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PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE IN THE TREATMENT OF OAB MODULE 4 1 DET 808 Prescribing information is available on last slide.

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Presentation on theme: "PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE IN THE TREATMENT OF OAB MODULE 4 1 DET 808 Prescribing information is available on last slide."— Presentation transcript:

1 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE IN THE TREATMENT OF OAB MODULE 4 1 DET 808 Prescribing information is available on last slide

2 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE 2 Prescribing information is available on last slide DETRUSITOL ® XL BACKGROUND INFORMATION

3 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE 3 Iris/Ciliary body 31 Lachrymal gland 32 Salivary glands 32 Heart 32 Stomach 32 Colon 32 Bladder (detrusor muscle) 32 CNS: Gall bladder 32 MUSCARINIC RECEPTORS – DISTRIBUTION THROUGHOUT THE BODY 31. Chapple CR, et al. Urology 2002;60(5 Suppl 1): Caulfield MP. Pharmacol Ther 1993;58(3): Prescribing information is available on last slide

4 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE 4 Acetylcholine stimulates M3 receptors, directly causing detrusor muscle contraction 31 Acetylcholine also stimulates M2 receptors, indirectly causing detrusor muscle contraction 31 Antimuscarinics such as Detrusitol ® XL block the action of acetylcholine, reducing involuntary bladder contractions 31 MUSCARINIC RECEPTORS – HOW THEY WORK 31. Chapple CR, et al. Urology 2002;60(5 Suppl 1):82-88; discussion Prescribing information is available on last slide

5 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE 5 Detrusitol ® is A potent antimuscarinic 36 With balanced selectivity for both M2 and M3 receptor subtypes 35 The first antimuscarinic agent to be developed specifically for the treatment of OAB 34 Demonstrated in vivo to have greater selectivity for the bladder than other organs such as the salivary glands 37 DETRUSITOL ® XL – MODE OF ACTION 34.Van Kerrebroeck P, et al. Urology 2001;57(3): Chess-Williams R. Expert Opin Ther Targets 2004;8(2): Van Kerrebroeck PE, et al. Neurourol Urodyn 1998;17(5): Nilvebrant L, et al. Eur J Pharmacol 1997;327(2-3): Prescribing information is available on last slide

6 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE 6 The balanced receptor profile may be the reason for the proven efficacy and high tolerability of Detrusitol ® XL 35 The human detrusor muscle contains a mixture of M2 and M3 receptors in an 80:20 ratio 38 Detrusitol ® combines activity at both M2 and M3 receptors and thus may be of more benefit than agents that are selective for M3 35 Detrusitol ® XL is highly bladder-selective compared with the salivary glands, which may explain low incidence of dry mouth compared with other antimuscarinics 37 DETRUSITOL ® XL – MODE OF ACTION (CONTINUED) 35. Chess-Williams R. Expert Opin Ther Targets 2004;8(2): Nilvebrant L, et al. Eur J Pharmacol 1997;327(2-3): Ehlert FJ, et al. Life Sci 1997;61(18): Prescribing information is available on last slide

7 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE 7 Detrusitol ® is metabolised 39 By the CYP450 enzyme system in the liver Primarily via enzyme CYP2D6 Secondary route via enzyme CYP3A4 DETRUSITOL ® XL – METABOLISM 39. Postlind H, et al. Drug Metab Dispos 1998;26(4): Prescribing information is available on last slide

8 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE Prescribing information is available on last slide DETRUSITOL ® XL EFFICACY

9 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE DETRUSITOL ® XL DECREASES URGE INCONTINENCE EPISODES 34. Van Kerrebroeck P, et al. Urology. 2001;57: –80 –60 –50 –30 –20 –10 –70 –40 *P= vs placebo 0 MEDIAN % REDUCTION FROM BASELINE * PLACEBODETRUSITOL ® XL 9 Prescribing information is available on last slide

10 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE † P<0.001 vs placebo COMPARABLE EFFICACY IN PATIENTS WITH SEVERE URGE INCONTINENCE Note: Severe urge incontinence is ≥21 episodes per week. 40. Landis JR, et al. ICS, MEDIAN % CHANGE FROM BASELINE OF URGE INCONTINENCE EPISODES † The average number of severe urge incontinence episodes was 42 per week Placebo Detrusitol ® XL 4mg PATIENTS WITH SEVERE URGE INCONTINENCE 10 Prescribing information is available on last slide

