qanastek/EMEA-V3 huggingface dataset:
The use of meperidine and ritonavir is contraindicated due to the increased concentrations of the metabolite, normeperidine, which has both analgesic and CNS stimulant activity.
L- użu ta ’ meperidine u ritonavir huwa kontro- indikat minħabba ż- żieda fil- konċentrazzjoni tal- metabolit normeperidine, li għandu attività analġesika,, kif ukoll attività stimulanti fuq is- sistema nervuża (CNS).
Elevated normeperidine concentrations may increase the risk of CNS effects (eg, seizures), see section 4.3.
Konċentrazzjoni għolja ta ’ normeperidine tista ’ żżid ir- riskju ta ’ l- effetti tas- CNS (eż attakki ta ’ l- epilessija), ara sezzjoni 4. 3.
1, single dose
1, doża waħda
200 q12h, 2 days
200 q12h, 2 (jumejn)
↑2.5 fold
↑b’ 2. 5 drabi
500 q12h, 10 days
500 q12h, 10 ijiem
18 Ritonavir effects on Non-antiretroviral Co-administered Drugs Co-administered Drug
20 L- Effetti ta ’ ritonovir fuq mediċini li ma humiex antiretrovirali, u li jittieħdu miegħu
Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent inhibits CYP3A and as a result is expected to increase the plasma concentrations of buspirone.
Ritonavir dożat biex iżid l- effett farmakokinetiku jew bħala aġent antiretrovirali jimpedixxi CYP3A, u għalhekk huwa mistenni li jżid il - konċentrazxzjonijiet fil- plażma ta ’ buspirone.
Careful monitoring of therapeutic and adverse effects is recommended when buspirone concomitantly administered with ritonavir.
Meta buspirone jingħata flimkien ma ’ ritonavir, huwa rrakkomandat li ssir osservazzjoni b’ attenzjoni ta ’ l- effetti terapewtiċi u ta ’ l- effetti avversi.
Sleeping agent Zolpidem
Mediċini li jraqqdu Zolpidem
200, 4 doses
200, 4 dożi
Zolpidem and ritonavir may be co-administered with careful monitoring for excessive sedative effects.
Jekk issir osservazzjoni b’ attenzjoni għall- effetti sedattivi eċċessivi, zolpidem u ritonavir jistgħu jingħataw flimkien.
Smoke cessation Bupropion
Waqfien mit- tipjip Bupropion
↓ 21% ↓ 62%
600 mg q12h ↓ 66%
Bupropion is primarily metabolised by CYP2B6.
Bupropion huwa primarjament metabolizzat b ’ CYP2B6.
Concurrent administration of bupropion with repeated doses of ritonavir is expected to decrease bupropion levels.
Huwa mistenni li l- livelli ta ’ bupropion jonqsu meta bupropion jingħata flimkien ma dożi repetuti ta ’ ritonavir.
These effects are thought to represent induction of bupropion metabolism.
Dawn l- effetti huma meqjusa li jirrapreżentaw induzzjoni tal- metaboliżmu ta ’ bupropion.
However, because ritonavir has also been shown to inhibit CYP2B6 in vitro, the recommended dose of bupropion should not be exceeded.
Mandankollu, peress li ritonavir wera li jinibixxi CYP2B6 in vitro, id- doza rakkomandata ta ’ bupropion ma għandekiex tiġi skorruta.
In contrast to long-term administration of ritonavir, there was no significant interaction with bupropion after short-term administration of low doses of ritonavir (200 mg twice daily for 2 days), suggesting reductions in bupropion concentrations may have onset several days after initiation of ritonavir co-administration.
Dan juri li t- tnaqqis fil - koncetrazzjonijiet ta ’ bupropion jista ’ jidher diversi ġranet wara li jibda jinghata ritonavir miegħu.
Steroids Fluticasone propionate aqueous nasal spray
Sterojdi Sprej għall- imnieħer fluticasone propionate akweju
↑ ~350-fold
↑ ~350 darba
↑ ~ 25-fold
↑ ~ 25 darba
Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression (plasma cortisol levels were noted to be decreased 86% in the above study) have been reported in patients receiving ritonavir and inhaled or intranasal fluticasone propionate; similar effects could also occur with other corticosteroids metabolised by CYP3A eg, budesonide.
Effetti tal- corticosteroids sistematiċi inkluż is- sindromu Cushing u soppressjoni adrenali (fl- istudju t’ hawn fuq ġie nnotat li l- livelli tal - cortisol fil- plażma naqsu 86%) ġew rapportati f’ pazjenti illi jieħdu ritonavir u li jiġbdu f’ imnifsejhom jew idaħħlu fl- imnieħer fluticasone propionate; jistgħu jirriżultaw effetti simili b’ corticosteroids oħra metabolizzati b ’ CYP3A eż, budesonide.
Careful monitoring of therapeutic and adverse effects is recommended when dexamethasone is concomitantly administered with ritonavir.
Għalhekk, l- għoti flimkien ta ’ ritonavir dożat bħala aġent antiretrovirali jew biex iżid l- effett farmakokinetiku u dawn il- glucocorticoids, m’ huwiex irrakkomandat, ħlief jekk il- benefiċju potenzjali li jista ’ jkollu t- trattament ikun jiżboq ir- riskju
19 Ritonavir effects on Non-antiretroviral Co-administered Drugs Co-administered Drug
21 L- Effetti ta ’ ritonovir fuq mediċini li ma humiex antiretrovirali, u li jittieħdu miegħu
Careful monitoring of therapeutic and adverse effects is recommended when prednisolone is concomitantly administered with ritonavir.
20 200 q12h ↑ 28% ↑ 9% Meta prednisolone jingħata flimkien ma ’ ritonavir, huwa rrakkomandat li ssir osservazzjoni b’ attenzjoni ta ’ l- effetti terapewtiċi u ta ’ l- effetti avversi.
The AUC of the metabolite prednisolone increased by 37 and 28% after 4 and 14 days ritonavir, respectively.
L- AUC tal- metabolit prednisolone żdied b’ 37 u 28% wara 4 u 14 - il ġurnata b’ ritonavir, rispettivament.
Sulfamethoxazole was co-administered with trimethoprim.
Sulfamethoxazole ingħata ma ’ trimethoprim.
Cardiac and neurologic events have been reported when ritonavir has been co-administered with disopyramide, mexiletine or nefazadone.
Effetti kardijaċi u newroloġiċi ġew irrapportati meta ritonavir ingħata flimkien ma ’ disopyramide, mexiletine jew nefazadone.
The possibility of drug interaction cannot be excluded.
Il- possibilità ta ’ interazzjoni mediċinali ma ’ tistax tiġi eskluża.
In addition to the interactions listed above, as ritonavir is highly protein bound, the possibility of increased therapeutic and toxic effects due to protein binding displacement of concomitant medications should be considered.
Ma ’ l- interazzjonijiet imniżżla hawn fuq, peress illi ritonavir jeħel ħafna mal- proteini tad- demm, għandu jiġi kkunsidrat il- fatt li jista ’ jkun hemm żieda fl- effetti terapewtiċi u tossiċi riżultanti mit - tqanqil minn mal- proteini tad- demm ta ’ medikazzjonijiet li jkunu ingħataw flimkien ma ’ ritonavir.
