METOCLOPRAMIDE HCL (Generic for REGLAN)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-Administer 30 minutes before each meal and at bedtime.
Oral Solid Formulations
Oral disintegrating tablets (Metosolv ODT):
-Remove only 1 dose from the packaging just prior to administration. If the ODT breaks or crumbles while handling, it should be discarded and a new tablet removed.
-Instruct the patient to place a tablet on the tongue, allow it to dissolve for approximately 1 minute, then swallow.
-Take without liquid.

Oral Liquid Formulations
-Measure doses with a calibrated oral syringe or other calibrated oral device to ensure accurate dosing.
-In neonates, a method of oral solution administration has been described where the commercial oral solution dose was given via oral syringe or nasogastric tube, followed by 10 mL of distilled water.



Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
IV Push
-No dilution is necessary for doses 10 mg or less in adults.
-Inject over 1 to 2 minutes.
-Dosages over 10 mg should be diluted and administered as an IV infusion.

Intermittent IV Infusion
-The dosage for infusion may be diluted to a concentration of 0.2 mg/mL.
-Dilute doses more than 10 mg in at least 50 mL of 0.9% Sodium Chloride Injection, 5% Dextrose Injection, or other compatible solution such as 5% Dextrose and 0.45% Sodium Chloride Injection, Ringer's Injection, or Lactated Ringer's Injection.
-Infuse IV slowly over at least 15 minutes.
-Stability: Any of the diluted infusions are stable under normal light conditions and room temperature for up to 24 hours; or, if refrigerated and protected from light, up to 48 hours. Metoclopramide is most stable when diluted with 0.9% Sodium Chloride Injection; dilutions in 0.9% Sodium Chloride Injection may be stored frozen up to 4 weeks.

Intramuscular Administration
-No dilution necessary.
-Inject deeply into a large muscle mass [e.g., anterolateral thigh or deltoid (children and adolescents only)].

Common adverse CNS effects that occur in roughly 10% of patients include drowsiness, fatigue, and lassitude at normal prescribed dosages; however, the incidence rises to 70% in with dosages of 1-2 mg/kg per dose (i.e., for reduction of nausea with chemotherapy). Insomnia, confusion, restlessness, depression, irritability, apnea, and headache may also occur. Depression has been reported during metoclopramide therapy in patients with and without prior history of depression; symptoms range from mild to severe and include suicidal ideation and suicide. There are isolated and rare reports of seizures in the literature, but a causal relationship to the use of metoclopramide is not established. Other rarely reported events include hallucinations.

Various CNS reactions can occur with metoclopramide, some of which are dose-related. An extrapyramidal and/or acute dystonic reaction is possible during metoclopramide therapy and occurs in roughly 0.2% (1/500) of adult patients treated with usual doses of 30 to 40 mg/day. The incidence of these reactions appears to be much higher in pediatric patients and many of the cases reported occur in children receiving metoclopramide at commonly prescribed pediatric doses. Extrapyramidal effects can include akathisia, bulbar type of speech (dysarthria), facial grimacing, oculogyric crisis, torticollis, or trismus. In adult patients, the incidence is higher with higher doses, such as those dosages used in the treatment of nausea due to chemotherapy (i.e., incidence roughly 2%) and in those cancer patients not administered diphenhydramine as a prophylactic medication. Motor restlessness (akathisia) may occur with feelings of anxiety, agitation, jitteriness, and insomnia, as well as inability to sit still, pacing, and foot tapping. These symptoms may disappear spontaneously or respond to a slowing of infusion rate or a reduction in dosage. Prolonged tardive dyskinesia was reported in an 8-year-old boy who received a single 0.4 mg/kg dose of metoclopramide and experienced torticollis, oculogyric spasms, and facial grimacing. The dose was decreased to 0.1 mg/kg four times daily for the next 3 months, however, the patient continued to have movement disorders and mental status changes. Metoclopramide was discontinued, but the child continued to have uncontrollable facial spasms for 15 months after drug discontinuation. In severe cases, stridor and dyspnea may occur or laryngospasm; the administration of diphenhydramine is indicated in cases of severe extrapyramidal symptoms. In adult patients, diphenhydramine hydrochloride (50 mg IM) or benztropine mesylate (1 to 2 mg IM) are recommended to help reverse these reactions. Extrapyramidal effects usually occur within 24 to 48 hours of treatment and generally disappear within 24 hours of discontinuation of the drug.

