Resolor 1 mg film-coated tablets

In section 7, change of address of the MAH (TPI-IB) from Block 3 Miesian Plaza, 50 – 58 Baggot Street Lower, Dublin 2, Ireland, to Block 2 Miesian Plaza, 50–58 Baggot Street Lower, Dublin 2, D02

In section 7, change of address of the MAH (TPI-IB) from Block 3 Miesian Plaza, 50 – 58 Baggot Street Lower, Dublin 2, Ireland, to Block 2 Miesian Plaza, 50–58 Baggot Street Lower, Dublin 2, D02

Marketing authorisation holder changed from Shire Pharmaceuticals Ireland Limited to Takeda Pharmaceuticals International AG Ireland Branch

Section 7: Marketing authorisation holder changed from Shire Pharmaceuticals Ireland Limited to Takeda Pharmaceuticals International AG Ireland Branch 

Section 10: Date of revision of the text update to 15 September 2021

• In section 4.4, the editorial changes have been made to the following text: The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose‑galactose malabsorption should not take this medicine.
• In section 4.8, ADR reporting details have been updated.
• In section 5.1, there has been a correction to the spelling of the word defaecation.
• The latest revision date has been updated to 25 June 2020.

SPC updated to include the male indication variation, to include data from a long term study and a pediatric study.

Various updates from prucalopride to Resolor throughout the document.

Section 4.1, replacement of “women” with “adults”.

Section 4.2, replacement of “women” with “adults”, removal of section stating that Resolor is not recommended for use in men.

Section 4.4, removal of section stating that Resolor is not recommended for use in men.

Section 4.5, removal of the following wording:

    Although 8 different metabolites are known, the most abundant of these, the carboxylic acid product of side-chain oxidative O-    demethylation, represents less than 4% of the dose.

Section 4.8, updated following study results detailed above.

Section 5.1, addition of a section on a human pharmacodynamic study, and addition of a section on the clinical study in males.

Section 5.2, updates to the sections on Biotransformation and Elimination.

4.2         Posology and method of administration

Paediatric population: Resolor is not recommended in children and adolescents younger than 18 years until further data become available. Currently available data are described in section 5.2. Resolor should not be used in children and adolescents younger than 18 years (see section 5.1)

4.6     Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential should use effective contraception during treatment with prucalopride

Pregnancy

Experience with prucalopride 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 prucalopride is unknown. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Resolor is not recommended during pregnancy. Women of childbearing potential should use effective contraception during treatment with prucalopride.

5.1     Pharmacodynamic properties 

Paediatric population

The efficacy and safety of prucalopride in paediatric patients (aged 6 months to 18 years) with

functional constipation, were evaluated in an 8-week double-blind, placebo-controlled trial (N = 213),

followed by a 16 week open-label comparator-controlled (Polyethylene glycol 4000) study of up to 24

weeks (N = 197). The starting dose administered was 0.04 mg/kg/day titrated between 0.02 and 0.06

mg/kg/day (to a maximum of 2 mg daily) for children weighing ≤ 50 kg given as an oral solution of

prucalopride or matching placebo. Children weighing > 50 kg received 2 mg/day prucalopride tablets

or matching placebo.

Response to the treatment was defined as having an average of ≥ 3 spontaneous bowel movements

(SBMs) per week and an average number of faecal incontinence episodes of ≤ 1 per 2 weeks. The

results of the study showed no differrence in efficacy between prucalopride and placebo with response

rates of 17% and 17.8% respectively (P= 0.9002). Prucalopride was generally well tolerated. The

incidence of subjects with at least 1 treatment-emergent adverse event (TEAE) was similar between

the prucalopride treatment group (69.8%) and the placebo treatment group (60.7%). Overall, the safety

profile of prucalopride in children was the same as in adults.


5.2       Pharmacokinetic properties

Paediatric population

After a single oral dose of 0.03 mg/kg in paediatric patients aged between 4 and 12 years, C_max of prucalopride was comparable to the C_max 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 paediatric subjects was about 19 hours (range 11.6 to 26.8 hours) (see section 4.2). 

5.3     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. A subcutaneous neonatal/juvenile toxicity study performed in rats 7-55 days of age resulted in a NOAEL of 10mg/kg/day. The AUC_0-24h exposure ratios at the NOAEL versus human children (dosed at approximately 0.04mg/kg daily) ranged between 21 and 71 providing adequate safety margins for the clinical dose.

10.     DATE OF REVISION OF THE TEXT

06/2014 07/2014 

4.2         Posology and method of administration

Posology

Women: 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.

