qanastek/EMEA-V3 huggingface dataset:
All patients had received at least two PI-based antiretroviral regimens and were failing a PI-based regimen at the time of study entry.
Il- pazjenti kollha kienu ngħataw mill- anqas żewġ trattamenti antiretrovirali bbażati fuq l- impedituri tal- protease (PI), u meta bdew f’ dan l- istudju fallilhom trattament ibbażat fuq l- impedituri tal- protease.
At least one primary protease gene mutation from among 30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M had to be present at baseline, with not more than two mutations on codons 33, 82, 84 or 90.
Mill- anqas mutazzjoni ewlenija waħda fil- gene tal- protease minn fost 30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V jew 90M kellha tkun preżenti fil- linja ta ’ referenza bażi, b’ mhux aktar minn żewġ mutazzjonijiet fuq codons 33, 82, 84 jew 90.
After Week 8, patients in the comparator arm who met the protocol defined criteria of initial lack of virologic response had the option of discontinuing treatment and switching over to APTIVUS/ ritonavir in a separate roll-over study.
Wara Ġimgħa 8, pazjenti bil- komparatur li ssodisfaw il- parametri mfissra fil- protokoll ta 'nuqqas inizjali ta' rispons viroloġiku kellhom l- għażla li jew jieqfu mit- trattament jew iduru fuq studju roll- over separat ta 'APTIVUS/ ritonavir.
The 1483 patients included in the primary analysis had a median age of 43 years (range 17-80), were 86% male, 75% white, 13% black and 1% Asian.
L- 1483 pazjent inklużi fl- analiżi temporanja primarja, kienu ta ’ età medja ta ’ 43 sena (firxa ta 'bejn 17- 80), fejn minnhom 86% kienu irġiel, 75% bojod, 13% suwed u 1% Asjatiċi.
In the APTIVUS and comparator arms median baseline CD4 cell counts were 158 and 166 cells/ mm3, respectively, (ranges 1-1893 and 1-1184 cells/ mm3); median baseline plasma HIV-1 RNA was 4.79 and 4.80 log10 copies/ ml, respectively (ranges 2.34-6.52 and 2.01-6.76 log10 copies/ ml).
Fil- grupp ta ’ APTIVUS u dak komparattiv, il- linja bażi ta ’ referenza medja ta ’ l- għadd ta ’ ċelluli ta 'CD4 kienet ta ’ 158 u 166 ċelluli/ mm3, rispettivament, (fuq firxa ta' bejn 1- 1893 u 1- 1184 ċelluli/ mm3); il- valur
Patients had prior exposure to a median of 6 NRTIs, 1 NNRTI, and 4 PIs.
Il- pazjenti kellhom espożizzjoni minn qabel għal medjan ta '6 NRTIs, 1 NNRTI, u 4 PIs.
In both studies, a total of 67% patient viruses were resistant and 22% were possibly resistant to the pre-selected comparator PIs.
Fiż- żewġ studji, total ta '67% viruses ta' pazjenti kienu reżistenti u 22% kienu possibilment reżistenti għal PIs komparaturi magħżula minn qabel.
A total of 10% of patients had previously used enfuvirtide.
B' kollox 10% tal- pazjenti kienu użaw enfuvirtide qabel.
With respect to mutations on codons 33, 82, 84 and 90 approximately 4% had no mutations, 24% had mutations at
D30N, L33F/ I, V46I/ L, G48V, I50V, V82A/ F/ T/ L, I84V, u L90M.
18 codons 82 (less than 1% of patients had the mutation V82L) and 90, 18% had mutations at codons 84 and 90 and 53% had at least one key mutation at codon 90.
Fir- rigward ta 'mutazzjonijiet fil- codons 33, 82, 84 u 90 madwar 4% ma kellhomx mutazzjonijiet, 24% kellhom mutazzjonijiet f' codons 82 (inqas minn 1% tal- pazjenti kellhom mutazzjoni f' V82L) u 90, 18% kellhom mutazzjonijiet f' codons 84 u 90 u 53% kellhom ta' lanqas mutazzjoni ewlenija f' codon 90.
One patient in the APTIVUS arm had four mutations.
Pazjent wieħed li kien qed jieħu APTIVUS kellu erba 'mutazzjonijiet.
In addition the majority of participants had mutations associated with both NRTI and NNRTI resistance.
Barra minn hekk il- maġġoranza tal- parteċipanti kellhom mutazzjonijiet assoċjati kemm ma 'reżistenza ta' NRTI u NNRTI.
Baseline phenotypic susceptibility was evaluated in 454 baseline patient samples.
Suxxetibilità fenotipika ta 'riferiment bażi ġiet evalwata f' 454 kampjun ta' pazjent ta 'riferiment bażi.
There was an average decrease in susceptibility of 2-fold wild type (WT) for tipranavir, 12-fold WT for amprenavir, 55-fold WT for atazanavir, 41-fold WT for indinavir, 87-fold WT for lopinavir, 41- fold WT for nelfinavir, 195-fold WT for ritonavir, and 20-fold WT for saquinavir.
Kien hemm tnaqqis medju fis- suxxettibilità ta 'darbtejn għat- tip selvaġġ (WT) għal tipranavir, 12- il darba għal amprenavir, 55 darba WT għal atazanavir, 41 darba WT għal indinavir, 87 darba WT għal lopinavir, 41 darba WT ghal nelfinavir, 195 darba WT għal ritonavir u 20 darba WT għal saquinavir.
Combined 48-week treatment response (composite endpoint defined as patients with a confirmed ≥ 1 log RNA drop from baseline and without evidence of treatment failure) for both studies was 34% in the APTIVUS/ ritonavir arm and 15% in the comparator arm.
Rispons ta 'trattament kombinat ta ’ 48 ġimgħa (Endpoint komposta hija mfissra hekk kif il- pazjenti jkunu kkonfermati b ’ ≥1 log RNA li taqa ’ mil- linja ta ’ referenza bażi u mingħajr ħjiel li t- trattament ifalli) għaż- żewġ studji kienu 34% bl- użu ta ’ APTIVUS/ ritonavir u 15% bil- komparatur.
Treatment response is presented for the overall population (displayed by enfuvirtide use), and detailed by PI strata for the subgroup of patients with genotypically resistant strains in the Table below.
Ir- rispons għat- trattament hu preżentat għall- popolazzjoni globali (murija bl- użu ta 'enfuvirtide), u dettaljata bi strata ta' PI għas- sottogrupp ta 'pazjenti b' razez ġenotipikament reżistenti fit- Tabella hawn isfel.
