IND 57,693 ‘
`EOPZ
`
`Page 2
`
`' FDA RESPONSE:
`
`The modified —’ method is acceptable as long as it provides needed resolution
`of all the impurities above 0.1% and the impurities are identified. The Division asked
`to submit an IND amendment for the new \ method and to make sure that the
`
`method is stability indicating.
`
`'
`
`2. Cubist plans to modify the existing manufacturing process for bulk daptomycin
`currently being used by
`.— ' to produce Qinical supplies. These changes have
`been outlined in the meeting package and will be submitted as an IND amendment.
`Does FDA agree that the proposed comparability testing for_bulk daptomycin
`and daptomycin drug product outlined in the meeting package is adequate to
`qualify material produced by the modified manufacturing process thereby
`allowing the material to be used in the Phase 3 clinical trials?
`
`FDA RESPONSE:
`
`~ . appears to be
`5 versus
`__
`The comparability protocol for
`acceptable, but the acceptance criteria for the sameness should be provided and
`justified. In addition, the impurity profiles of the drug substance before and after the
`change should be included.
`
`" , Cubist needs to
`
`3. Due to limitations for purification capacity at
`
`manufacture bulk daptomycin at
`_ for commercial manufacturing.
`——-—
`_ _
`“’ process will be submitted in the NDA as the sole manufacturer of bulk
`_——/
`daptomycin. Is the comparability testing between the bulk material produced at
`" L and
`adequate to support an NDA? Is the comparability
`testing of the daptomycin drug product produced using material produced at
`' and.
`——
`' adequate to support an NDA?
`
`FDA RESPONSE:
`
`The plan for bridging studies for the changein the manufacturing site from
`\——-
`'to
`\‘ acceptable for submission1n the NDA. The division’s
`understanding is that " material will not be usedin the clinical studies for NDA
`submission. The data and acceptance criteria will be reviewed to determine
`acceptance ofthe drug substance from the new site. Also, the data for the drug
`product manufactured from the new source of the drug substance will be reviewed in
`the NDA.
`'
`
`4. Primary drug product stability data for the NDA will be generated using bulk
`daptomycin produced at ~ and drug product produced by the commercial
`drug product manufacturer (either Abbott
`~—
`.Please
`be aware that the manufacturing procedures to produce bulk drug are essentially the
`“MV
`
`(a-
`
`

`

`1ND 57,693
`EOPZ
`
`Page 3
`
`same between ‘ and the commercial supplier \ Is the proposed
`approach of using —
`bulk drug for primary drug product stability
`studies acceptable providing the equivalence between bulk material produced by
`-’
`and
`__
`isestablished?
`
`FDA RESPONSE:
`
`Primary drug product stability data for the NDA will be acceptable if comparability is
`demonstrated between the drug substance batches manufactured at
`~—
`(clinical site) and at ‘,- (proposed commercial site).
`
`J daptomycin vials in \
`"f
`5. Abbott will produce
`. _— with varying capacities. For the primary stability studies, f
`
`will operate at
`~ capacity. Does the FDA agree with the proposed
`primary stability plan outlined in the meeting package?
`
`FDA RESPONSE:
`
`This is acceptable.
`
`‘ process, the firm claims that FDA
`'—'
`6. Since daptomycin is produced using a
`guidelines permit identification of impurities which occur at 0.3% or greater. Cubist
`plans to identify any impurity in the bulk daptomycin that is present at this level. Is
`this acceptable to the FDA?
`
`FDA RESPONSE:
`
`The acceptance criteria of 0.3% limit referenced in the “Guide for Inspection on
`Fermentation of Bulk Drug Substance” are contingent on review of the impurity
`profile data and methods for Optimized process.
`
`Agreements: See discussion/recommendation section
`
`Issues Requiring Further Discussion: See discussion/recommendation section
`
`Enclosure: None
`
`Action Items: None
`
`Minutes Preparer:
`
`Jose R. Cintron, R.Ph., M.A.
`Senior Regulatory Management Officer
`
`Chairs Concurrence: Dr. Chi Wan Chen,
`Office Director, DNDC-Ifl
`
`1"
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
`
`Chi Wan Chen
`7/24/02 02:50:26 PM
`
`

