(cid:1)
`
`Displaying title 21, up to date as of 12/23/2021. Title 21 was last amended 12/22/2021.
`
`Title 21
`
`EDITORIAL NOTE ON PART 201
`
`Editorial Note: Nomenc ature changes to part 201 appear at 69 FR 13717, Mar 24, 2004
`
`§ 201.57 Specific requirements on content and format of labeling for human prescription drug and biological products
`described in § 201.56(b)(1).
`
`The requ rements n th s sect on app y on y to prescr pt on drug products descr bed n § 201 56(b)(1) and must be mp emented accord ng to the
`schedu e spec Eed n § 201 56(c), except for the requ rement n paragraph (c)(18) of th s sect on to repr nt any FDA-approved pat ent abe ng at
`the end of prescr pt on drug abe ng or accompany the prescr pt on drug abe ng, wh ch must be mp emented no ater than June 30, 2007
`
`(a) Highlights of prescribing information. The fo ow ng nformat on must appear n a prescr pt on drug abe ng
`
`(1) Highlights limitation statement. The verbat m statement “These h gh ghts do not nc ude a the nformat on needed to use (insert
`name of drug product) safe y and effect ve y See fu prescr b ng nformat on for ( nsert name of drug product) ”
`
`(2) Drug names, dosage form, route of administration, and controlled substance symbol. The propr etary name and the estab shed
`name of the drug, f any, as deEned n sect on 502(e)(3) of the Federa Food, Drug, and Cosmet c Act (the act) or, for b o og ca
`products, the proper name (as deEned n § 600 3 of th s chapter) nc ud ng any appropr ate descr ptors Th s nformat on must be
`fo owed by the drug's dosage form and route of adm n strat on For contro ed substances, the contro ed substance symbo
`des gnat ng the schedu e n wh ch the contro ed substance s sted must be nc uded as requ red by § 1302 04 of th s chapter
`
`(3) Initial U.S. approval. The verbat m statement “ n t a U S Approva ” fo owed by the four-d g t year n wh ch FDA n t a y approved a
`new mo ecu ar ent ty, new b o og ca product, or new comb nat on of act ve ngred ents The statement must be p aced on the ne
`mmed ate y beneath the estab shed name or, for b o og ca products, proper name of the product
`
`(4) Boxed warning. A conc se summary of any boxed warn ng requ red by paragraph (c)(1) of th s sect on, not to exceed a ength of 20
`nes The summary must be preceded by a head ng, n upper-case etters, conta n ng the word “WARN NG” and other words that
`are appropr ate to dent fy the subject of the warn ng The head ng and the summary must be conta ned w th n a box and bo ded
`The fo ow ng verbat m statement must be p aced mmed ate y fo ow ng the head ng of the boxed warn ng “See fu prescr b ng
`nformat on for comp ete boxed warn ng ”
`
`(5) Recent major changes. A st of the sect on(s) of the fu prescr b ng nformat on, m ted to the abe ng sect ons descr bed n
`paragraphs (c)(1), (c)(2), (c)(3), (c)(5), and (c)(6) of th s sect on, that conta n(s) substant ve abe ng changes that have been
`approved by FDA or author zed under § 314 70(c)(6) or (d)(2), or § 601 12(f)(1) through (f)(3) of th s chapter The head ng(s) and,
`f appropr ate, the subhead ng(s) of the abe ng sect on(s) affected by the change must be sted together w th each sect on's
`dent fy ng number and the date (month/year) on wh ch the change was ncorporated n abe ng These abe ng sect ons must be
`sted n the order n wh ch they appear n the fu prescr b ng nformat on A changed sect on must be sted under th s head ng n
`H gh ghts for at east 1 year after the date of the abe ng change and must be removed at the Erst pr nt ng subsequent to the 1
`year per od
`
`(6) Indications and usage. A conc se statement of each of the product's nd cat ons, as requ red under paragraph (c)(2) of th s sect on,
`w th any appropr ate subhead ngs Major m tat ons of use (e g , ack of effect n part cu ar subsets of the popu at on, or second
`ne therapy status) must be br e`y noted f the product s a member of an estab shed pharmaco og c c ass, the conc se
`statement under th s head ng n H gh ghts must dent fy the c ass n the fo ow ng manner “(Drug) s a (name of c ass) nd cated
`for ( nd cat on(s)) ”
`
`(7) Dosage and administration. A conc se summary of the nformat on requ red under paragraph (c)(3) of th s sect on, w th any
`appropr ate subhead ngs, nc ud ng the recommended dosage reg men, start ng dose, dose range, cr t ca d fferences among
