CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`204592Orig1s000
`
`
`OTHER REVIEW(S)
`
`

`

`505(b)(2) ASSESSMENT
`
`NDA # 204592
`
`NDA Supplement #: 8-
`
`Efficacy Supplement Type SE-
`
`Proposed Indication(s): treatment of acute pain of mild to moderate
`
`Proprietary Name: Zorvolex
`Established/Proper Name: diclofenac
`Dosage Form: Capsules
`Stren S: 18m and 35 m_
`
`Applicant: Iroko Pharmaceuticals
`
`Date of Receipt: December 20, 2012
`
`PDUFA Goal Date: October 20, 2013
`
`RPM: Swati Patwardhan
`
`Action Goal Date (if different):
`October 18, 2013
`
`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
`
`NOIZ
`
`If “YES “contact the (b) (2) review staflin the Immediate Oflice, Ofiice ofNew Drugs.
`
`Reference ID: 3392878
`
`Page 1
`Version: Febrmuy 2013
`
`

`

`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)
`NDA 020142 Cataflam 50 mg
`
`Information relied-upon (e.g., specific
`sections of the application or labeling)
`
`FDA’s previous finding of safety and
`efficacy
`
`*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)
`
`Two Phase 1 studies were conducted.
`
`Study DICI-12-07, a pivotal study, was a randomized, single-dose, five-way crossover,
`relative bioavailability study of Zorvolex™ (diclofenac
`) capsules 18
`mg and 35 mg and cataflam® 50 mg tablets, in healthy subjects under fed and fasting
`conditions, conducted with commercial scale formulation.
`
`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)?
` YES
` NO
`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?
` YES
` NO
`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)?
` YES
` NO
`
`Page 2
`Version: February 2013
`
`Reference ID: 3392878
`
`(b) (4)
`
`

`

`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 #
`
`Cataflam
`
`020142
`
`Did applicant
`specify reliance on
`the product? (Y/N)
`Y
`
`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:
`
`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?
` NO
` YES
`If “YES”, please list which drug(s).
`
`Page 3
`Version: February 2013
`
`Reference ID: 3392878
`
`

`

`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?
` YES
` NO
`(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”).
`
`The proposed drug product is a reformulation of diclofenac with reduced particle size
`and is the free acid and not a salt. Cataflam is the potassium diclofenac salt. The
`proposed drug product is 20% lower in strength compared to the listed drug, Cataflam.
`The application also provides for a change in dosage from a tablet to a capsule.
`
`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)).
`
`Reference ID: 3392878
`
`Page 4
`Version: February 2013
`
`

`

`Note that for proposed combinations of one or more previously approved drugs, a pharmaceutical
`equivalent must also be a combination of the same drugs.
`
` 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?
` N/A
` YES
` NO
`
` 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)?
` N/A
` YES
` NO
`
`If this application relies only on non product-specific published literature, answer “N/A”
`
`Page 5
`Version: February 2013
`
`Reference ID: 3392878
`
`

`

`If “YES” and there are no additional pharmaceutical alternatives listed, proceed to question
`#12.
`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 021234 Flector by Inst Biochem
`NDA 022202 Zipsor by Depomed
`NDA 022165 Cambia by Nautilus Neuroscienc
`NDA 021005 Solaraze by Fougera Pharms
`NDA 022122 Voltaren y Novartis
`NDA 020947 Pennsaid by Mallinckrodt
`NDA 020607 Arthrotec by GD Searle LLC
`NDA 020142 Cataflam by Novartic Pharm
`And approved generics
`
`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):
`
` 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)
`
`Page 6
`Version: February 2013
`
`Reference ID: 3392878
`
`

`

`Patent number(s): N/A (There are no unexpired patents)
`
`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):
`
`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):
`(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)]?
` YES
` NO
`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):
`
`Page 7
`Version: February 2013
`
`Reference ID: 3392878
`
`

`

`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?
`
`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: 3392878
`
`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/
`----------------------------------------------------
`
`SWATI A PATWARDHAN
`10/18/2013
`
`Reference ID: 3392878
`
`

