qanastek/EMEA-V3 huggingface dataset:
Results from an interaction study with Kaletra and pravastatin reveal no clinically significant interaction.
Is- 16 - il virus li urew bidla ta ’ > 20 darba fis- suxxettibilità, kollha kien fihom mutazzjonijiet fil- pożizzjonijiet 10, 54, 63 u 82 u / jew 84.
The metabolism of pravastatin and fluvastatin is not dependent on CYP3A4, and interactions are not expected with Kaletra.
Barraminnhekk, dawn kien fihom medjan ta ’ 3 mutazzjonijiet fil - pożizzjonijiet ta ’ l- aċidi amminiċi 20, 24, 46, 53, 71 u 90.
If treatment with a HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended.
Mal- mutazzjonijiet deskritti hawn fuq, kienu ukoll osservati l- mutazzjonijiet V321 u I47A f’ iżolati li marru lura b’ suxxettibilità mnaqqsa għal lopinavir f’ pazjenti b’ esperjenza ta ’ impeditur protejaż li kienu qegħdin jirċievu terapija b’ Kaletra.
Dexamethasone: may induce CYP3A4 and may decrease lopinavir concentrations.
89 Flimkien mal- mutazzjonijiet imsemmija hawn fuq, ġew osservati wkoll mutazzjonijiet I47A u L76V fl - iżolati li marru lura b’ suxxettibilità mnaqqsa għal lopinavir f’ pazjenti li kienu qegħdin jirċievu t - terapija b’ Kaletra.
Phosphodiesterase inhibitors: phosphodiesterase inhibitors which are dependent on CYP3A4 metabolism, such as tadalafil and sildenafil, are expected to result in an approximately 2-fold and 11-fold increase in AUC respectively, when co-administered with ritonavir containing regimens including Kaletra and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, synope, visual changes and prolonged erection.
Attività antivirali ta ’ Kaletra f’ pazjenti li mhux qed ikollhom rispons għat- terapija b’ impeditur protejaż: ir- rilevanza klinika tas- suxxettibilità in vitro mnaqqsa għal lopinavir ġiet eżaminata billi ġie evalwat ir- rispons viroloġiku għat- terapija b’ Kaletra, fir- rigward tal- ġenotip u fenotip virali fil- linja bażi, f’ 56 pazjent li qabel ma kellhomx rispons għat- terapija b’ diversi impedituri protejaż.
Particular caution must be used when prescribing sildenafil or tadalafil in patients receiving Kaletra with increased monitoring for adverse events.
L- EC50 ta ’ lopinavir kontra is- 56 iżolat virali fil- linja bażi varja bejn 0. 6 u 96 darba aktar mill- EC50 kontra l- HIV ta ’ tip mhux ikkultivat.
Co-administration of vardenafil with rtionavir containing regimens including Kaletra is expected to result in 49-fold increase in vardenafil AUC.
Peress li dawn il- pazjenti ma kinux ġew esponuti qabel għal Kaletra jew għal efavirenz, parti mir- rispons tista ’ tiġi attribwita lill- attività antivirali ta ’ efavirenz, speċjalment f’ pazjenti li għandhom virus li hu reżistenti ħafna għal lopinavir.
The use of vardenafil with Kaletra is contraindicated (see section 4.3).
L- istudju ma kienx fih numru kbir ta ’ pazjenti li ma kinux qegħdin jirċievu Kaletra.
Cyclosporin, sirolimus (rapamycin) and tacrolimus: concentrations may be increased when co-administered with Kaletra.
Ġeneralment, iżolati li marru lura, jew żammew (jekk kienu cross- resistant fil- linja bażi) jew żviluppaw cross- resistance sinifikanti għal indinavir, saquinavir u atazanavir.
More frequent therapeutic concentration monitoring is recommended until plasma levels of these products have been stabilised.
Tnaqqis mhux kbir fl- attività ta ’ amprenavir ġie nnutat b’ żieda medjana ta ’ IC50 minn 3. 7 darbiet għal 8 darbiet aktar fl- iżolati tal- linja bażi jew li marru lura, rispettivament.
High doses of ketoconazole and itraconazole (> 200 mg/ day) are not recommended.
Tagħrif kliniku farmakodinamiku
Voriconazole: due to the potential for reduced voriconazole concentrations, co-administration of voriconazole and low dose ritonavir (100 mg twice daily) as contained in Kaletra should be avoided unless an assessment of the benefit/ risk to patient justifies the use of voriconazole.
L- effetti ta ’ Kaletra (użat flimkien ma ’ aġenti antiretrovirali oħra) fuq markaturi bijoloġiċi (livelli ta ’ HIV RNA fil- plażma u punti ta ’ CD4) ġew investigati fi studju kontrollat ta ’ Kaletra li dam 48 ġimgħa, u fi studji oħra ta ’ Kaletra li damu 360 ġimgħa.
Clarithromycin: moderate increases in clarithromycin AUC are expected when co-administered with Kaletra.
Pazjenti li qatt ma ħadu terapija antiretrovirali
For patients with renal or hepatic impairment dose reduction of clarithromycin should be considered (see section 4.4).
L- istudju M98- 863 huwa prova double- blind ta ’ 653 pazjent magħżula b’ ordni addoċċ u li qatt ma ħadu kura antiretrovirali, li jinvestiga lil Kaletra (400/ 100 mg darbtejn kuljum) kif imqabbel ma ’ nelfinavir
Buprenorphine: buprenorphine (dosed at 16 mg daily) co-administered with lopinavir/ ritonavir (dosed at 400/ 100 mg twice daily) showed no clinically significant interaction.
Il- medja ta ’ l- għadd ta ’ ċelloli CD4 tal- linja bażi kienet ta ’ 259 ċellola / mm3 (limiti: minn 2 sa 949 ċellola / mm3) u l- medja tal- plażma ta ’ HIV- 1 RNA fil- linja bażi kienet ta ’ 4. 9 log10 kopji/ ml (limiti: minn 2. 6 sa 6. 8 log10 kopji/ ml).
Kaletra can be co-administered with buprenorphine with no dose adjustment.
Matul 48 ġimgħa ta ’ terapija, il - proporzjon ta ’ pazjenti fis- sezzjoni ta ’ Kaletra bil- plażma RNA < 50 kopja/ ml kien ta ’ 67% u 52% fis - sezzjoni ta ’ nelfinavir.
Kaletra was demonstrated to lower plasma concentrations of methadone.
Iż- żieda medja mil- linja bażi fl- għadd ta ’ ċelloli CD4 kienet ta ’ 207 ċelloli/ mm3 fis- sezzjoni ta ’ Kaletra u 195 ċellola/ mm3 fis- sezzjoni ta ’ nelfinavir.
Monitoring plasma concentrations of methadone is recommended.
Matul 48 ġimgħa ta ’ terapija, proporzjon ogħla b’ mod li hu statistikament sinifikanti, ta ’ pazjenti fis- sezzjoni ta ’ Kaletra kellhom HIV RNA < 50 kopja/ ml meta mqabbla mas- sezzjoni ta ’ nelfinavir.
71 Contraceptives: levels of ethinyl oestradiol were decreased when oestrogen-based oral contraceptives were co-administered with Kaletra.
Ġiet osservata ukoll iż- żamma tar- rispons viroloġiku għal Kaletra (flimkien ma ’ impedituri nukleòside/ nukleòtide reverse transcriptase) fi studju żgħir ta ’ Fażi II (M97- 720) tul 360 ġimgħa ta ’ kura.
In case of co-administration of Kaletra with contraceptives containing ethinyl oestradiol (whatever the contraceptive formulation e. g. oral or patch), alternative methods of contraception are to be used.
