FDA label ce3e7997-b925-4b07-994e-b2e699e0d3a1

Ketek is contraindicated in patients with myasthenia gravis. There have been reports of fatal and life-threatening respiratory failure in patients with myasthenia gravis associated with the use of Ketek. (See CONTRAINDICATIONS .)

WARNINGS 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 . (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 and immediately seek medical evaluation, which should include liver function tests . (See ADVERSE REACTIONS , PRECAUTIONS, Information to Patients .) 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 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 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. Visual disturbances* 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. 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. 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. (See PRECAUTIONS, Information for Patients ) Drug Interactions 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 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 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, 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.

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: Table 5 All and Possibly Related Treatment-Emergent Adverse Events Reported in Controlled Phase III Clinical Studies (Percent Incidence) Adverse Event All TEAEs Possibly-Related TEAEs KETEK n= 2702 Comparator Includes comparators from all controlled Phase III studies. n= 2139 KETEK n= 2702 Comparator n= 2139 Diarrhea 10.8% 8.6% 10.0% 8.0% Nausea 7.9% 4.6% 7.0% 4.1% Headache 5.5% 5.8% 2.0% 2.5% Dizziness (excl. vertigo) 3.7% 2.7% 2.8% 1.5% Vomiting 2.9% 2.2% 2.4% 1.4% Loose Stools 2.3% 1.5% 2.1% 1.4% Dysgeusia 1.6% 3.6% 1.5% 3.6% The following events judged by investigators to be at least possibly drug related were observed infrequently (≥ 0.2% and < 2%), in KETEK-treated patients in the controlled Phase III studies. Gastrointestinal system: abdominal distension, dyspepsia, gastrointestinal upset, flatulence, constipation, gastroenteritis, gastritis, anorexia, oral candidiasis, glossitis, stomatitis, watery stools. Liver and biliary system: abnormal liver function tests: increased transaminases, increased liver enzymes (e.g., ALT, AST) were usually asymptomatic and reversible. ALT elevations above 3 times the upper limit of normal were observed in 1.6%, and 1.7% of patients treated with KETEK and comparators, respectively. Hepatitis, with or without jaundice, occurred in 0.07% of patients treated with KETEK, and was reversible. (See PRECAUTIONS, General .) Nervous system: dry mouth, somnolence, insomnia, vertigo, increased sweating Body as a whole: abdominal pain, upper abdominal pain, fatigue Special senses: Visual adverse events most often included blurred vision, diplopia, or difficulty focusing. Most events were mild to moderate; however, severe cases have been reported. Some patients discontinued therapy due to these adverse events. Visual adverse events were reported as having occurred after any dose during treatment, but most visual adverse events (65%) occurred following the first or second dose. Visual events lasted several hours and recurred upon subsequent dosing in some patients. For patients who continued treatment, some resolved on therapy while others continued to have symptoms until they completed the full course of treatment. (See WARNINGS and PRECAUTIONS, Information for patients .) Females and patients under 40 years old experienced a higher incidence of telithromycin-associated visual adverse events. (See CLINICAL STUDIES .) Urogenital system: vaginal candidiasis, vaginitis, vaginosis fungal Skin: rash Hematologic: increased platelet count Other possibly related clinically-relevant events occurring in <0.2% of patients treated with KETEK from the controlled Phase III studies included: anxiety, bradycardia, eczema, elevated blood bilirubin, erythema multiforme, flushing, hypotension, increased blood alkaline phosphatase, increased eosinophil count, paresthesia, pruritus, urticaria. Post-Marketing Adverse Event Reports In addition to adverse events reported from clinical trials, the following events have been reported from worldwide post-marketing experience with KETEK. Allergic: face edema, rare reports of severe allergic (hypersensitivity) reactions, including angioedema and anaphylaxis Cardiovascular: atrial arrhythmias, palpitations Gastrointestinal system: pancreatitis Liver and biliary system: Hepatic dysfunction has been reported. Severe and in some cases fatal hepatotoxicity, including fulminant hepatitis, hepatic necrosis and hepatic failure have been reported in patients treated with KETEK. These hepatic reactions were observed during or immediately after treatment. In some of these cases, liver injury progressed rapidly and occurred after administration of only a few doses of KETEK. (See CONTRAINDICATIONS and WARNINGS .) Severe reactions, in some but not all cases, have been associated with serious underlying diseases or concomitant medications. Data from post-marketing reports and clinical trials show that most cases of hepatic dysfunction were mild to moderate. (See PRECAUTIONS, General .) Musculoskeletal: muscle cramps, rare reports of exacerbation of myasthenia gravis. (See CONTRAINDICATIONS . ) arthralgia, myalgia Nervous system: loss of consciousness, in some cases associated with vagal syndrome. Psychiatric disorders: confusion, hallucinations (mostly visual) Special senses: taste/smell perversion and/or loss

