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Metozolv

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Metozolv ODT

CLINICAL PHARMACOLOGY

Mechanism of Action

Metoclopramide stimulates motility of the upper gastrointestinal tract without stimulating gastric, biliary, or pancreatic secretions. While its mode of action is unclear, it appears to sensitize tissues to the action of acetylcholine. The effect on motility is not dependent on intact vagal innervation, but 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.

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 1-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 [see WARNINGS AND PRECAUTIONS]. 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.

Pharmacodynamics

The onset of pharmacological action of metoclopramide is 30 to 60 minutes following an oral dose; pharmacological effects persist for 1 to 2 hours. 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 a 20 mg dose lasts between 2 and 3 hours. Increased rate of stomach emptying has been observed with single oral doses of 10 mg.

The principal effect of metoclopramide is on symptoms of post-prandial 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 taken four times a day. As there is no documented correlation between symptoms and healing of esophageal lesions, patients with documented lesions should be monitored endoscopically. For gastroparesis, the usual manifestations of delayed gastric emptying (e.g., nausea, vomiting, heartburn, persistent fullness after meals, and anorexia) appear to respond within different time intervals.

Pharmacokinetics

Adult PK of METOZOLV ODT

In a randomized, two-arm, two-way crossover study in 44 healthy adult (male and female) fasted subjects, METOZOLV ODT was bioequivalent to Reglan Tablets.

In a food-effect study with 28 subjects, METOZOLV ODT taken immediately after a high-fat meal had a 17% lower peak blood level than when taken after an overnight fast. The time to peak blood levels increased from about 1.75 hours under fasted conditions to 3 hours when taken immediately after a high-fat meal. The extent of metoclopramide absorbed (area under the curve) was comparable whether METOZOLV ODT was administered with or without food. The clinical effect of the decrease in peak plasma level if METOZOLV ODT is inadvertently taken with food is unknown.

Adult PK of Metoclopramide

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. A single dose study of 12 subjects showed that the area under the drug concentration-time curve increases linearly with doses from 20 to 100 mg (results summarized in Table 2). 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.

Table 2: Adult Pharmacokinetic Data

Parameter Value
Vd(L/kg) ~3.5
Plasma Protein Binding ~ 30%
T1/2 5 to 6 hours
Oral Bioavailability 80% ±15.5%

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.

The in vivo disintegration time (time reported between placing the tablet on the tongue and it completely disintegrated into fine particles) was approximately one minute (with a range of 10 seconds to 14 minutes). In the two clinical trials (N = 96) with a mean ± SD being 76.8 ± 110.6 seconds and a median of 53.5 seconds.

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

Last reviewed on RxList: 10/17/2011
This monograph has been modified to include the generic and brand name in many instances.

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