natgillin/translations-raw huggingface dataset:
The medicinal product must not be administered to breast feeding mothers (see section 4.3).
To zdravilo se ne sme dajati doječim materam (glejte poglavje 4. 3).
Care should be exercised during initiation of therapy until any effects on the individual have been determined.
Pri uvedbi zdravljenja je potrebna previdnost, dokler ni ugotovljeno, kako le- ta učinkuje na posameznika.
In patients experiencing hypotensive symptoms such as dizziness, the abilityto drive or operate machines may be affected.
Pri bolnikih s simptomi hipotenzije, kot je vrtoglavica, ima lahko zdravilo pomemben vpliv na sposobnost vožnje in upravljanja s stroji.
In addition to local effects resulting from administration of iloprost by inhalation such as increased cough, adverse reactions with iloprost are related to the pharmacological properties of prostacyclins.
Poleg lokalnih učinkov, kot je močnejši kašelj, ki so posledica aplikacije iloprosta z inhalacijami, so neželeni učinki iloprosta povezani s farmakološkim lastnostmi prostaciklinov.
The most common adverse reactions seen in clinical trials include vasodilatation, hypotension, headache and increased cough.
Najbolj pogosti neželeni učinki, ki so jih opažali v kliničnih preskušanjih so vazodilatacija, hipotenzija, glavobol in močnejši kašelj.
Frequencies of adverse reactions are reported as follows: very common ≥ 1/ 10; common ≥ 1/ 100 to < 1/ 10; uncommon ≥ 1/ 1,000 and < 1/ 100; rare ≥ 1/ 10,000 to < 1/ 1,000; very rare < 1/ 10,000.
Pogostnost neželenih učinkov, ki so navedeni v nadaljevanju: zelo pogosti ≥ 1/ 10, pogosti ≥ 1/ 100 < 1/ 10, občasni ≥ 1/ 1. 000 < 1/ 100, redki ≥ 1/ 10. 000 < 1/ 1. 000, zelo redki < 1/ 10. 000.
The incidences are based on clinical trial data.
Pogostnosti temeljijo na podatkih iz kliničnih preskušanj.
6 Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
V razvrstitvah pogostnosti so neželeni učinki navedeni po padajoči resnosti.
Headache
≥ 1/ 10
Vascular disorders
≥ 1/ 100 < 1/ 10 glavobol
Vasodilatation, Hypotension
Žilne bolezni
Syncope, Dizziness related to hypotension
vazodilatacija
Respiratory, thoracic and mediastinal disorders
sinkopa
Cough increased
hipotenzija
Musculoskeletal and connective tissue disorders
močnejši kašelj Bolezni dihal, prsnega koša in mediastinalnega prostora
Pain in jaw/ trismus
bolečine v čeljusti/ trismus Bolezni mišično – skeletnega in vezivnega tkiva
The increased occurrence of syncopes can be related to the deterioration of the disease or insufficient effectiveness of the product (see section 4.4).
Večja pogostnost sinkop je lahko povezana z napredovanjem bolezni ali nezadostno učinkovitostjo zdravila (glejte poglavje 4. 4).
Peripheral oedema is a very common symptom of the disease itself, but can also occur under therapy.
6 Periferni edem je zelo pogost simptom same bolezni, lahko pa se pojavi tudi med zdravljenjem.
The occurrence of peripheral oedema can be related to the deterioration of the disease or insufficient effectiveness of the product.
Pojavljanje perifernega edema je lahko povezana z napredovanjem bolezni ali nezadostno učinkovitostjo zdravila.
Bleeding events (mostly haematoma) were common as expected in this patient population with a high proportion of patients taking anticoagulant co-medication.
Kot je pričakovati pri populaciji bolnikov, ki v velikem odstotku sočasno jemljejo tudi antikoagulante, so bile krvavitve (po večini hematomi) pogoste.
The frequency of bleeding events did not differ between iloprost and placebo-treated patients.
Ni bilo razlike v pogostnosti krvavitev pri bolnikih, ki so prejemali iloprost in tistimi, ki so dobivali placebo.
Vomiting, nausea, diarrhoea and dyspnoea have been reported in association with Ventavis inhalation.
V povezavi z zdravilom Ventavis so poročali o bruhanju, navzei, driski in dispneji.
Bronchospasm and wheezing have also been reported in patients treated with Ventavis inhalation (see section 4.4 Special warnings and precautions for use).
Posebna opozorila in previdnostni ukrepi).
