Generic Name: Metoclopramide Hydrochloride
Class: Prokinetic Agents
VA Class: AU300
Molecular Formula: C14H22ClN3O22O
CAS Number: 54143-57-6
- Tardive Dyskinesia
May result in tardive dyskinesia.5 267 Risk increases with increasing duration of therapy and total cumulative dose.5 267 (See Tardive Dyskinesia under Cautions.)
Discontinue metoclopramide in patients who develop signs or symptoms of tardive dyskinesia.5 267 There is no known treatment for tardive dyskinesia; however, symptoms may lessen or resolve in some patients after discontinuance.5 267
Avoid use for >12 weeks in all but rare cases where therapeutic benefit is thought to outweigh risk of developing tardive dyskinesia.5 267
REMS:
FDA approved a REMS for metoclopramide to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of metoclopramide and consists of the following: medication guide. See the FDA REMS page () or the ASHP REMS Resource Center ().
Introduction
Antiemetic; stimulant of upper GI motility (prokinetic agent);1 2 3 4 5 6 7 8 9 263 267 potent dopamine-receptor antagonist.2 4 5 7 19 28 34 52 267
Uses for Reglan
Diabetic Gastric Stasis
Symptomatic treatment of acute and recurrent diabetic gastric stasis (gastroparesis).5 7 32 44 76 77 78 79 80 83 84 88 89 267 Successful therapy often requires long-term, intermittent use, since diabetic gastric stasis is a chronic, recurrent disease.5 9
Postsurgical Gastric Stasis
Has been used for the symptomatic treatment of acute and chronic postsurgical gastric stasis† following vagotomy and gastric resection or vagotomy and pyloroplasty.31 37 44 49 84 113 114 115 148 149 150
Prevention of Postoperative Nausea and Vomiting
Prevention of postoperative nausea and vomiting when nasogastric suction is considered undesirable.4 125 267
Prevention of Cancer Chemotherapy-induced Emesis
Used parenterally in high doses for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy including cisplatin alone or in combination with other antineoplastic agents.97 98 99 100 101 102 103 263 267
Prevention of nausea and vomiting associated with other antineoplastic agents (e.g., cyclophosphamide, dacarbazine, doxorubicin, methotrexate) and with cancer chemotherapy regimens that do not include cisplatin.103 144 145 146 147 218 263 267
ASCO does not consider metoclopramide an appropriate first-line antiemetic for any group of patients receiving chemotherapy of high emetic risk and states that this drug should be reserved for patients unable to tolerate or refractory to first-line agents (i.e., a type 3 serotonin [5-HT3] receptor antagonist [e.g., dolasetron, granisetron, ondansetron, palonosetron] with dexamethasone and aprepitant).263
ASCO states that the combination of a 5-HT3 receptor antagonist, dexamethasone, and aprepitant is preferred in patients receiving combination chemotherapy with an anthracycline and cyclophosphamide; ASCO recommends combined therapy with a 5-HT3 receptor antagonist and dexamethasone for other chemotherapy regimens of moderate emetic risk (i.e., 31–90% incidence of emesis without antiemetics) and dexamethasone alone for chemotherapy regimens of low emetic risk (i.e., 11–30% incidence).263
In patients experiencing nausea and vomiting despite recommended prophylaxis regimens, ASCO recommends that clinicians consider adding a benzodiazepine (e.g., alprazolam, lorazepam), butyrophenone, or phenothiazine to the regimen or substituting high-dose IV metoclopramide for the 5-HT3 receptor antagonist in the regimen.263
Antiemetics can be prescribed on an as-needed basis for chemotherapy regimens with minimal emetic risk (<10% incidence of emesis without antiemetics).263
Metoclopramide has been used orally† for the prevention of chemotherapy-induced nausea and vomiting. 177 218 221 224 263 264 265 266 275 Some experts state that patients receiving oral chemotherapy requiring only as-needed (“prn”) antiemetic therapy or receiving an IV chemotherapy regimen with low emetic risk may receive oral† metoclopramide.275
Oral† metoclopramide has been effective when given in combination with dexamethasone for the prevention of delayed emesis in patients receiving chemotherapy.263 264 265 266 For prevention of delayed emesis in patients receiving cisplatin or other chemotherapy of high emetic risk, ASCO recommends the combination of dexamethasone and aprepitant.263
