Gimoti

GIMOTI is indicated for the relief of symptoms in adults with acute and recurrent diabetic gastroparesis. GIMOTI is a dopamine-2 (D 2) antagonist indicated for the relief of symptoms in adults with acute and recurrent diabetic gastroparesis. (1) Limitations of Use: GIMOTI 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. (1, 8.4) moderate or severe hepatic impairment (Child-Pugh B or C), moderate or severe renal impairment (creatinine clearance less than 60 mL/minute), and patients concurrently using strong CYP2D6 inhibitors due to the risk of increased drug exposure and adverse reactions. (1, 5.9, 7.1) Limitations of Use: GIMOTI is not recommended for use in: pediatric patients due to the risk of developing tardive dyskinesia (TD) and other extrapyramidal symptoms as well as the risk of methemoglobinemia in neonates [see Use in Specific Populations (8.4)]. moderate or severe hepatic impairment (Child-Pugh B or C), moderate or severe renal impairment (creatinine clearance less than 60 mL/minute), and patients concurrently using strong CYP2D6 inhibitors due to the risk of increased drug exposure and adverse reactions [see Warnings and Precautions (5.9)].

Limitations of Use: GIMOTI is not recommended for use in: pediatric patients due to the risk of developing tardive dyskinesia (TD) and other extrapyramidal symptoms as well as the risk of methemoglobinemia in neonates [see Use in Specific Populations (8.4)]. moderate or severe hepatic impairment (Child-Pugh B or C), moderate or severe renal impairment (creatinine clearance less than 60 mL/minute), and patients concurrently using strong CYP2D6 inhibitors due to the risk of increased drug exposure and adverse reactions [see Warnings and Precautions (5.9)].

Administration See the full prescribing information for complete information on administration. (2.1) Recommended Dosage Adults less than 65 years of age: The recommended dosage is 1 spray (15 mg) in one nostril, 30 minutes before each meal and at bedtime (maximum of 4 sprays daily). (2.2) Adults 65 years of age and older: GIMOTI is not recommended in geriatric patients as initial therapy. Geriatric patients receiving an alternative metoclopramide product at a stable dosage of 10 mg four times daily can be switched to GIMOTI 1 spray (15 mg) in one nostril, 30 minutes before each meal and at bedtime (maximum four times daily). (2.2, 8.5)

2.1Important Administration and Storage Instructions

One spray in one nostril administers the appropriate dose. Before administering the first dose from a bottle, prime the pump by pressing down on the finger flange and releasing 10 sprays in the air. Place the spray nozzle tip under one nostril and lean the head slightly forward so the tip of spray nozzle is aimed away from the septum and toward the back of the nose. Close the other nostril with the other index finger. Move spray pump upwards so the tip of the nozzle is in the nostril. To ensure a full dose, hold the bottle upright while pressing down firmly and completely on finger flange and release while inhaling slowly through the open nostril. Remove spray pump nozzle tip from nostril and exhale slowly through the mouth. Wipe the spray nozzle with a clean tissue. Missed or Incomplete Doses If uncertain that the spray entered the nose, do not repeat the dose. Take the next dose at the scheduled time. If a dose is missed, take the next dose of GIMOTI at the regularly scheduled time. Do not make up for the missed dose or double the next dose. Storage Discard GIMOTI 4 weeks after opening even if the bottle contains unused drug. 2.2 Recommended Dosage Adults Less Than 65 Years of Age The recommended dosage of GIMOTI for the treatment of acute and recurrent diabetic gastroparesis in adults is 1 spray (15 mg) in one nostril, 30 minutes before each meal and at bedtime (maximum of four times daily). Adults 65 Years of Age and Older Elderly patients may be more sensitive to the adverse effects of metoclopramide and require a lower starting dosage [see Warnings and Precautions (5.1)]. GIMOTI is not recommended in geriatric patients as initial therapy. Geriatric patients receiving an alternative metoclopramide product at a stable dosage of 10 mg four times daily can be switched to GIMOTI 1 spray (15 mg) in one nostril, 30 minutes before each meal and at bedtime (maximum four times daily). Treatment Duration Use GIMOTI for the shortest duration of treatment and periodically reassess the need for continued treatment. Avoid treatment with metoclopramide, including GIMOTI, for longer than 12 weeks. If longer-term use is unavoidable, routinely monitor for signs and symptoms of TD [see Warnings and Precautions (5.1)].

