Metoclopramide hydrochloride is a dopamine D2-receptor antagonist, an antiemetic, and a stimulant of upper GI motility (prokinetic agent).5, 267
Metoclopramide is used for the symptomatic treatment of adults with acute and recurrent diabetic gastroparesis (gastric stasis).5, 267, 268, 269, 277, 278 Therapy with metoclopramide, 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.5, 267, 268, 269, 277, 278 Oral and nasal formulations of the drug are recommended for use only in adults due to the risk of developing tardive dyskinesia and other extrapyramidal symptoms, as well as the risk of methemoglobinemia in neonates.5, 267, 268, 269, 277, 278
In patients with diabetic gastroparesis, metoclopramide increases the rate of gastric emptying and decreases usual symptoms of gastroparesis including nausea, vomiting, heartburn, anorexia, persistent postprandial fullness, and early satiety.5, 44, 80 In most patients with diabetic gastroparesis, metoclopramide-induced reduction of symptoms does not correlate well with improvement in gastric emptying.80 In some patients, complete relief of symptoms occurs despite minimal increases in the rate of gastric emptying, while in others, symptoms of gastroparesis persist despite a normalization in gastric emptying.80
The nasal spray formulation of metoclopramide has been compared to oral metoclopramide tablets in a randomized, open label trial of 89 adults with diabetic gastroparesis.286 In this trial, oral metoclopramide 10 mg, intranasal metoclopramide 10 mg, and intranasal metoclopramide 20 mg (all given 4 times daily for 6 weeks) reduced symptoms of diabetic gastroparesis (nausea, vomiting, loss of appetite, bloating, feeling full after eating a small amount of food, and persistent fullness); the intranasal metoclopramide formulation improved symptoms to a greater extent than oral metoclopramide.286 Metoclopramide nasal spray has also been compared to placebo in a phase 2b randomized controlled trial that enrolled 285 patients and a phase 3 randomized controlled trial that enrolled 205 patients.287, 292 In the phase 2b trial, intranasal metoclopramide 10 mg or 14 mg (given 4 times daily for 28 days) improved diabetic gastroparesis symptom scores compared to placebo in women, but not in men.287 The phase 3 trial enrolled only women with diabetic gastroparesis; in this trial, metoclopramide nasal spray 10 mg administered 4 times daily did not substantially improve symptom scores at week 4 compared to placebo.292 However, patients with moderate-to-severe diabetic gastroparesis symptoms at baseline had significant reductions in nausea and upper abdominal pain with intranasal metoclopramide treatment.292
Treatment of diabetic gastroparesis is often challenging.293 Guidelines from the American Diabetes Association (ADA) state that some patients with diabetic gastroparesis may be managed with dietary modifications (e.g., low-fat, low-fiber diets, foods with small particle sizes) and/or changes to drug therapy (if the patient is receiving drugs that affect GI motility).293 However, severe cases of diabetic gastroparesis will require pharmacologic management.293 The American College of Gastroenterology (ACG) states that pharmacologic treatment should be considered to improve gastric emptying and gastroparesis symptoms in patients with diabetic gastroparesis, considering the benefits and risks of treatment.294
Metoclopramide is the only approved drug therapy for diabetic gastroparesis, but the ADA states that the evidence supporting its utility in this disease state is weak.293 Given the potential for serious adverse events (e.g., acute dystonic reactions, drug-induced parkinsonism, akathisia, tardive dyskinesia), the ADA recommends reserving its use for severe cases of diabetic gastroparesis that are unresponsive to other therapies.293 The ACG suggests treatment with metoclopramide over no treatment for the management of refractory gastroparesis symptoms.294 Other pharmacologic options for diabetic gastroparesis are limited, but may include domperidone (which is only available in the U.S. through an expanded access program) or erythromycin (which is typically only useful for short-term management due to tachyphylaxis).293, 294, 295
Cancer Chemotherapy-induced Nausea and Vomiting
Metoclopramide is used parenterally for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy.267 The drug also has been administered orally† for the prevention of chemotherapy-induced nausea and vomiting.177, 218, 264, 265, 266 In current practice, metoclopramide is not routinely used for the prophylaxis of chemotherapy-induced nausea and vomiting; instead, it is typically reserved for the treatment of breakthrough nausea and vomiting† in patients who received prophylactic antiemetic therapy with drugs from a different therapeutic class.263, 296, 297
Parenteral metoclopramide has been used effectively for the prevention of chemotherapy-induced emesis in patients receiving cisplatin alone or in combination with other antineoplastic agents.98, 99, 100, 101, 102 In patients receiving cisplatin, high-dose metoclopramide (2 mg/kg) reduces the number and duration of vomiting episodes and the volume of emesis.98, 99, 100, 101, 102 In some patients, cisplatin-induced nausea and vomiting are completely prevented with metoclopramide therapy.98 Clinical evaluations of metoclopramide in the prevention of cisplatin-induced emesis have shown that the antiemetic effect of metoclopramide is greater than that of placebo,98 prochlorperazine,98, 100 or tetrahydrocannabinol (THC).102 However, it appears that type 3 serotonergic (5-HT3) receptor antagonists (e.g., granisetron, ondansetron) generally are more effective and better tolerated than metoclopramide.236, 238, 243, 244, 245, 246 In several clinical trials, oral† metoclopramide has been effective when given in combination with dexamethasone for the prevention of delayed emesis in patients receiving chemotherapy.264, 265, 266
Metoclopramide has also been used for prevention of nausea and vomiting associated with other antineoplastic agents and cancer chemotherapy regimens that do not include cisplatin.144, 145, 218 In patients receiving dacarbazine, high-dose metoclopramide (2 mg/kg) appears to be an effective antiemetic.144 When oral metoclopramide (10 mg 1-2 hours before chemotherapy and then every 8 hours for a week) was combined with IV dexamethasone (10 mg immediately before initiation of IV chemotherapy) in patients receiving cyclophosphamide, methotrexate, and fluorouracil for breast cancer (a moderately emetogenic regimen), this antiemetic combination appeared to be comparably effective overall to oral ondansetron (8 mg 1-2 hours before chemotherapy and then every 8 hours for a week) in preventing emesis during the 7-day treatment period but was more effective than ondansetron in reducing the frequency of nausea during the first day of chemotherapy.218
Metoclopramide is no longer routinely used for the prophylaxis of chemotherapy-induced nausea and vomiting; other drugs with fewer adverse effects are now preferred, although some experts state that metoclopramide may be a reasonable prophylactic option in patients receiving low emetic risk chemotherapy.296, 297, 298
The American Society of Clinical Oncology (ASCO) guidelines on use of antiemetics for chemotherapy-induced nausea and vomiting recommend a 4-drug antiemetic regimen consisting of a neurokinin 1 (NK1) receptor antagonist, a type 3 serotonin (5-HT3) receptor antagonist, dexamethasone, and olanzapine for patients receiving high-emetic-risk agents.263 A 3-drug combination (an NK1 receptor antagonist, a 5-HT3 receptor antagonist, and dexamethasone) is recommended for carboplatin (AUC >4 mg/mL/min) and a 2-drug regimen (a 5-HT3 receptor antagonist and dexamethasone) for other moderate-emetic-risk chemotherapeutic agents.263 For moderate-risk agents (e.g., cyclophosphamide, doxorubicin, oxaliplatin) with known delayed nausea and vomiting, dexamethasone may be used.263 A single dose of a 5-HT3 receptor antagonist or dexamethasone may be offered for low-emetic-risk agents.263 For patients experiencing nausea and vomiting despite optimal prophylactic antiemetic therapy (breakthrough nausea and vomiting†), an antiemetic from a different therapeutic class (including a dopamine receptor antagonist such as metoclopramide) may be used in addition to continuing the standard antiemetic regimen.263
Intubation of the Small Intestine
Metoclopramide is used parenterally to facilitate intubation of the small intestine in adults and pediatric patients in whom the tube (e.g., endoscope, biopsy tube) does not pass through the pylorus with conventional maneuvers.105, 106, 107, 109, 176, 267
In several controlled trials in patients with or without GI disease (e.g., inflammatory bowel disease, chronic diarrhea, malabsorption, celiac disease, peptic ulcer) undergoing intubation of the small intestine, IV metoclopramide (10 mg) reduced the time required for intubation and facilitated performance of the procedure;105, 106, 107, 109 however, administration of the drug generally did not influence patient tolerance of the procedure.106 The utility of metoclopramide for facilitating postpyloric placement of naso-enteral feeding tubes has not been established, with systematic reviews finding insufficient evidence to support a beneficial effect.299, 300
Gastroesophageal Reflux Disease
Metoclopramide is used orally for the short-term (4-12 weeks) relief of symptomatic, documented gastroesophageal reflux disease (GERD) in adults who are unresponsive to conventional therapy.5, 39, 112, 116, 117, 186, 188, 268, 269, 278 In current practice, metoclopramide is typically reserved for patients with GERD and concomitant gastroparesis.258, 274 Therapy with metoclopramide, 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.5, 268, 269, 278 Oral formulations of the drug are recommended for use only in adults due to the risk of developing tardive dyskinesia and other extrapyramidal symptoms, as well as the risk of methemoglobinemia in neonates.5, 268, 269, 278
Based on data from a limited number of patients, metoclopramide appears to be more effective than an aluminum hydroxide antacid or placebo112, 116 and is about as effective as cimetidine in improving the symptoms of gastroesophageal reflux.117 In a study comparing single oral doses of metoclopramide (15 mg) with an aluminum hydroxide antacid (30 mL) or placebo in patients with reflux esophagitis, metoclopramide was reportedly more effective than antacid in reducing the symptoms associated with reflux.39 Metoclopramide increased the resting tone of the lower esophageal sphincter in all patients for at least 1 hour and prevented gastroesophageal reflux following administration of an intragastric acid load.39
