rfl
`
`CT
`
`mflaJ
`
`2m-----n----rT
`
`----c------
`
`---
`
`3-
`
`Exhibit
`2025
`
`"V
`
`V
`
`Lilly Ex. 2025
`Sandoz v. Lilly IPR2016-00318
`
`Lilly Ex. 2025
`Sandoz v. Lilly IPR2016-00318
`
`

`
`PDR
`52
`
`EDITION
`1998
`
`RI IYSOANS
`DISK
`RH RENCI
`
`Medical Consultant
`Ronald Arky MD Charles
`
`Davidson Professor of Medicine and Master Francis Weld Peabody Society Harvard Medical
`
`School
`
`Vice President of Directory Services
`
`Stephen
`
`Greenberg
`
`Product Manager Mark
`Friedman
`Barsamlan
`National Sales Manager Dikran
`National Account Manager Customized Projects Anthony Sorce
`Senior Account Manager Donald
`Account Managers
`Marion Gray RPh
`Lawrence
`Keary
`Pfohl
`
`Bruccoleri
`
`Silverberg
`
`Jeffrey
`Stephen
`Suzanne
`
`Yarrow
`Director of Trade and Direct Marketing Sales Robin
`National Sales Manager Trade Group Bill Gaffney
`PromotIon Manager Donna
`Lynn
`Director Professional Support Services Mukesh Mehta RPh
`Senior Drug information Specialist Thomas Fleming RPh
`Drug Information Specialist Maria Deutsch MS RPh CDE
`Editor Special Projects David
`
`Bartlett
`
`Sifton
`
`Vice President of Production David
`
`Pitler
`
`Director of Print Purchasing Maiorie
`Director of Database Services
`
`Lynne Handler
`
`Duffy
`
`Director of Production Carrie Williams
`
`Manager of Production Kimberly Hiller-Vivas
`Senior Production Coordinators Amy
`Brooks Dawn
`
`McCall
`
`Production Coordinator Mary Ellen
`
`Breun
`
`index/Format Manager Jeffrey
`Senior Format Editor Gregory
`Assistant Index Editor Johanna
`
`Schaefer
`
`Westley
`Mazur
`
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`
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`
`Joanne
`Electronic Publishing Coordinator
`imaging Coordinator Shawn
`
`Senior Digital
`
`Pearson
`
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`
`Digital
`
`Imaging Coordinator
`
`Frank
`
`McElroy Ill
`Grossman
`
`Electronic Publishing Designer Robert
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`
`Copyjight 1998 and published by Medical Economics Company mc at Montvale Ni 07645.1742 All
`None of the content of this pub
`rights reserved
`retrieval system resold redistributed or transmitted in any form or by rifly means electronic mechanical pho
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`The POP Family Guide
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`to Womens
`Nutrition and HealthTM The pop Family Guide Encyclopedia of Medicel Care FDA Electronic
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`Printed on recycled paper
`
`ISBN 156363-251.9
`
`Lilly Ex. 2025
`Sandoz v. Lilly IPR2016-00318
`
`

`
`DESCRIPTION
`
`Methotrexate formerly Assethapterin is on antimatabaiste
`used in the treatment of certain neapleetic
`diseases severe
`pasrissia and adult rheumatoid srthritie
`Chemically methotrexate is N-4-lI24-diaminn-6-pteridi-
`The
`nylmethyllmathylaminelbenaoyhj-i-glutamic acid
`formula is
`structural
`
`Ni-i2
`
`onoi1.--c-- -ccii
`
`are
`
`IMMUNEX CORPORATION/1281
`
`such as malignant cells bone marrow fatal colts buccal and
`inteatinal mucasa and cells of the urinai-y bladder are in
`general man eonoitieo to this effect of unethateexats
`When
`is greater than in
`cellular proliferation in cosligaant tissues
`mast normal
`tireuos -methotreixate may impair malignant
`growth withaot
`irreversible damage ts normal tiesuea
`ie un
`The mechanism of action irs
`rheumatoid arthritis
`known it may affect
`iaunune function Twa reports dean-ihe
`ia eiframethotrexate inhibition of DNA precursor uptake by
`in an
`atiurulatod mananuclear calte and another describes
`imel pslyartbritia partial correction by mathotrexata
`of
`and suppresra.d.lL2 produc
`spleen call hyparesponsiveneaa
`tian Other laboratariaa hewaver bass beqa unabla to desn
`onrtrats similar effects Clarification of nrethotrexataa of-
`fact on immune activity and its relatian to rheumatoid ins
`await furtbor studies
`snunopatisageneaia
`In patients with rheumatoid arthuitis effects of methotrex
`and
`ate on tu-ticular unveiling
`tenderness can be seen no
`LoS wapka Although nsathotrdxate
`claorly nose
`enrly es
`Iloratee ayraptoma of inflammation pain swellIng
