qanastek/EMEA-V3 huggingface dataset:
Hypogonadism male, Cushing syndrome, hypothyroidism
Palpitazzjoni, ilma fil- pulmun, Infart mijokardijaku1
Metabolic and nutritional disorders
Disturbi vaskulari
Avitaminosis, dehydration, oedema, increased appetite, lactic acidosis, obesity, anorexia, diabetes mellitus, hyperglycaemia, hypocholesteremia
Ipertensjoni, tromboflebite, vaskulite, vini varikożi, tromboflebite, problemi vaskulari
Psychiatric disorders
Disturbi respiratorji, toraċiċi u medjastinali
Insomnia
Qtugħ ta ’ nifs, riħ; żieda fis- sogħla
Uncommon
Disturbi Gastro- intestinali
Abnormal dreams, agitation, anxiety, confusion, depression, dyskinesia, emotional lability, decreased libido, nervousness, abnormal thinking
Komuni ħafna
Nervous system disorders
Diareja
Headache, paresthesia
Nawsja, vomtar, uġiegħ addominali, skart tal - ġisem mhux normali, ulċera fl- istonku, gass, problemi gastrointestinali
Dizziness, amnesia, ataxia, encephalopathy, facial paralysis, hypertonia, neuropathy, peripheral neuritis, somnolence, tremor, taste loss, taste perversion, migraine, extrapyramidal syndrome
Tinfiħ addominali, stitikezza, nixfa fil- ħalq, disfaġja, enterokolite erutazzjoni, esofaġite, inkontinenza ta ’ l- iskart tal- ġisem, gastrite, gastroenterite, kolite emorraġika, ulċerazzjoni tal- ħalq, pankreatite2, sialadenite, stomatite, stomatite ulċerativa, periodontite
Eye disorders Ear and labyrinth disorders Cardiac disorders Vascular disorders
Disturbi fil- fwied u fil- marrara
Uncommon Uncommon Uncommon Uncommon
Mhux komuni
Abnormal vision, eye disorder Tinnitus Palpitation, lung oedema, myocardial infarct1 Hypertension, thrombophlebitis, vasculitis, varicose vein, deep thrombophlebitis, vascular disorder
Koleċistite, epatite, epatomegalite, depositu tax- xaħam fil- fwied, sensittivita tal- fwied
Respiratory, thoracic and mediastinal disorders
Disturbi fil- ġilda u fit- tessuti ta ’ taħt il- ġilda
Dyspnoea, rhinitis, cough increased
Raxx, lipodistrofija, akne
Gastrointestinal disorders
Mhux komuni Mhux komuni
Very common
Qrugħa, ġilda niexfa, ekżema, dermatite esfoljativa, raxx makulopapulari, problemi tad- difer, prurite, seborreja, telf ta ’ kulur al - ġilda, ulċera tal- ġilda, edema tal- wiċċ, perspirazzjoni, strije fil- ġilda
Diarrhoea
Disturbi muskolu- skeltrali u tal - connective tissue
Common
Artralġja, artrożi, mialġja, uġigħ tad- dahar, Disturbi fil- ġogi
Nausea, vomiting, abdominal pain, abnormal stools, dyspepsia, flatulence, gastrointestinal disorder
Disturbi fil- kliewi u fis- sistema urinarja
Abdomen enlarged, constipation, dry mouth, dysphagia, enterocolitis, eructation, oesophagitis, faecal incontinence, gastritis, gastroenteritis, haemorrhagic colitis, mouth ulcerations, pancreatitis2, sialadenitis, stomatitis, ulcerative stomatitis, periodontitis
Ġebla fil- kliewi, urina mhux normali, albuminurja, iperkalċinurja, nefrite, iperuriċemija
Hepatobiliary disorders
Disturbi fis- sistema riproduttiva u fis- sider
Cholecystitis, hepatitis, hepatomegaly, liver fatty deposit, liver tenderness
Ejakulazzjoni mhux normali, amenorreja żieda fid- daqs tal- sider, ġinekomastja
54 Skin and subcutaneous tissue disorders
Disturbi ġenerali u kondizzjonijiet ta 'mnejn
Rash, lipodystrophy, acne
Astenja, uġigħ
Alopecia, dry skin, eczema, exfoliative dermatitis, maculopapular rash, nail disorder, pruritis, seborrhoea, skin discoloration, skin ulcer, face oedema, sweating, skin striae
Uġiegħ fis- sider, uġiegħ fis- sider substernali, dehx, deni, sindromu ta ’ l- influenza, tħossok mintix f’ siktek, edema periferali, interazzjoni ma mediċini oħra żieda fit- trigliċeridi, żieda fil- kolesterol totali,
Musculoskeletal and connective tissue disorders
(Grad 3 jew 4) żieda GGT Komuni
Uncommon
(Grad 3 jew 4)
Arthralgia, arthrosis, myalgia, back pain, joint disorder
żieda fil- glukożju, żieda fl- amilase, żieda
Renal and urinary disorders
SGOT/ AST, żieda SGPT/ ALT, testijiet tal -
Kidney calculus, urine abnormality, albuminuria, hypercalcinuria, nephritis, hyperuricemia
Khux komuni Tnaqqis fit- toleranza tal- glukożju, żieda fil - piż, tnaqqis fil- piż, żieda fil- bilirubin, livelli alterati ta ’ l- ormuni, testijiet tal- laboratorju mhux normali 1 Kellu effett fatali 2 ara sezzjoni 4. 4: pankreatite u lipidi
Reproductive system and breast disorders
62 Pazjenti Pedjatriċi
Uncommon
Infezzjoni virali
Abnormal ejaculation, amenorrhoea, breast enlargement, gynecomastia, impotence, menorrhagia
Disturbi fis- sistema nervuża Komuni Disturbi Gastro- Intestinali Komuni
General disorders and administration site conditions
Perverżjoni tat- togħma Stitikezza, vomtar, pankreatite *
Common
Disturbi fil- fwied u fil- marrara
Asthenia, pain
Komuni
Uncommon
Tkabbir fid- daqs tal- fwied
Chest pain, chest pain substernal, chills, fever, flu syndrome, malaise, peripheral oedema, drug interaction
Disturbi fil- ġilda u fit- tessuti ta ’ taħt il- ġilda
Investigations
Komuni
Very common (Grade 3 or 4)
Raxx, ġilda niexfa
Increased triglycerides, increased total cholesterol, increased GGT
Disturbi ġenerali u kondizzjonijiet ta 'mnejn jingħata
Increased glucose, increased amylase, increased
Investigazzjonijiet
SGOT/ AST, increased SGPT/ ALT, liver function tests abnormal
Żieda fil- ħin parzjali attivat tat - tromboplastina, tnaqqis fl- emoglobina, tnaqqis fil- pjastrini, żieda fis- sodju, żieda fil - potassju, żieda fil- kalċju, żieda fil- bilirubin, żieda fi SGPT/ ALT, żieda fi SGOT/ AST, żieda fil- kolosterol total, żieda fl- amilase, żieda fl- aċidu uriku, tnaqqis fis- sodju, tnaqqis fil- potassju, tnaqqis fil- kalċju, tnaqqis fin - newtrofili
Decreased glucose tolerance, weight gain, 1 2
* ara sezzjoni 4. 4
This event had a fatal outcome.
