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Hepatotoxicity

Acute hepatic failure and severe liver injury, in some cases fatal, have been reported in patients treated with KETEK (telithromycin) . 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. (See ADVERSE REACTIONS) 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 (telithromycin) and immediately seek medical evaluation, which should include liver function tests. (See ADVERSE REACTIONS, PATIENT INFORMATION.) If clinical hepatitis or transaminase elevations combined with other systemic symptoms occur, KETEK (telithromycin) should be permanently discontinued.

Ketek (telithromycin) must not be re-administered to patients with a previous history of hepatitis and/or jaundice associated with the use of KETEK (telithromycin) tablets, or any macrolide antibiotic. (See CONTRAINDICATIONS)

In addition, less severe hepatic dysfunction associated with increased liver enzymes, hepatitis and in some cases jaundice was reported with the use of KETEK (telithromycin) . These events associated with less severe forms of liver toxicity were reversible.

QTc prolongation

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 (telithromycin) . 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.

Visual disturbances*

KETEK (telithromycin) 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.

Loss of Consciousness*

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 (telithromycin) . If patients experience visual disorders or loss of consciousness while taking KETEK (telithromycin) , patients should not drive a motor vehicle, operate heavy machinery or engage in other hazardous activities. (See PATIENT INFORMATION)

Drug Interactions

Serious adverse reactions have been reported in patients taking KETEK (telithromycin) concomitantly with CYP 3A4 substrates. These include colchicine toxicity with colchicine; rhabdomyolysis with simvastatin, lovastatin, and atorvastatin; and hypotension with calcium channel blockers metabolized by CYP 3A4 (e.g., verapamil, amlodipine, diltiazem). (See PRECAUTIONS: DRUG INTERACTIONS.)

Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and strong CYP 3A4 inhibitors. Telithromycin is a strong CYP 3A4 inhibitor and this interaction may occur while using both drugs at their recommended doses. If co-administration of telithromycin and colchicine is necessary in patients with normal renal and hepatic function, the dose of colchicine should be reduced. Patients should be monitored for clinical symptoms of colchicine toxicity. Concomitant administration of KETEK (telithromycin) and colchicine is contraindicated in patients with renal or hepatic impairment. (See CONTRAINDICATIONS and PRECAUTIONS: DRUG INTERACTIONS.)

Pseudomembranous colitis

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including KETEK (telithromycin) , 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.

General

Prescribing KETEK (telithromycin) in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Telithromycin is principally excreted via the liver and kidney. Telithromycin may be administered without dosage adjustment in the presence of hepatic impairment. In the presence of severe renal impairment (CLCR < 30 mL/min), a reduced dosage of KETEK is recommended. (See DOSAGE AND ADMINISTRATION)

Information for patients

A Medication Guide is provided to patients when Ketek (telithromycin) is dispensed. Patients should be instructed to read the MedGuide when Ketek (telithromycin) is received. In addition, the complete text of the MedGuide is reprinted at the end of this document.

The following information and instructions should be communicated to the patient.

• KETEK (telithromycin) may cause problems with vision particularly when looking quickly between objects close by and objects far away. These events include blurred vision, difficulty focusing, and objects looking doubled. Most events were mild to moderate; however, severe cases have been reported. Problems with vision were reported as having occurred after any dose during treatment, but most occurred following the first or second dose. These problems lasted several hours and in some patients came back with the next dose. (See WARNINGS and ADVERSE REACTIONS.)

Patients should be advised that avoiding quick changes in viewing between objects in the distance and objects nearby may help to decrease the effects of these visual difficulties.

• Because of potential visual difficulties, loss of consciousness, confusion or hallucinations, 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 (telithromycin) .

If patients experience visual difficulties, loss of consciousness / fainting, confusion or hallucination

• patients should seek advice from their physician before taking another dose
• patients should not drive a motor vehicle, operate heavy machinery, or engage in otherwise hazardous activities.

