sign in sign up
<<
Home , Antispasmodic, Fesoterodine, Flavoxate, Propiverine, Renal colic

Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2015; 19: 719-731 : present and future

D. ARCANIOLO, S. CONQUY 1, T. TARCAN 2

Department of , University “Federico II”, Naples, Italy 1Department of Urology, Cochin Hospital, Paris Descartes University, Paris, France 2Department of Urology, Marmara University School of Medicine, Istanbul, Turkey

Abstract. – OBJECTIVE: This non-systemat - condition 1,2 . This condition has a high preva - ic review discusses the available evidence on lence, which has been estimated to be 17%-32% the use of flavoxate in the treatment of overac - in the general population 3-7 . The prevalence of tive bladder (OAB). OAB increases with age, and reaches 40% in METHODS: Medline was searched for inclu - 4,8 sion of relevant studies. No limitations in time subjects aged > 75 years , and is higher in men 9 were considered. of Afro-American or Hispanic ethnicity . RESULTS: Flavoxate hydrochloride is an anti - A marked proportion of patients with OAB (up spasmodic agent which exerts an inhibition of to 68% according to the recent EpiLUTS survey) the phosphodiesterases, a moderate calcium experience a marked deterioration in health-relat - antagonistic activity, and a local anesthetic ef - ed quality of life (QoL) 10-13 . In particular, impor - fect. Results from preclinical and clinical stud - ies show that flavoxate significantly increases tant reductions in mental health, with a possible bladder volume capacity (BVC), with greater re - association with anxiety and depression, health sults if compared to other drugs such as eme - perceptions and sexual health have been pronium bromide and propantheline. Moreover reported 10,14-15 . Patients affected from OAB show in clinical trials, both versus placebo or versus increased pain when compared with unaffected active comparators, flavoxate treatment was as - controls 13 . Moreover, about 30% of patients with sociated with a significant improvement in dif - OAB suffer from incontinence 16 , and OAB is fre - ferent low urinary tract symptoms, such as di - urnal and night frequency, urgency and urinary quently associated with infections of the low uri - 17 incontinence, suprapubic pain, , hesi - nary tract . Lastly, OAB results in lower levels tancy and burning. In addition flavoxate was as - of work productivity 18 . sociated with an overall more favourable safety The above-mentioned consequences of OAB profile than competitors. are particularly evident in the elderly 19 . In addi - CONCLUSIONS: Several researches and a tion, there are a number of other consequences: number of years of clinical practice have proven the efficacy and tolerability of flavoxate for instance, , and incon - administration in the treatment of OAB and as - tinence may be associated with an increased oc - sociated symptoms. However, new studies are currence of falls and fractures. Therefore, health - necessary to collect more evidence on the role care costs related to OAB will increase with the of this molecule in the treatment of OAB and to increasing life expectancy of the population 20 . further explore its use in other indications such Treatment of OAB may consist of behavioral as symptomatic treatment of lower urinary tract training (prompted voiding, bladder training, infections. pelvic muscle rehabilitation), non-pharmacologi - cal measures such as transcutaneous electrical Key words: nerve stimulation, catheterization, and use of ab - Flavoxate, OAB, Urodynamics, Lower urinary tract in - sorbent pads, and pharmacological therapy 17,21 . In fections. particular, pharmacological treatment for OAB is based on a number of like darife - nacin, flavoxate hydrochloride, , Introduction chloride, tartrate, trospi - um chloride, transdermal, and so - (OAB) syndrome is de - lifenacin succinate and the novel fu - fined by the International Continence Society marate 21,22 . (ICS) as ‘urgency, with or without urge inconti - Despite the availability of multiple pharmaco - nence, usually with frequency and nocturia in ab - logical options, uncertainty remains on the opti - sence of an underlying metabolic or pathological mal drug of choice 21,23,24 . agents

Corresponding Author: Davide Arcaniolo, MD; e-mail: [email protected] 719 D. Arcaniolo, S. Conquy, T. Tarcan are widely used, but when using these agents, it Criteria for Selection of Evidence is necessary to adequately consider adverse reac - tions due to systemic blockade of re - With the aim to identify the key publications ceptors, according to the Guidelines issued by on flavoxate for potential inclusion in this pa - Neurogenic Bladder Society 25 . per, a literature search was conducted in the on - Among different drugs, flavoxate hydrochlo - line database Medline using different combina - ride was the first agent to be ap - tions of pertinent keywords: “flavoxate ” AND proved by the FDA for the treatment of OAB 26 . (“overactive bladder ” OR “urinary inconti - This molecule is widely used in clinical practice, nence ”) Only articles written in English lan - and its efficacy and safety have been tested in guage were selected. The search was last updat - several clinical trials. The mechanism of action ed on the 17 th May 2013, without any limitation (MoA) of flavoxate also suggests the potential on the publication date. use of this molecule in indications other than Articles were selected for inclusion according OAB, such as low urinary infections , in combina - to their relevance, as judged by the Authors; tion with antibiotics. other references could also be retrieved by man - This review will discuss available evidence on ually browsing the reference list of the identi - the use of flavoxate in the treatment of OAB, and fied articles, and other papers from Authors’ will comment on the potential applications of personal collections of literature could be con - this drug. sidered as well.

Figure 1 . A, Inhibition of phosphodiesterase activity in bladder tissue induced by aminophylline, flavoxate and MFCA. B, Calcium antagonist activity of flavoxate on Guinea Pigs.

