FDA label 109d7894-b6d1-4e04-9e5a-76e7e6b1f9c8

WARNING: CONTRAINDICATION IN MYASTHENIA GRAVIS There have been reports of fatal and life-threatening respiratory failure in patients with myasthenia gravis associated with the use of KETEK. [see Contraindications (4.1) ] WARNING: CONTRAINDICATION IN MYASTHENIA GRAVIS See full prescribing information for complete boxed warning Fatal and life-threatening respiratory failure has been reported in patients with myasthenia gravis associated with use of KETEK ( 4.1 )

5 WARNINGS AND PRECAUTIONS Hepatotoxicity : Fatal acute liver injury has been reported. Discontinue immediately if signs and symptoms of hepatitis occur. ( 5.1 ) Prolongation of QTc interval : Increased risk for ventricular arrhythmias, including ventricular tachycardia and torsade de pointes with fatal outcomes. Avoid use in patients with known QTc prolongation, hypokalemia, and with class IA and III antiarrhythmics. ( 5.2 ) Visual disturbances and loss of consciousness : KETEK may impair accommodation. Avoid driving or other hazardous activity. ( 5.3 ) Serious Adverse Reactions with Concomitant Drugs: Fatalities with colchicine, rhabdomyolysis with HMG-CoA reductase inhibitors, and hypotension with calcium channel blockers have been reported. Avoid concomitant use. Monitor for toxicity and consider dose reduction of the concomitant medication, if concomitant use is unavoidable ( 5.4 , 7 ) Clostridium difficile -associated diarrhea : evaluate if diarrhea occurs. ( 5.5 ) 5.1 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 . Physicians and patients should monitor for the appearance of signs or symptoms of hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, alcoholic 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 . If clinical hepatitis or transaminase elevations combined with other systemic symptoms occur, KETEK should be permanently discontinued. KETEK is contraindicated in patients with a previous history of hepatitis and/or jaundice associated with the use of KETEK tablets, or any macrolide antibacterial. [see Contraindications (4.2) ] 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. 5.2 QTc Prolongation KETEK can prolong the QTc interval of the electrocardiogram in some patients leading to an increased risk for ventricular arrhythmias, including ventricular tachycardia and torsades de pointes with fatal outcomes. Thus, KETEK 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 ventricular arrhythmias (including ventricular tachycardia and torsades de pointes) have been reported post-marketing with KETEK and sometimes occurred within a few hours of the first dose . In clinical trials, no cardiovascular morbidity or mortality attributable to QTc prolongation occurred with KETEK treatment in 4780 patients, including 204 patients having a prolonged QTc at baseline. 5.3 Visual Disturbances and Loss of Consciousness KETEK may cause visual disturbances particularly in slowing the ability to accommodate and the ability to release accommodation. Visual disturbances, some of them severe, included blurred vision, difficulty focusing, and diplopia. [see Adverse Reactions (6.1) ] There have been post-marketing 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 . 5.4 Serious Adverse Reactions with Concomitant Drugs Serious adverse reactions have been reported in patients taking KETEK concomitantly with CYP3A4 substrates [see Drug Interactions (7) ] : Colchicine: colchicine toxicity Simvastatin, lovastatin, and atorvastatin: rhabdomyolysis Calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem): hypotension Colchicine Toxicity Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and strong CYP3A4 inhibitors. KETEK is a strong CYP3A4 inhibitor and this interaction may occur while using both drugs at their recommended dosages. If co-administration of KETEK and colchicine is necessary in patients with normal renal and hepatic function, reduce the dosage of colchicine. Monitor patients for clinical symptoms of colchicine toxicity. Concomitant administration of KETEK and colchicine is contraindicated in patients with renal or hepatic impairment. [see Contraindications (4.5) ; Drug Interactions (7) ] Rhabdomyolysis Simvastatin, lovastatin and atorvastatin are metabolized by CYP3A4. High levels of HMG-CoA reductase inhibitors increase the risk of myopathy and rhabdomyolysis. Avoid use of statins which are metabolized by CYP3A4 concomitantly with KETEK; suspend therapy with simvastatin, lovastatin, or atorvastatin during the course of treatment with KETEK. [see Drug Interactions (7) ] Hypotension Hypotension, bradyarrhythmia and loss of consciousness have been observed in patients receiving concomitant treatment with calcium channel blockers that are substrates of CYP3A4 (e.g., verapamil, amlodipine, diltiazem). Monitor for these adverse reactions and toxicity related to calcium channel blockers and adjust calcium channel blocker dosage as necessary. [see Drug Interactions (7) ] 5.5 Clostridum difficile -Associated Diarrhea 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 antibacterial 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 antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. 5.6 Development of Drug Resistant Bacteria Prescribing KETEK in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

