AUT HENTICATE~
`U.S. COVERNM.ENT
`JNFOkMATION
`GPO
`
`§201.57
`
`sub(cid:173)
`(2) Additional nonstandard
`headings that are used to enhance la(cid:173)
`beling organization, presentation, or
`ease of use (e.g., for individual warn(cid:173)
`ings or precautions, or for each drug
`interaction) must be assigned a dec(cid:173)
`imal number that corresponds to their
`placement in labeling. The decimal
`numbers must be consistent with the
`standardized identifying numbers list(cid:173)
`ed in paragraph (d)(l ) of this section
`(e.g., subheadings added to the "Warn(cid:173)
`ings and Precautions" section must be
`numbered 5.1, 5.2, and so on).
`(3) Any reference in Highlights to in(cid:173)
`formation appearing in the full pre(cid:173)
`scribing information must be accom(cid:173)
`panied by the identifying number (in
`parentheses) co1Tesponding to the loca(cid:173)
`tion of the information in the full pre(cid:173)
`scribing information.
`(4) Omit clearly inapplicable sec(cid:173)
`tions, subsections, or specific informa(cid:173)
`tion. If sections or subsections required
`under paragraph (d)(l) of this section
`are omitted from the full prescribing
`information, the heading " Full Pre(cid:173)
`scribing Information: Contents" must
`be followed by an asterisk and the fol(cid:173)
`lowing statement must appear at the
`end of Contents: " * Sections or sub(cid:173)
`sections omitted from the full pre(cid:173)
`scribing information are not listed."
`(5) Any risk information that is re(cid:173)
`qu1red under §201.57(c)(9)(1v) is consid(cid:173)
`ered " appropriate pediatric contra(cid:173)
`indications, warnings, or precautions"
`within the meaning of section 505A(l)(2)
`of the Federal Food, Drug, and Cos(cid:173)
`metic Act
`(the act)
`(21 U.S.C.
`355A(l)(2)), whether such information
`appears in the "Contraindications,"
`"Warnings and Precautions," or "Use
`in Specific Populations" section of la(cid:173)
`beling.
`(e) Labeling requirements for older pre(cid:173)
`scription drug products. This paragraph
`applies only to approved prescription
`drug products not described in para(cid:173)
`graph (b)(l ) of this section.
`(1) Prescription drug labeling de(cid:173)
`scribed in §201.l00(d) must contain the
`specific
`information requ1red under
`§201.80 under
`the following section
`headings and in the following order:
`Description
`Clinical Pharmacology
`Indications and Usage
`Contraindications
`
`21 CFR Ch. I (4-1-08 Edition)
`
`Warnings
`Precautions
`Adverse Reactions
`Drug Abuse and Dependence
`Overdosage
`Dosage and Administration
`How Supplied
`(2) The labeling may contain the fol(cid:173)
`lowing additional section headings if
`appropriate and 1f in compliance with
`§201.80(1) and (m):
`Animal Pharmacology and/or Animal
`Toxicology
`Clinical Studies
`References
`(3) Omit clearly inapplicable sec(cid:173)
`tions, subsections, or specific informa(cid:173)
`tion.
`(4) The
`labeling may contain a
`"Product Tit le" section preceding the
`"Description" section and containing
`only
`the
`information required by
`§201.80(a)(1)(1), (a)(1)(11), (a)(1)(111), and
`(a )(l )(iv) and §201.l00(e). The informa(cid:173)
`tion requ1red by §201.80(a)(1)(1) through
`(a)(l )(iv) must appear in the " Descrip(cid:173)
`tion" section of the labeling, whether
`or not it also appears in a " Product
`Title. "
`(5) The labeling must contain the
`date of the most recent revision of the
`labeling,
`identified as such, placed
`prominently immediately after the last
`section of the labeling.
`(6) The requirement in § 201.80(f)(2) to
`reprint any FDA-approved patient la(cid:173)
`beling at the end of prescription drug
`labeling or accompany the prescription
`drug labeling must be implemented no
`later than June 30, 2007.
