In the PCTs, urinary retention-related AEs/voiding dysfunction were reported by 43 patients (5.3%) who were receiving RTG/EZG compared with 11 patients (2.6%) who were receiving placebo. The most common events were urinary hesitation, residual urine volume, and urinary retention. No clear RTG/EZG dose relationship was observed. In the overall phase 2/3 program, urinary retention-related AEs/voiding dysfunction were reported by 118 (8.6%) patients, including urinary hesitation, urinary retention, residual urine volume, and decreased urine flow. Urinary retention-related AEs/voiding dysfunction were generally equally distributed among male and female patients and were reported in a similar proportion of both genders (PCTs: 5.6% and 5.0% of male and female patients receiving retigabine, 2.4% and 2.8% receiving placebo, respectively; phase 2/3 program: 9.3% and 8.0% of male and female patients, respectively). When assessed by age group in the PCTs, urinary retention-related AEs/voiding dysfunction were reported in one of three patients aged <18 years, 41 of 802 patients aged between 18 and 64 years, and 1 of 8 patients aged ≥65 years. Similarly in the phase 2/3 population, urinary retention–related AEs/voiding dysfunction were reported in one of 10 patients aged <18 years, 115 of 1,344 patients aged between 18 and 64 years, and two of 11 patients aged ≥65 years. The number of patients aged ≥65 years is considered too small to allow for an adequate assessment of the risk of urinary retention–related AEs/voiding dysfunction in elderly retigabine-treated patients, a population that may be at increased risk for urinary-related AEs. The number of patients aged <18 years is also considered too small for adequate assessment.
Although RTG/EZG is associated with a risk of urinary retention, the majority of events were judged by the investigator as mild or moderate in intensity and most patients were able to continue treatment. Of the six (0.4%) patients who withdrew due to urinary retention, the majority recovered rapidly, consistent with the reversal of a pharmacologic effect of RTG/EZG on bladder function. In the phase 2/3 program, six (0.4%) and one (<0.1%) patients withdrew due to urinary retention and hesitation, respectively. Four RTG/EZG-treated patients and one placebo-treated patient in the phase 2/3 population with urinary retention required catheterization, one RTG/EZG-treated patient continued to require long-term intermittent self-catheterization. This patient was a 31-year-old man with a history of drug-induced urinary retention (associated with an anticholinergic drug) prior to entry into the study. He experienced psychomotor agitation and urinary retention after 82 days of open-label RTG/EZG (1,200 mg/day) in study 303, and presented to the emergency room with psychosis and agitation after approximately 18 h of urinary retention (PVR urine volume of 900 ml, with approximately 1,200 ml released following catheterization). Study medication was withdrawn immediately, and although the clinical situation improved, as demonstrated by spontaneous voiding on a regular basis, the patient continued to require intermittent self-catheterization. He was considered to be stable with the sequelae of self-catheterization.
AUA SI scores and PVR urine volumes were collected in the phase 3 studies (baseline, titration [Week 4 or 6], early [Week 8 or 10], and late [Week 16 or 18] in the maintenance phase, and at the time of study completion or discontinuation [Week 20 or 22]) and their associated OLEs (month 1, 3, and 12, and then every 12 months), but as administered in this protocol these assessments at the scheduled times did not prove to be predictive of urinary retention. Although the AUA SI score was developed and validated to monitor symptoms of benign prostatic hyperplasia, it has since been used as a tool to measure symptoms in women (Groutz et al., 2000; Lee et al., 2007; Khan et al., 2010; Tai et al., 2010). The AUA SI consists of seven questions (each on scale of 0–5; maximum total score, 35) that assess symptoms of urinary frequency, urgency, and related effects (Barry et al., 1992a,b). By convention, a total score of 0–7 indicates mild symptoms (usually indicative of no requirement for treatment), a score of 8–18 indicates moderate symptoms, and a score of 19–35 indicates severe symptoms. The majority of AUA SI scores in patients treated with RTG/EZG or placebo in the PCTs were in the mild range throughout the studies. Similarly, scores were generally in the mild range with long-term RTG/EZG treatment in the OLEs for the phase 2/3 population. According to the Agency for Health Care Policy and Research (AHCPR) clinical practice guidelines on urinary incontinence in adults, PVR urine volumes of <50 ml are considered adequate bladder emptying, whereas PVR urine volumes ranging from 100–200 ml or higher are considered inadequate emptying (Fantl et al., 1996). The threshold PVR urine volume considered of potential clinical concern (PCC) was arbitrarily set at 150 ml in this analysis. However, the threshold is set differently in various urologic studies, and some experts consider a threshold of 150 ml to be conservative. Therefore, values above the threshold do not necessarily imply that any action is needed. In the PCTs, mean change from baseline to week 18 in PVR volume increased by 8.2 ml in the total RTG/EZG group compared with a 9.7 ml decrease in the placebo group; however, no consistent effect was observed over time. Values of PCC (arbitrarily set at 150 ml) were reported in 1.0%, 7.7%, 7.4%, and 10.1% of patients in the placebo, RTG/EZG 600-, 900-, and 1,200-mg/day groups, respectively. In the phase 2/3 population, mean increases in PVR volumes remained generally low with long-term RTG/EZG treatment. PCC values in the phase 2/3 population were reported in 8.3% of patients at any time postbaseline, and in 6.9% of patients without PCC values at baseline. This finding is consistent with the PCTs, suggesting no worsening of effect with long-term exposure to RTG/EZG.