qanastek/EMEA-V3 huggingface dataset:
Limited historical data indicate that treatment for 48 weeks might be associated with a higher sustained response rate (11/11) and with a lower risk of relapse (0/11 as compared to 7/96 following 24 weeks of treatment).
Dejta storika limitata tindika li kura għal 48 ġimgħa tista ’ tkum marbuta ma ’ rata ta ’ rispons sostnut ogħla (11/ 11) u ma ’ riskju aktar baxx li jirkadu (0/ 11 imqabbel ma ’ 7/ 96 fl- 24 ġimgħa ta ’ wara l- kura).
Predictability of sustained virological response in naïve patients Virological response by week 12, defined as a 2-log viral load decrease or undetectable levels of HCV RNA has been shown to be predictive for sustained response (Table 8).
Kemm jista ’ jitbassar ir- rispons viroloġiku sostnut f’ azjenti li qatt ma kienu ħadu din il- kura qabel
Predictability of sustained response by viral response at week 12 and genotype*
18 Ir- rispons viroloġiku sostnut mat- 12- il ġimgħa, definit bħala tnaqqis ta ’ 2- log tal- viral load jew livelli li ma jitkejjlux ta ’ HCV- RNA intweriet li jistgħu jintużaw biex jitbassar ir- rispons sostnut (Tabella 8).
Treatment
19 Tabella 8 Kura
Genotype Viral response at Sustained response Negative week 12 predictive value
Kemm jista ’ jitbassar ir- rispons sostnut mir- rispons viroloġiku mat- 12- il ġimgħa u ġenotip * Ġenotype Rispons viroloġiku Rispons sostnut Valur imbassar mat- 12- il ġimgħa negattiv
Rebetol (> 10.6mg/kg) 1 +peginterferon alfa-2b
Rebetol (> 10. 6mg/ kg) 1 +peginterferon alfa- 2b
Yes 75% (82/110)
Iva 75% (82/ 110)
1.5 48-week treatment
1. 5 Kura ta ’ 48- ġimgħa
No 25% (28/110)
Le 25% (28/ 110)
Rebetol 800-1400 mg 2 and 3 +peginterferon alfa-2b
Rebetol 800- 1400 mg 2 u 3 +peginterferon alfa- 2b
Yes 99% (213/215) 83%
Iva 99% (213/ 215)
1.5 24-week treatment *reflects patients with 12 week data available
1. 5 24- week treatment
No 1% (2/215)
Le 1% (2/ 215)
The response to treatment in both of these trials is presented in Table 9.
Ir- rispons għall- kura f ’ dawn iż- żewġ provi jidher f’ Tabella 9.
Patients were randomized to receive either Rebetol (800 mg/day) plus peginterferon alfa-2b (1.5 µg/kg/week) or Rebetol (800 mg/day) plus interferon alfa-2b (3 MIU TIW) for 48 weeks with a follow-up period of 6 months.
Il- pazjenti kienu randomized sabiex jirċievu Rebetol (800 mg/ jum) ma ’ peginterferon alfa- 2b (1. 5 µg/ kg/ ġimgħa) jew Rebetol (800 mg/ jum) ma ’ interferon alfa- 2b (3 MIU TIW) għal 48 ġimgħa b’ perijodu ta ’ follow up ta ’ 6 xhur.
Study 2 (P02080) was a randomized, single centre study that enrolled 95 previously untreated adult patients with chronic hepatitis C who were co- infected with HIV.
Studju 2 (P02080) kien randomized, f’ ċentru wieħed li fih ħadu sehem 95 pazjent adult li ma kienux ikkurati qabel b’ epatite C kronika li kellhom l - HIV fl- istess ħin.
Patients were randomized to receive either Rebetol (800-1,200 mg/day based on weight) plus peginterferon alfa-2b (100 or 150 µg/week based on weight) or Rebetol (800- 1,200 mg/day based on weight) plus interferon alfa-2b (3 MIU TIW).
Il- pazjenti kienu randomized biex jirċievu Rebetol (800- 1, 200 mg/ jum skond il- piż) ma ’ peginterferon alfa- 2b (100 jew 150 µg/ ġimgħa skond il- piż) jew Rebetol (800- 1, 200 mg/ jum skond il- piż) ma ’ interferon alfa- 2b (3 MIU TIW).
The duration of therapy was 18 48 weeks with a follow-up period of 6 months except for patients infected with genotypes 2 or 3 and viral load < 800,000 IU/ml (Amplicor) who were treated for 24 weeks with a 6 month follow-up period.
It- tul tat- terapija kien 48 ġimgħa bi perijodu ta ’ follow up ta ’ 6 xhur ħlief għall- pazjenti infettati b’ ġenotip 2 jew 3 u viral load < 800, 000 IU/ ml (Amplicor) li kienu ikkurati għal 24 ġimgħa bi perijodu follow up ta’ 6 xhur
Study 11
Tabella 9
Study 22
Rispons viroloġiku sostnut ibbażat fuq il- ġenotip wara Rebetol f’ kombinazzjoni ma ’ peginterferon alfa- 2b f’ pazjenti infettati fl- istess ħin b’ HCV/ HIV Studju 11 Studju 22 Rebetol (800 - 1, 200 mg/ jum Rebetol Rebetol (800 -) d + (800 mg/ jum) 1, 200 mg/ jum) d + Rebetol peginterferon (800 mg/ jum) + alfa- 2b (100 peginterferon + alfa- 2b Interferon alfa - or Interferon 150cµg/ ġimgħ (1. 5 µg/ kg / 2b (3 MIU valur - alfa- 2b pa TIW) a) ġimgħa) (3 MIU TIW)
µg/week)
valur - pb
All Genotype 1, 17 4
Kollha Ġenotip 1, 4
27% (56/205) 20%% (21/125)
27% (56/ 205) 20% (41/ 205) 0. 047 44% (23/ 52) 21% (9/ 43) 17% (21/ 125) 6% (8/ 129) 0. 006 38% (12/ 32) 7% (2/ 27)
Genotype 2, 44% (35/80) 3
Ġenotip 2, 3
Rebetol dosing was 800 mg for patients < 60 kg, 1,000 mg for patients 60-75 kg, and 1,200 mg for patients > 75 kg.
MIU = miljun unitajiet internazzjonali; TIW = tlett darbiet fil- ġimgħa. a: valur- p ibbażat fuq it- test Cochran- Mantel Haenszel Chi square. b: valur- p ibbażat fuq it- test chi- square. c: individwi < 75 kg ħadu 100 µg/ ġimgħa peginterferon alfa- 2b u individwi ≥ 75 kg irċevew 150 µg/ ġimgħa peginterferon alfa- 2b. d: dużaġġ ta ’ Rebetol kien 800 mg għall- pazjenti < 60 kg, 1, 000 mg għall- pazjenti 60- 75 kg, u 1, 200 mg għall- pazjenti > 75 kg.
1 Carrat F, Bani-Sadr F, Pol S et al.
20 1 Carrat F, Bani- Sadr F, Pol S et al.
Both the Metavir score and Ishak grade decreased among subjects treated with Rebetol in combination with peginterferon alfa-2b.
Kemm il- punteġġ Metavir u l- grad Ishak naqsu fost l- individwi kkkurati b’ Rebetol f’ kombinazzjoni ma ’ peginterferon alfa- 2b.
This decline was significant among responders (-0.3 for Metavir and -1.2 for Ishak) and stable (-0.1 for Metavir and -0.2 for Ishak) among non- responders.
