1

Bristafalm – EFFECTIVELY SAFE(OR SAFELY EFFECTIVE)?

A GLOBAL BRAND

Bristaflam

Bristaflam key dates

1982Bristaflam is synthesized

1986First human Clinical Trial

1992First launch in Spain

1997Approval by mutual recognition in Europe

2004Last launch in France

1992-1994

Bristaflam a global presence

1992Spain1993

PortugalDominican Republic

Costa RicaHondurasPanama

El SalvadorNicaraguaVenezuela

BoliviaParaguay

1994MexicoPeru

ArgentinaDate of launch

1995Korea

GuatemalaColombia

ChileSenegal

MaliBurkina Faso

NigerTogoBenin

Ivory CoastGabon

CameroonCongo1996UK

GreeceCyprusGhanaKenya

MadagascarMauritius

Brazil1997

IrelandSwedenDenmarkGermany

Bristaflam a global presence

1995-1997

Date of launch

1998Luxembourg

BelgiumMorocco

EgyptLebanon

1999Finland

SwitzerlandAustria2000

The Netherlands

1998-2000

Date of launch

Bristaflam a global presence

2001Hungary

2002Italy

Russia2003-2004

FrancePortugal (Relaunch)Greece (Relaunch)Eastern countries

2005Latvia2006

SlovakiaRomania

2001-2005

Bristaflam a global presence

Date of launch

Registered

in more than 60 countries

Bristaflam a global presence

UK

France

Aceclofenac present in all key European markets

Germany

Belgium

Italy

Spain

Portugal

Aceclofenac in Egypt is available as

100 mg/twice daily

TABLETS

PRODUCT OVERVIEW

Extensive experience that offers:

Bristaflam has been used in clinical practice for

Bristaflam is registered in more than

Bristaflam has over

have been treated with Bristaflam.

more than 15 years.

60 countries worldwide.

1.5 billion Defined Daily Doses Administered.

100 million patientsOver

… the guarantee of reliability.

Pharmacodynamics: Multifactorial mechanism of action

PHARMACODYNAMIC PROFILE

GASTRIC TISSUE

COX-1

PGE

GASTRIC PROTECTION

INJURYINFLAMMATION SITE

Adhesion molecules

Neutrophil migration

COX-2

PGE2

Pro-inflammatory cytokines Free radicals

INFLAMMATION

Pharmacodynamics: Multifactorial mechanism of action

PHARMACODYNAMIC PROFILE

GASTRIC TISSUE

COX-1

PGE

GASTRIC PROTECTION

Weak inhibitionof COX 1

TOLERABILITY EFFICACY

INFLAMMATION SITEINJURY

PGE2

Free radicals

INFLAMMATION

COX-2

Neutrophil migration

Adhesion molecules

Pro-inflammatory cytokines Reduces the expression of adhesion molecules

Reduces migrationand adhesionof neutrophils

Inhibitsproductionof PGE2

Presentsantioxidantproperties

inhibits the expression of COX-2

Multifactorial impact on inflammation

Inhibits production of IL-1

Inhibits production of TNF-

Inhibits prostaglandin synthesis (intense inhibition of PGE2)

Induces IL-1Ra synthesis (receptor antagonist of IL-1)

BRISTAFLAM PHARMACODYNAMIC PROFILE

Reduces cell adhesion molecule expression

Presents anti-oxidant properties: action on free radicals

CHRONICDISORDERS

OSTEOARTHRITIS (OA)The most common arthropathy

ANKYLOSING SPONDYLITIS (AS)Less common than RA

RHEUMATOID ARTHRITIS (RA)Affects young and elderly patients

CHRONIC DISEASES

Diclofenac

Piroxicam

Naproxen

EFFICACY DATA

Proven efficacy in Osteoarthritis

In Osteoarthritis, similar efficacy to

Proven efficacy in Osteoarthritis: key publications

EFFICACY DATA

Diaz C, Rodriguez de la Serna A, Geli C, et al. Efficacy and tolerabilityof Aceclofenac vs. Diclofenac in the treatment of knee Osteoarthritis. A multicenter study. Eur J Rheumatol Inflamm 1996; 16: 17–22.

