Ketec

Ketec is indicated for the treatment of community-acquired pneumonia (of mild to moderate severity) due to Streptococcus pneumoniae, (including multi-drug resistant S. pneumoniae [MDRSP¹]), Haemophilus influenzae, Moraxella catarrhalis, Chlamydophila pneumoniae, or Mycoplasma pneumoniae, for patients 18 years or older.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Ketec and other antibacterial drugs, Ketec 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.

REFERENCE

¹ 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 antibacterials: penicillin, 2 generation cephalosporins, e.g., cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole.

Recommended Dosage

The dosage of Ketec tablets is 800 mg (2 tablets of 400 mg) taken orally once daily for 7–10 days in patients 18 years or older. Ketec tablets can be administered with or without food.

Dosage In Patients With Renal And/Or Hepatic Impairment

In the presence of severe renal impairment (CL_CR less than 30 mL/min), including patients who need dialysis, reduce the dosage of Ketec to 600 mg once daily. In patients undergoing hemodialysis, give Ketec after the dialysis session on dialysis days.

In the presence of severe renal impairment (CL_CR less than 30 mL/min), with coexisting hepatic impairment, reduce the dosage of Ketec to 400 mg once daily. Patients with mild or moderate renal impairment (CL_CR of 30 mL/min or more) with or without coexisting hepatic impairment do not require a dosage adjustment. No dosage adjustments of Ketec are necessary in patients with hepatic impairment alone.

Myasthenia Gravis

Ketec is contraindicated in patients with myasthenia gravis. Exacerbations of myasthenia gravis have been reported in patients and sometimes occurred within a few hours of the first dose of Ketec. Reports have included fatal and life-threatening acute respiratory failure with a rapid onset and progression.

Hepatitis

Ketec is contraindicated in patients with previous history of hepatitis and/or jaundice associated with the use of Ketec tablets, or any macrolide antibacterial.

Hypersensitivity

Ketec is contraindicated in patients with a history of hypersensitivity to telithromycin, any components of Ketec tablets, or any macrolide antibacterial.

Cisapride/Pimozide

Concomitant administration of Ketec with cisapride or pimozide is contraindicated because coadministration can lead to life-threatening QT prolongation.

Colchicine

Concomitant administration of Ketec and colchicine is contraindicated in patients with renal or hepatic impairment due to increased plasma concentration of colchicine leading to life-threatening colchicine toxicity.

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 Ketec. 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 Ketec.

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 Ketec and immediately seek medical evaluation, which should include liver function tests. If clinical hepatitis or transaminase elevations combined with other systemic symptoms occur, Ketec should be permanently discontinued.

Ketec is contraindicated in patients with a previous history of hepatitis and/or jaundice associated with the use of Ketec tablets, or any macrolide antibacterial.

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

QTc Prolongation

Ketec 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, Ketec 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 Ketec 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 Ketec treatment in 4780 patients, including 204 patients having a prolonged QTc at baseline.

Visual Disturbances And Loss Of Consciousness

Ketec 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.

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 Ketec. If patients experience visual disorders or loss of consciousness while taking Ketec, 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 Ketec concomitantly with CYP3A4 substrates :

• 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. Ketec is a strong CYP3A4 inhibitor and this interaction may occur while using both drugs at their recommended dosages. If co-administration of Ketec 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 Ketec and colchicine is contraindicated in patients with renal or hepatic impairment.

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 Ketec; suspend therapy with simvastatin, lovastatin, or atorvastatin during the course of treatment with Ketec.

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.

Clostridum Difficile-Associated Diarrhea

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Ketec, 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 Ketec 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 Ketec should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Ketec 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 Ketec or other antibacterial drugs in the future.

Myasthenia Gravis

Advise patients not to take Ketec if they have myasthenia gravis

Liver Injury

Advise patients of the possibility of severe liver injury, associated with Ketec. Instruct them to discontinue Ketec 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 Ketec if they have a previous history of hepatitis/jaundice associated with the use of Ketec or macrolide antibacterials.

Changes In Electrocardiogram

Ketec may produce changes in the electrocardiogram (QTc interval prolongation). Advise patient to report any fainting or palpitations occurring during drug treatment.

Advise patients to avoid Ketec 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

Ketec 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.

Ketec may also cause transient loss of consciousness.

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 Ketec, 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 Ketec tablets can be taken with or without food.

Colchicine should be avoided in patients receiving Ketec. Advise patients with normal kidney and liver function that the dose of colchicine should be reduced while they are taking Ketec.

Simvastatin, lovastatin, or atorvastatin should be avoided in patients receiving Ketec. Advise patients that Ketec therapy with simvastatin, lovastatin, or atorvastatin should be stopped during the course of treatment with Ketec due to increased risk of rhabdomyolysis.

Taking Ketec 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.

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

Diarrhea

Diarrhea is a common problem caused by antibacterials including Ketec 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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term studies in animals to determine the carcinogenic potential of Ketec 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 Ketec is administered to a nursing mother.

Pediatric Use

The safety and effectiveness of Ketec 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.

Geriatric Use

Of the total number of patients in Phase 3 clinical trials (n=4,780), Ketec 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.

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.

The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:

• Myasthenia gravis
• Hepatotoxicity
• QTc prolongation
• Visual disturbances and loss of consciousness
• Clostridium difficile-associated diarrhea

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In Phase 3 clinical trials, 4,780 patients (n=2702 in controlled trials) received oral dosages of Ketec 800 mg once daily for 5 days or 7 to 10 days. Note that treatment with Ketec for 5 days duration is not a recommended dosage regimen.