Dan it- tnaqqis kien sinifikanti fost dawk li wrew rispons (- 0. 3 għal Metavir u - 1. 2 għal Ishak) u stabbli (- 0. 1 għal Metavir u - 0. 2 għal Ishak) fost dawk li ma kellhomx rispons.
In terms of activity, about one-third of sustained responders showed improvement and none showed worsening.
Mil- lat ta ’ attività, madwar terz ta ’ dawk li kellhom rispons sostnut urew titjib u ħadd ma mar għall- agħar.
There was no improvement in terms of fibrosis observed in this study.
Ma deherx titjib mil- lat ta ’ fibrożi f’ dan l- istudju.
Steatosis was significantly improved in patients infected with HCV Genotype 3.
Stejatożi tjiebet b’ mod sinifikanti f’ pazjenti infettati b’ HCV ta ’ Ġenotip 3.
Previous treatment failure patients Retreatment of prior treatment failures (relapse and non-responder patients) with peginterferon alfa- 2b in combination with Rebetol In a non-comparative trial, 2,293 patients with moderate to severe fibrosis who failed previous treatment with combination alpha interferon/ribavirin were retreated with peginterferon alfa 2b, 1.5 microgram/kg subcutaneously, once weekly, in combination with weight adjusted Rebetol.
Pazjenti bla rispons għall- kura li tkun ingħatat qabel Kura mill- ġdid ta ’ pazjenti li kienu fallew għall- kura li tkun ingħatat qabel (pazjenti li rkadew u li ma kellhomx rispons għall- kura) b’ peginterferon alfa- 2b flimkien ma ’ Rebetol Fi prova mhux kumparattiva, 2, 293 pazjent b’ fibrożi moderata għal severa li kienu fallew għall- kura li ngħataw qabel b’ taħlita ta ’ interferon alfa/ ribavirin kienu kkurati mill- ġdid b’ peginterferon alfa- 2b, 1. 5 mikrogramma/ kg mogħtija taħt il- ġilda, darba fil- ġimgħa, flimkien ma ’ Rebetol mogħti skond il - piż tal- pazjent.
Failure to prior therapy was defined as relapse or non-response (HCV-RNA positive at the end of a minimum of 12 weeks of treatment).
Falliment għal terapija li tkun ingħatat qabel kien definit bħala irkadar jew nuqqas ta ’ rispons (HCV- RNA pożittivi fi tmiem ta ’ mill- anqas 12- il ġimgħa ta ’ kura).
Sustained Virologic Response (SVR) is defined as undetectable HCV-RNA at 24 weeks post-treatment (Table 10).
Rispons Viroloġiku Sostnut (SVR) huwa definit bħala HCV- RNA li ma jistgħux jitkejlu ma ’ l- 24 ġimgħa wara l- kura (Tabella 10).
Table 10 Rates of Response to retreatment in prior treatment failures
Tabella 10 Rati ta ’ Rispons għall- kura mill- ġdid f’ każi fejn il- kura ta ’ qabel kienet falliet
Patients with undetectable HCV–RNA 19 at treatment Week 12 and SVR upon retreatement Overall
Pazjenti b’ HCV– RNA li ma setgħax jitkejjel f’ Ġimgħa tal- Kura 12 u SVR wara kura mill- ġdid Popolazzjoni
Response Week 12% (n/N)
Ġimgħa ta ’ Rispons 12% (n/ N)
Response SVR% (n/N) Week 12% 99% CI (n/N)
Response SVR% (n/ N) Week 12% 99% CI (n/ N)
59.6 (121/203) 50.7, 68.5
67. 7 (203/ 300) 59. 6 (121/ 203) 50. 7, 68. 5
52.5 (105/200) 43.4, 61.6
58. 1 (200/ 344) 52. 5 (105/ 200) 43. 4, 61. 6
51.2 (66/129) 39.8, 62.5
59. 7 (129/ 216) 51. 2 (66/ 129) 39. 8, 62. 5
44.3 (54/122) 32.7, 55.8
48. 6 (122/ 251) 44. 3 (54/ 122) 32. 7, 55. 8
Genotype 2/3 Genotype
Ġenotip 2/ 3
14.6 (270/1,846) 12.5, 16.7
14. 6 (270/ 1, 846) 12. 5, 16. 7
75.6 (96/127) 63.5 (61/96) 50.9, 76.2
63. 5 (61/ 96) 50. 9, 76. 2
44.4 (12/27) 50.0 (6/12) 12.8, 87.2
50. 0 (6/ 12) 12. 8, 87. 2
METAVIR Fibrosis score
Punteġġ Fibrożi METAVIR
Baseline Viral Load HVL (> 600,000 IU/ml)
Linja bażi tat - tagħbija virali HVL (> 600, 000 IU/ ml)
Plasma HCV-RNA is measured with a research-based quantitative polymerase chain reaction assay by a central laboratory * Intent to treat population includes 7 patients for whom at least 12 weeks of prior therapy could not be confirmed.
HCV- RNA fil- plażma jitkejjel b’ essej ta ’ reazzjoni katina tal- polymerase kwantitattiv ibbażat fuq riċerka minn laboratorju ċentrali. * Popolazzjoni bl- intenzjoni li tiġi kkurata tinkludi 7 pazjenti li għalihom mill- anqas 12- il ġimgħa ta ’ terapija minn qabel ma setgħetx tkun ikkonfermata.
Overall, approximately 36% (821/2,286) of patients had undetectable plasma HCV-RNA levels at Week 12 of therapy measured using a research-based test (limit of detection 125 IU/ml).
B’ mod globali, madwar 36% (821/ 2. 286) tal- pazjenti kellhom livelli ta ’ HCV- RNA fil- plażma li ma setgħux jitkejlu mat- 12- il Ġimgħa ta ’ terapija imkejjla permezz ta ’ test ibbażat fuq riċerka (limitu li seta ’ jitkejjel 125 IU/ ml).
Among 480 patients with > 2 log viral reduction but detectable virus at Week 12, altogether 188 patients continued therapy.
Fost 480 pazjent b ’ > 2 log tat- tnaqqis virali iżda b’ ammont ta ’ vajrus li jista ’ jiġi mkejjel ma ’ Ġimgħa 12, b’ kollox 188 pazjent komplew it- terapija.
20 Non-responders to prior therapy with pegylated interferon alpha/ribavirin were less likely to achieve a Week 12 response to retreatment than non-responders to nonpegylated interferon alpha/ribavirin (12.4% vs.
Dawk li ma kellhomx rispons għat- terapija li ngħatat qabel b’ interferon alpha pegilat/ ribavirin kellhom anqas ċans li jiksbu rispons f’ Ġimgħa 12 għall- kura mill- ġdid minn dawk li ma kellhomx rispons għal interferon alpha mhux pegilat/ ribavirin (12% vs 28. 6%).
Retreatment of relapse patients with Rebetol and interferon alfa-2b combination treatment Two trials examined the use of Rebetol and interferon alfa-2b combination treatment in relapse patients (C95-144 and I95-145); 345 chronic hepatitis patients who had relapsed after previous interferon treatment were treated for six months with a six month follow-up.
Kura mill- ġdid ta ’ pazjenti li rkadew b’ kura kkombinata ta ’ Rebetol ma ’ interferon alfa- 2b Żewġ studji li eżaminaw l- użu tal- kura imħallta ta ’ Rebetol + interferon alfa- 2b f’ pazjenti li jirkadu (C95- 144 u I95- 145); 345 pazjent b’ epatite kronika li kienu diġa ’ rkadew b’ kura ta ’ interferon li ngħatat qabel, kienu kkurati għal sitt xhur, b’ sitt xhur ta ’ follow- up.