Pseudoparkinsonism may develop including bradykinesia, tremor, cogwheel rigidity, and mask-like facies. The parkinsonian-like symptoms generally subside within 2 to 3 months after the discontinuation of metoclopramide. The risk of developing tardive dyskinesia increases with the duration of treatment and the total cumulative dose. It has been reported with long-term and high-dose use and especially among patients being treated for longer than 3 months. Tardive dyskinesia includes symptoms such as repetitive and involuntary movements of the extremities, lip smacking, grimacing, tongue protrusion, rapid eye movements, blinking, puckering and pursing of the lips, or impaired movement of the fingers. The symptoms are often irreversible. Tardive dyskinesia occurs more frequently in pediatric patients and in patients with diabetes. Although tardive dyskinesia is more likely to occur after prolonged therapy or high dosage, relatively brief therapy has been associated with this effect as well.

The cholinergic-like effects of metoclopramide increase gastric and duodenal motility, which can cause nausea or diarrhea. Data available do not permit an estimation of the incidence of these effects.

Metoclopramide can antagonize dopamine receptors in the pituitary gland and indirectly stimulate prolactin secretion. Hyperprolactinemia can develop in both males and females, causing gynecomastia in males and galactorrhea or menstrual irregularity in females. These effects are generally reversible upon discontinuation of the drug. Serum prolactin levels return to normal in about 1 week, and adverse effects diminish within several weeks to several months. Data available do not permit an estimation of the incidence of these effects. Bilateral gynecomastia with galactorrhea has been reported in a 37-week-gestation male neonate receiving metoclopramide 0.1 mg/kg/dose and later increased to 0.2 mg/kg/dose four times daily for gastroesophageal reflux. After 3 weeks of treatment, the neonate was noted to have prominent breasts with milk discharge. After metoclopramide discontinuation, the breast size decreased and gynecomastia resolved completely after a month. After 6 weeks, serum prolactin serum prolactin had normalized. Gynecomastia has also been reported in an 18 year old male who was treated with metoclopramide for 4 years.

Many reported adverse reactions with metoclopramide appear to be infrequent or isolated occurrences. Cardiovascular events have included AV block, hypotension, hypertension, sinus bradycardia, and supraventricular tachycardia (SVT). Data available do not permit an estimation of the incidence of these effects. Transient increases in fluid retention (edema, acute heart failure) may occur in certain predisposed individuals with heart failure or liver cirrhosis secondary to a transient elevation in aldosterone secretion induced by the pharmacologic action of metoclopramide.

Rare side effects of metoclopramide include hypersensitivity reactions like rash (unspecified), angioedema, urticaria. Bronchospasm may occur in patients with asthma. Transient flushing of the face and upper body, without alterations in vital signs, following high doses intravenously has been reported. Porphyria and visual disturbances have also been reported rarely with metoclopramide. Data available do not permit an estimation of the incidence of these effects.

Jaundice and altered liver function tests (elevated hepatic enzymes) have been reported in patients taking metoclopramide who were on medications with known hepatotoxic potential. Data available do not permit an estimation of causality or of the incidence of these effects.

Urinary adverse reactions to metoclopramide include urinary urgency and urinary incontinence. Data available do not permit an estimation of the incidence of these effects.

Rare occurrences of neuroleptic malignant syndrome (NMS) have been reported during metoclopramide therapy. This potentially fatal syndrome is comprised of the symptom complex of hyperthermia, altered consciousness, muscular rigidity, and autonomic dysfunction (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac arrhythmias).

Rarely, withdrawal symptoms such as dizziness, nervousness or headaches may occur after discontinuation of metoclopramide. A slower taper when stopping metoclopramide may be appropriate for some patients, although this is not typically recommended.

A few cases of leukopenia, neutropenia, and agranulocytosis have been reported in patients receiving metoclopramide. However, a causal relationship to metoclopramide is unclear and sufficient documentation of these events in the medical literature is lacking. Only one case report that recurred with drug rechallenge has been published. Methemoglobinemia has occurred in premature and full-term neonates who were given inadvertent overdoses of metoclopramide (1 to 4 mg/kg/day orally, intramuscularly or intravenously for 1 to 3 or more days). Neonates have reduced levels of NADH-cytochrome b5 reductase, which, in combination with pharmacokinetic factors that delay metoclopramide clearance, make neonates more susceptible to methemoglobinemia. Neonatal dosages should always be chosen with care to avoid inadvertent overdosage.

