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

Domperidone is a dopamine antagonist, having antiemetic properties. but domperidone poorly penetrates the blood-brain barrier. The use of domperidone is rarely accompanied by extrapyramidal side effects, especially in adults, but domperidone stimulates the release of prolactin from 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. Animal studies and low drug concentrations found in the brain indicate a central effect of domperidone on dopamine receptors.

When administered orally domperidone increases the duration of antrum and duodenal reductions,accelerates the emptying of the stomach and increases the pressure of the sphincter of the lower esophagus in healthy people. Domperidone has no effect on gastric secretion.

Pharmacokinetics:

Domperidone is rapidly absorbed after ingestion on an empty stomach, peak concentrations in the plasma are reached within 30-60 minutes. Low absolute bioavailability of domperidone when taken orally (approximately 15%) is associated with an intensive metabolism of the first passage in the intestinal wall and liver.

Domperidone should be taken 15-30 minutes before meals. Reduction of acidity in the stomach leads to a violation of absorption of domperidone. Bioavailability during ingestion decreases with the preliminary intake of cimetidine and sodium bicarbonate. When taking the drug after a meal, maximum time is required to achieve maximum absorption, and the area under the pharmacokinetic curve (AUC) slightly increases.

Ingestion domperidone Does not accumulate or induce its own metabolism; peak the 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 a peak plasma concentration of 18 ng / ml after the first dose. Domperidone binds to plasma proteins at 91-93%. Studies of distribution with a radioactive label in animals 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 undergoes rapid and intensive metabolism by hydroxylation and N-dealkylation. Metabolic Studies in vitro with diagnostic inhibitors have shown that isoenzyme CYP3A4 is the main form of cytochrome P450 involved in N-dealkylation of domperidone, while CYP3A4, CYP1A2 and CYP2E1 participate in 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 approximately 1% in urine). Plasma half-life after a single oral intake is 7-9 hours in healthy volunteers, but increases in patients with severe renal failure.

In these patients (serum creatinine> 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 plasma is lower than in healthy volunteers .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, B score for Child-Pugh) AUC and the maximum concentration in plasma (C_m_Oh) domperidone were 2.9 and 1.5 times higher than in healthy volunteers, respectively. The unbound fraction was increased by 25%, and the half-life increased from 15 to 23 hours. In patients with mild violations of liver function, slightly reduced systemic levels of the drug were observed compared with those in healthy volunteers based on C_m_Oh and AUC without changes in binding to proteins or half-life. Patients with severe impairment of liver function were not studied.

Indications:

a) Complex of dyspeptic symptoms, often associate with a delayed emptying of the stomach, gastroesophageal: reflux, esophagitis:

- a feeling of overflow in the epigastrium, a sensation of bloating, a pain in the upper abdomen;

- eructation, flatulence;

- nausea, vomiting;

- heartburn, belching.

b) Nausea and vomiting of a functional, organic, infectious origin, as well as caused by radiotherapy, drug therapy or a violation of diet.A specific indication is nausea and vomiting caused by dopamine agonists in the case of Parkinson's disease (such as levodopa and bromocriptine).

Contraindications:

- established intolerance of the drug and its components;

- prolactin-secreting pituitary tumor (prolactinoma);

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

- gastrointestinal bleeding, mechanical obstruction or perforation (i.e., when stimulation motor function of the stomach can be dangerous);

- children under 5 years of age (for this dosage form);

- violations of liver function of medium and severe degree;

- phenylketonuria.

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:

Application during pregnancy

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 given during pregnancy only if its use is justified by the expected therapeutic benefit.

Application during lactation

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 using the drug Motilium® during lactation should stop breastfeeding.

Dosing and Administration:

Inside. It is recommended to take Motilium® tablets before meals, in case of their intake after eating, the absorption of domperidone may slow down. Duration of continuous use of the drug without the doctor's recommendation should not exceed 28 days.

Adults and children over 12 years of age and body weight 35 kg and more:

1-2 tablets of 10 mg 3-4 times a day. The maximum daily dose is 8 tablets (80 mg).

Children aged 5 to 12 years and weighing 35 kg or more:

1 tablet of 10 mg 3-4 times a day. The maximum daily dose of domperidone is not more than 8 tablets (80 mg).

Use in children Resolute tablets Motilium® are indicated only for children weighing 35 kg or more, in pediatric practice, the Motilium® suspension should generally be used. Use in patients with impaired renal function The frequency of taking Motilium® should be reduced to 1-2 times per day, depending on the severity of the disorders, a dose reduction may also be required. A regular examination of such patients should be carried out (see section "Special instructions").

Use in patients with impaired hepatic function

Do not use Motilium ® for violations of the liver function of medium and severe degree. With light violations of liver function, dose adjustment is not required.

INDICATIONS FOR USE

Because the resorption tablets are rather fragile, they should not be pierced through the foil to avoid damage. In order to get a tablet from the blister, you need the following:

- Take the foil by the edge and completely remove it from the cell in which the tablet is located (Fig. 1);

- gently push downwards (Fig. 2);

- remove the tablet from the package (Fig. 3).

