natgillin/translations-raw huggingface dataset:
Administration af ambrisentan under henholdsvis faste og sammen med mad med højt fedtindhold viste, at Cmax faldt 12%, mens AUC var uændret.
A food-effect study involving administration of ambrisentan to healthy volunteers under fasting conditions and with a high-fat meal indicated that the Cmax was decreased 12% while the AUC remained unchanged.
Dette fald i peak- koncentration er ikke klinisk signifikant, og ambrisentan kan derfor tages med eller uden mad.
This decrease in peak concentration is not clinically significant, and therefore ambrisentan can be taken with or without food.
In vitro- plasmaproteinbindingen for ambrisentan var gennemsnitligt 98, 8% og uafhængig af koncentrationen i intervallet 0, 2 - 20 mikrogram/ ml.
The in vitro plasma protein binding of ambrisentan was, on average, 98.8% and independent of concentration over the range of 0.2 – 20 microgram/ ml.
Ambrisentan bindes primært til albumin (96, 5%) og i mindre grad til alfa1- syre glykoprotein.
Ambrisentan is primarily bound to albumin (96.5%) and to a lesser extent to alpha1-acid glycoprotein.
Fordelingen af ambrisentan i de røde blodlegemer er lav med et middel forhold mellem blod og plasma på henholdsvis 0, 57 og 0, 61 hos mænd og kvinder.
The distribution of ambrisentan into red blood cells is low, with a mean blood: plasma ratio of 0.57 and 0.61 in males and females, respectively.
Ambrisentan er et non- sulfonamid (propionsyre) ERA.
Ambrisentan is a non-sulphonamide (proprionic acid) ERA.
Ambrisentan bliver glukuronideret via adskillige UGT- isoenzymer (UGT1A9S, UGT2B7S og UGT1A3S), og derved dannes ambrisentan- glukuronid (13%).
Ambrisentan is glucuronidated via several UGT isoenzymes (UGT1A9S, UGT2B7S and UGT1A3S) to form ambrisentan glucuronide (13%).
Herved dannes 4- hydroxymetyl- ambrisentan (21%) som yderligere glukuronideres til 4- hydroxymetylambrisentanglukuronid (5%).
Ambrisentan also undergoes oxidative metabolism mainly by CYP3A4 and to a lesser extent by CYP3A5 and CYP2C19 to form 4-hydroxymethyl ambrisentan (21%) which is further glucuronidated to 4-hydroxymethyl ambrisentan glucuronide (5%).
Bindingsaffiniteten til den menneskelige endotelin- receptor er 65 gange mindre for 4- hydroxyetylambrisentan end for ambrisentan.
The binding affinity of 4-hydroxymethyl ambrisentan for the human endothelin receptor is 65-fold less than ambrisentan.
4% i forhold til oprindelig ambrisentan).
Therefore at concentrations observed in the plasma (approximately 4% relative to parent ambrisentan), 4-hydroxymethyl ambrisentan is not expected to contribute to pharmacological activity of ambrisentan.
In vitro- data har vist, at ved terapeutiske koncentrationer hæmmer ambrisentan hverken UGT1A1, UGT1A6, UGT1A9, UGT2B7 eller cytokrom- P450- enzymerne 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 og 3A4.
In vitro data have shown that at therapeutic concentrations, ambrisentan does not inhibit UGT1A1, UGT1A6, UGT1A9, UGT2B7 or cytochrome P450 enzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4.
Yderligere in vitro- forsøg viste, at ambrisentan ikke hæmmer NTCP, OATP eller BSEP.
Additional in vitro studies showed that ambrisentan does not inhibit NTCP, OATP or BSEP.
Ambrisentan fremmer heller ikke MRP2, Pgp eller BSEP.
Furthermore, ambrisentan does not induce MRP2, Pgp or BSEP.
PT og INR) blev undersøgt hos 20 raske frivillige.
10 The effects of steady-state ambrisentan (10 mg once daily) on the pharmacokinetics and pharmacodynamics of a single dose of warfarin (25 mg), as measured by PT and INR, were investigated in 20 healthy volunteers.
4. 5).
Similarly, co-administration with warfarin did not affect the pharmacokinetics of ambrisentan (see section 4.5).
Med undtagelse af en 13% stigning i Cmax for sildenafil var der ikke ændringer i de farmakokinetiske parametre for hverken sildenafil, N- desmetyl- sildenafil eller ambrisentan.
With the exception of a 13% increase in sildenafil Cmax following co-administration with ambrisentan, there were no other changes in the pharmacokinetic parameters of sildenafil, N-desmethyl-sildenafil and ambrisentan.
4. 5).
