qanastek/EMEA-V3 huggingface dataset:
At present there are insufficient data to be able to exclude the possibility that raltegravir might be associated with a risk of cancer (see section 4.8).
Fil- preżent, m’ hemmx biżżejjed tagħrif sabiex tiġi eskluża l- possibbiltà li raltegravir jista ’ jkun assoċjat mar- riskju ta ’ kanċer (ara sezzjoni 4. 8).
ISENTRESS contains lactose.
ISENTRESS fih il- lactose.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Pazjenti bi problemi ereditarji rari ta ’ intoleranza għall- galactose, defiċjenza Lapp lactase jew diffikultajiet fl- assorbiment tal- glucose- galactose m’ għandhomx jieħdu din il- mediċina.
Raltegravir is not a substrate of cytochrome P450 (CYP) enzymes, does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A, and does not induce CYP3A4.
Raltegravir m’ huwiex sottostrat ta ’ enzimi ċitokromi P450 (CYP), ma jimpedixxix CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 jew CYP3A u ma jinduċix CYP3A4.
Raltegravir is not an inhibitor of the UDP-glucuronosyltransferases (UGTs) 1A1 and 2B7, and raltegravir does not inhibit P-glycoprotein-mediated transport.
Raltegravir m’ huwiex inibitur tal- UDP- glucuronosyltransferases (UGTs) 1A1 u 2B7, u raltegravir ma jimpedixxix it- trasport imwettaq minn P- glycoprotein.
Based on these data, ISENTRESS is not expected to affect the pharmacokinetics of medicinal products that are substrates of these enzymes or P-glycoprotein.
Fuq il- bażi ta ’ dan it- tagħrif, ISENTRESS m’ huwiex mistenni li jaffettwa l- farmakokinetiċi ta ’ prodotti mediċinali li huma sottostrati ta ’ dawn l- enzimi jew P- glycoprotein.
Based on in vitro and in vivo studies, raltegravir is eliminated mainly by metabolism via a UGT1A1-mediated glucuronidation pathway.
Fuq il- bażi ta ’ studji in vitro u in vivo, raltegravir huwa eliminat prinċipalment permezz ta ’ metaboliżmu minn ġo mogħdija ta ’ glukuronidazzjoni mwettqa minn UGT1A1.
Considerable inter- and intra-individual variability was observed in the pharmacokinetics of raltegravir.
Kienet osservata varjabilità konsiderevoli bejn persuni differenti u fl- istess persuna fil- farmakokinetiċi ta ’ raltegravir.
The following drug interaction information is based on Geometric Mean values; the effect for an individual patient cannot be predicted precisely.
L- informazzjoni segwenti dwar l- interazzjoni tal- mediċina hija bbażata fuq valuri Medji Ġeometriċi; l- effett għall- pazjent individwali ma jistax jitbassar b’ mod preċiż.
Effect of raltegravir on the pharmacokinetics of other medicinal products In interaction studies, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of tenofovir, hormonal contraceptives, or midazolam.
Effett ta ’ raltegravir fuq il- farmakokinetiċi ta ’ prodotti mediċinali oħra Fi studji ta ’ interazzjoni, raltegravir ma kellux effett klinikament elokwenti fuq il- farmakokinetiċi ta ’ dawn li ġejjin: tenofovir, kontraċettivi ormonali jew midazolam.
Effect of other agents on the pharmacokinetics of raltegravir Given that raltegravir is metabolised primarily via UGT1A1, caution should be used when co-administering ISENTRESS with strong inducers of UGT1A1 (e. g., rifampicin).
Effett ta ’ aġenti oħra fuq il- farmakokinetiċi ta ’ raltegravir Minħabba li raltegravir huwa metabolizzat primarjament permezz tal- UGT1A1, għandha tintuża kawtela meta ISENTRESS jingħata fl- istess ħin ma ’ provokaturi b’ saħħithom oħra ta ’ UGT1A1 (eż., rifampicin).
Rifampicin reduces plasma levels of raltegravir; the impact on the efficacy of raltegravir is unknown.
Rifampicin inaqqas il- livelli tal- plasma ta ’ raltegravir; l- impatt fuq l- effikaċja ta ’ raltegravir mhuwiex magħruf.
However, if co-administration with rifampicin is unavoidable, a doubling of the dose of ISENTRESS can be considered (see section 4.4).
Madankollu jekk l- għoti flimkien ma ’ rifampicin ikun inevitabbli, l - irduppjar tad- doża ta ’ ISENTRESS jista ’ jiġi kkunsidrat (ara sezzjoni 4. 4).
The impact of other strong inducers of drug metabolizing enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown.
L- impatt ta ’ provokaturi qawwija oħra ta ’ enzimi li jimmetabolizzaw il- mediċina, bħal phenytoin u phenobarbital, fuq UGT1A1, mhuwiex magħruf.
Less potent inducers (e. g., efavirenz, nevirapine, rifabutin, glucocorticoids, St.
Provokaturi inqas qawwija (eż., efavirenz, nevirapine, rifabutin, glukocortikojdi, St.
John's wort, pioglitazone) may be used with the recommended dose of ISENTRESS.
John' s wort, pioglitazone) jistgħu jintużaw mad- doża rakkomandata ta ’ ISENTRESS.
Co-administration of ISENTRESS with medicinal products that are known to be potent UGT1A1 inhibitors (e. g., atazanavir) may increase plasma levels of raltegravir.
4 Għoti fl- istess ħin ta ’ ISENTRESS ma ’ prodotti mediċinali oħra, magħrufin li huma inibituri qawwija ta ’ UGT1A1 (eż., atazanavir) jistaw jgħollu l- livelli ta ’ raltegravir fil- plażma.
Less potent UGT1A1 inhibitors (e. g., indinavir, saquinavir) may also increase plasma levels of raltegravir, but to a lesser extent compared with atazanavir.
Impedituri UGT1A1 inqas potenti (eż. indinavir, saquinavir) jistgħu wkoll jgħollu l- livelli ta ’ raltegravir fil- plażma, imma fuq firxa anqas meta mqabbla ma ’ atazanavir.
In addition, tenofovir may increase plasma levels of raltegravir, however, the mechanism for this effect is unknown (see Table 1).
Barra minn hekk, tenofovir jista ’ jgħolli l- livelli ta ’ raltegravir fil- plażma, madankollu, il- mekkaniżmu għal dan l- effett mhuwiex magħruf (ara Tabella 1).
The safety profile observed in patients who used
Mill- provi kliniċi, proporzjon kbir ta ’ pazjenti użaw atazanavir u / jew tenofovir, it- tnejn li huma sustanzi li jirriżultaw f’ żidiet fil- livelli ta ’ raltegravir fil- plażma, fir- reġimi ta ’ sfond ottimizzat.
Therefore no dose adjustment is required.
Il - profil tas- sigurtà osservat f’ pazjenti li użaw atazanavir u / jew tenofovir kien ġeneralment simili għall - profil tas- sigurtà tal- pazjenti li ma użawx dawn is- sustanzi, Għalhekk, m’ hemmx bżonn ta ’ aġġustament fid- doża.
In healthy subjects, co-administration of ISENTRESS with omeprazole increases raltegravir plasma levels.
F’ suġġetti b’ saħħithom, l- għoti fl- istess ħin ta ’ ISENTRESS ma ’ omeprazole iżid il- livelli tal- plasma ta ’ raltegravir.
