Ketek - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Ketek 400 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film- coated tablet contains 400 mg of telithromycin.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet.

Light orange, oblong, biconvex tablet, imprinted with ‘H3647’ on one side and ‘40

4. CLINICAL PARTICULARS4.1 Therapeutic indications

When prescribing Ketek, consideration should be given to official guidance on the appropriate use of antibacterial agents and the local prevalence of resistance (see also sections 4.4 and 5.1).

Ketek is indicated for the treatment of the following infections:

In patients of 18 years and older:

• • Community-acquired pneumonia, mild or moderate (see section 4.4).
• • 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 (see sections 4.4 and 5.1):

• – Acute exacerbation of chronic bronchitis,

• – Acute sinusitis

In 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 prevalence of macrolide resistant S. pyogenes, when mediated by ermTR or mefA (see sections 4.4 and 5.1).

4.2 Posology and method of administration

Pos oiogy

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 by Streptococcus 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 population

No 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 (see section 5.2). Ketek is not recommended in this population.

Renal impairment

No 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, thes patients may be treated with alternating daily doses of 800 mg and 400 mg, starting with the 800 mg dose.

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In haemodialysed patients, the posology should be adjusted so that Ketek 800 mg is given dialysis session (see also section 5.2).

Hepatic impairment

No 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 (see also sections 4.4 and 5.2).

Method of administration

The tablets should be swallowed whole with a sufficient amo 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 (see section

4.3 Contraindications

Hypersensitivity to the active substance, excipients listed in section 6.1.

r jaundice associated with the use of telithromycin.

Concomitant administration with medicinal products that prolong the QT interval and are CYP3A4 substrates, such       pride, pimozide, astemizole, terfenadine, dronedarone, saquinavir (see section

4.5).

inistration with ergot alkaloid derivatives (such as ergotamine and e) (see section 4.5).

omitant administration with simvastatin, atorvastatin, and lovastatin. Treatment with these s should be interrupted during Ketek treatment (see section 4.5).

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 azole antifungals (e.g. ketoconazole, fluconazole), is contraindicated.

Concomitant administration of Ketek and colchicine in patients with renal and/or hepatic impairment (see section 4.5).

4.4 Special warnings and precautions for use

QT interval prolongation

Due to a potential to increase the QT interval, Ketek should be used with care in patients with coronary heart disease, a history of ventricular arrhythmias, uncorrected hypokalaemia and/or hypomagnesaemia, or bradycardia (<50 bpm), during concomitant administration of Ketek with QT interval prolonging agents, or in patients concomitantly treated with potent CYP 3A4 inhibitors such as protease inhibitors or azole antifungals (e.g. ketoconazole, fluconazole) (see sections 4.3 and 4.5). Ventricular arrhythmias (including ventricular tachycardia, torsade de pointes) have been reported in patients treated with telithromycin and sometimes occurred within a few hours of the first dose (see section 4.8).

Clostridium difficile-associated disease

Diarrhoea, particularly if severe, persistent and /or bloody, during or after treatment wi

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 gravis

Exacerbations 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 disorders

Alterations 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 (see section 4.8). 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 (see section 5.2).

urbances particularly in slowing the ability to accommodate and the ation. Visual disturbances included blurred vision, difficulty focusing,

and diplopia. Most events were mild to moderate; however, severe cases have been reported. The onset of the visual reaction may be sudden. It is important that patients prescribed telithromycin should be informed that visual adverse reactions may occur during the treatment (see sections 4.7 and

onsciousness

There have been post-marketing adverse reaction reports of transient loss of consciousness including some cases associated with vagal syndrome (see sections 4.7 and 4.8).

Consideration may be given to taking Ketek at bedtime, to reduce the potential impact of visual disturbances and loss of consciousness.

CYP3A4 inducers

Ketek 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 (see section 4.5).

CYP3A4 substrates

Ketek 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. (See sections 4.3 and 4.5).

