53
`t99
`
`EDITION
`
`Lilly Ex. 2020
`Sandoz V. Lilly IPR20l6-00318
`
`Lilly Ex. 2020
`Sandoz v. Lilly IPR2016-00318
`
`

`
` £2
`
`" W
`
`Lilly Ex. 2020
`Sandoz v. Lilly IPR2016-00318
`
`Lilly Ex. 2020
`Sandoz v. Lilly IPR2016-00318
`
`

`
`PDR
`53
`999
`
`EDITION
`
`Pt IYSLOANS
`DISK
`RI_rIR_NCL_
`
`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
`
`Reiss
`
`Director of Product Management David
`Senior Product Manager Mark
`Friedman
`Associate Product Manager Bill Shaughnessy
`Director of Sales Dlkran
`Barsamlan
`National Sales Manager Anthony Some
`Natlenal Account Manager Don Bnjccolerl
`Account Managers
`MarIon Gray RPh
`Lawrence
`Koary
`
`Jeffrey
`
`Pfohl
`
`SchmIdt
`
`Christopher
`Stephen
`Sllverberg
`arrow RN
`Suzanne
`National Sales Manager Trade Group Bill Gaffnoy
`Director of DIrect Marketlnt Michael Bennett
`DIrect Marketing Manager Lorraine
`Promotion Managar Donna
`Lyrn
`Director Professional Support Services Mukesh Mehta RPti
`
`Loening
`
`SenIor Drug Information Specialist Thomas Fleming RPh
`Drug Information SpecIalist Maria Deutsch MS RPh tOE
`Slfton
`Editor Special Projectar David
`Vice President of Production David
`
`Pitler
`
`Director of Print Purohaslnt Marjorie
`
`Duffy
`
`Director of Operations Carrie Williams
`Manager of Production Kimberly
`Vivas
`Senior Production CoordlnatorE Amy
`Production Coordinator Mary Ellen
`PDR Data Manager Jeffrey
`Schaefer
`Senior Format EdItor Gregory Westley
`Index EdItors Johanna
`Mazut Robert
`
`Broun
`
`Brooks Dawn McCall
`
`Art Aasoclate
`
`Digital
`
`Joan
`Akerilnd
`Imaging Coordinator Shawn
`SenIor DIgital
`Imaging Coordinator Frank
`McElroy III
`ElectronIc PublIshing Designer Robert
`Grossman
`Fulfillment Managers Stephanie DeNardi Kenneth Slebert
`
`Woemer
`
`Cahill
`
`Copn1gM 01999 and published by Medical EconornicsCompeny
`AU rights roserved None of the sonlerrt of this publIcation
`Inc at Momvele NJ 07645-1742
`may be reproduced dared In
`redistributed or transmitted In any term or by any means electronic moctrenloal photocopying record
`retrieval system reeokL
`the prIor written penulsalon of the publisher PHVSlClANS DESK REFERENCE POR P08 For Nonprescription Prugt P08 For
`Ing or diherwise wIthout
`Cphthalrrwloaf Pocket PDR and The PDR
`Family Gukie to Prescription Drugs are regIstered Irademerts used hereIn under lIcense P08 CompanIon Guide1
`PDR for Herbal Medidnos POR Medics DictionarytM POW Nurses HWiobOOk1M POR Nurses Dltortaif The PDR Family GuIde Encyclopedia of Medical
`Cart PDW Electronic lJbrarytt4 and PDR Drug lnteractlons Side Ettect
`Indications Contraindicatlona Syetemm are tredemailca used herein under icenae
`
`Men Woe PYesWent
`efitcers of MeScal Ecerienrics Cenrpsry Ptesldent end CflktEsecuthe Officer tunic
`sISIZ Corporate
`plew Media 1. Suzarwre BoDell Woe
`Bressler Senior Woe President Rnmoe and Chlcfllnanclal Officer Thomas
`Human Resoumos Pamela
`Bliash Ito hesklent and GYrlefjnlbrrngtkvr Officer Ste-mn
`Graenberg We President New Business Ptannlng
`Hope Erecutlte We Presklerrt
`Otartit Woe Aesithrrrt Directory SeMces Stephen
`linde
`trealthcare Publfslrfrrg
`and CommunIcatIons Themes
`Ketty Executive Wee President Maazlne PublisheS l.ee
`Maniscalco Wee Ptssldenr Group Publisher Terrence
`Woe
`Meaooctc
`PitIer Woe esAtn4 Group Publisher Thomas
`Plzon Woe President Mtazirm Business Men Wn3ent Eric Schlett
`.Serrlor Woe President
`
`Aeskient Pmrkrctlon David
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`CiperaUoas John
