natgillin/translations-raw huggingface dataset:
I post marketing perioden har der været sjældne rapporter om pulmonært ødem hos patienter i behandling med Tracleer, og som havde pulmonær veno- okklusiv sygdom som formodet diagnose.
In the post-marketing period there have been rare reports of pulmonary oedema in patients treated with Tracleer who had a suspected diagnosis of pulmonary veno-occlusive disease.
Imidlertid blev 1. 611 patienter (hvoraf 804 fik Tracleer og 807 placebo) med alvorlig kronisk hjerteinsufficiens (CHF) behandlet i gennemsnitligt 1½ år i en placebokontrolleret undersøgelse (studiet AC- 052- 301/ 302 [ENABLE 1 & 2]).
However, 1,611 patients (804 Tracleer- and 807 placebo-treated patients) with severe chronic heart failure (CHF) were treated for a mean duration of 1.5 years in a placebo- controlled study (study AC-052-301/ 302 [ENABLE 1 & 2]).
I denne undersøgelse var der en øget forekomst af hospitalsindlæggelser på grund af CHF i løbet af de første 4– 8 uger af behandling med Tracleer, som kan have været resultat af væskeretention.
In this study there was an increased incidence of hospitalisation due to CHF during the first 4 - 8 weeks of treatment with Tracleer, which could have been the result of fluid retention.
Ved undersøgelsens afslutning var der ingen forskel mellem det samlede antal indlæggelser på grund af hjerteinsufficiens eller mortalitet hos Tracleer - og placebobehandlede patienter.
At the end of this study, there was no difference in overall hospitalisations for heart failure nor in mortality between Tracleer- and placebo-treated patients.
Som følge heraf anbefales det, at patienter undersøges for tegn på væskeretention (f. eks. vægtøgning), især hvis de samtidig lider af alvorlig systolisk dysfunktion.
Consequently, it is recommended that patients be monitored for signs of fluid retention (e. g., weight gain), especially if they concomitantly suffer from severe systolic dysfunction.
Pulmonal arteriel hypertension associeret med HIV- infektion
Pulmonary arterial hypertension associated with HIV infection
Der er begrænset erfaring fra kliniske forsøg med anvendelse af Tracleer hos patienter med PAH associeret med HIV- infektion behandlet med antiretrovirale lægemidler (se pkt.
There is limited clinical trial experience with the use of Tracleer in patients with PAH associated with HIV infection, treated with antiretroviral medicinal products (see section 5.1).
Der er ikke udført specifikke interaktionsstudier med bosentan og antiretrovirale lægemidler.
No specific interaction studies between bosentan and antiretroviral medicinal products have been performed.
4. 5), som vil kunne påvirke virkningen af antiretrovitral behandling, bør disse patienter monitoreres omhyggeligt med hensyn til kontrol af deres HIV- infektion.
Due to the potential for such interactions especially related to the inducing effect of bosentan on CYP450 (see section 4.5), which could affect the efficacy of antiretroviral therapy, these patients should be monitored carefully regarding control of their HIV infection.
En øget risiko for hepatisk toksicitet og hæmatologiske bivirkninger kan ikke udelukkes, når bosentan anvendes i kombination med antiretrovirale lægemidler.
An increased risk of hepatic toxicity and haematological adverse events cannot be excluded when bosentan is used in combination with antiretroviral medicinal products.
Glibenclamid:
Glibenclamide:
Tracleer må ikke bruges samtidigt med glibenclamid på grund af en øget risiko for forhøjede leveraminotransferaser (se pkt.
Tracleer should not be used concomitantly with glibenclamide, due to an increased risk of elevated liver aminotransferases (see section 4.5).
Et alternativt antidiabetikum bør benyttes til patienter, for hvem en antidiabetisk behandling er indiceret.
An alternative antidiabetic medicinal product should be used in patients in whom an antidiabetic treatment is indicated.
4. 5).
Fluconazole: concomitant use of Tracleer with fluconazole is not recommended (see section 4.5).
Skønt den ikke er blevet undersøgt, kan denne kombination måske føre til en stor forøgelse af plasmakoncentrationerne af bosentan.
Although not studied, this combination may lead to large increases in plasma concentrations of bosentan.
4. 5)
Rifampicin: co-administration of Tracleer with rifampicin is not recommended (see section 4.5).
4. 5).
Concomitant administration of both a CYP3A4 inhibitor and a CYP2C9 inhibitor should be avoided (see section 4.5).
Bosentan har en fremmende virkning på cytochrom P450 (CYP) - isoenzymerne CYP2C9 og CYP3A4.
Bosentan is an inducer of the cytochrome P450 (CYP) isoenzymes CYP2C9 and CYP3A4.
In vitro data tyder endvidere på en induktion af CYP2C19.
In vitro data also suggest an induction of CYP2C19.
Muligheden for en ændret virkning af lægemiddelprodukter, som omsættes af disse isoenzymer, bør overvejes.
The possibility 6 of altered efficacy of medicinal products metabolised by these isoenzymes should be considered.
CYP2C9- inhibitorers indflydelse på bosentankoncentrationen er ikke blevet undersøgt.
The influence of CYP2C9 inhibitors on bosentan concentration has not been studied.
Samtidig administration af fluconazol, som hovedsagligt hæmmer CYP2C9, men også i en vis udstrækning CYP3A4, kan medføre store forøgelser af plasmakoncentrationerne af bosentan.
Concomitant administration with fluconazole, which inhibits mainly CYP2C9, but to some extent also CYP3A4, could lead to large increases in plasma concentrations of bosentan.
4. 4).
The combination is not recommended (see section 4.4).
4. 4).
For the same reason, concomitant administration of both a potent CYP3A4 inhibitor (such as ketoconazole, itraconazole and ritonavir) and a CYP2C9 inhibitor (such as voriconazole) with Tracleer is not recommended (see section 4.4).
Specifikke interaktionsstudier har påvist følgende:
Specific interaction studies have demonstrated the following:
Hormonale præventionsmidler:
Hormonal contraceptives:
Samtidig administration af Tracleer 125 mg to gange daglig i 7 dage og en enkeltdosis af et oralt antikonceptionsmiddel indeholdende norethisteron 1 mg + ethinylestradiol 35 mcg reducerede AUC for norethisteron og ethinylestradiol med henholdsvis 14% og 31%.
Co-administration of Tracleer 125 mg twice daily for 7 days with a single dose of oral contraceptive containing norethisterone 1 mg + ethinyl estradiol 35 mcg decreased the AUC of norethisterone and ethinyl estradiol by 14% and 31%, respectively.
4. 6).
Therefore, hormone- based contraceptives alone, regardless of the route of administration (i. e. oral, injectable, transdermal, and implantable forms), are not considered as reliable methods of contraception (see sections 4.4, 4.6).
4. 3).
Cyclosporine A: co-administration of Tracleer and cyclosporine A (a calcineurin inhibitor) is contraindicated (see section 4.3).
30 gange højere end dem, der blev målt efter indgift af bosentan alene.
Indeed, when co-administered, initial trough concentrations of bosentan were approximately 30-fold higher than those measured after bosentan alone.
Ved steady state var plasmakoncentrationen af bosentan 3- 4 gange højere end med bosentan alene.
At steady state, bosentan plasma concentrations were 3- to 4-fold higher than with bosentan alone.
Mekanismen for denne interaktion er ukendt.
The mechanism of this interaction is unknown.
50%.
The blood concentrations of cyclosporine A (a CYP3A4 substrate) decreased by approximately 50%.
Samtidig administration af tacrolimus eller sirolimus og Tracleer har ikke været undersøgt hos mennesker, men samtidig administration af tacrolimus eller sirolimus og Tracleer kan medføre forhøjede plasmakoncentrationer af bosentan ligesom ved samtidig administration af cyclosporin A.
Tacrolimus, sirolimus: co-administration of tacrolimus or sirolimus and Tracleer has not been studied in man but co-administration of tacrolimus or sirolimus and Tracleer may result in increased plasma concentrations of bosentan in analogy to co-administration with cyclosporine A.
Samtidigt kan Tracleer nedsætte plasmakoncentrationen af tacrolimus og sirolimus.
Concomitant Tracleer may reduce the plasma concentrations of tacrolimus and sirolimus.
Samtidig administration af Tracleer 125 mg to gange dagligt i 5 dage reducerede plasmakoncentrationen af glibenclamid (et CYP3A4- substrat) med 40% med potentiel betydelig reduktion af den hypoglykæmiske virkning.