720 Flavoxate: present and future

Mechanism of Action tivity 30,27 . In Guinea Pigs, flavoxate reduced peri - staltic motility, endoluminal pressure and longi - Flavoxate, administered as a (flavox - tudinal muscle contractility, thus, showing a my - ate hydrochloride) , acts as a direct spasmolytic orelaxant effect. In the same test, anticholinergic on and maintains anticholinergic compounds such as , hyoscine and eme - as well as local properties 21 . This drug pronium failed to relax this tissue. In another se - exerts an inhibition of the phosphodiesterases, a ries of experiments the effects of flavoxate and moderate calcium antagonistic activity, and a lo - anticholinergic drugs on the contraction elicited cal anesthetic effect 27 . by vagal electrical stimulation of the guinea-pig In particular, the phosphodiesterase enzymes isolated in toto were assayed: the results play a key role in the activity of the detrusor mus - obtained suggest that the action of flavoxate is cle of the bladder; therefore, the inhibition of these due to direct smooth muscle relaxation and does enzymes exerted by flavoxate contributes to a re - not involve anticholinergic activity 30 . duction of the contraction of this muscle. Of note, the inhibitory effect of flavoxate on the phosphodi - esterase activity in the bladder tissue is greater than Urodynamic Effects that associated with aminophylline, a non-selective inhibitor of phosphodiesterase (Figure 1A) 28-30 . The urodynamic effects of flavoxate were in - Flavoxate also presents a calcium antagonist vestigated in a number of preclinical studies. activity, as shown by studies on Guinea Pigs (Fig - More than 30 years ago, a preliminary experi - ure 1B) 29 . More in detail, flavoxate suppresses mental study 33 showed that both flavoxate and - and calcium ion (Ca 2+ )-induced con - propantheline significantly increased bladder ca - tractions of isolated detrusor strips in a noncom - pacity (from 383 ml at baseline to 425 ml with petitive and a competitive manner, respectively 31 . flavoxate and to 550 ml with propantheline). In addition, animal studies show that intra - However , the two drugs differed in their effect on venous flavoxate suppresses both initial phasic, residual : flavoxate induced a decrease in and later tonic, bladder contractions induced by volume from 60 ml at baseline to 45 ml, while electrical stimulation of the distal end of the pelvic propantheline administration resulted in an in - nerve 31 . This action abolishes isovolumetric rhyth - crease in residual urine volume, up to 105 ml. mic bladder contractions and the associated effer - The effects of flavoxate on urodynamics, ent pelvic nerve activity, without any effect on compared with those associated with other baseline vescical pressure and afferent pelvic drugs used for the stabilization of the detrusor nerve activity. When administered in cerebral ven - muscle, were further investigated in a rat model tricles or intrathecally, flavoxate abolishes isovolu - (Figure 2A and B) 34 . More in detail, emeproni - metric rhythmic bladder contractions. In cats, um bromide, oxybutynin and nifedipine affect - flavoxate microinjected into the nucleus reticularis ed, in a dose-dependent fashion, the micturition pontis oralis – the pontine micturition inhibitory pressure, with overall modest changes in blad - region – inhibited the reflex micturition; however, der volume capacity. induced signifi - this effect was not shown when the molecule was cant increases in bladder volume capacity injected into the locus coeruleus (pontine (BVC), but these changes were always not dose- micturition center) or locus subcoeruleus (pontine dependent. Indomethacin significantly increased urine storage center) 31 . BVC and determined a modest reduction in mi - These effects are corroborated by local anes - cronutrition pressure, but these effects were not thetic action, similar to that exerted by lidocaine. dose-related. Only flavoxate induced significant It has been observed 32 that intradermal injections increases in BVC, without any dose-effect rela - of flavoxate or lidocaine on the back of guinea tionship; in addition, this molecule did not de - pigs were able to induce a very similar anesthetic termine any change in micturition pressure. effect, with highly comparable IC 50 values The marked urodynamic effects of flavoxate (3.2x10 -3 and 3.8x10 -3 for flavoxate and lidocaine, have also been observed in men. In total, 13 hu - respectively). The Authors of the study suggested man urodynamic studies have been performed that this anesthetic activity could be linked to a with flavoxate 35-47 . Overall, all studies were con - reduction in the electrical activity of bladder and sistent in showing an increase in BVC associated . Of note, flavoxate presents only a very with flavoxate administration (Figure 3). In par - modest – virtually lacking – anticholinergic ac - ticular, a comparative study which analyzed sev -

721 D. Arcaniolo, S. Conquy, T. Tarcan

Figure 2 . A, Effects of flavoxate and other drugs for detrusor stability on micturi - tion pressure in rats. B, Effects of flavoxate and other drugs for detrusor stability on blad - der volume capacity in rats.

Figure 3 . Increase in bladder capacity reported in 13 urodynamic studies in flavoxate-treated patients.

722 Flavoxate: present and future eral hundred cases of motor urge incontinence in Studies Versus Placebo females showed that the increases in BVC asso - Overall, 8 studies versus placebo have been ciated with flavoxate were greater than those re - conducted to date; they included more than 700 ported with emepronium and propantheline. An patients with different conditions, who were increase in bladder capacity was observed 40 in treated over a period of 6-28 days. The results 56%, 44% and 50% of patients treated with observed in these trials , in terms of success rate flavoxate, emepronium and propantheline, re - achieved with either flavoxate or placebo , are spectively. However, the average increase regis - summarized in Table I 36,39,50-54 . tered with flavoxate (83 ml) was remarkably In a study by Servadio 36 , patients affected by higher than those observed with emepronium (39 either cystitis or urethrotrigonitis were treated ml) or propantheline (28 ml). with flavoxate 200 mg tid or placebo. More than The increase in bladder capacity determined 50% of flavoxate-treated patients reported a by flavoxate was evident also when considering “very good” or “moderate” response – and 47% a first urge to void 43,44,46,48 . In particular, a 4-week “very good” response – versus 32% of those as - double-blind, randomized trial in 27 patients signed to placebo. Moreover, flavoxate treatment showed that flavoxate at both 1200 mg/day and induced a statistically significant increase in 600 mg/day dosages determines a 40 ml increase bladder capacity ( p < 0.01) and a decrease in in bladder volume at first urge to void 43,44 , and bladder pressure ( p < 0.01), and it was overall as - overall similar results were observed in the other sociated to a significant improvement in several studies which investigated this parameter 46,48 . symptoms, such as diurnal and night frequency, Lastly, a small study, only published in an ab - urgency, suprapubic pain, dysuria, hesitancy and stract form 49 , to our knowledge, showed that burning. flavoxate was associated with a reduction in The placebo-controlled study conducted by post-void residual volume, although this effect Akasaka et al 53 on 120 subjects affected by fre - was greater in males than in females. quency and urgency of urination, sense of resid - ual urine and discomfort upon urination led to similar results. Overall response rate with flavox - Clinical Evidence ate was 80% – with 48% “excellent” or “good” responses – compared with a 52% response rate The MoA of flavoxate and its effects on blad - achieved with placebo; in addition flavoxate was der urodynamic represent the basis for its clini - more effective than placebo in reducing individ - cal efficacy, which has been extensively investi - ual symptoms. gated in a number of comparative studies versus Baert 51 evaluated the use of flavoxate in 60 pa - placebo or active comparators. In addition, two tients suffering from painful conditions of the well-conducted uncontrolled experiences have lower urinary tract, arising from inflammation been published and one meta-analysis has ex - and/or infection or from following diag - plored the use of flavoxate in the treatment of nostic or therapeutic procedures. A significant OAB. improvement was noted in frequency and supra -

Table I. Success rates of placebo-controlled trials on flavoxate.