6 ADVERSE REACTIONS The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling: Myasthenia gravis [see Contraindications (4.1) ] Hepatotoxicity [see Warnings and Precautions (5.1) ] QTc prolongation [see Warnings and Precautions (5.2) ] Visual disturbances and loss of consciousness [see Warnings and Precautions (5.3) ] Clostridium difficile -associated diarrhea [see Warnings and Precautions (5.5) ] The most common adverse reactions (2% or greater) are diarrhea, nausea, dizziness, and vomiting ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis U.S. LLC at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In Phase 3 clinical trials, 4,780 patients (n=2702 in controlled trials) received oral dosages of KETEK 800 mg once daily for 5 days or 7 to 10 days. Note that treatment with KETEK for 5 days duration is not a recommended dosage regimen. [see Dosage and Administration (2.1) ] In the combined Phase 3 studies, discontinuation due to adverse reactions 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 adverse reactions in the gastrointestinal body system, primarily diarrhea (0.9% for KETEK vs. 0.7% for comparators), and nausea (0.7% for KETEK vs. 0.5% for comparators). Adverse reactions (ARs) occurring in clinical studies in 2% or more of KETEK patients are included below. Table 1. Adverse Reactions Reported in 2% or more of Patients in Controlled Phase 3 Clinical Studies Adverse Reaction Based on a frequency of all and possibly related adverse reactions of 2% or more in KETEK or comparator groups. Percent Incidence KETEK n= 2702 Comparator Includes comparators from all controlled Phase 3 studies. n= 2139 Diarrhea 10% 8% Nausea 7% 4.1% Dizziness (excl. vertigo) 2.8% 1.5% Vomiting 2.4% 1.4% Less Common Adverse Reactions Frequency of 0.2% or more and less than 2% The following adverse reactions were observed at a frequency of 0.2% or more and less than 2% in KETEK-treated patients in clinical studies. Gastrointestinal system: abdominal distension, dyspepsia, gastrointestinal upset, flatulence, constipation, gastroenteritis, gastritis, anorexia, oral candidiasis, glossitis, stomatitis. Liver and biliary system: abnormal liver function tests: increased transaminases (i.e., ALT, AST). Hepatitis, with or without jaundice, occurred in 0.07% of patients treated with KETEK. [see Warnings and Precautions (5.1) ] Nervous system: dry mouth, somnolence, insomnia, vertigo, increased sweating Body as a whole: abdominal pain, fatigue Special senses: Visual adverse reactions, some of them severe, most often included blurred vision, diplopia, or difficulty focusing. Some patients discontinued therapy due to these adverse reactions. Visual adverse reactions were reported as having occurred after any dose during treatment, but most (65%) occurred following the first or second dose. Visual adverse reactions lasted several hours and recurred upon subsequent dosing in some patients. For patients who continued treatment, some visual adverse reactions resolved on therapy while others persisted through the full course of treatment. [see Warnings and Precautions (5.3) ] Females and patients under 40 years old experienced a higher incidence of KETEK-associated visual adverse reactions. Table 2 provides the incidence of all visual adverse reactions in controlled Phase 3 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 reactions similar to comparator-treated patients. Table 2. Incidence of All Visual Adverse Reactions in Controlled Phase 3 Studies Gender/Age Telithromycin Comparators Includes all comparators combined Female 40 and under 2.1% (14/682) 0.0% (0/534) Female greater than 40 1.0% (7/703) 0.35% (2/574) Male 40 and under 1.2% (7/563) 0.48% (2/417) Male greater than 40 0.27% (2/754) 0.33% (2/614) Total 1.1% (30/2702) 0.28% (6/2139) Urogenital system: vaginal candidiasis, vaginitis, vaginosis fungal Skin: rash Hematologic: increased platelet count Frequency of less than 0.2% Other clinically-significant adverse reactions occurring in less than 0.2% of patients treated with KETEK from the controlled Phase 3 studies included: anxiety, bradycardia, eczema, elevated blood bilirubin, erythema multiforme, flushing, hypotension, increased blood alkaline phosphatase, increased eosinophil count, paresthesia, pruritus, urticaria. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of KETEK. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Allergic: face edema, severe allergic (hypersensitivity) reactions, including angioedema and anaphylaxis Cardiovascular: atrial arrhythmias, ventricular arrhythmias (including ventricular tachycardia and torsades de pointes) with potential fatal outcome, palpitation, ischemic cardiac events in the context of hypersensitivity reactions [see Warnings and Precautions (5.2) ] Gastrointestinal system: pseudomembranous colitis, pancreatitis [see Warnings and Precautions (5.5 ] Liver and biliary system: Hepatic dysfunction, fulminant hepatitis, hepatic necrosis, and hepatic failure, chromaturia [see Contraindications (4.2) ; Warnings and Precautions (5.1) ] Musculoskeletal: muscle cramps, arthralgia, myalgia, exacerbation of myasthenia gravis [see Contraindications (4.1) ] Nervous system: loss of consciousness, in some cases associated with vagal syndrome, tremor, convulsions Psychiatric disorders: confusion, hallucinations (mostly visual) Special senses: taste/smell perversion and/or loss, hearing loss Respiratory, thoracic and mediastinal disorders: dyspnea