`stiff
`induces remission of thou
`tisas there is an avidinco that It
`demon
`ear bee
`bona8dal elfect-baea
`snntoidorthritii
`atratsd an bone erosions and other radialogic changes which
`result in impaired joint usa functional disability and defor
`mity
`Most studies of methatrexete in patients with rheumatoid
`to months Limited
`ertbritis are relatively abort term
`data from long-term studies indicate that an initial clinical
`is maintained far at least two years with con
`iropruvement
`tinued therapy
`In pserisais the rats of production of epithalial cells in the
`over normal akin This differential
`akin is greatly increaaad
`in proliferation rates is the basis far the eso ef mathatrexate
`to control
`the psoriatic process
`Methotrexato in high doses
`followed by leurevarin rescue
`part af the treatment of patients with non
`is used as
`metsatatic eatsesarcoma The original
`rationale far high
`does usethatraxate therapy was based an
`tho concept of se
`of normal
`tissues by leumvarin More recent
`that high dese methotrexats may also
`evidence
`auggeats
`by impaired ac
`avercnme methatsexate resistance ceuaed
`decreased affinity of dihydrefalic acid reduc
`
`lective rescue
`
`tive tranaport
`tase far methatrexate
`inco-aaaed levels of dihydrofelic acid
`reduetasa reeulting from gena amplifitatian or decreased
`of methotrexate The actual mechanism of
`palyglutamation
`action in unknawn
`l\vo Pediatric Oncohagr Group studies lone randomized and
`one non-randomized
`demonstrated
`improve
`significant
`in patients with non-mete-
`ment
`in relapse-free survival
`static ostoosarcema when high does methatrexote with leu
`cavern rescue was used in combination with other chemo
`resection of the
`agents following
`surgical
`therapeutic
`to demon-
`primary tamer These studies were not designed
`strata tha specific
`contribution of high dose mathotrexate/
`leumvorin rescue therapy to the efficacy of the combination
`contribution can be inferred from the reports of
`to this therapy in patients with mate-
`abjective
`responses
`tumor
`from reports of extoneive
`static estoaaareoma end
`following preoperative administratian of this ther
`necrosis
`apy to patients with non-inotsatatic eateoaareoma
`Phormacokinaties
`In adults oral absarptian sppaara
`to be dose
`Absorption
`dependent Peak serum levels are toothed within ens to two
`hears At doses of 30 mg/rn5 or less
`
`Hawaver
`
`methotrexats
`
`Molecular weight
`C25H55N505
`454.45
`Methetrexate Sodium Tablets for oral administration
`available in bottles of 100 and in
`system desig
`psckoging
`nated as the EHEUMATREX
`Methotrexate Sodium Dose
`weakly dosing schedule of mg 7.5
`Peck for therapy with
`mg 10mg 12.5 mg and 15 nig Methetrexate Sodium Tab
`an amount of methotraxate sodium equivalent
`lets contain
`to 2.6 cog of methotrexate and the following inactive ingre
`dients Lactoao Magnesium Stearate end Pregelatinized
`Starch May also mntsin Corn Starch
`Methotrexate Sodium Injection sad for Injection products
`are sterile and nsn-pyrogenic and may be given by the in
`tramusculai
`intravenous
`intrs-srtsrial
`or
`intrathecal
`route Sea DOSAGE AND ADMINISTRATION
`Hawever
`contains Benzyl Alcohol and
`tha preasrvotivo formulation
`must not be used for intratheesi or high dose therapy
`Methotrexote Sodium Injection Isotonic Liquid Coninins
`is available in 25 mglnsL mL 50 mg sad 10
`Preaeruottae
`mL 250 cog vials
`25 mglmL mL and 10 mLvial contains methatrex
`Each
`to 50 mg end 250 mg methotrexats
`ate sodium equivalent
`respectively 090% at/v of Benzyh Alrohal as
`preservative
`and the following inactive ingredients Sodium Chloride
`0.260% w/v and Water
`Sodium
`for Injection qe ad 100%
`Hydroxide end if necessary Hydrochloric Acid ore added to
`the ph to approximately 6.5
`adjust
`Methotrexote LPF Sodium mcthotrernte
`sodium injec
`tion botanic Liquid Frescruotisc Free far single usa only
`is available in 25 mghaL
`mL 50 rag mL 100 mgI
`mL 200 mgI and 10 mL 250 cog vials
`Each 25 mg/mL mL mL mL and 10 niL vial containo
`to 50 mg 100 cog 201 cog
`methotrexate sodium equivalent
`and 250 cog mathatrexate respectively and this following in