This slight increase in sildenafil Cmax is not considered clinically relevant (see section 4.5).
Virkningen af ambrisentan ved steady- state (10 mg en gang daglig) på farmakokinetikken af en enkeltdosis tadalafil, og virkningen af tadalafil ved steady- state (40 mg en gang daglig) på farmakokinetikken ved en enkeltdosis ambrisentan blev undersøgt hos 23 raske frivillige.
The effects of steady-state ambrisentan (10 mg once daily) on the pharmacokinetics of a single dose of tadalafil, and the effects of steady-state tadalafil (40 mg once daily) on the pharmacokinetics of a single dose of ambrisentan were studied in 23 healthy volunteers.
4. 5).
Similarly, co-administration with tadalafil did not affect the pharmacokinetics of ambrisentan (see section 4.5).
AUC( 0- inf) og Cmax og der sås en stigning på henholdsvis 35% og 20%.
Exposures of ambrisentan as measured by AUC(0-inf) and Cmax were increased by 35% and 20%, respectively.
Denne ændring i eksponering forventes ikke at have klinisk relevans, og Volibris kan derfor gives sammen med ketoconazol.
This change in exposure is unlikely to be of any clinical relevance and therefore Volibris may be co-administered with ketoconazole.
Adskillige doser ambrisentan resulterede i lette stigninger i digoxin AUC0- last og lavpunktskoncentrationer, samt en 29% stigning i digoxin Cmax.
Multiple doses of ambrisentan resulted in slight increases in digoxin AUC0-last and trough concentrations, and a 29% increase in digoxin Cmax.
4. 5).
The increase in digoxin exposure observed in the presence of multiple doses of ambrisentan was not considered clinically relevant, and no dose adjustment of digoxin is warranted (see section 4.5).
Virkningen af 12 dages behandling med ambrisentan (10 mg en gang daglig) på farmakokinetikken af en enkeltdosis oral antikonceptionsmiddel indeholdende ethinylestradiol (35 μg) og norethindron (1 mg) blev undersøgt hos raske frivillige kvinder.
The effects of 12 days dosing with ambrisentan (10 mg once daily) on the pharmacokinetics of a single dose of oral contraceptive containing ethinyl estradiol (35 μ g) and norethindrone (1 mg) were studied in healthy female volunteers.
13% og 14%).
The Cmax and AUC(0 –∞) were slightly decreased for ethinyl estradiol (8% and 4%, respectively), and slightly increased for norethindrone (13% and 14%, respectively).
4. 5).
These changes in exposure to ethinyl estradiol or norethindrone were small and are unlikely to be clinically significant (see section 4.5).
Ambrisentan og dets metabolitter udskilles primært med galden efter levermetabolisme og/ eller anden stofskifte.
Ambrisentan and its metabolites are eliminated primarily in the bile following hepatic and/ or extra-hepatic metabolism.
22% af den indgivne dosis i urinen, hvoraf 3, 3% er uændret ambrisentan.
Approximately 22% of the administered dose is recovered in the urine following oral administration with 3.3% being unchanged ambrisentan.
Plasmaeliminationens halveringstid hos mennesker varierer fra 13, 6 til 16, 5 timer.
Plasma elimination half-life in humans ranges from 13.6 to 16.5 hours.
4. 2).
Based on the results of a population pharmacokinetic analysis in healthy volunteers and patients with PAH, the pharmacokinetics of ambrisentan were not significantly influenced by gender or age (see section 4.2).
11 Ambrisentan metabiliseres eller udskilles ikke i signifikant grad via nyrerne.
11 Ambrisentan does not undergo significant renal metabolism or renal clearance (excretion).
Men størrelsesordenen i faldet i oral clearance er beskeden (20- 40% hos patienter med moderat nedsat nyrefunktion), og det er derfor usandsynligt, at det har nogen klinisk relevans.
The magnitude of the decrease in oral clearance is modest (20-40%) in patients with moderate renal impairment and therefore is unlikely to be of any clinical relevance.
4. 2).
However, caution should be used in patients with severe renal impairment (see section 4.2).
Ambrisentans primære metaboliseringsvej er via glucuronidering og oxidation med efterfølgende udskillelse i galden, og det forventes, at en nedsat leverfunktion vil øge eksponeringen (Cmax og AUC) af ambrisentan.
The main routes of metabolism of ambrisentan are glucuronidation and oxidation with subsequent elimination in the bile and therefore hepatic impairment would be expected to increase exposure (Cmax and AUC) of ambrisentan.
En populationsfarmakokinetisk analyse viste, at den orale clearance falder som funktion af stigende bilirubin- niveauer.
