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    Other Drugs for Gastric-Acid Related Disorders
    Propulsives

    BOXED WARNING

    Diabetes mellitus, parkinsonism, seizure disorder, seizures, tardive dyskinesia

    Various CNS reactions, including serious movement disorders, can occur with metoclopramide therapy and may be dose-dependent and duration-dependent. Extrapyramidal symptoms have also 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. 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. Elderly patients, especially elderly females, as well as patients with diabetes mellitus, are more likely to develop tardive dyskinesia and thus should be treated with caution. If dyskinetic symptoms occur, metoclopramide should be discontinued; there is no known treatment for tardive dyskinesia. 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several weeks of drug discontinuance, however dyskinetic movements can persist even after metoclopramide has been withdrawn.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 following drug discontinuation.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral and parenteral GI prokinetic agent chemically related to procainamide; devoid of anesthetic or antiarrhythmic activity.
    Facilitates GI intubation; treats GI hypomotility, GERD, or nausea; may induce lactation.
    Use should be kept to 12 weeks or less due to risk for tardive dyskinesia.

    COMMON BRAND NAMES

    Metozolv, Reglan

    HOW SUPPLIED

    Metoclopramide Hydrochloride Oral Sol: 5mg, 5mL
    Metoclopramide Hydrochloride/Metozolv Oral Tab Orally Dis: 5mg, 10mg
    Metoclopramide Hydrochloride/Reglan Intramuscular Inj Sol: 1mL, 5mg
    Metoclopramide Hydrochloride/Reglan Intravenous Inj Sol: 1mL, 5mg
    Metoclopramide Hydrochloride/Reglan Oral Tab: 5mg, 10mg

    DOSAGE & INDICATIONS

    For post-operative nausea/vomiting (PONV) and post-operative nausea/vomiting (PONV) prophylaxis.
    Intravenous or Intramuscular dosage
    Adults

    10 mg IM or IV near the end of the surgical procedure. Repeat every 4 to 6 hours as necessary. If required, a 20-mg dose may be used.

    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 emetogenic chemotherapy-induced nausea/vomiting and chemotherapy-induced nausea/vomiting prophylaxis.
    Intravenous dosage
    Adults

    1 to 2 mg/kg IV infusion given 30 minutes before beginning chemotherapy and repeated every 2 hours for 2 doses, and then every 3 hours for 3 doses. The initial 2 doses should be 2 mg/kg/dose if highly emetogenic drugs such as cisplatin or dacarbazine are used alone or in combination. For less emetogenic regimens, 1 mg/kg/dose may suffice. Per ASCO guidelines, a second line treatment to consider for those patients not responding to the usual standard antiemetic regimens. The manufacturer does not recommend metoclopramide use longer than 12 weeks in duration.

    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 risk for extrapyramidal side effects, which occur at 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. While not a first line recommended treatment, metoclopramide is sometimes used as a second line antiemetic treatment.

    To facilitate intestinal intubation and for use as a diagnostic aid during gastrointestinal radiography.
    Intravenous dosage
    Adults and Adolescents > 14 years

    10 mg IV as a single dose.

    Children and Adolescents 6 to 14 years

    2.5 to 5 mg IV as a single dose. The manufacturer does not recommend the use of metoclopramide in pediatric patients for any use outside of small bowel intubation.

    Children < 6 years

    0.1 mg/kg IV as a single dose. The manufacturer does not recommend the use of metoclopramide in pediatric patients for any use outside of small bowel intubation.

    For the treatment of symptomatic gastroesophageal reflux disease (GERD).
    Oral dosage
    Adults

    10 to 15 mg PO up to 4 times per day, 30 minutes before meals and at bedtime. Geriatric patients may respond to a dose of 5 mg. For intermittent symptoms, single doses up to 20 mg prior to the provoking situation may be preferred. Therapy for more than 12 weeks is not recommended. According to treatment guidelines, there is no clear role for the use of metoclopramide in the treatment of GERD. Evidence demonstrates that PPI therapy is central in the treatment of GERD symptoms. The added benefit of augmenting PPI therapy with metoclopramide has not been adequately studied. Likewise, combination therapy with metoclopramide and H2 antagonists has not been shown to be more effective than either agent used alone. In light of its safety profile, metoclopramide use in GERD should be limited.

    Neonates†, Infants†, Children† and Adolescents†

    0.1 mg/kg/dose PO given every 6 to 8 hours most commonly used in clinical practice; doses up to 0.2 mg/kg/dose PO have been studied in children. (Max: 0.8 mg/kg/day PO; in older children and adolescents, do not exceed 10 mg/dose PO for weight-based dosing). The manufacturer does not recommend the use of metoclopramide in pediatric patients. According to treatment guidelines, there is no clear role for the use of metoclopramide in the treatment of GERD. In light of its safety profile, metoclopramide use in GERD should be limited.

    Intravenous or Intramuscular dosage
    Adults

    10 mg IV or IM up to 4 times per day, 30 minutes before meals and at bedtime. Geriatric patients may respond to a dose of 5 mg. Switch to oral therapy as soon as feasible. Therapy for more than 12 weeks is not recommended. According to treatment guidelines, there is no clear role for the use of metoclopramide in the treatment of GERD. Evidence demonstrates that PPI therapy is central in the treatment of GERD symptoms. The added benefit of augmenting PPI therapy with metoclopramide has not been adequately studied. Likewise, combination therapy with metoclopramide and H2 antagonists has not been shown to be more effective than either agent used alone. In light of its safety profile, metoclopramide use in GERD should be limited.

    For the treatment of idiopathic or postsurgical gastroparesis† or diabetic gastroparesis.
    Oral, Intravenous, or Intramuscular dosage
    Adults

    10 mg PO, IV or IM 4 times per day, given 30 minutes before meals and at bedtime for 2 to 8 weeks is the FDA-approved dosage in the treatment of diabetic gastroparesis. Initiate oral therapy except in the case of severe symptoms; severe symptoms may require IV/IM therapy for up to 10 days before symptoms subside. According to gastroparesis treatment guidelines, oral therapy should be initiated at 5 to 10 mg PO 2 to 3 times daily, before meals. The oral liquid is often utilized because of rapid absorption and to facilitate dose modifications. A maximum daily dose of 40 mg/day is advocated along with “drug holidays” or dose reductions (e.g., 5 mg, before 2 main meals of the day) whenever clinically possible. Data on chronic use is lacking. The decision to use metoclopramide long-term should be weighed against the risk of developing tardive dyskinesia; routine monitoring may lessen the risks associated with metoclopramide therapy. Therapy for more than 12 weeks is not recommended.

    For the treatment of acute, severe migraine† prior to administration of dihydroergotamine (DHE) to offset DHE-induced nausea; or in patients who do not respond to dihydroergotamine; or as an alternative to other migraine therapies.
    Intravenous or Intramuscular dosage
    Adults

    10 mg IM or IV as a single dose.

    For the treatment of persistent singultus (hiccups)†.
    Oral, Intravenous, or Intramuscular dosage
    Adults

    Metoclopramide 10 mg PO or IV/IM every 6 hours has been given for persistent or intractable hiccup. If hiccups are relieved, maintenance therapy for at least 10 days is recommended.

    For lactation induction†.
    Oral dosage
    Adult Females

    Initially, 10 mg PO 2 or 3 times daily. Dosages of 15 mg/day or lower have not been effective. The typical effective dosage range is 20 to 45 mg/day PO, administered in divided doses; do not exceed 45 mg/day because of concerns of the effects of metoclopramide on the breast-feeding infant.

    For use as a radiation sensitizer in combination with radiation therapy in the treatment of patients with non-small cell lung cancer (NSCLC)†.
    Intramuscular or Intravenous dosage
    Adults

    As a radiosensitizing agent in the treatment of non-small cell lung cancer, a dose of 2 mg/kg IV (Sensamide) was administered 1 hour prior to radiation therapy 3 times per week in a phase II/III trial.

    For pregnancy-induced nausea/vomiting†.
    Oral dosage
    Pregnant Adult Females

    The American College of Obstetrics and Gynecology recommends 5 to 10 mg PO every 8 hours as needed if treatment with other options (e.g., vitamin B6, doxylamine, promethazine, dimenhydrinate) is not effective.

    Intravenous or Intramuscular dosage
    Pregnant Adult Females

    The American College of Obstetrics and Gynecology recommends 5 to 10 mg IM or IV every 8 hours as needed if treatment with other options (e.g., vitamin B6, doxylamine, promethazine, dimenhydrinate) is not effective.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    60 mg/day PO or 20 mg per single dose; therapy > 12 weeks not recommended by manufacturer.

    Geriatric

    60 mg/day PO or 20 mg per single dose. Lower dosage may be sufficient. The elderly may be more susceptible to the effects of metoclopramide; therapy > 12 weeks not recommended by manufacturer.

    Adolescents

    > 14 years: Safety and efficacy have not been established; however, 40 mg/day PO has been suggested for short term use.
    <= 14 years: Safety and efficacy have not been established; however, up to 0.8 mg/kg/day PO has been suggested for short-term use.

    Children

    Safety and efficacy have not been established; however, up to 0.8 mg/kg/day PO has been suggested for short-term use.

    Infants

    Safety and efficacy have not been established; however, up to 0.8 mg/kg/day PO has been suggested for short-term use.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustments are needed based on hepatic function alone.

    Renal Impairment

    CrCl 40 mL/min or more: No dosage adjustment needed.
    CrCl less than 40 mL/min: Reduce initial recommended dose by 50%. Thereafter, dose may be increased or decreased as appropriate based on clinical response and tolerability.
     
    Adult recommendations have also included the following renal dose adjustments:
    CrCl more than 50 mL/min: give 100% of the normal dose.
    CrCl 10 to 50 mL/min: give 75% of the normal dose.
    CrCl less than 10 mL/min: give 50% of the normal dose.
     
    Pediatric recommendations have also included the following renal dose adjustments:
    CrCl 30 to 50 mL/min: give 75% of the normal dose.
    CrCl 10 to 29 mL/min: give 50% of the normal dose.
    CrCl less than 10 mL/min: give 25% of the normal dose.
     
    Intermittent hemodialysis:
    Hemodialysis removes relatively little metoclopramide. Follow dose recommendations as for CrCl less than 10 mL/min; no supplementation following hemodialysis is recommended in adults. A supplement of 25% of a normal dose has been recommended following a dialysis session in pediatrics.
     
