Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Bayer AG, 51368, Leverkusen, Germany
Pharmacotherapeutic group: Antithrombotic agents, platelet aggregation inhibitors excluding heparin
ATC code: B01AC11
Iloprost, the active substance of Ventavis, is a synthetic prostacyclin analogue. The following pharmacological effects have been observed in vitro:
The pharmacological effects after inhalation of Ventavis are:
Direct vasodilatation of the pulmonary arterial bed occur with consecutive significant improvement of pulmonary artery pressure, pulmonary vascular resistance and cardiac output as well as mixed venous oxygen saturation.
In a small, randomised, 12-week double-blinded, placebo-controlled study (the STEP trial), 34 patients treated with bosentan 125 mg twice per day for at least 16 weeks who were in stable haemodynamic conditions before enrolment, tolerated the addition of inhaled iloprost at the concentration of 10 microgram/ml (up to 5 microgram 6 to 9 times per day during waking hours). The mean daily inhaled dose was 27 microgram and the mean number of inhalations per day was 5.6. The acute adverse effects in patients receiving concomitant bosentan and iloprost were consistent with those observed in the larger experience of the phase 3 study in patients receiving only iloprost. No reliable conclusion could be drawn on efficacy of the association as the sample size was limited and the study was of short duration.
No clinical trial data are available comparing directly in intra-patient observations the acute haemodynamic response after intravenous to that after inhaled iloprost. The haemodynamics observed suggest an acute response with preferential effect of inhaled treatment on the pulmonary vessels. The pulmonary vasodilatory effect of each single inhalation levels off within one to two hours.
However, the predictive value of these acute haemodynamic data are considered to be of limited value as acute response does not in all cases correlate with long-term benefit of treatment with inhaled iloprost.
A randomised, double-blind, multi-centre, placebo-controlled phase III trial (study RRA02997) has been conducted in 203 adult patients (inhaled iloprost at the concentration of 10 microgram/ml: N=101; placebo n=102) with stable pulmonary hypertension. 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). 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 medicinal product related. The baseline 6-minute walk test values reflected a moderate exercise limitation: in the iloprost group the mean was 332 metres (median value: 340 metres) and in the placebo group the mean was 315 metres (median value: 321 metres). In the iloprost group, the median daily inhaled dose was 30 microgram (range 12.5 to 45 microgram/day). 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. 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).
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 metres (-3.3 metres in the placebo group, no data imputation for death or missing values).
In the iloprost group the NYHA class was improved in 26% of patients (placebo: 15%) (p = 0.032), unchanged in 67.7% of patients (placebo: 76%) and deteriorated in 6.3% of patients (placebo: 9%). Invasive haemodynamic parameters were assessed at baseline and after 12 weeks treatment.
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. A mean increase in the 6-minute walk test of 44.7 metres from a baseline mean value of 329 metres vs. a change of -7.4 metres from a baseline mean value of 324 metres 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).
No study has been performed with Ventavis in children with pulmonary hypertension.
When iloprost at the concentration of 10 microgram/ml is administered via inhalation in patients with pulmonary hypertension or healthy volunteers (iloprost dose at the mouthpiece: 5 microgram: inhalation time in between 4.6–10.6 min), mean peak serum concentrations of about 100 to 200 picogram/ml were observed at the end of inhalation session. These concentrations decline with half-lives between approximately 5 and 25 minutes. Within 30 minutes to 2 hours after the end of inhalation, iloprost is not detectable in the central compartment (limit of quantification 25 picogram/ml).
No studies performed following inhalation.
Following intravenous infusion, the apparent steady-state volume of distribution was 0.6 to 0.8 l/kg in healthy subjects. Total plasma protein binding of iloprost is concentration-independent in the range of 30 to 3,000 picogram/ml and amounts to approximately 60%, of which 75% is due to albumin binding.
No studies to investigate the metabolism of iloprost were performed following inhalation of Ventavis. After intravenous administration, iloprost is extensively metabolised 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. Tetranor-iloprost is pharmacologically inactive as shown in animal experiments. Results of in vitro studies reveal that CYP 450-dependent metabolism plays only a minor role in the biotransformation of iloprost. Further in vitro studies suggest that metabolism of iloprost in the lungs is similar after intravenous administration or inhalation.