11 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE MICTURITIONS PER 24 HOURS REDUCED WITH DETRUSITOL ® XL AS EARLY AS 1 WEEK *P<0.01 versus baseline MEDIAN % REDUCTION IN DRUG-NAÏVE PATIENTS * 0 WEEK WEEK 12 (n=735) 41. Siami P, et al. Clin Ther. 2002;24: Prescribing information is available on last slide

12 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE 41. Siami P, et al. Clin Ther. 2002;24: URGENCY EPISODES PER 24 HOURS REDUCED WITH DETRUSITOL ® XL AS EARLY AS 1 WEEK *P<0.01 versus baseline MEDIAN % IMPROVEMENT FROM BASELINE IN DRUG NAÏVE PATIENTS * 0 AFTER 1 WEEK AFTER 12 WEEKS (n=735) Prescribing information is available on last slide

13 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE 42. Sussman D and Garely A. Current Med Research and Opinion, 2002:18(4): P<0.01 COMPARISON OF DETRUSITOL ® XL AND OXYBUTYNIN ER % PATIENTS % OF PATIENTS REPORTING IMPROVED BLADDER CONDITION AFTER 8 WEEKS DETRUSITOL ® XL 4 MG (n=336) OXYBUTYNIN ER 10 MG (n=307) Prescribing information is available on last slide

14 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE Prescribing information is available on last slide DETRUSITOL ® XL PATIENT-REPORTED OUTCOMES

15 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE 43. Freeman R, et al. Obstet Gynecol. 2003;102: SIXFOLD INCREASE IN ABILITY TO FINISH TASK BEFORE TOILET VISIT *P<0.001 vs placebo PATIENTS (%) * DETRUSITOL ® XL 4 MG PLACEBO Baseline 12 weeks 15 Prescribing information is available on last slide

16 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE UFI = urgency-free interval – the time between the last void and the onset of urgency. 44. Khullar V, et al. ICS, P=0.009 POSITIVE CHANGE IN UFI AT WEEK Placebo Detrusitol ® XL 4mg UFIs (min) DETRUSITOL ® XL THERAPY LENGTHENS URGENCY-FREE INTERVALS 16 Prescribing information is available on last slide

17 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE – Incontinent – Continent DETRUSITOL ® XL REDUCES BOTHERSOME SYMPTOMS 45. Michel MC, et al. J Urol 2004;172(2): Coyne K, et al. Abstract presented at ICS URGENCY RATING % 0F PATIENTS III III 9 MONTHS URGENCY RATING – Incontinent – Continent PROBLEMS BEING CAUSED % 0F PATIENTS NO 9 MONTHS BOTHER RATING FEW VERY MINOR FEW MINOR MODERATESEVEREMANY SEVERE Prescribing information is available on last slide

18 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE 41. Siami P, et al. Clin Ther. 2002;24: PATIENT PERCEPTION OF TREATMENT BENEFIT % REPORTING PERCEIVED BENEFIT FROM TREATMENT AT 1 WEEK DRUG NAÏVE (n=708) PREVIOUSLY TREATED (n=385) Patients’ Assessment DRUG NAÏVE (n=709) PREVIOUSLY TREATED (n=385) Physicians’ Assessment Prescribing information is available on last slide

19 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE PATIENT SATISFACTION WITH TREATMENT Week 12 PATIENTS (%) OVERALL TREATMENT BENEFIT SATISFIED WITH TREATMENT WILLINGNESS TO CONTINUE 47. Mattiasson A, et al. ICS, P= P=0.001 P= DETRUSITOL ® XL THERAPY ENHANCED PATIENT SATISFACTION Placebo Detrusitol ® XL 4mg 19 Prescribing information is available on last slide

20 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE 48. Kelleher CJ, et al. Am J Manag Care. 2002;8:S616-S630. Placebo Mean Change in King’s Health Questionnaire Domain Scores – Baseline to Month 12* DETRUSITOL ® XL IMPROVES MEASURES OF QUALITY OF LIFE Mean change from baseline to end of treatment 20 INCONTINENCE IMPACT ROLE LIMITATIONS PHYSICAL LIMITATIONS SOCIAL LIMITATIONS PERSONAL RELATIONSHIPS EMOTIONS SLEEP AND ENERGY SEVERITY (COPING) MEASURES GENERAL HEALTH PERCEPTION SYMPTOM SEVERITY Detrusitol ® XL (4mg od) Prescribing information is available on last slide

