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For the official FDA label of this metoclopramide drug and for further references included in the label please visit the National Institute of Health website: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=6756

Mayne Pharma Inc. Metoclopramide Injection

DESCRIPTION

Metoclopramide Injection is a sterile, nonpyrogenic solution. Each mL contains metoclopramide 5 mg (present as the hydrochloride), and 8.5 mg sodium chloride in Water for Injection, USP. The pH is adjusted to 2.5 – 6.5, when necessary, with hydrochloric acid and/or sodium hydroxide. The solution is intended for intravenous or intramuscular administration.

CONTAINS NO PRESERVATIVE

Metoclopramide hydrochloride is a white or practically white, crystalline, odorless or practically odorless powder. It is very soluble in water, freely soluble in alcohol, sparingly soluble in chloroform, practically insoluble in ether. Chemically, it is 4-amino-5-chloro-N-[2-(diethylamino) ethyl]-2-methoxy benzamide monohydrochloride monohydrate. Its structural formula is as follows:

Mol. Wt.: 354.27 C14H22CIN3O2• HCl • H20

CLINICAL PHARMACOLOGY

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 2 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 I-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 1 to 3 minutes following an intravenous dose, 10 to 15 minutes following intramuscular administration, and 30 to 60 minutes following an oral dose; pharmacological effects persist for 1 to 2 hours.

Pharmacokinetics

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 1 to 2 hr 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 20 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 5 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.

Adult Pharmacokinetic Data

Parameter Value
Vd (L/kg) ~ 3.5
Plasma Protein Binding ~ 30%
t1/2 (hr) 5-6
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 a 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 65 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 4 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 1060 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.

Pediatric Pharmacokinetic Studies

References Dose, Route t1/2
(hr) CI
(L/hr/kg) Vd
(L/kg) Cmax
(mcg/L)
a. SEM not available.
1. Bateman, DN, et al, Br J Clin Pharmac 15:557-559, 1983.
2. Ford, C. Clin Pharmac Ther 43:196, 1988.
1. 0.35 mg/kg,
IV over 5 min 4.4±0.56 0.56±0.10 3.0±0.38
(Dose/Cp0) 152±31
2. 2 mg/kg
30 min IV
Infusion 4-5 times
within 9.5 hours 4.5a 0.37a 1.93a 1060 to 5680a
INDICATIONS AND USAGE

Diabetic Gastroparesis (Diabetic Gastric Stasis): Metoclopramide Injection is indicated for the relief of severe symptoms associated with acute and recurrent diabetic gastric stasis.

The Prevention of Nausea and Vomiting Associated with Emetogenic Cancer Chemotherapy: Metoclopramide Injection is indicated for the prophylaxis of vomiting associated with emetogenic cancer chemotherapy.

The Prevention of Postoperative Nausea and Vomiting: Metoclopramide Injection is indicated for the prophylaxis of postoperative nausea and vomiting in those circumstances where nasogastric suction is undesirable.

Small Bowel Intubation: Metoclopramide Injection may be used to facilitate small bowel intubation in adults and pediatric patients in whom the tube does not pass the pylorus with conventional maneuvers.

Radiological Examination: Metoclopramide Injection may be used to stimulate gastric emptying and intestinal transit of barium in cases where delayed emptying interferes with radiological examination of the stomach and/or small intestine.

CONTRAINDICATIONS

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.

WARNINGS

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 1 in 500 patients treated with the usual adult dosages of 30 to 40 mg/day of metoclopramide. These usually are seen during the first 24 to 48 hours of treatment with metoclopramide, occur more frequently in pediatric patients and adult patients less than 30 years of age are even more frequent at the higher doses used in prophylaxis of vomiting due to cancer chemotherapy. 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 2 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.

Tardive Dyskinesia

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with metoclopramide. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients are likely to develop the syndrome. 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.

Less commonly, the syndrome can develop after relatively brief treatment periods at low doses; in these cases, symptoms appear more likely to be reversible.

There is no known treatment for established cases of tardive dyskinesia although the syndrome 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, the use of metoclopramide for the symptomatic control of tardive dyskinesia is not recommended.

Neuroleptic Malignant 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 extrapyrimidal 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, 3) treatment of any concomitant serious medical problems for which specific treatments are available. Bromocriptine and dantroline sodium have been used in treatment of NMS, but their effectiveness have not been established (see ADVERSE REACTIONS).

PRECAUTIONS

General

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.

Intravenous injections of undiluted metoclopramide should be made slowly allowing 1 to 2 minutes for 10 mg since a transient but intense feeling of anxiety and restlessness, followed by drowsiness, may occur with rapid administration.

Because metoclopramide produces a transient increase in plasma aldosterone, certain patients, especially those with cirrhosis or congestive heart failure, may be at risk of developing fluid retention and volume overload. If this occurs at any time during metoclopramide therapy, the drug should be discontinued.

Intravenous administration of Metoclopramide Injection diluted in a parenteral solution should be made slowly over a period of not less than 15 minutes.

Giving a promotility drug such as metoclopramide theoretically could put increased pressure on suture lines following a gut anastomosis or closure. This possibility should be considered and weighed when deciding whether to use metoclopramide or nasogastric suction in the prevention of postoperative nausea and vomiting.

Information For Patients

Metoclopramide may impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle. The ambulatory patient should be cautioned accordingly.

Drug Interactions

The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics or tranquilizers.

The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxidase inhibitors.

Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine).

Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dose or timing of dosage may require adjustment.

Carcinogenesis, Mutagenesis, Impairment of Fertility

A 77-week study was conducted in rats with oral doses up to about 40 times the maximum recommended human daily dose. Metoclopramide elevates prolactin levels and the elevation persists during chronic administration. 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 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 and metoclopramide. 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.

An Ames mutagenicity test performed on metoclopramide was negative.

Pregnancy Category B

Reproduction studies performed in rats, mice, and rabbits by the I.V., I.M., S.C. and oral routes at maximum levels ranging from 12 to 250 times the human dose have demonstrated no impairment of fertility or significant harm to the fetus due to metoclopramide. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

Metoclopramide is excreted in human milk. Caution should be exercised when metoclopramide is administered to a nursing mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established except as stated to facilitate small bowel intubation (see OVERDOSAGE and DOSAGE AND ADMINISTRATION).

Care should be exercised in administering metoclopramide to neonates since prolonged clearance may produce excessive serum concentrations (see CLINICAL PHARMACOLOGY: Pharmacokinetics). In addition, neonates have reduced levels of NADH-cytochrome b5 reductase which, in combination with the aforementioned pharmacokinetic factors, make neonates more susceptible to methemoglobinemia (see OVERDOSAGE).

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.)

Geriatric Use

Clinical studies of metoclopramide did not include sufficient numbers of subjects aged 65 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 elderly (see CLINICAL PHARMACOLOGY, PRECAUTIONS Information for Patients and ADVERSE REACTIONS-CNS Effects).

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).

Other Special Populations: Patients with NADH-cytochrome b5 reductase deficiency are at an increased risk of developing methemoglobinemia and/or sulfhemoglobinemia when metoclopramide is administered. In patients with G6PD deficiency who experience metoclopramide-induced methemoglobinemia, methylene blue treatment is not recommended (see OVERDOSAGE).

ADVERSE REACTIONS

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 may occur (see PRECAUTIONS). Insomnia, headache, confusion, dizziness or mental depression with suicidal ideation may also occur (see WARNINGS). In cancer chemotherapy patients being treated with 1 to 2 mg/kg per dose, incidence of drowsiness is about 70%. There are isolated reports of convulsive seizures without clear-cut relationship to metoclopramide. Rarely, hallucinations have been reported.

Extrapyramidal 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 30 to 40 mg of metoclopramide per day. In cancer chemotherapy patients receiving 1 to 2 mg/kg per dose, the incidence is 2% in patients over the ages of 30 to 35, and 25% or higher in pediatric patients and adult patients less than 30 years of age who have not had prophylactic administration of diphenhydramine. Symptoms included 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 faces (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.

Neuroleptic Malignant Syndrome: Rare occurrences of neuroleptic malignant syndrome (NMS) have been reported. This potentially fatal syndrome is comprised of the symptom complex of hyperthermia, muscular rigidity, altered consciousness, and autonomic instability (see WARNINGS).

Endocrine Disturbances: Galactorrhea, amenorrhea, gynecomastia, impotence secondary to hyperprolactinemia (see PRECAUTIONS). Fluid retention secondary to transient elevation of aldosterone (see CLINICAL PHARMACOLOGY).

Cardiovascular: Hypotension, hypertension, supraventricular tachycardia, bradycardia, fluid retention, acute congestive heart failure and possible AV block (see CONTRAINDICATIONS and PRECAUTIONS).

Gastrointestinal: Nausea and bowel disturbance, primarily diarrhea.

Hepatic: 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.

Renal: Urinary frequency and incontinence.

Hematologic: A few cases of neutropenia, leukopenia, or agranulocytosis, generally without clear-cut relationship to metoclopramide. Methemoglobinemia in adults and especially with overdosage in neonates (see OVERDOSAGE). Sulfhemoglobinemia in adults.

Allergic Reactions: A few cases of rash, urticaria, or bronchospasm, especially in patients with a history of asthma. Rarely, angioneurotic edema, including glossal or laryngeal edema.

Miscellaneous: Visual disturbances. Porphyria. Transient flushing of the face and upper body, without alterations in vital signs, following high doses intravenously.

OVERDOSAGE

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 1 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 (see PRECAUTIONS – Other Special Populations).

DOSAGE AND ADMINISTRATION

For The Relief Of Symptoms Associated With Diabetic Gastroparesis (Diabetic Gastric Stasis): 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 (IM or IV). Doses of 10 mg may be administered slowly by the intravenous route over a 1- to 2-minute period.

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

For The Prevention Of Nausea And Vomiting Associated With Emetogenic Cancer Chemotherapy: For doses in excess of 10 mg, Metoclopramide Injection should be diluted in 50 mL of a parenteral solution.

The preferred parenteral solution is Sodium Chloride Injection (normal saline), which when combined with Metoclopramide Injection, can be stored frozen for up to 4 weeks. Metoclopramide Injection is degraded when admixed and frozen with Dextrose-5% in Water. Metoclopramide Injection diluted in Sodium Chloride Injection, Dextrose-5% in Water, Dextrose-5% in 0.45% Sodium Chloride, Ringer’s Injection or Lactated Ringer’s Injection may be stored up to 48 hours (without freezing) after preparation if protected from light. All dilutions may be stored unprotected from light under normal light conditions up to 24 hours after preparation.

Intravenous infusions should be made slowly over a period of not less than 15 minutes, 30 minutes before beginning cancer chemotherapy and repeated every 2 hours for two doses, then every 3 hours for three doses.

The initial two doses should be 2 mg/kg if highly emetogenic drugs such as cisplatin or dacarbazine are used alone or in combination. For less emetogenic regimes, 1 mg/kg per dose may be adequate.

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

For The Prevention of Postoperative Nausea and Vomiting: Metoclopramide Injection should be given intramuscularly near the end of surgery. The usual adult dose is 10 mg; however, doses of 20 mg may be used.

To Facilitate Small Bowel Intubation: If the tube has not passed the pylorus with conventional maneuvers in 10 minutes, a single dose (undiluted) may be administered slowly by the intravenous route over a 1- to 2- minute period. The recommended single dose is: Pediatric patients above 14 years of age and adults – 10 mg metoclopramide base. Pediatric patients (6 to 14 years of age) – 2.5 to 5 mg metoclopramide base; (under 6 years of age) – 0.1 mg/kg metoclopramide base.

To Aid in Radiological Examinations: In patients where delayed gastric emptying interferes with radiological examination of the stomach and/or small intestine, a single dose may be administered slowly by the intravenous route over 1- to 2- minute period.

For dosage, see intubation above.

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.

See 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.

Admixture Compatibilities: Metoclopramide Injection is compatible for mixing and injection with the following injectable products to the extent indicated below:

Physically and Chemically Compatible up to 48 hours. Cimetidine Hydrochloride, Mannitol, Potassium Acetate, Potassium Phosphate.

Physically Compatible up to 48 hours. Ascorbic Acid, Benztropine Mesylate, Cytarabine, Dexamethasone Sodium Phosphate, Diphenhydramine Hydrochloride, Doxorubicin Hydrochloride, Heparin Sodium, Hydrocortisone Sodium Phosphate, Lidocaine Hydrochloride, Multi-Vitamin Infusion (must be refrigerated), Vitamin B Complex with Ascorbic Acid.

Physically Compatible up to 24 hours (Do not use if precipitation occurs). Clindamycin Phosphate, Cyclophosphamide, Insulin.

Conditionally Compatible (Use within one hour after mixing or may be infused directly into the same running IV line). Ampicillin Sodium, Cisplatin, Erythromycin Lactobionate, Methotrexate Sodium, Penicillin G Potassium, Tetracycline Hydrochloride.

Incompatible (Do Not Mix). Cephalothin Sodium, Chloramphenicol Sodium, Sodium Bicarbonate.

Parenteral products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

HOW SUPPLIED

Metoclopramide Injection, USP – 5 mg Metoclopramide (present as the hydrochloride) per mL – is available in the following packages:
NDC 61703-210-07 2 mL Single Dose Vial
10 mg/2 mL
Package of 25 Vials
NDC 61703-210-11 10 mL Single Dose Vial
50 mg/10 mL
Package of 25 Vials
NDC 61703-210-21 20 mL Single Dose Vial
100 mg/20 mL
Package of 10 Vials
NDC 61703-210-35 30 mL Single Dose Vial
150 mg/30 mL
Package of 1 Vial

Store at controlled room temperature between 15°- 30°C (59°- 86°F). Do not permit to freeze.

PROTECT FROM LIGHT. Store vial in carton until time of use.

CONTAINS NO PRESERVATIVE. Discard unused portion.

Manufactured for:
Mayne Pharma ( USA) Inc.
Paramus, NJ 07652
By: Mayne Pharma (PR) Inc.
Aguadilla, Puerto Rico 00604
Rev. March 2004 PI005/KC

Metoclopramide (Metoclopramide)
PRODUCT INFO
Product Code 61703-210 Dosage Form INJECTION, SOLUTION
Route Of Administration INTRAVENOUS, INTRAMUSCULAR DEA Schedule

INGREDIENTS
Name (Active Moiety) Type Strength
Metoclopramide (Metoclopramide) Active 5 MILLIGRAM In 1 MILLILITER
sodium chloride Inactive
hydrochloric acid Inactive
sodium hydroxide Inactive
Water Inactive

IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color Score
Shape Symbol
Imprint Code Coating
Size

PACKAGING
# NDC Package Description Multilevel Packaging
1 61703-210-07 25 VIAL In 1 PACKAGE contains a VIAL, SINGLE-DOSE
1 2 MILLILITER In 1 VIAL, SINGLE-DOSE This package is contained within the PACKAGE (61703-210-07)
2 61703-210-11 25 VIAL In 1 PACKAGE contains a VIAL, SINGLE-DOSE
2 10 MILLILITER In 1 VIAL, SINGLE-DOSE This package is contained within the PACKAGE (61703-210-11)
3 61703-210-21 10 VIAL In 1 PACKAGE contains a VIAL, SINGLE-DOSE
3 20 MILLILITER In 1 VIAL, SINGLE-DOSE This package is contained within the PACKAGE (61703-210-21)
4 61703-210-35 1 VIAL In 1 PACKAGE contains a VIAL, SINGLE-DOSE
4 30 MILLILITER In 1 VIAL, SINGLE-DOSE This package is contained within the PACKAGE (61703-210-35)
Revised: 05/2006Mayne Pharma (USA) Inc.

