Metoclopramide Hcl (metoclopramide HCl)

Although USP currently states that potency of metoclopramide hydrochloride preparations should be expressed both in terms of the salt and the base (''active moiety''), dosage currently is expressed in terms of the base.

Therapy with metoclopramide, including all dosage forms and routes of administration, should not exceed 12 weeks' duration because of the increased risk of developing tardive dyskinesia with longer-term use.

Metoclopramide nasal spray delivers 15 mg of metoclopramide per 70-mcL metered spray. Each bottle contains 9.8 mL of solution, which is sufficient for administration 4 times daily over a period of 4 weeks.

Metoclopramide is administered orally, intranasally, by IM or direct IV injection, or by IV infusion.

Therapy with the drug, including all dosage forms and routes of administration, should not exceed 12 weeks' duration because of the risk for developing tardive dyskinesia with longer-term use. Oral and intranasal preparations of metoclopramide are recommended for adults only.

Metoclopramide undergoes oxidative metabolism via cytochrome P-450 isoenzyme 2D6 (CYP2D6), as well as conjugation with glucuronic acid and sulfuric acid.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Gastric Stimulants/Pramlintide

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Pramlintide slows gastric emptying. Gastric stimulants may result in decreased effects.(1)

CLINICAL EFFECTS: Concurrent use of pramlintide and use of gastric stimulants may result in decreased effects of both agents.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of pramlintide states that pramlintide therapy should not be considered in patients requiring the use of drugs that stimulate gastrointestinal motility.(1)

DISCUSSION: Patients using drugs that alter gastrointestinal motility have not been studied in clinical trials for pramlintide.(1)

Metoclopramide/Cabergoline; Pergolide

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Dopamine antagonists such as metoclopramide may block the effects of cabergoline(1) and pergolide(2,3), dopamine agonists.

CLINICAL EFFECTS: Concurrent administration of cabergoline or pergolide with metoclopramide may decrease the effectiveness of cabergoline(1) and pergolide.(2,3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturers of cabergoline and pergolide state that cabergoline(1) and pergolide(2) should not be administered concurrently with dopamine antagonists such as metoclopramide.

DISCUSSION: The manufacturers of cabergoline and pergolide state that these agents should not be administered concurrently with dopamine antagonists such as metoclopramide.(1-3)

Metoclopramide/Fosfomycin, Oral

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Metoclopramide may decrease the amount of fosfomycin absorbed.(1)

CLINICAL EFFECTS: The concurrent use of metoclopramide may result in reduced levels of fosfomycin and treatment failure.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Fosfomycin should not be used in patients receiving metoclopramide.(1) Consider the use of alternative urinary tract anti-infectives in patients maintained on metoclopramide. If concurrent use is warranted, monitor patients for fosfomycin treatment failure.

DISCUSSION: Metoclopramide has been shown to reduce fosfomycin levels. Urinary levels of fosfomycin may not exceed required bactericidal levels for a long enough period of time to result in microbiological cure.(1)

Selected Cyp2d6 Substrates/Mavorixafor

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Mavorixafor is a strong inhibitor of CYP2D6 and is expected to inhibit the metabolism of agents through this pathway.(1)

CLINICAL EFFECTS: Concurrent use of mavorixafor may result in elevated levels of and toxicity from agents metabolized by CYP2D6.(1)

PREDISPOSING FACTORS: With tricyclic antidepressants, the risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). With anticholinergic agents, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(2)

PATIENT MANAGEMENT: The US manufacturer of mavorixafor states concurrent use with CYP2D6 substrate that are highly dependent on CYP2D6 metabolism is contraindicated.(1) The US manufacturer of doxepin states if concurrent use of doxepin and strong CYP2D6 inhibitors such as mavorixafor is warranted, monitor doxepin plasma concentrations and reduce the doxepin dose based on doxepin plasma concentrations.(5)

