Motilium of the tab. of p/o of 10 mg No. 30

Structure and form of release

Structure

Active ingredient: domperidone;

1 tablet supports a domperidon of 10 mg;

Excipients: tablet kernel: lactose monohydrate, starch corn cellulose microcrystalline corn potato starch; povidone, magnesium stearate the cottonseed oil hydrogenated sodium lauryl sulfate;

Film cover: gipromelloza, sodium lauryl sulfate.

release Form

Tablet, film coated.

Pharmacological properties

Pharmacodynamics. domperidon — the antagonist of dopamine with antiemetic properties. domperidon slightly gets through geb. application of a domperidon very seldom is followed by extrapyramidal side effects, especially at adults, but at the same time domperidon stimulates prolactin discharge from a hypophysis. its antiemetic action is caused, possibly, by a combination of peripheral (gastrokinetichesky) action and antagonism to dopamine receptors in the trigger zone of chemoceptors which is out of geb in the back field (area postrema). researches on animals and also indicate the low concentration defined in a brain prevalence of peripheral action of a domperidon on dopamine receptors.

Research at the person was shown that at intake domperidon increases pressure in lower parts of a gullet, improves antroduodenal motility and accelerates gastric emptying. Domperidon does not influence gastric secretion.

Pharmacokinetics. Absorption. Domperidon is quickly absorbed at oral administration on an empty stomach, the C _max in blood plasma is reached approximately in 60 min. The low absolute bioavailability of an oral domperidon (≈15%) is caused by extensive metabolism of the first passing in a wall of intestines and in a liver. Though at healthy people the bioavailability of a domperidon increases at its reception after a meal, patients with complaints of gastrointestinal character should accept domperidon in 15–30 min. prior to food. The lowered acidity of a stomach reduces absorption of a domperidon. At oral administration of medicine after a meal the maximum absorption slows down a little.

Distribution. At oral administration domperidon does not kumulirut and does not induce own exchange; The C _max in blood plasma is reached in 90 min. (21 ng/ml) after 2 weeks oral administration on 30 mg/days was almost same, as after reception of the first dose (18 ng/ml). Domperidon for 91–93% contacts proteins of blood plasma. The researches of distribution of a domperidon conducted on animals by means of medicine, marked by radioactive isotope showed its considerable distribution in fabrics, but low concentration in a brain. At animals small amounts of medicine get through a placenta.

Metabolism. Domperidon is quickly and extensively metabolized in a liver by hydroxylation and N-dealkylation.

Removal with urine and a stake makes respectively 31 and 66% of the dose accepted orally. Removal of medicine in not changed look makes a small share (10% — with a stake and 1% — with urine). T _½ after reception of a single dose makes 7–9 h at healthy volunteers of blood plasma, but lasts at patients with a heavy renal failure.

Indication

For reduction of expressiveness of symptoms of nausea and vomiting.

Use

For the reduction of expressiveness of symptoms of nausea and vomiting lasting 48 h

Adults and children are aged more senior than 12 years and with body weight not less than 35 kg: on 1 tablet (10 mg) 3 times a day. The maximum daily dose — 3 tablets (30 mg/days).

Is recommended to take the medicament Motilium ^® to food. Medicine absorption is delayed a little if to accept it after a meal. Duration of treatment should not exceed 1 week.

Contraindication

Motilium® it is contraindicated:

• sick with the established hypersensitivity to medicament or its excipients;
• sick with a prolaktinsekretiruyushchy tumor of a hypophysis (prolaktinomy);
• sick with heavy or moderate abnormal liver functions and/or kidneys (see. Special INSTRUCTIONS);

sick with the known lengthening of intervals of warm conductivity, in particular QTs sick with considerable violations of balance of electrolytes or with background diseases of heart, such as stagnant heart failure (see. Special INSTRUCTIONS);

• sick with a liver failure;
• if stimulation of motive function of a stomach can be dangerous, for example at gastrointestinal bleeding, mechanical impassability or perforation;
• contraindicated simultaneous application of a ketokonazol, erythromycin or other strong CYP inhibitors 3A4;
• contraindicated simultaneous use of the medicines extending an interval of QT such, as flukonazol, erythromycin, itrakonazol, peroral ketokonazol, posakonazol, ritonavir, sakvinavir, telaprevir, vorikonazol, klaritromitsin, Amiodaronum, telitromitsin (see. Special INSTRUCTIONS, INTERACTIONS).

