Metoclopramide (Page 5 of 7)

8.6 Renal Impairment

The clearance of metoclopramide is decreased and the systemic exposure is increased in patients with moderate to severe renal impairment compared to patients with normal renal function, which may increase the risk of adverse reactions. Reduce the metoclopramide dosage in patients with moderate and severe renal impairment (creatinine clearance less than or equal to 60 mL/minute), including those receiving hemodialysis and continuous ambulatory peritoneal dialysis [see Dosage and Administration (2.2, 2.3), Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Patients with severe hepatic impairment (Child-Pugh C) have reduced systemic metoclopramide clearance (by approximately 50%) compared to patients with normal hepatic function. The resulting increase in metoclopramide blood concentrations increases the risk of adverse reactions. There is no pharmacokinetic data in patients with moderate hepatic impairment (Child-Pugh B). Reduce metoclopramide dosage in patients with moderate or severe (Child-Pugh B or C) hepatic impairment [see Dosage and Administration (2.2, 2.3)]. There is no dosage adjustment required for patients with mild hepatic impairment (Child-Pugh A).

In addition, metoclopramide, by producing a transient increase in plasma aldosterone, may increase the risk of fluid retention in patients with hepatic impairment [see Warnings and Precautions (5.6) ].

Monitor patients with hepatic impairment for the occurrence of fluid retention and volume overload.

8.8 NADH-Cytochrome b5 Reductase Deficiency

Metoclopramide-treated patients with NADH-cytochrome b5 reductase deficiency are at an increased risk of developing methemoglobinemia and/or sulfhemoglobinemia. For patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with metoclopramide-induced methemoglobinemia, methylene blue treatment is not recommended. Methylene blue may cause hemolytic anemia in patients with G6PD deficiency, which may be fatal [see Overdosage (10) ].

8.9 CYP2D6 Poor Metabolizers

Metoclopramide is a substrate of CYP2D6. The elimination of metoclopramide may be slowed in patients who are CYP2D6 poor metabolizers (compared to patients who are CYP2D6 intermediate, extensive, or ultra-rapid metabolizers); possibly increasing the risk of dystonic and other adverse reactions to metoclopramide [see Clinical Pharmacology (12.3) ]. Reduce the metoclopramide dosage in patients who are poor CYP2D6 metabolizers [see Dosage and Administration (2.2, 2.3)].


Manifestations of metoclopramide overdosage included drowsiness, disorientation, extrapyramidal reactions, other adverse reactions associated with metoclopramide use (including, e.g., methemoglobinemia), and sometimes death. Neuroleptic malignant syndrome (NMS) has been reported in association with metoclopramide overdose and concomitant treatment with another drug associated with NMS [see Warnings and Precautions (5.1, 5.2, 5.3)].

There are no specific antidotes for metoclopramide overdosage. If over-exposure occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage.

Methemoglobinemia can be reversed by the intravenous administration of methylene blue. However, methylene blue may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, which may be fatal.

Hemodialysis and continuous ambulatory peritoneal dialysis do not remove significant amounts of metoclopramide.


Metoclopramide hydrochloride, USP, the active ingredient of metoclopramide tablets, USP is a dopamine-2 receptor antagonist. Metoclopramide hydrochloride (metoclopramide monohydrochloride monohydrate) 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 and 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:

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C14 H22 ClN3 O2 •HCl•H2 O M.W. 354.3

Metoclopramide tablets, USP are for oral administration. Metoclopramide tablets, USP are available in 5 mg and 10 mg tablets.

  • Each metoclopramide tablet USP, 5 mg contains 5 mg metoclopramide (equivalent to 5.91 mg of metoclopramide hydrochloride, USP).
  • Each metoclopramide tablet USP, 10 mg contains 10 mg metoclopramide (equivalent to 11.82 mg of metoclopramide hydrochloride, USP).

Inactive Ingredients

Corn starch, dibasic calcium phosphate anhydrous, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate.


12.1 Mechanism of Action

Metoclopramide stimulates motility of the upper gastrointestinal tract without stimulating gastric, biliary, or pancreatic secretions. The exact mechanism of action of metoclopramide in the treatment of gastroesophageal reflux and acute and recurrent diabetic gastroparesis has not been fully established. 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.

