Levviax - summary of medicine characteristics

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film- coated tablet contains 400 mg of telithromycin.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet.

Light orange, oblong, biconvex tablet, imprinted with H3647 on one

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

When prescribing Levviax, consideration should be given to o of antibacterial agents and the local prevalence of resistance (see also sections 4.4 and 5.1).

Levviax 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

The recommended dose is 800 mg once a day i.e. two 400 mg tablets once a day. The 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 Levviax at bedtime, to reduce the potential impact of visual disturbances and loss of consciousness (see section 4.4).

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,

• – 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.

In the elderly:

No dosage adjustment is required in elderly patients based on age alone.

In children:

Levviax is not recommended for use in children below 12 years of age due to lack of data on safety and efficacy (see section 5.2).

Impaired renal function:

No dosage adjustment is necessary in patients with mild or moderate renal impairment. Levviax is not recommended as first choice in patients with severe renal impairment (creatinine clearance <30ml/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 Levviax 800 mg is given after the dialysis session (see also section 5.2).

Impaired hepatic function:

No dosage adjustment is necessary in patients with mild, moderate, or severe hepatic impairment, unless renal function is severely impaired, however the experience in patients with impaired hepatic function is limited. Hence, Levviax should be used with caution (see also section 4.4 and 5.2).

4.3 Contraindications

Levviax is contraindicated in patients with myasthenia gravis (see section 4.4).

Hypersensitivity to the active substance, to any of the macrolide antibacterial agents, or to any of the excipients.

Levviax must not be used in patients with previous history of hepatitis and/or jaundice associated with the use of telithromycin.

astemizole and terfenadine (see section 4.5).

Levviax should not be used concomitantly with simvastatin, atorvastatin and lovastastin. Treatment with these agents should be interrupted during Levviax treatment (see section 4.5).

Levviax is contraindicated in patients with a 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 Levviax and strong CYP3A4 inhibitors, such as protease inhibitors or ketoconazole, is contraindicated.

4.4 Special warnings and precautions for useAs with macrolides, due to a potential to increase QT interval, Levviax should be used with care in

As with macrolides, due to a potential to increase QT interval, Levviax 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 Levviax with QT interval prolonging agents or potent CYP 3A4 inhibitors such as protease inhibitors and ketoconazole.

As with nearly all antibacterial agents, diarrhoea, particularly if severe, persistent and /or bloody, during or after treatment with Levviax may be caused by pseudomembranous colitis. If pseudomembranous colitis is suspected, the treatment must be stopped immediately and patients should be treated with supportive measures and/or specific therapy.

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).

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 medications), 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 sym disease develop such as anorexia, jaundice, dark urine, pruritus or tender abdomen.

Due to limited experience, Levviax should be used with caution in patients w section 5.2).

Levviax 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. (see sections 4.7 and 4.8).

There have been post-marketing adverse event 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 Levviax at disturbances and loss of consciousness.

Levviax 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).

Levviax is an inhibitor of CYP3A4 and should only be used under specific circumstances during treatment with other medicinal products that are metabolised by CYP3A4.

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 Levviax on other medicinal product

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, Levviax should not be used during treatment with medicinal products that are CYP3A4 substrates, unless plasma concentrations of the CYP3A4 substrate, efficacy or adverse events can be closely monitored. Alternatively, interruption in the treatment with the CYP3A4 substrate should be made during treatment with Levviax.

Medicinal products with a potential to prolong QT interval                      # GO

Levviax 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 Levviax and any of these medicinal products is contraindicated (see section 4.3).

Caution is warranted when Levviax is administered to patients taking other medicinal products with the potential to prolong QT interval (see section 4.4).

Ergot alkaloid derivatives (such as ergotamine and dihydroergotamine)

By extrapolation from erythromycin A and josamycin, concomitant medication of Levviax 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 Levviax, 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 simvastatine acid AUC. In vivo interaction studies with other statins have not been performed, but Levviax may produce a similar interaction with lovastatin and atorvastatin, a lesser interaction with cerivastatin and little or no interaction with pravastatin and fluvastatin. Levviax should not be used concomitantly with simvastatin, atorvastastin and lovastatin. Treatment with these agents should be interrupted during Levviax treatment. Cerivastatin should be used with caution and patients should be carefully monitored for signs and symptoms of myopathy.