Adverse events in healthy volunteers
Neželeni dogodki pri zdravih prostovoljcih
In a randomized placebo-controlled study in 160 healthy volunteers, inhaled doses of iloprost solution were given either with a fixed dose of 2.5 micrograms iloprost 6 times daily (total daily dose of 15 micrograms), or beginning with 5.0 microgram and increasing up to 20 micrograms, or the highest tolerated dose for a total of 6 dose inhalations (total daily dose of 70 micrograms).
V randomizirani, s placebom nadzorovani študiji na 160 zdravih prostovoljcih, so inhalacijske odmerke raztopine iloprosta dajali bodisi v obliki fiksnega odmerka 2, 5 mikrogramov iloprosta šestkrat dnevno (skupni dnevni odmerek 15 mikrogramov) ali pa so začeli s 5 mikrogrami in odmerek povečevali do 20 mikrogramov, oziroma do največjega odmerka, ki so ga prenašali, skupno šest inhalacijskih odmerkov (skupni dnevni odmerek 70 mikrogramov).
In the fixed dose group of 2.5 micrograms per inhalation chest pain, or chest discomfort (32.5%), pharyngolaryngeal pain, or throat irritation (22.5%) and nausea (7.5%) – (all non-serious and mild in intensity) – occurred more frequently in comparison with the adverse events obtained from the placebo controlled phase II and III studies in patients with doses of 2.5 micrograms or 5 micrograms per inhalation.
V skupini, v kateri so prejemali fiksni odmerek 2, 5 mikrogramov na inhalacijo, so se bolečine ali občutek neugodja v prsnem košu (32, 5%), bolečine v žrelu in grlu ali draženje grla (22, 5%) in navzea (7, 5%) (vsi so bili blagi) pojavljali pogosteje kot neželeni dogodki v s placebom nadzorovanih študijah II. in III. faze pri bolnikih, ki so prejemali odmerke 2, 5 mikrogramov ali 5 mikrogramov na inhalacijo.
Five volunteers were unable to increase the dose up to 20 micrograms per inhalation because of mild to moderate transient chest pain or chest discomfort, usually accompanied by headache, dizziness and nausea.
Odmerka pri petih prostovoljcih niso mogli povečati do 20 mikrogramov na inhalacijo zaradi blage do zmerne prehodne bolečine ali občutka neugodja v prsnem košu, ki so ju navadno spremljali glavobol, vrtoglavica in navzea.
• Symptoms
• Simptomi
Hypotensive/ vasovagal reaction might be anticipated as well as headache, flushing, nausea, vomiting, and diarrhoea.
Pričakovane so hipotenzivne/ vazovagalne reakcije kot tudi glavobol, zardevanje, slabost, bruhanje in driska.
• Therapy
• Zdravljenje
Interruption of the inhalation session, monitoring and symptomatic measures are recommended.
Priporoča se prekinitev inhalacije, opazovanje in simptomatsko ukrepanje.
Platelet aggregation inhibitors excluding heparin, ATC code:
Farmakoterapevtska skupina: zaviralci agregacije trombocitov brez heparina; oznaka ATC:
This medicinal product has been authorised under “ Exceptional Circumstances”.
Zdravilo je pridobilo dovoljenje za promet v » izjemnih okoliščinah «.
The European Medicines Agency (EMEA) will review any new information which may become available every year and this SPC will be updated as necessary.
Evropska agencija za zdravila (EMEA) bo vsako leto ponovno pregledala vse nove podatke, ki bodo na voljo, in posodobila Povzetek glavnih značilnosti zdravila, če bo potrebno.
Iloprost, the active substance of Ventavis, is a synthetic prostacyclin analogue.
7 Iloprost, zdravilna učinkovina zdravila Ventavis, je sintetični analog prostaciklina.
• Inhibition of platelet aggregation, platelet adhesion and release reaction
• zaviranje agregacije in adhezije trombocitov ter sproščanje • razširitev • arteriol in venul
• Increase of capillary density and reduction of increased vascular permeability caused by mediators such as serotonin or histamine in the microcirculation
• povečanje gostote kapilar in zmanjšanje povečane vaskularne permeabilnosti, ki jo povzročajo mediatorji kot so serotonin ali histamin v mikrocirkulaciji
• Stimulation of endogenous fibrinolytic potential
• stimulacija endogene fibrinolize
The pharmacological effects after inhalation of Ventavis are:
Farmakološki učinki po inhalaciji zdravila Ventavis so:
No clinical trial data are available comparing directly in intra-patient observations the acute haemodynamic response after intravenous to that after inhaled iloprost.
