`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`
`
`CUBICIN safely and effectively. See full prescribing information
`
`
`
`
`for CUBICIN.
`
`CUBICIN® (daptomycin for injection), for Intravenous Use
`
`Initial U.S. Approval: 2003
`
`
`
`--------------------------- RECENT MAJOR CHANGES ---------------------------
`Warnings and Precautions, Development of Drug-Resistant
`10/2021
`Bacteria (5.12)
`
`
`----------------------------INDICATIONS AND USAGE----------------------------
`
`
`
`CUBICIN is a lipopeptide antibacterial indicated for the treatment of:
`
`Complicated skin and skin structure infections (cSSSI) in adult
`
`
`and pediatric patients (1 to 17 years of age) (1.1) and,
`Staphylococcus aureus bloodstream infections (bacteremia), in
`
`
`including
`infective
`adult patients
`those with
`right-sided
`endocarditis, (1.2)
`
`Staphylococcus aureus bloodstream infections (bacteremia) in
`
`
`pediatric patients (1 to 17 years of age). (1.3)
`
`Limitations of Use:
`
`CUBICIN is not indicated for the treatment of pneumonia. (1.4)
`
`
`
`
`CUBICIN is not indicated for the treatment of left-sided infective
`
`
`
`
`endocarditis due to S. aureus. (1.4)
`
`CUBICIN is not recommended in pediatric patients younger than
`
`
`one year of age due to the risk of potential effects on muscular,
`
`neuromuscular, and/or nervous systems (either peripheral and/or
`
`
`central) observed in neonatal dogs. (1.4)
`
`To reduce the development of drug-resistant bacteria and maintain the
`effectiveness of CUBICIN and other antibacterial drugs, CUBICIN
`
`
`
`
`should be used to treat or prevent infections that are proven or strongly
`
`
`
`suspected to be caused by bacteria. (1.5)
`
`----------------------- DOSAGE AND ADMINISTRATION -----------------------
`
`
`
`
`Adult Patients
`Administer to adult patients intravenously in 0.9% sodium
`
`
`
`
`chloride, either by injection over a 2-minute period or by infusion
`
`over a 30-minute period. (2.1, 2.7)
`
`
`Recommended dosage regimen for adult patients (2.2, 2.4, 2.6):
`
`Creatinine
`Dosage Regimen
`Clearance
`
`cSSSI
`
`
`S. aureus
`(CLCR)
`For 7 to 14 days
`Bacteremia
`For 2 to 6 weeks
`
`6 mg/kg once
`every 24 hours
`6 mg/kg once
`every 48 hours*
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`≥30 mL/min
`
`
`4 mg/kg once every
`24 hours
`
`4 mg/kg once every
`48 hours*
`
`
`<30 mL/min,
`including
`hemodialysis and
`CAPD
`*Administered following hemodialysis on hemodialysis days.
`Pediatric Patients
`
`
`
`
`Unlike in adults, do NOT administer by injection over a two
`
`
`(2) minute period to pediatric patients. (2.1, 2.7)
`Administer to pediatric patients intravenously in 0.9% sodium
`
`
`chloride, by infusion over a 30- or 60-minute period, based on
`
`age. (2.1, 2.7)
`
`
`
`
`
`Recommended dosage regimen for pediatric patients (1 to 17
`
`years of age) with cSSSI, based on age (2.3):
`
`Age group
`Dosage*
`
`
`
`
`
`
`
`
`
`Duration of
`therapy
`
`12 to 17 years
`
`
`7 to 11 years
`
`
`2 to 6 years
`
`
`5 mg/kg once every 24 hours
`
`
`infused over 30 minutes
`
`7 mg/kg once every 24 hours
`infused over 30 minutes
`9 mg/kg once every 24 hours
`infused over 60 minutes
`10 mg/kg once every 24 hours
`1 to less than
`infused over 60 minutes
`2 years
`* Recommended dosage is for pediatric patients (1 to 17 years of
`age) with normal renal function. Dosage adjustment for pediatric
`patients with renal impairment has not been established.
