onabotulinumtoxina (botox®) for the treatment of overactive bladder

OnabotulinumtoxinA (Botox®) for the Treatment of Overactive Bladder

Reema ShahThomas Jefferson University School of Pharmacy

Doctor of Pharmacy Candidate March 13, 2013

Objectives• Describe the epidemiology, clinical presentation,

pathophysiology, and diagnosis of overactive bladder • Review the current guidelines for the treatment of

overactive bladder in adults according to the American Urological Association

• Explain the pharmacology of Botox®

• Evaluate the objectives, study design, results, and clinical significance of clinical trials conducted to examine the use of Botox® for the treatment of overactive bladder

• Assess the overall risks and benefits of the use of Botox® for the treatment of overactive bladder

Epidemiology • Overactive bladder (OAB) affects 12%-17% of

the general population in the U.S.– 1/3rd suffer from urinary incontinence

• Higher prevalence rates in women than men• Symptom prevalence and severity tends to

increase with age• Significant burden for patients

Nitti VW, et al. J Urol. 2012. doi:10.1016/j.juro.2012.12.022.Tyagi S, et al. Urol Clin N Am. 2006. 33: 433-438.

Clinical Presentation• Urinary frequency – >8 micturitions/day

• Urgency with OR without urge incontinence

• Nocturia – >1 micturition/night or nocturnal incontinence

(enuresis)

Rovner, et al. Pharmacotherapy: A Pathophysiological Approach. 2008. 1399-1412.

Pathophysiology

• Involuntary bladder contractions– Detrusor muscle is overactive and contracts

inappropriately during the filling phase– Contraction controlled through activation of

muscarinic receptors (primarily M3) by ACh


Etiology• Idiopathic (most common)• Normal aging• Neurologic disease– Stroke– Parkinson’s disease– Multiple sclerosis– Spinal cord injury

• Myogenic– Bladder outlet obstruction

• BPH• Prostate cancer


Diagnosis

• Based on patient’s symptoms

• Urinalysis and urine culture should be negative – rule out urinary tract infection as cause of

frequency


Current Guidelines for Treatment of Overactive Bladder

• 1st /2nd line for treatment: – Nonpharmacological• lifestyle modifications such as toilet scheduling

regimens and pelvic floor muscle rehabilitation– Anticholinergic medications• Oxybutynin, tolterodine, trospium, solifenacin,

darifenacin

• 3rd line for treatment: – Botox® injection

Gormley EA, et al. American Urological Association. 2012.

Pharmacology of Botox®• Mechanism of Action

– Cleaves SNARE protein• SNAP-25

– Prevents assembly of vesicles– Inhibition of ACh release

• Detrusor muscle relaxation

• Pharmacokinetics– Onset of action: ~ 2 weeks– Duration: ~ 24 weeks

Rowland LP. N Engl J Med. 2002; 347:382-383.OnabotulinumtoxinA. Lexi-Comp, Inc. 2013.

Dosing and Administration• Botox® 100 units reconstituted with 10 ml normal saline• Administered as 20 evenly distributed intradetrusor injections

– 0.5 ml per injection site– using a cytoscope

• Injections spaced ~ 1 cm apart• Needle inserted ~ 2mm into detrusor• Local anesthesia usually administered into the bladder prior to treatment

Botox® [package insert]. Allergan. Irvine, CA; January 2013.

Clinical Trial #1

OnabotulinumtoxinA for the Treatment of Patients with Overactive Bladder and Urinary Incontinence: Results

of a Phase 3 Randomized Placebo-Controlled Trial

Nitti VW, Dmochowski R, Herschorn S, et al. J Urol. 2012.

Purpose: To assess the safety and effectiveness of onabotulinumtoxinA in

treating patients with idiopathic overactive bladder with incontinence who were inadequately managed with anticholinergics

Nitti VW, et al. J Urol. 2012. doi:10.1016/j.juro.2012.12.022.

