qanastek/EMEA-V3 huggingface dataset:
Assessment of adverse reactions from clinical study data is based on experience in two studies in 653 treatment-experienced patients receiving treatment with tenofovir disoproxil fumarate (n = 443) or placebo (n = 210) in combination with other antiretroviral medicinal products for 24 weeks and also in a double-blind comparative controlled study in which 600 treatment-naïve patients received treatment with tenofovir disoproxil 245 mg (as fumarate) (n = 299) or stavudine (n = 301) in combination with lamivudine and efavirenz for 144 weeks.
L- istima ta ’ reazzjonijiet avversi minn dejta minn studju kliniku hija bbażata fuq l- esperjenza miksuba f’ żewġ studji f’ 653 pazjent esperjenzati bil- kura b’ tenofovir disoproxil fumarate (n = 443) jew plaċebo (n = 210) ikkombinati ma ’ prodotti mediċinali antiretrovirali oħra għal 24 ġimgħa u ukoll
Approximately one third of patients can be expected to experience adverse reactions following treatment with tenofovir disoproxil fumarate in combination with other antiretroviral agents.
Madwar terz tal- pazjenti jistgħu jkunu mistennija li jkollhom reazzjonijiet avversi wara t- trattament b’ tenofovir disoproxil fumarate meta mogħti ma ’ mediċini retrovirali oħra.
These reactions are usually mild to moderate gastrointestinal events.
Dawn ir- reazzjonijiet is - soltu huma effetti gastro- intestinali minn ħfief sa moderati.
The adverse reactions with suspected (at least possible) relationship to treatment are listed below by body system organ class and absolute frequency.
Ir- reazzjonjiet avversi b’ rabta suspetta (almenu possibbli) mat- trattament huma elenkati hawn taħt skond il- klassi ta ’ sistema ta ’ l- organi fil- ġisem u skond il- frekwenza assoluta.
Frequencies are defined as very common (≥ 1/ 10) or common (≥ 1/ 100, < 1/ 10).
Il- frekwenza hija deskritta bħala komuni ħafna (≥ 1/ 10) jew komuni (≥ 1/ 100, < 1/ 10).
See also Post-marketing experience below.
Ara wkoll Esperjenza ta ’ wara t- tqegħid fis- suq hawn taħt.
Very common: hypophosphataemia
Komuni ħafna: ipofosfatimja
Very common: dizziness
Komuni ħafna: sturdament
Very common: diarrhoea, vomiting, nausea Common: flatulence
Komuni ħafna: dijarrea, rimettar, tqalligħ Komuni: gass fl- istonku
Approximately 1% of tenofovir disoproxil fumarate-treated patients discontinued treatment due to the gastrointestinal events.
Madwar 1% tal- pazjenti li ħadu t- trattament b’ tenofovir disoproxil fumarate ma komplewx it - trattament minħabba l- effetti gastro- intestinali.
Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).
It- terapija antiretrovirali kombinata ġiet assoċjata mar- ridistribuzzjoni tax- xaħam fil- ġisem (lipodistrofija) f’ pazjenti bl- HIV fosthom it- telf tax- xaħam ta ’ taħt il- ġilda tal- wiċċ u fil- partijiet periferali tal- ġisem, żieda fix- xaħam intra- addominali u vixxerali, ipertrofija tas- sider u akkumulazzjoni ta ’ xaħam dorsoċervikali (ħotba tal- buflu).
In a 144-week controlled clinical study in antiretroviral-naïve patients that compared tenofovir disoproxil fumarate with stavudine in combination with lamivudine and efavirenz, patients who received tenofovir disoproxil had a significantly lower incidence of lipodystrophy compared with patients who received stavudine.
Pazjenti li ngħataw tenofovir disoproxil kellhom inċidenza ta ’ lipodistrofija mnaqqsa b’ mod sinifikanti meta mqabbla ma ’ pazjenti li ngħataw stavudine.
The tenofovir disoproxil fumarate arm also had significantly smaller mean increases in fasting triglycerides and total cholesterol than the comparator arm.
Il- fergħa ta ’ l- istudju ta ’ tenofovir disoproxil fumarate kellha ukoll medja ta ’ żidiet iżgħar b’ mod sinifikanti fit- triglycerides u kolesterol totali fl- istat sajjem mill- fergħa l- oħra ta ’ l- istudju.
10 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).
Kienu rrappurtati każijiet ta ’ osteonekrożi, partikularment f’ pazjenti li jkollhom fatturi ta ’ riskju li huma magħrufa b’ mod ġenerali, mard ta ’ l- HIV li jkun fi stadju avvanzat jew esponiment fit- tul għal terapija antiretrovirali kombinata (CART).
Assessment of adverse reactions from clinical study data is based on experience in two double-blind comparative controlled studies in which 641 patients with chronic hepatitis B and compensated liver disease received treatment with tenofovir disoproxil 245 mg (as fumarate) daily (n = 426) or adefovir dipivoxil 10 mg daily (n = 215) for 48 weeks.
L- istima ta ’ reazzjonijiet avversi minn dejta minn studju kliniku hija bbażata fuq l - esperjenza f’ żewġ studji komparattivi, double- blind u kkontrollati fuq 641 pazjent b’ epatite B kronika u mard tal- fwied kumpensat li rċivew trattament b’ tenofovir disoproxil 245 mg (bħala fumarate) kuljum (n = 426) jew adefovir dipivoxil 10 mg kuljum (n = 215) għal 48 ġimgħa.
The adverse reactions with suspected (at least possible) relationship to treatment are listed below by body system organ class and frequency.
11 Ir- reazzjonjiet avversi b’ rabta suspettata (almenu possibbli) mat- trattament huma elenkati hawn taħt skond il- klassi ta ’ sistema ta ’ l- organi fil- ġisem u skond il- frekwenza.
Frequencies are defined as common (≥ 1/ 100, < 1/ 10).
Il- frekwenza hija deskritta bħala komuni (≥ 1/ 100, < 1/ 10).
Common: diarrhoea, vomiting, abdominal pain, nausea, abdominal distension, flatulence
Komuni: dijarea, rimettar, uġigħ addominali, tqalligħ, nefħa addominali, gass fl- istonku
ALT increase
Komuni: żieda fl- ALT
Common: fatigue
Komuni: għeja kbira
Exacerbations during treatment:
Għall- agħar waqt it- trattament:
In studies with nucleoside-naïve patients, on-treatment ALT elevations > 10 times ULN (upper limit of normal) and > 2 times baseline occurred in 2.6% of tenofovir disoproxil fumarate-treated patients versus 1.9% of adefovir dipivoxil-treated patients.
Fi studji fuq pazjenti li qatt ma ’ ngħataw nukleosides żidiet ta ’ l- ALT waqt it- trattament ta ’ > 10 darbiet iżjed mill- ULN (limitu ta ’ fuq tan- normal) u iktar mid- doppju tal - linja bażi seħħew fi 2. 6% tal- pazjenti li kienu ttrattati b’ tenofovir disoproxil fumarate versus 1. 9% tal - pazjenti li kienu ttrattati b’ adefovir dipivoxil.
Among tenofovir disoproxil fumarate-treated patients, on-treatment ALT elevations had a median time to onset of 8 weeks, resolved with continued treatment, and, in a majority of cases, were associated with a ≥ 2 log10 copies/ ml reduction in viral load that preceded or coincided with the ALT elevation.
