Summary

Over active bladder (OAB) is a highly prevalent disease that causes extreme discomfort to the

patient and very often there is a delay in seeking treatment. The main characteristics of OAB are

increase in frequency of micturition and urgency of passage of urine along with urge incontinence.

Although several therapeutic options exist for the management of OAB, flavoxate hydrochloride

was the first drug in this class approved by the Food and Drug Administration (FDA) to treat OAB.

Flavoxate as an anticholinergic/antispasmodic drug suppresses premature detrusor contractions

and enhances bladder storage thus relieving symptoms of OAB. Flavoxate in particular acts by

superimposition of myotropic, calcium antagonistic and local anaesthetic activity. Numerous

clinical trials have highlighted the efficacy of flavoxate in providing relief to patients suffering from

OAB. Flavoxate hydrochloride was also found to be effective in patients with benign prostatic

hyperplasia (BPH) whose nocturia was not adequately relieved by an 1-adrenoceptor blocker.

Evidence from most clinical trials suggest that flavoxate hydrochloride was well tolerated in dosage

of 600 to 1200 mg/day with minimal side effects.

INTRA LABS

Therefore administration of flavoxate hydrochloride improved nocturia and QOL in BPH patients resistant to an 1-10

adrenoceptor blocker.

In a cross over study that comprised 46 patients suffering from urgency/urge incontinency, the efficacy of flavoxate

hydrochloride in comparison to propiverin hydrochloride on the bladder detrusor muscle was evaluated. The duration of the

study was 4 weeks and the dosage was 45 mg/d for propiverin hydrochloride and 300 mg/d for flavoxate hydrochloride. The

results showed that there was a significant reduction in the frequency of micturition and an increase in compliance with both

flavoxate hydrochloride and propiverin hydrochloride. Side effects observed with both drugs were minimal and did not lead 11

to any disruption in the treatment.

In a double-blind, randomized, parallel-group trial flavoxate hydrochloride was compared at a daily dosage of 600 mg to a

daily dosage of 1200 mg for the treatment of unstable bladder. Sample size of the trial was 27 patients, the trial was conducted

for a duration of 4 weeks. It was observed that both schedules showed significant results however, 1200 mg/day was found to

be more superior to 600 mg/day. Both regimens were well tolerated. The side-effects were minimal and treatment of urgency 12

and urge incontinence improved the patient's quality of life.

In a non-randomized trial, the efficacy of flavoxate hydrochloride in urinary urgency after pelvic radiotherapy was studied.

Thirty four females received flavoxate hydrochloride for duration of 4 weeks. Twenty one patients were given 600 mg/day of

flavoxate hydrochloride and 1200 mg/day of flavoxate hydrochloride was given to 13 patients. Both regimens showed

comparable results. However, treatment with 1200 mg/day showed urodynamically (first desire volume, bladder capacity and

pressure at capacity) significant results in comparison to 600 mg/day. There was no interruption in the treatment schedules as 13

flavoxate hydrochloride was well-tolerated by the patients.

Efficacy in patients suffering from urgency/urge incontinency and in patients with urinary urgency after pelvic

radiotherapy

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Introduction

Overactive bladder syndrome (OAB) is a constellation of lower urinary tract symptoms, including urinary urgency, with

or without urge incontinence, usually associated with frequency and nocturia. OAB is a chronic, debilitating condition

that affects people of all ages, although it is much more prevalent in the elderly. Overactive bladder syndrome may have a

deleterious effect on every aspect of daily life, including impaired mobility, social isolation, impaired work-related

productivity, depression, disturbed sleep, and impaired domestic and sexual function. Its negative impact is potentially 1

more pronounced in the elderly, a population already impaired by other medical comorbidities. According to a study,

OAB is equally prevalent in both men and women and is a more prevalent condition than chronic sinusitis or heart 2

disease. (Figure 1).

Flavoxate: Focus on its role in Treatment of Overactive Bladder

INTRA LABS

Flavoxate 200mg Tablets

References:

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Macdiarmid SA.Maximizing the treatment of overactive bladder in the elderly. Rev Urol. 2008 Winter;10(1):6-13. Newman DK. Overactive Bladder: Diagnosis

and Treatment in Primary Care. Accessed from website http://www.medscape.org/viewarticle/571913_print as on 08.08.2013. Tubaro A. Defining overactive

bladder: epidemiology and burden of disease. Urology. 2004 Dec;64(6 Suppl 1):2-6. Ouslander J. Management of Overactive Bladder. N Engl J Med