`

`SEALD Director Sign—Off Review of the End—of—Cycle Prescribing
`Information: Outstanding Format Deficiencies
`
`' Product Title
`
`Applicant
`
`' ZORVOLEX (diclofenac) capsules, for oral use
`
`Iroko Pharmaceuticals, LLC
`
`Application/Supplement Number
`_ Type of Application
`Indication(s)
`_ Established Pharmacologic Classl
`
`. NDA 204592
`' Original
`_ For treatment of mild to moderate acute pain in adults
`‘ Nonsteroidal Anti-inflammatory Drug
`
`_ Office/Division
`Division Project Manager
`_ Date FDA Received Application
`Goal Date
`
`_ ODE II/DAAAP
`' Swati Patwardhan
`_ December 20, 2012
`_ October 20, 2013
`
`Date PI Received by SEALD
`p SEALD Review Date
`SEALD Labeling Reviewer
`_ SEALD Division Director
`PI = prescribing information
`1 The established pharmacologic class (EPC) that appears in the final draft PI.
`
`_ October 17, 2013
`' October 17, 2013
`_ Abimbola Adebowale
`_ Laurie Burke
`
`This Study Endpoints and Labeling Development (SEALD) Director Sign-Off review of the end-of-
`cycle, draft prescribing information (PI) for critical format elements reveals outstanding labeling
`format deficiencies that must be corrected before the final PI is approved. Afier these outstanding
`labeling format deficiencies are corrected, the SEALD Director will have no objection to the
`approval of this PI.
`
`The critical format elements include labeling regulation (21 CFR 201.56 and 201.57), labeling
`guidance, and best labeling practices (see list below). This review does not include every
`regulation or guidance that pertains to P1 format.
`
`Guide to the Selected Requirements of Prescribing Information (SRP!) Checklist: For each SRPI
`item, one of the following 3 response options is selected:
`
`0 NO: The PI does not meet the requirement for this item (deficiency).
`YES: The PI meets the requirement for this item (not a deficiency).
`0 N/A (not applicable): This item does not apply to the specific PI under review.
`
`Reference ID: 3392126
`
`Page 1 of8
`
`

`

`Selected Requirements of Prescribing Information
`
`Highlights (HL)
`
`YES
`
`YES
`
`YES
`
`NO
`
`YES
`
`YES
`
`GENERAL FORMAT
`1. Highlights (HL) must be in two-column format, with ½ inch margins on all sides and in a
`minimum of 8-point font.
`Comment:
`
`2. The length of HL must be less than or equal to one-half page (the HL Boxed Warning does not
`count against the one-half page requirement) unless a waiver has been is granted in a previous
`submission (i.e., the application being reviewed is an efficacy supplement).
`Instructions to complete this item: If the length of the HL is less than or equal to one-half page
`then select “YES” in the drop-down menu because this item meets the requirement. However, if
`HL is longer than one-half page:
` For the Filing Period (for RPMs)
` For efficacy supplements: If a waiver was previously granted, select “YES” in the drop-
`down menu because this item meets the requirement.
` For NDAs/BLAs and PLR conversions: Select “NO” in the drop-down menu because this
`item does not meet the requirement (deficiency). The RPM notifies the Cross-Discipline
`Team Leader (CDTL) of the excessive HL length and the CDTL determines if this
`deficiency is included in the 74-day or advice letter to the applicant.
` For the End-of Cycle Period (for SEALD reviewers)
` The SEALD reviewer documents (based on information received from the RPM) that a
`waiver has been previously granted or will be granted by the review division in the
`approval letter.
`Comment:
`3. All headings in HL must be presented in the center of a horizontal line, in UPPER-CASE letters
`and bolded.
`Comment:
`4. White space must be present before each major heading in HL.
`Comment: There is no white space before the Product Title heading in HL. Insert white space.
`5. Each summarized statement in HL must reference the section(s) or subsection(s) of the Full
`Prescribing Information (FPI) that contains more detailed information. The preferred format is
`the numerical identifier in parenthesis [e.g., (1.1)] at the end of each information summary (e.g.
`end of each bullet).
`Comment:
`6. Section headings are presented in the following order in HL:
`Section
`Required/Optional
`Required
` Highlights Heading
`Required
` Highlights Limitation Statement
`Required
` Product Title
`Required
` Initial U.S. Approval
`Required if a Boxed Warning is in the FPI
` Boxed Warning
`
`Reference ID: 3392126
`
` Page 2 of 8
`
`

