METOCLOPRAMIDE HYDROCHLORIDE

Metoclopramide hydrochloride, the active ingredient of Metoclopramide Orally Disintegrating Tablets, is a dopamine-2 (D2) antagonist. Metoclopramide hydrochloride (metoclopramide monohydrochloride monohydrate), is a white or almost white crystalline powder, freely soluble in water. Chemically, it is 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxy benzamide monohydrochloride monohydrate. The molecular formula is C14H22ClN3O2•HCl•H2O. Its molecular weight is 354.3. The structural formula is: Metoclopramide Orally Disintegrating Tablets is an orally disintegrating tablet for oral administration and is available in 5 mg and 10 mg strengths. Each Metoclopramide Orally Disintegrating Tablets 5 mg tablet contains 5 mg metoclopramide (equivalent to 5.91 mg of metoclopramide hydrochloride USP). Each Metoclopramide Orally Disintegrating Tablets 10 mg tablet contains 10 mg metoclopramide (equivalent to 11.82 mg metoclopramide hydrochloride USP). Metoclopramide 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. Metoclopramide

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 )

GERD The recommended dosage is 10 mg to 15 mg up to four times daily at least 30 minutes before eating and at bedtime for 4 to 12 weeks. ( 2.2 ) Diabetic Gastroparesis (Gastric Stasis) The recommended dosage is 10 mg dose four times daily at least 30 minutes before eating and at bedtime for 2 to 8 weeks. ( 2.3 ) Dosage Adjustment in Specific Populations See Full Prescribing Information for recommended dosage reductions for elderly patients, patients with moderate or severe hepatic or renal impairment, and cytochrome P450 2D6 (CYP2D6) poor metabolizers. ( 2.2 , 2.3 ) 2.1 Important Administration Instructions Avoid treatment with Metoclopramide Orally Disintegrating Tablets for longer than 12 weeks because of the increased risk of developing TD with longer-term use [see Dosage and Administration ( 2.2 , 2.3), Warnings and Precautions ( 5.1 )]. Take on an empty stomach at least 30 minutes before eating [see Clinical Pharmacology ( 12.3 )]. Do not repeat dose if inadvertently taken with food. 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. Place the tablet on the tongue and allow it to disintegrate (takes approximately one minute) and swallow the granules without water [see Clinical Pharmacology ( 12.3 )]. 2.2 Dosage for GERD Metoclopramide Orally Disintegrating Tablets may be administered continuously or intermittently in patients with symptomatic GERD who fail to respond to conventional therapy: Continuous Dosing The recommended adult dosage of Metoclopramide Orally Disintegrating Tablets is 10 to 15 mg four times daily for 4 to 12 weeks. The treatment duration is determined by endoscopic response. Administer the dosage thirty minutes before each meal and at bedtime. The maximum recommended daily dosage is 60 mg. Table 1 displays the recommended daily dosage and maximum daily dosage for adults and dosage adjustments for patients with moderate or severe hepatic impairment (Child-Pugh B or C), in patients with creatinine clearance less than 60 mL/minute, in cytochrome P450 2D6 (CYP2D6) poor metabolizers, and with concomitant use with strong CYP2D6 inhibitors. Intermittent Dosing If symptoms only occur intermittently or at specific times of the day, administer Metoclopramide Orally Disintegrating Tablets in single dose up to 20 mg prior to the provoking situation. Consider dosage reductions for the populations and situations in Table 1. Table 1 Recommended Metoclopramide Orally Disintegrating Tablets Dosage in Patients with Gastroesophageal Reflux Recommended Dosage Maximum Recommended Daily Dosage Adult patients 10 to 15 mg four times daily (thirty minutes before each meal and at bedtime) 60 mg Mild hepatic impairment (Child-Pugh A) Elderly patients1 [see Use in Specific Populations ( 8.5 )] 5 mg four times daily (thirty minutes before each meal and at bedtime) Moderate or severe hepatic impairment (Child-Pugh B or C) [see Use in Specific Populations ( 8.7 )] 5 mg four times daily (thirty