prescribing information is available on last slide in the treatment of oab module 4 1 det 808...

PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE

IN THE TREATMENT OF OAB

MODULE 4

1DET 808

Prescribing information is available on last slide

PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE2 Prescribing information is available on last slide

DETRUSITOL® XL BACKGROUND INFORMATION

PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE3

Iris/Ciliary body31

Lachrymal gland32

Salivary glands32

Heart32

Stomach32

Colon32

Bladder (detrusor muscle) 32

CNS:

Gall bladder32

MUSCARINIC RECEPTORS – DISTRIBUTION THROUGHOUT THE BODY

31. Chapple CR, et al. Urology 2002;60(5 Suppl 1):82-89.32. Caulfield MP. Pharmacol Ther 1993;58(3):319-379.Prescribing information is available on last slide


• Acetylcholine stimulates M3 receptors, directly causing detrusor muscle contraction31

• Acetylcholine also stimulates M2 receptors, indirectly causing detrusor muscle contraction31

• Antimuscarinics such as Detrusitol® XL block the action of acetylcholine, reducing involuntary bladder contractions31

MUSCARINIC RECEPTORS – HOW THEY WORK

31. Chapple CR, et al. Urology 2002;60(5 Suppl 1):82-88; discussion 88-89.Prescribing information is available on last slide


Detrusitol® is

• A potent antimuscarinic36

• With balanced selectivity for both M2 and M3 receptor subtypes35

• The first antimuscarinic agent to be developed specifically for the treatment of OAB34

• Demonstrated in vivo to have greater selectivity for the bladder than other organs such as the salivary glands37

DETRUSITOL® XL – MODE OF ACTION

34. Van Kerrebroeck P, et al. Urology 2001;57(3):414-421.35. Chess-Williams R. Expert Opin Ther Targets 2004;8(2):95-106.36. Van Kerrebroeck PE, et al. Neurourol Urodyn 1998;17(5):499-512.

37. Nilvebrant L, et al. Eur J Pharmacol 1997;327(2-3):195-207.



The balanced receptor profile may be the reason for the proven efficacy and high tolerability of Detrusitol® XL35

• The human detrusor muscle contains a mixture of M2 and M3 receptors in an 80:20 ratio38

• Detrusitol® combines activity at both M2 and M3 receptors and thus may be of more benefit than agents that are selective for M335

• Detrusitol® XL is highly bladder-selective compared with the salivary glands, which may explain low incidence of dry mouth compared with other antimuscarinics37

DETRUSITOL® XL – MODE OF ACTION (CONTINUED)

35. Chess-Williams R. Expert Opin Ther Targets 2004;8(2):95-106.37. Nilvebrant L, et al. Eur J Pharmacol 1997;327(2-3):195-207.

38. Ehlert FJ, et al. Life Sci 1997;61(18):1729-1740.Prescribing information is available on last slide


Detrusitol® is metabolised39

• 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):289-293.Prescribing information is available on last slide

PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDEPrescribing information is available on last slide

DETRUSITOL® XL EFFICACY


DETRUSITOL® XL DECREASES URGE

INCONTINENCE EPISODES

34. Van Kerrebroeck P, et al. Urology. 2001;57:414-421.

–80

–60

–50

–30

–20

–10

–70

–40

*P=0.0001 vs placebo

0M

ED

IAN

% R

ED

UC

TIO

N F

RO

M B

AS

ELI

NE

*

PLACEBODETRUSITOL® XL

9 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, 2003.

ME

DIA

N %

CH

AN

GE

FR

OM

BA

SE

LIN

E O

F

UR

GE

INC

ON

TIN

EN

CE

EP

ISO

DE

S

†

-80

-70

-60

-50

-40

-30

-20

-10

0

• The average number of severe urge incontinence episodes was 42 per week

Placebo

Detrusitol® XL 4mg

PATIENTS WITH SEVERE URGE INCONTINENCE



MICTURITIONS PER 24 HOURS REDUCED WITH DETRUSITOL® XL AS EARLY AS 1 WEEK

*P<0.01 versus baseline

ME

DIA

N %

RE

DU

CT

ION

IN D

RU

G-N

AÏV

E P

AT

IEN

TS

*

0WEEK 1

5

10

15

20

25

30

35

WEEK 12(n=735)

41. Siami P, et al. Clin Ther. 2002;24:616-628.11 Prescribing information is available on last slide

PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE41. Siami P, et al. Clin Ther. 2002;24:616-628.