<table width="75%" ID="table1"> <caption>Table 1. Adverse Reactions Reported in 2% or more of Patients in Controlled Phase 3 Clinical Studies </caption> <col width="50%" align="left" valign="top"/> <col width="25%" align="center" valign="top"/> <col width="25%" align="center" valign="top"/> <thead> <tr styleCode="Botrule"> <th styleCode="Lrule Rrule">Adverse Reaction<footnote>Based on a frequency of all and possibly related adverse reactions of 2% or more in KETEK or comparator groups.</footnote> </th> <th styleCode="Rrule" colspan="2">Percent Incidence</th> </tr> <tr> <th styleCode="Lrule Rrule"/> <th styleCode="Rrule">KETEK n= 2702</th> <th styleCode="Rrule">Comparator<footnote>Includes comparators from all controlled Phase 3 studies.</footnote> n= 2139</th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Diarrhea</td> <td styleCode="Rrule">10%</td> <td styleCode="Rrule">8%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Nausea</td> <td styleCode="Rrule">7%</td> <td styleCode="Rrule">4.1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Dizziness (excl. vertigo)</td> <td styleCode="Rrule">2.8%</td> <td styleCode="Rrule">1.5%</td> </tr> <tr> <td styleCode="Lrule Rrule">Vomiting</td> <td styleCode="Rrule">2.4%</td> <td styleCode="Rrule">1.4%</td> </tr> </tbody> </table>

<table width="75%" ID="table2"> <caption>Table 2. Incidence of All Visual Adverse Reactions in Controlled Phase 3 Studies</caption> <col width="30%" align="left" valign="top"/> <col width="33%" align="center" valign="top"/> <col width="37%" align="center" valign="top"/> <thead> <tr> <th styleCode="Lrule Rrule">Gender/Age</th> <th styleCode="Rrule">Telithromycin</th> <th styleCode="Rrule">Comparators<footnote>Includes all comparators combined</footnote> </th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Female 40 and under</content> </td> <td styleCode="Rrule">2.1% (14/682)</td> <td styleCode="Rrule">0.0% (0/534)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Female greater than 40</content> </td> <td styleCode="Rrule">1.0% (7/703)</td> <td styleCode="Rrule">0.35% (2/574)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Male 40 and under</content> </td> <td styleCode="Rrule">1.2% (7/563)</td> <td styleCode="Rrule">0.48% (2/417)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Male greater than 40</content> </td> <td styleCode="Rrule">0.27% (2/754)</td> <td styleCode="Rrule">0.33% (2/614)</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold">Total</content> </td> <td styleCode="Rrule">1.1% (30/2702)</td> <td styleCode="Rrule">0.28% (6/2139)</td> </tr> </tbody> </table>