Adult population:

Metoclopramide 5 mg/ml Solution for Injection is indicated in adults for:

- Prevention of post operative nausea and vomiting (PONV).

- Symptomatic treatment of nausea and vomiting, including acute migraine induced nausea and vomiting.

- Prevention of radiotherapy induced nausea and vomiting (RINV).

Paediatric population

Metoclopramide 5 mg/ml Solution for Injection is indicated in children (aged 1-18 years) for:

- Prevention of delayed chemotherapy induced nausea and vomiting (CINV) as a second line option.

- Treatment of established postoperative nausea and vomiting (PONV) as a second line option.

Due to the risk of severe cardiovascular reactions such as cardiac arrest, the use of the solution for injection is limited to situations where the necessary resuscitation equipment is available (see sections 4.4 and 4.8).

The solution can be administered intravenously or intramuscularly.

Intravenous doses should be administered as a slow bolus (over at least 3 minutes).

All indications (adult patients)

For prevention of PONV a single dose of 10 mg is recommended.

For the symptomatic treatment of nausea and vomiting, including acute migraine induced nausea and vomiting and for the prevention of radiotherapy induced nausea and vomiting (RINV): the recommended single dose is 10 mg, repeated up to three times daily.

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

The injectable treatment duration should be as short as possible and a switch to oral or rectal treatment should be made as soon as possible.

All indications (paediatric population aged 1-18 years)

The recommended dose is 0.1 to 0.15 mg/kg body weight, repeated up to three times daily by intravenous route. The maximum dose in 24 hours is 0.5 mg/kg body weight.

Dosing table

The maximum treatment duration is 48 hours for treatment of established postoperative nausea and vomiting (PONV).

The maximum treatment duration is 5 days for prevention of delayed chemotherapy induced nausea and vomiting (CINV).

Special patient groups

Elderly patients

In elderly patients a dose reduction should be considered, based on renal and hepatic function and overall weakness.

Renal impairment:

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

In patients with moderate to severe renal impairment (Creatinine clearance 15-60 mL/min), the dose should be reduced by 50% (see section 5.2).

Hepatic impairment:

In patients with severe hepatic impairment, the dose should be reduced by 50% (see section 5.2).

Paediatric population

Metoclopramide 5 mg/ml Solution for Injection is contraindicated in children aged less than 1 year (see section 4.3).

Method of administration:

A minimal interval of 6 hours between two administrations is to be respected, even in case of vomiting of the dose (see section 4.4).

- Hypersensitivity to active substance or any of the excipients listed in section 6.1.

- Gastrointestinal haemorrhage, mechanical obstruction or gastrointestinal perforation for which the stimulation of gastrointestinal motility constitutes a risk.

- Confirmed or suspected phaeochromocytoma associated with the risk of severe hypertension episodes.

- History of neuroleptic or metoclopramide-induced tardive dyskinesia.

- Epilepsy (increased crisis frequency and intensity).

- Parkinson's disease.

- Combination with levodopa or dopaminergic agonists (see section 4.5).

- Known history of methaemoglobinaemia with metoclopramide or NADH cytochrome b5 deficiency.

- Use in children less than 1 year of age due to an increased risk of extrapyramidal disorders (see section 4.4).

Neurological disorders

Extrapyramidal disorders may occur, particularly in children and young adults, and/or when high doses are used. These reactions usually occur at the beginning of the treatment and can occur after a single administration. Metoclopramide should be discontinued immediately in the event of extrapyramidal symptoms. These effects are generally completely reversible after treatment discontinuation, but may require a symptomatic treatment (benzodiazepines in children and/or anticholinergic anti-Parkinsonian medicinal products in adults).

The time interval of at least 6 hours specified in section 4.2 should be respected between each metoclopramide administration, even in case of vomiting of the dose, in order to avoid overdose.

Prolonged treatment with metoclopramide may cause tardive dyskinesia, which is potentially irreversible, especially in the elderly. Treatment should not exceed 3 months because of the risk of tardive dyskinesia (see section 4.8). Treatment must be discontinued if clinical signs of tardive dyskinesia appear.

Neuroleptic malignant syndrome has been reported with metoclopramide in combination with neuroleptics as well as with metoclopramide monotherapy (see section 4.8). Metoclopramide should be discontinued immediately in the event of symptoms of neuroleptic malignant syndrome and appropriate treatment should be initiated.

