natgillin/translations-raw huggingface dataset:
En nedsættelse af rifabutin dosis med mindst 50% er anbefalet ved samtidig brug af Agenerase.
24 A reduction of rifabutin dosage of at least 50% is recommended when administered with Agenerase.
Agenerase kapsler indeholder vitamin E (109 IU/ 150 mg kapsel), derfor anbefales ekstra vitamin E - tilskud ikke.
Agenerase capsules contain vitamin E (109 IU/ 150 mg capsule), therefore additional vitamin E supplementation is not recommended.
Hos nogle patienter blev
In some
25 der givet ekstra faktor VIII.
25 patients, additional factor VIII was given.
Når amprenavir og ritonavir co- administreres vil ritonavirs metaboliske interaktion tilsyneladende dominere, idet ritonavir er en mere potent CYP3A4 hæmmer.
When amprenavir and ritonavir are co-administered, the ritonavir metabolic drug interaction profile may predominate because ritonavir is a more potent CYP3A4 inhibitor.
Herved øges deres plasmaniveau, hvilket kan medføre til alvorlige og / eller livstruende bivirkninger såsom hjertearytmi (f. eks. amiodaron, astemizol, bepridil, cisaprid, pimozid, quinidin, terfanadin) eller periferale 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 level 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) (see section 4.3).
Rifampicin Rifampicin er en potent CYP3A4 inducer og har vist sig at forårsage en reduktion i amprenavir AUC med 82%, hvilket kan føre til manglende virologisk effekt og resistensudvikling.
26 Rifampicin Rifampicin is a strong CYP3A4 inducer and has been shown to cause an 82% decrease in amprenavir AUC, which can result in virological failure and resistance development.
Den induktive effekt kan vedblive i op til 2 uger efter ophør af behandlingen med prikbladet perikum.
The inducing effect may persist for at least 2 weeks after cessation of treatment with St John’ s wort (see section 4.3).
AUC og Cmin for amprenavir blev forøget med henholdsvis 64% og 508% og Cmax blev nedsat med 30%, når ritonavir (100 mg 2 gange daglig) blev administreret sammen med amprenavir kapsler (600 mg 2 gange daglig), sammenlignet med værdier opnået efter administration af amprenavir kapsler i doseringen 1200 mg 2 gange daglig.
Ritonavir: the AUC and Cmin of amprenavir were increased by 64% and 508% respectively and the Cmax decreased by 30% when ritonavir (100 mg twice daily) was coadministered with amprenavir capsules (600 mg twice daily) compared to values achieved after 1200 mg twice daily doses of amprenavir capsules.
40- 50% lavere end da amprenavir (600 mg 2 gange daglig) blev givet i kombination med ritonavir (100 mg 2 gange daglig).
The amprenavir plasma Cmin values achieved with the combination of amprenavir (600 mg twice daily) in combination with Kaletra (400 mg lopinavir + 100 mg ritonavir twice daily) are approximately 40- 50% lower than when amprenavir (600 mg twice daily) is given in combination with ritonavir 100 mg
27 • Nukleosidanalog revers transkriptasehæmmere (NRTI)
Adding additional ritonavir to an amprenavir plus Kaletra regimen increase lopinavir Cmin values, but not amprenavir Cmin values.
AUC, Cmin og Cmax for abacavir var uændrede, når det blev givet med amprenavir.
Abacavir: the AUC, Cmin, and Cmax of abacavir were unaltered when given with amprenavir.
AUC, Cmin og Cmax for amprenavir var øget med henholdsvis 29%, 27% og 47%.
The AUC, Cmin, and Cmax of amprenavir were increased by 29%, 27%, and 47%, respectively.
40% hos voksne.
Efavirenz: efavirenz has been seen to decrease the Cmax, AUC, and Cmin, ss of amprenavir by approximately 40% in adults.
Der bør udvises forsigtighed ved anvendelse af disse medicinal - produkter samtidig.
If these medicinal products are used concomitantly care is advised, and
Klinisk og virologisk monitorering bør foretages og følges nøje, idet det er svært at forudsige effekten af den samtidige administration af amprenavir og ritonavir på delavirdine.
