natgillin/translations-raw huggingface dataset:
1, 5 (0, 75- 5, 0) timer efter dosering (tmax).
After multiple dose oral administration of fosamprenavir 700 mg with ritonavir 100 mg twice daily, amprenavir was rapidly absorbed with a geometric mean (95% CI) steady state peak plasma amprenavir concentration (Cmax) of 6.08 (5.38-6.86) µg/ ml occurring approximately 1.5 (0.75-5.0) hours after dosing (tmax).
Den gennemsnitlige steady state plasma amprenavir laveste koncentration (Cmin) var 2, 12 (1, 77 - 2, 54) μg/ ml og AUC0- tau var 39, 6 (34, 5- 45, 3) h* μg/ ml.
The mean steady state plasma amprenavir trough concentration (Cmin) was 2.12 (1.77-2.54) µg/ ml and AUC0-tau was 39.6 (34.5– 45.3) h*µg/ ml.
Administration af fosamprenavir tabletter efter fødeindtagelse (standardiseret meget fedtholdigt måltid:
Administration of the fosamprenavir tablet formulation in the fed state (standardised high fat meal:
967 kcal, 67 gram fedt, 33 gram protein, 58 gram kulhydrat) ændrede ikke på
967 kcal, 67 grams fat, 33 grams protein, 58 grams carbohydrate) did not alter plasma amprenavir pharmacokinetics (Cmax, tmax or AUC0- ∞) compared to the administration of this formulation in the fasted state.
Telzir tabletter kan tages uden hensyn til fødeindtagelse.
Telzir tablets may be taken without regard to food intake.
Dette tyder på et stort fordelingsvolumen med distribution af amprenavir frit ind i vævet uden om kredsløbet.
The apparent volume of distribution of amprenavir following administration of Telzir is approximately 430 l (6 l/ kg assuming a 70 kg body weight), suggesting a large volume of distribution, with penetration of amprenavir freely into tissues beyond the systemic circulation.
40%, når Telzir administreres sammen med ritonavir, muligvis pga. amprenavirs øgede biotilgængelighed.
This value is decreased by approximately 40% when Telzir is co-administered with ritonavir, most likely due to an increase in amprenavir bioavailability.
Amprenavir bindes hoved - sageligt til alfa- 1- syre glycoprotein (AAG), men også til albumin.
It is bound to the alpha-1- acid glycoprotein (AAG) and albumin, but has a higher affinity for AAG.
Mængden af ubundet amprenavir, som er den aktive del, er formentlig uændret.
This change will decrease the total active substance concentration in the plasma, however the amount of unbound amprenavir, which is the active moiety, is likely to be unchanged.
Amprenavir kan findes ind i sæd, men koncentrationen fundet i sæd er lavere end koncentrationen i plasma.
Amprenavir appears to penetrate into semen, though semen concentrations are lower than plasma concentrations.
Efter peroral administration bliver fosamprenavir hurtigt og næsten fuldstændigt hydrolyseret til amprenavir og uorganisk fosfat før det når kredsløbet.
Fosamprenavir is rapidly and almost completely hydrolysed to amprenavir and inorganic phosphate as it is absorbed through the gut epithelium, following oral administration.
Amprenavir metaboliseres hovedsageligt i leveren, og mindre end 1% udskilles uomdannet i urinen.
Amprenavir is primarily metabolised by the liver with less than 1% excreted unchanged in the urine.
Den primære metaboliseringsvej er via cytokrom P450 3A4 enzymet.
The primary route of metabolism is via the cytochrome P450 3A4 enzyme.
Amprenavir hæmmer endvidere CYP3A4 enzymet, dog i mindre omfang end ritonavir.
Amprenavir in addition is also an inhibitor of the CYP3A4 enzyme, although to a lesser extent than ritonavir.
4. 3 og 4. 5).
Therefore medicinal products that are inducers, inhibitors or substrates of CYP3A4 must be used with caution when administered concurrently with Telzir with ritonavir (see sections 4.3 and 4.5).
Efter administration af Telzir er halveringstiden for amprenavir 7, 7 timer.
Following administration of Telzir, the half-life of amprenavir is 7.7 hours.
