4.1. Therapeutic indications

Paediatric population:

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

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

• Treatment of established post-operative nausea and vomiting (PONV) as a second line option

For other indications, the use in the paediatric population is not recommended.

Adult population:

Metoclopramide 5 mg/ml 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)

4.2. Posology and method of administration

The solution can be administered intravenously or intramuscularly.

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

All indications (paediatric patients 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.

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

Dosing table

Age

Body Weight

Dose

Frequency

1-3 years

10-14kg

1 mg

Up to 3 times daily

3-5 years

15-19 kg

2 mg

Up to 3 times daily

5-9 years

20-29 kg

2.5 mg

Up to 3 times daily

9-18 years

30-60 kg

5 mg

Up to 3 times daily

15-18 years

Over 60 kg

10 mg

Up to 3 times daily

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

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

All indications (adult patients)

For prevention of PONV a single dose of 10mg 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 0.5mg/kg body weight.

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

The maximum recommended treatment duration is 5 days.

Special population

Elderly

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

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 is contraindicated in children aged less than 1 year (see section 4.3)

4.3. Contraindications

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

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

• Confirmed or suspected phaeochromocytoma, due to the risk of severe hypertension episodes

• History of neuroleptic or metoclopramide-induced tardive dyskinesia

• Epilepsy (increased crises frequency and intensity)

• Parkinson's disease

• Combination with levodopa or dopaminergic agonists (see section 4.5)

• Known history of methaemoglobinaemia with metoclopramide or of 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)

• Metoclopramide 5 mg/ml Injection should not be used during the first three to four days following operations such as pyloroplasty or gut anastomosis as vigorous muscular contractions may not help healing.

• Metoclopramide should not be used during breast-feeding (see Section 4.6).

4.4. Special warnings and precautions for use

Neurological Disorders

Extrapyramidal disorders may occur, particularly in children and young adults, and/or when high doses are used. These reactions occur usually 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 the section 4.2 should be respected between each metoclopramide administration, even in case of vomiting and rejection of the dose, in order to avoid overdose.

Prolonged treatment with metoclopramide may cause tardive dyskinesia, 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 centrally-acting drugs (see section 4.3).

Metoclopramide should be used with caution in patients with hypertension, since there is limited evidence that the drug may increase circulating catecholamines in such patients.

Because metoclopramide can stimulate gastro-intestinal mobility, the drug theoretically could produce increased pressure on the suture lines following gastro-intestinal anastomosis or closure.

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 4.8).

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

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

Metoclopramide may cause elevation of serum prolactin levels.

Care should be exercised when using Metoclopramide 5 mg/ml Injection in patients with a history of atopy (including asthma) or porphyria.

Special care should be taken when administering Metoclopramide 5 mg/ml Injection intravenously to patients with “sick sinus syndrome” or other cardiac conduction disturbances.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per ampoule (2 ml), that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Contraindicated combination

Levodopa or dopaminergic agonists and metoclopramide have a 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 both 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)

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.

Cyclosporine

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

Mivacurium and suxamethonium

Metoclopramide 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.

The effects of certain other drugs with potential central stimulant effects, e.g. monoamine oxidase inhibitors and sympathomimetics, may be modified when prescribed with metoclopramide and their dosage may need to be adjusted accordingly.

Aspirin, paracetamol

The effect of metoclopramide on gastric motility may modify the absorption of other concurrently administered oral drugs from the gastro-intestinal tract either by diminishing absorption from the stomach or by enhancing the absorption from the small intestine (e.g. the effects of paracetamol and aspirin are enhanced).

Atovaquone

Metoclopramide injection may reduce plasma concentrations of atovaquone.

Rifampicin

In a published study conducted in 12 healthy volunteers, the administration of 600 mg of rifampicin for 6 days led to reduced plasma metoclopramide exposure (AUC area under the curve) and maximum concentration (Cmax) by 68% and 35%, respectively. Although the clinical significance is uncertain when metoclopramide is combined with rifampicin, or with other strong inducers (e.g. carbamazepine, phenobarbital, phenytoin), patients should be monitored for a possible lack of anti-emetic activity.

4.6. Fertility, pregnancy and lactation

Pregnancy

A large amount of data on pregnant women (more than 1000 exposed outcomes) indicates no malformative toxicity nor foetotoxicity. Metoclopramide can be used during pregnancy if clinically needed. Due to pharmacological properties (as 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 breast milk at a low level. Adverse reactions in the breast-fed baby cannot be excluded. Therefore metoclopramide is not recommended during breastfeeding. Discontinuation of metoclopramide in breastfeeding women should be considered.

4.7. Effects on ability to drive and use machines

Metoclopramide has moderate influence on the ability to drive and use machines.

Metoclopramide may cause drowsiness, dizziness, dyskinesia and dystonias which could affect the vision and also interfere with the ability to drive and operate machinery.

4.8. Undesirable effects

Adverse reactions listed by System Organ Class. Frequencies are defined using the following convention: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), not known (cannot be estimated from the available data).

System Organ Class

Frequency

Adverse reactions

Blood and lymphatic system disorders

Not known

Methaemoglobinaemia, which could be related to NADH cytochrome b5 reductase deficiency, particularly in neonates (see section 4.4)

Sulfhaemoglobinaemia, mainly with concomitant administration of high doses of sulfur-releasing medicinal products

Cardiac disorders

Uncommon

Bradycardia, particularly with intravenous formulation

Not known

Cardiac arrest, occurring shortly after injectable use, and which can be subsequent to bradycardia (see section 4.4); Atrioventricular block, Sinus arrest particularly with intravenous formulation; Electrocardiogram QT prolonged; Torsade de Pointes

Endocrine disorders*

Uncommon

Amenorrhoea, Hyperprolactinaemia,

Rare

Galactorrhoea

Not known

Gynaecomastia

Gastrointestinal disorders

Common

Diarrhoea

General disorders and administration site conditions

Common

Asthenia

Not Known

Injection site inflammation and local phlebitis

Immune system disorders

Uncommon

Hypersensitivity

Not known

Anaphylactic reaction (including anaphylactic shock) particularly with intravenous formulation

Nervous system disorders

Very common

Somnolence

Common

Extrapyramidal disorders (particularly in children and young adults and/or when the recommended dose is exceeded, even following administration of a single dose of the drug) (see section 4.4), Parkinsonism, Akathisia

Uncommon

Dystonia (including visual disturbances and oculogyric crisis), Dyskinesia, Depressed level of consciousness

Rare

Convulsion especially in epileptic patients

Not known

Tardive dyskinesia which may be persistent, during or after prolonged treatment, particularly in elderly patients (see section 4.4), Neuroleptic malignant syndrome (see section 4.4)

Psychiatric disorders

Common

Depression

Uncommon

Hallucination

Rare

Confusional state

Vascular disorder

Common:

Hypotension, particularly with intravenous formulation

Not known

Shock, syncope after injectable use. Acute hypertension in patients with phaeochromocytoma (see section 4.3).

Transient increase in blood pressure

Skin disorder

Not known

Skin reactions such as rash, pruritus, angioedema and urticaria

*Endocrine disorders during prolonged treatment in relation with 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, akathisia, even following administration of a single dose of the medicinal product, particularly in children and young adults (see section 4.4).

- Drowsiness, decreased level of consciousness, confusion, 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 Yellow Card Scheme Website at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

.

4.9. Overdose

Symptoms

Extrapyramidal disorders, drowsiness, a decreased level of consciousness, confusion, hallucination and cardio-respiratory arrest may occur.

Management

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).

A symptomatic treatment and a continuous monitoring of the cardiovascular and respiratory functions should be carried out according to clinical status.