qanastek/EMEA-V3 huggingface dataset:
No definitive conclusion could be drawn regarding the effects of telbivudine on the pharmacokinetics of pegylated 5 interferon due to high interindividual variability of pegylated interferon alfa-2a concentrations.
Ma setgħetx tinstab konklużjoni definittiva dwar l- effetti ta ’ telbivudine fuq il - farmakokinetiċi ta ’ interferon alfa pegilat minħabba l- varjabbiltà kbira bejn individwu u ieħor fil - konċentrazzjonijiet ta ’ interferon alfa- 2a pegilat.
A clinical trial investigating the combination of telbivudine, 600 mg daily, with pegylated interferon alfa-2a, 180 micrograms once weekly by subcutaneous administration, indicates that this combination is associated with an increased risk of developing peripheral neuropathy.
Prova klinika li kienet qed tinvestiga it- taħlita ta ’ telbivudine, 600 mg kuljum, ma interferon alfa- 2a pegilat, 180 mikrogrammi darba fil- ġimgħa permezz ta ’ għotja taħt il- ġilda, tindika li din it- taħlita hija assoċjata ma ’ żieda fir- riskju li tiżviluppa newropatija periferali.
The mechanism behind these events is not known (see section 4.4).
Il- mekkaniżmu wara dawn l- eventi mhux magħruf (ara sezzjoni 4. 4).
Telbivudine is not a substrate, inhibitor or inducer of the cytochrome P450 (CYP450) enzyme system (see section 5.2). Therefore, the potential for CYP450-mediated drug interactions involving Sebivo is low.
Għaldaqstant, il- potenzjal li jkun hemm interazzjonijiet permezz ta ’ CYP450 li jinvolvu Sebivo huwa baxx.
For telbivudine no clinical data on exposed pregnancies are available.
Għal telbivudine m’ hemmx tagħrif kliniku dwar l- użu waqt it- tqala.
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/ foetal development, parturition or postnatal development (see section 5.3).
Studji fuq l- annimali ma jurux effetti ħżiena diretti fuq it- tqala, fuq l- iżvilupp ta 'l- embriju/ fetu, ħlas jew żvilupp wara t- twelid (ara sezzjoni 5. 3).
Studies in pregnant rats and rabbits showed that telbivudine crosses the placenta.
Studji f’ firien u fniek waqt it- tqala wrew li telbivudine jaqsam il- plaċenta.
Studies in pregnant rabbits showed early delivery and/ or abortion secondary to maternal toxicity.
Studji fi fniek waqt it- tqala wrew ħlas qabel il- waqt u/ jew abort wara li jkun hemm tossiċità fl- omm.
Sebivo should be used during pregnancy only if the benefit to the mother outweighs the potential risk to the foetus.
Sebivo għandu jintuża biss waqt it- tqala jekk il- benefiċċju għall- omm jegħleb ir- riskju potenzjali għall- fetu.
There are no data on the effect of telbivudine on transmission of HBV from mother to infant.
M’ hemmx tagħrif dwar l- effett ta ’ telbivudine fuq it- tixrid ta ’ HBV mill- omm għal binha.
Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV infection.
Għaldaqstant, għandhom isiru interventi xierqa biex jevitaw it- teħid ta ’ l- infezzjoni ta ’ l- HBV mit - tarbija tat- twelid.
Telbivudine is excreted in the milk of rats.
Telbivudine jgħaddi fil- ħalib tal- firien.
It is not known whether telbivudine is excreted in human milk.
Mhux magħruf jekk telbivudine joħroġx fil- ħalib tal- mara.
Women should not breast-feed if they are taking Sebivo.
In - nisa m’ għandhomx ireddgħu waqt li jkunu qed jieħdu Sebivo.
There are no clinical data on the effects of telbivudine on male or female fertility.
M’ hemmx tagħrif kliniku dwar l- effetti ta ’ telbivudine fuq il- fertilità maskili jew femminili.
In reproductive toxicology studies, no evidence of impaired fertility was seen in male or female rats at systemic exposures approximately 14 times those observed in humans at the therapeutic dose.
Fi studji dwar it- tossiċità fuq is- sistema riproduttiva, ma deherx li kien hemm xi telf fil- fertilità tal- firien maskili jew femminili f’ esponimenti sistemiċi madwar 14- il darba dawk ji jidhru fil- bniedem waqt dożi terapewtiċi.
Assessment of adverse reactions is mainly based on two studies (NV-02B-007 “ GLOBE” and NV- 02B-015) in which 1,699 patients with chronic hepatitis B received double-blind treatment with telbivudine 600 mg/ day (n = 847) or lamivudine (n = 852) for 104 weeks.
L- istima ta ’ reazzjonijiet avversi hija l- aktar bażata fuq żewġ studji (NV- 02B- 007 “ GLOBE ” u NV - 02B- 015) li fihom 1, 699 pazjent b’ epatite B kronika rċevew kura double- blind b’ telbivudine 600 mg/ jum (n = 847) jew lamivudine (n = 852) għal 104 ġimgħat.
In the 104-week clinical studies, reported adverse reactions were usually classified as mild or moderate in severity.
Fl- istudji kliniċi ta’ 104 ġimgħat, reazzjonijiet avversi li kienu rappurtati kienu s- soltu kklassifikati bħala ħfief jew moderati fis- severità tagħhom.
The most common adverse events with at least a possible relation to telbivudine were grade 3/ 4 blood creatine kinase elevations (6.8%), fatigue (4.4%), headache (3.0%) and nausea (2.6%).
L- aktar reazzjonijiet avversi komuni b’ relazzjoni possibli ma ’ telbivudine kienu elevazzjonijiet ta ’ creatine kinase fid- demm (6. 8%) ta ’ grad 3/ 4, għeja (4. 4%), uġigħ ta ’ ras (3. 0%) u tqalligħ (2. 6%).
Table 2 lists the adverse reactions recorded in the pooled 104-week NV-02B-007 GLOBE and NV- 02B-015 studies by system organ class and by frequency using the following convention: very common (≥ 1/ 10); common (≥ 1/ 100 to < 1/ 10); uncommon (≥ 1/ 1,000 to < 1/ 100); rare (≥ 1/ 10,000 to < 1/ 1,000); very rare (< 1/ 10,000).
6 Tabella 2 telenka r- reazzjonijiet avversi li kienu reġistrati b’ mod kollettiv fl- istudji NV- 02B- 007 GLOBE u NV- 02B- 015 ta ’ 104 ġimgħat skond il- klassi tas- sistema ta ’ l- organi u skond il- frekwenza billi ntużat il- konvenzjoni li ġejja: komuni ħafna (≥1/ 10); komuni (≥1/ 100 sa < 1/ 10); mhux komuni (≥1/ 1, 000 sa < 1/ 100); rari (≥1/ 10, 000 sa < 1/ 1, 000); rari ħafna (< 1/ 10, 000).