The current mainstay of treatment for patients with GERD is acid-reducing therapy, with proton-pump inhibitors (PPIs) being the acid-reducing treatment of choice.258, 274 The ACG recommends against treatment of GERD with any prokinetic agent (e.g., metoclopramide) unless there is objective evidence of gastroparesis.258 Data on the efficacy of metoclopramide in GERD are scarce, and significant adverse events may occur with long-term use of metoclopramide; therefore, metoclopramide is not recommended to be used solely for the treatment of GERD.258 Similarly, the American Gastroenterological Association (AGA) recommends against the use of metoclopramide for treatment of GERD, and states that prokinetic agents have not been shown to be useful in GERD (but may be useful for concomitant gastroparesis).273, 274
Metoclopramide is used parenterally for the prevention of postoperative nausea and vomiting when nasogastric suction is considered undesirable.267 However, evidence to support its efficacy for this use is limited.301, 302 Experts state that metoclopramide may be useful when other dopamine antagonists are not available.302
Metoclopramide has been used for aspiration prophylaxis in patients undergoing anesthesia†; routine use is not recommended, but preoperative metoclopramide may be considered for patients at high risk of aspiration and patients undergoing cesarean delivery or postpartum tubal ligation.307, 308
Metoclopramide has been used for the symptomatic treatment of acute and chronic postsurgical gastroparesis† following vagotomy and gastric resection or vagotomy and pyloroplasty.31, 37, 44, 49, 84, 113, 114, 115, 148, 149 The drug has improved gastric emptying and decreased the usual symptoms of gastroparesis in patients with these conditions.31, 37, 44, 49, 84, 113, 114, 115, 148, 149 It has also been used for gastroparesis related to other conditions (nondiabetic gastroparesis†).294
Metoclopramide has been used for the management of migraine †.284, 303 Some experts state that IV metoclopramide may be considered for relief of acute migraine pain.284
Metoclopramide has been used for breakthrough nausea and vomiting associated with low or minimal emetic risk radiation therapy†, 263 and it is considered an option for the treatment of nausea and vomiting in pregnancy† in patients who have not responded to first-line antiemetic therapies.309 It has also been used for nausea and vomiting due to other causes†, although evidence to support its efficacy is limited.304 The drug also has been used for the management of intractable hiccups†305 , for radiographic examination of the upper GI tract267 , and to promote lactation† .139, 154, 155, 167, 306
Dispensing and Administration Precautions
Metoclopramide is administered orally, intranasally, by IM or direct IV injection, or by IV infusion.5, 267, 277
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.5, 267, 268, 269, 277, 278 Oral and intranasal preparations of metoclopramide are recommended for adults only.5, 267, 268, 269, 277, 278
Metoclopramide is administered orally on an empty stomach (at least 30 minutes before eating) as conventional tablets, an oral solution, or orally disintegrating tablets.5, 268, 269, 278 At least one manufacturer states that the dose should not be repeated if inadvertently administered with food.278
Each dose of orally disintegrating tablets should be removed from the blister packaging with dry hands and immediately placed on the tongue.278 The tablet should disintegrate on the tongue in approximately 1 minute (range: 10 seconds to 14 minutes) and the granules should be swallowed without water.278 Any orally disintegrating tablet that breaks or crumbles during handling should be discarded.278
Store metoclopramide conventional tablets, oral solution, and orally disintegrating tablets in tight, light-resistant containers at 20-25°C.5, 268, 269, 278 Protect the oral solution from freezing conditions.268 Store the orally disintegrating tablets away from moisture.278 Do not remove orally disintegrating tablets from the blister pack until immediately before administration.278
Metoclopramide nasal spray is administered by nasal inhalation and is commercially available in a bottle with a metered-dose spray pump attachment.277 Patients should be instructed carefully in the use of the nasal spray pump, including the need to prime the pump prior to first use or after a period of nonuse (i.e., 2 weeks or more).277 To obtain optimum results, patients also should be given a copy of the patient instructions provided by the manufacturer.277 The manufacturer's instructions for use should be consulted for complete information on administration technique for the metered-dose spray pump.277
An extra dose or a double dose should not be administered to make up for a missed dose, and a dose should not be repeated if the patient is uncertain whether the spray entered the nostril; instead, the next dose should be administered at the regularly scheduled time.277
Metoclopramide hydrochloride nasal solution should be stored at 20-25°C, but may be exposed to temperatures ranging from 15-30°C.277 The nasal solution should be discarded 4 weeks after opening.277
For IM or direct IV injection, the commercially available metoclopramide injection is used without further dilution.267 For doses >10 mg, metoclopramide injection should be diluted in 50 mL of a compatible IV solution.267
For IV infusion, metoclopramide hydrochloride injection should be diluted in 50 mL of one of the following IV solutions: 5% dextrose, 0.9% sodium chloride, 5% dextrose and 0.45% sodium chloride, Ringer's, or lactated Ringer's.267 Because the drug is most stable when diluted in 0.9% sodium chloride injection, the manufacturers state that this is the preferred solution for preparing IV infusions.267 The manufacturer's prescribing information and specialized references should be consulted for specific information on compatibility with other drugs.124, 267
Metoclopramide is light-sensitive and vials should be stored at 20-25°C in the original carton; excursions are permitted between 15-30°C.267 Solutions of metoclopramide hydrochloride that have been prepared by dilution of the injection with 50 mL of a compatible IV solution are stable for up to 48 hours (without freezing) when protected from light or for up to 24 hours when exposed to normal light conditions (i.e., unprotected from light).267 When diluted in 0.9% sodium chloride (preferred solution), the solution may be stored frozen for up to 28 days.267 Degradation occurs if metoclopramide is diluted in 5% dextrose injection and frozen.267
For direct IV injection, each 10 mg of the drug should be administered slowly over 1-2 minutes, since a transient but intense feeling of anxiety and restlessness, followed by drowsiness, may occur with rapid IV injection.267
IV infusions should be given slowly over at least 15 minutes.267
Although USP currently states that potency of metoclopramide hydrochloride preparations should be expressed both in terms of the salt and the base (“active moiety”),216 dosage currently is expressed in terms of the base.5, 267
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. 5, 267, 268, 269, 277, 278
Metoclopramide nasal spray delivers 15 mg of metoclopramide per 70-µL metered spray.277 Each bottle contains 9.8 mL of solution, which is sufficient for administration 4 times daily over a period of 4 weeks.277
Intubation of the Small Intestine
For pediatric patients undergoing intubation of the small intestine in whom the tube has not passed through the pylorus during 10 minutes of conventional maneuvers, the usual dose of metoclopramide to facilitate intubation is a single IV dose of 0.1 mg/kg in patients <6 years of age or 2.5-5 mg in children 6-14 years of age.267 To facilitate intubation in pediatric patients >14 years of age, the usual dose of metoclopramide is 10 mg, given as a single, direct IV injection.267
For relief of symptoms associated with acute and recurrent diabetic gastroparesis, the usual adult oral dosage of metoclopramide is 10 mg 4 times daily, given 30 minutes before meals and at bedtime.5, 268, 269, 278 The maximum recommended dosage is 40 mg daily.5, 269, 278
In patients who have severe symptoms or when oral administration of metoclopramide is not feasible, the drug may be given by IM or direct IV injection.5, 267, 269, 278 The usual adult IM or IV dosage of metoclopramide for symptomatic relief of diabetic gastroparesis is 10 mg 4 times daily, given 30 minutes before meals and at bedtime; parenteral administration of metoclopramide for up 10 days may be required until symptoms subside sufficiently to allow oral administration of the drug.5, 267, 268 However, a thorough assessment of the risks and benefits should be made prior to continuing further metoclopramide therapy.267
The recommended adult dosage of intranasal metoclopramide for relief of symptoms associated with acute and recurrent diabetic gastroparesis is 15 mg (one spray in one nostril) administered 30 minutes before meals and at bedtime (maximum of 4 times daily).277
Therapy with metoclopramide is usually continued for 2-8 weeks, depending on patient response.5, 268, 269, 277, 278 Therapy with metoclopramide, including all dosage forms and routes of administration, should not exceed 12 weeks' duration.5, 267, 268, 269, 277, 278
Cancer Chemotherapy-induced Nausea and Vomiting
For the prevention of cancer chemotherapy-induced emesis, the manufacturer states that metoclopramide is usually given by IV infusion 30 minutes before administration of cancer chemotherapy, and repeated every 2 hours for 2 additional doses, then every 3 hours for 3 additional doses.267 For adults, the manufacturer states that the initial 2 doses of metoclopramide should be 2 mg/kg if highly emetogenic drugs (e.g., cisplatin, dacarbazine) are used alone or in combination, while a metoclopramide dose of 1 mg/kg may be sufficient for less emetogenic drugs or chemotherapy regimens.267 If extrapyramidal symptoms occur during these IV metoclopramide dosage regimens, the manufacturer states that diphenhydramine hydrochloride (e.g., 50 mg given IM) may be administered.267 Benztropine mesylate (e.g., 1-2 mg given IM) may also be given to reverse extrapyramidal symptoms.267 When used for the treatment of breakthrough nausea and vomiting† in patients who received prophylactic antiemetic therapy with drugs from a different therapeutic class, oral or IV metoclopramide dosages of 10-20 mg given every 6 hours as needed have been used.263 296 .