Glibenclamide: co-administration of Tracleer 125 mg twice daily for 5 days decreased the plasma concentrations of glibenclamide (a CYP3A4 substrate) by 40%, with potential significant decrease of the hypoglycaemic effect.
Både glibenclamid og bosentan inhiberer galdesalt- eksportpumpen, hvilket kunne forklare de forhøjede aminotransferaser.
Both glibenclamide and bosentan inhibit the bile salt export pump, which could explain the elevated aminotransferases.
4. 4).
In this context, this combination should not be used (see section 4.4).
Ved samtidig administration af bosentan 500 mg to gange dagligt i 6 dage faldt plasmakoncentrationen af både S- warfarin (et CYP2C9- substrat) og R- warfarin (et CYP3A4- substrat) med henholdsvis 29% og 38%.
Warfarin: co-administration of bosentan 500 mg twice daily for 6 days decreased the plasma concentrations of both S-warfarin (a CYP2C9 substrate) and R-warfarin (a CYP3A4 substrate) by 29% and 38%, respectively.
7 Normalized Ratio (INR) eller warfarindosis (initialværdi versus afslutning på de kliniske undersøgelser).
Clinical experience of concomitant administration of bosentan with warfarin in patients with pulmonary arterial hypertension did not result in clinically relevant changes in International Normalized Ratio (INR) or warfarin dose (baseline versus end of the clinical studies).
Den hyppighed, med hvilken warfarindoser blev ændret i løbet af undersøgelserne på grund af ændringer i INR eller på grund af bivirkninger, var desuden omtrent den samme blandt bosentan - og placebo- behandlede patienter.
In addition, the frequency of changes in warfarin dose during the trials due to changes in INR or due to adverse events was similar among bosentan- and placebo-treated patients.
Der kræves ingen dosisjustering for warfarin og tilsvarende orale antikoagulantia ved initiering af bosentan, men der anbefales en forstærket monitorering af INR, især i starten og i optitreringsperioden.
No dose adjustment is needed for warfarin and similar oral anticoagulant agents when bosentan is initiated but intensified monitoring of INR is recommended, especially during bosentan initiation and the up-titration period.
Samtidig administration af Tracleer 125 mg to gange dagligt i 5 dage medførte en reduktion af plasmakoncentrationen af simvastatin (et CYP3A4- substrat) og dets aktive β- hydroxysyremetabolit med henholdsvis 34% og 46%.
Simvastatin: co-administration of Tracleer 125 mg twice daily for 5 days decreased the plasma concentrations of simvastatin (a CYP3A4 substrate), and its active β -hydroxy acid metabolite by 34% 7 and 46%, respectively.
Samtidig administration af Tracleer 62, 5 mg to gange dagligt i 6 dage og ketoconazol, der er en stærk CYP3A4- inhibitor, medførte en stigning i plasmakoncentrationen af bosentan til ca. det dobbelte.
Ketoconazole: co-administration of Tracleer 62.5 mg twice daily for 6 days and ketoconazole, a potent CYP3A4 inhibitor, increased the plasma concentrations of bosentan approximately 2-fold.
En justering af Tracleer- dosis anses ikke for at være nødvendig.
No dose adjustment of Tracleer is considered necessary.
Skønt det ikke er blevet påvist ved in vivo undersøgelser, forventes lignende forhøjede plasmakoncentrationer af bosentan med de andre potente CYP3A4- inhibitorer (som f. eks. itraconazol og ritonavir).
Although not demonstrated through in vivo studies, similar increases in bosentan plasma concentrations are expected with the other potent CYP3A4 inhibitors (such as itraconazole and ritonavir).
Samtidig administration af bosentan 500 mg to gange dagligt i 7 dage reducerede AUC, Cmax og Cmin af digoxin med henholdsvis 12%, 9% of 23%.
Digoxin: co-administration of bosentan 500 mg twice daily for 7 days decreased the AUC, Cmax and Cmin of digoxin by 12%, 9% and 23%, respectively.
Mekanismen for denne interaktion kan være induktion af P- glycoprotein.
The mechanism for this interaction may be induction of P-glycoprotein.
5. 1).
