`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`NDA 21-572/S-053
`
`
`Cubist Pharmaceuticals LLC
`
`Cubicin
`Trade Name:
`
`
`Daptomycin for injection
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`Indications:
`
`July 7, 2016
`
` For complicated skin and skin structure infections,
`Staphylococcus aureus bloodstream infections
`(bacteremia), including those with right-sided
`infective endocarditis.
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`NDA 21-572/S-053
`
`
`CONTENTS
`
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Approvable Letter
`Labeling
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Other Review(s)
`Administrative/Correspondence Document(s)
`
`
`
`X
`
`X
`
`
`
`
`
`
`
`
`
`
`
`
`
`X
`X
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`NDA 21-572/S-053
`NDA 21-572/S-053
`
`
`APPLICA TION NUMBER:
`
`APPROVAL LETTER
`
`APPROVAL LETTER
`
`
`
`
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
` NDA 21-572/S-053
`
`
`
`
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`
`SUPPLEMENT APPROVAL
`
`
`
`Merck Sharp & Dohme Corp., agent for Cubist Pharmaceuticals, LLC
`Attention: Sandra Lynn Wood, PhD
`Director, Global Regulatory Affairs
`351 North Sumneytown Pike
`P.O. Box 1000, Mailstop UG-2D48
`
`North Wales, PA 19454-2505
`
`
`Dear Dr. Wood:
`
`Please refer to your Supplemental New Drug Application (sNDA) dated April 12, 2016, received
`April 12, 2016, and your amendments, submitted under section 505(b) of the Federal Food,
`Drug, and Cosmetic Act (FDCA) for Cubicin (daptomycin for injection) 500 mg/vial.
`
`
`This Prior Approval Supplemental Application proposes revisions to the DOSAGE AND
`ADMINISTRATION (2), Preparation of CUBICIN for Administration (2.5) and
`ADVERSE REACTIONS (6), Post-Marketing Experience (6.2) subsections of the package
`insert, along with the replacement of the term “single-use” with “single-dose” throughout the
`
`package insert, cartons and containers and other minor editorial revisions.
`
`
`APPROVAL & LABELING
`
`We have completed our review of this supplemental application, as amended and it is approved,
`effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
`text.
`
`CONTENT OF LABELING
`
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`automated drug registration and listing system (eLIST), as described at:
`
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm.
`
`Content of labeling must be identical to the enclosed labeling, with the addition of any labeling
`changes in pending “Changes Being Effected” (CBE) supplements, as well as annual reportable
`changes not included in the enclosed labeling.
`
`
`Reference ID: 3955960
`
`

`

`
`
`NDA 21-572/S-053
`Page 2
`
`
`
`Information on submitting SPL files using eList may be found in the guidance for industry titled
`“SPL Standard for Content of Labeling Technical Qs and As at:
`
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`
` CM072392.pdf
`
` The SPL will be accessible from publicly available labeling repositories.
`
`Also within 14 days, amend all pending supplemental applications that includes labeling changes
`for this NDA, including CBE supplements for which FDA has not yet issued an action letter,
`with the content of labeling [21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the
`changes approved in this supplemental application, as well as annual reportable changes and
`annotate each change. To facilitate review of your submission, provide a highlighted or marked-
`up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy
`should provide appropriate annotations, including supplement number(s) and annual report
`date(s).
`
`CARTON AND IMMEDIATE CONTAINER LABELS
`
`
`Submit final printed carton and immediate container labels that are identical to the carton and
`immediate container labels submitted on July 5, 2016, as soon as they are available, but no more
`than 30 days after they are printed. Please submit these labels electronically according to the
`guidance for industry Providing Regulatory Submissions in Electronic Format – Human
`Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications
`(June 2008). Alternatively, you may submit 12 paper copies, with 6 of the copies individually
`mounted on heavy-weight paper or similar material. For administrative purposes, designate this
`submission “Final Printed Carton and Container Labels for approved NDA 21-572/S-053.”
`Approval of this submission by FDA is not required before the labeling is used.
`
`Marketing the product(s) with FPL that is not identical to the approved labeling text may render
`the product misbranded and an unapproved new drug.
`
`REPORTING REQUIREMENTS
`
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3955960
`
`

`

`Sincerely,
`
`
`{See appended electronic signature page}
`
`Sumathi Nambiar, MD, MPH
`
` Director
`Division of Anti-Infective Products
`Office of Antimicrobial Products
`Center for Drug Evaluation and Research
`
`Content of Labeling
`Carton and Container Labeling
`
`
`
`NDA 21-572/S-053
`Page 3
`
`
`
`If you have any questions, call J. Christopher Davi, MS, Senior Regulatory Project Manager, at
`(301) 796-0702.
`
`
`
`
`
`ENCLOSURES:
`
`
`
`
`Reference ID: 3955960
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SUMATHI NAMBIAR
`07/07/2016
`
`Reference ID: 3955960
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`NDA 21-572/S-053
`NDA 21-572/S-053
`
`
`APPLICA TION NUMBER:
`
`LABELING
`
`LABELING
`
`
`
`
`
`