`popu at on subsets, mon tor ng recommendat ons, and other c n ca y s gn Ecant c n ca pharmaco og c nformat on
`
`(8) Dosage forms and strengths. A conc se summary of the nformat on requ red under paragraph (c)(4) of th s sect on, w th any
`appropr ate subhead ngs (e g , tab ets, capsu es, njectab e, suspens on), nc ud ng the strength or potency of the dosage form n
`metr c system (e g , 10-m gram tab ets) and whether the product s scored
`
`(9) Contraindications. A conc se statement of each of the product's contra nd cat ons, as requ red under paragraph (c)(5) of th s
`sect on, w th any appropr ate subhead ngs
`
`(10) Warnings and precautions. A conc se summary of the most c n ca y s gn Ecant nformat on requ red under paragraph (c)(6) of th s
`sect on, w th any appropr ate subhead ngs, nc ud ng nformat on that wou d affect dec s ons about whether to prescr be a drug,
`recommendat ons for pat ent mon tor ng that are cr t ca to safe use of the drug, and measures that can be taken to prevent or
`m t gate harm
`
`Novartis Exhibit 2193.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`(11) Adverse reactions.
`
`( )
`
` A st of the most frequent y occurr ng adverse react ons, as descr bed n paragraph (c)(7) of th s sect on, a ong w th the
`cr ter a used to determ ne nc us on (e g , nc dence rate) Adverse react ons mportant for other reasons (e g , because they
`are ser ous or frequent y ead to d scont nuat on or dosage adjustment) must not be repeated under th s head ng n H gh ghts
`f they are nc uded e sewhere n H gh ghts (e g , Warn ngs and Precaut ons, Contra nd cat ons)
`
`( ) For drug products other than vacc nes, the verbat m statement “To report SUSPECTED ADVERSE REACT ONS, contact (insert
`name of manufacturer) at (insert manufacturer s phone number) or FDA at (insert current FDA phone number and Web address
`for voluntary reporting of adverse reactions) ”
`
`(
`
`) For vacc nes, the verbat m statement “To report SUSPECTED ADVERSE REACT ONS, contact (insert name of manufacturer) at
`(insert manufacturer s phone number) or VAERS at (insert the current VAERS phone number and Web address for voluntary
`reporting of adverse reactions) ”
`
`( v) For manufacturers w th a Web s te for vo untary report ng of adverse react ons, the Web address of the d rect nk to the s te
`
`(12) Drug interactions. A conc se summary of the nformat on requ red under paragraph (c)(8) of th s sect on, w th any appropr ate
`subhead ngs
`
`(13) Use in speciEc populations. A conc se summary of the nformat on requ red under paragraph (c)(9) of th s sect on, w th any
`appropr ate subhead ngs
`
`(14) Patient counseling information statement. The verbat m statement “See 17 for Pat ent Counse ng nformat on” or, f the product
`has FDA-approved pat ent abe ng, the verbat m statement “See 17 for Pat ent Counse ng nformat on and ( nsert e ther FDA-
`approved pat ent abe ng or Med cat on Gu de) ”
`
`(15) Revision date. The date of the most recent rev s on of the abe ng, dent Eed as such, p aced at the end of H gh ghts
`
`(b) Full prescribing information: Contents. Contents must conta n a st of each head ng and subhead ng requ red n the fu prescr b ng
`nformat on under § 201 56(d)(1), f not om tted under § 201 56(d)(4), preceded by the dent fy ng number requ red under § 201 56(d)
`(1) Contents must a so conta n any add t ona subhead ng(s) nc uded n the fu prescr b ng nformat on preceded by the dent fy ng
`number ass gned n accordance w th § 201 56(d)(2)
`
`(c) Full prescribing information. The fu prescr b ng nformat on must conta n the nformat on n the order requ red under paragraphs (c)(1)
`through (c)(18) of th s sect on, together w th the head ngs, subhead ngs, and dent fy ng numbers requ red under § 201 56(d)(1), un ess
`om tted under § 201 56(d)(4) f add t ona subhead ngs are used w th n a abe ng sect on, they must be preceded by the dent fy ng
`number ass gned n accordance w th § 201 56(d)(2)
`
`(1) Boxed warning. Certa n contra nd cat ons or ser ous warn ngs, part cu ar y those that may ead to death or ser ous njury, may be
`requ red by the FDA to be presented n a box The boxed warn ng ord nar y must be based on c n ca data, but ser ous an ma
`tox c ty may a so be the bas s of a boxed warn ng n the absence of c n ca data The box must conta n, n uppercase etters, a