Prevention of Postoperative Nausea and Vomiting
For the prevention of postoperative nausea and vomiting when nasogastric suction is considered undesirable, the manufacturer states that the usual adult IM dose of metoclopramide is 10 mg administered near the end of the surgical procedure, although a 20-mg dose also may be used.267
Intubation of the Small Intestine
For patients undergoing intubation of the small intestine in whom the tube has not passed through the pylorus during 10 minutes of conventional maneuvers, the usual dose of metoclopramide to facilitate intubation in adults is 10 mg, given as a single, direct IV injection.267
Radiographic Examination of the Upper GI Tract
For patients in whom delayed gastric emptying interferes with radiographic examination of the stomach and/or small intestine, the usual adult dose of metoclopramide to stimulate gastric emptying and intestinal transit of barium is 10 mg, given as a single, direct IV injection.267
Gastroesophageal Reflux Disease
For the symptomatic treatment of gastroesophageal reflux in patients who have not responded to conventional therapy, the usual adult oral dosage of metoclopramide in those who require continuous dosing is 10-15 mg 4 times daily, given 30 minutes before meals and at bedtime, for 4-12 weeks; treatment duration should be based on endoscopic evaluation of response, but the duration should not exceed 12 weeks.5, 269, 278 The maximum recommended dosage is 60 mg daily.5, 269, 278
If symptoms occur only intermittently or at specific times of the day, single oral doses of up to 20 mg given prior to the provocative situation may be preferred to daily administration of multiple doses of the drug.5, 269, 278
Concomitant Use of Cytochrome P-450 (CYP) 2D6 Inhibitors
Dosage adjustment is required in patients receiving concomitant therapy with potent inhibitors of CYP2D6.5, 269, 278 In adults receiving a potent CYP2D6 inhibitor (e.g., quinidine, bupropion, fluoxetine, paroxetine), the recommended oral dosage of metoclopramide for the relief of symptoms associated with diabetic gastroparesis is 5 mg 4 times daily, given 30 minutes before meals and at bedtime.5, 269, 278 The maximum recommended oral dosage is 20 mg daily.5, 269, 278
Metoclopramide nasal spray is not recommended in patients receiving concomitant potent CYP2D6 inhibitors because the dosage cannot be adjusted, which may lead to increased exposure to metoclopramide and an increase in adverse reactions, including tardive dyskinesia.277
Gastroesophageal Reflux Disease
Dosage adjustment is required in patients receiving concomitant therapy with potent CYP2D6 inhibitors.5, 269, 278 In adults receiving a potent CYP2D6 inhibitor (e.g., quinidine, bupropion, fluoxetine, paroxetine), the recommended oral dosage of metoclopramide for the symptomatic treatment of gastroesophageal reflux is 5 mg 4 times daily, given 30 minutes before meals and at bedtime, or 10 mg 3 times daily.5, 269, 278 The maximum recommended oral dosage is 30 mg daily.5, 269, 278
Diabetic Gastroparesis: In adults with moderate or severe hepatic impairment (Child-Pugh class B or C), the recommended oral dosage of metoclopramide for the relief of symptoms associated with diabetic gastroparesis is 5 mg 4 times daily, given 30 minutes before meals and at bedtime; the maximum recommended oral dosage is 20 mg daily.5, 269, 278 Adults with mild hepatic impairment (Child-Pugh class A) may receive the usual recommended oral dosage.5, 269, 278 Metoclopramide nasal spray is not recommended for use in patients with moderate or severe hepatic impairment because the dosage of the drug cannot be adjusted to reduce systemic exposure.277 Adults with mild hepatic impairment may receive the usual recommended intranasal dosage.277
Gastroesophageal Reflux Disease: In adults with moderate or severe hepatic impairment, the recommended oral dosage of metoclopramide for the symptomatic treatment of gastroesophageal reflux is 5 mg 4 times daily, given 30 minutes before meals and at bedtime, or 10 mg 3 times daily; the maximum recommended oral dosage is 30 mg daily.5, 269, 278 Adults with mild hepatic impairment may receive the usual recommended oral dosage.5, 269, 278
The manufacturers of metoclopramide hydrochloride injection recommend that patients with creatinine clearances <40 mL/minute receive initial parenteral metoclopramide dosages that are approximately 50% of the usual recommended dosages.267 Dosage subsequently should be increased or decreased according to the patient's clinical response and tolerance.267
Diabetic Gastroparesis: In adults with moderate or severe renal impairment (creatinine clearance <60 mL/minute), the recommended oral dosage of metoclopramide for the relief of symptoms associated with diabetic gastroparesis is 5 mg 4 times daily given 30 minutes before meals and at bedtime; the maximum recommended dosage is 20 mg daily.5, 269, 278 In adults with end-stage renal disease (ESRD), including those undergoing hemodialysis or continuous ambulatory peritoneal dialysis, the recommended oral dosage for the relief of symptoms associated with diabetic gastroparesis is 5 mg twice daily and the maximum recommended oral dosage is 10 mg daily.5, 269, 278
Metoclopramide nasal spray is not recommended for use in patients with moderate or severe renal impairment (creatinine clearance <60 mL/minute), including those undergoing hemodialysis or continuous ambulatory peritoneal dialysis, because the dosage of the drug cannot be adjusted to reduce systemic exposure.277 Adults with mild renal impairment may receive the usual recommended intranasal dosage.277
Gastroesophageal Reflux Disease: In adults with moderate or severe renal impairment (creatinine clearance of ≤60 mL/minute), the recommended oral dosage of metoclopramide for the symptomatic treatment of gastroesophageal reflux is 5 mg 4 times daily, given 30 minutes before meals and at bedtime, or 10 mg 3 times daily; the maximum recommended oral dosage is 30 mg daily.5, 269, 278 In adults with ESRD, including those undergoing hemodialysis or continuous ambulatory peritoneal dialysis, the recommended oral dosage for the symptomatic treatment of gastroesophageal reflux is 5 mg 4 times daily, given 30 minutes before meals and at bedtime, or 10 mg twice daily; the maximum recommended oral dosage is 20 mg daily.5, 269, 278
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.5, 278
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.5, 269, 278 Dosage may be titrated to a dosage of 10 mg 4 times daily based on response and tolerability.5, 269, 278 The maximum recommended oral dosage is 40 mg daily.5, 269, 278 Metoclopramide nasal spray is not recommended as initial therapy for relief of acute and recurrent diabetic gastroparesis in geriatric patients ≥65 years of age.277 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.277
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.5, 269, 278 Dosage may be titrated to a dosage of 10-15 mg 4 times daily based on response and tolerability.5, 269, 278 The maximum recommended oral dosage is 60 mg daily.5, 269, 278
Pharmacogenomic Considerations in Dosing
Because metoclopramide is metabolized by CYP2D6, patients who are poor metabolizers of CYP2D6 may eliminate metoclopramide more slowly than individuals who are intermediate, extensive, or ultra-rapid metabolizers of CYP2D6.5, 269, 278 Poor metabolizers may be at increased risk of dystonic and other adverse reactions to the drug.5, 269, 278 Therefore, a reduced dosage is recommended in patients who are poor CYP2D6 metabolizers.5, 269, 278
The manufacturers make no specific recommendations for parenteral metoclopramide dosage in patients who are poor metabolizers of CYP2D6 substrates.267
Diabetic Gastroparesis: In adults who are poor CYP2D6 metabolizers, the recommended oral dosage of metoclopramide for the relief of symptoms associated with diabetic gastroparesis is 5 mg 4 times daily, given 30 minutes before meals and at bedtime.5, 269, 278 The maximum recommended oral dosage is 20 mg daily.5, 269, 278
Metoclopramide nasal spray is not recommended for use in poor CYP2D6 metabolizers because dosage of the drug cannot be adjusted to reduce systemic exposure.277
Gastroesophageal Reflux Disease: In adults who are poor CYP2D6 metabolizers, the recommended oral dosage of metoclopramide for the symptomatic treatment of gastroesophageal reflux is 5 mg 4 times daily, given 30 minutes before meals and at bedtime, or 10 mg 3 times daily.5, 269, 278 The maximum recommended oral dosage is 30 mg daily.5, 269, 278
A boxed warning is included in the prescribing information of metoclopramide concerning the increased risk of tardive dyskinesia.5, 267, 268, 269, 277, 278 Treatment with metoclopramide may result in tardive dyskinesia, a potentially irreversible disorder manifested by involuntary movements of the tongue or face, and sometimes by involuntary movements of the trunk and/or extremities; movements may be choreoathetotic in appearance.5, 267, 268, 269, 277, 278 The risk that patients receiving metoclopramide will develop tardive dyskinesia and the likelihood that it will become irreversible increase with duration of therapy and total cumulative dose.5, 267, 268, 269, 277, 278 An analysis of drug utilization patterns indicated that the syndrome occurs in about 20% of patients receiving the drug for >12 weeks.267, 268, 278 In addition, the risk of developing tardive dyskinesia is increased in geriatric patients, especially older women, and patients with diabetes mellitus.5, 267, 268, 269, 277, 278 Treatment with metoclopramide, including all dosage forms and routes of administration, for >12 weeks should be avoided, and dosage should be reduced in geriatric patients.5, 267, 269, 278 Metoclopramide nasal spray is not recommended as initial therapy in geriatric patients.277 Metoclopramide should be discontinued in patients who develop signs or symptoms of tardive dyskinesia.5, 267, 268, 269, 277, 278 The syndrome may remit, either partially or completely, in some patients within several weeks to months after metoclopramide is discontinued.5, 267, 268, 269, 277, 278 Metoclopramide itself may suppress or partially suppress the manifestations of tardive dyskinesia, thereby masking the underlying disease process.5, 267, 268, 269, 277, 278 Whether this symptomatic suppression affects the long-term course of tardive dyskinesia is unknown.5, 267, 268, 269, 277, 278 Therefore, metoclopramide should not be used for symptomatic control of tardive dyskinesia.267, 268 Metoclopramide is contraindicated in patients with a history of tardive dyskinesia.5, 269, 277, 278 Metoclopramide should be avoided in patients receiving other drug therapies that can cause tardive dyskinesia, such as antipsychotics.5, 269, 277, 278