Metoclopramide should not be used in those patients with hypersensitivity or intolerance to the drug or its components. Since metoclopramide is structurally related to procainamide, metoclopramide should be used cautiously in patients with a known procainamide hypersensitivity. Some oral liquid preparations may contain parabens (hydroxybenzoates) and should be used with caution in patients with a known paraben hypersensitivity.

Metoclopramide stimulates smooth muscle in the GI tract, and use may be dangerous in certain conditions that would be aggravated by increased motility (e.g., mechanical GI obstruction, GI perforation, and GI bleeding). Metoclopramide has been used to empty the stomach of blood prior to endoscopy. Theoretically, the use of a promotility agent could place increased pressure on suture lines following surgery for gut anastomosis or closures, but such events have not been reported clinically.

Because metoclopramide produces a transient increase in plasma aldosterone, certain patients, especially those with congestive heart failure, may be at risk of developing fluid retention and volume overload. If these side effects occur at any time during metoclopramide therapy, the drug should be discontinued. Caution is also recommended in patients with existing hypertension or other cardiac disease that may be sensitive to catecholamine release. Metoclopramide is contraindicated in patients with pheochromocytoma because it can stimulate the release of catecholamines, possibly leading to a hypertensive crisis.

Caution is warranted in patients with a history of major depression due to the occurrence of CNS depression. Reported symptoms in patients with and without a history of depression have ranged from mild to severe, and include suicidal ideation and suicide. In patients with a history of depression, metoclopramide should only be used when the expected benefits of therapy outweigh the potential risks. Metoclopramide should be used cautiously in patients requiring mental acuity; high-dose therapy causes drowsiness in 70% of patients. Patients should not perform activities requiring coordination and concentration, such as gymnastics, riding a bicycle or for older adolescents, operation of vehicles, until they are aware of how this medication affects them. A small number of patients may experience withdrawal-like symptoms such as dizziness, nervousness and/or headaches following abrupt discontinuation of metoclopramide. A slower taper when stopping metoclopramide may be appropriate for some patients, although this is not typically recommended.

Children and infants are more likely to experience extrapyramidal effects from metoclopramide. Intravenous metoclopramide is FDA-approved for use in pediatric patients to facilitate small bowel intubation, however, enteral metoclopramide is not FDA-approved for any indication, although it has been used off-label in pediatric patients for certain indications. Safety data in adults cannot be extrapolated to the pediatric population. Care should be exercised in administering metoclopramide to neonates since prolonged clearance may produce excessive serum concentrations; European product labels for metoclopramide contraindicate the drug's use in neonates, though the drug has not been explicitly contraindicated for neonatal use within the US. Neonates have reduced levels of NADH-cytochrome b5 reductase (methemoglobin reductase deficiency) which make neonates more susceptible to methemoglobinemia. Additionally, inadvertent overdose has been reported in infants and children; events included seizures, extrapyramidal reactions, lethargy, and methemoglobinemia (in premature and full-term neonates). Methylene blue may be administered in pediatric patients without G6PD deficiency for reversal of methemoglobinemia, however, methylene blue treatment may cause hemolytic anemia and is not recommended in patients with G6PD deficiency who experience metoclopramide-induced methemoglobinemia.

Use metoclopramide with caution in patients with renal impairment and renal failure, due to possible accumulation and toxicity. Reduced initial doses are recommended for patients with reduced creatinine clearance (CrCl less than 40 mL/minute).

Various CNS reactions, including serious movement disorders, can occur with metoclopramide therapy and may be dose-dependent and duration-dependent. Extrapyramidal symptoms have been reported and manifest as acute dystonic reactions usually occurring in the first 24 to 48 hours of treatment; symptoms generally disappear within 24 hours of drug discontinuation. Metoclopramide should not be used in patients with a seizure disorder (or acute seizures) or in patients receiving other drugs which are likely to cause extrapyramidal reactions, since the frequency and severity of seizures or extrapyramidal reactions may be increased. Extrapyramidal symptoms are dose-dependent and occur more frequently in pediatric patients and adult patients under the age of 30. Metoclopramide is contraindicated in patients with a history of tardive dyskinesia or a dystonic reaction. An FDA-required boxed warning in the prescribing information addresses the risk of tardive dyskinesia associated with high-dose or long-term use. The FDA noted that the risk of developing tardive dyskinesia is directly related to the length of therapy and recommends against use for durations longer than 3 months. The symptoms, which may include involuntary and repetitive movements of the face and body, are often irreversible. Pediatric patients and patients with diabetes are more likely to develop tardive dyskinesia and thus should be treated with caution. Due to the risk of developing tardive dyskinesia and other extrapyramidal symptoms, FDA-approved labeling recommends not using metoclopramide therapy in pediatric patients. If dyskinetic symptoms occur, discontinue metoclopramide. Some patients experience partial or complete remission of symptoms within several weeks of drug discontinuance, however dyskinetic movements can persist even after metoclopramide has been withdrawn. Parkinsonian-like symptoms (parkinsonism) have occurred, and while symptoms can develop at any time during therapy, they commonly occur within the first 6 months of treatment. Symptoms generally subside within 2 to 3 months after drug discontinuation.

