Restrictions to use of metoclopramide, which is used in the prevention and treatment of nausea and vomiting, have been recommended by the European Medicines Agency (EMA) Committee on Medicinal Products for Human Use (CHMP).
The recommendations are aimed at minimizing the known risks of potentially serious neurologic adverse effects. They include restricting the daily dose to a maximum of 30 mg and the duration of use to 5 days.
The review of metoclopramide was conducted at the request of the French medicines regulatory agency (ANSM), after continued safety concerns about adverse effects and efficacy. The ANSM asked the CHMP to review the benefits and risks of these medicines in all age groups and to recommend consistent indications for the European Union.
The review confirmed the well-known risk for neurologic effects, such as short-term extrapyramidal disorders and tardive dyskinesia, the EMA notes in a press release.
The risk for acute neurologic effects is higher in children, although tardive dyskinesia is reported more often in the elderly, and the risk is increased at high doses and with long-term treatment. The evidence indicates that these risks outweigh the benefits of metoclopramide in conditions requiring long-term treatment, according to the EMA.
New Restrictions
The CHMP announced that metoclopramide is now contraindicated in children younger than 1 year of age; in children older than 1 year, it should only be used as a second-choice treatment for the prevention of delayed nausea and vomiting after chemotherapy and for the treatment of postoperative nausea and vomiting.
In adults, metoclopramide can be used for the prevention and treatment of nausea and vomiting associated with such things as chemotherapy, radiotherapy, surgery, and migraine.
However, it should no longer be used in chronic conditions such as gastroparesis, dyspepsia, and gastroesophageal reflux disease, and should not be used as an adjunct in surgical or radiologic procedures.
In addition, the daily maximum dose is now 0.5 mg/kg body weight; for adults, the maximum is 30 mg daily (administered as 10 mg 3 times daily).
Products containing higher doses should be removed from the market, the committee ruled.
Oral liquid formulations have been particularly associated with overdose in children, the CHMP noted. Oral liquids containing more than 1 mg/mL will be withdrawn from the market, and oral doses of remaining formulations should be administered using an appropriately designed graduated oral syringe to ensure accuracy.
Intravenous formulations with concentrations above 5 mg/mL and suppositories containing 20 mg will also be withdrawn.
Details of Adverse Events
The CHMP provides some details of the adverse events that have been reported with metoclopramide.
The 1749 extrapyramidal disorders constituted nearly half of the 4005 spontaneously reported adverse effects in a manufacturer database as of December 2011. The reporting rate for these disorders was calculated to be 6 times higher in children than in adults, although it was not possible to accurately account for usage patterns in different age groups.
Extrapyramidal disorders were more likely to occur after several doses, although usually early in treatment, and were less likely at slower infusion rates when metoclopramide was given intravenously. Elderly patients seem to be at higher risk for potentially irreversible tardive dyskinesia after longer-term treatment. There were also a significant number of reports of overdose in children, particularly with oral liquid formulations.
The CHMP also described very rare cases of cardiovascular reactions, mainly associated with intravenous formulations given to patients with underlying risks for cardiac disease; they include hypotension, shock, syncope, bradycardia or atrioventricular block, and cardiac arrest.
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