`
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`
`
`full prescribing
`CUBICIN RF safely and effectively. See
`
`information for CUBICIN RF.
`
`
` CUBICIN® RF (daptomycin for injection), for Intravenous Use
` Initial U.S. Approval: 2003
`
`
` --------------------------- RECENT MAJOR CHANGES ---------------------------
`
`
` 9/2017
` Indications and Usage (1)
`
`
` Dosage and Administration (2)
`
`9/2017
` ----------------------------INDICATIONS AND USAGE----------------------------
`
`
`
`CUBICIN RF 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
`
`infective
`adult patients
`including
`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 RF is not indicated for the treatment of pneumonia.
`
`
`
`(1.4)
`
`CUBICIN RF is not indicated for the treatment of left-sided
`infective endocarditis due to S. aureus. (1.4)
`CUBICIN RF is not recommended in pediatric patients younger
`
`than one year of age due to the risk of potential effects on
`(either
`muscular, neuromuscular, and/or nervous systems
`
`peripheral and/or central) observed in neonatal dogs. (1.4)
`
`
`
`To reduce the development of drug-resistant bacteria and maintain the
`
`
`effectiveness of CUBICIN RF and other antibacterial drugs,
`
`CUBICIN RF should be used to treat 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
`
`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
`
`infused over 60 minutes
`
`Up to 14 days
`
`
`12 to 17 years
`
`
`7 to 11 years
`
`
`2 to 6 years
`
`
`1 to less than
`2 years
`
`
`
`Reference ID: 4147921
`
`* 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):
`
`
`Dosage*
`Age group
`Duration of
`
`
`therapy
`
`12 to 17 years
`
`
`7 to 11 years
`
`
`
`
`
`Up to 42 days
`
`
`if
`
`
`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 RF 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 RF. (5.2)
`
`
` Eosinophilic pneumonia: Discontinue CUBICIN RF and consider
`
`
`
`treatment with systemic steroids. (5.3)
`
` Peripheral neuropathy: Monitor for neuropathy and consider
`
`discontinuation. (5.4)
`
` Potential nervous system and/or muscular system effects in
`
`
`than 12 months: Avoid use of
`pediatric patients younger
`CUBICIN RF in this age group. (5.5)
`
` Clostridium difficile–associated diarrhea: Evaluate patients
`
`diarrhea occurs. (5.6)
`
` Persisting or relapsing S. aureus bacteremia/endocarditis: Perform
`
`
`susceptibility testing and rule out sequestered foci of infection.
`(5.7)
`
` Decreased efficacy was observed in adult patients with moderate
`
`
`
`baseline renal impairment. (5.8)
`
` ------------------------------ 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 creatinine 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: 9/2017
`
`
`

`

`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`INDICATIONS AND USAGE
`1
`
`1.1 Complicated Skin and Skin Structure Infections (cSSSI)
`1.2 Staphylococcus
`aureus
`Bloodstream
`Infections
`(Bacteremia) in Adult Patients, Including Those with Right-
`Infective Endocarditis, Caused by Methicillin-
`Sided
`
`Susceptible and Methicillin-Resistant Isolates
`aureus
`Bloodstream
`1.3 Staphylococcus
`Infections
`(Bacteremia) in Pedatric 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
`
`Infections
`aureus
`Bloodstream
`Staphylococcus
`(Bacteremia)
`
`2.6 Dosage in Patients with Renal Impairment
`
`2.7 Preparation and Administration of CUBICIN RF
`
`2.8 Compatible Intravenous Solutions
` Incompatibilities
`2.9
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
` Anaphylaxis/Hypersensitivity Reactions
`5.1
`
`5.2 Myopathy and Rhabdomyolysis
`5.3
` Eosinophilic Pneumonia
` Peripheral Neuropathy
`5.4
`
`5.5 Potential Nervous System and/or Muscular System Effects
`in Pediatric Patients Younger than 12 Months
`
`5.6 Clostridium difficile-Associated Diarrhea
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`1
`
` INDICATIONS AND USAGE
`
`5.7 Persisting or Relapsing S. aureus Bacteremia/Endocarditis
`5.8 Decreased Efficacy in Patients with Moderate Baseline
`
`Renal Impairment
` Drug-Laboratory Test Interactions
`5.9
`
`5.10 Non-Susceptible Microorganisms
`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
` Geriatric Use
`8.5
`
`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.
`
`1.1 Complicated Skin and Skin Structure Infections (cSSSI)
`CUBICIN® RF 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® RF 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® RF 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 RF is not indicated for the treatment of pneumonia.
`
`
`
`
`Reference ID: 4147921
`
`

