INTRODUCTION
Domperidone is a dopamine receptor blocker used orally
against nausea and vomiting1,2 (available over the counter in
numerous countries). In 2005, a large-scale population-based
study,3 focusing on sudden cardiac death (SCD) in noncardiac
drugs that prolong the QTc interval, reported that clinically
recommended doses of domperidone signicantly increase the
odds ratio for SCD to 5.4 [95% condence intervals (CI), 2.2
12.7]. Signicant increase of SCD was conrmed in 4 additional epidemiological studies.47
Received for publication September 5, 2012; accepted October 25, 2012.
From the Department of Pharmacology, Catholic University of Leuven, Leuven,
Belgium.
The authors report no conicts of interest.
Reprints: Luc M. Hondeghem, Westlaan 85, B-8400 Oostende, Belgium
(e-mail: luc.hondeghem@screenqt.com).
Copyright 2013 by Lippincott Williams & Wilkins
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Protocol
Throughout the equilibration periods, trains of 30 action
potentials at 1 Hz were recorded every minute for determination
of APD10APD90 (upstroke till 10, 20 . 90% repolarization).
TRIaD was measured over 3 minutes: triangulation was measured as average APD30 to APD90 (ms); reverse use dependence
was measured as the difference between the mean APD60 of 10
rst action potentials and the last 20 action potentials of three 30
beat trains; instability of APD60 was computed using the best
easy systematic for the last 20 action potentials in 3 trains26;
and dispersion was measured as the average difference between
septal and epicardial APD60. After a 10-minute baseline, the
preparations were perfused for 150 minutes with 30, 60, or
100 nM domperidone (n = 6, at each concentration).
Chemicals
Domperidone was obtained from Sigma (Brussels,
Belgium). A stock solution in dimethylsulfoxide was freshly
prepared and diluted in buffer to the required concentrations. The
nal dimethylsulfoxide concentration remained ,0.1%. The free
drug plasma concentrations of domperidone at the clinical
advised oral dose regimens in man range from 5 to 19 nM.21,27
Statistical Analysis
RESULTS
Experiments in Isolated Rabbit hearts
Effects of Domperidone Upon APD
At 100 nM domperidone, APD90 prolonged from 260 6
38.4 to 282 6 31.1 milliseconds (+8.4%) during a 15-minute
equilibration, which is similar to ndings in guinea pig
hearts.15 However, after 150 minutes, APD90 reached 385 6
35.7 milliseconds (+48%; Table 2). In all 6 preparations, the
control CI97.5 for prolongation of APD60 (45 ms) was exceeded (P , 1027). Because of this larger than previously
observed prolongation,15,16 long exposures at lower concentrations were also tested.
At 60 nM of domperidone (gray bar superimposed on
abscissa in Fig. 1), APD increased after some delay to
approach a steady state in ;45 minutes. After 150 minutes
equilibration for all 5 hearts, APD90 increased by 83 6 36.9
milliseconds (+32%). Again, the CI97.5 for APD60 prolongation was exceeded in all 6 preparations (P , 1027). At 30 nM
of domperidone, APD90 prolongation was 23 6 21.8 milliseconds (+9%) and the CI97.5 for APD60 prolongation was
exceeded in 3 of 6 preparations (P , 0.002).
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Hondeghem
Title
References
Pts
Bader et al
NA
Von Matushka
Janssen 1979
NA
De Loose et al
Janssen 1980
NA
Soewono et al
NA
Hersh
Janssen 1985
NA
Martin
Janssen 1980
NA
Shea
NA
De Loose
Haarmann et al
10
Verhaegen et al
11
Van Outryve et al
12
Van Ganse et al
13
Van de Mierop et al
14
Englert et al
15
Arts et al
16
Tatsuta et al
17
Bekhti et al
18
Agorastos et al
19
Nagler et al
20
Corazzao et al
Pharmatherapeutica
1979;2:140146
Postgrad Med J
1979;55:2427
Munch Med Wschr
1978;120:16891690
Postgrad Med J
1979;55:3335
Curr Ther Res
1978;23:695701
40, 67
23 D, 18 P
10
16 D, 22 P
36 D, 37P
Digestion
1979;19:244250
Postgrad Med J
1979;55:2829
J Int Med Res
1979; 7:158161
Aliment Pharmacol Ther
1992;6:221228
17 D, 15 P
Postgrad Med J
1979;55:3032
J Int Med Res
1981;9:143147
Am J Gastroenterol
1981;76:495499
20 D, 20 P
Ital J Gastroenterol
1996;28:317323
48
7D, 7P
8
9 DP, 9 PD
11
227 D, 401 P
Pts (Patients); NA (Not Available): FAMH (Federal Agency for Medicines and Health products) is restricted by condentiality and Janssen acknowledged request for the articles
but did not provide them; D: domperidone, P: placebo. The references were kindly provided by the FAMH.
