Active ingredient: Metoclopramide hydrochloride. Chemical name: 4-amino-5-chloro-N-(2-diethylaminoethyl)-2-methoxybenzamide hydrochloride monohydrate. Structural formula: .HCl. H2O Molecular formula: C14H22ClN3O2,HCl,H2O Molecular weight: 354.3 CAS Registry no. : 54143-57-6

Description

Metoclopramide hydrochloride is a white or almost white, crystalline powder; odourless or almost odourless. It is soluble in 0.7 parts of water, in 3 parts of ethanol (96%) and in 55 parts of chloroform. It is practically insoluble in ether. Each Pramin tablet contains metoclopramide hydrochloride equivalent to 10 mg of metoclopramide hydrochloride anhydrous. The tablets also contain the following excipients: lactose anhydrous, starch - pregelatinised maize, cellulose - microcrystalline, silica - colloidal anhydrous and magnesium stearate.

Pharmacology

Metoclopramide has dopamine antagonist activity. Like the phenothiazines and related drugs, which are also dopamine antagonists, it produces sedation and may produce extrapyramidal reactions (see Precautions). Metoclopramide inhibits the central and peripheral effects of apomorphine, induces release of prolactin and causes a transient increase in circulating aldosterone levels.

Metoclopramide increases the motility of the stomach, pylorus and small intestine without stimulating gastric, biliary or pancreatic secretions. Its mode of action is unclear, however it appears to sensitise tissues to the action of acetylcholine. The gastrointestinal stimulant action is exerted peripherally, not by central stimulation of the vagus nerve, and it is blocked by anticholinergic drugs such as atropine. The anti-emetic properties of metoclopramide result from its antagonism of central dopamine receptors and from its effect on the stomach. It increases the tone and amplitude of gastric (especially antral) contractions, relaxes the pyloric sphincter and the duodenal bulb, and increases peristalsis of the duodenum and jejunum resulting in accelerated gastric emptying and intestinal transit. It increases the resting tone of the lower oesophageal sphincter and has little, if any, effect on the motility of the colon or gall bladder. Metoclopramide causes increased prolactin secretion due to blocking of dopamine receptors in the hypothalamus and hypophysis which normally suppress prolactin secretion. Metoclopramide also increases the rate of secretion of aldosterone. In vitro studies suggest that metoclopramide acts directly on adrenal tissue to stimulate aldosterone secretion.

Pharmacokinetics

The onset of pharmacological action of metoclopramide is 30 to 60 minutes following an oral dose and effects persist for one to two hours.

After oral administration of metoclopramide there is marked variability in peak plasma concentrations observed. The variation in peak plasma levels between individuals is thought to be due to first- pass metabolism.

About 80% of the drug is excreted in urine in the first 24 hours. Approximately half the amount excreted is a glucuronide or sulphate conjugate with the remainder unchanged.

Elimination half-life varies in different studies from 2.5 to 5 hours. In one study 78% of the drug was excreted in the urine during the first 24 hours after a 10mg oral dose.

Impaired renal function results in reduced clearance of metoclopramide and an increased elimination half-life (15 hours). In a study of 6 patients with chronic renal failure total body clearance of metoclopramide was 16.7 litres/hour compared to 52.5 litres/hour in normal individuals. This difference in clearance was not explained by the change in renal clearance and suggested impaired metabolism or an alteration in enterohepatic circulation.

Contraindications

Hypertensive crises have been reported in three patients with this tumour who have been given metoclopramide, probably due to the release of catecholamines from the tumour. Such hypertensive crises may be controlled by phentolamine.

Patients with known hypersensitivity or intolerance to the drug or any other component of the tablet. Cases in which gastrointestinal stimulation might be dangerous, e.g., in the presence of gastrointestinal haemorrhage, mechanical obstruction, or perforation.

The frequency and severity of seizures may be increased in epileptic patients given metoclopramide.

The frequency and severity of extrapyramidal reactions may be increased with neuroleptics such as phenothiazines.

Metoclopramide should not be used in patients with epilepsy since it may increase the frequency and severity of seizures. 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.

