Novartis Pharmaceuticals UK Ltd

For thea full list of excipients, see section 6.1.

Non-susceptible micro-organisms

The use of antibiotics antibacterials may promote the overgrowth of non-susceptible micro-organisms. If superinfection occurs during therapy, appropriate measures should be taken.

Dose An adjustment of Cubicin dose interval is needed for patients whose creatinine clearance is < 30 ml/min (see sections 4.2 and 5.2). The safety and efficacy of the dose interval adjustment have not been evaluated in controlled clinical trials and the recommendation is mainly based on pharmacokinetic modelling data. Cubicin should only be used in such patients when it is considered that the expected clinical benefit outweighs the potential risk.

Although small changes in the pharmacokinetics of daptomycin and tobramycin were observed during coadministration by intravenous infusion over a 30-minute period using a Cubicin dose of 2 mg/kg, the changes were not statistically significant. The interaction between daptomycin and tobramycin with an approved dose of Cubicin is unknown. Caution is warranted when Cubicin is co-administered with tobramycin.

No clinical data on pregnancies are available for daptomycin. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).

Cubicin should not be used during pregnancy unless clearly necessary i.e., only if the potential expected benefit outweighs the possible risk.

Breast-feeding

In a single human case study, Cubicin was intravenously administered daily for 28 days to a nursing mother at a dose of 500 mg/day, and samples of the patient’s breast milk were collected over a 24-hour period on day 27. The highest measured concentration of daptomycin in the breast milk was 0.045 µmcg/ml, which is a low concentration. Therefore, until more experience is gained, breast-feeding should be discontinued when Cubicin is administered to nursing women.

Summary of the safety profile

In clinical studies, 2,011 subjects received Cubicin. Within these trials, 1,221 subjects received a daily dose of 4 mg/kg, of whom 1,108 were patients and 113 were healthy volunteers; 460 subjects received a daily dose of 6 mg/kg, of whom 304 were patients and 156 were healthy volunteers. Adverse reactions (i.e. considered by the investigator to be possibly, probably, or definitely related to the medicinal product) were reported at similar frequencies for Cubicin and comparator regimens.

The most frequently reported adverse reactions (frequency common (≥ 1/100 to < 1/10)) are:

Fungal infections, urinary tract infection, candida infection, anaemia, anxiety, insomnia, dizziness, headache, hypertension, hypotension, gastrointestinal and abdominal pain, nausea, vomiting, constipation, diarrhoea, flatulence, bloating and distension, liver function tests abnormal (increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase (ALP)), rash, pruritus, limb pain, serum creatine phosphokinase (CPK) increased, infusion site reactions, pyrexia, asthenia.

Less frequently reported, but more serious, adverse reactions include hypersensitivity reactions, eosinophilic pneumonia, drug rash with eosinophilia and systemic symptoms (DRESS), angioedema and rhabdomyolysis.

Tabulated list of adverse reactions

The following adverse reactions were reported during therapy and during follow-up with frequencies corresponding to very common (³ 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):

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

Table 1            Adverse reactions from clinical studies and post-marketing reports

*        Based on post-marketing reports. Since these reports reactions are reported voluntarily are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency which is therefore categorised as not knownor establish a causal relationship to exposure to the medicinal product.

**      See section 4.4.

¹           While the exact incidence of eosinophilic pneumonia associated with daptomycin is unknown, to date the reporting rate of spontaneous reports is very low (< 1/10,000).

²           In some cases of myopathy involving raised CPK and muscle symptoms, the patients also presented with elevated transaminases. These transaminase increases were likely to be related to the skeletal muscle effects. The majority of transaminase elevations were of Grade 1‑3 toxicity and resolved upon discontinuation of treatment.

³           When clinical information on the patients was available to make a judgement, approximately 50% of the cases occurred in patients with pre-existing renal impairment, or in those receiving concomitant medicinal products known to cause rhabdomyolysis.

The safety data for the administration of daptomycin via 2-minute intravenous injection are derived from two pharmacokinetic studies in healthy volunteers. Based on these study results, both methods of daptomycin administration, the 2-minute intravenous injection and the 30-minute intravenous infusion, had a similar safety and tolerability profile. There was no relevant difference in local tolerability or in the nature and frequency of adverse reactions.

After infusion of 14C-daptomycin in healthy adults, the plasma radioactivity was similar to the concentration determined by microbiological assay. Inactive metabolites were detected in urine, as determined by the difference in total radioactive concentrations and microbiologically active concentrations. In a separate study, no metabolites were observed in plasma, and minor amounts of three oxidative metabolites and one unidentified compound were detected in urine. The site of metabolism has not been identified.

Elderly

Following administration of a single 4 mg/kg intravenous dose of Cubicin over a 30-minute period, the mean total clearance of daptomycin was approximately 35% lower and the mean AUC_0-∞ was approximately 58% higher in elderly subjects (≥ 75 years of age) compared with those in healthy young subjects (18 to 30 years of age). There were no differences in C_max. The differences noted are most likely due to the normal reduction in renal function observed in the geriatric population.

A separate study was conducted to evaluate the pharmacokinetics of daptomycin after a single 8 mg/kg or 10 mg/kg dose of Cubicin as either a 1 or 2 hour infusion in paediatric subjects aged 2 to 6 years, inclusive, with proven or suspected Gram-positive infection who were receiving standard antibioticantibacterial therapy.

Following administration of a single 4 mg/kg or 6 mg/kg intravenous dose of daptomycin over a 30-minute period to subjects with various degrees of renal impairment, total daptomycin clearance (CL) decreased and systemic exposure (AUC) increased as renal function (creatinine clearance) decreased.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

4.2     Posology and method of administration

Clinical studies in patients employed infusion of daptomycin over 30 minutes. There is no clinical experience in patients with the administration of daptomycin as an injection over 2 minutes. This mode of administration was only studied in healthy subjects. However, when compared with the same doses given as intravenous infusions over 30 minutes there were no clinically important differences in the pharmacokinetics and safety profile of daptomycin (see also sections 4.8 and 5.2).

Posology

-                 cSSTI without concurrent Staphylococcus aureus bacteraemia: Cubicin 4 mg/kg is administered once every 24 hours for 7‑14 days or until the infection is resolved (see section 5.1).

-        cSSTI with concurrent Staphylococcus aureus bacteraemia: Cubicin 6 mg/kg is administered once every 24 hours. See below for dose adjustments in patients with renal impairmentinsufficiency. The duration of therapy may need to be longer than 14 days in accordance with the perceived risk of complications in the individual patient.

-                 Known or suspected right-sided infective endocarditis due to Staphylococcus aureus: Cubicin 6 mg/kg is administered once every 24 hours. See below for dose adjustments in patients with renal impairmentinsufficiency. The duration of therapy should be in accordance with available official recommendations.

Cubicin is administered intravenously in 0.9% sodium chloride (see section 6.6). Cubicin should not be used more frequently than once a day.

Renal insufficiencyimpairment

Daptomycin is eliminated primarily by the kidney.

Due to limited clinical experience (see table and footnotes below) Cubicin should only be used in patients with any degree of renal impairmentinsufficiency (CrCl < 80 ml/min) when it is considered that the expected clinical benefit outweighs the potential risk. The response to treatment, renal function and creatine phosphokinase (CPK) levels should be closely monitored in all patients with any degree of renal impairmentinsufficiency (see also sections 4.4 and 5.2).

Dose adjustments in patients with renal insufficiencyimpairment by indication and creatinine clearance

(1) The safety and efficacy of the dose interval adjustment have not been evaluated in controlled clinical trials and the recommendation is based on pharmacokinetic studies and modelling results (see sections 4.4 and 5.2).

(2) The same dose adjustments, which are based on pharmacokinetic data in volunteers including PK modelling results, are recommended for patients on haemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). Whenever possible, Cubicin should be administered following the completion of dialysis on dialysis days (see section 5.2).

Hepatic insufficiencyimpairment

No dose adjustment is necessary when administering Cubicin to patients with mild or moderate hepatic insufficiencyimpairment (Child-Pugh Class B) (see section 5.2). No data are available in patients with severe hepatic insufficiencyimpairment (Child-Pugh Class C). Therefore caution should be exercised if Cubicin is given to such patients.

Elderly patients

The recommended doses should be used in elderly patients except those with severe renal insufficiencyimpairment (see above and section 4.4). However, there are limited data on the safety and efficacy of daptomycin in patients aged > 65 years and caution should be exercised if Cubicin is given to such patients.

Method of administration

Cubicin is given by intravenous infusion (see section 6.6) and administered over a 30-minute period or by intravenous injection (see section 6.6) and administered over a 2-minute period.

4.4       Special warnings and precautions for use

General

If a focus of infection other than cSSTI or RIE is identified after initiation of Cubicin therapy consideration should be given to instituting alternative antibacterial therapy that has been demonstrated to be efficacious in the treatment of the specific type of infection(s) present.

Anaphylaxis/hypersensitivity reactions

Anaphylaxis/hypersensitivity reactions have been reported with Cubicin. If an allergic reaction to Cubicin occurs, discontinue use and institute appropriate therapy.

Pneumonia

It has been demonstrated in clinical studies that Cubicin is not effective in the treatment of pneumonia. Cubicin is therefore not indicated for the treatment of pneumonia.

