Resolor, 2 mg 28 pcs.

Pharmacodynamics

Mechanism of action

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

Pharmacokinetics

Absorption

Prucaloprid is rapidly absorbed; after a single oral dose of 2 mg, maximum concentration (Cmax) is reached after 2-3 hours. Absolute bioavailability after oral administration exceeds 90%. The bioavailability is not affected by taking the drug with meals.

Distribution

Prucalopride is distributed throughout the body; the volume of distribution in equilibrium (Vdss ) is 567 l. Binding to plasma proteins is approximately 30%.

Metabolism

Metabolism of the drug in the human liver in vitro is very slow, and only small amounts of metabolites are formed. After human oral administration of 14C-labeled prucalopride, 8 metabolites are detected in small amounts in the urine and feces. The major metabolite (R107504, formed by O-demethylation of prucalopride and oxidation of the resulting alcohol to carboxylic acid) is less than 4% of the administered dose of the drug. About 85% of the drug remains unchanged, as indicated by radioactive labeling studies; the metabolite R107504 is present in plasma in small amounts.

The majority of the orally administered dose of the active ingredient is excreted unchanged (approximately 60% by the kidneys and at least 6% in the feces). Excretion of unchanged pruncalopride by the kidneys includes passive filtration and active secretion. The plasma clearance of prucalopride averages 317 ml/min and the final T1/2 is approximately 1 day. The equilibrium state is reached after 3-4 days of drug administration, with minimum and maximum equilibrium plasma concentrations of 2.5 and 7 ng/ml, respectively, when taking prucalopride at a dose of 2 mg once daily. When administered once daily, the drug’s k-factor ranges from 1.9 to 2.3. Pharmacokinetics of prucalopride is linearly dose-dependent up to 20 mg/day. With long-term administration of the drug once daily, its pharmacokinetics are independent of the duration of administration.

Particular categories of patients

Population pharmacokinetics

A population pharmacokinetic analysis showed that total clearance of prucalopride correlated with creatinine clearance (CK) and was independent of patient age, body weight, sex, or race.

Elderly Patients

In elderly patients taking the drug at a dose of 1 mg once daily, the plasma Cmax and area under the concentration-time curve (AUC) of prucalopride were 26% and 28% greater, respectively, than in younger patients. This difference may be related to impaired renal function in the elderly.

Renal dysfunction

In comparison with patients with normal renal function, patients with mild (CK 50-79 mL/min) and moderately severe (CK 25-49 mL/min) renal dysfunction had a 25% and 51% increase in plasma concentration of prucalopride after a single dose of 2 mg, respectively. In patients with severe renal dysfunction (CKR less than 24 mL/min), plasma concentrations of prucalopride were 2.3 times higher than in healthy subjects.

Hepatic dysfunction

About 35% of prucalopride is excreted extrarenally, so hepatic dysfunction is unlikely to change the pharmacokinetics of the drug in a clinically significant way.

Children

After a single oral dose of 0.03 mg/kg of prucalopride in children aged 4-12 years, the Cmax of the drug was the same as after an adult dose of 2 mg, and the AUC of the unbound fraction of the drug was 30-40% lower than in adults and was independent of the age of children. The mean T1/2 of the drug in the terminal phase is approximately 19 h in children (range 11.6-26.8 h).

Indications

Resolor is for symptomatic treatment of chronic constipation in women for whom laxatives have not had sufficient effect in eliminating the symptoms.

Active ingredient

Composition

1 tablet contains:

Active ingredients:

Prucalopride succinate 2.642 mg, which corresponds to the content of prucalopride 2 mg.

Auxiliary substances:

the 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 the film coating pink as a percentage by weight:

Hypromellose 6 cP – 40%,

Red iron oxide dye (E172) – 0.09%,

titanium dioxide – 23.88%,

macrogol 3000 – 8%, indigo carmine (E132) – 0.02%,

iron oxide yellow dye (E172) – 0.01%.

There are 7 tablets in the blister.

There are 2 blisters in the package.

How to take, the dosage

The drug is taken orally, regardless of meals, at any time of day.

Patients with impaired renal function with severe renal impairment (glomerular filtration rate less than 30 ml/min/1.73 m) the dose is 1 mg once daily. No dose adjustment is required for patients with mild to moderately severe renal impairment.

Patients with hepatic impairment: In severe hepatic impairment (Child-Pugh class C) the dose is 1 mg once daily. No dose adjustment is required for patients with mild to moderate hepatic impairment.

Because of the specific mechanism of action of prucalopride (stimulation of intestinal motility), increasing the daily dose beyond 2 mg is unlikely to increase the effect. If prunalopride once daily for 4 weeks has no effect, the patient should be reevaluated to determine whether it is reasonable to continue treatment.

