Rezolor

General characteristics. Structure:

Tablets, film coated 1 mg:

Active component: a prukaloprida succinate of 1,321 mg in terms of 1 mg of a prukaloprid.

Excipients:

Tablet kernel: lactoses monohydrate - 149,969 mg, cellulose microcrystallic - 27,00 mg, silicon dioxide colloid - 0,36 mg, magnesium stearate - 1,35 mg, a film covering of white 1 - 6,00 mg.

Structure of a film covering white 1 as a percentage on weight:

Gipromelloza 6 Wednesday - 40%, titanium dioxide - 24%, a macrogoal of 3000 - 8%, triacetin - 6%, lactoses monohydrate - 22%.

Tablets, film coated 2 mg:

Active component: a prukaloprida succinate of 2,642 mg in terms of 2 mg of a prukaloprid.

Excipients:

Tablet kernel: lactoses monohydrate - 165,458 mg, cellulose microcrystallic - 30,00 mg, silicon dioxide colloid - 0,40 mg, magnesium stearate of-1,50 mg, a film covering pink 7,00 mg

Structure of a film covering pink as a percentage on weight:

Gipromelloza 6 Wednesday - 40%, dye ferrous oxide red (E172) – 0,09%, titanium dioxide – 23,88%, a macrogoal of 3000 - 8%, triacetin – 6%, lactoses monohydrate – 22%, indigo carmine (E132) – 0,02%, dye ferrous oxide yellow (E172) – 0,01%.

Description.

Tablets, film coated 1 mg:

Round biconvex tablets, film coated white or almost white color. On one party – an engraving of "PRU 1". On cross section a kernel of a tablet of white or almost white color.

Tablets, film coated 2 mg:

Round biconvex tablets, film coated pink color. On one party – an engraving of "PRU 2". On cross section a kernel of a tablet of white or almost white color. 

Pharmacological properties:

Action mechanism.

Prukaloprid is дигидробензофуранкарбоксамид, increasing motility of intestines. Prukaloprid is the selection, high-affine agonist 5HT4 - serotoninovy receptors that, most likely, explains its action on motility of intestines. Linkng with other types of receptors in vitro was observed only at the concentration of substance exceeding its affinity to HT4-receptors at least by 150 times.

Pharmacokinetics.

Absorption. Prukaloprid is quickly soaked up; after single oral administration of a dose of 2 mg the maximum concentration (Cmax) is reached in 2 – 3 h. Absolute bioavailability after oral administration exceeds 90%. Administration of drug during food does not influence bioavailability.

Distribution. Prukaloprid is distributed on all organism, distribution volume in an equilibrium state (Vdss) makes 567 l. Linkng with proteins of a blood plasma makes about 30%. 

Metabolism.

Metabolism of drug in a liver of the person of in vitro proceeds very slowly, and only a small amount of metabolites is formed. After oral administration by the person of a 14C-marked prukaloprid in urine and Calais in a small amount 8 metabolites are found. The main metabolite (R107504 which is formed by O-demethylation of a prukaloprid and oxidation of the formed alcohol to carboxyacid) makes less than 4% of the entered drug dose. As showed researches with a radioactive label, about 85% of drug remain in not changed look; the metabolite of R107504 is present at plasma in a small amount.

Removal. The most part of orally accepted dose of active component is removed in not changed look (about 60% by kidneys and at least 6% with a stake). Removal of not changed prukaloprid kidneys includes passive filtering and active secretion. The clearance of a prukaloprid from a blood plasma averages 317 ml/min., a final elimination half-life – about 1 day. The equilibrium state is reached in 3 – 4 days of administration of drug, and at reception of a prukaloprid in a dose of 2 mg once a day the minimum and maximum concentration in a blood plasma in an equilibrium state make 2,5 and 7 ng/ml, respectively. At reception once a day the coefficient of k of drug fluctuates from 1,9 to 2,3. The pharmacokinetics of a prukaloprid linearly depends on a dose in the range up to 20 mg/days. At long administration of drug once a day its pharmacokinetics does not depend on reception duration.

Special categories of patients.

Population pharmacokinetics. The population analysis of pharmacokinetics showed that the general clearance of a prukaloprid correlates with clearance of creatinine and does not depend on age, body weight, a floor or race of patients.

