Vegaprat 1 mg 30 pcs. film-coated tablets

Prucalopride is indicated for the symptomatic treatment of chronic constipation in adults for whom laxatives have not provided sufficient relief of symptoms.

Dosage regimen
Adults: 2 mg once daily, regardless of food intake, at any time of day.
Due to the specific mechanism of action of prucalopride (stimulation of propulsive peristalsis), exceeding the daily dose of 2 mg is unlikely to enhance the effect.
If prucalopride taken once daily is not effective after 4 weeks of treatment, the patient should be re-evaluated, and the appropriateness of continuing treatment should be reconsidered. The efficacy of prucalopride has been established in double-blind placebo-controlled studies lasting up to 3 months.
Efficacy after 3 months in placebo-controlled studies has not been demonstrated. In the case of long-term treatment, its appropriateness should be regularly reassessed.

Special patient groups
Elderly patients (over 65 years): start treatment with a dose of 1 mg once daily, and if necessary, increase the dose to 2 mg once daily.
Patients with renal impairment: in cases of severe renal impairment (glomerular filtration rate less than 30 ml/min/1.73 m²), the dose is 1 mg once daily. For patients with mild to moderate renal impairment, dose adjustment is not required.
Patients with hepatic impairment: patients with severe hepatic impairment (Child-Pugh class C) start with a dose of 1 mg once daily, which can be increased to 2 mg if needed for efficacy and if the 1 mg dose is well tolerated. For patients with mild to moderate hepatic impairment, dose adjustment is not required.
Pediatric patients: Vegaprat® is not recommended for use in children and adolescents under 18 years of age.
Route of administration
For oral use.

Composition per tablet:
Active ingredient:
Prucalopride succinate 1.321 mg, equivalent to prucalopride 1.000 mg
Excipients:
microcrystalline cellulose, sodium carboxymethyl starch, magnesium stearate, colloidal silicon dioxide.
Coating: hypromellose 6 cP, macrogol 6000, titanium dioxide, talc.

Round biconvex tablets coated with a film, white or almost white in color. On cross-section, the core of the tablet is white or almost white in color.

Hypersensitivity to the active ingredient or any excipient.
Kidney function impairment requiring dialysis.
Perforation or obstruction of the intestine 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.
With caution:
Data on patients with severe and clinically unstable comorbidities (kidney, lung, cardiovascular, neurological, endocrine, and oncological diseases, as well as mental disorders, AIDS) is limited. Caution should be exercised when prescribing Vegaprat® to patients with such conditions. In particular, the drug should be used with caution in patients with a history of arrhythmias or ischemic heart disease.

The primary route of elimination of prucalopride is through the kidneys. For patients with severe renal impairment, the recommended dose is 1 mg (see the section "Dosage and Administration").
In cases of severe diarrhea, the effectiveness of oral contraceptives may be reduced, and it is recommended to use additional contraceptive methods to prevent decreased effectiveness of oral contraceptives (see the instructions for use of oral contraceptives).
Caution should be exercised when prescribing Vegaprat® to patients with severe hepatic insufficiency (Child-Pugh class C) due to limited data on its use in patients with severe hepatic insufficiency.
Due to limited information on the safety and efficacy of Vegaprat® in patients with severe and clinically unstable comorbidities, special caution should be exercised when prescribing it to such patients (especially those with a history of arrhythmia or ischemic cardiovascular disease).
In clinical studies and post-marketing surveillance data, cases of suicides, suicide attempts, and suicidal thoughts have been reported. A causal relationship between prucalopride treatment and an increased risk of suicidal thoughts and behavior has not been established.
All patients receiving Vegaprat® should be monitored for persistent worsening of depression or the emergence of suicidal thoughts and behavior. Legal representatives of patients, caregivers, and family members should be informed of any unusual changes in mood or behavior and report them to a healthcare professional immediately.