`

`MEMORANDUM OF TELECON
`
`DATE: Apn'129, 2003
`
`TIME: 1:15 PM
`
`LOCATION: S-348
`
`APPLICATION NUMBER: NDA 21-572
`
`DRUG NAME: CIDECIN® (daptomycin for injection)
`
`BETWEEN:
`Name:
`
`David Schubert
`Judy Newbeme
`
`Vice President, Regulatory Affairs and Quality
`Director, Regfiatory Affairs
`
`Representing: Cubist Pharmaceuticals, Inc.
`
`AND
`Name:
`
`Janice Soreth, MD
`David Ross, MD, PhD
`
`Director, DAIDP
`Medical Team Leader
`
`Susan Thompson, MD
`Sumathi Nambiar, MD, MPH
`LT Daniel Nguyen, RPh _
`
`Medical Officer
`Medical Officer
`Regulatory Health Project Manager
`
`Representing: Division of Anti—Infective Drug Products, HFD-520
`
`BACKGROUND:
`
`On April 10, 2003 the Division informed the sponsor of the discrepancies in the data sets for study 9801.
`The Division emphasized the importance of resolving these discrepancies. This teleconference was held
`to further discuss action plans in addressing the discrepancies within the data sets.
`
`MEETING OBJECTIVE(S):
`
`To clarify action plans in resolving data set issues discovered by the Division.
`
`DISCUSSION AND RECOMMENDATIONS: -
`
`The sponsor conveyed the following to the Division:
`
`I. The sponsor will provide a written response outlining their understanding of the problem with the
`data sets.
`
`2. The sponsor will inform the Division of which data sets are involved.
`3. The sponsor will explain how the individual data sets, and 188 and 1813 data sets were derived.
`4 . The sponsor will provide a time frame for submission of corrected data sets.
`2.: “a.
`
`

`

`ACTION ITEMS:
`
`0 The sponsor will comply with the requests within the Discussion and Recommendation section
`after consulting with the contractor who constructed the data sets.
`
`0'
`
`Further discussion of data set issues will be addressed in a face-to-face meeting to be arranged
`between the sponsor and the Agency.
`
`(fl
`
`LT Daniel Nguyen, RPh
`Regulatory Health Project Manager
`Minutes Recorda—
`(7’?
`
`.. David Ross, MD, PhD
`Medical Team Leader
`
`ll
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`/S/
`
`Daniel Nguyen
`5/29/03 10:26:41 AM
`CSO
`04—29-03 Telecon
`
`Please sign off
`
`Frances LeSane
`
`5/29/03 10:29:33 AM
`CSO
`
`David Ross-
`
`5/29/03 10:33:46 AM
`MEDICAL OFFICER
`
`Janice Soreth
`5/29/03 01:05:55 PM
`MEDICAL OFFICER
`
`

`

`MEMORANDUM OF TELECON
`
`DATE:
`
`April 10, 2003
`
`NDA/IND:
`
`NDA 21-572
`
`DRUG:
`
`Cidecin
`
`BETWEEN:
`
`David Schubert
`Judy Newbeme
`Meri Bloom
`Ed Campanaro
`Conni Otradovec
`
`Bobbi Lemay
`Jeff Alder
`Grace Thome
`Barry Eisenstein
`Frank Tally
`.
`
`Vice PresidentiRegulatory Affairs and Quality
`Director, Regulatory Affairs
`Manager, Regulatory Affairs
`Executive Director, Clinical Operations
`. Director, Biostatistic's
`
`Biostatistician
`Senior Director, Pharmacology
`Director, Microbiology
`Executive VP, Research and Development
`Executive VP, Scientific Affairs and Chief
`Scientific Officer
`
`PHONE:
`
`1-888—742-8686
`
`REPRESENTING: Cubist Pharmaceuticals, Inc.
`
`AND Representatives ofDivision of Anti-Infective Drug Products, RFD-520
`David Ross
`Medical Team Leader
`
`Albert Sheldon
`Peter Coder-re
`Raquel Peat
`
`'
`
`Microbiology Team Leader
`Microbiology Reviewer
`Regulatory Health Project Manager
`
`SUBJECT:
`
`To discuss submission of microbiology and clinical data for NDA 21-572,
`Cidecin.
`
`DISCUSSION AND RECOMMENDATIONS: A summary of discussions and
`conclusions reached at the teleconference are listed below:
`
`1. Concentration offree calcium in blisterfluid and extracellular space oftissuefluids:
`The Agency request the calcium concentrations in animal models that mimic human
`infections.
`
`2. The Agency requested that an analysis of efficacy results for Studies 9801 and 9901,
`for both EOT and TOC responses, in which sponsor overrides of the
`evaluability/outcome algorithrn are mt performed. In addition, clinical questions
`about discrepancy in the datasets for study 980] will be sent via email. The Agency
`emphasized the importance of resolving these discrepancies to ensure that there are
`not more general issues with the accuracy of the datasets.
`.. -—--;
`
`