Intubation of the Small Intestine
Used parenterally to facilitate small intestine intubation when the tube (e.g., endoscope, biopsy tube) does not pass through the pylorus during 10 minutes of conventional maneuvers.105 106 107 109 176 267
Radiographic Examination of the Upper GI Tract
Used parenterally to stimulate gastric emptying and intestinal transit of barium when delayed emptying interferes with radiographic examination of the stomach and/or small intestine.4 43 110 184 267
Gastroesophageal Reflux
Short-term (≤12 weeks) relief of symptomatic, documented gastroesophageal reflux in adults who are unresponsive to conventional therapy (e.g., changes in lifestyle, habits, diet, weight reduction) alone.5 9 30 39 40 41 42 111 112 116 117 125 129 185 186 187 188 189 190
Regular use for this purpose has declined; proton-pump inhibitors provide greater control of acid reflux.258 273 274 Some experts recommend against use of metoclopramide for this purpose based on the drug’s adverse effect profile and lack of high-quality supporting data.273 274
Reglan Dosage and Administration
Administration
Administer orally, by direct IV injection or IV infusion, or IM.5 263 267
Metoclopramide therapy should not exceed 12 weeks’ duration.5 267 268 269
Oral Administration
Metoclopramide oral solution and tablets are recommended for use in adults only.5 268 269
IV Administration
For solution and drug compatibility information, see Compatibility under Stability.
Dilution
For direct IV injection, use without further dilution.267
If dose is >10 mg, dilute in 50 mL of a compatible IV solution.267
For IV infusion, manufacturer recommends dilution in 50 mL of 5% dextrose, 0.9% sodium chloride, 5% dextrose and 0.45% sodium chloride, Ringer’s, or lactated Ringer’s injection.267
Manufacturer states that 0.9% sodium chloride injection is preferred because metoclopramide hydrochloride is most stable in this solution.267
Rate of Administration
Direct IV injection: Administer each 10 mg slowly over 1–2 minutes.267 Rapid IV injection may cause transient but intense feelings of anxiety and restlessness, followed by drowsiness.267
IV infusion: Administer slowly over ≥15 minutes.267
IM Administration
Inject without further dilution.267
Dosage
Available as metoclopramide hydrochloride; dosage expressed in terms of metoclopramide.5 267
Pediatric Patients
Intubation of the Small Intestine
IV
Children <6 years of age: Usually, one 0.1-mg/kg dose given by direct IV injection.267
Children 6–14 years of age: Usually, one 2.5- to 5-mg dose given by direct IV injection.267
Children >14 years of age: Usually, one 10-mg dose given by direct IV injection.267
Adults
Diabetic Gastric Stasis
Oral
10 mg 4 times daily, given 30 minutes before meals and at bedtime.5 Continue for 2–8 weeks, depending on response and likelihood of continued well-being if drug is discontinued.5 Reinstitute at earliest symptom recurrence.5
IV
If symptoms are severe or oral use is not feasible, 10 mg 4 times daily, given by direct IV injection 30 minutes before meals and at bedtime.5 267 Continued use for up to 10 days may be required until symptoms subside enough to allow oral administration;5 267 however, thoroughly assess the risks and benefits prior to continuing therapy.267
IM
If symptoms are severe or oral use is not feasible, 10 mg 4 times daily, given 30 minutes before meals and at bedtime.5 267 Continued use for up to 10 days may be required until symptoms subside enough to allow oral administration;5 267 however, thoroughly assess the risks and benefits prior to continuing therapy.267
Prevention of Postoperative Nausea and Vomiting
IM
Manufacturer states that usual dose is 10 mg administered near the end of the surgical procedure; 20 mg also may be used.267
Prevention of Cancer Chemotherapy-induced Emesis
Oral†
Some experts state that patients receiving IV chemotherapy regimens with low emetic risk may receive 10–40 mg of metoclopramide before the chemotherapy dose and then every 4 or 6 hours as needed.275