Benzodiazepins

When midazolam was coadministered with Levviax, 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 Levviax should be avoided. Intravenous dosage of midazolam should be adjusted as necessary and monitoring of the patient be undertaken. The same precautions should also apply to the other benzodiazepins which are-metabolized by CYP3A4, (especially triazolam but also to a lesser extent alprazolam). For those benzodiazepins which are not metabolized by CYP3A4 (temazepam, nitrazepam, lorazepam) an interaction with Levviax is unlikely.

Cyclosporin, 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 Levviax, 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 Levviax and metoprolol, a CYP2D6 substrate, should be considered with caution.

Digoxin

Levviax 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 Levviax.

Theophylline

There is no clinically relevant pharmacokinetic interaction of Levviax 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 Levviax 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.

• • Effect of other medicinal products on Levviax

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. Levviax 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.

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

4.6 Pregnancy and lactation

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

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. Levviax should not be used by breast-feeding women.

4.7 Effects on ability to drive and use machines

Levviax may cause undesirable effects such as visual disturbances 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 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 Levviax. If patients experience visual disorders or loss of consciousness while taking Levviax 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 undesirable effects may occur as early as after the first dose of medication. Patients should be cautioned about the potential effects of these events on the ability to drive or operate machinery.

4.8 Undesirable effects

In 2461 patients treated by Levviax in phase III clinical trials, the following undesirable effects possibly or probably related to telithromycin have been reported. This is shown below.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Visual disturbances (<1%) associated with the use of Levviax, 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 (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, respectively. 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.

During post-marketing experience the following reactions have been reported (frequency unknown):

-Immune system disorders: Angioneurotic oedema, anaphylactic reactions including anaphylactic shock

-Cardiac disorders: QT/QTc interval prolongation

-Gastrointestinal disorders: Pancreatitis,

-Hepato-biliary disorders: Severe hepatitis and liver failure (see section 4.4)

-Nervous system disorders: Cases of rapid onset of exacerbation of myasthenia gravi

reported (see sections 4.3 and 4.4).

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: macrolides, lincosamides and streptogramins, ATC Code: J01FA15.

Telithromycin is a semisynthetic derivative of erythromycin A belonging to the ketolides, a class of antibacterial agents related to macrolides.

Mode of action

Telithromycin inhibits protein synthesis by acting at the ribosome level.

The affinity of telithromycin for the 50S bacterial subunit of ribosome is 10 fold higher than that of erythromycin A when the strain is susceptible to erythromycin A. Against erythromycin A resistant strains, due to an MLSB mechanism of resistance, telithromycin shows a more than 20 fold affinity compared to erythromycin A in the 50S bacterial subunit.

Telithromycin interferes with the ribosome translation at the 23S ribosomal RNA level, where it interacts with domain V and II. Furthermore, telithromycin is able to block the formation of the 50S and 30S ribosomal sub

The recommended MIC breakpoints for telithromycin, separating susceptible organisms from intermediately susceptible organisms and intermediately susceptible organisms from resistant organisms, are: susceptible <0.5 mg/l, resistant >2mg/l.

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.

This information provides only an approximate guidance on probabilities as to whether microorganisms will be susceptible to telithromycin.

Aerobic Gram-positive bacteria

Staphylococcus aureus methicillin susceptible (MSSA)

Lancefield group C and G ( ß haemolytic ) streptococci

Streptococcus agalactiae

Streptococcus pneumoniae

Viridans group streptococci _____________­_______________

Aerobic Gram- negative bacteria

Legionella pneumophila

Moraxella catarrhalis _____________­__________________

Other

Chlamydophila pneumoniae

Chlamydia psittaci

Mycoplasma pneumoniae

52  Pharmacokinetic roerties

5.3 Preclinical safety dataRepeated dose toxicity

1, 3 and 6 months duration with telithromycin conducted in rat, dog

and monkey showed that the liver was the principal target for toxicity with elevations of liver enzymes, and histological evidence of damage. 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., livkidney, lung, thymus, spleen, gall bladder, mesenteric lymph nodes, GI-tract) has been in rats and dogs administered telithromycin at repeated doses of 150 mg/kg/day or more for 1 nd 20 mg/kg/day or more for 3–6 months. This administration corresponds to free active e 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.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

6.2 Incompatibilities

6.3 Shelf life

6.4 Special precautions for storage

6.5 Nature and contents of container

Opaque PVC/Aluminium perforated unit dose blisters.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Aventis Pharma S.A.

20, Avenue Raymond Aron

F-92160 ANTONY

France

8. MARKETING AUTHORISATION NUMBERS

EU/1/01/192/001–005

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 9 July 2001

Date of first renewal: 9 July 2006