`

`
`
` CUBICIN RF 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 RF 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 (5.5) 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 RF and
`other antibacterial drugs, CUBICIN RF should be used only to treat 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
`
`Administer the appropriate volume of the reconstituted CUBICIN RF (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 RF by injection over a two (2) minute period to
`
`pediatric patients.
`
`
`
` Pediatric Patients 7 to 17 years of Age: Administer CUBICIN RF 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 RF 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 RF 4 mg/kg to adult patients intravenously 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 RF intravenously once every 24 hours for up to 14 days.
`
`
`
`
`
`
`
`3
`
`
`Reference ID: 4147921
`
`

`

`
`
`
`
` Table 1: Recommended Dosage of CUBICIN RF in Pediatric Patients (1 to 17 Years of Age) with
`
` cSSSI, Based on Age
`Dosage Regimen*
`
`
`
`Age Range
`
`
`Duration of therapy
`
`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 infused over 60 minutes
`
`12 to 17 years
`7 to 11 years
`2 to 6 years
`
`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 RF 6 mg/kg to adult patients intravenously 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 RF intravenously in 0.9% sodium
`chloride injection once every 24 hours for up to 42 days.
`
`Table 2: Recommended Dosage of CUBICIN RF in Pediatric Patients (1 to 17 Years of Age) with S.
`
`
`aureus Bacteremia, Based on Age
`
`Dosage*
`
`
`Duration of therapy
`
`
`Age group
`
`
`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 RF 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 RF should be administered following the completion of hemodialysis on hemodialysis
`days [see Warnings and Precautions (5.2, 5.8), Use in Specific Populations (8.6), and Clinical
`
`Pharmacology (12.3)].
`
`Reference ID: 4147921
`
`
`
`4
`
`

`

`
`
`
`
` Table 3: Recommended Dosage of CUBICIN RF 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 RF 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 RF in pediatric patients with renal impairment has not been
`
`established.
`
`2.7 Preparation and Administration of CUBICIN RF
`
`
`
`There are two formulations of daptomycin that have differences concerning storage and
`
`reconstitution. Carefully follow the reconstitution and storage procedures in labeling.
`Reconstitution of CUBICIN RF Vial
`
`
`CUBICIN RF must be reconstituted within the vial only with either Sterile Water for Injection or
`
`Bacteriostatic Water for Injection.
`Do NOT use saline based diluents for the reconstitution in the vial because this will result in a
`
`
`
`
`hyperosmotic solution that may result in infusion site reactions if the reconstituted product is administered
`
`as an intravenous injection over a period of 2 minutes.
`
`
`CUBICIN RF is supplied in single-dose vials, each containing 500 mg daptomycin as a sterile, lyophilized
`
`
`powder. The contents of a CUBICIN RF vial should be reconstituted, using aseptic technique, to
`50 mg/mL as follows:
`
`
`1. Remove the polypropylene flip-off cap from the CUBICIN RF vial to expose the central portion
`
`of the rubber stopper.
`
`2. 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.
`
`3. Transfer 10 mL of Sterile Water for Injection or Bacteriostatic Water for Injection through the
`
`
`center of the rubber stopper into the CUBICIN RF vial. Use a beveled sterile transfer needle
`that is 21 gauge or smaller in diameter, pointing the transfer needle toward the wall of the vial.
`
`4. 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:
`
`
`Reference ID: 4147921
`
`5
`
`
`

`

`
`
`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 RF (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 RF (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)
`
`Intravenous Infusion over a period of 30 or 60 minutes
` Unlike in Adults, do NOT administer CUBICIN RF by injection over a two (2) minute period to
`
`
`
`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
`
`appropriate volume of the reconstituted CUBICIN RF (concentration of 50 mg/mL) should be further
`
`
`
`diluted, using aseptic technique, into an intravenous infusion bag containing 25 mL of 0.9% sodium
`
`
`chloride injection. The infusion rate should be maintained at 0.42 mL/minute over the 60-minute
`period.
` For Intravenous infusion over a period of 30 minutes in pediatric patients 7 to 17 years of age: The
`
`
`appropriate volume of the reconstituted CUBICIN RF (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. The infusion rate should be maintained at 1.67 mL/minute over the 30-minute period.
`No preservative or bacteriostatic agent is present in this product. Aseptic technique must be used in the
`
`preparation of final IV solution. Table 4 below provides in-use storage conditions for reconstituted
`
`
`
`
`CUBICIN RF in acceptable intravenous diluents in the syringe, vial and intravenous bag (for reconstitution
`and dilution). Do not exceed the listed shelf-life of reconstituted and diluted solutions of CUBICIN RF.
`
`Discard unused portions of CUBICIN RF.
`Table 4: In-Use Storage Conditions for CUBICIN RF Once Reconstituted in Acceptable Intravenous
`Diluents
`
`Container
`
`Diluent
`
`Vial
`
`
`
`Syringe*
`
`
`Intravenous Bag
`
`Sterile Water for Injection
`
`Bacteriostatic Water for Injection
`
`Sterile Water for Injection
`
`Bacteriostatic Water for Injection
`
`Reconstitution: Sterile Water for
`Injection for immediate dilution
`
`with 0.9% sodium chloride
`injection
`
`In-Use Shelf-Life
`
`Room Temperature
`(20°C–25°C, 68°F–77°F)
`
`
`Refrigerated
`(2°C–8°C, 36°F–46°F)
`
`
`1 Day
`
`2 Days
`
`
`1 Day
`
`2 Days
`
`19 Hours
`
`3 Days
`
`3 Days
`
`3 Days
`
`5 Days
`
`3 Days
`
`Reference ID: 4147921
`
`6
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`