Clinical adverse reactions in patients with chronic hepatitis B, treated with telbivudine 600 mg in the pooled 104-week NV-02B-007 (GLOBE) and NV-02B-015 studies*
Tabella 2 Reazzjonijiet kliniċi avversi kollettivi f’ pazjenti b’ epatite B kronika, kurati b’ telbivudine 600 mg fl- istudji NV- 02B- 007 (GLOBE) u NV- 02B- 015 ta ’ 104 ġimgħat *
Dizziness, headache Peripheral neuropathy, dysgeusia, hypoaesthesia, paresthesia, sciatica
Sturdament, uġigħ ta ’ ras Newropatija periferali, disgewżja, ipoestesija, parestesija, xjatika
Blood amylase increased, diarrhoea, blood lipase increased, nausea, abdominal pain
Żieda fl- amylase tad- demm, dijarea, żieda fil - lipase fid- demm, tqalligħ u uġigħ addominali
Blood creatine phosphokinase increased Arthralgia, myalgia, myopathy/ myositis, pain in the extremities, back pain, muscle spasm, neck pain, flank pain
Creatine phosphokinase fid- demm jiżdied Artralġja, mijalġja, majopatija/ mijożite, uġigħ fl - idejn u fis- saqajn, uġigħ fid- dahar, spażmu tal - muskolu, uġigħ fl- għonq, uġigħ ’ l fuq mill - ġenbejn
Fatigue Malaise
Għeja Tħossok ma tiflaħx
Blood alanine aminotransferase increased Aspartate aminotransferase increased
Żieda fl- alanine aminotransferase fid- demm Żieda fl- aspartate aminotransferase
* Due to the sample size of the pooled analysis (NV-02B-007 [GLOBE] and NV-02B-015), there are insufficient numbers of telbivudine-treated patients to detect rare and very rare events.
* Minħabba d- daqs tal- kampjun ta ’ l- analiżi (NV- 02B- 007 [GLOBE] u NV- 02B- 015) kollettiva, m’ hemmx numru biżżejjed ta ’ pazjenti ikkurati b’ telbivudine sabiex jinstabu każijiet rari u rari ħafna.
In the pooled analysis, by 104 weeks of treatment Grade 3/ 4 creatine kinase elevations (> 7x ULN) occurred in 12.6% of telbivudine-treated patients and 4.0% of lamivudine-treated patients.
Fl- analiżi kollettiva, sa 104 ġimgħat ta ’ kura żidiet (> 7x ULN) fil- creatine kinase ta ’ Gradi 3/ 4 seħħew f’ 12. 6% tal- pazjenti kurati b’ telbivudine u f’ 4. 0% tal- pazjenti kurati b’ lamivudine.
Most creatine kinase elevations were asymptomatic and creatine kinase values typically decreased by the next visit on continued treatment.
Ħafna miż - żidiet fil- creatine kinase kienu mingħajr sintomi u bħala regola il- valuri ta ’ creatine kinase naqsu maż - żjara li kien imiss wara li titkompla l- kura.
In the pivotal study NV-02B-007 (GLOBE), higher pre-treatment CK values and Caucasian race were identified in both treatment groups as predictive factors for Grade 3/ 4 elevations by 104 weeks.
Fl- istudju pivitali NV- 02B- 007 (GLOBE), valuri CK ogħla qabel il- kura kif ukoll razza Kawkaża kienu identifikati fiż- żewġ gruppi ta ’ kura bħala fatturi ta ’ tbassir għal żidiet ta ’ Grad 3/ 4 sa 104 ġimgħat.
The incidence of on treatment alanine aminotransferase (ALT) flares in the two treatment arms according to AASLD (American Association for the Study of Liver Diseases) definition (ALT elevation > 2x baseline and > 10x ULN) are further described in Table 3 below.
In- numru ta ’ drabi li fihom seħħew żiediet f’ daqqa ta ’ alanine aminotransferase (ALT) waqt il- kura fiż- żewġ fergħat skond id- definizzjoni ta ’ l- AASLD (Assoċjazzjoni Amerikana għall- Istudji tal- Mard tal- Fwied) (żieda ta ’ l- ALT ta ’ > 2 darbiet mill- linja bażi u > 10 darbiet l- ULN) huma spjegati aktar f’ Tabella 3 taħt.
Summary of on treatment ALT (IU/ L) flare – Pooled NV-02B-007/ NV-02B-015
7 Tabella 3 Sommarju taż- żidiet f’ daqqa ta ’ l- ALT (IU/ L) – Kollettiva NV- 02B- 007/ NV- 02B- 015
ALT flare:
Żieda f’ daqqa ta ’ l- ALT:
ALT elevation > 2x baseline and > 10x ULN
Żieda ta ’ l- ALT > 2 darbiet il- linja bażi u > 10 darbiet ULN
Overall Baseline to week 24 Week 24 to end of study
B’ mod globali Linja bażi sa ’ ġimgħa 24 Ġimgħa 24 sa ’ tmiem l- istudju
67/ 852 (7.9) 25/ 852 (2.9) 44/ 837 (5.3)
67/ 852 (7. 9) 25/ 852 (2. 9) 44/ 837 (5. 3)
41/ 847 (4.8) 25/ 847 (3.0) 17/ 834 (2.0)
41/ 847 (4. 8) 25/ 847 (3. 0) 17/ 834 (2. 0)
Periodic monitoring of hepatic function is recommended during treatment (see section 4.4).
Monitoraġġ perjodiku tal- funzjoni epatika huwa kunsiljat waqt il- kura (ara sezzjoni 4. 4).
Exacerbations of hepatitis B after discontinuation of treatment Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti- hepatitis B therapy including telbivudine (see section 4.4).
Każijiet fejn l- epatite B tiħrax wara li titwaqqaf il- kura.
The incidence of post-treatment alanine aminotransferase (ALT) flares in the two treatment arms are further described in Table 4 below.
Każijiet fejn epatite B ħraxet f’ daqqa b’ mod sever kienu rrappurtati f’ pazjenti li waqqfu it- terapija kontra l- epatite B inkluż telbivudine (ara sezzjoni 4. 4).
Table 4
In- numru ta ’ drabi meta kien hemm żiediet f’ daqqa ta ’ alanine aminotransferase (ALT) fiż- żewġ fergħat ta ’ kura huma deskritti aktar f’ Tabella 4 hawn taħt.
Summary of post-treatment ALT flares – Pooled NV-02B-007/ NV-02B-015
Tabella 4 Sommarju taż- żiediet f’ daqqa wara l- kura ta ’ l- ALT – Kollettiva NV- 02B- 007/ NV - 02B- 015
ALT flare
Żieda f’ daqqa ta ’ l- ALT Żieda ta ’ l- ALT > 2 darbiet il- linja bażi u > 10
ALT elevation > 2x baseline and > 10x ULN
darbiet l- ULN
10/ 180 (5.6)
10/ 180 (5. 6)
9/ 154 (5.8)
9/ 154 (5. 8)
There is no information on intentional overdose of telbivudine, but one subject was given an unintentional overdose which was asymptomatic.
M’ hemmx tgħarif dwar doża eċċessiva b’ telbivudine intenzjonata, iżda individwu ingħata doża eċċessiva bla ħsieb li kienet mingħajr sintomi.
Tested doses up to 1,800 mg/ day, three times greater than the recommended daily dose, have been well tolerated.
Saru testijiet b’ dożi sa 1, 800 mg/ jum, tlett darbiet aktar mid- doża ta ’ kuljum kunsiljata, u dawn kienu tollerati sew.
A maximum tolerated dose of telbivudine has not been determined.
Għadha ma ġietx stabbilita d- doża massima li hija tollerata.
In the event of an overdose, Sebivo should be discontinued and appropriate general supportive treatment applied as necessary.
F’ każ ta ’ doża eċċessiva, Sebivo għandu jitwaqqaf u tingħata kura ta ’ support kif ikun xieraq.
Nucleoside and nucleotide reverse transcriptase inhibitors, ATC code:
Inibituri tan- nucleoside u tan- nucleotide reverse transcriptase, Kodiċi ATC:
Telbivudine is a synthetic thymidine nucleoside analogue with activity against HBV DNA polymerase.
Telbivudine huwa analogu ta ’ thymidine nucleoside sintetiku attiv kontra HBV DNA polymerase.
It is efficiently phosphorylated by cellular kinases to the active triphosphate form, which has an intracellular half-life of 14 hours.
Jiġi fosforilat b’ mod effiċjenti bil- kinases taċ- ċelluli fil- forma triphosphate attiva, li fiċ- ċelluli għandu half- life ta ’ 14- il siegħa.
