`
`2 to 6 years
`
`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 <2 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
`
`concerning storage and reconstitution. Carefully
`follow
`the
`reconstitution and storage procedures in labeling (2.6).
`
`
`
`Do not use in conjunction with ReadyMED® elastomeric infusion
`pumps in adult and pediatric patients. (2.8).
` --------------------- DOSAGE FORMS AND STRENGTHS ---------------------
`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
`pediatric patients younger
`than 12 months: Avoid use of
`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)
`
`if
`
`
`
`
`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: 3/2017
`
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`CUBICIN RF safely and effectively. See
`full prescribing
`information for CUBICIN RF.
`
`CUBICIN® RF (daptomycin for injection), for intravenous use
`Initial U.S. Approval: 2003
`
` --------------------------- RECENT MAJOR CHANGES ---------------------------
`Indications and Usage (1)
`3/2017
`3/2017
`Dosage and Administration (2)
` ----------------------------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),
`including those with right-sided infective endocarditis in adult
`patients (1.2)
`
`
`
`
`
`
`
`
`Limitations of Use:
`CUBICIN RF is not indicated for the treatment of pneumonia.
`
`(1.3)
`CUBICIN RF is not indicated for the treatment of left-sided
`infective endocarditis due to S. aureus.(1.3)
`CUBICIN RF 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. (1.3)
`
`
`
`≥30 mL/min
`
`
`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. (1.4)
` ----------------------- 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, 2.6)
`Recommended dosage regimen for adult patients (2.2, 2.4, 2.5):
`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*
`
`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, 2.6).
`Administer to pediatric patients intravenously in 0.9% sodium
`chloride, by infusion over a 30- or 60-minute period, based on
`age. (2.1, 2.6).
`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
`
`5 mg/kg once every 24 hours
`infused over 30 minutes
`
`Up to 14 days
`
`
`
`Reference ID: 4077171
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`1.1 Complicated Skin and Skin Structure Infections (cSSSI)
`1.2 Staphylococcus
`aureus
`Bloodstream
`Infections
`(Bacteremia), Including Those with Right-Sided Infective
`Endocarditis, Caused by Methicillin-Susceptible and
`Methicillin-Resistant Isolates
`1.3 Limitations of Use
`1.4 Usage
`2 DOSAGE AND ADMINISTRATION
`2.1
`Important Administration Duration Instructions
`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 Patients with Renal Impairment
`2.6 Preparation and Administration of CUBICIN RF
`2.7 Compatible Intravenous Solutions
`2.8
`Incompatibilities
`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 Peripheral Neuropathy
`5.5 Potential Nervous System and/or Muscular System Effects
`in Pediatric Patients Younger than 12 Months
`5.6 Clostridium difficile-Associated Diarrhea
`5.7 Persisting or Relapsing S. aureus Bacteremia/Endocarditis
`
`FULL PRESCRIBING INFORMATION
`
`1
`
`INDICATIONS AND USAGE
`
`5.8 Decreased Efficacy in Patients with Moderate Baseline
`Renal Impairment
`5.9 Drug-Laboratory Test Interactions
`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
`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.
`
`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), 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 those with right-sided infective endocarditis, caused by methicillin-
`susceptible and methicillin-resistant isolates.
`
`1.3 Limitations of Use
`CUBICIN RF is not indicated for the treatment of pneumonia.
`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.
`
`
`
`
`
`Reference ID: 4077171
`
`
`
`
`
`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)].
`
`1.4 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, 2.6)].
`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, 2.6)].
` 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, 2.6)].
`
`
`
`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.
`
`
`
`
`
`
`
`Reference ID: 4077171
`
`3
`
`
`
`
`
`Table 1: Recommended Dosage of CUBICIN RF in Pediatric Patients (1 to 17 Years of Age) with
`cSSSI, Based on Age
`
`Age Range
`
`Dosage Regimen*
`
`Duration of therapy
`
`12 to 17 years 5 mg/kg once every 24 hours infused over 30 minutes
`7 to 11 years
`7 mg/kg once every 24 hours infused over 30 minutes
`2 to 6 years
`9 mg/kg once every 24 hours infused over 60 minutes
`1 to < 2 years 10 mg/kg once every 24 hours infused over 60 minutes
`*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 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 2). 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)].
`
`Table 2: 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.
`
`Reference ID: 4077171
`
`4
`
`
`
`
`
`2.6 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:
`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 intravenous (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.
`
`Reference ID: 4077171
`
`5
`
`
`
`
`
` 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 3 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 3: In-Use Storage Conditions for CUBICIN RF Once Reconstituted in Acceptable Intravenous
`Diluents
`
`Container
`
`Diluent
`
`Vial
`
`Syringe*
`
`Sterile Water for Injection
`
`Bacteriostatic Water for Injection
`
`Sterile Water for Injection
`
`Bacteriostatic Water for Injection
`
`Intravenous Bag
`
`Reconstitution: Sterile Water for
`Injection for immediate dilution
`with 0.9% sodium chloride
`injection
`Reconstitution: Bacteriostatic
`Water for Injection for immediate
`dilution with 0.9% sodium chloride
`injection
`*Polypropylene syringe with elastomeric plunger stopper.