`ingredients Sodium Chloride 0.490% w/v and Water
`active
`Sodium Hydroxide and if nocea
`for Injection qa ad 100%
`the pH to ap
`sary Hydrochloric Acid are added
`to adjust
`coL mL and 10 mL solutions
`rnL
`proximately 5.5 The
`cantata approximately 0.43 mEq 086 mEq 1.72 ruEq and
`2.15 mEq nf Sodium per vial respectively and are isotonic
`solutions
`Methotrexole Sodizan for Injection Lyophilizcd Preasreative
`Free for single use only is available in 20 mg and
`gram
`vials
`Each
`
`vial of
`
`contains
`
`20 cog and
`powder
`lyaphilized
`sodium equivalent
`to 20 cog and
`metho
`coethotrexate
`titrate reapectively Contains no preservative Sodium Hy
`dioxide and if necessary Hydrochloric Add are added dur
`ing manufacture to sdjuat the pIT The 20 mg viol mntsine
`approximately 0.14 mEq of Sodium and the
`vial contains
`mEq Sodium
`approximately
`CLINICAL PHARMACOLOGY
`Methatrexste inhibits dihydrafolic acid reductase Dibydro
`folates must be redumd to tetrahydrafslates by this enzyme
`before they can be utilized ax carriers of one-carbon
`groups
`in the ayntheaia of purina nucleotidea and
`thymidylato
`Therafere mathatrexats interferes with DNA ayntheoia re
`pair and cellular replication Actively proliferating tissues
`
`00rREXATE Sodium Tablots
`TREXATESoIIUm for InjectIon
`LPF Sodium
`Sodium Injoction and
`oThEXATh
`nEXATE Soólum Injection
`
`i3
`
`Jr
`
`jqftWS
`piiOTREXATE SHOULD BE USED ONLY BY
`ILrveICIAHS WHOSE KSOWLEDGE AND EXPERT-
`INCLUDE TEE USE OF ANTIMETABOLITE
`nOAPY
`gCAU5E OF THE PoSSIBILITY OF SERIOUS
`xlc REACTIONS WHICH CAN BE FATAL
`SHOULD BE USED ONLY IN
`tPJrBOTRPXATE
`LIFE THREATENING NEOPLAST1C DISEASES
`GRIN PATIENTS.WITH PSORIABIS OR ItI4EUMA-
`OlD ARTJIRITIS WITH SEVERE BECALCI
`pjn DISABLING DISEASE WHICH IS NOT AD-
`UATELY RESPONSIVE TO OTHER FORMS OF
`IIERAPY
`DEATHS HAVE BEEN REPORTED WITH THE USE
`IN THE TREATMENT OF
`METHOTREXATE
`MALIGNANCY PSOELASIS AND RHEUMATOID
`ETm1ITIS
`pATIENTS SHOULD BE CLOSELY MONITORED
`IIONE MARROW LIVER LIJNG AND KIDNEY
`OXIC1TIES See PRECAUTIONS
`PATIET4TS SHOULD BR INFORMED BY THEIR
`ITEYSICL4N OF THE RISKS INVOLVED AND BE
`CARE THROUGHOUT
`UNDER
`PHYSICIANS
`ThERAPY
`USE UP METHOTREXATE HIGH DOSE REGI
`ENS RECOMMENDED FOR OSTEOSARCOMA RE
`CARE See DOSAGE AND
`QIJIRES METICULOUS
`ADMINISTRATION HIGH DOSE REGIMENS FOR
`HER NEOPLASTIC DISEASES ARE INVESTIGA
`-IIONAI AND
`THERAPEUTIC
`ADVANTAGE HAS
`IIYIBEE ESTABLISHED
`ANt HILt
`FORMULNIIONS
`IIIIIOTRJIX.ATE
`iIS CONTAINING PRESERVATIVES MUST NOT
`-$6 USED FOR INTRjtTIIECAL OR 111GB DOSE
`blETIICTgIjy THERAFC
`LMethtrmate baa beenraported
`esdfQT
`cOflgenjtal.anomaliea Thorcibre it
`is not roe
`asnded forwomen of childbearing potential uoiess
`nate 15 door medical evidence
`the benefits can
`that
`outweigh The cqnbideged
`risks .Erew
`espaeted.tn
`CWOLrI with padirineie
`or rheumatoid
`not
`stud
`methotreaste
`receive
`asNTh4lNDICATIONS
`tra4nte elinilnation is reduced
`in patients with
`aseites1 or ploura efinvione
`fonction
`require especially csreliil monitoring
`city and
`require doao reductiOn or in semé
`dmeuntui0
`of
`snothotrexata
`
`to cause fetal death
`
`arthritis
`See
`
`PlienI
`
`strati00
`
`bat
`
`Vet
`
`ean
`
`5pa41
`
`si
`
`Re05
`
`ties
`
`i0
`
`Ito
`eeprIdiy severe sometimes fatal bone morrow
`toxicity have been
`end gastrointestinal
`with concomitant administration of soothe
`etej8 nlly in high dosage along with annie non
`PIig5 Oti.infinmmotery drugs NSAIDo See
`e04
`Drug Intaracilona
`fibrosis and
`to ceuaea hepetntoxicity
`Eeneroly only alter prolonged usa Acutely
`eal Cleyotiaim are fraquectty Boon These
`trsnsie and aeymptomati and also do
`bQtive of subsequent hepstlc disease
`auetsined uo often shows hieto
`ted Eui and fibrosis and cirrhosis have been it-
`latter lesions may nut
`be preceded
`by
`abnormal
`functioa tests in the psn
`liver
`1lpa Far this reason periodic liver biop
`rlly recommended for psorintic patiente
`iong4orm trestsnant Persistent abner
`ICer tuU0 testis may precede
`
`appear-
`
`Lilly Ex. 2025
`Sandoz v. Lilly IPR2016-00318
`
`

`
`1282/IMMUNEX
`CORPORATION
`Methotrexate SodiumCent
`
`Heif-Life
`
`is
`
`to
`
`fold
`
`In dogs synovisi
`fluid concentrstions after oral dosing were