`head ng ns de the box that nc udes the word “WARN NG” and conveys the genera focus of the nformat on n the box The box
`must br e`y exp a n the r sk and refer to more deta ed nformat on n the “Contra nd cat ons” or “Warn ngs and Precaut ons”
`sect on, accompan ed by the dent fy ng number for the sect on or subsect on conta n ng the deta ed nformat on
`
`(2) 1 Indications and usage. Th s sect on must state that the drug s nd cated for the treatment, prevent on, m t gat on, cure, or
`d agnos s of a recogn zed d sease or cond t on, or of a man festat on of a recogn zed d sease or cond t on, or for the re ef of
`symptoms assoc ated w th a recogn zed d sease or cond t on
`
`( )
`
` Th s sect on must nc ude the fo ow ng nformat on when the cond t ons sted are app cab e
`
`(A) f the drug s used for an nd cat on on y n conjunct on w th a pr mary mode of therapy (e g , d et, surgery, behav or
`changes, or some other drug), a statement that the drug s nd cated as an adjunct to that mode of therapy
`
`(B) f ev dence s ava ab e to support the safety and effect veness of the drug or b o og ca product on y n se ected
`subgroups of the arger popu at on (e g , pat ents w th m d d sease or pat ents n a spec a age group), or f the
`nd cat on s approved based on a surrogate endpo nt under § 314 510 or § 601 41 of th s chapter, a succ nct descr pt on
`of the m tat ons of usefu ness of the drug and any uncerta nty about ant c pated c n ca beneEts, w th reference to the
`“C n ca Stud es” sect on for a d scuss on of the ava ab e ev dence
`
`(C) f spec Ec tests are necessary for se ect on or mon tor ng of the pat ents who need the drug (e g , m crobe suscept b ty
`tests), the dent ty of such tests
`
`(D) f nformat on on m tat ons of use or uncerta nty about ant c pated c n ca beneEts s re evant to the recommended
`nterva s between doses, to the appropr ate durat on of treatment when such treatment shou d be m ted, or to any
`mod Ecat on of dosage, a conc se descr pt on of the nformat on w th reference to the more deta ed nformat on n the
`“Dosage and Adm n strat on” sect on
`
`(E) f safety cons derat ons are such that the drug shou d be reserved for spec Ec s tuat ons (e g , cases refractory to other
`drugs), a statement of the nformat on
`
`Novartis Exhibit 2193.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`(F) f there are spec Ec cond t ons that shou d be met before the drug s used on a ong term bas s (e g , demonstrat on of
`respons veness to the drug n a short term tr a n a g ven pat ent), a statement of the cond t ons; or, f the nd cat ons for
`ong term use are d fferent from those for short term use, a statement of the spec Ec nd cat ons for each use
`
`( ) f there s a common be ef that the drug may be effect ve for a certa n use or f there s a common use of the drug for a
`cond t on, but the preponderance of ev dence re ated to the use or cond t on shows that the drug s neffect ve or that the
`therapeut c beneEts of the product do not genera y outwe gh ts r sks, FDA may requ re that th s sect on state that there s a
`ack of ev dence that the drug s effect ve or safe for that use or cond t on
`
`(
`
`) Any statements compar ng the safety or effect veness of the drug w th other agents for the same nd cat on must, except for
`b o og ca products, be supported by substant a ev dence der ved from adequate and we -contro ed stud es as deEned n §
`314 126(b) of th s chapter un ess th s requ rement s wa ved under § 201 58 or § 314 126(c) of th s chapter For b o og ca
`products, such statements must be supported by substant a ev dence
`
`( v) For drug products other than b o og ca products, a nd cat ons sted n th s sect on must be supported by substant a
`ev dence of effect veness based on adequate and we -contro ed stud es as deEned n § 314 126(b) of th s chapter un ess
`the requ rement s wa ved under § 201 58 or § 314 126(c) of th s chapter nd cat ons or uses must not be mp ed or
`suggested n other sect ons of the abe ng f not nc uded n th s sect on
`
`(v) For b o og ca products, a nd cat ons sted n th s sect on must be supported by substant a ev dence of effect veness
`nd cat ons or uses must not be mp ed or suggested n other sect ons of the abe ng f not nc uded n th s sect on
`
`(3) 2 Dosage and administration.
