CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`205029Orig1s000
`
`
`OTHER REVIEW(S)
`
`

`

`505(b)(2) ASSESSMENT
`
`A lication Information
`
`NDA # 205029
`
`NDA Supplement #2 8-
`
`Efficacy Supplement Type SE-
`
`associated with septic shock.
`
`Proprietary Name: N/A
`Established/Proper Name: epinephrine injection
`Dosage Form:
`injectable for IV administration
`hs:
`1 m mL
`
`Applicant: Belcher Pharmaceuticals
`
`Date of Receipt: 12/4/13 (resubmission received 1/29/ 14)
`
`PDUFA Goal Date: 7/29/14
`
`Action Goal Date (if different):
`7/25/14
`
`Proposed Indication(s): Epinephrine Injection USP. 1:1000 (1 mg/mL) is a solution for intravenous
`infusion indicated for use in increasing systemic arterial blood pressure in acute hypotensive states
`
`GENERAL INFORMATION
`
`1)
`
`Is this application for a recombinant or biologically-derived product and/or protein or peptide
`product OR is the applicant relying on a recombinant or biologically-derived product and/or
`protein or peptide product to support approval of the proposed product?
`
`YES|:I
`
`NOR]
`
`If ”YES "contact the (b)(2) review staflin the Immediate Oflice, Oflice ofNew Drugs.
`
`Reference ID: 3598038
`
`Page 1
`Version: Februmy 201 3
`
`

`

`INFORMATION PROVIDED VIA RELIANCE
`(LISTED DRUG OR LITERATURE)
`
`2) List the information essential to the approval of the proposed drug that is provided by reliance
`on our previous finding of safety and efficacy for a listed drug by reliance on published
`literature, or by reliance on a final OTC monograph. (If not clearly identified by the
`applicant, this information can usually be derived from annotated labeling.)
`
`Source of information* (e.g.,
`published literature, name of listed
`drug(s), OTC final drug
`monograph)
`published literature
`
`NDA 20800 Twinject
`
`Information relied-upon (e.g., specific
`sections of the application or labeling)
`
`To support the indication (to increase BP
`in septic shock)
`FDA’s previous finding of safety
`
`*each source of information should be listed on separate rows, however individual
`literature articles should not be listed separately
`
`3) Reliance on information regarding another product (whether a previously approved product
`or from published literature) must be scientifically appropriate. An applicant needs to
`provide a scientific “bridge” to demonstrate the relationship of the referenced and proposed
`products. Describe how the applicant bridged the proposed product to the referenced
`product(s). (Example: BA/BE studies)
`Because the product is injectable, and is titrated to effect for the new indication, we did not require
`BA/BE studies.
`
`RELIANCE ON PUBLISHED LITERATURE
`
`4)
`
`(a) Regardless of whether the applicant has explicitly stated a reliance on published literature
`to support their application, is reliance on published literature necessary to support the
`approval of the proposed drug product (i.e., the application cannot be approved without the
`published literature)?
` NO
` YES
`If “NO,” proceed to question #5.
`
`(b) Does any of the published literature necessary to support approval identify a specific (e.g.,
`brand name) listed drug product?
` NO
` YES
`If “NO”, proceed to question #5.
`If “YES”, list the listed drug(s) identified by name and answer question #4(c).
`
`(c) Are the drug product(s) listed in (b) identified by the applicant as the listed drug(s)?
` NO
` YES
`
`Reference ID: 3598038
`
`Page 2
`Version: February 2013
`
`