    Continuous renal replacement therapy (CRRT):
    Follow dose recommendations as for CrCl 10 to 50 mL/min in adults. For pediatric patients, follow dose recommendations as for CrCl less than 10 mL/min; a supplement of 75% of a normal dose has been recommended following 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 as for CrCl less than 10 mL/min.

    ADMINISTRATION

    Oral Administration

    Administer doses 30 minutes before each meal and at bedtime.

    Oral Solid Formulations

    Oral disintegrating tablets (Metosolv ODT):
    Since the ODT absorbs moisture rapidly, 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 the ODT without liquid.

    Injectable Administration

    Administer by IM or direct IV injection, or by IV infusion.
    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 in adults.
    Inject over 1—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 > 10 mg in at least 50 ml of 0.9% Sodium Chloride (NS), D5W, or other compatible solution such as D5/0.45% Sodium Chloride, Ringer's, 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 NS injection. (Dilutions in NS may be stored frozen up to 4 weeks).

    Intramuscular Administration

    No dilution necessary.
    Inject into a large muscle mass. Aspirate prior to injection to avoid injection into a blood vessel.

    STORAGE

    Generic:
    - Protect from freezing
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Metozolv:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Reglan:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Paraben hypersensitivity, procainamide hypersensitivity

    Metoclopramide should not be used in those patients with hypersensitivity 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.

    GI bleeding, GI obstruction, GI perforation

    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.

    Cardiac disease, heart failure, hepatic disease, hypertension, pheochromocytoma

    Because metoclopramide produces a transient increase in plasma aldosterone, certain patients, especially those with cirrhosis (hepatic disease) or 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.

    Diabetes mellitus, parkinsonism, seizure disorder, seizures, tardive dyskinesia

    Various CNS reactions, including serious movement disorders, can occur with metoclopramide therapy and may be dose-dependent and duration-dependent. Extrapyramidal symptoms have also 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. 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. Elderly patients, especially elderly females, as well as patients with diabetes mellitus, are more likely to develop tardive dyskinesia and thus should be treated with caution. If dyskinetic symptoms occur, metoclopramide should be discontinued; there is no known treatment for tardive dyskinesia. 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 following drug discontinuation.

    Abrupt discontinuation, depression, driving or operating machinery

    Various CNS reactions can occur with metoclopramide therapy and may be dose-dependent. Caution is warranted in patients with a history of major depression due to the possible 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 driving or operating machinery, 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, G6PD deficiency, infants, methemoglobin reductase deficiency, methemoglobinemia, neonates

    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.

    Renal failure, renal impairment

    Metoclopramide should be used 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 < 40 ml/min).

    Breast cancer, infertility

    Metoclopramide stimulates the release of prolactin. Some human breast cancer may be prolactin-dependent and therefore metoclopramide should be used extremely cautiously in patients who have a history of breast cancer. Neither clinical or epidemiological evidence to date have supported an association between metoclopramide use and breast cancer. Because metoclopramide stimulates the release of prolactin, it may induce infertility secondary to hyperprolactinemia in some men or women, or may induce other endocrine abnormalities (see Adverse Reactions).

    Pregnancy

    Metoclopramide is classified in FDA pregnancy category B. Currently available animal and human data do not support an association between the use of metoclopramide in pregnancy and congenital defects. The American College of Obstetricians and Gynecologists clinical practice guideline on the treatment of nausea and vomiting in pregnancy recommends metoclopramide as an option after other pharmacological therapies (e.g., vitamin B6, doxylamine, promethazine, dimenhydrinate) have failed. A retrospective cohort study compared infants exposed to metoclopramide through maternal use during the first trimester (n = 3458) to infants who were not exposed to metoclopramide (n = 78,245) and found no significant differences in major congenital malformations, birth weight, preterm delivery, or perinatal death. Metoclopramide has been used off-label as an adjunct, based on risk-benefit ratios, for the treatment of hyperemesis gravidarum. Placental transfer of metoclopramide in most stages of pregnancy is unknown; however, IV doses given just prior to caesarean section during labor have noted placental transfer at term, with umbilical venous to maternal plasma concentration ratios of approximately 0.6. Doses given during labor do not appear to have effects on fetal prolactin secretion or other hormones. No controlled human gestation studies are available; so this drug should be used during pregnancy only if necessary. In addition, chronic use (e.g., > 12 weeks) should be avoided due to the increased risk for the development of movement disorders such as tardive dyskinesia (see tardive diskinesia Precaution).

    Breast-feeding

    Metoclopramide is distributed into breast milk. The American Academy of Pediatrics continues to recommend caution during the use of metoclopramide in breast-feeding secondary to the potential for CNS effects from the use of the drug. Based on clinical use, maternal doses up to 10 mg orally three times per day, which translates to roughly a 1—45 mcg/kg/day ingestion in the infant, do not appear to pose a significant risk to the breast-feeding infant. The estimated ingestions are much lower than the oral dosages an infant would receive in therapeutic administration (i.e., 100 to 800 mcg/kg/day). Metoclopramide has been used off-label to stimulate the release of prolactin from the anterior pituitary, thus increasing lactation in women with inadequate or decreased milk production in dosages of 20—45 mg/day orally. Two studies, one in mothers of premature infants and one in mothers who experienced complete or partial lactation failure, showed no significant difference in breast milk volume, duration of breast-feeding, weight gain, or reduction in the amount of supplemental milk in infants whose mothers were treated with metoclopramide versus those who were not. Both studies employed education regarding optimal breast-feeding for all of the mothers. The Academy of Breast-feeding Medicine does not recommend any specific pharmacologic galactagogue based on inconclusive evidence of their efficacy and the risk of side effects in both mothers and their infants. In summary, dosages below 45 mg/day in the lactating woman are probably not harmful to the infant, but the drug should be used only when the benefit to the mother outweighs the potential risk to the infant.

    Malignant hyperthermia

    Rare occurrences of neuroleptic malignant syndrome (NMS) have been reported during metoclopramide therapy (see Adverse Reactions). 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).

    Geriatric, Parkinson's disease

    Geriatric patients must use metoclopramide with caution. Pseudoparkinsonism (e.g., bradykinesia, tremor, cogwheel rigidity, mask-like facies) may develop during treatment with metoclopramide. In addition, tardive dyskinesia (TD) has been reported, usually following long-term and high-dose use. TD occurs more frequently in geriatric patients, especially females. Symptoms of TD include 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 and there is no known cure; therefore, if dyskinetic symptoms occur, metoclopramide should be discontinued. 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. According to the Beers Criteria, metoclopramide is considered a potentially inappropriate medication (PIM) for use in geriatric patients and should generally be avoided due to the risk of tardive dyskinesia which may be increased in frail older adults. In addition, the Beers expert panel recommends avoiding dopamine receptor antagonists such as metoclopramide in geriatric patients with Parkinson's disease because of the potential for symptom exacerbation. The Beers expert panel considers the treatment of gastroparesis as an acceptable use for metoclopramide in the elderly. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, metoclopramide is a high-risk medication with limited clinical indications and effectiveness. Metoclopramide is not recommended for first-line treatment of gastroesophageal reflux disease (GERD), particularly in older adults, and may increase seizures in patients with a seizure disorder or exacerbate parkinsonian symptoms in patients with Parkinson's disease. When used for diabetic gastroparesis or other indications, the relative benefits versus risks should be evaluated and documented. Metoclopramide may cause restlessness, drowsiness, insomnia, depression, distress, anorexia, extrapyramidal symptoms, and lowering of the seizure threshold; these adverse consequences are of particular concern in older adults. It is essential to closely monitor at-risk patients for adverse effects.

    ADVERSE REACTIONS

    Severe

    suicidal ideation / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    laryngospasm / Rapid / Incidence not known
    torticollis / Delayed / Incidence not known
    tardive dyskinesia / Delayed / Incidence not known
    AV block / Early / Incidence not known
    heart failure / Delayed / Incidence not known
    bradycardia / Rapid / Incidence not known
    bronchospasm / Rapid / Incidence not known
    laryngeal edema / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    neuroleptic malignant syndrome / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    methemoglobinemia / Early / Incidence not known
    visual impairment / Early / Incidence not known
    porphyria / Delayed / Incidence not known

    Moderate

    dystonic reaction / Delayed / 0.2-0.2
    hallucinations / Early / Incidence not known
    confusion / Early / Incidence not known
    depression / Delayed / Incidence not known
    akathisia / Delayed / Incidence not known
    trismus / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    involuntary movements / Delayed / Incidence not known
    pseudoparkinsonism / Delayed / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    galactorrhea / Delayed / Incidence not known
    hyperprolactinemia / Delayed / Incidence not known
    infertility / Delayed / Incidence not known
    edema / Delayed / Incidence not known
    hypertension / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    supraventricular tachycardia (SVT) / Early / Incidence not known
    fluid retention / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    urinary incontinence / Early / Incidence not known
    withdrawal / Early / Incidence not known
    leukopenia / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known

    Mild

    drowsiness / Early / 10.0-70.0
    restlessness / Early / 10.0-10.0
    fatigue / Early / 10.0-10.0
    nausea / Early / 4.0-6.0
    headache / Early / 4.0-5.0
    vomiting / Early / 2.0-2.0
    diarrhea / Early / Incidence not known
    dizziness / Early / Incidence not known
    insomnia / Early / Incidence not known
    tremor / Early / Incidence not known
    gynecomastia / Delayed / Incidence not known
    amenorrhea / Delayed / Incidence not known
    breast enlargement / Delayed / Incidence not known
    menstrual irregularity / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    rash (unspecified) / Early / Incidence not known
    urinary urgency / Early / Incidence not known

