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All about: Cubicin Injection

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Generic Name: daptomycin
Dosage Form: Injection

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.

Cubicin 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.

Cubicin - 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.

Table 1. Mean (SD) Cubicin Pharmacokinetic Parameters in Healthy Volunteers at Steady-State
Pharmacokinetic Parameters*
Dose AUC0-24 t1/2 Vss CLT Cmax
(mg/kg) (µg*h/mL) (h) (L/kg) (mL/h/kg) (µg/mL)
*
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.
Doses of Cubicin in excess of 6 mg/kg have not been approved.
  4    (N=6) 494 (75) 8.1 (1.0) 0.096 (0.009) 8.3 (1.3) 57.8 (3.0)
  6    (N=6) 632 (78) 7.9 (1.0) 0.101 (0.007) 9.1 (1.5) 93.9 (6.0)
 8    (N=6) 858 (213) 8.3 (2.2) 0.101 (0.013) 9.0 (3.0) 123.3 (16.0)
10    (N=9) 1039 (178) 7.9 (0.6) 0.098 (0.017) 8.8 (2.2) 141.1 (24.0)
12    (N=9) 1277 (253) 7.7 (1.1) 0.097 (0.018) 9.0 (2.8) 183.7 (25.0)

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 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).

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
Renal Function t1/2* Vss* CLT* AUC0-∞* AUCss Cmin,ss
(h) (L/kg) (mL/h/kg) (µg*h/mL) (µg*h/mL) (µg*h/mL)
4 mg/kg 4 mg/kg 4 mg/kg 4 mg/kg 6 mg/kg 6 mg/kg
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.
*
Parameters obtained following a single dose from patients with complicated skin and skin structure infections and healthy subjects.
Parameters obtained at steady-state from patients with S. aureus bacteremia.
Normal 9.39 (4.74) 0.13 (0.05) 10.9 (4.0) 417 (155) 545 (296) 6.9 (3.5)
(CLCR>80 mL/min) N=165 N=165 N=165 N=165 N=62 N= 61
Mild Renal Impairment 10.75 (8.36) 0.12 (0.05) 9.9 (4.0) 466 (177) 637 (215) 12.4 (5.6)
(CLCR 50−80 mL/min) N=64 N=64 N=64 N=64 N=29 N=29
Moderate Renal Impairment 14.70 (10.50) 0.15 (0.06) 8.5 (3.4) 560 (258) 868 (349) 19.0 (9.0)
(CLCR 30−<50 mL/min) N=24 N=24 N=24 N=24 N=15 N=14
Severe Renal Impairment 27.83 (14.85) 0.20 (0.15) 5.9 (3.9) 925 (467) 1050, 892 24.4, 21.4
(CLCR<30 mL/min) N=8 N=8 N=8 N=8 N=2 N=2
Hemodialysis 29.81 (6.13) 0.15 (0.04) 3.7 (1.9) 1244 (374) NA NA
N=21 N=21 N=21 N=21

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 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 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 () ()
    and Streptococcus dysgalactiae subsp. equisimilis
Enterococcus faecalis ≤4 () ()
    (vancomycin-susceptible only)

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.

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.

Table 4. Acceptable Quality Control Ranges for Daptomycin to Be Used in Validation of Susceptibility Test Results
Quality Control Strain Broth Dilution MIC Range*
(μg/mL)
*
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.
This organism may be used for validation of susceptibility test results when testing Streptococcus spp. other than S. pneumoniae.
Enterococcus faecalis ATCC 29212 1−4
Staphylococcus aureus ATCC 29213 0.25−1
Streptococcus pneumoniae ATCC 49619 0.06−0.5

Indications and Usage for Cubicin

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.  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

Clostridium difficile–associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Cubicin, and may range in severity from mild diarrhea to fatal colitis.  Treatment with antibacterial agents alters the normal flora of the colon, leading to overgrowth of C. difficile.

C. difficile produces toxins A and B, which contribute to the development of CDAD.  Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, since these infections can be refractory to antimicrobial therapy and may require colectomy.  CDAD must be considered in all patients who present with diarrhea following antibiotic use.  Careful medical history is necessary because CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued.  Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

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.

Information for Patients

Diarrhea is a common problem caused by antibiotics that usually ends when the antibiotic is discontinued.  Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having received the last dose of the antibiotic.  If this occurs, patients should contact their physician as soon as possible.

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%) 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.

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 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 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 coadministration 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 false prolongation of prothrombin time (PT) and elevation of International Normalized Ratio (INR) when certain recombinant thromboplastin reagents are utilized for the assay.  The possibility of an erroneously elevated PT/INR result due to interaction with a recombinant thromboplastin reagent may be minimized by drawing specimens for PT or INR testing near the time of trough plasma concentrations of daptomycin.  However, sufficient daptomycin levels 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:


  1. 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.

  2. Evaluate for other causes of abnormally elevated PT/INR results.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies in animals have not been conducted to evaluate the carcinogenic potential of daptomycin.  However, neither mutagenic nor clastogenic potential was found in a battery of genotoxicity tests, including the Ames assay, a mammalian cell gene mutation assay, a test for chromosomal aberrations in Chinese hamster ovary cells, an in vivo micronucleus assay, an in vitro DNA repair assay, and an in vivo sister chromatid exchange assay in Chinese hamsters.

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.

Pregnancy

Teratogenic Effects: Pregnancy Category B

Reproductive and teratology studies performed in rats and rabbits at doses of up to 75 mg/kg, 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 fetus 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, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known if daptomycin is excreted in human milk.  Caution should be exercised when Cubicin is administered to nursing women.

Pediatric Use

Safety and efficacy of Cubicin in patients under the age of 18 have not been established.

Geriatric Use

Of the 534 patients treated with Cubicin in Phase 3 controlled clinical trials of cSSSI, 27.0% were 65 years of

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