Fl- istudju, mitt pazjent ġew oriġinarjament ikkurati b’ Kaletra (inklużi 51 pazjent li kienu qegħdin jirċievu 400/ 100 mg darbtejn kuljum u 49 pazjent li kienu qegħdin jirċievu jew 200/ 100 mg darbtejn kuljum jew 400/ 200 mg darbtejn kuljum).
Rifabutin: when rifabutin and Kaletra were co-administered for 10 days, rifabutin (parent substance and active 25-O-desacetyl metabolite) Cmax and AUC were increased by 3.5- and 5.7-fold, respectively.
Wieħed u sittin pazjent spiċċaw l- istudju kollu (35 pazjent irċevew id- doża rrakkomandata ta ’ 400/ 100 mg darbtejn kuljum matul l- istudju kollu).
On the basis of these data, a rifabutin dose reduction of 75% (i. e.
Matul 360 ġimgħa ta ’ kura, il- proporzjon ta ’ pazjenti b’ HIV RNA < 400 (< 50) kopja/ ml kien ta ’ 61% (59%), u ż- żieda medja ta ’ għadd ta ’ ċelluli CD4 li tikkorespondi, kienet ta ’ 501 ċelloli/ mm3.
150 mg every other day or 3 times per week) is recommended when administered with Kaletra.
Disgħa u tletin pazjent (39%) ma komplewx l- istudju, inklużi 16 (16%) - il waqfa minħabba effetti avversi, u waqfa minnhom kienet assoċjata ma ’ mewta.
Further reduction may be necessary.
Pazjenti li rċevew terapija antiretrovirali qabel
Rifampicin: co-administration of Kaletra with rifampicin is not recommended.
Il- linja bażi medjana fl - għadd ta ’ ċelluli CD4 kienet ta ’ 349 ċellula/ mm3 (limiti 72 sa 807 ċelloli/ mm3) u l- linja bażi medjana tal- plażma HIV- 1 RNA kienet ta ’ 4. 0 log10 kopja/ ml (limiti 2. 9 sa 5. 8 log10 kopja/ ml).
Rifampicin administered with Kaletra causes large decreases in lopinavir concentrations which may in turn significantly decrease the lopinavir therapeutic effect.
Bl- intenzjoni li jittrattaw l- analiżi fejn pazjenti b’ valuri nieqsa huma kkunsidrati fallimenti viroloġiċi, il- proporzjon ta ’ pazjenti b’ HIV RNA < 400 (< 50) kopja/ ml wara 24 ġimgħa kien ta ’ 75% (58%) u ż- żieda medja mil - linja bażi fl- għadd taċ- ċelluli CD4 kienet ta ’ 174 ċellola/ mm3 għas- 36 pazjent li kienu qegħdin jirċievu d- doża ta ’ Kaletra ta ’ 400/ 100 mg.
A dose adjustment of Kaletra 400 mg/ 400 mg twice daily has allowed compensating for the CYP 3A4 inducer effect of rifampicin.
M98- 957 huwa studju open- label li sar b’ ordni addoċċ fejn il- kura b’ Kaletra ġiet evalwata f’ żewġ livelli ta ’ dożi (400/ 100 mg u 533/ 133 mg, it- tnejn li huma darbtejn kuljum) u efavirenz (600 mg darba kuljum) u impedituri nukleòside reverse transcriptase f’ 57 pazjent b’ esperjenza ta ’ diversi impedituri protejaż, imma novizzi għal impedituri reverse transcriptase mhux nukleòside.
However, such a dose adjustment might be associated with ALT/ AST elevations and with increase in gastrointestinal disorders.
Bejn ġimgħa 24 u ġimgħa 48, pazjenti magħżula b’ ordni addoċċ mogħtija doża ta ’ 400/ 100 mg ġew maqluba fuq doża ta ’ 533/ 133 mg.
Therefore, this co-administration should be avoided unless judged strictly necessary.
Il- medjan tal- linja bażi fl- għadd taċ- ċelluli CD4 kien ta ’ 220 ċellula/ mm3 (limiti 13 sa 1030 ċelloli/ mm3).
If this co-administration is judged unavoidable, increased dose of Kaletra at 400 mg/ 400 mg twice daily may be administered with rifampicin under close safety and therapeutic drug monitoring.
M98- 940 huwa studju open- label tal- formulazzjoni likwida ta ’ Kaletra f’ 100 pazjent li kienu novizzi għat- terapji antiretrovirali (44%) u pazjenti pedjatriċi b’ esperjenza (56%) ta ’ dawn it- terapiji.
The Kaletra dose should be titrated upward only after rifampicin has been initiated (see section 4.4).
Il- pazjenti ġew
St John’ s wort: serum levels of lopinavir and ritonavir can be reduced by concomitant use of the herbal preparation St John’ s wort (Hypericum perforatum).
91 magħżula b’ ordni addoċċ biex jingħataw jew 230 mg lopinavir/ 57. 5 mg ritonavir kull m2 jew 300 mg lopinavir/ 75 mg ritonavir kull m2.
This is due to the induction of drug metabolising enzymes by St John’ s wort.
Pazjenti novizzi ngħataw ukoll impedituri nukleòside reverse transcriptase.
Herbal preparations containing St John’ s wort should therefore not be combined with lopinavir and ritonavir.
Il- pazjenti b’ esperjenza ngħataw nevirapine u sa żewġ impedituri nukleòside reverse transcriptase.
If a patient is already taking St John’ s wort, stop St John’ s wort and if possible check viral levels.
Il- profili tas- sigurtà, l- effikaċja u tal- farmakokinetika taż- żewġ reġimi ta ’ dożi ġew evalwati wara 3 ġimgħat ta ’ terapija f’ kull pazjent.
Lopinavir and ritonavir levels may increase on stopping St John’ s wort.
Sussegwentement, il- pazjenti kollha komplew fuq id- doża ta ’ 300/ 75 mg kull m2.
The dose of Kaletra may need adjusting.
Il- linja bażi medja fl- għadd ta ’ ċelluli CD4 kienet ta ’ 838 ċellola/ mm3 u l- plażma HIV- 1 RNA fil- linja bażi medja kienet ta ’ 4. 7 log10 kopji/ ml.
The inducing effect may persist for at least 2 weeks after cessation of treatment with St John’ s wort (see section 4.3).
5. 2 Tagħrif farmakokinetiku
Midazolam: midazolam is extensively metabolised by CYP3A4.
Essenzjalment, lopinavir huwa kompletament metabolizzat minn CYP3A.
Co-administration with Kaletra may cause a large increase in the concentration of this benzodiazepine.
Ritonavir jimpedixxi l- metaboliżmu ta ’ lopinavir, b’ konsegwenza li jżid il- livelli fil- plażma ta ’ lopinavir.
A phenotyping cocktail study in 14 healthy volunteers showed an increase of AUC by about 13 fold with oral midazolam and an increase by about 4 fold with parenteral midazolam.
Matul l - istudji, l- għoti ta ’ Kaletra 400/ 100 mg darbtejn kuljum iħalli, f’ pazjenti nfettati bl- HIV, medja fissa tal - konċentrazzjoni fil- plażma ta ’ liponavir minn 15 sa 20 darba aktar għolja minn dawk ta ’ ritonavir.
Therefore, Kaletra should not be co-administered with orally administered midazolam (see section 4.3), whereas caution should be used with co-administration of Kaletra and parenteral midazolam.
Il - livelli fil- plażma ta ’ ritonavir huma inqas minn 7% ta ’ dawk miksuba wara d- doża ta ’ ritonavir ta ’ 600 mg darbtejn kuljum.