URGENCY EPISODES PER 24 HOURS REDUCED WITH DETRUSITOL® XL AS EARLY AS 1 WEEK

*P<0.01 versus baseline

ME

DIA

N %

IMP

RO

VE

ME

NT

FR

OM

BA

SE

LIN

E

IN D

RU

G N

AÏV

E P

AT

IEN

TS

*

0AFTER 1 WEEK

10

20

30

40

50

60

70

AFTER 12 WEEKS(n=735)

80

90



42. Sussman D and Garely A. Current Med Researchand Opinion, 2002:18(4): 177-184

P<0.01

COMPARISON OF DETRUSITOL® XL AND OXYBUTYNIN ER

% P

AT

IEN

TS

50

40

30

20

10

0

% OF PATIENTS REPORTING IMPROVED BLADDER CONDITION AFTER 8 WEEKS

60

70

13

DETRUSITOL® XL 4 MG(n=336)

OXYBUTYNIN ER 10 MG(n=307)


PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDEPrescribing information is available on last slide

DETRUSITOL® XL PATIENT-REPORTED OUTCOMES


43. Freeman R, et al. Obstet Gynecol. 2003;102:605-611.

SIXFOLD INCREASE IN ABILITY TO FINISH TASK BEFORE TOILET VISIT

*P<0.001 vs placebo

PA

TIE

NT

S (

%)

*

DETRUSITOL® XL 4 MG0

10

20

30

40

50

PLACEBO

Baseline

12 weeks



UFI = urgency-free interval – the time between the last void and the onset of urgency.

44. Khullar V, et al. ICS, 2004.

P=0.009

POSITIVE CHANGE IN UFI AT WEEK 12

0

5

10

15

20

25

Placebo

Detrusitol® XL 4mg

UF

Is (

min

)30

35

DETRUSITOL® XL THERAPY LENGTHENS URGENCY-FREE INTERVALS



– Incontinent

– Continent

DETRUSITOL® XL REDUCES BOTHERSOME SYMPTOMS

45. Michel MC, et al. J Urol 2004;172(2):601-604.46. Coyne K, et al. Abstract presented at ICS 2005.17

URGENCY RATING

0

20

40

60

80

% 0

F P

AT

IEN

TS

I II III

9 MONTHS URGENCY RATING

– Incontinent

– Continent

PROBLEMS BEING CAUSED

0

10

20

30

40

50

% 0

F P

AT

IEN

TS

NO

9 MONTHS BOTHER RATING

FEW VERY MINOR

FEWMINOR

MODERATE SEVERE MANY SEVERE


PRESCRIBING INFORMATION IS AVAILABLE ON LAST SLIDE41. Siami P, et al. Clin Ther. 2002;24:616-628.

PATIENT PERCEPTION OF TREATMENT BENEFIT

% R

EP

OR

TIN

G P

ER

CE

IVE

D B

EN

EF

IT F

RO

M

TR

EA

TM

EN

T A

T 1

WE

EK

DRUG NAÏVE(n=708)

0

10

20

30

40

50

18

PREVIOUSLY TREATED

(n=385)

60

70

80

90

100Patients’

Assessment

DRUG NAÏVE(n=709)

PREVIOUSLY TREATED

(n=385)

Physicians’ Assessment



PATIENT SATISFACTION WITH TREATMENT

70

60

50

40

30

20

10

0

Week 12

PA

TIE

NT

S (

%)

OVERALL TREATMENT

BENEFIT

SATISFIED WITH TREATMENT

WILLINGNESS TO CONTINUE

47. Mattiasson A, et al. ICS, 2004.

P=0.0001P=0.001

P=0.0009

DETRUSITOL® XL THERAPY ENHANCED PATIENT

SATISFACTION

Placebo

Detrusitol® XL 4mg



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

0 -5 -10 -15 -20 -25

Mean change from baseline to end of treatment

20

INCONTINENCE IMPACT

ROLE LIMITATIONS

PHYSICAL LIMITATIONS

SOCIAL LIMITATIONS

PERSONALRELATIONSHIPS

EMOTIONS

SLEEP AND ENERGY

SEVERITY (COPING) MEASURES

GENERAL HEALTH PERCEPTION

SYMPTOM SEVERITY

Detrusitol® XL (4mg od)



