Terodiline-Induced Proarrhythmias

TERODILINE-INDUCED PROARRHYTHMIAS

One of the earliest suspicions of the proarrhythmic potential of terodiline arose from the sudden unex-pected death of a previously healthy 20-year-old man, following an overdose in 1987 (Cattini et al., 1989). Forensic toxicological analysis revealed the presence of a very high blood level of terodiline. His blood and urine levels were greater than 10 μg/mL. No other drugs or metabolites of terodiline were detected. At post-mortem, his organs did not reveal any natural disease. Although the death was suspected to have followed inhalation of vomitus, the probability of a proarrhythmic event preceding aspiration could not be excluded. Although the maximum steady-state serum concentrations of terodiline following 10–15 days of continuous twice-daily dosing with 25 mg are of the order of 0 5±0 23 μg/mL, peak serum concentrations following single oral doses of 12.5 and 25 mg are only 0.066 and 0 105 μg/mL respectively. Based on this kinetics, Boyd (1990) has estimated that this patient might have ingested close to 168 tablets (of 12.5 mg each) as a single dose.

The first proarrhythmic reactions to clinical doses of terodiline were also reported to have 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 these two reactions in 1988. Following its post-approval routine clinical use, the first three reports of torsade de pointes in association with terodiline were notified to the marketing authorization holder during 1988 and 1989, and the fourth report in 1990 (Wild, 1992). Beginning in early 1991, additional reports of QT interval prolongation and torsade de pointes began to appear (Andrews and Bevan, 1991; Connolly et al., 1991; Davis, Brecker and Stevenson, 1991; McLeod, Thorogood and Barnett, 1991). These events, reported individually to the Medicines Control Agency (MCA, the competent UK authority that preceded the current Medicines and Healthcare prod-ucts Regulatory Agency), did not raise any imme-diate concern at first because of the confounding factors associated with some of the reports. By May 1991, however, the marketing authorization holder was aware of 10 cases of torsade de pointes when the MCA was alerted of the potential hazard signalled collectively by these reports.

Additional reports followed, and by 21 July 1991 there were a total of 21 reports – 14 reports of ventricular tachycardias (including 13 of torsade de pointes) and 7 of bradyarrhythmias. None had a fatal outcome. Therefore, the Chairman of the then UK advisory body, the Committee on Safety of Medicines (CSM), wrote to all the doctors and phar-macists in the United Kingdom warning them of this potentially fatal adverse reaction (Anon, 1991a). On the basis of these reports, the prescribers were advised that the drug should not be used in the presence of risk factors such as age greater than 75 years, ischaemic heart disease, co-prescription with cardioactive drugs, diuretics, antidepressants and antipsychotic agents, hypokalaemia and patients with any cardiac arrhythmias including ECG evidence of (pre-existing) prolongation of QT interval. Age per se was not regarded as an absolute contraindication.

After this warning, there followed an avalanche of reports. An additional 48 case reports followed within the next 6 weeks, and by September 1991 there were a total of 69 reports of terodiline-induced seri-ous cardiac arrhythmias. The majority of these 48 additional reports were retrospective cases with the onset of terodiline-associated proarrhythmia antedat-ing the warning letter. Clearly, there were cases of cardiac effects of terodiline, but these were simply not reported because the association might have appeared too implausible to the prescribing commu-nity. However, after the alert, the real magnitude of the potential risk started to become apparent.

These 69 reports consisted of 50 reports of tach-yarrhythmias and 19 reports of bradyarrhythmias and heart blocks. Amongst these 69 cases were 14 cases of sudden or unexplained deaths (13 in the tachyarrhyth-mia group). Fifty-one cases had recovered and there was no information on outcome in the remaining 4 reports (but assumed non-fatal). Among the 55 non-fatal reports were 24 cases of torsade de pointes, 5 ventricular fibrillation, 7 unspecified ventricular tachycardia, one of multifocal ventricular ectopics and 18 of bradyarrhythmias.

Patient demography and pattern of drug usage was essentially similar in the tachyarrhythmia and brad-yarrhythmia groups. Of the 50 patients with tach-yarrhythmias, 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 tachyarrhy-thmias 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.

A further analysis of predisposing factors in these 69 reports of terodiline-induced cardiotoxicity confir-med previous conclusions on potential risk factors: (a) an age greater than 75 years, (b) concurrent use of cardioactive medication = 33 , (c) concurrent use of diuretics = 27 , (d) concurrent use of antide-pressants or antipsychotic agents and (e) hypokalaemia 8 . Ischaemic heart disease was present in 13 patients, and other cardiovascular pathologies were present in 39 patients. In 12 cases (18%), however, there were no clinically identifiable risk factors at all.

While the regulatory action was under consider-ation, the marketing authorization holder withdrew the drug voluntarily 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, 50 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. Follow-ing its withdrawal, there were isolated reports of terodiline-induced torsade de pointes published from Denmark and Norway, and additional ones from the Netherlands. There was also one report of sudden unexpected 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 was 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 post-marketing surveillance studies (Hall et al., 1993; Inman et al., 1993).