Prucalopride is an oral selective serotonin (5HT-4) receptor agonist with enterokinetic properties. Prucalopride is approved for the treatment of chronic idiopathic constipation (CIC) in adults. The efficacy of once-daily treatment with prucalopride was evaluated in 6 double-blind, placebo-controlled, randomized, multicenter clinical studies lasting 12 weeks (5 studies) or 24 weeks (1 study). During studies, significantly more patients taking prucalopride (2 mg/day or less) achieved the primary efficacy endpoint of an average of 3 or more spontaneous complete bowel movements per week than with placebo (19% to 38% prucalopride vs. 10% to 20% placebo) across 5 of 6 trials. A rapid response was seen with prucalopride as early as week 1, with improvements maintained throughout 12 weeks of treatment. While a causal association has not been established, monitor treated patients for depressed mood or suicidal thoughts or behaviors during use as these have been reported during clinical studies. In clinical studies, prucalopride did not demonstrate an increased risk of potential major adverse cardiovascular events (MACE) compared to placebo. Prucalopride was FDA-approved in December 2018.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-The tablets can be administered with or without food.
Hypersensitivity reactions including dyspnea, rash (unspecified), pruritus, urticaria, and facial edema have been observed with prucalopride.
In clinical trials with prucalopride, suicides, suicide attempts, and suicidal ideation have been reported. A casual association between prucalopride and an increased risk of suicidal ideation and behavior has not been established. In the double-blind trials with prucalopride, 1 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, 2 patients reported a suicide attempt and another patient reported suicidal ideation. Completed suicide was reported in 2 patients, previously treated with prucalopride 2 mg or 4 mg; both discontinued prucalopride for at least 1 month prior to the event. In addition, 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. Anxiety, insomnia, nightmares, and visual hallucinations have also been reported during postmarketing experience. Patients and caregivers should be informed of the increased risk of suicidal thoughts and behaviors and should be advised to immediately report the emergence of new or worsening of depression, suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior.
Abdominal pain, nausea, and diarrhea were the most common gastrointestinal (GI) adverse reactions reported with prucalopride in clinical trials. Abdominal pain was reported in 16% of patients receiving prucalopride and 11% of patients receiving placebo, and 1% of patients discontinued the drug due to abdominal pain. Nausea was reported in 14% of patients receiving prucalopride and 7% of patients receiving placebo; 2% of patients discontinued the drug due to nausea. Diarrhea was reported in 13% of patients receiving prucalopride and 5% of patients receiving placebo, and 1% of patients discontinued the drug due to 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. GI adverse reactions occurring in at least 2% of patients with chronic idiopathic constipation (CIC) receiving prucalopride 2 mg once daily at an incidence greater than in the placebo group in the 6 double-blind placebo-controlled trials were: abdominal distension (5% vs. 4% placebo), vomiting (3% vs. 2% placebo), and flatulence (3% vs. 2% placebo). Less common (less than 2%) GI adverse reactions included: abnormal GI sounds and decreased appetite (anorexia).
Headache was a common side effect reported in 19% of patients with chronic idiopathic constipation (CIC) receiving prucalopride 2 mg once daily and 9% of patients receiving placebo. Of the patients who reported headache, 66% (157 out of 237) treated with prucalopride 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; however, 1% of patients discontinued prucalopride due to headache. Migraine was reported in less than 2% of patients receiving prucalopride. Adverse reactions occurring in at least 2% of patients receiving prucalopride at an incidence greater than with placebo in the 6 double-blind placebo-controlled trials were: dizziness (4% vs. 2% placebo) and fatigue (2% vs. 1% placebo).
Pollakiuria (increased urinary frequency) was reported in less than 2% of patients receiving prucalopride 2 mg once daily during clinical trials for chronic idiopathic constipation (CIC).
Prucalopride is contraindicated in any patient with a known hypersensitivity to prucalopride or any of its excipients. Hypersensitivity reactions including dyspnea, rash, pruritis, urticara, and facial edema have been observed.
Avoid prucalopride in patients with end-stage renal disease (renal failure) requiring dialysis. Use caution in patients with severe renal impairment (CrCL less than 30 mL/minute) not requiring dialysis since renal excretion is the main route of elimination of prucalopride; dosages should be adjusted. Geriatric patients may experience higher exposure to prucalopride than younger patients due to decreased renal function.
Prucalopride is contraindicated in patients with a history of serious GI disease such as GI perforation or GI obstruction due to structural or functional disorder of the gut wall, obstructive ileus, or active severe inflammatory conditions of the intestinal tract, such as severe inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis), severe diverticulitis, toxic megacolon, or megarectum. Use with caution in patients with less severe GI disease, such as symptomatic uncomplicated diverticulitis, as safety and efficacy have not been established.
All patients beginning treatment with prucalopride should be closely monitored for emerging or worsening depression or suicidal thoughts/behavior or suicidal ideation. In clinical trials with prucalopride, suicides, suicide attempts, and suicidal ideation have been reported. In addition, 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. A casual association between prucalopride and an increased risk of suicidal ideation and behavior has not been established. Patients and caregivers should be informed of the increased risk of suicidal thoughts and behaviors and should be advised to immediately report the emergence of new or worsening of depression, suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior.
The limited data from case reports with prucalopride use in human pregnancy are insufficient to identify any drug-associated risks of miscarriage, major birth defects, or adverse maternal or fetal outcomes. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to prucalopride during pregnancy. Healthcare providers can enroll patients or encourage patients to enroll themselves by calling 1-877-311-8972 or visiting mothertobaby.org/pregnancy-studies/. 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.
Prucalopride is excreted in human breast milk. There are no data available regarding the the effects of prucalopride on the breast-fed infant or the effects on milk production. In an open-label study in 8 healthy lactating women in the weaning stage, plasma and milk samples were collected at pre-dose (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. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for prucalopride and any potential adverse effects on the breast-fed infant from the drug or the underlying maternal condition.
The safety and effectiveness of prucalopride in neonates, infants, children, and adolescents less than 18 years of age have not been established.
For the treatment of chronic idiopathic constipation (CIC):
Oral dosage:
Adults: 2 mg PO once daily.
Maximum Dosage Limits:
-Adults
2 mg/day PO.
-Geriatric
2 mg/day PO.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
No dosage adjustments are needed.
Patients with Renal Impairment Dosing
CrCl 30 mL/minute or more: No dosage adjustments are needed.
CrCl less than 30 mL/minute: Reduce dosage to 1 mg PO once daily. Avoid in patients with end-stage renal disease requiring dialysis.
*non-FDA-approved indication
Fosfomycin: (Moderate) Prucalopride may decrease the systemic absorption of fosfomycin due to the prokinetic action of prucalopride. This may result in lower fosfomycin serum concentrations and urinary excretion. Monitor for evidence of clinical effectiveness of fosfomycin. Since fosfomycin is given as a single dose, separating times of administration may limit the interaction.
Serotonin (5HT4) receptors are involved in initiating peristalsis. 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 did not have 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.
Prucalopride is administered orally. Prucalopride is approximately 30% protein-bound. Prucalopride exhibits dose-proportional pharmacokinetics within and beyond the therapeutic range (tested up to 20 mg, 10 times the maximum approved recommended human dose). Prucalopride has a steady-state volume of distribution (Vss) of 567 liters after intravenous administration. During prolonged administration, prucalopride displays time-independent kinetics. The plasma clearance of prucalopride averages 317 mL/minute. Prucalopride is a CYP3A4 substrate in vitro; however, prucalopride is primarily renally excreted and only 35% of the drug is removed via non-renal elimination. 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 the 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. The terminal half-life is approximately 1 day.
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: None
Prucalopride is a CYP3A4 substrate in vitro; however, the drug is primarily renally excreted, and clinical drug interaction studies have not indicated a potential for strong CYP3A4 inhibitors (e.g., ketoconazole) to cause clinically relevant drug interactions. In vitro data indicate low potential for prucalopride to inhibit CYP enzymes (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) and transporters (P-glycoprotein, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, MATE2-K, BSEP, and MRP2 transporters) or induce CYP enzymes (1A2, 2B6, and 3A4) at the clinically relevant concentrations.
Co-administration of oral erythromycin (500 mg PO 4 times daily) with prucalopride increased the erythromycin mean Cmax by 40% and mean exposure (AUC) by 28%. The mechanism for this pharmacokinetic change is not clear. The increased exposure to erythromycin is unlikely to result in a clinically significant drug interaction.
-Route-Specific Pharmacokinetics
Oral Route
Following a single oral dose of prucalopride 2 mg in healthy subjects, peak plasma concentrations are observed within 2 to 3 hours after administration. The absolute oral bioavailability is greater than 90%. Concomitant intake with a high-fat meal (1000 kcal total, 500 kcal from fat) does not influence the oral bioavailability of prucalopride. Following administration of prucalopride 2 mg PO once daily, steady-state is attained within 3 to 4 days, and steady-state plasma concentrations fluctuate between trough and peak values of 2.5 and 7 ng/mL, respectively, with mean plasma AUC of 109 hour x ng/mL. The accumulation ratio after once daily oral dosing ranged from 1.9 to 2.3.
-Special Populations
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.
Renal Impairment
Prucalopride is primarily eliminated by the kidney. Renal elimination of prucalopride involves both passive filtration and active secretion and dosages should be adjusted based on creatinine clearance (CrCl). After a single 2 mg oral dose, the exposure (mean AUC) of prucalopride increased 1.23-fold in subjects with mild renal impairment (CrCl 60 to 89 mL/minute), 1.4-fold in subjects with moderate renal impairment (CrCl 30 to 59 mL/minute), and 2.38-fold in subjects with severe renal impairment (CrCl 15 to 29 mL/minute), 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; avoidance of the drug in these populations is recommended.
Pediatrics
Pediatric pharmacokinetic data are not available.
Geriatric
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.
Gender Differences
Based on a pharmacokinetic analysis, gender does not have a clinically significant effect on the pharmacokinetics of prucalopride.
Ethnic Differences
Based on a pharmacokinetic analysis, ethnicity does not have a clinically significant effect on the pharmacokinetics of prucalopride.
Obesity
Based on a pharmacokinetic analysis, weight does not have a clinically significant effect on the pharmacokinetics of prucalopride.