Telbivudine-5'-triphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate, thymidine 5'-triphosphate.
Telbivudine- 5 ’ - triphosphate jinibixxi HBV DNA polymerase (reverse transcriptase) billi jikkompeti mas- sustrat naturali, thymidine- 5 ’ - triphosphate.
Incorporation of telbivudine-5'-triphosphate into viral DNA causes DNA chain termination, resulting in inhibition of HBV replication.
Meta telbivudine- 5 ’ - triphosphatase jiġi nkorporat fid- DNA tal- virus, il- katina tad- DNA tiġi terminata, u b’ hekk ir - replikazzjoni ta ’ HBV tieqaf.
Telbivudine is an inhibitor of both HBV first strand (EC50 = 0.4-1.3 μ M) and second strand (EC50 = 0.12-0.24 μ M) synthesis, and shows a distinct preference for inhibiting second strand production.
Telbivudine jinibixxi s- sinteżi kemm ta ’ l- ewwel strand (EC50 = 0. 4- 1. 3 μM) kif ukoll tat- tieni (EC50 = 0. 12- 0. 24 μM), u juri preferenza distinta għall - inibizzjoni tal- produzzjoni tat- tieni strand.
By contrast, telbivudine-5'-triphosphate at concentrations up to 100 μ M did not inhibit cellular DNA polymerases α, β, or γ.
B’ kuntrast, konċentrazzjonijiet ta ’ telbivudine- 5 ’ - triphosphate sa 100 μM ma wasslux għall- inibizzjoni ta ’ DNA polymerases ċellulari α, β, jew γ.
In assays relating to mitochondrial structure, function and DNA content, telbivudine lacked appreciable toxic effect at concentrations up to at 10 μ M and did not increase lactic acid production in vitro.
F’ assays dwar l- istruttura tal- mitokondriji, il- funzjoni u l- kontenut ta ’ DNA, telbivudine ma kellux effett tossiku rilevanti f’ konċentrazzjonijiet sa 10 μM u ma żiedx il- produzzjoni ta ’ lactic acid in vitro.
8 The in vitro antiviral activity of telbivudine was assessed in the HBV-expressing human hepatoma cell line 2.2.15.
8 L- attività antivirali in vitro ta ’ telbivudine kienet stmata fil- linja ta ’ ċelluli ta ’ epatoma tal- bniedem 2. 2. 15 li jesprimu HBV.
The concentration of telbivudine that effectively inhibited 50% of viral synthesis (EC50) was approximately 0.2 μ M.
Il- konċentrazzjoni ta ’ telbivudine li għamlet inibizzjoni effettiva ta ’ 50% tas - sinteżi virali (EC50) kienet madwar 0. 2 μM.
The antiviral activity of telbivudine is specific to the hepatitis B virus and related hepadnaviruses.
L- attività antivirali ta ’ telbivudine hija speċifika għall - virus ta ’ epatite B u l- ħepadnaviruses relatati.
Telbivudine was not active against HIV in vitro.
Telbivudine ma kienx attiv kontra HIV in vitro.
The absence of activity of telbivudine against HIV has not been evaluated in clinical trials.
In - nuqqas ta ’ attività ta ’ telbivudine kontra HIV ma ġietx stmata fi provi kliniċi.
Clinical experience The safety and efficacy of long-term (104 weeks) Sebivo treatment were evaluated in two active- controlled clinical studies that included 1,699 patients with chronic hepatitis B (NV-02B-007 GLOBE and NV-02B-015).
Esperjenza klinika Is- sigurtà u l- effikaċja ta ’ kura fit- tul (104 ġimgħat) ta ’ Sebivo ġew stmati f’ żewġ studji kliniċi kkontrollati b’ mod attiv li kienu jinkludu 1, 699 pazjent b’ epatite B kronika (NV- 02B- 007 GLOBE u NV- 02B- 015).
NV-02B-007 GLOBE study The NV-02B-007 GLOBE study is a randomised, double-blind, multinational phase III study of telbivudine compared to lamivudine for a treatment period of 104 weeks in 1,367 nucleoside-naïve chronic hepatitis B HBeAg-positive and HBeAg-negative patients.
Studju NV- 02B- 007 GLOBE L- istudju NV- 02B- 007 GLOBE huwa studju ta ’ telbivudine randomised, double- blind, multinazzjonali ta ’ fażi III imqabbel ma ’ dak ta ’ lamivudine għal perijodu ta ’ kura ta ’ 104 ġimgħat f ’ 1, 367 pazjent li qatt ma ingħataw nucleoside u li kellhom epatite B HBeAg- posittiva u HBeAg- negattiva kronika.
The majority of the population enrolled was Asian.
Il - maġġoranza tal- pazjenti reklutati kienu Ażiatiċi.
The most common HBV genotypes were B (26%) and C (51%).
L- aktar ġenotipi komuni ta ’ HBV kienu B (26%) u C (51%).
A small number (total of 98) of Caucasian patients were treated with telbivudine.
Numru żgħir (total ta ’ 98 pazjent biss li ngħataw telbuvidine kienu Kawkażi).
The primary data analysis was conducted after all patients had reached week 52.
L- ewwel analiżi primarja tat- tgħarif saret wara li l- pazjenti kollha kienu laħqu t- 52 ġimgħa.
HBeAg-positive patients:
Pazjenti HBeAg- pożittivi:
The mean age of patients was 32 years, 74% were male, 82% were Asian, 12% were Caucasian, and 6% had previously received alfa-interferon therapy.
L- età medja tal- pazjenti kienet 32 sena, 74% kienu rġiel, 82% kienu Ażjatiċi, 12% kienu Kawkażi, u 6% kienu rċevew qabel terapija b’ alfa- interferon.
HBeAg-negative patients:
Pazjenti HBeAg- negattivi:
The mean age of patients was 43 years, 79% were male, 65% were Asian, 23% were Caucasian, and 11% had previously received alfa-interferon therapy.
L- età medja tal- pazjenti kienet 43 sena, 79% kienu rġiel, 65% kienu Ażjatiċi, 23% kienu Kawkażi u 11% kienu rċevew qabel terapija b’ alfa- interferon.
Clinical results at week 52 Clinical and virological efficacy endpoints were evaluated separately in the HBeAg-positive and HBeAg-negative patient populations.
Riżultati kliniċi fit- 52 ġimgħa Endpoints ta ’ l- effikaċja klinika u viroloġika kienu evalwati b’ mod separat fil- popolazzjonijiet ta ’ pazjenti HBeAg- posittivi u HBeAg- negattivi.
The primary endpoint of therapeutic response was a composite serological endpoint requiring suppression of HBV DNA to < 5 log10 copies/ ml in conjunction with either loss of serum HBeAg or ALT normalised.
L- ewwel endpoint ta ’ rispons terapewtiku kien endpoint seroloġiku kombinat li kien jeħtieġ suppressjoni ta ’ HBV DNA għal < 5 log10 kopji/ ml flimkien ma ’ jew tnaqqis fl- HBeAg fis- serum jew normalizzazzjoni ta ’ ALT.
Secondary endpoints included histological response, ALT normalisation, and various measures of antiviral efficacy.
Endpoints sekondarji kienu jinkludu rispons istoloġiku, normalizzazzjoni ta ’ ALT u fatturi oħra li jkejlu l- effikaċja antivirali.
Regardless of baseline characteristics, the majority of patients taking Sebivo showed histological, virological, biochemical, and serological responses to treatment.
Kienu x’ kienu l- karatteristiċi mal- linja bażi, il- maġġoranza tal- pazjenti li kienu qed jieħdu Sebivo wrew rispons istoloġiku viroloġiku, biokimiku u seroloġiku għall- kura.