RIE due to Staphylococcus aureus

Clinical data on the use of Cubicin to treat RIE due to Staphylococcus aureus are limited to 19 patients (see “Information from clinical trials” in section 5.1).

The efficacy of Cubicin in patients with prosthetic valve infections or with left-sided infective endocarditis due to Staphylococcus aureus has not been demonstrated.

Deep-seated infections

Patients with deep-seated infections should receive any required surgical interventions (e.g. debridement, removal of prosthetic devices, valve replacement surgery) without delay.

Enterococcal infections

There is insufficient evidence to be able to draw any conclusions regarding the possible clinical efficacy of Cubicin against infections due to enterococci, including Enterococcus faecalis and Enterococcus faecium. In addition, dose regimens of daptomycin that might be appropriate for the treatment of enterococcal infections, with or without bacteraemia, have not been identified. Failures with daptomycin in the treatment of enterococcal infections that were mostly accompanied by bacteraemia have been reported. In some instances treatment failure has been associated with the selection of organisms with reduced susceptibility or frank resistance to daptomycin (see section 5.1).

Non-susceptible organisms

The use of antibiotics may promote the overgrowth of non-susceptible micro-organisms. If superinfection occurs during therapy, appropriate measures should be taken.

Clostridium difficile-associated diarrhoea

Clostridium difficile-associated diarrhoea (CDAD) has been reported with Cubicin (see section 4.8). If CDAD is suspected or confirmed, Cubicin may need to be discontinued and appropriate treatment instituted as clinically indicated.

Drug/laboratory test interactions

False prolongation of prothrombin time (PT) and elevation of international normalised ratio (INR) have been observed when certain recombinant thromboplastin reagents are utilised for the assay (see also section 4.5).

Creatine phosphokinase and myopathy

Increases in plasma creatine phosphokinase (CPK; MM isoenzyme) levels associated with muscular pains and/or weakness and cases of myositis, myoglobinaemia and rhabdomyolysis have been reported during therapy with Cubicin (see also sections 4.5, 4.8 and 5.3). In clinical studies, marked increases in plasma CPK to > 5x Upper Limit of Normal (ULN) without muscle symptoms occurred more commonly in Cubicin-treated patients (1.9%) than in those that received comparators (0.5%). Therefore, it is recommended that:

·                Plasma CPK should be measured at baseline and at regular intervals (at least once weekly) during therapy in all patients.

·                CPK should be measured more frequently (e.g. every 2‑3 days at least during the first two weeks of treatment) in patients who are at higher risk of developing myopathy. For example, patients with any degree of renal insufficiencyimpairment (creatinine clearance < 80 ml/min; see also section 4.2), including those on haemodialysis or CAPD, and patients taking other medicinal products known to be associated with myopathy (e.g. HMG-CoA reductase inhibitors, fibrates and ciclosporin).

·                It cannot be ruled out that those patients with CPK greater than 5 times upper limit of normal at baseline may be at increased risk of further increases during daptomycin therapy. This should be taken into account when initiating daptomycin therapy and, if daptomycin is given, these patients should be monitored more frequently than once weekly.

·                Cubicin should not be administered to patients who are taking other medicinal products associated with myopathy unless it is considered that the benefit to the patient outweighs the risk.

·                Patients should be reviewed regularly while on therapy for any signs or symptoms that might represent myopathy.

·                Any patient that develops unexplained muscle pain, tenderness, weakness or cramps should have CPK levels monitored every 2 days. Cubicin should be discontinued in the presence of unexplained muscle symptoms if the CPK level reaches greater than 5 times upper limit of normal.

Peripheral neuropathy

Patients who develop signs or symptoms that might represent a peripheral neuropathy during therapy with Cubicin should be investigated and consideration should be given to discontinuation of daptomycin (see sections 4.8 and 5.3).

Eosinophilic pneumonia

Eosinophilic pneumonia has been reported in patients receiving Cubicin (see section 4.8). In most reported cases associated with Cubicin, patients developed fever, dyspnoea with hypoxic respiratory insufficiency, and diffuse pulmonary infiltrates. The majority of cases occurred after more than 2 weeks of treatment with Cubicin and improved when Cubicin was discontinued and steroid therapy was initiated. Recurrence of eosinophilic pneumonia upon re-exposure has been reported. Patients who develop these signs and symptoms while receiving Cubicin should undergo prompt medical evaluation, including, if appropriate, bronchoalveolar lavage, to exclude other causes (e.g. bacterial infection, fungal infection, parasites, other medicinal products). Cubicin should be discontinued immediately and treatment with systemic steroids should be initiated when appropriate.

Renal insufficiencyimpairment

Renal insufficiencyimpairment has been reported during treatment with Cubicin. Severe renal insufficiencyimpairment may in itself also pre-dispose to elevations in daptomycin levels which may increase the risk of development of myopathy (see above).

Dose adjustment is needed for patients whose creatinine clearance is < 30 ml/min (see sections 4.2 and 5.2). The safety and efficacy of the dose interval adjustment have not been evaluated in controlled clinical trials and the recommendation is mainly based on pharmacokinetic modelling data. Cubicin should only be used in such patients when it is considered that the expected clinical benefit outweighs the potential risk.

Caution is advised when administering Cubicin to patients who already have some degree of renal insufficiencyimpairment (creatinine clearance < 80 ml/min) before commencing therapy with Cubicin. Regular monitoring of renal function is advised (see also section 5.2).

In addition, regular monitoring of renal function is advised during concomitant administration of potentially nephrotoxic agents, regardless of the patient’s pre-existing renal function (see also section 4.5).

Obesity

In obese subjects with Body Mass Index (BMI) > 40 kg/m² but with creatinine clearance > 70 ml/min, the AUC_0-∞ daptomycin was significantly increased (mean 42% higher) compared with non-obese matched controls. There is limited information on the safety and efficacy of daptomycin in the very obese and so caution is recommended. However, there is currently no evidence that a dose reduction is required (see section 5.2).

4.5     Interaction with other medicinal products and other forms of interaction

Daptomycin undergoes little to no Cytochrome P450 (CYP450)-mediated metabolism. It is unlikely that daptomycin will inhibit or induce the metabolism of medicinal products metabolised by the P450 system.

Interaction studies for Cubicin were performed with aztreonam, tobramycin, warfarin and probenecid. Daptomycin had no effect on the pharmacokinetics of warfarin or probenecid, nor did these medicinal products alter the pharmacokinetics of daptomycin. The pharmacokinetics of daptomycin were not significantly altered by aztreonam.

Although small changes in the pharmacokinetics of daptomycin and tobramycin were observed during coadministration using a Cubicin dose of 2 mg/kg, the changes were not statistically significant. The interaction between daptomycin and tobramycin with an approved dose of Cubicin is unknown. Caution is warranted when Cubicin is co-administered with tobramycin.

Experience with the concomitant administration of Cubicin and warfarin is limited. Studies of Cubicin with anticoagulants other than warfarin have not been conducted. Anticoagulant activity in patients receiving Cubicin and warfarin should be monitored for the first several days after therapy with Cubicin is initiated.

There is limited experience regarding concomitant administration of daptomycin with other medicinal products that may trigger myopathy (e.g. HMG-CoA reductase inhibitors). However, some cases of marked rises in CPK levels and cases of rhabdomyolysis occurred in patients taking one of these medicinal products at the same time as Cubicin. It is recommended that other medicinal products associated with myopathy should if possible be temporarily discontinued during treatment with Cubicin unless the benefits of concomitant administration outweigh the risk. If co-administration cannot be avoided, CPK levels should be measured more frequently than once weekly and patients should be closely monitored for any signs or symptoms that might represent myopathy. See sections 4.4, 4.8 and 5.3.

Daptomycin is primarily cleared by renal filtration and so plasma levels may be increased during co-administration with medicinal products that reduce renal filtration (e.g. NSAIDs and COX-2 inhibitors). In addition, there is a potential for a pharmacodynamic interaction to occur during co-administration due to additive renal effects. Therefore, caution is advised when daptomycin is co-administered with any other medicinal product known to reduce renal filtration.

During post–marketing surveillance, cases of interference between daptomycin and particular reagents used in some assays of prothrombin time/international normalised ratio (PT/INR) have been reported. This interference led to a false prolongation of PT and elevation of INR. If unexplained abnormalities of PT/INR are observed in patients taking daptomycin, consideration should be given to a possible in vitro interaction with the laboratory test. The possibility of erroneous results may be minimised by drawing samples for PT or INR testing near the time of trough plasma concentrations of daptomycin (see section 4.4).

4.6     Fertility, pPregnancy and lactation

Pregnancy

No clinical data on pregnancies are available for daptomycin. Animal studies do not indicate direct or indirect harmful effects with respect to fertility, pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).

Cubicin should not be used during pregnancy unless clearly necessary i.e., only if the potential benefit outweighs the possible risk.

Breast-feeding

In a single case study, Cubicin was administered daily for 28 days to a nursing mother at a dose of 500 mg/day, and samples of the patient’s breast milk were collected over a 24-hour period on day 27. The highest measured concentration of daptomycin in the breast milk was 0.045 µg/ml, which is a low concentration. Therefore, until more experience is gained, breast-feeding should be discontinued when Cubicin is administered to nursing women.