Combination therapy with Rebetol and interferon alfa-2b resulted in a sustained virological response that was ten-fold higher than that with interferon alfa-2b alone (49% vs 5%, p < 0.0001).
Terapija mħallta b’ Rebetol + interferon alfa- 2b irriżultat f’ rispons viroloġiku sostnut li kien għaxar darbiet ogħla minn dak b’ interferon alfa- 2b waħdu (49% vs 5%, p < 0. 0001).
This benefit was maintained irrespective of standard predictors of response to interferon alfa-2b such as virus level, HCV genotype and histological staging.
Dan il- benefiċċju baqa ’ jinżamm irrispettivament minn fatturi standard li jbassru r- rispons għal interferon alfa- 2b, bħal livell tal- vajrus, ġenotip ta ’ l- HCV, u l- istadji ħistoloġiċi.
Long-term efficacy data Two large long-term follow-up studies enrolled 1,071 patients and 567 patients after treatment in prior studies with nonpegylated interferon alfa-2b (with or without Rebetol) and pegylated interferon alfa- 2b (with or without Rebetol), respectively.
Tagħrif dwar l- effikaċja fit- Tul Żewġ studji kbar ta ’ follow up fit- tul ta ’ 1, 071 pazjent u 567 pazjent wara kura fi studji minn qabel b’ interferon alfa- 2b mhux pegilat (b’ Rebetol jew mingħajru) u interferon alfa- 2b pegilat (b’ Rebetol jew mingħajru), rispettivament.
The purpose of the studies was to evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes.
L- għan ta ’ l- istudji kien sabiex jiġi evalwat kemm idum ir- rispons viroloġiku sostnut (SVR) u jiġi stmat l- impatt ta ’ negattività virali kontinwa fuq ir- riżultati kliniċi.
At least 5 years of long-term follow-up was completed after treatment in 462 patients and 327 patients, respectively.
Mill- anqas 5 snin ta ’ follow up fit- tul intemm wara kura f’ 462 pazjent u 327 pazjent, rispettivament.
12 out of 492 sustained responders and only 3 out of 366 sustained responders relapsed, respectively, in the studies.
22 12 minn 492 li sostnew ir- rispons u 3 biss minn 366 pazjent li sostnew ir- rispons irkadew, rispettivament, fl- istudji.
The Kaplan-Meier estimate for continued sustained response over 5 years is 97% (95% CI:
L- istima Kaplan- Meier għal rispons sostnut kontinwu fuq tul ta ’ 5 snin huwa 97% (95% CI:
95-99%) for patients receiving nonpegylated interferon alfa-2b (with or without Rebetol), and is 99% (95% CI:
95 - 99%) għall- pazjenti li kienu qed jirċievu interferon alfa- 2b mhux pegilat (b’ Rebetol jew mingħajru), u huwa 99% (95% CI:
98-100%) for patients receiving pegylated interferon alfa-2b (with or without Rebetol).
98- 100%) għall- pazjenti li kienu qed jirċievu interferon alfa- 2b pegilat (b’ Rebetol jew mingħajru).
SVR after treatment of chronic HCV with interferon alfa-2b (pegylated and nonpegylated,with or without Rebetol) results in long-term clearance of the virus providing resolution of the hepatic infection and clinical'cure' from chronic HCV.
SVR wara kura ta’ HCV kronika b’ interferon alfa- 2b (pegilat u mhux pegilat, b’ Rebetol jew mingħajru) wassal għal tneħħija fit- tul tal- vajrus b’ hekk tgħaddi l- infezzjoni epatika “ b’ kura ” klinika minn HCV kronika.
However, this does not preclude the occurrence of hepatic events in patients with cirrhosis (including hepatocarcinoma).
Madankollu, dan ma jeliminax il- possibilità li jseħħu każijiet epatiċi f’ pazjenti b’ ċirrożi (inkluż kanċer epatiku).
Rebetol clinical trials in children and adolescents:
Provi kliniċi b’ Rebetol fi tfal u adolexxenti:
Children and adolescents 3 to 16 years of age with compensated chronic hepatitis C and detectable HCV-RNA (assessed by a central laboratory using a research-based RT-PCR assay) were enrolled in two multicentre trials and received Rebetol 15 mg/kg per day plus interferon alfa-2b 3 MIU/m2 3 times a week for 1 year followed by 6 months follow-up after treatment.
Tfal u adolexxenti 3 sa 16- il sena b’ epatite C kronika kumpensata u HCV- RNA li setgħu jitkejjlu (imkejjel minn laboratorju ċentrali bl- użu ta ’ assay RT- PCR li jintuża għar- riċerka) kienu reklutati f’ żewġ provi multiċentriċi u rċevew Rebetol 15 mg/ kg kull jum ma ’ interferon alfa- 2b 3 MIU/ m2 3 darbiet fil- ġimgħa għal sena 1 segwit b’ 6 xhur follow- up wara l- kura.
A total of 118 patients were enrolled:
Kienu reklutati totall ta ’ 118 pazjent:
57% male, 80% Caucasian, and 78% genotype 1, 64% ≤ 12 years of age.
57 raġel, 80% Kawkażi, u 78% ġenotip 1, 64% ≤ 12- il sena.
The population enrolled mainly consisted in children with mild to moderate hepatitis C.
Il- popolazzjoni reklutati kienet tikkonsisti l- aktar fi tfal b’ epatite C ħafifa għal moderata.
Sustained virological response rates in children and adolescents were similar to those in adults.
Rati ta ’ rispons viroloġiku sostnut fi tfal u adolexxenti kienu simili għal dawk ta ’ l- adulti.
Due to the lack of data in children with severe progression of the disease, and the potential for undesirable effects, the benefit/risk of the combination of ribavirin and interferon alfa-2b needs to be carefully considered in this population (see sections 4.1, 4.4 and 4.8).
Minħabba nuqqas ta ’ tagħrif fi tfal b’ avvanz sever tal- marda, u l- possibilità ta ’ effetti mhux mixtieqa, il- benefiċju/ riskju f’ din il- popolazzjoni tat - taħlita ta ’ ribavirin u interferon alfa- 2b għandu jiġi kkonsidrat b’ attenzjoni (ara sezzjonijiet 4. 1, 4. 4 u 4. 8).
Study results are summarized in Table 11.
Riżultati ta ’ dawn l- istudji qed jintwerew fil- qosor f’ Tabella 11.
Table 11.
23 Tabella 11.
Virological response in previously untreated children and adolescents Rebetol 15 mg/kg/day + interferon alfa-2b 3 MIU/m2 3 times a week
u adolexxenti li ma kienux kurati qabel Rebetol 15 mg/ kg/ jum + interferon alfa- 2b 3 MIU/ m2 3 darbiet fil- ġimgħa
Overall Response1 (n=118)
Rispons globali1 (n=118)
21 Genotype 2/3/4 (n=26) * Number (%) of patients
Ġenotip 2/ 3/ 4 (n=26) * Numru (%) ta ’ pazjent
Defined as HCV-RNA below limit of detection using a research based RT-PCR assay at end of treatment and during follow-up period
Definit bħala HCV- RNA taħt il- limitu li jista ’ jitkejjel b’ assay bażat fuq RT- PCR fl- aħħar tal- kura u fil- perijodu ta ’ follow- up.
