejn wieħed u ieħor 79. 5% u 13. 9% tad- doża amministrata ta ’ 14C- darunavir setgħet tinġabar lura mill- ipurgar u l- awrina, rispettivament.
Unchanged darunavir accounted for approximately 41.2% and 7.7% of the administered dose in faeces and urine,
L- ammont ta ’ darunavir mhux mibdul kien ta ’ bejn wieħed u ieħor 41. 2% u 7. 7% tad- doża amministrata fl - ippurgar u fl- awrina rispettivament.
The terminal elimination half-life of darunavir was approximately 15 hours when combined with ritonavir.
Il- half- life terminali ta ’ eliminazzjoni ta ’ darunavir kienet bejn wieħed u ieħor ta ’ 15- il siegħa meta kien flimkien ma ’ ritonavir.
The intravenous clearance of darunavir alone (150 mg) and in the presence of low dose ritonavir was 32.8 l/h and 5.9 l/h, respectively.
It- tneħħija ta ’ darunavir waħdu (150 mg) wara amministrazzjoni fil- vina u fil- preżenza ta ’ doża baxxa ta ’ ritonavir kienet ta ’ 32. 8 l/ siegħa u 5. 9 l/ siegħa rispettivament.
Special Populations Paediatrics There are no pharmacokinetic data available in children and adolescents.
Popolazzjonijiet Speċjali Pedjatriċi Ma hemm l- ebda tagħrif farmakokinetiku disponibbli fit- tfal u fl- adoloxxenti.
Elderly Population pharmacokinetic analysis in HIV infected patients showed that darunavir pharmacokinetics are not considerably different in the age range (18 to 75 years) evaluated in HIV infected patients (n=12, age ≥ 65) (see section 4.4).
Anzjani Analiżi farmakokinetika ta ’ popolazzjoni f’ pazjenti infettati bl- HIV uriet li l- farmakokinetika ta ’ darunavir m’ hijiex konsiderevolment differeni fil- medda ta ’ l- eta ’ (18 sa 75 sena) evalwati f’ pazjenti infettati bl- HIV (n=12, età ≥ 65) (ara sezzjoni 4. 4).
However, only limited data were available in patients above the age of 65 year.
Madanakollu, kien disponibbli tagħrif limitat biss f’ pazjenti li kellhom ’ il fuq minn 65 sena.
Gender Population pharmacokinetic analysis showed a slightly higher darunavir exposure (16.8%) in HIV infected females compared to males.
Sess Analiżi farmakokinetika ta ’ popolazzjoni uriet esponiment ftit aktar għoli għal darunavir (16. 8%) fin - nisa infettati bl- HIV meta mqabbla ma ’ l- irġiel.
This difference is not clinically relevant.
Id- differenza m’ hijiex klinikamnet rilevanti.
Renal impairment Results from a mass balance study with 14C-darunavir with ritonavir showed that approximately 7.7% of the administered dose of darunavir is excreted in the urine unchanged.
Indeboliment renali Riżultati minn studju ta ’ bilanċ tal- massa b’ 14C- darunavir ma ’ ritonavir wera li bejn wieħed u ieħor 7. 7% tad- doża ta ’ darunavir amministrata titneħħa fl- awrina mingħajr ma tinbidel.
Although darunavir has not been studied in patients with renal impairment, population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV infected patients with moderate renal impairment (CrCl between 30-60 ml/min, n=20) (see sections 4.2 and 4.4).
21 Għalkemm darunavir ma ġiex studjat fil- pazjenti b’ indeboliment renali, analiżi farmakokinetika ta ’ popolazzjoni wriet li l- farmakokinetika ta ’ darunavir m’ hijiex affettwata sinifikament fil- pazjenti infettati bl- HIV u li għandhom indeboliment renali moderat (CrCl bejn 30 - 60 ml/ min, n=20) (ara sezzjonijiet 4. 2 u 4. 4).
Hepatic impairment Darunavir is primarily metabolised and eliminated by the liver.
Indeboliment epatiku Darunavir huwa primarjament metabolizzat u eliminat mill- fwied.
In a multiple dose study with PREZISTA co-administered with ritonavir (600/100 mg) twice daily, it was demonstrated that the total plasma concentrations of darunavir in subjects with mild (Child-Pugh Class A, n=8) and moderate (Child-Pugh Class B, n=8) hepatic impairment were comparable with those in healthy subjects.
