PRUCALOPRIDE
MOTEGRITY TABLETS
DESCRIPTION
MOTEGRITY (PRUCALOPRIDE) TABLETS FOR ORAL USE CONTAIN PRUCALOPRIDE SUCCINATE, A DIHYDROBENZOFURANCARBOXAMIDE THAT IS A SEROTONIN TYPE 4 (5-HT 4) RECEPTOR AGONIST . THE IUPAC NAME IS: 4-AMINO-5-CHLORO-N-[1-(3-METHOXYPROPYL)PIPERIDIN-4-YL]-2,3-DIHYDROBENZOFURAN-7-CARBOXAMIDE SUCCINATE.
EACH 1-MG FILM-COATED TABLET OF MOTEGRITY CONTAINS 1 MG OF PRUCALOPRIDE (EQUIVALENT TO 1.32 MG PRUCALOPRIDE SUCCINATE), AND THE FOLLOWING INACTIVE INGREDIENTS: COLLOIDAL SILICON DIOXIDE, LACTOSE MONOHYDRATE, MAGNESIUM STEARATE, AND MICROCRYSTALLINE CELLULOSE. THE COATING FOR THE 1-MG TABLET CONTAINS HYPROMELLOSE, LACTOSE MONOHYDRATE, POLYETHYLENE GLYCOL 3000, TITANIUM DIOXIDE, AND TRIACETIN.
EACH 2-MG FILM-COATED TABLET OF MOTEGRITY CONTAINS 2 MG OF PRUCALOPRIDE (EQUIVALENT TO 2.64 MG PRUCALOPRIDE SUCCINATE), AND THE FOLLOWING INACTIVE INGREDIENTS: COLLOIDAL SILICON DIOXIDE, LACTOSE MONOHYDRATE, MAGNESIUM STEARATE, AND MICROCRYSTALLINE CELLULOSE. THE COATING FOR THE 2-MG TABLET CONTAINS HYPROMELLOSE, LACTOSE MONOHYDRATE, POLYETHYLENE GLYCOL 3000, TITANIUM DIOXIDE, TRIACETIN, RED IRON OXIDE, YELLOW IRON OXIDE, AND FD&C BLUE #2.
PRUCALOPRIDE IS A DIHYDROBENZOFURANCARBOXAMIDE DERIVATIVE FROM THE BENZOFURANE FAMILY THAT SELECTIVELY STIMULATES 5-HT4 RECEPTORS AND THUS, IT PRESENTS ENTEROKINETIC PROPERTIES. THE HIGH SELECTIVITY OF PRUCALOPRIDE ALLOWED FURTHER DEVELOPMENT AS IT PREVENTED THE CARDIAC ADVERSE REACTIONS OBSERVED DUE TO NON-TARGET EFFECTS OF PRECEDENT THERAPIES. PRUCALOPRIDE WAS DEVELOPED BY SHIRE DEVELOPMENT LLC AND APPROVED FOR USE IN EUROPE IN 2009, IN CANADA ON DECEMBER 7, 2011 AND BY THE FDA ON DECEMBER 17, 2018.
PHARMACOLOGY
INDICATION
PRUCALOPRIDE IS INDICATED FOR THE TREATMENT OF CHRONIC IDIOPATHIC CONSTIPATION (CIC) IN ADULTS.
CIC IS ONE OF THE MOST COMMON CHRONIC FUNCTIONAL GASTROINTESTINAL DISORDERS WORLDWIDE. THE DIAGNOSIS OF THIS AGENT IS VERY HARD AND IT CAN BE CONFIRMED IF THE PATIENT EXPERIENCE AT LEAST TWO OF THE FOLLOWING:
-STRAINING DURING MORE THAN 25% OF THE BOWEL MOVEMENTS.
-LUMPY OR HARD STOOLS IN 25% OF THE BOWEL MOVEMENTS.
-SENSATION OF INCOMPLETE EVACUATION IN MORE THAN 25% OF ALL BOWEL MOVEMENTS.
-SENSATION OF ANORECTAL BLOCKAGE OR OBSTRUCTION IN MORE THAN 25% OF THE BOWEL MOVEMENTS.
-MANUAL MANEUVERS REQUIRED IN MORE THAN 25% OF THE BOWEL MOVEMENTS.
-FEWER THAN 3 BOWEL MOVEMENTS PER WEEK.