`

`
`
` Reconstitution: Bacteriostatic
`
`Water for Injection for immediate
`
`dilution with 0.9% sodium chloride
`injection
`
`*Polypropylene syringe with elastomeric plunger stopper.
`
`2 Days
`
`5 Days
`
`
`2.8 Compatible Intravenous Solutions
`
`Reconstituted CUBICIN RF is compatible with Sterile Water for Injection, Bacteriostatic Water for
`Injection, and 0.9% sodium chloride injection. [See Dosage and Administration (2.7).]
`
`2.9
`Incompatibilities
`
`CUBICIN RF is not compatible with dextrose-containing diluents.
`CUBICIN RF should not be used in conjunction with ReadyMED® elastomeric infusion pumps. 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 RF with other IV substances,
`
`
`
`
`additives and other medications should not be added to CUBICIN RF single-dose vials or infusion bags,
`
`or infused simultaneously with CUBICIN RF 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 RF.
`
`DOSAGE FORMS AND STRENGTHS
`3
`For Injection: 500 mg daptomycin as a sterile, pale yellow to light brown lyophilized powder for
`
`
`reconstitution in a single-dose vial.
`
`
`4
`CONTRAINDICATIONS
`
`CUBICIN RF is contraindicated in patients with known hypersensitivity to daptomycin.
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 Anaphylaxis/Hypersensitivity Reactions
`
`Anaphylaxis/hypersensitivity reactions have been reported with the use of antibacterial agents, including
`
`
`CUBICIN, and may be life-threatening. If an allergic reaction to CUBICIN RF occurs, discontinue the drug
`and institute appropriate therapy [see Adverse Reactions (6.2)].
`
`5.2 Myopathy and Rhabdomyolysis
`
`
`Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine
`
`phosphokinase (CPK) values to greater than 10 times the upper limit of normal (ULN), has been reported
`with the use of CUBICIN. Rhabdomyolysis, with or without acute renal failure, has been reported [see
`Adverse Reactions (6.2)].
`
`
`Patients receiving CUBICIN RF should be monitored for the development of muscle pain or weakness,
`
`
`particularly of the distal extremities. In patients who receive CUBICIN RF, CPK levels should be
`
`
`monitored weekly, and more frequently in patients who received recent prior or concomitant therapy with
`an HMG-CoA reductase inhibitor or in whom elevations in CPK occur during treatment with CUBICIN RF.
`In adult patients with renal impairment, both renal function and CPK should be monitored more frequently
`
`than once weekly [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
`
`Reference ID: 4147921
`
`7
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`

