Prucalopride 1 mg Tablet, Film Coated, 30-count — NDC 83085-005-30 (Billing 83085-0005-30)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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.

12.2Pharmacodynamics 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, prucalopride does not prolong the QT interval to any clinically relevant extent.

12.3Pharmacokinetics The pharmacokinetics of prucalopride has been evaluated in healthy subjects and is dose-proportional within and beyond the therapeutic range (tested up to 20 mg, 10 times the maximum approved recommended dose). Prucalopride administered once daily displays time-independent kinetics during prolonged treatment. With once daily administration of 2 mg prucalopride, pharmacokinetic steady-state is attained within 3 days to 4 days, and steady-state plasma concentrations fluctuate between trough and peak values of 2.5 ng/mL and 7 ng/mL, respectively, with mean plasma AUC 0-24h of 109 ng∙h/mL.

The accumulation ratio after once daily dosing ranged from 1.9 to 2.3. The terminal half-life is approximately 1 day. Pharmacokinetic parameters in patients with CIC are similar to those seen in healthy subjects.

Absorption Following a single oral dose of 2 mg prucalopride in healthy subjects, peak plasma concentrations are observed within 2 hours to 3 hours after administration. The absolute oral bioavailability is > 90%. Effect of Food Concomitant intake with a high-fat meal (1,000 kcal total, 500 kcal from fat) does not influence the oral bioavailability of prucalopride [see Dosage and Administration (2) ] .

Distribution Prucalopride has a steady-state volume of distribution (V ss ) 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. Metabolism Prucalopride is a substrate of CYP3A4, in vitro.

In an oral dose study with radio-labeled 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. Excretion Following oral administration of radio-labeled prucalopride in healthy subjects, 60% to 65% of the administered dose is excreted unchanged in urine and abo… [Excerpted — this section continues on DailyMed.]

12.1Mechanism 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.

12.3Pharmacokinetics The pharmacokinetics of prucalopride has been evaluated in healthy subjects and is dose-proportional within and beyond the therapeutic range (tested up to 20 mg, 10 times the maximum approved recommended dose). Prucalopride administered once daily displays time-independent kinetics during prolonged treatment. With once daily administration of 2 mg prucalopride, pharmacokinetic steady-state is attained within 3 days to 4 days, and steady-state plasma concentrations fluctuate between trough and peak values of 2.5 ng/mL and 7 ng/mL, respectively, with mean plasma AUC 0-24h of 109 ng∙h/mL.

The accumulation ratio after once daily dosing ranged from 1.9 to 2.3. The terminal half-life is approximately 1 day. Pharmacokinetic parameters in patients with CIC are similar to those seen in healthy subjects.

Absorption Following a single oral dose of 2 mg prucalopride in healthy subjects, peak plasma concentrations are observed within 2 hours to 3 hours after administration. The absolute oral bioavailability is > 90%. Effect of Food Concomitant intake with a high-fat meal (1,000 kcal total, 500 kcal from fat) does not influence the oral bioavailability of prucalopride [see Dosage and Administration (2) ] .

Distribution Prucalopride has a steady-state volume of distribution (V ss ) 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. Metabolism Prucalopride is a substrate of CYP3A4, in vitro.

In an oral dose study with radio-labeled 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. Excretion Following oral administration of radio-labeled 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 1,343 subjects indicated that there were no clinically significant differences in the pharmacokinetics of prucalopride based on age (17 years to 95 years), sex, race (89% white, 7% black, 4% other), or body weight (37 kg to 161 kg), after accounting for the effect of renal function. Geriatric Patients After once daily dosing of 1 mg, peak plasma concentrations (C max ) 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 AUC 0-inf of prucalopride increased 1.23-fold in subjects with mild renal impairment (creatinine clearance 60 mL/min to ≤ 89 mL/min), 1.4-fold in subjects with moderate renal impairment (creatinine clearance 30 mL/min to ≤ 59 mL/min), and 2.38-fold in subjects with severe renal impairment (creatinine clearance 15 mL/min to ≤ 29 mL/min), compared to subjects with normal renal function.

