Drug Class Description
Macrolides, Lincosamides and Streptogramins

Generic Name
Telithromycin

Drug Description
Each film-coated tablet contains 400 mg of telithromycin.

Presentation
Film-coated tablet.Light orange, oblong, biconvex tablet, imprinted with 'H3647' on one side and '400' on the other.

Indications
When prescribing Ketek, consideration should be given to official guidance on the appropriate use of antibacterial agents and the local preva lence of resistance.Ketek is indicated for the treatment of the following infections:In patients of 18 years and older:• Community-acquired pneumonia, mild or moderate.• When treating infections caused by known or suspected beta-lactam and/or macrolide resistant strains (according to history of patients or national and/or regional resistance data) covered by the antibacterial spectrum of telithromycin:- Acute exacerbation of chronic bronchitis,- Acute sinusitisIn patients of 12 years and older:• Tonsillitis/pharyngitis caused by Streptococcus pyogenes, as an alternative when beta lactam antibiotics are not appropriate in countries/regions with a significant preva lence of macrolide resistantS. pyogenes, when mediated by ermTR or mefA

Adult Dosage
The recommended dose is 800 mg once a day i.e. two 400 mg tablets once a day.In patients of 18 years and older, according to the indication, the treatment regimen will be:- Community-acquired pneumonia: 800 mg once a day for 7 to 10 days,- Acute exacerbation of chronic bronchitis: 800 mg once a day for 5 days,- Acute sinusitis: 800 mg once a day for 5 days,- Tonsillitis/pharyngitis caused byStreptococcus pyogenes:800 mg once a day for 5 days.In patients of 12 to 18 years old, the treatment regimen will be:- Tonsillitis/pharyngitis caused by Streptococcus pyogenes:800 mg once a day for 5 days.Elderly populationNo dosage adjustment is required in elderly patients based on age alone.Paediatric population:The safety and efficacy of Ketek in children below 12 years of age have not been established. Ketek is not recommended in this population.Renal impairmentNo dosage adjustment is necessary in patients with mild or moderate renal impairment. Ketek is not recommended as first choice in patients with severe renal impairment (creatinine clearance <30 ml/min) or patients with both severe renal impairment and co-existing hepatic impairment, as an optimal dosage format (600 mg) is not available. If telithromycin treatment is deemed necessary, these patients may be treated with alternating daily doses of 800 mg and 400 mg, starting with the 800 mg dose.In haemodialysed patients, the posology should be adjusted so that Ketek 800 mg is given after the dialysis session.Hepatic impairmentNo dosage adjustment is necessary in patients with mild, moderate, or severe hepatic impairment, however the experience in patients with impaired hepatic function is limited. Hence, telithromycin should be used with caution.Method of administrationThe tablets should be swallowed whole with a sufficient amount of water. The tablets may be taken with or without food.Consideration may be given to taking Ketek at bedtime, to reduce the potential impact of visual disturbances and loss of consciousness

Child Dosage
The recommended dose is 800 mg once a day i.e. two 400 mg tablets once a day.In patients of 18 years and older, according to the indication, the treatment regimen will be:- Community-acquired pneumonia: 800 mg once a day for 7 to 10 days,- Acute exacerbation of chronic bronchitis: 800 mg once a day for 5 days,- Acute sinusitis: 800 mg once a day for 5 days,- Tonsillitis/pharyngitis caused byStreptococcus pyogenes:800 mg once a day for 5 days.In patients of 12 to 18 years old, the treatment regimen will be:- Tonsillitis/pharyngitis caused by Streptococcus pyogenes:800 mg once a day for 5 days.Elderly populationNo dosage adjustment is required in elderly patients based on age alone.Paediatric population:The safety and efficacy of Ketek in children below 12 years of age have not been established. Ketek is not recommended in this population.Renal impairmentNo dosage adjustment is necessary in patients with mild or moderate renal impairment. Ketek is not recommended as first choice in patients with severe renal impairment (creatinine clearance <30 ml/min) or patients with both severe renal impairment and co-existing hepatic impairment, as an optimal dosage format (600 mg) is not available. If telithromycin treatment is deemed necessary, these patients may be treated with alternating daily doses of 800 mg and 400 mg, starting with the 800 mg dose.In haemodialysed patients, the posology should be adjusted so that Ketek 800 mg is given after the dialysis session.Hepatic impairmentNo dosage adjustment is necessary in patients with mild, moderate, or severe hepatic impairment, however the experience in patients with impaired hepatic function is limited. Hence, telithromycin should be used with caution.Method of administrationThe tablets should be swallowed whole with a sufficient amount of water. The tablets may be taken with or without food.Consideration may be given to taking Ketek at bedtime, to reduce the potential impact of visual disturbances and loss of consciousness