Important information regarding drug interactions when ritonavir is used a pharmacokinetic enhancer is also contained in the Summary of Product Characteristics of the co-administered protease inhibitor.
Informazzjoni importanti dwar interazzjonijiet mediċinali meta ritonavir jintuża biex iżid l- effett farmakokinetiku tinsab ukoll fis- Sommarju tal- Karatteristiċi tal- Prodott ta ’ l- impeditur protejaż li jkun ingħata ma ’ ritonavir.
Proton pump inhibitors and H2-receptor antagonists: proton pump inhibitors and H2-receptor antagonists (e.g. omeprazole or ranitidine) may reduce concentrations for co-administered protease inhibitors.
Impedituri tal- pompa tal- proton u antagonisti ta ’ riċetturi ta ’ l- H2: l- impedituri tal- pompa tal- proton u antagonisti ta ’ riċetturi ta ’ l- H2 (eż. omeprazole jew ranitidine) jistgħu jnaqqsu l- konċentrazzjonijiet għall- impedituri protejaż meta jingħataw flimkien.
For specific information regarding the impact of co-administration of acid reducing agents, refer to the SmPC of the co-administered protease inhibitor.
Għal informazzjoni speċifika dwar l- impatt ta ’ l - għoti flimkien ta ’ aġenti li jnaqqsu l- aċidu, irreferi għas- Sommarju tal- Karatteristiċi tal- Prodott ta ’ l - impeditur protejaż li jkun qed jingħata fl- istess ħin.
Based on interaction studies with the ritonavir boosted protease inhibitors (lopinavir/ritonavir, atazanavir), concurrent administration of omeprazole or ranitidine does not significantly modify ritonavir efficacy as a pharmacokinetic enhancer despite a slight change of exposure (about 6 - 18%).
Skond studji li saru fuq l- interazzjoni ma ’ l - impedituri protejaż li huma msaħħa b’ ritonavir (lopinavir/ ritonavir, atazanavir), l- għoti flimkien ta ’ omeprazole jew ranitidine, minkejja li jkun hemm bidla żgħira fl- esponiment (madwar 6 - 18%), ma jbiddilx l- effikaċja ta ’ ritonavir b’ mod sinifikanti.
A limited number (> 800) of pregnant women were exposed to ritonavir during pregnancy; a very limited number (< 300) were exposed during the first trimester.
22 Numru limitat (> 800) ta ’ nisa tqal ġew esposti għal ritonavir waqt it- tqala; numru limitat ħafna (< 300) kienu esposti waqt l- ewwel tliet xhur tat- tqala.
These data largely refer to exposures where ritonavir was used in combination therapy and not at therapeutic ritonavir doses but at lower doses as a pharmacokinetic enhancer for other PIs.
Fil- biċċa l- kbira, din l- informazzjoni tirreferi għal esponimenti fejn ritonavir kien użat fit- terapija kombinata, u mhux f’ dożi terapewtiċi ta ’ ritonavir, imma f’ dożi iżgħar biex iżid l- effett farmakokinetiku għal PIs oħra.
These limited data indicate no increase in the rate of birth defects compared to rates observed in population-based birth defect surveillance systems.
Din l- informazzjoni limitata ma turi l- ebda żieda fir- rata tad- difetti tat- twelid meta mqabbla ma’ rati osservati f’ sistemi ta ’ sorveljanza ta ’ difetti tat- twelid bażati fuq il- poplazzjoni.
Animal data have shown reproductive toxicity (see 5.3).
Informazzjoni fuq l- annimali uriet tossiċità riproduttiva (ara 5. 3).
The use of Norvir may be considered in pregnancy only when the benefits outweigh the risk to the foetus.
L- użu ta ’ Norvir waqt it- tqala jista ’ jiġi kkunsidrat biss meta l- benefiċji jkunu akbar mir- riskju għall- fetu.
Ritonavir adversely interacts with oral contraceptives (OCs).
Ritonavir għandu effetti ħżiena fuq kontraċettivi orali (OCs).
Therefore, an alternative, effective and safe method of contraception should be used during treatment.
Għalhekk, waqt il- kura, għandu jintuża mezz ta ’ kontraċezzjoni ieħor, li hu effettiv u li ma jagħmilx ħsara.
It is not known whether this medicine is excreted in human milk.
M’ huwiex magħruf jekk din il - mediċina toħroġx mal- ħalib tal- bniedem.
Milk excretion has not been measured in the animal studies, however a study in rats showed some effects on offspring development during lactation which are compatible with excretion of ritonavir in milk in that species.
Il- ħruġ fil- ħalib ma ġiex imkejjel fl- istudji fuq il- bhejjem, però studju li sar fuq il- firien wera xi effetti fuq l- iżvilupp tal- frieħ waqt li huma kienu għadhom jiġu mredda ’, liema effetti huma kompatibbli mal- ħruġ ta ’ ritonavir fil- ħalib ta ’ dik l- ispeċi ta ’ annimali.
HIV infected women should not breast-feed their infants under any circumstances to avoid transmission of HIV.
Nisa infettati bl- HIV m’ għandhom ireddgħu lit- trabi taghħom taħt l- ebda ċirkostanza, u dan sabiex jiġi evitat li l- HIV tiġi trasmessa.
20 4.7 Effects on ability to drive and use machines
4. 7 Effetti fuq il- ħila biex issuq u tħaddem magni
As somnolence and dizziness are known undesirable effects, this should be taken into account when driving or using machinery.
Peress li n- ngħas u l - isturdament huma effetti mhux mixtieqa magħrufa, dan għandu jiġi kkunsidrat meta wieħed ikun qiegħed isuq jew iħaddem magni.
Norvir oral solution contains alcohol (43%).
Is- soluzzjoni orali Norvir fiha l- alkoħol (43%).
Adverse events associated with the use of ritonavir as a pharmacokinetic enhancer are dependent on the specific co-administered PI.
L- effetti avversi assoċjati ma ’ l- użu ta ’ ritonavir f’ dożi biex iżid l- effett farmakokinetiku jiddependu fuq il- PI speċifiku li jkun ġie mogħti miegħu.
For information on adverse events refer to the SPC of the specific co-administered PI.
Għal informazzjoni fuq l- effetti avversi irreferi għall - SPC tal- PI speċifiku li jkun ingħata ma ’ ritonavir.
In the original clinical studies (Phase II/III), adverse events with possible, probable or unknown relationship to ritonavir were reported in ≥ 2% of 1033 patients.
Fl- istudji kliniċi oriġinali (Fażi II/ III), effetti avversi b’ relazzjoni possibbli, probabbli jew mhux magħrufa ma ’ ritonavir ġew irrapurtati f ’ ≥ 2% ta ’ 1033 pazjent.
The following adverse reactions of moderate to severe intensity with possible or probable relationship to ritonavir have been reported.