`higher in inflamed than u.ninflomed
`salicyl
`joints.Although
`interfere with this penetration
`prier predni
`aloe did not
`sone treatment
`reduced penetration into inflamed joints to
`the level of norms joints
`Metshelism After absorption methatrexete undergoes he
`patic and intracellular metabolism to polyglutemated forms
`which con be converted
`back
`to mothotrexste by hydrolase
`enzymes These polyglstsmstea act as inhibitors of dibydro
`Small
`reductese
`end
`synthetase
`foIsts
`thynsidyiste
`amounts of methotrexato polyglutsmstes may remain in tis
`sues for extended periods The retention end prolonged drug
`action of those octive metabolites vary among different cells
`tissues sod tumors
`small smount of motsbolism to 7-hy-
`msy occur
`droxymethotrexato
`commonly pre
`at doses
`scribed.Accumulation
`of this metabolite may become signif
`kant at
`sarcoma The
`used in ustoogenic
`the high doses
`aqueous siolubility of 7-hydrexymethotroxata
`lower than Lbs parent esuopounil
`idathotcatiato is partially
`utotabulizud by intestinal
`tIara-after ornl edministration
`The terminal half-life reported for mothotrexate
`is approximately
`three to ten hours or patients receiving
`treatment
`psoriaeis or rheumatoid arthritis or low dose
`far
`antineopleatic therapy less then 30 mg/In2 For patients
`receiving high doses of snothotmlxnto tie terminal half-life
`to 15 hours
`is eight
`Bane excretion is
`the priniary route of elimina
`Excretion
`tion end is dependent
`upon dosage end route of adniinistra
`tion With XV administration 0% to 90% of the adminis
`in the urine within 24
`unchanged
`tered dose is excreted
`hours There is limited biliai-y
`excretion amounting to 10%
`or less of the administered dose Enterohepatic recirculetion
`of methotrexate has been proposed
`and actiye
`Renal excretion occurs by glomerular
`filtration
`tubular secretion Nonlinear elimination due to saturation
`roebsorption has been obServed
`tubular
`of renal
`in psurintic
`patients at doses betweon
`7.5 and $0 sng Impaired racial
`uso of drugs audi aa weak
`fenction
`as well as concurrent
`can merle
`organic acids that also undorgo tubularsecretion
`serum levels Excellent correla
`edly increase snethab-existu
`tion has been reported between methatrexate clearance
`end
`nndoganoua
`creatinine clearance
`Mathotrexate clearance
`rates vary widely and are generally
`has been
`decreased at higher doaea Delayed drug clearance
`identified as one of the snajar factors responsible for msth
`otrexete toxicity It has been postulated that
`the toxicity of
`methotrexate for normal
`tissues is more dependant
`ripen
`the duration of exposure to the drug rather
`then the peak
`level achieved When
`patiant baa delayed drug elinsine
`tion due to compromised renal
`spapo effu
`function .o third
`sion or other causes mathotrexate
`serum concentrations
`-may remain elevated
`far prolonged periods
`lhe potential or toxicity from high duse regimena or de
`layed excrotian is reduced
`by thi administration olleucovo
`rin culcium çlaring the final phase of niathotrexate plasma
`elimination Pharmacokinetic monitoring
`of methotrexata
`serum concentrations may help identil5r
`those patients at
`high risk far snethotrexeto toxicity sad aid in proper adjust
`ment of leesmvorin
`dosing Guidelines for monitoring serum
`methotrexate levels and tsr adjustment of loucuvorin dos
`ing to roducetha risk of methatrexato texicit are provided
`below icr DOSAGE AND AIMIN1SThATION
`to human brenat milk The
`Methatrexate has been detected
`highest breast milk to plasma concentration ratio reached
`was 0.051
`
`INDICATIONS AM USAGE
`
`Nenplastic Diseases
`Methotrexate
`ia indicated in the treatment of geatational
`chorioadenonia destruens and hydatidi
`churiocarcinoma
`form mole
`
`roll
`
`In acute lymphucytic laukuinia snutbetruxate is indicated in
`leukemia and is used in mom
`the pruphylaxis of meningeal
`tonance therapy in combination with other chumothurepou
`tic agents Mothotrexate is alan indicated in the tectathient
`leukemia
`of meningesl
`Methotrexate is used alone or in combination with other an
`in the treatment of breast cancer cpider
`ticancer agents
