CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`202231Orig1s000
`
`
`OTHER REVIEW(S)
`
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`

`

`
`
`REGULATORY PROJECT MANAGER
` PLR FORMAT LABELING REVIEW
`
`
`Application: NDA 202231
`
`Name of Drug: Proprietary name - none
` Established name - Levothyroxine Sodium for Injection
`
`Applicant: APP Pharmaceuticals, LLC
`Labeling Reviewed
`
`
`Submission Date: August 30, 2010
`
`
`Receipt Date: August 30, 2010
`
`Summary Description
`
`
`Indication: myxedema coma
`
`Dosage form: Lyophilized Powder for Injection
`
`Route of administration: Intravenous (IV)
`
`Proposes new indication, dosage form, dosing regimen, and route of administration
`
`
`Drug chemical classification: 7-Drug Already Marketed but Without an Approved NDA
`Review priority: Standard
`
`Review
`
`
`The submitted labeling was reviewed in accordance with 21 CFR 201.56 and 201.57 and relevant
`labeling guidance. Labeling issues are identified on the following pages with an “X.”
`
`
`Recommendations
`
`
`All labeling issues identified on the following pages with an “X” will be conveyed to the applicant.
`The applicant will be asked to resubmit labeling that addresses all the identified labeling issues. The
`resubmitted labeling will be used for further labeling discussions.
`
`
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`
`
`
`
`Linda Galgay
`
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`
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`Regulatory Project Manager
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`
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`
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`March 23, 2011
`Date
`
`
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`Reference ID: 2965516
`
`1
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`

`

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`LABELING CHECKLIST
`SECTION I: Highlights Overview
`
`For more information, see Draft Guidance for Industry: Labeling for
`Human Prescription Drug and Biological Products - Implementing the
`New Content and Format Requirements; also refer to
`http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/
`LawsActsandRules/ucm084159.htm.
`Check that the following items appear (in the following order):
`• Highlights Limitation Statement (required statement) (required
`bolding)
`• Drug names, dosage form, route of administration, and
`controlled substance symbol (required information) (required
`bolding)
`Initial U.S. Approval (required information) (required bolding)
`
`•
`
`• Boxed Warning (required bolding)
`• Recent Major Changes (for a supplement)
`•
`Indications and Usage
`• Dosage and Administration
`• Dosage Forms and Strengths
`• Contraindications (required heading – if no contraindications
`are known, it must state “None”)
`• Warnings and Precautions
`• Adverse Reactions (required AR contact reporting statement)
`(required bolding for AR contact reporting statement)
`• Drug Interactions (optional heading – can be omitted)
`• Use in Specific Populations (optional heading – can be omitted)
`• Patient Counseling Information Statement (required statement)
`(required bolding)
`• Revision Date (required information) (required bolding)
`[format] Highlights, excluding the boxed warning, must be limited in
`length to one-half page (e.g., would fit on one-half page if printed on 8.5” x
`11 paper, single spaced, minimum 8 point type with ½ inch margins on all
`sides, in a two-column format)
`[format] All headings and subheadings must be in bold type.
`[format] All headings must be presented in the center of a horizontal line
`in upper-case letters and bold type. The horizontal line can be a solid or
`dashed line.
`[format] If there are multiple subheadings, each subheading must be
`preceded by a bullet point.
`[format] The information should be concisely summarized without
`repetition and presented in an easily accessible format (e.g., bulleted,
`tabular). There should be no redundancy of information.
`[format] Use command language (e.g., use “Discontinue” instead of “You
`should discontinue.”)
`[format] Each summarized statement should be located under the
`appropriate Highlights heading and must reference the section(s) or
`
`FILING REVIEW
`08.30.10
`
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`X
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`X
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`X – Date of moiety approval
` 1969
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`X -Must keep heading with
`“None”
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`X
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`X – Not applicable
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`2
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`Reference ID: 2965516
`
`

