Submission Control Number: 119327

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 8 DRUG INTERACTIONS 13 DOSAGE AND ADMINISTRATION 18 OVERDOSAGE 19 ACTION AND CLINICAL PHARMACOLOGY 19 STORAGE AND STABILITY. 23 DOSAGE FORMS, COMPOSITION AND PACKAGING 23

PART II: SCIENTIFIC INFORMATION 24

PHARMACEUTICAL INFORMATION 24 CLINICAL TRIALS 25 DETAILED PHARMACOLOGY 28 MICROBIOLOGY 31 TOXICOLOGY 38 REFERENCES 50

PART III: CONSUMER INFORMATION 52

PrKETEK(r) (telithromycin film-coated tablets, 400 mg)

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Summary Product Information

CONTRAINDICATIONS

KETEK(r) (telithromycin) 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 death and life- threatening acute respiratory failure with a rapid onset and progression. KETEK(r) is contraindicated in patients with a previous history of hepatitis and/or jaundice associated with the use of KETEK(r) tablets, or any macrolide antibiotic. KETEK(r) is contraindicated in patients who are hypersensitive to telithromycin, any ingredient in the formulation, or to any macrolide antibiotic. For a complete listing, see the Dosage Forms, Composition and Packaging section of the Product Monograph. Concomitant administration of KETEK(r) with any of the following drugs is contraindicated: cisapride, pimozide, astemizole, terfenadine and ergot alkaloids.

WARNINGS AND PRECAUTIONS

General

Telithromycin is a strong inhibitor of CYP3A4 and a mild inhibitor of CYP2D6. Thus it is reasonable to expect that the concomitant administration of KETEK(r) and drugs primarily metabolized by these enzymes (i.e. CYP3A4 substrates) may result in increased plasma concentration levels of those drugs that could increase or prolong their therapeutic effect and/or increase adverse reactions. Caution should be exercised during concomitant administration of KETEK(r) and other drugs that are CYP3A4 substrates, especially those drugs with low bioavailability. Telithromycin is primarily metabolized by cytochrome P450 3A4 (CYP3A4) and to a lesser extent by cytochrome P450 1A (CYP1A). Concomitant administration of CYP3A4 inducers is likely to result in subtherapeutic levels of telithromycin and loss of effect. Concomitant administration of potent CYP3A4 inhibitors may lead to increases in plasma levels of telithromycin. (See DRUG INTERACTIONS, Drug-Drug Interactions).

Cardiovascular

KETEK(r) has the potential to prolong the QTc interval of the electrocardiogram in some patients as observed with some macrolides. QTc interval prolongation may lead to an increased risk for ventricular arrhythmias, including Torsades de Pointes (TdP). Thus, KETEK(r) should be avoided in patients with congenital prolongation of the QTc interval, history of long QT syndrome, and in patients with ongoing proarrythmic conditions such as uncorrected hypokalemia or hypomagnesaemia, clinically significant bradycardia (<50 bpm) and in patients receiving Class IA (e.g. quinidine and procainamide) or Class III (e.g. amiodarone, sotalol) antiarrhythmic agents. KETEK(r) should be avoided in patients who experienced a confirmed cardiogenic syncope, ventricular tachyarrhythmia or TdP while taking a medicinal product with QT-prolonging potential, such as a macrolide or quinolone antibiotic, or other non-antibiotic suspected of prolonging the QT interval. In clinical trials the effect on QTc interval was small (mean approximately 1 millisecond). There were no reports of TdP or other serious ventricular arrhythmias or related syncope in the clinical program and no subgroups at risk were identified. In clinical trials no increased cardiovascular morbidity or mortality attributable to the QTc interval prolongation occurred with KETEK(r) treatment in 4780 patients, including 204 patients having a prolonged QTc interval at baseline. Cases of torsades de pointes have been reported in post-marketing experience with KETEK(r).

Gastrointestinal

Clostridium difficile

-associated disease (CDAD)

Clostridium difficile-associated disease (CDAD) has been reported with use of many antibacterial agents, including KETEK(r). CDAD may range in severity from mild diarrhea to fatal colitis. It is important to consider this diagnosis in patients who present with diarrhea or symptoms of colitis, pseudomembranous colitis, toxic megacolon, or perforation of the colon subsequent to the administration of any antibacterial agent. CDAD has been reported to occur over 2 months after the administration of antibacterial agents. Treatment with antibacterial agents may alter the normal flora of the colon and may permit overgrowth of Clostridium difficile. C. difficile produces toxins A and B, which contribute to the development of CDAD. CDAD may cause significant morbidity and mortality. CDAD can be refractory to antimicrobial therapy. If the diagnosis of CDAD is suspected or confirmed, appropriate therapeutic measures should be initiated. Mild cases of CDAD usually respond to discontinuation of antibacterial agents not directed against Clostridium difficile. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial agent clinically effective against Clostridium difficile. Surgical evaluation should be instituted as clinically indicated since surgical intervention may be required in certain severe cases. (See ADVERSE REACTIONS).

Hepatic/Biliary/Pancreatic

Hepatotoxicity

Acute hepatic failure and severe liver injury, in some cases fatal have been reported in patients treated with KETEK(r).These hepatic reactions included fulminant hepatitis and hepatic necrosis leading to liver transplant, and were observed during or immediately after treatment with KETEK(r). Liver injury progressed rapidly and occurred after administration of only a few doses of KETEK(r). (See ADVERSE REACTIONS) In addition, less severe hepatic dysfunction associated with increased liver enzymes, hepatitis and in some cases jaundice was reported with the use of KETEK(r). These events associated with less severe forms of liver toxicity were reversible. 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, hepatomegaly or pruritus. Patients with signs or symptoms of hepatitis must be advised to discontinue KETEK(r) and immediately seek medical evaluation, which should include liver function tests. (See ADVERSE REACTIONS) If clinical hepatitis or transaminase elevations combined with other systemic symptoms occur, KETEK(r) 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(r) tablets, or any macrolide antibiotic. (See CONTRAINDICATIONS)

Use in patients with hepatic impairment

No dose adjustment is needed in patients with severe hepatic impairment, unless renal function is severely impaired. Experience in patients with impaired hepatic function is limited; hence, KETEK(r) should be used with caution in these patients. (See DOSAGE AND ADMINISTRATION, Dosing Considerations and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions). In patients with severely impaired renal and/or hepatic function, concomitant administration of KETEK(r) and strong CYP3A4 inhibitors, such as protease inhibitors or ketoconazole, is not recommended. (See ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions).

Immune

Hypersensitivity reactions

Serious allergic reactions, including anaphylaxis and angioedema have been very rarely reported in patients on KETEK(r) therapy. If an allergic reaction occurs, KETEK(r) should be discontinued and appropriate therapy should be instituted.

Neurologic

Loss of Consciousness

There have been post-marketing adverse event reports of loss of consciousness, including syncope, sometimes associated with vagal syndrome.

Ophthalmologic

Visual disturbances

KETEK(r) 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. (See ADVERSE REACTIONS, Less Common Clinical Trial Adverse Drug Reactions, Eye disorders).

