Current Management of OAB - PowerPoint Presentation

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Current Management of OAB

Dr Sandeep

Gupta

( M.S,

M.Ch

, Fellow- 3D Laparoscopic Urology)

Assistant Professor,

Urology

IPGMER Kolkata

Consultant Urologist And Renal Transplant Surgeon

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.

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Over active bladderOveractive bladder (OAB) is a syndrome characterized by the key symptom of urinary urgency, with or without urinary incontinence, usually associated with urinary frequency and nocturia.

Detrusor muscle over activity (DO) is often, but not always, the underlying condition.

The differential diagnosis with stress or mixed urinary incontinence, based on clinical examination and urodynamic investigations.

World J Obstet Gynecol 2013 November 10; 2(4): 65-73

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.

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Prevalence of OABEuropean countries ranging between 12-17%, United States the incidence at 17%. In Asia, the prevalence of OAB is reported at 53.1%

Indian J Urol. 2010 Apr-Jun; 26(2): 270–278

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Prevalence of OAB Indian scenarioThe symptoms of an overactive bladder (OAB) have been reported to occur in as many as 1 in 3 women over 75 years of age and 1 in 15 women over 40 years.

About half of these women are affected by incontinence.

J Obstet Gynecol India Vol. 56, No. 4 : July/Aug 06 Pg 295-297

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Why to treat OAB?OAB significantly impairs patient’s health-related quality of life (HRQL), is also associated to significant comorbidities and high socioeconomic costs

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Treatment options availableDrug therapyBladder training techniquesIntermittent self-catheterization

Incontinence pads and protective equipment

Surgery

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Drug TherapyDrug therapy is becoming increasingly important and is currently the mainstay in the treatment for overactive bladder.

However, nearly all of the older drugs produce some unwanted side-effects, which limits their use in some patients.

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Drugs Used to Treat Bladder Control Problems

Antimuscarinics are the mainstay in the pharmacological treatment of OAB.

Antimuscarinics act by competitively inhibiting the effects of acetylcholine at post junctional muscarinic M3 receptors on detrusor muscle cells

Oxybutynin

Tolterodine

Solifenacin

Darifenacin

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Limitations of Antimuscarinincs

Many patients on

antimuscarinic

do not get sufficient relief from

symptoms.

Antimuscarinics

are not completely bladder-selective causing bothersome adverse effects (AEs

).

Common side effects are dry eyes,

dry mouth

, blurred vision and constipation

.

Approximately 50% of patients discontinue treatment at 3 months [Wagg et al. 2012].

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Anticholinergic burden(higher serum anticholinergic activity levels)

Anticholinergic action may lead to a significantly raised anticholinergic burden and

Reduced cognitive function or

Dementia in the long term.

Ther Adv Drug Saf 2016, Vol. 7(5) 204–216

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MirabegronMirabegron approved in Japan, United States (Myrbetriq) and Europe (Betmiga).

The drug is formulated as Oral Controlled Absorption System (OCAS) tablets.

That allows a release of drug from the tablets for an extended period, with more steady absorption, and avoids high peak-to-trough fluctuations in plasma concentration and the considerable food effect of immediate-release formulations.

The drug product is available in two dosage strengths of

50 mg once daily dose, orally with or without food)and

25 mg (for patients with severe renal or moderate hepatic impairment)

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Rationale of β3-agonism for OABtreatment

β3-ARs

(

adreno

-receptor agonist) represent the

far most abundant subtype in the

human bladder

Preferentially expressed

on bladder tissues including

urothelium

, interstitial

cells, and detrusor smooth

muscle.

Detrusor muscle relaxes in response to β-AR

agonists

Targeting β3-ARs has a significant effect on

reducing spontaneous

uncoordinated detrusor contractile

activity in

human

bladder.

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Two types of contraction have been observed in the human detrusor muscle: voiding and spontaneous involuntary contractions (IDCs) during bladder filling.Preclinical and clinical studies showed β3 adrenoceptor agonists only reduce the bladder tone and no significant negative effect on the voiding contraction therefore no risk of urinary retention.

Rationale of β3-agonism for

OAB

treatment

Ther Adv Drug Saf 2016, Vol. 7(5) 204–216

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Rationale of β3-agonism for OABtreatment

Animal studies demonstrated that both non-selective and selective β3-AR agonists were able to increase bladder capacity and inhibit neurogenic or experimentally induced DO and bladder outlet obstruction (BOO)-associated OAB, without changing voiding detrusor pressure or increasing residual volume.

J Urol 2003; 170: 649-653

J Urol 1999; 161: 680-685

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Rationale of β3-agonism for OABtreatment

The limitations of antimuscarinics prompted the research of novel pharmacological principles with a distinct mechanism of action and aimed to improve bladder storage phase symptoms, without affecting the voiding phase, and with a better tolerability profile.

