NAME OF THE MEDICINAL PRODUCT

Maxolon® High Dose

Metoclopramide 5mg/ml Solution for Infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

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

3 PHARMACEUTICAL FORM

Clear colourless solution for intravenous infusion.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Adult population:

This medicine is indicated for the treatment of nausea and vomiting associated with intolerance to cytotoxic drugs.

Paediatric population including adolescents:

The use of metoclopramide in patients 1-20 years old should be restricted to the following: severe intractable vomiting of known cause, vomiting associated with radiotherapy and intolerance to cytotoxic drugs, as an aid to gastro-intestinal intubation, as part of the premedication before surgical prodcures.

Metoclopramide should not be used in children younger than 1 year as there are insufficient data regarding efficacy and safety of the product in this population.

4.2 Posology and method of administration

This medicine 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):

This medicine is given by IV infusion as a loading dose followed by a continuous infusion to maintain a metoclopramide serum concentration of 0.85p,g - 1.0p,g/ml. The loading dose should be given before starting cytotoxic chemotherapy.

	Maxolon 'High Dose' (Metoclopramide Infusion)	Volume Of Diluent	IV Infusion Time
Loading dose	2-4 mg/kg body weight	50-100 ml	15-20 minutes
Maintenance dose	3-5 mg/kg body weight	500 ml	8-12 hours

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 this medicine should be at least 3 mg/kg body weight and the maintenance dose at least 4 mg/kg body weight.

Intermittent Infusion (alternative regimen)

This medicine 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:

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

This medicine 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 this medicine in 1 litre of sodium chloride 0.9%.

Up to 40 mg doxorubicin hydrochloride (powder) per 100 mg/20 ml of this medicine.

Up to 4 g cyclophosphamide (1 g/50 ml) per 100 mg/20 ml of this medicine.

Compatibility with morphine/diamorphine:

This medicine 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 this medicine.

Up to 50 mg of diamorphine hydrochloride per 100 mg/20 ml of this medicine.

This medicine 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, this medicine 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.

R

Viaflex 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.

Paediatric population:

For the treatment of postoperative nausea and vomiting, metoclopramide should be administered after the termination of the surgical procedure.

The recommended dose is 0.15 mg/kg b.w. given as a slow injection (at least 3 minutes).

The maximum dose in 24 hours is 0.5 mg/kg b.w. If additional doses are needed, these should be separated by at least 6 hours.

Metoclopramide should not be used in children younger than 1 year as there are insufficient data regarding efficacy and safety of the product in this patient population.

4.3    Contraindications

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

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

This medicine 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.

This medicine should not be administered to patients with gastrointestinal obstruction, perforation or haemorrhage.

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

This medicine is contraindicated in neonates.

4.4    Special warnings and precautions for use

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).

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

Extrapyramidal disorders may occur, particularly in children and young adults and/or when high doses are used (see 4.8. undesirable effects).

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 this medicine in patients with a history of atopy (including asthma) or porphyria.

Special care should be taken when administering this medicine 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. This medicine should be used with care with other drugs affecting cardiac conduction.

Respect the time interval (at least 6 hours) specified for children in the dosage section between each metoclopramide administration, even in case of vomiting, in order to avoid overdose.

4.5 Interaction with other medicinal products and other forms of interaction

The action of this medicine 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 this medicine on gastric motility. Drugs known to be affected in this way include aspirin and paracetamol.

This medicine 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.

This medicine may potentiate the effects of alcohol.

Concomitant use of this medicine with ciclosporin or suxamethonium may increase plasma levels of either ciclosporin or suxamethonium.

Since extrapyramidal reactions may occur with this medicine, 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 this medicine with serotonergic drugs may increase the risk of serotonin syndrome. This medicine may reduce plasma concentrations of atovaquone.

4.6 Pregnancy and lactation

Animal tests in several mammalian species and clinical experience have not indicated a teratogenic effect. Nevertheless this medicine 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.

4.7 Effects on ability to drive and use machines

This medicine 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

Blood and lymphatic system disorders

Extremely rarely cases of red cell disorders such as methaemoglobinaemia, which could be related to NADH cytochrome b5 reductase deficiency particularly in neonates, 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

Extrapyramidal symptoms: acute dystonia and dyskinesia, parkinsonian syndrome, akathisia, even following administration of a single dose of the drug, particularly in children and young adults (see Section 4.4.). 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

4.9 Overdose

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

Treatment for extrapyramidal disorders is only symptomatic (benzodiazepines in children).

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

This medicine 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.

This medicine exerts a three-fold anti-emetic action: by inhibiting central dopamine receptors this medicine raises the threshold of the chemoreceptor trigger zone, and reduces the reaction of the adjacent vomiting centre to centrally-acting emetics. This medicine 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 this medicine promotes normal gastric emptying and it may thus abolish gastric stasis which is part of the vomiting reflex.

This medicine is not intended for use in the wider range of indications for which this medicine at standard dose is indicated.

5.2 Pharmacokinetic properties

Based on current literature, a metoclopramide concentration range of about 0.85pg/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.

5.3 Preclinical safety data No additional data available.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients Sodium chloride

Water for injections

6.2 Incompatibilities

Not applicable

6.3 Shelf life

Thirty six months

6.4 Special precautions for storage

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

6.5 Nature and contents of container

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

6.6 Special precautions for disposal

Protect from light.

7    MARKETING AUTHORISATION HOLDER

Amdipharm UK Limited

Capital House, 85 King William Street,

London EC4N 7BL, UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 20072/0052

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

16 June 1995

10 DATE OF REVISION OF THE TEXT

05/01/2015