Ġew irrapportati l- effetti avversi segwenti b’ relazzjoni possibbli jew probabbli ma ’ ritonavir, u li huma ta ’ intensità minn moderata sa severa.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1000 to < 1/100); rare( > 1/10,000 to < 1/1,000).
F’ kull klassifikazzjoni ta ’ frekwenza, l- effetti mhux mixtieqa huma preżentati f’ ordni li tibda mill- iktar effetti serji u tispiċċa fl- inqas effetti serji: komuni ħafna (> 1/ 10); komuni (> 1/ 100 sa < 1/ 10); mhux komuni (> 1/ 1000 sa < 1/ 100); rari (> 1/ 10, 000 sa < 1/ 1, 000).
Undesirable Effects in Clinical Studies and Post-marketing in Adult Patients Immune system disorders
Effetti mhux Mixtieqa f’ Pazjenti Adulti, fi Studji Kliniċi u wara li l- Prodott tqiegħed fuq is- Suq Komuni Disturbi fis- sistema immunitarja tal- ġisem
Allergic reactions including urticaria, mild skin eruptions, bronchospasm and angioedema
Reazzjonijiet allerġiċi li jinkludu urtikarja, tfaċċar f’ daqqa waħda ta ’ msiemer fil- ġilda tat- tip moderat, bronkospażmu u anġjodema
Anaphylaxis and Stevens Johnson syndrome
Anafilassi u s- sindromu Stevens Johnson
Blood and lymphatic system disorders
Komuni Disturbi tad- demm u tas- sistema limfatika
Decreased WBC, decreased haemoglobin, decreased neutrophils, increased eosinophils
Tnaqqis fid- WBC, tnaqqis fl- emoglobina, tnaqqis fin- neutrophils, żieda fl- ieosinophils
Increased WBC, increased neutrophils and increased prothrombin time
Zieda fid- WBC, żieda fin- neutrophils u żieda fil- ħin ta ’ prothrombin
Unknown frequency
Frekwenza mhux magħrufa Mhux komuni
Dehydration, diabetes mellitus
Deidratazzjoni, dijabete mellitus
Unknown frequency
Frekwenza
Hypertriglyceridaemia, hypercholesterolaemia, hyperuricaemia
Ipertrigliċeridemija, iperkolesterolemija u
Nervous system disorders
mhux magħrufa Komuni ħafna
Very common
iperurikemija
Taste perversion, circumoral and peripheral paresthesia, headache
Disturbi tat- togħma, parasteżija periferali u madwar il- ħalq, uġigħ ta ’ ras
Dizziness, paraesthesia, hyperaesthesia, somnolence, insomnia, anxiety
Sturdament, parasteżija, iperestesija, ngħas, nuqqas ta ’ rqad, ansjetà
Seizure, syncope
Attakk tal- epilessija, sinkope
Vascular disorders
mhux magħrufa Komuni Disturbi vaskulari
Vasodilation
Vażodilazzjoni
Unknown frequency
Frekwanza
Orthostatic hypotension
Pressjoni li titbaxxa meta tqum
Respiratory, thoracic and mediastinal disorders
mhux magħrufa Komuni Disturbi respiratorji, toraċiċi u medjastinali
Pharyngitis, cough increased
Farinġite, żieda fis- sogħla
Abdominal pain, nausea, diarrhoea, vomiting
Uġigħ addominali, nawseja, dijarea, rimettar
Dyspepsia, anorexia, local throat irritation, flatulence, dry mouth, eructation, mouth ulcer
Dispepsja, anoressija, irritazzjoni lokali fil - griżmejn, gass fl- istonku, ħalq xott, tifwiq, ulċera fil- ħalq
Hepatobiliary disorders
Mhux komuni Disturbi fil- fwied u fil- marrara
Hepatitis and jaundice
Epatite u suffejra
Rash, pruritus, sweating, lipodystrophy
Raxx, ħakk, ħruġ ta ’ għaraq, lipodistrofija
Musculosketal and connective tissue disorders
Disturbi muskolu- skeltrali u tal - connective tissue
Increased CPK, myalgia
Żieda fis- CPK, uġigħ fil- muskoli
Myositis, rhabdomyolysis
Mijusite, rabdomijoliżi
Unknown frequency
Frekwenza mhux magħrufa
Acute renal failure
Indeboliment renali akut
Unknown frequency
Unknown frequency
Menorrhagia
Menstrwazzjoni esaġerata
Fever, pain weight loss
Deni, uġigħ, tnaqqis fil- piż
Investigations
24 Investigazzjonijiet
Increased GGT, increased CPK, increased triglycerides, increased SGPT, increased SGOT, increased amylase, increased uric acid, decreased potassium, decreased free and total thyroxin
Żieda fis- CGT, żieda fis- CPK, żieda fil - trigliċeridi, żieda fl- SGPT, żieda fl- SGOT, żieda fl- amylase, żieda fl- aċidu uriku, tnaqqis fil- potassju, tnaqqis fit- thyroxin ħieles u totali
Increased glucose, decreased total calcium, increased magnesium, increased bilirubin, increased alkaline phosphatase
Żieda fil- glukows, tnaqqis fil- kalċju totali, żieda fil- manjesju, żieda fil- bilirubin, żieda fl- alkaline phosphatase
Events noted as having Unknown frequency were identified via post-marketing surveillance.
L- effetti innotati bħala li għandhom Frekwrenza mhux magħrufa ġew identifikati permezz ta ’ sorveljanza li saret wara li l- prodott tqiegħed fuq is- suq.
Hepatic transaminase elevations exceeding five times the upper limit or normal, clinical hepatitis, and jaundice have occurred in patients receiving ritonavir alone or in combination with other antiretrovirals.
Żieda fit- transaminase tal- fwied li huma aktar minn ħames darbiet akbar mill- ogħla limitu jew min - normal, l- epatite klinika, u s- suffejra rriżultaw f’ pazjenti li jirċievu ritonavir jew waħdu jew flimkien ma ’ mediċini antiretrovirali oħra.
Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).
It- terapija antiretrovirali kombinata ġiet assoċjata mar- ridistribuzzjoni tax- xaħam tal- ġisem (lipodistrofija) f’ pazjenti li jbatu mill- HIV, inkluż it- telf ta ’ xaħam periferali u ta ’ taħt il- ġilda fil - wiċċ, żieda fix- xaħam taż- żaqq u vixxerali, ipertrofija tas- sider u akkumulazzjoni ta ’ xaħam dorsoċervikali (buffalo hump).
Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (see section 4.4).
Terapija antiretrovirali kombinata ġiet assoċjata ma ’ abnormalitajiet metaboliċi bħal ipertrigliċeridemija, iperkolesterolemija, reżistenza għall- insulina, ipergliċemija u iperlaktatemija (ara sezzjoni 4. 4).
22 In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise (see section 4.4).
F’ pazjenti infettati bl- HIV li, meta tinbeda t- terapija antiretrovirali kombinata (CART), ikollhom defiċjenza immunitarja severa, tista ’ tirriżulta reazzjoni infjammatorja għall- patoġeni li ma jikkaġunawx sintomi jew li huma opportunisti residwali (ara sezzjonin 4. 4).