`Recommended dosage regimen for pediatric patients (1 to 17
`
`
`
`
`
`
`
`years of age) with S. aureus bacteremia, based on age (2.5):
`
`
`Up to 14 days
`
`
`
`
`Reference ID: 4878697
`
`Age group
`
`
`Dosage*
`
`Duration of
`therapy
`
`
`
`
`
`
`
`
`12 to 17 years
`
`
`7 to 11 years
`
`
`Up to 42 days
`
`
`
`7 mg/kg once every 24 hours
`
`
`infused over 30 minutes
`
`9 mg/kg once every 24 hours
`infused over 30 minutes
`12 mg/kg once every 24 hours
`1 to 6 years
`
`infused over 60 minutes
`*Recommended dosage is for pediatric patients (1 to 17 years of age)
`with normal renal function. Dosage adjustment for pediatric patients
`with renal impairment has not been established.
`There are two formulations of daptomycin that have differences
`
`
`
`follow
`the
`concerning storage and reconstitution. Carefully
`
`reconstitution and storage procedures in labeling. (2.7)
`
`Do not use in conjunction with ReadyMED® elastomeric infusion
`
`
`
`pumps in adult and pediatric patients. (2.9)
`
`
`--------------------- DOSAGE FORMS AND STRENGTHS ---------------------
`
`
`
`For Injection: 500 mg lyophilized powder for reconstitution in a single-
`dose vial (3)
`
`
`
`------------------------------- CONTRAINDICATIONS-------------------------------
`
` Known hypersensitivity to daptomycin (4)
`
`
`
`----------------------- WARNINGS AND PRECAUTIONS -----------------------
`
`
`
` Anaphylaxis/hypersensitivity reactions (including life-threatening):
`
`Discontinue CUBICIN and treat signs/symptoms. (5.1)
`
`
` Myopathy and rhabdomyolysis: Monitor CPK levels and follow
`
`muscle pain or weakness; if elevated CPK or myopathy occurs,
`
`consider discontinuation of CUBICIN. (5.2)
`
`
`
` Eosinophilic pneumonia: Discontinue CUBICIN and consider
`treatment with systemic steroids. (5.3)
`
` Drug Reaction with Eosinophilia and Systemic Symptoms
`
`institute appropriate
`(DRESS): Discontinue CUBICIN and
`treatment. (5.4)
`
`(TIN): Discontinue CUBICIN and
`Tubulointerstitial Nephritis
`institute appropriate treatment. (5.5)
`
`
`
`
` Peripheral neuropathy: Monitor for neuropathy and consider
`
`discontinuation. (5.6)
`
`
`
` Potential nervous system and/or muscular system effects in
`
`
`pediatric patients younger than 12 months: Avoid use of CUBICIN
`
`in this age group. (5.7)
`
`
` Clostridioides difficile–associated diarrhea: Evaluate patients if
`
`diarrhea occurs. (5.8)
`
`
`
` Persisting or relapsing S. aureus bacteremia/endocarditis: Perform
`
`
`susceptibility testing and rule out sequestered foci of infection.