Rare occurrences of neuroleptic malignant syndrome (NMS) have been reported during metoclopramide therapy. This potentially fatal syndrome is comprised of the symptom complex of malignant hyperthermia, altered consciousness, muscular rigidity, and autonomic dysfunction (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac arrhythmias).

Metoclopramide clearance is reduced in patients with hepatic disease. Dosage adjustments are required in patients with moderate or severe hepatic impairment (Child-Pugh B or C). Metoclopramide's metabolite is formed primarily by CYP2D6, an enzyme subject to genetic variability. Those patients who are CYP2D6 poor metabolizers (CYP2D6 PMs) have reduced clearance of metoclopramide and also require dose reductions. Because metoclopramide produces a transient increase in plasma aldosterone, certain patients, especially those with cirrhosis, may be at risk of developing fluid retention and volume overload. If these side effects occur at any time during metoclopramide therapy, the drug should be discontinued.

As with other dopamine D2 receptor antagonists, metoclopramide elevates prolactin levels. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may cause endocrine abnormalities in male and female patients. Galactorrhea, menstrual irregularity or amenorrhea, gynecomastia, and erectile dysfunction have been reported with prolactin-elevating drugs, including metoclopramide. Hyperprolactinemia may potentially stimulate prolactin-dependent breast cancer. However, some clinical studies and epidemiology studies have not shown an association between administration of dopamine D2 receptor antagonists and tumorigenesis in humans.

Description: Metoclopramide enhances GI motility and is an effective antinauseant. It is chemically related to procainamide and the generic name is derived from the chemical name 'methoxychloroprocainamide'. Metoclopramide, however, does not possess local anesthetic or antiarrhythmic properties. The intravenous formulation is approved to facilitate small bowel intubation during radiologic examination in both adult and pediatric patients. The oral formulation is not FDA-approved for any indication in pediatric patients. Metoclopramide may cause tardive dyskinesia (TD), which is often irreversible. The risk of TD increases with duration of treatment and cumulative dose. The risks versus benefits should be carefully considered along with limiting treatment to no more than 12 weeks. The oral formulation has been studied as a prokinetic agent for gastroesophageal reflux and an antiemetic for use during acute gastroenteritis in infants and children. The use as a prokinetic agent in the neonatal intensive care unit (NICU) increased significantly when cisapride was removed from the market in 2000. Metoclopramide has also been used in the emergency room for the treatment of migraine in pediatric patients and there are limited data in the treatment of Tourette's syndrome. The American Academy of Neurology practice guideline states that metoclopramide is possibly more likely than placebo to reduce tic severity in pediatric patients with Tourette's syndrome or chronic tic disorders; however, the benefits of use should outweigh the risks (e.g., increased prolactin, TD). Further, there is insufficient evidence to determine the relative efficacy of metoclopramide to other dopamine antagonists, such as antipsychotics.

To facilitate small bowel intestinal intubation, and also for use as a diagnostic aid during gastrointestinal radiography*:
Intravenous dosage:
Children 1 to 5 years: 0.1 mg/kg IV as a single dose administered over 1 to 2 minutes.
Children and Adolescents 6 to 14 years: 2.5 to 5 mg IV as a single dose administered over 1 to 2 minutes.
Adolescents 15 to 17 years: 10 mg IV as a single dose administered over 1 to 2 minutes.