Pancreatitis has been observed in patients receiving ritonavir therapy, including those who developed hypertriglyceridemia.
Il- pankreatite ġiet innutata f’ pazjenti li kienu qegħdin jirċievu t- terapija b’ Norvir, inkluż dawk li żviluppaw l- ipertrigliċeridemija.
In some cases fatalities have been observed.
F’ xi każi ġew osservati mwiet.
Patients with advanced HIV disease may be at risk of elevated triglycerides and pancreatitis (see section 4.4).
Pazjenti li jbatu mill- marda ta ’ l- HIV fi stadju avanzat jistgħu jkunu qegħdin jissugraw trigliċeridi elevati u pankreatite (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).
Ġew irrapportati każi ta ’ nekrosi ta ’ l- għadam, partikolarment f’ pazjenti li għandhom fatturi ta ’ riskju magħrufa, li jbatu mill- marda ta ’ l- HIV fi stat avanzat jew li kienu soġġetti għall- esponimenti tat - terapija antiretrovirali kombinata (CART) għal żmien twil.
The frequency of this is unknown (see section 4.4).
Il- frekwenza ta ’ dan mhux magħrufa (ara sezzjoni 4. 4).
Human experience of acute overdose with ritonavir is limited.
L- esperjenza ta ’ doża eċċessiva akuta b’ ritonavir fil- bniedem hija limitata.
One patient in clinical trials took ritonavir 1500 mg/day for two days and reported paraesthesia, which resolved after the dose was decreased.
Fi provi kliniċi pazjent wieħed ħa 1500 mg ritonavir kuljum għal jumejn u rrapporta parasteżija, li ġiet riżolta wara tnaqqis tad- doża.
A case of renal failure with eosinophilia has been reported.
Ġie rrapportat każ ta ’ indeboliment renali bl- eżinofilja.
The signs of toxicity observed in animals (mice and rats) included decreased activity, ataxia, dyspnoea and tremors.
Is- sinjali ta ’ tossiċità osservati fil- bhejjem (ġrieden u firien) kienu jinkludu tnaqqis fl- attività, atassja, qtugħ ta ’ nifs u tregħid.
There is no specific antidote for overdose with ritonavir.
M’ hemm l- ebda antidotu għal doża eċċessiva ta ’ ritonavir.
Treatment of overdose with ritonavir should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.
It- trattament għal doża eċċessiva ta ’ ritonavir għandu jikkonsisti f’ miżuri ġenerali ta ’ appoġġ, li jinkludu l- osservazzjoni ta ’ sinjali vitali u osservazzjoni ta ’ l- istat kliniku tal- pazjent.
Due to the solubility characteristics and possibility of transintestinal elimination, it is proposed that management of overdose could entail gastric lavage and administration of activated charcoal.
Minħabba l- karatteristika ta ’ solubilita ̀ u l- possibilita ’ ta ’ tneħħija transintestinali, huwa propost li l- kura għal doża eċċessiva tista ’ tinvolvi ħasil ta ’ l- istonku u l- għoti ta ’ faħam attivat.
Since ritonavir is extensively metabolised by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the medicine.
Peress li ritonavir jiġi fil- biċċa l- kbira tiegħu metabolizzat mill- fwied u jeħel ħafna mal- proteini tad- demm, probabilment id- dijaliżi ma tkunx ta ’ benefiċċju fit- tneħħija sinifikanti tal- mediċina.
Pharmaco-therapeutic group: antiviral for systemic use, ATC code:
Kategorija farmakoterapewtika: antiretrovirali għall- użu sistematiku, Kodiċi ATC:
Pharmacokinetic enhancement by ritonavir is based on ritonavir’s activity as a potent inhibitor of CYP3A- mediated metabolism.
Iż- żieda fl- effett farmakokinetiku permezz ta ’ ritonavir huwa bbażat fuq l- attivita` tiegħu bħala impeditur potenti tal- metaboliżmu medjat b’ CYP3A.
The degree of enhancement is related to the metabolic pathway of the co-administered protease inhibitor and the impact of the co-administered protease inhibitor on the metabolism of ritonavir.
L- ammont ta ’ żieda huwa relatat mal- passaġġ metaboliku ta ’ l- impeditur protejaż li jingħata ma ’ ritonavir u ma ’ l- impatt li għandu l- impeditur protejaż li jingħata ma ’ ritonavir fuq il- metaboliżmu ta ’ ritonavir.
Maximal inhibition of metabolism of the co-administered protease inhibitor is generally achieved with ritonavir doses of 100 mg daily to 200 mg twice daily, and is dependent on the co-administered protease inhibitor.
L- impediment massimali tal - metaboliżmu ta ’ l- impeditur protejaż li jingħata ma ’ ritonavir ġeneralment jintlaħaq b’ dożi ta ’ ritonavir ta ’ minn 100 mg kuljum sa 200 mg darbtejn kuljum, u dan jiddependi fuq l- impeditur protejaż li jingħata ma ’ ritonavir.
For additional information on the effect of ritonavir on co-administered protease inhibitor metabolism, see section 4.5 and refer to the Summary of Product Characteristics of the particular co-administered PIs.
Għal aktar informazzjoni fuq l- effett ta ’ ritonavir fuq il metaboliżmu ta ’ l- impeditur protejaż li jingħata miegħu, ara Sezzjoni 4. 5 u irreferi għas- Sommarju tal- Karatteristiċi tal- Prodott tal- PIs partikolari li jkunu ngħataw ma ’ ritonavir.
Ritonavir is an orally active peptidomimetic inhibitor of the HIV-1 and HIV-2 aspartyl proteases.
Ritonavir huwa impeditur attiv peptidomimetiku tal- protejaż aspartil HIV- 1 u HIV- 2 li jittieħed mill - ħalq.
Inhibition of HIV protease renders the enzyme incapable of processing the gag-pol polyprotein precursor which leads to the production of HIV particles with immature morphology that are unable to initiate new rounds of infection.
L- impediment tal- protejaż ta ’ l- HIV tirrendi inkapaċi l- enzima li tipproċessa l- prekursur poliproteina gag- pol li twassal għall- produzzjoni tal- partiċelli ta ’ l- HIV b’ morfologija immatura, li ma jkunux kapaċi jinizjaw ċirki ġodda ta ’ infezzjoni.
Ritonavir has selective affinity for the HIV protease and has little inhibitory activity against human aspartyl proteases.
Ritonavir għandu affinità selettiva għall- protejaż ta ’ l- HIV u l- attività li jimpedixxi kontra l- protejaż aspartyl fil- bniedem hija żgħira.
Ritonavir was the first protease inhibitor (approved in 1996) for which efficacy was proven in a study with clinical endpoints.
Ritonavir kien l- ewwel impeditur protejaż (approvat fl- 1996) li għalih kienet pruvata l- effikaċja fi studju kliniċi finalizzati.
However, due to ritonavir’s metabolic inhibitory properties its use as a 23 pharmacokinetic enhancer of other protease inhibitors is the prevalent use of ritonavir in clinical practice (see section 4.2).