Fertility

No clinical data on fertility are available for daptomycin. Animal studies do not indicate direct or indirect harmful effects with respect to fertility (see section 5.3).

4.8       Undesirable effects

In clinical studies, 2,011 subjects received Cubicin. Within these trials, 1,221 subjects received a daily dose of 4 mg/kg, of whom 1,108 were patients and 113 were healthy volunteers; 460 subjects received a daily dose of 6 mg/kg, of whom 304 were patients and 156 were healthy volunteers. Adverse reactions (i.e. considered by the investigator to be possibly, probably, or definitely related to the medicinal product) were reported at similar frequencies for Cubicin and comparator regimens.

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

Table 1            Adverse reactions from clinical studies and post-marketing reports

*        Based on post-marketing reports. Since these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency or establish a causal relationship to exposure to the medicinal product.

**      See section 4.4.

¹           While the exact incidence of eosinophilic pneumonia associated with daptomycin is unknown, to date the reporting rate of spontaneous reports is very low (< 1/10,000).

²¹         In some cases of myopathy involving raised CPK and muscle symptoms, the patients also presented with elevated transaminases. These transaminase increases were likely to be related to the skeletal muscle effects. The majority of transaminase elevations were of Grade 1‑3 toxicity and resolved upon discontinuation of treatment.

³²         When clinical information on the patients was available to make a judgement, approximately 50% of the cases occurred in patients with pre-existing renal insufficiencyimpairment, or in those receiving concomitant medicinal products known to cause rhabdomyolysis.

The safety data for the administration of daptomycin via 2-minute intravenous injection are derived from two pharmacokinetic studies in healthy volunteers. Based on these study results, both methods of daptomycin administration, the 2-minute intravenous injection and the 30-minute intravenous infusion, had a similar safety and tolerability profile. There was no relevant difference in local tolerability or in the nature and frequency of adverse reactions.

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use, Other antibacterials, ATC code: J01XX09

The mechanism of action involves binding (in the presence of calcium ions) to bacterial membranes of both growing and stationary phase cells causing depolarisation and leading to a rapid inhibition of protein, DNA, and RNA synthesis. This results in bacterial cell death with negligible cell lysis.

PK/PD relationship

Daptomycin exhibits rapid, concentration dependent bactericidal activity against Gram positive organisms in vitro and in in vivo animal models. In animal models AUC/MIC and C_max/MIC correlate with efficacy and predicted bacterial kill in vivo at single doses equivalent to human doses of 4 mg/kg and 6 mg/kg once daily.

Mechanisms of resistance

Strains with decreased susceptibility to daptomycin have been reported especially during the treatment of patients with difficult-to-treat infections and/or following administration for prolonged periods. In particular, there have been reports of treatment failures in patients infected with Staphylococcus aureus, Enterococcus faecalis or Enterococcus faecium, including bacteraemic patients, that have been associated with the selection of organisms with reduced susceptibility or frank resistance to daptomycin during therapy.

The mechanism(s) of daptomycin resistance is (are) not fully understoodto daptomycin has not yet been identified.

Breakpoints

Minimum inhibitory concentration (MIC) breakpoint established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for Staphylococci and Streptococci (except S. pneumoniae) are Susceptible ≤ 1 mg/l and Resistant > 1 mg/l.

Susceptibility

The prevalence of resistance may vary geographically and over 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.

* denotes species against which it is considered that activity has been satisfactorily demonstrated in clinical studies.

Information from clinical trials

In two clinical trials in complicated skin and soft tissues infections, 36% of patients treated with Cubicin met the criteria for systemic inflammatory response syndrome (SIRS). The most common type of infection treated was wound infection (38% of patients), while 21% had major abscesses. These limitations of the patients population treated should be taken into account when deciding to use Cubicin.

In a randomised controlled open-label study in 235 patients with Staphylococcus aureus bacteraemia (i.e, at least one positive blood culture of Staphylococcus aureus prior to receiving the first dose) 19 of 120 patients treated with Cubicin met the criteria for RIE. Of these 19 patients 11 were infected with methicillin-susceptible and 8 with methicillin-resistant Staphylococcus aureus. The success rates in RIE patients are shown in the table below.

Failure of treatment due to persisting or relapsing Staphylococcus aureus infections was observed in 19/120 (15.8%) patients treated with Cubicin, 9/53 (16.7%) patients treated with vancomycin and 2/62 (3.2%) patients treated with an anti-staphylococcal semi-synthetic penicillin. Among these failures six patients treated with Cubicin and one patient treated with vancomycin were infected with Staphylococcus aureus that developed increasing MICs of daptomycin on or following therapy (see “Mechanisms of resistance” above). Most patients who failed due to persisting or relapsing Staphylococcus aureus infection had deep-seated infection and did not receive necessary surgical intervention.

5.2     Pharmacokinetic properties

Daptomycin pharmacokinetics are generally linear and time-independent at doses of 4 to 12 mg/kg administered as a single daily dose by 30-minute intravenous infusion for up to 14 days in healthy volunteers. Steady‑state concentrations are achieved by the third daily dose.

Daptomycin administered as a 2-minute intravenous injection also exhibited dose proportional pharmacokinetics in the approved therapeutic dose range of 4 to 6 mg/kg. Comparable exposure (AUC and C_max) was demonstrated in healthy subjects following administration of daptomycin as a 30-minute intravenous infusion or as a 2-minute intravenous injection.

Animal studies showed that daptomycin is not absorbed to any significant extent after oral administration.

Distribution

The volume of distribution at steady state of daptomycin in healthy adult subjects was approximately 0.1 l/kg and was independent of dose. Tissue distribution studies in rats showed that daptomycin appears to only minimally penetrate the blood‑brain barrier and the placental barrier following single and multiple doses.

Daptomycin is reversibly bound to human plasma proteins in a concentration independent manner. In healthy volunteers and patients treated with daptomycin, protein binding averaged about 90% including subjects with renal insufficiencyimpairment.

Metabolism

In in vitro studies, daptomycin was not metabolised by human liver microsomes. In vitro studies with human hepatocytes indicate that daptomycin does not inhibit or induce the activities of the following human cytochrome P450 isoforms: 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4. It is unlikely that daptomycin will inhibit or induce the metabolism of medicinal products metabolised by the P450 system.

After infusion of 14C-daptomycin, the plasma radioactivity was similar to the concentration determined by microbiological assay. Inactive metabolites were detected in urine, as determined by the difference in total radioactive concentrations and microbiologically active concentrations. In a separate study, no metabolites were observed in plasma, and minor amounts of three oxidative metabolites and one unidentified compound were detected in urine. The site of metabolism has not been identified.

Elimination

Daptomycin is excreted primarily by the kidneys. Concomitant administration of probenecid and daptomycin has no effect on daptomycin pharmacokinetics in humans suggesting minimal to no active tubular secretion of daptomycin.

Following intravenous administration, plasma clearance of daptomycin is approximately 7 to 9 ml/h/kg and its renal clearance is 4 to 7 ml/h/kg.

In a mass balance study using radiolabelled material, 78% of the administered dose was recovered from the urine based on total radioactivity, whilst urinary recovery of unchanged daptomycin was approximately 50% of the dose. About 5% of the administered radiolabel was excreted in the faeces.

Special populations

Elderly

Following administration of a single 4 mg/kg intravenous dose of Cubicin, the mean total clearance of daptomycin wasdecreased approximately 35% lower and the mean AUC_0-∞ wasincreased approximately 58% higher in elderly subjects (≥ 75 years of age) compared with those in young healthy young subjects (18 to 30 years of age). There were no differences in C_max. The differences noted are most likely due to the normal reduction in renal function observed in the geriatric population.

No dose adjustment is necessary based on age alone. However, renal function should be assessed and the dose should be reduced if there is evidence of severe renal insufficiencyimpairment.

Children and adolescents (< 18 years of age)

The pharmacokinetics of daptomycin after a single 4 mg/kg dose of Cubicin were evaluated in three groups of paediatric patients with proven or suspected Gram-positive infection (2‑6 years, 7‑11 years and 12‑17 years). The pharmacokinetics of daptomycin following a single 4 mg/kg dose in adolescents aged 12‑17 years are generally similar to those of healthy adult subjects with normal renal function with trends towards lower AUC and C_max in adolescents. In the younger age groups (2‑6 years and 7‑11 years), total clearance was higher compared with that in adolescents, resulting in a lower level of exposure (AUC and C_max) and elimination half-lifeexposure (C_max and AUC) and elimination half-life for the same mg/kg dose were reduced compared with adolescents. Efficacy was not assessed in this study.

A separate study was conducted to evaluate the pharmacokinetics of daptomycin after a single 8 mg/kg or 10 mg/kg dose of Cubicin as either a 1 or 2 hour infusion in paediatric subjects aged 2 to 6 years, inclusive, with proven or suspected Gram-positive infection who were receiving standard antibiotic therapy.

The mean exposure (AUC_0-∞) was approximately 429 and 550 μg*hr/ml after the administration of 8 and 10 mg/kg single doses, respectively, similar to the exposure seen in adults at the 4 mg/kg dose at steady state (495 μg*hr/ml). The pharmacokinetics of daptomycin appears to be linear in the dose range studied. The half life, clearance and volume of distribution were similar at both dose levels.

