DESCRIPTION

CUBICIN contains daptomycin, a cyclic lipopeptide antibacterial agent derived from the fermentation of Streptomyces roseosporus.  The chemical name is 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 ε1-lactone.  The chemical structure is:

The empirical formula is C72H101N17O26; the molecular weight is 1620.67.  CUBICIN is supplied as a sterile, preservative-free, pale yellow to light brown, lyophilized cake containing approximately 900 mg/g of daptomycin for intravenous (IV) use following reconstitution with 0.9% sodium chloride injection.  The only inactive ingredient is sodium hydroxide, which is used in minimal quantities for pH adjustment.  Freshly reconstituted solutions of CUBICIN range in color from pale yellow to light brown.

CLINICAL PHARMACOLOGY

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 summarized in Table 1.

Daptomycin pharmacokinetics were generally linear and time-independent at 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) µg/mL, respectively.

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 hemodialysis (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 0.1 L/kg and was independent of dose.

Metabolism

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.  In in vitro studies, daptomycin was not metabolized by human liver microsomes.  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 radiolabeled 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 CUBICIN 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.

Excretion

Daptomycin is excreted primarily by the kidney.  In a mass balance study of 5 healthy subjects using radiolabeled 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 dose was recovered from feces (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 insufficiency (CLCR <30 mL/min) (see DOSAGE AND ADMINISTRATION).

Special Populations

Renal Insufficiency

Population derived pharmacokinetic parameters were determined for infected patients (complicated skin and skin structure infections and S. aureus bacteremia) and noninfected 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 bacteremia.  Following the administration of CUBICIN 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 hemodialysis (dosed post-dialysis) was approximately 2 and 3 times higher, respectively, than for patients with normal renal function.  Following the administration of CUBICIN 4 mg/kg q24h, the mean Cmax ranged from 60 to 70 µg/mL in patients with CLCR ≥30 mL/min, while the mean Cmax for patients with CLCR <30 mL/min ranged from 41 to 58 µg/mL.  The mean Cmax ranged from 80 to 114 µg/mL in patients with mild-to-moderate renal impairment and was similar to that of patients with normal renal function after the administration of CUBICIN 6 mg/kg q24h.  In patients with renal insufficiency, both renal function and creatine phosphokinase (CPK) should be monitored more frequently.  CUBICIN should be administered following the completion of hemodialysis on hemodialysis days (see DOSAGE AND ADMINISTRATION for recommended dosage regimens).

Hepatic Insufficiency

The pharmacokinetics of daptomycin were eva luated 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 were not altered in subjects with moderate hepatic impairment.  No dosage adjustment is warranted when administering CUBICIN to patients with mild-to-moderate hepatic impairment.  The pharmacokinetics of daptomycin in patients with severe hepatic insufficiency have not been eva luated.

Gender

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

Geriatric

The pharmacokinetics of daptomycin were eva luated 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 reduced approximately 35% and the mean AUC0-∞ increased approximately 58% 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.

Obesity

The pharmacokinetics of daptomycin were eva luated 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 nonobese controls.  The AUC0-∞ of daptomycin increased approximately 30% in moderately obese and 31% in extremely obese subjects compared with nonobese controls.  The differences were most likely due to differences in the renal clearance of daptomycin.  No dosage adjustment of CUBICIN is warranted in obese patients.

Pediatric

The pharmacokinetics of daptomycin in pediatric populations (<18 years of age) have not been established.

Drug-Drug Interactions

Drug-drug interaction studies were performed with CUBICIN and other drugs that are likely to be either coadministered or associated with overlapping toxicity.

Aztreonam

In a study in which 15 healthy adult subjects received a single dose of CUBICIN 6 mg/kg IV, aztreonam 1 g IV, and both in combination, the Cmax and AUC0-∞ of daptomycin were not significantly altered by aztreonam; the Cmax and AUC0-∞ of aztreonam also were not significantly altered by daptomycin.  No dosage adjustment of either antibiotic is warranted when coadministered.

Tobramycin

In a study in which 6 healthy adult males received a single dose of CUBICIN 2 mg/kg IV, tobramycin 1 mg/kg IV, and both in combination, the mean Cmax and AUC0-∞ of daptomycin increased 12.7% and 8.7%, respectively, when administered with tobramycin.  The mean Cmax and AUC0-∞ of tobramycin decreased 10.7% and 6.6%, respectively, when administered with CUBICIN.  These differences were not statistically significant.  The interaction between daptomycin and tobramycin with a clinical dose of CUBICIN is unknown.  Caution is warranted when CUBICIN is coadministered with tobramycin.

Warfarin

In 16 healthy subjects, concomitant administration of CUBICIN 6 mg/kg q24h for 5 days followed by a single oral dose of warfarin (25 mg) had no significant effect on the pharmacokinetics of either drug and did not significantly alter the INR (International Normalized Ratio) (see PRECAUTIONS, Drug Interactions).

Simvastatin

In 20 healthy subjects on a stable daily dose of simvastatin 40 mg, administration of CUBICIN 4 mg/kg IV q24h for 14 days (N=10) was not associated with a higher incidence of adverse events than in subjects receiving placebo once daily (N=10) (see PRECAUTIONS, Drug Interactions).