We represent all clients suffering from Reglan side effects on a contingency basis which means that there are never any legal fees unless we win compensation in your case. For a free no-obligation consultation please call toll free at 1-888-343-5375 or fill out our short online contact form and one of our Reglan lawyers will contact you to answer any of your questions.

For the official FDA label of this metoclopramide drug and for further references included in the label please visit the National Institute of Health website: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=3125

Mutual Pharmaceutical Company Metoclopramide Tablet

DESCRIPTION

Metoclopramide hydrochloride is a white crystalline, odorless substance, freely soluble in water. Chemically, it is 4-amino-5chloro-N-[2-(diethylamino)ethyl]-2-methoxy benzamide monohydrochloride monohydrate. Its molecular formula is C14H22ClN3O2•HCl•H2O. Its molecular weight is 354.3.

Each 5 mg tablet for oral administration contains metoclopramide hydrochloride, equivalent to 5 mg of metoclopramide.

Each 10 mg tablet for oral administration contains metoclopramide hydrochloride, equivalent to 10 mg of metoclopramide.

Inactive Ingredients: Microcrystalline Cellulose, Colloidal Silicon Dioxide, Magnesium Stearate, Mannitol, Sodium Starch Glycolate.

CLINICAL PHARMACOLOGY

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 2 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 1 to 3 minutes following an intravenous dose, 10 to 15 minutes following intramuscular administration, and 30 to 60 minutes following an oral dose; pharmacological effects persist for 1 to 2 hours.

Pharmacokinetics

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 1 to 2 hr 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 20 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 5 to 6 hr. 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 hr. 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.

Adult Pharmacokinetic Data

Parameter Value
Vd (L/Kg) ~3.5
Plasma Protein Binding ~30%
t1/2 (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 µg/L) higher compared to that observed after the first dose (29 µg/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 65 to 395 µg/L (mean, 152 µg/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 4 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 1060 to 5680 µg/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.

INDICATIONS AND USAGE

The use of metoclopramide tablets is recommended for adults only. Therapy should not exceed 12 weeks in duration.

Symptomatic Gastroesophageal Reflux

Metoclopramide tablets are indicated as short-term (4 to 12 weeks) therapy for adults with symptomatic, documented gastroesophageal reflux who fail to respond to conventional therapy.

The principal effect of metoclopramide is on symptoms of postprandial and daytime heartburn with less observed effect on nocturnal symptoms. If symptoms are confined to particular situations, such as following the evening meal, use of metoclopramide as single doses prior to the provocative situation should be considered, rather than using the drug throughout the day. Healing of esophageal ulcers and erosions has been endoscopically demonstrated at the end of a 12-week trial using doses of 15 mg q.i.d. As there is no documented correlation between symptoms and healing of esophageal lesions, patients with documented lesions should be monitored endoscopically.

Diabetic Gastroparesis (Diabetic Gastric Stasis)

Metoclopramide tablets, USP is indicated for the relief of symptoms associated with acute and recurrent diabetic gastric stasis. The usual manifestations of delayed gastric emptying (e.g., nausea, vomiting, heartburn, persistent fullness after meals and anorexia) appear to respond to metoclopramide within different time intervals. Significant relief of nausea occurs early and continues to improve over a three-week period. Relief of vomiting and anorexia may precede the relief of abdominal fullness by one week or more.

CONTRAINDICATIONS

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.

WARNINGS

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 1 in 500 patients treated with the usual adult dosages of 30 to 40 mg/day of metoclopramide. These usually are seen during the first 24 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 2 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.

Tardive Dyskinesia

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with metoclopramide. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients are likely to develop the syndrome. 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.

Less commonly, the syndrome can develop after relatively brief treatment periods at low doses; in these cases, symptoms appear more likely to be reversible.
There is no known treatment for established cases of tardive dyskinesia although the syndrome 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, the use of metoclopramide for the symptomatic control of tardive dyskinesia is not recommended.

Neuroleptic Malignant Syndrome (NMS)

There have been 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).

PRECAUTIONS

General

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.

Because metoclopramide produces a transient increase in plasma aldosterone, certain patients, especially those with cirrhosis or congestive heart failure, may be at risk of developing fluid retention and volume overload. If these side effects occur at any time during metoclopramide therapy, the drug should be discontinued.

Adverse reactions, especially those involving the nervous system, may occur after stopping the use of metoclopramide tablets. A small number of patients may experience a withdrawal period after stopping metoclopramide tablets that could include dizziness, nervousness, and/or headaches.

Information for Patients

The use of metoclopramide tablets is recommended for adults only. Metoclopramide may impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle. The ambulatory patient should be cautioned accordingly.

Drug Interactions

The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers.

The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxidase inhibitors.
Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine).

Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment.

Carcinogenesis, Mutagenesis, Impairment of Fertility

A 77-week study was conducted in rats with oral doses up to about 40 times the maximum recommended human daily dose. Metoclopramide elevates prolactin levels and the elevation persists during chronic administration. 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 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 and metoclopramide. 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.

An Ames mutagenicity test performed on metoclopramide was negative.

Pregnancy Category B

Reproduction studies performed in rats, mice and rabbits by the I.V., I.M., S.C., and oral routes at maximum levels ranging from 12 to 250 times the human dose have demonstrated no impairment of fertility or significant harm to the fetus due to metoclopramide. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

Metoclopramide is excreted in human milk. Caution should be exercised when metoclopramide is administered to a nursing mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established, (see OVERDOSAGE).

Care should be excercised in administering metoclopramide to neonates since prolonged clearance may produce excessive serum concentrations (see CLINICAL PHARMACOLOGY- Pharmacokinetics). In addition, neonates have reduced levels of NADH-cytochrome b5 reductase which, in combination with the aforementioned pharmacokinetic factors, make neonates more susceptible to methemoglobinemia (see OVERDOSAGE).

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.)

Geriatric Use

Clinical studies of metoclopramide did not include sufficient numbers of subjects aged 65 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 (see CLINICAL PHARMACOLOGY, PRECAUTIONS – Information for Patients and ADVERSE REACTIONS – CNS Effects).

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 dose range, reflecting the greater frequency of decreased real function, 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).

Other Special Populations

Patients with NADH-cytochrome b5 reductase deficiency are at an increased risk of developing methemoglobinemia and/or sulfhemoglobinemia when metoclopramide is administered. In patients with G6PD deficiency who experience metoclopramide-induced methemoglobinemia methylene blue treatment is not recommended (see OVERDOSAGE).

ADVERSE REACTIONS

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 q.i.d. (see PRECAUTIONS). 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.

Extrapyramidal 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 30 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.

Neuroleptic Malignant Syndrome. 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).

Endocrine Disturbances. Galactorrhea, amenorrhea, gynecomastia, impotence secondary to hyperprolactinemia (see PRECAUTIONS). Fluid retention secondary to transient elevation of aldosterone (see CLINICAL PHARMACOLOGY).

Cardiovascular. Hypotension, hypertension, supraventricular tachycardia, bradycardia, fluid retention, acute congestive heart failure and possible AV block (see CONTRAINDICATIONS and PRECAUTIONS).

Gastrointestinal. Nausea and bowel disturbances, primarily diarrhea.

Hepatic. 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.

Renal. Urinary frequency and incontinence.

Hematologic. A few cases of neutropenia, leukopenia, or agranulocytosis, generally without clearcut relationship to metoclopramide. Methemoglobinemia, in adults and especially with overdosage in neonates (see OVERDOSAGE). Sulfhemoglobinemia in adults.

Allergic Reactions. A few cases of rash, urticaria, or bronchospasm, especially in patients with a history of asthma. Rarely, angioneurotic edema, including glossal or laryngeal edema.

Miscellaneous. Visual disturbances. Porphyria.

OVERDOSAGE

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 1 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 (see PRECAUTIONS – Other Special Populations).

DOSAGE AND ADMINISTRATION

Therapy with metoclopramide tablets should not exceed 12 weeks in duration.

For the Relief of Symptomatic Gastroesophageal Reflux
Administer from 10 mg to 15 mg metoclopramide hydrochloride, USP, orally up to q.i.d. 30 minutes before each meal and at bedtime, depending upon symptoms being treated and clinical response (see CLINICAL PHARMACOLOGY and INDICATIONS AND USAGE). 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 q.i.d. 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 may be 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.

See 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.

HOW SUPPLIED

METOCLOPRAMIDE Tablets are supplied as follows:

Each white, round, tablet, debossed MP 148, contains Metoclopramide (as the hydrochloride) 5 mg. Available in:
Bottles of 20 unit of use NDC 53489-384-60
Bottles of 50 NDC 53489-384-02
Bottles of 100 NDC 53489-384-01
Bottles of 500 NDC 53489-384-05
Bottles of 1000 NDC 53489-384-10
Each white, round, scored tablet, debossed MP 36, contains Metoclopramide (as the hydrochloride) 10 mg. Available in:
Bottles of 50 NDC 53489-385-02
Bottles of 100 NDC 53489-385-01
Bottles of 500 NDC 53489-385-05
Bottles of 1000 NDC 53489-385-10
Store at 20° to 25°C (68° to 77°F). (See USP Controlled Room Temperature).
DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.
Manufactured by:
MUTUAL PHARMACEUTICAL COMPANY, INC.
Philadelphia, PA 19124 USA
Rev: May 2005Ch

Metoclopramide (Metoclopramide)
PRODUCT INFO
Product Code 53489-384 Dosage Form TABLET
Route Of Administration ORAL DEA Schedule

INGREDIENTS
Name (Active Moiety) Type Strength
Metoclopramide (Metoclopramide) Active 5 MILLIGRAM In 1 TABLET
Microcrystalline cellulose Inactive
colloidal silicon dioxide Inactive
magnesium stearate Inactive
mannitol Inactive
sodium starch glycolate Inactive

IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color WHITE Score 1
Shape ROUND Symbol false
Imprint Code MP;148 Coating false
Size 7mm

PACKAGING
# NDC Package Description Multilevel Packaging
1 53489-384-60 20 TABLET In 1 BOTTLE, PLASTIC None
2 53489-384-02 50 TABLET In 1 BOTTLE, PLASTIC None
3 53489-384-01 100 TABLET In 1 BOTTLE, PLASTIC None
4 53489-384-05 500 TABLET In 1 BOTTLE, PLASTIC None
5 53489-384-10 1000 TABLET In 1 BOTTLE, PLASTIC None
Metoclopramide (Metoclopramide)
PRODUCT INFO
Product Code 53489-385 Dosage Form TABLET
Route Of Administration ORAL DEA Schedule

INGREDIENTS
Name (Active Moiety) Type Strength
Metoclopramide (Metoclopramide) Active 10 MILLIGRAM In 1 TABLET
Microcrystalline cellulose Inactive
colloidal silicon dioxide Inactive
magnesium stearate Inactive
mannitol Inactive
sodium starch glycolate Inactive

IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color WHITE Score 2
Shape ROUND Symbol false
Imprint Code MP;36 Coating false
Size 7mm

PACKAGING
# NDC Package Description Multilevel Packaging
1 53489-385-02 50 TABLET In 1 BOTTLE, PLASTIC None
2 53489-385-01 100 TABLET In 1 BOTTLE, PLASTIC None
3 53489-385-05 500 TABLET In 1 BOTTLE, PLASTIC None
4 53489-385-10 1000 TABLET In 1 BOTTLE, PLASTIC None
Revised: 01/2007

We represent all clients suffering from Reglan side effects on a contingency basis which means that there are never any legal fees unless we win compensation in your case. For a free no-obligation consultation please call toll free at 1-888-343-5375 or fill out our short online contact form and a Reglan lawyer will contact you to answer any of your questions.

For the official FDA label of this metoclopramide drug and for further references included in the label please visit the National Institute of Health website: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=3450

Morton Grove Pharmaceuticals Metoclopramide Solution

DESCRIPTION

Metoclopramide Oral Solution, USP is an orange-colored, palatable, aromatic, sugar-free liquid.

Each 5 mL (teaspoonful) contains:

Metoclopramide, USP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 mg
(present as the hydrochloride)
Alcohol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . less than 0.1%
(contributed by flavorings)

Metoclopramide hydrochloride is a white or practically white, crystalline, odorless or practically odorless powder. Chemically, it is 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-o-anisamide monohydrochloride monohydrate. Its structural formula is as follows:

Inactive Ingredients: artificial butterscotch flavor, natural & artificial apple flavor, citric acid anhydrous, FD&C Yellow No. 6, glycerin, methylparaben, propylene glycol, propylparaben, purified water and sorbitol solution. It may contain 10% citric acid solution or 10% sodium citrate solution for pH adjustment. The pH range is between 2.0 and 5.5.

CLINICAL PHARMACOLOGY

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 2 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 1 to 3 minutes following an intravenous dose, 10 to 15 minutes following intramuscular administration, and 30 to 60 minutes following an oral dose; pharmacological effects persist for 1 to 2 hours.

Pharmacokinetics

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 1-2 hr 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 20 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 5-6 hr. 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 hr. 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.

Adult Pharmacokinetic Data
Parameter Value
Vd (L/Kg) ~ 3.5
Plasma Protein Binding ~ 30%
t1/2 (hr) 5-6
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), 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.

Pediatric Pharmacokinetic Studies
Reference Dose, Route t1/2
(hr) Cl
(L/hr/kg) Vd
(L/kg) Cmax
(mcg/L)
1. Kearns, GL, et al. J Pediatric Gastroenterol Nutr 7(6):823-829, 1988.
*
Data presented as means ± SEM.
†
SEM not available.
1. 0.15 mg/kg
oral soln,
multiple dose 4.1*.†
0.67±0.14 4.4±0.65
(Vdarea) 1st dose = 29±2.3
10th dose = 56.8±10.5

INDICATIONS AND USAGE

Symptomatic Gastroesophageal Reflux

Metoclopramide Oral Solution is indicated as short-term (4 to 12 weeks) therapy for adults with symptomatic, documented gastroesophageal reflux who fail to respond to conventional therapy.

The principal effect of metoclopramide is on symptoms of postprandial and daytime heartburn with less observed effect on nocturnal symptoms. If symptoms are confined to particular situations, such as following the evening meal, use of metoclopramide as single doses prior to the provocative situation should be considered, rather than using the drug throughout the day. Healing of esophageal ulcers and erosions has been endoscopically demonstrated at the end of a 12-week trial using doses of 15 mg q.i.d. As there is no documented correlation between symptoms and healing of esophageal lesions, patients with documented lesions should be monitored endoscopically.

Diabetic Gastroparesis (Diabetic Gastric Stasis)

Metoclopramide is indicated for the relief of symptoms associated with acute and recurrent diabetic gastric stasis. The usual manifestations of delayed gastric emptying (e.g., nausea, vomiting, heartburn, persistent fullness after meals, and anorexia) appear to respond to metoclopramide within different time intervals. Significant relief of nausea occurs early and continues to improve over a three-week period. Relief of vomiting and anorexia may precede the relief of abdominal fullness by one week or more.

CONTRAINDICATIONS

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.

WARNINGS

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 1 in 500 patients treated with the usual adult dosages of 30-40 mg/day of metoclopramide. These usually are seen during the first 24-48 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 Benadryl® (diphenhydramine hydrochloride) intramuscularly, and they usually will subside. Cogentin® (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 2-3 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.