Men: The safety and efficacy of Resolor for use in men has not been established in controlled clinical trials; therefore, Resolor is not recommended for use in men until further data becomes available.

Special populations

Elderly (>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 is not recommended in children and adolescents younger than 18 years until further data become available. Currently available data are described in section 5.2

Method of administration

Oral use 

5.       PHARMACOLOGICAL PROPERTIES

5.1     Pharmacodynamic 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 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 efficacy and safety
The efficacy of prucalopride was established in three multicentre, randomised, double‑blind, 12‑week placebo‑controlled studies in subjects with chronic constipation (n=1,279 on prucalopride, 1,124 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 three or more spontaneous, complete bowel movements (SCBM) per week over the 12‑week treatment period.

For the population targeted in this label, the results are the following:

The proportion of female patients in whom laxatives fail to provide adequate relief (target population) treated with the recommended dose of 2 mg prucalopride (n=458) that reached an average of ≥ 3 SCBM per week was 31.0% (week 4) and 24.7% (week 12), versus 8.6% (week 4) and 9.2% (week 12) on placebo. A clinically meaningful improvement of ≥ 1 SCBM per week, the most important secondary efficacy endpoint, was achieved in 51.0% (week 4) and 44.2% (week 12) treated with 2 mg prucalopride versus 21.7% (week 4) and 22.6% (week 12) of placebo patients.

Prucalopride’s effect on spontaneous bowel movements (SBM) also proved to be statistically superior to placebo for the portion of patients that had an increase of ≥1 SBM/week over the 12-week treatment period.  At week 12, 68.3% of patients treated with 2 mg prucalopride had an average increase of

≥1 SBM/week versus 37.0% of placebo patients (p<0.001 vs placebo).

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 (bloating, discomfort, pain and cramps), stool (incomplete bowel movements, false alarm, straining, too hard, too small) and rectal symptoms (painful bowel movements, burning, bleeding/tearing), determined at week 4 and week 12. At week 4, the proportion of patients with an improvement of ≥1 versus baseline in the PAC SYM abdominal, stool, and rectal symptom subscales was 41.3%, 41.6%, and 31.3% respectively in patients treated with prucalopride 2 mg compared with 26.9%, 24.4% and 22.9% in patients on placebo.  Similar results were observed at Week 12: 43.4%, 42.9%, and 31.7%  respectively in 2 mg prucalopride patients versus 26.9%, 27.2%, and 23.4% in placebo patients (p<0.001 vs placebo).

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. At Week 4, the proportion of patients with an improvement of ≥1 versus baseline in the Patient Assessment of Constipation-Quality of Life satisfaction subscale (PAC-QOL) was 47.7% in patients treated with prucalopride 2 mg compared with 20.2% in patients on placebo.  Similar results were observed at Week 12: 46.9% in 2 mg prucalopride patients versus 19.0% in placebo patients (p<0.001 vs placebo).

The efficacy and safety of prucalopride in patients (aged ≥18 or older) with chronic constipation, were evaluated in a 24 week multicentre, randomised, double-blind, placebo controlled study (N=364). The proportion of patients with an average weekly frequency of ≥3 Spontaneous Complete Bowel Movements (SCBMs) per week (ie, responders) over the 24-week double-blind treatment phase was not statistically different (p=0.367) between the prucalopride (25.1%) and placebo (20.7%) treatment groups. The difference between treatment groups in the average weekly frequency of ≥3 SCBMs per week was not statistically significant over Weeks 1-12 which is inconsistent with the 3 previous multicentre, randomised, double-blind, 12-week placebo controlled studies demonstrating efficacy at this timepoint in adult patients. The study is therefore considered to be inconclusive with respect to efficacy. However, the totality of the data including the previous double-blind placebo controlled 12 week studies support the efficacy of prucalopride. The safety profile of prucalopride in this 24 week study was consistent with that seen in the previous 12 week studies.

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.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 1mg prucalopride (as prucalopride succinate).

Excipients with known effect: Each film-coated tablet contains 165156.75mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL form

Film-coated tablet (tablet).

White to off-white, round, biconvex tablets marked "PRU 2" on one side.

4.2 Posology and method of administration

Posology

Women: 2mg 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 2mg 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.

Men: The safety and efficacy of Resolor for use in men has not been established in controlled clinical trials; therefore, Resolor is not recommended for use in men until further data becomes available.

