Metoclopramide-zdorovya

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT MEKLOPRAMID-ZDOROVYA (METOCLOPRAMIDE-ZDOROVYE)

Composition:

Active substance: metoclopramide;

One tablet contains metoclopramide hydrochloride monohydrate equivalent to 10 mg of metoclopramide hydrochloride;

Excipients: lactose monohydrate, microcrystalline cellulose, potato starch, polyethylene glycol 4000, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: white or almost white, flat cylindrical tablets with a score line and beveled edges.

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

Pharmacological properties.

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

Metoclopramide has two main effects: antiemetic and acceleration of gastric emptying and intestinal transit.

The antiemetic effect is due to its action on the chemoreceptor trigger zone (CTZ) in the brainstem, likely through 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 biliary dyskinesia.

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

Prolonged treatment with metoclopramide may lead to increased serum prolactin levels 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. After oral administration, the drug is rapidly and completely absorbed. The oral bioavailability of metoclopramide averages 60–80%. Only a small fraction of the administered dose binds to plasma proteins. The volume of distribution ranges from 2.2 to 3.4 L/kg. Cmax in plasma is reached within 30–120 minutes, on average within 1 hour. Onset of action on the gastrointestinal tract occurs within 20–40 minutes after oral administration. The antiemetic effect lasts up to 12 hours. Metoclopramide is metabolized in the liver. It crosses the blood-brain and placental barriers and is excreted into breast milk. The elimination half-life (T½) ranges from 2.6 to 4.6 hours. Approximately 20% of the dose is excreted unchanged, while the remainder (about 80%) is metabolized in the liver and excreted by the kidneys as conjugates with glucuronic or sulfuric acid.

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

In patients with liver 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 nausea and vomiting induced by radiotherapy, delayed nausea and vomiting induced by chemotherapy, as well as for symptomatic treatment of nausea and vomiting, including those associated with acute migraine (in combination with oral analgesics to enhance their absorption).

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

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

Interaction with other medicinal products and other forms of interaction.

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

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

Combinations requiring caution.

The prokinetic effect of metoclopramide may affect the absorption of certain medicinal products.

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

With central nervous system depressants (morphine derivatives, neuroleptics, sedative H1-antihistamines, 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., serotonin reuptake inhibitors (sertraline, fluoxetine)] – increased risk of serotonin syndrome.

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

With cyclosporine – increased bioavailability (Cmax 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 via 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 adverse reactions.

With succinylcholine – prolonged effect of the latter.

Metoclopramide may affect the absorption process of other substances. For example, it may slow the absorption of cimetidine, accelerate the absorption of paracetamol, various antibiotics (including tetracycline, pivampicillin), and lithium. Concomitant administration of metoclopramide tablets and lithium may lead to increased plasma levels of lithium.

Special precautions for use

Metoclopramide 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 must be discontinued immediately if extrapyramidal symptoms occur. These symptoms are usually fully reversible after discontinuation of treatment, but symptomatic therapy may be required (benzodiazepines for children and/or anticholinergic anti-Parkinson drugs for adults).

A minimum interval of at least 6 hours must be maintained between each administration of metoclopramide, even if vomiting and dose rejection occur, 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 must be discontinued immediately if symptoms of neuroleptic malignant syndrome occur, and appropriate treatment should be initiated.

Particular caution is required in patients with concomitant neurological disorders and in patients receiving other drugs acting on the central nervous system.

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

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

Dose reduction is recommended for patients with renal impairment or severe hepatic impairment.

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

The medicinal product contains lactose. If a patient has known intolerance to certain sugars, consultation with a physician is recommended before taking this medicinal product.

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. Use of metoclopramide should be avoided at the end of pregnancy. Newborns should be monitored following metoclopramide administration.

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 breastfeeding women.

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

Dosage and Administration.

Take orally before meals, without chewing, with sufficient amount of liquid.

To minimize the risk of adverse reactions from the nervous system and other side effects, metoclopramide should be used only for short-term treatment (up to 5 days).

Adults: the usual therapeutic dose of metoclopramide is 10 mg up to 3 times daily. Maximum daily dose – 30 mg or 0.5 mg/kg body weight.

Children: the recommended dose of metoclopramide for prevention of delayed nausea and vomiting induced by chemotherapy is 0.1–0.15 mg/kg body weight up to 3 times daily. Maximum daily dose – 0.5 mg/kg body weight.

The medicinal product can be used in children provided that the appropriate dosage can be achieved by dividing the tablet.

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

For patients with end-stage renal failure (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%.

Patients with severe hepatic impairment should receive half the dose due to increased half-life (T½).

The maximum duration of metoclopramide treatment is 5 days.

Children. Metoclopramide is contraindicated in children under 1 year of age due to an increased risk of extrapyramidal disorders. In children with body weight < 30 kg, metoclopramide should be administered in dosage forms allowing appropriate dose adjustment.

Overdose.

Symptoms: Drowsiness, decreased level of consciousness, confusion, irritability, restlessness and its exacerbation, seizures, extrapyramidal disorders, cardiovascular dysfunction with bradycardia and increased/decreased arterial blood pressure, hallucinations, respiratory arrest, cardiac arrest, dystonic reactions.

Treatment. In case of extrapyramidal symptoms, whether related to overdose or not, only symptomatic treatment is indicated (benzodiazepines for children and/or anticholinergic anti-parkinsonian drugs for adults).

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

Side effects.

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

Cardiovascular system disorders: bradycardia up to cardiac arrest, especially with intravenous administration; atrioventricular block; sinoatrial block, especially with intravenous administration; QT interval prolongation; torsades de pointes ventricular tachycardia; arterial hypotension; shock; acute arterial hypertension in patients with pheochromocytoma; transient increase in blood pressure.

Reproductive system and breast disorders: after prolonged treatment 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.

Immune system disorders: hypersensitivity, anaphylactic reactions (including anaphylactic shock), predominantly following intravenous administration.

Nervous system disorders: dyskinetic syndrome, mainly in children (involuntary spasmodic movements, particularly in the head, neck, and shoulders; tonic blepharospasm; spasms of facial and masticatory muscles; tongue deviation; pharyngeal and lingual muscle spasms; abnormal posture of head and neck; spinal muscle tension; spasmodic flexion of arms; spasmodic extension of legs); headache; dizziness; drowsiness; extrapyramidal disorders (which may occur even after a single dose, predominantly in children and adolescents and/or when the recommended dose is exceeded); parkinsonism (tremor, muscle rigidity, akinesia); akathisia; dystonia (including visual disturbances and oculogyric crisis); dyskinesia; decreased level of consciousness; tardive dyskinesia (which may be persistent during or after prolonged treatment, especially in elderly patients); neuroleptic malignant syndrome [characteristic symptoms: fever, muscle rigidity, loss of consciousness, fluctuations in blood pressure, seizures (mainly in patients with epilepsy)].

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 attention should be paid to monitoring for adverse reactions in adolescents and patients with severe renal impairment (renal insufficiency), which reduces metoclopramide elimination. If such reactions occur, the drug should be discontinued immediately.

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

When high doses are used, 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, decreased level of consciousness, confusion, hallucinations.

Shelf life. 4 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C. Keep out of reach of children.

Packaging. Tablets in blisters: 10×2, 10×5 in a box.

Prescription category. Prescription only.

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA".

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