Data Sheet

Metoclopramide

metoclopramide HCl

solution for injection (polyamps) 5 mg/mL

Presentation

5 mg/mL solution for injection (polyamps): a clear, colourless, particle-free solution, pH 3.0 - 5.0, containing 5 mg metoclopramide hydrochloride per mL.

Uses

Actions

Metoclopramide hydrochloride is a substituted benzamide which stimulates the motility of the upper gastrointestinal tract without affecting gastric, biliary, or pancreatic secretion. Gastric peristalsis is increased by METOCLOPRAMIDE which leads to accelerated gastric emptying. Duodenal peristalsis is also increased, which decreases intestinal transit time. The gastro-oesophageal sphincter resting tone is increased, while the pyloric sphincter is relaxed. The effect of METOCLOPRAMIDE on motility is not dependent on intact vagal innervation, but it can be abolished by anticholinergic agents. METOCLOPRAMIDE has little, if any effect on the motility of the colon or bladder.

The pharmacodynamic mechanism of action of METOCLOPRAMIDE has not yet been clarified.

METOCLOPRAMIDE possesses parasympathetic activity as well as being a dopamine-receptor antagonist. It may have serotonin-receptor (5HT₃) antagonist properties.

Pharmacokinetics

The onset of action following injection of metoclopramide hydrochloride is one to three minutes following intravenous administration, and 10 to 15 minutes following intramuscular administration. Pharmacological effects persist for one to two hours after onset.

Plasma protein binding ranges from 13 to 22%.

About 80% of METOCLOPRAMIDE is excreted in the urine in the first 24 hours, approximately half as the glucuronide and sulphate metabolites and half as unchanged medicine. Elimination half-life can vary from 2.5 to 6 hours. Impaired renal function prolongs the half-life of METOCLOPRAMIDE by up to 15 hours due to reduced clearance.

Indications

Adults (≥20 years)

1. For the treatment of nausea and vomiting associated with migraine, cancer therapy (either chemotherapy or radiation), anaesthesia, labour, or infectious diseases.
2. To facilitate small bowel intubation procedures.
3. To stimulate gastric emptying during radiographic examinations.
4. Intramuscular administration of METOCLOPRAMIDE facilitates the absorption of a range of oral migraine medications.
5. Treatment of mild to moderate diabetic gastroparesis. METOCLOPRAMIDE should only be used until diabetic control is established.
6. METOCLOPRAMIDE is of little benefit for the prevention or treatment of motion sickness.

Young Adults and Children

1. Severe intractable vomiting of known cause.
2. Vomiting associated with radiotherapy or intolerance to cytotoxic agents.
3. To facilitate small bowel intubation procedures.

Note: Indications in young adults and children are restricted because of the risk of adverse effects.

Dosage and Administration

The dosage recommendations given below should be strictly adhered to in order to minimise the possibility of dystonic side effects. METOCLOPRAMIDE should only be used after careful examination has excluded any underlying disorder (such as cerebral irritation) that may have induced the nausea and vomiting.

Maximum daily dose

This should not exceed 0.5 mg/kg body-weight, especially for children and young adults, when given by injection. However, when given diluted by intravenous infusion, a maximum of 10 mg/kg body-weight may be given in any 24 hour period.

Medical indications

Adults ≥20 years

10 mg three times a day, by intramuscular or slow (1 to 2 minutes) intravenous injection.

Young Adults 15 to 19 years

5 to 10 mg three times a day, starting at the lower dose, by intramuscular or slow (1 to 2 minutes) intravenous injection.

Children

To be given by intramuscular or slow (1 to 2 minutes) intravenous injection.

5 to 14 years: 2.5 to 5 mg three times a day.

3 to 5 years: 2 mg two or three times a day.

1 to 3 years: 1 mg two or three times a day.

Under 1 year: 1 mg twice daily.

Treatment of Nausea and Vomiting Due to Cytotoxic Medicine Therapy

Up to 2 mg/kg body-weight may be given diluted by intravenous infusion. The dose should be adjusted according to the dose of cytotoxic medicine used and its propensity to cause emesis.

The initial dose should be given prior to commencement of cytotoxic therapy. Each dose should be added to at least 50 mL of a suitable diluent (see Compatibilities) and infused over at least 15 minutes. Dosage may be repeated at two hourly intervals up to a maximum of 10 mg/kg body-weight in any 24 hours.

Aid to Gastrointestinal Intubation

A single dose of METOCLOPRAMIDE may be given 5 to 10 minutes before the examination. If the patient is lightly built the dose should be reduced.

Adults ≥20 years: 10 to 20 mg.