Resistance

In 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 as pneumococcal bacteraemia or age higher than 65 years.

Experience of treatment of infections caused by penicillin/or erythromycin resistant S. pneumoniae is limited, but so far, clinical efficacy and eradication rates have been similar compared with the treatment of susceptible S. pneumoniae. Caution should be taken when S. aureus is the suspected pathogen and there is a likelihood of erythromycin resistance based on local epidemiology.

• L. pneumophila is highly susceptible to telithromycin in vitro , however, the clinical experience of the treatment of pneumonia caused by legionella is limited.

As for macrolides, H. influenzae is classified as intermediately susceptible. This should be taken into account when treating infections caused by H. influenzae.

4.5 Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

Effect of Ketek on other medicinal products

Telithromycin is an inhibitor of CYP3A4 and a weak inhibitor of CYP2D6. In vivo studies 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.

Telithromycin is also a P-glycoprotein inhibitor. Concomitant administration of Ketek with drugs that are substrates of P-glycoprotein might result in increased exposure to the P-glycoprotein substrates such as digoxin and dabigatran etexilate. If telithromycin is co-administered with dabigatran etexilate close clinical monitoring (looking for signs of bleeding or anaemia) should be exercised.

Cy ciosporin, tacrolimus, sirolimus

Due 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.

Metoprolol

When metoprolol (a CYP2D6 substrate) was coadministered with Ketek, metropolol Cmax and 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 interval

Ketek is expected to increase the plasma levels of cisapride, pimozide, astemizole, terfenadine, dronedarone, saquinavir. 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 (see section 4.3).

Caution is warranted when Ketek is administered to patients taking other medicinal products with the potential to prolong the QT interval (see section 4.4). These include Class IA (e.g.quinidine, procainamide, disopyramide) and Class III (e.g. dofetilide, amiodarone) antiarrhythmic agents, citalopram, tricyclic antidepressants, methadone, some antipsychotics (e.g. phenothiazines), fluoroquinolones (e.g. moxifloxacin), some antifungals (e.g. fluconazole, pentamidine), and some antiviral drugs (e.g. telaprevir).

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 (see section 4.3).

Statins

When 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 Cmax and 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 (see section 4.3). 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.

Benzodiazepines

When 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 halflife 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.

Dig oxin

Ketek has been shown to increase the plasma concentrations of digoxin, a P-glycoprotein substrate. 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.

Theophylline

There 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 anticoagulants

Increased 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 contraceptives

There is no pharmacodynamic or clinically relevant pharmacokinetic interaction with low-dose triphasic oral contraceptives in healthy subjects.

Colchicine

Colchicine intoxication, including fatal cases, has been reported in patients treated with colchicine and strong CYP 3A4 inhibitors. Telithromycin is known to be a strong CYP3A4 inhibitor and is also P-glycoprotein inhibitor. Exposure to colchicine, a CYP3A4 and P-glycoprotein substrate, may therefore be expected to increase if Ketek and colchicine are co-administered. Concomitant administration of Ketek and colchicine is contraindicated in patients with renal and/or hepatic impairment (see section 4.3).

Calcium channel blockers that are metabolized by CYP3A4

Concomitant administration of strong CYP3A4 inhibitors (such as telithromycin) and calcium channel

blockers that are metabolized by CYP3A4 (e.g. verapamil, nifedipine, felodipine) may result in

hypotension, bradycardia or loss of consciousness, and should ther combination is considered necessary, the dose of the calcium channel blocker should be reduced and close clinical monitoring of efficacy and safety in the patient should be exercised.

Sotalol

Telithromycin has been shown to decrease the Cmax by 34 % and AUC of sotalol by 20 % due to decreased absorption.

Effect of other medicinal products on Ketek

During concomitant administration of rifampicin and telithromycin in repeated doses, Cmax and 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.

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 (see section 4.3).