Madanakollu, minħabba l- kwalitajiet li ritonavir għandu li jimpedixxi, l- akbar użu illi ritonavir għandu fil- prattika klinika huwa l- użu tiegħu biex iżid l- effett farmakokinetiku ta ’ impedituri protejaż oħra (ara sezzjoni 4. 2).
Effects on the Electrocardiogram
Effetti fuq l- Elettrokardjogramm
QTcF interval was evaluated in a randomised, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 45 healthy adults, with 10 measurements over 12 hours on Day 3.
L- intervall QTcF ġie evalwat fi studju tat- tip crossover li sar b’ ordni addoċċ li kien ikkontrollat mill - plaċebo u attiv (moxifloxacin 400 mg darba kuljum) li sar fuq 45 adult f’ saħħtu, fejn f’ Ġurnata 3, ġie mkejjel 10 darbiet fi 12- il siegħa.
The maximum mean (95% upper confidence bound) difference in QTcF from placebo was 5.5 (7.6) for 400 mg twice daily ritonavir.
Id- differenza medja massima (95% upper confidence bound) fil - QTcF mill- plaċebo kienet ta ’ 5. 5 (7. 6) fejn ingħatat doża ta ’ 400 mg ritonavir darbtejn kuljum.
The Day 3 ritonavir exposure was approximately 1.5 fold higher than that observed with the 600 mg twice daily dose at steady state.
L - esponiment ta ’ ritonavir f’ Ġurnata 3 kien ta ’ bejn wieħed u ieħor 1. 5 drabi aktar għoli minn dak osservat meta ngħatat doża ta ’ 600 mg darbtejn kuljum.
Modest prolongation of the PR interval was also noted in subjects receiving ritonavir in the same study on Day 3.
Titwil mhux kbir ta ’ l- intervall PR ġie nnutat ukoll fl- istess studju f’ Ġurnata 3, f’ suġġetti li kienu qegħdin jirċievu ritonavir.
The mean changes from baseline in PR interval ranged from 11.0 to 24.0 msec in the 12 hour interval post dose.
Fl- intervall ta ’ 12 - il siegħa wara li ngħatat id- doża, it- tibdil medju mil- linja bażi fl- intervall PR varja minn 11. 0 sa 24. 0 msec.
Maximum PR interval was 252 msec and no second or third degree heart block was observed (see section 4.4).
L- intervall PR massimu kien ta ’ 252 msec u ma ġie osservat l- ebda imblukkar tal- qalb tat- tieni jew tat- tielet grad (ara sezzjoni 4. 4).
Ritonavir-resistant isolates of HIV-1 have been selected in vitro and isolated from patients treated with therapeutic doses of ritonavir.
L- iżolati ta ’ l- HIV- 1 reżistenti għal ritonavir ġew magħżula in vitro, u ġew iżolati minn pazjenti kkurati b’ dożi terapewtiċi ta ’ ritonavir.
Reduction in the antiretroviral activity of ritonavir is primarily associated with the protease mutations V82A/F/T/S and I84V.
Nuqqas fl- attività antiretrovirali ta ’ ritonavir huwa primarjament assoċjat mal- mutazzjoni tal- protejaż V82A/ F/ T/ S u I84V.
Accumulation of other mutations in the protease gene (including at positions 20, 33, 36, 46, 54, 71, and 90) can also contribute to ritonavir resistance.
L- akkumulazzjoni ta ’ mutazzjonijiet oħra fil- ġene tal- protejaż (inkluż f’ pożizzjonijiet 20, 33, 36, 46, 54, 71, u 90) tista ’ tikkontribwixxi ukoll għar- resistenza għal ritonavir.
In general, as mutations associated with ritonavir resistance accumulate, susceptibility to select other PIs may decrease due to cross-resistance.
26 suxxettibilità biex jagħżel PIs oħra tista ’ tonqos minħabba cross- resistance.
The Summary of Product Characteristics of other protease inhibitors or official continuous updates should be consulted for specific information regarding protease mutations associated with reduced response to these agents.
Għal informazzjoni speċifika dwar mutazzjonijiet tal- protejaż assoċjat ma ’ nuqqas ta ’ rispons għal dawn l- aġenti, għandu jiġi konsultat is- Sommarju tal- Karatteristiċi tal- Prodott ta ’ impedituri protejaż oħra jew aġġornamenti uffiċjali li jsiru kontinwament.
Clinical pharmacodynamic data
Informazzjoni Klinika Farmakodinamika
The effects of ritonavir (alone or combined with other antiretroviral agents) on biological markers of disease activity such as CD4 cell count and viral RNA were evaluated in several studies involving HIV-1 infected patients.
L- effetti ta ’ ritonavir (waħdu jew flimkien ma ’ aġenti antiretrovirali oħra) fuq werrejja bijoloġiċi ta ’ l - attività tal- mard, bħal għadd ta ’ ċelluli CD4 u RNA virali, ġew evalwati f’ diversi studji li kienu jinvolvu pazjenti infettati bl- HIV- 1.
The following studies are the most important.
L- istudji segwenti huma l- iktar importanti.
Adult Use
Użu mill- Adulti
A controlled study completed in 1996 with ritonavir as add-on therapy in HIV-1 infected patients extensively pre-treated with nucleoside analogues and baseline CD4 cell counts ≤ 100 cells/μl showed a reduction in mortality and AIDS defining events.
Studju kkontrollat komplet fl- 1996 li sar b’ ritonavir bħala terapija addizzjonali fuq pazjenti infettati bl- HIV- 1 u li kienu preċedentement ikkurati estensivament b’ analogi ta’ nukleòside u b’ għadd ta ’ ċellulli tal- linja bażi CD4 ≤ 100 ċelluli / µl, urew tnaqqis fil- mortalità u fl- avvenimenti li jiddefinixxu l- AIDS.
The mean average change from baseline over 16 weeks for HIV RNA levels was -0.79 log10 (maximum mean decrease:
It- tibdil medju mill- linja bażi għal- livelli HIV RNA fuq perijodu ta’ 16 - il ġimgħa kien ta ’ 0. 79 log10 (medja ta ’ tnaqqis massimu:
1.29 log10) in the ritonavir group versus-0.01 log10 in the control group.
1. 29 log10) fil- grupp ta ’ ritonavir kontra - 0. 01 log10 fil- grupp ta ’ kontroll.
The most frequently used nucleosides in this study were zidovudine, stavudine, didanosine and zalcitabine.
L- iktar nukleòsidi użati frekwentement f’ dan l- istudju kienu zidovudine, stavudine, didanosine u zalcitabine.
In a study completed in 1996 recruiting less advanced HIV-1 infected patients (CD4 200-500 cells/μl) without previous antiretroviral therapy, ritonavir in combination with zidovudine or alone reduced viral load in plasma and increased CD4 count.
Fi studju komplet fl- 1996 li fih ħadu sehem pazjenti infettati bl- HIV però fi stadju inqas avanzat tal - marda (CD4 200- 500 ċellula/ µl) u li ma kinux ingħataw terapija antiretrovirali qabel, ritonavir flimkien ma ’ zidovudine jew waħdu naqqas it- tagħbija virali fil- plażma u żid l- għadd ta ’ CD4.
