2d6 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

ly 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 )

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). 5.2 other 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. 5.3 neuroleptic 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. 5.4 depression 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. 5.5 hypertension 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. 5.6 fluid 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. hyperprolactinemia may potentially stimulate prolactin-dependent breast cancer. however, some clinical studies and epidemiology studies have not shown an association between administration of dopamine d2 antagonists and tumorigenesis in humans [see nonclinical toxicology (13.1 )]. 5.8 effects on the ability to drive and operate machinery metoclopramide may impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle. concomitant use of central nervous system (cns) depressants or drugs associated with eps may increase this effect (e.g., alcohol, sedatives, hypnotics, opiates, and anxiolytics). avoid metoclopramide orally disintegrating tablets or the interacting drug, depending on the importance of the drug to the patient [see drug interactions (7.1) ].

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.

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.

2d6 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

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. 8.6 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 orally disintegrating tablets and any potential adverse effects on the breastfed child from metoclopramide orally disintegrating tablets 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 orally disintegrating tablets 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 orally disintegrating tablets in pediatric patients have not been established. dystonias and other extrapyramidal reactions associated with metoclopramide are more common in the pediatric patients than in adults [see warnings and precautions ( 5.1 , 5.2 )] . 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 [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 renal function [see use in specific populations ( 8.6 ), clinical pharmacology (12.3)] . elderly patients are more likely to have decreased renal function and may be more sensitive to the therapeutic or adverse effects of metoclopramide; therefore, consider a reduced dosage of metozolov odt in elderly patients [see dosage and administration ( 2.2 , 2.3 ), warnings and precautions (5.1) ]. 8.7 renal impairment the clearance of metoclopramide is decreased and the systemic exposure is increased in patients with moderate to severe renal impairment compared to patients with normal renal function, which may increase the risk of adverse reactions. reduce the metoclopramide orally disintegrating tablets dosage in patients with moderate and severe renal impairment (creatinine clearance less than or equal to 60 ml/minute), including those receiving hemodialysis and continuous ambulatory peritoneal dialysis [see dosage and administration ( 2.2 , 2.3 ), clinical pharmacology (12.3) ]. 8.8 hepatic impairment patients with severe hepatic impairment (child-pugh c) have reduced systemic metoclopramide clearance (by approximately 50%) compared to patients with normal hepatic function. the resulting increase in metoclopramide blood concentrations increases the risk of adverse reactions. there are no pharmacokinetic data in patients with moderate hepatic impairment (child-pugh b). reduce metoclopramide orally disintegrating tablets dosage in patients with moderate or severe (child-pugh b or c) hepatic impairment [see dosage and administration ( 2.2 , 2.3 )] . there is no dosage adjustment required for patients with mild hepatic impairment (child-pugh a). in addition, metoclopramide, by producing a transient increase in plasma aldosterone, may increase the risk of fluid retention in patients with hepatic impairment [see warnings and precautions ( 5.6 )] . monitor patients with hepatic impairment for the occurrence of fluid retention and volume overload. 8.9 nadh-cytochrome b5 reductase deficiency metoclopramide-treated patients with nadh-cytochrome b5 reductase deficiency are at an increased risk of developing methemoglobinemia and/or sulfhemoglobinemia. for patients with glucose-6-phosphate dehydrogenase (g6pd) deficiency the metoclopramide-induced methemoglobinemia, methylene blue treatment is not recommended. methylene blue may cause hemolytic anemia in patients with g6pd deficiency, which may be fatal [see overdosage (10) ] . 8.10 cyp2d6 poor metabolizers metoclopramide is a substrate of cyp2d6. the elimination of metoclopramide may be slowed in patients who are cyp2d6 poor metabolizers (compared to patients who are cyp2d6 intermediate, extensive, or ultra-rapid metabolizers); possibly increasing the risk of dystonic and other adverse reactions to metoclopramide orally disintegrating tablets [see clinical pharmacology (12.3)]. reduce the metoclopramide orally disintegrating tablets dosage in patients who are poor cyp2d6 metabolizers [see dosage and administration ( 2.2 , 2.3 )].

y. 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.

