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Why Another Antibiotic for Respiratory Tract Infections ?. C. Couturier. Community Acquired Pneumonia. No./an USA. Incidence2–3 millions Hospitalisations500 000 (env. 1/5) Mortalité 45 000 (env. 1/50). Bartlett et al. Clin Infect Dis 1998;26:811–38. Incidence increases with age.

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Why another antibiotic for respiratory tract infections

Why Another Antibiotic for Respiratory Tract Infections?

C. Couturier


Why another antibiotic for respiratory tract infections

Community Acquired Pneumonia

No./an USA

Incidence2–3 millions

Hospitalisations500 000 (env. 1/5)

Mortalité 45 000 (env. 1/50)

Bartlett et al. Clin Infect Dis 1998;26:811–38


Incidence increases with age

Incidence increases with age

Age (years)

16–19

20–29

30–39

40–49

50–59

60–69

70–79

0

20

40

60

80

100

120

140

Cases per 1000 population/year

MacFarlane et al. Lancet 1993;341:511–14


Why another antibiotic for respiratory tract infections

Community Acquired Pneumopathy Etiology

Other bacteria (12.5%)

Viral (12.6%)

H. influenzae(14.3%)

Mycoplasma (6.7%)

Legionella (5.2%)

Chlamydia (3.7%)

S. pneumoniae(44.9%)

Analysis of 16 studies of >3300 hospitalized patients (1960–1987)

LaForce. Clin Infect Dis 1992;14 (Suppl. 2):S233–7


Why another antibiotic for rti s pneumoniae resistance rates

Why Another Antibiotic for RTIS. pneumoniae Resistance Rates

% Resistance

Antimicrobial US Worldwide

agent(N=10,103)(N=16,672)

Penicillin G24.222.3

Erythromycin A31.730.7

Azithromycin31.530.9

Clarithromycin31.330.6

Clindamycin13.68.6

Cotrimoxazole31.133.9

Tetracycline22.115.9

Levofloxacin0.9 0.8

Source: PROTEKT US


Penicillin resistant s pneumoniae tend to be resistant to other lactams

Penicillin-resistant S. pneumoniae tend to be resistant to other -lactams

MIC distribution for ceftriaxone against S. pneumoniae

% isolates

80

70

Penicillin-sensitive

(MIC 0.06 mg/L)

60

Penicillin-resistant

(MIC 2 mg/L)

50

40

Penicillin-intermediate

(MIC 0.12–1 mg/L)

30

20

10

0

0.004

0.008

0.015

0.03

0.06

0.12

0.25

0.5

1

2

4

8

MIC (mg/L)

Goldstein et al. J Antimicrob Chemother 1996;38(Suppl. A):71–84


Telithromycin r d target

Tailored activity against pathogens from community RTIs:

common & atypicals

Excellent antipneumococcal activity

SPN is the leading organism in frequency and morbidity

includes activity against ERSP and PRSP

Telithromycin – R&D Target

Ketolides are developed in response to

Bacterial Resistance


Why another antibiotic for respiratory tract infections

Macrolides Target the 50S Subunit of the Bacterial Ribosome

AA-tRNA

Peptidyl

tRNA

50S Subunit

23S and 5S rRNA +

32 proteins

mRNA

Exit site for the

growing peptide

30S Subunit

16S rRNA +

20 proteins

J. Zhu, et al., J Struct Biol. 1997

118:197-219

  • Macrolide binding inhibits protein synthesis by interfering with elongation of peptide synthesis and preventing 50S subunit assembly


Telithromycin mechanism of action

Telithromycin Mechanism of Action

23S rRNA

Domain V

5S rRNA

30S

Domain II

Pocket: peptidyl transferase site

50S

Erythromycin A

Telithromycin

V

V

2058

2058

5S rRNA

O

O

5S rRNA

-cladinose

O

O

O

O

II

II

752

752


Consequence of double binding to 23s rrna

Consequence of Double Binding to 23S rRNA

Erythromycin A

Telithromycin

V

V

2058

2058

(methylation)

