Domperidone and risk of cardiac arrhythmia or sudden cardiac death

Domperidone has been registered as a Prescription-Only Medicine (POM) in Singapore since 1989 as Motilium® suspension 1mg/ml and Motilium® Tablet 10mg, by Janssen, a division of Johnson & Johnson Pte Ltd. Currently, there are 11 other generic domperidone products available. Domperidone is indicated for dyspeptic symptom complex often associated with delayed gastric emptying, gastro-oesophageal reflux and oesophagitis as well as for nausea and vomiting. Domperidone may also be supplied by pharmacists as a POM with exemptions for supply without a prescription* when used for the relief of postprandial symptoms of excessive fullness, nausea, epigastric bloating and belching occasionally accompanied by epigastric discomfort and heartburn, at a maximum daily dose of 40mg.

Concerns about the cardiac safety of domperidone surfaced in the early to mid-1980s with reports of cardiac arrest, ventricular arrhythmias, and sudden death associated with the use of the intravenous formulation of domperidone, which was most often administered with other medications with known cardiac side effects. As a result, intravenous domperidone was withdrawn from the market in 1985. More recently, several epidemiological studies describing an association of oral domperidone with an increased risk of serious ventricular arrhythmia (SVA) or sudden cardiac death (SCD) were published.^1-5 These studies also suggest the increased risk is observed only among those who use oral domperidone at higher doses (>30mg/day)¹, and those who are more than 60 years old.²

Summary of studies that investigated cardiac risk of oral domperidone

(i) Nested case-control study using the Saskatchaewan Health Electronic Database in Canada1

A case-control study nested in a retrospective cohort evaluated the combined risk of SVA and SCD in users of domperidone compared with users of proton pump inhibitors (PPIs), or non-users of these medications.

There were 83,212 individuals in the exposure cohort with the first dispensing of domperidone and/or a PPI between 1990 and 2005 (41,153 domperidone, 41,700 PPI and 359 both medications). From this exposure cohort, 49 SVA and 1,559 SCD cases were identified (mean age 79.4 years, females 52.9%, diabetes 22.3%) and 6,428 matched controls. The adjusted odds ratio (OR) for SVA/SCD with current domperidone use compared with non-use was (1.59, 95%CI: 1.28-1.98), or compared with current PPI use was (1.44, 95%CI: 1.12-1.86).

In stratified analyses, adjusted ORs were numerically higher in males, those more than 60 years old, and non-diabetics.

(ii) Domperidone and ventricular arrhythmia or SCD: a population-based case-control study in the Netherlands2

Another case-control study conducted between 1996 and 2007 in a longitudinal general practice research database in the Netherlands included patients aged ≥18 years without cancer in the source population. In this study, there were 1,366 cases (62 VA and 1,304 SCD) and matched 14,114 controls. Of all cases, ten patients were current domperidone users at the index date and all presented with SCD. The matched, unadjusted OR of domperidone and SCD was 3.72 (95% CI 1.72, 8.08). Daily doses >30 mg were associated with a significant increased risk of SCD (adjusted odds ratio 11.4 [95% CI 1.99, 65.2]). The effect of domperidone on non-fatal VA was not demonstrated due to the absence of exposed cases.

Actions taken by the European Medicines Agency (EMA)6

Based on the assessment of the data from the studies described earlier, the EMA's Pharmacovigilance Working Party (PhVWP), recommended further updates to the product label to reflect the current information on the risk of sudden cardiac death, particularly in patients >60 years old and in patients taking daily doses of >30mg, and emphasised that domperidone should be used at the lowest effective dose in adults and children. The PhVWP also recommended that the marketing authorisation holder conduct an additional well-designed, high-powered epidemiological study on the association between domperidone and cardiac disorders, with particular emphasis on dose to further clarify this risk.

Local Situation

Currently, the recommended dose for domperidone in adults and adolescents is 10 to 20mg to be taken three to four times per day, with a maximum dose of 80mg daily while that for children and infants is 0.25 to 0.5mg/kg three to four times a day (up to a maximum of 2.4mg/kg but no more than 80mg per day).⁷

To date, HSA has not received any adverse drug reaction (ADR) reports relating to serious ventricular arrhythmias and sudden cardiac death. Most of the ADR reports were minor reactions pertaining to skin rash.

HSA's actions and advisory

This safety issue was reviewed by the Vigilance Branch in 2009 and early 2010. Janssen had initiated package insert updates to reflect SVA and SCD under the “Undesirable effects- postmarketing” as follows:

“An increase in the risk of serious ventricular arrhythmias and sudden cardiac death has been reported in some epidemiology studies. Due to the limitations of these data, risk factors and the exact frequency of these adverse reactions could not be defined

HSA is currently working with relevant product licence holders to update the package inserts of domperidone products to reflect the current information on the risk of SVA and SCD associated with the use of the product.

Healthcare professionals should be aware of these risks and be cautious, particularly when treating high risk patients with domperidone eg, those who have existing prolongation of cardiac conduction intervals like QTc and patients with significant electrolyte disturbances or underlying cardiac diseases such as congestive heart failure. When supplying domperidone as a POM with exemptions for supply without prescription, pharmacists are advised to check their patient's medical history and avoid dispensing domperidone to patients with underlying cardiac disorders. They may wish to advise patients with underlying cardiac disorders to consider alternative medicines or to seek advice from their doctors on the suitability of domperidone.

_{*Exemptions for supply of POM without prescription is a new initiative to facilitate public access to commonly used medicines. Such medicines may be supplied without a prescription by pharmacists if they are deemed by HSA to be sufficiently safe for use with reduced medical supervision. More information is available at the HSA website.}

References

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

2. Pharmacoepidem Dr S 2010; 19:881-888

3. Br J Clin Pharm 2007; 63(2):216-23.

4. Eur Heart J 2005; 26(19): 2007-12.

5. Br J Clin Pharmaco 2009; 68(5): 743-51.

6. PhVWP Monthly Report 27 October 2011

7. Singapore package insert for Motilium® (domperidone)