Obesity

Relative to non-obese subjects daptomycin systemic exposure measured by AUC wasis increased by about 28% higher in moderately obese subjects (Body Mass Index of 25‑40 kg/m²) and by 42% higher in extremely obese subjects (Body Mass Index of > 40 kg/m²). However, no dose adjustment is considered to be necessary based on obesity alone.

Gender

No clinically significant gender-related differences in daptomycin pharmacokinetics have been observed.

Renal insufficiencyimpairment

Following administration of a single 4 mg/kg or 6 mg/kg dose of daptomycin to subjects with various degrees of renal insufficiencyimpairment, total daptomycin clearance (CL) decreased and systemic exposure (AUC) increased as renal function (creatinine clearance) decreased.

Based on pharmacokinetic data and modelling, the daptomycin AUC during the first day after administration of a 6 mg/kg dose to patients on HD or CAPD was 2-fold higher than that observed in patients with normal renal function who received the same dose. On the second day after administration of a 6 mg/kg dose to HD and CAPD patients the daptomcyin AUC was approximately 1.3-fold higher than that observed after a second 6 mg/kg dose in patients with normal renal function. On this basis, it is recommended that patients on HD or CAPD receive daptomycin once every 48 hours at the dose recommended for the type of infection being treated (see section 4.2).

Hepatic insufficiencyimpairment

The pharmacokinetics of daptomycin is not altered in subjects with moderate hepatic insufficiencyimpairment (Child‑Pugh B classification of hepatic insufficiencyimpairment) compared with healthy volunteers matched for gender, age and weight following a single 4 mg/kg dose. No dosage adjustment is necessary when administering daptomycin in patients with moderate hepatic insufficiencyimpairment. The pharmacokinetics of daptomycin in patients with severe hepatic insufficiencyimpairment (Child‑Pugh C classification) have not been evaluated.

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 19 January 2006

Date of latest renewal: 19 January 2011

10.     DATE OF REVISION OF THE TEXT

21 January 2011


Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

Cubicin 350 mg powder for solution for infusion or injection: Each vial contains 350 mg daptomycin.

One ml provides 50 mg of daptomycin after reconstitution with 7 ml of sodium chloride 9 mg/ml (0.9%) solution or water for injections.

Cubicin 500 mg powder for solution for infusion or injection: Each vial contains 500 mg daptomycin.

One ml provides 50 mg of daptomycin after reconstitution with 10 ml of sodium chloride 9 mg/ml (0.9%) solution or water for injections.

For a full list of excipients, see section 6.1.

4.2     Posology and method of administration

Clinical studies in patients employed infusion of daptomycin over 30 minutes. There is no clinical experience in patients with the administration of daptomycin as an injection over 2 minutes. This mode of administration was only studied in healthy subjects. However, when compared with the same doses given as intravenous infusions over 30 minutes there were no clinically important differences in the pharmacokinetics and safety profile of daptomycin (see also sections 4.8 and 5.2).

Posology

-              cSSTI without concurrent Staphylococcus aureus bacteraemia: The recommended dose isCubicin 4 mg/kg is administered once every 24 hours for 7‑14 days or until the infection is resolved (see section 5.1).

-        cSSTI with concurrent Staphylococcus aureus bacteraemia: The recommended dose is Cubicin 6 mg/kg is administered once every 24 hours. See below for dose adjustments in patients with renal insufficiency. The duration of therapy may need to be longer than 14 days in accordance with the perceived risk of complications in the individual patient.

-              Known or suspected right-sided infective endocarditis due to Staphylococcus aureus: CubicinThe recommended dose is 6 mg/kg is administered once every 24 hours. See below for dose adjustments in patients with renal insufficiency. The duration of therapy should be in accordance with available official recommendations.

Cubicin is administered intravenously in 0.9% sodium chloride (see section 6.6). Cubicin should not be used more frequently than once a day.

Renal insufficiency

Daptomycin is eliminated primarily by the kidney.

Due to limited clinical experience (see table and footnotes below) Cubicin should only be used in patients with any degree of renal insufficiency (Cr Cl < 80 ml/min) when it is considered that the expected clinical benefit outweighs the potential risk. The response to treatment and, renal function and creatine phosphokinase (CPK) levels should be closely monitored in all patients with anysome degree of renal insufficiency (see also sections 4.4 and 5.2).

Dose adjustments in patients with renal insufficiency by indication and creatinine clearance

(1) The safety and efficacy of the dose interval adjustment haves not been clinically evaluated in controlled clinical trials and the recommendation is based on pharmacokinetic studies and modelling resultsdata (see sections 4.4 and 5.2).

(2) The same dose adjustments, which are also based solely on pharmacokinetic data in volunteers including PK modelling results, are recommended for patients on haemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). Whenever possible, Cubicin should be administered following the completion of dialysis on dialysis days (see section 5.2).

(3) There are insufficient data to support a dose recommendation for patients with RIE or cSSTI associated with Staphylococcus aureus bacteraemia who have a creatinine clearance < 50 ml/min. There are no data available to support the efficacy of 4 mg/kg daily in patients with RIE or cSSTI associated with Staphylococcus aureus bacteraemia whose creatinine clearance is between 30‑49 ml/min or to support the use of 4 mg/kg every 48 hours in such patients whose creatinine clearance is < 30 ml/min.

Hepatic insufficiency

No dose adjustment is necessary when administering Cubicin to patients with mild or moderate hepatic insufficiency (Child-Pugh Class B) (see section 5.2). No data are available in patients with severe hepatic insufficiency (Child-Pugh Class C). Therefore caution should be exercised if Cubicin is given to such patients.

Elderly patients

The recommended doses should be used in elderly patients except those with severe renal insufficiency (see above and section 4.4). However, there are limited data on the safety and efficacy of daptomycin in patients aged > 65 years and caution should be exercised if Cubicin is given to such patients.

Children and adolescents

Cubicin is not recommended for use in children and adolescents below the age of 18 years due to a lack of data on safety and efficacy (see section 5.2).

Method of administration

Cubicin is given by intravenous infusion (see section 6.6) and administered over a 30-minute period or by intravenous injection (see section 6.6) and administered over a 2-minute period.

4.4       Special warnings and precautions for use

If a focus of infection other than cSSTI or RIE is identified after initiation of Cubicin therapy consideration should be given to instituting alternative antibacterial therapy that has been demonstrated to be efficacious in the treatment of the specific type of infection(s) present.

Anaphylaxis/hypersensitivity reactions have been reported with Cubicin. If an allergic reaction to Cubicin occurs, discontinue use and institute appropriate therapy.

It has been demonstrated in clinical studies that Cubicin is not effective in the treatment of pneumonia. Cubicin is therefore not indicated for the treatment of pneumonia.

Clinical data on the use of Cubicin to treat RIE due to Staphylococcus aureus are limited to 19 patients (see “Information from clinical trials” in section 5.1).

The efficacy of Cubicin in patients with prosthetic valve infections or with left-sided infective endocarditis due to Staphylococcus aureus has not been demonstrated.

Patients with deep-seated infections should receive any required surgical interventions (e.g. debridement, removal of prosthetic devices, valve replacement surgery) without delay.

There is insufficient evidence to be able to draw any conclusions regarding the possible clinical efficacy of Cubicin against infections due to enterococci, including Enterococcus faecalis and Enterococcus faecium. In addition, dose regimens of daptomycin that might be appropriate for the treatment of enterococcal infections, with or without bacteraemia, have not been identified. Failures with daptomycin in the treatment of enterococcal infections that were mostly accompanied by bacteraemia have been reported. In some instances treatment failure has been associated with the selection of organisms with reduced susceptibility or frank resistance to daptomycin (see section 5.1).

The use of antibiotics may promote the overgrowth of non-susceptible micro-organisms. If superinfection occurs during therapy, appropriate measures should be taken.

Clostridium difficile-associated diarrhoea (CDAD) has been reported with Cubicin. If CDAD is suspected or confirmed, Cubicin may need to be discontinued and appropriate treatment instituted as clinically indicated.

False prolongation of prothrombin time (PT) and elevation of international normalised ratio (INR) have been observed when certain recombinant thromboplastin reagents are utilised for the assay (see also section 4.5).

Creatine phosphokinase and myopathy

Increases in plasma creatine phosphokinase (CPK; MM isoenzyme) levels associated with muscular pains and/or weakness and cases of myositis, myoglobinaemia and rhabdomyolysis have been reported during therapy with Cubicin (see also sections 4.5, 4.8 and 5.3). In clinical studies, marked increases in plasma CPK to > 5x Upper Limit of Normal (ULN) without muscle symptoms occurred more commonly in Cubicin-treated patients (1.9%) than in those that received comparators (0.5%). Therefore, it is recommended that:

·             Plasma CPK should be measured at baseline and at regular intervals (at least once weekly) during therapy in all patients.

·             CPK should be measured more frequently (e.g. every 2‑3 days at least during the first two weeks of treatment) in patients who are at higher risk of developing myopathy. For example, patients with any degree of renal insufficiency (creatinine clearance < 80 ml/min; see also section 4.2), including those on haemodialysis or CAPD, and patients taking other medicinal products known to be associated with myopathy (e.g. HMG-CoA reductase inhibitors, fibrates and ciclosporin).