Young adults 15 to 19 years: 10 mg

Children:

9 to 14 years: 5 mg

5 to 9 years: 2.5mg

3 to 5 years: 2 mg

Under 3 years: 1mg

Impaired Renal and Hepatic Function

Clearance of METOCLOPRAMIDE is likely to be reduced in patients with clinically significant degrees of renal or hepatic impairment. The doses given above should be halved in these patients, with subsequent dose adjustment being made once the individual response has been determined.

Contraindications

1. Conditions where stimulation of gastric motility may be dangerous e.g. gastrointestinal haemorrhage, mechanical obstruction, perforation.
2. Phaeochromocytoma. METOCLOPRAMIDE may cause a hypertensive crisis in patients with phaeochromocytoma, probably due to release of catecholamines from the tumour.
3. Known hypersensitivity to METOCLOPRAMIDE. Note: patients sensitive to procaine and procainamide may be sensitive to METOCLOPRAMIDE.
4. METOCLOPRAMIDE is unsafe for use in patients with porphyria.
5. METOCLOPRAMIDE should not be used in patients with epilepsy since it may increase the frequency and severity of seizures.
6. METOCLOPRAMIDE should not be administered to patients receiving other drugs which are likely to cause extrapyramidal reactions, since the frequency and severity of extrapyramidal reactions may be increased.

Warnings and Precautions

1. Dystonia: Approximately 1% of patients given METOCLOPRAMIDE have dystonic reactions. These occur more frequently in children and young adults and may occur after a single dose. The rate in children under 10 years is approximately 10%.
2. Persistent tardive dyskinesia: Some patients on long term therapy may develop tardive dyskinesia during or after treatment. Elderly patients on high dose therapy appear to be at greatest risk, particularly female elderly patients. The symptoms are persistent and in some patients appear to be irreversible. Rhythmic, involuntary movements of the tongue, face, mouth or jaw is characteristic. These can include protrusion of the tongue, puffing of the cheeks, puckering of the mouth and chewing movements. Involuntary movements of the extremities may also be present. There is no known effective treatment for tardive dyskinesia. Antiparkinson agents are usually ineffective in alleviating the symptoms. If the symptoms do appear the dose of METOCLOPRAMIDE, and all other antipsychotic or antidopaminergic agents should be reduced progressively until discontinued if possible. Fine vermicular movements of the tongue may be the first signs of tardive dyskinesia, and if medication is stopped on the appearance of these the syndrome may not develop.
3. Prolactin levels: METOCLOPRAMIDE raises prolactin levels after a single dose and keeps them raised during chronic administration. This should be borne in mind when METOCLOPRAMIDE treatment is considered in patients with previously diagnosed breast cancer. Although prolactin elevating agents have been associated with disturbances such as galactorrhoea, amenorrhoea, gynaecomastia, and impotence, the clinical significance of elevated serum prolactin levels for most patients is unknown. Chronic administration of prolactin stimulating neuroleptic agents to rodents have shown an increase in mammary neoplasms. However, neither clinical nor epidemiological studies have shown an association between chronic administration of these medicines and mammary tumorigenesis in humans. The available evidence is too limited to be conclusive at this time.
4. Epilepsy: Patients with epilepsy may demonstrate an increased frequency or severity of seizures or extrapyramidal reactions if given METOCLOPRAMIDE. The frequency and severity of extrapyramidal reactions may be increased with neuroleptics such as phenothiazines.
5. Stomach operations: Following operations such as gut anastomosis or pyloroplasty, METOCLOPRAMIDE should not be given for three or four days, since vigorous muscle contractions may delay healing.
6. Neuroleptic malignant syndrome: METOCLOPRAMIDE is known to have caused fatal neuroleptic malignant syndrome.
7. Depression: METOCLOPRAMIDE-induced depression has been reported in patients without a prior history of depression. METOCLOPRAMIDE should be given to patients with a prior history of depression only if the expected benefits outweigh the potential risks.
8. Masking disease: The symptomatic relief provided by METOCLOPRAMIDE may delay recognition and diagnosis of disease. Diagnosis should be established prior to instituting METOCLOPRAMIDE treatment by appropriate investigations.
9. Children: METOCLOPRAMIDE should not be given to children unless a clear indication has been established for its use. Children run a greater risk of experiencing adverse reactions to METOCLOPRAMIDE.
10. Persistent vomiting: If vomiting persists in a patient being treated with METOCLOPRAMIDE, the patient should be reassessed to exclude the possibility of an underlying disorder such as cerebral irritation.
11. Intravenous injection: When given by intravenous injection, METOCLOPRAMIDE should be administered over a 1 to 2 minute period. Rapid administration may produce a transient but intense feeling of anxiety and restlessness, followed by drowsiness.
12. Mental alertness: Patients should be cautioned about engaging in activities requiring mental alertness (e.g. driving, operating machinery) for a few hours after the medicine is administered.
13. Extrapyramidal reactions: Like other dopamine antagonists, METOCLOPRAMIDE produces sedation and may cause extrapyramidal reactions. METOCLOPRAMIDE inhibits the central and peripheral effects of apomorphine, induces release of prolactin and produces a transient increase in circulating aldosterone levels.
14. Hypertension: Intravenously administered METOCLOPRAMIDE has been shown to release catecholamines, therefore caution should be taken when METOCLOPRAMIDE is used in patients with hypertension.
15. Prolonged therapy: Patients on prolonged METOCLOPRAMIDE therapy should be reviewed regularly.
16. Parkinson's disease: METOCLOPRAMIDE can exacerbate parkinsonian symptoms, therefore it should be used with caution, if at all, in patients with parkinsonian syndrome.
17. Renal insufficiency: Special care should be taken in cases of severe renal insufficiency.

