PRUCALOPRIDE tablet, film coated

PRUCALOPRIDE by

Drug Labeling and Warnings

PRUCALOPRIDE by is a Prescription medication manufactured, distributed, or labeled by SKG Pharma Inc., Ritsa Pharma Private Limited. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • 1 INDICATIONS AND USAGE

    Prucalopride tablets are indicated for the treatment of chronic idiopathic constipation (CIC) in adults.

  • 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 CICRecommended Oral Dose Regimen
    Adults2 mg once daily
    Patients with severe renal impairment (creatinine clearance (CrCL) less than 30 mL/min) [see Use in Specific Populations (8.5 and 8.6)].1 mg once daily

  • 3 DOSAGE FORMS AND STRENGTHS

    Prucalopride Tablets:

    • 1 mg prucalopride: White to off-white, round, biconvex film-coated tablets debossed with “P1” on one side and plain on other side.
    • 2 mg prucalopride: Yellow, round, biconvex film-coated tablets debossed with “P2” on one side and plain on the other side.
  • 4 CONTRAINDICATIONS

    Prucalopride is 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.
  • 5 WARNINGS AND PRECAUTIONS

    5.1 Suicidal Ideation and Behavior

    In clinical trials, suicides, suicide attempts, and suicidal ideation have been reported. Postmarketing cases of suicidal ideation and behavior as well as self-injurious ideation and new onset or worsening of depression have been reported within the first few weeks of starting prucalopride [see Adverse Reactions (6.1, 6.2)].

    A causal association between treatment with prucalopride and an increased risk of suicidal ideation and behavior has not been established.

    Monitor all patients treated with prucalopride for new onset or worsening of depression or the emergence of suicidal thoughts and behaviors. Counsel patients, their caregivers, and family members of patients to be aware of any unusual changes in mood or behavior and alert the healthcare provider. Instruct patients to discontinue prucalopride immediately and contact their healthcare provider if they experience any of these symptoms.

  • 6 ADVERSE REACTIONS

    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 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 years 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 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
  • * Reported in ≥ 2% of patients receiving prucalopride and a rate higher than patients receiving placebo.
  • † Includes 93 patients who started on prucalopride 1 mg and increased to prucalopride 2 mg.
  • ‡ Includes abdominal pain, upper abdominal pain, lower abdominal pain, abdominal tenderness, abdominal discomfort, and epigastric discomfort.
    		•
     Adverse Reaction Prucalopride
    2 mg Once Daily
    N = 1,251†
    %    		 Placebo
    N = 1,279
    %
     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

    Less Common Adverse Reactions

    Less common adverse reactions occurring in < 2% of patients receiving prucalopride 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 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 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 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, 1% placebo), headache (1% prucalopride, 1% placebo), diarrhea (1% prucalopride, < 1% placebo), or abdominal pain (1% prucalopride, 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 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 for CIC is 2 mg once daily). The total exposure in the double-blind trials was 565 patient-years in the prucalopride 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 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 1,000 patient-years for MACE for prucalopride was compared with the IR for placebo.

    In the double-blind trials, the IR for MACE was 3.5 (2 patients out of 3,366; 1 patient on 2 mg and 1 patient on 4 mg) in the prucalopride group and 5.2 (2 patients out of 2,019) in the placebo group. When combining the double-blind and open-label trials, the IR for MACE was 3.3 (9 patients out of 4,472, doses ranging between 0.5 mg to 4 mg) for prucalopride.

    Suicidal Ideation and Behavior

    In the double-blind trials, one patient reported a suicide attempt 7 days after the end of treatment with prucalopride 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 prucalopride 2 mg or 4 mg; both discontinued prucalopride for at least one month prior to the event.

    Observational Cardiovascular Cohort Study

    The overall cardiovascular safety of prucalopride was assessed using European healthcare databases in a population-based, retrospective, observational, cohort study of adults with constipation. New users of prucalopride (N = 5,715) 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.

    6.2 Postmarketing Experience

    The following adverse reactions have been identified during post-approval use of prucalopride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

    Hypersensitivity reactions: dyspnea, rash, pruritus, urticaria, and facial edema [see Contraindications (4)].

    Psychiatric disorders: Suicide, suicide attempts, suicidal ideation, self-injurious ideation, depression, anxiety, insomnia, nightmares, and visual hallucinations [see Warnings and Precautions (5.1)].

  • 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.