`maid cancers of the head
`and neck advanced mycosis fun
`goidea and lung cancer particularly squamous cell and
`types Methntrexste
`is else used in cuinbination
`small
`with other chmnotherapeutic agents in the treatment of ad
`vanced
`stage nnn.Hodgkine
`lymphomas
`Msthotrexate in high doses followed by leucovorin rescue in
`combination with other chamotharapeutic agonts is effective
`in patients with nan
`in prelonging relapse-free survival
`who hae undergone surgical re
`matastatic osteosarcoma
`section
`on- sinputcstian for the primary tumor
`Psoniaaii
`Methiatrexate is indicated in the symptomatic control of se
`yam rucalcntn.ant diaall in15 psorinals thisn is not adequately
`reaponaive
`to iither
`terms af Unenipy hint only iaheni
`the di
`agnosis lies been.catabljjivj
`aS by biopsy end/ar otter der
`
`to enaure that
`is important
`pao
`cenaeltotina It
`naotologic
`concomitant dis
`rissis flare is not due to an undiagnosed
`ease aflectiog immune reapanaeo
`Rheumatoid Arthritis
`Methotrexste is indicated in the nsansgament of aelected
`or definite rheumatoid
`adults with savory active classical
`arthritis ABA criteria who have hod un insufficient
`poutic response to or are intolerant ol
`tin edequoto
`first-line therapy induding full
`daoq NSAID5aitd
`usually
`trial of st best one or more disease-modifying oiitirlieu
`nisitic drugsi
`
`trial of
`
`thai-a
`
`ing aahicylstes
`
`nat beta
`
`potential
`
`is
`
`agents and/or
`Aepirin niaaateroidal
`low
`niiti-influnniiiatory
`doss steroids iiiay be continued nlthnugh the possibility of
`incaased toxicity with canrolnitent
`use of NSAIIa intliid
`bins not been fully explored See lIIECAU
`TIONS Drug hulernctiana.l Steroids ninj be reduced rod
`uslly in patients who respond
`to nietliatrexate Cuiirbmnod
`use of mothetrexate with geld ponicillaminc
`hydronnyclaf
`or cytotoxic ngauts baa
`roquine
`sulfaitalaxine
`studied and may increase
`of adverse-effects
`thu incidendo
`Itest and physiotherapy as indicated aliuald be csnntinuad
`CONTEAINDICATIONS
`Idethstrexate can cause fetal death or terstogenic effects
`pregnant woman Mathetrexate is
`when administered to
`contraindicated in pregnant women with psornasie or rheu
`matoid arthritis
`and should be used in tho treatment nInes-
`plastic diseases anly when
`the potential benefit outweighs
`the risk to the fetua Women
`of childbearing
`not be atorted on methotraxate until
`nnhuuld
`pregnancy
`and should be fully counseled
`on the serious risk to
`excluded
`the fetus see PRECAUTIONS should thsny become preg
`nant while undargeing Lrantmânt Pregncincy Should
`be
`is receiving methetrexste during
`if either partner
`avpidod
`and for mInimum of three manthb after therapy for male
`petienta nod duringand for at least one ovulatory cycle sf
`ten therapy for female patients Soc Boxed WARNINGS.I
`Because of the potential
`for eoriaus adverse
`reactions frem
`ix mntrsindncsted in
`muthotrmixate
`in breast fed infants it
`nursing nsathara
`Patients with psariasia or rheumatoid arthritis with alco
`holism alcoholic
`liver disease or other chronic liver disease
`shauld not receive mathetrexato
`rheumatoid
`
`arthritis who have
`
`Patients with paorissis on
`overt or laboratory
`immunodeficiency
`evidence
`of
`dromes should not receive methatrexate
`Patients with pssriaois or rhauniateid srtlu-itia who have
`such oe tone marrow hypopla
`preexisting blood dyscs-asiaa
`sia leukapsnia
`snemia
`throntbacytnpenia or significant
`should not receive methotiaxoto
`Patients with
`known hyperaenaitivity
`should not receive the drag
`WARNINGS SEE BOXED WARNINGS
`PRECAUTIONS
`Generel
`has the potential
`Methatrexate
`for serious toxicity Sac
`Boxed WARNINGS
`Toxic effects may be related in fre
`ond severity to dose or frequency of administration
`quency
`but have been seen at all doaes Because they can occur at
`any time during therapy it
`to follow patients
`ia necessary
`an methotrexate clasely Moat adverse
`reactions are revers
`ible if detected early When such reactions do occur
`the ding
`should be reduced
`in dosage or discontinued and appropri
`measures
`should be taken If
`ate corrective
`this
`neceasan-%