Esperjenza wara li l- prodott tpoġġa fuq is- suq
Uncommon
Epatite, u rarament suffejra, kienu rrapurtati f’ pazjenti fuq terapija ta ’ Kaletra fil- preżenza jew assenza ta ’ fatturi ta ’ riskju identifikabli għall- epatite.
weight loss, increased bilirubin, hormone level altered, lab test abnormal
Is- sindromi ta ’ Stevens- Johnsons u eritema multiforme ġew ukoll irrapurtati.
See section 4.4: pancreatitis and lipids
Il- frekwenza ta ’ dan m’ hijiex magħrufa (ara sezzjoni 4. 4).
55 Paediatric patients
4. 9 Doża eċċessiva
In children 2 years of age and older, the nature of the safety profile is similar to that seen in adults.
Preżentement, hemm esperjenza limitata fil- bnedmin b’ doża qawwija u eċċessiva ta ’ Kaletra.
Undesirable effects in clinical studies in paediatric patients Infections and infestations
Is- sinjali kliniċi avversi osservati fil- klieb kienu jinkludu salivazzjoni, emeżi u diareja/ skart tal- ġisem mhux normali.
Nervous system disorders
63 M’ hemm l- ebda antidotu speċifiku għal doża eċċessiva b’ Kaletra.
Taste perversion
TAGĦRIF FARMAKOLOĠIKU
Gastrointestinal disorders
5. 1 Tagħrif farmakodinamiku
Constipation, vomiting, pancreatitis*
Kategorija farmakoterapewtika: inibitur protejaż, Kodiċi ATC:
Hepatomegaly
Mekkaniżmu ta ’ azzjoni:
Skin and subcutaneous tissue disorders
Lopinavir huwa inibitur tal- proteases ta ’ HIV- 1 u HIV- 2.
Rash, dry skin
Effetti fuq l- elettrokardjogramm:
General disorders and administration site conditions
L- intervall PR massimu kien ta ’ 286 msec u ma ġie osservat l- ebda imblukkar tal- qalb tat- tieni jew tat- tielet grad (ara sezzjoni 4. 4).
Common
Fl- assenza ta ’ serum uman, il- medja IC50 ta ’ lopinavir kien 6. 5 nM kontra bosta iżolati kliniċi HIV- 1.
Fever
Reżistenza
Investigations
Selezzjoni ta ’ reżistenza in vitro:
Common (Grade 3 or 4)
Kollox ma kollox, il- karatterizazzjoni in vitro ta ’ cross -
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
64 resistance fenotipika bejn lopinavir u inibituri tal- protease oħrajn tissuġġerixxi li t- tnaqqis fis - suxxettibilità għal lopinavir tikkorrelata mill- qrib ma tnaqqis fis- suxxettibilità għal ritonavir u indinavir, iżda ma tikkorrelatax mill- qrib ma tnaqqis fis- suxxettibilità għal amprenavir, saquinavir, u nelfinavir.
*see section 4.4: pancreatitis and lipids
Analiżi ta ’ reżistenza f’ pazjenti li qatt ma esponew ruħhom qabel għal ARV:
Post marketing experience
Fi studju tat- tieni fażi (M98- 720) matul 204 ġimgħat ta ’ trattament, analiżi ġenotipika ta ’ virus iżolati kien mwettaq b’ suċċess fi 11 minn 16- il pazjent ikkonfermati b’ HIV RNA ogħla minn 400 kopji/ ml, ma irrivelaw l- ebda mutazzjonjiet primarji jew tas- sit attiv fi protease (amino aċidi fil- posizzjonijiet 8, 30, 32, 46, 47, 48, 50, 82, 84 u 90) jew resistenza fenotipika inibitorja tal- protease.
Hepatitis, and rarely jaundice, have been reported in patients on Kaletra therapy in the presence or absence of identifiable risk factors for hepatitis.
Reżistenza għal lopinavir, definita bħala l- preżenza ta ’ mutazzjonijiet tal- protease primarji jew tas- sit attiv (ara hawn fuq), kienet osservata f’ 0/ 51 (0%) tas- suġġetti.
Stevens-Johnson syndrome and erythema multiforme have been reported.
Nuqqas ta ’ reżistenza għal lopinavir kienet ikkonfermata minn analiżi fenotipika.
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).
Reżistenza inkrementali kienet l- iktar komuni f’ suġġetti li l- iżolati tal- linja bażi tagħhom kellhom ħafna mutazzjonijiet assoċjati ma ’ inibituri tal- proteases, imma b ’ < 40 inqas suxxettibilità għal lopinavir fil- linja bażi.
The frequency of this is unknown (see section 4.4).
Mutazzjonijiet V82A, I54V u M461 kienu l- iktar li ħarġu.
To date, there is limited human experience of acute overdose with Kaletra.
Mutazjonijiet L33F, I50V u V321 ikkombinati ma 147V/ A kienu wkoll osservati.
The adverse clinical signs observed in dogs included salivation, emesis and diarrhoea/ abnormal stool.
Id- 19- il iżolati wrew żieda ta ’ 4. 3- il darba f’ IC50 meta mqabbla ma iżolati tal- linja bażi (minn 6. 2- il darba għal 43- il darba, mqabbla ma virus tat - tip mhux kkultivat).
The signs of toxicity observed in mice, rats or dogs included decreased activity, ataxia, emaciation, dehydration and tremors.
F’ dan il- kwadru, il- mutazzjonijiet f’ HIV protease kienu assoċjati bi tnaqqis ta ’ suxxettibilità in vitro għal lopinavir:
There is no specific antidote for overdose with Kaletra.
L10F/ I/ R/ V, K20M/ R, L24I, M46I/ L, F53L, I54L/ T/ V, L63P, A71I/ L/ T/ V, V82A/ F/ T, I84V u L90M.
Treatment of overdose with Kaletra is to consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.
Il- medjan EC50 ta ’ lopinavir kontra l- iżolati bi 0 - 3, 4 - 5, 6 - 7 u 8 - 10 mutazzjonijiet fil- pożizzjonijiet tal- amino aċidi kif indikat hawn fuq kienu 0. 8, 2. 7 13. 5 u 44. 0 - il darba ogħla mill - EC50 kontra HIV tat- tip mhux ikkultivat, rispettivament.
If indicated, elimination of unabsorbed active substance is to be achieved by emesis or gastric lavage.
Is - 16 il- virus li urew > 20 - il darba bidla fis- suxxettibilità kollha kien fihom mutazzjonijiet fil- posizzjonijiet 10, 54, 63 u 82 u / jew 84.
Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance.
Madanakollu, kien fihom medjan ta ’ 3 mutazzjonijiet fil- pożizzjonijiet tal- amino aċidi 20, 24, 46, 53, 71 u 90.
Since Kaletra is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.
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.
56 5.
Il - EC50 ta ’ lopinavir kontra il - 56 iżolati virali tal - linja bażi varjaw bejn 0. 6 u 96- il darba ogħla mill - EC50 kontra HIV ta ’ tip mhux ikkultivat.