EUROPEAN UROLOGY 6 3 ( 2 0 1 3 ) 3 0 6 – 3 0 8

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Clinical PharmacologyMechanism of actionAgonist of the human beta-3 adrenergic receptor (AR)

Mirabegron relaxes the detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle by activation of beta-3 AR which increases bladder capacity.

It improves the storage capacity of the bladder with little effect on the contractile ability of the bladder.

http://www.rxlist.com/myrbetriq-drug/clinical-pharmacology.htm

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Pharmacokinetics Can be taken with or without food(Cmax) - approximately 3.5 hours.Absolute bioavailability - 29% at a dose of 25 mg to 35% at a dose of 50 mg

Metabolized via multiple pathways involving dealkylation, oxidation, (direct) glucuronidation, and amide hydrolysis.

Half life – 50hrs

Excretion - 55% in the urine and 34% in the faeces.

http://www.rxlist.com/myrbetriq-drug/clinical-pharmacology.htm

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IndicationsMirabegron beta-3 adrenergic agonist indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency.

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Dosage and administrationThe recommended starting dose of is 25 mg once daily with or without food. 25 mg is effective within 8 weeks.

Based on individual patient efficacy and tolerability the dose may be increased to 50 mg once daily.

It should be taken with water, swallowed whole and should not be chewed, divided, or crushed.

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Specific PopulationsGeriatric PatientsParameter similar to youngersPediatric PatientsThe pharmacokinetics not been evaluated.

http://www.rxlist.com/myrbetriq-drug/clinical-pharmacology.htm

Contraindicated

for use in patients with end stage renal disease (ESRD), or in patients with severe hepatic impairment (Child-Pugh Class C)

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Adverse effectsNausea, Headache, Hypertension,

Diarrhoea,

Constipation,

Dizziness and

Tachycardia

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To examine pooled efficacy data from three, large phase III studies comparing mirabegron (50 and 100 mg) with placebo, and pooled safety data including additional mirabegron 25 mg and tolterodine extended release (ER) 4 mg results.

Int J Clin Pract, July 2013, 67, 7, 619–632

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Overview of the individual phase III studies included in the pooled analyses

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Objectives of studiesEfficacy and safety of once-daily mirabegron 25 mg (safety analysis), 50 or 100 mg (efficacy and safety analyses) and tolterodine ER 4 mg (safety analysis) for the treatment of symptoms of overactive bladder (OAB).

Co-primary efficacy measures were

mean number of incontinence episodes/24 h and

mean number of micturitions/24 h.

Key secondary efficacy end-points included

mean number of urgency episodes/24 h and

mean volume voided/micturitions,

other end-points included –

Visual Analogue Scale (TS-VAS) and

responder analyses [dry rate (post treatment),

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ResultMirabegron (50 and 100 mg once daily) demonstrated statistically significant improvements compared with placebo for the co-primary end-points, key secondary efficacy variables, TS-VAS and responder analyses (all comparisons p < 0.05).

Mirabegron is well tolerated and demonstrates a good safety profile.

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mean number of incontinence episodes/24 h forthe pooled placebo, mirabegron

50 and 100 mg groups

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Adjusted mean change from baseline by time point in mean number of micturitions

/24 h

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key secondary end-points: (A) mean level of urgency (B) number of urgency episodes/24 h

and number of urgency incontinence episodes/24 h

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Conclusion

In three international, multicentre, phase

III studies

, comparing

mirabegron

, at doses of

25, 50

and 100 mg, with placebo,

M

irabegron

was associated

with significant improvements

in incontinence

episodes and micturition

frequency, and

was well tolerated.

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Comparative efficacy and safety of medical treatments for the management of overactive bladder: a systematic literature review and mixed treatment comparison.

CONTEXT:

Overactive bladder (OAB) treatment guidelines recommend

antimuscarinics

as

first

-line pharmacologic therapy.

Mirabegron

is a first-in-class β3-adrenoceptor agonist licensed for the treatment of OAB and has shown to be well tolerated and effective in the treatment of OAB symptoms.

OBJECTIVE:

To assess the relative efficacy and tolerability of OAB medications, specifically

mirabegron

50 mg versus

antimuscarinics

in patients with OAB.

EVIDENCE ACQUISITION:

A systematic literature search was performed on published peer-reviewed articles from 2000 to 2013. This review included

randomised

controlled trials (RCTs) studying changes in symptoms (

micturition

frequency, incontinence, and urgency urinary incontinence [UUI] episodes) and incidence of the most frequently reported adverse events (dry mouth, constipation) associated with current OAB medications. The following drugs were considered in addition to

mirabegron

:

darifenacin

,

tolterodine

immediate release (IR) and extended release (ER),

oxybutynin

IR/ER,

trospium

,

solifenacin

, and

fesoterodine. Bayesian mixed treatment comparisons (MTCs) were performed for efficacy (micturition, incontinence, UUI) and tolerability (dry mouth, constipation, blurred vision).