2004;350:786-99. Correia S, Dinis P, Lunet N. Urinary incontinence and overactive bladder- a Review. ARQUIVOS DE MEDICINA. 2009;23(1):13-21. En

Meng, Wei-Yu Lin, Wei-Chia Lee et al. Pathophysiology of overactive bladder. LUTS 2012;4:48-55. Hesch K. Agents for treatment of overactive bladder: a

therapeutic class review. Proc (Bayl Univ Med Cent) 2007;20(3):307314. Cazzulani P, Panzarasa R, Luca C, Oliva D, Graziani G. Pharmacological studies on the

mode of action of flavoxate. Arch Int Pharmacodyn Ther. 1984;268(2):301-312. Fehrmann-Zumpe P, Karbe K, Blessman G. Using flavoxate as primary

medication for patients suffering from urge symptomatology. Int Urogynecol J Pelvic Floor Dysfunct. 1999;10(2):91-95. Kato S, Kusaka M, Shiroki R et al.

Clinical evaluation of supplemental administration of flavoxat hydrochloride in benign prostatic hyperplasia patients with nocturia resistant to an alpha1-

adrenoceptor blocker. Hinyokika Kiyo. 2008;54(3):173-177. Wehnert J, Sage S. Comparative studies of the effect of mictonorm (propiverin hydrochloride) and

Spasuret (flavoxate hydrochloride) on the bladder detrusor muscle]. Z Urol Nephrol. 1989;82(5):259-263. Milani R, Scalambrino S, Carrera S et al. Comparison

of flavoxate hydrochloride in daily dosages of 600 versus 1200 mg for the treatment of urgency and urge incontinence. J Int Med Res. 1988;16(3):244-248.

Milani R, Scalambrino S, Carrera S et al. Flavoxate hydrochloride for urinary urgency after pelvic radiotherapy: comparison of 600 mg versus 1200 mg daily

dosages. J Int Med Res. 1988;16(1):71-74.

Dosage:

For Adults and children over 12 years of age:

One or two 100 mg tablets 3 or 4 times a day.

Figure 1. Prevalence of OAB in Men and Women

50

40

30

20

10

0

16 16.9

Men Women

Pre

vale

nce* (

%)

35

30

25

20

15

10

5

0

Men

Women

Flavoxate 200mg Tablets Flavoxate 200mg Tablets Flavoxate 200mg Tablets

Pathophysiology of OAB - Recent research advances

Impact on Quality of Life

Treatment Options for Overactive Bladder - Role of Flavoxate

Although many basic and clinical studies have been performed, the cause of OAB remains to be established. Three main

factors have been proposed regarding the cause of OAB: myogenic, neurogenic and urotheliogenic (Figure 4).

The myogenic factor states that alterations in the properties of the detrusor myocytes are a necessary prerequisite for the

production of an involuntary detrusor contraction, which in turn causes an unstable increase of intravesical pressure.

The neurogenic factor suggests that damage to central inhibitory pathways in the brain and spinal cord or sensitization of

peripheral afferent terminals in the bladder can unmask primitive voiding reflexes that trigger detrusor overactivity.

Increasing evidence has suggested that the urothelium is not just a passive barrier, but is also is a responsive structure that is

capable of detecting thermal, mechanical and chemical stimuli. Transmitters released from the urothelium may alter the

excitability of afferent nerves and affect detrusor muscle contractility. Absence of the urothelium may cause an increase in the 6

spontaneous activity of detrusor.

Patients with OAB experience a devastating impact on quality of life, with fear of wetting accidents leading to social isolation

and depression. Patients may become increasingly reluctant to leave home, severely limiting independence and potentially

increasing their incident disability secondary to lack of physical activity. Recurrent urinary tract infections and urinary

dermatitis are more prevalent among patients with urge incontinence versus those suffering from other symptoms of OAB or

controls. The risk of falls and associated nonspine fractures is significantly increased by the presence of urge incontinence, 1

presumably occasioned by urge-motivated haste in attempting to reach the bathroom or toilet.

Several therapeutic options exist for the management of OAB, flavoxate being the first drug in this class that was approved by

the Food and Drug Administration (FDA) to treat OAB. Flavoxate belongs to the group of anticholinergic/antispasmodic

drugs. Flavoxate is indicated for the symptomatic relief of cystitis, urethritis, prostatitis, and urethrocystitis/urethrotrigonitis.