Renal

Use in patients with renal insufficiency

No dose adjustment is needed in patients with mild to moderate renal impairment. In the presence of severe renal impairment (creatinine clearance < 30 mL/min), the dose should be reduced to 400 mg once daily. (See DOSAGE AND ADMINISTRATION, Dosing Considerations, ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions and WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, Use in patients with hepatic impairment). In patients with severely impaired renal and/or hepatic function, concomitant administration of KETEK(r) and strong CYP3A4 inhibitors, such as protease inhibitors or ketoconazole, is not recommended. (See ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions).

Special Populations

Pregnant women:

There are no adequate and well-controlled studies in pregnant women.

Studies in animals have shown embryofetal toxicity only at doses inducing maternal toxicity. The effects occurred at doses of 300 mg/kg/day in rats and 60 mg/kg/day in rabbits, which correspond to 18.8 and 3.75 times the recommended human clinical dose, respectively. The potential risk for humans is unknown. KETEK(r) should not be used during pregnancy unless the expected benefit to the mother outweighs any possible risk to the foetus. (Also see TOXICOLOGY, Reproduction and Teratology).

Nursing women:

It is not known whether telithromycin is excreted in human milk; however, it is excreted in the milk of lactating animals at concentrations about five times those of maternal plasma. Preweaned rats, exposed indirectly via consumption of milk from dams treated with

200 mg/kg/day for 3 weeks, were not adversely affected, despite data indicating higher drug levels in milk than in plasma. Because animal data are not always predictive of human response, KETEK(r) should not be used during lactation unless the expected benefit to the mother outweighs any possible risk to the baby. Pediatrics: (birth to 18 years old): The safety of KETEK(r) in pediatric populations less than 13 years of age has not been established. A total of 124 subjects aged 13 to 18 years were treated with KETEK(r) in 16 Phase III trials. Efficacy and safety were similar to that observed in older patients. Geriatrics: In the 16 Phase III clinical trials (n=4780 analysed for safety), KETEK(r) was administered to 694 patients who were 65 years and older, including 231 patients who were 75 years and older. Efficacy and safety were similar to that observed in younger patients. However, greater sensitivity of older individuals to KETEK(r) or telithromycin cannot be ruled out. No dosage adjustment is required based on age alone; however, a dosage adjustment is recommended in elderly patients with severe renal impairment (CLCR < 30 mL/min). (See DOSAGE AND ADMINISTRATION, Dosing Considerations and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Geriatrics).

Monitoring and Laboratory Tests

There are no reported laboratory test interactions.

Occupational Hazards

Visual disturbances

KETEK(r) 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. If a patient experiences these events, a healthcare professional should be consulted and consideration may be given to taking KETEK(r) at bedtime. (See ADVERSE REACTIONS, Less Common Clinical Trial Adverse Drug Reactions, Eye disorders). Loss of Consciousness There have been post-marketing adverse event reports of loss of consciousness, including syncope sometimes associated with vagal syndrome.

Driving a vehicle or operating machinery

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(r). If patients experience visual disorders or loss of consciousness while taking KETEK(r), patients should not drive a motor vehicle, operate heavy machinery or engage in other potentially hazardous activities.

DRUG INTERACTIONS

Telithromycin, like certain other macrolides, is primarily metabolized by CYP3A4 and inhibits CYP3A4. The concomitant administration of telithromycin and other drugs mainly metabolized by this enzyme may lead to increased plasma concentrations of the co-administered drugs (See Drug-Drug Interactions).

Overview

Drug-Drug

KETEK(r) (telithromycin) is primarily metabolized by cytochrome P450 3A4 (CYP3A4) and to a lesser extent by cytochrome P450 1A (CYP1A).

Effects of telithromycin on other drugs

In vitro drug interaction studies have demonstrated that telithromycin is a strong inhibitor of CYP3A4 and a mild inhibitor of CYP2D6. Thus it is reasonable to expect that the concomitant administration of KETEK(r) and drugs primarily metabolized by these enzymes (i.e. CYP3A4 substrates) may result in increased plasma concentration levels of those drugs that could increase or prolong their therapeutic effect and/or increase adverse reactions. Caution should be exercised during concomitant administration of KETEK(r) and other drugs that are CYP3A4 substrates, especially those drugs with low bioavailability. In vivo studies with midazolam, simvastatin and cisapride have demonstrated a potent inhibition of intestinal CYP3A4 and a moderate inhibition of hepatic CYP3A4 by telithromycin. The degree of inhibition with different CYP3A4 substrates is difficult to predict. Hence, patients taking medicinal products that are CYP3A4 substrates and have a narrow therapeutic window, should be clinically monitored while taking KETEK(r). Concomitant administration of drugs mainly metabolized by this enzyme may lead to increased plasma concentrations, possibly resulting in increased adverse events. Telithromycin is a mild inhibitor of CYP2D6.

Effects of other drugs on telithromycin

Concomitant administration of CYP3A4 inducers (such as rifampin, phenytoin, carbamazepine, phenobarbital, St John's wort) is likely to result in subtherapeutic levels of telithromycin and loss of effect. Concomitant administration of potent CYP3A4 inhibitors (such as ritonavir and ketoconazole) may lead to increases in plasma levels of telithromycin.

Drug-Drug Interactions

Established or Predicted Drug-Drug Interactions

C=Case Study; CT= Clinical Trial; T= Theoretical

No specific drug interaction studies have been performed to evaluate the following potential drug-drug interactions between KETEK(r) and drugs metabolized by cytochrome P450 systems, such as: carbamazepine, cyclosporine, disopyramide, hexobarbital, phenytoin, quinidine, and triazolam. However, drug interactions have been observed with macrolide products. Elevation of serum levels of these drugs may be observed when co-administered with telithromycin.

Drug-Food Interactions

Studies have shown that there is no interaction with food for the regular-size tablet1 and that the reduced-size tablet is bioequivalent to the regular-sized tablet in the fasted state. KETEK(r) tablets can be taken with or without food.

Regular size tablet was the previous formulation, no longer available on Canadian market.

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

Drug-Herb Interactions

Interactions with herbal products have not been established. (For information on St John's wort see WARNINGS AND PRECAUTIONS, General and DRUG INTERACTIONS, Overview, Drug-Drug.)

Drug-Laboratory Interactions

There are no reported laboratory test interactions.

DOSAGE AND ADMINISTRATION

Dosing Considerations

KETEK(r) (telithromycin) tablets can be administered with or without food. (See DRUG INTERACTIONS- Drug-Food Interactions) Consideration may be given to taking telithromycin at bedtime, to reduce the potential impact of visual disturbances and loss of consciousness. (See WARNINGS AND PRECAUTIONS- Occupational Hazards) Impaired renal function: No dosage adjustment for KETEK(r) is necessary in patients with mild to moderate renal impairment. In the presence of severe renal impairment (creatinine clearance < 30 mL/min), the dose should be reduced to 400 mg once daily. For hemodialysis patients, on dialysis days, KETEK(r) 800 mg should be given after each dialysis session. (See also WARNINGS AND PRECAUTIONS, Renal and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions). Impaired hepatic function: No dosage adjustment is required in patients with mild, moderate, or severe hepatic impairment, unless renal function is severely impaired in which case the dose of KETEK(r) should be reduced to 400 mg once daily. Experience in patients with impaired hepatic function is limited; hence, KETEK(r) should be used with caution in these patients. (See also WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions).

