qanastek/EMEA-V3 huggingface dataset:
There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses, in haemophilic patients type A and B treated with protease inhibitors (see section 4.4).
Kien hemm rapporti ta ’ żjieda ta ’ fsada, inkluż ematomi u ematrożi spontanji fil- ġilda, f’ pazjenti bl- emofilja tat- tip A u B kkurati b’ inibituri tal- protease (ara sezzjoni 4. 4).
• Hepato-biliary disorders:
• Mard epato- biljari:
Hepatitis.
Epatite.
• Musculoskeletal, connective tissue and bone disorders:
• Mard muskoloskeletali, fit- tessut konnettiv u fl- għadam:
Increased CPK, myalgia, myositis and rarely, rhabdomyolysis have been reported with protease inhibitors, particularly in combination with nucleoside analogues.
Żjieda f’ CPK, mijalġja, mijosite u rarament, rhabdomyolysis kienu rrappurtati b’ inibituri tal- protease, speċjalment f’ taħlita ma ’ analogi ta ’ nucleoside.
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART).
Każijiet ta ’ osteonekrożi kienu rrappurtati, speċjalment f’ pazjenti b’ fatturi ta ’ riskju ġeneralment magħrufa, marda ta ’ l- HIV avvanzata jew espożizzjoni fit- tul għal terapija antiretrovirali kombinata (CART).
The frequency of this is unknown (see section 4.4).
Il- frekwenza ta ’ dawn mhux magħrufa (ara sezzjoni 4. 4).
• Renal and urinary disorders:
• Mard tal- kliewi u s- sistema urinarja:
Renal impairment.
Indeboliment tal- kliewi.
• In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise (see section 4.4).
• F’ pazjenti nfettati bl- HIV b’ defiċjenza immunitarja severa fiż- żmien li nbdiet il- kura antiretrovirali kombinata (CART), jista ’ jkun hemm reazzjoni infjammatorja għal infezzjonijiet opportunistiċi bla sintomi jew li għad hemm (ara sezzjoni 4. 4).
There is limited experience of overdose with saquinavir.
Hemm esperjenza limitata ta ’ doża eċċessiva b’ saquinavir.
Whereas acute or chronic overdose of saquinavir alone did not result in major complications, in combination with other protease inhibitors, overdose symptoms and signs such as general weakness, fatigue, diarrhoea, nausea, vomiting, hair loss, dry mouth, hyponatraemia, weight loss and orthostatic hypotension have been observed.
Filwaqt li doża eċċessiva akuta jew kronika ta ’ saquinavir waħdu ma rriżultatx f’ kumplikazzjonijiet maġġuri, flimkien ma ’ inibituri ta ’ protease oħra ġew osservati sinjali u sintomi ta ’ doża eċċessiva bħal debbulizza ġenerali, għejja, dijarea, tqalligħ, rimettar, telf ta ’ xagħar, ħalq xott, iponatrimja, telf ta ’ piż u ipotensjoni ortostatika.
There is no specific antidote for overdose with saquinavir.
M’ hemmx antidotu speċifiku għal doża eċċessiva b’ saquinavir.
Treatment of overdose with saquinavir should consist of general supportive measures, including monitoring of vital signs and ECG, and observations of the patient ’ s clinical status.
Kura ta ’ doża eċċessiva b’ saquinavir għandha tikkonsisti minn miżuri ta ’ support ġenerali, inkluż sorveljanza tas- sinjali vitali u ECG, u osservazzjonijiet ta ’ l- istat kliniku tal- pazjent.
If indicated, prevention of further absorption can be considered.
Jekk indikat, prevenzjoni ta ’ aktar assorbiment tista ’ tiġi kkunsidrata.
Since saquinavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.
Minħabba li saquinavir jeħel b’ mod qawwi mal- proteini, x’ aktarx li dijalisi ma tkunx ta ’ benefiċċju biex tneħħi s- sustanza attiva b’ mod sinifikanti.
The HIV protease is an essential viral enzyme required for the specific cleavage of viral gag and gag-pol polyproteins.
Il- protease tal- HIV hija enżima virali essenzjali meħtieġa għall- qsim speċifiku tal- poliproteini virali gag u gag- pol.
Saquinavir selectively inhibits the HIV protease, thereby preventing the creation of mature infectious virus particles.
Saquinavir jinibixxi b’ mod selettiv il- protease tal- HIV u b’ hekk jipprevjeni il- formazzjoni ta ’ partiċelli nfettivi tal- virus maturi..
17 Antiviral activity in vitro:
Attività antivirali in vitro:
Saquinavir demonstrates antiviral activity against a panel of laboratory strains and clinical isolates of HIV-1 with typical EC50 and EC90 values in the range 1-10 nM and 5-50 nM, respectively, with no apparent difference between subtype B and non-B clades.
L- EC50 korrispondenti aġġustat tas -
The corresponding serum (50% human serum) adjusted EC50 ranged from 25-250 nM.
18 serum (50% serum uman) varja minn 25- 250 nM.
Clinical isolates of HIV-2 demonstrated EC50 values in the range of 0.3-2.4 nM.
Iżolati kliniċi ta ’ HIV- 2 urew valuri ta ’ EC50 fil - firxa ta ’ 0. 3- 2. 4 nM.
Antiviral activity according to baseline genotype and phenotype:
Attività antivirali skond il- ġenotip u fenotip fil- linja bażi:
Genotypic and phenotypic clinical cut-offs predicting the clinical efficacy of ritonavir boosted saquinavir have been derived from retrospective analyses of the RESIST 1 and 2 clinical studies and analysis of a large hospital cohort (Marcelin et al 2007).
Punti kliniċi ġenotipiċi u fenotipiċi ta ’ waqfien li jbassru l- effikaċja klinika ta ’ saquinavir imsaħħaħ b’ ritonavir ġew derivati minn analiżi retrospettiva ta ’ l- istudji kliniċi RESIST 1 u 2 u analiżi ta ’ ko- orti kbir ta ’ l- isptar (Marcelin et al 2007).
Baseline saquinavir phenotype (shift in susceptibility relative to reference, PhenoSense Assay) was shown to be a predictive factor of virological outcome.
Fenotip ta ’ saquinavir fil- linja bażi (bidla fis- suxxettibilità relattiva għar- referenza, PhenoSense Assay) intwera li huwa fattur ta ’ tbassir għar- riżultat virloġiku.
Virological response was first observed to decrease when the fold shift exceeded 2.3-fold; whereas virological benefit was not observed when the fold shift exceeded 12-fold.
Meta d- drabi ta ’ bidla kienet aktar minn 2. 3 darbiet, ir- rispons viroloġiku kien osservat li l- ewwel jonqos; filwaqt li l- benefiċċju viroloġiku ma kienx osservat meta d- drabi ta ’ bidla kienet aktar minn 12- il darba.
Marcelin et al (2007) identified nine protease codons (L10F/ I/ M/ R/ V, I15A/ V, K20I/ M/ R/ T, L24I, I62V, G73S/ T, V82A/ F/ S/ T, I84V, L90M) that were associated with decreased virological response to saquinavir/ ritonavir (1000/ 100 mg twice daily) in 138 saquinavir naive patients.
Marcelin et al (2007) identifika disa ’ kodons tal- protease (L10F/ I/ M/ R/ V, I15A/ V, K20I/ M/ R/ T, L24I, I62V, G73S/ T, V82A/ F/ S/ T, I84V, L90M) li kienu assoċjati ma ’ tnaqqis fir- rispons viroloġiku għal saquinavir/ ritonavir (1000/ 100 mg darbtejn kuljum) f’ 138 pazjent li qatt ma ħadu saquinavir qabel.
