New recommendations on the use of domperidone

Background

Domperidone is a pro-kinetic and anti-emetic drug registered in Singapore for the treatment of dyspepsia, as well as nausea and vomiting due to various conditions.

HSA has recently completed a re-assessment to determine if additional measures are necessary to further mitigate the cardiovascular (CV) risk associated with the use of domperidone. This follows an earlier assessment in 2012, which resulted in the strengthening of the package inserts (PIs) of domperidone  to include warnings of increased risk of ventricular arrhythmia (VA) and sudden cardiac death (SCD), especially in patients older than 60 years old or those taking oral doses of more than 30 mg daily. 

International regulatory actions

Several other drug regulatory agencies have also carried out assessments on domperidone and issued recommendations on its use. The European Medicines Agency (EMA) removed the indication for dyspepsia due to insufficient long-term efficacy data supporting this indication, and restricted the maximum oral daily dose to 30 mg for its use to treat nausea and vomiting.¹ Health Canada retained the use in gastritis and nausea and vomiting at a maximum daily dose of 30 mg as well as strengthened the safety warnings in the PI to highlight the risk of CV events.²

HSA’s benefit-risk re-assessment

Domperidone is a well-established pro-kinetic drug used in the treatment of nausea, vomiting and dyspepsia. HSA has reassessed its risk-benefit following a review of five epidemiology studies, which suggested an association with increased risk of VA and SCD.^3-4

The identified cardiotoxicity risk factors included advanced age (>60 years old), underlying CV conditions, high domperidone dose (>30 mg/day) and concomitant use with QT prolongation drugs and CYP3A4 inhibitors. Local reports of cardiotoxicity associated with domperidone use were found to be isolated. From 2006 to 2016, HSA received two cases of QT prolongation associated with domperidone.  Considering the long history of use in local clinical setting and the relatively low incidence of locally reported cardiac-related adverse events, HSA, in consultation with its Medicines Advisory Committee, concluded that the benefit-risk profile of domperidone remains favourable when used appropriately for the above indications. Additional measures were recommended to mitigate the risk of cardiotoxicity, which included restricting its use in high risk patients and strengthening the CV warnings in the PI.

HSA’s advisory

Healthcare professionals are advised of the following, when considering the use of domperidone:

• Domperidone is contraindicated in patients with existing prolongation of cardiac conduction intervals, particularly QTc, patients with significant electrolyte disturbances or underlying cardiac disease and when co-administrated with QT-prolonging medicines or potent CYP3A4 inhibitors.

• An increased risk of cardiotoxicity was observed in patients older than 60 years.

• Domperidone should be used at the lowest effective dose for the shortest possible duration.

• In adults and children aged ≥ 12 years old weighing ≥ 35 kg, the recommended maximum oral daily dose is 30 mg, given in doses of 10 mg up to three times daily. Taking into account the pharmacokinetic studies and bioavailability of rectal suppositories, the recommended rectal suppository dose is 30 mg twice daily.

• In children aged < 12 years old and those aged ≥ 12 years old weighing < 35 kg, the recommended dose is 0.25 mg/kg orally up to three times daily. For rectal administration, these patients may also be given 0.75 mg/kg twice daily as suppositories.

HSA is working with the product registrants to update the local PIs of products containing domperidone. These include new recommendations on the dosing regimen, treatment duration and the relevant safety information including contraindications.

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

References

1. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Domperidone-containing_
   medicines/human_referral_prac_000021.jsp&mid=
   WC0b01ac05805c516f

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

3. Drug Saf. 2010; 33: 1003-1014.

4. Pharmacoepidemiology and Drug Safety 2010; 19:881-888.