Study Design• Double blind, placebo controlled,

randomized trial at 72 sites in the US and Canada– Intention to treat

• Patients received one of the following interventions:– Botox® 100 unit intradetrusor injection – Placebo: 10ml normal saline intradetrusor

injection

• Stratified by site and ≤9 or >9 UUI episodes at baseline

• Follow up visits– Occurred at weeks 2, 6, and 12 and

thereafter every 6 weeks until exit at week 24 unless retreatment occurred• Retreatment only considered after week 12

Sample population and demographics:• Total: 557

– Botox® = 280– Placebo: = 277

• Baseline characteristics were balanced across treatment groups– About 90% were female– Average age: 61.3 years– Duration of OAB: about 6.7 years– Prior anticholinergic use:

• Duration: 2.4 years• # of anticholinergics: 2.5

– Daily UI episodes: 5.3• Of those, 4.6 episodes/day were UUI


Study DesignInclusion Criteria Exclusion Criteria

•Idiopathic OAB•≥18 years old•≥3 urgency UI episodes in 3 days•≥8 micturitions/day•Symptoms of OAB with urinary incontinence for at least 6 months•Inadequate response or intolerable side effects with anticholinergics •PVR volume of ≤100ml•Be willing to use clean intermittent catheterization (CIC) if required

•Use of anticholinergic within 7 days of screening or throughout the study•Patient has predominance of stress incontinence•History or evidence of pelvic or urological abnormality


Endpoints & ResultsPrimary outcome:• Change from baseline in average UI episodes/day (Weeks 2, 6, 12)

– Botox® significantly reduced the daily frequency of UI episodes vs. placebo (-2.65 vs -0.87)• Mean % reductions from baseline of 47.9% with Botox vs. 12.5% with placebo

• Analyzed using ANCOVA model– Covariates: baseline value and site

• Factor: treatment group

p <0.001 vs placebo. Error bars are ± 95% CI.


Power set at 82% (N=227) to detect a between group difference

Significance level=0.05

Endpoints & ResultsSecondary outcome:

– efficacy– All parameters showed

statistically significant improvement of outcomes with Botox® use compared to placebo• ↓ micturition

episodes/day• ↓urgency episodes/day• ↓nocturia episodes/day• ↑volume

voided/micturition– Evaluated using ANCOVA

Nitti VW, et al. J Urol. 2012. doi:10.1016/j.juro.2012.12.022. P<0.05

Endpoints & ResultsSecondary outcome:• efficacy• HRQOL (week 12)

– Incontinence-Specific Quality of Life Instrument (I-QOL)

– King’s Health Questionnaire (KHQ)

– Use of Botox® significantly improved patients’ HRQOL across all measures compared to placebo

• Analyzed using ANCOVA

p <0.001Nitti VW, et al. J Urol. 2012. doi:10.1016/j.juro.2012.12.022.

Endpoints & ResultsSecondary Outcome: • Side effect profile (safety)

– Most common ADR: UTI (15.5% in Botox® group vs. 5.9% in placebo group)– Urinary retention (5.4% in Botox® group vs. 0.4% in placebo)– Significant increase in PVR urine volume in Botox® group


Endpoints & ResultsSecondary outcome:• Proportion of patients who initiated clean intermittent catheterization (CIC) at any time during

treatment cycle– 6.1% (17/278) in the Botox® vs. 0% in the placebo group– Protocol: Initiated if PVR urine volume was ≥200ml and <350ml with associated symptoms

(voiding difficulties or sensation of bladder fullness) or if PVR urine volume was ≥350ml regardless of symptoms


Author’s Conclusions

• The results of this study suggest that Botox® is an important new alternative treatment option for OAB patients with UI who are inadequately managed by anticholinergic therapy– demonstrated significant and clinically relevant

improvements in all OAB symptoms and HRQOL in patients

• Overall well tolerated– But high incidence of UTI and urinary retention


Critique of Study

Strengths• Intent to treat• Randomized• Use of appropriate HRQOL

measures• Large sample size

Weaknesses• Sponsored/funded by

Allergan• Failed to mention other

medications patient’s were currently on

• Mostly women took part in trial (~ 90%)

Clinical Trial #2Anticholinergic Therapy vs. OnabotulinumtoxinA

for Urgency Urinary Incontinence

Visco AG, Brubaker L, Richter HE, et al. N Engl J Med. 2012.