    DRUG INTERACTIONS

    Abarelix: Drugs that cause hyperprolactinemia, such as metoclopramide, should generally not be administered concomitantly with GnRH analogs since hyperprolactinemia downregulates the number of pituitary GnRH receptors. Monitor the patient for the proper clinical response to GnRH therapy.
    Acetaminophen; Aspirin, ASA; Caffeine: Metoclopramide can increase the rate or extent of absorption of aspirin because of accelerated gastric emptying, which increases the contact time with the small bowel where this drug is absorbed.
    Acetaminophen; Dichloralphenazone; Isometheptene: Combined use of metoclopramide and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase possible sedation.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Aliskiren; Hydrochlorothiazide, HCTZ: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Alogliptin: Because metoclopramide can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents, including alogliptin. The dosing of antidiabetic agents may require adjustment in patients who receive metoclopramide concomitantly.
    Alogliptin; Metformin: Because metoclopramide can enhance gastric emptying in diabetic patients, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents. The dosing of metformin may require adjustment in patients who receive metoclopramide concomitantly. Because metoclopramide can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents, including alogliptin. The dosing of antidiabetic agents may require adjustment in patients who receive metoclopramide concomitantly.
    Alogliptin; Pioglitazone: Because metoclopramide can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents, including alogliptin. The dosing of antidiabetic agents may require adjustment in patients who receive metoclopramide concomitantly.
    Alosetron: Although a potential interaction has not been studied, metoclopramide might negate the effect of alosetron. Pharmacodynamic interactions between alosetron and drugs that enhance peristalsis are theoretically possible, based on opposing pharmacologic outcomes. It may be prudent to avoid use of metoclopramide during alosetron treatment.
    Alpha-glucosidase Inhibitors: Because metoclopramide can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents. The dosing of antidiabetic agents may require adjustment in patients who receive metoclopramide concomitantly.
    Amantadine: Metoclopramide is a central dopamine antagonist and can antagonize the actions of dopamine agonists such as amantadine. In addition, metoclopramide may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, tardive dyskinesia), and rarely, neuroleptic malignant syndrome. The manufacturer of metoclopramide does not specifically contraindicate the use of metoclopramide and dopamine agonists; however, coadministration should be avoided if possible.
    Amiloride; Hydrochlorothiazide, HCTZ: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Amoxapine: Metoclopramide is a central dopamine antagonist and may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, or tardive dyskinesia), and rarely, neuroleptic malignant syndrome. Metoclopramide is contraindicated with other drugs that are likely to cause extrapyramidal effects since the risk of these effects may be increased. Case reports and case series have implicated tricyclic antidepressants in causing a variety of extrapyramidal symptoms (EPS). Although the occurrence is infrequent compared to antipsychotic-induced EPS, the risk of these events may be increased during concurrent use of metoclopramide and tricyclic antidepressants compared to monotherapy with either agent. The related cyclic compound amoxapine has significant anti-dopaminergic properties, and several cases of EPS have been reported during use of this drug. It is advisable to avoid coadministration of metoclopramide and amoxapine if possible.
    Anticholinergics: Drugs with significant antimuscarinic activity, such as anticholinergics and antimuscarinics, may slow GI motility and thus may reduce the prokinetic actions of metoclopramide. Monitor patients for an increase in gastrointestinal complaints, such as reflux or constipation. Additive drowsiness may occur as well. The clinical significance is uncertain.
    Anxiolytics; Sedatives; and Hypnotics: Combined use of metoclopramide and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase possible sedation.
    Apomorphine: Agents with dopamine antagonist properties, like metoclopramide, may decrease the effectiveness of dopamine agonists. These agents can cause abrupt and severe worsening of Parkinson's disease symptoms. Metoclopramide should be avoided, if possible, in patients treated with dopamine agonists for Parkinson's disease.
    Aripiprazole: Concomitant use of metoclopramide and antipsychotics is contraindicated by the manufacturer of metoclopramide as the risk of extrapyramidal effects may be increased. Both metoclopramide and antipsychotics antagonize dopamine receptors, which can increase the risk of extrapyramidal effects, including tardive dyskinesia or other dystonic reactions. Additionally, because both antipsychotics and metoclopramide can cause sedation, seizures, or increased prolactin levels, it is possible that the risk of these effects may be increased during concurrent use.
    Artemether; Lumefantrine: Lumefantrine is an inhibitor and metoclopramide is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased metoclopramide concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Asenapine: Concomitant use of metoclopramide and antipsychotics is contraindicated by the manufacturer of metoclopramide as the risk of extrapyramidal effects may be increased. Both metoclopramide and antipsychotics antagonize dopamine receptors, which can increase the risk of extrapyramidal effects, including tardive dyskinesia or other dystonic reactions. Additionally, because both antipsychotics and metoclopramide can cause sedation, seizures, or increased prolactin levels, it is possible that the risk of these effects may be increased during concurrent use.
    Aspirin, ASA: Metoclopramide can increase the rate or extent of absorption of aspirin because of accelerated gastric emptying, which increases the contact time with the small bowel where this drug is absorbed.
    Aspirin, ASA; Butalbital; Caffeine: Metoclopramide can increase the rate or extent of absorption of aspirin because of accelerated gastric emptying, which increases the contact time with the small bowel where this drug is absorbed.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: Metoclopramide can increase the rate or extent of absorption of aspirin because of accelerated gastric emptying, which increases the contact time with the small bowel where this drug is absorbed.
    Aspirin, ASA; Caffeine; Dihydrocodeine: Metoclopramide can increase the rate or extent of absorption of aspirin because of accelerated gastric emptying, which increases the contact time with the small bowel where this drug is absorbed.
    Aspirin, ASA; Carisoprodol: Metoclopramide can increase the rate or extent of absorption of aspirin because of accelerated gastric emptying, which increases the contact time with the small bowel where this drug is absorbed.
    Aspirin, ASA; Carisoprodol; Codeine: Metoclopramide can increase the rate or extent of absorption of aspirin because of accelerated gastric emptying, which increases the contact time with the small bowel where this drug is absorbed.
    Aspirin, ASA; Dipyridamole: Metoclopramide can increase the rate or extent of absorption of aspirin because of accelerated gastric emptying, which increases the contact time with the small bowel where this drug is absorbed.
    Aspirin, ASA; Omeprazole: Metoclopramide can increase the rate or extent of absorption of aspirin because of accelerated gastric emptying, which increases the contact time with the small bowel where this drug is absorbed.
    Aspirin, ASA; Oxycodone: Metoclopramide can increase the rate or extent of absorption of aspirin because of accelerated gastric emptying, which increases the contact time with the small bowel where this drug is absorbed.
    Aspirin, ASA; Pravastatin: Metoclopramide can increase the rate or extent of absorption of aspirin because of accelerated gastric emptying, which increases the contact time with the small bowel where this drug is absorbed.
    Atazanavir; Cobicistat: Caution is warranted when cobicistat is administered with metoclopramide as there is a potential for elevated metoclopramide and cobicistat concentrations. Metoclopramide is a CYP2D6 substrate/inhibitor and cobicistat is a substrate/inhibitor of CYP2D6.
    Atenolol; Chlorthalidone: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Atovaquone: Metoclopramide may reduce the bioavailability of atovaquone. Use metoclopramide with atovaquone only if other antiemetics are not available.
    Atovaquone; Proguanil: Metoclopramide may reduce the bioavailability of atovaquone. Use metoclopramide with atovaquone only if other antiemetics are not available.
    Atropine; Difenoxin: Diphenoxylate/difenoxin decreases GI motility. Diphenoxylate/difenoxin may antagonize the muscarinic and/or prokinetic effects of other drugs, including metoclopramide.
    Atropine; Diphenoxylate: Diphenoxylate/difenoxin decreases GI motility. Diphenoxylate/difenoxin may antagonize the muscarinic and/or prokinetic effects of other drugs, including metoclopramide.
    atypical antipsychotic: Concomitant use of metoclopramide and antipsychotics is contraindicated by the manufacturer of metoclopramide as the risk of extrapyramidal effects may be increased. Both metoclopramide and antipsychotics antagonize dopamine receptors, which can increase the risk of extrapyramidal effects, including tardive dyskinesia or other dystonic reactions. Additionally, because both antipsychotics and metoclopramide can cause sedation, seizures, or increased prolactin levels, it is possible that the risk of these effects may be increased during concurrent use.
    Azilsartan; Chlorthalidone: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Barbiturates: Combined use of metoclopramide and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase possible sedation.
    Benazepril; Hydrochlorothiazide, HCTZ: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Bendroflumethiazide; Nadolol: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Benzodiazepines: Combined use of metoclopramide and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase possible sedation.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: Metoclopramide can increase the rate or extent of absorption of tetracycline because of accelerated gastric emptying, which increases the contact time with the small bowel where this drug is absorbed.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: Metoclopramide can increase the rate or extent of absorption of tetracycline because of accelerated gastric emptying, which increases the contact time with the small bowel where this drug is absorbed.
    Bisoprolol; Hydrochlorothiazide, HCTZ: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Brexpiprazole: Concomitant use of metoclopramide and antipsychotics is contraindicated by the manufacturer of metoclopramide as the risk of extrapyramidal effects may be increased. Both metoclopramide and antipsychotics antagonize dopamine receptors, which can increase the risk of extrapyramidal effects, including tardive dyskinesia or other dystonic reactions. Additionally, because both antipsychotics and metoclopramide can cause sedation, seizures, or increased prolactin levels, it is possible that the risk of these effects may be increased during concurrent use.
    Bromocriptine: Metoclopramide is a central dopamine antagonist. Metoclopramide can antagonize the actions of dopamine agonists such as bromocriptine; therefore, the combined use of these agents is not recommended.
    Buspirone: Combined use of metoclopramide and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase possible sedation.
    Cabergoline: The prolactin-lowering effect of cabergoline may be antagonized by medications that increase prolactin levels such as metoclopramide.
    Canagliflozin: Because metoclopramide can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents. The dosing of antidiabetic agents may require adjustment in patients who receive metoclopramide concomitantly.
    Canagliflozin; Metformin: Because metoclopramide can enhance gastric emptying in diabetic patients, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents. The dosing of metformin may require adjustment in patients who receive metoclopramide concomitantly. Because metoclopramide can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents. The dosing of antidiabetic agents may require adjustment in patients who receive metoclopramide concomitantly.
    Candesartan; Hydrochlorothiazide, HCTZ: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Captopril; Hydrochlorothiazide, HCTZ: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Carbidopa; Levodopa: Metoclopramide is a central dopamine antagonist. Metoclopramide can antagonize the actions of dopamine agonists such as levodopa. In addition, metoclopramide may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, tardive dyskinesia), and rarely, neuroleptic malignant syndrome. Dyskinesias and other extrapyramidal effects have been reported during treatment with various anti-parkinson's medications, particularly levodopa. A symptom complex resembling neuroleptic malignant syndrome in association with rapid dose reduction, withdrawal of, or changes in anti-parkinsonian therapy has also been observed. The manufacturer of metoclopramide does not specifically contraindicate the use of metoclopramide and dopamine agonists; however, coadministration should be avoided if possible.
    Carbidopa; Levodopa; Entacapone: Metoclopramide is a central dopamine antagonist. It should be noted that the therapeutic response to COMT inhibitors (entacapone and tolcapone) may be diminished during use of a centrally acting dopamine antagonist. In addition, metoclopramide may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, tardive dyskinesia), and rarely, neuroleptic malignant syndrome. Metoclopramide is contraindicated with other drugs that are likely to cause extrapyramidal effects since the risk of these effects may be increased. Dyskinesias and other extrapyramidal effects have been reported during treatment with various anti-parkinson's medications, particularly levodopa. A symptom complex resembling neuroleptic malignant syndrome in association with rapid dose reduction, withdrawal of, or changes in anti-parkinsonian therapy has also been observed. The manufacturer of metoclopramide does not specifically contraindicate the use of metoclopramide and dopamine agonists; however, coadministration should be avoided if possible. Metoclopramide is a central dopamine antagonist. Metoclopramide can antagonize the actions of dopamine agonists such as levodopa. In addition, metoclopramide may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, tardive dyskinesia), and rarely, neuroleptic malignant syndrome. Dyskinesias and other extrapyramidal effects have been reported during treatment with various anti-parkinson's medications, particularly levodopa. A symptom complex resembling neuroleptic malignant syndrome in association with rapid dose reduction, withdrawal of, or changes in anti-parkinsonian therapy has also been observed. The manufacturer of metoclopramide does not specifically contraindicate the use of metoclopramide and dopamine agonists; however, coadministration should be avoided if possible.