Recommended Dose and Dosage Adjustment

Recommended Dose and Dosage Adjustment

Missed Dose

If a dose is missed, it should be taken as soon as possible. However, if it is almost time for the next dose, no additional dose should be taken and the regular dosing schedule should be resumed. No more than one dose of KETEK(r) (2 tablets) should be taken in a 24-hour period.

OVERDOSAGE

For management of a suspected drug overdose, contact your regional Poison Control Centre. Administration of activated charcoal may be considered. The patient should be carefully observed (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(r) is unknown. Post-market reports indicate that an overdose with KETEK(r) (telithromycin) may produce gastrointestinal symptoms, such as nausea, vomiting and diarrhea. In animal studies, telithromycin had low acute toxicity with an LD50 value in the range of 1500- 2000 mg/kg in the mouse and a minimum lethal dose of greater than 2000 mg/kg in the rat. No clinical signs were observed in rats; in mice, hypotonia was seen at 1500 mg/kg and above, with tremors prior to death.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

KETEK(r) (telithromycin) is a novel antimicrobial that belongs to a new chemical family, the ketolides. Ketolides are recent additions to the macrolide-lincosamide streptogramin (MLS) class. Telithromycin exerts its antimicrobial effects by inhibiting bacterial protein synthesis. This occurs not only by directly blocking translation of the bacterial 23S ribosomal RNA but also by inhibiting the assembly of new bacterial ribosomes. Telithromycin blocks protein synthesis by binding to two sites on the 50S ribosomal subunit: domain II and V of the 23S rRNA. The affinity of telithromycin for the 23S rRNA has been measured to be 10 times greater than that of erythromycin A in erythromycin-susceptible strains and 25 times greater in macrolide-resistant strains. The difference in binding strength can be attributed to the C11-12 carbamate side chain. It allows telithromycin to maintain binding at domain II, even in the presence of resistance that alters the domain V binding site.

Pharmacokinetics

Telithromycin displays non-linear kinetics over a wide dose range. The mean pharmacokinetic characteristics of telithromycin after administration of single and multiple (7 days) once-daily 800 mg doses to healthy adult subjects are shown in the table below.

Summary of Telithromycin's Pharmacokinetic Parameters in Healthy Adult Subjects (single and multiple [7 days] once-daily 800 mg doses)

* Median values

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

Absorption:

Following oral administration, telithromycin reached maximal concentration at about 1 hour (0.5 to 4 hours). It has an absolute bioavailability of approximately 57% in both young and elderly subjects after a single dose of 800 mg (undergoes first-pass metabolism).

The rate and extent of absorption of the regular-size tablet2 are unaffected by food intake. Under fasting conditions in adult healthy volunteers the "reduced-size" tablet was found to be equivalent to the "regular-sized" tablet, and thus KETEK(r) tablets can be given without regard to food. In fasting healthy adult subjects, peak plasma telithromycin concentrations of approximately 2 mg/mL are attained within 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 and are approximately 1.5 times the single-dose concentration after 7 days of dosing.

1. Regular size tablet was the previous formulation, no longer available on Canadian market.

Comparative Bioavailability Study

In a 2-way crossover comparative bioavailability study, the reformulated 400 mg reduced-size tablet vs the 400 mg regular size tablet of telithromycin, after a single oral dose of 2 x 400 mg telithromycin under fasting conditions in adult healthy volunteers, was found to be bioequivalent with the regular size telithromycin tablets.

Summary table of the comparative bioavailability data for telithromycin

Telithromycin (2 x 400 mg)

From measured data Geometric Mean Arithmetic Mean (CV %)

Parameter Test * Reference+ % Ratio of

Confidence Interval (90%)

(ng.h/mL)

(ng.h/mL)

MAX

(ng/mL)

6723 (48)

7030 (46)

1161 (43)

7359 (42)

7558 (41)

1276 (39)

90.1 84.1; 96.6

92.4 86.7; 98.6

* Telithromycin 400 mg regular-size tablets, Quintiles, Kansas City. (Identical to the

telithromycin regular-size tablets no longer available on the Canadian market.)

+

Telithromycin 400 mg reduced size tablets, Quintiles, Kansas City. (Identical to the telithromycin regular-size tablets currently available on the Canadian market.)

Distribution: Over a clinically relevant concentration range, 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. Telithromycin is widely distributed throughout the body and the distribution is similar between young and elderly subjects. Rapid distribution of telithromycin into tissues results in significantly higher telithromycin concentrations in most target tissues than in plasma. (See DETAILED PHARMACOLOGY, Human Pharmacology for details).

Metabolism:

Telithromycin is primarily metabolized by the liver.

After oral administration, two-thirds of the dose is eliminated as metabolites and one third unchanged. The main circulating compound in plasma is telithromycin. Its main circulating metabolite represented 12.6% of the AUC of telithromycin and has little antimicrobial activity compared with the parent medicinal product. Three other plasma metabolites were detected in plasma, urine and faeces, each representing 3% or less of the AUC of telithromycin. It is estimated that approximately 50% of telithromycin's metabolism is mediated by cytochrome P450 (3A4) and the remaining 50% is cytochrome P450 independent.

Excretion:

Prior to entering the systemic circulation, 33% of the dose of telithromycin undergoes metabolism by a first-pass effect and 57% reaches the systemic circulation. The unchanged dose reaching the systemic circulation is eliminated by multiple pathways as follows: 7% of the dose is excreted unchanged in faeces by biliary and/or intestinal secretion; 13% is excreted unchanged in urine by renal excretion; and 37% is metabolized by the liver.

The main elimination half-life of telithromycin is 2-3 hours and the terminal elimination half-life is about 10 hours at a dose of 800 mg once daily.

Special Populations and Conditions

Pediatrics:

The pharmacokinetics of telithromycin in pediatric populations, 12 years of age and under, have not been studied. In clinical trials, population pharmacokinetic analysis, including limited data (n=18) obtained in pediatric patients 13 to 17 years of age, showed that telithromycin concentrations in this age group were similar to the concentrations in patients 18 to 60 years of age (n=1329).

