qanastek/EMEA-V3 huggingface dataset:
Darunavir was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks.
22 Darunavir ġie evalwat għal potenzjal kanċeroġeniku permezz ta ’ amministrazzjoni b’ tubu mill- ħalq lill- ġrieden u l- firien sa 104 ġimgħat.
Daily doses of 150, 450 and 1,000 mg/kg were administered to mice and doses of 50, 150 and 500 mg/kg were administered to rats.
Dożi kuljum ta ’ 150, 450 u 1, 000 mg/ kg kienu mogħtija lill - ġrieden u dożi ta ’ 50, 150 u 500 mg/ kg kienu mogħtija lill- firien.
Dose-related increases in the incidences of hepatocellular adenomas and carcinomas were observed in males and females of both species.
Żidiet relatati mad- doża fl- inċidenzi ta ’ adenomi epatoċellulari u karċinomi ġew osservati fin- nisa u l- irġiel taż- żewġ speċi.
Thyroid follicular cell adenomas were noted in male rats.
Adenomi taċ - ċelloli follikulari tat- tirojde kienu nnutati fil- firien irġiel.
Administration of darunavir did not cause a statistically significant increase in the incidence of any other benign or malignant neoplasm in mice or rats.
L- amministrazzjoni ta ’ darunavir ma kkawżatx żieda statistikament sinifikanti ta ’ kwalunkwe neoplażmu beninn jew malinn ieħor fil - ġrieden u l- firien.
The observed hepatocellular and thyroid tumours in rodents are considered to be of limited relevance to humans.
It- tumuri epatoċellulari u tat- tirojde li ġew osservati fl- annimali gerriema huma kkunsidrati ta ’ rilevanza limitata għall- bnedmin.
Repeated administration of darunavir to rats caused hepatic microsomal enzyme induction and increased thyroid hormone elimination, which predispose rats, but not humans, to thyroid neoplasms.
L- amministrazzjoni ripetuta ta ’ darunavir lill- firien ikkawżat induzzjoni ta ’ l- enzimi epatiċi mikrosomali u żiedet l- eliminazzjonni ta ’ l- ormon tat- tirojde, li jippredisponi lill- firien, iżda mhux lill- bnedmin, għal neoplażmi tat- tirojde.
At the highest tested doses, the systemic exposures (based on AUC) to darunavir were between 0.4- and 0.7-fold (mice) and 0.7- and 1-fold (rats), relative to those observed in humans at the recommended therapeutic doses.
Fl- ogħla dożi ittestjati, l - esponimenti sistemiċi (ibbażati fuq l- AUC) għal darunavir kienu bejn 0. 4 darbiet u 0. 7 darbiet (ġrieden) u 0. 7 darbiet u darba aktar (fil- firien) meta mqabbla ma ’ dawk osservati fil- bnedmin fid- dożi terapewtiċi rrakkomandati.
After 2 years administration of darunavir at exposures at or below the human exposure, kidney changes were observed in mice (nephrosis) and rats (chronic progressive nephropathy).
Wara l- amministrazzjoni ta ’ darunavir għal sentejn f’ esponimenti daqs jew anqas mill- esponimenti tal - bnedmin, bidliet fil- kliewi ġew osservati fil- ġrieden (nefrożi) u l- firien (nefropatija kronika progressiva).
Darunavir was not mutagenic or genotoxic in a battery of in vitro and in vivo assays including bacterial reverse mutation (Ames), chromosomal aberration in human lymphocytes and in vivo micronucleus test in mice.
Darunavir ma kienx mutaġeniku jew ġenotossiku f’ għadd ta ’ analiżi in vitro u in vivo inkluż mutazzjoni batterjali bil- kuntrarju (Ames), aberrazzjoni tal- kromożomi fil- limfoċit uman u t- test in vivo tal- mikronukleju fil- ġrieden.
Tablet core Microcrystalline cellulose Colloidal anhydrous silica Crospovidone Magnesium stearate
Qalba tal- pillola Microcrystalline cellulose Colloidal anhydrous silica Crospovidone Magnesium stearate
Tablet film-coat Poly(vinyl alcohol) – partially hydrolyzed Macrogol 3350 Titanium dioxide (E171) Talc Sunset yellow FCF (E110)
Rita ta ’ barra tal- pillola Poly( vinyl alkoħol) – parzjalment idrolizzat Macrogol 3350 Titanium dioxide (E171) Terra Sunset yellow FCF (E110)
Not applicable.
Ma jghoddx f’ dan il- każ
21 6.3 Shelf life
Żmien kemm idum tajjeb il- prodott mediċinali 6. 3
High density polyethylene (HDPE) plastic bottle containing 120 tablets, fitted with polypropylene (PP) child resistant closure.
Flixkun tal- plastik polethylene ta’ densità għolja (HDPE) li fih 120 pillola, magħluq b’ għatu tal - polypropylene (PP) li ma ’ jinfetaħx mit- tfal.
One bottle
Flixkun wieħed
6.6 Special precautions for disposal
6. 6 Prekawzjonijiet speċjali li għandhom jittiehdu meta jintrema
No special requirements.
23 L- ebda ħtiġijiet speċjali.
12 February 2007 Date of latest renewal:
12 ta ’ Frar 2007 Data ta ’ l- aħħar tiġdid:
12 February 2008
12 ta ’ Frar 2008
PREZISTA 400 mg film-coated tablets
PREZISTA 400 mg pilloli miksijin b’ rita
Each film-coated tablet contains 400 mg of darunavir (as ethanolate).
Kull pillola miksija b’ rita fiha 400 mg ta ’ darunavir (bħala ethanolate).
Each tablet contains 0.834 mg sunset yellow FCF (E110).
Kull pillola fiha 0. 834 mg sunset yellow FCF (E110).
Light orange oval shaped tablet, debossed with “400MG” on one side and “TMC” on the other side.
Pillola oranġjo ċara b’ forma ovali, li fiha mħaffra “ 400MG ” fuq naħa waħda u “ TMC ” fuq in- naħa l - oħra.
PREZISTA 400 mg, co-administered with low dose ritonavir is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV-1) infection in antiretroviral therapy (ART) naïve adults.
PREZISTA 400 mg, mogħti flimkien ma ’ doża baxxa ta ’ ritonavir huwa indikat, flimkien ma ’ prodotti mediċinali antiretrovirali oħra, għat- trattament ta ’ l- infezzjoni bil- virus uman ta ’ l- immunodefiċjenza (HIV- 1) f’ pażjenti adulti li qatt ma ħadu kura b’ antirertovirali (ART).
Adults ART-naïve patients The recommended dosage of PREZISTA is 800 mg once daily (q.d.) taken with ritonavir 100 mg q.d. and with food.
Adulti Pazjenti li qatt ma ħadu ART Id- doża rakkommandata ta ’ PREZISTA hija 800 mg darba kuljum (q. d.) meħuda flimkien ma ’ ritonavir 100 mg q. d. u ma ’ l- ikel.
Patients should be instructed to take PREZISTA with low dose ritonavir within 30 minutes after completion of a meal.
Il- pazjenti għandhom jingħataw istruzzjonijiet biex jieħdu PREZISTA flimkien ma ’ doża baxxa ta ’ ritonavir fi żmien 30 minuta wara li jispiċċaw ikla.