Use in pregnancy

Animal tests in several mammalian species and clinical experience have not indicated any teratogenic effect. However, METOCLOPRAMIDE is not recommended during the first three months of pregnancy unless there are compelling reasons to do so.

Use in lactation

METOCLOPRAMIDE is excreted in human breast milk. It is not known whether it has a harmful effect on the newborn. It is therefore not recommended for nursing mothers unless the benefits to the mother outweigh any potential risk to the child. The increased risk of adverse reactions in children should be considered when making a risk-benefit assessment.

Mutagenicity

METOCLOPRAMIDE has been shown in in vitro studies to induce DNA damage and inhibit DNA repair. The clinical implications of these observations are as yet unclear.

Adverse Effects

More common (>1%)

Restlessness, drowsiness, fatigue and lethargy occur in approximately 10% of patients and are the most common adverse reactions to METOCLOPRAMIDE.

Central Nervous System: Extrapyramidal symptoms are not uncommon during METOCLOPRAMIDE therapy and about 1% of patients treated have true dystonic reactions. High dose (0.5 mg/kg body-weight) intravenous treatment with METOCLOPRAMIDE can produce acute reversible extrapyramidal symptoms in from 2 to 30% of patients. Extrapyramidal symptoms occur most frequently in children and consist of trismus, torticollis, facial spasms, opisthotonos, oculogyric crisis and dysphagia.

They usually occur within 36 hours of therapy and subside within 24 hours of withdrawal of treatment. Most patients respond to anticholinergic agents such as benztropine or diazepam.

Patients with AIDS (acquired immunodeficiency syndrome) may have an increased incidence of extrapyramidal reactions.

Less common (<1%)

Blood: Agranulocytosis and methaemoglobinaemia (following overdose) have been reported in individual patients.

Cardiovascular: Oedema, palpitations, irregular heart beats, atrial fibrillation, ventricular fibrillation, bradycardia, heart block and supraventricular tachycardia have occurred infrequently.

Hypertensive crisis has been precipitated by METOCLOPRAMIDE. METOCLOPRAMIDE may also induce transient hypotension of varying severity.

Central Nervous System: Choreiform movements, dizziness, mania, depression, akathisia, agitation, anxiety, insomnia, headache, neuroleptic malignant syndrome, delirium, severe dysphoria, obsessive rumination.

Tardive dyskinesia has been reported in patients who have taken METOCLOPRAMIDE for prolonged (>1 year) periods of time. In most cases the tardive dyskinesia improved after discontinuation of METOCLOPRAMIDE.

Parkinson symptoms have been reported in patients receiving chronic METOCLOPRAMIDE therapy.

Endocrine: Galactorrhoea, breast enlargement, porphyria, hyperthermia and neuroleptic malignant syndrome have all been reported in association with metoclopramide therapy.

Gastrointestinal: Constipation, diarrhoea, taste disorders, nausea.

Respiratory: Respiratory failure, secondary to dystonic reaction, acute asthmatic symptoms of wheezing and dyspnoea.

Skin: Urticaria, maculopapular rash.

Other: Urinary frequency and incontinence, sexual dysfunction, priapism, muscle spasm. There have been isolated reports of blood disorders. Methaemoglobinaemia, particularly following overdose in neonates, has also occurred in patients receiving the drug. Agranulocytosis and hyperthermia have also been observed.

Interactions

In general, in view of the effects of METOCLOPRAMIDE on gastric emptying, caution must be used when administering METOCLOPRAMIDE concurrently with oral medicines having a narrow efficacy/toxicity ratio.

Increased absorption

Concomitant METOCLOPRAMIDE therapy increased the absorption or decreased the time to peak plasma levels of paracetamol, aspirin in patients with migraine, cyclosporin, diazepam, dopamine, levodopa, tetracycline, lithium and morphine controlled release tablets.

