1. ECONOMIC EVALUATION OF THE USE OF OXYBUTYNIN, TOLTERODINE AND SOLIFENACIN IN PATIENTS WITH OVERACTIVE BLADDER February 6, 2009

2. Study type and analysis method A complete cost-effectiveness economic evaluation was performed. This study was addressed from an institutional perspective in Public Health Institutions, particularly in IMSS (Mexico’s Social Security).

3. Comparators to manage Overactive Bladder in IMSS

4. Direct Medical Costs Include the total costs related to the intervention as a whole, general costs to manage Overactive Bladder, costs of complications and adverse events.

5. Direct Medical Costs –Consultations (Files Review) –Clinical Tests (FR) –Imaging Examinations (FR) –Surgery (FR) –Adjuvant Medications (FR) REF: File Review

6. The usage function was built based on a review of files in two second-level medical care units of IMSS. The evaluation results were expressed in both, the average cost-effectiveness ratio, and in the incremental cost-effectiveness ratio. Study type and analysis method

7. The evaluation will use the effectiveness data obtained from international literature, and especially from clinical trials, using an evidence-based medicine approach. A Markov model is the tool used to perform the cost-effectiveness analysis, Study type and analysis method

8. Markov Model Patient without Incontinence Patient with Slight Incontinence Patient with Moderate Incontinence Patient with Severe Incontinence Patient with Slight Incontinence Patient without Incontinence Patient with Slight Incontinence Patient with Moderate Incontinence Patient with Severe Incontinence Patient with Moderate Incontinence Patient without Incontinence Patient with Slight Incontinence Patient with Moderate Incontinence Patient with Severe Incontinence Patient with Severe Incontinence Tolterodine Oxyibutynin [+] Solifenacin [+] Patient with Overactive Bladder in IMSS

9. Developed with monthly cycles, adapted to model needs, and developed in Tree Age Pro 2008. Temporary analysis horizon of 12 months. A discount rate was not applied. –costs –consequences Study type and analysis method

10. Effectiveness Measures The effectiveness measures used in the model are: –Success : Patient without Incontinence –Failure: Patient with Slight Incontinence. Patient with Moderate Incontinence. Patient with Severe Incontinence.

11. Effectiveness Measures Chart***. Comparison of baseline characteristics of participants in the STAR and OBJECT studies, receiving tolterodine, oxybutynin or solifenacin. STAR Study OBJECT Study Variable Oxybutynin Tolterodine Solifenacin Sex: women 82.2% 84.5% 87.5% 87.1% Age:average (d.e) 58.6 (13.4) 59.6 (13.2) 56.9 (NA) 56.5 (NA) Race:Caucasian 87.6% 86.0% 99.3 99.3% Urge – incontinence (episodes/week) 25.5 (14.6) 24.6 (15.1) 1.66 x 7d* =11.52 1.97 x 7d* =13.79 Total incontinence (episodes/week) 28.4 (17.8) 28.0 (18.3) 2.01 x 7d* =14.07 2.32 x 7d* =16.24 Urination frequency (episodes/week) 92.9 (23.0) 91.8 (20.0) 11.36 x 7d* =79.52 11.10 x 7d* =77.70 NA: data not available * Data from the OBJECT study were reported every 24 hours, therefore, these were adjusted for the total week.

12. Chart***. Comparative effectiveness (number of total urinary incontinence episodes) of the three treatment regimes, according to the severity of the clinical profile observed after 4 weeks of treatment Treatment Slight Moderate cases Severe cases Tolterodine7.64 (21.505+7.64)=14.57 21.51 Oxybutynin 7.77 (21.159+7.77)=14.46 21.16 Solifenacin 7.14 (19.78+7.14)=13.46 19.78 Effectiveness Measures cases

13. Chart**. Transition probabilities of total urinary incontinence treatments after 4 weeks of treatment, according to the severity of the clinical profile. Severity after 4 weeks (%) Severity Drug None Slight Moderate Severe Severity before treatment Slight Tolterodine 44.19 42.56 13.04 0.21 Oxybutynin 44.23 42.27 13.30 0.21 Solifenacin 46.18 41.32 12.30 0.20 Moderate Tolterodine 23.79 46.83 28.33 1.05 Oxybutynin 24.38 46.30 28.22 1.09 Solifenacin 26.90 46.57 25.65 0.89 Severe Tolterodine 9.79 38.35 47.42 4.44 Oxybutynin 10.46 38.63 46.68 4.23 Solifenacin 12.63 41.16 42.95 3.27 Source: Adjusted results from the STAR and OBJECT Studies. (Appell & Chapple) Effectiveness Measures

14. Result of the review of the last bibliography sent by the Laboratory 1.ALEX C. WANG, 2006. Comparison of electric stimulation and oxybutynin chloride in management of overactive bladder with special reference to urinary urgency: a randomized placebo-controlled trial. Comment: Compared to placebo and electric stimulation, which are not management practices in Mexico. 2.Ananias Diokno, 2006. Oxybutynin in Detrusor Overactivity. Non-systematic review; not applicable to obtain effectiveness. Comment: Good review for marketing. 3.Regina D. Norris, 2008. A Prospective, Randomized, Double-Blinded Placebo-Controlled Comparison of Extended Release Oxybutynin Versus Phenazopyridine for the Management of Postoperative Ureteral Stent Discomfort. Comment: Clinical trial with a comparator not interesting for the Mexican Dromulary. 4.William D. Steers, 2006. Darifenacin: Pharmacology and Clinical Usage. Comment: Non- systematic review; not applicable to obtain effectiveness. Good review for marketing. 5.Ditropan XL Extended-Release Tablet (Tablet, Extended Release 5 mg). (Word document). Comment: Review document for laboratory use. 6.G. Willy Davila, 2006. Transdermal Oxybutynin for Overactive Bladder. Non-systematic review; not applicable to obtain effectiveness. Comment: Good review for marketing.

15. Results of the Cost-Effectiveness Analysis StrategyCost Incremental Cost Effectiveness Average Cost- Effectiveness Ratio Oxybutynin$5,576.777.113$784.03 Solifenacin$7,719.11$2,142.347.4640.351$1,034.21$6,106.69 Tolterodine$11,975.99$4,256.882.764-4.700$4,333.01(Dominated) Incremental Effectiveness Incremental Cost- Effectiveness Ratio

16. $0 $2,000 $4,000 $6,000 $8,000 $10,000 $12,000 $14,000 0.000.501.001.502.002.503.003.504.004.505.005.506.006.507.007.508.00 Costo Effectiveness Cost-Effectiveness Analysis Patient with Overactive Bladder in IMSS OxybutyninSolifenacinTolterodineNot Dominated Results of the Cost-Effectiveness Analysis

17. Recommendations Tolterodine resulted dominated by the effectiveness (low) and price (high). The effectiveness of solifenacin vs. oxybutynin has a marginal gain, but there is considerable difference in price. Therefore, the recommendation is: –Decrease the product price for the government to less than $87.5 pesos per box; with this, the monthly treatment cost of oxybutynin vs. solifenacin would allow to position it as a cost- effective alternative.