ASSOCIATED CONDITIONS
路 OPIOID INDUCED CONSTIPATION (OIC)
路 CHRONIC IDIOPATHIC CONSTIPATION (CIC)
路 REFRACTORY CHRONIC IDIOPATHIC CONSTIPATION
PHARMACODYNAMICS
IN ANIMAL STUDIES, PRUCALOPRIDE INDUCED A DOSE-DEPENDENT STIMULATION OF CONTRACTILE ACTIVITY IN THE PROXIMAL COLON AND INHIBITION OF THE CONTRACTILITY IN THE DISTAL COLON. AS WELL IT HAS BEEN SHOWN THAT PRUCALOPRIDE STIMULATES AND AMPLIFIES GIANT MIGRATORY CONTRACTION WHICH IS THE HIGH-AMPLITUDE TYPE OF CONTRACTION THAT INITIATES THE URGE TO DEFECATE. THUS, PRUCALOPRIDE NOT ONLY ACCELERATES THE COLONIC TRANSIT BUT ALSO ACCELERATES GASTRIC EMPTYING AND SMALL BOWEL TRANSIT.
IN SUPRATHERAPEUTIC CONCENTRATIONS, PRUCALOPRIDE CAN BE OBSERVED TO INTERACT WITH HERG POTASSIUM CHANNELS AND L-TYPE CALCIUM CHANNELS.
IN CLINICAL TRIALS, PRUCALOPRIDE SHOWED TO SIGNIFICANTLY INCREASE THE SPONTANEOUS BOWEL MOVEMENTS WITH A STANDARDIZED MEAN DIFFERENCE OF ABOUT 0.5 AFTER THE USE OF 1 MG WHEN COMPARED WITH THE PLACEBO GROUP. IN THIS STUDIES AS WELL, IT WAS OBSERVED A NUMERICAL IMPROVEMENT IN MEAN COLONIC TRANSIT TIME AND A SIGNIFICANT INCREASE IN SPONTANEOUS COMPLETE BOWEL MOVEMENT WITHOUT MARKED CHANGES IN THE ANORECTAL FUNCTION.
IN PHASE III CLINICAL TRIALS, 86% OF THE TESTED INDIVIDUALS OPTED TO CONTINUE WITH THE OPEN-LABEL STUDY AND BASED ON PATIENTS ASSESSMENTS, 67% OF THE PATIENTS INCREASE MORE THAN ONE POINT IMPROVEMENT IN THEIR SATISFACTION.
IN THE FINAL SET OF CLINICAL TRIALS FOR APPROVAL, THERE WAS A SIGNIFICANT INCREASE IN THE NUMBER OF PATIENTS THAT REACHED OVER 3 COMPLETE SPONTANEOUS BOWEL MOVEMENTS PER WEEK WHEN COMPARED WITH THE PLACEBO.
MECHANISM OF ACTION
PRUCALOPRIDE ACTS AS A SELECTIVE STIMULATOR OF THE 5-HT4 RECEPTORS WHILE HAVING NO INTERACTION WITH HERG CHANNEL OR 5-HT1 RECEPTORS WHICH REDUCES SIGNIFICANTLY THE CARDIOVASCULAR RISK FOUND IN OTHER SIMILAR DRUGS.
5-HT4 RECEPTORS CAN BE FOUND THROUGHOUT THE GASTROINTESTINAL TRACT PRIMARILY IN SMOOTH MUSCLE CELLS, ENTEROCHROMAFFIN CELLS, AND MYENTERIC PLEXUS. ITS ACTIVATION PRODUCES THE RELEASE OF ACETYLCHOLINE WHICH IS THE MAJOR EXCITATORY NEUROTRANSMITTER IN THE GI TRACT.
HENCE, PRUCALOPRIDE STIMULATES MOTILITY BY INTERACTING SPECIFICALLY WITH 5-HT4 RECEPTORS IN THE GI TRACT WHICH CAUSES A RELEASE OF ACETYLCHOLINE AND FURTHER CONTRACTION OF THE MUSCLE LAYER OF THE COLON AND RELAXATION OF THE CIRCULAR MUSCLE LAYER LEADING TO THE PROPULSION OF LUMINAL CONTENT.
ABSORPTION
PRUCALOPRIDE IS WELL ABSORBED AND IT REACHES MAXIMUM PLASMA CONCENTRATION OF 3.79NG/ML WITH A TMAX OF 2.77 HOURS AFTER INITIAL ADMINISTRATION. IT PRESENTS AN AUC OF 96.5 MN.H/ML. THE BIOAVAILABILITY OF PRUCALOPRIDE IS OF OVER 90% AND THIS BIOAVAILABILITY DOES NOT GET INFLUENCED BY THE INGESTION OF FOOD.10
VOLUME OF DISTRIBUTION
THE MEAN VOLUME OF DISTRIBUTION OF PRUCALOPRIDE IS REGISTERED TO BE 623 L.
