KETEKä (telithromycin)

 

 

Briefing Document
for the FDA Anti-Infective Drug Products
Advisory Committee Meeting

March 2001

 

AVAILABLE FOR PUBLIC DISCLOSURE
WITHOUT REDACTION

 

Executive summary 5

TABLE OF CONTENTS 12

LIST OF APPENDICES 16

LIST OF ABBREVIATIONS 17

1.   Background and medical need 20

2.   Claimed indications 22

3.   Microbiology 23

3.1   Ketolides:  A new chemical class 23

3.2   Telithromycin mode of action 24

3.2.1   Dual interaction of telithromycin with domain V and domain II 24

3.2.2   Inhibition of 30S and 50S ribosomal subunit formation by telithromycin 25

3.2.3   Telithromycin:  affinity for bacterial ribosomes 25

3.2.4   Conclusion 25

3.3   Antipneumococcal activity 25

3.3.1   In vitro antipneumococcal activity 25

3.3.2   Bactericidal activity of telithromycin against S. pneumoniae 27

3.3.3   In vivo activity in murine infection models 27

3.3.4   Intracellular antipneumococcal activity 28

3.4   Activity against other pathogens involved in lower respiratory tract infections 28

3.4.1   Activity against other common pathogens 28

3.4.2   Bordetella species 30

3.5   Activity against beta-hemolytic streptococci (Streptococcus pyogenes and other streptococci) 30

3.5.1   In vitro studies with beta-hemolytic streptococci 30

3.5.2   In vivo studies of activity against beta‑hemolytic streptococci 31

3.6   Activity against atypical and intracellular micro-organisms 31

3.6.1   Intracellular concentration of telithromycin 31

3.6.2   Activity against atypical or intracellular pathogens involved in lower respiratory tract infections 31

3.7   In vitro activity against other pathogens 33

3.7.1   Staphylococcus aureus 33

3.7.2   Enterococcus species 33

3.7.3   Anaerobes 34

3.7.4   Other bacterial species 34

3.8   Postantibiotic effect of telithromycin 34

3.8.1   Postantibiotic effect in vitro 34

3.8.2   Postantibiotic effect in vivo 35

3.9   Resistance 35

3.9.1   Mechanisms of resistance to erythromycin A 35

3.9.2   Resistance to telithromycin 37

3.9.3   Inducible MLSB resistance 38

3.9.4   Selection of resistant mutants 38

3.10   Microbiology summary 38

4.   Nonclinical toxicology, pharmacokinetics and pharmacology 39

4.1   Toxicology 39

4.2   Pharmacokinetics 40

4.3   Safety pharmacology 40

5. clinical pharmacokinetics and dose determination 41

5.1   Absorption, distribution, metabolism, and elimination 41

5.1.1   Absorption/Bioavailability 41

5.1.2   Distribution 41

5.1.3   Metabolites of telithromycin 42

5.1.4   Pathways of elimination 42

5.2   Pharmacokinetic characteristics of telithromycin 800 mg (single and multiple dose) 42

5.3   Pharmacokinetics in RTI patients from clinical trials 43

5.4   Pharmacokinetics in populations of special interest 43

5.4.1   Elderly subjects 43

5.4.2   Subjects with renal impairment 44

5.4.3   Subjects with hepatic impairment 44

5.4.4   Subjects with multiple impairment 45

5.5   Drug interactions 45

5.5.1   CYP3A4 inhibitors 45

5.5.2   CYP3A4 substrates 46

5.5.3   CYP2D6 substrates 46

5.5.4   Other drugs 46

5.6   Dose regimen determination 47

6.   Efficacy by indication 49

6.1   Scope of the clinical program 49

6.1.1   Indications 49

6.1.2   Studies performed 49

6.1.3   Number of subjects and enrollment 50

6.2   Study design 50

6.2.1   Schedule of efficacy assessments 53

6.2.2   Dosing 55

6.2.3   Standardization of processes 69

6.3   Statistical methods 127

6.3.1   Definition and analysis of study populations 128

6.3.2   Efficacy analyses 153

6.4   Clinical studies 174

6.4.1   Community-acquired pneumonia 185

6.4.2   Acute exacerbation of chronic bronchitis 84

6.4.3   Acute sinusitis 228

6.4.4   Tonsillitis/pharyngitis 474

6.4.5   S. pneumoniae susceptibility profile to telithromycin and other antibiotics across indications 653

6.5   Conclusions on clinical efficacy 682

7.   Safety 703

7.1   Definition of safety population 705

7.2   Phase III studies 713

7.2.1   Demographics of safety population 714

7.2.2   Extent of exposure 728

7.2.3   Treatment-emergent adverse events 743

7.2.4   TEAEs of special interest 773

7.2.5   Deaths and other serious adverse events 902

7.2.6   TEAEs in populations of special interest 1032

7.3   Clinical laboratory evaluations 1109

7.3.1   CNALVs in Phase III clinical studies 1128

7.4   Assessment of the effects of telithromycin on hepatic function 1151

7.4.1   Preclinical studies 1152

7.4.2   Phase III clinical studies 1159

7.4.3   Conclusion 1206

7.5   Assessment of the effects of telithromycin administration on cardiac repolarization 1208

7.5.1   Preclinical studies 1217

7.5.2   Telithromycin effect on heart rate 1232

7.5.3   Clinical studies 1240

7.5.4   Telithromycin exposure vs QTc interval 1371

7.5.5   TEAEs of potential relevance to electrocardiographic findings 1422

7.5.6   Analysis of special populations 1505

7.5.7   Studies comparing changes in QT at predefined heart rates with telithromycin 1672

7.5.8   Conclusions 1702

8.   Benefit/Risk Analysis 1711

9.   Reference List 1721

10.   Appendices 1809

 