Ward D, Veys E, Bowdler J. Comparison of Aceclofenac with Diclofenacin the treatment of Osteoarthritis. Clin Rheumatol 1995; 14: 656-62.

Torri G, Vignati C, Agrifoglio E, et al. Aceclofenac vs. Piroxicam in themanagement of Osteoarthritis of the knee: a double-blind controlled study.Curr Ther Res Clin Exp 1994; 55: 576–83.

Perez-Busquier M, Carero E, Rodriguez M, et al. Comparison of Aceclofenacwith Piroxicam in the treatment of Osteoarthritis. Clin Rheumatol 1997;16 (2): 154–9.

Kornasoff D, Frerick H, Bowdler J, et al. Aceclofenac is a well-tolerated alternativeto Naproxen in the treatment of Osteoarthritis. Clin Rheumatol 1997; 16 (1): 32–8.

Prospective, controlled, randomized, parallel double-blindclinical trial.

Aceclofenac showed significant improvements from baselineafter 15 days, for both Osteoarthritis Severity Index (OSI) and VAS(p<0.001) as well as for knee function, (p<0.01) which weresustained for the 6-month study period.

DESCRIPTION

PATIENTS

OBJECTIVE

RESULTS

Similar efficacy to Diclofenac in Osteoarthritis

EFFICACY DATA

To assess the efficacy and tolerability of Aceclofenac incomparison to Diclofenac in the treatment of Knee Osteoarthritis.

170 patients affected by Osteoarthritis were included in the Aceclofenac group (100mg bid) and 165 patientsin the Diclofenac group (50mg tid) for 6 months.

Diaz C, Rodriguez de la Serna A, Geli C, et al. Efficacy and tolerability of Aceclofenacvs. Diclofenac in the treatment of knee Osteoarthritis. A multicenter study. Eur J

Rheumatol Inflamm 1996; 16: 17–22.

Similar efficacy to Diclofenac in Osteoarthritis

Mean percentage of Osteoarthritis Severity Index.

Diaz C, Rodriguez de la Serna A, Geli C, et al. Efficacy and tolerability of Aceclofenac

vs. Diclofenac in the treatment of Knee Osteoarthritis. A multicenter study. Eur J

Rheumatol Inflamm 1996; 16: 17–22.

100Perc

en

tag

e (

OS

I)

80

60

40Baseline 0,5 1 2 3 4 5 6 months

Time

Aceclofenac (n=170)

Diclofenac (n=165)

*p<0.001 vs baseline

**

* * ** *

*

**

* * **

EFFICACY DATA

Diclofenac

Indomethacin

Ketoprofen

EFFICACY DATAProven efficacy in Rheumatoid Arthritis

In Rheumatoid Arthritis, similar efficacy to

Tenoxicam

Martín-Mola E, Gijón-Baños J, Ansoleaga JJ. Aceclofenac in comparison toKetoprofen in the treatment of Rheumatoid Arthritis. Rheumatol Int 1995;15: 111–16.

Kornasoff D, Maisenbacher J, Bowdler J et al. The efficacy and tolerabilityof Aceclofenac compared to Indomethacin in patients with Rheumatoid Arthritis.Rheumatol Int 1996; 15: 225–30.

Proven efficacy in Rheumatoid Arthritis: key publications

EFFICACY DATA

Pasero G, Marcolongo R, Serni U, et al. A multi-centre, double-blind comparativeStudy of the efficacy and safety of Aceclofenac and Diclofenac in the treatmentof Rheumatoid Arthritis. Curr Med Res Opin 1995; 13: 305–15.