Special populations

Elderly (>65 years): Start with 1mg once daily (see section 5.2); if needed the dose can be increased to 2mg 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 section 5.2

Patients with renal impairment: The dose for patients with severe renal impairment (GFR < 30ml/min/1.73m²) is 1mg 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 1mg once daily which may be increased to 2mg if required to improve efficacy and if the 1mg 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 is not recommended in children and adolescents younger than 18 years until further data become available. Currently available data are described in section 5.2

Due to the specific mode of action of prucalopride (stimulation of propulsive motility), exceeding the daily dose of 2mg 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 the case of prolonged treatment, the benefit should be reassessed at regular intervals.

Method of administration

Resolor film coated tablets are for oOral use and can be taken with or without food, at any time of the day.

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 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).

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) have not been established in controlled clinical trials. 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).

Men: The safety and efficacy of Resolor for use in men has not been established in controlled clinical trials; therefore, Resolor is not recommended for use in men until further data becomes available.

The tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption must 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. Although 8 different metabolites are known, the most abundant of these, the carboxylic 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 prucalopride on pharmacokinetics of other drugs 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 drugs medicinal products on pharmacokinetics of prucalopride

Ketoconazole (200mg b.i.d 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.

Effect of food

Interactions with food have not been observed



4.7 Effects on ability to drive and use machines

Resolor may have a minor influence on the ability to drive and use machines, since 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 have been observed in clinical studies, particularly during the first day of treatment, which may have an effect on driving and using machines (see section 4.8).

4.8 Undesirable effects

Summary of the safety profile

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

Tabulated list of adverse reactions

The following adverse reactions were reported in controlled clinical studies at the recommended dose of 2mg with frequencies corresponding to Vvery common (≥1/10), Ccommon (≥1/100 to <1/10), Uuncommon (≥1/1,000 to <1/100), Rrare (≥1/10,000 to <1/1,000) and Vvery 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 placebo-controlled clinical study data.

Description of selected adverse reactions

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 diarrhoea 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 1mg prucalopride patients, 0.7% of the 2mg prucalopride patients and 1.9% of the 4mg 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


4.9 Overdose

In a study in healthy volunteers, treatment with prucalopride was well tolerated when given in an up-titrating scheme up to 20mg once daily (10 times the recommended therapeutic dose). An overdose may result in symptoms resulting from an exaggeration of the medicinal product's 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

5.1 Pharmacodynamic 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 5mg/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 Clinical efficacy and safety
The efficacy of prucalopride was established in three multicentre, randomised, double-blind, 12-week placebo-controlled studies in subjects with chronic constipation (n=1,279 on prucalopride, 1,124 females, 155 males). The prucalopride doses studied in each of these three studies included 2mg and 4mg 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.

For the population targeted in this label, the results are the following:

The proportion of female patients in whom laxatives fail to provide adequate relief (target population) treated with the recommended dose of 2　mg prucalopride (n=458) that reached an average of ≥3SCBM per week was 31.0% (week 4) and 24.7% (week 12), versus 8.6% (week 4) and 9.2% (week 12) on placebo. A clinically meaningful improvement of ≥1SCBM per week, the most important secondary efficacy endpoint, was achieved in 51.0% (week 4) and 44.2% (week 12) treated with 2mg prucalopride versus 21.7% (week 4) and 22.6% (week 12) of placebo patients.

Prucalopride’s effect on spontaneous bowel movements (SBM) also proved to be statistically superior to placebo for the portion of patients that had an increase of ≥1SBM/week over the 12-week treatment period. At week 12, 68.3% of patients treated with 2mg prucalopride had an average increase of ≥1 SBM/week versus 37.0% of placebo patients (p<0.001 vs placebo).

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 (bloating, discomfort, pain and cramps), stool (incomplete bowel movements, false alarm, straining, too hard, too small) and rectal symptoms (painful bowel movements, burning, bleeding/tearing), determined at week 4 and week 12. At week 4, the proportion of patients with an improvement of ≥1 versus baseline in the PAC SYM abdominal, stool, and rectal symptom subscales was 41.3%, 41.6%, and 31.3% respectively in patients treated with prucalopride 2mg compared with 26.9%, 24.4% and 22.9% in patients on placebo. Similar results were observed at Week 12: 43.4%, 42.9%, and 31.7% respectively in 2mg prucalopride patients versus 26.9%, 27.2%, and 23.4% in placebo patients (p<0.001 vs placebo).

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. At Week 4, the proportion of patients with an improvement of ≥1 versus baseline in the Patient Assessment of Constipation-Quality of Life satisfaction subscale (PAC-QOL) was 47.7% in patients treated with prucalopride 2mg compared with 20.2% in patients on placebo. Similar results were observed at Week 12: 46.9% in 2mg prucalopride patients versus 19.0% in placebo patients (p<0.001 vs placebo).

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 (2mg) and supratherapeutic doses (10mg) 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.