The mean average change from baseline over 48 weeks for HIV RNA levels was -0.88 log10 in the ritonavir group versus -0.66 log10 in the ritonavir + zidovudine group versus -0.42 log10 in the zidovudine group.
It- tibdil medju mill- linja bażi għal- livelli HIV RNA fuq perijodu ta ’ 48 ġimgħa kien ta ’ - 0. 88 log10 fil- grupp ta ’ ritonavir kontra - 0. 42 log10 fil- grupp ta ’ zidovudine.
The continuation of ritonavir therapy should be evaluated by viral load because of the possibility of the emergence of resistance as described under section 4.1 Therapeutic indications.
It- tkomplija tat- terapija b’ ritonavir għandha tkun evalwata permezz tat- tgħabija virali, u dan minħabba l- possibilità ta ’ l- iżvilupp ta ’ reżistenza kif deskritta f’ sezzjoni 4. 1 Indikazzjonijiet terapewtiċi.
Paediatric Use
Użu Pedjatriku
24 In an open label trial completed in 1998 in HIV infected, clinically stable children there was a significant difference (p = 0.03) in the detectable RNA levels in favour of a triple regimen (ritonavir, zidovudine and lamivudine) following 48 weeks treatment.
Fi prova open label kompleta fl- 1998 fuq tfal klinikament stabbli infettati bl- HIV, kien hemm, wara kura ta ’ 48 ġimgħa, differenza sinifikanti (p = 0. 03) fil- livelli traċċabbli ta ’ RNA favur dożaġġ triplu (ritonavir, zidovudine u lamivudine).
In a study completed in 2003, 50 HIV-1 infected, protease inhibitor and lamivudine naïve children age 4 weeks to 2 years received ritonavir 350 or 450 mg/m2 every 12 hours co-administered with zidovudine 160 mg/m2 every 8 hours and lamivudine 4 mg/kg every 12 hours.
Fi studju komplet fl- 2003, 50 tifel u tifla ta ’ età ta ’ bejn 4 ġimgħat u sentejn, illi kienu infettati b’ HIV- 1 u qatt ma kienu esponew ruħom għal impedituri protejaż u lamivudine, kienu qegħdin jirċievu 350 jew 450 mg/ m2 ritonavir kull 12 - il siegħa flimkien ma ’ 160 mg/ m2 zidovudine kull 8 siegħat u 4 mg/ kg lamivudine kull 12 - il siegħa.
In intent to treat analyses, 72% and 36% of patients achieved reduction in plasma HIV-1 RNA of ≤ 400 copies/ml at Week 16 and 104, respectively.
F’ analażi ta ’ l- intenzjoni biex tfejjaq, 72% u 36% tal - pazjenti laħqu tnaqqis ta ’ l- HIV- 1 RNA fil- plażma ta ’ ≤ 400 kopja/ ml f’ Ġimgħa numru 16 u 104, rispettivament.
Response was similar in both dosing regimens and across patient age.
Ir- rispons kien simili kemm fil- pazjenti bl- istess żewġ dożaġġi, kif ukoll f’ pazjenti ta ’ l- istess età.
There is no parenteral formulation of ritonavir, therefore the extent of absorption and absolute bioavailability have not been determined.
M’ hemm l- ebda formulazzjoni parenterali ta ’ ritonavir, għalhekk l- ammont ta ’ kemm ritonavir jiġi assorbit u ta ’ kemm huwa assolutament bijodisponibbli għadhom ma ġewx stabbiliti.
The pharmacokinetics of ritonavir during multiple dose regimens were studied in non-fasting HIV-infected adult volunteers.
Il - farmakokinetika ta ’ ritonavir matul l- għoti ta ’ aktar minn doża waħda ġew studjati f’ pazjenti adulti voluntiera infettati bl- HIV li ma kinux sajma.
Upon multiple dosing, ritonavir accumulation is slightly less than predicted from a single dose due to a time and dose-related increase in apparent clearance (Cl/F).
Wara l- għoti ta ’ aktar minn doża waħda l - akkumulazzjoni ta ’ ritonavir hija ftit inqas minn dik maħsuba li jkun hemm minn doża waħda, u dan minħabba żieda fi- tneħħija apparenti (Cl/ F) relatata mal- ħin u mad- doża.
Trough concentrations of ritonavir decrease over time, possibly due to enzyme induction, but appeared to stabilise by the end of 2 weeks.
Maż- żieda fid- doża, il -
The time to maximum concentration (Tmax) remained constant at approximately 4 hours with increasing dose.
27 ħin biex tintlaħaq il- konċentrazzjoni massima (Tmax) baqa ’ l- istess, ta ’ bejn wieħed u ieħor 4 sigħat.
Renal clearance averaged less than 0.1 l/h and was relatively constant throughout the dosage range.
Il - medja tat- tneħħija permezz tal- kliewi kienet ta ’ inqas minn 0. 1 l/ siegħa, u baqgħet relattivament kostanti matul ix- xelta tad- dożaġġi.
The pharmacokinetic parameters observed with various dosing schemes of ritonavir alone are shown in the table below.
Il- parametri famakokinetiċi osservati ma ’ diversi skemi ta ’ dożaġġ ta ’ ritonavir waħdu huma murija fit- tabella t’ hawn taħt.
Ritonavir Dosing Regimen
L- Ammont ta ’ Dożaġġ ta ’ Ritonavir
100
100 mg 100 mg
Ctrough (µg/ml)
Ctrough (µg/ ml)
AUC12 or 24 (µg•h/ml)
AUC12 or 24 (µg• h/ ml)
21.92 ± 6.48
± 6. 48
Values expressed as geometric means.
Valuri espressi bħala mezzi ġeometriċi.
Note: ritonavir was dosed after a meal for all listed regimens.
Nota: ritonavir ingħata wara ikla fil- każ ta ’ l- ammonti kollha ta ’ dożaġġ,.
Effects of food on oral absorption:
Effetti ta ’ l- ikel fuq l- assorbiment mill- ħalq:
Ingestion of ritonavir with food results in higher ritonavir exposure than ingestion in the fasted state.
Meta ritonavir jinbela ’ ma ’ l- ikel jirriżulta esponiment aktar għoli ta ’ ritonavir minn meta jinbela ’ fi stat ta ’ sawm.
The apparent volume of distribution (VB/F) of ritonavir is approximately 20 - 40 l after a single 600 mg dose.
Il- volum apparenti ta ’ distribuzzjoni (VB/ F) ta ’ ritonavir hu bejn wieħed u ieħor 20 - 40 1 wara doża waħda ta ’ 600 mg.
The protein binding of ritonavir in human plasma is approximately 98 - 99% and is constant over the concentration range of 1.0 – 100 μg /ml.
It- tweħħil ta ’ ritonavir mal- proteini tad- demm fil- plażma tal- bniedem huwa ta ’ bejn wieħed u ieħor 98 - 99% u huwa kostanti tul il- medda ta ’ konċentrazzjoni ta ’ bejn 1. 0 - 100 µg/ ml.
