`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
`
`
`
`
` ----------------------------INDICATIONS AND USAGE ----------------------------
`
`
`
`
`CUBICIN RF is a lipopeptide antibacterial indicated for the treatment
`
`
`of:
`
`
`
`
`
`
`Complicated skin and skin structure infections (cSSSI) (1.1)
`
`
`infections (bacteremia),
`
`Staphylococcus aureus bloodstream
`
`including those with right-sided infective endocarditis (1.2)
`
`CUBICIN RF is not indicated for the treatment of pneumonia. (1.3)
`
`
`
`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 -----------------------
`
`
`
`
`Recommended dosage regimen for adult patients (2.2, 2.3, 2.4):
`
`
`
`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*
`
`
`--------------------- 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
`
`
`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 patients with moderate
`
`
`baseline renal impairment. (5.8)
`
` ------------------------------ ADVERSE REACTIONS ------------------------------
`
`
`The most clinically significant adverse reactions observed with
`
`(S. aureus
`CUBICIN 4 mg/kg
`(cSSSI
`trials) and 6 mg/kg
`
`bacteremia/endocarditis trial) were abnormal liver function tests,
`
`<30 mL/min,
`elevated CPK, and dyspnea. (6.1)
`including
`
`hemodialysis and
`To report SUSPECTED ADVERSE REACTIONS, contact Merck
`
`CAPD
`Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877­
`
`*Administered following hemodialysis on hemodialysis days.
`
`888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`Administered intravenously, either by injection over a 2-minute
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`period or by infusion over a 30-minute period. (2.1, 2.5)
`
`
`Do not use in conjunction with ReadyMED® elastomeric infusion
`
`
`Revised: 7/2016
`
`pumps. (2.7)
`
`_________________________________________________________________________________________________________________________
`FULL PRESCRIBING INFORMATION: CONTENTS*
`5.9
` Drug-Laboratory Test Interactions
`
`5.10 Non-Susceptible Microorganisms
` INDICATIONS AND USAGE
`1
`
` ADVERSE REACTIONS
`
`
`1.1 Complicated Skin and Skin Structure Infections
`6.1 Clinical Trials Experience
`Infections
`1.2 Staphylococcus
`aureus
`Bloodstream
`6.2
` Post-Marketing Experience
`
`(Bacteremia), Including Those with Right-Sided Infective
` DRUG INTERACTIONS
`
`Endocarditis, Caused by Methicillin-Susceptible and
`
`7.1 HMG-CoA Reductase Inhibitors
`Methicillin-Resistant Isolates
`7.2
` Drug-Laboratory Test Interactions
`
`1.3 Limitations of Use
`8 USE IN SPECIFIC POPULATIONS
`1.4
` Usage
`8.1
` Pregnancy
` DOSAGE AND ADMINISTRATION
`
`
`8.3
` Nursing Mothers
`
` Administration Duration
`2.1
`
`8.4
` Pediatric Use
`2.2 Complicated Skin and Skin Structure Infections
` Geriatric Use
`8.5
`
`Infections
`aureus
`Bloodstream
`2.3 Staphylococcus
`8.6 Patients with Renal Impairment
`
`(Bacteremia), Including Those with Right-Sided Infective
`10 OVERDOSAGE
`
`Endocarditis, Caused by Methicillin-Susceptible and
`
`11 DESCRIPTION
`
`Methicillin-Resistant Isolates
`12 CLINICAL PHARMACOLOGY
`
`
`2.4 Patients with Renal Impairment
`
`12.1 Mechanism of Action
`2.5 Preparation of CUBICIN RF for Administration
`12.2 Pharmacodynamics
`2.6 Compatible Intravenous Solutions
`12.3 Pharmacokinetics
` Incompatibilities
`2.7
`
`12.4 Microbiology
`3 DOSAGE FORMS AND STRENGTHS
`
` NONCLINICAL TOXICOLOGY
`
`
`4 CONTRAINDICATIONS
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`5 WARNINGS AND PRECAUTIONS
`
`13.2 Animal Toxicology and/or Pharmacology
` Anaphylaxis/Hypersensitivity Reactions
`5.1
`
` CLINICAL TRIALS
`
`5.2 Myopathy and Rhabdomyolysis
`14.1 Complicated Skin and Skin Structure Infections
`5.3
` Eosinophilic Pneumonia
`14.2 S. aureus Bacteremia/Endocarditis
` Peripheral Neuropathy
`5.4
`
`15 REFERENCES
`
`5.5 Potential Nervous System and/or Muscular System Effects
`16 HOW SUPPLIED/STORAGE AND HANDLING
`in Pediatric Patients Younger than 12 Months
`
`17 PATIENT COUNSELING INFORMATION
`
`5.6 Clostridium difficile-Associated Diarrhea
`
`*Sections or subsections omitted from the full prescribing information
`
`5.7 Persisting or Relapsing S. aureus Bacteremia/Endocarditis
`are not listed.
`5.8 Decreased Efficacy in Patients with Moderate Baseline
`
`Renal Impairment
`
`if
`
`
`6
`
`7
`
`13
`
`14
`
`≥30 mL/min
`
`
`4 mg/kg once every
`
`24 hours
`
`4 mg/kg once every
`
`48 hours*
`
`
`
`
`
`2
`
`
`
`Reference ID: 3955674
`
`