Special care should be exercised in patients with underlying neurological conditions and in patients being treated with other drugs that act on the central nervous system (see section 4.3).

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

Methaemoglobinaemia

Methaemoglobinaemia which could be related to NADH cytochrome b5 reductase deficiency has been reported. In such cases, metoclopramide should be immediately and permanently discontinued and appropriate measures initiated (such as treatment with methylene blue).

Cardiac disorders

There have been reports of serious cardiovascular undesirable effects including cases of circulatory collapse, severe bradycardia, cardiac arrest and QT prolongation following administration of metoclopramide by injection, particularly via the intravenous route (see section 4.2 and 4.8).

Special care should be taken when administering metoclopramide, particularly via the intravenous route to the elderly population, to patients with cardiac conduction disorders (including QT prolongation), patients with uncorrected electrolyte imbalance, bradycardia and those taking other drugs known to prolong QT interval (such as class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics (see section 4.8)).

Intravenous doses should be administered as a slow bolus (over at least 3 minutes) in order to reduce the risk of adverse effects (e.g. hypotension, akathisia).

Renal and hepatic impairment

In patients with renal impairment or with severe hepatic impairment, a dose reduction is recommended (see section 4.2).

Other precautions

Metoclopramide may cause elevation of serum prolactin levels.

Care should be exercised when using metoclopramide in patients with a history of atopy (including asthma) or porphyria.

Special care should be taken when administering metoclopramide intravenously to patients with “ sick sinus syndrome” or other cardiac conduction disturbances.

This medicinal product contains less than 1 mmol sodium (= 23 mg) per dose, that is to say essentially 'sodium- free'.

Contraindicated combination

Concomitant use of levodopa or dopaminergic agonists and metoclopramide is contraindicated due to mutual antagonism (see section 4.3).

Combination to be avoided

Alcohol potentiates the sedative effect of metoclopramide.

Combination to be taken into account

Due to the prokinetic effect of metoclopramide, the absorption of certain drugs may be modified.

Anticholinergics and morphine derivatives

Anticholinergics and morphine derivatives may have a mutual antagonism with metoclopramide on the digestive tract motility.

Central nervous system depressants (morphine derivatives, anxiolytics, sedative H1 antihistamines, sedative antidepressants, barbiturates, clonidine and related products) The sedative effects of Central Nervous System depressants and metoclopramide are potentiated.

Neuroleptics

Metoclopramide may have an additive effect with other neuroleptics on the occurrence of extrapyramidal disorders.

Serotonergic drugs

The use of metoclopramide with serotonergic drugs such as SSRIs may increase the risk of serotonin syndrome.

Digoxin

Metoclopramide may decrease digoxin bioavailability. Careful monitoring of digoxin plasma concentration is required.

Ciclosporin

Metoclopramide increases ciclosporin bioavailability (Cmax by 46% and exposure by 22%). Careful monitoring of ciclosporin plasma concentration is required. The clinical consequences are uncertain.

Mivacurium and suxamethonium

Metoclopramide 5 mg/ml Solution for Injection may prolong the duration of neuromuscular block (through inhibition of plasma cholinesterase).

Strong CYP2D6 inhibitors

Metoclopramide exposure levels are increased when co-administered with strong CYP2D6 inhibitors such as fluoxetine and paroxetine. Although the clinical significance is uncertain, patients should be monitored for adverse reactions.

Pregnancy

A large amount of data on pregnant women (more than 1,000 pregnancy outcomes) indicate no malformative nor feto-toxicity of metoclopramide. Metoclopramide can be used during pregnancy if clinically needed. Due to pharmacological properties (as with other neuroleptics), in case of metoclopramide administration at the end of pregnancy, extrapyramidal syndrome in the newborn cannot be excluded. Metoclopramide should be avoided at the end of pregnancy. If metoclopramide is used, neonatal monitoring should be undertaken.

Breastfeeding

Metoclopramide is excreted in human milk at low levels. Adverse reactions in the breastfed baby cannot be excluded. Therefore metoclopramide is not recommended during breastfeeding. Discontinuation of metoclopramide in breastfeeding women should be considered.

Metoclopramide 5 mg/ml Solution for Injection may cause sleepiness, dizziness, dyskinesia and dystonia which could affect vision and also interfere with the ability to drive and operate machinery.

Adverse reactions listed by System Organ Class. Frequencies are defined using the following convention: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).