Interaction

In vitro data indicate that prucaloprid is weakly able to interact, and in therapeutic concentrations it is unlikely to affect the cytochrome system enzyme metabolism of concomitantly administered drugs. Although prucalopride may bind weakly to P-glycoprotein (P-GP), it does not inhibit (P-GP) activity at clinically relevant concentrations.

The potent CYP3A4 and P-glycoprotein inhibitor ketoconazole, at a dose of 200 mg twice daily, increased the AUC (area under the concentration-time curve) of prucaloprid by approximately 40%. This effect is too small to be clinically significant and is likely related to the inhibition of active renal transport of prucalopride by P-glycoprotein.

The same interaction as with ketoconazole can also be observed with other active P-glycoprotein inhibitors such as verapamil, cyclosporine A and quinidine. Prucalopride is also likely to be transported in the kidneys by other transporters. Theoretically, inhibiting the activity of all the transporters involved in the active secretion of prucaloprid in the kidneys (including P-glycoprotein) could increase its systemic exposure by 75%.

Studies with healthy volunteers have shown no clinically significant effect of prucalopride on the pharmacokinetics of warfarin, digoxin, ethyl alcohol and paroxetine. When concomitant use of prócalopride and erythromycin, plasma concentrations of the latter are increased by 30%. The mechanism of this interaction is not entirely clear, but the evidence suggests that it is most likely not the result of the direct action of prócalopride, but a consequence of the high variability in the pharmacokinetics of erythromycin itself.

Probenecid, cimetidine, erythromycin and paroxetine at therapeutic doses had no effect on the pharmacokinetics of prucaloprid.

The drug Resolor should be used with caution concomitantly with drugs that may prolong the QTc interval.

Atropine-like substances may weaken the effects of prócalopride mediated through NT4 receptors.

No interaction with food has been detected.

Special Instructions

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

The efficacy of oral contraceptives may be reduced in severe diarrhea, and additional contraceptive methods are recommended to prevent decreased efficacy of oral contraceptives. Impaired liver function is unlikely to have a clinically significant effect on the metabolism and level of systemic exposure to 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; therefore, patients with congenital lactase deficiency, lactose intolerance or glucose-galactose malabsorption should not take the drug.

No ricochet phenomenon or development of dependence has been identified for prucalopride. A study of the effect of prucalopride on the QT interval in therapeutic (2 mg) and supratherapeutic (10 mg) doses showed no significant differences compared to placebo with respect to QT interval values.

The incidence of QT interval-related adverse events and ventricular arrhythmias was low and comparable to that of placebo.

The effect on the ability to drive vehicles and other mechanisms requiring increased concentration

There have been no studies of the effect of Pruncalopride on the ability to drive and operate moving mechanisms. In some cases, use of Rezolor has been associated with dizziness and weakness, especially in the first days of treatment, which may affect the ability to drive and operate moving machinery.

Contraindications

Side effects

The most common adverse reactions with Resolor were headache and adverse gastrointestinal reactions (abdominal pain, nausea, diarrhea), each seen in approximately 20% of patients.

The undesirable reactions developed predominantly at the start of treatment and usually disappeared after a few days without requiring treatment withdrawal. Other adverse reactions have been observed sporadically. Most adverse adverse reactions were mild to moderate in severity.

With a recommended dose of 2 mg of prucalopride, the following adverse reactions have been reported in clinical trials, and the frequency of these reactions is indicated as:

Central nervous system: very common – headache; common – dizziness; infrequent – tremor.

Cardiovascular system: infrequent – palpitations.

Gastrointestinal tract: very common – nausea, diarrhea, abdominal pain; common – vomiting, dyspepsia, rectal bleeding, flatulence, abnormal intestinal murmurs; infrequent – anorexia.

Urogenital system disorders: frequently – pollakiuria.

General: frequent – weakness; infrequent – fever, malaise.

Overdose

A study involving healthy volunteers showed that prucalopride was well tolerated when the dose was increased to 20 mg once daily (10 times the recommended therapeutic dose).

Overdose may result in 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 given if necessary. Large fluid loss due to diarrhea or vomiting may require correction of electrolyte imbalances.

Pregnancy use

Pregnancy

The experience with the use of pruncalopride during pregnancy is limited. Cases of miscarriage have been reported in clinical studies, although, given the presence of other risk factors, the association of these events with the use of prucalopride remains unproven.

Animal studies have shown no direct or indirect adverse effects on pregnancy, embryo/fetal development, labor and postnatal development of the offspring. Rezolor is not recommended for use during pregnancy. Women capable of childbearing should use adequate contraceptive methods during treatment with Prücalopride.

Lactation period

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