Ketek® (telithromycin) is the first in a new class of antibiotics known as ketolides and is indicated for the treatment of acute exacerbations of chronic bronchitis (AECB), acute bacterial sinusitis (ABS) and mild to moderate community-acquired pneumonia (CAP) due to susceptible pathogens*. Ketek is also indicated for treatment of mild to moderate CAP caused by multidrug-resistant Streptococcus pneumoniae (MDRSP)**. Ketek is approved for patients 18 years of age and above.
Prevalence and Consequences of Respiratory Tract Infections
Community-acquired respiratory tract infections (RTIs) are among the most frequent infectious diseases seen in outpatient doctor visits. RTIs caused by bacteria can be serious, and patients should consult with a doctor on the likelihood of bacterial infection and the need for an antibiotic. It is important to note that many RTIs are caused by viruses and are not treatable with antibiotics.
Community-acquired pneumonia (CAP) is an RTI of the lungs characterized by fever, cough, shortness of breath, chest pain or discomfort and is contracted in the community. S. pneumoniae is the most commonly identified bacterial pathogen in CAP. Approximately 5.6 million cases of CAP are diagnosed in the U.S. each year, with approximately 1.1 million requiring hospitalization. The cost of treating CAP is estimated at more than $8.4 billion with the incremental cost derived from hospital admission.
Annual costs associated with the management of acute exacerbations of chronic bronchitis (AECB) are estimated to exceed $2 billion in the U.S. Acute exacerbation of chronic bronchitis is a distinct event that is characterized by a period of unstable lung function with worsening airflow and other symptoms. AECB is often due to viral infection and does not always require antibiotics. However, antibiotics are one of the standard treatment regimens for patients with AECB who have increased cough, shortness of breath and increased production of mucus. It is estimated that 470,000 patients in the U.S. are hospitalized each year with a primary diagnosis of chronic bronchitis with bacterial or viral acute exacerbation. The average number of episodes of AECB per year for patients with chronic bronchitis is reported to range from 1.5 to three, putting a significant financial burden on the patient and the healthcare system for the cost of recurrent treatment.
Acute bacterial sinusitis (ABS) usually occurs as a complication from viral infections of the upper respiratory tract. These cases may need to be treated by a healthcare professional. Antibiotics are generally used to treat a sinus infection when signs and symptoms such as sinus tenderness, facial swelling or persistent fever are present for greater than five to 10 days.
Antibiotic Resistance and Treating RTIs
Community-acquired respiratory tract infections such as CAP and AECB account for a large proportion of visits to family practitioners. According to the U.S. Centers for Disease Control and Prevention (CDC), most infection-causing bacteria are becoming resistant to common antibiotics, making it harder to effectively treat patients with infections that can be life-threatening. In fact, the CDC has said that “the problem of antibiotic resistance has been called one of the world’s most pressing health problems,” and has identified it as one of its top concerns.
Antibiotic resistance is the inability of antimicrobial agents to be effective in vitro against bacterial strains that were once susceptible. Bacteria can mutate to become resistant to a particular antibiotic over time. Several classes of drugs have shown decreased antibacterial activity against S. pneumoniae, an important cause of CAP, AECB and ABS. In fact, across the U.S., it is estimated that 29 percent of S. pneumoniae isolates from patients with RTIs are resistant to multiple antibiotics.
Public Health Need
Over the past 10 years, infectious disease experts and medical societies in the U.S. have expressed the need for new treatments active against antibiotic drug resistant pathogens, including multidrug resistant S. pneumoniae. To help address this growing concern, Ketek was designed with a unique mechanism of action to overcome erythromycin resistance in S. pneumoniae isolates. Ketek delivers a targeted spectrum of activity in AECB, ABS and mild to moderate CAP. Ketek is also indicated for mild to moderate CAP caused by multi-drug resistant S. pneumoniae.
Findings from PROTEKT Global Year 5 (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) surveillance study, which was designed to track resistance of common bacterial RTI pathogens to antibiotics, show that pneumococcal bacteria are becoming increasingly resistant to many commonly used antibiotics including penicillin (24 percent of S. pnemoniae isolates) and macrolides (37 percent of S. pneumoniae isolates). However, in the PROTEKT study, resistance to Ketek was rare (0.1 percent of S. pneumoniae isolates).
