NAME OF THE MEDICINE

Active ingredient: daptomycin Chemical names: N-decanoyl-L-tryptophyl-D-asparaginyl-L-aspartyl-L-threonylglycyl- L-ornithyl-L-aspartyl-D-alanyl-L-aspartylglycyl-D-seryl-threo-3- methyl-L-glutamyl-3-anthraniloyl-L-alanine 1-lactone CAS number: 103060-53-3 Molecular weight: 1620.67 Molecular formula C72H101N17O26 Chemical structure:

O NH2

HO2C

NH

HN O

HO O O O

NH O

O O

H N

N N

H H

O

O

H

N (CH2)8CH3

O

HN

HN

NH CO2H

N

O H

HN

O

H

NH

N

O

N H

HO2C

DESCRIPTION

Daptomycin is the active ingredient in Cubicin. It is a cyclic lipopeptide antibacterial agent derived from the fermentation of Streptomyces roseosporus. Cubicin is supplied in a single-use 10 mL vial, as a sterile, preservative-free, pale yellow to light brown, lyophilised cake containing at least 900 mg/g of daptomycin for intravenous (IV) use following reconstitution with 0.9 % sodium chloride injection. Daptomycin has a high aqueous solubility ( 1 g/mL). The only inactive ingredient is sodium hydroxide, which is used in minimal quantities for pH adjustment.

PHARMACOLOGY

Pharmacodynamics

Daptomycin is an antibacterial agent of a new class of antibiotics, the cyclic lipopeptides. Daptomycin is a natural product that has clinical utility in the treatment of infections caused by aerobic Gram-positive bacteria. Daptomycin retains potency against antibiotic-resistant Gram- positive bacteria, including isolates resistant to methicillin, vancomycin, and linezolid. Mechanism of action: The mechanism of action of daptomycin is distinct from that of any other antibiotic. Daptomycin binds to bacterial membranes and causes a rapid depolarisation of membrane potential in both growing and stationary phase cells. This loss of membrane potential causes inhibition of protein, DNA, and RNA synthesis. This results in bacterial cell death with negligible cell lysis. Resistance: The mechanism of daptomycin resistance is not fully understood. There are no known transferable elements that confer resistance to daptomycin. There is no cross-resistance due to resistance mechanisms that are specific for another class of antibiotics. As documented with other antibiotics when used in patients with difficult to treat infections and/or for prolonged periods, emergent decreases in susceptibility have been observed in both S. aureus and enterococcal isolates following Cubicin therapy. PK/PD relationship: Daptomycin exhibits rapid, concentration dependent bactericidal activity against sensitive Gram- positive organisms in vitro. Pharmacokinetics The mean (SD) pharmacokinetic parameters of daptomycin at steady-state following IV administration of 4 to 12 mg/kg q24h to healthy young adults are summarised in Table 1 Daptomycin pharmacokinetics were generally linear (dose-proportional) and time-independent at Cubicin doses of 4 to 12 mg/kg q24h. Steady-state trough concentrations were achieved by the third daily dose. The mean (SD) steady-state trough concentrations attained following administration of 4, 6, 8, 10, and 12 mg/kg q24h were 5.9 (1.6), 6.7 (1.6), 10.3 (5.5), 12.9 (2.9), and 13.7 (5.2) ug/mL, respectively.

Table 1 Mean (SD) Daptomycin Pharmacokinetic Parameters in Healthy Volunteers at Steady-State

AUC0-24, area under the concentration-time curve from 0 to 24 hours; t1/2, terminal elimination half-life; Vss, volume of distribution at steady-state; CLT, plasma clearance; Cmax, maximum plasma concentration.

Doses of Daptomycin in excess of 6 mg/kg have not been approved.

Distribution: Daptomycin is reversibly bound to human plasma proteins, primarily to serum albumin, in a concentration-independent manner. The overall mean binding ranged from 90 to 93 %. In clinical studies, mean serum protein binding in subjects with CLCR >=30 mL/min was comparable to that observed in healthy subjects with normal renal function. However, there was a trend toward decreasing serum protein binding among subjects with CLCR <30 mL/min (87.6 %), including those receiving haemodialysis (85.9 %) and continuous ambulatory peritoneal dialysis (CAPD) (83.5 %). The protein binding of daptomycin in subjects with hepatic impairment (Child-Pugh B) was similar to that in healthy adult subjects. The volume of distribution at steady-state (Vss) of daptomycin in healthy adult subjects was approximately 0.10 L/kg and was independent of dose. 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 drugs metabolized by the P450 system. In 5 healthy young adults after infusion of radiolabelled 14C-daptomycin, the plasma total radioactivity was similar to the concentration determined by microbiological assay. In a separate study, no metabolites were observed in plasma on Day 1 following administration of daptomycin at 6 mg/kg to subjects. Inactive metabolites have been detected in urine, as determined by the difference in total radioactive concentrations and microbiologically active concentrations. 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 kidney. Concomitant administration of probenecid and daptomycin has no effect on daptomycin pharmacokinetics in humans suggesting minimal to no active tubular secretion of daptomycin. 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 of 5 healthy subjects using radiolabelled daptomycin, approximately 78 % of the administered dose was recovered from urine based on total radioactivity (approximately 52 % of the dose based on microbiologically active concentrations) and 5.7 % of the administered dose was recovered from faeces (collected for up to 9 days) based on total radioactivity. Because renal excretion is the primary route of elimination, dosage adjustment is necessary in patients with severe renal impairment (CLCR <30 mL/min) (see DOSAGE AND ADMINISTRATION). Pharmacokinetics in special patient groups: Elderly: The pharmacokinetics of daptomycin were evaluated in 12 healthy elderly subjects (>=75 years of age) and 11 healthy young controls (18 to 30 years of age). Following administration of a single 4 mg/kg IV dose, the mean total clearance of daptomycin was was approximately 35 % lower and the mean AUC0- was approximately 58 % higher in elderly subjects compared with young healthy subjects. There were no differences in Cmax. No dosage adjustment is warranted for elderly patients with normal renal function.

