Hoechst Marion Roussel
Modifier of Upper Gastrointestinal Tract Motility – Antiemetic
Action And Clinical Pharmacology: Metoclopramide is a benzamide derivative, structurally related to procainamide and sulpiride. As with sulpiride, it has dopamine-antagonist activity with selective affinity for D-2 (non-adenylate cyclase-linked) receptors. The behavioral, motor, and neuroendocrine effects of metoclopramide have been linked to its antidopaminergic activity.
Metoclopramide has antiemetic properties, which are believed to result from its action on the chemoreceptor trigger zone. A peripheral mechanism of action also may be involved.
Metoclopramide increases resting pressure in the lower esophageal sphincter and the gastric fundus, and gives rise to an increase in the amplitude of peristaltic movements in the esophagus, gastric antrum and small intestine. These actions result in hastened esophageal clearance, accelerated gastric emptying and shortened transit time through the small bowel. These effects are blocked by atropine and opioids but not by vagotomy. Metoclopramide elevates serum prolactin and also causes transient increases in circulating aldosterone levels. These effects are thought to be due to blockade of dopamine receptors at the pituitary and adrenocortical cellular level.
Following i.v. administration, peak plasma levels occur within minutes, and between 45 to 90 minutes after oral administration. The elimination half-life is approximately 3 to 5 hours. In patients with impaired renal function, the half-life is prolonged and may reach 14 hours or more. About 20% of the drug is eliminated unchanged in the urine, and 30 to 40% is eliminated as the sulfate conjugate. There is a first-pass effect after oral administration, and bioavailability varies between 30 to 70%. Metoclopramide is 15 to 20% bound to plasma proteins.
In some patients, metoclopramide may produce sedation, drowsiness, galactorrhea, menstrual disorders and extrapyramidal reactions. Extrapyramidal symptoms are more frequent at higher than recommended doses, but occur with therapeutic doses, particularly in children and in patients with impaired renal or hepatic function. Tardive dyskinesia has been reported following discontinuation of long-term treatment with metoclopramide.
Indications And Clinical Uses: An adjunct in the management of delayed gastric emptying associated with subacute and chronic gastritis or following vagotomy and pyloroplasty and other surgical procedures.
Metoclopramide has also been found useful as an adjunct to facilitate small bowel intubation.
Metoclopramide has been found useful as an adjunct to facilitate gastroduodenal evacuation of barium meals and improve radiological visualization of the gastroduodenal region in patients with gastric atonia, pylorospasm, spasm of the duodenal bulb, or with mechanical gastric outlet obstruction. Metoclopramide has also been shown to accelerate small bowel transit of the barium meal and to facilitate fluoroscopy of the terminal ileum.
Metoclopramide, when used preoperatively by the oral route, may be useful to reduce postoperative vomiting induced by narcotics.
Contra-Indications: Should not be used whenever stimulation of gastrointestinal motility might be dangerous; i.e., in the presence of gastrointestinal hemorrhage, mechanical obstruction or perforation. Metoclopramide is contraindicated in patients with known sensitivity or intolerance to the drug.
Manufacturers’ Warnings In Clinical States: Metoclopramide elevates prolactin levels and the elevation persists during chronic administration. Tissue culture experiments indicate that approximately 1/3 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 galactorrhea, amenorrhea, gynecomastia 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. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is too limited to be conclusive at this time.
Metoclopramide should not be used in patients with epilepsy or extrapyramidal symptoms unless the expected benefits outweigh the risk of increased frequency and severity of seizures or extrapyramidal reactions.
Pregnancy: The safe use of metoclopramide in pregnancy has not been established. Therefore, it should not be used in pregnant women, unless, in the opinion of the physician, the expected benefits to the patient outweigh potential risks to the fetus.
Children: Daily dose should not exceed 0.5 mg/kg, since with higher doses extrapyramidal symptoms frequently occur.
Precautions: The recommended dosage of metoclopramide should usually not be exceeded since a further increase in dosage will not produce a corresponding increase in clinical response.
