Composition:
Each 2 ml contains metoclopramide hydrochloride BP equivalent to 10 mg of anhydrous metoclopramide hydrochloride.

Mechanism of Action:
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 gastroesophageal sphincter is increased. Metoclopramide is a dopamine-receptor antagonist with a direct anti-emetic effect on the medullary chemoreceptor trigger zone.

Pharmacokinetic Properties:
Absorption:
Metoclopramide is rapidly absorbed from the gastrointestinal tract and undergoes variable first-pass metabolism in the liver.
Biotransformation and Elimination:
Metoclopramide is metabolised in the liver and the predominant route of elimination of metoclopramide and its metabolites is via the kidney. It crosses the placenta and is excreted in breast milk. The elimination half-life is about 6 hours.
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 <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.

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 pediatric 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).

Dosage 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.
Dosing table :

Side Effects:
Blood and lymphatic system disorders:
Not known: Methaemoglobinaemia, which could be related to NADH cytochrome b5 reductase deficiency, particularly in neonates
Sulfhaemoglobinaemia, mainly with concomitant administration of high doses of sulphur-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, 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), 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, Neuroleptic malignant syndrome
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
Transient increase in blood pressure
Skin disorder:
Not known: Skin reactions such as rash, pruritus, angioedema and urticaria

Contraindications:

• Hypersensitivity to the active substance or to any of the excipients.
• 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.
• 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.
• 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.

Precautions:

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 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. 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. 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.

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.

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 hepatic impairment, a dose reduction is recommended.

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.

Drug Interactions:

Contraindicated combination

Levodopa or dopaminergic agonists and metoclopramide have a mutual antagonism.

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 may both have a mutual antagonism with metoclopramide on the digestive tract motility.

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

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

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

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

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

Metoclopramide injection may prolong the duration of neuromuscular block such as (Mivacurium and Suxamethonium) through inhibition of plasma cholinesterase.

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.

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).

Metoclopramide injection may reduce plasma concentrations of atovaquone.

Use in Pregnancy or Lactation:

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

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.

Overdosage :

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.

Additional information:

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

Any dilutions of Metoclopramide 5 mg/ml Injection should be protected from light during infusion. Degradation is indicated by a yellow discoloration. Such solution must not be used.