METOCLOPRAMIDE: 10,911 Adverse Event Reports & Safety Profile

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

Each Metoclopramide Orally Disintegrating Tablets

5 mg tablet contains 5 mg metoclopramide (equivalent to 5.91 mg of metoclopramide hydrochloride USP).

Each Metoclopramide Orally Disintegrating Tablets

10 mg tablet contains 10 mg metoclopramide (equivalent to 11.82 mg metoclopramide hydrochloride USP).

Metoclopramide Orally Disintegrating

Tablets includes the following inactive ingredients: phosphoric acid, mannitol and starch, microcrystalline cellulose, colloidal silicon dioxide, amino methacrylate copolymer, butylated hydroxyanisole, butylated hydroxytoluene, crospovidone, aspartame, N-C mint flavor, magnesium stearate. Metoclopramide

AND USAGE 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 )].

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 tablets may be administered continuously or intermittently in patients with symptomatic gastroesophageal reflux who fail to respond to conventional therapy:Metoclopramide tablets 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.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.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 Tablet

Dosage in Patients with Gastroesophageal Reflux Recommended Dosage Maximum Recommended Daily Dosage Adult patientsAdult patients 10 to 15 mg four times daily (thirty minutes before each meal and at bedtime)10 to 15 mg four times daily (thirty minutes before each meal and at bedtime) 60 mg60 mg Mild hepatic impairment (Child-Pugh A)Mild hepatic impairment (Child-Pugh A) Elderly patients [ ] Elderly patients [ see Use in Specific Populations ( 8.5 ) ] 5 mg four times daily (thirty minutes before each meal and at bedtime) 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) [ ] 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), or5 mg four times daily (thirty minutes before each meal and at bedtime), or 10 mg taken three times daily10 mg taken three times daily 30 mg30 mg CYP2D6 poor metabolizers [ ] CYP2D6 poor metabolizers [ see Use in Specific Populations ( 8.9 ) ] Concomitant use with strong CYP2D6 inhibitors (e.g., quinidine, bupropion, fluoxetine, and paroxetine) [ ] 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) [ ] 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 [ ] 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 daily5 mg four times daily (thirty minutes before each meal and at bedtime) or 10 mg twice daily 20 mg20 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 [ ]. Administer the dosage thirty minutes before each meal and at bedtime. The maximum recommended daily dosage is 40 mg. 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 dosage thirty 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 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 tablets.If patients with diabetic gastroparesis have severe nausea or vomiting and are unable to take oral metoclopramide 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 tablets.

Table

2.

Recommended Metoclopramide Tablet

Dosage in Patients with Acute and Recurrent Diabetic Gastroparesis Recommended Dosage Maximum Recommended Daily Dosage Adult PatientsAdult Patients 10 mg four times daily (30 minutes before each meal and at bedtime)10 mg four times daily (30 minutes before each meal and at bedtime) 40 mg40 mg Mild hepatic impairment (Child-Pugh A)Mild hepatic impairment (Child-Pugh A) Elderly patients [ ] Elderly patients [ see Use in Specific Populations ( 8.5 ) ] 5 mg four times daily (30 minutes before each meal and at bedtime) 5 mg Elderly patients may be more sensitive to the therapeutic or adverse effects of metoclopramide; therefore, consider a lower dosage of 5 mg four times daily with titration to the recommended adult dosage of 10 mg four time daily based upon response and tolerability. four times daily (30 minutes before each meal and at bedtime) Moderate or severe hepatic impairment (Child-Pugh B or C) [ ] Moderate or severe hepatic impairment (Child-Pugh B or C) [ see Use in Specific Populations ( 8.7 ) ] 5 mg four times daily (30 minutes before each meal and at bedtime)5 mg four times daily (30 minutes before each meal and at bedtime) 20 mg20 mg CYP2D6 poor metabolizers [ ] CYP2D6 poor metabolizers [ see Use in Specific Populations ( 8.9 ) ] Concomitant use with strong CYP2D6 inhibitors (e.g., quinidine, bupropion, fluoxetine, and paroxetine) [ ] 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 60 mL/minute) [ ] Moderate or severe renal impairment (creatinine clearance less than 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 [ ] 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 daily5 mg twice daily 10 mg10 mg

