Prenylamine was the first drug to be withdrawn from the market worldwide in 1988 because of its high potential to prolong the QT interval and induce torsade de pointes, often with a fatal outcome (Anon, 1988).
PRENYLAMINE-INDUCED
PROARRHYTHMIAS
Prenylamine
was the first drug to be withdrawn from the market worldwide in 1988 because of
its high potential to prolong the QT interval and induce torsade de pointes,
often with a fatal outcome (Anon, 1988).
Although
prenylamine had been marketed since the 1960s, it was not until 1971 that
reports (mostly from France and the United Kingdom) linking preny-lamine with
prolongation of the QT interval, ventricu-lar tachycardia, ventricular
fibrillation and torsade de pointes began to appear (Picard, Auzepy and
Chauvin, 1971). Despite changes in dose schedules and warn-ings,
prenylamine-induced proarrhythmias continued to be reported, and by 1988, 158
cases of polymor-phic ventricular tachycardia were reported in associ-ation
with prenylamine, and the drug was withdrawn worldwide soon after its removal
from the UK market that year. Approximately 80% of these patients were females.
The mean age was 68 ±
11 years and 30 of the 109 patients had received prenylamine as the only medi-cation.
The vast majority of the patients were taking prenylamine at the usually
recommended daily dose of 180 mg. Hypokalaemia was present in 34 of the 82
patients for whom this information was available.
Strikingly,
despite being very potent torsadogens, neither prenylamine nor terodiline had
shown any evidence of its proarrhythmic potential during its development.
Cardiotoxicity following their routine clinical use did not become fully
manifest for about 2–3 years after marketing – a disturbing feature also shared
by other torsadogenic drugs removed from the market. A number of prospective
stud-ies with prenylamine were conducted to investigate its effect on QT
interval, but none could demon-strate a significant change after treatment with
the drug. A review of the pre-approval clinical trials data on terodiline
proved unhelpful for evaluation of its effect on ECG. However, in one study of
12 asymptomatic patients in sinus rhythm taking stable doses of terodiline
(undertaken after its withdrawal from the market), mean QTc interval and QT
disper-sion were significantly prolonged to 491 and 84 ms during treatment with
racemic terodiline compared with measurements of 443 and 42 ms, respectively,
made off therapy (Thomas et al.,
1995). The mean drug-induced increases were 48 ms for the QTc inter-val and 42
ms for QT dispersion. In this study, QT interval prolongation was shown to
correlate closely with steady-state plasma concentrations of (+) -(R)-and − -(S)-terodiline.
Both
prenylamine and terodiline further illustrate a more general difficulty in
successfully containing a clinical risk by revising the prescribing
information. These revisions may include reduced doses, additional
contraindications, special warnings and precautions for use, requirements for
monitoring patients and details of potentially cardiotoxic drug interactions.
Unfortunately, this strategy has proved to be highly disappointing in risk
management, as evidenced by the withdrawal of a number of high-profile drugs
such as terfenadine, astemizole, cisapride (all associated with proarrhythmias)
and troglitazone and bromfenac (both associated with hepatotoxicity) (Shah,
1999). The most recent casualty of inappropriate prescribing (resulting in
rhabdomyolysis) was cerivastatin, which continued to be prescribed at high
doses at the outset despite a recommendation to start treatment at lower doses,
or concurrently with gemfibrozil despite this combination being
contraindicated.
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