21 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE 21 Prescribing information is available on last slide DETRUSITOL ® XL IN THE URGE COMPONENT OF MIXED INCONTINENCE

22 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE 22 STRESS-INCONTINENCEOVERACTIVE BLADDER 49. Hunskaar S, et al. BJU Int 2004;93(3): WHAT IS MIXED INCONTINENCE? Urge to urinate but being unable to reach the toilet before leaking OR Having a strong urge to go to the toilet to urinate with no advance warning URGE INCONTINENCE (UI)SYMPTOMS 49 STRESS INCONTINENCE (SI) SYMPTOMS 49 Leak or loss of urine caused by: Sneezing Coughing Exercising Lifting Physical activity Mixed incontinence is defined as a condition where the patient experiences at least one UI and one SI symptom 49 Prescribing information is available on last slide

23 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE % PATIENTS REPORTING IMPROVEMENT AT 8 WEEKS Note: Detrusitol ® XL is not indicated for the stress component of mixed incontinence. 50. Khullar V. et al. Urology. 2004;64: MERIT STUDY: DETRUSITOL ® XL SIGNIFICANTLY REDUCES THE URGE COMPONENT OF MIXED INCONTINENCE DETRUSITOL ® XL 4 MGPLACEBO P< Prescribing information is available on last slide

24 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE Note: Detrusitol ® XL is not indicated for the stress component of mixed incontinence. 50. Khullar V, et al. Urology. 2004;64: Reduction in Impact (%) MERIT STUDY: EFFECT OF DETRUSITOL ® XL ON QUALITY OF LIFE OF PEOPLE WITH MIXED URINARY INCONTINENCE 24 GENERAL HEALTH PERCEPTION INCONTINENCE IMPACT ROLE LIMITATIONS PHYSICAL LIMITATIONS SOCIAL LIMITATIONS PERSONAL RELATIONSHIPS EMOTIONS SLEEP AND ENERGY SEVERITY (COPING) MEASURES SYMPTOM SEVERITY Detrusitol ® XL Placebo Prescribing information is available on last slide

25 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE 25 Prescribing information is available on last slide DETRUSITOL ® XL TOLERABILITY

26 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE Clinical Study Study Duration (wk) No. of Patients Patient Continuation Rate Van Kerrebroeck, et al % Kreder K, et al % STAT % MERIT % 34. Van Kerrebroeck P, et al. Urology. 2001;57: Kreder K, et al. Eur Urol. 2002;41: Siami P, et al. Clin Ther. 2002;24: Khullar V, et al. Urology. 2004;64: CLINICAL TRIAL CONTINUATION RATES WITH DETRUSITOL ® XL 26 Prescribing information is available on last slide

27 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE Body SystemAdverse EventPlacebo, % (n=507)Detrusitol ® XL, % (n=505) Autonomic nervousDry mouth823 GeneralHeadache56 Fatigue12 Central/Peripheral nervousDizziness12 GastrointestinalConstipation46 Abdominal pain24 Dyspepsia13 VisionDry eyes23 Abnormal vision01 PsychiatricSomnolence23 RespiratorySinusitis12 UrinaryDysuria01 *Reported by ≥5% of patients in any treatment group or relevant to antimuscarinic therapy during 12 weeks of treatment. 34. Van Kerrebroeck P, et al. Urology. 2001;57: INCIDENCE OF ADVERSE EVENTS* WITH DETRUSITOL ® XL 27 Prescribing information is available on last slide

28 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE 47. Mattiasson A, et al. ICS, DRY MOUTH % REPORTING ADVERSE EVENTS CONSTIPATIONBLURRED VISION NIGHT TIME DOSING Night time dosing with Detrusitol ® XL Placebo 28 Prescribing information is available on last slide

