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.

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 2769 patient-years in the double-blind and open-label clinical trials.

Observational Cardiovascular Cohort Study

The overall cardiovascular safety of MOTEGRITY was assessed using European healthcare databases in a population-based, retrospective, observational, cohort study of adults with constipation. New users of MOTEGRITY (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.

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

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.

High Amplitude Propagating Contractions

Following a single 2-mg dose of prucalopride in patients with CIC, prucalopride increased the number of high amplitude propagating contractions (HAPCs) during the first 12 hours as compared with an osmotic laxative treatment. In addition, prucalopride 4 mg once daily (2 times the maximum human recommended dose of 2 mg) for 7 days increased the amplitude of HAPCs in healthy subjects without affecting colonic phasic activity as compared with placebo.

Colonic Transit Time

An integrated analysis of 3 randomized, placebo-controlled, dose-finding studies in 280 patients with CIC showed that after once daily treatment with 2 mg of prucalopride, the mean colonic transit time was reduced by 12 hours from a baseline of 65 hours for prucalopride 2 mg, compared to an increase of 0.5 hours from a baseline of 66 hours in the placebo group.

Cardiac Electrophysiology

At a dose 5 times the maximum approved recommended dose, MOTEGRITY does not prolong the QT interval to any clinically relevant extent.

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%.

Distribution

Prucalopride has a steady-state volume of distribution (Vss) 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.

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.

Drug Interaction Studies

Carcinogenesis

In a 2-year carcinogenicity study in mice, prucalopride was given by daily oral gavage at doses of 10, 20, and 80 mg/kg. An increased incidence of mammary gland adenocarcinomas was observed in female mice at 80 mg/kg/day. The finding is considered rodent-specific. No significant neoplastic changes were seen in male mice dosed up to 80 mg/kg/day and in female mice dosed up to 20 mg/kg/day (exposure ratio of 219 and 24 times the human dosage of 2 mg per day in male and female mice, respectively, based on AUC).

In a 2-year carcinogenicity study in rats, prucalopride was given by daily oral gavage at doses of 5, 20, and 80 mg/kg in males and 5, 10, and 40 mg/kg in females. In male and female rats there was a significant increase in the incidences of benign tumors, including hepatocellular adenomas, thyroid follicular adenomas, and mammary gland fibroadenomas. An increased incidence of pituitary adenomas, pancreas islet cell adenomas, and adrenal gland benign pheochromocytomas was also seen in male rats. The increases in neoplastic changes occurred primarily at the high dose of 80 mg/kg/day in male rats and 40 mg/kg/day in female rats (exposure ratios 556 times (males) and 495 times (females) the human dosage of 2 mg per day, based on AUC). There was no significant increase in tumor incidence at doses up to 20 mg/kg/day in male rats and up to 10 mg/kg/day in female rats (exposure ratios of 63 and 40 times the human dosage of 2 mg per day in male and female rats, respectively, based on AUC).

In a 12-month carcinogenicity study in neonatal mice, prucalopride was administered by oral gavage at total dosages of 75, 150, and 300 mg/kg given across 2 doses on day 8 of age (one-third of total dosage) and day 15 of age (two-thirds of total dosage). Prucalopride was not tumorigenic at doses up to 300 mg/kg (>1600 times the human exposure at 2 mg per day, based on AUC).

Mechanistic studies demonstrated that the increase in tumor incidence in rodents related to stimulation of prolactin in endocrine tissues was associated with dopamine D2 antagonist activity. The hepatic and thyroid tumors were due to induction of enzymes in liver and subsequent disruption of thyroid homeostasis.

Mutagenesis

Prucalopride was tested in a battery of assays, including the Ames bacterial mutation assay in Salmonella typhimurium and Escherichia coli, mouse lymphoma assay, chromosomal aberration assays in human lymphocytes, micronucleus test in mice, Vitotox test, and in vitro Unscheduled DNA Synthesis (UDS) studies. Prucalopride tested positive in the Ames bacterial mutation assay in the S. typhimurium TA100 strain, at concentrations ≥500 mcg/plate, both in the presence and absence of metabolic activation. Prucalopride was negative in other assays evaluating mutagenesis, including in vitro mammalian-based assays (e.g., mouse lymphoma assay, chromosomal aberration assays in human lymphocytes) and in vivo tests (e.g., micronucleus test in mice, a UDS test, a gene mutation assay in Big Blue transgenic rats, and a 32P-postlabeling study in target tissues identified in the carcinogenicity studies, including liver, mammary gland, thyroid, and adrenal tissues). Based on the weight of evidence, prucalopride does not appear to have a mutagenic potential.

Impairment of Fertility

In an oral fertility and early embryonic development study performed in rats at doses of 5, 20, and 80 mg/kg/day, there was no evidence of adverse effects on fertility at doses up to 20 mg/kg. At the highest dose of 80 mg/kg (about 390 times the recommended human dose of 2 mg/day, based on body surface area), an increase in pre-coital interval, pseudo-pregnancies, and pre-implantation loss were seen. These effects could be secondary to increased prolactin secretion with prucalopride treatment.