natgillin/translations-raw huggingface dataset:
Amprenavir kan medføre øgede serumkoncentrationer af calciumkanalblokkere som amlodipin, diltiazem, felodipin, isradipin, nicardipin, nifedipin, nimodipin, nisoldipin og verapamil, hvilket muligvis vil medføre øget aktivitet og toksicitet af disse lægemidler.
Calcium-channel blockers: amprenavir may lead to increased serum concentrations of calcium channel blockers such as amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine and verapamil, possibly resulting in enhanced activity and toxicity of these medicinal products.
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.
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.
Samtidig administration med Agenerase kan føre til en betydelig stigning i plasmakoncentrationen af PDE5 hæmmerne og antallet af associerede bivirkninger, herunder hypotension, synsforstyrrelser og priapismus (se afsnit 4. 4).
Co- administration with Agenerase may substantially increase PDE5 inhibitor plasma concentrations and associated adverse events, including hypotension, visual changes and priapism (see section 4.4).
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%).
9 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%).
Hos patienter, der fik ritonavir og inhaleret eller intranasalt fluticason - propionat, er der rapporteret om systemiske bivirkninger forårsaget af kortikosteroider, herunder Cushings syndrom og binyrebarksuppression, hvilke også kan forekomme med andre kortikosteroider, som metaboliseres via P450 3A, for eksempel budesonid.
Systemic corticosteroid effects including Cushing’ s syndrome and adrenal suppression have been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate; this could also occur with other corticosteroids metabolised via the P450 3A pathway e. g. budesonide.
Samtidig administration af Agenerase med ritonavir og disse glukokortikoider anbefales derfor ikke, med mindre de potentielle fordele ved
Consequently, concomitant administration of Agenerase with ritonavir and these glucocorticoids is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects (see section 4.4).
Det bør overvejes at reducere dosis af glukokortikoidet samtidig med tæt monitorering af lokale og systemiske bivirkninger eller at skifte til et glukokortikoid, som ikke er substrat for CYP3A4 (for eksempel beclometason).
A dose reduction of the glucocorticoid should be considered with close monitoring of local and systemic effects or a switch to a glucocorticoid, which is not a substrate for CYP3A4 (e. g. beclomethasone).
HMG- CoA reduktase hæmmere:
HMG-CoA reductase inhibitors:
HMG- CoA reduktase hæmmere, der primært metaboliseres af CYP3A4 (f. eks. lovastation og simvastation), forventes at få en markant stigning af plasmakoncentrationen ved samtidig administration med Agenerase.
HMG-CoA reductase inhibitors which are highly dependent on CYP3A4 for metabolism, such as lovastatin and simvastatin, are expected to have markedly increased plasma concentrations when co-administered with Agenerase.
Da en øget koncentration af HMG- CoA reduktase hæmmere kan forårsage myopati, herunder rhabdomyolyse, kan samtidig administration med Agenerase ikke anbefales.
Since increased concentrations of HMG-CoA reductase inhibitors may cause myopathy, including rhabdomyolysis, the combination of these medicinal products with Agenerase is not recommended.
Hvis behandling med HMG- CoA reduktase hæmmere er indiceret, anbefales behandling med pravastatin eller fluvastatin.
If treatment with a HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended.
Hyppig terapeutisk koncentrationsmåling af immunosuppressantniveauerne anbefales indtil niveauerne er stabiliserede, idet plasmakoncentrationen af cyklosporin, rapamycin og tacrolimus kan være forhøjet, når stofferne administreres sammen med amprenavir (se afsnit 4. 4).
Immunosuppressants: frequent therapeutic concentration monitoring of immunosuppresant levels is recommended until levels have stabilised as plasma concentrations of cyclosporin, rapamycin and tacrolimus may be increased when co-administered with amprenavir (see section 4.4).
Midazolam metaboliseres i stor udstrækning af CYP3A4.
Midazolam: midazolam is extensively metabolized by CYP3A4.