PHARMACOLOGICAL PROPERTIES
Data Klinika farmakodinamika
5.1 Pharmacodynamic properties
Pazjenti li qatt ma ħadu terapija antiretrovirali
Pharmaco-therapeutic group: protease inhibitor, ATC code:
Il- linja bażi medja għadd ta ’ ċelluli CD4 kienet ta ’ 259 ċellula/ mm3( limiti:
J05AE06
2. 6 għal 6. 8
Mechanism of action:
66 log10 kopji/ ml).
Lopinavir provides the antiviral activity of Kaletra.
Tul 48 ġimgħa terapija, il- proporzjon ta ’ pazjenti fis- sezzjoni Kaletra bi plażma RNA < 50 kopji/ ml kien 67% u 52% fis- sezzjoni nelfinavir.
Lopinavir is an inhibitor of the HIV-1 and HIV-2 proteases.
Iż- żieda medja mill- linja bażi fl- għadd ta ’ ċelluli CD4 kienet ta ’ 207 ċelluli/ mm3 fis- sezzjoni Kaletra u 195 ċelluli/ mm3 fis- sezzjoni nelfinavir.
Inhibition of HIV protease prevents cleavage of the gag-pol polyprotein resulting in the production of immature, non-infectious virus.
Tul 48 ġimgħa ta ’ terapija, proporzjon ogħla statistikament sinifikattiv ta ’ pazjenti fis- sezzjoni Kaletra kellhom HIV RNA < 50 kopji/ ml mqabbla mas- sezzjoni nelfinavir.
QTcF interval was evaluated in a randomised, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 39 healthy adults, with 10 measurements over 12 hours on Day 3.
Respons viroloġiku sostenut għal Kaletra (ikkombinat ma ’ inibitur nukleòside/ nukleòtide reverse transcriptase) ġie osservat anke fi studju Fażi II żgħir (M97- 720) tul 360 ġimgħa ta ’ trattament.
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.
Fl - istudju, mitt pazjent oriġinarjament ġew ikkurati b’ Kaletra (inkluż 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).
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.
Wieħed u sittin pazjent spiċċaw l- istudju kollu (35 pazjent irċevew id- doża rakkomandata ta ’ 400/ 100 mg darbtejn kuljum matul l- istudju kollu.
The two regimens resulted in exposures on Day 3 which were approximately 1.5 and 3- fold higher than those observed with recommended once daily or twice daily LPV/ r doses at steady state.
Matul 360 ġimgħa tat- trattament il- proporzjon ta ’ pazjenti b’ HIV RNA < 400 (< 50) kopji/ ml kien ta ’ 61% (59%) u ż- żieda medja ta ’ għadd ta ’ ċelluli CD4 kienet ta ’ 501 ċelluli/ mm3.
No subject experienced an increase in QTcF of ≥ 60 msec from baseline or a QTcF interval exceeding the potentially clinically relevant threshold of 500 msec.
Disgħa u tletin pazjent (39%) ma komplewx l- istudju, inklużi 16 (16%) waqfiet minħabba eventi avversi, li waqfa minnhom kienet assoċjata ma ’ mewt.
Modest prolongation of the PR interval was also noted in subjects receiving lopinavir/ ritonavir in the same study on Day 3.
Il- linja bażi medjana fl- għadd ta ’ ċelluli CD4 kien 349 ċelluli/ mm3 (limiti 72 għal 807 ċelluli/ mm3) u l - linja bażi medjana tal- plażma HIV- 1 RNA kienet 4. 0 log10 kopji/ ml (limiti 2. 9 għal 5. 8 log10 kopji/ ml).
The mean changes from baseline in PR interval ranged from 11.6 ms to 24.4 ms in the 12 hour interval post dose.
Bejn il- ġimgħa 24 u 48, pazjenti fortuwitament mogħtija doża ta ’ 400/ 100 mg kienu konvertiti għal doża ta ’ 533/ 133 mg.
Maximum PR interval was 286 msec and no second or third degree heart block was observed (see section 4.4).
Il- medjan tal - linja bażi fl- għadd taċ- ċelluli CD4 kien 220 ċelluli/ ml (limiti 13 għal 1030 ċelluli/ ml).
Antiviral activity in vitro: the in vitro antiviral activity of lopinavir against laboratory and clinical HIV strains was evaluated in acutely infected lymphoblastic cell lines and peripheral blood lymphocytes, respectively.
Pazjenti novizzi ingħataw inibituri nucleoside reverse transcriptase.
In the absence of human serum, the mean IC50 of lopinavir against five different HIV-1 laboratory strains was 19 nM.
Pazjenti b’ esperjenza ingħataw nevirapine u sa żewġ inibituri nucleoside reverse transcriptase.
In the absence and presence of 50% human serum, the mean IC50 of lopinavir against HIV-1IIIB in MT4 cells was 17 nM and 102 nM, respectively.
Sigurta ’, effikaċja u l- profili farmakokinetiċi taż - żewġ duzaġġi kienu analiżati wara 3 ġimgħat terapija f’ kull pazjent.
In the absence of human serum, the mean IC50 of lopinavir was 6.5 nM against several HIV-1 clinical isolates.
Sussegwentement il- pazjenti kollha komplew fuq id- doża 300/ 75 mg kull m2.
Resistance
Tul 48 ġimgħa ta ’ terapija, il- proporzjon ta ’ pazjenti b’ HIV RNA < 400 kopji/ ml kien 84% għal pazjenti novizzi għat- terapiji antiretrovirali u 75% għal pazjenti b’ esperjenza ta ’ terapiji antiretrovirali, u żidiet medji mill- linja bażi fl- għadd taċ- ċelluli CD4 kien 404 ċelluli/ mm3 u 284 ċelluli/ mm3, rispettivament.
In vitro selection of resistance:
5. 2 Tagħrif farmakokinetiku
HIV-1 isolates with reduced susceptibility to lopinavir have been selected in vitro.
Essenzjalment il- lopinavir huwa kompletament metaboliżżat minn CYP3A.
HIV-1 has been passaged in vitro with lopinavir alone and with lopinavir plus ritonavir at concentration ratios representing the range of plasma concentration ratios observed during Kaletra therapy.
Ir- ritonavir jinibixxi l- metaboliżmu ta ’ lopinavir, b’ konsegwenza li jżid il- livelli fil- plażma ta ’ lopinavir.
Genotypic and phenotypic analysis of viruses selected in these passages suggest that the presence of ritonavir, at these concentration ratios, does not measurably influence the selection of lopinavir-resistant viruses.
Tul studji, s- somministrazzjoni tal- Kaletra 400/ 100 mg darbtejn kuljum tagħti medja tal- konċentrazzjonijiet tal- plażma ta ’ lopinavir steady- state 15 sa 20- darba ogħla minn dawk ta ’ ritonavir f’ pazjenti infettati bl - HIV.
Overall, the in vitro characterisation of phenotypic cross-resistance between lopinavir and other protease inhibitors suggest that decreased susceptibility to lopinavir correlated closely with decreased susceptibility to ritonavir and indinavir, but did not correlate closely with decreased susceptibility to amprenavir, saquinavir, and nelfinavir.
Għalhekk l- attività antivirali tal- Kaletra hija dovuta għal- lopinavir.