`

`Selected Requirements of Prescribing Information
`
`Required for only certain changes to PI*
` Recent Major Changes
`Required
` Indications and Usage
`Required
` Dosage and Administration
`Required
` Dosage Forms and Strengths
`Required (if no contraindications must state “None.”)
` Contraindications
`Not required by regulation, but should be present
` Warnings and Precautions
`Required
` Adverse Reactions
`Optional
` Drug Interactions
`Optional
` Use in Specific Populations
` Patient Counseling Information Statement Required
`Required
` Revision Date
`* RMC only applies to the Boxed Warning, Indications and Usage, Dosage and Administration, Contraindications,
`and Warnings and Precautions sections.
`Comment:
`7. A horizontal line must separate HL and Table of Contents (TOC).
`Comment:
`
`HIGHLIGHTS DETAILS
`Highlights Heading
`8. At the beginning of HL, the following heading must be bolded and appear in all UPPER CASE
`letters: “HIGHLIGHTS OF PRESCRIBING INFORMATION”.
`Comment:
`
`Highlights Limitation Statement
`9. The bolded HL Limitation Statement must be on the line immediately beneath the HL heading
`and must state: “These highlights do not include all the information needed to use (insert
`name of drug product in UPPER CASE) safely and effectively. See full prescribing
`information for (insert name of drug product in UPPER CASE).”
`Comment:
`
`Product Title
`10. Product title in HL must be bolded.
`Comment:
`
`Initial U.S. Approval
`11. Initial U.S. Approval in HL must be placed immediately beneath the product title, bolded, and
`include the verbatim statement “Initial U.S. Approval:” followed by the 4-digit year.
`Comment: The verbatim statement in HL is currently written as “Initial U.S. approval” instead
`of “Initial U.S. Approval.”
`
`Boxed Warning
`12. All text must be bolded.
`Comment:
`13. Must have a centered heading in UPPER-CASE, containing the word “WARNING” (even if
`more than one Warning, the term, “WARNING” and not “WARNINGS” should be used) and
`to identify the subject of the Warning (e.g., “WARNING: SERIOUS
`other words
`INFECTIONS”).
`
`Page 3 of 8
`
`YES
`
`YES
`
`YES
`
`YES
`
`NO
`
`YES
`
`YES
`
`Reference ID: 3392126
`
`

`

`Selected Requirements of Prescribing Information
`
`Comment:
`14. Must always have the verbatim statement “See full prescribing information for complete boxed
`warning.” in italics and centered immediately beneath the heading.
`Comment:
`15. Must be limited in length to 20 lines (this does not include the heading and statement “See full
`prescribing information for complete boxed warning.”)
`Comment:
`16. Use sentence case for summary (combination of uppercase and lowercase letters typical of that
`used in a sentence).
`Comment:
`
`Recent Major Changes (RMC)
`17. Pertains to only the following five sections of the FPI: Boxed Warning, Indications and Usage,
`Dosage and Administration, Contraindications, and Warnings and Precautions.
`Comment:
`18. Must be listed in the same order in HL as they appear in FPI.
`Comment:
`19. Includes heading(s) and, if appropriate, subheading(s) of labeling section(s) affected by the
`recent major change, together with each section’s identifying number and date (month/year
`format) on which the change was incorporated in the PI (supplement approval date). For
`example, “Dosage and Administration, Coronary Stenting (2.2) --- 3/2012”.
`Comment:
`20. Must list changes for at least one year after the supplement is approved and must be removed at
`the first printing subsequent to one year (e.g., no listing should be one year older than revision
`date).
`Comment:
`
`Indications and Usage
`21. If a product belongs to an established pharmacologic class, the following statement is required in
`the Indications and Usage section of HL: “(Product) is a (name of established pharmacologic
`class) indicated for (indication)”.
`Comment:
`
`Dosage Forms and Strengths
`22. For a product that has several dosage forms, bulleted subheadings (e.g., capsules, tablets,
`injection, suspension) or tabular presentations of information is used.
`Comment:
`
`Contraindications
`23. All contraindications listed in the FPI must also be listed in HL or must include the statement
`“None” if no contraindications are known.
`Comment:
`
`YES
`
`YES
`
`YES
`
`N/A
`
`N/A
`
`N/A
`
`N/A
`
`YES
`
`N/A
`
`YES
`
`Page 4 of 8
`
`Reference ID: 3392126
`
`