Executive summary

Telithromycin, the first ketolide, has been developed by Aventis Pharmaceuticals for the treatment of respiratory tract infections (RTIs). The proposed indications for telithromycin are:

·         Community-acquired pneumonia (CAP)

·         Acute exacerbation of chronic bronchitis (AECB)

·         Acute sinusitis (AS)

·         Tonsillitis/Pharyngitis (T/P) due to Group A beta-hemolytic streptococcus (GABHS)

RTIs are among the most frequent infectious diseases encountered in outpatients and can lead to significant morbidity and, occasionally mortality, if inadequately treated. The key pathogens associated with these infections include common bacterial pathogens such as Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pyogenes, as well as atypical, Mycoplasma pneumoniae, and intracellular pathogens such as Legionella pneumophila and Chlamydia pneumoniae. 

The choice of antimicrobial regimens for the indications listed above is complex because of the varied classes of pathogens and the emergence of resistance to many of the older agents.  Beta-lactams, a cornerstone of outpatient RTI therapy, are inactive against beta-lactamase-producing strains of H. influenzae and M. catarrhalis; they have no activity against atypical pathogens and are increasingly threatened by the emergence of penicillin G resistance among S. pneumoniae.  Fluoroquinolones have variable activity against S. pneumoniae, and their widespread use for common infections poses concerns about the long-term use of these drugs due to emergent resistance. 

The recently recognized increase in the prevalence of erythromycin A resistance now threatens the utility of this class [36,83]. In 1999, 20.3% of S. pneumoniae strains tested were resistant to erythromycin A in the US according to the Active Bacterial Core Surveillance (ABCs) Report, Emerging Infections Program Network [14]@@ CDC Report (www.cdc.gov/ncidod/dbmd/abcs ). While there has been some debate about the clinical importance of this rise in in vitro resistance [6,61], there are an increasing number of reports of adverse clinical outcomes in patients with erythromycin A-resistant S. pneumoniae who were treated with macrolides [13,35,45,48,52,79].Waterer etal; @@Jacksonetal; @@Lonks etal; @@Garau et al; @@Kelley etal; @@Carbon etal  Because most of these macrolide-resistant S. pneumoniae are resistant to most beta-lactams, cotrimoxazole, and tetracyclines, there remain few options for oral therapy in patients infected with these strains.

General characteristics of telithromycin (see Section 3, Microbiology)

Telithromycin is the first in a new chemical class of antibacterial agents, the  ketolides. It is derived from erythromycin A but has three structural features which result in a unique mechanism of action. It has a 3‑keto function that replaces the alpha L-cladinose, which was long thought to be essential for antibacterial activity, a C11-C12 carbamate, and an aryl alkyl side chain. Telithromycin binds to domain II of the 23S rRNA of the 50S ribosomal subunit and interferes with assembly of the 30S ribosomal subunit. Telithromycin also exhibits additional ribosomal activity associated with macrolides: binding to domain V of the 23S rRNA and disruption of assembly of the 50S ribosomal subunit. This novel mechanism of action results in excellent activity against macrolide-sensitive strains and maintains activity against macrolide-resistant strains of S. pneumoniae ([40], available in Appendix 1.  Relevant references@@App_Exec_1 Hansen, Mauvais, and Douthwaite, 1999). Telithromycin has an antibacterial spectrum of activity that is well suited to the treatment of outpatient RTIs.  It is active against the major organisms encountered in these infections, including S. pneumoniae (regardless of resistance phenotype), H. influenzae, M. catarrhalis, S. aureus, S. pyogenes, anaerobic bacteria, and atypical pathogens such as M. pneumoniae and intracellular pathogens such as L. pneumophila and C. pneumoniae.

In vitro activity (see Section 3, Microbiology)

Activity against S. pneumoniae is crucially important for a therapy for RTIs, both because of the prevalence of this pathogen and because this pathogen is more likely to be associated with comorbid sequelae than other respiratory pathogens.

Telithromycin is highly active in vitro against strains of S. pneumoniae sensitive to erythromycin A and penicillin G, as shown in the table below. Telithromycin retains activity against penicillin G-intermediate resistant isolates, penicillin G-resistant isolates (penicillin MIC >2 mg/mL), and erythromycin A isolates with MLSB or efflux-type resistance as well as quinolone-resistant isolates.

