英文药名: Ketek(Telithromycin Tablets)

中文药名: 泰利霉素片

生产厂家: Aventis

药品名称

通用名：泰利霉素
英文名：Telithromycin

规 格

片剂：400mg *20 片  400mg *60 片

药品简介

泰利霉素为第一个获准应用于临床的酮内酯类药物，体外试验显示对呼吸道病原菌，包括耐青霉素和大环内酯类／氮环类肺炎链球菌具有良好活性。半衰期长，社区获得性感染每天只需口服给药1次。替利霉素为CYP3A4的底物，能够抑制CYP3A4代谢的药物。轻中度消化道不良反应发生率较高。对照试验证明，替利霉素治疗社区获得性肺炎、急性副鼻窦炎、慢性支气管炎急性加剧和咽喉炎等所取得的临床和病原有效率与现有抗菌药物近似甚至更好，尤其是对耐青霉素和红霉素肺炎链球菌引起的呼吸道感染也可能取得良好疗效。
泰利霉素的作用机制与大环内酯类相似，即与细菌核糖体50S亚单位结合，并终止其蛋白合成，为一用于治疗对大环内酯类耐药细菌感染的新型大环内酯类药物。泰利霉素含有1、12环氨基甲酸盐，与红霉素A和芳香烃或芳香丙烯链的2个羟基团连接，其在体外抗菌活性与新型大环内酯类相同甚至更强，对多种病原核糖体的结合力比大环内酯类强6~10倍。
泰利霉素（每日800mg口服剂量）已经获准用于治疗18岁以上的轻中度社区获得性肺炎（CAP）、慢性支气管炎急性发作（AECB）、急性鼻窦炎以及A组β链球菌引起的扁桃体炎／咽炎患者，12岁以上不能使用β-内酰胺类抗生素治疗的病人也可替代使用该药。泰利霉素不仅对耐药的肺炎链球菌有效，而且比目前使用的抗生素更容易耐受，安全性也更高。Ⅲ期临床研究显示，报道最多的泰利霉素相关药物不良反应包括腹泻、恶心、头晕和呕吐。
泰利霉素对上下呼吸道感染都非常有效，包括那些耐药致病菌引起的感染由每日一次的短程治疗也可见显著疗效。泰利霉素属大环内酯－林可霉素－链阳性菌素（MLSb）类抗生素。体外实验（与实际临床情况未必相关）资料显示，Ketek通过结合核糖体的两个不同位点、抑制核糖体的蛋白装配来减少细菌繁殖必需的蛋白合成而发挥其抗菌作用。
上市情况
欧洲委员会于2001年7月授权允许泰利霉素投入市场。该药获准用于治疗社区获得性上下呼吸道感染，包括那些对常用抗生素耐药的细菌感染。泰利霉素也在墨西哥投入使用。
 
药 效 学

泰利霉素作用机制与大环内酯类抗生素相似，主要是通过直接与细菌核糖体的50s亚基结合，抑制蛋白质的合成，并阻抑其翻译和装配。泰利霉素与大环内酯类抗生素均可与23s核糖体RNA的Ⅱ和Ⅴ结构区的核苷酸结合，但最大区别在于泰利霉素对野生型核糖体的结合力较红霉素和克拉霉素分别强约10倍和6倍。对核糖体结构Ⅴ区修饰的微小差异就使MLSB类抗生素对细菌的耐受能力提高了20倍。也就是说，泰利霉素与Ⅱ、Ⅴ结构区的强大结合，使其成为一种可以覆盖所有对大环内酯耐药菌的有效、广谱的抗生素。泰利霉素对肺炎链球菌、肺炎球菌、嗜血流感杆菌和莫拉汉菌均有较好疗效，并较阿奇霉素等大环内酯类强。
泰利霉素口服吸收良好，口服生物利用度约为57％，食物不影响其吸收。口服后70％在肝脏被CYP3A4代谢为4种代谢产物：泰利醇；泰利酸；N―去甲脱氧酰胺衍生物；5N―氧吡啶衍生物。半衰期（t1／2）为9.81小时，肾清除率为12.5升／小时。其排泄为多种途径：1／3以原形从尿中排泄，3％以原形从粪便排泄，代谢产物有37％从肝脏排泄。老年人的药动学参数略大于青年人，而肾清除率则较青年人稍低。肝功能不全者最大血药度（Cmax）降低约20％，t1／2为较正常人延长1.4倍，代谢率亦减少。
 
适 应 症

社区获得性肺炎（CAP）、慢性支气管炎急性发作（AECB）和急性鼻窦炎。
据已有的研究报道表明，泰利霉素是一抗菌谱广、抗菌效果好的新一类抗菌药。特别是对那些耐多种抗生素的致病菌具有很强的抗菌活性，这无疑为选择新的抗生素替代药物指明了方向。而且泰利霉素口服生物利用度高，不影响其他药物的吸收和利用，副作用少，服用方便，病人耐受性好，是一治疗多种感染性疾病的非常有前途的药物。
 
临床应用

临床应用泰利霉素主要用于治疗呼吸道感染，包括社区获得性肺炎（CAP）、慢性支气管炎急性加剧（AECB）、急性上颌窦炎（AMS）、咽炎和扁桃体炎。
CAP：曾有报告，Barman等对1373例患者经7～10天治疗，临床治愈率为93％～94病菌清除率金葡菌为95％，嗜血流感杆菌为94％～100％。对于对青霉素或红霉素耐药的肺炎链球菌具有较好的治疗效果，治愈率可达88％～92％。对老年人的CAP治愈率为90％，对非典型呼吸道致病菌的治愈率为93％～100％。
AECB：曾有报告，Baltch等用本品800毫克，每天1次，服用5天与头孢呋肟酯500毫克，每天两次，服用10天疗效相似，临床治愈率分别为86％和83％，细菌清除率分别为76％和79％。
AMS：曾有报告，Baltch等用本品800毫克，每天1次，服用5天与10天的疗效相似，临床治愈率为91％，细菌清除率分别为93％和90％。本品5天疗效与阿莫西林／克拉维酸每天3次，服用10天的疗效相似，临床治愈率分别为73％和75％。
咽炎和扁桃体炎：曾有报告，Baltch等用本品对甲组β溶血性链球菌5天的疗效与克拉霉素250毫克，每天两次，服用10天的疗效相似，临床治愈率分别为93％和91％，细菌清除率分别为91％和88％。
用法与不良反应泰利霉素的用法为，每次800毫克，每天1次，疗程5～10天。本品800毫克／天的不良反应少，且为轻中度，发生率约4％。据9个Ⅲ期临床试验（2045例）报道，最常见的不良反应是腹泻（11.3％）、恶心（8.1％）、头痛（3.6％）、呕吐（2.8％）。经双盲、安慰剂对照研究，本品单剂800毫克／天～2400毫克／天，对QT间期均无明显影响。
与其他药物的相互作用CYP3A4抑制剂：如酮康唑、伊曲康唑可分别增加本品血药浓度―时间曲线下面积2倍和1.5倍。其他大环内酯类抗生素、西沙必利、辛伐他汀、咪达唑仑等也有类似的作用。
 
用法用量

口服，每次800mg，每日1次，疗程5～10天。

任何疑问，请遵医嘱！

KETEK (telithromycin) tablet, film coated
[sanofi-aventis U.S. LLC]
To reduce the development of drug-resistant bacteria and maintain the effectiveness of KETEK and other antibacterial drugs, KETEK should be used only to treat infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION
KETEK® tablets contain telithromycin, a semisynthetic antibacterial in the ketolide class for oral administration. Chemically, telithromycin is designated as Erythromycin, 3-de[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranosyl)oxy]-11,12-dideoxy-6-O-methyl-3-oxo-12,11-[oxycarbonyl[[4-[4-(3-pyridinyl)-1H-imidazol-1-yl]butyl]imino]]-.

Telithromycin, a ketolide, differs chemically from the macrolide group of antibacterials by the lack of α-L-cladinose at position 3 of the erythronolide A ring, resulting in a 3-keto function. It is further characterized by a C11-12 carbamate substituted by an imidazolyl and pyridyl ring through a butyl chain. Its empirical formula is C43H65N5O10 and its molecular weight is 812.03. Telithromycin is a white to off-white crystalline powder. The following represents the chemical structure of telithromycin.

KETEK tablets are available as light-orange, oval, film-coated tablets, each containing 400 mg or 300 mg of telithromycin, and the following inactive ingredients:  croscarmellose sodium, hypromellose,  magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, red ferric oxide, talc, titanium dioxide, and yellow ferric oxide.