In the combined Phase 3 studies, discontinuation due to adverse reactions occurred in 4.4% of Ketectreated patients and 4.3% of combined comparator-treated patients. Most discontinuations in the Ketec group were due to adverse reactions in the gastrointestinal body system, primarily diarrhea (0.9% for Ketec vs. 0.7% for comparators), and nausea (0.7% for Ketec vs. 0.5% for comparators).

Adverse reactions (ARs) occurring in clinical studies in 2% or more of Ketec patients are included below.

Table 1: Adverse Reactions Reported in 2% or more of Patients in Controlled Phase 3 Clinical Studies

Less Common Adverse Reactions

Frequency Of 0.2% Or More And Less Than 2%

The following adverse reactions were observed at a frequency of 0.2% or more and less than 2% in Ketec-treated patients in clinical studies.

Gastrointestinal system: abdominal distension, dyspepsia, gastrointestinal upset, flatulence, constipation, gastroenteritis, gastritis, anorexia, oral candidiasis, glossitis, stomatitis.

Liver and biliary system: abnormal liver function tests: increased transaminases (i.e., ALT, AST). Hepatitis, with or without jaundice, occurred in 0.07% of patients treated with Ketec.

Nervous system: dry mouth, somnolence, insomnia, vertigo, increased sweating

Body as a whole: abdominal pain, fatigue

Special senses: Visual adverse reactions, some of them severe, most often included blurred vision, diplopia, or difficulty focusing. Some patients discontinued therapy due to these adverse reactions. Visual adverse reactions were reported as having occurred after any dose during treatment, but most (65%) occurred following the first or second dose. Visual adverse reactions lasted several hours and recurred upon subsequent dosing in some patients. For patients who continued treatment, some visual adverse reactions resolved on therapy while others persisted through the full course of treatment.

Females and patients under 40 years old experienced a higher incidence of Ketec-associated visual adverse reactions. Table 2 provides the incidence of all visual adverse reactions in controlled Phase 3 studies by age and gender. The group with the highest incidence was females under the age of 40, while males over the age of 40 had rates of visual adverse reactions similar to comparator-treated patients.

Table 2: Incidence of All Visual Adverse Reactions in Controlled Phase 3 Studies

Urogenital system: vaginal candidiasis, vaginitis, vaginosis fungal

Skin: rash

Hematologic: increased platelet count

Frequency of Less Than 0.2%

Other clinically-significant adverse reactions occurring in less than 0.2% of patients treated with Ketec from the controlled Phase 3 studies included: anxiety, bradycardia, eczema, elevated blood bilirubin, erythema multiforme, flushing, hypotension, increased blood alkaline phosphatase, increased eosinophil count, paresthesia, pruritus, urticaria.

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of Ketec. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Allergic: face edema, severe allergic (hypersensitivity) reactions, including angioedema and anaphylaxis

Cardiovascular: atrial arrhythmias, ventricular arrhythmias (including ventricular tachycardia and torsades de pointes) with potential fatal outcome, palpitation, ischemic cardiac events in the context of hypersensitivity reactions

Gastrointestinal system: pseudomembranous colitis, pancreatitis

Liver and biliary system: Hepatic dysfunction, fulminant hepatitis, hepatic necrosis, and hepatic failure, chromaturia

Musculoskeletal: muscle cramps, arthralgia, myalgia, exacerbation of myasthenia gravis

Nervous system: loss of consciousness, in some cases associated with vagal syndrome, tremor, convulsions

Psychiatric disorders: confusion, hallucinations (mostly visual)

Special senses: taste/smell perversion and/or loss, hearing loss

Respiratory, thoracic and mediastinal disorders: dyspnea

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 Ketec is unknown.

The pharmacokinetics of telithromycin after administration of single and multiple (7 days) once daily 800-mg doses to healthy adult subjects are shown in Table 4.

Table 4: Pharmacokinetics of Telithromycin in Healthy Subjects

In patients, mean peak and trough plasma concentrations were 2.9 μg/mL (±1.55), (n=219) and 0.2 μg/mL (±0.22), (n=204), respectively, after 3 to 5 days of Ketec 800 mg once daily. Steady-state plasma concentrations are reached within 2 to 3 days of once daily dosing with Ketec 800 mg.

Absorption

Following oral administration, telithromycin reached maximal concentration at about 1 hour (0.5 – 4 hours). Ketec has an absolute bioavailability of 57% in both young and elderly subjects.

The rate and extent of absorption are unaffected by food intake, thus Ketec tablets can be given without regard to food.

Distribution

Total in vitro protein binding is approximately 60% to 70% and is primarily due to human serum albumin.

Protein binding is not modified in elderly subjects or in patients with hepatic impairment.

The volume of distribution of telithromycin after intravenous infusion is 2.9 L/kg.

Telithromycin concentrations in bronchial mucosa, epithelial lining fluid, and alveolar macrophages after 800 mg once daily dosing for 5 days in patients are displayed in Table 5.

Table 5

Metabolism

In total, approximately 70% of the telithromycin dose is metabolized. In plasma, the main circulating compound after administration of an 800-mg radio-labeled dose was parent compound, representing 56.7% of the total radioactivity. The main metabolite represented 12.6% of the AUC of telithromycin. Three other plasma metabolites were quantified, each representing 3% or less of the AUC of telithromycin.

It is estimated that approximately 50% of its metabolism is mediated by CYP3A4 and the remaining 50% is CYP -independent.

Excretion

The systemically available telithromycin is eliminated by multiple pathways as follows: 7% of the dose is excreted unchanged in feces by biliary and/or intestinal secretion; 13% of the dose is excreted unchanged in urine by renal excretion; and 37% of the dose is metabolized by the liver. Following oral dosing, the mean terminal elimination half-life of telithromycin is 10 hours.