`includa the use of leucovarin calcium See OVER
`DOSAGE If mathatrexats therapy is reinstituted it should
`be carried out with caution with adequate
`further nead for the drug and with increaaed
`possible recurrence of toxicity
`The clinical pharmaculogy of methotrexatni has not bean
`well studied in older lndividusla Due to diminished hepatic
`and renal function as well as decrcoaod
`fslate stores in this
`population relatively low daaea should be considered and
`be closely monitored for early signs of
`these patients should
`
`syn
`
`to methotrexate
`
`could
`
`consideration of
`
`alertness as to
`
`toxicity
`
`Datlothephysician
`
`Information for Patients
`be infsrmed of the csrly signs nod symp
`Patients shauld
`toting of toiticity of the need to see theirphiyaician promptly
`and the need for close follow-up including pen
`if thay occur
`iodic laboratory teats to monitor
`toxicity
`and pharinaciatahauld emphasize to the
`dose is taken wcclcly in Thea
`that the roconninendod
`pationt
`and psorieaic scud
`nnatoid arthritis
`that mistinltea djaiiy use
`of the recommended
`doss has led to fatal
`toxicity Patients
`ahould
`to read the Patient Instructions sheet
`be-encouringsd
`within the Dose Pack Prescriptions should not be written or
`PRN basis
`rofihled
`on
`Patients aliauld be informed of the potential benefit and riak
`the
`in
`
`lslonmalion will be superseded by supplements
`
`and aabaaquent
`
`editlans
`
`Lilly Ex. 2025
`Sandoz v. Lilly IPR2016-00318
`
`

`
`IMMUNEX CORPORATION/1283
`
`pstisnte have reported tran
`lowing low doses occasional
`or un
`dysfunction mood alteration
`sient subtle cognitive
`usual cranial sensations
`
`serious visual clsnges of un
`
`pneumonitis deaths have
`
`interstitial
`
`obstructive pulmo
`
`Opht/talenic conjunctivitis
`known etiology
`Pe/monory
`rteen interstitial
`bean reported and
`chronic
`nary diaease has occasionally
`accursed
`Shin erythematous rashes pruritus urticaria phetosensi
`changes alopecis ecchymosis telangiac
`tivity pigmentsry
`arythema nsultifo-me toxic opt
`tssis acne furuncuissis
`dermal necrolyais Stevens-Johnson
`syndrome
`Urogenitol System severe nephropathy or tenal
`acotemia cystitie hematuris
`defective
`eogenesis or sper
`motegeneass transient oiigospernaia menstrual dysfunction
`and vaginal discharge infertility
`shorten fetal defects
`Other rarer reactions related to or attributed to the use of
`methotrnxste euch as neduleois vasculitis opportunistic in
`fection ortlnalgiaimyslgia lose of libido/impotence diabe
`tes osteoporosis sudden death and reversible lymphomas
`Anaphylactoid reactions have been reported
`Adverse Reactions in Double-Blind Rheumatoid Arthritis
`StudIes
`of methetrexate attributed ie
`lho eppmximato incidences
`rsts subtmscted adverse
`in 12 to 15 week
`reoctions
`plscebe
`double-blind studies of pstionte n128 with rhaumotsid
`ersl 7.5 to 15 mg/week
`arthritis
`treated with lew-doso
`pulse enethutresata are listed below Vii toally sll of these
`
`failure
`
`pationts
`
`pationt
`
`re
`function tests and
`liver
`displays persistently abnortnal
`fuses liver biopsy or in say pationt whose liver biopsy shows
`nsdsrale to severe changes Resaigk grade lIDS or
`Iafectien or Immunologic Steter Methutresate should be
`used with exts-eme caution
`of active
`infsc
`in the presence
`ben and is ususily centraindicoted in patients with avert or
`laboratory evidesce of iinsaunadcficiency syndromes Immu
`nization may be ineffective when given during esthstrexste
`therapy Itamunicatien with live virus vaccines
`is generally
`recommended There
`have been reports of disseminated
`not
`vaccinis infections slier smallpox immunization in patients
`receiving methstroxate therapy Hypogammsglobulinemis
`has been reported rsrely
`
`of Pneumocyelis carinii
`
`in
`coritii
`Opportunistic infsctioes including Petesstocysri-s
`fections have been reported tardy in patients receiving low
`dose nothstrexste When
`patient presents with pulmo
`nary symptome the
`possibility
`should be considered
`pnsunsonia
`Neeroogic There have been reports of loukoencephalsps
`thy following intravenous administration of methotrexate to
`hove
`patients who
`irradiation Chronic