For the facilitation of gastric emptying in neonates with feeding intolerance*:
Oral dosage:
Preterm and Term Neonates: 0.033 to 0.1 mg/kg/dose PO 3 times daily; data are very limited; use in neonates not established. In a small study, 6 premature neonates (birth weight 790 to 1,040 grams, gestational ages 26 to 35 weeks) received metoclopramide 0.033 mg/kg/dose IV 3 times daily at a mean postnatal age of 35 days. During metoclopramide therapy, there was a significant difference in gastric aspirate (5 +/- 2 vs. 17 +/- 5 mL/day), weight gain (25 +/- 2 vs. 15 +/- 3.7 grams/day), intestinal transit times (14 +/- 2.4 vs. 30 +/- 3 hours), and volume of feeds (110 +/- 20 vs. 45 +/- 12 mL/kg/day) compared to values before metoclopramide (p < 0.01). In a retrospective review of 14 premature neonates (mean age 5 weeks, mean birth weight 1,100 grams, 29 weeks gestation,) who had tolerated no enteral feedings, metoclopramide 0.033 or 0.1 mg/kg/dose PO 3 times daily was administered for an average of 4 weeks. Treatment with metoclopramide decreased residual gastric volume and increased tolerance to feedings.
Intravenous dosage:
Preterm and Term Neonates: 0.033 to 0.1 mg/kg/dose IV 3 times daily; data are very limited; use in neonates not established. In a small study, 6 premature neonates (birth weight 790 to ,1040 grams, gestational ages 26 to 35 weeks) received metoclopramide 0.033 mg/kg/dose IV 3 times daily at a mean postnatal age of 35 days. During metoclopramide therapy, there was a significant difference in gastric aspirate (5 +/- 2 vs. 17 +/- 5 mL/day), weight gain (25 +/- 2 vs. 15 +/- 3.7 grams/day), intestinal transit times (14 +/- 2.4 vs. 30 +/- 3 hours), and volume of feeds (110 +/- 20 vs. 45 +/- 12 mL/kg/day) compared to values before metoclopramide (p < 0.01). In a retrospective review of 14 premature neonates (mean age 5 weeks, mean birth weight 1,100 grams, 29 weeks gestation,) who had tolerated no enteral feedings, metoclopramide 0.033 or 0.1 mg/kg/dose PO 3 times daily was administered for an average of 4 weeks. Treatment with metoclopramide decreased residual gastric volume and increased tolerance to feedings.

For the treatment of gastroesophageal reflux disease (GERD)*:
Oral dosage:
Neonates: 0.1 to 0.15 mg/kg/dose PO every 6 hours has been studied; limited data are available and neonatal use is not established. In a single-dose pharmacokinetic study of 0.1 to 0.15 mg/kg in 10 premature neonates (31 to 40 weeks postconceptional age), the investigators recommended 0.15 mg/kg/dose PO based on pharmacokinetic simulations. Doses greater than 0.15 mg/kg/dose could result in increased adverse effects and should be avoided.
Infants: 0.1 mg/kg/dose PO every 6 to 8 hours is commonly used in clinical practice; limited data are available. Doses ranging from 0.1 to 0.2 mg/kg/dose every 6 to 8 hours have been studied. In a double-blind, placebo-controlled trial, 30 infants (aged 1 to 9 months) received metoclopramide 0.1 mg/kg/dose PO 4 times daily. There was no significant difference in GERD symptoms between the metoclopramide and placebo treatment groups, but in infants older than 3 months, the daily weight gain was greater in the metoclopramide group compared to placebo (34 +/- 8 vs. 7 +/- 11 grams/day). The percentage of time the esophageal pH was 4 or less was also significantly changed in the metoclopramide group, 10.3% vs. 13.4% of the time in the metoclopramide and placebo group, respectively (p less than 0.005). In a study of 18 infants (mean age 6.5 months), metoclopramide 0.2 mg/kg/dose PO 4 times daily was compared to cisapride 0.33 mg/kg/dose PO 4 times daily and placebo. Metoclopramide significantly decreased the number of reflux episodes, the percentage of time pH less than 4, and the number of reflux episodes longer than 5 minutes relative to placebo (p less than 0.01). In a double-blind, randomized controlled trial of pediatric patients (including a limited number of infants 4 months and older), metoclopramide 0.17 mg/kg/dose PO 3 times daily did not reduce the frequency or duration of GERD symptoms compared to placebo.
Children and Adolescents: 0.1 mg/kg/dose PO (Max: 10 mg/dose) every 6 to 8 hours is commonly used in clinical practice; limited data are available. Doses ranging from 0.1 to 0.2 mg/kg/dose PO every 6 to 8 hours have been studied. In a double-blind, randomized controlled trial of pediatric patients (aged 4 months to 17 years), metoclopramide 0.17 mg/kg/dose PO 3 times daily did not reduce the frequency or duration of GERD symptoms compared to placebo.

