LOZARTAN 50/GIDROHLOROTIAZID 12,5 KRKA

INSTRUCTIONS FOR MEDICAL USE OF METOCLOPRAMIDE-DARNITSA (METOCLOPRAMIDE-DARNITSA)

METOCLOPRAMIDE-DARNITSA

(METOCLOPRAMIDE-DARNITSA)

Composition:

Active substance: metoclopramide;

1 ml of solution contains 5 mg of metoclopramide hydrochloride;

excipients: sodium chloride, disodium edetate, anhydrous sodium sulfite (E 221), propylene glycol, hydrochloric acid diluted, water for injections.

Pharmaceutical form.

Solution for injection.

Main physical and chemical properties:

Transparent colorless liquid.

Pharmacotherapeutic group.

Gastrointestinal motility stimulants (prokinetics).

ATC code A03F A01.

Pharmacological properties.

Pharmacodynamics.

Metoclopramide is a central dopamine antagonist that also exhibits peripheral cholinergic activity.

Two main effects of the drug are noted: antiemetic and accelerated gastric emptying and passage through the small intestine.

The antiemetic effect is caused by the action on the central point of the brain stem (chemoreceptors - the activation zone of the vomiting center), probably through the inhibition of dopaminergic neurons.

Enhanced peristalsis is also partially controlled by higher centers, but may also be partially involved in the mechanism of peripheral action, along with the activation of postganglionic cholinergic receptors and possibly the inhibition of dopaminergic receptors of the stomach and small intestine.

Through the hypothalamus and parasympathetic nervous system, it regulates and coordinates the motor activity of the upper gastrointestinal tract: increases the tone of the stomach and intestines, accelerates gastric emptying, reduces gastrosis, prevents pyloric and esophageal reflux, stimulates intestinal peristalsis.

Normalizes bile secretion, reduces spasm of the Oddi sphincter without changing its tone, eliminates biliary dyskinesia.

Undesirable effects

Are mainly related to extrapyramidal symptoms, the basis of which is the mechanism of dopamine receptor blocking action on the central nervous system.

Prolonged treatment with metoclopramide may cause an increase in prolactin concentration in blood serum due to the absence of dopaminergic inhibition of prolactin secretion.

In women, cases of galactorrhea and menstrual cycle disorders have been described, in men - gynecomastia.

However, these symptoms disappeared after discontinuation of treatment.

Pharmacokinetics.

In the case of intravenous administration, metoclopramide is rapidly distributed.

The onset of action on the gastrointestinal tract is noted within 1-3 minutes after intravenous administration and within 10-15 minutes after intramuscular administration.

The antiemetic effect lasts for 12 hours.

13-30% of the drug is bound to plasma proteins.

The volume of distribution is 2.2-3.4 l/kg of body weight.

Metabolized in the liver.

The half-life is 2.6-4.6 hours in healthy volunteers and approximately 14 hours in patients with renal insufficiency.

Penetrates the blood-brain and placental barriers, is excreted in breast milk.

A portion of the dose (approximately 20%) is excreted in its original form, and the rest (approximately 80%) after metabolic transformations in the liver is excreted by the kidneys along with urine in compounds with glucuronic or sulfuric acid.

In patients with severe renal insufficiency, creatinine clearance is reduced to 70%, and the half-life from plasma is increased (approximately 10 hours at a creatinine clearance of 10-50 ml/min and 15 hours at a creatinine clearance of <10 ml/min).

In patients with liver cirrhosis, an accumulation of metoclopramide was observed, accompanied by a 50% decrease in plasma clearance.

Clinical characteristics.

Indications.

For adults: prevention of postoperative nausea and vomiting; nausea and vomiting caused by radiotherapy; symptomatic treatment of nausea and vomiting, including those associated with acute migraines.

For children: as a second-line drug for the prevention of delayed nausea and vomiting caused by chemotherapy; treatment of postoperative nausea and vomiting.

Contraindications.

• Increased sensitivity to metoclopramide or to any other component of the drug;
• gastrointestinal bleeding;
• mechanical intestinal obstruction;
• gastrointestinal perforation;
• confirmed or suspected pheochromocytoma (due to the risk of severe attacks of arterial hypertension);
• late dyskinesia caused by neuroleptics or metoclopramide in the anamnesis;
• epilepsy (increased frequency and intensity of seizures);
• Parkinson's disease;
• concomitant use with levodopa or dopaminergic agonists;
• established methemoglobinemia when using metoclopramide or NADH-cytochrome-b5-reductase deficiency in the anamnesis;
• prolactin-dependent tumors;
• increased seizure susceptibility (extrapyramidal motor disorders);
• patient age under 1 year (due to the risk of developing extrapyramidal disorders).