Ni podatkov o kliničnih preskušanjih, ki bi pri bolnikih neposredno primerjale akutni hemodinamični odziv po intravenski in inhalacijski aplikaciji iloprosta.
The haemodynamics observed suggest an acute response with preferential effect of inhaled treatment on the pulmonary vessels.
Opazovani akutni hemodinamični odziv kaže, da je učinek na pljučno žilje pri inhalacijskem zdravljenju boljši.
The pulmonary vasodilatory effect of each single inhalation levels off within one to two hours.
Pljučni vazodilatorni učinek vsake posamezne inhalacije izzveni v eni do dveh urah.
• Efficacy in adult patients with pulmonary hypertension
• Učinkovitost pri odraslih bolnikih s pljučno hipertenzijo:
N=101; placebo n=102) with stable pulmonary hypertension.
V randomizirano, dvojno slepo, multicentrično, s placebom kontrolirano preskušanje faze III (študija RRA02997) so bili vključeni 203 odrasli bolniki (inhalacijski iloprost: n = 101, placebo: n = 102) s stabilno pljučno hipertenzijo.
Inhaled iloprost (or placebo) was added to patients' current therapy, which could include a combination of anticoagulants, vasodilators (e. g. calcium channel blockers), diuretics, oxygen, and digitalis, but not PGI2 (prostacyclin or its analogues).
Inhalacijski iloprost (ali placebo) je bil dodan bolnikovemu takratnemu zdravljenju, ki je lahko vključevalo kombinacijo antikoagulantov, vazodilatatorjev (npr. zaviralci kalcijevih kanalčkov), diuretikov, kisika in digitalisa, ne pa tudi PG12 (prostaciklina in njegovih analogov).
108 of the patients included were diagnosed with primary pulmonary hypertension, 95 were diagnosed with secondary pulmonary hypertension of which 56 were associated with chronic thromboembolic disease, 34 with connective tissue disease (including CREST and scleroderma) and 4 were considered appetite suppressant drug related.
Od vključenih bolnikov jih je 108 imelo diagnozo primarne pljučne hipertenzije, 95 pa diagnozo sekundarne pljučne hipertenzije, ki je bila pri 56 bolnikih povezana s kronično tromboembolijo, pri 34 z obolenjem vezivnih tkiv (vključno s CREST in sklerodermo), pri 4 pa s sredstvi za zmanjševanje apetita.
The baseline 6-minute walk test values reflected a moderate exercise limitation: in the iloprost group the mean was 332 meters (median value:
Izhodiščne vrednosti 6- minutnega testa hoje so pokazale zmerno omejitev fizične dejavnosti: v skupini, ki je prejemala iloprost, je bilo povprečje 332 metrov (mediana vrednost:
340 meters) and in the placebo group the mean was 315 meters (median value:
340 metrov), medtem, ko je bilo v skupini, ki je prejemala placebo, povprečje 315 metrov (mediana vrednost:
321 meters).
321 metrov).
In the iloprost group, the median daily inhaled dose was 30 micrograms (range 12.5 to 45 micrograms/ day).
V skupini, ki je prejemala iloprost, je bil mediani dnevni inhalirani odmerek 30 mikrogramov (razpon 12, 5 do 45 mikrogramov/ dan).
The primary efficacy endpoint defined for this study, was a combined response criterion consisting of improvement in exercise capacity (6 minute walk test) at 12 weeks by at least 10% versus baseline, and improvement by at least one NYHA class at 12 weeks versus baseline, and no deterioration of pulmonary hypertension or death at any time before 12 weeks.
V tej študiji je bila primarna učinkovitost opredeljena kot kombinacija kriterijev odziva, ki jo sestavljajo izboljšanje fizične zmogljivosti (6- minutni test hoje) po 12 tednih za najmanj 10% v primerjavi z izhodiščno vrednostjo in izboljšanje za vsaj en razred po NYHA klasifikaciji po 12 tednih glede na izhodiščno vrednost ter odsotnost primerov napredovale pljučne hipertenzije ali smrti kadarkoli pred iztekom 12 tednov.
The rate of responders to iloprost was 16.8% (17/ 101) and the rate of responders in the placebo group was 4.9% (5/ 102) (p=0.007).
Delež tistih, ki so se odzvali na iloprost, je bil 16, 8% (17/ 101), delež odzivov v placebo skupini pa 4, 9% (5/ 102) (p = 0. 007).