Some experts state that patients receiving oral chemotherapy requiring only as-needed (“prn”) antiemetic therapy may receive 10–40 mg of metoclopramide before the chemotherapy dose and then every 4 or 6 hours as needed.275
When given in combination with dexamethasone in clinical trials for the prevention of delayed emesis (i.e., vomiting occurring ≥24 hours after chemotherapy), 20–40 mg (or 0.5 mg/kg) of metoclopramide has been given 2–4 times daily for 3 or 4 days.263 264 265 266
IV
Manufacturer states that metoclopramide usually is given by IV infusion 30 minutes before administration of chemotherapy, and then repeated every 2 hours for 2 additional doses followed by every 3 hours for 3 additional doses.267 Manufacturer states that initial 2 doses should be 2 mg/kg if highly emetogenic chemotherapy used;267 for less emetogenic drugs or regimens, initial 1-mg/kg dose may be sufficient.267 However, combinations of other antiemetic agents generally are preferred as first-line regimens in patients receiving chemotherapy of moderate or high emetic risk (see Prevention of Cancer Chemotherapy-induced Emesis under Uses). 263 275
Some experts state that patients receiving IV chemotherapy regimens with low emetic risk may receive 10–40 mg of metoclopramide before the chemotherapy dose and then every 4 or 6 hours as needed.275
Intubation of the Small Intestine
IV
Usually, one 10-mg dose given by direct IV injection.267
Radiographic Examination of the Upper GI Tract
IV
Usually, one 10-mg dose given by direct IV injection.267
Gastroesophageal Reflux
Oral
Usually, 10–15 mg up to 4 times daily (30 minutes before each meal and at bedtime) for 4–12 weeks, depending on symptoms and response.5 Patients sensitive to therapeutic and/or adverse effects of metoclopramide may require initial dose of 5 mg.5
For intermittent symptoms or symptoms at specific times of the day, one 20-mg dose before the provoking situation may be preferred to daily administration of multiple doses.5
In patients with esophageal erosion and ulceration, 15 mg 4 times daily for 12 weeks has provided healing; monitor endoscopically because of the poor correlation between symptoms and healing.5
Prescribing Limits
Adults
Avoid use of metoclopramide for >12 weeks in all but rare cases where therapeutic benefit is thought to outweigh risk of developing tardive dyskinesia.5 267 (See Boxed Warning and see Tardive Dyskinesia under Cautions.)
Gastroesophageal Reflux
Oral
Safety and efficacy beyond 12 weeks not established; use beyond 12 weeks not recommended.5
Special Populations
Hepatic Impairment
Dosage modification does not appear to be necessary.5 267
Renal Impairment
Modify dosage according to degree of renal impairment.5 54 58 59 135 142 267
In patients with Clcr <40 mL/minute, manufacturers recommend an initial dosage of approximately 50% of the usual dosage.5 267 Subsequently, increase or decrease dosage according to response and tolerance.5 267
Geriatric Patients
Select dosage with caution, usually initiating therapy at the low end of the dosage range.5 267
Administer lowest effective dosage.5 267 In geriatric patients with gastroesophageal reflux, initial 5-mg dose may be required due to possible sensitivity to therapeutic and/or adverse effects of metoclopramide.5
Cautions for Reglan
Contraindications
Mechanical obstruction or perforation or other situations in which stimulation of GI motility might be dangerous.5 267
GI hemorrhage5 267 (however, has been used to empty the stomach of blood prior to endoscopy in patients with acute upper GI hemorrhage).4 125
Pheochromocytoma (due to potential for hypertensive crisis).5 267
History of seizure disorders.4 5 267
Concomitant therapy with drugs likely to cause extrapyramidal reactions (e.g., phenothiazines, butyrophenones).4 5 267
Known intolerance to metoclopramide.5 267
Known hypersensitivity to metoclopramide or any ingredient in the formulation.5 267
Warnings/Precautions
Warnings
Tardive Dyskinesia
Tardive dyskinesia, a syndrome of potentially irreversible, involuntary, dyskinetic movements involving the tongue, face, mouth, or jaw, and sometimes the trunk and/or extremities, may occur; movements may be choreoathetotic in appearance.5 93 94 130 157 158 159 267 270 271 272 (See Boxed Warning.)
