Resolor^® (Tablets) Instructions for Use

Marketing Authorization Holder

Amdipharm, Limited (Ireland)

Manufactured By

Janssen-Cilag S.p.A. (Italy)

Contact Information

JANSSEN, pharmaceutical division of JOHNSON & JOHNSON LLC

ATC Code

A06AX05 (Prucalopride)

Active Substance

Prucalopride (Rec.INN registered by WHO)

Dosage Forms

	Resolor®	Film-coated tablets, 1 mg: 28 pcs.
		Film-coated tablets, 2 mg: 28 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, round, biconvex, engraved with “PRU 1” on one side; the core of the tablet on a cross-section is white or almost white.

Excipients: tablet core: lactose monohydrate – 149.969 mg, microcrystalline cellulose – 27 mg, colloidal silicon dioxide – 0.36 mg, magnesium stearate – 1.35 mg, white film coating 1 – 6 mg.

Composition of white film coating 1 by weight percentage: hypromellose 6 cP – 40%, titanium dioxide – 24%, macrogol 3000 – 8%, triacetin – 6%, lactose monohydrate – 22%.

7 pcs. – blisters (4) – cardboard packs.

Film-coated tablets pink, round, biconvex, engraved with “PRU 2” on one side, the core of the tablet on a cross-section is white or almost white.

Excipients: tablet core lactose monohydrate – 165.458 mg, microcrystalline cellulose – 30 mg, colloidal silicon dioxide – 0.4 mg, magnesium stearate – 1.5 mg, pink film coating – 7 mg.

Composition of pink film coating by weight percentage: hypromellose 6 cP – 40%, iron oxide red dye (E172) – 0.09%, titanium dioxide – 23.88%, macrogol 3000 – 8%, triacetin – 6%, lactose monohydrate – 22%, indigo carmine (E132) – 0.02%, iron oxide yellow dye (E172) – 0.01%.

7 pcs. – blisters (4) – cardboard packs.

Clinical-Pharmacological Group

Selective serotonin 5-HT₄ receptor agonist

Pharmacotherapeutic Group

Serotonin receptor stimulant

Pharmacological Action

Mechanism of action

Prucalopride is a dihydrobenzofurancarboxamide that enhances intestinal motility. Prucalopride is a selective, high-affinity agonist of 5HT₄ serotonin receptors, which most likely explains its effect on intestinal motility. Binding to other receptor types in vitro was observed only at substance concentrations exceeding its affinity for HT₄ receptors by at least 150 times.

Pharmacokinetics

Absorption

Prucalopride is rapidly absorbed; after a single oral dose of 2 mg, the maximum concentration (C_max) is reached in 2-3 hours. Absolute bioavailability after oral administration exceeds 90%. Taking the drug with food does not affect bioavailability.

Distribution

Prucalopride is distributed throughout the body, the volume of distribution at steady state (V_d^ss) is 567 L. Binding to plasma proteins is approximately 30%.

Metabolism

The metabolism of the drug in the human liver in vitro proceeds very slowly, and only a small amount of metabolites is formed. After oral administration of ¹⁴C-labeled prucalopride to humans, 8 metabolites are detected in small amounts in urine and feces. The main metabolite (R107504, formed by O-demethylation of prucalopride and oxidation of the resulting alcohol to a carboxylic acid) accounts for less than 4% of the administered dose of the drug. As studies with a radioactive label have shown, about 85% of the drug remains unchanged; the R107504 metabolite is present in plasma in small amounts.

Excretion

Most of the orally administered dose of the active component is excreted unchanged (approximately 60% by the kidneys and at least 6% in feces). The excretion of unchanged prucalopride by the kidneys involves passive filtration and active secretion. The clearance of prucalopride from plasma averages 317 ml/min, the terminal T_1/2 is approximately 1 day. Steady state is reached after 3-4 days of taking the drug, and when taking prucalopride at a dose of 2 mg once a day, the minimum and maximum plasma concentrations at steady state are 2.5 and 7 ng/ml, respectively. When taken once a day, the accumulation coefficient of the drug ranges from 1.9 to 2.3. The pharmacokinetics of prucalopride are linear with respect to dose in the range up to 20 mg/day. With long-term use of the drug once a day, its pharmacokinetics do not depend on the duration of use.

Special patient categories

Population pharmacokinetics

Population pharmacokinetic analysis showed that the total clearance of prucalopride correlates with creatinine clearance (CrCl) and does not depend on the age, body weight, sex or race of patients.

