Antonella GiannantoniDipartimento di Scienze Chirurgiche e Biomediche

Clinica Urologica e AndrologicaUniversità degli studi di Perugia

Tossina botulinica A: indicazioni, risultati e limiti

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.

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

Nitti et al. J Urol 2013;189:2189–93.

STUDI REGISTRATIVI CHE HANNO CONDOTTO ALL’APPROVAZIONE DI BOTOX PER IL TRATTAMENTO DELLA OAB

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

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.

Results: adverse events ≥ 5%First 12 weeks, n (%) Any time in treatment cycle 1, n (%)

Adverse eventOnabotA 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 reasonDue 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.

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

-5

-4

-3

-2

-1

0

BOTOX® 100 U treatment number

1 2 3 4 5 6

UI e

piso

des/

day

(mea

n ch

ange

from

BL)

−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.

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.

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.

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.

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 OveractiveBladder 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

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

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

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

Long-term follow-up of repeated BOTOX® injections in patients with refractory OAB – personal experience

Since 2001: total No. of patients= 84Patients persisting with treatment= 69 pts (82.1%)ISC= noneBacteriuria: 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 slideGiannantoni et al. Urologia 2015

3. Mistakes during the injection procedure

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

3rd-line treatment

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