Metoclopramide hydrochloride

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT METOCLOPRAMIDE HYDROCHLORIDE (METOCLOPRAMIDE HYDROCHLORIDE)

Composition:

Active substance: metoclopramide hydrochloride;

1 ml of the preparation contains 5 mg of metoclopramide hydrochloride (as monohydrate);

Excipients: sodium sulfite anhydrous (E 221), disodium edetate, sodium chloride, water for injections.

Pharmaceutical form. Injection solution.

Main physico-chemical properties: clear, colorless liquid.

Pharmacotherapeutic group. Drugs affecting the gastrointestinal tract and metabolism. Prokinetic agents. ATC Code A03FA01.

Pharmacological Properties.

Pharmacodynamics.

A specific blocker of dopamine (D2) and serotonin (5-HT3) receptors, which inhibits chemoreceptor trigger zone in the brainstem, reduces sensitivity of visceral nerves transmitting impulses from the pylorus and duodenum to the vomiting center. Through the hypothalamus and the parasympathetic nervous system (innervation of the gastrointestinal tract), it exerts a regulatory and coordinating effect on the tone and motor activity of digestive organs.

Increases gastric and intestinal tone, accelerates gastric emptying, reduces hyperacid stasis, prevents pyloric and esophageal reflux, stimulates intestinal peristalsis. Normalizes bile secretion, reduces spasm of the sphincter of Oddi without altering its tone, eliminates gallbladder dyskinesia.

Stimulates prolactin secretion (similar to other dopamine receptor blockers).

Pharmacokinetics.

Onset of action on the gastrointestinal tract occurs within 10–15 minutes after intramuscular injection and within 1–3 minutes after intravenous administration, manifested by accelerated gastric emptying (lasting approximately 3 hours) and antiemetic effect (lasting up to 12 hours).

After parenteral administration, it is rapidly and completely absorbed. It is minimally metabolized in the liver via conjugation with sulfuric and glucuronic acids. The elimination half-life ranges from 2.5 to 6 hours. Approximately 85% of the dose is excreted in urine within 72 hours either unchanged or as metabolites; the remainder is excreted in feces. In patients with impaired renal function, the elimination half-life is prolonged.

It readily penetrates the blood-brain barrier and placental barrier, as well as into breast milk.

Clinical characteristics.

Indications.

Adults. Prevention of postoperative nausea and vomiting.

Symptomatic treatment of nausea and vomiting, including nausea and vomiting associated with acute migraine.

Prevention of radiation-induced nausea and vomiting.

Children. As a second-line agent for the prevention of delayed nausea and vomiting induced by chemotherapy.

As a second-line agent for the treatment of established postoperative nausea and vomiting.

Contraindications.

• Hypersensitivity to metoclopramide or to any of the other components of the medicinal product;
• gastrointestinal hemorrhage;
• mechanical intestinal obstruction;
• gastrointestinal perforation;
• confirmed or suspected pheochromocytoma due to the risk of severe episodes of arterial hypertension;
• history of tardive dyskinesia caused by neuroleptics or metoclopramide;
• epilepsy (increased frequency and intensity of seizures);
• Parkinson's disease;
• concomitant use with levodopa or dopaminergic agonists;
• history of methemoglobinemia induced by metoclopramide or of NADH-cytochrome-b5-reductase deficiency;
• prolactin-dependent tumors;
• increased seizure susceptibility (extrapyramidal movement disorders);
• use in children under 1 year of age due to the risk of developing extrapyramidal disorders.

Precautions.

Due to the presence of sodium sulfite, metoclopramide hydrochloride injection solution must not be administered to patients with bronchial 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, such as paracetamol, metoclopramide hydrochloride may alter their absorption due to metoclopramide's effect on gastric motility.

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, anxiolytics, neuroleptics, sedative H1-receptor antagonists, sedative antidepressants, barbiturates, clonidine, and similar agents): potentiate the sedative effect of metoclopramide.

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

Serotonergic agents: the use of metoclopramide in combination with serotonergic agents, such as selective serotonin reuptake inhibitors (SSRIs), increases the risk of serotonin syndrome.

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

Cyclosporine: metoclopramide increases cyclosporine bioavailability (Cmax by 46% and AUC by 22%). Careful monitoring of cyclosporine plasma concentrations 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: metoclopramide exposure levels increase when co-administered 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 may prolong the effect of succinylcholine.

Tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), sympathomimetics: metoclopramide may affect their action.

Thiamine (vitamin B1): due to the presence of sodium sulfite in the metoclopramide injection solution, concomitant administration may lead to rapid degradation of thiamine in the body.

Special precautions for use.

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

2 ml of metoclopramide hydrochloride solution contain less than 1 mmol (23 mg) of sodium, i.e. practically sodium-free.

Neurological disorders. Extrapyramidal disorders may occur, particularly in children and/or when high doses are used. These reactions usually occur at the beginning of treatment and may develop even after a single dose. If extrapyramidal symptoms occur, 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 in cases of vomiting and dose rejection, 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.

Cases of neuroleptic malignant syndrome have been reported with the use of metoclopramide 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.

Metoclopramide should be used with caution in patients with concomitant neurological disorders and in patients receiving treatment with other medicinal products acting on the central nervous system.

