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.

The dose for patients with severe renal impairment (GFR <30 ml/min/1.73 m²) is 1 mg once daily.

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.

A 30% increase in plasma concentrations of erythromycin was found during prucalopride co-administration. The mechanism for this interaction is not clear.

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). Prucalopride is not recommended during pregnancy and in women of childbearing potential not using contraception.

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.

Women of childbearing potential

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

Fertility

Animal studies indicate that there is no effect on male or female fertility.

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.

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 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.

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.

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.