Når Telzir administreres sammen med ritonavir er halveringstiden for amprenavir øget til 15- 23 timer.
When Telzir is co-administered with ritonavir, the half-life of amprenavir is increased to 15 – 23 hours.
Ca.
19 The primary route of elimination of amprenavir is via hepatic metabolism with less than 1% excreted unchanged in the urine and no detectable amprenavir in faeces.
75% af den indgivne dosis findes som metabolitter i fæces.
Metabolites account for approximately 14% of the administered amprenavir dose in the urine, and approximately 75% in the faeces.
Sammenlignet med historiske data for voksne behandlet med samme doser havde de 12 til 18- årige 20% lavere plasma APV AUC( 0- 24), 23% lavere Cmax, og 20% lavere Cmin- værdier.
Compared to the historical adult population receiving fosamprenavir / ritonavir 700 / 100 mg twice daily, 12 to 18 year old subjects had 20% lower plasma APV AUC(0- 24), 23% lower Cmax, and 20% lower Cmin values.
Sammenlignet med de historiske data for voksne havde de 6 til 11- årige 26% højere AUC( 0- 24), men samme Cmax og Cmin- værdier.
Children 6 to 11 years of age (n=9) receiving fosamprenavir / ritonavir 18 / 3 mg/ kg twice daily had 26% higher AUC(0-24) and similar Cmax and Cmin values when compared to the historical adult population receiving fosamprenavir / ritonavir 700 / 100 mg twice daily.
Hos 5 børn i alderen 6 til 24 måneder, der blev behandlet med 45 mg fosamprenavir/ kg og 7 mg ritonavir/ kg 2 gange daglig, blev det påvist, at på trods af en 5- fold stigning i doser af fosamprenavir og ritonavir, var AUC( 0- τ) for amprenavir i plasma cirka 48% lavere, Cmax 26% lavere og Cτ 29% lavere hos børnene.
Compared to the historical adult population receiving fosamprenavir with ritonavir 700 mg / 100 mg twice daily, a subset of five pediatric subjects ages 6 to < 24-months receiving fosamprenavir / ritonavir 45/ 7 mg/ kg twice daily demonstrated that despite an approximate 5-fold increase in fosamprenavir and ritonavir doses on a mg/ kg basis, plasma amprenavir AUC(0-τ) was approximately 48% lower, Cmax 26% lower, and Cτ 29% lower in the paediatric subjects.
4. 2).
No dosing recommendations can be made for the very young (children < 2 years of age) and Telzir with ritonavir is not recommended for this patient population (see section 4.2).
Farmakokinetikken af fosamprenavir i kombination med ritonavir er ikke blevet undersøgt hos patien - ter over 65 år.
The pharmacokinetics of fosamprenavir in combination with ritonavir has not been studied in patients over 65 years of age.
Mindre end 1% af den terapeutiske dosis af amprenavir udskilles uændret i urinen.
Less than 1% of the therapeutic dose of amprenavir is excreted unchanged in the urine.
Nyrernes udskillelse af ritonavir er ligeledes forsvind - ende lille, og derfor vurderes betydningen af nedsat nyrefunktion på eliminationen af amprenavir og ritonavir til at være minimal.
Renal clearance of ritonavir is also negligible, therefore the impact of renal impairment on amprenavir and ritonavir elimination should be minimal
Alle personer i forsøget fik fosamprenavir i kombination med ritonavir.
The plasma amprenavir pharmacokinetics were evaluated in a 14 day repeat-dose study in HIV-1 infected adult subjects with mild, moderate, or severe hepatic impairment receiving fosamprenavir with ritonavir compared to matched control subjects with normal hepatic function.
Hos personerne med let nedsat leverfunktion sås en let forhøjet plasma- Cmax for amprenavir (17%), en let forhøjet plasma- AUC( 0- 12) for amprenavir (22%), tilsvarende totale plasma- C12 - værdier for amprenavir og cirka 117% højere plasma- C12- værdier for ubundet amprenavir.