28 close clinical and virological monitoring should be performed since it is difficult to predict the effect of the combination of amprenavir and ritonavir on delavirdine.
Antibiotika/ svampemidler
Antibiotics/ antifungals
Øgningen i plasmaconcentrationen af rifabutin stammer sandsynligvis fra amprenavirs hæmning af CYP3A4- medieret metabolisme af rifabutin.
The increase in rifabutin plasma concentration is likely to result from inhibition of rifabutin CYP3A4 mediated metabolism by amprenavir.
AUC, Cmin og Cmax for amprenavir var øget med henholdsvis 18%, 39% og 15%.
The AUC, Cmin and Cmax of amprenavir were increased by 18%, 39%, and 15% respectively.
AUC og Cmax for ketoconazol var øget med henholdsvis 44% og 19%, når stoffet blev givet sammen med amprenavir alene.
Ketoconazole / Itraconazole: the AUC and Cmax of ketoconazole were increased by 44% and 19% respectively when given with amprenavir alone.
På baggrund af data fra andre proteasehæmmere, bør der udvises forsigtighed, hvis PDE5 hæmmere (f. eks. sildenafil og vardenafil) ordineres til patienter, der får Agenerase.
29 Erectile dysfunction agents: based on data for other protease inhibitors caution should be used when prescribing PDE5 inhibitors (e. g. sildenafil and vardenafil) to patients receiving Agenerase.
I et klinisk studie, hvor ritonavir 100 mg kapsler blev givet 2 gange daglig samtidig med 50 µg intranasal fluticasonpropionat (4 gange daglig) i 7 dage til raske personer, steg fluticasonpropionatplasmaniveauet signifikant, mens det interne kortisolniveau faldt med cirka 86% (90% konfidensinterval 82- 89%).
Fluticasone propionate (interaction with ritonavir): in a clinical study where ritonavir 100 mg capsules bid were co-administered with 50 µg intranasal fluticasone propionate (4 times daily) for 7 days in healthy subjects, the fluticasone propionate plasma levels increased significantly, whereas the intrinsic cortisol levels decreased by approximately 86% (90% confidence interval 82-89%).
Samtidig administration af methadon og amprenavir resulterede i en nedsættelse af Cmax og AUC af den aktive methadon enantiomer (R- enantiomeren) på henholdsvis 25% og 13%, mens Cmax, AUC og Cmin for den inaktive enantiomer (S- enantiomeren) blev nedsat med henholdsvis 48%, 40% og 23%.
Methadone and opiate derivatives: co-administration of methadone with amprenavir resulted in a decrease in the Cmax and AUC of the active methadone enantiomer (R-enantiomer) of 25% and 13% respectively, whilst the Cmax, AUC and Cmin of the inactive methadone enantiomer (S-enantiomer) were decreased by 48%, 40% and 23% respectively.
Til sammenligning viste samtidig administration af methadon og amprenavir i en historisk ikke - matched kontrolgruppe en nedsættelse af serum amprenavir AUC, Cmax og Cmin med henholdsvis 30%, 27% og 25%.
30 As compared to a non-matched historical control group, co-administration of methadone and amprenavir resulted in a 30%, 27% and 25% decrease in serum amprenavir AUC, Cmax and Cmin respectively.
Der kan på nuværende tidspunkt ikke gives anbefalinger vedrørende justering af amprenavirdoseringen, når amprenavir gives samtidig med methadon på grund af den naturligt lave reliabilitet af den ikke- matched historiske kontrol.
No recommendations can currently be made regarding adjustment of amprenavir dose when amprenavir is co-administered with methadone due to the inherent low reliability of non- matched historical controls.
Når warfarin eller andre orale antikoagulanter administreres samtidig med Agenerase, anbefales en øget monitorering af IRN (International Normaliseret Ratio) på grund af et muligt fald eller en mulig stigning i deres anti- thrombotiske virkning (se afsnit 4. 4).
Oral anticoagulants: a reinforced monitoring of the International Normalised Ratio is recommended in case of administration of Agenerase with warfarin or other oral anticoagulants, due to a possible decrease or increase of their antithrombotic effect (see section 4.4).