minutes before each meal and at bedtime), or 10 mg taken three times daily 30 mg CYP2D6 poor metabolizers [see Use in Specific Populations ( 8.9 )] Concomitant use with strong CYP2D6 inhibitors (e.g., quinidine, bupropion, fluoxetine, and paroxetine) [see Drug Interactions ( 7.1 )] Moderate or severe renal impairment (creatinine clearance less than or equal to 60 mL/minute) [see Use in Specific Populations ( 8.6 )] Patients with End-Stage Renal Disease (ESRD) including those treated with hemodialysis and continuous ambulatory peritoneal dialysis [see Use in Specific Populations ( 8.6 )] 5 mg four times daily (thirty minutes before each meal and at bedtime) or 10 mg twice daily 20 mg 1 Elderly patients may be more sensitive to the therapeutic or adverse effects of Metoclopramide Orally Disintegrating Tablets; therefore, consider a lower starting dosage of 5 mg four times daily with titration to the recommended adult dosage of 10 to 15 mg four times daily based upon response and tolerability. 2.3 Dosage for Acute and Recurrent Diabetic Gastroparesis (Gastric Stasis) The recommended adult dosage for the relief of symptoms associated with diabetic gastroparesis (gastric stasis) is 10 mg four times daily for 2 to 8 eight weeks, depending on symptomatic response. Avoid Metoclopramide Orally Disintegrating Tablets treatment for greater than 12 weeks [see Warnings and Precautions (5.1) ] . Administer the dosage at least 30 minutes before each meal and at bedtime. The maximum recommended daily dosage is 40 mg. Table 2 displays the recommended daily dosage and maximum daily dosage for adults and dosage adjustments for patients with moderate or severe hepatic impairment (Child-Pugh B or C), in patients with creatinine clearance less than 60 mL/minute, in cytochrome P450 2D6 (CYP2D6) poor metabolizers, and with concomitant use with strong CYP2D6 inhibitors. If patients with diabetic gastroparesis have severe nausea or vomiting and are unable to take oral Metoclopramide Orally Disintegrating Tablets tablets, consider starting therapy with metoclopramide injection given intramuscularly or intravenously for up to 10 days (see the prescribing information for metoclopramide injection). After patients are able to take oral therapy, switch to Metoclopramide Orally Disintegrating Tablets tablets. Table 2 Recommended Metoclopramide Orally Disintegrating Tablets Dosage in Patients with Acute and Recurrent Diabetic Gastroparesis Recommended Dosage Maximum Recommended Daily Dosage Adult patients 10 mg four times daily (thirty minutes before each meal and at bedtime) 40 mg Mild hepatic impairment (Child-Pugh A) Elderly patients [see Use in Specific Populations ( 8.5 )] 5 mg1 four times daily (thirty minutes before each meal and at bedtime) Moderate or severe hepatic impairment (Child-Pugh B or C) [see Use in Specific Populations ( 8.7 )] 5 mg four times daily (thirty minutes before each meal and at bedtime) 20 mg CYP2D6 poor metabolizers [see Use in Specific Populations ( 8.9 )] Concomitant use with strong CYP2D6 inhibitors (e.g., quinidine, bupropion, fluoxetine, and paroxetine) [see Drug Interactions ( 7.1 )] Moderate or severe renal impairment (creatinine clearance less than or equal to 60 mL/minute) [see Use in Specific Populations ( 8.6 )] Patients with End-Stage Renal Disease (ESRD) including those treated with hemodialysis and continuous ambulatory peritoneal dialysis [see Use in Specific Populations ( 8.6 )] 5 mg twice daily 10 mg 1 Elderly patients may be more sensitive to the therapeutic or adverse effects of Metoclopramide Orally Disintegrating Tablets; therefore, consider a lower dosage of 5 mg four times daily with titration to the recommended adult dosage of 10 mg four times daily based upon response and tolerability.

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 )

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.

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 ) 7.1 Effects 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. 7.2 Effects 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