Patients who achieve HBV DNA levels< 3 log10 copies/ml by week 24 had optimal responses to treatment; conversely patients with HBV DNA levels> 4 log10 copies/ ml at 24 weeks had less favourable outcomes at week 52.
Livelli ta ’ ALT fil- linja bażi ta ’ > 2 x ULN u linja bażi ta ’ HBV DNA ta ’ < 9 log10 kopji/ ml kienu assoċjati ma ’ rati ogħla ta ’ serokonverżjoni ta ’ eAg f’ pazjenti HBeAg- pożittivi. Pazjenti li jiksbu livelli ta ’ HBV DNA ta ’ < 3 log10 kopji/ ml ma ’ ġimgħa 24 kellhom l- aqwa rispons għall- kura, bil- kontra pazjenti b’ livelli ta ’ HBV DNA ta ’ > 4 log10 kopji/ ml ma ’ ġimgħa 24 ma kellhomx riżultati daqshekk tajbin ma ’ ġimgħa 52.
In HBeAg-positive patients, telbivudine was superior to lamivudine in therapeutic response (75.3% vs 67.0% responders; p = 0.0047).
F’ pazjenti HBeAg- pożittivi, telbivudine kien superjuri fuq lamivudine fir- rispons terapewtiku (75. 3% vs 67. 0% ta ’ dawk li wrew rispons; p = 0. 0047).
In HBeAg-negative patients, telbivudine was non-inferior to lamivudine (75.2% and 77.2% responders; p = 0.6187).
F’ pazjenti HBeAg- negattivi, telbivudine ma kienx inferjuri għal lamivudine (75. 2% u 77. 2% ta ’ dawk li wrew rispons; p = 0. 6187).
Caucasian ethnicity was associated with lower treatment response to both antiviral agents used in the GLOBE trial; however the Caucasian patient population was very limited (n = 98).
Madankollu, il- popolazzjoni ta ’ pazjenti Kawkażi kienet limitata ħafna (n = 98).
At week 24, 203 HBeAg-positive and 178 HBeAg-negative subjects achieved non-detectable HBV DNA levels.
Ma ’ l- 24 ġimgħa, 203 pazjenti HBeAg- pożittivi u 178 pazjenti HBeAg- negattivi kisbu livelli ta ’ HBV DNA li lanqas setgħu jitkejlu.
Of those HBeAg positive subjects, 95% achieved non-detectable HBV DNA, 39% achieved HBeAg seroconversion, 90% achieved ALT normalisation at week 52 and 0.5% exhibited resistance at week 48.
Minn dawk il- pazjenti HBeAg- pożittivi, 95% kisbu livelli ta ’ HBV DNA li ma setgħux jitkejlu, 39% kisbu serokonverżjoni HBeAg, 90% kisbu livelli normali ta ’ ALT mat- 52 ġimgħa u 0. 5% saru reżistenti mat- 48 ġimgħa.
Similarly of those HBeAg-negative subjects, 96% achieved non-detectable HBV DNA, 79% achieved ALT normalisation at week 52 and 0% exhibited resistance at week 48.
Bl- istess mod, f’ dawk l- individwi HBeAg - negattivi, 96% kisbu livelli ta ’ HBV DNA li ma setgħux jitkejlu, 79% kisbu livelli normali ta ’ ALT mat- 52 ġimgħa u 0% saru reżistenti mat- 48 ġimgħa.
Selected virological, biochemical and serological outcome measures are shown in Table 5 and histological response in Table 6.
Miżuri għall- konsegwenzi viroloġici, biokimiċi u seroloġiċi magħżula qed jintwerew f’ Tabella 5 u r - rispons istoloġiku f’ Tabella 6.
9 Table 5
9 Tabella 5 Endpoints viroloġiċi, biokimiċi u seroloġiċi fit- 52 ġimgħa (Studju NV- 02B- 007 GLOBE)
Virological, biochemical and serological endpoints at week 52 (NV-02B-007 GLOBE study)
HBeAg- posittivi (n = 921)
HBeAg-positive (n = 921) HBeAg-negative (n = 446)
HBeAg- negattivi (n = 446)
Response parameter
Parametru tar - rispons
Mean HBV DNA reduction from baseline (log10 copies/ ml) ± SEM1,2,3
Medja ta ’ tnaqqis ta ’ HBV DNA mil- linja bażi (log10 kopji/ ml) ± SEM1, 2, 3
-6.45 (0.11) *
- 6. 45 (0. 11) *
-5.54 (0.11)
- 5. 54 (0. 11)
-5.23 (0.13) *
- 5. 23 (0. 13) *
-4.40 (0.13)
- 4. 40 (0. 13)
% Patients HBV DNA negative by PCR
% Pazjenti HBV DNA negattivi bil - PCR
ALT normalisation4 HBeAg seroconversion4
Normalizzazzjoni ta ’ ALT4
HBeAg loss5 1
Telf ta ’ HbeAg5 1
Standard error of mean 2 Roche COBAS Amplicor® PCR Assay (lower limit of quantification ≤ 300 copies/ ml).
Żball standard tal- medja 2 Roche COBAS Amplicor® PCR Assay (L- anqas li jista ’ jaqra ≤ 300 kopji/ ml).
3 HBeAg-positive n = 443 and 444, HBeAg-negative n = 219 and 219, for both telbivudine and lamivudine groups, respectively.
3 HBeAg- posittivi n = 443 and 444, HBeAg- negattivi n = 219 and 219, għaż- żewġ gruppi telbivudine u lamivudine, rispettivament.
The difference in populations is due to patient discontinuation from the study and missing HBV DNA assessment at week 52.
Id- differenzi fil- popolazzjonijiet huma minħabba li kien hemm pazjenti li waqfu l- istudju u tilfu l- evalwazzjoni ta’ l- HBV DNA ma ’ ġimgħa 52.
4 HBeAg-positive n = 440 and 446, HBeAg-negative n = 203 and 207, for telbivudine and lamivudine groups, respectively.
4 HBeAg- posittivi n = 440 and 446, HBeAg- negattivi n = 203 and 207, għall- gruppi ta ’ telbivudine u lamivudine, rispettivament.
ALT normalisation assessed only in patients with ALT > ULN at baseline.
In- normalizzazzjoni ta ’ ALT kienet stmata biss f’ dawk il- pazjenti li kellhom ALT > ULN mal- linja bażi.
5 n = 432 and 442, for telbivudine and lamivudine groups, respectively.
5 n = 432 u 442, għall- gruppi ta ’ telbivudine u lamivudine, rispettivament.
HBeAg seroconversion and loss assessed only in patients with detectable HBeAg at baseline. *p < 0.0001
Serokonverżjoni HBeAg u telf stmat biss f’ dawk il- pazjenti li kellhom livelli ta ’ HBeAg mal- linja bażi li setgħu jinqraw. * p < 0. 0001
Histological improvement and change in Ishak Fibrosis Score at week 52 (NV-02B- 007 GLOBE study)
Tabella 6 Titjib istoloġiku u tibdil fil- Punteġġ Fibrożi Ishak mat- 52 ġimgħa (studju NV- 02B - 007 GLOBE)
HBeAg-positive (n = 921) HBeAg-negative (n = 446) Telbivudine Lamivudine Telbivudine Lamivudine 600 mg 100 mg 600 mg 100 mg (n = 384)1 (n = 386)1 (n = 199)1 (n = 207)1
HBeAg- posittivi (n = 921)
Histological response2
HBeAg- negattivi (n = 446)
Improvement No improvement
Telbivudine 600 mg 1
71%* 17%
Lamivudine Telbivudine 100 mg 600 mg (n = 386) 1 1
61% 24%
Lamivudine 100 mg (n = 207) 1
71% 21%
Rispons istoloġiku2
70% 24%
(n = 384)
Ishak Fibrosis Score3
(n = 199)
Improvement No change Worsening
Titjib L- ebda titjib Punteġġ Fibrożi Ishak3
47% 32% 7%
71% * 17%
Missing week 52 biopsy 1
Titjib Baqgħu l- istess Marru għall- agħar M’ hemmx bijopsija tat - 52 ġimgħa 1
Patients with ≥ one dose of study drug with evaluable baseline liver biopsies and baseline Knodell Histological Activity Index (HAI) score > 3.
