Instruction for use: Vegaprat

Dosage form: Film-coated tablets

Active substance: Prucalopride*

Official current instruction

Dosage form

The tablets covered with a film cover.

Composition

Composition per one tablet:

Active substance:

Prukalopride succinate

In terms of Prukalopride

1.321 mg 2.642 mg

1,000 mg 2,000 mg

Excipients:

Microcrystalline cellulose 96,000 mg 192,000 mg

Carboxymethyl starch sodium 1,419 mg 2,838 mg

Magnesium stearate 0,900 mg 1,800 mg

Silicon dioxide colloid 0,360 mg 0,720 mg

Uncoated tablet weight 100,000 mg 200,000 mg

Composition of the shell:

Gipromellose 6 cP 1,800 mg 3,600 mg

Macrogol 6000 0.600 mg 1.200 mg

Titanium dioxide 0.500 mg 1,000 mg

Talc 0.100 mg 0.200 mg

Weight of the tablet with a coat 103,000 mg 206,000 mg

Description of dosage form

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

Pharmachologic effect

Mode of action - Serotonin receptor stimulant.

Pharmacodynamics

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

Pharmacokinetics

Prukalopride is rapidly absorbed; After a single oral dose of 2 mg, the maximum concentration (C max) is achieved after 2-3 hours. Absolute bioavailability after oral administration exceeds 90%. The intake of the drug during meals does not affect bioavailability.

Prukalopride is distributed throughout the body, the volume of distribution in the equilibrium state is 567 liters. Binding to plasma proteins is approximately 30%.

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 ingestion of a 14C labeled prucalopride in urine and feces, 8 metabolites are found in small amounts. The main metabolite (R 107504, formed by O-demethelation of prucalopride and oxidation of the alcohol to carboxylic acid) is 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 metabolite R 107504 is present in the plasma in a small amount

Most of the orally taken dose of the active ingredient is excreted unchanged (approximately 60% by the kidneys and at least 6% with feces). Excretion of unchanged prucalopride by the kidneys includes passive filtration and active secretion. The clearance of prucalopride from plasma is an average of 317 ml / min, the final half-life is approximately 24 hours. The equilibrium state is achieved 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 in the equilibrium state are 2.5 and 7 ng / ml, respectively. When you take 1 time per day, the coefficient k of the drug ranges from 1.9 to 2.3. The pharmacokinetics of prucalopride linearly depend on the dose in the range up to 20 mg / day. With long-term use of the drug once a day, its pharmacokinetics does not depend on the duration of administration.

Pharmacokinetics in selected patient groups

Population pharmacokinetics

Population analysis of pharmacokinetics has shown that the total clearance of prucalopride correlates with creatinine clearance (CC) and does not depend on age, body weight, sex or race of patients.

Elderly patients

When administered to elderly patients at a dose of 1 mg once a day, the maximum concentration of Prucalopride in the blood plasma (C max) and the area under the concentration / time curve (AUC) were 26% and 28%, respectively, greater than in young patients. This difference may be due to the weakening of kidney function in the elderly.

Impaired renal function

Compared to patients with normal renal function, in patients with a weak (KK 50- 79 ml / min) and moderately expressed (KC 25-49 ml / min) renal dysfunction, the concentration of prucalopride in blood plasma after a single dose of 2 mg was Increased by 25% and 51% respectively. In patients with severe renal dysfunction (CC less than 24 ml / min), the concentration of prucalopride in plasma was 2.3 times higher than in healthy people.

Impaired liver function

About 35% of prucalopril is excreted extrarenally, therefore, a violation of liver function is unlikely to clinically significantly change the pharmacokinetics of the drug.

Children

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

Indications

Prukalopride is intended for symptomatic therapy of chronic constipation in women whose laxatives have not provided sufficient effect in eliminating symptoms.

Contraindications

Hypersensitivity to the active ingredient or any auxiliary substance.

Impaired renal function requiring dialysis.

Perforation or bowel obstruction due to anatomical or functional disorders of the intestinal wall, mechanical intestinal obstruction, severe intestinal inflammation, eg Crohn's disease, ulcerative colitis and toxic megalon / megarectum.

Carefully

The use of the drug in patients with severe and clinically unstable concomitant diseases (diseases of the kidneys, lungs, cardiovascular, neurological, endocrine diseases, psychiatric disorders, oncological diseases, AIDS) has not been studied. Caution should be exercised when prescribing Prucalopride in patients with a cardiac arrhythmia or ischemic heart disease in the anamnesis.

Application in pregnancy and breastfeeding

The experience with prucalopride during pregnancy is limited. In clinical trials, incidents of miscarriage have been reported, although, given the presence of other risk factors, the association of these phenomena with prucalopride remains unproven. Studies in animals showed no direct or indirect adverse effects on the course of pregnancy, embryo / fetus development, childbirth and postnatal development of offspring. The drug is not recommended for use during pregnancy. During treatment with prucalopride, women who are capable of giving birth should use adequate methods of contraception.

Prukalopride is excreted in breast milk, however, when applied in therapeutic doses, the drug is unlikely to affect newborns / infants. Due to the lack of data on the use of lactating mothers, the drug is not recommended for use during breastfeeding.