5.2 Pharmacokinetic properties

Absorption

Prucalopride is rapidly absorbed; after a single oral dose of 2mg, C_max 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 (Vd_ss) of 567litre. The plasma protein binding of prucalopride is about 30%.

MetabolismBiotransformation
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 317ml/min. Its terminal half-life is about one day. Steady-state is reached within three to four days. On once daily treatment with 2mg prucalopride, steady-state plasma concentrations fluctuate between trough and peak values of 2.5 and 7ng/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 20mg). Prucalopride o.d. 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 1mg, 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 (Cl_CR50-79ml/min) and moderate (Cl_CR25-49ml/min) renal impairment, respectively. In subjects with severe renal impairment (Cl_CR≤ 24ml/min), plasma concentrations were 2.3 times the levels in healthy subjects (see section 4.2 and 4.4).

Hepatic impairment

Non-renal elimination contributes to about 35% of total elimination. In a small pharmacokinetic study, the C_max and AUC of prucalopride were, on average, 10-20% higher in patients with moderate to severe hepatic impairment compared with healthy subjects (see sections 4.2 and 4.4).

Paediatric population

After a single oral dose of 0.03mg/kg in paediatric patients aged between 4 and 12 years, C_max of prucalopride was comparable to the C_max in adults after a single 2mg dose, while unbound AUC was 30-40% lower than after 2mg in adults. Unbound exposure was similar over the whole age-range (4-12 years). The average terminal half-life in the paediatric subjects was about 19 hours (range 11.6 to 26.8 hours) (see section 4.2).

6.1 List of excipients

Tablet core

Lactose monohydrate

Microcrystalline cellulose

Colloidal silicon dioxide

Magnesium stearate

Tablet Ccoating

Hypromellose

Lactose monohydrate

Triacetin

Titanium dioxide (E171)

Macrogol　

Iron oxide red (E172)

Iron oxide yellow (E172)

Indigo carmine aluminium lake (E132)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 15 October 2009

Date of latest renewal: 06 June 2014

10. DATE OF REVISION OF THE TEXT

09/2013 06/2014

Veedijk 58
B-2300 Turnhout
Belgium
Tel.: 008006683 8470

to:

Section 4.4 Special warnings and precautions for use (clarification of section on severe and clinically unstable concomitant disease)

Section 5.1 Pharmacodynamic properties (change in ATC code, additional information on spontaneous bowel movements (SBMs), specific symptoms associated with constipation and quality of life data)

Change to section 4.2 – Posology and method of administration;

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). The dose for patients with severe hepatic impairment (Child‑Pugh class C) is 1 mg once daily (see sections 4.4 and 5.2). No dose adjustment is required for patients with mild to moderate hepatic impairment.

Change to section 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 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).

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 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).

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 section 4.2).Men: The safety and efficacy of Resolor for use in men has not been established in controlled clinical trials therefore Resolor is not recommended for use in men until further data becomes available.

Change to section 4.5 – Interaction with other medicinal products and other forms of interaction;

In vitro data indicate that pPrucalopride 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 carboxylic 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 prucalopride on pharmacokinetics of other drugs  

For thea full list of excipients, see section 6.1.

-                Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.6 Fertility, pregnancy and lactation

Breast-feeding

Lactation

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=1,279 on prucalopride, 1,124 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 three or more spontaneous, complete bowel movements (SCBM) per week over the 12‑week treatment period. For the population targeted in this label, the results are the following: The proportion of female patients in whom laxatives fail to provide adequate relief (target population) treated with the recommended dose of 2 mg prucalopride (n=458) that reached an average of ≥ 3 SCBM per week was 31.0% (week 4) and 24.7% (week 12), versus 8.6% (week 4) and 9.2% (week 12) on placebo. A clinically meaningful improvement of ≥ 1 SCBM per week, the most important secondary efficacy endpoint, was achieved in 51.0% (week 4) and 44.2% (week 12) treated with 2 mg prucalopride versus 21.7% (week 4) and 22.6% (week 12) of placebo patients. Also for the target population prucalopride proved significantly superior (p<0.001) to placebo at the primary endpoint.

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 2 mg prucalopride 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 2 mg prucalopride versus 23.4% (week 4) and 24.6% (week 12) of placebo patients.

15 October 20/10/09

10. DATE OF REVISION OF THE TEXT 

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emaemea.europa.eu/.

In section 4.5 (Interaction) the following was added:

Studies in healthy subjects showed that there were no clinically relevant effects of prucalopride on the pharmacokinetics of warfarin, digoxin, alcohol, paroxetine or oral contraceptives.