Metoclopramide is contraindicated: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 ) ].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 [ 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 may occur in patients receiving the recommended prescribed dosage of metoclopramide injection. Insomnia, headache, confusion, dizziness, or mental depression with suicidal ideation also may occur (see WARNINGS ). In cancer chemotherapy patients being treated with 1 to 2 mg/kg per dose, incidence of drowsiness is about 70%. There are isolated reports of convulsive seizures without a clear-cut 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. In cancer chemotherapy patients receiving 1 to 2 mg/kg per dose, the incidence is 2% in patients over the ages of 30 to 35, and 25% or higher in pediatric patients and adult patients less than 30 years of age who have not had prophylactic administration of diphenhydramine. 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, and 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, muscular rigidity, altered consciousness, and autonomic instability (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 atrioventricular (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 a clear-cut 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. Transient flushing of the face and upper body, without alterations in vital signs, following high doses intravenously. To report SUSPECTED ADVERSE REACTIONS, contact Avenacy Inc. at 1-855-283-6229 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

AND PRECAUTIONS Tardive Dyskinesia (TD), Other Extrapyramidal Symptoms (EPS), and Neuroleptic Malignant Syndrome (NMS) : Avoid concomitant use of other drugs known to cause TD/EPS/NMS and avoid use in patients with Parkinson’s Disease. If symptoms occur, discontinue metoclopramide and seek immediate medical attention. ( 5.1 , 5.2 , 5.3 , 7.1 , 7.2 ) Depression and suicidal ideation/suicide : Avoid use. ( 5.4 )

5.1 Tardive Dyskinesia Metoclopramide 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. Movements may be choreoathetotic in appearance. 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 among the elderly, especially elderly women [ ], and in patients with diabetes mellitus. Due to the risk of developing TD, avoid treatment with metoclopramide for longer than 12 weeks and reduce the dosage in elderly patients [ ]. Metoclopramide 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. Movements may be choreoathetotic in appearance. 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 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 for longer than 12 weeks and reduce the dosage in elderly patients [ see Dosage and Administration ( 2.2 , 2.3 ) ]. Discontinue metoclopramide 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 is withdrawn.Discontinue metoclopramide 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 is withdrawn. Metoclopramide 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 is contraindicated in patients with a history of TD [ ]. Metoclopramide 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 is contraindicated in patients with a history of TD [ see Contraindications ( 4 ) ]. Avoid metoclopramide in patients receiving other drugs that are likely to 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.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. Extrapyramidal symptoms (EPS), such as acute dystonic reactions, occurred in patients treated with 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 (metoclopramide 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 in patients receiving other drugs that can cause EPS (e.g., antipsychotics).Avoid metoclopramide 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 metoclopramide in patients with Parkinson’s disease and other patients being treated with antiparkinsonian drugs due to potential exacerbation of symptoms. Avoid treatment with metoclopramide for more than 12 weeks [ see Dosage and Administration ( 2.2 , 2.3 ), Warnings and Precautions ( 5.1 ) ]. Avoid metoclopramide in patients with Parkinson’s disease and other patients being treated with antiparkinsonian drugs due to potential exacerbation of symptoms.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). Avoid metoclopramide in patients receiving other drugs associated with NMS, including typical and atypical antipsychotics. 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 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.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.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:Management of NMS includes: Immediate discontinuation of metoclopramide 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 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 Drug Interactions ( 7.1 ) ]. There are also clinical reports of hypertensive crises in patients with undiagnosed pheochromocytoma. Metoclopramide is contraindicated in patients with pheochromocytoma or other catecholamine-releasing paragangliomas [ see Contraindications ( 4 ) ]. Discontinue metoclopramide 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 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 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 D 2 receptor antagonists and tumorigenesis in humans [ see Nonclinical Toxicology ( 13.1 ) ].

5.8 Effects of 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 or the interacting drug, depending on the importance of the drug to the patient [ see Drug Interactions ( 7.1 ) ].

