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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
2 mg Once Daily
Includes 93 patients who started on MOTEGRITY 1 mg and increased to MOTEGRITY 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 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
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.
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.
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 MOTEGRITY 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 MOTEGRITY 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 MOTEGRITY.
Suicidal Ideation and Behavior
In the double-blind trials, one patient reported a suicide attempt 7 days after the end of treatment with MOTEGRITY 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 MOTEGRITY 2 mg or 4 mg; both discontinued MOTEGRITY for at least one month prior to the event.
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/.
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.
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.
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.
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.
At a dose 5 times the maximum approved recommended dose, MOTEGRITY does not prolong the QT interval to any clinically relevant extent.
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%.
Effect of Food
Concomitant intake with a high-fat meal (1000 kcal total, 500 kcal from fat) does not influence the oral bioavailability of prucalopride [see Dosage and Administration (2)].
Prucalopride has a steady-state volume of distribution (Vss) of 567 liters after intravenous administration. The plasma protein binding of prucalopride is approximately 30%.
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.
Prucalopride is a substrate of CYP3A4, in vitro. In an oral dose study with radiolabeled prucalopride in healthy subjects, prucalopride made up 92 to 94% of the total radioactivity in plasma. There are 7 different known minor metabolites, the most abundant metabolite (O-desmethyl prucalopride acid) represents 0 to 1.7% of the total plasma exposure.
Following oral administration of radiolabeled prucalopride in healthy subjects, 60 to 65% of the administered dose is excreted unchanged in urine and about 5% in feces. On average, 84.2% of administered radioactive dose was recovered in urine and 13.3% of the dose was recovered in feces. Seven metabolites were recovered in urine and feces, with the most abundant metabolite (O-desmethyl prucalopride acid) accounting for 3.2% and 3.1% of the dose in urine and feces, respectively. None of the other metabolites accounted for more than 3% of the dose. Renal elimination of prucalopride involves both passive filtration and active secretion.
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.
After once daily dosing of 1 mg, peak plasma concentrations (Cmax) and AUC of prucalopride in geriatric subjects were 26% to 28% higher than in younger adult subjects. The effect of age appeared to be related to decreased renal function in the elderly. Additionally, a population pharmacokinetic analysis indicated that age was not a significant covariate, after accounting for the effect of renal function [see Use in Specific Populations (8.5)].
Patients with Renal Impairment
After a single 2-mg oral dose, the mean AUC0-inf of prucalopride increased 1.23-fold in subjects with mild renal impairment (creatinine clearance 60 to ≤89 mL/min), 1.4-fold in subjects with moderate renal impairment (creatinine clearance 30 to ≤59 mL/min), and 2.38-fold in subjects with severe renal impairment (creatinine clearance 15 to ≤29 mL/min), compared to subjects with normal renal function. The pharmacokinetics of prucalopride in patients with end-stage renal disease or undergoing dialysis is not fully known [see Dosage and Administration (2), Use in Specific Populations (8.6)].
Patients with Hepatic Impairment
After a single oral dose of 2 mg, Cmax and AUC of prucalopride were on average 10 to 20% higher in subjects with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment than in subjects with normal hepatic function. This effect is not considered to be clinically significant.
Drug Interaction Studies
Effect of Prucalopride on Other Drugs
Co-administration of oral erythromycin (500 mg four times daily) with prucalopride increased the erythromycin mean Cmax by 40% and mean AUC0-24h by 28%. The mechanism for this interaction is not clear. The increased exposure to erythromycin is unlikely to be clinically significant.
No clinically significant differences in the pharmacokinetics (no more than a 10% change in AUC) of the following drugs were observed when co-administered with prucalopride: warfarin, digoxin, paroxetine, or oral contraceptives (ethinyl estradiol and norethisterone).
Effect of Other Drugs on Prucalopride
Ketoconazole (200 mg twice daily), a strong CYP3A inhibitor and inhibitor of P-gp and BCRP, increased the Cmax and AUC of prucalopride by approximately 40%. This effect is unlikely to be clinically significant.
No clinically significant differences in prucalopride pharmacokinetics (no more than a 10% change in AUC) were observed when co-administered with erythromycin, probenecid, cimetidine, or paroxetine.
In Vitro Studies
Based on in vitro study results, the potential for prucalopride to inhibit CYP enzymes (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) and transporters (P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, MATE2-K, BSEP, and MRP2 transporters) or induce CYP enzymes (1A2, 2B6, and 3A4) is low at the clinical concentration.
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.
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.
Primary Efficacy Results
For the primary efficacy endpoint, a responder was defined as a patient with an average of 3 or more CSBMs per week, over the 12-week treatment period. In the Intent-to-Treat [ITT] population in the 6 trials, 1237 received MOTEGRITY 1 or 2 mg and 1247 received placebo. Table 4 summarizes the results.
Table 4: Efficacy Responder Rates in Placebo-Controlled Studies of CIC: Proportion of Patients with an Average Weekly Frequency of ≥3 CSBMs per Week over 12 Weeks of Treatment (ITT Population)
|Study||MOTEGRITY 1 or 2 mg Once Daily||Placebo||Treatment Difference|
|N||n (%)||N||n (%)|
|p-value based on a Cochran-Mantel-Haenszel test|
N = number of patients per treatment group
n = number of responders
|Study 1||249||83 (33)||252||26 (10)||23|
|Study 2||177||67 (38)||181||32 (18)||20|
|Study 3||236||46 (19)||240||23 (10)||10|
|Study 4||190||55 (29)||193||25 (13)||16|
|Study 5||214||50 (24)||212||25 (12)||12|
|Study 6||171||43 (25)||169||34 (20)||5|
In all studies, improvement in the frequency of CSBMs/week was seen as early as week 1 and was maintained through week 12.
Across the six studies, the median time to first CSBM after dosing of MOTEGRITY on day 1 ranged from 1.4 to 4.7 days compared with 9.1 to 20.6 days in the placebo group. The median time to first SBM after dosing on day 1 ranged from 0.1 to 0.4 days in the MOTEGRITY group compared with 1.0 to 1.6 days in the placebo group.
Alternative Efficacy Endpoint
Using an alternative efficacy endpoint, a responder was defined as a patient who had at least 3 CSBMs and an increase of at least 1 CSBM from baseline in a given week for at least 9 weeks out of the 12-week treatment period and for at least 3 of the last 4 weeks of the treatment period. The differences in response rates between MOTEGRITY and placebo in the 6 studies are shown in Table 5.
Table 5: Efficacy Responder Rates in Placebo-Controlled Studies of CIC - Proportion of Patients with an Average of ≥3 CSBMs/week and an Increase of ≥1 CSBM per Week for at Least 9 out of the 12 Weeks, Including 3 of the Last 4 Weeks (ITT Population)
|Study||MOTEGRITY 1 or 2 mg Once Daily||Placebo||Treatment Difference|
|N||n (%)||N||n (%)|
|CSBM = complete spontaneous bowel movement|
N = number of patients per treatment group
n = number of responders
|Study 1||249||65 (26)||252||22 (9)||17|
|Study 2||177||57 (32)||181||25 (14)||18|
|Study 3||236||30 (13)||240||13 (5)||8|
|Study 4||190||37 (19)||193||15 (8)||11|
|Study 5||214||34 (16)||212||11 (5)||11|
|Study 6||171||29 (17)||169||22 (13)||4|
Advise patients to keep MOTEGRITY in the original container to protect from moisture.
Takeda Pharmaceuticals America, Inc.
Lexington, MA 02421
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