Patients should also be advised:

• Ketek (telithromycin) is contraindicated in patients with myasthenia gravis. (See CONTRAINDICATIONS)
• of the possibility of liver injury, associated with KETEK (telithromycin) , which in rare cases may be severe. Patients developing signs or symptoms of liver injury should be instructed to discontinue KETEK (telithromycin) and seek medical attention immediately. Symptoms of liver injury may include nausea, fatigue, anorexia, jaundice, dark urine, light-colored stools, pruritus, or tender abdomen. Ketek (telithromycin) must not be taken by patients with a previous history of hepatitis/jaundice associated with the use of KETEK or macrolide antibiotics. (See CONTRAINDICATIONS and WARNINGS)
• antibacterial drugs including KETEK (telithromycin) should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When KETEK (telithromycin) is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by KETEK (telithromycin) or other antibacterial drugs in the future.
• KETEK (telithromycin) has the potential to produce changes in the electrocardiogram (QTc interval prolongation) and that they should report any fainting occurring during drug treatment.
• KETEK (telithromycin) should be avoided in patients receiving Class 1A (e.g., quinidine, procainamide) or Class III (e.g., dofetilide) antiarrhythmic agents.
• to inform their physician of any personal or family history of QTc prolongation or proarrhythmic conditions such as uncorrected hypokalemia, or clinically significant bradycardia.
• diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
• simvastatin, lovastatin, or atorvastatin should be avoided in patients receiving KETEK (telithromycin) . If KETEK (telithromycin) is prescribed, therapy with simvastatin, lovastatin, or atorvastatin should be stopped during the course of treatment. (See CLINICAL PHARMACOLOGY, Drug-drug interactions)
• colchicine should be avoided in patients receiving KETEK (telithromycin) . If KETEK (telithromycin) is prescribed in patients with normal kidney and liver function, the dose is colchicine should be reduced. Concomitant treatment with KETEK (telithromycin) and colchicine is contraindicated in patients with kidney or liver impairment. (See CONTRAINDICATIONS and WARNINGS, DRUG INTERACTIONS.)
• KETEK (telithromycin) tablets can be taken with or without food.
• to inform their physician of any other medications taken concurrently with KETEK (telithromycin) , including over-the-counter medications and dietary supplements.

Carcinogenesis, mutagenesis, impairment of fertility

Long-term studies in animals to determine the carcinogenic potential of KETEK have not been conducted.

Telithromycin showed no evidence of genotoxicity in four tests: gene mutation in bacterial cells, gene mutation in mammalian cells, chromosome aberration in human lymphocytes, and the micronucleus test in the mouse.

No evidence of impaired fertility in the rat was observed at doses estimated to be 0.61 times the human daily dose on a mg/m² basis. At doses of 1.8-3.6 times the human daily dose, at which signs of parental toxicity were observed, moderate reductions in fertility indices were noted in male and female animals treated with telithromycin.

Pregnancy

Teratogenic effects

Pregnancy Category C. Telithromycin was not teratogenic in the rat or rabbit. Reproduction studies have been performed in rats and rabbits, with effect on pre-post natal development studied in the rat. At doses estimated to be 1.8 times (900 mg/m²) and 0.49 times (240 mg/m²) the daily human dose of 800 mg (492 mg/m²) in the rat and rabbit, respectively, no evidence of fetal terata was found. At doses higher than the 900 mg/m² and 240 mg/m² in rats and rabbits, respectively, maternal toxicity may have resulted in delayed fetal maturation. No adverse effects on prenatal and postnatal development of rat pups were observed at 1.5 times (750 mg/m²/d) the daily human dose.

There are no adequate and well-controlled studies in pregnant women. Telithromycin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing mothers

Telithromycin is excreted in breast milk of rats. Telithromycin may also be excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when KETEK (telithromycin) is administered to a nursing mother.

Pediatric use

The safety and effectiveness of KETEK (telithromycin) in pediatric patients has not been established.

Geriatric use

In all Phase III clinical trials (n=4,780), KETEK (telithromycin) was administered to 694 patients who were 65 years and older, including 231 patients who were 75 years and older. Efficacy and safety in elderly patients ≥ 65 years were generally similar to that observed in younger patients; however, greater sensitivity of some older individuals cannot be ruled out. No dosage adjustment is required based on age alone. (See CLINICAL PHARMACOLOGY, Special populations, Geriatric and DOSAGE AND ADMINISTRATION.)

Last reviewed on RxList: 1/27/2011
This monograph has been modified to include the generic and brand name in many instances.