Tardive Dyskinesia

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with metoclopramide. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients are likely to develop the syndrome. 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.

Less commonly, the syndrome can develop after relatively brief treatment periods at low doses; in these cases, symptoms appear more likely to be reversible.
There is no known treatment for established cases of tardive dyskinesia although the syndrome 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, the use of metoclopramide for the symptomatic control of tardive dyskinesia is not recommended.

PRECAUTIONS

General

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.

Because metoclopramide produces a transient increase in plasma aldosterone, certain patients, especially those with cirrhosis or congestive heart failure, may be at risk of developing fluid retention and volume overload. If these side effects occur at anytime during metoclopramide therapy, the drug should be discontinued.

Information for Patients

Metoclopramide may impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle. The ambulatory patient should be cautioned accordingly.

Drug Interactions

The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers.

The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxidase inhibitors.

Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine).

Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment.

Carcinogenesis, Mutagenesis, Impairment of Fertility

A 77-week study was conducted in rats with oral doses up to about 40 times the maximum recommended human daily dose. Metoclopramide elevates prolactin levels and the elevation persists during chronic administration. 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 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 and metoclopramide. 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.

An Ames mutagenicity test performed on metoclopramide was negative.

Pregnancy Category B

Reproduction studies performed in rats, mice and rabbits by the I.V., I.M., S.C., and oral routes at maximum levels ranging from 12 to 250 times the human dose have demonstrated no impairment of fertility or significant harm to the fetus due to metoclopramide. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

Metoclopramide is excreted in human milk. Caution should be exercised when metoclopramide is administered to a nursing mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established except as stated to facilitate small bowel intubation (see OVERDOSAGE and DOSAGE AND ADMINISTRATION).

Care should be exercised in administering metoclopramide to neonates since prolonged clearance may produce excessive serum concentrations (see CLINICAL PHARMACOLOGY-Pharmacokinetics). In addition, neonates have reduced levels of nicotinamide adenine dinucleotide-methemoglobin reductase which, in combination with the aforementioned pharmacokinetic factors, make neonates more susceptible to methemoglobinemia (see OVERDOSAGE).

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.)

ADVERSE REACTIONS

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 q.i.d. (see PRECAUTIONS). Insomnia, headache, confusion, dizziness, or mental depression with suicidal ideation (see WARNINGS) occur less frequently. There are isolated reports of convulsive seizures without clearcut relationship to metoclopramide. Rarely, hallucinations have been reported.

Extrapyramidal 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 30 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.

Endocrine Disturbances

Galactorrhea, amenorrhea, gynecomastia, impotence secondary to hyperprolactinemia (see PRECAUTIONS). Fluid retention secondary to transient elevation of aldosterone (see CLINICAL PHARMACOLOGY).

Cardiovascular

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

Gastrointestinal

Nausea and bowel disturbances, primarily diarrhea.

Hepatic

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.

Renal

Urinary frequency and incontinence.

Hematologic

A few cases of neutropenia, leukopenia, or agranulocytosis, generally without clearcut relationship to metoclopramide. Methemoglobinemia, especially with overdosage in neonates (see OVERDOSAGE).

Sulfhemoglobinemia in adults.

Allergic Reactions

A few cases of rash, urticaria, or bronchospasm, especially in patients with a history of asthma. Rarely, angioneurotic edema, including glossal or laryngeal edema.

Miscellaneous

Visual disturbances. Porphyria. 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.

OVERDOSAGE

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 (1-4 mg/kg/day orally, intramuscularly or intravenously for 1-3 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 the intravenous administration of methylene blue.

DOSAGE AND ADMINISTRATION

For the Relief of Symptomatic Gastroesophageal Reflux

Administer from 10 mg to 15 mg metoclopramide orally up to q.i.d. 30 minutes before each meal and at bedtime, depending upon symptoms being treated and clinical response (see CLINICAL PHARMACOLOGY and INDICATIONS AND USAGE). 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 q.i.d. 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 (I.M. or I.V.). Doses of 10 mg may be administered slowly by the intravenous route over a 1- to 2-minute period.

Administration of Metoclopramide Injection up to 10 days may be 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.
See 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.

HOW SUPPLIED

Metoclopramide Oral Solution, USP 5 mg/5 mL (contains Metoclopramide, USP present as the hydrochloride) is supplied as an orange-colored, palatable, aromatic, sugar-free liquid for oral administration and is available in the following size:
Pint (473 mL)

RECOMMENDED STORAGE

Store at 20 °-25 °C (68 °-77 °F) (See USP Controlled Room Temperature).

Protect from freezing.

Dispense in a tight, light-resistant container as defined in the USP, with child-resistant closure.

Rx Only
Product No.: 7622
Benadryl® is a registered trademark of Pfizer Inc.
Cogentin® is a registered trademark of Merck & Co., Inc.
Manufactured By: Morton Grove Pharmaceuticals, Inc.
Morton Grove, IL 60053
A50-7622-16
REV. 7-04

Metoclopramide (Metoclopramide Hydrochloride)
PRODUCT INFO
Product Code 60432-622 Dosage Form SOLUTION
Route Of Administration ORAL DEA Schedule

INGREDIENTS
Name (Active Moiety) Type Strength
Metoclopramide Hydrochloride (Metoclopramide) Active 5 MILLIGRAM In 5 MILLILITER
artificial butterscotch flavor Inactive
natural & artificial apple flavor Inactive
citric acid anhydrous Inactive
FD&C Yellow No. 6 Inactive
glycerin Inactive
methylparaben Inactive
propylene glycol Inactive
propylparaben Inactive
water Inactive
sorbitol solution Inactive

IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color Score
Shape Symbol
Imprint Code Coating
Size

PACKAGING
# NDC Package Description Multilevel Packaging
1 60432-622-16 473 MILLILITER In 1 BOTTLE None
Revised: 03/2007

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For the official FDA label of this metoclopramide drug and for further references included in the label please visit the National Institute of Health website: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=6756

Mayne Pharma Inc. Metoclopramide Injection

DESCRIPTION

Metoclopramide Injection is a sterile, nonpyrogenic solution. Each mL contains metoclopramide 5 mg (present as the hydrochloride), and 8.5 mg sodium chloride in Water for Injection, USP. The pH is adjusted to 2.5 – 6.5, when necessary, with hydrochloric acid and/or sodium hydroxide. The solution is intended for intravenous or intramuscular administration.

CONTAINS NO PRESERVATIVE

Metoclopramide hydrochloride is a white or practically white, crystalline, odorless or practically odorless powder. It is very soluble in water, freely soluble in alcohol, sparingly soluble in chloroform, practically insoluble in ether. Chemically, it is 4-amino-5-chloro-N-[2-(diethylamino) ethyl]-2-methoxy benzamide monohydrochloride monohydrate. Its structural formula is as follows:

Mol. Wt.: 354.27 C14H22CIN3O2• HCl • H20

CLINICAL PHARMACOLOGY

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 2 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 I-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 1 to 3 minutes following an intravenous dose, 10 to 15 minutes following intramuscular administration, and 30 to 60 minutes following an oral dose; pharmacological effects persist for 1 to 2 hours.

Pharmacokinetics

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 1 to 2 hr 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 20 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 5 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.

Adult Pharmacokinetic Data

Parameter Value
Vd (L/kg) ~ 3.5
Plasma Protein Binding ~ 30%
t1/2 (hr) 5-6
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 a 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 65 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 4 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 1060 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.

Pediatric Pharmacokinetic Studies

References Dose, Route t1/2
(hr) CI
(L/hr/kg) Vd
(L/kg) Cmax
(mcg/L)
a. SEM not available.
1. Bateman, DN, et al, Br J Clin Pharmac 15:557-559, 1983.
2. Ford, C. Clin Pharmac Ther 43:196, 1988.
1. 0.35 mg/kg,
IV over 5 min 4.4±0.56 0.56±0.10 3.0±0.38
(Dose/Cp0) 152±31
2. 2 mg/kg
30 min IV
Infusion 4-5 times
within 9.5 hours 4.5a 0.37a 1.93a 1060 to 5680a
INDICATIONS AND USAGE

Diabetic Gastroparesis (Diabetic Gastric Stasis): Metoclopramide Injection is indicated for the relief of severe symptoms associated with acute and recurrent diabetic gastric stasis.

The Prevention of Nausea and Vomiting Associated with Emetogenic Cancer Chemotherapy: Metoclopramide Injection is indicated for the prophylaxis of vomiting associated with emetogenic cancer chemotherapy.

The Prevention of Postoperative Nausea and Vomiting: Metoclopramide Injection is indicated for the prophylaxis of postoperative nausea and vomiting in those circumstances where nasogastric suction is undesirable.

Small Bowel Intubation: Metoclopramide Injection may be used to facilitate small bowel intubation in adults and pediatric patients in whom the tube does not pass the pylorus with conventional maneuvers.

Radiological Examination: Metoclopramide Injection may be used to stimulate gastric emptying and intestinal transit of barium in cases where delayed emptying interferes with radiological examination of the stomach and/or small intestine.

CONTRAINDICATIONS

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.

WARNINGS

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 1 in 500 patients treated with the usual adult dosages of 30 to 40 mg/day of metoclopramide. These usually are seen during the first 24 to 48 hours of treatment with metoclopramide, occur more frequently in pediatric patients and adult patients less than 30 years of age are even more frequent at the higher doses used in prophylaxis of vomiting due to cancer chemotherapy. 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 2 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.

Tardive Dyskinesia

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with metoclopramide. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients are likely to develop the syndrome. 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.

Less commonly, the syndrome can develop after relatively brief treatment periods at low doses; in these cases, symptoms appear more likely to be reversible.

There is no known treatment for established cases of tardive dyskinesia although the syndrome 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, the use of metoclopramide for the symptomatic control of tardive dyskinesia is not recommended.

Neuroleptic Malignant 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 extrapyrimidal 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, 3) treatment of any concomitant serious medical problems for which specific treatments are available. Bromocriptine and dantroline sodium have been used in treatment of NMS, but their effectiveness have not been established (see ADVERSE REACTIONS).

PRECAUTIONS

General

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.

Intravenous injections of undiluted metoclopramide should be made slowly allowing 1 to 2 minutes for 10 mg since a transient but intense feeling of anxiety and restlessness, followed by drowsiness, may occur with rapid administration.

Because metoclopramide produces a transient increase in plasma aldosterone, certain patients, especially those with cirrhosis or congestive heart failure, may be at risk of developing fluid retention and volume overload. If this occurs at any time during metoclopramide therapy, the drug should be discontinued.

Intravenous administration of Metoclopramide Injection diluted in a parenteral solution should be made slowly over a period of not less than 15 minutes.

Giving a promotility drug such as metoclopramide theoretically could put increased pressure on suture lines following a gut anastomosis or closure. This possibility should be considered and weighed when deciding whether to use metoclopramide or nasogastric suction in the prevention of postoperative nausea and vomiting.

Information For Patients

Metoclopramide may impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle. The ambulatory patient should be cautioned accordingly.

Drug Interactions

The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics or tranquilizers.

The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxidase inhibitors.

Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine).

Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dose or timing of dosage may require adjustment.

Carcinogenesis, Mutagenesis, Impairment of Fertility

A 77-week study was conducted in rats with oral doses up to about 40 times the maximum recommended human daily dose. Metoclopramide elevates prolactin levels and the elevation persists during chronic administration. 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 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 and metoclopramide. 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.

An Ames mutagenicity test performed on metoclopramide was negative.

Pregnancy Category B

Reproduction studies performed in rats, mice, and rabbits by the I.V., I.M., S.C. and oral routes at maximum levels ranging from 12 to 250 times the human dose have demonstrated no impairment of fertility or significant harm to the fetus due to metoclopramide. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

Metoclopramide is excreted in human milk. Caution should be exercised when metoclopramide is administered to a nursing mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established except as stated to facilitate small bowel intubation (see OVERDOSAGE and DOSAGE AND ADMINISTRATION).

Care should be exercised in administering metoclopramide to neonates since prolonged clearance may produce excessive serum concentrations (see CLINICAL PHARMACOLOGY: Pharmacokinetics). In addition, neonates have reduced levels of NADH-cytochrome b5 reductase which, in combination with the aforementioned pharmacokinetic factors, make neonates more susceptible to methemoglobinemia (see OVERDOSAGE).

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.)

Geriatric Use

Clinical studies of metoclopramide did not include sufficient numbers of subjects aged 65 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 elderly (see CLINICAL PHARMACOLOGY, PRECAUTIONS Information for Patients and ADVERSE REACTIONS-CNS Effects).

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).

Other Special Populations: Patients with NADH-cytochrome b5 reductase deficiency are at an increased risk of developing methemoglobinemia and/or sulfhemoglobinemia when metoclopramide is administered. In patients with G6PD deficiency who experience metoclopramide-induced methemoglobinemia, methylene blue treatment is not recommended (see OVERDOSAGE).

ADVERSE REACTIONS

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 may occur (see PRECAUTIONS). Insomnia, headache, confusion, dizziness or mental depression with suicidal ideation may also occur (see WARNINGS). In cancer chemotherapy patients being treated with 1 to 2 mg/kg per dose, incidence of drowsiness is about 70%. There are isolated reports of convulsive seizures without clear-cut relationship to metoclopramide. Rarely, hallucinations have been reported.

Extrapyramidal 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 30 to 40 mg of metoclopramide per day. In cancer chemotherapy patients receiving 1 to 2 mg/kg per dose, the incidence is 2% in patients over the ages of 30 to 35, and 25% or higher in pediatric patients and adult patients less than 30 years of age who have not had prophylactic administration of diphenhydramine. Symptoms included 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 faces (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.

Neuroleptic Malignant Syndrome: Rare occurrences of neuroleptic malignant syndrome (NMS) have been reported. This potentially fatal syndrome is comprised of the symptom complex of hyperthermia, muscular rigidity, altered consciousness, and autonomic instability (see WARNINGS).

Endocrine Disturbances: Galactorrhea, amenorrhea, gynecomastia, impotence secondary to hyperprolactinemia (see PRECAUTIONS). Fluid retention secondary to transient elevation of aldosterone (see CLINICAL PHARMACOLOGY).

Cardiovascular: Hypotension, hypertension, supraventricular tachycardia, bradycardia, fluid retention, acute congestive heart failure and possible AV block (see CONTRAINDICATIONS and PRECAUTIONS).

Gastrointestinal: Nausea and bowel disturbance, primarily diarrhea.

Hepatic: 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.

Renal: Urinary frequency and incontinence.

Hematologic: A few cases of neutropenia, leukopenia, or agranulocytosis, generally without clear-cut relationship to metoclopramide. Methemoglobinemia in adults and especially with overdosage in neonates (see OVERDOSAGE). Sulfhemoglobinemia in adults.

Allergic Reactions: A few cases of rash, urticaria, or bronchospasm, especially in patients with a history of asthma. Rarely, angioneurotic edema, including glossal or laryngeal edema.

Miscellaneous: Visual disturbances. Porphyria. Transient flushing of the face and upper body, without alterations in vital signs, following high doses intravenously.

OVERDOSAGE

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 1 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 (see PRECAUTIONS – Other Special Populations).

DOSAGE AND ADMINISTRATION

For The Relief Of Symptoms Associated With Diabetic Gastroparesis (Diabetic Gastric Stasis): 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 (IM or IV). Doses of 10 mg may be administered slowly by the intravenous route over a 1- to 2-minute period.