Geriatrics: In patients with respiratory infections, aged greater than 65 years (n = 20), plasma telithromycin Cmax and AUC were increased 30% and 40%, respectively, compared to patients less than 65 years of age (n = 142). In subjects aged 65 to 92 years (n=14), plasma telithromycin Cmax and AUC were increased 100% and 120%, respectively, compared to healthy adults aged 19 to 29 (n=12) after once daily dosing of 800 mg for 10 days. There was no statistically significant change in the elimination half-life. No dosage adjustment is required based on age alone; however, a dosage adjustment is recommended in elderly patients with severe renal impairment (CLCR <30 mL/min). (See WARNINGS AND PRECAUTIONS, Renal and DOSAGE AND ADMINISTRATION, Dosing Considerations). Gender: In 18 healthy young volunteers (20 to 34 years of age ) and in 14 healthy elderly volunteers (65 to 92 years of age) given single and multiple doses of 800 mg KETEK(r), there was no statistical difference between males and females in mean AUC, Cmax and elimination half-life. 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 compared 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 necessary in patients with mild, moderate, or severe hepatic impairment, unless renal function is severely impaired. Experience in patients with impaired hepatic function is limited; hence, KETEK(r) should be used with caution in these patients. (See WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic and DOSAGE AND ADMINISTRATION, Dosing Considerations). Renal Insufficiency: In 20 patients with mild to severe renal impairment, increases in Cmax and AUC values ranged from 37 to 38% and 41 to 52%, respectively, compared to normal healthy subjects. In the presence of severe renal impairment (creatinine clearance <30 mL/min), the dose should be reduced to 400 mg once daily. (See DOSAGE AND ADMINISTRATION, Dosing Considerations). 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 telithromycin was administered 2 hours post-dialysis. (See WARNINGS AND PRECAUTIONS, Renal and DOSAGE AND ADMINISTRATION, Dosing Considerations). Multiple Insufficiency: The effects of impairment of multiple elimination pathways were studied in 12 subjects >=60 years of age, with diminished renal function (CLCR= 24 to 80 mL/min) and given ketoconazole to block the CYP3A4 pathway. In this study, when severe renal insufficiency (CLCR < 30 mL/min) and concomitant impairment of hepatic metabolism were present, telithromycin exposure was at the highest end of values observed in Phase III clinical studies. In the presence of severe renal impairment (CLCR < 30 mL/min), with or without coexisting hepatic impairment, a reduced dosage of KETEK(r) is recommended. (See WARNINGS AND PRECAUTIONS, Renal, Hepatic/Biliary/Pancreatic and DOSAGE AND ADMINISTRATION, Dosing Considerations).

STORAGE AND STABILITY

Store at room temperature between 15-30degC. Protect from exposure to heat and light and keep in a safe place out of the reach of children.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Reduced size tablets (New formulation without lactose and corn starch)

KETEK(r) (telithromycin) 400 mg tablets are supplied as light-orange, oval, film-coated tablets (approx. 8.7 x 13.9 mm), imprinted "H3647" on one side and "400" on the other side in the following packaging sizes: bottles of 60 and 10-tablet cards (2 tablets per blister cavity). Core tablet: Telithromycin, microcrystalline cellulose, povidone, croscarmellose sodium, magnesium stearate. Tablet coating: polyethylene glycol, hydroxypropyl methylcellulose, talc, titanium dioxide, yellow ferric oxide, red ferric oxide.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name:

telithromycin

Chemical name: erythromycin, 3-de[(2,6-dideoxy-3-C-methyl-3-O-methyl-a-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]- Molecular formula: C43 H65 N5 O10 Structural formula: Molecular weight: 812.0 Physical form: white to practically white powder Solubility: Freely soluble in Dichloromethane, Ethanol, Methanol, Acetonitrile and Acetone; very slightly soluble in Water pKa: 2.4 (pyridinium ring), 5.1 (imidazole ring), 8.7 (dimethylamine function) Partition coefficient: c = 3.05 mg/ 0.1 mL of octanol at 25degC

CLINICAL TRIALS

Community-acquired Pneumonia

KETEK(r) (telithromycin) was studied for the treatment of community-acquired pneumonia in eight clinical trials.

Study demographics and trial design

Summary of Patient Demographics for Clinical Trials in Community-acquired Pneumonia

*This study was discontinued prematurely after trovafloxacin was restricted to inpatient use for severe infections as a result of safety concerns that arose during post-marketing surveillance.

Study results

Community-acquired Pneumonia: Clinical Cure Rate by Study at Posttherapy Follow-up (17-24 days)

*This study was discontinued prematurely after trovafloxacin was restricted to inpatient use for severe infections as a result of safety concerns that arose during post-marketing surveillance.

a

95% confidence interval of the difference in cure rates between the treatment groups

b

Two-sided 95% confidence interval

The overall clinical outcome for KETEK(r) treated patients and for high risk subsets from the eight CAP studies is displayed in the table below.

Community-acquired Pneumonia: Clinical Cure Rate in High Risk * Patients at Posttherapy Follow-up (17-24 Days)

* KETEK(r) is not indicated for the treatment of severe CAP or suspected pneumococcal bacteremia Clinical cure rate for KETEK(r) against the most common pathogens, including atypical pathogens from the eight CAP clinical trials is displayed in the table below.

Community-acquired Pneumonia: Clinical Cure Rate by Pathogen in Microbiologically Evaluable Patients at Posttherapy Follow-up (17-24 days)

a Multi-drug resistant Streptococcus pneumoniae (MDRSP) are isolates resistant to two or more of the following antibiotics: penicillin (penicillin-resistant Streptococcus pneumoniae or PRSP), macrolides (erythromycin- / macrolide-resistant Streptococcus pneumoniae or ERSP/MRSP), 2nd generation cephalosporins (e.g., cefuroxime), tetracyclines and trimethoprim- sulfamethoxazole. Clinical cure rates for KETEK(r)against strains of pencillin-, macrolide- or multi-drug resistant

Streptococcus pneumoniae

from the eight CAP clinical trials are displayed in the table below.

KETEK(r) Clinical Cure Rates for Patients with Antibiotic-Resistant Isolates in CAP Studies

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

b

Includes isolates resistant to tetracycline or doxycycline.

KETEK(r) clinical cure rates against MDRSP are comparable to those for the overall CAP population (90.9%) as well as to those against Streptococcus pneumoniae in CAP studies (93.8%). Furthermore, cure rates against MDRSP were similar irrespective of the class of antibiotic to which the organism exhibited resistance

DETAILED PHARMACOLOGY

Animal Pharmacology

General introduction

In safety pharmacology studies, telithromycin was evaluated at doses up to 300 mg/kg p.o. (approximately 23 times the clinical dose) and 15 mg/kg i.v. (a maximum dose limited by solubility); in vitro studies investigated concentrations up to 500 mM (the maximum free concentration in plasma in the clinic is approximately 1 mM). Principal effects were seen on the central nervous, digestive and cardiovascular systems.

Central nervous system effects

Studies on the central nervous system showed few effects of telithromycin, and only at high doses. In combination with ketamine, oxotremorine and yohimbine in mice, 100 and 300 mg/kg of telithromycin given by oral route caused mortality; this was also seen after intravenous dosing in combination with ketamine, but not yohimbine or oxotremorine. A similar effect was already described with some but not all other macrolides. No interaction was seen in combining telithromycin with hexobarbital or isoflurane. Studies designed to investigate these observations failed to completely elucidate the underlying mechanism, although a facilitation of cholinergic systems appears to be responsible for the oxotremorine interaction.

Gastrointestinal effects

Telithromycin was given orally to dogs at 5, 15 and 30 mg/kg; emesis was noted sporadically at 5 and 30 mg/kg, with a much lower incidence than in the other macrolides given under similar conditions; it did not induce diarrhea in this species.