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

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

Cardiac disorders. Severe adverse reactions affecting the cardiovascular system have been reported, including cases of acute circulatory failure, severe bradycardia, cardiac arrest, and QT interval prolongation, observed after administration of metoclopramide by injection, particularly after intravenous administration.

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

The intravenous formulation should be administered 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.

The drug should be used with caution in patients at risk, namely: elderly patients, patients with cardiac conduction disorders, arterial hypertension, diabetes mellitus, history of depression (only if the expected benefit outweighs the potential risks), uncorrected electrolyte imbalance or bradycardia, and patients receiving drugs that prolong the QT interval.

The drug 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.

If nausea and vomiting persist during metoclopramide therapy, cerebral disorders should be ruled out.

The drug should not be administered after gastrointestinal surgery (pyloroplasty or intestinal anastomosis), as vigorous muscular contractions may interfere with wound healing.

The product contains sodium sulfite and therefore should not be administered to patients with bronchial asthma or hypersensitivity to sulfites. Rarely, it may cause hypersensitivity reactions and bronchospasm, which may be life-threatening.

Ineffective in vestibular-origin vomiting.

Use during pregnancy or breastfeeding.

Clinical data indicate the absence of teratogenic or fetoneonatal toxicity. Metoclopramide may be used during pregnancy if there is a clinical need. However, due to its pharmacological properties (as with other neuroleptics), the use of metoclopramide at the end of pregnancy cannot exclude the possibility of extrapyramidal symptoms in the newborn. The use of metoclopramide at the end of pregnancy should be avoided. Newborns should be monitored if metoclopramide is used.

Metoclopramide passes into breast milk in small amounts. An effect of metoclopramide on the breastfed infant cannot be excluded. 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 affect vision as well as the ability to drive or operate machinery.

Method of administration and dosage.

The injection solution should be administered intramuscularly or slowly intravenously.

Metoclopramide for intravenous administration should be given as a slow bolus injection over at least 3 minutes.

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 migraine, as well as for prevention of nausea and vomiting induced 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 metoclopramide formulations.

Children. When used 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 treatment is required, the interval between doses should be no less than 6 hours.

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.

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

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%.

Depending on clinical efficacy and safety, the dosage may be increased or decreased.

In patients with clinically significant hepatic insufficiency, due to prolonged elimination half-life, start with a half dose; the subsequent dose should be based on individual response to metoclopramide.

Children.

Metoclopramide hydrochloride, solution for injection, is contraindicated in children under 1 year of age.

Overdose.

Symptoms: drowsiness, decreased level of consciousness, confusion, irritability, hallucinations, disorientation, motor restlessness, seizures, extrapyramidal-motor disorders, dystonic reactions, cardiovascular dysfunction with bradycardia, increased or decreased arterial pressure, respiratory arrest, and cardiac arrest. Methemoglobinemia may develop, especially in children.

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

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

Adverse Reactions

Immune system: hypersensitivity reactions, anaphylactic reactions (including anaphylactic shock, especially with intravenous administration), bronchospasm, particularly in patients with a history of bronchial asthma.

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

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

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

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

Nervous system: malignant neuroleptic syndrome (characteristic symptoms: fever, muscle rigidity, impaired consciousness, fluctuations in blood pressure); seizures (mainly in patients with epilepsy); headache, dizziness, drowsiness, depressed level of consciousness.

Extrapyramidal disorders, which may occur even after a single dose, primarily in children and adolescents and/or when the recommended dose is exceeded (see section "Special precautions"):

• Dyskinetic syndrome (involuntary spasmodic movements, particularly in the head, neck, and shoulders; tonic blepharospasm; spasms of facial and masticatory muscles; tongue deviation; spasm of pharyngeal and tongue muscles; unnatural positions of the head and neck; spinal hyperextension; spasmodic flexion of arms; spasmodic extension of legs);
• Parkinsonism (tremor, rigidity, akinesia);
• Acute dystonia (including visual disturbances and oculogyric crisis);
• Tardive dyskinesia (may be persistent during or after prolonged treatment, especially in elderly patients);
• Akathisia.

Skin and subcutaneous tissue: rash, urticaria, skin erythema and itching, angioneurotic edema (including laryngeal and tongue edema).

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

Hepatobiliary system: cases of hepatotoxicity characterized by manifestations such as jaundice, elevated serum liver transaminases, usually when metoclopramide is administered with other potentially hepatotoxic drugs.

Urinary system: frequent urination, urinary incontinence.

Injection site reactions: inflammatory reactions at the injection site, including phlebitis.

General disorders: asthenia, visual disturbances, tinnitus, porphyria, increased fatigue.

In adolescents and patients with severe renal impairment (renal insufficiency), which leads to reduced elimination of metoclopramide, careful monitoring for adverse reactions is essential. If such reactions occur, the drug should be discontinued immediately.

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

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

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 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;

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

Shelf life. 4 years.

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

Keep out of reach of children.

Incompatibility.

Metoclopramide hydrochloride injection solution must not be mixed with alkaline infusion solutions. Metoclopramide hydrochloride 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 tray; 2 trays in a carton;

2 ml in an ampoule, 10 ampoules in a tray, 1 tray in a carton.

Prescription status. Prescription only.

Manufacturer. Public Joint-Stock Company "Scientific and Production Center "Borshchagivskiy Chemical and Pharmaceutical Plant".

Manufacturer's address and location of business activity.

17 Myru Street, Kyiv, 03134, Ukraine.