As the effects of increasing gastric pH on the absorption of raltegravir in HIV-infected patients are uncertain, use ISENTRESS with medicinal products that increase gastric pH (e. g., proton pump inhibitors and H2 antagonists) only if unavoidable.
Minħabba li l- effetti taż- żieda ta ’ pH gastrika fuq l- assorbiment ta ’ raltegravir f’ pazjenti infettati bl- HIV għadhom mhux magħrufa b’ ċertezza, uża ISENTRESS ma ’ prodotti mediċinali li jżidu l- pH gastrika (eż., inibituri proton pump u antagonisti H2) biss jekk mhux inevitabbli.
Table 1 Pharmacokinetic Interaction Data
Tabella 1 Tagħrif dwar l- Interazzjonijiet Farmakokinetiċi
Medicinal products by therapeutic area ANTI-RETROVIRAL Protease inhibitors (PI)
Prodotti mediċinali skond il- qasam terapewtiku
Interaction (mechanism, if known)
Interazzjoni (mekkaniżmu, jekk magħruf)
Recommendations concerning co-administration
Rakkomandazzjonijiet dwar l- għoti fl- istess ħin
atazanavir / ritonavir (raltegravir 400 mg BID)
(raltegravir 400 mg BID)
raltegravir AUC ↑ 41% raltegravir C12hr ↑ 77% raltegravir Cmax ↑ 24%
raltegravir Cmax ↑24%
No dose adjustment required for ISENTRESS.
aġġustament fid- doża għal ISENTRESS.
(UGT1A1 inhibition)
(inibizzjoni ta ’ UGT1A1)
tipranavir / ritonavir (raltegravir 400 mg BID)
(raltegravir 400 mg BID)
raltegravir AUC ↓ 24% raltegravir C12hr ↓ 55% raltegravir Cmax ↓ 18%
raltegravir Cmax ↓18%
(UGT1A1 induction) Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
(induzzjoni ta ’ UGT1A1) Non- nucleoside reverse transcriptase inhibitors (NNRTIs) raltegravir AUC ↓36%
efavirenz (raltegravir 400 mg SD)
(raltegravir 400 mg SD)
No dose adjustment required for ISENTRESS
aġġustament fid- doża għal ISENTRESS
(UGT1A1 induction)
(induzzjoni ta ’ UGT1A1)
Nucleoside/ tide reverse transcriptase inhibitors
Nucleoside/ tide reverse transcriptase inhibitors raltegravir AUC ↑49%
tenofovir (raltegravir 400 mg BID)
(raltegravir 400 mg BID)
raltegravir AUC ↑ 49% raltegravir C12hr ↑ 3% raltegravir Cmax ↑ 64%
raltegravir Cmax ↑64% (il- mekkaniżmu ta ’ l - interazzjoni mhux magħruf)
No dose adjustment required for ISENTRESS or tenofovir disoproxil fumarate.
aġġustament fid- doża għal ISENTRESS jew tenofovir disoproxil fumarate.
(mechanism of interaction unknown)
Interazzjoni (mekkaniżmu, jekk magħruf)
tenofovir AUC ↓ 10% tenofovir C12hr ↓ 13% tenofovir Cmax ↓ 23% ANTIMICROBIALS Antimycobacterial
raltegravir C12hr ↓61%
rifampicin (raltegravir 400 mg SD)
(raltegravir 400 mg SD)
raltegravir AUC ↓ 40% raltegravir C12hr ↓ 61% raltegravir Cmax ↓ 38%
raltegravir Cmax ↓38%
Rifampicin reduces plasma levels of ISENTRESS.
ta ’ ISENTRESS fil- plażma.
If co-administration with rifampicin is unavoidable, a
Jekk l- għoti fl- istess ħin ma ’ rifampicin ikun inevitabbli, l -
(UGT1A1 induction)
(induzzjoni ta ’ UGT1A1) midazolam AUC ↓8%
doubling of the dose of ISENTRESS can be considered (see section 4.4).
irduppjar tad- doża ta ’ ISENTRESS jista ’ jiġi kkunsidrat (ara sezzjoni 4. 4).
Recommendations concerning co-administration
M’ hemmx bżonn ta ’
midazolam (raltegravir 400 mg BID)
(raltegravir 400 mg BID)
No dosage adjustment required for ISENTRESS or midazolam.
aġġustament fid- doża għal ISENTRESS jew midazolam.
These results indicate that raltegravir is not an inducer or inhibitor of CYP3A4, and raltegravir is thus not anticipated to affect the pharmacokinetics of medicinal products which are CYP3A4 substrates.
Dawn ir- riżultati jindikaw li raltegravir mhuwiex provokatur jew inibitur ta ’ CYP3A4, u għalhekk raltegravir mhuwiex mistenni li jaffettwa l- farmakokinetiċi ta ’ prodotti mediċinali li huma sottostrati ta ’ CYP3A4.
omeprazole (raltegravir 400 mg SD)
ANTI- ULĊERI omeprazole (raltegravir 400 mg SD)
raltegravir AUC ↑ 212% raltegravir C12 hr ↑ 46% raltegravir Cmax ↑ 315%
raltegravir AUC ↑ 212% raltegravir C12 hr ↑ 46% raltegravir Cmax ↑ 315%
Co-administration of proton pump inhibitors or other antiulcer medicinal products may increase plasma levels of raltegravir.
L- għoti fl- istess ħin ta ’ inibituri tal- proton pump jew prodotti mediċinali oħra kontra l- ulċeri jista ’ jżid il - livelli ta ’ raltegravir fil - plażma.
Do not use ISENTRESS with medicinal products that increase gastric pH unless this is unavoidable.
Tużax ISENTRESS ma ’ prodotti mediċinali oħra li jżidu l- pH gastriku, sakemm dan ma jkunx inevitabbli.
HORMONAL CONTRACEPTIVES Ethinyl Estradiol Norelgestromin (raltegravir 400 mg BID)
(raltegravir 400 mg BID)
Ehinyl Estradiol AUC ↓ 2% Ehinyl Estradiol Cmax ↑ 1% Norelgestromin AUC ↑ 14% Norelgestromin Cmax ↑ 29%
Norelgestromin Cmax ↑ 29%
No dosage adjustment required for ISENTRESS or hormonal contraceptives (estrogen- and/ or progesterone-based)
ISENTRESS jew tal- kontraċettivi orali (bażati fuq estroġen u/ jew progesterone)
Pregnancy There are no adequate data from the use of raltegravir in pregnant women.
Tqala Ma hemm l- ebda tagħrif adegwat dwar l- użu ta ’ raltegravir f’ nisa tqal.
Studies in animals have shown reproductive toxicity (see section 5.3).
Studji fuq bhejjem urew ħsara fuq is- sistema riproduttiva (ara 5. 3).
ISENTRESS should not be used during pregnancy.
ISENTRESS m’ għandux jintuża waqt it- tqala.
Anti-retroviral Pregnancy Registry To monitor maternal-foetal outcomes in patients inadvertently administered ISENTRESS while pregnant, an Anti-retroviral Pregnancy Registry has been established.
Reġistru ta ’ Tqala Antiretrovirali Ġie stabbilit Reġistru ta ’ Tqala Antiretrovirali biex jissorvelja r- riżultati materni- fetali f’ pazjenti li aċċidentalment ingħataw ISENTRESS waqt it- tqala.
Physicians are encouraged to register patients in this registry.
