Terodilineinduced Proarrhythmias

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One of the fist indications of proarrhythmic activity of terodiline was a sudden unexpected death following an overdose in 1987 reported by Cattini et al. (1989). Forensic toxicological analysis on this 20-year-old previously healthy man with fatal overdose of terodiline revealed the presence of a potentially fatal blood level of terodiline. His blood and urine levels were greater than 10 mg/mL, whereas therapeutic concentrations in serum are usually not more than 1 mg/mL. No other drugs were detected. At post-mortem, his organs did not reveal any natural diseases. Although death was suspected to have followed inhalation of vomitus, the probability of a proarrhythmic event preceding aspiration cannot be excluded. Boyd (1990) has attempted to provide a clarification on the probable dose ingested. The first proarrhythmic reactions to clinical doses of terodiline were reported to have actually occurred in 1987 when there was one case of ventricular tachycardia and one of bradycardia. These reports were followed by an additional one report each of the two reactions in 1988.

The first three reports of torsade de pointes in association with the use of terodiline, following its post-approval routine clinical use, were notified to the licence holder during 1988 and 1989 and the fourth report in 1990 (Wild, 1992). Beginning early 1991, additional reports of QT interval prolongation and torsades de pointes began to appear (Andrews and Bevan, 1991; Connolly et al., 1991; Davis et al., 1991; Mcleod et al., 1991). These events, reported individually to the Medicines Control Agency (MCA), did not raise any immediate concern at first because of the associated confounding factors. However, by May 1991 the marketing authorisation holder was aware of 10 cases of torsades de pointes when the MCA was alerted of the potential hazard collectively signalled by these reports.

Additional reports followed and by 21 July 1991, there were 14 reports of ventricular tachycardias (including 13 of torsades de pointes) and 7 of bradyarrhythmias. None had a fatal outcome. Therefore, the Chairman of the UK Committee on Safety of Medicines (CSM) wrote to all doctors in the United Kingdom warning them of this potentially fatal adverse reaction and summarising the risk factors (Anon, 1991a). On the basis of the reports received, the prescribers were advised of the risk factors such as age greater than 75 years, ischaemic heart disease, co-prescription with cardioactive drugs, diuretics, antidepressants and antipsychotics, hypokalaemia and patients with any cardiac arrhythmias including ECG evidence of prolonged QT interval. Age per se was not regarded as an absolute contraindication.

Following this warning, many additional reports were received and by September 1991 there were 69 reports of serious cardiac arrhythmias. These consisted of 50 reports of tachyarrhythmias and 19 reports of bradyarrhythmias and heart blocks. Amongst these 69 cases were 14 cases of sudden or unexplained deaths (13 in the tachyar-rhythmia group). Fifty-one cases had recovered and there was no information on outcome in 4 reports. Of the 55 non-fatal cases, 24 were ventricular tachycardia of the torsades de pointes variety, 5 ventricular fibrillation, 7 unspecified ventricular tachycardia, one of multifocal ventricular ectopics and 18 of bradyarrhythmias including all degrees of heart blocks.

Patient demography and pattern of drug usage was essentially similar in the tachyarrhythmias and bradyarrhythmias groups. Of the 50 patients with tachyarrhythmias, 40 were females and 43 were aged 61 years or more. A dose of 25 mg daily or less was taken by 25 (56%) of the 45 patients with tachyarrhythmias in whom the dose was stated. Information on duration of treatment was available in 40 of these 50 patients. It was less than 1 month in 8 cases, up to 2 months in 10 cases, up to 6 months in 8 cases and more than 6 months in the remaining 14 cases. A dose of 25 mg or less was taken by 11 (65%) of the 17 patients with bradyarrhythmias and heart blocks in whom the information on dose was available.

An analysis of predisposing factors in the 69 reports of cardiotoxicity due to terodiline confirmed previous conclusions on potential risk factors: (a) an age greater than 75 years, (b) concurrent use of cardioactive medication (n = 33), (c) concurrent use of diuretics (n = 27), (d) concurrent use of antidepressants or anti-psychotic agents, and (e) hypokalaemia (n = 8). Ischaemic heart disease was present in 13 and other cardiovascular pathology in 39 patients. In 12 cases (18%), there were no clinically identifiable risk factors at all.

Of the 69 cases, 21 had been reported at the time of the warning from the Chairman of CSM and an additional 48 cases were reported within 2 months following this warning. Clearly, there were cases of cardiac effects of terodiline but were simply not reported—the association may have appeared too implausible to the prescribing community. However, once alerted, the real magnitude of the potential risk began to become clearer. While the regulatory action was under consideration, the drug was withdrawn voluntarily by the licence holder from the market worldwide on 13 September 1991 (Anon, 1991b).

Interestingly enough, at the time of its withdrawal, only 3 reports had come from Sweden (daily doses were 37.5 mg, 50 mg and 50 mg), 1 from the Netherlands (dose unknown) and none from Japan. There were no reports of cardiac arrhythmias from Denmark, Germany or Ireland. There was no information from Luxembourg. The drug was not marketed in Belgium, France, Greece, Italy, Spain, or Portugal. Following its withdrawal, there were isolated reports of terodi-line-induced torsades de pointes published from Denmark and Norway and additional ones from the Netherlands and one report of sudden expected death from Germany.

At the time of its withdrawal, about one million patients had been treated with terodiline worldwide, including about 450 000 in the United Kingdom. Even assuming a generous spontaneous reporting rate of 20%, the incidence of the risk is estimated at 1 in 1300 patients exposed. This remarkably high cardiotoxic potential of terodiline, uncovered through a spontaneous reporting system, is in sharp contrast to the generally reassuring safety profile that was being asserted on the basis of observations from postmarketing surveillance studies.

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