DISCUSSION: Mavorixafor (400 mg) increased dextromethorphan (CYP2D6 substrate) maximum concentration (Cmax) and area-under-curve (AUC) by 6-fold and 9-fold, respectively.(1) Selected CYP2D6 substrates linked to this monograph include: aripiprazole, atomoxetine, brexpiprazole, desipramine, deutetrabenazine, dextromethorphan, doxepin, encainide, fenfluramine, metoclopramide, methoxyphenamine, metoprolol, mexiletine, nebivolol, paroxetine, perphenazine, risperidone, tetrabenazine, trimipramine, venlafaxine, and yohimbine.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Metoclopramide/Antipsychotics; Phenothiazines; Rivastigmine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: These agents block dopamine (D2) receptors. D2 blockade can cause extrapyramidal reactions, such acute dystonic reactions, pseudoparkinsonian tremors, akathisia, or tardive dyskinesia. Neuroleptic malignant syndrome may also occur in patients receiving D2 blockers. The risk of these adverse effects may be increased by concurrent use.(1-3)

CLINICAL EFFECTS: Concurrent use may increase the risk of extrapyramidal reactions (e.g. acute dystonic reactions, pseudoparkinsonian tremors, akathisia, or tardive dyskinesia) and neuroleptic malignant syndrome. Tardive dyskinesia, which may be permanent, typically affects the facial muscles and may result in uncontrollable lip smacking, chewing, puckering of the mouth, frowning or scowling, sticking out the tongue, blinking and moving the eyes, and shaking of the arms and/or legs.(1-3) Symptoms of neuroleptic malignant syndrome include hyperpyrexia, muscle rigidity, altered mental status, an autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac arrhythmias), elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.(1)

PREDISPOSING FACTORS: Patients with Parkinson's or Lewy Body Disease may be more likely to have extrapyramidal reactions or unmasking of their primary disease symptoms. The risk of extrapyramidal symptoms is also increased in patients on metoclopramide for longer than 12 weeks. Elderly patients, especially elderly women, and diabetics are at higher risk of developing tardive dyskinesia. Other extrapyramidal symptoms, like acute dystonia, have occurred more frequently in patients younger than 30 years old.(1)

PATIENT MANAGEMENT: The concurrent use of metoclopramide and agents likely to cause extrapyramidal reactions should be avoided.(1) If concurrent use is warranted, monitor patients closely for extrapyramidal reactions and neuroleptic malignant syndrome. The manufacturer of metoclopramide says to avoid treatment with metoclopramide for longer than 12 weeks, and to use the lowest possible dose.(1) Discontinue therapy if symptoms occur. Instruct patients to seek immediate medical attention if symptoms develop. Symptoms of extrapyramidal reactions, including tardive dyskinesia, include involuntary movements of limbs and facial grimacing, torticollis, oculogyric crisis, rhythmic protrusion of the tongue, bulbar type of speech, trismus, and/or dystonic reactions resembling tetanus/stridor/dyspnea.(3)

DISCUSSION: Both metoclopramide and phenothiazines can cause extrapyramidal reactions, such as tardive dyskinesia, and neuroleptic malignant syndrome. The risk may be increased by concurrent use.(1,2) Extrapyramidal symptoms have been reported with concurrent metoclopramide and neuroleptics, prochlorperazine, and chlorpromazine.(4-6)

Metoclopramide/Atovaquone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Metoclopramide decreases the absorption of atovaquone.(1-3)

CLINICAL EFFECTS: The concurrent use of metoclopramide may result in decreased levels and effectiveness of atovaquone.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Metoclopramide should only be used in patients receiving atovaquone if no other antiemetic is available.(1-3)

DISCUSSION: Concurrent metoclopramide has been associated with a 50% decrease in atovaquone plasma concentrations.(1)

Metoclopramide/Maois

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: In patients treated with MAOIs, metoclopramide may result in the release of a large quantity of catecholamines.(1-3)

CLINICAL EFFECTS: Use of metoclopramide in patients treated with a MAOI may result in hypertensive crisis.(1-3)

PREDISPOSING FACTORS: The risk for hypertensive crisis may be greater in patients with hypertension, pheochromocytoma, or other catecholamine-releasing paragangliomas.

