| Change to section 4.2 – Posology and method of administration;
Patients with hepatic impairment: Patients with severe hepatic impairment (Child-Pugh class C) start with 1 mg once daily which may be increased to 2 mg if required to improve efficacy and if the 1 mg dose is well tolerated (see sections 4.4 and 5.2). The dose for patients with severe hepatic impairment (Child‑Pugh class C) is 1 mg once daily (see sections 4.4 and 5.2). No dose adjustment is required for patients with mild to moderate hepatic impairment.
Change to section 4.4 – Special warnings and precautions for use;
Renal excretion is the main route of elimination of prucalopride (see section 5.2). A dose of 1 mg is recommended in subjects with severe renal impairment (see section 4.2).
Caution should be exercised when prescribing Resolor to patients with severe hepatic impairment (Child-Pugh class C) due to limited data in patients with severe hepatic impairment (see section 4.2).
Patients with severe and clinically unstable concomitant disease (e.g. liver, cardiovascular or lung disease, neurological or psychiatric disorders, cancer or AIDS and other endocrine disorders) have not been studied. Caution should be exercised when prescribing Resolor to patients with these conditions. In particular Resolor should be used with caution in patients with a history of arrhythmias or ischaemic cardiovascular disease.
In case of severe diarrhoea, the efficacy of oral contraceptives may be reduced and the use of an additional contraceptive method is recommended to prevent possible failure of oral contraception (see the prescribing information of the oral contraceptive).
It is unlikely that hepatic impairment will affect prucalopride metabolism and exposure in man to a clinically relevant extent. No data are available in patients with mild, moderate or severe hepatic impairment, and therefore a lower dose is recommended for patients with severe hepatic impairment (see section 4.2).Men: The safety and efficacy of Resolor for use in men has not been established in controlled clinical trials therefore Resolor is not recommended for use in men until further data becomes available.
Change to section 4.5 – Interaction with other medicinal products and other forms of interaction;
In vitro data indicate that pPrucalopride has a low pharmacokinetic interaction potential. It is extensively excreted unchanged in urine (approximately 60% of the dose), and in vitro metabolism is very slow. Although 8 different metabolites are known, the most abundant of these, the carboxylic acid product of side-chain oxidative O-demethylation, represents less than 4% of the dose.
Prucalopride did not inhibit specific CYP450 activities in in vitro studies in human liver microsomes at therapeutically relevant concentrations.
Although prucalopride may be a weak substrate for P-glycoprotein (P‑gp), it is not an inhibitor of P-gp at clinically relevant concentrations.
Effects of prucalopride on pharmacokinetics of other drugs
A 30% increase in plasma concentrations of erythromycin was found during prucalopride co-administration. The mechanism for this interaction is not clear.
Prucalopride had no clinically relevant effects on the pharmacokinetics of warfarin, digoxin, alcohol, paroxetine or oral contraceptives.
Effects of other drugs on pharmacokinetics of prucalopride
Ketoconazole (200 mg b.i.d.), a potent inhibitor of CYP3A4 and of P‑gp, increased the area under the curve (AUC) of systemic exposure to prucalopride by approximately 40%. This effect is too small to be clinically relevant. and is likely attributable to inhibition of P-gp mediated renal transport. Interactions of similar magnitude as observed with ketoconazole may also occur be expected with other potent inhibitors of P‑gp such as verapamil, cyclosporine A and quinidine.
Therapeutic doses of probenecid, cimetidine, erythromycin and paroxetine did not affect the pharmacokinetics of prucalopride.
Prucalopride is likely also secreted via another renal transporter(s). Inhibition of all transporters involved in the active secretion of prucalopride (including P‑gp) may theoretically increase the exposure by up to 75%.
Studies in healthy subjects showed that there were no clinically relevant effects of prucalopride on the pharmacokinetics of warfarin, digoxin, alcohol, and paroxetine and oral contraceptives. A 30% increase in the plasma concentrations of erythromycin was found during prucalopride co-treatment. The mechanism for this interaction is not fully known, but the available data support that this is the consequence of the high intrinsic variability in erythromycin kinetics, rather than a direct effect of prucalopride.
Resolor should be used with caution in patients receiving concomitant drugs known to cause QTc prolongation.
Because of the mechanism of action, the use of atropine-like substances may reduce the 5‑HT4 receptor mediated effects of prucalopride.
Effect of food
Interactions with food have not been observed.
Change to section 4.8 – Undesirable effects;
The following adverse reactions were reported in controlled clinical studies at the recommended dose of 2 mg with frequencies corresponding to Very common (≥ 1/10), Common (≥ 1/100 to < 1/10), Uncommon (≥> 1/1,000 to < 1/100), Rare (≥> 1/10,000 to < 1/1,000) and Very rare (≤< 1/10,000).
Change to section 5.1 – Pharmacodynamic properties;
Mechanism of action
Prucalopride is a dihydrobenzofurancarboxamide with enterokinetic gastrointestinal prokinetic activities. Prucalopride is a selective, high affinity serotonin (5‑HT4) receptor agonist, which is likely to explain its enterokinetic prokinetic effects.
Change to section 5.2 – Pharmacokinetic properties;
Hepatic impairment
Non-renal elimination contributes to about 35% of total elimination. In a small pharmacokinetic study, the Cmax and AUC of prucalopride were, on average, 10-20% higher in patients with moderate to severe hepatic impairment compared with healthy subjects (see sections 4.2 and 4.4).
, and hepatic impairment is unlikely to affect the pharmacokinetics of prucalopride to a clinically relevant extent (see section 4.2 and 4.4)
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