Metoclopramide Orally DisintegratingTablets

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.

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

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 Metoclopramide Hydrochloride Orally Disintegrating Tablets 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)]

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 Metoclopramide Hydrochloride Orally Disintegrating Tablets 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 Metoclopramide Hydrochloride Orally Disintegrating Tablets 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, Metoclopramide Hydrochloride Orally Disintegrating Tablets therapy should be reinstituted at the earliest manifestation.

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.

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 Metoclopramide Hydrochloride Orally Disintegrating Tablets; 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 Metoclopramide Hydrochloride Orally Disintegrating Tablets formulation.

The adverse experience profile seen with Metoclopramide Hydrochloride Orally Disintegrating Tablets was similar to metoclopramide tablets. Thirty-three (33) adverse reactions were reported after receiving Metoclopramide Hydrochloride Orally Disintegrating Tablets and 30 adverse reactions were reported after receiving metoclopramide tablets.

The most frequently reported adverse reactions (greater than 2%) associated with Metoclopramide Hydrochloride Orally Disintegrating Tablets 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 Metoclopramide Hydrochloride Orally Disintegrating Tablets compared to metoclopramide tablets.

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.

Metoclopramide Hydrochloride Orally Disintegrating Tablet is an orally disintegrating tablet formulation of metoclopramide hydrochloride. The 5 mg strength tablets are round, white to off-white, flat faced beveled edge tablet debossed with 'N' on one side and "581" on the other side; it is comprised of 5 mg metoclopramide (as 5.91 mg of metoclopramide hydrochloride). The 10 mg tablets are round, white to off-white, flat faced beveled edge tablet debossed with 'N' on one side and "580" on the other side; it is comprised of 10 mg metoclopramide (as 11.82 mg of metoclopramide hydrochloride).

The active ingredient, 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 C14H22ClN3O2•HCl•H2O. Its molecular weight is 354.3. The structural formula is shown in Figure 1.

Figure 1

Metoclopramide Hydrochloride Orally Disintegrating Tablets includes the following inactive ingredients: phosphoric acid, mannitol and starch, microcrystalline cellulose, colloidal silicon dioxide, amino methacrylate copolymer, butylated hydroxyanisole, butylated hydroxytoluene, crospovidone, aspartame, N-C mint flavor, magnesium stearate.

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.

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 Metoclopramide Hydrochloride Orally Disintegrating Tablets

In a randomized, two-arm, two-way crossover study in 44 healthy adult (male and female) fasted subjects, Metoclopramide Hydrochloride Orally Disintegrating Tablet was bioequivalent to Reglan Tablets.

In a food-effect study with 28 subjects, Metoclopramide Hydrochloride Orally Disintegrating Tablets 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 Metoclopramide Hydrochloride Orally Disintegrating Tablets was administered with or without food. The clinical effect of the decrease in peak plasma level if Metoclopramide Hydrochloride Orally Disintegrating Tablet 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.

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.

• Instruct patients to take Metoclopramide Hydrochloride Orally Disintegrating Tablets at least 30 minutes before eating and at bedtime.
• A patient Medication Guide is available for Metoclopramide Hydrochloride Orally Disintegrating Tablets and printed at the end of the prescribing information. Instruct patients, families, and caregivers to read the Medication Guide and assist them in understanding its contents.
• Inform patients or their caregivers of serious potential issues associated with metoclopramide use such as tardive dyskinesia, extrapyramidal symptoms, and neuroleptic malignant syndrome. Advise patients to inform their physician if symptoms associated with these disorders occur during or after treatment with Metoclopramide Hydrochloride Orally Disintegrating Tablets.
• Inform patients that Metoclopramide Hydrochloride Orally Disintegrating Tablets may cause drowsiness, dizziness, or otherwise impair mental alertness or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle. Sedation may be more pronounced in the elderly.
• Inform patients that the most common adverse reactions in patients treated with Metoclopramide Hydrochloride Orally Disintegrating Tablets or other metoclopramide-containing products are headache, nausea, vomiting, tiredness, sleepiness, dizziness, and restlessness.

Manufactured by:

Novel Laboratories, Inc

Somerset, NJ 08873

USA

Manufactured for:

Lupin Pharmaceuticals, Inc.

Baltimore, MD  21202

PI5800000202    Rev. 05/2017

NDC 43386-580-30

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Metoclopramide Hydrochloride Orally Disintegrating Tablets

10 mg

NDC 43386-580-30

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Metoclopramide Hydrochloride Orally Disintegrating Tablets

10 mg

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NDC 40032-581-30

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Metoclopramide Hydrochloride Orally Disintegrating Tablets

5 mg

NDC 40032-581-30

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Metoclopramide Hydrochloride Orally Disintegrating Tablets

5 mg

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