If Kaletra is co-administered with parenteral midazolam, it should be done in an intensive care unit (ICU) or similar setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/ or prolonged sedation.
L- EC50 antivirali in vitro ta ’ lopinavir huwa bejn wieħed u ieħor 10 darbiet inqas minn dak ta ’ ritonavir.
Dosage adjustment for midazolam should be considered especially if more than a single dose of midazolam is administered.
Għalhekk, l- attività antivirali ta ’ Kaletra hija dovuta lil lopinavir.
Fluticasone propionate (interaction with ritonavir): in a clinical study where ritonavir 100 mg capsules twice daily were co − administered with 50 μ g intranasal fluticasone propionate (4 times daily) for seven days in healthy subjects, the fluticasone propionate plasma levels increased significantly, whereas the intrinsic cortisol levels decreased by approximately 86% (90% confidence interval 82 − 89%).
Assorbiment: dożaġġ multiplu b’ 400/ 100 mg Kaletra darbtejn kuljum għal 3 sa 4 ġimgħat u mingħajr restrizzjoni fuq l- ikel, ipproduċa ± SD ta ’ l- ogħla konċentrazzjoni fil- plażma ta ’ lopinavir (Cmax) medja ta ’ 9. 6 ± 4. 4 μg/ ml, li ntlaħqet bejn wieħed u ieħor 4 siegħat wara li ġie meħud id- dożaġġ.
Greater effects may be expected when fluticasone propionate is inhaled.
Il - konċentrazzjoni minimali medja fissa qabel id- doża ta ’ filgħodu kienet ta ’ 5. 5 ± 4. 0 μg/ ml.
Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate; this could also occur with other corticosteroids metabolised via the P450 3A pathway eg budesonide.
Il - bijodisponibilità assoluta ta ’ lopinavir ko- formulat ma ’ ritonavir fil- bniedem ma ’ ġietx stabbilita.
Consequently, concomitant administration of Kaletra and these glucocorticoids is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects (see section 4.4).
Effetti ta ’ l- ikel fuq l- assorbiment mill- ħalq: it- teħid ta ’ doża waħda ta ’ 400/ 100 mg tal- pilloli Kaletra f’ kundizzjonijiet fejn il- pazjent ikun kiel (ammont għoli ta ’ xaħam, 872 kcal, 56% mix- xaħam) meta mqabbel ma ’ stat fejn il- pazjent ikun sajjem, ma kien assoċjat ma ’ l- ebda tibdil sinfikanti fis- Cmax u fl - AUCinf.
A dose reduction of the glucocorticoid should be considered with close monitoring of local and systemic effects or a switch to a glucocorticoid, which is not a substrate for CYP3A4 (eg beclomethasone).
Il- pilloli Kaletra urew ukoll inqas varjabilità farmakokinetika taħt kundizzjonijiet fejn il- pazjent ikun kiel, meta mqabbel mal- kapsuli rotob Kaletra.
Moreover, in case of withdrawal of glucocorticoids progressive dose reduction may have to be performed over a longer period.
Distribuzzjoni: fi stat fiss, lopinavir huwa bejn wieħed u ieħor 98 - 99% marbut mal- proteini tas- serum.
The effects of high fluticasone systemic exposure on ritonavir plasma levels is yet unknown.
Lopinavir jingħaqad ma ’ l- aċidu glikoproteina alpha- 1( AAG) u ma ’ l- albumina, imma għandu affinità ogħla għall- AAG.
72 Based on known metabolic profiles, clinically significant interactions are not expected between Kaletra and fluvastatin, dapsone, trimethoprim/ sulfamethoxazole, azithromycin or fluconazole.
Lopinavir huwa, fil- biċċa l- kbira tiegħu, metabolizzat mis- sistema ċitokroma P450 tal- fwied, kważi esklussivament mill- iżożima CYP3A.
4.6 Pregnancy and lactation
92 żgħar ħafna mit- total kollu tar- radjoattività fil- plażma.
There are no data from the use of Kaletra in pregnant women.
Wara dożaġġ multiplu, inqas minn 3% tad- doża ta ’ lopinavir hija mneħħija bħala mhux mibdula fl- awrina.
Studies in animals have shown reproductive toxicity (see section 5.3).
Il- half- life effettiva ta ’ lopinavir (mill- massimu sal- minimu) matul intervall ta ’ dożaġġ ta ’ 12 - il siegħa, kellu medja ta ’ 5 - 6 siegħat, u t- tneħħija orali evidenti (CL/ F) ta ’ lopinavir hi minn 6 sa 7 l/ siegħa.
The potential risk for humans is unknown.
Hemm tagħrif farmakokinetiku limitat fi tfal ta ’ taħt is- sentejn.
Kaletra should not be used during pregnancy unless clearly necessary.
Il- farmakokinetika tas- soluzzjoni orali Kaletra 300/ 75 mg/ m2 darbtejn kuljum u 230/ 57. 5 mg/ m2 darbtejn kuljum ġiet studjata f’ total ta ’ 53 pazjent pedjatriku, li jvarjaw fl- età minn 6 xhur sa 12 - il sena.
Studies in rats revealed that lopinavir is excreted in the milk.
Il- farmakokinetika ta ’ Kaletra ma ’ ġietx studjata fl- anzjani.
It is not known whether this medicinal product is excreted in human milk.
F’ pazjenti adulti ma ’ ġew innutati l- ebda differenzi farmakokinetiċi li huma relatati ma ’ l- età jew mas- sess.
HIV infected women must not breast-feed their infants under any circumstances to avoid transmission of HIV.
Ma ’ ġewx identifikati differenzi farmakokinetiċi relatati mar- razza.
4.7 Effects on ability to drive and use machines
Insuffiċjenza Renali:
Patients should be informed that nausea has been reported during treatment with Kaletra (see section 4.8).
Il- farmakokinetika ta ’ Kaletra ma ’ ġietx studjata f’ pazjenti li jsofru minn insuffiċjenza renali; madanakollu, peress li t- tneħħija ta ’ lopinavir mill- kliewi hija negliġibbli, tnaqqis fit- total tat- tneħħija mill- ġisem m ’ hijiex mistennija f’ pazjenti li jbatu minn insuffiċjenza renali.
4.8 Undesirable effects
Insuffiċjenza tal- fwied:
The safety of Kaletra has been investigated in 612 patients in Phase II/ III clinical trials, of which 442 have received a dose of 400/ 100 mg twice daily.
Fi studju ta ’ dożi multipli b’ lopinavir/ ritonavir 400/ 100 mg darbtejn kuljum, il- parametri farmakokinetiċi fissi ta ’ lopinavir f’ pazjenti infettati bl- HIV li għandhom indeboliment tal- fwied minn ħafif sa moderat, ġew imqabbla ma ’ pazjenti infettati bl- HIV li għandhom funzjoni tal- fwied normali.
In some studies, Kaletra was used in combination with efavirenz or nevirapine.
Ġiet osservata żieda limitata ta ’ bejn wieħed u ieħor 30% fil- konċentrazzjonijiet totali ta ’ lopinavir, li mhix mistennija li tkun ta ’ rilevanza klinika (ara sezzjoni 4. 2).
The most common adverse reaction associated with Kaletra therapy was diarrhoea and was generally of mild to moderate severity.
L- anisoċitożi Coombs- negative u l- pojkiloċitożi ġew osservati fil - firien, iżda mhux fil- ġrieden u fil- klieb.
Discontinuation due to adverse reactions was 4.5% (naïve patients) and 9% (experienced patients) over a 48 week period.