Fost pazjenti ttrattati b’ tenofovir disoproxil fumarate, żidiet ta ’ l- ALT waqt it- trattament kellhom medjan ta ’ ħin biex jibdew ta ’ 8 ġimgħat, fiequ bit - tkomplija tat- trattament, u, fil- maġġoranza tal- każijiet, kienu assoċjati ma ’ tnaqqis ta ’ ≥ 2 log10 kopja/ ml ta ’ viri li seħħet qabel jew fl- istess ħin maż- żieda fl- ALT.
Periodic monitoring of hepatic function is recommended during treatment.
Il- monitoraġġ perjodiku tal- funzjoni epatika hu rakkomandat matul it- trattament.
Post-marketing experience:
Esperjenza ta ’ wara t- tqegħid fis- suq:
In addition to adverse reaction reports from clinical studies the following possible adverse reactions have also been identified during post-marketing safety surveillance of tenofovir disoproxil fumarate.
Flimkien ma ’ rapporti ta ’ reazzjonijiet avversi minn studji kliniċi, ir- reazzjonijiet avversi possibbli li ġejjin kienu wkoll identifikati matul is- sorveljanza tas - sigurtà ta ’ wara t- tqegħid fis- suq ta ’ tenofovir disoproxil fumarate.
Frequencies are defined as rare (≥ 1/ 10,000, < 1/ 1,000) or very rare (< 1/ 10,000) including isolated reports.
Il- frekwenzi huma definiti bħala rari (≥ 1/ 10, 000, < 1/ 1, 000) jew rari ħafna (< 1/ 10, 000) inklużi rapporti iżolati.
Because these events have been reported voluntarily from a population of unknown size, estimates of frequency cannot always be made.
Minħabba li dawn l - avvenimenti kienu rrappurtati b’ mod volontarju minn popolazzjoni ta ’ daqs mhux magħruf, mhux dejjem jistgħu jsiru stimi dwar il- frekwenza.
Rare: lactic acidosis Not known: hypokalaemia
Rari: aċidożi lattika Mhux magħrufa: ipokalimja
Rare: pancreatitis
Rari: pankreatite
Rare: increased transaminases Very rare: hepatitis Not known: hepatic steatosis
Rari: żieda fit- transaminases Rari ħafna: epatite Mhux magħrufa: stejatożi epatika
Rare: rash
Rari: raxx
11 Musculoskeletal and connective tissue disorders:
Disturbi muskolu- skeltrali u tal- connective tissue:
Not known: rhabdomyolysis, osteomalacia (manifested as bone pain and infrequently contributing to fractures), muscular weakness, myopathy
Mhux magħrufa: rabdomijolosi, osteomalaċja (li tidher bħala wġigħ fl- għadam u b’ mod mhux frekwenti tikkontribwixxi għal ksur), dgħjufija fil- muskoli, majopatija
Renal and urinary disorders:
12 Disturbi fil- kliewi u fis- sistema urinarja:
Rare: acute renal failure, renal failure, proximal renal tubulopathy (including Fanconi syndrome), increased creatinine Very rare: acute tubular necrosis Not known: nephritis (including acute interstitial nephritis), nephrogenic diabetes insipidus
Rari: kollass tal- kliewi akut, kollass tal- kliewi, tubulopatija renali prossimali (inkluż is- sindromu ta ’ Fanconi), żieda fil- krejatinina Rari ħafna: nekrożi tubulari akuta Mhux magħrufa: nefrite (li tinkludi nefrite interstinali akuta), dijabete insipidus nefroġenika
Very rare: asthenia
Rari ħafna: astenja
If overdose occurs the patient must be monitored for evidence of toxicity (see sections 4.8 and 5.3), and standard supportive treatment applied as necessary.
Jekk iseħħ każ ta ’ doża eċċessiva, il- pazjent għandu jiġi mmonitorjat għal sinjali ta ’ tossiċità (ara sezzjonijiet 4. 8 u 5. 3), u t- trattament ta ’ appoġġ regolari għandu jingħata kif meħtieġ.
Tenofovir can be removed by haemodialysis; the median haemodialysis clearance of tenofovir is 134 ml/ min.
Tenofovir jista ’ jitneħħa permezz ta ’ dijaliżi tad- demm; it- tneħħija b’ dijaliżi tad- demm medjana ta ’ tenofovir hi ta ’ 134 ml/ min.
The elimination of tenofovir by peritoneal dialysis has not been studied.
It- tneħħija ta ’ tenofovir bid- dijaliżi peritoneali ma ġietx studjata.
Nucleoside and nucleotide reverse transcriptase inhibitors, ATC code:
Impedituri ta ’ nukleoside u nukleotide reverse transcriptase, kodiċi ATC:
Tenofovir disoproxil fumarate is the fumarate salt of the prodrug tenofovir disoproxil.
Tenofovir disoproxil fumarate huwa sustanza ta ’ fumarate tal- prodroga tenofovir disoproxil.
Tenofovir disoproxil is absorbed and converted to the active substance tenofovir, which is a nucleoside monophosphate (nucleotide) analogue.
Tenofovir disoproxil huwa assorbit u mibdul għas- sustanza attiva tenofovir, li hija analoga ta ’ nukleoside monophosphate (nukleotide).
Tenofovir is then converted to the active metabolite, tenofovir diphosphate, an obligate chain terminator, by constitutively expressed cellular enzymes.
Imbagħad tenofovir jinbidel għall- metabolit attiv, tenofovir diphosphate, terminatur tal- katina obligate, permezz ta ’ enzimi ċellulari espressi b’ mod konstituttiv.
Tenofovir diphosphate has an intracellular half-life of 10 hours in activated and 50 hours in resting peripheral blood mononuclear cells (PBMCs).
Il- ħin biex il- livell ta ’ tenofovir diphosphate jonqos bin- nofs huwa ta ’ 10 sigħat ġewwa ċ - ċellula f’ celluli mononukleari tad- demm periferali (peripheral blood mononuclear cells, PBMCs) attivati u 50 siegħa f’ dawk li qed jistrieħu.
Tenofovir diphosphate inhibits HIV-1 reverse transcriptase and the HBV polymerase by direct binding competition with the natural deoxyribonucleotide substrate and, after incorporation into DNA, by DNA chain termination.
Tenofovir diphosphate jinibixxi l- polimerases tar- reverse transcriptase tal- HIV u l- polymerase tal- HBV permezz ta ’ kompetizzjoni diretta li teħel mas- sottostrat naturali tad- deoxyribonukleotide u, wara l- inkorporazzjoni ġod- DNA, permezz tat- terminazzjoni tal - katina tad- DNA.
Tenofovir diphosphate is a weak inhibitor of cellular polymerases α, β, and γ.
Tenofovir diphosphate huwa impeditur dgħajjef tal- polimerases ċellulari α, β, u γ.
At concentrations of up to 300 µmol/ l, tenofovir has also shown no effect on the synthesis of mitochondrial DNA or the production of lactic acid in in vitro assays.
F’ konċentrazzjonijiet sa 300 µmol/ l, tenofovir ma wera l- ebda effett fuq is- sintesi mitokondrijali tad - DNA jew fuq il- produzzjoni ta ’ l- aċidu lattiku f’ assay in vitro.
Data pertaining to HIV:
Dejta dwar l- HIV:
HIV antiviral activity in vitro:
Attività antivirali HIV in vitro:
The concentration of tenofovir required for 50% inhibition (EC50) of the wild-type laboratory strain HIV-1IIIB is 1-6 µmol/ l in lymphoid cell lines and 1.1 µmol/ l against primary HIV-1 subtype B isolates in PBMCs.