Table ES-1.  MIC values for telithromycin against S. pneumoniae strains

Strain of S. pneumoniae:

N

MIC50 range

MIC90 range

Penicillin G susceptible (Pen-S)

1495

0.004 – 0.06

0.004 – 0.06

Penicillin G intermediate (Pen-I)

365

0.01 – 0.03

0.01 – 0.06

Penicillin G resistant (Pen-R) a

867

0.004 – 0.12

0.007 – 2.0

Erythromycin A susceptible (Ery-S)

491

0.001 – 0.06

0.001 – 0.06

Erythromycin A resistant (Ery-R)

455

0.0001 – 0.06

0.01 – 2.0

Quinolone resistant (Quinolone-R) b

41

0.01 – 0.03

0.03 – 0.06

a Includes macrolide-resistant strains.

b Includes macrolide-susceptible and macrolide-resistant strains. Telithromycin activity is independent of
quinolone MIC values.

Therapy for community-acquired RTIs must be effective against all major pathogens, including common, atypical and intracellular pathogens, associated with these infections. The table below shows the high in vitro activity of telithromycin against the pathogens most frequently causative of these infections.

Table ES-2.   MIC values for telithromycin against pathogens associated with
community-acquired RTIs

Pathogen

N

MIC50 range
(
mg/mL)

MIC90 range
(
mg/mL)

H. influenzae

2300

0.025 – 2.0

0.5 – 4.0

M. catarrhalis

1108

0.02 – 0.25

0.03 – 0.5

S. pyogenes

1145

£0.008 – 0.03

0.01 – 0.06

S. aureusa

2263

0.06 – 0.12

0.12 – 0.25

C. pneumoniaeb

23

0.01 – 2.0

0.03 – 2.0

L. pneumophila

136

0.01 – 0.06

0.03 – 0.12

M. pneumoniae

90

0.001 – 0.005

0.001 – 0.005

a For S. aureus susceptible to erythromycin A or resistant to erythromycin A by an MLSB inducible mechanism of resistance.  When a constitutive MLSB mechanism of resistance is harbored by a S. aureus  strain, the telithromyci MIC is above 16 mg/mL.

bC. pneumoniae:  MIC(mg/mL)  and MCC (mg/mL)

Clinical pharmacokinetics and dose determination (see Section 5, Clinical pharmacokinetics and dose determination)

After oral administration, absorption of telithromycin is almost complete (90%), and the absolute bioavailability is 57% in both young and elderly subjects. The rate and extent of absorption are not influenced by food.  Mean maximum concentration (Cmax) of telithromycin in plasma is 1.9 µg/mL after a single oral dose of 800 mg, and 2.27 µg/mL at steady state, attained after 2 to 3 days of oral dosing with 800 mg once daily.  The pharmacokinetics of telithromycin were comparable in RTI patients (Cmax 2.89 µg/mL). Telithromycin has a terminal half-life (after multiple dosing) of 9.8 hours. It is distributed extensively in human tissues. The Cmax in pulmonary epithelial lining fluid of patients with RTIs was 14.9 µg/mL, and Cmax in white blood cells of healthy subjects was 83 µg/mL, with a substantial concentration, 8.9 µg/mL, at 48 hours after dosing. Telithromycin is 60 to 70% bound to serum proteins.

After oral administration of an 800 mg radiolabeled dose, the main circulating compound is unchanged telithromycin (57% of radioactivity AUC). The main plasma metabolite (RU 76363) represents 13% of the dose, and three other metabolites each represent 3% or less. None of these metabolites contribute appreciably to the clinical antibacterial activity of telithromycin.

Prior to entering the systemic circulation, about 33% of the administered telithromycin is metabolized. The absorbed telithromycin is eliminated via multiple pathways, with 7% excreted unchanged in feces by biliary and/or intestinal secretion, 13% excreted unchanged in urine by renal excretion, and 37% metabolized by the liver.

The overall metabolism of telithromycin accounts for 70% of the dose (33% presystemic, 37% systemic), and is mediated by CYP3A4- and non-CYP3A4-mediated pathways to approximately equal degrees. The multiplicity of elimination pathways for telithromycin suggests that significant impairment of a single pathway is unlikely to have a clinically relevant effect on systemic exposure to telithromycin because of the availability of compensatory pathways. This principle has been verified for a number of populations of special interest.

The observed pharmacokinetic profile in elderly patients with RTIs, in subjects with hepatic impairment, and in subjects with renal impairment was not substantially different from that of young and/or healthy subjects, as was anticipated (exposure did not exceed 2-fold in any of these populations).

Phase I studies have shown that the risk of increased telithromycin exposure due to inhibition of CYP3A4 is minimal.  A potent inhibitor such as ketoconazole results in only a 1.5-fold increase in the Cmax of telithromycin in plasma, and a 2-fold increase in AUC.

Telithromycin, like clarithromycin, has been shown to increase the plasma concentrations of drugs metabolized by CYP3A4, such as cisapride, simvastatin, and midazolam. Caution is therefore advised, as with macrolides, if telithromycin is administered concomitantly with CYP3A4 substrates that have a narrow therapeutic margin.  As with clarithromycin, use of telithromycin with cisapride or pimozide is contraindicated. There were no clinically relevant interactions between telithromycin and theophylline or warfarin.