Ritonavir binds to both human alpha 1-acid glycoprotein (AAG) and human serum albumin (HSA) with comparable affinities.
Ritonavir jeħel b’ affinitajiet komparabbli, kemm ma ’ alpha 1- acid glycoprotein (AAG) uman, kif ukoll mas- serum tal- albumina (HSA) tal- bniedem.
Tissue distribution studies with 14C-labelled ritonavir in rats showed the liver, adrenals, pancreas, kidneys and thyroid to have the highest concentrations of ritonavir.
Studji fuq id- distribuzzjoni fit- tessuti b’ ritonavir tikkettat 14C li saru fuq il- firien, urew li l- fwied, l - adrenali, il- frixa, il- kliewi u t- tirojde kellhom l- ogħla konċentrazzjoni ta ’ ritonavir.
Tissue to plasma ratios of approximately 1 measured in rat lymph nodes suggests that ritonavir distributes into lymphatic tissues.
Il- proporzjon ta ’ bejn it- tessuti u l- plażma ta ’ bejn wieħed u ieħor 1 imkejjel fin- nodi limfatiċi tal- firien jindika li ritonavir jinfirex fit- tessuti limfatiċi.
Ritonavir penetrates minimally into the brain.
Ritonavir jippenetra minimament fil- moħħ.
Ritonavir was noted to be extensively metabolised by the hepatic cytochrome P450 system, primarily by the CYP3A isozyme family and to a lesser extent by the CYP2D6 isoform.
Ġie innutat li ritonavir jiġi fil- biċċa l- kbira tiegħu metabolizzat mis- sistema epatika cytochrome P450, primarjament mill- familja ta ’ l- iżożima CYP3A, u b’ mod inqas mill- iżoforma CYP2D6.
Animal studies as well as in vitro experiments with human hepatic microsomes indicated that ritonavir primarily underwent oxidative metabolism.
Studji fuq il - bhejjem, kif ukoll esperimenti in vitro b’ mikrosomi epatiċi tal- bniedem urew li primarjament ritonavir għadda minn metaboliżmu ossidattiv.
Four ritonavir metabolites have been identified in man.
Fil- bniedem ġew identifikati erba ’ metaboliti ta ’ ritonavir.
The isopropylthiazole 25 oxidation metabolite (M-2) is the major metabolite and has antiviral activity similar to that of parent drug.
Il - metabolit ta ’ ossidifikazzjoni ta ’ isopropylthiazole (M- 2) huwa l- metabolit prinċipali u għandhu attività antiretrovirali simili għal dik tal- mediċina prinċipali (parent drug).
However, the AUC of the M-2 metabolite was approximately 3% of the AUC of parent drug.
Iżda l- AUC tal- metabolit M- 2 kien bejn wieħed u ieħor 3% ta ’ l- AUC tal- mediċina prinċipali.
Low doses of ritonavir have shown profound effects on the pharmacokinetics of other protease inhibitors (and other products metabolised by CYP3A4) and other protease inhibitors may influence the pharmacokinetics of ritonavir (see section 4.5).
Dożi baxxi ta ’ ritonavir urew effetti profondi fuq il- farmakokinetika ta ’ impedituri protejaż oħra (u prodotti oħra metabolizzati b’ CYP3A4), u impedituri oħra protejaż jistgħu jinfluwenzaw il - farmakokinetika ta ’ ritonavir (ara sezzjoni 4. 5).
Human studies with radiolabelled ritonavir demonstrated that the elimination of ritonavir was primarily via the hepatobiliary system; approximately 86% of radiolabel was recovered from stool, part of which is expected to be unabsorbed ritonavir.
Studji fuq il- bniedem li saru b’ ritonavir radjotikkettat urew li l- eliminazzjoni ta ’ ritonavir saret prinċipalment permezz tas- sistema epatobiljarja: bejn wieħed u ieħor 86% tar- radjotikkettar kien prelevat mill- iskart tal- ġisem, li parti minnu hu mistenni li jkun ritonavir li ma jkunx ġie assorbit.
In these studies renal elimination was not found to be a major route of elimination of ritonavir.
28 F’ dawn l- istudji ġie misjub li l- eliminazzjoni permezz tal- kliewi m’ hijiex ir- rotta prinċipali għall - eliminazzjoni ta ’ ritonavir.
This was consistent with the observations in animal studies.
Dan kien konsistenti ma ’ dak li ġie osservat fi studju fuq il- bhejjem.
No clinically significant differences in AUC or Cmax were noted between males and females.
Ma ġew innutati l- ebda differenzi klinikament sinifikanti fl- AUC jew f’ Cmax bejn irġiel u nisa.
Ritonavir pharmacokinetic parameters were not statistically significantly associated with body weight or lean body mass.
Il- parametri farmakokinetiċi ta ’ ritonavir ma kinux statistikament assoċjati b’ mod sinifikanti mal- piż tal- ġisem jew mal- massa tal- ġisem bla xaħam.
Ritonavir plasma exposures in patients 50 – 70 years of age when dosed 100 mg in combination with lopinavir or at higher doses in the absence of other protease inhibitors is similar to that observed in younger adults.
L- esponimenti fil- plażma b’ ritonavir f’ pazjenti ta ’ bejn 50 – 70 sena meta dożati b’ 100 mg jew dożi akbar flimkien ma ’ lopinavir, huma simili għall- esponimenti osservati f’ adulti iżgħar meta ma jkunx hemm impedituri ta ’ protejaż oħra.
Patients with impaired liver function: after multiple dosing of ritonavir to healthy volunteers (500 mg twice daily) and subjects with mild to moderate hepatic impairment (Child Pugh Class A and B, 400 mg twice daily) exposure to ritonavir after dose normalisation was not significantly different between the two groups.
Pazjenti b’ indeboliment funzjonali tal- fwied: wara l- għoti ta ’ aktar minn doża waħda ta ’ ritonavir lil voluntiera b’ saħħithom (500 mg darbtejn kuljum) u lil soġġetti b’ indeboliment tal- fwied li jvarja minn ħafif għal moderat (Child Pugh Klassi A u B, 400 mg darbtejn kuljum), l- esponiment għal ritonavir wara li d- dożaġġ reġa ’ beda jingħata b’ mod normali ma kienx differenti b’ mod sinifikanti bejn iż - żewġ gruppi.
Patients with impaired renal function:
Pazjenti b’ indeboliment funzjonali renali:
Ritonavir pharmacokinetic parameters have not been studied in patients with renal impairment.
Il- parametri farmakokinetiċi ta ’ ritonavir ma ġewx studjati f’ pazjenti li jbatu minn indeboliment renali.
However, since the renal clearance of ritonavir is negligible, no changes in the total body clearance are expected in patients with renal impairment.
Madanakollu, peress illi huwa biss ammont żgħir ħafna ta ’ ritonavir li jitneħħa permezz tal- kliewi, m’ huwa mistenni l- ebda tibdil fit- tneħħija totali mill- ġisem f’ pazjenti li jbatu minn indeboliment renali.
