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Sanofi-Aventis Announces Update to Ketek (Telithromycin) U.S. Prescribing Information

BRIDGEWATER, NJ -- June 30, 2006 -- Sanofi-aventis today announced that the U.S. prescribing information for its antibiotic Ketek(R) (telithromycin) has been revised after discussion with the U.S. Food and Drug Administration (FDA) to provide healthcare professionals and patients with updated information about adverse events reported in connection with the use of the product.

The revised prescribing information contains a bolded warning and additional information relating to the nature and characterization of hepatic events, as well as revised recommendations for the use of Ketek in patients with myasthenia gravis. These changes have been reviewed and agreed to by the FDA.

"This update is based on a rigorous analysis of the available data, including consultation with leading experts to ensure that we had the most informed understanding possible with respect to hepatic and myasthenia gravis adverse events. Based on the in-depth review of the clinical trial and post- marketing data, we continue to believe that the benefits of Ketek outweigh the risks when the drug is used as directed for its approved indications," said Sol Rajfer MD, President of U.S. Science and Medical Affairs at sanofi-aventis U.S.

Over the past 10 years infectious disease experts and medical societies throughout the world have expressed the need for new compounds active against antibiotic drug resistant S. pneumoniae. Ketek is effective and safe when used as directed for its approved indications in the treatment of acute bacterial exacerbation of chronic bronchitis (AECB), acute bacterial sinusitis (ABS), and mild to moderate community-acquired pneumonia (CAP) caused by susceptible pathogens.

Ketek is indicated for the treatment of mild to moderate CAP caused by multi-drug resistant S. pneumoniae (MDRSP).

Earlier this month, sanofi-aventis voluntarily paused enrollment of its Ketek pediatric clinical trials. This pause is to allow the company to confirm that the current program remains consistent with the FDA's current thinking on the design of pediatric trials. It is important to note that no safety reason has been identified to warrant the pause in the enrollment of the pediatric clinical trials.

Ketek has been available in the U.S. since 2004, where sales in the first half of 2006 are estimated to be 50 million dollars.

Additional Information
In the U.S., sanofi-aventis is taking several steps to inform healthcare professionals about the revisions to the U.S. prescribing information, including a "Dear Healthcare Professional" letter, sales force educational communications to healthcare professionals and the posting of package insert information for patients on the company and product Web sites.

About Ketek(R) (telithromycin) tablets
Ketek is the first in a new class of antibiotics known as ketolides. Ketek tablets are indicated for the treatment of infections caused by susceptible strains of the designated microorganisms in the conditions listed below for patients 18 years old and above.

- Acute bacterial exacerbation of chronic bronchitis due to Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis.

- Acute bacterial sinusitis due to Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, or Staphylococcus aureus.

- 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.

*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 a history of hypersensitivity to telithromycin and/or any components of Ketek tablets, or any macrolide antibiotic.

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

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.

Telithromycin should not be used in patients with myasthenia gravis unless no other therapeutic alternatives are available. Exacerbations of myasthenia gravis have been reported in patients with myasthenia gravis treated with telithromycin. Reports have included death and life-threatening acute respiratory failure with a rapid onset in patients with myasthenia gravis treated for respiratory tract infections with telithromycin.

Concomitant administration of Ketek with cisapride or pimozide is contraindicated.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including telithromycin, and may range in severity from mild to life- threatening.

Ketek 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, Ketek should be avoided in patients with congenital prolongation of the QTc interval, and in patients with ongoing proarrythmic 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., dofetelide) antiarrthythmic agents.

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.

There have been post marketing adverse event reports of syncope. Patients should be cautioned about the potential effects of visual disturbance and syncope on driving or engaging in potentially hazardous activities.

Use of simvastatin, lovastatin, or atorvastatin concomitantly with Ketek should be avoided. If Ketek is prescribed, therapy with simvastatin, lovastatin, or atorvastatin should be suspended during the course of treatment. 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.


SOURCE: sanofi-aventis

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