`hod craniespinel
`leukoencephalepathy
`bas sloe
`been seperted in patients
`who received
`dosss of high-dose methotrexats with
`repeated
`leucovorin rascue oven without cranial
`irradiation Discon
`tinuation of metbotrexste doss net always result
`in cam-
`plots recovery
`traneient scute neurelogic syndrome has been observed
`patients treated situ high dosage regimens Maoifoetations
`encephalopsthy may include confusion
`of this stcoke-liko
`seicurss and coma The
`cause is un
`exact
`
`in
`
`homiparesis
`knewn
`the central net
`use of mothotrexate
`Altar the intisthecal
`veus system toxicity which may occur
`can be classified as
`follows acute chomical arschnsidilis manifested by seth
`and fe
`symptoms as besdstho back pain nuchsi rigidity
`ver sub-acute zuyelopatliy cheractoriccd by psrapsresis/
`psraplsgis associsted with involvement
`ivith one or more
`leukoencephslepsthy manifested
`spinal nerve rests chrenic
`by confusion irritability
`somnolence atasis dementia sei
`zures and coma This mnditien can hs progressive and oven
`fatal
`
`dry nonpre
`Pulmonary Pulmsnsry symptoms especially
`pneuntouitis occurring dur
`ductive cough or
`nonspecific
`ing methotrexsts therapy maybe indicative of
`potentially
`dangerous lesion and require interruption
`of treatment and
`
`tha typi
`investigatisn Although clinically variable
`careful
`cal patient with methotroxste-inducad
`lung disosse pre
`santo with fever cough dyspnea hypexemia end an mill
`to ha sxcludsd This
`bate en chest X-ray infection needs
`lesion can occur at all dosagos
`Renol High doses of motbotreicato used in the treatment of
`eeteosarcema may cause renal damege
`re
`leading to scuto
`is due primarily to the precipita
`nal failure Nephrotsxicity
`tion ef metbetraxato and
`hydroxynsethotrexato in the re
`function including ad
`nal tubules Cisse attentisa to renal
`equate hydration urine olkalinitstian and meseurement of
`serum methetreaste and crestinina levels ore asssntiol
`for
`safe administration
`Other Precautions Methstrexate should be used with ex
`treme caution ma
`the
`of debility
`presence
`Methotrexate exits slowly frem third apace compartments
`effisoions or asrites This results in
`leg pleural
`prslsnged
`In pa
`and unexpected
`terminal plasma half
`toxicity
`is ad
`third space accumulations
`tients with significant
`it
`the fiutd before treatment
`and to moth-
`visable to evacuate
`
`life
`
`tsr plasma methotcoxate levels
`by concomitant ex
`Lesions of pasriasis may ho aggravated
`and
`rodiation Radiation dermatitis
`to ultraviolet
`posure
`sunburn msy be rer.alled by the use of mathotrexate
`ADVERSE REACTIONS
`IN GENERAL THE INCIDENCE AND SEVERITY OF ACUTE
`SIDE EFFECTS ARE RELATED TO DOSE AND FREQUENCY
`OF ADMINISTRATION THE MOST SERIOUS
`REACTIONS
`ARE DISCUSSED ABOVE UNDER ORGAN SYSTEM TOXIC
`PRECAUTION
`SECTION THAT
`ITY IN THE
`SECTION
`SHOULO ALSO BE CONSULTED WHEN LOOKING
`FOR IN
`ABOUT ADVERSE REACTIONS WITH METHO
`FORMATION
`TREXATE
`The most frequently reported adverse
`reactions include ul
`cerative stometitis leskspenia nausea and abdominsl dis
`tress Other frequently reported sdverse effects arc malaiae
`undue
`fatigue chills and fever disztoess and decreased
`re
`
`sistance
`to infection
`Other sdverss reactions that have heon reported with meth
`are hated below by organ system In the oncology
`etcexato
`eettiog concomitant
`and the midst-lying diaeaae
`treotmetit
`maks specific attribution of
`reaction to methetrexate dif
`ficulL
`
`Alimentary System gingivitis pliaryngitie etonistitis
`rexia nausea vunuting diarrhea hetnetamesis melena
`gsetrointestinsI ulceration sad bleeding entaritia pancres
`titis
`drowsiness blurred vi
`Central Nereoas System headaches
`hsve
`sion Aphasio hemiparesis paresis and convulsions
`following administration of nosthotrexata Fol
`also eccurred
`
`ano
`
`scan suppress humatepoiesis nod
`thmmbocytopenia
`and/ar
`In
`pa-
`end preexisting hcmatopoietic lot
`sheuld.bu need with caution
`In
`at tilt
`trials in rheumatoid arthritis ln1211
`31100/sam5 was seen
`in
`platelets 100000/nun5 in
`in
`patients
`amid srthsitiA mothotrexate should
`
`patielits
`
`patients
`
`trtstsitt
`
`the
`