ART-experienced patients For dosage recommendations in ART-experienced patients see the Summary of Product Characteristics for PREZISTA 300 mg and 600 mg tablets.
Pazjenti li diġà ħadu ART Għal rakkomandazzjonijiet tad- doża f’ pazjenti li digà ħadu ART ara s- Sommarju tal- Karatteristiċi tal - Prodott għal pilloli PREZISTA ta ’ 300 mg u 600 mg.
After therapy with PREZISTA has been initiated, patients should be advised not to alter the dosage or discontinue therapy without instruction of their physician.
Wara li tkun inbdiet kura bi PREZISTA, il- pazjenti għandhom jiġu mwissija biex ma jibdlux id- doża jew iwaqqfu l- kura mingħajr istruzzjonijiet mingħand it- tabib tagħhom.
Children and adolescents PREZISTA is not recommended for use in children and adolescents because due to insufficient data on safety, efficacy and pharmacokinetics.
Tfal u adoloxxenti PREZISTA mhux rakkomandat għall- użu fit- tfal u fl- adoloxxenti minħabba li m’ hemmx tagħrif biżżejjed dwar sigurtà, effikaċja u farmakokinetika.
23 Limited information is available in this population and therefore PREZISTA should be used with caution in this age group (see sections 4.4 and 5.2).
25 Informazzjoni limitata hija disponibbli f’ din il- popolazzjoni u għalhekk PREŻISTA għandu jintuża b’ attenzjoni fil- grupp ta ’ din l- età (ara sezzjonijiet 4. 4 and 5. 2).
Hepatic impairment Darunavir is metabolised by the hepatic system.
Indeboliment epatiku Darunavir huwa mmetabolizzat permezz tas- sistema epatika.
No pharmacokinetic data are available in patients with severe hepatic impairment.
L - ebda dejta farmakokinetika ma hija disponibbli f’ pazjenti b’ indeboliment epatiku serju.
Renal impairment No dose adjustment is required in patients with renal impairment (see sections 4.4 and 5.2).
Indeboliment renali Ma hemm bżonn l- ebda aġġustament tad- doża f’ pazjenti b’ indeboliment renali serju (ara sezzjonijiet 4. 4 u 5. 2).
If an 800/100 mg once daily dose of PREZISTA/ritonavir is missed within 12 hours of the time it is usually taken, patients should be instructed to take the prescribed dose of PREZISTA and ritonavir with food as soon as possible.
F’ każ li doża ta ’ 800 mg/ 100 mg ta ’ PREZISTA/ ritonavir li tittieħed kuljum tinqabeż u tiġi nnutata fi żmien 12- il siegħa minn meta din is- soltu tittieħed, il- pazjenti għandhom jiġu nfurmati biex jieħdu d - doża preskritta ta ’ PREZISTA u ritonavir ma ’ l- ikel malajr kemm jista ’ jkun.
If this is noticed later than 12 hours of the time it is usually taken, the missed dose should not be taken and the patient should resume the usual dosing schedule.
Jekk id- doża maqbuża tiġi nnutata wara li jgħaddu 12- il siegħa minn meta tiġi meħuda s- soltu, id- doża maqbuża m’ għandiex tittieħed u l- pazjent għandu jkompli l- iskeda tad- dożi tas- soltu.
This guidance is based on the 15 hour half-life of darunavir in the presence of ritonavir and the recommended dosing interval of approximately 24 hours.
Din il- gwida hija bbażata fuq il- 15- il siegħa half life ta ’ darunavir fil- preżenza ta ’ ritonavir u l - intervall ta ’ bejn wieħed u ieħor 24 siegħa li huwa rakkommandat li jinżamm bejn doża u oħra.
The combination product lopinavir/ritonavir should not be used with PREZISTA because co-administration causes large decreases in darunavir concentrations, which may in turn significantly decrease the darunavir therapeutic effect (see section 4.5).
Il- prodott li fih lopinavir u ritonavir flimkien m’ għandux jintuża flimkien ma PREZISTA minħabba li l- amministrazzjoni tagħhom flimkien toħloq tnaqqis kbir fil- konċentrazzjonijiet ta ’ darunavir, u konsegwenza ta ’ dan jonqos sinifikament l- effett terapewtiku ta ’ darunavir (ara sezzjoni 4. 5).
Herbal preparations containing St John’s wort (Hypericum perforatum) must not be used while taking PREZISTA due to the risk of decreased plasma concentrations and reduced clinical effects of darunavir (see section 4.5).
Mediċini tal- ħxejjex li fihom St John’ s Wort (Hypericum perforatum) m’ għandhomx jintużaw waqt li qed jittieħed PREZISTA minħabba r- riskju ta ’ konċentrazzjonijiet imnaqqsa fil- plażma u tnaqqis fl - effetti kliniċi ta’ darunavir (ara sezzjoni 4. 5).
Co-administration of PREZISTA with 100 mg ritonavir, with active substances that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated.
L- għoti flimkien ta ’ PREZISTA u 100 mg ritonavir, ma ’ sustanzi attivi li jiddependu ħafna minn CYP3A għat- tneħħija tagħhom u li l- konċentrazzjonijiet għoljin tagħhom fil- plażma huma assoċjati ma ’ ġrajjiet serji u/ jew ta ’ periklu għall- ħajja, huma kontra- indikati.
These active substances include e.g. antiarrhythmics (amiodarone, bepridil, quinidine, systemic lidocaine), antihistamines (astemizole, terfenadine), ergot derivatives (e.g. dihydroergotamine, ergonovine, ergotamine, methylergonovine), gastrointestinal motility agents (cisapride), neuroleptics (pimozide, sertindole), sedatives/hypnotics [triazolam, midazolam administered orally (for caution on parenterally administered midazolam, see section 4.5)] and HMG-CoA reductase inhibitors (simvastatin and lovastatin) (see section 4.5).
Dawn is- sustanzi attivi jinkludu e. ż. antiarritmiċi (amiodarone, bepridil, quinidine, lidocaine sistemiku), antistamini (astemizole, terfenadine), derivattivi ta ’ l- ergot (e. ż. dihydroergotamine, ergonovine, ergotamine, methylergonovine), aġenti tal- mobilità gastro- intestinali (cisapride), newrolettiċi (pimozide, sertindole), sedattivi/ ipnotiċi [triazolam, midazolam mogħti mill- ħalq (għal attenzjoni dwar midazolam li jingħata b’ mod parenterali, ara sezzjoni 4. 5)] u impedituri ta ’ l- HMG- CoA reductase (simvastatin u lovastatin) (ara sezzjoni 4. 5).
PREZISTA should only be used in combination with 100 mg of ritonavir as a pharmacokinetic enhancer (see section 5.2).
26 PREZISTA għandu jintuża biss flimkien ma 100 mg ritonavir li jservi ta ’ intensifikatur farmakokinetiku (ara sezzjoni 5. 2).
24 Elderly:
Anzjani:
Darunavir binds predominantly to α1-acid glycoprotein.
Darunavir jeħel b’ mod predominanti ma ’ l- α1- glikoproteina aċida.
This protein binding is concentration dependent indicative for saturation of binding.
Dan it- twaħħil mal- proteini tad - Demm huwa dipendenti fuq konċentrazzjoni u indikattiv tas- saturazzjoni tat- twaħħil.