`
`(5.9)
`
` Decreased efficacy was observed in adult patients with moderate
`baseline renal impairment. (5.10)
`------------------------------ ADVERSE REACTIONS ------------------------------
`
`
`
` Adult cSSSI Patients: The most common adverse reactions that
`
`
`occurred in ≥2% of adult cSSSI patients receiving CUBICIN
`
`
`
`4 mg/kg were diarrhea, headache, dizziness, rash, abnormal liver
`function tests, elevated creatine phosphokinase (CPK), urinary
`tract infections, hypotension, and dyspnea. (6.1)
`
` Pediatric cSSSI Patients: The most common adverse reactions
`
`
`that occurred in ≥2% of pediatric patients receiving CUBICIN were
`
`
`
`diarrhea, vomiting, abdominal pain, pruritus, pyrexia, elevated
`
`CPK, and headache. (6.1)
`
` Adult S. aureus bacteremia/endocarditis Patients: The most
`
`
`common adverse reactions that occurred in ≥5% of S. aureus
`
`bacteremia/endocarditis patients receiving CUBICIN 6 mg/kg
`
`were sepsis, bacteremia, abdominal pain, chest pain, edema,
`
`pharyngolaryngeal pain, pruritus, increased sweating, insomnia,
`
`
`elevated CPK, and hypertension. (6.1)
`
` Pediatric S. aureus bacteremia Patients: The most common
`
`
`
`
`adverse reactions that occurred in ≥5% of pediatric patients
`
`
`receiving CUBICIN were vomiting and elevated CPK. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Merck
`
`Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-
`
`888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`
`Revised: 10/2021
`
`
`
`
`

`

`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1
` INDICATIONS AND USAGE
`1.1 Complicated Skin and Skin Structure Infections (cSSSI)
`
`Bloodstream
`1.2 Staphylococcus
`Infections
`
`
`aureus
`(Bacteremia) in Adult Patients, Including those with Right-
`
`
`Infective Endocarditis, Caused by Methicillin-
`
`Sided
`Susceptible and Methicillin-Resistant Isolates
`
`Infections
`
`Bloodstream
`1.3 Staphylococcus
`
`aureus
`(Bacteremia) in Pediatric Patients (1 to 17 Years of Age)
`
`
`1.4 Limitations of Use
`
`1.5 Usage
`
`2 DOSAGE AND ADMINISTRATION
`
`
`Important Administration Duration Instructions
`
`2.1
`2.2 Dosage in Adults for cSSSI
`
`2.3 Dosage in Pediatric Patients (1 to 17 Years of Age) for
`
`
`cSSSI
`
`
`2.4 Dosage in Adult Patients with Staphylococcus aureus
`
`
`Bloodstream Infections (Bacteremia), Including Those with
`
`Right-Sided Infective Endocarditis, Caused by Methicillin-
`
`Susceptible and Methicillin-Resistant Isolates
`
`2.5 Dosage in Pediatric Patients (1 to 17 Years of Age) with
`
`
`
`Bloodstream
`Infections
`
`
`aureus
`Staphylococcus
`(Bacteremia)
`
`
`2.6 Dosage in Patients with Renal Impairment
`
`
`2.7 Preparation and Administration of CUBICIN
`
`2.8 Compatible Intravenous Solutions
`
`Incompatibilities
`
`2.9
`
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Anaphylaxis/Hypersensitivity Reactions
`
`5.2 Myopathy and Rhabdomyolysis
`
`5.3 Eosinophilic Pneumonia
`
`5.4 Drug Reaction with Eosinophilia and Systemic Symptoms
`
`
`
`(DRESS)
`
`
`5.5 Tubulointerstitial Nephritis (TIN)
`
`5.6 Peripheral Neuropathy
`
`5.7 Potential Nervous System and/or Muscular System Effects
`
`
`in Pediatric Patients Younger than 12 Months
`
`
`
`
`
`
`
`
`
`
`5.8 Clostridioides difficile-Associated Diarrhea
`
`
`5.9 Persisting or Relapsing S. aureus Bacteremia/Endocarditis
`
`5.10 Decreased Efficacy in Patients with Moderate Baseline
`
`
`Renal Impairment
`
`5.11 Increased International Normalized Ratio (INR)/Prolonged
`
`Prothrombin Time
`
`5.12 Development of Drug-Resistant Bacteria
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`6.2 Post-Marketing Experience
`
`7 DRUG INTERACTIONS
`7.1 HMG-CoA Reductase Inhibitors
`
`7.2 Drug-Laboratory Test Interactions
`
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`
`8.2 Lactation
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`
`8.6 Patients with Renal Impairment
`
`10 OVERDOSAGE
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`12.2 Pharmacodynamics
`
`12.3 Pharmacokinetics
`
`12.4 Microbiology
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`13.2 Animal Toxicology and/or Pharmacology
`
`14 CLINICAL STUDIES
`14.1 Complicated Skin and Skin Structure Infections
`
`14.2 S. aureus Bacteremia/Endocarditis
`
`15 REFERENCES
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`17 PATIENT COUNSELING INFORMATION
`
`
`*Sections or subsections omitted from the full prescribing information
`
`are not listed.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4878697
`
`

`

`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`1
`
`INDICATIONS AND USAGE
`
`1.1 Complicated Skin and Skin Structure Infections (cSSSI)
`CUBICIN® is indicated for the treatment of adult and pediatric patients (1 to 17 years of age) with
`
`
`
`
`complicated skin and skin structure infections (cSSSI) caused by susceptible isolates of the following
`
`
`
`Gram-positive bacteria: Staphylococcus aureus (including methicillin-resistant isolates), Streptococcus
`
`pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp. equisimilis, and Enterococcus
`
`
`
`
`
`faecalis (vancomycin-susceptible isolates only).
