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%. 

BRIEF SUMMARY

PRUCALOPRIDE --(Dec 2018)

Indn-           To treat chronic idiopathic constipation

Comp-      Tablets: 1 mg, 2 mg of prucalopride  •Take with or without food. • Recommended dosage by patient population: Population with CIC        Recommended Oral Dose Regimen Adults 2 mg once daily. 

ADR-   Most common adverse reactions (=2%) are headache, abdominal pain, nausea, diarrhea, abdominal distension, dizziness, vomiting, flatulence, and fatigue. 

CI-    ­ • Hypersensitivity     • 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. 

 WARNINGS-­ Suicidal Ideation and Behavior: Monitor patients for persistent worsening of depression and emergence of suicidal thoughts and behavior.

Pat Infm-

Suicidal Ideation and Behavior: Inform patients, their caregivers, and family members that suicidal ideation and behavior have been reported in patients treated the drug

Advise them to be aware of any unusual changes in mood or behavior, persistent worsening of symptoms of depression, or the emergence of suicidal thoughts or behavior.

==============================================================

U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  56

 ADVERSE REACTIONS

­ Most common adverse reactions (=2%) are headache, abdominal pain, nausea, diarrhea, abdominal distension, dizziness, vomiting, flatulence, and fatigue. 

CONTRAINDICATIONS

­ • Hypersensitivity to MOTEGRITY

• 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. 

 WARNINGS AND PRECAUTIONS

­ Suicidal Ideation and Behavior: Monitor patients for persistent worsening of depression and emergence of suicidal thoughts and behavior.

Instruct patients to discontinue MOTEGRITY immediately and contact their healthcare provider if their depression is persistently worse, or they experience emerging suicidal thoughts or behaviors. 

 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 have been reported in patients treated with MOTEGRITY.

Advise them to be aware of any unusual changes in mood or behavior, persistent worsening of symptoms of depression, or the emergence of suicidal thoughts or behavior.

Instruct patients, caregivers, and family members that if any of these symptoms occur, they should discontinue MOTEGRITY immediately and contact their healthcare provider 

Storage

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

Manufactured for: Shire US Inc. 300 Shire Way Lexington, MA 02421 For more information go to www.motegrity.com or call 1-800-828-2088

Motegrity is a trademark or registered trademark of Shire LLC, a wholly-owned, indirect subsidiary of Shire plc.

Shire and the Shire Logo are trademarks or registered trademarks of Shire Pharmaceutical Holdings Ireland Limited or its affiliates. Copyright © 2018 Shire LLC.

 CLINICAL PHARMACOLOGY

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. 

2. Pharmacodynamics

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

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 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 AUC0-24h of 109 ng·h/mL.

Absorption

Following a single oral dose of 2 mg prucalopride in healthy subjects, peak plasma concentrations are observed within 2 to 3 hours after administration. The absolute oral bioavailability is >90%.

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)].

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 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.

Excretion

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 (Odesmethyl 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.

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 

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 

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%.

 USE IN SPECIFIC POPULATIONS

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.

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.

2. Lactation Risk Summary

Prucalopride is present in breast milk . 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.

3. Pediatric Use

The safety and effectiveness of MOTEGRITY have not been established in pediatric patients.

4.Geriatric Use

Of the 2484 patients treated with MOTEGRITY 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 

No overall differences in safety and effectiveness were observed between elderly and younger patients.

The effect of age on the pharmacokinetics of prucalopride appeared to be related to decreased renal function 

Adjust the dosage in elderly patients based on renal function 

5. 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).

MOTEGRITY 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) 

Avoid MOTEGRITY in patients with end-stage renal disease requiring dialysis [see Clinical Pharmacology 

 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 MOTEGRITY 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.