Resolor

Film-coated tablets, each containing 1 mg prucalopride as prucalopride succinate.
Film-coated tablets, each containing 2 mg prucalopride as prucalopride succinate.
Prucalopride succinate (Resolor) 1 mg is a white to off-white, circular, biconvex, film-coated tablet with the inscription "PRU 1" on one side, and no inscription on the other side.
Prucalopride succinate (Resolor) 2 mg is a pink, circular, biconvex, film-coated tablet with the inscription "PRU 2" on one side, and no inscription on the other side.
Excipients/Inactive Ingredients: The excipients are: Tablet core: Lactose monohydrate, Microcrystalline cellulose, Colloidal silicon dioxide, Magnesium stearate.
Coating: Hypromellose, Lactose monohydrate, Triacetin, Titanium dioxide (E171), Macrogol (polyethylene glycol [PEG] 3000), Iron oxide red (E172)*, Iron oxide yellow (E172)*, Indigo carmine aluminum lake (FD&C blue #2) (E132)*.
*2 mg.

Pharmacology: Pharmacodynamics: Mechanism of action: Prucalopride, a high affinity selective, serotonin type 4 (5‑HT₄) receptor agonist, is a gastrointestinal prokinetic agent that stimulates colonic peristalsis increasing bowel motility. This peristalsis is referred to as high-amplitude propagating contractions (HAPCs) in humans and giant migrating contractions in dogs.
Prucalopride does not antagonize 5-HT_2A, 5-HT_2B, 5-HT₃, motilin or CCK₁ receptors or hERG ion channels, with affinity for other receptors or ion channels detected in vitro at concentrations exceeding 5‑HT₄ receptor affinity by 150‑fold or greater. Additional in vitro studies demonstrated no effect on either contractile responses in human, canine, and porcine coronary arteries at concentrations up to 10 μM (500 times the human clinical C_max) or on human platelet aggregation at concentrations up to 200 nM (10 times the human clinical C_max).
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.
Pharmacodynamic Effects: High Amplitude Propagating Contractions: The pharmacodynamic effects of prucalopride have been confirmed in human subjects with chronic constipation using manometry in an open-label, randomized, 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.
Pharmacodynamic effects of prucalopride related to prokinetic activity were studied in healthy subjects and in patients with chronic constipation at doses ranging from 0.5‑4 mg once daily. In a double-blind, randomized, placebo-controlled, crossover manometry study in healthy subjects receiving prucalopride 4 mg once daily (2 times the maximum human recommended dose of 2 mg) or placebo for 7 days showed that prucalopride increased the amplitude of HAPCs without affecting colonic phasic activity.
Colonic Transit Times: Prucalopride accelerates colonic transit at a dose of 2 mg. An integrated analysis of 3 randomized, placebo-controlled, dose-finding studies in 280 subjects with chronic idiopathic constipation showed that after treatment with prucalopride at once-daily doses of 2 mg or 4 mg (2 times the maximum human recommended dose), the colonic transit time was reduced by 12 hours and 13.9 hours, respectively, compared to an increase of 0.5 hours in the placebo group. Furthermore, a positive correlation between constipation symptom severity and decreased colonic transit time was found.
Clinical Studies: The efficacy of Prucalopride succinate (Resolor) was established in 3 multicenter, randomized, double-blind, 12-week placebo-controlled studies in patients with chronic constipation (n=1279 on Prucalopride succinate (Resolor): 1124 females, 155 males). The Prucalopride succinate (Resolor) doses studied in each of these 3 studies included 2 mg and 4 mg dosing once daily. The primary efficacy endpoint was the proportion (%) of patients that reached normalization of bowel movements defined as an average of 3 or more spontaneous, complete bowel movements (SCBM) per week over the 12-week treatment period. Both doses were statistically superior (p<0.001) to placebo at the primary endpoint in each of the 3 studies, with no incremental benefit of the 4 mg dose over the 2 mg dose. The proportion of patients treated with the recommended dose of 2 mg Prucalopride succinate (Resolor) that reached an average of ≥3 SCBM per week was 27.8% (week 4) and 23.6% (week 12), vs 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 succinate (Resolor) vs 23.4% (week 4) and 24.6% (week 12) of placebo patients.
In all 3 studies, treatment with Prucalopride succinate (Resolor) also resulted in significant improvements in the Patient Assessment of Constipation Symptoms (PAC SYM), a validated and disease-specific set of symptom measures, including abdominal, stool and rectal symptoms, determined at week 4 and week 12. At the 4- and 12-week assessment time points, significant improvement in several quality of life measures was also observed, such as degree of satisfaction with treatment and bowel habits, physical and psychosocial discomfort and worries and concerns resulting from constipation symptoms. In addition, the efficacy, safety and tolerability of Prucalopride succinate (Resolor) in male patients with chronic constipation were evaluated in a 12-week, multi-center, randomized, double-blind, placebo-controlled study (N=370). The primary endpoint of the study was met: a statistically significantly higher percentage of subjects in the Prucalopride succinate (Resolor) group (37.9%) had an average of ≥3 SCBMs/week compared with subjects in the placebo treatment group (17.7%) (p<0.0001) over the 12-week, double-blind treatment period. The safety profile of Prucalopride succinate (Resolor) was consistent with that seen in female patients.