    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 age on the pharmacokinetics of prucalopride appeared to be related to decreased renal function [see Clinical Pharmacology (12.3)]. Adjust the dosage in elderly patients based on renal function [see Dosage and Administration (2), Use in Specific Populations (8.6)].

    8.6 Renal Impairment

    No dosage adjustment is required for patients with mild and moderate renal impairment (creatinine clearance at least 30 mL/min, as determined from a 24-hour urine collection in the clinical trial).

    Prucalopride is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. A decreased dosage is recommended in patients with severe renal impairment (creatinine clearance less than 30 mL/min, as determined from a 24-hour urine collection in the clinical trial) [see Dosage and Administration (2)].

    Avoid prucalopride in patients with end-stage renal disease requiring dialysis [see Clinical Pharmacology (12.3)].

  • 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 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.

  • 11 DESCRIPTION

    Prucalopride tablets for oral use contain prucalopride succinate, a dihydrobenzofurancarboxamide that is a serotonin type 4 (5-HT4) 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 C18H26ClN3O3.C4H6O4 and the molecular weight is 485.96 g/mol. The structural formula is:

    structure

    Prucalopride succinate is a white to almost white powder. It is sparingly soluble in dimethyl sulphoxide, methanol and soluble in water.

    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: anhydrous lactose, colloidal silicon dioxide, magnesium stearate, and microcrystalline cellulose. The coating for the 1 mg tablet contains hypromellose, lactose monohydrate, polyethylene glycol, titanium dioxide, 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: anhydrous lactose, colloidal silicon dioxide, magnesium stearate, and microcrystalline cellulose. The coating for the 2 mg tablet contains hypromellose, lactose monohydrate, polyethylene glycol, titanium dioxide, triacetin, red iron oxide, and yellow iron oxide.

  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    Prucalopride, a selective serotonin type 4 (5-HT4) 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-HT2A, 5-HT2B, 5-HT3, motilin or CCK-A receptors in vitro at concentrations exceeding 5-HT4 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.

    12.2 Pharmacodynamics

    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.

    12.3 Pharmacokinetics

    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 AUC0-24h 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 (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.

    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 (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 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 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

    Clinical Studies

    Effect of Prucalopride on Other Drugs

    Erythromycin

    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.

    Other Drugs

    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

    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.

    Other Drugs

    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.

  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, 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 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 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.

    13.2 Animal Toxicology and/or Pharmacology

    In safety pharmacology studies, no relevant effects were observed in any of the cardiovascular studies at concentrations at least 50 times the human therapeutic Cmax. Prucalopride had no effect on potassium current in hERG-transfected HEK cells at concentrations up to 1 micromolar (50 times the human therapeutic Cmax). At concentrations ≥ 3 micromolar, concentration-dependent inhibition of the current was observed (IC50 = 22 micromolar; 1,100 times the human therapeutic Cmax). In studies in pigs, minor and transient increases in heart rate and blood pressure were noted upon first exposure to prucalopride, at plasma levels at least 10 times the human therapeutic Cmax.

    In repeated-dose toxicology studies in male rats, increases in heart weight (up to 9%) were observed at doses of 20 mg/kg/day or higher (at least 75 times the human therapeutic AUC). Cardiac histology revealed an increase in focal infiltration of chronic inflammatory cells in the heart at a dose of 80 mg/kg/day (at least 785 times the human therapeutic AUC). In dogs, no changes in heart rate, blood pressure, electrocardiogram parameters, heart weight, or cardiac histology were observed at any dose tested (the highest dose of 30 mg/kg/day was 572 times the human therapeutic AUC).

    In vitro studies demonstrated no effect of prucalopride on either contractile responses in human, canine, and porcine coronary arteries at concentrations up to 10 micromolar (500 times the human clinical Cmax) or on platelet aggregation at concentrations up to 200 nanomolar (10 times the human clinical Cmax).