The mouse thigh infection model with S. pneumoniae (Craig) was used as a pharmacokinetic/ pharmacodynamic model to support selection of the telithromycin dosing regimen. Over 24 hours, the effective dose of telithromycin is independent of the dosing frequency, and the efficacy is concentration-dependent rather than time-dependent. The key parameters determining efficacy are the AUC/MIC and Cmax/MIC ratios.  The peak concentrations in respiratory tissue are well above the MIC90 of the targeted pathogens, and the excellent tissue penetration and maintenance of tissue concentrations favor a prolonged effect at the site of infection. The favorable pharmacokinetic profile, combined with potent intrinsic antibacterial activity, permits once-daily dosing and a shortened treatment duration of 5 days in RTIs such as AECB, acute sinusitis, and tonsillitis/pharyngitis caused by GABHS. 

Clinical efficacy  (see Section 6, Efficacy by indication)

Thirteen Phase III clinical trials, including 9 double-blind, randomized, active controlled studies, demonstrated that telithromycin given once daily is at least as effective as a broad range of antimicrobial therapies currently used for the treatment of RTIs, most given more than once daily (see table below). In addition, the analysis of outcomes in CAP patients with erythromycin or penicillin resistant S. pneumoniae includes data obtained in a Phase II dose comparison study carried out in Japan (Study 2105). As agreed with the FDA, other data from this study will not be presented.

Table ES-3.  13 Phase III telithromycin clinical trials

 

Study

Telithromycin

Comparator

Indication

No.

Dose

Duration

Drug/

Dose

Duration

CAP

3000

800 mg qd

7-10 d

-

-

-

 

3001

800 mg qd

10 d

AMX

1000 mg tid

10 d

 

3006

800 mg qd

10 d

CLA

500 mg bid

10 d

 

3009a

800 mg qd

7-10 d

TVA

200 mg qd

7-10 d

 

3009OL b

800 mg qd

7-10 d

-

-

-

 

3010

800 mg qd

7 d

-

-

-

AECB

3003

800 mg qd

5 d

AMC

500/125 mg tid

10 d

 

3007

800 mg qd

5 d

CXM

500 mg bid

10 d

AS

3002

800 mg qd

5 d/10 d

-

-

-

 

3005

800 mg qd

5 d/10 d

AMC

500/125 mg tid

10 d

 

3011

800 mg qd

5 d

CXM

250 mg bid

10 d

T/P

3004

800 mg qd

5 d

PEN VK

500 mg tid

10 d

 

3008

800 mg qd

5 d

CLA

250 mg bid

10 d

CAP = community-acquired pneumonia, AECB = acute exacerbation of chronic bronchitis, AS = acute sinusitis, T/P = tonsillitis/pharyngitis.  AMX=amoxicillin; CLA=clarithromycin; TVA=trovafloxacin; AMC=coadministration of amoxicillin and clavulanic acid; CXM=cefuroxime axetil; PEN VK=penicillin VK

a Study 3009 was stopped prematurely after the FDA restricted trovafloxacin to inpatient use for severe infections as a result of safety concerns that arose during postmarketing surveillance.

b No subjects from Study 3009OL were enrolled in Study 3009.

The main analysis populations in the Phase III studies are defined as follows:

·         Safety population: All subjects who received at least one dose of study medication and had at least one safety assessment following randomization.

·         mITT (modified intent-to-treat population): All subjects with disease who received at least one dose of study medication.

·         PPc (per-protocol population for analysis of clinical outcome): The primary analysis group.  Includes all mITT subjects excluding major protocol violators and subjects with an indeterminate response.

·         PPb (per-protocol population for analysis of bacteriological outcome): All PPc subjects with a causative pathogen isolated at pretherapy/entry.

A breakdown of subjects in each population in the 13 Phase III trials by indication is given in the following table.

Table ES-4.  Number of telithromycin-treated subjects in 13 Phase III  trial populations by indication

Indication

Population

 

Safety

mITT

PPc

PPb

CAP

1415

1373

1132

344

AECB

340

342

255

64

Acute sinusitis

1083

980

731

253

Tonsillitis/pharyngitis

427

430

265

265

TOTAL

3265

3125

2383

926

mITT=modified intent-to-treat; PPc=clinically evaluable per protocol;
PPb=bacteriologically evaluable per protocol.

As shown in the following table of the 9 Phase III active-controlled trials, the clinical cure rates for clinically evaluable telithromycin-treated subjects (PPc, the primary analysis population) were equivalent to active comparators across all indications. Equivalence to active comparators was also demonstrated for clinical cure rates in the mITT population. Study 3009, was prematurely discontinued due to safety concerns about trovafloxacin, the comparator.