Therefore, protein displacement of medicinal products highly bound to α1-acid glycoprotein cannot be ruled out.
Għalhekk spostament ta ’ proteini ta ’ prodotti mediċinali li jeħlu ħafna ma ’ l- α1- glikoproteina aċida, ma tistax ma tikkunsidraħx.
Severe skin rash, which may be accompanied with fever and/or elevations of transaminases, has occurred in 0.5% of patients treated with PREZISTA.
Raxx qawwi fil- ġilda, li jista ’ jseħħ flimkien ma ’ deni u/ jew livelli għoljin ta ’ transaminases, ġraw f’ 0. 5% tal- pazjenti kkurati bi PREZISTA.
Erythema multiforme and Stevens-Johnson Syndrome have been rarely (< 0.1%) observed.
Eritema multiforme u s- Sindrome ta ’ Stevens- Johnson kienu osservati b’ mod rari (< 0. 1%).
Due to an increase in the unbound darunavir plasma concentrations, PREZIST A should be used with caution in patients with mild or moderate hepatic impairment (see sections 4.2, 4.3 and 5.2).
Minħabba żieda fil - konċentrazzjonijiet ta ’ darunavir mhux imwaħħal mal- proteini fil- plażma, PREZISTA għandu jintuża b’ attenzjoni f’ pazjenti b’ indeboliment epatiku ħafif jew moderat (ara sezzjonijiet 4. 2, 4. 3 u 5. 2).
Diabetes mellitus/Hyperglycaemia New onset diabetes mellitus, hyperglycaemia, or exacerbation of existing diabetes mellitus has been reported in patients receiving antiretroviral therapy, including PIs.
27 Dijabete mellitus li seħħet għall- ewwel darba, ipergliċemija, jew taħrix ta ’ djabete mellitus li kienet diġà teżisti ġew irrappurtati f’ pazjenti li qed jieħdu terapija antiretrovirali, inkluż l- Impedituri ta ’ Protease.
25 Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV infected patients.
Ridistribuzzjoni tax- xaħam u disturbi metaboliċi Terapija antiretrovirali b’ għadd ta ’ mediċini kienet assoċjata ma ’ ridistribuzzjoni tax- xaħam fil- ġisem (lipodistrofija) fil- pazjenti infettati bl- HIV.
A higher risk of lipodystrophy has been associated with individual factors such as older age and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances.
Riskju ogħla ta ’ lipodistrofija kien assoċjat ma fatturi individwali bħal kobor fl- età, u ma ’ fatturi relatati mal - mediċini bħal- trattament aktar fit- tul b’ antiretrovirali u d- disturbi metaboliċi assoċjati magħhom.
Osteonecrosis Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long-term exposure to combination antiretroviral therapy (CART).
Osteonekrożi Għalkemm l- etjoloġija hija kkunsidrata li ġejja minn ħafna fatturi (inkluż l- użu ta ’ kortikosterojd, il - konsum ta ’ l- alkoħol, immunosoppressjoni serja, indiċi tal- massa tal- ġisem ogħla), każijiet ta ’ osteonekrożi ġew irrappurtati b’ mod partikolari f’ pazjenti bil- marda tal- HIV avvanzata u/ jew esponiment fit- tul għal terapija antiretrovirali b’ taħlita ta ’ għadd ta ’ mediċini (CART).
Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and pneumonia caused by Pneumocystis jiroveci (formerly known as Pneumocystis carinii).
Eżempji rilevanti huma ċ- ċitomegalovirus retinite, infezzjonijiet mikobatterjali ġeneralizzati jew fokali u pnewmonja ikkawżata minn Pneumocystis jiroveci (li qabel kien magħruf bħala Pneumocystis carinii).
PREZISTA co-administered with 100 mg ritonavir must not be combined with medicinal products that are highly dependent on CYP3A4 for clearance and for which increased systemic exposure is associated with serious and/or life-threatening events (narrow therapeutic index).
Dawn il- mediċini jinkludu amiodarone, bepridil, quinidine, lidocaine
These medicinal products include amiodarone, bepridil, quinidine, systemic lidocaine, astemizole, terfenadine, midazolam administered orally, triazolam, cisapride, pimozide, sertindole, simvastatin, lovastatin and the ergot alkaloids (e.g. ergotamine, dihydroergotamine, ergonovine and methylergonovine) (see section 4.3).
28 sistemiku, astemizole, terfenadine, midazolam mogħti mill- ħalq, triazolam, cisapride, pimozide, sertindole, simvastatin, lovastatin u l- alkalojdi ergot (e. ż. ergotamine, dihydroergotamine, ergonovine u methylergonovine) (ara sezzjoni 4. 3).
The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in the systemic exposure of darunavir when a single dose of 600 mg darunavir was given orally in combination with ritonavir at 100 mg b.i.d.
L- effett totali ta ’ l- intensifikazzjoni ta ’ l- effett farmakokinetiku permezz ta ’ ritonavir kien bejn wieħed u ieħor żieda ta ’ 14- il darba fl- esponimnet sistemiku ta ’ darunavir meta doża waħda ta ’ 600 mg darunavir ingħatat mill- ħalq flimkien ma ’ ritonavir 100 mg b. i. d.
A clinical study utilising a cocktail of drugs that are metabolised by cytochromes CYP2C9, CYP2C19 and CYP2D6 demonstrated an increase in CYP2C9 and CYP2C19 activity and inhibition of CYP2D6
Studju kliniku bl- użu ta ’ taħlita ta ’ mediċini li jiġu mmetabolizzati miċ- ċitokromi CYP2C9, CYP2C19 u CYP2D6 urew żieda fl- attività ta ’ CYP2C9 u CYP2C19 u impediment fl- attività ta ’ CYP2D6 fil - preżenza ta ’ PREZISTA/ rtv, li tista ’ tkun attribwita għall- preżenza ta ’ doża baxxa ta ’ ritonavir.
Co-administration of darunavir and ritonavir and medicinal products which are primarily metabolised by CYP2D6 (such as flecainide, propafenone, metoprolol) may result in increased plasma concentrations of these medicinal products, which could increase or prolong their therapeutic effect and adverse reactions.
L - amministrazzjoni ta ’ darunavir flimkien ma ’ ritonavir u ma ’ prodotti mediċinali li huma primarjament immetabolizzati minn CYP2D6 (bħal flecainide, propafenone, metoprolol) tista ’ twassal għal żieda ta ’ konċentrazzjonjiet fil- plażma ta ’ dawn il- prodotti mediċinali, li jistgħu jżidu jew itawwlu l- effett terapewtiku tagħhom u r- reazzjonijiet avversi.
Medicinal products that affect darunavir/ritonavir exposure Darunavir and ritonavir are metabolised by CYP3A.
Prodotti mediċinali li jaffettwaw l- esponiment ta ’ darunavir/ ritonavir Darunavir u ritonavir huma metabolizzati permezz ta ’ CYP3A.
Medicinal products that induce CYP3A activity would be expected to increase the clearance of darunavir and ritonavir, resulting in lowered plasma concentrations of darunavir and ritonavir (e.g. rifampicin, St John’s wort, lopinavir).