`

`RELIANCE ON LISTED DRUG(S)
`
`Reliance on published literature which identifies a specific approved (listed) drug constitutes
`reliance on that listed drug. Please answer questions #5-9 accordingly.
`
`5) Regardless of whether the applicant has explicitly cited reliance on listed drug(s), does the
`application rely on the finding of safety and effectiveness for one or more listed drugs
`(approved drugs) to support the approval of the proposed drug product (i.e., the application
`cannot be approved without this reliance)?
` YES
` NO
`If “NO,” proceed to question #10.
`
`6) Name of listed drug(s) relied upon, and the NDA #(s). Please indicate if the applicant
`explicitly identified the product as being relied upon (see note below):
`
`Name of Listed Drug
`
`NDA #
`
`Twinject
`
`20800
`
`Did applicant
`specify reliance on
`the product? (Y/N)
`Yes
`
`Applicants should specify reliance on the 356h, in the cover letter, and/or with their patent
`certification/statement. If you believe there is reliance on a listed product that has not been
`explicitly identified as such by the applicant, please contact the (b)(2) review staff in the
`Immediate Office, Office of New Drugs.
`
`7)
`
`If this is a (b)(2) supplement to an original (b)(2) application, does the supplement rely upon
`the same listed drug(s) as the original (b)(2) application?
` NO
` YES
` N/A
`If this application is a (b)(2) supplement to an original (b)(1) application or not a supplemental
`application, answer “N/A”.
`If “NO”, please contact the (b)(2) review staff in the Immediate Office, Office of New Drugs.
`
`8) Were any of the listed drug(s) relied upon for this application:
`a) Approved in a 505(b)(2) application?
` NO
` YES
`If “YES”, please list which drug(s).
`Name of drug(s) approved in a 505(b)(2) application: NDA 20800 Twinject
`
`b) Approved by the DESI process?
` NO
` YES
`If “YES”, please list which drug(s).
`Name of drug(s) approved via the DESI process:
`
`c) Described in a final OTC drug monograph?
` YES
`
` NO
`
`Page 3
`Version: February 2013
`
`Reference ID: 3598038
`
`

`

`If “YES”, please list which drug(s).
`
`Name of drug(s) described in a final OTC drug monograph:
`
`d) Discontinued from marketing?
` NO
` YES
`If “YES”, please list which drug(s) and answer question d) i. below.
`If “NO”, proceed to question #9.
`
`Name of drug(s) discontinued from marketing:
`
`i) Were the products discontinued for reasons related to safety or effectiveness?
` NO
` YES
`(Information regarding whether a drug has been discontinued from marketing for
`reasons of safety or effectiveness may be available in the Orange Book. Refer to
`section 1.11 for an explanation, and section 6.1 for the list of discontinued drugs. If
`a determination of the reason for discontinuation has not been published in the
`Federal Register (and noted in the Orange Book), you will need to research the
`archive file and/or consult with the review team. Do not rely solely on any
`statements made by the sponsor.)
`
`9) Describe the change from the listed drug(s) relied upon to support this (b)(2) application (for
`example, “This application provides for a new indication, otitis media” or “This application
`provides for a change in dosage form, from capsule to solution”).
`
`This application provides for a new indication, to increase BP in septic shock.
`
`The purpose of the following two questions is to determine if there is an approved drug product
`that is equivalent or very similar to the product proposed for approval that should be referenced
`as a listed drug in the pending application.
`
`The assessment of pharmaceutical equivalence for a recombinant or biologically-derived product
`and/or protein or peptide product is complex. If you answered YES to question #1, proceed to
`question #12; if you answered NO to question #1, proceed to question #10 below.
`
`10) (a) Is there a pharmaceutical equivalent(s) to the product proposed in the 505(b)(2)
`application that is already approved (via an NDA or ANDA)?
`
`(Pharmaceutical equivalents are drug products in identical dosage forms intended for the
`same route of administration that: (1) contain identical amounts of the identical active drug
`ingredient, i.e., the same salt or ester of the same therapeutic moiety, or, in the case of
`modified release dosage forms that require a reservoir or overage or such forms as prefilled
`syringes where residual volume may vary, that deliver identical amounts of the active drug
`ingredient over the identical dosing period; (2) do not necessarily contain the same inactive
`ingredients; and (3) meet the identical compendial or other applicable standard of identity,
`strength, quality, and purity, including potency and, where applicable, content uniformity,
`disintegration times, and/or dissolution rates. (21 CFR 320.1(c), FDA’s “Approved Drug
`Products with Therapeutic Equivalence Evaluations” (the Orange Book)).
`
`Note that for proposed combinations of one or more previously approved drugs, a pharmaceutical
`equivalent must also be a combination of the same drugs.
`
`Reference ID: 3598038
`
`Page 4
`Version: February 2013
`
`