`
`( )
`
` Th s sect on must state the recommended dose and, as appropr ate
`
`(A) The dosage range,
`
`(B) An upper m t beyond wh ch safety and effect veness have not been estab shed, or beyond wh ch ncreas ng the dose
`does not resu t n ncreas ng effect veness,
`
`(C) Dosages for each nd cat on and subpopu at on,
`
`(D) The nterva s recommended between doses,
`
`(E) The opt ma method of t trat ng dosage,
`
`(F) The usua durat on of treatment when treatment durat on shou d be m ted,
`
`(G) Dos ng recommendat ons based on c n ca pharmaco og c data (e g , c n ca y s gn Ecant food effects),
`
`(H) Mod Ecat on of dosage needed because of drug nteract ons or n spec a pat ent popu at ons (e g , n ch dren, n
`ger atr c age groups, n groups deEned by genet c character st cs, or n pat ents w th rena or hepat c d sease),
`
`( )
`
` mportant cons derat ons concern ng comp ance w th the dosage reg men,
`
`(J) Ehcac ous or tox c concentrat on ranges and therapeut c concentrat on w ndows of the drug or ts metabo tes, f
`estab shed and c n ca y s gn Ecant nformat on on therapeut c drug concentrat on mon tor ng (TDM) must a so be
`nc uded n th s sect on when TDM s necessary
`
`( ) Dos ng reg mens must not be mp ed or suggested n other sect ons of the abe ng f not nc uded n th s sect on
`
`(
`
`) Rad at on dos metry nformat on must be stated for both the pat ent rece v ng a rad oact ve drug and the person adm n ster ng
`t
`
`( v) Th s sect on must a so conta n spec Ec d rect on on d ut on, preparat on ( nc ud ng the strength of the Ena dosage so ut on,
`when prepared accord ng to nstruct ons, n terms of m grams of act ve ngred ent per m ter of reconst tuted so ut on,
`un ess another measure of the strength s more appropr ate), and adm n strat on of the dosage form, f needed (e g , the rate
`of adm n strat on of parentera drug n m grams per m nute; storage cond t ons for stab ty of the reconst tuted drug, when
`mportant; essent a nformat on on drug ncompat b t es f the drug s m xed n v tro w th other drugs or d uents; and the
`fo ow ng verbat m statement for parentera s “Parentera drug products shou d be nspected v sua y for part cu ate matter
`and d sco orat on pr or to adm n strat on, whenever so ut on and conta ner perm t ”)
`
`(4) 3 Dosage forms and strengths. Th s sect on must conta n nformat on on the ava ab e dosage forms to wh ch the abe ng app es
`and for wh ch the manufacturer or d str butor s respons b e, nc ud ng
`
`( )
`
` The strength or potency of the dosage form n metr c system (e g , 10 m gram tab ets), and, f the apothecary system s
`used, a statement of the strength n parentheses after the metr c des gnat on; and
`
`( ) A descr pt on of the dent fy ng character st cs of the dosage forms, nc ud ng shape, co or, coat ng, scor ng, and mpr nt ng,
`when app cab e The Nat ona Drug Code number(s) for the drug product must not be nc uded n th s sect on
`
`(5) 4 Contraindications. Th s sect on must descr be any s tuat ons n wh ch the drug shou d not be used because the r sk of use (e g ,
`certa n potent a y fata adverse react ons) c ear y outwe ghs any poss b e therapeut c beneEt Those s tuat ons nc ude use of the
`drug n pat ents who, because of the r part cu ar age, sex, concom tant therapy, d sease state, or other cond t on, have a substant a
`
`Novartis Exhibit 2193.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`r sk of be ng harmed by the drug and for whom no potent a beneEt makes the r sk acceptab e Known hazards and not theoret ca
`poss b t es must be sted (e g , f severe hypersens t v ty to the drug has not been demonstrated, t shou d not be sted as a
`contra nd cat on) f no contra nd cat ons are known, th s sect on must state “None ”
`
`(6) 5 Warnings and precautions.