Elderly Dosage
The recommended dose is 800 mg once a day i.e. two 400 mg tablets once a day.In patients of 18 years and older, according to the indication, the treatment regimen will be:- Community-acquired pneumonia: 800 mg once a day for 7 to 10 days,- Acute exacerbation of chronic bronchitis: 800 mg once a day for 5 days,- Acute sinusitis: 800 mg once a day for 5 days,- Tonsillitis/pharyngitis caused byStreptococcus pyogenes:800 mg once a day for 5 days.In patients of 12 to 18 years old, the treatment regimen will be:- Tonsillitis/pharyngitis caused by Streptococcus pyogenes:800 mg once a day for 5 days.Elderly populationNo dosage adjustment is required in elderly patients based on age alone.Paediatric population:The safety and efficacy of Ketek in children below 12 years of age have not been established. Ketek is not recommended in this population.Renal impairmentNo dosage adjustment is necessary in patients with mild or moderate renal impairment. Ketek is not recommended as first choice in patients with severe renal impairment (creatinine clearance <30 ml/min) or patients with both severe renal impairment and co-existing hepatic impairment, as an optimal dosage format (600 mg) is not available. If telithromycin treatment is deemed necessary, these patients may be treated with alternating daily doses of 800 mg and 400 mg, starting with the 800 mg dose.In haemodialysed patients, the posology should be adjusted so that Ketek 800 mg is given after the dialysis session.Hepatic impairmentNo dosage adjustment is necessary in patients with mild, moderate, or severe hepatic impairment, however the experience in patients with impaired hepatic function is limited. Hence, telithromycin should be used with caution.Method of administrationThe tablets should be swallowed whole with a sufficient amount of water. The tablets may be taken with or without food.Consideration may be given to taking Ketek at bedtime, to reduce the potential impact of visual disturbances and loss of consciousness

Contra Indications
Hypersensitivity to the active substance, to any of the macrolide antibacterial agents, or to any of the excipients.Myasthenia gravis.Previous history of hepatitis and/or jaundice associated with the use of telithromycin.Concomitant administration with any of the following substances: cisapride, ergot alkaloid derivatives (such as ergotamine and dihydroergotamine), pimozide, astemizole and terfenadine.Concomitant administration with simvastatin, atorvastatin, and lovastatin. Treatment with these agents should be interrupted during Ketek treatment.History of congenital or a family history of long QT syndrome (if not excluded by ECG) and in patients with known acquired QT interval prolongation.In patients with severely impaired renal and/or hepatic function, concomitant administration of Ketek and strong CYP3A4 inhibitors, such as protease inhibitors or ketoconazole, is contraindicated.