`
`
`1.2 Staphylococcus aureus Bloodstream Infections (Bacteremia) in Adult Patients, Including
`
`
`Those with Right-Sided Infective Endocarditis, Caused by Methicillin-Susceptible and
`
`
`
`
`Methicillin-Resistant Isolates
`CUBICIN is indicated for the treatment of adult patients with Staphylococcus aureus bloodstream
`
`
`
`infections (bacteremia), including adult patients with right-sided infective endocarditis, caused by
`
`methicillin-susceptible and methicillin-resistant isolates.
`1.3 Staphylococcus aureus Bloodstream Infections (Bacteremia) in Pediatric Patients (1 to 17
`
`Years of Age)
`CUBICIN is indicated for the treatment of pediatric patients (1 to 17 years of age) with Staphylococcus
`
`
`
`aureus bloodstream infections (bacteremia).
`
`
`1.4 Limitations of Use
`
`CUBICIN is not indicated for the treatment of pneumonia.
`
`CUBICIN is not indicated for the treatment of left-sided infective endocarditis due to S. aureus. The
`
`
`
`clinical trial of CUBICIN in adult 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
`(14.2)]. CUBICIN has not been studied in patients with prosthetic valve endocarditis.
`CUBICIN is not recommended in pediatric patients younger than 1 year of age due to the risk of
`
`
`
`
`potential effects on muscular, neuromuscular, and/or nervous systems (either peripheral and/or
`
`
`central) observed in neonatal dogs [see Warnings and Precautions (5.7) and Nonclinical Toxicology
`
`
`(13.2)].
`
`1.5 Usage
`
`Appropriate specimens for microbiological examination should be obtained in order to isolate and identify
`
`the causative pathogens and to determine their susceptibility to daptomycin.
`
`
`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 is available, it 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. Empiric therapy may be initiated while awaiting test results.
`
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`Important Administration Duration Instructions
`2.1
`Adults
`
`Reference ID: 4878697
`
`3
`
`
`

`

`
`
` Administer the appropriate volume of the reconstituted CUBICIN (concentration of 50 mg/mL) to adult
`
`
`
` patients intravenously either by injection over a two (2) minute period or by intravenous infusion over a
`
`
`
`
`
`thirty (30) minute period [see Dosage and Administration (2.2, 2.4, 2.7)].
`Pediatric Patients (1 to 17 Years of Age)
`
`
`
`
`
`
`Unlike in adults, do NOT administer CUBICIN by injection over a two (2) minute period to pediatric
`
`patients.
`
`
` Pediatric Patients 7 to 17 years of Age: Administer CUBICIN intravenously by infusion over a 30-
`
`minute period [see Dosage and Administration (2.3, 2.5, 2.7)].
`
`
`
` Pediatric Patients 1 to 6 years of Age: Administer CUBICIN intravenously by infusion over a 60-
`
`minute period [see Dosage and Administration (2.3, 2.5, 2.7)].
`
`
`2.2 Dosage in Adults for cSSSI
`
`Administer CUBICIN 4 mg/kg to adult patients intravenously in 0.9% sodium chloride injection once every
`
`24 hours for 7 to 14 days.
`2.3 Dosage in Pediatric Patients (1 to 17 Years of Age) for cSSSI
`The recommended dosage regimens based on age for pediatric patients with cSSSI are shown in Table
`
`
`1. Administer CUBICIN intravenously in 0.9% sodium chloride injection once every 24 hours for up to 14
`
`
`
`
`days.