`[71 FR 3986, Jan. 24, 2006)
`
`§ 201.57 Specific requirements on con(cid:173)
`tent and format of labeling
`for
`human prescription drug and bio(cid:173)
`logical
`products
`described
`in
`§ 201.56(b)(l ).
`The requ1rements in this section
`apply only to prescription drug prod(cid:173)
`ucts described in §201.56(b)(l) and must
`be
`implemented according
`to
`the
`schedule specified in §201.56(c), except
`for the requirement in paragraph (c)(18)
`of this section to reprint any FDA-ap(cid:173)
`proved patient labeling at the end of
`prescription drug labeling or accom(cid:173)
`pany the prescription drug labeling,
`which must be implemented no later
`than June 30, 2007.
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`24
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`Novartis Exhibit 2192.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Food and Drug Administration, HHS
`
`(a) Highlights of prescribing informa-
`tion. The following information must
`appear in all prescription drug label-
`ing:
`(1) Highlights limitation statement. The
`verbatim statement ‘‘These highlights
`do not include all the information
`needed to use (insert name of drug prod-
`uct) safely and effectively. See full pre-
`scribing information for (insert name
`of drug product).’’
`(2) Drug names, dosage form, route of
`administration, and controlled substance
`symbol. The proprietary name and the
`established name of the drug, if any, as
`defined in section 502(e)(3) of the Fed-
`eral Food, Drug, and Cosmetic Act (the
`act) or, for biological products, the
`proper name (as defined in § 600.3 of this
`chapter)
`including any appropriate
`descriptors. This information must be
`followed by the drug’s dosage form and
`route of administration. For controlled
`substances, the controlled substance
`symbol designating the schedule in
`which the controlled substance is listed
`must be
`included as required by
`§ 1302.04 of this chapter.
`(3) Initial U.S. approval. The verbatim
`statement ‘‘Initial U.S. Approval’’ fol-
`lowed by the four-digit year in which
`FDA initially approved a new molec-
`ular entity, new biological product, or
`new combination of active ingredients.
`The statement must be placed on the
`line immediately beneath the estab-
`lished name or, for biological products,
`proper name of the product.
`(4) Boxed warning. A concise sum-
`mary of any boxed warning required by
`paragraph (c)(1) of this section, not to
`exceed a length of 20 lines. The sum-
`mary must be preceded by a heading, in
`upper-case letters, containing the word
`‘‘WARNING’’ and other words that are
`appropriate to identify the subject of
`the warning. The heading and the sum-
`mary must be contained within a box
`and bolded. The following verbatim
`statement must be placed immediately
`following the heading of the boxed
`warning: ‘‘See full prescribing informa-
`tion for complete boxed warning.’’
`(5) Recent major changes. A list of the
`section(s) of the full prescribing infor-
`mation, limited to the labeling sec-
`tions described in paragraphs (c)(1),
`(c)(2), (c)(3), (c)(5), and (c)(6) of this sec-
`tion, that contain(s) substantive label-
`
`§ 201.57
`
`ing changes that have been approved
`by FDA
`or
`authorized
`under
`§ 314.70(c)(6) or (d)(2), or § 601.12(f)(1)
`through (f)(3) of this chapter. The head-
`ing(s) and, if appropriate, the sub-
`heading(s) of the labeling section(s) af-
`fected by the change must be listed to-
`gether with each section’s identifying
`number and the date (month/year) on
`which the change was incorporated in
`labeling. These labeling sections must
`be listed in the order in which they ap-
`pear in the full prescribing informa-
`tion. A changed section must be listed
`under this heading in Highlights for at
`least 1 year after the date of the label-
`ing change and must be removed at the
`first printing subsequent to the 1 year
`period.
