Questions and Answers on Telithromycin (marketed as Ketek)
July 5, 2006  

 1. What is telithromycin?

Telithromycin is an FDA approved antibiotic drug, which belongs to the ketolide class, marketed in the U.S. by Sanofi-Aventis under the brand name Ketek. Telithromycin was approved in the U.S., in April 2004.

2. What is Ketek (telithromycin) used to treat?

Ketek (telithromycin) is indicated for the treatment of the following types of bacterial infections: community-acquired pneumonia (including multi-drug resistant Streptococcus pneumoniae), acute bacterial sinusitis, and acute bacterial exacerbation of chronic bronchitis.

3. What actions were taken by FDA on June 29, 2006? 

FDA approved a labeling supplement submitted by Sanofi-Aventis as a “Changes Being Effected” (CBE) supplement, which highlights the WARNINGS section of the labeling to raise attention to the risk of liver toxicity associated with Ketek and strengthen the WARNINGS for patients with myasthenia gravis.

4. What is a “Changes Being Effected” (CBE) supplement?

A CBE is a mechanism available under FDA regulations to allow a company and FDA to promptly address an important safety issue.  This process allows a firm and FDA to expedite the review, approval process, and distribution for revised prescribing information when safety issues arise. A labeling supplement can be submitted to the FDA as a CBE for the following reasons.

1. to add or strengthen a contraindication, warning, precaution, or adverse reaction;
2. to add or strengthen a statement about drug abuse, dependence, psychological effect, or overdosage;
3. to add or strengthen an instruction about dosage and administration that is intended to increase the safe use of the drug product;
4. to delete false, misleading, or unsupported indications for use or claims for effectiveness; or
5. any labeling change normally requiring a supplement submission and approval prior to distribution of the drug product that FDA specifically requests be submitted under this provision.

5. What is the significance of this action?

The new labeling information is based on a review of safety data relating to hepatic adverse event reports.  This labeling supplement or CBE—“Changes Being Effected"— highlights the WARNINGS section of the labeling to raise attention to the risk of liver toxicity associated with Ketek and strengthen the WARNINGS for patients with myasthenia gravis. It also provides enhanced safety information for health practitioners and patients.

6. Why did FDA take this action?

FDA determined that these updates to the labeling were necessary based on the agency’s safety review and assessment of the drug.

7. Why is FDA revising the labeling and keeping this drug on the market instead of withdrawing the drug from the market?

When new, unanticipated risks are detected after approval, an FDA review team (consisting of medical doctors, statisticians, safety evaluators, epidemiologists, and other experts) carefully evaluates the information provided by the sponsor and/or the information gathered from the postmarketing surveillance program.   As part of its review the FDA must assess the severity and frequency of the adverse event and reach a determination regarding the benefit/risk profile of the drug.  No drug is absolutely safe. All drugs have side effects. When FDA determines that a drug is safe and effective "Safe" means that the benefits of the drug appear to outweigh the risks when used as directed in the FDA approved labeling. For Ketek, the FDA continues to believe that the benefits of the drug outweigh the risks when used appropriately and that the benefit/risk profile for Ketek is similar to that of other approved antibiotic drugs used to treat the same types of infections.  FDA will continue to monitor reports of adverse events with Ketek and will take appropriate additional regulatory actions if new information leads to a different conclusion about Ketek’s benefit/risk profile.

8. What should patients do regarding this new information?

Patients who have been prescribed telithromycin and are not suffering side effects such as jaundice should continue taking their medicine as prescribed.

Patients who notice any yellowing of their eyes or skin or other problems like blurry vision should contact their healthcare providers.

9. What should healthcare providers do in response to this new information?

Healthcare providers should monitor patients taking telithromycin for signs or symptoms of liver problems. Telithromycin should be stopped in patients who develop signs or symptoms of liver problems. As with all antibiotics, telithromycin should only be used for infections by a susceptible microorganism; telithromycin is not effective on viral infections, so a patient with a viral infection who took telithromycin would be taking a risk without any benefit.

10. What information was known about liver problems related to telithromycin at the time of approval?

At the time of approval, the Ketek (telithromycin) product label included a precautionary statement advising doctors that hepatic adverse events (hepatic dysfunction, increased liver enzymes and hepatitis, with or without jaundice) had been reported with Ketek and that these events were generally reversible. This precaution was based upon the findings from the phase 3 clinical studies and postmarketing data from other countries.

11. How does FDA monitor the safety profile of a drug after it is approved?

Benefit and risk information emerges continually throughout a product’s lifecycle (i.e., during the investigational and marketing phases) and can reflect the results of both labeled and off-label uses.  Benefits and risks can result in a range of corresponding positive and negative effects on patient outcomes that may

1. be cosmetic, symptomatic, or curative;
2. alter the course of the disease; or
3. affect mortality

Benefits and risks are difficult to quantify and compare because they may apply to different individuals and are usually measured and valued differently.  Examples of factors to weigh are

1. population risks and benefits,
2. individual benefits from treatment,
3. risks of nontreatment or alternative products, and
4. modest population benefits in the context of a serious adverse effect that occurs rarely or unpredictably.

Benefits as well as risks are also patient-specific and are influenced by such factors as

1. the severity of the disease being treated,
2. the outcome of the disease if untreated,
3. the probability and magnitude of any treatment effect,
4. existing therapeutic options, and
5. the individual’s understanding of risks and benefits and the value they attach to each of them. 

Thus, assessment and comparison of a product’s benefits and risks is a complicated process that is influenced by a wide range of societal, healthcare, and individualized patient factors. 

Once a drug is approved for sale in the United States, CDER monitors the use of marketed drugs for unexpected health risks. Because premarket review can't catch all potential problems with a drug, the FDA continues to track approved drugs for adverse events through a postmarketing surveillance program. If new, unanticipated risks are detected after approval, CDER takes action to inform the public, change a drug's label, or even remove a product from the market. In addition to evaluating regular reports from manufacturers, the FDA's MedWatch program enables health care professionals and consumers to report suspected problems with their drugs.

12. What prompted this safety assessment?

FDA regularly monitors drug safety through its postmarketing adverse event reporting system (AERS).  In addition, a one year post-approval assessment was performed (June 2005).  At that time, the safety concerns regarding liver toxicity were consistent with those seen prior to approval, and consistent with the product labeling.

As with any drug, Ketek labeling contains known adverse events that are described in the product labeling, however after the one year post-approval assessment FDA was alerted to an increased rate of liver toxicity through AERS.  FDA promptly initiated another safety assessment which was recently completed and provides support for the action that FDA took on June 29, 2006. 

13. Did the Annals of Internal Medicine article prompt the FDA to do anything?

FDA was aware of the three reports described in the Annals of Internal Medicine. After online publication of the Annals article, FDA initiated its two-year review of Ketek safety information earlier than planned. The article also prompted the FDA to issue a Public Health Advisory (PHA) on January 20, 2006, which provided recommendations to the health care providers and patients while FDA was continuing its investigation of the issue. Based on preliminary safety information and reports of adverse events, the PHA included recommendations to physicians to monitor for signs and symptoms of liver disease or failure.

14. How will this drug continue to be monitored for adverse events?

FDA and Sanofi-Aventis will continue to monitor the safety profile of Ketek and FDA is advising physicians to closely monitor patients for signs of liver problems.

16. Do these actions have any impact on the pediatric studies that were ?paused? by the company?

No, not directly at this time. On June 7, 2006, the FDA was notified in writing that Sanofi-Aventis US will voluntarily pause enrollment in ongoing pediatric clinical trials.