Table ES-5.  Clinical cure rates in the PPc population of 9 Phase III active-controlled trials

Indication/

Treatment

95% confidence

Study

Telithromycin

Comparator

intervals

 

n/N

(%)

n/N

(%)

 

CAP:    3001

141/149

(94.6)

137/152

(90.1)

[-2.1; 11.1]

            3006

143/162

(88.3)

138/156

(88.5)

[-7.9; 7.5]

            3009

72/80

(90.0)

81/86

(94.2)

[-13.6; 5.2]

AECB:  3003

99/115

(86.1)

92/112

(82.1)

[-6.4; 14.3]

            3007

121/140

(86.4)

118/142

(83.1)

[-5.8; 12.4]

AS:       3005 (5 days Tel)

110/146

(75.3)

 

 

[-9.9; 11.7] a

3005 (10 days Tel)

102/140

(72.9)

102/137

(74.5)

[-12.7; 9.5] b

 

 

 

 

 

[-8.4; 13.3] c

            3011

161/189

(85.2)

73/89

(82.0)

[-7.1; 13.4] c

T/P:      3004

109/115

(94.8)

112/119

(94.1)

[-6.1; 7.4]

            3008

139/150

(92.7)

123/135

(91.1)

[-5.5; 8.6]

Comparators = amoxicillin (Study 3001); amoxicillin/clavulanic acid (Studies 3003 and 3005); clarithromycin (Studies 3006 and 3008); cefuroxime axetil (Studies 3007 and 3011); penicillin VK (Study 3004); trovafloxacin (Study 3009).

aPairwise comparison between 5-day telithromycin treatment regimen and amoxicillin/clavulanic acid regimen.

b Pairwise comparison between 10-day telithromycin treatment regimen and amoxicillin/clavulanic acid regimen.

c Pairwise comparison between 5-day and 10-day telithromycin treatment regimens.

The clinical cure rates by pathogen in the PPb population, pooled by indication, are shown in the table below.

Table ES-6.  Clinical cure rates for major pathogens in telithromycin-treated subjects -
PPb population (13 Phase III studies)

Key pathogen

n/N (%) Subjects

 

CAP

AECB

Acute sinusitis

Tonsillitis/
pharyngitis

S. pneumoniae

165/174

(94.8)

12/14

(87.5)

82/91

(90.1)

0/0

(0)

H. influenzae

95/105

(90.5)

17/25

(68.0)

57/64

(89.1)

0/0

(0)

M. catarrhalis

26/30

(86.7)

10/10

(100)

16/18

(88.9)

0/0

(0)

S. aureus

15/19

(78.9)

2/2

(100)

22/23

(95.6)

0/0

(0)

S. pyogenes

0/0

(0)

0/0

(0)

5/5

(100)

248/265

(93.6)

C. pneumoniae

32/34

(94.1)

10/11

(90.9)

0/0

(0)

0/0

(0)

M. pneumoniae

30/31

(96.8)

1/1

(100)

0/0

(0)

0/0

(0)

L. pneumophila

12/12

(100)

0/0

(0)

0/0

(0)

0/0

(0)

 [source data = v08/0000171t.lst 12 Jan 2001]

In CAP (Section 6.4.1, Community-acquired pneumonia), telithromycin administered orally 800 mg once a day for 7 to 10 days has a comparable efficacy to a broad range of active comparators administered more than once daily for 10 days (amoxicillin high dosage, 1 g three times a day; clarithromycin 500 mg twice a day), and against trovafloxacin 200 mg once a day. Particularly noteworthy results are:

·         Telithromycin demonstrated efficacy in the most vulnerable patients in the community:  the elderly (90.3%, 139/154 cases cured) and subjects with pneumococcal bacteremia (91.5%, 43/47 cases cured).  In addition, excellent results have been obtained in subjects with a diagnosis of S. pneumoniae infections (94.8%, 165/174 cases cured) and Legionella infections (100%, 12/12 cases cured), which are the infections most frequently associated with morbidity. This is particularly important because increasing numbers of elderly patients and patients at high risk are being treated as outpatients within the community.

·         High efficacy was also obtained in resistant S. pneumoniae isolates:  For penicillin G-resistant S. pneumoniae isolated as a single or mixed pathogen infection, the clinical outcome was cure in 16/19 isolates.  For erythromycin A-resistant S. pneumoniae isolated as a single or mixed pathogen infection, the clinical outcome was cure in 21/25 isolates.  When only single pathogen infections are considered, 11/12 of S. pneumoniae resistant to penicillin G and 15/17 of S. pneumoniae resistant to erythromycin A were clinically cured.

Telithromycin can therefore be used effectively in the therapy of pneumonia in outpatients.

In AECB (Section 6.4.2, Acute exacerbation of chronic bronchitis), telithromycin 800 mg given once daily for 5 days was effective and comparable to widely prescribed drugs considered the standards of care (cefuroxime axetil, amoxicillin/clavulanic acid,) given 2 to 3 times daily for 10 days.  Efficacy was maintained in patients more likely to require hospitalization such as the elderly and patients with COPD, even with significant obstruction (FEV1/FVC <60%).

In acute sinusitis (Section 6.4.3, Acute sinusitis), telithromycin 800 mg given once daily for 5 days was effective and comparable to cefuroxime axetil and amoxicillin/clavulanic acid given 2 to 3 times daily for 10 days.  In this indication it was also demonstrated in two studies that 10 days of treatment with telithromycin was comparable to 5 days of telithromycin treatment. When only single pathogen infections are considered, 9/11 of S. pneumoniae resistant to penicillin G and 13/16 of S. pneumoniae resistant to erythromycin A were clinically cured.  A 5 day regimen has the advantage of reducing the likelihood of missing doses at the end of a prolonged treatment period, which could promote the selection of resistant pathogens.

