METOPRAM

Diabetic gastroparesis is a condition that causes frequent nausea and vomiting, which has a negative impact on quality of life and poses a significant burden on the healthcare system.

Metoclopramide is a dopamine antagonist used to treat nausea and vomiting that may be associated with diabetic gastroparesis in addition to gastroesophageal reflux disease (GERD).

It can also be used to prevent nausea or vomiting associated with chemotherapy or certain surgical or diagnostic procedures.

One unique property of this drug is that it does not increase gastric acid secretion.

It is available in the oral tablet form or in solution, and can also be administered through the intravenous route.

Metoclopramide was initially approved by the

FDA in 1980.

Metoclopramide in the oral tablet form is used for symptomatic treatment of both acute and recurrent diabetic gastroparesis, in addition to the treatment of gastroesophageal reflux disease (GERD) in patients who have failed to respond to traditional therapy.

A nasal spray formulation is also indicated to treat adults with acute, recurrent diabetic gastroparesis.

In the intravenous injection form, it is indicated for the above conditions as well as for the prevention of vomiting that may follow emetogenic chemotherapy or nausea and vomiting after surgery.

Intravenous metoclopramide facilitates intubation of the small bowel and stimulates gastric emptying and barium flow in patients who require radiological examination of the stomach or small intestine.

In some cases, the delay of gastrointestinal emptying interferes with the radiographic visualization of the gastrointestinal tract, and metoclopramide is used to facilitate emptying in these cases, allowing for adequate diagnostic visualization.

Some off-label uses of metoclopramide include the management of radiation-induced nausea and vomiting, gastric bezoars, intractable hiccups, and migraine pain. 8, 9, 10,

Metoclopramide increases gastric emptying by decreasing lower esophageal sphincter (LES) pressure.

It also exerts effects on the area postrema of the brain, preventing and relieving the symptoms of nausea and vomiting.

In addition, this drug increases gastrointestinal motility without increasing biliary, gastric, or pancreatic secretions. 17, 18, 19 Because of its antidopaminergic activity, metoclopramide can cause symptoms of tardive dyskinesia (TD), dystonia, and akathisia, and should therefore not be administered for longer than 12 weeks. 4, 18.

5-hydroxytryptamine receptor 4 Agonist 5-hydroxytryptamine receptor 3A Antagonist Muscarinic acetylcholine receptor M1 Agonist + 1 more target.

Metoclopramide is rapidly absorbed in the gastrointestinal tract with an absorption rate of about 84%.

The bioavailability of the oral preparation is reported to be about 40.7%, but can range from 30-100%. 2, 7 Nasal metoclopramide is 47% bioavailable.

A 15 mg dose reaches a C max of 41.0 ng/mL, with a T max of 1.25 h, and an AUC of 367 ng*h/mL.

The volume of distribution of metoclopramide is approximately 3.5 L/kg. This implies a high level of tissue distribution.

Metoclopramide crosses the placental barrier and can cause extrapyramidal symptoms in the fetus. 13, 18.

Metoclopramide undergoes first-pass metabolism and its metabolism varies according to the individual.

This drug is metabolized by cytochrome

P450 enzymes in the liver.

CYP2D6 and CYP3A4 both contribute to its metabolism, with CYP2D6 being more heavily involved.

CYP1A2 is also a minor contributing enzyme.

The process of

N-4 sulphate conjugation is a primary metabolic pathway of metoclopramide.

Hover over products below to view reaction partners Metoclopramide Monodeethylmetoclopramide Conjugated metabolite, Metoclopramide.

About 85% of an Oral administered dose was measured in the urine within 72 hours during a pharmacokinetic study.

An average of 18% to 22% of 10-20 mg dose was recovered as free drug within 3 days of administration.

The mean elimination half-life of metoclopramide in people with healthy renal function ranges from 5-6 hours but is prolonged in patients with renal impairment.

Downward dose adjustment should be considered. 4, 13, 18.

The renal clearance of metoclopramide is 0.16 L/h/kg with a total clearance of 0.7 L/h/kg. Clinical studies showed that the clearance of metoclopramide may be reduced by up to 50% in patients with renal impairment.

After high intravenous doses, total metoclopramide clearance ranged from 0.31-0.69 L/kg/h.

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The rat oral

LD50 of metoclopramide is 750 mg/kg.

Some symptoms of an overdose with metoclopramide include drowsiness, disorientation, and extrapyramidal reactions.

Drugs that manage

Parkinson's disease or anticholinergic drugs or antihistamines with anticholinergic properties 15 should be employed to treat extrapyramidal symptoms.