Perez-Ruiz F, Alonso-Ruiz A, Ansoleaga JJ. Comparative study of the efficacy andsafety of Aceclofenac and Tenoxicam in Rheumatoid Arthritis. Clin Rheumatol1996; 15 (5): 473–7.

To investigate the efficacy and safety of Aceclofenac in comparisonwith Diclofenac in patients with active Rheumatoid Arthritis.

Long-term multicenter, double-blind, parallel group study.

Both treatment groups showed significant improvement frombaseline in evaluations of pain (VAS) and inflammation (RitchieIndex) and a reduction in morning stiffness. There were nosignificant differences between the groups. However, a trend towardsgreater improvement in hand grip strength with Aceclofenac(22% improvement vs. 17% with Diclofenac) was found.

DESCRIPTION

PATIENTS

OBJECTIVE

RESULTS

Similar efficacy to Diclofenac in Rheumatoid Arthritis

EFFICACY DATA

131 patients affected by Rheumatoid Arthritis were analysed in the Aceclofenac group (100mg bid) and 130 patients in the Diclofenac group (50mg tid) for 6 months.

Pasero G, Marcolongo R, Serni U, et al. A multi-centre, double-blind comparative studyof the efficacy and safety of Aceclofenac and Diclofenac in the treatment

of Rheumatoid Arthritis. Curr Med Res Opin 1995; 13: 305–15.

Pasero G, Marcolongo R, Serni U, et al. A multi-centre, double-blind comparative studyof the efficacy and safety of Aceclofenac and Diclofenac in the treatment

of Rheumatoid Arthritis. Curr Med Res Opin 1995; 13: 305–15.

Rit

chie

In

dex (

mean

valu

es)

Baseline

Time

Aceclofenac (n=131)

Diclofenac (n=130)

*p<0.01vs. Baseline

Similar efficacy to Diclofenac in Rheumatoid Arthritis

20

18

16

14

12

10

22

0.5 1 2 4 6 months

24

*

*

*

*

*

*

*

**

*

Improvement in the Ritchie Index. Assessmentof joint inflammation

EFFICACY DATA

Indomethacin

Tenoxicam

Naproxen

EFFICACY DATA

Proven efficacy in Ankylosing Spondylitis

In Ankylosing Spondylitis, Similar efficacy to

Proven efficacy in Ankylosing Spondylitis: key publications

EFFICACY DATA

Pasero G, Ruju G, Marcolongo R, et al. Aceclofenac vs. Naproxen in the treatmentof Ankylosing Spondylitis: a double-blind, controlled study. Curr Ther Res ClinExp 1994; 55: 833–42.

Batlle-Gualda E, Figueroa M, Ivorra J, et al. The efficacy and tolerability of Aceclofenacin the treatment of patients with Ankylosing Spondylitis. A multicenter controlledclinical trial. J Rheumatol 1996; 23 (7): 1200–6. Abstract.

Villa Alcázar LF, Álvarez de Buergo M, Rico Lenza H, et al. Aceclofenac is as safeand effective as Tenoxicam in the treatment of Ankylosing Spondylitis: a 3 monthmulticentre comparative trial. J Rheumatol 1996; 27 (7): 1194-9.

Similar efficacy to Naproxen in Ankylosing Spondylitis

EFFICACY DATA

To compare the efficacy and tolerability of Aceclofenac and Naproxen in thetreatment of Ankylosing Spondylitis. Efficacy was evaluated using a visualanalogue scale for spontaneous pain, a scale for pain on movement and atrest, and measurements of chest expansion, hand-to-floor distance, Schober’stest and normal daily activities.

Double-blind, multicenter, controlled study.

Both drugs provided effective analgesia and a correspondingimprovement in functional activity. Overall efficacy assessmentwas not significantly different between both groups.

60 patients with Ankylosing Spondylitis were included in the Aceclofenac group (100mg bid) and 66 patients in the Naproxen group (500mg bid) for 3 months.