Epoprostenol: limited data obtained from a study (AC-052-356, BREATHE-3) in which 10 paediatric patients received the combination of Tracleer and epoprostenol indicate that after both single- and multiple-dose administration, the Cmax and AUC values of bosentan were similar in patients with or without continuous infusion of epoprostenol (see section 5.1).
Samtidig administration af Tracleer 125 mg 2 gange daglig i 7 dage og rifampicin, en potent inducer af CYP2C9 og CYP3A4, til 9 raske forsøgspersoner reducerede plasmakoncentrationen af bosentan med 58% og denne reduktion kunne være op til næsten 90% i et enkelt tilfælde.
Rifampicin: co-administration in 9 healthy subjects of Tracleer 125 mg twice daily for 7 days and rifampicin, a potent inducer of CYP2C9 and CYP3A4, decreased the plasma concentrations of bosentan by 58%, and this decrease could achieve almost 90% in an individual case.
En deraf følgende signifikant reduktion i virkningen af bosentan kan forventes ved samtidig administration af rifampicin.
A subsequent significantly reduced effect of bosentan is expected when it is co-administered with rifampicin.
Data fra andre CYP3A4 inducere f. eks. carbamazepin, phenobarbital, phenytoin og hypericum perforatum savnes, men samtidig administration forventes at medføre reduceret systemisk eksponering for bosentan.
Data on other CYP3A4 inducers, e. g. carbamazepine, phenobarbital, phenytoin and St John's wort are lacking, but their concomitant administration is expected to lead to reduced systemic exposure to bosentan.
Samtidig administration af Tracleer 125 mg to gange daglig (steady state) og sildenafil 80 mg tre gange daglig (ved steady state) i 6 dage til raske forsøgspersoner resulterede i en reduktion i sildenafils AUC på 63% og en stigning i bosentans AUC på 50%.
Sildenafil: co-administration of Tracleer 125 mg twice daily (steady state) with sildenafil 80 mg three times a day (at steady state) concomitantly administered during 6 days in healthy volunteers resulted in a 63% decrease of the sildenafil AUC and a 50% increase of the bosentan AUC.
Forsigtighed tilrådes ved samtidig administration.
Caution is recommended in case of co-administration.
5. 3).
Studies in animals have shown reproductive toxicity (teratogenicity, embryotoxicity, see section 5.3).
Der foreligger kun få data vedr. brug af Tracleer til gravide kvinder.
There are minimal data on the use of Tracleer in pregnant women.
4. 3).
Tracleer is contraindicated in pregnancy (see section 4.3).
Patienten og den ordinerende læge skal være opmærksom på, at Tracleer, på grund af de mulige
Patients and prescribers must be aware that due to potential pharmacokinetic interactions, Tracleer may render hormonal contraceptives ineffective (see section 4.5).
Kvinder i den fødedygtige alder må derfor ikke anvende hormonale præventionsmetoder (inklusive orale, injicerbare, transkutane og implantable former) som den eneste form for prævention, men skal anvende en supplerende eller en alternativ pålidelig form for prævention.
Therefore, women of childbearing potential must not use hormonal contraceptives (including oral, injectable, transdermal, and implantable forms) as the sole method of contraception but must use an additional or an alternative reliable method of contraception.
Hvis der hos den individuelle patient er nogen som helst tvivl om, hvilken form for præventionsrådgivning der skal gives, bør rådgivning finde sted hos en gynækolog.
If there is any doubt on what contraceptive advice should be given to the individual patient, consultation with a gynaecologist is recommended.
Anvendelse under amning
8 Use during lactation
Det vides ikke, om lægemidlet udskilles i modermælk.
It is not known whether bosentan is excreted into human milk.
Der er ikke foretaget undersøgelser af indflydelsen på evnen til at føre bil eller betjene maskiner.
No studies on the effect of Tracleer on the ability to drive and use machines have been performed.
Tracleer kan give svimmelhed, hvilket kan påvirke evnen til at køre bil eller betjene maskiner.
Tracleer may cause dizziness, which could influence the ability to drive or use machines.
Integrerede resultater fra placebokontrollerede undersøgelser
Integrated findings from placebo-controlled trials
I otte placebokontrollerede undersøgelser, heraf seks for andre indikationer end pulmonal arteriel hypertension, blev i alt 677 patienter behandlet med bosentan med daglige doser på mellem 100 mg og 2000 mg, og 288 patienter fik placebo.