It- tobba huma mħeġġa sabiex jirreġistraw lil - pazjenti f’ dan ir- reġistru.
Lactation It is not known whether raltegravir is secreted in human milk.
6 Treddigħ Mhux magħruf jekk raltegravir huwiex eliminat fil- ħalib tal- bniedem.
However, raltegravir is secreted in the milk of lactating rats.
Madankollu, raltegravir huwa eliminat fil- ħalib ta ’ firien li qegħdin ireddgħu.
In rats, at a maternal dose of 600 mg/ kg/ day, mean active substance concentrations in milk were approximately 3-fold greater than in maternal plasma.
Fil- firien, f’ doża materna ta ’ 600 mg/ kg/ kuljum, il - - konċentrazzjoniet medji tas- sustanza attiva fil- ħalib kienu madwar 3 darbiet akbar milli fil- plażma materna.
Breastfeeding is not recommended while taking ISENTRESS.
It- treddigħ mhuwiex irrikkmandat waqt it- teħid ta ’ ISENTRESS.
In addition, it is recommended that HIV-infected mothers should not breastfeed their infants to avoid risking postnatal transmission of HIV.
Barra minn hekk, huwa rrikkmandat li l- ommijiet infettati b’ HIV ma għandhomx ireddgħu lit- trabi tagħhom biex ikun evitat ir- riskju ta ’ trasmissjoni tal- HIV wara t- twelid.
No studies have been performed on the effects of ISENTRESS on the ability to drive and use machines.
Ma sarux studji dwar l- effetti fuq il- ħila biex issuq jew tħaddem magni.
However, dizziness has been reported in some patients during treatment with regimens containing ISENTRESS, which may influence some patients' ability to drive and use machines (see section 4.8).
Madankollu, ġie rrappurtat sturdament f’ xi pazjenti waqt trattament b’ reġimi li fihom ISENTRESS, li jista ’ jinfluwenza l- ħila ta ’ xi wħud mill- pazjenti biex isuqu u jħaddmu magni (ara sezzjoni 4. 8).
Treatment-experienced The safety assessment of ISENTRESS in treatment-experienced patients is based on the pooled safety data from three randomised clinical studies.
Pazjenti li rċevew it- trattament qabel Il- valutazzjoni tas- sigurtà ta ’ ISENTRESS f’ pazjenti li rċevew it- trattament qabel hija bbażata fuq tagħrif ta ’ sigurtà miġbur minn tliet studji kliniċi randomizzati.
These studies used the recommended dose of 400 mg twice daily in combination with optimised background therapy (OBT) in 507 patients, in comparison to 282 patients taking placebo in combination with OBT.
Dawn l- istudji użaw id- doża rakkomandata ta ’ 400 mg darbtejn kuljum f’ kombinazzjoni ma ’ terapija ottimizzata fl- isfond (OBT) f’ 507 pazjenti, meta mqabbla ma ’ 282 pazjent li kienu qed jieħdu plaċebo f’ kombinazzjoni ma ’ OBT.
During double-blind treatment, the total follow-up was 504.1 patient-years in the ISENTRESS 400 mg b. i. d. group and 202.5 patient-years in the placebo group.
Waqt trattament double- blind, il- follow- up kien 504. 1 pazjent- snin fil- grupp ISENTRESS 400 mg b. i. d. u 202. 5 pazjent- snin fil- grupp tal- plaċebo.
For patients in the ISENTRESS 400 mg twice daily + OBT arm and the comparator placebo + OBT arm, the most commonly reported adverse reactions (> 10% in either group), of all intensities and regardless of causality were: diarrhoea in 17.6% and 20.6%, nausea in 11.2% and 15.2%, headache in 10.1% and 12.4%, pyrexia in 6.3% and 11.0% of patients, respectively.
Għal pazjenti fil- fergħa ISENTRESS 400 mg darbtejn kuljum + OBT u fil- fergħa ta ’ tqabbil plaċebo + OBT, l- aktar reazzjonijiet avversi rrapportati b’ mod komuni (> 10% fiż- żewġ gruppi), ta ’ l - intensitajiet kollha u irrispettivament mill- kawżalità kienu: dijarea fi 17. 6% u 20. 6%, dardir f’ 11. 2% u 15. 2%, uġigħ ta ’ ras f’ 10. 1% u 12. 4%, deni f’ 6. 3% u 11. 0% tal- pazjenti, rispettivament.
In this pooled analysis, the rates of discontinuation of therapy due to adverse reactions were 2.4% in patients receiving ISENTRESS + OBT and 2.8% in patients receiving placebo + OBT.
F’ din l - analiżi ippuljata, ir- rati ta ’ twaqqif tat- terapija minħabba reazzjonijiet avversi kienu 2. 4.% f’ pazjenti li kienu qed jirċievu ISENTRESS + OBT u 2. 8% f’ pazjenti li kienu qed jirċievu plaċebo + OBT.
Adverse reactions considered by investigators to be causally related to ISENTRESS (alone or in combination with OBT) are listed below by System Organ Class.
Ir- reazzjonijiet avversi kkunsidrati mill- investigaturi bħala relatati b’ mod kawżali ma ’ ISENTRESS (waħdu jew f’ kombinazzjoni ma ’ OBT) huma elenkati hawn taħt skond is- sistema tal- klassifika ta ’ l- organi.
Any term that includes at least one serious adverse reaction is identified with a dagger (†).
Kull terminu li jinkludi tal- anqas reazzjoni avversa serja waħda huwa identifikat bi stalett (†).
Adverse reactions identified from post-marketing experience are included in italics.
Reazzjonijiet avversi identifikati minn esperjenza wara t- tqiegħed fis- suq huma inklużi fil- korsiv.
Frequencies are defined as common (≥ 1/ 100 to < 1/ 10), uncommon (≥ 1/ 1,000 to < 1/ 100), and not known (cannot be estimated from the available data).
