Metoclopramide Orally Disintegrating Tablets is indicated in adults for the: Treatment for 4 to 12 weeks of symptomatic, documented gastroesophageal reflux disease (GERD) who fail to respond to conventional therapy. Relief of symptoms associated with acute and recurrent diabetic gastroparesis (gastric stasis). Limitations of Use : Metoclopramide Orally Disintegrating Tablets is not recommended for use in pediatric patients due to the risk of developing tardive dyskinesia (TD) and other extrapyramidal symptoms and the risk of methemoglobinemia in neonates [see Use in Specific Populations ( 8.4 )] Metoclopramide Orally Disintegrating Tablets is a dopamine-2 (D2) antagonist indicated in adults for: Treatment of symptomatic, documented gastroesophageal reflux disease (GERD) in adults with who fail to respond to conventional therapy.
Relief of symptoms associated with acute and recurrent diabetic gastroparesis (gastric stasis). Limitations of Use: Metoclopramide Orally Disintegrating Tablets is not recommended for use in pediatric patients due to the risk of developing tardive dyskinesia (TD) and other extrapyramidal symptoms and the risk of methemoglobinemia in neonates. (1, 8.4 )
Contraindications
Metoclopramide Orally Disintegrating Tablets is contraindicated: In patients with a history of tardive dyskinesia (TD) or a dystonic reaction to metoclopramide [see Warnings and Precautions (5.1, 5.2)]. When stimulation of gastrointestinal motility might be dangerous (e.g., in the presence of gastrointestinal hemorrhage, mechanical obstruction, or perforation). In patients with pheochromocytoma or other catecholamine-releasing paragangliomas.
Reglan may cause a hypertensive/pheochromocytoma crisis, probably due to release of catecholamines from the tumor [ see Warnings and Precautions (5.5 )]. In patients with epilepsy. Reglan may increase the frequency and severity of seizures [see Adverse Reactions (6) ]. In patients with hypersensitivity to metoclopramide. Reactions have included laryngeal and glossal angioedema and bronchospasm [see Adverse Reactions (6) ].
History of TD or dystonic reaction to metoclopramide ( 4 ) When stimulation of gastrointestinal motility might be dangerous ( 4 ) Pheochromocytoma, catecholamine-releasing paragangliomas ( 4 ) Epilepsy ( 4 ) Hypersensitivity to metoclopramide ( 4 )
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Tardive Dyskinesia (TD), Other Extrapyramidal Symptoms (EPS), and Neuroleptic Malignant Syndrome (NMS): Avoid concomitant use of other drugs known to cause TD/EPS/NMS and avoid use in patients with Parkinson's disease. If symptoms occur, discontinue Metoclopramide Orally Disintegrating Tablets and seek immediate medical attention. ( 5.1 , 5.2 , 5.3 , 7.1 , 7.2 ) Depression and suicidal ideation/suicide : Avoid use. ( 5.4 )
5.1Tardive Dyskinesia
Metoclopramide can cause tardive dyskinesia (TD), a potentially irreversible and disfiguring disorder characterized by involuntary movements of the face or tongue, and sometimes of the trunk and/or extremities. Movements may be choreoathetoic in appearance. The risk of developing TD and the likelihood that TD will become irreversible increases with the duration of treatment and total cumulative dosage. 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. Additionally, the risk of developing TD is increased among the elderly, especially elderly women [see Use in Specific Populations (8.5 )] , and in patients with diabetes mellitus. Due to the risk of developing TD, avoid treatment with Metoclopramide Orally Disintegrating Tablets for longer than 12 weeks and reduce the dosage in elderly patients [see Dosage and Administration ( 2.2 , 2.3 )].
Discontinue Metoclopramide Orally Disintegrating Tablets immediately in patients who develop signs and 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 Orally Disintegrating Tablets is withdrawn. Metoclopramide Orally Disintegrating Tablets 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. Metoclopramide Orally Disintegrating Tablets is contraindicated in patients with a history of TD [see Contraindications (4) ]. Avoid Metoclopramide Orally Disintegrating Tablets in patients receiving other drugs that can cause TD (e.g., antipsychotics).
