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Special Alerts
Metoclopramide: Tardive Dyskinesia with Chronic Treatment - February 2009
The U.S. Food and Drug Administration (FDA) is notifying healthcare professionals of the requirement for manufacturers to add a boxed warning to the metoclopramide prescribing information related to a link between chronic use and the development of tardive dyskinesia (involuntary and repetitive movements of the body). Current labeling warns of the risk, but the warning will now become a boxed warning. This labeling change was prompted by study data analysis and continued spontaneous reports of tardive dyskinesia to the FDA. The majority of reports are associated with higher doses, long-term use (>3 months), and use in the elderly (particularly older women). Metoclopramide-induced tardive dyskinesia symptoms include impaired movement of the fingers, lip smacking, rapid eye movements or blinking, and tongue protrusion. These symptoms are rarely reversible following discontinuation of metoclopramide and treatment is not available at this time. The FDA is also requiring manufacturers to provide a medication guide to patients discussing the risk of tardive dyskinesia.
Additional information can be found at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm106942.htm
ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Medication Safety Issues
Sound-alike/look-alike issues:
Metoclopramide may be confused with metolazone, metoprolol, metroNIDAZOLE
Reglan® may be confused with Megace®, Regonol®, Renagel®
Pronunciation
(met oh KLOE pra mide)
U.S. Brand Names
Generic Available
Yes: Excludes oral-disintegrating tablet
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Oral: Symptomatic treatment of diabetic gastroparesis; gastroesophageal reflux
I.V., I.M.: Symptomatic treatment of diabetic gastroparesis; postpyloric placement of enteral feeding tubes; prevention and/or treatment of nausea and vomiting associated with chemotherapy, or postsurgery; to stimulate gastric emptying and intestinal transit of barium during radiological examination of the stomach/small intestine
Pregnancy Risk Factor
B
Pregnancy Considerations
Teratogenic effects were not observed in animal studies; however, there are no adequate and well-controlled studies in pregnant women. Crosses the placenta; available evidence suggests safe use during pregnancy.
Lactation
Enters breast milk/use caution
Breast-Feeding Considerations
Enters breast milk; may increase milk production
Contraindications
Hypersensitivity to metoclopramide or any component of the formulation; GI obstruction, perforation or hemorrhage; pheochromocytoma; history of seizures or concomitant use of other agents likely to increase extrapyramidal reactions
Warnings/Precautions
Boxed warnings:
• Tardive dyskinesia: See “Concerns related to adverse effects” below.
Concerns related to adverse effects:
• Depression: Mental depression has occurred, symptoms range from mild to severe (suicidal ideation and suicide); use with caution in patients with a history of mental illness.
• Extrapyramidal symptoms (EPS): May cause extrapyramidal symptoms, generally manifested as acute dystonic reactions within the initial 24-48 hours of use. Risk of these reactions is increased at higher doses, and in pediatric patients and adults <30 years of age. Pseudoparkinsonism (eg, bradykinesia, tremor, rigidity) may also occur (usually within first 6 months of therapy) and is generally reversible following discontinuation.
• Neuroleptic malignant syndrome (NMS): Use may be associated (rarely) with neuroleptic malignant syndrome (NMS); monitor for mental status changes, fever, muscle rigidity and/or autonomic instability; discontinue use if signs/symptoms appear.
• Tardive dyskinesia: [U.S. Boxed Warning]: May cause tardive dyskinesia, which is often irreversible; duration of treatment and total cumulative dose are associated with an increased risk. Therapy durations >12 weeks should be avoided (except in rare cases following risk:benefit assessment). Risk appears to be increased in the elderly, women, and diabetics; however, it is not possible to predict which patients will develop tardive dyskinesia. Therapy should be discontinued in any patient if signs/symptoms appear.
Disease-related concerns:
• Edematous conditions: Use with caution in patients who are at risk of fluid overload (HF, cirrhosis). May cause transient increase in serum aldosterone; use lowest recommended doses initially and discontinue use if signs/symptoms appear.
• Hypertension: Use with caution in patients with hypertension.
• NADH-cytochrome b5 reductase deficiency: Patients with NADH-cytochrome b5 reductase deficiency are at increased risk of methemoglobinemia and/or sulfhemoglobinemia.
• Parkinson's disease: Use with caution or avoid in patients with parkinson's disease; may have increased risk of EPS.
• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment may be needed.
• Surgical anastomosis/closure: Use with caution following surgical anastomosis/closure; promotility agents may theoretically increase pressure in suture lines.