Put the tablet on the tongue. Within a few seconds it will break up on the surface of the tongue, it can be swallowed with saliva, without washing down 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, galactorrhea, gynecomastia, pain and sensitivity in mammary glands, menstrual disorders and amenorrhea, lactation, asthenia.

Undesirable reactions, observed in <1% of patients taking Motilium®: hypersensitivity, urticaria, swelling and 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. Very rarely: anaphylactic reactions, including anaphylactic shock.

Mental disorders. Very rarely: agitation, nervousness (mainly in newborns and children).

Violations from the nervous system. Very rarely: extrapyramidal disorders, convulsions (mainly in newborns and children).

Disorders from the cardiovascular system. Very rarely: lengthening the interval QT, ventricular arrhythmia *, sudden coronary death *.

Disturbances from the skin and subcutaneous tissues. Very rarely: Quincke's edema, hives.

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

Laboratory and instrumental data. Very rarely: abnormalities in laboratory parameters of liver function, increased prolactin levels of 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 death. The risk of these events is more likely in patients over 60 years of age and in patients taking the drug at 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 occur most often in infants and children and can include: agitation, impaired consciousness, convulsions, disorientation, drowsiness and extrapyramidal disorders.

Treatment

There is no specific antidote for domperidone. In case of an overdose, it is recommended to wash the stomach and take activated charcoal, close supervision and supportive therapy. To correct extrapyramidal manifestations, anticholinergics and anti-Parkinsonics can be used.

Interaction:

Anticholinergic drugs can neutralize the effect of the drug Motilium®. Bioavailability of the drug Motilium® at ingestion decreases after the previous intake of cimetidine or sodium bicarbonate. Do not take antacid and antisecretory drugs at the same time as domperidone, 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. Research results 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 powerful inhibitors CYP3A4 relate:

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

- Antibiotics from the macrolide group, 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;

- Telithromycin *.

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

In a number of research pharmacokinetic and pharmacodynamic interactions of domperidone with ketoconazole and erythromycin when ingested in healthy volunteers have been shown that these drugs significantly inhibit the metabolism of the first passage through the isoenzyme CYP3A4. With the simultaneous administration of 10 mg of domperidone 4 times a day and 200 mg of ketoconazole 2 times a day, the interval QT on average by 9.8 ms during the whole period of observation, at some moments the changes ranged from 1.2 to 17.5 ms. With the simultaneous administration of 10 mg of domperidone 4 times a day and 500 mg of erythromycin 3 times a day, there was an elongation interval QT on average by 9.9 ms during the whole period of observation, at certain moments the changes ranged from 1.6 to 14.3 ms. In each of these studies, C_m_Oh and AUC domperidone were increased approximately three times (see the section "Contraindications").

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

In these studies, monotherapy with domperidone (10 mg four times a day) resulted in lengthening of the interval QT 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 QT at 3.8 and 4.9 msec respectively during the entire observation period.

In another study using multiple doses of healthy volunteers did not find a significant lengthening interval QT 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 on 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 enhance;

- with dopaminergic receptor agonists (bromocriptine, levodopa), 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 meals, and not before meals, i.e. they should not be taken concurrently with Motilium®.

Use in children

Motilium ® in rare cases can cause neurological side effects (see the section "Side Effects").The risk of neurological side effects in young children is higher, since metabolic functions and the blood-brain barrier in the first months of life are not developed completely. In this connection, one should strictly adhere to recommended dose (see 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 a very small percentage of the drug is excreted by the kidneys unchanged, the correction of a single dose in patients with renal insufficiency is not required. However, with the re-appointment of Motilium®, the frequency of application should be reduced to one or two times a day, depending on the severity of renal dysfunction, and it may also be necessary to reduce the dose. With prolonged therapy, patients should be under regular supervision.

Effects on the 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 death (cf.See "Side Effects" 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 effect on the ability to drive and work with machinery.

Form release / dosage:Tablets for resorption of 10 mg.

Packaging:

Primary packaging: 10 tablets for resorption in a blister of PVC-PE-PVDC / aluminum. Secondary packaging: 1 or 3 blisters together with instructions for medical use in a cardboard bundle.

Storage conditions:

Store in a dry place at a temperature of no higher than 25 ° C.

Keep out of the reach of children. Keep in original packaging.

Shelf life:2 years. Do not use after the expiration date.

Terms of leave from pharmacies:Without recipe

Registration number:П N011655 / 01

Date of registration:04.08.2016 / 08.09.2016

Expiration Date:Unlimited

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

Manufacturer: & nbsp

CATALENT UK SWINDON ZYDIS, Ltd. United Kingdom

Representation: & nbspJohnson & Johnson LLC Johnson & Johnson LLC Russia

Information update date: & nbsp10.10.2016

Illustrated instructions

Instructions

Motilium®Express (Motilium®Express)