2.1Important Administration and Storage Instructions

One spray in one nostril administers the appropriate dose. Before administering the first dose from a bottle, prime the pump by pressing down on the finger flange and releasing 10 sprays in the air. Place the spray nozzle tip under one nostril and lean the head slightly forward so the tip of spray nozzle is aimed away from the septum and toward the back of the nose. Close the other nostril with the other index finger. Move spray pump upwards so the tip of the nozzle is in the nostril. To ensure a full dose, hold the bottle upright while pressing down firmly and completely on finger flange and release while inhaling slowly through the open nostril. Remove spray pump nozzle tip from nostril and exhale slowly through the mouth. Wipe the spray nozzle with a clean tissue. Missed or Incomplete Doses If uncertain that the spray entered the nose, do not repeat the dose. Take the next dose at the scheduled time. If a dose is missed, take the next dose of GIMOTI at the regularly scheduled time. Do not make up for the missed dose or double the next dose. Storage Discard GIMOTI 4 weeks after opening even if the bottle contains unused drug.

Missed or Incomplete Doses If uncertain that the spray entered the nose, do not repeat the dose. Take the next dose at the scheduled time. If a dose is missed, take the next dose of GIMOTI at the regularly scheduled time. Do not make up for the missed dose or double the next dose.

Storage Discard GIMOTI 4 weeks after opening even if the bottle contains unused drug.

2.2Recommended Dosage Adults Less Than

65 Years of Age The recommended dosage of GIMOTI for the treatment of acute and recurrent diabetic gastroparesis in adults is 1 spray (15 mg) in one nostril, 30 minutes before each meal and at bedtime (maximum of four times daily). Adults 65 Years of Age and Older Elderly patients may be more sensitive to the adverse effects of metoclopramide and require a lower starting dosage [see Warnings and Precautions (5.1)]. GIMOTI is not recommended in geriatric patients as initial therapy. Geriatric patients receiving an alternative metoclopramide product at a stable dosage of 10 mg four times daily can be switched to GIMOTI 1 spray (15 mg) in one nostril, 30 minutes before each meal and at bedtime (maximum four times daily). Treatment Duration Use GIMOTI for the shortest duration of treatment and periodically reassess the need for continued treatment. Avoid treatment with metoclopramide, including GIMOTI, for longer than 12 weeks. If longer-term use is unavoidable, routinely monitor for signs and symptoms of TD [see Warnings and Precautions (5.1)].