Pazjenti b ’ ≥ doża waħda tal- mediċina li qed tiġi studjata b’ bijopsiji tal- fwied li ttieħdu mal- linja bażi li setgħu jiġu evalwati u b’ punteġġ ta ’ l- Indiċi ta ’ Attività Istoloġika Knodell (HAI) mal- linja bażi > 3.
2 Histological response defined as a ≥ 2 point decrease in Knodell Necroinflammatory Score from baseline with no worsening of the Knodell Fibrosis Score.
2 Rispons Istoloġiku definit bħala tnaqqis ta ’ ≥ 2 punti fil- Punteġġ Nekro- infjammatorju Knodell mil- linja bażi mingħajr ma l- Punteġġ ta ’ Fibrożi Knodell ma jmur għall- agħar.
3 For Ishak Fibrosis Score, improvement measured as ≥ 1 point reduction in Ishak Fibrosis Score from baseline to week 52. *p = 0.0024
3 Għall- Punteġġ Fibrożi Ishak Score, it- titjib imkejjel bħala tnaqqis ta ’ ≥ 1 fil- Punteġġ Fibrożi Ishak mil- linja bażi sat- 52 ġimgħa. * p = 0. 0024
10 Clinical results at week 104 Overall, clinical results at week 104 in telbivudine-treated patients were consistent with those at week 52, demonstrating durability of efficacy responses for telbivudine-treated patients with continued treatment.
10 Riżultati kliniċi fil- ġimgħa 104 Globalment, riżultati kliniċi fil- ġimgħa 104 f’ pazjenti kkurati b’ telbivudine kienu konsistenti ma ’ dawk tat- 52 ġimgħa, li juri li r- rispons ta ’ effikaċja għal pazjenti kkurati b’ telbivudine jservi għal żmien twil meta titkompla l- kura.
Among HBeAg-positive patients, therapeutic response (63% vs 48%; p < 0.0001) and key secondary endpoints (mean log10 HBV DNA reduction: -5.74 vs -4.42; p < 0.0001, PCR negativity:
Fost il- pazjenti HBeAg- pożittivi, ir- rispons terapewtiku (63% vs 48%; p < 0. 0001) u l- endpoints sekondarji importanti (tnaqqis medju log10 ta ’ HBV DNA: - 5. 74 vs - 4. 42; p < 0. 0001, negattività tal - PCR:
56% vs 39%; p < 0.0001 and ALT normalisation of 70% vs 62%) demonstrated a widening difference at week 104 between telbivudine and lamivudine, respectively.
56% vs 39%; p < 0. 0001 u normalizzazzjoni ta ’ l- ALT ta ’ 70% vs 62%) wriet differenza li tiżdied fil- ġimgħa 104 bejn telbivudine u lamivudine, rispettivament.
A trend towards higher rates of HBeAg loss (35% vs 29%) and seroconversion (30% vs 25%) was also observed for telbivudine.
Tendenza lejn rati ogħla ta ’ telf ta ’ HBeAg (35% vs 29%) u serokonverżjoni (30% vs 25%) kien osservat ukoll għal telbivudine.
Moreover, in the subgroup of patients with baseline ALT levels ≥ 2x ULN (320), a significantly higher proportion of telbivudine patients than lamivudine patients achieved HBeAg seroconversions at week 104 (36% vs 28%, respectively).
Minbarra hekk, fis- sottogrupp ta ’ pazjenti bil- livelli ta ’ ALT fil- linja bażi ≥ 2x ULN (320), proporzjon ogħla b’ mod sinifikanti ta ’ pazjenti fuq telbivudine minn dawk fuq lamivudine kisbu serokonverżjoni ta ’ HBeAg f’ ġimgħa 104 (36% vs 28%, rispettivament).
82% vs 57%; p < 0.0001) were higher for telbivudine up to week 104.
Fost pazjenti HBeAg- negattivi, id- differenzi fir- rispons terapewtiku (78% vs 66%) u l- endpoints sekondarji importanti (tnaqqis medju log10 ta ’ HBV DNA: - 5. 00 vs - 4. 17, u negattività tal- PCR 82% vs 57%; p < 0. 0001) kienu ogħla għal telbivudine sal- ġimgħa 104.
ALT normalisation rates (78% vs 70%) continued to be higher by week 104.
Ir- rati ta ’ normalizzazzjoni ta ’ l - ALT (78% vs 70%) komplew ikunu ogħla sal- ġimgħa 104.
Predictability at week 24 At week 24, 203 HBeAg-positive (44%) and 177 HBeAg-negative (80%) telbivudine-treated subjects achieved non-detectable HBV DNA levels.
Tbassir fil- ġimgħa 24 F’ Ġimgħa 24, 203 individwu pożittiv għall- HBeAg (44%) u 177 negattiv għall- HBeAg (80%) ikkurati b’ telbivudine kisbu livelli ta ’ HBV DNA li ma setgħux jitkejlu.
For both HBeAg positive and negative patients, week 24 HBV DNA results were a predictor of long- term favourable outcomes.
Kemm għal pazjenti HBeAg- pożittivi kif ukoll għal dawk negattivi, ir- riżultati ta ’ l- HBV DNA ta ’ l - 24 ġimgħa kienu ta ’ tbassir għar- riżultati favorevoli fuq tul ta ’ żmien.
Telbivudine-treated patients who achieved PCR negativity by week 24 had the highest rates of PCR negativity and HBeAg seroconversion (in HBeAg-positive patients), and the lowest overall rates of virological breakthrough at week 104.
Pazjenti kkurati b’ telbivudine li kisbu negattività tal- PCR sa l- 24 ġimgħa kellhom l- ogħla rati ta ’ negattività tal- PCR u serokonverżjoni ta ’ HBeAg (f’ pazjenti HBeAg- pożittivi), u l- aktar rati baxxi globalment ta ’ penetrazzjoni viroloġika fil- ġimgħa 104.
Outcome results at week 104, based on level of HBV DNA at week 24, for either HBeAg-positive or HBeAg-negative patients are presented in Table 7.
Ir- riżultati fil- ġimgħa 104, ibbażati fuq il- livell ta ’ HBV DNA fl- 24 ġimgħa, għal pazjenti li jew huma HBeAg- pożittivi jew HBeAg- negattivi huma ppreżentati fit- Tabella 7.