5.2Other Extrapyramidal Symptoms
In addition to TD, metoclopramide may cause other extrapyramidal symptoms (EPS), parkinsonian symptoms, and motor restlessness. Advise patients to seek immediate medical attention if such symptoms occur and to discontinue Metoclopramide Orally Disintegrating Tablets. Extrapyramidal symptoms (EPS), such as acute dystonic reactions, occurred in patients treated with metoclopramide dosages of 30 to 40 mg daily. Such reactions occurred more frequently in adults less than 30 years of age and at higher than recommended dosages.
EPS occurred more frequently in pediatric patients compared to adults (Metoclopramide Orally Disintegrating Tablets is not approved for use in pediatric patients). Symptoms can occur in the first 24 to 48 hours after starting metoclopramide. Symptoms included 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 were present as stridor and dyspnea, possibly due to laryngospasm. Diphenhydramine hydrochloride or benztropine mesylate may be used to treat these adverse reactions. Avoid Metoclopramide Orally Disintegrating Tablets in patients receiving other drugs that can cause EPS (e.g., antipsychotics). Parkinsonism symptoms (bradykinesia, tremor, cogwheel rigidity, mask-like facies) have occurred after starting metoclopramide, more commonly within the first 6 months, but also after longer periods.
Symptoms generally have subsided within 2 to 3 months following discontinuation of metoclopramide. Avoid Metoclopramide Orally Disintegrating Tablets in patients with Parkinson's disease and other patients being treated with antiparkinsonian drugs due to potential exacerbation of symptoms. Avoid treatment with Metoclopramide Orally Disintegrating Tablets for more than 12 weeks [see Dosage and Administration ( 2.2 , 2.3 ), Warnings and Precautions (5.1) ].
Motor restlessness (akathisia) has developed and consisted of feelings of anxiety, agitation, jitteriness, and insomnia, as well as inability to sit still, pacing, and foot tapping. If symptoms resolve, consider restarting at a lower dosage.
5.3Neuroleptic Malignant Syndrome
Metoclopramide may cause a potentially fatal symptom complex called Neuroleptic Malignant Syndrome (NMS). NMS has been reported in association with metoclopramide overdosage and concomitant treatment with another drug associated with NMS. Avoid Metoclopramide Orally Disintegrating Tablets in patients receiving other drugs associated with NMS, including typical and atypical antipsychotics. Clinical manifestations of NMS include hyperthermia, muscle rigidity, altered mental status, and manifestations of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac arrhythmias).
Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Patients with such symptoms should be evaluated immediately. In the diagnostic evaluation, consider the presence of other serious medical illness (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms. Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, malignant hyperthermia, drug fever, serotonin syndrome and primary central nervous system pathology.
Management of NMS includes: Immediate discontinuation of Metoclopramide Orally Disintegrating Tablets and other drugs not essential to concurrent therapy [see Drug Interactions (7.1) ]. Intensive symptomatic treatment and medical monitoring. Treatment of any concomitant serious medical problems for which specific treatments are available.
5.4Depression
Depression has occurred in metoclopramide-treated patients with and without a history of depression. Symptoms have included suicidal ideation and suicide. Avoid Metoclopramide Orally Disintegrating Tablets use in patients with a history of depression.
5.5Hypertension
Metoclopramide may elevate blood pressure. In one study in hypertensive patients, intravenously administered metoclopramide was shown to release catecholamines; hence, avoid use in patients with hypertension or in patients taking monoamine oxidase inhibitors [see Drugs Interactions (7.1) ] . There are also clinical reports of hypertensive crises in some patients with undiagnosed pheochromocytoma. Metoclopramide Orally Disintegrating Tablets is contraindicated in patients with pheochromocytoma or other catecholamine-releasing paragangliomas [see Contraindications (4) ] .
Discontinue Metoclopramide Orally Disintegrating Tablets in any patient with a rapid rise in blood pressure.
5.6Fluid Retention
Because 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. Discontinue Metoclopramide Orally Disintegrating Tablets if any of these adverse reactions occur.
5.7 Hyperprolactinemia As with other dopamine D2 antagonists, metoclopramide elevates prolactin levels. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating drugs, including metoclopramide.
