1. Name Of The Medicinal Product
Maxolon®High Dose
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
Maxolon 'High Dose' is indicated for the treatment of nausea and vomiting associated with intolerance to cytotoxic drugs.
4.2 Posology And Method Of Administration
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.
Maxolon 'High Dose' | 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 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.
Maxolon 'High Dose' | Volume Of Diluent | IV Infusion Time | |
Initial dose | Up to 2 mg/kg body weight | at least 50 ml | at least 15 minutes |
Repeat doses at 2 hourly intervals | Up to 2 mg/kg body weight | at least 50 ml | at least 15 minutes |
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. ViaflexR 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.
4.3 Contraindications
'Maxolon' should not be used in patients with phaeochromocytoma as it may induce an acute hypertensive response.
'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 contra-indicated in patients who have previously shown hypersensitivity to metoclopramide or any of its components.
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 epileptic patients and patients being treated with other centrally acting drugs.
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.
The neuroleptic malignant syndrome has been reported with metoclopramide in combination with neuroleptics as well as with metoclopramide monotherapy (see section 4.8 Undesirable effects).
Maxolon should be used with care in combination with other serotonergic drugs including SSRIs.
Special care should be taken in cases of severe renal and hepatic insufficiency (see also section 4.2 Posology and method of administration).
Care should be exercised when using Maxolon in patients with a history of atopy (including asthma) or porphyria.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
The action of 'Maxolon' on the gastro-intestinal 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.
Since extrapyramidal reactions may occur with 'Maxolon', Phenothiazines and Tetrabenazine, care should be exercised in the event of co-administration of these drugs.
'Maxolon' should be used with care in association with other drugs acting at central dopamine receptors, such as levodopa, bromocriptine and pergolide.
The use of Maxolon with serotonergic drugs may increase the risk of serotonin syndrome.
'Maxolon' 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 '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.
4.7 Effects On Ability To Drive And Use Machines
1'Maxolon' may cause drowsiness, dyskinesia and dystonias which could affect the vision and also interfere with the ability to drive and operate machinery.
1 PL 20072/0052-0007; 27/07/09
4.8 Undesirable Effects
When given at high dose in association with cancer chemotherapy, 'Maxolon' has been found to be well tolerated with few adverse events. Various extrapyramidal reactions to 'Maxolon', usually of the dystonic type, have been reported. Studies of 'Maxolon' given in doses up to 10mg/kg body weight/day by IV infusion report an incidence of extrapyramidal reactions of less than 10%. The incidence of such reactions may be increased in the younger patient. Reactions to 'Maxolon' have included 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.
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.
There have been very rare reports of abnormalities of cardiac conduction (such as bradycardia and heart block) in association with intravenous metoclopramide.
Very rarely hypersensitivity, including anaphylaxis, has been reported.
Mild drowsiness, confusion, anxiety and diarrhoea have been noted. Depression has been reported extremely rarely.
Raised serum prolactin levels have been observed during metoclopramide therapy: this may result in galactorrhoea, irregular periods and gynaecomastia.
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.
A small number of skin reactions such as rashes, urticaria, pruritus and oedema have also been reported.
4.9 Overdose
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.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
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.
5.2 Pharmacokinetic Properties
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.
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 20 ml ampoules (Ph. Eur. Type I neutral glass) packed in boxes of 10
6.6 Special Precautions For Disposal And Other Handling
Protect from light.
7. Marketing Authorisation Holder
Amdipharm PLC
Regency House
Miles Gray Road
Basildon
Essex
SS14 3AF
United Kingdom
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
July 2009
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