In a population pharmacokinetic analysis, the oral clearance was shown to be decreased as a function of increasing bilirubin levels.
30% lavere oral clearance af ambrisentan).
However, the magnitude of effect of bilirubin is modest (compared to the typical patient with a bilirubin of 0.6 mg/ dl, a patient with an elevated bilirubin of 4.5 mg/ dl would have approximately 30% lower oral clearance of ambrisentan).
Ambrisentans farmakokinetik er ikke undersøgt hos patienter med svært nedsat leverfunktion (med eller uden cirrose).
The pharmacokinetics of ambrisentan in patients with severe hepatic impairment (with or without cirrhosis) has not been studied.
4. 3 og 4. 4).
Therefore Volibris should not be initiated in patients with severe hepatic impairment or clinically significant elevated hepatic aminotransferases (> 3xULN) (see sections 4.3 and 4.4).
ERA- klassens primære farmakologiske virkning kan en enkelt stor dosis af ambrisentan (dvs. en overdosis) sænke blodtrykket og muligvis forårsage hypotension og symptomer relateret til vasodilatation.
Due to the class primary pharmacologic effect, a large single dose of ambrisentan (i. e. an overdose) could lower arterial pressure and have the potential for causing hypotension and symptoms related to vasodilation.
Det er ikke påvist, at Ambrisentan hæmmer galdesyretransporten eller producerer åbenlys hepatotoksicitet.
Ambrisentan was not shown to be an inhibitor of bile acid transport or to produce overt hepatotoxicity.
Inflammation og ændringer i næsehulens epitel er set hos gnavere ved eksponering under de terapeutiske niveauer til mennesker.
Inflammation and changes in the nasal cavity epithelium have been seen in rodents after chronic administration at exposures below the therapeutic levels in humans.
Hos hunde sås lette inflammatoriske reaktioner efter kroniske, høje doser ambrisentan ved eksponeringer på mere end 20 gange mere end hos patienter.
In dogs, slight inflammatory responses were observed following chronic high dose administration of ambrisentan at exposures greater than 20– fold that observed in patients.
Der sås ingen tegn på mutagen eller genotoksisk virkning ved ambrisentan i bakterier eller i to in vivo- gnaverforsøg.
No evidence for mutagenic or genotoxic effects of ambrisentan were seen in bacteria or in two in vivo rodent studies.
Der var ingen behandlingsrelaterede stigninger i forekomsten af tumorer efter to års orale forsøg hos rotter og mus.
There were no treatment-related increases in the incidence of tumours in 2 year oral studies in rats and mice.
Testikelatrofi, som lejlighedsvis er forbundet med aspermi, sås efter orale, gentagne dosis- toksicitets - og fertilitetsforsøg med hanrotter og - mus uden sikkerhedsmargin.
Testicular tubular atrophy, which was occasionally associated with aspermia, was observed in oral repeat dose toxicity and fertility studies with male rats and mice without safety margin.
Men der sås ingen testikelændringer i hundeforsøg med op til 39 ugers varighed ved en eksponering, der var 35 gange det til mennesker ud fra AUC.
However no testicular changes were observed in dog studies of up to 39 weeks duration at an exposure 35– fold that seen in humans based on AUC.
Ambrisentans virkning på den mandlige fertilitet hos mennesker kendes ikke.
The effect of ambrisentan on male human fertility is not known.
Det har vist sig, at ambrisentan er teratogen hos rotter og kaniner.
12 Ambrisentan has been shown to be teratogenic in rats and rabbits.
Abnormiteter i underkæbe, tunge og/ eller gane sås ved alle testede doser.
Abnormalities of the lower jaw, tongue, and/ or palate were seen at all doses tested.
Desuden blev der i rotteforsøget observeret interventrikulære, septale defekter, defekter i kroppens kar, abnormiteter i skjoldbruskkirtlen og brisslen, forbening af basisphenoid- knoglen og øget forekomst af venstre navlestrengsblodkar.
In addition, interventricular septal defects, trunk vessel defects, thyroid and thymus abnormalities, ossification of the basisphenoid bone and increased incidence of left umbilical artery were seen in the rat study.
12 Indgift af ambrisentan til hunrotter fra sidst i graviditeten til og med amningen forårsagede bivirkninger på moderens adfærd, nedsat overlevelse hos afkommet og nedsættelse af reproduktionsevnen hos afkommet (med observation af små testikler ved obduktion) ved eksponering på 3 gange AUC ved den maksimalt anbefalede dosis til mennesker.
Administration of ambrisentan to female rats from late-pregnancy through lactation caused adverse events on maternal behaviour, reduced pup survival and impairment of the reproductive capability of the offspring (with observation of small testes at necropsy), at exposure 3-fold the AUC at the maximum recommended human dose.
