Motilium - instructions for use, dose, side effects, contraindications

Excipients (per ml suspension): cellulose microcrystalline and carmellose sodium 12.0 mg, sorbitol liquid, non-crystallized 70% 455.4 mg, methylparahydroxybenzoate 1.8 mg, propyl parahydroxybenzoate 0.20 mg, sodium saccharinate 0.20 mg, polysorbate 20 0.10 mg, sodium hydroxide about 10 μg *, water up to 1.0 ml.

* 0 to 30 mcg.

Description:Homogeneous suspension of white color.

Pharmacotherapeutic group:Antiemetic, dopamine receptor blocker central

ATX: & nbsp

A.03.F.A.03 Domperidone

Pharmacodynamics:

Domperidone is a dopamine antagonist with antiemetic properties. Domperidone poorly penetrates the blood-brain barrier (BBB). The use of domperidone is very rarely accompanied by extrapyramidal side effects, especially in adults, but domperidone stimulates the production of prolactin by the pituitary gland. Its antiemetic effect may be due to a combination of peripheral (gastrokinetic) action and antagonism to dopamine receptors in the chemoreceptor trigger zone located outside the BBB in area postrema. Studies on animals, as well as low concentrations of the drug found in the brain, indicate a predominantly peripheral effect domperidone to dopamine receptors.

When used orally in humans domperidone increases the pressure of the lower sphincter of the esophagus, improves the antroduodenal motility and accelerates the emptying of the stomach. Domperidone has no effect on gastric secretion.

Pharmacokinetics:

Domperidone is rapidly absorbed after ingestion on an empty stomach, the maximum concentration in the blood plasma (C_m_Oh) is reached within 30-60 minutes. Low absolute bioavailability of domperidone when taken orally (about 15%) is associated with extensive metabolism of the first passage in the wall of the intestine and liver. Despite the fact that the bioavailability of domperidone in healthy people increases with taking the drug after a meal, patients with complaints of the gastrointestinal tract (GIT) should take domperidone 15-30 minutes before meals. Reduction of gastric acidity juice reduces the absorption of domperidone. Bioavailability during ingestion decreases with the preliminary intake of cimetidine and sodium bicarbonate. When taking the drug after a meal for maximum absorption, it takes more time, and the area under the curve "concentration of active substance - time" (AUC) slightly increases.

Ingestion domperidone Does not accumulate or induce its own metabolism; the maximum plasma concentration of 21 ng / ml 90 minutes after 2 weeks of oral administration at a dose of 30 mg per day was almost the same as the maximum plasma concentration of 18 ng / ml after the first dose. Domperidone binds to blood plasma proteins by 91-93%, Studies of distribution in animals using a drug labeled with a radioactive isotope showed a significant distribution of the drug in the tissues, but low concentrations in the brain. Small amounts of the drug penetrate the placenta in rats.

Domperidone is rapidly and extensively metabolized in the liver by hydroxylation and N-dealkylation. Metabolic Studies in vitro with the use of diagnostic inhibitors showed that the isoenzyme CYP3A4 is the main form of cytochrome P450 involved in N- dealkylation of domperidone, while isoenzymes CYP3A4, CYP1A2 and CYP2E1 participate in the aromatic hydroxylation of domperidone. Excretion in urine and feces is 31% and 66% of the dose when taken orally, respectively.The proportion of the drug excreted unchanged is small (10% - with feces and about 1% - with urine). The half-life of plasma after a single dose inside is 7-9 hours in healthy people, but increases in patients with severe renal failure. In such patients (serum creatinine level> 6 mg / 100 ml, i.e.> 0.6 mmol / L), the half-life of domperidone increases from 7.4 to 20.8 hours, but the drug concentration in the blood plasma is lower than that of people with normal renal function. A small amount of unchanged drug (about 1%) is excreted by the kidneys.