Normally, these symptoms subside within 24 hours.

Unintentional overdose in infants receiving the oral solution of metoclopramide resulted in seizures, extrapyramidal symptoms, in addition to a lethargic state.

In addition, methemoglobinemia has been found to occur in premature and full-term neonates after a metoclopramide overdose.

Intravenous methylene blue may treat metoclopramide-associated methemoglobinemia.

It is important to note that methylene blue administration may lead to hemolytic anemia in patients who suffer from G6PD deficiency, which can result in fatality.

Dialysis has not been shown to be effective in sufficiently eliminating metoclopramide in an overdose situation due to low plasma distribution of this drug.

Mental depression has occurred in patients with and without prior history of depression.

Symptoms have ranged from mild to severe and have included suicidal ideation and suicide.

Metoclopramide should be given to patients with a prior history of depression only if the expected benefits outweigh the potential risks.

Extrapyramidal symptoms, manifested primarily as acute dystonic reactions, occur in approximately in 500 patients treated with the usual adult dosages of to 40 mg/day of metoclopramide.

These usually are seen during the first to 48 hours of treatment with metoclopramide, occur more frequently in pediatric patients and adult patients less than 30 years of age and are even more frequent at the higher doses.

These symptoms may include involuntary movements of limbs and facial grimacing, torticollis, oculogyric crisis, rhythmic protrusion of tongue, bulbar type of speech, trismus, or dystonic reactions resembling tetanus.

Rarely, dystonic reactions may present as stridor and dyspnea, possibly due to laryngospasm.

If these symptoms should occur, inject 50 mg diphenhydramine hydrochloride intramuscularly, and they usually will subside.

Benztropine mesylate, 1 to 2 mg intramuscularly, may also be used to reverse these reactions.

Parkinsonian-like symptoms have occurred, more commonly within the first 6 months after beginning treatment with metoclopramide, but occasionally after longer periods.

These symptoms generally subside within to 3 months following discontinuance of metoclopramide.

Patients with preexisting

Parkinson’s disease should be given metoclopramide cautiously, if at all, since such patients may experience exacerbation of parkinsonian symptoms when taking metoclopramide.

Treatment with metoclopramide can cause tardive dyskinesia (TD), a potentially irreversible and disfiguring disorder characterized by involuntary movements of the face, tongue, or extremities.

The risk of developing tardive dyskinesia increases with duration of treatment and the total cumulative dose.

An analysis of utilization patterns showed that about 20% of patients who used metoclopramide took it for longer than 12 weeks.

Treatment with metoclopramide for longer than the recommended 12 weeks should be avoided in all but rare cases where therapeutic benefit is thought to outweigh the risk of developing TD.

Although the risk of developing

TD in the general population may be increased among the elderly, women, and diabetics, it is not possible to predict which patients will develop metoclopramide-induced TD.

Both the risk of developing TD and the likelihood that TD will become irreversible increase with duration of treatment and total cumulative dose.

Metoclopramide should be discontinued in patients who develop signs or symptoms of TD.

There is no known effective treatment for established cases of TD, although in some patients, TD may remit, partially or completely, within several weeks to months after metoclopramide is withdrawn.

Metoclopramide itself may suppress, or partially suppress, the signs of TD, thereby masking the underlying disease process.

The effect of this symptomatic suppression upon the long term course of TD is unknown.

Therefore, metoclopramide should not be used for the symptomatic control of TD.

Syndrome (NMS) There have been rare reports of an uncommon but potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) associated with metoclopramide.

Clinical manifestations of

NMS include hyperthermia, muscle rigidity, altered consciousness, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac arrhythmias).

The diagnostic evaluation of patients with this syndrome is complicated.

In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc). and untreated or inadequately treated extrapyramidal signs and symptoms (EPS).

Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, malignant hyperthermia, drug fever and primary central nervous system (CNS) pathology.

The management of

NMS should include 1) immediate discontinuation of metoclopramide and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available.

Bromocriptine and dantrolene sodium have been used in treatment of NMS, but their effectiveness have not been established See ADVERSE REACTIONS.

Metoclopramide should not be used whenever stimulation of gastrointestinal motility might be dangerous, e.g., in the presence of gastrointestinal hemorrhage, mechanical obstruction, or perforation.

Metoclopramide is contraindicated in patients with pheochromocytoma because the drug may cause a hypertensive crisis, probably due to release of catecholamines from the tumor.

Such hypertensive crises may be controlled by phentolamine.

Metoclopramide is contraindicated in patients with known sensitivity or intolerance to the drug.