In tonsillitis/pharyngitis (Section 6.4.4, Tonsillitis/pharyngitis) due to Group A beta hemolytic streptococcus in patients aged 13 years or older, telithromycin 800 mg given once daily for 5 days was equivalent in clinical and bacteriological efficacy to 10 days of penicillin VK, the standard first line therapy for this indication, and to 10 days of clarithromycin treatment, the standard therapy for subjects allergic to beta-lactams.

Clinical safety (see Section 7, Safety)

A total of 4937 subjects were evaluated for safety in the 13 Phase III trials (9 controlled and 4 uncontrolled):  3265 subjects received telithromycin (2045 in comparative trials) and 1672 subjects received comparator drugs.  Rates for adverse events are based on these 13 trials, with emphasis on rates for the 9 controlled studies.

Telithromycin is generally well tolerated. The rates of all treatment-emergent adverse events (TEAEs), serious adverse events and discontinuations due to adverse events were comparable between telithromycin and comparators.  No specific risk was associated with age group, sex, race, or indication.  Safety was assessed in 372 subjects ³65 years of age and in 95 subjects ³13 to 18 years of age.

Frequencies of possibly related TEAEs in controlled Phase III studies are summarized in the table below.

Table ES-7.  Frequency of possibly related TEAEs in controlled Phase III studies a

 

Coded Term

Number (%) of Subjects

 

Possibly related TEAEs

 

 

 

Telithromycin

N=2045

Comparator

N=1672

 

 

Total

712 (34.8)

465 (27.8)

 

 

Diarrhea

272 (13.3)

158 (9.4)

 

 

Nausea

166 (8.1)

64 (3.8)

 

 

Headache

45 (2.2)

51 (3.1)

 

 

Dizziness

73 (3.6)

26 (1.6)

 

 

Vomiting

57 (2.8)

24 (1.4)

 

 

Dyspepsia

39 (1.9)

20 (1.2)

 

 

Abdominal pain

32 (1.6)

19 (1.1)

 

 

Rhinitis

1 (0.05)

1 (0.1)

 

 

Taste perversion

34 (1.7)

35 (2.1)

 

 

Upper respiratory infection

1 (0.05)

3 (0.2)

 

 

aBased on a frequency of at least 2.0% for all TEAEs.

Source data: v09/0000018t.lst

 

Because telithromycin, a ketolide, is derived from macrolide antibiotics, gastrointestinal safety, hepatic safety, effect on cardiac repolarization, and possible drug-drug interactions were potential safety issues.  Each was thoroughly examined in the clinical development program in addition to the overall adverse event profile.

Gastrointestinal safety (see Section 7.2.4, TEAEs of special interest)

The incidences of gastrointestinal drug-related TEAEs in the 9 active-controlled Phase III studies are shown below:

Table ES-8.  Frequency of severe and discontinuations due to possibly related diarrhea, nausea and vomiting TEAEs in 9 controlled Phase III studies

 

Number (%) of Subjects

Coded term

Telithromycin

(N=2045)

Comparator

(N=1672)

Diarrhea

 

 

Possibly related TEAEs

272 (13.3)

158 (9.4)

Severe possibly related TEAEs

18 (0.9)

5 (0.3)

Discontinuation due to TEAEs

19 (0.9)

13 (0.8)

Nausea

 

 

Possibly related TEAEs

166 (8.1)

64 (3.8)

Severe possibly related TEAEs

13 (0.6)

4 (0.2)

Discontinuation due to TEAEs

18 (0.9)

9 (0.5)

Vomiting

 

 

Possibly related TEAEs

57 (2.8)

24 (1.4)

Severe possibly related TEAEs

8 (0.4)

4 (0.2)

Discontinuation due to TEAEs

19 (0.9)

6 (0.4)

The incidence of possibly related treatment-emergent diarrhea in telithromycin-treated subjects was higher (13.3%) than that for pooled-comparator subjects (9.4%);  this incidence was higher than that observed for clarithromycin (7.3%) but was lower than that of subjects treated with amoxicillin/clavulanic acid (18.0%).  These events were generally mild or moderate in intensity. Only 2.6% of subjects treated with telithromycin in the controlled Phase III studies discontinued their treatment due to gastrointestinal related adverse events.  It is noteworthy that 0.9% of subjects treated with telithromycin discontinued treatment due to diarrhea, compared with 2.4% of subjects treated with amoxicillin/clavulanic acid alone and 0.8% of subjects treated with all active comparators (including amoxicillin/clavulanic acid).

Hepatic safety (see Section 7.4.2.2, Hepatic adverse events)

The frequency of ALT ³3 times the upper limit of the normal range (ULN) in the controlled Phase III studies at baseline and during treatment is summarized in the table below. Because patients with CAP are known to have a higher incidence of disease-related abnormal liver functions, data for CAP and non-CAP studies are presented.