The most common adverse reactions associated with the use of Vegaprat® 2 mg were headache (17.8%) and gastrointestinal adverse reactions (abdominal pain (13.7%), nausea (13.7%), and diarrhea (12%)). Adverse reactions primarily developed at the beginning of treatment and usually resolved within a few days without requiring discontinuation of therapy. Other adverse reactions were observed occasionally.
Most adverse reactions were of mild or moderate severity.
The following adverse reactions were recorded in controlled clinical studies at the recommended dose of 2 mg with a frequency corresponding to the following classification: very common (> 1/10), common (> 1/100 to 1/1,000 to 1/10,000 to < 1/1,000), very rare (< 1/10,000), and with unknown frequency (cannot be estimated based on available data). Within each frequency group, adverse reactions are listed in order of decreasing severity. Metabolism and nutrition disorders: common - decreased appetite. Nervous system disorders: very common - headache; common - dizziness; uncommon - tremor, migraine. Cardiac disorders: uncommon - palpitations. Ear and labyrinth disorders: uncommon - vertigo. Gastrointestinal disorders: very common - nausea, diarrhea, abdominal pain; common - vomiting, dyspepsia, flatulence, pathological bowel sounds; uncommon - rectal bleeding. Kidney and urinary tract disorders: common - pollakiuria. General disorders and administration site reactions: common - weakness; uncommon - fever, malaise. Description of individual adverse reactions After the first day of treatment, the most frequent adverse reactions were recorded with the same frequency (the occurrence rate of reactions differed by no more than 1% between the prucalopride and placebo groups) during prucalopride therapy, as well as in the placebo group, except for nausea and diarrhea, which occurred more frequently during prucalopride therapy but were less pronounced (the differences in occurrence rates between the prucalopride and placebo groups were 1.3% and 3.4%, respectively). Palpitations were reported in 0.7% of patients receiving placebo, 0.9% of patients receiving prucalopride at a dose of 1 mg, 0.9% of patients receiving prucalopride at a dose of 2 mg, and 1.9% of patients receiving prucalopride at a dose of 4 mg. Most patients continued taking prucalopride. If any adverse reactions occur, it is necessary to consult a healthcare professional. This recommendation applies to any possible adverse reactions, including those not listed in this instruction.A study involving healthy volunteers showed that prucalopride is well tolerated at doses increased to 20 mg once daily (10 times the recommended therapeutic dose). Overdose may lead to symptoms caused by the enhancement of known pharmacodynamic effects of prucalopride, including headache, nausea, and diarrhea. There is no specific antidote for Vegaprat®. In case of overdose, symptomatic and supportive therapy should be provided as necessary. Significant fluid loss due to diarrhea or vomiting may require correction of electrolyte imbalances.Prucalopride has a low potential for pharmacokinetic interactions. It is primarily excreted unchanged in the urine (approximately 60% of the dose), and its metabolism is very slow. In in vitro studies on human liver microsomes, prucalopride at therapeutically relevant concentrations did not inhibit the specific activity of cytochrome P450. Although prucalopride may be a weak substrate for P-glycoprotein, it is not an inhibitor at clinically significant concentrations. Effects of prucalopride on the pharmacokinetics of other drugs Co-administration of prucalopride resulted in a 30% increase in plasma concentrations of erythromycin. The mechanism of this interaction is unclear. Prucalopride did not have a clinically significant effect on the pharmacokinetics of warfarin, digoxin, ethanol, paroxetine, or oral contraceptives. Effects of other drugs on the pharmacokinetics of prucalopride Ketoconazole at a dose of 200 mg twice daily (a potent inhibitor of CYP3A4 and P-glycoprotein) increased the systemic exposure of prucalopride by approximately 40% (an effect too small to be clinically significant). Similar interactions can be expected with other potent P-glycoprotein inhibitors such as verapamil, cyclosporine, and quinidine. Therapeutic doses of probenecid, cimetidine, erythromycin, and paroxetine did not affect the pharmacokinetics of prucalopride.

Prucalopride is a dihydrobenzofuran-carboxamide that enhances intestinal motility. Prucalopride is a selective, high-affinity agonist of 5-HT4 serotonin receptors, which likely explains its action on intestinal motility. Binding to other types of receptors in vitro was observed only at concentrations of the substance exceeding its affinity for 5-HT4 receptors by at least 150 times. In rats in vivo, prucalopride at doses above 5 mg/kg (30-70 times higher than doses used in clinical practice) induced hyperprolactinemia due to antagonistic action on the D2 receptor.