Data for andre CYP3A4- hæmmere indikerer, at midazolamkoncentrationen bliver signifikant højere, når midazolam gives oralt.
Based on data for other CYP3A4 inhibitors, plasma concentrations of midazolam are expected to be significantly higher when midazolam is given orally.
Derfor må Agenerase ikke anvendes i kombination med oral midazolam (se afsnit 4. 3), og der bør udvises forsigtighed, når Agenerase anvendes i kombination med parenteral midazolam.
Therefore Agenerase should not be co-administered with orally administered midazolam (see section 4.3), whereas caution should be used with co-administration of Agenerase and parenteral midazolam.
Data for samtidig brug af parenteral midazolam og andre proteasehæmmere indikerer en mulig 3- 4 fold stigning i plasmaniveauet af midazolam.
Data from concomitant use of parenteral midazolam with other protease inhibitors suggest a possible 3-4 fold increase in midazolam plasma levels.
Hvis Agenerase, med eller uden ritonavir, gives i kombination med parenteral midazolam, skal det gøres på en intensivafdeling eller under tilsvarende forhold, som sikrer tæt klinisk monitorering og tilgængelig medicinsk behandling i tilfælde af, at der skulle opstå respiratorisk depression og/ eller forlænget sedation.
If Agenerase with or without ritonavir is co-administered with parenteral midazolam, it should be done in an intensive care unit (ICU) or similar setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/ or prolonged sedation.
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) faldt 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%.
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 naturlige 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 INR (International Normaliseret Ratio) på grund af et muligt fald eller en mulig stigning i deres anti- thrombotiske virkning (se afsnit 4. 4).
10 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).
Østrogener og progesteroner kan interagere med amprenavir.
Steroids: oestrogens and progestogens may interact with amprenavir.
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.
Cmin for ethinylestradiol steg med 32%, mens AUC og Cmin for norethidrom forøgedes med henholdsvis 18% og 45%.
The Cmin of ethinyl estradiol was increased by 32%, whilst the AUC and Cmin of norethindrone were increased by 18% and 45% respectively.
Alternative svangerskabsfore - byggende metoder anbefales til kvinder i den frugtbare alder.
Alternative methods of contraception are recommended for women of childbearing potential.
10 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.
Effekten og bivirkninger af tricykliske antidepressiva bør overvåges omhyggeligt, når disse (f. eks. desipramin og nortriptylin) anvendes samtidig med Agenerase (se afsnit 4. 4).
Tricyclic antidepressants: careful monitoring of the therapeutic and adverse reactions of tricyclic antidepressants is recommended when they (for example desipramine and nortriptyline) are concomitantly administered with Agenerase (see section 4.4).
Amprenavir kan øge plasmakoncentrationerne af andre stoffer.
Other substances: plasma concentrations of other substances may be increased by amprenavir.
Visse stoffer (f. eks. lidocain (systemisk) og halofantrin) administreret samtidig med Agenerase kan give alvorlige bivirkninger.
Some substances (e. g. lidocaine (by systemic route) and halofantrine) given with Agenerase may cause serious adverse reactions.
Samtidig administration er ikke anbefalet (se afsnit 4. 4).
Concomitant use is not recommended (see section 4.4).
Der foreligger ikke fyldestgørende data om brugen af amprenavir under graviditet.
Pregnancy: there are no adequate data from the use of amprenavir in pregnant women.
I dyreforsøg er der observeret reproduktiv toksicitet (se afsnit 5. 3).
Studies in animals have shown reproductive toxicity (see section 5.3).
Der er fundet amprenavirbeslægtet materiale i rottemælk, men det vides ikke, om amprenavir udskilles i modermælk.
Lactation: amprenavir-related material was found in rat milk, but it is not known whether amprenavir is excreted in human milk.
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.
Der er ikke foretaget undersøgelser af virkningen på evnen til at føre motorkøretøj eller betjene maskiner (se afsnit 4. 8).
No studies on the effects on ability to drive and use machines have been performed (see section 4.8).
