Composition, form of production and packaging
The tablets covered with a film shell of white or almost white color, round biconcave, on one side engraving "PRU 1"; on the cross-section the core of the tablet is white or almost white.
prukalopride succinate 1.321 mg,
which corresponds to the content of prucalopride 1 mg
[PRING] tablet core: lactose monohydrate - 149.969 mg, microcrystalline cellulose - 27 mg, silicon dioxide colloid - 0.36 mg, magnesium stearate - 1.35 mg, film coating white 1 - 6 mg.
The composition of the film coating of white 1 in percent by weight: hypromellose 6 cP - 40%, titanium dioxide - 24%, macrogol 3000 - 8%, triacetin - 6%, lactose monohydrate - 22%.
7 pcs. - blisters (4) - packs of cardboard.
The tablets covered with a film cover of pink color, round biconcave, on one side - engraving "PRU 2", on a cross section the core of a tablet of white or almost white color.
prukalopride succinate 2.642 mg,
which corresponds to the content of prukalopride 2 mg
[PRING] tablet core: lactose monohydrate - 165.458 mg, microcrystalline cellulose - 30 mg, silicon dioxide colloid - 0.4 mg, magnesium stearate - 1.5 mg, film coating pink - 7 mg.
The composition of the film coating of pink in percentage by mass: hypromellose 6 cP - 40%, iron dye oxide red (E172) - 0.09%, titanium dioxide 23.88%, macrogol 3000 8%, triacetin 6%, lactose monohydrate 22% indigo carmine (E132) - 0.02%, iron dye oxide yellow (E172) - 0.01%.
7 pcs. - blisters (4) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2014.
Mechanism of action
Prukalopride is a dihydrobenzofurancarboxamide that enhances intestinal motility. Prukalopride is a selective, high affinity agonist of 5HT 4 -serotonin 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 HT 4 receptors by at least 150 times.
Prukalopride is rapidly absorbed; after a single oral dose of 2 mg, the maximum concentration (C max ) is reached after 2-3 hours. Absolute bioavailability after oral administration exceeds 90%. The intake of the drug during meals does not affect the bioavailability.
Prukalopride is distributed throughout the body, the volume of distribution in the equilibrium state (V d ss ) is 567 liters. Binding to plasma proteins is approximately 30%.
The metabolism of the drug in the human liver in vitro is very slow, and only a small amount of metabolites is formed. After oral administration of 14 C-labeled prukalopride in human urine and feces, 8 metabolites are detected in small amounts. The main metabolite (R107504, formed by O-demethylation of prukalopride 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; Metabolite R107504 is present in the plasma in small amounts.
Most of the orally taken dose of the active ingredient is excreted unchanged (approximately 60% by the kidneys and at least 6% with feces). The excretion of unchanged prucalopride by the kidneys includes passive filtration and active secretion. The clearance of prucalopride from blood plasma is on average 317 ml / min, the final T 1/2 is approximately 1 day. 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 administered once a day, the k-factor varies 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.
Special categories of patients
Population pharmacokinetics analysis showed that the total clearance of prucalopride correlates with creatinine clearance (CC) and does not depend on the age, body weight, sex or race of patients.
When receiving the drug in elderly patients at a dose of 1 mg 1 time per day, C max prukalopride in plasma and the area under the concentration-time curve (AUC) were 26% and 28%, respectively, higher than in young patients. This difference may be due to the weakening of kidney function in the elderly.
Impaired renal function
Compared with patients with normal renal function, in patients with a weak (KK 50-79 ml / min) and moderately expressed (KK 25-49 ml / min) impaired renal function, the concentration of prucalopride in the 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 blood 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.
After a single oral dose of prucalopride at a dose of 0.03 mg / kg in children aged 4-12 years, the C max 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% than in adults, and did not depend on the age of the children. The median T 1/2 of the drug in the terminal phase is approximately 19 hours in children (range 11.6-26.8 h).
- Resolor is intended for symptomatic therapy of chronic constipation in women, in whom laxatives have not provided sufficient effect in eliminating symptoms.
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 of age) : begin with 1 mg 1 time per day, if necessary, increase the dose to 2 mg 1 time per day. Children and adolescents : Resolor is not recommended for children and adolescents under the age of 18 years.
Patients with impaired renal function with severe renal dysfunction (glomerular filtration rate less than 30 ml / min / 1.73 m) dose is 1 mg 1 time per day. For patients with mild and moderate impairment of renal function, dose adjustment is not required.
Patients with impaired hepatic function: with severe violations of the liver (class C in Child-Pugh), the dose is 1 mg 1 time per day. For patients with a mild and moderately severe impairment of liver function, dose adjustment is not required.
