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NEW ZEALAND DATA SHEET
1. PRODUCT NAME
Metoclopramide Injection Ampoule
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Metoclopramide Injection contains metoclopramide hydrochloride monohydrate 10.54 mg/2 mL, equivalent to metoclopramide hydrochloride 10 mg/2 mL.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Solution for Injection.
Metoclopramide Injection is a clear, colourless, sterile, preservative-free solution.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Adults (20 years and over)
Relief of nausea and vomiting associated with migraine, cancer therapy (chemotherapy or radiation), malignant disease, labour, infectious disease and uraemia Control of post-operative vomiting Assist in small bowel intubation
Metoclopramide is of little benefit for the prevention or treatment of motion sickness.
Young Adults and Children (over 1 year of age)
Metoclopramide should be restricted to the following conditions and only used as second line therapy, when used to treat children and young adults under 20 years of age because of the risk of adverse effects: Severe intractable vomiting of known cause Vomiting associated with radiation therapy or intolerance to cytotoxic drugs Assist in small bowel intubation
4.2 Dose and method of administration
The dosage recommendations 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 nausea and vomiting.
Total daily doses of metoclopramide should not normally exceed 0.5 mg/kg bodyweight with a maximum of 30 mg daily. This should be less (if possible) in children and young adults, when given by injection. Maximum recommended treatment duration is 5 days in all age groups.
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Usual dosage is as follows and should be administered intramuscularly or by slow intravenous injection over 1 to 2 minutes.
Adults
20 years and over: Maximum of 10 mg three times a day.
Young Adults
Treatment of young adults should commence at the lower dosage, and used as second line therapy only. 15 - 19 years: 5 mg to 10 mg three times a day.
Children
Treatment of children should commence at the lower dosage, where stated, and used as second line therapy only. 5 - 14 years: 2.5 mg to 5 mg three times a day.
3 - 5 years: 2 mg two to three times a day.
1 - 3 years: 1 mg two to three times a day.
Diagnostic Indications
A single dose of metoclopramide may be given 5 to 10 minutes before the examination. Subject to bodyweight considerations, the following dosages are recommended:
Adults 20 years and over: 10 mg to 20 mg
Young Adults 15 - 19 years: 10 mg
Children 9 - 14 years: 5 mg 5 - 9 years: 2.5 mg 3 - 5 years: 2 mg 1 - 3 years: 1 mg
Use in Special Patient Populations
Elderly Patients To avoid adverse reactions strict adherence to dosage recommendations is advised and, where prolonged therapy is considered necessary, patients should be regularly reviewed.
Patients with Renal Impairment Since metoclopramide is excreted principally through the kidneys, in those patients whose creatinine clearance is below 40 mL/min, therapy should be initiated at approximately one-half the usual dose. Subsequent dosage will depend on individual clinical response.
Patients with Hepatic Impairment Metoclopramide undergoes hepatic metabolism via simple conjugation. Its safe use has been described in patients with advanced liver disease whose renal function was normal. It is suggested that therapy
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4.4 Special warnings and precautions for use
Persistent Tardive Dyskinesia
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 often at times 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 movement 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 the 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 (see section 4.5). The frequency and severity of seizures or extrapyramidal reactions may be increased in epileptic patients given metoclopramide.
Dystonic Reactions
Dystonic reactions occur in approximately 1% of patients given metoclopramide. These occur more often in children and young adults and may occur after a single dose.
Neuroleptic Malignant Syndrome
Neuroleptic malignant syndrome has been reported when metoclopramide has been used alone or in combination with neuroleptics (see section 4.8).
Prolactin Levels
Metoclopramide elevates prolactin levels and the elevation persists during chronic administration (see Section 4.8). This may be of importance in patients with previously detected breast cancer, in which the breast cancer is prolactin dependent. Tissue culture experiments indicate that approximately one-
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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 prolactin elevating drugs have been associated with disturbances such as galactorrhoea, amenorrhoea, gynaecomastia and impotence, the clinical significance of elevated serum prolactin levels is not known for most patients. Chronic administration of prolactin stimulating neuroleptic drugs to rodents has shown an increase in mammary neoplasms. However, neither clinical or epidemiological studies have shown an association between chronic administration of these drugs and mammary tumorogenesis in humans and the available evidence is too limited to be conclusive at this time.
Other
Metoclopramide should be withheld for three to four days following operations such as pyloroplasty or gut surgery as vigorous muscular contractions may inhibit healing.
Special care should be taken in cases of severe renal insufficiency (see section 4.2).
The effects of metoclopramide may mask symptoms and delay the recognition of a 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.
If vomiting persists in a patient being treated with metoclopramide, the patient’s condition should be re-assessed to exclude the possibility of a more serious underlying disorder such as cerebral irritation.
Metoclopramide Injection should be administered slowly over 1-2 minutes by intravenous injection to avoid a transient but intense feeling of anxiety and restlessness, followed by drowsiness, which may occur with rapid administration.
Patients should be cautioned about engaging in activities requiring mental alertness for a few hours after the drug has been administered.
Metoclopramide induced depression has been reported in patients without a prior history of depression. Symptoms have ranged from mild to severe and have included suicidal ideation and suicide (see section 4.8). Metoclopramide should be given to patients with a prior history of depression only if the expected benefits outweigh the potential risks.
Metoclopramide should be used with caution in patients with hypertension as intravenously administered metoclopramide has been shown to release catecholamines.
Patients receiving prolonged treatment with metoclopramide should be reviewed regularly.
Metoclopramide can exacerbate parkinsonian symptoms; therefore it should be used with caution, if at all, in patients with parkinsonian syndrome (see section 4.8).
Use in hepatic impairment
In patients with clinically significant degrees of hepatic impairment, clearance of metoclopramide is likely to be reduced (see section 4.2).