reflux in patients with gastroesophageal reflux and low lower esophageal sphincter pressure (lesp), single oral doses of reglan produced dose-related increases in lesp. effects began at about 5 mg and increased through 20 mg. the increase in lesp from a 5 mg dose lasted about 45 minutes and that of 20 mg lasted between 2 and 3 hours. increased rate of stomach emptying was observed with single oral doses of 10 mg. 12.3 pharmacokinetics unless otherwise specified the pk of metoclopramide described below was obtained using other oral formulations of metoclopramide. absorption relative to an intravenous dose of 20 mg, the absolute oral bioavailability of metoclopramide was 80% ± 15.5% as demonstrated in a crossover study of 18 subjects. following metoclopramide orally disintegrating tablets tablet administration, the 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 two clinical trials (n = 96) with a mean ± sd being 77 ± 111 seconds and a median of 54 seconds [see dosage and administration ( 2.1 )] . peak plasma concentrations occurred at about 1 to 2 hours after a single oral dose. similar time to peak is observed after individual doses at steady state. in 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 of metoclopramide (5 times the maximum recommended single dose of metoclopramide orally disintegrating tablets). cmax increased linearly with dose; tmax remained the same; whole body clearance was unchanged; and the elimination rate remained the same. linear kinetic processes adequately describe the absorption and elimination of metoclopramide. the pharmacokinetic characteristics following single oral administration of 10 mg metoclopramide hydrochloride orally disintegrating tablets under fasting conditions are shown in table 5. table 5 mean (± sd) pharmacokinetic parameters in healthy subjects following a single oral dose of 10 mg metoclopramide orally disintegrating tablets under fasting conditions treatment c max (ng/ml) t max (h)* auc 0-inf (ng*h/ml) single 10 mg metoclopramide orally disintegrating tablets (n=41) 28±7.4 2.0 (0.7 to 4.0) 268±72.6 *presented as median (range). effect of food when metoclopramide orally disintegrating tablets was taken immediately after a high-fat meal (approximately 900 total calories based on the composition being 150 protein calories, 250 carbohydrate calories and 500 fat calories), the cmax was 17% lower than when taken after an overnight fast. the tmax increased from about 1.8 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 orally disintegrating tablets was administered with or without food. the clinical relevance of a lower cmax with a high-fat meal is unknown [see dosage and administration (2.1) ] . distribution metoclopramide 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. elimination the average elimination half-life of metoclopramide in subjects with normal renal function was 5 to 6 hours metabolism metoclopramide undergoes enzymatic metabolism via oxidation as well as glucuronide and sulfate conjugation reactions in the liver. monodeethylmetoclopramide, a major oxidative metabolite, is formed primarily by cyp2d6, an enzyme subject to genetic variability [see dosage and administration ( 2.2 , 2.3 ), use in specific populations ( 8.9 )] . excretion approximately 85% of the radioactivity of an orally administered dose appears in the urine within 72 hours. after oral administration of 10 or 20 mg, a mean of 18% and 22% of the dose, respectively, was recovered as free metoclopramide in urine within 36 hours. specific populations patients with renal impairment in a study of 24 patients with varying degrees of renal impairment (moderate, severe, and end-stage renal disease (esrd) requiring dialysis), the systemic exposure (auc) of metoclopramide in patients with moderate to severe renal impairment was about 2-fold the auc in subjects with normal renal function. the auc of metoclopramide in patients with esrd on dialysis was about 3.5-fold the auc in subjects with normal renal function [see dosage and administration ( 2.2 , 2.3 ), use in specific populations ( 8.6 )]. patients with hepatic impairment in a group of 8 patients with severe hepatic impairment (child-pugh c), the average metoclopramide clearance was reduced by approximately 50% compared to patients with normal hepatic function [see dosage and administration ( 2.2 , 2.3 ), use in specific populations ( 8.7 )]. drug interaction studies effect of metoclopramide on cyp2d6 substrates although in vitro studies suggest that metoclopramide can inhibit cyp2d6, metoclopramide is unlikely to interact with cyp2d6 substrates in vivo at therapeutically relevant concentrations. effect of cyp2d6 inhibitors on metoclopramide in healthy subjects, 20 mg of oral metoclopramide and 60 mg of fluoxetine (a strong cyp2d6 inhibitor) were administered, following prior exposure to 60 mg fluoxetine orally for 8 days. the patients who received concomitant metoclopramide and fluoxetine had a 40% and 90% increase in metoclopramide cmax and auc0-∞, respectively, compared to patients who received metoclopramide alone (see table 6 metoclopramide pharmacokinetic parameters in healthy subjects with and without fluoxetine) [see drug interactions ( 7.1 )] . table 6 metoclopramide pharmacokinetic parameters in healthy subjects with and without fluoxetine parameter metoclopramide alone (mean ± sd) metoclopramide with fluoxetine (mean ± sd) cmax (ng/ml) 44 ±15 62.7 ± 9.2 auc0-∞ (ngˑh/ml) 313 ± 113 591 ± 140 t1/2 (h) 5.5 ± 1.1 8.5 ± 2.2