Ribavirin is absorbed rapidly following oral administration of a single dose (mean Tmax= 1.5 hours), followed by rapid distribution and prolonged elimination phases (single dose half-lives of absorption, distribution and elimination are 0.05, 3.73 and 79 hours, respectively).
Ribavirin huwa assorbit malajr wara li tingħata mill- ħalq doża waħda (il- medja Tmax= 1. 5 sigħat), segwit minn distribuzzjoni mgħaġġla u fażijiet ta ’ eliminazzjoni mtawwla (half- lives ta ’ assorbiment b’ dożi waħidhom, distribuzzjoni u eliminazzjoni huma 0. 05, 3. 73 u 79 sigħat, rispettivament).
Absorption is extensive with approximately 10% of a radiolabelled dose excreted in the faeces.
L- assorbiment huwa estensiv b’ madwar 10% ta ’ doża radjutikkettata imneħħija ma ’ l- ippurgar.
However, absolute bioavailability is approximately 45 %-65%, which appears to be due to first pass metabolism.
Madankollu, ir- rata assoluta tal- bijodisponibilità hija ta ’ madwar 45% - 65%, li tidher li hi minħabba l- metaboliżmu ta ’ l - ewwel passaġġ.
There is a linear relationship between dose and AUCtf following single doses of 200-1,200 mg ribavirin.
Hemm relazzjoni linjari bejn id- doża u l- AUCtf wara dożi waħidhom ta ’ 200- 1, 200 mg ta ’ ribavirin.
Volume of distribution is approximately 5,000 l.
Il- volum tad- distribuzzjoni huwa ta ’ madwar 5, 000 l.
Ribavirin does not bind to plasma proteins.
Ribavirin ma tintrabatax mal- proteini tal- plażma.
Ribavirin has been shown to produce high inter- and intra-subject pharmacokinetic variability following single oral doses (intrasubject variability of approximately 30% for both AUC and Cmax), which may be due to extensive first pass metabolism and transfer within and beyond the blood compartment.
Ribavirin intwera li jipproduċi varjabilità farmakokinetika għolja bejn u fis- suġġetti wara dożi waħidhom mill- ħalq (b’ varjabilità ta ’ bejn is- suġġetti ta ’ madwar 30% kemm għall- AUC kif ukoll għas- Cmax), li għandha mnejn tkun minħabba l- metaboliżmu estensiv ta ’ l- ewwel passaġġ u t - trasferiment ġo u ’ l barra mill- kompartiment tad- demm.
Ribavirin transport in non-plasma compartments has been most extensively studied in red cells, and has been identified to be primarily via an es-type equilibrative nucleoside transporter.
It- trasport ta ’ ribavirin f’ kompartamenti mhux tal- plażma kien studjat bl- aktar mod estensiv fiċ- ċelluli ħomor, u kien identifikat li jseħħ primarjament permezz tat- trasportatur ekwilibrattiv tan- nuklejosajd tat - tip es.
This type of transporter is present on virtually all cell types and may account for the high volume of distribution of ribavirin.
Dan it- tip ta ’ trasportatur huwa preżenti kważi fit- tipi kollha ta ’ ċelluli u jista ’ jkun il- kawża tal - volum għoli tad- distribuzzjoni ta ’ ribavirin.
The ratio of whole blood:plasma ribavirin concentrations is approximately 60: 1; the excess of ribavirin in whole blood exists as ribavirin nucleotides sequestered in erythrocytes.
Il- proporzjon ta ’ demm sħih: konċentrazzjonijiet ta ’ ribavirin fil- plażma huwa ta ’ madwar 60: 1; ribavirin żejjed fid- demm sħih jeżisti bħala nuklejotidi ta ’ ribavirin li jinsabu fl- eritroċiti.
Ribavirin has two pathways of metabolism:
Ribavirin għandu żewġ passaġġi ta ’ metaboliżmu:
1) a reversible phosphorylation pathway; 2) a degradative pathway involving deribosylation and amide hydrolysis to yield a triazole carboxyacid metabolite.
1) passaġġ riversibbli tal- fosforilazzjoni; 2) degradazzjoni li tinvolvi t- tneħħija ta ’ ribose (deribosylation) u amide hydrolysis li tipproduċi metabolu triazole carboxyacid.
Both ribavirin and its triazole carboxamide and triazole carboxylic acid metabolites are also excreted renally.
Kemm Ribavirin u l- metaboli tiegħu triazole carboxymide u triazole carboxylic acids jitneħħew ukoll mill- kliewi.
Upon multiple dosing, ribavirin accumulates extensively in plasma with a six-fold ratio of multiple-dose to single-dose AUC12hr.
Wara dożaġġ multiplu, ribavirin jakkumula b’ mod estensiv fil- plażma bi proporzjon ta ’ sitt darbiet għal kull doża ta ’ AUC12hr.
Following oral dosing with 600 mg BID, steady-state was reached by approximately four weeks, with mean steady state plasma concentrations approximately 2,200 ng/ml.
Wara d- dożaġġ mill- ħalq b’ 600 mg BID, stat ta ’ ekwilibriju intlaħaq f’ madwar erba ’ ġimgħat, b’ medja tal- konċentrazzjonijiet fil- plażma fi stat fiss ta ’ madwar 2, 200 ng/ ml.
Upon discontinuation of dosing the half-life was approximately 298 hours, which probably reflects slow elimination from non-plasma compartments.
Wara l - waqfien tad- dożaġġ, il- half- life kienet ta ’ madwar 298 siegħa, li probabbilment tirrifletti l- eliminazzjoni bil- mod mill- kompartamenti mhux tal- plażma.
Food effect:
L- effett ta ’ l- ikel:
The bioavailability of a single oral dose of ribavirin was increased by co-administration of a high fat meal (AUCtf and Cmax both increased by 70%).
Il- biodisponibilità ta ’ doża waħda mill- ħalq ta ’ ribavirin żdiedet meta ngħatat flimkien ma ’ ikla b’ ħafna xaħam (AUCtf u s- Cmax it- tnejn żdiedu b’ 70%).
It is possible that the increased bioavailability in this study was due to delayed transit of ribavirin or modified pH.
Jista ’ jkun li ż- żieda fil - biodisponibbilita’ f’ dan l- istudju kienet minħabba dewmien fil- ġarr ta ’ ribavirin jew bidla tal- pH.
The clinical relevance of results from this single dose study is unknown.
Ir - relevanza klinika tar- riżultati minn dan l- istudju ta ’ doża waħda mhix magħrufa.
In the pivotal clinical efficacy trial, patients were instructed to take ribavirin with food to achieve the maximal plasma concentration of ribavirin.
Fi studju pivitali dwar l- effikaċja klinika, il- pazjenti kienu istruwiti biex jieħdu ribavirin ma ’ l- ikel biex tintlaħaq il - konċentrazzjoni massima ta ’ ribavirin fil- plażma.
Renal function:
24 Funzjoni renali:
Single-dose ribavirin pharmacokinetics were altered (increased AUCtf and Cmax) in patients with renal dysfunction compared with control subjects (creatinine clearance > 90 ml/minute).
Il- farmakokinetika ta ’ doża waħda ta ’ ribavirin kienet mibdula (żieda fl- AUCtf u fis - Cmax) f’ pazjenti li l- kliewi tagħhom ma kinux qed jaħdmu tajjeb meta mqabbla mas- suġġetti tal- kontroll (ir- rata li biha titneħħa l- krejatinina > 90 ml/ minuta).