Reported in about 20% of patients receiving the drug for ≥12 weeks.5 267 270 271 Avoid use of metoclopramide for >12 weeks in all but rare cases where therapeutic benefit is thought to outweigh risk of developing tardive dyskinesia.5 267 272
Although risk of developing tardive dyskinesia may be increased in geriatric patients, women, and patients with diabetes mellitus, it is not possible to predict which patients will develop metoclopramide-induced tardive dyskinesia.5 267 270 271 272 Risk of occurrence and irreversibility increases with increasing duration of therapy and total cumulative dose.5 267 271 272
Discontinue metoclopramide in patients who develop signs or symptoms of tardive dyskinesia.5 267 270 271 There is no known effective treatment for tardive dyskinesia; however, tardive dyskinesia may remit, either partially or completely, in some patients within several weeks to months after discontinuance.5 267 271
Metoclopramide may suppress or partially suppress signs of tardive dyskinesia, thereby masking the underlying disease process; effect of this suppression on the long-term course of tardive dyskinesia is unknown.5 267 Do not use metoclopramide for symptomatic control of tardive dyskinesia.5 267
Extrapyramidal Symptoms
Potential for extrapyramidal reactions,4 5 90 91 125 169 205 206 207 267 especially in pediatric patients and adults <30 years of age or when high doses (e.g., IV doses for prophylaxis of cancer chemotherapy-induced nausea and vomiting) are administered.5 91 169 267
Commonly manifested as acute dystonic reactions or akathisia; stridor and dyspnea (possibly due to laryngospasm) reported rarely.5 267
Generally occur within 24–48 hours after starting therapy5 205 206 207 267 and usually subside within 24 hours following drug discontinuance.4 90 205
Most patients respond rapidly to treatment with diazepam4 or an agent with central anticholinergic activity (e.g., diphenhydramine hydrochloride 20–50 mg orally, IM, or IV;5 267 275 276 benztropine 1–2 mg IM5 267 ).4 5 170 206 207 267
Parkinsonian Symptoms
Parkinsonian symptoms (e.g., tremor, rigidity, bradykinesia, akinesia) occur rarely; may be associated with usual160 or excessive metoclopramide doses62 or decreased renal function.9 54
Possible exacerbation of parkinsonian symptoms;5 9 54 62 160 267 use with caution, if at all, in patients with parkinsonian syndrome.5 267
More common during first 6 months of therapy but occur occasionally after longer periods.5 267
Symptoms generally subside within 2–3 months following drug discontinuance.5 267
Neuroleptic Malignant Syndrome (NMS)
NMS (characterized by hyperthermia, varying levels of consciousness, muscular rigidity, and autonomic dysfunction) reported rarely.5 208 267
Important to determine whether untreated or inadequately treated extrapyramidal reactions and serious medical illness (e.g., pneumonia, systemic infection) may coexist.5 267 Also consider the possibility of central anticholinergic toxicity, heat stroke, malignant hyperthermia, drug fever, and primary CNS pathology.5 267
Immediately discontinue metoclopramide and other drugs not considered essential, provide intensive symptomatic treatment, monitor patient, and treat any concomitant serious medical condition for which specific therapies are available.5 267 Dantrolene and bromocriptine have been used in the treatment of NMS, but their efficacy has not been established and there currently is no specific drug therapy.5 267
Depression
Mild to severe depression (including suicidal ideation and suicide) has occurred in patients with or without prior history of depression.5 210 211 215 267
Use with extreme caution and only when anticipated benefits outweigh possible risks in patients with a history of mental depression, especially those with suicidal tendencies.5 267
Sensitivity Reactions
Procainamide Cross-sensitivity
