Metoclopramide: Package Insert and Label Information
METOCLOPRAMIDE- metoclopramide hydrochloride injection, solution
Medical Purchasing Solutions, LLC
Injection, USP
Fliptop Vial
Rx only
WARNING: TARDIVE DYSKINESIA
Treatment with metoclopramide can cause tardive dyskinesia, a serious movement disorder that is often irreversible. The risk of developing tardive dyskinesia increases with duration of treatment and total cumulative dose.
Metoclopramide therapy should be discontinued in patients who develop signs or symptoms of tardive dyskinesia. There is no known treatment for tardive dyskinesia. In some patients, symptoms may lessen or resolve after metoclopramide treatment is stopped.
Treatment with metoclopramide for longer than 12 weeks should be avoided in all but rare cases where therapeutic benefit is thought to outweigh the risk of developing tardive dyskinesia (see WARNINGS).
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: C 14 H 22 ClN 3 O 2 • HCl • H 2 O
Metoclopramide Injection, USP is a sterile, nonpyrogenic solution of metoclopramide hydrochloride in water for injection. Each milliliter contains metoclopramide base 5 mg (as the hydrochloride 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-use 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 to 2 hours after a single oral dose. Similar time to peak is observed after individual doses at steady state.
In a single-use 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.
| Parameter | Value |
| Vd (L/kg) | ~3.5 |
| Plasma Protein Binding | ~30% |
| t 1/2 (hr) | 5 to 6 |
| Oral Bioavailability | 80% ± 15.5% |
In pediatric patients, the pharmacodynamics of metoclopramide following oral and intravenous administration are highly variable and a concentration-effect relationship has not been established.
There are insufficient reliable data to conclude whether the pharmacokinetics of metoclopramide in adults and the pediatric population are similar. Although there are insufficient data to support the efficacy of metoclopramide in pediatric patients with symptomatic gastroesophageal reflux (GER) or cancer chemotherapy-related nausea and vomiting, its pharmacokinetics have been studied in these patient populations.
In an open-label study, six pediatric patients (age range, 3.5 weeks to 5.4 months) with GER received metoclopramide 0.15 mg/kg oral solution every 6 hours for 10 doses. The mean peak plasma concentration of metoclopramide after the tenth dose was 2-fold (56.8 mcg/L) higher compared to that observed after the first dose (29 mcg/L) indicating drug accumulation with repeated dosing. After the tenth dose, the mean time to reach peak concentrations (2.2 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.
| 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. | |||||||
| Reference | Dose, Route | t 1/2 (hr) | CI (L/hr/kg) | Vd (L/kg) | C max (mcg/L) | ||
| 1. | 0.35 mg/kg IV over 5 min | 4.4 ± 0.56 | 0.56 ± 0.10 | 3.0 ± 0.38 (Dose/Cp 0) | 152 ± 31 | ||
| 2. | 2 mg/kg 30 min IV infusion 4 to 5 times within 9.5 hours | 4.5 a | 0.37 a | 1.93 a | 1060 to 5680 a | ||
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 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
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).
Extrapyramidal Symptoms (EPS)
Acute Dystonic Reactions
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 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.
Tardive Dyskinesia (see Boxed Warnings)
Treatment with metoclopramide can cause tardive dyskinesia (TD), a potentially irreversible and disfiguring disorder characterized by involuntary movements of the face, tongue, or extremities. The risk of tardive dyskinesia increases with the duration of treatment and the total cumulative dose. An analysis of utilization patterns showed that about 20% of patients who used metoclopramide took it longer than 12 weeks. Treatment with metoclopramide for longer than the recommended 12 weeks should be avoided in all but rare cases where therapeutic benefit is thought to outweigh the risk of developing TD.
Although the risk of developing TD in the general population may be increased among the elderly, women, and diabetics, it is not possible to predict which patients will develop metoclopramide-induced TD. Both the risk of developing TD and the likelihood that TD will become irreversible increase with duration of treatment and total cumulative dose.
Metoclopramide should be discontinued in patients who develop signs or symptoms of TD. There is no known effective treatment for established cases of TD, although in some patients, TD may remit, partially or completely, within several weeks to months after metoclopramide is withdrawn.
Metoclopramide itself may suppress, or partially suppress, the signs of TD, thereby masking the underlying disease process. The effect of this symptomatic suppression upon the long-term course of TD is unknown. Therefore, metoclopramide should not be used for the symptomatic control of TD.
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