`(6) Indications and usage. A concise
`statement of each of the product’s indi-
`cations, as required under paragraph
`(c)(2) of this section, with any appro-
`priate subheadings. Major limitations
`of use (e.g., lack of effect in particular
`subsets of the population, or second
`line therapy status) must be briefly
`noted. If the product is a member of an
`established pharmacologic class, the
`concise statement under this heading
`in Highlights must identify the class in
`the following manner: ‘‘(Drug) is a
`(name of class) indicated for (indica-
`tion(s)).’’
`(7) Dosage and administration. A con-
`cise summary of the information re-
`quired under paragraph (c)(3) of this
`section, with any appropriate sub-
`headings, including the recommended
`dosage regimen, starting dose, dose
`range, critical differences among popu-
`lation
`subsets, monitoring
`rec-
`ommendations, and other clinically
`significant clinical pharmacologic in-
`formation.
`(8) Dosage forms and strengths. A con-
`cise summary of the information re-
`quired under paragraph (c)(4) of this
`section, with any appropriate sub-
`headings
`(e.g.,
`tablets,
`capsules,
`injectable, suspension), including the
`strength or potency of the dosage form
`in metric system (e.g., 10-milligram
`tablets) and whether the product is
`scored.
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`Novartis Exhibit 2192.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`§ 201.57
`
`(9) Contraindications. A concise state-
`ment of each of the product’s contra-
`indications, as required under para-
`graph (c)(5) of this section, with any
`appropriate subheadings.
`(10) Warnings and precautions. A con-
`cise summary of the most clinically
`significant information required under
`paragraph (c)(6) of this section, with
`any appropriate subheadings, including
`information that would affect decisions
`about whether to prescribe a drug, rec-
`ommendations for patient monitoring
`that are critical to safe use of the drug,
`and measures that can be taken to pre-
`vent or mitigate harm.
`(11) Adverse reactions. (i) A list of the
`most frequently occurring adverse re-
`actions, as described in paragraph (c)(7)
`of this section, along with the criteria
`used to determine inclusion (e.g., inci-
`dence rate). Adverse reactions impor-
`tant for other reasons (e.g., because
`they are serious or frequently lead to
`discontinuation or dosage adjustment)
`must not be repeated under this head-
`ing in Highlights if they are included
`elsewhere in Highlights (e.g., Warnings
`and Precautions, Contraindications).
`(ii) For drug products other than vac-
`cines, the verbatim statement ‘‘To re-
`port SUSPECTED ADVERSE REAC-
`TIONS, contact (insert name of manu-
`facturer) at (insert manufacturer’s phone
`number) or FDA at (insert current FDA
`phone number and Web address for vol-
`untary reporting of adverse reactions).’’
`(iii) For vaccines, the verbatim state-
`ment ‘‘To report SUSPECTED AD-
`VERSE REACTIONS, contact (insert
`name of manufacturer) at (insert manu-
`facturer’s phone number) or VAERS at
`(insert the current VAERS phone number
`and Web address for voluntary reporting
`of adverse reactions).’’
`(iv) For manufacturers with a Web
`site for voluntary reporting of adverse
`reactions, the Web address of the direct
`link to the site.
`(12) Drug interactions. A concise sum-
`mary of the information required under
`paragraph (c)(8) of this section, with
`any appropriate subheadings.
`(13) Use in specific populations. A con-
`cise summary of the information re-
`quired under paragraph (c)(9) of this
`section, with any appropriate sub-
`headings.
`
`21 CFR Ch. I (4–1–08 Edition)
`
`(14) Patient counseling
`information
`statement. The verbatim statement
`‘‘See 17 for Patient Counseling Infor-
`mation’’ or, if the product has FDA-ap-
`proved patient labeling, the verbatim
`statement ‘‘See 17 for Patient Coun-
`seling Information and (insert either
`FDA-approved patient
`labeling or
`Medication Guide).’’
`(15) Revision date. The date of the
`most recent revision of the labeling,
`identified as such, placed at the end of
`Highlights.