The presence of 3 or more mutations was associated with reduced response to saquinavir/ ritonavir.
Il - preżenza ta ’ 3 mutazzjonijiet jew aktar kienet assoċjata ma ’ rispons imnaqqas għal saquinavir/ ritonavir.
The association between the number of these saquinavir-associated resistance mutations and virological response was confirmed in an independent clinical study (RESIST 1 and 2) involving a more heavily treatment experienced patient population, including 54% who had received prior saquinavir (p=0.0133, see Table 3).
L- assoċazzjoni bejn in- numru ta ’ dawn il- mutazzjonijiet ta ’ reżistenza assoċjati ma ’ saquinavir u rispons viroloġiku kien ikkonfermat fi studju kliniku indipendenti (RESIST 1 u 2) li nvolva popolazzjoni ta ’ pazjenti b’ esperjenza ta ’ kura aktar qawwija, inkluż 54% li kienu rċevew saquinavir minn qabel (p=0. 0133, ara Tabella 3).
The G48V mutation, previously identified in vitro as a saquinavir signature mutation, was present at baseline in virus from three patients, none of whom responded to therapy.
Il- mutazzjoni G48V, identifikat qabel in vitro bħala mutazzjoni karatteristika ta ’ saquinavir, kienet preżenti fil- linja bażi fil- virus minn tliet pazjenti, li l - ebda wieħed minnhom ma rrisponda għat- terapija.
Virological response to saquinavir/ ritonavir stratified by the number of baseline saquinavir- associated resistance mutations
Rispons viroloġiku għal saquinavir/ ritonavir stratifikat bin- numru ta ’ mutazzjonijiet ta ’ reżistenza assoċjati ma ’ saquinavir fil- linja bażi
Number of
Numru ta ’
SQV Naive/ Experienced Population
Mutazzjonijiet Popolazzjoni li Qatt ma Ħadu SQV Popolazzjoni li Qatt ma Ħadu SQV ta ’ Reżistenza
Resistance
qabel
Change in Baseline
Qabel/ b’ Esperjenza ta ’ SQV
Change in Baseline
Assoċjati ma ’
N=138
Bidla
Plasma HIV-1 RNA at
fl- RNA ta ’ HIV- 1
N=114 Plasma HIV-1 RNA at
Bidla fl- RNA ta ’ HIV- 1 fil -
at Baseline*
Saquinavir fil - N=138 fil- Plażma Linja Bażi *
Weeks 12-20
fil- Linja Bażi N=114 f’ Ġimgħa 12- 20
Week 4
Plażma fil- Linja Bażi f’ Ġimgħa 4
-2.24 -1.88 -1.43 -0.52 -0.18 -0.11 -0.30 -
- 1. 43 - 0. 52 - 0. 18 - 0. 11 - 0. 30 -
* Saquinavir Mutation Score Mutations:
* Mutazzjonijiet ta ’ Punteġġ ta ’ Mutazzjoni għal Saquinavir:
Clinical results from studies with treatment naïve and experienced patients
Riżultati kliniċi mill- istudji b’ pazjenti li qatt ma ħadu kura qabel u pazjenti b’ esperjenza ta ’ kura
The combination of saquinavir and ritonavir
Fl- istudju MaxCmin1, is- sikurtà u l- effikaċja ta ’ kapsoli rotob ta ’ saquinavir/ ritonavir 1000/ 100 mg darbtejn kuljum ma ’ 2 NRTIs/ Inibituri tar - Reverse Transcriptase Non- Nucleoside (NNRTIs) kienu mqabbla ma ’ indinavir/ ritonavir 800/ 100 mg darbtejn kuljum ma ’ 2 NRTIs/ NNRTIs f’ aktar minn 300 (kemm b’ esperjenza ta ’ kura b’ inibituri tal- protease kif ukoll bla esperjenza) soġġett.
18 exhibited a superior virological activity compared with the indinavir and ritonavir arm when switch from the assigned treatment was counted as virological failure.
It- taħlita ta ’ saquinavir u ritonavir uriet attività viraloġika superjuri meta mqabbla mal- kategorija ta ’ indinavir u ritonavir meta bdil mill- kura assenjata kienet meqjusa bħala falliment viroloġiku.
In the MaxCmin2 study, the safety and efficacy of saquinavir soft capsules/ ritonavir 1000/ 100 mg twice daily plus 2 NRTIs/ NNRTIs was compared with lopinavir/ ritonavir 400/ 100 mg twice daily plus 2 NRTIs/ NNRTIs in 324 (both protease inhibitor treatment naïve and experienced) subjects.
19 Fl- istudju MaxCmin2, is- sikurtà u l- effikaċja ta ’ kapsoli rotob ta ’ saquinavir/ ritonavir 1000/ 100 mg darbtejn kuljum flimkien ma ’ 2 NRTIs/ NNRTIs kienu mqabbla ma ’ lopinavir/ ritonavir 400/ 100 mg darbtejn kuljum ma ’ 2 NRTIs/ NNRTIs f’ 324 (kemm b’ esperjenza ta ’ kura b’ inibituri tal- protease kif ukoll bla esperjenza) soġġett.
None of the subjects in the lopinavir/ ritonavir arm had been exposed to lopinavir prior to randomisation whereas 16 of the subjects in the saquinavir/ ritonavir arm had previously been exposed to saquinavir.
L- ebda wieħed mis- soġġetti fil- kategorija ta ’ lopinavir/ ritonavir ma kien espost għal lopinavir qabel ma saret l- għażla bl- addoċċ, filwaqt li 16- il soġġett fil- kategorija saquinavir/ ritonavir kienu esposti minn qabel għal saquinavir.
Table 4:
20 Tabella 4:
Subject Demographics MaxCmin1 and MaxCmin2 †
Demografija tas- Suġġetti f’ MaxCmin1 u MaxCmin2 †
Sex
Sess
Male Race (White/Black/Asian)% Age, median, yrs CDC Category C (%) Antiretroviral naïve (%) PI naïve (%) Median Baseline HIV-1 RNA, log10 copies/ml (IQR) Median Baseline CD4+ Cell Count, cells/mm3 (IQR) data from clinical study report
log10 kopji/ ml( IQR) Linja bażi Medjana ta ’ l- Għadd taċ- ċelluli CD4+, ċelluli/ mm3 (IQR)
82% 86/9/1 39 32% 28% 41% 4.0 (1.7-5.1) 272 (135-420)
(1. 7- 5. 1) 272 (135- 420)
74% 82/12/4 40 28% 22% 38% 3.9 (1.7-5.2) 280 (139-453)
(1. 7- 5. 2) 280 (139- 453)
81% 75/19/1 40 32% 31% 48% 4.4 (3.1-5.1) 241 (86-400)
(3. 1- 5. 1) 241 (86- 400)
76% 74/ 19/2 40 31% 34% 48% 4.6 (3.5-5.3) 239 (95-420)
(3. 5- 5. 3) 239 (95- 420)
Outcomes at Week 48 MaxCmin1 and MaxCmin2†
Riżultati wara 48 Ġimgħa f’ MaxCmin1 u MaxCmin2 †
Initiated assigned treatment, n (%) Discontinued assigned treatment, n (%)
Bdew il- kura assenjata, n (%) Waqqfu il- kura assenjata, n (%)
Virological failure ITT/e*#
Falliment viroloġiku ITT/ e * #
36/148 (24%) P=0.76
36/ 148 (24%) P=0. 76
53/161 (33%) P=0.002
53/ 161 (33%) P=0. 002
Proportion with VL < 50 copies/ml at week 48, ITT/e#
Proporzjon b’ VL < 50 kopji/ ml wara 48 ġimgħa, ITT/ e #
Proportion with VL < 50 copies/ml at week 48, On Treatment
Proporzjon b’ VL < 50
Median increase in CD4 cell count at week 48 (cells/mm3)
Żjieda medjana fl- għadd taċ - ċelluli wara 48 ġimgħa (ċelluli/ mm3)
* For both studies:
* Għaż- żewġ studji:
For patients entering study with VL < 200 copies/ml, VF defined as > 200 copies/ml.