Treatment response* at week 48 (pooled studies RESIST-1 and RESIST-2 in treatment- experienced patients)
Riżultati tar- rispons għat- trattament * f' ġimgħa 48 (pazjenti b' esperjenza fi trattamenti fl- istudji RESIST- 1 u RESIST- 2)
RESIST study
studju RESIST
Overall population
Popolazzjoni globali
FAS PP - with ENF (FAS) - without ENF (FAS) Genotypically Resistant LPV/ rtv
- b' ENF (FAS)
255 (34.2) 171 (37.7) 85 (50.0) 170 (29.5)
85 (50. 0)
114 (15.5) 74 (17.1) 28 (20.7) 86 (14.3)
28 (20. 7)
< 0.0001 < 0.0001 < 0.0001 < 0.0001
< 0. 0001
66 (28.9) 47 (32.2)
47 (32. 2)
23 (9.5) 13 (9.1)
13 (9. 1)
50 (33.3) 38 (39.2)
50 (33. 3)
22 (14.9) 17 (18.3)
22 (14. 9)
< 0.0001 0.0010
0. 0010 < 0. 0001
22 (30.6) 11 (28.2)
11 (28. 2)
5 (7.0) 2 (5.7)
2 (5. 7)
< 0.0001 0.0650
0. 0650
6 (46.2) 3 (50.0)
6 (46. 2) 34 (50. 0)
1 (5.3) 1 (7.1)
1 (5. 3) 1 (7. 1)
* Composite endpoint defined as patients with a confirmed 1 log RNA drop from baseline and without evidence of treatment failure ** Comparator PI/ RTV:
* Endpoint komposta hija mfissra hekk kif il- pazjenti jkunu kkonfermati b’ 1 log RNA li taqa ’ mill - linja ta ’ referenza bażi u mingħajr ħjiel li t- trattament ifalli ** PI/ RTV komparatur:
LPV/ r 400/ 100 mg bid (n=358), IDV/ r 800/ 100 mg bid (n=23), SQV/ r 1000/ 100 mg bid or 800/ 200 mg bid (n=162), APV/ r 600/ 100 mg bid (n=194) ENF Enfuvirtide; FAS Full Analysis Set; PP Per Protocol; APV/ rtv Amprenavir/ ritonavir; IDV/ rtv Indinavir/ ritonavir; LPV/ rtv Lopinavir/ ritonavir; SQV/ rtv Saquinavir/ ritonavir
LPV/ r 400/ 100 mg bid (n=358), IDV/ r 800/ 100 mg bid (n=23), SQV/ r 1000/ 100 mg bid jew 800/ 200 mg bid (n=162), APV/ r 600/ 100 mg bid (n=194) ENF Enfurvirtide; FAS Full Analysis Set; PP Per Protocol; APV/ rtv Amprenavir/ ritonavir; IDV/ rtv Indinavir/ ritonavir; LPV/ rtv Lopinavir/ ritonavir; SQT/ rtv Saquinavir/ ritonavir
Combined 48-week median time to treatment failure for both studies was 115 days in the APTIVUS/ ritonavir arm and 0 days in the comparator arm (no treatment response was imputed to day 0).
19 Ħin medjan ikkombinat ta ’ 48 ġimgħa għal falliment fit- trattament għaż- żewġ studji kien ta ’ 115- il jum fid- driegħ ta ’ APTIVUS/ ritonavir u 0 t’ jiem għad- driegħ komparatur (l- ebda rispons għat - trattament ma ġie imputat fil- jum 0)
Through 48 weeks of treatment, the proportion of patients in the APTIVUS/ ritonavir arm compared to the comparator PI/ ritonavir arm with HIV-1 RNA < 400 copies/ ml was 30% and 14% respectively, and with HIV-1 RNA < 50 copies/ ml was 23% and 10% respectively.
Fi 48 ġimgħa ta 'trattament, il- proporzjon ta' pazjenti li użaw APTIVUS/ ritonavir meta mqabbel mal - komparatur ta 'PI/ ritonavir b' HIV- 1 RNA < 400 kopji/ ml kien ta' 30% u 14% rispettivament, u b' HIV- 1 RNA < 50 kopji/ ml kien 23% u 10% rispettivament.
Among all randomised and treated patients, the median change from baseline in HIV-1 RNA at the last measurement up to Week 48 was -0.64 log10 copies/ ml in patients receiving APTIVUS/ ritonavir versus -0.22 log10 copies/ ml in the comparator PI/ ritonavir arm.
Fost il- pazjenti kollha magħżula bl- addoċċ u trattati, il- bidla medja mil- livell ta 'riferiment bażi f' HIV- 1 RNA fl- aħħar kejl sa Ġimgħa 48 kien - 0. 64 log10 kopji/ ml f' pazjenti li jirċievu APTIVUS/ ritonavir kontra - 0. 22 log10 kopji/ ml li ngħataw il- komparatur ta' PI/ ritonavir.
19 Among all randomised and treated patients, the median change from baseline in CD4+ cell count at the last measurement up to Week 48 was +23 cells/ mm3 in patients receiving APTIVUS/ ritonavir (N=740) versus +4 cells/ mm3 in the comparator PI/ ritonavir (N=727) arm.
Fost il- pazjenti kollha li ntagħżlu bl- addoċċ u li ġew trattati, il- bidla medjan mil- livell ta 'riferiment fl- għadd ta' ċelluli ta 'CD4+ mill- aħħar kejl sa Ġimgħa 48 kien ta' +23 ċelluli/ mm3 f' pazjenti li qed jirċievu APTIVUS/ ritonavir (N=740) kontra +4 ċelluli/ mm3 f’ pazjenti bil- komparatur PI/ ritonavir (N=727).
The superiority of APTIVUS co-administered with low dose ritonavir over the comparator protease inhibitor/ ritonavir arm was observed for all efficacy parameters at week 48.
Is- superjorità ta 'APTIVUS, mogħti flimkien ma' doża baxxa ta 'ritonavir fuq il- komparatur, impeditur tal- protease/ ritonavir kien osservat fuq il- parametri ta' effikaċja kollha f' ġimgħa 48.
It has not been shown that APTIVUS is superior to these boosted comparator protease inhibitors in patients harbouring strains susceptible to these protease inhibitors.
Ma ntweriex li APTIVUS huwa superjuri għal dawn l- impedituri tal- protease tal- komparatur mqawwija f' pazjenti li fihom hemm razez suxxetibbli għal dawn l- impedituri tal- protease.
RESIST data also demonstrate that APTIVUS co- administered with low dose ritonavir exhibits a better treatment response at 48 weeks when the OBR contains genotypically available antiretroviral agents (eg enfuvirtide).
Id- dejta minn RESIST turi wkoll li meta APTIVUS jiġi mogħti flimkien ma 'doża baxxa ta' ritonavir ikun hemm rispons għat- trattament aħjar fl- 48 ġimgħa meta l- OBR ikun fih mediċini ġenotipiċi antiretrovirali disponibbli (eg enfuvirtide).
At present there are no results from controlled trials evaluating the effect of APTIVUS on clinical progression of HIV.
Attwalment, m’ hemmx riżultati minn provi kkontrollati li jevalwaw l- effett ta ’ APTIVUS fuq kif jiżviluppa klinikament l- HIV.
Analyses of tipranavir resistance in treatment experienced patients:
Analiżi ta ’ reżistenza għal tipranavir f’ pazjenti li kienu diġà trattati qabel:
APTIVUS/ ritonavir response rates in the RESIST studies were assessed by baseline tipranavir genotype and phenotype.
Ir- rati ta ’ rispons ta ’ APTIVUS/ ritonavir fl- istudju RESIST ġew assessjati skond il- linja ta ’ riferiment ġenotipiku u fenotipiku ta ’ tipranavir.
Relationships between baseline phenotypic susceptibility to tipranavir, primary PI mutations, protease mutations at codons 33, 82, 84 and 90, tipranavir resistance-associated mutations, and response to APTIVUS/ ritonavir therapy were assessed.
Ir- relazzjonijiet bejn is- suxxetibilità fenotipika ta ’ riferiment għal tipranavir, il- mutazzjonijiet primarji ta ’ PI, mutazzjonijiet tal- protease f’ kodons 33, 82, 84 u 90, il- mutazzjonijiet assoċjati mar- reżistenza ta ’ tipranavir, u r- rispons għat- terapija ta ’ APTIVUS/ ritonavir ġew assessjati.