`(b) Full prescribing information: Con-
`tents. Contents must contain a list of
`each heading and subheading required
`in the full prescribing information
`under § 201.56(d)(1), if not omitted under
`§ 201.56(d)(4), preceded by the identi-
`fying
`number
`required
`under
`§ 201.56(d)(1). Contents must also con-
`tain any additional subheading(s) in-
`cluded in the full prescribing informa-
`tion preceded by the identifying num-
`ber assigned
`in accordance with
`§ 201.56(d)(2).
`(c) Full prescribing information. The
`full prescribing information must con-
`tain the information in the order re-
`quired under paragraphs (c)(1) through
`(c)(18) of this section, together with the
`headings, subheadings, and identifying
`numbers required under § 201.56(d)(1),
`unless omitted under § 201.56(d)(4). If
`additional subheadings are used within
`a labeling section, they must be pre-
`ceded by the identifying number as-
`signed in accordance with § 201.56(d)(2).
`(1) Boxed warning. Certain contra-
`indications or serious warnings, par-
`ticularly those that may lead to death
`or serious injury, may be required by
`the FDA to be presented in a box. The
`boxed warning ordinarily must be
`based on clinical data, but serious ani-
`mal toxicity may also be the basis of a
`boxed warning in the absence of clin-
`ical data. The box must contain, in up-
`percase letters, a heading inside the
`box that includes the word ‘‘WARN-
`ING’’ and conveys the general focus of
`the information in the box. The box
`must briefly explain the risk and refer
`to more detailed information in the
`‘‘Contraindications’’ or ‘‘Warnings and
`Precautions’’ section, accompanied by
`the identifying number for the section
`or subsection containing the detailed
`information.
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`Novartis Exhibit 2192.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Food and Drug Administration, HHS
`
`(2) 1 Indications and usage. This sec-
`tion must state that the drug is indi-
`cated for the treatment, prevention,
`mitigation, cure, or diagnosis of a rec-
`ognized disease or condition, or of a
`manifestation of a recognized disease
`or condition, or for the relief of symp-
`toms associated with a recognized dis-
`ease or condition.
`(i) This section must include the fol-
`lowing information when the condi-
`tions listed are applicable:
`(A) If the drug is used for an indica-
`tion only in conjunction with a pri-
`mary mode of therapy (e.g., diet, sur-
`gery, behavior changes, or some other
`drug), a statement that the drug is in-
`dicated as an adjunct to that mode of
`therapy.
`(B) If evidence is available to support
`the safety and effectiveness of the drug
`or biological product only in selected
`subgroups of the larger population
`(e.g., patients with mild disease or pa-
`tients in a special age group), or if the
`indication is approved based on a sur-
`rogate endpoint under § 314.510 or
`§ 601.41 of this chapter, a succinct de-
`scription of the limitations of useful-
`ness of the drug and any uncertainty
`about anticipated clinical benefits,
`with reference to the ‘‘Clinical Stud-
`ies’’ section for a discussion of the
`available evidence.
`(C) If specific tests are necessary for
`selection or monitoring of the patients
`who need the drug (e.g., microbe sus-
`ceptibility tests), the identity of such
`tests.
`(D) If information on limitations of
`use or uncertainty about anticipated
`clinical benefits is relevant to the rec-
`ommended intervals between doses, to
`the appropriate duration of treatment
`when such treatment should be lim-
`ited, or to any modification of dosage,
`a concise description of the informa-
`tion with reference to the more de-
`tailed information in the ‘‘Dosage and
`Administration’’ section.
`(E) If safety considerations are such
`that the drug should be reserved for
`specific situations (e.g., cases refrac-
`tory to other drugs), a statement of the
`information.
`(F) If there are specific conditions
`that should be met before the drug is
`used on a long term basis (e.g., dem-
`onstration of responsiveness to the
`
`§ 201.57
`
`drug in a short term trial in a given pa-
`tient), a statement of the conditions;
`or, if the indications for long term use
`are different from those for short term
`use, a statement of the specific indica-
`tions for each use.