`

` YES
`
` NO
`
`If “NO” to (a) proceed to question #11.
`If “YES” to (a), answer (b) and (c) then proceed to question #12.
`
`(b) Is the pharmaceutical equivalent approved for the same indication for which the
`505(b)(2) application is seeking approval?
` YES
`
`
`(c) Is the listed drug(s) referenced by the application a pharmaceutical equivalent?
` YES
` NO
` N/A
`
` NO
`
`If this application relies only on non product-specific published literature, answer “N/A”
`If “YES” to (c) and there are no additional pharmaceutical equivalents listed, proceed to
`question #12.
`If “NO” or if there are additional pharmaceutical equivalents that are not referenced by the
`application, list the NDA pharmaceutical equivalent(s); you do not have to individually list all
`of the products approved as ANDAs, but please note below if approved approved generics are
`listed in the Orange Book. Please also contact the (b)(2) review staff in the Immediate Office,
`Office of New Drugs.
`
`Pharmaceutical equivalent(s):
`
`11) (a) Is there a pharmaceutical alternative(s) already approved (via an NDA or ANDA)?
`
`(Pharmaceutical alternatives are drug products that contain the identical therapeutic moiety, or its
`precursor, but not necessarily in the same amount or dosage form or as the same salt or ester. Each
`such drug product individually meets either the identical or its own respective compendial or other
`applicable standard of identity, strength, quality, and purity, including potency and, where applicable,
`content uniformity, disintegration times and/or dissolution rates. (21 CFR 320.1(d)) Different dosage
`forms and strengths within a product line by a single manufacturer are thus pharmaceutical
`alternatives, as are extended-release products when compared with immediate- or standard-release
`formulations of the same active ingredient.)
`
`Note that for proposed combinations of one or more previously approved drugs, a pharmaceutical
`alternative must also be a combination of the same drugs.
`
` NO
` YES
`If “NO”, proceed to question #12.
`
`(b) Is the pharmaceutical alternative approved for the same indication for which the
`505(b)(2) application is seeking approval?
` YES
`
` NO
`
`(c) Is the approved pharmaceutical alternative(s) referenced as the listed drug(s)?
` YES
` NO
` N/A
`
`If this application relies only on non product-specific published literature, answer “N/A”
`If “YES” and there are no additional pharmaceutical alternatives listed, proceed to question
`#12.
`
`Reference ID: 3598038
`
`Page 5
`Version: February 2013
`
`

`

`If “NO” or if there are additional pharmaceutical alternatives that are not referenced by the
`application, list the NDA pharmaceutical alternative(s); you do not have to individually list all
`of the products approved as ANDAs, but please note below if approved generics are listed in
`the Orange Book. Please also contact the (b)(2) review staff in the Immediate Office, Office of
`New Drugs.
`
`Pharmaceutical alternative(s):
`NDA 201739 AUVI-Q
`NDA 19430 EPIPEN
`NDA 204200 ADRENALIN (approved after the Belcher application was submitted)
`
`PATENT CERTIFICATION/STATEMENTS
`
`12) List the patent numbers of all unexpired patents listed in the Orange Book for the listed
`drug(s) for which our finding of safety and effectiveness is relied upon to support approval of
`the (b)(2) product.
`
`Listed drug/Patent number(s): NDA 20800 Twinject
`Patent # 7297136
`Patent # 7621891
`
` No patents listed
`
`proceed to question #14
`
`13) Did the applicant address (with an appropriate certification or statement) all of the unexpired
`patents listed in the Orange Book for the listed drug(s) relied upon to support approval of the
`(b)(2) product?
` NO
` YES
`If “NO”, list which patents (and which listed drugs) were not addressed by the applicant.
`
`Listed drug/Patent number(s):
`
`14) Which of the following patent certifications does the application contain? (Check all that
`apply and identify the patents to which each type of certification was made, as appropriate.)
`
`No patent certifications are required (e.g., because application is based solely on
`published literature that does not cite a specific innovator product)
`
`21 CFR 314.50(i)(1)(i)(A)(1): The patent information has not been submitted to
`FDA. (Paragraph I certification)
`
`21 CFR 314.50(i)(1)(i)(A)(2): The patent has expired. (Paragraph II certification)
`
`Patent number(s):
`
`21 CFR 314.50(i)(1)(i)(A)(3): The date on which the patent will expire. (Paragraph
`III certification)
`
`Patent number(s):
`
`Expiry date(s):
`
`Page 6
`Version: February 2013
`
`Reference ID: 3598038
`
`