Samtidig administration af 0, 035 mg ethinylestradiol og 1, 0 mg norethidrom resulterede i et fald i AUC og Cmin for Agenerase på henholdsvis 22% og 20%, Cmax var uændret.
Co-administration of 0.035 mg ethinyl estradiol plus 1.0 mg norethindrone resulted in a decrease of the amprenavir AUC and Cmin of 22% and 20% respectively, Cmax being unchanged.
30 effekten på koncentrationen af de kontraceptive hormoner ikke forudsiges, og derfor anbefales andre svangerskabsforebyggende metoder.
When ritonavir is co-administered, the effect on hormonal contraceptive concentrations cannot be predicted, therefore, alternative methods of contraception are also recommended.
Desuden anbefales det, at HIV- inficerede kvinder ikke ammer deres spædbørn for at undgå at overføre HIV.
Additionally, it is recommended that HIV infected women do not breast-feed their infants in order to avoid transmission of HIV.
Bivirkninger, som betragtes forbundet med anvendelsen af Agenerase, er gastrointestinale symptomer, udslæt og oral/ perioral paræstesi.
Adverse events considered associated with the use of Agenerase are gastro-intestinal symptoms, rash and oral/ peri-oral
31 Placeringen af nedenfor nævnte bivirkninger med hensyn til frekvens er baseret på data fra kliniske undersøgelser og postmarketing data.
Frequency categories for the events below have been based on clinical trials and postmarketing data.
Mave- tarmkanalen
32 Gastrointestinal disorders
32 Hud og subkutane væv
Skin and subcutaneous tissue disorders
Hvis der forekommer overdosering, bør patienten overvåges for tegn på toksicitet (se afsnit 4. 8), og standard symptomatisk behandling iværksættes om nødvendigt.
If overdose occurs, the patient should be monitored for evidence of toxicity (see section 4.8), and standard supportive treatment provided as necessary.
Farmakoterapeutisk klassifikation: proteasehæmmer, ATC- kode:
Pharmacotherapeutic group; protease inhibitor; ATC Code:
33 Antiviral in vitro- aktivitet
Antiviral activity in vitro
Reduceret følsomhed over for amprenavir var associeret med virus, som havde udviklet I50V, I84V, V32I+I47V eller I54M mutationer.
HIV-1 isolates with decreased susceptibility to amprenavir have been selected during in vitro serial passage experiments Reduced susceptibility to amprenavir was associated with virus that had developed I50V or I84V or V32I+I47V or I54M mutations.
b) Patienter, der tidligere har været behandlet med PI’ er
34 b) PI-experienced patients
I forbindelse med studier af patienter, som fik behandling med PI’ er, observeredes følgende mutationer hos de patienter, der fik virologisk svigt:
In the studies of PI-experienced patients, PRO30017 (amprenavir 600 mg / ritonavir 100 mg twice daily in sub-study A and B with 80 and 37 patients respectively), the following mutations emerged in patients with virological failure:
34 Fosamprenavir
Fosamprenavir
Den bevarede aktivitet afhænger af antallet og typen af protease- resistente mutationer i isolaterne.
Conversely amprenavir retains activity against some isolates with resistance to other PIs and this retained activity would depend on the number and type of protease resistance mutations present in the isolates.
Antallet af mutationer, der har betydning for PI- resistens øges væsentligt, jo længere et regime med svigtende proteasehæmmere fortsættes.
35 The number of key PI-resistance mutations increases markedly the longer a failing PI-containing regimen is continued.
35 Klinisk erfaring
Clinical experience:
36 Resultater ved uge 16
Results at week 16
4, 10 (2, 34 – 6, 07)
(2.34– 6.07)
322 (36 – 955)
322
1, 0 (interval 0 - 2)
(range 0-2)
Plasma HIV- 1 RNA under 400 kopier/ ml (%) a
Plasma HIV-1 RNA below 400 copies/ ml (%)
37 5. 2 Farmakokinetiske egenskaber
5.2 Pharmacokinetic properties
Amprenavir er primært bundet til alfa- 1- syreglycoprotein (AAG), men også til albumin.
Amprenavir is primarily bound to the alpha– 1-acid glycoprotein (AAG), but also to albumin.
