Patient safety is our highest priority at sanofi-aventis, and our thousands of employees are dedicated to discovering, developing, and distributing pharmaceutical products designed to improve human health and alleviate the burden of illness.  In that regard, we are steadfast in our commitment to conducting rigorous, ethical, and compliant clinical trials.  We take our ethical and regulatory responsibilities very seriously in all our actions, and we take pride in the fact that our company manufactures and distributes life-saving drugs.
 
Certain recent reports relating to the conduct of one clinical study (Study 3014) for the antibiotic Ketek suggest or imply wrongful conduct on the part of one of our predecessor companies, Aventis.  We strongly object to any such characterizations, which are not based on the facts.  Study 3014 was the first large, comparative study in the usual care setting conducted prior to FDA approval.  Aventis consulted with the FDA and outside experts in designing Study 3014, and the company engaged a clinical research organization, PPD Development LLC. (PPD), which had significant experience in monitoring large clinical studies.  The study was conducted at over 1800 study sites across the United States, and enrolled over 24,000 patients during a single winter season.
 
Good clinical practice (GCP) violations were noted during the course of the study at a number of the independent clinical study sites, including certain high-enrolling sites.  In addition, investigator fraud was identified at one of those sites after the study data had been submitted by Aventis to the FDA.  As a result of these data integrity issues, the FDA ultimately decided not to rely on Study 3014 as a basis for approval, and data from Study 3014 were not included or referenced in the Ketek labeling in the U.S.  Aventis respects the FDA’s decision.
 
We regret the GCP violations at external study sites, and the case of fraud by the one external investigator that occurred during Study 3014.  However, Aventis was not aware of the fraud until after it had submitted Study 3014 to the FDA.  It was only after FDA criminal investigators conducted an evaluation, having tools at their disposal that may not be available to study sponsors, that the fraud was discovered.  As stated by the former FDA Director of the Division of Scientific Investigations at FDA at the FDA Joint Advisory Committee meeting held in December 2006 to review Ketek, "In my experience, even when fraud exists, monitors often don't find it.  Even when serious [problems] exist, monitors often don't find it."  The former Director also stated that "… there were problems definitely identified. But, considering the nature of the trial and the extent of the problem, we did not see direct evidence that this information was ignored by the company."
 
Although Study 3014 was ultimately deemed compromised because of GCP deviations and fraud by one of the independent investigators, a substantial body of other data continue to support the efficacy and safety of Ketek for its labeled indication, and the product has been the subject of exhaustive review by the FDA and expert advisors. Sanofi-aventis continues to believe that Ketek is safe and effective for its labeled indication, which is supported by the recommendations of the FDA Joint Advisory Committee in December 2006.
 
Sanofi-aventis shares the public interest in excluding unethical investigators from participation in clinical research. We have cooperated fully in all investigations regarding this matter, and take our ethical and regulatory obligations seriously.
 
Indications and Important Safety Information

Ketek is contraindicated in patients with myasthenia gravis. There have been reports of fatal and life-threatening respiratory failure in patients with myasthenia gravis associated with the use of Ketek.

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 [MDRSP*]), Haemophilus influenzae, Moraxella catarrhalis, Chlamydophila pneumoniae, or Mycoplasma pneumoniae, for patients 18 years old and above.
 
*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.
 
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.
 
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, 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.  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. 
 
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. 
 
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.
 
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.
 
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. 
 
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.
 
Therapy with simvastatin, lovastatin, or atorvastatin should be suspended during the course of KETEK treatment. Concomitant treatment of KETEK with rifampin, a CYP 3A4 inducer, should be avoided.
 
Most adverse events were mild to moderate and included diarrhea, nausea, headache, dizziness, and vomiting. 
 
 
US.TEL.07.01.070