`(ii) If there is a common belief that
`the drug may be effective for a certain
`use or if there is a common use of the
`drug for a condition, but the prepon-
`derance of evidence related to the use
`or condition shows that the drug is in-
`effective or that the therapeutic bene-
`fits of the product do not generally
`outweigh its risks, FDA may require
`that this section state that there is a
`lack of evidence that the drug is effec-
`tive or safe for that use or condition.
`(iii) Any statements comparing the
`safety or effectiveness of the drug with
`other agents for the same indication
`must, except for biological products, be
`supported by substantial evidence de-
`rived from adequate and well-con-
`trolled studies as defined in § 314.126(b)
`of this chapter unless this requirement
`is waived under § 201.58 or § 314.126(c) of
`this chapter. For biological products,
`such statements must be supported by
`substantial evidence.
`(iv) For drug products other than bio-
`logical products, all indications listed
`in this section must be supported by
`substantial evidence of effectiveness
`based on adequate and well-controlled
`studies as defined in § 314.126(b) of this
`chapter unless the requirement
`is
`waived under § 201.58 or § 314.126(c) of
`this chapter. Indications or uses must
`not be implied or suggested in other
`sections of the labeling if not included
`in this section.
`(v) For biological products, all indi-
`cations listed in this section must be
`supported by substantial evidence of ef-
`fectiveness. Indications or uses must
`not be implied or suggested in other
`sections of the labeling if not included
`in this section.
`(3) 2 Dosage and administration. (i)
`This section must state the rec-
`ommended dose and, as appropriate:
`(A) The dosage range,
`(B) An upper limit beyond which
`safety and effectiveness have not been
`established, or beyond which increas-
`ing the dose does not result in increas-
`ing effectiveness,
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`Novartis Exhibit 2192.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`§ 201.57
`
`(C) Dosages for each indication and
`subpopulation,
`(D) The intervals recommended be-
`tween doses,
`(E) The optimal method of titrating
`dosage,
`(F) The usual duration of treatment
`when treatment duration should be
`limited,
`(G) Dosing recommendations based
`on clinical pharmacologic data (e.g.,
`clinically significant food effects),
`(H) Modification of dosage needed be-
`cause of drug interactions or in special
`patient populations (e.g., in children,
`in geriatric age groups, in groups de-
`fined by genetic characteristics, or in
`patients with renal or hepatic disease),
`(I) Important considerations con-
`cerning compliance with the dosage
`regimen,
`(J) Efficacious or toxic concentration
`ranges and therapeutic concentration
`windows of the drug or its metabolites,
`if established and clinically signifi-
`cant. Information on therapeutic drug
`concentration monitoring (TDM) must
`also be included in this section when
`TDM is necessary.
`(ii) Dosing regimens must not be im-
`plied or suggested in other sections of
`the labeling if not included in this sec-
`tion.
`(iii) Radiation dosimetry information
`must be stated for both the patient re-
`ceiving a radioactive drug and the per-
`son administering it.
`(iv) This section must also contain
`specific direction on dilution, prepara-
`tion (including the strength of the final
`dosage solution, when prepared accord-
`ing to instructions, in terms of milli-
`grams of active ingredient per milli-
`liter of reconstituted solution, unless
`another measure of the strength is
`more appropriate), and administration
`of the dosage form, if needed (e.g., the
`rate of administration of parenteral
`drug in milligrams per minute; storage
`conditions for stability of the reconsti-
`tuted drug, when important; essential
`information on drug incompatibilities
`if the drug is mixed in vitro with other
`drugs or diluents; and the following
`verbatim statement for parenterals:
`‘‘Parenteral drug products should be
`inspected visually for particulate mat-
`ter and discoloration prior to adminis-
`
`21 CFR Ch. I (4–1–08 Edition)
`
`tration, whenever solution and con-
`tainer permit.’’)