·             It cannot be ruled out that those patients with CPK greater than 5 times upper limit of normal at baseline may be at increased risk of further increases during daptomycin therapy. This should be taken into account when initiating daptomycin therapy and, if daptomycin is given, these patients should be monitored more frequently than once weekly.

·                CPK should be measured more frequently than once weekly in patients who are at higher risk of developing myopathy. These patients include those with severe renal insufficiency (creatinine clearance < 30 ml/min; see also section 4.2) and patients taking other medicinal products known to be associated with myopathy (e.g. HMG-CoA reductase inhibitors, fibrates and ciclosporin).

·             Cubicin should not be administered to patients who are taking other medicinal products associated with myopathy unless it is considered that the benefit to the patient outweighs the risk.

·             Patients should be reviewed regularly while on therapy for any signs or symptoms that might represent myopathy.

·             Any patient that develops unexplained muscle pain, tenderness, weakness or cramps should have CPK levels monitored every 2 days. Cubicin should be discontinued in the presence of unexplained muscle symptoms if the CPK level reaches greater than 5 times upper limit of normal.

Peripheral neuropathy

Patients who develop signs or symptoms that might represent a peripheral neuropathy during therapy with Cubicin should be investigated and consideration should be given to discontinuation of daptomycin (see sections 4.8 and 5.3).

Renal insufficiency

Renal insufficiency has been reported during treatment with Cubicin. Severe renal insufficiency may in itself also pre-dispose to elevations in daptomycin levels which may increase the risk of development of myopathy (see above).

Dose adjustment is needed for patients with cSSTI without bacteraemia whose creatinine clearance is < 30 ml/min (see sections 4.2 and 5.2). The safety and efficacy of the dose interval adjustment have not been evaluated in controlled clinical trials and the recommendation is mainlyguidelines provided in section 4.2 are based on pharmacokinetic modelling dataand have not been clinically evaluated. In addition there are no data to support the use of 6 mg/kg daptomycin once daily in patients with RIE or with cSSTI associated with bacteraemia whose creatinine clearance is < 50 ml/min. Cubicin should only be used in such patients when it is considered that the expected clinical benefit outweighs the potential risk.

Caution is advised when administering Cubicin to patients who already have some degree of renal insufficiency (creatinine clearance < 80 ml/min) before commencing therapy with Cubicin. Regular monitoring of renal function is advised (see also section 5.2).

In addition, regular monitoring of renal function is advised during concomitant administration of potentially nephrotoxic agents, regardless of the patient’s pre-existing renal function (see also section 4.5).

Obesity

In obese subjects with Body Mass Index (BMI) > 40 kg/m² but with creatinine clearance > 70 ml/min, the AUC_0-∞ daptomycin was significantly increased (mean 42% higher) compared with non-obese matched controls. There is limited information on the safety and efficacy of daptomycin in the very obese and so caution is recommended. However, there is currently no evidence that a dose reduction is required (see section 5.2).

The use of antibiotics may promote the overgrowth of non-susceptible micro-organisms. If superinfection occurs during therapy, appropriate measures should be taken.

Antibiotic-associated colitis and pseudomembranous colitis have been reported with nearly all antibacterial agents and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or shortly following treatment.

4.5     Interaction with other medicinal products and other forms of interaction

Daptomycin undergoes little to no Cytochrome P450 (CYP450)- mediated metabolism. It is unlikely that daptomycin will inhibit or induce the metabolism of medicinal products metabolised by the P450 system.

Interaction studies for Cubicin were performed with aztreonam, tobramycin, warfarin and probenecid. Daptomycin had no effect on the pharmacokinetics of warfarin or probenecid, nor did these medicinal products alter the pharmacokinetics of daptomycin. The pharmacokinetics of daptomycin were not significantly altered by aztreonam.

Although small changes in the pharmacokinetics of daptomycin and tobramycin were observed during coadministration using a Cubicin dose of 2 mg/kg, the changes were not statistically significant. The interaction between daptomycin and tobramycin with an approved dose of Cubicin is unknown. Caution is warranted when Cubicin is co-administered with tobramycin.

Experience with the concomitant administration of Cubicin and warfarin is limited. Studies of Cubicin with anticoagulants other than warfarin have not been conducted. Anticoagulant activity in patients receiving Cubicin and warfarin should be monitored for the first several days after therapy with Cubicin is initiated. In vitro studies have determined that daptomycin does not inhibit or induce the activities of clinically significant human CYP isoforms (1A2, 2A6, 2C9, 2C19, 2D6, 2E1, 3A4). Therefore, no CYP450-related drug interactions are to be expected.

There is limited experience regarding concomitant administration of daptomycin with other medicinal products that may trigger myopathy (e.g. HMG-CoA reductase inhibitors). However, some cases of marked rises in CPK levels and cases of rhabdomyolysis occurred in patients taking one of these medicinal products at the same time as Cubicin. It is recommended that other medicinal products associated with myopathy should if possible be temporarily discontinued during treatment with Cubicin unless the benefits of concomitant administration outweigh the risk. If co-administration cannot be avoided, CPK levels should be measured more frequently than once weekly and patients should be closely monitored for any signs or symptoms that might represent myopathy. See sections 4.4, 4.8 and 5.3.

Daptomycin is primarily cleared by renal filtration and so plasma levels may be increased during co-administration with medicinal products that reduce renal filtration (e.g. NSAIDs and COX-2 inhibitors). In addition, there is a potential for a pharmacodynamic interaction to occur during co-administration due to additive renal effects. Therefore, caution is advised when daptomycin is co-administered with any other medicinal product known to reduce renal filtration.

During post–marketing surveillance, cases of interference between daptomycin and particular reagents used in some assays of pProthrombin tTime/iInternational nNormalised rRatio (PT/INR) have been reported. This interference led to a falsen apparent prolongation of PT and elevation of INR. If unexplained abnormalities of PT/INR are observed in patients taking daptomycin, consideration should be given to a possible in vitro interaction with the laboratory test. The possibility of erroneous results may be minimised by drawing samples for PT or INR testing near the time of trough plasma concentrations of daptomycin.

4.6     Pregnancy and lactation

No clinical data on pregnancies are available for daptomycin. Animal studies do not indicate direct or indirect harmful effects with respect to fertility, pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).

Cubicin should not be used during pregnancy unless clearly necessary i.e., only if the potential benefit outweighs the possible risk.

In a single case study, Cubicin was administered daily for 28 days to a nursing mother at a dose of 500 mg/day, and samples of the patient’s breast milk were collected over a 24-hour period on day 27. The highest measured concentration of daptomycin in the breast milk was 0.045 µg/ml, which is a low concentration. Therefore, until more experience is gained, breast-feeding should be discontinued when Cubicin is administered to nursing women.It is not known whether daptomycin is excreted in human milk. Therefore, breastfeeding should be discontinued during treatment with Cubicin.

4.8       Undesirable effects

In clinical studies, 2,011 subjects received Cubicin. Within these trials, 1,221 subjects received a daily dose of 4 mg/kg, of whom 1,108 were patients and 113 were healthy volunteers; 460 subjects received a daily dose of 6 mg/kg, of whom 304 were patients and 156 were healthy volunteers. Adverse reactions (i.e. considered by the investigator to be possibly, probably, or definitely related to the medicinal product) were reported at similar frequencies for Cubicin and comparator regimens.

For subjects who received Cubicin, the adverse reactions that were most frequently reported during therapy plus follow-up were: headache, nausea, vomiting, diarrhoea, fungal infections, rash, infusion site reaction, increased Creatine phosphokinase (CPK) and abnormal liver enzymes; Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase.

The following adverse reactions were reported during therapy and during follow-up with frequencies corresponding to 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):

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

Table 1 Adverse reactions from clinical studies and post-marketing reports

*        Based on post-marketing reports. Since these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency or establish a causal relationship to exposure to the medicinal product.

¹              In some cases of myopathy involving raised CPK and muscle symptoms, the patients also presented with elevated transaminases. These transaminase increases were likely to be related to the skeletal muscle effects. The majority of transaminase elevations were of Grade 1‑3 toxicity and resolved upon discontinuation of treatment.

²              When clinical information on the patients was available to make a judgement, approximately 50% of the cases occurred in patients with pre-existing renal insufficiency, or in those receiving concomitant medicinal products known to cause rhabdomyolysis.