Il- frekwenzi huma definiti bħala komuni (≥1/ 100 sa < 1/ 10), mhux komuni (≥1/ 1, 000 sa < 1/ 100), u mhux magħrufa (ma setgħux jiġu stmati mit- tagħrif disponibbli)
System Organ Class
Sistema tal- Klassifika
Adverse reactions
Reazzjonijiet avversi
ISENTRESS (alone or in combination with OBT) Infections and infestations
ISENTRESS (waħdu jew f’ kombinazzjoni ma ’ OBT)
genital herpes†, folliculitis, herpes simplex, herpes virus infection, herpes zoster, influenza, molluscum contagiosum
herpes ġenitali †, follikulite, herpes simplex, Infezzjonijiet u infestazzjonijiet
Immune system disorders Metabolism and nutrition disorders
infezzjoni virali b’ herpes, herpes zoster, influwenza, molluscum contagiosum
Psychiatric disorders
Disturbi tad- demm u tas- sistema limfatika
suicidal ideation, suicidal behaviour (particularly in patients with a pre-existing history of psychiatric illness)
anemija minħabba nuqqas ta ’ ħadid sensittività eċċessiva għal mediċina †
Nervous system disorders
Disturbi fis- sistema immuni
common
mhux komuni
dizziness, headache
Disturbi fil- metaboliżmu u n- nutrizzjon
Eye disorders Ear and labyrinth disorders Cardiac disorders Respiratory, thoracic and mediastinal disorders
obesità ċentrali, tnaqqis fl- aptit, dijabete mellitus, dislipidemija, iperkolesterolemja, żieda fl- aptit
ISENTRESS (alone
Reazzjonijiet avversi
Adverse reactions or in combination with OBT)
ISENTRESS (waħdu jew f’ kombinazzjoni ma ’ OBT)
Gastrointestinal disorders
insomnija Disturbi psikjatriċi
abdominal distention, abdominal pain, constipation, diarrhoea, flatulence, nausea, vomiting
ideat ta ’ suwiċidju, imġiba suwiċidali (b’ mod mhux partikolari f’ pazjenti bi storja pre- eżistenti ta ’ mard magħruf psikjatriku) sturdament, uġigħ ta ’ ras Disturbi fis- sistema nervuża
gastritis†, abdominal discomfort, abdominal pain upper, anal discomfort, dry mouth, dyspepsia, eructation, gastrooesophageal reflux disease, glossitis, odynophagia, oral pain, pancreatitis acute, peptic ulcer, rectal haemorrahage, stomach discomfort
sindromu tal- mini karpali, disturbi fl- attenzjoni, sturdament minħabba l- pożizzjoni, tibdil fis- sens tat- togħma, ipersomnija, ipoestesja, sfinit, newropatija, newropatija periferali, paraestesija, ngħas, uġigħ minħabba tensjoni, rogħda
Hepato-biliary disorders Skin and subcutaneous tissue disorders
Disturbi fil- widnejn u fis- sistema labirintika
uncommon common
mhux komuni
hepatitis† hyperhidrosis, night sweats, pruritus, rash
Disturbi kardijaċi
acne, dermatitis acneiforme, dry skin, erythema, facial wasting, lipoatrophy, lipodystrophy acquired, lipohypertrophy, prurigo, pruritis generalised, rash macular, rash maculo-papular, rash pruritic, xeroderma
disfonja, epistassi, konġestjoni nażali, eritema farinġeali distensjoni addominali, uġigħ addominali,
not known
komuni
Stevens Johnson syndrome
stitikezza, dijarea, gass, tqalligħ, remettar
Musculoskeletal and connective tissue disorders
gastrite †, skonfort addominali, uġigħ addominali mhux
arthralgia
Disturbi fil- fwied u fil- marrara
back pain, muscle atrophy, musculoskeletal pain, myalgia, myositis, pain in extremity, tendonitis
Disturbi fil- ġilda u fit- tessuti ta ’ taħt il- ġilda
Renal and urinary disorders
Sindromu ta ’ Stevens Johnson artralġja
uncommon
komuni mhux komuni
renal failure†, nephritis interstitial, nephrolithiasis, nocturia, pollakiuria
Disturbi fil- kliewi u fis- sistema
Reproductive system and breast disorders
urinarja Disturbi fis- sistema riproduttiva u fis- sider
erectile dysfunction, gynaecomastia, menopausal symptoms
ISENTRESS (waħdu jew f’ kombinazzjoni ma ’ OBT)
General disorders and administration site conditions
astenja, għeja Disturbi ġenerali u kondizzjonijiet ta 'mnejn
asthenia, fatigue
jingħata
chest discomfort, chills, face oedema, fat tissue increased, feeling hot, feeling jittery, pyrexia, xerosis
fit- tessut tal- grass, tħossok sħun, tħossok trid tiċċaqlaq, deni, xerosi
alanine aminotransferase increased, aspartate aminotransferase increased, blood triglycerides increased, serum creatinine kinase increased, lipase increased
żieda f’ alanine aminotransferase, żieda f’ aspartate aminotransferase, żieda tal- trigliċeridi fid- demm, żieda ta ’ creatinine kinase fis- serum, żieda fil- lipase
absolute neutrophil count decreased, blood amylase increased, blood cholesterol increased, blood creatinine increased, blood glucose increased, blood urea nitrogen increased, fasting blood glucose increased, glucose urine present, high density lipoprotein increased, low density lipoprotein increased, platelet count decreased, red blood cells urine positive, weight increased, white blood cell count decreased
tnaqqis fl- għadd ta ’ newtrofili assoluti, żieda tal- amylase fid- demm, żieda tal- kolesterol fid- demm, żieda tal- kreatinina fid- demm, żieda taz- zokkor fid- demm, żieda tan- nitroġenu fl- urea fid- demm, żieda fil- glukosju fid- demm waqt is- sawm, glukosju fl- awrina preżenti, żieda fil- lipoproteina ta ’ densità għolja, żieda fil- lipoproteina ta ’ densità baxxa, l- għadd ta ’ plejtlits imnaqqsa, pożittiv għal ċelluli ħomor tad- demm fl- awrina, żieda fil- piż, l- għadd ta ’ ċelluli bojod tad- demm imnaqqsa doża eċċessiva aċċidentali †
Injury, poisoning and procedural complications †
mhux Korriment, avvelenament u komuni komplikazzjonijiet ta ’ xi proċedura † jinkludi tal- anqas reazzjoni avversa serja waħda
Cancers were reported in treatment-experienced patients who initiated ISENTRESS with OBT; several were recurrent.
Kienu rrappurtati kanċers f’ pazjenti li diġà kienu rċevew it- trattament li bdew b’ ISENTRESS ma ’ OBT; bosta kienu rikorrenti.
The types and rates of specific cancers were those expected in a highly immunodeficient population (many had CD4 cell counts below 50 cells/ mm3 and most had prior AIDS diagnoses).
It- tipi u r- rati ta ’ kanċers speċifiċi kienu dawk mistennija f’ popolazzjoni immunodefiċjenti bil- bosta (bosta kellhom għadd ta ’ ċelloli CD4 taħt 50 ċellola/ mm3 u l- maġġoranza diġà kellhom dijanjożi ta ’ AIDS).
The cancers included Kaposi’ s sarcoma, lymphoma, squamous cell carcinoma, hepatocellular carcinoma and anal cancer.
Il- kanċers inkludew sarkoma ta ’ Kaposi, limfoma, karċinoma taċ - ċellola skwamuża, karċinoma epatoċellolari u kanċer ta ’ l- anus.
Most patients had other risk factors for cancer including 8 tobacco use, papillomavirus and active hepatitis B virus infection.
Il- maġġoranza tal- pazjenti kellhom fatturi ta ’ riskju għal kanċer oħra inklużi l- użu tat- tabakk, papillomavirus u infezzjoni attiva bil- virus ta ’ l- epatite B.
It is unknown if these cancer diagnoses were related to ISENTRESS use (see section 4.4).
Mhux magħruf jekk dawn id- dijanjosijiet ta ’ kanċer kinux relatati ma ’ użu ta ’ ISENTRESS (ara sezzjoni 4. 4).
Grade 2-4 creatine kinase laboratory abnormalities were observed in subjects treated with ISENTRESS.
Anormalitajiet tal- laboratorju ta ’ grad 2- 4 fil- creatine kinase ġew osservati f’ pazjenti ttrattati b’ ISENTRESS.
Myopathy and rhabdomyolysis have been reported; however, the relationship of ISENTRESS to these events is not known.
Ġew irrappurtati mijopatija u rabdomijolisi; madankollu, ir- relazzjoni ta ’ ISENTRESS ma ’ dawn l- episodji mhix magħrufa.
Use with caution in patients who have had myopathy or rhabdomyolysis in the past or have any predisposing issues including other medicinal products associated with these conditions (see section 4.4).
