Metoclopramide-darnitsa

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT METOCLOPRAMIDE-DARNITSA (METOCLOPRAMIDE-DARNITSA)

Composition:

Active substance: metoclopramide;

One tablet contains metoclopramide hydrochloride 10 mg;

Excipients: potato starch, lactose monohydrate, microcrystalline cellulose, povidone, calcium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: white or white with a yellowish tint, flat cylindrical tablets with a bevel.

Pharmacotherapeutic group. Prokinetic agents (propulsants).

ATC code A03FA01.

Pharmacological properties.

Pharmacodynamics.

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

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

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

Enhanced gastrointestinal motility 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, metoclopramide regulates and coordinates motor activity of the upper gastrointestinal tract: it 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 alleviates biliary dyskinesia.

Adverse effects primarily involve extrapyramidal symptoms, which are based on dopamine receptor blockade 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 bioavailability averages 60–80%. Only a small fraction of the administered dose of metoclopramide is protein-bound in plasma. The volume of distribution ranges from 2.2 to 3.4 L/kg. Maximum plasma concentration is reached within 30–120 minutes, on average after 1 hour. Onset of action on the gastrointestinal tract occurs within 20–40 minutes after oral administration.

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 ranges from 2.6 to 4.6 hours. Only a minor portion of the administered dose is protein-bound in plasma. 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, metoclopramide clearance is reduced by up to 70%, and the elimination half-life from plasma is prolonged (approximately 10 hours when creatinine clearance is 10–50 mL/min and 15 hours when creatinine clearance is <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 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 intestinal obstruction;
• gastrointestinal perforation;
• confirmed or suspected pheochromocytoma — due to the risk of severe hypertensive crisis;
• history of tardive dyskinesia induced by neuroleptics or metoclopramide;
• epilepsy (increased frequency and intensity of seizures);
• Parkinson's disease;
• concomitant use with levodopa or dopaminergic agonists (see section "Interaction with other medicinal products and other forms of interaction");
• history of methemoglobinemia associated with metoclopramide use or deficiency of NADH-cytochrome-b5-reductase;
• prolactin-dependent tumors;
• increased seizure susceptibility (extrapyramidal movement disorders);
• use in children under 1 year of age — due to increased risk of extrapyramidal disorders (see section "Special precautions for use").

Interaction with other medicinal products and other forms of interaction.

Contraindicated combinations.

Levodopa or dopaminergic agonists and metoclopramide exhibit mutual antagonism.

Combinations 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.

Anticholinergic agents and morphine derivatives: anticholinergic agents and morphine derivatives exhibit mutual antagonism with metoclopramide regarding their effects on gastrointestinal motility.

Central nervous system depressants (morphine derivatives, neuroleptics, sedative H1-receptor antihistamines, sedative antidepressants, barbiturates, clonidine and related agents): central nervous system depressants potentiate the sedative effect of metoclopramide.

Neuroleptics: when metoclopramide is used in combination with other neuroleptics, cumulative effects and occurrence of extrapyramidal disorders may arise.

Serotonergic agents: concomitant use of metoclopramide with serotonergic medicinal products, such as selective serotonin reuptake inhibitors (SSRIs), may increase the risk of serotonin syndrome.

Digoxin: metoclopramide may reduce digoxin bioavailability. Close monitoring of digoxin plasma concentrations is required.

Cyclosporine: metoclopramide increases cyclosporine bioavailability (Cmax by 46% and AUC by 22%). Close monitoring of cyclosporine plasma concentrations is required. The clinical significance of this interaction is not fully established.

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

Strong CYP2D6 inhibitors: exposure levels of metoclopramide are increased when used concomitantly with strong CYP2D6 inhibitors, such as fluoxetine and paroxetine. Although the clinical significance is not fully known, patients should be monitored for adverse reactions.

Metoclopramide tablets may prolong the effect of succinylcholine.

Metoclopramide may affect the absorption process of other substances. For example, it may delay 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

The medicinal product 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.

