A UTHENTICATE.~
`V.S. COVERNMEN T
`INFORMATION
`GPO
`
`§201.57
`
`required by
`information
`the
`only
`§201.57(a)(l)(i), (ii), (iii) , and (iv) and
`§201.lOO(e). The inform at ion required
`by §201.57(a)(l)(i) , (ii), (iii) , and (iv)
`shall appear in the " Description " sec (cid:173)
`tion of the labeling, whether or not it
`also appears in a "Product Title."
`(e) The labeling shall contain the
`date of the most recent rev ision of the
`la be ling,
`identified as such , placed
`prominently immediately after the last
`section of the labeling.
`[44 F R 37462,June26, 1979]
`
`§ 201-57 Specific requirements on con(cid:173)
`tent and format of
`labeling
`for
`human prescription drugs.
`in
`Each
`section heading
`listed
`§201.56(d) ,
`if not
`omitted under
`§201.56(d)(3), shall contain
`the
`fo l (cid:173)
`lowing information in the following
`order:
`(a) Description. (1) Under this section
`heading, the labeling shall contain:
`(i) The proprietary name and the es(cid:173)
`tablished name, if any, as defined in
`sect ion 502(e)(2) of the act , of the drug;
`(ii) The type of dosage form and the
`route of administration to which the
`labeling applies;
`(iii) The same qualitative and/or
`quantitative ingredient information as
`required under §201.lOO(b) for labels ;
`(iv) If the product is sterile , a state (cid:173)
`ment of that fact;
`(v) The pharmacological or thera (cid:173)
`peutic class oft he drug ;
`(vi) The chemical name and struc(cid:173)
`tural formula of the drug ;
`(vii) If the product is radioactive, a
`statement of the important nuclear
`physical characteristics , such as the
`principal radiation em ission data, ex(cid:173)
`ternal radiation, and physical decay
`char act eris t ics .
`(2) If appropriate , other important
`chemical or physic a 1 information, such
`as physica l constants , or pH , shall be
`stated.
`(b) Clin ical Pharmacology . (1) Under
`this section heading , the labeling shall
`contain a concise factua l summary of
`the clinical pharmacology and actions
`of the drug in humans . The summary
`may include information based on in
`vitro and/or anima l data if the infor (cid:173)
`mation is essential to a description of
`the biochemica l and/or physiological
`mode of action of the drug or is other -
`
`21 CFR Ch. I (4-1 -04 Edition)
`
`w ise pertinent to human therapeutics.
`Pharmacok inetic information that is
`important to safe and effective use of
`the drug is required , if known , e.g., de(cid:173)
`gree and rate of absorptio n , pathways
`of biot ransform at ion , percent age of
`dose as unchanged drug and metabo(cid:173)
`lites , rate or half-time of elimination ,
`concentration in body fluids associated
`with therapeutic and/or toxic effects ,
`degree of binding to plasma proteins,
`degree of uptake by a particular organ
`or in the fetus, and passage across the
`blood brain barrier . Inclusion of phar (cid:173)
`m acok inet ic information is restricted
`to that which relates to clinica l use of
`the drug. If the pharmacologica l mode
`of action of the drug is u nk now n or if
`important metabolic or pharmaco(cid:173)
`k inetic data in humans are unavai l (cid:173)
`able, the labeling shall contain a state (cid:173)
`ment about the lack of information.
`(2) Data that demonstrate activity or
`effectivene-ss in in vitro or animal tests
`and that ha ve not been s hown by ade(cid:173)
`quate and well-controlled clinical stud(cid:173)
`ies to be pertinent to clinical use may
`be included under th is section of the la(cid:173)
`beling only under the following cir(cid:173)
`cumstances:
`(i) In vitro data for anti-infective
`drugs may be included if the data are
`immediately preceded by
`the state(cid:173)
`me n t " The following in vitro data are
`available but their clinical significance
`is un k nown ."
`(ii) For other classes of drugs, in
`vitro and animal data that have not
`been s hown by adequate and well-con(cid:173)
`trolled clinical studies , as defined in
`§314.126(b) of this chapter , to be perti(cid:173)
`nent to clinical use may be used only if
`a waiver is granted under §201.58 or
`§314.126(b) of this chapter .
`(c) Indications and Usage. (1) Under
`this section heading , the labeling shall
`state that:
`(i) The drug is indicated in the treat (cid:173)
`ment, prevention, or diagnosis of a rec (cid:173)
`ognized disease or condition, e.g ., peni(cid:173)
`cillin is indicated for the treatment of
`pneumonia
`due
`to
`susceptible
`pneumococci ; and/or
`(ii) The drug is indicated for the
`treatment , prevent ion, or diagnosis of
`an important manifestation of a dis (cid:173)
`ease or condition, e.g., chlorot hiazide
`is indicated for the treatment of edema
`
`22
`
`Novartis Exhibit 2191.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Food and Drug Administration, HHS
`in pa t ien t s wit h con gest ive h ea r t fa il-
`u r e; a n d/or
`(iii) T h e dr u g is in dica t ed for t h e r e-
`lief of sy m pt om s a ssocia t ed wit h a dis-
`ea se
`or
`sy n dr om e,
`e.g.,
`ch lor ph en ir a m in e is in dica t ed for t h e
`sy m pt om a t ic r elief of n a sa l con gest ion
`in pa t ien t s wit h va som ot or r h in it is;
`a n d/or
`(iv) T h e dr u g, if u sed for a pa r t icu la r
`in dica t ion on ly in con ju ct ion wit h a
`pr im a r y m ode of t h er a py , e.g., diet ,
`su r ger y , or som e ot h er dr u g, is a n a d-
`ju n ct t o t h e m ode of t h er a py .