Children and adolescents

:

The pharmacokinetics of daptomycin after a single 4 mg/kg dose of Cubicin were evaluated in three groups of paediatric patients with Gram-positive infections. The pharmacokinetic profile in adolescents, 12-17 years of age, was similar to that in healthy adults, although exposure was reduced. In the two younger age groups (7 to 11 years and 2 to 6 years),

total clearance was higher compared with that in adolescents, resulting in lower exposure (AUC and Cmax) and elimination half-life. Efficacy was not assessed in this study. Obesity: The pharmacokinetics of daptomycin were evaluated in 6 moderately obese (Body Mass Index [BMI] 25 to 39.9 kg/m2) and 6 extremely obese (BMI >= 40 kg/m2) subjects and controls matched for age, sex, and renal function. Following administration of a single 4 mg/kg IV dose based on total body weight, the plasma clearance of daptomycin normalized to total body weight was approximately 15 % lower in moderately obese subjects and 23 % lower in extremely obese subjects compared with non-obese controls. The AUC0- of daptomycin was approximately 30 % higher in moderately obese and 31 % higher in extremely obese subjects compared with non-obese controls. The differences were most likely due to differences in the renal clearance of daptomycin. No dosage adjustment of daptomycin is warranted in obese subjects.

Gender

:

No clinically significant gender-related differences in daptomycin pharmacokinetics have been observed. No dosage adjustment is warranted based on gender when administering daptomycin.

Renal Impairment: Population derived pharmacokinetic parameters were determined for infected patients (complicated skin and skin structure infections and S. aureus bacteraemia) and non-infected subjects with varying degrees of renal function (Table 2). Plasma clearance (CLT), elimination half- life (t1/2), and volume of distribution (Vss) were similar in patients with complicated skin and skin structure infections compared with those with S. aureus bacteraemia. Following the administration of daptomycin 4 mg/kg q24h, the mean CLT was 9 %, 22 %, and 46 % lower among subjects and patients with mild (CLCR 50-80 mL/min), moderate (CLCR 30-50 mL/min), and severe (CLCR < 30 mL/min) renal impairment, respectively, than in those with normal renal function (CLCR > 80 mL/min). The mean steady-state systemic exposure (AUC), t1/2, and Vss increased with decreasing renal function, although the mean AUC was not markedly different for patients with CLCR 30-80 mL/min compared with those with normal renal function. The mean AUC for patients with CLCR <30 mL/min and for patients on haemodialysis (dosed post-dialysis) was approximately 2 and 3 times higher, respectively, than for patients with normal renal function. Following the administration of daptomycin 4 mg/kg q24h, the mean Cmax ranged from 60 to 70 ug/mL in patients with CLCR >= 30 mL/min, while the mean Cmax for patients with CLCR < 30 mL/min ranged from 41 to 58 ug/mL. The mean Cmax ranged from 80 to 114 ug/mL in patients with mild-to-moderate renal impairment and was similar to that of patients with normal renal function after the administration of daptomycin 6 mg/kg q24h. In patients with renal impairment, both renal function and creatine phosphokinase (CPK) should be monitored more frequently. Daptomycin should be administered following the completion of haemodialysis on haemodialysis days (see DOSAGE AND ADMINISTRATION for recommended dosage regimens).

Hepatic Impairment

:

The pharmacokinetics of daptomycin were evaluated in 10 subjects with moderate hepatic impairment (Child-Pugh Class B) and compared with healthy volunteers (N= 9) matched for gender, age, and weight. The pharmacokinetics of daptomycin was not altered in subjects with moderate hepatic impairment. No dosage adjustment is warranted when administering daptomycin to patients with mild to moderate hepatic impairment. The pharmacokinetics of daptomycin in patients with severe hepatic impairment (Child-Pugh Class C)

has not been evaluated.

Table 2 Mean (SD) Daptomycin Population Pharmacokinetic Parameters Following Infusion of 4 mg/kg or 6 mg/kg to Infected Patients and Non-infected Subjects with Varying Degrees of Renal Function

CLINICAL TRIALS

Complicated Skin and Skin Structure Infections (cSSSI)

