Prucalopride

1 INDICATIONS AND USAGE Prucalopride tablets are 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 , 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 )

3 DOSAGE FORMS & STRENGTHS Prucalopride Tablets: 1 mg prucalopride: White to off-white, round, biconvex film-coated tablets debossed with "N 596" on one side and plain on the other side, free from physical defects. 2 mg prucalopride: Pink, round, biconvex film-coated tablets debossed with "N 597" on one side and plain on the other side, free from physical defects. Tablets: 1 mg, 2 mg of prucalopride (3)

4 CONTRAINDICATIONS Prucalopride tablets are contraindicated in patients with: A history of hypersensitivity to prucalopride. 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 (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)

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 ANI Pharmaceuticals, Inc. at 1-855-204-1431 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 Tablets 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 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. ‡ 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 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 …

8 USE IN SPECIFIC POPULATIONS 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 mg/kg/day, 20 mg/kg/day, 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 mg/kg/day, 20 mg/kg/day, 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 and any potential adverse effects on the breastfed child from prucalopride 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 hours, 4 hours, 8 hours, 12 hours, 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 have not been established in pediatric patients. Pediatric information describing a clinical study in which efficacy was not demonstrated is approved for Takeda Pharmaceuticals U.S.A., Inc’s MOTEGRITY (prucalopride) tablets. However, due to Takeda Pharmaceuticals U.S.A., Inc’s marketing exclusivity rights, this drug product is not labeled with that information. 8.5 Geriatric Use Of the 2,484 patients treated with prucalopride 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 ag …

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.

11 DESCRIPTION Prucalopride tablets for oral use contain prucalopride succinate, a dihydrobenzofurancarboxamide that is a serotonin type 4 (5-HT 4 ) receptor agonist. The IUPAC name is: 4-Amino-5-chloro-N-[1-(3-methoxypropyl) piperidin-4-yl]-2,3-dihydro-1-benzofuran-7-carboxamide succinate. The molecular formula is C 22 H 32 CIN 3 O 7 and the molecular weight is 485.96. The structural formula is: Prucalopride succinate is a white to almost white powder. It is soluble in dimethylacetamide, dimethyl formamide and sparingly soluble in methanol. Each 1-mg film-coated tablet of prucalopride contains 1 mg of prucalopride (equivalent to 1.32 mg prucalopride succinate), and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, colloidal silicon dioxide and magnesium stearate. The coating for the 1-mg tablet contains Opadry II 33G28707 White which contains hypromellose, titanium dioxide, lactose monohydrate, macrogol and triacetin. Each 2-mg film-coated tablet of prucalopride contains 2 mg of prucalopride (equivalent to 2.64 mg prucalopride succinate), and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, colloidal silicon dioxide and magnesium stearate. The coating for the 2-mg tablet contains Opadry II 33G34847 Pink which contains hypromellose, titanium dioxide, lactose monohydrate, macrogol, triacetin, iron oxide red, FD & C Blue #2/ indigo carmine aluminium lake and iron oxide yellow. structure

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.

16 HOW SUPPLIED/STORAGE AND HANDLING Prucalopride Tablets containing 1 mg prucalopride are white to off-white, round, biconvex film-coated tablets debossed with "N 596" on one side and plain on the other side, free from physical defects. . They are supplied as: NDC 70954-596-10: HDPE bottle of 30 tablets, with child-resistant closure. Prucalopride Tablets containing 2 mg prucalopride are pink, round, biconvex film-coated tablets debossed with "N 597" on one side and plain on the other side, free from physical defects. . They are supplied as: NDC 70954-597-10: HDPE bottle of 30 tablets, with child-resistant closure. Store prucalopride tablets at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (between 59° to 86°F) [see USP Controlled Room Temperature]. Store prucalopride tablets in the original container to protect from moisture.