`

`AGREEMENTS (DECISIONS) REACHED:
`
`1. The sponsor agreed to submit a response addressing clinical and microbiology
`. questions.
`
`Val
`
`Minutes Prepared by: LTJG Raquel Peat, M.S., M.P.H.
`
`
`
`
`Chair Concurreric'ev avid Ross, M.D., Ph.D.
`
`
`
`ATTACHMENT: Questions and comments emailed to sponsor on April 10, 2003.
`
`

`

`--—-Original M55392—
`From:
`Peat, Raquel
`Sent:
`Thursday, April 10, 2003 1:42 PM
`To:
`David Schubert (E-mail)
`Subject:
`NDA 21,572, Cidecin
`Importance:
`High
`
`Follow up questions from our teleconference that was held today:
`
`Clinical Comments:
`
`Please clarify the following for study 9801:
`
`Patient number 001600042: Though the patient is reported to have missed the test of
`cure (TOC) visit, the CLINRESP dataset has visit number 4, i.e. the TOC visit, listed
`as ‘6/9/99’. Although the patient satisfies criteria 7 and 10 for evaluability in Table
`16.2.3.5, in the STATUS dataset the value for criterion 7 is ‘0’ and for criterion 10
`the value is ‘missing’.
`
`Patient number 0144100044: The CLINRESP dataset lists end of therapy (BOT) visit
`date as ‘5/13/00’, and TOC visit date as ‘missing’. However, in Table 16.2.3.5 in the
`final study report, the patient is not listed as having satisfied criterion 10. If the TOC
`visit is missing, per the algorithm provided, the patient should be classified as non-
`evaluable, since at the EOT visit the investigator had classified the patient as
`‘improved’. However, the sponsor's outcome for this patient is ‘cure’.
`
`The 2 examples were found by chance, it is important to understand how they came about
`and whether they reflect more general problems in the accuracy of the datasets.
`
`Page 78 of the final study report states that a total of 102 subjects in the daptomycin
`group and 103 in the comparator group underwent a surgical procedure related to the
`infection site during the study. In Table 11-6 only 44 patients in the daptomycin arm
`and 47 patients in the comparator arm are listed has having had a surgical
`intervention. Please clarify the reason for this difference.
`
`Microbiology Comments:
`
`What is the concentration of free calcium in blister fluid? In the extracellular space of
`skin tissues around epithelial cells?
`
`LTJG Raquel Peat, M.S., M.P.H., USPHS
`Regulatory Health Project Manager
`Division ofAnti-lnfective Drug Products
`Center for Drug Evaluation and Research
`Food and Drug Administration
`9201 Corporate Boulevard, HFD-SZO
`Rockville, MD 20850
`'
`ph: 301-827-2125
`fax: 301-827-2325/2327
`
`email: peatr@cder.fda.gov
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Raquel Peat
`5/2/03 12:56:23 PM
`CSO
`
`4/10/03 Telecon '
`ready for sign off
`
`David Ross
`5/5/03 04:48:32 PM
`MEDICAL OFFICER
`
`

`

`Redégted 3 .
`
`__
`
`pageg of trade
`
`sécfét and/or
`
`‘confidential-
`
`commerCi§l_
`
`'infOrmation
`
`

`

`
`
`Memo
`
`To:
`
`Janice Soreth, MD.
`Director, Division of Anti—lnfective Drug Products
`HEB-520
`
`.
`
`From:
`
`Alina R Mahmud, R.Ph.
`
`Team Leader, Division of Medication Errors and Technical Support
`HPD—420
`
`1
`
`Through:
`
`Carol Holquist, R.Ph.
`Deputy Director, Division of Medication Errors and Technical Support
`BED-420
`
`Jerry Phillips, RPh.
`Associate Director, Office of Drug Safety
`HFD-400
`
`CC:
`
`Raquel Peat
`Project Manager
`HFD-520
`
`Date:
`
`September 17, 2003
`
`Re:
`
`ODS Consult 03-0233-1; Cubicin (Daptomycin for Injection); NDA 21-572.
`
`DMETS reviewed the proprietary name, Cubicin, on August 25, 2003, and found the unacceptable due to
`potential for with Ambien, Calcium, Libriurn, and Eulexin (see ODS consult 03-0233). However, the
`application was approved on September 12, 2003 with the proprietary name Cubicin.
`
`This memo is in response to a request from the Division of Anti-lnfective Dmg Products (HPD-SZO), the
`Division of Medication Errors and Technical Support (DMETS) conducted a review of the proposed risk
`management plan for the approved product Cubicin. The sponsor contends that they will manage any risk
`associated with possible confusion of prOprietary name with other medications through education, fair
`balanced promotion and surveillance.
`
`0 Page 1
`
`