`

`Selected Requirements of Prescribing Information
`
`YES
`
`YES
`
`YES
`
`YES
`
`NO
`
`YES
`
`YES
`
`YES
`
`YES
`
`24. Each contraindication is bulleted when there is more than one contraindication.
`Comment:
`
`Adverse Reactions
`25. For drug products other than vaccines, the verbatim bolded statement must be present: “To
`report SUSPECTED ADVERSE REACTIONS, contact (insert name of manufacturer) at
`(insert manufacturer’s U.S. phone number) or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch”.
`Comment:
`
`Patient Counseling Information Statement
`26. Must include one of the following three bolded verbatim statements (without quotation marks):
`If a product does not have FDA-approved patient labeling:
` “See 17 for PATIENT COUNSELING INFORMATION”
`If a product has FDA-approved patient labeling:
` “See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.”
` “See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.”
`Comment:
`
`Revision Date
`27. Bolded revision date (i.e., “Revised: MM/YYYY or Month Year”) must be at the end of HL.
`Comment:
`Contents: Table of Contents (TOC)
`
`GENERAL FORMAT
`28. A horizontal line must separate TOC from the FPI.
`Comment: A horizontal line separating the TOC from the FPI is missing. Insert.
`29. The following bolded heading in all UPPER CASE letters must appear at the beginning of TOC:
`“FULL PRESCRIBING INFORMATION: CONTENTS”.
`Comment:
`30. The section headings and subheadings (including title of the Boxed Warning) in the TOC must
`match the headings and subheadings in the FPI.
`Comment:
`31. The same title for the Boxed Warning that appears in the HL and FPI must also appear at the
`beginning of the TOC in UPPER-CASE letters and bolded.
`Comment:
`32. All section headings must be bolded and in UPPER CASE.
`
`Reference ID: 3392126
`
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`Selected Requirements of Prescribing Information
`
`Comment:
`33. All subsection headings must be indented, not bolded, and in title case.
`Comment:
`34. When a section or subsection is omitted, the numbering does not change.
`Comment:
`35. If a section or subsection from 201.56(d)(1) is omitted from the FPI and TOC, the heading
`“FULL PRESCRIBING INFORMATION: CONTENTS” must be followed by an asterisk
`and the following statement must appear at the end of TOC: “*Sections or subsections omitted
`from the Full Prescribing Information are not listed.”
`Comment:
`
`Full Prescribing Information (FPI)
`
`GENERAL FORMAT
`36. The following heading must appear at the beginning of the FPI in UPPER CASE and bolded:
`“FULL PRESCRIBING INFORMATION”.
`Comment:
`37. All section and subsection headings and numbers must be bolded.
`Comment:
`
`38. The bolded section and subsection headings must be named and numbered in accordance with
`21 CFR 201.56(d)(1) as noted below. If a section/subsection is omitted, the numbering does not
`change.
`
`YES
`
`YES
`
`YES
`
`YES
`
`YES
`
`YES
`
`Boxed Warning
`1 INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`6 ADVERSE REACTIONS
`7 DRUG INTERACTIONS
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Labor and Delivery
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`9 DRUG ABUSE AND DEPENDENCE
`9.1 Controlled Substance
`9.2 Abuse
`9.3 Dependence
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`
`Reference ID: 3392126
`
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`

`Selected Requirements of Prescribing Information
`
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`12.4 Microbiology (by guidance)
`12.5 Pharmacogenomics (by guidance)
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.2 Animal Toxicology and/or Pharmacology
`14 CLINICAL STUDIES
`15 REFERENCES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`YES
`
`NO
`
`Comment:
`39. FDA-approved patient labeling (e.g., Medication Guide, Patient Information, or Instructions for
`Use) must not be included as a subsection under Section 17 (Patient Counseling Information).
`All patient labeling must appear at the end of the PI upon approval.
`Comment:
`40. The preferred presentation for cross-references in the FPI is the section heading (not subsection
`heading) followed by the numerical identifier in italics. For example, “[see Warnings and
`Precautions (5.2)]”.
`Comment: The cross-references in the Boxed Warning in the FPI are not in the preferred
`presentation shown above. They should read as follows: “[see Warnings and Precautions
`(5.1)]”, “[see Contraindications (4)]” and “[see Warnings and Precautions (5.2)]”
`respectively, instead of “(5.1)”, “(4)” and “(5.2)” as currently presented.
`
`Under subsection 5.9 “Pregnancy” the cross-reference should read as “[see Use in Specific
`Populations (8.1)]” instead of “[See Use in Special Populations (8.1)].”
`
`N/A
`
`41. If RMCs are listed in HL, the corresponding new or modified text in the FPI sections or
`subsections must be marked with a vertical line on the left edge.
`Comment:
`
`FULL PRESCRIBING INFORMATION DETAILS
`Boxed Warning
`42. All text is bolded.
`Comment:
`43. Must have a heading in UPPER-CASE, containing the word “WARNING” (even if more than
`one Warning, the term, “WARNING” and not “WARNINGS” should be used) and other