In subjects with mild hepatic impairment (Child-Pugh score of 5-6), the dosage regimen of fosamprenavir 700 mg twice daily with a reduced dosing frequency of ritonavir 100 mg once daily provided slightly higher plasma amprenavir Cmax (17%), slightly higher plasma amprenavir AUC(0-12) (22%), similar plasma total amprenavir C12 values and approximately 117% higher plasma unbound amprenavir C12 values compared to subjects with normal hepatic function receiving the standard fosamprenavir / ritonavir 700 mg / 100 mg twice daily regimen.
De totale plasma- C12- værdier for amprenavir forventes at være 35% lavere og cirka 88% højere plasma- C12- værdier for ubundet amprenavir.
In subjects with moderate hepatic impairment (Child-Pugh score of 7-9), a reduced dose of fosamprenavir 450 mg twice daily with a reduced dosing frequency of ritonavir 100 mg once daily is 20 predicted to deliver similar plasma amprenavir Cmax and AUC(0-12), but approximately 35% lower plasma total amprenavir C12 values and approximately 88% higher plasma unbound amprenavir C12 values than achieved in subjects with normal hepatic function receiving the standard fosamprenavir with ritonavir 700 mg / 100 mg twice daily regimen.
Plasma- C12- værdier for ubundet amprenavir var ens i de to grupper.
In subjects with severe hepatic impairment (Child-Pugh score of 10-13), a reduced dose of fosamprenavir 300 mg twice daily with a reduced dosing frequency of ritonavir 100 mg once daily delivered 19% lower plasma amprenavir Cmax, 23% lower AUC(0-12), and 38% lower C12 values, but similar unbound plasma amprenavir C12 values than achieved in subjects with normal hepatic function receiving the standard fosamprenavir with ritonavir 700 mg / 100 mg twice daily regimen.
På trods af den reducerede doseringshyppighed af ritonavir havde personer med svært nedsat leverfunktion en 64% højere plasma- Cmax, 40% højere plasma- AUC( 0- 24) og 38% højere plasma- C12- værdier for ritonavir i forhold til patienter med normal leverfunktion, der fik standardbehandlingen 700 mg fosamprenavir i kombination med 100 mg ritonavir to gange daglig.
Despite reducing the dosing frequency of ritonavir, subjects with severe hepatic impairment had 64% higher ritonavir Cmax, 40% higher ritonavir AUC(0-24), and 38% higher ritonavir C12 than achieved in subjects with normal hepatic function receiving the standard fosamprenavir with ritonavir 700 mg / 100 mg twice daily regimen.
Ovennævnte studier viste samme bivirkningsprofil og samme kliniske laboratorieværdier som tidligere studier af HIV- 1- inficerede personer med normal leverfunktion.
Fosamprenavir with ritonavir was generally well-tolerated in subjects with mild, moderate, or severe hepatic impairment, and these regimens had similar adverse event and clinical laboratory profiles as previous studies of HIV-1 infected subjects with normal hepatic function.
Toksiciteten forekom ved plasmakoncentrationer som var lavere end plasmakoncentrationen hos mennesker ved behandling med fosamprenavir i kombination med ritonavir ved den anbefalede dosis.
Toxicity was similar to that of amprenavir and occurred at amprenavir plasma exposure levels below human exposure after treatment with fosamprenavir in combination with ritonavir at the recommended dose.
Ved gentagne dosistoksicitetsundersøgelser med både voksne rotter og hunde har man for fosamprenavir påvist gastrointestinale forstyrrelser (spytafsondring, opkast og blød til flydende fæces) og ændringer i leveren (øget levervægt, øget serumleverenzymaktivitet, og mikroskopiske ændringer, herunder hepatocyt nekrose).
In repeated dose toxicity studies in adult rats and dogs, fosamprenavir produced evidence of gastrointestinal disturbances (salivation, vomiting and soft to liquid faeces), and hepatic changes (increased liver weights, raised serum liver enzyme activities and microscopic changes, including hepatocyte necrosis).
I reproduktive toksikologiske undersøgelser af fosamprenavir i rotter var fertiliteten hos hanrotterne upåvirket.
In reproductive toxicity studies with fosamprenavir in rats, male fertility was not affected, but in females gravid uterine weights, numbers of ovarian corpora lutea and uterine implantation sites were reduced.
Hos hunrotterne var vægten af den drægtige livmoder, antallet af ovarie corpora lutea og livmoderimplantationssteder nedsat.