Skin and skin structure infections are defined as infections of the epidermis, dermis or subcutaneous tissue, and have highly diverse aetiologies and clinical manifestations. The complicated category includes deep soft tissue infections which require significant medical intervention, and abnormal skin or wound infections, which typically occur in compromised patients and may require surgical intervention. Adult patients with clinically documented cSSSI (Table 3) were enrolled in two randomised, multinational, multicentre, investigator-blinded studies comparing daptomycin (4 mg/kg IV q24h) with either vancomycin (1 g IV q12h) or an anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; 4 to 12 g IV per day). In these trials cSSSIs included wound infections, major abscesses, severe carbunculosis, infected ulcers and infections in the presence of a complicating factor, such as infections involving deep soft tissue, fascia, or muscle and infections in immunosuppressed patients (e.g. HIV infection, chronic systemic steroids, diabetes mellitus). Patients known to have bacteraemia at baseline were excluded. Patients with creatinine clearance (CLCR) between 30 and 70 mL/min were to receive a lower dose of daptomycin as specified in the protocol; however, the majority of patients in this subpopulation did not have the dose of daptomycin adjusted. In Study DAP-SST-9801 (9801), 16 % of the ITT patients treated with daptomycin had their regimen adjusted for renal function. In Study DAP-SST-9901 (9901), only 2 % had their regimen adjusted. Patients could switch to oral therapy after a minimum of 4 days of IV treatment if clinical improvement was demonstrated. Study 9801 was conducted primarily in the United States and South Africa, whilst Study 9901 was conducted outside of the US, including 5 sites in Australia. Both studies were similar in design but differed in patient characteristics, including history of diabetes and peripheral vascular disease. There were a total of 534 patients treated with daptomycin and 558 treated with comparator in the two studies. The majority (89.7 %) of patients received IV medication exclusively. The efficacy endpoints in both studies were the clinical success rates in the intent-to-treat (ITT) population and in the clinically evaluable (CE) population. The ITT population included all enrolled subjects who had a complicated skin and soft tissue infection and received at least one dose of study medication. The CE population consisted of all subjects in the ITT population who met specific pre-defined criteria such that the clinical outcome of their infection could be inferred to reflect the effect of the study drug. In study 9801, clinical success rates in the ITT population were 62.5 % (165/264) in patients treated with daptomycin and 60.9 % (162/266) in patients treated with comparator drugs. Clinical success rates in the CE population were 76.0 % (158/208) in patients treated with daptomycin and 76.7 % (158/206) in patients treated with comparator drugs. In study 9901, clinical success rates in the ITT population were 80.4 % (217/270) in patients treated with daptomycin and 80.5 % (235/292) in patients treated with comparator drugs. Clinical success rates in the CE population were 89.9 % (214/238) in patients treated with daptomycin and 90.4 % (226/250) in patients treated with comparator drugs. The success rates by pathogen for microbiologically evaluable patients are presented in Table 4. Overall clinical efficacy results are provided in Tables 5 and 6 in terms of the sponsor-defined primary clinical efficacy parameters at the Test of Cure visit (7-12 days after cessation of antibiotic treatment) for MITT and CE populations.

Table 3 Investigator's Primary Diagnosis in the cSSSI Studies (Population: ITT)

Vancomycin or anti-staphylococcal semi-synthetic penicillins.

The majority of cases were subsequently categorised as complicated cellulitis, major abscesses, or traumatic wound infections.

Table 4 Clinical Success Rates by Infecting Pathogen, Primary Comparative cSSSI Studies (Population: Microbiologically Evaluable)

Vancomycin or anti-staphylococcal semi-synthetic penicillins

As determined by the central laboratory

Table 5 Clinical efficacy outcome (MITT population)

a

Vancomycin or anti-staphylococcal semi-synthetic penicillins

Table 6 Clinical efficacy outcome (CE population)