    Cariprazine: Concomitant use of metoclopramide and antipsychotics is contraindicated by the manufacturer of metoclopramide as the risk of extrapyramidal effects may be increased. Both metoclopramide and antipsychotics antagonize dopamine receptors, which can increase the risk of extrapyramidal effects, including tardive dyskinesia or other dystonic reactions. Additionally, because both antipsychotics and metoclopramide can cause sedation, seizures, or increased prolactin levels, it is possible that the risk of these effects may be increased during concurrent use.
    Cetrorelix: Drugs that cause hyperprolactinemia, such as metoclopramide, should generally not be administered concomitantly with GnRH analogs since hyperprolactinemia downregulates the number of pituitary GnRH receptors. Monitor the patient for the proper clinical response to GnRH therapy.
    Chloral Hydrate: Combined use of metoclopramide and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase possible sedation.
    Chlorothiazide: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Chlorthalidone: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Chlorthalidone; Clonidine: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Ciprofloxacin: Metoclopramide accelerates the absorption of oral ciprofloxacin. This results in shorter time to reach maximum ciprofloxacin plasma concentrations. No effect was seen on the bioavailability of ciprofloxacin.
    Clobazam: A dosage reduction of CYP2D6 substrates, such as metoclopramide, may be necessary during co-administration of clobazam. Limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. If these agents are used in combination, it is advisable to monitor the patient for metoclopramide-related adverse reactions.
    Clozapine: Concomitant use of metoclopramide and antipsychotics is contraindicated by the manufacturer of metoclopramide as the risk of extrapyramidal effects may be increased. Both metoclopramide and antipsychotics antagonize dopamine receptors, which can increase the risk of extrapyramidal effects, including tardive dyskinesia or other dystonic reactions. Additionally, because both antipsychotics and metoclopramide can cause sedation, seizures, or increased prolactin levels, it is possible that the risk of these effects may be increased during concurrent use.
    Cobicistat: Caution is warranted when cobicistat is administered with metoclopramide as there is a potential for elevated metoclopramide and cobicistat concentrations. Metoclopramide is a CYP2D6 substrate/inhibitor and cobicistat is a substrate/inhibitor of CYP2D6.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: Caution is warranted when cobicistat is administered with metoclopramide as there is a potential for elevated metoclopramide and cobicistat concentrations. Metoclopramide is a CYP2D6 substrate/inhibitor and cobicistat is a substrate/inhibitor of CYP2D6.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: Caution is warranted when cobicistat is administered with metoclopramide as there is a potential for elevated metoclopramide and cobicistat concentrations. Metoclopramide is a CYP2D6 substrate/inhibitor and cobicistat is a substrate/inhibitor of CYP2D6.
    Codeine; Phenylephrine; Promethazine: Metoclopramide is a central dopamine antagonist and may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, tardive dyskinesia), and rarely, neuroleptic malignant syndrome. Metoclopramide is contraindicated with other drugs that are likely to cause extrapyramidal effects since the risk of these effects may be increased. Phenothiazine antiemetics (i.e., promethazine, prochlorperazine, thiethylperazine) are also central dopamine antagonists and have been associated with extrapyramidal symptoms and rarely, neuroleptic malignant syndrome. In addition, because both phenothiazines and metoclopramide can cause sedation, seizures, or increased prolactin levels, it is possible that the risk of these effects may be increased during concurrent use. The manufacturer of metoclopramide does not specifically contraindicate the use of metoclopramide and phenothiazine antiemetics; however, coadministration should generally be avoided if possible.
    Codeine; Promethazine: Metoclopramide is a central dopamine antagonist and may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, tardive dyskinesia), and rarely, neuroleptic malignant syndrome. Metoclopramide is contraindicated with other drugs that are likely to cause extrapyramidal effects since the risk of these effects may be increased. Phenothiazine antiemetics (i.e., promethazine, prochlorperazine, thiethylperazine) are also central dopamine antagonists and have been associated with extrapyramidal symptoms and rarely, neuroleptic malignant syndrome. In addition, because both phenothiazines and metoclopramide can cause sedation, seizures, or increased prolactin levels, it is possible that the risk of these effects may be increased during concurrent use. The manufacturer of metoclopramide does not specifically contraindicate the use of metoclopramide and phenothiazine antiemetics; however, coadministration should generally be avoided if possible.
    COMT inhibitors: Metoclopramide is a central dopamine antagonist. It should be noted that the therapeutic response to COMT inhibitors (entacapone and tolcapone) may be diminished during use of a centrally acting dopamine antagonist. In addition, metoclopramide may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, tardive dyskinesia), and rarely, neuroleptic malignant syndrome. Metoclopramide is contraindicated with other drugs that are likely to cause extrapyramidal effects since the risk of these effects may be increased. Dyskinesias and other extrapyramidal effects have been reported during treatment with various anti-parkinson's medications, particularly levodopa. A symptom complex resembling neuroleptic malignant syndrome in association with rapid dose reduction, withdrawal of, or changes in anti-parkinsonian therapy has also been observed. The manufacturer of metoclopramide does not specifically contraindicate the use of metoclopramide and dopamine agonists; however, coadministration should be avoided if possible.
    Cyclosporine: Oral metoclopramide has been shown to increase the mean bioavailability of oral cyclosporine by roughly 30%, probably due to decreased GI motility. Until more data are available, cyclosporine serum concentrations should be monitored carefully if metoclopramide is added.
    Dapagliflozin: Because metoclopramide can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents, including dapagliflozin.The dosing of antidiabetic agents may require adjustment in patients who receive metoclopramide concomitantly.
    Dapagliflozin; Metformin: Because metoclopramide can enhance gastric emptying in diabetic patients, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents. The dosing of metformin may require adjustment in patients who receive metoclopramide concomitantly. Because metoclopramide can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents, including dapagliflozin.The dosing of antidiabetic agents may require adjustment in patients who receive metoclopramide concomitantly.
    Darunavir; Cobicistat: Caution is warranted when cobicistat is administered with metoclopramide as there is a potential for elevated metoclopramide and cobicistat concentrations. Metoclopramide is a CYP2D6 substrate/inhibitor and cobicistat is a substrate/inhibitor of CYP2D6.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: Concurrent administration of metoclopramide with ritonavir may result in elevated plasma concentrations of metoclopramide. Metoclopromide is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Degarelix: Drugs that cause hyperprolactinemia, such as metoclopramide, should generally not be administered concomitantly with GnRH analogs since hyperprolactinemia downregulates the number of pituitary GnRH receptors. Monitor the patient for the proper clinical response to GnRH therapy.
    Dexmethylphenidate: Methylphenidate is an inhibitor of dopamine reuptake. Pharmacodynamic interactions may occur between methylphenidate and dopamine antagonists such as metoclopramide. Patients receiving methylphenidate in combination with metoclopramide should be monitored for a decrease in clinical effectiveness of either agent.
    Dextromethorphan; Promethazine: Metoclopramide is a central dopamine antagonist and may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, tardive dyskinesia), and rarely, neuroleptic malignant syndrome. Metoclopramide is contraindicated with other drugs that are likely to cause extrapyramidal effects since the risk of these effects may be increased. Phenothiazine antiemetics (i.e., promethazine, prochlorperazine, thiethylperazine) are also central dopamine antagonists and have been associated with extrapyramidal symptoms and rarely, neuroleptic malignant syndrome. In addition, because both phenothiazines and metoclopramide can cause sedation, seizures, or increased prolactin levels, it is possible that the risk of these effects may be increased during concurrent use. The manufacturer of metoclopramide does not specifically contraindicate the use of metoclopramide and phenothiazine antiemetics; however, coadministration should generally be avoided if possible.
    Digoxin: Digoxin absorption and bioavailability may be diminished in some patients on metoclopramide due to the increased rate of transit from the stomach, where digoxin is normally absorbed. The manufacturer of digoxin recommends measuring serum digoxin concentrations prior to initiation of metoclopramide. Continue monitoring during concomitant treatment and increase the digoxin dose by 20 to 40% as necessary.
    dopamine agonists: Agents with dopamine antagonist properties, like metoclopramide, may decrease the effectiveness of dopamine agonists. These agents can cause abrupt and severe worsening of Parkinson's disease symptoms. Metoclopramide should be avoided, if possible, in patients treated with dopamine agonists for Parkinson's disease.
    Doxorubicin: Metoclopramide is a CYP2D6 inhibitor and doxorubicin is a major substrate of CYP2D6. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of metoclopramide and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Dronedarone: Dronedarone is an inhibitor of CYP2D6. Metoclopramide is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Droperidol: Metoclopramide is a central dopamine antagonist and may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, tardive dyskinesia), and rarely, neuroleptic malignant syndrome. Metoclopramide is contraindicated with other drugs that are likely to cause extrapyramidal effects since the risk of these effects may be increased. Droperidol, a dopamine antagonist, has been associated with extrapyramidal symptoms and rarely, neuroleptic malignant syndrome. The manufacturer of metoclopramide does not specifically contraindicate the use of metoclopramide and droperidol; however, coadministration should be avoided if possible.
    Empagliflozin: Because metoclopramide can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents, including empagliflozin. The dosing of antidiabetic agents may require adjustment in patients who receive metoclopramide concomitantly.
    Empagliflozin; Linagliptin: Because metoclopramide can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents, including empagliflozin. The dosing of antidiabetic agents may require adjustment in patients who receive metoclopramide concomitantly. Because metoclopramide can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents, including linagliptin. The dosing of antidiabetic agents may require adjustment in patients who receive metoclopramide concomitantly.
    Empagliflozin; Metformin: Because metoclopramide can enhance gastric emptying in diabetic patients, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents. The dosing of metformin may require adjustment in patients who receive metoclopramide concomitantly. Because metoclopramide can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents, including empagliflozin. The dosing of antidiabetic agents may require adjustment in patients who receive metoclopramide concomitantly.
    Enalapril; Hydrochlorothiazide, HCTZ: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Entacapone: Metoclopramide is a central dopamine antagonist. It should be noted that the therapeutic response to COMT inhibitors (entacapone and tolcapone) may be diminished during use of a centrally acting dopamine antagonist. In addition, metoclopramide may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, tardive dyskinesia), and rarely, neuroleptic malignant syndrome. Metoclopramide is contraindicated with other drugs that are likely to cause extrapyramidal effects since the risk of these effects may be increased. Dyskinesias and other extrapyramidal effects have been reported during treatment with various anti-parkinson's medications, particularly levodopa. A symptom complex resembling neuroleptic malignant syndrome in association with rapid dose reduction, withdrawal of, or changes in anti-parkinsonian therapy has also been observed. The manufacturer of metoclopramide does not specifically contraindicate the use of metoclopramide and dopamine agonists; however, coadministration should be avoided if possible.
    Eprosartan; Hydrochlorothiazide, HCTZ: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Eszopiclone: Combined use of metoclopramide and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase possible sedation.
    Ethanol: Concurrent use of ethanol can increase the CNS depressant effects of metoclopramide.
    Fenoldopam: Metoclopramide or other peripherally acting dopamine antagonists may inhibit the blood pressure effects of fenoldopam. In one in vitro study, the vasodilatory response to fenoldopam was attenuated by pretreatment with metoclopramide, a nonselective dopamine antagonist, and SCH 23390, a selective DA1-receptor antagonist.