* Endocrine disorders during prolonged treatment in relation to hyperprolactinaemia (amenorrhoea, galactorrhoea, gynaecomastia).

The following reactions, sometimes associated, occur more frequently when high doses are used:

- Extrapyramidal symptoms: acute dystonia and dyskinesia, Parkinsonian syndrome, acathesia, even following administration of a single dose of the medicinal product, particularly in children and young adults (see section 4.4).

- Sleepiness, depressed level of consciousness, fuzzy thinking, hallucination.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the United KingdomYellow Card Scheme. Website: www.mhra.gov.uk/yellowcard.

Symptoms

Extrapyramidal disorders, sleepiness, depressed level of consciousness, fuzzy thinking, hallucination, and cardio-respiratory arrest may occur.

Treatment

In case of extrapyramidal symptoms related or not to overdose, the treatment is only symptomatic (benzodiazepines in children and/or anticholinergic anti-Parkinsonian medicinal products in adults).

Symptomatic treatment and continuous monitoring of cardiovascular and respiratory functions should be carried out according to clinical status.

Pharmacotherapeutic group: Propulsives.

ATC code: A03F (A).

Metoclopramide is a substituted benzamide. It is used among other things for its anti-emetic properties. Its anti-emetic effect due to two central-acting mechanisms of action:

• antagonism of the dopaminergic D2 receptors in the chemoceptor trigger zone and in the vomiting centre of the medulla involved in apomorphine-induced vomiting;

• antagonism of the serotoninergic 5HT3 receptors and agonism of the 5HT4 receptors involved in chemotherapy-induced vomiting.

In addition to its central action, metoclopramide has a stimulatory effect on digestive motor activity through a peripheral mode of action. It has an anti-dopaminergic effect and potentiates the action of acetylcholine. This results in an accelerated gastric emptying and increase in the pressure of the lower oesophageal sphincter. Metoclopramide does not affect gastric secretion.

After intramuscular administration, the relative bioavailability compared to intravenous administration is 60 to 100%. Peak plasma levels are reached within 0.5 to 2 hours.

The volume of distribution is 2-3 L/kg; 13-22% is bound to plasma proteins.

Metoclopramide is mainly excreted in the urine, both in unchanged form and in sulphate or glucuronide conjugate form. The main metabolite is N-4 sulphur conjugate.

The plasma elimination half-life is 5 to 6 hours, regardless of route of administration.

Renal impairment

The clearance of metoclopramide is reduced by up to 70% in patients with severe renal impairment, while the plasma elimination half-life is increased (approximately 10 hours for a creatinine clearance 10-50 mL/minute and 15 hours for a creatinine clearance <10 mL/minute).

Hepatic impairment

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

No indications of a safety risk in humans were found in laboratory animals. This is based on data from safety pharmacology studies, and data on repeated dose toxicity, genotoxicity, carcinogenicity and reproductive toxicity.

Citric Acid Monohydrate (E330)

Sodium citrate (E331)

Sodium chloride

Sodium hydroxide (E524) (for pH adjustment)

Hydrochloric acid (E507) (for pH adjustment)

Water for injection.

The medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6

Before Opening: 2 Years

Chemical and physical in-use stability has been demonstrated for 24 hrs at 25° C.

From a microbiology point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to used are the responsibility of the user and would normally not be longer than 24 hrs at 2 to 8° C, unless reconstitution has taken place in controlled and validated aseptic condition.

Store ampoule in the original package in order to protect from light.

Do not store in the refrigerator or freezer

For storage conditions after first opening of the medicinal product, see section 6.3

Type I clear glass ampoule of 2 ml fill volume and 10 mL fill volume.

Metoclopramide 5mg/ml Solution for Injection is available in glass ampoule containing 2 ml solution and 10 mL solution which are packed in blister and further packed in cardboard boxpack as below:

5 x 2 mL, 10 x 2 mL and 25 x 2 mL

5 x 10 mL and 10 x 10 mL.

Not all pack sizes may be marketed.

If only part of an ampoule is used, discard the remaining solution.

After opening: from a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Metoclopramide 5 mg/ml Solution for Injection is compatible with the following solutions for infusion for 24 hours:

1) 0.9 % Sodium Chloride Injection

2) 5% Dextrose Injection

3) 4% Dextrose in 0.18 % Sodium chloride

4) Ringer lactate solution