`
`( )
`
` General. Th s sect on must descr be c n ca y s gn Ecant adverse react ons ( nc ud ng any that are potent a y fata , are ser ous
`even f nfrequent, or can be prevented or m t gated through appropr ate use of the drug), other potent a safety hazards
`( nc ud ng those that are expected for the pharmaco og ca c ass or those resu t ng from drug/drug nteract ons), m tat ons
`n use mposed by them (e g , avo d ng certa n concom tant therapy), and steps that shou d be taken f they occur (e g ,
`dosage mod Ecat on) The frequency of a c n ca y s gn Ecant adverse react ons and the approx mate morta ty and
`morb d ty rates for pat ents exper enc ng the react on, f known and necessary for the safe and effect ve use of the drug, must
`be expressed as prov ded under paragraph (c)(7) of th s sect on n accordance w th §§ 314 70 and 601 12 of th s chapter,
`the abe ng must be rev sed to nc ude a warn ng about a c n ca y s gn Ecant hazard as soon as there s reasonab e ev dence
`of a causa assoc at on w th a drug; a causa re at onsh p need not have been deEn te y estab shed A spec Ec warn ng
`re at ng to a use not prov ded for under the “ nd cat ons and Usage” sect on may be requ red by FDA n accordance w th
`sect ons 201(n) and 502(a) of the act f the drug s common y prescr bed for a d sease or cond t on and such usage s
`assoc ated w th a c n ca y s gn Ecant r sk or hazard
`
`( ) Other special care precautions. Th s sect on must conta n nformat on regard ng any spec a care to be exerc sed by the
`pract t oner for safe and effect ve use of the drug (e g , precaut ons not requ red under any other spec Ec sect on or
`subsect on)
`
`(
`
`) Monitoring: Laboratory tests. Th s sect on must dent fy any aboratory tests he pfu n fo ow ng the pat ent's response or n
`dent fy ng poss b e adverse react ons f appropr ate, nformat on must be prov ded on such factors as the range of norma
`and abnorma va ues expected n the part cu ar s tuat on and the recommended frequency w th wh ch tests shou d be
`performed before, dur ng, and after therapy
`
`( v) Interference with laboratory tests. Th s sect on must br e`y note nformat on on any known nterference by the product w th
`aboratory tests and reference the sect on where the deta ed nformat on s presented (e g , “Drug nteract ons” sect on)
`
`(7) 6 Adverse reactions. Th s sect on must descr be the overa adverse react on proE e of the drug based on the ent re safety
`database For purposes of prescr pt on drug abe ng, an adverse react on s an undes rab e effect, reasonab y assoc ated w th use
`of a drug, that may occur as part of the pharmaco og ca act on of the drug or may be unpred ctab e n ts occurrence Th s
`deEn t on does not nc ude a adverse events observed dur ng use of a drug, on y those adverse events for wh ch there s some
`bas s to be eve there s a causa re at onsh p between the drug and the occurrence of the adverse event
`
`( )
`
` Listing of adverse reactions. Th s sect on must st the adverse react ons that occur w th the drug and w th drugs n the same
`pharmaco og ca y act ve and chem ca y re ated c ass, f app cab e The st or sts must be preceded by the nformat on
`necessary to nterpret the adverse react ons (e g , for c n ca tr a s, tota number exposed, extent and nature of exposure)
`
`( ) Categorization of adverse reactions. W th n a st ng, adverse react ons must be categor zed by body system, by sever ty of the
`react on, or n order of decreas ng frequency, or by a comb nat on of these, as appropr ate W th n a category, adverse
`react ons must be sted n decreas ng order of frequency f frequency nformat on cannot be re ab y determ ned, adverse
`react ons must be sted n decreas ng order of sever ty
`
`(A) Clinical trials experience. Th s sect on must st the adverse react ons dent Eed n c n ca tr a s that occurred at or above
`a spec Eed rate appropr ate to the safety database The rate of occurrence of an adverse react on for the drug and
`comparators (e g , p acebo) must be presented, un ess such data cannot be determ ned or presentat on of comparator