`

`21 CFR 314.50(i)(1)(i)(A)(4): The patent is invalid, unenforceable, or will not be
`infringed by the manufacture, use, or sale of the drug product for which the
`application is submitted. (Paragraph IV certification). If Paragraph IV certification
`was submitted, proceed to question #15.
`
`21 CFR 314.50(i)(3): Statement that applicant has a licensing agreement with the
`NDA holder/patent owner (must also submit certification under 21 CFR
`314.50(i)(1)(i)(A)(4) above). If the applicant has a licensing agreement with the
`NDA holder/patent owner, proceed to question #15.
`
`21 CFR 314.50(i)(1)(ii): No relevant patents.
`
`
`21 CFR 314.50(i)(1)(iii): The patent on the listed drug is a method of use patent
`and the labeling for the drug product for which the applicant is seeking approval
`does not include any indications that are covered by the use patent as described in
`the corresponding use code in the Orange Book. Applicant must provide a
`statement that the method of use patent does not claim any of the proposed
`indications. (Section viii statement)
`
`Patent number(s):
`Method(s) of Use/Code(s):
`
`15) Complete the following checklist ONLY for applications containing Paragraph IV
`certification and/or applications in which the applicant and patent holder have a licensing
`agreement:
`
`(a) Patent number(s):
`
`7297136
`7621891
`(b) Did the applicant submit a signed certification stating that the NDA holder and patent
`owner(s) were notified that this b(2) application was filed [21 CFR 314.52(b)]?
` NO
` YES
`If “NO”, please contact the applicant and request the signed certification.
`
`(c) Did the applicant submit documentation showing that the NDA holder and patent
`owner(s) received the notification [21 CFR 314.52(e)]? This is generally provided in the
`form of a registered mail receipt.
` NO
` YES
`If “NO”, please contact the applicant and request the documentation.
`
`(d) What is/are the date(s) on the registered mail receipt(s) (i.e., the date(s) the NDA holder
`and patent owner(s) received notification):
`
`Date(s): 2/27/13
`
`Note, the date(s) entered should be the date the notification occurred (i.e., delivery
`date(s)), not the date of the submission in which proof of notification was provided
`
`(e) Has the applicant been sued for patent infringement within 45-days of receipt of the
`notification listed above?
`
`Page 7
`Version: February 2013
`
`Reference ID: 3598038
`
`

`

`Note that you may need to call the applicant (after 45 days of receipt of the notification)
`to verify this information UNLESS the applicant provided a written statement from the
`notified patent owner(s) that it consents to an immediate effective date of approval.
`
`YES
`
`NO
`
`Patent owner(s) consent(s) to an immediate effective date of
`approval
`
`Reference ID: 3598038
`
`Page 8
`Version: February 2013
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`RUSSELL FORTNEY
`07/23/2014
`
`Reference ID: 3598038
`
`

`

`LABEL AND LABELING MEMO
`Division of Medication Error Prevention and Analysis (DMEPA)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`*** This document contains proprietary information that cannot be released to the public***
`
`Date of This Review:
`July 16, 2014
`Requesting Office or Division:
`Division of Cardiovascular & Renal Products (DCRP)
`Application Type and Number: NDA 205029
`Product Name and Strength:
`Epinephrine Injection USP, 1 mg/mL (1:1,000)
`Product Type:
`Single Ingredient Product
`Rx or OTC:
`Rx
`Applicant/Sponsor Name:
`Belcher Pharmaceuticals, LLC
`Submission Date:
`July 1, 2014
`OSE RCM #:
`2014-310-1
`DMEPA Primary Reviewer:
`Janine Stewart, PharmD
`DMEPA Team Leader:
`Chi-Ming (Alice) Tu, PharmD
`
`Reference ID: 3594202
`
`1
`
`