`(4) 3 Dosage forms and strengths. This
`section must contain information on
`the available dosage forms to which
`the labeling applies and for which the
`manufacturer or distributor is respon-
`sible, including:
`(i) The strength or potency of the
`dosage form in metric system (e.g., 10
`milligram tablets), and, if the apothe-
`cary system is used, a statement of the
`strength in parentheses after the met-
`ric designation; and
`(ii) A description of the identifying
`characteristics of the dosage forms, in-
`cluding shape, color, coating, scoring,
`and imprinting, when applicable. The
`National Drug Code number(s) for the
`drug product must not be included in
`this section.
`(5) 4 Contraindications. This section
`must describe any situations in which
`the drug should not be used because
`the risk of use (e.g., certain potentially
`fatal adverse reactions) clearly out-
`weighs any possible therapeutic ben-
`efit. Those situations include use of the
`drug in patients who, because of their
`particular age, sex, concomitant ther-
`apy, disease state, or other condition,
`have a substantial risk of being harmed
`by the drug and for whom no potential
`benefit makes the risk acceptable.
`Known hazards and not theoretical pos-
`sibilities must be listed (e.g., if severe
`hypersensitivity to the drug has not
`been demonstrated, it should not be
`listed as a contraindication). If no con-
`traindications are known, this section
`must state ‘‘None.’’
`(6) 5 Warnings and precautions. (i)
`General. This section must describe
`clinically significant adverse reactions
`(including any that are potentially
`fatal, are serious even if infrequent, or
`can be prevented or mitigated through
`appropriate use of the drug), other po-
`tential safety hazards (including those
`that are expected for the pharma-
`cological class or those resulting from
`drug/drug interactions), limitations in
`use imposed by them (e.g., avoiding
`certain concomitant therapy), and
`steps that should be taken if they
`occur (e.g., dosage modification). The
`frequency of all clinically significant
`adverse reactions and the approximate
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`Novartis Exhibit 2192.005
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Food and Drug Administration, HHS
`
`mortality and morbidity rates for pa-
`tients experiencing the reaction, if
`known and necessary for the safe and
`effective use of the drug, must be ex-
`pressed as provided under paragraph
`(c)(7) of this section. In accordance
`with §§ 314.70 and 601.12 of this chapter,
`the labeling must be revised to include
`a warning about a clinically significant
`hazard as soon as there is reasonable
`evidence of a causal association with a
`drug; a causal relationship need not
`have been definitely established. A spe-
`cific warning relating to a use not pro-
`vided for under the ‘‘Indications and
`Usage’’ section may be required by
`FDA in accordance with sections 201(n)
`and 502(a) of the act if the drug is com-
`monly prescribed for a disease or con-
`dition and such usage is associated
`with a clinically significant risk or
`hazard.
`(ii) Other special care precautions. This
`section must contain information re-
`garding any special care to be exer-
`cised by the practitioner for safe and
`effective use of the drug (e.g., pre-
`cautions not required under any other
`specific section or subsection).
`(iii) Monitoring: Laboratory tests. This
`section must identify any laboratory
`tests helpful in following the patient’s
`response or in identifying possible ad-
`verse reactions. If appropriate, infor-
`mation must be provided on such fac-
`tors as the range of normal and abnor-
`mal values expected in the particular
`situation and the recommended fre-
`quency with which tests should be per-
`formed before, during, and after ther-
`apy.
`(iv) Interference with laboratory tests.
`This section must briefly note informa-
`tion on any known interference by the
`product with laboratory tests and ref-
`erence the section where the detailed
`information is presented (e.g., ‘‘Drug
`Interactions’’ section).