`(2) All in dica t ion s sh a ll be su ppor t ed
`by su bst a n t ia l eviden ce of effect iven ess
`ba sed on a dequ a t e a n d well-con t r olled
`st u dies a s defin ed in §314.126(b) of t h is
`ch a pt er u n less
`t h e
`r equ ir em en t
`is
`wa ived u n der §201.58 or §314.126(b) of
`t h is ch a pt er .
`(3) T h is sect ion of t h e la belin g sh a ll
`a lso con t a in t h e followin g a ddit ion a l
`in for m a t ion :
`(i) If eviden ce is a va ila ble t o su ppor t
`t h e sa fet y a n d effect iven ess of t h e dr u g
`on ly in select ed su bgr ou ps of t h e la r ger
`popu la t ion wit h a disea se, sy n dr om e,
`or sy m pt om u n der con sider a t ion , e.g.,
`pa t ien t s wit h m ild disea se or pa t ien t s
`in a specia l a ge gr ou p, t h e la belin g
`sh a ll descr ibe t h e a va ila ble eviden ce
`a n d st a t e t h e lim it a t ion s of u sefu ln ess
`of t h e dr u g. T h e la belin g sh a ll a lso
`iden t ify specific t est s n eeded for selec-
`t ion or m on it or in g of t h e pa t ien t s wh o
`n eed t h e dr u g, e.g., m icr obe su scept i-
`bilit y t est s. In for m a t ion on t h e a ppr ox-
`im a t e k in d, degr ee, a n d du r a t ion of im -
`pr ovem en t t o be a n t icipa t ed sh a ll be
`st a t ed if a va ila ble a n d sh a ll be ba sed
`on su bst a n t ia l eviden ce der ived fr om
`a dequ a t e a n d well-con t r olled st u dies a s
`defin ed in §314.126(b) of t h is ch a pt er
`u n less t h e r equ ir em en t is wa ived u n der
`§201.58 or §314.126(b) of t h is ch a pt er . If
`t h e in for m a t ion is r eleva n t t o t h e r ec-
`om m en ded in t er va ls bet ween doses, t h e
`u su a l du r a t ion of t r ea t m en t , or a n y
`m odifica t ion of dosa ge, it sh a ll be st a t -
`ed in t h e ‘‘Dosa ge a n d Adm in ist r a t ion ’’
`sect ion of t h e la belin g a n d r efer en ced
`in t h is sect ion .
`(ii) If sa fet y con sider a t ion s a r e su ch
`t h a t t h e dr u g sh ou ld be r eser ved for
`cer t a in sit u a t ion s, e.g., ca ses r efr a c-
`t or y t o ot h er dr u gs, t h is in for m a t ion
`sh a ll be st a t ed in t h is sect ion .
`
`§ 201.57
`(iii) If t h er e a r e specific con dit ion s
`t h a t sh ou ld be m et befor e t h e dr u g is
`u sed on a lon g-t er m ba sis, e.g., dem -
`on st r a t ion of
`r espon siven ess
`t o
`t h e
`dr u g in a sh or t -t er m t r ia l, t h e la belin g
`sh a ll iden t ify t h e con dit ion s; or , if t h e
`in dica t ion s for lon g-t er m u se a r e dif-
`fer en t fr om t h ose for sh or t -t er m u se,
`t h e la belin g sh a ll iden t ify t h e specific
`in dica t ion s for ea ch u se.
`(iv) If t h er e is a com m on belief t h a t
`t h e dr u g m a y be effect ive for a cer t a in
`u se or if t h er e is a com m on u se of t h e
`dr u g for a con dit ion , bu t t h e pr epon -
`der a n ce of eviden ce r ela t ed t o t h e u se
`or con dit ion sh ows t h a t t h e dr u g is in -
`effect ive, t h e F ood a n d Dr u g Adm in is-
`t r a t ion m a y r equ ir e t h a t t h e la belin g
`st a t e t h a t t h er e is a la ck of eviden ce
`t h a t t h e dr u g is effect ive for t h a t u se
`or con dit ion .
`(v) An y st a t em en t s com pa r in g t h e
`sa fet y or effect iven ess, eit h er gr ea t er
`or less, of t h e dr u g wit h ot h er a gen t s
`for t h e sa m e in dica t ion sh a ll be su p-
`por t ed by a dequ a t e a n d well-con t r olled
`st u dies a s defin ed in §314.126(b) of t h is
`ch a pt er u n less
`t h is
`r equ ir em en t
`is
`wa ived u n der §201.58 or §314.126(b) of
`t h is ch a pt er .