Ritonavir steady-state pharmacokinetic parameters were evaluated in HIV infected children above 2 years of age receiving doses ranging from 250 mg/m² twice daily to 400 mg/m² twice daily.
Il- parametri farmakokinetiċi fissi ta ’ ritonavir ġew evalwati fi tfal infettati bl- HIV ta’ età ta ’ iżjed minn sentejn, li kienu qegħdin jirċievu dożi li jvarjaw minn 250 mg/ m² darbtejn kuljum għal 400 mg/ m² darbtejn kuljum.
Ritonavir concentrations obtained after 350 to 400 mg/m² twice daily in paediatric patients were comparable to those obtained in adults receiving 600 mg (approximately 330 mg/m²) twice daily.
Il- konċentrazzjoni ta ’ ritonavir li ntlaħqet f’ pazjenti pedjatriċi wara doża ta ’ bejn 350 u 400 mg/ m² darbtejn kuljum kienet komparabbli ma ’ dik li ntlaħqet mill- adulti li kienu qegħdin jirċievu 600 mg (bejn wieħed u ieħor 330 mg/ m²) darbtejn kuljum.
Across dose groups, ritonavir oral clearance (CL/F/m2) was approximately 1.5 to 1.7 times faster in paediatric patients above 2 years of age than in adult subjects.
Bejn il- gruppi ta’ doża differenti it- tneħħija ta ’ ritonavir mill- ħalq (cl/ F/ m2) kienet ta ’ bejn wieħed u ieħor minn 1. 5 sa 1. 7 drabi aktar mgħaġġla f’ pazjenti pedjatriċi li kellhom iżjed minn sentejn, milli minn suġġetti adulti.
Ritonavir steady-state pharmacokinetic parameters were evaluated in HIV infected children less than 2 years of age receiving doses ranging from 350 to 450 mg/m² twice daily.
Il- parametri farmakokinetiċi fi stat fiss ta ’ ritonavir ġew evalwati fi tfal ta’ età ta ’ inqas minn sentejn infettati bl- HIV, li kienu qegħdin jirċievu dożi li jvarjaw minn 350 sa 450 mg/ m² darbtejn kuljum.
Ritonavir concentrations in this study were highly variable and somewhat lower than those obtained in adults receiving 600 mg (approximately 330 mg/m²) twice daily.
Il - konċentrazzjoni ta ’ ritonavir f’ dan l- istudju kienu jvarjaw ħafna, u b’ xi mod, kienu inqas minn dak li ntlaħaq mill- adulti li kienu qegħdin jirċievu 600 mg (bejn wieħed u ieħor 330 mg/ m²) darbtejn kuljum.
Across dose groups, ritonavir oral clearance (CL/F/m2) declined with age with median values of 9.0 L/h/m2 in children less than 3 months of age, 7.8 L/h/m2 in children between 3 and 6 months of age and 4.4 L/h/m2 in children between 6 and 24 months of age.
Bejn il- gruppi ta’ doża differenti, it- tneħħija ta ’ ritonavir mill- ħalq (cl/ F/ m2) naqqset ma ’ l- età, b’ valuri medji ta ’ 9. 0 L/ h/ m2 fi tfal ta ’ inqas minn 3 xhur fl- età, 7. 8 L/ h/ m2 fi tfal ta’ l- età ta ’ bejn it- 3 xhur u s- 6 xhur u 4. 4 L/ h/ m2 fi tfal ta ’ età ta ’ bejn is- 6 xhur u l- 24 xhar.
Repeated dose toxicity studies in animals identified major target organs as the liver, retina, thyroid gland and kidney.
Studji ripetuti dwar tossiċità fil- bhejjem identifikaw bħala l- organi prinċipali li jistgħu jiġu milquta bħala l- fwied, ir- retina, l- glandola tat- tirojde u l- kilwa.
Hepatic changes involved hepatocellular, biliary and phagocytic elements and were accompanied by increases in hepatic enzymes.
Tibdil fil- fwied kien jinvolvi elementi epatoċellulari, biljarji u fagoċitiċi u kienu akkompanjati b’ żidiet fl- enzimi epatiċi.
Hyperplasia of the retinal pigment epithelium (RPE) and retinal degeneration have been seen in all of the rodent studies conducted with ritonavir, but have not been seen in dogs.
L- iperplasija ta ’ l - epiteljum pigmentali tar- retina (RPE) u deġenerazzjoni fir- retina ġew osservati fl- istudji kollha li saru b’ ritonavir fuq l- annimali gerriema, iżda ma ġewx innutati fil- klieb.
Ultrastructural evidence suggests that these retinal changes may be secondary to phospholipidosis.
Evidenza ultrastrutturali tissuġġerixxi illi dan it- tibdil retinali jista ’ jkun sekondarju għall- fosfolipidosi.
However, clinical trials revealed no evidence of drug-induced ocular changes in humans.
Iżda provi kliniċi ma ’ żvelaw l- ebda prova ta ’ tibdil fl- għajnejn fil- bniedem ikawżat mill- mediċina.
All thyroid changes were reversible upon discontinuation of ritonavir.
Kull tibdil fit- tirojde ġie imreġġa ’ lura wara li twaqqaf l- użu ta ’ ritonavir.
Clinical investigation in humans has revealed no clinically significant alteration in thyroid function tests.
Investigazzjonijiet kliniċi fuq il- bniedem ma ’ żvelaw l- ebda tibdil kliniku sinifikanti fi provi dwar il- funzjoni tat- tirojde.
Renal changes including tubular degeneration, chronic inflammation and proteinurea were noted in rats and are felt to be attributable to species-specific spontaneous disease.
Tibdil fil- kliewi, inkluża deġenerazzjoni tubolari, infjammazzjoni kronika u proteinureja ġew innutati fil- firien, u huma kkunsidrati bħala li jistgħu jiġu attribwiti għall- mard spontanju relatat speċifikatament ma ’ speċje partikolari.
Furthermore, no clinically significant renal abnormalities were noted in clinical trials.
Barra minn dan, fi provi kliniċi ma ġew innotati l- ebda abnormalitajiet sinifikanti fil - kliewi.
26 Developmental toxicity observed in rats (embryolethality, decreased foetal body weight and ossification delays and visceral changes, including delayed testicular descent) occurred mainly at a maternally toxic dosage.
Tossiċità li hija relatata ma ’ l- iżvilupp li ġiet osservata fil- firien (mewt ta ’ l- embriju, tnaqqis fil- massa tal- ġisem tal- fetu u dewmin fl- ossifikazzjoni, u tibdil vixxerali, li jinkludi dewmin fl- inżul tat- testikoli fil- borża) irrevelat ruħha prinċiparjament f’ dożaġġ tossiku għall- omm.
Developmental toxicity in rabbits (embryolethality, decreased litter size and decreased foetal weights) occurred at a maternally toxic dosage.
Tossiċità li hija relatata ma ’ l - 29 iżvilupp li ġiet osservata fil- fniek (mewt ta ’ l- embriju, tnaqqis fin- numru tal- boton u tnaqqis fil- massa tal- ġisem tal- fetu) irrevelat ruħha prinċiparjament f’ dożaġġ tossiku għall- omm.