`rates wou d be m s ead ng f adverse react ons that occurred be ow the spec Eed rate are nc uded, they must be
`nc uded n a separate st ng f comparat ve rates of occurrence cannot be re ab y determ ned (e g , adverse react ons
`were observed on y n the uncontro ed tr a port on of the overa safety database), adverse react ons must be grouped
`w th n spec Eed frequency ranges as appropr ate to the safety database for the drug (e g , adverse react ons occurr ng at
`a rate of ess than 1/100, adverse react ons occurr ng at a rate of ess than 1/500) or descr pt ve y dent Eed, f frequency
`ranges cannot be determ ned For adverse react ons w th s gn Ecant c n ca mp cat ons, the st ngs must be
`supp emented w th add t ona deta about the nature, frequency, and sever ty of the adverse react on and the
`re at onsh p of the adverse react on to drug dose and demograph c character st cs, f data are ava ab e and mportant
`
`(B) Postmarketing experience. Th s sect on of the abe ng must st the adverse react ons, as deEned n paragraph (c)(7) of
`th s sect on, that are dent Eed from domest c and fore gn spontaneous reports Th s st ng must be separate from the
`st ng of adverse react ons dent Eed n c n ca tr a s
`
`(
`
`) Comparisons of adverse reactions between drugs. For drug products other than b o og ca products, any c a m compar ng the
`drug to wh ch the abe ng app es w th other drugs n terms of frequency, sever ty, or character of adverse react ons must be
`based on adequate and we -contro ed stud es as deEned n § 314 126(b) of th s chapter un ess th s requ rement s wa ved
`under § 201 58 or § 314 126(c) of th s chapter For b o og ca products, any such c a m must be based on substant a
`ev dence
`
`(8) 7 Drug interactions.
`
`Novartis Exhibit 2193.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`( )
`
` Th s sect on must conta n a descr pt on of c n ca y s gn Ecant nteract ons, e ther observed or pred cted, w th other
`prescr pt on or over-the-counter drugs, c asses of drugs, or foods (e g , d etary supp ements, grapefru t ju ce), and spec Ec
`pract ca nstruct ons for prevent ng or manag ng them The mechan sm(s) of the nteract on, f known, must be br e`y
`descr bed nteract ons that are descr bed n the “Contra nd cat ons” or “Warn ngs and Precaut ons” sect ons must be
`d scussed n more deta under th s sect on Deta s of drug nteract on pharmacok net c stud es that are nc uded n the
`“C n ca Pharmaco ogy” sect on that are pert nent to c n ca use of the drug must not be repeated n th s sect on
`
`( ) Th s sect on must a so conta n pract ca gu dance on known nterference of the drug w th aboratory tests
`
`(9) 8 Use in speciEc populations. Th s sect on must conta n the fo ow ng subsect ons
`
`( )
`
` 8.1 Pregnancy. Th s subsect on of the abe ng must conta n the fo ow ng nformat on n the fo ow ng order under the
`subhead ngs “Pregnancy Exposure Reg stry,” “R sk Summary,” “C n ca Cons derat ons,” and “Data”
`
`(A) Pregnancy exposure registry. f there s a sc ent Eca y acceptab e pregnancy exposure reg stry for the drug, contact
`nformat on needed to enro n the reg stry or to obta n nformat on about the reg stry must be prov ded fo ow ng the
`statement “There s a pregnancy exposure reg stry that mon tors pregnancy outcomes n women exposed to (name of
`drug) dur ng pregnancy ”
`
`(B) Risk summary. The R sk Summary must conta n r sk statement(s) based on data from a re evant sources (human,
`an ma , and/or pharmaco og c) that descr be, for the drug, the r sk of adverse deve opmenta outcomes (i.e., structura
`abnorma t es, embryo-feta and/or nfant morta ty, funct ona mpa rment, a terat ons to growth) When mu t p e data
`sources are ava ab e, the statements must be presented n the fo ow ng order Human, an ma , pharmaco og c The
`source(s) of the data must be stated The abe ng must state the percentage range of ve b rths n the Un ted States
`w th a major b rth defect and the percentage range of pregnanc es n the Un ted States that end n m scarr age,
`regard ess of drug exposure f such nformat on s ava ab e for the popu at on(s) for wh ch the drug s abe ed, t must