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 GIMOTI 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, including GIMOTI, can cause tardive dyskinesia (TD), a syndrome of potentially irreversible and disfiguring involuntary movements of the face or tongue, and sometimes of the trunk and/or extremities. Metoclopramide, including GIMOTI, may also suppress, or partially suppress, the signs of TD, and may delay the diagnosis of TD because it may mask the underlying disease process. The effect of this symptomatic suppression upon the long-term course of TD is unknown. TD may remit, partially or completely, if GIMOTI treatment is discontinued. In patients treated with metoclopramide, including GIMOTI, the risk of developing TD and the likelihood that TD will become irreversible increases with duration of treatment and total cumulative dosage. Additionally, the risk of developing TD is increased in elderly patients, especially in elderly women [see Use in Specific Populations (8.5)], and in patients with diabetes mellitus. Prevention, Mitigation, and Monitoring for TD GIMOTI is contraindicated in patients with a history of TD. Avoid use of GIMOTI in patients receiving concomitant antipsychotics due to the potential additive effects of TD [see Drug Interactions (7.1)]. GIMOTI is not recommended in geriatric patients as initial therapy [see Dosage and Administration (2.2)]. Use GIMOTI for the shortest duration of treatment and periodically reassess the need for continued treatment. Immediately discontinue GIMOTI immediately in patients who develop signs and symptoms of TD. Avoid a total duration of treatment with metoclopramide products, including GIMOTI, for longer than 12 weeks. If longer-term use is unavoidable, routinely monitor for signs and symptoms of TD. If patients have continued TD symptoms, consider TD treatment. 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 GIMOTI. Extrapyramidal symptoms (EPS), such as acute dystonic reactions, occurred in patients treated with oral metoclopramide dosages of 30 mg 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 (GIMOTI 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 GIMOTI in patients receiving other drugs that can cause EPS (e.g., antipsychotics). Parkinsonian 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 after discontinuation of metoclopramide. Avoid GIMOTI in patients with Parkinson’s disease and other patients being treated with antiparkinsonian drugs due to potential exacerbation of symptoms. If treatment is unavoidable, use GIMOTI for the shortest duration of treatment and periodically reassess the need for continued treatment. Routinely monitor for signs and symptoms of Parkinson’s disease [see Dosage and Administration (2.2)]. 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. Discontinue GIMOTI if these symptoms develop. 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 GIMOTI in patients receiving other drugs associated with NMS, including typical and atypical antipsychotics. Clinical manifestations of NMS include hyperpyrexia, 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 conditions (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 GIMOTI 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 GIMOTI 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 GIMOTI use in patients with hypertension or in patients taking monoamine oxidase inhibitors [see Drug Interactions (7.1)]. There are also clinical reports of hypertensive crises in patients with undiagnosed pheochromocytoma. GIMOTI is contraindicated in patients with pheochromocytoma or other catecholamine-releasing paragangliomas [see Contraindications (4)]. Discontinue GIMOTI 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 GIMOTI if any of these adverse reactions occur. 5.7 Hyperprolactinemia As with other dopamine D 2 receptor antagonists, metoclopramide elevates prolactin levels. Hyperprolactinemia may suppress hypothalamic gonadotropin-releasing hormone, 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 D 2 receptor 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 GIMOTI or the interacting drug, depending on the importance of the drug to the patient [see Drug Interactions (7.1)]. 5.9 Risk of Adverse Reactions with GIMOTI in Patients with Moderate or Severe Renal and Hepatic Impairment, CYP2D6 Poor Metabolizers and Patients Taking Strong CYP2D6 Inhibitors Patients with moderate or severe renal or hepatic impairment, patients who are CYP2D6 poor metabolizers, and patients concurrently using strong CYP2D6 inhibitors have increased exposure to metoclopramide from GIMOTI due to reduced metabolism or excretion which may lead to an increased risk of adverse reactions, including tardive dyskinesia. Use of GIMOTI is not recommended in these patient populations since the dose of GIMOTI cannot be adjusted to reduce exposure [see Drug Interactions (7.1), Use in Specific Populations (8.6, 8.7, 8.9)].

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 symptoms [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)] 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 safety of GIMOTI was evaluated in clinical trials of patients with gastroparesis and established in clinical trials of oral metoclopramide. Most common adverse reactions (≥5%) are: dysgeusia, headache, and fatigue. (6) To report SUSPECTED ADVERSE REACTIONS, contact Evoke Pharma, Inc. at 1-833-4-GIMOTI (1-833-444-6684), or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Safety of GIMOTI In a randomized, placebo-controlled clinical trial of 190 male and female patients of GIMOTI 14 mg, a slightly lower than recommended dosage, administered nasally four times daily for 4 weeks, dysgeusia was the most commonly reported adverse reaction (15% of GIMOTI-treated patients and 4% of placebo-treated patients). Other adverse reactions were similar to those reported for oral metoclopramide. Safety of Oral Metoclopramide The most common adverse reactions (in approximately 10% of patients receiving the recommended oral metoclopramide dosage of 10 mg 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 metoclopramide orally 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