Il- kolesterol fis- serum żdied fil- gerriema iżda mhux fil- klieb, waqt li t- trigliċeridi żdiedu biss fil- ġrieden.
It is important to note that cases of pancreatitis have been reported in patients receiving Kaletra, including those who developed hypertriglyceridaemia.
B’ kuntrast għal dan, konċentrazzjoni simili ta ’ lopinavir/ ritonavir ma ’ uriet l- ebda dewmien fir- ripolarizzazjoni fil- fibri kardijaċi Purkinje tal- klieb.
Furthermore, rare increases in PR interval have been reported during Kaletra therapy (see section 4.4: sections pancreatitis and lipid elevations).
Konċentrazzjoni iktar baxxa ta ’ lopinavir/ ritonavir ma ’ ipproduċitx imblokk kurrenti għall- potassju (HERG) li hu sinifikanti.
Increased CPK, myalgia, myositis, and rarely, rhabdomyolysis have been reported with protease inhibitors, particularly in combination with nucleoside reverse transcriptase inhibitors.
Studji dwar id- distribuzzjoni tat- tessuti li saru fuq il - far, ma ’ issuġġerewx żamma kardijaka sinifikanti tas- sustanza attiva; 72 siegħa AUC fil- qalb kienet bejn wieħed u ieħor 50% tal- plażma AUC imkejla.
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).
Huwa preżunt li dawn l- effetti huma kkawżati minn disturb kkawżat mill - elettrolit.
Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (see section 4.4).
Ir- rilevanza klinika ta ’ dan it- tagħrif ta ’ qabel l- użu kliniku għada mhix magħrufa, madanakollu, l- effetti kardijaċi li jistgħu jirriżultaw b’ dan il- prodott fil- bniedem ma jistgħux jiġu esklużi (ara ukoll sezzjoni 4. 4 u 4. 8).
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).
Fil- firien, it- tossiċità fil- fetu u fl- embriju (telf ta ’ tqala, tnaqqis fil- vijabilità tal- fetu, tnaqqis fil- piżijiet totali tal- ġisem tal- fetu, frekwenza akbar ta ’ varjazzjonijiet skeletriċi) u t- tossiċità li tiżviluppa wara t - twelid (tnaqqis fis- sopravivenza taż- żgħar) ġew osservati f’ dożaġġi li huma tossiċi għall- omm.
Adult patients
Studji karċinoġeniċi ta ’ lopinavir/ ritonavir fil- ġrieden li saru fuq perijodu twil, żvelaw induzzjoni mhux ġenotossika u mitoġenika ta ’ tumuri fil- fwied, li ġeneralment huma kkunsidrati li għandhom ftit rilevanza għar- riskju għall bniedem.
The adverse reactions are displayed by system organ class.
Studji karċinoġeniċi fil- firien ma ’ żvelaw l- ebda sejbiet tumoriġeniċi.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness: very common > 1/ 10, common > 1/ 100 ,< 1/10, uncommon > 1/ 1000, < 1/ 100.
F’ serje sħiħa ta ’ analiżi in vitro u in vivo, inklużi l- analiżi Ames bacterial reverse mutation, l- analiżi tal- limfoma fil- ġurdien, it- test tal - mikronukleu fil- ġurdien u l- analiżi tat- telfien tal- kromosomi fil- limfoċiti umani, lopinavir/ ritonavir ma ’ instabx li hu mutaġeniku jew klastoġeniku
73 Undesirable effects in clinical studies in adult patients Infections and infestations
TAGĦRIF FARMAĊEWTIKU
Uncommon
6. 1 Lista ta ’ sustanzi mhux attivi
Otitis media, bronchitis, sinusitis, furunculosis, bacterial infection, viral infection
Copovidone Sorbitan laurate Colloidal anhydrous silica Sodium stearyl fumarate
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Polimer ta ’ l- alkoħol (Polyvinyl alcohol) Dijossidu tat- titanju Talkum Macrogols tat- tip 3350 (glikolu tal- polyethylene 3350) Ossidu isfar tal- ħadid (Yellow ferric oxide) E172
Uncommon
6. 2 Inkompatibilitajiet
Skin benign neoplasm, cyst
Ma jgħoddx f’ dan il- każ.
Blood and lymphatic system disorders
6. 3 Żmien kemm idum tajjeb il- prodott mediċinali
Uncommon
Sentejn.
Anaemia, leucopenia and lymphadenopathy
6. 4 Prekawzjonijiet speċjali għall- ħażna
Endocrine disorders
Din il- mediċina m’ għandhiex bżonn ħażna speċjali.
Uncommon
6. 5 In- natura tal- kontenitur u ta ’ dak li hemm ġo fih
Hypogonadism male, Cushing syndrome, hypothyroidism
Kull pakkett fih flixkun wieħed (60 pillola).
Metabolic and nutritional disorders
6. 6 Prekawzjonijiet speċjali li għandhom jittieħdu meta jintrema < u għal immaniġġar ieħor >
Uncommon
L- ebda ħtiġijiet speċjali.
Avitaminosis, dehydration, oedema, increased appetite, lactic acidosis, obesity, anorexia, diabetes mellitus, hyperglycaemia, hypocholesteremia
ID- DETENTUR TA ’ L- AWTORIZZAZZJONI GĦAT- TQEGĦID FIS- SUQ
Psychiatric disorders
Abbott Laboratories Limited Queenborough Kent ME11 5EL Renju Unit
Insomnia
EU/ 1/ 01/ 172/ 00
Uncommon
95 9.
Abnormal dreams, agitation, anxiety, confusion, depression, dyskinesia, emotional lability, decreased libido, nervousness, abnormal thinking
20 Marzu 2001 Data ta ’ l- aħħar tiġdid:
Nervous system disorders
20 ta ’ Marzu 2006
Headache, paresthesia
96 ANNESS II
Uncommon
A.
Dizziness, amnesia, ataxia, encephalopathy, facial paralysis, hypertonia, neuropathy, peripheral neuritis, somnolence, tremor, taste loss, taste perversion, migraine, extrapyramidal syndrome
KUNDIZZJONIJIET TA 'L- AWTORIZZAZZJONI GĦAT - TQEGĦID FIS- SUQ
Eye disorders Ear and labyrinth disorders Cardiac disorders Vascular disorders
DETENTUR TA ’ L- AWTORIZZAZZJONI TAL- MANIFATTURA RESPONSABBLI MILL- HRUĠ TAL- LOTT
Uncommon Uncommon Uncommon Uncommon
Isem u indirizz tal- manifattur( i) responsabbli għall- ħruġ tal- lott.
Abnormal vision, eye disorder Tinnitus Palpitation, lung oedema, myocardial infarct1 Hypertension, thrombophlebitis, vasculitis, varicose vein, deep thrombophlebitis, vascular disorder
Kaletra soluzzjoni orali, Kaletra kapsuli rotob, Kaletra pilloli miksija b’ rita Aesica Queenborough Limited, Queenborough, Kent ME11 5EL, Renju Unit.
Respiratory, thoracic and mediastinal disorders
Kaletra pilloli miksija b’ rita Abbott GmbH & Co.
Dyspnoea, rhinitis, cough increased
KG, Knollstrasse, 67061 Ludwigshafen, Ġermanja
Gastrointestinal disorders
Fuq il- fuljett ta 'tagħrif tal- prodott mediċinali għandu jkun hemm l- isem u l- indirizz tal- manifattur responsabbli mill- ħruġ tal- lott konċernat.
Common
B.