PATIENT MANAGEMENT: The US manufacturer of metoclopramide states avoid the concurrent use of metoclopramide and MAOIs.(1) The Australian manufacturer of metoclopramide states metoclopramide should be used cautiously, it at all, in patients on MAOIs.(2) The Canadian manufacturer of metoclopramide states care should be exercised with concurrent use of metoclopramide and MAOIs.(3) If concurrent use is warranted, monitor blood pressure closely for hypertensive crisis. Consider using the lowest possible dose of both metoclopramide and the MAOI.(1-3) If a rapid rise in blood pressure occurs or hypertensive crisis is suspected, discontinue metoclopramide.(1-3)

DISCUSSION: In patients treated with MAOIs, metoclopramide may result in the release of a large quantity of catecholamines, which may result in hypertensive crisis.(1-3) Metaxalone is a weak inhibitor of MAO.(4,5)

Metoclopramide/Posaconazole Oral Suspension

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Metoclopramide decreases the absorption of posaconazole oral suspension increasing gastric motility.(1-3)

CLINICAL EFFECTS: Concurrent use of metoclopramide may result in decreased levels and effectiveness of posaconazole oral suspension.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If possible, use the tablet formulation of posaconazole in patients requiring metoclopramide therapy. If concurrent use of metoclopramide and posaconazole suspension is required, monitor the patient for breakthrough fungal infections.(1,2)

DISCUSSION: In a cross-over study in 12 healthy subjects, use of metoclopramide (10 mg TID for 2 days) with Boost decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of posaconazole suspension (400 mg) by 21% and 19%, respectively.(2,3) In a cross-over study in 20 healthy subjects, use of metoclopramide (15 mg TID for 2 days) decreased the Cmax and AUC of a single dose of posaconazole tablets (400 mg) by 14% and 7%, respectively. This was not considered clinically significant.(2,4)

Metoclopramide/Prochlorperazine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Both metoclopramide and prochlorperazine block dopamine (D2) receptors. D2 blockade can cause extrapyramidal reactions, such acute dystonic reactions, pseudoparkinsonian tremors, akathisia, or tardive dyskinesia. Neuroleptic malignant syndrome may also occur in patients receiving D2 blockers. The risk of these adverse effects may be increased by concurrent use.(1-3)

CLINICAL EFFECTS: Concurrent use may increase the risk of extrapyramidal reactions (e.g. acute dystonic reactions, pseudoparkinsonian tremors, akathisia, or tardive dyskinesia) and neuroleptic malignant syndrome. Tardive dyskinesia, which may be permanent, typically affects the facial muscles and may result in uncontrollable lip smacking, chewing, puckering of the mouth, frowning or scowling, sticking out the tongue, blinking and moving the eyes, and shaking of the arms and/or legs.(1-3) Symptoms of neuroleptic malignant syndrome include hyperpyrexia, muscle rigidity, altered mental status, an autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac arrhythmias), elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.(1)

PREDISPOSING FACTORS: Patients with Parkinson's or Lewy Body Disease may be more likely to have extrapyramidal reactions or unmasking of their primary disease symptoms. The risk of extrapyramidal symptoms is also increased in patients on metoclopramide for longer than 12 weeks. Elderly patients, especially elderly women, and diabetics are at higher risk of developing tardive dyskinesia. Other extrapyramidal symptoms, like acute dystonia, have occurred more frequently in patients younger than 30 years old.(1)

PATIENT MANAGEMENT: The concurrent use of metoclopramide and agents likely to cause extrapyramidal reactions should be avoided.(1) If concurrent use is warranted, monitor patients closely for extrapyramidal reactions and neuroleptic malignant syndrome. The manufacturer of metoclopramide says to avoid treatment with metoclopramide for longer than 12 weeks, and to use the lowest possible dose.(1) Discontinue therapy if symptoms occur. Instruct patients to seek immediate medical attention if symptoms develop. Symptoms of extrapyramidal reactions, including tardive dyskinesia, include involuntary movements of limbs and facial grimacing, torticollis, oculogyric crisis, rhythmic protrusion of the tongue, bulbar type of speech, trismus, and/or dystonic reactions resembling tetanus/stridor/dyspnea.

