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Metoclopramide

Medically reviewed on Nov 15, 2018

Pronunciation

See also: Emgality

(met oh KLOE pra mide)

Index Terms

  • Metoclopramide HCl
  • Reglan

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Injection:

Generic: 5 mg/mL (2 mL)

Solution, Injection [preservative free]:

Generic: 5 mg/mL (2 mL)

Solution, Oral:

Generic: 5 mg/5 mL (10 mL, 473 mL); 10 mg/10 mL (10 mL)

Tablet, Oral:

Reglan: 5 mg [contains fd&c blue #1 aluminum lake, fd&c yellow #10 aluminum lake]

Reglan: 10 mg [dye free]

Generic: 5 mg, 10 mg

Tablet Disintegrating, Oral:

Metozolv ODT: 5 mg [DSC]

Generic: 5 mg, 10 mg

Brand Names: U.S.

  • Metozolv ODT [DSC]
  • Reglan

Pharmacologic Category

  • Antiemetic
  • Gastrointestinal Agent, Prokinetic

Pharmacology

Blocks dopamine receptors and (when given in higher doses) also blocks serotonin receptors in chemoreceptor trigger zone of the CNS; enhances the response to acetylcholine of tissue in upper GI tract causing enhanced motility and accelerated gastric emptying without stimulating gastric, biliary, or pancreatic secretions; increases lower esophageal sphincter tone

Absorption

Oral: Rapid, well absorbed

Distribution

Vd: Neonates, PMA 31 to 40 weeks: 6.94 L/kg (Kearns 1998); Infants: 4.4 L/kg; Children: 3 L/kg; Adults: ~3.5 L/kg

Excretion

Urine (~85%); feces

Onset of Action

Oral: 30 to 60 minutes; IV: 1 to 3 minutes; IM: 10 to 15 minutes

Time to Peak

Serum: Oral: Neonates, PMA 31 to 40 weeks: 2.45 hours (Kearns 1998); Infants: 2.2 hours; Adults: 1 to 2 hours

Duration of Action

Therapeutic: 1 to 2 hours, regardless of route

Half-Life Elimination

Normal renal function: Neonates, PMA 31 to 40 weeks: 5.4 hours (Kearns 1998); Infants: 4.15 hours (range: 2.23 to 10.3 hours) (Kearns 1988); Children: ~4 hours (range: 2 to 12.5 hours); half-life and clearance may be dose-dependent; Adults: 5 to 6 hours (may be dose dependent)

Protein Binding

~30%

Special Populations: Renal Function Impairment

AUC increased ~2-fold in patients with moderate to severe renal impairment and ~3.5 fold in patients with ESRD on dialysis.

Special Populations: Hepatic Function Impairment

Clearance was reduced by ~50% in patients with severe hepatic impairment.

Special Populations Note

CYP2D6 poor metabolizers: Elimination may be slowed.

Use: Labeled Indications

Injection:

Chemotherapy-induced nausea and vomiting, prophylaxis

Gastroparesis, diabetic: Relief of symptoms associated with acute and recurrent diabetic gastric stasis.

Postoperative nausea and vomiting, prophylaxis: Note: Metoclopramide, a relatively weak antiemetic, is rarely used in the setting of PONV prophylaxis; alternative antiemetics are preferred for routine use (Feinleib 2018; Gan 2014).

Radiological examination, barium studies (adjunctive agent): To stimulate gastric emptying and intestinal transit of barium when delayed emptying interferes with radiological examination of the stomach and/or small intestine.

Oral:

Gastroesophageal reflux disease (GERD), refractory: Short-term (4 to 12 weeks) treatment in adults with documented symptomatic GERD who fail to respond to conventional therapy.

Note: The American College of Gastroenterology (ACG) guidelines for the treatment of GERD recommend that diagnostic evaluation to confirm underlying gastroparesis be performed prior to considering the use of prokinetic agents; metoclopramide may be used as an adjunctive therapy only if gastroparesis is confirmed (ACG [Katz 2013]). In addition, guidelines from the American Gastroenterological Association (AGA) for the treatment of GERD recommend against the use of metoclopramide as monotherapy or adjunctive therapy in patients with GERD (AGA [Kahrilas 2008]).

Gastroparesis, diabetic: Relief of symptoms associated with acute and recurrent diabetic gastroparesis in adults.

Off Label Uses

Aspiration prophylaxis in patients undergoing anesthesia

Data from multiple studies of varying methodologies (including randomized, double-blind, placebo-controlled trials) support the use of metoclopramide for the prevention of aspiration in patients undergoing anesthesia [Manchikanti 1982], [Olsson 1982], [Orr 1993], [Rocke 1994], [Stuart 1996]. Studies have encompassed a wide variety of patient populations and surgical and procedural settings, including (but not limited to) elective and emergency surgeries, rapid sequence intubation, and scheduled or emergent cesarean deliveries. Clinical experience and case reports also suggest use may be especially beneficial in patients at high risk for aspiration (eg, patients with a full stomach, severe GERD, gastroparesis and/or pregnant patients undergoing anesthesia for electroconvulsive therapy [ECT]) [Berkow 2018], [Hagberg 2018], [Kellner 2018], [Lovas 2011], [O'Reardon 2011], [Rabheru 2001].

Based on the American Society of Anesthesiologists (ASA) Practice Guidelines for Obstetric Anesthesia, metoclopramide is an effective and recommended prophylactic agent for the prevention of aspiration during surgical procedures (eg, cesarean delivery, postpartum tubal ligation) in pregnant patients.

Bowel obstruction (partial), malignant

Clinical experience suggests the utility of metoclopramide in the management of patients with partial malignant bowel obstruction [Gupta 2013], [Ripamonti 2002].

Based on the 2016 MASCC/ESMO guidelines for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting and of nausea and vomiting in advanced cancer patients, metoclopramide may be used cautiously in the management of partial malignant bowel obstruction. Do not use for complete bowel obstruction[ MASCC/ESMO [Roila 2016]].