`(d) Con train dication s. Un der t h is sec-
`t ion h ea din g,
`t h e
`la belin g sh a ll de-
`scr ibe t h ose sit u a t ion s in wh ich t h e
`dr u g sh ou ld n ot be u sed beca u se t h e
`r isk of u se clea r ly ou t weigh s a n y pos-
`sible ben efit . T h ese sit u a t ion s in clu de
`a dm in ist r a t ion of t h e dr u g t o pa t ien t s
`k n own t o h a ve a h y per sen sit ivit y t o it ;
`u se of t h e dr u g in pa t ien t s wh o, be-
`ca u se of t h eir pa r t icu la r a ge, sex, con -
`com it a n t
`t h er a py , disea se st a t e, or
`ot h er con dit ion , h a ve a su bst a n t ia l
`r isk of bein g h a r m ed by it ; or con t in -
`u ed u se of t h e dr u g in t h e fa ce of a n u n -
`a ccept a bly h a za r dou s a dver se r ea ct ion .
`Kn own h a za r ds a n d n ot t h eor et ica l pos-
`sibilit ies sh a ll be list ed, e.g., if h y per -
`sen sit ivit y t o t h e dr u g h a s n ot been
`dem on st r a t ed, it sh ou ld n ot be list ed a s
`a con t r a in dica t ion . If n o con t r a in dica -
`t ion s a r e k n own , t h is sect ion of t h e la -
`belin g sh a ll st a t e ‘‘Non e k n own .’’
`(e) W arn in gs. Un der t h is sect ion h ea d-
`in g, t h e la belin g sh a ll descr ibe ser iou s
`a dver se r ea ct ion s a n d pot en t ia l sa fet y
`h a za r ds, lim it a t ion s in u se im posed by
`t h em , a n d st eps t h a t sh ou ld be t a k en if
`t h ey occu r . T h e la belin g sh a ll be r e-
`vised t o in clu de a wa r n in g a s soon a s
`23
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`Novartis Exhibit 2191.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`21 CFR Ch. I (4–1–04 Edition)
`§ 201.57
`r epr in t ed a t t h e en d of t h e la belin g.
`t h er e is r ea son a ble eviden ce of a n a sso-
`T h e pr in t size r equ ir em en t s for
`t h e
`cia t ion of a ser iou s h a za r d wit h a dr u g;
`Medica t ion Gu ide set for t h in §208.20 of
`a ca u sa l r ela t ion sh ip n eed n ot h a ve
`t h is ch a pt er , h owever , do n ot a pply t o
`been pr oved. A specific wa r n in g r ela t -
`t h e Medica t ion Gu ide t h a t is r epr in t ed
`in g t o a u se n ot pr ovided for u n der t h e
`in t h e pr ofession a l la belin g.
`‘‘In dica t ion s a n d Usa ge’’ sect ion of t h e
`(3) L aboratory tests. T h is su bsect ion of
`la belin g m a y be r equ ir ed by t h e F ood
`t h e la belin g sh a ll iden t ify a n y la bor a -
`a n d Dr u g Adm in ist r a t ion if t h e dr u g is
`t or y t est s t h a t m a y be h elpfu l in fol-
`com m on ly pr escr ibed for a disea se or
`lowin g
`t h e pa t ien t ’s r espon se or
`in
`con dit ion , a n d t h er e is la ck of su bst a n -
`iden t ify in g possible a dver se r ea ct ion s.
`t ia l eviden ce of effect iven es for t h a t
`If a ppr opr ia t e,
`in for m a t ion sh a ll be
`disea se or con dit ion , a n d su ch u sa ge is
`pr ovided on su ch fa ct or s a s t h e r a n ge
`a ssocia t ed wit h ser iou s r isk or h a za r d.
`of n or m a l a n d a bn or m a l va lu es ex-
`S pecia l pr oblem s, pa r t icu la r ly
`t h ose
`pect ed in t h e pa r t icu la r sit u a t ion a n d
`t h a t m a y lea d t o dea t h or ser iou s in -
`t h e
`r ecom m en ded
`fr equ en cy wit h
`ju r y , m a y be r equ ir ed by t h e F ood a n d
`wh ich t est s sh ou ld be don e befor e, du r -
`Dr u g Adm in ist r a t ion t o be pla ced in a
`in g, a n d a ft er t h er a py .
`pr om in en t ly displa y ed box. T h e boxed
`(4)(i) Dru g
`in teraction s. T h is
`su b-
`wa r n in g or din a r ily sh a ll be ba sed on
`sect ion of t h e la belin g sh a ll con t a in
`clin ica l da t a , bu t ser iou s a n im a l t ox-
`specific pr a ct ica l gu ida n ce for t h e ph y -
`icit y m a y a lso be t h e ba sis of a boxed
`sicia n on pr even t in g clin ica lly sign ifi-
`wa r n in g in t h e a bsen ce of clin ica l da t a .