CLINICAL PHARMACOLOGY

Pharmacokinetics

Absorption

Following oral administration, telithromycin reached maximal concentration at about 1 hour (0.5 – 4 hours).

It has an absolute bioavailability of 57% in both young and elderly subjects.

The rate and extent of absorption are unaffected by food intake, thus KETEK tablets can be given without regard to food.

In healthy adult subjects, peak plasma telithromycin concentrations of approximately 2 µg/mL are attained at a median of 1 hour after an 800-mg oral dose.

Steady-state plasma concentrations are reached within 2 to 3 days of once daily dosing with telithromycin 800 mg.

Following oral dosing, the mean terminal elimination half-life of telithromycin is 10 hours.

The pharmacokinetics of telithromycin after administration of single and multiple (7 days) once daily 800-mg doses to healthy adult subjects are shown in Table 1.

Table 1

	Mean (SD)
Parameter	Single dose (n=18)	Multiple dose (n=18)
SD=Standard deviation
Cmax=Maximum plasma concentration
Tmax=Time to Cmax
AUC=Area under concentration vs. time curve
t1/2=Terminal plasma half-life
C24h=Plasma concentration at 24 hours post-dose
* Median (min–max) values
Cmax (µg/mL)	1.9 (0.80)	2.27 (0.71)
Tmax (h)*	1.0 (0.5–4.0)	1.0 (0.5–3.0)
AUC(0–24) (µg∙h/mL)	8.25 (2.6)	12.5 (5.4)
Terminal t1/2 (h)	7.16 (1.3)	9.81 (1.9)
C24h (µg/mL)	0.03 (0.013)	0.07 (0.051)

In a patient population, mean peak and trough plasma concentrations were 2.9 µg/mL (±1.55), (n=219) and 0.2 µg/mL (±0.22), (n=204), respectively, after 3 to 5 days of KETEK 800 mg once daily.

Distribution

Total in vitro protein binding is approximately 60% to 70% and is primarily due to human serum albumin.

Protein binding is not modified in elderly subjects and in patients with hepatic impairment.

The volume of distribution of telithromycin after intravenous infusion is 2.9 L/kg.

Telithromycin concentrations in bronchial mucosa, epithelial lining fluid, and alveolar macrophages after 800 mg once daily dosing for 5 days in patients are displayed in Table 2.

Table 2

	Hours post-dose	Mean concentration (µg/mL)		Tissue/Plasma Ratio
		Tissue or fluid	Plasma
Units in mg/kg
Bronchial mucosa	2	3.88*	1.86	2.11
	12	1.41*	0.23	6.33
	24	0.78*	0.08	12.11
Epithelial lining fluid	2	14.89	1.86	8.57
	12	3.27	0.23	13.8
	24	0.84	0.08	14.41
Alveolar macrophages	2	65	1.07	55
	8	100	0.605	180
	24	41	0.073	540

Telithromycin concentration in white blood cells exceeds the concentration in plasma and is eliminated more slowly from white blood cells than from plasma. Mean white blood cell concentrations of telithromycin peaked at 72.1 µg/mL at 6 hours, and remained at 14.1 µg/mL 24 hours after 5 days of repeated dosing of 600 mg once daily. After 10 days, repeated dosing of 600 mg once daily, white blood cell concentrations remained at 8.9 µg/mL 48 hours after the last dose.

Metabolism

In total, metabolism accounts for approximately 70% of the dose. In plasma, the main circulating compound after administration of an 800-mg radio-labeled dose was parent compound, representing 56.7% of the total radioactivity. The main metabolite represented 12.6% of the AUC of telithromycin. Three other plasma metabolites were quantified, each representing 3% or less of the AUC of telithromycin.

It is estimated that approximately 50% of its metabolism is mediated by CYP 450 3A4 and the remaining 50% is CYP 450-independent.

Elimination

The systemically available telithromycin is eliminated by multiple pathways as follows: 7% of the dose is excreted unchanged in feces by biliary and/or intestinal secretion; 13% of the dose is excreted unchanged in urine by renal excretion; and 37% of the dose is metabolized by the liver.

Special populations

Gender

There was no significant difference between males and females in mean AUC, Cmax, and elimination half-life in two studies; one in 18 healthy young volunteers (18 to 40 years of age) and the other in 14 healthy elderly volunteers (65 to 92 years of age), given single and multiple once daily doses of 800 mg of KETEK.

Hepatic insufficiency

In a single-dose study (800 mg) in 12 patients and a multiple-dose study (800 mg) in 13 patients with mild to severe hepatic insufficiency (Child Pugh Class A, B and C), the Cmax, AUC and t1/2 of telithromycin were similar to those obtained in age- and sex-matched healthy subjects. In both studies, an increase in renal elimination was observed in hepatically impaired patients indicating that this pathway may compensate for some of the decrease in metabolic clearance. No dosage adjustment is recommended due to hepatic impairment.

(See PRECAUTIONS, General and DOSAGE AND ADMINISTRATION)

Renal insufficiency

In a multiple-dose study, 36 subjects with varying degrees of renal impairment received 400 mg, 600 mg, or 800 mg KETEK once daily for 5 days. There was a 1.4-fold increase in Cmax,ss, and a 1.9-fold increase in AUC (0–24)ss at 800 mg multiple doses in the severely renally impaired group (CLCR < 30 mL/min) compared to healthy volunteers. Renal excretion may serve as a compensatory elimination pathway for telithromycin in situations where metabolic clearance is impaired. Patients with severe renal impairment are prone to conditions that may impair their metabolic clearance. Therefore, in the presence of severe renal impairment (CLCR < 30 mL/min), a reduced dosage of KETEK is recommended. (See DOSAGE AND ADMINISTRATION)

In a single-dose study in patients with end-stage renal failure on hemodialysis (n=10), the mean Cmax and AUC values were similar to normal healthy subjects when KETEK was administered 2 hours post-dialysis. However, the effect of dialysis on removing telithromycin from the body has not been studied.

Multiple insufficiency

The effects of co-administration of ketoconazole in 12 subjects (age ≥ 60 years), with impaired renal function were studied (CLCR= 24 to 80 mL/min). In this study, when severe renal insufficiency (CLCR < 30 mL/min, n=2) and concomitant impairment of CYP 3A4 metabolism pathway were present, telithromycin exposure (AUC (0–24)) was increased by approximately 4- to 5-fold compared with the exposure in healthy subjects with normal renal function receiving telithromycin alone. In the presence of severe renal impairment (CLCR < 30 mL/min), with coexisting hepatic impairment, a reduced dosage of KETEK is recommended.  (See PRECAUTIONS, General and DOSAGE AND ADMINISTRATION)

Geriatric

Pharmacokinetic data show that there is an increase of 1.4-fold in exposure (AUC) in 20 patients ≥ 65 years of age with community acquired pneumonia in a Phase III study, and a 2.0-fold increase in exposure (AUC) in 14 subjects ≥ 65 years of age as compared with subjects less than 65 years of age in a Phase I study.  No dosage adjustment is required based on age alone.

Drug-drug interactions

In vitro interactions

In vitro studies using a model compound have shown that telithromycin may act as an inhibitor for the hepatic uptake transporters OATP1B1 and OATP1B3. Although the clinical relevance of this finding is unknown, it is possible that concomitant administration of telithromycin with drugs that are substrates of OATP family members could result in increased plasma concentrations of the co-administered drug.

In vivo interactions

Studies were performed to evaluate the effect of CYP 3A4 inhibitors on telithromycin and the effect of telithromycin on drugs that are substrates of CYP 3A4 and CYP 2D6. In addition, drug interaction studies were conducted with several other concomitantly prescribed drugs.

CYP 3A4 inhibitors

Itraconazole

A multiple-dose interaction study with itraconazole showed that Cmax of telithromycin was increased by 22% and AUC by 54%.

Ketoconazole

A multiple-dose interaction study with ketoconazole showed that Cmax of telithromycin was increased by 51% and AUC by 95%.

Grapefruit juice

When telithromycin was given with 240 mL of grapefruit juice after an overnight fast to healthy subjects, the pharmacokinetics of telithromycin were not affected.