Special populations:
• Elderly: Use with caution in the elderly; may have increased risk of tardive dyskinesia, particularly older women.
• Pediatrics: EPS are increased in pediatric patients. In neonates, prolonged clearance of metoclopramide may lead to increased serum concentrations. Neonates may also have decreased levels of NADH-cytochrome b5 reductase which increases the risk of methemoglobinemia.
Other warnings/precautions:
• Discontinuation of therapy: Abrupt discontinuation may (rarely) result in withdrawal symptoms (dizziness, headache, nervousness).
Adverse Reactions
Frequency not always defined.
Cardiovascular: AV block, bradycardia, HF, fluid retention, flushing (following high I.V. doses), hyper-/hypotension, supraventricular tachycardia
Central nervous system: Drowsiness (~10% to 70%; dose related), acute dystonic reactions (<1% to 25%; dose and age related), fatigue (2% to 10%), lassitude (~10%), restlessness (~10%), headache (4% to 5%), dizziness (1% to 4%), somnolence (2% to 3%), akathisia, confusion, depression, hallucinations (rare), insomnia, neuroleptic malignant syndrome (rare), Parkinsonian-like symptoms, suicidal ideation, seizure, tardive dyskinesia
Dermatologic: Angioneurotic edema (rare), rash, urticaria
Endocrine & metabolic: Amenorrhea, galactorrhea, gynecomastia, hyperprolactinemia, impotence
Gastrointestinal: Nausea (4% to 6%), vomiting (1% to 2%), diarrhea
Genitourinary: Incontinence, urinary frequency
Hematologic: Agranulocytosis, leukopenia, neutropenia, porphyria
Hepatic: Hepatotoxicity (rare)
Ocular: Visual disturbance
Respiratory: Bronchospasm, laryngeal edema (rare), laryngospasm (rare)
Miscellaneous: Allergic reactions, methemoglobinemia, sulfhemoglobinemia
Metabolism/Transport Effects
Substrate (minor) of CYP1A2, 2D6; Inhibits CYP2D6 (weak)
Drug Interactions
Anti-Parkinson's Agents (Dopamine Agonist): Metoclopramide may diminish the therapeutic effect of Anti-Parkinson's Agents (Dopamine Agonist). Risk C: Monitor therapy
CycloSPORINE: Metoclopramide may increase the absorption of CycloSPORINE. Risk C: Monitor therapy
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
Posaconazole: Metoclopramide may decrease the serum concentration of Posaconazole. Risk C: Monitor therapy
Sertraline: Metoclopramide may enhance the adverse/toxic effect of Sertraline. Specifically, the risk of serotonin syndrome may be increased. Risk C: Monitor therapy
Venlafaxine: Metoclopramide may enhance the adverse/toxic effect of Venlafaxine. Specifically, the risk of serotonin syndrome may be increased. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (may increase CNS depression).
Storage
Injection: Store intact vial at controlled room temperature; injection is photosensitive and should be protected from light during storage; parenteral admixtures in D5W or NS are stable for at least 24 hours and do not require light protection if used within 24 hours.
Tablet: Store at controlled room temperature of 20°C to 25°C (68°F to 77°F).
Compatibility
Stable in D51/2NS, D5W, mannitol 20%, LR, NS; variable stability (consult detailed reference) in TPN.
Y-site administration: Compatible: Acyclovir, aldesleukin, amifostine, aztreonam, bleomycin, caffeine citrate, ciprofloxacin, cisatracurium, cisplatin, cladribine, clarithromycin, cyclophosphamide, cytarabine, diltiazem, docetaxel, doxorubicin, droperidol, etoposide phosphate, famotidine, filgrastim, fluconazole, fludarabine, fluorouracil, foscarnet, gatifloxacin, gemcitabine, granisetron, heparin, hetastarch in lactated electrolyte injection, idarubicin, leucovorin, levofloxacin, linezolid, melphalan, meperidine, meropenem, methotrexate, mitomycin, morphine, ondansetron, paclitaxel, palonosetron, piperacillin/tazobactam, remifentanil, sargramostim, sufentanil, tacrolimus, teniposide, thiotepa, topotecan, vinblastine, vincristine, vinorelbine, zidovudine. Incompatible: Allopurinol, amphotericin B cholesteryl sulfate complex, amsacrine, cefepime, doxorubicin liposome, furosemide, pantoprazole, propofol. Variable (consult detailed reference): TPN.