Ranitidine (taken 1 hour before Ketek) and antacid containing aluminium and magnesium hydroxide has no clinically relevant influence on telithromycin pharmacokinetics.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of Ketek in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Ketek should not be used during pregnancy unless clearly necessary.

Breastfeeding

Telithromycin is excreted in the milk of lactating animals, at concentrations about 5 times those of maternal plasma. Corresponding data for humans is not available. Ketek should not be used by breastfeeding wo­men.

Fertility

I n studi es wi th rats a reducti on in fertility i ndi ces was observed at parental l y toxi c doses (see sect on 5.3).

4.7 Effects on ability to drive and use machines

Ketek may cause adverse reactions such as visual disturbances, confusion or hallucination which may reduce the capacity for the completion of certain tasks. In addition, rare cases of transient loss of consciousness, which may be preceded by vagal symptoms, have been reported (see section 4.8). Because of potential visual difficulties, loss of consciousness, confusion or hallucination, 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, loss of consciousness, confusion or hallucination while taking Ketek, patients should not drive a motor vehicle, operate heavy machinery or engage in other hazardous activities (see sections 4.4 and 4.8).

Patients should be informed that these adverse reactions may occur as early as after the first dose of medicinal product. Patients should be cautioned about the potential effects of these events on the ability to drive or operate machinery.

4.8 Undesirable effects

Tabulated list of adverse reaction.

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 class	Very 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 disorders			Eosinophilia

System organ class	Very 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)
Immune system disorders					(	Angioneurotic oedema, anaphylactic reactions including anaphylactic shock, hyper-se nsitivity
Psychiatric disorders						Confusion, hallucination
Nervous system disorders		Dizziness, headache, disturbance of taste	Vertigo somnolence, nervousness, insomnia,	Transient loss of consciousness, paraesthesia y	Parosmia	Cases of rapid onset of exacerbation of myasthenia gravis have been reported (see sections 4.3 and 4.4). Ageusia, anosmia, tremors, convulsions
Eye disorders			Blurred vision	Diplopia
Cardiac disorders		>	Flush Palpitations	Atrial arrhythmia, hypotension, bradycardia		QT/QTc interval prolongation, ventricular arrhythmia (including ventricular tachycardia, torsade de pointes) with potential fatal outcome (see section 4.4)
Ga str oimestinal disorders **	Diarrhoe a	Nausea, vomiting, gastrointestinal pain, flatulence	Oral Candida infection, stomatitis anorexia, constipation		Pseudo-membranou s colitis (see section 4.4)	Pancreatitis

System organ class	Very 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)*
Hepatobiliary disorders		Increase in liver enzymes (AST, ALT, alkaline phosphatase, gammaglutamyl transferase)	Hepatitis	Cholestatic jaundice		Severe hepatitis and liver failure (see section 4.4)
Skin and subcutaneous tissue disorders			Rash, urticaria, pruritus	Eczema	Erythema multiforme
Musculoskeletal and connective tissue disorders					Muscle cramps	Arthralgia, myalgia
Reproductive system and breast disorders		Vaginal Candida infection

*post-marketing experience

Description of selected adverse reactions

Visual disturbances (<1%) associated with the use of Ketek, including blurred vision, difficulty focusing and diplopia, were mostly mild to moderate, but severe reactions have also been reported. 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. The onset of the visual reaction may be sudden. These events have not been associated with signs of ocular abnormality (see sections 4.4 and 4.7).

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 AQTc >30 msec in 7.6% and 7.0% of cases, res pectively. No patient in either group developed a AQTc >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.

Reporting o f suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare prof essionals are asked to report any suspected adverse reactions via the national reporting system ’isted in Appendix V.

4.9 Overdose

In the event of acute overdose the stomach should be emptied. The patients should be carefully observed and given symptomatic and supportive treatment. Adequate hydration should be maintained. Blood electrolytes (especially potassium) must be controlled. Due to the potential for the prolongation of the QT interval and increased risk of arrhythmia, ECG monitoring must take place.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antibacterials for systemic use, macrolides, lincosamides and streptogramins, ATC Code: J01FA15.