    Fluoxetine; Olanzapine: Concomitant use of metoclopramide and antipsychotics is contraindicated by the manufacturer of metoclopramide as the risk of extrapyramidal effects may be increased. Both metoclopramide and antipsychotics antagonize dopamine receptors, which can increase the risk of extrapyramidal effects, including tardive dyskinesia or other dystonic reactions. Additionally, because both antipsychotics and metoclopramide can cause sedation, seizures, or increased prolactin levels, it is possible that the risk of these effects may be increased during concurrent use.
    Fosfomycin: Metoclopramide, a gastrointestinal motility agent, decreased the systemic absorption of fosfomycin when the drugs were coadministered. This results in lower fosfomycin serum concentrations and urinary excretion.
    Fosinopril; Hydrochlorothiazide, HCTZ: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Ganirelix: Drugs that cause hyperprolactinemia, such as metoclopramide, should generally not be administered concomitantly with GnRH analogs since hyperprolactinemia downregulates the number of pituitary GnRH receptors. Monitor the patient for the proper clinical response to GnRH therapy.
    Gefitinib: Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and metoclopramide are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; in vitro, metoclopramide is a CYP2D6 inhibitor. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with CYP2D6 inhibitors, in patients with poor CYP2D6 metabolism, the mean exposure to gefitinib was 2-fold higher when compared to extensive metabolizers; the contribution of drugs that inhibit CYP2D6 on gefitinib exposure has not been evaluated.
    Glipizide; Metformin: Because metoclopramide can enhance gastric emptying in diabetic patients, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents. The dosing of metformin may require adjustment in patients who receive metoclopramide concomitantly.
    Glyburide; Metformin: Because metoclopramide can enhance gastric emptying in diabetic patients, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents. The dosing of metformin may require adjustment in patients who receive metoclopramide concomitantly.
    Gonadotropin-Releasing Hormone Analogs: Drugs that cause hyperprolactinemia, such as metoclopramide, should generally not be administered concomitantly with GnRH analogs since hyperprolactinemia downregulates the number of pituitary GnRH receptors. Monitor the patient for the proper clinical response to GnRH therapy.
    Goserelin: Drugs that cause hyperprolactinemia, such as metoclopramide, should generally not be administered concomitantly with GnRH analogs since hyperprolactinemia downregulates the number of pituitary GnRH receptors. Monitor the patient for the proper clinical response to GnRH therapy.
    Haloperidol: Metoclopramide is a central dopamine antagonist and may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, tardive dyskinesia), and rarely, neuroleptic malignant syndrome. Metoclopramide is contraindicated with other drugs that are likely to cause extrapyramidal effects since the risk of these effects may be increased. Antipsychotics are associated with a well-established risk of extrapyramidal effects. High potency agents (e.g., haloperidol) generally cause acute extrapyramidal symptoms more commonly than low potency agents or atypical antipsychotics. Additionally, because both antipsychotics and metoclopramide can cause sedation, seizures, or increased prolactin levels, it is possible that the risk of these effects may be increased during concurrent use.
    Histrelin: Drugs that cause hyperprolactinemia, such as metoclopramide, should generally not be administered concomitantly with GnRH analogs since hyperprolactinemia downregulates the number of pituitary GnRH receptors. Monitor the patient for the proper clinical response to GnRH therapy.
    Hydralazine; Hydrochlorothiazide, HCTZ: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Hydrochlorothiazide, HCTZ: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Hydrochlorothiazide, HCTZ; Irbesartan: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Hydrochlorothiazide, HCTZ; Lisinopril: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Hydrochlorothiazide, HCTZ; Losartan: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Hydrochlorothiazide, HCTZ; Methyldopa: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Hydrochlorothiazide, HCTZ; Metoprolol: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Hydrochlorothiazide, HCTZ; Moexipril: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Hydrochlorothiazide, HCTZ; Olmesartan: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Hydrochlorothiazide, HCTZ; Propranolol: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Hydrochlorothiazide, HCTZ; Quinapril: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Hydrochlorothiazide, HCTZ; Spironolactone: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Hydrochlorothiazide, HCTZ; Telmisartan: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Hydrochlorothiazide, HCTZ; Triamterene: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Hydrochlorothiazide, HCTZ; Valsartan: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Iloperidone: Concomitant use of metoclopramide and antipsychotics is contraindicated by the manufacturer of metoclopramide as the risk of extrapyramidal effects may be increased. Both metoclopramide and antipsychotics antagonize dopamine receptors, which can increase the risk of extrapyramidal effects, including tardive dyskinesia or other dystonic reactions. Additionally, because both antipsychotics and metoclopramide can cause sedation, seizures, or increased prolactin levels, it is possible that the risk of these effects may be increased during concurrent use.
    Incretin Mimetics: Metoclopramide can enhance gastric emptying in patients with diabetes. Typically, blood glucose could be affected, which, in turn, may affect the clinical response to antidiabetic agents. However, incretin mimetics have been shown to slow gastric emptying. The clinical effects of these competing mechanisms are not known. The dosing of antidiabetic agents may require adjustment in patients who receive metoclopramide. Blood glucose should be closely monitored and antidiabetic agents adjusted accordingly in this situation.
    Insulins: Because metoclopramide can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents, including insulin. The dosing of insulin may require adjustment in patients who receive metoclopramide concomitantly.
    Ipecac: Ipecac has been shown to be effective in producing emesis in patients who have ingested antiemetics, provided ipecac is given promptly (usually within 1 hour of antiemetic consumption). If ipecac is administered after antiemetic therapy has begun to exert therapeutic effects, ipecac may be less effective. It is suggested the irritating GI effects of ipecac lead to emesis following antiemetic consumption.
    Isocarboxazid: Because metoclopramide causes release of catecholamines in patients with essential hypertension, it should be administered cautiously to patients receiving MAOIs.
    Leuprolide: Drugs that cause hyperprolactinemia, such as metoclopramide, should generally not be administered concomitantly with GnRH analogs since hyperprolactinemia downregulates the number of pituitary GnRH receptors. Monitor the patient for the proper clinical response to GnRH therapy.
    Leuprolide; Norethindrone: Drugs that cause hyperprolactinemia, such as metoclopramide, should generally not be administered concomitantly with GnRH analogs since hyperprolactinemia downregulates the number of pituitary GnRH receptors. Monitor the patient for the proper clinical response to GnRH therapy.
    Levodopa: Metoclopramide is a central dopamine antagonist. Metoclopramide can antagonize the actions of dopamine agonists such as levodopa. In addition, metoclopramide may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, tardive dyskinesia), and rarely, neuroleptic malignant syndrome. Dyskinesias and other extrapyramidal effects have been reported during treatment with various anti-parkinson's medications, particularly levodopa. A symptom complex resembling neuroleptic malignant syndrome in association with rapid dose reduction, withdrawal of, or changes in anti-parkinsonian therapy has also been observed. The manufacturer of metoclopramide does not specifically contraindicate the use of metoclopramide and dopamine agonists; however, coadministration should be avoided if possible.
    Linagliptin: Because metoclopramide can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents, including linagliptin. The dosing of antidiabetic agents may require adjustment in patients who receive metoclopramide concomitantly.
    Linagliptin; Metformin: Because metoclopramide can enhance gastric emptying in diabetic patients, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents. The dosing of metformin may require adjustment in patients who receive metoclopramide concomitantly. Because metoclopramide can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents, including linagliptin. The dosing of antidiabetic agents may require adjustment in patients who receive metoclopramide concomitantly.
    Linezolid: Because metoclopramide causes release of catecholamines in patients with essential hypertension, it should be administered cautiously to patients receiving MAOIs or drugs that possess MAOI-like activity, such as linezolid.
    Lithium: The absorption of lithium is affected by changes in gastrointestinal transit time. Due to accelerated gastric emptying induced by metoclopramide, the absorption of some drugs within the small bowel may be increased. Narrow therapeutic ratio drugs or drugs that need to be carefully titrated need to be followed closely when used with prokinetic agents. Serum concentration assessment of the possibly affected drug is recommended before and after concurrent prokinetic agent use.
    Loperamide: Pharmacodynamic interactions between loperamide and drugs that enhance peristalsis are theoretically possible. It is wise to avoid use loperamide in patients who metoclopramide.
    Loperamide; Simethicone: Pharmacodynamic interactions between loperamide and drugs that enhance peristalsis are theoretically possible. It is wise to avoid use loperamide in patients who metoclopramide.
    Lopinavir; Ritonavir: Concurrent administration of metoclopramide with ritonavir may result in elevated plasma concentrations of metoclopramide. Metoclopromide is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Loxapine: Concomitant use of metoclopramide and antipsychotics is contraindicated by the manufacturer of metoclopramide as the risk of extrapyramidal effects may be increased. Both metoclopramide and antipsychotics antagonize dopamine receptors, which can increase the risk of extrapyramidal effects, including tardive dyskinesia or other dystonic reactions.
    Lurasidone: Concomitant use of metoclopramide and antipsychotics is contraindicated by the manufacturer of metoclopramide as the risk of extrapyramidal effects may be increased. Both metoclopramide and antipsychotics antagonize dopamine receptors, which can increase the risk of extrapyramidal effects, including tardive dyskinesia or other dystonic reactions. Additionally, because both antipsychotics and metoclopramide can cause sedation, seizures, or increased prolactin levels, it is possible that the risk of these effects may be increased during concurrent use.
    Meperidine; Promethazine: Metoclopramide is a central dopamine antagonist and may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, tardive dyskinesia), and rarely, neuroleptic malignant syndrome. Metoclopramide is contraindicated with other drugs that are likely to cause extrapyramidal effects since the risk of these effects may be increased. Phenothiazine antiemetics (i.e., promethazine, prochlorperazine, thiethylperazine) are also central dopamine antagonists and have been associated with extrapyramidal symptoms and rarely, neuroleptic malignant syndrome. In addition, because both phenothiazines and metoclopramide can cause sedation, seizures, or increased prolactin levels, it is possible that the risk of these effects may be increased during concurrent use. The manufacturer of metoclopramide does not specifically contraindicate the use of metoclopramide and phenothiazine antiemetics; however, coadministration should generally be avoided if possible.
    Meprobamate: Combined use of metoclopramide and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase possible sedation.
    Metformin: Because metoclopramide can enhance gastric emptying in diabetic patients, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents. The dosing of metformin may require adjustment in patients who receive metoclopramide concomitantly.
    Metformin; Pioglitazone: Because metoclopramide can enhance gastric emptying in diabetic patients, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents. The dosing of metformin may require adjustment in patients who receive metoclopramide concomitantly.
    Metformin; Repaglinide: Because metoclopramide can enhance gastric emptying in diabetic patients, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents. The dosing of metformin may require adjustment in patients who receive metoclopramide concomitantly. Because metoclopramide can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents, including repaglinide. The dosing of antidiabetic agents may require adjustment in patients who receive metoclopramide concomitantly.
    Metformin; Rosiglitazone: Because metoclopramide can enhance gastric emptying in diabetic patients, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents. The dosing of metformin may require adjustment in patients who receive metoclopramide concomitantly.
    Metformin; Saxagliptin: Because metoclopramide can enhance gastric emptying in diabetic patients, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents. The dosing of metformin may require adjustment in patients who receive metoclopramide concomitantly. Because metoclopramide can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents, including saxagliptin. The dosing of antidiabetic agents may require adjustment in patients who receive metoclopramide concomitantly.
    Metformin; Sitagliptin: Because metoclopramide can enhance gastric emptying in diabetic patients, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents. The dosing of metformin may require adjustment in patients who receive metoclopramide concomitantly. Because metoclopramide can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents, including sitagliptin. The dosing of antidiabetic agents may require adjustment in patients who receive metoclopramide concomitantly.
    Methyclothiazide: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Methylphenidate: Methylphenidate is an inhibitor of dopamine reuptake. Pharmacodynamic interactions may occur between methylphenidate and dopamine antagonists such as metoclopramide. Patients receiving methylphenidate in combination with metoclopramide should be monitored for a decrease in clinical effectiveness of either agent.