DETRUSITOL® XL IN THE URGE COMPONENT OF MIXED INCONTINENCE


STRESS-INCONTINENCEOVERACTIVE BLADDER

49. Hunskaar S, et al. BJU Int 2004;93(3):324-330.

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)SYMPTOMS49 STRESS INCONTINENCE (SI) SYMPTOMS49

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 symptom49



100

90

80

70

60

50

40

30

20

10

0% P

AT

IEN

TS

RE

PO

RT

ING

IMP

RO

VE

ME

NT

A

T 8

WE

EK

S

Note: Detrusitol® XL is not indicated for the stress component of mixed incontinence.

50. Khullar V. et al. Urology. 2004;64:269-274.

MERIT STUDY: DETRUSITOL® XL SIGNIFICANTLY REDUCES THE URGE COMPONENT OF MIXED INCONTINENCE

DETRUSITOL® XL 4 MG PLACEBO

P<0.0001



Note: Detrusitol® XL is not indicated for the stress component of mixed incontinence.

50. Khullar V, et al. Urology. 2004;64:269-274.

Reduction in Impact (%)

0 -5 -10 -15 -20 -25

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® XLPlacebo



DETRUSITOL® XL TOLERABILITY


Clinical StudyStudy Duration

(wk)No. of Patients

Patient Continuation Rate

Van Kerrebroeck, et al34 12 507 95%

Kreder K, et al51 52 1077 71%

STAT41 12 1138 80%

MERIT50 8 854 95%

34. Van Kerrebroeck P, et al. Urology. 2001;57:414-421.51. Kreder K, et al. Eur Urol. 2002;41:588-595.41. Siami P, et al. Clin Ther. 2002;24:616-628.50. Khullar V, et al. Urology. 2004;64:269-274.

CLINICAL TRIAL CONTINUATION RATES WITH DETRUSITOL® XL



Body System Adverse Event Placebo, % (n=507) Detrusitol® XL, % (n=505)

Autonomic nervous Dry mouth 8 23

General Headache 5 6

Fatigue 1 2

Central/Peripheral nervous Dizziness 1 2

Gastrointestinal Constipation 4 6

Abdominal pain 2 4

Dyspepsia 1 3

Vision Dry eyes 2 3

Abnormal vision 0 1

Psychiatric Somnolence 2 3

Respiratory Sinusitis 1 2

Urinary Dysuria 0 1

*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;57:414-421.

INCIDENCE OF ADVERSE EVENTS* WITH DETRUSITOL® XL



47. Mattiasson A, et al. ICS, 2004.

DRY MOUTH

% R

EP

OR

TIN

G A

DV

ER

SE

EV

EN

TS

20

10

0 CONSTIPATION BLURRED VISION

NIGHT TIME DOSING

Night time dosing with Detrusitol® XL

Placebo



53. Diokno AC, et al. Mayo Clin Proc. 2003;78:687-695.

Adverse Event* Oxybutynin ER, % (n=391)Detrusitol® XL, %

(n=399)

Dry mouth 29.7† 22.3

Diarrhoea 7.9 6.3

Constipation 6.4 7.8

Headache 5.6 6.0

Urinary tract infection 5.1 3.3

Discontinuation rates 13.3 10.5

*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



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, 2001

30 Previous slidePrescribing 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, 2003

31 Previous 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), 2002



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), 2002



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, 2003

34 Prescribing information is available on last slide Previous 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, 2004



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, 2005



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, 2005



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, 2004



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, 2002



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), 2004



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, 2002



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, 2003



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, <1/10) dry mouth, dyspepsia, constipation, abdominal pain, flatulence, vomiting, headache, dry eyes, abnormal vision (including abnormal accommodation), dry skin, somnolence, nervousness and paraesthesia, dizziness, fatigue and chest pain; uncommon (>1/1000, <1/100) peripheral oedema, urinary retention, confusion, hypersensitivity not otherwise specified; rare (>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) £29.03. 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 2004. DT3_0

prescribing information is available on last slide in the treatment of oab module 4 1 det 808...

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