Cubicin®
`(daptomycin for injection)
`Rx only
`
`To reduce the development of drug-resistant bacteria and maintain the effectiveness of CUBICIN
`and other antibacterial drugs, CUBICIN should be used only to treat or prevent infections caused
`by bacteria.
`
`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:
`
`
`
`
`(CH2)8CH3
`
`O
`
`HN
`
`CONH2
`O
`
`NH
`
`NH
`
`HN
`
`O
`CO2H
`
`NH2
`
`O
`
`NH2
`
`HO2C
`
`HN
`
`NH
`
`O
`
`HO
`
`O
`
`O
`
`O
`
`O
`
`NH
`
`O
`
`NH
`
`HN
`
`O
`
`O
`
`HN
`
`NH
`
`O
`
`HN
`
`O
`
`NH
`
`HO2C
`
`HN
`
`O
`
`O
`
`HO2C
`
`
`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.
`
`
`
`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.
`
`Table 1. Mean (SD) CUBICIN Pharmacokinetic Parameters in Healthy Volunteers at Steady-State
`
`Pharmacokinetic Parametersa
`Doseb
`AUC0-24
`Cmax
`CLT
`Vss
`t1/2
`(mg/kg)
`(µg/mL)
`(mL/h/kg)
`(L/kg)
`(h)
`(µg*h/mL)
`4
`(N=6)
`57.8 (3.0)
`8.3 (1.3)
`0.096 (0.009)
`8.1 (1.0)
`494 (75)
`6
`(N=6)
`93.9 (6.0)
`9.1 (1.5)
`0.101 (0.007)
`7.9 (1.0)
`632 (78)
`8
`(N=6)
`123.3 (16.0)
`9.0 (3.0)
`0.101 (0.013)
`8.3 (2.2)
`858 (213)
`10 (N=9)
`141.1 (24.0)
`8.8 (2.2)
`0.098 (0.017)
`7.9 (0.6)
`1039 (178)
`12 (N=9)
`183.7 (25.0)
`9.0 (2.8)
`0.097 (0.018)
`7.7 (1.1)
`1277 (253)
`a. AUC0-24, area under the concentration-time curve from 0 to 24 hours; t½, terminal elimination half-life;
`Vss, volume of distribution at steady-state; CLT, plasma clearance; Cmax, maximum plasma concentration.
`b. Doses of CUBICIN 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 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 0.10 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
`
`
`
`2
`
`
`
`

`

`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).
`
`
`
`3
`
`
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`

`

`Table 2. Mean (SD) Daptomycin Population Pharmacokinetic Parameters Following Infusion of 4 mg/kg or 6
`mg/kg to Infected Patients and Noninfected Subjects with Varying Degrees of Renal Function
`a
`a
`a
`a
`b
`Vss
`CLT
`AUC0-∞
`AUCss
`t1/2
`(h)
`(L/kg)
`(mL/h/kg)
`(µg*h/mL)
`(µg*h/mL)
`4 mg/kg
`4 mg/kg
`4 mg/kg
`4 mg/kg
`6 mg/kg
`9.39 (4.74)
`0.13 (0.05)
`10.9 (4.0)
`417 (155)
`545 (296)
`N=165
`N=165
`N=165
`N=165
`N=62
`
`b
`Cmin,ss
`(µg*h/mL)
`6 mg/kg
`6.9 (3.5)
`N= 61
`
`Renal Function
`
`Normal
`(CLCR >80 mL/min)
`
`Mild Renal Impairment
`(CLCR 50-80 mL/min)
`
`10.75 (8.36)
`N=64
`
`0.12 (0.05)
`N=64
`
`Moderate Renal
`Impairment
`(CLCR 30-<50 mL/min)
`Severe Renal
`Impairment
`(CLCR <30 mL/min)
`Hemodialysis
`
`14.70 (10.50)
`N=24
`
`0.15 (0.06)
`N=24
`
`27.83 (14.85)
`N=8
`
`0.20 (0.15)
`N=8
`
`29.81 (6.13)
`N=21
`
`0.15 (0.04)
`N=21
`
`9.9 (4.0)
`N=64
`
`8.5 (3.4)
`N=24
`
`5.9 (3.9)
`N=8
`
`3.7 (1.9)
`N=21
`
`466 (177)
`N=64
`
`560 (258)
`N=24
`
`637 (215)
`N=29
`
`868 (349)
`N=15
`
`12.4 (5.6)
`N=29
`
`19.0 (9.0)
`N=14
`
`925 (467)
`N=8
`
`1050, 892
`N=2
`
`24.4, 21.4
`N=2
`
`1244 (374)
`N=21
`
`NA
`
`NA
`
`Note: CLCR, creatinine clearance estimated using the Cockcroft-Gault equation with actual body weight;
`AUC0-∞, area under the concentration-time curve extrapolated to infinity; AUCss, area under the concentration-time
`curve calculated over the 24-hour dosing interval at steady-state; Cmin,ss, trough concentration at steady-state;
`NA, not applicable.
`a. Parameters obtained following a single dose from patients with complicated skin and skin structure infections
`
`and healthy subjects.
`b. Parameters obtained at steady-state from patients with S. aureus bacteremia.
`
`Hepatic Insufficiency
`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 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 evaluated.
`
`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 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 reduced approximately 35% and
`the mean AUC0-∞ increased approximately 58% in elderly subjects compared with young healthy
`
`
`
`4
`
`
`
`

