Resolor® [Prucalopride]

Brand Janssen Pharmaceuticals N.V.

All payments are SSL encrypted
Full Refund if you haven't received your order
International shipping to the USA, UK and Europe

Clinical Pharmacology

Pharmacodynamics

Mechanism of action

Prukaloprid is dihydrobenzofurancarboxamide, which enhances intestinal motility. Prucalopride is a selective, high affinity 5HT agonist.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 NT₄receptors at least 150 times.

Pharmacokinetics

Suction

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

Distribution

Prukaloprid is distributed throughout the body, the volume of distribution in the equilibrium state (V_d^ss ) is 567 liters. Plasma protein binding is approximately 30%.

Metabolism

The drug's metabolism in the human liver in vitro is very slow, and only a small amount of metabolites is formed. After oral administration by man ¹⁴C-labeled prucaloprid in the urine and feces in a small amount are found 8 metabolites. The main 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. Studies have shown with a radioactive label, about 85% of the drug remains unchanged; metabolite R107504 is present in plasma in a small amount.

Removal

Most of the orally taken dose of the active component 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 plasma clearance of prucalopride is on average 317 ml / min, the final T_1/2 - about 1 day. The equilibrium state is reached after 3-4 days of taking the drug, and when taking prukaloprid 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 taken once a day, the coefficient k of the drug ranges from 1.9 to 2.3. The pharmacokinetics of prucalopride is linearly dependent on the dose in the range of up to 20 mg / day. With long-term use of the drug 1 time per day, its pharmacokinetics does not depend on the duration of administration.

Special categories of patients

Population pharmacokinetics

A population analysis of pharmacokinetics showed that total clearance of prucalopride correlates with creatinine clearance (CK) and does not depend on the age, body weight, gender, or race of the patients.

Elderly Sick

When taking the drug in elderly patients at a dose of 1 mg 1 time per day C_max Prucalopride in plasma and the area under the concentration-time curve (AUC) were 26% and 28%, respectively, larger than in younger patients. This difference may be due to impaired kidney function in the elderly.

Renal dysfunction

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

Liver dysfunction

About 35% of prucaloprid is excreted extrarenally, therefore, an abnormal liver function is unlikely to clinically significantly change the pharmacokinetics of the drug.

Children

After a single oral administration of prucaloprid at a dose of 0.03 mg / kg in children aged 4–12 years C_max the drug was the same as after taking the drug by 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. Average t_1/2 drug in the terminal phase is approximately 19 hours in children (range 11.6-26.8 hours).

Indications

Resolor is intended for the symptomatic treatment of chronic constipation in women whose laxatives have not provided sufficient effect in the elimination of symptoms.

Composition

1 tablet contains:

Active substances: prukaloprid succinate 1,321 mg, which corresponds to the content of prukaloprid 1 mg.

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.

The composition of the film coating white 1 in percent by weight: hypromellose 6 cP - 40%, titanium dioxide - 24%, macrogol 3000 - 8%, triacetin - 6%, lactose monohydrate - 22%.

No customer reviews for the moment.

Write your review

Dosage and Administration

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

Adults: 2 mg once a day.
Older people (over 65): Start with 1 mg once a day, if necessary, increase the dose to 2 mg once a day.
Children and teenagers: Resolor is not recommended for use in children and adolescents younger than 18 years.

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

Patients with impaired liver function: in severe hepatic impairment (class C on Child-Pugh) dose is 1 mg 1 time per day. For patients with mild and moderate hepatic impairment dose adjustment is not required.

Due to the specific mechanism of action of prucaloprid (stimulation of intestinal motility), an increase in the daily dose of more than 2 mg is unlikely to increase the effect. If taking prukaloprid 1 time per day for 4 weeks does not give effect, you should re-examine the patient and determine the feasibility of continuing treatment.

Adverse reactions

The most frequent adverse reactions in the use of the drug Resolor were headache and adverse reactions from the gastrointestinal tract (abdominal pain, nausea, diarrhea), each of which was observed in about 20% of patients. Adverse reactions developed predominantly at the beginning of treatment and usually disappeared after a few days, without requiring cancellation of treatment. Other undesirable reactions were observed sporadically. Most adverse reactions were mild or moderate.