Neurological disorders.

Extrapyramidal disorders may occur, particularly in children and/or with high-dose administration. These reactions are usually observed at the beginning of treatment and may appear even after a single dose. If extrapyramidal symptoms develop, metoclopramide must be discontinued immediately. In general, these effects resolve completely after discontinuation of treatment, but symptomatic treatment may be required (benzodiazepines for children and/or anticholinergic anti-Parkinson drugs for adults).

An interval of at least 6 hours must be maintained between each administration of metoclopramide, even if vomiting occurs and the dose is expelled with vomitus, to avoid overdose.

Prolonged treatment with metoclopramide may lead to tardive dyskinesia, which may be potentially irreversible, especially in elderly patients. Treatment should not exceed 3 months due to the risk of developing tardive dyskinesia. Treatment must be discontinued if clinical signs of tardive dyskinesia appear (see section "Adverse reactions").

Cases of neuroleptic malignant syndrome have been reported with metoclopramide used in combination with neuroleptics, as well as with metoclopramide monotherapy (see section "Adverse reactions"). If symptoms of neuroleptic malignant syndrome occur, metoclopramide must be discontinued immediately and appropriate treatment initiated.

Extreme caution is required in patients with concomitant neurological disorders and in patients receiving treatment with other medicinal products acting on the central nervous system (see section "Contraindications").

Symptoms of Parkinson's disease may also be exacerbated during metoclopramide use.

Methemoglobinemia.

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

Cardiac disorders.

Severe adverse reactions affecting the cardiovascular system have been reported, including acute circulatory failure, severe bradycardia, cardiac arrest, and QT interval prolongation, observed after administration of metoclopramide in injectable form, particularly following intravenous administration (see section "Adverse reactions").

Caution is advised when administering metoclopramide to elderly patients, especially when the drug is given intravenously, to patients with impaired cardiac conduction (including QT interval prolongation), electrolyte imbalance, bradycardia, and to patients taking medicinal products that prolong the QT interval.

Renal and hepatic impairment.

Dose reduction is recommended in patients with renal impairment or severe hepatic impairment (see section "Dosage and administration").

Due to very rare reports of severe cardiovascular reactions associated with metoclopramide use, particular caution is required when administering the drug to elderly patients, patients with cardiac conduction disorders, uncorrected electrolyte imbalances or bradycardia, and patients taking medicinal products that prolong the QT interval.

If a patient has known intolerance to certain sugars, they should consult their physician before taking this medicinal product.

The medicinal product contains lactose and therefore should not be administered to patients with rare hereditary conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Pregnancy. Extensive data from pregnant women (over 1000 documented exposures) indicate no teratogenic or fetotoxic effects. Metoclopramide may be used during pregnancy if clinically indicated. However, due to its pharmacological properties (as with other neuroleptics), administration of metoclopramide at the end of pregnancy cannot exclude the possibility of extrapyramidal symptoms in the newborn. Metoclopramide use should be avoided at the end of pregnancy. Newborns exposed to metoclopramide should be closely monitored.

Breastfeeding. Metoclopramide passes into breast milk in small amounts. There is a potential risk of adverse effects on breastfed infants. 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 when driving or operating machinery.

Metoclopramide may cause drowsiness, dizziness, dyskinesia, and dystonia, which may affect vision as well as the ability to drive vehicles or operate other 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 prescribed only for short-term treatment (up to 5 days).

Adults.

The usual therapeutic dose of metoclopramide is 10 mg three times daily. The maximum daily dose is 30 mg or 0.5 mg/kg body weight. The maximum duration of metoclopramide treatment is 5 days.

Children.

The recommended dose of metoclopramide for prevention of delayed nausea and vomiting caused by chemotherapy is 0.1–0.15 mg/kg body weight, up to three times daily. The maximum daily dose is 0.5 mg/kg body weight.

Dosing Schedule

The maximum duration of metoclopramide use is 5 days.

elderly patients.

