Questions arise, inevitably in retrospect, as to whether terodiline should have been approved at all and whether its proarrhythmic potential could have been anticipated.
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.
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