Tabletkerne Lactosemonohydrat Mikrokrystallinsk cellulose Croscarmellosenatium Magnesiumstearat
Tablet core Lactose monohydrate Microcrystalline cellulose Croscarmellose sodium Magnesium stearate
Filmovertræk Polyvinylalkohol (delvist hydrolyseret) Talcum (E553b) Titandioxid (E171) Macrogol / PEG 3350 Lecitin (soja) (E322) Allura red AC Aluminium Lake (E129)
Film coat Polyvinyl alcohol (Partially Hydrolyzed) Talc (E553b) Titanium dioxide (E171) Macrogol / PEG 3350 Lecithin (Soya) (E322) Allura red AC Aluminium Lake (E129)
PVC/ PVDC/ aluminium- folie blisterpakninger.
PVC/ PVDC/ aluminium foil blisters.
Pakninger med 10 eller 30 filmovertrukne tabletter.
Pack sizes of 10 or 30 film-coated tablets.
0, 45 mg).
Each tablet contains lactose monohydrate (approximately 90 mg), Lecithin (Soya) (E322) (approximately 0.25 mg) and Allura red AC Aluminium Lake (E129) (approximately 0.45 mg).
Mørk pink, oval, konveks filmovertrukket tablet, der er præget ” GS ” på den ene side og ” KE3 ” på den anden side.
Deep-pink, oval, convex, film-coated tablet with “ GS ” debossed on one side and “ KE3” on the other side.
Volibris bør ikke anvendes til patienter under 18 år pga. manglende dokumentation for sikkerhed og virkning.
15 Volibris is not recommended for use in patients below 18 years of age due to a lack of data on safety and efficacy.
15 Ældre
Elderly
Abnormiteter i leverfunktionen er blevet forbundet med PAH.
16 Liver function abnormalities have been associated with PAH.
16 Der anbefales månedlige monitoreringer af ALAT og ASAT.
Monthly monitoring of ALT and AST is recommended.
Volibris- tabletter indeholder lactosemonohydrat.
17 Volibris tablets contain lactose monohydrate.
17 4. 5 Interaktion med andre lægemidler og andre former for interaktion
4.5 Interaction with other medicinal products and other forms of interaction
5. 2).
18 Steady-state administration of ambrisentan in healthy volunteers had no clinically relevant effects on the single-dose pharmacokinetics of digoxin, a substrate for Pgp (see section 5.2).
18 Volibris er kontraindiceret under graviditet (se pkt.
Volibris is contraindicated in pregnancy (see section 4.3).
19 Hjerte Palpitation
19 Palpitation
20 Post- marketing data
20 In addition to adverse reactions identified from clinical studies, the following adverse reactions were identified during post-approval use of Volibris.
21 Der er gennemført to randomiserede, dobbeltblinde, multicenter, placebokontrollerede, fase 3 pivotale forsøg (ARIES- 1 og - 2).
21 Two randomised, double-blind, multi-centre, placebo controlled, Phase 3 pivotal studies were conducted (ARIES-1 and 2).
22 Anden klinisk information:
Other clinical information
I et fase 2- forsøg (AMB220) blev der efter 12 uger observeret forbedrede hæmodynamiske parametre hos patienter med PAH (n = 29).
22 An improvement in haemodynamic parameters was observed in patients with PAH after 12 weeks (n=29) in a Phase 2 study (AMB220).
PT og INR) blev undersøgt hos 20 raske frivillige.
23 The effects of steady-state ambrisentan (10 mg once daily) on the pharmacokinetics and pharmacodynamics of a single dose of warfarin (25 mg), as measured by PT and INR, were investigated in 20 healthy volunteers.
24 Ambrisentan metabiliseres eller udskilles ikke i signifikant grad via nyrerne.
24 Ambrisentan does not undergo significant renal metabolism or renal clearance (excretion).
Det har vist sig, at ambrisentan er teratogen hos rotter og kaniner.
25 Ambrisentan has been shown to be teratogenic in rats and rabbits.
25 Indgift af ambrisentan til hunrotter fra sidst i graviditeten til og med amningen forårsagede bivirkninger på moderens adfærd, nedsat overlevelse hos afkommet og nedsættelse af reproduktionsevnen hos afkommet (med observation af små testikler ved obduktion) ved eksponering på 3 gange AUC ved den maksimalt anbefalede dosis til mennesker.
Administration of ambrisentan to female rats from late-pregnancy through lactation caused adverse events on maternal behaviour, reduced pup survival and impairment of the reproductive capability of the offspring (with observation of small testes at necropsy), at exposure 3-fold the AUC at the maximum recommended human dose.