Għandu jintuża b’ attenzjoni f’ pazjenti li kellhom mijopatija jew rabdomijaliżi fil- passat jew li għandhom xi predispożizzjonijiet inkluż prodotti mediċinali assoċjati ma ’ dawn il- kundizzjonijiet (ara sezzjoni 4. 4).
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART).
Każijiet ta’ osteonekrożi ġew irrapportati b’ mod partikolari f’ pazjenti b’ fatturi ta ’ riskju magħrufin b’ mod ġenerali, mard ta ’ l- HIV avvanzat jew espożizzjoni fit- tul għal terapija antiretrovirali ta ’ kombinazzjoni (CART).
Patients co-infected with hepatitis B and/ or hepatitis C virus In Phase III studies, patients with chronic active hepatitis B and/ or hepatitis C co-infection (N = 113/ 699 or 16.2%; HBV=6%, HCV=9%, HBV+HCV=1%) were permitted to enrol provided that AST, ALT, and alkaline phosphatase tests did not exceed 5 times the upper limit of normal.
Pazjenti ko- infettati bil- virus ta ’ l- epatite B u/ jew ta ’ l- epatite Ċ Fi studji ta ’ Fażi II, pazjenti b’ epatite B kronika attiva u/ jew b’ ko- infezzjoni ta ’ l- epatite Ċ (N = 113/ 699 jew 16. 2%; HBV=6%, HCV=9%, HBV+HCV=1%) tħallew jidħlu diment li t- testijiet ta ’ l- AST, ALT, u l- alkaline phosphatase ma qabżux 5 darbiet il- limitu ta ’ fuq tan- normal.
In general the safety profile of ISENTRESS in patients with hepatitis B and/ or hepatitis C virus co- infection was similar to that in patients without hepatitis B and/ or hepatitis C virus co-infection.
B’ mod ġenerali, il- profil ta ’ sigurtà ta ’ ISENTRESS f’ pazjenti b’ infezzjoni fl- istess ħin bil- virus ta ’ l- epatite B u/ jew epatite Ċ kien simili għal dak f’ pazjenti mingħajr infezzjoni fl- istess ħin bil- virus ta ’ l- epatite B u/ jew epatite Ċ.
Grade 2 or higher laboratory abnormalities that represent a worsening from baseline of AST, ALT or total bilirubin occurred in 31%, 31% and 16%, respectively, of raltegravir-treated co-infected subjects as compared to 9%, 8% and 8% of all other raltegravir-treated subjects.
Anormalitajiet tal- laboratorju ta ’ Grad 2 jew ogħla li jirrappreżentaw taħżin mil - linja bażi ta ’ l- AST, ALT jew bilirubina totali seħħew f’ 31%, 31% u 16%, rispettivament, tas -
No specific information is available on the treatment of overdosage with ISENTRESS.
Ma hemm l- ebda informazzjoni speċifika disponibbli fuq it- trattament ta ’ doża eċċessiva b’ ISENTRESS.
In the event of an overdose, it is reasonable to employ the standard supportive measures, e. g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy if required.
Fl- eventwalità ta ’ teħid ta ’ doża eċċessiva, huwa raġeonevoli li jintużaw miżuri standard ta ’ appoġġ, eż., tneħħija ta ’ materjal mhux assorbit minn ġol- passaġġ gastrointestinali, monitoraġġ kliniku (inkluż il- kisba ta ’ elettrokardjogramma), u bidu ta ’ terapija ta ’ appoġġ jekk meħtieġa.
It should be taken into account that raltegravir is presented for clinical use as the potassium salt.
Għandu jiġi kkunsidrat li raltegravir huwa ppreżentat għall- użu kliniku bħala l- melħ tal- potassju.
The extent to which ISENTRESS may be dialysable is unknown.
Għadu mhux magħruf kemm ISENTRESS huwa dijalizzabbli.
Antiviral for systemic use, Other Antivirals, ATC code:
Antivirali Oħra, kodiċi ATC:
Mechanism of action Raltegravir is an integrase strand transfer inhibitor active against the Human Immunodeficiency Virus (HIV-1).
Mekkaniżmu ta ’ azzjoni Raltegravir huwa inibitur tat- trasferiment ta ’ l- istrand integrase attiv kontra l- Virus ta ’ l- Immunodefiċjenza Umana (HIV- 1).
Raltegravir inhibits the catalytic activity of integrase, an HIV-encoded enzyme that is required for viral replication.
Raltegravir jimpedixxi l- attività katalitika ta ’ integrase, enzima kkodifikata ta ’ l- HIV li hija meħtieġa għar- replikazzjoni virali.
Inhibition of integrase prevents the covalent insertion, or integration, of the HIV genome into the host cell genome.
Impediment ta ’ integrase ma jħallix id - dħul kovalenti, jew integrazzjoni, tal- ġenom tal- HIV għal ġol- ġenom taċ- ċellola ospiti.
HIV genomes that fail to integrate cannot direct the production of new infectious viral particles, so inhibiting integration prevents propagation of the viral infection.
Ġenomi tal- HIV li jonqsu milli jintegraw ma jistgħux jidderieġu l- produzzjoni ta ’ partikuli virali infettivi ġodda, allura impediment ta ’ integrazzjoni ma jħallix propagazzjoni ta ’ l- infezzjoni virali.
Antiviral activity in vitro Raltegravir at concentrations of 31 ± 20 nM resulted in 95% inhibition (IC95) of HIV-1 replication (relative to an untreated virus-infected culture) in human T-lymphoid cell cultures infected with the cell-line adapted HIV-1 variant H9IIIB.
Attività antivirali in vitro Konċentrazzjonijiet ta ’ raltegravir fi 31 ± 20 nM irriżultaw f’ impediment ta ’ 95% (IC95) tar- replikazzjoni virali (meta mqabbla ma ’ kultura infettata bil- virus mhux ittrattata) f’ kulturi ta ’ ċelloli T- limfojde umani infettati b’ H9IIIB, varjant HIV- 1 tal- linja taċ- ċellola addattata.
In addition, raltegravir inhibited viral replication in cultures of mitogen-activated human peripheral blood mononuclear cells infected with diverse, primary clinical isolates of HIV-1, including isolates resistant to reverse transcriptase inhibitors and protease inhibitors.
Barra minn hekk, raltegravir impedixxa r- replikazzjoni virali f’ kulturi ta ’ ċelloli mononukleari tad- demm periferali uman attivati b’ mitoġen, infettati b’ iżolati kliniċi primarji differenti ta ’ l- HIV- 1, inklużi iżolati reżistenti għal inibituri ta ’ reverse transcriptase u inibituri protease.
9 Resistance Most viruses isolated from patients failing raltegravir had high-level raltegravir resistance resulting from the appearance of two or more mutations.
Reżistenza Il- biċċa l- kbira tal- virusijiet iżolati minn pazjenti li raltegravir ma ħadimx fuqhom kellhom livell għoli ta ’ reżistenza għal raltegravir li rriżultat mit- tfaċċar ta ’ żewġ bidliet jew aktar.
Most had a signature mutation at amino acid 155 (N155 changed to H), amino acid 148 (Q148 changed to H, K, or R), or amino acid 143 (Y143 changed to H, C, or R), along with one or more additional integrase mutations.