Det er vist, at koncentrationerne af AAG falder under det antiretrovirale behandlingsforløb.
Concentrations of AAG have
Denne ændring vil nedsætte den totale koncentration af aktivt stof i plasma.
37 been shown to decrease during the course of antiretroviral therapy.
Lægemidler, som inducerer, hæmmer eller er substrater for CYP3A4, skal derfor bruges med forsigtighed, hvis de gives sammen med Agenerase (se afsnit 4. 3, 4. 4 og 4. 5).
Therefore medicinal products that are inducers, inhibitors or substrates of CYP3A4 must be used with caution when administered concurrently with Agenerase (see sections 4.3, 4.4 and 4.5).
Ca.
The primary route of elimination of amprenavir is via hepatic metabolism with less than 3% excreted unchanged in the urine.
75% i fæces.
The metabolites and unchanged amprenavir account for approximately 14% of the administered amprenavir dose in the urine, and approximately 75% in the faeces.
38 Særlige populationer:
Special populations:
En højere incidens af hepatocellulær carcinom sås hos alle hanmus i amprenavir behandlingsgrupperne.
38 A higher incidence of hepatocellular carcinoma was seen in all amprenavir male mouse treatment groups.
Disse resultater antyder, at unge dyr
Toxicity studies in young animals, treated from four days of age, resulted in high mortality in both the control animals and those receiving amprenavir.
39 mangler fuldt udviklede metaboliseringsveje, der gør dem i stand til at udskille amprenavir eller nogle kritiske bestanddele af formuleringen (f. eks. propylenglycol, PEG 400).
These results imply that young animals lack fully developed metabolic pathways enabling them to excrete amprenavir or some critical components of the formulation (e. g. propylene glycol, PEG400).
6. 3 Opbevaringstid
39 6.3 Shelf life
En eller to hvide High Density Polyethylene (HDPE) - beholdere med 240 kapsler.
One or two white High Density Polyethylene (HDPE) bottles, each containing 240 capsules.
Glaxo Group Ltd Glaxo Wellcome House
MARKETING AUTHORISATION HOLDER
40 Berkeley Avenue Greenford Middlesex UB6 0NN Storbritannien
Glaxo Group Ltd Glaxo Wellcome House Berkeley Avenue Greenford Middlesex UB6 0NN United Kingdom
Yderligere information om dette lægemiddel er tilgængelig på Det europæiske Lægemiddelagenturs (EMEAs) hjemmeside http: // www. emea. europa. eu
Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http: / /www. emea. europa. eu
41 1.
40 1.
Agenerase 15 mg/ ml oral opløsning
Agenerase 15 mg/ ml oral solution.
Agenerase oral opløsning indeholder amprenavir 15 mg/ ml.
Agenerase oral solution contains 15 mg/ ml of amprenavir.
Den o rale opløsning er klar, svagt gullig til gul med drue -, tyggegummi - og pebermyntesmagsstof.
The oral solution is clear, pale yellow to yellow with grape, bubblegum and peppermint flavouring.
Agenerase oral opløsning, i kombination med andre antiretrovirale midler, er indiceret til behandling af HIV- 1- inficerede voksne og børn over 4 år, som tidligere er behandlet med proteasehæmmere (PI’ er).
Agenerase oral solution, in combination with other antiretroviral agents, is indicated for the treatment of protease inhibitor (PI) experienced HIV-1 infected adults and children above the age of 4 years.
Fordelen ved Agenerase oral opløsning boostet med ritonavir er ikke påvist hos PI- naive patienter og hos patienter, der tidligere er behandlet med PI’ er.
The benefit of Agenerase oral solution boosted with ritonavir has not been demonstrated either in PI naïve patients or in PI experienced patients.
Agenerase oral opløsning administreres peroralt og kan tages med eller uden mad.
Agenerase oral solution is administered orally and can be taken with or without food.
Agenerase kapsler og oral opløsning kan derfor ikke erstatte hinanden på basis af milligram til milligram (se afsnit 5. 2).
Amprenavir is 14% less bioavailable from the Agenerase oral solution than from the capsules; therefore, Agenerase capsules and Agenerase oral solution are not interchangeable on a milligram per milligram basis (see section 5.2).
Patienter bør ophøre med Agenerase oral opløsning ligeså snart de er i stand til at synke kapslerne (se afsnit 4. 4).
Patients should discontinue Agenerase oral solution as soon as they are able to swallow the capsule formulation (see section 4.4).
Den anbefalede dosis Agenerase oral opløsning er 17 mg (1, 1 ml) / kg 3 gange daglig i kombination med andre antiretrovirale midler, uden at den totale daglige dosis overstiger 2800 mg (se afsnit 5. 1).
Patients of 4 years and older unable to swallow Agenerase capsules: the recommended dose of Agenerase oral solution is 17 mg (1.1 ml)/ kg three times a day, in combination with other antiretroviral agents, without exceeding a total daily dose of 2800 mg (see section 5.1).
Da der derfor ikke kan gives doseringsanbefa - linger for kombinationen af Agenerase oral opløsning og lave doser af retronavir skal kombinationen undgås til denne patientgruppe.
Additionally, as no dosing recommendations can be made regarding the concomitant use of Agenerase oral solution and low dose ritonavir, the use of this combination must be avoided in these patient populations.
42 Børn under 4 år:
41 Children less than 4 years of age:
Agenerase oral opløsning er kontraindiceret til børn under 4 år (se afsnit 4. 3 og 5. 3).
(see sections 4.3 and 5.3).
Farmakokinetikken, effekten og sikkerheden af amprenavir er ikke undersøgt hos patienter over 65 år (se afsnit 5. 2).
(see section 5.2).
Selvom dosisjustering ikke vurderes at være nødvendig for amprenavir, er Agenerase oral opløsning kontraindiceret i patienter med nedsat nyrefunktion (se afsnit 4. 3).
Renal impairment: although no dose adjustment is considered necessary for amprenavir, Agenerase oral solution is contraindicated in patients with renal failure (see section 4.3).
Agenerase oral opløsning er kontraindiceret til patienter med nedsat leverfunktion eller leversvigt (se afsnit 4. 3) (se produktresuméet for Agenerase kapsler for yderligere oplysninger).
Agenerase oral solution is contraindicated in patients with hepatic impairment or failure (see section 4.3) (see Summary of Product Characteristics of Agenerase Capsules for prescribing information)
Agenerase oral opløsning er også kontraindiceret til patienter i behandling med disulfiram eller andre lægemidler, der reducerer alkoholmetabolismen (f. eks. metronidazol) og præparater, som indeholder alkohol (f. eks. ritonavir oral opløsning) eller yderligere propylenglycol (se afsnit 4. 4 og 5. 1).
Agenerase oral solution is also contraindicated in patients treated with disulfiram or other medicinal products that reduce alcohol metabolism (e. g. metronidazole) and preparations that contain alcohol (e. g. ritonavir oral solution) or additional propylene glycol (see section 4.4and 5.1).
Samtidig administration kan resultere i kompetitiv hæmning af metabolismen af disse lægemidler og skabe grundlag for alvorlige og/ eller livstruende bivirkninger såsom hjertearytmier (f. eks. amiodaron, bepridil, quinidin, terfenadin, astemizol, cisaprid, pimozid), respiratorisk depression og/ eller forlænget sedation (f. eks. oral triazolam og oral midazolam (se afsnit 4. 5 mht parenteral midazolam)), perifere vasospasmer eller iskæmi og iskæmi i andre væv, herunder iskæmi i hjernen henholdsvis hjertet (f. eks. ergotaminderivater).
Co-administration may result in competitive inhibition of the metabolism of these medicinal products and create the potential for serious and/ or life-threatening adverse events such as cardiac arrhythmia (e. g. amiodarone, bepridil, quinidine, terfenadine, astemizole, cisapride, pimozide), respiratory depression and / or prolonged sedation (e. g. oral triazolam and oral midazolam (for caution on parenterally administred midazolam, see section 4.5)) or peripheral vasospasm or ischaemia and ischaemia of other tissues, including cerebral or myocardial ischaemia (e. g. ergot derivatives).
