Prucalopride

A03A - Drugs for functional bowel disorders ATC A03AE04 Small molecule approved 2009 Oral Natural product

JFDA label: Resolor 1mg tab

Mechanism of Action

Agonist of 5-hydroxytryptamine receptor 4 — Serotonin 4 (5-HT4) receptor agonist

Target	Action	Gene / class
5-hydroxytryptamine receptor 4 efficacy	AGONIST	HTR4

Indications

Approved

Chronic idiopathic constipation

Off-label

Chronic constipation in men
Opioid-induced constipation in patients with chronic pain (noncancer)

Contraindications

Source: Lexicomp

Hypersensitivity to prucalopride or any component of the formulation Absolute
intestinal perforation or obstruction due to structural or functional disorder of the gut wall, obstructive ileus, severe inflammatory conditions of the GI tract (eg, Crohn disease, ulcerative colitis, toxic megacolon/megarectum) Absolute
renal impairment requiring dialysis Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Nervous system disorders (4)

Very Common Headache

Common Dizziness · fatigue · malaise

Renal and urinary disorders (1)

Common Pollakiuria

Gastrointestinal disorders (10)

Very Common abdominal pain · diarrhea · Nausea

Common abnormal bowel sounds · anorexia · dyspepsia · Flatulence · gastroenteritis · upper abdominal pain · vomiting

Musculoskeletal and connective tissue disorders (1)

Common Muscle spasm

General disorders and administration site conditions (1)

Common Fever

Dosing

Source: Lexicomp

Chronic idiopathic constipation: Females or males (off-label population [Yiannakou 2015]): Oral: 2 mg once daily; Note: If no bowel movement within 3 to 4 days, consider adjunctive laxative therapy for acute treatment. Discontinue use if therapy is not effective within 4 weeks of initiation. Reassess for therapeutic benefit at regular intervals if prolonged therapy (>3 months) is needed.

Chronic idiopathic constipation: Females >65 years or males ≥65 years (off-label population [Yiannakou 2015]): Oral: Initial: 1 mg once daily; may increase to 2 mg once daily if necessary; Note: If no bowel movement within 3 to 4 days, consider adjunctive laxative therapy for acute treatment. Discontinue use if therapy is not effective within 4 weeks of initiation. Reassess for therapeutic benefit at regular intervals if prolonged therapy (>3 months) is needed.

GFR ≥30 mL/minute/1.73 m2: No dosage adjustment necessary GFR 2: 1 mg once daily Dialysis: Use is contraindicated

Mild or moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary. Severe impairment (Child-Pugh class C): Initial: 1 mg once daily; may increase to 2 mg once daily if needed and well tolerated.

Warnings & Precautions

Source: Lexicomp

CNS depression

May cause CNS depression (particularly during the first day of treatment), which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).

Diarrhea

If severe or persistent diarrhea occurs, discontinue therapy and advise patient to consult health care provider.

Ischemic colitis

May occur (rare); discontinue therapy if severe, persistent, and/or worsening abdominal symptoms, bloody diarrhea, or rectal bleeding develops and advise patient to consult health care provider. Disease-related concerns:

Cardiovascular disease

Use with caution in patients with a history of arrhythmias, ischemic cardiovascular disease, pre-excitation syndromes (eg, Wolff-Parkinson-White syndrome), or A-V nodal rhythm disorders. Slight increases in heart rate and shortened PR intervals have been observed; treatment-related effects on QRS duration or QTc interval were not observed. Palpitations have also been observed; monitoring of cardiovascular status is recommended. Instruct patients to report severe or persistent palpitations.

Concomitant disease

Use with caution in patients with severe and unstable concomitant disease (eg, cancer, AIDS, neurological or psychiatric, pulmonary, insulin-dependent diabetes mellitus or other endocrine disorders); has not been studied.

Hepatic impairment

Use with caution in patients with severe hepatic impairment (Child-Pugh class C); initial dose reduction is recommended.

Renal impairment

Use with caution in patients with renal impairment; prucalopride mainly undergoes renal elimination. Dose reduction is required in severe impairment; contraindicated in patients requiring dialysis. Special populations:

Elderly

Use with caution in the elderly (limited data); dose reductions may be necessary.