`ca n t dr u g/dr u g a n d dr u g/food
`in t er -
`If a boxed wa r n in g is r equ ir ed, it s loca -
`a ct ion s t h a t m a y occu r in vivo in pa -
`t ion will be specified by t h e F ood a n d
`t ien t s t a k in g t h e dr u g. S pecific dr u gs
`Dr u g Adm in ist r a t ion . T h e fr equ en cy of
`or cla sses of dr u gs wit h wh ich t h e dr u g
`t h ese ser iou s a dver se r ea ct ion s a n d, if
`t o wh ich
`t h e
`la belin g a pplies m a y
`k n own , t h e a ppr oxim a t e m or t a lit y a n d
`in t er a ct in vivo sh a ll be iden t ified, a n d
`m or bidit y r a t es for pa t ien t s su st a in in g
`t h e m ech a n ism (s) of
`t h e
`in t er a ct ion
`t h e r ea ct ion , wh ich a r e im por t a n t t o
`sh a ll be br iefly descr ibed. In for m a t ion
`sa fe a n d effect ive u se of t h e dr u g, sh a ll
`in t h is su bsect ion of t h e la belin g sh a ll
`be expr essed a s pr ovided u n der
`t h e
`be lim it ed t o t h a t per t a in in g t o clin -
`‘‘Adver se R ea ct ion s’’ sect ion of t h e la -
`ica l u se of t h e dr u g in pa t ien t s. Dr u g
`belin g.
`in t er a ct ion s su ppor t ed on ly by a n im a l
`(f) Precau tion s. Un der
`t h is sect ion
`or in vit r o exper im en t s m a y n ot or di-
`h ea din g, t h e la belin g sh a ll con t a in t h e
`n a r ily be in clu ded, bu t a n im a l or in
`followin g su bsect ion s a s a ppr opr ia t e
`vit r o da t a m a y be u sed if sh own t o be
`for t h e dr u g:
`clin ica lly
`r eleva n t . Dr u g
`in com pa t i-
`(1) Gen eral. T h is su bsect ion of t h e la -
`bilit ies,
`i.e., dr u g
`in t er a ct ion s
`t h a t
`belin g sh a ll con t a in
`in for m a t ion r e-
`m a y occu r wh en dr u gs a r e m ixed in
`ga r din g a n y specia l ca r e t o be exer -
`vit r o, a s in a solu t ion for in t r a ven ou s
`cised by t h e pr a ct it ion er for sa fe a n d
`a dm in ist r a t ion ,
`sh a ll
`be
`discu ssed
`effect ive u se of
`t h e dr u g, e.g., pr e-
`u n der
`t h e ‘‘Dosa ge a n d Adm in ist r a -
`ca u t ion s n ot r equ ir ed u n der a n y ot h er
`t ion ’’ sect ion of t h e la belin g r a t h er
`specific sect ion or su bsect ion of t h e la -
`t h a n u n der t h is su bsect ion of t h e la bel-
`belin g.
`in g.
`(2) In formation for patien ts. T h is su b-
`(ii) Dru g/laboratory
`sect ion of t h e la belin g sh a ll con t a in in -
`test
`in teraction s.
`T h is su bsect ion of t h e la belin g sh a ll
`for m a t ion t o be given t o pa t ien t s for
`con t a in pr a ct ica l gu ida n ce on k n own
`sa fe a n d effect ive u se of t h e dr u g, e.g.,
`in t er fer en ce of t h e dr u g wit h la bor a -
`pr eca u t ion s con cer n in g dr ivin g or t h e
`t or y t est s.
`con com it a n t u se of ot h er su bst a n ces
`(5) Carcin ogen esis, mu tagen esis, impair-
`t h a t m a y h a ve h a r m fu l a ddit ive ef-
`men t of fertility . T h is su bsect ion of t h e
`fect s. An y pr in t ed pa t ien t in for m a t ion
`la belin g sh a ll st a t e wh et h er lon g-t er m
`or Medica t ion Gu ide r equ ir ed u n der
`st u dies in a n im a ls h a ve been per for m ed
`t h is ch a pt er t o be dist r ibu t ed t o t h e
`t o eva lu a t e ca r cin ogen ic pot en t ia l a n d,
`pa t ien t sh a ll be r efer r ed t o u n der t h e
`if so, t h e species a n d r esu lt s. If r epr o-
`‘‘P r eca u t ion s’’ sect ion of t h e la belin g
`du ct ion st u dies or ot h er da t a in a n i-
`a n d t h e fu ll t ext of su ch pa t ien t in for -
`m a t ion or Medica t ion Gu ide sh a ll be
`m a ls r evea l a pr oblem or pot en t ia l
`24
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`Novartis Exhibit 2191.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`§ 201.57
`Food and Drug Administration, HHS
`la belin g sh a ll a lso con t a in a descr ip-
`pr oblem con cer n in g m u t a gen esis or im -
`t ion of a va ila ble da t a on t h e effect of
`pa ir m en t of fer t ilit y in eit h er m a les or
`t h e dr u g on t h e la t er gr owt h , develop-
`fem a les, t h e in for m a t ion sh a ll be de-
`m en t , a n d fu n ct ion a l m a t u r a t ion of t h e
`scr ibed. An y pr eca u t ion a r y st a t em en t
`ch ild.