`

`LABELING CHECKLIST
`subsection(s) of the Full Prescribing Information (FPI) that contains more
`detailed information.
`[format] The preferred presentation of referencing in Highlights is the
`numerical identifier in parentheses [e.g., (1.1)] following the summarized
`labeling information, corresponding to the location of information in the
`FPI.
`[format] There should be white space between each major heading in
`Highlights.
`[format] The type size for all labeling information, headings, and
`subheadings must be a minimum of 8 points, except for labeling
`information that is on or within the package from which the drug is to be
`dispensed (i.e., trade labeling), which must be a minimum of 6 points. See
`Appendix E of Implementation Guidance for type size requirements.
`[format] There is no requirement for a specific typeface for labeling as long
`as it is clear and legible. However, Arial Narrow font is not recommended
`because it may render the labeling illegible.
`[format] Do not use the asterisk (*) to footnote information in tables in
`Highlights since this symbol is used in the Table of Contents (i.e.,
`*Sections or subsections omitted from the full prescribing information are
`not listed.)
`[format] We are no longer going to review the labeling for the “TM” or
`“R” symbols. Companies can add these symbols at will in Word and
`Adobe versions. These symbols will not appear in the rendering of
`labeling in SPL format due to style sheet restrictions.
`
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`FILING REVIEW
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`X
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`3
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`Reference ID: 2965516
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`

`

`4
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`FILING REVIEW
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`X
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` X
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`N/A
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`LABELING CHECKLIST
`SECTION II: Highlights Details
`Highlights Limitation Statement
`Must appear at beginning of Highlights in bold type and be placed on the
`line immediately beneath the heading – HIGHLIGHTS OF
`PRESCRIBING INFORMATION
`The verbatim statement must read: “These highlights do not include all
`the information needed to use (insert name of drug product in upper
`case letters) safely and effectively. See full prescribing information for
`(insert name of drug product in upper case letters).”
`
`Drug names, dosage form, route of administration,
`and controlled substance symbol (must appear in bold type)
`• With SPL R4, the product title in HL is no longer added
`automatically. Since this field is added as free text, check
`carefully.
`Include proprietary name and either established name of drug,
`OR proper name of biological product.
`• For the established name of a drug, the active moiety is generally
`used if the product is a salt. The salt is sometimes included in
`the name when it is important to know what salt is present for
`therapeutic reasons (e.g., a lot of Na or K; affect on therapeutic
`performance is known - absorption, distribution, metabolism,
`excretion). Include the entire drug substance name for esters,
`chelates, and complexes.
`
`•
`
` •
`
` Also, the established name and expression of strength should
`match. As a general rule, if the strength is in terms of the
`salt/ester, the name includes the salt/ester. If the strength is in
`terms of the active moiety, the name is in terms of the active
`moiety.
`• The drug names must be followed by drug’s dosage form and
`route of administration.
`• Note that for biologic products, the dosage form and route of
`administration must be on the next line (i.e., underneath the
`proper name) since the proper name does not include the drug’s
`dosage form or route of administration. See 21 CFR 600.3 (k)
`and Section 351 of the PHS Act
`If the route of administration is typical for the dosage form and is
`commonly understood (e.g., tablets or capsules), omit the route of
`administration (for oral use). If the route of administration is not
`typical, it must be included.
`If applicable, must include the controlled substance symbol
`designating the schedule in which the controlled substance is
`listed.
`• However, do not include a controlled substance symbol after drug
`names, dosage forms, and route of administration unless DEA
`scheduling action is final.
`
`•
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`•
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`
`
`Reference ID: 2965516
`
`