29 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE 53. Diokno AC, et al. Mayo Clin Proc. 2003;78: Adverse Event*Oxybutynin ER, % (n=391) Detrusitol ® XL, % (n=399) Dry mouth29.7 † 22.3 Diarrhoea Constipation Headache Urinary tract infection Discontinuation rates *Adverse events reported by at least 5% of subjects in 1 of the treatment groups. † P=0.02, none of the other differences were statistically significant. COMPARISON OF ADVERSE EVENTS WITH OXYBUTYNIN ER AND DETRUSITOL ® XL 29 Prescribing information is available on last slide

30 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE 12-week, randomised, double-blind, placebo-controlled, multicentre study comparing efficacy and safety of Detrusitol ® XL (4mg od) with placebo in 1,015 adults with urinary frequency and urge incontinence. Primary objective of this study was to evaluate the effect of active drugs or placebo on incontinence episodes per week. Secondary objectives included evaluations of patient perceptions of urgency and frequency. VAN KERREBROECK ET AL, Previous slide Prescribing information is available on last slide

31 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE 12 week, multinational, randomised, double-blind, placebo-controlled trial involving 986 OAB patients with severe incontinence to examine efficacy of Detrusitol ® XL (4mg od) in terms of incontinence episodes/week and micturition frequency. LANDIS ET AL, Previous slide

32 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE 12 week, open label, multicentre trial to assess the speed of onset of therapeutic benefit with Detrusitol ® XL (4mg od) in 1,138 patients with OAB. Efficacy was assessed at 1, 4 and 12 weeks, measured by micturition diary and patient and physician perception of improvement. SIAMI ET AL (STAT), Previous slide Prescribing information is available on last slide

33 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE Two 8-week, parallel, open-label, randomised, multicentre trials comparing Detrusitol ® 2mg bd to Detrusitol ® XL 4mg od and Detrusitol ® XL 4mg od to oxybutynin (5mg or 10mg od) in 1,289 OAB patients. The primary analysis compared tolterodine 4mg od with oxybutynin 10mg od. SUSSMAN AND GARELY (ACET), Previous slide Prescribing information is available on last slide

34 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE 12-week, multinational, double-blind, placebo-controlled trial that compared the efficacy and perception of efficacy of Detrusitol ® XL (4 mg od) with placebo in terms of urinary urgency in 772 patients with OAB. The results presented are a secondary analysis from this study. FREEMAN ET AL, Prescribing information is available on last slide Previous slide

35 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE 12-week, placebo-controlled, randomised trial comparing the effect of Detrusitol ® XL (4 mg od) with placebo in 597 patients in terms of mean urgency-free interval as recorded by use of voiding diaries. KHULLAR ET AL, Previous slide Prescribing information is available on last slide

36 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE 9-month open-label observational study involving 3,824 patients with OAB symptoms comparing the effect of Detrusitol ® XL (4 mg od) against baseline in terms of number of urgency episodes, total urination frequency, daytime frequency, nocturia and 3 scales of OAB severity. MICHEL ET AL, Previous slide Prescribing information is available on last slide

37 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE Post-hoc analysis of 596 patients in a 12-week, double blind, placebo-controlled trial of Detrusitol ® XL (4mg od) examining the correlation between urgency and frequency and HRQL. COYNE ET AL, Previous slide Prescribing information is available on last slide

38 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE Pooled results from two 12-week placebo-controlled trials, involving 1,698 patients with OAB symptoms of frequency, nighttime frequency and urgency with or without incontinence, examining the efficacy of Detrusitol ® XL (4 mg od) following nighttime dosing. MATTIASSON ET AL, Previous slide Prescribing information is available on last slide

39 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE 12-month open-label continuation trial (following on from 12-week randomised, double-blind safety and efficacy trial) involving 1,077 patients to assess the long-term safety and tolerability of Detrusitol ® XL (4 mg od) using the King’s Health Questionnaire and the SF-36 form. KELLEHER ET AL, Previous slide Prescribing information is available on last slide

40 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE 8-week, double-blind, placebo-controlled, randomised trial of Detrusitol ® XL (4mg od) in 854 women with urge-predominant mixed incontinence. Outcomes measures included urge incontinence episodes/week, stress incontinence episodes/week, micturition frequency/24 hours, urgency episodes/24 hours, volume voided/micturition, patient perception of bladder condition and assessment of treatment benefit. KHULLER AT AL (MERIT), Prescribing information is available on last slide Previous slide