`

`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 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 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 subjects.
`
`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 co-administered 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 co-
`administered.
`
`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 co-administered 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).
`
`
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`

`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 co-administered 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
`
`
`
`6
`
`
`
`

`

`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 a 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.
`
`
`
`7
`
`
`
`

`

`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.
`
`Diffusion Technique
`Quantitative methods that require measurement of zone diameters have not been shown to
`provide reproducible estimates of the susceptibility of bacteria to daptomycin. The use of the
`disk diffusion method is not recommended with daptomycin2, 3.
`
`Table 3. Susceptibility Interpretive Criteria for Daptomycin
`
`Pathogen
`
`Broth Dilution MIC
`(µg/mL)a
`I
`
`S
`
`R
`
`≤1
`
`≤1
`
`(b)
`
`(b)
`
`Staphylococcus aureus
`(methicillin-susceptible and methicillin-resistant)
`Streptococcus pyogenes, Streptococcus agalactiae,
`and Streptococcus dysgalactiae subsp. equisimilis
`Enterococcus faecalis
`(b)
`(b)
`≤4
`(vancomycin-susceptible only)
`a. 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.
`b. 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.
`
`(b)
`
`(b)
`
`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.
`
`Quality Control
`Standardized susceptibility test procedures require the use of quality control microorganisms to
`control the technical aspects of the procedures. Standard daptomycin powder should provide the
`range of values noted in Table 4. Quality control microorganisms are specific strains of
`organisms with intrinsic biological properties relating to resistance mechanisms and their genetic
`expression within bacteria; the specific strains used for microbiological quality control are not
`clinically significant.
`
`
`
`8
`
`
`
`

`

`Table 4. Acceptable Quality Control Ranges for Daptomycin to Be Used in Validation of Susceptibility Test
`Results
`
`Quality Control Strain
`
`Enterococcus faecalis ATCC 29212
`
`Staphylococcus aureus ATCC 29213
`
`Broth Dilution MIC Range
`(μg/mL)a
`
`1–4
`
`0.25–1
`
`Streptococcus pneumoniae ATCC 49619b
`0.06–0.5
`a. The quality control ranges 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 quality control ranges for
`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.
`b. This organism may be used for validation of susceptibility test results when testing Streptococcus spp. other
`than S. pneumoniae.
`
`INDICATIONS AND USAGE
`CUBICIN (daptomycin for injection) is indicated for the following infections (see also
`DOSAGE AND ADMINISTRATION and CLINICAL STUDIES):
`Complicated skin and skin structure infections (cSSSI) caused by susceptible isolates of the
`following Gram-positive microorganisms: Staphylococcus aureus (including methicillin-
`resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae
`subsp. equisimilis, and Enterococcus faecalis (vancomycin-susceptible isolates only).
`Combination therapy may be clinically indicated if the documented or presumed pathogens
`include Gram-negative or anaerobic organisms.
`Staphylococcus aureus bloodstream infections (bacteremia), including those with right-sided
`infective endocarditis, caused by methicillin-susceptible and methicillin-resistant isolates.
`Combination therapy may be clinically indicated if the documented or presumed pathogens
`include Gram-negative or anaerobic organisms.
`The efficacy of CUBICIN in patients with left-sided infective endocarditis due to S. aureus has
`not been demonstrated. The clinical trial of CUBICIN in patients with S. aureus bloodstream
`infections included limited data from patients with left-sided infective endocarditis; outcomes in
`these patients were poor (see CLINICAL STUDIES). CUBICIN has not been studied in
`patients with prosthetic valve endocarditis or meningitis.
`
`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 (see PRECAUTIONS).
`CUBICIN is not indicated for the treatment of pneumonia.
`Appropriate specimens for microbiological examination should be obtained in order to isolate
`and identify the causative pathogens and to determine their susceptibility to daptomycin.
`
`
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`