Infections and infestations

Common: Fungal infections

Uncommon: Urinary tract infection

Blood and lymphatic system disorders

Uncommon: Thrombocythaemia, anaemia, eosinophilia

Metabolism and nutrition disorders

Uncommon: Anorexia, hyperglycaemia

Psychiatric disorders

Uncommon: Anxiety, insomnia

Nervous system disorders

Common: Headache

Uncommon: Dizziness, paraesthesiae, taste disorder

Cardiac disorders

Uncommon: Supraventricular tachycardia, extrasystole

Vascular disorders

Uncommon: Flushes, hypertension, hypotension

Gastrointestinal disorders

Common: Nausea, vomiting, diarrhoea

Uncommon: Constipation, abdominal pain, dyspepsia, glossitis

Hepatobiliary disorders

Uncommon: Jaundice

Skin and subcutaneous tissue disorders

Common: Rash

Uncommon: Pruritis, urticaria

Musculoskeletal, connective tissue and bone disorders

Uncommon: Myositis, muscle weakness, muscle pain, arthralgia

Renal and urinary disorders

Uncommon: Renal insufficiency, including renal impairment and renal failure

Reproductive system and breast disorders

Uncommon: Vaginitis

General disorders and administration site conditions

Common: Infusion site reactions

Uncommon: Pyrexia, weakness, fatigue, pain

Investigations

Common: Liver function tests abnormal (increased AST, ALT and alkaline phosphatase), increased CPK

Uncommon: Electrolyte imbalance, increased serum creatinine, increased myoglobin, Lactic dehydrogenase (LDH) increased

The safety data for the administration of daptomycin via 2-minute intravenous injection are derived from two pharmacokinetic studies in healthy volunteers. Based on these study results, both methods of daptomycin administration, the 2-minute intravenous injection and the 30-minute intravenous infusion, had a similar safety and tolerability profile. There was no relevant difference in local tolerability or in the nature and frequency of adverse reactions.

Post-marketing

Adverse reactions that have been reported during post-marketing and that are not listed above are:

Immune system disorders

Hypersensitivity, manifested by isolated spontaneous reports including, but not limited to; pulmonary eosinophilia, vesicobullous rash with mucous membrane involvement and sensation of oropharyngeal swelling.

Anaphylaxis

Infusion reactions including the following symptoms: tachycardia, wheezing, pyrexia, rigors, systemic flushing, vertigo, syncope and metallic taste.

Infections and infestations

Clostridium difficile-associated diarrhoea

Musculoskeletal, connective tissue and bone disorders

Rhabdomyolysis

When clinical information on the patients was available to make a judgement, approximately 50% of the cases occurred in patients with pre-existing renal insufficiency, or in those receiving concomitant medicinal products known to cause rhabdomyolysis.

Nervous system disorders

Peripheral neuropathy

Investigations

In some cases of myopathy involving raised CPK and muscle symptoms, the patients also presented with elevated transaminases. These transaminase increases were likely to be related to the skeletal muscle effects. The majority of transaminase elevations were of Grade 1‑3 toxicity and resolved upon discontinuation of treatment.

In Section 5.1 the following amendments have been made to the paragraph entitled "PK/PD relationships":

PK/PD relationship

Daptomycin exhibits rapid, concentration dependent bactericidal activity against sensitive Gram positive organisms in vitro and in in vivo animal models. In animal models AUC/MIC and C_max/MIC correlate with efficacy and predicted bacterial kill in vivo at single doses equivalent to human doses of 4 mg/kg and 6 mg/kg once daily.

5.2     Pharmacokinetic properties

Daptomycin pharmacokinetics are generally linear and time-independent at doses of 4 to 12 mg/kg administered as a single daily dose by 30-minute intravenous infusion for up to 14 days in healthy volunteers. Steady‑state concentrations are achieved by the third daily dose.

Daptomycin administered as a 2-minute intravenous injection also exhibited dose proportional pharmacokinetics in the approved therapeutic dose range of 4 to 6 mg/kg. Comparable exposure (AUC and C_max) was demonstrated in healthy subjects following administration of daptomycin as a 30-minute intravenous infusion or as a 2-minute intravenous injection.

Animal studies showed that daptomycin is not absorbed to any significant extent after oral administration.

Distribution

The steady state volume of distribution at steady state of daptomycin in healthy adult subjects was approximately 0.1 l/kg and was independent of dose in healthy adult volunteers, consistent with distribution primarily within the extracellular space. Tissue distribution studies in rats showedanimals have shown that daptomycin appears to only minimally penetratepreferentially distributes into highly vascularised tissues and to a lesser degree penetrates the blood‑brain barrier and the placental barrier following single and multiple doses.

Daptomycin is reversibly bound to human plasma proteins in a concentration independent manner. In healthy volunteers and patients treated with daptomycin, protein binding averaged about 90% including subjects with renal insufficiency.

Metabolism

In in vitro studies, daptomycin was not metabolised by human liver microsomes. In vitro studies with human hepatocytes indicate that daptomycin does not inhibit or induce the activities of the following human cytochrome P450 isoforms: 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4. It is unlikely that daptomycin will inhibit or induce the metabolism of medicinal products metabolised by the P450 system.

After infusion of 14C-daptomycin, the plasma radioactivity was similar to the concentration determined by microbiological assay. Inactive metabolites were detected in urine, as determined by the difference in total radioactive concentrations and microbiologically active concentrations. In a separate study, no metabolites were observed in plasma, and minor amounts of three oxidative metabolites and one unidentified compound were detected in urine. The site of metabolism has not been identified.

In vitro studies have demonstrated that there is no or limited liver microsomal mediated metabolism of daptomycin in humans and that CYP450 involvement in daptomycin metabolism is minimal. Analysis of plasma samples from subjects who received a 6 mg/kg dose of daptomycin did not show any trace of metabolism, suggesting little to no systemic metabolism.

Furthermore, no metabolites have been observed in plasma following administration of radiolabelled drug to humans based on total radiolabel and microbiologically active concentrations. Of the four minor metabolites detected in urine, two are Phase I oxidative metabolites present in low concentrations.

Elimination

Daptomycin is excreted primarily by the kidneys. Concomitant administration of probenecid and daptomycin has no effect on daptomycin pharmacokinetics in humans suggesting minimal to no active tubular secretion of daptomycin.

Following intravenous administration, plasma clearance of daptomycin is approximately 7 to 9 ml/h/kg and its renal clearance is 4 to 7 ml/h/kg.

In a mass balance study using radiolabelled material, 78% of the administered dose was recovered from the urine based on total radioactivity, whilst urinary recovery of unchanged daptomycin was approximately 50% of the dose. About 5% of the administered radiolabel was excreted in the faeces.

Special populations

Elderly

Following administration of a single 4 mg/kg intravenous dose of Cubicin, the mean total clearance of daptomycin decreased approximately 35% and the mean AUC_0-∞ increased approximately 58% in elderly subjects (≥ 75 years of age) compared with those in young healthy subjects (18 to 30 years of age). There were no differences in C_max. The differences noted are most likely due to the normal reduction in renal function observed in the geriatric population.

No dose adjustment is necessary based on age alone. However, renal function should be assessed and the dose should be reduced if there is evidence of severe renal insufficiency.

Children and adolescents (< 18 years of age)

The pharmacokinetics of daptomycin after a single 4 mg/kg dose of Cubicin were evaluated in three groups of paediatric patientsPharmacokinetic profiles were obtained following single intravenous administration of daptomycin 4 mg/kg in paediatric patients with proven or suspected Gram-positive infection, divided into three age groups (2‑6 years, 7‑11 years and 12‑17 years). The pharmacokinetics of daptomycin following a single 4 mg/kg dose in adolescents aged 12‑17 years are generally similar to those of healthy adult subjects with normal renal function with trends towards lower AUC and C_max in adolescents. In the younger age groups (2‑6 years and 7‑11 years), exposure (C_max and AUC) and elimination half-life for the same mg/kg dose were reduced compared with adolescents. Efficacy was not assessed in this study.

A separate study was conducted to evaluate the pharmacokinetics of daptomycin after a single 8 mg/kg or 10 mg/kg dose of Cubicin as either a 1 or 2 hour infusion in paediatric subjects aged 2 to 6 years, inclusive, with proven or suspected Gram-positive infection who were receiving standard antibiotic therapy.

The mean exposure (AUC_0-∞) was approximately 429 and 550 μg*hr/ml after the administration of 8 and 10 mg/kg single doses, respectively, similar to the exposure seen in adults at the 4 mg/kg dose at steady state (495 μg*hr/ml). The pharmacokinetics of daptomycin appears to be linear in the dose range studied. The half life, clearance and volume of distribution were similar at both dose levels.

Obesity

Relative to non-obese subjects daptomycin systemic exposure measured by AUC is increased by about 28% in moderately obese subjects (Body Mass Index of 25‑40 kg/m²) and by 42% in extremely obese subjects (Body Mass Index of > 40 kg/m²). However, no dose adjustment is considered to be necessary based on obesity alone.

Gender

No clinically significant gender-related differences in daptomycin pharmacokinetics have been observed.

Renal insufficiency

Following administration of a single 4 mg/kg or 6 mg/kg dose of daptomycin to subjects with various degrees of renal insufficiency, daptomycin clearance (CL) decreasedwas reduced and systemic exposure (AUC) was increased as renal function (creatinine clearance) decreased.

Based on pharmacokinetic data and modelling, the daptomycin AUC during the first day after administration of a 6 mg/kg dose to patients on HD or CAPD was 2-fold higher than that observed in patients with normal renal function who received the same dose. On the second day after administration of a 6 mg/kg dose to HD and CAPD patients the daptomcyin AUC was approximately 1.3-fold higher than that observed after a second 6 mg/kg dose in patients with normal renal function. On this basis, it is recommended that patients on HD or CAPD receive daptomycin once every 48 hours at the dose recommended for the type of infection being treated (see section 4.2).In subjects with severe renal insufficiency (CLcr < 30 ml/min) and end‑stage renal disease, exposure (AUC) and elimination half life were increased between 2‑3‑fold relative to healthy subjects. See section 4.2 regarding the need for dose adjustment.