In pregnant rats and rabbits there were no major effects on embryo-foetal development.
Hos drægtige rotter og kaniner var der ingen større effekt på em - bryo- foster udviklingen, men antallet af aborter var forøget.
However, the number of abortions increased.
Hos kaniner var den systemiske eksponering af den højeste dosis kun 0, 3 gange den dosis for human eksponering ved maksimum klinisk dosis og derfor er den udviklingsrelaterede toksicitet af fosamprenavir ikke klarlagt.
In rabbits, systemic exposure at the high dose level was only 0.3 times human exposure at the maximum clinical dose and thus the developmental toxicity of fosamprenavir has not been fully determined.
Ydermere var antallet af implantationssteder per kuld nedsat og gestations- perioden var forlænget hos ungerne, når disse efter at være blevet kønsmodne blev parret.
In addition, decreased number of implantation sites per litter and a prolongation of gestation were seen when pups were mated after reaching maturity.
Hos rotter sås stigninger i hepatocellulære adenomaer og thyroid follikel celle- adenomaer ved eksponeringsniveauer 0, 3- 0, 6 gange større end den humane dosis på 700 mg fosamprenavir plus 100 mg ritonavir 2 gange daglig.
In long-term carcinogenicity studies with fosamprenavir in mice and rats, there were increases in hepatocellular adenomas and hepatocellular carcinomas in mice at exposure levels equivalent to 0.1 to 0.3-fold those in humans given 700 mg of fosamprenavir plus 100mg ritonavir twice daily, and increases in hepatocellular adenomas and thyroid follicular cell adenomas in rats at exposure levels equivalent to 0.3 to 0.6-fold those in humans given 700 mg of fosamprenavir plus 100mg ritonavir twice daily.
Forsøg med rotter, der fik gentagne doser af fosamprenavir, viste påvirkninger forenelig med enzyminduktion i leveren, hvilket prædisponerer rotter for thyroide neoplasmaer.
Repeat dose studies with fosamprenavir in rats produced effects consistent with hepatic enzyme induction, which predisposes rats to thyroid neoplasms.
Hos hanrotter sås en højere forekomst af interstitiel celle- hyperplasi ved eksponeringsniveauer 0, 5 gange større end den humane, og i hunrotter sås en stigning i uterin endometrial adenocarcinomaer ved eksponeringsniveauer 1, 1 gange større end den humane.
In rats 21 only there was an increase in interstitial cell hyperplasia in males at exposure levels equivalent to 0.5- fold those in humans, and an increase in uterine endometrial adenocarcinoma in females at an exposure level equivalent to 1.1-fold those in humans.
Mikrokrystallinsk cellulose Croscarmellosenatrium Povidon K30 Magnesiumstearat Kolloid vandfri silica
Microcrystalline cellulose Croscarmellose sodium Povidone K30 Magnesium stearate Colloidal anhydrous silica
21 Filmovertræk:
Tablet film-coat:
Hypromellose Titandioxid (E171) Glyceroltriacetat Rød jernoxid (E172)
Hypromellose Titanium dioxide (E171) Glycerol triacetate Iron oxide red (E172)
Beholderen indeholder 60 tabletter.
HDPE bottles with a child resistant polypropylene closure containing 60 tablets.
Ikke anvendte lægemidler samt affald heraf bør destrueres i henhold til lokale retningslinier.
Any unused product should be disposed of in accordance with local requirements..
Glaxo Group Ltd Greenford Road Greenford Middlesex UB6 0NN Storbritannien
Glaxo Group Ltd Greenford Road Greenford
Telzir 50 mg/ ml oral suspension.
Telzir 50 mg/ ml oral suspension.
43 mg amprenavir).
Each ml of oral suspension contains 50 mg fosamprenavir as fosamprenavir calcium (equivalent to approximately 43 mg amprenavir).
Suspensionens farve er hvid til off- white.
The suspension is white to off-white in colour.
5. 1).
In protease inhibitor (PI) experienced patients, the choice of Telzir should be based on individual viral resistance testing and treatment history (see section 5.1).
Produktresumeet for ritonavir skal derfor konsulteres før påbegyndelse af behandlingen med Telzir.