PRECAUTIONS General In one study in hypertensive patients, intravenously administered metoclopramide was shown to release catecholamines; hence, caution should be exercised when metoclopramide is used in patients with hypertension. Intravenous injections of undiluted metoclopramide should be made slowly allowing 1 to 2 minutes for 10 mg since a transient but intense feeling of anxiety and restlessness, followed by drowsiness, may occur with rapid administration. Because metoclopramide produces a transient increase in plasma aldosterone, certain patients, especially those with cirrhosis or congestive heart failure, may be at risk of developing fluid retention and volume overload. If these side effects occur at any time during metoclopramide therapy, the drug should be discontinued. Intravenous administration of Metoclopramide Injection diluted in a parenteral solution should be made slowly over a period of not less than 15 minutes. Giving a promotility drug such as metoclopramide theoretically could put increased pressure on suture lines following a gut anastomosis or closure. This possibility should be considered and weighed when deciding whether to use metoclopramide or nasogastric suction in the prevention of postoperative nausea and vomiting. Information for Patients A patient Medication Guide is available for Metoclopramide Injection. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. Refer to accompanying Medication Guide. 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. The ambulatory patient should be cautioned accordingly.

Drug Interactions

The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxidase inhibitors. Absorption of drugs from the stomach may be diminished (e.g. digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g. acetaminophen, tetracycline, levodopa, ethanol, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. Carcinogenesis, Mutagenesis, Impairment of Fertility A 77-week study was conducted in rats with oral doses up to about 40 times the maximum recommended human daily dose. Metoclopramide elevates prolactin levels and the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the prescription of metoclopramide is contemplated in a patient with previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating drugs, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of prolactin-stimulating neuroleptic drugs and metoclopramide. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is too limited to be conclusive at this time.

An

Ames mutagenicity test performed on metoclopramide was negative. Pregnancy: Teratogenic Effects: Pregnancy Category B Reproduction studies performed in rats, mice and rabbits by the intramuscular, intravenous, subcutaneous (SC), and oral routes at maximum levels ranging from 12 to 250 times the human dose have demonstrated no impairment of fertility or significant harm to the fetus due to metoclopramide. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

Metoclopramide is excreted in human milk. Caution should be exercised when metoclopramide is administered to a nursing mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established except as stated to facilitate small bowel intubation (see OVERDOSAGE and DOSAGE & ADMINISTRATION ). Care should be exercised in administering metoclopramide to neonates since prolonged clearance may produce excessive serum concentrations (see CLINICAL PHARMACOLOGY , Pharmacokinetics). In addition, neonates have reduced levels of NADH-cytochrome b5 reductase which, in combination with the aforementioned pharmacokinetic factors, make neonates more susceptible to methemoglobinemia (see OVERDOSAGE ). The safety profile of metoclopramide in adults cannot be extrapolated to pediatric patients. Dystonias and other extrapyramidal reactions associated with metoclopramide are more common in the pediatric population than in adults. (See WARNINGS and ADVERSE REACTIONS , Extrapyramidal Reactions.)

Geriatric Use

Clinical studies of Metoclopramide Injection did not include sufficient numbers of subjects aged 65 and over to determine whether elderly subjects respond differently from younger subjects. The risk of developing Parkinsonian-like side effects increases with ascending dose. Geriatric patients should receive the lowest dose of Metoclopramide Injection that is effective.

If

Parkinsonian-like symptoms develop in a geriatric patient receiving Metoclopramide Injection, Metoclopramide Injection should generally be discontinued before initiating any specific anti-Parkinsonian agents (see WARNINGS ). The elderly may be at greater risk for tardive dyskinesia (see WARNINGS , Tardive Dyskinesia). Sedation has been reported in Metoclopramide Injection users. Sedation may cause confusion and manifest as over-sedation in elderly (see CLINICAL PHARMACOLOGY , PRECAUTIONS , Information for Patients and ADVERSE REACTIONS , CNS Effects).

Metoclopramide

Injection is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function (see DOSAGE & ADMINISTRATION , Use in Patients with Renal or Hepatic Impairment). For these reasons, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased renal function, concomitant disease, or other drug therapy in the elderly (see Use in Patients with Renal or Hepatic Impairment).

Other Special Populations

Patients with NADH-cytochrome b5 reductase deficiency are at an increased risk of developing methemoglobinemia and/or sulfhemoglobinemia when metoclopramide is administered. In patients with G6PD deficiency who experience metoclopramide-induced methemoglobinemia, methylene blue treatment is not recommended (see OVERDOSAGE ).

INTERACTIONS

• 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 )
• Strong CYP2D6 inhibitors (e.g., quinidine, bupropion, fluoxetine, and paroxetine) : See Full Prescribing Information for recommended dosage reductions. ( 2.1 , 2.2 , 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 )

7.1 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 Reglan dosage [see Dosage and Administration ( 2.1 , 2.2 )] . 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

Reglan 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*, 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