Special Precautions
QT interval prolongationDue to a potential to increase QT interval, Ketek should be used with care in patients with coronary heart disease, a history of ventricular arrhythmias, uncorrected hypokalaemia and or hypomagnesaemia, bradycardia (<50 bpm), or during concomitant administration of Ketek with QT interval prolonging agents or potent CYP 3A4 inhibitors such as protease inhibitors and ketoconazole.Clostridium difficile-associated diseaseDiarrhoea, particularly if severe, persistent and /or bloody, during or after treatment with Ketek may be caused by pseudomembranous colitis (see section 4.8). If pseudomembranous colitis is suspected, the treatment must be stopped immediately and patients should be treated with supportive measures and/or specific therapy.Myasthenia gravisExacerbations of myasthenia gravis have been reported in patients treated with telithromycin and sometimes occurred within a few hours of the first dose. Reports have included death and life threatening acute respiratory failure with rapid onset (see section 4.8).Hepatobiliary disordesAlterations in hepatic enzymes have been commonly observed in clinical studies with telithromycin. Post-marketing cases of severe hepatitis and liver failure, including fatal cases (which have generally been associated with serious underlying diseases or concomitant medicinal products), have been reported. These hepatic reactions were observed during or immediately after treatment, and in most cases were reversible after discontinuation of telithromycin.Patients should be advised to stop treatment and contact their doctor if signs and symptoms of hepatic disease develop such as anorexia, jaundice, dark urine, pruritus or tender abdomen.Due to limited experience, Ketek should be used with caution in patients with liver impairment.Visual disturbancesKetek 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 consciousnessThere have been post-marketing adverse reaction reports of transient loss of consciousness including some cases associated with vagal syndrome.Consideration may be given to taking Ketek at bedtime, to reduce the potential impact of visual disturbances and loss of consciousness.CYP3A4 inducersKetek should not be used during and 2 weeks after treatment with CYP3A4 inducers (such as rifampicin, phenytoin, carbamazepine, phenobarbital, St John's wort). Concomitant treatment with these medicinal products is likely to result in subtherapeutic levels of telithromycin and therefore encompass a risk of treatment failure.CYP3A4 substratesKetek is an inhibitor of CYP3A4 and should only be used under specific circumstances during treatment with other medicinal products that are metabolised by CYP3A4. Patients with concomitant treatment of pravastatin, rosuvastatin or fluvastatin should be carefully monitored for signs and symptoms of myopathy and rhabdomyolysis.ResistanceIn areas with a high incidence of erythromycin A resistance, it is especially important to take into consideration the evolution of the pattern of susceptibility to telithromycin and other antibiotics.In community acquired pneumonia, efficacy has been demonstrated in a limited number of patients with risk factors such aspneumococcal bacteraemiaor age higher than 65 years.Experience of treatment of infections caused by penicillin/or erythromycin resistantS. pneumoniaeis limited, but so far, clinical efficacy and eradication rates have been similar compared with the treatment of susceptibleS. pneumoniae. Caution should be taken whenS. aureusis the suspected pathogen and there is a likelihood of erythromycin resistance based on local epidemiology.L. pneumophilais highly susceptible to telithromycinin vitro, however, the clinical experience of the treatment of pneumonia caused bylegionellais limited.As for macrolides,H. influenzaeis classified as intermediately susceptible. This should be taken into account when treating infections caused byH. influenzae.