Compatibility in syringe: Compatible: Aminophylline, ascorbic acid injection, atropine, benztropine, bleomycin, butorphanol, chlorpromazine, cisplatin, cyclophosphamide, cytarabine, dexamethasone sodium phosphate, diamorphine, dimenhydrinate, diphenhydramine, doxorubicin, droperidol, fentanyl, fluorouracil, heparin, hydrocortisone sodium phosphate, hydroxyzine, insulin (regular), leucovorin, lidocaine, magnesium sulfate, meperidine, methotrimeprazine, methylprednisolone sodium succinate, midazolam, mitomycin, morphine, ondansetron, pentazocine, perphenazine, prochlorperazine edisylate, promazine, promethazine, ranitidine, scopolamine, sufentanil, vinblastine, vincristine, vitamin B complex with C. Incompatible: Ampicillin, calcium gluconate, chloramphenicol, furosemide, penicillin G potassium, sodium bicarbonate. Variable (consult detailed reference): Methotrexate.
Compatibility when admixed: Compatible: Cimetidine, clindamycin, meperidine, meropenem, morphine, multivitamins, potassium acetate, potassium chloride, potassium phosphate, verapamil. Incompatible: Dexamethasone sodium phosphate with lorazepam and diphenhydramine, erythromycin lactobionate, floxacillin, fluorouracil, furosemide.
Mechanism of Action
Blocks dopamine receptors and (when given in higher doses) also blocks serotonin receptors in chemoreceptor trigger zone of the CNS; enhances the response to acetylcholine of tissue in upper GI tract causing enhanced motility and accelerated gastric emptying without stimulating gastric, biliary, or pancreatic secretions; increases lower esophageal sphincter tone
Pharmacodynamics/Kinetics
Onset of action: Oral: 30-60 minutes; I.V.: 1-3 minutes; I.M.: 10-15 minutes
Duration: Therapeutic: 1-2 hours, regardless of route
Absorption: Oral: Rapid
Distribution: Vd: ~3.5 L/kg
Protein binding: ~30%
Bioavailability: Oral: Range: 65% to 95%
Half-life elimination: Normal renal function: Children: ~4 hours; Adults: 5-6 hours (may be dose dependent)
Time to peak, serum: Oral: 1-2 hours
Excretion: Urine (~85%)
Dosage
Children:
Gastroesophageal reflux (unlabeled use): Oral: 0.1-0.2 mg/kg/dose 4 times/day
Antiemetic (chemotherapy-induced emesis) (unlabeled): I.V.: 1-2 mg/kg 30 minutes before chemotherapy and every 2-4 hours (maximum: 5 doses/day); pretreatment with diphenhydramine will decrease risk of extrapyramidal reactions to this dosage
Postpyloric feeding tube placement: I.V.:
<6 years: 0.1 mg/kg as a single dose
6-14 years: 2.5-5 mg as a single dose
>14 years: Refer to adult dosing.
Adults:
Gastroesophageal reflux: Oral: 10-15 mg/dose up to 4 times/day 30 minutes before meals or food and at bedtime; single doses of 20 mg are occasionally needed prior to provoking situations. Treatment >12 weeks is not recommended.
Diabetic gastroparesis:
Oral: 10 mg/dose up to 4 times/day 30 minutes before meals or food and at bedtime for 2-8 weeks
I.M., I.V. (for severe symptoms): 10 mg over 1-2 minutes; 10 days of I.V. therapy may be necessary before symptoms are controlled to allow transition to oral administration
Chemotherapy-induced emesis prophylaxis: I.V.: 1-2 mg/kg 30 minutes before chemotherapy and repeated every 2 hours for 2 doses, then every 3 hours for 3 doses (manufacturer labeling); pretreatment with diphenhydramine will decrease risk of extrapyramidal reactions
Alternate dosing: Note: Metoclopramide is considered an antiemetic with a low therapeutic index; use is generally reserved for agents with low emetogenic potential or in patients intolerant/refractory to first-line antiemetics.
Low-risk chemotherapy (unlabeled): I.V., Oral: 10-40 mg prior to dose, then every 4-6 hours as needed (NCCN Antiemesis guidelines, v.4.2009)
Breakthrough treatment (unlabeled): I.V., Oral: 10-40 mg every 4-6 hours (NCCN Antiemesis guidelines, v.4.2009)
Delayed-emesis prophylaxis (unlabeled): Oral: 20-40 mg/dose (or 0.5 mg/kg/dose) 2-4 times/day for 3-4 days (in combination with dexamethasone [ASCO guidelines, 2006])
Refractory or intolerant to antiemetics with a higher therapeutic index (unlabeled; Hesketh, 2008):
I.V.: 1-2 mg/kg/dose before chemotherapy and repeat 2 hours after chemotherapy
Oral: 0.5 mg/kg every 6 hours on days 2-4
Postoperative nausea and vomiting prophylaxis: I.M.: 10-20 mg near end of surgery
Postpyloric feeding tube placement, radiological exam: I.V.: 10 mg as a single dose
Elderly: Initial: Dose at the lower end of the recommended range. Refer to adult dosing.