`(7) 6 Adverse reactions. This section
`must describe the overall adverse reac-
`tion profile of the drug based on the en-
`tire safety database. For purposes of
`prescription drug labeling, an adverse
`reaction is an undesirable effect, rea-
`sonably associated with use of a drug,
`that may occur as part of the pharma-
`cological action of the drug or may be
`unpredictable in its occurrence. This
`definition does not include all adverse
`
`§ 201.57
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`events observed during use of a drug,
`only those adverse events for which
`there is some basis to believe there is a
`causal relationship between the drug
`and the occurrence of the adverse
`event.
`(i) Listing of adverse reactions. This
`section must list the adverse reactions
`that occur with the drug and with
`drugs in the same pharmacologically
`active and chemically related class, if
`applicable. The list or lists must be
`preceded by the information necessary
`to interpret the adverse reactions (e.g.,
`for clinical trials, total number ex-
`posed, extent and nature of exposure).
`(ii) Categorization of adverse reactions.
`Within a listing, adverse reactions
`must be categorized by body system,
`by severity of the reaction, or in order
`of decreasing frequency, or by a com-
`bination of these, as appropriate. With-
`in a category, adverse reactions must
`be listed in decreasing order of fre-
`quency. If frequency information can-
`not be reliably determined, adverse re-
`actions must be listed in decreasing
`order of severity.
`(A) Clinical trials experience. This sec-
`tion must list the adverse reactions
`identified in clinical trials that oc-
`curred at or above a specified rate ap-
`propriate to the safety database. The
`rate of occurrence of an adverse reac-
`tion for the drug and comparators (e.g.,
`placebo) must be presented, unless such
`data cannot be determined or presen-
`tation of comparator rates would be
`misleading. If adverse reactions that
`occurred below the specified rate are
`included, they must be included in a
`separate listing. If comparative rates
`of occurrence cannot be reliably deter-
`mined (e.g., adverse reactions were ob-
`served only in the uncontrolled trial
`portion of the overall safety database),
`adverse reactions must be grouped
`within specified frequency ranges as
`appropriate to the safety database for
`the drug (e.g., adverse reactions occur-
`ring at a rate of less than 1/100, adverse
`reactions occurring at a rate of less
`than 1/500) or descriptively identified,
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`Novartis Exhibit 2192.006
`Regeneron v. Novartis, IPR2021-00816
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`

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`§ 201.57
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`if frequency ranges cannot be deter-
`mined. For adverse reactions with sig-
`nificant clinical implications, the list-
`ings must be supplemented with addi-
`tional detail about the nature, fre-
`quency, and severity of the adverse re-
`action and the relationship of the ad-
`verse reaction to drug dose and demo-
`graphic characteristics, if data are
`available and important.
`(B) Postmarketing experience. This sec-
`tion of the labeling must list the ad-
`verse reactions, as defined in paragraph
`(c)(7) of this section, that are identified
`from domestic and foreign spontaneous
`reports. This listing must be separate
`from the listing of adverse reactions
`identified in clinical trials.
`(iii) Comparisons of adverse reactions
`between drugs. For drug products other
`than biological products, any claim
`comparing the drug to which the label-
`ing applies with other drugs in terms of
`frequency, severity, or character of ad-
`verse reactions must be based on ade-
`quate and well-controlled studies as de-
`fined in § 314.126(b) of this chapter un-
`less this requirement is waived under
`§ 201.58 or § 314.126(c) of this chapter.
`For biological products, any such claim
`must be based on substantial evidence.
`(8) 7 Drug interactions. (i) This section
`must contain a description of clinically
`significant
`interactions, either ob-
`served or predicted, with other pre-
`scription or over-the-counter drugs,
`classes of drugs, or foods (e.g., dietary
`supplements, grapefruit juice), and spe-
`cific practical instructions for pre-
`venting or managing them. The mecha-
`nism(s) of the interaction, if known,
`must be briefly described. Interactions
`that are described in the ‘‘Contra-
`indications’’ or ‘‘Warnings and Pre-
`cautions’’ sections must be discussed in
`more detail under this section. Details
`of drug interaction pharmacokinetic
`studies that are included in the ‘‘Clin-
`ical Pharmacology’’ section that are
`pertinent to clinical use of the drug
`must not be repeated in this section.