Elderly patients

When the drug was taken by elderly patients at a dose of 1 mg once a day, the C_max of prucalopride in plasma and the area under the concentration-time curve (AUC) were 26% and 28% higher, respectively, than in young patients. This difference may be due to impaired renal function in the elderly.

Renal impairment

Compared with patients with normal renal function, in patients with mild (CrCl 50-79 ml/min) and moderate (CrCl 25-49 ml/min) renal impairment, the plasma concentration of prucalopride after a single dose of 2 mg was increased by 25% and 51%, respectively. In patients with severe renal impairment (CrCl less than 24 ml/min), the plasma concentration of prucalopride was 2.3 times higher than in healthy individuals.

Hepatic impairment

About 35% of prucalopride is excreted extrarenally, so hepatic impairment is unlikely to clinically significantly alter the pharmacokinetics of the drug.

Children

After a single oral dose of prucalopride 0.03 mg/kg in children aged 4-12 years, the C_max of the drug was the same as after adults took the drug at a dose of 2 mg, and the AUC of the unbound fraction of the drug was 30-40% lower than in adults and did not depend on the age of the children. The mean terminal phase T_1/2 of the drug in children is approximately 19 hours (range 11.6-26.8 hours).

Indications

• Resolor^® is intended for the symptomatic treatment of chronic constipation in women in whom laxatives have not provided adequate relief of symptoms.

ICD codes

Dosage Regimen

The drug is taken orally, regardless of food intake, at any time of the day.

Adults: 2 mg once a day. Elderly (over 65 years): start with 1 mg once a day, if necessary, the dose can be increased to 2 mg once a day. Children and adolescents: Resolor^® is not recommended for use in children and adolescents under 18 years of age.

Patients with renal impairment with severe renal impairment (glomerular filtration rate less than 30 ml/min/1.73 m²) the dose is 1 mg once a day. For patients with mild and moderate renal impairment, no dose adjustment is required.

Patients with hepatic impairment with severe hepatic impairment (Child-Pugh class C) the dose is 1 mg once a day. For patients with mild and moderate hepatic impairment, no dose adjustment is required.

Due to the specific mechanism of action of prucalopride (stimulation of intestinal motility), increasing the daily dose above 2 mg is unlikely to enhance the effect. If taking prucalopride once a day for 4 weeks does not produce an effect, the patient should be re-examined and the advisability of continuing treatment should be determined.

Adverse Reactions

The most frequent adverse reactions when using Resolor^® were headache and gastrointestinal adverse reactions (abdominal pain, nausea, diarrhea), each of which was observed in approximately 20% of patients. Adverse reactions occurred mainly at the beginning of treatment and usually disappeared after a few days, without requiring discontinuation of treatment. Other adverse reactions were observed sporadically. Most adverse reactions were mild or moderate in severity.

At the recommended dose of prucalopride 2 mg, the following adverse reactions have been registered in clinical studies, the frequency of which is designated as very common (> 1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10000, <1/1000), very rare (<1/10000), including isolated cases.

From the central nervous system very common – headache; common – dizziness; uncommon – tremor.

From the cardiovascular system uncommon – palpitations.

From the gastrointestinal tract very common – nausea, diarrhea, abdominal pain; common – vomiting, dyspepsia, rectal bleeding, flatulence, abnormal bowel sounds; uncommon – anorexia.

From the genitourinary system common – pollakiuria.

General common – weakness; uncommon – fever, malaise.

Contraindications

• Hypersensitivity to the active component or any excipient;
• Renal impairment requiring dialysis;
• Intestinal perforation or obstruction due to anatomical or functional disorders of the intestinal wall, mechanical intestinal obstruction, severe intestinal inflammation, such as Crohn’s disease, ulcerative colitis and toxic megacolon/megarectum;
• Congenital lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

With caution the use of the drug in patients with severe and clinically unstable concomitant diseases (liver, lung, cardiovascular, neurological, endocrine diseases, mental disorders, oncological diseases, AIDS) has not been studied. Caution should be exercised when prescribing Resolor^® to patients with such diseases. In particular, the drug should be used with caution in patients with a history of cardiac arrhythmia or ischemic heart disease.

Use in Pregnancy and Lactation

Pregnancy

Experience with the use of prucalopride during pregnancy is limited. Cases of miscarriage have been reported in clinical studies, although, given the presence of other risk factors, the connection of these events with the use of prucalopride remains unproven. Animal studies have not revealed direct or indirect adverse effects on pregnancy, embryo/fetal development, childbirth and postnatal development of offspring. Resolor^® is not recommended for use during pregnancy. During treatment with prucalopride, women of childbearing potential should use adequate methods of contraception.

Lactation period

Prucalopride is excreted in breast milk, but when used in therapeutic doses, the drug is unlikely to affect newborns/infants. Due to the lack of data on use in nursing mothers, the drug is not recommended for use during breastfeeding.

Fertility

Animal studies have not revealed any effect of the drug on the fertility of males and females.

Use in Hepatic Impairment

In severe hepatic impairment (Child-Pugh class C), the dose is 1 mg once/day. For patients with mild and moderate hepatic impairment, no dose adjustment is required.

Use in Renal Impairment

In severe renal impairment (glomerular filtration rate less than 30 ml/min/1.73 m²), the dose is 1 mg once/day. For patients with mild and moderate renal impairment, no dose adjustment is required.

Pediatric Use

Resolor^® is not recommended for use in children and adolescents under 18 years of age.

Geriatric Use

Elderly (over 65 years): start with 1 mg once a day, if necessary, the dose can be increased to 2 mg once a day.

Special Precautions

The main route of excretion of prucalopride is through the kidneys. For patients with severe renal impairment, the recommended dose is 1 mg.

In case of severe diarrhea, the effectiveness of oral contraceptives may decrease, and it is recommended to use additional methods of contraception to prevent a decrease in the effectiveness of oral contraceptives.

Hepatic impairment is unlikely to clinically significantly affect the metabolism and systemic exposure of prucalopride in humans. There are no data on the use of the drug in patients with mild, moderate or severe hepatic impairment, so a lower dose is recommended for patients with severe hepatic impairment.

The drug contains lactose monohydrate, so the drug should not be taken by patients with congenital lactase deficiency, lactose intolerance or glucose-galactose malabsorption.

No rebound phenomenon or development of dependence has been identified for prucalopride. A study of the effect of prucalopride on the QT interval at therapeutic (2 mg) and supratherapeutic (10 mg) doses did not show significant differences compared to placebo in terms of QT interval values.

The frequency of adverse events related to the QT interval and ventricular arrhythmias was low and comparable to that with placebo.

Effect on ability to drive vehicles and machinery

No studies have been conducted on the effect of prucalopride on the ability to drive a car and operate machinery. In some cases, the use of Resolor^® has been associated with the development of dizziness and weakness, especially in the first days of treatment, which may affect the ability to drive a car and operate machinery.

Overdose

A study involving healthy volunteers showed that Prucalopride is well tolerated when the dose is increased to 20 mg once a day (10 times the recommended therapeutic dose).

Overdose may lead to symptoms due to an increase in the known side effects of the drug, including headache, nausea and diarrhea.

There is no specific antidote for Resolor^®. In case of overdose, symptomatic and supportive therapy should be provided as necessary. Significant fluid loss as a result of diarrhea or vomiting may require correction of electrolyte imbalances.

Drug Interactions

In vitro data indicate a low potential for interaction of prucalopride, and at therapeutic concentrations it is unlikely to affect the cytochrome system enzyme-mediated metabolism of concomitantly used drugs. Although Prucalopride may weakly bind to P-glycoprotein (P-gp), at clinically significant concentrations it does not inhibit (P-gp) activity.

The potent CYP3A4 and P-glycoprotein inhibitor ketoconazole at a dose of 200 mg twice a day increased the AUC (area under the concentration-time curve) of prucalopride by approximately 40%. This effect is too small to be clinically significant and is most likely due to suppression of P-glycoprotein-mediated active transport of prucalopride in the kidneys. The same interaction as with ketoconazole may be observed with other active P-glycoprotein inhibitors, for example, verapamil, cyclosporine A and quinidine. Prucalopride is also likely transported in the kidneys by other transporters. Theoretically, suppression of the activity of all transporters involved in the active secretion of prucalopride in the kidneys (including P-glycoprotein) may increase its systemic exposure by 75%.

Studies involving healthy volunteers have shown no clinically significant effect of prucalopride on the pharmacokinetics of warfarin, digoxin, ethyl alcohol and paroxetine. When prucalopride and erythromycin are used concomitantly, the plasma concentration of the latter increases by 30%. The mechanism of this interaction is not fully understood, but available data indicate that it is most likely not the result of a direct action of prucalopride, but a consequence of the high variability of the pharmacokinetics of erythromycin itself.

Probenecid, cimetidine, erythromycin and paroxetine at therapeutic doses did not affect the pharmacokinetics of prucalopride.

Resolor^® should be used with caution concomitantly with drugs that can prolong the QTc interval.

Atropine-like substances may weaken the effects of prucalopride mediated through HT₄ receptors.

No interaction with food has been detected.

Storage Conditions

The drug should be stored in the original packaging to protect from moisture in a place inaccessible to children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.