Study Success rate p value Flavoxate Placebo

Servadio, 1974 36 60% 26% n.a. Wehnert and Sage, 1989 39 n.a. n.a. n.a. (+142% score improvement) (+73% score improvement) Yoshida and Kazuko, 1975 50 55% 28.6% < 0.05 Baert, 1974-1975 51 n.a. n.a. n.a. (discontinued for inefficiency 6) (discontinued for inefficiency 12) Fukushige, et al 1975 52 83.4% 58.8% < 0.01 Akasaka, et al 1975 53 80% 51.7% 0 .005 Miyazaki, et al 1975 35 80% 52.1% < 0.05 Sonoda, et al 1975 54 59.3% 18.7% < 0.05 n.a.: not available

723 D. Arcaniolo, S. Conquy, T. Tarcan pubic pain, and marked relief of dysuria, hesitan - Similar results were disclosed in another study cy and burning was also reported, thus support - on 20 patients affected by urgency, frequency ing the effect of flavoxate on different low uri - and urge incontinence, who were administered nary tract symptoms. either flavoxate 200 mg qid or propantheline 30 Overall similar results on flavoxate effects were mg qid. The results showed that the clinical ef - observed in other placebo-controlled trials 35,39,50-52,54 . fect of flavoxate was comparable to that of propantheline in terms of therapeutic response Studies Versus Active Comparators and increase in the overall bladder capacity. Flavoxate has been studied in several con - However, only flavoxate determined a reduction trolled and open label studies against active com - in residual urine volume, while propantheline parators including emepronium, propantheline, produced a marked rise of this parameter (up to butylscopolamine, oxybutynin, , 105 ml) 33 . (Table II) 33,39,40,54-59 . In a randomized controlled trial on 43 patients, Stanton 55 compared the efficacy and tolerabili - Herbst 56 reported an overall therapeutic response ty of flavoxate 200 mg and emepronium 200 mg of 52% with flavoxate 200 mg qid, compared in the treatment of 38 patients with urinary in - with 27% achieved with propantheline 15 mg continence affected by either detrusor instability qid 56 . Similar findings were reported when com - or sphincter dysfunction. The results of this ran - paring flavoxate with butylscopolamine (success domized study showed that flavoxate was more rate 59-65% with flavoxate vs 42-44% with effective than emepronium in decreasing stress butylscopolamine) 54,57 and with oxybutynin (82% incontinence, relieving symptoms of urgency and vs 65-79%, respectively) 58 . in reducing diurnal frequency. Overall, 86% of In particular, Niijima et al 57 performed a dou - patients receiving flavoxate experienced an im - ble-blind controlled trial to investigate the effects provement in , versus 66% of flavoxate and butylscopolamine on neurogenic of those assigned to emepronium; however, the frequency and irritable bladder. Overall, flavox - difference did not reach statistical significance. ate showed a marked therapeutic effect, with a Flavoxate was also more effective than emepro - more evident improvement in urination, urinary nium in reducing intravescical pressure and in in - urgency and discomfort after urination than creasing overall bladder capacity, even though butylscopolamine. Flavoxate was also superior in the difference did not reach statistical signifi - the treatment of urinary incontinence, while no cance. Neither drugs produced any significant in - differences were reported between the two drugs crease in residual urine. in terms of amount of residual urine. Flavoxate was also associated with a higher Flavoxate 1200 mg/day was also compared to success rate than propantheline in three compara - oxybutynin 15 mg/day in a randomized trial 58 on tive studies 33,40,56 . Overall, the success rate deter - 50 women with motor or sensory urgency. Re - mined by flavoxate therapy was 50% or higher, sults showed a higher therapeutic response versus 15-30% reported with propantheline. achieved with flavoxate, with 82% of patients Gaudenz and Weil 40 reported the results of a cured or improved, compared with 79% reported comparative study on more than 100 women af - with oxybutynin. In addition, flavoxate was asso - fected from motor urge incontinency, treated with ciated with a more marked decrease in several either flavoxate 200 mg tid, propantheline 30 mg symptoms such as incontinence, urgency, pads tid or emepronium 200 mg tid. The therapeutic re - use and dysuria, and it was overall preferred by sponses were 50% with flavoxate, 44% with 61% of patients. propantheline and 34% with emepronium, with an Another analysis of nine clinical trials 59 , con - overall higher response rate achieved with flavox - ducted in the ’70s, showed a numerically higher ate. Flavoxate was also associated with a higher success rate with flavoxate than with phenazopy - percentage of cure or improvement of the main ridine, in patients with prostatitis (66% vs 31%) symptoms associated with motor urge inconti - or other urinary disorders (80% vs 56%). Simi - nence, such as urgency incontinence, urinary fre - larly, the evaluation of symptom-severity per - quency, urgency imperative, nocturia and stress formed after two and five days of therapy re - urinary incontinence. Bladder capacity was also vealed that the majority of symptoms improved increased by all three drugs, with a slightly better in a higher percentage of patients on flavoxate result achieved with flavoxate: 56% versus 50% therapy than in those treated with phenazopyri - with propantheline and 44% with emepronium. dine.

724 Flavoxate: present and future

Wehnert and Sage 39 accomplisched a cross- events in the anticholinergic groups, while in the over, placebo-controlled study on 46 patients suf - remaining four trials significant differences be - fering from urgency/urge incontinence, who were tween flavoxate and anticholinergic drug were treated with propiverine 45 mg/day and flavoxate observed, with more adverse effects registered in 300 mg/day for 4 weeks. Both groups showed a the anticholinergic group. However, the Authors significant reduction of micturition frequency of this analysis concluded that there is inade - and an increase in compliance, whereas the quate evidence as to determine whether flavox - placebo was ineffective. Both agents were associ - ate is better or worse than anticholinergic med - ated with a similar improvement of symptoms or ications. urgency/urge incontinence .