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

For The Prevention Of Nausea And Vomiting Associated With Emetogenic Cancer Chemotherapy: For doses in excess of 10 mg, Metoclopramide Injection should be diluted in 50 mL of a parenteral solution.

The preferred parenteral solution is Sodium Chloride Injection (normal saline), which when combined with Metoclopramide Injection, can be stored frozen for up to 4 weeks. Metoclopramide Injection is degraded when admixed and frozen with Dextrose-5% in Water. Metoclopramide Injection diluted in Sodium Chloride Injection, Dextrose-5% in Water, Dextrose-5% in 0.45% Sodium Chloride, Ringer’s Injection or Lactated Ringer’s Injection may be stored up to 48 hours (without freezing) after preparation if protected from light. All dilutions may be stored unprotected from light under normal light conditions up to 24 hours after preparation.

Intravenous infusions should be made slowly over a period of not less than 15 minutes, 30 minutes before beginning cancer chemotherapy and repeated every 2 hours for two doses, then every 3 hours for three doses.

The initial two doses should be 2 mg/kg if highly emetogenic drugs such as cisplatin or dacarbazine are used alone or in combination. For less emetogenic regimes, 1 mg/kg per dose may be adequate.

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

For The Prevention of Postoperative Nausea and Vomiting: Metoclopramide Injection should be given intramuscularly near the end of surgery. The usual adult dose is 10 mg; however, doses of 20 mg may be used.

To Facilitate Small Bowel Intubation: If the tube has not passed the pylorus with conventional maneuvers in 10 minutes, a single dose (undiluted) may be administered slowly by the intravenous route over a 1- to 2- minute period. The recommended single dose is: Pediatric patients above 14 years of age and adults – 10 mg metoclopramide base. Pediatric patients (6 to 14 years of age) – 2.5 to 5 mg metoclopramide base; (under 6 years of age) – 0.1 mg/kg metoclopramide base.

To Aid in Radiological Examinations: In patients where delayed gastric emptying interferes with radiological examination of the stomach and/or small intestine, a single dose may be administered slowly by the intravenous route over 1- to 2- minute period.

For dosage, see intubation above.

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.

See 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.

Admixture Compatibilities: Metoclopramide Injection is compatible for mixing and injection with the following injectable products to the extent indicated below:

Physically and Chemically Compatible up to 48 hours. Cimetidine Hydrochloride, Mannitol, Potassium Acetate, Potassium Phosphate.

Physically Compatible up to 48 hours. Ascorbic Acid, Benztropine Mesylate, Cytarabine, Dexamethasone Sodium Phosphate, Diphenhydramine Hydrochloride, Doxorubicin Hydrochloride, Heparin Sodium, Hydrocortisone Sodium Phosphate, Lidocaine Hydrochloride, Multi-Vitamin Infusion (must be refrigerated), Vitamin B Complex with Ascorbic Acid.

Physically Compatible up to 24 hours (Do not use if precipitation occurs). Clindamycin Phosphate, Cyclophosphamide, Insulin.

Conditionally Compatible (Use within one hour after mixing or may be infused directly into the same running IV line). Ampicillin Sodium, Cisplatin, Erythromycin Lactobionate, Methotrexate Sodium, Penicillin G Potassium, Tetracycline Hydrochloride.

Incompatible (Do Not Mix). Cephalothin Sodium, Chloramphenicol Sodium, Sodium Bicarbonate.

Parenteral products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

HOW SUPPLIED

Metoclopramide Injection, USP – 5 mg Metoclopramide (present as the hydrochloride) per mL – is available in the following packages:
NDC 61703-210-07 2 mL Single Dose Vial
10 mg/2 mL
Package of 25 Vials
NDC 61703-210-11 10 mL Single Dose Vial
50 mg/10 mL
Package of 25 Vials
NDC 61703-210-21 20 mL Single Dose Vial
100 mg/20 mL
Package of 10 Vials
NDC 61703-210-35 30 mL Single Dose Vial
150 mg/30 mL
Package of 1 Vial

Store at controlled room temperature between 15°- 30°C (59°- 86°F). Do not permit to freeze.

PROTECT FROM LIGHT. Store vial in carton until time of use.

CONTAINS NO PRESERVATIVE. Discard unused portion.

Manufactured for:
Mayne Pharma ( USA) Inc.
Paramus, NJ 07652
By: Mayne Pharma (PR) Inc.
Aguadilla, Puerto Rico 00604
Rev. March 2004 PI005/KC

Metoclopramide (Metoclopramide)
PRODUCT INFO
Product Code 61703-210 Dosage Form INJECTION, SOLUTION
Route Of Administration INTRAVENOUS, INTRAMUSCULAR DEA Schedule

INGREDIENTS
Name (Active Moiety) Type Strength
Metoclopramide (Metoclopramide) Active 5 MILLIGRAM In 1 MILLILITER
sodium chloride Inactive
hydrochloric acid Inactive
sodium hydroxide Inactive
Water Inactive

IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color Score
Shape Symbol
Imprint Code Coating
Size

PACKAGING
# NDC Package Description Multilevel Packaging
1 61703-210-07 25 VIAL In 1 PACKAGE contains a VIAL, SINGLE-DOSE
1 2 MILLILITER In 1 VIAL, SINGLE-DOSE This package is contained within the PACKAGE (61703-210-07)
2 61703-210-11 25 VIAL In 1 PACKAGE contains a VIAL, SINGLE-DOSE
2 10 MILLILITER In 1 VIAL, SINGLE-DOSE This package is contained within the PACKAGE (61703-210-11)
3 61703-210-21 10 VIAL In 1 PACKAGE contains a VIAL, SINGLE-DOSE
3 20 MILLILITER In 1 VIAL, SINGLE-DOSE This package is contained within the PACKAGE (61703-210-21)
4 61703-210-35 1 VIAL In 1 PACKAGE contains a VIAL, SINGLE-DOSE
4 30 MILLILITER In 1 VIAL, SINGLE-DOSE This package is contained within the PACKAGE (61703-210-35)
Revised: 05/2006Mayne Pharma (USA) Inc.

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For the official FDA label of this metoclopramide drug and for further references included in the label please visit the National Institute of Health website: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1079

Baxter Healthcare Corporation Reglan Injection

DESCRIPTION

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. Molecular weight: 354.3.

C14H22ClN3O2•HCl•H2O

REGLAN Injection (metoclopramide injection, USP) is a clear, colorless, sterile solution with a pH of 4.5-6.5 for intravenous (IV) or intramuscular (IM) administration.

This product is light sensitive. It should be inspected before use and discarded if either color or particulate is observed.

2 mL single dose vials; 10 mL and 30 mL single dose vials

Each 1 mL contains: Metoclopramide base 5 mg (as the monohydrochloride monohydrate) Sodium Chloride, USP 8.5 mg, Water for Injection, USP q.s. pH adjusted, when necessary, with hydrochloric acid and/or sodium hydroxide.

CLINICAL PHARMACOLOGY

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 2 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 1 to 3 minutes following an intravenous dose, 10 to 15 minutes following intramuscular administration, and 30 to 60 minutes following an oral dose; pharmacological effects persist for 1 to 2 hours.

Pharmacokinetics

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 1-2 hr 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 20 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 5 6 hr. 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 hr. 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.

Adult Pharmacokinetic Data
Parameter Value
Vd (L/kg) ~ 3.5
Plasma Protein Binding ~ 30%
T1/2 (hr) 5-6
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 a 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 ?g/L) higher compared to that observed after the first dose (29 ?g/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 65 to 395 ?g/L (mean, 152 ?g/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 4 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 1060 to 5680 ?g/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.

Pediatric Pharmacokinetic Studies

Reference Dose, Route t1/2
(hr) Cl
(L/hr/kg) Vd
(L/kg) Cmax
(µg/L)
1
0.35 mg/kg,
IV over 5 min 4.4±0.56 0.56±0.10 3.0±0.38 (Dose/Cp0) 152±31
2
2 mg/kg 30 min IV infusion 4-5 times within 9.5 hours 4.5a 0.37a 1.93a 1060 to 5680a
a. SEM not available
________________________________________

1
Bateman, DN, et al. Br J Clin Pharmac 15:557-559, 1983.

2
Ford, C. Clin Pharmac Ther 43:196, 1988.

INDICATIONS AND USAGE

Diabetic Gastroparesis (Diabetic Gastric Stasis)

REGLAN (metoclopramide hydrochloride, USP) is indicated for the relief of symptoms associated with acute and recurrent diabetic gastric stasis.

The Prevention of Nausea and Vomiting Associated with Emetogenic Cancer Chemotherapy

REGLAN Injection is indicated for the prophylaxis of vomiting associated with emetogenic cancer chemotherapy.

The Prevention of Postoperative Nausea and Vomiting

REGLAN Injection is indicated for the prophylaxis of postoperative nausea and vomiting in those circumstances where nasogastric suction is undesirable.

Small Bowel Intubation

REGLAN Injection may be used to facilitate small bowel intubation in adults and pediatric patients in whom the tube does not pass the pylorus with conventional maneuvers.

Radiological Examination

REGLAN Injection may be used to stimulate gastric emptying and intestinal transit of barium in cases where delayed emptying interferes with radiological examination of the stomach and/or small intestine.

CONTRAINDICATIONS

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.

WARNINGS

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 1 in 500 patients treated with the usual adult dosages of 30 40 mg/day of metoclopramide. These usually are seen during the first 24 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 used in prophylaxis of vomiting due to cancer chemotherapy. 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 Benadryl® (diphenhydramine hydrochloride) intramuscularly, and they usually will subside. Cogentin® (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 2 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.

Tardive Dyskinesia

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with metoclopramide. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients are likely to develop the syndrome. 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.

Less commonly, the syndrome can develop after relatively brief treatment periods at low doses; in these cases, symptoms appear more likely to be reversible.
There is no known treatment for established cases of tardive dyskinesia although the syndrome 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, the use of metoclopramide for the symptomatic control of tardive dyskinesia is not recommended.

Neuroleptic Malignant 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).

PRECAUTIONS

General

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.

Intravenous injections of undiluted metoclopramide should be made slowly allowing 1 to 2 minutes for 10 mg since a transient but intense feeling of anxiety and restlessness, followed by drowsiness, may occur with rapid administration.

Because metoclopramide produces a transient increase in plasma aldosterone, certain patients, especially those with cirrhosis or congestive heart failure, may be at risk of developing fluid retention and volume overload. If these side effects occur at any time during metoclopramide therapy, the drug should be discontinued.

Intravenous administration of REGLAN Injection diluted in a parenteral solution should be made slowly over a period of not less than 15 minutes.

Giving a promotility drug such as metoclopramide theoretically could put increased pressure on suture lines following a gut anastomosis or closure. This possibility should be considered and weighed when deciding whether to use metoclopramide or nasogastric suction in the prevention of postoperative nausea and vomiting.

Information for Patients

Metoclopramide may impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle. The ambulatory patient should be cautioned accordingly.

Drug Interactions

The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers.

The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxidase inhibitors.

Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine).

Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment.

Carcinogenesis and Mutagenesis and Impairment of Fertility

A 77 week study was conducted in rats with oral doses up to about 40 times the maximum recommended human daily dose. Metoclopramide elevates prolactin levels and the elevation persists during chronic administration. 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 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 and metoclopramide. 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.

An Ames mutagenicity test performed on metoclopramide was negative.

Pregnancy Category B

Reproduction studies performed in rats, mice and rabbits by the IM, IV, subcutaneous (SC), and oral routes at maximum levels ranging from 12 to 250 times the human dose have demonstrated no impairment of fertility or significant harm to the fetus due to metoclopramide. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

Metoclopramide is excreted in human milk. Caution should be exercised when metoclopramide is administered to a nursing mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established except as stated to facilitate small bowel intubation (see OVERDOSAGE and DOSAGE AND ADMINISTRATION).

Care should be exercised in administering metoclopramide to neonates since prolonged clearance may produce excessive serum concentrations (see CLINICAL PHARMACOLOGY – Pharmacokinetics). In addition, neonates have reduced levels of NADH-cytochrome b5 reductase which, in combination with the aforementioned pharmacokinetic factors, make neonates more susceptible to methemoglobinemia (see OVERDOSAGE).

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.)

Geriatric Use

Clinical studies of REGLAN did not include sufficient numbers of subjects aged 65 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 REGLAN that is effective. If parkinsonian-like symptoms develop in a geriatric patient receiving REGLAN, REGLAN should generally be discontinued before initiating any specific anti-parkinsonian agents (see WARNINGS).

The elderly may be at greater risk for tardive dyskinesia (see WARNINGS – Tardive Dyskinesia).

Sedation has been reported in REGLAN users. Sedation may cause confusion and manifest as over-sedation in elderly (see CLINICAL PHARMACOLOGY, PRECAUTIONS – Information for Patientsand ADVERSE REACTIONS – CNS Effects).

REGLAN 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 function, concomitant disease, or other drug therapy in the elderly (see Use in Patients With Renal or Hepatic Impairment).

Other Special Populations

Patients with NADH-cytochrome b5 reductase deficiency are at an increased risk of developing methemoglobinemia and/or sulfhemoglobinemia when metoclopramide is administered. In patients with G6PD deficiency who experience metoclopramide-induced methemoglobinemia, methylene blue treatment is not recommended (see OVERDOSAGE).

ADVERSE REACTIONS

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 may occur in patients receiving the recommended prescribed dosage of REGLAN Injection. Insomnia, headache, confusion, dizziness, or mental depression with suicidal ideation also may occur (see WARNINGS). In cancer chemotherapy patients being treated with 1-2 mg/kg per dose, incidence of drowsiness is about 70%. There are isolated reports of convulsive seizures without clear-cut relationship to metoclopramide. Rarely, hallucinations have been reported.

Extrapyramidal 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 30 to 40 mg of metoclopramide per day. In cancer chemotherapy patients receiving 1 2 mg/kg per dose, the incidence is 2% in patients over the ages of 30 35, and 25% or higher in pediatric patients and adult patients less than 30 years of age who have not had prophylactic administration of diphenhydramine. 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.

Neuroleptic Malignant Syndrome

Rare occurrences of neuroleptic malignant syndrome (NMS) have been reported. This potentially fatal syndrome is comprised of the symptom complex of hyperthermia, muscular rigidity, altered consciousness, and autonomic instability (see WARNINGS).

Endocrine Disturbances

Galactorrhea, amenorrhea, gynecomastia, impotence secondary to hyperprolactinemia (see PRECAUTIONS). Fluid retention secondary to transient elevation of aldosterone (see CLINICAL PHARMACOLOGY).

Cardiovascular

Hypotension, hypertension, supraventricular tachycardia, bradycardia, fluid retention, acute congestive heart failure and possible atrioventricular (AV) block (see CONTRAINDICATIONS and PRECAUTIONS).

Gastrointestinal

Nausea and bowel disturbances, primarily diarrhea.

Hepatic

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.

Renal

Urinary frequency and incontinence.

Hematologic

A few cases of neutropenia, leukopenia, or agranulocytosis, generally without clear-cut relationship to metoclopramide. Methemoglobinemia in adults and especially with overdosage in neonates (see OVERDOSAGE). Sulfhemoglobinemia in adults.

Allergic Reactions

A few cases of rash, urticaria, or bronchospasm, especially in patients with a history of asthma. Rarely, angioneurotic edema, including glossal or laryngeal edema.