(methylation)

x

x

O

O

5S rRNA

5S rRNA

-cladinose

O

O

O

O

II

II

752

752

No link with

domain V

Link with

domain II

Resistance to erythromycin A

Telithromycin retains activity

against erythromycin A-

resistant organisms


Ribosomal depletion

Ribosomal Depletion

  • Inhibition of ribosomal subunit formation

30S

50S

50S

30S

Erythromycin A

30S

Depletion of

ribosome in the

bacterial cells

Telithromycin


Why another antibiotic for respiratory tract infections

Macrolide Resistance

  • Inactivating Enzymes

    • Staphylococci

    • Gram Negative Rods

  • Efflux

    • Wildly distributed

    • Multi drug activity

  • Target modification

    • 23S Methylases

    • 23 S Mutations

    • r-Proteins Mutations


Erm a s pneumoniae are inducibly resistant to ml antibiotics

erm(A) S. pneumoniae are Inducibly Resistant to ML Antibiotics

  • Telithromycin activity is not altered by inducible methylases in S.pneumoniae

erm(A)


In vitro activity of telithromycin against s pneumoniae

In vitro Activity of Telithromycin Against S. pneumoniae

MIC (µg/mL)

Resistance Phenotype (N)MIC50MIC90 Range

Macrolide-susceptible (11,384)0.0150.0150.004 - 1

Macrolide-resistant (5,288) 0.121.00.008 - 8

erm(B) (657)0.060.50.008 - 8

mef(A) (436)0.120.50.008 - 1

mef(A)+erm(B) (71)0.50.50.06 - 1

Penicillin-resistant (4,027)0.121.00.004 - 8

Levofloxacin-resistant (154)0.030.50.004 - 1

Multi-drug resistant (1,500) a 0.121.00.008 - 8

a resistant to the macrolides, penicillin, cotrimoxazole, and tetracycline Data from PROTEKT Worldwide, N = 16,672


Activities of telithromycin and macrolides erythromycin resistant s pneumoniae n 3 131

Activities of Telithromycin and Macrolides Erythromycin-Resistant S. pneumoniae (N=3,131)

2500

2000

1500

Number of Isolates

1000

Azithromycin

500

Clarithromycin

Erythromycin

0

Telithromycin

1

2

4

8

0.5

0.03

0.06

0.12

0.25

16

0.015

MIC (µg/mL)

Data from PROTEKT US 2000/2001


Bactericidal activity of telithromycin in vitro

Control

TEL at 2x MIC (0–0.6 mg/L)

TEL at 4x MIC (0–12 mg/L)

TEL at 8x MIC (0–25 mg/L)

AZI at 2x MIC (0–25 mg/L)

AZI at 4x MIC (0–5 mg/L)

AZI at 8x MIC (1 mg/L)

Bactericidal activity of telithromycin in vitro

Counts (log10 CFU/mL)

10

9

PenS EryS

S. pneumoniae

8

7

6

5

4

3

2

1

0

-5

0

5

10

15

20

25

30

-5

Time (hours)

Starting inoculum 105 CFU/mL

Felmingham et al. 38th ICAAC 1998


Bactericidal activity of telithromycin against macrolide resistant s pneumoniae

0 µg/mL

0.06

0.125

0.25

0.5

1

2

4

8

16

Bactericidal Activity of telithromycin Against Macrolide-Resistant S. pneumoniae

S. pneumoniae Strain 5467 mef(A)

S.pneumoniae Strain 5991 erm(B)

10

10

8

8

LOG10cfu/mL

LOG10cfu/mL

6

6

4

4

2

2

0

2

4

6

8

12

0

2

4

6

8

12

Hours

Hours


In vitro activity of telithromycin

In vitro Activity of Telithromycin

Organism (N)MIC50MIC90Range

S. pneumoniae (10,103)0.0150.50.015 - 8

H. influenzae (2,706)2.04.00.12 - 32

(-lactamase positive; 769)2.04.00.12 - 16

M. catarrhalis (1,896) a0.060.120.004 - 0.5

S. pyogenes (3,918)0.030.030.015 - 16

MIC (µg/mL)