For post-operative nausea/vomiting (PONV) prophylaxis*:
Intravenous dosage:
Children and Adolescents: Dose regimens administered in clinical practice and studies vary and include 0.1 mg/kg/dose IV, 0.15 mg/kg/dose IV, and up to 0.25 mg/kg/dose IV for early (within 6 hours) PONV. Usual Max: 10 mg/dose IV. Repeat doses of 0.1 to 0.2 mg/kg IV (Max: 10 mg/dose IV) have been administered every 6 to 8 hours if needed. In 3 randomized, double-blind, placebo-controlled trials, metoclopramide 0.25 mg/kg/dose IV was compared to ondansetron 0.1 to 0.15 mg/kg/dose IV for PONV. In each trial, prophylactic administration of ondansetron was more effective than metoclopramide or placebo in controlling postoperative emesis. No adverse effects were reported for metoclopramide in these studies.

For chemotherapy-induced nausea/vomiting prophylaxis*:
Intravenous dosage:
Children and Adolescents: 2 mg/kg/dose IV infusion, given 30 minutes prior to chemotherapy, then repeated at intervals 2 to 4 hours later (Max: 5 doses/day) have been used for highly emetogenic chemotherapy regimens. 1 mg/kg/dose IV infusion regimens have been used clinically for less emetogenic chemotherapy. Pretreatment with diphenhydramine has been recommended to reduce the risk for extrapyramidal side effects, which occur at a significant incidence at repeated doses of 2 mg/kg/dose IV or more. Metoclopramide is significantly less effective than serotonin 5HT3 agonists at reducing emesis, and it is less tolerable. Metoclopramide is sometimes used as a second-line antiemetic treatment.

For the treatment of Tourette's syndrome* or chronic tic disorders*:
Oral dosage:
Children and Adolescents 6 years and older: 0.5 mg/kg/day PO, given in 3 to 4 divided doses, up to a maximum of 40 mg/day PO, has been used. One trial used a range of 5 to 40 mg/day, given in divided doses. Initiate at the low end of the dosage range and titrate according to tolerability and response. Use the lowest effective dose to minimize the risk of adverse effects. Metoclopramide is generally not recommended for use in pediatric patients since tardive dyskinesia (TD) and other extrapyramidal symptoms associated with metoclopramide are more common in pediatric patients than adults. Avoid use of metoclopramide for longer than 12 weeks because of the increased risk of developing TD with longer-term use. The American Academy of Neurology practice guideline states that metoclopramide is possibly more likely than placebo to reduce tic severity in pediatric patients with Tourette's syndrome or chronic tic disorders; however, the benefits of use should outweigh the risks (e.g., increased prolactin, TD). Further, there is insufficient evidence to determine the relative efficacy of metoclopramide to other dopamine antagonists, such as antipsychotics.

For the treatment of acute migraine*:
Intravenous dosage:
Children and Adolescents: 0.1 to 0.2 mg/kg/dose IV (Max: 10 mg/dose); may repeat once.

Maximum Dosage Limits:
-Neonates
Data are limited; safety and efficacy not established. 0.1 mg/kg/dose IV and 0.15 mg/kg/dose PO (Max: 0.6 mg/kg/day PO) have been reported.
-Infants
0.1 mg/kg/dose IV and 0.2 mg/kg/dose PO (Max: 0.8 mg/kg/day PO) have been most commonly reported.
-Children
0.2 mg/kg/dose IV (Max: 10 mg/dose IV) and 0.2 mg/kg/dose PO (Max: 10 mg/dose or 0.8 mg/kg/day PO) have been reported; 2 mg/kg/dose IV infusion has been used for emetogenic chemotherapy.
-Adolescents
0.2 mg/kg/dose IV (Max: 10 mg/dose IV) and 0.2 mg/kg/dose PO (Max: 10 mg/dose or 0.8 mg/kg/day PO) have been reported; 2 mg/kg/dose IV infusion has been used for emetogenic chemotherapy.

Patients with Hepatic Impairment Dosing
No pediatric specific adjustments are available; the following recommendations are for oral dosing in adult patients with gastroesophageal reflux :

Mild hepatic impairment (Child-Pugh Class A): 10 to 15 mg PO 4 times daily (Max: 60 mg).
Moderate or severe hepatic impairment (Child-Pugh Class B or C): 5 mg PO 4 times daily or 10 mg PO 3 times daily (Max: 30 mg).