Għall- pazjenti li daħlu fl- istudju b’ VL < 200 kopji/ ml, VF iddefinit bħala > 200 kopji/ ml.
For those entering with VL > 200 copies/ml, VF defined as any increase > 0.5 logs and/or VL > 50,000 copies/ml at week 4, > 5,000 copies/ml at week 12, or > 200 copies/ml at week 24 or thereafter.
Għal dawk li daħlu fl- istudju b’ VL > 200 kopji/ ml, VF iddefinit bħala kull żjieda > 0. 5 logs u/ jew VL > 50, 000 kopji/ ml wara 4 ġimgħat, > 5, 000 kopji/ ml wara 12- il ġimgħa, jew > 200 kopji/ ml wara 24- il ġimgħa u il- quddiem.
MaxCmin2: any rise > 0.5 log at a specific visit; < 0.5 log reduction if VL > 200 copies/ml at week 4; < 1.0 log reduction from base line if VL > 200 copies/ml at week 12; and a VL > 200 copies/ml at week 24. # ITT/e = Intent-to-treat/exposed † Data from clinical study report ‡ Data from MaxCmin1 publication
MaxCmin2: kull żjieda > 0. 5 log f’ vista speċifika; < 0. 5 log tnaqqis jekkVL > 200 kopji/ ml wara 4 ġimgħat; < 1. 0 log tnaqqis mill- linja bażi jekk VL > 200 kopji/ ml wara 12- il ġimgħa; u VL > 200 kopji/ ml wara 24 ġimgħa. # ITT/ e = Ħsieb- biex- tikkura/ espost † Tagħrif miġbur mir- rapport ta ’ l- istudju kliniku ‡ Tagħrif mill- publikazzjoni ta ’ MaxCmin1
Saquinavir is essentially completely metabolised by CYP3A4.
Saquinavir huwa essenzjalment metabolizzat kompletament minn CYP3A4.
Ritonavir inhibits the metabolism of saquinavir, thereby increasing ("boosting") the plasma levels of saquinavir.
Ritonavir jinibixxi l - metaboliżmu ta ’ saquinavir, u b’ hekk iżid (“ isaħħaħ ”) il- livelli fil- plażma ta ’ saquinavir.
Absorption and bioavailability in adults:
21 Assorbiment u biodisponibilità fl- adulti:
In HIV-infected patients, Invirase in combination with ritonavir at doses of 1000/100 mg twice daily provides saquinavir systemic exposures over a 24-hour period similar to or greater than those achieved with saquinavir soft capsules 1200 mg tid (see Table 6).
F’ pazjenti infettati b’ HIV, Invirase flimkien ma ’ ritonavir f’ dożi ta ’ 1000/ 100 mg mogħtija darbtejn kuljum jipprovdu espożizzjonijiet sistemiċi ta ’ saquinavir fuq perijodu ta ’ 24 siegħa simili għal, jew akbar minn dawk miksuba b’ 1200 mg ta ’ kapsoli rotob ta ’ saquinavir tliet darbiet kuljum (ara Tabella 6).
The pharmacokinetics of saquinavir is stable during long-term treatment.
Il- farmakokinetiċi ta ’ saquinavir huma stabbli waqt kura fit- tul.
Mean (% CV) AUC, Cmax and Cmin of saquinavir in patients following multiple dosing of Invirase, saquinavir soft capsules, Invirase/ritonavir, and saquinavir soft capsules/ritonavir
Medja (% CV) ta ’ AUC, tas- Cmax u tac- Cmin f’ pazjenti wara dożi multipli ta ’ Invirase, kapsoli rotob ta ’ saquinavir, u Invirase/ ritonavir, u kapsoli rotob ta ’ saquinavir/ ritonavir
AUCτ
AUCτ (ng· h/ ml)
AUC0-24
AUC0- 24 (ng· h/ ml)
(ng·h/ ml)
Cmax (ng/ ml)
(ng/ ml)
Cmin (ng/ ml)
10
Invirase (kapsula iebsa) 10 600 mg tid
saquinavir soft capsule 1200 mg tid
kapsuli rotob ta ’ saquinavir 1200 mg tid
Invirase (tablet)
Invirase (pillola)
313
313 (70- 1, 725) ††
1000 mg bid plus ritonavir 100 mg bid* (fasting condition)
1000 mg bid ma ’ ritonavir 100 mg bid * (stat sajjem)
1,179
1, 179 (334- 5, 176) ††
1000 mg bid plus ritonavir 100 mg bid* (high fat meal)
1000 mg bid ma ’ ritonavir 100 mg bid * (ikla b’ ħafna xaħam)
(11,826- 105,992)
(11, 826 - 105, 992)
(1,536-14,369)
(1, 536- 14, 369)
8 hour for tid
τ = interval tad- dożaġġ, i. e.
Cmin = the observed plasma concentration at the end of the dose interval bid = twice daily tid = three times daily * results are geometric mean (min - max) † derived from tid or bid dosing schedule †† Ctrough values
8 siegħa għal tid u 12- il siegħa għal għotja tad- dożi bid Cmin = il- konċentrazzjoni fil- plażma osservata fl- aħħar ta ’ l- intervall tad- doża bid = darbtejn kuljum tid = tlett darbiet kuljum * riżultati huma l- medja ġejometrika (min - max) † derivati minn skeda ta ’ dożaġġ ta ’ tid jew bid †† valuri ta ’ Ctrough
Absolute bioavailability averaged 4% (CV 73%, range:
Il- bijodisponibilità assoluta kienet medja ta ’ 4% (CV 73%, varjazzjoni:
1% to 9%) in 8 healthy volunteers who received a single 600 mg dose (3 x 200 mg hard capsule) of Invirase following a heavy breakfast.
1% għal 9%) fi 8 volontiera b’ saħħithom li ngħataw doża waħda ta ’ 600 mg (3 x 200 mg kapsula iebsa) ta ’ Invirase wara kolazzjon kbira.
The low bioavailability is thought to be due to a combination of incomplete absorption and extensive first- pass metabolism.
Il- bijodisponibilità baxxa huwa maħsub li hija minħabba l- kombinazzjoni ta ’ assorbiment inkomplut u metaboliżmu first- pass estensiv.
Gastric pH has been shown to be only a minor component in the large increase in bioavailability seen when given with food.
Intwera li l- pH ta ’ l- istonku huwa biss komponent minuri fiż- żjieda kbira fil- bijodisponibilità li sseħħ meta jingħata ma ’ l- ikel.
The absolute bioavailability of saquinavir co-administered with ritonavir has not been established in humans.
