This document discusses the use of botulinum toxin type A (Botox) injections for the treatment of overactive bladder. It provides guidelines from medical organizations on when Botox is an appropriate treatment option. It summarizes several clinical studies that demonstrated the efficacy of Botox in improving overactive bladder symptoms like urinary incontinence and urgency. The studies also showed Botox had manageable side effects like urinary tract infections. However, long-term use of Botox can cause some patients to discontinue treatment due to issues like urinary retention requiring clean intermittent catheterization. The document discusses techniques to optimize outcomes from Botox injections like modifying injection locations and methods.

1. Antonella Giannantoni
Dipartimento di Scienze Chirurgiche e Biomediche
Clinica Urologica e Andrologica
Università degli studi di Perugia
Tossina botulinica A:
indicazioni, risultati e limiti

2. BOTOX indication: Refractory OAB patient
AUA/SUFU guidelines
 The patient who has failed a trial of symptom appropriate behavioural therapy of
sufficient length,
8 to 12 weeks, to evaluate potential efficacy and who has failed a trial of at least
one antimuscarinic medication administered for 4 to 8 weeks
 Failure of an antimuscarinic medication may include lack of efficacy and/or inability
to tolerate adverse drug effects
AUA, American Urological Association; OAB, overactive bladder.
Gormley et al. J Urol 2015;193:1572–80.

3. Systematic review of BOTOX® (botulinum toxin type A)
for IDO 2010
 23 articles: three RCT, 20 observational studies,
one systematic review
 Intravesical BOTOX® improves refractory OAB
symptoms
 Significant risk of increased PVR and symptomatic
urinary retention
 Optimal administration to be determined
IDO, idiopathic detrusor overactivity; PVR, postvoid residual.
Anger et al. J Urol 2010; 183:2258

4. Nitti et al. J Urol 2013;189:2189–93.
STUDI REGISTRATIVI CHE HANNO CONDOTTO ALL’APPROVAZIONE DI
BOTOX PER IL TRATTAMENTO DELLA OAB

5. Chapple et al. Eur Urol 2013;64:249–56.

6. Results: percentage change from baseline
in all OAB symptoms
Change at Week 12 (%)
OAB symptom BOTOX® 100 U Placebo
Urinary incontinence episodes −47.9 −12.5
Micturition episodes −16.9 +4.1
Urgency episodes −31.6 −10.0
Nocturia episodes −20.2 +0.2
Volume voided +37.3 +10.1
Nitti et al. J Urol 2013;189:2189–93.

7. Results: adverse events ≥ 5%
First 12 weeks, n (%) Any time in treatment cycle 1, n (%)
Adverse event
OnabotA 100 U
(N = 278)
Placebo
(N = 272)
OnabotA 100 U
(N = 278)
Placebo
(N = 272)
Urinary tract
infection1* 43 (15.5) 16 (5.9) 68 (24.5) 25 (9.2)
Dysuria1 34 (12.2) 26 (9.6) 40 (14.4) 27 (9.9)
Bacteriuria1 14 (5.0) 5 (1.8) 23 (8.3) 10 (3.7)
Urinary retention1† 15 (5.4) 1 (0.4) 16 (5.8) 1 (0.4)
Haematuria2 7 (2.5) 15 (5.5) 8 (2.9) 16 (5.9)
Discontinuations1
For any reason
Due to adverse
events
13 (4.6)
4 (1.4)
21 (7.6)
2 (0.7)
31 (11.1)
5 (1.8)
34 (12.3)
4 (1.4)
*Defined as positive urine culture with bacteriuria count of > 105 CFU/mL and leukocyturia of > 5/high-power fields.
†Defined as PVR ≥ 200 mL with symptoms that required clean intermittent catheterisation (CIC), or PVR ≥ 350 mL with
CIC regardless of symptoms.
1. Nitti et al. J Urol 2013;189:2189–93.
2. Content provided by the speaker.

8. Long-term Extension Trial
Final Data
De Ridder D, Nitti V, Sussman D, Sand P, Sievert K, Radomski S, Jenkins B,
Zheng Y, Chapple C
Posters presented at EAU 2015, AUA 2015, ICS 2015.
BOTOX and Overactive bladder

9. -5
-4
-3
-2
-1
0
BOTOX® 100 U treatment number
1 2 3 4 5 6
UIepisodes/day
(meanchangefromBL)
−3.3 −3.6 −3.8 −3.5 −3.3 −3.1
n= 812 597 372 264 181 136
BL = 5.6 5.7 5.7 5.8 5.5 5.7
Overall population results: consistent reduction
in UI episodes/day at Week 12
n values denote the number of patients with data available at Week 12.
Error bars represent 95% confidence intervals.
BL, baseline.
Nitti et al. Presented at AUA 2015; Oral PI-04.

10. Long-term study conclusions
 74–83% reported improved or greatly improved symptoms
after each treatment1
 Consistent reductions in daily UI episodes2
 Consistent reductions in daily urgency episodes
(3–4/day)1
 Median duration of effect 7.6 months; consistent
or increased duration of effect compared with
first treatment2
 No new safety signals1
1. De Ridder et al. Presented at EUA 2015; Poster 149.
2. Nitti et al. Presented at AUA 2015; Oral PI-04.