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For compatibility with other medications see sections 4.2 and 6.2.
4.6 Fertility, pregnancy and lactation
Fertility
No Data Available
Pregnancy
Category A
As there are no adequate or well controlled studies in pregnant women, metoclopramide should be used only if clearly needed. 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.
Lactation
As metoclopramide is excreted in human breast milk, its use is not recommended in nursing mothers unless the expected benefit outweighs the potential risk. The increased risk of adverse reactions in children should be considered when making a risk-benefit assessment.
4.7 Effects on ability to drive and use machinery
Patients should be cautioned about engaging in activities requiring mental alertness for a few hours after the drug has been administered.
4.8 Undesirable effects
Neurological
The most frequent adverse reactions to metoclopramide are restlessness, drowsiness, fatigue and lassitude, which occur in approximately 10% of patients.
Less frequently, insomnia, headache, dizziness may occur. Rare (less than 1 in 1,000 cases) of acute depression have been reported. Symptoms of metoclopramide induced depression have ranged from mild to severe and have included suicidal ideation and suicide (see section 4.4). Anxiety or agitation may occur, especially after rapid injection. Delirium, severe dysphoria, obsessive rumination and mania have been reported occasionally.
Although uncommon at normal dosage, 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 mg to 40 mg of metoclopramide per day. In cancer chemotherapy patients receiving 1 mg/kg to 2 mg/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
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reactions an antiparkinson drug such as benztropine or an anticholinergic antihistamine such as diphenhydramine should be given.
A fatal dystonic reaction has been reported in a patient who received hexamethylmelamine, cisplatin and high dose metoclopramide. 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) undergoing 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 section 4.4).
Very rare (less than 1 in 10,000) occurrences of neuroleptic malignant syndrome (NMS) have been reported. 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.
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.
Gastrointestinal
Less frequently, nausea or bowel disturbances, may occur.
Cardiovascular
A single case of supraventricular tachycardia following intramuscular administration has been reported. There have been very rare (less than 1 in 10,000) cases of abnormalities of cardiac conduction (such as bradycardia and heart block) in association with intravenous metoclopramide. Hypertension, hypotension, cardiac arrest, atrial fibrillation (AF), oedema, ventricular fibrillation, tachycardia, ventricular tachycardia and palpitations have also been associated with the use of metoclopramide. In one study in hypertensive patients, intravenously administered metoclopramide was shown to release catecholamines; hence, caution should be exercised when metoclopramide is used in patients with hypertension.
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 (such as urticaria, maculopapular rash) in patients receiving metoclopramide.
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5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Class of Drug
Antiemetic.
Mode of Action
Metoclopramide has antiemetic, antinauseant and gastrokinetic activity. It stimulates motility of the upper gastrointestinal tract without stimulating gastric, biliary or pancreatic secretions. The rate of gastric emptying is increased due to increased peristalsis of the jejunum and duodenum. The tone and amplitude of gastric contractions are increased, with relaxation of the pyloric sphincter and duodenal bulb. These effects combine to result in decreased intestinal transit time. The effect of metoclopramide on motility is not dependent on intact vagal innervation, but it can be abolished by anticholinergic drugs. Metoclopramide has little, if any, effect on the motility of the colon or bladder. Metoclopramide also exhibits dopamine antagonist activity and consequently produces sedation and, rarely, other extrapyramidal reactions. It may have serotonin receptor (5HT3) antagonist properties. Metoclopramide inhibits the central and peripheral effects of apomorphine, induces release of prolactin and produces a transient increase in circulating aldosterone levels.
5.2 Pharmacokinetic properties Absorption
Following intravenous administration, the onset of action is within 1 to 3 minutes and after intramuscular administration, this interval is extended to 10 to 15 minutes. The effect usually lasts from 1 to 2 hours.
Distribution
Plasma protein binding is 13% to 22%.
Metabolism
About 80% of the drug is excreted in the urine in the first 24 hours after administration. Approximately half is unchanged metoclopramide and half is the glucuronide and sulphate conjugate.
Elimination
Metabolism mainly occurs in the liver and elimination half-life may vary from 2.5 to 6 hours. Impaired renal function results in a reduced clearance and an increased half-life, up to 15 hours.
5.3 Preclinical safety data
Genotoxicity
No Data Available
Carcinogenicity
No Data Available
Reproductive and developmental toxicity
No Data Available
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6. PHARMACEUTICAL PARTICUALRS
6.1 List of excipients
Sodium Chloride
Sodium Hydroxide and/or Hydrochloric Acid for pH adjustment
Water for Injections
6.2 Incompatibilities
See section 4.2 (Dose and method of administration – Compatibilities).
If the standard formulation of metoclopramide is used for the treatment of nausea and vomiting associated with cytotoxic drugs, the cytotoxic agent should be administered as a separate infusion.
6.3 Shelf life
24 Months.
6.4 Special precautions for storage
Store below 25ºC. Protect from light. If ampoules are removed from their carton, they should be stored away from light. If inadvertent exposure occurs, ampoules showing a yellow discolouration must be discarded.
6.5 Nature and contents of container
Metoclopramide Injection 10 mg in 2 mL (sterile) Steriluer®^ ampoule (10s) Metoclopramide Injection 10 mg in 2 mL (sterile) Steriluer®^ ampoule (50s)
6.6 Special precautions for disposal
ANY UNUSED MEDICINE OR WASTE MATERIAL SHOULD BE DISPOSED OF IN
ACCORDANCE WITH LOCAL REQUIREMENTS.
7. MEDICINE SCHEDULE
Prescription Only Medicine
8. SPONSOR
Pfizer New Zealand Limited PO Box 3998 Auckland New Zealand
