Ketek Information
Ketek ()
Ketek ()
Ketek () Description
Ketek () tablets contain telithromycin, a semisynthetic antibacterial in the ketolide class for oral administration. Chemically, telithromycin is designated as Erythromycin, 3-de[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranosyl)oxy]-11,12-dideoxy-6-O-methyl-3-oxo-12,11-[oxycarbonyl[[4-[4-(3-pyridinyl)-1H-imidazol-1-yl]butyl]imino]]-.
Telithromycin, a ketolide, differs chemically from the macrolide group of antibacterials by the lack of α-L-cladinose at position 3 of the erythronolide A ring, resulting in a 3-keto function. It is further characterized by a C11-12 carbamate substituted by an imidazolyl and pyridyl ring through a butyl chain. Its empirical formula is CHNOand its molecular weight is 812.03. Telithromycin is a white to off-white crystalline powder. The following represents the chemical structure of telithromycin.
Ketek () tablets are available as light-orange, oval, film-coated tablets, each containing 400 mg or 300 mg of telithromycin, and the following inactive ingredients: croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, red ferric oxide, talc, titanium dioxide, and yellow ferric oxide.
Ketek () Clinical Pharmacology
Ketek () tablets are indicated for the treatment of community-acquired pneumonia (of mild to moderate severity) due to, (including multi-drug resistant isolates [MDRSP]), , , , or , for patients 18 years old and above.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Ketek () and other antibacterial drugs, Ketek () should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
Ketek () Contraindications
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 with a history of hypersensitivity to telithromycin and/or any components of Ketek () tablets, or any macrolide antibiotic.
Concomitant administration of Ketek () with cisapride or pimozide is contraindicated. (See and .)
Concomitant administration of Ketek () and colchicine is contraindicated in patients with renal or hepatic impairment. (See and .)
Ketek () Warnings
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. . (See .) 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. (See )
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.
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 () . 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.
Ketek () may cause visual disturbances particularly in slowing the ability to accommodate and the ability to release accommodation.
There have been post-marketing adverse event reports of transient loss of consciousness including some cases associated with vagal syndrome.
Serious adverse reactions have been reported in patients taking Ketek () 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 .)
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 () and colchicine is contraindicated in patients with renal or hepatic impairment. (See and .)
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of and surgical evaluation should be instituted as clinically indicated.
Ketek () Precautions
Prescribing Ketek () 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 (CL
A Medication Guide is provided to patients when Ketek () is dispensed. Patients should be instructed to read the MedGuide when Ketek () 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.
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.
If patients experience visual difficulties, loss of consciousness / fainting, confusion or hallucination
Patients should also be advised:
Telithromycin is a strong inhibitor of the cytochrome P450 3A4 system. Co-administration of Ketek () tablets and a drug primarily metabolized by the cytochrome P450 3A4 enzyme system may result in increased plasma concentration of the drug co-administered with telithromycin that could increase or prolong both the therapeutic and adverse effects. Therefore, appropriate dosage adjustments may be necessary for the drug co-administered with telithromycin.
The use of Ketek () is contraindicated with cisapride. (See and )
The use of Ketek () is contraindicated with pimozide. Although there are no studies looking at the interaction between Ketek () and pimozide, there is a potential risk of increased pimozide plasma levels by inhibition of CYP 3A4 pathways by Ketek () as with macrolides. (See )
In a pharmacokinetic study, simvastatin levels were increased due to CYP 3A4 inhibition by telithromycin. (See ) Similarly, an interaction may occur with lovastatin or atorvastatin but not with statins which are not metabolized by CYP3A4.
High levels of HMG-CoA reductase inhibitors increase the risk of myopathy and rhabdomyolysis. 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. Patients concomitantly treated with statins should be carefully monitored for signs and symptoms of myopathy and rhabdomyolysis.
Colchicine is a substrate for both CYP 3A4 and the efflux transporter, P-glycoprotein (P-gp), and a significant increase in colchicine plasma concentration is anticipated when co-administered with strong CYP 3A4 inhibitors such as telithromycin. (See and
Monitoring of digoxin side effects or serum levels should be considered during concomitant administration of digoxin and Ketek () . (See
Hypotension, bradyarrhythmia and loss of consciousness have been observed in patients receiving concomitant treatment with calcium channel blockers that are substrates of CYP 3A4 (e.g., verapamil, amlodipine, diltiazem).
Patients should be monitored with concomitant administration of midazolam and dosage adjustment of midazolam should be considered if necessary. Precaution should be used with other benzodiazepines, which are metabolized by CYP 3A4 and undergo a high first-pass effect (e.g., triazolam). (See )
Concomitant treatment of Ketek () with rifampin, a CYP 3A4 inducer, should be avoided. Concomitant administration of other CYP 3A4 inducers such as phenytoin, carbamazepine, or phenobarbital is likely to result in subtherapeutic levels of telithromycin and loss of effect. (See .)