Il- konċentrazzjoni ta ’ tenofovir meħtieġa għall- inibizzjoni ta ’ 50% (EC50) ta ’ l- istrejn naturali mrobbi fil- laboratorju HIV- 1IIIB huwa 1- 6 μmol/ l f’ razza ta ’ ċelluli tal - limfojde u 1. 1 µmol/ l kontra HIV- 1 primarja sottotip B iżolati f’ PBMCs.
Tenofovir is also active against HIV-1 subtypes A, C, D, E, F, G, and O and against HIVBaL in primary monocyte/ macrophage cells.
Tenofovir huwa ukoll attiv kontra s- sottotipi A, Ċ, D, E, F, Ġ, u O ta ’ HIV- 1 u kontra HIVBaL f’ ċelluli makrofaġi/ monoċistiċi primarji.
Tenofovir shows activity in vitro against HIV-2, with an EC50 of 4.9 µmol/ l in MT-4 cells.
Tenofovir juri attività in vitro kontra HIV- 2, b’ EC50 ta ’ 4. 9 µmol/ l f’ ċelluli MT- 4.
Strains of HIV-1 with reduced susceptibility to tenofovir and a K65R mutation in reverse transcriptase have been selected in vitro and in some patients (see Clinical results).
Strejns ta ’ HIV- 1 bi tnaqqis fis- sensittività għal tenofovir u b’ mutazzjoni K65R f’ reverse transcriptase intagħżlu in vitro u f’ xi pazjenti (ara Riżultati kliniċi).
Tenofovir 12 disoproxil fumarate should be avoided in antiretroviral experienced patients with strains harbouring the K65R mutation (see section 4.4).
Tenofovir disoproxil fumarate għandu jkun evitat f’ pazjenti li mhux l- ewwel darba li ngħataw sustanzi antiretrovirali bi strejns bil - mutazzjoni K65R (ara sezzjoni 4. 4).
Clinical studies in treatment-experienced patients have assessed the anti-HIV activity of tenofovir disoproxil 245 mg (as fumarate) against strains of HIV-1 with resistance to nucleoside inhibitors.
13 Studji kliniċi fuq pazjenti esperjenzati bil- kura evalwaw l- attività kontra l- HIV ta ’ tenofovir disoproxil 245 mg (bħala fumarate) kontra strejns ta ’ HIV- 1 b’ reżistenza għal impedituri ta ’ nukleoside.
The results indicate that patients whose HIV expressed 3 or more thymidine-analogue associated mutations (TAMs) that included either the M41L or L210W reverse transcriptase mutation showed reduced response to tenofovir disoproxil 245 mg (as fumarate) therapy.
Ir - riżultati jindikaw li pazjenti li l- marda tal- HIV tagħhom kellha 3 jew aktar mutazzjonijiet assoċjati ma ’ l- analogi ta ’ thymidine (TAMs) li kienu jinkludu l- mutazzjoni M41L jew L210W reverse transcriptase wrew tnaqqis fir- respons għat- terapija ta ’ 245 mg tenofovir disoproxil (bħala fumarate).
Clinical results:
Riżultati kliniċi:
The effects of tenofovir disoproxil fumarate in treatment-experienced and treatment-naïve HIV-1 infected adults have been demonstrated in trials of 48 weeks duration in treatment-experienced HIV-1 infected adults.
L- effetti ta ’ tenofovir disoproxil fumarate f’ pazjenti adulti infettati b’ HIV- 1 esperjenzati bil- kura u pazjenti li qatt ma kienu ħadu din it- terapija qabel ġew ippruvati fi provi fuq medda ta ’ 48 ġimgħa f’ adulti infettati b’ HIV- 1 esperjenzati bil- kura.
In study GS-99-907, 550 treatment-experienced patients were treated with placebo or tenofovir disoproxil 245 mg (as fumarate) for 24 weeks.
Fl- istudju GS- 99- 907, 550 pazjenti esperjenzati bil- kura u kienu ttrattati bi plaċebo jew 245 mg tenofovir disoproxil (bħala fumarate) għal 24 ġimgħa.
The mean baseline CD4 cell count was 427 cells/ mm3, the mean baseline plasma HIV-1 RNA was 3.4 log10 copies/ ml (78% of patients had a viral load of < 5,000 copies/ ml) and the mean duration of prior HIV treatment was 5.4 years.
Il- medja bażi ta ’ l- għadd taċ- ċelluli CD4 kien ta ’ 427 ċelluli/ mm3, il- medja bażi tal- plażma HIV- 1 RNA kienet ta ’ 3. 4 log10 kopja/ ml (78% tal - pazjenti kellhom ammont ta ’ viri ta ’ < 5, 000 kopja/ ml) u d- dewmien medju tat- trattament għal HIV mogħti qabel kien ta ’ 5. 4 snin.
Baseline genotypic analysis of HIV isolates from 253 patients revealed that 94% of patients had HIV-1 resistance mutations associated with nucleoside reverse transcriptase inhibitors, 58% had mutations associated with protease inhibitors and 48% had mutations associated with non-nucleoside reverse transcriptase inhibitors.
L- analiżi ġenotipika bażi ta ’ HIV iżolati minn 253 pazjenti wriet li 94% tal- pazjenti kellhom mutazzjonijiet reżistenti għal HIV- 1 assoċjat ma ’ l- impedituri ta ’ nukleoside reverse transcriptase, 58% kellhom mutazzjonijiet assoċjati ma ’ l- impedituri ta ’ protease u 48% kellhom mutazzjonijiet assoċjati ma ’ l- impedituri ta ’ non- nukleoside reverse transcriptase.
At week 24 the time-weighted average change from baseline in log10 plasma HIV-1 RNA levels (DAVG24) was -0.03 log10 copies/ ml and -0.61 log10 copies/ ml for the placebo and tenofovir disoproxil 245 mg (as fumarate) recipients (p < 0.0001).
F’ Ġimgħa 24, il- bidla medja imkejla fuq ħin bil- linja bażi f’ log10 livelli ta ’ plażma HIV- 1 RNA (DAVG24) kienet ta ’ - 0. 03 log10 kopja/ ml u ta ’ - 0. 61 log10 kopja/ ml għall- plaċebo u reċipjenti ta ’ 245 mg tenofovir disoproxil (bħala fumarate) (p < 0. 0001).
A statistically significant difference in favour of tenofovir disoproxil 245 mg (as fumarate) was seen in the time-weighted average change from baseline at week 24 (DAVG24) for CD4 count (+13 cells/ mm3 for tenofovir disoproxil 245 mg (as fumarate) versus -11 cells/ mm3 for placebo, p-value = 0.0008).
Differenza sinifikanti fl- istatistika favur 245 mg tenofovir disoproxil (bħala fumarate) dehret fil- bidla medja imkejla fuq ħin minn linja bażi f’ Ġimgħa 24 (DAVG24) għall- għadd ta ’ CD4 (+13 ċelluli/ mm3 għal 245 mg tenofovir disoproxil (bħala fumarate) kontra - 11 ċelluli/ mm3 għall- plaċebo, valur p = 0. 0008).
The antiviral response to tenofovir disoproxil fumarate was durable through 48 weeks (DAVG48 was -0.57 log10 copies/ ml, proportion of patients with HIV-1 RNA below 400 or 50 copies/ ml was 41% and 18% respectively).