<table width="90%" ID="ie2329bce-618d-41f0-86a4-8a3548bc1d35"> <caption>Table 5</caption> <col align="left" width="40%" valign="middle"/> <col align="center" width="15%" valign="middle"/> <col align="center" width="15%" valign="middle"/> <col align="center" width="15%" valign="middle"/> <col align="center" width="15%" valign="middle"/> <thead> <tr> <th align="center" colspan="5" styleCode="Lrule Botrule Rrule">All and Possibly Related Treatment-Emergent Adverse Events Reported in Controlled Phase III Clinical Studies (Percent Incidence)</th> </tr> <tr> <th styleCode="Lrule Botrule">Adverse Event </th> <th colspan="2" styleCode="Lrule Botrule">All TEAEs</th> <th colspan="2" styleCode="Lrule Botrule Rrule">Possibly-Related TEAEs</th> </tr> <tr> <th styleCode="Lrule Botrule"/> <th styleCode="Lrule Botrule">KETEK n= 2702 </th> <th styleCode="Lrule Botrule">Comparator<footnote ID="fn_5.2">Includes comparators from all controlled Phase III studies.</footnote> n= 2139 </th> <th styleCode="Lrule Botrule">KETEK n= 2702</th> <th styleCode="Lrule Botrule Rrule">Comparator<footnoteRef IDREF="fn_5.2"/> n= 2139</th> </tr> </thead> <tbody> <tr> <td styleCode="Lrule Botrule">Diarrhea</td> <td styleCode="Lrule Botrule">10.8%</td> <td styleCode="Lrule Botrule">8.6%</td> <td styleCode="Lrule Botrule">10.0%</td> <td styleCode="Lrule Botrule Rrule">8.0%</td> </tr> <tr> <td styleCode="Lrule Botrule">Nausea</td> <td styleCode="Lrule Botrule">7.9%</td> <td styleCode="Lrule Botrule">4.6%</td> <td styleCode="Lrule Botrule">7.0%</td> <td styleCode="Lrule Botrule Rrule">4.1%</td> </tr> <tr> <td styleCode="Lrule Botrule">Headache</td> <td styleCode="Lrule Botrule">5.5%</td> <td styleCode="Lrule Botrule">5.8%</td> <td styleCode="Lrule Botrule">2.0%</td> <td styleCode="Lrule Botrule Rrule">2.5%</td> </tr> <tr> <td styleCode="Lrule Botrule">Dizziness (excl. vertigo)</td> <td styleCode="Lrule Botrule">3.7%</td> <td styleCode="Lrule Botrule">2.7%</td> <td styleCode="Lrule Botrule">2.8%</td> <td styleCode="Lrule Botrule Rrule">1.5%</td> </tr> <tr> <td styleCode="Lrule Botrule">Vomiting</td> <td styleCode="Lrule Botrule">2.9%</td> <td styleCode="Lrule Botrule">2.2%</td> <td styleCode="Lrule Botrule">2.4%</td> <td styleCode="Lrule Botrule Rrule">1.4%</td> </tr> <tr> <td styleCode="Lrule Botrule">Loose Stools</td> <td styleCode="Lrule Botrule">2.3%</td> <td styleCode="Lrule Botrule">1.5%</td> <td styleCode="Lrule Botrule">2.1%</td> <td styleCode="Lrule Botrule Rrule">1.4%</td> </tr> <tr> <td styleCode="Lrule Botrule">Dysgeusia</td> <td styleCode="Lrule Botrule">1.6%</td> <td styleCode="Lrule Botrule">3.6%</td> <td styleCode="Lrule Botrule">1.5%</td> <td styleCode="Lrule Botrule Rrule">3.6%</td> </tr> </tbody> </table>