    Metolazone: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Metyrosine: Metoclopramide is a central dopamine antagonist and may cause extrapyramidal reactions such as acute dystonic reactions, pseudo-parkinsonism, akathisia, or tardive dyskinesia. Metyrosine decreases the endogenous production of catecholamines. Metyrosine precipitates extrapyramidal symptoms in approximately 10% of patients receiving the drug. The manufacturer of metoclopramide does not specifically contraindicate the use of metoclopramide and metyrosine; however, coadministration should be avoided if possible.
    Mirabegron: Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as metoclopramide may be increased when co-administered with mirabegron. Metoclopramide has been shown to be a CYP2D6 substrate in vitro. Appropriate monitoring and dose adjustment may be necessary.
    Molindone: Concomitant use of metoclopramide and antipsychotics is contraindicated by the manufacturer of metoclopramide as the risk of extrapyramidal effects may be increased. Both metoclopramide and antipsychotics antagonize dopamine receptors, which can increase the risk of tardive dyskinesia or other extrapyramidal effects.
    Nafarelin: Drugs that cause hyperprolactinemia, such as metoclopramide, should generally not be administered concomitantly with GnRH analogs since hyperprolactinemia downregulates the number of pituitary GnRH receptors. Monitor the patient for the proper clinical response to GnRH therapy.
    Nateglinide: Because metoclopramide can enhance gastric emptying in diabetic patients, blood glucose levels can be affected by changes in the intestinal transit of food, which, in turn, may affect the dosing of antidiabetic agents, including nateglinide. The dosing of antidiabetic agents may require adjustment in patients who receive metoclopramide concomitantly.
    Nebivolol: Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with metoclopramide. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as metoclopramide, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Nebivolol; Valsartan: Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with metoclopramide. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as metoclopramide, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Olanzapine: Concomitant use of metoclopramide and antipsychotics is contraindicated by the manufacturer of metoclopramide as the risk of extrapyramidal effects may be increased. Both metoclopramide and antipsychotics antagonize dopamine receptors, which can increase the risk of extrapyramidal effects, including tardive dyskinesia or other dystonic reactions. Additionally, because both antipsychotics and metoclopramide can cause sedation, seizures, or increased prolactin levels, it is possible that the risk of these effects may be increased during concurrent use.
    Ombitasvir; Paritaprevir; Ritonavir: Concurrent administration of metoclopramide with ritonavir may result in elevated plasma concentrations of metoclopramide. Metoclopromide is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Opiate Agonists: Opiate agonists antagonize GI motility and can decrease the GI motility enhancing effects of metoclopramide. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as metoclopramide, may result in a reduction in the analgesic effect of hydrocodone.
    Oritavancin: Metoclopramide is metabolized by CYP2D6; oritavancin is a weak CYP2D6 inducer. Plasma concentrations and efficacy of metoclopramide may be reduced if these drugs are administered concurrently.
    Paliperidone: Concomitant use of metoclopramide and antipsychotics is contraindicated by the manufacturer of metoclopramide as the risk of extrapyramidal effects may be increased. Both metoclopramide and antipsychotics antagonize dopamine receptors, which can increase the risk of extrapyramidal effects, including tardive dyskinesia or other dystonic reactions. Additionally, because both antipsychotics and metoclopramide can cause sedation, seizures, or increased prolactin levels, it is possible that the risk of these effects may be increased during concurrent use.
    Peginterferon Alfa-2b: Monitor for adverse effects associated with increased exposure to metoclopramide if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP2D6 inhibitor, while metoclopramide is a CYP2D6 substrate.
    Pergolide: Agents with dopamine antagonist properties, like metoclopramide, may decrease the effectiveness of dopamine agonists. These agents can cause abrupt and severe worsening of Parkinson's disease symptoms. Metoclopramide should be avoided, if possible, in patients treated with dopamine agonists for Parkinson's disease.
    Phenelzine: Because metoclopramide causes release of catecholamines in patients with essential hypertension, it should be administered cautiously to patients receiving MAOIs.
    Phenothiazines: Metoclopramide is a central dopamine antagonist and may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, tardive dyskinesia), and rarely, neuroleptic malignant syndrome. Metoclopramide is contraindicated with other drugs that are likely to cause extrapyramidal effects since the risk of these effects may be increased. Phenothiazine antiemetics are also central dopamine antagonists and have been associated with extrapyramidal symptoms and rarely, neuroleptic malignant syndrome. In addition, because both phenothiazines and metoclopramide can cause sedation, seizures, or increased prolactin levels, it is possible that the risk of these effects may be increased during concurrent use. The manufacturer of metoclopramide does not specifically contraindicate the use of metoclopramide and phenothiazine antiemetics; however, coadministration should generally be avoided if possible.
    Phenylephrine; Promethazine: Metoclopramide is a central dopamine antagonist and may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, tardive dyskinesia), and rarely, neuroleptic malignant syndrome. Metoclopramide is contraindicated with other drugs that are likely to cause extrapyramidal effects since the risk of these effects may be increased. Phenothiazine antiemetics (i.e., promethazine, prochlorperazine, thiethylperazine) are also central dopamine antagonists and have been associated with extrapyramidal symptoms and rarely, neuroleptic malignant syndrome. In addition, because both phenothiazines and metoclopramide can cause sedation, seizures, or increased prolactin levels, it is possible that the risk of these effects may be increased during concurrent use. The manufacturer of metoclopramide does not specifically contraindicate the use of metoclopramide and phenothiazine antiemetics; however, coadministration should generally be avoided if possible.
    Pimavanserin: Concomitant use of metoclopramide and antipsychotics is contraindicated by the manufacturer of metoclopramide as the risk of extrapyramidal effects may be increased. Both metoclopramide and antipsychotics antagonize dopamine receptors, which can increase the risk of extrapyramidal effects, including tardive dyskinesia or other dystonic reactions. Additionally, because both antipsychotics and metoclopramide can cause sedation, seizures, or increased prolactin levels, it is possible that the risk of these effects may be increased during concurrent use.
    Pimozide: Metoclopramide is a central dopamine antagonist and may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, tardive dyskinesia), and rarely, neuroleptic malignant syndrome. Metoclopramide is contraindicated with other drugs that are likely to cause extrapyramidal effects since the risk of these effects may be increased. Antipsychotics are associated with a well-established risk of extrapyramidal effects. High potency agents (e.g., pimozide) generally cause acute extrapyramidal symptoms more commonly than low potency agents or atypical antipsychotics. Additionally, because both antipsychotics and metoclopramide can cause sedation, seizures, or increased prolactin levels, it is possible that the risk of these effects may be increased during concurrent use.
    Posaconazole: The concomitant use of metoclopramide with posaconazole oral suspension should be avoided unless the benefits outweigh the risks of decreased posaconazole efficacy. If used in combination, closely monitor for breakthrough fungal infections. Metoclopramide increases gastric motility resulting in decreased posaconazole absorption and lower posaconazole plasma concentrations. When a single 400 mg dose of posaconazole oral suspension was administered with metoclopramide (10 mg PO three times daily for 2 days), the mean reductions in Cmax were 21% and the mean reductions in AUC were 19% for posaconazole. The pharmacokinetics of posaconazole delayed-release tablets are not significantly affected by metoclopramide.
    Pramipexole: Agents with dopamine antagonist properties, like metoclopramide, may decrease the effectiveness of dopamine agonists. These agents can cause abrupt and severe worsening of Parkinson's disease symptoms. Metoclopramide should be avoided, if possible, in patients treated with dopamine agonists for Parkinson's disease.
    Pramlintide: Drugs that stimulate GI motility could antagonize the effects of pramlintide. Furthermore, the effects of pramlintide on patients with gastroparesis or those requiring drugs used to stimulate GI motility have not been studied. Until more information is available, patients using metoclopramide should not be considered for pramlintide therapy.
    Promethazine: Metoclopramide is a central dopamine antagonist and may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, tardive dyskinesia), and rarely, neuroleptic malignant syndrome. Metoclopramide is contraindicated with other drugs that are likely to cause extrapyramidal effects since the risk of these effects may be increased. Phenothiazine antiemetics (i.e., promethazine, prochlorperazine, thiethylperazine) are also central dopamine antagonists and have been associated with extrapyramidal symptoms and rarely, neuroleptic malignant syndrome. In addition, because both phenothiazines and metoclopramide can cause sedation, seizures, or increased prolactin levels, it is possible that the risk of these effects may be increased during concurrent use. The manufacturer of metoclopramide does not specifically contraindicate the use of metoclopramide and phenothiazine antiemetics; however, coadministration should generally be avoided if possible.
    Quetiapine: Concomitant use of metoclopramide and antipsychotics is contraindicated by the manufacturer of metoclopramide as the risk of extrapyramidal effects may be increased. Both metoclopramide and antipsychotics antagonize dopamine receptors, which can increase the risk of extrapyramidal effects, including tardive dyskinesia or other dystonic reactions. Additionally, because both antipsychotics and metoclopramide can cause sedation, seizures, or increased prolactin levels, it is possible that the risk of these effects may be increased during concurrent use.
    Ramelteon: Combined use of metoclopramide and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase possible sedation.
    Ranolazine: Ranolazine is metabolized mainly by CYP3A and to a lesser extent by CYP2D6. Metoclopramide is a known CYP2D6 inhibitor; coadministration with ranolazine may result in increased plasma concentrations of ranolazine. The manufacturer specifies that no dosage adjustment of ranolazine is necessary when coadministering CYP2D6 inhibitors. Until further data are available, it is prudent to cautiously monitor the concurrent use of ranolazine and significant CYP2D6 inhibitors since potential increases in plasma concentrations of ranolazine may result in adverse effects.
    Rasagiline: Close monitoring is advisable if combination therapy is necessary. The risk of extrapyramidal effects may be increased during concurrent use of metoclopramide and rasagiline, and the therapeutic benefits of rasagiline in treating Parkinson's disease may be diminished during use of a central dopamine antagonist such as metoclopramide. In addition, because metoclopramide causes release of catecholamines in patients with essential hypertension, it should be administered cautiously to patients receiving MAOIs. Rasagiline is a selective MAO-B inhibitor at manufacturer recommended doses; therefore, serious interactions with medications affecting catecholamine release are theoretically less likely.
    Repaglinide: Because metoclopramide can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents, including repaglinide. The dosing of antidiabetic agents may require adjustment in patients who receive metoclopramide concomitantly.
    Risperidone: Concomitant use of metoclopramide and antipsychotics is contraindicated by the manufacturer of metoclopramide as the risk of extrapyramidal effects may be increased. Both metoclopramide and antipsychotics antagonize dopamine receptors, which can increase the risk of extrapyramidal effects, including tardive dyskinesia or other dystonic reactions. Additionally, because both antipsychotics and metoclopramide can cause sedation, seizures, or increased prolactin levels, it is possible that the risk of these effects may be increased during concurrent use.
    Ritonavir: Concurrent administration of metoclopramide with ritonavir may result in elevated plasma concentrations of metoclopramide. Metoclopromide is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Rivastigmine: Metoclopramide is a central dopamine antagonist and may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, or tardive dyskinesia), and rarely, neuroleptic malignant syndrome. Metoclopramide is contraindicated with other drugs that are likely to cause extrapyramidal effects since the risk of these effects may be increased. Cholinomimetics such as rivastigmine may cause or worsen extrapyramidal symptoms such as pseudoparkinsonism, dyskinesia, and dystonia, although the incidences of these effects during clinical trials with rivastigmine were infrequent. The risk of extrapyramidal effects may be increased during concurrent use of metoclopramide and rivastigmine; close monitoring is advisable if combination therapy is necessary.
    Rolapitant: Use caution if metoclopramide and rolapitant are used concurrently, and monitor for metoclopramide-related adverse effects. Metoclopramide is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant lasts for at least 7 days, and may last longer after single dose administration. The Cmax and AUC of another CYP2D6 substrate, dextromethorphan, were increased by 120% and 160%, respectively, on day 1 with rolapitant, and by 180% and 230%, respectively, on day 8 after rolapitant administration.
    Ropinirole: Agents with dopamine antagonist properties, like metoclopramide, may decrease the effectiveness of dopamine agonists. These agents can cause abrupt and severe worsening of Parkinson's disease symptoms. Metoclopramide should be avoided, if possible, in patients treated with dopamine agonists for Parkinson's disease.