Filmovertræk Polyvinylalkohol (delvist hydrolyseret) Talcum (E553b) Titandioxid (E171) Macrogol / PEG 3350 Allura red AC Aluminium Lake (E129) Lecitin (soja) (E322)
Film coat Polyvinyl alcohol (Partially Hydrolyzed) Talc (E553b) Titanium dioxide (E171) Macrogol / PEG 3350 Allura red AC Aluminium Lake (E129) Lecithin (Soya) (E322)
Industriestrasse 32- 36 D- 23843 Bad Oldesloe Tyskland
KG Industriestrasse 32-36 D-23843 Bad Oldesloe Germany
Indehaveren af markedsføringstilladelsen skal opstille et post- marketingovervågningsstudie, som beskrevet i EU- Risikohåndteringsplanens synopsis.
The MAH shall set up a post-marketing surveillance study as per the synopsis in the EU-Risk Management Plan.
Detaljerne omkring implementering af post- marketingovervågningsstudiet skal aftales med den kompentente nationale myndighed i hvert medlemsland, og det skal sikres, at studiet er klart inden markedsføring af produktet.
Details of the implementation of the post-marketing surveillance study should be agreed with the National Competent Authorities in each member state and put in place prior to marketing of the product.
Indehaveren af markedsføringstilladelsen skal implementere programmet nationalt for at sikre, at alt sundhedspersonale, som har til hensigt at ordinere (og hvor det er relevant, og efter aftale med den kompetente, nationale myndighed, udlevere) Volibris, har fået udleveret følgende:
The MAH must agree the details of a controlled distribution system with the National Competent Authorities and must implement such programme nationally to ensure that prior to prescribing (and where appropriate and in agreement with the National Competent Authority, dispensing) all health care professionals who intend to prescribe (and where appropriate, dispense) Volibris have been provided with the following:
• Produktinformation (produktresume og indlægsseddel) • Information om Volibris til sundhedspersonale • Tjekliste, der skal anvendes forud for lægens ordination • Information om post- marketingovervågningsstudiet • Informationsbrochure til patienter • Informationsbrochure til mandlige partnere til kvinder i den fødedygtige alder • Patientpåmindelseskort • Graviditetsindberetningsskemaer • Bivirkningsindberetningsskemaer
• Product information (Summary of Product Characteristics (SPC) and Package Leaflet) • Healthcare professional information regarding Volibris • Pre-prescription checklist for physicians • Information about the post marketing surveillance study • Information booklets for patients • Information booklets for male partners of female patients with child-bearing potential • Patient reminder cards • Pregnancy reporting forms • Adverse drug reaction reporting forms
Sundhedspersonalets forpligtigelser i forbindelse med ordination af Volibris:
Obligations of health care professionals in relation to the prescribing of Volibris:
29 • Sikre at patienterne er i stand til at efterleve kravene til en sikker brug af Volibris. • Give udførlig vejledning og rådgivning til patienterne. • Aflevere relevante informationsbrochurer og patientpåmindelseskort til patienterne. • Overveje behov for månedlig ordination for således at kunne sikre at patienter og testresultater bliver vurderet inden næste ordination. • Bivirkningsdatabasen for Volibris er begrænset, og læger opfordres til at involvere patienterne i et post- marketingovervågningsstudie. • Indrapportere formodede bivirkninger og graviditeter.
29 • That patients should be capable of complying with the requirements for the safe use of Volibris. • The need to provide comprehensive advice and counselling to patients. • The need to provide patients with the appropriate information booklet(s) and patient reminder card. • Should consider monthly prescription of 30 day supply to ensure that patients and key test results are reviewed prior to further prescription. • That the safety database of Volibris is limited and physicians are encouraged to enrol patients in a post marketing surveillance study. • To report suspected adverse reactions and pregnancy.
Information om at Volibris er teratogent
That Volibris is teratogenic
• Volibris er kontraindiceret ved graviditet og til kvinder i den fødedygtige alder som ikke bruger sikker prævention. • Kvinder, der behandles med Volibris, skal informeres om risikoen for fosterskader. • Vejledning i at identificere kvinder i den fødedygtige alder, og information om, hvad lægen skal gøre hvis der er usikkerhed.
• Volibris is contraindicated in pregnancy and in women of child-bearing potential who are not using reliable contraception. • That women receiving Volibris should be advised of the risk of foetal harm. • Guidance for identifying women of child-bearing potential and the actions the physician should take if unsure.
Kvinder i den fødedygtige alder:
For women with child-bearing potential: