FrancophonIA/ELRC3.0 huggingface dataset:
English: The long-term effects of ivabradine on growth, puberty and general development as well as the longterm efficacy of therapy with ivabradine in childhood to reduce cardiovascular morbidity and mortality have not been studied.
Croatian: Nisu ispitani dugoročni učinci ivabradina na rast, pubertet i opći razvoj, kao ni dugoročna djelotvornost liječenja ivabradinom u djetinjstvu na smanjenje kardiovaskularnog pobola i smrtnosti.
English: Do not use this medicine after the expiry date which is stated on the label and carton after “EXP”.
Croatian: Ovaj lijek se ne smije upotrijebiti nakon isteka roka valjanosti navedenog na blisteru i kutiji iza oznake „Rok valjanosti“ ili „EXP“.
English: No safety issue has been raised on the combination of ivabradine with nitrates and dihydropyridine calcium channel blockers such as amlodipine.
Croatian: Nema sigurnosnih pitanja povezanih s primjenom ivabradina u kombinaciji s nitratima i dihidropiridinskim blokatorima kalcijevih kanala kao što je amlodipin.
English: - Some types of diuretics which may cause decrease in blood potassium level, such as furosemide, hydrochlorothiazide, indapamide (used to treat oedema, high blood pressure).
Croatian: − neke vrste diuretika koji mogu sniziti razinu kalija u krvi, poput furosemida, hidroklorotiazida, indapamida (koriste se za liječenje edema, visokog krvnog tlaka)
English: Limited data are available in patients with mild to moderate hypotension, and ivabradine should therefore be used with caution in these patients.
Croatian: Ograničeni su podaci o primjeni u bolesnika s blagom do umjerenom hipotenzijom, pa ivabradin u tih bolesnika treba primjenjivati uz oprez.
English: Lack of benefit on clinical outcomes in patients with symptomatic chronic stable angina pectoris
Croatian: Izostanak koristi za kliničke ishode u bolesnika sa simptomatskom kroničnom stabilnom anginom pektoris
English: It is also used in combination with beta-blockers in adult patients whose condition is not fully controlled with a beta-blocker.
Croatian: Lijek se koristi i u kombinaciji s beta-blokatorima u odraslih bolesnika čije se stanje ne može u potpunosti kontrolirati beta-blokatorima.
English: It is used in combination with standard therapy, including beta-blocker therapy or when beta-blockers are contraindicated or not tolerated.
Croatian: Lijek se koristi u kombinaciji sa standardnom terapijom, uključujući beta-blokatore, ili kada su beta-blokatori kontraindicirani ili ih bolesnik ne podnosi.
English: Tablets are available in packs of 14, 28, 56, 84, 98, 100, 112 film-coated tablets.
Croatian: Tablete su dostupne u pakiranjima od 14, 28, 56, 84, 98, 100, 112 filmom obloženih tableta.
English: Rare (may affect up to 1 in 1,000 people) - Urticaria, itching, skin reddening, feeling unwell.
Croatian: Rijetke (mogu se javiti u do 1 na 1000 osoba) − koprivnjača, svrbež, crvenilo kože, loše osjećanje
English: Furthermore as elevated heart rate adversely affects the heart functioning and vital prognosis in patients with chronic heart failure, the specific heart rate lowering action of ivabradine helps to improve the heart functioning and vital prognosis in these patients.
Croatian: Nadalje, budući da povećan broj otkucaja srca negativno utječe na srčanu funkciju i životnu prognozu bolesnika s kroničnim zatajivanjem srca, specifičan učinak ivabradina na usporavanje pulsa pomaže poboljšati rad srca i životnu prognozu u tih bolesnika.
English: Luminous phenomena (phosphenes) are described as a transient enhanced brightness in a limited area of the visual field (see section 4.8).
Croatian: Svjetlosni fenomeni (fosfeni) opisuju se kao prolazno pojačana svjetlost u ograničenom dijelu vidnog polja (vidjeti dio 4.8).
English: In this study, ivabradine was administered as oral liquid formulation or tablet twice daily.
Croatian: U ovom se ispitivanju ivabradin primjenjivao u obliku oralne otopine ili tablete dvaput na dan.
English: Fertility Studies in rats have shown no effect on fertility in males and females (see section 5.3).
Croatian: Plodnost Ispitivanja nisu pokazala učinke na plodnost mužjaka i ženki štakora (vidjeti dio 5.3).
English: Inversely, potent inhibitors and inducers may substantially affect ivabradine plasma concentrations (see section 4.5).
Croatian: Nasuprot tome, snažni inhibitori i induktori mogu značajno utjecati na koncentracije ivabradina u plazmi (vidjeti dio 4.5).
English: The most common symptom of angina is chest pain or discomfort.
Croatian: Najčešći simptom angine je bol ili nelagoda u prsnom košu.
English: - Chronic heart failure in adult patients whose heart rate is over or equal to 75 beats per minute.
Croatian: − kroničnog zatajivanje srca u odraslih bolesnika koji imaju puls od 75 ili više otkucaja u minuti.
English: 14 film-coated tablets 28 film-coated tablets 56 film-coated tablets 84 film-coated tablets 98 film-coated tablets 100 film-coated tablets 112 film-coated tablets
Croatian: 14 filmom obloženih tableta 28 filmom obloženih tableta 56 filmom obloženih tableta 84 filmom obložene tablete 98 filmom obloženih tableta 100 filmom obloženih tableta 112 filmom obloženih tableta
English: Very common (may affect more than 1 in 10 people) - Luminous visual phenomena (brief moments of increased brightness, most often caused by sudden changes in light intensity).
Croatian: Svjetlosni vidni fenomeni (kratkotrajni trenuci pojačane svjetlosti, najčešće uzrokovani iznenadnim promjenama intenziteta svjetlosti).
English: The onset of phosphenes is generally within the first two months of treatment after which they may occur repeatedly.
Croatian: Fosfeni obično nastupaju unutar prva dva mjeseca liječenja, nakon čega se mogu opetovano javljati.
English: What Ivabradine Zentiva is and what it is used for
Croatian: Što je Ivabradine Zentiva i za što se koristi
English: - Sino-atrial block.
Croatian: Sinusatrijski blok
English: - If your heartbeat is exclusively imposed by your pacemaker.
Croatian: − ako Vam kucanje srca isključivo potiče elektrostimulator (pacemaker)
English: Drug-drug interaction studies have established that CYP3A4 inhibitors increase ivabradine plasma concentrations, while inducers decrease them.
Croatian: U ispitivanjima interakcije između lijekova utvrđeno je da inhibitori CYP3A4 povećavaju koncentraciju ivabradina u plazmi, dok je induktori smanjuju.
English: Ivabradine is approximately 70% plasma protein bound and the volume of distribution at steady-state is close to 100 L in patients.
Croatian: Približno 70% ivabradina veže se za proteine plazme, a volumen distribucije u stanju dinamičke ravnoteže iznosi blizu 100 litara u bolesnika.
English: Given that the heart rate may fluctuate considerably over time, serial heart rate measurements, ECG or ambulatory 24-hour monitoring should be considered when determining resting heart rate before initiation of ivabradine treatment and in patients on treatment with ivabradine when titration is considered.
Croatian: Budući da srčana frekvencija može značajno fluktuirati tijekom vremena, treba razmotriti provođenje serijskog mjerenja srčane frekvencije putem EKG-a ili ambulantnog 24-satnog mjerenja kod određivanja srčane frekvencije u mirovanju prije početka liječenja ivabradinom, kao i u bolesnika koji već uzimaju ivabradin kada se razmatra titriranje doze.
English: Heart rate reduction, as caused by ivabradine, may exacerbate QT prolongation, which may give rise to severe arrhythmias, in particular Torsade de pointes.
Croatian: Smanjenje srčane frekvencije, poput onoga koje uzrokuje ivabradin, može pogoršati produljenje QT-intervala, što može dovesti do teških aritmija, osobito torsade de pointes.
English: The potent CYP3A4 inhibitors ketoconazole (200 mg once daily) and josamycin (1 g twice daily) increased ivabradine mean plasma exposure by 7 to 8-fold.
Croatian: Snažni inhibitori CYP3A4 - ketokonazol (200 mg jedanput na dan) i jozamicin (1 g dvaput na dan) povećali su srednju vrijednost izloženosti ivabradinu u plazmi za 7 do 8 puta.
English: When treatment modifications are made in chronic heart failure patients treated with ivabradine blood pressure should be monitored at an appropriate interval (see section 4.8).
Croatian: Kada se prilagođava terapija za krvni tlak u bolesnika s kroničnim zatajivanjem srca liječenih ivabradinom, potrebno je kontrolirati krvni tlak u odgovarajućim intervalima (vidjeti dio 4.8).
English: Chronic heart failure patients with intraventricular conduction defects (bundle branch block left, bundle branch block right) and ventricular dyssynchrony should be monitored closely.
Croatian: Bolesnike s kroničnim zatajivanjem srca koji imaju intraventrikulske poremećaje provođenja (blok lijeve grane, blok desne grane) i ventrikulsku disinkroniju treba pažljivo pratiti.
English: Ivabradine Zentiva 5 mg film-coated tablets: EU/1/16/1144/001
Croatian: Ivabradine Zentiva 5 mg filmom obložene tablete: EU/1/16/1144/001
English: If the combination appears necessary, close cardiac monitoring is needed (see section 4.4).
Croatian: Ako se ta kombinacija čini neophodnom, potrebno je pažljivo pratiti srčanu funkciju (vidjeti dio 4.4).
English: Ivabradine was shown not to influence the metabolism and plasma concentrations of other CYP3A4 substrates (mild, moderate and strong inhibitors).
Croatian: Pokazalo se da ivabradin ne utječe na metabolizam i plazmatske koncentracije drugih supstrata CYP3A4 (blagih, umjerenih i jakih inhibitora).
English: Ivabradine is indicated only for symptomatic treatment of chronic stable angina pectoris because ivabradine has no benefits on cardiovascular outcomes (e.g. myocardial infarction or cardiovascular death) (see section 5.1).
Croatian: Ivabradin je indiciran samo za simptomatsko liječenje kronične stabilne angine pektoris jer nema koristi s obzirom na kardiovaskularne ishode (npr. infarkt miokarda ili smrt zbog kardiovaskularnih uzroka) (vidjeti dio 5.1).
English: Ivabradine is contra-indicated for use in patients with severe hepatic insufficiency, since it has not been studied in this population and a large increase in systemic exposure is anticipated (see sections 4.3 and 5.2).
Croatian: Primjena ivabradina kontraindicirana je u bolesnika s teškom jetrenom insuficijencijom jer nije ispitivan u toj populaciji i predviđa se veliko povećanje sistemske izloženosti lijeku (vidjeti dijelove 4.3 i 5.2).
English: In this subgroup of patients, the safety profile of ivabradine is in line with the one of the overall population.
Croatian: U toj je podskupini bolesnika sigurnosni profil ivabradina jednak profilu u cjelokupnoj populaciji.
English: Ivabradine is metabolised by CYP3A4 only and it is a very weak inhibitor of this cytochrome.
Croatian: Ivabradin se metabolizira jedino putem CYP3A4 i vrlo je slab inhibitor tog citokroma.
English: • Quinidine, disopyramide, ibutilide, sotalol, amiodarone (to treat heart rhythm disorders).
Croatian: • kinidin, dizopiramid, ibutilid, sotalol, amiodaron (za liječenje poremećaja srčanog ritma)
English: Linearity/non linearity The kinetics of ivabradine is linear over an oral dose range of 0.5 - 24 mg.
Croatian: Linearnost/nelinearnost Kinetika ivabradina je linearna u rasponu peroralnih doza od 0,5 do 24 mg.
English: In the SIGNIFY study atrial fibrillation was observed in 5.3% of patients taking ivabradine compared to 3.8% in the placebo group.
Croatian: U ispitivanju SIGNIFY, fibrilacija atrija zabilježena je u 5,3% bolesnika koji su uzimali ivabradin u usporedbi s 3,8% u skupini koja je primala placebo.
English: or nefazodone (medicine to treat depression) or diltiazem, verapamil (used for high blood pressure or angina pectoris).
Croatian: nefazodon (lijek za liječenje depresije) ili diltiazem, verapamil (za liječenje visokog krvnog tlaka ili angine pektoris)
English: Uncommon (may affect up to 1 in 100 people) - Palpitations and cardiac extra beats, feeling sick (nausea), constipation, diarrhoea, abdominal pain, spinning sensation (vertigo), difficulty breathing (dyspnoea), muscle cramps, changes in laboratory parameters : high blood levels of uric acid, an excess of eosinophils (a type of white blood cell) and elevated creatinine in blood (a breakdown product of muscle), skin rash, angioedema (such as swollen face, tongue or throat, difficulty in breathing or swallowing), low blood pressure, fainting, feeling of tiredness, feeling of weakness, abnormal ECG heart tracing, double vision, impaired vision.
Croatian: − osjećaj lupanja srca i dodatni otkucaji srca, mučnina, zatvor, proljev, bol u trbuhu, osjećaj vrtnje (vrtoglavica), otežano disanje (zaduha), grčevi u mišićima, promjene u nalazima laboratorijskih pretraga: visoka razina mokraćne kiseline u krvi, prekomjeran broj eozinofila (jedne vrste bijelih krvnih stanica) i povišena razina kreatinina u krvi (nastaje zbog razgradnje mišića), kožni osip, angioedem (npr. oticanje lica, jezika ili grla, otežano disanje ili gutanje), nizak krvni tlak, nesvjestica, osjećaj umora, osjećaj slabosti, odstupanja u nalazima EKG-a, dvoslike, poremećaj vida
English: The usual recommended starting dose of ivabradine is 5 mg twice daily.
Croatian: Uobičajena preporučena početna doza ivabradina je 5 mg dvaput na dan.
English: In patients with mild hepatic impairment (Child Pugh score up to 7) unbound AUC of ivabradine and the main active metabolite were about 20% higher than in subjects with normal hepatic function.
Croatian: U bolesnika s blagim oštećenjem funkcije jetre (Child Pugh skor do 7) vrijednosti AUC-a nevezanog ivabradina i njegova glavnog aktivnog metabolita bile su približno 20% više nego u ispitanika s normalnom jetrenom funkcijom.
English: Ivabradine 5 mg twice daily was shown to be effective on exercise test parameters within 3 to 4 weeks of treatment.
Croatian: Pokazalo se da je ivabradin u dozi od 5 mg dvaput na dan utjecao na parametre testa fizičkog opterećenja unutar 3 - 4 tjedna liječenja.
English: The efficacy of 5 and 7.5 mg twice daily was consistent across studies on exercise test parameters (total exercise duration, time to limiting angina, time to angina onset and time to 1 mm ST segment depression) and was associated with a decrease of about 70% in the rate of angina attacks.
Croatian: Djelotvornost doza od 5 i 7,5 mg dvaput na dan bila je dosljedna u svim ispitivanjima učinaka na parametre testa fizičkog opterećenja (ukupno trajanje fizičkog opterećenja, vrijeme do ograničavajuće angine, vrijeme do nastupa angine te vrijeme do depresije ST-segmenta od 1 mm) te je bila povezana sa smanjenjem stope napadaja angine za približno 70%.
English: The combination of ivabradine 10 mg twice daily with St. John's Wort was shown to reduce ivabradine AUC by half.
Croatian: Pokazalo se da kombinacija ivabradina u dozi od 10 mg dvaput na dan s gospinom travom smanjuje AUC ivabradina na polovicu.
English: The environmental risk assessment of ivabradine has been conducted in accordance to European guidelines on ERA.
Croatian: Procjena rizika koji ivabradin može predstavljati za okoliš provedena je u skladu s europskim smjernicama za procjenu rizika za okoliš.
English: The cardiac effects are specific to the sinus node with no effect on intra-atrial, atrioventricular or intraventricular conduction times, nor on myocardial contractility or ventricular repolarisation.
Croatian: Učinci na srce odnose se specifično na sinusni čvor, a nema učinka na intraatrijsko, atrioventrikulsko ili intraventrikulsko vrijeme provođenja, niti na kontraktilnost miokarda ili ventrikulsku repolarizaciju.
English: High exposures to ivabradine that may occur when ivabradine is given in combination with strong CYP3A4 inhibitors may result in an excessive decrease in heart rate although this risk is reduced with moderate CYP3A4 inhibitors (see sections 4.3, 4.4 and 4.5).
Croatian: Visoke razine izloženosti ivabradinu, do kojih može doći kada se ivabradin primjenjuje u kombinaciji s jakim inhibitorima CYP3A4, mogu rezultirati prekomjernim usporenjem srčane frekvencije, ali je taj rizik manji kod umjerenih inhibitora CYP3A4 (vidjeti dijelove 4.3, 4.4 i 4.5).
English: In a 97-patient randomised placebo-controlled study, the data collected during specific ophthalmologic investigations, aiming at documenting the function of the cone and rod systems and the ascending visual pathway (i.e. electroretinogram, static and kinetic visual fields, colour vision, visual acuity), in patients treated with ivabradine for chronic stable angina pectoris over 3 years, did not show any retinal toxicity.
Croatian: U randomiziranom, placebom kontroliranom ispitivanju provedenom u 97 bolesnika, podaci prikupljeni tijekom specifičnih oftalmoloških pretraga s ciljem utvrđivanja funkcije sustava čunjića i štapića te ascendentnog vidnog puta (npr. elektroretinogram, statička i kinetička perimetrija, opažanje boja, oštrina vida), nisu ukazali na toksično djelovanje ivabradina na mrežnicu u bolesnika s kroničnom stabilnom anginom pektoris liječenih ivabradinom tijekom 3 godine.
English: After dose reduction, heart rate should be monitored (see section 4.4).
Croatian: Nakon smanjenja doze treba pratiti srčanu frekvenciju (vidjeti dio 4.4).
English: As ivabradine may cause bradycardia, the resulting combination of hypokalaemia and bradycardia is a predisposing factor to the onset of severe arrhythmias, especially in patients with long QT syndrome, whether congenital or substance-induced.
Croatian: Budući da ivabradin može uzrokovati bradikardiju, posljedična kombinacija hipokalijemije i bradikardije predstavlja predisponirajući faktor za nastup teških aritmija, osobito u bolesnika sa sindromom dugog QT-intervala, neovisno o tome je li on urođen ili uzrokovan lijekovima.
English: A randomised, double blind, placebo controlled study was performed in 116 paediatric patients (17 aged [6 - 12] months, 36 aged [1 - 3] years and 63 aged [3 - 18] years) with CHF and dilated cardiomyopathy (DCM) on top of optimal background treatment.
Croatian: Provedeno je randomizirano, dvostruko slijepo, placebom kontrolirano ispitivanje u 116 pedijatrijskih bolesnika (17 bolesnika u dobi od 6 - 12 mjeseci, 36 bolesnika u dobi od 1 - 3 godine i 63 bolesnika u dobi od 3 - 18 godina) s kroničnim zatajivanjem srca i dilatativnom kardiomiopatijom (DKM) koji su primali optimalnu osnovnu terapiju.
English: It is recommended to regularly clinically monitor ivabradine treated patients for the occurrence of atrial fibrillation (sustained or paroxysmal), which should also include ECG monitoring if clinically indicated (e.g. in case of exacerbated angina, palpitations, irregular pulse).
Croatian: Preporučuje se redovita klinička kontrola bolesnika koji se liječe ivabradinom zbog mogućeg razvoja fibrilacije atrija (perzistentne ili paroksizmalne), koja treba uključivati i EKG praćenje ako je to klinički indicirano (npr. u slučaju pogoršanja angine, palpitacija, nepravilnog pulsa).
English: - Severe hepatic insufficiency.
Croatian: Teška insuficijencija jetre
English: Ivabradine is indicated in chronic heart failure NYHA II to IV class with systolic dysfunction, in patients in sinus rhythm and whose heart rate is ≥ 75 bpm, in combination with standard therapy including betablocker therapy or when beta-blocker therapy is contraindicated or not tolerated (see section 5.1).
Croatian: Ivabradin je indiciran kod kroničnog zatajivanja srca NYHA stupnja II - IV sa sistoličkom disfunkcijom, u bolesnika u sinusnom ritmu kojima je srčana frekvencija ≥ 75 otkucaja u minuti, u kombinaciji sa standardnom terapijom uključujući beta-blokatore ili kada je terapija beta-blokatorima kontraindicirana ili se ne podnosi (vidjeti dio 5.1).
English: CYP3A4 inhibitors and inducers are liable to interact with ivabradine and influence its metabolism and pharmacokinetics to a clinically significant extent.
Croatian: Inhibitori i induktori CYP3A4 mogu stupiti u interakciju s ivabradinom i u klinički značajnoj mjeri utjecati na njegov metabolizam i farmakokinetiku.
English: Symptomatic treatment of chronic stable angina pectoris It is recommended that the decision to initiate or titrate treatment takes place with the availability of serial heart rate measurements, ECG or ambulatory 24-hour monitoring.
Croatian: Simptomatsko liječenje kronične stabilne angine pektoris Preporučuje se da se odluka o početku liječenja ili titriranju doze donese temeljem serijskog mjerenja srčane frekvencije putem EKG-a ili 24-satnog ambulantnog mjerenja.
English: Potassium-depleting diuretics (thiazide diuretics and loop diuretics) Hypokalaemia can increase the risk of arrhythmia.
Croatian: Diuretici koji troše kalij (tiazidni diuretici i diuretici Henleove petlje) Hipokalijemija može povećati rizik od aritmije.
English: The use of ivabradine in patients with congenital QT syndrome or treated with QT prolonging medicinal products should be avoided (see section 4.5).
Croatian: Treba izbjegavati primjenu ivabradina u bolesnika s QT-sindromom ili onih koji se liječe lijekovima koji produljuju QT-interval (vidjeti dio 4.5).
English: Talk to your doctor if you are breast-feeding or intending to breast-feed as breastfeeding should be discontinued if you take Ivabradine Zentiva.
Croatian: Obratite se svom liječniku ako dojite ili planirate dojiti jer se dojenje mora prekinuti ako počnete uzimati Ivabradine Zentiva.
English: The usual recommended starting dose is one tablet of Ivabradine Zentiva 5 mg twice daily increasing if necessary to one tablet of Ivabradine Zentiva 7.5 mg twice daily.
Croatian: Uobičajena preporučena početna doza je jedna tableta lijeka Ivabradine Zentiva od 5 mg dvaput na dan, koja se, ako je potrebno, može povećati na jednu tabletu lijeka Ivabradine Zentiva od 7,5 mg dvaput na dan.
English: - If you suffer from severe heart failure or heart failure with abnormality of ECG called “bundle branch block”.
Croatian: − ako bolujete od teškog zatajivanja srca ili zatajivanja srca praćenog odstupanjem na EKG-u koje se naziva „blokom grane“
English: There was a significant improvement in NYHA class at last recorded value, 887 (28%) of patients on ivabradine improved versus 776 (24%) of patients on placebo (p = 0.001).
Croatian: Zabilježeno je značajno poboljšanje NYHA stupnja kod posljednje zabilježene vrijednosti: poboljšanje je zabilježeno u 887 (28%) bolesnika liječenih ivabradinom naspram 776 (24%) bolesnika koji su primali placebo (p = 0,001).
English: Analysis of heart rate reduction with doses up to 20 mg twice daily indicates a trend towards a plateau effect which is consistent with a reduced risk of severe bradycardia below 40 bpm (see section
Croatian: Analiza usporenja srčane frekvencije uz doze do 20 mg dvaput na dan ukazuje na postojanje trenda prema plato učinku, što se slaže sa smanjenim rizikom od teške bradikardije, uz manje od 40/min (vidjeti dio 4.8).
English: Ivabradine has low affinity for CYP3A4, shows no clinically relevant CYP3A4 induction or inhibition and is therefore unlikely to modify CYP3A4 substrate metabolism or plasma concentrations.
Croatian: Ivabradin ima nizak afinitet za CYP3A4 i ne pokazuje klinički značajnu indukciju ni inhibiciju CYP3A4, pa vjerojatno neće promijeniti metabolizam ni plazmatske koncentracije supstrata CYP3A4.
English: The PK/PD relationship of ivabradine in paediatric chronic heart failure patients aged 6 months to less than 18 years is similar to the PK/PD relationship described in adults.
Croatian: PK/PD odnos ivabradina u pedijatrijskih bolesnika u dobi od 6 mjeseci do manje od 18 godina koji boluju od kroničnog zatajivanja srca sličan je PK/PD odnosu opisanom u odraslih.
English: Ivabradine Zentiva 7.5 mg film-coated tablets: EU/1/16/1144/008
Croatian: Ivabradine Zentiva 7,5 mg filmom obložene tablete: EU/1/16/1144/008
English: When pregnant animals were treated during organogenesis at exposures close to therapeutic doses, there was a higher incidence of foetuses with cardiac defects in the rat and a small number of foetuses with ectrodactylia in the rabbit.
Croatian: Kada su skotne životinje tijekom organogeneze primale doze kojima se postiže razina izloženosti približna onoj koja se postiže terapijskim dozama, u štakora je zabilježena veća incidencija fetusa sa srčanim manama, a u kunića mali broj fetusa sa ektrodaktilijom.