Il- biċċa l- kbira kellhom signature mutation fl- aċidu amminiku 155 (N155 inbidel għal H), l- aċidu amminiku 148 (148 inbidel għal H, K, jew R), jew l- aċidu amminiku 143 (Y143 inbidel għal H, C, jew R), flimkien ma ’ bidla waħda jew aktar addizzjonali ta ’ integrase.
These signature mutations decrease viral susceptibility to raltegravir and addition of other mutations results in a further decrease in raltegravir susceptibility.
Dawn is- signature mutations inaqqsu s- suxxettibilità virali għal raltegravir, u ż- żieda ta ’ bidliet oħra tirriżulta f’ aktar tnaqqis fis- suxxettibilità għal raltegravir.
Factors that reduced the likelihood of developing resistance included lower baseline viral load and use of other active anti-retroviral agents.
Fatturi li naqqsu l- probabbiltà li tiġi żviluppata reżistenza kienu jinkludu viral load bażika aktar baxxa u l- użu ta ’ sustanzi antiretrovirali attivi oħra.
Preliminary data indicate that there is potential for at least some degree of cross-resistance to occur between raltegravir and other integrase inhibitors.
Informazzjoni preliminari tindika li hemm ċans li jkun hemm mill- anqas xi livell ta ’ cross- resistance bejn raltegravir u inibituri oħra integrase.
Clinical experience Efficacy of ISENTRESS in treatment-experienced patients BENCHMRK 1 and BENCHMRK 2 (ongoing multi-centre, randomised, double-blind, placebo- controlled trials) evaluate the safety and anti-retroviral activity of ISENTRESS 400 mg b. i. d. vs. placebo in a combination with optimized background therapy (OBT), in HIV-infected patients, 16 years or older, with documented resistance to at least 1 drug in each of 3 classes (NRTIs, NNRTIs, PIs) of anti-retroviral therapies.
Qabel ir- randomizzazzjoni, l- OBT
Prior to randomization, OBT were selected by the investigator based on the patient's prior treatment history, as well as baseline genotypic and phenotypic viral resistance testing.
10 ġew magħżula mill- investigatur fuq il- bażi ta ’ l- istorja preċedenti tal- pazjent, kif ukoll fuq il- bażi ta ’ l - ittestjar tar- reżistenza virali ġenotipika u fenotipika fil- linja bażi.
Patient demographics (gender, age and race) and baseline characteristics were comparable between ISENTRESS 400 mg b. i. d. and placebo groups.
Id- demografiċi tal- pazjenti (sess, età u razza) u l- karatteristiċi fil- linja bażi kienu komparabbli bejn ISENTRESS 400 mg b. i. d. u gruppi plaċebo.
Patients had prior exposure to a median of 12 anti-retrovirals for a median of 10 years.
Il- pazjenti kellhom espożizzjoni minn qabel għal medjan ta ’ 12- il antiretrovirali għal medjan ta ’ 10 snin.
A median of 4 ARTs was used in OBT.
Fl- OBT intuża medjan ta ’ 4 ARTs.
Results 48 week analyses Durable week 48 outcomes for patients on the recommended dose ISENTRESS 400 mg b. i. d. from the pooled studies BENCHMRK 1 and BENCHMRK 2 are shown in Table 2.
Riżultati ta ’ analiżi ta ’ 48 ġimgħaIr- riżultati wara ġimgħa 48 għall- pazjenti fuq id- doża rrikkmandata ta ’ ISENTRESS 400 mg b. i. d. mill- istudji BENCHMRK 1 u BENCHMRK 2 miġburin flimkien huma murija f’ tabella 2.
Table 2 Efficacy Outcome at Week 48
Tabella 2 Riżultati ta ’ l- Effikaċja f’ Ġimgħa 48
BENCHMRK 1 and 2 Pooled Parameter Percent HIV-RNA < 400 copies/ ml (95% CI)
Parametru HIV- RNA perċentwali < 400 kopja/ ml (95% CI)
ISENTRESS 400 mg b. i. d. + OBT (N = 462)
b. i. d. + OBT (N = 462)
All patients† Baseline Characteristic‡
Il- pazjenti kollha † Karatteristika tal- Linja bażi ‡
HIV-RNA > 100,000 copies/ ml ≤ 100,000 copies/ ml CD4-count ≤ 50 cells/ mm3 > 50 and ≤ 200 cells/ mm3 > 200 cells/ mm3 Sensitivity score (GSS) §
HIV- RNA > 100, 000 kopja/ ml ≤ 100, 000 kopja/ ml Għadd ta ’ CD4 ≤ 50 ċellola/ mm3 > 50 u ≤ 200 ċellola/ mm3 > 200 ċellola/ mm3 Punteġġ tas- sensittività (GSS) §
0 1 2 and above Percent HIV-RNA < 50 copies/ ml (95% CI)
0 1 2 u ogħla HIV- RNA perċentwali < 50 kopja/ ml (95% CI)
HIV-RNA > 100,000 copies/ ml ≤ 100,000 copies/ ml CD4-count ≤ 50 cells/ mm3 > 50 and ≤ 200 cells/ mm3 > 200 cells/ mm3 Sensitivity score (GSS) §
HIV- RNA > 100, 000 kopja/ ml ≤ 100, 000 kopja/ ml Għadd ta ’ CD4 ≤ 50 ċellola/ mm3 > 50 u ≤ 200 ċellola/ mm3 > 200 ċellola/ mm3 Punteġġ tas- Sensittività (GSS) §
0 1
0 1 2 u ogħla Bidla Medja fiċ- Ċelloli CD4 (95% CI), ċelloli/ mm3
All patients‡ Baseline Characteristic‡
Il- pazjenti kollha ‡ Karatteristiċi tal- Linja bażi ‡
HIV-RNA > 100,000 copies/ ml ≤ 100,000 copies/ ml CD4-count ≤ 50 cells/ mm3 > 50 and ≤ 200 cells/ mm3 > 200 cells/ mm3 § Sensitivity score (GSS)
HIV- RNA > 100, 000 kopja/ ml ≤ 100, 000 kopja/ ml Għadd ta ’ CD4 ≤ 50 ċellola/ mm3 > 50 u ≤ 200 ċellola/ mm3 > 200 ċellola/ mm3 Punteġġ tas- sensittività (GSS)
0 1 2 and above †
0 1 2 u ogħla †
Non-completer is failure imputation: patients who discontinued prematurely are imputed as failure thereafter.
Pazjent li ma jtemmx it- trattament huwa imputazzjoni ta ’ falliment: il- pazjenti li waqfu qabel iż- żmien huma imputati bħala falliment wara.
Percent of patients with response and associated 95% confidence interval (CI) are reported. ‡ For analysis by prognostic factors, virologic failures were carried forward for percent < 400 and 50 copies/ ml.
11 Huma rrappurtati l- perċentwali ta ’ pazjenti b’ rispons u l- intervall ta ’ kunfidenza (CI) relatat ta ’ 95% ‡ Għal analiżi skond il- fatturi pronjostiċi, il- fallimenti viroloġiċi ġew avanzati għal perċentwali < 400 u 50 kopja/ ml.
For mean CD4 changes, baseline-carry-forward was used for virologic failures. § The Genotypic Sensitivity Score (GSS) was defined as the total oral ARTs in the optimised background therapy (OBT) to which a patient's viral isolate showed genotypic sensitivity based upon genotypic resistance test.