CYP 3A4 substrates

Cisapride

Steady-state peak plasma concentrations of cisapride (an agent with the potential to increase QT interval) were increased by 95% when co-administered with repeated doses of telithromycin, resulting in significant increases in QTc. (See CONTRAINDICATIONS)

Simvastatin

When simvastatin was co-administered with telithromycin, there was a 5.3-fold increase in simvastatin Cmax, an 8.9-fold increase in simvastatin AUC, a 15-fold increase in the simvastatin active metabolite Cmax, and a 12-fold increase in the simvastatin active metabolite AUC. (See PRECAUTIONS)

In another study, when simvastatin and telithromycin were administered 12 hours apart, there was a 3.4-fold increase in simvastatin Cmax, a 4.0-fold increase in simvastatin AUC, a 3.2-fold increase in the active metabolite Cmax, and a 4.3-fold increase in the active metabolite AUC. (See PRECAUTIONS)

Midazolam

Concomitant administration of telithromycin with intravenous or oral midazolam resulted in 2- and 6-fold increases, respectively, in the AUC of midazolam due to inhibition of CYP 3A4-dependent metabolism of midazolam. (See PRECAUTIONS)

CYP 2D6 substrates

Paroxetine

There was no pharmacokinetic effect on paroxetine when telithromycin was co-administered.

Metoprolol

When metoprolol was co-administered with telithromycin, there was an increase of approximately 38% on the Cmax and AUC of metoprolol, however, there was no effect on the elimination half-life of metoprolol. Telithromycin exposure is not modified with concomitant single-dose administration of metoprolol. (See PRECAUTIONS, Drug interactions)

Other drug interactions

Digoxin

The plasma peak and trough levels of digoxin were increased by 73% and 21%, respectively, in healthy volunteers when co-administered with telithromycin. However, trough plasma concentrations of digoxin (when equilibrium between plasma and tissue concentrations has been achieved) ranged from 0.74 to 2.17 ng/mL. There were no significant changes in ECG parameters and no signs of digoxin toxicity. (See PRECAUTIONS)

Theophylline

When theophylline was co-administered with repeated doses of telithromycin, there was an increase of approximately 16% and 17% on the steady-state Cmax and AUC of theophylline. Co-administration of theophylline may worsen gastrointestinal side effects such as nausea and vomiting, especially in female patients. It is recommended that telithromycin should be taken with theophylline 1 hour apart to decrease the likelihood of gastrointestinal side effects.

Sotalol

Telithromycin has been shown to decrease the Cmax and AUC of sotalol by 34% and 20%, respectively, due to decreased absorption.

Warfarin

When co-administered with telithromycin in healthy subjects, there were no pharmacodynamic or pharmacokinetic effects on racemic warfarin.

Oral contraceptives

When oral contraceptives containing ethinyl estradiol and levonorgestrel were co-administered with telithromycin, the steady-state AUC of ethinyl estradiol did not change and the steady-state AUC of levonorgestrel was increased by 50%. The pharmacokinetic/pharmacodynamic study showed that telithromycin did not interfere with the antiovulatory effect of oral contraceptives containing ethinyl estradiol and levonorgestrel.

Ranitidine, antacid

There was no clinically relevant pharmacokinetic interaction of ranitidine or antacids containing aluminum and magnesium hydroxide on telithromycin.

Rifampin

During concomitant administration of rifampin and KETEK in repeated doses, Cmax and AUC of telithromycin were decreased by 79%, and 86%, respectively. (See PRECAUTIONS, Drug Interactions)

Microbiology

Telithromycin belongs to the ketolide class of antibacterials and is structurally related to the macrolide family of antibiotics. Telithromycin concentrates in phagocytes where it exhibits activity against intracellular respiratory pathogens. In vitro, telithromycin has been shown to demonstrate concentration-dependent bactericidal activity against isolates of Streptococcus pneumoniae (including multi-drug resistant isolates [MDRSP1]).

MDRSP=Multi-drug resistant Streptococcus pneumoniae includes isolates known as PRSP (penicillin-resistant Streptococcus pneumoniae), and are isolates resistant to two or more of the following antimicrobials: penicillin, 2nd generation cephalosporins (e.g., cefuroxime), macrolides, tetracyclines, and trimethoprim/sulfamethoxazole.

Mechanism of action

Telithromycin blocks protein synthesis by binding to domains II and V of 23S rRNA of the 50S ribosomal subunit. By binding at domain II, telithromycin retains activity against gram-positive cocci (e.g., Streptococcus pneumoniae) in the presence of resistance mediated by methylases (erm genes) that alter the domain V binding site of telithromycin. Telithromycin may also inhibit the assembly of nascent ribosomal units.

Mechanism of resistance

Staphylococcus aureus and Streptococcus pyogenes with the constitutive macrolide-lincosamide-streptogramin B (cMLSB) phenotype are resistant to telithromycin.

Mutants of Streptococcus pneumoniae derived in the laboratory by serial passage in subinhibitory concentrations of telithromycin have demonstrated resistance based on L22 riboprotein mutations (telithromycin MICs are elevated but still within the susceptible range), one of two reported mutations affecting the L4 riboprotein, and production of K-peptide. The clinical significance of these laboratory mutants is not known.

Cross resistance

Telithromycin does not induce resistance through methylase gene expression in erythromycin-inducibly resistant bacteria, a function of its 3-keto moiety. Telithromycin has not been shown to induce resistance to itself.

List of Microorganisms

Telithromycin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical settings as described in the INDICATIONS AND USAGE section.

Aerobic gram-positive microorganisms

Streptococcus pneumoniae (including multi-drug resistant isolates [MDRSP2])

Aerobic gram-negative microorganisms

Haemophilus influenzae

Moraxella catarrhalis

Other microorganisms

Chlamydophila (Chlamydia) pneumoniae

Mycoplasma pneumoniae

The following in vitro data are available, but their clinical significance is unknown.

At least 90% of the following microorganisms exhibit in vitro minimum inhibitory concentrations (MICs) less than or equal to the susceptible breakpoint for telithromycin. However, the safety and efficacy of telithromycin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic gram-positive microorganisms

Staphylococcus aureus (methicillin and erythromycin susceptible isolates only)

Streptococcus pyogenes (erythromycin susceptible isolates only)

Streptococci (Lancefield groups C and G)

Other microorganisms

Legionella pneumophila

MDRSP=Multi-drug resistant Streptococcus pneumoniae includes isolates known as PRSP (penicillin-resistant S. pneumoniae), and are isolates resistant to two or more of the following antimicrobials: penicillin, 2nd generation cephalosporins (e.g., cefuroxime), macrolides, tetracyclines, and trimethoprim/sulfamethoxazole.

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide cumulative results of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens.  These reports should aid the physician in selecting the most effective antimicrobial.

Dilution techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antibacterial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on dilution methods (broth or agar dilution)1,3 or equivalent with standardized inoculum and  concentrations of telithromycin powder. The MIC values should be interpreted according to criteria provided in Table 3.

Diffusion techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antibiotics. One such standardized procedure2,3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 15 µg telithromycin to test the susceptibility of microorganisms to telithromycin. Disc diffusion zone sizes should be interpreted according to criteria in Table 3.

Table 3. Susceptibility Test Result Interpretive Criteria for Telithromycin

	Minimal Inhibitory Concentrations (µg/mL)			Disk Diffusion (zone diameters in mm)
Pathogen	S	I	R	S	I	R
Streptococcus pneumoniae	≤ 1	2	≥ 4	≥ 19	16–18	≤ 15
Haemophilus influenzae	≤ 4	8	≥ 16	≥ 15	12–14	≤ 11

A report of "Susceptible" indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antibacterial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Quality control

Standardized susceptibility test procedures require the use of quality control microorganisms to determine the performance of the test procedures1,2,3. Standard telithromycin powder should provide the MIC ranges for the quality control organisms in Table 4. For the disk diffusion technique, the 15-µg telithromycin disk should provide the zone diameter ranges for the quality control organisms in Table 4.

Table 4. Acceptable Quality Control Ranges for Telithromycin

QC Strain	Minimum Inhibitory Concentrations (µg/mL)	Disk Diffusion (Zone diameter in mm)
ATCC = American Type Culture Collection
Streptococcus pneumoniae ATCC 49619	0.004–0.03	27–33
Haemophilus influenzae ATCC 49247	1.0–4.0	17–23

INDICATIONS AND USAGE

KETEK tablets are indicated for the treatment of community-acquired pneumonia (of mild to moderate severity) due to Streptococcus pneumoniae, (including multi-drug resistant isolates [MDRSP3]), Haemophilus influenzae, Moraxella catarrhalis, Chlamydophila pneumoniae, or Mycoplasma pneumoniae, for patients 18 years old and above.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of KETEK and other antibacterial drugs, KETEK should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria.  When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy.  In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

MDRSP, Multi-drug resistant Streptococcus pneumoniae includes isolates known as PRSP (penicillin-resistant Streptococcus pneumoniae), and are isolates resistant to two or more of the following antibiotics: penicillin, 2nd generation cephalosporins, e.g., cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole.

