11/2010
`08/2010
`
`11/2010
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`------------------------------ADVERSE REACTIONS-------------------------------
`The most clinically significant adverse reactions observed with CUBICIN
`4 mg/kg (cSSSI trials) and 6 mg/kg (S. aureus bacteremia/endocarditis trial)
`
`
`were abnormal liver function tests, elevated CPK, dyspnea, and pneumonia.
`(6.1)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Cubist
`Pharmaceuticals, Inc., at 1-866-793-2786 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`
`
`---------------------DOSAGE FORMS AND STRENGTHS---------------------­
`500 mg lyophilized powder for reconstitution in a single-use vial (3)
`
`-------------------------------CONTRAINDICATIONS------------------------------
`
`Known hypersensitivity to daptomycin (4)
`•
`
`-----------------------WARNINGS AND PRECAUTIONS------------------------
`
`Anaphylaxis/hypersensitivity reactions (including life-threatening):
`•
`
`Discontinue CUBICIN and treat signs/symptoms. (5.1)
`
`• Myopathy and rhabdomyolysis: Monitor CPK levels and follow muscle
`
`pain or weakness; if elevated CPK or myopathy occurs, consider
`
`discontinuation of CUBICIN. (5.2)
`
`Eosinophilic pneumonia: Discontinue CUBICIN and consider treatment
`with systemic steroids. (5.3)
`
`Peripheral neuropathy: Monitor for neuropathy and consider
`
`discontinuation. (5.4)
`Clostridium difficile–associated diarrhea: Evaluate patients if diarrhea
`occurs. (5.5)
`Persisting or relapsing S. aureus bacteremia/endocarditis: Perform
`
`susceptibility testing and rule out sequestered foci of infection. (5.6)
`Decreased efficacy was observed in patients with moderate baseline
`
`
`renal impairment. (5.7)
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`
` CUBICIN® safely and effectively. See full prescribing information for
`CUBICIN.
`
`CUBICIN® (daptomycin for injection) for Intravenous Use
`
`Initial U.S. Approval: 2003
`
`
`To reduce the development of drug-resistant bacteria and maintain the
`
`effectiveness of CUBICIN and other antibacterial drugs, CUBICIN should be
`
`used to treat infections that are proven or strongly suspected to be caused by
`bacteria.
`----------------------------RECENT MAJOR CHANGES--------------------------
`
`Dosage and Administration, Administration Duration (2.1)
` 11/2010
`
`Dosage and Administration, Preparation of CUBICIN for
`
`
`
`
`
`Administration (2.5)
`Warnings and Precautions, Eosinophilic Pneumonia (5.3)
`Warnings and Precautions, Decreased Efficacy in Patients with
`Moderate Baseline Renal Impairment (5.7)
`
`
`
`----------------------------INDICATIONS AND USAGE---------------------------
`CUBICIN is a lipopeptide antibacterial indicated for the treatment of:
`
`Complicated skin and skin structure infections (cSSSI) (1.1)
`•
`
`Staphylococcus aureus bloodstream infections (bacteremia), including
`•
`those with right-sided infective endocarditis (1.2)
`CUBICIN is not indicated for the treatment of pneumonia. (1.3)
`
`
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`
`
`Recommended dosage regimen for adult patients (2.2, 2.3, 2.4):
`•
`Dosage Regimen
`Creatinine Clearance
`S. aureus Bacteremia
`cSSSI
`
`(CLCR)
`
`For 2 to 6 weeks
`For 7 to 14 days
`
`≥30 mL/min
`6 mg/kg once every
`4 mg/kg once every
`
`
`24 hours
`24 hours
`6 mg/kg once every
`4 mg/kg once every
`<30 mL/min, including
`
`
`
`48 hours*
`hemodialysis and CAPD
`48 hours*
`* Administered following hemodialysis on hemodialysis days.
`
`
`Administered intravenously in 0.9% sodium chloride, either by injection
`•
`over a 2-minute period or by infusion over a 30-minute period. (2.1, 2.5)
`