In connection with the content of sodium sulfite, the drug should not be prescribed to patients with bronchial asthma with increased sensitivity to sulfite.

Interaction with other medicinal products and other types of interactions.

Prohibited combinations.

Levodopa or dopaminergic agonists and metoclopramide are characterized by mutual antagonism.

Combinations to be avoided.

Alcohol enhances the sedative effect of metoclopramide.

Combinations to be taken into account.

When used concomitantly with oral medications, such as paracetamol, metoclopramide may affect their absorption due to its effect on gastric motility.

Anticholinergic agents and morphine derivatives: anticholinergic agents and morphine derivatives are characterized by mutual antagonism with metoclopramide in relation to their effect on the motor activity of the digestive tract.

CNS inhibitors (morphine derivatives, neuroleptics, sedative antihistamines, sedative antidepressants, barbiturates, clonidine, and related products): potentiate the sedative effect of metoclopramide.

Neuroleptics: when metoclopramide is used in combination with other neuroleptics, a cumulative effect and the occurrence of extrapyramidal disorders may occur.

Serotoninergic preparations: the use of metoclopramide in combination with serotoninergic preparations, such as selective serotonin reuptake inhibitors (SSRIs), may increase the risk of developing serotonin syndrome.

Digoxin: metoclopramide may reduce the bioavailability of digoxin.

Cyclosporine: metoclopramide increases the bioavailability of cyclosporine (Cmax by 46% and an effect of 22%).

Mivacurium and succinylcholine: injection of metoclopramide may prolong the duration of neuromuscular blockade (due to inhibition of plasma cholinesterase).

Potent CYP2D6 inhibitors: metoclopramide exposure levels are increased when co-administered with strong CYP2D6 inhibitors, such as fluoxetine and paroxetine.

Metoclopramide may prolong the action of succinylcholine.

Due to the content of sodium sulfite in the injection solution, thiamine (vitamin B1) taken simultaneously with metoclopramide may rapidly decompose in the body.

Special warnings and precautions for use.

Metoclopramide-Darnitsa, solution for injection, contains sodium: 1 ml of solution for injection contains less than 1 mmol (23 mg) of sodium, i.e., this medicinal product is practically sodium-free.

Ampoules removed from the packaging should not be left in the sun for a long time.

Neurological disorders.

Extrapyramidal disorders may occur, especially in children, and/or when using high doses.

These reactions are usually observed at the beginning of treatment and may occur after a single administration.

In case of development of extrapyramidal symptoms, metoclopramide should be immediately discontinued.

Generally, these effects disappear completely after discontinuation of treatment, but may require symptomatic treatment (benzodiazepines in children and/or anticholinergic antiparkinsonian medications in adults).

Between each administration of metoclopramide, even in case of vomiting and rejection of the dose, to avoid overdose, it is necessary to maintain an interval of at least 6 hours.

Prolonged treatment with metoclopramide may lead to late dyskinesia, which is potentially irreversible, especially in elderly patients.

Treatment should not last more than 3 months due to the risk of developing late dyskinesia.

Treatment should be discontinued if clinical signs of late dyskinesia appear (see section "Adverse reactions").

When using metoclopramide in combination with neuroleptics, as well as with monotherapy with metoclopramide, the development of malignant neuroleptic syndrome has been reported.

In case of symptoms of malignant neuroleptic syndrome, the use of metoclopramide should be immediately discontinued and appropriate treatment started.

When treating patients with concomitant neurological diseases and patients receiving other medications that affect the central nervous system, it is necessary to be especially careful (see section "Contraindications").

Metoclopramide may also exacerbate symptoms of Parkinson's disease.

Methemoglobinemia.

Cases of methemoglobinemia have been reported, which may be associated with a deficiency of NADH-cytochrome-b5-reductase.

In such cases, metoclopramide should be immediately and finally discontinued, and appropriate measures should be taken (e.g., treatment with methylene blue).

Cardiovascular disorders.

Severe adverse reactions from the cardiovascular system have been reported, including cases of acute vascular failure, severe bradycardia, cardiac arrest, and QT interval prolongation, which were observed after administration of metoclopramide in the form of injections, most often after intravenous administration (see section "Adverse reactions").

Particular caution is needed when metoclopramide is administered intravenously to elderly patients, patients with impaired cardiac conduction (including QT interval prolongation), patients with impaired electrolyte balance, bradycardia, as well as patients taking medications that prolong the QT interval.

