Restrictions on the use of metoclopramide-containing products

HSA had issued a Dear Healthcare Professional Letter in July 2015 and its amendment in March 2016 to healthcare professionals regarding new restrictions on the use of metoclopramide-containing products in order to reduce the risk of neurological and other dose-related adverse reactions. This article serves as a consolidation of the two letters and a reminder on the restrictions and revised indications for its use.

Metoclopramide is a pro-kinetic drug that has been licensed in Singapore since 1989 for the prevention and treatment of nausea and vomiting due to various conditions. Locally, there are 12 registered metoclopramide-containing products, which are available in various dosage forms such as tablets, syrups and injections.

Background

In December 2011, a benefit-risk assessment of metoclopramide use in different age groups in the European Union (EU) was initiated by the European Medicines Agency (EMA), following concerns from the French National Agency for the Safety of Medicine and Health Products (ANSM) regarding the benefit-risk balance of metoclopramide. ANSM expressed that despite its long use for a wide range of indications, there was limited evidence of efficacy for approved indications of metoclopramide, while the risks of neurological and cardiovascular adverse events are known.² The review, completed in December 2013, confirmed the relationship between the use of high doses or long-term use of metoclopramide and the increased risks of neurological adverse reactions, such as acute extrapyramidal symptoms and irreversible tardive dyskinesia. In addition, there were also very rare reports of serious cardiovascular reactions, particularly if metoclopramide was administered intravenously. Patients at risk of cardiovascular reactions include the elderly population, patients with cardiac conduction disturbances (including QT prolongation), uncorrected electrolyte balance, bradycardia, and those taking other medicinal products known to prolong the QT interval.

In order to minimise the risk of potentially serious neurological adverse reactions, the EMA’s Committee for Medicinal Products for Human Use (CHMP) recommended restrictions on the indications, dose and duration of use of metoclopramide-containing products in the EU.² It was recommended that the use of metoclopramide should be restricted to the short term (i.e. up to 5 days). Indications involving long-term treatment (e.g., gastroparesis, dyspepsia) were no longer supported. As it is indicative that adverse events increased with dose, the dose should be restricted to the minimum effective dose with a recommended maximum daily dose of 30 mg and 0.5mg/kg, in adults and children, respectively. In addition, metoclopramide should be contraindicated in children below one year of age due to increased risks of extrapyramidal disorders and methaemoglobinaemia.

Other international regulatory actions

The United States Food and Drug Administration (US FDA) and Health Canada have reported the increased risk of irreversible tardive dyskinesia beyond 12 weeks of metoclopramide treatment in 2009 and 2011.^3,4 Both agencies retained the indications involving long-term treatment but recommended that the maximum treatment duration for metoclopramide should not exceed 12 weeks. The Australian Therapeutic Goods Administration (TGA) adopted the CHMP’s recommendations in February 2015, including restricting the use to short-term indications with a maximum treatment duration of 5 days.⁵ In addition, both Health Canada and TGA have recommended that the maximum daily dose of metoclopramide should not exceed 30 mg in adults and 0.5 mg/kg in children, and that the product should be contraindicated in children below one year of age.^5,6

HSA’s benefit-risk assessment and advisory

Locally, nearly 1 in 5 neurological adverse reports associated with metoclopramide received by HSA from 1993 to August 2014 were reported in children. Overall, the local incidence rate of neurological side effects in adults and children did not exceed those reported overseas.

Taking into consideration the current available scientific evidence, the local incidence of adverse drug reactions, the input from local clinical experts and international regulatory actions, HSA has reviewed the benefits versus the risks of metoclopramide and is recommending the following restrictions on the indications, dose and duration of use of metoclopramide-containing products in Singapore:

• In adults, metoclopramide will be indicated for the following:

The recommended maximum daily dose is 30 mg by the oral, intravenous or intramuscular route.

• In children (aged one to 18 years old), metoclopramide should be restricted to the second-line treatment of established post-operative nausea and vomiting (only via the intravenous route). The recommended maximum daily dose is 0.5 mg/kg.

• Metoclopramide is contraindicated in infants less than one year of age.

• Treatment should be kept as short as possible, in accordance to one’s clinical judgement. Treatment duration beyond 12 weeks should be avoided unless the therapeutic benefit is judged to outweigh the risk to the patient.

• Intravenous doses should be administered as a slow bolus (over at least three minutes).

HSA is working with the companies of metoclopramide-containing products to update their local package inserts with the new restrictions.

Healthcare professionals are encouraged to take into consideration the above recommendations when prescribing metoclopramide. They are also encouraged to report any suspected serious adverse events related to metoclopramide to the Vigilance and Compliance Branch of HSA.

References

1. https://www.hsa.gov.sg/announcements/Dear-Healthcare-Professional-Letters

2. http://www.ema.europa.eu/docs/en_GB/document_library/
   Referrals_document/Metoclopramide_31/WC500146610.pdf

3. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/
   2009/ucm149533.htm

4. http://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2011/13627a-eng.php

5. http://www.tga.gov.au/publication-issue/medicines-safety-update-volume-6-number-1-february-2015 (Metoclopramide and neurological adverse events)

6. http://www.hc-sc.gc.ca/dhp-mps/medeff/reviews-examens/metoclopramide-eng.php