Sanofi-Aventis Announces Update To U.S. Prescribing Information For Ketek(R) (Telithromycin)

Sanofi-aventis today announced that the U.S. Food and Drug Administration (FDA) has approved revisions to the US Prescribing Information for Ketek(R) (telithromycin).

These revisions follow discussions with the FDA and are based on recommendations of a FDA Joint Advisory Committee meeting of the Drug Safety and Risk Management Advisory Committee and Anti-infective Drug Advisory Committee held in December 2006. The revisions include:

- A boxed warning to alert physicians and patients that the use of the drug is contraindicated in patients with myasthenia gravis (a rare autoimmune disease),

- Updated warnings about possible visual disturbances and loss of consciousness (syncope).

- Deletion of the indications for acute exacerbation of chronic bronchitis (AECB) and acute bacterial sinusitis (ABS).

Ketek(R) remains indicated in patients with mild to moderate community- acquired pneumonia (CAP) caused by susceptible pathogens, including multidrug- resistant Streptococcus pneumoniae (MDRSP).

Ketek(R), when used as directed in its approved indication continues to be an important option in the anti-infective armamentarium and helps to satisfy a medical need.

Ketek(R) is currently approved and marketed in over 50 countries. Since its launch, it is estimated that 28 million patients have been treated with Ketek(R) worldwide.

MORE INFORMATION

In consultation with the FDA, sanofi-aventis has prepared a Medication Guide to be distributed to patients along with every prescription of Ketek. The Medication Guide communicates the rare but potentially serious adverse events associated with the use of Ketek.

In the U.S., sanofi-aventis will inform healthcare professionals about the revisions to the U.S. prescribing information through a "Dear Healthcare Professional" letter, sales force educational communications to healthcare professionals and the posting of the updated prescribing information and Medication Guide on the company and product Web sites (http://www.sanofi- aventis.us and http://www.Ketek.com).

Sanofi-aventis will also be contacting several patient organizations concerned with myasthenia gravis to ensure these parties have the most updated information regarding the label change of Ketek.

Additional information regarding the Medication Guide and update to the Ketek prescribing information can be found on the FDA Web site.

About Ketek

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.

About sanofi-aventis

Sanofi-aventis is one of the world's leading pharmaceutical companies. Backed by a world-class R&D organization, sanofi-aventis is developing leading positions in seven major therapeutic areas: cardiovascular, thrombosis, oncology, metabolic diseases, central nervous system, internal medicine and vaccines. Sanofi-aventis is listed in Paris (EURONEXT: SAN) and in New York (NYSE: SNY).

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