prucalopride: prescribing information – dosing, contraindications, interactions, side effects

Resolor is indicated for symptomatic treatment of chronic constipation in adults in whom laxatives fail to provide adequate relief.

Posology
Adults: 2 mg once daily with or without food, at any time of the day.
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. Efficacy beyond three months has not been demonstrated in placebo-controlled studies (see Section 5.1). In case of prolonged treatment, the benefit should be reassessed at regular intervals.
Special populations
Older people (>65 years): Start with 1 mg once daily (see section 5.2); if needed the dose can be increased to 2 mg once daily.
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 sections 4.3 and 5.2). No dose adjustment is required for patients with mild to moderate renal impairment.
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). No dose adjustment is required for patients with mild to moderate hepatic impairment.

Paediatric population: Resolor should not be used in children and adolescents younger than 18 years (see section 5.1).
Method of administration
Oral use

Posology
Adults: 2 mg once daily with or without food, at any time of day.
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. Efficacy beyond three months has not been demonstrated in placebo-controlled studies (see Section 5.1). In case of prolonged treatment, the benefit should be reassessed at regular intervals.
Special populations
Older people (>65 years): Start with 1 mg once daily (see section 5.2); if needed the dose can be increased to 2 mg once daily.
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 sections 4.3 and 5.2). No dose adjustment is required for patients with mild to moderate renal impairment.
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). No dose adjustment is required for patients with mild to moderate hepatic impairment.
Paediatric population: Resolor should not be used in children and adolescents younger than 18 years (see section 5.1).

Method of administration
Oral use

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• 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, and ulcerative colitis and toxic megacolon/megarectum.

Summary of the safety profile
In an integrated analysis of 17 double-blind placebo-controlled studies, Resolor was given orally to approximately 3,300 patients with chronic constipation. Of these, over 1,500 patients received Resolor at the recommended dose of 2 mg per day, while approximately 1,360 patients were treated with 4 mg prucalopride daily. The most frequently reported adverse reactions associated with Resolor 2 mg therapy are headache (17.8%) and gastrointestinal symptoms (abdominal pain (13.7%), nausea (13.7%) and diarrhoea (12.0%)). 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), 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 integrated analysis of 17 double-blind placebo-controlled clinical studies.

Table 1: Adverse Drug Reactions (ADRs) Associated with Resolor
System/Organ Class
Incidence Category
Adverse Drug Reaction
Metabolism and nutrition disorders
Common
Decreased appetite
Nervous system disorders
Very common
Headache
Common
Dizziness
Uncommon
Tremors, migraine
Cardiac disorders
Uncommon
Palpitations
Ear and labyrinth disorders
Uncommon
Vertigo
Gastrointestinal disorders
Very common
Nausea, diarrhoea, abdominal pain
Common
Vomiting, dyspepsia, flatulence, gastrointestinal sounds abnormal
Uncommon
Rectal haemorrhage
Renal and urinary disorders
Uncommon
Pollakiuria
General disorders and administration site conditions
Common
Fatigue
Uncommon
Pyrexia, malaise
Description of selected adverse reactions
After the first day of treatment, the most common adverse reactions were reported in similar frequencies (incidence no more 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 (differences in incidence between Resolor and placebo of 1.3% and 3.4%, respectively).
Palpitations were reported in 0.7% of the placebo patients, 0.9% of the 1 mg prucalopride patients, 0.9% 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

Summary of the safety profile
In an integrated analysis of 17 double-blind placebo-controlled studies, Resolor was given orally to approximately 3,300 patients with chronic constipation. Of these, over 1,500 patients received Resolor at the recommended dose of 2 mg per day, while approximately 1,360 patients were treated with 4 mg prucalopride daily. The most frequently reported adverse reactions associated with Resolor 2 mg therapy are headache (17.8%) and gastrointestinal symptoms (abdominal pain (13.7%), nausea (13.7%) and diarrhoea (12.0%)). 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 available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are calculated based on the integrated analysis of 17 double-blind placebo-controlled clinical studies.