In patients with impaired liver function of moderate severity (score of 7-9 points for Pugh, Class B on the Child-Pugh scale) AUC and Cmah domperidona in 2.9 and 1.5 times higher than in healthy people, respectively. Unbound fraction is increased by 25%, and the final half-life is increased from 15 to 23 hours. In patients with mild violations of liver function, the systemic effect is somewhat reduced in comparison with that of healthy people on the basis of the values of Cmax and AUC without change binding with proteins or a terminal half-life. Data for patients with severe liver dysfunction are not available. There are no pharmacokinetic data for children.

Indications:

- A complex of dyspeptic symptoms, often associated with delayed emptying of the stomach, gastroesophageal reflux, esophagitis:

- a feeling of overfilling in the epigastrium, early satiety, a sensation of bloating, pain in the upper abdomen;

- eructation, flatulence;

- nausea, vomiting;

- heartburn, regurgitation with or without gastric contents.

- Nausea and vomiting of a functional, organic, infectious origin, caused by radiotherapy, drug therapy or a violation of diet. A specific indication is nausea and vomiting caused by dopamine agonists if used in Parkinson's disease (such as L-opa and bromocriptine).

Contraindications:

- Hypersensitivity to domperidone or any of the components of the drug;

- prolactin-secreting pituitary tumor (prolactinoma);

- simultaneous administration of oral forms of ketoconazole, erythromycin or other strong inhibitors of isoenzyme CYP3A4, causing an elongation interval QT, such as fluconazole, voriconazole, clarithromycin, amiodarone and telithromycin (see section "Interaction with other drugs");

- in cases where the stimulation of gastric motility may be dangerous, for example, with gastrointestinal bleeding, mechanical obstruction or perforation;

- violations of the liver's moderate or severe degree.

Carefully:

- Impaired renal function;

- disturbance of rhythm and conduction of the heart, including prolongation of QT interval, electrolyte balance disturbance, congestive heart failure.

Pregnancy and lactation:

Data on the use of domperidone during pregnancy is not enough. To date, there is no evidence of an increased risk of developmental malformations in humans. Nevertheless, Motilium® should be administered during pregnancy only if its use is justified by the expected therapeutic benefit.

In women, the concentration of domperidone in breast milk is 10 to 50% of the corresponding plasma concentration and does not exceed 10 ng / ml. The total amount of domperidone excreted into breast milk is less than 7 μg per day when the maximum permissible doses of domperidone are administered. It is not known whether this level has a negative effect on newborns.In this regard, when applying MOTILIUM during lactation should stop breastfeeding.

Dosing and Administration:

It is recommended to take Motilium® before meals, in case of reception after eating, absorption of domperidone slightly slows down.

The duration of continuous use of the drug without a doctor's recommendation should not exceed 28 days.

Adults and adolescents older than 12 years and weighing 35 kg or more: 10-20 ml 3-4 times a day. The maximum daily dose is 80 ml (80 mg).

Infants and children under 12 years: 0.25-0.5 mg per 1 kg of body weight 3-4 times a day. The maximum daily dose of domperidone is 2.4 mg / kg, but not more than 80 ml (80 mg). To determine the dose, use the child's body weight scale "0-20 kg” on a syringe.

Use in patients with impaired renal function

Since the half-life of domperidone increases with severe renal dysfunction, the frequency of taking Motilium® should be reduced 1-2 times a day depending on the severity of the disturbances, and a dose reduction may also be required. With prolonged therapy, a regular examination of such patients should be carried out (see section "Special instructions").

Use in patients with impaired hepatic function

Motilium® is contraindicated in patients with moderate or severe liver dysfunction. With light violations of liver function, dose adjustment is not required.

INDICATIONS FOR USE

Before use, mix the contents of the vial, gently shaking to avoid foam formation.

Fig. 1 Suspension is supplied in a package protected from accidental opening by children. The bottle should be opened as follows:

- Press on top of the plastic bottle cap while turning it counter-clockwise;

- remove the unscrewed cover.

Syringe

Fig. 2 Place the syringe in the vial. While holding the lower ring in place, lift the top ring up to the mark that corresponds to your child's weight in kg.

Fig. 3 While holding the lower ring, take out the filled syringe from the vial. Empty the syringe. Close the vial. Rinse the syringe with water.