1The correlation between macrolide MICs and clinical outcome is weak for H. influenzae. Therefore the MIC breakpoint for telithromycin was set to categorise wild-type H. influenzae as having intermediate susceptibility.

Antibacterial spectrum

The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Commonly susceptible species

Aerobic Gram-positive bacteria

Staphylococcus aureus methicillin susceptible (MSSA)

Streptococcus pneumoniae

Streptococcus species

Viridans group streptococci

Aerobic Gram- negative bacteria

Haemophilus influenzae $

Haemophilus parainfluenzae $

Legionella pneumophila

Moraxella catarrhalis

Other

Chlamydophila pneumoniae

Chlamydia psittaci

Mycoplasma pneumoniae

Species for which acquired resistance may be a problem

Aerobic Gram-positive bacter i a

Staphylococcus aureus methicillin resistant (MRSA)+

Streptococcus pyogenes

Inherently resistant organisms

Aerobic Gram- r egative bacteria

Acinetobacter

Enterobacteri­aceae

Pseudomonas

rate and extent of absorption is unaffected by food intake, and thus Ketek tablets can be given without regard to food.

Mean steady-state trough plasma concentrations of between 0.04 and 0.07 mg/l are reached within 3 to 4 days with once-daily dosing of telithromycin 800 mg. At steady-state AUC is approximately 1.5 fold increased compared to the single dose.

Mean peak and trough plasma concentrations at steady state in patients were 2.9± 1.6 mg/l (range 0.02–7.6 mg/l) and 0.2± 0.2 mg/l (range 0.010 to 1.29 mg/l), during a therapeutic 800 mg once-daily dose regimen.

Distribution

The in vitro protein binding is approximately 60% to 70%. Telithromycin is widely distrib throughout the body. The volume of distribution is 2.9±1.0 l/kg. Rapid distribution of telithromycin into tissues results in significantly higher telithromycin concentrations in most target tissues than in plasma. The maximum total tissue concentration in epithelial lining fluid, alveolar macrophages, bronchial mucosa, tonsils and sinus tissue were 14.9±11.4 mg/l, 318.1±231 mg/l, 3.88±1.87 mg/kg,

3.95±0.53 mg/kg and 6.96±1.58 mg/kg, respectively. The total tissue concent

epithelial lining fluid, alveolar macrophages, bronchial mucosa, tonsils 0.84±0.65 mg/l, 162±96 mg/l, 0.78±0.39 mg/kg, 0.72±0.29 mg/kg and 1

The mean maximum white blood cell concentration of telithromycin wa

Biotransformation

Telithromycin is metabolised primarily by the liver. Aft

is eliminated as metabolites and one-third unchanged. The main circulating compound in plasma is telithromycin. Its principal circulating metabolite represents approximately 13% of telithromycin AUC, and has little antimicrobial activity compared with the parent medicinal product. Other metabolites were detected in plasma, urine and faeces and represent less or equal than 3% of plasma AUC.

Telithromycin is metabolised both by CYP450 isoenzymes and non-CYP enzymes. The major CYP450 enzyme involved in the metabolism of telithromycin is CYP3A4. Telithromycin is an inhibitor of CYP3A4 and CYP2D6, but has no or limited effect on CYP1A, 2A6, 2B6, 2C8, 2C9, 2C19 and 2E1.

After oral administration of radiolabelled telithromycin, 76% of the radioactivity was recovered from faeces, and 17% from the urine. Approximately one-third of telithromycin was eliminated unchanged; 20% in faeces and 12% in urine. Telithromycin displays moderate non-linear pharmacokinetics. The non-renal clearance is decreased as the dose is increased. The total clearance (mean ±SD) is approximately 58±5 l/h after an intravenous administration with renal clearance accounting for about of this. Telithromycin displays a tri-exponential decay from plasma, with a rapid distribution life of 0.17 h. The main elimination half-life of telithromycin is 2–3 h and the terminal, less portant, half-life is about 10 h at the dose 800 mg once daily.