Prodotti mediċinali li jinduċu l- attività ta ’ CYP3A jkunu mistennija li jżidu t- tneħħija ta ’ darunavir u ritonavir bir- riżultat ta ’ konċentrazzjonijiet imnaqqsa ta ’ darunavir u ritonavir fil- plażma (e. ż. rifampicin, St John’ s wort, lopinavir).
Co-administration of darunavir and ritonavir and other medicinal products that inhibit CYP3A may decrease the clearance of darunavir and ritonavir and may result in increased plasma concentrations of darunavir and ritonavir (e.g. indinavir, systemic azoles like ketoconazole and clotrimazole).
L- amministrazzjoni ta ’ darunavir u ritonavir flimkien ma ’ prodotti mediċinali oħra li jimpedixxu CYP3A jistgħu jnaqqsu t- tneħħija ta ’ darunavir u ritonavir u jistgħu jwasslu għal konċentrazzjonijiet ogħla ta ’ darunavir u ritonavir fil- plażma (e. ż. indinavir, azoles sistemiċi bħal ketoconazole u clotrimazole).
Interaction table Interactions between darunavir/ritonavir and protease inhibitors, antiretroviral agents other than protease inhibitors and other non-antiretroviral medicinal products are listed in the tables below (increase is indicated as “↑”, decrease as “↓”, no change as “↔”, not determined as “ND”, twice daily as “b.i.d.”, once daily as “q.d.” and once every other day as “q.o.d.”).
Tabella ta ’ prodotti mediċinali li ma jaqblux flimkien Interazzjonijiet bejn darunavir/ ritonavir u Impedituri ta ’ Protease, mediċini antiretrovirali li ma humiex Impedituri ta ’ Protease u prodotti mediċinali oħrajn li ma humiex antiretrovirali huma elenkati fit- tabelli t’ hawn taħt (żieda hija indikata bħala “ ↑ ”, tnaqqis bħala “ ↓ ”, l- ebda bidla bħala “ ↔ ”, ma tistax tittieħed stima bħala “ ND ”, darbtejn kuljum bħala “ b. i. d. ”, darba kuljum bħala “ q. d. ” u ġurnata iva u oħra le bħala “ q. o. d. ”).
Interactions – Darunavir/ritonavir with Protease Inhibitors The efficacy and safety of the use of PREZISTA with 100 mg ritonavir and any other PI (e.g.
Interazzjonijiet – Darunavir/ ritonavir ma ’ Impedituri ta ’ Protease L- effikaċja u s- sigurtà ta ’ l- użu ta ’ PREZISTA ma ’ 100 mg ritonavir u kwalunkwe Impeditur ta ’ Protease ieħor (e. ż.
1,200/100 b.i.d.
1, 200/ 100 b. i. d.
Interactions – Darunavir/ritonavir with Antiretroviral Agents other than Protease Inhibitors
Interazzjonijiet – Darunavir/ ritonavir ma ’ Mediċini Antiretrovirali li ma humiex Impedituri ta ’ Protease Prodott Mediċinali
Dose of Dose of
Doża t
Medicinal
Prodott Mediċinali Doża tal- Prodott Doża ta ’ Prodott
Efavirenz decreases the plasma concentrations of darunavir as a result of CYP3A4 induction.
Efavirenz inaqqas il- konċentazzjonijiet ta ’ darunavir fil- plażma minħabba induzzjoni ta ’ CYP3A4.
Zidovudine Zalcitabine Emtricitabine Stavudine Lamivudine Abacavir
30 Zidovudine Zalcitabine Emtricitabine Stavudine Lamivudine Abacavir
600/100 b.
Digoxin doża waħda ta ’ 600/ 100 b. i. d.
Darunavir/ritonavir increases the plasma concentrations of clarithromycin as a result of CYP3A4 inhibition and possible Pgp inhibition.
Darunavir/ ritonavir iżidu l- konċentrazzjonijiet ta ’ clarithromycin fil- plażma minħabba impediment ta ’ CYP3A4 u possibbilment impedimnet ta ’ Ppg.
Carbamazepine Antifungals
Carbamazepine
Carbamazepine ↑ 45% ↑ 54% Darunavir ↔ ↔ Exposure to darunavir, co-administered with ritonavir, was unaffected by carbamazepine.
Carbamazepine ↔ ↔ Darunavir
Ritonavir exposure (AUC12h) was decreased by 49%.
31 Espożizzjoni għal darunavir, amministrat flimkien ma ’ ritonavir, ma ġiex affettwat minn carbamazepine.
Voriconazole
Antifungali Voriconazole
400/100 b.i.d.
Voriconazole m’ għandux jingħata ma ’ PREZISTA flimkien ma ’ 100 mg ritonavir sakemm eżami tal - proporzjon tar- riskju mqabbel mal- benefiċċju ma jiġġustifikax l- użu ta ’ voriconazole.
Ketoconazole 200 b.i.d.
400/ 100 b. i. d. # ↑ 212% ↑ 868%
400/100 b.i.d.# Ketoconazole
Ketoconazole
Ketoconazole is a potent inhibitor as well as substrate of CYP3A4.
Ketoconazole ↑ 42% ↑ 73% Darunavir Ketoconazole huwa impeditur potenti kif ukoll sustrat ta ’ CYP3A4.
29 Clotrimazole
Clotrimazole
HMG Co-A Reductase Inhibitors Lovastatin Simvastatin
Impedituri ta ’ HMG Co- A Reductase Lovastatin u simvastatin, li huma dipendenti ħafna fuq metaboliżmu ta ’ CYP3A4 huma Lovastatin Simvastatin
Pravastatin
32 Pravastatin
600/100 b
600/ 100
Patients using oestrogens as hormone replacement therapy should be clinically monitored for signs of oestrogen deficiency.
Pazjenti li qed jużaw l- estroġeni bħala terapija ta ’ sostituzzjoni ta’ l- ormoni għandhom jiġu segwiti klinikamnet għal sinjali ta ’ defiċjenza ta ’ l- estroġenu.
Immunosupressants Cyclosporine Tacrolimus Sirolimus
Immunosoppressanti Cyclosporine Tacrolimus Sirolimus
(dosed for 7 days)
(doża mogħtija għall- 7 ijiem) Fuq bażi ta ’ sejbiet kliniċi u farmakokinetiċi, id- doża ta ’ methadone m’ hemmx bżonn tiġi aġġustata meta dan jibda jingħata flimkien ma ’ PREZISTA/ ritonavir.
30 Based on pharmacokinetic and clinical findings, no adjustment of methadone dosage is required when initiating co-administration with PREZISTA/ritonavir.
Madankollu, jista ’ jkun hemm bżonn doża ogħla ta ’ methadone meta l- amministrazzjoni konkomitanti tieħu fit- tul minħabba induzzjoni tal- metabolizmu minn ritonavir.
Rifabutin Sedatives/Hypnotics
33 Rifabutin
Rifabutin* 1.6 ND times ↑ ↑ 53% Darunavir ↑ 68% * sum of active moieties of rifabutin (parent drug + 25-O-desacetyl metabolite) A dosage reduction of rifabutin by 75% of the usual dose of 300 mg/day [i.e. rifabutin 150 mg q.o.d.
* l- għadd tan- nofsijiet attivi ta ’ rifabutin (mediċina oriġinali + metabolit 25- O- desacetyl) Tnaqqis fid- doża ta ’ rifabutin b’ 75% mid- doża tas- soltu ta ’ 300 mg/ kuljum [i. e. rifabutin 150 mg q. o. d.
Parenteral midazolam
Sedattivi/ Ipnotiċi Midazolam parenterali
Selective Serotonin Reuptake Inhibitors (SSRIs)
Impedituri tar- Riassorbiment Selettiv tas- Serotonin (SSRIs) Paroxetine
In addition, patients on a stable dose of sertraline or paroxetine who start treatment with PREZISTA co-administered with 100 mg ritonavir should be monitored for antidepressant response.
Sterojdi
Steroids Fluticasone propionate Budesonide
34 Fluticasone propionate Budesonide
Breast-feeding It is not known whether darunavir is excreted in human milk.
Treddigħ Ma huwiex magħruf jekk darunavir jgħaddix fil- ħalib uman.
Because of both the potential for HIV transmission and the potential for adverse reactions in breast-fed infants, mothers should be instructed not to breast-feed under any circumstances if they are receiving PREZISTA.
Kemm minħabba l- potenzjal ta ’ trasmissjoni ta ’ l- HIV kif ukoll il- potenzjal ta ’ reazzjonijiet avversi fit- trabi li qed jitreddgħu, l - ommijiet għandhom jiġu mwissija biex ma jreddgħux fl- ebda ċikustanza jekk ikunu qed jirċievu PREZISTA.
4.7 Effects on ability to drive and use machines 32 No studies on the effects of PREZISTA in combination with ritonavir on the ability to drive and use machines have been performed.
Madanakollu, kien irrappurtat sturdament f’ xi wħud mill- pazjenti waqt trattament
However, dizziness has been reported in some patients during treatment with regimens containing PREZISTA co-administered with 100 mg ritonavir and should be borne in mind when considering a patient’s ability to drive or operate machinery (see section 4.8).
35 b’ kors ta ’ mediċini li kien fihom PREZISTA flimkien ma ’ 100 mg ritonavir u dan għandu jinżamm fil - moħħ meta jiġi kkunsidrat jekk pazjent għandux ħila jsuq jew iħaddem magni (ara sezzjoni 4. 8).
The adverse drug reactions are derived from Phase IIb and Phase III trials, in which a total of 1,968 treatment-experienced patients initiated therapy with the recommended dose of PREZISTA 600 mg with ritonavir 100 mg twice daily.Median exposure to PREZISTA/ritonavir in this group was 37.3 weeks.
L- esponiment medjan għal - PREZISTA/ ritonavir f’ dan il- grupp kien 37. 3 ġimgħat.
Nervous system disorders 33 common
Disturbi fis- sistema nervuża
uncommon Vascular disorders
mhux komuni Disturbi vaskulari
34 uncommon
37 mhux komuni
Uncommon: hyperlipidaemia, vomiting, abdominal pain, increased aspartate aminotransferase, rash (including maculopapular rash), allergic dermatitis, pruritus.
38 Mhux komuni: iperlipidimja, rimettar, uġigħ fl- addome, żieda fl- aspartate aminotransferase, raxx (inkluż raxx makulopapulari), dermatite allerġika, ħakk.
Common: hypertriglyceridaemia, hypercholesterolaemia, anorexia, insomnia, headache, dizziness, dysgeusia, vomiting, abdominal pain, abdominal discomfort, abdominal distension, flatulence,
Komuni: ipertrigliċeridimja, iperkolesterolimja, anoreksja, insomnja, uġigħ ta ’ ras, sturdament, disgewżja, rimettar, uġigħ fl- addome, skonfort fl- addome, nefħa fl- addome, gass, żieda fl- alanine aminotransferase, raxx (inkluż makulopapulari, raxx papulari) alopeċja, ġilda xotta, ħakk, għejja.
Combination antiretroviral therapy has also been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (see section 4.4).
Terapija b’ taħlita ta ’ għadd ta ’ mediċini antiretrovirali kienet ukoll assoċjata ma ’ anormalitajiet metaboliċi bħal ipertrigliserajdimja, iperkolesterolimja, reżistenza għall- insulina, iperġliċemija u iperlaktatemija (ara sezzjoni 4. 4).
36 Darunavir is an inhibitor of the dimerisation and of the catalytic activity of the HIV-1 protease (KD of 4.5 x 10-12M).
Mod ta ’ kif jaħdem Darunavir huwa impeditur tad- dimerizzazzjoni u l- attività katalittika ta ’ l - HIV- 1 protease (KD ta ’ 4. 5 x 10- 12M).
The EC50 value of darunavir increases by a median factor of 5.4 in the presence of human serum.
Il- valur EC50 ta ’ darunavir jiżdied b’ fattur medjan ta ’ 5. 4 fil- preżenza tas- serum uman.
In the 48 week analysis of the ARTEMIS trial (see Clinical experience subsection ART-naïve patients), 9.9% virologic failures were observed in patients receiving PREZISTA/ritonavir 800/100 mg q.d.
F’ analiżi ta ’ 48 ġimgħa tal- prova ARTEMIS (ara s- sottosezzjoni Esperjenza klinika, Pazjenti li qatt ma ħadu ART), 9. 9% ta ’ fallimenti viroloġiċi kienu osservati f’ pazjenti li qed jirċievu PREZISTA/ ritonavir 800 mg/ 100 mg q. d.
In these virologic failures no developing PI RAMs were identified.
F’ dawn il- fallimenti viroloġiċi ma ġew identifikati l- ebda żviluppi ta ’ RAMs għal PI.
In 1 virologic failure of the PREZISTA/ritonavir group, 1 developing NRTI RAM at position 184 was identified, which was associated with a decreased susceptibility to emtricitabine included in the background regimen.
F’ falliment viroloġiku wieħed tal- grupp PREZISTA/ ritonavir, żvilupp wieħed ta ’ RAM għal NRTI f’ pożizzjoni 184 ġie identifikat, li kien assoċjat ma ’ tnaqqis fis - suxxettibilità għal emtricitabine li kien inkluż fil- kura tal- isfond.
In a pooled analysis of the POWER 1, 2 and 3 (see Clinical experience subsection ART-experienced patients) and DUET 1 and 2 (TMC125-C206 and TMC125-C216) trials the amino acid substitutions identified that developed on PREZISTA co-administered with ritonavir (600/100 mg b.i.d.) in ≥ 20% of the isolates from subjects who experienced virologic failure by rebound were V32I, I54L and L89V.
F’ analiżi pooled tal- provi POWER 1, 2 u 3 (ara s- sottosezzjoni Esperjenza klinika, Pazjenti li diġà ħadu ART) u DUET 1 u 2 (TMC125- C206 u TMC125- C216) is- sostituzzjonijiet ta ’ l- aċidu amminiku identifikati li żviluppaw bi PREZISTA amministrat flimkien ma ’ ritonavir (600/ 100 mg b. i. d) f’ ≥ 20% taċ- ċelluli tal- virus iżolati minn individwi li esperjenzaw falliment viroloġiku permezz ta ’ reazzjoni opposta kienu V32I, I54L u L89V.
Of the viruses isolated from patients experiencing virologic failure by rebound from the PREZISTA/rtv 600/100 mg b.i.d. group of the POWER and DUET trials, 85% of those susceptible to darunavir at baseline developed decreased susceptibility to darunavir during treatment.