`

`LABELING CHECKLIST
`[format] To conserve space in Highlights, the proprietary and established
`names should be presented on the same line, unless they are too long.
`(This does not apply for biological products – see above).
`Product Titles: Because the drug names, dosage form, route of
`administration appears at the beginning of labeling, a “Product Title”
`section is not needed for labeling in the new format (See comment #39 to
`Preamble) and should be deleted from the prescribing information.
`Logos: Current regulations (21 CFR 201.57) fully describe the format and
`content for labeling, including Highlights. There is no provision for a
`logo. Therefore, do not include logos in Highlights or in the SPL file
`since logos interfere with repurposing of the labeling in SPL. However, in
`WORD labeling documents, a small company logo can appear at the end
`of the labeling with the manufacturer information.
`Barcodes in Final Printed Labeling: The barcode is not required to be on
`the labeling, only the label (see 21 CFR 201.25). If the barcode is
`compliant with 21 CFR 201.25, it is acceptable to include the barcode for
`the TRADE labeling. However, it should not be included in SPL.
`
`Initial U.S. Approval (must appear in bold type)
`•
`[format] The verbatim statement “Initial U.S. Approval” followed
`by the four-digit year in which FDA initially approved a new
`molecular entity, new biological product, or new combination of
`active ingredients
`• Ensure that the 4-digit year is entered. If this is a NME, the year
`will correspond to the current approval action.
`[format] The statement must be placed on the line immediately
`beneath established name or, for biological products, proper
`name of the product.
`• For DESI drugs: Use the original date of approval of the NDA as
`the “Initial U.S. Approval” date and not the post-approval DESI
`update date. Therefore:
`o Do not list the DESI update date in the “Initial U.S.
`Approval” date field.
`o Do not list multiple “Initial U.S. Approval” dates or use
`an asterisk after the date with a footnote regarding DESI
`approval.
`• For new formulations: Use the original date of approval of the
`active ingredient, even if the labeling does not refer to the older
`formulations.
`• For a combination product: If a combination product is on the
`market first (Active Moiety A and Active Moiety B approved in
`1950) and one of the active moieties (A or B) is approved at a
`later date (1982) as a single moiety, the initial U.S. approval date
`would be the date/first time there was general exposure to the
`molecular entity. In this case, it would be the date that the
`combination product was first approved (1950).
`• For racemates: A racemate is not an NME. Use the originally
`approved racemic mixture approval date. The name of the
`
`•
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`FILING REVIEW
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`X
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`X
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`X
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`5
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`Reference ID: 2965516
`
`

`

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`
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`LABELING CHECKLIST
`originally approved racemate or racemic mixture may be included
`in parentheses. For example, Nexium (esomeprazole magnesium)
`capsules would read: Initial U.S. Approval: 1989 (omeprazole).
`o
`In the Description section, the following clarification
`may appear: Esomeprazole is the S-isomer of
`omeprazole, which is a mixture of the S- and R- isomers.
` (Initial U.S. Approval of esomeprazole magnesium:
`2001).
`For systemic antibacterial drug products, the required statement about
`antibiotic resistance [see 21 CFR 201.24(a)] should be placed directly
`under the Initial U.S. Approval date.
`Boxed Warning
`(Also see Draft Guidance for Industry: Warnings and Precautions,
`Contraindications, and Boxed Warning Sections of Labeling for Human
`Prescription Drug and Biological Products – Content and Format)
`•
`[format] Not to exceed a length of 20 lines. Summarize, rather
`than repeat verbatim, the warning from the FPI. Boxed Warning
`lines do not count against the ½ page Highlights’ requirement.
`Summary must be preceded by a heading, in upper-case letters,
`containing the word “WARNING” and other words that are
`appropriate to identify subject of the warning.
`[format] Heading and summary must be contained within a box
`and bolded. Use lower-case letters for the summary.
`• The verbatim statement “See full prescribing information for
`complete boxed warning” must be placed immediately following
`the heading of the boxed warning. If the boxed warning in HL is
`identical to the boxed warning in the FPI, this statement is not
`necessary.
`[format] Summarize information in a bulleted format, with each
`bullet communicating a discrete warning or contraindication.
`• List each bulleted item in the boxed warning in decreasing order
`of importance (i.e., should reflect the relative public health
`significance).
`
`•
`
`•
`
`•
`
`
`Recent Major Changes (applies only to supplements)
`A list of the section(s) in the FPI, limited to 5 labeling sections that
`contain “substantive labeling changes” (i.e., to the content of the Boxed
`Warning, Indications and Usage, Dosage and Administration,
`Contraindications, Warning and Precautions sections) that have been
`approved by FDA
`•
`[format] The heading(s), and if appropriate, the subheading(s) of
`the labeling section(s) affected by the change must be listed
`together with each section’s identifying number and the date
`(month/year format) on which the change was incorporated in
`labeling. The date will be the month/year that the supplement
`is approved. Remember to update before approval.
`[format] Highlights labeling sections must be listed in the order
`in which they appear in the full prescribing information.
`
`•
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`FILING REVIEW
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`X
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`X
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`6
`
`Reference ID: 2965516
`
`

