Prucalopride Succinate

1 INDICATIONS AND USAGE Prucalopride tablet is indicated for the treatment of chronic idiopathic constipation (CIC) in adults. Prucalopride tablet is a serotonin-4 (5-HT 4 ) receptor agonist indicated for the treatment of chronic idiopathic constipation (CIC) in adults. (1)

2 DOSAGE AND ADMINISTRATION Prucalopride tablets can be taken with or without food. The recommended dosage by patient population is shown in Table 1. Table 1: Recommended Dosage Regimen and Dosage Adjustments by Population Population with CIC Recommended Oral Dose Regimen Adults 2 mg once daily Patients with severe renal impairment (creatinine clearance (CrCL) less than 30 mL/min) [see Use in Specific Populations (8.5 and 8.6)] . 1 mg once daily Take with or without food. (2) Recommended dosage by patient population: Population with CIC Recommended Oral Dose Regimen Adults 2 mg once daily. (2) Patients with severe renal impairment (creatinine clearance (CrCL) less than 30 mL/min 1 mg once daily. (2, 8.5, 8.6)

6 ADVERSE REACTIONS Most common adverse reactions (≥2%) are headache, abdominal pain, nausea, diarrhea, abdominal distension, dizziness, vomiting, flatulence, and fatigue. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Somerset Therapeutics, LLC at 1- 800-417-9175 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below represent 2530 patients (1251 received prucalopride tablets 2 mg once daily and 1279 received placebo) with CIC from 6 double-blind, placebo-controlled clinical trials of 12 weeks to 24 weeks in duration. In these trials overall, patients were primarily female (76%) and white (76%). The mean age was 47 years (range 17 to 95 years) [see Clinical Studies (14)] . Common Adverse Reactions Table 2 below summarizes the incidence (%) of common adverse reactions occurring in at least 2% of patients with CIC receiving either 2 mg of prucalopride tablets once daily or placebo and at an incidence greater than in the placebo group from the six double-blind placebo-controlled trials described above. Table 2: Common Adverse Reactions* in Double-Blind Placebo-Controlled Trials of CIC of at least 12 Weeks Duration Adverse Reaction PRUCALOPRIDE TABLET 2 mg Once Daily N=1251 † % Placebo N=1279 % Headache 19 9 Abdominal pain ‡ 16 11 Nausea 14 7 Diarrhea 13 5 Abdominal distension 5 4 Dizziness 4 2 Vomiting 3 2 Flatulence 3 2 Fatigue 2 1 *Reported in ≥2% of patients receiving prucalopride tablet and a rate higher than patients receiving placebo. †Includes 93 patients who started on prucalopride tablet 1 mg and increased to prucalopride tablet 2 mg. ǂIncludes abdominal pain, upper abdominal pain, lower abdominal pain, abdominal tenderness, abdominal discomfort, and epigastric discomfort. Less Common Adverse Reactions Less common adverse reactions occurring in <2% of patients receiving prucalopride tablet 2 mg once daily include: Gastrointestinal disorders : abnormal gastrointestinal sounds Metabolism and nutrition disorders : decreased appetite Nervous system disorders : migraine Renal and urinary disorders : pollakiuria Diarrhea Of the patients who reported diarrhea, 70% (110 out of 157) reported it in the first week of treatment. Diarrhea typically resolved within a few days in 73% (80 out of 110) of those patients. Severe diarrhea was reported in 1.8% of patients treated with prucalopride tablets 2 mg compared to 1% of patients in the placebo group, and had a similar onset and duration as diarrhea overall. Headache Of the patients who reported headache, 66% (157 out of 237) treated with prucalopride tablets 2 mg once daily reported onset in the first 2 days of treatment. Symptoms typically resolved within a few days in 65% (102 out of 157) of those patients. Adverse Reactions Leading to Discontinuation In the 6 clinical trials described above, 5% of patients treated with 2 mg of prucalopride tablets once daily discontinued due to adverse reactions, compared to 3% of patients in the placebo group. The most common adverse reactions leading to discontinuation were nausea (2% prucalopride tablets, 1% placebo), headache (1% prucalopride tablets, 1% placebo), diarrhea (1% prucalopride tablets, <1% placebo), or abdominal pain (1% prucalopride tablets, 1% placebo). Adverse Reactions of Special Interest Adverse reactions of special interest were evaluated in a pool of 