`
`
`Table 1: Recommended Dosage of CUBICIN in Pediatric Patients (1 to 17 Years of Age) with cSSSI,
`Based on Age
`
`
`Dosage Regimen*
`
`Duration of therapy
`
`
`Age Range
`
`12 to 17 years 5 mg/kg once every 24 hours infused over 30 minutes
`
`7 mg/kg once every 24 hours infused over 30 minutes
`7 to 11 years
`
`9 mg/kg once every 24 hours infused over 60 minutes
`2 to 6 years
`10 mg/kg once every 24 hours infused over 60 minutes
`1 to less than 2
`
`
`years
`
`*Recommended dosage regimen is for pediatric patients (1 to 17 years of age) with normal renal function.
`
`Dosage adjustment for pediatric patients with renal impairment has not been established.
`
`Up to 14 days
`
`
`
`
`
`
`
`2.4 Dosage in Adult Patients with Staphylococcus aureus Bloodstream Infections (Bacteremia),
`
`
`Including Those with Right-Sided Infective Endocarditis, Caused by Methicillin-Susceptible
`and Methicillin-Resistant Isolates
`
`Administer CUBICIN 6 mg/kg to adult patients 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 adult patients who were treated with CUBICIN for
`
`more than 28 days.
`
`
`2.5 Dosage in Pediatric Patients (1 to 17 Years of Age) with Staphylococcus aureus
`Bloodstream Infections (Bacteremia)
`
`
`The recommended dosage regimens based on age for pediatric patients with S. aureus bloodstream
`
`
`infections (bacteremia) are shown in Table 2. Administer CUBICIN intravenously in 0.9% sodium chloride
`
`injection once every 24 hours for up to 42 days.
`Table 2: Recommended Dosage of CUBICIN in Pediatric Patients (1 to 17 Years of Age) with S.
`
`
`aureus Bacteremia, Based on Age
`
`Reference ID: 4878697
`
`4
`
`
`

`

`
`
`
`
` Age group
`
`
`
` Dosage*
`
`Duration of therapy
`
`
`12 to 17 years 7 mg/kg once every 24 hours infused over 30 minutes
`
`
`7 to 11 years 9 mg/kg once every 24 hours infused over 30 minutes
`
`12 mg/kg once every 24 hours infused over 60 minutes
`1 to 6 years
`*Recommended dosage is for pediatric patients (1 to 17 years of age) with normal renal function. Dosage
`
`adjustment for pediatric patients with renal impairment has not been established.
`
`Up to 42 days
`
`
`2.6 Dosage in Patients with Renal Impairment
`Adult Patients:
`
`
` No dosage adjustment is required in adult patients with creatinine clearance (CLCR) greater than or equal
` to 30 mL/min. The recommended dosage regimen for CUBICIN in adult patients with CLCR less than
`
`
`
`30 mL/min, including adult patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD),
`
`
`is 4 mg/kg (cSSSI) or 6 mg/kg (S. aureus bloodstream infections) once every 48 hours (Table 3). When
`
`
`
`
`
`
`
`possible, CUBICIN should be administered following the completion of hemodialysis on hemodialysis
`
`
`
`
`days [see Warnings and Precautions (5.2, 5.10), Use in Specific Populations (8.6), and Clinical
`Pharmacology (12.3)].
`
`
`Table 3: Recommended Dosage of CUBICIN in Adult Patients
`Dosage Regimen in Adults
` S. aureus Bloodstream Infections
`
`
`
`cSSSI
`
`Creatinine
`Clearance
`
`(CLCR)
`
`Greater than or
`equal to
`
`30 mL/min
`Less than
`30 mL/min,
`including
`
`hemodialysis
`
`and CAPD
`
`*When possible, administer CUBICIN following the completion of hemodialysis on hemodialysis days.
`
`
`4 mg/kg once
`every 24 hours
`
`
`4 mg/kg once
`
`every 48 hours*
`
`6 mg/kg once every 24 hours
`
`
`6 mg/kg once every 48 hours*
`
`Pediatric Patients:
`
`
`The dosage regimen for CUBICIN in pediatric patients with renal impairment has not been established.
`
`2.7 Preparation and Administration of CUBICIN
`
`
`There are other formulations of daptomycin that have differences concerning reconstitution and
`storage. Carefully follow the reconstitution and storage procedures described in this labeling.