`Do not use in conjunction with ReadyMED® elastomeric infusion pumps.
`(2.7)
`_______________________________________________________________________________________________________________________________________
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`
`6 ADVERSE REACTIONS
`1
`INDICATIONS AND USAGE
`
`
`
`
`6.1 Clinical Trials Experience
`1.1 Complicated Skin and Skin Structure Infections
`
`
`
`Staphylococcus aureus Bloodstream Infections (Bacteremia),
`6.2 Post-Marketing Experience
`1.2
`
`
`
`7 DRUG INTERACTIONS
`Including Those with Right-Sided Infective Endocarditis, Caused
`
`
`
`7.1 HMG-CoA Reductase Inhibitors
`by Methicillin-Susceptible and 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
`2 DOSAGE AND ADMINISTRATION
`
`
`
`
`8.3 Nursing Mothers
`2.1 Administration Duration
`
`
`
`
`8.4 Pediatric Use
`2.2 Complicated Skin and Skin Structure Infections
`
`
`
`Staphylococcus aureus Bloodstream Infections (Bacteremia),
`8.5 Geriatric Use
`2.3
`
`
`
`8.6 Patients with Renal Impairment
`Including Those with Right-Sided Infective Endocarditis, Caused
`
`
`
`10 OVERDOSAGE
`by Methicillin-Susceptible and Methicillin-Resistant Isolates
`
`
`
`
`11 DESCRIPTION
`2.4 Patients with Renal Impairment
`
`
`
`
`12 CLINICAL PHARMACOLOGY
`2.5 Preparation of CUBICIN for Administration
`
`
`
`
`12.1 Mechanism of Action
`2.6 Compatible Intravenous Solutions
`
`
`
`
`2.7
`Incompatibilities
`12.2 Pharmacodynamics
`
`
`
`
`12.3 Pharmacokinetics
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`
`4 CONTRAINDICATIONS
`12.4 Microbiology
`
`
`
`
`5 WARNINGS AND PRECAUTIONS
`13 NONCLINICAL TOXICOLOGY
`
`
`
`
`5.1 Anaphylaxis/Hypersensitivity Reactions
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`13.2 Animal Toxicology and/or Pharmacology
`5.2 Myopathy and Rhabdomyolysis
`
`
`
`
`5.3 Eosinophilic Pneumonia
`14 CLINICAL TRIALS
`
`
`
`
`5.4 Peripheral Neuropathy
`14.1 Complicated Skin and Skin Structure Infections
`
`
`
`
`14.2 S. aureus Bacteremia/Endocarditis
`5.5 Clostridium difficile–Associated Diarrhea
`
`
`
`
`5.6 Persisting or Relapsing S. aureus Bacteremia/Endocarditis
`15 REFERENCES
`
`
`
`5.7 Decreased Efficacy in Patients with Moderate Baseline Renal
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`Impairment
`17 PATIENT COUNSELING INFORMATION
`
`
`5.8 Drug-Laboratory Test Interactions
`
`
`
`* Sections or subsections omitted from the full prescribing information are not
`5.9 Non-Susceptible Microorganisms
`
`listed
`
`
`
`
`
`
`
`
`
`
`
` Revised: 11/2010
`
`
`•
`
`
`
`Reference ID: 2870481
`_______________________________________________________________________________________________________________________________________
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`
`CUBICIN® (daptomycin for injection)
`
`1
`
`INDICATIONS AND USAGE
`
`CUBICIN is indicated for the treatment of the infections listed below.
`
`1.1 Complicated Skin and Skin Structure Infections
`
`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
`
`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 is not indicated for the treatment of pneumonia.
`
`CUBICIN is not indicated for the treatment of left-sided infective endocarditis due to S. aureus.
`The clinical trial of CUBICIN in 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
`and other antibacterial drugs, CUBICIN should be used only to treat infections that are proven or
`strongly suspected to be caused by susceptible bacteria.
`
`When culture and susceptibility information are available, they should be considered in selecting
`or modifying antibacterial therapy. In the absence of such data, local epidemiology and
`
`Reference ID: 2870481
`
`2
`
`