Cardiovascular effects

Cardiovascular studies in the dog showed telithromycin to increase heart rate and increase QTc at free plasma concentrations approximately 10 or more times those in the clinic. A comparative study with two other macrolides, all compounds administered to conscious dogs at 15 mg/kg as an intravenous bolus, showed qualitatively and quantitatively similar effects for all three compounds. Studies in isolated rabbit Purkinje fibres with telithromycin showed an increase in the duration of action potentials at concentrations of 10 mM and above; such increases were also observed with comparator macrolides at concentrations similar to or slightly above those of telithromycin. Telithromycin inhibited the HERG (Human ether-a-go-go-related gene) and Kv1.5 cloned potassium channels with inhibition of 50% of the HERG channel at 42.5 mM, and of 56% of the Kv1.5 channel at 100 mM, with an overall similar magnitude of effects as for the other comparator macrolides.

Drug metabolism and pharmacokinetics

Telithromycin was rapidly absorbed after oral administration to animals with bioavailability of 53, 36 and 54 % in the mouse, rat and dog respectively. Corresponding volumes of distribution in these species were 1.4, 10.6 and 4.9 L/kg. Radioactivity was widely distributed in rats after oral and intravenous dosing, although levels in the central nervous system were low. Levels of radioactivity in tissues decreased in parallel to plasma levels with almost complete elimination of radioactivity by 24 hours after dosing. Studies on metabolism showed that RU 76363, the principal circulating metabolite in man, resulting from loss of the aryl rings, circulated little or not at all in rats and dogs but was present in monkeys. Telithromycin also represented the major fraction identified in rat and dog urine and faeces, with other identified compounds being present only at low levels. In vitro protein binding showed differences between species -- 90, 60, 45, 50 and 70 % at approximately 1 mg/L in mouse, rat, dog, monkey and human, respectively. Binding was saturable at high concentrations and was primarily to albumin and, to a lesser extent, to a1- acid glycoprotein. Faecal elimination predominated (>=80%) in rats and dogs. A study in rats after intravenous dosing showed 58% of administered radioactivity to be excreted in the bile within 24 hours and 16% to appear in the faeces as a result of direct secretion into the gut lumen.

Enzymatic activity

In vitro studies to identify cytochrome P450 isoenzymes involved in the metabolism of telithromycin showed CYP3A4 to be the major pathway involved in human liver microsomes, indicating a potential for drug-drug interactions. Studies also showed inhibition of CYP3A4 and CYP2D6, with respective Ki values of 58 and 46 mM.

Human Pharmacology

Pharmacokinetics

The pharmacokinetics of telithromycin are described under ACTION AND CLINICAL PHARMACOLOGY. Details regarding the distribution of telithromycin are given below.

Distribution

Telithromycin is widely distributed throughout the body. Concentrations of telithromycin observed in respiratory tissues, white blood cells, and alveolar macrophages are greater than the MIC for telithromycin against the indicated respiratory pathogens. The drug persisted 48 hours after dosing in epithelial lining fluid and alveolar macrophages. The concentrations of telithromycin observed in respiratory tissues, including bronchial mucosa and epithelial lining fluid, after 800 mg once-daily dosing for 5 days are presented in the following table.

Penetration and Persistence of Telithromycin into Respiratory Tissues

*Units in mg/kg

a

tissue obtained from patients with bronchial inflammation eligible for bronchial fibroscopy

Telithromycin is highly concentrated in white blood cells (WBC) and is eliminated more slowly from white blood cells than from plasma. Mean white blood cell concentrations of telithromycin peaked at 72.1 mg/mL at 6 hours and remained at 14.1 mg/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 mg/mL 48 hours after the last dose. The high concentration of telithromycin in white blood cells and alveolar macrophages may contribute to drug distribution to inflamed tissues. Similarly, telithromycin is eliminated slowly from alveolar macrophages with concentrations of 41 mg/mL at 24 hours after repeated doses of 800 mg once daily. The optimal dose is 800 mg once daily. (See DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment). The mean concentration of telithromycin in white blood cells (WBC) and alveolar macrophages is summarized in the table below.

Mean Concentrations of Telithromycin in WBC and Alveolar Macrophages

Hours post-

Cell type

Healthy subjects

dose Dose (mg) n Concentration (mg/mL) Ratio

Intracellular Plasma

White blood cells (WBC) 2 600 5 64.6 0.775 87

6 600 5 72.1 0.201 380

12 600 5 39.4 0.049 1046

24 600 5 14.1 0.014 1085

Alveolar macrophages 2 800 5 65 1.07 55

8 800 6 100 0.605 180

24 800 6 41 0.073 540

Patients

Alveolar macrophagesa 2 800 6 69.3 1.86 40.9

12 800 6 318 0.23 1204

24 800 7 162 0.08 2160

a

tissue obtained from patients with bronchial inflammation eligible for bronchial fibroscopy

MICROBIOLOGY

KETEK(r) (telithromycin) is a novel antimicrobial that belongs to a new chemical family, the ketolides. Ketolides are recent additions to the macrolide-lincosamide streptogramin (MLS) class. Telithromycin exerts its antibacterial effects by inhibiting bacterial protein synthesis. This occurs not only by directly blocking translation of the bacterial 23S ribosomal RNA but also by inhibiting the assembly of new bacterial ribosomes. Telithromycin has been shown to bind more tightly to the bacterial ribosome than erythromycin A, 10-fold more tightly in erythromycin A susceptible ribosomes and > 20-fold more tightly in MLSB-resistant ribosomes (data from Escherichia coli). This enhanced binding appears to be related to the presence of the C11-12 side chain, and correlates with the distinctly different modes of interaction that telithromycin and erythromycin A exhibit in domain II of the 23S ribosomal RNA. It may also explain the high activity of telithromycin against common pathogens and its ability to overcome cross-resistance in gram-positive cocci. The individual activity of telithromycin against various bacterial isolates is provided in the following table:

Antibacterial Spectrum of Activity

In Vitro Activity of Telithromycin

*MSSA: methicillin-susceptile S. aureus * *MRSA: methicillin-resistant S. aureus

MIC: minimum inhibitory concentration

Peni: penicillin G; clin: clindamycin; Ery: erythromycin A; OXA-S: oxacillin-(methicillin-) susceptible; OXA-R: oxacillin-(methicillin-) resistant

Telithromycin exhibits activity against S. pneumoniae irrespective of their susceptibility to other antibacterial classes, such as penicillins and macrolides, including organisms expressing the two most common mechanisms of macrolide resistance, antibiotic efflux (mef) and ribosomal methylation (erm). In addition, telithromycin exhibits activity against S. pneumoniae resistant to cephalosporins, cotrimoxazole, clindamycin, tetracyclines and the fluoroquinolones. Among common respiratory pathogens, telithromycin does not induce MLSB resistance in vitro, an attribute related to its 3 keto function. It has been shown in vitro that resistance to telithromycin due to spontaneous mutation occurs very rarely. Telithromycin is highly concentrated in phagocytes and has good activity against intracellular and atypical respiratory pathogens.