In the iloprost group, the mean change from baseline after 12 weeks of treatment in the 6 minute walking distance was an increase of 22 meters (-3.3 meters in the placebo group, no data imputation for death or missing values).
V skupini z iloprostom je bilo povprečno povečanje prehojene razdalje (od izhodiščne vrednosti po 12 tednih zdravljenja pri 6- minutnem testu hoje) 22 metrov (v placebo skupini - 3, 3 metre, brez vključitve podatkov o smrtih ali manjkajočih vrednostih).
In the iloprost group the NYHA class was improved in 26% of patients (placebo:
V skupini z iloprostom se je razred po NYHA klasifikaciji izboljšal pri 26% bolnikov (placebo:
15%) (p = 0.032), unchanged in 67.7% of patients (placebo:
15%) (p = 0. 032), ostal nespremenjen pri 67, 7% bolnikov (placebo:
76%) and deteriorated in 6.3% of patients (placebo:
76%) in se poslabšal pri 6, 3% bolnikov (placebo:
A subgroup analysis showed that no treatment effect was observed as compared to placebo on the 6-minute walk test in the subgroup of patients with secondary pulmonary hypertension.
8 Analiza po podskupinah je pokazala, da pri podskupini s sekundarno hipertenzijo v primerjavi s placebom ni bilo opaziti učinka zdravljenja na rezultate testa 6- minutne hoje.
A mean increase in the 6-minute walk test of 44.7 meters from a baseline mean value of 329 meters vs. a change of -7.4 meters from a baseline mean value of 324 meters in the placebo group (no data imputation for death or missing values) was observed in the subgroup of 49 patients with primary pulmonary hypertension receiving treatment of inhaled iloprost for 12 weeks (46 patients in the placebo group).
V podskupini 49 bolnikov s primarno pljučno hipertenzijo, ki so 12 tednov prejemali inhalacije iloprosta (46 bolnikov v placebo skupini), je bila po 6- minutni hoji povprečna razlika v prehojeni razdalji 44, 7 m glede na povprečno izhodiščno razdaljo 329 metrov, v placebo skupini pa je bila ta razlika - 7, 4 m od povprečne izhodiščne razdalje 324 m (brez vključitve podatkov o smrtih ali manjkajočih vrednostih).
• Absorption
• Absorpcija
When iloprost is administered via inhalation in patients with pulmonary hypertension (iloprost dose at the mouthpiece:
Ob inhalacijski aplikaciji iloprosta pri bolnikih s pljučno hipertenzijo (odmerek iloprosta pri ustniku:
5 micrograms), peak serum levels of 100 to 200 picograms/ ml were observed at the end of inhalation session.
5 mikrogramov), so bile najvišje serumske vrednosti ob koncu inhalacije 100 – 200 pikogramov/ ml.
These levels decline with half-lives between approximately 5 and 25 minutes.
Te vrednosti padajo z razpolovno dobo približno 5 do 25 min.
Within 30 minutes to 1 hour after the end of inhalation, iloprost is not detectable in the central compartment (limit of quantification 25 picograms/ ml).
25 pikogramov/ ml).
• Distribution
• Porazdelitev
No studies performed following inhalation.
Študij inhalacijske uporabe niso izvedli.
Following intravenous infusion, the apparent steady-state volume of distribution was 0.6 to 0.8 l/ kg in healthy subjects.
Po intravenski infuziji je bil volumen porazdelitve v stanju dinamičnega ravnovesja pri zdravih osebah 0, 6 do 0, 8 l/ kg.
Total plasma protein binding of iloprost is concentration-independent in the range of 30 to 3000 picograms/ ml and amounts to approximately 60%, of which 75% is due to albumin binding.
Celotna vezava iloprosta na proteine v plazmi je neodvisna od koncentracije v mejah od 30 do 3000 pikogramov/ ml in znaša približno 60%, od tega 75% predstavlja vezavo na beljakovine.
9 • Metabolism
• Presnova
Iloprost is extensively metabolised principally via ß-oxidation of the carboxyl side chain.
Iloprost se presnavlja predvsem preko ß- oksidacije karboksilne stranske verige.
The main metabolite is tetranor-iloprost, which is found in the urine in free and conjugated form in 4 diastereoisomers.
Glavni presnovek je tetranor- iloprost, ki se v seču nahaja v prosti obliki in v konjugirani obliki v 4 diastereoizomerih.