Theoretical potential for patients who are allergic to procainamide to exhibit cross-sensitivity to metoclopramide (since the drugs are structurally similar).11 12
General Precautions
GI Anastomosis or Closure
When deciding whether to use metoclopramide or NG suction to prevent postoperative nausea and vomiting, consider the possibility that metoclopramide theoretically could produce increased pressure on suture lines following GI anastomosis or closure.267
Fluid and Electrolyte Effects
Possible transient increases in plasma aldosterone concentrations and sodium retention; closely monitor patients (e.g., those with CHF or cirrhosis) at risk of developing fluid retention and volume overload or hypokalemia.3 5 69 267
Discontinue metoclopramide if fluid retention or volume overload occurs at any time during therapy.5 267
Hypertension
Possible increase in circulating catecholamines in hypertensive patients; use with caution in these patients.5 267
CNS Depression
Drowsiness may occur, particularly at higher dosages.5 267 Performance of activities requiring mental alertness and physical coordination (operating machinery, driving a motor vehicle) may be impaired.5 267
Withdrawal Effects
Adverse reactions, particularly CNS reactions, may occur following discontinuance of drug.5 Some patients may experience withdrawal symptoms including dizziness, nervousness, and/or headaches following discontinuance.5
Patients with Cytochrome-b5 Reductase Deficiency
Patients with cytochrome-b5 reductase deficiency have an increased risk of methemoglobinemia and/or sulfhemoglobinemia when metoclopramide is administered.5 267
Patients with Glucose-6-phosphate Dehydrogenase Deficiency
Methylene blue is not recommended for treatment of metoclopramide-induced methemoglobinemia in patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.5 267
Specific Populations
Pregnancy
Category B.5 267
Lactation
Distributed into milk.5 139 140 267 Use caution in nursing women.5 267
Pediatric Use
Manufacturers currently recommend use in children only to facilitate intubation of the small intestine;267 however, has been effective for the management of gastric stasis†178 180 181 and gastroesophageal reflux†179 182 in infants and children.
Use with caution; incidence of extrapyramidal reactions is increased in children.5 91 125 156 267
Use with caution in neonates.5 267 Neonatal susceptibility to methemoglobinemia is increased due to prolonged clearance (may cause excessive serum concentrations) in combination with decreased neonatal levels of cytochrome-b5 reductase.5 267
Geriatric Use
Insufficient experience in patients ≥65 years of age to determine whether geriatric patients repond differently than younger adults.5 267
Possible increased risk of tardive dyskinesia.5 267
Risk of adverse parkinsonian effects increases with increasing dosage; administer lowest effective dosage in geriatric patients.5 267 If parkinsonian symptoms develop, generally should discontinue metoclopramide before initiating specific antiparkinsonian therapy.5 267
Confusion and oversedation may occur.5 267
Substantially eliminated by kidneys; risk of adverse reactions may be greater in patients with impaired renal function.5 267 (See Renal Impairment under Dosage and Administration.)
Select dosage with caution because of age-related decreases in renal function and concomitant disease and drug therapy.5 267 (See Geriatric Patients under Dosage and Administration).
Hepatic Impairment
Possible increased risk of fluid retention and hypokalemia in patients with cirrhosis.3 5 69 267 (See Fluid and Electrolyte Effects under Cautions.)
Discontinue if fluid retention or volume overload occurs at any time during therapy.5 267
Renal Impairment
Clearance may be reduced.5 54 59 142 192 267 Possible increased risk of adverse effects.5 267 Use with caution; reduce dosage during prolonged therapy in patients with renal impairment.5 54 58 59 69 135 142 267 (See Renal Impairment under Dosage and Administration.)