`

`
`
`
`
`In Phase 1 studies and Phase 2 clinical trials in adults, CPK elevations appeared to be more frequent
`
`
`
`
`
`when CUBICIN was dosed more than once daily. Therefore, CUBICIN RF should not be dosed more
`frequently than once a day.
`
`
`
`
`CUBICIN RF should be discontinued in patients with unexplained signs and symptoms of myopathy in
`
`conjunction with CPK elevations to levels >1,000 U/L (~5× ULN), and in patients without reported
`
`symptoms who have marked elevations in CPK, with levels >2,000 U/L (≥10× ULN). In addition,
`consideration should be given to suspending agents associated with rhabdomyolysis, such as HMG-CoA
`
`
`reductase inhibitors, temporarily in patients receiving CUBICIN RF [see Drug Interactions (7.1)].
`
` Eosinophilic Pneumonia
`5.3
`
`
`Eosinophilic pneumonia has been reported in patients receiving CUBICIN [see Adverse Reactions (6.2)].
`
`In reported cases associated with CUBICIN, patients developed fever, dyspnea with hypoxic respiratory
`
`insufficiency, and diffuse pulmonary infiltrates or organizing pneumonia. In general, patients developed
`
`
`
`
`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
`
`has been reported. Patients who develop these signs and symptoms while receiving CUBICIN RF should
`
`
`undergo prompt medical evaluation, and CUBICIN RF should be discontinued immediately. Treatment
`
`with systemic steroids is recommended.
`
`
`5.4
` Peripheral Neuropathy
`
`
`Cases of peripheral neuropathy have been reported during the CUBICIN postmarketing experience [see
`
`Adverse Reactions (6.2)]. Therefore, physicians should be alert to signs and symptoms of peripheral
`
`neuropathy in patients receiving CUBICIN RF. Monitor for neuropathy and consider discontinuation.
`
`5.5 Potential Nervous System and/or Muscular System Effects in Pediatric Patients Younger
`
`than 12 Months
`
`
`Avoid use of CUBICIN RF in pediatric patients younger than 12 months due to the risk of potential effects
`
`on muscular, neuromuscular, and/or nervous systems (either peripheral and/or central) observed in
`
`neonatal dogs with intravenous daptomycin [see Nonclinical Toxicology (13.2)].
`
`
`5.6 Clostridium difficile-Associated Diarrhea
`
`Clostridium 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
`Adverse Reactions (6.2)]. 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 antibacterial use. Careful medical history is necessary because CDAD has been
`reported to occur more than 2 months after the administration of antibacterial agents.
`
`If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to
`
`be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial
`treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
`
`
`5.7 Persisting or Relapsing S. aureus Bacteremia/Endocarditis
`
`Patients with persisting or relapsing S. aureus bacteremia/endocarditis or poor clinical response should
`
`have repeat blood cultures. If a blood culture is positive for S. aureus, minimum inhibitory concentration
`(MIC) susceptibility testing of the isolate should be performed using a standardized procedure, and
`
`diagnostic evaluation of the patient should be performed 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 antibacterial regimen may be required.
`
`Reference ID: 4147921
`
`8
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`
`

`

`
`
`
` Failure of treatment due to persisting or relapsing S. aureus bacteremia/endocarditis may be due to
`
` reduced daptomycin susceptibility (as evidenced by increasing MIC of the S. aureus isolate) [see Clinical
`
` Studies (14.2)].
`
` 5.8 Decreased Efficacy in Patients with Moderate Baseline Renal Impairment
`
`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)
`<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 5 shows the number of adult patients by renal function and treatment
`group who were clinical successes in the Phase 3 cSSSI trials.
`
`Table 5: Clinical Success Rates by Renal Function and Treatment Group in Phase 3 cSSSI
`Trials in Adult Patients (Population: ITT)
`
`
`CLCR
`
`
`50-70 mL/min
`30-<50 mL/min
`
`Success Rate
`n/N (%)
`
`
`CUBICIN
`
`4 mg/kg q24h
`25/38 (66%)
`7/15 (47%)
`
`
`Comparator
`
`30/48 (63%)
`20/35 (57%)
`
`In a subgroup analysis of the ITT population in the Phase 3 S. aureus bacteremia/endocarditis trial,
`clinical success rates, as determined by a treatment-blinded Adjudication Committee [see Clinical Studies
`
` (14.2)], in the CUBICIN-treated adult patients were lower in patients with baseline CLCR <50 mL/min (see
`
` Table 6). A decrease of the magnitude shown in Table 6 was not observed in comparator-treated
`
`
` patients.
`
`Table 6: Adjudication Committee Clinical Success Rates at Test of Cure by Baseline
`Creatinine Clearance and Treatment Subgroup in the S. aureus Bacteremia/Endocarditis Trial in
`Adult Patients (Population: ITT)
`Success Rate
`n/N (%)
`
`
`CUBICIN
`
`6 mg/kg q24h
`Right-Sided
`Infective
`
`Endocarditis
`7/14 (50%)
`1/4 (25%)
`0/1 (0%)
`
`Bacteremia
`
`30/50 (60%)
`12/26 (46%)
`2/14 (14%)
`
`
`
` Baseline CLCR
`
`
`>80 mL/min
`
`50–80 mL/min
`30–<50 mL/min
`
`
`Comparator
`Right-Sided
`Infective
`
`Endocarditis
`5/11 (46%)
`1/2 (50%)
`1/1 (100%)
`
`Bacteremia
`
`19/42 (45%)
`13/31 (42%)
`7/17 (41%)
`
`Consider these data when selecting antibacterial therapy for use in adult patients with baseline moderate
`to severe renal impairment.
`
`
`5.9 Drug-Laboratory Test Interactions
`
`Clinically relevant plasma concentrations of daptomycin have been observed to cause a significant
`concentration-dependent false prolongation of prothrombin time (PT) and elevation of International
`
`Reference ID: 4147921
`
`9
`
`

`

`
`
`Normalized Ratio (INR) when certain recombinant thromboplastin reagents are utilized for the assay [see
`Drug Interact