`
`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
`
`2 Days
`
`3 Days
`
`3 Days
`
`3 Days
`
`5 Days
`
`3 Days
`
`5 Days
`
`2.7 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 (2.5).]
`
`Incompatibilities
`2.8
`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.
`
`Reference ID: 4077171
`
`6
`
`
`
`
`
`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.
`
`CONTRAINDICATIONS
`4
`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)].
`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)].
`
`5.3 Eosinophilic Pneumonia
`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. 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.
`
`Reference ID: 4077171
`
`7
`
`
`
`
`
`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.
`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 4 shows the number of adult patients by renal function and treatment
`group who were clinical successes in the Phase 3 cSSSI trials.
`
`
`
`
`
`
`
`8
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`Reference ID: 4077171
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`CLCR
`
`50-70 mL/min
`30-<50 mL/min
`
`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 (%)
`
`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 5). A decrease of the magnitude shown in Table 5 was not observed in comparator-treated
`patients.
`
`Table 5: 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 (%)
`
`Baseline CLCR
`
`>80 mL/min
`50–80 mL/min
`30–<50 mL/min
`
`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%)
`
`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
`Normalized Ratio (INR) when certain recombinant thromboplastin reagents are utilized for the assay [see
`Drug Interactions (7.2)].
`
`5.10 Non-Susceptible Microorganisms
`The use of antibacterials may promote the overgrowth of non-susceptible microorganisms. If these
`infections occur during therapy, appropriate measures should be taken.
`Prescribing CUBICIN RF 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.
`
`Reference ID: 4077171
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`9
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` 6
`
`ADVERSE REACTIONS
`
`The following adverse reactions are described, or described in greater detail, in other sections:
` Anaphylaxis/hypersensitivity reactions [see Warnings and Precautions (5.1)]
` Myopathy and rhabdomyolysis [see Warnings and Precautions (5.2)]
` Eosinophilic pneumonia [see Warnings and Precautions (5.3)]
` Peripheral neuropathy [see Warnings and Precautions (5.4)]
`Increased International Normalized Ratio (INR)/prolonged prothrombin time [see Warnings
`
`and Precautions (5.9) and Drug Interactions (7.2)]
`
`6.1 Clinical Trials Experience
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in
`the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and
`may not reflect the rates observed in practice.
`Clinical Trial Experience in Adult Patients
`Clinical trials enrolled 1,864 adult patients treated with CUBICIN and 1,416 treated with comparator.
`
`Complicated Skin and Skin Structure Infection Trials in Adults
`In Phase 3 complicated skin and skin structure infection (cSSSI) trials in adult patients, CUBICIN was
`discontinued in 15/534 (2.8%) patients due to an adverse reaction, while comparator was discontinued in
`17/558 (3.0%) patients.
`The rates of the most common adverse reactions, organized by body system, observed in adult patients
`with cSSSI (receiving 4 mg/kg CUBICIN) are displayed in Table 6.
`
`Table 6: Incidence of Adverse Reactions that Occurred in ≥2% of Adult Patients in the CUBICIN
`Treatment Group and ≥ the Comparator Treatment Group in Phase 3 cSSSI Trials
`
`Adverse Reaction
`
`Adult Patients (%)
`
`CUBICIN 4 mg/kg
`(N=534)
`
`Comparator*
`(N=558)
`
`Gastrointestinal disorders
`
`
`
`
`
`Diarrhea
`
`Nervous system disorders
`
`Headache
`
`Dizziness
`
`Skin/subcutaneous disorders
`
`Rash
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`Reference ID: 4077171
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`5.2
`
`
`
`5.4
`
`2.2
`
`
`
`4.3
`
`10
`
`4.3
`
`
`
`5.4
`
`2.0
`
`
`
`3.8
`
`
`
`
`
`Diagnostic investigations
`
`Abnormal liver function tests
`
`Elevated CPK
`
`Infections
`
`Urinary tract infections
`
`Vascular disorders
`
`Hypotension
`
`Respiratory disorders
`
`Dyspnea
`
`
`
`3.0
`
`2.8
`
`
`
`2.4
`
`
`
`2.4
`
`
`
`2.1
`
`
`
`1.6
`
`1.8
`
`
`
`0.5
`
`
`
`1.4
`
`
`
`1.6
`
`*Comparator: vancomycin (1 g IV q12h) or an anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin,
`oxacillin, cloxacillin, or flucloxacillin; 4 to 12 g/day IV in divided doses).
`
`Drug-related adverse reactions (possibly or probably drug-related) that occurred in <1% of adult patients
`receiving CUBICIN in the cSSSI trials are as follows:
`Body as a Whole: fatigue, weakness, rigors, flushing, hypersensitivity
`Blood/Lymphatic System: leukocytosis, thrombocytopenia, thrombocytosis, eosinophilia, increased
`International Normalized Ratio (INR)
`Cardiovascular System: supraventricular arrhythmia
`Dermatologic System: eczema
`Digestive System: abdominal distension, stomatitis, jaundice, increased serum lactate dehydrogenase
`Metabolic/Nutritional System: hypomagnesemia, increased serum bicarbonate, electrolyte disturbance
`Musculoskeletal S