Data from PROTEKT US; a PROTEKT Worldwide, 2000-2001


Telithromycin selection of antibiotic resistance

Telithromycin Selection of Antibiotic Resistance

  • Telithromycin does not induce MLSB resistance in pneumococci

  • In serial passage experiments, telithromycin was less efficient in selecting resistant mutants of pneumococci than azithromycin, clarithromycin, erythromycin, or clindamycin

  • Selection of resistant strains of viridans group streptococci and other usual oropharyngeal flora less efficient with telithromycin than azithromycin

  • Selection of resistant strains of viridans group streptococci and intestinal enterococci less efficient with telithromycin than clarithromycin


Telithromycin

Telithromycin

  • Ketolide antibiotic, derived from macrolides

  • Novel mechanism of action

  • Tailored activity against pathogens from community RTIs: common & atypicals

  • Excellent antipneumococcal activity:

    • leading organism in frequency and morbidity

    • includes activity against ERSP and PRSP

  • Short, simple course of treatment


Telithromycin development strategy

Global development ( +Japan specificities)

Sharing indications

Only one Database

Resulting in 2 dossiers FDA & EMEA

Telithromycin – Development Strategy


Telithromycin development strategy1

In vitro studies

PK

PK/PD animal

Telithromycin – Development Strategy

Dose Ranging Phase II study was not performed

Short duration treatment choosen


Indications

Indications

  • Community-acquired pneumonia (CAP)

  • Acute exacerbation of chronic bronchitis (AECB)

  • Acute sinusitis (AS)


Antibacterial studies difficulties

Antibacterial studies difficulties

  • Bacteriological End Point difficult to monitor

  • Strains are fastidious

  • Efficacy results in absence of sputum


Large number of patients few strains

Large number of Patients >> few Strains

CAP Studies

  • mITT

  • PPc

  • S. pneumoniae

  • ERSP

  • PRSP

2511

1925

318

50

27


Human pharmacology program

Human Pharmacology Program

  • Clinical pharmacokinetics of telithromycin have been studied extensively:

    • studies on plasma PK, studies on tissue penetration

    • interaction studies

    • special population studies (elderly; renal, hepatic, and multiple impairment)


Pharmacokinetics of oral telithromycin in healthy subjects

Pharmacokinetics of Oral Telithromycin in Healthy Subjects

800 mg single dose

800 mg

multiple dose (7 d)

tmax (h)

1.0 a

[0.5-4]

1.0 a

[0.5-3]

Cmax (mg/L)

1.9

(42)

2.3

(31)

C24h (mg/L)

0.03

(45)

0.07

(72)

AUC(0-24h) (mg.h/L)

8.3

(31)

12.5

(43)

t½,z (h)

7.2

(19)

9.8

(20)

Data are mean (CV%) [Min-Max], N = 18

a Median


Tissue and fluid penetration of telithromycin in patients

Tissue and Fluid Penetration of Telithromycin in Patients

Mean (CV%) telithromycin concentration after 800 mg dose (mg/L)

Tissue

2-3h

12h

24h

Epithelial lining fluid a

14.9

3.3

0.8

(76)

(51)

(62)

Alveolar macrophages a

69.3

318.1

161.6

(60)

(73)

(59)

Tonsils(µg/g) b

4.0

0.9

0.7

(13)

(56)

(40)

a Data from Honeybourne and Wise, N = 5-7

b Data from Gehanno, N = 6-8


Pathways of telithromycin disposition

Pathways of Telithromycin Disposition

Oral administration ( 90% absorbed, <10% unabsorbed)

First pass effect

Metabolism in liver and GI tract

(33%)

Systemic bioavailability (57%)

GI tract/biliary

Renal excretion

Hepatic excretion

(37%)

(7%)

(13%)

Unchanged drug

in feces

Unchanged drug

in urine

Metabolized drug*

½

½

CYP3A4-mediated

Non-P450 mediated

*Telithromycin is not metabolized by CYP2D6


Pk modifications under various conditions comparisons with healthy control subjects