Patients with Renal Impairment Dosing
CrCl 40 mL/minute or more: No dosage adjustment needed.
CrCl less than 40 mL/minute: Reduce initial recommended dose by 50%. Thereafter, dose may be increased or decreased as appropriate based on clinical response and tolerability.

Pediatric recommendations have also included the following renal dose adjustments:
CrCl 30 to 50 mL/minute: give 75% of the normal dose.
CrCl 10 to 29 mL/minute: give 50% of the normal dose.
CrCl less than 10 mL/minute: give 25% of the normal dose.

Intermittent Hemodialysis:
Hemodialysis removes relatively little metoclopramide. Follow dose recommendations for CrCl less than 10 mL/minute; a supplement of 25% of a normal dose has been recommended after a dialysis session in pediatrics.

Continuous renal replacement therapy (CRRT):
Follow dose recommendations for CrCl less than 10 mL/minute; a supplement of 75% of a normal dose has been recommended after a CRRT session in pediatrics.

Continuous ambulatory peritoneal dialysis (CAPD)
Continuous ambulatory peritoneal dialysis does not remove significant amounts of the drug. Follow dose recommendations for CrCl less than 10 mL/minute.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Metoclopramide's mechanism of action is complex. Unlike bethanechol, metoclopramide enhances gastric motility without stimulating gastric secretions. Peripherally, metoclopramide augments cholinergic activity either by causing release of acetylcholine from postganglionic nerve endings or by sensitizing muscarinic receptors on smooth muscle. Vagotomy does not inhibit metoclopramide effects on the GI tract as much as pretreatment with atropine does. Further confounding the issue is the fact that high doses of metoclopramide depress mechanical activity of GI smooth muscle, while low doses stimulate it. Effects on the resting tone of the lower esophageal sphincter combined with increased gastric emptying reduce gastroesophageal reflux, although this benefit is greater during the day than at night. The net effect of metoclopramide is a remarkable coordination of gastric and duodenal motility.

Centrally, metoclopramide blocks dopaminergic receptors, specifically, the D2 subtype, in the chemoreceptor trigger zone as do other clinically useful antinauseants such as prochlorperazine. Unlike the phenothiazines, however, metoclopramide does not possess antipsychotic or tranquilizing activity. Metoclopramide also appears to be less sedating than other central dopamine antagonists. Metoclopramide effectively antagonizes the actions of apomorphine, a known central dopamine agonist. Antiemetic effects of metoclopramide are mainly the result of central dopamine antagonism and increased gastric motility, however, metoclopramide also possesses weak 5-HT3 (e.g., serotonin type 3) receptor antagonism. Discovery of this minor action of metoclopramide lead to the development of potent 5-HT3 antagonists such as ondansetron and granisetron. Central dopaminergic blockade produces antiemesis but also sedation and extrapyramidal effects. Inhibition of dopamine receptors in the pituitary and hypothalamus increases prolactin secretion, which can produce other adverse effects. Metoclopramide also acts on adrenal tissue to increase secretion of aldosterone.

Pharmacokinetics: Metoclopramide is administered orally and parenterally. Metoclopramide is distributed into breast milk, and it crosses the blood-brain barrier and the placenta. Metoclopramide is only weakly bound to plasma protein (about 30%). The volume of distribution is approximately 3.5 L/kg, suggesting extensive distribution to body tissues. Metoclopramide undergoes enzymatic metabolism via oxidation as well as glucuronide and sulfate conjugation reactions in the liver. Monodeethylmetoclopramide, a major oxidative metabolite, is formed primarily by CYP2D6, an enzyme subject to genetic variability. Plasma concentrations decline in a biphasic manner, with a half-life of about 5 minutes in the initial phase and 2.5 to 6 hours in the terminal phase. Within 72 hours, approximately 85% of a dose is excreted in the urine as unchanged drug (20%) or as the glucuronide or sulfate in patients with normal renal function, and about 5% of an oral dose is excreted in the feces via the bile.

Affected cytochrome P450 isoenzymes and drug transporters: CYP2D6
Metoclopramide is a substrate of the CYP2D6. Those patients who are CYP2D6 poor metabolizers (CYP2D6 PMs) require dose reductions, as well as patients who are receiving strong CYP2D6 inhibitors. Although in vitro studies suggest that metoclopramide can inhibit CYP2D6, metoclopramide is unlikely to interact with CYP2D6 substrates in vivo at therapeutically relevant concentrations.


