1.1 Symptomatic Gastroesophageal Reflux Disease

METOZOLV®ODT is indicated as short-term (4 to 12 weeks) therapy for adults with symptomatic, documented gastroesophageal reflux disease (GERD) who fail to respond to conventional therapy.

1.2 Diabetic Gastroparesis (Diabetic Gastric Stasis)

METOZOLV ODT is indicated for the relief of symptoms associated with acute and recurrent diabetic gastroparesis (gastric stasis) in adults.

1.3 Important Limitations

METOZOLV ODT is indicated for adults only.  Therapy should not exceed 12 weeks in duration.  The safety and effectiveness in pediatric patients have not been established.

2.1 Important Instructions for Use

Take on an empty stomach at least 30 minutes before eating since food can decrease the peak concentrations of drug in the bloodstream and/or the time it takes to achieve the maximum drug level in the bloodstream [see Clinical Pharmacology (12.3)].  Do not repeat dose if inadvertently taken with food.

Since the tablet absorbs moisture rapidly, only remove each dose from the packaging just prior to taking.  Handle the tablet with dry hands and place on the tongue.  If the tablet should break or crumble while handling, discard and remove a new tablet.

METOZOLV ODT disintegrates on the tongue in approximately one minute (with a range of 10 seconds to 14 minutes). METOZOLV ODT is designed to be taken without liquid; however, the effect on the pharmacokinetics of METOZOLV ODT taken with liquid is unknown.

2.2 Symptomatic Gastroesophageal Reflux Disease

For the relief of symptomatic, documented gastroesophageal reflux disease (GERD), therapy should not exceed 12 weeks in duration. 

Take 10 mg to 15 mg dose of METOZOLV ODT up to four times daily (e.g., at least 30 minutes before each meal and at bedtime).  Doses may vary depending upon the symptoms being treated and the clinical response.  If symptoms only occur intermittently or at specific times of the day, metoclopramide may be used in single doses up to 20 mg prior to the symptoms rather than continuous treatment.

Since there is a poor correlation between symptomatic relief and healing of esophageal lesions, any therapy directed at esophageal lesions is best confirmed by endoscopic evaluation.  Although experience with the effects of metoclopramide on esophageal erosions and ulcerations is limited, healing was documented in a controlled trial using four times daily therapy at 15 mg/dose.  Prolonged treatment (>12 weeks) with metoclopramide should be avoided in all but rare cases where therapeutic benefit is thought to counterbalance the risks to the patient of developing tardive dyskinesia. [see Warnings and Precautions (5.1)]

2.3 Diabetic Gastroparesis (Diabetic Gastric Stasis)

For the relief of symptoms associated with diabetic gastroparesis (diabetic gastric stasis), therapy of two to eight weeks is recommended.  Therapy should not exceed 12 weeks in duration. 

Take a 10 mg dose of METOZOLV ODT up to four times a day (e.g., at least 30 minutes before each meal and at bedtime). 

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 METOZOLV ODT may be initiated.  However, if severe symptoms are present, therapy should begin with metoclopramide injection.

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, METOZOLV ODT therapy should be reinstituted at the earliest manifestation.

2.4 Renal Impairment

Some patients, such as the elderly or those with impaired kidney function (creatinine clearance below 40 mL/min) may be more sensitive to the therapeutic dose or the adverse effects of metoclopramide.  Therefore, these patients should start therapy at a lower dose (approximately half the recommended dosage) and the dose should be titrated according to their overall clinical response and/or adverse event profile. Dialysis is not likely to be an effective method of drug removal in overdose situations.

4.1 Intestinal Obstruction, Hemorrhage, or Perforation

Do not use metoclopramide whenever stimulation of gastrointestinal motility may be dangerous such as in the presence of gastrointestinal hemorrhage, mechanical obstruction, or perforation.

4.2 Pheochromocytoma

Metoclopramide is contraindicated in patients with pheochromocytoma because the drug may precipitate a hypertensive crisis, most likely due to release of catecholamines from the tumor.  Such hypertensive crises may be controlled by phentolamine. 

4.3 Known Sensitivity or Intolerance

Metoclopramide is contraindicated in patients with known sensitivity or intolerance to the drug. 

4.4 Epilepsy

Do not use metoclopramide in patients with epilepsy since the frequency and severity of seizures may be increased.

4.5 Concomitant Medications with Extrapyramidal Reactions

Do not use metoclopramide in patients receiving other drugs which are likely to cause extrapyramidal reactions, since the frequency and severity of extrapyramidal reactions may be increased [see Warnings and Precautions (5.2), Adverse Reactions (6.2) and Drug Interactions (7.5)].