Analysis of resistance in ARV-naïve patients:
Assorbiment:
In a Phase II study (M97-720) through 204 weeks of treatment, genotypic analysis of viral isolates was successfully conducted in 11 of 16 patients with confirmed HIV RNA above 400 copies/ ml revealed no primary or active site mutations in protease (amino acids at positions 8, 30, 32, 46, 47, 48, 50, 82, 84 and 90) or protease inhibitor phenotypic resistance.
Dużaġġ multiplu b ’ 400/ 100 mg Kaletra darbtejn kuljum għal 3 sa 4 ġimgħat u mingħajr restrizzjoni fuq l- ikel ipproduċiet medja ± SD l- ogħla konċentrazzjoni ta ’ lopinavir fil- plażma lopinavir (Cmax) ta ’ 9. 6 ± 4. 4 μg/ ml, li ntlaħqet approssimattivament 4 sigħat wara s- somministrazzjoni.
In a Phase III study (M98-863) of 653 patients randomised to receive stavudine plus lamivudine with either lopinavir/ ritonavir or nelfinavir, 113 nelfinavir-treated subjects and 74 lopinavir/ ritonavir- treated subjects had an HIV RNA above 400 copies/ ml while on treatment from Week 24 through Week 96.
Lopinavir AUC fuq intervall ta ’ dożaġġ ta ’ 12 il- siegħa kellu medja ta ’ 82. 8 ± 44. 5 μg/ ml.
Of these, isolates from 96 nelfinavir-treated subject and 51 lopinavir/ ritonavir-treated
Il- bijodisponibilita ’ assoluta ta ’ lopinavir ko- formulata ma’ ritonavir fil- bniedem, ma ’ ġietx stabbilita.
57 subjects could be amplified for resistance testing.
Effetti tal- Ikel fuq l- assorbiment mill- ħalq:
Resistance to nelfinavir, defined as the presence of the D30N or L90M mutation in protease, was observed in 41/ 96 (43%) subjects.
Kapsuli rotob u likwidu Kaletra ġew murija li huma bijoekwivalenti taħt kundizzjonijiet mhux ta ’ sawm, (ikla b’ kontenut ta ’ xaħam moderat).
Resistance to lopinavir, defined as the presence of any primary or active site mutations in protease (see above), was observed in 0/ 51 (0%) subjects.
Għat- taħlita likwida orali ta ’ Kaletra, iż- żidiet korrispondenti f’ lopinavir AUC u Cmax kienu 80% u 54%, rispettivament.
Lack of resistance to lopinavir was confirmed by phenotypic analysis.
Sabiex tkabbar il- bijodisponibilita ’ u timminimizza l - varjabilita ’ l- Kaletra għandha tittieħed mal- ikel.
Analysis of resistance in PI-experienced patients:
Distribuzzjoni:
Incremental resistance was most common in subjects whose baseline isolates had several protease inhibitor-associated mutations, but < 40-fold reduced susceptibility to lopinavir at baseline.
Fi steady- state lopinavir huwa approssimattivament 98 - 99% marbut mal- proteini tas - serum.
Mutations L33F, I50V and V32I combined with I47V/ A were also observed.
Lopinavir jgħaqqad kemm mal- aċidu glikoproteina alpha- 1( AAG) u mal- albumina, imma għandha affinita ogħla mal- AAG.
The 19 isolates demonstrated a 4.3-fold increase in IC50 compared to baseline isolates (from 6.2- to 43-fold, compared to wild-type virus).
Fi steady- state t- tagħqid tal- proteina ta ’ lopinavir jibqa kostanti fuq l- medda ta ’ konċentrazzjonijiet osservati wara 400/ 100 mg Kaletra darbtejn kuljum, u hija simili bejn volontiera b’ saħħithom u pazjenti li huma HIV- posittivi.
Genotypic correlates of reduced phenotypic susceptibility to lopinavir in viruses selected by other protease inhibitors.
Esperimenti in vitro b’ mikrożomi epatiċi umani jindikaw illi primarjament lopinavir jgħaddi minn metaboliżmu ossidattiv.
The in vitro antiviral activity of lopinavir against 112 clinical isolates taken from patients failing therapy with one or more protease inhibitors was assessed.
Il- lopinavir huwa estensivament metabolizzat mis- sistema ċitokroma epatika P450, kważi esklussivament mill- iżożima CYP3A.
Within this panel, the following mutations in HIV protease were associated with reduced in vitro susceptibility to lopinavir:
Ir- ritonavir huwa inibitur ta’ CYP3A potenti li jinibixxi il- metaboliżmu ta’ lopinavir u għalhekk iżid il- livelli tal- plażma ta’ lopinavir.
L10F/ I/ R/ V, K20M/ R, L24I, M46I/ L, F53L, I54L/ T/ V, L63P, A71I/ L/ T/ V, V82A/ F/ T, I84V and L90M.
Mill- inqas 13- il metabolita ossidattivi ta’ lopinavir ġew identifikati fil- bniedem.
The median EC50 of lopinavir against isolates with 0 − 3, 4 − 5, 6 − 7 and 8 − 10 mutations at the above amino acid positions was 0.8, 2.7 13.5 and 44.0-fold higher than the EC50 against wild type HIV, respectively.
Il- par (koppja) epimeriku/ a 4- oxo u 4 - idroximetabolita huma l- metaboliti maġġuri b’ attività antivirali, imma jikkomprendu biss ammonti żgħar ħafna mit- total kollu tar- radjoattivita tal- plażma.
The 16 viruses that displayed > 20-fold change in susceptibility all contained mutations at positions 10, 54, 63 plus 82 and/ or 84.
Ritonavir ġie muri li jinduċi l- enżimi metaboliċi, b’ hekk jirriżulta fl- induzzjoni tal- metaboliżmu tiegħu stess u aktarx l- induzzjoni tal -
In addition, they contained a median of 3 mutations at amino acid positions 20, 24, 46, 53, 71 and 90.
68 metaboliżmu ta’ lopinavir.
In addition to the mutations described above, mutations V32I and I47A have been observed in rebound isolates with reduced lopinavir susceptibility from protease inhibitor experienced patients receiving Kaletra therapy.
Konċentrazzjonijiet ta’ lopinavir ta ’ qabel id- doża maż- żmien jonqsu matul l - għoti ta ’ dużaġġ multiplu, u jistabiliżżaw ruħhom wara approssimattivament 10 tijiem sa 2 gimgħat.
Antiviral activity of Kaletra in patients failing protease inhibitor therapy: the clinical relevance of reduced in vitro susceptibility to lopinavir has been examined by assessing the virologic response to Kaletra therapy, with respect to baseline viral genotype and phenotype, in 56 patients previous failing therapy with multiple protease inhibitors.
Wara doża ta ’ 400/ 100 mg 14C- lopinavir/ ritonavir, approssimattivament 10. 4 ± 2. 3% u 82. 6 ± 2. 5% ta ’ doża somministrata ta ’ 14C- lopinavir tista tiġi stabbilita fl- urina u fl- iskart imneħħi mill - ġisem, rispettivament.
The EC50 of lopinavir against the 56 baseline viral isolates ranged from 0.6 to 96-fold higher than the EC50 against wild type HIV.