`
`Primed on recycled paper
`
`IraN 1.563626O
`
`Lilly Ex. 2020
`Sandoz v. Lilly IPR2016-00318
`
`

`
`PRODUCT INFORMATION
`
`et
`
`Re
`IS Bucbner BR Hiddemann
`Koenigamann
`cornbioant human granylocyte-macrophage
`colony etim
`ulating factor after chemotherapy in patients with acute
`myeloid leukemia at higher age or after relapse BlooM
`1991 785l.i9O1197
`16 Bla2ar BR Kersey JH McGlave ci at In duo adminia
`ti-scion of recombinant human granylocytelmacrophage
`pa
`colony stimulating factor
`in acute lymphoblastic
`tients receiving purged autographs Blood 1989 733
`849857
`IMMUNEXS
`LEUKINE is
`registered trademark of Immunex Corpo
`ration Seattle WA 98101
`1998 Iminunex Corporation All rights reeerved Immu
`nez U.S Patent Nos 5391485 5393870 and 5229496
`U.S Pa
`under Research Corporation Thchnologies
`Licensed
`tent No 6602007
`
`Rev 0230-02
`Iseued
`02/98
`
`METHOTREXATE SODIUM TABLETS
`METHOTREXATE SODIUM FOR INJECTION
`METHOTREXATE LPFS SODIUM
`IMETHOTREXATE
`Sodium Injsetlon and
`METHOTREXATE SODIUM INJECTION
`
`ljc
`
`1c
`
`WARNNGS
`SHOULD BE USED ONLY BY
`METHOTHEXATE
`PHYSICIANS WHOSE KNOWLEDGE AND EXPEItI
`ENCE INCLUDE THE USE OF ANTIMETABOLITE
`THERAPY
`OF SERIOUS
`BECAUSE OF THE POSSIBILITY
`TOXIC REACTIONS WHICH CAN BE FATAL
`SHOULD BE USED ONLY IN
`METHOTREXATE
`LIFE THREATENING
`NEOPLASTIC
`DISEASES
`OR IN PATIENTS WITH PSORIASIS OR RHEUMA
`TOIl ARTHRITIS WITH
`SEVERE RECALCI
`TRAfl DISABLING DISEASE WHICH IS NOT AD
`EQUATELY RESPONSIVE TO OTHER FORMS OF
`THERAPY
`DEATHS RAVE BEEN REPORTED WITH THE USE
`OF METBOTREXATE
`IN THE TREATMENT OF
`MALIGNANCY
`PSORIASIS AND RHEUMATOID
`
`ARt
`
`PATIENTS SHOULD BE CLOSELY MONITORED
`FOR BONE MARROW LIVER LUNG AND KIDNEY
`TOXICITIES See PRECAUTIONS
`PATIENTS SHOULD BE INFORMED
`BY THEIR
`PHYSICIAN OF THE RISKS INVOLVED AND BE
`UNDER
`CARE THROUGHOUT
`PHYSICIANS
`THERAPY
`THE USE OF METHOTREXATE HIGH DOSE REGI
`MENS RECOMMENDED FOR OSTEOSARCOMA RE
`QUIRES METICULOUS CARE See DOSAGE AND
`ADMINISTRATION HIGH DOSE REGIMENS FOE
`OTHER NEOPLASTIC DISEASES ARE INVESTIGA
`TIONAL AND
`THERAPEUTIC ADVANTAGE HAS
`NOT BEEN ESTABLISHED
`METHOTREXATE
`AND DILU
`FORMULATIONS
`ENTS CONTAINING PRESERVATIVES MUST NOT
`OR HIGH DOSE
`BE USED FOR INTRATHECAL
`METHOTREXATE THERAPY
`Methotraxate has been reported to cause fetal death
`andAr congenital anomalies Therefbra it
`ie not rec
`ommended for women of childbearing potential un
`lees there ia clear medical evidence
`that
`the benefits
`can be
`to outweigh the considered risks
`expected
`Pregnant women with paoriasis or rhaumatoid ar
`receive methotrexate See CON
`thritis should not
`TRAINDICATIONS
`Mothotrexate elimination is reduced in patients
`ascitee or pleural af
`with impaired renal
`function
`fusions Such patients require especially careful
`monitoring fin toxicity and require dose reduction
`or in some cases
`of metbotrexate
`discontinuation
`administration
`Unexpectedly severe sometimes fhtal bone marrow
`suppression and gastrointestinal
`toxicity have been
`of math
`reported with concomitant administration
`otrexate usually in high dosage along with some
`nonsteroidal anti-inflammatory drugs NSAIDs
`See PRECAUTIONS
`Drug Intsrsclions
`Methotrexate causes hepatotoxicity flbroeia and cir
`rbusia but generally only after prolonged use
`are frequently
`Acutely
`liver enzyme elevations
`seen- These are usually transient and asymptom
`atic sad also do not appear predictive of subsequent