Il- bijodisponibilità assoluta ta ’ saquinavir meta jingħata flimkien ma ’ ritanovir ma ġiex stabbilita fil- bnedmin.
In combination with ritonavir, bioequivalence of Invirase hard capsules and film-coated tablets was demonstrated under fed conditions.
F’ taħlita flimkien ma ’ ritonavir, ġiet dimostrata bijoekwivalenza ta ’ kapsoli iebsa ta ’ Invirase u pilloli miksija b’ rita taħt kondizzjonijiet ta ’ wara l- ikel.
Effective therapy in treatment naïve patients is associated with a Cmin of approximately 50 ng/ml and an AUC0-24 of about 20,000 ng·h/ml.
Terapija effettiva fil- kura ta ’ pażjenti bla esperjenza tal- kura hija assoċjata ma ’ Cmin ta ’ bejn wieħed u ieħor 50 ng/ ml u AUC0- 24 ta ’ madwar 20, 000 ng* h/ ml.
Effective therapy in treatment experienced patients is associated with a Cmin of approximately 100 ng/ml and an AUC0-24 of about 20,000 ng·h/ml.
It- terapija effettiva fil- kura ta ’ pazjenti b’ esperjenza hija assoċjata ma ’ Cmin ta ’ bejn wieħed u ieħor 100 ng/ ml u AUC0- 24 ta ’ madwar 20, 000 ng* h/ ml.
In vitro studies have shown that saquinavir is a substrate for P-glycoprotein (P-gp).
Studji in vitro wrew li saquinavir huwa sottostrat għall- glikoproteina P (P- gp).
Effect of food:
Effett ta ’ l- ikel:
In a cross-over study in 22 HIV-infected patients treated with Invirase/ritonavir 1000 mg/100 mg twice daily and receiving three consecutive doses under fasting conditions or after a high-fat, high-calorie meal (46 g fat, 1,091 Kcal), the AUC0-12, Cmax and Ctrough values of saquinavir under fasting conditions were about 70 per cent lower than with a high-fat meal.
Fi studju cross- over f’ 22 pazjenti infetti b’ HIV kkurati b’ Invirase/ ritonavir 1000 mg/ 100 mg darbtejn kuljum u li rċevew tliet dożi konsekuttivi fi stat sajjem jew wara ikla b’ ħafna xaħam u ħafna kaloriji (46 g xaħam, 1, 091 Kcal), il- valuri ta ’ l- AUC0- 12, Cmax u Ctrough ta ’ saquinavir fi stat sajjem kienu madwar 70 fil- mija inqas minn dawk ma ’ ikla b’ ħafna xaħam.
All but one of the patients achieved Ctrough values of saquinavir above the therapeutic threshold (100 ng/ml) in the fasted state.
Il - pazjenti kollha minbarra wieħed laħqu valuri ta ’ Ctrough ta ’ saquinavir ’ l fuq mill- limitu terapewtiku (100 ng/ ml) fi stat sajjem.
There were no clinically significant differences in the pharmacokinetic profile of ritonavir in fasting and fed conditions but the ritonavir Ctrough (geometric mean 245 vs.
Ma kienx hemm differenzi kliniċi sinifikanti fil- profil farmakokinetiku ta ’ ritonavir fi stat sajjem u wara l- ikel iżda Ctrough ta ’ ritanovir (medja ġejometrika 245 vs.
348 ng/ml) was lower in the fasting state compared to the administration with a meal.
348 ng/ ml)
Invirase/ritonavir should be administered with or after food.
Invirase/ ritonavir għandu jingħata ma ’ l- ikel jew wara l- ikel.
Distribution in adults:
Distribuzzjoni fl- adulti:
Saquinavir partitions extensively into the tissues.
Saquinavir jitqassam b’ mod estensiv fit- tessuti.
The mean steady-state volume of distribution following intravenous administration of a 12 mg dose of saquinavir was 700 l (CV 39%).
Il- medja tal- volum tad - distribuzzjoni fi stat fiss wara l- għotja ġol- vini ta ’ doża ta ’ 12 mg ta ’ saquinavir kienet ta ’ 700 l (CV 39%).
It has been shown that saquinavir is approximately 97% bound to plasma proteins up to 30 μg/ml.
Intwera li saquinavir huwa bejn wieħed u ieħor 97% magħqud mal- proteini tal- plażma sa 30 μg/ ml.
In two patients receiving Invirase 600 mg three times daily, cerebrospinal fluid concentrations of saquinavir were negligible when compared to concentrations from matching plasma samples.
F’ żewġ pazjenti li kienu qed jirċievu 600 mg ta ’ Invirase tlett darbiet kuljum, il - konċentrazzjonijiet fil- fluwidu ċerebrospinali ta ’ saquinavir kienu negliġibbli meta mqabbla mal - konċentrazzjonijiet f’ kampjuni pariġġhom tal- plażma.
21 Metabolism and elimination in adults:
Metaboliżmu u eliminazzjoni fl- adulti:
In vitro studies using human liver microsomes have shown that the metabolism of saquinavir is cytochrome P450 mediated with the specific isoenzyme, CYP3A4, responsible for more than 90% of the hepatic metabolism.
Studji in vitro li użaw mikrosomi tal- fwied uman urew li l - metaboliżmu ta ’ saquinavir huwa medjat miċ- ċitokromju P450 permezz ta ’ l- iżosima speċifika, CYP3A4, responsabbli għal aktar minn 90% tal- metaboliżmu fil- fwied.
Based on in vitro studies, saquinavir is rapidly metabolised to a range of mono- and di-hydroxylated inactive compounds.
Ibbażat fuq studji in vitro, saquinavir huwa metabolizzat malajr għal sustanzi inattivi tat- tip mono - u di- hydroxylated.
In a mass bal ance study using 600 mg 14C-saquinavir (n = 8), 88% and 1% of the orally administered radioactivity, was recovered in faeces and urine, respectively, within 4 days of dosing.
Fi studju mass balance bl- użu ta ’ 600 mg ta ’ 14C- saquinavir (n = 8), 88% u 1% tar- radjuattività mogħtija mill - ħalq, kienet irkuprata fl- ippurgar u fl- awrina, rispettivament, sa 4 ijiem mill- għotja tad- doża.
In an additional four subjects administered 10.5 mg 14C-saquinavir intravenously, 81% and 3% of the intravenously administered radioactivity was recovered in faeces and urine, respectively, within 4 days of dosing.
F’ erba ’ soġġetti oħra li ngħataw 10. 5 mg ta ’ 14C- saquinavir ġol- vina 81% u 3% tar- radjuattività mogħtija ġol - vina kienet irkuprata fl- ippurgar u fl- awrina, rispettivament, sa 4 ijiem mill- għotja tad- doża.
13% of circulating saquinavir in plasma was present as unchanged compound after oral administration and the remainder as metabolites.
13% ta ’ saquinavir li kien jiċċirkola fil- plażma kien preżenti bħala mediċina mhux mibdula, wara l- għotja mill - ħalq u l- bqija bħala metaboli.
Following intravenous administration 66% of circulating saquinavir was present as unchanged compound and the remainder as metabolites, suggesting that saquinavir undergoes extensive first pass metabolism.
Wara għotja ġol- vini, 66% ta ’ saquinavir li kien jiċċirkola kien preżenti bħala mediċina mhux mibdula u l- bqija bħala metaboli, li jissuġġerixxi li saquinavir jgħaddi minn metaboliżmu first pass estensiv.