Purpose: • To directly compare/contrast the use of a Botox® injection with the

use of an oral anticholinergic for the treatment of urgency urinary incontinence by assessing the reduction in episodes of incontinence, improvement in quality of life, and side effect profiles

Visco AG, et al. N Engl J Med. 2012. 367:1803-1813.

Study Design• 10 center, randomized, double blind, double placebo, controlled trial• Intention to treat

Sample population and demographics:– Enrollment: 249 underwent randomization

• Anticholinergic group: 126 treated• Botox® group: 121 treated

– None of the characteristics differed significantly between the treatment groups– Average age: 56.7-59.3 years– 100% women– 78.5% caucasian– Mean urgency incontinence episodes/day: 5.0– 41% had not previously received anticholinergic therapy


Study Design• Assigned into one of the following groups for a period of 6 months:

– Oral anticholinergic daily + one time intradetrusor saline injection (placebo)• Solifenacin 5mg PO daily, with possible dose escalation

– Oral placebo daily + one time Botox® 100 unit intradetrusor injection

• Randomization was stratified according to:– previous exposure or no previous exposure to anticholinergic drugs– baseline severity of UUI

• 5-8 episodes vs. ≥ 9 episodes of urgency urinary incontinence in a 3 day period

– site


Study DesignInclusion Criteria Exclusion Criteria

•Idiopathic •Females ≥ 21 years of age•≥5 urge urinary incontinence episodes on a 3-day voiding diary •Demonstrated ability (or have caregiver demonstrate ability) to perform clean intermittent self-catheterization •Undergone 3-week washout period if subject were on anticholinergic therapy prior to enrollment

•Any previous therapy with trospium chloride, solifenacin, or darifenacin•Failed 3 or more anticholinergic drugs•Contraindication or allergies to any of the therapies used in the study•Current symptomatic urinary tract infection that has not resolved prior to randomization•PVR >150ml on 2 occasions with void(s) of greater than 150ml•Any prior urinary incontinence therapy with onabotulinumtoxinA•known neurologic disease


Study DesignFollow Up Evaluation:• Office visits scheduled every 2 months• Patient Global Symptom Control (PGSC)

– used to assess whether current treatment was providing adequate control of urinary leakage– Patient’s answered this statement:

• “This treatment has given me adequate control of my urinary leakage”– Range from 1 (disagree strongly) to 5 (agree strongly)

– Dose escalation was allowed at months 2 and 4 only if– inadequate symptom control (if PGSC score was 1 to 3)– side effects were intolerable

• Month 2: switch to solifenacin 10mg daily• Month 4: switch to trospium XR 60mg daily

– PGSC score > 3: continue same regimen until next 2 month visit

Month 6:– all oral medications were discontinued– Participants that had adequate symptom control and who did not receive off protocol

treatment for OAB were followed monthly for up to 6 additional months in order to assess the duration of effect of the medications


Endpoints & ResultsPrimary outcome:• Mean reduction from baseline in # of episodes of UUI per day over the 6-month,

as reported for 3 day periods in monthly bladder diaries• Anticholinergic group: reduction of 3.4 episodes/day• Botox® group: reduction of 3.3 episodes/day • Reduction in episodes per day was similar in the two groups• Evaluated using linear mixed model

Bars indicate 95% CI


P value =0.81 (statistically insignificant)

Power set at ≥80% (N=121) to detect a between group difference

in reduction of UUITwo sided type 1 error rate of 0.05

(Significance level=0.05)

Endpoints & ResultsSecondary outcome: (efficacy)• Change in QOL outcomes from baseline

– Overactive Bladder Questionnaire (OABq-SF)

– Pelvic Floor Distress Inventory (PFDI-SF)– Pelvic Floor Impact Questionnaire

(PFIQ-SF)– Patient Global Impression of

Improvement (PGI-I)

– No statistically significant differences in the magnitude of improvement between both groups

P<0.05


Endpoints & ResultsSecondary Outcome: (safety)•Side effect profile• Statistically significant side effects

-Dry mouth: Higher rates in anticholinergic group (46%)-# of patients requiring catheterization: higher rates in Botox ® group

-Due to PVR urine volume > 300ml or >150ml in patients who felt moderately bothered

