Maxolon^® High Dose

Each 20ml ampoule contains Metoclopramide Hydrochloride BP equivalent to 100mg of the anhydrous substance.

Clear colourless solution for intravenous infusion.

Maxolon 'High Dose' is indicated for the treatment of nausea and vomiting associated with intolerance to cytotoxic drugs.

Maxolon 'High Dose' is administered by IV infusion, suitably diluted. The recommended method of administration is by continuous infusion which allows steady serum levels of metoclopramide to be maintained.

Continuous infusion (recommended method):

Maxolon 'High Dose' is given by IV infusion as a loading dose followed by a continuous infusion to maintain a metoclopramide serum concentration of 0.85µg - 1.0µg/ml. The loading dose should be given before starting cytotoxic chemotherapy.

Total dosage in any 24 hour period should not normally exceed 10 mg/kg body weight.

Where cisplatin is to be used the loading dose of Maxolon 'High Dose' should be at least 3 mg/kg body weight and the maintenance dose at least 4 mg/kg body weight.

Intermittent Infusion (alternative regimen)

Maxolon 'High Dose' can be given by intermittent IV infusion suitably diluted. The initial dose should be given before starting cytotoxic chemotherapy.

Total dosage in any 24 hour period should not normally exceed 10 mg/kg body weight.

Abnormal renal or hepatic function:

In patients with clinically significant degrees of renal or hepatic impairment, therapy should be at reduced dosage. Metoclopramide is metabolised in the liver and the predominant route of elimination of metoclopramide and its metabolites is via the kidney.

Compatibility with cytotoxic agents:

Maxolon 'High Dose' is compatible with a number of cytotoxic drugs; however it should not be mixed in solution with therapeutic agents other than those stated.

Maxolon 'High Dose' is compatible with cisplatin, cyclophosphamide and doxorubicin hydrochloride and is stable over the concentration ranges listed below for 24 hours at room temperature when protected from light.

40-200 ml cisplatin (1 mg/ml) per 100 mg/20 ml of Maxolon 'High Dose' in 1 litre of sodium chloride 0.9%.

Up to 40 mg doxorubicin hydrochloride (powder) per 100 mg/20 ml of Maxolon 'High Dose'.

Up to 4 g cyclophosphamide (1 g/50 ml) per 100 mg/20 ml of Maxolon 'High Dose'.

Compatibility with morphine/diamorphine:

Maxolon 'High Dose' is compatible with morphine hydrochloride and diamorphine hydrochloride and is stable over the concentration ranges listed below for 48 hours at room temperature under normal fluorescent lighting.

Up to 100 mg of morphine hydrochloride per 100 mg/20 ml of Maxolon 'High Dose'.

Up to 50 mg of diamorphine hydrochloride per 100 mg/20 ml of Maxolon 'High Dose'.

Maxolon 'High Dose' 100 mg/20 ml also remains stable for 48 hours at room temperature with 100 mg of morphine hydrochloride, or 50 mg diamorphine hydrochloride, when diluted 1 in 10 with sodium chloride 0.9%.

Stability in intravenous fluids:

Ideally intravenous solutions should be prepared at the time of infusion.

However, Maxolon 'High Dose' has been shown to be stable for at least 48 hours at room temperature in the following solutions when administered in a PVC infusion bag (e.g. Viaflex^R Travenol).

Sodium chloride intravenous infusion B.P. (0.9% w/v)

Glucose intravenous infusion B.P. (5% w/v)

Sodium chloride and glucose intravenous infusion B.P. (sodium chloride 0.18% w/v; glucose 4% w/v)

Compound sodium lactate intravenous infusion B.P. (ringer-lactate solution; Hartmann's solution)

Note: preparation must be under appropriate aseptic conditions if the above extended storage periods are required. The high dose ampoule presentation is not suitable for multidose use.

Elderly patients:

As for adults. To avoid adverse reactions adhere strictly to dosage recommendations.

Young adults and children:

'Maxolon' should only be used after careful examination to avoid masking an underlying disorder, e.g. cerebral irritation. In the dosage of this patient group attention should be given primarily to body weight.