40 Mill- virusis iżolati minn pazjenti li kienu qed jesperjenzaw falliment viroloġiku permezz ta ’ rebound mill- grupp PREZISTA/ rtv 600/ 100 mg b. i. d. tal- provi POWER u DUET, 85% ta ’ dawk suxxettibbli għal darunavir fil- linja bażi żviluppaw suxxettibilità mnaqqsa għal darunavir waqt il- kura.
Cross-resistance Darunavir has a < 10-fold decreased susceptibility against 90% of 3,309 clinical isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and/or tipranavir showing that viruses resistant to most PIs remain susceptible to darunavir.
Cross- resistance Darunavir għandu < 10- darbiet suxxettibilità imnaqqsa kontra 90% minn 3, 309 virusis iżolati klinikament reżistenti għal amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir u/ jew tipranavir li juri li l- virusis reżistenti għall- maġġoranza tal- PIs jibqgħu suxxettibbli għal darunavir.
In the virologic failures of the ARTEMIS trial no cross-resistance with other PIs was observed.
Fil- fallimenti viroloġiċi tal- prova ARTEMIS l- ebda cross- resistance ma ’ PIs oħra ma kienet osservata.
37 Clinical experience Efficacy of PREZISTA co-administered with 100 mg ritonavir in ART-naïve patients The evidence of efficacy of PREZISTA/ritonavir 800/100 mg q.d. is based on the analyses of 48 week data from the ongoing, randomised, controlled, open-label Phase III trial ARTEMIS in antiretroviral treatment-naïve HIV-1 infected patients comparing PREZISTA/ritonavir 800/100 mg q.d. with lopinavir/ritonavir 800/200 mg per day (given as a twice-daily or as a once-daily regimen).
Esperjenza klinika Effikaċja ta ’ PREZISTA amministrat flimkien ma ’ 100 mg ritonavir f’ pazjenti li qatt ma ħadu ART L- evidenza tal- effikaċja ta ’ PREZISTA/ ritonavir 800/ 100 mg q. d. hija bbażata fuq l- analiżi ta ’ dejta minn 48 ġimgħa ta ’ prova tal- Fażi III ARTEMIS, randomised, ikkontrollata, open- label, li għada sejra, f’ pazjenti infettati bl- HIV- 1 li qatt ma ħadu kura antiretrovirali qabel li tqabbel PREZISTA/ ritonavir 800/ 100 mg q. d. ma ’ lopinavir/ ritonavir 800/ 200 mg kuljum (mogħti bħala doża darbtejn kuljum jew darba kuljum).
Both arms used a fixed background regimen consisting of tenofovir disoproxil fumarate 300 mg q.d. and emtricitabine 200 mg q.d.
Iż- żewġ fergħat użaw dożi ta ’ kura fissi fl- isfond li kienu jikkonsistu f’ tenofovir disoproxil fumarate 300 mg q. d. u emtricitabine 200 mg q. d.
HIV-1 infected patients who were eligible for this trial had plasma HIV-1 RNA > 5,000 copies/ml.
Pazjenti infettati bl- HIV- 1 li kienu eliġibbli għal din il- prova kellhom > 5, 000 kopja/ ml HIV- 1 RNA fil- plażma.
Randomisation was stratified by screening plasma viral load and screening CD4+ cell count.
Randomisation kienet stratifikata permezz ta ’ eżaminar tat- tagħbija virali fil- plażma u eżaminar tal- għadd ta ’ ċelluli CD4+.
The mean baseline plasma HIV-1 RNA was 4.86 log10 copies/ml and the median baseline CD4+ cell count was 228 x 106 cells/l (range 4–750 x 106 cells/l).
Il- linja bażi medja ta ’ HIV- 1 RNA fil- plażma kien 4. 86 log10 kopji/ ml u l- linja bażi medjana għall- għadd ta ’ ċelluli CD4+ kienet ta ’ 228 x 106 ċellula/ l (medda minn 4– 750 x 106 ċellula/ l).
The table below shows the efficacy data of the 48 week analyses from the ARTEMIS trial:
It- tabella hawn taħt turi dejta tal- effikaċja mill- analiżi ta ’ 48 ġimgħa mill- prova ARTEMIS:
ARTEMIS Outcomes
ARTEMIS Riżultati HIV- 1 RNA < 50 kopja/ mla
N=343
N=343 287 (83. 7%)
lopinavir/rtv 800/200 mg per day N=346
lopinavir/ rtv 800/ 200 mg kuljum N=346 271 (78. 3%)
treatment difference (95% CI of difference)
differenza fil- kura (95% CI ta ’ differenza) 5. 3 (- 0. 5; 11. 2) b
HIV-1 RNA < 50 copies/mla HIV-1 RNA < 400 copies/mla
HIV- 1 RNA < 400 kopja/ mla
287 (83.7%) 301 (87.8%)
301 (87. 8%)
271 (78.3%) 295 (85.3%)
295 (85. 3%)
5.3 (-0.5; 11.2)b 2.5 (-2.6; 7.6)b
2. 5 (- 2. 6; 7. 6) b - 0. 11d
mean HIV-1 RNA log change from baseline (log10 copies/ml)c
medja tal- bidla log fl - HIV- 1 RNA mill- linja bażi (log10 kopja/ ml) c
-2.77
- 2. 77
-2.65
- 2. 65
-0.11d (-0.30; 0.07)b
(- 0. 30; 0. 07) b
median CD4+ cell count change from baseline (x 106/l)c a
medjan tal- bidla fl- għadd taċ - ċelluli CD4+ mill- linja bażi (x 106/ l) c a Imputazzjonijiet skont l- algoriżmu TLOVR b
Imputations according to the TLOVR algorithm b Based on normal approximation to the difference in% response c Non-completer is failure imputation: patients who discontinued prematurely are imputed with a change equal to 0 d Difference in means
Ibbażat fuq l- approssimazzjoni normali għad- diferenza fil -% tar- rispons c Non- completer hija imputazzjoni ta ’ falliment: pazjenti li waqfu qabel huma imdaħħlin bħala bidla ugwali għal 0 d Differenza fil- medji
In the 48 week analysis, the virologic response (HIV-1 RNA < 50 copies/ml) for the PREZISTA/ritonavir arm was 83.7% and for the lopinavir/rtv arm 78.3%.
Fl- analiżi ta ’ 48 ġimgħa, ir- rispons viroloġiku (< 50 kopja/ ml HIV- 1 RNA) għal fergħa PREZISTA/ ritonavir kien ta ’ 83. 7% u għal fergħa lopinavir/ rtv kien ta ’ 78. 3%.
Non-inferiority in virologic response, defined as the percentage of subjects with plasma HIV-1 RNA level < 50 copies/ml, was demonstrated (at the pre-defined 12% non-inferiority margin) for both Intent-To-Treat and On Protocol populations.
Il- fatt li l- kura mhijiex inferjuri għall- kura standard f’ termini ta ’ rispons viroloġiku, definita bħala l - perċentwal ta ’ individwi b’ livell ta ’ < 50 kopja/ ml ta ’ HIV- 1 RNA fil- plażma, intwera (fil- marġini magħżula ta ’ 12% għall- fatt li l- kura mhijiex inferjuri għall- kura standard) kemm għal popolazzjonijiet li kien hemm l- intenzjoni li jiġu kkurati kif ukoll dawk li kienu kkurati skont protokoll.