•Evaluated using Mantel-Haenszel test


Endpoints & ResultsSecondary Outcome: (safety)• Side effect profile

– Statistically significant side effects in Botox® group• Urinary tract infection (33%)• Residual volume after voiding >150ml (Urinary retention)

P<0.05


Endpoints & ResultsSecondary Outcome:• Duration of effect of medications after cessation of treatment

– % of participants with adequate symptom control (PGSC score of 4 or 5) with time• evaluated with the use of Kaplan-Meier product limit estimates and associated log

rank tests

% of Adequate control of symptoms during off-treatment follow up

Botox® Anti-cholinergic

P value

Significance

Month 7 62% 50% 0.006 Significant

Month 12 38% 25% 0.61 Insignificant

•1 month after discontinuation, significantly fewer women in the anticholinergic group than in the Botox® group had adequate control of symptoms•at month 12, results considered insignificant•Duration of effect of Botox is longer


Author’s Conclusion• No significant difference between oral anticholinergic drug

and Botox® injection therapy in regards to:– reduction of the frequency of episodes of urgency incontinence– improvements in quality of life

• both were effective treatments and the magnitude of the reductions did not differ significantly between the groups

• Choice between these therapies should take into account:– Route of administration– Side effect profile

• Anticholinergic: more frequent occurrence of dry mouth• Botox®: higher risks of catheterization because of urinary retention and higher risk

of urinary tract infection


Critique of StudyStrengths

• No industry support (funding or provision of medications) was received

• Randomized, double blind, comparative effectiveness study

• Inclusion of possible dose escalation/switching medication – represents usual clinical

practice

Weaknesses

• Did not include patient adherence rates of the oral medications

• Did not compare cost-effectiveness of the therapies

• Only women used


Clinical Significance

• Botox® serves as an effective alternative treatment for overactive bladder with urge incontinence episodes for patients who have treatment failure with anticholinergic medications

• Should not be first line in treatment of OAB due to higher incidence of serious side effects – UTI and urinary retention

Benefits/Risks of Botox® Use

Benefits Risks•Good alternative for treatment failure with anticholinergics•Do not have to worry about daily adherence•Longer duration of effect

•Invasive•Presents risk for infection•Potential need for self catheterization•Higher risk of side effects: urinary retention, UTI•Higher cost

References1. Nitti VW, Dmochowski R, Herschorn S, et al. OnabotulinumtoxinA for the treatment of patients

with overactive bladder and urinary incontinence: results of a phase 3 randomized placebo-controlled trial, J. Urol. 2012. doi:10.1016/j.juro.2012.12.022.

2. Tyagi S, Thomas CA, Hayashi Y, Chancellor MB. The overactive bladder: epidemiology and morbidity. Urol Clin N Am. 2006. 33: 433-438.

3. Rovner ES, Wyman J, Lackner L, Guay,D. Urinary Incontinence. In: Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiological Approach. 7th ed. New York, NY: McGraw-Hill; 2008. 1399-1412.

4. Gormley EA, Lightner DJ, Burgio, KL, et al. Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline. American Urological Association. May 2012. Available at : http://www.auanet.org/content/media/OAB_guideline.pdf. Accessed March 7, 2013.

5. OnabotulinumtoxinA. In: Lexi-Drugs Online [database on the internet]. Hudson, OH: Lexi-Comp, Inc.; 2013. Available at: http://online.lexi.com. Accessed March 7, 2013.

6. Rowland LP. Stroke, spasticity, and botulinum toxin. N Engl J Med. 2002. 347:382-383. 7. Botox® [package insert]. Allergan. Irvine, CA; January 2013. Available at:

http://www.allergan.com/assets/pdf/botox_pi.pdf. Accessed March 7, 2013.8. Visco AG, Brubaker L, Richter HE, et al. Anticholinergic therapy vs. onabotulinumtoxinA for

urgency urinary incontinence. N Engl J Med. 2012. 367(19):1803-13.

Questions?

onabotulinumtoxina (botox®) for the treatment of overactive bladder

Documents

poor bladder control

lack of bladder control

use of botox

incontinence nocturia

weekly urge incontinence

anticholinergic medication

mensymptom prevalence

majority of patients