July 26, 2016
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Ketek

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Ketek




Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hepatotoxicity

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, alcoholic 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 is contraindicated in patients with a previous history of hepatitis and/or jaundice associated with the use of KETEK tablets, or any macrolide antibacterial. [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. These events associated with less severe forms of liver toxicity were reversible.

QTc Prolongation

KETEK can prolong the QTc interval of the electrocardiogram in some patients leading to an increased risk for ventricular arrhythmias, including ventricular tachycardia and torsades de pointes with fatal outcomes. 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 (e.g., quinidine and procainamide) or Class III (e.g., dofetilide) antiarrhythmic agents.

Cases of ventricular arrhythmias (including ventricular tachycardia and torsades de pointes) have been reported post-marketing with KETEK and sometimes occurred within a few hours of the first dose. In clinical trials, no cardiovascular morbidity or mortality attributable to QTc prolongation occurred with KETEK treatment in 4780 patients, including 204 patients having a prolonged QTc at baseline.

Visual Disturbances And Loss Of Consciousness

KETEK may cause visual disturbances particularly in slowing the ability to accommodate and the ability to release accommodation. Visual disturbances, some of them severe, included blurred vision, difficulty focusing, and diplopia. [see ADVERSE REACTIONS]

There have been post-marketing 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.

Serious Adverse Reactions With Concomitant Drugs

Serious adverse reactions have been reported in patients taking KETEK concomitantly with CYP3A4 substrates [see DRUG INTERACTIONS]:

  • Colchicine: colchicine toxicity
  • Simvastatin, lovastatin, and atorvastatin: rhabdomyolysis
  • Calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem):hypotension
Colchicine Toxicity

Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and strong CYP3A4 inhibitors. KETEK is a strong CYP3A4 inhibitor and this interaction may occur while using both drugs at their recommended dosages. If co-administration of KETEK and colchicine is necessary in patients with normal renal and hepatic function, reduce the dosage of colchicine. Monitor patients for clinical symptoms of colchicine toxicity. Concomitant administration of KETEK and colchicine is contraindicated in patients with renal or hepatic impairment. [see CONTRAINDICATIONS; DRUG INTERACTIONS]

Rhabdomyolysis

Simvastatin, lovastatin and atorvastatin are metabolized by CYP3A4. High levels of HMG-CoA reductase inhibitors increase the risk of myopathy and rhabdomyolysis. Avoid use of statins which are metabolized by CYP3A4 concomitantly with KETEK; suspend therapy with simvastatin, lovastatin, or atorvastatin during the course of treatment with KETEK. [see DRUG INTERACTIONS]

Hypotension

Hypotension, bradyarrhythmia and loss of consciousness have been observed in patients receiving concomitant treatment with calcium channel blockers that are substrates of CYP3A4 (e.g., verapamil, amlodipine, diltiazem). Monitor for these adverse reactions and toxicity related to calcium channel blockers and adjust calcium channel blocker dosage as necessary. [see DRUG INTERACTIONS]

Clostridum Difficile-Associated Diarrhea

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 antibacterial 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 antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Development Of Drug Resistant Bacteria

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

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (MEDICATION GUIDE).

Communicate the following information and instructions to the patient:

Drug Resistance

Antibacterial drugs including KETEK should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When KETEK is prescribed to treat a bacterial infection, inform patients 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 or other antibacterial drugs in the future.

Myasthenia Gravis

Advise patients not to take KETEK if they have myasthenia gravis [see CONTRAINDICATIONS]

Liver Injury

Advise patients of the possibility of severe liver injury, associated with KETEK. Instruct them to discontinue KETEK and seek medical attention immediately if they develop nausea, fatigue, anorexia, jaundice, dark urine, light-colored stools, pruritus, or tender abdomen. These problems may occur after any dose during treatment or after treatment had stopped. Advise patients not to take KETEK if they have a previous history of hepatitis/jaundice associated with the use of KETEK or macrolide antibacterials. [see CONTRAINDICATIONS; WARNINGS AND PRECAUTIONS]

Changes In Electrocardiogram

KETEK may produce changes in the electrocardiogram (QTc interval prolongation). Advise patient to report any fainting or palpitations occurring during drug treatment. [see WARNINGS AND PRECAUTIONS; ADVERSE REACTIONS]

Advise patients to avoid KETEK if they are receiving Class 1A (e.g., quinidine, procainamide) or Class III (e.g., dofetilide) antiarrhythmic agents.