Studies in animals have not revealed any effect of the drug on the fertility of males and females.

Dosing and Administration

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

Adults: 2 mg once daily

Elderly (over 65 years): begin with 1 mg I once a day, if necessary, increase the dose to 2 mg once a day.

Children and adolescents:

Prukalopride is not recommended for use in children and adolescents under 18 years of age.

Freeloaders with impaired renal function: with severe renal dysfunction (glomerular filtration rate less than 30 ml / min / 1.73 m2), the dose is 1 mg 1 time per day.

For patients with mild and moderate renal impairment, dose adjustment is not required.

Freestands with a violation of liver function: with severe liver damage (class C in Child-Pugh), the dose is 1 mg 1 time per day. For patients with mild and moderately severe impairment of liver function, dose adjustment is not required.

Because of the specific mechanism of action of prucalopride (stimulation of intestinal motility) an increase in the daily dose of more than 2 mg is unlikely to lead to an intensification of the effect. If taking prucalopride once a day for 4 weeks does not have an effect, the patient should be re-examined and the expediency of continuing treatment should be determined.

Side effects

The incidence of adverse events following the use of the drug is classified according to WHO recommendations: very often ≥1 / 10; Often ≥1 / 100, <1/10; Infrequently ≥1 / 1000, <1/100; Rarely ≥1 / 10000, <1/1000; Very rarely <1/10000, including isolated cases.

From the nervous system: very often - headache; Often - dizziness; Infrequently - a tremor.

From the side of the cardiovascular system: infrequently - palpitation.

From the side of the digestive system: very often - nausea, diarrhea, abdominal pain; Often - decreased appetite, vomiting, dyspepsia, flatulence, pathological intestinal noises; Infrequently - rectal bleeding, anorexia.

From the genitourinary system: often - pollakiuria.

Other: often - weakness; Infrequently - a fever, bad state of health.

Overdose

Symptoms: are caused by an increase in known side effects of the drug, including headache, nausea and diarrhea. There is no specific antidote for prucalopride.

Treatment: symptomatic and maintenance therapy. A large loss of fluid due to diarrhea or vomiting may require correction of electrolyte imbalance.

Interaction

In vitro data indicate a weak ability of prukalopride to interact, and in therapeutic concentrations it is unlikely to affect the metabolism of concomitant drugs carried out by the enzymes of the cytochrome system. Although prucalopride may mildly bind to P-glycoprotein (P-GP), at clinically significant concentrations it does not inhibit activity (P-GP). A potent inhibitor of CYP 3 A 4 and P-glycoprotein ketoconazole 200 mg twice daily 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 related to the suppression of the pr-glycoprotein-active prucalopride in the kidneys. The same interaction as with ketoconazole can be observed with other inhibitors of P-glycoproteins, for example, verapamil, cyclosporin A and quinidine. Prukalopride, most likely, is also transported in the kidney and other vectors. Theoretically, suppression of the activity of all carriers participating in active secretion of prucalopride in the kidneys (including P-glycoprotein) can increase the level of its systemic exposure by 75%. Studies involving healthy volunteers showed no clinically significant effect of prucalopride on the pharmacokinetics of warfarin, digoxin, ethyl alcohol, and paroxetine. With simultaneous application of prucalopride and erythromycin, the concentration of the latter in the blood plasma increases by 30%. The mechanism of this interaction is not completely clear, but the available data indicate that it is most likely not the result of direct action of prucalopride, but a consequence of the high variability of the pharmacokinetics of erythromycin itself.

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

Interaction with food was not detected.

Special instructions

The main way of deducing prukalopride is through the kidneys. For patients with severe renal dysfunction, the recommended dose is 1 mg.

Severe diarrhea can reduce the effectiveness of oral contraceptives, and additional methods of contraception are recommended to prevent a decrease in the effectiveness of oral contraceptives (see instructions for the use of oral contraceptives).

Violation of the function of the liver is unlikely to have a clinically significant effect on the metabolism and the level of systemic exposure of prucalopride in humans. Data on the use of the drug in patients with mild, moderate or severe impairment of liver function is not available, therefore a lower dose is recommended for patients with severe impairment of liver function.

For prucalopride, neither the rebound phenomenon nor the development of dependence was detected. The study of the effect of prucalopride on the QT interval in therapeutic (2 mg) and suprapatherapeutic (K) mg) dosages did not show any significant differences compared to placebo with respect to QT interval values. The incidence of adverse events associated with QT interval and ventricular arrhythmias was low and comparable to that of placebo.

Influence on ability to drive vehicles or work with mechanisms

Care must be taken when driving a vehicle and servicing moving machinery, because Dizziness and weakness are possible, especially in the first days of treatment.

Release form

Tablets, film-coated, 1 mg and 2 mg. For 10 tablets in a planar cell pack. For 1, 2, 3, 4, 5 or 6 contour mesh packages together with instructions for use in a pack of cardboard.

Storage conditions

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life

2 years. Do not use the product after the expiration date printed on the package.

Terms of leave from pharmacies

According to the doctor's prescription.