Prucalopride

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

12.1 Mechanism of Action 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.

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, 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 Apotex Corp. at 1-800-706-5575 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 2,530 patients (1,251 received prucalopride tablets 2 mg once daily and 1,279 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 2 mg Once Daily N=1,251 † % Placebo N=1,279 % 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 tablets and a rate higher than patients receiving placebo. † Includes 93 patients who started on prucalopride tablets 1 mg and increased to prucalopride tablets 2 mg. ǂ Includes 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 tablets 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, 1% placebo), headache (1% prucalopride, 1% placebo), diarrhea (1% prucalopride, <1% placebo), or abdominal pain (1% prucalopride, 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 group, 384 patient-years in the placebo group, and 2,769 patient-years

5 WARNINGS AND PRECAUTIONS 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.

4 CONTRAINDICATIONS 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 )

10 OVERDOSAGE An overdose may result in appearance of symptoms from an exaggeration of the known pharmacodynamic effects of prucalopride and includes headache, nausea, and diarrhea. Specific treatment is not available for prucalopride tablets overdose. Should an overdose occur, treat symptomatically and institute supportive measures, as required. Extensive fluid loss from diarrhea or vomiting may require correction of electrolyte disturbances.