The urinary safety profile and secondary renal effects of retigabine (ezogabine): A first-in-class antiepileptic drug that targets KCNQ (K_v7) potassium channels

Summary

Retigabine (RTG; international nonproprietary name)/ezogabine (EZG; North American adopted name), a first-in-class antiepileptic drug (AED) that reduces neuronal excitability primarily by enhancing the activity of KCNQ2/3 (K_v7.2/7.3) potassium channels, has recently been approved by the European Medicines Agency and the U.S. Food and Drug Administration as adjunctive therapy in adults with partial-onset seizures. Much of the RTG/EZG safety profile will be familiar to health care professionals who are experienced with the clinical use of AEDs. RTG/EZG, as a potassium channel opener, also has a pharmacologic effect on smooth muscle of the urinary bladder. Consequently, the adverse event (AE) profile of RTG/EZG includes a potential risk of effects on the urinary system. This review summarizes the urinary safety profile and any secondary renal effects of RTG/EZG using data from patients in the pivotal controlled trials and the overall phase 2/3 clinical development program. Urinary AEs were reported more frequently in patients receiving RTG/EZG compared with placebo, although most patients were able to continue with treatment. Specifically, there is an increased risk of urinary retention with RTG/EZG, with urinary hesitation representing the most frequently reported urinary retention-related AE. Potential secondary renal effects, which may be caused by an inability to empty the bladder, were evaluated. Crystals with a bilirubin-like appearance were detected in the urine of patients receiving RTG/EZG. Although investigations indicated that these crystals were not bilirubin, their composition remains undetermined. There was no causal association with urinary tract infections, and nephrolithiasis was uncommon. The reported clinical effects of RTG/EZG are consistent with its documented effects on bladder smooth muscle in preclinical studies. RTG/EZG should be used with caution in patients at risk of urinary retention.

Retigabine (RTG; international nonproprietary name)/ezogabine (EZG; North American adopted name) (N-[2-amino-4(4-fluorobenzylamino)-phenyl] carbamic acid ethyl ester) is a first-in-class antiepileptic drug (AED) that reduces neuronal excitability primarily by enhancing the activity of the KCNQ2/3 (K_v7.2/7.3) channels (Rundfeldt & Netzer, 2000). RTG/EZG has demonstrated effectiveness across a broad spectrum of seizure/epilepsy models (Daily et al., 1995; Rostock et al., 1996; Tober et al., 1996; Srivastava & White, 2005; Smith et al., 2007). The efficacy of RTG/EZG 600, 900, and 1,200 mg/day as adjunctive therapy in patients with partial-onset seizures has been demonstrated in three pivotal controlled trials (PCTs): studies 205 (Porter et al., 2007), 301 (ClinicalTrials.gov identifier NCT00232596; French et al., 2011), and 302 (NCT00235755; Brodie et al., 2010). The efficacy of RTG/EZG was maintained in the patients who continued in the open-label extension (OLE) studies of studies 205, 301, and 302.

The most frequently reported adverse events (AEs) with RTG/EZG involve the central nervous system (CNS; e.g., dizziness and somnolence), and are familiar to physicians who treat patients with epilepsy and are experienced with the clinical use of AEDs. However, unlike the majority of other AEDs, RTG/EZG may have pharmacologic effects on urinary bladder function that may be less familiar to patients with epilepsy and the health care professionals who care for them. Using data from the 813 patients in the PCTs and the 1,365 patients in the phase 2/3 clinical program, this review summarizes the urinary and renal safety profile of RTG/EZG and provides valuable information on its clinical use.

Potassium Channel Activity in Smooth Muscle

The smooth muscle of the urinary bladder relaxes to accommodate increasing volumes of urine when the bladder fills, and contracts to expel the urine during voiding. The urinary bladder contains smooth muscle and is richly innervated by sensory and sympathetic nerves, which contribute to regulation of bladder function. Urinary bladder smooth muscle contractility is regulated by the cell membrane potential and a contraction occurs in response to spontaneous action potentials (Andersson & Arner, 2004; Chen et al., 2010). Various potassium channels play differential roles in the phasic contractions by regulating both urinary bladder smooth muscle resting-membrane potential and action potentials. Voltage-gated potassium (K_v) channels (the products of KCNQ genes) may mediate repolarization of the action potential, a prolonged after-hyperpolarization state, and the resting membrane potential of the urinary bladder smooth muscle (Andersson & Arner, 2004; Chen et al., 2010).