In patients treated with metoprolol for heart failure, the increased exposure to metoprolol, a CYP 2D6 substrate, may be of clinical importance. Therefore, co-administration of Ketek () and metoprolol in patients with heart failure should be considered with caution. (See )
Spontaneous post-marketing reports suggest that administration of Ketek () and oral anticoagulants concomitantly may potentiate the effects of the oral anticoagulants. Consideration should be given to monitoring prothrombin times/INR while patients are receiving Ketek () and oral anticoagulants simultaneously.
No specific drug interaction studies have been performed to evaluate the following potential drug-drug interactions with Ketek () . However, these drug interactions have been observed with macrolide products.
Drugs metabolized by the cytochrome P450 system such as carbamazepine, cyclosporine, tacrolimus, sirolimus, hexobarbital, and phenytoin: elevation of serum levels of these drugs may be observed when co-administered with telithromycin. As a result, increases or prolongation of the therapeutic and/or adverse effects of the concomitant drug may be observed.
Ergot alkaloid derivatives (such as ergotamine or dihydroergotamine): acute ergot toxicity characterized by severe peripheral vasospasm and dysesthesia has been reported when macrolide antibiotics were co-administered. Without further data, the co-administration of Ketek () and these drugs is not recommended.
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/m 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.
Ketek () Adverse Reactions
In Phase III clinical trials, 4,780 patients (n=2702 in controlled trials) received daily oral doses of Ketek () 800 mg once daily for 5 days or 7 to 10 days. Most adverse events were mild to moderate in severity. In the combined Phase III studies, discontinuation due to treatment-emergent adverse events occurred in 4.4% of Ketek () -treated patients and 4.3% of combined comparator-treated patients. Most discontinuations in the Ketek () group were due to treatment-emergent adverse events in the gastrointestinal body system, primarily diarrhea (0.9% for Ketek () vs. 0.7% for comparators), nausea (0.7% for Ketek () vs. 0.5% for comparators).
All and possibly related treatment-emergent adverse events (TEAEs) occurring in controlled clinical studies in ≥ 2.0% of all patients are included below:
The following events judged by investigators to be at least possibly drug related were observed infrequently (≥ 0.2% and
Females and patients under 40 years old experienced a higher incidence of telithromycin-associated visual adverse events. (See .)
Ketek () Overdosage
In the event of acute overdosage, the stomach should be emptied by gastric lavage. The patient should be carefully monitored (e.g., ECG, electrolytes) and given symptomatic and supportive treatment. Adequate hydration should be maintained. The effectiveness of hemodialysis in an overdose situation with Ketek () is unknown.
Ketek () Dosage And Administration
The dose of Ketek () tablets is 800 mg (2 tablets of 400 mg) taken orally once every 24 hours, for 7–10 days. Ketek () tablets can be administered with or without food.
Ketek () may be administered without dosage adjustment in the presence of hepatic impairment.
In the presence of severe renal impairment (CL
In the presence of severe renal impairment (CL
Ketek () How Supplied
Ketek () 400 mg tablets are supplied as light-orange, oval, film-coated tablets, imprinted "H3647" on one side and "400" on the other side. These are packaged in bottles and blister cards (Ketek () Pak™ and unit dose) as follows:
Bottles of 60 (NDC 0088-2225-41)Ketek () Pak™, 10-tablet cards (2 tablets per blister cavity) (NDC 0088-2225-07)Unit dose package of 100 (blister pack) (NDC 0088-2225-49)
Ketek () 300 mg tablets are supplied as light-orange, oval, film-coated tablets, imprinted "38AV" on one side and blank on the other side. These are packaged in bottles as follows:
Bottles of 20 (NDC 0088-2223-20)
Ketek () Clinical Studies
Ketek () was studied in four randomized, double-blind, controlled studies and four open-label studies for the treatment of community-acquired pneumonia. Patients with mild to moderate CAP who were considered appropriate for oral outpatient treatment were enrolled in these trials. Patients with severe pneumonia were excluded based on any one of the following: ICU admission, need for parenteral antibiotics, respiratory rate > 30/minute, hypotension, altered mental status,
Clinical cure rates by pathogen from the four CAP controlled clinical trials in microbiologically evaluable patients given Ketek () for 7–10 days or a comparator are displayed in Table 7.
Clinical cure rates for patients with CAP due to were determined from patients in controlled and uncontrolled trials. Of 333 evaluable patients with CAP due to , 312 (93.7%) achieved clinical success. Only patients considered appropriate for oral outpatient therapy were included in these trials. More severely ill patients were not enrolled. Blood cultures were obtained in all patients participating in the clinical trials of mild to moderate community-acquired pneumonia. In a limited number of outpatients with incidental pneumococcal bacteremia treated with Ketek () , a clinical cure rate of 88% (67/76) has been observed. Ketek () is not indicated for the treatment of severe community-acquired pneumonia or suspected pneumococcal bacteremia.
