CLOPRAMID

USP is an orange-colored, vanilla-flavored, palatable, aromatic, sugar-free liquid for oral administration.

Each 5 mL (teaspoonful) contains: Metoclopramide base (as the monohydrochloride monohydrate) 5 mg. Inactive ingredients: Citric Acid Anhydrous, FD&C Yellow No. 5 (tartrazine), FD&C Red No. 40, Glycerin, Methylparaben, Propylparaben, Purified Water, Sorbitol Solution 70%, Vanilla Flavor.

Metoclopramide hydrochloride is a white, crystalline, odorless substance, freely soluble in water.

Chemically, it is 4-amino-5-chloro.

• N -[2-(diethylamino)ethyl]-2-methoxy benzamide monohydrochloride monohydrate.

Its molecular formula is

C 14 H 22 ClN 3 O 2 •HCl•H 2 O, with a molecular weight of 354.3.

Its structural formula is

Meteolabramid is used for the following cases: nausea and vomiting therapy associated with chemotherapy, or surgery.

Vector retrograde therapy, stomach burn, and the infectious ulcer associated with esophagus retrograde, if the body does not respond to other drugs.

It is important to consult a doctor before using medication in the following cases: breast-feeding period, because it is released in the mother's milk; Barkinson disease, where it may increase the severity of symptoms; kidney failure; liver disorders; heart disease; hypertension; vascular edema; breast cancer.

Metoclopramide stimulates motility of the upper gastrointestinal tract without stimulating gastric, biliary or pancreatic secretions.

Its mode of action is unclear.

It seems to sensitize tissues to the action of acetylcholine.

The effect of metoclopramide on motility is not dependent on intact vagal innervation, but it can be abolished by anticholinergic drugs.

Metoclopramide 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 esophageal sphincter.

It has little, if any, effect on the motility of the colon or gallbladder.

In patients with gastroesophageal reflux and low LESP (lower esophageal sphincter pressure), single oral doses of metoclopramide produce dose-related increases in LESP.

Effects begin at about 5 mg and increase through 20 mg (the largest dose tested).

The increase in

LESP from a 5 mg dose lasts about 45 minutes and that of 20 mg lasts between and 3 hours.

Increased rate of stomach emptying has been observed with single oral doses of 10 mg. The antiemetic properties of metoclopramide appear to be a result of its antagonism of central and peripheral dopamine receptors.

Dopamine produces nausea and vomiting by stimulation of the medullary chemoreceptor trigger zone (CTZ), and metoclopramide blocks stimulation of the CTZ by agents like l-dopa or apomorphine, which are known to increase dopamine levels or to possess dopamine-like effects.

Metoclopramide also abolishes the slowing of gastric emptying caused by apomorphine.

Like the phenothiazines and related drugs, which are also dopamine antagonists, metoclopramide produces sedation and may produce extrapyramidal reactions, although these are comparatively rare See WARNINGS.

Metoclopramide inhibits the central and peripheral effects of apomorphine, induces release of prolactin and causes a transient increase in circulating aldosterone levels, which may be associated with transient fluid retention.

The onset of pharmacological action of metoclopramide is to 3 minutes following an intravenous dose, 10 to 15 minutes following intramuscular administration, and to 60 minutes following an oral dose; pharmacological effects persist for to 2 hours.

Metoclopramide is rapidly and well absorbed.

Relative to an intravenous dose of 20 mg, the absolute oral bioavailability of metoclopramide is 80% ±15.5% as demonstrated in a crossover study of 18 subjects.

Peak plasma concentrations occur at about to 2 hours after a single oral dose.

Similar time to peak is observed after individual doses at steady state.

In a single dose study of 12 subjects, the area under the drug concentration-time curve increases linearly with doses from to 100 mg. Peak concentrations increase linearly with dose; time to peak concentrations remains the same; whole body clearance is unchanged; and the elimination rate remains the same.