In eight placebo-controlled studies, six of which were for indications other than pulmonary arterial hypertension, a total of 677 patients were treated with bosentan at daily doses ranging from 100 mg to 2000 mg and 288 patients were treated with placebo.
Behandlingsperioden strakte sig fra 2 uger til 6 måneder.
The foreseen duration of treatment ranged from 2 weeks to 6 months.
De bivirkninger, som optrådte hyppigere hos patienter, der blev behandlet med bosentan, end hos dem, der fik placebo (≥ 3% af patienter behandlet med bosentan med ≥ 2% forskel), var hovedpine (15, 8% versus 12, 8%), rødme (6, 6% versus 1, 7%), anormal leverfunktion (5, 9% versus 2, 1%), ødem i ben (4, 7% versus 1, 4%) og anæmi (3, 4% versus 1, 0%), som alle var dosisrelaterede.
The adverse drug reactions that occurred more frequently on bosentan than on placebo (≥ 3% of bosentan-treated patients, with ≥ 2% difference) were headache (15.8% vs 12.8%), flushing (6.6% vs 1.7%), abnormal hepatic function (5.9% vs 2.1%), leg oedema (4.7% vs 1.4%), and anaemia (3.4% vs 1.0%), all of which were dose related.
Placebokontrollerede undersøgelser af primær (idiopatisk/ familiær) PAH og PAH associeret med bindevævssygdom
Placebo-controlled trials in primary (idiopathic/ familial) PAH and PAH associated with connective tissue diseases
Nedenstående tabel viser de bivirkninger, som optrådte hos ≥ 3% af patienter, der blev behandlet med Tracleer (125 og 250 mg to gange dagligt) i fase 3 placebokontrollerede undersøgelser af pulmonal arteriel hypertension, og som optrådte hyppigere hos disse patienter:
The table below shows the adverse drug reactions that occurred in ≥ 3% of patients treated with Tracleer (125 and 250 mg twice daily) in the phase 3 placebo-controlled trials in pulmonary arterial hypertension, and which were more frequent in these patients:
Bivirkninger som optrådte hos ≥ 3% af patienter, og hyppigere hos patienter, der blev behandlet med Tracleer (125 og 250 mg to gange dagligt) i placebokontrollerede undersøgelser ved pulmonal arteriel hypertension
Adverse drug reactions occurring in ≥ 3% of patients, and more frequently in patients on Tracleer (125 and 250 mg twice daily), in placebo-controlled trials in pulmonary arterial hypertension
Systemorganklasse / Bivirkning
Body system / Adverse event
Placebo N = 172
Placebo N = 172
Tracleer (alle) N = 258
Tracleer (all) N = 258
Infektion i de øvre luftveje Nasofaryngitis Luftvejsinfektion Sinusitis Blod og lymfesystem
Upper respiratory tract infection Nasopharyngitis Respiratory tract infection
6. 4% 8, 1% 2, 9% 2, 3%
6.4% 8.1% 2.9%
24 9, 3% 24 9, 3% 9 3, 5% 9 3, 5%
24 9.3% 24 9.3% 9 3.5%
Anæmi
3.5%
9 Nervesystmet Hovedpine Syncope Hjerte
Headache Syncope Cardiac disorders
Palpitationer Vaskulære sygdomme
Palpitations Vascular disorders
Rødme Hypotension Knogler, led, muskler og bindevæv
Flushing Hypotension Musculoskeletal and connective tissue disorders
Artralgi Almene symptomer og reaktioner på administrationsstedet
Arthralgia General disorders and administration site conditions
Perifert ødem Brystsmerter Ødem Undersøgelser
Oedema peripheral Chest pain Oedema Investigations
Unormal leverfunktionstest
Liver function test abnormal
Kun bivirkninger, der forekom fra starten af behandlingen til 1 kalenderdag efter behandlingsophør, er medtaget.
Note: only AEs with onset from start of treatment to 1 calendar day after end of treatment are included.
En patient kan have haft mere end én bivirkning.
One patient could have had more than one AE.
125 eller 250 mg to gange dagligt) var de mest almindelige bivirkninger, som optrådte hyppigere hos patienter, der fik Tracleer, end hos dem, der fik placebo (hos ≥ 3% af patienter, der blev behandlet med Tracleer med ≥ 2% forskel) infektion i de øvre luftveje, hypotension og anæmi.