`

`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`1
`
` INDICATIONS AND USAGE
`
`1.1 Complicated Skin and Skin Structure Infections
`
`CUBICIN® RF is indicated for the treatment of 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 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 patients with S. aureus bloodstream infections included limited data from patients with left-sided infective
`
`
`
`
`endocarditis; outcomes in these patients were poor [see Clinical Trials (14.2)]. CUBICIN has not been studied in patients
`
`with prosthetic valve endocarditis.
`
`
`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
`
`
`2.1
` Administration Duration
`
`
`CUBICIN RF should be administered intravenously either by injection over a two (2) minute period or by infusion over a
`thirty (30) minute period.
`
`2.2 Complicated Skin and Skin Structure Infections
`
`
`CUBICIN RF 4 mg/kg should be administered intravenously once every 24 hours for 7 to 14 days.
`
`2.3 Staphylococcus aureus Bloodstream Infections (Bacteremia), Including Those with Right-Sided Infective
`
`
`Endocarditis, Caused by Methicillin-Susceptible and Methicillin-Resistant Isolates
`
`
`CUBICIN RF 6 mg/kg should be administered 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 patients
`who were treated with CUBICIN for more than 28 days.
`
`2.4 Patients with Renal Impairment
`The recommended dosage regimen for patients with creatinine clearance (CLCR) less than 30 mL/min, including patients
`
`
`
`on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), is 4 mg/kg (cSSSI) or 6 mg/kg (S. aureus
`
`
`
`Reference ID: 3955674
`
`

`

`
` bloodstream infections) once every 48 hours (Table 1). 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)].
`
`Creatinine
`
`Clearance
`(CLCR)
`≥30 mL/min
`
`
`
`Table 1: Recommended Dosage of CUBICIN RF in Adult Patients
`
`Dosage Regimen
`S. aureus Bloodstream Infections
`
`
`cSSSI
`
`6 mg/kg once every 24 hours
`
`4 mg/kg once
`
`every 24 hours
`4 mg/kg once
`
`every 48 hours*
`
`
`<30 mL/min,
`including
`hemodialysis
`
`and CAPD
`
`
`* When possible, administer CUBICIN RF following the completion of hemodialysis on hemodialysis days.
`
`6 mg/kg once every 48 hours*
`
`
`
`2.5 Preparation of CUBICIN RF for Administration
`
`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 containing daptomycin (50 mg/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:
`
`
`Intravenous Injection over a period of 2 minutes
`For intravenous (IV) injection over a period of 2 minutes, 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, the appropriate volume of the reconstituted CUBICIN RF
`
`
`(concentration of 50 mg/mL) should be further diluted, into a 50 mL IV infusion bag containing 0.9% sodium chloride
`
`injection. This transfer should be done using aseptic technique involving a beveled sterile needle that is 21 gauge or
`
`smaller in diameter.
`
`
`Reference ID: 3955674
`
`3
`
`
`

`

`
` No preservative or bacteriostatic agent is present in this product. Aseptic technique must be used in the preparation of
`
`
`
`
` final IV solution. Table 2 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 2: 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
`
`
`2.6 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).]
`
`2.7
`Incompatibilities
`
`
`CUBICIN RF is incompatible 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
`
`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.
`
`Reference ID: 3955674
`
`4
`
`
`

`

`
`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 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, 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.
`
`
`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.
`
`
`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.
`
`Reference ID: 3955674
`
`5
`
`
`

`

`
` 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 Trials (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 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 3 shows the number
`of patients by renal function and treatment group who were clinical successes in the Phase 3 cSSSI trials.
`
`Table 3: Clinical Success Rates by Renal Function and Treatment Group in Phase 3 cSSSI Trials
`(Population: ITT)
`Success Rate
`n/N (%)
`
`
`CLCR
`
`
`50-70 mL/min
`30-<50 mL/min
`
`
`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 Trials (14.2)], in the CUBICIN-treated patients
`were lower in patients with baseline CLCR <50 mL/min (see Table 4). A decrease of the magnitude shown in Table 4 was
`not observed in comparator-treated patients.
`
`Table 4: Adjudication Committee Clinical Success Rates at Test of Cure by Baseline Creatinine Clearance
`and Treatment Subgroup in the S. aureus Bacteremia/Endocarditis Trial (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 patients with baseline moderate to severe renal
`impairment.
`
`Reference ID: 3955674
`
`6
`
`