Interactions
Interaction studies have only been performed in adults.•Effect of Ketek on other medicinal productsTelithromycin is an inhibitor of CYP3A4 and a weak inhibitor of CYP2D6.In vivostudies with simvastatin, midazolam and cisapride have demonstrated a potent inhibition of intestinal CYP3A4 and a moderate inhibition of hepatic CYP3A4. The degree of inhibition with different CYP3A4 substrates is difficult to predict. Hence, Ketek should not be used during treatment with medicinal products that are CYP3A4 substrates, unless plasma concentrations of the CYP3A4 substrate, efficacy or adverse reactions can be closely monitored. Alternatively, interruption in the treatment with the CYP3A4 substrate should be made during treatment with Ketek.Cyclosporin, tacrolimus, sirolimusDue to its CYP3A4 inhibitory potential, telithromycin can increase blood concentrations of these CYP34A4 substrates. Thus, when initiating telithromycin in patients already receiving any of theses immunosuppressive agents, cyclosporin, tacrolimus or sirolimus levels must be carefully monitored and their doses decreased as necessary. When telithromycin is discontinued, cyclosporin, tacrolimus or sirolimus levels must be again carefully monitored and their dose increased as necessary.MetoprololWhen metoprolol (a CYP2D6 substrate) was coadministered with Ketek, metropolol Cmaxand AUC were increased by approximately 38%, however, there was no effect on the elimination half-life of metoprolol. The increase exposure to metoprolol may be of clinical importance in patients with heart failure treated with metoprolol. In these patients, co-administration of Ketek and metoprolol, a CYP2D6 substrate, should be considered with caution.Medicinal products with a potential to prolong QT intervalKetek is expected to increase the plasma levels of cisapride, pimozide, astemizole and terfenadine. This could result in QT interval prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and torsades de pointes. Concomitant administration of Ketek and any of these medicinal products is contraindicated.Caution is warranted when Ketek is administered to patients taking other medicinal products with the potential to prolong QT interval.Ergot alkaloid derivatives (such as ergotamine and dihydroergotamine)By extrapolation from erythromycin A and josamycin, concomitant medication of Ketek and alkaloid derivatives could lead to severe vasoconstriction (“ergotism”) with possibly necrosis of the extremities. The combination is contraindicated.StatinsWhen simvastatin was coadministered with Ketek, there was a 5.3 fold increase in simvastatin Cmax, an 8.9 fold increase in simvastatin AUC, a 15-fold increase in simvastatin acid Cmaxand an 11-fold increase in simvastatin acid AUC. Ketek may produce a similar interaction with lovastatin and atorvastatin which are also mainly metabolised by CYP3A4. Ketek should therefore not be used concomitantly with simvastatin, atorvastatin, or lovastatin. Treatment with these agents should be interrupted during Ketek treatment. The exposure of pravastatin, rosuvastatin and to a lesser extent fluvastatin, may be increased due to possible involvement of transporters proteins, but this increase is expected to be lesser than interactions involving CYP3A4 inhibition. However, patients should be carefully monitored for signs and symptoms of myopathy and rhabdomyolysis when co-treated with pravastatin, rosuvastatin and fluvastatin.BenzodiazepinesWhen midazolam was coadministered with Ketek, midazolam AUC was increased 2.2-fold after intravenous administration of midazolam and 6.1-fold after oral administration. The midazolam half-life was increased about 2.5-fold. Oral administration of midazolam concomitantly with Ketek should be avoided. Intravenous dosage of midazolam should be adjusted as necessary and monitoring of the patient should be undertaken. The same precautions should also apply to the other benzodiazepines which are metabolised by CYP3A4, (especially triazolam but also to a lesser extent alprazolam). For those benzodiazepines which are not metabolised by CYP3A4 (temazepam, nitrazepam, lorazepam) an interaction with Ketek is unlikely.DigoxinKetek has been shown to increase the plasma concentrations of digoxin. The plasma trough levels, Cmax, AUC and renal clearance were increased by 20%, 73%, 37% and 27% respectively, in healthy volunteers. There were no significant changes in ECG parameters and no signs of digoxin toxicity were observed. Nevertheless, monitoring of serum digoxin level should be considered during concomitant administration of digoxin and Ketek.TheophyllineThere is no clinically relevant pharmacokinetic interaction of Ketek and theophylline administered as extended release formulation. However, the co-administration of both medicinal products should be separated by one hour in order to avoid possible digestive side effects such as nausea and vomiting.Oral anticoagulantsIncreased anticoagulant activity has been reported in patients simultaneously treated with anticoagulants and antibiotics, including telithromycin. The mechanisms are incompletely known. Although Ketek has no clinically relevant pharmacokinetic or pharmacodynamic interaction with warfarin after single dose administration, more frequent monitoring of prothrombin time/INR (International Normalised Ratio) values should be considered during concomitant treatment.Oral contraceptivesThere is no pharmacodynamic or clinically relevant pharmacokinetic interaction with low-dose triphasic oral contraceptives in healthy subjects.•Effect of other medicinal products on KetekDuring concomitant administration of rifampicin and telithromycin in repeated doses, Cmaxand AUC of telithromycin were on average decreased by 79% and 86% respectively. Therefore, concomitant administration of CYP3A4 inducers (such as rifampicin, phenytoin, carbamazepine, phenobarbital, St John's wort) is likely to result in subtherapeutic levels of telithromycin and loss of effect. The induction gradually decreases during 2 weeks after cessation of treatment with CYP3A4 inducers. Ketek should not be used during and 2 weeks after treatment with CYP3A4 inducers.Interaction studies with itraconazole and ketoconazole, two CYP3A4 inhibitors, showed that maximum plasma concentrations of telithromycin were increased respectively by 1.22 and 1.51 fold and AUC by respectively 1.54 fold and 2.0 fold. These changes in the pharmacokinetics of telithromycin do not necessitate dosage adjustment as telithromycin exposure remains within a well tolerated range. The effect of ritonavir on telithromycin has not been studied and could lead to larger increase in telithromycin exposure. The combination should be used with caution.Strong CYP3A4 inhibitors must not be co-administered with Ketek in patients with severe renal/or hepatic dysfunction.Ranitidine (taken 1 hour before Ketek) and antacid containing aluminium and magnesium hydroxide has no clinically relevant influence on telithromycin pharmacokinetics.