DESCRIPTION

PATIENTS

OBJECTIVE

RESULTS

Pasero G, Ruju G, Marcolongo R, et al. Aceclofenac vs. Naproxen in the treatment of AnkylosingSpondylitis : a double-blind, controlled study. Curr Ther Res Clin Exp 1994; 55: 833–42.

Similar efficacy to Naproxen in Ankylosing Spondylitis

Reduction in pain scores after 3 months

Pasero G, Ruju G, Marcolongo R, et al. Aceclofenac vs. Naproxen in the treatment of AnkylosingSpondylitis : a double-blind, controlled study. Curr Ther Res Clin Exp 1994; 55: 833–42.

M

ean

sp

on

tan

eou

s p

ain

sco

re (

VA

S)

BaselineTime

Aceclofenac (n=47)

Naproxen (n=57)

*p<0.01 vs. baseline60

50

40

30

200.5 1 2 3 months

**

**

**

*

*

EFFICACY DATA

ACUTEDISORDERS

VIRAL PHARYNGOTONSILLITIS

LOW BACK PAIN

ODONTALGIA

DYSMENORRHOEA

ACUTE DISEASES

POST- SURGICAL PAIN

MINOR MUSCULOSKELETAL INJURY

35

Superior efficacy to Diclofenac in Low Back Pain

EFFICACY DATA

To evaluate the clinical analgesic effect (change in painassessed by VAS score) in patients affected by LowBack Pain.

Multi-center, double blind, randomized clinical trial.

Aceclofenac is not inferior to Diclofenac resinate in analgesicefficacy and a trend towards a better safety and tolerability profilewas found.

114 patients affected by Low Back Pain were studied in the Aceclofenac group (100mg bid) and 113 patients in the Indomethacin group (75mg bid) for 10 days.

DESCRIPTION

PATIENTS

OBJECTIVE

RESULTS

Schattenkirchner M, Milachowski KA. A double blind, multicentre, randomised clinical trial comparing the efficacyand tolerability of Aceclofenac with Diclofenac resinate in patients with acute Low Back Pain. Clin

Rheum 2003;22:127-35.

36

Superior efficacy to Diclofenac in Low Back Pain

Mean changes in pain scores at rest at visit 3

Pain

sco

res

(VA

S m

ean

valu

es

in m

m)

ITT Population

–53

Schattenkirchner M, Milachowski KA. A double blind, multicentre, randomised clinical trial comparing the efficacyand tolerability of Aceclofenac with Diclofenac resinate in patients with acute Low Back Pain. Clin

Rheum 2003;22:127-35.

–54

–55–56

–57

–58

–59–60

–61

–62

–63PP PopulationITT Population

ACF (n=114) DCF (n=113) ACF (n=100) DCF (n=105)

EFFICACY DATA

37

BRISTAFLAMSAFETY DATA

Multicentre, case-control study.

Among all NSAIDs included in the primary analysis, Aceclofenac was associatedwith a low risk of UGIB, while Meloxicam and Rofecoxib were associated witha medium risk.The results do not confirm that greater selectivity for COX-2 confers less risk ofUpper Gastrointestinal Bleeding.

DESCRIPTION

PATIENTS

OBJECTIVE

RESULTS

A low rate of Upper Gastrointestinal Bleeding (UGIB)

SAFETY DATA

All incident community cases of upper gastrointestinal bleeding from gastric orduodenal lesion in patients aged >18 years of age (4,309 cases). After secondaryexclusions, 2,813 cases and 7,193 matched controls were included in the analysis. Setting: 18 hospitals in Spain and Italy with total study experience of 10,734,897person-years.

To estimate the risk of UGIB associated with the use of analgesics and NSAIDs.

Laporte J.R., Ibáñez L., Vidal X. et al. Upper Gastro-Intestinal Bleeding associated with the use of NSAIDs New vs. Older Agents. Drug Safety 2004; 27(6): 411-20.