Problems With Vision And Loss Of Consciousness

KETEK may cause blurred vision, difficulty focusing, and objects looking doubled. These problems may occur after any dose during treatment, last for several hours, and come back with the next dose. [See WARNINGS AND PRECAUTIONS; ADVERSE REACTIONS]

KETEK may also cause transient loss of consciousness. [See WARNINGS AND PRECAUTIONS]

Advise patients to avoid quick changes in viewing between objects in the distance and objects nearby to help decrease the effects of these visual difficulties.

Advise patients to minimize activities such as driving a motor vehicle, operating heavy machinery or engaging in other hazardous activities during treatment with KETEK, because of potential visual difficulties, loss of consciousness, confusion or hallucinations.

Advise patients that if visual difficulties, loss of consciousness / fainting, confusion or hallucination occur, to seek advice from their physician before taking another dose and to refrain from hazardous activities.

Drug/Food Interactions

Advise patients that KETEK tablets can be taken with or without food.

Colchicine should be avoided in patients receiving KETEK. Advise patients with normal kidney and liver function that the dose of colchicine should be reduced while they are taking KETEK. [see WARNINGS AND PRECAUTIONS; DRUG INTERACTIONS]

Simvastatin, lovastatin, or atorvastatin should be avoided in patients receiving KETEK. Advise patients that KETEK therapy with simvastatin, lovastatin, or atorvastatin should be stopped during the course of treatment with KETEK due to increased risk of rhabdomyolysis. [see WARNINGS AND PRECAUTIONS; DRUG INTERACTIONS]

Taking KETEK with calcium channel blockers may cause severe hypotension, bradycardia and loss of consciousness. Advise patients that if these symptoms occur to contact their physician as soon as possible. [see WARNINGS AND PRECAUTIONS; DRUG INTERACTIONS]

Advise patients to inform their physician of any other medications taken concurrently with KETEK, including over-the-counter medications and dietary supplements.

Diarrhea

Diarrhea is a common problem caused by antibacterials including KETEK which usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterials, 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 antibacterial. If this occurs, patients should contact their physician as soon as possible. [see WARNINGS AND PRECAUTIONS]

Nonclinical Toxicology

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 0.6 times the human daily dose on a body surface area basis (50 mg/kg/day). At doses of 2–4 times the human daily dose (150 and 300 mg/kg/day, at which signs of parental toxicity were observed), moderate reductions in fertility indices were noted in male and female animals treated with telithromycin.

Use In Specific Populations

Pregnancy

Pregnancy Category C.

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.

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 of 150 and 20 mg/kg/day in rats and rabbits respectively (approximately 2 and 0.5 times the recommended clinical dose), no evidence of fetal terata was found. At doses higher than 150 or 20 mg/kg 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 125 mg/kg/day (1.5 times) the daily human dose.

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 is administered to a nursing mother.

Pediatric Use

The safety and effectiveness of KETEK in pediatric patients less than18 years of age has not been established. Pediatric clinical trials were halted prematurely due to concern of serious postmarketing hepatic adverse reactions observed in adults. [see WARNINGS AND PRECAUTIONS]

Geriatric Use

Of the total number of patients in Phase 3 clinical trials (n=4,780), KETEK was administered to 694 patients who were 65 years and older, including 231 patients who were 75 years and older. Efficacy and safety in patients 65 years and older were generally similar to that observed in younger patients; however, greater sensitivity of some older individuals cannot be ruled out. [see CLINICAL PHARMACOLOGY]

Renal And/Or Hepatic Impairment

Dose adjustment is required in patients with severe renal impairment (CL less than 30 mL/min) or on dialysis. Further dose adjustment is required in patients with severe renal impairment and coexisting hepatic impairment. [see DOSAGE AND ADMINISTRATION]

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 5/19/2016

Warnings
Precautions

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