In vitro experiments have shown that the hepatic metabolism of saquinavir becomes saturable at concentrations above 2 μg/ml.
Esperimenti in vitro wrew li l- metaboliżmu fil- fwied ta ’ saquinavir isir saturabbli f’ konċentrazzjonijiet ta ’ ’ l fuq minn 2 μg/ ml.
Systemic clearance of saquinavir was high, 1.14 l/h/kg (CV 12%), slightly above the hepatic plasma flow, and constant after intravenous doses of 6, 36 and 72 mg.
It- tneħħija sistematika ta ’ saquinavir kienet għolja, 1. 14 l/ h/ kg (CV ta ’ 12%), ftit aktar miċ - ċirkolazzjoni tal- plażma fil- fwied, u kostanti wara l- għotja ta ’ dożi ġol- vini ta ’ 6, 36 u 72 mg.
The mean residence time of saquinavir was 7 hours (n = 8).
Il- ħin ta ’ residenza medja ta ’ saquinavir kien ta ’ 7 sigħat (n = 8).
Effect of gender following treatment with Invirase/ritonavir:
Effett tas- sess wara kura b’ Invirase/ ritonavir:
A gender difference was observed with females showing higher saquinavir exposure than males (AUC on average 56% higher and Cmax on average 26% higher) in the bioequivalence study comparing Invirase 500 mg film coated tablets with Invirase 200 mg hard capsules both in combination with ritonavir.
Kienet osservata differenza fis- sess, bin- nisa juru espożizzjoni ta ’ saquinavir għola mill- irġiel (AUC b’ medja ta ’ 56% għola u Cmax b’ medja ta ’ 26% għola) fl- istudju ta ’ bijoekwivalenza li qabbel pilloli miksija b’ rita ta ’ Invirase 500 mg ma ’ kapsoli iebsa ta ’ Invirase 200 mg, it- tnejn f’ taħlita ma ’ ritonavir.
There was no evidence that age and body-weight explained the gender difference in this study.
Ma kienx hemm evidenza li eta ’ u piż tal - ġisem jispjegaw id- differenza fis- sess f’ dan l- istudju.
Limited data from controlled clinical studies with the approved dosage regimen do not indicate a major difference in the efficacy and safety profile between men and women.
Tagħrif limitat minn studji kliniċi kontrollati b’ kors ta ’ dożaġġ approvat ma jindikawx differenza maġġuri fil- profil tal- effikaċja u s- sikurtà bejn rġiel u nisa.
Acute and chronic toxicity:
Tossiċità akuta u kronika:
Saquinavir was well tolerated in oral acute and chronic toxicity studies in mice, rats, dogs and marmosets.
Saquinavir kien ittolerat tajjeb fi studji dwar it- tossiċità akuta u kronika mill- ħalq, fi ġrieden, firien, klieb u marmoseti.
Mutagenesis:
Mutaġenesi:
Mutagenicity and genotoxicity studies, with and without metabolic activation where appropriate, have shown that saquinavir has no mutagenic activity in vitro in either bacterial (Ames test) or mammalian cells (Chinese hamster lung V79/HPRT test).
Studji ta ’ mutaġeniċità u ġenotossiċità, bi jew bla attivazzjoni metabolika fejn xieraq, urew li saquinavir m’ għandu l- ebda attività mutaġenika in vitro f’ ċelluli tal- batterja (test ta ’ Ames) jew tal- mammali (test V79/ HPRT tal- pulmun tal- ħamster Ċiniż).
Saquinavir does not induce chromosomal damage in vivo in the mouse micronucleus assay or in vitro in human peripheral blood lymphocytes and does not induce primary DNA damage in vitro in the unscheduled DNA synthesis test.
Saquinavir ma jinduċix ħsara lill- kromosomi in vivo fl- assay tal- mikronukleju tal- ġrieden jew in vitro fil- limfoċiti umani periferali tad- demm u ma jinduċix ħsara primarja fid- DNA in vitro fit- test ta ’ sintesi mhux ipprogrammata tad- DNA.
Carcinogenesis:
Karċinoġenesi:
The re was no evidence of carcinogenic activity after the administration of saquinavir mesilate for 96 to 104 weeks to rats and mice.
Ma kien hemm l- ebda evidenza ta ’ attività karċinoġenika wara l- għotja ta ’ saquinavir mesylate għal 96 sa 104 ġimgħa lill- firien u ġrieden.
The plasma exposures (AUC values) in rats (maximum dose 1000 mg/kg/day) and in mice (maximum dose 2500 mg/kg/day) were lower than the expected plasma exposures obtained in humans at the recommended clinical dose of ritonavir boosted Invirase.
L- espożizzjonijiet fil- plażma (valuri ta ’ l- AUC) fil- firien (doża massima ta ’ 1000 mg/ kg/ kuljum) u fil- ġrieden (doża massima ta ’ 2500 mg/ kg/ kuljum) kienu inqas mill- espożizzjonijiet mistennija fil- plażma miksuba fil- bniedem fid- doża klinika rakkomandata ta ’ Invirase imsaħħaħ b’ ritonavir.
Reproductive toxicity:
Tossiċità fis- sistema riproduttiva:
Fertility, peri- and postnatal development were not affected, and embryotoxic / teratogenic effects were not observed in rats or rabbits at plasma exposures lower than those achieved in humans at the recommended clinical dose of ritonavir boosted Invirase.
effetti embrijotossiċi / teratoġeniċi ma kienux osservati fil- firien jew fniek f’ espożizzjonijiet fil - plażma inqas minn dawk li ntlaħqu fil- bnedmin bid- doża klinikament irrakkomandata ta ’ Invirase
Distribution studies in these species showed that the placental transfer of saquinavir is low (less than 5% of maternal plasma concentrations).
Studji tad- distribuzzjoni f’ dawn l- ispeċi wera li t- trasferiment ta ’ saquinavir mill- plaċenta huwa baxx (inqas minn 5% tal- konċentrazzjonijiet tal- plażma matern).
Capsule filling:
Mili tal- kapsula:
22 Lactose (anhydrous), Microcrystalline cellulose, Povidone, Sodium starch glycollate, Talc, Magnesium stearate.
Lattosju (anhydrous), Microcrystalline cellulose, Povidone Sodium starch glycollate, Talc, Magnesium stearate.
Gelatine, Iron oxide black, red and yellow (E172), Indigo carmine (E132), Titanium dioxide (E171).
Gelatine, Iron oxide iswed, aħmar u isfar( E172), Indigo carmine (E132), Titanium dioxide (E171).
Printing ink:
Linka għall- istampar:
Titanium dioxide (E 171), Shellac, Soya lecithin, Polydimethylsiloxane.
Titanium dioxide (E 171), Shellac, Soya lecithin, Polydimethylsiloxane.
6.2 Incompatibilities
6. 2 Ma ’ jaqblux
Store in the original container.
Aħżen fil- kontenitur oriġinali.
Amber glass bottles with plastic screw cap containing 270 capsules of Invirase.
Fliexken amber tal- ħġieġ b’ għatu tal- plastik bil- kamin li fihom 270 kapsula ta ’ Invirase.
No special requirements.
L- ebda ħtieġa speċjali.