`a so be nc uded When use of a drug s contra nd cated dur ng pregnancy, th s nformat on must be stated Erst n the
`R sk Summary When app cab e, r sk statements as descr bed n paragraphs (c)(9)( )(B)(1) and (2) of th s sect on must
`nc ude a cross-reference to add t ona deta s n the re evant port on of the “Data” subhead ng n the “Pregnancy”
`subsect on of the abe ng f data demonstrate that a drug s not system ca y absorbed fo ow ng a part cu ar route of
`adm n strat on, the R sk Summary must conta n on y the fo ow ng statement “(Name of drug) s not absorbed
`system ca y fo ow ng (route of adm n strat on), and materna use s not expected to resu t n feta exposure to the drug ”
`
`(1) Risk statement based on human data. When human data are ava ab e that estab sh the presence or absence of any
`adverse deve opmenta outcome(s) assoc ated w th materna use of the drug, the R sk Summary must summar ze
`the spec Ec deve opmenta outcome(s); the r nc dence; and the effects of dose, durat on of exposure, and
`gestat ona t m ng of exposure f human data nd cate that there s an ncreased r sk for a spec Ec adverse
`deve opmenta outcome n nfants born to women exposed to the drug dur ng pregnancy, th s r sk must be
`quant tat ve y compared to the r sk for the same outcome n nfants born to women who were not exposed to the
`drug but who have the d sease or cond t on for wh ch the drug s nd cated to be used When r sk nformat on s not
`ava ab e for women w th the d sease or cond t on for wh ch the drug s nd cated, the r sk for the spec Ec outcome
`must be compared to the rate at wh ch the outcome occurs n the genera popu at on The R sk Summary must
`state when there are no human data or when ava ab e human data do not estab sh the presence or absence of
`drug-assoc ated r sk
`
`(2) Risk statement based on animal data. When an ma data are ava ab e, the R sk Summary must summar ze the
`End ngs n an ma s and based on these End ngs, descr be, for the drug, the potent a r sk of any adverse
`deve opmenta outcome(s) n humans Th s statement must nc ude The number and type(s) of spec es affected,
`t m ng of exposure, an ma doses expressed n terms of human dose or exposure equ va ents, and outcomes for
`pregnant an ma s and offspr ng When an ma stud es do not meet current standards for nonc n ca deve opmenta
`tox c ty stud es, the R sk Summary must so state When there are no an ma data, the R sk Summary must so state
`
`(3) Risk statement based on pharmacology. When the drug has a we -understood mechan sm of act on that may resu t
`n adverse deve opmenta outcome(s), the R sk Summary must exp a n the mechan sm of act on and the potent a
`assoc ated r sks
`
`(C) Clinical considerations. Under the subhead ng “C n ca Cons derat ons,” the abe ng must prov de re evant nformat on,
`to the extent t s ava ab e, under the head ngs “D sease-assoc ated materna and/or embryo/feta r sk,” “Dose
`adjustments dur ng pregnancy and the postpartum per od,” “Materna adverse react ons,” “Feta /Neonata adverse
`react ons,” and “Labor or de very”
`
`(1) Disease-associated maternal and/or embryo/fetal risk. f there s a ser ous known or potent a r sk to the pregnant
`woman and/or the embryo/fetus assoc ated w th the d sease or cond t on for wh ch the drug s nd cated to be
`used, the abe ng must descr be the r sk
`
`(2) Dose adjustments during pregnancy and the postpartum period. f there are pharmacok net c data that support dose
`adjustment(s) dur ng pregnancy and the postpartum per od, a summary of th s nformat on must be prov ded
`
`(3) Maternal adverse reactions. f use of the drug s assoc ated w th a materna adverse react on that s un que to
`pregnancy or f a known adverse react on occurs w th ncreased frequency or sever ty n pregnant women, the
`abe ng must descr be the adverse react on and ava ab e ntervent on(s) for mon tor ng or m t gat ng the react on
`
`Novartis Exhibit 2193.005
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`The abe ng must descr be, f known, the effect of dose, t m ng, and durat on of exposure on the r sk to the