Għall- bidliet medji fil - CD4, intuża l- carry- forward tal- linja bażi għall- fallimenti viroloġiċi. § Il- Punteġġ tas- Sensittività Ġenotipika (GSS) ġie definit bħala l- ARTs orali totali fit- terapija ta ’ sfond ottimizzata (OBT) li għalihom iżolat virali ta ’ pazjent wera sensittività ġenotipika bbażata fuq test tar- reżistenza ġenotipika.
Enfuvirtide use in OBT in enfuvirtide-naïve patients was counted as one active drug in OBT.
L- użu ta ’ enfuvirtide f’ OBT f’ pazjenti li ma kinux ħadu enfuvirtide qabel ġie meqjus bħala mediċina attiva waħda f’ OBT.
Similarly, darunavir use in OBT in darunavir-naïve patients was counted as one active drug in OBT.
Bl- istess mod, l- użu ta ’ darunavir f’ OBT f’ pazjenti li ma ħadux darunavir qabel ġie meqjus bħala mediċina attiva waħda f’ OBT.
Raltegravir achieved virologic responses (using Not Completer=Failure approach) of HIV RNA < 50 copies/ ml in 61.7% of patients at Week 16 and in 62.1% at Week 48.
Raltegravir laħaq risponsi viroloġiċi (permezz tal- metodu Mhux Mlesti = Falliment) għal HIV RNA < 50 kopja/ ml f’ 61. 7% tal- pazjenti f’ Ġimgħa 16 u 62. 1% f’ Ġimgħa 48.
Some patients experienced viral rebound between Week 16 and Week 48.
Xi pazjenti esperjenzaw rebound virali bejn Ġimgħa 16 u Ġimgħa 48.
Factors associated with failure include high baseline viral load and OBT that did not include at least one potent active agent.
Fatturi assoċjati ma ’ falliment jinkludu viral load b’ linja bażi ta ’ riferiment għoli u OBT li ma kinetx tinkludi tal- anqas sustanza attiva qawwija waħda.
Long-term efficacy data of ISENTRESS 400 mg b. i. d. in treatment-experienced patients up to 48 weeks are also available from the Phase II dose-finding study (Protocol 005).
Dejta dwar l- effikaċja fuq tul ta ’ żmien ta ’ ISENTRESS 400 mg b. i. d. f’ pazjenti li diġà rċevew it- trattament qabel sa 48 ġimgħa hija disponibbli wkoll mill- istudju ta ’ tisjib tad- doża ta ’ Fażi II (Protokoll 005).
At week 24, 71% of patients receiving ISENTRESS 400 mg b. i. d. maintained HIV RNA < 400 copies/ ml and 56% also maintained HIV RNA < 50 copies/ ml.
F’ ġimgħa 24, 71% tal- pazjenti li kienu qegħdin jirċievu ISENTRESS 400 mg b. i. d. żammew HIV RNA < 400 kopja/ ml u 56% żammew ukoll HIV RNA < 50 kopja/ ml.
Through 48 weeks of treatment, 64% receiving ISENTRESS 400 mg b. i. d. maintained HIV RNA < 400 copies/ ml and 46% also maintained HIV RNA < 50 copies/ ml.
Matul it- 48 ġimgħa ta ’ trattament, 64% li kienu qegħdin jirċievu ISENTRESS 400 mg b. i. d. żammew HIV- 1 RNA < 400 kopji/ ml u 46% żammew ukoll HIV RNA < 50 kopji/ ml.
This medicinal product has been authorised under a so-called “ conditional approval” scheme.
Dan il- prodott mediċinali ġie awtorizzat taħt hekk imsejħa skema ta ’ “ approvazzjoni b’ kondizzjonai ”.
This means that further evidence on this medicinal product is awaited.
Dan ifisser li għadha mistennija aktar evidenza fuq dan il- prodott mediċinali.
The European Medicines Agency (EMEA) will review new information on the product every year and this SPC will be updated as necessary.
L- Aġenzija Ewropea dwar il- Mediċini (EMEA) sejra tirrevedi informazzjoni ġdida fuq il- prodott kull sena u dan l- SPC sejjer jiġi aġġornat bix- xieraq.
Absorption As demonstrated in healthy volunteers administered single oral doses of raltegravir in the fasted state, raltegravir is rapidly absorbed with a tmax of approximately 3 hours postdose.
Assorbiment Kif muri f’ voluntiera b’ saħħithom li ngħataw dożi orali singoli ta ’ raltegravir fuq stonku vojt, raltegravir jiġi assorbit malajr b’ tmax ta ’ madwar 3 sigħat wara d- doża.
Raltegravir AUC and Cmax increase dose proportionally over the dose range 100 mg to 1600 mg.
L- AUC u s - Cmax ta ’ raltegravir jiżdiedu proporzjonalment fuq il- firxa tad- doża ta ’ 100 mg sa 1600 mg.
Raltegravir C12 hr increases dose proportionally over the dose range of 100 to 800 mg and increases slightly less than dose proportionally over the dose range 100 mg to 1600 mg.
Is- C12 hr ta ’ raltegravir tiżdied proporzjonalment fuq il- firxa tad- doża 100 mg sa 800 mg u tiżdied xi ftit anqas mid- doża proporzjonalment fuq il- firxa tad- doża 100 mg sa 1600 mg.
Dose proportionality has not been established in patients.
Il- proporzjonalità tad- doża ma ġietx stabbilita fil- pazjenti.
With twice-daily dosing, pharmacokinetic steady state is achieved rapidly, within approximately the first 2 days of dosing.
B’ doża ta ’ darbtejn kuljum, l- istat farmakokinetiku fiss jinkiseb malajr, fi żmien madwar l- ewwel jumejn tat- teħid tad- doża.
There is little to no accumulation in AUC and Cmax and evidence of slight accumulation in C12 hr.
Hemm minn ftit sa l- ebda akkumulazzjoni fl- AUC jew fis- Cmax u evidenza ta ’ ftit akkumulazzjoni fis- C12 hr.
The absolute bioavailability of raltegravir has not been established.
Il- bijodisponibbilità assoluta ta ’ raltegravir ma ġietx stabbilita.
ISENTRESS may be administered with or without food.
ISENTRESS jista ’ jingħata ma ’ l- ikel jew fuq stonku vojt.
Raltegravir was administered without regard to food in the pivotal safety and efficacy studies in HIV-infected patients.
Raltegravir ġie mogħti mingħajr konsiderazzjoni għall- ikel fl- istudji pivitali dwar is- sigurtà u l- effikaċja fuq pazjenti pożittivi għall - HIV.
Administration of multiple doses of raltegravir following a moderate-fat meal did not affect raltegravir AUC to a clinically
L- għoti ta ’ diversi dożi ta ’ raltegravir wara ikla li kien fiha kontenut moderat ta ’ xaħam ma affettwax l- AUC ta ’ raltegravir fi grad klinikament sinifikanti, b’ żieda ta ’ 13% meta mqabbel mas - sawm.
Raltegravir C12 hr was 66% higher and Cmax was 5% higher following a moderate-fat meal compared to fasting.
Il- C12 hr ta ’ raltegravir kienet 66% ogħla u l- Cmax kienet 5% ogħla wara ikla b’ kontenut moderat ta ’ xaħam meta mqabbel mas- sawm.
Administration of raltegravir following a high-fat meal increased AUC and Cmax by approximately 2-fold and increased C12 hr by 4.1-fold.
L- għoti ta ’ raltegravir wara ikla b’ kontenut għoli ta ’ xaħam żied l- AUC u l- Cmax b’ madwar darbtejn u żied il- C12 hr b’ 4. 1 darbiet.