The safety and efficacy of Prucalopride succinate (Resolor) in adult male and female patients (51 male, 450 female) with chronic constipation in the Asia Pacific region (China 62%, South Korea 19%, Australia 8%, Thailand 6%, Taiwan 5%) was evaluated in a 12-week randomized, double-blind, placebo-controlled multi-center study with parallel group design. The primary endpoint of the study was the proportion (%) of patients achieving ≥3 SCBMs per week during the entire 12 week treatment phase. The key secondary endpoint was the proportion of patients achieving ≥3 SCBMs per week during the first 4 weeks of the treatment phase of the study. Results for the primary endpoint in the ITT analysis set showed that the percentage of responders in the Prucalopride succinate (Resolor) 2 mg group (33.3%) was significantly higher (p<0.001) than that in the placebo group (10.3%). Results for the key secondary endpoint showed that the percentage of responders (34.5%) was significantly higher (p<0.001) than that in the placebo group (11.1%). The overall safety profile in this study was consistent with that established in previous studies with Prucalopride succinate (Resolor) 2 mg in subjects from Western populations. It has been shown that prucalopride does not cause rebound phenomena, or induce dependency.
A thorough placebo- and positive-controlled QT study (N=120) was performed to evaluate the effects of prucalopride on QT interval at therapeutic (2 mg) and supratherapeutic doses (10 mg). This study did not show significant differences between prucalopride succinate (Resolor) and placebo at either dose, based on mean QTc measurements (largest increase in mean double-delta QTc [subject-specific correlation] was 3.83 msec for 2 mg and 3.03 msec for 10 mg) and outlier analysis. This confirmed the results of two earlier, placebo-controlled QT studies which included QT measurements. The three studies confirm that, the incidence of QT-related adverse events and ventricular arrhythmias was low and comparable to placebo.
The efficacy, safety and tolerability of prucalopride in pediatric 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. The primary endpoint of the study was not met: there was no difference in the proportion of patients having an average of ≥3 spontaneous bowel movements (SBMs) per week AND an average number of fecal incontinence episodes of ≤1 per 2 weeks during week 5 to week 8 of the double-blind treatment period in the prucalopride and placebo groups, 17% versus 17.8%, respectively, (p=0.9002). Overall, the safety profile in children was similar to that in adults.
The efficacy and safety of Prucalopride succinate (Resolor) in patients (aged 18 years or older) with chronic constipation, were evaluated in a 24 week multi-center, randomized, double-blind, placebo-controlled study (N=361). The proportion of patients with an average weekly frequency of ≥3 Spontaneous Complete Bowel Movements (SCBMs) per week (i.e., responders) over the 24-week double-blind treatment phase was not statistically different (p=0.367) between the Prucalopride succinate (Resolor) (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 5 other multi-center, randomized, 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.
The totality of the data including the other double-blind placebo-controlled 12 week studies support the efficacy of Prucalopride succinate (Resolor). The safety profile of Prucalopride succinate (Resolor) in this 24 week study was consistent with that seen in the other 12 week studies.
Pharmacokinetics: Absorption: Prucalopride is rapidly absorbed; after a single oral dose of 2 mg in healthy subjects, 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 567 liters. The plasma protein binding of prucalopride is about 30%.
Metabolism: 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. Cytochrome P450 3A4 has been shown in vitro to be the only enzyme involved in the metabolism of prucalopride. In an oral dose study with radiolabeled prucalopride in man, small amounts of 7 metabolites were recovered in urine and feces. The quantitatively most important metabolite in excreta, R107504, accounted for 3.2% and 3.1% of the dose in urine and feces respectively. Other metabolites identified and quantified in urine and feces 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: In healthy subjects a large fraction of the active substance is excreted unchanged (60-65% of the administered dose in urine and about 5% in feces). Renal excretion of unchanged prucalopride involves both passive filtration and active secretion. The plasma clearance of prucalopride averages 317 mL/min. Its terminal half-life is about 1 day. Steady-state is reached within 3-4 days. On once daily treatment with 2 mg prucalopride steady-state plasma concentrations fluctuate between trough and peak values of 2.5 and 7 ng/mL, respectively. The accumulation ratio after once daily dosing ranged from 1.9-2.3. The pharmacokinetics of prucalopride is dose proportional within and beyond the therapeutic range (tested up to 20 mg). Once daily prucalopride displays time independent kinetics during prolonged treatment.
A population pharmacokinetic analysis based on combined data from Phase I, II, and III studies showed that the apparent total clearance of prucalopride correlated with creatinine clearance, but not with age, body weight, gender, or race.
Toxicology: Non-Clinical Information: 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 (including neonatal/juvenile toxicity).