The KCNQ (K_v7) gene family encodes five voltage-gated potassium channels (tetrameric subunits KCNQ1–5 [K_v7.1–7.5]) (Jentsch, 2000). KCNQ1 (K_v7.1) is expressed in the heart, pancreas, gastrointestinal tract, thyroid gland, brain, portal vein, and the inner ear. KCNQ2–5 (K_v7.2–7.5) genes are expressed primarily in the central nervous system, inner ear (KCNQ4 [K_v7.4]), and skeletal muscle (KCNQ5 [K_v7.5]) (Jentsch, 2000). KCNQ4 (K_v7.4) is the primary voltage-gated potassium channel expressed in the bladder, with lower levels of KCNQ1 (K_v7.1) and KCNQ5 (K_v7.5) also expressed (Svalø et al., 2011). KCNQ2/3 (K_v7.2/7.3) mutations are known to cause benign familial neonatal convulsions, and functional expression of known KCNQ (K_v7) mutations has revealed a consistent reduction of the resulting potassium current that can depolarize the cell membranes, rendering them hyperexcitable (Maljevic et al., 2008). The role of KCNQ (K_v7) channels in the control of neural excitability and their potential as a novel target for the treatment of epilepsy has heightened interest in the clinical development of RTG/EZG. However, KCNQ (K_v7) gene expression has also been demonstrated in smooth muscle (including KCNQ4 and 5 [K_v7.4 and 7.5] in murine bladder smooth muscle) and the channels have been shown to play a critical role in regulating smooth muscle contractility (Greenwood & Ohya, 2009). Enhancement of the KCNQ (K_v7) channel activity in smooth muscle should lead to membrane hyperpolarization and a resultant reduction in contractile response (Jentsch, 2000; Greenwood & Ohya, 2009).

As a result of preclinical findings in animals, the clinical effects of RTG/EZG on urinary bladder in humans were assessed during the clinical program by evaluating urinary and renal AEs, and the phase 3 studies incorporated serial collection of American Urological Association Symptom Index (AUA SI) scores and postvoid residual (PVR) bladder ultrasounds to estimate PVR urine volume. The pharmacologic effects of RTG/EZG as a potassium channel opener have been demonstrated on bladder smooth muscle and bladder function in preclinical studies. RTG/EZG increased micturition volume and voiding intervals in rats (Streng et al., 2004) and was shown to reduce both the contractility and overall tone of isolated rat bladder tissue (Rode et al., 2010). Furthermore, an effect of RTG/EZG on the urinary tract and bladder function was also observed in the nonclinical safety studies performed as part of the development program for this agent. Rodents that were chronically exposed to RTG/EZG developed distended urinary bladders, thought to be the result of RTG/EZG–induced inhibition of bladder contraction. A number of animals also had renal lesions that may have been caused by increased mechanical back pressure because of their inability to empty their bladders.

The RTG/EZG Clinical Program

The PCTs (studies 205, 301, and 302) were randomized, double-blind, placebo-controlled, parallel-group studies designed to assess the efficacy and safety of RTG/EZG 600 and 900 mg/day (studies 205 and 302), and 1,200 mg/day (studies 205 and 301) as adjunctive therapy in adult patients with partial-onset seizures. In addition to the PCTs, the phase 2/3 clinical program also includes four completed phase 2 trials (studies 200/201, 202, 209, and 214) and six long-term OLEs (completed: studies 208, 212, 216, 8,017; ongoing: studies 303 [NCT00310375] and 304 [NCT00310388]). Patients who transitioned into OLEs after completing their parent study were counted only once in this analysis and their safety data were evaluated throughout the entire duration of exposure to RTG/EZG. Patients who received placebo during a double-blind parent study and received RTG/EZG during an OLE were included from the time of RTG/EZG dosing. Data for the phase 2/3 program are included up to October 2, 2009.

