Revocation of marketing authorizations for metoclopramide 4 mg/ml drops, including update 10/27/2014.
Metoclopramide has been approved in the European Union since the 1960s. It is available in several dosage forms (e.g., tablet, sustained-release tablet, oral solution, suppository, or solution for injection). Each drug is approved for one or more indications, and in some cases the indications are specific to adults and/or children.
Action at EU level
The European Commission, on the recommendation of the European Medicines Agency (EMA), has prescribed measures for the safe and effective use of these medicines. These include the withdrawal of marketing authorization for all metoclopramide-containing medicinal products approved in the EU in a dosage form as oral drops with a concentration higher than 1 mg/ml.
Initially, the French competent authority initiated a procedure under Article 31 of Directive 2001/83/EC, requesting the Committee for Human Medicinal Products (CHMP) to examine the risk-benefit balance of metoclopramide-containing medicinal products for all populations, particularly children and elderly patients. This was prompted by the risk of neurological and cardiovascular adverse events to be investigated, as well as limited evidence of efficacy for all approved indications.
The investigation confirmed the already well-recognized neurologic risks, such as extrapyramidal disorders and tardive dyskenisia. The risk for short-term neurologic reactions was found to be higher in children and increased with higher doses and longer duration of therapy. Thus, the risk associated with use outweighs the benefit in those indications requiring long-term therapy. In addition, serious cardiovascular reactions have been reported in very rare cases, particularly after injection. With regard to use in children, there are a considerable number of reports of cases of overdose. The majority of cases involve the use of highly concentrated oral liquid formulations, which are currently approved in the EU in several different dosage forms (oral drops, oral solution, syrup) with different concentrations and a range of different application devices.
This has raised questions regarding dosing accuracy, particularly for the highly concentrated formulations. It was precisely those highly concentrated and thus poorly dosed dosage forms that could explain at least some of the reports of accidental overdoses in children and adolescents. In Austria, however, the use in children was not recommended according to the product information. As part of this review, which included all available benefit-risk data in all age groups, particularly for children and elderly patients, the CHMP accordingly confirmed the EU-wide potential risk for unintended use of the highly concentrated oral liquid formulations leading to accidental overdoses. After reviewing the data presented, the CHMP recommended, and subsequently the European Commission decreed, that further action is required to ensure the safe and effective use of the metoclopramide-containing proprietary medicinal products:
Revocation of marketing authorizations for
- oral liquid formulations with a concentration above 1 mg/ml
- parenteral formulations with a concentration greater than 5 mg/ml
- 20 mg/ml rectal formulations
and:
- That all oral liquid formulations at concentrations below or up to 1 mg/ml intended for use in children, to ensure accurate dose measurement and to prevent accidental overdose, must be supplied with an appropriate measuring device (e.g., graduated syringe for oral use).
The risk-benefit ratio of metoclopramide-containing drugs thus remains positive, taking into account the recommended changes in product information and risk minimization measures. Situation in Austria In Austria, the following medicinal products were previously approved:
- Metoceolate 4 mg/ml drops
- Metogastron 10 mg ampoules
- Metogastron 4 mg/ml drops
- Paspertin film-coated tablets
- Paspertin 10 mg ampoules
- Paspertin 4 mg/ml drops
- Paspertin 50 mg concentrate for infusion preparation
According to the decision of the EU Commission, all marketing authorizations of liquid formulations containing metoclopramide with a concentration of more than 1 mg/ml will be revoked as of April 30 , 2014.
This affects the following products in Austria:
- Metoceolate 4 mg/ml drops
- Metogastron 4 mg/ml drops
- Paspertin 4 mg/ml drops
Negotiations are currently underway in Austria with pharmaceutical companies to provide low concentration drop forms (i.e. compliant with the EU Commission Regulation) in a concentration of max. 1mg/ml by means of new marketing authorizations, probably by the end of next year.
Update 10/27/2014:
In the meantime, a low-concentration dosage form is again available in Austria by means of a new approval as a 1mg/ml solution for oral use.
Recommendations of the BASG
Recommendations for users and pharmacists: to minimize the risk of neurological and other adverse reactions, metoclopramide should only be used for a maximum duration of five days. Use in chronic conditions such as gastroparesis, dyspepsia, and gastroesophageal reflux should be discontinued, as should use as an adjunct to surgical or radiologic procedures. For adults, the following indications remain:
- Prevention of delayed chemotherapy-induced nausea and vomiting.
- Prevention of radiation therapy-induced nausea and vomiting
- prevention of nausea and vomiting after surgery
- Symptomatic treatment of nausea and vomiting, including acute migraine-induced nausea and vomiting (parenteral route of administration)
For children 1-18 years of age, metoclopramide should be used only for the following indications:
- Prevention of delayed chemotherapy-induced nausea and vomiting, as a second-line option.
- Treatment of confirmed nausea and vomiting after surgery, as a second-line option
Use in children less than one year of age is generally contraindicated.
Patient Recommendations:
- If you have any questions, please contact your physician
Further information:
BASG Official News (04/28/2014):
www.basg.gv.at/pharmakovigilanz/amtliche-nachrichten/amtliche-nachrichten-2014/
BASG Safety Information (07/26/2013):
EU Commission publication:
http://ec.europa.eu/health/documents/community-register/html/ho25026.htm
European Medicines Agency release:
Queries (technical): Dr. Christoph Baumgärtel, Tel: 050555/36004 E-mail: christoph.baumgaertel@ages.at Queries (for media): Communications Management, Tel: 050555/25000 E-mail: presse@ages.at
