Re-Birth of Terodiline

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Chapter: Pharmacovigilance: Withdrawal of Terodiline: A Tale of Two Toxicities

Terodiline was first marketed in 1965 as an antianginal agent (‘Bicor’) in Scandinavia, a relatively small market.


RE-BIRTH OF TERODILINE

Terodiline was first marketed in 1965 as an antianginal agent (‘Bicor’) in Scandinavia, a relatively small market (Wibell, 1968). This period of original market-ing of terodiline in the 1960s is worthy of note because it antedates (a) any serious regulatory or clinical inter-est in drug-induced prolongation of the QT interval and (b) the first description of torsade de pointes as a unique proarrhythmia associated with prolonged QT interval (Dessertenne, 1966). Moreover, the re-development of terodiline in the early 1980s coincided with increasing number of reports of QT interval prolon-gation and torsade de pointes in association with two other antianginal drugs, prenylamine (Picard, Auzepy and Chauvin, 1971; Oakley et al., 1980; Abinader and Shahar, 1983) and lidoflazine (Kaden and Kubler, 1977; Hanley and Hampton, 1983). These two drugs ceased to be available for clinical use in the UK – prenylamine in 1988 and lidoflazine in 1989.

Because of the potent anticholinergic properties of terodiline, urinary retention proved to be a frequent and troublesome side effect during its use as an antiang-inal agent. Terodiline was therefore re-developed in the early 1980s for clinical use in urinary incontinence due to detrusor instability. In isolated airway prepa-rations from rats, terodiline had also been shown to block the bronchoconstrictor effect of acetylcholine. The shift in the acetylcholine dose-response curve induced by terodiline indicated that its anticholiner-gic property might also explain its observed cilio-stimulatory effect (Iravani and Melville, 1975). It is therefore not surprising that in the period inter-vening between these two indications, terodiline was also being investigated for use in chronic obstruc-tive airways disease (Castenfors, Hedenstiarna and Glenne, 1975), presumably in an attempt to harness the same, otherwise unwanted, pharmacological property observed during its use as an antianginal agent.

Terodiline was first introduced in the United King-dom under the brand name of ‘Terolin’ (later changed to ‘Micturin’) in July 1986 for use in urinary frequency, urgency and incontinence in patients with detrusor instability and neurogenic bladder disorders. In the EU, it was also approved in Denmark, Ireland, Luxembourg, Belgium, the Netherlands, Spain and West Germany, but not in France, Greece, Italy or Portugal. Overall, the drug was approved in 20 coun-tries worldwide and marketed in a number of these, but the major markets were the UK, Sweden and Japan. The recommended dose in the United King-dom was 12.5–25 mg twice daily in young adults and otherwise healthy elderly patients, but 12.5 mg twice daily in frail elderly patients. In general, the doses used in Sweden were lower than those used in the United Kingdom, and the dose approved in Japan was half the UK recommended dose.

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