Probenecid

Concomitant administration of probenecid (500 mg 4 times daily) and a single dose of CUBICIN 4 mg/kg IV did not significantly alter the Cmax and AUC0-∞ of daptomycin.  No dosage adjustment of CUBICIN is warranted when CUBICIN is coadministered with probenecid.

MICROBIOLOGY

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.  The in vitro spectrum of activity of daptomycin encompasses most clinically relevant Gram-positive pathogenic bacteria.  Daptomycin retains potency against antibiotic-resistant Gram-positive bacteria, including isolates resistant to methicillin, vancomycin, and linezolid.

Daptomycin exhibits rapid, concentration-dependent bactericidal activity against Gram-positive organisms in vitro.  This has been demonstrated both by time-kill curves and by MBC/MIC ratios (minimum bactericidal concentration/minimum inhibitory concentration) using broth dilution methodology.  Daptomycin maintained bactericidal activity in vitro against stationary phase S. aureus in simulated endocardial vegetations.  The clinical significance of this is not known.

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 depolarization of membrane potential.  This loss of membrane potential causes inhibition of protein, DNA, and RNA synthesis, which results in bacterial cell death.

Mechanism of Resistance

At this time, no mechanism of resistance to daptomycin has been identified.  Currently, there are no known transferable elements that confer resistance to daptomycin.

Cross-Resistance

Cross-resistance has not been observed with any other antibiotic class.

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, β-lactam antibiotics, and rifampin have been shown against some isolates of staphylococci (including some methicillin-resistant isolates) and enterococci (including some vancomycin-resistant isolates).

Complicated Skin and Skin Structure Infection (cSSSI) Studies

The emergence of daptomycin non-susceptible isolates occurred in 2 infected patients across the set of Phase 2 and pivotal Phase 3 clinical trials.  In one case, a non-susceptible S. aureus was isolated from a patient in a Phase 2 study who received CUBICIN at less than the protocol-specified dose for the initial 5 days of therapy.  In the second case, a non-susceptible Enterococcus faecalis was isolated from a patient with an infected chronic decubitus ulcer enrolled in a salvage trial.

S. aureus Bacteremia/Endocarditis and Other Post-Approval Studies

In subsequent clinical trials, non-susceptible isolates were recovered.  S. aureus was isolated from a patient in a compassionate-use study and from 7 patients in the S. aureus bacteremia/endocarditis study (see PRECAUTIONS).  An E. faecium was isolated from a patient in a VRE study.

Daptomycin has been shown to be active against most isolates of the following microorganisms both in vitro and in clinical infections, as described in the INDICATIONS AND USAGE section.

Aerobic and facultative Gram-positive microorganisms:

Enterococcus faecalis (vancomycin-susceptible isolates only)
Staphylococcus aureus (including methicillin-resistant isolates)
Streptococcus agalactiae
Streptococcus dysgalactiae subsp. equisimilis
Streptococcus pyogenes

The following in vitro data are available, but their clinical significance is unknown.  Greater than 90% of the following microorganisms demonstrate an in vitro MIC less than or equal to the susceptible breakpoint for daptomycin versus the bacterial genus.  The efficacy of daptomycin in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.

Aerobic and facultative Gram-positive microorganisms:

Corynebacterium jeikeium
Enterococcus faecalis (vancomycin-resistant isolates)
Enterococcus faecium (including vancomycin-resistant isolates)
Staphylococcus epidermidis (including methicillin-resistant isolates)
Staphylococcus haemolyticus

Susceptibility Testing Methods

Susceptibility testing by dilution methods requires the use of daptomycin susceptibility powder.  The testing of daptomycin also requires the presence of physiological levels of free calcium ions (50 mg/L of calcium, using calcium chloride) in Mueller-Hinton broth medium.

Dilution Technique

Quantitative methods are used to determine antimicrobial MICs.  These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds.  The MICs should be determined using a standardized procedure1, 2 based on a broth dilution method or equivalent using standardized inoculum and concentrations of daptomycin.  The use of the agar dilution method is not recommended with daptomycin2.  The MICs should be interpreted according to the criteria in Table 3.

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable.

Table 3. Susceptibility Interpretive Criteria for Daptomycin

Pathogen	Broth Dilution MIC*
	(µg/mL)
	S	I	R
Note: S, Susceptible; I, Intermediate; R, Resistant.
* The MIC interpretive criteria for S. aureus and E. faecalis are applicable only to tests performed by broth dilution using Mueller-Hinton broth adjusted to a calcium content of 50 mg/L; the MIC interpretive criteria for Streptococcus spp. other than S. pneumoniae are applicable only to tests performed by broth dilution using Mueller-Hinton broth adjusted to a calcium content of 50 mg/L, supplemented with 2 to 5% lysed horse blood, inoculated with a direct colony suspension and incubated in ambient air at 35ºC for 20 to 24 hours. The current absence of data on daptomycin-resistant isolates precludes defining any categories other than “Susceptible.” Isolates yielding test results suggestive of a “Non-Susceptible” category should be retested, and if the result is confirmed, the isolate should be submitted to a reference laboratory for further testing. †
Staphylococcus aureus	≤1	(†)	(†)
(methicillin-susceptible and methicillin-resistant)
Streptococcus pyogenes, Streptococcus agalactiae,	≤1	(
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