'Maxolon' should not be used in patients with phaeochromocytoma as it may induce an acute hypertensive response.

'Maxolon' should not be used in patients suffering from epilepsy, since the frequency and severity of seizures may be increased.

'Maxolon' 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.

'Maxolon' should not be administered to patients with gastrointestinal obstruction, perforation or haemorrhage.

'Maxolon' is contraindicated in patients who have previously shown hypersensitivity to metoclopramide or any of its components.

Precautions:

If vomiting persists the patient should be reassessed to exclude the possibility of an underlying disorder e.g. cerebral irritation.

Care should be exercised in patients being treated with other centrally acting drugs.

Risk-benefit should be carefully considered in patients with significant hepatic or renal impairment (loss of conjugation and increased risk of extrapyramidal effects) or with Parkinson's disease (symptoms may be exacerbated).

The neuroleptic malignant syndrome has been reported with metoclopramide in combination with neuroleptics as well as with metoclopramide monotherapy (see adverse reactions).

Maxolon should be used with care in combination with other serotonergic drugs including SSRIs.

Since extrapyramidal symptoms may occur with both metoclopramide and neuroleptics such as the phenothiazines, particular care should be exercised in the event of these drugs being prescribed concurrently.

Patients receiving this drug for the disorders associated with delayed gastric emptying should be reviewed at an early stage for response to treatment.

Metoclopramide may cause elevation of serum prolactin levels.

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

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

There have been very rare reports of abnormalities of cardiac conduction with intravenous metoclopramide. Maxolon should be used with care with other drugs affecting cardiac conduction.

The action of 'Maxolon' on the gastrointestinal tract is antagonised by anticholinergics and opioid analgesics. The absorption of any concurrently administered oral medication may be modified by the effect of 'Maxolon' on gastric motility. Drugs known to be affected in this way include aspirin and paracetamol.

'Maxolon' should be used with care in association with other drugs acting at central dopamine receptors, such as levodopa, bromocriptine and pergolide.

Concomitant use of anticholinergic drugs may inhibit the favourable effects on gastrointestinal motility.

Since metoclopramide influences gastrointestinal motility and absorption, the dosage of other drugs used concomitantly may possibly need adjustment.

'Maxolon' may potentiate the effects of alcohol.

Concomitant use of 'Maxolon' with ciclosporin or suxamethonium may increase plasma levels of either ciclosporin or suxamethonium.

Since extrapyramidal reactions may occur with 'Maxolon', Phenothiazines and Tetrabenazine, care should be exercised in the event of co-administration of these drugs.

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 use of Maxolon with serotonergic drugs may increase the risk of serotonin syndrome.

'Maxolon' may reduce plasma concentrations of atovaquone.

Animal tests in several mammalian species and clinical experience have not indicated a teratogenic effect. Nevertheless 'Maxolon' should only be used when there are compelling reasons and is not advised during the first trimester.

During lactation metoclopramide is found in breast milk, therefore it should not be used during lactation.

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

Blood and lymphatic system disorders

Extremely rarely cases of red cell disorders such as methaemoglobinaemia and sulphaemoglobinaemia have been reported, particularly at high doses of metoclopramide. If this occurs the drug should be withdrawn. Methaemoglobinaemia may be treated using methylene blue.

Immune system disorders

Very rarely hypersensitivity, including anaphylactic/anaphylactoid reactions, have been reported (including symptoms such as tongue swelling/oedema).

Endocrine disorders

Raised serum prolactin levels have been observed during metoclopramide therapy: this may result in galactorrhoea, irregular periods and gynaecomastia.

Psychiatric disorders

Rarely, restlessness, confusion, agitation and anxiety have been reported in patients receiving metoclopramide therapy. Depression has been reported extremely rarely.