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

Dosage: Adults: 2 mg once daily.
Geriatrics (>65 years): Start with one 1 mg once daily (see Use in the Elderly under Precautions); if needed, the dose can be increased to 2 mg once daily.
Children and adolescents: Prucalopride succinate (Resolor) is not recommended in children and adolescents younger than 18 years (see Use in Children under Precautions and Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
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 Contraindications and Special Populations: Renal Impairment under Actions). No dose adjustment is required for patients with mild to moderate renal impairment.
Patients with hepatic impairment: No dose adjustment is required for patients with hepatic impairment.
In clinical trials, a doubling of the daily dose to 4 mg did not lead to an increase in efficacy.
If the intake of once daily Prucalopride succinate (Resolor) is not effective after 4 weeks of treatment, the patient should be re-examined and the benefit of continuing treatment reconsidered.
If treatment is continued longer than 3 months, the benefit should be reassessed at regular intervals.
Administration: Prucalopride succinate (Resolor) film-coated tablets are for oral use and can be taken with or without food.

In a study in 24 healthy subjects, treatment with Prucalopride succinate (Resolor) 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 the medicinal product’s known pharmacodynamic effects and include headache, nausea and diarrhea. Specific treatment is not available for Prucalopride succinate (Resolor) overdose. Should an overdose occur, the patient should be treated symptomatically and supportive measures instituted, as required. Extensive fluid loss by diarrhea or vomiting may require correction of electrolyte disturbances.

Hypersensitivity to the active substance or to any of the excipients.
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, ulcerative colitis and toxic megacolon/megarectum.

Patients with Renal Impairment: Renal excretion is the main route of elimination of prucalopride (see Pharmacokinetics). A dose of 1 mg is recommended in subjects with severe renal impairment (see Dosage & Administration).
Concomitant Disease: 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 Prucalopride succinate (Resolor) to patients with these conditions.
Oral Contraceptives: In case of severe diarrhea, 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).
Suicidal Ideation and Behavior: In clinical trials and postmarketing experience, cases of suicide, suicide attempts and suicidal ideation have been reported. A causal association between the treatment with Prucalopride succinate (Resolor) and an increased risk of suicidal ideation and behavior has not been established.
Monitor all patients treated with Prucalopride succinate (Resolor) for persistent worsening of depression or the emergence of suicidal thoughts and behaviors. Counsel patients, their caregivers, and family members of patients to be aware of any unusual changes in mood or behavior and alert the healthcare provider immediately.
Special Populations: Hepatic Impairment: Non-renal elimination contributes up to about 35% of total elimination. After a single oral dose of 2 mg, C_max and AUC of prucalopride were on average 10-20% higher in subjects with moderate and severe hepatic impairment than in subjects with normal hepatic function.
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_CR 50-≤79 mL/min/1.73 m²) and moderate (Cl_CR 25-≤49 mL/min/1.73 m²) renal impairment, respectively. In subjects with severe renal impairment (Cl_CR ≤24 mL/min/1.73 m²), plasma concentrations were 2.3 times the levels in healthy subjects. (see Dosage & Administration and Precautions).
Use in Children: After a single oral dose of 0.03 mg/kg in pediatric patients aged 4-12 years, C_max of prucalopride was comparable to the C_max in adults after a single 2 mg dose. 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 pediatric patients was about 19 hours (range 11.6-26.8 hours). Safety and efficacy of prucalopride in pediatric patients was evaluated in a double-blind, placebo controlled study. Efficacy results do not support the use of Prucalopride succinate (Resolor) in pediatric patients and therefore Prucalopride succinate (Resolor) is not recommended in this patient population (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Use in the Elderly: After once daily dosing of 1 mg, peak plasma concentrations and AUC of prucalopride in geriatric patients were 26%-28% higher than in young adults. This effect can be attributed to a diminished renal function in elderly.