DISCUSSION: Both metoclopramide and phenothiazines can cause extrapyramidal reactions, such as tardive dyskinesia, and neuroleptic malignant syndrome. The risk may be increased by concurrent use.(1,2) Extrapyramidal symptoms have been reported with concurrent metoclopramide and neuroleptics, prochlorperazine, and chlorpromazine.(3-6)

Metoclopramide/Promethazine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Both metoclopramide and promethazine block dopamine (D2) receptors. D2 blockade can cause extrapyramidal reactions, such acute dystonic reactions, pseudoparkinsonian tremors, akathisia, or tardive dyskinesia. Neuroleptic malignant syndrome may also occur in patients receiving D2 blockers. The risk of these adverse effects may be increased by concurrent use.(1-3)

CLINICAL EFFECTS: Concurrent use may increase the risk of extrapyramidal reactions (e.g. acute dystonic reactions, pseudoparkinsonian tremors, akathisia, or tardive dyskinesia) and neuroleptic malignant syndrome. Tardive dyskinesia, which may be permanent, typically affects the facial muscles and may result in uncontrollable lip smacking, chewing, puckering of the mouth, frowning or scowling, sticking out the tongue, blinking and moving the eyes, and shaking of the arms and/or legs.(1-3) Symptoms of neuroleptic malignant syndrome include hyperpyrexia, muscle rigidity, altered mental status, an autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac arrhythmias), elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.(1)

PREDISPOSING FACTORS: Patients with Parkinson's or Lewy Body Disease may be more likely to have extrapyramidal reactions or unmasking of their primary disease symptoms. The risk of extrapyramidal symptoms is also increased in patients on metoclopramide for longer than 12 weeks. Elderly patients, especially elderly women, and diabetics are at higher risk of developing tardive dyskinesia. Other extrapyramidal symptoms, like acute dystonia, have occurred more frequently in patients younger than 30 years old.(1)

PATIENT MANAGEMENT: The concurrent use of metoclopramide and agents likely to cause extrapyramidal reactions should be avoided.(1) If concurrent use is warranted, monitor patients closely for extrapyramidal reactions and neuroleptic malignant syndrome. The manufacturer of metoclopramide says to avoid treatment with metoclopramide for longer than 12 weeks, and to use the lowest possible dose.(1) Discontinue therapy if symptoms occur. Instruct patients to seek immediate medical attention if symptoms develop. Symptoms of extrapyramidal reactions, including tardive dyskinesia, include involuntary movements of limbs and facial grimacing, torticollis, oculogyric crisis, rhythmic protrusion of the tongue, bulbar type of speech, trismus, and/or dystonic reactions resembling tetanus/stridor/dyspnea.

DISCUSSION: Both metoclopramide and phenothiazines can cause extrapyramidal reactions, such as tardive dyskinesia, and neuroleptic malignant syndrome. The risk may be increased by concurrent use.(1,2) Extrapyramidal symptoms have been reported with concurrent metoclopramide and neuroleptics, prochlorperazine, and chlorpromazine.(3-5)

Selected Antiemetics/Selected Dopamine Agonists

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Selected dopamine agonists are used to treat neurologic conditions such as Parkinson Disease (PD)or restless legs syndrome (RLS), and endocrine disorders such as hyperprolactinemia by directly or indirectly increasing dopamine concentrations at dopamine-2 (D2) receptors in the central nervous system (CNS). Antiemetic agents which block CNS D2 receptors may counteract this effect.(1-5)

CLINICAL EFFECTS: The efficacy of the dopamine agonist may be decreased, leading to exacerbation of the disease being treated. In patients with Parkinson disease motor symptoms may worsen, increasing the risk for falls, dysphagia or aspiration.(5) Patients with other conditions such as restless legs syndrome may also experience symptom exacerbation due to this combination.

PREDISPOSING FACTORS: Patients with Parkinson or Diffuse Lewy Body (DLB) disease are particularly susceptible to adverse effects of dopamine blockade.