`hepatic disease Liver biopsy after auatained uae of
`ten shows histologic changes and
`fibresie and cir
`rhosis have been reportsd these latter lesions may
`by symptoma or ebnormal
`not be preceded
`liver
`
`potentisily
`
`the psorinais population For thia
`function teeta
`reason periodic liver biopaiee are usually recom
`for psoriatic patients who are under
`mended
`long-
`term treatment Persistent
`ebnonnalities
`in liver
`function tests may precede
`of fibrosis or
`appearance
`rheumatoid
`arthritis population
`cirrhosis in the
`See PRECAUTIONS Orgsn System Toxicity He
`patic
`lung disease is
`Methotrexato-induced
`lesion which may occur
`acutely at any
`dengereua
`time during therapy and which has been reported at
`doses as low as 7.5 mg/weelc
`ia not always fully
`It
`reversible Pulmonary
`dry
`symptoms especially
`nonpreductive cough may require interruption of
`and careful
`treatment
`investigation
`Diarrhea end ulcorativo alomatitie require interrup
`tion of therapy otherwise
`hemorrhagic enteritis
`end death from intestinal
`perforation may occut
`lyinphomaa which may regress following
`Malignant
`withdrawal of mothotroxate may occur
`in patients
`receiving low-dose methotrexate and thus may not
`require cytotoxic treatment Discontinue methotrex
`eta first and if
`the lymphoma does not regress ap
`prspriate treatment should ho instituted
`Like other cytotoxic drugs methotroxate may in-
`dune tumor lysis syndrome in patients with rap
`idly gruwiug tusuura Apprepriate
`suppurtiva and
`pharmacologic measures may prevent or alleviate
`this complication
`Severe occasionally fetal skin reactions have been
`reported following single or multiple doses of math
`otrexate Reactions have occurred within days of
`oral
`intramuscular
`intravenous or intrathacal
`methotrexate administration Recovery
`baa been re
`of therapy See PRE
`ported with discontinustion
`CAUTIONS Organ Systam Toxicity Skin
`10 Potentially fatal opportunistic
`infections especially
`Pneumocysis carinii pnoumonia may occur with
`methotraxate thorepy
`
`DESCRIPTION
`
`IMMUNEX CORPORATION/i
`
`397
`
`vial contains
`
`Met hotrexote Sodium for Injection Zgophiiired Preservotiue
`Free fur singlo use only is available in 20 mg end
`gram
`vials
`20 mg and
`Each
`powder contains
`vial of lyophilized
`to 20 mg end
`metbotrexate sodium equivalent
`mothu
`troxate reapoctively Contains no preservative Sodium Hy
`droxido and if necessary Hydrochloric Acid are added dur
`the pH The 20 mg vial contains
`ing manufacture to adjust
`sppreximetoly 0.14 mEq of Sodium and the
`mEq Sodium
`approximately
`CLINICAL PHARMACOLOGY
`acid reducteae Dihy
`Methotrexato
`inhibits dihydrofolic
`to totrahydrofolates bythis en
`drololstes must he reduced
`they can be utilized as carriers of one-carbon
`zyme before
`in the synthesis of purina nucleotides and thymidy
`grouph
`lath Therefore methotrexate interferes with DNA syntho
`als repair and cellular
`repliontion Actively preliferating
`tissues such
`as malignant cells bone marrow fatal cells
`huccal and intostlnel mucoss and calls of the urinary blad
`der are in general more sensitive to this effect of mothotrox
`ate When
`cellular prehforation
`in malignant
`tissues is
`tissues mothotrexate may im
`greater then in most normal
`pair malignant gmwth without
`irreversible damage
`to nor
`mal tissues
`The mechanism of action in rheumatoid arthritis is on-
`known it may effect
`immune function
`Tteo reports describe