Hyp
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Interactions
Antipsychotics: Potential for additive effects, including TD, EPS, and NMS ; avoid concomitant use. ( 7.1 ) CNS depressants : Increased risk of CNS depression; avoid concomitant use and monitor for adverse reactions. ( 7.1 ) Strong CYP2D6 inhibitors (e.g., quinidine, bupropion, fluoxetine, and paroxetine) : See Full Prescribing Information for recommended dosage reductions. ( 2.2 , 2.3 , 7.1 ) MAO inhibitors : Increased risk of hypertension; avoid concomitant use.
( 5.5 , 7.1 ) Additional drug interactions : See Full Prescribing Information. ( 7.1 , 7.2 )
7.1Effects of Other Drugs on Metoclopramide Table
3 displays the effects of other drugs on metoclopramide. Antipsychotics Clinical Impact Potential for additive effects, including increased frequency and severity of tardive dyskinesia (TD), other extrapyramidal symptoms (EPS), and neuroleptic malignant syndrome (NMS). Intervention Avoid concomitant use [see Warnings and Precautions ( 5.1 , 5.2 , 5.3 )]. Strong CYP2D6 Inhibitors, not Included in Antipsychotic Category Above Clinical Impact Increased plasma concentrations of metoclopramide; risk of exacerbation of extrapyramidal symptoms [see Clinical Pharmacology ( 12.3 )].
Intervention Reduce the Metoclopramide Orally Disintegrating Tablets dosage [ see Dosage and Administration ( 2.2 , 2.3 )] . Examples quinidine, bupropion, fluoxetine, and paroxetine. Monoamine Oxidase Inhibitors Clinical Impact Increased risk of hypertension [see Warnings and Precautions (5.5) ]. Intervention Avoid concomitant use. Central Nervous System (CNS) Depressants Clinical Impact Increased risk of CNS depression [see Warnings and Precautions (5.8) ].
Intervention Avoid Metoclopramide Orally Disintegrating Tablets or the interacting drug, depending on the importance of the drug to the patient. Examples alcohol, sedatives, hypnotics, opiates and anxiolytics. Drugs that Impair Gastrointestinal Motility Clinical Impact Decreased systemic absorption of metoclopramide. Intervention Monitor for reduced therapeutic effect. Examples antiperistaltic antidiarrheal drugs, anticholinergic drugs, and opiates.
Dopaminergic Agonists and Other Drugs that Increase Dopamine Concentrations Clinical Impact Decreased therapeutic effect of metoclopramide, a D2 antagonist, due to opposing effects on dopamine. Intervention Monitor for reduced therapeutic effect. Examples Apomorphine, bromocriptine, cabergoline, levodopa, pramipexole, ropinirole, and rotigotine.
7.2Effects of Metoclopramide on Other Drugs Table
4 displays the effects of metoclopramide on other drugs. Dopaminergic Agonists and Other Drugs that Increase Dopamine Concentrations: Clinical Impact Opposing effects of metoclopramide and the interacting drug on dopamine. Potential exacerbation of symptoms (e.g., parkinsonian symptoms). Intervention Avoid concomitant use [see Warnings and Precautions (5.2) ] . Examples Apomorphine, bromocriptine, cabergoline, levodopa, pramipexole, ropinirole, rotigotine.
Succinylcholine, Mivacurium: Clinical Impact Metoclopramide inhibits plasma cholinesterase leading to enhanced neuromuscular blockade. Intervention Monitor for signs and symptoms of prolonged neuromuscular blockade. Drugs with Absorption Altered due to Increased Gastrointestinal Motility: Clinical Impact The effect of metoclopramide on other drugs is variable. Increased gastrointestinal (GI) motility by metoclopramide may impact absorption of other drugs leading to decreased or increased drug exposure.
Intervention Drugs with Decreased Absorption (e.g., digoxin, atovaquone, posaconazole oral suspension*, fosfomycin) : Monitor for reduced therapeutic effect of the interacting drug. For digoxin monitor therapeutic drug concentrations and increase the digoxin dose as needed (see prescribing information for digoxin). Drugs with Increased Absorption (e.g., sirolimus, tacrolimus, cyclosporine) : Monitor therapeutic drug concentrations and adjust the dose as needed.