`

`]. Sponsor‘s RMP proposal:
`
`We will educate health care professionals, particularly pharmacists, on the prOper use of Cubicin. The
`package insert will be the primary basis for education conceming the product and management of risk. The
`unique features of Cubicin, such as once daily dosing, will help clearly differentiate Cubicin from other
`medications. The dosing of for Cubicin is on a weight basis and requires reconstitution (with normal saline)
`and instillation of proper dose to a secondary l.V. bag. This multiple step process lends itself to several
`checks by the health care professions to ensure that the proper medication and dose is being prepared. This
`multiple step process lends itself to several checks by the health care professions to ensure that the proper
`medication and dose is being prepared. This is quite unlike Cleocin or clindarnycin phosphate.
`
`DMETS' response:
`
`DMETS acknowledges that the package insert provided with Cubicin instructs practitioners on the proper
`.-
`use; however, labels and labeling, will not prevent the misinterpretation of a prescription due to look-alike
`and’or sound-alike similarities. Once a prescription is read as a drug other than the intended drug product, in'
`this case Cubicin, dosing and reconstitution instructions contained within the package insert will not prevent
`a medication error from occurring. Therefore, the package insert should not be used as the primary basis for
`educating health care practitioners, especially pharmacists. Rather, health care practitioners should be
`educated in proactive manner with mailings of "Dear Healthcare Practitioner" letters, detailed by company
`sales representatives at the launch of the product, etc.
`
`Additionally, the Sponsor only references the currently marketed drug product, Cleocin, as having a potential
`. for confusiOn with Cubicin. DMETS refers the sponsor to ODS consult 03—0233 where the drug products
`Ambien, Calcium, Librium, and Eulexin are identified as having the potential for confusion with Cubicin.
`DMETS recommends that the sponsor acknowledge the potential for confusion with these products as well.
`
`2. Sponsor‘s RMP proposal:
`
`Cubist is willing to submit all medication error reports relating to proprietary name confusion, both potential
`and actual, that occur with Cubicin for a period of one year following the date of approval. All actual and
`potential errors will be submitted as a 15-day reports regardless of the patient outcome. Cubist agrees to
`evaluate these data with FDA and, if warranted, implement interventions to further minimize risk of
`medication errors.
`
`DMETS' Comment:
`
`DMETS commends the sponsor for taking the initiative in monitoring and reporting medication errors
`pertaining to Cubicin; however, DMETS recommends that the Sponsor continue this practice for a period of
`three years rather than one year. A time-period of one year does not provide the Agency with a true
`depiction of the potential for medication errors as it may take practitioners some time after the launch of the
`product to begin prescribing.
`
`DMETS would be willing to meet with the Division for further discussion, if needed. If you have fiirther
`questions or need clarification, please contact Sammie Beam, Project Manager, at 301-827-3242.
`...- ‘A .,
`__ “.1
`
`o Page 2
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Alina Mahmud
`
`9/22/03 09:57:20 AM
`DRUG SAFETY OFFICE REVIEWER
`
`Carol Holquist
`9/22/03 10:05:08 AM
`
`DRUG SAFETY OFFICE REVIEWER
`
`Jerry Phillips
`9/22/03 01:12:54 PM
`DRUG SAFETY OFFICE REVIEWER
`
`

`

`RedéétEd._J§:—fi
`
`page? of trade
`
`secfet and/0r
`
`'confidential
`
`IcommerCial.
`
`'infOrmation.
`
`