Other Warnings and Precautions
In addition to tardive dyskinesia, other extrapyramidal reactions (e.g., acute dystonic reactions, parkinsonian symptoms, akathisia) may occur in patients receiving metoclopramide.5, 267, 268, 269, 277, 278 Advise patients to seek immediate medical attention if such symptoms occur and to discontinue metoclopramide.5, 269, 277, 278 Although extrapyramidal reactions may occur in all age groups and at any dose, they occur more frequently in pediatric patients and adults <30 years of age,5, 267, 268, 269, 277, 278 and following IV administration of high doses of the drug (e.g., those used in prophylaxis of cancer chemotherapy-induced vomiting).267 Extrapyramidal reactions generally occur within 24-48 hours after starting therapy.5, 267, 268, 269, 277, 278 If these symptoms occur, diphenhydramine hydrochloride (e.g., 50 mg given IM) or benztropine mesylate (e.g., 1-2 mg given IM) may also be given to reverse symptoms.267, 268 Avoid the use of metoclopramide with other drugs that cause extrapyramidal symptoms (e.g., antipsychotics).5, 269, 277, 278
Acute dystonic reactions reportedly occur in <1% of adults receiving usual dosages of metoclopramide (e.g., 30-40 mg daily).267, 268 Dystonic reactions associated with metoclopramide therapy include involuntary movements of limbs, trismus, torticollis, facial grimacing, rhythmic protrusions of the tongue, bulbar type of speech, oculogyric crisis, and dystonic reactions resembling tetanus.5, 267, 268, 269, 277, 278 Dystonic reactions rarely may present as stridor and dyspnea, possibly secondary to laryngospasm.5, 267, 268, 269, 277, 278
Parkinsonian symptoms, including tremor, cogwheel rigidity, bradykinesia, and mask-like facies, have occurred in patients receiving metoclopramide.5, 267, 268, 269, 277, 278 Such symptoms develop more commonly during the first 6 months of metoclopramide therapy but also may occur after longer periods; following discontinuance of the drug, parkinsonian symptoms generally subside within 2-3 months.5, 267, 268, 269, 277, 278 While some manufacturers state that the drug can be used cautiously in patients with Parkinson's disease,267, 268 other manufacturers recommend to avoid the use of metoclopramide in patients with Parkinson's disease and in patients receiving antiparkinsonian drugs due to the potential for exacerbation of symptoms.5, 269, 277, 278
Akathisia, consisting of feelings of anxiety, agitation, jitteriness, insomnia, an inability to sit still, pacing, and foot tapping, has been reported.5, 267, 268, 269, 277, 278 If symptoms resolve, reinitiation of therapy at a lower dosage may be considered.5, 269, 278 The manufacturer of intranasal metoclopramide recommends discontinuing the drug if these symptoms occur.277
Neuroleptic Malignant Syndrome
Neuroleptic malignant syndrome (NMS), a potentially fatal symptom complex characterized by hyperpyrexia, muscular rigidity, altered mental status, and autonomic dysfunction, has been reported with dopamine antagonists.5, 267, 268, 269, 277, 278 Other symptoms may include elevations in CPK, rhabdomyolysis, and acute renal failure.5, 269, 277, 278 Patients with these symptoms should undergo immediate evaluation.5, 269, 277, 278 NMS has occurred following metoclopramide overdosage in patients receiving concomitant therapy with other drugs known to be associated with NMS.5, 269, 277, 278 Avoid the use of metoclopramide in patients receiving other drugs known to be associated with NMS (e.g., typical and atypical antipsychotics).5, 269, 277, 278 In patients with clinical manifestations consistent with NMS, it is important to determine whether untreated or inadequately treated extrapyramidal reactions and serious medical illness (e.g., pneumonia, systemic infection) may coexist.5, 267, 268, 269, 277, 278 Other important considerations in the differential diagnosis of NMS include the possibility of central anticholinergic toxicity, heat stroke, malignant hyperthermia, drug fever, serotonin syndrome, and primary CNS pathology.5, 267, 268, 269, 277, 278 Treatment of NMS includes immediate discontinuance of metoclopramide therapy and other drugs not considered essential to concurrent therapy, intensive symptomatic treatment and medical monitoring, and treatment of any concomitant serious medical condition for which specific therapies are available.5, 267, 268, 269, 277, 278
Depression has been reported in patients receiving metoclopramide, including patients with or without a history of an underlying depressive disorder.5, 267, 268, 269, 277, 278 In some patients, depression has been severe and included episodes of suicidal ideation and suicide.5, 267, 268, 269, 277, 278 Some manufacturers recommend avoiding the use of metoclopramide in patients with a history of depression,5, 269, 277, 278 while others state it can be given if the expected benefits outweigh the expected risks.267, 268
Because metoclopramide may increase blood pressure and there is some evidence in hypertensive patients that the drug may increase circulating catecholamines, metoclopramide should be avoided in patients with hypertension and in those receiving monoamine oxidase (MAO) inhibitors.5, 269, 277, 278 Hypertensive crisis has been reported in patients with undiagnosed pheochromocytoma, and metoclopramide should be discontinued in any patient who experiences a rapid increase in blood pressure.5, 269, 277, 278 Use of metoclopramide is contraindicated in the presence of pheochromocytomas or other catecholamine-releasing paragangliomas.5, 269, 277, 278
Because of the potential for transient increases in plasma aldosterone concentrations and sodium retention, the manufacturers of metoclopramide state that certain patients (e.g., those with cirrhosis or congestive heart failure) may be at risk of developing fluid retention and volume overload.5, 267, 268, 269, 277, 278 Monitor patients with hepatic impairment for fluid retention and volume overload.5, 269, 277, 278 The manufacturers state that if fluid retention or volume overload occurs at any time during metoclopramide therapy, the drug should be discontinued.5, 267, 268, 269, 277, 278
Metoclopramide may cause elevations in prolactin levels that persist with long-term administration.268 Hyperprolactinemia may suppress hypothalamic gonadotropin-releasing hormone secretion, resulting in reduced pituitary gonadotropin secretion, which may inhibit reproductive function by impairing gonadal steroidogenesis in males and females.5, 269, 277, 278 Like other prolactin-stimulating drugs, metoclopramide may be associated with galactorrhea, amenorrhea, gynecomastia, and impotence.5, 267, 269, 277, 278
Hyperprolactinemia may potentially stimulate prolactin-dependent breast cancer;5, 269, 277, 278 however, some clinical and epidemiologic studies have not shown an association between administration of dopamine D2-receptor antagonists and tumorigenesis in humans.5, 269, 277, 278 In a 77-week study in rats receiving metoclopramide at dosages of approximately 6 times the maximum recommended human dosage (MRHD), persistent elevation of prolactin concentrations and an increase in mammary neoplasms were observed following long-term administration.5, 269, 277, 278 In a rat model assessing tumor promotion potential, administration of metoclopramide at a dosage of approximately 35 times the MRHD for 2 weeks enhanced the tumorigenic effect of N-nitrosodiethylamine.5, 269, 277, 278
Effects on the Ability to Drive and Operate Machinery
Patients should be warned that metoclopramide may impair their ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle).5, 267, 268, 269, 277, 278 Patients also should be warned that concomitant use of metoclopramide with CNS depressants (e.g., alcohol, sedatives, hypnotics, opiate analgesics, anxiolytics) or drugs known to cause extrapyramidal reactions may increase mental and/or physical impairment; such concomitant use should be avoided.5, 269, 277, 278
Individuals who must restrict their intake of phenylalanine should be advised that each 5- or 10-mg orally disintegrating tablet of metoclopramide contains aspartame, which is metabolized in the GI tract to provide 4.7 mg of phenylalanine per tablet.278
Pressure on Suture Lines Following GI Anastomosis or Closure
Because metoclopramide can stimulate GI motility, the drug theoretically could produce increased pressure on suture lines following GI anastomosis or closure.267 This possibility should be considered and weighed when deciding whether to use parenteral metoclopramide or nasogastric suction for the prevention of postoperative nausea and vomiting.267
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.5, 269, 277, 278 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.5, 269, 277, 278
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.5, 269, 277, 278
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.5, 269, 277, 278 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.5, 269, 277, 278 Exposure is expected to be similar following maternal doses of 10 mg administered orally or 15 mg administered intranasally.277 Adverse GI effects, including intestinal discomfort and increased intestinal gas formation, have been reported in breast-fed infants who were exposed to metoclopramide.5, 269, 277, 278 Although metoclopramide increases prolactin concentrations, data are not adequate to support drug-related effects on milk production.5, 269, 277, 278
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.5, 269, 277, 278 Nursing neonates should be monitored for extrapyramidal effects (dystonias) and methemoglobinemia.5, 269, 277, 278
Females and Males of Reproductive Potential
Reproduction studies in male and female rats using metoclopramide dosages of up to approximately 3 times the MRHD have not revealed evidence of impaired fertility or altered reproductive performance.5, 269, 277, 278 Menstrual disturbances and impotence have occurred in some individuals during metoclopramide therapy.5, 269, 277, 278