The pharmacokinetics of prucalopride in patien… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics 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, prucalopride does not prolong the QT interval to any clinically relevant extent.

14 CLINICAL STUDIES The efficacy of prucalopride for the treatment of CIC was evaluated in six double-blind, placebo-controlled, randomized, multicenter clinical trials in 2,484 adult patients (Studies 1 to 6; see Table 3). Studies 1 through 5 were 12-week treatment duration and Study 6 included 24 weeks of treatment. Patients less than 65 years were dosed with prucalopride 2 mg once daily.

In Studies 2 and 6, the geriatric patients started on prucalopride 1 mg once daily and, if necessary, the dose was increased to 2 mg after 2 weeks or 4 weeks of treatment in the event of insufficient response at 1 mg; of these patients 81% increased to 2 mg. Overall, the majority of patients were female (76%) and white (76%), and also included Asian (19%) and black (3%). The mean adult age was 47 years ± 16 years (range 17 years to 95 years) and the mean duration of constipation was 16 years ± 15 years with 28% of patients having chronic constipation for at least 20 years.

Table 3: Main Studies in the Prucalopride Clinical Program Study Number Duration Study 1 (PRU-CRC-3001, NCT01116206 ) 12 Weeks Study 2 (SPD555-302, NCT01147926 ) 12 Weeks Study 3 (PRU-INT-6, NCT00488137 ) 12 Weeks Study 4 (PRU-USA-11, NCT00483886 ) 12 Weeks Study 5 (PRU-USA-13, NCT00485940 ) 12 Weeks Study 6 (SPD-555-401, NCT01424228 ) 24 Weeks Eligible patients required a history of chronic constipation defined as having fewer than 3 spontaneous bowel movements (SBMs) per week that resulted in a feeling of complete evacuation (complete, spontaneous bowel movement [CSBM]) and 1 or more of the following symptoms for greater than 25% of bowel movements in the preceding 3 months, with symptoms onset more than 6 months prior to screening: Lumpy or hard stools Sensation of incomplete evacuation Straining at defecation Patients who never had SBMs were eligible.

In Study 1, eligibility also included sensation of ano-rectal obstruction or blockade or the need for digital manipulation in more than 25% of bowel movements. In all studies, patients were excluded if constipation was due to secondary causes or suspected to be drug-induced. Efficacy was assessed using information provided by patients in a daily diary.

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, 1,237 received prucalopride 1 or 2 mg and 1,247 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 Prucalopride 1 mg or 2 mg Once Daily Placebo Treatment Difference (95% CI) p value 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 (16, 30) p < 0.001 Study 2 177 67 (38) 181 32 (18) 20 (11, 29) p < 0.001 Study 3 236 46 (19) 240 23 (10) 10 (4, 16) p = 0.002 Study 4 190 55 (29) 193 25 (13) 16 (8, 24) p < 0.001 Study 5 214 50 (24) 212 25 (12) 12 (4, 19) p < 0.001 Study 6 171 43 (25) 169 34 (20) 5 (-4, 14) p = 0.341 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 prucalopride on day 1 ranged from 1.4 days to 4.7 days compared with 9.1 days to 20.6 days in the placebo group. The median time to first SBM after dosing on day 1 ranged from 0.1 days to 0.4 days in the prucalopride group compared with 1.0 days 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 a… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a 2-year carcinogenicity study in mice, prucalopride was given by daily oral gavage at doses of 10 mg/kg, 20 mg/kg, 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 times 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 mg/kg, 20 mg/kg, and 80 mg/kg in males and 5 mg/kg, 10 mg/kg, 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 times 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 mg/kg, 150 mg/kg, 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 (> 1,600 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 32 P-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 mg/kg/day, 20 mg/kg/day, 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.

13.2Animal Toxicology… [Excerpted — this section continues on DailyMed.]