Nausea, vomiting, abdominal pain, abnormal stools, dyspepsia, flatulence, gastrointestinal disorder
• KUNDIZZJONIJIET JEW RESTRIZZJONIJIET FUQ IL- FORNIMENT U L- UŻU IMPOSTI FUQ ID- DETENTUR TA ’ L- AWTORIZZAZZJONI GĦAT- TQEGĦID FIS - SUQ
Uncommon
Sommarju tal- Karatteristiċi tal - Prodott, sezzjoni 4. 2)
Abdomen enlarged, constipation, dry mouth, dysphagia, enterocolitis, eructation, oesophagitis, faecal incontinence, gastritis, gastroenteritis, haemorrhagic colitis, mouth ulcerations, pancreatitis2, sialadenitis, stomatitis, ulcerative stomatitis, periodontitis
• KUNDIZZJONIJIET JEW RESTRIZZJONIJIET FIR- RIGWARD TA ’ L- UŻU MINGĦAJR PERIKLU U EFFETTIV TAL- PRODOTT MEDIĊINALI
Hepatobiliary disorders
Ma jgħoddx f’ dan il- każ.
Uncommon
• KUNDIZZJONIJIET OĦRA
Skin and subcutaneous tissue disorders
Is- sistema ta ’ farmakoviġilanza
Common
Id- Detentur ta ’ l- Awtorizzazzjoni għat- Tqegħid fis- Suq għandu jassigura li, is- sistema ta ’ famakoviġilanza, kif deskritta f’ verżjoni 2 ippreżentata f’ Modulu 1. 8. 1 ta ’ l- Applikazzjoni ta ’ l - Awtorizzazzjoni għat- Tqegħid fis- Suq, hija kif għandha tkun u taħdem tajjeb kemm qabel, kif ukoll waqt li l- prodott ikun fis- suq.
Rash, lipodystrophy, acne
Il- Pjan Dwar l- Immaniġġar tar- Riskju
Uncommon
Id- Detentur ta ’ l- Awtorizzazzjoni għat- Tqegħid fis- Suq jikkommetti ruħu sabiex iwettaq l- istudji u l - attivitajiet farmakoviġilanti addizzjonali li jinsabu imniżżla fid- dettall fil- Pjan ta ’ Farmakoviġilanza, kif mifthiem f’ verżjoni 2. 3 tal- Pjan Dwar l- Immaniġġar tar- Riskju (RMP) ippreżentat f’ Modulu 1. 8. 2. ta ’ l- Applikazzjoni ta ’ l- Awtorizzazzjoni għat- Tqegħid fis- Suq, u aġġornamenti sussegwenti oħra ta ’ l - RMP aċċettati mis- CHMP.
Alopecia, dry skin, eczema, exfoliative dermatitis, maculopapular rash, nail disorder, pruritis, seborrhoea, skin discoloration, skin ulcer, face oedema, sweating, skin striae
Skond il- Linja Gwida tas- CHMP li tittratta dwar is- Sistemi ta ’ l- Immaniġġar tar- Riskju għal prodotti mediċinali magħmula għall- użu mill- bniedem, il- RMP aġġornat għandu jiġi ssottomettat flimkien mar - Rapport Perjodiku ta’ Aġġornamenti dwar is- Sigurtà (PSUR).
74 Musculoskeletal and connective tissue disorders
98 Barra minn dan, għandu jiġi ssottomettat RMP aġġornat • meta jkun hemm informazzjoni ġdida li tista ’ taffetwa l- Ispeċifikazzjoni dwar is- Sigurtà applikabbli bħalissa, il- Pjan ta ’ Farmakoviġilanza jew attivitajiet relatati mat- tnaqqis tar - riskju • fi żmien 60 ġurnata mid- data meta jseħħ avveniment importanti (relatat ma ’ farmakoviġilanza jew ma ’ tanqqis tar- riskju) • fuq talba ta ’ l- EMEA
Arthralgia, arthrosis, myalgia, back pain, joint disorder
Rapporti Perjodiċi ta ’ Aġġornament dwar is- Sigurtà
Renal and urinary disorders
Id- detentur ta ’ l- awtorizzazzjoni għat- tqegħid fis- suq għandu jinbgħat PSUR Periodic Safety Update Report, darba fis- sena.
Uncommon
99 ANNESS III
Reproductive system and breast disorders
TIKKETTA U FULJETT TA ’ TAGĦRIF
Uncommon
TIKKETTA
Abnormal ejaculation, amenorrhoea, breast enlargement, gynecomastia, impotence, menorrhagia
101 TAGĦRIF LI GĦANDU JIDHER FUQ IL- PAKKETT TA ’ BARRA
General disorders and administration site conditions
KAPSULI - KAXXA TA ’ 2 FLIXKEN
Asthenia, pain
Kaletra 133. 3 mg/ 33. 3 mg kapsuli rotob lopinavir/ ritonavir
Chest pain, chest pain substernal, chills, fever, flu syndrome, malaise, peripheral oedema, drug interaction
Kull kapsula ratba fiha: lopinavir 133. 3 mg u ritonavir 33. 3 mg (qanqiel farmakokinetiku).
Very common (Grade 3 or 4)
LISTA TA ’ SUSTANZI MHUX ATTIVI
Increased triglycerides, increased total cholesterol, increased GGT
Fih fost oħrajn: propylene glycol, polyoxyl 35 castor oil, anhydrized liquid sorbitol (taħlita ta ’ sorbitol, sorbitol anhydrides u mannitol), glycerol u sunset yellow (E110).
Increased glucose, increased amylase, increased
GĦAMLA FARMAĊEWTIKA U KONTENUT
Common (Grade 3 or 4)
180 kapsuli rotob (2 flixken ta ’ 90 kapsula il- waħda)
SGOT/ AST, increased SGPT/ ALT, liver function tests abnormal
MOD TA ’ KIF U MNEJN JINGĦATA
Decreased glucose tolerance, weight gain, 1 2
Jittieħed mill- ħalq Aqra il- fuljett ta ’ tagħrif qabel l- użu
This event had a fatal outcome.
Żomm fejn ma jintlaħaqx u ma jidhirx mit- tfal
weight loss, increased bilirubin, hormone level altered, lab test abnormal
Għatu li ma jinfetaħx mit- tfal
See section 4.4: pancreatitis and lipids
DATA TA ’ META JISKADI
Paediatric patients
JIS: {XX/ SS}
In children 2 years of age and older, the nature of the safety profile is similar to that seen in adults.
KUNDIZZJONIJIET SPEĊJALI TA 'KIF JINĦAŻEN
Undesirable effects in clinical studies in paediatric patients Infections and infestations
Huwa rrikmandat li tikteb id- data tat- tneħħija mill - friġġ fuq il- pakkett ta ’ barra.
Nervous system disorders
Abbott Laboratories Limited Queenborough Kent ME11 5EL Renju Unit
Gastrointestinal disorders
NUMRU TAL- LOTT
Common
Lott:
Constipation, vomiting, pancreatitis*
KLASSIFIKAZZJONI ĠENERALI TA ’ KIF JINGĦATA
Hepatobiliary disorders
Prodott mediċinali jingħata bir- riċetta tat- tabib.
Hepatomegaly
INFORMAZZJONI BIL- BRAILLE
Skin and subcutaneous tissue disorders
103 TAGĦRIF LI GĦANDU JIDHER FUQ IL- PAKKETT LI JMISS MAL- PRODOTT
Common
KAPSULI - FLIXKUN
Rash, dry skin
ISEM TAL- PRODOTT MEDIĊINALI
General disorders and administration site conditions
Kaletra 133. 3 mg/ 33. 3 mg kapsuli rotob lopinavir/ ritonavir
Investigations
Kull kapsula ratba fiha: lopinavir 133. 3 mg u ritonavir 33. 3 mg (qanqiel farmakokinetiku).