Precautions

Tardive dyskinesia may appear in some patients on long-term therapy or may appear after drug therapy has been discontinued. The risk appears to be greater in elderly patients on high-dose therapy, especially females. The symptoms are persistent and can oftentimes appear to be irreversible. The syndrome is characterised by rhythmical involuntary movement of the tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of extremities. There is no known effective treatment for tardive dyskinesia; however, in some patients symptoms may lessen or resolve after metoclopramide treatment is stopped. Antiparkinson agents usually do not alleviate the symptoms of this syndrome. Although the risk of tardive dyskinesia with metoclopramide has not been extensively studied, one published study reported a tardive dyskinesia prevalence of 20% among patients treated for at least 3 months. Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase with the duration of treatment and the total cumulative dose. Metoclopramide therapy should routinely be discontinued in patients who develop signs or symptoms of tardive dyskinesia. It has been suggested that fine vermicular movements of the tongue may be an early sign of the syndrome, and, if the medication is stopped at that time, the syndrome may not develop. Tardive dyskinesia may remit, partially or completely, within several weeks to months after metoclopramide is withdrawn. Metoclopramide itself, however, may suppress (or partially suppress) the signs of tardive dyskinesia, thereby masking the underlying disease process. The effect of this symptomatic suppression upon the long-term course of the syndrome is unknown. Therefore, metoclopramide should not be used for the symptomatic control of tardive dyskinesia. Prolonged treatment (greater than 12 weeks) with metoclopramide should be avoided in all but rare cases where therapeutic benefit is thought to outweigh the risks to the patient of developing tardive dyskinesia. Care should be exercised in patients being treated with other centrally active drugs. Since extrapyramidal symptoms may occur with both metoclopramide and neuroleptics such as phenothiazines, care should be exercised in the event of both drugs being prescribed concurrently.

Since metoclopramide elevates prolactin levels and the elevation persists during chronic administration, it should be used with caution in patients with breast cancer. Tissue culture experiments indicate that approximately one- third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of metoclopramide is contemplated in a patient with previously detected breast cancer. Although disturbances such as galactorrhoea, amenorrhoea, gynaecomastia and impotence have been reported with prolactin elevating drugs, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of prolactin stimulating neuroleptic drugs. However, neither clinical nor epidemiological studies conducted to date have shown an association between chronic administration of these drugs and mammary tumourigenesis; the available evidence is too limited to be conclusive at this time.

Dystonic reactions occur in approximately 1% of patients given metoclopramide. These occur more frequently in children and young adults, and may occur after a single dose (see Adverse Effects).

Has been reported with metoclopramide in combination with neuroleptics as well as with metoclopramide monotherapy.

Metoclopramide can exacerbate Parkinsonian symptoms, thus it should be used with caution, if at all, in patients with Parkinsonian syndrome.

After operations such as pyloroplasty or gut anastomosis, metoclopramide therapy should be withheld for three or four days as vigorous muscular contractions may impede healing.

The symptomatic relief provided by metoclopramide may delay recognition of serious disease. It should not be prescribed until diagnosis has been established, and should not be substituted for appropriate investigation of the patient's symptoms.

Metoclopramide-induced depression has been reported in patients without a prior history of depression. Symptoms have ranged from mild to severe and have included episodes of spontaneous, uncontrollable crying, somnolence, suicide ideation and suicide. Metoclopramide should be given to patients with a prior history of depression only if the expected benefits outweigh the potential risks.

In one study in hypertensive patients, intravenously administered metoclopramide was shown to release catecholamines. Caution should be exercised when metoclopramide is used in patients with hypertension. If vomiting persists in a patient receiving metoclopramide, the patient should be reassessed to exclude the possibility of an underlying disorder; e.g. cerebral irritation.

Metoclopramide should not be given to children less than 20 years of age unless a clear indication has been established for its use, because of the higher incidence of adverse reactions in this age group.

Patients should be warned about engaging in activities requiring mental alertness for a few hours after metoclopramide has been administered.

Special care should be taken in cases of severe renal insufficiency (See Dosage and Administration).