No studies performed following inhalation.
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 done using 3 H-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 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.
Pharmacokinetics of iloprost were investigated in a randomised, crossover study with 27 patients, stable on Ventavis 10 microgram/ml inhaled with I-Neb, following inhalation of single doses of 2.5 or 5 microgram iloprost using the Breelib or the I-Neb AAD nebuliser. Following inhalation of these doses with the Breelib the maximum plasma concentrations (Cmax) and systemic exposures (AUC (0-tlast)) increased dose-proportionally.
Cmax and AUC (0-tlast) after inhalation of 5 microgram iloprost administered as Ventavis 20 microgram/ml using the Breelib were 77% and 42%, respectively higher compared to inhalation of the same dose using Ventavis 10 microgram/ml and the I-Neb AAD system. Cmax and AUC (0-tlast) of iloprost after inhalation with Breelib were, however, still in the range of values observed with Ventavis 10 microgram/ml using other inhalers across different studies.
Pharmacokinetics under the specific study conditions of extended inhalation time, were investigated in a randomised, crossover study with 19 healthy adult men following inhalation of single doses of Ventavis 10 microgram/ml and Ventavis 20 microgram/ml (dose of 5 microgram iloprost at the mouthpiece) using the I-Neb. Comparable systemic exposures (AUC (0-tlast)) and approximately 30% higher maximum serum concentrations (Cmax) were found following inhalation of Ventavis 20 microgram/ml compared to Ventavis 10 microgram/ml which was in line with the observed shorter inhalation time using Ventavis 20 microgram/ml.
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).
Because iloprost is extensively metabolised by the liver, the plasma levels of the active substance are influenced by changes in hepatic function. In an intravenous study, results were obtained involving 8 patients suffering from liver cirrhosis. The mean clearance of iloprost is estimated to be 10 ml/minute/kg.
Gender is not of clinical relevance to the pharmacokinetics of iloprost.
Pharmacokinetics in elderly patients have not been investigated.
In acute toxicity studies, single intravenous and oral doses of iloprost caused severe symptoms of intoxication or death (intravenous) at doses 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 disturbances, and postural changes.
Continuous intravenous/subcutaneous 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). Only expected pharmacological effects like hypotension, reddening of skin, dyspnoea, increased intestinal motility were observed.
In a chronic inhalation study in rats over 26 weeks, the highest achievable dose of 48.7 microgram/kg/day was identified as ‘no observed adverse effect level’ (NOAEL). Systemic exposures exceeded human therapeutic exposures after inhalation by factors of more than 10 (Cmax, cumulative AUC).
In vitro (bacterial, mammalian cells, human lymphocytes) and in vivo studies (micronucleus test) for genotoxic effects have not produced any evidence for a mutagenic potential.
No tumourigenic potential of iloprost was observed in tumourigenicity studies in rats and mice.
In embryo- and foetotoxicity studies in rats continuous intravenous administration of iloprost led to anomalies of single phalanges of the forepaws in a few foetuses/pups without dose dependence.
These alterations are not considered as teratogenic effects, but are most likely related to iloprost induced growth retardation in late organogenesis due to haemodynamic alterations in the foetoplacental unit. No disturbance of postnatal development and reproductive performance was seen in the offspring that were raised, indicating that the observed retardation in rats was compensated during the postnatal development. In comparable embryotoxicity studies in rabbits and monkeys no such digit anomalies or other gross-structural anomalies were observed even after considerably higher dose levels which exceeded the human dose multiple times. In rats, passage of low levels of iloprost and/or metabolites into the milk was observed (less than 1% of iloprost dose given intravenously). No disturbance of post-natal development and reproductive performance was seen in animals exposed during lactation.
Local tolerance, contact sensitising and antigenicity potential
In inhalation studies in rats, the administration of an iloprost formulation with a concentration of 20 microgram/ml up to 26 weeks did not cause any local irritation of the upper and lower respiratory tract.
A dermal sensitisation (maximisation test) and an antigenicity study in guinea pigs showed no sensitising potential.
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