CONTRAINDICATIONS

KETEK is contraindicated in patients with myasthenia gravis. Exacerbations of myasthenia gravis have been reported in patients and sometimes occurred within a few hours of the first dose of telithromycin. Reports have included fatal and life-threatening acute respiratory failure with a rapid onset and progression.

KETEK is contraindicated in patients with previous history of hepatitis and/or jaundice associated with the use of KETEK tablets, or any macrolide antibiotic.

KETEK is contraindicated in patients with a history of hypersensitivity to telithromycin and/or any components of KETEK tablets, or any macrolide antibiotic.

Concomitant administration of KETEK with cisapride or pimozide is contraindicated. (See CLINICAL PHARMACOLOGY, Drug-drug Interactions and PRECAUTIONS.)

Concomitant administration of KETEK and colchicine is contraindicated in patients with renal or hepatic impairment. (See WARNINGS, Drug Interactions and PRECAUTIONS, Drug interactions.)

WARNINGS

Hepatotoxicity

Acute hepatic failure and severe liver injury, in some cases fatal, have been reported in patients treated with KETEK. These hepatic reactions included fulminant hepatitis and hepatic necrosis leading to liver transplant, and were observed during or immediately after treatment. In some of these cases, liver injury progressed rapidly and occurred after administration of a few doses of KETEK. (See ADVERSE REACTIONS)

Physicians and patients should monitor for the appearance of signs or symptoms of hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness or hepatomegaly. Patients with signs or symptoms of hepatitis must be advised to discontinue KETEK and immediately seek medical evaluation, which should include liver function tests. (See ADVERSE REACTIONS, PRECAUTIONS, Information to Patients.) If clinical hepatitis or transaminase elevations combined with other systemic symptoms occur, KETEK should be permanently discontinued.

Ketek must not be re-administered to patients with a previous history of hepatitis and/or jaundice associated with the use of KETEK tablets, or any macrolide antibiotic. (See CONTRAINDICATIONS)

In addition, less severe hepatic dysfunction associated with increased liver enzymes, hepatitis and in some cases jaundice was reported with the use of KETEK. These events associated with less severe forms of liver toxicity were reversible.

QTc prolongation

Telithromycin has the potential to prolong the QTc interval of the electrocardiogram in some patients. QTc prolongation may lead to an increased risk for ventricular arrhythmias, including torsades de pointes. Thus, telithromycin should be avoided in patients with congenital prolongation of the QTc interval, and in patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia, and in patients receiving Class IA (e.g., quinidine and procainamide) or Class III (e.g., dofetilide) antiarrhythmic agents.

Cases of torsades de pointes have been reported post-marketing with KETEK. In clinical trials, no cardiovascular morbidity or mortality attributable to QTc prolongation occurred with telithromycin treatment in 4780 patients in clinical trials, including 204 patients having a prolonged QTc at baseline.

Visual disturbances*

KETEK may cause visual disturbances particularly in slowing the ability to accommodate and the ability to release accommodation. Visual disturbances included blurred vision, difficulty focusing, and diplopia. Most events were mild to moderate; however, severe cases have been reported.

Loss of Consciousness*

There have been post-marketing adverse event reports of transient loss of consciousness including some cases associated with vagal syndrome.

*Because of potential visual difficulties or loss of consciousness, patients should attempt to minimize activities such as driving a motor vehicle, operating heavy machinery or engaging in other hazardous activities during treatment with KETEK. If patients experience visual disorders or loss of consciousness while taking KETEK, patients should not drive a motor vehicle, operate heavy machinery or engage in other hazardous activities.
(See PRECAUTIONS, Information for Patients)

Drug Interactions

Serious adverse reactions have been reported in patients taking KETEK concomitantly with CYP 3A4 substrates. These include colchicine toxicity with colchicine; rhabdomyolysis with simvastatin, lovastatin, and atorvastatin; and hypotension with calcium channel blockers metabolized by CYP 3A4 (e.g., verapamil, amlodipine, diltiazem). (See PRECAUTIONS, Drug interactions.)

Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and strong CYP 3A4 inhibitors. Telithromycin is a strong CYP 3A4 inhibitor and this interaction may occur while using both drugs at their recommended doses. If co-administration of telithromycin and colchicine is necessary in patients with normal renal and hepatic function, the dose of colchicine should be reduced. Patients should be monitored for clinical symptoms of colchicine toxicity. Concomitant administration of KETEK and colchicine is contraindicated in patients with renal or hepatic impairment. (See CONTRAINDICATIONS and PRECAUTIONS, Drug interactions.)

Pseudomembranous colitis

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including KETEK, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C difficile, and surgical evaluation should be instituted as clinically indicated.

PRECAUTIONS

General

Prescribing KETEK in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Telithromycin is principally excreted via the liver and kidney. Telithromycin may be administered without dosage adjustment in the presence of hepatic impairment. In the presence of severe renal impairment (CLCR < 30 mL/min), a reduced dosage of KETEK is recommended. (See DOSAGE AND ADMINISTRATION)

Information for patients

A Medication Guide is provided to patients when Ketek is dispensed. Patients should be instructed to read the MedGuide when Ketek is received. In addition, the complete text of the MedGuide is reprinted at the end of this document.

The following information and instructions should be communicated to the patient.

• KETEK may cause problems with vision particularly when looking quickly between objects close by and objects far away.  These events include blurred vision, difficulty focusing, and objects looking doubled. Most events were mild to moderate; however, severe cases have been reported. Problems with vision were reported as having occurred after any dose during treatment, but most occurred following the first or second dose. These problems lasted several hours and in some patients came back with the next dose. (See WARNINGS and ADVERSE REACTIONS.)

Patients should be advised that avoiding quick changes in viewing between objects in the distance and objects nearby may help to decrease the effects of these visual difficulties.

• Because of potential visual difficulties, loss of consciousness, confusion or hallucinations, patients should attempt to minimize activities such as driving a motor vehicle, operating heavy machinery or engaging in other hazardous activities during treatment with KETEK.

If patients experience visual difficulties, loss of consciousness / fainting, confusion or hallucination

• patients should seek advice from their physician before taking another dose
• patients should not drive a motor vehicle, operate heavy machinery, or engage in otherwise hazardous activities.

Patients should also be advised:

• Ketek is contraindicated in patients with myasthenia gravis.
  (See CONTRAINDICATIONS)
• of the possibility of liver injury, associated with KETEK, which in rare cases may be severe. Patients developing signs or symptoms of liver injury should be instructed to discontinue KETEK and seek medical attention immediately. Symptoms of liver injury may include nausea, fatigue, anorexia, jaundice, dark urine, light-colored stools, pruritus, or tender abdomen. Ketek must not be taken by patients with a previous history of hepatitis/jaundice associated with the use of KETEK or macrolide antibiotics.
  (See CONTRAINDICATIONS and WARNINGS)
• antibacterial drugs including KETEK should only be used to treat bacterial infections.  They do not treat viral infections (e.g., the common cold).  When KETEK is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed.  Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by KETEK or other antibacterial drugs in the future.
• KETEK has the potential to produce changes in the electrocardiogram (QTc interval prolongation) and that they should report any fainting occurring during drug treatment.
• KETEK should be avoided in patients receiving Class 1A (e.g., quinidine, procainamide) or Class III (e.g., dofetilide) antiarrhythmic agents.
• to inform their physician of any personal or family history of QTc prolongation or proarrhythmic conditions such as uncorrected hypokalemia, or clinically significant bradycardia.
• diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
• simvastatin, lovastatin, or atorvastatin should be avoided in patients receiving KETEK.  If KETEK is prescribed, therapy with simvastatin, lovastatin, or atorvastatin should be stopped during the course of treatment. (See CLINICAL PHARMACOLOGY, Drug-drug interactions)
• colchicine should be avoided in patients receiving KETEK. If KETEK is prescribed in patients with normal kidney and liver function, the dose is colchicine should be reduced. Concomitant treatment with KETEK and colchicine is contraindicated in patients with kidney or liver impairment. (See CONTRAINDICATIONS and WARNINGS, Drug interactions.)
• KETEK tablets can be taken with or without food.
• to inform their physician of any other medications taken concurrently with KETEK, including over-the-counter medications and dietary supplements.

Drug interactions

Telithromycin is a strong inhibitor of the cytochrome P450 3A4 system. Co-administration of KETEK tablets and a drug primarily metabolized by the cytochrome P450 3A4 enzyme system may result in increased plasma concentration of the drug co-administered with telithromycin that could increase or prolong both the therapeutic and adverse effects. Therefore, appropriate dosage adjustments may be necessary for the drug co-administered with telithromycin.