Chemotherapy-associated nausea and vomiting, prophylaxis (pediatrics)

Based on the Pediatric Oncology Group of Ontario (POGO) guidelines for Prevention of Acute Nausea and Vomiting Due to Antineoplastic Medication in Pediatric Cancer Patients, metoclopramide may be used for moderately emetogenic chemotherapy in patients who cannot receive corticosteroids.

Chemotherapy-induced nausea and vomiting, prophylaxis of delayed-emesis (high-risk regimen)

Limited data from a randomized, double-blind trial evaluating metoclopramide, in combination with dexamethasone, for prophylaxis against cisplatin-induced delayed emesis showed similar efficacy and similar toxicity with the metoclopramide regimen compared to the comparator regimen (aprepitant in combination with dexamethasone) [Roila 2015]. Routine use of metoclopramide use is not recommended for prevention of delayed-emesis (alternative agents recommended); therefore, the significance, if any, of this trial is still unknown.

Chemotherapy-induced nausea and vomiting, prophylaxis in patients refractory to or intolerant to a first-line antiemetic regimen

Clinical experience suggests metoclopramide may be considered prior to high- or moderate-emetic risk chemotherapy only in patients who are intolerant or refractory to first-line antiemetic agents.

Dyspepsia, refractory

Data from two double-blind, placebo-controlled trials that compared different doses and formulations of metoclopramide [Banani 2008] and metoclopramide and other prokinetic agents [De Loose 1979] support the efficacy of metoclopramide in the treatment of dyspepsia. However, guidelines from the American College of Gastroenterology (ACG) and the Canadian Association of Gastroenterology (CAG) on the treatment of dyspepsia recommend limiting the use of metoclopramide to patients <60 years of age with dyspepsia unresponsive to proton pump inhibitors (PPI) or H. pylori eradication therapy or in any patient (including those ≥60 years of age) with functional dyspepsia that have not responded to PPIs, H. pylori eradication therapy, or tricyclic antidepressants [[ACG/CAG [Moayyedi 2017]].

Gastric bezoars (adjunctive agent)

Limited data are available regarding the use of metoclopramide for treatment of gastric bezoars. Noncontrolled studies and case reports have demonstrated efficacy. However, without more robust controlled studies, a definitive role of metoclopramide for this use cannot be determined.

Gastroparesis, malignancy-associated

Clinical experience suggests the utility of metoclopramide for malignancy-associated gastroparesis [Bruera 2018], [Donthireddy 2007], [Kelly 2014], [Leung 2009], [Shivshanker 1983].

Gastroparesis, nondiabetic

Based on the American College of Gastroenterology Clinical Guideline: Management of Gastroparesis, metoclopramide given for treatment of gastroparesis regardless of the etiology is effective and recommended in the management of this condition.

Hiccups (singultus)

In small controlled trials and noncontrolled evaluations, metoclopramide was effective for prevention and treatment of hiccups. However, when used as a preventive measure, some patients still experienced hiccups, [Stav 1992] and when used for treatment, cases of delayed onset of efficacy and cases of only partial efficacy were reported [Homer 2005], [Middleton 1973], [Wang 2014].

Medication-overuse headache (MOH) or status migrainosus (adjunctive agent)

Data from non-blinded, non-randomized descriptive and observational trials suggest that metoclopramide may be beneficial as an adjunctive agent when used in combination with dihydroergotamine for the treatment of medication-overuse headache or status migrainosus [Ford 1997], [Raskin 1986], [Silberstein 1990], [Silberstein 1992].

Migraine, severe (acute) (emergency setting)

Based on the American Headache Society and the European Federation of Neurological Societies (EFNS) guidelines on the drug treatment of migraine, the use of IV metoclopramide for the treatment of migraines is effective and recommended in the management of acute migraine [AHS [Orr 2016]], [EFNS [Evers 2009]]. While IV administration is preferred, the IM, oral, and subcutaneous routes may also be used [EFNS [Evers 2009]].

Nausea and/or vomiting, undifferentiated

Limited data from a small number of randomized trials, primarily in the emergency department setting in patients presenting with undifferentiated acute nausea and/or vomiting, suggest metoclopramide's utility in this condition [Barrett 2011], [Egerton-Warburton 2014]. However, definitive, high-quality trials supporting efficacy are lacking [Furyk 2015].

Clinical experience also suggests the utility of metoclopramide in the treatment of acute nausea and/or vomiting due to a variety of medical conditions associated with acute self-limiting nausea/vomiting [Longstreth 2018].

Nausea and vomiting in patients with advanced cancer

Clinical experience suggests the utility of metoclopramide in the treatment of nausea and vomiting in patients with advanced cancer without an identifiable etiology [Gupta 2013], in the palliative care setting [Bruera 1996], [Del Fabbro 2018], with malignant partial bowel obstruction [MASCC/ESMO [Roila 2016]], [Ripamonti 2002], or with malignancy-associated gastroparesis [Bruera 2018 ].

Pregnancy-associated nausea and vomiting, severe or refractory

Data from randomized, double-blind, active-controlled studies support the use of metoclopramide in the treatment of severe nausea and vomiting of pregnancy [Abas 2014], [Tan 2010].

Based on the American College of Obstetricians and Gynecologists (ACOG) Nausea and Vomiting in Pregnancy guidelines, the use of metoclopramide may be considered for adjunctive treatment of nausea and vomiting in pregnant women when symptoms persist following initial pharmacologic therapy.

Radiation therapy-induced nausea and vomiting (rescue therapy)

Based on the American Society of Clinical Oncology Clinical Practice Guideline Update for Antiemesis, metoclopramide may be used rescue therapy on an as-needed basis for the prevention of radiation therapy-induced nausea and vomiting when emetic risk is low or minimal.

