4.1. Therapeutic indications

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

4.2. Posology and method of administration

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

Prucalopride should not be used in children and adolescents younger than 18 years (see section 5.1).

Method of administration

Oral use.

4.3. Contraindications

• 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.

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 prucalopride 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 prucalopride 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 prucalopride 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 medicinal product.

4.5. 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.

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 coadministration. 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.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential have to use effective contraception during treatment with prucalopride.

Pregnancy

There is 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). Prucalopride 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 prucalopride, no effects on breast-fed newborns/infants are anticipated. In the absence of human data in women who actively breast-fed while taking prucalopride, a decision should be made whether to discontinue breast-feeding or to discontinue prucalopride 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.

4.7. Effects on ability to drive and use machines

Prucalopride 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).

4.8. Undesirable effects

Summary of the safety profile

In an integrated analysis of 17 double-blind placebo-controlled studies, prucalopride was given orally to approximately 3,300 patients with chronic constipation. Of these, over 1,500 patients received prucalopride 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 prucalopride 2mg 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 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 prucalopride

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 prucalopride therapy as during placebo, with the exception of nausea and diarrhoea that still occurred more frequently during prucalopride therapy, but less pronounced (differences in incidence between prucalopride 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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for 'MHRA Yellow Card' in the Google Play or Apple App Store.

4.9. 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 prucalopride 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.