Tetranor-iloprost is pharmacologically inactive as shown in animal experiments.
Kot je razvidno iz poskusov na živalih, je tetranor- iloprost farmakološko neaktiven.
Results of in vitro studies reveal that CYP 450-dependent metabolism plays only a minor role in the biotransformation of iloprost.
Rezultati in vitro študij kažejo, da ima od CYP 450 odvisna presnova ile manjšo vlogo v biotransformaciji iloprosta.
Further in vitro studies suggest that metabolism of iloprost in the lungs is similar after intravenous administration or inhalation.
Nadaljnje in vitro študije nakazujejo, da je presnova iloprosta v pljučih po intravenski aplikaciji ali inhalaciji podobna.
• Elimination
• Izločanje
In subjects with normal renal and hepatic function, the disposition of iloprost following intravenous infusion is characterised in most cases by a two-phase profile with mean half-lives of 3 to 5 minutes and 15 to 30 minutes.
Pri osebah z normalnim ledvičnim in jetrnim delovanjem je za dispozicijo iloprosta po intravenski infuziji v večini primerov značilen dvostopenjski profil s povprečnimi razpolovnimi časi od 3 do 5 min in od 15 do 30 min.
A mass-balance study was done using 3H-iloprost in healthy subjects.
Študija masne porazdelitve je bila opravljena pri zdravih osebah s pomočjo 3H- iloprosta.
Following intravenous infusion, the recovery of total radioactivity is 81%, and the respective recoveries in urine and faeces are 68% and 12%.
Po intravenski infuziji je skupna radioaktivnost 81%, v seču in blatu pa 68% in 12%.
The metabolites are eliminated from plasma and urine in 2 phases, for which half-lives of about 2 and 5 hours (plasma) and 2 and 18 hours (urine) have been calculated.
Presnovki se iz plazme in seča izločajo v dveh stopnjah, izračunani razpolovni čas pa je približno 2 in 5 ur (plazma) ter 2 in 18 ur (seč).
• Pharmacokinetics after use with different nebulisers
9 • Farmakokinetika pri uporabi različnih nebulatorjev
In a randomized, crossover study with 20 healthy adult men, pharmacokinetics was investigated following inhalation of Ventavis (5 mcg iloprost) by the I-Neb AAD in comparison to the ProDose (5 mcg disk).
V randomizirani, navzkrižni študiji, v kateri je sodelovalo 20 zdravih prostovoljcev so primerjali farmakokinetiko zdravila Ventavis (5 mikrogramov iloprost) po aplikaciji skozi nebulatorja I- Neb AAD in ProDose (5 mikrogramov disk).
Higher maximum serum level (Cmax) and systemic exposure (AUC(0-tlast)) as well as a shorter time to reach maximum serum concentration (tmax) were found following Ventavis inhalation via the I-Neb AAD in comparison to the ProDose nebulizer.
Po inhalacijah zdravila Ventavis skozi nebulator I- Neb AAD so bili opaženi višja največja serumska koncentracija (Cmax) in sistemska izpostavljenost (AUC( 0- tlast)) kot tudi krajši čas za dosego največje serumske koncentracije (tmax) v primerjavi z nebulatorjem ProDose.
The pharmacokinetic results reflect the slightly different in vitro characteristics of these nebulizers (see Section 4.2).
Različna farmakokinetika je posledica manjših razlik v lastnostih teh nebulatorjev in vitro.
ProDose
Farmakokinetika iloprosta po inhalaciji 5 mikrogramov iloprosta skozi nebulator I- Neb AAD v primerjavi z nebulatorjem ProDose
(pg·h/ mL)
(pg. h/ ml)
geometric mean (CV%)
geometrična sredina (CV%)
I-Neb
I- Neb ProDose
119 (41.2%)
119 (41, 2%) 80, 0 (46, 7%)
0.183 (0.133 – 0.279)
0, 147 (0, 086 – 0, 268) 0, 183 (0, 133 – 0, 279)
18.7 (50.5%)
28, 9 (47, 4%) 18, 7 (50, 5%)
Area under the concentration time curve from 0h data point up to last measurable
AUC( 0- tlast) = področje pod krivuljo koncentracija čas od točke 0 h do zadnje izmerjene serumske vrednosti CV – koeficient spremembe
10 • Characteristics in patients
• Značilnosti pri bolnikih
Renal dysfunction:
Okvara ledvic
In a study with intravenous infusion of iloprost, patients with end-stage renal failure undergoing intermittent dialysis treatment are shown to have a significantly lower clearance (mean CL = 5 ± 2 ml/ minute/ kg) than that observed in patients with renal failure not undergoing intermittent dialysis treatment (mean CL = 18 ± 2 ml/ minute/ kg).
