`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`NDA 21-572/S-052
`
`
`Cubist Pharmaceuticals LLC
`
`Cubicin® RF
`Trade Name:
`
`
`daptomycin for injection
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`Indications:
`
`July 6, 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-052
`
`
`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-052
`NDA 21-572/S-052
`
`
`APPLICA TION NUMBER:
`
`APPROVAL LETTER
`
`APPROVAL LETTER
`
`
`
`
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`NDA 21-572/S-052
`
`
`
`
`
`
`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 February 9, 2016,
`received February 9, 2016, and your amendments, submitted under section 505(b) of the Federal
`Food, Drug, and Cosmetic Act (FDCA) for Cubicin RF (daptomycin for injection), 500 mg/vial.
`
`This Prior Approval supplemental new drug application provides for a re-formulated Cubicin
`product, Cubicin RF. The package insert (PI) and carton and container labels have been revised
`accordingly, the former including changes to the HIGHLIGHTS OF PRESCRIBING
`INFORMATION section, DOSAGE AND ADMINISTRATION (2), Preparation of
`CUBICIN RF for Administration (2.5), Compatible Intravenous Solutions (2.6), and
`Incompatibilities (2.7) subsections, DESCRIPTION (11) section, and the HOW
`SUPPLIED/STORAGE AND HANDLING (16) section.
`
`Additionally, the following has been added to the ADVERSE REACTIONS (6),
`Postmarketing Experience (6.2) subsection:
`
`
` Blood and lymphatic system disorders: anemia
` General and administration site conditions: pyrexia
` Renal and urinary disorders: acute kidney injury, renal insufficiency, and renal failure
` Skin and Subcutaneous Tissue Disorders: acute generalized exanthematous pustulosis
`
`
`Further, the term “single-use” has been replaced with “single-dose” throughout the package
`insert, cartons and containers.
`
`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.
`
`Reference ID: 3955674
`
`

`

`NDA 21-572/S-052
`Page 2
`
`
`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 (text for the package insert), 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. 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 June 22, 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-052.”
`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.
`
`MARKET PACKAGE
`
`Please submit one market package of the drug product when it is available to the following
`address:
`
`Reference ID: 3955674
`
`

`

`NDA 21-572/S-052
`Page 3
`
`
`
`J. Christopher Davi, MS, Senior Regulatory Project Manager
`Food and Drug Administration
`Center for Drug Evaluation and Research
`White Oak Building 22, Room: 6230
`10903 New Hampshire Avenue
`Silver Spring, Maryland
`
`Use zip code 20903 if shipping via United States Postal Service (USPS).
`Use zip code 20993 if sending via any carrier other than USPS (e.g., UPS, DHL, FedEx).
`
`
`
`PROMOTIONAL MATERIALS
`
`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory
`comments, (2) the proposed materials in draft or mock-up form with annotated references, and
`(3) the package insert(s) to:
`
`
`OPDP Regulatory Project Manager
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion (OPDP)
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`Alternatively, you may submit a request for advisory comments electronically in eCTD format.
`For more information about submitting promotional materials in eCTD format, see the draft
`Guidance for Industry (available at:
`
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM443702.pdf ).
`
`You must submit final promotional materials and package insert(s), accompanied by a Form
`FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form
`FDA 2253 is available at:
`
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
`
`Information and Instructions for completing the form can be found at:
`
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf.
`
`Reference ID: 3955674
`
`

`

`NDA 21-572/S-052
`Page 4
`
`
`
`For more information about submission of promotional materials to the Office of Prescription
`Drug Promotion (OPDP), see:
`
`http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`If you have any questions, call J. Christopher Davi, MS, Senior Regulatory Project Manager, at
`(301) 796-0702.
`
`
`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
`
`
`
`
`
`
`ENCLOSURES:
`
`Reference ID: 3955674
`
`

`

`Barcode)
`(Component Number
`For Position Only
`
`See enclosed package insert for
`reconstitution instructions and
`complete information on dosage
`and administration.
`
`Cubicin® RF (daptomycin for injection)
`contains 500 mg/vial of daptomycin.
`Reconstitute with 10 mL Sterile Water
`for Injection or Bacteriostatic Water
`for Injection to obtain a final
`concentration of 50 mg/mL.
`
`Each vial also contains sucrose
`(713 mg). Sodium hydroxide is used
`to adjust pH.
`
`Contains no preservatives.
`
`Note: Parenteral drug products should
`be inspected visually for particulate
`matter prior to administration.
`
`NDC 67919-012-01
`
`
`
`For Intravenous Use
`Reconstitute vial only with
`
`Sterile Water for Injection or
`Bacteriostatic Water for Injection.
`
`Single-dose vial –
`Discard Unused Portion
`
`Rx only
`
`For Position Only
`(Component Number Barcode)
`
`XXXXXX-XX
`
`This package contains one single-dose
`vial of sterile Cubicin® RF (daptomycin
`for injection) and one package insert.
`Store at 20°C to 25°C (68°F to 77°F);
`excursions permitted to 15°C to 30°C
`(59°F to 86°F) [see USP Controlled Room
`Temperature]. See package insert for
`storage of reconstituted and further
`diluted product.
`
`
`
`Manuf. for: Merck Sharp & Dohme Corp.,
`a subsidiary of
`
`Whitehouse Station, NJ 08889, USA
`Manuf. by: OSO Biopharmaceuticals
`Manufacturing, LLC
`Albuquerque, NM 87109, USA
`Daptomycin (active ingred.) Made in Italy.
`Formulated in USA.
`
`Rx only
`
`Discard Unused Portion
`Single-dose vial –
`
`For Intravenous Use
`
`
`
`NDC 67919-012-01
`
`
`
`For Intravenous Use
`Single-dose vial –
`
`Discard Unused Portion
`
` 67919-012-01 3
`
`N3
`
`For Position Only
`
`(Component Number
`
`Barcode)
`
`Lot/Exp. Area: All legends and encoding
`information to be printed online.
`
`For Position Only
`(Component Number
`Barcode)
`
`For Position Only
`(Component Number Barcode)
`
`Reference ID: 3955674
`
`

`

`Lot and Expiry Area.
`Legends Printed Online.
`
`NDC 67919-012-01
`
`X-XXXX-XX
`
`Rx only
`
`For Intravenous Use
`Single-dose vial –
`Discard Unused Portion
`
`USUAL DOSAGE:
`See Package Insert.
`Store at 20°C to 25°C (68°F to
`77°F). See package insert for
`storage of reconstituted and
`further diluted product.
`Use 10 mL Sterile or Bacterio-
`static Water for Injection for
`reconstitution only.
`Manuf. for: Merck Sharp & Dohme Corp.,
`a subsidiary of Merck & Co., Inc.
`
`(01)00367919012013
`
`Reference ID: 3955674
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`07/06/2016
`
`Reference ID: 3955674
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`NDA 21-572/S-052
`NDA 21-572/S-052
`
`
`APPLICA TION NUMBER:
`
`LABELING
`
`LABELING
`
`
`
`
`
`

`

`
`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
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`3
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`
`

`

`
` 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.
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`Reference ID: 3955674
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`4
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`
`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
`
`