PROTEIN BINDING
THE PLASMA PROTEIN BINDING OF PRUCALOPRIDE IS OF 30%.10
METABOLISM
PRUCALOPRIDE IS NOT EXTENSIVELY METABOLIZED IN THE BODY AND DOES NOT INTERACT WITH THE ENZYMES OF THE FAMILY OF THE CYTOCHROME P450 ENZYMES NOR THE P GLYCOPROTEIN. THE METABOLISM OF PRUCALOPRIDE ONLY REPRESENTS 6% OF THE ADMINISTERED DOSE AND THE REMAINING 94% IS FOUND AS THE UNCHANGED DRUG. FROM STUDIES, IT WAS REPORTED THE RECOVERY OF 8 METABOLITES BEING THE MAJOR METABOLITE R107504 WHICH IS FORMED AFTER THE O-DEMETHYLATION AND OXIDATION OF THE RESULTING ALCOHOL TO A CARBOXYLIC ACID.10
ROUTE OF ELIMINATION
AFTER MAXIMUM PLASMA CONCENTRATION, PRUCALOPRIDE CONCENTRATION DECLINE IN A BIPHASIC MANNER. PRUCALOPRIDE IS MAINLY EXCRETED BY THE URINE, REPRESENTING 84% OF THE ADMINISTERED DOSE WHILE ONLY 13% OF THE DOSE IS RECOVERED IN FECES.
HALF LIFE
THE REPORTED HALF-LIFE OF PRUCALOPRIDE IS OF AROUND 18-20 HOURS.
CLEARANCE
PRUCALOPRIDE RENAL CLEARANCE IS REPORTED TO BE OF 17 L/H WHICH ACTUALLY EXCEEDS THE GLOMERULAR FILTRATION RATE OF THE KIDNEY.
TOXICITY
PRUCALOPRIDE IS WELL TOLERATED IN DOSES REACHING 10 TIMES THE RECOMMENDED THERAPEUTIC DOSE AND SIGNS OF OVERDOSE ARE THOUGHT TO BE STARED BY THE PRESENCE OF HEADACHES, NAUSEA AND DIARRHEA.10 CARCINOGENICITY STUDIES IN MICE INDICATED AN INCREASED INCIDENCE OF MAMMARY GLAND ADENOCARCINOMA AT A DOSE OF 80 MG/KG/DAY. IN RATS, HIGH DOSES WERE LINKED TO INCREASED INCIDENCE OF BENIGN ADRENAL PHEOCHROMOCYTOMA, PITUITARY ADENOMA, PANCREATIC ADENOMA, HEPATOCELLULAR ADENOMA AND THYROID FOLLICULAR TUMORS.11
FOR GENOTOXICITY, PRUCALOPRIDE SHOWED ONLY ONE WEAK POSITIVE RESULT IN ONE OF THE FIVE BACTERIAL STRAIN REVERSE MUTATION TEST AT HIGH CONCENTRATIONS.11 AS WELL, THERE IS NO EVIDENCE OF ADVERSE EFFECTS ON FERTILITY, EVEN IN HIGH DOSES.LABEL
4-HYDROXYCOUMARIN THE METABOLISM OF 4-HYDROXYCOUMARIN CAN BE DECREASED WHEN COMBINED WITH PRUCALOPRIDE.
6-DEOXYERYTHRONOLIDE B THE METABOLISM OF PRUCALOPRIDE CAN BE DECREASED WHEN COMBINED WITH 6-DEOXYERYTHRONOLIDE B.
7-ETHYL-10-HYDROXYCAMPTOTHECIN THE METABOLISM OF PRUCALOPRIDE CAN BE DECREASED WHEN COMBINED WITH 7-ETHYL-10-HYDROXYCAMPTOTHECIN.
9-AMINOCAMPTOTHECIN THE METABOLISM OF 9-AMINOCAMPTOTHECIN CAN BE DECREASED WHEN COMBINED WITH PRUCALOPRIDE.
ABACAVIR ABACAVIR MAY DECREASE THE EXCRETION RATE OF PRUCALOPRIDE WHICH COULD RESULT IN A HIGHER SERUM LEVEL.