Clinical cure rates for patients with CAP due to multi-drug resistant (MDRSP*) were determined from patients in controlled and uncontrolled trials. Of 36 evaluable patients with CAP due to MDRSP, 33 (91.7%) achieved clinical success.
nd
Ketek () Animal Pharmacology
Repeated dose toxicity studies of 1, 3, and 6 months' duration with telithromycin conducted in rat, dog and monkey showed that the liver was the principal target for toxicity with elevations of liver enzymes and histological evidence of damage. There was evidence of reversibility after cessation of treatment. Plasma exposures based on free fraction of drug at the no observed adverse effect levels ranged from 1 to 10 times the expected clinical exposure.
Phospholipidosis (intracellular phospholipid accumulation) affecting a number of organs and tissues (e.g., liver, kidney, lung, thymus, spleen, gall bladder, mesenteric lymph nodes, GI-tract) has been observed with the administration of telithromycin in rats at repeated doses of 900 mg/m/day (1.8× the human dose) or more for 1 month, and 300 mg/m/day (0.61× the human dose) or more for 3–6 months. Similarly, phospholipidosis has been observed in dogs with telithromycin at repeated doses of 3000 mg/m/day (6.1× the human dose) or more for 1 month and 1000 mg/m/day (2.0× the human dose) or more for 3 months. The significance of these findings for humans is unknown.
Pharmacology/toxicology studies showed an effect both in prolonging QTc interval in dogs and action potential duration (APD) in rabbit Purkinje fibers. These effects were observed at concentrations of free drug at least 8.8 (in dogs) times those circulating in clinical use. electrophysiological studies (hERG assays) suggested an inhibition of the rapid activating component of the delayed rectifier potassium current (I) as an underlying mechanism.
Ketek ()
Ketek () Medication Guide
Read the Medication Guide that comes with Ketek () before you start taking it and each time you get a new prescription. There may be new information. Talk to your doctor if you have any questions about Ketek () . This Medication Guide does not take the place of talking with your doctor about your medical condition or treatment.
Do not take Ketek () if you have ever had liver problems while taking Ketek () or macrolide antibiotics. Macrolide antibiotics include:
See
Ketek () is an antibiotic. Ketek () is used to treat adults 18 years of age and older with a lung infection called "community acquired pneumonia" that is caused by certain germs called bacteria.
Do not take Ketek () if you:
Talk to your doctor before taking Ketek () if you have any of the conditions listed above.
Tell your doctor about all of the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Ketek () and other medicines may affect or interact with each other, sometimes causing serious side effects.
Especially tell your doctor if you take:
Ask your doctor if you are not sure if the medicine you take is included in the list of medicines above.
Know the medicines you take. Keep a list of your medicines with you to show your doctor or pharmacist.
Do not take other medicines with Ketek () without first checking with your doctor. Your doctor will tell you if you can take other medicines while taking Ketek () .
See ""
Ketek () may cause serious side effects, including:
The most common side effects of Ketek () are:
Tell your doctor if you have any side effect that bothers you or that does not go away.
These are not all of the possible side effects of Ketek () . For more information ask your doctor or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
You may also report side effects to sanofi-aventis U.S. at 1-800-633-1610.
This Medication Guide summarizes the most important information about Ketek () . If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Ketek () that was written for healthcare professionals. This information is also available on the Ketek () website at www.Ketek () .com or call 1-800-446-6267.
Revised December 2010
This Medication Guide has been approved by the U.S. Food and Drug Administration.
sanofi-aventis U.S. LLCBridgewater, NJ 08807
© 2010 sanofi-aventis U.S. LLC
BIAXIN (clarithromycin) is a registered trademark of Abbott Laboratories.ZITHROMAX (azithromycin) is a registered trademark of Pfizer Inc.DYNABAC (dirithromycin) is a registered trademark of Eli Lilly and Company.PROPULSID (cisapride) is a registered trademark of Johnson & Johnson.ORAP (pimozide) is a registered trademark of Teva Pharmaceuticals USA, Inc.LIPITOR (atorvastatin) is a registered trademark of Pfizer Inc.ZOCOR (simvastatin) is a registered trademark of Merck & Co Inc.VYTORIN (simvastatin and ezetimibe) is a registered trademark of Merck/Schering Plough Pharmaceuticals.MEVACOR (lovastatin) is a registered trademark of Merck & Co Inc.
Ketek () Principal Display Panel - Mg Tablets
Ketek () Principal Display Panel - Mg Tablets