Elderly patients. At administration of drug by elderly patients in a dose of 1 mg once a day the maximum concentration of a prukaloprid in a blood plasma (Cmax) and the area under a curve "concentration - time" (AUC) were for 26% and 28% respectively it is, more, than at young patients. This distinction can be connected with weakening of function of kidneys at elderly people.

Renal failure. In comparison with patients with normal function of kidneys, at patients with weak (clearance of creatinine of 50-79 ml/min.) and moderately expressed (KK of 25-49 ml/min.) a renal failure concentration of a prukaloprid in a blood plasma after a single dose in a dose of 2 mg was increased for 25% and 51%, respectively. At patients with a heavy renal failure (clearance of creatinine less than 24 ml/min.) concentration of a prukaloprid in a blood plasma was 2,3 times higher, than at healthy people.

Abnormal liver function. About 35% of a prukaloprid are removed ekstrarenalno therefore the abnormal liver function will hardly clinically significantly change drug pharmacokinetics.

Children. After single oral administration of a prukaloprid in a dose of 0,03 mg/kg by children at the age of 4 – 12 years the maximum concentration (Cmax) of drug was same as after administration of drug by adults in a dose of 2 mg, and the area under a curve "concentration time" (AUC) of untied fraction of drug was 30 - 40% less, than at adults, and did not depend on age of children. The average elimination half-life of drug in a terminal phase makes at children about 19 h (range of 11,6 - 26,8 h). 

Indications to use:

Rezolor is intended for symptomatic therapy of a chronic lock at women at whom purgatives did not provide sufficient effect in elimination of symptoms.

Route of administration and doses:

Drug is accepted inside, irrespective of meal, at any time. Adults: 2 mg once a day. 

Elderly (65 years are more senior): begin with 1 mg once a day, if necessary, raise a dose to 2 mg once a day.

Children and teenagers: Rezolor is not recommended to apply at children and teenagers 18 years are younger.

Patients with a renal failure: at a heavy renal failure (a glomerular filtration rate less than 30 ml/min./1,73 sq.m) the dose makes 1 mg once a day. For patients with the weak and moderately expressed renal failure of dose adjustment it is not required.

Patients with an abnormal liver function: at a heavy abnormal liver function (a class C on Chayld-Pyyu) the dose makes 1 mg once a day. For patients with the weak and moderately expressed abnormal liver function of dose adjustment it is not required. Because of the specific mechanism of action of a prukaloprid (stimulation of motility of intestines) more than 2 mg will hardly lead increase in a daily dose to strengthening of effect. If reception of a prukaloprid once a day within 4 weeks does not give effect, it is necessary to inspect repeatedly the patient and to define expediency of continuation of treatment.

Features of use:

The main way of removal of a prukaloprid – through kidneys. For patients with a heavy renal failure the recommended dose makes 1 mg.

At heavy diarrhea efficiency of oral contraceptives can decrease, and it is recommended to use additional methods of contraception for prevention of decrease in efficiency of oral contraceptives (see application instructions of oral contraceptives).

The abnormal liver function hardly clinically significantly influences metabolism and level of system influence of a prukaloprid at people. There are no data on use of drug for patients with the weak, moderately expressed or heavy abnormal liver function therefore for patients with a heavy abnormal liver function the smaller dose is recommended.

Drug contains lactoses monohydrate therefore patients cannot accept drug with inborn deficit of lactase, a lactose intolerance or with glyukozo-galaktozny malabsorption. For a prukaloprid neither the phenomenon of a ricochet, nor dependence development was revealed. Studying of influence of a prukaloprid on QT interval in therapeutic (2 mg) and supraterapevtichesky (10 mg) dosages did not show essential differences in comparison with placebo concerning values of an interval of QT. Frequency of the undesirable phenomena connected with QT interval and ventricular arrhythmias was low and comparable to that against the background of placebo reception.

Influence on ability to drive the car and other mechanical means. Researches of influence of a prukaloprid on ability to drive the car and moving mechanisms were not conducted. In certain cases drug use Rezolor contacted development of dizziness and weakness, especially in the first days of treatment that can influence ability to drive the car and moving mechanisms.

Side effects:

Rezolor the headache and undesirable reactions from digestive tract (an abdominal pain, nausea, diarrhea) were the most frequent undesirable reactions at drug use, each of which was observed approximately at 20% of patients. Undesirable reactions developed preferential in an initiation of treatment and usually disappeared in several days, without demanding treatment cancellation. Other undesirable reactions were observed incidentally. The majority of adverse undesirable reactions were weak or moderate severity.