`(ii) This section must also contain
`practical guidance on known inter-
`ference of the drug with laboratory
`tests.
`(9) 8 Use in specific populations. This
`section must contain the following sub-
`sections:
`
`21 CFR Ch. I (4–1–08 Edition)
`
`(i) 8.1 Pregnancy. This subsection
`may be omitted only if the drug is not
`absorbed systemically and the drug is
`not known to have a potential for indi-
`rect harm to the fetus. For all other
`drugs, this subsection must contain the
`following information:
`(A) Teratogenic effects. Under this sub-
`heading, the labeling must identify one
`of the following categories that applies
`to the drug, and the labeling must bear
`the statement required under the cat-
`egory:
`(1) Pregnancy category A. If adequate
`and well-controlled studies in pregnant
`women have failed to demonstrate a
`risk to the fetus in the first trimester
`of pregnancy (and there is no evidence
`of a risk in later trimesters), the label-
`ing must state: ‘‘Pregnancy Category
`A. Studies in pregnant women have not
`shown that (name of drug) increases the
`risk of fetal abnormalities if adminis-
`tered during the first (second, third, or
`all) trimester(s) of pregnancy. If this
`drug is used during pregnancy, the pos-
`sibility of fetal harm appears remote.
`Because studies cannot rule out the
`possibility of harm, however, (name of
`drug) should be used during pregnancy
`only if clearly needed.’’ The labeling
`must also contain a description of the
`human studies. If animal reproduction
`studies are also available and they fail
`to demonstrate a risk to the fetus, the
`labeling must also state: ‘‘Reproduc-
`tion studies have been performed in
`(kinds of animal(s)) at doses up to (x)
`times the human dose and have re-
`vealed no evidence of impaired fertility
`or harm to the fetus due to (name of
`drug).’’ The labeling must also contain
`a description of available data on the
`effect of the drug on the later growth,
`development, and functional matura-
`tion of the child.
`(2) Pregnancy category B. If animal re-
`production studies have failed to dem-
`onstrate a risk to the fetus and there
`are no adequate and well-controlled
`studies in pregnant women, the label-
`ing must state: ‘‘Pregnancy Category
`B. Reproduction studies have been per-
`formed in (kind(s) of animal(s)) at doses
`up to (x) times the human dose and
`have revealed no evidence of impaired
`fertility or harm to the fetus due to
`(name of drug). There are, however, no
`adequate and well-controlled studies in
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`Novartis Exhibit 2192.007
`Regeneron v. Novartis, IPR2021-00816
`
`

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`Food and Drug Administration, HHS
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`pregnant women. Because animal re-
`production studies are not always pre-
`dictive of human response, this drug
`should be used during pregnancy only
`if clearly needed.’’ If animal reproduc-
`tion studies have shown an adverse ef-
`fect (other than decrease in fertility),
`but adequate and well-controlled stud-
`ies in pregnant women have failed to
`demonstrate a risk to the fetus during
`the first trimester of pregnancy (and
`there is no evidence of a risk in later
`trimesters), the labeling must state:
`‘‘Pregnancy Category B. Reproduction
`studies in (kind(s) of animal(s)) have
`shown (describe findings) at (x) times
`the human dose. Studies in pregnant
`women, however, have not shown that
`(name of drug) increases the risk of ab-
`normalities when administered during
`the first (second, third, or all) tri-
`mester(s) of pregnancy. Despite the
`animal findings, it would appear that
`the possibility of fetal harm is remote,
`if the drug is used during pregnancy.
`Nevertheless, because the studies in
`humans cannot rule out the possibility
`of harm, (name of drug) should be used
`during pregnancy only if clearly need-
`ed.’’ The labeling must also contain a
`description of the human studies and a
`description of available data on the ef-
`fect of the drug on the later growth,
`development, and functional matura-
`tion of t