Because of the specific mechanism of action of prukalopride (stimulation of intestinal motility) an increase in the daily dose of more than 2 mg is unlikely to lead to an enhanced 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.
The most frequent undesirable reactions with the use of the Resolor drug were headache and undesirable reactions from the gastrointestinal tract (abdominal pain, nausea, diarrhea), each of which was observed in approximately 20% of patients. Unwanted reactions developed mainly at the beginning of treatment and usually disappeared after a few days, without requiring the withdrawal of treatment. Other adverse reactions were observed episodically. Most adverse adverse reactions were of mild to moderate severity.
At the recommended dose of prucalopride 2 mg, the following undesirable reactions were recorded in clinical trials, the frequency of which is indicated as 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 side of the central nervous system: very often - headache; often - dizziness; infrequently - a tremor.
From the side of the cardiovascular system: infrequently - palpitations.
From the gastrointestinal tract: very often - nausea, diarrhea, abdominal pain; often - vomiting, indigestion, rectal bleeding, flatulence, pathological intestinal noises;infrequently - anorexia.
From the genitourinary system: often - pollakiuria.
General: often - weakness; infrequently - a fever, bad state of health.
- hypersensitivity to the active component or any auxiliary substance;
- renal dysfunction, requiring dialysis;
- perforation or bowel obstruction due to anatomical or functional disturbances of the intestinal wall, mechanical intestinal obstruction, severe intestinal inflammation, eg 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, psychiatric disorders, oncological diseases, AIDS) has not been studied. Care should be taken when prescribing Resolor to patients with such diseases. In particular, caution should be used in patients with cardiac arrhythmia or ischemic heart disease in history.
PREGNANCY AND LACTATION
The experience with prucalopride during pregnancy is limited. In clinical trials, cases of miscarriage have been recorded, 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 / fetal development, childbirth and postnatal development of offspring. The drug Resolor is not recommended for use during pregnancy. During the treatment with prukalopride, women who are capable of giving birth should use adequate methods of contraception.
Prukalopride is excreted in breast milk, but 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.
Ability to conceive
Studies in animals have not revealed any effect of the drug on the fertility of males and females.
APPLICATION FOR FUNCTIONS OF THE LIVER
With severe renal dysfunction (glomerular filtration rate less than 30 ml / min / 1.73 m 2 ) the dose is 1 mg 1 time / day. For patients with mild and moderate impairment of renal function, dose adjustment is not required.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
In severe violations of the liver (class C on Child-Pugh) dose is 1 mg 1 time / day. For patients with a mild and moderately severe impairment of liver function, dose adjustment is not required.
APPLICATION FOR CHILDREN
Resolor is not recommended for use in children and adolescents under the age of 18 years.
APPLICATION IN ELDERLY PATIENTS
Elderly (over 65 years): begin with 1 mg 1 time per day, if necessary, increase the dose to 2 mg once a day.
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.
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.
The drug contains lactose monohydrate, so the drug can not be taken by patients with congenital deficiency of lactase, lactose intolerance or glucose-galactose malabsorption.
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 supra-therapeutic (10 mg) dosages did not show significant differences compared to placebo for QT interval values.
The incidence of adverse events associated with QT interval and ventricular arrhythmias was low and comparable to that of placebo.
Impact on the ability to drive vehicles and manage mechanisms
Studies of the effect of prucalopride on the ability to drive and move vehicles have not been carried out. In some cases, the use of Resolor has been associated with the development of dizziness and weakness, especially in the early days of treatment, which may affect the ability to drive and move vehicles.
A study with healthy volunteers showed that prucalopride is well tolerated when the dose is raised to 20 mg once a day (10 times the recommended therapeutic dose).
Overdose can lead to symptoms caused by an increase in known side effects of the drug, including headache, nausea and diarrhea.
Specific antidote for the drug Resolor does not exist. In case of an overdose, symptomatic and supportive therapy should be carried out if necessary. A large loss of fluid due to diarrhea or vomiting may require correction of electrolyte imbalance.
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), it does not inhibit activity (P-GP) at clinically significant concentrations.
A potent inhibitor of CYP3A4 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 active inhibitors of the P-glycoprotein, 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 is increased 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.
The drug Resolor should be used with caution at the same time with drugs that can extend the QTc interval.
Atropine-like substances can weaken the effects of prucalopride mediated through HT4 receptors.
Interactions with food not detected
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored in the original packaging packaging to protect it from moisture out of reach of children at a temperature of no higher than 25 В° C. Shelf life - 3 years. Do not use after the expiration date.