Each film-coated tablet contains 1 mg prucalopride (as succinate). Excipients with known effect: Each film-coated tablet contains 142.5 mg lactose (as monohydrate). For the full list of excipients, see section 6.1.

PHARMACEUTICAL FORM

Film-coated tablet (tablet). White to off-white, round, biconvex tablets marked "PRU 1" on one side.

CLINICAL PARTICULARS

Posology and method of administration

Due to the specific mode of action of prucalopride (stimulation of propulsive motility), exceeding the daily dose of 2 mg is not expected to increase efficacy. If the intake of once daily prucalopride is not effective after 4 weeks of treatment, the patient should be re-examined and the benefit of continuing treatment reconsidered. The efficacy of prucalopride has been established in double-blind, placebo-controlled studies for up to 3 months. In case of prolonged treatment, the benefit should be reassessed at regular intervals.

: 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.

: Start with 1 mg once daily (see section 5.2); if needed the dose can be increased to 2 mg once daily.

(GFR < 30 ml/min/1.73 m2) is 1 mg once daily (see sections 4.3 and 5.2). No dose adjustment is required for patients with mild to moderate renal 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). No dose adjustment is required for patients with mild to moderate hepatic impairment.

: Resolor is not recommended in children and adolescents younger than 18 years until further data become available. Currently available data are described in section 5.2

Contraindications

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). The safety and efficacy of Resolor for use in patients with severe and clinically unstable concomitant disease (e.g. cardiovascular or lung disease, neurological or psychiatric disorders, cancer or AIDS and other endocrine disorders) have not been established in controlled clinical trials. Caution should be exercised when prescribing Resolor to patients with these conditions especially when used 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). 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. The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Interaction with other medicinal products and other forms of interaction

Prucalopride 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.

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.

Ketoconazole (200 mg twice daily), a potent inhibitor of CYP3A4 and of P-gp, increased the systemic exposure to prucalopride by approximately 40%. This effect is too small to be clinically relevant. Interactions of similar magnitude may 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.

Fertility, pregnancy and lactation

Experience with prucalopride during pregnancy is limited. Cases of spontaneous abortion have been observed during clinical studies, although, in the presence of other risk factors, the relationship to prucalopride is unknown. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Resolor is not recommended during pregnancy. Women of childbearing potential should use effective contraception during treatment with prucalopride.

Prucalopride is excreted in breast milk. However, at therapeutic doses of Resolor, no effects on breastfed newborns/infants are anticipated. In the absence of human data, it is not recommended to use Resolor during breast-feeding.

Effects on ability to drive and use machines

Resolor may have a minor influence on the ability to drive and use machines, since dizziness and fatigue have been observed in clinical studies, particularly during the first day of treatment (see section 4.8).

Undesirable effects

Summary of the safety profile

Resolor has been given orally to approximately 2,700 patients with chronic constipation in controlled clinical studies. Of these patients, almost 1,000 patients received Resolor at the recommended dose of 2 mg per day, while about 1,300 patients were treated with 4 mg prucalopride daily. Total exposure in the clinical development plan exceeded 2,600 patient years. The most frequently reported adverse reactions associated with Resolor therapy are headache and gastrointestinal symptoms (abdominal pain, nausea or diarrhoea) occurring in approximately 20% of patients each. The adverse reactions occur predominantly at the start of therapy and usually disappear within a few days with continued treatment. Other adverse reactions have been reported occasionally. The majority of adverse events were mild to moderate in intensity.

Tabulated list of adverse reactions

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) and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are calculated based on the placebo-controlled clinical study data. Metabolism and nutrition disorders Uncommon:anorexia Nervous system disorders Very common:headache Common:dizziness Uncommon:tremors Cardiac disorders Uncommon:palpitations Gastrointestinal disorders Very common:nausea, diarrhoea, abdominal pain Common:vomiting, dyspepsia, rectal haemorrhage, flatulence, abnormal bowel sounds Renal and urinary disorders Common:pollakiuria General disorders and administration site conditions Common:fatigue Uncommon:fever, malaise

Description of selected adverse reactions

After the first day of treatment, the most common adverse reactions were reported in similar frequencies (incidence less than 1% different between prucalopride and placebo) during Resolor therapy as during placebo, with the exception of nausea and diarrhoea that still occurred more frequently during Resolor therapy, but less pronounced (difference in incidence between prucalopride and placebo between 1 and 3%). Palpitations were reported in 0.7% of the placebo patients, 1.0% of the 1 mg prucalopride patients, 0.7% of the 2 mg prucalopride patients and 1.9% of the 4 mg prucalopride patients. The majority of patients continued using prucalopride. As with any new symptom, patients should discuss the new onset of palpitations with their physician.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V