`in vitro msthotrexate inhibition of DNA precursor uptako by
`in en
`atimulated mononuclear eels and another describes
`imal polyartbritia partial corroction by methutrexste
`of
`and suppressed IL 2produc-
`spleen cell hyporosponsivensast
`ton Other laboratories however have been unablo to dem
`onstrate similar effects Clarification of methotrexates ef
`fect on immune activity end ito relation to rheumatoid im
`munopathoganesia await
`further studies
`In pationts with rheumatoid arthritis effects of methotrox
`ate on articulsr swelling and tenderness can
`
`lite
`
`Methotroxate formerly Amethopterine is an antionetabo
`used in the treatment of certain neoplaetic diseases
`rheumatoid arthritis
`sever psoriaais and adult
`Chemically methatrexate is N-l4l24-dismino-8-pteridinyl
`add The struc
`
`methyllinethylaminolbonzoylj.t..glutamic
`formula is
`
`tural
`
`%OCNfO-cor
`
`NOOCCH5CI-32-
`
`-C--COON
`
`Molecser weigh 4s4.45
`
`Ii
`
`C20HNO5
`
`Mathotrexate Sodium Tablets for oral administration
`are
`available in bottles of 100 and in
`packaging system desig
`nated as the R3EUMATREX Mothotroxato Sodium Dose
`weakly dosing schedule of mg 7.6
`Pack for therapy with
`mg 10 mg 12.5 mg and 15 mg Mothotrexate Sodium Tab-
`an amount of methotrexate
`sodium equivalent
`late contain
`to 25 mg of methotrexace and the following inactive ingre
`dients Lactose Magnesium Stesreto and Progelatinizod
`Starch May also contain Corn Starch
`Methotrexats Sodium Injection and for injection products
`era sterile sad nan-pyroganic end may be given by the in
`tramuecular
`intravenous
`intra-srterial
`or
`intrethecsl
`How
`route See DOSAGE AND ADMINISTRATION
`ever
`contoina Benzyl Alcohol
`the preservative formulation
`and must not be used for intrethocal
`or high dose therapy
`
`MetAotrexote Sodium Injection
`Isotonic Liquid Cnntoins
`mL 60 mg and 10
`Preserootiue is available in 25 mg/mL
`mL 250 mg vials
`10 mL vial contains methotrax
`mL and
`Each 25 mg/mL
`to 50 mg and 250 mg methotrexate
`ate sodium equivalent
`respectively 0.90% w/v of Benayl Alcohol as
`preservative
`and the following inactive ingredients Sodium Chloride
`0.260% w/v end Water
`Sodium
`for Injection qs ad 100%
`Hydroxide and if necessary Hydrochloric Acid are added to
`adjust the pH to approximately 8.6
`Methotrexoie LPFR Sodium methotrexate
`sodium injec
`toni
`Isotonic Liquid afleervotive Free for single use only
`mL 50 mg mL 100 mgI
`is available in 25 mg/mL
`mL 200 mg and 10 mL 260 mg vials
`Each 25 mg/mL mL mL mL and 10 mL vial contains
`to 50 ing 100 mg 200 cog
`methotrexate sodium equivalent
`and 250 mg mothotrezete respectively
`and the following in
`ingredients Sodium Chloride 0.490% w/v and Water
`active
`Sodium Hydroxide and if neces
`for Injection qa ad 100%
`sary Hydrochloric Acid are added
`to adjust the p11th ap
`proximately 8.5 Tho mL mL mL and 10 ml solutions
`0.43 mEq 0.86 mEq 1.72 mEq and
`contain approxImately
`2.15 mEq of Sodium per vial respectively end era isotonic
`solutions
`
`Lilly Ex. 2020
`Sandoz v. Lilly IPR2016-00318
`
`

`
`1398/IMMLJNEX CORPORATION
`
`Methotrexate Sodium.cont
`
`.lethotrexate
`
`is generally completely absorbed
`from paren
`Intramuscular
`total routes of injection AStor
`injection peak
`serum concentrations occur
`in 80 to OQ minutes
`Djefrjbution After intravenous administration the initial
`volume of distribution
`is approximately 0.18 11kg 18% of
`body weight end ateady.stete volume of distribution
`is np
`proxImately 0.4 to 0.8 11kg 40% to 80% of body weight