`

`LABELING CHECKLIST
`•
`[format] The corresponding new or modified text in the FPI
`sections listed under Recent Major Changes must be marked with
`a vertical line (“margin mark”) on the left edge.
`• A section or subsection that is removed should be noted as such
`in Recent Major Changes. The text noting the change should
`include the title of the section/subsection removed, followed by
`the term “removal” and date of removal. For example, Dosage
`and Administration, Subsection Title (2.X) ---removal XX/2010.
`• A changed section must be listed under this heading in
`Highlights for at least one year after the date of the labeling
`change and must be removed at the first printing subsequent to
`the one year period.
`• Refer to draft guidance for Implementing the New Content and
`Format Requirements (pages 8-10) for additional information and
`examples of RMC.
`
`•
`
`
`Indications and Usage
`(Also see Guidance for Industry and Review Staff: Labeling for Human
`Prescription Drugs and Biological Products – Determining Established
`Pharmacologic Class for Use in the Highlights of Prescribing Information)
`[format] A concise statement of each of the drug’s indications (presented
`in bulleted format), with any appropriate subheadings
`•
`If the drug is a member of an established pharmacologic class, the
`concise statement under this heading in Highlights must identify
`the class as follows: “(Drug) is a (name of class) indicated for
`(indications(s)).” If the drug is not a member of an established
`pharmacologic class, the statement should be omitted.
`For the pharmacological class web page see
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProd
`uctLabeling/ucm162549.htm.
`• Major limitations of use must be briefly noted.
`For accelerated approvals [i.e., biological products approved under
`Subpart E (21 CFR 601.41) and drugs approved under Subpart H (21 CFR
`314.510)], include a statement regarding the basis of approval. Suggest the
`following language: “[Drug] is indicated for the [treatment/prevention] of .
`. . . The effectiveness of [drug] is based on [describe the outcome, e.g., an
`improvement in drug activity/response rate/tumor shrinkage]. There are
`no controlled trials demonstrating a direct treatment benefit, such as
`improvement in disease-related symptoms, functioning, or increased
`survival.
`
`Dosage and Administration
`A concise summary including the following:
`• Recommended dosage regimen
`•
`Starting dose
`• Dose range
`• Critical differences among population subsets
`
`
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`FILING REVIEW
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`
`X
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`X
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`X
`X
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`
`7
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`Reference ID: 2965516
`
`

`

`
`
`
`
`LABELING CHECKLIST
`• Monitoring recommendations
`• Other clinically significant clinical pharmacologic information
`that affects dosing recommendations.
`• When applicable and important, special storage or handling
`information can be mentioned under this heading (e.g., special
`handling of chemotherapeutic agents, need for refrigeration,
`reconstitution prior to administration of the drug.)
`[format] Should use tabular format to enhance accessibility of
`information (e.g., when there are different dosing regimens for
`different indications).
`[format] Avoid error-prone abbreviations, symbols and dose
`designations when describing dosage and administration
`information. Refer to the Institute for Safe Medication Practices’
`website at http://www.ismp.org/Tools/abbreviationslist.pdf.
`[format] Avoid using “IV” as it is commonly mistaken for Roman
`numeral IV. Instead, use “intravenous.”
`[format] Do not use a “slash mark” (/) since it may be mistaken
`for the number 1. Use “per.” For example, do not use 5 mg/10
`mL. Use 5 mg per 10 mL.
`
`•
`
`•
`
`•
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`•
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`
`Dosage Forms and Strengths
`A concise summary of dosage forms and strengths including:
`• Any appropriate subheadings (e.g., tablets, capsules, injection,
`suspension)
`• The strength or potency of the dosage form in metric system (e.g.,
`10 mg tablets) and whether the product is scored. If the product
`is not scored, do not say “not scored.”
`[format] If a drug product has numerous dosage forms, bulleted
`subheadings (e.g., capsules, tablets, injection, suspension) or tabular
`presentations are recommended.
`Do not include “How Supplied” information.
`
`Contraindications
`All contraindications listed in the FPI must also be listed in HL.
`Must include either a concise summary of the situations in which the drug
`should not be used because the risk clearly outweighs any possible
`therapeutic benefit, or the statement “None” if no contraindicated
`situations have been identified.
`List known hazards and not theoretical possibilities (i.e., hypersensitivity to
`the drug). If the contraindication is not theoretical, then it must be
`worded to explain the type and nature of the adverse reaction.
`Use of pregnancy Category X drugs are contraindicated in pregnancy.
`Therefore, under Contraindications in HL, state “Pregnancy” and cross-
`reference to Contraindications section (4) and Pregnancy subsection (8.1).
`
`Warnings and Precautions
`A concise summary of the most clinically significant information, with any
`
`FILING REVIEW
`
`X
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`X
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`X
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`X
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`X
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`8
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`Reference ID: 2965516
`
`