The average elimination half-life in individuals with normal renal function is to 6 hours.

Linear kinetic processes adequately describe the absorption and elimination of metoclopramide.

Approximately 85% of the radioactivity of an orally administered dose appears in the urine within 72 hours.

Of the 85% eliminated in the urine, about half is present as free or conjugated metoclopramide.

The drug is not extensively bound to plasma proteins (about 30%).

The whole body volume of distribution is high (about 3.5 L/kg) which suggests extensive distribution of drug to the tissues.

Renal impairment affects the clearance of metoclopramide.

In a study with patients with varying degrees of renal impairment, a reduction in creatinine clearance was correlated with a reduction in plasma clearance, renal clearance, non-renal clearance, and increase in elimination half-life.

The kinetics of metoclopramide in the presence of renal impairment remained linear however.

The reduction in clearance as a result of renal impairment suggests that adjustment downward of maintenance dosage should be done to avoid drug accumulation.

Vd (L/Kg) ~3.5 Plasma Protein Binding ~30% t 1/2 (hr) 5 to 6 Oral Bioavailability 80% ±15.5% In pediatric patients, the pharmacodynamics of metoclopramide following oral and intravenous administration are highly variable and a concentration-effect relationship has not been established.

There are insufficient reliable data to conclude whether the pharmacokinetics of metoclopramide in adults and the pediatric population are similar.

Although there are insufficient data to support the efficacy of metoclopramide in pediatric patients with symptomatic gastroesophageal reflux (GER) or cancer chemotherapy-related nausea and vomiting, its pharmacokinetics have been studied in these patient populations.

In an open-label study, six pediatric patients (age range, 3.5 weeks to 5.4 months) with GER received metoclopramide 0.15 mg/kg oral solution every 6 hours for 10 doses.

The mean peak plasma concentration of metoclopramide after the tenth dose was 2-fold (56.8 mcg/L) higher compared to that observed after the first dose (29 mcg/L) indicating drug accumulation with repeated dosing.

After the tenth dose, the mean time to reach peak concentrations (2.2 hr), half-life (4.1 hr), clearance (0.67 L/h/kg), and volume of distribution (4.4 L/kg) of metoclopramide were similar to those observed after the first dose.

In the youngest patient (age, 3.5 weeks), metoclopramide half-life after the first and the tenth dose (23.1 and 10.3 hr, respectively) was significantly longer compared to other infants due to reduced clearance.

This may be attributed to immature hepatic and renal systems at birth.

Single intravenous doses of metoclopramide 0.22 to 0.46 mg/kg (mean, 0.35 mg/kg) were administered over 5 minutes to 9 pediatric cancer patients receiving chemotherapy (mean age, 11.7 years; range, 7 to 14 yr) for prophylaxis of cytotoxic-induced vomiting.

The metoclopramide plasma concentrations extrapolated to time zero ranged from to 395 mcg/L (mean, 152 mcg/L).

The mean elimination half-life, clearance, and volume of distribution of metoclopramide were 4.4 hr (range, 1.7 to 8.3 hr), 0.56 L/h/kg (range, 0.12 to 1.20 L/h/kg), and 3.0 L/kg (range, 1.0 to 4.8 L/kg), respectively.

In another study, nine pediatric cancer patients (age range, 1 to 9 yr) received to 5 intravenous infusions (over 30 minutes) of metoclopramide at a dose of 2 mg/kg to control emesis.

After the last dose, the peak serum concentrations of metoclopramide ranged from to 5680 mcg/L. The mean elimination half-life, clearance, and volume of distribution of metoclopramide were 4.5 hr (range, 2.0 to 12.5 hr), 0.37 L/h/kg (range, 0.10 to 1.24 L/h/kg), and 1.93 L/kg (range, 0.95 to 5.50 L/kg), respectively.

Metoclobramid is used to treat stomach and intestinal problems, as it accelerates the discharge of stomach content, by stimulating muscle contractions.