Roche Registration Limited 6 Falcon Way Shire Park Welwyn Garden City AL7 1TW United Kingdom
Roche Registration Limited, 6 Falcon Way Shire Park Welwyn Garden City, AL7 1TW, Ir- Renju Unit
MARKETING AUTHORISATION NUMBER
NUMRU( I) TA ’ L- AWTORIZZAZZJONI GĦALL- KUMMERĊ
23 Date of first authorisation:
Data ta ’ l- ewwel awtorizzazzjoni:
04 October 1996 Date of last renewal:
4 t’ Ottubru, 1996 Data ta ’ l- aħħar tiġdid:
04 October 2006
04 ta ’ Ottubru 2006
Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/.
Informazzjoni dettaljata dwar dan il- prodott tinsab fuq il- website ta ’ l- Aġenzija Ewropeja dwar il - Mediċini (EMEA) http: // www. emea. europa. eu /.
INVIRASE 500 mg film-coated tablets.
INVIRASE 500 mg pilloli miksija b’ rita.
One film-coated tablet contains 500 mg of saquinavir as saquinavir mesilate.
Pillola waħda miksija b’ rita fiha 500 mg saquinavir bħala saquinavir mesylate.
Contains lactose monohydrate:
Fih lactose anhydrous:
38.5 mg.
63. 3 mg.
Light orange to greyish or brownish orange film-coated tablet of oval cylindrical biconvex shape with the marking "SQV 500" on the one side and "ROCHE" on the other side.
Pillola miksija b’ rita oranġjo ċar għal griż jew kannella, b’ forma ovali ċilindrika u tonda miż- żewġ naħat bil- marki "SQV 500" fuq naħa u "ROCHE" fuq in- naħa l- oħra.
Invirase should only be given in combination with ritonavir and other antiretroviral medicinal products (see section 4.2).
Invirase għandu jingħata biss flimkien ma ’ ritonavir u prodotti mediċinali antiretrovirali oħrajn (ara sezzjoni 4. 2).
In combination with ritonavir The recommended dose of Invirase is 1000 mg (2 x 500 mg film-coated tablets) two times daily with ritonavir 100 mg two times daily in combination with other antiretroviral agents.
Flimkien ma ’ ritonavir Id- doża rakkomandata ta ’ Invirase hija ta ’ 1000 mg (5 kapsuli ta ’ 200 mg) mogħtija darbtejn kuljum flimkien ma ’ 100 mg ta ’ ritonavir mogħtija darbtejn kuljum, flimkien ma ’ sustanzi antitretrovirali oħrajn.
Invirase film-coated tablets should be swallowed whole and taken at the same time as ritonavir with or after food (see section 5.2).
Il- kapsuli ta ’ Invirase għandhom jinbelgħu sħaħ u jittieħdu fl- istess ħin ma ’ ritonavir ma ’ l- ikel jew wara l- ikel (ara sezzjoni 5. 2).
No dosage adjustment is necessary for patients with mild to moderate renal or mild hepatic impairment.
M’ hemmx bżonn ta ’ aġġustament fid- dożaġġ f’ pazjenti b’ indeboliment ħafif sa moderat tal- kliewi jew indeboliment ħafif tal- fwied.
Invirase/ritonavir is contraindicated in patients with decompensated hepatic impairment (see sections 4.3 and 4.4).
Invirase/ ritanovir huwa kontra- indikat f’ pazjenti b’ indeboliment dekompensat tal- fwied (ara sezzjonijiet 4. 3 u 4. 4).
The experience with In virase in children below the age of 16 and adults over 60 years is limited.
L- esperjenza b ’ Invirase fit- tfal taħt l- eta ’ ta ’ 16 u adulti akbar minn 60 sena hija limitata.
Invirase/ritonavir is contraindicated in decompensated liver disease (see section 4.4).
Invirase/ ritanovir huwa kontra- indikat fil- marda tal- fwied dekompensat (ara sezzjoni 4. 4).
25 Invirase/ritonavir should not be given together with other medicinal products which may interact and result in potentially life threatening undesirable effects.
26 Invirase/ ritanovir m’ għandux jingħata flimkien ma ’ prodotti mediċinali oħra li jistgħu jinterferixxu u jwasslu għall- effetti mhux mixtieqa potenżjalment fatali.
Medicinal products which should not be given with Invirase/ritonavir include: • terfenadine, astemizole, pimozide, cisapride, amiodarone, propafenone and flecainide (potential for life threatening cardiac arrhythmia) • midazolam administered orally (for caution on parenterally administered midazolam, see section 4.5), triazolam (potential for prolonged or increased sedation, respiratory depression) • simvastatin, lovastatin (increased risk of myopathy including rhabdomyolysis) • ergot alkaloids (e.g. ergotamine, dihydroergotamine, ergonovine, and methylergonovine) (potential for acute ergot toxicity) • rifampicin (risk of severe hepatocellular toxicity) (see sections 4.4, 4.5, and 4.8).
Prodotti mediċinali li m’ għandhomx jingħataw ma ’ Invirase/ ritonavir jinkludu: terfenadine, astemizole, pimozide, cisapride, amiodarone, propafenone u flecainide (potenzjal għal arritmija kardijaka li tista ’ twassal għall- mewt) midazolam mogħti mill- ħalq (għall- kawtela dwar midazolam mogħti b’ mod parenterali, ara sezzjoni 4. 5), triazolam (potenzjal għal sedazzjoni mtawla jew aktar qawwija, dipressjoni respiratorja) simvastatin, lovastatin (żjieda fir- riskju ta ’ mijopatija inkluż rhabdomyolysis) ergot alkaloids (e. ż. ergotamine, dihydroergotamine, ergonovine, u methylergonovine) (potenzjal għal tossiċità akuta ta ’ ergot) rifampicin (riskju ta ’ tossiċità epatoċellolari severa) (ara sezzjonijiet 4. 4, 4. 5, u 4. 8).
Patients should be informed that saquinavir is not a cure for HIV infection and that they may continue to acquire illnesses associated with advanced HIV infection, including opportunistic infections.
Il- pazjenti għandhom ikunu nfurmati li saquinavir mhuwiex xi kura għall- infezzjoni ta ’ l- HIV u li huma jistgħu jkomplu jieħdu l- mard assoċjat ma ’ infezzjoni avvanzata ta ’ l- HIV, inkluż infezzjonijiet opportunistiċi.
The safety and efficacy of saquinavir/ritonavir has not been established in patients with significant underlying liver disorders, therefore saquinavir/ritonavir should be used cautiously in this patient population.
Is- sigurtà u l- effikaċja ta ’ saquinavir/ ritanovir ma kinetx stabbilita f’ pazjenti b’ mard prinċipali sinifikattiv tal- fwied, għalhekk saquinavir/ ritanovir għandu jintuża b’ attenzjoni f’ din il - popolazzjoni ta ’ pazjenti.
Invirase/ritonavir is contraindicated in patients with decompensated liver disease (see section 4.3).
Invirase/ ritanovir huwa kontra- indikat f’ pazjenti b’ marda tal - fwied dikompensat (ara sezzjoni 4. 3).
Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse events.
Pazjenti b’ epatite kronika B jew C u kkurati b’ terapija mħallta antiretrovirali huma f’ riskju akbar għall- effetti avversi serji u potenzjalment fatali tal- fwied.
In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products.
Fil- każ ta ’ terapija antivirali fl- istess waqt għall- epatite B jew C, jekk jogħġbok irreferi wkoll għall- informazzjoni rilevanti tal- prodott għal dawn il- prodotti mediċinali.
Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice.