`

`
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`
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`LABELING CHECKLIST
`appropriate subheadings, including information:
`• That would affect decisions whether to prescribe the drug
`• Recommendations for patient monitoring that are critical to safe
`use of the drug
`• Measures that can be taken to prevent or mitigate harm
`All critical safety concerns should be addressed.
`List W&P in decreasing order of importance (i.e., reflecting the relative
`public health significance) regardless of drug class.
`Pregnancy Category D drugs have positive human risk findings. These
`findings must be noted as a warning. Therefore, under W&P in HL state
`the following based on data: “Pregnancy: Can cause fetal harm. Advise
`women of potential risk to the fetus.” If a pregnancy registry exists, state:
`“Pregnancy registry available.” Conclude the entire statement with a cross-
`reference to Warnings and Precautions section (5.X ) and Pregnancy
`subsection (8.1).
`
`Adverse Reactions
`A list of the most frequently occurring adverse reactions, along with the
`criteria used to determine inclusion (e.g., incidence rate greater than x%).
`•
`If some of the most frequently occurring adverse reactions are
`included elsewhere in Highlights (e.g., Warnings and Precautions,
`Contraindications because they are serious) they should still be
`included in this list since it would be misleading to have a list of
`“most common” if it does not include all of the “most common”
`adverse reactions.
`• Adverse reactions important for reasons other than frequency
`(e.g., because they are serious or frequently lead to
`discontinuation or dosage adjustment) must not be included
`under this heading in Highlights unless they meet the criteria as
`described above.
`• Only “adverse reactions” as defined in 21 CFR 201.57(a)(11) are
`included in Highlights. Other terms, such as “adverse events” or
`“treatment-emergent adverse events” should be avoided.
`• Do not include “adverse events” from postmarketing experience.
`•
`*For drug products other than vaccines, the verbatim statement,
`“To report SUSPECTED ADVERSE REACTIONS, contact
`(insert name of manufacturer) at (insert manufacturer’s phone
`number) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.”
` This statement must be in bold type.
`*For vaccines, the verbatim statement “To report SUSPECTED
`ADVERSE REACTIONS, contact (insert name of manufacturer)
`at (insert manufacturer’s phone number) or VAERS at 1-800-822-
`7967 or www.vaers.hhs.gov.” This statement must be in bold
`type.
`*With SPL Release 4, the Adverse Reactions Reporting Statement
`is no longer added automatically. The verbatim language
`required by regulation must be added as free text; therefore,
`check carefully.
`
`•
`
`•
`
`FILING REVIEW
`
`
`X
`
`X
`
`X
`
`
`
`
`
`X
`
`
`
`
`
`
`
`9
`
`Reference ID: 2965516
`
`