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 paraesthesia.
Sikkerhedsprofilen, som den tegner sig hos børn, er af samme karakter som hos voksne.
11 In children, the nature of the safety profile is similar to that seen in adults.
11 Bivirkninger er nævnt nedenfor fordelt efter MedDRA organklasser og frekvens.
Adverse reactions are listed below by MedDRA body system organ class and by frequency.
≥1/ 10 ≥1/ 100 og < 1/ 10 ≥1/ 1000 og < 1/ 100 ≥1/ 10. 000 og < 1/ 1000
≥ 1 in 10 ≥ 1 in 100 and < 1 in 10 ≥ 1 in 1,000 and < 1 in 100 ≥ 1 in 10,000 and < 1 in 1,000
Hovedvægten af nedenfor nævnte bivirkninger er set i 2 kliniske undersøgelser (PROAB3001, PROAB3006) med PI- naive patienter, som modtog Agenerase 1200 mg 2 gange daglig.
Most of the adverse events below come from two clinical trials (PROAB3001, PROAB3006) involving PI naïve subjects receiving Agenerase 1200mg twice daily.
Virkninger (grad 2- 4), som er rapporteret af investigator som henførende til undersøgelsesmedicinen er inkluderet, såvel som grad 3- 4 behandlings relaterede abnormiteter set ved undersøgelser i laboratoriet.
Events (grade 2-4) reported by study investigators as attributable to study medication and occurring in > 1% of patients, are included as well as grade 3-4 treatment emergent laboratory abnormalities.
Forhøjede triglycerider, forhøjet amylase, abnorm fedtomfordeling, anorexi Hyperglykæmi, hypercholesterolæmi
Elevated triglycerides, elevated amylase, abnormal fat redistribution, anorexia Hyperglycaemia, hypercholesterolaemia
Forhøjede triglycerider, forhøjet amylase og hyperglykæmi (grad 3- 4) blev primært rapporteret hos patienter med unormale udgangsværdier.
Elevated triglycerides, elevated amylase and hyperglycaemia (grade 3-4) were reported primarily in patients with abnormal values at baseline.
Forhøjet cholesterol var grad 3- 4 i intensitet.
Elevations in cholesterol were of grade 3-4 intensity.
Antiretroviral kombinationsbehandling er forbundet med en omfordeling af legemsfedt (lipodystrofi) hos HIV patienter, herunder tab af subkutant fedt perifert og i ansigtet, øget intraabdominalt og visceralt fedt, bryst hypertrofi og dorso- cervikal fedtophobning (buffalo hump).
Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).
Kun ét tilfælde (Buffalo hump) blev rapporteret blandt 113 (< 1%) patienter, som ikke før havde fået antiretroviral behandling, og som fik amprenavir i kombination med lamivudin/ zidovudin af en middelvarighed på 36 uger.
Only one case (a buffalo hump) was reported in 113 (< 1%) antiretroviral naive subjects treated with amprenavir in combination with lamivudine/ zidovudine for a median duration of 36 weeks.
I undersøgelsen PROAB3006 blev der rapporteret 7 (3%) tilfælde blandt 245 patienter, der tidligere havde fået NRTI, og som fik amprenavir, samt 27 tilfælde (11%) ud af 241 patienter, som fik indinavir, i kombination med forskellige NRTI af en middelvarighed på 56 uger (p < 0, 001).
In study PROAB3006, seven cases (3%) were reported in 245 NRTI-experienced subjects treated with amprenavir and in 27 (11%) of 241 subjects treated with indinavir, in combination with various NRTIs for a median duration of 56 weeks (p < 0.001).
Antiretroviral kombinationsbehandling er forbundet med metaboliske abnormiteter såsom hypertriglyceridæmi, hypercholesterolæmi, insulinresistens og hyperglykæmi og hyperlaktæmi (se afsnit 4. 4).
Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (see section 4.4).