Table 1: Adverse Drug Reactions (ADRs) Associated with Resolor
System/Organ Class
Incidence Category
Adverse Drug Reaction
Metabolism and nutrition disorders
Common
Decreased appetite
Nervous system disorders
Very common
Headache
Common
Dizziness
Uncommon
Tremors, migraine
Cardiac disorders
Uncommon
Palpitations
Ear and labyrinth disorders
Uncommon
Vertigo
Gastrointestinal disorders
Very common
Nausea, diarrhoea, abdominal pain
Common
Vomiting, dyspepsia, flatulence, gastrointestinal sounds abnormal
Uncommon
Rectal haemorrhage
Renal and urinary disorders
Uncommon
Pollakiuria
General disorders and administration site conditions
Common
Fatigue
Uncommon
Pyrexia, malaise
Description of selected adverse reactions
After the first day of treatment, the most common adverse reactions were reported in similar frequencies (incidence no more 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 (differences in incidence between Resolor and placebo of 1.3% and 3.4%, respectively).
Palpitations were reported in 0.7% of the placebo patients, 0.9% of the 1 mg prucalopride patients, 0.9% 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

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).
There is limited information on 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). 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).
The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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.
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 medicinal products
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 medicinal products on pharmacokinetics of prucalopride
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.

Women of childbearing potential
Women of childbearing potential have to use effective contraception during treatment with prucalopride Pregnancy There is a limited amount of data from the use of prucalopride in pregnant women. 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 reproductive toxicity (including pregnancy, embryonal/foetal development, parturition or postnatal development) (see section 5.3). Resolor is not recommended during pregnancy and in women of childbearing potential not using contraception.
Breast-feeding
A human study has shown that prucalopride is excreted in breast milk. At therapeutic doses of Resolor, no effects on breast-fed newborns/infants are anticipated. In the absence of human data in women who actively breast-fed while taking Resolor, a decision should be made whether to discontinue breast-feeding or to discontinue Resolor therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility
Animal studies indicate that there is no effect on male or female fertility.

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).

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.

5.
PHARMACOLOGICAL 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 defaecation. 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.
These pharmacodynamic effects of prucalopride have been confirmed in human subjects with chronic constipation using manometry in an open-label, randomised, crossover, reader-blinded study investigating the effect of prucalopride 2 mg and an osmotic laxative on colon motility as determined by the number of colonic high-amplitude propagating contractions (HAPCs, also known as giant migrating contractions). Compared with a constipation treatment working through osmotic action, prokinetic stimulation with prucalopride increased colonic motility as measured by the number of HAPCs during the first 12 hours after intake of the investigational product. The clinical significance or benefit of this mechanism of action when compared with other laxatives has not been investigated.
Clinical efficacy and safety
Adult population
The efficacy of Resolor was established in three multicentre, randomised, double-blind, 12-week placebo-controlled studies in subjects with chronic constipation (n=1,279 on Resolor, 1,124 females, 155 males). The Resolor 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.

Absorption
Prucalopride is rapidly absorbed; after a single oral dose of 2 mg in healthy subjects, 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.
Distribution
Prucalopride is extensively distributed, and has a steady-state volume of distribution (Vdss) of 567 litres. The plasma protein binding of prucalopride is about 30%.
Biotransformation
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 seven metabolites were recovered in urine and faeces. The quantitatively most important metabolite in excreta, R107504, accounted for 3.2% and 3.1% of the dose in urine and faeces, respectively. Other metabolites identified and quantified in urine and faeces were R084536 (formed by N-dealkylation) accounting for 3% of the dose and products of hydroxylation (3% of the dose) and N-oxidation (2% of the dose). Unchanged active substance made up about 92-94% of the total radioactivity in plasma. R107504, R084536 and R104065 (formed by O-demethylation) were identified as minor plasma metabolites.
Elimination