Of note, patients in the RESIST studies had a specific mutational pattern at baseline of at least one primary protease gene mutation among codons 30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M, and no more than two mutations on codons 33, 82, 84 or 90.
Ta ’ min jinnota, il- pazjenti fl- istudji RESIST kellhom skema ta ’ mutazzjoni speċifika fil- linja ta ’ riferiment ta ’ mil- lanqas mutazzjoni primarja waħda ta ’ ġene fost kodons 30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V jew 90M, u mhux aktar minn żewġ mutazzjonijiet fuq kodons 33, 82, 84 jew 90.
The following observations were made:
Saru l- osservazzjonijiet li ġejjin:
− Primary PI mutations:
- Mutazzjonijiet primarji ta ’ PIs
Analyses were conducted to assess virological outcome by the number of primary PI mutations (any change at protease codons 30, 32, 36, 46, 47, 48, 50, 53, 54, 82, 84, 88 and 90) present at baseline.
Analiżi sar ukoll sabiex jassessja ukoll l- eżitu viroloġiku skond l- għadd ta 'mutazzjonijiet primarji ta' PIs (kull bidla fil- protease codons 30, 32, 36, 46, 47, 48, 50, 53, 54, 82, 84, 88 u 90) preżenti fil- livell ta 'riferiment bażi.
Response rates were higher in APTIVUS/ ritonavir patients than comparator PI boosted with ritonavir in new enfuvirtide patients, or patients without new enfuvirtide.
Ir- rati ta 'rispons kienu ogħla fil- pazjenti li qegħdin fuq APTIVUS/ ritonavir milli fil- mediċina ta ’ tqabbil msaħħa b’ ritonavir f’ pazjenti fuq enfuvirtide ġdid, jew pazjenti mingħajr enfuvirtide ġdid.
However, without new enfuvirtide some patients began to lose antiviral activity between weeks 4 and 8.
Madankollu, mingħajr enfuvirtide ġdid xi pazjenti bdew jitilfu l- attività antivirali bejn il- ġimgħat 4 u 8
− Mutations at protease codons 33, 82, 84 and 90:
- Mutazzjonijiet f’ protease codons 33, 82, 84 u 90:
A reduced virological response was observed in patients with viral strains harbouring two or more mutations at HIV protease codons 33, 82, 84 or 90, and not receiving new enfuvirtide.
Tnaqqis fir- rispons viroloġiku ġie osservat f’ pazjenti b’ razez virali li għandhom żewġ mutazzjonijiet jew aktar fil- codons tal- protease ta ’ HIV 33, 82, 84 jew 90, u li mhux qed jirċievu enfuvirtide ġdid.
− Tipranavir resistance-associated mutations:
- Mutazzjonijiet assoċjati ma ’ reżiztenza għal Tipranavir:
Virological response to APTIVUS/ ritonavir therapy has been evaluated using a tipranavir-associated mutation score based on baseline genotype in RESIST-1 and RESIST-2 patients.
Rispons viroloġiku għal terapija b' APTIVUS/ ritonavir ġiet evalwata permezz ta ’ punteġġ ta ’ suxxetibilità assoċjat ma ’ tipranavir msejjes fuq ġenotip fil- livell ta 'riferiment bażi f' pazjenti b' esperjenza fit- trattament li ipparteċipaw fil- provi ta' RESIST- 1 u RESIST- 2.
This score (counting the 16 amino acids that have been associated with reduced tipranavir susceptibility and/ or reduced viral load response:
Dan il- punteġġ (li jgħodd 16- il aċidu amminiku huwa assoċjat ma ’ tnaqqis fis- suxxettibblità għal tipranavir u/ jew tnaqqis ta ’ 24 ġimgħa fl- għadd tal- viruses:
10V, 13V, 20M/ R/ V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/ M/ V, 58E, 69K, 74P, 82L/ T, 83D and 84V) was applied to baseline viral protease sequences.
10V, 13V, 20M/ R/ V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/ M/ V,
A correlation between the tipranavir mutation score and response to APTIVUS/ ritonavir therapy at week 48 has been established.
Ġiet stabbilita korrelazzjoni bejn il- punteġġ ta 'suxxetibilità ta' tipranavir u r- rispons għat- terapija ta 'APTIVUS/ ritonavir f' ġimgħa 48.
This score has been determined from the selected RESIST patient population having specific mutation inclusion criteria and therefore extrapolation to a wider population mandates caution.
Dan il- punteġġ ġie stabbilit mill- popolazzjoni magħżula ta ’ pazjenti fil- prova RESIST li għandha kriterja ta ’ mutazzjoni speċifika ta ’ inklużjoni u għalhekk l- ekstrapolazzjoni għal popolazzjoni aktar wiesgħa teħtieġ attenzjoni
At 48-weeks, a higher proportion of patients receiving APTIVUS/ ritonavir achieved a treatment response in comparison to the comparator protease inhibitor/ ritonavir for nearly all of the possible combinations of genotypic resistance mutations (see table below).
Fit- 48 ġimgħa, proporzjon ogħla ta 'pazjenti li jirċievu APTIVUS / ritonavir, laħqu rispons għat - trattament li jitqabbel ma ’ l- impeditur tal- protease/ ritonavir tal- komparatur għal kważi l- kombinazzjonijiet kollha possibbli ta' mutazzjonijiet ta ’ reżistenza ġenotipika.
20 Proportion of patients achieving treatment response at Week 48 (confirmed ≥ 1 log10 copies/ ml decrease in viral load compared to baseline), according to tipranavir baseline mutation score and enfuvirtide use in RESIST patients
Il- proporzjon ta ’ pazjenti li jiksbu rispons għat- trattament f’ Ġimgħa 48 (tnaqqis ikkonfermat fil- viral load ta ’ ≥1 log10/ kopji/ ml meta mqabbel mal- linja ta ’ riferiment bażi), skond il- punteġġ ta ’ suxxetibilità ta ’ riferiment bażi u l- użu ta ’ enfuvirtide f’ pazjenti fil- provi RESIST
New ENF
ENF ġdid
No New ENF*
L- ebda
Number of TPV Score Mutations**
ENF * ġdid L- għadd ta ’ Punteġġi TPV għas - Suxxetibilità **
0,1 2 3 4 ≥ 5 All patients
0, 1 2 3 4 ≥5 Pazjenti kollha
* Includes patients who did not receive ENF and those who were previously treated with and continued ENF **Mutations in HIV protease at positions L10V, I13V, K20M/ R/ V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/ M/ V, 58E, H69K, T74P, V82L/ T, N83D or I84V ENF Enfuvirtide; TPV/ r Tipranavir/ ritonavir
* Jinkludi pazjenti li ma rċevewx ENF u dawk li qabel kienu ttrattati bi u kontinwament b’ ENF ** Mutazzjonijiet f’ HIV protease fil- pożizzjonijiet L10V, I13V, K20M/ R/ V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/ M/ V, 58E, H69K, T74P, V82L/ T, N83D jew I84V ENF Enfuvirtide; TPV/ r Tipranavir/ ritonavir
Sustained HIV-1 RNA decreases up to week 48 were mainly observed in patients who received APTIVUS/ ritonavir and new enfuvirtide.
Tnaqqis sostnut ta 'HIV- 1 RNA sa Ġimgħa 48 kien osservat f' pazjenti li ħadu APTIVUS/ ritonavir u enfuvirtide ġdid.
