ILOPROST Concentrate for solution for infusion Ref.[9900] Active ingredients: Iloprost

Distribution

Steady-state plasma levels are achieved as early as 10-20 minutes after the start of an intravenous infusion. The steady-state plasma levels are linearly related to the infusion rate. Plasma levels of about 135 ± 24 pg/ml are obtained at an infusion rate of 3 ng/kg/min. The plasma concentration of iloprost drops very rapidly after the end of the infusion, because of the high rate of metabolism. The metabolic clearance of the substance from plasma is about 20 ± 5 ml/kg/min. The half-life of the terminal elimination phase from plasma is 0.5 hours, as a result of which the plasma level falls to less than 10% of the steady-state concentration, just two hours after the end of infusion.

Interactions with other medicines at the level of plasma protein binding are minimal, because the greater portion of iloprost is bound to the plasma albumin (protein binding: 60%) and only very low iloprost concentration is reached.

An effect of iloprost therapy on the biotransformation of other medicines is also extremely unlikely because of the metabolic pathways and the low absolute dose.

Metabolism

Iloprost is extensively metabolised principally via β-oxidation of the carboxyl side chain. No unchanged substance is eliminated. The main metabolite is tetranor-iloprost, which is found in the urine in free and conjugated form in 4 diastereoisomers. Tetranor-iloprost is pharmacologically inactive as shown in animal experiments. In vitro studies suggest that metabolism of iloprost in the lungs is similar following intravenous administration or inhalation.

Elimination

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. The total clearance of iloprost is about 20 ml/kg/min, which indicates extrahepatic contribution to the metabolism of iloprost. A mass-balance study was conducted using 3H-iloprost in healthy subjects. Following intravenous infusion, the recovery of total radioactivity is 81%, and the respective recoveries in urine and faeces are 68% and 12%. The metabolites are eliminated with plasma and with urine in 2 phases for which half-lives of about 2 and 5 hours (plasma) and 2 and 18 hours (urine) have been calculated.

Characteristics in patients

Renal impairment

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/min/kg) than that observed in patients with renal failure not undergoing intermittent dialysis treatment (mean CL = 18 ± 2 ml/min/kg).

Hepatic impairment

Because iloprost is extensively metabolised by the liver, the plasma levels of the medicine are affected by changes in hepatic function. In an intravenous administration study, results were obtained involving 8 patients suffering from liver cirrhosis. The mean clearance of iloprost was estimated to be 10 ml/min/kg.

Age and gender

Age and gender are not of clinical relevance to the pharmacokinetics of iloprost.

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenicity. Preclinical study effects were observed only at exposures considered considerably higher than the maximum human exposure indicating little relevance to clinical use.

Systemic toxicity

In acute toxicity studies, single intravenous and oral doses of iloprost caused severe symptoms of intoxication or death (IV – intravenous delivery) at dosages about two orders of magnitude above the intravenous therapeutic dose. 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. 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 disorders, and postural changes.

In systemic toxicity studies with repeated (continuous) intravenous infusion, a slight reduction of the blood pressure occurred at doses above 14 ng/kg/min and severe adverse effects (hypotension, respiratory function disorder) occurred only after extremely high doses.

Continuous intravenous/subcutaneous infusion of iloprost up to 26 weeks in rodents and non-rodents at dose levels which exceeded the human therapeutic systemic exposure by 14-47 times (based on plasma levels) did not cause any organ toxicity. Only expected pharmacological effects such as hypotension, reddening of skin, dyspnoea and increased intestinal motility were observed.

Genotoxic potential, tumorigenicity

In vitro and in vivo studies for genotoxic effects have not produced any evidence of mutagenic potential.

No tumorigenic potential of iloprost could be demonstrated in tumorigenicity studies in rats and mice.

Reproductive toxicology

In early and late embryo- and fetotoxicity studies in rats, continuous intravenous administration of iloprost led to anomalies of single phalanges of the forepaws in a few pups without dose-dependence.

These alterations are not considered as true teratogenic effects, but are most likely related to iloprost-induced growth retardation in late organogenesis due to haemodynamic alterations in the fetoplacental unit. It can be assumed that this growth retardation is widely reversible during the postnatal development. In comparable embryotoxicity studies in rabbits and monkeys, no such digit anomalies or other macroscopic abnormalities in the gross body structure were observed even after considerably higher doses, which exceeded the human dose by multiple times.

In rats, extremely low levels of iloprost excretion into the milk were observed.