Efficacy of PREZISTA co-administered with 100 mg ritonavir in ART-experienced patients The evidence of efficacy of PREZISTA co-administered with ritonavir (600/100 mg b.i.d.) in treatment-experienced patients is based on the 48 weeks analysis of the Phase III trial TITAN in treatment-experienced lopinavir naïve patients and on the analyses of 96 weeks data from the Phase IIb trials POWER 1, 2 and 3 in patients with high level of PI resistance.
41 L- evidenza tal- effikaċja tal- kura bi PREZISTA mogħti flimkien ma ’ ritonavir (600/ 100 mg b. i. d.) f’ pazjenti li diġà ħadu kura qabel huwa bbażat fuq l- analiżi ta ’ 48 ġimgħa tal- prova tal- Fażi III TITAN f’ pazjenti li diġà ħadu kura qabel iżda qatt ma ħadu lopinavir u fuq l- analiżi ta ’ dejta ta ’ 96 ġimgħa mill- provi tal- Fażi IIb POWER 1, 2 u 3 f’ pazjenti b’ livell għoli ta ’ reżistenza għall- PI.
HIV-1 infected patients who were eligible for these trials had previously failed more than 1 PI containing regimen.PREZISTA co-administered with 100 mg ritonavir plus an optimised background regimen (OBR) was compared to a control group receiving an investigator-selected PI(s) regimen plus an OBR.
Pazjenti infettati bl- HIV- 1 li kienu eliġibli għal dawn il- provi, kienu qabel fallew aktar minn kors ta ’ trattament wieħed li kien fih PI. PREZISTA amministrat flimkien ma ’ 100 mg ritonavir flimkien ma ’ kors ta ’ trattament ottimali fl- isfond (OBR) kien imqabbel ma grupp ta ’ kontroll li kien qed jieħu kors ta ’ trattament ta ’ PI( s) magħżul mill- investigatur u OBR.
POWER 1 and POWER 2 pooled data Outcomes at 48 weeks
POWER 1 u POWER 2 tagħrif miġbur flimkien
81 (61.8%) 20 (16.1%) 45.7% (35.0%; 56.4%)d 39
81 (61. 8%) 20 (16. 1%) 45. 7% (35. 0%; 56. 4%) d
Baseline genotype or phenotype and virologic outcome In a pooled analysis of the 600/100 mg b.i.d. groups of the POWER and DUET trials, the presence at baseline of 3 or more of mutations V11I, V32I, L33F, I47V, I50V, I54L or M, T74P, L76V, I84V or L89V was associated with a decreased virologic response to PREZISTA co-administered with 100 mg ritonavir.
Linja bażi ġenotipika jew fenotipika u l- effetti viroloġiċi F’ analizi pooled tal- gruppi 600/ 100 mg b. i. d. tal- provi POWER u DUET, il- preżenza fil- linja bażi ta ’ 3 tibdiliet ġenetiċi jew aktar V11I, V32I, L33F, I47V, I50V, I54L jew M, T74P, L76V, I84V jew L89V kienet assoċjata ma ’ tnaqqis fir- rispons viroloġiku għal PREZISTA amministrat flimkien ma ’ 100 mg ritonavir.
Response (HIV-1 RNA < 50 copies/ml at week 24) to PREZISTA co-administered with ritonavir (600/100 mg b.i.d.) by baseline genotype * and by use of enfuvirtide (ENF):
Rispons (HIV- 1 RNA < 50 kopja/ ml fl- 24 ġimgħa) għal PREZISTA amministrat flimkien ma ’ ritonavir (600 mg/ 100 mg b. i. d) skond il- ġenotip tal- linja bażi * u permezz ta ’ l- użu ta ’ enfuvirtide (ENF):
Number of mutations at baseline*
43 Numru ta ’ tibdiliet ġenetiċi fil- linja bażi *
* Number of mutations from the list of mutations associated with a diminished response to PREZISTA/ritonavir (V11I, V32I, L33F, I47V, I 50V, I54L or M, T74P, L76V, I84V or L89V)
* Numru ta ’ tibdiliet ġenetiċi mill- lista ta ’ tibdiliet ġenetiċi assoċjati ma ’ nuqqas ta ’ rispons għall- PREZISTA/ ritonavir (V11I, V32I, L33F, I47V, I50V, I54L jew M, T74P, L76V, I84V jew L89V)
40 Baseline darunavir phenotype
Il- fenotip tal- linja bażi ta ’ darunavir
Darunavir is primarily metabolised by CYP3A.
Darunavir huwa mmetabolizzat primarjament mis- CYP3A.
When administered without food, the relative bioavailability of darunavir in the presence of low dose ritonavir is 30% lower as compared to intake with food.
44 Meta amministrat mingħajr ikel, il- biodisponibiltà ta ’ darunavir fil- preżenza ta ’ doża baxxa ta ’ ritonavir hija 30% anqas meta mqabbla ma ’ teħid ma ’ l- ikel.
Elderly Population pharmacokinetic analysis in HIV infected patients showed that darunavir pharmacokinetics are not considerably different in the age range (18 to 75 years) evaluated in HIV infected patients (see section 4.4).
Anzjani Analiżi farmakokinetika ta ’ popolazzjoni f’ pazjenti infettati bl- HIV uriet li l- farmakokinetika ta ’ darunavir m’ hijiex konsiderevolment differeni fil- medda ta ’ l- eta ’ (18 sa 75 sena) evalwati f’ pazjenti infettati bl- HIV (ara sezzjoni 4. 4).
Gender Population pharmacokinetic analysis showed a slightly higher darunavir exposure in HIV infected females compared to males.
Sess Analiżi farmakokinetika ta ’ popolazzjoni uriet esponiment ftit aktar għoli għal darunavir fin- nisa infettati bl- HIV meta mqabbla ma ’ l- irġiel.
Although darunavir has not been studied in patients with renal impairment, population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV infected patients with moderate renal impairment (CrCl between 30-60 ml/min, n=20) (see sections 4.2 and 4.4).
Għalkemm darunavir ma ġiex studjat fil- pazjenti b’ indeboliment renali, analiżi farmakokinetika ta ’ popolazzjoni wriet li l- farmakokinetika ta ’ darunavir m’ hijiex affettwata sinifikament fil- pazjenti infettati bl- HIV u li għandhom indeboliment renali moderat (CrCl bejn 30 - 60 ml/ min, n=20) (ara sezzjonijiet 4. 2 u 4. 4).
However, unbound darunavir concentrations were approximately 55% (Child-Pugh Class A) and 100% (Child-Pugh Class B) higher, respectively.
Madankollu, konċentrazzjonijiet ta ’ darunavir mhux imwaħħla mal- proteini
In repeated-dose toxicology studies in mice, rats and dogs, there were only limited effects of treatment with darunavir.
Fi studji tossikoloġiċi b’ doża ripetuta fil- ġrieden, il- firien u l- klieb, kien hemm biss effetti limitati tat - trattament b’ darunavir.
Up to same dose levels, there was no teratogenicity with darunavir in rats and rabbits when treated alone nor in mice when treated in combination with ritonavir.
