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  • CLASSES

    Serotonin Receptor Agonists for Constipation

    DEA CLASS

    Rx

    DESCRIPTION

    An oral selective serotonin (5HT-4) receptor agonist
    Used once daily for the treatment of chronic idiopathic constipation (CIC) in adults
    Promotes spontaneous bowel movements; monitor for depressed mood or suicidal thoughts or behaviors

    COMMON BRAND NAMES

    Motegrity

    HOW SUPPLIED

    MOTEGRITY/Prucalopride Oral Tab: 1mg, 2mg

    DOSAGE & INDICATIONS

    For the treatment of chronic idiopathic constipation (CIC).
    Oral dosage
    Adults

    2 mg PO once daily.

    MAXIMUM DOSAGE

    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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustments are needed.

    Renal Impairment

    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.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    The tablets can be administered with or without food.

    STORAGE

    Motegrity:
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    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.

    Dialysis, geriatric, renal failure, renal impairment

    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.[63829]

    Crohn's disease, diverticulitis, GI obstruction, GI perforation, ileus, inflammatory bowel disease, toxic megacolon, ulcerative colitis

    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.

    Depression, suicidal ideation

    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.[63829]

    Pregnancy

    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.

    Breast-feeding

    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.

    Children, infants, neonates

    The safety and effectiveness of prucalopride in neonates, infants, children, and adolescents less than 18 years of age have not been established.

    ADVERSE REACTIONS

    Severe

    suicidal ideation / Delayed / Incidence not known

    Moderate

    migraine / Early / 0-2.0
    dyspnea / Early / Incidence not known
    edema / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    hallucinations / Early / Incidence not known

    Mild

    headache / Early / 19.0-19.0
    abdominal pain / Early / 16.0-16.0
    nausea / Early / 14.0-14.0
    diarrhea / Early / 13.0-13.0
    dizziness / Early / 4.0-4.0
    flatulence / Early / 3.0-3.0
    vomiting / Early / 3.0-3.0
    anorexia / Delayed / 0-2.0
    fatigue / Early / 2.0-2.0
    increased urinary frequency / Early / 0-2.0
    pruritus / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    rash / Early / Incidence not known
    insomnia / Early / Incidence not known
    nightmares / Early / Incidence not known
    anxiety / Delayed / Incidence not known

    DRUG INTERACTIONS

    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.

    PREGNANCY AND LACTATION

    Pregnancy

    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.

    MECHANISM OF ACTION

    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.[63829]

    PHARMACOKINETICS

    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.[63829]
     
    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.[63829]
     
    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.[63829]

    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.