Each film-coated tablet contains: 1 mg prucalopride (equivalent to 1.321 mg prucalopride succinate). 2 mg prucalopride (equivalent to 2.642 mg prucalopride succinate).
Excipients/Inactive Ingredients: Tablet core: Lactose monohydrate, microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate.
Coating: Hypromellose (E464), lactose monohydrate, triacetin, titaniumd dioxide (E171), macrogol 3000, iron oxide red (E172)*, iron oxide yellow (E172)*, FD&C blue no.2 aluminum lake (E132)*.
Pharmacotherapeutic Group: Drugs acting on serotonin receptors. ATC Code: A03AE04.
Pharmacology: Pharmacodynamics: Mechanism of action: Prucalopride is a dihydrobenzofurancarboxamide with enterokinetic activities. Prucalopride is a selective, high affinity serotonin (5-HT4) receptor agonist, which is likely to explain its enterokinetic 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.
Clinical experience: The efficacy of prucalopride was established in three multicentre, randomised, double-blind, 12-week placebo-controlled studies in subjects with chronic constipation (n=1279 on prucalopride, 1124 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 3 or more spontaneous, complete bowel movements (SCBM) per week over the 12-week treatment period. Both doses were statistically superior (p<0.001) to placebo at the primary endpoint in each of the three studies, with no incremental
benefit of the 4 mg over the 2 mg dose. The proportion of patients treated with the recommended dose of prucalopride 2 mg that reached an average of ≥3 SCBM per week was 27.8% (week 4) and 23.6% (week 12), versus 10.5% (week 4) and 11.3% (week 12) on placebo. A clinically meaningful improvement of ≥1 SCBM per week, the most important secondary efficacy endpoint, was achieved in 48.1% (week 4) and 43.1% (week 12) of patients treated with prucalopride 2 mg versus 23.4% (week 4) and 24.6% (week 12) of placebo patients.
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, stool and rectal symptoms, determined at week 4 and week 12. 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.
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.
Pharmacokinetics: Absorption: Prucalopride is rapidly absorbed; after a single oral dose of 2 mg, Cmax was attained in 2-3 hrs. The absolute oral bioavailability is >90%. Concomitant intake of food does not influence the oral bioavailability of prucalopride.
Distribution: 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: 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.
Elimination: 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 once daily displays time-independent kinetics during prolonged treatment.
Special Populations: Population pharmacokinetics: 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.
Elderly: 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.
Renal impairment: 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 Dosage & Administration and Precautions).
Hepatic impairment: Non-renal elimination contributes to about 35% of total elimination, and hepatic impairment is unlikely to affect the pharmacokinetics of prucalopride to a clinically relevant extent (see Dosage & Administration and Precautions).
Pediatric population: After a single oral dose of 0.03 mg/kg in pediatric patients 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 pediatric subjects was about 19 hrs (range 11.6-26.8 hours) (see Dosage & Administration).
Toxicology: 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.
RESOLOR is indicated for symptomatic treatment of chronic constipation in patients whom laxatives fail to provide adequate relief.
Adults: 2 mg once daily.
Elderly (>65 yrs): Start with 1 mg once daily (see Pharmacology: Pharmacokinetics under Actions); if needed, the dose can be increased to 2 mg once daily.
Children and adolescents: RESOLOR is not recommended in children and adolescents younger than 18 years until further data become available. Currently available data are described in Pharmacology: Pharmacokinetics under Actions.
Patients with renal impairment: The dose for patients with severe renal impairment (GFR <30 ml/min/1.73 m2) is 1 mg once daily (see Contraindications and Pharmacology: Pharmacokinetics under Actions). No dose adjustment is required for patients with mild to moderate renal impairment.
Patients with hepatic impairment: The dose for patients with severe hepatic impairment (Child-Pugh class C) is 1 mg once daily (see Precautions and Pharmacology: Pharmacokinetics under Actions). No dose adjustment is required for patients with mild to moderate hepatic impairment.
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.