Uncontrolled Experiences Fehrmann-Zumpe et al 60 studied the efficacy Safety Profile of flavoxate in an observational study conducted on 1,800 patients with urge incontinence treated To date, all studies agree that the flavoxate with flavoxate over a period of 2 weeks. A sub - treatment of OAB is well tolerated. It causes no group of 618 patients without urinary tract infec - additional adverse consequences due to residual tions or benign prostatic hyperplasia were treated urine and it is not associated with risks of ven - with flavoxate only, and showed a reduction of tricular arrhythmia 62 . dysuria (37%), nocturia (53%), and both daytime Available data show that the occurrence of all- (61%) and nighttime urge (69%). Bladder vol - grade adverse events ranges from 3.9% with the ume at first urge sensation increased by 36%. In 600 mg/day dosage to 5.0% with the 1200 89.2% of all patients the residual urine volume mg/day dosage, and only sporadic severe adverse was stable or decreased. Both groups showed events (n=8 in the period 2008-2010) related to better results with flavoxate qid (800 mg) com - study drug were reported (Figure 4) (data on pared to tid (600 mg). file). In another unblinded, uncontrolled clinical Flavoxate was also associated with an overall study, Gu et al 61 studied flavoxate on 361 patients more favourable safety profile than competitors with urgency/incontinence. Patients received in a number of head-to-head studies 33,40,44,56,57 . flavoxate 200 mg tid, orally, for 2 weeks (al - Compared with oxybutynin, flavoxate was asso - though 33 patients received a daily dosage of ciated with a significant lower percentage of side 1.200 mg). Overall, among 336 evaluated pa - effects: 26,8% versus more than 90% observed tients, 228 (67%) were completely cured of ur - with oxybutynin 44 . Also when compared with gency/incontinence symptoms, 66 (20%) were propantheline or emepronium, flavoxate had a improved and 42 (13%) did not report any favourable tolerability profile, ranked as “good” change. Flavoxate was also effective in 77.4% of in nearly 90% of the cases 33 . In addition , pro - patients who were refractory to previous anti - phanteline was associated with a higher preva - treatment. lence of side effects such as difficulties in urina - tion, blurred vision and dry mouth, which were Meta-Analysis absent or rare with flavoxate treatment 33 . A Cochrane meta-analysis 23 evaluated 12 tri - Of note, in the comparative study by Gau - als on the treatment of OAB in adults, among denz et al 40 no withdrawals were reported for which nine trials compared flavoxate with anti - patients treated with flavoxate, while the per - cholinergic agents. Overall, there was no evi - centages of withdrawal for safety reasons were dence of a difference in cure rates between anti - 11% and 8% for propantheline and emeproni - and flavoxate: most of the studies um, respectively. The tolerability of flavoxate is reported no statistically significant difference further supported by the results of the large between the two drugs, while some studies sug - Cochrane meta-analysis of anticholinergic gested that patients actually preferred flavoxate drugs versus other medications for OAB in treatment but objective assessment with urody - adults 23 . Statistical analysis demonstrated how namics was equivocal. One study reported no flavoxate was associated with a reduced risk of difference in the number of patients affected adverse events than anticholinergc agents (Rel - from nocturia after treatment. With respect to ative Risk: 2,28; 95% Confidence Interval 1.45- tolerability, three studies reported worse adverse 3.56).

725 D. Arcaniolo, S. Conquy, T. Tarcan d e : u g t n % i u p 8 t r 1 : n d : t g o g p c u e % r n s e i h 1 t 0 % d l t t : p t 3 5 a b e r g p f : : a t h 3 t t s n t g g o T t t n i % % % 1 1 p p t n n f e p p 9 4 8 : : i i a n t t 1 1 o c 5 5 8 d d t t n t 1 3 a a o i i t : : n i : : : p p n i p : : o o t t r t o o p g g o e e e t r r o n n p p u c v v 1 1 p n n i c c c 1 s a h h 1 i i t o o t y : : t t l l n n n : 1 1 i i u n n n n 1 a / : / t s s p i i i i e e a a a s s i n : : u : n s s h h h r i r i r l e e t t t i i e e s o 3 e e y y y y n f f e e e v v i t t t t t i s l u u l u l h h : n n b l l l l t s e i i n d d o o o o o o c c d d a s u u u u n a t t t s s e e n a a e e o e e r c c c c t t i o m m m r r s r i i i i d d c g g g w w r a r a z c e f f f f a a u p s l o u y y u y o u s f z f f f u o u o i i e r r i r e r i r i r a e r i i r l l l l o D H D D D B D D H D D B D D B T D N D D D B D D % % % 5 7 4 2 1 1 : : : O n 2 n n o O o o i H 2 i i t t t c H c c m a a a r l c : : : r r t l m t t y y y n l l m 6 c % % % % % % % % % t t t n n m . o i i i 4 7 5 6 2 6 0 0 0 o o m 6 m 5 9 % c l c c c . 7 3 2 1 6 5 8 3 5 5 c c 5 - - a a a l r 9 5 6 2 : : : : : : : : : % . s s m r r p p p : : o 5 1 1 4 e e e e e e e e e s s 1 6 m % % o o a a a e e s s s s s s s s s s 0 e e 5 6 s s r r 5 5 c c c r r + + + + u n n n n n n n n n 5 9 . . t t : : u u u u r r r r : : : : o o o o o o o o o 1 0 2 s s r r t s s y y t t + - e e e y y y y s p p p p p p p p p s s 3 6 c c t t t t s s n n : : d d d s s s s s s s s s e e e i i i i l : : i i n n e e l l r r e e e e e e e e e e e d d d d c c c c e e e e t t r r r r r r r r r d d m p p n n a a a a a a a c c f m m g g i i l l l n n f f s l l c c c c c c c c c p p p p r r r r n n o 3 e e b b b i i i i i i i i i 9 8 o o a a a a a a e e e t t t t t t t t t u u u u 8 c c n 3 2 c c c c m m d d d n n u u u u u u u u u l l f f i i n n + i i m o e e e e e + + r r r r e e e e e e e e e s s a a t t o o o o i , s s s v v e e e e i i t e e ; ; p p p p p p p p p o u u n n t f t f i a a a o o d d d d a a a a a a a a a v v c d d o o e e b b r b r e e e r r r r r r r r r % % % i i t a a i i d d d d i i i c c r r r l l s s e e e e e e e e e r p r p 0 4 6 a a a a u c h c t h c t h n n e e l l l e l e h h h h h h h h h 5 4 i 5 i n n n n n m n n n m I I T I I T R I I T I T I R O T B B B R B T I T R I T T . s r o t a r a e e e d d p d d d d . . n n n . . . . d d i i m m t d i i i i . i . i i . . m . . . . . l l l i i u u i n t . t q . q t t i i o e e e . e e e e q t q e c t t t t n n h h h g g g g g g t t t a a a a k k o o g g g e m r n n r n m m m m m m x x x x v w w t a a a p p i m m m o o o o 0 0 0 0 0 0 t a e p p e p v v v v 1 1 c 0 5 0 0 0 0 0 0 0 o o o e a a a a m m a r r l l r l l 2 – 1 – 3 2 2 3 2 2 2 r E P P E T F F P F F s u s d e r n c e a v n ) e 9 e y n t 1 i c a t y = r n x n c e n y e o e o ( c o n r t u c v c e n a o y q n a e n g n c l e i e i r m n f n r r i n u f e e t i u h n n , t t g g n h i o r y r o n h t o i t c i u u o s w t c i l , n c ) w , n ) a a e w i n l i 8 , 2 8 i u r , 1 u 1 e 3 0 2 t q 8 d = g 4 2 1 = p e 3 d r n n r n e o a = = u ( ( = f = l l P n n n n o r t , n d o n d i l c l e a l f i b l e r o l o t e b r l s r t l t u g l e a n l o i n u v a o i r d i s t o s c r , e t s r e d d d s r v e e e d i e o z z z t r n i i i v a c a r o n m m m - , a s s o o o d g p c l s i i d d d n a t s i o m n n n i l s r r e i a a a o t c b r R R R D C e t c a r a 3 3 h 5 7 5 c 6 5 7 3 0 n d 0 4 9 7 i n 7 0 1 9 a a 9 8 , 1 1 M 9 z n , e , 1 n n . t s I e y l o s r I i t d d e b e n r u e % d u a l e a e t t 1 W b P 1 S H S G a T

