Initial Regulatory Deliberations

Questions arise, inevitably in retrospect, as to whether terodiline should have been approved at all and whether its proarrhythmic potential could have been anticipated. While it may be easy to answer these in retrospect, the commentary that follows is not based entirely on the benefit of hindsight because the nature of the problem had become apparent at the regulatory authority immediately on receipt of the first two to three reports of cardiotoxicity.

There is little doubt that urinary incontinence, although relatively benign in terms of morbidity, is a highly prevalent condition that has a serious adverse effect on the quality of life. No other drug with a comparably satisfactory and favourable risk-benefit ratio was available at the time of the approval of terodiline in 1986. Clinical trials had shown terodiline to be effective and, by all accounts, relatively safe. The efficacy of terodiline had been demonstrated in a number of studies (Yoshihara et al., 1992; Anon, 1993; Norton et al., 1994). The majority of the reactions reported were mild and anticholinergic. The safety of terodiline 50 mg daily was evaluated in a 6-month study in 100 women with urgency/urge incontinence by recording of adverse reactions and measurements of haematol-ogy, liver function, creatinine, ESR, heart rate and blood pressure (Fischer-Rasmussen, 1984). Mean levels of all variables on clinical chemistry were well within the normal range. Ninety-one patients were evaluated after 3 months and 70 after both 3 and 6 months. No significant changes were seen except for a small increase in platelet, serum creatinine and ESR. No significant changes in heart rate or blood pressure occurred except for a small but statistically significant increase (about 2 mmHg) in resting diastolic blood pressure after 6 months. Adverse reactions, usually those to be expected from the anticholinergic pharmacological effects of the drug, caused withdrawals in 12 patients. In a randomised, double-blind, two-period cross-over (3-week period) trial in 89 women with motor urge incontinence without other neurological symptoms, no statistically significant difference in incidence of side-effects could be demonstrated between 37.5 mg daily of terodiline and placebo (Peters, 1984).

Given the therapeutic options available at the time, there is no question that its approval was a highly justified decision. Even during the few months immediately following its withdrawal, many patients and urologists continued to write to the Agency, testifying to its benefits, how the lives of many patients had been transformed and complaining about the abrupt loss of a highly valuable drug. An option to make the drug available on a named patient basis was considered but never followed through. The withdrawal of terodiline was an equally less difficult decision since its risk-benefit was found to be clearly unfavourable and another drug, oxybutynin, had already been approved in January 1991.

However, four vital pieces of information that might have heralded the potential proarrhythmic hazard of terodiline were already available at the time of its redevelopment. The analogy between terodiline and prenylamine extends well beyond their structures into their pharmacology and toxicity profiles. Firstly, the association between prenylamine, also an antianginal agent, and its propensity to prolong the QT interval and induce torsades de pointes; secondly, the stereoselectivity in the proarrhythmic potential of prenylamine; thirdly, the stereoselectivity in the pharmacody-namic activities of the two enantiomers of terodi-line and the unexpectedly high frequency of anticholinergic effect observed during its use as an antianginal agent should have suggested an unusual behaviour of one of the enantiomers, and lastly, the wide inter-individual variability in the metabolism of terodiline with aberrant pharmaco-kinetic behaviour of one of the enantiomers.

To illustrate the regulatory thinking at the time, frequent references will be made to prenylamine in this commentary. This will highlight the striking similarity between these two drugs and, hence, the logic that should have supported the re-development of the drug. Importantly, this comparison emphasises the strengths of a scientific synthesis of all the available information when evaluating the significance of the first two to three reports and determining the best regulatory options.

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