natgillin/translations-raw huggingface dataset:
4. 8).
Peripheral oedema was reported more frequently with 10 mg ambrisentan (see section 4.8).
Intervention med diuretika eller indlæggelse for at væskebehandle eller behandle dekompenseret hjerteinsufficiens har i nogle tilfælde været nødvendigt.
Post-marketing reports of fluid retention occurring within weeks after starting ambrisentan have been received and, in some cases, have required intervention with a diuretic or hospitalisation for fluid management or decompensated heart failure.
Hvis patienterne har eksisterende væskeophobning, skal dette varetages med passende klinisk behandling før opstart med ambrisentan.
If patients have pre-existing fluid overload, this should be managed as clinically appropriate prior to starting ambrisentan.
Årsagen kan fx være ambrisentan eller eksisterende hjerteinsufficiens, og det vurderes om der kræves specifik behandling eller seponering af ambrisentanbehandlingen.
If clinically significant fluid retention develops during therapy with ambrisentan, with or without associated weight gain, further evaluation should be undertaken to determine the cause, such as ambrisentan or underlying heart failure, and the possible need for specific treatment or discontinuation of ambrisentan therapy.
Behandling med Volibris må ikke indledes hos kvinder i den fødedygtige alder, medmindre der foreligger negativ graviditetstest, og der anvendes sikker prævention.
Volibris treatment must not be initiated in women of child-bearing potential unless the result of a pre-treatment pregnancy test is negative and reliable contraception is practiced.
Hvis der er tvivl om, hvilken prævention den enkelte patient skal have, bør henvisning til en gynækolog overvejes.
If there is any doubt on what contraceptive advice should be given to the individual patient, consultation with a gynaecologist should be considered.
4. 3 og 4. 6).
Monthly pregnancy tests during treatment with Volibris are recommended (see sections 4.3 and 4.6).
Volibris- tabletter indeholder lactosemonohydrat.
4 Volibris tablets contain lactose monohydrate.
Patienter med sjældne arvelige galactoseintolerans, Lapp lactasemangel eller glucose- galactose- malabsorption bør ikke tage denne medicin.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Volibris- tabletter indeholder farvestoffet Allura red AC Aluminium Lake (E129), som kan fremkalde allergiske reaktioner.
Volibris tablets contain the azo colouring agent Allura red AC Aluminium Lake (E129), which can cause allergic reactions.
Dette tyder på, at ambrisentan ikke ændrer profilen for lægemidler, som metaboliseres af disse pathways.
Ambrisentan does not inhibit or induce phase I or II drug metabolizing enzymes at clinically relevant concentrations in in vitro and in vivo non-clinical studies, suggesting a low potential for ambrisentan to alter the profile of medicinal products metabolized by these pathways.
Resultaterne tyder på, at ambrisentan ikke har induktiv effekt på CYP3A4- isoenzymet.
The potential for ambrisentan to induce CYP3A4 activity was explored in healthy volunteers with results suggesting a lack of inductive effect of ambrisentan on the CYP3A4 isoenzyme.
5. 2).
Co-administration of ambrisentan with a phosphodiesterase inhibitor, either sildenafil or tadalafil (both substrates of CYP3A4) in healthy volunteers did not significantly affect the pharmacokinetics of the phosphodiesterase inhibitor or ambrisentan (see section 5.2).
5. 2).
Steady state administration of ketoconazole (a strong inhibitor of CYP3A4) did not result in a clinically significant increase in exposure to ambrisentan (see section 5.2).
Virkningen af samtidig administration af Volibris og inducere af CYP3A4 og 2C19 er ukendt.
The impact of the co-administration of Volibris with inducers of CYP3A4 and 2C19 is unknown.
5. 2).
Ambrisentan had no effects on the steady state pharmacokinetics and anti-coagulant activity of warfarin in a healthy volunteer study (see section 5.2).
Ambrisentan havde heller ingen samlet virkning på den ugentlige dosis af warfarinantikoagulant, protrombintid (PT) og international normalized ratio (INR) hos patienterne.
In addition, in patients, ambrisentan had no overall effect on the weekly warfarin-type anticoagulant dose, prothrombin time (PT) and international normalized ratio (INR).
Cyclosporin A er en hæmmer af multiple metaboliske enzymer og transportører.
Cyclosporine A is an inhibitor of multiple metabolic enzymes and transporters.
Der skal udvises forsigtighed, hvis Volibris skal administreres sammen med cyclosporin A.
Use caution when Volibris is co-administered with cyclosporine A.
5. 2).
In a clinical study in healthy volunteers, steady-state dosing with ambrisentan 10 mg once daily did not significantly affect the single-dose pharmacokinetics of the ethinyl estradiol and norethindrone components of a combined oral contraceptive (see section 5.2).
På baggrund af dette farmakokinetikstudie forventes ambrisentan ikke signifikant at påvirke eksponeringen af antikonceptionsmidler baseret på østrogen eller progestogen.
Based on this pharmacokinetic study, ambrisentan would not be expected to significantly affect exposure to oestrogen- or progestogen- based contraceptives.
5. 1).
The efficacy and safety of Volibris when co-administered with other treatments for PAH (e. g. prostanoids and phosphodiesterase type V inhibitors) has not been specifically studied in controlled clinical trials (see section 5.1).
Der skal derfor udvises forsigtighed, når disse administreres samtidig.
Therefore, caution is recommended in the case of co-administration.
In vitro har ambrisentan ingen hæmmende effekt på P- glycoprotein (Pgp) - medieret effluks af digoxin, og det er et svagt substrat for Pgp- medieret effluks.
In vitro, ambrisentan has no inhibitory effect on the P-glycoprotein (Pgp)-mediated efflux of digoxin and is a weak substrate for Pgp-mediated efflux.
Desuden har in vitro- forsøg med rotter og hepatocytter fra mennesker vist, at ambrisentan hverken hæmmer natriumtaurocholat co- transporter (NTCP), organisk anion eksportpumpe (OATP), galdesalteksportpumpe (BSEP) eller multistofresistensproteinisoform- 2 (MRP2).
Additional in vitro studies in rat and human hepatocytes showed that ambrisentan did not inhibit sodium-taurocholate co-transporter (NTCP), organic anion export pump (OATP), bile salt export pump (BSEP) and multi-drug resistance protein isoform-2 (MRP2).
In vitro- forsøg har desuden vist, at ambrisentan ikke har induktiv effekt på Pgp, BSEP eller MRP2.
In vitro studies in rat hepatocytes also showed that ambrisentan has no inductive effects on Pgp, BSEP or MRP2.
5. 2).
5 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).
5 Volibris er kontraindiceret under graviditet (se pkt.
Volibris is contraindicated in pregnancy (see section 4.3).
Dyreforsøg har vist, at ambrisentan er teratogent.
Animal studies have shown that ambrisentan is teratogenic.
Det anbefales, at der tages en graviditetstest hver måned under behandling med Volibris.
Monthly pregnancy tests during treatment with Volibris are recommended.
4. 3, 4. 4 og 5. 3).
Women receiving Volibris must be advised of the risk of foetal harm and alternative therapy initiated if pregnancy occurs (see sections 4.3, 4.4 and 5.3).
Det vides ikke, om ambrisentan udskilles i modermælk.
It is not known whether ambrisentan is excreted in human breast milk.
Det er ikke undersøgt i dyreforsøg om ambrisentan udskilles i modermælk.
The excretion of ambrisentan in milk has not been studied in animals.
4. 3).
Therefore lactation is contraindicated in patients taking Volibris (see section 4.3).
5. 3).
The development of testicular tubular atrophy in male animals has been linked to the chronic administration of ERAs, including ambrisentan (see section 5.3).
Virkningen på fertiliteten hos mennesker kendes ikke.
The effect on male human fertility is not known.
I kliniske forsøg er kronisk administration af ambrisentan ikke blevet forbundet med en ændring i plasmatestosteron.
Chronic administration of ambrisentan was not associated with a change in plasma testosterone in clinical studies.
Erfaring fra kliniske forsøg
Experience from clinical studies
5. 1).
Safety of Volibris has been evaluated in clinical trials of more than 483 patients with PAH (see section 5.1).
Bivirkningerne, som blev identificeret fra 12 ugers placebokontrollerede kliniske forsøgsdata, er listet nedenfor opdelt efter systemorganklasse og hyppighed.
Adverse drug reactions (ADR) identified from 12 week placebo controlled clinical trial data are listed below by system organ class and frequency.
Ved længere tids observation i ukontrollerede forsøg (middelobservation på 79 uger) svarede sikkerhedsprofilen til den, der blev set i korttidsforsøgene.
With longer observation in uncontrolled studies (mean observation of 79 weeks), the safety profile was similar to that observed in the short term studies.
Meget almindelig (> 1/ 10), almindelig (> 1/ 100 til < 1/ 10), ikke almindelig (> 1/ 1. 000 til < 1/ 100), sjælden (> 1/ 10. 000 til < 1/ 1. 000) og meget sjælden (< 1/ 10. 000).
Frequencies are defined as: very common (≥ 1/ 10); common (≥ 1/ 100 to < 1/ 10); uncommon (≥ 1/ 1,000 to < 1/ 100); rare (≥ 1/ 10,000 to < 1/ 1,000); very rare (< 1/ 10,000).
For dosisrelaterede bivirkninger afspejler hyppighedskategorien den høje dosis af Volibris.
For dose-related adverse reactions the frequency category reflects the higher dose of Volibris.
Hyppighedskategorierne tager ikke højde for andre faktorer såsom varierende forsøgslængde, forud eksisterende tilstande og patientkarakteristika ved baseline.
Frequency categories do not account for other factors including varying study duration, pre-existing conditions and baseline patient characteristics.
Bivirkningshyppighederne basseret på erfaring fra kliniske forsøg afspejler ikke nødvendigvis hyppigheden, der vil ses ved normal klinisk praksis.
Adverse reaction frequency categories assigned based on clinical trial experience may not reflect the frequency of adverse events occurring during normal clinical practice.
Inden for hver hyppighedsgruppe er bivirkningerne opstillet efter hvor alvorlige de er med de mest alvorlige først.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
6 Hjerte Palpitation
6 Palpitation
Anæmi (lavt hæmoglobin, lavt hæmatokrit)
Anaemia (decreased haemoglobin, decreased haematocrit)
Hovedpine (inkl. sinushovedpine, migræne) 1
Headache (including sinus headache, migraine)1
Kongestion i de øvre luftveje (fx næse2, bihuler), bihulebetændelse og nasopharyngitis, rhinitis
Upper respiratory (e. g. nasal2, sinus) congestion, sinusitis, nasopharyngitis, rhinitis
Mavesmerter Obstipation
Abdominal pain Constipation
Vaskulære sygdomme Rødmen
Vascular disorders Flushing
Perifert ødem, væskeretention3
Peripheral oedema, fluid retention3
Overfølsomhedsreaktioner (fx angioneurotisk ødem, udslæt)
Hypersensitivity reactions (e. g. angioedema, rash)
1 Forekomsten af hovedpine var højere med 10 mg Volibris.
1 The frequency of headache appeared higher with 10 mg Volibris.
2 Forekomsten af tilstoppet næse var dosisafhængig under behandling med Volibris.
2 The incidence of nasal congestion was dose related during Volibris therapy.
3 Perifert ødem blev hyppigere rapporteret ved behandling med 10 mg Volibris.
3 Peripheral oedema was reported more frequently with 10 mg Volibris.
4. 4).
In clinical studies peripheral oedema was reported more commonly and tended to be more severe in patients ≥ 65 years (see section 4.4).
4. 4).
Decreased haemoglobin (see section 4.4).
Forekomsten af lavt hæmoglobin (anæmi) var højere med 10 mg Volibris.
The frequency of decreased haemoglobin (anaemia) was higher with 10 mg Volibris.
Middelændringerne i forhold til baseline så ud til at blive stabiliseret i løbet af de efterfølgende 8 uger.
Across the 12 week placebo controlled Phase III clinical studies, mean haemoglobin concentrations decreased for patients in the Volibris groups and were detected as early as week 4 (decrease by 0.83 g/ dl); mean changes from baseline appeared to stabilise over the subsequent 8 weeks.
17 patienter (6, 5%) i Volibris- gruppen havde et fald i hæmoglobin som var ≥ 15% i forhold til baseline og som faldt til under normalgrænsen.
A total of 17 patients (6.5%) in the Volibris treatment groups had decreases in haemoglobin of ≥ 15% from baseline and which fell below the lower limit of normal.
7 Post- marketing data
Post-marketing data
Udover de bivirkninger, som blev set i de kliniske forsøg, er følgende bivirkninger set efter markedsføringen af Volibris.
7 In addition to adverse reactions identified from clinical studies, the following adverse reactions were identified during post-approval use of Volibris.
Frekvensen er defineret som: "ikke kendt" (kan ikke estimeres ud fra forhåndenværende data).
Frequencies are defined as: ‘ not known’ (cannot be estimated from the available data).
Hjerteinsufficiens4
Cardiac failure4
Ikke kendt.
Not known
Dyspnø5
Dyspnoea5
4 De fleste tilfælde af hjerteinsufficiens var forbundet med væskeretention.
4 Most of the reported cases of cardiac failure were associated with fluid retention.
5 Tilfælde af forværret dyspnø af ukendt ætiologi er set kort efter behandlingsstart med Volibris.
5 Cases of worsening dyspnoea of unclear aetiology have been reported shortly after starting Volibris therapy.
Der er ingen erfaring med Volibris i større doser end 10 mg/ dag til PAH- patienter.
There is no experience in PAH patients of Volibris at daily doses greater than 10 mg.
Hos raske frivillige blev der i forbindelse med enkeltdoser på 50 og 100 mg (5- 10 gange den maksimalt anbefalede dosis) set hovedpine, rødmen, svimmelhed, kvalme og tilstopning af næsen.
In healthy volunteers, single doses of 50 and 100 mg (5 to 10 times the maximum recommended dose) were associated with headache, flushing, dizziness, nausea and nasal congestion.
5. 3).
Due to the mechanism of action, an overdose of Volibris could potentially result in hypotension (see section 5.3).
Farmakoterapeutisk klassifikation: andre antihypertensiva, ATC- kode:
Pharmacotherapeutic group: other anti-hypertensives, ATC code:
Ambrisentan er et oralt aktivt ERA af gruppen propionsyre, som er selektiv for endotelin A- receptoren (ETA).
Ambrisentan is an orally active, propanoic acid-class, ERA selective for the endothelin A (ETA) receptor.
• Ambrisentan blokkerer ETA- receptor- undertypen, som hovedsagelig findes på karrenes glatte muskelceller og på hjertemyocytter.
• Ambrisentan blocks the ETA receptor subtype, localized predominantly on vascular smooth muscle cells and cardiac myocytes.
Blokkeringen forhindrer endotelin- medieret aktivering af ” second messenger ” - systemer, der ellers ville resultere i vasokonstriktion og muskelcelleformering. • Ambrisentans selektivitet over for ETA- receptoren forventes at medføre bevaret ETB- receptor- medieret produktion af vasodilatatorernes nitrogenoxid og prostacyklin.
This prevents endothelin-mediated activation of second messenger systems that result in vasoconstriction and smooth muscle cell proliferation. • The selectivity of ambrisentan for the ETA over the ETB receptor is expected to retain ETB receptor mediated production of the vasodilators nitric oxide and prostacyclin.
8 Der er gennemført to randomiserede, dobbeltblinde, multicenter, placebokontrollerede, fase 3 pivotale forsøg (ARIES- 1 og - 2).
8 Two randomised, double-blind, multi-centre, placebo controlled, Phase 3 pivotal studies were conducted (ARIES-1 and 2).
ARIES- 1 omfattede 201 patienter og sammenlignede 5 mg og 10 mg Volibris med placebo.
ARIES-1 included 201 patients and compared Volibris 5 mg and 10 mg with placebo.
ARIES- 2 omfattede 192 patienter og sammenlignede 2, 5 mg og 5 mg Volibris med placebo.
ARIES-2 included 192 patients and compared Volibris 2.5 mg and 5 mg with placebo.
I begge forsøg blev Volibris tilføjet til patienternes støttende/ bagvedliggende behandling, som kunne omfatte en kombination af digoxin, antikoagulantia, diuretika, oxygen og vasodilatatorer (kalciumkanalblokkere, ACE- hæmmere).
In both studies, Volibris was added to patients’ supportive/ background medication, which could have included a combination of digoxin, anticoagulants, diuretics, oxygen and vasodilators (calcium channel blockers, ACE inhibitors).
De patienter, der indgik i forsøget, havde IPAH eller PAH associeret med sygdom i bindevævet.
Patients enrolled had IPAH or PAH associated with connective tissue disease.
Hovedparten af patienterne havde symptomer i WHO’ s funktionsklasse II (38, 4%) eller III (55, 0%).
The majority of patients had WHO functional Class II (38.4%) or Class III (55.0%) symptoms.
Patienter med forud eksisterende leversygdom (cirrose eller klinisk signifikant, forhøjede aminotransferaser) og patienter, som var i anden behandling for PAH (f. eks. prostanoider), blev udelukket.
Patients with pre-existent hepatic disease (cirrhosis or clinically significantly elevated aminotransferases) and patients using other targeted therapy for PAH (e. g. prostanoids) were excluded.
Hæmodynamiske parametre blev ikke vurderet i disse forsøg.
Haemodynamic parameters were not assessed in these studies.
Funktionskapaciteten blev opgjort som ændring i forhold til baseline efter 12 ugers behandling.
The primary endpoint defined for the Phase 3 studies was improvement in exercise capacity assessed by change from baseline in 6 minute walk distance (6MWD) at 12 weeks.
I begge forsøg resulterede behandling med Volibris, uanset styrke, i en signifikant forbedring af 6MWD.
In both studies, treatment with Volibris resulted in a significant improvement in 6MWD for each dose of Volibris.
For 5 mg- gruppen i ARIES- 1 og - 2 var den placebojusterede forbedring i middel- 6MWD efter 12 uger henholdsvis 30, 6 m (95% CI:
The placebo-adjusted improvement in mean 6MWD at week 12 compared to baseline was 30.6 m (95% CI:
2, 9 til 58, 3; p = 0, 008) og 59, 4 m (95% CI:
2.9 to 58.3; p=0.008) and 59.4 m (95% CI:
29, 6 til 89, 3; p < 0, 001) sammenlignet med baseline.
29.6 to 89.3; p < 0.001) for the 5 mg group, in ARIES 1 and 2 respectively.
For 10 mg- gruppen i ARIES- 1 var den placebojusterede forbedring i middel- 6MWD efter 12 uger 51, 4 m (95% CI:
The placebo-adjusted improvement in mean 6MWD at week 12 in patients in the 10 mg group in ARIES-1 was 51.4 m (95% CI:
26, 6 to 76, 2; p < 0, 001).
26.6 to 76.2; p < 0.001).
Der blev gennemført en pre- specificeret kombinationsanalyse af fase 3- forsøgene (ARIES- C).
A pre-specified combined analysis of the Phase 3 studies (ARIES-C) was conducted.
44, 6 m (95% CI:
The placebo-adjusted mean improvement in 6MWD was 44.6 m (95% CI:
52, 5 m (95% CI:
24.3 to 64.9; p < 0.001) for the 5 mg dose, and 52.5 m (95% CI:
28, 8 til 76, 2; p < 0, 001).
28.8 to 76.2; p < 0.001) for the 10 mg dose.
Hazard- ratioen viste en reduktion på 80% (95% CI:
In ARIES-2, Volibris (combined dose group) significantly delayed the time to clinical worsening of PAH compared to placebo (p < 0.001), the hazard ratio demonstrated a 80% reduction (95% CI:
47% til 92%).
47% to 92%).
PAH, atrieseptostomi, tilføjelse af endnu et lægemiddel til behandling af PAH samt kriterierne for udtræden før tid.
The measure included: death, lung transplantation, hospitalisation for PAH, atrial septostomy, addition of other PAH therapeutic agents and early escape criteria.
I gruppen, der blev behandlet med kombineret dosis, blev der observeret en statistisk signifikant stigning (3, 41 + / - 6, 96) i den fysiske funktionsskala på helbredsskemaet SF- 36 sammenlignet med placebo (- 0, 20 + / - 8, 14; p = 0, 005).
A statistically significant increase (3.41 ± 6.96) was observed for the combined dose group in the physical functioning scale of the SF-36 Health Survey compared with placebo (-0.20 ± 8.14, p=0.005).