The safety profile of metoclopramide in adults cannot be extrapolated to pediatric patients.267, 268 Dystonias and other extrapyramidal reactions to metoclopramide are more common in pediatric patients than in adults.5, 267, 268, 269
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.5, 268, 269, 277, 278
Safety and efficacy of metoclopramide injection in pediatric patients have been established only for use to facilitate intubation of the small intestine.267 Metoclopramide injection should be used with caution in pediatric patients, since the incidence of extrapyramidal reactions is increased in these patients.267 Metoclopramide injection should be administered with caution to neonates because decreased clearance may result in increased serum concentrations of the drug.267 In addition, since neonates have reduced concentrations of cytochrome-b5 reductase, they may be more susceptible to methemoglobinemia.5, 267
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.267 Data are insufficient to determine whether the pharmacokinetics of the drug in pediatric patients are similar to those in adults.267
Geriatric patients are more likely to have decreased renal function and may be more sensitive to therapeutic or adverse effects of metoclopramide.5, 268 Geriatric patients, especially older women, are at increased risk for tardive dyskinesia.5, 267, 268, 269, 277 In addition, the risk of developing parkinsonian symptoms increases with increasing dosage.5, 267, 268 Therefore, geriatric patients should receive the lowest effective dosage of metoclopramide.267, 268 If parkinsonian symptoms develop in a geriatric patient receiving metoclopramide, metoclopramide generally should be discontinued before any specific antiparkinsonian therapy is considered.267, 268 Sedation has been reported in patients receiving metoclopramide and may manifest as confusion and oversedation in geriatric patients.267, 268
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.5, 267, 268, 269, 277, 278 A reduced dosage should be considered in geriatric patients.5, 278 In general, the dosage should be selected carefully, usually initiating therapy at the low end of the dosage ran the greater frequency of decreased renal function and of concomitant disease and drug therapy observed in geriatric patients also should be considered.267, 268
In patients with severe hepatic impairment (Child-Pugh class C), clearance of metoclopramide is decreased by approximately 50%, resulting in increased systemic exposure to the drug and the potential for increased adverse effects.5, 269, 277, 278 Pharmacokinetic data are lacking in patients with moderate hepatic impairment (Child-Pugh class B).5, 269, 277, 278 Therefore, patients with moderate or severe hepatic impairment (Child-Pugh class B or C) should receive reduced dosages of the drug5, 269, 278 Avoid use of intranasal metoclopramide in patients with moderate to severe hepatic impairment.277
Because metoclopramide can cause transient increases in plasma aldosterone levels, the risk of fluid retention is increased in patients with hepatic impairment.5, 269, 277, 278 Monitor patients with hepatic impairment for fluid retention and volume overload.5, 269, 277, 278
In patients with moderate or severe renal impairment (creatinine clearance <60 mL/minute), systemic exposure to metoclopramide, as measured by AUC, following oral administration is approximately 2-fold that observed in individuals with normal renal function; in those with end-stage renal disease (ESRD) requiring dialysis, systemic exposure is approximately 3.5-fold that observed in individuals with normal renal function.5, 269, 277, 278 Therefore, patients with moderate to severe renal impairment, including those undergoing hemodialysis or continuous ambulatory peritoneal dialysis, should receive reduced oral dosages of the drug.5, 278
Intranasal metoclopramide is not recommended in patients with moderate to severe renal impairment, including those undergoing hemodialysis or continuous ambulatory peritoneal dialysis.277
The manufacturers recommend that patients with creatinine clearances <40 mL/minute receive reduced initial parenteral dosages of metoclopramide.267 Subsequently, the dosage should be increased or decreased according to the patient's clinical response and tolerance.267
Adverse effects reported in >10% of patients receiving oral metoclopramide include restlessness, drowsiness, fatigue, and lassitude.5, 269, 278
The most common adverse effects reported in patients receiving parenteral metoclopramide include restlessness, sleepiness, tiredness, dizziness, exhaustion, headache, confusion, and difficulty sleeping.267
Adverse effects reported in ≥5% of patients receiving metoclopramide nasal spray include dysgeusia, headache, and fatigue.277
Metoclopramide undergoes oxidative metabolism via cytochrome P-450 isoenzyme 2D6 (CYP2D6), as well as conjugation with glucuronic acid and sulfuric acid.5, 269, 277, 278
Effects on GI Absorption of Drugs
Because of its pharmacologic effects on transit time in the stomach and small intestine, metoclopramide may alter the absorption of certain drugs.5, 267 Because of increased GI motility, the extent of absorption of certain drugs is variable.5, 269, 277, 278 Absorption of drugs that disintegrate, dissolve, and/or are absorbed in the stomach (e.g., digoxin) may be diminished by metoclopramide.267, 268 The rate and extent of absorption of other drugs (e.g., acetaminophen, cyclosporine, alcohol, levodopa, tetracycline) that are absorbed from the small intestine, however, may be enhanced.267, 268 Absorption of atovaquone, fosfomycin, and posaconazole oral suspension (but not posaconazole delayed-release tablets) also may be diminished by metoclopramide.5, 269, 277, 278 Patients receiving drugs with possible diminished GI absorption should be monitored for reduced efficacy.5, 269, 277, 278 In patients receiving digoxin concomitantly with metoclopramide, digoxin concentrations should be monitored and digoxin dosage should be increased as needed.5, 269, 277, 278 Because absorption of orally administered cyclosporine, sirolimus, or tacrolimus may be increased by metoclopramide, concentrations of these drugs should be monitored and dosage of the immunosuppressive agent should be adjusted as needed.5, 269, 277, 278
The effects of metoclopramide on GI motility are antagonized by anticholinergic agents.5, 267, 268, 269, 277, 278
Drugs that impair GI motility (e.g., antiperistaltic antidiarrheal agents, anticholinergic drugs, opiates) may reduce oral absorption of metoclopramide; patients requiring such concomitant therapy should be monitored for reduced efficacy of metoclopramide.5, 269, 277, 278
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Concomitant administration of metoclopramide (20-mg oral dose) and the potent CYP2D6 inhibitor fluoxetine (60 mg orally daily) in healthy individuals increased peak plasma concentration and area under the concentration-time curve (AUC) of metoclopramide by 40 and 90%, respectively, compared with administration of metoclopramide alone.5, 277 Such increases in plasma concentrations of metoclopramide may be associated with exacerbation of extrapyramidal symptoms.5
If metoclopramide is used concomitantly with a potent CYP2D6 inhibitor (e.g., bupropion, fluoxetine, paroxetine, quinidine), metoclopramide dosage should be reduced.5, 269, 278 In adults receiving potent CYP2D6 inhibitors, the recommended oral dosage of metoclopramide for the relief of symptoms associated with diabetic gastroparesis is 5 mg given 4 times daily (maximum 20 mg daily) and the recommended oral dosage for the symptomatic treatment of gastroesophageal reflux is 5 mg given 4 times daily or 10 mg given 3 times daily (maximum 30 mg daily).5, 269, 278 The manufacturers make no specific recommendations for parenteral metoclopramide dosage in patients receiving potent CYP2D6 inhibitors.267 Concomitant use of intranasal metoclopramide and potent CYP2D6 inhibitors is not recommended since dosage of the intranasal preparation cannot be adjusted to reduce exposure.277
Although in vitro studies suggest that metoclopramide can inhibit CYP2D6, metoclopramide is unlikely to interact with CYP2D6 substrates in vivo at clinically relevant concentrations.5, 269, 278
Drugs with Similar Adverse Effect Profiles
Because of the potential for additive adverse effects, metoclopramide should be avoided in patients receiving drugs that are likely to cause extrapyramidal reactions or drugs that are associated with tardive dyskinesia or neuroleptic malignant syndrome (NMS).5, 267, 269, 277, 278
Concomitant use of metoclopramide and antipsychotic agents may result in additive adverse effects, including increased frequency and severity of tardive dyskinesia, parkinsonian or other extrapyramidal symptoms, and NMS.5, 269, 277, 278 Such concomitant use should be avoided.5, 269, 277, 278
Metoclopramide adverse CNS effects may be additive with, or may potentiate the action of, other CNS depressants such as opiates or other analgesics, sedatives or hypnotics, anxiolytic agents, anesthetics, or alcohol.5, 267 Such concomitant use should be avoided.5, 269, 277, 278
Concomitant use of metoclopramide and dopamine receptor agonists (e.g., apomorphine, bromocriptine, cabergoline, pramipexole, ropinirole, rotigotine) or other drugs that increase dopamine concentrations (e.g., levodopa) may result in reduced efficacy of metoclopramide and possible exacerbation of parkinsonian symptoms because of the opposing effects of the drugs on dopamine.5, 269, 277, 278 Because of the potential for exacerbation of parkinsonian symptoms, such concomitant use should be avoided.5, 269, 277, 278 However, if such concomitant therapy is required, therapeutic effects of the drugs should be monitored.5, 269, 277, 278
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, potentially resulting in hypoglycemia.267, 268 Increases in blood glucose concentrations may occur secondary to metoclopramide-induced increases in GI motility and increased delivery of food to the intestines.5, 269, 277, 278 Monitoring of blood glucose concentrations and adjustment of the insulin regimen may be necessary in patients with insulin-controlled diabetes mellitus.5, 269, 277, 278