ABATACEPT THE METABOLISM OF PRUCALOPRIDE CAN BE INCREASED WHEN COMBINED WITH ABATACEPT.
ABIRATERONE THE METABOLISM OF ABIRATERONE CAN BE DECREASED WHEN COMBINED WITH PRUCALOPRIDE.
ACALABRUTINIB THE METABOLISM OF PRUCALOPRIDE CAN BE DECREASED WHEN COMBINED WITH ACALABRUTINIB.
ACARBOSE ACARBOSE MAY DECREASE THE EXCRETION RATE OF PRUCALOPRIDE WHICH COULD RESULT IN A HIGHER SERUM LEVEL.
ACECLOFENAC ACECLOFENAC MAY DECREASE THE EXCRETION RATE OF PRUCALOPRIDE WHICH COULD RESULT IN A HIGHER SERUM LEVEL.
ACEMETACIN ACEMETACIN MAY DECREASE THE EXCRETION RATE OF PRUCALOPRIDE WHICH COULD RESULT IN A HIGHER SERUM LEVEL.
ACENOCOUMAROL THE METABOLISM OF ACENOCOUMAROL CAN BE DECREASED WHEN COMBINED WITH PRUCALOPRIDE.
ACETAMINOPHEN THE METABOLISM OF PRUCALOPRIDE CAN BE DECREASED WHEN COMBINED WITH ACETAMINOPHEN.
ACETAZOLAMIDE THE METABOLISM OF PRUCALOPRIDE CAN BE DECREASED WHEN COMBINED WITH ACETAZOLAMIDE.
ACETYLSALICYLIC ACID ACETYLSALICYLIC ACID MAY DECREASE THE EXCRETION RATE OF PRUCALOPRIDE WHICH COULD RESULT IN A HIGHER SERUM LEVEL.
ACLIDINIUM ACLIDINIUM MAY DECREASE THE EXCRETION RATE OF PRUCALOPRIDE WHICH COULD RESULT IN A HIGHER SERUM LEVEL.
ACRIVASTINE PRUCALOPRIDE MAY DECREASE THE EXCRETION RATE OF ACRIVASTINE WHICH COULD RESULT IN A HIGHER SERUM LEVEL.
ACYCLOVIR ACYCLOVIR MAY DECREASE THE EXCRETION RATE OF PRUCALOPRIDE WHICH COULD RESULT IN A HIGHER SERUM LEVEL.
ADALIMUMAB THE METABOLISM OF PRUCALOPRIDE CAN BE INCREASED WHEN COMBINED WITH ADALIMUMAB.
ADEFOVIR ADEFOVIR MAY DECREASE THE EXCRETION RATE OF PRUCALOPRIDE WHICH COULD RESULT IN A HIGHER SERUM LEVEL.
ADEFOVIR DIPIVOXIL ADEFOVIR DIPIVOXIL MAY DECREASE THE EXCRETION RATE OF PRUCALOPRIDE WHICH COULD RESULT IN A HIGHER SERUM LEVEL.
AFATINIB THE SERUM CONCENTRATION OF PRUCALOPRIDE CAN BE INCREASED WHEN IT IS COMBINED WITH AFATINIB.
AFELIMOMAB THE METABOLISM OF PRUCALOPRIDE CAN BE INCREASED WHEN COMBINED WITH AFELIMOMAB.
AGMATINE THE THERAPEUTIC EFFICACY OF PRUCALOPRIDE CAN BE DECREASED WHEN USED IN COMBINATION WITH AGMATINE.
ALBENDAZOLE THE METABOLISM OF PRUCALOPRIDE CAN BE DECREASED WHEN COMBINED WITH ALBENDAZOLE.
ALBUTREPENONACOG ALFA PRUCALOPRIDE MAY DECREASE THE EXCRETION RATE OF ALBUTREPENONACOG ALFA WHICH COULD RESULT IN A HIGHER SERUM LEVEL.
ALCLOFENAC ALCLOFENAC MAY DECREASE THE EXCRETION RATE OF PRUCALOPRIDE WHICH COULD RESULT IN A HIGHER SERUM LEVEL.
ALCURONIUM THE THERAPEUTIC EFFICACY OF PRUCALOPRIDE CAN BE DECREASED WHEN USED IN COMBINATION WITH ALCURONIUM.
ALDESLEUKIN THE METABOLISM OF PRUCALOPRIDE CAN BE DECREASED WHEN COMBINED WITH ALDESLEUKIN.
ALECTINIB THE METABOLISM OF ALECTINIB CAN BE DECREASED WHEN COMBINED WITH PRUCALOPRIDE.