See prescribing information for the interacting drug. Insulin Clinical Impact Increased GI motility by metoclopramide may increase delivery of food to the intestines and increase blood glucose. Intervention Monitor blood glucose and adjust insulin dosage regimen as needed. * Interaction does not apply to posaconazole delayed-release tablets
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
Published studies, including retrospective cohort studies, national registry studies, and meta-analyses, do not report an increased risk of adverse pregnancy-related outcomes with use of metoclopramide during pregnancy. There are potential risks to the neonate following exposure in utero to metoclopramide during delivery (see Clinical Considerations) . In animal reproduction studies, no adverse developmental effects were observed with oral administration of metoclopramide to pregnant rats and rabbits at exposures about 6 and 12 times the maximum recommended human dose (MRHD) (see Data) .
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Metoclopramide crosses the placental barrier and may cause extrapyramidal signs and methemoglobinemia in neonates with maternal administration during delivery.
Monitor neonates for extrapyramidal signs [see Warnings and Precautions ( 5.1 , 5.2 ), Use in Specific Populations ( 8.4 )] . Data Animal Data Reproduction studies have been performed following administration of oral metoclopramide during organogenesis in pregnant rats at about 6 times the MRHD calculated on body surface area and in pregnant rabbits at about 12 times the MRHD calculated on body surface area. No evidence of adverse developmental effects due to metoclopramide were observed.
Adverse reactions
The following adverse reactions are described, or described in greater detail, in other sections of the labeling: Tardive dyskinesia [see Boxed Warning and Warnings and Precautions ( 5.1 )] Other extrapyramidal effects [see Warnings and Precautions ( 5.2 )] Neuroleptic malignant syndrome [see Warnings and Precautions ( 5.3 )] Depression [see Warnings and Precautions ( 5.4 )] Hypertension [see Warnings and Precautions ( 5.5 )] Fluid retention [see Warnings and Precautions ( 5.6 )] Hyperprolactinemia [see Warnings and Precautions ( 5.7 )] Effects on the ability to drive and operate machinery [see Warnings and Precautions (5.8) ] Metoclopramide The following adverse reactions have been identified from clinical studies or postmarketing reports of metoclopramide.
Because these 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. The most common adverse reactions (in approximately 10% of patients receiving 10 mg of metoclopramide four times daily) were restlessness, drowsiness, fatigue, and lassitude. In general, the incidence of adverse reactions correlated with the dosage and duration of metoclopramide administration.
Adverse reactions, especially those involving the nervous system, occurred after stopping metoclopramide including dizziness, nervousness, and headaches. Central Nervous System Disorders Tardive dyskinesia, acute dystonic reactions, drug-induced parkinsonism, akathisia, and other extrapyramidal symptoms Convulsive seizures Hallucinations Restlessness, drowsiness, fatigue, and lassitude occurred in approximately 10% of patients who received 10 mg four times daily.
Insomnia, headache, confusion, dizziness, or depression with suicidal ideation occurred less frequently Neuroleptic malignant syndrome, serotonin syndrome (in combination with serotonergic agents) Endocrine Disorders : Fluid retention secondary to transient elevation of aldosterone. Galactorrhea, amenorrhea, gynecomastia, impotence secondary to hyperprolactinemia Cardiovascular Disorders : Acute congestive heart failure, possible atrioventricular block, hypotension, hypertension, supraventricular tachycardia, bradycardia, fluid retention Gastrointestinal Disorders : Nausea, bowel disturbances (primarily diarrhea) Hepatic Disorders : Hepatotoxicity, characterized by, e.g., jaundice and altered liver function tests, when metoclopramide was administered with other drugs with known hepatotoxic potential Renal and Urinary Disorders : Urinary frequency, urinary incontinence Hematologic Disorders : Agranulocytosis, neutropenia, leukopenia, methemoglobinemia, sulfhemoglobinemia Hypersensitivity Reactions : Bronchospasm (especially in patients with a history of asthma), urticaria; rash; angioedema, including glossal or laryngeal edema Eye Disorders : Visual disturbances Metabolism Disorders : Porphyria Most common adverse reactions (> 10%) are restlessness, drowsiness, fatigue, and lassitude.
To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-866-403-7592 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Composition
Active ingredients
METOCLOPRAMIDE HYDROCHLORIDE EQ 10MG BASE
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
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