Tension-type headache, acute (emergency setting)

Data from two prospective, randomized, double-blind trials support the use of metoclopramide, either alone [Cicek 2004] or in combination with diphenhydramine [Friedman 2013], for the treatment of acute tension-type headaches in the emergency department setting.

Vertigo-associated nausea and vomiting

Clinical experience suggests the utility of metoclopramide in the acute treatment of nausea and vomiting associated with vertigo [Furman 2018].

Contraindications

Hypersensitivity (eg, laryngeal and glossal angioedema, bronchospasm) to metoclopramide or any component of the formulation; situations where stimulation of gastrointestinal (GI) motility may be dangerous, including mechanical GI obstruction, perforation, or hemorrhage (except when used prior to endoscopy for evaluation of acute upper GI bleeding [Barkun 2010]); pheochromocytoma or other catecholamine-releasing paragangliomas; seizure disorder (eg, epilepsy); history of tardive dyskinesia or dystonic reaction to metoclopramide; concomitant use with other agents likely to increase extrapyramidal reactions.

Canadian labeling: Additional contraindications (not in the US labeling): Infants <1 year of age.

Dosing: Adult

Note: To decrease the risk of tardive dyskinesia (TD), metoclopramide should not be used continuously for ≥12 weeks. Discontinue immediately if the diagnosis of TD is made; consider the use of alternative agents.

Aspiration prophylaxis in patients undergoing anesthesia (off-label use): Note: May be considered in patients at high risk for aspiration (eg, patients with a full stomach, severe gastrointestinal reflux disease [GERD], gastroparesis, and/or pregnant patients) (ASA 2016; Berkow 2018; Hagberg 2018; Lovas 2011; O'Reardon 2011; Rabheru 2001):

IV: 10 mg administered over 1 to 2 minutes as a single dose ~30 to 60 minutes prior to induction of anesthesia; may give in combination with nonparticulate antacids (eg, oral sodium citrate/citric acid) and/or an H2 receptor blocker (ASA 2016; ASA 2017; Lovas 2011; McCammon 1986; Nixon 2018; O'Reardon 2011; Orr 1993; Rocke 1994).

Bowel obstruction (partial), malignant (off-label use): Note: Use with caution in patients with partial bowel obstruction; do not use in patients with a complete mechanical obstruction (or symptoms indicative of complete obstruction, such as colicky, cramping, continuous pain), pseudo-obstruction, toxic-megacolon, or typhlitis (Gupta 2013; MASCC/ESMO [Roila 2016]; Ripamonti 2002). Usually given in combination with other appropriate agents (an antisecretory agent, a corticosteroid, and/or an anticholinergic agent) (Berger 2016; Gupta 2013).

Oral: 10 mg before meals and at bedtime (Gupta 2013) or 10 mg every 4 to 6 hours (Glare 2008)

IV, SubQ (off-label): Initial: 40 to 60 mg/day in divided doses (usually every 6 hours), titrated up to 120 mg/day (Gupta 2013) or 40 to 60 mg/24 hours via continuous SubQ infusion (Glare 2008)

Chemotherapy-induced nausea and vomiting, prophylaxis: Note: Not for routine use; may be considered in select patients (eg, refractory to first-line agents or in patients with a history of nausea/vomiting following low emetic risk regimens) (Hesketh 2018).

Low emetic risk chemotherapy regimen: Note: May be considered for patients who have a prior history of nausea/vomiting following low emetic risk IV chemotherapy regimens or who develop nausea/vomiting during treatment with oral low emetic risk chemotherapy regimens.

Oral: Limited data available; dosing regimen based on expert opinion: 10 to 20 mg every 6 hours as needed (Hesketh 2018)

Patients refractory to or intolerant of a first-line antiemetic regimen (alternative agent) (off-label use): Note: Not recommended prior to high- or moderate-emetic risk IV or oral chemotherapy regimens (alternative antiemetic agents recommended) (ASCO [Hesketh 2017]); metoclopramide is only appropriate for patients who are refractory to or intolerant of a first-line antiemetic regimen appropriate for the emetic risk of the chemotherapy regimen and which already includes olanzapine as a component (Hesketh 2018). Diphenhydramine should also be given concurrently to reduce the risk of extrapyramidal effects associated with high-dose metoclopramide.

Day of chemotherapy: Substitute metoclopramide for the 5-HT3 antagonist in the antiemetic regimen: High-dose metoclopramide: IV: 1 to 2 mg/kg administered before chemotherapy and repeated 2 hours after chemotherapy (Hesketh 2008).

Postchemotherapy days: Oral: 0.5 mg/kg every 6 hours on days 2 to 4 (Hesketh 2008)

Prophylaxis of delayed-emesis (high-emetic risk chemotherapy regimen) (alternative agent) (off-label use): Note: Routine use is not recommended for prophylaxis of delayed-emesis (alternative agents recommended); however, metoclopramide has been evaluated for this use in the setting of cisplatin-induced delayed nausea and vomiting.

Oral: 20 mg 4 times daily on postchemotherapy days 2 through 4; given in combination with dexamethasone (Roila 2015)

Dyspepsia, refractory (off-label use): Note: May be considered in patients <60 years of age with dyspepsia unresponsive to proton pump inhibitors (PPI) or H. pylori eradication therapy or in any patient (including those ≥ 60 years of age) with functional dyspepsia that have not responded to PPIs, H. pylori eradication therapy, or tricyclic antidepressants (ACG/CAG [Moayyedi 2017]):

Oral: 5 to 10 mg 3 to 4 times daily administered prior to meals and at bedtime (Banani 2008; De Loose 1979). A lower dose (2 mg 3 times daily) has been described when the oral liquid formulation was used (Banani 2008).

Gastric bezoars (adjunctive agent) (off-label use): Limited data exists; may be considered as an adjunct to endoscopic therapy and/or chemical dissolution in patients with gastric bezoars to shorten the time to resolution (Delpre 1984; Gaya 2002; Winkler 1983). Additional data may be necessary to further define the role of metoclopramide in patients with gastric bezoars as the data is scarce and has not been validated.