`Methotrexate
`competes with roduced folatos
`active
`single toni
`transport eaves cell membranes by means df
`or.njedited active transport process At serum concontre
`than t00 micromolar passive diffusion be
`Liens greater
`pmaa major pathway by which eWectlve Intracellular con
`can he achieved
`centrationa
`Idethotreanto in serum is
`pproxlnrately 80% protein bound Laboratory studies
`it may be displaced
`from plasma albumin by
`castrate that
`various compounds
`lneluding sulfonamides ealicylatoe tet
`chiorampbanicol and phenytoin
`racycline.
`MethotSate dose not penetrate the
`blood-cerebroapinsi
`fluid bonier In therapeutic emounte when given orally or
`111gb CSF concentrations of the drug may be
`psrenterally
`attained byintrathecal administration
`in dogs syeovtsl fluid concentrations after oral dosing were
`higher in inflamed than rmiszflamed Joints ASthough aelicyl
`else did not
`this penetration prior predni
`lnterfere.wlth
`lone treatment
`reduced
`penetration Into inflamed joints to
`the 1ev oQnormal joints
`After absorption methotrexate
`Mctobojj.rn
`undergoce
`hepatic end
`intracellular matabollsm to polyglutameted
`forms which an be otsiverted beck to mathotrexata by by
`drolaas enzyme itoes potyglutametee act as Inhibitore of
`dihytlrolase reductase end thymidylate aynthetaie
`Smell
`amounts of methotrezate polyglutamatee may remain in tis
`sue firr extended
`periods Theretention and prolonged drug
`action ofths.e active meiabolltes vary amcerg diffbrent cells
`tissue and tumors
`small emout of metabolism to 7-by
`droxyuiethotrexate may occur at doses
`commonly pro
`of this metabolize may become signif
`ecribedAricomulation
`the high doses used in eeteogenic
`icant at
`sarcoma The
`solubility of 7-bydroxymsthotrexg is
`aquonus
`to
`ibId
`lower than the parent compouad..Merbotrexata is partially
`metabolized by Intestinal Core eSteE oral admInistration
`RolfLjfa The terminal half life reported Sir mothotresese
`three to ten hours for patients receiving
`is approximately
`treatment
`for psorisaia or theumatold arthritis or low dose
`therapy less than 80 mg/n3 For patients
`aotin.oplsstic
`the terminal half4ife
`receiving high doses of mathntrexsts
`to 18 hoort
`ls eIght
`Renal excretion is the primary route of elimi
`Excretion
`nation and is dependent open dosage and route of adminia
`fretion With IV administration 80% to 90% of the adinin
`Istored dose is excreted
`unchanged
`in the ugine withjn 24
`hours There is limited billsy excretion amounting to 10%
`orion of the administered dose Enterohspetlc recirculation
`of methotrexeta has been propoeed
`Renal excretion occurs by glornerular
`sad active
`filtration
`tubular secretion Nonlinear elimination due to saturation
`reabsorption has been ebssrved Iopaoriatic
`of renal
`tubular
`petlanta at doses between 74 and 30 cag lippeired renal
`function a.ewell as conravrent use of drugs such as weak
`can mark
`organic acids that also undergo tubular secretion1
`edly increase methotrexate serum levels Excellent correla
`lien baa been reported between methotrexste cloaranpeand
`endagenous
`clearance
`Metwtrexate
`reles vary-widely and are generally
`clearance
`decreased at higher doses Delayed drug clearance has been
`Identified as one of the mor factors responsible for tooth
`ft has been peatulatsd that the toxicity of
`otrexnte toxicIty
`matheteexste for normal
`La more dependent
`tiaeuea
`upon
`the duration of exposure totha drug rathgr than the peak