`

`LABELING CHECKLIST
`•
`For reporting suspected adverse reactions, the manufacturer must
`use a U.S. phone number (that should be a toll-free number) and
`not a foreign phone number. Using a foreign phone number
`would not meet the contact information requirement for U.S.
`labeling.
`For manufacturers with a Web site for voluntary reporting of
`adverse reactions, the Web address of the direct link to the site.
`NOTE: An email address or general link to a company’s website
`cannot be used to meet the requirement to have adverse reactions
`reporting contact information in Highlights. It would not
`provide a structured format for reporting. Delete this
`information if it appears in Highlights.
`
`•
`
`
`Drug Interactions (This heading can be omitted.)
`A concise summary of the drug interactions includes:
`• A list of other drugs (or classes of drugs) or foods that interact or
`are predicted to interact in clinically significant ways with the
`drug
`• A concise summary of the outcome of the interaction
`•
`Practical instructions for preventing or decreasing the likelihood
`of the interaction
`[format] A tabular format is recommended for presentation of drug
`interaction information for drugs with numerous clinically significant
`interactions.
`
`Use in Specific Populations (This heading can be omitted.)
`A concise summary of any clinically important differences in response or
`use of the drug in specific populations (e.g., differences between adult and
`pediatric responses, need for specific monitoring in patients with hepatic
`impairment, need for dosing adjustments in patients with renal
`impairment).
`Ordinarily, the absence of information about the safety and effectiveness
`of a drug in a specific population (e.g., pregnant women, children) should
`not be included under this heading.
`The pregnancy category designation is not appropriate for inclusion in
`Highlights because the pregnancy category, in isolation, tends to
`oversimplify the risks of drugs in pregnancy, and, as a result, may be
`confusing. Therefore, do not include the pregnancy category in
`Highlights. (See comment #34 to Preamble)
`For pregnancy category C drugs, you may use the following statement:
`“Pregnancy: Based on animal data, may cause fetal harm,” or “No human
`or animal data. Use only if clearly needed.” Conclude the entire
`statement with a cross-reference to Pregnancy subsection (8.1).
`In Highlights, if a pregnancy registry exists, state “Pregnancy registry
`available.” Cross-reference to Pregnancy subsection (8.1). DO NOT
`include the telephone number or information on how to enroll patients in
`the study. This information should appear under the Pregnancy
`subsection (8.1) in the FPI.
`
`
`
`
`
`FILING REVIEW
`
`
`
`
`
`
`X
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`
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`
`
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`
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`
`
`10
`
`Reference ID: 2965516
`
`

`

`LABELING CHECKLIST
`
`Patient Counseling Information Statement (must
`appear in bold type)
`If the product does not have FDA-approved patient labeling, use the
`verbatim statement: See 17 for PATIENT COUNSELING
`INFORMATION
`If the product has (or will have) FDA-approved patient labeling, use the
`verbatim statement: See 17 for PATIENT COUNSELING
`INFORMATION and FDA-approved patient labeling
`If the product has (or will have) a Medication Guide, use the verbatim
`statement: See 17 for PATIENT COUNSELING INFORMATION and
`Medication Guide
`In rare circumstances, there may be two pieces of patient labeling (i.e.,
`Medication Guide and Instructions for Use). Both would not be cited in
`the patient counseling information statement. The Medication Guide
`takes precedence. Use the verbatim statement: See 17 for PATIENT
`COUNSELING INFORMATION and Medication Guide.
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`Revision Date (must appear in bold type)
`The date of the most recent revision of the labeling must be presented at
`the end of Highlights.
`[format] The preferred format is “Revised: Month Year” or “Revised:
`Month/Year” (i.e., Revised: June 2003 or Revised: 6/2003).
`For a new NDA, BLA, or supplement, the revision date will be the
`month/year that the application or supplement is approved. Remember to
`update before approval.
`The revision date at the end of highlights replaces the “revision” or
`“issued” date at the end of the full prescribing information and should not
`appear in both places. A revision date may appear at the end of FDA-
`approved patient labeling. A Medication Guide will always have a revision
`date because it is required by regulation (see 21 CFR Part 208).
`
`
`SECTION III: Contents - Table of
`Contents
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`[format] The heading – FULL PRESCRIBING INFORMATION:
`CONTENTS - must appear at the beginning of the table of contents in
`upper-case letters and bold type.
`[format] Agency recommends use of a two-column format for the Table of
`Contents, and if possible, that it be limited in length to one-half page.
`[format] If the Highlights and Table of Contents do not fit on one page,
`insert the Table of Contents on page 2 of the labeling.
`[format] A horizontal line must be located between Highlights and Table
`of Contents to separate Highlights information from the table of contents.
` A horizontal line must also be located between the Table of Contents and
`the FPI.
`[format] There are no periods after the numbers for the section and
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`FILING REVIEW
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`11
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`Reference ID: 2965516
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`