At the recommended dose of prucaloprid 2 mg, the following adverse reactions were recorded in clinical studies, 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 - tremor.

Since the cardiovascular system: infrequently - heartbeat.

From the gastrointestinal tract: very often - nausea, diarrhea, abdominal pain; often - vomiting, dyspepsia, rectal bleeding, flatulence, abnormal intestinal noise; infrequently - anorexia.

From the genitourinary system: often - pollakiuria.

Are common: often - weakness; infrequently - fever, feeling unwell.

Contraindications

Carefully: The use of the drug in patients with severe and clinically unstable concomitant diseases (diseases of the liver, lungs, cardiovascular, neurological, endocrine diseases, mental disorders, oncological diseases, AIDS) has not been studied. Caution should be exercised in the appointment of the drug Resolor® patients with such diseases. In particular, the drug should be used with caution in patients with cardiac arrhythmias or ischemic heart disease in history.

Drug interactions

In vitro data indicate a weak ability of prucaloprid to interact, and at therapeutic concentrations it is unlikely to affect the metabolism of simultaneously used drugs by cytochrome system enzymes. Although prucalopride may poorly bind to P-glycoprotein (P-HP), in clinically significant concentrations it does not inhibit activity (P-HP).

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

Studies with healthy volunteers showed no clinically significant effect of prucalopride on the pharmacokinetics of warfarin, digoxin, ethyl alcohol, and paroxetine. With the simultaneous use of prucaloprid 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 the direct action of prucalopride, but the result of the high variability of the pharmacokinetics of erythromycin itself.

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

Resolor should be used with caution along with drugs that can lengthen the QTc interval.

Atropin-like substances may weaken the effects of prucalopride mediated through NT receptors.₄.

No interaction with food detected.

Pregnancy and Lactation

Pregnancy

Experience with prucalopride during pregnancy is limited. In clinical studies, cases of miscarriage have been reported, although, given the presence of other risk factors, the association of these phenomena with the use of prucalopride remains unproven. Animal studies have not revealed a direct or indirect adverse effect on the course of pregnancy, embryo / fetus development, childbirth, and postnatal development of the offspring. The drug Resolor is not recommended for use during pregnancy. During the period of treatment with prucalopride, women capable of childbirth should use adequate methods of contraception.

Lactation period

Prukaloprid 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 the use of nursing mothers, the drug is not recommended for use during breastfeeding.

Ability to conceive

Animal studies have not revealed any effect of the drug on the fertility of the male and female individuals.

Special instructions

The main route of elimination of prucaloprid is through the kidneys. For patients with severely impaired renal function, the recommended dose is 1 mg.

In 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. Impaired liver function is unlikely to have a clinically significant effect on metabolism and the level of systemic exposure to prucalopride in humans. There is no data on the use of the drug in patients with mild, moderate or severe liver dysfunction, therefore, a lower dose is recommended for patients with severe liver dysfunction.

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

For prucalopride, neither the rebound phenomenon nor the development of dependence was identified. Studying the effect of prucalopride on the QT interval in therapeutic (2 mg) and supra-therapeutic (10 mg) dosages did not show significant differences compared with placebo in relation to the values of the QT interval.

The incidence of adverse events associated with the QT interval and ventricular arrhythmias was low and comparable with placebo.

Impact on the ability to drive vehicles and other mechanisms that require high concentration of attention

Studies of the effect of prucalopride on the ability to drive and moving machinery was not conducted. In some cases, the use of the drug Resolor® was 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 moving machinery.

Overdosage

A study with healthy volunteers showed that prukaloprid was well tolerated when the dose was increased to 20 mg 1 time per day (10 times the recommended therapeutic dose).

Overdose can lead to symptoms due to increased 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 carried out if necessary. Large fluid loss due to diarrhea or vomiting may require correction of electrolyte imbalance.