`

`’ CONSIDAAONF MOE
`
`Division Of Medication Errors and Technical Support
`Office of Drug Safety
`DMETS; HFD-420
`
`DATERECEIVED: AU: 20, 2003 DUE DATE: Am 30, 2003
`TO:
`
`ODS CONSULT: 03-0233
`
`Janice Soreth. MD.
`Director, Division of Anti-lnfective Drug Products
`_ HFD—520
`
`THROUGH:
`
`Raquel Peat
`Project Manager, Division of Anti~|nfective Drug Products
`HFD~520
`'
`'
`PRODUCT NAME:
`
`NDA SPONSOR:
`
`Cubicin
`
`'
`
`(Daptomycin for injection)
`
`Cubist Pharmaceuticals, Inc.
`
`500 mg/vial and 250 mg/vial NDA #: 21-572
`
`SAFETY EVALUATOR: Alina R. Mahmud. RPh.
`
`in response to a consult from the Division of Anti-lnfective Drug Products (HFD~520), the
`SUMMARY:
`Division of Medication Errors and Technical Support (DMETS) conducted a review of the proposed
`oprietary name “Cubicin" to determine the potential for confusion with approved proprietary and
`stablished names as well as unendin names.
`RECOMMENDATIONS:
`
`1.. DMETS does not recommend the use of the proprietary name, Cubicin.
`
`2. DDMAC finds the o-rorieta
`
`name, Cubicin, acce-table from a oromotional oversective.
`
`
`
`
`
` [g]
`'
`IS]
`'
`
`.
`
`Jerry Phillips. RPh
`Carol Holquist, RPh
`
`
`Associate Director
`Deputy Director,
`
`
`Office of Drug Safety
`Division of Medication Errors and Technical Support
`Center for Drug Evaluation and Research
`Office of Drug Safety
`
`
`Fax: 301—443-9664
`Food and Dru Administration
`7 Phone: 301-827-3242
`
`

`

`Division of Medication Errors and Technical Support
`Office of Drug Safety
`HFD-420; Parklawn Rm. 6-34
`
`Center for Drug Evaluation and Research
`
`PROPRIETARY NAME REVIEW
`
`DATE OF REVIEW:
`
`August 25, 2003
`
`NDA NUMBER:
`
`21-572-
`
`NAME OF DRUG:
`
`Cubicin (Daptomycin for Injection)
`500 mg/vial and 250 mg/vial
`
`NDA SPONSOR:
`
`Cubist Pharmaceuticals. Inc.
`
`I.
`
`INTRODUCTION
`
`This consult was written in response to a request from the Division of Anti-lnfective Drug
`Products (HFD-520), for assessment of the tradename “Cubicin", regarding potential name
`confusion with other proprietary or established drug names. Additionally, an independent
`
`trademark evaluation summary conducted by
`was submitted in support of the
`proposed proprietary name Cubicin.
`
`Cubicin is the second proposed proprietary name for this application. The sponsor had initially
`submitted the name "Cidecin" for review. DMETS found "Cidecin" unacceptable from a safety
`perspective on May 28, 2003 (see ODS consult 03-0001).
`
`PRODUCT INFORMATION
`
`Cubicin (Daptomycin for Injection).is indicated for the treatment of complicated skin and skin
`structure infections
`/
`.
`'
`'
`.
`/
`. A Cubicin dose of 4 mg/kg
`should be administered over a 30 minute period by intravenous infusion in 0.9% Sodium
`Chloride Injection, USP once every 24 hours for 7-14 days. Patients with a creatinine
`clearance of less than or equal to 40 mL/min should receive a 4 mg/kg dose every 48 hours.
`Cubicin will be supplied in single-use vials containing either 250 mg or 500 mg daptomycin as
`”a sterile, lyophilized powder. The contents of a 250 mg vial should be reconstituted with 5 mL
`of 0.9% sodium chloride injection, USP. The contents of a 500 mg vial should be reconstituted
`with 10 mL of 0.9% sodium chloride injection. USP, Reconstituted Cubicin should be further
`diluted with 0.9% sodium chloride injection, USP to be administered by intravenous infusion
`over a period of 30 minutes.
`
`