Because concomitant use of metoclopramide and monoamine oxidase (MAO) inhibitors increases the risk of hypertension, concomitant use of these drugs should be avoided.5, 269, 277, 278
Metoclopramide inhibits plasma cholinesterase leading to enhanced neuromuscular blockade by neuromuscular blocking agents (e.g., succinylcholine).5, 269, 277, 278 Patients receiving such concomitant therapy should be monitored for prolonged neuromuscular blockade.5, 269, 277, 278
Metoclopramide hydrochloride is a dopamine D2-receptor antagonist, an antiemetic, and a stimulant of upper GI motility (prokinetic agent). 5, 267 The principal pharmacologic effects of metoclopramide involve the GI tract and CNS.267 Although the exact mechanism of action of metoclopramide in GI disorders is unclear, it appears to sensitize tissue to the actions of acetylcholine, resulting in stimulation of the upper GI tract, without causing stimulation of gastric, biliary, or pancreatic secretions.5, 267, 268, 269, 277, 278 The activity of metoclopramide can be inhibited by anticholinergic drugs, and its effects on motility are not dependent on intact vagal innervation.5, 267, 268, 269, 277, 278 Metoclopramide increases gastric contraction tone and amplitude, relaxes the pyloric sphincter and duodenal bulb, and increases peristalsis of the duodenum and jejunum.5, 267, 268, 269, 277, 278 Together, these effects result in the acceleration of gastric emptying and intestinal transit.5, 267, 268, 269, 277, 278 Metoclopramide increases the resting tone of the lower esophageal sphincter, while having minimal to no effects on colon or gallbladder motility.5, 267, 268, 269, 277, 278 The antiemetic effects of metoclopramide are likely due to the drug's effects on dopamine, which typically causes nausea and vomiting through stimulation of the medullary chemoreceptor trigger zone (CTZ).267, 268 Metoclopramide reduces nausea and vomiting through the blockade of central and peripheral dopamine receptors, resulting in decreased stimulation of the CTZ.267, 268
Metoclopramide is rapidly and well-absorbed from the GI tract following oral administration.267, 268, 269 Relative to a 20 mg intravenous dose, the absolute bioavailability of orally administered metoclopramide is about 80%.5, 267, 268, 269, 278 Following administration of a single oral dose, peak plasma concentrations are attained within 1-2 hours; peak plasma concentrations are attained in a similar time frame at steady state.5, 267, 268, 269 Metoclopramide exposure based on AUC increases linearly for doses 20-100 mg.5, 267, 268, 269 In a study in infants (3.5 weeks-5.4 months of age) with gastroesophageal reflux who received 0.15-mg/kg oral doses of metoclopramide every 6 hours for 10 doses as an oral solution, the mean peak plasma concentration (56.8 ng/mL) of the drug after the 10th dose was 2-fold higher compared with that after the first dose (29 ng/mL), suggesting that metoclopramide accumulates in plasma following multiple oral dosing in this age group.267 When administered under fasting conditions in adults, metoclopramide orally disintegrating tablets are bioequivalent to metoclopramide conventional tablets.278 Administration of the orally disintegrating tablets immediately after a high-fat meal did not affect the extent of absorption, but decreased the peak blood concentration by 17%; the time to peak concentration was increased from approximately 1.8 hours when administered under fasting conditions to 3 hours when administered immediately after a high-fat meal.278 The clinical importance of the decrease in peak blood concentration if the orally disintegrating tablets are inadvertently administered with food is unknown.278 Following intranasal or IV administration of metoclopramide 10 mg, bioavailability of intranasally administered metoclopramide was 47% that of IV metoclopramide.277 Absorption of the drug is reduced following intranasal administration compared with oral administration; systemic exposure (peak concentration and AUC) and time to reach peak concentration are similar following a 15-mg intranasal dose or a 10-mg oral dose.277 Over an intranasal dose range of 10-80 mg, exposure to the drug is proportional to dose.277 Metoclopramide AUC and peak concentration following intranasal administration are increased by 34 and 42%, respectively, in females compared with males.277 Lean body weight (range: 34-94 kg) also appears to affect the pharmacokinetics of the intranasally administered drug, with lower systemic exposure expected in individuals with higher lean body weight.277 The clinical relevance of these findings is unknown.277 The onset of the principal pharmacologic actions of metoclopramide on the GI tract is 1-3 minutes following IV administration, 10-15 minutes following IM administration, and 30-60 minutes following oral administration.267 Pharmacologic effects persist for 1-2 hours following administration of a single dose.267
Metoclopramide is 30% protein bound.5, 267, 268, 269, 277, 278 Metoclopramide undergoes enzymatic metabolism via oxidation as well as conjugation with glucuronic acid and sulfuric acid in the liver.5, 269, 277, 278 Monodeethylmetoclopramide, a major oxidative metabolite, is formed mainly by cytochrome P-450 isoenzyme 2D6 (CYP2D6), an enzyme subject to genetic variability.5, 269, 277, 278
In adults with normal renal function, the half-life of metoclopramide ranges from 5-6 hours.5, 267, 268 A half-life of 8.1 hours has been reported following intranasal administration.277 In pediatric patients receiving oral or IV metoclopramide, the elimination half-life of the drug reportedly is 4.1-4.5 hours.267, 268 Following oral administration of 0.15-mg/kg doses of metoclopramide every 6 hours for 10 doses in an infant (3.5 weeks of age), elimination half-lives of 23.1 and 10.3 hours were observed after the first and tenth dose, respectively, which were substantially longer than those reported in older infants, suggesting a reduced clearance in the neonate possibly associated with immature renal and hepatic functions present at birth.267, 268
In a limited number of adults with normal renal function, approximately 85% of an oral dose of radiolabeled metoclopramide was excreted in urine within 72 hours of administration;5, 267, 268, 269, 277, 278 approximately 50% of the drug excreted in urine is present as free or conjugated metoclopramide.267, 268 About 18 and 22% of a 10 mg and 20 mg oral dose of metoclopramide, respectively, is excreted in urine as unchanged drug within 36 hours.5, 269, 277, 278
Clearance of metoclopramide is decreased, and the half-life of metoclopramide is prolonged in patients with impaired renal function.267, 268 In patients with moderate or severe renal impairment (creatinine clearance <60 mL/minute), systemic exposure to metoclopramide, as measured by AUC, following oral administration is approximately 2-fold that observed in individuals with normal renal function; in those with end-stage renal disease (ESRD) requiring dialysis, systemic exposure is approximately 3.5-fold that observed in individuals with normal renal function.5, 269, 277, 278 Metoclopramide is only minimally removed by hemodialysis or peritoneal dialysis. 5, 267, 268
In a limited number of patients with severe hepatic impairment (Child-Pugh class C), average clearance of metoclopramide following oral administration was reduced by approximately 50% compared with patients with normal hepatic function.5, 269, 277, 278
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Nasal | Solution | 15 mg (of metoclopramide) per metered spray | Gimoti® | Evoke |
Oral | Solution | 5 mg (of metoclopramide) per 5 mL* | Metoclopramide Hydrochloride Oral Solution | |
Tablets | 5 mg (of metoclopramide)* | Metoclopramide Hydrochloride Tablets | ||
ANI | ||||
10 mg (of metoclopramide)* | Metoclopramide Hydrochloride Tablets | |||
Reglan® (scored) | ANI | |||
Tablets, orally disintegrating | 5 mg (of metoclopramide)* | Metoclopramide Hydrochloride Orally Disintegrating Tablets | ||
10 mg (of metoclopramide)* | Metoclopramide Hydrochloride Orally Disintegrating Tablets | |||
Parenteral | Injection | 5 mg (of metoclopramide) per mL* | Metoclopramide Hydrochloride Injection |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
5. ANI Pharmaceuticals. Metoclopramide hydrochloride tablets prescribing information. Baudette, MN; 2021 July. [Web]
31. Stadaas J, Aune S. The effect of metoclopramide (Primperan®) on gastric motility before and after vagotomy in man. Scand J Gastroenterol . 1971; 6:17-21. [PubMed 5100064]
37. Hancock BD, Bowen-Jones E, Dixon R et al. The effect of metoclopramide on gastric emptying of solid meals. Gut . 1974; 15:462-7. [PubMed 4605245]
39. Behar J, Biancani P. Effect of oral metoclopramide on gastroesophageal reflux in the post-cibal state. Gastroenterology . 1976; 70:331-5. [PubMed 765184]
43. James WB, Hume R. Action of metoclopramide on gastric emptying and small bowel transit time. Gut . 1968; 9:203-5. [PubMed 5655030]
44. Perkel MS, Moore C, Hersch T et al. Metoclopramide therapy in patients with delayed gastric emptying: a randomized double-blind study. Dig Dis Sci . 1979; 24:662-6. [PubMed 385260]
49. Malagelada JR, Ress WDW, Mazzotta LJ et al. Gastric motor abnormalities in diabetic and postvagotomy gastroparesis: effect of metoclopramide and bethanecol. Gastroenterology . 1980; 78:286-93. [PubMed 7350052]
80. Snape WJ, Battle WM, Schwartz SS et al. Metoclopramide to treat gastroparesis due to diabetes mellitus. Ann Intern Med . 1982; 96:444-6. [PubMed 7065559]
81. Carey RM, Thorner MO, Ortt EM. Effects of metoclopramide and bromocriptine on the renin-angiotensin-aldosterone system in man: dopaminergic control of aldosterone. J Clin Invest . 1979; 63:727-35. [PubMed 438333]
82. Aono T, Shioji T, Kinugasa T et al. Clinical and endocrinological analyses of patients with galactorrhea and menstrual disorders due to sulpiride or metoclopramide. J Clin Endocrinol Metab . 1978; 47:675-80. [PubMed 122411]
83. Campbell IW, Heading RC, Tothill P et al. Gastric emptying in diabetic autonomic neuropathy. Gut . 1977; 18:462-7. [PubMed 873328]
84. Saltzman M, Meyer C, Callachan C et al. Effect of metoclopramide on chronic gastric stasis in diabetic and post-gastric surgery patients. Gastroenterology . 1981; 80:1268.