Common Adverse Effects
Restlessness, drowsiness, fatigue, lassitude, nausea, bowel disturbances (principally diarrhea).4 5 90 125 267
Interactions for Reglan
Orally Administered Drugs
Possible decreased absorption of certain drugs that disintegrate, dissolve, and/or are absorbed mainly in the stomach.4 5 119 125 267 Clinical importance not determined.c
Possible enhanced rate and extent of absorption of drugs mainly absorbed in the small intestine.4 5 120 125 267 Clinical importance not determined.c
Specific Drugs
Drug | Interaction | Comments |
|---|---|---|
Acetaminophen | Possible enhanced rate and extent of acetaminophen absorption4 5 120 125 267 | Clinical importance not determinedc |
Anesthetic agents | Acute hypotension reported with concomitant IV metoclopramide and hypotensive anesthetic agents (with or without ganglionic blocking agents) during neurosurgical procedures162 163 | Clinical importance not known125 162 163 |
Anticholinergic agents (e.g., atropine) | Antagonism of GI motility effects of metoclopramide 5 267 | |
Aspirin | Possible enhanced rate and extent of aspirin absorption4 120 125 | Clinical importance not determinedc |
Butyrophenones | Potential for extrapyramidal reactions4 5 267 and worsening of symptoms in patients with parkinsonian syndrome130 158 160 | Concomitant use contraindicated4 5 267 |
Cholinergic agents | Potentiation of GI motility effects of metoclopramide5 | |
CNS depressants (alcohol, opiates or other analgesics, barbiturates or other sedatives, anesthetics) | Increased CNS depressant effects;5 267 possible enhanced rate and extent of alcohol absorption4 5 125 267 | Use caution to avoid excessive sedation;c clinical importance of enhanced alcohol absorption not determinedc |
Cyclosporine | Possible enhanced rate and extent of cyclosporine absorption4 5 120 125 267 | Clinical importance not determinedc |
Diazepam | Possible enhanced rate and extent of diazepam absorption4 120 125 | Clinical importance not determinedc |
Digoxin | Possible decreased digoxin absorption; Lanoxin tablets apparently not affected because of small drug-particle size and rapid absorption4 5 119 125 267 | |
Insulin | Possible alteration of glycemic control secondary to metoclopramide-related changes in the delivery of food to and the rate of absorption in the intestine5 267 | Adjustment of insulin dose or timing may be necessary5 267 |
Levodopa | Possible enhanced rate and extent of levodopa absorption4 5 120 125 267 | Clinical importance not determinedc |
Lithium | Possible enhanced rate and extent of lithium absorption4 120 125 | Clinical importance not determinedc |
MAO inhibitors | Possible hypertensive reaction due to metoclopramide-induced release of catcholamines5 267 | Use with caution, if at all5 267 |
Opiate analgesics | Antagonism of GI motility effects of metoclopramide5 15 33 267 | |
Phenothiazines | Potential for extrapyramidal reactions4 5 267 and worsening of symptoms in patients with parkinsonian syndrome130 158 160 | Concomitant use contraindicated4 5 267 |
Tetracycline | Possible enhanced rate and extent of tetracycline absorption4 5 120 125 267 | Clinical importance not determinedc |
Reglan Pharmacokinetics
Absorption
Bioavailability
Following oral administration, rapidly and almost completely absorbed;4 5 7 53 54 55 56 133 134 135 267 limited data indicate that 30–100% of an oral dose reaches systemic circulation as unchanged metoclopramide.5 54 56 133 134 135 267 Peak plasma concentration usually attained at 1–2 hours.5 55 267
Following IM administration, absolute bioavailability is 74–96%.7
Onset
Following oral administration, 30–60 minutes for effects on GI tract.5 7 267
Following IM administration, 10–15 minutes for effects on GI tract.5 7 267
Following IV administration, 1–3 minutes for effects on GI tract.5 7 267
Duration
1–2 hours.5 267
Special Populations
In patients with gastric stasis, absorption may be delayed or diminished.14
In infants, metoclopramide may accumulate in plasma after multiple doses; mean peak plasma concentration was 2-fold higher after 10th dose compared with that after first dose in infants (3.5 weeks–5.4 months of age) with gastroesophageal reflux receiving metoclopramide oral solution.5 267
Distribution
Extent
In mice, distributed into most body tissues and fluids; high concentrations in GI mucosa, liver, biliary tract, and salivary glands, with lower concentrations in brain, heart, thymus, adrenals, adipose tissue, and bone marrow.4 7
Crosses the placenta138
Distributed into milk in humans;5 139 140 267 milk concentrations are higher than plasma concentrations 2 hours after oral administration.139 140
Plasma Protein Binding
13–30% (principally albumin).5 7 267
Elimination
Metabolism
Minimally metabolized; not known whether major metabolite found in urine is active.5 53 267
Elimination Route
Excreted in urine (85%) as unchanged drug and metabolites5 7 53 54 133 267 and also in feces (about 5%).7 53
Minimally removed by hemodialysis5 129 192 267 or peritoneal dia
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