Common (Grade 3 or 4)
LISTA TA ’ SUSTANZI MHUX ATTIVI
Increased activated partial thromboplastin time, decreased haemoglobin, decreased platelets, increased sodium, increased potassium, increased calcium, increased bilirubin, increased SGPT/ ALT, increased SGOT/ AST, increased total cholesterol, increased amylase, increased uric acid, decreased sodium, decreased potassium, decreased calcium, decreased neutrophils
Fih fost oħrajn: propylene glycol, polyoxyl 35 castor oil, anhydrized liquid sorbitol (taħlita ta ’ sorbitol, sorbitol anhydrides u mannitol), glycerol u sunset yellow (E110).
*see section 4.4: pancreatitis and lipids
GĦAMLA FARMAĊEWTIKA U KONTENUT
75 Post marketing experience
90 kapsuli rotob
Hepatitis, and rarely jaundice, have been reported in patients on Kaletra therapy in the presence or absence of identifiable risk factors for hepatitis.
MOD TA ’ KIF U MNEJN JINGĦATA
Stevens-Johnson syndrome and erythema multiforme have been reported.
Jittieħed mill- ħalq Aqra il- fuljett ta ’ tagħrif qabel l- użu
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).
TWISSIJA SPEĊJALI LI L- PRODOTT MEDIĊINALI GĦANDU JINŻAMM FEJN MA JINTLAĦAQX U MA JIDHIRX MIT- TFAL
To date, there is limited human experience of acute overdose with Kaletra.
Żomm fejn ma jintlaħaqx u ma jidhirx mit- tfal
The adverse clinical signs observed in dogs included salivation, emesis and diarrhoea/ abnormal stool.
TWISSIJA/ IET SPEĊJALI OĦRA, JEKK MEĦTIEĠA
There is no specific antidote for overdose with Kaletra.
Għatu li ma jinfetaħx mit- tfal
PHARMACOLOGICAL PROPERTIES
DATA TA ’ META JISKADI
5.1 Pharmacodynamic properties
JIS: {XX/ SS}
J05AE06
104 9.
Mechanism of action: lopinavir provides the antiviral activity of Kaletra.
KUNDIZZJONIJIET SPEĊJALI TA 'KIF JINĦAŻEN Aħżen f’ temperatura ta ’ bejn 2°C – 8°C (fil- friġġ) Ħażna waqt l- użu:
Lopinavir is an inhibitor of the HIV-1 and HIV-2 proteases.
Jekk miżmum barra mill- friġġ, Taħżinx f’ temperatura 'l fuq minn 25°C u armi l - kontenut mhux użat wara 42 ġurnata (6 ġimgħat).
Inhibition of HIV protease prevents cleavage of the gag-pol polyprotein resulting in the production of immature, non-infectious virus.
Evita l- esponiment għall- sħana eċċessiva.
The maximum mean (95% upper confidence bound) differences in QTcF from placebo were 3.6 (6.3) and 13.1(15.8) for 400/ 100 mg twice daily and supratherapeutic 800/ 200 mg twice daily LPV/ r, respectively.
PREKAWZJONIJIET SPEĊJALI GĦAR- RIMI TA ’ PRODOTTI MEDIĊINALI MHUX UŻATI JEW SKART MINN DAWN IL- PRODOTTI MEDIĊINALI, JEKK HEMM BŻONN
The induced QRS interval prolongation from 6 ms to 9.5 ms with high dose lopinavir/ ritonavir (800/ 200 mg twice daily) contributes to QT prolongation.
ISEM U INDIRIZZ TAD- DETENTUR TA ’ L- AWTORIZZAZZJONI GĦAT- TQEGĦID FIS- SUQ
Modest prolongation of the PR interval was also noted in subjects receiving lopinavir/ ritonavir in the same study on Day 3.
Abbott Laboratories Limited Queenborough Kent ME11 5EL Renju Unit
Maximum PR interval was 286 msec and no second or third degree heart block was observed (see section 4.4).
NUMRU( I) TA ’ L- AWTORIZZAZZJONI GĦAT- TQEGĦID FIS- SUQ
76 lopinavir against HIV-1IIIB in MT4 cells was 17 nM and 102 nM, respectively.
13.
Resistance
NUMRU TAL- LOTT
In vitro selection of resistance:
Lott:
HIV-1 isolates with reduced susceptibility to lopinavir have been selected in vitro.
14.
Analysis of resistance in ARV-naïve patients:
KLASSIFIKAZZJONI ĠENERALI TA ’ KIF JINGĦATA
Lack of resistance to lopinavir was confirmed by phenotypic analysis.
Prodott mediċinali jingħata bir- riċetta tat- tabib.
Analysis of resistance in PI-experienced patients:
STRUZZJONIJIET DWAR L- UŻU
Mutations V82A, I54V and M46I emerged most frequently.
INFORMAZZJONI BIL- BRAILLE
L10F/ I/ R/ V, K20M/ R, L24I, M46I/ L, F53L, I54L/ T/ V, L63P, A71I/ L/ T/ V, V82A/ F/ T, I84V and L90M.
105 TAGĦRIF LI GĦANDU JIDHER FUQ IL- PAKKETT TA ’ BARRA
In addition, virologic response was observed in 91% (21/ 23), 71% (15/ 21) and 33% (2/ 6) patients with 0 − 5, 6 − 7, and 8 − 10 mutations of the above mutations in HIV protease associated with reduced in vitro susceptibility to lopinavir.
KAPSULI – PAKKETT TA ’ 180 (5 KAXXI B’ 6 FULJETTI TA ’ 6 KAPSULI)
Cross-resistance:
1.
Clinical pharmacodynamic data
ISEM TAL- PRODOTT MEDIĊINALI
Patients without prior antiretroviral therapy
Kaletra 133. 3 mg/ 33. 3 mg kapsuli rotob lopinavir/ ritonavir
2.6 to 6.8 log10 copies/ ml).
DIKJARAZZJONI TAS- SUSTANZA( I) ATTIVA
One hundred patients were originally treated with Kaletra in the study (including 51 patients receiving 400/ 100 mg twice daily and 49 patients at either 200/ 100 mg twice daily or 400/ 200 mg twice daily).
Kull kapsula ratba fiha: lopinavir 133. 3 mg u ritonavir 33. 3 mg (qanqiel farmakokinetiku).
78 dose between week 48 and week 72.
LISTA TA ’ SUSTANZI MHUX ATTIVI
Thirty-nine patients (39%) discontinued the study, including 16 (16%) discontinuations due to adverse events, one of which was associated with a death.
Fih fost oħrajn: propylene glycol, polyoxyl 35 castor oil, anhydrized liquid sorbitol (taħlita ta ’ sorbitol, sorbitol anhydrides u mannitol), glycerol u sunset yellow (E110).
Patients with prior antiretroviral therapy
GĦAMLA FARMAĊEWTIKA U KONTENUT
Median baseline CD4 cell count was 220 cells/ mm3 (range 13 to 1030 cells/ mm3).
180 kapsuli rotob (5 kaxxi b’ 6 fuljetti ta ’ 6 kapsuli)
Paediatric Use
MOD TA ’ KIF U MNEJN JINGĦATA
All patients were non-nucleoside reverse transcriptase inhibitor naïve.
Jittieħed mill- ħalq Aqra il- fuljett ta ’ tagħrif qabel l- użu
Patients were randomised to either 230 mg lopinavir/ 57.5 mg ritonavir per m2 or 300 mg lopinavir/ 75 mg ritonavir per m2.
