RESOTRANS Film-coated tablet Ref.[50730] Active ingredients: Prucalopride

There is limited information in 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). Therefore, caution should be exercised when prescribing RESOTRANS to patients with these conditions. In particular, RESOTRANS should be used with caution 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 monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption must not take this medicinal product.

Special populations

Use in Patients with Renal Impairment

Renal excretion is the main route of elimination of prucalopride (see section 5.2). A dose of 1 mg is recommended in patients with severe renal impairment (see section 4.2).

Use in Patients with Hepatic Impairment

A lower dose is recommended for patients with severe hepatic impairment (see section 4.2).

Use in Children and Adolescents

RESOTRANS is not recommended in children and adolescents younger than 18 years.

Use in the Elderly

Elderly (>65 years): Start with one 1 mg tablet once daily (see sections 4.2 and 5.2). If needed, the dose can be increased to 2 mg once daily.

Suicidal Ideation and Behaviour

In clinical trials and postmarketing experience, cases of suicide, suicide attempts, and suicidal ideation have been reported. A casual association between treatment with RESOTRANS and an increased risk of suicidal ideation and behaviour has not been established.

Monitor all patients treated with RESOTRANS for persistent worsening of depression or the emergence of suicidal thoughts and behaviours. Counsel patients, their caregivers, and family members of patients to be aware of any unusual changes in mood or behaviour and alert the healthcare provider immediately.

In vitro data indicate that RESOTRANS has a low interaction potential, and therapeutic concentrations of RESOTRANS are not expected to affect the CYP-mediated metabolism of comedicated medicinal products.

Prucalopride is a weak substrate for P-glycoprotein (P-gp). Prucalopride is a weak in vitro inhibitor of P-gp and BCRP transporters, and it is not a significant inhibitor of OATP1B1, OATP1B3, OAT1, OAT3, BSEP and MRP2 transporters.

Ketoconazole (200 mg twice/day), a potent inhibitor of CYP3A4 and of P-gp, increased the area under the curve (AUC) of RESOTRANS by approximately 40%. This effect is too small to be clinically relevant and is likely attributable to inhibition of P-gp mediated renal transport. Interactions of similar magnitude as observed with ketoconazole may also occur with other potent inhibitors of P-gp such as verapamil, cyclosporine A and quinidine. RESOTRANS is likely also secreted via another renal transporter(s). Inhibition of all transporters involved in the active secretion of RESOTRANS (including P-gp) may theoretically increase the exposure by up to 75%.

Studies in healthy subjects showed that there were no clinically relevant effects of RESOTRANS on the pharmacokinetics of warfarin, digoxin, alcohol, paroxetine and oral contraceptives. A 30% increase in the plasma concentrations of erythromycin was found during prucalopride cotreatment. The mechanism for this interaction is not fully known, but the available data support that this is the consequence of the high intrinsic variability in erythromycin kinetics, rather than a direct effect of RESOTRANS.

Therapeutic doses of probenecid, cimetidine, erythromycin and paroxetine did not affect the pharmacokinetics of RESOTRANS.

RESOTRANS 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 RESOTRANS. Interactions with food have not been observed.

Effects on Laboratory Tests

No effects are known.

Use in Pregnancy

Category B2.

Experience with RESOTRANS 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 RESOTRANS is unknown. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. RESOTRANS is not recommended during pregnancy. Women of childbearing potential should use effective contraception during treatment with RESOTRANS.

Use in Lactation

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

Effects on Fertility

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

No studies on the effects of RESOTRANS on the ability to drive and use machines have been performed. RESOTRANS 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 section 4.8).

RESOTRANS was given orally to approximately 2,700 patients with chronic constipation in controlled clinical studies. Of these patients, almost 1,000 patients received RESOTRANS at the recommended dose of 2 mg per day, while about 1,300 patients were treated with 4 mg RESOTRANS daily. Total exposure in the clinical development plan exceeded 2,600 patient years. The most frequently reported adverse reactions associated with RESOTRANS 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.