ALFENTANIL THE THERAPEUTIC EFFICACY OF PRUCALOPRIDE CAN BE DECREASED WHEN USED IN COMBINATION WITH ALFENTANIL.
ALLOIN THE RISK OR SEVERITY OF ADVERSE EFFECTS CAN BE INCREASED WHEN PRUCALOPRIDE IS COMBINED WITH ALLOIN.
ALLOPURINOL ALLOPURINOL MAY DECREASE THE EXCRETION RATE OF PRUCALOPRIDE WHICH COULD RESULT IN A HIGHER SERUM LEVEL.
ALLYLESTRENOL THE METABOLISM OF PRUCALOPRIDE CAN BE DECREASED WHEN COMBINED WITH ALLYLESTRENOL.
ALMASILATE PRUCALOPRIDE MAY DECREASE THE EXCRETION RATE OF ALMASILATE WHICH COULD RESULT IN A HIGHER SERUM LEVEL.
ALMINOPROFEN ALMINOPROFEN MAY DECREASE THE EXCRETION RATE OF PRUCALOPRIDE WHICH COULD RESULT IN A HIGHER SERUM LEVEL.
ALMOTRIPTAN ALMOTRIPTAN MAY DECREASE THE EXCRETION RATE OF PRUCALOPRIDE WHICH COULD RESULT IN A HIGHER SERUM LEVEL.
ALOGLIPTIN ALOGLIPTIN MAY DECREASE THE EXCRETION RATE OF PRUCALOPRIDE WHICH COULD RESULT IN A HIGHER SERUM LEVEL.
ALPELISIB THE METABOLISM OF PRUCALOPRIDE CAN BE DECREASED WHEN COMBINED WITH ALPELISIB.
ALPHACETYLMETHADOL THE THERAPEUTIC EFFICACY OF PRUCALOPRIDE CAN BE DECREASED WHEN USED IN COMBINATION WITH ALPHACETYLMETHADOL.
ALPHAPRODINE THE THERAPEUTIC EFFICACY OF PRUCALOPRIDE CAN BE DECREASED WHEN USED IN COMBINATION WITH ALPHAPRODINE.
ALPRAZOLAM ALPRAZOLAM MAY DECREASE THE EXCRETION RATE OF PRUCALOPRIDE WHICH COULD RESULT IN A HIGHER SERUM LEVEL.
AMANTADINE AMANTADINE MAY DECREASE THE EXCRETION RATE OF PRUCALOPRIDE WHICH COULD RESULT IN A HIGHER SERUM LEVEL.
AMIKACIN AMIKACIN MAY DECREASE THE EXCRETION RATE OF PRUCALOPRIDE WHICH COULD RESULT IN A HIGHER SERUM LEVEL.
AMILORIDE THE RISK OR SEVERITY OF ADVERSE EFFECTS CAN BE INCREASED WHEN AMILORIDE IS COMBINED WITH PRUCALOPRIDE.
AMINOGLUTETHIMIDE THE METABOLISM OF PRUCALOPRIDE CAN BE INCREASED WHEN COMBINED WITH AMINOGLUTETHIMIDE.
AMINOPHENAZONE AMINOPHENAZONE MAY DECREASE THE EXCRETION RATE OF PRUCALOPRIDE WHICH COULD RESULT IN A HIGHER SERUM LEVEL.
AMINOPHYLLINE THE METABOLISM OF AMINOPHYLLINE CAN BE DECREASED WHEN COMBINED WITH PRUCALOPRIDE.
AMIODARONE THE SERUM CONCENTRATION OF PRUCALOPRIDE CAN BE INCREASED WHEN IT IS COMBINED WITH AMIODARONE.
AMITRIPTYLINE AMITRIPTYLINE MAY DECREASE THE EXCRETION RATE OF PRUCALOPRIDE WHICH COULD RESULT IN A HIGHER SERUM LEVEL.
ADDITIONAL DATA AVAILABLE
路 EXTENDED DESCRIPTION
Extended Description
Extended description of the mechanism of action and particular properties of each drug interaction.
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路 SEVERITY
Severity
A severity rating for each drug interaction, from minor to major.
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路 EVIDENCE LEVEL
Evidence Level
A rating for the strength of the evidence supporting each drug interaction.
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路 ACTION
Action
An effect category for each drug interaction. Know how this interaction affects the subject drug.
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FOOD INTERACTIONS
路 TAKE WITH OR WITHOUT FOOD.