Pazjenti b’ disfunzjoni tal- fwied li kienet teżisti minn qabel inkluż epatite attiva kronika għandhom frekwenza akbar ta ’ abnormalitajiet fil- funzjoni tal- fwied waqt it- terapija mħallta antiretrovirali u għandhom ikunu osservati skond il- prattika stàndard.
If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.
Jekk hemm evidenza ta ’ mard tal- fwied li qed imur għall- agħar f’ dawn il- pazjenti, l- interruzjoni jew il- waqfien tal- kura irid ikun kunsidrat.
The use of Invirase in combination with ritonavir in patients with moderate hepatic impairment has not been studied.
L- użu ta ’ Invirase flimkien ma ’ ritonavir f’ pazjenti b’ indeboliment tal- fwied moderat ma kienx studjat.
In the absence of such studies, caution should be exercised, as increases in saquinavir levels and/or increases in liver enzymes may occur.
Fin- nuqqas ta ’ studji bħal dawn, attenzjoni għandha tingħata, għax żidiet fil- livelli ta ’ saquinavir u/ jew żidiet fl- enżimi tal- fwied jistgħu jseħħu.
There have been reports of exacerbation of chronic liver dysfunction, including portal hypertension, in patients with underlying hepatitis B or C, cirrhosis and other underlying liver abnormalities.
Kien hemm rapporti ta ’ aggravar ta ’ abnormalità kronika tal- fwied, li tinkludi pressjoni portali għolja, f’ pazjenti b’ epatite B jew C prinċipali, ċirrożi u abnormalitajiet prinċipali oħrajn tal- fwied.
However, patients with severe renal impairment have not been studied and caution should be exercised when prescribing saquinavir/ritonavir in this population.
Madankollu, pazjenti b’ indeboliment serju tal- kliewi għadhom ma kienux studjati u attenzjoni għandha tingħata meta saquinavir/ ritanovir ikun preskritt f’ dan il- grupp ta ’ nies.
The experience with In virase in children below the age of 16 and adults over 60 years is limited.
L- esperjenza b’ Invirase fit- tfal taħt l- eta ’ ta ’ 16 u adulti akbar minn 60 sena hija limitata.
26 Lactose intolerance:
27 Intolleranza għall- lattosju:
Invirase 500 mg film-coated tablets contain lactose.
Kapsuli ta ’ Invirase 200 mg fihom lattosju.
Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV–disease and/or long-term exposure to combination antiretroviral therapy (CART).
Għalkemm l- etjoloġija hija kkunsidrata bħala multifattorjali (inkluż użu ta ’ kortikosterojdi, konsum ta ’ alkoħol, immunosoppressjoni severa, indiċi tal- massa tal- ġisem għola), każijiet ta ’ osteonekrożi kienu rrappurtati speċjalment f’ pazjenti b’ marda ta ’ l- HIV avvanzata u/ jew espożizzjoni fit- tul għal terapija antiretrovirali kombinata (CART).
Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis carinii pneumonia.
Eżempji rilevanti huma retinite minn cytomegalovirus, infezzjonijiet ġeneralizzati u/ jew lokalizzati minn mikobakterja, u pnewmonja ikkawżata minn Pneumocystis carinii.
Caution must be exercised if Invirase/ritonavir is used concurrently with atorvastatin, which is metabolised to a lesser extent by CYP3A4.
Attenzjoni trid tittieħed jekk Invirase/ ritonavir jkun użat flimkien ma ’ atorvastatin, li huwa metabolizzat fi grad inqas mis- CYP3A4.
27 Oral contraceptives:
28 Kontraċettivi mill- ħalq:
Because concentration of ethinyl estradiol may be decreased when co- administered with Invirase/ritonavir, alternative or additional contraceptive measures should be used when oestrogen-based oral contraceptives are co-administered (see section 4.5).
Minħabba li l- konċentrazzjoni ta ’ ethinyl estradiol tista ’ tonqos meta jingħata fimkien ma ’ Invirase/ ritonavir, miżuri alternattivi jew addizzjonali ta ’ kontraċezzjoni iridu jintużaw meta kontraċettivi b’ bażi ta ’ estroġenu jingħataw fl- istess ħin (ara sezzjoni 4. 5).
Observations from drug interaction studies done with unboosted saquinavir might not be representative of the effects seen with saquinavir/ritonavir therapy.
Osservazzjonijiet minn studji ta ’ interazzjoni li saru b’ saquinavir mhux msaħħaħ jistgħu ma jkunux rappresentattivi ta ’ l- effetti li dehru b’ kura ta ’ saquinavir / ritonavir.
Furthermore, results seen with saquinavir soft capsules may not predict the magnitude of these interactions with Invirase/ritonavir.
Ukoll, ir- riżultati li dehru b’ kapsuli rotob ta ’ saquinavir jistgħu ma jipprevedux il- qawwa ta ’ dawn l- interazzjonijiet ma ’ Invirase/ ritonavir.
Therefore, medicinal products that either share this metabolic pathway or modify CYP3A4 and/or P-gp activity (see "Other potential interactions") may modify the pharmacokinetics of saquinavir.
Għalhekk, prodotti mediċinali li jew jaqsmu l- istess passaġġ metaboliku jew jimmodifikaw lil CYP3A4 u/ jew l- attività ta ’ P- gpn (ara “ Interazzjonijiet potenzjali oħra ”) jistgħu jimmodifikaw il- farmakokinetika ta ’ saquinavir.
28 Table 1:
29 Tabella 1:
Recommendations concerning co- administration
Rakkomandazzjonijiet li jikkonċernaw l- għoti fl- istess waqt - M’ hemmx bżonn ta ’ aġġustament fid- doża.
Nucleoside reverse transcriptase inhibitors (NRTIs) -
Didanosine doża waħda ta ’ 400 mg Saquinavir Cmax ↓ 25% (saquinavir/ ritonavir Saquinavir Cmin ↔ 1600/ 100 mg qd) Saquinavir AUC ↓ 1%
Zalcitabine and/or Zidovudine (saquinavir/ritonavir)
M’ hemmx bżonn ta ’ aġġustament fid- doża.
Interaction with zalcitabine is unlikely due to different routes of metabolism and excretion.
Tenofovir disoproxil fumarate 300 mg qd Saquinavir Cmax ↓ 7% (saquinavir/ ritonavir Saquinavir Cmin ↔ 1000/ 100 mg bid) Inibituri ta ’ non- nucleoside reverse transcriptase (NNRTIs) - Delavirdine - L- interazzjoni ma ’ Invirase/ ritonavir (saquinavir/ ritonavir) ma ’ ġietx studjata. - Saquinavir AUC ↑ 348%. - Delavirdine Hemm tagħrif limtat dwar is- sigurtà (saquinavir mhux u m’ hemmx tagħrif disponibbli dwar imsaħħaħ) l- effikaċja mill- użu ta ’ din it- taħlita.
For zidovudine (200 mg every 8 hours) a 25% decrease in AUC was reported when combined with ritonavir (300 mg every 6 hours).
Fi studju żgħir, preliminari, żjiedet fl- enżima epatoċellulari seħħew fi 13% ta ’ l- individwi matul l- ewwel diversi ġimgħat tat- taħlita ta ’ delavirdine u saquinavir (6% kienu ta ’ Grad 3 jew 4).
The pharmacokinetics of ritonavir remained unchanged.
Saquinavir ↔
- No dose adjustment required.
M’ hemmx bżonn ta ’ aġġustament fid- doża. - Bidliet epatoċellulari għandhom jiġu sorveljati ta ’ spiss jekk din it - taħlita tiġi preskritta.