`if there is neigiulloant drop in blood
`of neoplastic diseases mochotrux
`the potential benefit yes
`be cuatinued
`only if
`of savers myelosuppressiett Patients with
`and
`fever should be evaluated
`
`brosd-spcc
`
`risk
`ulecytopenia
`sad usually require psrenternl
`therapy
`for acute elevated
`hoe the potential
`cravats
`and chrpnic fibrosis and cirrhosis hgpntn
`toxicity is potentially fate it generally has
`use geaarslly two years or niece
`laset 1.5 grams In studies in
`tots dose of at
`patients hepstetexicity appeared to be
`function
`dose and appeared to be enhanced
`by
`anaulistlee
`and advanced
`age An accurate
`rss obesity diabetes
`irate lisa not been determined
`the rate of progree
`iverelbullly of lesions is not known Special cau
`mled In the presence of preexisting liver doms0e
`function
`hopntic
`
`slier prolonged
`
`liver
`
`function tests including serum albumin
`srforntsd periodically prior to dosing but are of-
`in the face of developing fibrosis or cirrhosis
`as may be detectable
`only hy biopsy The usual
`pretherepy
`lotion is to obtain
`liver biopsy at
`months
`after initiatioo of therapy
`total
`is dase of 1.5 grams end 31 stIes each sdditiaael
`Lb grama Moderate libmais or any cirrhosis nor-
`leads to disrentinualion
`of the drug mild fibrosis nar
`months Milder histo
`repee.t biopsy in
`and low grade portal in
`is such as fetty change
`are reistivoly commun prutherapy Although
`reason to ovoid or die
`changes are usually ant
`sesTaethotreate
`the drug should bo used
`
`IsIs
`
`mild
`
`therapy
`
`aid
`
`orthritis sge st first use of mothotrexate and
`therapy have been reported as risk fritters for
`ether risk factors similar to those observed
`may be present
`in rheumacaid arthritis but
`to date Persistent absteruuslitlen
`eeafu-um4
`lasts may precede appesrsnce of fibrosis or
`pulatien There is
`combined reported
`patients with liver
`houtastaid arthritis
`and during treatment alter
`eunsulo
`1.5 gland in 714 patients with
`tot There are 64 7% canes of fibrosis
`feirrhasie Of the 54 coxes of fibrosis 60
`Else retirulin stain is enuru sensitive fur
`its use amy increase those
`avon longer use will
`increese these risks
`tests
`he performed at baseline and at
`ehuuld
`patients receiving methotroxate
`for
`nthnt5 Prel.ruantent
`liveer biopsy should he
`Pahent with
`history of excessive
`uttly abnonnol baseline liver
`1uring
`infection
`Ic hepsticis 13 or
`should be perfarmed if
`there are per-
`test abnormalities
`do
`or there is
`an below the normol range itt
`rheumatoid arthritis
`biopsy show mild ehoegta Roenigh
`liver
`niethotrexate may be continued and the
`Out per recommendations
`listed above
`be discoatinuod in any patient who
`
`biopsy
`
`figures It
`
`is
`
`alcohol
`
`function
`
`the set-
`
`Lilly Ex. 2025
`Sandoz v. Lilly IPR2016-00318
`
`

`
`tliao5
`
`PHYSICIANS DESK REF1
`
`I-Il mothotrexate
`tumor Stages
`i-emissions in some cases Rocani
`daya
`In
`
`to
`
`to
`
`lation and may csusa syateinie mcthistiexate toxicity There
`therapy with the drug should be
`fore systesui antileukeinit
`appropnately adjusted reduced or disrontinued
`lou
`Focal
`kemie involvement of the central nervous system may nut
`chemotherapy and is best
`respond
`tmeatod
`to intrathocal
`with radiotherapy
`1ymphamae In llorkitts
`baa produced
`prolonged
`manded
`dosage is 10
`Ic 25 mg/day orsily far
`III mrthotrexate
`ia consnmoniy gioen
`contasutantly
`SInge
`with other antitsmar agents Tieetnment
`iii all stages use-
`with
`ally ronaisto of several courses sf the dreg interpeoed
`Lympheasrcosnaa
`to 10 day i-oat periods
`in Stage III niay
`to combioed diug therapy with methotrexate given
`respond
`in doses of 0.625 to
`nsg/kg daily
`Mycosis Fungoidea Therapy vith methctrexatc
`appears
`produce clinical
`remiasians in one half of
`the rasco ti-rated
`to 10 mg daily by mouth for weeks or
`Deoage is usually lii
`months Dose lovcla of dreg and adjuatnient of dose regimen
`of drug are guided by natient re
`by ieductiomm or ceeoatien
`sponse and hensstologic monitoring Methiotrexate has alas
`in doses of 50mg once weekly or
`been given intramascolsrly
`25 mg
`times weekly
`Osteoaarconsa
`An effective adjuvant them