`Reconstitution of CUBICIN Vial
`
`
`
`CUBICIN is supplied in single-dose 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:
`
`
`
`1. To minimize foaming, AVOID vigorous agitation or shaking of the vial during or after
`reconstitution.
`
`2. Remove the polypropylene flip-off cap from the CUBICIN vial to expose the central portion of the
`
`rubber stopper.
`
`Reference ID: 4878697
`
`5
`
`
`

`

`
`
` 3. Wipe the top of the rubber stopper with an alcohol swab or other antiseptic solution and allow to
`
` dry. After cleaning, do not touch the rubber stopper or allow it to touch any other surface.
`
`
`4. 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. It is recommended
` that a beveled sterile transfer needle that is 21 gauge or smaller in diameter, or a needleless
`
`
`device is used, pointing the transfer needle toward the wall of the vial.
` 5. Ensure that all of the CUBICIN powder is wetted by gently rotating the vial.
`1. Allow the wetted product to stand undisturbed for 10 minutes.
`2. Gently rotate or swirl the vial contents for a few minutes, as needed, to obtain a completely
`
`
`reconstituted solution.
`
`
`
`
`
`
` Administration Instructions
`
`
`Parenteral drug products should be inspected visually for particulate matter prior to administration.
`Slowly remove reconstituted liquid (50 mg daptomycin/mL) from the vial using a beveled sterile needle
`
`that is 21 gauge or smaller in diameter. Administer as an intravenous injection or infusion as described
`
`
`
`
`
`below:
`Adults
`
`Intravenous Injection over a period of 2 minutes
` For intravenous (IV) injection over a period of 2 minutes in adult patients only: Administer the
`
`
`
`appropriate volume of the reconstituted CUBICIN (concentration of 50 mg/mL).
`
`
`Intravenous Infusion over a period of 30 minutes
` For IV infusion over a period of 30 minutes in adult patients: 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.
`
`Pediatric Patients (1 to 17 Years of Age)
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`Intravenous Infusion over a period of 30 or 60 minutes
` Unlike in Adults, do NOT administer CUBICIN by injection over a two (2) minute period to
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`pediatric patients [see Dosage and Administration (2.1)].
` For Intravenous infusion over a period of 60 minutes in pediatric patients 1 to 6 years of age: The
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`appropriate volume of the reconstituted CUBICIN (concentration of 50 mg/mL) should be further
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`diluted, using aseptic technique, into an intravenous infusion bag containing 25 mL of 0.9% sodium
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`chloride injection. The infusion rate should be maintained at 0.42 mL/minute over the 60-minute
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`period.
` For Intravenous infusion over a period of 30 minutes in pediatric patients 7 to 17 years of age: The
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`appropriate volume of the reconstituted CUBICIN (concentration of 50 mg/mL) should be further
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`diluted, using aseptic technique, into a 50 mL IV infusion bag containing 0.9% sodium chloride
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`injection. The infusion rate should be maintained at 1.67 mL/minute over the 30-minute period.
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`No preservative or bacteriostatic agent is present in this product. Aseptic technique must be used in the
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`preparation of final IV solution. Do not exceed the In-Use storage conditions of the reconstituted and
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`diluted solutions of CUBICIN described below. Discard unused portions of CUBICIN.
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`In-Use Storage Conditions for CUBICIN Once Reconstituted in Acceptable Intravenous Diluents
`Stability studies have shown that the reconstituted solution is stable in the vial for 12 hours at room
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`temperature and up to 48 hours if stored under refrigeration at 2C to 8C (36 to 46F).
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`The diluted solution is stable in the infusion bag for 12 hours at room temperature and 48 hours if stored
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`under refrigeration. The combined storage time (reconstituted solution in vial and diluted solution in
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`infusion bag) should not exceed 12 hours at room temperature or 48 hours under refrigeration.
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`2.8 Compatible Intravenous Solutions
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`CUBICIN is compatible with 0.9% sodium chloride injection and Lactated Ringer’s injection.
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`Incompatibilities
`2.9
`CUBICIN is not compatible with dextrose-containing diluents.