-Route-Specific Pharmacokinetics
Oral Route
Metoclopramide is rapidly and well absorbed; oral bioavailability is approximately 80% +/- 15.5%. Onset of action is 30 to 60 minutes after oral dosing. In the absence of gastroparesis, metoclopramide is rapidly absorbed from the GI tract. Peak plasma levels are generally achieved within 2 hours after oral dosing. Metoclopramide orally disintegrating tablets (ODT) were found to be bioequivalent to metoclopramide tablets.

Intravenous Route
Metoclopramide's onset of action is 1 to 3 minutes after IV injection.

Intramuscular Route
Metoclopramide's onset of action is 10 to 15 minutes after IM injection.


-Special Populations
Pediatrics
Neonates
In a single-dose pharmacokinetic study of metoclopramide 0.1 to 0.15 mg/kg oral solution in 10 premature neonates (weight: 1.1 to 3.2 kg; postconceptional age: 31 to 40 weeks), the mean time to reach peak concentrations was 2.45 hours, mean elimination half-life was 5.4 hours, clearance was 0.795 L//kg/hour, and volume of distribution was 6.94 L/kg. The mean clearance and volume of distribution were approximately 1.4- and 2.1- fold higher, respectively, than adult values. Neonates in general exhibit prolonged clearance of metoclopramide relative to other populations, and this may produce excessive serum concentrations. In a newborn of 3.5 weeks, the metoclopramide half-life after the first and the tenth oral dose (23.1 hours and 10.3 hours, respectively) was significantly longer compared to other infants. In addition, neonates have reduced levels of NADH-cytochrome b5 reductase which, in combination with delayed clearance, make neonates more susceptible to methemoglobinemia.

Infants
In an open-label study, 6 infants (age range: 3.5 weeks to 5.4 months) with gastroesophageal reflux (GER) received metoclopramide 0.15 mg/kg oral solution every 6 hours for 10 doses. The mean time to reach peak concentrations was 2.2 hours, half-life was 4.1 hours, clearance was 0.67 L/kg/hour, and volume of distribution was 4.4 L/kg. In the youngest patient (a newborn of 3.5 weeks), metoclopramide half-life after the first and the tenth dose (23.1 and 10.3 hours, respectively) was significantly longer compared to other infants.

Children and Adolescents
In study evaluating 4 to 5 intravenous infusions of metoclopramide at a dose of 2 mg/kg IV to control emesis in 9 pediatric cancer patients (age range: 1 to 9 years), the peak serum concentrations of metoclopramide ranged from 1,060 to 5,680 mg/L. The mean elimination half-life was 4.5 hours (range: 2 to 12.5 hours), the mean clearance was 0.37 L/kg/hour (range: 0.1 to 1.24 L/kg/hour), and the mean volume of distribution of metoclopramide was 1.93 L/kg (range: 0.95 to 5.5 L/kg). In another study, single intravenous doses of metoclopramide 0.22 mg/kg to 0.46 mg/kg (mean, 0.35 mg/kg) were administered over 5 minutes to 9 pediatric cancer patients receiving chemotherapy (age range: 7 to 14 years) for prophylaxis of cytotoxic-induced vomiting. The mean elimination half-life was 4.4 hours (range: 1.7 to 8.3 hours), the mean clearance was 0.56 L/kg/hour (range: 0.12 to 1.2 L/kg/hour), and the mean volume of distribution of metoclopramide was 3 L/kg (range: 1 to 4.8 L/kg).

Hepatic Impairment
In 8 adult patients with severe hepatic impairment (Child-Pugh C), the average metoclopramide clearance was reduced by approximately 50% compared to patients with normal hepatic function.

Renal Impairment
In a study of 24 adult patients with varying degrees of renal impairment (moderate, severe, and ESRD requiring dialysis), the AUC of metoclopramide in patients with moderate to severe renal impairment was about 2-fold the AUC in patients with normal renal function. In patients with ESRD on dialysis, the AUC was about 3.5-fold the AUC in patients with normal renal function.

Other
CYP2D6 Poor Metabolizers (CYP2D6 PMs)
Metoclopramide's metabolite is formed primarily by CYP2D6, an enzyme subject to genetic variability. Those patients who are CYP2D6 poor metabolizers (CYP2D6 PMs) have reduced clearance of metoclopramide and require dose reductions.