`on t h ese t opics sh a ll in clu de pr a ct ica l,
`(b) Pregn an cy category B . If a n im a l r e-
`r eleva n t a dvice t o t h e ph y sicia n on t h e
`pr odu ct ion st u dies h a ve fa iled t o dem -
`sign ifica n ce of t h ese a n im a l fin din gs. If
`on st r a t e a r isk t o t h e fet u s a n d t h er e
`t h er e is eviden ce fr om h u m a n da t a t h a t
`a r e n o a dequ a t e a n d well-con t r olled
`t h e dr u g m a y be ca r cin ogen ic or m u t a -
`st u dies in pr egn a n t wom en , t h e la bel-
`gen ic or t h a t it im pa ir s fer t ilit y , t h is
`in g sh a ll st a t e: ‘‘P r egn a n cy Ca t egor y
`in for m a t ion sh a ll be in clu ded u n der t h e
`B. R epr odu ct ion st u dies h a ve been per -
`‘‘Wa r n in gs’’ sect ion of
`t h e
`la belin g.
`for m ed in (k in d (s) of an imal(s)) a t doses
`Also, u n der ‘‘P r eca u t ion s,’’ t h e la bel-
`u p t o (x) t im es t h e h u m a n dose a n d
`in g sh a ll st a t e: ‘‘S ee ‘Wa r n in gs’ sect ion
`h a ve r evea led n o eviden ce of im pa ir ed
`for
`in for m a t ion
`on
`ca r cin ogen esis,
`fer t ilit y or h a r m t o t h e fet u s du e t o
`m u t a gen esis, a n d im pa ir m en t of fer -
`(n ame of dru g). T h er e a r e, h owever , n o
`t ilit y .’’
`a dequ a t e a n d well-con t r olled st u dies in
`(6) Pregn an cy . T h is su bsect ion of t h e
`pr egn a n t wom en . Beca u se a n im a l r e-
`la belin g m a y be om it t ed on ly if t h e
`pr odu ct ion st u dies a r e n ot a lwa y s pr e-
`dr u g is n ot a bsor bed sy st em ica lly a n d
`dict ive of h u m a n r espon se, t h is dr u g
`t h e dr u g is n ot k n own t o h a ve a pot en -
`sh ou ld be u sed du r in g pr egn a n cy on ly
`t ia l for in dir ect h a r m t o t h e fet u s. F or
`if clea r ly n eeded.’’ If a n im a l r epr odu c-
`a ll ot h er dr u gs, t h is su bsect ion of t h e
`t ion st u dies h a ve sh own a n a dver se ef-
`la belin g sh a ll con t a in t h e followin g in -
`fect (ot h er t h a n decr ea se in fer t ilit y ),
`for m a t ion :
`bu t a dequ a t e a n d well-con t r olled st u d-
`(i) T eratogen ic effects. Un der
`t h is
`ies in pr egn a n t wom en h a ve fa iled t o
`h ea din g t h e la belin g sh a ll iden t ify on e
`dem on st r a t e a r isk t o t h e fet u s du r in g
`of t h e followin g ca t egor ies t h a t a pplies
`t h e fir st t r im est er of pr egn a n cy (a n d
`t o t h e dr u g, a n d t h e la belin g sh a ll bea r
`t h er e is n o eviden ce of a r isk in la t er
`t h e st a t em en t r equ ir ed u n der t h e ca t -
`t r im est er s), t h e la belin g sh a ll st a t e:
`egor y :
`‘‘P r egn a n cy Ca t egor y B. R epr odu ct ion
`(a) Pregn an cy category A . If a dequ a t e
`st u dies in (k in d(s) of an imal(s)) h a ve
`a n d well-con t r olled st u dies in pr egn a n t
`sh own (describe fin din gs) a t (x ) t im es
`wom en h a ve fa iled t o dem on st r a t e a
`t h e h u m a n dose. S t u dies in pr egn a n t
`r isk t o t h e fet u s in t h e fir st t r im est er
`wom en , h owever , h a ve n ot sh own t h a t
`of pr egn a n cy (a n d t h er e is n o eviden ce
`(n ame of dru g) in cr ea ses t h e r isk of a b-
`of a r isk in la t er t r im est er s), t h e la bel-
`n or m a lit ies wh en a dm in ist er ed du r in g
`in g sh a ll st a t e: ‘‘P r egn a n cy Ca t egor y
`t h e
`fir st
`(secon d,
`th ird, or all)
`t r i-
`A. S t u dies in pr egn a n t wom en h a ve n ot
`m est er (s) of pr egn a n cy . Despit e
`t h e
`sh own t h a t (n ame of dru g) in cr ea ses t h e
`a n im a l fin din gs, it wou ld a ppea r t h a t
`r isk of fet a l a bn or m a lit ies if a dm in is-
`t h e possibilit y of fet a l h a r m is r em ot e,
`t er ed du r in g t h e fir st (secon d, th ird, or
`if t h e dr u g is u sed du r in g pr egn a n cy .