Adverse events reported by more than 2.0% of the patients in the ‘All prucalopride’ treatment group in the Phase II and III double-blind placebo-controlled trials in patients with chronic constipation are shown in Table 1.

Table 1. Chronic constipation: adverse events reported by ≥2% of prucalopride-treated subjects in Phase II and III double-blind placebo-controlled studies. Population: All patients:

Note: AEs reported any time during treatment or within 5 days of end of treatment are included

A total of 564 elderly patients (≥65 years) with chronic constipation were treated with RESOTRANS in double-blind studies, with a total exposure of 63 person-years. Most patients in the Phase II/III double-blind placebo-controlled studies were younger than 65 years. The incidence of adverse events in the <65 years old group was 71.2% (1534 out of 2153 patients) in the prucalopride group, and 61.6% (712 out of 1155) in the placebo group. In the group of patients older than 65 years, the incidence of adverse events in the RESOTRANS group was 58.7% (331 out of 564) and in the placebo group 52.8% (113 out of 214). Similar to the younger age group, the most common adverse events with RESOTRANS treatment among the elderly (>65 years) groups were gastrointestinal disorders and headache. No clinically meaningful increase of adverse events was observed in RESOTRANS treated groups as compared to placebo group.

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). 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

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, rectal haemorrhage, flatulence, abnormal bowel sounds

Renal and urinary disorders

Common: polyuria

General disorders and administration site conditions

Common: fatigue

Uncommon: fever, malaise

After the first day of treatment, the most common adverse reactions were reported in similar frequencies (incidence less than 1% difference between RESOTRANS and placebo) during RESOTRANS therapy as during placebo, with the exception of nausea and diarrhoea that still occurred more frequently during RESOTRANS therapy, but less pronounced (difference in incidence between RESOTRANS and placebo between 1 and 3%).

Palpitations were reported in 0.7% of the placebo patients, 1.0% of the 1 mg RESOTRANS patients, 0.7% of the 2 mg RESOTRANS patients and 1.9% of the 4 mg RESOTRANS patients. The majority of patients continued using RESOTRANS. As with any new symptom, patients should discuss the new onset of palpitations with their physician.

Cardiovascular Safety Analysis

An evaluation was performed by an independent adjudication committee of all potential major adverse cardiovascular events (MACE) across 28 completed double-blind and open-label clinical studies for RESOTRANS in adult patients with chronic idiopathic constipation. The standardized incidence rate (IR) per 1000 subject-years for MACE for RESOTRANS was compared with the IR for placebo. The total exposure in the double-blind studies was 565.2 subject-years in the RESOTRANS group, 384 subject-years in the placebo group and 2769 subject-years in the double-blind and open-label clinical studies. The IR for MACE was 3.5 (2 subjects out of 3366) in the double-blind RESOTRANS group, 5.2 (2 subjects out of 2019) in the placebo group, and 3.3 (9 subjects out of 4472) for RESOTRANS in the combined double-blind and open-label clinical studies. The data do not indicate an increased risk of MACE attributable to RESOTRANS when compared to placebo.

Observational Cardiovascular Cohort Study

The overall (CV) safety of RESOTRANS was assessed in an observational population-based cohort study using European healthcare databases. New users of RESOTRANS (N=5715) were matched to new users of polyethylene glycol 3350 (PEG) (N=29,372) to determine the standardized incidence rate (IR) and the adjusted incidence rate ratio (IRR) per 1,000 personyears for MACE. In this cohort study, the pooled, standardized IR for MACE was 6.57 (95% CI: 3.90, 10.39) for RESOTRANS compared to an IR of 10.24 (95% CI: 6.97, 14.13) for PEG and the IRR for MACE was 0.64 (95% CI: 0.36, 1.14). These data do not indicate an increased risk of MACE in patients using RESOTRANS as compared with patients using PEG for chronic idiopathic constipation.

Not applicable.