Lopinavir mhux mibdul kien approssimattivament 2. 2% u 19. 8% tad- doża somministrata fl- urina u fl- iskart imneħħi mill- ġisem, rispettivament.
After 48 weeks of treatment with Kaletra, efavirenz and nucleoside reverse transcriptase inhibitors, plasma HIV RNA ≤ 400 copies/ ml was observed in 93% (25/ 27), 73% (11/ 15), and 25% (2/ 8) of patients with< 10-fold, 10 to 40-fold, and > 40-fold reduced susceptibility to lopinavir at baseline, respectively.
Wara dużaġġ multiplu inqas minn 3% tad- doża ta ’ lopinavir hija mneħħija mhux mibdula fl- urina.
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.
Il- half- life effettiva ta ’ lopinavir (massimu sa minimu) tul intervall ta ’ dużaġġ ta’ 12 il- siegħa kellu medja ta ’ 5 - 6 sigħat, u t- tneħħija orali (CL/ F) apparenti ta ’ lopinavir hi 6 sa 7 l/ siegħa.
The study did not contain a control arm of patients not receiving Kaletra.
Pazjenti Speċjali
Cross-resistance:
Pedjatriċi:
Activity of other protease inhibitors against isolates that developed incremental resistance to lopinavir after Kaletra therapy in protease inhibitor experienced patients:
Il- farmakokinetika ta ’ Kaletra 300/ 75 mg/ m2 darbtejn kuljum u 230/ 57. 5 mg/ m2 darbtejn kuljum ġew studjati f’ total ta ’ 53 pazjent pedjatriku li jvarjaw fl- età minn 6 xhur sa 12 il- sena.
The presence of cross resistance to other protease inhibitors was analysed in 18 rebound isolates that had demonstrated evolution of resistance to lopinavir during 3 Phase II and one Phase III studies of Kaletra in protease inhibitor-experienced patients.
Il- medja fi steady- state tal- AUC, Cmax, u Cmin ta ’ lopinavir kien72. 6± 31, 1μg• h/ ml, 8. 2± 2. 9μg• h/ ml and 3. 4± 2. 1μg• h/ ml rispettivament wara Kaletra 230/ 57. 5 mg/ m2 darbtejn kuljum mingħajr nevirapine (n=12), u kienu 85. 8 ± 36. 9 μg• h/ ml, 10. 0 ± 3. 3 μg/ ml u 3. 6 ± 3. 5 μg/ ml, rispettivament wara 300/ 75 mg/ m2 darbtejn kuljum b’ nevirapine (n=12).
The median fold IC50 of lopinavir for these 18 isolates at baseline and rebound was 6.9- and 63-fold, respectively, compared to wild type virus.
Il - 230/ 57. 5 mg/ m2 dożaġġ darbtejn kuljum mingħajr nevirapine u t - 300/ 75 mg/ m2 dożaġġ darbtejn kuljum b’ nevirapine pprovdew konċentrazzjonijiet tal- plażma ta ’ lopinavir simili għal dawk ottenuti f’ pazjenti adulti li kienu qed jirċievu 400/ 100 mg dożaġġ darbtejn kuljum mingħajr nevirapine.
In general, rebound isolates either retained (if cross-resistant at baseline) or developed significant cross-resistance to indinavir, saquinavir and atazanavir.
Taħt kundizzjonijiet mhux ta ’ sawm il- kapsuli rotob Kaletra u t- taħlita likwida orali Kaletra huma bijoekwivalenti.
Modest decreases in amprenavir activity were noted with a median increase of IC50 from 3.7- to 8-fold in the baseline and rebound isolates, respectively.
Il- farmakokinetika ta ’ Kaletra ma ’ ġietx studjata fl- anzjani.
Isolates retained susceptibility to tipranavir with a median increase of IC50 in baseline and rebound isolates of 1.9- and 1.8– fold, respectively, compared to wild type virus.
F’ pazjenti adulti ma ’ ġiet innutata l- ebda differenza farmakokinetika li huma relatati ma ’ l- età jew is- sess.
Please refer to the Aptivus Summary of Product
Differenzi farmakokinetiċi minħabba razza ma ’ ġewx identifikati.
58 Characteristics for additional information on the use of tipranavir, including genotypic predictors of response, in treatment of lopinavir-resistant HIV-1 infection.
Iżda peress li t- tneħħija ta ’ lopinavir mill- kliewi hija negliġibbli, f’ pazjenti bi problemi fil- kliewi tnaqqis fit- total tat- tneħħija mill- ġisem ma ’ hijiex mistennija.
Clinical pharmacodynamic data
Problemi Epatiċi:
The effects of Kaletra (in combination with other antiretroviral agents) on biological markers (plasma HIV RNA levels and CD4 counts) have been investigated in a controlled study of Kaletra of 48 weeks duration, and in additional studies of Kaletra of 360 weeks duration.
Żieda limitata ta ’ approssimament 30% fil- konċentrazzjonijiet ta ’ lopinavir ġiet osservata, imma mhix mistennija li tkun ta ’ ebda relevanza klinika (ara sezzjoni 4. 2).
Adult Use
5. 3 Tagħrif ta 'qabel l- użu kliniku dwar is- sigurtà tal- mediċina
Patients without prior antiretroviral therapy
Fil- waqt li l- esposizzjoni li minnu ħarġu dawn il- bidliet kien
Study M98-863 is a randomised, double-blind trial of 653 antiretroviral treatment naïve patients investigating Kaletra (400/ 100 mg twice daily) compared to nelfinavir (750 mg three times daily) plus nucleoside reverse transcriptase inhibitors.
69 komparabbli mal jew inqas mill- esponiment kliniku uman, dożi fl- annimali kienu iktar minn 6 darbiet id- doża klinika rakkomandata.
By intent to treat analysis where patients with missing values are considered virologic failures, the proportion of patients at 48 weeks with HIV RNA < 400 copies/ ml in the Kaletra arm was 75% and 63% in the nelfinavir arm.
Deġenerazzjoni renali tubulari ħafifa kienet ristretta għall ġrieden esposti b’ almenu darbtejn l- esponiment rakkomandat għall bniedem; il- kilwa ma ’ kenitx effettwata fil- far u fil - klieb.
Mean baseline CD4 cell count was 259 cells/ mm3 (range:
Serum thyroxine imnaqqas wassal għall rilaxxament akbar ta ’ TSH li rriżulta f’ ipertrofija taċ - ċellula follikulari fil- glandola tajrod tal- far.
2.6 to 6.8 log10 copies/ ml).
Dawn il- bidliet kienu mreġġa lura wara l- irtirar tas- sustanza attiva u kienu assenti fil- ġrieden u fil- klieb.
Through 48 weeks of therapy, the proportion of patients in the Kaletra arm with plasma RNA < 50 copies/ ml was 67% and 52% in the nelfinavir arm.
Anisoċitożi Coombs- negative u pojkiloċitożi kienu osservati fil- far, iżda mhux fil- ġrieden u l- klieb.
The mean increase from baseline in CD4 cell count was 207 cells/ mm3 in the Kaletra arm and 195 cells/ mm3 in the nelfinavir arm.
Marrari minfuħa bl- istjoċitożi ġew innutati fil- far iżda mhux fi speċi oħra.