41 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE 12-month, open label, non-randomised extension study involving 759 patients who had previously received Detrusitol  XL, Detrusitol  Standard or placebo in a 12-week study. The primary objective was to assess the safety and tolerability of Detrusitol  XL 4 mg daily over a 12-month period by tracking adverse events and withdrawals. The secondary objective was to evaluate the efficacy of Detrusitol  XL 4 mg daily over the treatment period. Efficacy variables were: number of incontinence episodes per week, number of micturitions per 24 hours, volume voided per micturition and patient perception of bladder condition and urgency. KREDER ET AL, Prescribing information is available on last slide Previous slide

42 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE 12-week, multicentre, randomised, double-blind, active-control trial involving 790 women, comparing Detrusitol ® XL 4 mg od with extended release oxybutynin in their effect on episodes of UUI, total (urge and non urge) incontinence and micturition frequency. Adverse events were also recorded. Diokno et al, Prescribing information is available on last slide Previous slide

43 PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE PRESCRIBING INFORMATION 43 Detrusitol ® XL. Abbreviated Prescribing Information. Presentation: 4mg prolonged release capsule: blue with white printing (symbol and 4) containing tolterodine tartrate corresponding to 2.74mg tolterodine. Indication: Symptomatic treatment of urge incontinence and/or increased urinary frequency and urgency as may occur in patients with overactive bladder syndrome. Dosage: Adults (including the elderly): 4mg od except in patients with impaired liver function or severely impaired renal function for whom the recommended dosage is 2mg daily. For troublesome side effects the dose may be reduced from 4mg to 2mg daily*. Review after 2-3 months. Children: Not recommended. Contraindications: Patients with urinary retention, uncontrolled narrow angle glaucoma, myasthenia gravis, known hypersensitivity to tolterodine or excipients, severe ulcerative colitis or toxic megacolon. Warnings and precautions: Use with caution in patients with significant bladder outlet obstruction at risk of urinary retention, gastrointestinal obstructive disorders (e.g. pyloric stenosis), risk of decreased gastrointestinal motility, renal impairment and hepatic disease (see dosage), known risk factors for QT prolongation, relevant pre-existing cardiac diseases, autonomic neuropathy or hiatus hernia. Organic reasons for urge and frequency should be considered before treatment. Drug interactions: Concomitant treatment with potent CYP3A4 inhibitors, such as macrolide antibiotics (e.g. erythromycin) or antifungal agents (e.g. ketoconazole) should be avoided until further data are available. A more pronounced therapeutic effect and side effects may be seen if used with other drugs that possess anticholinergic properties. Muscarinic cholinergic receptor agonists may reduce the effect of tolterodine, whereas tolterodine may reduce the effect of metoclopramide and cisapride. Pharmacokinetic interactions are possible with other drugs metabolised by or inhibiting cytochrome P450 2D6 (CYP2D6), or CYP3A4. No interactions seen with warfarin or combined oral contraceptives (ethinyloestradiol/levonorgestrel). No clinically significant interaction with fluoxetine. Pregnancy and lactation: Until more information is available tolterodine should not be used during pregnancy or lactation. Women of fertile age should be using adequate contraception. Side effects: Those reported include: common (>1/100, 1/1000, 1/10000, <1/1000) tachycardia and hallucinations. Other adverse reactions reported very rarely with tolterodine are anaphylactoid reactions including angioedema and cardiac failure. Palpitations and arrhythmia (rare) are known adverse effects for this drug class. Driving and operating machinery: The ability to drive and use machines may be affected by visual accommodation disturbances. Overdose: In the event of tolterodine overdose, treat with gastric lavage and give activated charcoal. Treat symptomatically. Legal category: POM. Pack sizes: Detrusitol ® XL 4mg in cartons of 28 containing 4 blister strips of 7 capsules each; NHS price: Detrusitol ® XL 4mg (28) £ Marketing authorisation numbers: Detrusitol ® XL 4mg prolonged release capsules PL 0032/0287. Marketing authorisation holder: Pharmacia Limited, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK. *currently available in 1mg bd presentation. Further information on request: Pfizer Limited, Walton Oaks, Dorking Road, Tadworth, Surrey, KT20 7NS. Date Detrusitol ® XL Prescribing Information UK last revised: 28th October DT3_0


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