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30 nM (n = 6)
60 nM (n = 5)*
100 nM (n = 5)*
44 6 15.2 (25)
26 6 21.7 (12)
23 6 21.8 (9)
84 6 42.1 (44)
82 6 37.3 (35)
83 6 37 (32)
87 6 59.8 (48)
109 6 47.3 (48)
125 6 60.3 (48)
APD was measured at a basic cycle length of 1000 milliseconds. APD prolongations
are represented as mean 6 SD after ;150 minutes equilibration at each concentration.
Percent changes are shown in parentheses. All observed prolongations were signicant
(P , 0.05) with reference to baseline as well as to 100 control experiments.
*At 60 and 100 nM one experiment dropped out, respectively, because of repetitive
Torsades de Pointes and excessive APD prolongation (preventing to follow the
computer stimulation).
FIGURE 2. Development of TRIaD as a function of domperidone concentration and of equilibration time. The incidence
of TRIaD is given as the sum of triangulation, reverse use
dependence, instability and dispersion.
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Hondeghem
Literature Analysis
Risk of SCD
In a large population study3 on noncardiac medication
that prolongs QTc, the odds ratio for SCD by oral domperidone increased 5.4-fold (2.212.7). After adjustment for diabetes mellitus, arrhythmias, heart failure, hypertension,
smoking, alcohol abuse, cerebrovascular and cardiovascular
ischemia, current use of diuretics, and cardiac glycosides,
the odds ratio remained 3.8 (1.59.7). Furthermore, among 7
offending drugs, domperidone scored the greatest increased
risk for SCD. A prospective in-hospital casecontrol study4
for cardiac arrest by non-antiarrhythmic QTc prolonging drugs
showed similarly that domperidone generated the highest odds
ratio for cardiac arrest 4.7 (1.416).
A large epidemiological study5 identied 41 incidents
related to domperidone exposure in 12,096 person-years (incidence = 0.0034). In the population at large, SCD has an average incidence of ;0.00125 (0.00050.002)5 and thus the odds
ratio for domperidone computes to 2.72 (1.76.8). In all 3
above studies,35 the incidence of SCD with domperidone substantially exceeds that of cisapride, a prokinetic agent withdrawn from market because of its arrhythmogenic liability.
A remake of the original Straus study3 was requested by
the marketing authorization holder to focus on domperidone
singly, using a larger population and also taking into account
dose dependence. During use of domperidone, the odds ratio
for SCD remained signicant: 3.72 (1.728.08).6 However, for
patients using only 30 mg/day, the odds ratio dropped to 2.57
(0.798.36), but when using .30 mg/day, the odds ratio
steeply increased to 16 (3.4973.6). In parallel, authors
used/supported by Johnson & Johnson also published that
domperidone signicantly increased the odds ratio for SCD
to 1.59 (1.281.98),7 and this increased risk for SCD remained
after adjustment for multiple covariates.
Thus, in all 5 large population-based studies,37 oral
domperidone consistently increased the odds ratio for SCD
and its average weighed to the inverse of the variance of the
estimates computes to 2.8 (1.536.21).
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DISCUSSION
The present experimental results show that concentrations as low as 30 nM domperidone signicantly prolong
APD, whereas 60 nM also induces disturbances of repolarization (TRIaD), EADs, and serious proarrhythmia (PVT). In
5 of 5 large population studies, domperidone signicantly
increases SCD 2.8-fold (1.536.21-fold). At the same time,
expert reviews and a large blinded trial show that the benets
of oral domperidone at the dened daily dose of 30 mg/day
do not exceed those of placebo. Only at 80 mg/day does the
prokinetic effects of domperidone sometimes become detectable, but then the risk for SCD is markedly increased.
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Hondeghem
drugs can alter cytoplasmic drug levels (including for domperidone),44 marked modulation of drug toxicity can occur.
Risk of SCD
It is then not surprising that numerous cases of SCD
have been reported with domperidone.814 However, spontaneous reporting of relatively rare events and small case
control studies do not have the power to establish a correct
incidence of side effects.45 That all 5 population studies
detected a signicant increase in SCD is quite worrisome,
as epidemiological studies are notoriously ineffective to
detect such liability, even for drugs known to prolong the
QTc interval and to posses proarrhythmic liabilities.5,45 Thus,
the 2.8-fold increase of SCD may be somewhat optimistic,
especially at dosages above 30 mg/day, where an odds ratio
for SCD of 16 (3.49 to 73.6) has been reported.6 It must also
be pointed out that the reported odds ratios in the literature
were not fully adjusted, that only one study6 considered dose
response and most studies were not large enough so that the
condence intervals around the estimate are rather large. Nevertheless, the fact that all 5 studies detected a signicant
increase of SCD is strong evidence for a high risk, but there
remains a large uncertainty about its precise magnitude.
In 2010 (last year available at Pharma.be), 32,484,962
dened daily doses of domperidone (30 mg) were sold
in Belgium. This is enough to medicate 88,999 patients throughout the year. In 88,999 patients not on domperidone, one estimates ;111 SCD/year (88,999 0.00125), which in patients on
domperidone increases to ;310 SCD/year (88,999 0.00125
2.8), that is, ;199 excess SCD/year with a lowest estimate of
only 60 SCD/year, but 580 extra SCD/year can also not be
ruled out. Extrapolation of these Belgian numbers to the more
than 100 countries where domperidone is used renders even the
most optimistic estimate tragic.
Alarmingly, domperidone is now also used for (unapproved) stimulation of milk production, in dosages up to
160 mg/day.46 The dangers of such usage for mother and
baby are unknown, but the incidence of SCD at lower dosages
renders the potential for sudden maternal death dreadful.
CONCLUSIONS
1. Cardiac electrophysiology: domperidone signicantly prolongs APD starting at 1.5 the therapeutic concentration.
Around 3 times the therapeutic concentration domperidone
markedly disturbs repolarization (TRIaD) with EADs and
PVT.
2. Domperidones safety index (;2.5) is 12-fold below
the minimum margin for a safe drug.
3. In clinical use, domperidone signicantly increases the odds
ratio for SCD, which steeply increases with increasing doses.
4. Domperidones benets against various gastrointestinal disorders and symptoms do not signicantly differ from
placebo.
A placebo-like agent with narrow safety margin and
lethal side effects should not be used in medicine.
RiskBenefit Assessment
In 2002, De Ponti et al45 warned that use of drugs with
published reports on ventricular arrhythmias,314 especially
when associated with APD/QT prolongation,15,16,45,47 Torsades
de Pointes,14 or ofcial warnings,20 should prompt careful
riskbenet assessment. For domperidone, the risks for SCD
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ACKNOWLEDGMENTS
The author thanks Bruno Hespel and Elisabeth Beck for
their assistance with the experimental work and Dr Johan Frans
for his careful reviewing and numerous good suggestions.
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induced by spatial disorientation and effect of domperidone. Am J Gastroenterol. 1999;94:12241229.
3. Straus SM, Sturkenboom MC, Bleumink GS, et al. Non-cardiac QTcprolonging drugs and the risk of sudden cardiac death. Eur Heart J.
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4. De Bruin ML, Langendijk PN, Koopmans RP, et al. In-hospital cardiac
arrest is associated with use of non-antiarrhythmic QTc-prolonging
drugs. Br J Clin Pharmacol. 2006;63:216223.
5. Hennessy S, Leonard CE, Palumbo CM, et al. Diagnostic codes for
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