At the recommended dose of a prukaloprid of 2 mg in clinical trials the following undesirable reactions which frequency is designated as are registered:

- very often (≥1/10);

- often (≥1/100, <1/10);

- infrequently (≥1/1000, <1/100);

- seldom (≥1/10000, <1/1000);

- very seldom (<1/10000), including isolated cases.

From the central nervous system:

- very often: headache;

- often: dizziness;

- infrequently: tremor.

From cardiovascular system:

- infrequently: heartbeat.

From digestive tract:

- very often: nausea, diarrhea, abdominal pain;

- often: vomiting, dyspepsia, rectal bleeding, meteorism, pathological intestinal noise;

- infrequently: anorexia.

From urinogenital system

- often: pollakiuria.

The general:

- often: weakness;

- infrequently: fever, feeling sick.

Interaction with other medicines:

These in vitro testify to weak ability of a prukaloprid to interaction, and in therapeutic concentration it hardly influences the metabolism of at the same time used drugs which is carried out by enzymes of system of cytochrome. Though прукалоприд can poorly contact the R-glycoprotein (R-GP), in clinically significant concentration it does not brake activity (R-GP).

Powerful CYP3A4 inhibitor and the R-glycoprotein кетоконазол in a dose of 200 mg 2 times a day increased AUC (the area under a curve "concentration time") a prukaloprida approximately by 40%. This effect is too small to be clinically significant, and, most likely, is connected with suppression of the active transport of a prukaloprid which is carried out by the R-glycoprotein in kidneys. The same interaction as with ketokonazoly, it can be observed also with other active inhibitors of the R-glycoprotein, for example, verapamil, cyclosporine A and quinidine. Prukaloprid, most likely, is also transported in kidneys and other carriers. Theoretically, suppression of activity of all carriers participating in active secretion of a prukaloprid in kidneys (including the R-glycoprotein), can increase the level of its system impact on 75%.

Researches with participation of healthy volunteers showed lack of clinically significant influence of a prukaloprid on pharmacokinetics of warfarin, digoxin, alcohol and a paroksetin. At simultaneous use of a prukaloprid and erythromycin concentration of the last in a blood plasma increases by 30%. The mechanism of this interaction is up to the end not clear, but the available data indicate that it, most likely, is result not of direct action of a prukaloprid, and a consequence of high variability of pharmacokinetics of the erythromycin.

Probenetsid, Cimetidinum, erythromycin and пароксетин in therapeutic doses did not influence pharmacokinetics of a prukaloprid.

Drug Rezolor should be used with care along with the drugs capable to extend QTc interval.

Atropinopodobny substances can weaken the effects of a prukaloprid mediated through HT4 receptors. Interaction with food is not revealed.

Contraindications:

Hypersensitivity to active component or any excipient.

The renal failure demanding carrying out dialysis.

Perforation or obstruction of intestines owing to anatomic or functional disturbances of a wall of intestines, mechanical intestinal impassability, a heavy inflammation of intestines, for example, a disease Krone, ulcer colitis and toxic megacolon / megarectum.

Inborn deficit of lactase, lactose intolerance, glyukozo-galaktozny malabsorption.

With care:

Use of drug for patients with heavy and clinically unstable associated diseases (diseases of a liver, lungs, cardiovascular, neurologic, endocrine diseases, mental disorders, oncological diseases, AIDS) was not studied. It is necessary to show care at purpose of drug Rezolor the patient with such diseases. In particular, it is necessary to use with care drug at patients with cardiac arrhythmia or coronary heart disease in the anamnesis.

Overdose:

The research with participation of healthy volunteers showed what прукалоприд is well transferred at increase in a dose to 20 mg once a day (in 10 times more of the recommended therapeutic dose). The overdose can lead to the symptoms caused by strengthening of the known side effects of drug including a headache, nausea and diarrhea. The specific antidote for drug Rezolor does not exist. In case of overdose it is necessary to carry out a symptomatic and maintenance therapy if necessary. Big loss of liquid as a result of diarrhea or vomiting can demand correction of disturbances of electrolytic balance. 

Storage conditions:

To store in original packaging at a temperature not above 25 °C. To store in the place, unavailable to children. To store in original packaging for protection against moisture.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated 1 mg and 2 mg. On 7 tablets in the blister from AL/AL. On 1, 2, 3, 4, 5, 6, 7 or 8 blisters together with the application instruction in a pack cardboard.