TWISSIJA SPEĊJALI LI L- PRODOTT MEDIĊINALI GĦANDU JINŻAMM FEJN MA JINTLAĦAQX U MA JIDHIRX MIT- TFAL
Naïve patients also received nucleoside reverse transcriptase inhibitors.
Żomm fejn ma jintlaħaqx u ma jidhirx mit- tfal
Subsequently, all patients were continued on the 300/ 75 mg per m2 dose.
TWISSIJA/ IET SPEĊJALI OĦRA, JEKK MEĦTIEĠA
Mean baseline CD4 cell count was 838 cells/ mm3 and mean baseline plasma HIV-1 RNA was 4.7 log10 copies/ ml.
Għatu li ma jinfetaħx mit- tfal
5.2 Pharmacokinetic properties
DATA TA ’ META JISKADI
Lopinavir is essentially completely metabolised by CYP3A.
KUNDIZZJONIJIET SPEĊJALI TA 'KIF JINĦAŻEN
Ritonavir inhibits the metabolism of lopinavir, thereby increasing the plasma levels of lopinavir.
Aħżen f’ temperatura ta ’ bejn 2°C – 8°C (fil- friġġ) Ħażna waqt l- użu:
The plasma levels of ritonavir are less than 7% of those obtained after the ritonavir dose of 600 mg twice daily.
Jekk miżmum barra mill- friġġ, Taħżinx f’ temperatura 'l fuq minn 25°C u armi l - kontenut mhux użat wara 42 ġurnata (6 ġimgħat).
The in vitro antiviral EC50 of lopinavir is approximately 10-fold lower than that of ritonavir.
Huwa rrikmandat li tikteb id- data tat- tneħħija mill - friġġ fuq il- pakkett ta ’ barra.
Therefore, the antiviral activity of Kaletra is due to lopinavir.
Evita l- esponiment għall- sħana eċċessiva.
79 Absorption: multiple dosing with 400/ 100 mg Kaletra twice daily for 3 to 4 weeks and without meal restriction produced a mean ± SD lopinavir peak plasma concentration (Cmax) of 9.6 ± 4.4 μ g/ ml, occurring approximately 4 hours after administration.
PREKAWZJONIJIET SPEĊJALI GĦAR- RIMI TA ’ PRODOTTI MEDIĊINALI MHUX UŻATI JEW SKART MINN DAWN IL- PRODOTTI MEDIĊINALI, JEKK HEMM BŻONN
The mean steady-state trough concentration prior to the morning dose was 5.5 ± 4.0 μ g/ ml.
ISEM U INDIRIZZ TAD- DETENTUR TA ’ L- AWTORIZZAZZJONI GĦAT- TQEGĦID FIS- SUQ
The absolute bioavailability of lopinavir co-formulated with ritonavir in humans has not been established.
NUMRU( I) TA ’ L- AWTORIZZAZZJONI GĦAT- TQEGĦID FIS- SUQ
At least 13 lopinavir oxidative metabolites have been identified in man.
NUMRU TAL- LOTT
The 4-oxo and 4-hydroxymetabolite epimeric pair are the major metabolites with antiviral activity, but comprise only minute amounts of total plasma radioactivity.
Lott:
Pre-dose lopinavir concentrations decline with time during multiple dosing, stabilising after approximately 10 days to 2 weeks.
KLASSIFIKAZZJONI ĠENERALI TA ’ KIF JINGĦATA
Unchanged lopinavir accounted for approximately 2.2% and 19.8% of the administered dose in urine and faeces, respectively.
Prodott mediċinali jingħata bir- riċetta tat- tabib.
After multiple dosing, less than 3% of the lopinavir dose is excreted unchanged in the urine.
107 TAGĦRIF LI GĦANDU JIDHER FUQ IL- PAKKETT TA ’ BARRA
The effective (peak to trough) half-life of lopinavir over a 12 hour dosing interval averaged 5 − 6 hours, and the apparent oral clearance (CL/ F) of lopinavir is 6 to 7 l/ h.
KAPSULI – KAXXA TA ’ 36 KAPSULA (6 FOLJI TA ’ 6 KAPSULI)
Paediatrics:
Kaletra 133. 3 mg/ 33. 3 mg kapsuli rotob lopinavir/ ritonavir
Gender, Race and Age:
DIKJARAZZJONI TAS- SUSTANZA( I) ATTIVA
No age or gender related pharmacokinetic differences have been observed in adult patients.
Kull kapsula ratba fiha: lopinavir 133. 3 mg u ritonavir 33. 3 mg (qanqiel farmakokinetiku).
80 Renal Insufficiency:
LISTA TA ’ SUSTANZI MHUX ATTIVI
Kaletra pharmacokinetics have not been studied in patients with renal insufficiency; however, since the renal clearance of lopinavir is negligible, a decrease in total body clearance is not expected in patients with renal insufficiency.
Fih fost oħrajn: propylene glycol, polyoxyl 35 castor oil, anhydrized liquid sorbitol (taħlita ta ’ sorbitol, sorbitol anhydrides u mannitol), glycerol u sunset yellow (E110).
Hepatic Insufficiency:
GĦAMLA FARMAĊEWTIKA U KONTENUT
A limited increase in total lopinavir concentrations of approximately 30% has been observed which is not expected to be of clinical relevance (see section 4.2).
36 kapsuli rotob (6 fuljetti ta ’ 6 kapsuli)
5.3 Preclinical safety data
MOD TA ’ KIF U MNEJN JINGĦATA
Hepatic changes indicated cellular swelling with focal degeneration.
Jittieħed mill- ħalq Aqra il- fuljett ta ’ tagħrif qabel l- użu
Reduced serum thyroxine led to an increased release of TSH with resultant follicular cell hypertrophy in the thyroid glands of rats.
TWISSIJA SPEĊJALI LI L- PRODOTT MEDIĊINALI GĦANDU JINŻAMM FEJN MA JINTLAĦAQX U MA JIDHIRX MIT- TFAL
These changes were reversible with withdrawal of the active substance and were absent in mice and dogs.
Żomm fejn ma jintlaħaqx u ma jidhirx mit- tfal
Coombs-negative anisocytosis and poikilocytosis were observed in rats, but not in mice or dogs.
TWISSIJA/ IET SPEĊJALI OĦRA, JEKK MEĦTIEĠA
Enlarged spleens with histiocytosis were seen in rats but not other species.
Għatu li ma jinfetaħx mit- tfal
Serum cholesterol was elevated in rodents but not dogs, while triglycerides were elevated only in mice.
KUNDIZZJONIJIET SPEĊJALI TA 'KIF JINĦAŻEN
In contrast, similar concentrations of lopinavir/ ritonavir demonstrated no repolarisation delay in the canine cardiac Purkinje fibres.
Aħżen f’ temperatura ta ’ bejn 2°C – 8°C (fil- friġġ) Ħażna waqt l- użu:
Lower concentrations of lopinavir/ ritonavir did not produce significant potassium (HERG) current blockade.
Jekk miżmum barra mill- friġġ, Taħżinx f’ temperatura 'l fuq minn 25°C u armi l - kontenut mhux użat wara 42 ġurnata (6 ġimgħat).
Tissue distribution studies conducted in the rat did not suggest significant cardiac retention of the active substance; 72-hour AUC in heart was approximately 50% of measured plasma AUC.
Huwa rrikmandat li tikteb id- data tat- tneħħija mill - friġġ fuq il- pakkett ta ’ barra.
Therefore, it is reasonable to expect that cardiac lopinavir levels would not be significantly higher than plasma levels.
Evita l- esponiment għall- sħana eċċessiva.
In dogs, prominent U waves on the electrocardiogram have been observed associated with prolonged PR interval and bradycardia.