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`CUBICIN should not be used in conjunction with ReadyMED® elastomeric infusion pumps. Stability
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`studies of CUBICIN solutions stored in ReadyMED® elastomeric infusion pumps identified an impurity (2-
`mercaptobenzothiazole) leaching from this pump system into the CUBICIN solution.
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`Because only limited data are available on the compatibility of CUBICIN with other IV substances,
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`additives and other medications should not be added to CUBICIN single-dose vials or infusion bags, or
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`infused simultaneously with CUBICIN through the same IV line. If the same IV line is used for sequential
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`infusion of different drugs, the line should be flushed with a compatible intravenous solution before and
`after infusion with CUBICIN.
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`3
`DOSAGE FORMS AND STRENGTHS
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`For Injection: 500 mg daptomycin as a sterile, pale yellow to light brown lyophilized powder for
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`reconstitution in a single-dose vial.
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`4
`CONTRAINDICATIONS
`CUBICIN is contraindicated in patients with known hypersensitivity to daptomycin [see Warnings and
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`Precautions (5.1)].
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`5 WARNINGS AND PRECAUTIONS
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`5.1 Anaphylaxis/Hypersensitivity Reactions
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`Anaphylaxis/hypersensitivity reactions have been reported with the use of antibacterial agents, including
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`CUBICIN, and may be life-threatening. If an allergic reaction to CUBICIN occurs, discontinue the drug
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`and institute appropriate therapy [see Adverse Reactions (6.2)].
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`5.2 Myopathy and Rhabdomyolysis
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`Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine
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`phosphokinase (CPK) values to greater than 10 times the upper limit of normal (ULN), has been reported
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`with the use of CUBICIN. Rhabdomyolysis, with or without acute renal failure, has been reported [see
`Adverse Reactions (6.2)].
`Patients receiving CUBICIN should be monitored for the development of muscle pain or weakness,
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`particularly of the distal extremities. In patients who receive CUBICIN, CPK levels should be monitored
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`weekly, and more frequently in patients who received recent prior or concomitant therapy with an HMG-
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`CoA reductase inhibitor or in whom elevations in CPK occur during treatment with CUBICIN.
`In adult patients with renal impairment, both renal function and CPK should be monitored more frequently
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`than once weekly [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
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`In Phase 1 studies and Phase 2 clinical trials in adults, CPK elevations appeared to be more frequent
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`when CUBICIN was dosed more than once daily. Therefore, CUBICIN should not be dosed more
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`frequently than once a day.
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`CUBICIN should be discontinued in patients with unexplained signs and symptoms of myopathy in
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`conjunction with CPK elevations to levels >1,000 U/L (~5× ULN), and in patients without reported
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`symptoms who have marked elevations in CPK, with levels >2,000 U/L (≥10× ULN).
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`In addition, consideration should be given to suspending agents associated with rhabdomyolysis, such as
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`HMG-CoA reductase inhibitors, temporarily in patients receiving CUBICIN [see Drug Interactions (7.1)].
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`5.3 Eosinophilic Pneumonia
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`Eosinophilic pneumonia has been reported in patients receiving CUBICIN [see Adverse Reactions (6.2)].
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`In reported cases associated with CUBICIN, patients developed fever, dyspnea with hypoxic respiratory
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`insufficiency, and diffuse pulmonary infiltrates or organizing pneumonia. In general, patients developed
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`eosinophilic pneumonia 2 to 4 weeks after starting CUBICIN and improved when CUBICIN was
`discontinued and steroid therapy was initiated. Recurrence of eosinophilic pneumonia upon re-exposure
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`has been reported. Patients who develop these signs and symptoms while receiving CUBICIN should
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`undergo prompt medical evaluation, and CUBICIN should be discontinued immediately. Treatment with
`systemic steroids is recommended.
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`5.4 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
`DRESS has been reported in post-marketing experience with CUBICIN [see Adverse Reactions (6.2)].
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`Patients who develop skin rash, fever, peripheral eosinophilia, and systemic organ (for example, hepatic,
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`renal, pulmonary) impairment while receiving CUBICIN should undergo medical evaluation. If DRESS is
`suspected, discontinue CUBICIN promptly and institute appropriate treatment.