Special populations -Renal impairment

In a multiple-dose study, 36 subjects with varying degrees of renal impairment, a 1.4-fold increase in Cmax,ss, and a 2-fold increase in AUC (0–24)ss at 800 mg multiple doses in the severe renally impaired group (CLCR < 30 ml/min) compared to healthy volunteers were observed and a reduced dosage of Ketek is recommended (see section 4.2). Based on observed data, a 600 mg daily dose is approximately equivalent with the target exposure observed in healthy subjects. Based on simulation data, an alternating daily dosing regimen of 800 mg and 400 mg in patients with severe renal impairment can approximate the AUC (0–48h) in healthy subjects receiving 800 mg once daily.

The effect of dialysis on the elimination of telithromycin has not been assessed.

• - Hepatic impairment

In a single-dose study (800 mg) in 12 patients and a multiple-dose study (800 mg) in 13 patients with mild to severe hepatic insufficiency (Child Pugh Class A, B and C), the Cmax, AUC and t1/2 of telithromycin were similar compared to those obtained in age- and sex-matched healthy subjects. In both studies, higher renal elimination was observed in the hepatically impaired patients. Due to limited experience in patients with decreased metabolic capacity of the liver, Ketek should be used with caution in patients with hepatic impairment (see also section 4.4).

• - Elderly subjects

In subjects over 65 (median 75 years), the maximum plasma concentration and AUC of telithromycin were increased approximately 2-fold compared with those achieved in young healthy adults. These changes in pharmacokinetics do not necessitate dosage adjustment.

• - Paediatric population

Limited data, obtained in paediatric patients 13 to 17 years of age, showed that telithromycin concentrations in this age group were similar to the concentrations in patients 18 to 40 years of age.

-Gender

The pharmacokinetics of telithromycin is similar between males and females.

5.3 Preclinical safety data

Repeated dose toxicity studies of 1, 3 and 6 month 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. These effects showed a tendency to regress after cessation of treatment. Plasma exposures based on free fraction of active substance, at the no observed adverse effect levels ranged from 1.6 to 13 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 in rats and dogs administered telithromycin at repeated doses of 150 mg/kg/day or more for 1 month and 20 mg/kg/day or more for 3–6 months. This administration corresponds to free active substance systemic exposure levels of at least 9 times the expected levels in human after 1 month and less than the expected level in humans after 6 months, respectively. There was evidence of reversibility upon cessation of treatment. The significance of these findings for humans is unknown.

In similarity to some macrolides, telithromycin caused a prolongation of QTc interval in dogs and on action potential duration in rabbit Purkinje fibers in vitro. Effects were evident at plasma levels of free drug 8 to 13 times the expected clinical level. Hypokalaemia and quinidine had additive/supra-additive effects in vitro while potentiation was evident with sotalol. Telithromycin, but not its major human metabolites, had inhibitory activity on HERG and Kv1.5 channels.

Reproduction toxicity studies showed reduced gamete maturation in rat and adverse effects on fertilization. Slight reductions in fertility indices were seen in rats at parentally toxic doses higher than 150 mg/kg. At high doses embryotoxicity was apparent and an increase in incomplete ossification and in skeletal anomalies was seen. Studies in rats and rabbits were inconclusive with respect to potential for teratogenicity; there was equivocal evidence of adverse effects on foetal development at high doses.

Telithromycin, and its principal human metabolites, were negative in tests on genotoxic potential in vitro and in vivo. No carcinogenicity studies have been conducted with telithromycin.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

• 3 years.

6.4 Special precautions for storage

6.5 Nature and contents of container

7. MARKETING AUTHORISATION HOLDER

8. MARKETING AUTHORISATION NUMBERS

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION