Torsade de pointes associated with the combination of solifenacin and clenbuterol for urinary incontinence

Torsade de pointes (TdP) occurs in several clinical settings such as drug treatment and inherited abnormalities of cardiac ion channels and can be fatal. This condition is associated with ventricular action potential prolongation, which can be recognized non-invasively on the electrocardiogram (ECG) by QT interval prolongation. TdP may be caused by some non-cardiac drugs [, , ] as well as antiarrhythmic drugs []. Not only do drugs differ in their potential to cause TdP, but also there are several other risk factors for drug-induced TdP such as female sex, hypokalemia, hypomagnesemia, bradycardia, simultaneous administration of metabolic inhibitors, and genetic factors [, , , ]. Here, we report a rare case of TdP that appeared to be caused by the combination of solifenacin and clenbuterol to treat urinary incontinence.

A 79-year-old woman was admitted to our hospital because of recurrent syncope. She had been treated for two years with 5 mg/day solifenacin in combination with 20 μg/day clenbuterol for urinary incontinence. One year before admission, the dose of solifenacin was increased to 10 mg/day, and one month before admission, the dose of clenbuterol was increased to 40 μg/day. After an increase in solifenacin dose from 5 to 10 mg/day, QTc interval slightly increased from 419 ms to 428 ms. After an additional increase in clenbuterol dose from 20 to 40 μg/day, more QTc prolongation was observed from 428 ms to 442 ms. Thereafter, she developed recurrent syncope. At the time of admission, her 12-lead ECG showed no P waves and a regular atrioventricular junctional rhythm with QTc 442 ms (Fig. 1). Serum levels of electrolytes and hepatic function were normal, but her creatinine clearance was slightly decreased. The echocardiogram showed no structural heart disease. After hospitalization, the ECG monitor showed frequent premature ventricular contractions (PVCs) with short runs. TdP was evident on the Holter ECG at the time she developed syncope (Fig. 2). Just before the occurrence of TdP, the T wave was biphasic in shape with prolonged QTc interval to 560 ms (Fig. 2). We believed that the increase in the dose of solifenacin and clenbuterol was the cause of TdP. Therefore, we discontinued these two medications and prescribed amiodarone (100 mg; 12 h apart) for the first 24 h. Thereafter, the ECG monitor showed a decrease in the frequency of PVCs. Her heart rate decreased to 40/min, and to prevent more QTc prolongation, amioradone was discontinued. QTc interval decreased to 438 ms after withdrawing these drugs. She was at high risk for sudden death, therefore, a cardioverter-defibrillator with dual chamber pacing capability was implanted. After the implantation of a cardioverter-defibrillator with dual chamber pacing capability, she was free from syncope.

Solifenacin, a bladder-selective antimuscarinic drug, is widely used for the treatment of urinary incontinence []. Solifenacin has not been shown to have severe adverse cardiac effects, although another antimuscarinic agent, telodiline, has been reported to cause QT prolongation and TdP [, , ]. However, Asajima et al. [] reported a case of solifenacin-induced TdP associated with QT prolongation. The case was an 81-year-old woman who was on 5 mg/day solifenacin when TdP appeared. Clenbuterol, a long-acting β2-adrenergic agonist, is also used for the treatment of urinary incontinence. Clenbuterol also has not been reported to have severe cardiac adverse effects except for supraventricular tachycardia and atrial fibrillation in a body builder who took an acute overdose [].

The combination of solifenacin and clenbuterol is often used for the treatment of urinary incontinence. In our case, syncope appeared after the doses of solifenacin and clenbuterol were increased from 5 to 10 mg/day and from 20 to 40 μg/day, respectively. Based on previous reports, solifenacin rather than clenbuterol might have been the drug responsible for TdP associated with QT prolongation. However, a drug–drug interaction is also an important issue that should be considered. The metabolism of solifenacin occurs via CYP3A4 [], so its combination with other agents that potentially inhibit CYP3A4 could increase solifenacin levels resulting in adverse effects. However, clenbuterol is not a CYP3A4 inhibitor. Furthermore, no structural heart disease was present, serum electrolytes levels such as potassium and magnesium and hepatic function were normal, and age and mild renal dysfunction had no clinically relevant effects on the pharmacokinetics of solifenacin. Therefore, we speculate that the combination of solifenacin with clenbuterol had an impact on the development of TdP, although the exact mechanism is unknown.

In our case, amiodarone was effective in preventing TdP. However, amiodarone induced bradycardia and might cause QTc prolongation with increasing the risk of TdP, so we were obliged to discontinue amiodarone. After the implantation of a cardioverter-defibrillator with dual chamber pacing capability, she was free from syncope. Although we did not investigate genetic factors and plasma drug concentrations in this case, these approaches would be a sound strategy to evaluate the potential adverse effects of her drug therapy.

To our knowledge, this is the first report of TdP associated with the combination of solifenacin and clenbuterol for urinary incontinence.

All authors of this paper listed have participated sufficiently in the conception and design of the work, in the analysis of the data, and in writing the manuscript to take public responsibility for it. T Kato and T Adachi designed the work. K Takano, T Kamijima, S Toyoda, and T Taguchi analyzed the data. T Kato and T Inoue wrote the manuscript. All authors revised this manuscript.

The institute's ethical committee approved the access to this patient's records.

All authors disclose no financial and personal relationships with other people or organizations that could inappropriately influence (bias) the work.

None of the authors have potential conflicts to declare that could inappropriately influence the results.