1. Name Of The Medicinal Product
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.
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.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Powder for solution for injection or infusion
A pale yellow to light brown lyophilised powder.
4. Clinical Particulars
4.1 Therapeutic Indications
Cubicin is indicated for the treatment of the following infections in adults (see sections 4.4 and 5.1).
- Complicated skin and soft-tissue infections (cSSTI).
- Right-sided infective endocarditis (RIE) due to Staphylococcus aureus. It is recommended that the decision to use daptomycin should take into account the antibacterial susceptibility of the organism and should be based on expert advice. See sections 4.4 and 5.1.
- Staphylococcus aureus bacteraemia (SAB) when associated with RIE or with cSSTI.
Daptomycin is active against Gram positive bacteria only (see section 5.1). In mixed infections where Gram negative and/or certain types of anaerobic bacteria are suspected, Cubicin should be co-administered with appropriate antibacterial agent(s).
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
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
- 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 impairment. 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 impairment. 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 impairment
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 impairment (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 impairment (see also sections 4.4 and 5.2).
Dose adjustments in patients with renal impairment by indication and creatinine clearance
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(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 impairment
No dose adjustment is necessary when administering Cubicin to patients with mild or moderate hepatic impairment (Child-Pugh Class B) (see section 5.2). No data are available in patients with severe hepatic impairment (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 impairment (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.
Paediatric population
The safety and efficacy of Cubicin in children and adolescents below the age of 18 have not been established. Currently available data are described in section 5.2 but no recommendation on a posology can be made.
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.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
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
• 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 impairment
Renal impairment has been reported during treatment with Cubicin. Severe renal impairment 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 impairment (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 AUC0- 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 Pregnancy 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 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).
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects on the ability to drive and use machines have been performed.
On the basis of reported adverse drug reactions, Cubicin is presumed to be unlikely to produce an effect on the ability to drive or use machinery.
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.
The following adverse reactions were reported during therapy and during follow-up with frequencies corresponding to very common (
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 1 Adverse reactions from clinical studies and post-marketing reports
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* 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).
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 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.
4.9 Overdose
In the event of overdose, supportive care is advised. Daptomycin is slowly cleared from the body by haemodialysis (approximately 15% of the administered dose is removed over 4 hours) or by peritoneal dialysis (approximately 11% of the administered dose is removed over 48 hours).
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Antibacterials for systemic use, Other antibacterials, ATC code: J01XX09
Mechanism of action
Daptomycin is a cyclic lipopeptide natural product that is active against Gram positive bacteria only.
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 Cmax/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 understood.
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
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.
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* 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.
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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
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 Cmax) 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
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 impairment.
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 was approximately 35% lower and the mean AUC0- was approximately 58% higher in elderly subjects (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 impairment.
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 (2max in adolescents. In the younger age groups (2max) and elimination half-life. 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 (AUC0-) 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 was about 28% higher in moderately o