5.1 Tardive Dyskinesia

(see Boxed Warning)

Treatment with metoclopramide can cause tardive dyskinesia (TD), a potentially irreversible and disfiguring disorder characterized by involuntary movements of the face, tongue, or extremities. The risk of developing tardive dyskinesia increases with 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 for longer than 12 weeks.  Treatment with metoclopramide for longer than the recommended 12 weeks should be avoided in all but rare cases where therapeutic benefit is thought to outweigh the risk of developing TD.

Although the risk of developing TD in the general population may be increased among the elderly, women, and diabetics, it is not possible to predict which patients will develop metoclopramide-induced TD.  Both the risk of developing TD and the likelihood that TD will become irreversible increase with duration of treatment and total cumulative dose.

Metoclopramide should be discontinued in patients who develop signs or symptoms of TD.  There is no known effective treatment for established cases of TD, although in some patients, TD may remit, partially or completely, within several weeks to months after metoclopramide is withdrawn. 

Metoclopramide itself may suppress, or partially suppress, the signs of TD, thereby masking the underlying disease process.  The effect of this symptomatic suppression upon the long-term course of TD is unknown. Therefore, metoclopramide should not be used for the symptomatic control of TD.

5.2 Acute Dystonic Reactions, Drug-induced Parkinsonism, and Other Extrapyramidal Symptoms

Extrapyramidal symptoms (EPS), 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 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 occur, inject 50 mg diphenhydramine hydrochloride intramuscularly. Benztropine mesylate, 1 to 2 mg intramuscularly, may also be used to reverse these reactions.

Drug-induced Parkinsonism can occur during metoclopramide therapy, more commonly within the first 6 months after beginning treatment, but also after longer periods.  Parkinsonian symptoms generally subside within 2 to 3 months following discontinuation of metoclopramide.  Patients with a history of Parkinson’s disease should be given metoclopramide cautiously, if at all, since such patients can experience exacerbation of Parkinsonian symptoms when taking metoclopramide.

5.3 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) 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 immediate discontinuation of metoclopramide and other drugs not essential to concurrent therapy; intensive symptomatic treatment and medical monitoring; and, 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 has not been established [see Adverse Reactions (6)].

5.4 Depression

Depression associated with metoclopramide use has occurred in patients with and without a history of depression.  Symptoms ranged from mild to severe and included suicidal ideation and suicide.  For those patients with a prior history of depression, metoclopramide should only be given if the expected benefits outweigh the potential risks.

5.5 Hypertension

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.  There are also clinical reports of hypertensive crises in some patients with undiagnosed pheochromocytoma, thus any rapid rise in blood pressure associated with METOZOLV ODT use should result in immediate cessation of metoclopramide use in those patients [see Contraindications (4.2)].

5.6 Congestive Heart Failure and Ventricular Arrhythmia

Since metoclopramide produces a transient increase in plasma aldosterone, patients 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 in any patients during metoclopramide therapy, the drug should be discontinued.

5.7 Withdrawal from Metoclopramide

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

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.

A total of 86 subjects entered three studies with METOZOLV ODT; 12 subjects entered a pilot bioavailability study (BA); 44 subjects entered a bioequivalence (BE) study, and 30 subjects entered a food-effect study.  The adverse reactions from the BE and food-effect study are summarized in Table 1.  The pilot BA study data are not included because it was performed with a formulation different from the METOZOLV ODT formulation.    

The adverse experience profile seen with METOZOLV ODT was similar to metoclopramide tablets.  Thirty-three (33) adverse reactions were reported after receiving METOZOLV ODT and 30 adverse reactions were reported after receiving metoclopramide tablets.

The most frequently reported adverse reactions (greater than 2%) associated with METOZOLV ODT were:  nausea, vomiting, fatigue, somnolence and headache.  The most frequently reported adverse reactions (greater than 2%) associated with metoclopramide tablets were:  nausea, headache, fatigue, somnolence, and dizziness.  The combined data from the fasted BE study and the food-effect study did not demonstrate any significant differences in the adverse event profile for METOZOLV ODT compared to metoclopramide tablets.

6.2 Post-Marketing Experience

The following adverse reactions are from the cumulative post-marketing experience with metoclopramide tablets.  Since the reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

CNS Effects:  Restlessness, drowsiness, fatigue, and lassitude occur in approximately 10% of patients receiving the most commonly prescribed dosage of 10 mg four times a day.  Insomnia, headache, confusion, dizziness, or depression with suicidal ideation occurs less frequently.  The incidence of drowsiness is greater at higher doses.  There are isolated reports of seizures without clear-cut relationship to metoclopramide.  Rarely, hallucinations have been reported.