The Summary of Product Characteristics of ritonavir must therefore be consulted prior to initiation of therapy with Telzir.
4. 4).
24 Caution is advised if the recommended dose of fosamprenavir with ritonavir detailed below are exceeded (see section 4.4).
Ryst flasken 5 sekunder før efterfølgende brug.
Shake the bottle vigorously for 20 seconds before first dose is removed and 5 seconds before each subsequent dose.
5. 2).
In paediatric patients, the oral suspension should be taken with food in order to aid palatability and assist compliance (see section 5.2).
24 Der kan ikke gives doseringsanbefalinger til børn under 25 kg.
No dosing recommendations can be made for children weighing less than 25 kg.
Voksne (≥ 18
Adult (> 18
år)
years)
Den orale suspension bør tages uden mad 6- 17 år
Oral suspension should be taken without food 6-17 years
≥ 39 kg
> 39 kg
700 mg eller 14 ml
18 mg/ kg (0.36 ml/ kg); maximum 700 mg or 14 ml
25 Til voksne med moderat nedsat leverfunktion (Child- Pugh Score:
For adults with moderate hepatic impairment (Child-Pugh score:
7- 9) er den anbefalede dosis 450 mg fosamprenavir (fx 9 ml Telzir oral suspension) to gange daglig i kombination med 100 mg ritonavir en gang daglig.
9 ml Telzir oral suspension) twice daily with 100 mg ritonavir once daily.
Derfor er tæt monitorering af sikkerhed og virologisk respons påkrævet.
Even with these dose adjustments for adults with, some patients with hepatic impairment may have higher or lower than anticipated amprenavir and/ or ritonavir plasma concentrations as compared to patients with normal hepatic function, due to increased inter-patient variability (see section 5.2), therefore a close monitoring of safety and virologic response is warranted.
4. 5 mht parenteral midazolam), oral triazolam.
26 Telzir must not be administered concurrently with medicinal products with narrow therapeutic windows that are substrates of cytochrome P450 3A4 (CYP3A4), e. g. amiodarone, astemizole, bepridil, cisapride, dihydroergotamine, ergotamine, pimozide, quinidine, terfenadine, oral midazolam (for caution on parenterally administered midazolam, see section 4.5), oral triazolam.
4. 5).
Telzir with ritonavir must not be co-administered with medicinal products with narrow therapeutic windows that are highly dependent on CYP2D6 metabolism e. g. flecainide and propafenone (see section 4.5).
Patienterne kan fortsat udvikle opportunistiske infektioner eller andre komplikationer af HIV- infektionen.
Patients should be advised that treatment with the Telzir, or any other current antiretroviral therapy, does not cure HIV and that they may still develop opportunistic infections and other complications of HIV infection.
I pivotale studier af Telzir, med patienter behandlet med fosamprenavir og ritonavir, fandt man ingen tegn på forøget risiko for udslæt hos patienter med kendt sulfonamidallergi, sammenlignet med patienter som ikke havde sulfonamidallergi.
In the pivotal studies of Telzir, in patients receiving fosamprenavir with ritonavir there was no evidence of an increased risk of rashes in patients with a history of sulphonamide allergy versus those who did not have a sulphonamide allergy.
Telzir oral suspension indeholder propyl - og methylparahydroxybenzoat.
The Telzir oral suspension contains propyl and methyl parahydroxybenzoate.
26 Samtidig administration af Telzir 700 mg 2 gange daglig og ritonavir i doser større end 100 mg 2 gange daglig er ikke blevet klinisk undersøgt.
Co-administration of Telzir 700 mg twice daily with ritonavir in doses greater than 100 mg twice daily has not been clinically evaluated.
Patienter med kronisk hepatitis B eller C behandlet med antiretroviral kombinationsbehandling har større risiko for alvorlige og potentielt fatale leverpåvirkninger.
Telzir with ritonavir should be used with caution and at reduced doses in adults with mild, moderate or severe hepatic impairment (see section 4.2). Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk of severe and potentially fatal hepatic adverse events.
Brugen af Telzir sammen med halofantrin eller lidokain (systemisk) kan ikke anbefales.
The use of Telzir concomitantly with halofantrine or lidocaine (systemic) is not recommended.