`

`
`
`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 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 4 mg/kg should be administered intravenously in 0.9% sodium chloride injection 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 6 mg/kg should be administered intravenously in 0.9% sodium chloride injection once
`every 24 hours for 2 to 6 weeks. There are limited safety data for the use of CUBICIN for more
`than 28 days of therapy. In the Phase 3 trial, there were a total of 14 patients who were treated
`with CUBICIN for more than 28 days.
`
`2.4
`
`
`Patients with Renal Impairment
`
`The recommended dosage regimen for patients with creatinine clearance (CLCR) <30 mL/min,
`including those 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 1).
`When possible, CUBICIN should be administered following the completion of hemodialysis on
`hemodialysis days [see Warnings and Precautions (5.2, 5.7), Use in Specific Populations (8.6),
`
`
`and Clinical Pharmacology (12.3)].
`
`
`Table 1. Recommended Dosage of CUBICIN in Adult Patients
`
`Creatinine Clearance
`(CLCR)
`
`≥30 mL/min
`
`
`<30 mL/min, including
`
`hemodialysis and CAPD
`
`* When possible, administer CUBICIN following the completion of hemodialysis on hemodialysis days.
`
`
`
`
`cSSSI
`4 mg/kg once every 24 hours
`4 mg/kg once every 48 hours*
`
`
`Dosage Regimen
`S. aureus Bloodstream Infections
`6 mg/kg once every 24 hours
`6 mg/kg once every 48 hours*
`
`
`Reference ID: 2870481
`
`3
`
`

`

`
`
`2.5 Preparation of CUBICIN for Administration
`
`
`CUBICIN is supplied in single-use vials, each containing 500 mg daptomycin as a sterile,
`lyophilized powder. The contents of a CUBICIN vial should be reconstituted, using aseptic
`technique, to 50 mg/mL as follows:
`
`Note: To minimize foaming, AVOID vigorous agitation or shaking of the vial during or after
`reconstitution.
`
`1. Remove the polypropylene flip-off cap from the CUBICIN vial to expose the central
`portion of the rubber stopper.
`
`2. Slowly transfer 10 mL of 0.9% sodium chloride injection through the center of the
`rubber stopper into the CUBICIN vial, pointing the transfer needle toward the wall of
`
`the vial.
`
`3. Ensure that all of the CUBICIN powder is wetted by gently rotating the vial.
`
`4. Allow the wetted product to stand undisturbed for 10 minutes.
`
`5. Gently rotate or swirl the vial contents for a few minutes, as needed, to obtain a
`
`completely reconstituted solution.
`
`
`
`For intravenous (IV) injection over a period of 2 minutes, administer the appropriate volume of
`the reconstituted CUBICIN (concentration of 50 mg/mL).
`
`For IV infusion over a period of 30 minutes, the appropriate volume of the reconstituted
`CUBICIN (concentration of 50 mg/mL) should be further diluted, using aseptic technique, into a
`50 mL IV infusion bag containing 0.9% sodium chloride injection.
`
`Parenteral drug products should be inspected visually for particulate matter prior to
`administration.
`
`No preservative or bacteriostatic agent is present in this product. Aseptic technique must be used
`in the preparation of final IV solution. Stability studies have shown that the reconstituted
`solution is stable in the vial for 12 hours at room temperature and up to 48 hours if stored under
`refrigeration at 2 to 8°C (36 to 46°F).
`
`The diluted solution is stable in the infusion bag for 12 hours at room temperature and 48 hours
`if stored under refrigeration. The combined storage time (reconstituted solution in vial and
`diluted solution in infusion bag) should not exceed 12 hours at room temperature or 48 hours
`under refrigeration.
`
`CUBICIN vials are for single use only.
`
`2.6 Compatible Intravenous Solutions
`
`CUBICIN is compatible with 0.9% sodium chloride injection and lactated Ringer’s injection.
`
`Reference ID: 2870481
`
`4
`
`

`

`
`
`2.7
`
`Incompatibilities
`
`CUBICIN is not compatible with dextrose-containing diluents.
`
`CUBICIN should not be used in conjunction with ReadyMED® elastomeric infusion pumps
`
` (Cardinal Health, Inc.). Stability studies of CUBICIN solutions stored in ReadyMED®
`elastomeric infusion pumps identified an impurity (2-mercaptobenzothiazole) leaching from this
`pump system into the CUBICIN solution.
`
`Because only limited data are available on the compatibility of CUBICIN with other IV
`substances, additives and other medications should not be added to CUBICIN single-use vials or
`infusion bags, or infused simultaneously through the same IV line. If the same IV line is used
`for sequential infusion of different drugs, the line should be flushed with a compatible
`intravenous solution before and after infusion with CUBICIN.
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`
`500 mg daptomycin as a sterile, pale yellow to light brown lyophilized powder for reconstitution
`in a single-use vial.
`
`4
`
`CONTRAINDICATIONS
`
`CUBICIN 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 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 should be monitored for the development of muscle pain or
`weakness, particularly of the distal extremities. In patients who receive CUBICIN, 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.
`
`Reference ID: 2870481
`
`5
`
`