A total of 813 patients received RTG/EZG in the PCTs, with 281 assigned to 600 mg/day, 273 to 900 mg/day, and 259 to 1,200 mg/day. The extent of exposure to RTG/EZG was approximately 211 patient-years, with a median exposure duration of 112 days (range, 1–196 days). The median age of patients receiving RTG/EZG in the PCTs was 37.0 years, with the vast majority (802/813; 98.6%) aged between 18 and 64 years; 3 (<1.0%) patients were aged <18 years and 8 (<1.0%) were aged ≥65 years. Approximately half of the patients (48.5%) were male, with the majority (89.3%) being Caucasian. Five hundred fifty-nine patients (68.8%) completed the study in which they were participating; 181 (22.3%) discontinued because of an AE, and 73 (9.0%) discontinued for other reasons. In the phase 2/3 program overall as of the October 2, 2009 data cutoff, a total of 1,365 patients were exposed to at least one dose of RTG/EZG, representing a total exposure to RTG/EZG of approximately 1,420 patient-years. The mean total exposure was 302.7 days (range, 1–1,736 days). The demographic characteristics of this population were similar to those seen in the PCTs. In the phase 2/3 population, 922 (67.5%) patients discontinued prematurely, including 401 (29.4%), 169 (12.4%), and 352 (25.8%) discontinuing due to an AE, lack of efficacy, and other reasons (including failed to return, patient request, protocol violation, intercurrent disease, noncompliance, and withdrawal of consent/noncompliance), respectively.

Urinary and Renal Safety Profile of RTG/EZG

In the PCTs, urinary and renal AEs were reported more frequently in patients receiving RTG/EZG than placebo (Table 1). The relative risk (RR) of reporting a urinary/renal disorder was calculated as 1.32 (95% confidence interval [CI] 0.986–1.761) in the total RTG/EZG group, and as 1.05 (95% CI 0.714–1.543) in the 600-mg/day group, 0.995 (95% CI 0.67–1.478) in the 900-mg/day group, and 1.948 (95% CI 1.409–2.695) in the 1,200-mg/day group. The most common urinary/renal AEs were urinary tract infection (UTI), dysuria, urinary hesitation, chromaturia, hematuria, abnormal urinalysis, and polyuria. The increases in dysuria, chromaturia, abnormal urinalysis, and polyuria appeared to be dose-related. It should be noted that most urinary/renal AEs in patients receiving RTG/EZG were reported in the initial 8 weeks of treatment. In the phase 2/3 population, a total of 351 patients reported a urinary/renal AE (Table 2), with the most frequently reported including UTI, urinary hesitation, abnormal urinalysis, dysuria, and urinary retention. Of these AEs, the majority were judged by the investigator as mild in intensity, with most patients able to continue treatment.

Table 1.   Treatment-emergent adverse events of urinary/renal disorders reported by ≥1% of patients in any treatment group in the pivotal controlled trials (studies 205, 301, and 302; safety population)

Preferred term, n (%)	Placebo (n = 427)	RTG/EZG
		600 mg/day (n = 281)	900 mg/day (n = 273)	1,200 mg/day (n = 259)	Total (n = 813)
Adverse events that emerged after treatment was started (treatment-emergent adverse events) are spontaneously reported.
Any event	55 (12.9)	38 (13.5)	35 (12.8)	65 (25.1)	138 (17.0)
Urinary tract infection	20 (4.7)	5 (1.8)	9 (3.3)	21 (8.1)	35 (4.3)
Dysuria	3 (0.7)	4 (1.4)	5 (1.8)	10 (3.9)	19 (2.3)
Urinary hesitation	4 (0.9)	6 (2.1)	3 (1.1)	9 (3.5)	18 (2.2)
Chromaturia	1 (0.2)	2 (0.7)	4 (1.5)	7 (2.7)	13 (1.6)
Hematuria	3 (0.7)	6 (2.1)	3 (1.1)	4 (1.5)	13 (1.6)
Abnormal urinalysis	4 (0.9)	2 (0.7)	3 (1.1)	8 (3.1)	13 (1.6)
Polyuria	7 (1.6)	2 (0.7)	3 (1.1)	6 (2.3)	11 (1.4)
Residual urine volume	1 (0.2)	0	4 (1.5)	4 (1.5)	8 (1.0)
Urinary retention	2 (0.5)	1 (0.4)	4 (1.5)	2 (0.8)	7 (0.9)
Nephrolithiasis	0	0	0	4 (1.5)	4 (0.5)
Leukocyturia	2 (0.5)	3 (1.1)	0	0	3 (0.4)
Proteinuria	3 (0.7)	3 (1.1)	0	0	3 (0.4)

Table 2.   Treatment-emergent adverse events of urinary/renal disorders reported by ≥1% of patients in the phase 2/3 analysis set (safety population)

Preferred term, n (%)	RTG/EZG (N = 1,365)
Any event	351 (25.7)
Urinary tract infection	107 (7.8)
Urinary hesitation	42 (3.1)
Abnormal urinalysis	35 (2.6)
Dysuria	33 (2.4)
Urinary retention	26 (1.9)
Hematuria	25 (1.8)
Chromaturia	23 (1.7)
Polyuria	23 (1.7)
Residual urine volume	16 (1.2)
Leukocyturia	13 (1.0)
Proteinuria	13 (1.0)

Urinary AEs

Urinary retention and voiding dysfunction

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.