In vitro, bactericidal activity has been demonstrated against isolates of: Streptococcus pneumoniae (including penicillin G and/or macrolide resistant strains), Streptococcus pyogenes, Haemophilus influenzae, Chlamydophila (Chlamydia) pneumoniae, Legionella pneumophila and Mycoplasma pneumoniae. In vitro, telithromycin has been shown to be affected by erm(B)- and mef(A)-related macrolide resistance mechanisms but to a lesser extent than erythromycin. While exposure to telithromycin did select for pneumococcal mutants with increased minimum inhibitory concentrations (MICs), the MICs remained within the susceptibility range approved by the Clinical Laboratory Standards Institute (CLSI; formerly called the NCCLS). Selection of mutants resistant to telithromycin among strains of S. pneumoniae lacking an inducible erm(B) gene was very uncommon (1.5 X 10-8 at 0.1 mg/mL; < 4.8 X 10-9 at 0.2 mg/mL). By comparison, selection of resistant mutants to telithromycin occurred more frequently among pneumococci containing an inducible erm(B) gene (1.4 X 10-7 to 9 X 10-8 at 0.1 mg/mL; 3.5 X 10-8 to 2 X 10-9 at 0.2 mg/mL). In vitro, telithromycin has demonstrated a lower propensity to select for antibiotic resistant mutants to itself or to other related antibacterial agents, potentially reducing the impact of antibiotic resistance among Streptococcus pneumoniae to these compounds.

Susceptibility Tests

Dilution techniques:

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on dilution method1 (broth or agar dilution), or equivalent, with standardized inoculum concentrations and standardized concentrations of telithromycin powder. The MIC values should be interpreted according to the following criteria:

National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Susceptibility Testing: Twelfth Informational Supplement; Approved Standard, NCCLS Document M2-A7 and M7-A5, Vol 21, No 1, NCCLS, Wayne, PA, January 2002.

For testing Staphylococcus aureus:

MIC (mg/mL)

<= 0.25

Interpretation

Susceptible (S)

For testing Streptococci including Streptococcus pneumoniaea:

MIC (mg/mL)

<=1.0 2.0 >=4.0

Interpretation

Susceptible (S) Intermediate (I) Resistant (R)

a

This interpretive standard is applicable to tests performed following NCCLS guidelines using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood.

For testing Haemophilus influenzaeb (irrespective of ss-lactamase production):

MIC (mg/mL)

<= 4.0 8.0 >=16.0

Interpretation

Susceptible (S) Intermediate (I) Resistant (R)

b

This interpretive standard is applicable to test performed on Haemophilus Test Medium (HTM) broth incubated at 35degC in ambient air for 20 to 24 hours.

A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in 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 pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected. Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard telithromycin powder should provide the following MIC values:

MIC Values of Telithromycin with Control Microorganisms

cThis quality control range is applicable to only S. pneumoniae ATCC 49619 tested on cation- adjusted Mueller-Hinton broth with 2-5% lysed-horse blood (LHB) incubated at 35degC in ambient air for 20-24 hours. dThis quality control range is applicable to only H. influenzae ATCC 49247 tested on Haemophilus Test Medium (HTM) broth incubated at 35degC in ambient air for 20 to 24 hours.

Diffusion techniques:

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 15 mg telithromycin to test the susceptibility of microorganisms to telithromycin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 15 mg telithromycin disk should be interpreted according to the following criteria: 2 National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Susceptibility Testing: Twelfth Informational Supplement; Approved Standard, NCCLS Document M2-A7 and M7-A5, Vol 21, No 1, NCCLS, Wayne, PA, January 2002. The following zone diameter interpretive criteria should be used for testing Staphylococcus aureus:

Zone diameter (mm)

>=22

Interpretation

Susceptible (S)

For testing Streptococcus pneumoniaee:

Zone diameter (mm)

>=19 16-18 <=15

Interpretation

Susceptible (S) Intermediate (I) Resistant (R)

eThis interpretive standard is applicable to test performed on Mueller-Hinton agar with 5% sheep blood and incubated in 5% CO2. For testing Haemophilus influenzaef (irrespective of b-lactamase production):

Zone diameter (mm)

>= 15 12-14

Interpretation

Susceptible (S) Intermediate (I) Resistant (R)

fThis interpretive standard is applicable to test performed on HTM agar and incubated in 5% CO2. Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for telithromycin. As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 15 mg telithromycin disk should provide the following zone diameters in these laboratory test quality control strains:

Zone Diameters Using 15 mg Telithromycin Disk and Control Microorganisms

gThese quality control limits are applicable to only S. pneumoniae ATCC 49619 tested on Mueller-Hinton agar with 5% sheep blood and incubated in 5% CO2. hThese quality control limits are applicable to only H. influenzae ATCC 49247 tested on HTM agar and incubated in 5% CO2.

TOXICOLOGY

Acute Toxicity Studies

The results of the acute toxicity studies are outlined in the following tables.

Multidose Toxicity Studies

The results of the multidose toxicity studies are outlined in the following tables.

Carcinogenicity Studies

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

Mutagenicity Studies

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

Reproduction and Teratology

A study to investigate possible effects on fertility and early embryonic development was carried out in the rat at doses of 0, 50, 150, 300 mg/kg/day. No evidence of impaired fertility was observed at doses estimated to be 3.8 times (50 mg/kg/day) the daily human dose of 800 mg. Slight reductions in fertility indices were seen in rats at parentally toxic doses higher than 150 mg/kg.

Teratogenic Effects:

Telithromycin was not teratogenic in the rat or rabbit. Reproduction studies have been performed in the rat (doses of 0, 50, 150, 300 mg/kg/day), and rabbit (doses of 0, 20, 60, 180 mg/kg/day), with effects on pre/post natal development studied in the rat (doses of 0, 50, 125, 200 mg/kg/day). At doses estimated to be 11.5 times (150 mg/kg) and 1.5 times (20 mg/kg) the daily human dose of 800 mg in the rat and rabbit, respectively, no evidence of fetal harm was observed. At doses higher than 150 mg/kg and 20 mg/kg in rats and rabbits, respectively, maternal toxicity resulted in delayed fetal maturation. No adverse effects on prenatal and neonatal development of rat pups was observed at 9.6 times (125 mg/kg/day) the daily human dose.

Other toxicity

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 in all 3 test species, and histological evidence of damage in rats. In addition, phospholipidosis-associated changes were seen in the rat and dog. All these effects showed a tendency to regress after cessation of treatment. Plasma exposures based on free fraction of drug, at the no observed adverse effect levels ranged from 0.16 to 9.5 times the expected clinical exposure. Pharmacology studies showed an effect in prolonging both QTc in dogs and on action potential duration in rabbit Purkinje fibres in vitro. These effects were observed at concentrations of free drug 8 to 13 times those circulating in clinical use.

-S9: without metabolic activation system

+S9: with metabolic activation system (prepared from liver microsomal fraction (S9 fraction))

REFERENCES

1. Arpin C, Canron MH, Maugein J, Quentin C. Incidence of mefA and mefE genes in viridans group streptococci. Antimicrob Agents Chemother 1999; 43(9):2335-6.