Use in Pregnancy (Category A)

Although animal tests in several mammalian species have shown no teratogenic effects, the safety of metoclopramide in pregnancy has not been established. Adequate human data is not available. Therefore, the drug should only be used in pregnant women when the expected benefit outweighs any potential risk.

Use in Lactation

Metoclopramide is excreted in human milk. It is not known whether it has a harmful effect on the newborn. Administration of metoclopramide to breastfeeding mothers is not recommended unless the expected benefits to the mother outweigh any potential risk to the baby. The increased risk of adverse reactions in young children should be taken into account in making a risk-benefit assessment.

Interactions with Other Medicines

Due to its pharmacologic effects on transit time in the stomach and small intestine, metoclopramide may alter the absorption of certain drugs. The extent of absorption of drugs that disintegrate, dissolve, and/or are absorbed mainly in the stomach (eg. digoxin) may be diminished by metoclopramide, whereas the rate and extent of absorption of drugs that are mainly absorbed in the small intestine (eg. paracetamol, aspirin, diazepam, ethanol, levodopa, lithium, tetracycline) may be enhanced. The clinical importance of these effects has not been established.

The effects of metoclopramide on gastrointestinal motility can be antagonised by anticholinergic drugs and opioid analgesics.

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

Metoclopramide may potentiate the action of other CNS depressants such as opiates or other analgesics, barbiturates or other sedatives, hypnotics, tranquillisers, anaesthetics or alcohol.

Metoclopramide may cause extrapyramidal symptoms in some patients. Therefore, when metoclopramide is used concomitantly with other drugs that are likely to cause extrapyramidal reactions (eg. neuroleptics such as phenothiazines), caution should be exercised (see Contraindications).

(MAOI). The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving MAOIs.

If the standard formulation of Pramin is used for the treatment of nausea and vomiting associated with cytotoxic drugs, the cytotoxic agent should be administered as a separate infusion.

When metoclopramide is given concurrently with suxamethonium the recovery time is prolonged. Since metoclopramide influences the delivery of food to the intestine and thus, the rate of its absorption, the administration of metoclopramide may result in poor diabetic control in some patients. Therefore adjustment in, or timing of, insulin dosage may be necessary in insulin controlled diabetics.

Effects on Laboratory Tests

Metoclopramide may blunt the response to the gonadorelin diagnostic test, by increasing serum prolactin levels. Metoclopramide may alter hepatic function test results.

Adverse Effects

Neurological

Adverse effects to metoclopramide that are most frequently seen are restlessness, drowsiness, fatigue and lassitude, which occur in approximately 10% of patients. Insomnia, headache, dizziness, have been reported less frequently. Acute depression has been reported rarely (less than 1 in 1000 cases). Anxiety or agitation may occur. Delirium, severe dysphoria, obsessive rumination and mania have been reported occasionally. Parkinsonian symptoms, including tremor, rigidity, bradykinesia and akinesia, occur rarely in patients receiving metoclopramide but may be associated with usual or excessive doses or with decreased renal function. Various extrapyramidal reactions to metoclopramide, usually of the dystonic type, have been reported. Acute dystonic reactions occur in approximately 0.2% of patients treated with 30 to 40 mg of metoclopramide per day. In cancer chemotherapy patients receiving 1 to 2mg/kg per dose, the incidence is 2% in patients over the ages of 30 to 35 and 25% or higher in children and young adults who have not had prophylactic administration of diphenhydramine. Reactions include spasm of the facial muscles, trismus, rhythmic protrusion of the tongue, a bulbar type of speech, spasm of the extraocular muscles including oculogyric crisis, 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. However, close observation is required and in cases of more severe reactions an antiparkinson drug such as benztropine or an anticholinergic antihistamine such as diphenhydramine should be given. A fatal acute dystonic reaction has been reported in a patient who received hexamethylmelamine, cisplatin and metoclopramide high dose. Dystonic reactions may present rarely as upper airway obstruction with stridor and dyspnoea, possibly secondary to laryngospasm or supraglottic dystonia. A fatal cardiorespiratory arrest occurred in at least one patient with an acute dystonic reaction. Tardive dyskinesia, which may be persistent, has been reported particularly in elderly patients (particularly women) following long term therapy with metoclopramide. Tardive dyskinesia is most frequently characterised by involuntary movements of the tongue, face, mouth or jaw and sometimes by involuntary movements of the trunk and/or extremities. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase with increasing duration of therapy and total cumulative dose. Although tardive dyskinesia can occur after relatively brief therapy with the drug at low doses, it appears to be more readily reversible under such circumstances (see Precautions).