`all) t r im est er (s) of pr egn a n cy . If t h is
`Never t h eless, beca u se
`t h e st u dies
`in
`dr u g is u sed du r in g pr egn a n cy , t h e pos-
`h u m a n s ca n n ot r u le ou t t h e possibilit y
`sibilit y of fet a l h a r m a ppea r s r em ot e.
`of h a r m , (n ame of dru g) sh ou ld be u sed
`Beca u se st u dies ca n n ot r u le ou t t h e
`du r in g pr egn a n cy on ly if clea r ly n eed-
`possibilit y of h a r m , h owever , (n ame of
`ed.’’ T h e la belin g sh a ll a lso con t a in a
`dru g) sh ou ld be u sed du r in g pr egn a n cy
`descr ipt ion of t h e h u m a n st u dies a n d a
`on ly if clea r ly n eeded.’’ T h e la belin g
`descr ipt ion of a va ila ble da t a on t h e ef-
`sh a ll a lso con t a in a descr ipt ion of t h e
`fect of t h e dr u g on t h e la t er gr owt h ,
`h u m a n st u dies. If a n im a l r epr odu ct ion
`developm en t , a n d fu n ct ion a l m a t u r a -
`st u dies a r e a va ila ble a n d t h ey fa il t o
`t ion of t h e ch ild.
`dem on st r a t e a r isk t o t h e fet u s, t h e la -
`(c) Pregn an cy category C. If a n im a l r e-
`belin g sh a ll a lso st a t e: ‘‘R epr odu ct ion
`pr odu ct ion st u dies h a ve sh own a n a d-
`st u dies h a ve been per for m ed in (k in ds
`ver se effect on t h e fet u s, if t h er e a r e n o
`of an imal(s)) a t doses u p t o (x) t im es t h e
`a dequ a t e a n d well-con t r olled st u dies in
`h u m a n dose a n d h a ve r evea led n o evi-
`h u m a n s, a n d if t h e ben efit s fr om t h e
`den ce of im pa ir ed fer t ilit y or h a r m t o
`t h e fet u s du e t o (n ame of dru g).’’ T h e
`u se of t h e dr u g in pr egn a n t wom en m a y
`25
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`Novartis Exhibit 2191.004
`Regeneron v. Novartis, IPR2021-00816
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`

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`21 CFR Ch. I (4–1–04 Edition)
`§ 201.57
`bot h , a n d t h e r isk of t h e u se of t h e
`it s pot en t ia l
`be a ccept a ble despit e
`r isk s, t h e la belin g sh a ll st a t e: ‘‘P r eg-
`dr u g in a pr egn a n t wom a n clea r ly ou t -
`n a n cy Ca t egor y C. (Name of dru g) h a s
`weigh s a n y possible ben efit (for exa m -
`been sh own t o be t er a t ogen ic (or t o
`ple, sa fer dr u gs or ot h er for m s of t h er -
`h a ve a n em br y ocida l effect or ot h er a d-
`a py a r e a va ila ble), t h e la belin g sh a ll
`ver se effect ) in (n ame(s) of species) wh en
`st a t e:
`‘‘P r egn a n cy Ca t egor y X. S ee
`given in doses (x) t im es t h e h u m a n
`‘Con t r a in dica t ion s’
`sect ion .’’ Un der
`dose. T h er e a r e n o a dequ a t e a n d well-
`‘‘Con t r a in dica t ion s,’’ t h e la belin g sh a ll
`con t r olled st u dies in pr egn a n t wom en .
`st a t e: ‘‘(Name of dru g) m a y (can ) ca u se
`(Name of dru g) sh ou ld be u sed du r in g
`fet a l h a r m wh en a dm in ist er ed
`t o a
`pr egn a n cy on ly if t h e pot en t ia l ben efit
`pr egn a n t wom a n . (Describe th e h u man
`ju st ifies
`t h e pot en t ia l
`r isk
`t o
`t h e
`data an d an y pertin an t an imal data.)
`fet u s.’’ T h e la belin g sh a ll con t a in a de-
`(Name of dru g) is con t r a in dica t ed in
`scr ipt ion of t h e a n im a l st u dies. If t h er e
`wom en wh o a r e or m a y becom e pr eg-
`a r e n o a n im a l r epr odu ct ion st u dies a n d
`n a n t . If t h is dr u g is u sed du r in g pr eg-
`n o a dequ a t e a n d well-con t r olled st u dies
`n a n cy , or if t h e pa t ien t becom es pr eg-
`in h u m a n s, t h e la belin g sh a ll st a t e:
`n a n t wh ile t a k in g t h is dr u g, t h e pa -
`‘‘P r egn a n cy Ca t egor y C. An im a l r epr o-
`t ien t sh ou ld be a ppr ised of t h e pot en -
`du ct ion st u dies h a ve n ot been con -
`t ia l h a za r d t o t h e fet u s.’’
