Metoclopramide-zdorovya

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT METOCLOPRAMIDE-ZDOROV'YA (METOCLOPRAMIDE-ZDOROVYE)

Composition:

Active substance: metoclopramide;

1 ml of solution contains 5 mg of metoclopramide hydrochloride;

Excipients: sodium chloride, sodium metabisulfite (E 223), disodium edetate, propylene glycol, concentrated hydrochloric acid, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group. Peristaltic stimulants (prokinetics). ATC code A03FA01.

Pharmacological properties.

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

Two main effects of metoclopramide are recognized: antiemetic effect and acceleration of gastric emptying and intestinal transit.

The antiemetic effect is mediated through action on the central chemoreceptor trigger zone (CTZ) in the brainstem, likely via inhibition of dopaminergic neurons.

Enhanced peristalsis is partially regulated by higher centers, but a peripheral mechanism may also be involved, including activation of postganglionic cholinergic receptors and possibly blockade of dopaminergic receptors in the stomach and small intestine. Through the hypothalamus and the parasympathetic nervous system, it regulates and coordinates motor activity of the upper gastrointestinal tract: increases gastric and intestinal tone, accelerates gastric emptying, reduces gastroparesis, prevents pyloric and esophageal reflux, and stimulates intestinal peristalsis. It normalizes bile secretion, reduces spasm of the sphincter of Oddi without altering its tone, and relieves gallbladder dyskinesia.

Adverse effects primarily involve extrapyramidal symptoms, which are based on the dopamine receptor-blocking action of the drug on the central nervous system.

Prolonged treatment with metoclopramide may lead to increased serum prolactin concentrations due to lack of dopaminergic inhibition of prolactin secretion. Cases of galactorrhea and menstrual cycle disturbances have been reported in women, and gynecomastia in men. However, these symptoms resolved after discontinuation of treatment.

Pharmacokinetics. Onset of action on the gastrointestinal tract occurs within 1–3 minutes after intravenous administration and within 10–15 minutes after intramuscular administration. The antiemetic effect lasts for up to 12 hours. Plasma protein binding ranges from 13% to 30%. Volume of distribution is 3.5 L/kg. The drug penetrates the blood-brain barrier and placental barrier, and is excreted into breast milk. It is metabolized in the liver. Elimination half-life (T½) is 4–6 hours. Approximately 20% of the dose is excreted unchanged, while the remainder (about 80%) is metabolized in the liver and subsequently excreted by the kidneys as conjugates with glucuronic or sulfuric acid.

In patients with severe renal impairment, creatinine clearance (Cl_CR) is reduced to 70%, and plasma T½ is prolonged (approximately 10 hours when Cl_CR is 10–50 mL/min and 15 hours when Cl_CR < 10 mL/min).

In patients with hepatic cirrhosis, accumulation of metoclopramide has been observed, accompanied by a 50% reduction in plasma clearance.

Clinical Characteristics.

Indications. In adults, metoclopramide is indicated for the prevention of postoperative nausea and vomiting, nausea and vomiting induced by radiotherapy, as well as for symptomatic treatment of nausea and vomiting, including those associated with acute migraine.

In children, metoclopramide should be used only as a second-line agent for the prevention of delayed nausea and vomiting induced by chemotherapy, and for the treatment of postoperative nausea and vomiting.

Contraindications. Hypersensitivity to metoclopramide or to any other component of the medicinal product; gastrointestinal bleeding; mechanical intestinal obstruction; gastrointestinal perforation; confirmed or suspected pheochromocytoma – due to the risk of severe hypertensive crises; tardive dyskinesia caused by neuroleptics or metoclopramide in medical history; epilepsy (increased frequency and intensity of seizures); Parkinson's disease; concomitant use with levodopa or dopaminergic agonists; documented methemoglobinemia during metoclopramide use or history of NADH-cytochrome-b5-reductase deficiency; prolactin-dependent tumors; increased seizure susceptibility (extrapyramidal movement disorders); bronchial asthma with sulfite hypersensitivity. Use in children under 1 year of age — due to the risk of developing extrapyramidal disorders.

Interaction with other medicinal products and other types of interactions.

Contraindicated combination. Levodopa/dopaminergic agonists and metoclopramide are mutual antagonists.

Combination to be avoided. Alcohol enhances the sedative effect of metoclopramide.

Combinations requiring caution.

With oral medicinal products (e.g., paracetamol) – metoclopramide may affect their absorption due to its influence on gastric motility.

With anticholinergic agents and morphine derivatives – possible mutual antagonism regarding effects on gastrointestinal motility.

With central nervous system depressants (morphine derivatives, anxiolytics, sedative H1-histamine blockers, sedative antidepressants, barbiturates, clonidine and related agents) – potentiation of the sedative effect of metoclopramide.

With neuroleptics – cumulative effect and occurrence of extrapyramidal disorders.