726 Flavoxate: present and future - a p : % % s 6 t 4 3 2 p : ; n t n i i n a a e p p i t h h a c c p a a : % t m m 8 p o % . % % o t % t ; 2 8 4 5 s s 8 % y 2 1 8 2 r r 7 2 a y : : : : o o : : t s s s s d l i l t t t t h h l a a t t c c c c a i n n e e e e u u i b i s f f f f o o f f f f e a m m e e e e r m m o o m e e e e e i ...... d d l y y t d d d d a a a a a a a a r r b b i i i i ...... o r A D n A T D S n S S n n n n n S n u o f : , , ) ) d 3 i s s 8 i i . q t t i i 0 ; t t t : a a s 8 t t * r n 7 s s e . o a r o o 0 e r r o w : p p c M ( ( * s = e s r 2 % % % % % % % % % % o m 2 4 2 9 5 2 9 1 4 6 c o o t 8 6 8 7 6 4 5 3 4 6 s t : : : : : : : : : : t s p s e e e e e e e e e e s s s s s s s s s s e m m n n n n n n n n n n b o y t o o o o o o o o o o s 5 p = 9 p p p p p p p p p p . n 0 s s s s s s s s s s i . m 0 0 2 2 ) ) e e e e e e e e e e 2 6 1 r r r r r r r r r r y : s s 7 7 e : 9 6 r r s e e 0 0 . . g s m c c c c c c c c c c . . e e c i i i i i i i i i i c 0 0 n o n e t t t t t t t t t t 0 0 h h 1 9 n i n r a t t : : u u u u u u u u u u e f : : 7 5 e h m o o y y . . e e e e e e e e e e e n a a n ( ( c c c i i i i 0 0 d g p p p p p p p p p p o t t r r n n e n a a a a a a a a a a : : c n n t n u u r r r r r r r r r r e e % % s s t a a a o s s o . . e e e e e e e e e e g g 6 0 d d h e u c c a a u r y r y h h h h h h h h h h a a 5 . c 8 . l n n a U P D I T I M O U P D T T T n T T T T T n T . s v r e o e e , t n n e e a i i s r n i a u m m y y d p . a d a a a y i d . l l t r d . d d i a n n y e a m . o . o / / i i y d i d a n t y n p o . . p p g g / n n e e e e e e i p a i d t e c t t t t t t r . o o g g / y y o d d t m m a a a a a a t t e c c / g g e z n m m m x x x x x x s s u u v g g v 0 0 a t l l a i i m m o o o o o o b b 0 0 0 0 n t y y a p v v v v v v m m y y t t a e c 0 2 2 0 0 5 o i e a a a a a a x x u u a l l l l l h r l r 5 2 1 1 5 2 3 4 r u F 1 F T F O F O B F P B P F s s u y s r d r e , o c s v e t y i r l c o n e e b t r n e d a m a e o t g r e y i x g c o o g h s r r o r t r i s r n i t i i u v u u i e / t d a e , w g d l y a r e n f t y n e e c c u r s l a c h n n n n a a o t n y e i o r e y o n r e i i g m c p n s w r o r t n i r e l n i t s f , u u h a t e a e t l n n i , 1 , r n d i u r e o u 0 0 6 t e o d q s c w 5 1 4 h c a p . . e d t r l n r s n a a i e o t . = = = o o f i . b l , l n n n P n n P y o c r t n e n e v r i o u t e d c q a v e r l f e o l r a - o f o s p r s s l t l l l t m l a o a a n a r i i i o l u n o r r r c r c a s t t t c i , e u r r t d r e e t d d e c n v v e e t r i d i i o l z z t t e n n i i n a a b e v a r r n c m m o d e a a s - l i o o g n p p c s t i b . i l d d l a s t l s y u a m m n n u o s l i a a e o i a a r o o i r a r t m d r n R R C D D C t C e r t a c u s i a e r d a : m h i e t r c 0 , o 6 9 e n 4 7 8 9 3 c d o e 5 i 5 5 5 5 9 s r n n a 7 3 8 5 5 i 8 h a 9 s 9 8 7 7 r t 9 M t , 1 , 9 9 9 9 b : r m 1 , a a . , 1 1 1 1 i d e I o m y i d d e t I l l l l n m t n l a o i d g a a a a l a p h ; j u l e a n a i t t t t s u i e l o i m t c o t e e e S e b y n G S M W N S S e S a i * T t

727 D. Arcaniolo, S. Conquy, T. Tarcan

Figure 4 . Occurrence of all-grade adverse events with flavoxate 600 mg/day or 1200 mg/day.