-
Efavirenz 600 mg qd (saquinavir/ ritonavir Efavirenz ↔ 1600/ 200 mg qd, jew saquinavir/ ritonavir 1000/ 100 mg bid, jew saquinavir/ ritonavir 1200/ 100 mg qd) - Nevirapine - L- interazzjoni ma ’ (saquinavir/ ritonavir) Invirase/ ritonavir ma ’ ġietx studjata.
- Saquinavir ↔ Zalcitabine ↔ Zidovudine ↔
M’ hemmx bżonn ta ’ aġġustament fid- doża.
Saquinavir AUC ↓ 30% Saquinavir Cmax ↓ 25% Saquinavir Cmin ↔
- Saquinavir AUC ↓ 24% - Nevirapine (saquinavir mhux Nevirapine AUC ↔ imsaħħaħ) Indiċi: ↓ tnaqqis, ↑ żjieda, ↔ mhux mibdul, ↑↑ żjieda sostanzjali
No dose adjustment required.
- M’ hemmx bżonn ta ’ aġġustament fid- doża.
Tenofovir disoproxil fumarate 300 mg qd (saquinavir/ritonavir 1000/100 mg bid)
30 Prodott mediċinali skond Interazzjoni is- settur terapewtiku (doża ta ’ Invirase użata fl- istudju)
Saquinavir AUC ↓ 1% Saquinavir Cmax ↓ 7% Saquinavir Cmin ↔
Rakkomandazzjonijiet li jikkonċernaw l- għoti fl- istess waqt
No dose adjustment required.
Saquinavir AUC ↓ 15%
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) -
Fosamprenavir 700 mg bid Saquinavir Cmax ↓ 9% (saquinavir/ ritonavir Saquinavir Cmin ↓ 24% (baqgħet il - 1000/ 100 mg bid) fuq mil- livell immirat għal terapija effettiva.)
Delavirdine (saquinavir/ritonavir)
M’ hemmx bżonn ta ’ aġġustament fid- doża għal Invirase/ ritonavir.
Interaction with Invirase/ritonavir not studied.
Indinavir (saquinavir/ ritonavir)
Delavirdine (unboosted saquinavir)
Doża baxxa ta ’ ritonavir iżżid il - konċentrazzjoni ta ’ indinavir.
Saquinavir AUC ↑ 348%.
Indinavir 800 mg tid (saquinavir 600- 1200 mg
Saquinavir ↔ Efavirenz ↔
Saquinavir AUC ↑ 4. 6- 7. 2 darbiet Indinavir ↔
No dose adjustment required.
doża waħda)
- Nevirapine (saquinavir/ritonavir)
Ma ġewx stabbiliti d - dożi xierqa għal din it- taħlita.
- Interaction with Invirase/ritonavir not studied.
Lopinavir/ ritonavir
- Saquinavir AUC ↓ 24% Nevirapine AUC ↔
Saquinavir ↔
- No dose adjustment required.
M’ hemmx bżonn ta ’ aġġustament
Key: ↓ reduced, ↑ increased,
400/ 100 mg bid
↔ unchanged, ↑↑ markedly increased
Ritonavir ↓ (l- effettività bħala
Interaction
fid- doża.
Saquinavir AUC ↑ 60% Saquinavir Cmax ↑ 42% Ritonavir AUC ↑ 41% Ritonavir Cmax ↑ 34% Atazanavir ↔ No clinical data available for the combination of saquinavir/ritonavir 1000/100 mg bid and atazanavir.
(saquinavir/ ritonavir 1000/ 100 mg bid f’ taħlita
Fosamprenavir 700 mg bid (saquinavir/ritonavir 1000/100 mg bid)
sustanza li ssaħħaħ ma nbidlitx).
No dose adjustment required for Invirase/ritonavir.
Lopinavir ↔ (ibbażat fuq paragun
Appropriate doses of combination not established.
ma ’ 2 jew 3 NRTIs)
Increased concentrations of indinavir may result in nephrolithiasis.
storiku b’ lopinavir mhux imsaħħaħ)
Lopinavir/ritonavir 400/100 mg bid (saquinavir/ritonavir 1000/100 mg bid in combination with 2 or 3 NRTIs)
Saquinavir AUC ↑ 13% Nelfinavir 1250 mg bid (saquinavir/ ritonavir
Lopinavir ↔ (based on historical comparison with unboosted lopinavir)
27↓ - 74↑)
- Nelfinavir 1250 mg bid (saquinavir/ritonavir 1000/100 mg bid)
1000/ 100 mg bid)
- Saquinavir AUC ↑ 13% (90% CI:
Saquinavir Cmax ↑ 9% (90% CI:
- No dose adjustment required.
31 Prodott mediċinali skond Interazzjoni is- settur terapewtiku (doża ta ’ Invirase użata fl- istudju)
- Nelfinavir 750 mg tid (unboosted saquinavir 1200 mg tid)
Rakkomandazzjonijiet li jikkonċernaw l- għoti fl- istess waqt
- Saquinavir AUC ↑ 392% Saquinavir Cmax ↑ 179% Nelfinavir AUC ↑ 18% Nelfinavir Cmax ↔
- Nelfinavir 750 mg tid - Saquinavir AUC ↑ 392% (saquinavir mhux Saquinavir Cmax ↑ 179% imsaħħaħ 1200 mg tid) Nelfinavir AUC ↑ 18% Nelfinavir Cmax ↔
- Quadruple therapy, including saquinavir soft capsules and nelfinavir in addition to two nucleoside reverse transcriptase inhibitors gave a more durable response (prolongation of time to virological relapse) than triple therapy with either single protease inhibitor.
- Terapija kwadrupla, inkluż kapsuli rotob ta ’ saquinavir u nelfinavir flimkien ma ’ żewġ inibituri ta ’ nucleoside reverse transcriptase urew rispons aktar fit- tul (titwil taż- żmien sa rikaduta viroloġika) minn terapija tripla b’ xi wieħed mill- inibituri tal- protease waħdu.
Recommendations concerning co- administration
Ritonavir 100 mg bid Saquinavir ↑ Ritonavir ↔
Ritonavir 100 mg bid (saquinavir 1000 mg bid)
Dan huwa l- kors ta ’ taħlita approvat.
Saquinavir ↑ Ritonavir ↔ In HIV-infected patients, Invirase or saquinavir soft capsules in combination with ritonavir at doses of 1000/100 mg twice daily provide a systemic exposure of saquinavir over a 24 hour period similar to or greater than that achieved with saquinavir soft capsules 1200 mg three times daily (see section 5.2).
(saquinavir 1000 mg bid) F’ pazjenti infettati b’ HIV, Invirase jew kapsuli rotob ta ’ saquinavir flimkien ma ’ ritonavir f’ dożi ta ’ 1000/ 100 mg darbtejn kuljum jipprovdu esponiment sistemiku ta ’ saquinavir tul perijodu ta ’ 24 siegħa simili jew aktar minn dak li ntlaħaq b’ kapsuli rotob ta ’ saquinavir 1200 mg tliet darbiet kuljum (ara sezzjoni 5. 2).
Tipranavir/ritonavir (saquinavir/ritonavir) HIV fusion inhibitor
Saquinavir Cmin ↓ 78% Tipranavir/ ritonavir (saquinavir/ ritonavir) Terapija kombinata imsaħħa b’ żewġ inibituri tal- protease f’ pazjenti adulti bl- HIV b’ esperjenza ta ’ kura multipla.