PK Modifications Under Various Conditions Comparisons with Healthy Control Subjects

CmaxAUC

Renal impairment

CLCR <30 mL/min 1.5 x  2.0 x 

30-80 1.1 x  1.2 x 

CYP3A4 inhibition

Ketoconazole 1.5 x  2 x 

Itraconazole 1.2 x  1.5 x 

Grapefruit juice 

Hepatic impairment 

Renal impairment+ ketoconazole

CLCR <30 mL/min 3.4 x  4.5 x 

30-80 1.7 x  2.7 x 


Effects of multiple impairments elderly renal ketoconazole

(41)

(31)

AUC(0-24)(mg.h/L)

112.2

33.4

51.7, 61.6

Cmax,ss (mg/mL)

6.2

(36)

3.6

(22)

5.4, 8.8

Effects of Multiple Impairments (Elderly, Renal, +Ketoconazole)

Clarithromycin

Telithromycin

30-80

N=6

30-80

N=10

<30

N=2

Creatinine clearance

(mL/min)

Data are mean (CV%).


Telithromycin interaction with cyp3a4 substrate midazolam

Telithromycin Interaction with CYP3A4 Substrate: Midazolam

Change in exposure

MidazolamParameterTELCLAKET

IntravenousAUC 2.2 x 2.7 x 5 x 

OralAUC 6.1 x  7 x 16 x 

Dose of iv midazolam was 2 mg for TEL and KET and 0.05 mg/kg for CLA

Dose of oral midazolam was 6 mg for TEL and KET and 4 mg for CLA

TEL = Telithromycin; CLA = Clarithromycin; KET = Ketoconazole


Summary of human pharmacology

Summary of Human Pharmacology

  • PK of telithromycin have been well characterized, and are reproducible or predictable under various conditions

  • Telithromycin rapidly achieved targeted plasma and respiratory tissue concentrations

  • Multiple elimination pathways limit the potential for increased exposure in special populations. CYP3A4 metabolism accounts for a small fraction of total drug clearance

  • Similar inhibition of CYP3A4 to clarithromycin and erythromycin but for less time because of the short treatment duration


Telithromycin dosage regimens in phase iii studies

Telithromycin Dosage Regimens in Phase III Studies

CAP800 mg qd7-10 days

AECB800 mg qd5 days

Acute sinusitis800 mg qd5 days

800 mg qd10 days

IndicationDosageDuration


Generalized study design

Visit 1

(Day 1)

Visit 2

(Day 3 to 5)

Visit 3

(Day 10 to 13)

Visit 4

(Day 17 to 21)

Visit 5

(Day 31 to 36)

TEL:

5 days

Placebo:

5 days

End of

Therapy

Posttherapy/TOC

Late Posttherapy

Pretherapy/

Entry

Telithromycin: 10 days

Comparator: 10 days

On Therapy

Off Therapy

Generalized Study Design


Clinical efficacy of telithromycin

Clinical Efficacy of Telithromycin

  • Clinical efficacy by indication:

    • community-acquired pneumonia (CAP)

    • acute exacerbation of chronic bronchitis (AECB)

    • acute sinusitis


Cap phase iii controlled studies

CAP: Phase III Controlled Studies

  • 4 randomized, controlled, double-blind, comparative trials (Western countries)

Study No.

Treatment

N (mITT)

3001

TEL

10 d

800 mg qd

199

AMX

10 d

1000 mg tid

205

3006

TEL

10 d

800 mg qd

204

CLA

10 d

500 mg bid

212

3009

TEL

7-10 d

800 mg qd

100

TVA

7-10 d

200 mg qd

104

4003

TEL

5 d

800 mg qd

187

TEL

7 d

800 mg qd

191

CLA

10 d

500 mg qd

181

TEL = Telithromycin; AMX = Amoxicillin; CLA = Clarithromycin; TVA = Trovafloxacin


Cap other studies

CAP: Other Studies

  • 4 Phase III open-label studies (Western countries)

Study No.