Expert Opinion of this bothersome condition. While this evi - dence appears eagerly awaited, we believe that Flavoxate was the first antispasmodic agent to there is a place for flavoxate in clinical practice. be approved by the FDA for the treatment of In fact, clinical experience on flavoxate in OAB, and since its approval it has been largely routine daily practice is wide; although the effi - used in clinical practice: ‘field-practice’ experi - cacy of this molecule seems at least not-inferior ence on this molecule is broad. Available phar - than the efficacy of other agents used in the macovigilance data show that that up to Decem - same setting, the good tolerability profile ber 2010 more than 20,210,000 patients have shown by flavoxate should be taken into ac - been treated with flavoxate (Recordati S.p.A., count when selecting an agent for OAB. Only a Milan, Itatly, data on file). few adverse events have been reported with the Flavoxate has been tested on different popu - use of flavoxate such as nausea, vomiting, dry lations of patients in a number of clinical stud - mouth, headache, dizziness, blurred vision, and ies, which proved its efficacy and tolerability in nervousness. However, caution is recommended the treatment of OAB and associated symp - when the drug is given to patients with glauco - toms. However, despite evidence collected from ma, as, like all anticholinergic drugs, flavoxate those studies seems well-grounded, it is neces - may present the risk of precipitating angle clo - sary to point out that most studies have been sure glaucoma 63 . Administration of the drug conducted more than 20 years ago, were of lim - during pregnancy/lactation should also be ited sample size, and compared flavoxate with avoided. other medications which are no longer used in Interestingly, the peculiar MoA of flavoxate clinical practice. On these bases, the Authors of might suggest the possible use of this molecule the most comprehensive Cochrane Review con - in indications other than OAB. For instance, we ducted on OAB treatments 23 and the recom - speculate that the prompt local anesthetic and mendations issued by the 4 th International Con - urodynamic effects exerted by flavoxate can have sultation on Incontinence 62 concluded that, de - a role in the symptomatic treatment of lower uri - spite the favorable results shown in clinical tri - nary tract infections, while antibiotics exert their als, there is currently no enough evidence to microbicidal action. Similarly, flavoxate, thanks clearly identify the role of flavoxate in the to its analgesic effect, can help control pain and treatment of OAB. discomfort during bothersome interventional pro - A consensus on the optimal pharmacological cedures such as catheterization. We do believe treatment of OAB however still lacks. This unde - that ad hoc trials are needed to investigate these fined scenario suggests the need of new, well- intriguing hypotheses, which – if confirmed – grounded pieces of evidence on the use of will add further ground for a wider use of flavox - flavoxate and other molecules for the treatment ate in clinical practice.

728 Flavoxate: present and future

Conclusions 8) WEIN AJ, R OVNER ES. The overactive bladder: an overview for primary care health providers. Int J Flavoxate appears as a well-established drug in Fertil Womens Med 1999; 44: 56-66. the current treatment scenario of OAB; more evi - 9) COYNE KS, M ARGOLIS MK, K OPP ZS, K APLAN SA. Racial differences in the prevalence of overac - dence is anyhow required to further explore its use tive bladder in the United States from the epi - in this and – potentially – in other indications. demiology of LUTS (EpiLUTS) study. Urology 2012; 79: 95-101. 10) MILSOM I, K APLAN SA, C OYNE KS, S EXTON CC, K OPP ZS. ––––––––––––– –– ––– –-–– Effect of bothersome overactive bladder symp - Acknowledgements toms on health-related quality of life, anxiety, de - Sophie Conquy was a consultant for Bouchara Recordati pression, and treatment seeking in the United France. Editorial assistance for the preparation of this manu - States: results from EpiLUTS. Urology 2012; 80: script was provided by Luca Giacomelli, PhD, and Ambra 90-96. Corti, on behalf of Content Ed Net; this assistance was sup - 11) KOBELT G, K IRCHBERGER I, M ALONE -L EE J. Quality-of ported by Recordati International. life aspects of the overactive bladder and the ef - fect of treatment with tolterodine. BJU Int 1998; 83: 583-590. ––––––––––––– –– ––– –-–– Conflict of interest 12) O’C ONOR R, J OHANNESSON M, H ASS S, K OBELT -N GUYEN G. Urge incontinence: quality of life and patients’ The Authors declare that there are no conflicts of interest. valuation of symptom reduction. Pharmacoeco - nomics 1998; 14: 531-539. 13) LIBERMAN JN, H UNT TL, S TEWART WF, W EIN A, Z HOU Z, References HERZOG AR, L IPTON RB, D IOKNO AC. Health-related quality of life among adults with symptoms of overactive bladder: results from a US community- 1) ABRAMS P, C ARDOZO L, F ALL M, G RIFFITHS D, R OSIER P, based survey. Urology 2001; 57: 1044–1450. ULMSTEN U, VAN KERREBROECK P, V ICTOR A, W EIN A. Standardisation Sub-committee of the Interna - 14) COYNE KS, K VASZ M, I RELAND AM, M ILSOM I, K OPP ZS, tional Continence Society. The standardization of CHAPPLE CR. Urinary incontinence and its relation - terminology of lower urinary tract function: report ship to mental health and health-related quality of for the Standardization Sub-committee of the In - life in men and women in Sweden, the United ternational Continence Society. Neurourol Urody - Kingdom, and the United States. Eur Urol 2012; nam 2002; 21: 167-178. 61: 88-95. 2) ABRAMS P, C ARDOZO L, W EIN A. ICUD-EAU 5th Inter - 15) COYNE KS, S EXTON CC, T HOMPSON C, K OPP ZS, M IL - national Consultation on Incontinence, Paris, SOM I, K APLAN SA. The impact of OAB on sexual 2012. health in men and women: results from EpiLUTS. 3) MCKILLOP C. Interview with Chris Chapple overac - J Sex Med 2011; 8: 1603-1615. tive bladder: tackling the problem. Eur Urol 2006; 16) STEWART WF, V AN ROOYEN JB, C UNDIFF GW, A BRAMS P, 49: 921-923. HERZOG AR, C OREY R, H UNT TL, W EIN AJ. Preva - 4) CHAPPLE CR, A RTIBANI W, C ARDOZO LD, C ASTRO -D IAZ lence and burden of overactive bladder in the D, C RAGGS M, H AAB F, K HULLAR V, V ERSI E. The role United States. World J Urol 2003; 20: 327-336. of urinary urgency and its measurement in the 17) SAHAI A, K HAN MS, A RYA M, J OHN J, S INGH R, P ATEL overactive bladder symptom syndrome: current HR . The overactive bladder: review of current concepts and future prospects. BJU Int 2005; 95: pharmacotherapy in adults. Part 1: pathophysiolo - 335-340. gy and anticholinergic therapy. Expert Opin Phar - 5) MILSOM I, A BRAMS P, C ARDOZO L, R OBERTS RG, T HÜROFF macother 2006; 7: 509-527. J, W EIN AJ. How widespread are the symptoms of 18) SEXTON CC, C OYNE KS, V ATS V, K OPP ZS, I RWIN DE, an overactive bladder and how are they man - WAGNER TH. Impact of overactive bladder on work aged? A population-based prevalence study. BJU productivity in the United States: results from Epi - Int 2001; 87: 760-766. LUTS. Am J Manag Care 2009; 15: S98-107. 6) COYNE KS, S EXTON CC, T HOMPSON CL, M ILSOM I, I R- 19) SEXTON CC, C OYNE KS, T HOMPSON C, B AVENDAM T, WIN D, K OPP ZS, C HAPPLE CR, K APLAN S, T UBARO A, CHEN CI, M ARKLAND A. Prevalence and effect on AIYER LP, W EIN AJ. The prevalence of lower uri - health-related quality of life of overactive bladder nary tract symptoms (LUTS) in the USA, the UK in older Americans: results from the epidemiology and Sweden: results from the Epidemiology of of lower urinary tract symptoms study. J Am Geri - LUTS (Epi LUTS) study. BJU Int 2009; 104: 352- atr Soc 2011; 59: 1465-1470. 360. 20) US C ENSUS BUREAU : Projections of the total resident 7) COYNE KS, S EXTON CC, V ATS V, T HOMPSON C, K OPP ZS, population by 5-year age groups, and sex with MILSOM I. National community prevalence of over - special age categories. Population Projections active bladder in the United States stratified by Program, Population Division, US Census Bu - sex and age. Urology 2011; 77: 1081-1087. reau, 2000.