A low rate of Upper Gastrointestinal Bleeding (UGIB)

25

20

15

10

5

0

Laporte J.R., Ibáñez L., Vidal X. et al. Upper Gastro-Intestinal Bleeding associated with the use of NSAIDs New vs. Older Agents. Drug Safety 2004; 27(6): 411-20.

Od

ds

rati

os

Risk of UGIB with NSAIDs taken the weekbefore the Index Day*

SAFETY DATA

1,43,1 3,2 3,7

4.9 5,77,2 8,0

10,010,010,0

15.516,6

24,7

Ace

clofe

nac

Ibu

pro

fen

Nim

esu

lide

Dic

lofe

nac

Dexke

top

rofe

n

Melo

xic

am

Rofe

coxib

Asp

irin

(A

.aci

d)

Ind

om

eth

aci

n

Nap

roxen

Keto

pro

fen

Pir

oxic

am

NS

AID

+an

ti-P

l.

Keto

rola

c

* Index day: the day on which the upper gastrointestinal bleeding started

40

An open-label, multicenter, observational surveillance study complyingwith the Safety Assessment of Marketed Medicines (SAMM) guidelines.

Adverse events (p<0.001), gastrointestinal adverse events (p<0.001)and patients withdrawing from treatment (p<0.001) were significantlyless common with Aceclofenac than with Diclofenac.

DESCRIPTION

PATIENTS

OBJECTIVE

RESULTS

Better gastrointestinal tolerability than Diclofenacin Rheumatic Diseases

SAFETY DATA

7,890 patients affected by rheumatic diseases were included in the Aceclofenac group (100mg bid) and 2,252 patients in the Diclofenac group (75mg bid) for 12 months.

To investigate the safety and tolerance of Aceclofenac and Diclofenac inpatients with Rheumatic Diseases in normal clinical practice.

Huskisson E, Irani M, Murray F. A large prospective open-label, multicentre SAMM study, comparing the safety of Aceclofenac in patients with Rheumatic Disease. Eur J Rheumatol Inflamm 2000; 17 (1):1-7.

41

20

Aceclofenac vs. Diclofenac : AEs and withdrawals

Huskisson E, Irani M, Murray F. A large prospective open-label, multicentre SAMM study, comparing the safety of Aceclofenac in patients with Rheumatic Disease. Eur J Rheumatol Inflamm 2000 ; 17 (1):1-7.

Perc

en

tag

es

Adverse events

0

Discontinuation dueto adverse events

Aceclofenac n= 7890

Diclofenac n= 2252

* p<0.001 vs. Diclofenac

5

15

10

30

25

**

*

GI adverse events

Better gastrointestinal tolerability than Diclofenacin Rheumatic Diseases

SAFETY DATA

42

4

Aceclofenac vs. Diclofenac: adverse events 1%

Huskisson E, Irani M, Murray F. A large prospective open-label, multicentre SAMM study, comparing the safety of Aceclofenac in patients with Rheumatic Disease. Eur J Rheumatol Inflamm 2000;1 7 (1):1-7.

Perc

en

tag

es

Dyspepsia

0

Diarrhoea

Aceclofenac n= 7890

Diclofenac n= 2252

* p=0.017 vs. Diclofenac ** p=0.01 vs. Diclofenac *** p<0.001 vs. Diclofenac

1

3

2

6

5

Abdominal pain

***

*** **

*

Nausea

Better gastrointestinal tolerability than Diclofenacin Rheumatic Diseases

SAFETY DATA

CONCLUSIONS

Bristaflam

Aceclofenac is as effective or even more effectivethan classic NSAIDs, as confirmed by clinical trials and in dailyclinical practice (over 12 years)

Better gastrointestinal safety profile than gold standard NSAIDs

Its efficacy and tolerability make for higher levels of treatmentcompliance

CONCLUSIONS

Aceclofenac has extensive experience worldwide

A GLOBAL BRAND

Thank you for your attention!!

Bristaflam