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

Renal impairment.

In patients with end-stage renal disease (creatinine clearance ≤ 15 mL/min), the dose of metoclopramide should be reduced by 75%.

In patients with moderate to severe renal impairment (creatinine clearance 15–60 mL/min), the dose of metoclopramide should be reduced by 50%.

Hepatic impairment.

In patients with severe hepatic insufficiency, half the dose of metoclopramide should be administered.

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, depressed level of consciousness, confusion, irritability, restlessness and its exacerbation, seizures, extrapyramidal disorders, cardiovascular dysfunction with bradycardia and either elevated or reduced arterial pressure, hallucinations, respiratory arrest, and cardiac arrest. Isolated cases of methemoglobinemia have been reported.

Treatment. In case of extrapyramidal symptoms related to overdose, symptomatic treatment is administered (benzodiazepines – in children and/or anticholinergic antiparkinson drugs – in adults). Following ingestion of large doses of metoclopramide, it should be removed from the gastrointestinal tract by gastric lavage or administration of activated charcoal and sodium sulfate.

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

Adverse reactions.

Gastrointestinal system: nausea, dry mouth, dyspepsia, constipation, diarrhea.

Nervous system: dyskinetic syndrome, mainly in children (involuntary spasmodic movements, particularly in the head, neck, and shoulder areas; tonic blepharospasm; facial and masticatory muscle spasms; tongue deviation; pharyngeal and tongue muscle spasms; abnormal head and neck posture; spinal strain; spasmodic flexion of arms; spasmodic extension of legs), headache, dizziness, increased fatigue, somnolence, extrapyramidal disorders (which may occur even after a single dose, primarily in children and adolescents and/or in case of exceeding the recommended dose) (see section "Special precautions"), parkinsonism (tremor, muscle rigidity, akinesia), akathisia, dystonia (including visual disturbances and oculogyric crisis), dyskinesia, impaired 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).

There is a higher risk of acute (transient) neurological disorders in children, and of tardive dyskinesia in elderly patients. The risk of developing nervous system adverse reactions increases with high-dose administration and prolonged treatment.

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

− extrapyramidal symptoms: acute dystonia and dyskinesia, parkinsonism, akathisia, even after a single dose of the drug, especially in children and adolescents;

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

Psychiatric disorders: asthenia, depression, hallucinations, confusion, anxiety, restlessness, disorientation, tinnitus.

Cardiovascular system: bradycardia, particularly with intravenous administration; transient cardiac arrest shortly after injection, which may result from bradycardia (see section "Special precautions"); atrioventricular block, sinoatrial node block, particularly with intravenous administration; QT interval prolongation; torsades de pointes ventricular tachycardia; arterial hypotension, particularly with intravenous administration; shock; syncope with parenteral administration; acute arterial hypertension in patients with pheochromocytoma (see section "Contraindications"); transient increase in blood pressure.

Blood and lymphatic system: 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.

Immune system: hypersensitivity reactions including urticaria, angioedema, anaphylactic reactions (including anaphylactic shock), mainly with intravenous administration.

Skin and subcutaneous tissue: rash, urticaria, skin hyperemia, and pruritus.

Reproductive system and mammary gland function*: amenorrhea, hyperprolactinemia, galactorrhea, gynecomastia, menstrual cycle disturbances. In such cases, the drug must be discontinued.

Laboratory parameters: increased liver enzyme levels, elevated serum creatine phosphokinase levels.

In adolescents and patients with severe renal impairment (renal insufficiency), which reduces metoclopramide elimination, careful monitoring for adverse reactions is required. If such reactions occur, the drug must be discontinued immediately.

* Endocrine disorders during prolonged treatment are associated with hyperprolactinemia (amenorrhea, galactorrhea, gynecomastia). In such cases, the drug must be discontinued.

Shelf life. 4 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 tablets in a blister pack; 5 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address.

13 Borispilska Street, Kyiv, 02093, Ukraine.