Intravenously, the drug should be administered by slow bolus injection (at least 3 minutes) to reduce the risk of adverse reactions (e.g., hypotension, akathisia).

Impaired renal and hepatic function.

Patient with impaired renal function or severe impaired hepatic function is recommended to reduce the dose (see section "Method of administration and dosage").

The drug should not be used to treat chronic conditions such as gastroparesis, dyspepsia, and gastroesophageal reflux disease, or as an adjunct to surgical or radiological procedures.

The preparation contains sodium sulfite, which in some cases can cause severe hypersensitivity reactions and bronchospasm.

Use during pregnancy or breastfeeding.

Pregnancy.

A large amount of data on pregnant women (over 1000 results of drug use) indicates the absence of any toxicity leading to malformations or fetal/neonatal toxicity.

Metoclopramide can be used during pregnancy if there is a clinical need.

Due to the pharmacological properties (as with other neuroleptics), when using metoclopramide at the end of pregnancy, the appearance of an extrapyramidal syndrome in the newborn cannot be excluded.

It is necessary to avoid the use of metoclopramide at the end of pregnancy.

When using metoclopramide, it is necessary to monitor the newborn.

Breastfeeding.

Metoclopramide penetrates into breast milk in small amounts.

Possible influence of metoclopramide on newborns who are breastfed.

Therefore, it is not recommended to use metoclopramide during breastfeeding.

It is necessary to consider the possibility of discontinuing the use of metoclopramide in women who are breastfeeding.

Influence on the ability to drive vehicles and operate machinery.

Metoclopramide can cause drowsiness, dizziness, dyskinesia, and dystonia, which can affect vision and the ability to drive vehicles or work with other automated systems.

Method of administration and dosage.

Solution for injection is administered intramuscularly or intravenously in the form of a slow bolus injection for at least 3 minutes.

As a solvent, 0.9% sodium chloride solution or 5% glucose solution is used.

Adults.

For the prevention of postoperative nausea and vomiting, the recommended single dose of metoclopramide is 10 mg.

For symptomatic treatment of nausea and vomiting, including those associated with acute migraines, as well as for the prevention of nausea and vomiting caused by radiotherapy, the recommended single dose of metoclopramide is 10 mg up to 3 times a day.

The maximum recommended daily dose is 30 mg or 0.5 mg/kg of body weight.

The use of injectable forms should be carried out for as short a period as possible, with as rapid a transition as possible to the use of oral or rectal forms of metoclopramide.

Children.

When used to prevent postoperative nausea and vomiting, metoclopramide should be administered after the end of the operation.

The recommended dose of metoclopramide is 0.1-0.15 mg/kg of body weight up to 3 times a day.

The maximum daily dose is 0.5 mg/kg of body weight.

If it is necessary to continue the use of the drug, it is necessary to maintain intervals of at least 6 hours.

The maximum duration of metoclopramide use for the treatment of established postoperative nausea and vomiting is 48 hours.

The maximum duration of metoclopramide use for the prevention of delayed nausea and vomiting caused by chemotherapy is 5 days.

Patient with impaired renal function

In patients with terminal stage of impaired renal function (creatinine clearance ≤ 15 ml/min), the dose of metoclopramide should be reduced by 75%.

In patients with moderate and severe impaired renal function (creatinine clearance 15-60 ml/min), the dose of metoclopramide should be reduced by 50%.

Patient with hepatic insufficiency

For patients with severe impaired liver function, the dose of metoclopramide should be reduced by 50%.

Elderly patients.

It is necessary to consider the possibility of reducing the dose in elderly patients due to the age-related decrease in renal and hepatic function.

Children.

Metoclopramide is contraindicated in children under 1 year of age.

Overdose.

Symptoms: drowsiness, decreased level of consciousness, confusion, irritability, restlessness and its intensification, seizures, extrapyramidal motor disorders, cardiovascular system disorders with bradycardia and increased or decreased blood pressure, hallucinations, respiratory and cardiac arrest, dystonic reactions.

There have been reports of individual cases of methemoglobinemia.

Treatment: in case of development of extrapyramidal symptoms, associated or not associated with overdose, only symptomatic treatment is carried out (benzodiazepines in children and/or anticholinergic antiparkinsonian medications in adults).

According to the clinical condition, symptomatic treatment and constant monitoring of the functions of the cardiovascular and respiratory systems should be carried out.

Adverse reactions.

From the gastrointestinal tract: nausea, dyspepsia, dry mouth, constipation.

When using metoclopramide in doses higher than the daily dose, diarrhea may occur in patients.