4. 5).
27 The use of Telzir concomitantly with PDE5 inhibitors (e. g. sildenafil and vardenafil) is not recommended (see section 4.5).
4. 5).
Therapeutic concentration monitoring is recommended for immunosuppressant medicinal products (cyclosporine, tacrolimus, rapamycin) when co-administered with Telzir (see section 4.5).
4. 5).
Therapeutic concentration monitoring is recommended for tricyclic antidepressants (e. g. desipramine and nortriptyline) when co-administered with Telzir (see section 4.5).
4. 5).
When warfarin or other oral anticoagulants are co-administered with Telzir a reinforced monitoring of INR (International normalised ratio) is recommended (see section 4.5).
27 Udslæt/ hudreaktioner
Rash / cutaneous reactions
Der er rapporteret om øget blødningstendens, herunder spontane hudhæmatomer og hæmarthroner, hos hæmofilipatienter type A og B, som blev behandlet med proteasehæmmere (PI’ er).
There have been reports of increased bleeding including spontaneous skin haematomas and haemarthroses in haemophiliac patients type A and B treated with protease inhibitors (PIs).
Nye tilfælde af diabetes mellitus, hyperglykæmi eller forværring af eksisterende diabetes mellitus er konstateret hos patienter behandlet med antiretroviral terapi, herunder proteasehæmmere.
28 New onset of diabetes mellitus, hyperglycaemia or exacerbations of existing diabetes mellitus have been reported in patients receiving antiretroviral therapy, including protease inhibitors.
En højere risiko for at få lipodystrofi er blevet sat i forbindelse med individuelle faktorer såsom højere alder og lægemiddelrelaterede faktorer såsom længere antiretroviral behandlingstid og ledsagende metaboliske forstyrrelser.
A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances.
28 4. 5 Interaktion med andre lægemidler og andre former for interaktion
4.5 Interaction with other medicinal products and other forms of interaction
Derfor kan lægemidler, som har samme metaboliseringsvej eller modificerer aktiviteten af CYP3A4, eventuelt ændre farmakokinetikken af amprenavir og ritonavir.
Therefore, any medicinal products that either share this metabolic pathway or modify CYP3A4 activity may modify the pharmacokinetics of amprenavir and ritonavir.
CYP3A4- substrater med smalt terapeutisk vindue Telzir må ikke administreres samtidig med lægemidler med smalt terapeutisk vindue hvis aktive stoffer er substrater for cytokrom P450 3A4 (CYP3A4).
CYP3A4 substrates with narrow therapeutic index
Samtidig administration kan resultere i kompetitiv hæmning af metabolismen af disse aktive stoffer.
29 Telzir must not be administered concurrently with medicinal products with narrow therapeutic windows containing active substances that are substrates of cytochrome P450 3A4 (CYP3A4).
Hermed øges plasmaniveauet af disse aktive stoffer, hvilket kan medføre alvorlige og/ eller livstruende bivirkninger såsom hjertearytmi (f. eks. amiodaron, astemizol, bepridil, cisaprid, pimozid, quinidin, terfanain), perifere vasospasmer eller iskæmi (f. eks. ergotamin, dihydroergotamin).
Co-administration may result in competitive inhibition of the metabolism of these active substances thus increasing their plasma levels and leading to serious and / or life-threatening adverse reactions such as cardiac arrhythmia (e. g. amiodarone, astemizole, bepridil, cisapride, pimozide, quinidine, terfenadine) or peripheral vasospasm or ischaemia (e. g. ergotamine, dihydroergotamine).
CYP2D6- substrater med smalt terapeutisk vindue Kombinationsbehandlingen med Telzir og ritonavir må ikke administreres samtidig med lægemidler indeholdende aktive stoffer der i høj grad afhænger af CYP2D6 metabolismen og for hvilke en forøget plasmakoncentration kan medføre alvorlige og/ eller livstruende bivirkninger.
CYP2D6 substrates with narrow therapeutic index Telzir with ritonavir must not be co-administered with medicinal products containing active substances that are highly dependent on CYP2D6 metabolism and for which elevated plasma concentrations are associated with serious and / or life-threatening adverse reactions.