    Rotigotine: The concurrent use of rotigotine, a dopamine agonist, and antiemetic agents with dopamine antagonist properties may decrease the effectiveness of either agent. Abrupt and severe worsening of Parkinson's disease symptoms can occur. In addition, sedation caused by the individual agents can be potentiated with combined use. Metoclopramide should be avoided if possible in patients treated with rotigotine.
    Saxagliptin: Because metoclopramide can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents, including saxagliptin. The dosing of antidiabetic agents may require adjustment in patients who receive metoclopramide concomitantly.
    Sedating H1-blockers: Combined use of metoclopramide and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase possible sedation.
    Selective serotonin reuptake inhibitors: A few published case reports have documented possible interactions between metoclopramide and SSRIs that have resulted in either serotonin syndrome-type events and/or movement disorders (e.g., dystonia). The mechanism of the interactions is unknown but is thought to be a pharmacodynamic interaction; the interactions do not appear common. In most of the cases reported, a single drug effect was not ruled out; however, the time course of the events are enough to raise suspicion that a drug interaction might be possible. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving sertraline and metoclopramide should be monitored for the emergence of serotonin syndrome or other adverse effects.
    Selegiline: Close monitoring is advisable if combination therapy is necessary. Metoclopramide is a central dopamine antagonist and may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, or tardive dyskinesia), and rarely, neuroleptic malignant syndrome. The risk of extrapyramidal effects may be increased during concurrent use of metoclopramide and selegiline, and the therapeutic benefits of selegiline in treating Parkinson's disease may be diminished during use of a central dopamine antagonist such as metoclopramide. In addition, because metoclopramide causes release of catecholamines in patients with essential hypertension, it should be administered cautiously to patients receiving MAOIs.
    Serotonin norepinephrine reuptake inhibitors: Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that are dopamine antagonists such as metoclopramide. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, metoclopramide may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, or tardive dyskinesia) and is contraindicated with other drugs that are likely to cause extrapyramidal effects. Dystonia, akathisia, trismus, torticollis, dyskinesia, tardive dyskinesia, pseudo-parkinsonism, and/or extrapyramidal disorder (unspecified) have been reported during use of SNRIs; however, these effects appear uncommon. Patients receiving concurrent treatment with dopamine antagonists may be more predisposed to these reactions. Case reports documenting an interaction between metoclopramide and other serotonergic agents (i.e., SSRIs) suggest that serotonin syndrome and/or movement disorders are possible during combined use of metoclopramide and SNRIs. Patients receiving SNRIs and metoclopramide should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
    Sibutramine: Sibutramine is a serotonin reuptake inhibitor. Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering sibutramine with drugs that are dopamine antagonists such as metoclopramide. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Simvastatin; Sitagliptin: Because metoclopramide can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents, including sitagliptin. The dosing of antidiabetic agents may require adjustment in patients who receive metoclopramide concomitantly.
    Sirolimus: Increased sirolimus whole blood concentrations may be observed if gastrointestinal prokinetic agents like metoclopramide are added to therapy. Monitor sirolimus serum concentrations carefully if a GI prokinetic agent is used concomitantly.
    Sitagliptin: Because metoclopramide can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents, including sitagliptin. The dosing of antidiabetic agents may require adjustment in patients who receive metoclopramide concomitantly.
    Solifenacin: Solifenacin has antimuscarinic activity and may slow GI motility.in some patients and thus may potentially reduce the actions of drugs that enhance gastrointestinal motility, like metoclopramide. Monitor patients for an increase in gastrointestinal complaints, such as reflux or constipation. Additive drowsiness may occur rarely. The clinical significance of this potential interaction is uncertain.
    Succinylcholine: Metoclopramide has been implicated in prolonging neuromuscular blockade from succinylcholine. Patients receiving metoclopramide and succinylcholine should be monitored for this effect. Succinylcholine doses may need to be reduced.
    Sulfonylureas: Because metoclopramide can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents. The dosing of antidiabetic agents may require adjustment in patients who receive metoclopramide concomitantly.
    Tacrine: Metoclopramide is a central dopamine antagonist and may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, or tardive dyskinesia), and rarely, neuroleptic malignant syndrome. Metoclopramide is contraindicated with other drugs that are likely to cause extrapyramidal effects since the risk of these effects may be increased. Cholinomimetics such as tacrine may cause or worsen extrapyramidal symptoms such as pseudoparkinsonism, dyskinesia, and dystonia. During clinical trials, unspecified movement disorders and extrapyramidal syndrome were reported infrequently, and dystonia, tardive dyskinesia, akathisia, and facial dyskinesia occurred rarely. The risk of extrapyramidal effects may be increased during concurrent use of metoclopramide and tacrine; close monitoring is advisable if combination therapy is necessary.
    Tacrolimus: Increased tacrolimus whole blood concentrations may be observed if a GI prokinetic agent like metoclopramide is added to therapy. Monitor tacrolimus serum concentrations carefully if a GI prokinetic agent is used concomitantly.
    Tamoxifen: Tamoxifen, a selective estrogen receptor modulator (SERM), is converted to endoxifen and other active metabolites by cytochrome P450 (CYP) enzymes (e.g., 2D6, 3A4). Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors. Metoclopramide is an inhibitor of CYP2D6. A trial of 1,298 patients with breast cancer compared the rate of breast cancer recurrence in patients treated with tamoxifen with or without a CYP2D6 inhibitor. Patients who received tamoxifen in combination with a CYP2D6 inhibitor had a significantly higher rate of breast cancer recurrence at 2 years (13.9% v. 7.5%, p < 0.001). A separate observational study of 1,990 patients assessed event free time with adjuvant tamoxifen treatment for breast cancer. Only 215 of these patients were administered a CYP2D6 inhibitor, however no clinically significant differences were observed with the addition of a CYP2D6 inhibitor. Consider avoiding concomitant use of CYP2D6 inhibitors and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen.
    Tedizolid: Because metoclopramide causes release of catecholamines in patients with essential hypertension, it should be administered cautiously to patients receiving MAOIs or drugs that possess MAOI-like activity, such as tedizolid, a weak reversible, non-selective inhibitor of MAO.
    Teniposide: Acute central nervous system (CNS) depression, hypotension, and metabolic acidosis have been observed in patients receiving investigational infusions of high-dose teniposide who were pretreated with antiemetics with CNS-depressant activities (e.g., phenothiazine and related antiemetics). The depressant effects of the antiemetic agents and the alcohol content of the teniposide formulation may place patients receiving higher than recommended doses of teniposide at risk for central nervous system depression.
    Tetrabenazine: Metoclopramide is a central dopamine antagonist and may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, or tardive dyskinesia), and rarely, neuroleptic malignant syndrome. Metoclopramide is contraindicated with other drugs that are likely to cause extrapyramidal effects since the risk of these effects may be increased. Tetrabenazine is a centrally-acting dopamine depleting drug. Pseudoparkinsonism (6 to12%) and akathisia (9%) were among the most frequently reported side effects during clinical trials with tetrabenazine. Neuroleptic malignant syndrome and acute dystonic reactions have also been noted rarely. The manufacturer of metoclopramide does not specifically contraindicate the use of metoclopramide and tetrabenazine; however, concurrent use should be avoided if possible.
    Tetracycline: Metoclopramide can increase the rate or extent of absorption of tetracycline because of accelerated gastric emptying, which increases the contact time with the small bowel where this drug is absorbed.
    Thiazide diuretics: Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Thiazolidinediones: Because metoclopramide can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents. The dosing of antidiabetic agents may require adjustment in patients who receive metoclopramide concomitantly.
    Thiothixene: Concomitant use of metoclopramide and antipsychotics is contraindicated by the manufacturer of metoclopramide as the risk of extrapyramidal effects may be increased. Both metoclopramide and antipsychotics antagonize dopamine receptors, which can increase the risk of extrapyramidal effects, including tardive dyskinesia or other dystonic reactions.
    Tolcapone: Metoclopramide is a central dopamine antagonist. It should be noted that the therapeutic response to COMT inhibitors (entacapone and tolcapone) may be diminished during use of a centrally acting dopamine antagonist. In addition, metoclopramide may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, tardive dyskinesia), and rarely, neuroleptic malignant syndrome. Metoclopramide is contraindicated with other drugs that are likely to cause extrapyramidal effects since the risk of these effects may be increased. Dyskinesias and other extrapyramidal effects have been reported during treatment with various anti-parkinson's medications, particularly levodopa. A symptom complex resembling neuroleptic malignant syndrome in association with rapid dose reduction, withdrawal of, or changes in anti-parkinsonian therapy has also been observed. The manufacturer of metoclopramide does not specifically contraindicate the use of metoclopramide and dopamine agonists; however, coadministration should be avoided if possible.
    Tolterodine: Tolterodine has antimuscarinic activity and may slow GI motility.in some patients and thus may potentially reduce the actions of drugs that enhance gastrointestinal motility, like metoclopramide. Monitor patients for an increase in gastrointestinal complaints, such as reflux or constipation. Additive drowsiness may occur rarely. The clinical significance of this potential interaction is uncertain.
    Tranylcypromine: Because metoclopramide causes release of catecholamines in patients with essential hypertension, it should be administered cautiously to patients receiving MAOIs.
    Tricyclic antidepressants: Metoclopramide is a central dopamine antagonist and may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, or tardive dyskinesia), and rarely, neuroleptic malignant syndrome. Metoclopramide is contraindicated with other drugs that are likely to cause extrapyramidal effects since the risk of these effects may be increased. Case reports and case series have implicated tricyclic antidepressants in causing a variety of extrapyramidal symptoms (EPS). Although the occurrence is infrequent compared to antipsychotic-induced EPS, the risk of these events may be increased during concurrent use of metoclopramide and tricyclic antidepressants compared to monotherapy with either agent.
    Triptorelin: Drugs that cause hyperprolactinemia, such as metoclopramide, should generally not be administered concomitantly with GnRH analogs since hyperprolactinemia downregulates the number of pituitary GnRH receptors. Monitor the patient for the proper clinical response to GnRH therapy.
    Trospium: Trospium has antimuscarinic activity and may slow GI motility.in some patients and thus may potentially reduce the actions of drugs that enhance gastrointestinal motility, like metoclopramide. Monitor patients for an increase in gastrointestinal complaints, such as reflux or constipation. Additive drowsiness may occur rarely. The clinical significance of this potential interaction is uncertain.
    Vemurafenib: Concomitant use of vemurafenib and metoclopramide may result in increased metoclopramide concentrations. Metoclopramide is metabolized by CYP2D6 and vemurafenib is a weak CYP2D6 inhibitor. Monitor patients for toxicity.
    Vilazodone: Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering vilazodone with drugs that are dopamine antagonists such as metoclopramide. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, metoclopramide may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, or tardive dyskinesia) and is contraindicated with other drugs that are likely to cause extrapyramidal effects. Agents similar to vilazodone appear to be moderately associated with extrapyramidal effects compared to other antidepressants although the frequency appears to be low overall. Patients receiving concurrent treatment with dopamine antagonists may be more predisposed to these reactions. Patients receiving vilazodone and metoclopramide should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
    Zalcitabine, ddC: The coadministration of zalcitabine, ddC and metoclopramide appears to result in a slight reduction in zalcitabine bioavailability, by approximately 10%. This is not expected to be a clinically significant interaction and no changes in dosage are suggested.
    Zaleplon: Combined use of metoclopramide and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase possible sedation.
    Ziprasidone: Concomitant use of metoclopramide and antipsychotics is contraindicated by the manufacturer of metoclopramide as the risk of extrapyramidal effects may be increased. Both metoclopramide and antipsychotics antagonize dopamine receptors, which can increase the risk of extrapyramidal effects, including tardive dyskinesia or other dystonic reactions. Additionally, because both antipsychotics and metoclopramide can cause sedation, seizures, or increased prolactin levels, it is possible that the risk of these effects may be increased during concurrent use.
    Zolpidem: Combined use of metoclopramide and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase possible sedation.