This appears to be due to reduction of apparent clearance in these patients.
Jidher li dan kien minħabba t- tnaqqis fit- tneħħija apparenti f’ dawn il- pazjenti.
Ribavirin concentrations are essentially unchanged by haemodialysis.
Id- dijaliżi tad- demm ma tbiddilx il- konċentrazzjonijiet ta ’ ribavirin.
Single-dose pharmacokinetics of ribavirin in patients with mild, moderate or severe hepatic dysfunction (Child-Pugh Classification A, B or C) are similar to those of normal controls.
Il- farmakokinetika ta ’ doża waħda ta ’ ribavirin f’ każi ħfief, moderati jew severi ta ’ pazjenti li għandhom il- fwied mhux qed jaħdem normali (Klassifikazzjoni ta ’ Child- Pugh ta ’ A, B jew C) jixbhu lil dawk tal- kontrolli normali.
Elderly patients (≥ 65 years of age):
Pazjenti anzjani (età ≥ 65 sena):
Specific pharmacokinetic evaluations for elderly subjects have not been performed.
Ma sarux evalwazzjonijiet farmakokinetiċi speċifiċi f’ pazjenti anzjani.
However, in a population pharmacokinetic study, age was not a key factor in the kinetics of ribavirin; renal function is the determining factor.
Madankollu, fi studju farmakokinetiku dwar il- popolazzjoni, l- età ma kinetx fattur importanti fil - kinetika ta ’ ribavarine; il- funzjoni renali hija l- fattur determinanti.
Population pharmacokinetic analysis was performed using sparsely sampled serum concentration values from four controlled clinical trials.
Analiżi tal- farmakokinetika tal- popolazzjoni saret permezz ta ’ valuri tal- konċentrazzjoni fis- serum miġbura minn ftit kampjuni ’ l bogħod minn xulxin minn erba ’ provi kliniċi kkontrollati.
The clearance model developed showed that body weight, gender, age, and serum creatinine were the main covariates.
Il- mudell tat - tneħħija li żviluppa wera li l- piż tal- ġisem, is- sess, l- età, u l- krejatinina fis- serum kienu l- ko- varjanti prinċipali.
For males, clearance was approximately 20% higher than 22 for females.
Għall- irġiel, it- tneħħija kienet madwar 20% ogħla milli fin- nisa.
Clearance increased as a function of body weight and was reduced at ages greater than 40 years.
It- tneħħija żdiedet skond il - piż tal- ġisem u naqset f’ etàjiet `l fuq minn 40 sena.
Effects of these covariates on ribavirin clearance appear to be of limited clinical significance due to the substantial residual variability not accounted for by the model.
L- effetti ta ’ dawn il- ko- varjanti fuq it- tneħħija ta ’ ribavirin jidhru li huma ta ’ importanza klinika limitata minħabba l- varjabbilita ’ sostanzjali residwa li ma tteħditx in konsiderazzjoni mill- mudell.
Multiple-dose pharmacokinetic properties for Rebetol capsules and interferon alfa-2b in children and adolescents with chronic hepatitis C between 5 and 16 years of age are summarized in Table 12.
Il- karatteristiċi tal- farmakokinetiċi b’ ħafna dożi għall- kapsuli Rebetol u interferon alfa- 2b fi tfal u adolexxenti b’ epatite C kronika ta ’ età bejn 5 u 16- il sena qed jintwerew fil- qosor f’ Tabella 12.
The pharmacokinetics of Rebetol and interferon alfa-2b (dose-normalized) are similar in adults and children or adolescents.
Il- farmakokinetika ta ’ Rebetol u interferon alfa- 2b (doża normalizzata) huma simili fl - adulti u fit- tfal jew adolexxenti.
Table 12.
Tabella 12.
Mean (% CV) multiple-dose pharmacokinetic parameters for interferon alfa-2b and Rebetol capsules when administered to children or adolescents with chronic hepatitis C
Medja (% CV) parametri tal- farmakokinetiċi b’ ħafna dożi għal interferon alfa- 2b u kapsuli Rebetol meta jingħataw lit- tfal jew adolexxenti b’ epatite C kronika
15 mg/kg/day as 2 divided doses (n = 17)
3 MIU/ m2 3 darbiet fil- ġimgħa 15 mg/ kg/ jum maqsuma f’ 2
3 MIU/m2
dożi = 17)
622 (48)
622 (48) Ma sarx
Apparent
Tneħħija
clearance l/hr/kg
apparenti l/ hr/ kg
*AUC12 (ng.hr/ml) for Rebetol; AUC0-24 (IU.hr/ml) for interferon alfa-2b
* AUC12 (ng. hr/ ml) għal Rebetol; AUC0- 24 (IU. hr/ ml) għal interferon alfa- 2b
Ribavirin is embryotoxic or teratogenic, or both, at doses well below the recommended human dose in all animal species in which studies have been conducted.
Ribavirin huwa tossiku għall- embriju jew teratoġeniku, jew it- tnejn, f’ dożi ħafna inqas mid - dożi irrakkomandati fil- bniedem, fl- ispeċi kollha ta ’ annimali li dwarhom saru studji.
Malformations of the skull, palate, eye, jaw, limbs, skeleton and gastrointestinal tract were noted.
Kienu nnotati suriet difettużi tal- kranju, tas- saqaf tal- ħalq, ta ’ l- għajnejn, tax- xedaq, tar- riġlejn jew tad- dirgħajn, ta ’ l - iskeletru u tas- sistema gastro- intestinali.
The incidence and severity of teratogenic effects increased with escalation of the dose.
L- inċidenza u s- severità ta ’ l- effetti teratoġeniċi żdiedu maż - żieda fid- doża.
Survival of foetuses and offspring was reduced.
Iż- zmien li damu ħajjin il- feti u l- frieħ kien inqas.
In a juvenile rat toxicity study, pups dosed from postnatal day 7 to 63 with 10, 25 and 50 mg/kg of ribavirin demonstrated a dose-related decrease in overall growth, which was subsequently manifested as slight decreases in body weight, crown-rump length and bone length.
Fi studju dwar firien ta ’ età żgħira, frieħ li ngħataw doża bejn 7 u 63 jum wara t- twelid b’ 10, 25 u 50 mg/ kg ta ’ ribavirin urew tnaqqis ġenerali fit- tkabbir skond id- doża, li wara deher bħala tnaqqis żgħir fil- piż tal- ġisem, it- tul tal- crown rump u t- tul ta ’ l- għadam.
At the end of the recovery period, tibial and femoral changes were minimal although generally statistically significant compared to controls in males at all dose levels and in females dosed with the two highest doses compared to controls.
Fi tmiem il- perijodu ta konvalexxenza, bidliet fit- tibja u fil- femori kienu żgħar ħafna għalkemm statitistikament sinifikanti b’ mod ġenerali meta mqabbla
No histopathological effects on bone were observed.
Ma kienx hemm effetti istopatoloġiċi fuq l- għadam.
No ribavirin effects were observed regarding neurobehavioural or reproductive development.
Ribavirin ma kellux effett f’ dak li għandu x’ jaqsam ma ’ żvilupp newrkomportattiv jew riproduttiv.
Plasma concentrations achieved in rat pups were below human plasma concentrations at the therapeutic dose.
Konċentrazzjonijiet fil - plażma li nkisbu fil- frieħ tal- firien kienu anqas mill- konċentrazzjonijiet fil- plażma li jintlaħqu fil- bniedem bid- doża terapewtika.