98. Gralla RJ, Itri LM, Pisko SE et al. Antiemetic efficacy of high-dose metoclopramide: randomized trials with placebo and prochlorperazine in patients with chemotherapy-induced nausea and vomiting. N Engl J Med . 1981; 305:905-9. [PubMed 7024807]
99. Strum SB, McDermed JE, Opfell RW et al. Intravenous metoclopramide: an effective antiemetic in cancer chemotherapy. JAMA . 1982; 247:2683-6. [PubMed 7043002]
100. Carr B, Palone B, Pertrand M et al. A double-blind comparison of metoclopramide (MCP) and proclorperazine (PCP) for cis-platinum (DDP) induced emesis. Proc Am Soc Clin Oncol . 1982; 1:66.
101. Daniels M, Belt RJ. High dose metoclopramide as an antiemetic for patients receiving chemotherapy with cis-platinum. Oncol Nurs Forum . 1982; 9:20-2. [PubMed 6921788]
102. Gralla RJ, Tyson LB, Clark RA et al. Antiemetic trials with high dose metoclopramide superiority over THC, and preservation of efficacy in subsequent chemotherapy courses. Proc Am Soc Clin Oncol . 1982; 1:58.
105. Moshal MG. A rapid jejunal biopsy technique aided by metoclopramide: a double-blind trial with 50 patients. Postgrad Med J . 1973; 49(Suppl 4):87-9.
106. Arvanitakis C, Gonzalez G, Rhodes JB. The role of metoclopramide in peroral jejunal biopsy: a controlled randomized trial. Am J Dig Dis . 1976; 21:880-4. [PubMed 1015496]
107. Cristie DL, Ament ME. A double blind crossover study of metoclopramide versus placebo for facilitating passage of multipurpose biopsy tube. Gastroenterology . 1976; 71:726-8. [PubMed 786773]
109. Bolin TD. The facilitation of duodenal intubation with metoclopramide. Med J Aust . 1969; 1:1078-9.
110. Margieson GR, Sorby WA, Williams HBL. The action of metoclopramide on gastric emptying: a radiological assessment. Med J Aust . 1966; 2:1272-4. [PubMed 5957603]
112. McCallum RW, Ippoliti AF, Cooney C et al. A controlled trial of metoclopramide in symptomatic gastroesophageal reflux. N Engl J Med . 1977; 296:354-7. [PubMed 319356]
113. Stadaas JO, Aune S. Clinical trial of metoclopramide in postvagotomy gastric stasis. Arch Surg . 1972; 104:684-5. [PubMed 4554726]
114. Metzger W, Cano R, Sturdevant RAL. Effect of metoclopramide in chronic gastric retention after gastric surgery. Gastroenterology . 1975; 68:954.
115. McCallum RW, Saltzman M, Meyer C. Effect of metoclopramide in chronic gastric retention after gastric surgery. Clin Res . 1980; 28:765A.
116. Winnan J, Avella J, Callachan C et al. Double-blind trial of metoclopramide versus placebo-antacid in symptomatic gastroesophageal reflux. Gastroenterology . 1980; 78:1292.
117. Bright-Asare P, El-Bassoussi M. Cimetidine, metoclopramide or placebo in the treatment of symptomatic gastroesophageal reflux. J Clin Gastroenterol . 1980; 2:149-56. [PubMed 7002998]
124. ASHP injectable drug information. Metoclopramide. Bethesda, MD: American Society of Health-System Pharmacists; Updated 2024 Aug 24. Accessed 2024 Oct 4. [Web]
139. Lewis PJ, Devenish C, Kahn C. Controlled trial of metoclopramide in the initiation of breast feeding. Br J Clin Pharmacol . 1980; 9:217-9. [PubMed 6986894]
144. Tyson LB, Clark RA, Gralla RJ. High-dose metoclopramide: control of dacarbazine-induced emesis in a preliminary trial. Cancer Treat Rep . 1982; 66:2108. [PubMed 7139656]
145. Cox R, Newman CE, Leyland MJ. Metoclopramide in the reduction of nausea and vomiting associated with combined chemotherapy. Cancer Chemother Pharmacol . 1982; 8:133-5. [PubMed 7046974]
148. Metzger WH, Cano R, Sturdevant RAL. Effect of metoclopramide in chronic gastric retention after gastric surgery. Gastroenterology . 1976; 71:30-2. [PubMed 1278647]
149. Davidson ED, Hersh T, Iiaun C et al. Use of metoclopramide in patients with delayed gastric emptying following gastric surgery. Am Surg . 1977; 43:40-4. [PubMed 831608]
154. Guzman V, Toscano G, Canales ES et al. Improvement of defective lactation by using oral metoclopramide. Acta Obstet Gynecol Scand . 1979; 58:53-5. [PubMed 369279]
155. Kauppila A, Kivinen S, Ylikorkala O. A dose response relation between improved lactation and metoclopramide. Lancet . 1981; 1:1175-7. [PubMed 6112526]
167. Kauppila A, Kivinen S, Ylikorkala O. Metoclopramide increases prolactin release and milk secretion in puerperium without stimulating the secretion of thyrotropin and thyroid hormones. J Clin Endocrinol Metab . 1981; 52:436-9. [PubMed 6780593]
176. Hradsky M, Stockbrugger R. The effect of metoclopramide (Primperan®) during gastroscopic observation of the antrum and the pylorus. Gastrointest Endosc . 1974; 21:55-7. [PubMed 4452458]
177. Garnick MB. Oral metoclopramide and cisplatin chemotherapy. Ann Intern Med . 1983; 99:127. [PubMed 6683089]
184. James WB, Melrose AG. Metoclopramide in gastro-intestinal radiology. Clin Radiol . 1969; 20:57-60. [PubMed 5774092]
186. Fuchs B, Bartolomeo RS. Prevention of meal-induced heartburn and regurgitation with metoclopramide in patients with gastroesophageal reflux. Clin Ther . 1982; 5:179-85. [PubMed 6760968]
188. McCallum RW, Fink SM, Winnan GR et al. Metoclopramide in gastroesophageal reflux disease: rationale for its use and results of a double-blind trial. Am J Gastroenterol . 1984; 79:165-72. [PubMed 6367434]
216. The United States pharmacopeia, 24th rev, and the national formulary, 19th ed. Rockville, MD: The United States Pharmacopeial Convention, Inc; 2000:1097-9.
218. Levitt M, Warr D, Yelle L et al. Ondansetron compared with dexamethasone and metoclopramide as antiemetics in the chemotherapy of breast cancer with cyclophosphamide, methotresate, and fluorouracil. N Engl J Med . 1993; 328:1081-4. [PubMed 8455665]
236. De Mulder PHM, Seynaeve C, Vermorken JB et al. Ondansetron compared with high-dose metoclopramide in prophylaxis of acute and delayed cisplatin-induced nausea and vomiting: a multicenter, randomized, double-blind, crossover study. Ann Intern Med . 1990; 113:834-40. [PubMed 2146911]
238. Italian Group for Antiemetic Research. Ondansetron + dexamethasone vs metoclopramide + dexamethasone + diphenhydramine in prevention of cisplatin-induced emesis. Lancet . 1992; 340:96-99. [PubMed 1352024]
243. Marty M. A comparison of granisetron as a single agent with conventional combination antiemetic therapies in the treatment of cytostatic-induced emesis. The Granisetron Study Group. Eur J Cancer . 1992; 28A(Suppl 1):S12-6.
244. Ohmatsu H, Eguchi K, Shinkai T et al. A randomized cross-over study of high-dose metoclopramide plus dexamethasone versus granisetron plus dexamethasone in patients receiving chemotherapy with high-dose cisplatin. Jpn J Cancer Res . 1994; 85:1151-8. [PubMed 7829401]
245. Heron JF, Goedhals L, Jordaan JP et al. Oral granisetron alone and in combination with dexamethasone: a double-blind randomized comparison against high-dose metoclopramide plus dexamethasone in prevention of cisplatin-induced emesis. The Granisetron Study Group. Ann Oncol . 1994; 5:579-4. [PubMed 7993831]
246. The Granisetron Study Group. The antiemetic efficacy and safety of granisetron compared with metoclopramide plus dexamethasone in patients receiving fractionated chemotherapy over 5 days. J Cancer Res Clin Oncol . 1993; 119:555-9. [PubMed 8392077]
256. Aapro MS. 5-HT3 receptor antagonists: an overview of their present status and future potential in cancer therapy-induced emesis. Drugs . 1991; 551-68.