Fi studju b’ dożi multipli ta ’ PREZISTA amministrat flimkien ma ’ ritonavir (600/ 100 mg) darbtejn kuljum, intwera bil- provi li l - konċentrazzjonijiet totali ta ’ darunavir fil- plażma f’ individwi b’ indeboliment epatiku ħafif (Child- Pugh Klassi A, n=8) u moderat (Child- Pugh Klass B, n=8) kienu kumparabbli ma dawk ta ’ individwi b’ saħħithom.
However, unbound darunavir concentrations were approximately 55% (Child-Pugh Class A) and 100% (Child-Pugh Class B) higher, respectively.
Madankollu, konċentrazzjonijiet ta ’ darunavir mhux imwaħħla mal- proteini kienu bejn wieħed u ieħor 55% (Child- Pugh Klassi A) u 100% (Child- Pugh Klassi B) ogħla rispettivament.
The clinical relevance of this increase is unknown therefore, PREZISTA should be used with caution.
Ir- rilevanza klinika ta ’ din iż- żieda m’ hijiex magħrufa għalhekk PREZISTA għandu jintuża b’ attenzjoni.
The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been studied (see sections 4.2, 4.3 and 4.4).
L- effett ta ’ indeboliment epatiku serju fuq il- farmakokinetika ta ’ darunavir għadu ma ġiex studjat (ara sezzjonijiet 4. 2, 4. 3 u 4. 4).
Animal toxicology studies have been conducted at exposures up to clinical exposure levels with darunavir alone, in mice, rats and dogs and in combination with ritonavir in rats and dogs.
Studji tossikoloġiċi fil- bhejjem saru f’ esponimenti sal- livelli ta ’ esponiment kliniku b’ darunavir waħdu fil- ġrieden, il- firien u l- klieb u flimkien ma’ ritonavir fil- firien u l- klieb.
In repe ated-dose toxicology studies in mice, rats and dogs, there were only limited effects of treatment with darunavir.
Fi studji tossikoloġiċi b’ doża ripetuta fil- ġrieden, il- firien u l- klieb, kien hemm biss effetti limitati tat - trattament b’ darunavir.
In rodents the target organs identified were the haematopoietic system, the blood coagulation system, liver and thyroid.
F’ annimali gerriema l- organi mimsusa identifikati kienu s- sistema ematopoietika, is- sistema tat- tgħaqqid tad- demm, il- fwied u t- tirojde.
A variable but limited decrease in red blood cell-related parameters was observed, together with increases in activated partial thromboplastin time.
Tnaqqis varjabbli iżda limitat kien osservat fil- parametri li għandhom x’ jaqsmu maċ- ċelluli ħomor tad- demm, flimkien ma ’ żieda fil- ħin parzjali tat- tromboplastin attivat.
Changes were observed in liver (hepatocyte hypertrophy, vacuolation, increased liver enzymes) and thyroid (follicular hypertrophy).
Bidliet ġew osservati fil- fwied (ipertrofija ta ’ l- epatoċiti, vakwolazzjoni, żieda fl- enzimi tal - fwied) u t- tirojde (ipertrofija follikulari).
In the rat, the combination of darunavir with ritonavir lead to a small increase in effect on RBC parameters, liver and thyroid and increased incidence of islet fibrosis in the pancreas (in male rats only) compared to treatment with darunavir alone.
Fil- far, it- taħlita ta ’ darunavir ma ’ ritonavir wasslet għal żieda żgħira fl- effett fuq il- parametri taċ- ċelluli ħomor, tal- fwied, u tat- tirojde u żieda fl- inċidenza ta ’ fibrożi fl - iżoli tal- frixa (fil- firien irġiel biss) meta mqabbla ma ’ trattament b’ darunavir waħdu.
In the dog, no major toxicity findings or target organs were identified up to exposures equivalent to clinical exposure at the recommended dose.
Fil- kelb, l- ebda sejbiet ta ’ tossiċità maġġuri jew organi mimsusa ma ’ kienu identifikati sa esponimenti ekwivalenti għal esponiment kliniku fid- doża rrakkomandata.
In a study conducted in rats, the number of corpora lutea and implantations were decreased in the presence of maternal toxicity.
Fi studju li sar fil- firien, in- numru ta ’ corpora lutea u implantazzjonijiet kienu mnaqqsa fil- preżenza ta ’ tossiċità ta ’ l- omm.
Otherwise, there were no effects on mating or fertility with darunavir treatment up to 1,000 mg/kg/day and exposure levels below (AUC-0.5 fold) of that in human at the clinically recommended dose.