Oral, IV: 5 to 10 mg 3 to 4 times daily until resolution (Gaya 2002; Winkler 1983)

IV: Continuous infusion: 40 mg administered over 24 hours for 3 days; may repeat if bezoar is not cleared (Delpre 1984)

Gastroparesis, diabetic: Note: Reserve for severe cases that are unresponsive to other therapies (ADA 2018). The treatment strategy should also include improving glycemic control, dietary considerations, and discontinuing drugs that may impair gastrointestinal motility (including pramlintide and GLP-1 receptor agonists) (ACG [Camilleri 2013]; ADA 2018). Initiating with an oral liquid formulation is preferred to increase absorption (ACG [Camilleri 2013]); may use IM or IV routes for patients who cannot tolerate oral administration or for whom delayed gastric emptying or nausea and vomiting impacts the efficacy of prokinetic therapy.

Oral (preferred), IM, IV: 5 to 10 mg 2 to 3 times daily administered prior to meals; duration should be limited to ≤5 days (ACG [Camilleri 2013]; ADA 2018). Titrate to the lowest effective dose; maximum dose: 40 mg/day in 4 divided doses (ACG [Camilleri 2013]; manufacturer's labeling).

Manufacturer's labeling: Manufacturer's labeled dosing is based on dosing in product labeling and may not reflect current clinical practice.

Oral: 10 mg 4 times daily (maximum: 40 mg/day)

IM, IV: 10 mg

Gastroparesis, malignancy-associated (off-label use): Oral, IM, IV, SubQ (off-label): 5 to 10 mg every 6 hours or 3 to 4 times daily (before meals and at night) (Donthireddy 2007; Kelly 2014; Leung 2009; Shivshanker 1986); some experts titrate up to 120 mg/day (Bruera 2018).

Gastroparesis, nondiabetic (off-label use): Note: Use in addition to dietary therapy for the treatment of gastroparesis (ACG [Camilleri 2013]). Initiating with an oral liquid formulation is preferred to increase absorption (ACG [Camilleri 2013]); may use IM or IV routes for patients who cannot tolerate oral administration or for whom delayed gastric emptying or nausea and vomiting impacts the efficacy of prokinetic therapy; subcutaneous, intraperitoneal, and intranasal administration have also been described in case reports (McCallum 1991; Parkman 2015; Seibert 1989).

Oral (preferred), IM, IV: 5 to 10 mg 2 to 3 times daily administered prior to meals (ACG [Camilleri 2013]). Titrate to the lowest effective dose; maximum 40 mg/day in 4 divided doses (ACG [Camilleri 2013]; manufacturer's labeling).

Duration: ≤12 weeks unless patients have a therapeutic benefit that outweighs the risk. Note: Consider a "drug holiday" or dose reduction every 12 weeks when clinically possible to evaluate efficacy and necessity of continued treatment (ACG [Camilleri 2013]; Camilleri 2018). Reduce the dose to 5 mg twice daily before the two main meals of the day or temporarily discontinue for ~2 weeks (ACG [Camilleri 2013]; Camilleri 2018).

Gastroesophageal reflux disease (GERD), refractory: Note: Perform diagnostic evaluation to confirm underlying gastroparesis prior to considering the use of adjunctive prokinetic agents (ACG [Katz 2013]).

Continuous dosing: Oral: 10 to 15 mg 4 times daily administered 30 minutes before each meal and at bedtime for 4 to 12 weeks (maximum: 60 mg/day) (manufacturer's labeling)

Intermittent dosing: Oral: In patients who only experience symptoms intermittently or at specific times of the day, consider a single dose up to 20 mg administered prior to the provoking situation. Do not treat >12 weeks (manufacturer's labeling).

Hiccups (singultus) (off-label use): Note: Limited data exists.

Prevention:

IV: 0.17 mg/kg as a single dose starting the day of or 1 day before anticipated hiccup-precipitating event (Stav 1992).

Oral: 10 mg every 6 to 8 hours starting the day of or 1 day before anticipated hiccup-precipitating event (Baethge 1986; Cersosimo 1998).

Treatment:

IV, IM: 5 to 10 mg every 8 hours (Madanagopolan 1975; Middleton 1973)

Oral: 10 mg every 6 to 8 hours (Madanagopolan 1975; Middleton 1973; Wang 2014)

Note: Therapy may begin with parenteral dosing and transition to oral dosing when hiccups are controlled (Friedman 1996). Usually, treatment continues for up to 5 to 10 days, but some patients may require longer treatment durations when hiccups recur or even indefinite treatment (eg, palliative care). May discontinue treatment the day after hiccups cease; if hiccups recur, longer treatment duration may be needed (Lembo 2018).

Medication-overuse headache (MOH) or status migrainosus (adjunctive agent) (off-label use): Administer as an adjunctive agent for the prevention of nausea and vomiting in patients who are receiving intermittent or continuous dihydroergotamine for the acute treatment of MOH or status migrainosus (Ford 1997; Raskin 1986; Silberstein 1990; Silberstein 1992):

IV: Initial: 10 mg administered over 30 minutes immediately prior to the initiation of dihydroergotamine therapy (Ford 1997; Raskin 1986; Silberstein 1990; Silberstein 1992). Doses of metoclopramide up to 20 mg have been used to allow for higher doses of dihydroergotamine or if the patient experiences severe nausea (Garza 2018; Silberstein 1990). Subsequent doses of metoclopramide may be administered as needed up to every 8 hours prior to each intermittent dose or during continuous administration of dihydroergotamine for a total duration of 24 to 48 hours (Ford 1997; Raskin 1986; Silberstein 1990; Silberstein 1992).