258. Katz PO, Dunbar KB, Schnoll-Sussman FH, Greer KB, Yadlapati R, Spechler SJ. ACG Clinical Guideline for the Diagnosis and Management of Gastroesophageal Reflux Disease. Am J Gastroenterol. 2022 Jan 1;117(1):27-56.
263. Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: ASCO Guideline Update. J Clin Oncol. 2020;38(24):2782-2797.
264. Kris MG, Hesketh PJ, Somerfield MR et al. Ondansetron versus metoclopramide, both combined with dexamethasone, in the prevention of cisplatin-induced delayed emesis: the Italian Group for Antiemetic Research. J Clin Oncol . 1997; 15:124-30. [PubMed 8996133]
265. Aapro MS, Thuerlimann B, Sessa C for the Swiss Group for Clinical Cancer Research et al. A randomized double-blind trial to compare the clinical efficacy of granisetron with metoclopramide, both combined with dexamethasone in the prophylaxis of chemotherapy-induced delayed emesis. Ann Oncol . 2003; 14:291-7. [PubMed 12562658]
266. Kris MG, Gralla RJ, Tyson LB et al. Controlling delayed vomiting: double-blind, randomized trial comparing placebo, dexamethasone alone, and metoclopramide plus dexamethasone in patients receiving cisplatin. J Clin Oncol . 1989; 7:108-14. [PubMed 2642536]
267. Avet Pharmaceuticals. Metoclopramide hydrochloride injection prescribing information. East Brunswick, NJ; 2024 May.
268. ANI Pharmaceuticals. Metoclopramide hydrochloride oral solution prescribing information. Baudette, MN; 2019 Nov.
269. Pharmaceutical Associates. Metoclopramide hydrochloride oral solution prescribing information. Greenville, SC; 2023 Mar.
273. Kahrilas PJ, Shaheen NJ, Vaezi MF et al. American Gastroenterological Association Medical Position Statement on the management of gastroesophageal reflux disease. Gastroenterology . 2008; 135:1383-1391, 1391.e1-5. [PubMed 18789939]
274. Yadlapati R, Gyawali CP, Pandolfino JE; CGIT GERD Consensus Conference Participants. AGA Clinical Practice Update on the Personalized Approach to the Evaluation and Management of GERD: Expert Review. Clin Gastroenterol Hepatol. 2022 May;20(5):984-994.e1.
277. Evoke Pharma. Gimoti® (metoclopramide hydrochloride) nasal spray prescribing information. Solana Beach, CA; 2021 Jan.
278. Lupin Pharmaceuticals. Metoclopramide hydrochloride orally disintegrating tablets prescribing information. Baltimore, MD; 2020 Dec.
284. Orr SL, Friedman BW, Christie S et al. Management of Adults With Acute Migraine in the Emergency Department: The American Headache Society Evidence Assessment of Parenteral Pharmacotherapies. Headache . 2016; 56:911-40. [PubMed 27300483]
286. Parkman HP, Carlson MR, Gonyer D. Metoclopramide nasal spray is effective in symptoms of gastroparesis in diabetics compared to conventional oral tablet. Neurogastroenterol Motil . 2014; 26:521-8. [PubMed 24372829]
287. Parkman HP, Carlson MR, Gonyer D. Metoclopramide Nasal Spray Reduces Symptoms of Gastroparesis in Women, but not Men, With Diabetes: Results of a Phase 2B Randomized Study. Clin Gastroenterol Hepatol . 2015; 13:1256-1263.e1. [PubMed 25576687]
290. Pasricha PJ, Camilleri M, Hasler WL et al. White Paper AGA: Gastroparesis: Clinical and Regulatory Insights for Clinical Trials. Clin Gastroenterol Hepatol . 2017; 15:1184-1190. [PubMed 28410896]
292. McCallum RW, Parkman HP, Fass R, Bhandari BR, Carlson MR, Buck RD. Metoclopramide Nasal Spray in Women with Symptomatic Diabetic Gastroparesis: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study. Clin Gastroenterol Hepatol. 2023 Nov 2:S1542-3565(23)00866-2.
293. American Diabetes Association Professional Practice Committee. 12. Retinopathy, Neuropathy, and Foot Care: Standards of Care in Diabetes-2024. Diabetes Care. 2024 Jan 1;47(Suppl 1):S231-S243.
294. Camilleri M, Kuo B, Nguyen L, Vaughn VM, Petrey J, Greer K, Yadlapati R, Abell TL. ACG Clinical Guideline: Gastroparesis. Am J Gastroenterol. 2022 Aug 1;117(8):1197-1220.
295. US Food and Drug Administration. How to Request Domperidone for Expanded Access Use. From FDA website. Accessed 2024 October 2. [Web]
296. Lohr L. Chemotherapy-induced nausea and vomiting. Cancer J. 2008 Mar-Apr;14(2):85-93.
297. Natale JJ. Overview of the prevention and management of CINV. Am J Manag Care. 2018 Oct;24(18 Suppl):S391-S397.
298. Kennedy SKF, Goodall S, Lee SF, DeAngelis C, Jocko A, Charbonneau F, Wang K, Pasetka M, Ko YJ, Wong HCY, Chan AW, Rajeswaran T, Gojsevic M, Chow E, Gralla RJ, Ng TL, Jerzak KJ. 2020 ASCO, 2023 NCCN, 2023 MASCC/ESMO, and 2019 CCO: a comparison of antiemetic guidelines for the treatment of chemotherapy-induced nausea and vomiting in cancer patients. Support Care Cancer. 2024 Apr 10;32(5):280.
299. Ouyang X, Qu R, Hu B, Wang Y, Yao F, Lv B, Sun C, Deng Y, Chen C. Is metoclopramide beneficial for the postpyloric placement of nasoenteric tubes? A systematic review and meta-analysis of randomized controlled trials. Nutr Clin Pract. 2022 Apr;37(2):316-327.
300. Silva CC, Bennett C, Saconato H, Atallah ÁN. Metoclopramide for post-pyloric placement of naso-enteral feeding tubes. Cochrane Database Syst Rev. 2015 Jan 7;1(1):CD003353.
301. Weibel S, Schaefer MS, Raj D, Rücker G, Pace NL, Schlesinger T, Meybohm P, Kienbaum P, Eberhart LHJ, Kranke P. Drugs for preventing postoperative nausea and vomiting in adults after general anaesthesia: an abridged Cochrane network meta-analysis. Anaesthesia. 2021 Jul;76(7):962-973.
302. Gan TJ, Belani KG, Bergese S, Chung F, Diemunsch P, Habib AS, Jin Z, Kovac AL, Meyer TA, Urman RD, Apfel CC, Ayad S, Beagley L, Candiotti K, Englesakis M, Hedrick TL, Kranke P, Lee S, Lipman D, Minkowitz HS, Morton J, Philip BK. Fourth Consensus Guidelines for the Management of Postoperative Nausea and Vomiting. Anesth Analg. 2020 Aug;131(2):411-448.
303. Kirkland SW, Visser L, Meyer J, Junqueira DR, Campbell S, Villa-Roel C, Friedman BW, Essel NO, Rowe BH. The effectiveness of parenteral agents for pain reduction in patients with migraine presenting to emergency settings: A systematic review and network analysis. Headache. 2024 Apr;64(4):424-447.
304. Furyk JS, Meek RA, Egerton-Warburton D. Drugs for the treatment of nausea and vomiting in adults in the emergency department setting. Cochrane Database Syst Rev. 2015 Sep 28;2015(9):CD010106.
305. Polito NB, Fellows SE. Pharmacologic Interventions for Intractable and Persistent Hiccups: A Systematic Review. J Emerg Med. 2017 Oct;53(4):540-549.
306. Breastfeeding Challenges: ACOG Committee Opinion, Number 820. Obstet Gynecol. 2021 Feb 1;137(2):e42-e53.
307. Practice Guidelines for Preoperative Fasting and the Use of Pharmacologic Agents to Reduce the Risk of Pulmonary Aspiration: Application to Healthy Patients Undergoing Elective Procedures: An Updated Report by the American Society of Anesthesiologists Task Force on Preoperative Fasting and the Use of Pharmacologic Agents to Reduce the Risk of Pulmonary Aspiration. Anesthesiology. 2017 Mar;126(3):376-393.
308. Practice Guidelines for Obstetric Anesthesia: An Updated Report by the American Society of Anesthesiologists Task Force on Obstetric Anesthesia and the Society for Obstetric Anesthesia and Perinatology. Anesthesiology. 2016 Feb;124(2):270-300.
309. Committee on Practice Bulletins-Obstetrics. ACOG Practice Bulletin No. 189: Nausea And Vomiting Of Pregnancy. Obstet Gynecol. 2018 Jan;131(1):e15-e30.
999. By the 2023 American Geriatrics Society Beers Criteria® Update Expert Panel. American Geriatrics Society 2023 updated AGS Beers Criteria® for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2023 Jul;71(7):2052-2081. doi: 10.1111/jgs.18372. Epub 2023 May 4. PMID: 37139824.