In dogs, prucalopride alters the nature of colonic motility: it stimulates motility in the proximal sections of the colon, enhances motility in the gastro-duodenal area, and accelerates delayed gastric emptying. Additionally, prucalopride causes giant migrating contractions. This is equivalent to enhanced colonic peristalsis in humans and provides the primary driving force for defecation. In dogs, the effects observed in the gastrointestinal tract are sensitive to blockade by selective antagonists of 5-HT4 receptors, indicating that the observed effects manifest through selective action on 5-HT4 receptors. These pharmacodynamic effects of prucalopride have been confirmed in humans with chronic constipation using manometry in an open-label, randomized, crossover, "blind" study, which assessed the impact of 2 mg of prucalopride and an osmotic laxative on colonic peristalsis, determined by the number of high-amplitude propagating contractions (HAPCs, also known as giant migrating contractions). Compared to osmotic agents, the prokinetic stimulation by prucalopride increased colonic peristalsis, measured by the number of HAPCs over 12 hours after administration (the clinical significance or benefit of this mechanism of action compared to other laxatives has not been evaluated).

Absorption

Prucalopride is rapidly absorbed; after a single oral dose of 2 mg, the maximum concentration (Cmax) is reached within 2-3 hours. The absolute bioavailability after oral administration exceeds 90%. The intake of the drug with food does not affect its bioavailability.

Distribution

The volume of distribution of prucalopride at steady state is 567 L.

The binding to plasma proteins is approximately 30%.

Metabolism

Prucalopride is primarily excreted unchanged. The metabolism of the drug in the human liver in vitro occurs slowly, resulting in the formation of a small number of metabolites. After oral administration of 14C-labeled prucalopride, seven metabolites are detected in urine and feces in small amounts. The main metabolite in feces, R107504, accounted for 3.2% and 3.1% of the dose in urine and feces, respectively.

Other metabolites identified and quantitatively determined in urine and feces included R084536 (formed by N-dealkylation - 3% of the dose) and hydroxylation products (3% of the dose) and N-oxidation (2% of the dose). The unchanged active substance constituted about 92-94% of the total radioactivity in plasma. R107504, R084536, and R104065 (formed by O-demethylation) were identified as secondary plasma metabolites.

Excretion

The majority of orally administered prucalopride is excreted unchanged (approximately 60-65% via the kidneys and at least 5% with feces). The excretion of unchanged prucalopride by the kidneys involves passive filtration and active secretion. The clearance of prucalopride from plasma is on average 317 mL/min, with a terminal half-life of approximately 24 hours.

Steady state is achieved after 3-4 days of drug administration, with a daily dose of 2 mg resulting in minimum and maximum plasma concentrations at steady state of 2.5 and 7 ng/mL, respectively. With once-daily administration, the accumulation ratio of the drug ranges from 1.9 to 2.3.

The pharmacokinetics of prucalopride is linearly dose-dependent up to 20 mg/day. With long-term once-daily administration, its pharmacokinetics do not depend on the duration of treatment.

Special Patient Groups

Population Pharmacokinetics

Population pharmacokinetic analysis showed that the overall clearance of prucalopride correlates with creatinine clearance and is independent of age, body weight, sex, or race of the patients.

Elderly Patients

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

Renal Impairment

Compared to patients with normal kidney function, in patients with mild (creatinine clearance 50-79 mL/min) and moderate (creatinine clearance 25-49 mL/min) renal impairment, the plasma concentration of prucalopride after a single 2 mg dose was increased by 25% and 51%, respectively. In patients with severe renal impairment (creatinine clearance < 24 mL/min), the plasma concentration of prucalopride was 2.3 times higher than in healthy individuals (see sections "Dosage and Administration" and "Special Precautions").Liver ImpairmentApproximately 35% of prucalopride is excreted extrarenally. In a small pharmacokinetic study, Cmax and AUC of prucalopride were on average 10-20% higher in patients with moderate and severe liver impairment compared to healthy subjects (see sections "Dosage and Administration" and "Special Precautions").