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Intravenous Dilution Guidelines

Daptomycin - Cubicin ®

The authors make no claims of the accuracy of the information contained herein; and these suggested doses and/or guidelines are not a substitute for clinical judgment. Neither GlobalRPh Inc. nor any other party involved in the preparation of this document shall be liable for any special, consequential, or exemplary damages resulting in whole or part from any user's use of or reliance upon this material.    PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING THIS SITE. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER.

Usual Diluents

NS

Standard Dilutions   [Amount of drug] [Infusion volume] [Infusion rate]

Standard 30 minute infusion (IVPB):
[(4 mg/kg) ] [ 50 ml] [30 min]
[(6 mg/kg) ] [ 50 ml] [30 min]


Two minute infusion:
For intravenous (IV) injection over a period of 2 minutes, administer the appropriate volume of the reconstituted CUBICIN (concentration of 50 mg/mL).

Preparation.

Stability / Miscellaneous

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, ß-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 package insert for 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


CLINICAL PHARMACOLOGY
Pharmacokinetics
---------------------------------
CUBICIN Administered over a 30-Minute Period
The mean and standard deviation (SD) pharmacokinetic parameters of daptomycin at steady-state following intravenous (IV) administration of CUBICIN over a 30-minute period at 4 to 12 mg/kg q24h to healthy young adults are summarized in Table 7.

Table 7. Mean (SD) Daptomycin Pharmacokinetic Parameters in Healthy Volunteers at Steady-State
Dose*†
(mg/kg)
Pharmacokinetic Parameters‡
AUC0-24
(mcg•h/mL)
t1/2
(h)
Vss
(L/kg)
CLT
(mL/h/kg)
Cmax
(mcg/mL)
  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)
*CUBICIN was administered by infusion over a 30-minute period.


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


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

Daptomycin pharmacokinetics were generally linear and time-independent at CUBICIN doses of 4 to 12 mg/kg q24h administered for up to 14 days. Steady-state trough concentrations were achieved by the third daily dose. The mean (SD) steady-state trough concentrations attained following the 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) mcg/mL, respectively.

CUBICIN Administered over a 2-Minute Period
Following IV administration of CUBICIN over a 2-minute period to healthy volunteers at doses of 4 mg/kg (N=8) and 6 mg/kg (N=12), the mean (SD) steady-state systemic exposure (AUC) values were 475 (71) and 701 (82) mcg•h/mL, respectively. Values for maximum plasma concentration (Cmax) at the end of the 2-minute period could not be determined adequately in this study. However, using pharmacokinetic parameters from 14 healthy volunteers who received a single dose of CUBICIN 6 mg/kg IV administered over a 30-minute period in a separate study, steady-state Cmax values were simulated for CUBICIN 4 and 6 mg/kg IV administered over a 2-minute period. The simulated mean (SD) steady-state Cmax values were 77.7 (8.1) and 116.6 (12.2) mcg/mL, respectively.

Distribution
Daptomycin is reversibly bound to human plasma proteins, primarily to serum albumin, in a concentration-independent manner. The overall mean binding ranges from 90 to 93%.

In clinical studies, mean serum protein binding in subjects with creatinine clearance (CLCR) geq30 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 (88%), including those receiving hemodialysis (86%) and continuous ambulatory peritoneal dialysis (CAPD) (84%). The protein binding of daptomycin in subjects with moderate hepatic impairment (Child-Pugh Class 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 in vitro studies, daptomycin was not metabolized by human liver microsomes.

In 5 healthy young adults after infusion of radiolabeled 14C-daptomycin, the plasma total radioactivity was similar to the concentration determined by microbiological assay. Inactive metabolites were detected in urine, as determined by the difference between total radioactive concentrations and microbiologically active concentrations. In a separate study, no metabolites were observed in plasma on Day 1 following the administration of CUBICIN at 6 mg/kg to subjects. 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 kidneys. 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 administered dose was recovered from feces (collected for up to 9 days) based on total radioactivity.




INDICATIONS AND USAGE
CUBICIN (daptomycin for injection) is indicated for the following infections (see also DOSAGE AND ADMINISTRATION and the package insert for 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



OVERDOSAGE
In the event of overdosage, supportive care is advised with maintenance of glomerular filtration. Daptomycin is slowly cleared from the body by hemodialysis (approximately 15% recovered over 4 hours) or peritoneal dialysis (approximately 11% recovered over 48 hours). The use of high-flux dialysis membranes during 4 hours of hemodialysis may increase the percentage of dose removed compared with low-flux membranes.


DOSAGE AND ADMINISTRATION

Administration Duration:
CUBICIN should be administered intravenously either by injection over a two (2) minute period or by infusion over a thirty (30) minute period.

Complicated Skin and Skin Structure Infections:
CUBICIN 4 mg/kg should be administered intravenously in 0.9% sodium chloride injection once every 24 hours for 7 to 14 days.

Staphylococcus aureus Bloodstream Infections (Bacteremia), Including Those with Right-Sided Infective Endocarditis, Caused by Methicillin-Susceptible and Methicillin-Resistant Isolates:
CUBICIN 6 mg/kg should be administered intravenously in 0.9% sodium chloride injection once every 24 hours for 2 to 6 weeks. There are limited safety data for the use of CUBICIN for more than 28 days of therapy. In the Phase 3 trial, there were a total of 14 patients who were treated with CUBICIN for more than 28 days.