`level achieved When
`patient baa delayed drug elimina
`tion due to compromised renal
`function
`third apace eflus
`sian or other cauaes methoteexato serum concentrntlona
`may remain elevated
`prolonged periods
`The potential
`for -toxicity from high dose reglmeoa or de
`layed excretion is reduced
`by the adminiatratlon
`of leucovo
`rim calcium during the 6nal phase of urethotrexate plasma
`elimination Phermacokinstic monitoring if nethntrexate
`serum concentrotions may help Identify those
`patients at
`high risk for methotrexate toxicity end aid in proper adjust
`montofloucovorin
`dosing Guidelines for monitoring serum
`methntrexato levels and for adjustment of leucovorin dos
`ing to reduce
`thn risk of methotrexete toxicity ste provided
`below in DOSAGE AND ADMINIflAXJON
`in human breast milk The
`Methotrexnte has been detected
`highest breast milk to plasma concentration ratio reached
`0.01
`INDICAnONS AND USAOE
`PJsoplaarlc Dlaeaaaa
`Methotrexate
`
`is indicated in the treatment of gestational
`choriocarcinoma
`chorinadenoma destruens end hydatidi
`form mole
`In acute lymphocytir
`leukemia methotrexate is Indicated in
`the prophyleris of neningeal
`leukemia and is used in main-
`
`therapy in combination with ether chemotherepeu
`tenance
`tic agents Methotroxete is also indicated in the treatment
`leukemia
`of meningeal
`Methotrexate is used alone or in combination with other an
`in the treatment of breast cancer epider
`ticancer agents
`moid cancers of the head and neck advanced mycosis on
`goidee and
`lung cancer particularly squamous cell and
`typea Methotrexate is also used in comhinetion
`email cell
`with other chemotherapeutic agents in the treatment of ed
`vanced
`atsge non-Hodgkins Iymphomas
`Methotrexate in high dcaea
`followed by leucoverin rescue in
`combination with other chemotherapeutic agents is effective
`in patients with non
`in prolonging rçlapeefrue survival
`who have
`metestatic oeteosercoma
`undergone
`iv
`surgical
`eection or amputation for the primary tumor
`
`Methotrexate is indicated in the symptomatic control of ee
`vera recalcitrant disabling psoriaais that is not adequately
`responsive to other forms of therapy but only when the di
`ognosis has been eetobli.hed as by bispsy cord/or oftsr dot
`to ensure that
`is important
`pee
`consultation It
`moto/ogic
`rissia flare is not due to en undiagnosed concomitant die-
`ease effecting immuns responses
`RheumstoM Athdth
`Methotrexate is indicated in the management of selected
`adults with severe acbve
`classical or definite vheu.metoid
`arthritis ABA criteria who have had an insufficient
`there
`to or are intolerant of an adequate
`trial of
`peutic reeponse
`and usually
`first-line therapy including full dose NSAJDs
`trial of at least one or more disease-modifying antlrheu
`matic drugs
`low
`Aspirin nunsteruidel anti-inRsn.nistory agents end/or
`does steroids may be continued although the possibility of
`increased toxicity with concomitant use of NSAIDe includ
`ing ealicylstes has net been fully explored See PRECAU
`TIONS Drug brtsr.ctlon. Steroids may be reduced grad
`to methotrexete Combined
`ually in patients who respond
`use of methothrexate with gold penicillamnina hydroxychle
`or cytotoxic agents has not been
`roquine
`eulfasalexins
`studied and may increase
`of adverse
`the incidence
`effects
`Rest and physiotherapy as indicated should he continued
`
`CONTRAINDICATIONS
`con cause fbtel death or torstogenic effects