Key efficacy endpoints at week 104 by serum HBV DNA levels at week 24, telbivudine patients (NV-02B-007 GLOBE)
Endpoints importanti ta ’ effikaċja fil- ġimgħa 104 permezz ta ’ livelli ta ’ HBV DNA fis- serum fil- ġimgħa 24, pazjenti ta ’ telbivudine (NV- 02B- 007 GLOBE)
HBV DNA at week 24
HBV DNA fl - 24 ġimgħa
Outcome for key efficacy end points at 104 weeks based on week 24 results Therapeutic PCR-negative HBeAg ALT Virological response HBV DNA seroconversion normalisation breakthrough* n/ N (%) n/ N (%) n/ N (%) n/ N (%) n/ N (%)
Rispons HBV DNA Serokonverżjoni Normalizzazzjoni Penetrazzjoni terapewtiku b’ PCR - ta ’ HBeAg ta ’ l- ALT viroloġika * n/ N (%) negattiv n/ N (%) n/ N (%) n/ N (%) n/ N (%)
HBeAg-positive < 300 copies/ ml 300 copies/ ml to < 3 log10 copies/ ml
HBeAg- pożittivi < 300 kopja/ ml 300 kopja/ ml to < 3 log10 kopji/ ml
≥ 3 log10 copies/ ml
≥ 3 log10 kopji/ ml
HBeAg-negative
HBeAg- negattivi
< 300 copies/ ml 300 copies/ ml to < 3 log10 copies/ ml
< 300 kopja/ ml 300 kopja/ ml sa < 3 log10 kopji/ ml
N/ A N/ A
Ma japplikax Ma japplikax
≥ 3 log10 copies/ ml N/ A = not applicable
≥ 3 log10 kopji/ ml
N/ A
Ma japplikax
* Virological breakthrough: “ 1 log above nadir” definition assessed at week 104
* Penetrazzjoni viroloġika: “ 1 log fuq in- nadir ” tifsira stmata fil- ġimgħa 104
11 Study NV-02B-015 The efficacy and safety results of the 007 GLOBE study were confirmed in study NV-02B-015.
11 Studju NV- 02B- 015 Ir- riżultati ta ’ l- effikaċja u s- sigurtà ta ’ l- istudju 007 GLOBE kienu ikkonfermati fi studju NV- 02B - 015.
This study is a phase III, randomised, double-blind study of telbivudine 600 mg once daily compared to lamivudine 100 mg once daily for a treatment period of 104 weeks in 332 nucleoside-naïve chronic hepatitis B HBeAg-positive and HBeAg-negative Chinese patients.
Dan l- istudju huwa studju ta ’ fażi III, randomized, double- blind ta ’ telbivudine 600 mg darba kuljum imqabbel ma ’ lamivudine 100 mg darba kuljum għal perijodu ta ’ kura ta ’ 104 ġimgħat f’ 332 pazjent Ċiniż li ma ngħatawx nucleoside qabel pożittivi għall- HBeAg u negattivi għal HBeAg b’ epatite B kronika.
Durability of HBeAg-seroconversion Durability of HBeAg-seroconversion was assessed from pooled data from studies NV-02B-007 and NV-02B-015.
It- tul ta ’ żmien kemm iddum isservi s- serokonverżjoni ta ’ HBeAg It- tul ta ’ żmien kemm iddum isservi s- serokonverżjoni ta ’ HBeAg kienet stmata minn tagħrif kollettiv minn studji NV- 02B- 007 u NV- 02B- 015.
The Kaplan-Meier estimates of the proportion of patients who maintained HBeAg seroconversion for at least 52 weeks following treatment discontinuation were 86.2% for telbivudine and 92.8% for lamivudine.
L- estimi Kaplan- Meier tal- proporzjon ta ’ pazjenti li żammew is- serokonverżjoni għal mill- anqas 52 ġimgħa wara li ma tkomplietx il- kura kienu ta ’ 86. 2% għal telbivudine u 92. 8% għal lamivudine.
Patients included in this analysis had completed ≥ 52 weeks of study drug treatment and exhibited HBeAg loss for ≥ 24 weeks, with HBV DNA < 5 log10 copies/ ml at the last visit, or, if they were HBeAg-negative at entry, completed ≥ 52 weeks of study drug treatment AND had HBsAg loss documented on ≥ 2 consecutive study visits.
Pazjenti inklużi f’ din l- analiżi kienu spiċċaw ≥ 52 ġimgħa ta ’ kura bil- mediċina ta ’ l- istudju u wrew telf ta ’ HBeAg għal ≥ 24 ġimgħa, b ’ HBV DNA < 5 log10 kopji/ ml waqt l- aħħar vista, jew, jekk kienu HBeAg- negattivi meta daħlu, spiċċaw ≥ 52 ġimgħa ta ’ kura bil- mediċina ta ’ l- istudju U kellhom telf ta ’ HBsAg iddokumentat f’ ≥ 2 visti konsekuttivi ta ’ l - istudju.
Clinical resistance Analysis of patients with virological rebound (confirmed increase of ≥ 1 log10 copies/ ml HBV DNA from nadir) in the pivotal study (NV-02B-007) at week 48 indicated that, among HBeAg-positive and HBeAg-negative patients, 5% (23/ 458) and 2% (5/ 222), of telbivudine recipients, respectively, had virological rebound with detectable HBV resistance mutations.
Reżistenza klinika L- analiżi tal- pazjenti li kellhom rebound viroloġiku (żieda kkonfermata ta ’ ≥ 1 log10 kopji/ ml HBV DNA minn- nadir) fl- istudju l- aktar importanti (NV- 02B- 007) fil- ġimgħa 48 wriet li, fost il- pazjenti HBeAg- pożittivi u HBeAg- negattivi, 5% (23/ 458) u 2% (5/ 222), ta ’ dawk li rċevew telbivudine, rispettivament, kellhom rebound istoloġiku b’ mutazzjonijiet ta ’ reżistenza HBV li setgħu jitkejlu.
The cumulative rates of genotypically confirmed telbivudine resistance by week 104 were 25.1% (115/ 458) for HBeAg-positive patients and 10.8% (24/ 222) for HBeAg-negative patients.
Ir - rati kumulattivi ta ’ reżistenza għal telbivudine kkonfermata b’ mod ġenotipiku sal- ġimgħa 104 kienu 25. 1% (115/ 458) għall- pazjenti HBeAg- pożittivi u 10. 8% (24/ 222) għall- pazjenti HBeAg- negattivi.
Genotypic analysis of 203 evaluable sample pairs with HBV DNA ≥ 1,000 copies/ ml at week 104 demonstrated that the primary mutation associated with telbivudine resistance was rtM204I, often associated with mutations rtL180M and rtL80I/ V and infrequently with rtV27A, rtL82M, rtV173L, rtT184I and rtA200V.
Analiżi ġenotipika ta ’ 203 pari kampjun li setgħu jiġu evalwati b’ HBV DNA ≥ 1, 000 kopja/ ml fil - ġimgħa 104 wriet li l- mutazzjoni primarja assoċjata mar- reżistenza għal telbivudine kienet rtM204I, ħafna drabi assoċjata ma ’ mutazzjonijiet rtL180M u rtL80I/ V u b’ mod mhux frekwenti ma ’ rtV27A, rtL82M, rtV173L, rtT184I u rtA200V.
Baseline factors associated with development of genotypic drug resistance included: lamivudine treatment, higher baseline HBV DNA, lower baseline serum ALT, and increased body weight/ BMI.
Fatturi tal- linja bażi assoċjati ma ’ l- iżvilupp ta ’ reżistenza ġenotipika kienu jinkludu: kura b’ lamivudine, linja bażi ogħla ta ’ HBV DNA, linja bażi aktar baxxa ta ’ ALT fis- serum, u żieda fil- piż tal- ġisem/ BMI.
On-treatment response parameters at week 24 that predicted emergence of drug resistant virus by week 104 were HBV DNA > 300 copies/ ml and elevation of serum ALT.
Il- parametri ta ’ rispons waqt il- kura fil- ġimgħa 24 li bassret l- itfaċċar tal- virus reżistenti għall- mediċina sal- ġimgħa 104, kienu > 300 kopja/ ml ta ’ HBV DNA u żieda ta’ ALT fis- serum.
When considering patients with viral breakthrough by 104 weeks, the rate of resistance was lower in patients with HBV DNA < 300 copies/ ml at week 24 than in patients with HBV DNA ≥ 300 copies/ ml at week 24.
Meta tikkunsidra pazjenti b’ penetrazzjoni virali sal- ġimgħa 104, ir- rata ta ’ reżistenza kienet inqas f’ pazjenti b ’ < 300 kopja/ ml ta ’ HBV DNA fil- ġimgħa 24 milli f’ pazjenti b’ ≥ 300 kopja/ ml ta ’ HBV DNA fil- ġimgħa 24.