`

`REASON FOR REVIEW
`1
`This review evaluates the revised container label and carton labeling for Epinephrine Injection
`USP, 1 mg/mL (1:1,000), NDA 205029 received on July 1, 2014 from the Applicant. The Division
`of Medication Error Prevention and Analysis (DMEPA) previously reviewed the labels and
`labeling under OSE Review #2014-310 dated May 28, 2014 (See DARRTS NDA 205029 Labeling
`Review dated 5/29/2014).
`
`2 MATERIALS REVIEWED
`
`The Division of Medication Error Prevention and Analysis (DMEPA) reviewed the following:
`
`! Container Label submitted July 1, 2014
`! Carton Labeling submitted July 1, 2014
`We compared the revised labels and labeling with our recommendations provided in OSE
`Review #2014-310 dated May 28, 2014 to assess whether the revised labels and labeling
`address our concerns from a medication error perspective.
`
`CONCLUSION & RECOMMENDATIONS
`3
`Belcher Pharmaceuticals, LLC incorporated all of our recommendations so the revised labels
`and labeling adequately address our concerns from a medication error perspective. We have
`no additional comments at this time.
`Please copy the Division of Medication Error Prevention and Analysis on any communication to
`the Applicant with regard to this review. If you have further questions or need clarifications,
`please contact OSE Regulatory Project Manager: Cherye Milburn, at 301-796-2084.
`
`Reference ID: 3594202
`
`2
`
`

`

`APPENDIX A. LABELS AND LABELING
`
`A.1
`
`List of Labels and Labeling Reviewed
`
`We reviewed the following Epinephrine Injection USP, 1 mg/mL (1:1,000) container label and
`
`carton labeling submitted by Belcher Pharmaceuticals, LLC on July 1, 2014.
`
`0 Container label
`
`0 Carton labeling
`
`A.2
`
`Label and Labeling Images
`
`Container Label
`
`
`
`Reference ID: 3594202
`
`

`

`Carton Labeling
`
`
`
`Reference ID: 3594202
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`JANINE A STEWART
`07/16/2014
`
`CHI-MING TU
`07/16/2014
`
`Reference ID: 3594202
`
`

`

`LABEL AND LABELING REVIEW
`Division of Medication Error Prevention and Analysis (DMEPA)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`*** This document contains proprietary information that cannot be released to the public***
`
`Date of This Review:
`May 28, 2014
`Requesting Office or Division:
`Division of Cardiovascular & Renal Products (DCRP)
`Application Type and Number: NDA 205029
`Product Name and Strength:
`Epinephrine Injection USP, 1 mg/mL (1:1,000)
`Product Type:
`Single Ingredient Product
`Rx or OTC:
`Rx
`Applicant/Sponsor Name:
`Belcher Pharmaceuticals, LLC
`Submission Date:
`January 29, 2014
`OSE RCM #:
`2014-310
`DMEPA Primary Reviewer:
`Janine Stewart, PharmD
`DMEPA Team Leader:
`Lisa Khosla, PharmD, MHA
`
`Reference ID: 3514240
`
`1
`
`

`

`1
`
`REASON FOR REVIEW
`
`As part of the approval of this new drug application, this review evaluates the proposed
`
`container label, carton, and insert labeling for Epinephrine Injection USP, 1 mg/mL (1:1,000) for
`
`areas of vulnerability that can lead to medication errors.
`
`2 MATERIALS REVIEWED
`
`We considered the materials listed in Table 1 for this review. The Appendices provide the
`methods and results for each material reviewed.
`
`Table 1. Materials Considered for this Label and Labeling Review
`
`Material Reviewed
`
`Appendix Section (for Methods
`
`and Results)
`
`G N
`
`Product Information/Prescribing Information
`
`FDA Adverse Event Reporting System (FAERS)
`
`Previous DMEPA Reviews
`
`Human Factors Study
`
`ISMP Newsletters
`
`Labels and Labeling
`
`/A=not applicable for this review
`
`Reference ID: 3514240
`
`