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`LABELING CHECKLIST
`subsection headings.
`[format] The section and subsection headings in the Table of Contents
`must match the section and subsection headings in the FPI.
`[format] The same title for the boxed warning that appears in the HL and
`FPI must also appear at the beginning of the Table of Contents in upper-
`case letters and bold type. For example, WARNING: ANAPHYLAXIS.
`[format] Table of Contents section headings must be in bold type and
`should be in upper-case letters.
`[format] Table of Contents subsection headings must be indented and not
`bolded and should be in lower-case letters.
`[format] Only include section and subsection headings in the Table of
`Contents. Do not include headings within a subsection.
`[format] When a section or subsection is omitted from the FPI, the section
`or subsection must also be omitted from the Contents. The heading “Full
`Prescribing Information: Contents” must be followed by an asterisk and
`the following statement must appear at the end of the Contents:
`“*Sections or subsections omitted from the Full Prescribing Information
`are not listed.”
`Create subsection headings that identify the content. Avoid using the
`words “General” “Other” “Miscellaneous” for a subsection heading.
`Avoid using acronyms in subsection headings. Spell out. For example, do
`not use “CHF” as a subsection heading. Use “Congestive Heart Failure.”
`[format] Since SPL R4 validation does not permit the inclusion of the MG
`as a subsection under the Patient Counseling Information section, do not
`include the MG or PPI as a subsection heading in the Table of Contents.
`
`
`SECTION IV: Full Prescribing
`Information – Overview
`
`[format] The heading – FULL PRESCRIBING INFORMATION – must
`appear at the beginning of the FPI in upper-case letters and bold type.
`Check that the following headings and subheadings are named and
`numbered correctly as outlined under 21 CFR 201.56 (d)(1):
`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
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`FILING REVIEW
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`12
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`Reference ID: 2965516
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`LABELING CHECKLIST
`9.1 Controlled Substance
`9.2 Abuse
`9.3 Dependence
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`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
`[format] There are no periods after the numbers for the section or
`subsection headings (see above).
`[format] Any required section, subsection, or specific information that is
`clearly inapplicable may be omitted from the FPI. However, the
`numbering does not change. This is important to remember for the
`required subsections in Sections 8 (Use in Specific Populations), 12
`(Clinical Pharmacology) and 13 (Nonclinical Toxicology).
`[format] The use of subheadings to organize information in the FPI is
`encouraged. Each subheading that is used must be assigned a decimal
`number that corresponds to its placement and order in the FPI [e.g., (12.3
`Pharmacokinetics)]. Do not number headings within a subsection [e.g.,
`(12.3.1 Metabolism)]. Use headings within a subsection without
`numbering [e.g., Metabolism].
`[format] All headings and subheadings must be highlighted by bold type
`that prominently distinguishes the headings and subheadings from other
`labeling information. Therefore, for other labeling information, use bold
`type sparingly. Use another method for emphasis such as italics or
`underline.
`[format] Identifying numbers must be presented in bold print and must
`precede the heading or subheading by at least two square em’s (i.e., two
`squares of the size of the letter “m” in 8 point type).
`Create subsection headings that identify the content. Avoid using the
`words “General” “Other” “Miscellaneous” for the title of a subsection.
`[format] The preferred presentation of cross-references in the FPI is the
`section heading followed by the numerical identifier. For example, [see
`Indications and Usage (1.1)]. Do not include subsection headings or
`headings within a subsection in the cross reference. Because cross-
`references are embedded in the text in the FPI, the use of italics to achieve
`emphasis is encouraged. Do not use all capital letters or bold print.
`[format] The proprietary and established names can be repeated at the
`beginning of the FPI, or at the beginning of each page of the FPI (e.g., as a
`header), if this enhances product identification on subsequent pages of
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`FILING REVIEW
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`13
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`Reference ID: 2965516
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`

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`LABELING CHECKLIST
`labeling (See Implementation Guidance - FAQ #4).
`
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`•
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`•
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`SECTION V: Full Prescribing
`Information – Details
`BOXED WARNING
`(Also see Draft Guidance for Industry: Warnings and Precautions,
`Contraindications, and Boxed Warning Sections of Labeling for Human
`Prescription Drug and Biolog