Overdose

In a study in healthy volunteers, treatment with prucalopride was well tolerated when given in an up-titrating scheme up to 20 mg once daily (10 times the recommended therapeutic dose). An overdose may result in symptoms resulting from an exaggeration of prucalopride's known pharmacodynamic effects and include headache, nausea and diarrhoea. Specific treatment is not available for Resolor overdose. Should an overdose occur, the patient should be treated symptomatically and supportive measures instituted, as required. Extensive fluid loss by diarrhoea or vomiting may require correction of electrolyte disturbances.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: Other drugs for constipation, ATC code: A06AX05. Mechanism of action Prucalopride is a dihydrobenzofurancarboxamide with gastrointestinal prokinetic activities. Prucalopride is a selective, high affinity serotonin (5-HT4 ) receptor agonist, which is likely to explain its prokinetic effects. In vitro, only at concentrations exceeding its 5-HT4 receptor affinity by at least 150-fold, affinity for other receptors was detected. In rats, prucalopride in vivo, at doses above 5 mg/kg (at and above 30-70 times the clinical exposure), induced hyperprolactinaemia caused by an antagonistic action at the D2 receptor. In dogs, prucalopride alters colonic motility patterns via serotonin 5-HT4 receptor stimulation: it stimulates proximal colonic motility, enhances gastroduodenal motility and accelerates delayed gastric emptying. Furthermore, giant migrating contractions are induced by prucalopride. These are equivalent to the colonic mass movements in humans, and provide the main propulsive force to defecation. In dogs, the effects observed in the gastrointestinal tract are sensitive to blockade with selective 5-HT4 receptor antagonists illustrating that the observed effects are exerted via selective action on 5-HT4 receptors.

The efficacy of prucalopride was established in three multicentre, randomised, double-blind, 12-week placebo-controlled studies in subjects with chronic constipation (n=1,279 on prucalopride, 1,124 females, 155 males). The prucalopride doses studied in each of these three studies included 2 mg and 4 mg once daily. The primary efficacy endpoint was the proportion (%) of subjects that reached normalisation of bowel movements defined as an average of three or more spontaneous, complete bowel movements (SCBM) per week over the 12-week treatment period. For the population targeted in this label, the results are the following: The proportion of female patients in whom laxatives fail to provide adequate relief (target population) treated with the recommended dose of 2 mg prucalopride (n=458) that reached an average of >= 3 SCBM per week was 31.0% (week 4) and 24.7% (week 12), versus 8.6% (week 4) and 9.2% (week 12) on placebo. A clinically meaningful improvement of >= 1 SCBM per week, the most important secondary efficacy endpoint, was achieved in 51.0% (week 4) and 44.2% (week 12) treated with 2 mg prucalopride versus 21.7% (week 4) and 22.6% (week 12) of placebo patients. Prucalopride's effect on spontaneous bowel movements (SBM) also proved to be statistically superior to placebo for the portion of patients that had an increase of >=1 SBM/week over the 12-week treatment period. At week 12, 68.3% of patients treated with 2 mg prucalopride had an average increase of >=1 SBM/week versus 37.0% of placebo patients (p<0.001 vs placebo). In all three studies, treatment with prucalopride also resulted in significant improvements in a validated and disease specific set of symptom measures (PAC SYM), including abdominal (bloating, discomfort, pain and cramps), stool (incomplete bowel movements, false alarm, straining, too hard, too small) and rectal symptoms (painful bowel movements, burning, bleeding/tearing), determined at week 4 and week 12. At week 4, the proportion of patients with an improvement of >=1 versus baseline in the PAC SYM abdominal, stool, and rectal symptom subscales was 41.3%, 41.6%, and 31.3% respectively in patients treated with prucalopride 2 mg compared with 26.9%, 24.4% and 22.9% in patients on placebo. Similar results were observed at Week 12: 43.4%, 42.9%, and 31.7% respectively in 2 mg prucalopride patients versus 26.9%, 27.2%, and 23.4% in placebo patients (p<0.001 vs placebo). A significant benefit on a number of Quality of Life measures, such as degree of satisfaction with treatment and with bowel habits, physical and psychosocial discomfort and worries and concerns, was also observed at both the 4 and 12 week assessment time points. At Week 4, the proportion of patients with an improvement of >=1 versus baseline in the Patient Assessment of Constipation-Quality of Life satisfaction subscale (PAC-QOL) was 47.7% in patients treated with prucalopride 2 mg compared with 20.2% in patients on placebo. Similar results were observed at Week 12: 46.9% in 2 mg prucalopride patients versus 19.0% in placebo patients (p<0.001 vs placebo). Prucalopride has been shown not to cause rebound phenomena, nor to induce dependency. A thorough QT study was performed to evaluate the effects of prucalopride on the QT interval at therapeutic (2 mg) and supratherapeutic doses (10 mg) and compared with the effects of placebo and a positive control. This study did not show significant differences between prucalopride and placebo at either dose, based on mean QT measurements and outlier analysis. This confirmed the results of two placebo controlled QT studies. In double-blind clinical studies, the incidence of QT-related adverse events and ventricular arrhythmias was low and comparable to placebo. Data from open-label studies up to 2.6 years offer some evidence for longer-term safety and efficacy; however, no placebo-controlled efficacy data for treatments longer than 12 weeks duration are available.