Študije z intravensko infuzijo iloprosta kažejo, da imajo bolniki z odpovedjo ledvic, ki se zdravijo z intermitentno dializo, značilno nižji očistek (povprečni Cl = 5 ± 2 ml/ min/ kg) kot bolniki z okvaro ledvic, ki se ne zdravijo z dializo (povprečni Cl = 18 ± 2 ml/ min/ kg).
Hepatic dysfunction:
Okvara jeter
Because iloprost is extensively metabolised by the liver, the plasma levels of the active substance are influenced by changes in hepatic function.
Ker se iloprost v glavnem presnavlja v jetrih, spremembe v delovanju jeter vplivajo na koncentracije zdravilne učinkovine v plazmi.
In an intravenous study, results were obtained involving 8 patients suffering from liver cirrhosis.
V študiji z intravensko uporabo so dobili rezultate pri 8 bolnikih z jetrno cirozo.
The mean clearance of iloprost is estimated to be 10 ml/ minute/ kg.
Povprečni očistek iloprosta je približno 10 ml/ min/ kg.
Age and gender:
Starost in spol
Age and gender are not of clinical relevance to the pharmacokinetics of iloprost.
Starost in spol ne vplivata klinično pomembno na farmakokinetiko iloprosta.
• Systemic toxicity
• Sistemska toksičnost
In acute toxicity studies, single intravenous and oral doses of iloprost caused severe symptoms of intoxication or death (IV) at doses about two orders of magnitude above the intravenous therapeutic dose.
V študijah akutne toksičnosti so enkratni intravenski in peroralni odmerki iloprosta povzročili hude znake zastrupitve ali smrt (i. v.) pri odmerkih, ki so dvakratno presegali intravenske terapevtske odmerke.
Considering the high pharmacological potency of iloprost and the absolute doses required for therapeutic purposes the results obtained in acute toxicity studies do not indicate a risk of acute adverse effects in humans.
Ob upoštevanju visoke farmakološke učinkovitosti iloprosta ter absolutne odmerke, ki so potrebni za dosego učinka zdravljenja, rezultati študij akutne toksičnosti ne kažejo, da bi pri človeku obstajalo tveganje za pojav akutnih neželenih učinkov.
As expected for a prostacyclin, iloprost produced haemodynamic effects (vasodilatation, reddening of skin, hypotension, inhibition of platelet function, respiratory distress) and general signs of intoxication such as apathy, gait disturbances, and postural changes.
Kot običajno pri prostaciklinih, je iloprost povzročil hemodinamske učinke (vazodilatacija, pordela koža, hipotenzija, zaviranje delovanja trombocitov, dihalna stiska) in splošne znake zastrupitve, kot so apatija, motnje ravnotežja (hoje) in spremembe zaradi spremembe položaja (posturalne spremembe).
Continuous IV/ SC infusion of iloprost up to 26 weeks in rodents and non-rodents did not cause any organ toxicity at dose levels which exceeded the human therapeutic systemic exposure between 14 and 47 times (based on plasma levels).
10 Neprekinjena i. v. / s. c. infuzija iloprosta pri glodalcih in ne- glodalcih, ki je trajala 26 tednov, ni povzročila organske toksičnosti pri odmerkih, ki so od 14 - do 47- krat presegali sistemsko terapevtsko izpostavljenost pri človeku (na osnovi koncentracij v plazmi).
Based on Cmax values in rats the systemic exposure in these parenteral studies was approximately 3.5 times higher than the maximum achievable exposure after inhalation.
Na osnovi Cmax vrednosti pri podganah je bila sistemska izpostavljenost v študijah parenteralne uporabe približno 3, 5- krat višja kot največja izpostavljenost dosežena po inhalaciji.
This highest achievable dose of 48.7 micrograms/ kg/ day was also the “ no observed adverse effect level” (NOAEL) as evaluated in inhalation toxicity studies in rats up to 26 weeks.
Najvišji dosegljivi odmerek 48, 7 mikrogramov/ kg/ dan je bil hkrati » stopnja brez opaznih neželenih učinkov « (no observed adverse event level - NOAEL), kot je bilo ugotovljeno v 26- tedenski študiji inhalacijske toksičnosti pri podganah.