Mill’ bqija, ma kienx hemm effetti fuq tgħammir u fertilità bi trattament ta ’ darunavir sa 1, 000 mg/ kg/ ġurnata u b’ livelli ta ’ esponiment anqas minn (AUC - 0. 5 drabi) dawk fil - bnedmin fid- doża rakkomandata klinikament.
The
Sa l- istess livelli tad- doża, ma kien hemm l- ebda ’ teratoġeniċità fil- firien u l- fniek bi trattament ta ’ darunavir waħdu u lanqas fil- ġrieden bi trattament ta ’ ritonavir flimkien miegħu.
20 exposure levels were lower than those with the recommended clinical dose in humans.
Il- livelli ta ’ esponiment kienu anqas minn dawk bid- doża klinikament rakkomandata fil- bnedmin.
In a pre- and postnatal development assessment in rats, darunavir with and without ritonavir, caused a transient reduction in body weight gain of the offspring pre-weaning and there was a slight delay in the opening of eyes and ears.
Fi stima ta ’ żvilupp fil- firien qabel u wara t- twelid, darunavir ma ’ jew mingħajr ritonavir, ikkawża tnaqqis għaddieni fiż- żieda fil- piż tal- ġisem qabel il- ftim u kien hemm ftit dewmien sakemm infetħu l- għajnejn u l- widnejn.
Darunavir in combination with ritonavir caused a reduction in the number of pups that exhibited the startle response on day 15 of lactation and a reduced pup survival during lactation.
Darunavir flimkien ma ’ ritonavir ikkawża tnaqqis fin- numru ta’ frieħ li wrew ir- rispons għall- ħasda fil- 15- il ġurnata ta ’ treddiegħ u naqqas is - soppravivenza tal- frieħ waqt it- treddiegħ.
These effects may be secondary to pup exposure to the active substance via the milk and/or maternal toxicity.
Dawn l- effetti jistgħu jkunu sekondarji għall- esponiment tal - frieħ għas- sustanza attiva mill- ħalib u/ jew tossiċità ta ’ l- omm.
No post weaning functions were affected with darunavir alone or in combination with ritonavir.
L- ebda funzjonijiet wara l- ftim ma kienu affetwati minn darunavir waħdu jew flimkien ma ’ ritonavir.
In juvenile rats receiving darunavir up to days 23-26, increased mortality was observed with convulsions in some animals.
Fil- firien żgħażagħ li kienu qed jirċievu darunavir sal- ġranet 23- 26, kienet osservata mortalità ogħla b’ konvulżjonijiet f’ xi wħud mill - annimali.
Exposure in plasma, liver and brain was considerably higher than in adult rats after comparable doses in mg/kg between days 5 and 11 of age.
Esponiment fil- plażma, fil- fwied u fil- moħħ kien konsiderevolment ogħla milli fil- firien adulti wara dożi komparabbli f’ mg/ kg bejn l- età ta ’ 5 u 11- il jum.
After day 23 of life, the exposure was comparable to that in adult rats.
Wara t- 23 jum ta ’ ħajja, l - esponiment kien komparabbli ma dak ta ’ firien adulti.
The increased exposure was likely at least partly due to immaturity of the drug-metabolising enzymes in juvenile animals.
Iż- żieda fl- esponiment, x’ aktarx ta ’ l- anqas parti minnha, kienet minħabba l- immaturutà ta ’ l- enżemi li jimmetabolizzaw il- mediċina fl- annimali żgħażagħ.
No treatment related mortalities were noted in juvenile rats dosed at 1,000 mg/kg darunavir (single dose) on day 26 of age or at 500 mg/kg (repeated dose) from day 23 to 50 of age, and the exposures and toxicity profile were comparable to those observed in adult rats.
L- ebda mortalitajiet relatati mal- kura ma ġew innutati fil- firien żgħażagħ li ngħataw doża ta ’ 1, 000 mg/ kg darunavir (doża waħda) ta ’ 26 ġurnata jew 500mg/ kg (doża ripetuta) mill- età ta ’ 23 sa 50 ġurnata, u l- esponimenti u l- profil ta ’ tossiċità kienu komparabbli ma ’ dawk osservati f’ firien adulti.
In humans, the activity of drug-metabolising enzymes approaches adult values by 1 to 3 years of age.
Fil- bnedmin, l- attività ta ’ l- enżemi li jimmetabolizzaw il- mediċina toqrob il- valuri ta ’ l- adulti sa l- età ta ’ bejn 1 u 3 snin.