`

`OVERALL ASSESSMENT OF THE MATERIALS REVIEWED
`3
`In 2012, during the previous review, there were discussions between the Division, DMEPA,
`USP, and ISMP regarding the presentation of the ratio since there were medication error cases
`which reported confusion between the epinephrine ratio, and one case resulting in death of a
`patient. DMEPA and ISMP identified cases that would warrant the removal of the ratio from
`the container and carton labeling, and as such ISMP tried to petition USP for the removal of the
`ratio from the labeling. USP monograph has no requirement to label epinephrine with a ratio
`and deferred back to FDA to decide if the ratio would be necessary on the labeling. At that
`time, the Division wanted to keep the ratio on the labeling since some practicing doctors still
`use the ratio for prescribing and believes that removal of the ratio would introduce more errors
`than it would mitigate.
`
`During our current review of Epinephrine Injection USP, 1 mg/mL (1:1,000) under NDA 205029,
`we identified additional Institute of Safety Medication Practices (ISMP) reports of confusion
`between the ratio and strength, including 2 death cases. DMEPA notified the Division of these
`findings and asked for an update on the Division’s position on retaining the ratio expression.
`The Division remains in favor of retaining the ratio expression.
`
`DMEPA performed a risk assessment of the proposed full prescribing information, container
`label, and carton labeling to identify deficiencies that may lead to medication errors and areas
`for improvement. We also compared the labels and labeling with the recommendations
`provided in OSE Review # 2013-83 for NDA 205029, dated August 7, 2013. While the majority
`of the recommendations from the previous review have been implemented, we note that the
`proposed container label and carton labeling present the established name in all capital letters,
`which may diminish the readability of the product name. We also note that the prominence of
`the primary strength expression in milligrams per milliliter is diminished by the use of
`parentheses, which makes the secondary expression of the ratio strength more prominent.
`This is inconsistent with the way the mg/mL strength and the ratio strength are expressed in
`the full prescribing information. Additionally, we note the absence of the “Usual Dose:”
`statement on the container label and the carton labeling. Furthermore, we note the statement
` can be revised to eliminate redundancy of information on
`the container label and the carton labeling. Thus, we have provided recommendations in
`Section 4 to address these deficiencies.
`
`CONCLUSION & RECOMMENDATIONS
`4
`DMEPA concludes that the proposed container label and carton labeling can be improved to
`increase the readability and prominence of important information on the label and labeling to
`promote the safe use of the product and to mitigate any confusion.
`
`Reference ID: 3514240
`
`3
`
`(b) (4)
`
`

`

`Based on this review, DMEPA recommends the following be implemented prior to approval of
`this NDA:
`
`4.1
`
`RECOMMENDATIONS FOR THE APPLICANT
`
`A. General Comments for Container Label and Carton Labeling
`
`1. Revise the presentation of the established name from all caps (i.e. EPINEPHRINE
`INJECTION, USP) to title case (i.e. Epinephrine Injection, USP) to improve readability of
`the name. Words set in title case are easier to read than the rectangular shape that is
`formed by words set in all capital letters.
`
`2. Revise the statement of strength to increase clarity and mitigate confusion between the
`product strength and product ratio. Express the mg/mL and ratio strength expressions
`in the manner that is consistent with the way they are expressed in the Full Prescribing
`Information by placing the parentheses around the ratio strength. For example:
`
`Epinephrine Injection, USP
`1 mg/mL
`(1:1,000)
`
`3.
`
` to “Dilute before use.”
`
`
`revise the statement
`
`B. Carton Labeling
` statement from the principal display panel to reduce
`1. Remove the
`clutter and eliminate redundancy of information. It also appears on the top panel.
`
`2.
`
`Include a “Usual Dose: See insert labeling” statement on the principal display panel per
`21 CFR 201.55.
`
`C. Container Label
`1. Revise the
`
` statement on the side panel to
`
`
`
`APPENDICES: METHODS & RESULTS FOR EACH MATERIALS REVIEWED
`
`APPENDIX A. PRODUCT INFORMATION/PRESCRIBING INFORMATION
`Table 2 presents relevant product information for Epinephrine Injection, USP that Belcher
`Pharmaceuticals, LLC submitted on January 29, 2014.
`
`4
`
`Reference ID: 3514240
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Table 2. Relevant Product Information for Epinephrine Injection, USP
`
`Active Ingredient
`
`Epinephrine Injection, USP
`
`To increase mean arterial blood pressure in hypotension
`
`associated with septic shock
`
`Route of Administration
`
`Intravenous Infusion
`
`Dosage Form
`
`1mg] mL( 1:1,000)
`
`Dose and Frequency
`
`Suggested intravenous infusion rate of 0.05 mcg/kg/min to
`
`
`
`2 mcg/kg/min, titrated closely with minimum close as
`
`needed to achieve MAP goal, e.g., 2 70 mmHg. Wean
`
`dosage down incrementally over time, after stabilization.
`
`Dilute Epinephrine (e.g., 1:1000) in 5% dextrose solution or
`
`5% dextrose in sodium solution prior to infusion.
`
`Epinephrine should be infused into a large vein, e.g.,
`
`antecubital or femoral vein, and not with a catheter tie-in
`
`technique
`
`A sterile solution containing 1 mg epinephrine as the
`
`hydrochloride in each 1 mL ampule. Epinephrine contains
`
`no preservatives, such as sulfites. Supplied in a box of 10
`
`ampules (NDC 62250-xxxx-xx)
`
`Protect from light until ready to use. Do not refrigerate.
`
`Protect from freezing. Store at room temperature, between
`nu) Protect from alkalis and
`
`oxidizing agents. Solutions for intravenous use should be
`
`inspected visually for particulate matter and discoloration,
`
`whenever solution and container permit. Do not use after
`
`the expiration date.
`
`The primary packaging is Type I (USP) 2 mL clear colorless
`
`glass ampoules with score-break. The ampoules have an
`
`adhesive label and are packed, with a leaflet, in
`
`lithographed cardboard-boxes. The cardboard-box contains
`
`10 ampoules of Epinephrine USP 1:1000, 1 mg/mL,
`
`How Supplied
`
`Container Closure
`
`preservative free and sulphite free.
`
`APPENDIX 8. FDA ADVERSE EVENT REPORTING SYSTEM (FAERS)
`8.1 Methods
`
`Reference ID: 3514240
`
`