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EVIDENCE SYNTHESIS:Overall, 44 RCTs involving 27,309 patients were included. The MTCs showed that mirabegron 50 mg was as efficacious as antimuscarinics in reducing the frequency of micturition incontinence and UUI episodes, with the exception of

solifenacin

10 mg that was more efficacious than

mirabegron

50 mg in improving

micturition

frequency and frequency of UUI.

Mirabegron

50 mg had an incidence of dry mouth similar to placebo and significantly lower than all included

antimuscarinics

.

CONCLUSIONS:

Mirabegron

50 mg had similar efficacy to most

antimuscarinics

and lower incidence of dry mouth, the most common adverse event reported with

antimuscarinics

and one of the main causes of discontinuation of treatment. Despite being a powerful tool for evidence-based health care evaluation, the Bayesian MTC method has limitations. Further head-to-head comparisons between

mirabegron

and

antimuscarinics

should be conducted to confirm our results

.

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OAB Guidelines recommendations

OAB guidelines, such as those from the

European Association

of Urology [Lucas et al. 2015]

and

The

National Institute of Clinical

Excellence [NICE

, 2010], currently recommend an

anticholinergic as

first-line medical treatment and

recommend

mirabegron

as second-line

medical treatment.

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Efficacy in combinationMirabegron and Solifenacin

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Combination therapyMirabegron and Tamsulosin

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Combination therapy

A randomized controlled study of the efficacy of

tamsulosin

monotherapy

and its combination with

mirabegron

for overactive bladder induced by benign prostatic obstruction.

Ichihara K

1

, 

Masumori

N

2

, 

Fukuta

F

1

, 

Tsukamoto T

1

, 

Iwasawa

A

3

, 

Tanaka

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AbstractPURPOSE:We evaluated the efficacy and safety of add-on treatment with a β3-adrenoceptor agonist (mirabegron

) for overactive bladder symptoms remaining after α1-blocker (

tamsulosin

) treatment in men with benign prostatic obstruction.

RESULTS

:

From January 2012 through September 2013 a total of 94 patients were randomized. Of these patients 76 completed the protocol treatment. In the full analysis set the change in total OABSS during the treatment period was significantly greater in the combination group than in the

monotherapy

group (-2.21 vs -0.87, p=0.012). The changes in scores for urinary urgency, daytime frequency, International Prostate Symptom Score storage symptom

subscore

and quality of life index at 8 weeks were significantly greater in the combination group. The change in post-void residual urine volume was significantly greater in the combination group. Although 6 patients experienced adverse events in the combination group, urinary retention was observed in only 1 patient.

CONCLUSIONS:

Combined

tamsulosin

and

mirabegron

treatment is effective and safe for patients with

benign

prostatic obstruction who have overactive bladder symptoms after

tamsulosin

monotherapy

.

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A randomized controlled study to evaluate the efficacy of tamsulosin

monotherapy

and its combination with

mirabegron

on patients with overactive bladder induced by benign prostatic hyperplasia

Hypothesis / aims of study- This study was conducted to evaluate the efficacy and safety of add-on treatment with a beta 3-adrenoceptor agonist (

mirabegron

) for overactive bladder (OAB) symptoms remaining after alpha 1-blocker (

tamsulosin

) treatment in male patients with benign prostatic hyperplasia (BPH).

Interpretation of results- There is solid evidence supporting the efficacy and safety of add-on treatment with anti-

muscarinic

agents such as

propiverine

hydrochloride,

solifenacin

and

imidafenacin

. The present study demonstrated that add-on treatment with the beta 3-adrenoceptor agonist

mirabegron

was effective for the patients with BPH whose OAB symptoms were not

controled

by alpha 1-blocker

monotherapy

, similarly to anti-

muscarinic

agents. However, attention should be paid to whether voiding difficulty, acute urinary retention and an increased amount of PVR develop.

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Summary points

N

ew

compound, with a novel mechanism of action, is

for the

first time available in the pharmacological armamentarium aimed to treat

OAB.

Mirabegron

has proven

effective across

multiple randomized controlled

trials, and

showed a favourable

safety profile

Improve

adherence to OAB treatment

,

It can

be used for patients with contraindications

to

antimuscarinics

I

ts

effectiveness has been

confirmed in

patients who discontinued previous

antimuscarinic

therapy.

Decision – Must Go.

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Alembic Ouron

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Available in 25mg and 50mg

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