11. BOTOX® systematic review and
meta-analysis
 931 articles identified; eight included
 Eight RCTs with 1875 patients
 BOTOX® significantly better than placebo in terms
of frequency, urgency, UI, urgency urinary
incontinence and nocturia
 More AEs vs placebo: urinary tract infection (UTI),
bacteriuria, retention, PVR
 Effective, with manageable AEs
Sun et al. Int Urol Neph 2015;47:1779–88.

12. Long-term use of BOTOX®
• 137 patients (idiopathic 104; neuropathic 33) followed for
≥ 36 months
• Real-life study
Mohee et al. BJUI 2013;111:106–13.

13. Possible reasons for discontinuing treatment with BOTOX® (botulinum toxin type A)
1. Dowson C. et al: Repeated botulinum toxin type A injections for refractory overactive bladder: medium-term outcomes, safety profile, and discontinuation
rates. Eur Urol 2012
2. Osborn et al. Urinary Retention Rates after Intravesical OnabotulinumtoxinA Injection for Idiopathic Overactive
Bladder in Clinical Practice and Predictors of this Outcome. Neururol urodyn 2015
In a single centre study of 100 pts with OAB:1
The most common reasons for discontinuing
treatment were:
• Poor efficacy: 13% of pts
• ISC-related issues: 11% of pts
Aes:
• ISC after the 1th injection: 35% of pts
• Bacteriuria: 21% of pts
BUT: the majority of patients were injected
with high doses
(200 U) of BOTOX®
In a single centre study of 160 pts with
OAB (retrospective)2
Rate of retention: 35%
The Authors stated that:
The inclusion of patients with a
preoperative PVR >100 ml and a lower
threshold to initiate clean intermittent
catheterization contributed to this
high rate of retention

14. Possible reasons for discontinuing treatment with
BOTOX®
In a retrospective evaluation of 137
patients followed for ≥ 3 yrs (80 for
≥ 60 months)1
• Drop out: at 36 months: 61.3%
at 60 months: 63.8%
• Who did stop treatment?
incontinent pts and younger pts
at baseline ( <50 yrs)
• Main reason for discontinuation:
tolerability issues (UTIs and ISC)
In 125 pts with IDO and NDO,
median follow up of 38 months2
• 26 % required ISC (PVR ≥ 150
ml)
• 18% developed recurrent UTIs
• Discontinuation rate
at 60 months: 25%
1. Mohee A. et al. Long-term outcome of the use of intravesical botulinum toxin for the treatment of overactive bladder (OAB). BJU Int 2013
2. Veeratterapillary R. et al. Discontinuation rates and inter-injection interval for repeated intravesical botulinum toxin type A injections for detrusor
overactivity. Int J Urol 2014

15. Botox injections for voiding dysfunction:
failure due to AEs or poor efficacy?
• Among 100 OAB pts (1):
- poor efficacy: 13% of pts
2. dose optimization protocol improved
outcomes in 5 of 9 (56%) non responder
patients (2)
Among 268 OAB pts (3):
- primary failure: 23 pts (8.5%)
- secondary failure: 14 pts (5.2%)
Among 125 pts (OAB and NDO) (4)
- non responders: 17 pts (14%)
1. Dowson C. et al. Eur Urol 2012; 2. Osborn et al. Neururol Urodyn 2015; 3. Mohee A. BJU Int 2013;
4. Veeratterapillary R. et al. Int J Urol 2014
Rate of poor efficacy is low
Failure due to AES is a major problem

16. Possible reasons for intra-patient variation
in response to treatment
1. Procedure-related factors that may affect response to
treatment
2. Possible antibodies production against the neurotoxin
3. Mistakes during the injection procedure

17. Long-term follow-up of repeated BOTOX® injections in patients with refractory OAB –
personal experience
Since 2001: total No. of patients= 84
Patients persisting with treatment= 69 pts (82.1%)
ISC= none
Bacteriuria: 7 pts (10.1%)
Discontinuation rate: 15 pts (17.8%)
• 8 cases: lack of efficacy (after 3 and 4 repeat injections);
• These patients with reduced efficacy after repeat injections were treated again with Botox
injections performing a different injection modality, as follows in the next slide
Giannantoni et al. Urologia 2015
3. Mistakes during the injection procedure

18. New Botox injection’s technique:
personal experience
 when injecting the blue solution into the detrusor muscle, wait longer (at least five seconds)
before removing the needle; in this way you do not observe any leakage of the solution;
 perform each single injection deeper and perpendicular into the bladder wall; when injecting the
solution into the sub-mucosa, try to be deeper (into the detrusor muscle)
 the injected solutions spread about 2 cm of diameter from the injection site within the bladder
wall.
At 1 month follow up, all the 8 patients were completely continent and the frequency of daily
urgency episodes was substantially reduced.
These benefits persisted along the whole follow up.
Italian Urological Association Annual Meeting 2015

20. 3rd-line treatment
AUA. Available from https://www.auanet.org/common/pdf/education/clinical-guidance/Overactive-Bladder-Algorithm.pdf. Accessed February 2016.