With serotonergic agents [e.g., selective serotonin reuptake inhibitors (SSRIs)] – increased risk of serotonin syndrome.

With digoxin – reduced bioavailability of digoxin. Careful monitoring of digoxin plasma concentration is required.

With cyclosporine – increased bioavailability of the latter (Cmax increased by 46%, exposure by 22%). Careful monitoring of cyclosporine plasma concentration is required. Clinical significance is uncertain.

With mivacurium and succinylcholine – possible prolongation of neuromuscular blockade due to inhibition of plasma cholinesterase.

With potent CYP2D6 inhibitors (such as fluoxetine and paroxetine) – increased exposure to metoclopramide. Although clinical significance is uncertain, patients should be monitored for possible adverse reactions.

With succinylcholine – prolonged effect of the latter.

Due to the presence of sodium metabisulfite in the medicinal product, concomitant administration with thiamine (vitamin B1) may lead to rapid degradation of thiamine in the body.

Special precautions for use

The drug should not be used for the treatment of chronic conditions such as gastroparesis, dyspepsia, and gastroesophageal reflux disease, or as an adjunct in surgical or radiological procedures.

Extrapyramidal disorders may occur, particularly in children and/or with high-dose administration. These reactions usually occur at the beginning of treatment and may appear even after a single dose. Metoclopramide should be discontinued immediately if extrapyramidal symptoms develop. These symptoms are usually fully reversible after discontinuation of treatment, but symptomatic treatment may be required (benzodiazepines for children and/or anticholinergic antiparkinsonian agents for adults).

A minimum interval of at least 6 hours should be maintained between each administration of metoclopramide, even in cases of vomiting and dose rejection, to avoid overdose.

Prolonged treatment with metoclopramide may lead to tardive dyskinesia, potentially irreversible, especially in elderly patients. Treatment should not exceed 3 months due to the risk of tardive dyskinesia. Treatment must be discontinued if clinical signs of tardive dyskinesia appear.

Cases of neuroleptic malignant syndrome have been reported with metoclopramide, both in combination with neuroleptics and as monotherapy. Metoclopramide should be discontinued immediately if symptoms of neuroleptic malignant syndrome occur, and appropriate treatment should be initiated.

Particular attention should be paid to patients with concomitant neurological disorders and to patients receiving other drugs acting on the central nervous system.

Symptoms of Parkinson's disease may be exacerbated by metoclopramide.

Cases of methemoglobinemia, possibly associated with NADH-cytochrome b5 reductase deficiency, have been reported. In such cases, metoclopramide must be immediately and permanently discontinued, and appropriate measures initiated (e.g., treatment with methylene blue).

Severe cardiovascular adverse reactions have been reported, including acute circulatory failure, severe bradycardia, cardiac arrest, and QT interval prolongation, occurring after administration of metoclopramide by injection, particularly after intravenous administration.

For patients with impaired renal function or severe hepatic impairment, dose reduction is recommended.

Metoclopramide should be used with caution, especially when administered intravenously, in elderly patients, in patients with cardiac conduction disorders (including QT interval prolongation), in patients with electrolyte imbalance, bradycardia, and in patients taking drugs that prolong the QT interval.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially "sodium-free".

Sodium metabisulfite (E 223) may rarely cause hypersensitivity reactions and bronchospasm.

Use during pregnancy or breastfeeding. Extensive data from pregnant women (more than 1000 documented outcomes) indicate no evidence of teratogenic or fetotoxic effects. Metoclopramide may be used during pregnancy if clinically necessary. However, due to its pharmacological properties (similar to other neuroleptics), extrapyramidal syndrome in the newborn cannot be excluded if metoclopramide is administered at the end of pregnancy. The use of metoclopramide should be avoided at the end of pregnancy. Newborns exposed to metoclopramide should be closely monitored.

Metoclopramide passes into breast milk in small amounts. Therefore, the use of metoclopramide during breastfeeding is not recommended. The possibility of discontinuing metoclopramide should be considered in women who are breastfeeding.

Ability to affect reaction speed while driving or operating machinery. Metoclopramide may cause drowsiness, dizziness, dyskinesia, and dystonia, which may impair vision and the ability to drive or operate machinery.

Administration and Dosage

The drug should be administered intramuscularly or by slow intravenous injection.

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

To reduce the risk of adverse reactions (including arterial hypotension and akathisia), metoclopramide should be administered intravenously as a slow bolus injection over at least 3 minutes.

The use of injectable forms should be as short-term as possible, with a prompt transition to oral or rectal forms of metoclopramide.

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

For symptomatic treatment of nausea and vomiting, including that associated with acute migraine, the recommended dose of metoclopramide is 10 mg three times daily.

Maximum daily dose – 30 mg or 0.5 mg/kg body weight.

Children:
The recommended dose of metoclopramide is 0.1–0.15 mg/kg body weight, up to three times daily. When used for prevention of postoperative nausea and vomiting, metoclopramide should be administered after completion of surgery.