Neuroleptic Malignant Syndrome (NMS)

NMS has been reported very rarely (less than 1 in 10,000). NMS is potentially fatal and comprises hyperpyrexia, altered consciousness, muscle rigidity, autonomic instability and elevated levels of CPK, and must be treated urgently (recognised treatments include dantrolene and bromocriptine). Metoclopramide should be stopped immediately if NMS occurs.

Gastrointestinal

Nausea or bowel disturbances have been reported.

Hepatic

Rarely, cases of hepatotoxicity, characterised by such findings as jaundice and altered liver function tests, when metoclopramide was administered with other drugs with known hepatotoxic potential.

Renal

Urinary frequency and incontinence.

Cardiovascular

Atrial fibrillation, oedema, ventricular fibrillation, ventricular tachycardia, palpitations and tachycardia have been associated with the use of metoclopramide.

Endocrine

Raised serum prolactin levels have been observed during metoclopramide therapy; this effect is similar to that noted with many other compounds. Galactorrhoea and breast enlargement have also been observed during metoclopramide therapy.

Hypersensitivity

There have been isolated reports of hypersensitivity reactions in patients receiving metoclopramide.

Respiratory

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

Other Effects

There have been isolated reports of blood disorders. Methaemoglobinaemia, particularly following overdose in neonates, has also occurred in patients receiving the drug. A few cases of neutropenia, leucopenia or agranulocytosis, generally without clearcut relationship to metoclopramide. There have been isolated reports of hypersensitivity reactions (such as urticaria, maculopapular rash) in patients receiving metoclopramide. Sexual dysfunction, priapism and muscle spasm may also occur. Hyperthermia has also been observed. Sulfhaemoglobinaemia in adults.

Dosage and Administration

The dosage recommendations given below should be strictly adhered to if side effects of the dystonic type are to be avoided.

As for adults. To avoid adverse reactions, adhere strictly to dosage recommendations. When prolonged therapy is considered necessary, patients should be regularly reviewed. Total daily dosage should not usually exceed 500 microgram per kg bodyweight. Metoclopramide should only be used after careful examination to avoid masking an underlying disorder, e.g. cerebral irritation.

In patients with clinically significant degrees of renal or hepatic impairment, clearance of Pramin is likely to be reduced. It is suggested that therapy be initiated at half the recommended dose. Subsequent dosage will depend on individual clinical response.

Overdosage

Overdose of metoclopramide may be expected to produce effects that are extensions of common adverse reactions: drowsiness, disorientation and extrapyramidal reactions have been the principal effects reported. Other reported effects associated with metoclopramide overdose have included feelings of anxiety or restlessness, headache, vertigo, nausea, vomiting, constipation, weakness, hypotension and xerostomia. AV block has been observed very rarely.

Treatment of metoclopramide overdosage generally involves symptomatic and supportive care. Extrapyramidal reactions may be controlled by anti-Parkinsonian agents such as benztropine, or antihistamines with anticholinergic action such as diphenhydramine. Appropriate therapy should be instituted if hypotension or excessive sedation occurs. Methaemoglobinaemia should be treated with methylene blue. Haemodialysis and continuous ambulatory peritoneal dialysis appears ineffective in removing metoclopramide. Contact the Poisons Information Centre on 131126 (Australia) for advice on management of overdosage.

Presentation and Storage Conditions

white, normal convex, marked "ME" over "10" on one side, G on reverse; available in bottles of 6 *, 25, 30 *, 50 *, 90 *, 100 and 1000 * tablets. * Not marketed in Australia. Store below 30degC.

Name and Address of the Sponsor

Level 1, 30 The Bond 30-34 Hickson Road Millers Point NSW 2000 ABN 93 002 359 739 www.alphapharm.com.au

PRODUCT INFORMATION

Name of the Medicine