The use of KETEK is contraindicated with cisapride. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY, Drug-drug interactions)

The use of KETEK is contraindicated with pimozide. Although there are no studies looking at the interaction between KETEK and pimozide, there is a potential risk of increased pimozide plasma levels by inhibition of CYP 3A4 pathways by KETEK as with macrolides. (See CONTRAINDICATIONS)

In a pharmacokinetic study, simvastatin levels were increased due to CYP 3A4 inhibition by telithromycin. (See CLINICAL PHARMACOLOGY, Drug-drug interactions) Similarly, an interaction may occur with lovastatin or atorvastatin but not with statins which are not metabolized by CYP3A4.

High levels of HMG-CoA reductase inhibitors increase the risk of myopathy and rhabdomyolysis. Use of simvastatin, lovastatin, or atorvastatin concomitantly with KETEK should be avoided. If KETEK is prescribed, therapy with simvastatin, lovastatin, or atorvastatin should be suspended during the course of treatment. Patients concomitantly treated with statins should be carefully monitored for signs and symptoms of myopathy and rhabdomyolysis.

Colchicine is a substrate for both CYP 3A4 and the efflux transporter, P-glycoprotein (P-gp), and a significant increase in colchicine plasma concentration is anticipated when co-administered with strong CYP 3A4 inhibitors such as telithromycin. (See CONTRAINDICATIONS and WARNINGS, Drug interactions).

Monitoring of digoxin side effects or serum levels should be considered during concomitant administration of digoxin and KETEK. (See CLINICAL PHARMACOLOGY, Drug-drug interactions.)

Hypotension, bradyarrhythmia and loss of consciousness have been observed in patients receiving concomitant treatment with calcium channel blockers that are substrates of CYP 3A4 (e.g., verapamil, amlodipine, diltiazem).

Patients should be monitored with concomitant administration of midazolam and dosage adjustment of midazolam should be considered if necessary. Precaution should be used with other benzodiazepines, which are metabolized by CYP 3A4 and undergo a high first-pass effect (e.g., triazolam). (See CLINICAL PHARMACOLOGY, Drug-drug interactions.)

Concomitant treatment of KETEK with rifampin, a CYP 3A4 inducer, should be avoided. Concomitant administration of other CYP 3A4 inducers such as phenytoin, carbamazepine, or phenobarbital is likely to result in subtherapeutic levels of telithromycin and loss of effect. (See CLINICAL PHARMACOLOGY, Other drug interactions.)

In patients treated with metoprolol for heart failure, the increased exposure to metoprolol, a CYP 2D6 substrate, may be of clinical importance. Therefore, co-administration of KETEK and metoprolol in patients with heart failure should be considered with caution. (See CLINICAL PHARMACOLOGY, Drug-drug interactions.)

Spontaneous post-marketing reports suggest that administration of KETEK and oral anticoagulants concomitantly may potentiate the effects of the oral anticoagulants.  Consideration should be given to monitoring prothrombin times/INR while patients are receiving KETEK and oral anticoagulants simultaneously.

No specific drug interaction studies have been performed to evaluate the following potential drug-drug interactions with KETEK. However, these drug interactions have been observed with macrolide products.

Drugs metabolized by the cytochrome P450 system such as carbamazepine, cyclosporine, tacrolimus, sirolimus, hexobarbital, and phenytoin: elevation of serum levels of these drugs may be observed when co-administered with telithromycin.  As a result, increases or prolongation of the therapeutic and/or adverse effects of the concomitant drug may be observed.

Ergot alkaloid derivatives (such as ergotamine or dihydroergotamine): acute ergot toxicity characterized by severe peripheral vasospasm and dysesthesia has been reported when macrolide antibiotics were co-administered. Without further data, the co-administration of KETEK and these drugs is not recommended.

Laboratory test interactions

There are no reported laboratory test interactions.

Carcinogenesis, mutagenesis, impairment of fertility

Long-term studies in animals to determine the carcinogenic potential of KETEK have not been conducted.

Telithromycin showed no evidence of genotoxicity in four tests: gene mutation in bacterial cells, gene mutation in mammalian cells, chromosome aberration in human lymphocytes, and the micronucleus test in the mouse.

No evidence of impaired fertility in the rat was observed at doses estimated to be 0.61 times the human daily dose on a mg/m2 basis. At doses of 1.8–3.6 times the human daily dose, at which signs of parental toxicity were observed, moderate reductions in fertility indices were noted in male and female animals treated with telithromycin.

Pregnancy

Teratogenic effects

Pregnancy Category C

Telithromycin was not teratogenic in the rat or rabbit. Reproduction studies have been performed in rats and rabbits, with effect on pre-post natal development studied in the rat.  At doses estimated to be 1.8 times (900 mg/m2) and 0.49 times (240 mg/m2) the daily human dose of 800 mg (492 mg/m2) in the rat and rabbit, respectively, no evidence of fetal terata was found. At doses higher than the 900 mg/m2 and 240 mg/m2 in rats and rabbits, respectively, maternal toxicity may have resulted in delayed fetal maturation. No adverse effects on prenatal and postnatal development of rat pups were observed at 1.5 times (750 mg/m2/d) the daily human dose.

There are no adequate and well-controlled studies in pregnant women. Telithromycin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing mothers

Telithromycin is excreted in breast milk of rats. Telithromycin may also be excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when KETEK is administered to a nursing mother.

Pediatric use

The safety and effectiveness of KETEK in pediatric patients has not been established.

Geriatric use

In all Phase III clinical trials (n=4,780), KETEK was administered to 694 patients who were 65 years and older, including 231 patients who were 75 years and older. Efficacy and safety in elderly patients ≥ 65 years were generally similar to that observed in younger patients; however, greater sensitivity of some older individuals cannot be ruled out. No dosage adjustment is required based on age alone. (See CLINICAL PHARMACOLOGY, Special populations, Geriatric and DOSAGE AND ADMINISTRATION.)

ADVERSE REACTIONS

In Phase III clinical trials, 4,780 patients (n=2702 in controlled trials) received daily oral doses of KETEK 800 mg once daily for 5 days or 7 to 10 days. Most adverse events were mild to moderate in severity. In the combined Phase III studies, discontinuation due to treatment-emergent adverse events occurred in 4.4% of KETEK-treated patients and 4.3% of combined comparator-treated patients. Most discontinuations in the KETEK group were due to treatment-emergent adverse events in the gastrointestinal body system, primarily diarrhea (0.9% for KETEK vs. 0.7% for comparators), nausea (0.7% for KETEK vs. 0.5% for comparators).

All and possibly related treatment-emergent adverse events (TEAEs) occurring in controlled clinical studies in ≥ 2.0% of all patients are included below:

Table 5

All and Possibly Related Treatment-Emergent Adverse Events Reported in Controlled Phase III Clinical Studies (Percent Incidence)
Adverse Event*	All TEAEs		Possibly-Related TEAEs
	KETEK n= 2702	Comparator† n= 2139	KETEK n= 2702	Comparator† n= 2139
Based on a frequency of all and possibly related treatment-emergent adverse events of ≥ 2% in KETEK or comparator groups. Includes comparators from all controlled Phase III studies.
Diarrhea	10.8%	8.6%	10.0%	8.0%
Nausea	7.9%	4.6%	7.0%	4.1%
Headache	5.5%	5.8%	2.0%	2.5%
Dizziness (excl. vertigo)	3.7%	2.7%	2.8%	1.5%
Vomiting	2.9%	2.2%	2.4%	1.4%
Loose Stools	2.3%	1.5%	2.1%	1.4%
Dysgeusia	1.6%	3.6%	1.5%	3.6%

The following events judged by investigators to be at least possibly drug related were observed infrequently (≥ 0.2% and < 2%), in KETEK-treated patients in the controlled Phase III studies.

Gastrointestinal system: abdominal distension, dyspepsia, gastrointestinal upset, flatulence, constipation, gastroenteritis, gastritis, anorexia, oral candidiasis, glossitis, stomatitis, watery stools.

Liver and biliary system: abnormal liver function tests: increased transaminases, increased liver enzymes (e.g., ALT, AST) were usually asymptomatic and reversible. ALT elevations above 3 times the upper limit of normal were observed in 1.6%, and 1.7% of patients treated with KETEK and comparators, respectively. Hepatitis, with or without jaundice, occurred in 0.07% of patients treated with KETEK, and was reversible. (See PRECAUTIONS, General.)