`

`
`
`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 should not be dosed more
`frequently than once a day.
`
`CUBICIN 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 [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 should undergo prompt medical evaluation, and CUBICIN 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.
`
`5.5 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: 2870481
`
`6
`
`

`

`
`
`
`
` 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.
`
`5.6 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)].
`
`5.7 Decreased Efficacy in Patients with Moderate Baseline Renal Impairment
`
`There are limited data available from the cSSSI clinical trials regarding clinical efficacy of
`daptomycin treatment in patients with CrCL <50 mL/min; only 31/534 (6%) patients treated with
`daptomycin in the intent-to-treat (ITT) population had a baseline CrCL <50 mL/min. Table 2
`shows the number of patients by CrCL and treatment group who were clinical successes in the
`cSSSI trials.
`
`
`
` Table 2. Clinical Success Rates by Treatment Group and Renal Function in the Daptomycin cSSSI Clinical
`Trials (Population: ITT)
`
`
`
`CrCL
`
`
`50-70 mL/min
`30-<50 mL/min
`
`
`
`
`Success Rate
`n/N (%)
`
`
`Daptomycin
`
`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 S. aureus bacteremia/endocarditis trial,
`clinical success rates, as determined by a treatment-blinded Adjudication Committee [see
`Clinical Trials (14.2)], in the daptomycin-treated patients were lower in patients with baseline
`CrCL <50 mL/min (Table 3). A decrease of the magnitude shown in Table 3 was not observed
`in comparator-treated patients.
`
`Reference ID: 2870481
`
`7
`
`

`

`
`
`Table 3. Adjudication Committee Success Rates at TOC Stratified by Baseline Creatinine Clearance in the
`S. aureus Bacteremia/Endocarditis Trial (Population: ITT)
`
`
`Success Rate
`n/N (%)
`
`Baseline CrCL
`
`
`>80 mL/min
`
`50-80 mL/min
`30-50 mL/min
`
`
`
`
`
`Daptomycin
`Right-Sided
`Infective Endocardtis
`
`7/14 (50%)
`1/4 (25%)
`0/1 (0%)
`
`Bacteremia
`
`30/50 (60%)
`12/26 (46%)
`2/14 (14%)
`
`Comparator
`Right-Sided
`Infective Endocardtis
`
`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.
`
`5.8 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-Laboratory Interactions (7.2)].
`
`
`5.9 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 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.
`
`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)]
`
`Reference ID: 2870481
`
`8
`
`

`

`
`
`-
`
`Increased International Normalized Ratio (INR)/prolonged prothrombin time [see
`Warnings and Precautions (5.8) and Drug-Laboratory Test 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 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 4.
`
`Reference ID: 2870481
`
`9
`
`

`

`
`
`Table 4. Incidence of Adverse Reactions that Occurred in ≥2% of Patients in the
`
`
`CUBICIN Treatment Group and ≥ the Comparator Treatment Groups in Phase 3
`cSSSI Trials
`
`Adverse Reaction
`
`Patients (%)
`
`
`CUBICIN 4 mg/kg
`Comparator*
`(N=534)
`(N=558)
`Gastrointestinal disorders
`
`
`
`5.2
`4.3
` Diarrhea
`Nervous system disorders
`
`
`
`5.4
`5.4
` Headache
`
`2.2
`2.0
` Dizziness
`
`Skin/subcutaneous disorders
`
`
`
`4.3
`3.8
` Rash
`Diagnostic investigations
`
`
`
`3.0
`1.6
` Abnormal liver function tests
`
`2.8
`1.8
` Elevated CPK
`Infections
`
`
`
`
`2.4
`0.5
` Urinary tract infections
`Vascular disorders
`
`
`
`
`2.4
`1.4
` Hypotension
`Respiratory disorders
`
`
`
`2.1
`1.6
` Dyspnea
`* 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
`
`
`Reference ID: 2870481
`
`10
`
`