If patients did not receive APTIVUS/ ritonavir with new enfuvirtide, diminished treatment responses at week 48 were observed, relative to new enfuvirtide use (see Table below).
Jekk il- pazjenti ma rċevewx APTIVUS/ ritonavir ma enfuvirtude ġdid, deher tnaqqis fir- rispons f ’ Ġimgħa 48, meta mqabbel ma ’ l- użu ta ’ enfuvirtide ġdid (Ara Tabella isfel).
Mean decrease in viral load from baseline to week 48, according to tipranavir baseline mutation score and enfuvirtide use in RESIST patients
Tnaqqis medju fil- viral load mil- livell ta ’ riferiment sa ġimgħa 48, skond il- punteġġ ta ’ riferiment bażi dwar mutazzjonijiet għal tipranavir u l- użu ta ’ enfuvirtide f’ pazjenti fil- provi ta ’ RESIST.
0, 1 2 3 4 ≥ 5 All patients
0, 1 2 3 4 ≥5
-2.3 -2.1 -2.4 -1.7 -1.9 -2.0
- 2. 3 - 2. 1 - 2. 4 - 1. 7 - 1. 9
-1.6 -1.1 -0.9 -0.8 -0.6 -1.0
- 1. 6 - 1. 1 - 0. 9 - 0. 8 - 0. 6
* Includes patients who did not receive ENF and those who were previously treated with and continued ENF ** **Mutations in HIV protease at positions L10V, I13V, K20M/ R/ V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/ M/ V, 58E, H69K, T74P, V82L/ T, N83D or I84V ENF Enfuvirtide; TPV/ r Tipranavir/ ritonavir
21 ** Mutazzjonijiet f’ HIV protease fil- pożizzjonijiet L10V, I13V, K20M/ R/ V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/ M/ V, 58E, H69K, T74P, V82L/ T, N83D jew I84V ENF Enfuvirtide; TPV/ r Tipranavir/ ritonavir
− Tipranavir phenotypic resistance:
- Reżistenza fenotipika għal tipanavir:
Increasing baseline phenotypic fold change to tipranavir in isolates is correlated to decreasing virological response.
Żieda fil- bidla tal- linja bażi ta ’ riferiment fenotipiku għal tipranavir f’ kampjuni iżolati hija korrelata ma tnaqqis fir- rispons viroloġiku.
Isolates with baseline fold change of > 0 to 3 are considered susceptible; isolates with > 3 to 10 fold changes have decreased susceptibility; isolates with > 10 fold changes are resistant.
Kampjuni iżolati b’ bidla fil- linja ta ’ riferiment ta ’ bejn > 0 sa 3 huma kkonsidrati suxxetibbli: kampjuni iżolati b’ bidla ta ’ bejn > 3 sa 10 għandhom suxxetibilità mnaqqsa; Kampjuni iżolati b’ bidliet ta ’ > 10huma reżistenti.
Conclusions regarding the relevance of particular mutations or mutational patterns are subject to change with additional data, and it is recommended to always consult current interpretation systems for analysing resistance test results.
Konklużjonijiet dwar ir- rilevanza ta 'mutazzjonijiet partikolari jew skemi mutazzjonali huma suġġetti għal bidla skond dejta addizzjonali pendenti, u huwa rakkomandat li dejjem għandek tikkonsulta sistemi ta ’ interpretazzjoni attwali meta tiġi biex tanalizza riżultati ta ’ testijiet ta ’ reżistenza.
In order to achieve effective tipranavir plasma concentrations and a twice daily dosing regimen, coadministration of tipranavir with low dose ritonavir twice daily is essential (see section 4.2).
5. 2 Tagħrif farmakokinetiku
Ritonavir acts by inhibiting hepatic cytochrome P450 CYP3A, the intestinal P-glycoprotein (Pgp) efflux pump and possibly intestinal cytochrome P450 CYP3A as well.
Ritonavir jaġixxi billi jimpedixxi ċ- ċitokroma epatika P450 CYP3A, P- glycoprotein (Pgp) efflux pump ta ’ l- imsaren u possibbilment ċ- ċitokroma ta ’ l- imsaren P450 CYP3A ukoll.
As demonstrated in a dose- ranging evaluation in 113 HIV-negative healthy male and female volunteers, ritonavir increases AUC0- 12h, Cmax and Cmin and decreases the clearance of tipranavir.
Prova b’ diversi dożi fuq 113- il voluntiera rġiel u nisa f’ saħħithom, li rriżultaw negattivi għal HIV, uriet li ritonavir iżid l- AUC 0- 12h, Cmax and Cmin u jnaqqas ir- rata ta ’ l- eliminazzjoni totali mill- ġisem ta ’ tipranavir.
Tipranavir co-administered with low dose ritonavir (500 mg/ 200 mg twice daily) was associated with a 29-fold increase in the geometric mean morning steady-state trough plasma concentrations compared to tipranavir 500 mg twice daily without ritonavir.
Meta tipranavir jingħata flimkien ma ’ doża baxxa ta 'ritonavir (500 mg/ 200 mg darbtejn kuljum), dan kien assoċjat ma ’ żieda ta ’ 29 darba fil- medja ġeometrika fissa tal- konċentrazzjoni ta ’ tipranavir fil- plażma ta ’ fil- għodu, meta mqabbel ma ’ doża ta ’ 500 mg mogħtija darbtejn kuljum mingħajr ritonavir.
Absorption of tipranavir in humans is limited, though no absolute quantification of absorption is available.
L- assorbiment ta ’ tipranavir fil- bniedem huwa limitat, għalkemm ma kienx kwantifikat b’ mod assolut.
Tipranavir is a Pgp substrate, a weak Pgp inhibitor and appears to be a potent Pgp inducer as well.
Tipranavir huwa sustrat ta 'Pgp, impeditur dgħajjef ta ’ Pgp u jidher li jista' jkun anke aġent induċenti ta ’ Pgp.
Data suggest that, although ritonavir is a Pgp inhibitor, the net effect of APTIVUS, co-administered with low dose ritonavir, at the proposed dose regimen at steady-state, is Pgp induction.
Id- dejta tissuġerixxi li, minkejja li ritonavir huwa impeditur ta 'PgP, l- effett nett ta' APTIVUS, mogħti flimkien ma 'doża baxxa ta' ritonavir, fir- reġimen tad- doża proposta fl- istat fiss, hu ta 'induzzjoni għal Pgp.
Peak plasma concentrations are reached within 1 to 5 hours after dose administration depending upon the dosage used.
L- ogħla konċentrazzjonijiet fil- plażma jintlaħqu f’ bejn siegħa u 5 sigħat wara li tkun ingħatat id- doża u skond il- qawwa tad- doża.
With repeated dosing, tipranavir plasma concentrations are lower than predicted from single dose data, presumably due to hepatic enzyme induction.
Meta jingħataw dożi ripetuti, il- konċentrazzjonijiet ta ’ tipranavir fil- plażma huma aktar baxxi minn dawk mistennija fuq doża waħda, aktarx minħabba s- sensitizzazzjoni ta ’ l- enżimi epatiċi.
Steady-state is attained in most subjects after 7 days of dosing.
L- istat fiss jinlaħaq fil- biċċa l- kbira tas- suġġetti, wara 7 t’ ijiem bit- trattament tad- doża.
Tipranavir, co-administered with low dose ritonavir, exhibits linear pharmacokinetics at steady state.
Meta tipranavir jingħata ma ’ ritonavir b’ doża baxxa, jkollu farmakokinetika lineari waqt stat fiss.
Dosing with APTIVUS 500 mg concomitant with 200 mg ritonavir twice daily for 2 to 4 weeks and without meal restriction produced a mean tipranavir peak plasma concentration (Cmax) of 94.8 ± 22.8 µM for female patients (n=14) and 77.6 ± 16.6 µM for male patients (n=106), occurring approximately 3 hours after administration.
Dożaġġ b' APTIVUS 500 mg flimkien ma '200 mg ritonavir darbtejn kuljum għal bejn ġimagħtejn sa 4 ġimgħat u mingħajr restrizzjoni ta' ikel irriżulta f' konċentrazzjoni medja l- aktar għolja ta 'tipranavir fil- plażma (Cmax) ta' 94. 8 ± 22. 8 µM għal pazjenti femminili (n=14) u 77. 6 ± 16. 6 µM għal pazjenti maskili (n=106), li seħħet f' madwar 3 sigħat wara t- teħid.
The mean steady-state trough concentration prior to the morning dose was 41.6 ± 24.3 µM for female patients and 35.6 ± 16.7 µM for male patients.
Il- konċentrazzjoni medja l- aktar baxxa ta 'l- istat fiss qabel id- doża ta' filgħodu kienet ta '41. 6 ± 24. 3 µM għal pazjenti nisa u 35. 6 ± 16. 7 µM għal pazjenti rġiel.
Tipranavir AUC over a 12 hour dosing interval averaged 851 ± 309 µM• h (CL=1.15 l/ h) for female patients and 710 ± 207 µM • h (CL=1.27 l/ h) for male patients.
L- AUC ta 'tipranavir fuq intervall medju ta' dożaġġ ta '12- il siegħa kienet ta' 851 ± 309 µM• h (CL=1. 15 l/ h) għal pazjenti nisa u 710 ± 207 µM• h (CL=1. 27 l/ h) għal pazjenti rġiel.
The mean half-life was 5.5 (females) or 6.0 hours (males).
Il- half- life medja kienet ta '5. 5 (nisa) jew 6. 0 sigħat (irġiel).
Effects of food on oral absorption:
L- effetti ta ’ l- ikel fuq l- assorbiment mill- ħalq:
Food improves the tolerability of tipranavir/ ritonavir.
L- ikel itejjeb it- tollerabilità ta 'tipranavir/ ritonavir.
Therefore APTIVUS, co-administered with low dose ritonavir, should be given with food.
Għalhekk APTIVUS, mogħti flimkien ma 'doża baxxa ta' ritonavir, għandu jingħata ma ’ l- ikel.
Data are awaited to substantiate the influence of food on oral absorption.
Dejta biex tissustanzja l- influwenza ta 'l- ikel fuq l- assorbiment orali għadha mistennija.
Absorption of tipranavir, co-administered with low dose ritonavir, is reduced in the presence of antacids (see section 4.5).
L- assorbiment ta 'tipranavir, mogħti flimkien ma' doża baxxa ta 'ritonavir, hu mnaqqas fil- preżenza ta' antaċidi (ara sezzjoni 4. 5).
Tipranavir is extensively bound to plasma proteins (> 99.9%).
Tipranavir jeħel b’ mod qawwi mal- proteini tal- plażma (> 99. 9%).
From clinical samples of healthy volunteers and HIV-1 positive subjects who received tipranavir without ritonavir the mean fraction of tipranavir unbound in plasma was similar in both populations (healthy volunteers 0.015% ± 0.006%; HIV-positive subjects 0.019% ± 0.076%).
Minn kampjuni kliniċi meta tipranavir ingħata mingħajr ritonavir, instab li kampjuni kliniċi meħuda minn voluntiera f’ saħħithom u pazjenti pożittivi għal HIV- 1, kellhom valur medju kważi l- istess, tal- proporzjon ta ’ tipranavir liberu fil- plażma (voluntiera f’ saħħithom 0. 015% ± 0. 006%; suġġetti pożittivi għal HIV
Total plasma tipranavir concentrations for these samples ranged from 9 to 82 µM.
Il- livelli totali ta ’ tipranavir fil- plażma f’ dawn il- kampjuni, kien bejn 9 u 82 µM.
The unbound fraction of tipranavir appeared to be independent of total drug concentration over this concentration range.
Il- proporzjon ta ’ tipranavir li ma jeħilx deher li ma jiddependix fuq l- konċentrazzjoni totali tal- mediċina fuq din il- firxa ta 'konċentrazzjonijiet.
No studies have been conducted to determine the distribution of tipranavir into human cerebrospinal fluid or semen.
Ma kienx hemm studji mwettqa sabiex tiġi stabbilita d- distribuzzjoni ta ’ tipranavir fil- fluwidu ċerebrospinali uman u s- semen.
In vitro metabolism studies with human liver microsomes indicated that CYP3A4 is the predominant CYP isoform involved in tipranavir metabolism.
Studji fuq il- metaboliżmu in vitro fuq mikrosomi tal- fwied uman, indikaw li CYP3A4 hija l- isoform prinċipali ta ’ CYP li tieħu sehem fil- metaboliżmu ta ’ tipranavir.
The oral clearance of tipranavir decreased after the addition of ritonavir which may represent diminished first-pass clearance of the drug at the gastrointestinal tract as well as the liver.
Ir- rata ta ’ l- eliminazzjoni mill- ġisem ta ’ meta jingħata tipranavir mill- ħalq, tonqos meta jingħata ma ’ ritonavir li jista ’ jikkaġuna tnaqqis fir- rata ta ’ l- eliminazzjoni first pass fis- sistema gastro- intestinali, kif ukoll fil- fwied.
The metabolism of tipranavir in the presence of low dose ritonavir is minimal.
Il- metaboliżmu ta 'tipranavir fil- preżenza ta' doża baxxa ta 'ritonavir hu minimu.
In a 14C-tipranavir human study (14C-tipranavir/ ritonavir, 500 mg/ 200 mg twice daily), unchanged tipranavir was predominant and accounted for 98.4% or greater of the total plasma radioactivity circulating at 3, 8, or
Studju fil- bniedem permezz ta '14C- tipranavir (14C- tipranavir/ ritonavir, 500 mg/ 200 mg, darbtejn kuljum), irriżulta li tipranavir mhux mibdul kien aktar predominanti u kien jammonta għal 98. 4% jew iżjed tar- radjuattività totali tal- plażma li kienet qed tiċċirkula 3, 8, jew 12- il siegħa wara li ttieħdet id- doża.
Only a few metabolites were found in plasma, and all were at trace levels (0.2% or less of the plasma radioactivity).
Kienu ftit wisq il- metaboliti li nstabu fil- plażma u dawn kienu f’ ammonti ta ’ traċċi (0. 2% jew anqas tar- radjuattività fil- plażma).
In faeces, unchanged tipranavir represented the majority of faecal radioactivity (79.9% of faecal radioactivity).
Fl- ippurgar, tipranavir mhux mibdul, kien jirrapreżenta l- biċċa l- kbira tar - radjuattività li kien hemm (79. 9% tar- radjuattività fl- ippurgar).
The most abundant faecal metabolite, at 4.9% of faecal radioactivity (3.2% of dose), was a hydroxyl metabolite of tipranavir.
