Metoclopramide-darnitsa

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT 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, diluted hydrochloric acid, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical characteristics: clear, colorless liquid.

Pharmacotherapeutic group. Prokinetic agents (propulsants).

ATC code A03F A01.

Pharmacological properties.

Pharmacodynamics.

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

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

The antiemetic effect is mediated through action on the chemoreceptor trigger zone of the brainstem (the central vomiting center), probably 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, metoclopramide 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 dopamine receptor-blocking action in the central nervous system.

Prolonged treatment with metoclopramide may lead to increased serum prolactin concentration 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 intravenous administration, metoclopramide is rapidly distributed.

Onset of action on the gastrointestinal tract occurs within 1–3 minutes after intravenous injection and within 10–15 minutes after intramuscular injection. The antiemetic effect lasts for up to 12 hours. The drug is 13–30% bound to plasma proteins. Volume of distribution is 2.2–3.4 L/kg body weight. Metoclopramide is metabolized in the liver. Elimination half-life is 2.6–4.6 hours in healthy volunteers and approximately 14 hours in patients with renal impairment. The drug crosses the blood-brain and placental barriers and is excreted in breast milk. Approximately 20% of the dose is excreted unchanged, while the remainder (approximately 80%) is metabolized in the liver and excreted by the kidneys in the form of conjugates with glucuronic or sulfuric acid.

In patients with severe renal impairment, creatinine clearance is reduced by up to 70%, and the plasma elimination half-life 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 liver cirrhosis, accumulation of metoclopramide has been observed, accompanied by a 50% reduction in plasma clearance.

Clinical characteristics.

Indications.

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

For children: as a second-line medicinal product for the prevention of delayed nausea and vomiting induced by chemotherapy; 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 crisis);
• 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;
• history of methemoglobinemia associated with metoclopramide use or NADH-cytochrome-b5-reductase deficiency;
• prolactin-dependent tumors;
• increased seizure susceptibility (extrapyramidal movement disorders);
• patient age under 1 year (due to risk of developing extrapyramidal disorders).

Due to the presence of sodium sulfite, the medicinal product must not be administered to patients with asthma who are hypersensitive to sulfites.

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.

When administered concomitantly with oral medicinal products, e.g. paracetamol, metoclopramide may affect their absorption due to its influence on gastric motility.

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

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

Neuroleptics: when metoclopramide is used in combination with other neuroleptics, a cumulative effect may occur, leading to extrapyramidal disorders.

Serotonergic drugs: concomitant use of metoclopramide with serotonergic agents, e.g. selective serotonin reuptake inhibitors (SSRIs), may increase the risk of serotonin syndrome.

Digoxin: metoclopramide may reduce digoxin bioavailability. Careful monitoring of digoxin plasma concentration is required.

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

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

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

Metoclopramide may prolong the effect of succinylcholine.

Due to the presence of sodium sulfite in the injectable solution, thiamine (vitamin B1) administered concomitantly with metoclopramide may rapidly degrade in the body.

Special precautions for use.

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

Ampoules removed from the packaging must not be left in sunlight for prolonged periods.

Neurological disorders.

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. In case of development of extrapyramidal symptoms, metoclopramide must be discontinued immediately. Generally, these effects resolve completely after discontinuation of treatment, but symptomatic treatment may be required (benzodiazepines in children and/or anticholinergic anti-Parkinson drugs in adults).

An interval of at least 6 hours must be maintained between each administration of metoclopramide, even in case of vomiting and rejection of the dose, to avoid overdose.

Prolonged treatment with metoclopramide may lead to tardive dyskinesia, which may be irreversible, particularly 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. If symptoms of neuroleptic malignant syndrome occur, metoclopramide must be discontinued immediately and appropriate treatment initiated.

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

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

Methemoglobinemia.

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

Cardiac disorders.

Serious adverse reactions affecting the cardiovascular system have been reported, including acute vascular failure, severe bradycardia, cardiac arrest, and QT interval prolongation, observed after administration of metoclopramide by injection, most frequently following intravenous administration (see section "Adverse reactions").

Particular caution is required when metoclopramide is administered intravenously to elderly patients, patients with conduction disorders (including QT interval prolongation), patients with electrolyte imbalance, bradycardia, and patients taking medications that prolong the QT interval. The medicinal product should be administered intravenously by slow bolus injection (over a minimum of 3 minutes) to reduce the risk of adverse reactions (e.g., hypotension, akathisia).

Renal and hepatic impairment.

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

The medicinal product should not be used for the treatment of chronic conditions such as gastroparesis, dyspepsia, and gastroesophageal reflux disease, or as an adjunctive agent during surgical or radiological procedures.

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

Use during pregnancy or breastfeeding.