Anticholinergic and antispasmodic agents antagonize cholinergic muscarinic receptors, through which various

parasympathetic nerve impulses induce detrusor contraction. Anticholinergic drugs have been proven to be the most 7

effective agents as they suppress premature detrusor contractions, enhance bladder storage thus relieve symptoms. It is

known that flavoxate exerts a selective and direct muscle relaxant activity. Inhibition of cyclic AMP phosphodiesterase leads

to antispasmodic properties of the drug. Flavoxate exerts a PDE inhibitory activity and shows the same local anaesthetic

activity of lidocaine. Hence, the mode of action of flavoxate can be attributed to a superimposition of myotropic, calcium 8

antagonistic and local anaesthetic activity.

Other drugs that are known to be efficacious in relieving OAB symptoms are oxybutynin and tolterodine. New drugs such as 7

darifenacin, solifenacin, and trospium have also emerged.

Several clinical studies have been conducted in the past that highlight the efficacy of Flavoxate in OAB.

In an observation study that comprised 1800 patients, flavoxate was prescribed for a duration of 2 weeks for urge

incontinence. A subgroup of 618 patients without urinary tract infections or benign prostatic hyperplasia were treated with

flavoxate only. Following completion of the study, it was observed that in the subgroup analysis there was a significant

decrease in most symptoms seen in OAB. The subgroup (n = 618) showed a reduction of dysuria (37%), nocturia (53%), and 9

both daytime (61%) and night time urge (69% Figure 5).

It was observed that in 89.2% of patients the residual urine volume was stable or reduced. Better results were seen in patients

who received flavoxate four times daily (800 mg), in comparison to those patients who were given flavoxate three times daily

(600 mg). Side effects occurred in less than 2% of cases.

Flavoxate hydrochloride was found to be effective in patients with benign prostatic hyperplasia (BPH) whose nocturia was

not adequately relieved by an 1-adrenoceptor blocker. The study comprised 52 patients who were suffering from two or

more episodes of nocturnal micturition after administration of tamsulosin hydrochloride or naftopidil for 4 weeks or

more. These patients received 400-600 mg of flavoxate hydrochloride in addition to an 1-adrenoceptor blocker for a

period of 8-12 weeks. Following administration of flavoxate hydrochloride, there was significant improvement in the

number of nocturnal micturition, total International Prostate Symptom Score, quality of life score and BPH impact index.

In this review, we highlight the efficacy of Flavoxate - the first drug

that was approved by USFDA for the management of OAB.

Flavoxate as primary medication for patients suffering from urge symptomatology

Flavoxate improves nocturia and QOL in BPH patients resistant to an 1-adrenoceptor blocker

Therapeutic Efficacy of Flavoxate in OAB

Urge incontinence affects only a segment of the OAB patients: OAB with urge incontinence (OAB wet) is seen in 33% of 3

patients, while OAB without urge incontinence (OAB dry) is seen in 66% of patients suffering from OAB (Figure 2).

Overactive bladder (OAB) is characterized by frequency and urgency of passage of urine with or without urge

incontinence (Figure 3) . These symptoms are seen alone or in combination. The frequency of voiding urine is eight or

more times in a 24-hour period, along with nocturia (awakening two or more times at night to void). Increase in the

frequency of daytime voiding is the complaint by the patient who considers that he/she voids too often by day.

Nocturia is the complaint that the person has to get up at night one or more times to void and urgency is a sudden 4,5

compelling need to pass urine which is difficult to differ.

33%

66%

OAB with urge incontinence (OAB wet)

OAB without urge incontinence (OAB dry)

Figure 2. Prevalence of Urge Incontinence in Overactive Bladder (OAB)

Urgency

Over Active

Bladder

(OAB)

Urge

IncontinenceFrequency

Figure 3. Characteristics of OAB

Figure 4. Possible pathophysiology of overactive bladder Ach, acetylcholine; ATP, adenosine triphosphate;

BOO, bladder outlet obstruction; DM diabetes mellitus; NGF, nerve growth factor; TRPV1, transient

receptor potential vanilloid 1.

% v

alu

es

-37

-61

-53

Night time urge

-69

Nocturia Daytime urge

Reduction of

Dysuria

0

-10

-20

-30

-40

-50

-60

-70

-80

Figure 5. Reduction in symptoms with flavoxate therapy

Uroepithelial factor:

Sensor molcculars,

Ach, ATP, NGF, TRPV1

Ion channel change

Specific conditions

BOO

Metabolic syndrome and DM

Inflamation

Pathophysiology of OAB

Myogenic factor:

Detrusor spontaneous

contraction,

hypersensitivity to

incoming signals

Neurogenic factor:

Abnormal afferent

excitability

Abnormal central

sensory processing