Migraine, severe acute (emergency setting) (off-label use): Note: May be used alone or in combination with other antimigraine medications for the relief of migraine pain as well as for the treatment of nausea and vomiting associated with acute migraine (Colman 2004; Silberstein 2000). IV administration has been shown to be more efficacious and is preferred over IM, oral, or subcutaneous administration (Kelley 2012; AHS [Orr 2016]; Silberstein 2000). Premedication with diphenhydramine to prevent metoclopramide-induced akathisia and other dystonic reactions may be considered (Kelley 2012).

IV (preferred), Oral: 10 to 20 mg as a single dose (AHS [Orr 2016]; EFNS [Evers 2009]) or some patients may require more aggressive dosing such as 20 mg IV every 30 minutes as needed for up to 4 doses; use in combination with IV diphenhydramine (Friedman 2005).

IM, SubQ: 10 mg as a single dose (EFNS [Evers 2009]).

Nausea and/or vomiting:

Undifferentiated or due to a variety of medical conditions associated with acute self-limiting nausea/vomiting (off-label use): Limited data available: IV: 10 mg or 20 mg as a single dose (Barrett 2011; Braude 2006; Cham 2004; Egerton-Warburton 2014)

Advanced cancer-associated (off-label use): Note: Data are limited; dosing recommendations based primarily on expert opinion:

Empiric therapy in patients without an identifiable etiology:

Oral: Initial: 10 mg before meals and at bedtime (Gupta 2013)

IV, SubQ: Initial: 40 mg/day in divided doses (Gupta 2013)

Palliative care setting:

Oral, SubQ: Initial: 10 mg every 4 to 6 hours (Bruera 1996; Del Fabbro 2018; Glare 2011). If no relief with intermittent dosing, may switch to an IV or SubQ continuous infusion.

IV, SubQ: Continuous infusion: 2.5 mg/hour; if needed for relief, may further increase to 5 mg/hour (Bruera 1996).

Pregnancy-associated, severe or refractory (off-label use): Note: May be considered for adjunctive treatment of nausea and vomiting when symptoms persist following initial pharmacologic therapy (ACOG 2018).

Patients without hypovolemia: Oral, IM: 5 to 10 mg every 6 hours, added to current treatment regimen (ACOG 2018)

Patients with hypovolemia (following IV fluid replacement with persistent symptoms): IV: 5 to 10 mg every 8 hours, added to current treatment regimen (ACOG 2018)

Vertigo-associated (off-label use):

Oral, IV: 5 to 10 mg every 6 hours (Muncie 2017)

Discontinuation of therapy: After severe symptoms have resolved (usually after 1 to 2 days), discontinue metoclopramide as soon as possible to avoid compromising long-term adaptation to vestibular loss by the brain (Furman 2018; Swartz 2005).

Postoperative nausea and vomiting (PONV), prophylaxis (alternative agent): Note: Rarely used in the setting of postoperative nausea/vomiting (PONV) prophylaxis; alternative antiemetics are preferred for routine use due to greater efficacy (Feinleib 2018; Gan 2014).

IV: 10 mg administered near the end of surgery; some patients may require 20 mg (manufacturer's labeling). Note: In some previous clinical trials, the 10 mg dose was associated with lack of efficacy and has been discouraged by guidelines (Gan 2014; Wallenborn 2006); however, several of the clinical trials providing the basis of these recommendations have been retracted. A subsequent analysis excluding these trials, however, suggested that the 10 mg dose is effective (De Oliveira 2012). Other studies have indicated that higher dosing (20 mg, 25 mg or 50 mg) may be efficacious, but some experts avoid use of a high dose due to concern for an increased risk of adverse events (eg, extrapyramidal symptoms) (Feinleib 2018; Quaynor 2002; Wallenborn 2006).

Radiation therapy-induced nausea and vomiting (rescue therapy) (off-label use):

Low-emetic risk radiation therapy (head and neck, thorax, or pelvis): Oral, IV: 5 to 20 mg/dose as needed; may administer up to 3 to 4 times daily (maximum: 4 times daily); depending on symptom severity and remaining duration of radiation therapy, patients can receive subsequent rescue therapy as needed or begin prophylactic therapy (ASCO [Hesketh 2017])

Minimal-emetic risk radiation therapy (extremities, breast): Oral, IV: 5 to 20 mg/dose as needed (ASCO [Hesketh 2017])

Radiological examination, barium studies (adjunctive agent): Metoclopramide may facilitate gastroduodenal evacuation of barium meals in patients undergoing radiologic visualization of the gastroduodenal region or fluoroscopy of the terminal ileum.

IV: 10 mg as a single dose administered over 1 to 2 minutes (manufacturer's labeling)

Oral: 20 mg as a single dose 5 to 10 minutes prior to exam (manufacturer's labeling [Metonia Canadian product]).

Tension-type headache, acute (emergency setting) (off-label): Note: It is not clear what parenteral treatment strategy is preferred for patients who present to an emergency setting with acute tension-type headache (Weinman 2014). Successful pain relief has been demonstrated with metoclopramide either alone or in combination with diphenhydramine (Cicek 2004; Friedman 2013).

IV: 10 mg as a single dose (Cicek 2004) or 20 mg as a single dose in combination with IV diphenhydramine (Friedman 2013)

Dosing: Geriatric

Initial: Dose at the lower end of the recommended range (may require only 5 mg/dose) and use the lowest effective dose. Refer to adult dosing.

Dosing: Pediatric

Chemotherapy-associated nausea and vomiting, prophylaxis (off-label use): Children and Adolescents: Moderately emetogenic chemotherapy (patients who cannot receive corticosteroids): IV: 1 mg/kg prior to chemotherapy, followed by Oral: 0.0375 mg/kg every 6 hours; regimen also includes ondansetron or granisetron; coadministration of diphenhydramine or benztropine is recommended to prevent metoclopramide-induced adverse effects (Dupuis 2013).

Dosing: Renal Impairment

IV:

CrCl ≥40 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling.