`pregnant woman of exper enc ng the adverse react on
`
`(4) Fetal/Neonatal adverse reactions. f t s known or ant c pated that treatment of the pregnant woman ncreases or
`may ncrease the r sk of an adverse react on n the fetus or neonate, the abe ng must descr be the adverse
`react on, the potent a sever ty and revers b ty of the adverse react on, and ava ab e ntervent on(s) for mon tor ng
`or m t gat ng the react on The abe ng must descr be, f known, the effect of dose, t m ng, and durat on of exposure
`on the r sk
`
`(5) Labor or delivery. f the drug s expected to affect abor or de very, the abe ng must prov de nformat on about the
`effect of the drug on the pregnant woman and the fetus or neonate; the effect of the drug on the durat on of abor
`and de very; any ncreased r sk of adverse react ons, nc ud ng the r potent a sever ty and revers b ty; and must
`prov de nformat on about ava ab e ntervent on(s) that can m t gate these effects and/or adverse react ons The
`nformat on descr bed under th s head ng s not requ red for drugs approved for use on y dur ng abor and de very
`
`(D) Data -
`
`(1) “Data” subheading. Under the subhead ng “Data,” the abe ng must descr be the data that are the bas s for the R sk
`Summary and C n ca Cons derat ons
`
`(2) Human and animal data headings. Human and an ma data must be presented separate y, beneath the head ngs
`“Human Data” and “An ma Data,” and human data must be presented Erst
`
`(3) Description of human data. For human data, the abe ng must descr be adverse deve opmenta outcomes, adverse
`react ons, and other adverse effects To the extent app cab e, the abe ng must descr be the types of stud es or
`reports, number of subjects and the durat on of each study, exposure nformat on, and m tat ons of the data Both
`pos t ve and negat ve study End ngs must be nc uded
`
`(4) Description of animal data. For an ma data, the abe ng must descr be the fo ow ng Types of stud es, an ma
`spec es, dose, durat on and t m ng of exposure, study End ngs, presence or absence of materna tox c ty, and
`m tat ons of the data Descr pt on of materna and offspr ng End ngs must nc ude dose-response and sever ty of
`adverse deve opmenta outcomes An ma doses or exposures must be descr bed n terms of human dose or
`exposure equ va ents and the bas s for those ca cu at ons must be nc uded
`
`( ) 8.2 Lactation. Th s subsect on of the abe ng must conta n the fo ow ng nformat on n the fo ow ng order under the
`subhead ngs “R sk Summary,” “C n ca Cons derat ons,” and “Data”
`
`(A) Risk summary. When re evant human and/or an ma actat on data are ava ab e, the R sk Summary must nc ude a cross-
`reference to the “Data” subhead ng n the “Lactat on” subsect on of the abe ng When human data are ava ab e, an ma
`data must not be nc uded un ess the an ma mode s spec Eca y known to be pred ct ve for humans When use of a
`drug s contra nd cated dur ng breastfeed ng, th s nformat on must be stated Erst n the R sk Summary
`
`(1) Drug not absorbed systemically. f data demonstrate that the drug s not system ca y absorbed by the mother, the
`R sk Summary must conta n on y the fo ow ng statement “(Name of drug) s not absorbed system ca y by the
`mother fo ow ng (route of adm n strat on), and breastfeed ng s not expected to resu t n exposure of the ch d to
`(name of drug) ”
`
`(2) Drug absorbed systemically. f the drug s absorbed system ca y, the R sk Summary must descr be the fo ow ng to
`the extent re evant nformat on s ava ab e
`
`(i)
`
` Presence of drug in human milk. The R sk Summary must state whether the drug and/or ts act ve
`metabo te(s) are present n human m k f there are no data to assess th s, the R sk Summary must so state
`f stud es demonstrate that the drug and/or ts act ve metabo te(s) are not detectab e n human m k, the R sk
`Summary must state the m ts of the assay used f stud es demonstrate the presence of the drug and/or ts
`act ve metabo te(s) n human m k, the R sk Summary must state the concentrat on of the drug and/or ts
`act ve metabo te(s) n hu