Sa l- istess livelli tad- doża, ma kien hemm l- ebda ’ teratoġeniċità fil- firien u l- fniek bi trattament ta ’ darunavir waħdu u lanqas fil- ġrieden bi trattament ta ’ ritonavir flimkien miegħu.
In a pre- and
Il- livelli ta ’ esponiment kienu anqas minn dawk bid- doża klinikament rakkomandata fil- bnedmin.
42 postnatal development assessment in rats, darunavir with and without ritonavir, caused a transient reduction in body weight gain of the offspring pre-weaning and there was a slight delay in the opening of eyes and ears.
Fi stima ta ’ żvilupp fil- firien qabel u wara t- twelid, darunavir ma ’ jew mingħajr ritonavir, ikkawża tnaqqis għaddieni fiż- żieda fil- piż tal- ġisem qabel il- ftim u kien hemm ftit dewmien sakemm infetħu l- għajnejn u l- widnejn.
Darunavir was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks.
Darunavir ġie evalwat għal potenzjal kanċeroġeniku permezz ta ’ amministrazzjoni b’ tubu mill- ħalq lill- ġrieden u l- firien sa 104 ġimgħat.
At the highest tested doses, the systemic exposures (based on AUC) to darunavir were between 0.4- and 0.7-fold (mice) and 0.7- and 1-fold (rats), relative to those observed in humans at the recommended therapeutic doses.
Fl- ogħla dożi ittestjati, l - esponimenti sistemiċi (ibbażati fuq l- AUC) għal darunavir kienu bejn 0. 4 darbiet u 0. 7 darbiet
43 2 years
Sentejn
Opaque, white, high density polyethylene (HDPE) plastic, 160 ml bottle containing 60 tablets, fitted with polypropylene (PP) child resistant closure.
Flixkun opak, abjad, tal- plastik polethylene ta’ densità għolja (HDPE) ta ’ 160 ml li fih 60 pillola, magħluq b’ għatu tal- polypropylene (PP) li ma ’ jinfetaħx mit- tfal.
PREZISTA 600 mg film-coated tablets
PREZISTA 600 mg pilloli miksijin b’ rita
Each film-coated tablet contains 600 mg of darunavir (as ethanolate).
Kull pillola miksija b’ rita fiha 600 mg ta ’ darunavir (bħala ethanolate).
Each tablet contains 2.750 mg sunset yellow FCF (E110).
Kull pillola fiha 2. 750 mg sunset yellow FCF (E110).
Orange oval shaped tablet, debossed with “600MG” on one side and “TMC” on the other side.
Pillola oranġjo b’ forma ovali, li fiha mħaffra “ 600MG ” fuq naħa waħda u “ TMC ” fuq in- naħa l- oħra.
Adults The recommended dosage of PREZISTA is 600 mg twice daily (b.i.d.) taken with ritonavir 100 mg b.i.d. and with food.
Adulti Id- doża rakkommandata ta ’ PREZISTA hija 600 mg darbtejn kuljum (b. i. d.) meħuda flimkien ma ’ ritonavir 100 mg b. i. d. u ma ’ l- ikel.
Children and adolescents PREZISTA is not recommended for use in children and adolescents due to insufficient data on safety, efficacy and pharmacokinetics.
Tfal u adoloxxenti PREZISTA mhux rakkomandat għall- użu fit- tfal u fl- adoloxxenti minħabba li m’ hemmx tagħrif biżżejjed dwar sigurtà, effikaċja u farmakokinetika.
Elderly Limited information is available in this population and therefore PREZISTA should be used with caution in this age group (see sections 4.4 and 5.2).
Anzjani Informazzjoni limitata hija disponibbli f’ din il- popolazzjoni u għalhekk PREŻISTA għandu jintuża b’ attenzjoni fil- grupp ta ’ din l- età (ara sezzjonijiet 4. 4 and 5. 2).
No pharmacokinetic data are available in
L -
45 patients with severe hepatic impairment.
49 ebda dejta farmakokinetika ma hija disponibbli f’ pazjenti b’ indeboliment epatiku serju.
In case a dose of PREZISTA and/or ritonavir was missed within 6 hours of the time it is usually taken, patients should be instructed to take the prescribed dose of PREZISTA and ritonavir with food as soon as possible.
F’ każ li tinqabeż doża ta ’ PREZISTA u/ jew ritonavir fi żmien 6 sigħat minn meta din is- soltu tittieħed, il- pazjenti għandhom jiġu nfurmati biex jieħdu d- doża preskritta ta ’ PREZISTA u ritonavir ma ’ l- ikel malajr kemm jista ’ jkun.
These active substances include e.g. antiarrhythmics (amiodarone, bepridil, quinidine, systemic lidocaine), antihistamines (astemizole, terfenadine), ergot derivatives (e.g. dihydroergotamine, ergonovine, ergotamine, methylergonovine), gastrointestinal motility agents (cisapride), neuroleptics (pimozide, sertindole), sedatives/hypnotics (triazolam, midazolam administered orally (for caution on parenterally administered midazolam, see section 4.5)) and HMG-CoA reductase inhibitors (simvastatin and lovastatin) (see section 4.5).
Dawn is- sustanzi attivi jinkludu e. ż. antiarritmiċi (amiodarone, bepridil, quinidine, lidocaine sistemiku), antistamini (astemizole, terfenadine), derivattivi ta ’ l- ergot (e. ż. dihydroergotamine, ergonovine, ergotamine, methylergonovine), aġenti tal- mobilità gastro- intestinali (cisapride), newrolettiċi (pimozide, sertindole), sedattivi/ ipnotiċi (triazolam, midazolam mogħti mill- ħalq (għal attenzjoni dwar midazolam li jingħata b’ mod parenterali, ara sezzjoni 4. 5)) u impedituri ta ’ l- HMG- CoA reductase (simvastatin u lovastatin) (ara sezzjoni 4. 5).
As limited information is available on the use of PREZISTA in patients aged 65 and over, caution should be exercised in the administration of PREZISTA in elderly patients, reflecting the greater frequency of decreased hepatic function and of concomitant disease or other therapy (see sections 4.2 and 5.2).
Minħabba li teżisti informazzjoni limitata dwar l- użu ta ’ PREZISTA f’ pazjenti li għandhom 65 sena jew aktar, għandu jkun hemm attenzjoni meta PREZISTA jiġi ammministrat lill- pazjenti
46 Darunavir binds predominantly to α1-acid glycoprotein.
Darunavir jeħel b’ mod predominanti ma ’ l- α1- glikoproteina aċida.
PREZIST A should be used with caution in patients with a known sulphonamide allergy.
PREZISTA għandu jintuża b’ attenzjoni f’ pazjenti li huma magħrufa li għandhom allerġija għal sulphonamide.
Diabetes mellitus/Hyperglycaemia New onset diabetes mellitus, hyperglycaemia, or exacerbation of existing diabetes mellitus has been reported in patients receiving antiretroviral therapy, including PIs.
Dijabete mellitus/ Ipergliċemija Dijabete mellitus li seħħet għall- ewwel darba, ipergliċemija, jew taħrix ta ’ djabete mellitus li kienet diġà teżisti ġew irrappurtati f’ pazjenti li qed jieħdu terapija antiretrovirali, inkluż l- Impedituri ta ’ Protease.