Through 48 weeks of therapy, a statistically significantly higher proportion of patients in the Kaletra arm had HIV RNA < 50 copies/ ml compared to the nelfinavir arm.
Is- serum kolosterol kien għoli fil- gerriema iżda mhux fil- klieb, waqt li t- trigliċeridi kienu għolja biss fil- ġrieden.
Sustained virological response to Kaletra (in combination with nucleoside/ nucleotide reverse transcriptase inhibitors) has been also observed in a small Phase II study (M97-720) through 360 weeks of treatment.
Waqt studju in vitro kanali kardijaċi tal- potassju umani klonati (HERG) kienu inibiti bi 30% fl- ogħla konċentrazzjonijiet ta ’ lopinavir/ ritonavir ippruvati, li kienu jikkorrispondu għal esponiment għal lopinavir ta ’ total ta ’ 7 darbiet u 15 il- darba livelli ta ’ plażma quċċata libera li ġew ottenuti fil- bniedem bid- doża terapewtika massima li ġiet irrikmandata.
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).
B’ kuntrast, konċentrazzjonijiet simili ta ’ lopinavir/ ritonavir ma ’ urew l- ebda dewmien fir- ripolarizzazjoni fil- fibri kardijaċi Purkinje tal- klieb.
Sixty-one patients completed the study (35 patients received the recommended 400/ 100 mg twice daily dose throughout the study).
Konċentrazzjonijiet iktar baxxi ta ’ lopinavir/ ritonavir ma’ ipproduċewx imblokk kurrenti tal- potassju (HERG) sinifikanti.
Through 360 weeks of treatment, the proportion of patients with HIV RNA < 400 (< 50) copies/ ml was 61% (59%), and the corresponding mean increase in CD4 cell count was 501 cells/ mm3.
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 approssimattivament 50% tal - plażma AUC imkejjla.
Thirty-nine patients (39%) discontinued the study, including 16 (16%) discontinuations due to adverse events, one of which was associated with a death.
Għalhekk huwa raġjonevoli li wieħed jistenna li l- livelli kardijaċi ta ’ lopinavir ma ’ jkunux sinifikantement ogħla mill- livelli tal- plażma.
Patients with prior antiretroviral therapy
Huwa preżunt li dawn l- effetti huma kawża ta ’ disturb minn elektrolite.
Study M97-765 is a randomised, double-blind trial evaluating Kaletra at two dose levels (400/ 100 mg and 400/ 200 mg, both twice daily) plus nevirapine (200 mg twice daily) and two nucleoside reverse transcriptase inhibitors in 70 single protease inhibitor experienced, non-nucleoside reverse transcriptase inhibitor naïve patients.
Ir- rilevanza klinika ta ’ dan it- tagħrif ta ’ qabel l- użu kliniku, ma ’ huwiex magħruf, iżda l- effetti potenzjali kardijaċi ta ’ dan il- prodott fil- bniedem ma ’ jista jiġi eskluż (ara ukoll sezzjoni 4. 4. u 4. 8).
Median baseline CD4 cell count was 349 cells/ mm3 (range 72 to 807 cells/ mm3) and median baseline plasma HIV-1 RNA was 4.0 log10 copies/ ml (range 2.9 to 5.8 log10 copies/ ml).
Fil- far, embrijofetotossiċita (telf ta ’ tqala, vijabilita ’ fetali imnaqqsa, piżijiet tal- korp fetali imnaqqsa, frekwenza akbar ta ’ varjazzjonijiet skeletali) u tossiċita ’ ta ’ l- iżvilupp ta ’ wara t- twelid (għixien imnaqqsa taż- żgħar) ġiet osservata f’ dożaġġi tossiċi materni.
By intent to treat analysis where patients with missing values are considered virologic failures, the proportion of patients with HIV RNA < 400 (< 50) copies/ ml at 24 weeks was 75% (58%) and the mean increase from baseline in CD4 cell count was 174 cells/ mm3 for the 36 patients receiving the 400/ 100 mg dose of Kaletra.
L- esponiment sitematiku għall lopinavir/ ritonavir fid- dożaggi materni u żviluppatorji kien iktar baxx mill- esposizzjoni terapewtiku ppjanat fil- bniedem.
M98-957 is a randomised, open-label study evaluating Kaletra treatment at two dose levels (400/ 100 mg and 533/ 133 mg, both twice daily) plus efavirenz (600 mg once daily) and nucleoside reverse transcriptase inhibitors in 57 multiple protease inhibitor experienced, non-nucleoside reverse transcriptase inhibitor naïve patients.
Studji karċinoġeniċi fuq perijodu twil, tal- lopinavir/ ritonavir fil- ġrieden żvela induzzjoni mhux ġenotossika u mitoġenika ta ’ tumuri fil- fwied, li ġeneralment huma kkunsidrati li għandhom ftit rilevanza ta ’ riskju għall bniedem.
Between week 24 and 48, patients randomised to a dose of 400/ 100 mg were converted to a dose of 533/ 133 mg.
Studji karċinoġeniċi fil- far ma ’ żvelaw l- ebda sejbiet tumoriġeniċi.
By intent-to-treat analysis of both dose groups combined (n=57), where patients with missing values are considered virologic failures, the proportion of patients
Lopinavir/ ritonavir ma ’ instabx li hu mutaġeniku jew klastoġeniku f’ serje sħiħa ta ’ provi in vitro u in vivo inklużi l- prova Ames bacterial reverse mutation, il- prova tal- limfoma fil- ġurdien, it- test mikronukleju fil- ġurdien u provi ta ’ aberrazzjoni kromosomatika fil- limfoċiti umani.
59 with HIV RNA < 400 copies/ ml at 48 weeks was 65% and the mean increase from baseline CD4 cell count was 94 cells/ mm3.
6. 1 Lista ta ’ sustanzi mhux attivi
Paediatric Use
Kontenut tal- pillola:
M98-940 is an open-label study of a liquid formulation of Kaletra in 100 antiretroviral naïve (44%) and experienced (56%) paediatric patients.
Hypromellose Titanium dioxide Macrogols type 400 (Polyethylene glycol 400) Hydroxypropyl cellulose Talc Colloidal anhydrous silica Macrogols type 3350 (Polyethylene glycol 3350) Yellow ferric oxide E172 Polysorbate 80
All patients were non-nucleoside reverse transcriptase inhibitor naïve.
6. 2 Inkompatibilitajiet
Naïve patients also received nucleoside reverse transcriptase inhibitors.
Ma jgħoddx f’ dan il- każ.
Experienced patients received nevirapine plus up to two nucleoside reverse transcriptase inhibitors.
6. 3 Żmien kemm idum tajjeb il- prodott mediċinali
Safety, efficacy and pharmacokinetic profiles of the two dose regimens were assessed after 3 weeks of therapy in each patient.
3 snin.
Patients had a mean age of 5 years (range 6 months to 12 years) with 14 patients less than 2 years old and 6 patients one year or less.
6. 4 Prekawzjonijiet speċjali għall- ħażna Din il- mediċina ma teħtieġ l- ebda kundizzjoni ta ’ ħażna speċjali.