2. Barry AL, Fuchs PC, Brown SD. Antipneumococcal activity of a ketolide (HMR3647), a streptogramin (quinupristine-dalfopristin, a macrolide (erythromycin) and a lincosamide (clindamycin). Antimicrob Agents Chemother 1998; 42(4):945-6.

3. Barry AL, Fuchs PC, Brown SD. In vitro activities of the ketolide HMR 3647 against recent Gram-positive clinical isolates and Haemophilus influenzae. Antimicrob Agents Chemother 1998; 42(8):2138-40.

4. Boswell FJ, Andrews JM, Ashby JP, Fogarty C, Brenwald NP, Wise R. The in vitro activity of HMR 3647, a new ketolide antimicrobial agent. J Antimicrob Chemother 1998; 42(6):703-9.

5. Canu A, Malbruny B, Coquemont M, Davies TA, Appelbaum PC, Leclercq R. Diversity of ribosomal mutations conferring resistance to macrolides, clindamycin, streptogramin, and telithromycin in S. pneumoniae. Antimicrob Agents Chemother 2002; 46:125-31.

6. Carbon C, Moola S, Velancsics I, Leroy B, Rangaraju M, Decosta P. Telithromycin 800 mg once daily for seven to ten days in an effective and well-tolerated treatment for community-acquired pneumonia. Clin Microbiol Infect 2003; 9(7):691-703 (Study 3000).

7. Carbon C. A pooled analysis of telithromycin in the treatment of community-acquired respiratory tract infections in adults. Infection 2003; 31(5):308-317. (Studies 3000-3009, 3009OL).

8. Dunbar LM, Hassman J, Tellier G. Efficacy and tolerability of once-daily oral telithromycin compared with clarithromycin for the treatment of community-acquired pneumonia in adults. Clinical Therapeutics 2004; 26(1): 48-62 (Study 3006).

9. Edlund C, Alvan G, Barkholt L, Vacheron F, Nord CE. Pharmacokinetics and comparative effects of telithromycin (HMR 3647) and clarithromycin on the oropharyngeal and intestinal microflora. JAntimicrob Chemother 2000; 46:741-9.

10. Goldstein EJC, Citron DM, Merriam CV, Warren Y, Tyrrell K. Activities of telithromycin (HMR 3647, RU 66647) compared to those of erythromycin, azithromycin, clarithromycin, roxithromycin, and other antimicrobial agents against unusual anaerobes. Antimicrob Agents Chemother 1999; 43(11):2801-5.

11. Hagberg L, Torres A, Van Rensburg D, Leroy B, Rangaraju M, Ruuth E. Efficacy and tolerability of once-daily therapy with telithromycin compared with high-dose amoxicillin for the treatment of community-acquired pneumonia. Infection 2002 30(6):378-386 (Study 3001).

12. Jones RN, Biedenbach DJ. Antimicrobial activity of RU-66647, a new ketolide. Diagn Microbiol Infect Dis 1997; 27:7-12.

13. Pankuch GA, Hoellman DB, Lin G, Bajaksouzian S, Jacobs MR, Appelbaum PC. Activity of HMR 3647 compared to those of five agents against Haemophilis influenzae and Moraxella catarrhalis by MIC determination and time-kill assay. Antimicrob Agent Chemother 1998; 42(11):3032-4.

14. Performance Standards, for Antimicrobial Susceptibility Testing: Twelfth Informational Supplement; Approved Standard NCCLS Document M2-A7 and M7-A5, Vol 21, No 1, NCCLS, Wayne, PA, January 2002.

15. Piper KE, Rouse MS, Steckelberg JM, Wilson WR, Patel R. Ketolide Treatment of Haemophilus influenzae Experimental Pneumonia. Antimicrob Agent Chemother 1999; 43(3):708.

16. Pullman J, Champlin J, Vrooman P. Efficacy and tolerability of once-daily oral therapy with telithromycin compared with trovafloxacin for the treatment of community-acquired pneumonia in adults. Int J Clin Practice 2003; 57(5):377-384 (Study 3009).

17. Tellier, G, Chang, J, Asche, C, Lavin, B, Stewart, J, Sullivan, S. Comparison of hospitalization rates in patients with community-acquired pneumonia treated with telithromycin for 5 or 7 days or clarithromycin for 10 days. Current Medical Research & Opinion 2004; 20 (5):739-47 (Study 4003).

18. Van Rensburg, DJ, Matthews, PA, Leroy, B. Efficacy and safety of telithromycin in community-acquired pneumonia. Current Medical Research & Opinion 2002; 18(7):397-

400. (Study 3009OL).

IMPORTANT: PLEASE READ

PART III: CONSUMER INFORMATION

Pr KETEK(r)

(telithromycin film-coated tablets, 400 mg)

This leaflet is part III of a three-part "Product Monograph" published when the drug is approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about KETEK(r). Contact your doctor or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

The following bacterial infections can be treated by KETEK(r):

Mild to moderate pneumonia (patients of 18 years old and over)

What it does

KETEK(r) is used to kill the bacteria or "germs" which cause infections. You may begin to feel better quickly; however, in order to make sure that all the bacteria are killed, you should complete the full course of medication. KETEK(r), like other antibiotics, does not kill viruses.

When it should not be used:

Do not take KETEK(r) if you have a muscular disease known as myasthenia gravis. Worsening

of myasthenia gravis symptoms including life-

threatening breathing problems have happened in patients with myasthenia gravis after taking KETEK(r) in some cases leading to death.

You have had an allergic reaction to telithromycin and/or any components of KETEK(r) tablets (see What the nonmedicinal ingredients are), or to any macrolide antibiotic, such as erythromycin, azithromycin (Zithromax), or clarithromycin (Biaxin).

You are using any of the following drugs: astemizole, cisapride, ergot alkaloids (i.e. dihydroergotamine, ergotamine), pimozide (also called Orap), terfenadine. (Astemizole, terfenadine and cisapride are no longer marketed in Canada.)

You have a history of liver problems (e.g. hepatitis and/or jaundice (yellow colour to the skin and/or eyes)) associated with taking KETEK(r) or any macrolide antibiotic.

What the medicinal ingredient is:

KETEK(r) contains telithromycin and it belongs to a new family of antibiotics called ketolides.

Reduced size tablet (New formulation without lactose and corn starch)

Coloring agents (red iron oxide, yellow iron oxide), croscarmellose sodium, hydroxypropyl

methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol,

povidone, talc, and titanium dioxide.

What dosage forms it comes in

: Reduced size tablets: 400 mg

WARNINGS AND PRECAUTIONS

KETEK(r) may cause fainting (especially if you are already experiencing severe nausea, vomiting, and/or light-headedness) and visual problems such as blurred vision, trouble focussing and double vision. If these symptoms occur, avoid driving, operating machinery, or engaging in hazardous activities. Do not take your next dose until you call your doctor or go to a clinic.

BEFORE using KETEK(r), tell your doctor if any of the following applies to you and discuss with your doctor if:

You have ever had a severe allergic reaction to any of the group of antibiotics known as "macrolides" such as erythromycin, azithromycin (Zithromax), or clarithromycin (Biaxin).

