Metoclopramide

Boxed Warning 8/2017 Indications and Usage ( 1 ) 8/2017 Dosage and Administration, Dosage for Gastroesophageal Reflux ( 2.2 ) 8/2017 Dosage and Administration, Dosage for Acute and Recurrent Diabetic Gastroparesis ( 2.3 ) 8/2017 Contraindications ( 4 ) 8/2017 Warnings and Precautions, Tardive Dyskinesia ( 5.1 ) 8/2017 Warnings and Precautions, Other Extrapyramidal Symptoms ( 5.2 ) 8/2017 Warnings and Precautions, Neuroleptic Malignant Syndrome ( 5.3 ) 8/2017 Warnings and Precautions, Hyperprolactinemia ( 5.7 ) 8/2017

INDICATIONS AND USAGE The use of Metoclopramide Oral Solution is recommended for adults only. Therapy should not exceed 12 weeks in duration. Symptomatic Gastroesophageal Reflux Metoclopramide Oral Solution is indicated as short-term (4 to 12 weeks) therapy for adults with symptomatic, documented gastroesophageal reflux who fail to respond to conventional therapy. 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 12-week trial using doses of 15 mg 4 times daily. As there is no documented correlation between symptoms and healing of esophageal lesions, patients with documented lesions should be monitored endoscopically. Diabetic Gastroparesis (Diabetic Gastric Stasis) Metoclopramide is indicated for the relief of symptoms associated with acute and recurrent diabetic gastric stasis. The usual manifestations of delayed gastric emptying (e.g., nausea, vomiting, heartburn, persistent fullness after meals, and anorexia) appear to respond to metoclopramide within different time intervals. Significant relief of nausea occurs early and continues to improve over a three-week period. Relief of vomiting and anorexia may precede the relief of abdominal fullness by one week or more.

2 DOSAGE AND ADMINISTRATION Gastroesophageal Reflux ( 2.2 ) Administer metoclopramide continuously or intermittently: Continuous: Administer 10 to 15 mg, 30 minutes before each meal and at bedtime (maximum of 60 mg per day) for 4 to 12 weeks. Intermittent: Single doses up to 20 mg prior to provoking situation. Acute and Recurrent Diabetic Gastroparesis ( 2.3 ) Administer 10 mg, 30 minutes before each meal and at bedtime (maximum of 40 mg per day) for 2 to 8 weeks Dosage Adjustment in Specific Populations ( 2.2 , 2.3 ) For gastroesophageal reflux and acute and recurrent diabetic gastroparesis, see Full Prescribing Information for recommended dosage reductions for elderly patients, in patients with moderate or severe hepatic or renal impairment, and cytochrome P450 2D6 (CYP2D6) poor metabolizers. 2.1 Important Administration Instructions Avoid treatment with metoclopramide 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) ]. 2.2 Dosage for Gastroesophageal Reflux Metoclopramide may be administered continuously or intermittently in patients with symptomatic gastroesophageal reflux who fail to respond to conventional therapy: Continuous Dosing The recommended adult dosage of metoclopramide 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 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 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 patients [see Use in Specific Populations (8.5) ] 5 mg Elderly patients may be more sensitive to the therapeutic or adverse effects of metoclopramide; 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. 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 2.3 Dosage for Acute and Recurrent Diabetic Gastroparesis The recommended adult dosage for the treatment of acute and recurrent diabetic gastroparesis is 10 mg four times daily for 2 to 8 weeks, depending on symptomatic response. Avoid metoclopramide treatment for greater than 12 weeks [see Warnings and Precautions (5.1) ]. Administer the d …

3 DOSAGE FORMS AND STRENGTHS Oral Solution: 10 mg/10 mL metoclopramide Oral Solution: 10 mg/10 mL metoclopramide ( 3 )

4 CONTRAINDICATIONS Metoclopramide 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. Metoclopramide may cause a hypertensive/pheochromocytoma crisis, probably due to release of catecholamines from the tumor . Metoclopramide 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. Metoclopramide 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 )