Nervous system: dry mouth, somnolence, insomnia, vertigo, increased sweating

Body as a whole: abdominal pain, upper abdominal pain, fatigue

Special senses: Visual adverse events most often included blurred vision, diplopia, or difficulty focusing. Most events were mild to moderate; however, severe cases have been reported. Some patients discontinued therapy due to these adverse events.  Visual adverse events were reported as having occurred after any dose during treatment, but most visual adverse events (65%) occurred following the first or second dose. Visual events lasted several hours and recurred upon subsequent dosing in some patients. For patients who continued treatment, some resolved on therapy while others continued to have symptoms until they completed the full course of treatment. (See WARNINGS and PRECAUTIONS, Information for patients.)

Females and patients under 40 years old experienced a higher incidence of telithromycin-associated visual adverse events. (See CLINICAL STUDIES.)

Urogenital system: vaginal candidiasis, vaginitis, vaginosis fungal

Skin: rash

Hematologic: increased platelet count

Other possibly related clinically-relevant events occurring in <0.2% of patients treated with KETEK from the controlled Phase III studies included: anxiety, bradycardia, eczema, elevated blood bilirubin, erythema multiforme, flushing, hypotension, increased blood alkaline phosphatase, increased eosinophil count, paresthesia, pruritus, urticaria.

Post-Marketing Adverse Event Reports

In addition to adverse events reported from clinical trials, the following events have been reported from worldwide post-marketing experience with KETEK. 

Allergic: face edema, rare reports of severe allergic (hypersensitivity) reactions, including angioedema and anaphylaxis

Cardiovascular: atrial arrhythmias, palpitations

Gastrointestinal system: pancreatitis

Liver and biliary system: Hepatic dysfunction has been reported.

Severe and in some cases fatal hepatotoxicity, including fulminant hepatitis, hepatic necrosis and hepatic failure have been reported in patients treated with KETEK. These hepatic reactions were observed during or immediately after treatment. In some of these cases, liver injury progressed rapidly and occurred after administration of only a few doses of KETEK. (See CONTRAINDICATIONS and WARNINGS.) Severe reactions, in some but not all cases, have been associated with serious underlying diseases or concomitant medications.

Data from post-marketing reports and clinical trials show that most cases of hepatic dysfunction were mild to moderate. (See PRECAUTIONS, General.)

Musculoskeletal: muscle cramps, rare reports of exacerbation of myasthenia gravis. (See CONTRAINDICATIONS.) arthralgia, myalgia

Nervous system: loss of consciousness, in some cases associated with vagal syndrome.

Psychiatric disorders: confusion, hallucinations (mostly visual)

Special senses: taste/smell perversion and/or loss

OVERDOSAGE

In the event of acute overdosage, the stomach should be emptied by gastric lavage. The patient should be carefully monitored (e.g., ECG, electrolytes) and given symptomatic and supportive treatment. Adequate hydration should be maintained. The effectiveness of hemodialysis in an overdose situation with KETEK is unknown.

DOSAGE AND ADMINISTRATION

The dose of KETEK tablets is 800 mg (2 tablets of 400 mg) taken orally once every 24 hours, for 7–10 days. KETEK tablets can be administered with or without food.

KETEK may be administered without dosage adjustment in the presence of hepatic impairment.

In the presence of severe renal impairment (CLCR < 30 mL/min), including patients who need dialysis, the dose should be reduced to KETEK 600 mg once daily. In patients undergoing hemodialysis, KETEK should be given after the dialysis session on dialysis days. (See CLINICAL PHARMACOLOGY, Renal insufficiency.)

In the presence of severe renal impairment (CLCR < 30 mL/min), with coexisting hepatic impairment, the dose should be reduced to KETEK 400 mg once daily. (See CLINICAL PHARMACOLOGY, Multiple insufficiency.)

HOW SUPPLIED

KETEK® 400 mg tablets are supplied as light-orange, oval, film-coated tablets, imprinted "H3647" on one side and "400" on the other side. These are packaged in bottles and blister cards (Ketek Pak™ and unit dose) as follows:

Bottles of 60                                                                         (NDC 0088-2225-41)
Ketek Pak™, 10-tablet cards (2 tablets per blister cavity)     (NDC 0088-2225-07)
Unit dose package of 100 (blister pack)                                (NDC 0088-2225-49)

KETEK® 300 mg tablets are supplied as light-orange, oval, film-coated tablets, imprinted "38AV" on one side and blank on the other side. These are packaged in bottles as follows:

Bottles of 20                                                                         (NDC 0088-2223-20)

Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature].

CLINICAL STUDIES

Community-acquired pneumonia (CAP)

KETEK was studied in four randomized, double-blind, controlled studies and four open-label studies for the treatment of community-acquired pneumonia. Patients with mild to moderate CAP who were considered appropriate for oral outpatient treatment were enrolled in these trials.  Patients with severe pneumonia were excluded based on any one of the following: ICU admission, need for parenteral antibiotics, respiratory rate > 30/minute, hypotension, altered mental status, < 90% oxygen saturation by pulse oximetry, or white blood cell count < 4000/mm3. Total number of clinically evaluable patients in the telithromycin group included 2016 patients.

Table 6. CAP: Clinical cure rate at post-therapy follow-up (17–24 days)

	Patients (n)		Clinical cure rate
Controlled Studies	KETEK	Comparator	KETEK	Comparator
This study was stopped prematurely after trovafloxacin was restricted for use in hospitalized patients with severe infection.
KETEK vs. clarithromycin 500 mg BID for 10 days	162	156	88.3%	88.5%
KETEK vs. trovafloxacin* 200 mg QD for 7 to 10 days	80	86	90.0%	94.2%
KETEK vs. amoxicillin 1000 mg TID for 10 days	149	152	94.6%	90.1%
KETEK for 7 days vs. clarithromycin 500 mg BID for 10 days	161	146	88.8%	91.8%

Clinical cure rates by pathogen from the four CAP controlled clinical trials in microbiologically evaluable patients given KETEK for 7–10 days or a comparator are displayed in Table 7.

Table 7. CAP: Clinical cure rate by pathogen at post-therapy follow-up (17–24 days)

Pathogen	KETEK	Comparator
Streptococcus pneumoniae	73/78 (93.6%)	63/70 (90.0%)
Haemophilus influenzae	39/47 (83.0%)	42/44 (95.5%)
Moraxella catarrhalis	12/14 (85.7%)	7/9 (77.8%)
Chlamydophila (Chlamydia) pneumoniae	23/25 (92.0%)	18/19 (94.7%)
Mycoplasma pneumoniae	22/23 (95.7%)	20/22 (90.9%)

Clinical cure rates for patients with CAP due to Streptococcus pneumoniae were determined from patients in controlled and uncontrolled trials.  Of 333 evaluable patients with CAP due to Streptococcus pneumoniae, 312 (93.7%) achieved clinical success.  Only patients considered appropriate for oral outpatient therapy were included in these trials.  More severely ill patients were not enrolled.  Blood cultures were obtained in all patients participating in the clinical trials of mild to moderate community-acquired pneumonia. In a limited number of outpatients with incidental pneumococcal bacteremia treated with KETEK, a clinical cure rate of 88% (67/76) has been observed. KETEK is not indicated for the treatment of severe community-acquired pneumonia or suspected pneumococcal bacteremia.

Clinical cure rates for patients with CAP due to multi-drug resistant Streptococcus pneumoniae (MDRSP*) were determined from patients in controlled and uncontrolled trials. Of 36 evaluable patients with CAP due to MDRSP, 33 (91.7%) achieved clinical success. 

*MDRSP: Multi-drug resistant Streptococcus pneumoniae includes isolates known as PRSP (penicillin-resistant Streptococcus pneumoniae), and are isolates resistant to two or more of the following antibiotics: penicillin, 2nd generation cephalosporins, e.g., cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole.

Table 8. Clinical cure rate for 36 evaluable patients with MDRSP treated with KETEK in studies of community-acquired pneumonia

Screening Susceptibility	Clinical Success in Evaluable MDRSP Patients
	n/N*	%
n = the number of patients successfully treated; N = the number with resistance to the listed drug of the 36 evaluable patients with CAP due to MDRSP. Includes isolates tested for resistance to either tetracycline or doxycycline.
Penicillin-resistant	20/23	86.9
2nd generation cephalosporin-resistant	20/22	90.9
Macrolide-resistant	25/28	89.3
Trimethoprim/sulfamethoxazole-resistant	24/27	88.9
Tetracycline-resistant†	11/13	84.6

Visual Adverse Events

Table 9 provides the incidence of all treatment-emergent visual adverse events in controlled Phase III studies by age and gender. The group with the highest incidence was females under the age of 40, while males over the age of 40 had rates of visual adverse events similar to comparator-treated patients.