`

`
`
`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 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 5.
`
`Table 5. Incidence of Adverse Reactions that Occurred in ≥5% of Patients in the CUBICIN
`
`
`
`
`Treatment Group and ≥ to the Comparator Treatment Group in the S. aureus
`Bacteremia/Endocarditis Trial
`
`Adverse Reaction*
`
`
`
`
`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
`
`Patients
`n (%)
`CUBICIN 6 mg/kg
`(N=120)
`
`
`6 (5%)
`
`6 (5%)
`
`
`7 (6%)
`
`Comparator†
`
`(N=116)
`
`
`3 (3%)
`
`0 (0%)
`
`
`4 (3%)
`
`
`
`8 (7%)
`
`8 (7%)
`
`
`10 (8%)
`
`
`
`7 (6%)
`
`5 (4%)
`
`
`
`2 (2%)
`
`Reference ID: 2870481
`
`11
`
`

`

`
`
`Adverse Reaction*
`
`
`
`Patients
`n (%)
`CUBICIN 6 mg/kg
`(N=120)
`
`
`7 (6%)
`
`6 (5%)
`
`
`11 (9%)
`
`
`8 (7%)
`
`
`7 (6%)
`
` Comparator†
`
`(N=116)
`
`
`6 (5%)
`
`0 (0%)
`
`
`8 (7%)
`
`
`1 (1%)
`
`
`3 (3%)
`
`
`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.
`
`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
`
`
`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
`
`
`Reference ID: 2870481
`
`12
`
`

`

`
`
`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 6 summarizes the CPK shifts from Baseline through End of Therapy in the cSSSI
`trials.
`
` Table 6. Incidence of CPK Elevations from Baseline during Therapy in Either the CUBICIN Treatment
`
`
`
`
`
` Group or the Comparator Treatment Groups in Phase 3 cSSSI Trials
`
`
`
`
`Change in CPK
`
`Patients with
`
`Normal CPK at Baseline
`
`All Patients
`Comparator*
`CUBICIN
`CUBICIN
`Comparator*
`
`
`
`
`(N=374)
`(N=459)
`(N=430)
`(N=392)
`%
` n
`%
` n
`%
` n
`%
` n
`
`
`
`
`
`
`
`
`
`No Increase
`91.2
`341
`91.1
`418
`90.7
`390
`91.1
`357
`
`
`
`
`
`
`
`
`Maximum Value >1× ULN†
`
`
`
`
`
`
`
`9.3
`40
`8.9
`41
`8.8
`33
`8.9
`35
`14
`22
`21
`>2× ULN
`12
`4.9
`4.8
`3.7
`3.1
`
`
`
`
`
`4
`7
`6
`4
`>4× ULN
`1.4
`1.5
`1.1
`1.0
`
`
`
`
`
`4
`2
`6
`0
`>5× ULN
`1.4
`0.4
`1.1
`0.0
`
`
`
`
`
`0.5
`1
`1
`2
`0
`>10× ULN
`0.2
`0.2
`0.0
`
`
`
`
`
`Note: Elevations in CPK observed in patients treated with CUBICIN or comparator were not clinically or
`
`
`
`
`statistically significantly different.
`
`Reference ID: 2870481
`
`13
`
`

`

`
`
`* 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).
`
`
`† ULN (Upper Limit of Normal) is defined as 200 U/L.
`
`S. aureus Bacteremia/Endocarditis Trial
`
`In the S. aureus bacteremia/endocarditis trial, at a dose of 6 mg/kg, 11/120 (9.2%) CUBICIN-
`treated patients, including two patients with baseline CPK levels >500 U/L, had CPK elevations
`to levels >500 U/L, compared with 1/116 (0.9%) comparator-treated patients. Of the 11
`CUBICIN-treated patients, 4 had prior or concomitant treatment with an HMG-CoA reductase
`inhibitor. Three of these 11 CUBICIN-treated patients discontinued therapy due to CPK
`elevation, while the one comparator-treated patient did not discontinue therapy [see Warnings
`and Precautions (5.2)].
`
`
`6.2 Post-Marketing Experience
`
`The following adverse reactions have been identified during postapproval use of CUBICIN.
`Because these reactions are reported voluntarily from a population of uncertain size, it is not
`always possible to estimate their frequency reliably or establish a causal relationship to drug
`exposure.
`
`Immune System Disorders: anaphylaxis; hypersensitivity reactions, including pruritus, hives,
`shortness of breath, difficulty swallowing, truncal erythema, and pulmonary eos