Dosing adjustment in renal impairment: Clcr <40 mL/minute: Administer at 50% of normal dose
Hemodialysis: Not dialyzable (0% to 5%); supplemental dose is not necessary
Administration: Oral
Orally-disintegrating tablets: Administer on an empty stomach at least 30 minutes prior to food. Do not remove from packaging until time of administration. If tablet breaks or crumbles while handling, discard and remove new tablet. Using dry hands, place tablet on tongue and allow to dissolve. Swallow with saliva.
Administration: I.M.
May be administered I.M.
Administration: I.V.
Injection solution may be given I.M., direct I.V. push, short infusion (15-30 minutes), or continuous infusion; lower doses (?10 mg) of metoclopramide can be given I.V. push undiluted over 1-2 minutes; higher doses (>10 mg) to be diluted in 50 mL of compatible solution (preferably NS) and given IVPB over at least 15 minutes; continuous SubQ infusion and rectal administration have been reported. Note: Rapid I.V. administration may be associated with a transient (but intense) feeling of anxiety and restlessness, followed by drowsiness.
Administration: Other
Continuous SubQ infusion and rectal administration have been reported
Administration: I.V. Detail
pH: 3.0-6.5
Monitoring Parameters
Dystonic reactions; signs of hypoglycemia in patients using insulin and those being treated for gastroparesis; agitation, and confusion
Test Interactions
Increased aminotransferase [ALT/AST] (S), increased amylase (S)
Patient Education
Do not take any new medication during therapy unless approved by prescriber. Oral: Take this drug as prescribed, 30 minutes prior to eating. Do not increase dosage. Avoid alcohol; may increase adverse effects. May cause dizziness, drowsiness, or blurred vision (use caution when driving or engaging in tasks that require alertness until response to drug is known); cause restlessness, anxiety, depression, or insomnia (will reverse when medication is discontinued). Report any CNS changes, spasticity or involuntary movements, unresolved diarrhea, fluid retention (swelling of extremities, weight gain); visual disturbances; palpitations or rapid heart beat; or any other persistent adverse effects. Breast-feeding precaution: Breast-feeding is not recommended.
Geriatric Considerations
Elderly are more likely to develop tardive dyskinesia syndrome (especially elderly females) reactions than younger adults. Use lowest recommended doses initially. Must consider renal function (estimate creatinine clearance). It is recommended to do involuntary movement assessments on elderly using this medication at high doses and for long-term therapy.
Anesthesia and Critical Care Concerns/Other Considerations
Evidence-Based Information: The consensus guidelines for postoperative nausea and vomiting (Gan, 2003) does not recommend the use of metoclopramide.
Cardiovascular Considerations
Metoclopramide dose not cause QT prolongation.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation).
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
Drowsiness and restlessness are common; may cause insomnia or depression. Depression has occurred in patients with and without a prior history of depression. Symptoms have ranged from mild to severe, and have included suicidal ideation and suicide. Metoclopramide is a D2 blocker; may cause extrapyramidal symptoms especially when used in high dosages (dystonia) or in the elderly (tardive dyskinesia). Dystonic reactions occur in approximately 1 in 500 patients with the usual adult dosage of 30-40 mg/day. These reactions are usually seen during the first 1-2 days of therapy with metoclopramide, occurring more frequently in pediatric patients and adults <30 years of age, and are more frequent when higher doses are used in prophylaxis of vomiting due to cancer chemotherapy. NMS has rarely been reported.
Mental Health: Effects on Psychiatric Treatment
Anticholinergics may antagonize metoclopramide's effects; concurrent use with psychotropic may produce additive sedation
Nursing: Physical Assessment/Monitoring
Assess potential for interactions with other pharmacological agents patient may be taking (eg, any antipsychotic agents, opioids, anticholinergics). Vital signs should be monitored during intravenous administration. Inpatients should use safety measures (eg, side rails up, call light within reach) and caution patient to call for assistance with ambulation. Assess results of laboratory tests (periodic renal function tests), therapeutic effectiveness (relief of symptoms), and adverse reactions (eg, extrapyramidal effects, parkinsonian-like reactions, seizures, fluid retention, adverse CNS changes). Teach patient proper use, possible side effects/appropriate interventions, and adverse symptoms to report (eg, CNS restlessness, drowsiness, depression, rash).