Pregnancy. Extensive data from pregnant women (over 1000 outcomes of drug use) indicate no evidence of teratogenic toxicity or fetal/neonatal toxicity. Metoclopramide may be used during pregnancy if clinically indicated. However, due to its pharmacological properties (similar to other neuroleptics), administration of metoclopramide at the end of pregnancy cannot exclude the possibility of extrapyramidal syndrome in the newborn. Administration of metoclopramide at the end of pregnancy should be avoided. Newborns should be monitored if metoclopramide is used.

Breastfeeding. Metoclopramide passes into breast milk in small amounts. There may be an effect of metoclopramide on breastfed newborns. Therefore, the use of metoclopramide during breastfeeding is not recommended. The possibility of discontinuing metoclopramide use 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 or operate machinery.

Administration and Dosage

The injection solution should be administered intramuscularly or intravenously as a slow bolus injection over at least 3 minutes.

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

Adults.

For 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 migraine, as well as for prevention of nausea and vomiting caused by radiotherapy, the recommended single dose of metoclopramide is 10 mg up to 3 times daily.

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

Use of injectable forms should be as short-term as possible, with the earliest possible switch to oral or rectal forms of metoclopramide.

Children.

For prevention of postoperative nausea and vomiting, metoclopramide should be administered after completion of surgery.

The recommended dose of metoclopramide is 0.1–0.15 mg/kg body weight up to 3 times daily. The 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.

Dosing Schedule

The maximum duration of administration of metoclopramide for the treatment of established 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.

Patients with renal impairment

In patients with end-stage renal impairment (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%.

Patients with hepatic impairment

For patients with severe hepatic impairment, the dose of metoclopramide should be reduced by 50%.

Elderly patients

Dose reduction should be considered in elderly patients due to age-related decline 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 exacerbation, seizures, extrapyramidal-motor disorders, cardiovascular dysfunction with bradycardia and increased or decreased arterial pressure, hallucinations, respiratory arrest and cardiac arrest, dystonic reactions. Isolated cases of methemoglobinemia have been reported.

Treatment: in case of development of extrapyramidal symptoms, whether related to overdose or not, only symptomatic treatment is administered (benzodiazepines — for children and/or anticholinergic anti-Parkinson drugs — for adults).

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

Adverse reactions.

Gastrointestinal system: nausea, dyspepsia, dry mouth, constipation. Diarrhea may occur in patients treated with metoclopramide at doses exceeding the daily recommended dose.

Nervous system:

• Extrapyramidal disorders, which may occur even after a single dose, predominantly in children and adolescents and/or in cases of exceeding the recommended dose (see section "Special precautions");
• Parkinsonism (tremor, muscle rigidity, akinesia);
• Dyskinetic syndrome (involuntary spasmodic movements, particularly in the head, neck, and shoulders area; tonic blepharospasm; spasms of facial and masticatory muscles; tongue protrusion; spasm of pharyngeal and tongue muscles; abnormal head and neck posture; spinal strain; spasmodic flexion of arms; spasmodic extension of legs);
• Neuroleptic malignant syndrome (characterized by symptoms such as hyperthermia, muscle rigidity, impaired consciousness, fluctuations in arterial blood pressure), seizures (mainly in patients with epilepsy), headache, dizziness, drowsiness, depressed level of consciousness;
• Acute dystonia, dystonia (including visual disturbances and oculogyric crisis);
• Tardive dyskinesia (may be persistent during or after prolonged treatment, especially in elderly patients);
• Akathisia.

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

Cardiovascular system: bradycardia, particularly after intravenous administration; transient cardiac arrest shortly after injection, possibly due to bradycardia (see section "Special precautions"); atrioventricular block, sinoatrial block (especially with intravenous administration), QT interval prolongation, supraventricular extrasystole, ventricular extrasystole, torsades de pointes ventricular tachycardia, arterial hypotension (mainly with intravenous administration), shock, syncope after parenteral administration, acute arterial hypertension in patients with pheochromocytoma, transient increase in blood pressure.

Endocrine system: amenorrhea, hyperprolactinemia, galactorrhea, gynecomastia, menstrual cycle disturbances.

Blood and lymphatic system: 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.

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

Skin and subcutaneous tissue: hypersensitivity reactions, including skin rashes, skin hyperemia and itching, angioneurotic edema.

Laboratory parameters: increased liver enzyme levels.

General disorders: asthenia, increased fatigue.

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

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

The risk of acute (short-term) neurological disorders is higher in children, while the risk of tardive dyskinesia is higher in elderly patients. The risk of 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, particularly in children and adolescents;

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

Due to the presence of sodium sulfite in the medicinal product, hypersensitivity reactions may occur in some cases, particularly in patients with bronchial asthma, manifesting as nausea, diarrhea, dyspnea, acute asthma attack, confusion, or shock. These reactions may present in various forms and may 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. Metoclopramide injection solution must not be mixed with alkaline infusion solutions.

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

Packaging.

2 ml in an ampoule; 5 ampoules in a blister pack; 1 or 2 blister packs per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address.

13, Boryspilska Street, Kyiv, 02093, Ukraine.