28 completed clinical trials (19 double- blind and 9 open-label) for prucalopride tablets at doses including 0.5 mg, 1 mg, 2 mg, or 4 mg per day in adult patients with CIC (the recommended dosage of prucalopride tablets for CIC is 2 mg once daily). The total exposure in the double-blind trials was 565 patient-years in the prucalopride tablets group, 384 patient-years in the placebo group, and 2769 patient-years in the double-blind and open-label clinical trials. Cardiovascular Safety Analysis In an evaluation by an independent adjudication committee of all potential major adverse cardiovascular events (MACE), defined as cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke, the standardized incidence rate (IR) per 1000 patient-years for MACE for prucalopride tablet was compared with the IR for placebo. In the double-blind trials, the IR for MACE was 3.5 (2 patients out of 3366; 1 patient on 2 mg and 1 patient on 4 mg) in the prucalopride tablets group and 5.2 (2 patients out of 2019) in the placebo group. When combining the double-blind and open-label trials, the IR for MACE was 3.3 (9 patients out of 4472, doses ranging between 0.5 to 4 mg) for prucalopride tablets. Suicidal Ideation and Behavior In the double-blind trials, one patient reported a suicide attempt 7 days after the end of treatment with prucalopride tablet 2 mg once daily; none were reported in patients on placebo. In the open-label trials, two patients reported a suicide attempt and another patient reported suicidal ideation. Completed suicide was reported in two patients, previously treated with prucalopride tablet 2 mg or 4 mg; both discontinued prucalopride tablet for at least one month prior to the event. Observational Cardiovascular Cohort Study The overall cardiovascular safety of prucalopride tablet was assessed using European healthcare databases in a population-based, retrospective, observational, cohort study of adults with constipation. New users of prucalopride tablets (N=5715) were matched to new users of polyethylene glycol 3350 (PEG) (N=29,372) to estimate the standardized incidence rate ratio (SIRR) for MACE, pooled across four data sources. The 95% confidence interval for the pooled estimate of the SIRR did not demonstrate an increased MACE risk and excluded a pre-specified safety margin of a three-fold risk of MACE during prucalopride use relative to PEG use. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of prucalopride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity reactions : dyspnea, rash, pruritus, urticaria, and facial edema [see Contraindications (4)] . Psychiatric disorders: Suicide, suicide attempts, suicidal ideation, self-injurious ideation, depression, anxiety, insomnia, nightmares, and visual hallucinations [see Warnings and Precautions (5.1)].

12.3 Pharmacokinetics The pharmacokinetics of prucalopride has been evaluated in healthy subjects and is dose-proportional within and beyond the therapeutic range (tested up to 20 mg, 10 times the maximum approved recommended dose). Prucalopride administered once daily displays time-independent kinetics during prolonged treatment. With once daily administration of 2 mg prucalopride, pharmacokinetic steady-state is attained within 3 to 4 days, and steady-state plasma concentrations fluctuate between trough and peak values of 2.5 and 7 ng/mL, respectively, with mean plasma AUC 0-24h of 109 ng∙h/mL. The accumulation ratio after once daily dosing ranged from 1.9 to 2.3. The terminal half-life is approximately 1 day. Pharmacokinetic parameters in patients with CIC are similar to those seen in healthy subjects. Absorption Following a single oral dose of 2 mg prucalopride in healthy subjects, peak plasma concentrations are observed within 2 to 3 hours after administration. The absolute oral bioavailability is >90%. Effect of Food Concomitant intake with a high-fat meal (1000 kcal total, 500 kcal from fat) does not influence the oral bioavailability of prucalopride [see Dosage and Administration (2)] . Distribution Prucalopride has a steady-state volume of distribution (V ss ) of 567 liters after intravenous administration. The plasma protein binding of prucalopride is approximately 30%. Elimination Renal excretion is the main route of elimination of prucalopride. Non-renal elimination contributes up to about 35% of