es linearly with doses from 20 to 100 mg of metoclopramide (5 times the maximum recommended single dose of metoclopramide orally disintegrating tablets). cmax increased linearly with dose; tmax remained the same; whole body clearance was unchanged; and the elimination rate remained the same. linear kinetic processes adequately describe the absorption and elimination of metoclopramide. the pharmacokinetic characteristics following single oral administration of 10 mg metoclopramide hydrochloride orally disintegrating tablets under fasting conditions are shown in table 5. table 5 mean (± sd) pharmacokinetic parameters in healthy subjects following a single oral dose of 10 mg metoclopramide orally disintegrating tablets under fasting conditions treatment c max (ng/ml) t max (h)* auc 0-inf (ng*h/ml) single 10 mg metoclopramide orally disintegrating tablets (n=41) 28±7.4 2.0 (0.7 to 4.0) 268±72.6 *presented as median (range). effect of food when metoclopramide orally disintegrating tablets was taken immediately after a high-fat meal (approximately 900 total calories based on the composition being 150 protein calories, 250 carbohydrate calories and 500 fat calories), the cmax was 17% lower than when taken after an overnight fast. the tmax increased from about 1.8 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 orally disintegrating tablets was administered with or without food. the clinical relevance of a lower cmax with a high-fat meal is unknown [see dosage and administration (2.1) ] . distribution metoclopramide 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. elimination the average elimination half-life of metoclopramide in subjects with normal renal function was 5 to 6 hours metabolism metoclopramide undergoes enzymatic metabolism via oxidation as well as glucuronide and sulfate conjugation reactions in the liver. monodeethylmetoclopramide, a major oxidative metabolite, is formed primarily by cyp2d6, an enzyme subject to genetic variability [see dosage and administration ( 2.2 , 2.3 ), use in specific populations ( 8.9 )] . excretion approximately 85% of the radioactivity of an orally administered dose appears in the urine within 72 hours. after oral administration of 10 or 20 mg, a mean of 18% and 22% of the dose, respectively, was recovered as free metoclopramide in urine within 36 hours. specific populations patients with renal impairment in a study of 24 patients with varying degrees of renal impairment (moderate, severe, and end-stage renal disease (esrd) requiring dialysis), the systemic exposure (auc) of metoclopramide in patients with moderate to severe renal impairment was about 2-fold the auc in subjects with normal renal function. the auc of metoclopramide in patients with esrd on dialysis was about 3.5-fold the auc in subjects with normal renal function [see dosage and administration ( 2.2 , 2.3 ), use in specific populations ( 8.6 )]. patients with hepatic impairment in a group of 8 patients with severe hepatic impairment (child-pugh c), the average metoclopramide clearance was reduced by approximately 50% compared to patients with normal hepatic function [see dosage and administration ( 2.2 , 2.3 ), use in specific populations ( 8.7 )]. drug interaction studies effect of metoclopramide on cyp2d6 substrates although in vitro studies suggest that metoclopramide can inhibit cyp2d6, metoclopramide is unlikely to interact with cyp2d6 substrates in vivo at therapeutically relevant concentrations. effect of cyp2d6 inhibitors on metoclopramide in healthy subjects, 20 mg of oral metoclopramide and 60 mg of fluoxetine (a strong cyp2d6 inhibitor) were administered, following prior exposure to 60 mg fluoxetine orally for 8 days. the patients who received concomitant metoclopramide and fluoxetine had a 40% and 90% increase in metoclopramide cmax and auc0-∞, respectively, compared to patients who received metoclopramide alone (see table 6 metoclopramide pharmacokinetic parameters in healthy subjects with and without fluoxetine) [see drug interactions ( 7.1 )] . table 6 metoclopramide pharmacokinetic parameters in healthy subjects with and without fluoxetine parameter metoclopramide alone (mean ± sd) metoclopramide with fluoxetine (mean ± sd) cmax (ng/ml) 44 ±15 62.7 ± 9.2 auc0-∞ (ngˑh/ml) 313 ± 113 591 ± 140 t1/2 (h) 5.5 ± 1.1 8.5 ± 2.2

t was negative in the in vitro ames mutation assay, the in vitro unscheduled dna synthesis assay with rat and human hepatocytes and the in vivo rat micronucleus assay. impairment of fertility 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.

itro ames mutation assay, the in vitro unscheduled dna synthesis assay with rat and human hepatocytes and the in vivo rat micronucleus assay. impairment of fertility 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.

er of any other medication must be made aware that the patient is taking metoclopramide orally disintegrating tablets. inform patients or their caregivers that metoclopramide orally disintegrating tablets can cause drowsiness or dizziness, or otherwise impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle [see warnings and precautions (5.8) ] . administration instruct patients to: take on an empty stomach at least 30 minutes before eating. 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 dosage and administration (2.1) ]. manufactured by: novel laboratories, inc. somerset, nj 08873 usa manufactured for: lupin pharmaceuticals, inc. baltimore, md 21202 pi5800000203 sap code: 260278 rev. 10/2019