`du ct ed wit h (n ame of dru g). It is a lso
`(ii) Non teratogen ic effects. Un der t h is
`n ot k n own wh et h er (n ame of dru g) ca n
`h ea din g
`t h e
`la belin g
`sh a ll con t a in
`ca u se fet a l h a r m wh en a dm in ist er ed t o
`ot h er in for m a t ion on t h e dr u g’s effect s
`a pr egn a n t wom a n or ca n a ffect r epr o-
`on r epr odu ct ion a n d t h e dr u g’s u se du r -
`du ct ion ca pa cit y . (Name of dru g) sh ou ld
`in g pr egn a n cy t h a t is n ot r equ ir ed spe-
`be given t o a pr egn a n t wom a n on ly if
`cifica lly by on e of t h e pr egn a n cy ca t -
`clea r ly n eeded.’’ T h e
`la belin g sh a ll
`egor ies, if t h e in for m a t ion is r eleva n t
`con t a in a descr ipt ion of a n y a va ila ble
`t o t h e sa fe a n d effect ive u se of t h e
`da t a on t h e effect of t h e dr u g on t h e
`dr u g. In for m a t ion r equ ir ed u n der t h is
`la t er gr owt h , developm en t , a n d fu n c-
`h ea din g sh a ll in clu de n on t er a t ogen ic
`t ion a l m a t u r a t ion of t h e ch ild.
`effect s in t h e fet u s or n ewbor n in fa n t
`(d) Pregn an cy category D. If t h er e is
`(for exa m ple, wit h dr a wa l sy m pt om s or
`posit ive eviden ce of h u m a n fet a l r isk
`h y pogly cem ia ) t h a t m a y occu r beca u se
`ba sed on a dver se r ea ct ion da t a fr om in -
`of a pr egn a n t wom a n ’s ch r on ic u se of
`vest iga t ion a l or m a r k et in g exper ien ce
`t h e dr u g for a pr eexist in g con dit ion or
`or st u dies in h u m a n s, bu t t h e pot en t ia l
`disea se.
`ben efit s fr om t h e u se of t h e dr u g in
`(7) L abor an d delivery . If t h e dr u g h a s
`pr egn a n t wom en m a y be a ccept a ble de-
`a r ecogn ized u se du r in g la bor or deliv-
`spit e it s pot en t ia l r isk s (for exa m ple, if
`er y (va gin a l or a bdom in a l deliver y ),
`t h e dr u g is n eeded in a life-t h r ea t en in g
`wh et h er or n ot t h e u se is st a t ed in t h e
`sit u a t ion or ser iou s disea se for wh ich
`in dica t ion s sect ion of t h e la belin g, t h is
`sa fer dr u gs ca n n ot be u sed or a r e in ef-
`su bsect ion of
`t h e
`la belin g sh a ll de-
`fect ive),
`t h e
`la belin g
`sh a ll
`st a t e:
`scr ibe t h e a va ila ble in for m a t ion a bou t
`‘‘P r egn a n cy Ca t egor y D. S ee ‘Wa r n -
`t h e effect of t h e dr u g on t h e m ot h er
`in gs’ sect ion .’’ Un der t h e ‘‘Wa r n in gs’’
`a n d t h e fet u s, on t h e du r a t ion of la bor
`sect ion , t h e la belin g st a t es: ‘‘(Name of
`or deliver y , on t h e possibilit y t h a t for -
`dru g) ca n ca u se fet a l h a r m wh en a d-
`ceps deliver y or ot h er in t er ven t ion or
`m in ist er ed
`t o
`a pr egn a n t wom a n .
`r esu scit a t ion of t h e n ewbor n will be
`(Describe th e h u man data an d an y perti-
`n ecessa r y , a n d t h e effect of t h e dr u g on
`n en t an imal data.) If t h is dr u g is u sed
`t h e
`la t er gr owt h , developm en t , a n d
`du r in g pr egn a n cy , or if t h e pa t ien t be-
`fu n ct ion a l m a t u r a t ion of t h e ch ild. If
`com es pr egn a n t wh ile t a k in g t h is dr u g,
`a n y in for m a t ion r equ ir ed u n der t h is
`t h e pa t ien t sh ou ld be a ppr ised of t h e
`su bsect ion is u n k n own , t h is su bsect ion
`pot en t ia l h a za r d t o t h e fet u s.’’
`of t h e la belin g sh a ll st a t e t h a t t h e in -
`(e) Pregn an cy category X . If st u dies in
`for m a t ion is u n k n own .
`a n im a ls or h u m a n s h a ve dem on st r a t ed
`(8) Nu rsin g moth ers. (i) If a dr u g is a b-
`fet a l a bn or m a lit ies or if t h er e is posi-
`sor bed sy st em ica lly , t h is su bsect ion of
`t ive eviden ce of fet a l r isk ba sed on a d-
`t h e la belin g sh a ll con t a in , if k n own , in -
`ver se r ea ct ion r epor t s fr om in vest iga -
`for m a t ion a bou t excr et ion of t h e dr u g
`t ion a l or m a r k et in g exper ien ce, or
`26
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`Novartis Exhibit 2191.005
`Regeneron v. Novartis, IPR2021-00816
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`

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`Food and Drug Administration, HHS
`in h u m a n m ilk a n d effect s on t h e n u r s-
`in g in fa n t . P er t in en t a dver se effect s
`obser ved in a n im a l offspr in g sh a ll be
`descr ibed.