Ir- reazzjoni antivirali għal tenofovir disoproxil fumarate kienet tajba tul it- 48 ġimgħa (DAVG48 kien ta ’ - 0. 57 log10 kopja/ ml, il - proporzjon ta ’ pazjenti b’ HIV- 1 RNA taħt 400 jew 50 kopja/ ml kien ta ’ 41% u 18% rispettivament).
Eight (2%) tenofovir disoproxil 245 mg (as fumarate) treated patients developed the K65R mutation within the first 48 weeks.
Tmien pazjenti (2%) li ħadu t- trattament b’ 245 mg tenofovir disoproxil 245 mg (bħala fumarate) żviluppaw il- mutazzjoni K65R matul l- ewwel 48 ġimgħa.
The 144-week, double-blind, active controlled phase of study GS-99-903 evaluated the efficacy and safety of tenofovir disoproxil 245 mg (as fumarate) versus stavudine when used in combination with lamivudine and efavirenz in HIV-1 infected patients naïve to antiretroviral therapy.
Il- fażi ta ’ l- istudju GS- 99- 903 ikkontrollat b’ mod attiv li sar matul 144 ġimgħa u double- blind evalwa l- effiċjenza u s- sigurtà ta ’ 245 mg tenofovir disoproxil (bħala fumarate) kontra stavudine meta użat f’ kumbinazzjoni ma ’ lamivudine u efavirenz f’ pazjenti infettati b’ HIV- 1, li qatt ma ħadu terapija antiretrovirali.
The mean baseline CD4 cell count was 279 cells/ mm3, the mean baseline plasma HIV-1 RNA was 4.91 log10 copies/ ml, 19% of patients had symptomatic HIV-1 infection and 18% had AIDS.
Il- medja tal- linja bażi ta ’ l- għadd taċ- ċelluli CD4 kien ta ’ 279 ċellula/ mm3, il- medja bażi tal- plażma HIV- 1 RNA kienet ta ’ 4. 91 log10 kopja/ ml, 19% tal- pazjenti kellhom infezzjoni sintomatika ta ’ HIV- 1 u 18% kellhom AIDS.
Patients were stratified by baseline HIV-1 RNA and CD4 count.
Il- pazjenti kienu mqassmin skond il- linja bażi HIV- 1 RNA u l- għadd ta ’ CD4.
Forty-three percent of patients had baseline viral loads > 100,000 copies/ ml and 39% had CD4 cell counts < 200 cells/ ml.
Tlieta u erbgħin fil- mija tal- pazjenti kellhom ammont ta ’ viri bażi ta ’ > 100, 000 kopja/ ml u 39% kellhom għadd taċ- ċelluli CD4 < 200 ċellula/ ml.
By intent to treat analysis (Missing data and switch in antiretroviral therapy (ART) considered as failure), the proportion of patients with HIV-1 RNA below 400 copies/ ml and 50 copies/ ml at 48 weeks of treatment was 80% and 76% respectively in the tenofovir disoproxil 245 mg (as fumarate) arm, compared to 84% and 80% in the stavudine arm.
B’ analiżi bil- ħsieb li tfejjaq (tagħrif nieqes u tibdil fit- terapija antiretrovirali (ART) hu kkunsidrat bhala falliment), il- proporzjon ta ’ pazjenti b’ HIV- 1 RNA taħt l- 400 kopja/ ml u l- 50 kopja/ ml fl - 48 ġimgħa ta ’ trattament kien ta ’ 80% u 76% rispettivament fil- fergħa ta ’ 245 mg tenofovir disoproxil (bħala fumarate), meta mqabbel ma ’ 84% u 80% fil- fergħa ta ’ stavudine.
At 144 weeks, the proportion of patients with HIV-1 RNA below 400 copies/ ml and 50 copies/ ml was 71% and 68% respectively in the tenofovir disoproxil 245 mg (as fumarate) arm, compared to 64% and 63% in the stavudine arm.
F’ 144 ġimgħa, il- proporzjon ta ’ pazjenti b’ HIV- 1 RNA taħt l- 400 kopja/ ml u l- 50 kopja/ ml kien ta ’ 71% u 68% rispettivament fil - fergħa ta ’ 245 mg tenofovir disoproxil (bħala fumarate), meta mqabbel ma ’ 64% u 63% fil- fergħa ta ’ stavudine.
The average change from baseline for HIV-1 RNA and CD4 count at 48 weeks of treatment was similar in both treatment groups (-3.09 and -3.09 log10 copies/ ml; +169 and 167 cells/ mm3 in the tenofovir disoproxil 245 mg (as fumarate) and stavudine groups, respectively).
Il- bidla medja tal- linja bażi għal HIV- 1 RNA u l- għadd ta ’ CD4 fi 48 ġimgħa ta ’ trattament kienu simili fiż- żewġ gruppi li ħadu t- trattament (- 3. 09 u - 3. 09 log10 kopja/ ml; +169 u 167 ċellula/ mm3 fil - gruppi ta ’ 245 mg tenofovir disoproxil (bħala fumarate) u stavudine, rispettivament).
At 144 weeks of treatment, the average change from baseline remained similar in both treatment groups (-3.07 and -3.03 log10 copies/ ml; +263 and +283 cells/ mm3 in the tenofovir disoproxil 245 mg (as fumarate) and stavudine groups, respectively).
F’ 144 ġimgħa ta ’ trattament, il- bidla medja mil- linja bażi baqgħet simili fiż- żewġ gruppi li ħadu t- trattament (- 3. 07 u - 3. 03 log10 kopja/ ml; +263 u +283 ċellula/ mm3 fil- gruppi ta ’ 245 mg tenofovir disoproxil (bħala fumarate) u stavudine, rispettivament).
A consistent response to treatment with tenofovir disoproxil 245 mg (as fumarate) was seen regardless of baseline HIV-1 RNA and CD4 count.
Reazzjoni konsistenti għat- trattament b’ 245 mg tenofovir disoproxil (bħala fumarate) dehret irrispettivament bil- linja bażi ta ’ HIV- 1 RNA u l- għadd ta ’ CD4.
13 The K65R mutation occurred in a slightly higher percentage of patients in the tenofovir disoproxil fumarate group than the active control group (2.7% versus 0.7%).
Reżistenza għal efavirenz jew
Efavirenz or lamivudine resistance either preceded or was coincident with the development of K65R in all cases.
14 lamivudine jew seħħet qabel jew fl- istess ħin ma ’ l- iżvilupp ta ’ K65R fil- każijiet kollha.
Eight patients had HIV that expressed K65R in the tenofovir disoproxil 245 mg (as fumarate) arm, 7 of these occurred during the first 48 weeks of treatment and the last one at week 96.
Tmien pazjenti kellhom HIV li wriet K65R fil- fergħa ta ’ 245 mg tenofovir disoproxil (bħala fumarate), 7 minn dawn il- każijiet seħħew matul l- ewwel 48 ġimgħa tat- trattament u l- aħħar wieħed seħħ fis - 96 ġimgħa.
No further K65R development was observed up to week 144.
L- ebda żvilupp ieħor ta ’ K65R ma kien osservat sal- 144 ġimgħa.
From both the genotypic and phenotypic analyses there was no evidence for other pathways of resistance to tenofovir.
Miż- żewġ analiżi ġenotipiċi u fenotipiċi ma ’ kienx hemm evidenza ta ’ rotot oħra għar- reżistenza għal tenofovir.
Data pertaining to HBV:
Dejta dwar l- HBV:
HBV antiviral activity in vitro:
Attività antivirali ta ’ l- HBV in vitro:
The in vitro antiviral activity of tenofovir against HBV was assessed in the HepG2 2.2.15 cell line.
L- attività antivirali in vitro ta ’ tenofovir kontra l- HBV kienet evalwata fir- razza ta ’ ċelluli HepG2 2. 2. 15.
The EC50 values for tenofovir were in the range of 0.14 to 1.5 µmol/ l, with CC50 (50% cytotoxicity concentration) values > 100 µmol/ l.
Il- valuri EC50 għal tenofovir kienu fil- medda ta ’ 0. 14 sa 1. 5 µmol/ l, bil- valuri CC50 (50% ta ’ konċentrazzjoni taċ- ċitotossiċità) ta ’ > 100 µmol/ l.
No HBV mutations associated with tenofovir disoproxil fumarate resistance have been identified (see Clinical results).
Ma kienu identifikati l- ebda mutazzjonijiet ta ’ l- HBV assoċjati mar- reżistenza għal tenofovir disoproxil fumarate (ara Riżultati kliniċi).
In cell based assays, HBV strains expressing the rtV173L, rtL180M, and rtM204I/ V mutations associated with resistance to lamivudine and telbivudine showed a susceptibility to tenofovir ranging from 0.7- to 3.4-fold that of wild-type virus.
F’ assaġġi bbażati fuq iċ- ċelluli, strejns tal- HBV li jesprimu l- mutazzjonijiet rtV173L, rtL180M, u rtM204I/ V assoċjati ma ’ reżistenza għal lamivudine u telbivudine, urew sensittività għal tenofovir li tvarja minn 0. 7 sa 3. 4 darbiet iktar minn dik ta ’ l- istrejn naturali tal- virus.
HBV strains expressing the rtL180M, rtT184G, rtS202G/ I, rtM204V and rtM250V mutations associated with resistance to entecavir showed a susceptibility to tenofovir ranging from 0.6- to 6.9-fold that of wild- type virus.
Strejns tal- HBV li jesprimu l- mutazzjonijiet rtL180M, rtT184G, rtS202G/ I, rtM204V u rtM250V assoċjati ma ’ reżistenza għal entecavir, urew sensittività għal tenofovir li tvarja minn 0. 6 sa 6. 9 darbiet iktar minn dik ta ’ l- istrejn naturali tal- virus.
HBV strains expressing the adefovir-associated resistance mutations rtA181V and rtN236T showed a susceptibility to tenofovir ranging from 2.9- to 10-fold that of wild-type virus.
Strejns tal- HBV li jesprimu mutazzjonijiet rtA181V u rtN236T assoċjati ma ’ reżistenza għal adefovir, urew sensittività għal tenofovir li tvarja minn 2. 9 sa 10 darbiet iktar minn dik ta ’ l- istrejn naturali tal- virus.
Viruses containing the rtA181T mutation remained susceptible to tenofovir with EC50 values 1.5-fold that of wild-type virus.
Viruses li kien fihom il- mutazzjoni rtA181T baqgħu sensittivi għal tenofovir b’ valuri EC50 li kienu 1. 5 drabi iżjed minn dik ta ’ l- istrejn naturali tal- virus.
The demonstration of benefit of tenofovir disoproxil fumarate is based on histological, virological, biochemical and serological responses mainly in treatment-naïve adults with HBeAg positive and HBeAg negative chronic hepatitis B with compensated liver disease.
Id- dimostrazzjoni tal- benefiċċju ta ’ tenofovir disoproxil fumarate hi bbażata fuq risponsi istoloġiċi, viroloġiċi, bijokimiċi u serologiċi prinċipalment f’ pazjenti adulti li qatt ma kienu ħadu din it- terapija qabel, b’ epatite B kronika b’ HBeAg pożittiv u b’ HBeAg negattiv b’ mard tal- fwied kumpensat.
Results through 48 weeks from two randomised, phase 3 double-blind studies comparing tenofovir disoproxil fumarate to adefovir dipivoxil in patients with compensated liver disease are presented in Table 2 below.
Riżultati wara 48 ġimgħa minn żewġ studji ta ’ fażi 3 li kienu randomised u double- blind li qabblu tenofovir disoproxil fumarate ma ’ adefovir dipivoxil f’ pazjenti b’ mard tal- fwied kumpensat huma ppreżentati f’ Tabella 2 hawn taħt.
Study GS-US-174-0103 was conducted in 266 (randomised and treated) HBeAg positive patients while study GS-US-174-0102 was conducted in 375 (randomised and treated) patients negative for HBeAg and positive for HBeAb.
Studju GS- US- 174- 0103 twettaq fuq 266 (randomised u ttrattati) pazjenti li kienu HBeAg pożittivi filwaqt li studju GS- US- 174- 0102 twettaq fi 375 (randomised u ttrattati) pazjenti li kienu HBeAg negattivi u HBeAb pożittivi.
In both of these studies tenofovir disoproxil fumarate was significantly superior to adefovir dipivoxil for the primary efficacy endpoint of complete response (defined as HBV DNA levels < 400 copies/ ml and Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis).
F’ dawn iż- żewġ studji, tenofovir disoproxil fumarate kien superjuri b’ mod sinifikanti għal adefovir dipivoxil għar- riżultat aħħari ta ’ l- effikaċja primarja ta ’ rispons sħiħ (definit bħala livelli tad- DNA tal - HBV ta ’ < 400 kopja/ ml u titjib fil- punteġġ nekroinfjammatorju ta ’ Knodell ta ’ mill- inqas 2 punti mingħajr ma marret għall- agħar il- fibrożi ta ’ Knodell.
Treatment with tenofovir disoproxil 245 mg (as fumarate) was also associated with significantly greater proportions of patients with HBV DNA < 400 copies/ ml, when compared to adefovir dipivoxil 10 mg treatment.
It- trattament b’ tenofovir disoproxil 245 mg (bħala fumarate) kien ukoll assoċjat ma ’ porzjonijiet akbar b’ mod sinifikanti ta ’ pazjenti b’ DNA tal - HBV ta ’ < 400 kopja/ ml, meta mqabbel mat- trattament b’ adefovir dipivoxil 10 mg.
Both treatments produced similar results with regard to histological response (defined as Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis) at week 48 (see Table 2 below).
Iż- żewġ trattamenti pproduċew riżultati simili fir- rigward ta ’ rispons istoloġiku (definit bħala titjib fil- punteġġ nekroinfjammatorju ta ’ Knodell ta ’ mill- inqas 2 punti mingħajr ma marret għall- agħar il- fibrożi ta ’ Knodell) f’ ġimgħa 48 (ara Tabella 2 hawn taħt).
In study GS-US-174-0103 a significantly greater proportion of patients in the tenofovir disoproxil fumarate group than in the adefovir dipivoxil group had normalised ALT and achieved HBsAg loss at week 48 (see Table 2 below).
Fi studju GS- US- 174- 0103, proporzjon akbar b’ mod sinifikanti ta ’ pazjenti fil- grupp ta ’ tenofovir disoproxil fumarate milli fil- grupp ta ’ adefovir dipivoxil, kellu ALT normalizzat u kiseb tnaqqis ta ’ HBsAg f’ ġimgħa 48 (ara Tabella 2 hawn taħt).
14 Table 2:
15 Tabella 2:
Efficacy parameters in compensated HBeAg positive and HBeAg negative patients at week 48
Parametri ta ’ l- effikaċja f’ pazjenti li kienu pożittivi għal HBeAg kumpensat u f’ pazjenti li kienu negattivi għal HBeAg kumpensat f’ ġimgħa 48
Study 174-0102 (HBeAg negative)
Studju 174- 0102 (HBeAg
Study 174-0103 (HBeAg positive)
Studju 174- 0103 (HBeAg
Parameter
Tenofovir
Tenofovir Adefovir dipivoxil
Adefovir dipivoxil
disoproxil 245 mg (as fumarate)
disoproxil 245 mg (bħala fumarate)
mg disoproxil 245 mg (as fumarate)
mg disoproxil 245 mg (bħala fumarate)
Complete response (%)a Histology
Rispons sħiħ (%) a Istoloġija
Histological response (%)b
Rispons istoloġiku (%) b
Median HBV DNA reduction from baselinec (log10 copies/ ml) HBV DNA (%)
Tnaqqis medjan fid - DNA tal- HBV mil - linja bażic (log10 kopji/ ml) DNA ta ’ l- HBV (%)
-4.7*
- 4. 7 *
-4.0 -6.4*
- 4. 0 - 6. 4 *
-3.7
- 3. 7
< 400 copies/ ml (< 69 IU/ ml) ALT (%)
< 400 kopja/ ml (< 69 IU/ ml) ALT (%)
Normalised ALTd Serology (%)
ALT normalizzatd Seroloġija (%)
HBeAg loss/ seroconversion
Tnaqqis/ serokon - verżjoni ta ’ HBeAg
N/ A N/ A
Mhux Applikabbli Mhux Applikabbli
HBsAg loss/ seroconversion
Tnaqqis/ serokon - verżjoni ta ’ HBsAg
* p-value versus adefovir dipivoxil < 0.05, a Complete response defined as HBV DNA levels < 400 copies/ ml and Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis, b Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis, c Median change from baseline HBV DNA merely reflects the difference between baseline HBV DNA and the limit of detection (LOD) of the assay, d The population used for analysis of ALT normalisation included only patients with ALT above ULN at baseline.
* valur p versus adefovir dipivoxil ta ’ < 0. 05, a rispons sħiħ definit bħala livelli tad- DNA tal- HBV ta ’ < 400 kopja/ ml u titjib fil- punteġġ nekroinfjammatorju ta ’ Knodell ta ’ mill- inqas 2 punti mingħajr ma marret għall- agħar il- fibrożi ta ’ Knodell, b titjib fil- punteġġ nekroinfjammatorju ta ’ Knodell ta ’ mill- inqas 2 punti mingħajr ma marret għall- agħar il- fibrożi ta ’ Knodell, c Tibdil medjan mil- linja bażi DNA tal- HBV sempliċiment tirrifletti d- differenza bejn id- DNA tal- HBV fil- linja bażi u l - limitu ta ’ l- osservazzjoni (LOD) ta ’ l- assaġġ, d Il- popolazzjoni wżata għal analiżi tan- normalizzazzjoni ta ’ l- ALT kienet tinkludi biss pazjenti b’ ALT li kien ogħla mill- ULN fil- linja bażi.
Tenofovir disoproxil fumarate was associated with significantly greater proportions of patients with undetectable HBV DNA (< 169 copies/ ml [< 29 IU/ ml]; the limit of quantification of the Roche Cobas Taqman HBV assay), when compared to adefovir dipivoxil (study GS-US-174-0102; 91%, 56% and study GS-US-174-0103; 69%, 9%), respectively.
Tenofovir disoproxil fumarate kien assoċjat ma ’ porzjonijiet akbar b’ mod sinifikanti ta ’ pazjenti b’ DNA ta ’ l- HBV li ma setgħetx tkun osservata (< 169 kopja/ ml [< 29 IU/ ml]; il- limitu tal - kwantifikazzjoni ta ’ l- assaġġ Roche Cobas Taqman HBV), meta mqabbel ma ’ adefovir dipivoxil (studju GS- US- 174- 0102; 91%, 56% u studju GS- US- 174- 0103; 69%, 9%), rispettivament.
Response to treatment with tenofovir disoproxil fumarate was comparable in nucleoside-experienced (n = 51) and nucleoside-naïve (n = 375) patients and in patients with normal ALT (n = 21) and abnormal ALT (n = 405) at baseline when studies GS-US-174-0102 and GS-US-174-0103 were combined.
Ir- rispons għat- trattament b’ tenofovir disoproxil fumarate kien komparabbli f’ pazjenti li fil- passat ingħataw nukleosides (n = 51) u pazjenti li qatt ma ’ ngħataw nukleosides (n = 375) u f’ pazjenti b’ ALT normali (n = 21) u ALT anormali (n = 405) fil- linja bażi meta l- istudji GS- US- 174- 0102 u GS- US- 174- 0103 kienu kkombinati.
Forty-nine of the 51 nucleoside-experienced patients were previously treated with lamivudine.
Disa ’ u erbgħin mill- 51 pazjenti li fil- passat ingħataw in - nukleosides, kienu ttrattati b’ lamivudine fil- passat.
Seventy-three percent of nucleoside-experienced and 69% of nucleoside-naïve patients achieved complete response to treatment; 90% of nucleoside-naïve and 88% of nucleoside-experienced patients achieved HBV DNA suppression < 400 copies/ ml.
Tlieta u sebgħin fil- mija ta ’ pazjenti li fil- passat ingħataw in- nukleosides u 69% tal- pazjenti li qatt ma ’ ngħataw nukleosides irnexxielhom jiksbu rispons sħiħ għat- trattament; 90% tal- pazjenti li qatt ma ’ ngħataw nukleosides u 88% li fil- passat ingħataw nukleosides kisbu trażżin tad- DNA tal- HBV ta ’ < 400 kopja/ ml.
All patients with normal ALT at baseline and 88% of patients with abnormal ALT at baseline achieved HBV DNA suppression < 400 copies/ ml.
Il- pazjenti kollha b’ ALT normali fil- linja bażi u 88% ta ’ pazjenti b’ ALT anormali fil- linja bażi kisbu trażżin tad- DNA tal- HBV ta ’ < 400 kopja/ ml.
In a randomised, 48-week double-blind, controlled study of tenofovir disoproxil 245 mg (as fumarate) in patients co-infected with HIV-1 and chronic hepatitis B with prior lamivudine experience (study ACTG 5127), the mean serum HBV DNA levels at baseline in patients randomised to the tenofovir
Fi studju randomised li dam 48 ġimgħa, ikkontrollat u double- blind, dwar tenofovir disoproxil 245 mg (bħala fumarate) f’ pazjenti ko- infettati bl- HIV- 1 u bl- epatite B kronika li fil- passat ingħataw lamivudine (studju ACTG 5127), il- medja tal- livelli tas- serum DNA tal- HBV fil- linja bażi f’ pazjenti randomised fil- parti ta ’ l- istudju dwar tenofovir kienet ta ’ 9. 45 log10 kopja/ ml (n = 27).
Treatment with tenofovir disoproxil 245 mg (as fumarate) was associated with a mean change in serum HBV DNA from baseline, in the patients for whom there was 48-week data, of -5.74 log10 copies/ ml (n = 18).