Table 9. Incidence of All Treatment-Emergent Visual Adverse Events in Controlled Phase III Studies

Gender/Age	Telithromycin	Comparators*
Includes all comparators combined
Female ≤ 40	2.1% (14/682)	0.0% (0/534)
Female > 40	1.0% (7/703)	0.35% (2/574)
Male ≤ 40	1.2% (7/563)	0.48% (2/417)
Male > 40	0.27% (2/754)	0.33% (2/614)
Total	1.1% (30/2702)	0.28% (6/2139)

ANIMAL PHARMACOLOGY

Repeated dose toxicity studies of 1, 3, and 6 months' duration with telithromycin conducted in rat, dog and monkey showed that the liver was the principal target for toxicity with elevations of liver enzymes and histological evidence of damage. There was evidence of reversibility after cessation of treatment. Plasma exposures based on free fraction of drug at the no observed adverse effect levels ranged from 1 to 10 times the expected clinical exposure.

Phospholipidosis (intracellular phospholipid accumulation) affecting a number of organs and tissues (e.g., liver, kidney, lung, thymus, spleen, gall bladder, mesenteric lymph nodes, GI-tract) has been observed with the administration of telithromycin in rats at repeated doses of 900 mg/m2/day (1.8× the human dose) or more for 1 month, and 300 mg/m2/day (0.61× the human dose) or more for 3–6 months.  Similarly, phospholipidosis has been observed in dogs with telithromycin at repeated doses of 3000 mg/m2/day (6.1× the human dose) or more for 1 month and 1000 mg/m2/day (2.0× the human dose) or more for 3 months. The significance of these findings for humans is unknown.

Pharmacology/toxicology studies showed an effect both in prolonging QTc interval in dogs in vivo and in vitro action potential duration (APD) in rabbit Purkinje fibers. These effects were observed at concentrations of free drug at least 8.8 (in dogs) times those circulating in clinical use. In vitro electrophysiological studies (hERG assays) suggested an inhibition of the rapid activating component of the delayed rectifier potassium current (IKr) as an underlying mechanism.

Revised December 2010

sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
© 2010 sanofi-aventis U.S. LLC

REFERENCES

1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically – Sixth Edition; Approved Standard, NCCLS Document M7-A6, Vol. 23, No. 2, NCCLS, Wayne, PA, January, 2003.
2. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests - Eighth Edition; Approved Standard, NCCLS Document M2-A8, Vol. 23, No. 1, NCCLS, Wayne, PA, January, 2003.
3. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Susceptibility Testing: Twelfth Informational Supplement; Approved Standard, NCCLS Document M2-A8 and M7-A6, Vol. 23, No. 1, NCCLS, Wayne, PA, January, 2004.

Medication Guide

KETEK® (KEE tek)
(telithromycin)
Tablets

Read the Medication Guide that comes with KETEK before you start taking it and each time you get a new prescription. There may be new information. Talk to your doctor if you have any questions about KETEK. This Medication Guide does not take the place of talking with your doctor about your medical condition or treatment.

What is the most important information I should know about KETEK?

Do not take KETEK if you have myasthenia gravis (a rare disease which causes muscle weakness). Worsening of myasthenia gravis symptoms including life-threatening breathing problems have happened in people with myasthenia gravis after taking KETEK, in some cases leading to death.

KETEK can cause other serious side effects, including:

1.

Severe liver damage (hepatotoxicity). Severe liver damage, in some cases leading to a liver transplant or death has happened in people treated with KETEK. Severe liver damage has happened during treatment, even after a few doses, or right after treatment with KETEK has ended.

Stop taking KETEK and call your doctor right away if you have signs of liver problems. Do not take another dose of KETEK unless your doctor tells you to.

Signs of liver problems include:

increased tiredness loss of appetite nausea yellowing of your skin or whites of your eyes

dark colored urine (tea colored) light colored stools right upper belly pain itchy skin

Do not take KETEK if you have ever had liver problems while taking KETEK or macrolide antibiotics. Macrolide antibiotics include:

• erythromycin
• azithromycin (Zithromax®, Zmax®)
• clarithromycin (Biaxin®)
• dirithromycin (Dynabac®)

2.

Vision problems. KETEK may cause you to have blurred vision, trouble focusing your eyes, and double vision. You may especially notice vision problems if you look quickly between objects close to you and objects far away from you.

3.

Fainting. KETEK may cause you to faint, especially if you also have nausea, vomiting, and lightheadedness.

Do not drive, operate heavy machinery, or do other dangerous activities while taking KETEK if you have:

• vision problems
• fainting
• confusion
• seeing things that are not there (visual hallucinations)

Stop taking KETEK and call your doctor right away if you have any of these symptoms. Do not take another dose of KETEK unless your doctor tells you to.

4. Low blood pressure, slow heart rate, and fainting. Ketek may cause you to have low blood pressure, a slow heart rate, and fainting when you also take certain medicines called calcium channel blockers. Calcium channel blockers include:

• verapamil (Calan®)
• amlodipine (Norvasc®)
• diltiazem (Cardizem®)
• or other medications containing these products.

See "What are the possible side effects of KETEK?"

What is KETEK?

KETEK is an antibiotic. KETEK is used to treat adults 18 years of age and older with a lung infection called "community acquired pneumonia" that is caused by certain germs called bacteria.

• KETEK is not for other types of infections.
• KETEK does not kill viruses like the common cold.

Who should not take KETEK?

Do not take KETEK if you:

• have myasthenia gravis
• have had liver problems while taking KETEK or macrolide antibiotics.
• have ever had an allergic reaction to telithromycin in KETEK or macrolide antibiotics.
• take cisapride (Propulsid®) or pimozide (Orap®).
• take colchicine (Colcrys®) and have kidney or liver problems.

Talk to your doctor before taking KETEK if you have any of the conditions listed above.

What should I tell my doctor before taking KETEK?

Before taking KETEK, tell your doctor if you:

• have liver problems
• have a heart problem called "QTc prolongation" or have a family history of QTc prolongation
• have other heart problems
• are pregnant or plan to become pregnant. It is not known if KETEK will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.
• are breast-feeding or plan to breast-feed. It is not known if KETEK passes into your breast milk. Talk to your doctor about the best way to feed your baby if you take KETEK.

Tell your doctor about all of the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. KETEK and other medicines may affect or interact with each other, sometimes causing serious side effects.

Especially tell your doctor if you take:

• colchicine (Colcrys®) while you take KETEK
• certain medicines called calcium channel blockers, such as: verapamil (Calan®), amlodipine (Norvasc®), diltiazem (Cardizem®), or other medications containing these products while you take KETEK
• cholesterol lowering medicines; you should not take these cholesterol lowering medicines while taking KETEK:
  • simvastatin (Zocor®, Vytorin®)
  • lovastatin (Mevacor®)
  • atorvastatin (Lipitor®)

Ask your doctor if you are not sure if the medicine you take is included in the list of medicines above.

Know the medicines you take. Keep a list of your medicines with you to show your doctor or pharmacist.

Do not take other medicines with KETEK without first checking with your doctor. Your doctor will tell you if you can take other medicines while taking KETEK.

How should I take KETEK?

• Take KETEK exactly as your doctor tells you.
• Skipping doses or not taking all of an antibiotic may:
  • make the treatment not work as well
  • increase the chance that the bacteria will develop resistance to the antibiotic
• If you have kidney disease, your doctor may prescribe a lower dose for you.
• Take KETEK with or without food.
• Swallow KETEK tablets whole.
• If you take too much KETEK, call your doctor, or go to the nearest hospital emergency room right away.

What are the possible side effects of KETEK?

See "What is the most important information I should know about KETEK?"

KETEK may cause serious side effects, including:

• Pseudomembranous colitis (an intestine infection). Pseudomembranous colitis can happen with most antibiotics, including KETEK. Call your doctor if you get watery diarrhea, diarrhea that does not go away, or bloody stools. You may also have stomach cramps and a fever. Pseudomembranous colitis can happen up to 2 months after you have finished your antibiotic.

The most common side effects of KETEK are:

• nausea
• headache
• dizziness
• vomiting
• diarrhea
• problems with taste

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effects of KETEK. For more information ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

You may also report side effects to sanofi-aventis U.S. at 1-800-633-1610.

How should I store KETEK?

• Store KETEK tablets at room temperature, between 59°F to 86°F (15°C to 30°C).
• Keep KETEK and all medicines out of the reach of children.

General Information about KETEK

• Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use KETEK for a condition for which it was not prescribed. Do not share KETEK with other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about KETEK. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about KETEK that was written for healthcare professionals. This information is also available on the KETEK website at www.KETEK.com or call 1-800-446-6267.