`(ii) If a dr u g is a bsor bed sy st em ica lly
`a n d is k n own t o be excr et ed in h u m a n
`m ilk , t h is su bsect ion of t h e la belin g
`sh a ll con t a in on e of
`t h e
`followin g
`st a t em en t s, a s a ppr opr ia t e. If t h e dr u g
`is a ssocia t ed wit h ser iou s a dver se r ea c-
`t ion s or
`if
`t h e dr u g h a s a k n own
`t u m or igen ic pot en t ia l,
`t h e
`la belin g
`sh a ll st a t e: ‘‘Beca u se of t h e pot en t ia l
`for ser iou s a dver se r ea ct ion s in n u r sin g
`in fa n t s fr om (n ame of dru g) (or , ‘‘Be-
`ca u se
`of
`t h e
`pot en t ia l
`for
`t u m or igen icit y
`sh own
`for
`(n ame of
`dru g) in (an imal or h u man ) st u dies), a
`decision sh ou ld be m a de wh et h er t o
`discon t in u e n u r sin g or t o discon t in u e
`t h e dr u g, t a k in g in t o a ccou n t t h e im -
`por t a n ce of t h e dr u g t o t h e m ot h er .’’ If
`t h e dr u g is n ot a ssocia t ed wit h ser iou s
`a dver se r ea ct ion s a n d does n ot h a ve a
`k n own t u m or igen ic pot en t ia l, t h e la -
`belin g sh a ll st a t e: ‘‘Ca u t ion sh ou ld be
`exer cised wh en (n ame of dru g) is a dm in -
`ist er ed t o a n u r sin g wom a n .’’
`(iii) If a dr u g is a bsor bed sy st em -
`ica lly a n d in for m a t ion on excr et ion in
`h u m a n m ilk
`is u n k n own ,
`t h is su b-
`sect ion of t h e la belin g sh a ll con t a in
`on e of t h e followin g st a t em en t s, a s a p-
`pr opr ia t e. If t h e dr u g is a ssocia t ed wit h
`ser iou s a dver se
`r ea ct ion s or h a s a
`k n own t u m or igen ic pot en t ia l, t h e la -
`belin g sh a ll st a t e: ‘‘It is n ot k n own
`wh et h er t h is dr u g is excr et ed in h u m a n
`m ilk . Beca u se m a n y dr u gs a r e excr et ed
`in h u m a n m ilk a n d beca u se of t h e po-
`t en t ia l for ser iou s a dver se r ea ct ion s in
`n u r sin g in fa n t s fr om (n ame of dru g) (or ,
`‘‘Beca u se
`of
`t h e
`pot en t ia l
`for
`t u m or igen icit y
`sh own
`for
`(n ame of
`dru g) in (an imal or h u man ) st u dies), a
`decision sh ou ld be m a de wh et h er t o
`discon t in u e n u r sin g or t o discon t in u e
`t h e dr u g, t a k in g in t o a ccou n t t h e im -
`por t a n ce of t h e dr u g t o t h e m ot h er .’’ If
`t h e dr u g is n ot a ssocia t ed wit h ser iou s
`a dver se r ea ct ion s a n d does n ot h a ve a
`k n own t u m or igen ic pot en t ia l, t h e la -
`belin g sh a ll st a t e: ‘‘It is n ot k n own
`wh et h er t h is dr u g is excr et ed in h u m a n
`m ilk . Beca u se m a n y dr u gs a r e excr et ed
`in h u m a n m ilk , ca u t ion sh ou ld be exer -
`cised wh en (n ame of dru g) is a dm in is-
`t er ed t o a n u r sin g wom a n .’’
`
`§ 201.57
`(9) Pediatric u se. (i) P edia t r ic popu -
`la t ion (s)/pedia t r ic pa t ien t (s): F or t h e
`pu r poses
`of
`pa r a gr a ph s
`(f)(9)(ii)
`t h r ou gh (f)(9)(viii) of t h is set ion , t h e
`t er m s pediatric popu lation (s) a n d pedi-
`atric patien t(s) a r e defin ed a s t h e pedi-
`a t r ic a ge gr ou p, fr om bir t h t o 16 y ea r s,
`in clu din g a ge gr ou ps oft en ca lled n eo-
`n a t es,
`in fa n t s, ch ildr en , a n d a doles-
`cen t s.
`(ii) If t h er e is a specific pedia t r ic in -
`dica t ion (i.e., a n in dica t ion differ en t
`fr om t h ose a ppr oved for a du lt s) t h a t is
`su ppor t ed by a dequ a t e a n d well-con -
`t r olled st u dies in t h e pedia t r ic popu -
`la t ion , it sh a ll be descr ibed u