Side effects:

According to clinical research

Undesirable reactions, observed in ≥1 % patients taking Motilium®: depression, anxiety, decreased or absent libido, headache, drowsiness, akathisia, dry mouth, diarrhea, rash, itching,gynecomastia / breast enlargement, breast sensitivity, galactorrhea, amenorrhea, pain in the mammary glands, menstrual irregularities, lactation, asthenia.

Undesirable reactions, observed in <1% of patientsMotilium®: Hypersensitivity, urticaria, swelling of the mammary glands, discharge from the mammary glands.

According to spontaneous reports of undesirable phenomena

The undesirable effects listed below classified in the following way: very frequent (≥10 %), frequent (≥1%, but <10%), not frequent (≥0.1%, but <1%), rare (≥0,01 %, but <0,1 %) and very rare (<0,01 %), including individual cases.

Impaired immune system. Rarely: anaphylactic reactions, including anaphylactic shock.

Mental disorders. Very rarely: agitation, nervousness (mainly in newborns and children of the first year of life).

Violations from the nervous system. Rarely: extrapyramidal disorders, seizures (mainly in newborns and children of the first year of life).

Disorders from the cardiovascular system. Very rare: prolongation of the QT interval, severe ventricular arrhythmias *, sudden coronary death *.

Disturbances from the skin and subcutaneous tissues. Very rarely: angioedema, hives.

Disorders from the kidneys and urinary tract. Very rarely: retention of urine.

Laboratory and instrumental data. Very rarely: deviations in laboratory parameters of liver function, increased prolactin levels in the blood.

* Some epidemiological studies have shown that the use of domperidone may be associated with an increased risk of developing serious ventricular arrhythmias or sudden coronary death. The risk of these phenomena is more likely in patients over 60 years of age and in patients taking the drug in a daily dose of more than 30 mg. It is recommended to use domperidone in the lowest effective dose in adults and children.

Overdose:

Symptoms

Symptoms of overdose may be: drowsiness, disorientation and extrapyramidal reactions, especially in children.

Treatment

There is no specific antidote of domperidone. In case of overdosage, gastric lavage and the use of activated charcoal are recommended. It is recommended to closely monitor the patient's condition and conduct supportive therapy. Anticholinergics, drugs used to treat parkinsonism, or antihistamines may be effective in the occurrence of extrapyramidal reactions.

Interaction:

Anticholinergic drugs can neutralize the effect of the MOTILUM. The oral bioavailability of the MOTILUM decreases after previous administration of cimetidine or sodium bicarbonate. Do not take antacid and antisecretory drugs at the same time as Motilium, as they reduce its bioavailability after ingestion (see section "Special instructions").

The main role in the metabolism of domperidone is played by the isoenzyme CYP3A4. results research in vitro and clinical experience show that simultaneous use of drugs that significantly inhibit this isoenzyme may cause an increase in domperidone concentrations in plasma. Among the strong inhibitors CYP3A4 relate:

- Azole antifungal drugs, such as fluconazole *, itraconazole, ketoconazole * and voriconazole *;

- Antibiotics-macrolides, for example clarithromycin * and erythromycin *;

- HIV protease inhibitors, for example amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir and saquinavir;

- Calcium antagonists, such as diltiazem and verapamil;

- Amiodarone *;

- Aprepitant;

- Nefazodone.

(Drugs marked with an asterisk, in addition, extend the interval QTc (cm.section "Contraindications")).

In a number of studies on the pharmacokinetic and pharmacodynamic interactions of domperidone with oral ketoconazole and oral erythromycin in healthy volunteers, it has been shown that these drugs significantly inhibit the primary metabolism of domperidone, carried out by the isoenzyme CYP3A4.

When simultaneous administration of 10 mg of domperidone 4 times a day, and 200 mg of ketoconazole 2 times daily observed lengthening the interval QTc on average by 9.8 ms during the whole observation period, at some moments the changes varied from 1.2 to 17.5 ms. With simultaneous administration of 10 mg of domperidone 4 times a day and 500 mg of erythromycin 3 times a day, the interval QTc on average by 9.9 ms during the whole period of observation, at some moments the changes varied from 1.6 to 14.3 ms. In each of these studies, Cmax and AUC domperidone were increased approximately three times (see the section "Contraindications").