5.2 Pharmacokinetic properties
6. 5 In- natura tal- kontenitur u ta ’ dak li hemm ġo fih
The pharmacokinetic properties of lopinavir co-administered with ritonavir have been evaluated in healthy adult volunteers and in HIV-infected patients; no substantial differences were observed between the two groups.
Polyethylene ta ’ densità għolja (HDPE) fliexken magħluqin b’ kappi ta ’ polypropylene.
Lopinavir is essentially completely metabolised by CYP3A.
Kull flixkun fih 120 pillola.
Ritonavir inhibits the metabolism of lopinavir, thereby increasing the plasma levels of lopinavir.
Kull pakkett fih flixkun (120 pillola) Folji jikkonsistu f’ PVC/ fojl tal- fluoropolymer.
The in vitro antiviral EC50 of lopinavir is approximately 10-fold lower than that of ritonavir.
Kull kartuna fiha 5 folji tal- fojl li kull waħda fiha 8 pilloli miksija b’ rita (40 pillola).
Therefore, the antiviral activity of Kaletra is due to lopinavir.
Kull pakkett fih 3 kartuniet (120 pillola).
The mean steady-state trough concentration prior to the morning dose was 5.5 ± 4.0 μ g/ ml.
6. 6 Prekawzjonijiet speċjali li għandhom jittieħdu meta jintrema
Lopinavir AUC over a 12 hour dosing interval averaged 82.8 ± 44.5 μ g• h/ ml.
L- ebda ħtiġijiet speċjali.
Effects of food on oral absorption:
7.
Therefore, Kaletra tablets may be taken with or without food.
ID- DETENTURTA ’ L- AWTORIZZAZZJONI GĦAT- TQEGĦID FIS- SUQ
Distribution: at steady state, lopinavir is approximately 98 − 99% bound to serum proteins.
Abbott Laboratories Limited Queenborough Kent ME11 5EL Renju Unit
Lopinavir binds to both alpha-1-acid glycoprotein (AAG) and albumin, however, it has a higher affinity for AAG.
NUMRU( I) TA ’ L- AWTORIZZAZZJONI GĦAT- TQEGĦID FIS- SUQ
At least 13 lopinavir oxidative metabolites have been identified in man.
EU/ 1/ 01/ 172/ 004 EU/ 1/ 01/ 172/ 005
The 4-oxo and 4-hydroxymetabolite epimeric pair are the major metabolites with
DATA TA ’ L- EWWEL AWTORIZZAZZJONI/ TIĠDID TA ’ L- AWTORIZZAZZJONI
60 antiviral activity, but comprise only minute amounts of total plasma radioactivity.
Data ta ’ l- ewwel awtorizzazzjoni:
Ritonavir has been shown to induce metabolic enzymes, resulting in the induction of its own metabolism, and likely the induction of lopinavir metabolism.
20 ta ’ Marzu 2006
Pre-dose lopinavir concentrations decline with time during multiple dosing, stabilising after approximately 10 days to 2 weeks.
10.
After multiple dosing, less than 3% of the lopinavir dose is excreted unchanged in the urine.
DATA TA ’ META ĠIET RIVEDUTA L- KITBA
Special Populations
ISEM TAL- PRODOTT MEDIĊINALI
Paediatrics:
Kaletra 100 mg/ 25 mg pilloli miksija b’ rita
Gender, Race and Age:
GĦAMLA KWALITATTIVA U KWANTITATTIVA
No age or gender related pharmacokinetic differences have been observed in adult patients.
Kull pillola miksija b’ rita fiha 100 mg lopinavir ko- formulat ma ’ 25 mg ritonavir biex iżid il - farmakokinetika.
Pharmacokinetic differences due to race have not been identified.
Għal- lista kompleta ta ’ sustanzi mhux attivi, ara sezzjoni 6. 1.
Renal Insufficiency:
GĦAMLA FARMAĊEWTIKA
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.
Pillola miksija b’ rita
Hepatic Insufficiency:
Safra ċara [bil- logo ta ’ Abbott] u “ KC ” imnaqqxa.
The steady state pharmacokinetic parameters of lopinavir in HIV-infected patients with mild to moderate hepatic impairment were compared with those of HIV-infected patients with normal hepatic function in a multiple dose study with lopinavir/ ritonavir 400/ 100 mg twice daily.
TAGĦRIF KLINIKU
5.3 Preclinical safety data
4. 1 Indikazzjonijiet terapewtiċi
Repeat-dose toxicity studies in rodents and dogs identified major target organs as the liver, kidney, thyroid, spleen and circulating red blood cells.
Kaletra huwa indikat, flimkien ma ’ aġenti antiretrovirali oħra, għall- kura ta ’ tfal ta ’ ’ il fuq minn sentejn, u ta ’ adulti, li huma nfettati b’ HIV- 1.
Hepatic changes indicated cellular swelling with focal degeneration.
L- aktar esperjenza eżistenti b’ Kaletra ġejja mill- użu ta ’ dan il- prodott f’ terapija antiretrovirali f’ pazjenti novizzi għal din it- terapija.
While exposure eliciting these changes were comparable to or below human clinical exposure, dosages in animals were over 6-fold the recommended clinical dose.
Tagħrif fuq pazjenti li kienu diġà ġew trattati bil- qawwa b’ impedituri protejaż, hija limitata.
Mild renal tubular degeneration was confined to mice exposed with at least twice the recommended human exposure; the kidney was unaffected in rats and dogs.
Hemm tagħrif limitat dwar terapija ta ’ salvataġġ f’ pazjenti li fuqhom ma ħadmitx il- kura b’ Kaletra.
These changes were reversible with withdrawal of the active substance and were absent in mice and dogs.
L- għażla ta ’ Kaletra għall- kura ta ’ pazjenti infettati b’ HIV- 1 li kienu diġà ġew trattati b’ impedituri protejaż, għandha tkun ibbażata fuq testijiet individwali ta ’ reżistenza virali u fuq l- istorja ta ’ kura tal - pazjenti (ara sezzjoni 4. 4 u 5. 1).
Coombs-negative anisocytosis and poikilocytosis were observed in rats, but not in mice or dogs.
4. 2 Pożoloġija u metodu ta ’ kif għandu jingħata
61 histiocytosis were seen in rats but not other species.
Kaletra għandu jingħata mit- tobba li għandhom esperjenza fil- kura ta ’ l- infezzjoni ta ’ l- HIV.
Serum cholesterol was elevated in rodents but not dogs, while triglycerides were elevated only in mice.
Il- pilloli Kaletra għandhom jinbelgħu sħaħ u m’ għandhomx jiġu mimgħudin, imkissra jew mgħaffġa.
During in vitro studies, cloned human cardiac potassium channels (HERG) were inhibited by 30% at the highest concentrations of lopinavir/ ritonavir tested, corresponding to a lopinavir exposure 7-fold total and 15-fold free peak plasma levels achieved in humans at the maximum recommended therapeutic dose.
Is- soluzzjoni orali hija disponibbli għal pazjenti li għandhom diffikultà biex jibilgħu.
In contrast, similar concentrations of lopinavir/ ritonavir demonstrated no repolarisation delay in the canine cardiac Purkinje fibres.