`

`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`
`CUBICIN safely and effectively. See full prescribing information
`
`for CUBICIN.
`
`
`CUBICIN® (daptomycin for injection) for Intravenous Use
`
`
`Initial U.S. Approval: 2003
`
`
`
`
`--------------------------- RECENT MAJOR CHANGES ---------------------------
`
`Dosage and Administration (2.5)------ ----------------------------------- 7/2016
`
`
` ----------------------------INDICATIONS AND USAGE ----------------------------
`
`CUBICIN 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 is not indicated for the treatment of pneumonia. (1.3)
`
`
`To reduce the development of drug-resistant bacteria and maintain the
`effectiveness of CUBICIN and other ant bacterial drugs, CUBICIN
`should be used to treat infections that are proven or strongly suspected
`to be caused by bacteria.
`
` ----------------------- 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*
`
`
`
`4 mg/kg once every
`
`24 hours
`4 mg/kg once every
`
`48 hours*
`
`
`
`≥30 mL/min
`
`<30 mL/min,
`including
`hemodialysis and
`CAPD
`
`*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)
`
`
`
`
`2
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
` INDICATIONS AND USAGE
`1
`
`
`1.1 Complicated Skin and Skin Structure Infections
`Infections
`1.2 Staphylococcus
`aureus
`Bloodstream
`(Bacteremia), Including Those with Right-Sided Infective
`Endocarditis, Caused by Methicillin-Susceptible and
`
`Methicillin-Resistant Isolates
`1.3 Limitations of Use
`1.4
` Usage
` DOSAGE AND ADMINISTRATION
`
`
` Administration Duration
`2.1
`
`2.2 Complicated Skin and Skin Structure Infections
`Infections
`aureus
`Bloodstream
`2.3 Staphylococcus
`(Bacteremia), Including Those with Right-Sided Infective
`Endocarditis, Caused by Methicillin-Susceptible and
`
`Methicillin-Resistant Isolates
`2.4 Patients with Renal Impairment
`
`2.5 Preparation of CUBICIN for Administration
`2.6 Compat ble Intravenous Solutions
` Incompat bilities
`2.7
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
` Anaphylaxis/Hypersensitivity Reactions
`5.1
`
`5.2 Myopathy and Rhabdomyolysis
`5.3
` Eosinophilic Pneumonia
` Peripheral Neuropathy
`5.4
`
`5.5 Potential Nervous System and/or Muscular System Effects
`in Pediatric Patients Younger than 12 Months
`
`5.6 Clostridium difficile-Associated Diarrhea
`
`
`
`
`Reference ID: 3955960
`
`
`
`
`--------------------- 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 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)
`
` Potential nervous system and/or muscular system effects in
`
`
`pediatric patients younger than 12 months: Avoid use of CUBICIN
`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,
`
`elevated CPK, and dyspnea. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Merck
`
`Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877­
`
`888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`
`
`
`Revised: 7/2016
`
`
`if
`
`
`6
`
`7
`
`5.7 Persisting or Relapsing S. aureus Bacteremia/Endocarditis
`5.8 Decreased Efficacy in Patients with Moderate Baseline
`
`Renal Impairment
` Drug-Laboratory Test Interactions
`5.9
`
`5.10 Non-Susceptible Microorganisms
` ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`6.2
` Post-Marketing Experience
`
` DRUG INTERACTIONS
`
`7.1 HMG-CoA Reductase Inhibitors
`7.2
` Drug-Laboratory Test Interactions
`
`8 USE IN SPECIFIC POPULATIONS
`8.1
` Pregnancy
`8.3
` Nursing Mothers
`
`8.4
` Pediatric Use
` Geriatric Use
`8.5
`
`8.6 Patients with Renal Impairment
`
`10 OVERDOSAGE
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`12.4 Microbiology
` NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`13.2 Animal Toxicology and/or Pharmacology
` CLINICAL TRIALS
`
`14.1 Complicated Skin and Skin Structure Infections
`14.2 S. aureus Bacteremia/Endocarditis
`
`13
`
`14
`
`

`

`
`15 REFERENCES
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`CUBICIN® (daptomycin for injection)
`
`
`*Sections or subsections omitted from the full prescribing information
`
`are not listed.
`
` INDICATIONS AND USAGE
`1
`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 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 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.
`
`
`
`
`Reference ID: 3955960
`
`