Pharmacokinetic properties

Prucalopride is rapidly absorbed; after a single oral dose of 2 mg, Cmax was attained in 2-3 hours. The absolute oral bioavailability is >90%. Concomitant intake of food does not influence the oral bioavailability of prucalopride.

Prucalopride is extensively distributed, and has a steady-state volume of distribution (Vdss ) of 567 litre. The plasma protein binding of prucalopride is about 30%.

Metabolism is not the major route of elimination of prucalopride. In vitro, human liver metabolism is very slow and only minor amounts of metabolites are found. In an oral dose study with radiolabelled prucalopride in man, small amounts of eight metabolites were recovered in urine and faeces. The major metabolite (R107504, formed by O-demethylation and oxidation of the resulting alcohol function to a carboxylic acid) accounted for less than 4% of the dose. Unchanged active substance made up about 85% of the total radioactivity in plasma and only R107504 was a minor plasma metabolite.

A large fraction of the active substance is excreted unchanged (about 60% of the administered dose in urine and at least 6% in faeces). Renal excretion of unchanged prucalopride involves both passive filtration and active secretion. The plasma clearance of prucalopride averages 317 ml/min. Its terminal half-life is about one day. Steady-state is reached within three to four days. On once daily treatment with 2 mg prucalopride, steady-state plasma concentrations fluctuate between trough and peak values of 2.5 and 7 ng/ml, respectively. The accumulation ratio after once daily dosing ranged from 1.9 to 2.3. The pharmacokinetics of prucalopride is dose-proportional within and beyond the therapeutic range (tested up to 20 mg). Prucalopride o.d. displays time-independent kinetics during prolonged treatment.

A population pharmacokinetic analysis showed that the apparent total clearance of prucalopride was correlated with creatinine clearance, but that age, body weight, sex or race had no influence.

After once daily dosing of 1 mg, peak plasma concentrations and AUC of prucalopride in elderly subjects were 26% to 28% higher than in young adults. This effect can be attributed to a diminished renal function in elderly.

Compared to subjects with normal renal function, plasma concentrations of prucalopride after a single 2 mg dose were on average 25% and 51% higher in subjects with mild (ClCR 50-79 ml/min) and moderate (ClCR 25-49 ml/min) renal impairment, respectively. In subjects with severe renal impairment (ClCR <= 24 ml/min), plasma concentrations were 2.3 times the levels in healthy subjects (see section 4.2 and 4.4).

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).

After a single oral dose of 0.03 mg/kg in paediatric patients aged between 4 and 12 years, Cmax of prucalopride was comparable to the Cmax in adults after a single 2 mg dose, while unbound AUC was 30-40% lower than after 2 mg in adults. Unbound exposure was similar over the whole age-range (4-12 years). The average terminal half-life in the paediatric subjects was about 19 hours (range 11.6 to 26.8 hours) (see section 4.2).

Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development. An extended series of safety pharmacology studies with special emphasis on cardiovascular parameters showed no relevant changes in haemodynamic and ECG derived parameters (QTc) with the exception of a modest increase in heart rate and blood pressure observed in anaesthesized pigs after intravenous administration, and an increase in blood pressure in conscious dogs after bolus intravenous administration, which was not observed either in anaesthetized dogs or after oral administration in dogs reaching similar plasma levels.

PHARMACEUTICAL PARTICULARS

List of excipients

Lactose monohydrate Microcrystalline cellulose Colloidal silicon dioxide Magnesium stearate

Incompatibilities

Shelf life

Special precautions for storage

Nature and contents of container

Aluminium/aluminium perforated unit dose blisters (calendar marked) containing 7 tablets. Each pack contains 7 x 1, 14 x 1, 28 x 1 or 84 x 1 film-coated tablet. Not all pack sizes may be marketed.

Special precautions for disposal

MARKETING AUTHORISATION HOLDER

Shire Pharmaceuticals Ireland Limited 5 Riverwalk Citywest Business Campus Dublin 24 Ireland

MARKETING AUTHORISATION NUMBER(S)

EU/1/09/581/001 (28 tablets) EU/1/09/581/003 (7 tablets) EU/1/09/581/005 (14 tablets) EU/1/09/581/007 (84 tablets)

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/.

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

NAME OF THE MEDICINAL PRODUCT

QUALITATIVE AND QUANTITATIVE COMPOSITION