`

`
` 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 superinfection occurs 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.
`
`
`
` ADVERSE REACTIONS
`6
`
` 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)]
` 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.
`
`6.1 Clinical Trials Experience
`Clinical trials enrolled 1,864 patients treated with CUBICIN and 1,416 treated with comparator.
`
` Complicated Skin and Skin Structure Infection Trials
`
`In Phase 3 complicated skin and skin structure infection (cSSSI) trials, 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 cSSSI (4 mg/kg CUBICIN)
`patients are displayed in Table 5.
`
`
`Table 5: Incidence of Adverse Reactions that Occurred in ≥2% of Patients in the CUBICIN Treatment Group and ≥
`
`the Comparator Treatment Group in Phase 3 cSSSI Trials
`
`Adverse Reaction
`
`
`Patients (%)
`
`CUBICIN 4 mg/kg
`(N=534)
`
`
`Comparator*
`
`(N=558)
`
`
`Gastrointestinal disorders
`
`
`
`
`
`Diarrhea
`
`
`Nervous system disorders
`
`Headache
`
`
`Dizziness
`
`Reference ID: 3955674
`
`5.2
`
`
`
`5.4
`
`2.2
`
`7
`
`4.3
`
`
`
`5.4
`
`2.0
`
`

`

`
` Skin/subcutaneous disorders
`
`
`
`
`Rash
`
`Diagnostic investigations
`
`Abnormal liver function tests
`
`Elevated CPK
`
`Infections
`
`Urinary tract infections
`
`
`Vascular disorders
`
`
`Hypotension
`
`
`Respiratory disorders
`
`
`Dyspnea
`
`
`
`4.3
`
`
`
`3.0
`
`2.8
`
`
`
`2.4
`
`
`
`2.4
`
`
`
`2.1
`
`
`
`3.8
`
`
`
`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 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 System: myalgia, muscle cramps, muscle weakness, arthralgia
`
`Nervous System: vertigo, mental status change, paresthesia
`
`Special Senses: taste disturbance, eye irritation
`
`
`S. aureus Bacteremia/Endocarditis Trial
`In the S. aureus bacteremia/endocarditis trial, CUBICIN was discontinued in 20/120 (16.7%) patients due to an adverse
`
`
`reaction, while comparator was discontinued in 21/116 (18.1%) patients.
`
`Serious Gram-negative infections (including bloodstream infections) were reported in 10/120 (8.3%) CUBICIN-treated
`
`
`patients and 0/115 comparator-treated patients. Comparator-treated patients received dual therapy that included initial
`
`gentamicin for 4 days. Infections were reported during treatment and during early and late follow-up. Gram-negative
`
`
`
`infections included cholangitis, alcoholic pancreatitis, sternal osteomyelitis/mediastinitis, bowel infarction, recurrent
`Crohn’s disease, recurrent line sepsis, and recurrent urosepsis caused by a number of different Gram-negative bacteria.
`The rates of the most common adverse reactions, organized by System Organ Class (SOC), observed in S. aureus
`
`bacteremia/endocarditis (6 mg/kg CUBICIN) patients are displayed in Table 6.
`
`Reference ID: 3955674
`
`8
`
`
`