`Empiric therapy may be initiated while awaiting test results. Antimicrobial therapy should be
`adjusted as needed based upon test results.
`To reduce the development of drug-resistant bacteria and maintain the effectiveness of CUBICIN
`and other antibacterial drugs, CUBICIN should be used only to treat or prevent infections that
`are proven or strongly suspected to be caused by susceptible bacteria. When culture and
`susceptibility information are available, they should be considered in selecting or modifying
`antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns
`may contribute to the empiric selection of therapy.
`
`CONTRAINDICATIONS
`CUBICIN is contraindicated in patients with known hypersensitivity to daptomycin.
`
`WARNINGS
`Pseudomembranous colitis has been reported with nearly all antibacterial agents, including
`CUBICIN, and may range in severity from mild to life-threatening. Therefore, it is important to
`consider this diagnosis in patients who present with diarrhea 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.
`
`PRECAUTIONS
`
`General
`The use of antibiotics may promote the selection of non-susceptible organisms. Should
`superinfection occur during therapy, appropriate measures should be taken.
`Prescribing CUBICIN 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.
`
`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.
`
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`Failure of treatment due to persisting or relapsing S. aureus infections was assessed by the
`Adjudication Committee in 19/120 (15.8%) CUBICIN-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 CUBICIN-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
`In a Phase 1 study examining doses up to 12 mg/kg q24h of CUBICIN for 14 days, no skeletal
`muscle effects or CPK elevations were observed.
`In Phase 3 cSSSI trials of CUBICIN at a dose of 4 mg/kg, elevations in CPK were reported as
`clinical adverse events in 15/534 (2.8%) CUBICIN-treated patients, compared with 10/558
`(1.8%) comparator-treated patients.
`In the S. aureus bacteremia/endocarditis trial, at a dose of 6 mg/kg, elevations in CPK were
`reported as clinical adverse events in 8/120 (6.7%) CUBICIN-treated patients compared with
`1/116 (<1%) comparator-treated patients. There were a total of 11 patients who experienced
`CPK elevations to above 500 U/L. Of these 11 patients, 4 had prior or concomitant treatment
`with an HMG-CoA reductase inhibitor.
`Skeletal muscle effects associated with CUBICIN were observed in animals (see ANIMAL
`PHARMACOLOGY).
`Patients receiving CUBICIN should be monitored for the development of muscle pain or
`weakness, particularly of the distal extremities. In patients who receive CUBICIN, CPK levels
`should be monitored weekly, and more frequently in patients who received recent prior or
`concomitant therapy with an HMG-CoA reductase inhibitor. In patients with renal insufficiency,
`both renal function and CPK should be monitored more frequently. Patients who develop
`unexplained elevations in CPK while receiving CUBICIN should be monitored more frequently.
`In the cSSSI studies, among patients with abnormal CPK (>500 U/L) at baseline, 2/19 (10.5%)
`treated with CUBICIN and 4/24 (16.7%) treated with comparator developed further increases in
`CPK while on therapy. In this same population, no patients developed myopathy. CUBICIN-
`treated patients with baseline CPK >500 U/L (N=19) did not experience an increased incidence
`of CPK elevations or myopathy relative to those treated with comparator (N=24). In the
`S. aureus bacteremia/endocarditis study, 3 (2.6%) CUBICIN-treated patients, including 1 with
`trauma associated with a heroin overdose and 1 with spinal cord compression, had an elevation
`in CPK >500 U/L with associated musculoskeletal symptoms. None of the patients in the
`comparator group had an elevation in CPK >500 U/L with associated musculoskeletal
`symptoms.
`CUBICIN 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 (≥10X ULN). In addition,
`consideration should be given to temporarily suspending agents associated with rhabdomyolysis,
`such as HMG-CoA reductase inhibitors, in patients receiving CUBICIN.
`
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`In a Phase 1 study examining doses up to 12 mg/kg q24h of CUBICIN for 14 days, no evidence
`of nerve conduction deficits or symptoms of periperal 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
`CUBICIN was associated with decreases in nerve conduction velocity and with adverse events
`(e.g., paresthesias, Bell’s palsy) possibly reflective of peripheral or cranial neuropathy. 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%)
`CUBICIN-treated patients and 7/1,018 (0.7%) comparator-treated patients experienced
`paresthesias. New or worsening peripheral neuropathy was not diagnosed in any of these
`patients. In the S. aureus bacteremia/endocarditis trial, a total of 11/120 (9.2%) CUBICIN-
`treated patients had treatment-emergent adverse events related to 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 CUBICIN or were likely due to an alternative etiology.
`In animals, effects of CUBICIN on peripheral nerve were observed (see ANIMAL
`PHARMACOLOGY). Therefore, physicians should be alert to the possibility of signs and
`symptoms of neuropathy in patients receiving CUBICIN.
`
`Drug Interactions
`
`Warfarin
`Concomitant administration of CUBICIN (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 CUBICIN and
`warfarin is limited, anticoagulant activity in patients receiving CUBICIN and warfarin should be
`monitored for the first several days after initiating therapy with CUBICIN (see CLINICAL
`PHARMACOLOGY, Drug-Drug Interactions).
`
`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 CUBICIN (4 mg/kg q24h) for 14 days. In the Phase 3 S. aureus
`bacteremia/endocarditis trial, 5/22 CUBICIN-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 CUBICIN in patients
`is limited; therefore, consideration should be given to temporarily suspending use of HMG-CoA
`reductase inhibitors in patients receiving CUBICIN (see ADVERSE REACTIONS, Post-
`Marketing Experience).
`
`Drug-Laboratory Test Interactions
`Clinically relevant plasma levels of daptomycin have been observed to cause a significant
`concentration-dependent fal