Humørsvingninger, depressive sygdomme
Mood disorders, depressive disorders
Almindelg:
Common:
Hovedpine Oral/ perioral paræstesi, rystelser, søvnforstyrrelser
Headache Oral/ perioral paraesthesia, tremors, sleep disorders
Diarré, kvalme, flatulens, opkastning Mavesmerter, abdominalt ubehag, dyspeptiske symptomer, løs afføring
Diarrhoea, nausea, flatulence, vomiting Abdominal pain, abdominal discomfort, dyspeptic symptoms, loose stools
12 Lever og galdeveje
12 Hepatobiliary disorders
Forhøjet transaminase Hyperbilirubinæmi
Elevated transaminases Hyperbilirubinaemia
hyperbilirubinæmi blev primært rapporteret hos patienter med unormale
Elevated transaminases and hyperbilirubinaemia (grade 3-4) were reported primarily in patients with abnormal values at baseline.
Udslæt Angioødem Stevens- Johnsons syndrom
Rash Angioedema Stevens Johnson syndrome
De forekom i den anden uge af behandlingen og svandt spontant inden for to uger uden seponering af amprenavir.
Rashes were usually mild to moderate, erythematous or maculopapular cutaneous eruptions, with or without pruritus, occurring during the second week of therapy and resolving spontaneously within two weeks, without discontinuation of treatment with amprenavir.
Alvorlige eller livstruende hudreaktioner er forekommet hos patienter i behandling med amprenavir (se afsnit 4. 4).
Severe or life-threatening skin reactions have also occurred in patients treated with amprenavir (see section 4.4).
Særligt hos patienter med generelt anerkendte risikofaktorer, fremskreden HIV- sygdom eller langvarig kombinationsbehandling med antiretrovirale lægemidler (CART) er der rapporteret om tilfælde af osteonekrose.
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).
Hyppigheden heraf er ukendt (se afsnit 4. 4).
The frequency of this is unknown (see section 4.4).
Hos HIV- inficerede patienter med svær immuninsufficiens kan der ved påbegyndelse af antiretroviral kombinationsbehandling (CART) opstå en inflammatorisk reaktion på asymptomatiske eller residuale opportunistiske infektioner (se afsnit 4. 4).
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).
Eneste undtagelse var forhøjet niveau af triglycerider og CPK, som var meget almindelig forekommende hos patienter behandlet med både Agenerase og ritonavir.
In PI experienced patients receiving Agenerase capsules 600 mg twice daily and low dose ritonavir, 100 mg twice daily, the nature and frequency of adverse events (grade 2-4) and Grade 3/ 4 laboratory abnormalities were similar to those observed with Agenerase alone, with the exception of elevated triglyceride levels, and elevated CPK levels which were very common in patients receiving Agenerase and low dose ritonavir.
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:
13 Pharmacotherapeutic group; protease inhibitor; ATC Code:
Amprenavir er en kompetitiv hæmmer af HIV- 1- proteasen.
Amprenavir is a competitive inhibitor of HIV-1 protease.
Amprenavir binder til det aktive site på HIV- 1- proteasen og forebygger dermed spaltningen af viral gag og gag- pol polyprotein forstadier, og der dannes umodne, ikke- infektiøse viruspartikler.
Amprenavir binds to the active site of HIV-1 protease and thereby prevents the processing of viral gag and gag-pol polyprotein precursors, resulting in the formation of immature non-infectious viral particles.
Den antivirale in vitro- aktivitet, der er observeret for fosamprenavir, skyldes tilstedeværelsen af spormængder af amprenavir.
The in vitro antiviral activity observed with fosamprenavir is due to the presence of trace amounts of amprenavir.
Antiviral in vitro- aktivitet
Antiviral activity in vitro
Amprenavirs antivirale in vitro- aktivitet blev evalueret over for HIV- 1- IIIB i både akut og kronisk inficerede lymfoblastiske cellelinier (MT- 4, CEM- CCRF, H9) og perifere blodlymfocytter.