From the nervous system:

• extrapyramidal disorders, which can occur even after the use of a single dose of the drug, mainly in children and adolescents and/or when exceeding the recommended dose (see section "Special warnings and precautions for use");
• Parkinsonism (tremor, muscle rigidity, akinesia).
• Dyskinetic syndrome (involuntary spasmodic movements, particularly in the head, neck, and shoulder area, tonic blepharospasm, spasm of facial and chewing muscles, deviation of the tongue, spasm of pharyngeal and tongue muscles, and incorrect head and neck positioning, hyperextension of the spine, spastic flexion of the arms, spastic extension of the legs);
• neuroleptic malignant syndrome, (characteristic symptoms: fever, muscle rigidity, loss of consciousness, fluctuation of blood pressure), seizures (mainly in patients with epilepsy), headache, dizziness, drowsiness, decreased level of consciousness;
• acute dystonia, dystonia (including visual disturbances and oculogyric crisis);
• late dyskinesia (may be permanent during or after prolonged treatment, especially in elderly patients);
• akathisia.

From the psyche: depression, hallucinations, confusion, anxiety, restlessness.

From the cardiovascular system: bradycardia, especially with intravenous use, cardiac arrest for a short time after injection, which can be a consequence of bradycardia (see section "Special warnings and precautions for use"), atrioventricular block, blockage of the sinus node, especially with intravenous use, prolongation of the QT interval, supraventricular extrasystole, ventricular extrasystole, ventricular tachycardia, starting from bradycardia to cardiac arrest, arterial hypotension (mainly with intravenous administration), shock, syncope with parenteral use, acute arterial hypertension in patients with pheochromocytoma, temporary increase in blood pressure.

From the endocrine system*: amenorrhea, hyperprolactinemia, galactorrhea, gynecomastia, menstrual cycle disorders.

From the blood and lymphatic system: methemoglobinemia, which may be associated with a deficiency of NADH-cytochrome-b5-reductase, especially in infants, sulfhemoglobinemia, which is associated mainly with the concomitant use of high doses of sulfur-releasing drugs.

From the immune system: hypersensitivity reactions, anaphylactic reactions (including anaphylactic shock, especially with intravenous use).

From the skin and subcutaneous tissue: hypersensitivity reactions, including: skin rash, hyperemia and itching of the skin, angioedema.

Laboratory indicators: increased levels of liver enzymes.

General disorders: asthenia, increased fatigue.

* Endocrine disorders during prolonged treatment are associated with hyperprolactinemia (amenorrhea, galactorrhea, gynecomastia).

In such cases, the use of the drug should be discontinued.

In children and patients with severe impaired renal function (renal insufficiency), due to which the elimination of metoclopramide is weakened, it is necessary to carefully monitor the development of adverse reactions.

In case of their occurrence, the use of the drug should be immediately discontinued.

There have been reports of the development of severe cardiovascular reactions caused by intravenous administration of metoclopramide (arrhythmia, for example, in the form of supraventricular extrasystole, ventricular extrasystole, tachycardia, starting from bradycardia to cardiac arrest).

The risk of acute (short-term) neurological disorders is higher in children, and the risk of late dyskinesia is higher in elderly patients.

The risk of developing adverse reactions from the nervous system increases with the use of the drug in high doses and with prolonged treatment.

When using high doses, the following reactions occur more frequently (sometimes simultaneously):

- extrapyramidal symptoms: acute dystonia and dyskinesia, Parkinson's syndrome, akathisia, even after the use of a single dose of the drug, especially in children and adolescents;

- drowsiness, decreased level of consciousness, confusion, hallucinations.

Due to the content of sodium sulfite in the drug, in some cases, especially in patients with bronchial asthma, hypersensitivity may occur, which manifests as nausea, diarrhea, difficulty breathing, acute asthma attack, confusion, or shock.

These reactions can occur in various forms and can be life-threatening.

Shelf life.

4 years.

Storage conditions.

Store in a place inaccessible to children in the original packaging at a temperature not exceeding 25 °C.

Do not freeze.

Incompatibility.

The injection solution of metoclopramide should not be mixed with alkaline infusion solutions.

Metoclopramide-Darnitsa, solution for injection, is incompatible with the following drugs: chloramphenicol, cisplatin, erythromycin, furosemide, calcium gluconate, methotrexate, sodium hydrocarbonate, penicillin G.

Packaging.

2 ml in an ampoule; 5 ampoules in a contour cell packaging, 1 or 2 contour cell packages in a pack.

Release category.

By prescription.

Manufacturer.

PrJSC "Pharmaceutical company "Darnitsa".

Location of the manufacturer and its address.

Ukraine, 02093, Kiev, Borispol street, 13.