In HBeAg positive patients with HBV DNA < 300 copies/ ml at week 24, resistance was 1% (3/ 203) at 48 weeks and 9% (18/ 203) at week 104, whilst in patients with HBV DNA ≥ 300 copies/ ml resistance was 8% (20/ 247) at 48 weeks and 39% (97/ 247) at week 104.
Fil- pazjenti HBeAg- pożittivi b ’ < 300 kopja/ ml ta ’ HBV DNA fil- ġimgħa 24, ir - reżistenza kienet ta ’ 1% (3/ 203) fit- 48 ġimgħa u 9% (18/ 203) fil- ġimgħa 104, filwaqt li f’ pazjenti b ’ ≥ 300 kopja/ ml ta ’ HBV DNA ir- reżistenza kienet ta ’ 8% (20/ 247) fit- 48 ġimgħa u 39% (97/ 247) fil - ġimgħa 104.
In HBeAg- negative patients with HBV DNA < 300 copies/ ml at week 24, resistance was 0% (0/ 177) at 48 weeks and 5% (9/ 177) at week 104, whilst in patients with HBV DNA ≥ 300 copies/ ml resistance was 11% (5/ 44) at 48 weeks and 34% (15/ 44) at week 104.
Fil- pazjenti HBeAg- negattivi b ’ < 300 kopja/ ml ta ’ HBV DNA fil- ġimgħa 24, ir - reżistenza kient ta ’ 0% (0/ 177) fit - 48 ġimgħa u 5% (9/ 177) fil- ġimgħa 104, filwaqt li f’ pazjenti b ’ ≥ 300 kopja/ ml ta ’ HBV DNA r- reżistenza kienet ta’ 11% (5/ 44) fit- 48 ġimgħa u 34% (15/ 44) fil - ġimgħa 104.
Cross-resistance Cross-resistance has been observed among HBV nucleoside analogues (see section 4.4).
Cross- resistance Cross- resistance dehret fost l- analogi ta ’ HBV nucleoside (ara sezzjoni 4. 4).
In cell-based assays, lamivudine-resistant HBV strains containing either the rtM204I mutation or the rtL180M/ rtM204V double mutation had ≥ 1,000-fold reduced susceptibility to telbivudine.
F’ assays bażati fuq ċelluli, razzez ta ’ HBV reżistenti għal lamivudine li kien fihom jew l- mutazzjoni rtM204I jew il - mutazzjoni doppja rtL180M/ rtM204V kellhom tnaqqis fis- suxxettibilità għal telbivudine ta ’ ≥ 1, 000 darba.
HBV encoding the adefovir resistance-associated substitutions rtN236T or rtA181V had 0.5- and 3.7-fold change in susceptibility to telbivudine in cell culture, respectively (see section 4.4).
HBV li kien jesprimi s- sostituzzjonijiet rtN236T jew rtA181V assoċjati mar- reżistenza għal adefovir kellu bejn 0. 5 - u 3. 7 drabi ta ’ bidla fis- suxxettibilità għal telbivudine fil- koltura taċ - ċellula, rispettivament (ara sezzjoni 4. 4).
The single- and multiple-dose pharmacokinetics of telbivudine were evaluated in healthy subjects and in patients with chronic hepatitis B.
Il- farmakokinetiċi ta ’ dożi ta ’ telbivudine b’ waħdiet jew b’ ħafna kienu stmati f’ individwi b’ saħħithom u f’ pazjenti b’ epatite B kronika.
The pharmacokinetics of telbivudine were not evaluated with the recommended dose of 600 mg in patients with chronic hepatitis B.
L- farmakokinetiċi ta ’ telbivudine ma kienux evalwati bid- doża rakkomandata ta ’ 600 mg f’ pazjenti b’ epatite B kronika.
However telbivudine pharmacokinetics are similar between both populations.
Madankollu, il- farmakokinetiċi ta ’ telbivudine huma simili bejn iż- żewġ popolazzjonijiet.
12 Absorption Following oral administration of a 600 mg single dose of telbivudine to healthy subjects (n = 42), the peak plasma concentration (Cmax) of telbivudine was 3.2 ± 1.1 μ g/ ml (mean ± SD) and occurred at median 3.0 hours post dose.
Assorbiment Wara l- għotja ta ’ doża orali ta ’ 600 mg telbivudine lill- individwi b’ saħħithom (n = 42), il- quċċata tal - konċentrazzjoni fil- plażma (Cmax) ta ’ telbivudine kienet 3. 2 ± 1. 1 μg/ ml (medja ± SD) u seħħet medja ta ’ 3. 0 sigħat wara li ngħatat id- doża.
The telbivudine area under the plasma concentration-time curve (AUC0-∞) was 28.0 ± 8.5 μ g h/ ml (mean ± SD).
L- erja taħt il- kurva tal- konċentrazzjoni fil- plażma ta ’ telbivudine kontra l- ħin (AUC0- ∞) kienet 28. 0 ± 8. 5 μg h/ ml (medja ± SD).
Inter-subject variability (CV%) for measures of systemic exposures (Cmax, AUC) was typically approximately 30%.
Il- varjabilità bejn l- individwi (CV%) għall- miżuri ta ’ esponimenti sistemiċi (Cmax, AUC) kienet bħala regola madwar 30%.
Effect of food on oral absorption Telbivudine absorption and exposure were unaffected when a single 600 mg dose was administered with food.
L- effett ta ’ l- ikel fuq l- assorbiment orali L- assorbiment ta ’ telbivudine u l- esponiment ma kienux effettwati meta doża waħda ta’ 600 mg ingħatat ma ’ l- ikel.
Distribution In vitro binding of telbivudine to human plasma proteins is low (3.3%).
Distribuzzjoni L- irbit ta ’ telbivudine mal- proteini tal- plażma fil- bniedem huwa baxx (3. 3%).
Biotransformation No metabolites of telbivudine were detected following administration of 14C-telbivudine in humans.
Biotrasformazzjoni Ma ġewx imkejla metaboli ta ’ telbivudine wara li ngħata 14C- telbivudine fil- bnedmin.
Telbivudine is not a substrate, inhibitor or inducer of the cytochrome P450 (CYP450) enzyme system.
Telbivudine mhuwiex sustrat, inibitur jew induttur tas- sistema ta ’ enzimi cytochrome P450 (CYP450).
Elimination After reaching peak concentration, plasma disposition of telbivudine declined in an bi-exponential manner with a terminal elimination half-life (t1/ 2) of 41.8 ± 11.8 hours.
Eliminazzjoni Wara li jilħaq il- quċċata tal- konċentrazzjoni, it- tneħħija ta ’ telbivudine mill- plażma naqset b’ mod bi - esponenzjali b’ half- life ta ’ eliminazzjoni terminali (t1/ 2) ta ’ 41. 8 ± 11. 8 sigħat.
Telbivudine is eliminated primarily by urinary excretion of unchanged substance.
Telbivudine jitneħħa l - aktar bħala sustanza mhux mibdula ma ’ l- awrina.
The renal clearance of telbivudine approaches normal glomerular filtration rate, suggesting that filtration is the main mechanism of excretion.
It- tneħħija renali ta ’ telbivudine tqarreb ir- rata normali ta ’ filtrazzjoni mill- glomeruli, li jindika li l- filtazzjoni hija l- mekkaniżmu ewlieni ta ’ l - eskrezzjoni.
Approximately 42% of the dose is recovered in the urine over 7 days following a single 600 mg oral dose of telbivudine.
Madwar 42% tad- doża tiġi rkuprata mill- awrina fuq medda ta ’ 7 ijiem wara li tingħata doża waħda orali ta ’ 600 mg telbivudine.