a

Vancomycin or anti-staphylococcal semi-synthetic penicillins

S. aureus

Bacteraemia/Endocarditis

The efficacy of daptomycin in the treatment of patients with S. aureus bacteraemia (SAB) was demonstrated in a randomised, controlled, multinational, multicentre open-label study. In this study, adult patients with at least one positive blood culture for S. aureus obtained within 2 calendar days prior to the first dose of study drug and irrespective of source were enrolled and randomized to either daptomycin (6 mg/kg IV q24h) or standard of care [anti-staphylococcal semi-synthetic penicillin 2 g IV q4h (nafcillin, oxacillin, cloxacillin, or flucloxacillin) or vancomycin 1 g IV q12h, both with initial gentamicin 1 mg/kg IV every 8 hours for first 4 days]. Of the patients in the comparator group, 93 % received initial gentamicin for a median of 4 days compared with 1 patient (< 1 %) in the daptomycin group. Patients with prosthetic heart valves, intravascular foreign material that was not planned for removal within 4 days after the first dose of study medication, severe neutropenia, known osteomyelitis, polymicrobial bloodstream infections, creatinine clearance < 30 mL/min, shock unresponsive to treatment for 4 hours and pneumonia were excluded. Upon entry, patients were classified for likelihood of endocarditis using the modified Duke criteria (Possible, Definite, or Not Endocarditis). Echocardiography, including a transoesophageal echocardiogram (TEE), was performed within 5 days following study enrolment. The choice of comparator agent was based on the oxacillin susceptibility of the S. aureus isolate. The duration of study treatment was based on the investigator's clinical diagnosis. Final diagnoses and outcome assessments at Test of Cure (6 weeks after the last treatment dose) were made by a treatment- blinded Adjudication Committee, using protocol-specified clinical definitions and a composite primary efficacy endpoint (clinical and microbiological success) at the Test of Cure visit. A total of 246 patients >= 18 years of age (124 daptomycin, 122 comparator) with S. aureus bacteraemia were randomized from 48 centres in the US and Europe. In the ITT population, 120 patients received daptomycin and 115 received comparator (62 anti-staphylococcal semi-synthetic penicillin and 53 vancomycin). Thirty-five patients treated with anti-staphylococcal semi-synthetic penicillins received vancomycin initially for 1 to 3 days, pending final susceptibility results for the S aureus isolates. The median age among the 235 patients in the ITT population was 53 years (range: 21 to 91 years); 30/120 (25 %) in the daptomycin group and 37/115 (32 %) in the comparator group were >=65 years of age. Of the 235 ITT patients, there were 141 (60 %) males and 156 (66 %) Caucasians across the two treatment groups. In addition, 176 (75 %) of the ITT population had systemic inflammatory response syndrome (SIRS) and 85 (36 %) had surgical procedures within 30 days of onset of the S. aureus bacteraemia. Eighty-eight patients (38 %) had bacteraemia caused by MRSA. Entry diagnosis was based on the modified Duke criteria and included 37 (16 %) Definite, 144 (61 %) Possible, and 54 (23 %) Not Endocarditis. Of the 37 patients with an entry diagnosis of Definite Endocarditis, all (100 %) had a final diagnosis of infective endocarditis, and of the 144 patients with an entry diagnosis of Possible Endocarditis, 15 (10 %) had a final diagnosis of infective endocarditis as assessed by the Adjudication Committee. Of the 54 patients with an entry diagnosis of Not Endocarditis, 1 (2 %) had a final diagnosis of infective endocarditis as assessed by the Adjudication Committee. There were 182 patients with bacteraemia and 53 patients with infective endocarditis as assessed by the Adjudication Committee in the ITT population, including 35 with right-sided and 18 with left- sided endocarditis. The 182 patients with bacteraemia included 121 with complicated and 61 with uncomplicated S. aureus bacteraemia. Complicated bacteraemia was defined as S. aureus isolated from blood cultures obtained on at least 2 different calendar days, and/or metastatic foci of infection (deep tissue involvement), and classification of the patient as not having endocarditis according to the modified Duke criteria. Uncomplicated bacteraemia was defined as S. aureus isolated from blood culture(s) obtained on a single calendar day, no metastatic foci of infection, no infection of prosthetic material, and classification of the patient as not having endocarditis according to the modified Duke criteria. The definition of right-sided endocarditis (RIE) used in the clinical trial was Definite or Possible Endocarditis according to the modified Duke criteria and no echocardiographic evidence of predisposing pathology or active involvement of either the mitral or aortic valve. Complicated RIE included patients who were not intravenous drug users, had a positive blood culture for MRSA, serum creatinine >= 2.5 mg/dL, or evidence of extrapulmonary sites of infection. Patients who were intravenous drug users, had a positive blood culture for MSSA, serum creatinine < 2.5 mg/dL, and were without evidence of extrapulmonary sites of infection were considered to have uncomplicated RIE. The co-primary efficacy endpoints in the study were the Adjudication Committee success rates at the Test of Cure visit (6 weeks after the last treatment dose) in the ITT and Per Protocol (PP) populations. The overall Adjudication Committee success rates in the ITT population were 44.2 % (53/120) in patients treated with daptomycin and 41.7 % (48/115) in patients treated with comparator (difference = 2.4 % [95 % CI - 10.2, 15.1]). The success rates in the PP population were 54.4 % (43/79) in patients treated with daptomycin and 53.3 % (32/60) in patients treated with comparator (difference = 1.1 % [95 % CI - 15.6, 17.8]). Adjudication Committee success rates are shown in Table 7. Eighteen (18/120) patients in the daptomycin arm and 19/116 patients in the comparator arm died during the study. These include 3/28 daptomycin -treated and 8/26 comparator-treated patients with endocarditis, as well as 15/92 daptomycin -treated and 11/90 comparator-treated patients with bacteraemia. Among patients with persisting or relapsing S. aureus infections, 8/19 daptomycin - treated and 7/11 comparator-treated patients died. Overall, there was no difference in time to clearance of S. aureus bacteraemia between daptomycin and comparator. The median time to clearance in patients with MSSA was 4 days and in patients with MRSA was 8 days. Failure of treatment due to persisting or relapsing S. aureus infections was assessed by the Adjudication Committee in 19/120 (15.8 %) daptomycin-treated patients (12 with MRSA and 7 with MSSA) and 11/115 (9.6 %) comparator-treated patients (9 with MRSA treated with vancomycin and 2 with MSSA treated with anti-staphylococcal semi-synthetic penicillin). Among all failures, 6 daptomycin-treated patients and 1 vancomycin-treated patient developed increasing MICs for daptomycin (reduced susceptibility) by central laboratory testing on or following therapy. Most patients who failed due to persisting or relapsing S. aureus infection had deep-seated infection and did not receive necessary surgical intervention (see PRECAUTIONS).

Table 7 Adjudication Committee Success Rates at Test of Cure (ITT)

Comparator: vancomycin (1 g IV q12h) or anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, flucloxacillin; 2 g IV q4h), each with initial low-dose gentamicin

According to the modified Duke criteria

95 % Confidence Interval

97.5 % Confidence Interval (adjusted for multiplicity) 99 % Confidence Interval (adjusted for multiplicity)

CONTRAINDICATIONS

Cubicin is contraindicated in patients with known hypersensitivity to daptomycin or to the excipient.

PRECAUTIONS

General

Although daptomycin is indicated for the treatment of right-sided endocarditis caused by Staphylococcus aureus, its efficacy in patients with left-sided infective endocarditis has not been demonstrated in controlled clinical trials. Therefore, use of daptomycin in left-sided endocarditis caused by S. aureus is not recommended and consideration should be given to instituting alternative antibacterial therapy.

Anaphylaxis/hypersensitivity reactions

Anaphylaxis/hypersensitivity reactions have been reported with nearly all antibacterial agents including Cubicin. If an allergic reaction to Cubicin occurs, discontinue the medicine and institute appropriate therapy. Pneumonia Daptomycin is not indicated for the treatment of pneumonia. It has been demonstrated in clinical studies that Cubicin is not effective in the treatment of community-acquired pneumonia (inhalational or airborne), due to binding to pulmonary surfactant and consequent inactivation (see INDICATIONS). Eosinophilic pneumonia Eosinophilic pneumonia has been reported in patients receiving Cubicin (see ADVERSE EFFECTS). In reported cases associated with Cubicin, patients developed fever, dyspnoea with hypoxic respiratory insufficiency, and diffuse pulmonary infiltrates. In general, patients developed eosinophilic pneumonia 2 to 4 weeks after starting 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 drugs), and Cubicin should be discontinued immediately. Treatment with systemic steroids is recommended.

Non-susceptible organisms

The use of antibiotics may promote the selection of non-susceptible organisms. Should superinfection occur during therapy, appropriate measures should be taken. Prescribing daptomycin in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Patients with deep seated infections should receive any required surgical interventions (e.g. debridement, removal of prosthetic devices, valve replacement surgery) without delay so as not to compromise successful therapy. 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. As documented with other antibiotics when used in patients with difficult to treat infections and/or for prolonged periods, emergent decreases in susceptibility have been observed in a limited number of enterococcal isolates following daptomycin therapy. Failures with daptomycin in the treatment of enterococcal bloodstream infections have been reported. Resistance or lack of susceptibility needs to be monitored during therapy.

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 Effect on Laboratory Tests).

Antibiotic-associated Colitis

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including daptomycin, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of any antibacterial agent. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicated that a toxin produced by Clostridium difficile is a primary cause of "antibiotic-associated colitis". If a diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate-to-severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial agent clinically effective against C. difficile.

Persisting or Relapsing S. aureus Infection

Patients with persisting or relapsing S. aureus infection or poor clinical response should have repeat blood cultures. If a culture is positive for S. aureus, MIC susceptibility testing of the isolate should be performed using a standardized procedure, as well as diagnostic evaluation to rule out sequestered foci of infection. Appropriate surgical intervention (e.g., debridement, removal of prosthetic devices, valve replacement surgery) and/or consideration of a change in antibiotic regimen may be required. Failure of treatment due to persisting or relapsing S. aureus infections was assessed by the Adjudication Committee in 19/120 (15.8 %) daptomycin-treated patients (12 with MRSA and 7 with MSSA) and 11/115 (9.6 %) comparator-treated patients (9 with MRSA treated with vancomycin and 2 with MSSA treated with anti-staphylococcal semi-synthetic penicillin). Among all failures, 6 daptomycin -treated patients and 1 vancomycin-treated patient developed increasing MICs (reduced susceptibility) by central laboratory testing on or following therapy. Most patients who failed due to persisting or relapsing S. aureus infection had deep-seated infection and did not receive necessary surgical intervention (see CLINICAL STUDIES).

Skeletal muscle effects

Increases in plasma creatine phosphokinase (CPK) levels associated with muscular pains, weakness and/or rhabdomyolysis have been reported during therapy with Cubicin (see ADVERSE EFFECTS). In studies of clinically-relevant duration (14-28 days), skeletal muscle effects associated with daptomycin were observed in rats and dogs with no changes in cardiac or smooth muscle. The lowest observed effect level (LOEL) for myopathy in rats and dogs occurred at exposure levels of 0.8 to 2.3-fold the mean AUC in patients with normal renal function following 30-minute continuous infusion dosing of 6 mg/kg. Skeletal muscle effects were characterized by degenerative/regenerative changes and variable elevations in creatine phosphokinase (CPK). No fibrosis or rhabdomyolysis was observed up to the highest doses tested in rats and dogs (approximately 9 and 5 times the human AUC at 6 mg/kg/day, respectively). All muscle effects, including microscopic changes, were fully reversible in rats within 30 days and in dogs within 2 months following cessation of dosing. In a Phase 1 study examining doses up to 12 mg/kg q24h of daptomycin for 14 days, no skeletal muscle effects or CPK elevations were observed. In the two Phase 3 cSSSI trials of daptomycin at a dose of 4 mg/kg, elevations in CPK were reported as adverse events in 15/534 (2.8 %) daptomycin -treated patients, compared with 10/558 (1.8 %) comparator-treated patients. In only one of these two trials an elevation in CPK > 500 was detected in association with a musculoskeletal event - these findings were reported in two patients, one in each treatment group. In the S. aureus bacteraemia/endocarditis trial, at a daptomycin dose of 6 mg/kg, elevations in CPK were reported as clinical adverse events in 8/120 (6.7 %) daptomycin -treated patients compared with 1/116 ( < 1 %) comparator-treated patients. In patients with normal CPK at baseline, 25.0 % in the daptomycin group and 12.5 % in the comparator group had CPK >= ULN during therapy or up to 3 days post-treatment. Eighteen (75.0 %) of the 24 daptomycin patients with CPK >=ULN at baseline had CPK return to the normal range during treatment. A total of 11 daptomycin patients had treatment-emergent elevations in CPK to > 500U/L, including 3 patients with CPK ULN at baseline. Of these 11 patients, 4 had prior or concomitant treatment with an HMG-CoA reductase inhibitor which may have contributed to these laboratory findings. Three of these 11 daptomycin patients had an elevation in CPK > 500 U/L with an associated musculoskeletal or asthenia event, 2 of whom had an alternative aetiology for these events. Patients should be reviewed regularly while on therapy for any signs or symptoms that might represent myopathy such as muscle pain or weakness, particularly of the distal extremities. Plasma CPK levels should be monitored at baseline and at regular intervals (at least once weekly) during therapy in all patients. Patients with unexplained elevations of CPK or unexplained muscle pain, tenderness or weakness 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 impairment (creatinine clearance < 30 ml/min) and patients taking other medications known to be associated with myopathy (e.g. HMG-CoA reductase inhibitors, fibrates and cyclosporin). 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. During post-marketing surveillance very rare isolated cases of rhabdomyolysis in patients receiving daptomycin have been reported; when clinical information on the patients was available, approximately 50 % of the cases occurred in patients with pre-existing renal impairment, or in those receiving concomitant medications known to cause rhabdomyolysis. It is recommended that other medications associated with myopathy should if possible be temporarily discontinued during treatment with daptomycin unless the benefits of concomitant administration outweigh the risk. Daptomycin should be discontinued in patients with unexplained signs and symptoms of myopathy in conjunction with CPK elevation > 1,000 U/L ( ~ 5X ULN), or in patients without reported symptoms who have marked elevations in CPK >2,000 U/L ( >= 10 X ULN). In addition, consideration should be given to temporarily suspending agents associated with rhabdomyolysis, such as HMG-CoA reductase inhibitors, in patients receiving daptomycin.

Peripheral nerve effects

Physicians should be alert to signs and symptoms of peripheral neuropathy in patients receiving Cubicin (see ADVERSE EFFECTS). In rats and dogs, effects of daptomycin on peripheral and/or spinal nerve (characterised by axonal degeneration and frequently accompanied in dogs by functional changes in nerve conduction and/or loss of reflexes, decreased pain perception, tremor and motor incoordination) were observed at doses higher than those associated with skeletal myopathy. Reversal of both the microscopic and functional effects was almost complete within 6 months post dose. Exposure margins for peripheral nerve effects in rats and dogs are 8- and 6- fold, respectively based on comparison of Cmax values at the No Observed Effect Level (NOEL) with the Cmax achieved with 30-minute continuous infusion dosing of 6mg/kg once daily in patients with normal renal function. Therefore, physicians should be alert to the possibility of signs and symptoms of neuropathy in patients receiving daptomycin. In a Phase 1 study examining doses up to 12 mg/kg q24h of daptomycin for 14 days, no evidence of nerve conduction deficits or symptoms of peripheral neuropathy was observed. In a small number of patients in Phase 1 and Phase 2 studies at doses up to 6 mg/kg, administration of daptomycin was associated with decreases in nerve conduction velocity and with adverse events (e.g., paraesthesias, Bell's palsy) possibly reflective of peripheral or cranial neuropathy. However, nerve conduction deficits were also detected in a similar number of comparator subjects in these studies. In Phase 3 cSSSI and community-acquired pneumonia (CAP) studies, 7/989 (0.7 %) daptomycin- treated patients and 7/1,018 (0.7 %) comparator-treated patients experienced paraesthesias. New or worsening peripheral neuropathy was not diagnosed in any of these patients. In the S. aureus bacteraemia/endocarditis trial, a total of 11/120 (9.2 %) patients in the daptomycin group and 2 (1.7 %) patients in the comparator group were identified who had experienced adverse events associated with the peripheral nervous system. All of the events were classified as mild to moderate in severity; most were of short duration and resolved during continued treatment with daptomycin or were likely due to an alternative aetiology.

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 the development of myopathy or neuropathy (see above). In patients with renal impairment, both renal function and CPK should be monitored more frequently than once a week.

Effects on Fertility

Daptomycin did not affect the fertility or reproductive performance of male and female rats when administered intravenously at doses up to 150 mg/kg/day, which is approximately 9 times the estimated human exposure level based upon AUCs.

Use In Pregnancy (Category B1)

Embryo/fetal development studies performed in rats and rabbits at doses of up to 75 mg/kg, approximately 2 and 4 times the 6 mg/kg human dose, respectively, on a body surface area basis, have revealed no evidence of harm to the foetus due to daptomycin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Cubicin should be used during pregnancy only if the potential benefit outweighs the possible risk.

Use in Lactation

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 ug/mL, which is a low concentration. Women should be instructed to avoid breast-feeding while receiving Cubicin.

Use in Children

The safety and effectiveness of daptomycin in patients under the age of 18 years have not been established.

Use in Elderly

Of the 534 patients treated with daptomycin in Phase 3 controlled clinical trials of cSSSI, 27.0 % were 65 years of age or older and 12.4 % were 75 years of age or older. Of the 120 patients treated with daptomycin in the Phase 3 controlled clinical trial of S. aureus bacteraemia/endocarditis, 25.0 % were 65 years of age or older and 15.8 % were 75 years of age or older. In Phase 3 clinical studies of cSSSI and S. aureus bacteraemia/endocarditis, lower clinical success rates were seen in patients >= 65 years of age compared with those < 65 years of age. In addition, treatment-emergent adverse events were more common in patients >= 65 years old than in patients < 65 years of age.

Carcinogenicity

Long-term carcinogenicity studies in animals have not been conducted to evaluate the carcinogenic potential of daptomycin.

Genotoxicity

Daptomycin was not mutagenic or clastogenic in a battery of in vivo and in vitro genotoxicity tests comprising mutation in bacteria and mammalian cells, chromosomal aberrations and DNA damage in mammalian cells, a bone marrow micronucleus assay in mice and a sister chromatid exchange assay in Chinese hamsters.

Interaction with Other Medicines

Daptomycin undergoes little or no Cytochrome P450 (CYP450) mediated metabolism. It is unlikely that daptomycin will inhibit or induce the metabolism of drugs metabolized by the CYP450 system. Warfarin Concomitant administration of daptomycin (6 mg/kg q24h for 5 days) and warfarin (25 mg single oral dose) had no significant effect on the pharmacokinetics of either drug, and the INR was not significantly altered. As experience with the concomitant administration of daptomycin and warfarin is limited, anticoagulant activity in patients receiving daptomycin and warfarin should be monitored for the first several days after initiating therapy with daptomycin (see PHARMACOLOGY). Other Anticoagulants Studies of Cubicin with anticoagulants, other than warfarin, have not been conducted. HMG-CoA reductase inhibitors Inhibitors of HMG-CoA reductase may cause myopathy, which is manifested as muscle pain or weakness associated with elevated levels of CPK. There were no reports of skeletal myopathy in a placebo-controlled Phase 1 trial in which 10 healthy subjects on stable simvastatin therapy were treated concurrently with daptomycin (4 mg/kg q24h) for 14 days. In the Phase 3 S. aureus bacteraemia/endocarditis trial, 5/22 daptomycin -treated patients who received prior or concomitant therapy with an HMG-CoA reductase inhibitor developed CPK elevations > 500 U/L. Experience with co-administration of HMG-CoA reductase inhibitors and daptomycin in patients is limited; therefore, consideration should be given to temporarily suspending use of HMG-CoA reductase inhibitors in patients receiving daptomycin (see ADVERSE REACTIONS). Aztreonam, tobramycin and probenecid Cubicin was studied in human drug/drug interaction studies with aztreonam, tobramycin and probenecid. Aztreonam: The pharmacokinetics of daptomycin were not significantly altered by aztreonam. Daptomycin had no effect on the bioavailability of aztreonam. Probenecid: Daptomycin had no effect on the pharmacokinetics of probenecid, and nor did probenecid alter the pharmacokinetics of daptomycin. Tobramycin: 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 a clinical dose of Cubicin is unknown. Caution is warranted when daptomycin is co-administered with tobramycin. Interactions with other antibiotics:

In vitro studies have investigated daptomycin interactions with other antibiotics. Antagonism, as determined by kill curve studies, has not been observed. In vitro synergistic interactions of daptomycin with aminoglycosides, b-lactam antibiotics, and rifampin have been shown against some isolates of staphylococci (including some methicillin-resistant isolates) and enterococci (including some vancomycin-resistant isolates). The clinical significance of these in vitro studies is unclear.

Effect on Laboratory Tests

Clinically relevant plasma concentrations of daptomycin have been observed to cause a significant concentration-dependant false prolongation of prothrombin time (PT) and elevation of the International Normalized rRatio (INR) when certain recombinant thromboplastin reagents are used in the assay. The possibility of an erroneously elevated PT/INR result may be minimized by drawing samples for PT or INR testing near the time of trough plasma concentrations of daptomycin. However, sufficient daptomycin concentrations may be present at trough to cause interaction. If confronted with an abnormally high PT/INR result in a patient being treated with Cubicin, it is recommended that clinicians: Repeat the assessment of PT/INR, requesting that the specimen be drawn just prior to the next Cubicin dose (i.e., at trough concentration). If the PT/INR value drawn at trough remains substantially elevated over what would otherwise be expected, consider evaluating PT/INR utilizing an alternative method. Evaluate for other causes of abnormally elevated PT/INR results.

DOSAGE AND ADMINISTRATION

Adult Dosage Regimens

Cubicin in 0.9 % sodium chloride is administered either by injection over a 2-minute period or infusion over a 30 minute period. Do not dose Cubicin more frequently than once a day. Measure creatinine phosphokinase levels at baseline and at regular intervals (at least weekly (see PRECAUTIONS)). For complicated skin and skin structure infections (CSSSI): Cubicin 4 mg/kg once daily for 7 - 14 days or until the infection is resolved. For bacteraemia or right-sided endocarditis caused by S. aureus (SAB/RIE): Cubicin 6 mg/kg is administered once daily for 2 - 6 weeks depending on the diagnosis. Patients with renal impairment: Because daptomycin is eliminated primarily by the kidneys, a dosage adjustment is recommended for patients with creatinine clearance (CLcr) < 30 mL/min, including patients receiving haemodialysis or continuous ambulatory peritoneal dialysis. Patients with creatinine clearance >= 30 mL/min: No dose adjustment is required in patients whose creatinine clearance is 30 mL/min. Response to treatment and renal function should be closely monitored in all patients with renal insufficiency.

Patients with creatinine clearance < 30 mL/min:

The dosing interval should be lengthened to a single dose once every 48 hours for these patients. Alternatively, patients on haemodialysis can be dosed three times per week after haemodialysis. Clinical response to treatment and renal function should be closely monitored in these patients.

The same dose adjustment and advice is recommended for patients on haemodialysis or continuous ambulatory peritoneal dialysis (CAPD). Whenever possible, daptomycin should be administered following the completion of haemodialysis on haemodialysis days. In patients with renal impairment, monitor both renal function and CPK more frequently than once weekly. Patients with hepatic impairment: No dosage adjustment is warranted when administering Cubicin to patients with mild or moderate hepatic impairment (Child-Pugh Class B). The pharmacokinetics of daptomycin in patients with severe hepatic impairment (Child-Pugh Class C) have not been evaluated. Elderly patients: No adjustment of Cubicin dosage is warranted for elderly patients with CLcr >= 30 mL/min. Children: Safety and efficacy of daptomycin in patients under the age of 18 has not been established. Therefore, daptomycin is not recommended for use in children.

Instructions for Use and Handling

Cubicin is given intravenously either by injection over 2 minutes or infusion over 30 minutes. Cubicin vials are for single use in one patient. Any residue should be discarded. Cubicin contains no preservative or bacteriostatic agent. Aseptic technique must be used in preparation of final IV solution. Cubicin should be reconstituted with 0.9 % sodium chloride. Prior to injection, the reconstituted product should contain no visible particulate matter. Note: To minimise foaming, AVOID vigorous agitation or shaking of the vial during or after reconstitution.

Cubicin given as 2-minute intravenous injection

Remove the polypropylene flip-off cap from the Cubicin vial to expose the central portion of the rubber stopper. Slowly transfer 7 mL of 0.9 % sodium chloride injection (for 350 mg vials) or 10 mL of 0.9 % sodium chloride injection (for 500 mg vial) through the centre of the rubber stopper into the Cubicin vial, pointing the transfer needle toward the wall of the vial. Ensure that the entire Cubicin product is wetted by gently rotating the vial. Allow the product to stand undisturbed for 10 minutes. Gently rotate or swirl the vial contents for a few minutes, as needed, to obtain a completely reconstituted solution.

Cubicin given as 30-minute intravenous infusion

Follow steps above for the 2-minute itravenous injection. Reconstituted Cubicin should be further diluted with 0.9 % sodium chloride injection (typical volume 50 mL) to be administered by IV infusion over a period of 30 minutes. The final concentration of the diluted solution should be between 2.5 mg/mL and 20 mg/mL.

Stability after reconstitution and dilution:

In the vial

: Chemical and physical in-use stability of the reconstituted solution in the vial has been

demonstrated for 12 hours at room temperature or up to 48 hours if stored under refrigeration (2deg to 8C).

In the infusion bag

: Chemical and physical in-use stability of the diluted solution in the infusion bag has been established for 12 hours at room temperature or 48 hours if stored under refrigeration (2deg to 8degC).

However, to reduce microbiological hazard, the reconstituted solution and the diluted solution should be used as soon as practicable after reconstitution and after dilution. If storage of the reconstituted or further diluted solution is necessary, solutions should be stored under refrigeration at 2 to 8degC for a combined time (vial and infusion bag) of no more than 24 hours. Because only limited data are available on the compatibility of Cubicin with other IV substances, additives or other medications should not be added to Cubicin single-use vials or infused simultaneously through the same IV line. If the same IV line is used for sequential infusion of several different drugs, the line should be flushed with a compatible infusion solution before and after infusion with Cubicin.

Compatibility:

Compatible Intravenous Solutions

Cubicin is compatible with 0.9 % sodium chloride injection and lactated Ringer's injection.

Incompatibilities

Cubicin is not compatible with glucose-containing diluents, including dextrose. Because only limited data are available on the compatibility of Cubicin with other IV substances, additives and other medications should not be added to Cubicin single-use vials or infusion bags or infused simultaneously through the same IV line (see PRECAUTIONS - Interactions with other medicines). If the same IV line is used for sequential infusion of different drugs, flush the line with a compatible intravenous solution before and after infusion with Cubicin.

OVERDOSAGE

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). Contact Poisons Information Centre on 13 11 26 for advice on management of overdosage.

PRESENTATION AND STORAGE CONDITIONS

Presentation

Cubicin is supplied in single-use vials containing 350 mg or 500 mg daptomycin as a sterile, lyophilised powder. Single-use 10 mL capacity vial: Package of 1.

Storage

Store in original packages at refrigerated temperatures of between 2deg to 8 C; avoid excessive heat.

NAME AND ADDRESS OF THE SPONSOR

Novartis Pharmaceuticals Australia Pty Limited ABN 18 004 244 160 54 Waterloo Road North Ryde NSW 2113

= Registered Trademark

POISON SCHEDULE OF THE MEDICINE

Prescription Only Medicine (Schedule 4)

DATE OF FIRST INCLUSION IN THE ARTG

8 December 2008

DATE OF MOST RECENT AMENDMENT

15 February 2012