UTIs and related signs and symptoms

In the PCTs, UTI-related AEs were reported in similar proportions of patients receiving RTG/EZG or placebo (8.9% and 7.7%, respectively), with the most common events including UTI, dysuria, and abnormal urinalysis (Table 1). Although a higher rate was reported at the RTG/EZG 1,200-mg/day dose, data analysis revealed that the overall frequency of reported UTIs across the three studies varied greatly, with the highest frequency reported in study 301 for three sites that enrolled 11% (33/305) of the patients accounting for 39% (12/31) of the UTIs. It is notable that none of the UTIs were preceded by an AE of urinary retention. In the phase 2/3 population, UTI-related AEs were reported by 195 patients (14.3%), and included UTIs, abnormal urinalysis, dysuria, leukocyturia, and cystitis (Table 2). These results are further complicated by the fact that UTIs were diagnosed primarily based on the investigator’s clinical assessment of the patient’s signs, symptoms, and/or urinalysis results. Urine cultures were not required by the study protocols and most UTIs were not confirmed by urine cultures. In this population, only one of 135 UTI events was preceded by an AE report of urinary retention.

Renal AEs

Renal dysfunction

In the PCTs, renal dysfunction-related AEs were reported by four patients (0.5%) who were treated with RTG/EZG, including decreased urine output, nephritis, and renal failure, in one patient each receiving RTG/EZG 600 mg/day, and increased urine output in one patient receiving RTG/EZG 900 mg/day. The event of renal failure was related to urinary retention and fully resolved with catheterization and discontinuation of RTG/EZG treatment. No renal dysfunction AEs were reported in patients receiving placebo or RTG/EZG 1,200 mg/day. In the phase 2/3 population, renal dysfunction was reported in nine patients (0.7%), including blood creatinine increased in two patients.

Urinary crystals and chromaturia

Crystals with a bilirubin-like appearance were detected on urine microscopy in 15.1% (127 of 843) of patients in the phase 3 program (studies 301 and 302 and OLE studies 303 and 304). RTG/EZG is poorly water-soluble and develops a bluish/purple color over 24–72 h when dissolved in water. In addition, because the physicochemical properties of RTG/EZG are photometrically similar to bilirubin, this can result in a false-positive urinalysis for bilirubin. It is important to note that although these crystals occurred only in patients receiving RTG/EZG, they were neither reported in association with nephrolithiasis nor were there any effects observed on relevant laboratory data or PVR volumes. A chemical analysis of urine samples determined that the crystals were not bilirubin. Indeed, urinary crystals (e.g., calcium oxalate, uric acid, calcium phosphate, triple phosphate) are common and vary according to urine pH (Fogazzi, 1996). Cloudy urine is also often the result of precipitated crystals (Simerville et al., 2005), and it is likely that these results observed in the phase 3 program patients are normal urine crystallization, or ex vivo RTG/EZG or metabolite crystal formation. The light-refractory properties of these bilirubin-like crystals together with the color formation of RTG/EZG in solution may also contribute to the reports of chromaturia, and urine turbidity and discoloration.

As a result of the crystals detected in the urine, AEs related to urinary crystals were evaluated further. In the PCTs, urinary crystal-related AEs of nephrolithiasis, renal colic, crystalluria, and abnormal urinalysis were reported in 0.5%, 0.4%, 0.1%, and 0.1% of patients in the total RTG/EZG group, respectively (compared with 0, 0.2%, 0%, and 0.2%, respectively, in the placebo group). In the phase 2/3 population, the overall number of patients reporting urinary crystal-related AEs was 23 (1.7%), including nephrolithiasis (0.7%), renal colic (0.5%), crystals in urine (0.2%), crystalluria (0.1%), and abnormal urinalysis (0.1%). There were no trends identified for symptoms, AEs, laboratory findings, or PVR volumes in the affected patients. The incidence rate calculated for RTG/EZG of 10 cases in 1,365 patients equals 7.0 per 1,000 years of exposure, and is in line with rates seen for other AEDs in the literature (Saigal et al., 2005; Mente et al., 2007; Worcester & Coe, 2008).