`

`
`
`
`
` Table 6: Incidence of Adverse Reactions that Occurred in ≥5% of Patients in the CUBICIN Treatment Group and ≥
`the Comparator Treatment Group in the S. aureus Bacteremia/Endocarditis Trial
`
`
`Adverse Reaction*
`
`Patients
`n (%)
`
`CUBICIN 6 mg/kg
`
`(N=120)
`
`6 (5%)
`6 (5%)
`
`7 (6%)
`
`Infections and infestations
`
`Sepsis NOS
`
`Bacteremia
`Gastrointestinal disorders
`
`Abdominal pain NOS
`General disorders and
`
`administration site conditions
`
`Chest pain
`Edema NOS
`
`Respiratory, thoracic and
`
`mediastinal disorders
`
`Pharyngolaryngeal pain
`Skin and subcutaneous tissue
`
`disorders
`
`Pruritus
`
`Sweating increased
`
`Psychiatric disorders
`
`Insomnia
`Investigations
`Blood creatine
`phosphokinase increased
`
`Vascular disorders
`
`Hypertension NOS
`NOS, not otherwise specified.
`*
`†
`Comparator: vancomycin (1 g IV q12h) or an anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin,
`
`
` cloxacillin, or flucloxacillin; 2 g IV q4h), each with initial low-dose gentamicin.
`
`
`8 (7%)
`8 (7%)
`
`
`10 (8%)
`
`
`7 (6%)
`6 (5%)
`
`11 (9%)
`
`
`8 (7%)
`
`7 (6%)
`
`Comparator†
`
`
` (N=116)
`
`3 (3%)
`0 (0%)
`
`4 (3%)
`
`
`7 (6%)
`5 (4%)
`
`
`2 (2%)
`
`
`6 (5%)
`0 (0%)
`
`8 (7%)
`
`
`1 (1%)
`
`3 (3%)
`
`
`
`
`
` The following reactions, not included above, were reported as possibly or probably drug-related in the CUBICIN-treated
`group:
` Blood and Lymphatic System Disorders: eosinophilia, lymphadenopathy, thrombocythemia, thrombocytopenia
`Cardiac Disorders: atrial fibrillation, atrial flutter, cardiac arrest
`Ear and Labyrinth Disorders: tinnitus
`Eye Disorders: vision blurred
`
`Gastrointestinal Disorders: dry mouth, epigastric discomfort, gingival pain, hypoesthesia oral
`
`Infections and Infestations: candidal infection NOS, vaginal candidiasis, fungemia, oral candidiasis, urinary tract infection
`fungal
`
`
`Reference ID: 3955674
`
`9
`
`
`

`

`
`Investigations: blood phosphorous increased, blood alkaline phosphatase increased, INR increased, liver function test
`abnormal, alanine aminotransferase increased, aspartate aminotransferase increased, prothrombin time prolonged
`
`Metabolism and Nutrition Disorders: appetite decreased NOS
`
`Musculoskeletal and Connective Tissue Disorders: myalgia
`
`Nervous System Disorders: dyskinesia, paresthesia
`
`Psychiatric Disorders: hallucination NOS
`
`Renal and Urinary Disorders: proteinuria, renal impairment NOS
`
`Skin and Subcutaneous Tissue Disorders: pruritus generalized, rash vesicular
`
`Other Trials
`
`In Phase 3 trials of community-acquired pneumonia (CAP), the death rate and rates of serious cardiorespiratory adverse
`
`events were higher in CUBICIN-treated patients than in comparator-treated patients. These differences were due to lack
`
`
`of therapeutic effectiveness of CUBICIN in the treatment of CAP in patients experiencing these adverse events [see
`
`Indications and Usage (1.3)].
`
`Laboratory Changes
`
`Complicated Skin and Skin Structure Infection Trials
`
`In Phase 3 cSSSI trials of CUBICIN at a dose of 4 mg/kg, elevations in CPK were reported as clinical adverse events in
`
`15/534 (2.8%) CUBICIN-treated patients, compared with 10/558 (1.8%) comparator-treated patients. Of the 534 patients
`treated with CUBICIN, 1 (0.2%) had symptoms of muscle pain or weakness associated with CPK elevations to greater
`than 4 times the upper limit of normal (ULN). The symptoms resolved within 3 days and CPK returned to normal within 7
`to 10 days after treatment was discontinued [see Warnings and Precautions (5.2)]. Table 7 summarizes the CPK shifts
`
`
`from Baseline through End of Therapy in the cSSSI trials.
`
`Table 7: Incidence of CPK Elevations from Baseline during Therapy in Either the CUBICIN Treatment Group or the
`Comparator Treatment Group in Phase 3 cSSSI Trials
`
`Change in CPK
`
`%
`
`
`90.7
`No Increase
`Maximum Value >1× ULN† 9.3
`
`>2× ULN 4.9
`
`All Patients
`
`CUBICIN
`
`4 mg/kg
`(N=430)
`
`n
`390
`40
`21
`
`Comparator*
`
`(N=459)
`
`
`%
`
`91.1
`8.9
`4.8
`
`n
`418
`41
`22
`
`Patients with
`
`Normal CPK at Baseline
`
`CUBICIN
`
`4 mg/kg
`(N=374)
`
`n
`
`341
`
` 33
`14
`
`
`Comparator*
`
`(N=392)
`
`
`%
`
`91.1
`8.9
`3.1
`
`n
`
`357
`
` 35
`12
`
`
`%
`
`91.2
`8.8
`3.7
`
`4
`1.0
`4
`1.1
`7
`1.5
`6
`>4×