Domperidone: an indication of how many sudden deaths in France could be prevented by avoiding this low-efficacy drug Abstract In 2004, the French Pharmaco - ment after the drugs have been dis- economic Committee (Commission de la pensed at a community phar- ● Domperidone is a “hidden” neuro- Transparence) reviewed the therapeutic macy (11). leptic that has been used since the value of domperidone, using data from a 1980s to treat common nausea and European referral procedure that had About 3 million adults exposed vomiting and similar symptoms, with been conducted in order to harmonise annually. In 2012, domperidone was modest efficacy. It prolongs the QT in- the summaries of product characteris- dispensed at least once for 49 354 pa- terval on ECG and exposes patients to tics (SPCs) for domperidone-containing tients in the EGB, i.e. 7.7% on average the risk of cardiac arrhythmias. Case- drugs across the European Commu- (up to 18% in children 0 to 4 years control studies have shown that sud- nity. Without mentioning cardiac old) (12). den cardiac death is about 1.6 to harms, it rated domperidone’s thera - The 2 Dutch studies that showed an 3.7 times more frequent with domperi- peutic value “insufficient”, except in the increased risk of sudden death with done exposure. relief of nausea and vomiting, for domperidone excluded children and which it was rated “moderate” (a)(6). cancer patients (7,9). We aimed to de- ● Data from the “General Sample of Since 2005, it has been established termine the domperidone exposure of Beneficiaries” of France’s mandatory that domperidone prolongs the QT in- this population in France, i.e. adults health insurance system show that, in terval on ECG, as do the other neuro - without cancer. In 2012, among the 2012, domperidone was dispensed at leptics, and Dutch and Canadian adults in the EGB who were not least once to about 7% of the coun- case-control studies have shown an in- flagged as having cancer as a long- try’s adult population, i.e. to about creased incidence of sudden cardiac term illness, we identified 31 190 3 million adults. Another drug known death in adults exposed to domperi- (6.4%) to whom domperidone had been to potentially increase the risk of ar- done (b)(3,7,8,9,10). According to dispensed at least once. Scaled up to rhythmia associated with domperi- these studies, the incidence was about the entire insured population of done was co-dispensed on the same 1.6-fold to 3.7-fold higher in patients France, that would correspond to day to about 23% of these patients. taking domperidone. The risk appeared about 3 million adults (12). Domperi- even higher for patients taking more done had been dispensed at least once ● In France, given the incidence of than 30 mg of domperidone a day, while to 11.8% of adults flagged as having sudden death, a prudent assumption the SPC authorises a maximum daily cancer as a long-term illness. makes it plausible that domperidone dose of 80 mg. This level of exposure has remained caused about 25 to 120 premature How many patients in France are more or less constant for years. The deaths in 2012. exposed to domperidone and the asso- EGB data suggest that between 2003 ciated risk of sudden death? and 2013, domperidone was dispensed ● In practice, domperidone can easily at least once to about 27 million peo- be replaced with solutions that are ple in France (12). The numbers ex- better for patients. About 8% of the French posed to the drug fell by only about population exposed each year 6% between 2011 and 2012. As its international nonproprietary The French Health Data Often one box during the year. name (INN) indicates, domperidone is Institute (IDS) allowed Prescrire to In 2012, adults without cancer in the related to various neuroleptics, such as study domperidone exposure using the EGB to whom domperidone was dis- risperidone (1,2,3). It has been used “General Sample of Health Insurance pensed at least once received 1.6 boxes since the early 1980s, not as a psycho - Beneficiaries” (EGB), established and on average (12). About 80% received tropic drug, but to alleviate nausea and regularly updated by the French Na- one box only. In most cases they were vomiting and various common gastro - tional Health Insurance Fund for boxes of 40 tablets, usually of the intestinal disorders: hence it is a “hid- Salaried Workers (CNAMTS) to repre- 10-mg strength, although one-fifth den” neuroleptic (4,5). sent 1/97th of the population covered contained the 20-mg strength. In 1986, the injectable form of dom- by France’s mandatory health insur- The data in the EGB do not specify peridone was withdrawn from the mar- ance system. Patient and prescriber the daily dose prescribed. The French ket due to the cardiac arrhythmias and data are anonymised in the EGB. Drug Pharmacoeconomic Committee re- deaths it caused. The oral forms re- exposure data are obtained from pre- ported in 2007 that the average daily main on the market (4). scriptions presented for reimburse- dose prescribed for adults was Prescrire Analysis 19 February 2014 • Page 1 Downloaded from english.prescrire.org Copyright(c)Prescrire. For personal use only. 31 mg for the 10-mg strength, and done caused about 25 deaths in France In late 2013, the French Agency sum- 54 mg for the 20-mg strength, corres - in 2012. This figure would be about marised the review of domperidone-con- ponding to 2 weeks’ treatment for one 120 if we assume an approximately taining medicines that the European box of 40 10-mg or 20 mg tablets (13). 3.7-fold increased incidence during Pharmacovigilance Risk Assessment Prolongation of the QT interval is exposure to domperidone (as reported Committee (PRAC) began in March detectable from the third day of dom- in the Dutch studies). It would be even 2013, thus (our translation): “(…) the peridone treatment, and the authors of higher if the incidence of sudden car- cardiac risk profile has been confirmed. In the Canadian study reported that sud- diac death is greater than 29 per order to enable appropriate risk minimisa- den death was more frequent the first 100 000, as reported in other Euro- tion measures to be put in place, particularly time the drug was dispensed than with pean studies. as regards the optimal dosage and treatment subsequent prescriptions (no quanti- duration and the measures to take concern- tative data provided) (10,14). The Possible sources of over- and ing the various pack sizes available within plasma elimination half-life of domperi- under-estimation. These numbers the EU, an additional list of questions has done is generally about 7 to 9 hours, may be overestimated, notably because been drawn up” (22). The PRAC’s recom- and longer for patients with renal im- some patients do not take or complete mendation is due in March 2014 (22). pairment (5). prescribed treatments. However, the same limitation applies to the Dutch Very frequent interactions, in- and Canadian studies that showed the In practice: provide better creasing cardiac risks. In 2012, increased risk with domperidone. patient care without about 22.8% of the adults in the EGB These numbers are probably under- domperidone who were not flagged as having cancer estimated, because the increase in the and who received domperidone were incidence of sudden death appears The modest symptomatic “efficacy” also given, on the same day, at least even greater in patients taking more of domperidone does not justify the as- one drug known to increase the risk of than 30 mg of domperidone daily, which sociated risk of premature death. torsades de pointes, either by further is very easily done with the 20-mg This has been known for years. In increasing the risk of QT interval pro- strength. France, the warning issued by the longation, or by slowing the heart rate, Additional deaths would have oc- Agency and one drug company in late inducing hypokalaemia, or increasing curred in cancer patients. In the EGB, 2011 has resulted in only a marginal the plasma concentration of domperi- adults flagged as having cancer were decrease in exposure, and about 3 mil- done through inhibition of cytochrome twice as likely to be exposed to dom- lion adults were exposed to domperi- P450 3A4 (12,15,16). peridone as the others (12). done the following year. For example, domperidone was co- Additional deaths would have oc- In practice, the disorders for which dispensed on the same day as another curred in hospitalised patients. One domperidone is prescribed are often self- neuroleptic for 2.9% of this population, study showed that, in this population, limiting or resolve with simple dietary while 4.3% were co-dispensed a drug domperidone therapy increases the in- measures (23). For patients who never - that inhibits cytochrome P450 3A4 (12). cidence of cardiac arrest about theless want drug therapy, one option 5-fold (8). is a truly harm-free placebo. For symp- Child deaths may also have oc- toms caused by gastroesophageal reflux An indication of the number curred, since in 2012, domperidone was disease, a proton pump inhibitor such of sudden deaths in France dispensed for 18% of children aged as omeprazole is preferable to domperi- 4 years or less, corresponding to about done. And in the rare situations in Sudden cardiac deaths are not re- 680 000 children in total; but sudden which a gastric “motility modifier” ap- ported in the EGB. But EGB data can cardiac death is much rarer in children pears justified, metoclopramide can be be used to estimate the number of than in adults (18).