PATIENT MANAGEMENT: Reassess antiemetic therapy and use an antiemetic without dopamine (D2) blocking effects if possible. If clinically appropriate and available, consider the use of a 5HT3 blocker (e.g. ondansetron) or domperidone (not available in the US).(4) If concomitant treatment is needed, monitor for loss of efficacy for the disease being treated by the dopamine agonist (e.g. Parkinson disease, restless legs syndrome) and adjust medication(s) or dosage if needed.(1-4) Counsel patients to report symptoms of disease exacerbation.

DISCUSSION: Patients with Parkinson or DLB disease are particularly susceptible to adverse effects of dopamine blockade. The European Academy of Neurology guideline for late Parkinson disease states that metoclopramide, cinnarizine and prochlorperazine must be avoided. Ondansetron or domperidone(not available in the US) may be used for nausea and vomiting.(5) Prescribing information for dopamine agonists warn of the risk for disease exacerbation when dopamine blocking agents are co-prescribed.(1-4)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Metoclopramide/Cyclosporine; Sirolimus

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown but is possibly due to a metoclopramide-induced increase in gastric emptying time leading to an increase in cyclosporine absorption.(1)

CLINICAL EFFECTS: The pharmacological and toxic effects of cyclosporine and sirolimus may be increased.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor serum cyclosporine or sirolimus concentrations and adjust dose as necessary.

DISCUSSION: In a study involving 14 renal transplant patients, a single oral dose of metoclopramide 20 mg produced nearly a 30% increase in cyclosporine bioavailability.(2,3) Similar results were reported in a patient receiving cyclosporine and metoclopramide concurrently.(4) Additional studies with varying dosage schedules of metoclopramide administration are needed to determine the extent of this interaction.

Metoclopramide/Digoxin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Metoclopramide stimulates the smooth muscle in the gastrointestinal tract to increase peristalsis. This action may reduce the time digoxin is at the absorption site, causing less drug to be absorbed since digoxin absorption is dissolution rate-limited.(1-3) Metoclopramide may alter digoxin levels by increasing digoxin biliary excretion.(4)

CLINICAL EFFECTS: Concurrent use of metoclopramide with digoxin may result in decreased levels and effectiveness of digoxin.(5-7)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Separate the administration time of metoclopramide and digoxin by as much time as possible. Monitor digoxin levels if metoclopramide is initiated or discontinued. The dosage of digoxin may need to be increased by 20% to 40%.

DISCUSSION: Steady-state serum digoxin concentrations were reduced by approximately one-third in a group of elderly female patients receiving metoclopramide. When metoclopramide was discontinued, digoxin concentrations returned to previous levels.(8) In a study, 6 healthy subjects received digoxin (0.25 mg twice daily) for for 1 week alone and during concurrent metoclopramide (10 mg 3 times daily). Metoclopramide decreased digoxin maximum concentration (Cmax) and AUC by 27% and 19%, respectively. Metoclopramide prolonged time to reach Cmax (Tmax) by 35%.(9) In a study involving 16 healthy subjects who received digoxin (two 0.25 mg tablets), a single dose of metoclopramide reduced digoxin's area-under-curve (AUC) and cumulative urinary digoxin excretion as compared to digoxin alone. However, metoclopramide did not affect the same parameters for the soft gelatin capsule form of digoxin (two 0.2 mg capsules). Metoclopramide reduced digoxin Tmax for both dosage forms.(10) In a study in 10 healthy subjects, a single dose of metoclopramide (10 mg) given 30 minutes before a single dose of digoxin (two standard Lanoxin 0.25 mg tablets) decreased digoxin urinary excretion by 8%.(11)

Metoclopramide/Selected Strong Cyp2d6 Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP2D6 inhibitors may inhibit the metabolism of metoclopramide.

