MOTEGRITY

1 INDICATIONS AND USAGE MOTEGRITY ® is indicated for the treatment of chronic idiopathic constipation (CIC) in adults. MOTEGRITY 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 MOTEGRITY 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 AND STRENGTHS MOTEGRITY Tablets: 1 mg prucalopride: White to off-white, round, biconvex film-coated tablet debossed with "PRU 1" on one side and no debossing on the other side. 2 mg prucalopride: Pink, round, biconvex film-coated tablet debossed with "PRU 2" on one side and no debossing on the other side. Tablets: 1 mg, 2 mg of prucalopride. ( 3 )

4 CONTRAINDICATIONS MOTEGRITY is contraindicated in patients with: A history of hypersensitivity to MOTEGRITY. 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 MOTEGRITY. ( 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 Takeda Pharmaceuticals at 1-800-828-2088 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 MOTEGRITY 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 MOTEGRITY 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 Reported in ≥2% of patients receiving MOTEGRITY and a rate higher than patients receiving placebo. in Double-Blind Placebo-Controlled Trials of CIC of at least 12 Weeks Duration Adverse Reaction MOTEGRITY 2 mg Once Daily N=1,251 Includes 93 patients who started on MOTEGRITY 1 mg and increased to MOTEGRITY 2 mg. % Placebo N=1,279 % Headache 19 9 Abdominal pain Includes abdominal pain, upper abdominal pain, lower abdominal pain, abdominal tenderness, abdominal discomfort, and epigastric discomfort. 16 11 Nausea 14 7 Diarrhea 13 5 Abdominal distension 5 4 Dizziness 4 2 Vomiting 3 2 Flatulence 3 2 Fatigue 2 1 Less Common Adverse Reactions Less common adverse reactions occurring in <2% of patients receiving MOTEGRITY 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 MOTEGRITY 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 MOTEGRITY 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 MOTEGRITY 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% MOTEGRITY, 1% placebo), headache (1% MOTEGRITY, 1% placebo), diarrhea (1% MOTEGRITY, <1% placebo), or abdominal pain (1% MOTEGRITY, 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 MOTEGRITY at doses including 0.5 mg, 1 mg, 2 mg, or 4 mg per day in adult patients with CIC (the recommended dosage of MOTEGRITY for CIC is 2 mg once daily). The total exposure in the double-blind trials was 565 patient-years in the MOTEGRITY group, 384 patient-years in the placebo group, and 2,769 patient-years in the double-blind and open-label clinical trials. Cardiovascular Safety Analysis In an evaluation by an independent adjudication comm …

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to MOTEGRITY during pregnancy. Healthcare providers are encouraged to register patients by contacting MotherToBaby Pregnancy Studies conducted by the Organization of Teratology Information Specialists (OTIS) at 1-877-311-8972 or visiting https://mothertobaby.org/pregnancy-studies/ . 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 MOTEGRITY and any potential adverse effects on the breastfed child from MOTEGRITY 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 MOTEGRITY have not been established in pediatric patients. MOTEGRITY was evaluated in a 12-week randomized, double-blind, placebo-controlled study, followed by a 36-week double-blind extension study in patients 6 months to 17 years with functional constipation. The interim analysis of the primary endpoint showed that the number of spontaneous bowel movements per week over 12 weeks was similar between the MOTEGRITY and placebo groups, indicating that the study was unlikely to demonstrate effectiveness. Therefore, the study was terminated early for futility. Adverse reactions reported in pediatric patients in this study were similar to those reported in adults. 8.5 Geriatric Use Of the 2,484 patients treated …

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 MOTEGRITY (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-dihydrobenzofuran-7-carboxamide succinate. The molecular formula is C 18 H 26 ClN 3 O 3 .C 4 H 6 O 4 and the molecular weight is 485.96. The structural formula is: Prucalopride succinate is a white to almost white powder. It is highly soluble in acidic aqueous media and alkaline aqueous media up to a pH of approximately 9. Each 1-mg film-coated tablet of MOTEGRITY contains 1 mg of prucalopride (equivalent to 1.32 mg prucalopride succinate), and the following inactive ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The coating for the 1-mg tablet contains hypromellose, lactose monohydrate, polyethylene glycol 3000, titanium dioxide, and triacetin. Each 2-mg film-coated tablet of MOTEGRITY contains 2 mg of prucalopride (equivalent to 2.64 mg prucalopride succinate), and the following inactive ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The coating for the 2-mg tablet contains hypromellose, lactose monohydrate, polyethylene glycol 3000, titanium dioxide, triacetin, red iron oxide, yellow iron oxide, and FD&C Blue #2. Chemical 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 MOTEGRITY 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 MOTEGRITY tablets containing 1 mg prucalopride are white to off-white, round, biconvex film-coated tablets debossed with "PRU 1" on one side and no debossing on the other side. They are supplied as: NDC 54092-546-01: HDPE bottle of 30 tablets, with child-resistant closure. MOTEGRITY tablets containing 2 mg prucalopride are pink, round, biconvex film-coated tablets debossed with "PRU 2" on one side and no debossing on the other side. They are supplied as: NDC 54092-547-01: HDPE bottle of 30 tablets, with child-resistant closure. Store MOTEGRITY at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (between 59°F to 86°F) [see USP Controlled Room Temperature]. Store MOTEGRITY in the original container to protect from moisture.