Method of administration: RESOLOR film-coated tablets are for oral use and can be taken with or without food, at any time of the day.
In a study in healthy volunteers, treatment with RESOLOR 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 the medicinal product's known pharmacodynamic effects and include headache, nausea and diarrhea. 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 diarrhea or vomiting may require correction of electrolyte disturbances.
Hypersensitivity to the active substance or to any of the excipients.
Renal impairment requiring dialysis.
Intestinal perforation or obstruction due to structural or functional disorder of the gut wall, obstructive ileus, severe inflammatory conditions of the intestinal tract, such as Crohn's disease, ulcerative colitis and toxic megacolon/megarectum.
Renal excretion is the main route of elimination of prucalopride (see Pharmacology: Pharmacokinetics under Actions). A dose of 1 mg is recommended in subjects with severe renal impairment (see Dosage & Administration).
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 diarrhea, 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.
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 Dosage & Administration).
Resolor film-coated tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp-lactase deficiency or glucose-galactose malabsorption must not take Resolor.
Effects on ability to drive and use machines: No studies on the effects of prucalopride on the ability to drive and use machines have been performed. RESOLOR has been associated with dizziness and fatigue particularly during the first day of treatment which may have an effect on driving and using machines (see Adverse Reactions).
Impairment of Fertility: Animal studies indicate that there is no effect on male or female fertility.
Use in Pregnancy: Experience with RESOLOR 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 RESOLOR is unknown. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). RESOLOR is not recommended during pregnancy. Women of childbearing potential should use effective contraception during treatment with prucalopride.
Use in Lactation: Prucalopride is excreted in breast milk. However, at therapeutic doses of RESOLOR no effects on the breastfed newborns/infants are anticipated. In the absence of human data, it is not recommended to use RESOLOR during breast-feeding.
In the original clinical development program comprising 14 double-blind placebo-controlled studies, RESOLOR was given orally to approximately 2700 patients with chronic constipation. Of these patients, almost 1000 patients received RESOLOR at the recommended dose of 2 mg per day, while about 1300 patients were treated with 4 mg prucalopride daily. Total exposure in the clinical development plan exceeded 2600 patient years. The most frequently reported adverse reactions associated with RESOLOR therapy are headache and gastrointestinal symptoms (abdominal pain, nausea or diarrhea) 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.
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 (≥1/1000 to <1/100), Rare (≥1/10,000 to <1/1000) and Very rare (≤1/10,000). 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:
Nervous system disorders:
Very common: Headache.
Very common: Nausea, diarrhea, abdominal pain.
Common: Vomiting, dyspepsia, rectal haemorrhage, flatulence, abnormal bowel sounds.
Renal and urinary disorders:
General disorders and administration site conditions:
Uncommon: Fever, malaise.
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 diarrhea 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.
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 carboyxlic 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 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 prucalopride by approximately 40%. This effect is too small to be clinically relevant. Interactions of similar magnitude as observed with ketoconazole may be expected with other potent inhibitors of P-gp such as verapamil, cyclosporine A and quinidine. 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%.
Therapeutic doses of probenecid, cimetidine, erythromycin and paroxetine did not affect the pharmacokinetics 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.
Effects of Prucalopride on Pharmacokinetics of Other Drugs: Prucalopride has no clinically relevant effects of on the pharmacokinetics of warfarin, digoxin, alcohol, paroxetine and oral contraceptives.
Prucalopride co-administration increased erythromycin Cmax by 40% and AUC24 h by 28%. The mechanism for this interaction is not clear. The effect is not regarded as being clinically significant.
Effect of Food: Interactions with food have not been observed.
Instructions for Use and Handling and Disposal: No special requirements.
Do not store above 30°C. Protect from moisture.
A06AX05 - prucalopride ; Belongs to the class of other laxatives.
FC tab 1 mg (white to off-white, round, biconvex, marked "PRU 1" on one side) x 28's. 2 mg (pink, round, biconvex, marked "PRU 2" on one side) x 28's.