CLINICAL EFFECTS: Concurrent use may result in elevated levels of metoclopramide, which may increase the risk of extrapyramidal symptoms such as tardive dyskinesia, which may be permanent. Tardive dyskinesia typically affects the facial muscles and may result in uncontrollable lip smacking, chewing, puckering of the mouth, frowning or scowling, sticking out the tongue, blinking and moving the eyes, and shaking of the arms and/or legs. Concurrent use may also result in serotonin syndrome. Symptoms of serotonin syndrome include irritability, altered consciousness, double vision, nausea, confusion, anxiety, hyperthermia, increased muscle tone, rigidity, myoclonus, rapid fluctuations in vital signs, and coma. Serotonin syndrome may result in death.

PREDISPOSING FACTORS: Patients with renal and/or hepatic impairment may have an increased risk from this combination.

PATIENT MANAGEMENT: Concurrent use of a strong 2D6 inhibitor requires a dosage adjustment of metoclopramide. For gastroesophageal reflux, reduce the dosage of metoclopramide to 5 mg four times daily (thirty minutes before each meal and at bedtime) or 10 mg taken three times daily for a maximum daily dosage of 30 mg in patients taking strong CYP2D6 inhibitors.(1) For acute and recurrent diabetic gastroparesis, reduce the dosage of metoclopramide to 5 mg four times daily (30 minutes before each meal and at bedtime) for a maximum daily dosage of 20 mg in patients taking strong CYP2D6 inhibitors.(1) If concurrent therapy is warranted, patients should be monitored for extrapyramidal symptoms and signs and symptoms of serotonin syndrome. Instruct patients to report any abnormal/uncontrollable muscle movements, muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: In a study in 20 healthy male subjects, concurrent fluoxetine (60 mg daily, another strong CYP2D6 inhibitor) increased the maximum concentration (Cmax) and area-under-curve (AUC) of metoclopramide (20 mg single dose) by 42% and 89%, respectively.(1,2) There have been case reports of serotonin syndrome in patients receiving concurrent metoclopramide and fluoxetine,(3) fluvoxamine,(3) sertraline,(5-7) and venlafaxine.(7) Strong CYP2D6 inhibitors linked to this monograph include: bupropion, dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(8)

Metoclopramide/Succinylcholine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Metoclopramide inhibits plasma cholinesterase, decreasing the inactivation of succinylcholine.

CLINICAL EFFECTS: The pharmacologic effects of succinylcholine may be increased, resulting in profound sedation, respiratory depression, coma, and/or death.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor neuromuscular function and supply mechanical respiratory support if prolonged respiratory depression occurs. If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: In controlled studies, administration of metoclopramide to patients receiving intubating doses of succinylcholine prolonged the neuromuscular blockade produced by succinylcholine by 23% to 228%.

Metoclopramide/Tacrolimus

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown but is possibly due to a metoclopramide-induced increase in gastric emptying time leading to an increase in tacrolimus absorption.(1)

CLINICAL EFFECTS: Concurrent use of metoclopramide may result in elevated levels of and toxicity from tacrolimus, including nephrotoxicity, neurotoxicity, and prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Monitor tacrolimus levels in patients receiving concurrent metoclopramide. The dosage of tacrolimus may need to be adjusted if metoclopramide is initiated or discontinued.(1) When concurrent therapy of metoclopramide and tacrolimus is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: A 47-year-old lung transplant patient on a stable dose of tacrolimus 3 mg every 12 hours with tacrolimus levels of 7-8 ng/mL was admitted for acute rejection and lymphocytic bronchiolitis. On hospital day 3, he was started on IV metoclopramide 10 mg every 8 hours for nausea and vomiting. After 2 days, his tacrolimus level had increased from 8.4 ng/mL at baseline to 36 ng/mL. Metoclopramide was discontinued and tacrolimus dose was reduced. Tacrolimus levels normalized after 3 days, and after 15 days, the patient was back on tacrolimus 3.5 mg every 12 hours with normal tacrolimus levels.(3) A 52-year-old liver transplant recipient who was stable on tacrolimus developed subtherapeutic tacrolimus levels that were subsequently thought to be due to impaired gastric emptying. Despite increase of tacrolimus dose from 7 mg to 28 mg twice daily, tacrolimus levels remained undetectable. Concurrently, as a result of nausea and vomiting, she was started on metoclopramide 10 mg 4 times daily. Two days later, her tacrolimus levels exceed the maximum detectable level of 30 ng/mL, and she developed nephrotoxicity and neurotoxicity.(4)

*Concomitant use of other drugs likely to cause extrapyramidal reactions.