Decreased absorption

Concomitant METOCLOPRAMIDE therapy decreased the absorption or increased the time to peak plasma levels of acidic agents, bromocriptine, cimetidine, digoxin, penicillin and quinidine.

Cyclosporin

The decrease in gastric emptying time caused by METOCLOPRAMIDE may increase the bioavailability of cyclosporin. Monitoring of cyclosporin concentrations may be necessary.

Monoamine Oxidase Inhibitors

METOCLOPRAMIDE should be used cautiously, if at all, in patients receiving monoamine oxidase inhibitors.

Anticholinergic Drugs and Opioid Analgesics

Anticholinergic drugs and narcotic analgesics may antagonise the effects of METOCLOPRAMIDE on gastrointestinal motility.

No significant interaction

The following agents have been demonstrated to be unaffected by concomitant administration of METOCLOPRAMIDE: atenolol, propranolol and TheoDur™ (slow release theophylline).

Suxamethonium

When METOCLOPRAMIDE is given concurrently with suxamethonium or mivacurium the recovery time is prolonged.

Alcohol

METOCLOPRAMIDE has been shown to significantly increase the absorption of alcohol.

CNS depressants or medication causing extrapyramidal effects

METOCLOPRAMIDE should be used cautiously with other CNS depressants such as sedatives, hypnotics, narcotics, tranquillizers or anaesthetics and medicines that can cause extrapyramidal effects, as the adverse effects will be additive.

Laboratory tests

METOCLOPRAMIDE increases serum prolactin acutely after each dose with a gradual return to normal; by 6 to 12 hours.

Overdosage

Symptoms

The most frequently reported adverse reactions to an overdose of METOCLOPRAMIDE are drowsiness, disorientation and extrapyramidal symptoms. Other reported effects associated with METOCLOPRAMIDE overdosage have included feelings of anxiety or restlessness, headache, vertigo, nausea, vomiting, constipation, weakness, hypotension and xerostomia; in addition generalised seizures and methaemoglobinaemia have occurred in infants. AV block has been observed very rarely.

Management

Close observation of the patient, in addition to gastric emptying and supportive measures are required. Extrapyramidal reactions have been successfully controlled by antiparkinson and antihistamine/anticholinergic agents such as diphenhydramine hydrochloride.

Pharmaceutical Precautions

Shelf-life and storage

Protect from light.

Polyamp: 18 months when stored at or below 25°C.

Medicine Classification

Prescription Medicine.

Package Quantities

Polyamps: 50 x 2 mL

Further Information

Compatibilities

Cytotoxic medicines:

Bleomycin sulphate

3 units/mL with METOCLOPRAMIDE 5 mg/mL visually compatible when injected sequentially into Y-site without flushing the Y-side arm between injections.

Cisplatin

1 mg/mL with 5 mg/mL METOCLOPRAMIDE visually compatible when injected sequentially into Y-site without flushing the Y-side arm between injections.

Cyclophosphamide

20 mg/mL with METOCLOPRAMIDE 5 mg/mL visually compatible when injected sequentially into Y-site without flushing the Y-side arm between injections.

Fluorouracil

50 mg/mL with METOCLOPRAMIDE 5 mg/mL visually compatible when injected sequentially into Y-site without flushing the Y-side arm between injections.

Vinblastine sulphate

1 mg/mL with METOCLOPRAMIDE 5 mg/mL visually compatible when injected sequentially into Y-site without flushing the Y-side arm between injections.

Narcotic analgesics:

Morphine sulphate

1 mg/mL with METOCLOPRAMIDE 0.2 mg/mL in dextrose 5% in water visually compatible for a 4 hour study period at 25°C under fluorescent light.

Pethidine HCl

10 mg/mL with METOCLOPRAMIDE 0.2 mg/mL in dextrose 5% in water visually compatible for a 4 hour study period at 25°C under fluorescent light.

Intravenous fluids

No preservative is included in the formulation of METOCLOPRAMIDE injection BP, therefore admixture to intravenous fluids should be performed under aseptic conditions and the infusion carried out within 24 hours of preparation. If storage is necessary, keep at 2 to 8°C

METOCLOPRAMIDE injection BP may be added to the following solutions: Dextrose 5% in sodium chloride 0.45%; Dextrose 5% in water; Mannitol 20%; Sodium chloride 0.9%; Ringer's injection; Ringer's injection, lactated.

Further information on the compatibility of METOCLOPRAMIDE may be obtained from the manufacturer or standard texts.

Name and Address

AstraZeneca Limited
303 Manukau Road, Epsom
P O Box 1301
Auckland
Telephone: (09) 623 6300

Date of Preparation

30 October 2003

TGA Approved: 18 May 1995 (safety related changes 27 June 2003)