Irreferi għas- Sommarju tal- Karatteristiċi tal- Prodott tas- soluzzjoni orali Kaletra għall- istruzzjonijiet dwar id- dożaġġ.
Lower concentrations of lopinavir/ ritonavir did not produce significant potassium (HERG) current blockade.
Użu pedjatriku (minn sentejn ’ il fuq): id- doża tal- pilloli Kaletra għall- adulti (400/ 100 mg darbtejn kuljum) tista ’ tintuża fi tfal li jiżnu 40 kg jew aktar jew li għandhom l- Erja tas- Superfiċje tal- Ġisem (BSA) * akbar minn 1. 4 m2.
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.
Fil- każ ta ’ tfal li jiżnu inqas minn 40 kg jew li għandhom l- erja tas - superfiċje tal- ġisem (BSA) bejn 0. 5 u 1. 4 m2 li jafu jibilgħu l- pilloli, irreferi għat- tabelli ta ’ linji gwida għad- dożaġġ imniżżla hawn taħt.
Therefore, it is reasonable to expect that cardiac lopinavir levels would not be significantly higher than plasma levels.
Fil- każ ta ’ tfal li ma jafux jibilgħu l- pilloli, jekk jogħġbok irreferi għas- Sommarju tal- Karatteristiċi tal- Prodott tas- soluzzjoni orali Kaletra.
In dogs, prominent U waves on the electrocardiogram have been observed associated with prolonged PR interval and bradycardia.
73 Qabel ma jingħataw il- pilloli Kaletra 100/ 25 mg, it- tfal iż- żgħar għandhom jiġu evalwati għall- kapaċità tagħhom biex jibilgħu pilloli intatti.
These effects have been assumed to be caused by electrolyte disturbance.
Jekk it- tifel/ tifla mhux/ mhix kapaċi jibla ’ / tibla ’ il- pillola Kaletra bil- mod kif sippost, ghandha tingħata l- formulazzjoni tas- soluzzjoni orali Kaletra.
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).
It- tabella li jmiss fiha linji gwida għad- dożaġġ tal- pilloli Kaletra 100/ 25 mg ibbażat fuq l- erje tas - superfiċje tal- ġisem (BSA).
The systemic exposure to lopinavir/ ritonavir at the maternal and developmental toxic dosages was lower than the intended therapeutic exposure in humans.
Linji Gwida għad- Dożaġġ għal Pazjenti Pedjatriċi
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.
tas- Superfiċje tal - Ġisem (m2)
Carcinogenicity studies in rats revealed no tumourigenic findings.
Numru rrakkomandat ta ’ pilloli ta ’ 100/ 25 mg darbtejn kuljum
PHARMACEUTICAL PARTICULARS
≥ 0. 5 sa < 0. 9 ≥ 0. 9 sa < 1. 4
6.1 List of excipients
2 pilloli (200/ 50 mg) 3 pilloli (300/ 75 mg)
Tablet contents:
4 pilloli (400/ 100 mg)
Copovidone Sorbitan laurate Colloidal anhydrous silica Sodium stearyl fumarate
* L- erja tas- superfiċje tal- ġisem tista ’ tiġi kkalkulata bil- formula li jmiss:
Film-coating:
Terapija konkomitanti:
Hypromellose Titanium dioxide Macrogols type 400 (Polyethylene glycol 400) Hydroxypropyl cellulose Talc Colloidal anhydrous silica Macrogols type 3350 (Polyethylene glycol 3350) Yellow ferric oxide E172 Polysorbate 80
It- tabella li jmiss fiha linji gwida għad- dożaġġ tal- pilloli Kaletra 100/ 25 mg ibbażat fuq l- erja tas - superfiċje tal- ġisem (BSA), meta jintużaw fit- tfal flimkien ma ’ efavirenz jew nevirapine.
62 6.2 Incompatibilities
tas- superfiċje tal - ġisem (m2)
Not applicable.
≥ 0. 5 sa < 0. 8 ≥ 0. 8 sa < 1. 2
6.3 Shelf life
≥ 1. 2 sa < 1. 4 ≥ 1. 4
3 years.
Kaletra m’ għandux jingħata lil dawn il- pazjenti (ara sezzjoni 4. 3).
6.4 Special precautions for storage
4. 3 Kontra- indikazzjonijiet
This medicinal product does not require any special storage conditions.
Sensittività eċċessiva għas- sustanzi attivi jew għal xi sustanzi mhux attivi.
6.5 Nature and content of container
Pazjenti b’ insuffiċjenza serja ħafna tal- fwied.
Each bottle contains 120 tablets.
Kaletra fih lopinavir u ritonavir, it- tnejn li huma impedituri ta ’ l- iżoforma ta ’ P450, CYP3A.
Blisters consisting of PVC/ fluoropolymer foil.
Kaletra m’ għandux jingħata flimkien ma ’ prodotti mediċinali li huma dipendenti ħafna fuq CYP3A għat - tneħħija mill- ġisem, u li l- konċentrazzjoni elevata tagħhom fil- plażma hija assoċjata ma ’ effetti serji u/ jew li huma ta ’ periklu għall- ħajja.
Each pack contains 3 cartons (120 tablets).
Preparazzjonijiet mill- ħxejjex li fihom il- fexfiex tar- raba ’ (St John’ s Wort) (Hypericum perforatum) m’ għandhomx jintużaw waqt it- teħid ta ’ lopinavir u ritonavir minħabba r- riskju ta ’ tnaqqis fil - konċentrazzjoni fil- plażma u tnaqqis fl- effetti kliniċi ta ’ lopinavir u ritonavir (ara sezzjoni 4. 5).
6.6 Special precautions for disposal
4. 4 Twissijiet speċjali u prekawzjonijiet għall- użu
No special requirements.
Pazjenti b’ kundizzjonijiet ko - eżistenti
MARKETING AUTHORISATION HOLDER
F’ każ li terapiji antivirali għall- epatite B jew Ċ jittieħdu fl- istess waqt, jekk jogħġbok irreferi għall- informazzjoni tal- prodott rilevanti għal dawn il - prodotti mediċinali.
Abbott Laboratories Limited Queenborough Kent ME11 5EL United Kingdom
Jekk ikun hemm evidenza ta ’ aggravar ta ’ mard tal- fwied f’ dawn il- pazjenti, għandu jiġi kkunsidrat l- interruzzjoni jew it- twaqqif tal - kura.
MARKETING AUTHORISATION NUMBERS
F’ xi pazjenti ngħata ukoll il- fattur VIII.
EU/ 1/ 01/ 172/ 004 EU/ 1/ 01/ 172/ 005
Żidiet fil- lipidi
DATE OF FIRST AUTHORISATION/ RENEWAL OF THE AUTHORISATION
Il- kura b’ Kaletra rriżultat f’ żidiet, xi kultant immarkati, fil- konċentrazzjoni tal- kolesterol totali u tat - trigliċeridi.
20 March 2006
Pankreatite
DATE OF REVISION OF THE TEXT
Iż - żieda ċara fit- trigliċerida hija fattur ta ’ riskju għall- iżvilupp tal- pankreatite. Pazjenti bil- marda ta ’ l- HIV fi stadju avanzat jista ’ jkollhom riskju ta ’ żieda fit- trigliċeridi u pankreatite.