L- aktar metabolit ta ’ tipranavir li nstab fl- ippurgar kien il- hydroxyl u ta riżultat ta ’ 4. 9% tar- radjuattivita ta ’ l- ippurgar (3. 2% tad- doża).
In urine, unchanged tipranavir was found in trace amounts (0.5% of urine radioactivity).
Instabu traċċi ta ’ tipranavir mhux mibdul fl- awrina (0. 5% tar- radjuattività fl- awrina).
The most abundant urinary metabolite, at 11.0% of urine radioactivity (0.5% of dose) was a glucuronide conjugate of tipranavir.
L- aktar metabolit abbundanti fl- awrina kien glucuronide conjugate li kien jirrapreżenta 11. 0% tar- radjuattività fl- awrina (0. 5% tad- doża).
Administration of 14C-tipranavir to subjects (n = 8) that received tipranavir/ ritonavir 500 mg/ 200 mg twice daily dosed to steady-state demonstrated that most radioactivity (median 82.3%) was excreted in faeces, while only a median of 4.4% of the radioactive dose administered was recovered in urine.
L- għoti ta '14C- tipranavir lis- suġġetti (n = 8) li ħadu tipranavir/ ritonavir 500 mg/ 200 mg, darbtejn kuljum, f’ dożi biex jintlaħaq l- istat fiss, wera li r- radjuattività (medja ta ’ 82. 3%) l- aktar għolja kienet eliminata fl- ippurgar, filwaqt li kien biss ammont medju ta ’ 4. 4% tad- doża radjuattiva li kienet irkuprata mill- awrina.
In addition, most radioactivity (56%) was excreted between 24 and 96 hours after dosing.
Barra minn hekk, l- ogħla radjuattività (56%) kienet eliminata bejn 24 u 96 siegħa wara t- teħid tad- doża.
The effective mean elimination half-life of tipranavir/ ritonavir in healthy volunteers (n = 67) and HIV- infected adult patients (n = 120) was approximately 4.8 and 6.0 hours, respectively, at steady state following a dose of 500 mg/ 200 mg twice daily with a light meal.
Il- valur medju effettiv tal- half life ta ’ l- eliminazzjoni ta ’ tipranavir/ ritonavir f’ volontiera b’ saħħithom (n = 67) u f’ pazjenti adulti infettati bl- HIV (n = 120) kien ta ’ madwar 4. 8 u 6. 0 sigħat, rispettivament, waqt l- istat fiss u wara li ntużat doża ta ’ 500 mg/ 200 mg, darbtejn kuljum ma ’ ikla ħafifa.
Although data available at this stage are currently limited to allow a definitive analysis, they suggest that the pharmacokinetic profile is unchanged in elderly and comparable between races.
Għalkemm id- dejta disponibbli f' dan l- istadju hi attwalment ristretta biex tippermetti analiżi definittiva, din tindika li l- profil farmakokinetiku mhux mibdul f' anzjani u hu komparabbli bejn ir- razzez.
By contrast, evaluation of the steady-state plasma tipranavir trough concentrations at 10-14 h after dosing from the RESIST-1 and RESIST-2 studies demonstrate that females generally had higher tipranavir concentrations than males.
B' kuntrast, l- evalwazzjoni ta 'l- istat fiss ta' konċentrazzjonijiet minimi ta 'tipranavir fil- plażma f' 10- 14- il siegħa wara li tingħata d- doża mill- istudji ta' RESIST- 1 u RESIST- 2 turi li n- nisa ġeneralment għandhom konċentrazzjonijiet ta 'tipranavir ogħla mill- irġiel.
After four weeks of APTIVUS/ ritonavir (500 mg/ 200 mg twice daily) the median plasma trough concentration of tipranavir was 43.9 µM for females and 31.1 µM for males.
Wara erba 'ġimgħat ta' APTIVUS/ ritonavir (500 mg/ 200 mg darbtejn kuljum) il- konċentrazzjoni minima medja ta 'tipranavir fil- plażma kienet ta' 43. 9 µM għan- nisa u 31. 1 µM għall- irġiel.
This difference in concentrations does not warrant a dose adjustment.
Din id- differenza fil- konċentrazzjonijiet m' għandiex bżonn ta 'aġġustament tad- doża.
Renal dysfunction:
Indeboliment renali:
Tipranavir pharmacokinetics have not been studied in patients with renal impairment.
Il- farmakokinetika ta ’ tipranavir ma ġietx mistħarrġa f’ pazjenti li għandhom indeboliment renali.
However, since the renal clearance of tipranavir is negligible, a decrease in total body clearance is not expected in patients with renal impairment.
Madankollu, la darba r- rata ta ’ eliminazzjoni awrinali ta ’ tipranavir hija ftit li xejn, mhux mistenni li jkun hemm tnaqqis fir- rata ta ’ l- eliminazzjoni mill- ġisem f’ pazjenti b’ insuffiċjenza tal- kliewi.
Hepatic dysfunction:
Indeboliment epatiku:
In a study comparing 9 patients with mild (Child-Pugh A) hepatic impairment to 9 controls, the single and multiple dose exposure of tipranavir and ritonavir were increased in patients with hepatic impairment but still within the range observed in clinical studies.
Waqt studju fejn 9 pazjenti li kellhom indeboliment ħafif tal- fwied (Child- Pugh A) ġew mqabbla ma ’ 9 kontrolli, instab li meta ntużat doża waħda jew dożi ripetuti, id- dispożizzjoni farmakokinetika għal tipranavir u ritonavir żdiedet, iżda xorta kienet fil- medda osservata waqt l- istudji kliniċi.
No dosing adjustment is required in patients with mild hepatic impairment but patients should be closely monitored (see sections 4.2 and 4.4).
M’ hemmx bżonn ta ’ aġġustamenti fid- dożi f’ pazjenti b’ indeboliment ħafif tal- fwied imma l- pazjenti għandhom jiġu monitorati mill- qrib (ara sezzjonijiet 4. 2 u 4. 4).
The influence of moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment on the multiple dose pharmacokinetics of either tipranavir or ritonavir has so far not been investigated.
23 L- influwenza ta ’ indeboliment moderat (Child- Pugh B) jew qawwi (Child- Pugh C) tal- fwied fuq il- farmakokinetika ta ’ dożi multipli ta 'tipranavir jew ritonavir għadha ma ġietx mistħarrġa.
APTIVUS is contraindicated in moderate or severe hepatic impairment (see sections 4.2 and 4.3).
APTIVUS huwa kontra- indikat f' indeboliment epatiku moderat jew serju (ara sezzjonijiet 4. 2 u 4. 3).
Paediatrics:
Użu pedjatriku:
The pharmacokinetic profile of tipranavir in paediatric patients has not been established.
Il- profil pedjatriku ta 'tipranavir f' pazjenti pedjatri għadu ma ġiex stabbilit.
Animal toxicology studies have been conducted with tipranavir alone, in mice, rats and dogs, and co- administered with ritonavir (3.75:1 w/ w ratio) in rats and dogs.
Saru studji tossikoloġiċi fuq l- annimali b’ tipranavir biss, fuq ġriedien, firien u klieb, u b’ tipranavir flimkien ma ’ ritonavir (bi proporzjon ta ’ 3. 75: 1 w/ w) fuq firien u klieb.
Studies with co-administration of tipranavir and ritonavir did not reveal any additional toxicological effects when compared to those seen in the tipranavir single agent toxicological studies.