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`5.5 Tubulointerstitial Nephritis (TIN)
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`TIN has been reported in post-marketing experience with CUBICIN [see Adverse Reactions (6.2)].
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`Patients who develop new or worsening renal impairment while receiving CUBICIN should undergo
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`medical evaluation. If TIN is suspected, discontinue CUBICIN promptly and institute appropriate
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`treatment.
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`5.6 Peripheral Neuropathy
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`Cases of peripheral neuropathy have been reported during the CUBICIN postmarketing experience [see
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`Adverse Reactions (6.2)]. Therefore, physicians should be alert to signs and symptoms of peripheral
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`neuropathy in patients receiving CUBICIN. Monitor for neuropathy and consider discontinuation.
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`5.7 Potential Nervous System and/or Muscular System Effects in Pediatric Patients Younger
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`than 12 Months
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`Avoid use of CUBICIN in pediatric patients younger than 12 months due to the risk of potential effects on
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`muscular, neuromuscular, and/or nervous systems (either peripheral and/or central) observed in neonatal
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`dogs with intravenous daptomycin [see Nonclinical Toxicology (13.2)].
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`5.8 Clostridioides difficile-Associated Diarrhea
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`Clostridioides difficile–associated diarrhea (CDAD) has been reported with the use of nearly all systemic
`antibacterial agents, including CUBICIN, and may range in severity from mild diarrhea to fatal colitis [see
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`Adverse Reactions (6.2)]. Treatment with antibacterial agents alters the normal flora of the colon, leading
`to overgrowth of C. difficile.
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`C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing
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`strains of C. difficile cause increased morbidity and mortality, since these infections can be refractory to
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`antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present
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`with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been
`reported to occur more than 2 months after the administration of antibacterial agents.
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` If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to
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` be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial
`treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
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` 5.9 Persisting or Relapsing S. aureus Bacteremia/Endocarditis
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` Patients with persisting or relapsing S. aureus bacteremia/endocarditis or poor clinical response should
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` have repeat blood cultures. If a blood culture is positive for S. aureus, minimum inhibitory concentration
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` (MIC) susceptibility testing of the isolate should be performed using a standardized procedure, and
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`diagnostic evaluation of the patient should be performed to rule out sequestered foci of infection.
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`Appropriate surgical intervention (e.g., debridement, removal of prosthetic devices, valve replacement
`surgery) and/or consideration of a change in antibacterial regimen may be required.
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`Failure of treatment due to persisting or relapsing S. aureus bacteremia/endocarditis may be due to
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`reduced daptomycin susceptibility (as evidenced by increasing MIC of the S. aureus isolate) [see Clinical
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`Studies (14.2)].
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`5.10 Decreased Efficacy in Patients with Moderate Baseline Renal Impairment
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`Limited data are available from the two Phase 3 complicated skin and skin structure infection (cSSSI)
`trials regarding clinical efficacy of CUBICIN treatment in adult patients with creatinine clearance (CLCR)
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`<50 mL/min; only 31/534 (6%) patients treated with CUBICIN in the intent-to-treat (ITT) population had a
`baseline CLCR <50 mL/min. Table 4 shows the number of adult patients by renal function and treatment
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`group who were clinical successes in the Phase 3 cSSSI trials.
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`Table 4: Clinical Success Rates by Renal Function and Treatment Group in Phase 3 cSSSI
`Trials in Adult Patients (Population: ITT)
`Success Rate
`n/N (%)
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`CLCR
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`50-70 mL/min
`30-<50 mL/min
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` CUBICIN
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` 4 mg/kg every 24h
`25/38 (66%)
`7/15 (47%)
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` Comparator
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`30/48 (63%)
`20/35 (57%)
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` In a subgroup analysis of the ITT population in the Phase 3 S. aureus bacteremia/endocarditis trial,
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`clinical success rates, as determined by a treatment-blinded Adjudication Committee [see Clinical Studies
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`(14.2)], in the CUBICIN-treated adult patients were lower in patients with baseline CLCR <50 mL/min (see
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`Table 5). A decrease of the magnit