CrCl <40 mL/minute: Initial: Administer ~50% of normal dose.

Oral:

Diabetic gastroparesis:

CrCl > 60 mL/minute: No dosage adjustment necessary.

CrCl ≤60 mL/minute: 5 mg 4 times daily (maximum: 20 mg/day).

ESRD: 5 mg twice daily (maximum: 10 mg/day).

Hemodialysis and continuous ambulatory peritoneal dialysis: 5 mg twice daily (maximum: 10 mg/day).

Gastroesophageal reflux:

CrCl > 60 mL/minute: No dosage adjustment necessary.

CrCl ≤60 mL/minute: 5 mg 4 times daily or 10 mg 3 times daily (maximum: 30 mg/day).

ESRD: 5 mg 4 times daily or 10 mg twice daily (maximum: 20 mg/day).

Hemodialysis and continuous ambulatory peritoneal dialysis: 5 mg 4 times daily or 10 mg twice daily (maximum: 20 mg/day).

Dosing: Hepatic Impairment

IV: There are no dosage adjustments provided in the manufacturer's labeling. However, metoclopramide has been used safely in patients with advanced liver disease with normal renal function.

Oral:

Diabetic gastroparesis:

Mild impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate or severe impairment (Child-Pugh class B or C): 5 mg 4 times daily (maximum: 20 mg/day).

Gastroesophageal reflux:

Mild impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate or severe impairment (Child-Pugh class B or C): 5 mg 4 times daily or 10 mg 3 times daily (maximum: 30 mg/day).

Reconstitution

Injection: Lower doses (≤10 mg): No dilution required; Higher doses (>10 mg): Dilute in 50 mL of compatible solution (preferably NS).

Administration

Injection: May be given IM, direct IV push, short infusion (at least 15 minutes), or continuous infusion; lower doses (≤10 mg) of metoclopramide can be given IV push undiluted over 1 to 2 minutes; higher doses (>10 mg) to be diluted in 50 mL of compatible solution (preferably NS) and given IVPB over at least 15 minutes. Note: Rapid IV administration may be associated with a transient (but intense) feeling of anxiety and restlessness, followed by drowsiness.

Tablets and oral solution: Administer 30 minutes prior to meals and at bedtime.

Orally disintegrating tablets: Administer on an empty stomach at least 30 minutes prior to food and at bedtime (do not repeat if inadvertently taken with food). Do not remove from packaging until time of administration. If tablet breaks or crumbles while handling, discard and remove new tablet. Using dry hands, place tablet on tongue and allow to dissolve (disintegrates within ~1 minute [range: 10 seconds to 14 minutes]). Swallow with saliva (formulation is designed to be taken without liquids).

Subcutaneous administration (off-label route) has been reported, either as an intermittent bolus injection or as continuous infusion (Bruera 1996; McCallum 1991).

Storage

Injection: Store intact vials at 20°C to 25°C (68°F to 77°F); protect from light. Injection is photosensitive and should be protected from light during storage; parenteral admixtures in D5W, D51/2NS, NS, LR, or Ringer's injection are stable for up to 24 hours after preparation at normal light conditions or up to 48 hours if protected from light. When mixed with NS, can be stored frozen for up to 4 weeks; metoclopramide is degraded when admixed and frozen with D5W.

Oral solution/orally disintegrating tablet/tablet: Store at 20°C to 25°C (68°F to 77°F). Protect from light. Do not freeze oral solution. Keep orally disintegrating tablet in original packaging until just prior to use.

Drug Interactions

Anticholinergic Agents: May diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Monitor therapy

Anti-Parkinson Agents (Dopamine Agonist): Metoclopramide may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Monitor therapy

Antipsychotic Agents: Metoclopramide may enhance the adverse/toxic effect of Antipsychotic Agents. Avoid combination

Atovaquone: Metoclopramide may decrease the serum concentration of Atovaquone. Management: Consider alternatives to metoclopramide when possible; atovaquone should only be used with metoclopramide if no other antiemetics are available. Consider therapy modification

CycloSPORINE (Systemic): Metoclopramide may increase the absorption of CycloSPORINE (Systemic). Monitor therapy

Dapsone (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Monitor therapy

Deutetrabenazine: May enhance the adverse/toxic effect of Metoclopramide. Specifically, the risk for akathisia, parkinsonism, or neuroleptic malignant syndrome may be increased. Monitor therapy

Droperidol: May enhance the adverse/toxic effect of Metoclopramide. Avoid combination

Levosulpiride: Benzamide Derivatives may enhance the adverse/toxic effect of Levosulpiride. Monitor therapy

MetyroSINE: May enhance the adverse/toxic effect of Metoclopramide. Management: Seek alternatives to this combination when possible. Monitor patients receiving metoclopramide with metyrosine for development of extrapyramidal symptoms. Consider therapy modification

Nitric Oxide: May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when nitric oxide is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine. Monitor therapy

Opioid Analgesics: May diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Monitor therapy

Posaconazole: Metoclopramide may decrease the serum concentration of Posaconazole. Monitor therapy

Prilocaine: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine in infants receiving such agents. Monitor therapy

Promethazine: Metoclopramide may enhance the adverse/toxic effect of Promethazine. Avoid combination

Quinagolide: Metoclopramide may diminish the therapeutic effect of Quinagolide. Monitor therapy

Rivastigmine: May enhance the adverse/toxic effect of Metoclopramide. Specifically, the risk of extrapyramidal adverse reactions may be increased with this combination. Avoid combination

Selective Serotonin Reuptake Inhibitors: Metoclopramide may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Management: Seek alternatives to this combination when possible. Monitor patients receiving metoclopramide with selective serotonin reuptake inhibitors for signs of extrapyramidal symptoms, neuroleptic malignant syndrome, and serotonin syndrome. Consider therapy modification