Erythrocytes are a primary target of toxicity for ribavirin in animal studies.
L- eritroċiti huma l- aktar li intlaqtu mit- tossiċità għal ribavirin fi studji dwar l- annimali.
Anaemia occurs shortly after initiation of dosing, but is rapidly reversible upon cessation of treatment.
L- anemija sseħħ ftit wara l- bidu tad- dożaġġ, iżda hija riversibbli malajr wara l- waqfien tal- kura.
In 3- and 6-month studies in mice to investigate ribavirin-induced testicular and sperm effects, abnormalities in sperm, occurred at doses of 15 mg/kg and above.
Fi studji ta ’ 3 u 6 xhur fuq il- ġrieden biex ikunu investigati l- effetti testikulari u ta ’ l- isperma kkaġunati minn ribavirin, anormalitajiet fl- isperma seħħew f’ dożi ta ’ 15 mg/ kg u aktar.
These doses in animals produce systemic exposures well below those achieved in humans at therapeutic doses.
Dawn id- dożi fl- annimali jipproduċu espożizzjonijiet sistematiċi ħafna inqas minn dawk li ntlaħqu fil- bnedmin f’ dożi terapewtiċi.
Upon cessation of treatment, essentially total recovery from ribavirin-induced testicular toxicity occurred within one or two spermatogenic cycles (see section 4.6).
Wara l- waqfien tal- kura, l- irkupru tista tgħid totali mit- tossiċità testikulari kkaġunata minn ribavirin seħħet fi żmien wieħed jew żewġ ċikli spermatoġeniċi (ara sezzjoni 4. 6).
Genotoxicity studies have demonstrated that ribavirin does exert some genotoxic activity.
Studji dwar il- ġenotossiċità wrew li ribavirin għandu xi effett ġenotossiku.
Ribavirin was active in the Balb/3T3 in vitro Transformation Assay.
Ribavirin kien attiv fit- Test tat- Trasformazzjoni tal- Balb/ 3T3 in vitro.
Genotoxic activity was observed in the mouse lymphoma assay, and at doses of 20-200 mg/kg in a mouse micronucleus assay.
Attività ġenotossika kienet osservata f’ assay tal- limfoma tal - ġrieden, u b’ doża ta ’ 20- 200 mg/ kg f’ test tal- mikronukleju tal- ġurdien.
A dominant lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted through male gametes.
Assay dominanti li jikkaġuna l - mewt fil- firien kien negattiv, li jindika li jekk iseħħu mutazzjonijiet fil- firien, dawn ma jkunux trasmessi permezz tal- gamiti tar- raġel.
Conventional carcinogenicity rodent studies with low exposures compared to human exposure under therapeutic conditions (factor 0.1 in rats and 1 in mice) did not reveal tumorigenicity of ribavirin.
Studji konvenzjonali dwar il- karċinoġeneċità f’ annimali gerriema f’ espożizzjonijiet baxxi meta mqabbla ma ’ espożizzjonijiet fil- bniedem skond kundizzjonijiet terawpewtiċi (fattur 0. 1 fil- firien u 1 fil- ġrieden) ma wrewx tumoriġeneċità ta ’ ribavirin.
In addition, in a 26 week carcinogenicity study using the heterozygous p53(+/-) mouse model, ribavirin did not produce tumours at the maximally tolerated dose of 300 mg/kg (plasma exposure factor
Ma ’ dan, fi studju dwar il- karċinoġeneċità ta ’ 26 ġimgħa bl- użu tal- mudell heterozygous p53( + / -) tal- ġurdien, ribavirin ma kkawżax tumuri fid- doża massima ttolerata ta ’ 300 mg/ kg (fattur ta ’ l- espożizzjoni fil- plażma ta ’ madwar 2. 5 meta mqabbel ma ’ l- espożizzjoni umana).
These studies suggest that a carcinogenic potential of ribavirin in humans is unlikely.
Dawn l- istudji jissuġġerixxu li l- potenzjal karċinoġeniku ta ’ ribavirin fil - bnedmin x’ aktarx li ma jseħħx.
Ribavirin plus interferon alfa-2b:
Ribavirin ma ’ l- interferon alfa- 2b:
When used in combination with peginterferon alfa-2b or interferon alfa-2b, ribavirin did not cause any effects not previously seen with either active substance alone.
Meta ntuża flimkien ma ’ peginterferon alfa- 2b jew interferon alfa - 2b, ribavirin ma kkawżax xi effetti li ma kinux innotati qabel b’ xi waħda miż- żewġ sustanzi attivi waħidhom.
The major treatment-related change was a reversible mild to moderate anaemia, the severity of which was greater than that produced by either active substance alone.
Il- bidla prinċipali konnessa mal- kura kienet anemija bejn ħafifa u moderata riversibbli, li s- severità tagħha kienet akbar minn dik prodotta minn xi waħda mis- sustanzi attivi waħidha.
Microcrystalline cellulose, Lactose monohydrate, Croscarmellose sodium, Magnesium stearate.
Microcrystalline cellulose, Lactose monohydrate, Croscarmellose sodium, Magnesium stearate Qoxra tal- kapsula:
Capsule imprint:
Gelatine, Titanium dioxide L- istampar tal- kapsula:
Shellac, Propylene glycol, Ammonium hydroxide, Colouring agent (E 132).
Shellac, Propylene glycol, Ammonium hydroxide, Colouring agent (E 132).
Ribavirin capsules are packaged in blisters consisting of polyvinyl chloride (PVC)/polyethylene (PE)/polyvinylidene chloride (PVdC).
Il- kapsuli ta ’ ribavirin huma ppakkjat ġo folji li huma magħmula minn polyvinyl chloride (PVC) / polyethylene (PE) / polyvinylidene chloride (PVdC).
Packs of 84, 112, 140 and 168 capsules.
Pakketti ta ’ 84, 112, 140 u 168 kapsula.
SP Europe 73, rue de Stalle B-1180 Bruxelles 24 Belgium
SP Europe 73, rue de Stalle B- 1180 Bruxelles Il- Belġju
EU/1/99/107/001 EU/1/99/107/005 EU/1/99/107/002 EU/1/99/107/003
EU/ 1/ 99/ 107/ 005 EU/ 1/ 99/ 107/ 002 EU/ 1/ 99/ 107/ 003
84 hard capsules 112 hard capsules 140 hard capsules 168 hard capsules
112 kapsuli ibsin 140 kapsuli ibsin 168 kapsuli ibsin
7 May 1999 Date of last renewal:
7 Mejju 1999 Data ta ’ l- aħħar tiġdid:
02 September 2004
02 Settembru 2004
Rebetol 40 mg/ml oral solution
Rebetol 40 mg/ ml soluzzjoni orali
Each ml of oral solution contains 40 mg of ribavirin.
Kull ml ta ’ Rebetol fih 40 mg ta ’ ribavirin.
Rebetol contains 142 mg of sorbitol and 300 mg of sucrose per ml.
Rebetol fih 142 mg ta ’ sorbitol u 300 mg sucrose f’ kull ml.
Clear, colourless to pale or light yellow oral solution
Soluzzjoni orali ċara, bla kulur għal pallida jew safra ċara.
Rebetol is intended for use, in a combination regimen with interferon alfa-2b, for the treatment of children and adolescents 3 years of age and older, who have chronic hepatitis C, not previously treated, without liver decompensation, and who are positive for serum HCV-RNA.