It- trattament 16 b’ tenofovir disoproxil 245 mg (bħala fumarate) kien assoċjat ma ’ bidla medja tad- DNA tal- HBV fis - serum mil- linja bażi, fil- pazjenti li għalihom kien hemm dejta ta ’ 48 ġimgħa, ta ’ - 5. 74 log10 kopja/ ml (n = 18).
In addition, 61% of patients had normal ALT at week 48.
Flimkien ma ’ dan, 61% tal- pazjenti kellhom ALT normali f’ ġimgħa 48.
Experience in patients with persistent viral replication:
L- esperjenza f’ pazjenti b’ replikazzjoni virali persistenti:
The efficacy and safety of tenofovir disoproxil 245 mg (as fumarate) or tenofovir disoproxil 245 mg (as fumarate) plus 200 mg emtricitabine is being evaluated in a randomised, double-blind study (study GS-US-174-0106), in HBeAg positive and HBeAg negative patients who had persistent viraemia (HBV DNA ≥ 1,000 copies/ ml) while receiving adefovir dipivoxil 10 mg for more than 24 weeks.
L- effikaċja u s- sigurtà ta ’ tenofovir disoproxil 245 mg (bħala fumarate) jew ta ’ tenofovir disoproxil 245 mg (bħala fumarate) flimkien ma ’ 200 mg ta ’ emtricitabine qed ikunu evalwati fi studju randomised u double- blind (studju GS- US- 174- 0106), f’ pazjenti li kienu HBeAg pożittivi u pazjenti li kienu HBeAg negattivi li kellhom viremija persistenti (DNA tal- HBV ta ’ ≥ 1, 000 kopja/ ml) waqt li kienu qed jirċievu adefovir dipivoxil 10 mg għal iktar minn 24 ġimgħa.
Overall at week 24, treatment with a tenofovir-containing regimen resulted in 77% (46/ 60) of patients with HBV DNA < 400 copies/ ml (< 69 IU/ ml) and 62% (37/ 60) of patients with undetectable HBV DNA (below 169 copies/ ml [< 29 IU/ ml]; the limit of quantification of the Roche Cobas TaqMan HBV assay).
Globalment, f’ ġimgħa 24, it- trattament b’ kors li kien fih tenofovir, irriżulta f’ 77% (46/ 60) tal- pazjenti b’ DNA tal- HBV ta ’ < 400 kopja/ ml (< 69 IU/ ml) u 62% (37/ 60) tal- pazjenti b’ DNA tal- HBV li ma setgħetx tkun osservata (taħt 169 kopja/ ml [< 29 IU/ ml]; il- limitu tal- kwantifikazzjoni ta ’ l- assaġġ ta ’ l- HBV ta ’ Roche Cobas TaqMan).
In addition, at week 24, the percentage of patients who had normal ALT was 68% (42/ 62).
Flimkien ma ’ dan, f’ ġimgħa 24, il- perċentwali ta ’ pazjenti li kellhom ALT normali kien ta ’ 68% (42/ 62).
Four hundred and twenty-six HBeAg negative (GS-US-174-0102, n = 250) and HBeAg positive (GS-US-174-0103, n = 176) patients were evaluated for genotypic changes in HBV polymerase.
Erba ’ mija u sitta u għoxrin pazjent li kienu HBeAg negattivi (GS- US- 174- 0102, n = 250) u HBeAg pożittivi (GS- US- 174- 0103, n = 176) kienu evalwati għal tibdil ġenotipiku fil - polymerase tal- HBV.
Genotypic evaluations were performed on all patients with HBV DNA > 400 copies/ ml at week 48.
Evalwazzjonijiet ġenotipiċi saru fuq il- pazjenti kollha b’ DNA tal- HBV ta ’ > 400 kopja/ ml f’ ġimgħa 48.
No mutations associated with tenofovir disoproxil fumarate resistance have been identified.
L- ebda mutazzjonijiet assoċjati mar- reżistenza ta ’ tenofovir disoproxil fumarate ma kienu identifikati.
Tenofovir disoproxil fumarate is a water soluble ester prodrug which is rapidly converted in vivo to tenofovir and formaldehyde.
Tenofovir disoproxil fumarate huwa prodrug ta ’ l- ester li jinħall fl- ilma li jinbidel malajr in vivo għal tenofovir u formaldehyde.
Tenofovir is converted intracellularly to tenofovir monophosphate and to the active component, tenofovir diphosphate.
Tenofovir jinbidel intraċellularment għall- monophosphate ta ’ tenofovir u għall- komponent attiv, tenofovir diphosphate.
Absorption Following oral administration of tenofovir disoproxil fumarate to HIV infected patients, tenofovir disoproxil fumarate is rapidly absorbed and converted to tenofovir.
Assorbiment Wara l- għoti mill- ħalq ta ’ tenofovir disoproxil fumarate lill- pazjenti infettati b’ HIV, tenofovir disoproxil fumarate jiġi assorbit malajr u jinbidel f’ tenofovir.
Administration of multiple doses of tenofovir disoproxil fumarate with a meal to HIV infected patients resulted in mean (%CV) tenofovir Cmax, AUC0-∞, and Cmin values of 326 (36.6%) ng/ ml, 3,324 (41.2%) ng·h/ ml and 64.4 (39.4%) ng/ ml, respectively.
L- għoti ta ’ dożi multipli ta ’ tenofovir disoproxil fumarate ma ’ l- ikel lill- pazjenti infettati b’ HIV irriżulta f’ medja (% CV) ta ’ valuri ta ’ tenofovir Cmax, AUC0- ∞, u Cmin ta ’ 326 (36. 6%) ng/ ml, 3, 324 (41. 2%) ng· h/ ml u 64. 4 (39. 4%) ng/ ml, rispettivament.
Maximum tenofovir concentrations are observed in serum within one hour of dosing in the fasted state and within two hours when taken with food.
Konċentrazzjonijiet massimi ta ’ tenofovir jidhru fis- serum fi żmien siegħa mill- għoti tad- doża fl- istat sajjem u fi żmien sagħtejn minn meta jittieħed ma ’ l- ikel.
The oral bioavailability of tenofovir from tenofovir disoproxil fumarate in fasted patients was approximately 25%.
Il- biodisponibilità orali ta ’ tenofovir minn tenofovir disoproxil fumarate f’ pazjenti sajmin kienet ta ’ madwar 25%.
Administration of tenofovir disoproxil fumarate with a high fat meal enhanced the oral bioavailability, with an increase in tenofovir AUC by approximately 40% and Cmax by approximately 14%.
L- għoti ta ’ tenofovir disoproxil fumarate ma ’ ikla li fiha ħafna xaħam għolliet il- biodisponibilità orali, bi żieda fl - AUC ta ’ tenofovir ta ’ madwar 40% u Cmax b’ madwar 14%.
Following the first dose of tenofovir disoproxil fumarate in fed patients, the median Cmax in serum ranged from 213 to 375 ng/ ml.
Wara l- ewwel doża ta ’ tenofovir disoproxil fumarate f’ pazjenti li kienu kielu, il- medjana ta ’ Cmax fis- serum kienet ta ’ bejn 213 u 375 ng/ ml.
However, administration of tenofovir disoproxil fumarate with a light meal did not have a significant effect on the pharmacokinetics of tenofovir.
Madankollu, l- għoti ta ’ tenofovir disoproxil fumarate ma ’ ikla ħafifa ma kellhiex effett sinifikanti fuq il- farmakokinetiċi ta ’ tenofovir.
Distribution Following intravenous administration the steady-state volume of distribution of tenofovir was estimated to be approximately 800 ml/ kg.