Table ES-9.  Frequency of subjects with normal and elevated ALT values (³3x ULN) at baseline and during treatment in the 9 controlled Phase III studies

ALT status at baseline

n/N (%) Subjects with elevated ALT during treatment

 

Telithromycin

Comparator

CAP studies

 

 

Normal

5/395 (1.3)

3/388 (0.8)

Elevated

10/101 (9.9)

13/96 (13.5)

Non-CAP studies

 

 

Normal

3/1251 (0.2)

2/936 (0.2)

Elevated

14/182 (7.7)

12/130 (9.2)

The incidences of elevated ALT >3xULN were similar in the telithromycin and comparator groups.  As anticipated, the frequency of patients with elevated ALT values was higher in CAP subjects than in non-CAP subjects. In the CAP and non-CAP studies, the incidence of elevated ALT values during treatment with telithromycin or comparator was higher in subjects with elevated ALT values at baseline. No subjects in either the CAP or the non-CAP studies had ALT or AST ³3xULN together in combination with total bilirubin ³1.5xULN.

One patient treated with telithromycin had a serious adverse event of hepatitis that was considered by the investigator to be possibly related to the study medication. However, this patient had a second episode of hepatitis nine months later, which occurred in the absence of telithromycin treatment. A full description of this patient can be found in Appendix 19.  Narratives for subjects treated with telithromycin who experienced serious hepatic events.

Electrocardiographic QT interval (see Section 7.5, Assessment of the effects of telithromycin administration on cardiac repolarization)

Because telithromycin has structural similarities to erythromycin, a comprehensive assessment of the effects on cardiac repolarization was conducted. Data were obtained from 25 preclinical studies, 8 clinical pharmacology studies, and 10 Phase III studies, including almost 2200 subjects.

This extensive analysis revealed the following:

·         In patients with RTIs, the mean change in electrocardiographic QTc interval (QT interval corrected for heart rate by the Bazett formula [see Section 7.5.3.1, Electrocardiographic QT interval findings in patients receiving telithromycin]) following treatment with telithromycin was small (~1 ms).

·         A shallow relationship of telthromycin concentration to QTc interval was established across a wide range of observed plasma concentrations.

·         There was no difference in the frequency of QTc outliers (>500 ms) between telithromycin and macrolide and non-macrolide antibiotics.

·         An extensive analysis of at-risk subpopulations did not reveal a propensity for enhanced effect on cardiac repolarization in such patients.

·         No increase in the incidence of cardiovascular adverse events was noted when compared to macrolide and non-macrolide active comparators.

Conclusions

Telithromycin is the first in a new class of antimicrobial agents, the ketolides. It has a novel mechanism of action that results in outstanding activity against sensitive strains of S. pneumoniae, as well as potent activity against macrolide- resistant strains.  S. pneumoniae is the pathogen most associated with risk of morbidity and mortality in community-acquired RTIs. Reliable activity against this pathogen is the most important feature of an antibiotic for treatment of these infections.  In addition to its outstanding activity against S. pneumoniae, telithromycin is active against the full spectrum of respiratory pathogens, both common and atypical, including L. pneumophila, which is associated with mortality in pneumonia. Its activity against penicillin- and erythromycin-resistant pathogens is crucial in this age of increasing resistance.  As would be expected from its mechanism of action, there is no cross resistance to beta lactams or quinolones.

The pharmacokinetic profile of telithromycin, with sustained levels in tissue and therapeutic concentrations in plasma, support a brief and convenient, once-daily oral dosing regimen. This assures efficacy in infected tissues as well as in undetected bacteremia in outpatients.  The brief, simple regimen will promote patient compliance, an important factor in reducing further pressure for development of resistance due to missed doses at the end of prolonged therapy [39]. @@ Guillermot, 1998.

The clinical efficacy of telithromycin was studied in 3125 patients with the following community-acquired RTIs:  community acquired pneumonia (CAP, 1,373 patients), acute bacterial sinusitis (980 patients), acute exacerbation of chronic bronchitis (AECB, 342 patients), and tonsillitis/pharyngitis due to S. pyogenes (430 patients).  Excellent efficacy was demonstrated in all patient populations and against all key pathogens in each of the clinical trials in the four proposed indications. Telithromycin was effective in treating CAP subjects with pneumococcal bacteremia, with Legionella pneumophila, in the elderly in both CAP and AECB, in AECB subjects with severe bronchial obstruction, and in subjects at greater risk for morbid sequelae. Telithromycin demonstrated efficacy in AECB, acute sinusitis, and tonsillitis/pharyngitis with a treatment regimen of 5 days.

Telithromycin is effective in vitro against macrolide-, beta-lactam-, and quinolone-resistant S. pneumoniae.  Clinical efficacy in infections due to S. pneumoniae resistant to penicillin G or erythromycin was demonstrated with overall cure rates of 91.7% (11/12 subjects)  in CAP subjects with single pathogen infections of penicillin G-resistant strains and 88.2% (15/17 subjects) for erythromycin A-resistant strains. Similarly, efficacy against penicillin G- and erythromycin A-resistant S. pneumoniae was also demonstrated in patients with acute sinusitis.