Serotonin Modulators: May enhance the adverse/toxic effect of Metoclopramide. This may be manifest as symptoms consistent with serotonin syndrome or neuroleptic malignant syndrome. Exceptions: Nicergoline. Monitor therapy

Serotonin/Norepinephrine Reuptake Inhibitors: Metoclopramide may enhance the adverse/toxic effect of Serotonin/Norepinephrine Reuptake Inhibitors. Management: Seek alternatives to this combination when possible. Monitor patients receiving metoclopramide with serotonin/norepinephrine reuptake inhibitors for signs of extrapyramidal symptoms, neuroleptic malignant syndrome, and serotonin syndrome. Consider therapy modification

Sodium Nitrite: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Sodium Nitrite. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Monitor therapy

Tetrabenazine: Metoclopramide may enhance the adverse/toxic effect of Tetrabenazine. Avoid combination

Tetracaine (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Monitor therapy

Thiopental: Metoclopramide may enhance the therapeutic effect of Thiopental. Management: Consider thiopental dose reduction when used concomitantly with metoclopramide. Monitor patient response to treatment closely if using this combination. Consider therapy modification

Tricyclic Antidepressants: Metoclopramide may enhance the adverse/toxic effect of Tricyclic Antidepressants. Management: Seek alternatives to this combination when possible. Monitor patients receiving metoclopramide with tricyclic antidepressants for signs of extrapyramidal symptoms, neuroleptic malignant syndrome, and serotonin syndrome. Consider therapy modification

Trimetazidine: Metoclopramide may enhance the adverse/toxic effect of Trimetazidine. Specifically, the risk of extrapyramidal symptoms may be enhanced. Avoid combination

Adverse Reactions

Frequency not always defined.

Cardiovascular: Atrioventricular block, bradycardia, cardiac failure, flushing (following high IV doses), hypertension, hypotension, supraventricular tachycardia

Central nervous system: Drowsiness (~10% to 70%; dose related), dystonic reaction (<1% to 25%; dose and age related), lassitude (~10%), restlessness (~10%), fatigue (2% to 10%), headache (4% to 5%), dizziness (1% to 4%), somnolence (2% to 3%), akathisia, confusion, depression, drug-induced Parkinson's disease, hallucination (rare), insomnia, neuroleptic malignant syndrome (rare), seizure, suicidal ideation, tardive dyskinesia

Dermatologic: Skin rash, urticaria

Endocrine & metabolic: Amenorrhea, fluid retention, galactorrhea, gynecomastia, hyperprolactinemia, porphyria

Gastrointestinal: Nausea (4% to 6%), vomiting (1% to 2%), diarrhea

Genitourinary: Impotence, urinary frequency, urinary incontinence

Hematologic & oncologic: Agranulocytosis, leukopenia, methemoglobinemia, neutropenia, sulfhemoglobinemia

Hepatic: Hepatotoxicity (rare)

Hypersensitivity: Angioedema (rare), hypersensitivity reaction

Neuromuscular & skeletal: Laryngospasm (rare)

Ophthalmic: Visual disturbance

Respiratory: Bronchospasm, laryngeal edema (rare)

ALERT: U.S. Boxed Warning

Tardive dyskinesia:

Metoclopramide can cause tardive dyskinesia, a serious movement disorder that is often irreversible. There is no known treatment for tardive dyskinesia. The risk of developing tardive dyskinesia increases with duration of treatment and total cumulative dose. Discontinue metoclopramide in patients who develop signs or symptoms of tardive dyskinesia. In some patients, symptoms lessen or resolve after metoclopramide is stopped. Avoid treatment with metoclopramide for longer than 12 weeks because of the increased risk of developing tardive dyskinesia with longer-term use.

Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).

• Depression: Depression has occurred (in patients with and without a history of depression); symptoms have included suicidal ideation and suicide; avoid use in patients with a history of depression.

• Extrapyramidal symptoms (EPS): May cause extrapyramidal symptoms, generally manifested as acute dystonic reactions within the initial 24 to 48 hours of use at the usual adult dose (30 to 40 mg/day). Risk of these reactions is increased at higher than recommended doses, and in patients <30 years of age. Symptoms may include involuntary limb movements, facial grimacing, torticollis, oculogyric crisis, rhythmic tongue protrusion, bulbar type speech, trismus, or dystonic reactions resembling tetanus. May also rarely present as stridor and dyspnea (may be due to laryngospasm). Dystonic symptoms may be managed with IM diphenhydramine or benztropine. Pseudoparkinsonism (eg, bradykinesia, tremor, cogwheel rigidity, mask-like facies) may also occur (usually within first 6 months of therapy but also after longer periods) and is generally reversible within 2 to 3 months following discontinuation. Motor restlessness (eg, anxiety, agitation, jitteriness, insomnia) may occur; if symptoms resolve, consider restarting at a lower dosage. Avoid metoclopramide in patients receiving other drugs that are likely to cause EPS (eg, antipsychotics).

• Hyperprolactinemia: Metoclopramide elevates prolactin levels. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported. Hyperprolactinemia may potentially stimulate prolactin-dependent breast cancer. However, some clinical studies and epidemiology studies have not shown an association between administration of dopamine D2 receptor antagonists and tumorigenesis in humans.

• Hypertension: May elevate blood pressure; avoid use in patients with hypertension (IV administration was shown to release catecholamines). There are reports of hypertensive crises in patients with undiagnosed pheochromocytoma; use is contraindicated in patients with pheochromocytoma or other catecholamine-releasing paragangliomas. Discontinue therapy in any patient with a rapid rise in blood pressure.

• Neuroleptic malignant syndrome: Use may be associated with neuroleptic malignant syndrome (NMS); may be fatal. Monitor for manifestations of NMS, which include hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac arrhythmias); additional signs may include elevated creatine phosphokinase, myoglobinuria, and acute renal failure. Discontinue immediately if signs/symptoms of NMS appear and begin intensive symptomatic management and monitoring.