Adverse Reactions
In 2,461 patients treated by Ketek in phase III clinical trials, and during post-marketing experience, the following undesirable effects possibly or probably related to telithromycin have been reported. This is shown in the table below. Diarrhoea, nausea and dizziness were the most commonly reported adverse reactions in phase III clinical trials.Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.System organ classVery common(1/10)Common(1/100 to <1/10 )Uncommon(1/1,000 to <1/100)Rare(1/10,000 to <1/1,000)Very rare(< 1/10,000)Not known (cannot be estimated from the available data)*Blood and the lymphatic system disordersEosinophiliaImmune system disordersAngioneurotic oedema, anaphylactic reactions including anaphylactic shock, hyper-sensitivityPsychiatric disordersConfusion, hallucinationNervous system disordersDizziness, headache, disturbance of tasteVertigo somnolence, nervousness, insomnia,Transient loss of consciousness, paraesthesiaParosmiaCases of rapid onset of exacerbation of myasthenia gravis have been reported. Ageusia, anosmia,Eye disordersBlurred visionDiplopiaCardiac disordersFlushPalpitationsAtrial arrhythmia, hypotension, bradycardiaQT/QTc interval prolongationGastrointestinal disordersDiarrhoeaNausea, vomiting, gastrointestinal pain, flatulenceOralCandidainfection, stomatitis anorexia, constipationPseudomembranous colitisPancreatitisHepatobiliary disordersIncrease in liver enzymes (AST, ALT, alkaline phosphatase)HepatitisCholestatic jaundiceSevere hepatitis and liver failureSkin and subcutaneous tissue disordersRash, urticaria, pruritusEczemaErythema multiformeMusculoskeletal and connective tissue disordersMuscle crampsArthralgia, myalgiaReproductive system and breast disordersVaginalCandidainfection*post-marketing experienceDescription of selected adverse reactionsVisual disturbances (<1%) associated with the use of Ketek, including blurred vision, difficulty focusing and diplopia, were mostly mild to moderate. They typically occurred within a few hours after the first or second dose, recurred upon subsequent dosing, lasted several hours and were fully reversible either during therapy or following the end of treatment. These events have not been associated with signs of ocular abnormality.In clinical trials the effect on QTc was small (mean of approximately 1 msec). In comparative trials, similar effects to those observed with clarithromycin were seen with an on-therapy ΔQTc >30 msec in 7.6% and 7.0% of cases, respectively. No patient in either group developed a ΔQTc >60 msec. There were no reports of TdP or other serious ventricular arrhythmias or related syncope in the clinical program and no subgroups at risk were identified.

Manufacturer
Sanofi-Aventis

Drug Availability
(POM)

Updated
23 November 2011