The safety of telithromycin was assessed in 3265 patients with RTIs.  This population included a broad spectrum of  patients with underlying diseases, who received a wide variety of concomitant medications as well as elderly patients with additional risk factors for morbidity and mortality.  Telithromycin exhibited an excellent safety profile, comparable to that of other marketed outpatient antibiotics and in particular to that of the macrolides.  The incidence of gastrointestinal adverse events, while slightly higher than that of the new macrolides, falls within the range of marketed antibiotics.  There is no evidence of excess risk of hepatic adverse events. Treatment with telithromycin, which has a weak inhibitory effect on the cardiac Ikr channel, was associated with a small (approximately 1 ms) change in the electrocardiographic QT interval (corrected for heart rate).  No excess in adverse cardiovascular events was observed with telithromycin administration.

Telithromycin is metabolized in part by cytochrome P450 (CYP3A4).  Concomitant administration with a potent inhibitor of CYP3A4 (ketoconazole) was associated with a modest elevation in plasma concentrations in a clinical pharmacology study.  No excess of adverse events was observed in telithromycin treated patients who received concomitant therapy with CYP3A4 inhibitors.

Thus, telithromycin is highly effective in the treatment of outpatient RTIs.  It has excellent activity against S. pneumoniae, including macrolide- and penicillin G-resistant strains, and all the other major common, intracellular and atypical pathogens. Telithromycin  provides an alternative to quinolones for physicians who are increasingly concerned about beta-lactam- and macrolide-resistant S. pneumoniae and atypical and intracellular pathogens in community respiratory infections. Telithromycin can be given in a convenient regimen and can be given to patients intolerant to beta lactams or quinolones.  Few oral antibiotics fulfill all of these requirements.  Telithromycin will therefore be an important addition to the outpatient antimicrobial therapeutic armamentarium.

LIST OF APPENDICES

 

No.

Title

1

Relevant references

2

Dose response

3

Schedule of efficacy assessments

4

ITT analyses

5

Number of telithromycin-treated subjects in populations by study

6

Flow chart of Phase III subject disposition

7

Key inclusion/exclusion criteria

8

Narratives for subjects with S. pneumoniae from single or mixed pathogen infections at entry who failed therapy

9

Listing of subjects with resistant S. pneumoniae – bmITT not PPb population

10

Listing of subjects with resistant S. pneumoniae treated with active comparators – PPb and bmITT not PPb populations

11

Narratives for subjects with S. pneumoniae positive blood cultures who failed therapy

12

Listing of subjects with pneumococcal bacteremia – bmITT but not PPb population

13

Clinical cure rates without indeterminate responses – mITT and bmITT populations

14

TEAEs in clinical pharmacology studies

15

Deaths and discontinuations for Phase III uncontrolled studies

16

Narratives for deaths in Phase III studies

17

Narratives for possibly related serious adverse events in the completed Phase III studies

18

Shift tables for ALT (SGPT)

19

Narratives for subjects treated with telithromycin who experienced serious hepatic events

 

LIST OF ABBREVIATIONS

 

 

AECB

Acute exacerbation of chronic bronchitis

ALT

Alanine transaminase (also referred to as SGPT)

AMC

Coadministration of amoxicillin + clavulanic acid

AS

Acute sinusitis

AST

Aspartate transaminase (also referred to as SGOT)

AMX

Amoxicillin

AUC

Area under the plasma concentration vs time curve

AUCss

Area under the curve at steady state

BAL

Bronchial alveolar lavage

BCYEa

Buffered charcoal yeast extract

bmITT population

Bacteriologically evaluable modified intent to treat population:  all mITT subjects with a bacteriological sample at pretherapy/entry containing at least one pathogen considered by the investigator to be responsible for infection

bid

Two times daily

BYE

Buffered yeast extract agar

CAP

Community-acquired pneumonia

C/E ratio

Intracellular/extracellular ratio

cfu

Colony forming units

CHO

Chinese hamster ovary

CI

Confidence interval

CLA

Clarithromycin

CLCR

Creatinine clearance

CLR

Renal clearance

Cmax

Maximum plasma concentration

Cmax,ss

Maximum plasma concentration at steady state

CMI

Clinical Microbiology Institute, Inc

CNALV

Clinically noteworthy abnormal laboratory value

COPD

Chronic obstructive pulmonary disease

CXM

Cefuroxime axetil

CV

Coefficient of variation

CYP

Cytochrome P450

ECG

Electrocardiogram

ED50

Median effective dose

ELISA

Enzyme-linked immunosorbent assay

ENT

Ear, nose, and throat

Ery-A

Erytthromycin A

Ery-R

Erythromycin A-resistant

Ery-S

Erythromycin A-susceptible

EU

European Union

FDA

Food and Drug Administration

FEV1

Forced expiratory volume in 1 second

FVC

Forced vital capacity

GABHS

Group A beta-hemolytic streptococcus

HDL

High density lipoprotein

HTM

Haemophilus test medium

IC50

50% inhibitory concentration

Ig

Immunoglobulin

INR

International normaliz