As renal excretion is the predominant route of elimination, patients with moderate to severe renal dysfunction and those undergoing haemodialysis require a dose interval adjustment (see section 4.2).
(ara sezzjoni 4. 2).
Linearity / non-linearity Telbivudine pharmacokinetics are dose proportional over the range of 25 to 1,800 mg.
Linjarità / nuqqas ta ’ linjarità Il- farmakokinetiċi ta ’ telbivudine huma proporzjonali mad- doża fuq il- medda ta 25 sa 1, 800 mg.
Steady state was achieved after 5 to 7 days of once-daily administration with an approximate 1.5-fold accumulation in systemic exposure, suggesting an effective accumulation half-life of approximately 15 hours.
Stat fiss inkiseb wara 5 sa 7 ijiem ta għotja ta ’ darba kuljum b’ akkumulazzjoni ta ’ madwar 1. 5- il darba fl - esponiment sistemiku, li jindika akkumulazzjoni ta ’ half- life effettiv ta ’ madwar 15- il siegħa.
Following once-daily administration of telbivudine 600 mg, steady-state trough plasma concentrations were approximately 0.2-0.3 μ g/ ml.
Wara l - għotja ta ’ 600 mg telbivudine darba kuljum, stat- fiss tal- konċentrazzjonijiet fil- plażma l- aktar baxxi kienu madwar 0. 2- 0. 3 μg/ ml.
Special populations Gender There are no significant gender-related differences in telbivudine pharmacokinetics.
Popolazzjonijiet speċjali Sess M’ hemmx differenzi sinifikanti relatati mas- sess fil- farmakokinetiċi ta ’ telbivudine.
Race There are no significant race-related differences in telbivudine pharmacokinetics.
Razza M’ hemm differenzi sinifikanti relatati mar- razza fil- farmakokinetiċi ta ’ telbivudine.
Paediatrics and geriatrics Pharmacokinetic studies have not been conducted in paediatric or elderly subjects.
Pedjatriċi u ġerjatriċi Ma sarux studji farmakokinetiċi f’ individwi pedjatriċi u ġerjatriċi.
Renal impairment The single-dose pharmacokinetics of telbivudine (200, 400 and 600 mg) have been evaluated in patients (without chronic hepatitis B) with various degrees of renal impairment (as assessed by creatinine clearance).
13 Indeboliment renali Il- farmakoiknetiċi ta ’ doża waħda ta ’ telbivudine (200, 400 u 600 mg) kienu stmati f’ pazjenti (mingħajr epatite B kronika) b’ gradi varji ta ’ indeboliment renali (kif stmat mit- tneħħija tal - krejatinina).
Based on the results shown in Table 8, adjustment of the dose interval for telbivudine is recommended in patients with creatinine clearance of < 50 ml/ min (see sections 4.2 and 4.4).
Bażat fuq ir- riżultati li jidhru f’ Tabella 8, aġġustar ta ’ l- intervall tad- doża għal telbivudine huwa kunsiljat f’ pazjenti bi tneħħija tal- krejatinina ta ’ < 50 ml/ min (ara sezzjonijiet 4. 2 u 4. 4).
Pharmacokinetic parameters (mean ± SD) of telbivudine in subjects with various degrees of renal function
Tabella 8 Parametri tal- farmakokinetiċi (medja ± SD) ta ’ telbivudine f’ individwi bi gradi varji ta ’ funzjoni renali
Renal function (creatinine clearance in ml/ min)
Funzjoni Renali (tneħħija tal- krejatinina mfissra f ’ ml/ min)
Normal Mild (50-80) Moderate Severe (< 30)
Severa (< 30)
Haemodialysis
Ħemodijaliżi
3.4 ± 0.9
3. 4 ± 0. 9
3.2 ± 0.9
3. 2 ± 0. 9
2.8 ± 1.3
2. 8 ± 1. 3
1.6 ± 0.8
1. 6 ± 0. 8
2.1 ± 0.9
2. 1 ± 0. 9
28.5 ± 9.6
28. 5 ± 9. 6
32.5 ± 10.1
32. 5 ± 10. 1
36.0 ± 13.2
36. 0 ± 13. 2
32.5 ± 13.2
32. 5 ± 13. 2
67.4 ± 36.9
67. 4 ± 36. 9
CLRENAL (ml/ min)
CLRENALI (ml/ min)
126.7 ± 48.3
126. 7 ± 48. 3
83.3 ± 20.0
83. 3 ± 20. 0
43.3 ± 20.0
43. 3 ± 20. 0
11.7 ± 6.7
11. 7 ± 6. 7
Renally impaired patients on haemodialysis Haemodialysis (up to 4 hours) reduces systemic telbivudine exposure by approximately 23%.
Pazjenti b’ indeboliment renali fuq il- ħemodijaliżi Il- ħemodijaliżi (sa 4 sigħat) tnaqqas l- esponiment ta ’ telbivudine sistemiku b’ madwar 23%.
Following dose interval adjustment for creatinine clearance, no additional dose modification is necessary during routine haemodialysis (see section 4.2).
Wara aġġustar ta ’ l- intervall bejn id- dożi għat- tneħħija tal- krejatinina, m’ hemmx bżonn ta ’ aktar tibdil fid - doża waqt il- ħemodijaliżi ta ’ rutina (ara sezzjoni 4. 2).
Telbivudine should be administered after haemodialysis.
Telbivudine għandu jingħata wara l - ħemodijaliżi.
Hepatic impairment The pharmacokinetics of telbivudine following a single 600 mg dose have been studied in patients (without chronic hepatitis B) with various degrees of hepatic impairment.
Indeboliment epatiku Il- farmakoiknetiċi ta ’ doża waħda ta ’ telbivudine 600 mg kienu studjati f’ pazjenti (mingħajr epatite B kronika) b’ gradi varji ta ’ indeboliment epatiku.
There were no changes in telbivudine pharmacokinetics in hepatically impaired subjects compared to unimpaired subjects.
Ma kienx hemm tibdil fil- farmakokinetiċi ta ’ telbivudine f’ individwi b’ indeboliment epatiku meta mqabbla ma ’ individwi mingħajr indeboliment.
Results of these studies indicate that no dosage adjustment is necessary for patients with hepatic impairment (see section 4.2).
Ir- riżultati ta ’ dawn l- istudji juru li m’ hemmx bżonn ta ’ aġġustar fid- dożaggi għal pazjenti b’ indeboliment epatiku (ara sezzjoni 4. 2).
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.
Informazzjoni mhux klinika, ibbażata fuq studji konvenzjonali ta ’ sigurtà farmakoloġika, effett tossiku minn dożi ripetuti u effett tossiku fuq il- ġeni, ma turi l- ebda periklu speċjali għall- bnedmin.
Telbivudine did not show any carcinogenic potential.
Telbivudine ma deherx li kellu xi potenzjal kanċeroġenu.
No evidence of a direct toxic effect of telbivudine was seen in standard tests of reproduction toxicology.
F’ testijiet standard dwar it- tossiċità fuq is - sistema riproduttiva ma kienx hemm evidenza ta ’ effett tossiku dirett.
In rabbits doses of telbivudine providing exposure levels of 37 times those observed in humans at the therapeutic dose (600 mg) were associated with an increased incidence of abortion and early delivery.
Fil- fniek, dożi ta ’ telbivudine li kienu jipprovdu livelli ta ’ esponiment 37 darba dawk osservati fil- bnedmin b’ doża terapewtika (600 mg) kienu assoċjati ma ’ żieda fin- numru ta ’ każijiet ta ’ abort u ħlas qabel il- waqt.
This effect was considered to be secondary to maternal toxicity.
Dan kien meqjus li ġara wara li kien hemm tossiċità fl- omm.