    PREGNANCY AND LACTATION

    Pregnancy

    Metoclopramide is classified in FDA pregnancy category B. Currently available animal and human data do not support an association between the use of metoclopramide in pregnancy and congenital defects. The American College of Obstetricians and Gynecologists clinical practice guideline on the treatment of nausea and vomiting in pregnancy recommends metoclopramide as an option after other pharmacological therapies (e.g., vitamin B6, doxylamine, promethazine, dimenhydrinate) have failed. A retrospective cohort study compared infants exposed to metoclopramide through maternal use during the first trimester (n = 3458) to infants who were not exposed to metoclopramide (n = 78,245) and found no significant differences in major congenital malformations, birth weight, preterm delivery, or perinatal death. Metoclopramide has been used off-label as an adjunct, based on risk-benefit ratios, for the treatment of hyperemesis gravidarum. Placental transfer of metoclopramide in most stages of pregnancy is unknown; however, IV doses given just prior to caesarean section during labor have noted placental transfer at term, with umbilical venous to maternal plasma concentration ratios of approximately 0.6. Doses given during labor do not appear to have effects on fetal prolactin secretion or other hormones. No controlled human gestation studies are available; so this drug should be used during pregnancy only if necessary. In addition, chronic use (e.g., > 12 weeks) should be avoided due to the increased risk for the development of movement disorders such as tardive dyskinesia (see tardive diskinesia Precaution).

    Metoclopramide is distributed into breast milk. The American Academy of Pediatrics continues to recommend caution during the use of metoclopramide in breast-feeding secondary to the potential for CNS effects from the use of the drug. Based on clinical use, maternal doses up to 10 mg orally three times per day, which translates to roughly a 1—45 mcg/kg/day ingestion in the infant, do not appear to pose a significant risk to the breast-feeding infant. The estimated ingestions are much lower than the oral dosages an infant would receive in therapeutic administration (i.e., 100 to 800 mcg/kg/day). Metoclopramide has been used off-label to stimulate the release of prolactin from the anterior pituitary, thus increasing lactation in women with inadequate or decreased milk production in dosages of 20—45 mg/day orally. Two studies, one in mothers of premature infants and one in mothers who experienced complete or partial lactation failure, showed no significant difference in breast milk volume, duration of breast-feeding, weight gain, or reduction in the amount of supplemental milk in infants whose mothers were treated with metoclopramide versus those who were not. Both studies employed education regarding optimal breast-feeding for all of the mothers. The Academy of Breast-feeding Medicine does not recommend any specific pharmacologic galactagogue based on inconclusive evidence of their efficacy and the risk of side effects in both mothers and their infants. In summary, dosages below 45 mg/day in the lactating woman are probably not harmful to the infant, but the drug should be used only when the benefit to the mother outweighs the potential risk to the infant.

    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. Metoclopramide appears to undergo minimal metabolism but is conjugated with sulfuric acid or glucuronic acid. It is unknown if the major metabolite 2-[(4-amino-5-chloro-2-methoxybenzoyl)amino]acetic acid has any activity. 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 and inhibitor of the cytochrome (CYP) P450 isoenzyme 2D6.

    Oral Route

    Metoclopramide is rapidly and well absorbed; oral bioavailability is approximately 80% +/- 15.5% relative to intravenous dosing. Onset of action is 30—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.

    Other Route(s)

    Intranasal Route
    An intranasal dosage form is under investigation, and metoclopramide is well absorbed by this route.