`

`RISK ASSESSMENT
`
`The DMETS medication error staff conducted a search of szeveral standard published drug
`product reference texts as well as several FDA databases2 for existing drug names which
`sound- alike or look-alike to "Cubicin" to a degree where potential confusion between drug
`names could occur under the usual clinical practice settings. The Saegis3 Pharma- In-Use
`database was searched for drug names with potential for confusion. An Expert Panel
`discussion was conducted to review all findings from the searches. In addition, DMETS
`conducted three prescription analysis studies, to simulate the prescription ordering process.
`
`A.
`
`EXPERT PANEL DISCUSSION
`
`An Expert Panel discussion was held by DMETS to gather professional opinions on the safety
`of the proprietary name, Cubicin. Potential concerns regarding drug marketing and promotion
`related to the proposed name were also discussed. This group is composed of DMETS
`Medication Errors Prevention Staff and representation from the Division of Drug Marketing,
`Advertising and Communications (DDMAC) The group relies on their clinical and other
`professional experiences and a number of standard references when making a decision on the
`acceptability of a proprietary name.
`
`1. Five product names were identified in the Expert Panel Discussion (EPD) that were thought
`to have potential for confusion with Cubicin. One product name, Kinesid, was identified
`following a search in the POCA‘ (Phonologic and Orthographic Computer Analysis)
`database. The drug product, Calcium, was identifiedIn DMETS’ prescription studies.
`These products are listed in Table 1, along with the dosage forms available and usual FDA-
`approved dosage.
`
`2. DDMAC did not have concerns about the name, Cubicin, with regard to promotional claims.
`
`Table 1. Potential sound-alike and look-alike names identified b DMETS Ex-ert Panel
`
`
`
`
`
`Product
`Name
`
`
`Dosage form(s), Generic
`name
`'
`
`Usual dose"
`
`Daptomycin for Injection
`500 mg/vial and 250 mg/vial
`. Single Use Vial
`
`
`4 mg/kg IV every 24 hours
`ESRD patients: 4 mg/kg IV every 48
`hours.
`
`
`
`
`
`Look-alike
`or Sound—
`
`alike
`
`
`
`
`
`
`
`patient according to the particular
`1 mg, 2 mg, 2.5 mg, 3 mg, 4
`
`
`
`
`
`patient’s PT/INR response to the
`mg, 5 mg, 6 mg, 7.5 mg, and
`drug. The dosage should be
`10 mg.
`
`
`
`
`adjusted based upon the patient's
`
`
`PT/INR.
`Warfarin Sodium Powder for
`
`
`
`ln‘ection, L o-hilized 5.4 m-
`
`
`Coumadin
`
`Warfarin Sodium Tablets,
`USP
`
`The dosage and administration of
`must be individualized for each
`
`Sound-alike
`
`' Facts and Comparisons. 2003, Facts and Comparisons, SL Louis, MO. hgp:Ilwfiu‘efactswebcom’indexasp MICROMEDEX Integrated Index,
`2003, MICROMEDEX, Inc., 6200 South Syracuse Way, Suite 300, Englewood, Colorado 80] I I—4740, which includes all products/databases
`within ChemKnovIIedge DrugKnouledge, and RegsKnowIedge Systems and PDR’Physician's Desk Reference (Medical Economics Company
`Inc. 2003).
`The Division of Medication Errors and Technical Support [DMETS] database of Proprietary name consultation requests, New Drug
`Approvals 98-03, and the electronic online version of the FDA Orange Book
`3 Data prodded by Thomson 8; Thomson‘s SAEGIS 1"“ OnIinc Service. available at “uw.thomson-thornson.com
`4 POCA (Phonologic and Onhographic Computer Analysis) database owned by the Di\'ision of Medication Error and Technical SupporL
`3
`
`

`

`Look-alike
`Usual dose‘
`
`
`Product
`
`Dosage form(s). Generic
`name
`or Sound-
`Name
`
`
`
`alike
`
`
`
`
`
`Daptomycin tor Injection
`Cubicin'
`
`500 mg/vial and 250 mg/vial
`
`
`
`Single Use Vial
`
`
`
`
`
`
`
`
`Quelicin
`Sound-alike
`Succinylcholine Chloride
`Short surgical procedures:
`Initial dose: 0.6 mg/kg lV.
`Injection 20 mg/mL and
`
`
`
`Maintenance dose: may range from
`50 mg/mL
`
`
`
`0.3 to 1.1 rfig/kg. Long surgical
`
`
`procedures:
`'
`.
`
`Average rate for an adult ranges
`
`between 2.5 and 4.3 mg/min.
`
`Solutions containing 0.1% to 0.2%
`
`(1 to 2 mg/ml) are commonly used
`
`for continuous lVdrip.
`
`Prolonged muscular relaxation:
`
`Prolonged muscular relaxation may
`
`be achieved with intermittent IV
`
`injections. Give an initial dose of 0.3
`
`to 1.1 mg/kg then give 0.04 to 0.07
`
`mg/kg at appropriate intervals to
`
`maintain the required degree of
`
`
`relaxation.
`
`
`
`
` Ambien
`
`
`Zolpidem Tartrate Tablets 5 mg
`and 10 mg
`
`
`‘- This preparation is no longer marketed. Sound-alike
`Phenobarbital, Hyoscyamine
`
`
`
`Sulfate, Atropine Sulfate,
`
`
`H oscine Sulfate
`
`
` Cleocin
`Oral: 150 mg to 450 mg every 6 hours
`
`lM/lV: 600 mg to 4.8 grams/day in 2 to 4
`
`
`divided doses
`
`
`Peds one month and older:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`4 mg/kg IV every 24 hours
`ESRD patients: 4 mg/kg IV every 48
`hours. .
`
`10 mg immediately before bedtime.
`
`Look-alike
`
`Sound-alike
`
`Clindamycin HCI
`Capsules
`75 mg, 150 mg, 300 mg
`Clindamycin Palmitate
`Oral solution 75 mg/5 mL
`Clindamycin Phosphate
`Injection 150 mg/mL
`Cream 2%
`
`Suppository 100 mg
`Gel. Lotion, Topical Solution,
`To-ical Sus-ension - 10 m- '
`Variety of Calcium salts and
`preparations
`
`
`
`
`
`
`
`
`
`350 mg to 450 mg/m2lday
`Neonates less than one month
`
`15 to 20 mg/kg/day in 3 to 4 divided
`doses
`
`Topical: apply twice daily
`
`Varies according to patient needs.
`
`
`
`Calcium
`
`Cubicin
`
`Herbal supplement
`-
`
`Used in the treatment of prostate
`cancer.
`
`_' Frequently used. not all inclusive
`
`
`
`
`Look-alike
`
`Look-alike,
`Sound-alike
`
`
`
`