Rebetol huwa indikat għall użu, f’ reġimen kombinat ma ’ interferon alfa- 2b, għall- kura ta ’ tfal u adolexxenti minn 3 snin ’ l fuq, li għandhom epatite C kronika, li ma kinux ikkurati qabel, mingħajr fwied mhux kompensat, u li huma pożittivi għall- HCV- RNA fis- serum.
The decision to treat should be made on a case by case basis, taking into account any evidence of disease progression such as hepatic inflammation and fibrosis, as well as prognostic factors for response, HCV genotype and viral load.
Id- deċiżjoni jekk għandhiex tingħata l- kura għandha tittieħed fuq bażi individwali skond il- każ, billi jitqies kull sinjal ta ’ avvanz tal- marda bħall- infjammazzjoni epatika u fibrożi, kif ukoll fatturi ta ’ pronjożi għar- rispons, il- ġenotip HCV u l- viral- load.
The expected benefit of treatment should be weighed against the safety findings observed for paediatric subjects in the clinical trials (See sections 4.4, 4.8 and 5.1).
Il- benefiċċju mistenni mill- kura għandu jintiżen mas- sejbiet dwar is- sigurtà li jkunu jidhru f’ individwi pedjatriċi fil- provi kliniċi (ara sezzjonijiet 4. 4, 4. 8 u 5. 1).
Rebetol monotherapy must not be used.
Monoterapija b’ Rebetol waħdu m’ għandhiex tintuża.
There is no safety or efficacy information in children or adolescents on the use of Rebetol with pegylated or other forms of interferon (i.e., not alfa-2b).
M’ hemmx informazzjoni dwar is- sigurtà jew l- effikaċja dwar l- użu ta ’ Rebetol ma ’ forom xorta oħra ta ’ interferon (i. e., mhux alfa- 2b), jew fuq l- użu ta ’ Rebetol ma ’ peginterferon alfa- 2b fi tfal jew adolexxenti.
Dose to be administered Rebetol oral solution is supplied in a concentration of 40 mg/ml.
Doża li trid tingħata Soluzzjoni orali ta ’ Rebetol tiġi f’ konċentrazzjoni ta ’ 40 mg/ ml.
Rebetol oral solution is administered in two divided doses (morning and evening) with food.
Soluzzjoni orali ta ’ Rebetol tingħata f’ żewġ dożi maqsumin (filgħodu u filgħaxija) ma ’ l- ikel.
In clinical studies performed in this population ribavirin was used in a dose of 15 mg/kg/day (Table 1).
Fi provi kliniċi li saru f’ din il- popolazzjoni ribavirin intuża b’ doża ta ’ 15 mg/ kg/ jum (Tabella 1).
Rebetol must be used in combination with interferon alfa-2b solution for injection, administered at a dose of 3 million international units (MIU)/m2 three times a week.
Rebetol għandu jintuża fl- istess ħin ma ’ interferon alfa- 2b soluzzjoni għall- injezzjoni, mogħti b’ doża ta ’ 3 miljun unitajiet internazzjonali (MIU) / m2 tlett darbiet fil- ġimgħa.
26 Please refer also to the interferon alfa-2b Summary of Product Characteristics (SPC).
28 Jekk jogħġbok irreferi wkoll għas- Sommarju tal- Karatteristiċi tal- Prodott (SPC) ta ’ interferon alfa- 2b.
Rebetol Oral Solution - Paediatric Dosage
Soluzzjoni Orali ta ’ Rebetol Dożaġġ Pedjatriku
Measured Dose
Doża mkejjla
(Morning / Evening)
(Filgħodu / Filgħaxija)
Patients who weigh > 47 kg and are able to swallow capsules may take the equivalent dose of ribavirin 200 mg capsules in two divided doses (Please see SPC for ribavirin capsules).
Pazjenti li jiżnu > 47 kg u li jistgħu jibilgħu kapsuli jistgħu jieħdu d- doża ekwivalenti għall- kapsuli ta ’ 200 mg ribavirin maqsumin f’ żewġ dożi (jekk jogħġbok ara SPC tal- kapsuli ribavirin).
Duration of treatment Genotype 1.
Kemm għandha ddum il- kura Ġenotip 1.
The recommended duration of treatment is one year.
Huwa irrakkomandat li l- kura għandha ddum sena 1.
Patients who fail to achieve virological response at 6 months are highly unlikely to become sustained virological responders (negative predictive value 96%).
Pazjenti li ma jkollhomx rispons viroloġiku mas- 6 xhur għandhom ferm anqas probabbilità li jiksbu rispons viroloġiku sostnut (valur negattiv imbassar 96%).
Virological response is defined as absence of detectable HCV-RNA at 12 weeks of treatment.
Rispons viroloġiku huwa definit bħala każ fejn HCV- RNA ma jkunx jista ’ jitkejjel mat- 12- il ġimgħa ta ’ kura.
Genotype 2/3:
Ġenotip 2 jew 3:
Virological responses after 1 year of treatment and 6 months of follow-up were 36% for genotype 1 and 81% for genotype 2/3/4.
Rispons viroloġiku wara sena 1 ta ’ kura u 6 xhur follow- up deher f’ 36% ta ’ dawk b’ ġenotip 1 u 81% ta ’ dawk b’ ġenotip 2/ 3/ 4.
Dose modification If severe adverse reactions or laboratory abnormalities develop during therapy with Rebetol oral solution and interferon alfa-2b, modify the dosages of each product if appropriate, until the adverse reactions abate.
Tibdil fid- doża għall- pazjenti kollha Jekk ikun hemm reazzjonijiet severi jew anormalitajiet fir- riżultati tal- laboratorju waqt it- terapija bis - soluzzjoni orali ta ’ Rebetol u interferon alfa- 2b, ibdel dawn id- dożaġġi ta ’ kull prodott jekk ikun xieraq, sakemm ir- reazzjonijiet avversi jbattu..
Guidelines were developed in clinical trials for dose modification (see Dosage modification guidelines, Table 2).
Saru linji gwida fi provi kliniċi għal tibdil fid- doża (ara Linji Gwida Għat- tibdil fid- Doża, Tabella 2).
As adherence might be of importance for outcome of therapy, the dose should be kept as close as possible to the recommended standard dose.
Minħabba li kemm il- pazjent jieħu l- kura kif suppost jista ’ jkun importanti għar- riżultat tat- terapija, id- doża għandha tinżamm kemm jista ’ jkun qrib għad - doża rrakkomandata.
The potential negative impact of ribavirin dose reduction on efficacy results could not be ruled out.
Ma jistax jiġi eskluż il- fatt li tnaqqis fid- doża ta ’ ribavirin jista ’ jkollu impatt negattiv fuq ir- riżultati ta ’ l- effikaċja.