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution [preservative free]: 5 mg/mL (2 mL)
Reglan®: 5 mg/mL (2 mL, 10 mL, 30 mL)
Solution, oral: 5 mg/5 mL (10 mL, 480 mL)
Tablet: 5 mg, 10 mg
Reglan®: 5 mg, 10 mg
Tablet, orally disintegrating:
Metozolv™ ODT: 5 mg, 10 mg [mint flavor]
Pricing: U.S. (www.drugstore.com)
Solution (Metoclopramide HCl)
5 mg/5 mL (240): $15.00
Tablets (Metoclopramide HCl)
5 mg (30): $12.99
10 mg (90): $15.99
Tablets (Reglan)
5 mg (30): $41.39
10 mg (30): $60.49
References
“American Academy of Pediatrics Committee on Drugs. The Transfer of Drugs and Other Chemicals Into Human Milk,” Pediatrics, 2001, 108(3):776-89.
Bruera E, Seifert L, Watanabe S, et al, "Chronic Nausea in Advanced Cancer Patients: A Retrospective Assessment of a Metoclopramide-Based Antiemetic Regimen," J Pain Symptom Manage, 1996, 11(3):147-53.
Desmond PV and Watson KJ, "Metoclopramide - A Review," Med J Aust, 1986, 144(7):366-9.
DiPalma JR, “Metoclopramide: A Dopamine Receptor Antagonist,” Am Fam Physician, 1990, 41(3):919-24.
Gan TJ, Meyer T, Apfel CC, et al, “Consensus Guidelines for Managing Postoperative Nausea and Vomiting,” Anesth Analg, 2003, 97(1):62-71.
Harrington RA, Hamilton CW, Brogden RN, et al, “Metoclopramide. An Updated Review of Its Pharmacological Properties and Clinical Use,” Drugs, 1983, 25(5):451-94.
Hart J, "Pediatric Gastroesophageal Reflux," Am Fam Physician, 1996, 54(8):2463-72.
Hesketh PJ, “Chemotherapy-Induced Nausea and Vomiting,” N Engl J Med, 2008, 358(23):2482-94.
Karadsheh NS, Shaker Q, and Ratroat B, “Metoclopramide-induced Methemoglobinemia in a Patient With Co-Existing Deficiency of Glucose-6-Phosphate Dehydrogenase and NADH-Cytochrome b5 Reductase: Failure of Methylene Blue Treatment,” Haematologica, 2001, 86(6):659-60.
Kris MG, Hesketh PJ, Somerfield MR, et al, “American Society of Clinical Oncology Guideline for Antiemetics in Oncology: Update 2006,” J Clin Oncol, 2006, 24(18):2932-46.
Mary AM and Bhupalam L, “Metoclopramide-induced Methemoglobinemia in an Adult,” J KY Med Assoc, 2000, 98(6):245-7.
Matok I, Gorodischer R, Koren G, et al, “The Safety of Metoclopramide Use in the First Trimester of Pregnancy,” N Engl J Med, 2009, 360(24):2528-35.
McGovern EM, Grevel J, and Bryson SM, “Pharmacokinetics of High-Dose Metoclopramide in Cancer Patients,” Clin Pharmacokinet, 1986, 11(6):415-24.
Multinational Association of Supportive Care in Cancer (MASCC), “Antiemetic Guidelines,” Updated March 2008. Available at http://data.memberclicks.com/site/mascc/MASCC_Guidelines_Update.pdf
National Comprehensive Cancer Network® (NCCN), “Clinical Practice Guidelines in Oncology™: Antiemesis,” Version 4.2009. Available at http://www.nccn.org/professionals/physician_gls/PDF/antiemesis.pdf.
Parrish RH and Bonzo SM, “Use of Metoclopramide Suppositories,” Clin Pharm, 1983, 2:395-6.
Patterson JF, “Neuroleptic Malignant Syndrome Associated With Metoclopramide,” South Med J, 1988, 81(5):674-5.
Schulze-Delrieu K, “Drug Therapy. Metoclopramide,” N Engl J Med, 1981, 305(1):28-33.
Van Veldhuizen PJ and Wyatt A, “Metoclopramide-induced Sulfhemoglobinemia,” Am J Gastroenterol, 1995, 90(6):1010-1.
International Brand Names
Lexi-Comp.com
Last full review/revision October 2009
Content last modified October 2009
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