`

`B. PRESCRIPTION ANALYSIS STUDIES
`
`1. Methodology for Cubicin studies
`
`Studies were conducted within FDA for the proposed proprietary name to determine the
`degree of confusion of Cubicin with other US. drug names due to similarity in visual
`appearance with handwritten prescriptions or verbal pronunciation of the drug name.
`These studies employed a total of 128 health care professionals (nurses, pharmacists, and
`physicians). This exercise was conducted in an attempt to simulate the prescription
`ordering process. DMETS staff members wrote inpatient and outpatient prescriptions for
`Cubicin, each consisting of a combination of marketed and unapproved drug products.
`These written prescriptions were optically scanned and one prescription was delivered via
`e-mail to each study participant.
`In addition, one DMETS staff member recorded a verbal
`outpatient prescription that was then delivered to a group of study participants via
`telephone voicemail. Each reviewer was then requested to provide an interpretation of the
`prescription via e-mail.
`
`HANDWRITTEN PRESCRIPTIONS
`
`VERBAL PRESCRIPTION
`
`Inpatient:
`
`Outpatient:
`
`these.”
`
`Jam
`
`Verbal:
`Dispense four vials of
`Cubicin, two hundred and
`fifty milligrams. The home
`nurse will be administering
`
`2. Results for Cubicin studies
`
`Results of these exercises are summarized below:
`
`-_ res-onses
`
`
`
`
`
`ln-atient
`
`Out-atient
`
`
`
`Verbal:
`
`Total:
`
`
`
`res-onse
`
`'
`
`res-onse
`
`
`
`
`18 (41%)
`
`3 (17%)
`
`'
`
`
`
`58 (73%)
`
`9 (16%)
`
`15 (83%)
`
`49 (84%)
`
`-
`
`
`
`
`
`
`

`

`
` /
`
`
`NO
`
`
`
`.a 0
`
`When examining the interpretations from the written inpatient prescriptions, 11 of 17
`(65%) respondents interpreted the name incorrectly.
`In addition, all 23 respondents
`(100%) from the written outpatient prescriptions interpreted the name incorrectly.
`Incorrect responses included Cabicin (4), Cabicur, Cubiis (2), Cubirin, Cubricin, Cubiia,
`Cibium, Cubrium (3), Culin's, Cabrica (2), Cabris, Cubrius, Cabica, Cabiun, Cubrien,
`Cubrism, Cubrisi, Cubien, Cubrison, and Cubiin. Two respondents provided the
`interpretation Ambien which is the name of a currently marketed drug product. Two
`additional participants commented that the name looks "strikingly" and "a lot" like
`Ambien. One respondent provided the interpretation "Calcium" which is the name of a
`currently marketed over~the counter vitamin and prescription drug product.
`
`Among the verbal outpatient Cidecin prescriptions, 15 of 18 (83%) respondents
`interpreted the name incorrectly. However, many of the misinterpretations were
`phonetically equivalent to "Cubicin”. These included Cubisan (2). Cubisin (3), Cubisan.
`Cubacin, Cubison (3). Tubersyn, Juvicen, Quebecin, Cubeson, and Qubicin. None of
`the interpretations are similar to a currently marketed drug product.
`
`SAFETY EVALUATOR RISK ASSESSMENT
`
`1. Sound-alike, Look-alike Names
`
`In reviewing the proprietary name “Cubicin", the primary concerns raised were related to
`look—alike and/or sound-alike names that are currently available in the US. marketplace:
`Coumadin, Cleocin, Quelicin, Ambien, Calcium, and Kinesed. Upon further review,
`DMETS discovered that Kinesed is no longer marketed. thus this name will not be
`discussed below. Additionally, the Expert Panel identified the name of an herbal
`supplement as Cubicin. which is identical to the proposed proprietary name. A search
`of online references and textbooks did not reveal a product with the name of Cubicin.
`The name Cubicin appears on the following website:
`http://wwwdotgharmacycom/uprostathtml.
`
`Prescription studies were conducted to simulate the prescription ordering process.
`this case, there was confirmation that Cubicin could be confused with Ambien and
`Calcium. Two respondents from the written outpatient prescription study provided the
`interpretation Ambien which is the name of a currently marketed drug product. Two
`additional participants commented that the name looks "strikingly" and "a lot" like
`Ambien. One respondent provided the interpretation "Calcium" which is the name of a
`currently marketed ov‘Er-‘the counter and presciption drug product. Although there are
`limitations to the predictive value of these studies, primarily due to sample size, we have
`acquired safety concerns due to the positive interpretation with this drug product. A
`
`In
`
`6
`
`

`

`.v"\
`
`positive finding in a study with a small sample size may indicate a high risk and potential
`for medication errors when extrapolated to the general US. population.
`
`Coumadin has potential for sound-alike confusion with Cubicin. Coumadin contains
`warfarin and is indicated for the prophylaxis and/or treatment of venous thrombosis and
`its extension, and pulmonary embolism. Coumadin is also indicated for the prophylaxis
`and/or treatment of the thromboembolic complications associated with atrial fibrillation
`and/or cardiac valve replacement. Lastly, Coumadin is indicated to reduce the risk of
`death, recurrent myocardial infarction, and thromboembolic events such as stroke or
`systemic embolization after myocardial infarction. Coumadin and Cubicin contain three
`syllables and share a similar prefix sound ("ku-"). The second syllable "ma" in
`Coumadin vs. "bi" in Cubicin is somewhat distinguishable. Although the last syllable
`"din" vs. "cin" end with "in", this suffix is distinguishable in sound due to the first letter
`difference. Coumadin and Cubicin overlap in dosage form; however, the drug products
`differ in dosage strength, dose and storage (room temperature vs. refrigeration).
`Additionally, PT/INR levels must be assessed frequently for patients on Coumadin.
`Given these differences and the lack of convincing sound-alike potential, the likelihood.
`for confusion is minimal.
`
`Quelicin has potential for sound-alike confusion with Cubicin. Quelicin contains
`succinylcholine chloride and is indicated as an adjunct to general anesthesia to
`facilitateendotracheal intubation, and to induceskeletal muscle relaxation during surgery
`or mechanical ventilation. Quelicin and Cubicin each contain three syllables and share
`the suffix "cin". However, the first and second syllable distinguishes one name from the
`other. Quelicin and Cubicin overlap in dosage form (injection) and route of
`administration (intravenous). Additionally, the products share a numerically similar dose
`(0.4 mg/kg vs. 4 mg/kg) and strength (50 mg/mL vs. 500 mg/vial). The products differ
`with respect to other characteristics such as storage (room temperature vs.
`refrigeration) and preparation (reconstituted vs. ready for injection). Additionally,
`Quelicin is to be used only if skilled in the management of artificial respiration and when
`facilities are instantly available for tracheal intubation and for providing adequate
`ventilation of the patient, including the administration of oxygen under positive pressure
`and the elimination of carbon dioxide. The clinician'must be prepared to assist or control
`respiration. DMETS believes that the potential for confusion is minimal especially since
`the products lack strong sound-alike potential.
`
`In fact, two study
`Ambien and Cubicin were found to have look-alike potential.
`participants from the written outpatient study misinterpreted Cubicin as Ambien while
`two other participants noted the similarity in appearance. Ambien is the proprietary
`name for zolpidem and is indicated for the short-term treatment of insomnia. When
`scripted, the first letter "A" in Ambien vs. "C" in Cubicin may look similar if the letter "A”
`is not fully looped. The remaining letters in each name look almost identical when
`scripted (see writing on page 8). Ambien and Cubicin differ in dosage form, route of
`administration, strength, dose, and storage (room temperature vs. refrigeration).
`Ambien is recommended for use at bedtime whereas Cubicin can be given at