Miscellaneous

Visual disturbances. Porphyria.

Transient flushing of the face and upper body, without alterations in vital signs, following high doses intravenously.

OVERDOSAGE

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 REGLAN syrup. 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 4 mg/kg/day orally, intramuscularly or intravenously for 1 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 (see PRECAUTIONS – Other Special Populations).

DOSAGE AND ADMINISTRATION

For the Relief of Symptoms Associated with Diabetic Gastroparesis (Diabetic Gastric Stasis)

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 REGLAN Injection (IM or IV). Doses of 10 mg may be administered slowly by the intravenous route over a 1- to 2-minute period.

Administration of REGLAN Injection (metoclopramide injection, USP) up to 10 days may be required before symptoms subside, at which time oral administration of metoclopramide may be instituted.

For the Prevention of Nausea and Vomiting Associated with Emetogenic Cancer Chemotherapy

For doses in excess of 10 mg, REGLAN Injection should be diluted in 50 mL of a parenteral solution.

The preferred parenteral solution is Sodium Chloride Injection (normal saline), which when combined with REGLAN Injection, can be stored frozen for up to 4 weeks. REGLAN Injection is degraded when admixed and frozen with Dextrose-5% in Water. REGLAN Injection diluted in Sodium Chloride Injection, Dextrose-5% in Water, Dextrose-5% in 0.45% Sodium Chloride, Ringer’s Injection, or Lactated Ringer’s Injection may be stored up to 48 hours (without freezing) after preparation if protected from light. All dilutions may be stored unprotected from light under normal light conditions up to 24 hours after preparation.

Intravenous infusions should be made slowly over a period of not less than 15 minutes, 30 minutes before beginning cancer chemotherapy and repeated every 2 hours for two doses, then every 3 hours for three doses.

The initial two doses should be 2 mg/kg if highly emetogenic drugs such as cisplatin or dacarbazine are used alone or in combination. For less emetogenic regimens, 1 mg/kg per dose may be adequate.

If extrapyramidal symptoms should occur, inject 50 mg Benadryl® (diphenhydramine hydrochloride) intramuscularly, and EPS usually will subside.

For the Prevention of Postoperative Nausea and Vomiting

REGLAN Injection should be given intramuscularly near the end of surgery. The usual adult dose is 10 mg; however, doses of 20 mg may be used.

To Facilitate Small Bowel Intubation

If the tube has not passed the pylorus with conventional maneuvers in 10 minutes, a single dose (undiluted) may be administered slowly by the intravenous route over a 1- to 2-minute period.

The recommended single dose is: Pediatric patients above 14 years of age and adults – 10 mg metoclopramide base. Pediatric patients (6-14 years of age) – 2.5 to 5 mg metoclopramide base; (under 6 years of age) – 0.1 mg/kg metoclopramide base.

To Aid in Radiological Examinations

In patients where delayed gastric emptying interferes with radiological examination of the stomach and/or small intestine, a single dose may be administered slowly by the intravenous route over a 1- to 2-minute period.

For dosage, see intubation above.

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.

See 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.

NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

ADMIXTURES COMPATIBILITIES

REGLAN Injection (metoclopramide injection, USP) is compatible for mixing and injection with the following dosage forms to the extent indicated below:

Physically and Chemically Compatible Up to 48 Hours

Cimetidine Hydrochloride (SK&F), Mannitol, USP (Abbott), Potassium Acetate, USP (Invenex), Potassium Phosphate, USP (Invenex).

Physically Compatible Up to 48 Hours

Ascorbic Acid, USP (Abbott), Benztropine Mesylate, USP (MS&D), Cytarabine, USP (Upjohn), Dexamethasone Sodium Phosphate, USP (ESI, MS&D), Diphenhydramine Hydrochloride, USP (Parke-Davis), Doxorubicin Hydrochloride, USP (Adria), Heparin Sodium, USP (ESI), Hydrocortisone Sodium Phosphate (MS&D), Lidocaine Hydrochloride, USP (ESI), Multi-Vitamin Infusion (must be refrigerated-USV), Vitamin B Complex with Ascorbic Acid (Roche).

Physically Compatible Up to 24 Hours (Do not use if precipitation occurs)
Clindamycin Phosphate, USP (Upjohn), Cyclophosphamide, USP (Mead-Johnson), Insulin, USP (Lilly).

Conditionally Compatible (Use within one hour after mixing or may be infused directly into the same running IV line)
Ampicillin Sodium, USP (Bristol), Cisplatin (Bristol), Erythromycin Lactobionate, USP (Abbott), Methotrexate Sodium, USP (Lederle), Penicillin G Potassium, USP (Squibb), Tetracycline Hydrochloride, USP (Lederle).

Incompatible (Do Not Mix)

Cephalothin Sodium, USP (Lilly), Chloramphenicol Sodium, USP (Parke-Davis), Sodium Bicarbonate, USP (Abbott).

HOW SUPPLIED

REGLAN Injection (metoclopramide injection, USP) 5 mg metoclopramide base (as the monohydrochloride monohydrate) per mL; available in:

2 mL single dose vials in cartons of 25 (NDC 60977-451-01),
10 mL single dose vials in cartons of 25 (NDC 60977-451-02),
30 mL single dose vials in cartons of 25 (NDC 60977-451-03).
Container Total Contents# Concentration# Administration
2 mL single dose vial 10 mg 5 mg/mL FOR IV or IM ADMINISTRATION
10 mL single dose vial 50 mg 5 mg/mL FOR IV INFUSION ONLY;
DILUTE BEFORE USING
30 mL single dose vial 150 mg 5 mg/mL FOR IV INFUSION ONLY;

DILUTE BEFORE USING

# Metoclopramide base (as the monohydrochloride monohydrate)

Store vials in carton until used. Do not store open single dose vials for later use, as they contain no preservative.

This product is light sensitive. It should be inspected before use and discarded if either color or particulate is observed.

Dilutions may be stored unprotected from light under normal light conditions up to 24 hours after preparation.

REGLAN Injection should be stored at Controlled Room Temperature, 20°-25°C (68°-77°F) [see USP Controlled Room Temperature].

Reglan is a registered trademark of Schwartz Pharma, Inc.

Manufactured by
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
For Product Inquiry 1 800 ANA DRUG (1-800-262-3784)
MLT-23/2.0

Reglan (Metoclopramide hydrochloride)
PRODUCT INFO
Product Code 60977-451 Dosage Form INJECTION, SOLUTION
Route Of Administration INTRAVENOUS DEA Schedule

INGREDIENTS
Name (Active Moiety) Type Strength
Metoclopramide hydrochloride (Metoclopramide) Active 5.0 MILLIGRAM In 1.0 MILLILITER
Sodium Chloride Inactive 8.5 MILLIGRAM In 1.0 MILLILITER
Water Inactive
hydrochloric acid Inactive
sodium hydroxide Inactive

IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color Score
Shape Symbol
Imprint Code Coating
Size

PACKAGING
# NDC Package Description Multilevel Packaging
1 60977-451-02 25 VIAL In 1 CARTON contains a VIAL, SINGLE-DOSE
1 10.0 MILLILITER In 1 VIAL, SINGLE-DOSE This package is contained within the CARTON (60977-451-02)
2 60977-451-03 25 VIAL In 1 CARTON contains a VIAL, SINGLE-DOSE
2 30 MILLILITER In 1 VIAL, SINGLE-DOSE This package is contained within the CARTON (60977-451-03)
Reglan (Metoclopramide hydrochloride)
PRODUCT INFO
Product Code 60977-451 Dosage Form INJECTION, SOLUTION
Route Of Administration INTRAVENOUS, INTRAMUSCULAR DEA Schedule

INGREDIENTS
Name (Active Moiety) Type Strength
Metoclopramide hydrochloride (Metoclopramide) Active 5.0 MILLIGRAM In 1.0 MILLILITER
Sodium Chloride Inactive 8.5 MILLIGRAM In 1.0 MILLILITER
Water Inactive
hydrochloric acid Inactive
sodium hydroxide Inactive

IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color Score
Shape Symbol
Imprint Code Coating
Size

PACKAGING
# NDC Package Description Multilevel Packaging
1 60977-451-01 25 VIAL In 1 CARTON contains a VIAL, SINGLE-DOSE
1 2.0 MILLILITER In 1 VIAL, SINGLE-DOSE This package is contained within the CARTON (60977-451-01)
Revised: 04/2006

We represent all clients suffering metoclopramide tardive dyskinesia side effects on a contingency basis which means that there are never any legal fees unless we win compensation in your case. For a free no-obligation consultation please call toll free at 1-888-343-5375 or fill out our short online contact form and a Reglan attorney will contact you to answer any of your questions.

For the official FDA label of this metoclopramide drug and for further references included in the label please visit the National Institute of Health website: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=7478

Hospira, Inc. Metoclopramide Injection Solution

Ampul

Rx only

Fliptop Vial

DESCRIPTION

Metoclopramide hydrochloride is a white or practically white, crystalline, odorless or practically odorless powder. It is very soluble in water, freely soluble in alcohol, sparingly soluble in chloroform, practically insoluble in ether. Chemically it is 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide monohydrochloride monohydrate. It has the following structural formula:

Molecular formula: C14H22ClN3O2• HCl • H2O

Metoclopramide Injection, USP is a sterile, nonpyrogenic solution of metoclopramide hydrochloride in water for injection. Each milliliter contains metoclopramide base 5 mg (as the monohydrochloride monohydrate); 8.5 mg sodium chloride. May contain hydrochloric acid and/or sodium hydroxide for pH adjustment; pH 4.4 (2.5 to 6.5).
The solution contains no bacteriostat, antimicrobial agent or added buffer and is intended for use only as a single-dose injection. When smaller doses are required, the unused portion should be discarded.

This product is light sensitive. It should be inspected before use and discarded if either color or particulate is observed.

Metoclopramide Injection is intended for intravenous or intramuscular administration.

CLINICAL PHARMACOLOGY

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 2 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 1 to 3 minutes following an intravenous dose, 10 to 15 minutes following intramuscular administration, and 30 to 60 minutes following an oral dose, pharmacological effects persist for 1 to 2 hours.
Pharmacokinetics: 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 1-2 hrs 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 20 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 5-6 hrs. 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 hrs. 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.

Adult Pharmacokinetic Data

Parameter Value
Vd (L/kg) ~ 3.5
Plasma Protein Binding ~ 30%
t1/2 (hr) 5-6
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 hrs), half-life (4.1 hrs), 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 hrs, 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 nine pediatric cancer patients receiving chemotherapy (mean age, 11.7 years; range, 7 to 14 yrs) for prophylaxis of cytotoxic-induced vomiting. The metoclopramide plasma concentrations extrapolated to time zero ranged from 65 to 395 mcg/L (mean, 152 mcg/L). The mean elimination half-life, clearance, and volume of distribution of metoclopramide were 4.4 hrs (range, 1.7 to 8.3 hrs), 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 yrs) received 4 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 1060 to 5680 mcg/L. The mean elimination half-life, clearance, and volume of distribution of metoclopramide were 4.5 hrs (range, 2.0 to 12.5 hrs), 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.

Pediatric Pharmacokinetic Studies

Reference Dose, Route t1/2
(hr) CI
(L/hr/kg) Vd
(L/kg) Cmax
(mcg/L)
1. 0.35 mg/kg
IV over 5 min 4.4 ± 0.56 0.56 ± 0.10 3.0 ± 0.38
(Dose/Cp0) 152 ± 31
2. 2 mg/kg
30 min IV
infusion 4-5 times
within 9.5 hours 4.5a 0.37a 1.93a 1060 to 5680a

a. SEM not available.

1. Bateman, DN, et al. Br J Clin Pharmac 15:557-559, 1983.

2. Ford, C. Clin Pharmac Ther 43:196, 1988.

INDICATIONS AND USAGE

Diabetic Gastroparesis (Diabetic Gastric Stasis). Metoclopramide is indicated for the relief of symptoms associated with acute and recurrent diabetic gastric stasis.

The Prevention of Nausea and Vomiting Associated with Emetogenic Cancer Chemotherapy. Metoclopramide Injection, USP is indicated for the prophylaxis of vomiting associated with emetogenic cancer chemotherapy.

The Prevention of Postoperative Nausea and Vomiting. Metoclopramide Injection, USP is indicated for the prophylaxis of postoperative nausea and vomiting in those circumstances where nasogastric suction is undesirable.

Small Bowel Intubation. Metoclopramide Injection, USP may be used to facilitate small bowel intubation in adults and pediatric patients in whom the tube does not pass the pylorus with conventional maneuvers.

Radiological Examination. Metoclopramide Injection, USP may be used to stimulate gastric emptying and intestinaltransit of barium in cases where delayed emptying interferes with radiological examination of the stomach and/or small intestine.

CONTRAINDICATIONS

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.

WARNINGS

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 1 in 500 patients treated with the usual adult dosages of 30-40 mg/day of metoclopramide. These usually are seen during the first 24-48 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 used in prophylaxis of vomiting due to cancer chemotherapy. 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 Benadryl® (diphenhydramine hydrochloride) intramuscularly, and they usually will subside. Cogentin® (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 2-3 months following discontinuance of metoclopramide. Patients with pre-existing Parkinson’s disease should be given metoclopramide cautiously, if at all, since such patients may experience exacerbation of parkinsonian symptoms when taking metoclopramide.

Tardive Dyskinesia: Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with metoclopramide. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients are likely to develop the syndrome. 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.

Less commonly, the syndrome can develop after relatively brief treatment periods at low doses; in these cases, symptoms appear more likely to be reversible.

There is no known treatment for established cases of tardive dyskinesia although the syndrome 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, the use of metoclopramide for the symptomatic control of tardive dyskinesia is not recommended.

Neuroleptic Malignant 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).

PRECAUTIONS

General.

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.

Intravenous injections of undiluted metoclopramide should be made slowly allowing 1 to 2 minutes for 10 mg since a transient but intense feeling of anxiety and restlessness, followed by drowsiness, may occur with rapid administration.

Because metoclopramide produces a transient increase in plasma aldosterone, certain patients, especially those with cirrhosis or congestive heart failure, may be at risk of developing fluid retention and volume overload. If these side effects occur at any time during metoclopramide therapy,the drug should be discontinued.

Intravenous administration of Metoclopramide Injection, USP, diluted in a parenteral solution should be made slowly over a period of not less than 15 minutes.

Giving a promotility drug such as metoclopramide theoretically could put increased pressure on suture lines following a gut anastomosis or closure. This possibility should be considered and weighed when deciding whether to use metoclopramide or nasogastric suction in the prevention of postoperative nausea and vomiting.

Information for Patients.

Metoclopramide may impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle. The ambulatory patient should be cautioned accordingly.

Drug Interactions.

The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics or tranquilizers.

The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxidase inhibitors.

Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine).

Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

A 77-week study was conducted in rats with oral doses up to about 40 times the maximum recommended human daily dose. Metoclopramide elevates prolactin levels and the elevation persists during chronic administration. 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 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 and metoclopramide. 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.

An Ames mutagenicity test performed on metoclopramide was negative.

Pregnancy, Teratogenic Effects, Pregnancy Category B:

Reproduction studies performed in rats, mice, and rabbits by the IV, IM, subcutaneous (SC), and oral routes at maximum levels ranging from 12 to 250 times the human dose have demonstrated no impairment of fertility or significant harm to the fetus due to metoclopramide. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers:

Metoclopramide is excreted in human milk. Caution should be exercised when metoclopramide is administered to a nursing mother.