12.2 Pharmacodynamics

Gastroesophageal Reflux

In patients with gastroesophageal reflux and low lower esophageal sphincter pressure (LESP), single oral doses of metoclopramide produced dose-related increases in LESP. Effects began at about 5 mg and increased through 20 mg. The increase in LESP from a 5 mg dose lasted about 45 minutes and that of 20 mg lasted between 2 and 3 hours. Increased rate of stomach emptying was observed with single oral doses of 10 mg.

12.3 Pharmacokinetics


Relative to an intravenous dose of 20 mg, the absolute bioavailability of oral metoclopramide is 80% ± 15.5% as demonstrated in a crossover study of 18 subjects. Peak plasma concentrations occurred at about 1 to 2 hours after a single oral dose. Similar time to peak was observed after individual doses at steady state.

In a single dose study of 12 subjects, the area under the drug concentration-time curve increased linearly with doses from 20 to 100 mg (5 times the maximum recommended single dose). Peak concentrations increased linearly with dose; time to peak concentrations remained the same; whole body clearance was unchanged; and the elimination rate remained the same. The mean elimination half-life in subjects with normal renal function was 5 to 6 hours. Linear kinetic processes adequately describe the absorption and elimination of metoclopramide.


Metoclopramide 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.


Metabolism: Metoclopramide undergoes enzymatic metabolism via oxidation as well as glucuronide and sulfate conjugation reactions in the liver. Monodeethylmetoclopramide, a major oxidative metabolite, is formed primarily by CYP2D6, an enzyme subject to genetic variability [see Dosage and Administration (2.2, 2.3), Use in Specific Populations (8.9)].

Excretion: Approximately 85% of the radioactivity of an orally administered dose appeared in the urine within 72 hours. After oral administration of 10 or 20 mg, a mean of 18% and 22% of the dose, respectively, was recovered as free metoclopramide in urine within 36 hours.

Specific Populations

Patients with Renal Impairment: In a study of 24 patients with varying degrees of renal impairment (moderate, severe, and end-stage renal disease (ESRD) requiring dialysis), the systemic exposure (AUC) of metoclopramide in patients with moderate to severe renal impairment was about 2-fold the AUC in subjects with normal renal function. The AUC of metoclopramide in patients with ESRD on dialysis was about 3.5-fold the AUC in subjects with normal renal function [see Dosage and Administration (2.2, 2.3) and Use in Specific Populations (8.6)].

Patients with Hepatic Impairment: In a group of 8 patients with severe hepatic impairment (Child-Pugh C), the average metoclopramide clearance was reduced by approximately 50% compared to patients with normal hepatic function [see Dosage and Administration (2.2, 2.3) and Use in Specific Populations (8.7)].

Drug Interaction Studies

Effect of Metoclopramide on CYP2D6 Substrates
Although in vitro studies suggest that metoclopramide can inhibit CYP2D6, metoclopramide is unlikely to interact with CYP2D6 substrates in vivo at therapeutically relevant concentrations.

Effect of CYP2D6 Inhibitors on Metoclopramide
In healthy subjects, 20 mg of metoclopramide and 60 mg of fluoxetine (a strong CYP2D6 inhibitor) were administered, following prior exposure to 60 mg fluoxetine orally for 8 days. The patients who received concomitant metoclopramide and fluoxetine had a 40% and 90% increase in metoclopramide Cmax and AUC0-∞ , respectively, compared to patients who received metoclopramide alone (see Table 5) [see Drug Interactions (7.1) ].

Table 5. Metoclopramide Pharmacokinetic Parameters in Healthy Subjects with and without Fluoxetine


Metoclopramide alone
(mean SD)

Metoclopramide with fluoxetine
(mean SD)

Cmax (ng/mL)

44 ± 15

62.7 ± 9.2

AUC0-∞ (ng∙h/mL)

313 ± 113

591 ± 140

t1/2 (h)

5.5 ± 1.1

8.5 ± 2.2

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