Patients with Renal Impairment
Because daptomycin is eliminated primarily by the kidney, a dosage modification is recommended for patients with creatinine clearance <30 mL/min, including patients receiving hemodialysis or CAPD, as listed in Table 9. The recommended dosing regimen is 4 mg/kg (cSSSI) or 6 mg/kg (S. aureus bloodstream infections) once every 24 hours for patients with CLCR greater than or equal30 mL/min and 4 mg/kg (cSSSI) or 6 mg/kg (S. aureus bloodstream infections) once every 48 hours for patients with CLCR <30 mL/min, including those on hemodialysis or CAPD. In patients with renal insufficiency, both renal function and CPK should be monitored more frequently. When possible, CUBICIN should be administered following hemodialysis on hemodialysis days (see package insert for CLINICAL PHARMACOLOGY).


Table 9. Recommended Dosage of CUBICIN (daptomycin for injection) in Adult Patients

Creatinine Clearance
(CLCR)
Dosage Regimen
cSSSI S. aureus Bloodstream Infections
greater than or equal30 mL/min 4 mg/kg once every 24 hours 6 mg/kg once every 24 hours
<30 mL/min, including
hemodialysis or CAPD
4 mg/kg once every 48 hours 6 mg/kg once every 48 hours


Preparation of CUBICIN for Administration top of page icon
CUBICIN is supplied in single-use vials, each containing 500 mg daptomycin as a sterile, lyophilized powder. The contents of a CUBICIN vial should be reconstituted, using aseptic technique, to 50 mg/mL as follows:
Note: To minimize foaming, AVOID vigorous agitation or shaking of the vial during or after reconstitution.
  1. Remove the polypropylene flip-off cap from the CUBICIN vial to expose the central portion of the rubber stopper.
  2. Slowly transfer 10 mL of 0.9% sodium chloride injection through the center of the rubber stopper into the CUBICIN vial, pointing the transfer needle toward the wall of the vial.
  3. Ensure that all of the CUBICIN powder is wetted by gently rotating the vial.
  4. Allow the wetted product to stand undisturbed for 10 minutes.
  5. Gently rotate or swirl the vial contents for a few minutes, as needed, to obtain a completely reconstituted solution.
For intravenous (IV) injection over a period of 2 minutes, administer the appropriate volume of the reconstituted CUBICIN (concentration of 50 mg/mL).

For IV infusion over a period of 30 minutes, the appropriate volume of the reconstituted CUBICIN (concentration of 50 mg/mL) should be further diluted, using aseptic technique, into a 50 mL IV infusion bag containing 0.9% sodium chloride injection.

Parenteral drug products should be inspected visually for particulate matter prior to administration.

No preservative or bacteriostatic agent is present in this product. Aseptic technique must be used in the preparation of final IV solution. Stability studies have shown that the reconstituted solution is stable in the vial for 12 hours at room temperature and up to 48 hours if stored under refrigeration at 2 to 8°C (36 to 46°F).

The diluted solution is stable in the infusion bag for 12 hours at room temperature and 48 hours if stored under refrigeration. The combined storage time (reconstituted solution in vial and diluted solution in infusion bag) should not exceed 12 hours at room temperature or 48 hours under refrigeration.

CUBICIN vials are for single use only.

Compatible Intravenous Solutions
CUBICIN is compatible with 0.9% sodium chloride injection and lactated Ringer's injection.

Incompatibilities
CUBICIN is not compatible with dextrose-containing diluents.

CUBICIN should not be used in conjunction with ReadyMED® elastomeric infusion pumps (Cardinal Health, Inc.). Stability studies of CUBICIN solutions stored in ReadyMED® elastomeric infusion pumps identified an impurity (2-mercaptobenzothiazole) leaching from this pump system into the CUBICIN solution.

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. If the same IV line is used for sequential infusion of different drugs, the line should be flushed with a compatible intravenous solution before and after infusion with CUBICIN.


HOW SUPPLIED
CUBICIN (daptomycin for injection) – Pale yellow to light brown lyophilized cake
Single-use 10 mL capacity vial, 500 mg/vial: Package of 1 (NDC 67919-011-01)


STORAGE
Store original packages at refrigerated temperatures, 2 to 8ºC (36 to 46ºF); avoid excessive heat.


Rx only
CUBICIN is a registered trademark of Cubist Pharmaceuticals, Inc. All other trademarks are property of their respective owners.

Manufactured for:
Cubist Pharmaceuticals, Inc.
Lexington, MA 02421 USA

For all medical inquiries call: (866) 793-2786

Source: CUBICIN [package insert]. Lexington, MA 02421 USA: Cubist Pharmaceuticals, Inc., November 2010.
Disclaimer
The authors make no claims of the accuracy of the information contained herein; and these suggested doses are not a substitute for clinical judgment. Neither GlobalRPh Inc. nor any other party involved in the preparation of this program shall be liable for any special, consequential, or exemplary damages resulting in whole or part from any user's use of or reliance upon this material.  PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING THIS SITE. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER.
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