Initial Regulatory Deliberations

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 some of these questions in retrospect, the commentary that follows is not based entirely on the benefit of hind-sight, because the nature of the problem had become apparent at the regulatory authority immediately on receipt of the first two to three reports of terodiline-induced proarrhythmias.

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. At the time of the approval of terodiline in 1986, there was no other drug avail-able with a comparable efficacy and favourable risk– benefit ratio. Clinical trials had shown terodiline to be effective and, by all accounts, relatively safe. The effi-cacy of terodiline had been demonstrated in a number of studies (Fischer-Rasmussen, 1984; Yoshihara et al., 1992; Anon, 1993a; Norton et al., 1994). The major-ity of adverse reactions reported were anticholinergic in nature and mild in severity. In one randomized, double-blind, two-periods cross-over (3 weeks dura-tion for each period) study in 89 women with motor urge incontinence without other neurological symp-toms, no statistically significant difference in inci-dence of side effects could be demonstrated between 37.5 mg daily of terodiline and placebo (Peters, 1984). The safety of terodiline at a higher dose of 50 mg daily was also evaluated in a 6-month study in 100 women with urgency/urge incontinence (Fischer-Rasmussen, 1984). Ninety-one patients were evaluated after 3 months and 70 after both 3 and 6 months. Adverse reactions, usually those to be expected from the anticholinergic pharmacological effects of the drug, resulted in 12 patients discontinuing the treatment. 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. Mean levels of all clini-cal chemistry variables were well within the normal range. No significant laboratory changes were seen except for a small increase in platelet, serum creatinine and ESR. Unfortunately, ECGs were not recorded in either of these pre-approval studies.

Given the therapeutic options available at the time, there is no question that approval of terodiline was the most appropriate decision in 1986. Even during the few months immediately following its withdrawal, many patients and physicians continued to write to the Agency, testifying to its efficacy and positive impact in transforming the quality of life of many patients, and complaining about the abrupt loss of a clinically useful drug. An option to make the drug available on a named patient basis was under consideration but never followed through. Equally, the withdrawal of terodiline in September 1991 was not a difficult deci-sion, since its risk–benefit was shown conclusively by then to be unfavourable and another equally effective drug, oxybutynin, had already been approved for use in urinary incontinence in January 1991.