Maximum daily dose is 0.5 mg/kg body weight. If continued administration of the drug is necessary, intervals of at least 6 hours should be maintained.

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

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

For elderly patients, dose reduction should be considered due to age-related decline in renal and hepatic function.

For patients with end-stage renal impairment (CrCl ≤ 15 mL/min), the dose of metoclopramide should be reduced by 75%. For patients with moderate to severe renal impairment (CrCl 15–60 mL/min), the dose of metoclopramide should be reduced by 50%.

Dose reduction by 50% is required in patients with severe hepatic impairment.

Children. Metoclopramide is contraindicated in children under 1 year of age due to the increased risk of developing extrapyramidal disorders.

Overdose.

Symptoms: Somnolence, decreased level of consciousness, confusion, irritability and worsening of restlessness, seizures, extrapyramidal disorders, cardiovascular dysfunction with bradycardia and either increased or decreased blood pressure, hallucinations, respiratory arrest, and cardiac arrest, dystonic reactions.

Treatment. In case of development of extrapyramidal symptoms, whether related or unrelated to overdose, only symptomatic treatment is administered (benzodiazepines for children and/or anticholinergic antiparkinsonian drugs for adults).

Depending on the clinical condition, symptomatic treatment and continuous monitoring of cardiovascular and respiratory functions should be performed.

Adverse reactions.

Immune system disorders: hypersensitivity reactions, anaphylactic reactions (including anaphylactic shock, especially with intravenous administration).

Blood and lymphatic system disorders: methemoglobinemia, which may be associated with NADH-cytochrome-b5-reductase deficiency, particularly in infants; sulfhemoglobinemia, mainly related to concomitant use of high doses of sulfur-releasing drugs.

Cardiovascular system disorders: bradycardia, especially with intravenous administration; transient cardiac arrest shortly after injection, which may result from bradycardia; atrioventricular block, sinoatrial block, particularly with intravenous administration; QT interval prolongation; torsade de pointes ventricular tachycardia; arterial hypotension; shock; syncope following intravenous administration; acute arterial hypertension in patients with pheochromocytoma; transient increase in blood pressure.

Reproductive system and breast disorders: following prolonged therapy with the drug, due to stimulation of prolactin secretion, amenorrhea, hyperprolactinemia, gynecomastia, galactorrhea, or menstrual cycle disturbances may occur; if these effects develop, metoclopramide should be discontinued.

Gastrointestinal disorders: nausea, dry mouth, constipation, diarrhea.

Nervous system disorders: neuroleptic malignant syndrome (characteristic symptoms: fever, muscle rigidity, altered consciousness, fluctuations in blood pressure, seizures), predominantly in patients with epilepsy; headache, dizziness, drowsiness, depressed level of consciousness, dystonia (including visual disturbances and oculogyric crisis), including acute forms.

Extrapyramidal disorders, which may occur even after a single dose, primarily in children and adolescents and/or when the recommended dose is exceeded:

• Dyskinetic syndrome (involuntary spasmodic movements, particularly in the head, neck, and shoulders; tonic blepharospasm; spasms of facial and masticatory muscles; tongue deviation; spasms of pharyngeal and tongue muscles; abnormal head and neck posture; back muscle strain; spasmodic flexion of arms; spasmodic extension of legs);
• Parkinsonism (tremor, rigidity, akinesia);
• Tardive dyskinesia (may be persistent during or after prolonged treatment, especially in elderly patients);
• Akathisia.

Skin disorders: rash, urticaria, skin hyperemia and itching, angioneurotic edema.

Psychiatric disorders: depression, hallucinations, confusion, anxiety, restlessness.

Laboratory investigations: increased liver enzyme levels.

General disorders: asthenia, increased fatigue.

Particular caution is required regarding the development of adverse reactions in adolescents and patients with severe renal function impairment (renal insufficiency), due to reduced elimination of metoclopramide. If such reactions occur, the drug should be discontinued immediately.

Severe cardiovascular reactions have been reported following intravenous administration of metoclopramide (arrhythmias, such as supraventricular extrasystoles, ventricular extrasystoles, tachycardia, ranging from bradycardia to cardiac arrest).

There is an increased risk of acute (transient) neurological disorders in children, and of tardive dyskinesia in elderly patients. The risk of nervous system-related adverse reactions increases with high-dose and prolonged use of the drug.

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

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

− drowsiness, depressed level of consciousness, confusion, hallucinations.

Shelf life. 5 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Incompatibility. Do not mix with alkaline infusion solutions.

Packaging. 2 ml in ampoules, pack of 10 in a box; 5×2, 10 in blisters in a box.

Prescription status. Prescription only.

Manufacturer: LIMITED LIABILITY COMPANY "CORPORATION "ZDOROV'YA".

Manufacturer's address and place of business. 22 Shevchenka Street, Kharkiv, Kharkiv Oblast, 61013, Ukraine.