Dosage modification guidelines for children and adolescents Reduce only Rebetol Reduce only interferon
għall- modifikazzjoni fid- dożaġġ għal tfal u adolexxenti Naqqas id- doża ta ’ Naqqas id- doża ta ’
Discontinue
Waqqaf
Laboratory Values
Valuri tal -
dose to 7.5 mg/kg* per
kuljum ta ’ Rebetol
alfa-2b dose
interferon alfa- 2b biss
combination therapy
it- terapija mħallta
day, if:
Laboratorju:
if:
jekk:
White blood cells Neutrophils Platelets Bilirubin – Direct
Ċelluli bojod tad - demm
< 1.5 x 109/l < 0.75 x 109/l < 80 x 109/l -
< 0. 75 x 109/ l < 80 x 109/ l
< 1.0 x 109/l < 0.5 x 109/l < 50 x 109/l 2.5 x ULN**
< 0. 5 x 109/ l < 50 x 109/ l 2. 5 x ULN **
(for > 4 weeks)
(for > 4 ġimgħat)
> 10 x ULN**
> 2. 0 mg/ dl 2 x linja bażi u > 10 x ULN **
Children and adolescent patients whose dose of Rebetol is reduced to 7.5 mg/kg per day receive the dose in two divided amounts, in the morning and the evening ** Upper limit of normal
* Pazjenti tfal u adolexxenti li jkollhom doża ta ’ Rebetol imnaqqsa għal 7. 5 mg/ kh kuljum jirċievu d- doża maqsuma f’ żewġ dożi, filgħodu u filgħaxija ** Il- Limitu ta ’ Fuq tan- Normali
The pharmacokinetics of ribavirin are altered in patients with renal dysfunction due to reduction of apparent clearance in these patients (see section 5.2).
Il- farmakokinetika ta ’ ribavirin tinbidel f’ pazjenti li għandhom il- kliewi mhux qed jaħdmu tajjeb minħabba li jidher t- tnaqqis ta ’ eliminazzjoni f’ dawn il- pazjenti (ara sezzjoni 5. 2).
Subjects with impaired renal function should be more carefully monitored with respect to the development of anaemia.
Pazjenti li għandhom rata tat- tneħħija mill- ġisem tal - krejatinina ta ’ < 50 ml/ minuta m’ għandhomx ikunu kkurati b’ Rebetol (ara sezzjoni 4. 3). Individwi li għandhom indeboliment fil- funzjoni renali għandhom ikunu monitorati b’ aktar attenzjoni għal dak li għandu x’ jaqsam ma ’ l- anemija.
If serum creatinine rises to > 2 mg/dl (see Table 2), Rebetol and interferon alfa-2b must be discontinued.
Jekk il- krejatinina fis- serum titla ’ għal > 2 mg/ dl (ara Tabella 2), Rebetol u peginterferon alfa- 2b/ interferon alfa- 2b għandhom jitwaqqfu.
Patients taking NRTI treatment in association with ribavirin and interferon alfa-2b or peginterferon alfa-2b may be at increased risk of mitochondrial toxicity, lactic acidosis and hepatic decompensation (see section 4.4).
Pazjenti li fl- istess waqt ikollhom ukoll infezzjoni b’ HCV/ HIV: Pazjenti li qed jieħdu kura b’ NRTI flimkien ma ’ Ribavirin u interferon alfa- 2b jew peginterferon alfa- 2b jista ’ jkollhom riskju akbar ta ’ tossiċità mitokondrijali, aċidożi lattika u dikompensazzjoni epatika (ara sezzjoni 4. 4).
- Pregnant women (see section 4.4).
- Nisa waqt it- tqala (ara sezzjoni 4. 4).
In females of childbearing potential, Rebetol must not be
F’ nisa li jista ’ jkollhom it- tfal Rebetol m’ għandux jinbeda
initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy.
qabel ma jinkiseb rapport ta ’ riżultat negattiv għat- test tat- tqala eżatt qabel tinbeda t- terapija.
- Women who are breast-feed ing.
- Nisa li qed ireddgħu.
with creatinine clearance < 50 ml/minute and/or on haemodialysis.
b’ rata ta ’ < 50 ml/ minuta li biha titneħħa l- krejatinina u/ jew fuq magni tad- dijaliżi tad- demm.
- Haemoglobinopathies (e.g., thalassemia, sickle-cell anaemia).
- Mard tad- demm (eż., talessimja, anemija tas- sickle cell)
Because of co-administration with interferon alfa-2b:
Minħabba l- għoti flimkien ta ’ peginterferon alfa- 2b jew interferon alfa- 2b:
Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been observed in some patients during Rebetol combination therapy with interferon alfa-2b, and even after treatment discontinuation mainly during the 6-month follow-up period.
Effetti severi tas- CNS, l- aktar dipressjoni, ħsiebijiet ta ’ suwiċidju jew tentattivi ta ’ suwiċidju dehru f’ xi pazjenti waqt l- użu b’ terapija kombinata b’ Rebetol ma ’ interferon alfa- 2b, u anki wara li titwaqqaf il- kura u fil- perijodu ta ’ 6- xhur ta ’ wara.
As in adult patients, 28 children and adolescents experienced other psychiatric adverse events (e.g., depression, emotional lability, and somnolence).
Bħal ma ġara f’ pazjenti adulti, tfal u adolexxenti kellhom effetti avversi psikjatriċi oħra (eż dipressjoni, burdati emozzjonali u ħedla).
If such symptoms appear, the potential seriousness of these undesirable effects must be borne in mind by the prescribing physician and the need for adequate therapeutic management should be considered.
Jekk jidhru dan it- tip ta ’ sintomi, it- tabib li qed jordna l- mediċini għandu jżomm f’ rasu kemm jistgħu jkunu serji dawn l- effetti mhux mixtieqa, u għandu jitqies il- bżonn għall - maniġġjar terapewtiku xieraq.
If psychiatric symptoms persist or worsen, or suicidal ideation is identified, it is recommended that treatment with Rebetol and interferon alfa-2b be discontinued, and the patient followed, with psychiatric intervention as appropriate.
Jekk sintomi psikjatriċi jippersistu jew imorru għall- agħar, jew jinstab li hemm fisazzjoni ta ’ suwiċidju, huwa rakkomandat li l- kura b’ Rebetol u b’ interferon alfa- 2b titwaqqaf, u l- pazjent jibqa taħt osservazzjoni, u jkun hemm support psikjatriku kif jixraq.
The use of Rebetol and interferon alfa-2b in children and adolescents with existence of or history of severe psychiatric conditions is contraindicated (see section 4.3).
L- użu ta ’ Rebetol u interferon alfa- 2b fi tfal u adolexxenti li jkollhom jew kellhom fil- passat kundizzjonijiet psikjatriċi huwa kontra- indikat (ara sezzjoni 4. 3).
The safety and efficacy of this combination have been established only using ribavirin together with interferon alfa-2b.
Is- sigurtà u l- effikaċja ta ’ din it- taħlita kienet stabbilita biss bl- użu ta ’ ribavirin flimkien ma ’ interferon alfa- 2b.
A decrease in haemoglobin levels to < 10 g/dl was observed in up to 14% of adult patients and in 7% of children and adolescents treated with Rebetol in combination with peginterferon alfa-2b (adults only) or interferon alfa-2b (adult, children and adolescents) in clinical trials.
Tnaqqis fil- livelli ta ’ l- emoglobina għal < 10 g/ dl kien osservat f’ sa 14% tal- pazjenti adulti u f’ 7% ta ’ tfal u adolexxenti kkurati b’ Rebetol flimkien ma ’ peginterferon alfa- 2b (adulti biss) jew interferon alfa- 2b (adulti u tfal jew adolexxenti) fi provi kliniċi.
Although ribavirin has no direct cardiovascular effects, anaemia associated with Rebetol may result in deterioration of cardiac function, or exacerbation of the symptoms of coronary disease or both.
Għalkemm ribavirin m’ għandu l- ebda effetti kardjovaskulari diretti, anemija assoċjata ma ’ Rebetol tista ’ tirriżulta f’ deterjorament tal- funzjoni kardijaka, jew it- taħrix tas- sintomi ta ’ mard koronarju, jew it- tnejn.