natgillin/translations-raw huggingface dataset:
In patients already taking beta-blockers at time of dronedarone initiation, an ECG should be performed and the dose of beta-blocker should be adjusted if needed (see section 4.4).
U bolesnika koji već uzimaju beta-blokatore u vrijeme započinjanja liječenja dronedaronom, potrebno je napraviti EKG i ako je potrebno prilagoditi dozu beta-blokatora (vidjeti dio 4.4).
In elderly patients ≥75 years with multiple co-morbidities, clinical signs of heart failure and ECG should be monitored on a regular basis (see sections 4.2 and 5.1).
U bolesnika u dobi od ≥ 75 godina s popratnim bolestima (vidjeti dio 4.3, 4.4 i 5.1), nužno je redovito pratiti kliničke znakove zatajenja srca i EKG.
The educational material is a Prescriber Guide to:
Edukacijski materijal je Vodič za liječnike propisivače za: • probir bolesnika prije početka liječenja
Based on clinical experience, dronedarone has a low pro-arrhythmic effect and has shown a decrease in arrhythmic death in the ATHENA study (see section 5.1).
Kliničko iskustvo pokazalo je da dronedaron ima slab proaritmijski učinak, a u ispitivanju ATHENA
Moderate/weak CYP 3A4 inhibitors
Umjereni/slabi inhibitori CYP3A4
Renal impairment
Bolji dronedaron
Other moderate/weak CYP 3A4 Inhibitors
Ostali umjereni/slabi inhibitori CYP3A4
MAO inhibitors
Inhibitori monoaminooksidaze
Adverse reactions are presented by system organ class.
Nuspojave su prikazane prema klasifikaciji organskih sustava.
Potent CYP 3A4 inhibitors
Potentni inhibitori CYP3A4
Beta-blockers that are metabolised by CYP 2D6 can have their exposure increased by dronedarone.
Dronedaron može povećati izloženost beta-blokatorima koji se metaboliziraju pomoću CYP2D6.
Interactions (see section 4.5)
Interakcije (vidjeti dio 4.5) Digoksin
Patients with history of, or current heart failure or left ventricular systolic dysfunction
Bolesnici s u anamnezi zabilježenim ili trenutnim zatajenjem srca ili sistoličkom disfunkcijom lijeve klijetke
If you have had a pacemaker fitted for this problem, you can use MULTAQ, - if you have a very slow heart beat (less than 50 beats a minute), - if your ECG (electrocardiogram) shows a heart problem called “prolonged QT corrected interval” (this interval is more than 500 milliseconds), - if you have a type of atrial fibrillation called permanent atrial fibrillation (AF).
QT-interval" (interval traje dulje od 500 milisekundi), - ako imate jednu vrstu fibrilacije atrija koja se naziva permanentnom fibrilacijom atrija.
• other medicines used to control an irregular or fast heart beat such as flecainide, propafenone,
• druge lijekove koji se koriste za regulaciju nepravilnih ili ubrzanih otkucaja srca, kao što su flekainid, propafenon, kinidin, disopiramid, dofetilid, sotalol, amiodaron,
Patients developing permanent AF during treatment
Bolesnici u kojih se tijekom liječenja razvije permanentna fibrilacija atrija
Digoxin
Digitalis
NAME OF THE MEDICINAL PRODUCT MULTAQ 400 mg film-coated tablets
NAZIV LIJEKA MULTAQ 400 mg filmom obložene tablete
Screen patients before treatment initiation Contra indication of Permanent Atrial fibrillation Contra indication of history, or current heart failure or left ventricular systolic dysfunction (LVSD)
- kontraindikacija - permanentna fibrilacija atrija - kontraindikacija - trenutačno ili u anamnezi zabilježeno zatajenje srca ili sistolička disfunkcija lijeve klijetke - prevencija interakcija lijekova
- if you are allergic to dronedarone or to any of the other ingredients of this medicine (listed in section 6), - if you have a problem with the nerves in your heart (heart block).
Nemojte uzimati MULTAQ - ako ste alergični na dronedaron ili neki drugi sastojak ovog lijeka (naveden u dijelu 6),
The study was stopped prematurely due to an observed imbalance of deaths in the dronedarone group [n = 25 versus 12 (placebo), p = 0.027] (see sections 4.3 and 4.4).
(placebo), p = 0,027] (vidjeti dio 4.3 i 4.4).
Moreover, digitalis has the potential to interact with dronedarone from a pharmacodynamic point of view.
Nadalje, s farmakodinamičkog stajališta, digitalis može ući u interakciju s dronedaronom.
Nervous system disorders
Poremećaji živčanog sustava disgeuzija ageuzija
• MULTAQ is not recommended if you are pregnant or you think you may be pregnant.
• Ako ste trudni ili mislite da biste mogli biti trudni, ne preporučuje se primjena lijeka MULTAQ.
After oral administration in fed conditions, peak plasma concentrations of dronedarone and the main circulating active metabolite (N-debutyl metabolite) are reached within 3 to 6 hours.
Nakon peroralne primjene uz obrok vršne koncentracije dronedarona i glavnog aktivnog cirkulirajućeg metabolita
Pharmacodynamic properties
Farmakodinamički učinci
5 How to store MULTAQ Contents of the pack and other information
Kako MULTAQ izgleda i sadržaj pakiranja
A clinical study in patients with permanent AF (AF duration for at least 6 months) and cardiovascular risk factors was stopped early due to an excess of cardiovascular death, stroke and heart failure in patients receiving dronedarone (see section 5.1).
i faktorima kardiovaskularnog rizika prijevremeno je prekinuto zbog prevelikog broja slučajeva smrti zbog kardiovaskularnih uzroka, moždanog udara i zatajenja srca u bolesnika koji su primali dronedaron
Liver, pulmonary, coagulation and renal function tests Counsel patients about its use
- testovi funkcije jetre, pluća, koagulacije i bubrega
In patients already on calcium antagonists at time of dronedarone initiation, an ECG should be performed and the calcium antagonist dose should be adjusted if needed (see section 4.4).
U bolesnika koji u vrijeme započinjanja liječenja dronedaronom već uzimaju antagoniste kalcija ili beta-blokatore treba snimiti EKG i po potrebi prilagoditi dozu antagonista kalcija (vidjeti dio 4.4).
Dronedarone is contraindicated in patients in unstable hemodynamic conditions, with history of, or current heart failure or left ventricular systolic dysfunction (see section 4.3).
Dronedaron je kontraindiciran u bolesnika u nestabilnom hemodinamičkom stanju koji pate od zatajenja srca ili sistoličke disfunkcije lijeve klijetke ili imaju zatajenje srca ili sistoličku disfunkciju lijeve klijetke u anamnezi.
Titanium dioxide (E171) Carnauba wax (E903)
hipromeloza (E464), makrogol 6000, titanijev dioksid (E171), karnauba vosak (E903).
100x1 film-coated tablets
20 filmom obloženih tableta 50 filmom obloženih tableta 60 filmom obloženih tableta 100x1 filmom obložena tableta
An increase in plasma creatinine (mean increase 10 μmol/L) has been observed with dronedarone 400 mg twice daily in healthy subjects and in patients.
Kod primjene dronedarona u dozi od 400 mg dvaput na dan u zdravih ispitanika i u bolesnika primijećeno je povišenje razine kreatinina u plazmi (srednje povišenje 10 µmol/l).
If AF reoccurs, discontinuation of dronedarone should be considered.
Ako se ponovno javi fibrilacija atrija, treba razmotriti prekid liječenja dronedaronom.
• Severe hepatic impairment
• intersticijska bolest pluća
In permanent AF, the AF has been present for a long time (at least during 6 months) and a decision has been made not to change back your heart rhythm to atrial normal rhythm with a treatment called cardioversion, - if you have instability (drops) in your blood pressure which can lead to inadequate arterial blood flow to your organs,
U slučaju permanentne fibrilacije atrija, fibrilacija je prisutna dulje vrijeme (najmanje 6 mjeseci) te je donesena odluka da se srčani ritam ne vraća u normalan atrijski ritam postupkom koji se zove kardioverzija,
• you have swollen feet or legs, trouble breathing when lying down or sleeping, shortness of breath when moving around, or weight increase (which are signs and symptoms of heart failure),
Možete imati otečena stopala ili noge, tegobe s disanjem u ležećem položaju ili dok spavate ili možete osjetiti nedostatak zraka kad ste u pokretu,
Some cases also reported increases in blood urea nitrogen possibly due to hypoperfusion secondary to developing CHF (pre-renal azotaemia).
vjerojatno zbog hipoperfuzije kao posljedice razvoja kongestivnog zatajenja srca (prerenalna azotemija).
Heart Failure (including use in patients with unstable hemodynamic conditions with history of, or current heart failure or left ventricular systolic dysfunction, and pre-renal azotemia) Use in Permanent atrial fibrillation defined as an AF duration ≥6 months (or duration unknown) and attempts to restore sinus rhythm no longer considered by the physician Pulmonary-interstitial lung disease (ILD)
• zatajenje srca (uključujući primjenu u bolesnika s nestabilnim hemodinamičkim stanjima, sa trenutnim ili u anamnezi zabilježenim zatajenjem srca ili sistoličkom disfunkcijom lijeve klijetke i prerenalnom azotemijom)
Signs include stomach (abdominal) area pain or discomfort, loss of appetite, nausea, vomiting, yellowing of the skin or the whites of the eyes (jaundice), unusual darkening of the urine, fatigue (especially in association with other symptoms listed above), itching.
Znakovi uključuju bol ili nelagodu u području trbuha (abdomena), gubitak apetita, mučninu, povraćanje, žutu boju kože ili bjeloočnica
Tablet coat
Ovojnica tablete:
sinus node dysfunction, atrial conduction defects, or sick sinus syndrome (except when used in conjunction with a functioning pacemaker)
• Atrioventrikularni blok drugog ili trećeg stupnja, potpuni blok grane Hisova snopa, distalni blok, disfunkcija sinusnog čvora, poremećaj atrijskog provođenja ili sindrom bolesnog sinusnog čvora (osim u bolesnika s ugrađenim elektrostimulatorom)
What is in this leaflet
(vidjeti ispod)
You may have swollen feet or legs, trouble breathing when lying down or sleeping, or shortness of breath when moving around, - if the percentage of blood leaving your heart each time it contracts is too low (condition called left ventricular dysfunction), - if you took amiodarone (another antiarrhythmic medicine) previously and experienced lung or liver problems, - if you take medicines for infection (including fungal infection or AIDS), allergies, heart beat problems, depression, after a transplant (see section below on “Other medicines and MULTAQ”.
- ako uzimate lijekove za liječenje infekcije (uključujući gljivičnu infekciju ili AIDS), alergije, problema s otkucajima srca, depresije ili lijekove koji se propisuju nakon presađivanja organa (pogledajte dio "Drugi lijekovi i MULTAQ" u nastavku.
itraconazole, voriconazole, posaconazole, telithromycin, clarithromycin, nefazodone and ritonavir (see section 4.5)
• Istodobna primjena s potentnim inhibitorima CYP3A4 citokroma P450, poput ketokonazola, itrakonazola, vorikonazola, posakonazola, telitromicina, klaritromicina, nefazodona i ritonavira (vidjeti dio 4.5)
Cases of interstitial lung disease including pneumonitis and pulmonary fibrosis have been reported in post-marketing experience.
Nakon stavljanja lijeka u promet prijavljeni su slučajevi intersticijske bolesti pluća, uključujući pneumonitis i plućnu fibrozu.
What MULTAQ is and what it is used for What you need to know before you take MULTAQ How to take MULTAQ
Što se nalazi u ovoj uputi Što je MULTAQ i za što se koristi
Ageusia
ATHENA.
• Problem where your heart does not adequately pump the blood round your body as well as it should (congestive heart failure) In clinical studies, this side effect was observed at a similar rate in patients receiving MULTAQ and in patients receiving placebo.
U kliničkim je ispitivanjima ta nuspojava primijećena jednako često u bolesnika koji su primali MULTAQ i u bolesnika koji su primali placebo.
machine.
OBLIK
In patients already on calcium antagonists or beta blockers at time of dronedarone initiation, an ECG should be performed and the dose should be adjusted if needed.
U bolesnika koji u vrijeme započinjanja liječenja dronedaronom već uzimaju antagoniste kalcija ili beta-blokatore treba snimiti EKG
NAME OF THE MEDICINAL PRODUCT MULTAQ 400 mg film-coated tablets dronedarone
Uputa o lijeku: Informacije za bolesnika MULTAQ 400 mg filmom obložene tablete dronedaron
• History of, or current heart failure or left ventricular systolic dysfunction
• Bolesnici sa trenutnim ili u anamnezi zabilježenim zatajenjem srca ili sistoličkom disfunkcijom lijeve klijetke
How to store MULTAQ
Moguće nuspojave Kako čuvati MULTAQ
quinidine, disopyramide, dofetilide, sotalol, amiodarone,
propafenona, kinidina, dizopiramida, dofetilida, sotalola, amiodarona).
Lactose monohydrate Colloidal anhydrous silica Magnesium stearate (E572)
hipromeloza (E464), kukuruzni škrob, krospovidon (E1202), poloksamer 407, laktoza hidrat, silicijev dioksid, koloidni, bezvodni, magnezijev stearat (E572).
and III antiarrhythmics (see section 4.5)
(poput eritromicina), terfenadina te antiaritmika skupine I i III (vidjeti dio 4.3).
• your atrial fibrillation becomes permanent while you are taking MULTAQ.
Dok uzimate MULTAQ, obavijestite svog liječnika: • ako fibrilacija atrija postane permanentna tijekom liječenja lijekom MULTAQ.
Dronedarone 800 mg daily increased metoprolol exposure by 1.6-fold and propranolol exposure by 1.3-fold (i.e. much below the 6-fold differences observed between poor and extensive CYP 2D6 metabolisers).
Primjena dronedarona u dozi od 800 mg na dan povećala je izloženost metoprololu 1,6 puta, a propranololu 1,3 puta
MULTAQ.
Ne
Consequently, INR should be closely monitored after initiating dronedarone in patients taking vitamin K antagonists as per their label.
K mora pažljivo pratiti INR nakon početka liječenja dronedaronom.
The tablets should be taken at the same time each day.
Tablete treba uzimati svakog dana u isto vrijeme.
The company is also carrying out an observational study on the long-term safety of the medicine.
Tvrtka također provodi opservacijsko ispitivanje o dugoročnoj sigurnosti lijeka.
This overview was last updated in 03-2018.
Pregled informacija posljednji je put ažuriran u 03-2018.
FEV1 is the most air a person can breathe out in one second.
FEV1 je najveća količina zraka koju osoba može izdahnuti u jednoj sekundi.
Further information on Daxas can be found on the Agency's website: ema.europa/Find medicine/Human medicine/European public assessment reports.
Više informacija o lijeku Daxas nalazi se na internetskim stranicama Agencije: ema.europa/Find medicine/Human medicine/European public assessment reports.
This benefit was seen on top of the effects of the treatments that the patients were already receiving.
Ta se korist smatrala dodatkom drugim terapijama koje su već primali bolesnici.
Daxas received a marketing authorisation valid throughout the EU on 5 July 2010.
Lijek Daxas dobio je odobrenje za stavljanje lijeka u promet koje je na snazi u EU-u od 5. srpnja 2010.
What measures are being taken to ensure the safe and effective use of Daxas?
Koje se mjere poduzimaju kako bi se osigurala sigurna i učinkovita primjena lijeka Daxas?
At the beginning of the studies, both groups of patients had an FEV1 of around 1 litre (1,000 ml).
Na početku ispitivanja obje su skupine bolesnika imale FEV1 od otprilike 1 litre (1000 ml).
The doctor may stop treatment with Daxas if the patient loses too much weight.
Liječnik može zaustaviti liječenje lijekom Daxas ako bolesnik izgubi previše tjelesne težine.
By blocking the action of PDE4, roflumilast reduces the inflammation in the lungs, helping to reduce the patient's symptoms or to prevent them from getting worse.
Blokiranjem djelovanja PDE4 roflumilast smanjuje upalu u plućima i time pomaže pri ublažavanju simptoma bolesnika ili sprečava njihovo pogoršavanje.
What is Daxas and what is it used for?
Što je Daxas i za što se koristi?
The company will also provide cards for patients, telling them what information about their symptoms and past illnesses they need to give their doctor to help the doctor determine whether Daxas is appropriate for them.
Tvrtka će također osigurati kartice za bolesnike na kojima je navedeno što moraju reći liječniku o svojim simptomima i povijesti bolesti kako bi liječnik mogao utvrditi je li Daxas odgovarajući lijek za njih.
The main measure of effectiveness was the improvement in forced expiratory volumes (FEV1) and the reduction in the number of moderate or severe flare-ups of their COPD over a year of treatment.
Glavno mjerilo djelotvornosti bio je napredak u odnosu na forsirani ekspiratorni volumen (FEV1) i smanjenje broja umjerenih ili teških izbijanja KOPB-a tijekom jedne godine liječenja.
The most common side effects with Daxas (seen in between 1 and 10 patients in 100) are decreased weight, decreased appetite, insomnia (difficulty sleeping), headache, diarrhoea, nausea (feeling sick) and abdominal pain (stomach ache).
Najčešće nuspojave lijeka Daxas (uočene u između 1 i 10 na 100 bolesnika) jesu smanjenje težine, smanjenje teka, nesanica (poteškoće sa spavanjem), glavobolja, proljev, mučnina (slabost) i abdominalna bol (bol u trbuhu).
The active substance in Daxas, roflumilast, belongs to a group of medicines called ‘phosphodiesterase type 4 (PDE4) inhibitors'.
Djelatna tvar u lijeku Daxas, roflumilast, pripada skupini lijekova zvanih inhibitori fosfodiesteraze tipa 4 (PDE4).
The company that makes Daxas will ensure that healthcare professionals who will prescribe the medicine in all Member States of the European Union (EU) are provided with educational materials containing information on the medicine's side effects and how it should be used.
Tvrtka koja stavlja lijek Daxas u promet osigurat će da zdravstveni radnici koji će propisivati lijek u svim državama članicama Europske unije (EU) prime edukacijski paket koji sadrži informacije o nuspojavama lijeka i kako ga treba koristiti.
After considering all of the available data on the effects of the medicine, the Agency decided that Daxas's benefits are greater than its risks and it can be authorised for use in the EU.
Nakon razmatranja svih dostupnih podataka o učincima lijeka, Agencija je zaključila da koristi od lijeka Daxas nadmašuju s njim povezane rizike te da lijek može biti odobren za primjenu u Europskoj uniji.
Why is Daxas authorised in the EU?
Zašto je lijek Daxas odobren u EU-u?
Daxas contains the active substance roflumilast.
Daxas sadrži djelatnu tvar roflumilast.
Side effects reported with Daxas are carefully evaluated and any necessary action taken to protect patients.
Nuspojave prijavljene za lijek Daxas pažljivo se procjenjuju i poduzimaju se potrebne mjere za zaštitu bolesnika.
Recommendations and precautions to be followed by healthcare professionals and patients for the safe and effective use of Daxas have also been included in the summary of product characteristics and the package leaflet.
Preporuke i mjere opreza kojih se zdravstveni radnici i bolesnici trebaju pridržavati u cilju sigurne i učinkovite primjene lijeka Daxas također se nalaze u sažetku opisa svojstava i u uputi o lijeku.
COPD is a long-term disease in which the airways and air sacs inside the lungs become damaged or blocked, leading to difficulty breathing air in and out of the lungs.
KOBP je dugotrajna bolest kod koje su dišni putevi i zračne vrećice u plućima oštećeni ili blokirani, što uzrokuje otežano udisanje i izdisanje zraka iz pluća.
These involved over 3,000 adults with severe COPD who had had at least one flare-up of their disease in the past year.
Ispitivanja su obuhvatila više od 3000 odraslih osoba s teškim KOPB-om kojima se bolest pogoršala barem jedanput tijekom prethodne godine.
The benefits in improving FEV1 were similar in both groups at the end of the study; however, patients who could not take 500 micrograms daily and were then just given 250 micrograms daily did not show an improvement in lung function.
Koristi u pogledu poboljšanja FEV1 bile su slične u obje skupine na kraju ispitivanja; međutim, u bolesnika koji nisu mogli uzimati dnevnu dozu od 500 mikrograma te su potom prebačeni na dnevnu dozu od 250 mikrograma nije zabilježeno poboljšanje funkcije pluća.
Because patients taking Daxas may lose weight, they are advised to weigh themselves on a regular basis.
S obzirom na to da je u bolesnika koji uzimaju Daxas moguć gubitak tjelesne težine, savjetuje im se da se redovito važu.
Around 18% (81 of 441 patients) of those started at 250 micrograms daily dropped out of the study, compared with 25% (109 of 443) of those starting with 500 micrograms daily.
Otprilike 18 % (81 od 441) bolesnika koji su započeli liječenje dnevnom dozom od 250 mikrograma prekinulo je sudjelovanje u ispitivanju, u usporedbi s 25 % (109 od 443) bolesnika koji su započeli liječenje dnevnom dozom od 500 mikrograma.
Daxas is not used on its own but as an ‘add-on' to treatment with bronchodilators (medicines that widen the airways in the lungs).
Daxas se ne primjenjuje kao samostalni lijek, nego kao dodatak liječenju bronhodilatatorima (lijekovi koji šire dišne puteve u plućima).
For more information about using Daxas, see the package leaflet or contact your doctor or pharmacist.
Za više informacija o primjeni lijeka Daxas pogledajte uputu o lijeku, odnosno obratite se liječniku ili ljekarniku.
The European Medicines Agency noted that there was a need for new COPD treatments and that the main studies showed a modest benefit of Daxas 500 micrograms in patients with severe COPD.
Europska agencija za lijekove istaknula je potrebu za novim načinima liječenja KOPB-a te da su glavna ispitivanja pokazala umjerenu korist od liječenja lijekom Daxas od 500 mikrograma u bolesnika s teškim KOPB-om.
As for all medicines, data on the use of Daxas are continuously monitored.
Kao i za sve lijekove, podatci o primjeni lijeka Daxas kontinuirano se prate.
Daxas is a medicine used to treat severe chronic obstructive pulmonary disease (COPD) in adults who have chronic bronchitis (long-term inflammation of the airways), and whose COPD flares up frequently.
Daxas je lijek koji se primjenjuje za liječenje teške kronične opstruktivne plućne bolesti (KOPB) u odraslih osoba koje imaju kronični bronhitis (dugotrajnu upalu dišnih puteva) i u kojih se KOPB često pogoršava.
Although a dose of 250 micrograms daily does not improve lung function it was useful in preventing patients from dropping out because of side effects when starting treatment.
Iako dnevna doza od 250 mikrograma ne utječe na poboljšanje funkcije pluća, bila je korisna u sprječavanju prekida liječenja bolesnika zbog nuspojava na počeku liječenja.
Patients started on the lower dose had fewer side effects.
U bolesnika koji su započeli liječenje nižom dozom zabilježeno je manje nuspojava.
In addition, the patients who took Daxas had an average of 1.1 moderate or severe flare-ups of their disease, compared with 1.4 flare-ups in the patients who took placebo.
Osim toga, u bolesnika koji su uzimali lijek Daxas u prosjeku je zabilježeno 1,1 umjereno ili teško izbijanje bolesti, u usporedbi s prosjekom izbijanja od 1,4 u bolesnika koji su uzimali placebo.
Daxas is available as tablets (250 and 500 micrograms) and can only be obtained with a prescription.
Lijek Daxas dostupan je u obliku tableta (od 250 i 500 mikrograma) te se izdaje samo na liječnički recept.
What are the risks associated with Daxas?
Koji su rizici povezani s lijekom Daxas?
After a year, the patients who took Daxas had an average increase of 40 ml while those given placebo had an average decrease of 9 ml.
Nakon godine dana u bolesnika koji su uzimali lijek Daxas zabilježeno je prosječno povećanje od 40 ml, dok je u bolesnika koji su primali placebo prosječno smanjenje iznosilo 9 ml.
Other information about Daxas:
Ostale informacije o lijeku Daxas
The recommended dose of Daxas for treatment is one 500-microgram tablet once a day, but treatment is started with one 250-microgram tablet daily to reduce side effects that might make patients stop taking the medicine.
Preporučena doza lijeka Daxas jest jedna tableta od 500 mikrograma jedanput na dan, ali liječenje se započinje s jednom tabletom od 250 mikrograma dnevno kako bi se smanjile nuspojave koje bi mogle prisiliti bolesnike na prekid liječenja.
Patients may need to take Daxas 500 micrograms for several weeks before it starts to have an effect.
Bolesnici će ponekad morati uzimati dozu lijeka Daxas od 500 mikrograma nekoliko tjedana prije nego što on počne djelovati.
After taking 250 micrograms daily for 4 weeks, the dose is increased to 500 micrograms daily.
Nakon četiri tjedna uzimanja jedne tablete od 250 mikrograma na dan doza se povećava na 500 mikrograma dnevno.