ADVERSE REACTIONS In general, the incidence of adverse reactions correlates with the dose and duration of metoclopramide administration. The following reactions have been reported, although in most instances, data do not permit an estimate of frequency: CNS Effects Restlessness, drowsiness, fatigue, and lassitude occur in approximately 10% of patients receiving the most commonly prescribed dosage of 10 mg 4 times daily. (see PRECAUTIONS ). Insomnia, headache, confusion, dizziness or mental depression with suicidal ideation (see WARNINGS ) occur less frequently. The incidence of drowsiness is greater at higher doses. There are isolated reports of convulsive seizures without clearcut relationship to metoclopramide. Rarely, hallucinations have been reported. Extrapyramidal Reactions (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 ). Parkinsonian-like symptoms may include bradykinesia, tremor, cogwheel rigidity, mask-like facies (see WARNINGS ). Tardive dyskinesia most frequently is 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 (see WARNINGS ). Motor restlessness (akathisia) may consist of feelings of anxiety, agitation, jitteriness, and insomnia, as well as inability to sit still, pacing, 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. This potentially fatal syndrome is comprised of the symptom complex of hyperthermia, altered consciousness, muscular rigidity, and autonomic dysfunction (see WARNINGS ). Endocrine Disturbances Galactorrhea, amenorrhea, gynecomastia, impotence secondary to hyperprolactinemia (see PRECAUTIONS ). Fluid retention secondary to transient elevation of aldosterone (see CLINICAL PHARMACOLOGY ). Cardiovascular Hypotension, hypertension, supraventricular tachycardia, bradycardia, fluid retention, acute congestive heart failure, and possible AV block (see CONTRAINDICATIONS and PRECAUTIONS ). Gastrointestinal Nausea and 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 clearcut relationship to metoclopramide. Methemoglobinemia, in adults and especially with overdosage in neonates (see OVERDOSAGE ). 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. To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-855-204-1431 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG 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 ) 7.1 Effects of Other Drugs on Metoclopramide Table 3 displays the effects of other drugs on metoclopramide. Table 3. 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 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 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 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. Table 4. Effects of Metoclopramide on Other Drugs Dopaminergic Agonists and Drugs Increasing 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 Interaction does not apply to posaconazole delayed-release tablets , 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 …

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 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. 8.2 Lactation Risk Summary Limited published data report the presence of metoclopramide in human milk in variable amounts. Breastfed infants exposed to metoclopramide have experienced gastrointestinal adverse reactions, including intestinal discomfort and increased intestinal gas formation [see Data ] . Metoclopramide elevates prolactin levels [see Warnings and Precautions (5.7) ] ; however, the published data are not adequate to support drug effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for metoclopramide and any potential adverse effects on the breastfed child from metoclopramide or from the underlying maternal condition. Clinical Considerations Monitor breastfeeding neonates because metoclopramide may cause extrapyramidal signs (dystonias) and methemoglobinemia [see Warnings and Precautions (5.1 , 5.2) , Use in Specific Populations (8.4) ] . Data In published clinical studies, the estimated amount of metoclopramide received by the breastfed infant was less than 10% of the maternal weight-adjusted dose. In one study, the estimated daily amount of metoclopramide received by infants from breast milk ranged from 6 to 24 mcg/kg/day in early puerperium (3 to 9 days postpartum) and from 1 to 13 mcg/kg/day at 8 to 12 weeks postpartum. 8.4 Pediatric Use Metoclopramide is not recommended for use in pediatric patients due to the risk of tardive dyskinesia (TD) and other extrapyramidal symptoms as well as the risk of methemoglobinemia in neonates. The safety and effectiveness of metoclopramide in pediatric patients have not been established. Dystonias and other extrapyramidal symptoms associated with metoclopramide are more common in pediatric patients than in adults [see Warnings and Precautions (5.1 , 5.2) ] . In addition, neonates have reduced levels of NADH-cytochrome b 5 reductase, making them more susceptible to methemoglobinemia, a possible adverse reaction of metoclopramide use in neonates [see Use in Specific Populations (8.8) ] . 8.5 Geriatric Use Metoclopramide is known to be substantially excreted by the kidney, and the risk of adverse reactions, including tardive dyskinesia (TD), may be greater in patients with impaired …