• Proarrhythmic effects: Metoclopramide has been known to cause sinus arrest (usually with rapid IV administration or higher doses) (Bentsen 2002; Malkoff 1995). The torsadogenic potential for metoclopramide is considered to be low (Claassen 2005). Based on case reports, however, metoclopramide may cause QT prolongation and torsades de pointes in certain individuals (eg, heart failure patients with renal impairment) (Siddique 2009). There is data in healthy male volunteers to show that metoclopramide actually shortens the QT interval while at the same time increasing QT variance (Ellidokuz 2003). No human data other than case reports, however, has demonstrated a consistent QT prolonging effect with metoclopramide nor is there any substantiated evidence to show a direct association with the development of torsades de pointes.

• Tardive dyskinesia: [US Boxed Warning]: May cause tardive dyskinesia, a serious movement disorder that is often irreversible with no known treatment; the risk of developing tardive dyskinesia increases with duration of treatment and total cumulative dose. Discontinue metoclopramide in patients who develop signs/symptoms of tardive dyskinesia; in some patients, symptoms may lessen or resolve after metoclopramide is stopped. Avoid treatment with metoclopramide for longer than 12 weeks because of the increased risk of developing tardive dyskinesia with longer-term use. Avoid metoclopramide in patients receiving other drugs that are likely to cause tardive dyskinesia (eg, antipsychotics). Tardive dyskinesia is characterized by disfiguring involuntary movements of the face, tongue, and sometimes of the trunk and/or extremities; movements may be choreoathetotic in appearance. Metoclopramide may mask underlying tardive disease by suppressing or partially suppressing tardive dyskinesia signs; the effect of this symptomatic suppression upon the long-term course of tardive dyskinesia is unknown. The risk of developing tardive dyskinesia is increased in the elderly, especially elderly women, and diabetics, although it is not possible to predict which patients will develop tardive dyskinesia. Discontinue metoclopramide immediately in patients who develop signs/symptoms of tardive dyskinesia. There is no known effective treatment for established cases of tardive dyskinesia, although in some patients, tardive dyskinesia may remit (partially or completely) within several weeks to months after metoclopramide is withdrawn.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with heart failure and concomitant renal impairment; may be at risk for development of QT prolongation and torsades de pointes (Siddique 2009).

• Edematous conditions: Use with caution in patients who are at risk of fluid overload (HF, cirrhosis). Metoclopramide causes a transient increase in serum aldosterone and increases the risk for fluid retention and volume overload. Discontinue if adverse events or signs/symptoms appear.

• Hepatic impairment: Use caution in patients with moderate to severe hepatic impairment; risk of adverse reactions may be increased due to increased systemic exposure; dosage adjustment recommended.

• Nicotinamide adenine dinucleotide hydrogen (NADH)-cytochrome b5 reductase deficiency: Patients with NADH-cytochrome b5 reductase deficiency are at increased risk of methemoglobinemia and/or sulfhemoglobinemia.

• Parkinson disease: Symptoms of Parkinson disease may be exacerbated; avoid use in patients with Parkinson disease and other patients being treated with antiparkinsonian drugs.

• Renal impairment: Use with caution in patients with moderate to severe renal impairment; risk of adverse reactions may be increased due to increased systemic exposure; dosage adjustment recommended.

• Surgical anastomosis/closure: Use with caution following surgical anastomosis/closure; promotility agents may theoretically increase pressure in suture lines.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• CYP2D6 poor metabolizers: Elimination of metoclopramide may be slowed possibly increasing the risk of dystonic and other adverse reactions; dosage reduction recommended.

• Elderly: Risk of tardive dyskinesia may be increased in elderly, especially in elderly women.

• Pediatric: Not recommended for use (oral formulation) due to increased risk of tardive dyskinesia and other extrapyramidal symptoms as well as the risk of methemoglobinemia in neonates (neonates may have decreased levels of NADH-cytochrome b5 reductase, which increases the risk of methemoglobinemia).

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggest that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.

Monitoring Parameters

Signs of tardive dyskinesias, extrapyramidal symptoms; signs/symptoms of neuroleptic malignant syndrome

Pregnancy Considerations

Metoclopramide crosses the placenta and can be detected in cord blood and amniotic fluid (Arvela 1983; Bylsma-Howell 1983). Available studies do not report an increased risk of adverse pregnancy-related outcomes following maternal use. Extrapyramidal symptoms or methemoglobinemia may potentially occur in the neonate.

Metoclopramide is one of the agents that may be considered for adjunctive treatment of nausea and vomiting in pregnant women when symptoms persist following initial pharmacologic therapy. Oral or IM therapy may be given in patients who are not dehydrated; IV therapy should be used when dehydration is present (ACOG 189 2018). Metoclopramide may be used for prophylaxis of nausea and vomiting associated with cesarean delivery (ASA 2016; Smith 2011).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience diarrhea, fatigue, nausea, or loss of strength and energy. Have patient report immediately to prescriber signs of serotonin syndrome (dizziness, severe headache, agitation, hallucinations, tachycardia, abnormal heartbeat, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea), signs of tardive dyskinesia (unable to control body movements; tongue, face, mouth, or jaw sticking out; mouth puckering; or puffing cheeks), signs of neuroleptic malignant syndrome (fever, muscle cramps or stiffness, dizziness, severe headache, confusion, change in thinking, tachycardia, abnormal heartbeat, or sweating a lot), signs of depression (suicidal ideation, anxiety, emotional instability, or confusion), severe headache, severe dizziness, passing out, vision changes, tremors, difficulty moving, rigidity, enlarged breasts, nipple discharge, sexual dysfunction, menstrual changes, agitation, abnormal movements, twitching, change in balance, difficulty swallowing, difficulty speaking, panic attacks irritability, shortness of breath, excessive weight gain, or swelling of arms or legs (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Further information

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