Drug Interactions: Anticholinergic drugs antagonize the effects of metoclopramide on gastrointestinal motility. Metoclopramide should not be used in conjunction with ganglioplegic or neuroleptic drugs since potentiation of effects might occur. The sedative effects of metoclopramide may be potentiated by sedatives, hypnotics, narcotics and anxiolytics.
Metoclopramide may decrease the absorption of drugs from the stomach (e.g. digoxin) whereas absorption from the small bowel may be accelerated (e.g., acetaminophen, tetracyclines, levodopa, ethanol).
Care should be exercised when metoclopramide is administered in combination with a MAO inhibitor. In an animal study, pre-treatment with a MAO inhibitor increased the toxicity of i.v. metoclopramide.
In patients with pheochromocytoma, i.v. administered metoclopramide may cause an hypertensive crisis. These crisis may be controlled by i.v. phentolamine.
Adverse Reactions: Drowsiness, fatigue and lassitude occur in approximately 10% of patients at the usual recommended dosage. Less frequent adverse reactions, occurring in approximately 5% of patients are insomnia, headache, dizziness and bowel disturbances. Galactorrhea and menstrual disorders have also been reported.
The more serious adverse reactions associated with the use of metoclopramide are parkinsonism and/or other extrapyramidal reactions. These consist often of a feeling of restlessness, facial spasms, involuntary movements and in some cases, torticollis, muscular twitching, trismus, oculogyric crisis, and opisthotonos. Dystonic reactions resembling tetanus have been reported. Extrapyramidal side effects appear to occur more frequently at dosages higher than the usual recommended dosage. Tardive dyskinesia, which in some cases appears to be irreversible, has been reported after discontinuation of long-term metoclopramide therapy. Therefore, prolonged treatment with metoclopramide should be avoided.
Symptoms And Treatment Of Overdose: Symptoms: Symptoms of overdosage may include drowsiness, disorientation and extrapyramidal reactions. Anticholinergic, antiparkinson drugs or antihistamines with anticholinergic properties such as diphenhydramine have effectively controlled extrapyramidal reactions. Symptoms are self-limiting and usually disappear within 24 hours.
Treatment: Management of overdosage consists of gastric emptying, close observation and supportive therapy.
Hemodialysis removes relatively little metoclopramide probably because of the small amount of the drug in blood relative to tissues. Similarly, continuous ambulatory peritoneal dialysis does not remove significant amounts of drug. It is unlikely that dosage would need to be adjusted to compensate for losses through dialysis. Dialysis is not likely to be an effective method of drug removal in overdose situations. Methemoglobinemia has occurred in premature and fullterm neonates who were given overdoses of metoclopramide (1 to 4 mg/kg/day orally, i.m. or i.v. for 1 to 3 or more days). Methemoglobinemia has not been reported in neonates treated with 0.5 mg/kg/day in divided doses. Methemoglobinemia can be reversed by i.v. administration of methylene blue.
Dosage And Administration: Note: The total adult and pediatric daily dosage must not exceed 0.5 mg/kg/body weight.
Delayed Gastric Emptying: Adults: 5 to 10 mL (5 to 10 mg) 3 or 4 times a day before meals, depending upon response and body weight.
Children (5 to 14 years): 2.5 to 5 mL (2.5 to 5 mg) 3 times a day before meals, depending on response and body weight.
Diagnostic Radiology: Adults: 20 mL (20 mg) 5 to 10 minutes before barium swallow.
Renal or Hepatic 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 recommended dosage. Depending upon clinical efficacy and safety considerations, the dosage may be increased or decreased as appropriate.
See Overdose section for information regarding dialysis. Metoclopramide undergoes minimal hepatic metabolism, except for simple conjugation. Its safe use has been described in patients with advanced liver disease whose renal function was normal.
Availability And Storage: Each mL contains: metoclopramide HCl 1 mg. Nonmedicinal ingredients: artificial and natural orange flavors, citric acid, FD&C Yellow No. 6, methylparaben, natural apricot flavor, propylparaben, purified water and sorbitol. Bottles of 500 mL. (Shown in Product Recognition Section)
MAXERAN® Hoechst Marion Roussel Metoclopramide HCl Modifier of Upper Gastrointestinal Tract Motility – Antiemetic