Pediatric Use:

Safety and effectiveness in pediatric patients have not been established except as stated to facilitate small bowel intubation (see OVERDOSAGE and DOSAGE AND ADMINISTRATION ).

Care should be exercised in administering metoclopramide to neonates since prolonged clearance may produce excessive serum concentrations (see CLINICAL PHARMACOLOGY – Pharmacokinetics).

In addition, neonates have reduced levels of NADH-cytochrome b5 reductase which, in combination with the aforementioned pharmacokinetic factors, make neonates more susceptible to methemoglobinemia (see OVERDOSAGE).

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.)

Geriatric Use:

Clinical studies of metoclopramide did not include sufficient numbers of subjects aged 65 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).

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 elderly (see CLINICAL PHARMACOLOGY, PRECAUTIONS-Information for Patients and ADVERSE REACTIONS-CNS Effects).

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 function, concomitant disease, or other drug therapy in the elderly (see USE IN PATIENTS WITH RENAL OR HEPATIC IMPAIRMENT).

Other Special Populations: Patients with NADH-cytochrome b5 reductase deficiency are at an increased risk of developing methemoglobinemia and/or sulfhemoglobinemia when metoclopramide is administered. In patients with G6PD deficiency who experience metoclopramide-induced methemoglobinemia, methylene blue treatment is not recommended (see OVERDOSAGE).

ADVERSE REACTIONS

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 may occur in patients receiving the recommended prescribed dose of metoclopramide injection. Insomnia, headache, confusion, dizziness and mental depression with suicidal ideation also may occur (see WARNINGS). In cancer chemotherapy patients being treated with 1-2 mg/kg per dose, incidence of drowsiness is about 70%. There are isolated reports of convulsive seizures without a clear-cut relationship to metoclopramide. Rarely, hallucinations have been reported.

Extrapyramidal 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 30 to 40 mg of metoclopramide per day. In cancer chemotherapy patients receiving 1-2 mg/kg per dose, the incidence is 2% in patients over the ages of 30-35, and 25% or higher in pediatric patients and adult patients less than 30 years of age who have not had prophylactic administration of diphenhydramine. 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, and foot tapping. These symptoms may disappear spontaneously or respond to a reduction in dosage.
Neuroleptic Malignant Syndrome. Rare occurrences of neuroleptic malignant syndrome (NMS) have been reported. This potentially fatal syndrome is comprised of the symptom complex of hyperthermia, muscular rigidity, altered consciousness, and autonomic instability (see WARNINGS).

Endocrine Disturbances. Galactorrhea, amenorrhea, gynecomastia, impotence secondary to hyperprolactinemia (see PRECAUTIONS). Fluid retention secondary to transient elevation of aldosterone (see CLINICAL PHARMACOLOGY ).

Cardiovascular. Hypotension, hypertension, supraventricular tachycardia, bradycardia, fluid retention, acute congestive heart failure, and possible atrioventricular (AV) block (see CONTRAINDICATIONS and PRECAUTIONS).

Gastrointestinal. Nausea and bowel disturbances, primarily diarrhea.

Hepatic. 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.

Renal. Urinary frequency and incontinence.

Hematologic. A few cases of neutropenia, leukopenia, or agranulocytosis, generally without a clear-cut relationship to metoclopramide. Methemoglobinemia, in adults and especially with overdosage in neonates (see OVERDOSAGE). Sulfhemoglobinemia in adults.

Allergic Reactions. A few cases of rash, urticaria, or bronchospasm, especially in patients with a history of asthma. Rarely, angioneurotic edema, including glossal or laryngeal edema.

Miscellaneous. Visual disturbances, Porphyria.

Transient flushing of the face and upper body, without alterations in vital signs, following high doses intravenously.

OVERDOSAGE

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 syrup. 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 1 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 (see PRECAUTIONS-Other Special Populations).

DOSAGE AND ADMINISTRATION

For the Relief of Symptoms Associated with Diabetic Gastroparesis (Diabetic Gastric Stasis): 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 (IM or IV). Doses of 10 mg may be administered slowly by the intravenous route over a 1 to 2 minute period.

Administration of Metoclopramide Injection, USP up to 10 days may be required before symptoms subside, at which time oral administration of metoclopramide may be instituted.

For the Prevention of Nausea and Vomiting Associated with Emetogenic Cancer Chemotherapy: For doses in excess of 10 mg, Metoclopramide Injection, USP should be diluted in 50 mL of a parenteral solution.

The preferred parenteral solution is Sodium Chloride Injection (normal saline), which when combined with Metoclopramide Injection, USP, can be stored frozen for up to 4 weeks. Metoclopramide Injection, USP is degraded when admixed and frozen with Dextrose-5% in Water. Metoclopramide Injection, USP diluted in Sodium Chloride Injection, Dextrose-5% in Water, Dextrose-5% in 0.45% Sodium Chloride, Ringer’s Injection, or Lactated Ringer’s Injection may be stored up to 48 hours (without freezing) after preparation if protected from light. All dilutions may be stored unprotected from light under normal light conditions up to 24 hours after preparation. Intravenous infusions should be made slowly over a period of not less than 15 minutes, 30 minutes before beginning cancer chemotherapy and repeated every 2 hours for two doses, then every 3 hours for three doses. The initial two doses should be 2 mg/kg if highly emetogenic drugs such as cisplatin or dacarbazine are used alone or in combination. For less emetogenic regimens, 1 mg/kg per dose may be adequate. If extrapyramidal symptoms should occur, inject 50 mg Benadryl® (diphenhydramine hydrochloride) intramuscularly, and EPS usually will subside.

For the Prevention of Postoperative Nausea and Vomiting: Metoclopramide Injection, USP should be given intramuscularly near the end of surgery. The usual adult dose is 10 mg; however, doses of 20 mg may be used.

To Facilitate Small Bowel Intubation: If the tube has not passed the pylorus with conventional maneuvers in 10 minutes, a single dose (undiluted) may be administered slowly by the intravenous route over a 1 to 2 minute period.

The recommended single dose is: Pediatric patients above 14 years of age and adults – 10 mg metoclopramide base. Pediatric patients (6 – 14 years of age) – 2.5 to 5 mg metoclopramide base; (under 6 years of age) – 0.1 mg/kg metoclopramide base.

To Aid in Radiological Examinations: In patients where delayed gastric emptying interferes with radiological examination of the stomach and/or small intestine, a single dose may be administered slowly by the intravenous route over a 1 to 2 minute period.

For dosage, see intubation, above.

Use in Patients with Renal or Hepatic Impairment: Since metoclopramide is excreted principally through the kidneys, in those patients whose creatinine clearanceis 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 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.

NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

ADMIXTURE COMPATIBILITIES

Metoclopramide Injection, USP is compatible for mixing and injection with the following dosage forms to the extent indicated below:

Physically and Chemically Compatible Up to 48 Hours

Cimetidine Hydrochloride (SK&F), Mannitol, USP (Hospira), Potassium Acetate, USP (Invenex), Potassium Phosphate, USP (Invenex).

Physically Compatible Up to 48 Hours

Ascorbic Acid, USP (Hospira), Benztropine Mesylate, USP (MS&D), Cytarabine, USP (Upjohn), Dexamethasone Sodium Phosphate, USP (Baxter, MS&D), Diphenhydramine Hydrochloride, USP (Parke-Davis), Doxorubicin Hydrochloride, USP (Adria), Heparin Sodium, USP (Baxter), Hydrocortisone Sodium Phosphate (MS&D), Lidocaine Hydrochloride, USP (Baxter), Multi-Vitamin Infusion (must be refrigerated-USV), Vitamin B Complex with Ascorbic Acid (Roche).

Physically Compatible Up to 24 Hours (Do not use if precipitation occurs)

Clindamycin Phosphate, USP (Upjohn), Cyclophosphamide, USP (Mead-Johnson), Insulin, USP (Lilly).

Conditionally Compatible(Use within one hour after mixing or may be infused directly into the same running I.V. line)

Ampicillin Sodium, USP (Bristol), Cisplatin (Bristol), Erythromycin Lactobionate, USP (Hospira), Methotrexate Sodium, USP (Lederle), Penicillin G Potassium, USP (Squibb), Tetracycline Hydrochloride, USP (Lederle).

Incompatible (Do Not Mix)

Cephalothin Sodium, USP (Lilly), Chloramphenicol Sodium, USP (Parke-Davis), Sodium Bicarbonate, USP (Hospira).

HOW SUPPLIED

PRESERVATIVE FREE.

Metoclopramide Injection, USP, 5 mg/mL metoclopramide base (present as the monohydrochloride monohydrate) is supplied in the following:

NDC No. Container Concentration Size Quantity
0409-3413-01 Ampul 5 mg/mL 2 mL 25 per container
0409-3414-01 Fliptop Glass Vial 5 mg/mL 2 mL 25 per tray

Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.]

Protect from light by retaining in package until time of use.

This product is light sensitive. It should be inspected before use and discarded if either color or particulate is observed.

Do not store open single-dose vials or ampuls for later use, as they contain no preservative. Discard unused portion.

Benadryl® is a registered trademark of Warner-Lambert Company.

Cogentin® is a registered trademark of Merck & Co., Inc.

Revised: October, 2006

Printed in USA EN- 1225
Hospira, Inc., Lake Forest, IL 60045 USA

Metoclopramide (Metoclopramide hydrochloride)

PRODUCT INFO
Product Code 0409-3413 Dosage Form INJECTION, SOLUTION
Route Of Administration INTRAMUSCULAR, INTRAVENOUS DEA Schedule

INGREDIENTS
Name (Active Moiety) Type Strength
metoclopramide hydrochloride (metoclopramide) Active 5 MILLIGRAM In 1 MILLILITER
Sodium Chloride Inactive 8.5 MILLIGRAM In 1 MILLILITER
Hydrochloric Acid Inactive
Sodium Hydroxide Inactive

IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color Score
Shape Symbol
Imprint Code Coating
Size

PACKAGING
# NDC Package Description Multilevel Packaging
1 0409-3413-01 16 CONTAINER In 1 CASE contains a CONTAINER
1 25 AMPULE In 1 CONTAINER This package is contained within the CASE (0409-3413-01) and contains a AMPULE
1 2 MILLILITER In 1 AMPULE This package is contained within a CONTAINER and a CASE (0409-3413-01)

Metoclopramide (Metoclopramide hydrochloride)

PRODUCT INFO
Product Code 0409-3414 Dosage Form INJECTION, SOLUTION
Route Of Administration INTRAMUSCULAR, INTRAVENOUS DEA Schedule

INGREDIENTS
Name (Active Moiety) Type Strength
metoclopramide hydrochloride (metoclopramide) Active 5 MILLIGRAM In 1 MILLILITER
Sodium Chloride Inactive 8.5 MILLIGRAM In 1 MILLILITER
Hydrochloric Acid Inactive
Sodium Hydroxide Inactive

IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color Score
Shape Symbol
Imprint Code Coating
Size

PACKAGING
# NDC Package Description Multilevel Packaging
1 0409-3414-01 4 TRAY In 1 CASE contains a TRAY
1 25 VIAL In 1 TRAY This package is contained within the CASE (0409-3414-01) and contains a VIAL
1 2 MILLILITER In 1 VIAL This package is contained within a TRAY and a CASE (0409-3414-01)

Revised: 05/2008Hospira, Inc.

We represent all clients suffering Reglan tardive dyskinesia side effects on a contingency basis which means that there are never any legal fees unless we win compensation in your case. For a free no-obligation consultation please call toll free at 1-888-343-5375 or fill out our short online contact form and a Reglan attorney will contact you to answer any of your questions.

For the official FDA label of this metoclopramide drug and for further references included in the label please visit the National Institute of Health website: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=896

Baxter Healthcare Corporation Metoclopramide Injection

DESCRIPTION

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. Molecular weight: 354.3.

C14H22CIN3O2•HCl•H2O

Metoclopramide Injection, USP is a clear, colorless, sterile solution with a pH of 4.5-6.5 for intravenous (IV) or intramuscular (IM) administration.

This product is light sensitive. It should be inspected before use and discarded if either color or particulate is observed.

2 mL single dose vials

Each 1 mL contains: Metoclopramide base 5 mg (as the monohydrochloride monohydrate) Sodium Chloride, USP 8.5 mg, Water for Injection, USP q.s. pH adjusted, when necessary, with hydrochloric acid and/or sodium hydroxide.

CLINICAL PHARMACOLOGY

Metoclopramidestimulates 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 2 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 1 to 3 minutes following an intravenous dose, 10 to 15 minutes following intramuscular administration, and 30 to 60 minutes following an oral dose; pharmacological effects persist for 1 to 2 hours.

Pharmacokinetics

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 1-2 hr 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 20 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 5 6 hr. 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 hr. 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.

Adult Pharmacokinetic Data

Parameter Value
Vd (L/kg) ~ 3.5
Plasma Protein Binding ~ 30%
t1/2 (hr) 5-6
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 weeksto 5.4 months) with GER received a 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 ?g/L) higher compared to that observed after the first dose (29 ?g/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 65 to 395 ?g/L (mean, 152 ?g/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 4 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 1060 to 5680 ?g/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.

Pediatric Pharmacokinetic Studies
*
SEM not available.
Reference Dose, Route t1/2
(hr) Cl
(L/hr/kg) Vd
(L/kg) Cmax
(µg/L)
1. 0.35 mg/kg,
IV over 5 min 4.4±0.56 0.56±0.10 3.0±0.38 (Dose/Cp0) 152±31
2. 2 mg/kg
30 min IV
infusion 4-5
times
within 9.5 hours 4.5*
0.37*
1.93*
1060 to 5680*
1. Bateman, DN, et al. Br J Clin Pharmac 15:557-559, 1983.
2. Ford, C. Clin Pharmac Ther43:196, 1988.

INDICATIONS AND USAGE

Diabetic Gastroparesis (Diabetic Gastric Stasis)

Metoclopramide Injection is indicated for the relief of symptoms associated with acute and recurrent diabetic gastric stasis.

The Prevention of Nausea and Vomiting Associated with Emetogenic Cancer Chemotherapy

Metoclopramide Injection is indicated for the prophylaxis of vomiting associated with emetogenic cancer chemotherapy.

The Prevention of Postoperative Nausea and Vomiting

Metoclopramide Injection is indicated for the prophylaxis of postoperative nausea and vomiting in those circumstances where nasogastric suction is undesirable.

Small Bowel Intubation

Metoclopramide Injection may be used to facilitate small bowel intubation in adults and pediatric patients in whom the tube does not pass the pylorus with conventional maneuvers.

Radiological Examination

Metoclopramide Injection may be used to stimulate gastric emptying and intestinal transit of barium in cases where delayed emptying interferes with radiological examination of the stomach and/or small intestine.

CONTRAINDICATIONS

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.

WARNINGS

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 1 in 500 patients treated with the usual adult dosages of 30 40 mg/day of metoclopramide. These usually are seen during the first 24 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 used in prophylaxis of vomiting due to cancer chemotherapy. 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 Benadryl®(diphenhydramine hydrochloride) intramuscularly, and they usually will subside. Cogentin®(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 2 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.

Tardive Dyskinesia

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with metoclopramide. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients are likely to develop the syndrome. 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.