At the recommended maintenance dose or double the dose (i.e., 125 or 250 mg twice daily) the adverse drug reactions that occurred more frequently with Tracleer than with placebo (in ≥ 3% of Tracleer-treated patients, with ≥ 2% difference) were upper respiratory tract infection, hypotension, and anaemia.
Bivirkninger, som optrådte hos ≥ 1% og < 3% af disse patienter og hyppigere hos patienter, der fik Tracleer, end hos dem, der fik placebo (≥ 2% forskel) var stigning i leverenzymer (2, 7% for Tracleer versus 0% for placebo) og rødme (2, 47% for Tracleer versus 0, 6% for placebo).
Adverse drug reactions that occurred in ≥ 1% and < 3% of these patients and more frequently on Tracleer than on placebo (≥ 2% difference) were hepatic enzyme increased (2.7% on Tracleer versus 0% on placebo) and flushing (2.7% on Tracleer versus 0.6% on placebo).
Under de kliniske undersøgelser forekom behandlingsafbrydelser, der skyldtes bivirkninger hos patienter med pulmonal arteriel hypertension, der modtog doser på 125 og 250 mg to gange dagligt med samme hyppighed (5, 8%) hos bosentan - og placebobehandlede patienter.
Treatment discontinuations due to adverse events, during the clinical trials in patients with pulmonary arterial hypertension, at doses of 125 and 250 mg twice daily, occurred with the same frequency (5.8%) in bosentan and placebo-treated patients.
Placebokontrollerede forsøg med PAH associeret med kongenit hjertesygdom (BREATHE- 5)
Placebo-controlled trial in PAH associated with congenital heart disease (BREATHE-5)
Sikkerhedsprofilen af Tracleer hos denne population svarede til den, der var observeret i de pivotale forsøg med patienter med PAH.
The safety profile of Tracleer in this population was similar to that observed in the pivotal trials in patients with PAH.
Bivirkninger, som forekom hos en større del af patienterne behandlet med Tracleer 62, 5 mg to gange dagligt i fire uger efterfulgt af 125 mg to gange dagligt (n = 37) end med placebo (n = 17), omfattede perifert ødem (18, 9% vs.
Adverse events that occurred in a greater proportion of patients on Tracleer 62.5 mg twice daily for four weeks, followed by 125 mg twice daily (n = 37) than on placebo (n = 17) included peripheral oedema (18.9% vs.
5, 9%), hovedpine (13, 5% vs.
5.9%), headache (13.5% vs.
11, 8%), palpitationer (10, 8% vs.
11.8%), palpitations (1 0.8% vs.
0%), svimmelhed (8, 1% vs.
0%), dizziness (8.1% vs.
5, 9%) og brystsmerter (8, 1% vs.
5.9%) and chest pain (8.1% vs.
Fire patienter afbrød på grund af bivirkninger, to (5, 4%) i bosentangruppen og to (11, 8%) i placebogruppen.
Four patients discontinued due to adverse events, two (5.4%) in the bosentan group and two (11.8%) in the placebo group.
Ukontrollerede forsøg med patienter med PAH associeret med HIV- infektion (BREATHE- 4)
Uncontrolled trial in patients with PAH associated with HIV infection (BREATHE-4)
Sikkerhedsprofilen hos denne population (n = 16) ved behandling med Tracleer 62, 5 mg to gange dagligt i fire uger efterfulgt af 125 mg to gange dagligt, svarede til den, der blev observeret i de pivotale forsøg med patienter med PAH.
The safety profile in this population (n = 16) when treated with Tracleer 62.5 mg twice daily for four weeks, followed by 125 mg twice daily was similar to that observed in the pivotal trials in patients with PAH.
De hyppigste bivirkninger var perifert ødem (31%), hovedpine (19%), anormal leverfunktion (13%), muskelkramper (13%), væskeretention (13%) og opkastning (13%).
The most frequent adverse events were peripheral oedema (31%), headache (19%), abnormal liver function (13%), muscle cramps (13%), fluid retention (13%) and vomiting (13%).
4. 4).
Haematological abnormalities (anaemia and decrease in neutrophil count) were observed in some patients (see section 4.4).