Cerucal®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Cerucal® (Cerucal®)

Composition:

Active substance: metoclopramide hydrochloride;

1 ampoule (2 mL) contains 10 mg of metoclopramide hydrochloride in the form of metoclopramide hydrochloride monohydrate;

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

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group. Prokinetic agents (propulsives). ATC code A03F A01.

Pharmacological properties.

Pharmacodynamics.

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

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

The antiemetic effect is due to action on the chemoreceptor trigger zone of the brainstem (the chemoreceptor-activating area of the vomiting center), probably via inhibition of dopaminergic neurons. Enhanced peristalsis is partly 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. 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 eliminates gallbladder dyskinesia.

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

Prolonged treatment with metoclopramide may lead to increased serum prolactin concentration due to lack of dopaminergic inhibition of prolactin secretion. Galactorrhea and menstrual cycle disturbances have been reported in women, and gynecomastia in men; however, these symptoms disappeared 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. Antiemetic effect lasts up to 12 hours. Metoclopramide is bound to plasma proteins by 13–30%. Volume of distribution ranges from 2.2 to 3.4 L/kg body weight. It 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. Metoclopramide crosses the blood-brain and placental barriers and is excreted into breast milk. About 20% of the dose is excreted unchanged, while the remainder (about 80%) is metabolized in the liver and excreted by the kidneys in conjugation with glucuronic or sulfuric acid.

Renal impairment.

In patients with severe renal impairment, metoclopramide clearance is reduced by up to 70%, and 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).

Hepatic impairment.

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

Clinical characteristics.

Indications.

Adults.

Prevention of postoperative nausea and vomiting.

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

Prevention of nausea and vomiting caused by radiotherapy.

Children.

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

As a second-line agent for treatment of established 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 induced by neuroleptics or metoclopramide in medical history;
• 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 NADH-cytochrome-b5-reductase deficiency;
• prolactin-dependent tumors;
• increased seizure susceptibility (extrapyramidal movement disorders);
• age under 1 year in children, due to the risk of developing extrapyramidal disorders (see section "Special precautions").

Precautions.

Due to the presence of sodium sulfite, the injectable solution of Cerucal® 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 (see section "Contraindications").

Combinations to be avoided.

Alcohol enhances the sedative effect of metoclopramide.

Combinations requiring caution.

When administered concomitantly with oral medicinal products, such as paracetamol, Cerucal® may affect their absorption due to metoclopramide’s influence on gastric motility.

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

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

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

Serotonergic agents: concomitant use of metoclopramide with serotonergic agents, such as selective serotonin reuptake inhibitors (SSRIs), may increase 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%, exposure by 22%). Careful monitoring of cyclosporine plasma concentrations is required. The clinical significance of this interaction has not been fully established.

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

Potent CYP2D6 inhibitors: metoclopramide exposure levels increase when used concomitantly with strong CYP2D6 inhibitors, such as fluoxetine and paroxetine. Although the clinical significance of this interaction is not fully established, patients should be monitored for adverse reactions.

Thiamine (Vitamin B1): sodium sulfite is a highly reactive compound. Therefore, it should be noted that thiamine (vitamin B1) may degrade when administered simultaneously with the injectable solution of Cerucal®.

Special precautions for use.

Cerucal® for injections contains sodium; 2 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. If extrapyramidal symptoms develop, metoclopramide must be discontinued immediately. In general, these effects resolve completely after treatment is stopped, 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 cases of vomiting and dose rejection, to avoid overdose.

Prolonged treatment with metoclopramide may lead to tardive dyskinesia, which can potentially be irreversible, especially in elderly patients. Treatment should not exceed 3 months due to the risk of developing tardive dyskinesia (see section "Side effects"). 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 (see section "Side effects"). If symptoms of neuroleptic malignant syndrome occur, metoclopramide must be discontinued immediately and appropriate treatment initiated.

Particular 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 by the use of metoclopramide.

Methemoglobinemia.

Cases of methemoglobinemia have been reported, which may be associated with deficiency of NADH-cytochrome-b5-reductase. In such cases, metoclopramide must be immediately and permanently discontinued 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 following intravenous administration (see section "Side effects").

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 taking medicinal products that prolong the QT interval.

The drug should be administered intravenously as a 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 impaired renal function or severe hepatic impairment (see section "Dosage and administration").

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 in 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 studies in pregnant women (over 1000 outcomes with drug exposure) indicate no evidence of teratogenic or fetotoxic/neonatal toxic effects. Metoclopramide may be used during pregnancy if clinically indicated. However, due to its pharmacological properties (similar to other neuroleptics), extrapyramidal syndrome in the newborn cannot be excluded if metoclopramide is used at the end of pregnancy. Therefore, metoclopramide use should be avoided at the end of pregnancy. Newborns should be monitored if metoclopramide is administered.

Breastfeeding.

Metoclopramide passes into breast milk in small amounts. Effects 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.

Effects on ability to drive and use machines.

Metoclopramide may cause drowsiness, dizziness, dyskinesia, and dystonia, which may affect vision as well as the ability to drive vehicles or operate machinery.

Administration and Dosage

The injection solution is administered intramuscularly or by slow intravenous injection.

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 that 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 prompt transition to oral or rectal forms of metoclopramide.

Children.

When used for the 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 is required, dosing intervals 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.

Geriatric patients.

Dosage 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 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%.

Hepatic insufficiency.

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

Children.

Metoclopramide is contraindicated in children under 1 year of age (see section "Contraindications").

Overdose.

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

Treatment. In case of development of extrapyramidal symptoms, whether related to overdose or not, symptomatic treatment only should be 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 (see section "Special precautions"); atrioventricular block, sinus 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 disorders*: amenorrhea, hyperprolactinemia, galactorrhea, gynecomastia, menstrual cycle disturbances.

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

Nervous system disorders: 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, particularly in children and adolescents and/or when the recommended dose is exceeded (see section "Special precautions"):

• dyskinetic syndrome (involuntary spasmodic movements, especially in the head, neck, and shoulders; tonic blepharospasm; spasms of facial and masticatory muscles; tongue protrusion; spasm of pharyngeal and lingual muscles; abnormal head and neck posture; spinal hyperextension; spasmodic flexion of arms; spasmodic extension of legs);
• parkinsonism (tremor, rigidity, akinesia);
• acute dystonia, dystonia (including visual disturbances and oculogyric crisis);
• tardive dyskinesia (may be persistent during or after prolonged treatment, especially in elderly patients);
• akathisia.

Skin disorders: rash, urticaria, erythema and pruritus, angioneurotic edema.

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

Laboratory investigations: 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.

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

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.

Due to the presence of sodium sulfite in the injectable solution Cerucal® hypersensitivity reactions may occur in some cases, particularly in patients with bronchial asthma, manifesting as nausea, diarrhea, respiratory difficulty, acute asthma attack, confusion, or shock. These reactions may vary in severity and may be life-threatening.

Shelf life. 5 years.

Storage conditions.

Store in the original packaging protected from light at a temperature not exceeding 30 °C and out of reach of children. Do not freeze.

Incompatibilities. Cerucal®, injection solution, must not be mixed with alkaline infusion solutions. Cerucal®, injection solution, is incompatible with the following drugs: chloramphenicol, cisplatin, erythromycin, furosemide, calcium gluconate, methotrexate, sodium bicarbonate, penicillin G.

Packaging. 2 ml solution in an ampoule; 10 ampoules per box.

Prescription status. Prescription only.

Manufacturer.

Merckle GmbH.

Manufacturer's address and place of business.

Ludwig-Merckle-Strasse 3, 89143 Blaubeuren, Germany.