Less commonly, the syndrome can develop after relatively brief treatment periods at low doses; in these cases, symptoms appear more likely to be reversible.

There is no known treatment for established cases of tardive dyskinesia although the syndrome 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, the use of metoclopramide for the symptomatic control of tardive dyskinesia is not recommended.

Neuroleptic Malignant 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).

PRECAUTIONS

General

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.

Intravenous injections of undiluted metoclopramide should be made slowly allowing 1 to 2 minutes for 10 mg since a transient but intense feeling of anxiety and restlessness, followed by drowsiness, may occur with rapid administration.

Because metoclopramide produces a transient increase in plasma aldosterone, certain patients, especially those with cirrhosis or congestive heart failure, may be at risk of developing fluid retention and volume overload. If these side effects occur at any time during metoclopramide therapy, the drug should be discontinued.

Intravenous administration of Metoclopramide Injection diluted in a parenteral solution should be made slowly over a period of not less than 15 minutes.

Giving a promotility drug such as metoclopramide theoretically could put increased pressure on suture lines following a gut anastomosis or closure. This possibility should be considered and weighed when deciding whether to use metoclopramide or nasogastric suction in the prevention of postoperative nausea and vomiting.

Information for Patients

Metoclopramide may impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle. The ambulatory patient should be cautioned accordingly.

Drug Interactions

The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers.

The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxidase inhibitors.

Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine).

Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment.

Carcinogenesis and Mutagenesis and Impairment of Fertility

A 77 week study was conducted in rats with oral doses up to about 40 times the maximum recommended human daily dose. Metoclopramide elevates prolactin levels and the elevation persists during chronic administration. 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 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 and metoclopramide. 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.

An Ames mutagenicity test performed on metoclopramide was negative.

Pregnancy Category B

Reproduction studies performed in rats, mice and rabbits by the IM, IV, subcutaneous (SC), and oral routes at maximum levels ranging from 12 to 250 times the human dose have demonstrated no impairment of fertility or significant harm to the fetus due to metoclopramide. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

Metoclopramide is excreted in human milk. Caution should be exercised when metoclopramide is administered to a nursing mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established except as stated to facilitate small bowel intubation (see OVERDOSAGE and DOSAGE AND ADMINISTRATION).

Care should be exercised in administering metoclopramide to neonates since prolonged clearance may produce excessive serum concentrations (see CLINICAL PHARMACOLOGY – Pharmacokinetics). In addition, neonates have reduced levels of NADH-cytochrome b5 reductase which, in combination with the aforementioned pharmacokinetic factors, make neonates more susceptible to methemoglobinemia (see OVERDOSAGE).

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.)

Geriatric Use

Clinical studies of metoclopramide did not include sufficient numbers of subjects aged 65 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).

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 elderly (see CLINICAL PHARMACOLOGY, PRECAUTIONS- Information for Patients and ADVERSE REACTIONS – CNS Effects).

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 function, concomitant disease, or other drug therapy in the elderly (see Use in Patients With Renal or Hepatic Impairment).

Other Special Populations

Patients with NADH-cytochrome b5 reductase deficiency are at an increased risk of developing methemoglobinemia and/or sulfhemoglobinemia when metoclopramide is administered. In patients with G6PD deficiency who experience metoclopramide-induced methemoglobinemia, methylene blue treatment is not recommended (see OVERDOSAGE).

ADVERSE REACTIONS

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 may occur in patients receiving the recommended prescribed dosage of Metoclopramide Injection. Insomnia, headache, confusion, dizziness, or mental depression with suicidal ideation also may occur (see WARNINGS). In cancer chemotherapy patients being treated with 1 2 mg/kg per dose, incidence of drowsiness is about 70%. There are isolated reports of convulsive seizures without clear-cut relationship to metoclopramide. Rarely, hallucinations have been reported.

Extrapyramidal 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 30 to 40 mg of metoclopramide per day. In cancer chemotherapy patients receiving 1 2 mg/kg per dose, the incidence is 2% in patients over the ages of 30 35, and 25% or higher in pediatric patients and adult patients less than 30 years of age who have not had prophylactic administration of diphenhydramine. 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.

Neuroleptic Malignant Syndrome

Rare occurrences of neuroleptic malignant syndrome (NMS) have been reported. This potentially fatal syndrome is comprised of the symptom complex of hyperthermia, muscular rigidity, altered consciousness, and autonomic instability (see WARNINGS).

Endocrine Disturbances

Galactorrhea, amenorrhea, gynecomastia, impotence secondary to hyperprolactinemia (see PRECAUTIONS). Fluid retention secondary to transient elevation of aldosterone (see CLINICAL PHARMACOLOGY).

Cardiovascular

Hypotension, hypertension, supraventricular tachycardia, bradycardia, fluid retention, acute congestive heart failure and possible atrioventricular (AV) block (see CONTRAINDICATIONS and PRECAUTIONS).

Gastrointestinal

Nausea and bowel disturbances, primarily diarrhea.

Hepatic

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.

Renal

Urinary frequency and incontinence.

Hematologic

A few cases of neutropenia, leukopenia, or agranulocytosis, generally without clear-cut relationship to metoclopramide. Methemoglobinemia in adults and especially with overdosage in neonates (see OVERDOSAGE). Sulfhemoglobinemia in adults.

Allergic Reactions

A few cases of rash, urticaria, or bronchospasm, especially in patients with a history of asthma. Rarely, angioneurotic edema, including glossal or laryngeal edema.

Miscellaneous

Visual disturbances. Porphyria.

Transient flushing of the face and upper body, without alterations in vital signs, following high doses intravenously.

OVERDOSAGE

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 syrup. 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 4 mg/kg/day orally, intramuscularly or intravenously for 1 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 (see PRECAUTIONS – Other Special Populations).

DOSAGE AND ADMINISTRATION

For the Relief of Symptoms Associated with Diabetic Gastroparesis (Diabetic Gastric Stasis)

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 (IM or IV). Doses of 10 mg may be administered slowly by the intravenous route over a 1- to 2-minute period.

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

For the Prevention of Nausea and Vomiting Associated with Emetogenic Cancer Chemotherapy

For doses in excess of 10 mg, Metoclopramide Injection should be diluted in 50 mL of a parenteral solution.

The preferred parenteral solution is Sodium Chloride Injection (normal saline), which when combined with Metoclopramide Injection, can be stored frozen for up to 4 weeks. Metoclopramide Injection is degraded when admixed and frozen with Dextrose-5% in Water. Metoclopramide Injection diluted in Sodium Chloride Injection, Dextrose-5% in Water, Dextrose-5% in 0.45% Sodium Chloride, Ringer’s Injection, or Lactated Ringer’s Injection may be stored up to 48 hours (without freezing) after preparation if protected from light. All dilutions may be stored unprotected from light under normal light conditions up to 24 hours after preparation.

Intravenous infusions should be made slowly over a period of not less than 15 minutes, 30 minutes before beginning cancer chemotherapy and repeated every 2 hours for two doses, then every 3 hours for three doses.

The initial two doses should be 2 mg/kg if highly emetogenic drugs such as cisplatin or dacarbazine are used alone or in combination. For less emetogenic regimens, 1 mg/kg per dose may be adequate.

If extrapyramidal symptoms should occur, inject 50 mg Benadryl® (diphenhydramine hydrochloride) intramuscularly, and EPS usually will subside.

For the Prevention of Postoperative Nausea and Vomiting

Metoclopramide Injection should be given intramuscularly near the end of surgery. The usual adult dose is 10 mg; however, doses of 20 mg may be used.

To Facilitate Small Bowel Intubation

If the tube has not passed the pylorus with conventional maneuvers in 10 minutes, a single dose (undiluted) may be administered slowly by the intravenous route over a 1- to 2-minute period.

The recommended single dose is: Pediatric patients above 14 years of age and adults – 10 mg metoclopramide base. Pediatric patients (6-14 years of age) – 2.5 to 5 mg metoclopramide base; (under 6 years of age) – 0.1 mg/kg metoclopramide base.

To Aid in Radiological Examinations

In patients where delayed gastric emptying interferes with radiological examination of the stomach and/or small intestine, a single dose may be administered slowly by the intravenous route over a 1- to 2-minute period.

For dosage, see intubation above.

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.

See 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.

NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

ADMIXTURES COMPATIBILITIES

Metoclopramide Injection is compatible for mixing and injection with the following dosage forms to the extent indicated below:

Physically and Chemically Compatible Up to 48 Hours

Cimetidine Hydrochloride (SK&F), Mannitol, USP (Abbott), Potassium Acetate, USP (Invenex), Potassium Phosphate, USP (Invenex).

Physically Compatible Up to 48 Hours

Ascorbic Acid, USP (Abbott), Benztropine Mesylate, USP (MS&D), Cytarabine, USP (Upjohn), Dexamethasone Sodium Phosphate, USP (ESI, MS&D), Diphenhydramine Hydrochloride, USP (Parke-Davis), Doxorubicin Hydrochloride, USP (Adria), Heparin Sodium, USP (ESI), Hydrocortisone Sodium Phosphate (MS&D), Lidocaine Hydrochloride, USP (ESI), Multi-Vitamin Infusion (must be refrigerated-USV), Vitamin B Complex with Ascorbic Acid (Roche).

Physically Compatible Up to 24 Hours (Do not use if precipitation occurs)

Clindamycin Phosphate, USP (Upjohn), Cyclophosphamide, USP (Mead-Johnson), Insulin, USP (Lilly).

Conditionally Compatible (Use within one hour after mixing or may be infused directly into the same running IV line)]

Ampicillin Sodium, USP (Bristol), Cisplatin (Bristol), Erythromycin Lactobionate, USP (Abbott), Methotrexate Sodium, USP (Lederle), Penicillin G Potassium, USP (Squibb), Tetracycline Hydrochloride, USP (Lederle).

Incompatible (Do Not Mix)

Cephalothin Sodium, USP (Lilly), Chloramphenicol Sodium, USP (Parke-Davis), Sodium Bicarbonate, USP (Abbott).

HOW SUPPLIED

Metoclopramide Injection, USP 5 mg metoclopramide base (as the monohydrochloride monohydrate) per mL; available in:

2 mL single dose vials in cartons of 25 (NDC 10019-450-02)
*

Metoclopramide base (as the monohydrochloride monohydrate)

Container Total Contents*
Concentration*
Administration
2 mL single
dose vial 10 mg 5 mg/mL FOR IV or IM ADMINISTRATION

Store vials in carton until used. Do not store open single dose vials for later use, as they contain no preservative.

This product is light sensitive. It should be inspected before use and discarded if either color or particulate is observed.

Dilutions may be stored unprotected from light under normal light conditions up to 24 hours after preparation.

Metoclopramide Injection should be stored at Controlled Room Temperature, 20°-25°C (68°-77°F) [see USP Controlled Room Temperature].

Manufactured by

Baxter Healthcare Corporation
Deerfield, IL 60015 USA
For Product Inquiry 1 800 ANA DRUG (1-800-262-3784)
MLT-34/1.0

Metoclopramide (Metoclopramide hydrochloride)
PRODUCT INFO
Product Code 10019-450 Dosage Form INJECTION, SOLUTION
Route Of Administration INTRAVENOUS, INTRAMUSCULAR DEA Schedule

INGREDIENTS
Name (Active Moiety) Type Strength
Metoclopramide hydrochloride (Metoclopramide) Active 5 MILLIGRAM In 1 MILLILITER
Sodium Chloride Inactive 8.50 MILLIGRAM In 1 MILLILITER
Water Inactive
hydrochloric acid Inactive
sodium hydroxide Inactive

IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color Score
Shape Symbol
Imprint Code Coating
Size

PACKAGING
# NDC Package Description Multilevel Packaging
1 10019-450-02 25 VIAL In 1 CARTON contains a VIAL, SINGLE-DOSE (10019-450-39)
1 10019-450-39 2 MILLILITER In 1 VIAL, SINGLE-DOSE This package is contained within the CARTON (10019-450-02)
Revised: 06/2006
Copyright, Privacy, Accessibility

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For the official FDA label of this metoclopramide drug and for further references included in the label please visit the National Institute of Health website: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=8423

ANI Pharmaceuticals Inc. Metoclopramide solution
5 mg/5 mL

Rx Only

DESCRIPTION

Metoclopramide Oral Solution USP is an orange-colored, 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, Methylparaben, Propylparaben, Purified Water, Saccharin Sodium, 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 C14H22CIN3O2•HCl•H2O, with a molecular weight of 354.3. Its structural formula is :

CLINICAL PHARMACOLOGY

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 gall bladder.

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 2 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 1 to 3 minutes following an intravenous dose, 10 to 15 minutes following intramuscular administration, and 30 to 60 minutes following an oral dose; pharmacological effects persist for 1 to 2 hours.

Pharmacokinetics

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 1 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 20 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 5 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.

Adult Pharmacokinetic Data

Parameter Value
Vd (L/Kg) ~3.5
Plasma Protein Binding ~30%
t ½ (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 65 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 L/kg (range, 1 to 4.8 L/kg), respectively.

In another study, nine pediatric cancer patients (age range, 1 to 9 yr) received 4 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 1060 to 5680 mcg/L. The mean elimination half-life, clearance, and volume of distribution of metoclopramide were 4.5 hr (range, 2 to 12.5 hr), 0.37 L/h/kg (range, 0.1 to 1.24 L/h/kg), and 1.93 L/kg (range, 0.95 to 5.5 L/kg), respectively.

INDICATIONS AND USAGE

The use of Metoclopramide Oral Solution is recommended for adults only. Therapy should not exceed 12 weeks in duration.

Symptomatic Gastroesophageal Reflux

Metoclopramide Oral Solution is indicated as short-term (4 to 12 weeks) therapy for adults with symptomatic, documented gastroesophageal reflux who fail to respond to conventional therapy.

The principal effect of metoclopramide is on symptoms of postprandial and daytime heartburn with less observed effect on nocturnal symptoms. If symptoms are confined to particular situations, such as following the evening meal, use of metoclopramide as single doses prior to the provocative situation should be considered, rather than using the drug throughout the day. Healing of esophageal ulcers and erosions has been endoscopically demonstrated at the end of 12- week trial using doses of 15 mg q.i.d. As there is no documented correlation between symptoms and healing of esophageal lesions, patients with documented lesions should be monitored endoscopically.

Diabetic Gastroparesis (diabetic gastric stasis)

Metoclopramide is indicated for the relief of symptoms associated with acute and recurrent diabetic gastric stasis. The usual manifestations of delayed gastric emptying (e.g., nausea, vomiting, heartburn, persistent fullness after meals and anorexia) appear to respond to metoclopramide within different time intervals. Significant relief of nausea occurs early and continues to improve over a three-week period. Relief of vomiting and anorexia may precede the relief of abdominal fullness by one week or more.

CONTRAINDICATIONS

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.

WARNINGS

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 1 in 500 patients treated with the usual adult dosages of 30 to 40 mg/day of metoclopramide. These usually are seen during the first 24 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 2 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.

Tardive Dyskinesia

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with metoclopramide. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients are likely to develop the syndrome. 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.

Less commonly, the syndrome can develop after relatively brief treatment periods at low doses; in these cases, symptoms appear more likely to be reversible.

There is no known treatment for established cases of tardive dyskinesia although the syndrome 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, the use of metoclopramide for the symptomatic control of tardive dyskinesia is not recommended.

Neuroleptic Malignant Syndrome

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).

PRECAUTIONS

General

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.