Side effects

Assessment of frequency of emergence of side reactions: very often (≥1/10); often (≥1/100 to 1/10); infrequently (≥1/1000 to 1/100); seldom (≥1/10,000 to 1/1000); very seldom (1/10,000), including the isolated data.

on condition of observance of recommendations about dosing and duration of treatment domperidon it is usually transferred well, the undesirable phenomena arise infrequently.

from the immune system: very seldom — allergic reactions, including an anaphylaxis, an acute anaphylaxis, hypersensitivity.

from an endocrine system: seldom — increase in level of prolactin.

Mental violations: very seldom — nervousness, irritability, excitement, a depression, uneasiness, decrease or lack of a libido.

from nervous system: very seldom — insomnia, dizziness, thirst, spasms, slackness, a headache, drowsiness, an akathisia, extrapyramidal frustration.

from a cardiovascular system: very seldom — hypostasis, heart consciousness, violation of frequency and a rhythm of warm reductions, lengthening of an interval of QT (frequency is unknown) heavy ventricular arrhythmias, ventricular arrhythmias as torsade de pointes, sudden death.

from a digestive tract: seldom — gastrointestinal violations, including abdominal pain, regurgitation, change of appetite, nausea, heartburn, a lock; very seldom — dryness in a mouth, short-term intestinal spasms, diarrhea.

from skin and hypodermic fabrics: very seldom — an itch, a rash; frequency is unknown — urticaria, a Quincke's disease.

from a reproductive system and mammary glands: seldom — a galactorrhoea, increase in mammary glands / a gynecomastia, sensitivity of mammary glands, discharges from mammary glands, an amenorrhea, hypostasis of mammary glands, pain in mammary glands, violation of a lactation, an irregular menstrual cycle.

from a musculoskeletal system and connective tissue: seldom — an onychalgia.

from an urinary system: very seldom — an ischuria, a dysuria, frequent urination.

General frustration: seldom — an adynamy.

from an organ of sight: frequency is unknown — okulogirny crises.

Another: conjunctivitis, stomatitis.

Change of laboratory indicators: very seldom — increase in the AlAT, AsAT and XC level; infrequently — an aberration of indicators of functional tests of a liver; seldom — increase in level of prolactin in blood.

As the hypophysis is out of GEB, domperidon can cause increase in level of prolactin. In isolated cases such giperprolaktinemiya can result in neuroendocrinal side effects, such as galactorrhoea, gynecomastia and amenorrhea.

during post-marketing use of medicine of differences in a profile of safety of a domperidon at adults and children it is not revealed, except for the extrapyramidal frustration and other phenomena (spasms, excitement) connected with central nervous system, noted mainly at children. Special instructions

Motilium® it is not recommended by

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Motilium ^® should be applied with care to patients of advanced age or patients with the available heart disease or a heart disease in the anamnesis.

Cardiovascular effects. Domperidon was connected with prolongation of an interval of QT on the ECG. During post-marketing observation very exceptional cases of prolongation of QT and trembling/fibrillation of ventricles at the patients accepting domperidon are celebrated. These messages included information on patients with other risk factors, electrolytic violations and the accompanying therapy which can be the promoting factors.

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According to the management of ICH-El4, conducted a research with thorough study of an interval of QT at healthy faces. Lengthening of an interval of QT which was observed in a research at application of a domperidon, according to the recommended dosing mode in usual therapeutic doses (on 10 or 20 mg 4 times a day) has no clinical value.

Caution. Domperidon patients should apply with care with a slight abnormal liver function and/or kidneys.