Ketek Clinical Data
Clinical trial data and information submitted to support FDA approval of Ketek included 14 Phase III studies demonstrating efficacy and safety involving more than 4,700 patients, and two additional Phase III studies containing safety data. In trials, Ketek demonstrated activity against common pathogens, including MDRSP and is indicated for mild to moderate CAP caused by MDRSP.
Controlled clinical trials for Ketek, similar to clinical trials of most antibiotics on the market, were designed to meet the guidelines and standards of the FDA at the time for antibiotic development (Ketek vs. an active comparator). The FDA requires adequate and well-controlled clinical trials demonstrating the safety and efficacy of a prescription drug prior to approval. Antibiotic treatment is the current standard of care to treat suspected bacterial RTIs, thus placebo-controlled studies may be considered ethically unacceptable or impractical because effective therapy is available.
To date, Ketek was used to treat more than 6 million patients in the U.S. and more than 28 million patients worldwide, and it is approved in more than 90 countries in North America, Europe, Asia and Latin America. In fact, no antibiotic has launched in the U.S. with more patient experience.
Large Simple Safety Study (Study A3014)
Study A3014 was the first comparative large simple safety study (LSSS) performed in a usual care setting for an antibiotic prior to approval. There is increased interest in the scientific community to perform such studies in a broad population in the usual care setting to reflect daily clinical practice. Study A3014 was conducted in the usual care setting in response to a request in a FDA approvable letter and designed after consultation with the FDA and advice from external experts. The study enrolled approximately 24,000 patients and was completed in May 2002. The final study report was submitted to the FDA in July 2002. Subsequently, the FDA expressed concerns over the integrity of Study A3014 data and did not rely on it as a basis for approval of Ketek. The FDA approved Ketek based on pivotal Phase III clinical studies, postmarketing experience outside the U.S. (about 6 million patients) and additional information provided by sanofi-aventis. Study A3014 data are not referenced in the U.S. label.
Ketek Efficacy and Safety
Ketek has demonstrated activity against common bacterial RTI pathogens, including penicillin-, macrolide- and multidrug-resistant strains of S. pneumoniae, which is important in an era of increasing incidence of antibiotic resistance. Additionally, Ketek provides tailored coverage against the most common respiratory tract pathogens without affecting protective bacteria (anaerobic and Gram-negative) that are essential for normal body function.
The overall safety profile of Ketek, as seen in Phase III clinical trials and postmarketing safety data, is comparable to commonly used antibiotics for community-acquired RTIs, including ß-lactams, macrolides and fluoroquinolones, although the specific adverse event profiles may differ among these drugs. Over the past two years, attention has been given to postmarketing reports of adverse events with Ketek involving liver, loss of consciousness, syncope and exacerbations of myasthenia gravis. In each case, sanofi-aventis has worked with the FDA and other regulatory bodies worldwide to assess the events and update the prescribing information for Ketek to ensure that healthcare providers continue to have the information they need to prescribe the drug appropriately. The U.S. prescribing information revision in June 2006 contains a bolded warning and additional information relating to the nature and characterization of hepatic events, as well as revised recommendations limiting the use of Ketek in patients with myasthenia gravis. This revision was also communicated through a "Dear Healthcare Professional" letter.
Sanofi-aventis treats patient safety as a matter of the highest priority and takes its responsibilities relating to patient safety very seriously. We rigorously monitor and evaluate all reports of adverse events and regularly provide postmarketing safety surveillance data and clinical trial data to the FDA and other health authorities around the world. Based on the in-depth review of the clinical trial and postmarketing and epidemiological data available today, and after consultation with leading external experts, sanofi-aventis continues to believe that the benefits of Ketek outweigh the risks when the drug is used as directed for its approved indications.
Important Safety Information
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 taking cisapride or pimozide and in patients with a history of hypersensitivity to telithromycin or any macrolide antibiotic.
KETEK 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 KETEK. 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 KETEK.
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.
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.
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. 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 (eg, quinidine and procainamide) or Class III (eg, dofetilide) antiarrhythmic 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.
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.
Please see accompanying full prescribing information.
For additional important information, visit www.Ketek.com.
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* 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.
US.TEL.06.12.006