12 ugers behandling med Volibris medførte en statistisk signifikant forbedring på Borgs dyspnøskala (BDI) (placebojusteret BDI på - 1, 1 (95% CI: - 1, 8 til - 0, 4; p = 0, 019; kombineret dosis- gruppe)).
Treatment with Volibris led to a statistically significant improvement in Borg Dyspnea Index (BDI) at week 12 (placebo-adjusted BDI of -1.1 (95% CI: -1.8 to -0.4; p=0.019; combined dose group)).
Patienterne, der indgik i ARIES- 1 og - 2, var egnede til at indgå i et langtids, ublindet forlængelsesforsøg; ARIES- E (n = 383).
Patients enrolled into ARIES 1 and 2 were eligible to enter a long term open label extension study ARIES E (n=383).
Volibris ’ virkning på sygdommen er ukendt.
The effect of Volibris on the outcome of the disease is unknown.
Hos de personer, der fik Volibris (kombineret dosis- gruppe), var den observerede sandsynlighed for overlevelse efter 1 år 95% og efter 2 år 84%.
The observed probability of survival at 1 year for subjects receiving Volibris (combined Volibris dose group) was 95% and at 2 years was 84%.
I et ublindet forsøg (AMB222) blev Volibris undersøgt hos 36 patienter til vurdering af forekomst af øgede serumaminotransferasekoncentrationer hos patienter, som tidligere var ophørt med anden ERA- behandling pga. abnormiteter i aminotransferase.
In an open label study (AMB222), Volibris was studied in 36 patients to evaluate the incidence of increased serum aminotransferase concentrations in patients who had previously discontinued other ERA therapy due to aminotransferase abnormalities.
Efter en middelbehandlingstid på 53 uger med Volibris havde ingen af de inkluderede patienter et bekræftet serum- ALAT > 3 x ULN, som krævede permanent ophør med behandlingen.
During a mean of 53 weeks of treatment with Volibris, none of the patients enrolled had a confirmed serum ALT > 3xULN that required permanent discontinuation of treatment.
I løbet af den tid var 50% af patienterne skiftet fra 5 mg til 10 mg Volibris.
Fifty percent of patients had increased from 5 mg to 10 mg Volibris during this time.
Den kumulative forekomst af abnormiteter i serumaminotransferase > 3 x ULN for alle fase 2 - og fase 3- forsøgene (inkl. respektive ublindede forlængelser) var 17 ud af 483 forsøgspersoner i løbet af en middel eksponeringsvarighed på 79, 5 uger.
The cumulative incidence of serum aminotransferase abnormalities > 3xULN in all Phase 2 and 3 studies (including respective open label extensions) was 17 of 483 subjects over a mean exposure duration of 79.5 weeks.
100 patientår på Volibris.
This is an event rate of 2.3 events per 100 patient years of exposure for Volibris.
9 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).
9 An improvement in haemodynamic parameters was observed in patients with PAH after 12 weeks (n=29) in a Phase 2 study (AMB220).
Behandling med Volibris resulterede i en stigning i middel hjerteindeks, et fald i middel lungearterietryk og et fald i middel pulmonal vaskulær resistens.
Treatment with Volibris resulted in an increase in mean cardiac index, a decrease in mean pulmonary artery pressure, and a decrease in mean pulmonary vascular resistance.
Antallet af patienter, der fik Volibris og sildenafil samtidig i ARIES- E og AMB222, var henholdsvis 22 (5, 7%) og 17 (47%).
The number of patients who received concomitant Volibris and sildenafil in ARIES-E and AMB222 was 22 patients (5.7%) and 17 patients (47%), respectively.
1, 5 timer efter indgift ved både faste og sammen med mad.
After oral administration, maximum plasma concentrations (Cmax) of ambrisentan typically occur around 1.5 hours post-dose under both fasted and fed conditions.
Cmax og arealet under plasmakoncentations- tidskurven (AUC) stiger dosisproportionalt over hele det terapeutiske interval.
Cmax and area under the plasma concentration-time curve (AUC) increase dose proportionally over the therapeutic dose range.
Steady- state nås generelt efter 4 dage med gentagen indgift.
Steady-state is generally achieved following 4 days of repeat dosing.