Den primære metaboliseringsvej for amprenavir og indholdsstoffet propylenglycol er via leveren, og derfor er Agenerase oral opløsning kontraindikeret til patienter med nedsat leverfunktion eller leversvigt (se afsnit 4. 3).
The principal route of metabolism of amprenavir and the propylene glycol excipient is via the liver, Agenerase oral solution is contraindicated in patients with hepatic impairment or failure (see section 4.3).
43 Patienter, som tager Agenerase oral opløsning, særligt dem med nedsat nyrefunktion eller dem med nedsat evne til at metabolisere propylenglycol (f. eks. patienter af asiatisk oprindelse), bør monitoreres for bivirkninger der muligvis kan være knyttet til det høje indhold af propylenglycol (550 mg/ ml), såsom kramper, stupor, takykardi, hyperosmolaritet, laktatacidose, nyretoksicitet, hæmolyse.
42 Patients taking the oral solution of Agenerase, particularly those with renal impairment or those with decreased ability to metabolise propylene glycol (e. g. those of Asian origin), should be monitored for adverse reactions potentially related to the high propylene glycol content (550 mg/ ml), such as seizures, stupor, tachycardia, hyperosmolarity, lactic acidosis, renal toxicity, haemolysis.
Vedrørende patienter med nyresvigt, nedsat leverfunktion eller leversvigt, børn og gravide kvinder (se afsnit 4. 3).
For patients with renal failure, hepatic impairment or failure, children and pregnant women, see section 4.3.
Samtidig administration af Agenerase oral opløsning og disulfiram eller andre lægemidler, som nedsætter metabolismen af alkohol (f. eks. metronidazol) eller præparater, som indeholder alkohol (f. eks. ritonavir oral opløsning) eller yderligere propylenglycol er kontraindiceret (se afsnit 4. 3 og 4. 5).
The concomitant administration of Agenerase oral solution with disulfiram or other medicinal products that reduce alcohol metabolism (e. g. metronidazole), or preparations that contain alcohol (e. g. ritonavir oral solution) or additional propylene glycol is contraindicated (see sections 4.3and 4.5).
Forsigtighed er tilrådet ved samtidig brug af Agenerase og delavirdin (se afsnit 4. 5).
Caution is advised when Agenerase is used concomitantly with delavirdine (see section 4.5).
En nedsættelse af rifabutin dosis med mindst 50% er anbefalet ved samtidig brug af Agenerase.
A reduction of rifabutin dosage of at least 50% is recommended when administered with Agenerase (see section 4.5).
Agenerase oral opløsning indeholder vitamin E (46 IU/ ml), derfor anbefales ekstra vitamin E- tilskud ikke.
43 Agenerase oral solution contains vitamin E (46 IU/ ml), therefore additional vitamin E supplementation is not recommended.
44 Agenerase oral opløsning indeholder 1 mg kalium pr. ml.
Agenerase oral solution contains 1 mg potassium per ml.
Osteonekrose
44 Osteonecrosis
Ætiologien anses dog for at være multifaktoriel (omfattende anvendelse af
Although the etiology 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).
Rifampicin Rifampicin er en potent CYP3A4 inducer og har vist sig at forårsage en reduktion i amprenavir AUC med 82%, hvilket kan føre til manglende virologisk effekt og resistensudvikling.
Rifampicin Rifampicin is a strong CYP3A4 inducer and has been shown to cause an 82% decrease in amprenavir AUC, which can result in virological failure and resistance development.
AUC, Cmin og Cmax for saquinavir var henholdsvis nedsat med 19% og 48% og øget med 21%, når det blev givet med amprenavir.
45 Saquinavir: the AUC, Cmin and Cmax of saquinavir were decreased by 19% and 48% and increased by 21%, respectively, when given with amprenavir.
AUC, Cmin og Cmax for amprenavir var nedsat med henholdsvis 32%, 14% og 37%.
The AUC, Cmin and Cmax of amprenavir were decreased by 32%, 14% and 37%, respectively.
AUC, Cmin og Cmax for nelfinavir var øget med henholdsvis 15%, 14% og 12%, når det blev givet med amprenavir.
Nelfinavir: the AUC, Cmin and Cmax of nelfinavir were increased by 15%, 14%, and 12% respectively when given with amprenavir.