Meta ntuża tipranavir flimkien ma ’ ritonavir ma nstab l- ebda effett tossiku addizzjonali meta mqabbel ma 'dak użat meta tipranavir kien ingħata waħdu fl- istudju tossikoloġiċi.
The predominant effects of repeated administration of tipranavir across all species toxicologically tested were on the gastrointestinal tract (emesis, soft stool, diarrhoea) and the liver (hypertrophy).
L- effetti ewlenin ta ’ l- użu ripetut ta ’ tipranavir fuq l- ispeċi kollha li ġew studjati minħabba l- effetti tossiċi, kienu fuq l- apparat gastro- intestinali (emesi, ippurgar merħi u dijarrea) u l- fwied (ipertrofija).
The effects were reversible with termination of treatment.
L- effetti kienu riversibbli meta waqaf it- trattament.
Additional changes included bleeding in rats at high doses (rodents specific).
Il- bidliet addizzjonali kienu jinkludu fsada fil- firien meta ngħataw dożi għoljin (speċifiċi għal firien).
Bleeding observed in rats was associated with prolonged prothrombin time (PT), activated partial thromboplastin time (APTT) and a decrease in some vitamin K dependent factors.
Il- fsada osservata fil- firien kienet assoċjata ma 'prothrombin time (PT) mdewwem, activated partial thromboplastin time (APTT) u tnaqqis f’ fatturi li huma dipendenti fuq il- vitamina K.
The co-administration of tipranavir with vitamin E in the form of TPGS (d-alphatocopherol polyethylene glycol 1000 succinate) from 2,322 IU/ m² upwards in rats resulted in a significant increase in effects on coagulation parameters, bleeding events and death.
L- għoti flimkien ta ’ tipranavir ma ’ vitamina E f’ għamla ta ’ TPGS (d- alphatocopherol polyethylene glycol 1000 succinate) minn 2322 IU/ m² ’ il fuq fil- firien irriżultaw f’ żieda sinifikanti fl- effetti tal- parametri ta ’ koagulazzjoni, każijiet ta ’ fsada u mwiet.
In preclinical studies of tipranavir in dogs, an effect on coagulation parameters was not seen.
Fi studji ta ’ qabel l- użu kliniku fi klieb, ma deher ebda effett fuq il- parametri ta ’ koagulazzjoni.
Co-administration of tipranavir and vitamin E has not been studied in dogs.
L- għoti flimkien ta ’ tipranavir u vitamina E ma ġiex studjat fil- klieb.
23 The majority of the effects in repeat-dose toxicity studies appeared at systemic exposure levels which are equivalent to or even below the human exposure levels at the recommended clinical dose.
Il- maġġoranza ta 'l- effetti fi studji dwar l- effetti tat- tossiċità minħabba dożi ripetuti dehru f' livelli ta' espożizzjoni sistematiċi li huma ekwivalenti għal jew anke taħt il- livelli għall- espożizzjoni tal - bniedem fid- doża klinika rakkomandata.
In in-vitro studies, tipranavir was found to inhibit platelet aggregation when using human platelets (see section 4.4) and thromboxane A2 binding in an in vitro cell model at levels consistent with exposure observed in patients receiving APTIVUS/ ritonavir.
Fi studji in vitro, tipranavir instab li jimpedixxi l- aggregazzjoni ta ’ plejtlets meta intużaw plejtlets tal - bniedem (ara sezzjoni 4. 4) u thromboxane A2 binding f’ mudell ta ’ ċelluli in vitro f’ livelli konsistenti ma ’ l- espożizzjoni osservata f’ pazjenti li qed jirċievu APTIVUS/ ritonavir.
The clinical implications of these findings are not known.
L- implikazzjonijiet kliniċi ta ’ dawn ir- riżultati m’ humiex magħrufa
In a study conducted in rats with tipranavir at systemic exposure levels (AUC) equivalent to human exposure at the recommended clinical dose, no adverse effects on mating or fertility were observed.
Fi studju mwettaq fuq il- firien b' tipranavir f' livelli ta 'espożizzjoni sistematika (AUC) ekwivalenti għall- espożizzjoni tal- bniedem fid- doża klinika rakkomandata, ma dehru l- ebda effetti avversi fuq tgħammir jew fertilità.
At maternal doses producing systemic drug exposure levels similar to or below those at the recommended clinical dose, tipranavir did not produce teratogenic effects.
Fid- dożi maternali li jipproduċu livelli ta 'espożizzjoni sistematiċi għall- mediċina simili għal jew taħt id- doża klinika rakkomandata, tipranavir ma pproduċiex effetti teratoġeniċi.
At tipranavir exposures in rats at 0.8-fold human exposure at the clinical dose, foetal toxicity (decreased sternebrae ossification and body weights) was observed.
Fl- espożizzjonijiet ta 'tipranavir fil- firien 0. 8 darbiet aktar mill- espożizzjoni tal- bniedem tad- doża klinika, kienet osservata tossiċità fetali (tnaqqis ta' ossifikazzjoni sternebrae u piżijiet tal- ġisem).
In pre- and post-natal development studies with tipranavir in rats, growth inhibition of pups was observed at maternally toxic doses approximating 0.8-fold human exposure.
Fi studju ta 'l- iżvilupp ta' qabel jew wara t- twelid b' tipranavar fil- firien, l- impediment għall- iżvilupp tal- frieħ kien osservat f' dożi tossiċi maternali ta 'madwar 0. 8 darbiet l- espożizzjoni tal- bniedem.
Carcinogenicity studies of tipranavir in mice and rats revealed tumourigenic potential specific for these species, which are regarded as of no clinical relevance.
Studji dwar il - kanċeroġeniċità fil- ġrieden u l- firien żevelaw potenzjal tumoriġeniku li hu speċifiku għal dawn l- ispeċi, li hu meqjus bħala li mhumiex ta ’ rilevanza klinika.
Tipranavir showed no evidence of genetic toxicity in a battery of in vitro and in vivo tests.
Tipranavir ma wera l- ebda prova ta 'tossiċità għal materjal ġenetiku wara li saru sensiela ta' testijiet in vitro u in vivo.
Macrogolglycerol ricinoleate Ethanol Mono/ diglycerides of caprylic/ capric acid Propylene glycol Purified water Trometamol Propyl gallate.
Macrogolglycerol ricinoleate Ethanol Mono/ diglycerides of caprylic/ capric acid Propylene glycol
Gelatin Red iron oxide (E172) Propylene glycol Purified water ‘ Sorbitol special-glycerin blend’ (d-sorbitol, 1,4 sorbitan, mannitol and glycerin) Titanium dioxide (E171).
Ġelatina Red iron oxide (E 172) Propylene glycol Ilma purifikat ‘ Sorbitol special- glycerin blend ’ (d- sorbitol, 1, 4 sorbitan, mannitol u glycerin) Titanium dioxide (E 171)
Black printing ink:
Linka ta 'l- istampar sewda:
Propylene glycol Black iron oxide (E172) Polyvinyl acetate phthalate Macrogol Ammonium hydroxide.
Propylene glycol Black iron oxide (E 172) Polyvinyl acetate phthalate Macrogol Ammonium hydroxide.
60 days (below 25 °C), after first opening of the bottle.
Ħażna waqt l- użu: sa 60 jum (f’ temperatura taħt 25 °C), wara li jinfetaħ il- flixkun l- ewwel darba.
It is advisable that the patient writes the date of opening the bottle on the label and/ or carton.