PREKAWZJONIJIET SPEĊJALI GĦAR- RIMI TA ’ PRODOTTI MEDIĊINALI MHUX UŻATI JEW SKART MINN DAWN IL- PRODOTTI MEDIĊINALI, JEKK HEMM BŻONN
These effects have been assumed to be caused by electrolyte disturbance.
ISEM U INDIRIZZ TAD- DETENTUR TA ’ L- AWTORIZZAZZJONI GĦAT- TQEGĦID FIS- SUQ
The clinical relevance of these preclinical data is unknown, however, the potential cardiac effects of this product in humans cannot be ruled out (see also sections 4.4 and 4.8).
Abbott Laboratories Limited Queenborough Kent ME11 5EL Renju Unit
The systemic exposure to lopinavir/ ritonavir at the maternal and developmental toxic dosages was lower than the intended therapeutic exposure in humans.
NUMRU( I) TA ’ L- AWTORIZZAZZJONI GĦAT- TQEGĦID FIS- SUQ
Long-term carcinogenicity studies of lopinavir/ ritonavir in mice revealed a nongenotoxic, mitogenic induction of liver tumours, generally considered to have little relevance to human risk.
EU/ 1/ 01/ 172/ 002
Carcinogenicity studies in rats revealed no tumourigenic findings.
NUMRU TAL- LOTT
81 reverse mutation assay, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes.
Lott:
PHARMACEUTICAL PARTICULARS
KLASSIFIKAZZJONI ĠENERALI TA ’ KIF JINGĦATA
6.1 List of excipients
Prodott mediċinali jingħata bir- riċetta tat- tabib.
Tablet contents:
STRUZZJONIJIET DWAR L- UŻU
Film-coating:
INFORMAZZJONI BIL- BRAILLE
Polyvinyl alcohol Titanium dioxide Talc Macrogols type 3350 (Polyethylene glycol 3350) Yellow ferric oxide E172
109 TAGĦRIF MINIMU LI GĦANDU JIDHER FUQ L- ISTRIXXI JEW FUQ IL- FOLJI
6.2 Incompatibilities
KAPSULI – FOLJA TA ’ 6 KAPSULI
Not applicable.
ISEM TAL- PRODOTT MEDIĊINALI
6.3 Shelf life
Kaletra 133. 3 mg/ 33. 3 mg kapsuli rotob lopinavir/ ritonavir
6.4 Special precautions for storage
Abbott Laboratories Limited
This medicinal product does not require any special storage conditions.
DATA TA ’ META JISKADI
6.5 Nature and content of container
NUMRU TAL- LOTT
High density polyethylene (HDPE) bottles closed with propylene caps.
110 TAGĦRIF LI GĦANDU JIDHER FUQ IL- PAKKETT TA ’ BARRA
Each bottle contains 60 tablets.
PAKKETT TAS- SOLUZZJONI ORALI - 300 ml TA ’ SOLUZZJONI (5 FLIEXKEN TA ’ 60 ml KULL WIEĦED)
6.6 Special precautions for disposal
ISEM TAL- PRODOTT MEDIĊINALI
No special requirements.
Kaletra (80 mg + 20 mg) / ml soluzzjoni orali (lopinavir + ritonavir)
MARKETING AUTHORISATION HOLDER
DIKJARAZZJONI TAS- SUSTANZA( I) ATTIVA
Abbott Laboratories Limited Queenborough Kent ME11 5EL United Kingdom
Kull ml fih: lopinavir 80 mg u ritonavir 20 mg (qanqiel farmakokinetiku).
MARKETING AUTHORISATION NUMBERS
LISTA TA ’ SUSTANZI MHUX ATTIVI
EU/ 1/ 01/ 172/ 00
Fih fost oħrajn: alkoħol (42% v/ v ara l- fuljett), high fructose corn syrup, propylene glycol, glycerol, polyoxyl 40 hydrogenated castor oil, potassju (bħala axesulfame potassium)
DATE OF FIRST AUTHORISATION/ RENEWAL OF THE AUTHORISATION
GĦAMLA FARMAĊEWTIKA U KONTENUT
20 March 2006
300 ml ta ’ soluzzjoni (5 fliexken ta ’ 60 ml kull wieħed)
DATE OF REVISION OF THE TEXT
MOD TA ’ KIF U MNEJN JINGĦATA
{MM/ YYYY}
Jittieħed mill- ħalq Aqra il- fuljett ta ’ tagħrif qabel l- użu
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE
TWISSIJA SPEĊJALI LI L- PRODOTT MEDIĊINALI GĦANDU JINŻAMM FEJN MA JINTLAĦAQX U MA JIDHIRX MIT- TFAL
CONDITIONS OF THE MARKETING AUTHORISATION
Żomm fejn ma jintlaħaqx u ma jidhirx mit- tfal
84 A.
7.
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE
TWISSIJA/ IET SPEĊJALI OĦRA, JEKK MEĦTIEĠA
Name and address of the manufacturer(s) responsible for batch release
Għatu li ma jinfetaħx mit- tfal
Aesica Queenborough Limited, Queenborough, Kent ME11 5EL, United Kingdom
DATA TA ’ META JISKADI
Kaletra film-coated tablets:
JIS: {XX/ SS}
Abbott GmbH & Co.
111 9.
KG, Knollstrasse, 67061 Ludwigshafen, Germany
KUNDIZZJONIJIET SPEĊJALI TA 'KIF JINĦAŻEN
The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch.
Jekk miżmum barra mill- friġġ, Taħżinx f’ temperatura 'l fuq minn 25°C u armi l - kontenut mhux użat wara 42 ġurnata (6 ġimgħat).
CONDITIONS OF THE MARKETING AUTHORISATION
Evita l- esponiment għall- sħana eċċessiva.
• CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON THE MARKETING AUTHORISATION HOLDER
PREKAWZJONIJIET SPEĊJALI GĦAR- RIMI TA ’ PRODOTTI MEDIĊINALI MHUX UŻATI JEW SKART MINN DAWN IL- PRODOTTI MEDIĊINALI, JEKK HEMM BŻONN
Summary of Product Characteristics, 4.2).
ISEM U INDIRIZZ TAD- DETENTUR TA ’ L- AWTORIZZAZZJONI GĦAT- TQEGĦID FIS- SUQ
• CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
Abbott Laboratories Limited Queenborough Kent ME11 5EL Renju Unit
Not applicable.
12.
• OTHER CONDITIONS
EU/ 1/ 01/ 172/ 003
Pharmacovigilance system
NUMRU TAL- LOTT
The Marketing Authorisation Holder must ensure that the system of pharmacovigilance, as described in version 2 presented in Module 1.8.1 of the Marketing Authorisation Application, is in place and functioning before and whilst the product is on the market.
Lott:
Risk Management Plan
KLASSIFIKAZZJONI ĠENERALI TA ’ KIF JINGĦATA
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the updated RMP should be submitted at the same time as the next Periodic Safety Update Report (PSUR).
Prodott mediċinali jingħata bir- riċetta tat- tabib.
In addition, an updated RMP should be submitted • When new information is received that may impact on the current Safety Specification, Pharmacovigilance Plan or risk minimisation activities • Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being reached • At the request of the EMEA
STRUZZJONIJIET DWAR L- UŻU
Periodic Safety Update Reports
INFORMAZZJONI BIL- BRAILLE
The Marketing Authorisation Holder will submit Periodic Safety Update Reports on an annual cycle.
Kaletra
85 86 ANNEX III
112 TAGĦRIF LI GĦANDU JIDHER FUQ IL- PAKKETT LI JMISS MAL- PRODOTT