In view of the increased risk of developing ventricular arrhythmia Motilium ^® QTc, to patients with considerable violations of balance of electrolytes (hypopotassemia, a hyperpotassemia, a hypomagnesiemia) either bradycardia or to patients with background diseases of heart, such as stagnant heart failure is contraindicated to apply

at patients with lengthening of intervals of warm conductivity, in particular. It is known that violation of balance of electrolytes (a hypopotassemia, a hyperpotassemia, a hypomagnesiemia) and bradycardia are the states increasing proaritmogenny risk.

in case of signs or symptoms which can be connected with cardiac arrhythmia Motilium's ^{application ®} should be stopped, and to the patient immediately to consult with the doctor.

Renal failure. T _½ a domperidona at a heavy renal failure is extended. At prolonged use the frequency of dosing of a domperidon should be reduced to 1–2 times a day depending on weight of violation. Also there can be a need for a dose decline.

Antiacid or anti-secretory medicines should not take along with oral forms the medicament Motilium ^® as they reduce oral bioavailability of a domperidon (see INTERACTIONS). At the combined application the medicine Motilium ^® should be accepted before food, and antiacid or anti-secretory medicines — after a meal.

Use with ketokonazoly. In interaction researches with an oral form of a ketokonazol the lengthening of a QT interval was noted. Though the value of this research accurately is not established, it is necessary to choose alternative treatment if antifungal therapy ketokonazoly is shown (see INTERACTIONS).

Tablet Motilium ^® contain lactose therefore medicament should not be used at patients with a lactose intolerance, a galactosemia and malabsorption of a glucose/galactose.

Should consider the following information concerning risk of development of complications of the cardiovascular diseases caused by the medicines containing domperidon:

• some epidemiological researches showed that domperidon can be associated with the increased risk of serious ventricular arrhythmias or a sudden cardiac death;
risk of serious ventricular arrhythmias or a sudden cardiac death can be higher than
• at patients aged from 60 years or at oral administration of doses of medicine of 30 mg/days. Therefore it is necessary to apply with care Motilium ^® at patients of advanced age. Patients aged from 60 years before reception Motilium ^® should consult with the doctor;
domperidon should appoint
• adults and children in the lowest effective dose.

Ratio of risk and advantage of a domperidon remains to

favorable.

Use during pregnancy and feeding by a breast. Data of post-marketing application of a domperidon for pregnant women are limited. Therefore Motilium ^® during pregnancy should appoint only when, according to the doctor, the expected positive effect for mother exceeds potential risk for a fruit.

Quantity of a domperidon which can get to an organism of the baby through breast milk, extremely low. The maximum relative dose for babies (%) is estimated at the level of about 0.1% of a dose for mother adjusted for body weight. It is unknown whether it harms the baby, therefore to mothers accepting Motilium ^® , it is necessary to refrain from feeding by a breast. It is necessary to show care with risk factors of lengthening of an interval of QTs at the children who are on breastfeeding. After exposure as a result of penetration of medicine with breast milk it is impossible to exclude emergence of side effects, in particular cardiological.

Children. To use medicament for treatment of children aged from 12 years and with a body weight not less than 35 kg. Domperidon children should appoint in the lowest effective dose during the shortest period.

Influence on ability to steer vehicles or to work with other mechanisms. Considering side effects from nervous system, patients need to be attentive at control of vehicles or work with other mechanisms.

Interaction

Anticholinergic medicines can neutralize anti-dispeptic effect of medicine мотилиум®. in connection with pharmakodinamichesky and/or pharmacokinetic interaction the risk of lengthening of a qt-interval increases.

should not take the antiacid and anti-secretory medicaments along with the medicine Motilium ^® as they reduce its bioavailability after intake (see. Special INSTRUCTIONS).

mainly by means of CYP 3A4. According to the researches in vitro, the combined use of the medicines considerably suppressing this enzyme can lead to increase in level of a domperidon in blood plasma.

At application of a domperidon along with the powerful CYP inhibitors 3A4 capable to extend QT interval, noted clinically significant changes of an interval of QT. Therefore simultaneous application of a domperidon with certain medicines is contraindicated.