Hepatic insufficiency

The pharmacokinetics of daptomycin is not altered in subjects with moderate hepatic insufficiency (Child‑Pugh B classification of hepatic insufficiency) compared with healthy volunteers matched for gender, age and weight following a single 4 mg/kg dose. No dosage adjustment is necessary when administering daptomycin in patients with moderate hepatic insufficiency. The pharmacokinetics of daptomycin in patients with severe hepatic insufficiency (Child‑Pugh C classification) have not been evaluated.

6.3     Shelf life

3 years

After reconstitution: Chemical and physical in-use stability of the reconstituted solution in the vial has been demonstrated for 12 hours at 25°C and up to 48 hours at 2°C – 8°C. Chemical and physical stability of the diluted solution in infusion bags is established as 12 hours at 25°C or 24 hours at 2°C – 8°C.

For the 30-minute intravenous infusion, the combined storage time (reconstituted solution in vial and diluted solution in infusion bag; see section 6.6) at 25°C mustshould not exceed 12 hours (or 24 at 2°C – 8°C).

For the 2-minute intravenous injection, the storage time of the reconstituted solution in the vial (see section 6.6) at 25°C mustshould not exceed 12 hours (or 48 at 2°C – 8°C).

However, from a microbiological point of view the product should be used immediately. No preservative or bacteriostatic agent is present in this product. If not used immediately, in-use storage times are the responsibility of the user and would not normally be longer than 24 hours at 2°C – 8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.

6.5     Nature and contents of container

Single use 10 ml type I clear glass vials with type I rubber stoppers and aluminium closures with yellow plastic flip off caps.

Available in packs containing 1 vial or 5 vials.

6.6     Special precautions for disposal and other handling

Cubicin 350mg powder for solution for injection or infusion

Daptomycin may be administered intravenously as an infusion over 30 minutes or as an injection over 2 minutes (see sections 4.2 and 5.2). Preparation of the solution for infusion requires an additional dilution step as detailed below.

Cubicin given as 30-minute intravenous infusion

A 50 mg/ml concentration of Cubicin for infusion is obtained by reconstituting the lyophilised product with 7 ml of sodium chloride 9 mg/ml (0.9%) solution for injection, or water for injections.

The lyophilised product takes approximately 15 minutes to dissolve. The fully reconstituted product will appear clear and may have a few small bubbles or foam around the edge of the vial.

To prepare Cubicin for intravenous infusion, please adhere to the following instructions:

Aseptic technique should be used throughout to reconstitute lyophilised Cubicin.

1.       The polypropylene flip off cap should be removed to expose the central portions of the rubber stopper. Draw 7 ml of either sodium chloride 9 mg/ml (0.9%) solution for injection or water for injections into a syringe, then slowly inject through the centre of the rubber stopper into the vial pointing the needle towards the wall of the vial.

2.       The vial should be gently rotated to ensure complete wetting of the product and then allowed to stand for 10 minutes.

3.       Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clear reconstituted solution. Vigorous shaking/agitation should be avoided to prevent foaming of the product.

4.       The reconstituted solution should be checked carefully to ensure that the product is in solution and visually inspected for the absence of particulates prior to use. Reconstituted solutions of Cubicin range in colour from pale yellow to light brown.

5.       The reconstituted solution should then be diluted with sodium chloride 9 mg/ml (0.9%) (typical volume 50 ml).

6.       Invert the vial in order to allow the solution to drain towards the stopper. Using a new syringe, insert the needle into the inverted vial. Keeping the vial inverted, position the needle tip at the very bottom of the solution in the vial when drawing the solution into the syringe. Before removing the needle from the vial, pull the plunger all the way back to the end of the syringe barrel in order to remove all of the solution from the inverted vial.

7.       Replace needle with a new needle for the intravenous infusion.

8.       Expel air, large bubbles, and any excess solution in order to obtain the required dose.

9.       The reconstituted and diluted solution should then be infused intravenously over 30 minutes as directed in section 4.2.

The following have been shown to be compatible when added to Cubicin containing infusion solutions: aztreonam, ceftazidime, ceftriaxone, gentamicin, fluconazole, levofloxacin, dopamine, heparin and lidocaine.

Cubicin given as 2-minute intravenous injection

Water should not be used for reconstitution of Cubicin for intravenous injection. Cubicin should only be reconstituted with sodium chloride 9 mg/ml (0.9%).

A 50 mg/ml concentration of Cubicin for injection is obtained by reconstituting the lyophilised product with 7 ml of sodium chloride 9 mg/ml (0.9%) solution for injection.

The lyophilised product takes approximately 15 minutes to dissolve. The fully reconstituted product will appear clear and may have a few small bubbles or foam around the edge of the vial.

To prepare Cubicin for intravenous injection, please adhere to the following instructions:

Aseptic technique should be used throughout to reconstitute lyophilised Cubicin.

1.       The polypropylene flip off cap should be removed to expose the central portions of the rubber stopper. Draw 7 ml of sodium chloride 9 mg/ml (0.9%) solution for injection into a syringe, then slowly inject through the centre of the rubber stopper into the vial pointing the needle towards the wall of the vial.

2.       The vial should be gently rotated to ensure complete wetting of the product and then allowed to stand for 10 minutes.

3.       Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clear reconstituted solution. Vigorous shaking/agitation should be avoided to prevent foaming of the product.

4.       The reconstituted solution should be checked carefully to ensure that the product is in solution and visually inspected for the absence of particulates prior to use. Reconstituted solutions of Cubicin range in colour from pale yellow to light brown.

5.       Invert the vial in order to allow the solution to drain towards the stopper. Using a new syringe, insert the needle into the inverted vial. Keeping the vial inverted, position the needle tip at the very bottom of the solution in the vial when drawing the solution into the syringe. Before removing the needle from the vial, pull the plunger all the way back to the end of the syringe barrel in order to remove all of the solution from the inverted vial.

6.       Replace needle with a new needle for the intravenous injection.

7.       Expel air, large bubbles, and any excess solution in order to obtain the required dose.

8.       The reconstituted solution should then be injected intravenously slowly over 2 minutes as directed in section 4.2.

Cubicin vials are for single-use only.

From a microbiological point of view, the product should be used immediately after reconstitution (see section 6.3).

Any unused product or waste material should be disposed of in accordance with local requirements.

Cubicin 500mg powder for solution for injection or infusion

Daptomycin may be administered intravenously as an infusion over 30 minutes or as an injection over 2 minutes (see sections 4.2 and 5.2). Preparation of the solution for infusion requires an additional dilution step as detailed below.

Cubicin given as 30-minute intravenous infusion

A 50 mg/ml concentration of Cubicin for infusion is obtained by reconstituting the lyophilised product with 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection, or water for injections.

The lyophilised product takes approximately 15 minutes to dissolve. The fully reconstituted product will appear clear and may have a few small bubbles or foam around the edge of the vial.

To prepare Cubicin for intravenous infusion, please adhere to the following instructions:

Aseptic technique should be used throughout to reconstitute lyophilised Cubicin.

1.       The polypropylene flip off cap should be removed to expose the central portions of the rubber stopper. Draw 10 ml of either sodium chloride 9 mg/ml (0.9%) solution for injection or water for injections into a syringe, then slowly inject through the centre of the rubber stopper into the vial pointing the needle towards the wall of the vial.

2.       The vial should be gently rotated to ensure complete wetting of the product and then allowed to stand for 10 minutes.

3.       Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clear reconstituted solution. Vigorous shaking/agitation should be avoided to prevent foaming of the product.

4.       The reconstituted solution should be checked carefully to ensure that the product is in solution and visually inspected for the absence of particulates prior to use. Reconstituted solutions of Cubicin range in colour from pale yellow to light brown.

5.       The reconstituted solution should then be diluted with sodium chloride 9 mg/ml (0.9%) (typical volume 50 ml).

6.       Invert the vial in order to allow the solution to drain towards the stopper. Using a new syringe, insert the needle into the inverted vial. Keeping the vial inverted, position the needle tip at the very bottom of the solution in the vial when drawing the solution into the syringe. Before removing the needle from the vial, pull the plunger all the way back to the end of the syringe barrel in order to remove all of the solution from the inverted vial.

7.       Replace needle with a new needle for the intravenous infusion.

8.       Expel air, large bubbles, and any excess solution in order to obtain the required dose.

9.       The reconstituted and diluted solution should then be infused intravenously over 30 minutes as directed in section 4.2.

The following have been shown to be compatible when added to Cubicin containing infusion solutions: aztreonam, ceftazidime, ceftriaxone, gentamicin, fluconazole, levofloxacin, dopamine, heparin and lidocaine.

Cubicin given as 2-minute intravenous injection

Water should not be used for reconstitution of Cubicin for intravenous injection. Cubicin should only be reconstituted with sodium chloride 9 mg/ml (0.9%).

A 50 mg/ml concentration of Cubicin for injection is obtained by reconstituting the lyophilised product with 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection.

The lyophilised product takes approximately 15 minutes to dissolve. The fully reconstituted product will appear clear and may have a few small bubbles or foam around the edge of the vial.

To prepare Cubicin for intravenous injection, please adhere to the following instructions:

Aseptic technique should be used throughout to reconstitute lyophilised Cubicin.