`

`We searched the FDA Adverse Event Reporting System (FAERS) on March 21, 2014 using the
`
`criteria in Table 3, and then individually reviewed each case. We limited our analysis to cases
`
`that described errors possibly associated with the label and labeling. We used the NCC MERP
`
`Taxonomy of Medication Errors to code the type and factors contributing to the errors when
`sufficient information was provided by the reporter2
`
`Table 3: FAERS Search Strategy
`
`Date Range
`
`April 30, 2013 (date of last FAERS search in OSE
`
`Review #2013—45) to March 21, 2014
`
`Drug Names
`
`Epinephrine, Epinephrine Hydrochloride [active
`
`ingredient]
`
`MedDRA Search Strategy
`
`Medication Errors [HLGT]
`
`Product Packaging Issues [HLT]
`
`Product Label Issues [HLT]
`
`Product Quality Issues (NEC)[HLT]
`
`|VDRP;|VES;IVP;|VPB;IVPICC;INJ;INJECTION;1V
`
`administration (inciuded a"
`
`NOS;|VB;|VBOL;IVBOLUS;IVD;IVDP;IVDR|P;
`
`intravenous terms)
`
`3.2
`
`Results
`
`Our search identified 13 cases, of which 4 described errors possibly associated with the current
`
`labels and labeling for Epinephrine. The search was limited by the intravenous route of
`
`administration to eliminate cases involving EpiPen (which is approved for the treatment of
`
`allergic reactions and administered by intramuscular injection) and racemic epinephrine (which
`
`is approved for the treatment of allergic reactions, asthma and croup syndrome and
`
`administered by inhalation).
`
`Each case was reviewed for relevancy and duplication. After initial review, 7 duplicate cases
`
`and 2 drug interaction reports were excluded from further analysis. Following exclusions, 4
`
`medication errors remain for our detailed analysis:
`
`0 Wrong Route of Administration (n=3)
`
`2 The National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP) Taxonomy of
`Medication Errors. Website http://www.nccmerp.org/pdf/tax02001—07—31.pdf.
`
`6
`
`Reference ID: 3514240
`
`

`

`We identified 3 cases as wrong route of administration medication errors. The first case
`involved racemic epinephrine (1:10,000) intended for inhalation but given intravenously
`to a 13- month old child with croup. The nurse recognized that she had inadvertently
`administered the racemic epinephrine by intravenous injection instead of by the
`intended nebulized route. The child required continued emergency care but was
`successfully extubated 80 hours later. No contributing factors were reported and no
`additional information was provided.
`The second and third case reported epinephrine being administered intravenously
`instead of through intravenous infusion or by subcutaneous route. The second case
`reported the nurse rushing and inadvertently administered 0.3 mL of epinephrine
`intravenously instead of subcutaneously as ordered when patient was presented with
`anaphylactic reaction. The patient immediately experienced projectile vomiting and
`became acutely diaphoretic and uncomfortable. The patient was transferred to a
`critical care bed for further evaluation.
`The third case involved a