the total. The plasma clearance of prucalopride averages 317 mL/min. Metabolism Prucalopride is a substrate of CYP3A4, in vitro. In an oral dose study with radiolabeled prucalopride in healthy subjects, prucalopride made up 92 to 94% of the total radioactivity in plasma. There are 7 different known minor metabolites, the most abundant metabolite (O-desmethyl prucalopride acid) represents 0 to 1.7% of the total plasma exposure. Excretion Following oral administration of radiolabeled prucalopride in healthy subjects, 60 to 65% of the administered dose is excreted unchanged in urine and about 5% in feces. On average, 84.2% of administered radioactive dose was recovered in urine and 13.3% of the dose was recovered in feces. Seven metabolites were recovered in urine and feces, with the most abundant metabolite (O-desmethyl prucalopride acid) accounting for 3.2% and 3.1% of the dose in urine and feces, respectively. None of the other metabolites accounted for more than 3% of the dose. Renal elimination of prucalopride involves both passive filtration and active secretion. Use in Specific Populations Population pharmacokinetic analysis of a combined study population of 1343 subjects indicated that there were no clinically significant differences in the pharmacokinetics of prucalopride based on age (17-95 years), sex, race (89% white, 7% black, 4% other), or body weight (37-161 kg), after accounting for the effect of renal function. Geriatric Patients After once daily dosing of 1 mg, peak plasma concentrations (C max ) and AUC of prucalopride in geriatric subjects were 26% to 28% higher than in younger adult subjects. The effect of age appeared to be related to decreased renal function in the elderly. Additionally, a population pharmacokinetic analysis indicated that age was not a significant covariate, after accounting for the effect of renal function [see Use in Specific Populations (8.5)] . Patients with Renal Impairment After a single 2-mg oral dose, the mean AUC 0-inf of prucalopride increased 1.23-fold in subjects with mild renal impairment (creatinine clearance 60 to ≤89 mL/min), 1.4-fold in subjects with moderate renal impairment (creatinine clearance 30 to ≤59 mL/min), and 2.38-fold in subjects with severe renal impairment (creatinine clearance 15 to ≤29 mL/min), compared to subjects with normal renal function. The pharmacokinetics of prucalopride in patients with end-stage renal disease or undergoing dialysis is not fully known [see Dosage and Administration (2), Use in Specific Populations (8.6)] . Patients with Hepatic Impairment After a single oral dose of 2 mg, C max and AUC of prucalopride were on average 10 to 20% higher in subjects with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment than in subjects with normal hepatic function. This effect is not considered to be clinically significant. Drug Interaction Studies Clinical Studies Effect of Prucalopride on Other Drugs Erythromycin Co-administration of oral erythromycin (500 mg four times daily) with prucalopride increased the erythromycin mean C max by 40% and mean AUC 0-24h by 28%. The mechanism for this interaction is not clear. The increased exposure to erythromycin is unlikely to be clinically significant. Other Drugs No clinically significant differences in the pharmacokinetics (no more than a 10% change in AUC) of the following drugs were observed when co-administered with prucalopride: warfarin, digoxin, paroxetine, or oral contraceptives (ethinyl estradiol and norethisterone). Effect of Other Drugs on Prucalopride Ketoconazole Ketoconazole (200 mg twice daily), a strong CYP3A inhibitor and inhibitor of P-gp and BCRP, increased the C max and AUC of prucalopride by approximately 40%. This effect is unlikely to be clinically significant. Other Drugs No clinically significant differences in prucalopride pharmacokinetics (no more than a 10% change in AUC) were observed when co-administered with erythromycin, probenecid, cimetidine, or paroxetine. In Vitro Studies Based on in vitro study results, the potential for prucalopride to inhibit CYP enzymes (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) and transporters (P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, MATE2-K, BSEP, and MRP2 transporters) or induce CYP enzymes (1A2, 2B6, and 3A4) is low at the clinical concentration.