Prucalopride Succinate

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)

Prucalopride Tablets: 1 mg prucalopride: White to off-white, round biconvex, film-coated tablet debossed with "P1" on one side and no debossing on the other side. 2 mg prucalopride: Pink, round biconvex, film-coated tablet debossed with "P2" on one side and no debossing on the other side. Tablets: 1 mg, 2 mg of prucalopride (3)

Prucalopride tablets are contraindicated in patients with: A history of hypersensitivity to prucalopride tablets. Reactions including dyspnea, rash, pruritus, urticaria, and facial edema have been observed [(see Adverse Reactions (6.2)] . 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. Hypersensitivity to prucalopride tablets (4) 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. (4)

Suicidal Ideation and Behavior : Monitor patients for suicidal ideation and behavior as well as self-injurious ideation and new-onset or worsening of depression. Instruct patients to discontinue prucalopride tablets immediately and contact their healthcare provider if they experience any unusual changes in mood or behavior,or they experience emerging suicidal thoughts or behaviors. (5.1)

5.1 Suicidal Ideation and Behavior In clinical trials, suicides, suicide attempts, and suicidal ideation have been reported. Postmarketing cases of suicidal ideation and behavior as well as self-injurious ideation and new onset or worsening of depression have been reported within the first few weeks of starting prucalopride tablets [see Adverse Reactions (6.1, 6.2)] . A causal association between treatment with prucalopride tablets and an increased risk of suicidal ideation and behavior has not been established. Monitor all patients treated with prucalopride tablets for new onset or 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. Instruct patients to discontinue prucalopride tablets immediately and contact their healthcare provider if they experience any of these symptoms.

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)].

8.1 Pregnancy Risk Summary Available data from case reports with prucalopride use in pregnant women are insufficient to identify any drug-associated risks of miscarriage, major birth defects, or adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental effects were observed with prucalopride administration during the period of organogenesis to pregnant rats and rabbits at doses up to approximately 390 times and 780 times, respectively, the recommended human dose of 2 mg/day (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In oral embryofetal development studies in rats and rabbits, prucalopride was administered to pregnant animals at doses of 5, 20, and 80 mg/kg/day throughout the period of organogenesis. No adverse embryofetal developmental effects were observed in either rats or rabbits up to the highest oral dose of 80 mg/kg/day (about 390 times and 780 times the recommended human dose of 2 mg/day, respectively, based on body surface area). In an oral pre- and post-natal development study in rats, prucalopride was administered at doses of 5, 20, and 80 mg/kg/day. At the 80-mg/kg dose(about 390 times the recommended human dose of 2 mg/day, based on body surface area), a slight decrease in overall survival rate of pups after 7 days was observed, which could be due to maternal toxicity observed at this dose.

8.2 Lactation Risk Summary Prucalopride is present in breast milk (see Data) . There are no data on the effects of prucalopride on the breastfed child or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for prucalopride tablets and any potential adverse effects on the breastfed child from prucalopride tablets or from the underlying maternal condition. Data In an open-label study in 8 healthy lactating women in the weaning stage, plasma and milk samples were collected at predose (day 1 and 4), and then 2, 4, 8, 12, and 24 hours (day 4) after a 2-mg dose of prucalopride was administered once daily for 4 days. Prucalopride is excreted in breast milk with a milk to plasma AUC ratio of 2.65:1; the average amount passed to the infant was estimated to be 1.74 mcg/kg/day, which is about 6% of the maternal dose, adjusted for body weight. The prucalopride concentration detected in breast milk during weaning may not reflect the prucalopride concentration in breast milk during full milk production.

8.4 Pediatric Use The safety and effectiveness of prucalopride tablets have not been established in pediatric patients.

8.5 Geriatric Use Of the 2484 patients treated with prucalopride tablets 1 mg or 2 mg once daily in 6 controlled trials of at least 12-week duration in patients with CIC, 15% were 65 years of age and over, and 5% were 75 years of age and over [see Clinical Studies (14)] . No overall differences in safety and effectiveness were observed between elderly and younger patients. In an additional 4-week double-blind, placebo-controlled dose escalation study in 89 elderly nursing home residents with CIC (PRU-USA-26, NCT00627692), no unanticipated safety issues were identified. Elderly subjects had higher prucalopride exposure compared to younger subjects. However, the effect of age on the pharmacokinetics of prucalopride appeared to be related to decreased renal function [see Clinical Pharmacology (12.3)] . Adjust the dosage in elderly patients based on renal function [see Dosage and Administration (2), Use in Specific Populations (8.6)] .

8.6 Renal Impairment No dosage adjustment is required for patients with mild and moderate renal impairment (creatinine clearance at least 30 mL/min, as determined from a 24-hour urine collection in the clinical trial). Prucalopride tablets is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. A decreased dosage is recommended in patients with severe renal impairment (creatinine clearance less than 30 mL/min, as determined from a 24-hour urine collection in the clinical trial) [see Dosage and Administration (2)] . Avoid prucalopride tablets in patients with end-stage renal disease requiring dialysis [see Clinical Pharmacology (12.3)] .

Prucalopride, a selective serotonin type 4 (5-HT 4 ) receptor agonist, is a gastrointestinal (GI) prokinetic agent that stimulates colonic peristalsis (high-amplitude propagating contractions [HAPCs]), which increases bowel motility. Prucalopride was devoid of effects mediated via 5-HT 2A , 5-HT 2B , 5-HT 3 , motilin or CCK-A receptors in vitro at concentrations exceeding 5-HT 4 receptor affinity by 150-fold or greater. In isolated GI tissues from various animal species, prucalopride facilitated acetylcholine release to enhance the amplitude of contractions and stimulate peristalsis. In rats and dogs, prucalopride stimulated gastrointestinal motility with contractions starting from the proximal colon to the anal sphincter.