`

`
`
` 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) 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
`
`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, 5.8), Use in Specific Populations
`(8.6), and Clinical Pharmacology (12.3)].
`
`Creatinine
`
`Clearance
`(CLCR)
`≥30 mL/min
`
`
`
`Table 1: Recommended Dosage of CUBICIN 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 following the completion of hemodialysis on hemodialysis days.
`
`
`6 mg/kg once every 48 hours*
`
`
`
`2.5 Preparation of CUBICIN for Administration
`
`Reconstitution of CUBICIN Vial
`
`CUBICIN is supplied in single-dose vials, each containing 500 mg daptomycin as a sterile, lyophilized powder. The
`contents of a CUBICIN vial should be reconstituted, using aseptic technique, to 50 mg/mL as follows:
`1. To minimize foaming, AVOID vigorous agitation or shaking of the vial during or after reconstitution.
`2. Remove the polypropylene flip-off cap from the CUBICIN vial to expose the central portion of the rubber stopper.
`
`3. Wipe the top of the rubber stopper with an alcohol swab or other antiseptic solution and allow to dry. After
`
`cleaning, do not touch the rubber stopper or allow it to touch any other surface.
`
`4. Slowly transfer 10 mL of 0.9% sodium chloride injection through the center of the rubber stopper into the
`
`CUBICIN vial, pointing the transfer needle toward the wall of the vial. It is recommended that a beveled sterile
`
`
`transfer needle that is 21 gauge or smaller in diameter, or a needleless device is used, pointing the transfer
`
`
`
`needle toward the wall of the vial.
`5. Ensure that all of the CUBICIN powder is wetted by gently rotating the vial.
`1. Allow the wetted product to stand undisturbed for 10 minutes.
`
`2. Gently rotate or swirl the vial contents for a few minutes, as needed, to obtain a completely reconstituted
`solution.
`
`
`Administration Instructions
`
`Parenteral drug products should be inspected visually for particulate matter prior to administration.
`Slowly remove reconstituted liquid (50 mg daptomycin/mL) from the vial using a beveled sterile needle that is 21 gauge or
`
`smaller in diameter. Administer as an intravenous injection or infusion as described below:
`
`
`Intravenous Injection over a period of 2 minutes
`
`Reference ID: 3955960
`
`3
`
`
`

`

`
`
`
` For intravenous (IV) injection over a period of 2 minutes, administer the appropriate volume of the reconstituted CUBICIN
`
` (concentration of 50 mg/mL).
` Intravenous Infusion over a period of 30 minutes
`
`For IV infusion over a period of 30 minutes, 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.
`No preservative or bacteriostatic agent is present in this product. Aseptic technique must be used in the preparation of
`
`
`final IV solution. Do not exceed the In-Use storage conditions of the reconstituted and diluted solutions of CUBICIN
`described below. Discard unused portions of CUBICIN.
`
`In-Use Storage Conditions for CUBICIN Once Reconstituted in Acceptable Intravenous Diluents
`
`Stability studies have shown that the reconstituted solution is stable in the vial for 12 hours at room 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.
`
`2.6 Compatible Intravenous Solutions
`
`CUBICIN is compatible with 0.9% sodium chloride injection and lactated Ringer’s injection.
`
`
`Incompatibilities
`2.7
`CUBICIN is not compatible with dextrose-containing diluents.
`CUBICIN 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 with other IV substances, additives and other
`
`medications should not be added to CUBICIN single-dose vials or infusion bags, or infused simultaneously with CUBICIN
`
`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.
`
`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 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: 3955960
`
`4
`
`
`

`

`
`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 Potential Nervous System and/or Muscular System Effects in Pediatric Patients Younger than 12 Months
`
`Avoid use of CUBICIN 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 Trials (14.2)].
`
`Reference ID: 3955960
`
`5
`
`
`

`

`
` 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 2 shows the number
`of patients by renal function and treatment group who were clinical successes in the Phase 3 cSSSI trials.
`
`Table 2: 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 3). A decrease of the magnitude shown in Table 3 was
`not observed in comparator-treated patients.
`
`Table 3: 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.
`
`
`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 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: 3955960
`
`6
`
`
`

`

`
`
`
` 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 4.
`
`
`Table 4: 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
`
`Skin/subcutaneous disorders
`
`
`Rash
`
`
`Diagnostic investigations
`
`Abnormal liver function tests
`
`Elevated CPK
`
`5.2
`
`
`
`5.4
`
`2.2
`
`
`
`4.3
`
`
`
`3.0
`
`2.8
`
`Reference ID: 3955960
`
`7
`
`4.3
`
`
`
`5.4
`
`2.0
`
`
`
`3.8
`
`
`
`1.6
`
`1.8
`
`

`

`
`Infections
`
`Urinary tract infections
`
`
`Vascular disorders
`
`
`Hypotension
`
`
`Respiratory disorders
`
`
`Dyspnea
`
`
`
`2.4
`
`
`
`2.4
`
`
`
`2.1
`
`
`
`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 Whol