  • 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 NumberDuration
    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)
    StudyPrucalopride 1 mg or 2 mg Once DailyPlaceboTreatment Difference
    (95% CI)    		p value
    Nn (%)Nn (%)
    p-value based on a Cochran-Mantel-Haenszel test
    N = number of patients per treatment group
    n = number of responders
    Study 124983 (33)25226 (10)23
    (16, 30)    		p < 0.001
    Study 217767 (38)18132 (18)20
    (11, 29)    		p < 0.001
    Study 323646 (19)24023 (10)10
    (4, 16)    		p = 0.002
    Study 419055 (29)19325 (13)16
    (8, 24)    		p < 0.001
    Study 521450 (24)21225 (12)12
    (4, 19)    		p < 0.001
    Study 617143 (25)16934 (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 at least 3 of the last 4 weeks of the treatment period. The differences in response rates between prucalopride 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)
    StudyPrucalopride 1 mg or 2 mg Once DailyPlaceboTreatment Difference
    (95% CI)
    Nn (%)Nn (%)
    CSBM = complete spontaneous bowel movement
    N = number of patients per treatment group
    n = number of responders
    Study 124965 (26)25222 (9)17
    (11, 24)
    Study 217757 (32)18125 (14)18
    (10, 27)
    Study 323630 (13)24013 (5)8
    (2, 12)
    Study 419037 (19)19315 (8)11
    (5, 18)
    Study 521434 (16)21211 (5)11
    (5, 16)
    Study 617129 (17)16922 (13)4
    (-4, 12)

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    Prucalopride tablets containing 1 mg prucalopride are white to off-white, round, biconvex film-coated tablets debossed with “P1” on one side and plain on other side. They are supplied as:

    • NDC: 83085-005-30: HDPE bottle of 30 tablets, with child-resistant closure.

    Prucalopride tablets containing 2 mg prucalopride are yellow, round, biconvex film-coated tablets debossed with “P2” on one side and plain on other side. They are supplied as:

    • NDC: 83085-006-30: HDPE bottle of 30 tablets, with child-resistant closure.

    Store prucalopride tablets at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].


    Store prucalopride tablets in the original container to protect from moisture.

  • 17 PATIENT COUNSELING INFORMATION

    Advise the patient to read the FDA-approved patient labeling (Patient Information)

    Suicidal Ideation and Behavior: Inform patients, their caregivers, and family members that suicidal ideation and behavior, self-injurious ideation as well as new onset or worsening depression have been reported in patients treated with prucalopride tablets. Advise them to be aware of any unusual changes in mood or behavior, new onset or worsening of depression, or the emergence of suicidal thoughts or behavior. Instruct patients, caregivers, and family members to discontinue prucalopride tablets immediately and contact their healthcare provider if any of these symptoms occur [see Warnings and Precautions (5.1)].

    Storage

    Advise patients to keep prucalopride tablets in the original container to protect from moisture.

  • SPL UNCLASSIFIED SECTION

    Distributed by:
    SKG Pharma Inc.
    South Plainfield
    NJ 07080-2434 USA
    MADE IN INDIA
    For more information call 1-866-495-2621.
    Revised: 03/2024

  • PATIENT PACKAGE INSERT

    This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: March 2024

    PATIENT INFORMATION

    Prucalopride

    (proo-KAL-oh-pride)

    tablets, for oral use

    What are prucalopride tablets?
    Prucalopride tablets are a prescription medicine used in adults to treat a type of constipation called chronic idiopathic constipation (CIC). Idiopathic means the cause of the constipation is unknown.
    It is not known if prucalopride tablets are safe and effective in children.
    Do not take prucalopride tablets if you:
    • are allergic to prucalopride tablets. Allergic reaction symptoms may include trouble breathing, rash, itching and swelling of your face, lips, tongue or throat.
    • have a tear in your stomach or intestinal wall (bowel perforation), a bowel blockage (intestinal obstruction) or serious conditions of the intestinal wall such as Crohn's disease or ulcerative colitis.
    Before taking prucalopride tablets, tell your healthcare provider about all of your medical conditions, including if you:
    • have or have had depression, suicidal thoughts or actions, or mood problems.
    • have kidney problems. Your healthcare provider may give you a lower dose of prucalopride tablets.
    • are pregnant or plan to become pregnant. It is not known if prucalopride tablets will harm your unborn baby.
    • are breastfeeding or plan to breastfeed. Prucalopride can pass into your breastmilk. Talk with your healthcare provider about the best way to feed your baby if you take prucalopride tablets.
    Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
    How should I take prucalopride tablets?
    • Take 1 prucalopride tablet each day or as directed by your healthcare provider.
    • Take prucalopride tablets exactly as your healthcare provider tells you to take it.
    • Take prucalopride tablets with or without food.

    What are the possible side effects of prucalopride tablets?
    Prucalopride tablets may cause serious side effects, including:

    unusual changes in mood or behavior, thoughts of hurting yourself, trying to hurt yourself, or suicide. Stop taking prucalopride tablets right away and tell your healthcare provider immediately if your depression gets worse, you feel sad, hopeless, begin to have thoughts of suicide, thoughts of hurting yourself or you have tried to hurt yourself or if you develop new depression.
    The most common side effects of prucalopride tablets include:
    • headache
    • stomach area (abdominal) pain or bloating
    • nausea
    • diarrhea
    • dizziness
    • vomiting
    • gas
    • fatigue
    These are not all the possible side effects of prucalopride tablets.
    Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
    How should I store prucalopride tablets?
    • Store prucalopride tablets at room temperature between 68°F to 77°F (20°C to 25°C).
    • Store prucalopride tablets in the original container to protect from moisture.
    Keep prucalopride tablets and all medicines out of the reach of children.
    General information about the safe and effective use of prucalopride tablets.
    Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use prucalopride tablets for a condition for which it was not prescribed. Do not give prucalopride tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about prucalopride tablets that is written for health professionals.
    What are the ingredients in prucalopride tablets?
    Active ingredient: prucalopride
    Inactive ingredients: anhydrous lactose, colloidal silicon dioxide, magnesium stearate and microcrystalline cellulose. The coating contains hypromellose, lactose monohydrate, polyethylene glycol, titanium dioxide and triacetin. The 2 mg tablet also contains red iron oxide, and yellow iron oxide.

    Distributed by:
    SKG Pharma Inc.
    South Plainfield
    NJ 07080-2434 USA
    MADE IN INDIA

    For more information, call SKG Pharma Inc. at 1-866-495-2621.

  • PRINCIPAL DISPLAY PANEL - 1 mg Tablet Bottle Label

    NDC: 83085-005-30
    Prucalopride Tablets
    1 mg

    Usual Dose: One tablet once daily.
    Rx only
    30 Tablets

    PRINCIPAL DISPLAY PANEL - 1 mg Tablet Bottle Label

  • PRINCIPAL DISPLAY PANEL - 2 mg Tablet Bottle Label

    NDC: 83085-006-30
    Prucalopride Tablets
    2 mg

    Usual Dose: One tablet once daily.
    Rx only
    30 Tablets

    PRINCIPAL DISPLAY PANEL - 2 mg Tablet Bottle Label

  • INGREDIENTS AND APPEARANCE
    PRUCALOPRIDE 
    prucalopride tablet, film coated
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 83085-005
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    PRUCALOPRIDE SUCCINATE (UNII: 4V2G75E1CK) (PRUCALOPRIDE - UNII:0A09IUW5TP) PRUCALOPRIDE1 mg
    Inactive Ingredients
    Ingredient NameStrength
    ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)  
    MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    HYPROMELLOSE 2910 (6 MPA.S) (UNII: 0WZ8WG20P6)  
    TRIACETIN (UNII: XHX3C3X673)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)  
    LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
    Product Characteristics
    ColorWHITE (white to off-white) Scoreno score
    ShapeROUND (biconvex) Size7mm
    FlavorImprint Code P1
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 83085-005-3030 in 1 BOTTLE; Type 0: Not a Combination Product06/24/2025
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA21881206/24/2025
    PRUCALOPRIDE 
    prucalopride tablet, film coated
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 83085-006
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    PRUCALOPRIDE SUCCINATE (UNII: 4V2G75E1CK) (PRUCALOPRIDE - UNII:0A09IUW5TP) PRUCALOPRIDE2 mg
    Inactive Ingredients
    Ingredient NameStrength
    ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)  
    MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    HYPROMELLOSE 2910 (6 MPA.S) (UNII: 0WZ8WG20P6)  
    TRIACETIN (UNII: XHX3C3X673)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)  
    FERRIC OXIDE RED (UNII: 1K09F3G675)  
    FERRIC OXIDE YELLOW (UNII: EX438O2MRT)  
    LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
    Product Characteristics
    ColoryellowScoreno score
    ShapeROUND (biconvex) Size9mm
    FlavorImprint Code P2
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 83085-006-3030 in 1 BOTTLE; Type 0: Not a Combination Product06/24/2025
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA21881206/24/2025
    Labeler - SKG Pharma Inc. (096442797)
    Registrant - SKG Pharma Inc. (096442797)
    Establishment
    NameAddressID/FEIBusiness Operations
    Ritsa Pharma Private Limited854240874manufacture(83085-005, 83085-006)
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