Pregnancy: Experience with Prucalopride succinate (Resolor 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 succinate (Resolor) is unknown. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development (see Pharmacology: Toxicology: Non-Clinical Information under Actions). Prucalopride succinate (Resolor) is not recommended during pregnancy. Women of childbearing potential should use effective contraception during treatment with Prucalopride succinate (Resolor).
Nursing Mothers: Prucalopride is excreted in breast milk. However, at therapeutic doses of Prucalopride succinate (Resolor) no effects on the breastfed newborns/infants are anticipated. In the absence of human data in women who breastfed while taking Prucalopride succinate (Resolor), it is not recommended to use Prucalopride succinate (Resolor) during breast-feeding.
Fertility: Animal studies indicate that there is no effect on male or female fertility.

In an integrated analysis of 17 double-blind placebo-controlled studies, Prucalopride succinate (Resolor) was given orally to approximately 3300 patients with chronic constipation. Of these patients over 1500 patients received Prucalopride succinate (Resolor) at the recommended dose of 2 mg per day, while about 1360 patients were treated with 4 mg Prucalopride succinate (Resolor) daily. The most frequently reported adverse reactions associated with Prucalopride succinate (Resolor) at the 2 mg daily dose are headache (17.8%) and gastrointestinal symptoms (abdominal pain (13.7%), nausea (13.7%) and diarrhea (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.
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 (≥1/1000 to <1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are calculated based an integrated analysis of 17 double-blind placebo-controlled clinical studies. (See table.)

Click on icon to see table/diagram/image

Description of Selected Adverse Reactions: Palpitations: Palpitations were reported in 0.7% of the placebo patients, 0.9% of the 1 mg Prucalopride succinate (Resolor) patients, 0.9% of the 2 mg Prucalopride succinate (Resolor) patients and 1.9% of the 4 mg Prucalopride succinate (Resolor) patients. The majority of patients continued using Prucalopride succinate (Resolor). 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 Prucalopride succinate (Resolor) in adult patients with chronic idiopathic constipation. The standardized incidence rate (IR) per 1000 subject-years for MACE for Prucalopride succinate (Resolor) was compared with the IR for placebo. The total exposure in the double-blind studies was 565.2 subject-years in the Prucalopride succinate (Resolor) 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 Prucalopride succinate (Resolor) group, 5.2 (2 subjects out of 2019) in the placebo group, and 3.3 (9 subjects out of 4472) for Prucalopride succinate (Resolor) in the combined double-blind and open-label clinical studies. The data do not indicate an increased risk of MACE attributable to Prucalopride succinate (Resolor) when compared to placebo.
Observational Cardiovascular Cohort Study: The overall (CV) safety of Prucalopride succinate (Resolor) was assessed in an observational population-based cohort study using European healthcare databases. New users of Prucalopride succinate (Resolor) (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 person-years for MACE. In this cohort study, the pooled, standardized IR for MACE was 6.57 (95% CI: 3.90, 10.39) for Prucalopride succinate (Resolor) 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 Prucalopride succinate (Resolor) as compared with patients using PEG for chronic idiopathic constipation.

Prucalopride has a low pharmacokinetic interaction potential. It is extensively excreted unchanged in urine (approximately 60% of the dose) via both passive filtration and active renal transporters (P-gp and BCRP) and in vitro metabolism is very slow. Although 7 different metabolites are known, the most abundant of these in plasma, R107504 (formed by O-demethylation and oxidation of the resulting alcohol function to a carboxylic acid) represents 0-1.7% of the plasma total radioactivity AUC_0-24.
Prucalopride did not inhibit specific CYP450 activities in in vitro studies in human liver microsomes at therapeutically relevant concentrations. 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.
Effects of prucalopride on pharmacokinetics of other drugs: Prucalopride co-administration increased erythromycin C_max by 40% and AUC_24h by 28%. The mechanism for this interaction is not clear. The effect is not regarded as being clinically significant.
Prucalopride had no clinically relevant effects on the pharmacokinetics of warfarin, digoxin, alcohol, paroxetine or oral contraceptives.
Effects of other drugs on pharmacokinetics of prucalopride: Ketoconazole (200 mg twice/day), 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.

Incompatibilities: None.
Instructions for Use and Handling: No special requirements.

Store at temperatures not exceeding 30°C. Store in the original blister package to protect from moisture.

GIT Regulators, Antiflatulents & Anti-Inflammatories

A06AX05 - prucalopride ; Belongs to the class of other laxatives.

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