*History of tardive dyskinesia or dystonic reaction to metoclopramide.

*Mechanical obstruction or perforation or other situations in which stimulation of GI motility might be dangerous.

*GI hemorrhage.

*Pheochromocytoma or other catecholamine-releasing paragangliomas (due to potential for hypertensive/pheochromocytoma crisis).

*History of seizure disorders.

*Known hypersensitivity to metoclopramide.

• Acquired dystonia
• Gastrointestinal perforation
• Mechanical intestinal obstruction
• Neuroleptic malignant syndrome
• Parkinsonism
• Pheochromocytoma
• Seizure disorder
• Tardive dyskinesia

• Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• CYp2d6 poor metabolizer
• Depression
• Disease of liver
• Gastrointestinal hemorrhage
• Hypertension
• NADH methemoglobin reductase deficiency
• Porphyria
• Suicidal ideation

• Aldosteronism
• Chronic heart failure
• Edema
• Hepatic cirrhosis
• Hyperprolactinemia
• Intestinal anastomosis

Adverse effects reported in >10% of patients receiving oral metoclopramide include restlessness, drowsiness, fatigue, and lassitude.

The most common adverse effects reported in patients receiving parenteral metoclopramide include restlessness, sleepiness, tiredness, dizziness, exhaustion, headache, confusion, and difficulty sleeping.

Adverse effects reported in >=5% of patients receiving metoclopramide nasal spray include dysgeusia, headache, and fatigue.

Rare or Very Rare

• Abnormal hepatic function tests
• Acquired dystonia
• Agitation
• Agranulocytosis
• Akathisia
• Angioedema
• Atrioventricular block
• Bradycardia
• Bronchospastic pulmonary disease
• Chronic heart failure
• Extrapyramidal disease
• Hypertension
• Hypotension
• Jaundice
• Laryngeal edema
• Leukopenia
• Methemoglobinemia
• Neuroleptic malignant syndrome
• Neutropenic disorder
• Oculogyric crisis
• Panic disorder
• Parkinsonism
• Porphyria
• Seizure disorder
• Suicidal
• Suicidal ideation
• Supraventricular tachycardia
• Tachycardia
• Tardive dyskinesia

More Frequent

• Diarrhea
• Drowsy
• Fatigue
• Nervousness

Less Frequent

• Dizziness
• Gynecomastia
• Headache disorder
• Mastalgia

Rare or Very Rare

• Accidental fall
• Acute cognitive impairment
• Amenorrhea
• Anticholinergic toxicity
• Body fluid retention
• Depression
• Erectile dysfunction
• Galactorrhea not associated with childbirth
• Hyperprolactinemia
• Increased urinary frequency
• Insomnia
• Irregular menstrual periods
• Irritability
• Nausea
• Skin rash
• Urinary incontinence
• Urticaria
• Visual changes

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The safety profile of metoclopramide in adults cannot be extrapolated to pediatric patients. Dystonias and other extrapyramidal reactions to metoclopramide are more common in pediatric patients than in adults.

Safety and efficacy of oral and intranasal formulations of metoclopramide have not been established in pediatric patients, and these formulations are not recommended for use in pediatric patients because of the risk of tardive dyskinesia and other extrapyramidal reactions, as well as the risk of methemoglobinemia in neonates.

Safety and efficacy of metoclopramide injection in pediatric patients have been established only for use to facilitate intubation of the small intestine. Metoclopramide injection should be used with caution in pediatric patients, since the incidence of extrapyramidal reactions is increased in these patients. Metoclopramide injection should be administered with caution to neonates because decreased clearance may result in increased serum concentrations of the drug. In addition, since neonates have reduced concentrations of cytochrome-b5 reductase, they may be more susceptible to methemoglobinemia.