Because metoclopramide produces a transient increase in plasma aldosterone, certain patients, especially those with cirrhosis or congestive heart failure, may be at risk of developing fluid retention and volume overload. If these side effects occur at anytime during metoclopramide therapy, the drug should be discontinued.

Adverse reactions, especially those involving the nervous system, may occur after stopping the use of metoclopramide. A small number of patients may experience a withdrawal period after stopping metoclopramide that could cause dizziness, nervousness, and/or headaches.

Information for Patients

The use of metoclopramide oral solution is recommended for adults only. Metoclopramide may impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle. The ambulatory patient should be cautioned accordingly.

Drug Interactions

The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics or tranquilizers.

The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxidase inhibitors.

Absorption of drugs from the stomach may be diminished (e.g. digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine).

Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment.

Carcinogenesis, Mutagenesis, Impairment of Fertility

A 77-week study was conducted in rats with oral doses up to about 40 times the maximum recommended human daily dose. Metoclopramide elevates prolactin levels and the elevation persists during chronic administration. 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 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 and metoclopramide. 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.

An Ames mutagenicity test performed on metoclopramide was negative.

Pregnancy Category B

Reproduction studies performed in rats, mice and rabbits by the I.V., I.M., S.C. and oral routes at maximum levels ranging from 12 to 250 times the human dose have demonstrated no impairment of fertility or significant harm to the fetus due to metoclopramide. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

Metoclopramide is excreted in human milk. Caution should be exercised when metoclopramide is administered to a nursing mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established (see OVERDOSAGE).

Care should be exercised in administering metoclopramide to neonates since prolonged clearance may produce excessive serum concentrations (see CLINICAL PHARMACOLOGY-Pharmacokinetics). In addition, neonates have reduced levels of NADH-cytochrome b5 reductase, which, in combination with the aforementioned pharmacokinetic factors, make neonates more susceptible to methemoglobinemia (see OVERDOSAGE).

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.)

Geriatric Use

Clinical studies of metoclopramide did not include sufficient numbers of subjects aged 65 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 antiparkinsonian agents (see WARNINGS and DOSAGE AND ADMINISTRATION-For the Relief of Symptomatic Gastroesphogeal 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 (see CLINICAL PHARMACOLOGY, PRECAUTIONS- Information for Patients and ADVERSE REACTIONS-CNS Effects).

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 Gastroesphogeal Reflux and USE IN PATIENTS WITH RENAL OR HEPATIC IMPAIRMENT).

Other Special Populations

Patients with NADH-cytochrome b5 reductase deficiency are at an increased risk of developing methemoglobinemia and/or sulfhemoglobinemia when metoclopramide is administered. In patients with G6PD deficiency who experience metoclopramide-induced methemoglobinemia, methylene blue treatment is not recommended (see OVERDOSAGE).

ADVERSE REACTIONS

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 q.i.d. (see PRECAUTIONS). Insomnia, headache, confusion, dizziness or mental depression with suicidal ideation (see WARNINGS) occurs 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.

Extrapyramidal 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 30 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, cog-wheel 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.

Neuroleptic Malignant Syndrome

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).

Endocrine Disturbances

Galactorrhea, amenorrhea, gynecomastia, impotence secondary to hyperprolactinemia (see PRECAUTIONS). Fluid retention secondary to transient elevation of aldosterone (see CLINICAL PHARMACOLOGY).

Cardiovascular

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

Gastrointestinal

Nausea and bowel disturbances, primarily diarrhea.
Hepatic

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.

Renal

Urinary frequency and incontinence.

Hematologic

A few cases of neutropenia, leukopenia, or agranulocytosis, generally without clearcut relationship to metoclopramide. Methemoglobinemia, in adults and especially with overdosage in neonates (see OVERDOSAGE).

Sulfhemoglobinemia in adults.

Allergic Reactions

A few cases of rash, urticaria, or bronchospasm, especially in patients with a history of asthma. Rarely, angioneurotic edema, including glossal or laryngeal edema.

Miscellaneous

Visual disturbances. Porphyria.

OVERDOSAGE

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 1 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 (see PRECAUTIONS- Other Special Populations).

DOSAGE AND ADMINISTRATION

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 q.i.d. 30 minutes before each meal and at bedtime, depending upon symptoms being treated and clinical response (see CLINICAL PHARMACOLOGY and INDICATIONS AND USAGE). 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 q.i.d. 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 may be 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.

See 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.

HOW SUPPLIED

Metoclopramide Oral Solution USP, 5 mg metoclopramide base (as the monohydrochloride monohydrate) per 5 mL (teaspoonful) is available as an orange-colored, palatable, aromatic, sugar-free and alcohol-free liquid for oral administration and is available in the following size:

NDC 62559-1106-6 – bottle of 16 fl. oz. (473 mL)

Dispense in a tight, light-resistant container.

RECOMMENDED STORAGE

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

Manufactured by

ANI Pharmaceuticals, Inc.
Baltimore, MD 21244
501-110616-1
Rev 07/08

METOCLOPRAMIDE
metoclopramide hydrochloride solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 62559-1106
Route of Administration ORAL DEA Schedule

INGREDIENTS
Name (Active Moiety) Type Strength
Metoclopramide Hydrochloride (Metoclopramide) Active 5 MILLIGRAM In 5 MILLILITER
Citric Acid Anhydrous Inactive
FD&C Yellow No. 5 (tartrazine) Inactive
FD&C Red No. 40 Inactive
Methylparaben Inactive
Propylparaben Inactive
Water Inactive
Saccharin Sodium Inactive
Sorbitol Solution 70% Inactive
Vanilla Flavor Inactive

Product Characteristics
Color Score
Shape Size
Flavor Imprint Code
Contains

Packaging
# NDC Package Description Multilevel Packaging
1 62559-1106-6 473 mL (MILLILITER) In 1 BOTTLE None
Revised: 10/2008ANI Pharmaceuticals Inc.

We represent all clients suffering side effects from Reglan / metoclopramide on a contingency basis which means that there are never any legal fees unless we win compensation in your case. For a free no-obligation consultation please call toll free at 1-888-343-5375 or fill out our short online contact form and a Reglan lawyer will contact you to answer any of your questions.

For the official FDA label of this metoclopramide drug and for further references included in the label please visit the National Institute of Health website: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=8949

Actavis Elizabeth Metoclopramide Tablet

DESCRIPTION

Metoclopramide hydrochloride is a white, crystalline, odorless substance, freely soluble in water. Chemically, it is 4-amino-5-chloro-N-[2-(diethylamino)ethyl] -o-anisamide monohydrochloride monohydrate. Its molecular formula is C14H22CIN3O2•HCl•H2O. Its molecular weight is 354.27.

Each tablet, for oral administration, contains metoclopramide hydrochloride, equivalent to 10 mg of metoclopramide. In addition each tablet contains the following inactive ingredients: colloidal silicon dioxide, corn starch, magnesium stearate, mannitol and pregelatinized starch.

CLINICAL PHARMACOLOGY

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 2 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 1 to 3 minutes following an intravenous dose, 10 to 15 minutes following intramuscular administration, and 30 to 60 minutes following an oral dose; pharmacological effects persist for 1 to 2 hours.

Pharmacokinetics: 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 1 to 2 hrs. 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 20 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 5 to 6 hrs. 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 hrs. 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.

Adult Pharmacokinetic Data

Parameter Value
Vd (L/kg) ~3.5

Plasma Protein Binding ~30%

t1/2 (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 65 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 4 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 1060 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.

INDICATIONS AND USAGE

The use of metoclopramide tablets is recommended for adults only. Therapy should not exceed 12 weeks in duration.

Symptomatic Gastroesophageal Reflux: Metoclopramide tablets are indicated as short-term (4 to 12 weeks) therapy for adults with symptomatic, documented gastroesophageal reflux who fail to respond to conventional therapy.

The principal effect of metoclopramide is on symptoms of postprandial and daytime heartburn with less observed effect on nocturnal symptoms. If symptoms are confined to particular situations, such as following the evening meal, use of metoclopramide as single doses prior to the provocative situation should be considered, rather than using the drug throughout the day. Healing of esophageal ulcers and erosions has been endoscopically demonstrated at the end of a 12-week trial using doses of 15 mg q.i.d. As there is no documented correlation between symptoms and healing of esophageal lesions, patients with documented lesions should be monitored endoscopically.

Diabetic Gastroparesis (Diabetic Gastric Stasis): Metoclopramide tablets are indicated for the relief of symptoms associated with acute and recurrent diabetic gastric stasis. The usual manifestations of delayed gastric emptying (e.g., nausea, vomiting, heartburn, persistent fullness after meals and anorexia) appear to respond to metoclopramide within different time intervals. Significant relief of nausea occurs early and continues to improve over a three-week period. Relief of vomiting and anorexia may precede the relief of abdominal fullness by one week or more.

CONTRAINDICATIONS

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.

WARNINGS

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 1 in 500 patients treated with the usual adult dosages of 30 to 40 mg/day of metoclopramide. These usually are seen during the first 24 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 2 to 3 months following discontinuance of metoclopramide. Patients with pre-existing Parkinson’s disease should be given metoclopramide cautiously, if at all, since such patients may experience exacerbation of parkinsonian symptoms when taking metoclopramide.

Tardive Dyskinesia: Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with metoclopramide. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients are likely to develop the syndrome. 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.

Less commonly, the syndrome can develop after relatively brief treatment periods at low doses; in these cases, symptoms appear more likely to be reversible.

There is no known treatment for established cases of tardive dyskinesia although the syndrome 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, the use of metoclopramide for the symptomatic control of tardive dyskinesia is not recommended.

Neuroleptic Malignant 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).

PRECAUTIONS

General

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.

Because metoclopramide produces a transient increase in plasma aldosterone, certain patients, especially those with cirrhosis or congestive heart failure, may be at risk of developing fluid retention and volume overload. If these side effects occur at any time during metoclopramide therapy, the drug should be discontinued.

Adverse reactions, especially those involving the nervous system, may occur after stopping the use of metoclopramide. A small number of patients may experience a withdrawal period after stopping metoclopramide that could include dizziness, nervousness, and/or headaches.

Information for Patients

The use of metoclopramide is recommended for adults only. Metoclopramide may impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle. The ambulatory patient should be cautioned accordingly.

Drug Interactions

The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics or tranquilizers.

The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxidase inhibitors.

Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine).

Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment.

Carcinogenesis, Mutagenesis, Impairment of Fertility

A 77-week study was conducted in rats with oral doses up to about 40 times the maximum recommended human daily dose. Metoclopramide elevates prolactin levels and the elevation persists during chronic administration. 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 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 and metoclopramide. 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.

An Ames mutagenicity test performed on metoclopramide was negative.

Pregnancy Category B: Reproduction studies performed in rats, mice, and rabbits by the I.V., I.M., S.C., and oral routes at maximum levels ranging from 12 to 250 times the human dose have demonstrated no impairment of fertility or significant harm to the fetus due to metoclopramide. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

Metoclopramide is excreted in human milk. Caution should be exercised when metoclopramide is administered to a nursing mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established (see OVERDOSAGE).

Care should be exercised in administering metoclopramide to neonates since prolonged clearance may produce excessive serum concentrations (see CLINICAL PHARMACOLOGY – Pharmacokinetics). In addition, neonates have reduced levels of NADH-cytochrome b5 reductase which, in combination with the aforementioned pharmacokinetic factors, make neonates more susceptible to methemoglobinemia (see OVERDOSAGE).

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.)

Geriatric Use

Clinical studies of metoclopramide did not include sufficient numbers of subjects aged 65 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 (see CLINICAL PHARMACOLOGY, PRECAUTIONS – Information for Patients and ADVERSE REACTIONS – CNS Effects).

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 function, concomitant disease, or other drug therapy in the elderly (see DOSAGE AND ADMINISTRATION – For the Relief of Symptomatic Gastroesophageal Refluxand Use in Patients with Renal or Hepatic Impairment).

Other Special Populations: Patients with NADH-cytochrome b5 reductase deficiency are at an increased risk of developing methemoglobinemia and/or sulfhemoglobinemia when metoclopramide is administered. In patients with G6PD deficiency who experience metoclopramide-induced methemoglobinemia, methylene blue treatment is not recommended (see OVERDOSAGE).

ADVERSE REACTIONS

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 q.i.d. (see PRECAUTIONS). 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.

Extrapyramidal 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 30 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.

Neuroleptic Malignant Syndrome: 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).

Endocrine Disturbances: Galactorrhea, amenorrhea, gynecomastia, impotence secondary to hyperprolactinemia (see PRECAUTlONS). Fluid retention secondary to transient elevation of aldosterone (see CLINICAL PHARMACOLOGY).

Cardiovascular: Hypotension, hypertension, supraventricular tachycardia, bradycardia, fluid retention, acute congestive heart failure and possible AV block (see CONTRAINDICATIONSand PRECAUTIONS).

Gastrointestinal: Nausea and bowel disturbances, primarily diarrhea.

Hepatic: 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.

Renal: Urinary frequency and incontinence.

Hematologic: A few cases of neutropenia, leukopenia, or agranulocytosis, generally without clearcut relationship to metoclopramide. Methemoglobinemia, in adults and especially with overdosage in neonates (see OVERDOSAGE).

Sulfhemoglobinemia in adults.

Allergic Reactions: A few cases of rash, urticaria, or bronchospasm, especially in patients with a history of asthma. Rarely, angioneurotic edema, including glossal or laryngeal edema.

Miscellaneous: Visual disturbances. Porphyria.

OVERDOSAGE

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 1 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 (see PRECAUTIONS – Other Special Populations).

DOSAGE AND ADMINISTRATION

Therapy with metoclopramide tablets should not exceed 12 weeks in duration.

For The Relief Of Symptomatic Gastroesophageal Reflux: Administer from 10 mg to

15 mg of metoclopramide tablets, USP orally up to q.i.d. 30 minutes before each meal and at bedtime, depending upon symptoms being treated and clinical response (see CLINICAL PHARMACOLOGY and INDICATIONS AND USAGE). 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 q.i.d. 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 may be 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, inthose 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 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.

HOW SUPPLIED

10 mg – Each white, round tablet imprinted with on one side and 269 and bisect on the other side contains 10 mg of metoclopramide (as the hydrochloride). Tablets are supplied in bottles of 100 (NDC 0228-2269-10) and 500 (NDC 0228-2269-50).

Dispense in a tight, light-resistant container as defined in the USP.

Store at 20°-25°C (68° – 77°F) (See USP Controlled Room Temperature).

Manufactured by:
Actavis Elizabeth LLC
Elizabeth, NJ 07207 USA
40-9003
Revised – April 2006

METOCLOPRAMIDE
metoclopramide tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0228-2269
Route of Administration ORAL DEA Schedule

INGREDIENTS
Name (Active Moiety) Type Strength
Metoclopramide (Metoclopramide) Active 10 MILLIGRAM In 1 TABLET
colloidal silicon dioxide Inactive
corn starch Inactive
magnesium stearate Inactive
mannitol Inactive
pregelatinized starch Inactive

Product Characteristics
Color white Score 2 pieces
Shape ROUND Size 8mm
Flavor Imprint Code R269
Contains
Coating false Symbol true

Packaging
# NDC Package Description Multilevel Packaging
1 0228-2269-10 100 TABLET In 1 BOTTLE None
2 0228-2269-50 500 TABLET In 1 BOTTLE None
Revised: 12/2008Actavis Elizabeth LLC