What are the ingredients in KETEK?

Active Ingredient: telithromycin

Inactive Ingredients: croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, red ferric oxide, talc, titanium dioxide, and yellow ferric oxide

Revised December 2010

Aventis公司新的每日一次的酮内酯(Ketolide)类抗菌素Ketek(telithromycin)的关键性的临床数据证实了它在呼吸道感染方面的潜力。

最近在加拿大多伦多举行的ICAAC会议上发表了来自于2500多位患者中10项多国的第三阶段研究的结果。数据是以Ketek的批准申请为基础的，它在2000年早期在美国和欧盟申报用于治疗呼吸道感染，包括由耐青霉素的肺炎链球菌引起的呼吸道感染。

◆新的抗菌素家族
Ketek是从大环内酯中衍生的抗菌素新家族中新的先进的产品，称做为Ketolides(酮内酯)，它是大环丙酯-lincosamide－链阳性菌素b(MlSb)抗菌素种类的新成员。该公司希望它在治疗呼吸道感染方面将填补新的氟喹诺酮和较老的MLSb类抗菌素之间的空白，特别是在日前抗菌素抵抗力的年代中,它将占抗菌素处方的一半多。一些其它的公司也正在开发酮内酯抗菌素，包括雅培(Abbott)公司的ABT-773正处于第二阶段的研究中。

这个领域的专家同意酮内酯在抗菌素的治疗中具有重要的地位。威斯康星大学的William Craig博士说：它们甚至是大环内酯的救星。对公共场所获得的感染，包括公共场所获得的肺炎(CAP)的大多数的指南，包括了大环内酯类药物的使用，使对这些产品的抵抗力在上升。

他说：已经观察到用大环内酯类药物的临床失败（虽然用于呼吸道感染还没有观察到）。最终这个种类会失去。为了取得更佳的效果，被迫在这些普通的感染中使用氟喹诺酮类药物，酮内酯的上市用于具有抵抗力细菌的患者能使保持大环丙酯作为医疗用药的一部分，留下氟喹诺酮类药物用于更难治疗的感染。

◆较短的治疗
与其它的显示取决于浓度杀伤的大环丙酯类和阿齐霉素相比较，也具有优点。在一些适应症中允许较短的五天的剂量方法，这似乎可以作为抗菌素治疗中将来的指导，因为较短的治疗持续时间通过减少细菌在药物中存在的时间和增加患者的顺从性减少了抵抗力发展的潜力。

但是Ketek是否应用于一线治疗仍需讨论。Aventis公司说：这种产品应遵照治疗指南处方里使用。在这些产品的市场中有空白，在美国仅有一种氟喹诺酮药物已被批准用于有抵抗力的肺炎链球菌感染。它是Ortho-McNeil公司的左氧氟沙星(Levaquin Levofloxacin)。

◆危险/利益轮廓
该公司说：在Ketek被留在后面用于更难以治疗的感染之前，需要考虑危险/利益的轮廓，它认为：在这些适应症中大环内酯和酮内酯类药物，比氟喹诺酮类药物更适于用作为一线的治疗剂。而Ketek的使用应取决于局部抵抗力的类型。在高抵抗力水平的区域内，在较强的病例的情况下，可使用较强的一线抗菌素消灭感染。

发表的临床数据显示telithromycin在呼吸道感染中对最常见的病原体具有较高的活性。如：肺mg的telithromycin每日一次，7-10天的治疗与用200mg的曲沃水沙星(trovafloxacin)每日一次使用7-10天同样有效(临床治愈率分别为91.1%和94.8%)。

在欧洲的南非进行的第三项研究中，404位轻微到中等程度的公共场所获得肺炎的患者接受800mg每日一次的telithromycin或高剂量的羟氨苄青霉素(1000mg，每日三次)使用10天。治愈率分别为94.6%和90.1％。

◆用于其它的呼吸道感染
Ketek在其它的常见的呼吸道感染中，包括慢性支气管炎的急性加重(AECB)、窦炎、咽炎和扁桃体炎中，使用一半的治疗时间，也显示出与比较的药品同样有效。

在496位慢性支气管炎的急性加重的患者中，800mg的telithromycin(每日一次，使用五天)与标准的500mg头孢呋新酯(每日二次使用10天)同样有效，(临床治愈率分别为89.2%和86.3%)。另一项在325位慢性支气管炎的急性加重患者的研究中，显示出五天的telithromycin治疗(每日800mg)与用羟氨苄青霉素/克拉维酸(500mg/125mg,每日三次)的10天的治疗炎链球菌、酿脓链球菌、金黄色酿脓葡萄球菌、流感嗜血杆菌和摩拉克氏菌以及抗非典型的细菌，衣原体肺炎球菌，支原体肺炎球菌素。

迄今为止，这种产品对抵抗力的发展也显示了很小的倾向性。在活体外，它很难选择有抵抗力的菌株。没有与其它的MLSb抗菌素的交叉的抵抗力。在研究中报告的最常见的付作用为腹泻(8.3-23.9%)、恶心(2.9-11.7%)、头昏(1.3-7.4%)和头痛(4.1-6.6%)。

◆用于CAP公共场所获得的肺炎
在三项公共场获得的肺炎的综合性研究中，Ketek显示出耐受性良好，并且与比较的药物一样有效。可以作为这种病况中的方便的可选择的治疗剂。

在北美的患者有公共场所获得的肺炎的448位成人的研究中，800mg的telithromycin(每日一次，使用10天)具有与500mg的甲红霉素(每日二次，使用10天)相同的功效(临床治愈率分别为88.3%和88.5%)，总的来说，耐受性良好，在北美的患者公共场所获得的肺炎的248位成人的第二项研究中,用800mg有样有效。临床治愈率分别为86.1%和82.1%。

在窦炎中，在790位患者中，800mg/每日的telithromycin使用五天和10天与用羟氨苄青霉素/克拉维酸(500mg/125mg，每日三次)使用10天的方法相比较，结果显示:用telithromycin治疗五天与用比较药品治疗10天功效一样，临床治愈率分别为75.8%,74.1%和74.6%。在欧洲和北美336位窦炎患者中的进行的第二项研究证实了在五天和10天的telithromycin的方法之间的比较的治愈率。

在396位患有A组β-溶血的链球菌咽炎/扁桃体炎的患者中，800mg的telithromycin每日一次，使用五天与20和30剂量的青霉素V(每日三次，使用10天)相比较，临床治愈率为94.8%和94.1%。在相同适应症的另一项研究显示telithromycin(800mg每日，使用五天)与甲红霉素(250mg每日二次，使用10天)，同样有效，临床治愈率为91.3%和88.1%。

KETEK TAB 400MG 60 

Generic Name: TELITHROMYCIN
Class: R
Manufacture: SANOFI-AVENTIS U.S. LLC
Strength: 400MG
Size: 60
Unit: TAB

美国食品暨药物管理局（FDA）一份内部备忘录指出，应对抗生素肯立克（Ketek）对肝脏的副作用提出更严格警告，有越来越多报告显示，肯立克恐将引起肝衰竭，其中4人不治。卫生署药政处处长廖继洲表示，肯立克在民国92年取得卫生署药证，台湾过去就已要求药厂加注警语，且肯立克属于后线抗生素，使用率非常低。

卫署早已要求加注警语

这份在5月16日作成的备忘录表示，FDA已接获12起肯立克使用者出现急性肝衰竭的病例报告，药物安全评估官也发现另有23位病患在使用肯立克后，出现严重的肝损伤。

备忘录中，FDA药物风险评估部门的专家威索与布尔克建议，万一肯立克引起的肝衰竭率高到与另一抗生素Trovan于1999年被限制使用前相当，则FDA应考虑限制它的使用，甚至回收肯立克。不过，两人也提到，他们无法断定肯立克目前的危险性是否比其它也引发肝问题的各类抗生素还高，“然而，越来越多与酮环类抗生素有关的通报比率是关切的重点”。

FDA发言人布洛女士表示，目前FDA核准的肯立克商品标示警告其引起的肝脏功能障碍可能很严重，但“通常是可逆转的”。

生产肯立克的药商赛诺菲安万特表示，若依照指示使用，相信肯立克是安全且有效的，该公司声明指出:"在任何最后结论出炉前，需要首屈一指的专家对这些复杂的评估进行严谨、严格的分析。"

内科医学年鉴于1月间刊出一篇重要报告，该报告详述在北卡罗莱纳一家医院接受治疗的3位患者开始使用肯立克后，出现严重的肝问题，其中1人死亡。