Metoclopramide should not be used in epileptics or patients receiving other drugs which are likely to cause extrapyramidal reactions, since the frequency and severity of seizures or extrapyramidal reactions may be increased.

Therapy with metoclopramide oral solution should not exceed 12 weeks in duration.

For the Relief of Symptomatic Gastroesophageal Reflux Administer from 10 mg to 15 mg metoclopramide orally up to 4 times daily 30 minutes before each meal and at bedtime, depending upon symptoms being treated and clinical response.

If symptoms occur only intermittently or at specific times of the day, use of metoclopramide in single doses up to 20 mg prior to the provoking situation may be preferred rather than continuous treatment.

Occasionally, patients (such as elderly patients) who are more sensitive to the therapeutic or adverse effects of metoclopramide will require only 5 mg per dose.

Experience with esophageal erosions and ulcerations is limited, but healing has thus far been documented in one controlled trial using 4 times daily therapy at 15 mg/dose, and this regimen should be used when lesions are present, so long as it is tolerated See ADVERSE REACTIONS.

Because of the poor correlation between symptoms and endoscopic appearance of the esophagus, therapy directed at esophageal lesions is best guided by endoscopic evaluation.

Therapy longer than 12 weeks has not been evaluated and cannot be recommended.

For the Relief of Symptoms Associated with Diabetic Gastroparesis (Diabetic Gastric Stasis) Administer 10 mg of metoclopramide 30 minutes before each meal and at bedtime for two to eight weeks, depending upon response and the likelihood of continued well-being upon drug discontinuation.

The initial route of administration should be determined by the severity of the presenting symptoms.

If only the earliest manifestations of diabetic gastric stasis are present, oral administration of metoclopramide may be initiated.

However, if severe symptoms are present, therapy should begin with metoclopramide injection (consult labeling of the injection prior to initiating parenteral administration).

Administration of metoclopramide injection up to 10 days maybe required before symptoms subside at which time oral administration may be instituted.

Since diabetic gastric stasis is frequently recurrent, metoclopramide therapy should be reinstituted at the earliest manifestation.

Use in Patients with 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.

OVERDOSAGE 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.

USP, 5 mg metoclopramide base (as the monohydrochloride monohydrate) per 5 mL (teaspoonful) is available as an orange-colored, vanilla-flavored, palatable, aromatic, sugar-free and alcohol-free liquid for oral administration and is available in the following size: 10 mL unit dose cups: 100 cups (10 x 10) NDC 60687-837-56 RECOMMENDED STORAGE Store at controlled room temperature, between 20°C and 25°C (68° to 77°F) .

Protect from freezing.

Store at controlled room temperature, between 20°C and 25°C (68° to 77°F) .

Protect from freezing.

Metoclopramide is excreted in human milk.

Caution should be exercised when metoclopramide is administered to a nursing mother.

Safety and effectiveness in pediatric patients have not been established.

Care should be exercised in administering metoclopramide to neonates since prolonged clearance may produce excessive serum concentrations.

In addition, neonates have reduced levels of NADH-cytochrome b 5 reductase which, in combination with the aforementioned pharmacokinetic factors, make neonates more susceptible to methemoglobinemia.

The safety profile of metoclopramide in adults cannot be extrapolated to pediatric patients.

Dystonias and other extrapyramidal reactions associated with metoclopramide are more common in the pediatric population than in adults. See WARNINGS and ADVERSE REACTIONS-Extrapyramidal Reactions.

Clinical studies of metoclopramide did not include sufficient numbers of subjects aged and over to determine whether elderly subjects respond differently from younger subjects.

The risk of developing parkinsonian-like side effects increases with ascending dose.

Geriatric patients should receive the lowest dose of metoclopramide that is effective.

If parkinsonian-like symptoms develop in a geriatric patient receiving metoclopramide, metoclopramide should generally be discontinued before initiating any specific anti-parkinsonian agents See WARNINGS and DOSAGE AND ADMINISTRATION-For the Relief of Symptomatic Gastroesophageal Reflux.

The elderly may be at greater risk for tardive dyskinesia See WARNINGS-Tardive Dyskinesia.

Sedation has been reported in metoclopramide users.

Sedation may cause confusion and manifest as over-sedation in the elderly.

Metoclopramide is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function See DOSAGE AND ADMINISTRATION-Use in Patients with Renal or Hepatic Impairment.

For these reasons, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased renal functions, concomitant disease, or other drug therapy in the elderly See DOSAGE AND ADMINISTRATION-For the Relief of Symptomatic Gastroesophageal Reflux and Use in Patients with Renal or Hepatic Impairment .