729 D. Arcaniolo, S. Conquy, T. Tarcan

21) MCDONAGH MS, S ELOVER D, S ANTA J, T HAKURTA S. 36) SERVADIO C. The use of flavoxate in cystitis and DRUG CLASS REVIEW : Agents for Overactive Bladder: renal . Curr Med Res Opin 1974; 2: 449- Final Report Update 4. Portland (OR): Oregon 454 . Health & Science University, 2009. 37) DAHM TL, O STRI P, K RISTENSEN JK, W ALTER S, F RIMODT - 22) TUBARO A, D E NUNZIO C. Flexible dose fesoterodine MØLLER C, R ASMUSSEN RB, N ØHR M, A LEXANDER N. in the treatment of overactive bladder (OAB). BJU Flavoxate treatment of micturition disorders ac - Int 2013; 112: 281-282. companying benign prostatic hypertrophy: a dou - 23) ROXBURGH C, C OOK J, D UBLIN N. Anticholinergic ble-blind placebo-controlled multicenter investiga - drugs versus other medications for overactive tion. Urol Int 1995; 55: 205-208. bladder syndrome in adults. Cochrane Database 38) GRUNEBERGER A. Treatment of motor urge inconti - Syst Rev 2007; 18: CD003190. nence with clenbuterol and flavoxate hydrochlo - 24) NOVARA G, G ALFANO A, S ECCO S, D'E LIA C, C AVALLERI ride. Br J Obstet Gynaecol 1984; 91: 275-278. S, F ICARRA V, A RTIBANI W. A systematic review and 39) WEHNERT J, S AGE S. Comparative studies of the ef - meta-analysis of randomized controlled trials with fect of mictonorm (propiverin hydrochloride) and antimuscarinic drugs for overactive bladder. Eur Spasuret (flavoxate hydrochloride) on the bladder Urol 2008; 54: 740-763. detrusor muscle. Z Urol Nephrol 1989; 82: 259- 25) YAMAGUCHI O, N ISHIZAWA O, T AKEDA M, Y OKOYAMA O, 283. HOMMA Y, K AKIZAKI H, O BARA K, G OTOH M, I GAWA Y, 40) GAUDENZ R, W EIL A. Motor urge incontinence – di - SEKI N, Y OSHIDA M; Neurogenic Bladder Society. agnosis and treatment. Urol Int 1980; 35: 1-12. Clinical guidelines for overactive bladder. Int J 41) KOHLER FP, M ORALES PA. Cystometric evaluation of Urol 2009; 16: 126-142. flavoxate hydrochloride in normal and neurogenic 26) HESCH K. A GENTS FOR TREATMENT OF OVERACTIVE BLAD - bladders. J Urol 1968; 100: 729-730. DER : a therapeutic class review. Proc (Bayl Univ 42) PEDERSEN E, B JARNASON EV, H ANSEN PH. Neuro - Med Cent) 2007; 20: 307-314. genic disturbances of the bladder treated with 27) GUARNERI L, R OBINSON E, T ESTA R. A REVIEW OF FLAVOX - flavoxate (Urispadol). Ugeskr Laeg 1973; 43: ATE : pharmacology and mechanism of action. 2313-2317 . Drugs Today 1994; 30: 91. 43) MILANI R, S CALAMBRINO S, C ARRERA S, P EZZOLI P, R UFF - 28) GUARNERI L, I BBA M, A NGELICO P, C OLOMBO D, F REDEL - MANN R. Flavoxate hydrochloride for urinary ur - LA B, T ESTA R. Effects of drugs used in the therapy gency after pelvic radiotherapy: comparison of of detrusor hyperactivity on the volume-induced 600 mg versus 1200 mg daily dosages. J Int Med contractions of the rat . Pharmacol Res 1988; 16: 71-74. Res 1993; 27: 173-187. 44) MILANI R, S CALAMBRINO S, C ARRERA S, P EZZOLI P, R UFF - 29) GRAZIANI G, C AZZULANI P, P ANZARASA R. Pharmaco - MANN R. Comparison of flavoxate hydrochloride in logical studies on the mode of action of flavoxate. daily dosages of 600 versus 1200 mg for the In: Flavoxate. Cornelli U, Graziani G. Bioscience treatment of urgency and urge incontinence. J Int Ediprint Inc, 1983. Med Res 1988; 16: 244-248. 30) CAZZULANI P, P ANZARASA R, D E STEFANI C, G RAZIANI G. 45) ZANOLLO A, C ATANZARO F. Effects of flavoxate on de - Mechanism of flavoxate antispasmodic activity trusor irritability. Proc 48 Congr I Soc Urol 1975; comparative in vitro studies. Arch Int Pharmaco - 27: 99-106. dyn Ther 1985; 274: 189-200. 46) BRIGGS RS, C ASTLEDEN CM, A SHER MJ. The effect of 31) KIMURA Y, S ASAKI Y, H AMADA K, F UKUI H, U KAI Y, flavoxate on uninhibited detrusor contractions and YOSHIKUNI Y, K IMURA K, S UGAYA K, N ISHIZAWA O. urinary incontinence in the elderly. J Urol 1980; Mechanisms of the suppression of the bladder 123: 665-666. activity by flavoxate. Int J Urol 1996; 3: 218- 47) JONAS U, P ETRI E, K ISSEL J. Effect of flavoxate on hy - 227. peractive detrusor muscle. Eur Urol 1979; 5: 106- 32) CAZZULANI P, P ANZARASA R, L UCA C, O LIVA D, G RAZIANI 109. G. Pharmacological studies on the mode of action 48) CHAPPLE CR, P ARKHOUSE H, G ARDENER C, M ILROY EJ. of flavoxate. Arch Int Pharmacodyn Ther 1984; Double-blind, placebo-controlled, cross-over 268: 301-312. study of flavoxate in the treatment of idiopathic 33) PEDERSEN E. Studies on the effect and mode of ac - detrusor instability. Br J Urol 1990; 66: 491-494. tion of flavoxate in human urinary bladder and 49) FEHRMANN -Z UMPE P, K ARBE K, U YSAL A. Poster pre - sphincter. Urol Int 1977; 32: 202-208. sented at the XXth ICS Congress – Athens, 34) GUARNERI L, C OVA R, A NGELICO P, C OLLI E, T ESTA R. Ef - 1996. fects of different drugs on the cystometrogram in 50) YOSHIDA H, K AZUKO I. Clinical trial of flavoxate hy - conscious rats. Pharmacol Res 1991; 24: 175-187. drochloride for the patients with irritable condi - 35) MIYAZAKI S, O NO S, F URUKAWA M, ET AL . Clinico-phar - tion of the bladder. Acta Urol Jap 1975; 21: 583. macological evaluation of Flavoxate hydrochloride 51) BAERT L. Controlled double-blind trail of flavoxate based on cystometry: The Second Report – A Si - in painful conditions of the lower urinary tract. multaneous control study on double blind method. Curr Med Res Opin 1974-1975; 2: 631-635. Acta Urol Jap 1975; 21: 853.