Huwa rakkomandat li l- pazjent jikteb id- data ta ’ meta fetaħ il- flixkun fuq it- tikketta u/ jew il- kartuna.
Store in a refrigerator (2 - 8°C).
Aħżen fi friġġ (f' temperatura ta '2 - 8°C).
High density polyethylene (HDPE) bottle with two-piece child-resistant closure (outer shell HDPE, inner shell polypropylene, with a pulpboard/ aluminium liner).
Fliexken tal- polyethylene ta ’ densità għolja (HDPE) li fihom għatu magħmul minn żewġ partijiet li ma jinfetaħx mit- tfal (qoxra ta ’ barra HDPE, qoxra ta ’ ġewwa polypropylene, b’ inforra ta ’ pulpboard/ aluminju).
Each bottle contains 120 soft capsules.
Kull flixkun fih 120 kapsula ratba.
Boehringer Ingelheim International GmbH Binger Strasse 173 D-55216 Ingelheim am Rhein Germany
Boehringer Ingelheim International GmbH Binger Strasse 173 D- 55216 Ingelheim am Rhein Il- Ġermanja
25 October 2005
25 t' Ottubru 2005
Name and address of the manufacturer responsible for batch release
KUNDIZZJONIJIET TA 'L- AWTORIZZAZZJONI GĦAT- TQEGĦID FIS- SUQ
Boehringer Ingelheim Pharma GmbH & Co.
Isem u indirizz tal- manifattur responsabbli għall- ħruġ tal- lott
KG, Binger Strasse 173, D-55216 Ingelheim am Rhein, Germany.
Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Strasse 173, D- 55216 Ingelheim am Rhein, Il- Ġermanja.
Risk Management Plan The MAH commits to performing the studies and additional pharmacovigilance activities detailed in the Pharmacovigilance Plan, as agreed in version 4.0 of the Risk Management Plan (RMP) presented in Module 1.8.2. of the Marketing Authorisation Dossier and any subsequent updates of the RMP agreed by the CHMP.
Pjan ta ’ Ġestjoni tar- Riskju Id- Detentur ta ’ l- Awtorizzazzjoni għat- Tqegħid fis- Suq jimpenja ruħu li jwettaq l- istudji u l- attivitajiet ta ’ farmakoviġilanza addizzjonali detalljati fil- Pjan ta ’ Farmakoviġilanza, kif miftiehem f’ verżjoni 4. 0 tal- Pjan ta ’ Ġestjoni dwar ir- Riskju (RMP) ippreżentat f’ Modulu 1. 8. 2 tad- Dossier għall - Awtorizzazzjoni għat- Tqegħid fis- Suq u kull aġġornament sussegwenti ieħor ta ’ l- RMP miftiehem mis- CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the updated RMP should be submitted at the same time as the next Periodic Safety Update Report (PSUR).
Skond il- Linja Gwida tas- CHMP dwar Sistemi ta ’ Ġestjoni tar- Riskju għal prodotti mediċinali għal użu mill- bniedem, l- RMP aġġornat għandu jiġi sottomess fl- istess żmien tar- Rapport Perijodiku Aġġornat dwar is- Sigurtà (PSUR) li jmiss.
In addition, an updated RMP should be submitted • When new information is received that may impact on the current Safety Specification, Pharmacovigilance Plan or risk minimisation activities • Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being reached • At the request of the EMEA
Barraminhekk, RMP aġġornat għandu jiġi sottomess • Meta jasal tagħrif ġdid li jista ’ jkollu impatt fuq l- Ispeċifikazzjoni Speċjali attwali, il- Pjan ta ’ Farmakoviġilanza jew attivitajiet li jnaqqsu r- riskju • Fi żmien 60 jum minn meta jkun intlaħaq tragward importanti (farmakoviġilanza jew tnaqqis ta ’ riskju) • Fuq talba ta ’ l- EMEA
29 PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE PACKAGING
TIKKETTA
FOLDING BOX/ OUTER PACKAGING
30 TAGĦRIF LI GĦANDU JIDHER FUQ IL- PAKKETT TA ’ BARRA U IL- PAKKETT LI JMISS MAL- PRODOTT
APTIVUS 250 mg soft capsules Tipranavir
APTIVUS 250 mg kapsuli rotob Tipranavir
Each soft capsule contains 250 mg tipranavir
Kull kapsula ratba fiha 250 mg tipranavir
Contains macrogolglycerol ricinoleate, sorbitol and ethanol (see package leaflet)
Fih macrogolglycerol ricinoleate, sorbitol u ethanol (ara l- fuljett tal- pakkett)
120 soft capsules (one bottle)
120 kapsula ratba (flixkun wieħed)
Oral use Read the package leaflet before use.
Użu orali Aqra l- fuljett ta 'tagħrif qabel l- użu.
60 days (below 25 °C) after first opening of the bottle.
JIS (XX/ SSSS) Ħażna waqt l- użu: sa 60 jum (temperatura taħt 25 °C) wara li jinfetaħ il- flixkun l- ewwel darba.
Date of first opening of the bottle:
Data ta 'meta jinfetaħ l- ewwel darba l- flixkun:
31 PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE PACKAGING
32 TAGĦRIF LI GĦANDU JIDHER FUQ IL- PAKKETT TA ’ BARRA U IL- PAKKETT LI JMISS MAL- PRODOTT
BOTTLE/ IMMEDIATE PACKAGING
FLIXKUN/ PAKKETT LI JMISS MAL- PRODOTT
120 soft capsules
120 kapsula ratba
34 PACKAGE LEAFLET:
FULJETT TA 'TAGĦRIF
INFORMATION FOR THE USER
35 FULJETT TA 'TAGĦRIF:
if their symptoms are the same as yours.
il- ħsara anki jekk ikollhom l- istess sintomi bħal tiegħek.
What APTIVUS is and what it is used for 2.
X’ inhu APTIVUS u għalxiex jintuża 2.
Before you take APTIVUS 3.
Qabel ma tieħu APTIVUS 3.
How to take APTIVUS 4.
Kif għandek tieħu APTIVUS 4.
Possible side effects 5 How to store APTIVUS 6.
Effetti sekondarji li jista ’ jkollu 5 Kif taħżen APTIVUS 6.
WHAT APTIVUS IS AND WHAT IT IS USED FOR
X’ INHU APTIVUS U GĦALXIEX JINTUŻA
The active substance tipranavir is an antiretroviral agent used in the treatment of Human Immunodeficiency Virus (HIV) infection.
Is- sustanza attiva tipranavir hija mediċina antiretrovirali li tintuża fit- trattament ta 'l- infezzjonijiet tal- Virus ta' Immunodefiċjenza Umana (HIV).
Tipranavir belongs to a group of medicines called protease inhibitors.
Tipranavir jagħmel parti minn grupp ta ’ mediċini msejħa impedituri ta 'l- enżimi protease.
Tipranavir is an inhibitor of the HIV protease enzyme which the HIV needs to multiply.
Tipranavir huwa impeditur ta 'l- enżima HIV protease li l- HIV jeħtieġ biex jimmultiplika.
By inhibiting the protease enzyme APTIVUS helps control HIV infection.
Meta jimpedixxi l- enżima tal- protease APTIVUS jgħin jikkontrolla l- infezzjoni ta ’ l- HIV.
APTIVUS is prescribed for use in combination with low dose ritonavir and other antiretrovirals.
APTIVUS jiġi preskritt ma ’ doża baxxa ta 'ritonavir u mediċini antiretrovirali oħrajn.