Treatment

N (mITT)

3000

TEL

7-10 d

800 mg qd

240

3009 OL

TEL

7-10 d

800 mg qd

212

3010

TEL

7 d

800 mg qd

418

3012

TEL

7 d

800 mg qd

538

  • 2 Phase II/III comparative studies (Japan)

2105

TEL

7 d

600 mg qd

46

TEL

7 d

800 mg qd

50

3107

TEL

7 d

600 mg qd

126

LVX

7 d

100 mg tid

111

LVX = Levofloxacin


Cap clinical cure at toc ppc controlled western studies

TEL (7-10 d)

Comparator (10 d)

TEL (5 d)

CAP: Clinical Cure at TOC, PPc (Controlled Western Studies)

[–9.7; 4.7] a,b

[–2.1; 11.1] a

[–7.9; 7.5] a

[–13.6; 5.2] a

[–10.2; 4.3] a,c

100%

95%

94%

92%

90%

90%

89%

88%

89%

89%

80%

60%

40%

141149

137152

143162

138156

7280

8186

20%

142159

143161

134146

0%

4003 vs CLA

3001 vs AMX

3006 vs CLA

3009 vs TVA

c TEL (7 d) vs CLA

a 95% confidence intervals

b TEL (5 d) vs CLA


Cap clinical cure at test of cure perprotocol clinical uncontrolled western studies

CAP: Clinical Cure at Test Of Cure, PerProtocol(clinical)(Uncontrolled Western Studies)

TEL

Study

n/N (%)

3000183/197(93)

3009 OL175/187(94)

3010332/357(93)

3012424/473(90)


Cap clinical cure by pathogen all western studies

CAP: Clinical Cure by Pathogen(All Western Studies)

TELComparators a

All Cultures:n/N (%)n/N(%)

Key pathogens (PPb at TOC)

S. pneumoniae300/318(94)63/70(90)

H. influenzae206/229(90)42/44(95)

M. catarrhalis44/50(88)7/9(78)

Atypical pathogens (PPc at TOC)

M. pneumoniae 36/37(97) 20/22(91)

C. pneumoniae 34/36(94) 18/19(95)

L. pneumophila 13/13(100)2/3(67)

a Study 3001: Amoxicillin; Studies 3006 and 4003: Clarithromycin; Study 3009: Trovafloxacin


Cap clinical cure for resistant s pneumoniae isolates

CAP: Clinical Cure for Resistant S. pneumoniae Isolates

TEL: PPb population at TOC (Western + Japanese studies)

n/N (%) Subjects

Single and multiple pathogens

PRSP24/27(89)

ERSP44/50(88)PRSP and ERSP16/19(84)

Single pathogens

PRSP 15/16(94)

ERSP29/32(91)

PRSP and ERSP9/10(90)

PRSP = Penicillin G-resistant (MIC 2.0 µg/mL); ERSP = Erythromycin A (macrolide)-resistant (MIC 1.0 µg/mL)

a Excludes strains that are both PRSP and ERSP


Cap clinical cure for erythromycin resistant s pneumoniae by genotype

CAP: Clinical Cure for Erythromycin-Resistant S. pneumoniae by genotype

TEL: PPb population at TOC (Western + Japanese studies)

n/N (%) Subjects

Single and multiple pathogens

ERSP44/50(88)

erm(B)24/28(86)

mef(A)16/18(89)

erm(B)/mef(A)3/3(100)

Negative for erm(B) and mef(A)1/1(100)

PRSP = Penicillin G-resistant (MIC 2.0 µg/mL); ERSP = Erythromycin A (macrolide)-resistant (MIC 1.0 µg/mL)


Summary of efficacy in cap

Summary of Efficacy in CAP

  • Effective in outpatients at risk for complications (elderly, pneumococcal bacteremia, Legionella)

  • Treatment with telithromycin 800 mg once daily for 7 to 10 days is effective in CAP due to:

Common pathogens

  • S. pneumoniae

    • Pen-R strains

    • Ery-R strains

  • H. influenzae

  • M. catarrhalis

Atypical pathogens

  • M. pneumoniae

  • C. pneumoniae

  • L. pneumophila


Summary of efficacy in rtis 1

Summary of Efficacy in RTIs (1)

  • Efficacy of telithromycin demonstrated in 14 studies in 3 indications:

    • 5-day treatment for AECB and acute sinusitis

    • 7- to 10-day treatment for CAP

  • Effective in subjects at risk for complications:

    • CAP: elderly, pneumococcal bacteremia

    • AECB: elderly, significant obstruction (FEV1/FVC < 60%)


Summary of efficacy in rtis 2

Summary of Efficacy in RTIs (2)

  • Effective against S. pneumoniae resistant to penicillin G and macrolides (erythromycin A)

  • Effective against atypical and intracllular organisms:

    • C. pneumoniae

    • M. pneumoniae

    • L. pneumophila


Clinical safety of telithromycin

Clinical Safety of Telithromycin

  • Phase III clinical efficacy studies

  • Large study in usual care setting (Study 3014)

  • Post-marketing experience


Current extent of exposure

Current Extent of Exposure

  • Significant global exposure to TEL:

    • 4,472 subjects in 16 Phase III clinical efficacy studies

    • 12,159 subjects in large comparative study in usual care setting (Study 3014)

    • >24,000 patients in post-marketing survey

    • >750 000 global post-marketing exposures*

  • * based upon Aventis internal sales data to retail and outpatient pharmacies as of 09 July 2002 (PSUR n°2 submitted September 9, 2002)


Subjects with treatment emergent adverse events 2 controlled efficacy studies

Subjects (%) with Treatment-Emergent Adverse Events (2%) (Controlled Efficacy Studies)

TELComparator

N=2702N=2139

Subjects with TEAEs 1348(49.9)1035(48.4)

Diarrhea292(10.8)184(8.6)

Nausea213(7.9)99(4.6)

Dizziness (excl vertigo)99(3.7)57(2.7)

Vomiting79(2.9)48(2.2)

Loose stools63(2.3)33(1.5)

Headache148(5.5)125(5.5)

Dysguesia43(1.6)77(3.6)


Deaths in clinical efficacy studies

Deaths in Clinical Efficacy Studies

  • Reports of deaths balanced between TEL and comparators:

    • TEL: 7 (0.3%), comparators: 9 (0.4%)

    • (uncontrolled studies: 10; 0.6%)

  • No treatment related deaths


Serious adverse events controlled efficacy studies

Serious Adverse Events(Controlled Efficacy Studies)

N (%) Subjects

TELComparatorN=2702N=2139

All serious adverse events 59(2.2)61(2.9)

All treatment-related serious AEs 9(0.3)6(0.3)

  • Most SAEs were in the infections and respiratory SOCs, and were related to the underlying infection


Subjects with discontinuations due to adverse events controlled efficacy studies

Subjects (%) with Discontinuations due to Adverse Events (Controlled Efficacy Studies)

TELComparator

N=2702N=2139

Subjects with D/C 119 (4.4)92 (4.3)

GI related events58 (2.1)37 (1.7)

– Diarrhea23 (0.9)13 (0.6)

– Nausea19 (0.7)10 (0.5)

– Vomiting21 (0.8)10 (0.5)


Clinical safety of telithromycin1

Clinical Safety of Telithromycin

  • Phase III clinical efficacy studies

  • Large study in usual care setting (Study 3014)

  • Post-marketing experience


Study 3014 key design features

Study 3014: Key Design features

  • Designed in consultation with the FDA:

    • randomized, open-label comparative safety study

    • Telithromycin vs Augmentin

    • 24,000 subjects

    • treatment: 5 days for AS, 7-10 days for AECB and CAP

  • Usual care setting:

    • primary care physicians

    • minimal exclusion criteria

  • Targeted subjects with comorbidities:

    • 35% subjects 50 years or older

    • 40% with CAP or AECB


Study 3014 collection of safety data

Study 3014: Collection of Safety Data

  • Clinic visits at Visit 1 (Day 1) and Visit 2 (Day 17-22); late follow-up contact at Visit 3 (up to Day 30-35)

  • Hepatic laboratory analytes collected at Visits 1 and 2

  • Investigators monitored for all AEs, with particular focus on adverse events of special interest (AESIs)


Study 3014 aesi definitions

Study 3014: AESI definitions

  • Hepatic: hepatitis, jaundice, any worsening of a pre-existing hepatic condition, alanine aminotransferase (ALT) values 3x ULN

  • Cardiac: torsades de pointes, ventricular arrhythmias, syncope as defined by total loss of consciousness, cardiac arrest, or unwitnessed or unexplained death

  • Visual: blurred vision

  • Vasculitic: purpura or other signs of vasculitis


Study 3014 investigation of aesis

Study 3014: Investigation of AESIs

  • AESIs followed up using standardized questionnaires and clinical work-up

  • All adverse events and laboratory values reviewed regularly to ensure collection of all AESIs

  • All predefined safety endpoints adjudicated by clinical events committees (CECs)

  • Final adjudication data used for primary endpoint incidence rates


Subjects with treatment emergent adverse events 1 study 3014

Subjects (%) with Treatment-Emergent Adverse Events (1%) (Study 3014)

TELComparator

N=12,159N=11,978

Subjects with TEAEs 2807(23.1)2745(22.9)

Diarrhea423(3.5)813(6.8)

Nausea382(3.1)286(2.4)

Headache230(1.9)144(1.2)

Dizziness (excl vertigo)192(1.6)59(0.5)

Abdominal pain106(0.9)100(0.8)

Vomiting102(0.8)115(1.0)

Vaginosis fungal58(0.5)162(1.4)


Clinical safety of telithromycin2

Clinical Safety of Telithromycin

  • Phase III efficacy studies

  • Large study in usual care setting (Study 3014)

  • Post-marketing experience


Safety in post marketing experience

Safety in Post-Marketing Experience

  • >750 000 global post-marketing exposures* to TEL since first approval in Europe in July 2001

    • Germany, Italy, Spain, Mexico, Brazil and France

  • Overall safety profile in first year of post-marketing experience confirms findings in clinical development

    • no new or unanticipated safety signals identified

*As of July 9, 2002


Summary of telithromycin safety 1

Summary of Telithromycin Safety (1)

  • Extensive patient safety data available to date:

    • including 16,000 subjects in controlled clinical trials and >1 million post-marketing exposures

  • Well-characterized and well-tolerated safety profile:

    • pattern of adverse events similar to variety of marketed antibiotics

    • no excess toxicity in at-risk populations

    • low incidence of serious adverse events and discontinuations, similar to comparators


Summary of telithromycin safety 2

Summary of Telithromycin Safety (2)

  • Acceptable hepatic safety profile:

    • tendency toward slightly more frequent and predominantly minimal transaminase elevations, with no increase in clinically significant events

    • no severe hepatotoxicity in >1 million exposures

  • Acceptable cardiac safety profile

    • small mean change in QTc Bazett (~1.5 msec), of no detectible clinical significance

    • no excess in cardiac mortality or arrhythmia


Summary of telithromycin safety 3

Summary of Telithromycin Safety (3)

  • Well-characterized and consistent visual effects:

    • uncommon, generally mild, transient, and reversible events most consistent with a slight delay in accommodation

  • No signal for severe vasculitis detected


Telithromycin registration status

Around 20 European countries including all EU countries

17 south American countries

14 other countries (i.e. NZ, Singapore, Hongkong, Egypt, Vietnam)

Approved in the USA

Awaited in Canada, Australia and Japan

Telithromycin Registration Status


Telithromycin marketing status

Marketed in the following major countries

France, Germany, Spain, Italy

Brazil, Mexico

More than 1 Million subjects were treated with Ketek

Expected to increase sharply during the coming winter

Telithromycin – Marketing Status


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