Following oral or IV administration of metoclopramide in pediatric patients, pharmacodynamics of the drug are highly variable, and a relationship between drug plasma concentrations and pharmacodynamic effects has not been established. Data are insufficient to determine whether the pharmacokinetics of the drug in pediatric patients are similar to those in adults.

Published studies, including retrospective cohort studies, national registry studies, and meta-analyses, have not revealed an increased risk of adverse pregnancy-related outcomes with metoclopramide use during pregnancy. However, metoclopramide crosses the placenta and may cause extrapyramidal reactions and methemoglobinemia in neonates whose mothers received the drug during delivery; these neonates should be monitored for extrapyramidal effects.

Reproduction studies in pregnant rats and rabbits using metoclopramide dosages of approximately 6 and 12 times, respectively, the MRHD have not revealed evidence of adverse developmental effects.

Limited published data indicate that metoclopramide is distributed into milk; the estimated dose received by breast-fed infants is <10% of the maternal weight-adjusted oral dose. In one study, the estimated dose received by infants from breast milk ranged from 6-24 mcg/kg daily at 3-9 days postpartum and from 1-13 mcg/kg daily at 8-12 weeks postpartum. Exposure is expected to be similar following maternal doses of 10 mg administered orally or 15 mg administered intranasally. Adverse GI effects, including intestinal discomfort and increased intestinal gas formation, have been reported in breast-fed infants who were exposed to metoclopramide. Although metoclopramide increases prolactin concentrations, data are not adequate to support drug-related effects on milk production.

The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for metoclopramide and any potential adverse effects on the breast-fed child from the drug or from the underlying maternal condition. Nursing neonates should be monitored for extrapyramidal effects (dystonias) and methemoglobinemia.

Because geriatric adults are more likely to have reduced renal function and may be more sensitive to the therapeutic or adverse effects of metoclopramide, a reduced initial dosage of the drug is recommended.

Diabetic Gastroparesis: For relief of symptoms associated with diabetic gastroparesis in geriatric patients, a reduced initial oral metoclopramide dosage of 5 mg 4 times daily, given 30 minutes before meals and at bedtime, should be considered. Dosage may be titrated to a dosage of 10 mg 4 times daily based on response and tolerability. The maximum recommended oral dosage is 40 mg daily. Metoclopramide nasal spray is not recommended as initial therapy for relief of acute and recurrent diabetic gastroparesis in geriatric patients >=65 years of age. Geriatric patients may be switched from an alternative metoclopramide preparation administered at a stable dosage of 10 mg 4 times daily to the nasal formulation administered at a dosage of 15 mg (one spray in one nostril) given 30 minutes before meals and at bedtime (maximum 4 times daily) for 2 to 8 weeks, depending on symptomatic response.

Gastroesophageal Reflux Disease: For the symptomatic treatment of gastroesophageal reflux in geriatric patients, a reduced initial oral metoclopramide dosage of 5 mg 4 times daily, given 30 minutes before meals and at bedtime, should be considered. Dosage may be titrated to a dosage of 10-15 mg 4 times daily based on response and tolerability. The maximum recommended oral dosage is 60 mg daily.

Geriatric patients are more likely to have decreased renal function and may be more sensitive to therapeutic or adverse effects of metoclopramide. Geriatric patients, especially older women, are at increased risk for tardive dyskinesia. In addition, the risk of developing parkinsonian symptoms increases with increasing dosage. Therefore, geriatric patients should receive the lowest effective dosage of metoclopramide. If parkinsonian symptoms develop in a geriatric patient receiving metoclopramide, metoclopramide generally should be discontinued before any specific antiparkinsonian therapy is considered. Sedation has been reported in patients receiving metoclopramide and may manifest as confusion and oversedation in geriatric patients.

Metoclopramide is known to be substantially eliminated by the kidneys, and the risk of adverse reactions to the drug, including tardive dyskinesia, may be increased in patients with impaired renal function. A reduced dosage should be considered in geriatric patients. In general, the dosage should be selected carefully, usually initiating therapy at the low end of the dosage range; the greater frequency of decreased renal function and of concomitant disease and drug therapy observed in geriatric patients also should be considered.