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]. 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). 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 MLS_B 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. aureus^a	2263	0.06 – 0.12	0.12 – 0.25
C. pneumoniae^b	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

^aFor S. aureus susceptible to erythromycin A or resistant to erythromycin A by an MLS_B inducible mechanism of resistance. When a constitutive MLS_B 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 (C_max) 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 (C_max 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 C_max in pulmonary epithelial lining fluid of patients with RTIs was 14.9 µg/mL, and C_max 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 C_max 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 C_max/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
	3009^a	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. ^bNo 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. ^bPairwise 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)

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
AUC_ss	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
CL_CR	Creatinine clearance
CL_R	Renal clearance
C_max	Maximum plasma concentration
C_max,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