Depressing the impact of dopamine, by preventing it from relating to its central nervous system.

In general, the incidence of adverse reactions correlates with the dose and duration of metoclopramide administration.

The following reactions have been reported, although in most instances, data do not permit an estimate of frequency: CNS Effects Restlessness, drowsiness, fatigue, and lassitude occur in approximately 10% of patients receiving the most commonly prescribed dosage of 10 mg 4 times daily. .

Insomnia, headache, confusion, dizziness or mental depression with suicidal ideation See WARNINGS occur less frequently.

The incidence of drowsiness is greater at higher doses.

There are isolated reports of convulsive seizures without clearcut relationship to metoclopramide.

Rarely, hallucinations have been reported.

Reactions (EPS) Acute dystonic reactions, the most common type of EPS associated with metoclopramide, occur in approximately 0.2% of patients (1 in 500) treated with to 40 mg of metoclopramide per day. Symptoms include involuntary movements of limbs, facial grimacing, torticollis, oculogyric crisis, rhythmic protrusion of tongue, bulbar type of speech, trismus, opisthotonus (tetanus-like reactions), and, rarely, stridor and dyspnea possibly due to laryngospasm; ordinarily these symptoms are readily reversed by diphenhydramine See WARNINGS.

Parkinsonian-like symptoms may include bradykinesia, tremor, cogwheel rigidity, mask-like facies See WARNINGS.

Tardive dyskinesia most frequently is characterized by involuntary movements of the tongue, face, mouth, or jaw, and sometimes by involuntary movements of the trunk and/or extremities; movements may be choreoathetotic in appearance See WARNINGS.

Motor restlessness (akathisia) may consist of feelings of anxiety, agitation, jitteriness, and insomnia, as well as inability to sit still, pacing, foot tapping.

These symptoms may disappear spontaneously or respond to a reduction in dosage.

Rare occurrences of neuroleptic malignant syndrome (NMS) have been reported.

This potentially fatal syndrome is comprised of the symptom complex of hyperthermia, altered consciousness, muscular rigidity, and autonomic dysfunction See WARNINGS.

Galactorrhea, amenorrhea, gynecomastia, impotence secondary to hyperprolactinemia.

Fluid retention secondary to transient elevation of aldosterone.

Hypotension, hypertension, supraventricular tachycardia, bradycardia, fluid retention, acute congestive heart failure, and possible AV block See CONTRAINDICATIONS and PRECAUTIONS.

Nausea and bowel disturbances, primarily diarrhea.

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

Urinary frequency and incontinence.

A few cases of neutropenia, leukopenia, or agranulocytosis, generally without clearcut relationship to metoclopramide.

Methemoglobinemia, in adults and especially with overdosage in neonates.

Sulfhemoglobinemia in adults.

A few cases of rash, urticaria, or bronchospasm, especially in patients with a history of asthma.

Rarely, angioneurotic edema, including glossal or laryngeal edema.

Visual disturbances.

Symptoms of overdosage may include drowsiness, disorientation and extrapyramidal reactions.

Anticholinergic or antiparkinson drugs or antihistamines with anticholinergic properties may be helpful in controlling the extrapyramidal reactions.

Symptoms are self-limiting and usually disappear within 24 hours.

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.

Unintentional overdose due to misadministration has been reported in infants and children with the use of metoclopramide oral solution.

While there was no consistent pattern to the reports associated with these overdoses, events included seizures, extrapyramidal reactions, and lethargy.

Methemoglobinemia has occurred in premature and full-term neonates who were given overdoses of metoclopramide (1 to 4 mg/kg/day orally, intramuscularly or intravenously for to 3 or more days).

Methemoglobinemia can be reversed by the intravenous administration of methylene blue.

However, methylene blue may cause hemolytic anemia in patients with G6PD deficiency, which may be fatal.

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 .