SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Metoclopramide 5mg/ml Injection

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of solution contains metoclopramide hydrochloride BP equivalent to 5mg of the anhydrous salt.

Also contains sodium metabisulphite (E223) 1.48mg per ml.

For the full list of excipients see section 6.1

3    PHARMACEUTICAL FORM

Injection, as 10mg/2ml and 100mg/20ml ampoules.

|    4.1 Therapeutic indications

Adult

population

10mg/2ml and 100mg/20ml Injection_______________________________V

|    Metoclopramide 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)

I A_______________________________________________________________

Paediatric population:

|    Metoclopramide is indicated in children (aged 1 - 18 years) for:

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

-    The treatment of established postoperative nausea and vomiting (PONV) as a second line option

v

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

may be repeated 2 hourly up to a maximum of 10mg/kg body weight in any 24 hour period. It is recommended that each dose be added to at least 50ml of an appropriate diluent (see below) and infused over at least 15 minutes.

The cytotoxic agent should be administered as a separate infusion.

Note: the high dose ampoule presentation is not suitable for multidose use. Stability in intravenous fluids:

Intravenous solutions should be prepared as near as possible to the time of infusion. However Metoclopramide Injection has been shown to be stable in the solutions listed below for at least 24 hours at room temperature.

Intravenous

infusions:

Sodium chloride intravenous infusion BP (0.9%w/v). Glucose intravenous infusion BP

(5%w/v)

Sodium chloride and glucose intravenous infusion BP (sodium chloride

0.18%w/v; glucose 4%w/v)

Potassium chloride (0.15% or 0.3%).

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 < 15ml/min), the daily dose should be reduced by 75%.

In patients with moderate to severe renal impairment (Creatinine clearance 15 - 60ml/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

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

Confirmed or suspected phaeochromocytoma due to the risk of severe hypertensive episode.

Epilepsy (increased crises frequency and intensity

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

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

History of neuroleptic or metoclopramide-induced tardive dyskinesia. 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.

It should not be administered to patients where gastro intestinal conditions might be adversely affected, as in gastrointestinal obstruction, perforation, haemorrhage or immediately after surgery.

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

4.4 Special warnings and precautions for use

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

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)

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

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.

Methaemo globinemia

Methemoglobinemia 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.

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 hepatc impairment, a dose reduction is recommended (see section 4.2).

This medicine also contains E223- sodium metabisulphite. This may rarely cause severe hypersensitivity reactions and bronchospasm.

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 have both 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.

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 may reduce its plasma concentrations. trations of atovaquone.

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 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 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 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)

		cytochrome b5 reductase deficiency, particularly in neonates (see section 4.4) Sulfhaemoglobinaemia, mainly with concomitant administration of high doses of sulphur-releasing medical 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
1 Common I Asthenia
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, 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)

* 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 at: www.mhra.gov.uk/yellowcard

4.9 Overdose

Symptoms

Extrapyramidal disorders, drowsiness, 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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

The action of metoclopramide is closely associated with parasympathetic nervous control of the upper gastro-intestinal tract, where it has the effect of encouraging normal peristaltic action. This provides for a fundamental approach to the control of those conditions where disturbed gastro-intestinal motility is a common underlying factor.

Metoclopramide stimulates activity of the upper gastro-intestinal tract and restores normal co-ordination and tone.

Gastric emptying is accelerated and the resting tone of the gastrooesophageal sphincter is increased. Metoclopramide is a dopamine-receptor antagonist with a direct anti-emetic effect on the medullary chemoreceptor trigger zone.

5.2 Pharmacokinetic properties

Metoclopramide is metabolised in the liver and the predominant route of elimination of metoclopramide and its metabolites is via the kidney.

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 of 10 - 50 ml/ minute and 15 hours for a creatinine clearance <10ml/minute).

Hepatic impairment

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

5.3 Preclinical safety data

Not required.

6.1    List of excipients

Sodium metabisulphite (E223), sodium chloride and water for injection.

6.2    Incompatibilities

Not known.

6.3 Shelf life

24 months.

6.4 Special precautions for storage

Store in a cool dry place. Protect from light.

6.5. Nature and contents of the container

10mg/2ml injection: box of 10 ampoules 10mg/2ml injection: box of 5 ampoules 100mg/20ml injection: box of 10 ampoules

6.6 Special precautions for disposal

100mg/20ml ampoules are not suitable for multidose use. Protect from light

7 MARKETING AUTHORISATION HOLDER

Ennogen Pharma Limited Unit G4,

Riverside Industrial Estate,

Riverside Way,

Dartford DA1 5BS UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 40147/0059

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

25 May 1982/1 June 199

10 DATE OF REVISION OF THE TEXT

07/03/2016