Distribuzzjoni Wara l- għoti minn ġol- vina, il- livell ta ’ distribuzzjoni ta ’ tenofovir fiss kien stmat li huwa ta ’ madwar 800 ml/ kg.
After oral administration of tenofovir disoproxil fumarate, tenofovir is distributed to most tissues with the highest concentrations occurring in the kidney, liver and the intestinal contents (preclinical studies).
Wara l- għoti mill- ħalq tenofovir disoproxil fumarate, tenofovir jiġi mqassam lill- biċċa l - kbira fit- tessuti bl- ogħla konċentrazzjonijiet iseħħu fil- kontenut tal- kliewi, tal- fwied u ta ’ l- imsaren (studji prekliniċi).
In vitro protein binding of tenofovir to plasma or serum protein was less than 0.7 and 7.2%, respectively, over the tenofovir concentration range 0.01 to 25 µg/ ml.
Ir- rabta in vitro ta ’ tenofovir ma ’ proteini tal- plażma jew proteini fis- serum kienet anqas minn 0. 7 and 7. 2%, rispettivament, ogħla mill- medda tal- konċentrazzjoni ta ’ tenofovir 0. 01 sa 25 µg/ ml.
Biotransformation In vitro studies have determined that neither tenofovir disoproxil fumarate nor tenofovir are substrates for the CYP450 enzymes.
Bijotrasformazzjoni Studji in vitro wrew li la tenofovir disoproxil fumarate u lanqas tenofovir ma huma sottostrati għall - enzimi CYP450.
Tenofovir disoproxil fumarate at a concentration of 100 µmol/ l had no
Barra minn hekk, f’ konċentrazzjonijiet li huma sostanzjalment ogħla (madwar 300 darba iżjed) minn dawk osservati in vivo, tenofovir ma inibixxiex in vitro l- metaboliżmu tal - mediċina medjata minn xi wieħed mill- iżoformi umani maġġuri ta ’ CYP450 involuti fil - bijotrasformazzjoni tad- mediċina (CYP3A4, CYP2D6, CYP2C9, CYP2E1, jew CYP1A1/ 2).
16 effect on any of the CYP450 isoforms, except CYP1A1/ 2, where a small (6%) but statistically significant reduction in metabolism of CYP1A1/ 2 substrate was observed.
17 Tenofovir disoproxil fumarate f’ konċentrazzjoni ta ’ 100 µmol/ l ma kellux effett fuq xi iżoformi ta ’ CYP450 ħlief CYP1A1/ 2, fejn tnaqqis żgħir (6%) imma statistikament sinifikanti fil- metaboliżmu tas - sottostrat CYP1A1/ 2 kien osservat.
Based on these data, it is unlikely that clinically significant interactions involving tenofovir disoproxil fumarate and medicinal products metabolised by CYP450 would occur.
Skond din l- informazzjoni, mhuwiex probabbli li jseħħu interazzjonijiet klinikament sinifikanti li jinvolvu tenofovir disoproxil fumarate u prodotti mediċinali metabolizzati minn CYP450.
Elimination Tenofovir is primarily excreted by the kidney by both filtration and an active tubular transport system with approximately 70-80% of the dose excreted unchanged in urine following intravenous administration.
Eliminazzjoni Tenofovir jitneħħa mill- ġisem prinċipalment mill- kliewi kemm permezz tal- filtrazzjoni kif ukoll permezz ta ’ sistema attiva ta ’ trasport tubulari b’ madwar 70- 80% tad- doża titneħħa mingħajr tibdil fl- awrina wara l- għoti minn ġol- vina.
Total clearance has been estimated to be approximately 230 ml/ h/ kg (approximately 300 ml/ min).
It- tneħħija totali ġiet stmata li hi madwar 230 ml/ h/ kg (madwar 300 ml/ min).
Renal clearance has been estimated to be approximately 160 ml/ h/ kg (approximately 210 ml/ min), which is in excess of the glomerular filtration rate.
It- tneħħija mill- kliewi ġiet stmata li hi madwar 160 ml/ h/ kg (madwar 210 ml/ min), li huwa iżjed mir- rata tal- filtrazzjoni glomerulari.
Following oral administration the terminal half-life of tenofovir is approximately 12 to 18 hours.
Wara li jittieħed mill- ħalq il- ħin terminali biex tenofovir jonqos bin- nofs hu ta ’ madwar 12 sa 18- il siegħa.
Studies have established the pathway of active tubular secretion of tenofovir to be influx into proximal tubule cell by the human organic anion transporters (hOAT) 1 and 3 and efflux into the urine by the multidrug resistant protein 4 (MRP 4).
L- istudji stabbilixxew il- passaġġ tas- sekrezzjoni tubulari attiva ta ’ tenofovir li jkun influss ġoċ- ċellula tat- tubulu prossimali mit- trasportaturi enajoniċi organiċi umani (hOAT) 1 u 3 u l- effluss ġol- awrina mill- proteina 4 reżistenti kontra ħafna mediċini (MRP 4 - multidrug resistant protein 4).
Linearity/ non-linearity The pharmacokinetics of tenofovir were independent of tenofovir disoproxil fumarate dose over the dose range 75 to 600 mg and were not affected by repeated dosing at any dose level.
Linejarità/ non- linejarità Il- farmakokinetiċi ta ’ tenofovir independenti mid- doża ta ’ tenofovir disoproxil fumarate kontra l- medda tad- dożaġġ ta ’ 75 sa 600 mg u ma kienux affettwati b’ doża ripetuta f’ xi livell ta ’ dożaġġ.
Age and gender Limited data on the pharmacokinetics of tenofovir in women indicate no major gender effect.
Età u sess Informazzjoni limitata dwar il- farmakokinetiċi ta ’ tenofovir fin- nisa ma jindika l- ebda effett importanti fuq is- sess.
Pharmacokinetic studies have not been performed in children and adolescents (under 18) or in the elderly (over 65).
Studji farmakokinetiċi ma ’ sarux fuq it- tfal u l- adolexxenti (taħt it- 18- il sena) jew fuq l- anzjani (’ l fuq minn 65 sena).
Pharmacokinetics have not been specifically studied in different ethnic groups.
Il- farmakokinetiċi ma ġewx studjati speċifikament fi gruppi etniċi differenti.
Renal impairment Pharmacokinetic parameters of tenofovir were determined following administration of a single dose of tenofovir disoproxil 245 mg to 40 non-HIV, non-HBV infected patients with varying degrees of renal impairment defined according to baseline creatinine clearance (CrCl) (normal renal function when CrCl > 80 ml/ min; mild with CrCl = 50-79 ml/ min; moderate with CrCl = 30-49 ml/ min and severe with CrCl = 10-29 ml/ min).
Indeboliment renali Il- parametri farmakokinetiċi ta ’ tenofovir kienu deċiżi wara l- għoti ta ’ doża waħda ta ’ 245 mg tenofovir disoproxil lil 40 pazjent mhux infettati b’ HIV, u dawk mhux infettati bl- HBV b’ livelli differenti ta ’ indeboliment renali definiti skond il- linja bażi tat- tneħħija tal- krejatinina (CrCl) (funzjoni renali normali meta CrCl > 80 ml/ min; indeboliment ħafif b’ CrCl = 50- 79 ml/ min; indeboliment moderat b’ CrCl = 30- 49 ml/ min u indeboliment sever b’ CrCl = 10- 29 ml/ min).