1.       The polypropylene flip off cap should be removed to expose the central portions of the rubber stopper. Draw 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection into a syringe, then slowly inject through the centre of the rubber stopper into the vial pointing the needle towards the wall of the vial.

2.       The vial should be gently rotated to ensure complete wetting of the product and then allowed to stand for 10 minutes.

3.       Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clear reconstituted solution. Vigorous shaking/agitation should be avoided to prevent foaming of the product.

4.       The reconstituted solution should be checked carefully to ensure that the product is in solution and visually inspected for the absence of particulates prior to use. Reconstituted solutions of Cubicin range in colour from pale yellow to light brown.

5.       Invert the vial in order to allow the solution to drain towards the stopper. Using a new syringe, insert the needle into the inverted vial. Keeping the vial inverted, position the needle tip at the very bottom of the solution in the vial when drawing the solution into the syringe. Before removing the needle from the vial, pull the plunger all the way back to the end of the syringe barrel in order to remove all of the solution from the inverted vial.

6.       Replace needle with a new needle for the intravenous injection.

7.       Expel air, large bubbles, and any excess solution in order to obtain the required dose.

8.       The reconstituted solution should then be injected intravenously slowly over 2 minutes as directed in section 4.2.

Cubicin vials are for single-use only.

From a microbiological point of view, the product should be used immediately after reconstitution (see section 6.3).

Any unused product or waste material should be disposed of in accordance with local requirements.

5.3     Preclinical safety data (bold and underline is new text)

In studies of clinically-relevant duration (14‑28 days), daptomycin administration was associated with minimal to mild degenerative/regenerative changes in skeletal muscle in the rat and dog. Microscopic changes in skeletal muscle were minimal (approximately 0.05% of myofibres affected) and at the higher doses were accompanied by elevations in CPK. No fibrosis or rhabdomyolysis was observed. Depending on the study duration, all muscle effects, including microscopic changes, were fully reversible within 1‑3 months following cessation of dosing. No functional or pathological changes in smooth or cardiac muscle were observed.

The lowest observable effect level (LOEL) for myopathy in rats and dogs occurred at exposure levels of 0.8 to 2.3-fold the human therapeutic levels at 6 mg/kg (30-minute intravenous infusion) for patients with normal renal function. As the pharmacokinetics (see section 5.2) is comparable, the safety margins for both methods of administration are very similar.

A study in dogs demonstrated that skeletal myopathy was reduced upon once daily administration as compared to fractionated dosing at same total daily dose, suggesting that myopathic effects in animals were primarily related to time between doses.

Effects on peripheral nerves were observed at higher doses than those associated with skeletal muscle effects in adult rats and dogs, and were primarily related to plasma C_max. Peripheral nerve changes were characterised by minimal to slight axonal degeneration and were frequently accompanied by functional changes. Reversal of both the microscopic and functional effects was complete within 6 months post-dose. Safety margins for peripheral nerve effects in rats and dogs are 8- and 6-fold, respectively, based on comparison of C_max values at the No Observed Effect Level (NOEL) with the C_max achieved on dosing with 30-minute intravenous infusion of 6 mg/kg once daily in patients with normal renal function.

The findings of in vitro and some in vivo studies designed to investigate the mechanism of daptomycin myotoxicity indicate that the plasma membrane of differentiated spontaneously contracting muscle cells is the target of toxicity. The specific cell surface component directly targeted has not been identified. Mitochondrial loss/damage was also observed; however the role and significance of this finding in the overall pathology are unknown. This finding was not associated with an effect on muscle contraction.

In contrast to adult dogs, juvenile dogs appeared to be more sensitive to peripheral nerve lesions as compared to skeletal myopathy. Juvenile dogs developed peripheral and spinal nerve lesions at doses lower than those associated with skeletal muscle toxicity.

Reproductive toxicity testing showed no evidence of effects on fertility, embryofetal, or postnatal development. However, daptomycin can cross the placenta in pregnant rats (see section 5.2). Excretion of daptomycin into milk of lactating animals has not been studied.

Long-term carcinogenicity studies in rodents were not conducted. Daptomycin was not mutagenic or clastogenic in a battery of in vivo and in vitro genotoxicity tests.

SECTION 4.4

• The following has been added:

There is insufficient evidence to be able to draw any conclusions regarding the possible clinical efficacy of Cubicin against infections due to enterococci, including Enterococcus faecalis and Enterococcus faecium. In addition, dose regimens of daptomycin that might be appropriate for the treatment of enterococcal infections, with or without bacteraemia, have not been identified.

Failures with daptomycin in the treatment of enterococcal infections that were mostly accompanied by bacteraemia have been reported. In some instances treatment failure has been associated with the selection of organisms with reduced susceptibility or frank resistance to daptomycin (see section 5.1).

SECTION 5.1

Mechanisms of resistance:

• First sentance: The word "especially" has been inserted to read:

"Strains with decreased susceptibility to daptomycin have been reported especially during the ....."

• The following has been deleted:

"In a clinical trial in which daptomycin was used for the treatment of endocarditis and complicated bacteraemia there were six patients in whom the observed decrease in susceptibility to daptomycin may have contributed to their failure to respond to therapy"

            and replaced by:

In particular, there have been reports of treatment failures in patients infected with Staphylococcus aureus, Enterococcus faecalis or Enterococcus faecium, including bacteraemic patients, that have been associated with the selection of organisms with reduced susceptibility or frank resistance to daptomycin during therapy.

Information from clinical trials

• The following has been deleted:

"There is insufficient evidence to be able to draw any conclusions regarding the possible clinical effocacy of Cubicin against Enterococcus faccalis and Enterococcus faccium."

There is insufficient evidence to be able to draw any conclusions regarding the possible clinical efficacy of Cubicin against infections due to enterococci, including Enterococcus faecalis and Enterococcus faecium. In addition, dose regimens of daptomycin that might be appropriate for the treatment of enterococcal infections, with or without bacteraemia, have not been identified.

Failures with daptomycin in the treatment of enterococcal infections that were mostly accompanied by bacteraemia have been reported. In some instances treatment failure has been associated with the selection of organisms with reduced susceptibility or frank resistance to daptomycin (see section 5.1).

In a clinical trial in which daptomycin was used for the treatment of endocarditis and complicated bacteraemia there were six patients in whom the observed decrease in susceptibility to daptomycin may have contributed to their failure to respond to therapy.

The mechanism of resistance to daptomycin has not yet been identified.

In particular, there have been reports of treatment failures in patients infected with Staphylococcus aureus, Enterococcus faecalis or Enterococcus faecium, including bacteraemic patients, that have been associated with the selection of organisms with reduced susceptibility or frank resistance to daptomycin during therapy.

The Summary of Product Characteristics has been updated to include the following changes:

• Section 4.4 - Section reworded as follows:

“. . . Renal Insufficiency: Renal insufficiency has been reported during treatment with Cubicin. Severe renal insufficiency may in itself also pre-dispose to elevations in daptomycin levels which may increase the risk of development of myopathy. . . ”

• Section 4.5 – Section reworded as follows:

“. . . During post–marketing surveillance, cases of interference between daptomycin and particular reagents used in some assays of Prothrombin Time/International Normalised Ratio (PT/INR) have been reported. This interference led to an apparent prolongation of PT and elevation of INR. . . “

• Section 4.8 -  The following highlighted text has been added:

“Renal and urinary disorders

Uncommon: Renal insufficiency, including renal impairment and renal failure.”

• Section 4.8- The following post-marketing safety information has been amended and now reads as follows:

“Post-Marketing

Adverse reactions that have been reported Post-Marketing that are not listed above are:

Immune system disorders

Hypersensitivity, manifested by isolated spontaneous reports including, but not limited to; pulmonary eosinophilia, vesicobullous rash with mucous membrane involvement and sensation of oropharyngeal swelling.

Anaphylaxis

Infusion reactions including the following symptoms: tachycardia, wheezing, pyrexia, rigors, systemic flushing, vertigo, syncope and metallic taste.

Musculoskeletal, connective tissue and bone disorders

Rhabdomyolysis

When clinical information on the patients was available to make a judgement, approximately 50% of the cases occurred in patients with pre-existing renal insufficiency, or in those receiving concomitant medications known to cause rhabdomyolysis.”

• Section 4.8 - Addition of the following undesirable effect to ‘Post Marketing’ section:

“Nervous system disorders

Peripheral neuropathy”

• Minor amendments have also been made to sections 2, 5.1 5.2 and 6.6.

• New indication: Right-sided infective endocarditis (RIE) due to Staphylococcus aureus.......
• New indication: Staphylococcus aureus bacteraemia (SAB) when associated with RIE or with cSSTI

• Posology: Reworded and information on the new indications added
• Renal insufficieny: Reworded and additional information relating to the new indications added

• Updated in line with the new indications.
• Creatinine phosphokinase and myopathy: paragraph 1 - incidence figures updated

• Clinical studies: updated with additional data (increased patient numbers) and reworded
• Eosinophilia moved from section on post marketing events to clinical studies section
• Renal insufficiency added

• Mechanism of resistance: reqorded
• Information from clinical trials: additional data from RIE and SAB added

• Paragraph 1: information on higher doses added
• Additional data added regarding children and adolescents
• Renal insufficiency: info on 6 mg/kg dose added