Males

Efficacy not established in males (clinical trials had an insufficient number of males to determine efficacy); however, a potential benefit has been observed in some studies (Yiannakou 2015). Dosage form specific issues:

Lactose

May contain lactose; do not use in patients with galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndromes.

Pregnancy & Lactation

Pregnancy

Adverse events have not been observed in animal reproduction studies. Spontaneous abortion has been observed in pregnant women during clinical trials, although a causal association with prucalopride has not been established. Use during pregnancy is not recommended. Women of childbearing potential should employ effective contraception during therapy. An additional method of contraception is recommended for patients experiencing severe diarrhea and receiving oral contraceptives due to the potential for decreased efficacy of the oral contraceptive; cases of unintended pregnancies have been reported with prucalopride.

Lactation

Avoid

Prucalopride is excreted in breast milk. Breast-feeding is not recommended by the manufacturer.

LactMed: monitor the infant.

Monitoring

Clinical pearl	Cardiovascular symptoms (eg, palpitations) particularly in patients with cardiovascular disease; frequency of bowel movements

Chemistry & Properties

Formula	C18H26ClN3O3
Molecular weight	367.88 g/mol
IUPAC name	4-amino-5-chloro-N-[1-(3-methoxypropyl)piperidin-4-yl]-2,3-dihydro-1-benzofuran-7-carboxamide
CAS	179474-81-8
PubChem CID	3052762
InChIKey	`ZPMNHBXQOOVQJL-UHFFFAOYSA-N`
logP	2.09 (XLogP 2.0)
Polar surface area	76.82 Å²
H-bond acceptors / donors	5 / 2
Drug-likeness (QED)	0.59
Lipinski violations	0

SMILES

COCCCN1CCC(NC(=O)c2cc(Cl)c(N)c3c2OCC3)CC1

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	Yes (logBB -0.1)

Enzyme interactions

Enzyme	Role	Detail
CYP2C19	Substrate	—
CYP2D6	Inhibitor	—
CYP3A4	Substrate	—

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)BCRP (Substrate)MATE1 (Substrate)MATE2 (Substrate)MDR1 (Substrate)OAT1 (Substrate)OAT3 (Substrate)OATP1B1 (Substrate)OATP1B3 (Substrate)OCT2 (Substrate)P-gp (Substrate)

Drug–drug interactions (97, DDInter)

Interacting drug	Severity	Management
Aclidinium	moderate
Atropine	moderate
Belladonna	moderate
Benzatropine	moderate
Biperiden	moderate
Clidinium	moderate
Cyclizine	moderate
Darifenacin	moderate
Dicyclomine	moderate
Dienogest	moderate
Dimenhydrinate	moderate
Diphenhydramine	moderate
Erdafitinib	moderate
Ethinylestradiol	moderate
Fesoterodine	moderate
Flavoxate	moderate
Gilteritinib	moderate
Glycopyrronium	moderate
Glycopyrronium (topical)	moderate
Hyoscyamine	moderate
Idelalisib	moderate
Ipratropium	moderate
Lasmiditan	moderate
Levonorgestrel	moderate
Lisdexamfetamine	moderate
Meclizine	moderate
Mepenzolate	moderate
Mestranol	moderate
Methscopolamine	moderate
Norethisterone	moderate
Norgestrel	moderate
Oxybutynin	moderate
Procyclidine	moderate
Propantheline	moderate
Revefenacin	moderate
Scopolamine	moderate
Solifenacin	moderate
Tiotropium	moderate
Tolterodine	moderate
Trihexyphenidyl	moderate

Showing 40 of 97.

Registered Products (6)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Motility	Tablet 1 mg	30 tab	Misk Pharma Pharmaceutical Industries/Jordan	16.810
Motility	Tablet 1 mg	30 tab	Misk Pharma Pharmaceutical Industries/Jordan	16.810
Resolor	Tablet 1 mg	28 tab	Arab Company for Medical & Agricultural Products	25.210
Motility	Tablet 2 mg	30 tab	Misk Pharma Pharmaceutical Industries/Jordan	27.580
Motility	Tablet 2 mg	30 tab	Misk Pharma Pharmaceutical Industries/Jordan	27.580
Resolor 2 mg F.C Tab	Film-Coated Tablet 2 mg	28 tab	Arab Company for Medical & Agricultural Products	41.440