730 Flavoxate: present and future

52) FUKUSHIGE M, N AKANO H, N IHIRA H, K AJIO K, H AYASHI affected by urinary urge syndrome. Int Urogy - M, F UJIMOTO Y, H IROMOTO N, H IRAYAMA T, O NO H, M I- necol J 1993; 4: 3-8. ZOGUCHI V, T ANAKA MH. Clinical effect of flavoxate 59) GOULD S. Urinary tract disorders. Clinical compari - for various dysuric symptoms: a double blind son of flavoxate and phenazopyridine. Urology study. Acta Urol Jap 1975; 20: 885. 1975; 5: 612-615. 53) AKASAKA H, A NDO K, I KEDA N, I MAMURA K, I RIKI M, 60) FEHRMANN -Z UMPE P, K ARBE K, B LESSMAN G. Using KAWAI H, K OBAYASHI M, M ATSUMOTO H, M INAMI T, flavoxate as primary forpatients suffer - NAKATA E, N AKAYAMA K, O GAWA Y, T OFUKUJI H, ing from urge symptomatology. Int Urogynecol J UCHIZONO K, Y AMAUCHI A, Y OKOGAWA M. Effects of Pelvic Floor Dysfunct 1999; 10: 91-95. flavoxate hydrochloride for disturbance of urina - tion. Acta Urol Jap 1975; 21: 523. 61) GU FL, R ENG ZY, S HANG GZ, S HAO HX, W ANG B, CHENG ZD, J IANG Y, Z HAO WP, Z HENG JF, Q U CT; 54) SONODA T, K URODA M, I WASA K, N AKARAAI K. C LINI - Treatment of urgency and urge incontinence with CAL EVALUATION OF FLAVOXATE FOR NEUROGENIC (RE - flavoxate in the People’s Republic of China. J Int FLEX ) BLADDER : crossover controlled study by the Med Res 1987; 15: 312-318. double- blind method. Acta Urol Jap 1975; 21: 165. 62) ABRAMS P, A NDERSSON KE, B IRDER L, B RUBAKER L, C ARDO - ZO L, C HAPPLE C, C OTTENDEN A, D AVILA W, DE RIDDER D, 55) STANTON SL. A comparison of emepronium bro - mide and flavoxate hydrochloride in the treatment DMOCHOWSKI R, D RAKE M, D UBEAU C, F RY C, H ANNO P, of urinary incontinence. J Urol 1973; 110: 529- SMITH JH, H ERSCHORN S, H OSKER G, K ELLEHER C, K OELBL 532. H, K HOURY S, M ADOFF R, M ILSOM I, M OORE K, N EWMAN D, N ITTI V, N ORTON C, N YGAARD I, P AYNE C, S MITH A, 56) HERBST WP. Double-blind comparison of flavoxate STASKIN D, T EKGUL S, T HUROFF J, T UBARO A, V ODUSEK D, and propantheline as urologic anti-spasmodics. J WEIN A, W YNDAELE JJ ; Members of Committees; Am Chem 1970; 1: 65-67. Fourth International Consultation on Incontinence. 57) NIIJIMA T, F UJITA Y, T AKATA M, K ONDO T, Y ASUHIRO K, Fourth International Consultation on Incontinence. ISHI M, O MORI H, K ONDO J, O NODA Y, N ANBA K, S HI - Fourth International Consultation on Incontinence ROKAMI T, I NOKI K. Clinical effect of flavoxate for irri - Recommendations of the International Scientific table condition of the urinary bladder: a study with Committee: Evaluation and treatment of urinary in - a double blind method. Acta Urol Jap 1975; 21: continence, pelvic prolapse, and fecal inconti - 557-578. nence. Neurourol Urodyn 2010; 29: 213-240. 58) MILANI R, S CALAMBRINO S, M ILIA R, S AMBRUNI I, R IVA D, 63) TRIPATHI RC, T RIPATHI BJ, H AGGERTY C. Drug-induced PULICI L, A VALDI F, V IGANO R. Double-blind crossover glaucomas, mechanism and management. Drug comparison of flavoxate and oxybutynin in women Saf. 2003; 26: 749-767.

731