Administration of raltegravir following a low-fat meal decreased AUC and Cmax by 46% and 52%, respectively; C12 hr was essentially unchanged.
L- għoti ta ’ raltegravir wara ikla b’ kontenut baxx ta ’ xaħam naqqas l- AUC u l- Cmax b’ 46% u 52%, rispettivament; il- C12 hr baqa ’ prattikament mhux mibdul.
Food appears to increase pharmacokinetic variability relative to fasting.
L- ikel jidher li jżid il- varjabilità farmakokinetika meta mqabbel mas - sawm.
Overall, considerable variability was observed in the pharmacokinetics of raltegravir.
B’ mod ġenerali, kienet osservata varjabilità konsiderevoli fil- farmakokinetiċi ta ’ raltegravir.
For observed C12hr in BENCHMRK 1 and 2 the coefficient of variation (CV) for inter-subject variability = 212% and the CV for intra-subject variability = 122%.
Għall - C12hr osservat f‘ BENCHMRK 1 u 2, il- koeffiċjent tal- varjazzjoni (CV) għall- varjabilità bejn persuna u oħra = 212% u CV għall- varjabilità fl- istess persuna = 122%.
Sources of variability may include differences in co-administration with food and concomitant medications.
Is- sorsi tal- varjabilità jistgħu jinkludu differenzi fl- għoti fl- istess ħin ma ’ l- ikel u medikazzjonijiet konkomitanti.
Distribution Raltegravir is approximately 83% bound to human plasma protein over the concentration range of 2 to 10 µM.
12 Distribuzzjoni Raltegravir huwa madwar 83% marbut mal- proteina fil- plażma fuq firxa ta ’ konċentrazzjoni ta ’ 2 sa 10 µM.
Raltegravir readily crossed the placenta in rats, but did not penetrate the brain to any appreciable extent.
Raltegravir malajr għadda mis- sekonda fil- firien, iżda ma ppenetrax il- moħħ b’ xi ammonti sinjifikanti.
Metabolism and excretion The apparent terminal half-life of raltegravir is approximately 9 hours, with a shorter α -phase half-life (~1 hour) accounting for much of the AUC.
Metaboliżmu u eskrezzjoni Il- half- life terminali apparenti huwa ta ’ madwar 9 sigħat, b’ half- life ta ’ α- phase iqsar (~1 siegħa) li tammonta għal ħafna mill- AUC.
Following administration of an oral dose of radiolabeled raltegravir, approximately 51 and 32% of the dose was excreted in faeces and urine, respectively.
Wara l- għoti ta ’ doża orali ta ’ raltegravir radjutikkettat, madwar 51 sa 32% tad- doża ġiet eliminata fl- ippurgar u fl- awrina, rispettivament.
In faeces, only raltegravir was present, most of which is likely to be derived from hydrolysis of raltegravir-glucuronide secreted in bile as observed in preclinical species.
Fl- ippurgar, kien hemm biss raltegravir, li l- parti l- kbira minnu x’ aktarx li tiġi minn idroliżi ta ’ raltegravir- glucuronide merħi fil - bajl kif osservat fi speċijiet ta ’ qabel l- użu kliniku.
Two components, namely raltegravir and raltegravir-glucuronide, were detected in urine and accounted for approximately 9 and 23% of the dose, respectively.
Żewġ komponenti, jiġifieri raltegravir u raltegravir - glucuronide, instabu fl- awrina u kkontribwixxew għal madwar 9 u 23% tad- doża, rispettivament.
The major circulating entity was raltegravir and represented approximately 70% of the total radioactivity; the remaining radioactivity in plasma was accounted for by raltegravir-glucuronide.
L - entità maġġura li kienet qed tiċċirkola kienet raltegravir u din irrappreżentat madwar 70% tar - radjuattività totali; ir- radjuattività li baqgħet fil- plażma kienet irrappreżentata minn raltegravir - glucuronide.
Studies using isoform-selective chemical inhibitors and cDNA-expressed UDP-glucuronosyltransferases (UGT) show that UGT1A1 is the main enzyme responsible for the formation of raltegravir-glucuronide.
Studji b’ inibituri kimiċi iżoformi- selettivi u cDNA- expressed UDP - glucuronosyltransferases (UGT) juru li UGT1A1 hija l- enzima ewlenija responsabbli għal formazzjoni ta ’ raltegravir- glucuronide.
Thus the data indicate that the major mechanism of clearance of raltegravir in humans is UGT1A1-mediated glucuronidation.
B’ hekk id- dejta tindika li l- mekkaniżmu ta ’ eliminazzjoni maġġur ta ’ raltegravir fil- bnedmin huwa glukuronidazzjoni medjata minn UGT1A1.
UGT1A1 Polymorphism In a comparison of 30 subjects with *28/ *28 genotype to 27 subjects with wild-type genotype, the geometric mean ratio (90% CI) of AUC was 1.41 (0.96, 2.09) and the geometric mean ratio of C12 hr was 1.91 (1.43, 2.55).
Polymorfiżmu UGT1A1 Fi tqabbil ta ’ 30 soġġett b’ ġenotip * 28 / * 28 ma ’ 27 suġġett b’ ġenotip ta ’ tip selvaġġ, il- proporzjon tal - medja ġeometrika (90% CI) ta ’ AUC kien 1. 41 (0. 96, 2. 09) u l- proporzjon tal- medja ġeometrika ta ’ C12 hr kien 1. 91 (1. 43, 2. 55).
Dose adjustment is not considered necessary in subjects with reduced UGT1A1 activity due to genetic polymorphism.
Aġġustament fid- doża mhuwiex meqjus neċessarju f’ suġġetti b’ attività UGT1A1 imnaqqsa minħabba polimorfiżmu ġenetiku.
Children The pharmacokinetics of raltegravir in paediatric patients has not been established.
Tfal Il- farmakokinetiċi ta ’ raltegravir f’ pazjenti pedjatriċi ma ġewx stabbiliti.
Elderly There was no clinically meaningful effect of age on raltegravir pharmacokinetics over the age range studied (19 to 71 years, with few (8) subjects over the age of 65).
Anzjani Ma kien hemm l- ebda effett kliniku sinifikanti ta ’ l- età fuq il- farmakokinetiċi ta ’ raltegravir fuq il - medda ta ’ etajiet studjata (19 sa 71 sena, bi ftit (8) pazjenti li kellhom aktar minn 65 sena).
Gender, Race and BMI There were no clinically important pharmacokinetic differences due to gender, race or body mass index (BMI).
Sess, Razza u BMI Ma kien hemm ebda differenzi farmakokinetiċi klinikament importanti minħabba s- sess, razza jew indiċi tal- massa tal- ġisem (BMI).
Renal impairment Renal clearance of unchanged medicinal product is a minor pathway of elimination.
Indeboliment tal- kliewi L- eliminazzjoni mill- kliewi ta ’ prodott mediċinali mhux mibdul hija mogħdija ta ’ eliminazzjoni minuri.
There were no clinically important pharmacokinetic differences between patients with severe renal insufficiency and healthy subjects (see section 4.2).
Ma kien hemm l- ebda differenza farmakokinetika klinikament importanti bejn pazjenti b’ indeboliment tal- kliewi serju u suġġetti f’ saħħithom (ara sezzjoni 4. 2).