Antipsychotics: Potential for additive effects, including TD, EPS, and NMS; avoid concomitant use. (7.1) Central nervous system (CNS) depressants: Increased risk of CNS depression. Avoid concomitant use and monitor for adverse reactions. (7.1) Monoamine oxidase (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

1 displays the effects of other drugs on metoclopramide. Table 1. 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 Use of GIMOTI is not recommended [see Warnings and Precautions (5.9)]. 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 GIMOTI 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 Potential for decreased effect of metoclopramide due to opposing effects on gastrointestinal motility. Intervention Monitor for reduced effect on gastrointestinal motility. 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

7.2Effects of Metoclopramide on Other Drugs Table

2 displays the effects of metoclopramide on other drugs. Table 2. 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 tablet., 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.

8.1Pregnancy Risk Summary

Published studies, including retrospective cohort studies, national registry studies, and meta-analyses, do not report a consistent pattern or a consistently increased risk of adverse pregnancy-related outcomes with oral use of metoclopramide during pregnancy. However, available data from a case report of GIMOTI use in pregnancy is insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. 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 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 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 was observed. 8.2 Lactation Risk Summary There are no data on the presence of metoclopramide in human milk following nasal administration; however, published data report the presence of metoclopramide in human milk in variable amounts following oral administration (see Data). Systemic exposure following nasal administration of GIMOTI 15 mg is expected to be similar to oral administration of metoclopramide 10 mg [see Clinical Pharmacology (12.3)]. Breastfed infants exposed to metoclopramide have experienced gastrointestinal adverse reactions, including intestinal discomfort and increased intestinal gas formation (see Clinical Considerations). 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 GIMOTI and any potential adverse effects on the breastfed child from GIMOTI 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 oral 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 GIMOTI 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 Indications and Usage (1), 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 renal function [see Warnings and Precautions (5.1), 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 adverse effects of metoclopramide, especially elderly women, and require a lower starting dosage. GIMOTI is not recommended in geriatric patients as initial therapy. Geriatric patients receiving an alternative metoclopramide product at a stable dosage of 10 mg four times daily can be switched to GIMOTI [see Dosage and Administration (2.2)]. 8.6 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 [see Clinical Pharmacology (12.3)]. GIMOTI is not recommended in patients with moderate and severe renal impairment (creatinine clearance less than 60 mL/minute), including those receiving hemodialysis and continuous ambulatory peritoneal dialysis [see Warnings and Precautions (5.9)]. Use the recommended dosage of GIMOTI in patients with mild renal impairment (creatinine clearance 60 mL/minute or greater) [see Dosage and Administration (2.2)]. 8.7 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 [see Clinical Pharmacology (12.3)]. 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). GIMOTI is not recommended in patients with moderate or severe (Child-Pugh B or C) hepatic impairment [see Warnings and Precautions (5.9)]. Use the recommended dosage of GIMOTI in patients with mild hepatic impairment (Child-Pugh A) [see Dosage and Administration (2.2)]. 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. 8.8 NADH-Cytochrome b 5 Reductase Deficiency Metoclopramide-treated patients with NADH-cytochrome b 5 reductase deficiency are at an increased risk of developing methemoglobinemia and/or sulfhemoglobinemia. For patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with 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)]. 8.9 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 [see Clinical Pharmacology (12.3)]. GIMOTI is not recommended in patients who are CYP2D6 poor metabolizers [see Warnings and Precautions (5.9)].

Risk Summary Published studies, including retrospective cohort studies, national registry studies, and meta-analyses, do not report a consistent pattern or a consistently increased risk of adverse pregnancy-related outcomes with oral use of metoclopramide during pregnancy. However, available data from a case report of GIMOTI use in pregnancy is insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. 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 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 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 was observed.