Nervous system disorders

Various extrapyramidal reactions to 'Maxolon', usually of the dystonic type, have been reported. The incidence of dystonic reactions, particularly in children and young adults, is increased if daily dosages higher than 0.5mg per kg body weight are administered. Dystonic reactions include: spasm of the facial muscles, trismus, rhythmic protrusion of the tongue, a bulbar type of speech, spasm of extra-ocular muscles including oculogyric crises, unnatural positioning of the head and shoulders and opisthotonos. There may be a generalised increase in muscle tone. The majority of reactions occur within 36 hours of starting treatment and the effects usually disappear within 24 hours of withdrawal of the drug. Should treatment of a dystonic reaction be required an anticholinergic anti-Parkinsonian drug, or a benzodiazepine may be used.

Tardive dyskinesia, which may be persistent, has been reported as a side effect in elderly patients undergoing long-term therapy with metoclopramide. Prolonged therapy in such patients should be carefully reviewed. The likelihood of the occurrence of this serious effect is increased when neuroleptic agents are used concurrently.

Very rare occurrences of the neuroleptic malignant syndrome have been reported. This syndrome is potentially fatal and comprises hyperpyrexia, altered consciousness, muscle rigidity, autonomic instability and elevated levels of creatine phosphokinase (CPK) and must be treated urgently (recognised treatments include dantrolene and bromocriptine). Metoclopramide should be stopped immediately if this syndrome occurs.

Drowsiness, dizziness and tremor may occur.

Eye disorders

Visual disturbances have been reported.

Cardiac disorders

Very rare reports of abnormalities of cardiac conduction (bradycardia, asystole, heart block, sinus arrest and cardiac arrest) have been reported following intravenous administration.

Vascular disorders

Acute hypertension may occur in patients with phaeochromocytoma (see section 4.3 Contraindications). Hypotension has also been reported.

Respiratory, thoracic and mediastinal disorders

Dyspnoea may occur.

Gastrointestinal disorders

Diarrhoea

Skin and subcutaneous tissue disorders

A small number of skin reactions such as rashes, urticaria, pruritus and angioedema have also been reported.

General disorders and administration site conditions

Oedema

In cases of overdosage, acute dystonic reactions have occurred. Very rarely AV block has been observed. Should treatment of a dystonic reaction be required, an anticholinergic anti-Parkinsonian drug or a benzodiazepine may be used.

Maxolon 'High Dose' is indicated for the treatment of nausea and vomiting associated with intolerance to cytotoxic drugs. It is specially formulated to ensure compatibility in solution with cisplatin.

Maxolon exerts a three-fold anti-emetic action: by inhibiting central dopamine receptors Maxolon raises the threshold of the chemoreceptor trigger zone, and reduces the reaction of the adjacent vomiting centre to centrally-acting emetics. Maxolon decreases the sensitivity of the visceral afferent nerves to the vomiting centre, reducing the effect of locally-acting emetics and irritant substances. In the upper gastro-intestinal tract Maxolon promotes normal gastric emptying and it may thus abolish gastric stasis which is part of the vomiting reflex.

Maxolon 'High Dose' is not intended for use in the wider range of indications for which Maxolon at standard dose is indicated.

Based on current literature, a metoclopramide concentration range of about 0.85µg/ml would appear desirable for the control of cytotoxic drug induced emesis. Such plasma concentrations may be achieved by the administration of a loading dose of 2-4 mg/kg infused over 15-30 minutes prior to cytotoxic drug therapy followed by a maintenance continuous infusion of 3-5 mg/kg over 8-12 hours.

Metoclopramide is metabolised in the liver and the predominant route of elimination of metoclopramide and its metabolites is via the kidney. In patients with clinically significant degrees of renal or hepatic impairment, therapy should be at reduced dosage.

No additional data available.

Sodium chloride

Water for injections.

Not applicable.

Thirty six months.

If ampoules are removed from their carton, they should be stored away from light. If inadvertent exposure occurs, ampoules showing discolouration must be discarded.

Clear glass 20 ml ampoules (Ph. Eur. Type I neutral glass) packed in boxes of 10

Protect from light.

Amdipharm PLC

Regency House

Miles Gray Road

Basildon

Essex

SS14 3AF

United Kingdom

PL 20072/0052

16 June 1995

January 2011