At present, it is not known what contribution to changing the interval QTc increased concentrations of domperidone in plasma.

In these studies, monotherapy with domperidone (10 mg four times a day) extended the interval QTc at 1.6 ms (ketoconazole study) and 2.5 ms (erythromycin study), whereas monotherapy with ketoconazole (200 mg twice daily) and monotherapy with erythromycin (500 mg three times a day) resulted in lengthening of the interval QTc at 3.8 and 4.9 msec respectively during the entire observation period.

In another study using multiple doses in healthy volunteers, there was no significant lengthening of the interval QTc during stationary monotherapy with domperidone (40 mg four times a day, total daily dose of 160 mg, which is 2 times the recommended maximum daily dose). At the same time, the concentrations of domperidone in plasma were similar to those in studies of the interaction of domperidone with other drugs.

Theoretically, since MOTILIUM® has a gastrokinetic effect, it could affect the absorption of concomitant oral preparations, in particular, sustained-release preparations or enteric-coated preparations. However, the use of domperidone in patients with paracetamol or digoxin did not affect the level of these drugs in the blood.

MOTILIUM® can be taken at the same time as:

- Neuroleptics, the effect of which it does not increase;

- with dopaminergic receptor agonists (bromocriptine, L-dopa), as it depresses their unwanted peripheral effects, such as digestive disorders, nausea and vomiting, without affecting their central effects.

Special instructions:

When combined with the use of the drug Motilium® with antacid or antisecretory drugs, the latter should be taken after, and not before eating, i.e. they should not be taken at the same time as with Motilium®.

Suspension for oral administration of Motilium® contains sorbitol and is not recommended for use by patients with sorbitol intolerance.

Use in children

Motilium ® in rare cases can cause neurological side effects (see section "Side effect"). The risk of neurological side effects in young children is higher, since the metabolic functions and the blood-brain barrier in the first months of life is not completely developed. In this connection, it follows that it is very accurate to calculate the dose of the drug Motilium® for newborns, children of the first year of life and children of early preschool age and strictly adhere to this dose (see the section "Method of administration and dose").

Neurological adverse effects may be caused in children by an overdose of the drug, but other possible causes of such effects should be taken into account.

Application in diseases of the kidneys

Since the half-life of domperidone increases with severe impairment of kidney function, with repeated use of Motilium®, the frequency of use should be reduced to 1-2 times per day, depending on the severity of renal dysfunction, and it may also be necessary to reduce the dose. With prolonged therapy, a regular examination of such patients should be carried out.

Effects on cardio-cardiovascular system

In some epidemiological studies, it has been shown that the use of domperidone may be associated with an increased risk of serious ventricular arrhythmias or sudden coronary death (see "Side effect" section). Risk may be more likely in patients over 60 years of age and in patients taking the drug at daily doses of more than 30 mg. It is recommended to use domperidone in the lowest effective dose in adults and children.

If the medicine has become unusable or the expiration date has expired, do not throw it into the waste water and into the street!Place the drug in a bag and put it in the trash. These measures will help protect the environment!

Effect on the ability to drive transp. cf. and fur:Motilium® does not have or has a negligible impact on the ability to drive and work with machinery.

Form release / dosage:Suspension for oral administration 1 ml / ml.

Packaging:For 100 ml in a vial of dark glass with a screw cap, protected from accidental opening by children and with a schematic image of the opening of the vial, it is placed together with a dosing syringe and instructions for use in a cardboard pack.

Storage conditions:Store at temperatures between 15 and 30 ° C. Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:П N014062 / 01

Date of registration:19.11.2008 / 17.11.2015

The owner of the registration certificate:Johnson & Johnson, LLC Johnson & Johnson, LLC Russia

Manufacturer: & nbsp

JANSSEN PHARMACEUTICA, N.V. Belgium

Information update date: & nbsp10.01.2016

Illustrated instructions

Instructions

Motilium® (Motilium®)