Nephrolithiasis is a common condition; up to 13% of men and 7% of women in the United States are expected to have at least one kidney stone during their lifetime (Goldfarb, 2009). The prevalence of nephrolithiasis in the United States in adults aged between 18 and 64 years was 1.12% for the year 2000 (Saigal et al., 2005). Although the prevalence of nephrolithiasis in the United States appears to have stabilized, the global incidence is increasing (Romero et al., 2010), with changes in dietary practices and associated conditions (e.g., hypertension, diabetes, and obesity) thought to be a major driving force. Topiramate is associated with an increased risk of nephrolithiasis due to the inhibition of specific carbonic anhydrase enzymes in the kidney (Vega et al., 2007), and there are reports of urinary lithiasis with zonisamide (Kubota et al., 2000), a sulfonamide with carbonic anhydrase activity. Although retigabine is not associated with carbonic anhydrase activity, 10 patients receiving RTG/EZG reported nephrolithiasis, three of whom had a history of kidney stones, five were also receiving adjunctive topiramate, and one had been treated for a UTI 2 weeks earlier. The kidney stone was analyzed in one case and determined to be calcium oxalate. There were two hospitalizations related to nephrolithiasis, but no patient withdrew from treatment and the event resolved in all patients. Taken together, these results suggest that RTG/EZG is not implicated in nephrolithogenic processes; the urinary retention–related AEs observed during treatment are likely to be associated with the pharmacologic effects of RTG/EZG on the bladder rather than as a consequence of lithiasis.

Conclusions

RTG/EZG, a first-in-class potassium channel opener, has a pharmacologic effect on urinary bladder smooth muscle and may be associated with urinary AEs. In this integrated analysis, urinary AEs were observed more often in patients receiving RTG/EZG than in those receiving placebo. However, most AEs were judged by the investigator as mild and were reported in the first 8 weeks of therapy with RTG/EZG, the majority of patients being able to continue treatment. There was an increased risk of urinary retention–related AEs/voiding dysfunction with RTG/EZG, which was most commonly seen at the 1,200-mg/day dose in forced-titration placebo-controlled trials, and is consistent with previously reported effects on the bladder in preclinical studies. The cases of urinary retention were not associated with UTIs or nephrolithiasis. A small number of secondary renal AEs were reported, but there is no evidence that RTG/EZG is nephrotoxic.

RTG/EZG should be used with caution in patients at risk of urinary retention, and urologic symptoms should be carefully monitored. Closer monitoring is recommended for patients who have other risk factors for urinary retention (e.g., benign prostatic hyperplasia [BPH]), patients who are unable to communicate clinical symptoms (e.g., cognitively impaired patients), or patients who use concomitant medications that may affect voiding (e.g., anticholinergics). In these patients, a comprehensive evaluation of urologic symptoms before and during treatment with RTG/EZG may be appropriate. There are few data on the safety and efficacy of RTG/EZG in patients aged ≥65 years. RTG/EZG must be used with caution in elderly patients and a reduction in initial and maintenance dose is recommended.

In clinical practice, the treatment of patients with epilepsy is based on titration of an AED to an initial maintenance dose, and observing the patient for seizure control and toxicity. Subsequent increases in AED dose are then based on efficacy and tolerability. The effects of RTG/EZG on urinary function using this treatment paradigm are not yet known. It is important to note that a robust risk management plan will be implemented and is intended to minimize the risk of urinary retention with RTG/EZG.

Acknowledgments

The authors thank Dana Fox, PhD, CMPP and David Gibson, PhD, CMPP of Caudex Medical, New York, NY, U.S.A. (supported by Valeant Pharmaceuticals International), for professional medical writing and editorial assistance with the preparation of this manuscript.

Disclosure

Neil Brickel, Paul Gandhi, Sarah DeRossett, and Kevan VanLandingham are employees of GlaxoSmithKline and have received stock and stock options. Janet Hammond is an employee of Roche and a former employee of Valeant Pharmaceuticals International, and has received stock and stock options.

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