12.1 Mechanism of Action Metoclopramide stimulates motility of the upper gastrointestinal tract without stimulating gastric, biliary, or pancreatic secretions. The exact mechanism of action of metoclopramide in the treatment of gastroesophageal reflux and acute and recurrent diabetic gastroparesis has not been fully established. It seems to sensitize tissues to the action of acetylcholine. The effect of metoclopramide on motility is not dependent on intact vagal innervation, but it 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.

11 DESCRIPTION Metoclopramide, is a dopamine-2 receptor antagonist. Metoclopramide hydrochloride (metoclopramide monohydrochloride monohydrate) is a white crystalline, odorless substance, freely soluble in water. Its chemical name is 4-amino -5-chloro-N-[2-(diethylamino)ethyl]-2-methoxy benzamide monohydrochloride monohydrate. The molecular formula is C 14 H 22 ClN 3 O 2 ∙HCl∙H 2 O. Its molecular weight is 354.3. The structural formula is: Metoclopramide Oral Solution USP is an orange-colored, berry-citrus flavored liquid for oral administration and is available in 10 mg/10 mL oral solution. Each 5 mL (teaspoonful) for oral administration contains: Metoclopramide base (as the monohydrochloride monohydrate) 5 mg. Inactive ingredients: Citric acid, FD&C Yellow No. 6 (Sunset Yellow), flavoring, glycerin, methylparaben, propylparaben, purified water, and sorbitol solution. Chemical Structure

OVERDOSAGE Symptoms of overdosage may include drowsiness, disorientation and extrapyramidal reactions. Anticholinergic or antiparkinson drugs or antihistamines with anticholinergic properties may be helpful in controlling the extrapyramidal reactions. Symptoms are self-limiting and usually disappear within 24 hours. Hemodialysis removes relatively little metoclopramide, probably because of the small amount of the drug in blood relative to tissues. Similarly, continuous ambulatory peritoneal dialysis does not remove significant amounts of drug. It is unlikely that dosage would need to be adjusted to compensate for losses through dialysis. Dialysis is not likely to be an effective method of drug removal in overdose situations. Unintentional overdose due to misadministration has been reported in infants and children with the use of metoclopramide oral solution. While there was no consistent pattern to the reports associated with these overdoses, events included seizures, extrapyramidal reactions, and lethargy. Methemoglobinemia has occurred in premature and full-term neonates who were given overdoses of metoclopramide (1 to 4 mg/kg/day orally, intramuscularly or intravenously for 1 to 3 or more days). Methemoglobinemia can be reversed by the intravenous administration of methylene blue. However, methylene blue may cause hemolytic anemia in patients with G6PD deficiency, which may be fatal. (see ). PRECAUTIONS - Other Special Populations

HOW SUPPLIED Metoclopramide Oral Solution USP, 5 mg metoclopramide base (as the monohydrochloride monohydrate) per 5 mL (teaspoonful) is available as an orange-colored, vanilla-flavored, palatable, aromatic, sugar-free, and alcohol-free liquid for oral administration and is available in the following size: NDC..........17856-1190-01 - 5 mL CUP UD NDC..........17856-1190-02 - 1 mL Enfit Syringe UD Dispense in a tight, light-resistant container. RECOMMENDED STORAGE Store at controlled room temperature, between 20°C and 25°C (68° to 77°F) (see USP). Protect from freezing. Distributed by ATLANTIC BIOLOGICALS CORP. MIAMI, FL 33179