You have a rare heart condition that results in the lengthening of the heartbeat on an ECG test (congenital QTc interval prolongation) or you are related by blood to someone who has this condition.

You have fainted or had an irregular heart beat after taking any medication.

You have low blood potassium (hypokalemia) or low blood magnesium (hypomagnesemia).

You have heart, kidney, liver or other disease.

You have ever had jaundice (yellowing of the skin and eyes, dark urine while taking Ketek.

You are using any other prescription or nonprescription medications.

You are pregnant, planning to become pregnant or nursing your baby.

MEDICATION INTERACTIONS

It is important to let your doctor and your pharmacist know about all the medicines you are taking including those obtained without a prescription.

In addition to the medications listed above under "When it should not be used", drugs that may interact with KETEK(r) include:

• Alprazolam

• Antiarrythmic drugs (a drug for the treatment of irregular heartbeats, such as procainamide quinidine, amiodaron, sotalol)

• Anticoagulants (a drug that reduces clot formation in the blood) such as warfarin (Coumadin)

• Carbamazepine

• Cholesterol-lowering medications: simvastatin (Zocor), lovastatin (Mevacor) and atorvastatin (Lipitor)

• Digoxin

• Metoprolol for heart failure (Betaloc or Lopressor)

• Midazolam

• Phenobarbital

• Phenytoin

• Rifampin

If you are not sure how many tablets to take, or how often to take them, or for how long, consult your doctor or pharmacist. Do not increase the dose of KETEK(r) unless your doctor tells you to do so.

Do not share KETEK(r) with other people, even if they have the same symptoms that you have. It may harm them.

Overdose:

In case of overdosage, contact your doctor or nearest hospital immediately. If possible, take your tablets or the box with you to show the doctor.

Missed Dose:

If a dose of this medication is missed, it should be taken as soon as possible. This will help to keep a constant amount of medication in the blood.

However, if it is almost time for the next dose, skip

the missed dose and go back to the regular dosing schedule. Do not take more than one dose of

(r)

St. John's Wort

KETEK

in a 24-hour period.

Triazolam

Do not take other medicines with KETEK(r) without first checking with your doctor. Your doctor will tell you if you can take other medicines with KETEK(r).

PROPER USE OF THIS MEDICATION

Usual dose:

The usual dose in patients with pneumonia and age 18 years and older is:

Two 400 mg tablets, taken together as one dose (that is 800 mg), once a day, for 7 to 10 days.

KETEK(r) may be taken with or without food. However, it is best if you take it at the same time each day. Your doctor may suggest that you take this medication at bedtime, to avoid potential side effects such as visual disturbances or fainting.

KETEK(r) has a bitter taste, therefore, do not chew or crush the tablets but swallow each one whole with a glass of water.

The length of treatment is 7 to 10 days. You may begin to feel better quickly; however, in order to make sure that all bacteria are killed, you should complete the full course of medication. If your symptoms do not improve within a few days, or if they become worse, check with your doctor.

If you have a severe kidney disease you should talk to your doctor because the dose you need may be different.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

The most common side effect that may occur with KETEK(r) is diarrhea, which is usually mild and goes away on its own.

KETEK(r) may cause unwanted effects such as visual disturbances, including blurred vision, trouble focusing and double vision, which may affect your daily activities. Problems with vision were usually mild to moderate and occurred at any dose, mostly after the first or second dose. These reversible problems may last for a few hours, may recur at any time, and usually disappear at the end of treatment. If you experience these visual symptoms consideration should be given to not driving a vehicle or operating machinery. If visual problems do affect your daily activities you should tell your doctor and consider taking KETEK(r) at bedtime.

If you experience fainting and vision problems do not take your next dose of KETEK(r) until you call your doctor or go to a clinic.

If you develop vaginitis (a vaginal infection associated with local itching, burning and white discharge) you may wish to consult your health professional.

Other side effects, which may occur with KETEK(r) are nausea, vomiting, headaches, stomach pain, flatulence (excess wind), dizziness and disturbances

of taste. Side effects usually disappear after the end of treatment.

If you have other side effects not mentioned in this section or have concerns about side effects be sure to tell your health professional.

If you feel worse or have taken all the tablets and do not feel better tell your doctor as soon as possible.

SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEM

Severe liver damage, in some cases leading to a liver transplant or death has happened in patients treated with KETEK(r). Severe liver damage has happened during treatment, even after a few doses, or right after treatment with KETEK(r) has ended. You should stop treatment with KETEK(r) and contact your doctor immediately if signs and symptoms of liver disease develop such as loss of appetite, nausea, fatigue, jaundice (yellow colour to the skin and/or eyes), dark urine, light-coloured stools, generalised itching or abdominal pain. Do not take your next dose of KETEK(r) until you call your doctor or go to a clinic.

If you think you are having an allergic reaction or if you have a skin reaction such as itching, swelling or red spots and blisters, stop taking KETEK(r) and call your doctor or go to a clinic.

If you experience fainting, irregular heartbeat or vision problems do not take your next dose of KETEK(r) until you call your doctor or go to a clinic.

If you have severe diarrhea (prolonged or bloody), call your doctor. If you still have tablets left, do not take any more unless your doctor tells you so.

This is not a complete list of side effects. If you have any unexpected effects while taking this drug, contact your doctor or pharmacist.

HOW TO STORE IT

Keep your tablets in a safe place where children cannot reach them.

KETEK(r) should be stored at room temperature (15 to 30degC) in a tightly closed container away from heat and direct light. Do not use the tablets in this package after the expiry date shown on the container label.

If your doctor decides to stop the treatment, do not keep any leftover medicine unless your doctor tells you to. Please discard all unused KETEK(r) tablets.

REPORTING SUSPECTED SIDE EFFECTS

NOTE: THIS IS NOT AN EMERGENCY NUMBER

To monitor drug safety, Health Canada through the Canada Vigilance Program collects information on serious and unexpected side effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Canada Vigilance:

By toll-free telephone: 866-234-2345 By toll-free fax: 866-678-6789

Online: www.healthcanada.gc.ca/medeffect By email: CanadaVigilance @hc-sc.gc.ca

By regular mail:

Canada Vigilance National Office Marketed Health Products Safety and Effectiveness Information Division Marketed Health Products Directorate Health Products and Food Branch Health Canada

Tunney's Pasture, AL 0701C Ottawa ON K1A 0K9

NOTE: Before contacting Canada Vigilance, you should contact your physician or pharmacist. The Canada Vigilance Program does not provide medical advice.

MORE INFORMATION

This document plus the full product monograph, prepared for health professionals, can be obtained by contacting the sponsor at: http://www.sanofi- aventis.ca or by contacting the sponsor, sanofi-aventis Canada Inc. at:

sanofi-aventis Canada Inc. 2150 St. Elzear Blvd. West Laval, Quebec

H7L 4A8

Telephone: 1-800-265-7927

This leaflet was prepared by: sanofi-aventis Canada Inc.

Last revised: August 20, 2008