All medicines extending QT interval:

• antiarrhytmic medicines of the class IA (for example Disopyramidum, quinidine, hydroquinidine);
• antiarrhytmic medicines of class III (Amiodaronum, dofetilid, dronedaron, ibutilid, sotalol);
• some neuroleptics (for example haloperidol, Pimozidum, sertindol);
• some antidepressants (for example to tsitalopra, estsitalopra);
• some antibiotics (for example levofloxacin, moxifloxacin, erythromycin, Spheromycinum);
• some antifungal medicines (for example pentamidine);
• some antimalarial medicines (for example galofantrin, lyumefantrin);
• some gastrointestinal medicines (for example tsizaprid, dolasetron, prukaloprid);
• some antihistaminic medicines (for example mekvitazin, mizolastin);
• some medicaments used at oncological diseases (for example toremifen, vandetanib, Vincaminum);
• some other medicines (for example bepridit, methadone, difemanit).

Examples of strong CYP inhibitors 3A4 with which it is contraindicated to apply Motilium ^® :

• azolny antifungal medicines, such, as flukonazol *, itrakonazol, ketokonazol * and vorikonazol *;
• makrolidny antibiotics, such, as klaritromitsin * and erythromycin *; protease inhibitors *;
• HIV protease inhibitors, such, as amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir and sakvinavir;
• antagonists of calcium, such as diltiazem and verapamil; Amiodaronum *;
• aprepitant; nefazodon;
• telitromitsin*.

* Prolong QTc interval.

Simultaneous use of the following substances demands care

is careful to apply with the medicines causing bradycardia and a hypopotassemia and also with the following macroleads which can cause lengthening of an interval of QT: azithromycin and roksitromitsin (klaritromitsin it is contraindicated as it is powerful CYP inhibitor 3A4).

Should be applied with care domperidon along with powerful CYP inhibitors 3A4 which did not cause lengthening of an interval of QT, such as indinavir, and patients should be observed carefully in case of signs or symptoms of side effects.

Above-stated list is representative, but not exhaustive.

Motilium can be combined with:

• neuroleptics which action it does not strengthen;
• dofaminergichesky agonists (Bromocriptinum, L-finish singing), which undesirable peripheral effects, such as digestion violation, nausea, vomiting, it suppresses without neutralization of the main properties.

In separate researches pharmacokinetic / pharmakodinamicheskogo interactions of in Vivo at simultaneous oral administration of a ketokonazol or erythromycin at healthy volunteers it is confirmed that these medicines considerably suppress the presistemny metabolism of a domperidon mediated by CYP 3A4. At simultaneous application of 10 mg of a domperidon orally 4 times a day and 200 mg of a ketokonazol orally 2 times a day during observation are noted lengthening of an interval of QTc on average on 9.8 ms; separate values fluctuated from 1.2 to 17.5 ms. At simultaneous application of 10 mg of a domperidon 4 times a day and 500 mg of erythromycin in 3 times a day QTc interval during observation lasted on average on 9.9 ms, the interval of separate values made from 1.6 to 14.3 ms. Equilibrium _{value C max} and AUC of a domperidon were trebled approximately in each of these researches of interaction. Influence of the increased plasma concentration of a domperidon on observed effect of QTc is unknown. In these researches in case of monotherapy domperidony (10 mg orally 4 times a day) the interval of QTc lasted on average on 1.6 ms (research of a ketokonazol) and 2.5 ms (erythromycin research) while application only a ketokonazol (2 times a day) or erythromycin (500 mg 3 times a day) led 200 mg to increase in an interval of QTc during observation on 3.8 and 4.9 ms respectively. Theoretically, as Motilium has pro-kinetic effect on a stomach, it can influence absorption of the oral medicaments used at the same time, in particular on dosage forms of the prolonged release or enterosoluble. However at patients whose condition was already stabilized against the background of use of digoxin or paracetamol the simultaneous application of a domperidon did not influence levels of these medicines in blood.

Symptoms of overdose agitation, violation of consciousness, a spasm, a disorientation, drowsiness and extrapyramidal reactions can be p>

.

Treatment. There is no specific antidote of a domperidon, but in case of considerable overdose the gastric lavage during 1 h after administration of medicament and use of activated carbon and also careful observation of a condition of the patient and maintenance therapy is recommended. Anticholinergic medicines, means for treatment of Parkinson's disease can be effective for control of extrapyramidal reactions.

Storage conditions

Special storage conditions are not required for

. a period of storage — 3 years.