Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: J. Uriach y Compañía, S.A., Av. Camí Reial, 51-57, 08184 Palau-solità i Plegamans (Spain)
Pharmacotherapeutic group: other antihistamines for systemic use
ATC code: R06AX28
Rupatadine is a second-generation antihistamine, long-acting histamine antagonist, with selective peripheral H1-receptor antagonist activity. Some of the metabolites (desloratadine and its hydroxylated metabolites) retain an antihistaminic activity and may partially contribute to the overall efficacy of the drug.
In vitro studies with rupatadine at high concentration have shown an inhibition of the degranulation of mast cells induced by immunological and non-immunological stimuli as well as the release of cytokines, particularly of the TNFα in human mast cells and monocytes. The clinical relevance of the observed experimental data remains to be confirmed.
Clinical trials in volunteers (n=375) and patients (n=2650) with allergic rhinitis and chronic idiopathic urticaria did not show significant effect on the electrocardiogram when rupatadine was administered at doses ranging from 2 mg to 100 mg.
Chronic idiopathic urticaria was studied as a clinical model for urticarial conditions, since the underlying pathophysiology is similar, regardless of etiology, and because chronic patients can be more easily recruited prospectively. Since histamine release is a causal factor in all urticarial diseases, rupatadine is expected to be effective in providing symptomatic relief for other urticarial conditions, in addition to chronic idiopathic urticaria, as advised in clinical guidelines.
In a placebo-controlled trials in patients with Chronic Idiopathic Urticaria, rupatadine was effective reducing the mean pruritus score from baseline over the 4 week treatment period (change vs baseline: rupatadine 57.5%, placebo 44.9%) and decreasing the mean number of wheals (54.3% vs 39.7%).
Rupatadine is rapidly absorbed after oral administration, with a tmax of approximately 0.75 hours after intake. The mean Cmax was 2.6 ng/ml after a single oral dose of 10 mg and 4.6 ng/ml after a single oral dose of 20 mg. Pharmacokinetics of rupatadine was linear for a dose between 10 and 20 mg after single and repeated doses. After a dose of 10 mg once a day for 7 days, the mean Cmax was 3.8 ng/ml. The plasma concentration followed a bi-exponential drop-off with a mean elimination half-life of 5.9 hours. The binding-rate of rupatadine to plasma proteins was 98.5-99%.
As rupatadine has never been administered to humans by intravenous route, no data is available on its absolute bioavailability.
Intake of food increased the systemic exposure (AUC) to rupatadine by about 23%. The exposure to one of its active metabolites and to the main inactive metabolite was practically the same (reduction of about 5% and 3% respectively). The time taken to reach the maximum plasma concentration (tmax) of rupatadine was delayed by 1 hour. The maximum plasma concentration (Cmax) was not affected by food intake. These differences had no clinical significance.
In a study of excretion in humans (40 mg of 14C-rupatadine), 34.6% of the radioactivity administered was recovered in urine and 60.9% in faeces collected over 7 days. Rupatadine undergoes considerable pre-systemic metabolism when administered by oral route. The amounts of unaltered active substance found in urine and faeces were insignificant. This means that rupatadine is almost completely metabolised. Roughly, the active metabolites desloratadine and other hydroxylated derivatives accounted for 27% and 48%, respectively, of the total systemic exposure of the active substances. In vitro metabolism studies in human liver microsomes indicate that rupatadine is mainly metabolised by the cytochrome P450 (CYP 3A4).
In a study on healthy volunteers to compare the results in young adults and elderly patients, the values for AUC and Cmax for rupatadine were higher in the elderly than in young adults. This is probably due to a decrease of the first-pass hepatic metabolism in the elderly. These differences were not observed in the metabolites analysed. The mean elimination half-life of rupatadine in elderly and young volunteers was 8.7 hours and 5.9 hours respectively. As these results for rupatadine and for its metabolites were not clinically significant, it was concluded that it is not necessary to make any adjustment when using a dose of 10 mg in the elderly.
Preclinical data reveal no special hazard for humans based on conventional studies of pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential.
More than 100 times the clinically recommended dose (10 mg) of rupatadine did neither extend the QTc or QRS interval nor produce arrhythmia in various species of animals such as rats, guinea pigs and dogs. Rupatadine and one of its main active metabolites in humans, 3-hydroxydesloratadine, did not affect the cardiac action potential in isolated dog Purkinje fibres at concentrations at least 2000 times greater than the Cmax reached after the administration of a dose of 10 mg in humans. In a study that evaluated the effect on cloned human HERG channel, rupatadine inhibited that channel at a concentration 1685 times greater than the Cmax obtained after the administration of 10 mg of rupatadine. Desloratadine, the metabolite with the greatest activity, had no effect at a 10 micromolar concentration. Studies of tissue distribution in rats with radiolabelled rupatadine showed that rupatadine does not accumulate in heart tissue.
In the rat, a significant reduction of male and female fertility occurred at the high dose of 120 mg/kg/day, providing Cmax 268 times those measured in humans at the therapeutic dose (10 mg/day). Foetal toxicity (growth delay, incomplete ossification, minor skeletal findings) was reported in rats at maternotoxic dose-levels only (25 and 120 mg/kg/day). In rabbits, no evidence of developmental toxicity was noted at doses up to 100 mg/kg. The developmental No Adverse Effect Levels were determined at 5 mg/kg/day in rats and 100 mg/kg/day in rabbits, yielding Cmax 45 and 116 times higher, respectively, than those measured in humans at the therapeutic dose (10 mg/day).
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