The in vitro antiviral activity of amprenavir was evaluated against HIV-1 IIIB in both acutely and chronically infected lymphoblastic cell lines (MT-4, CEM-CCRF, H9) and in peripheral blood lymphocytes.
Den 50% hæmmende koncentration (IC50) for amprenavir varierede fra 0, 012 til 0, 08 μM i akut inficerede celler og var 0, 41 μM i kronisk inficerede celler (1 μM = 0, 50 μg/ ml).
The 50% inhibitory concentration (IC50) of amprenavir ranged from 0.012 to 0.08 µM in acutely infected cells and was 0.41 µM in chronically infected cells (1 µM = 0.50 µg/ ml).
Sammenhængen mellem amprenavirs in vitro- anti- HIV- 1- aktivitet og hæmningen af HIV- 1- replikationen i mennesker kendes ikke.
The relationship between in vitro anti-HIV-1 activity of amprenavir and the inhibition of HIV-1 replication in humans has not been defined.
HIV- 1- isolater med en nedsat følsomhed over for amprenavir er fremkommet efter en række in vitro - passager.
HIV-1 isolates with decreased susceptibility to amprenavir have been selected during in vitro serial passage experiments.
a) ART- naive eller PI- naive patienter
a) ART-naïve or PI-naïve patients
(Bemærk:
(Note:
Agenerase er ikke godkendt til ART- naive eller PI- naive patienter).
Agenerase is not approved in ART-naive or PI-naive patients).
Adskillige behandlingsregimer både med og uden samtidig administration af ritonavir er undersøgt i forbindelse med udviklingsprogrammet for amprenavir/ fosamprenavir.
Various regimens have been assessed in the amprenavir/ fosamprenavir development programs with and without co-administration of ritonavir.
Fra disse regimer er prøver fra patienter med virologisk svigt blevet undersøgt og følgende fire resistensmønstre er fremkommet:
Analysis of the virological failure samples across these regimens defined four main resistance pathways:
V32I+I47V, I50V, I54L/ M og I84V.
V32I+I47V, I50V, I54L/ M and I84V.
Følgende mutationer, som også kan bidrage til resistens, blev ligeledes observeret:
Additional mutations observed which may contribute to resistance were:
L10V/ F/ R, I13V, K20R/ T, L33F/ V, M36I, M46I/ L, I47V/ L Q58E, I62V, L63P, V77I, I85V og I93L.
L10V/ F/ R, I13V, K20R/ T, L33F/ V, M36I, M46I/ L, I47V/ L Q58E, I62V, L63P, V77I, I85V, and I93L.
Det samme er gældende for andre regimer boostet med ritonavir.
When ART naïve patients were treated with the currently approved doses of fosamprenavir/ ritonavir, as for other ritonavir boosted PI regimens, the mutations described were infrequently observed.
I studiet ESS100732 fik 16 ud af 434 ART- naive patienter, der blev behandlet med 700 mg fosamprenavir/ 100 mg ritonavir to gange daglig, virologisk svigt efter 48 ugers behandling.
Sixteen of 434 ART-naïve patients who received fosamprenavir 700mg/ ritonavir 100mg twice daily in ESS100732 experienced virological failure by Week 48 with 14 isolates genotyped.
14 af disse isolater blev genotypeanalyseret, hvoraf tre isolater havde mutationer med proteaseresistens.
One resistance mutation was observed in each of 3 isolates:
En resistensmutation forekom i alle 3 isolater: henholdsvis K20K/ R, I54I/ L og I93I/ L.
K20K/ R, I54I/ L and I93I/ L respectively.
Blandt de 59 involverede PI- naive patienter viste genotypeanalyser af isolater fra 13 ud af 14 pædiatriske patienter med virologisk svigt resistensmønstre, som var magen til dem observeret hos voksne.
Genotypic analysis of isolates from 13 of 14 paediatric patients exhibiting virological failure among the 59 PI-naïve patients enrolled, demonstrated resistance patterns similar to those observed in adults.
14 b) Patienter, der tidligere har været behandlet med PI’ er
b) PI-experienced patients