Extrapyramidal Syndromes (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 and Precautions (5.1)].

Drug-induced Parkinsonian-like symptoms may include bradykinesia, tremor, cogwheel rigidity, mask-like facies [see Warnings and Precautions (5.2)].

Tardive dyskinesia is most frequently 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.  Motor restlessness (akathisia) may include 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 [see Warnings and Precautions (5.3)]. 

Endocrine Disturbances:  Galactorrhea, amenorrhea, gynecomastia, and impotence secondary to hyperprolactinemia. Fluid retention secondary to transient elevation of aldosterone.

Cardiovascular:  Hypotension, hypertension, supraventricular tachycardia, bradycardia, fluid retention, acute congestive heart failure, possible AV block.

Gastrointestinal:  Nausea, 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.  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.

7.1 Anticholinergic and Narcotic Analgesic Drugs

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.

7.2 Monoamine Oxidase Inhibitors

Metoclopramide has been shown to release catecholamines in patients with essential hypertension suggesting that it should be used cautiously, if at all, in patients taking monoamine oxidase (MAO) inhibitors.

7.3 Drug Absorption

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

7.4 Insulin

Because the action of metoclopramide will hasten the movement of food to the intestines and therefore the rate of absorption, insulin dosage or timing of dosage may require adjustment.  Increasing movement of food to the intestines may lead to absorption of less glucose from a meal, hence less glucose in the circulation for a particular dose of administered insulin to act upon, resulting in hypoglycemia.

7.5 Antidepressants, Antipsychotics, and Neuroleptics

Concomitant use of metoclopramide should be avoided in patients taking antidepressants, antipsychotics, and/or neuroleptics that have been associated with  extrapyramidal reactions such as tardive dyskinesia or Neuroleptic Malignant Syndrome (NMS) that have occurred in association with metoclopramide [see Warnings and Precautions (5.2), (5.3) and Adverse Reactions (6.2)].

8.1 Pregnancy

8.2 Labor and Delivery

The use of metoclopramide in labor and delivery has not been studied.

8.3 Nursing Mothers

Metoclopramide is excreted in human milk.  Caution should be exercised when metoclopramide is administered to a nursing mother.  Because of the potential for serious adverse reactions from metoclopramide in nursing infants and because of the potential for tumorigenicity (including tumor promoting potential in rats), a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

The safety and effectiveness of METOZOLV ODT in pediatric patients have not been established.

The safety profile of METOZOLV ODT 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.  In addition, neonates have reduced levels of NADH-cytochrome b5 reductase making them more susceptible to methemoglobinemia, a possible side effect of metoclopramide use in neonates.

8.5 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 drug-induced Parkinsonism due to metoclopramide is dose-related.  Geriatric patients should receive the lowest dose that is effective.  If drug-induced Parkinsonism symptoms develop in a geriatric patient, METOZOLV ODT should be discontinued.  The elderly may be at greater risk for tardive dyskinesia [see Warnings and Precautions (5.1)]. 

Sedation is a potential adverse event associated with metoclopramide use in the elderly.

Metoclopramide is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. For these reasons, dose selection for an elderly patient should be cautious, starting at the low end of the dosing range, due to the greater frequency of decreased renal function, concomitant disease, or other drug therapy in the elderly.  [see Warnings and Precautions (5.4)].

8.6 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.

Since metoclopramide is excreted principally through the kidneys, therapy should be initiated at approximately one-half the recommended dose in those patients whose creatinine clearance is below 40 mL/min.  Depending upon clinical efficacy and safety considerations, the dosage may be increased or decreased as appropriate.  Metoclopramide has been safely used in patients with advanced liver disease whose renal function was normal.

12.1 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 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 [see Warnings and Precautions (5.2), (5.3)]. 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. 

12.2 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. 

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

A 77-week study was conducted in rats with oral doses up to 40 mg/kg/day (about 5 times the maximum recommended human dose on surface area basis).  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.

In a rat model for assessing the tumor promotion potential, a two-week oral treatment with metoclopramide at a dose of 260 mg/kg/day (about 35 times the maximum recommended human dose based on body surface area) enhanced the tumorigenic effect of N-nitrosodiethylamine.

Metoclopramide was positive in the in vitro Chinese hamster lung cell / HGPRT forward mutation assay for mutagenic effects and the in vitro human lymphocyte chromosome aberration assay for clastogenic effects.  It was negative in the in vitro Ames mutation assay, the in vitro unscheduled DNA synthesis (UDS) assay with rat and human hepatocytes and the in vivo rat micronucleus assay.

Metoclopramide at intramuscular doses up to 20 mg/kg/day (about 3 times the maximum recommended human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.