`Methotrexate
`pregnant women Methotrexate is
`when administered to
`contraindicatod in pregnant women with peoriaais or rheu
`matoid arthritis end ehould be ubed in the treatment nina-
`plastic diseases only when
`the potential benefit outweighs
`the risk to the fetus Women
`of childbearing
`potential
`should not be atarted on methotrexate until pregnancy is
`on the serious risk to
`and should be fully counseled
`excluded
`the fetus see PRECAUTIONS
`should they become preg
`nant while undergoing treatment Pregnancy should be
`if either partner is receiving methotrexsta
`avoided
`during
`end for minimum of three months alter
`therapy for male
`patients and during end for et least one ovulatory cycle af
`ter therapy for fomale patients See Boxed WARNINGS
`reactions from
`Because of the potential Sir serioua adverse
`methotrexsts in breast fad infants It
`is contrsindicated in
`nursing mothers
`
`or rlleumstoid arthritis with alco
`Patients with.psoriasis
`holism alcoholic liver disease or other chronic liver disease
`should not receive methotroxata
`Patients with psorisaia or rheumatoid arthritis who hsve
`eye
`of immunodeflcisncy
`evidence
`avert or laboratory
`dromes should not receive meihotrexate
`Patients with peoriasis or rheumatoid arthritie who have
`preexisting blood dyscrasias such as bone marrow hypopla
`anomie
`sie leukopenia
`thromhocytopenia or significant
`receive methotrexate
`should not
`
`Patients with
`
`known
`hypersensitivity
`the drug
`ehould not
`receive
`WARNINGSSEE BOXED WARNINGS
`
`to methotrexate
`
`PRECAUTIONS
`G.nrsl
`for serious toxicity See
`Methotrexate
`has the potential
`Boxed WARNINGS Ibxic effects may be related in fre
`and aeverity to don or frequency of administration
`quency
`but have been seen at all doses Because they can occur at
`any time during therapy it
`is neoesssmy to follow patients
`on methotrexste closely Most adverse reactions era revere
`ihle if detected early When such reactions do occur the drug
`in dosage nr discontinued and appropri
`should be reduced
`ate corrective measures should be taken If naceasar
`this
`include tho use of leucovorin calcium See OVER-
`could
`DOSAGE If methotrexate
`therapy is
`reinstituted it
`should be carried out with caution with adequate
`consider
`ation of further need for the drug and with increased alert-
`ness eats possible recurrence
`of toxicity
`The clinical pharmacology of methotrexate has not been
`hepatic
`well studied in older individuals Due toadminished
`
`Lilly Ex. 2020
`Sandoz v. Lilly IPR2016-00318
`
`

`
`IMMUNEX CORPORATION/1399
`
`Nephr
`
`PRODUCT INFORMATION
`
`huruvorii enter the CSF primarily as 6-methyltetrahydro-
`felate and in humane remain 13 ordera of magnitude
`than the usual methotrexate concentrations follewing
`lewer
`intrathecal administration However high doses of leucovo
`the efficacy
`na may reduce
`adminiatarod
`of intrathecally
`mothotrexate
`
`in
`
`states may increase methotroxata toxicity
`Palate deficiency
`haa been reported rarely to
`lrimethoprim/eulfamethoxazole
`hone marrow auppreasion in patients receiving
`iecreaeo
`niethotrexate probably by an additive entifolate effect
`Csrcinogensals Mutagenesla and ImpaIrment of Fertility
`We controlled human data exist regarding the riek of neo
`plasia with methotrexete Methatroxate hea been evaluated
`number of animal studies for carcinogenic
`potential
`results Although there is evidence
`with inconclueive
`that
`reethotrexata caueea chromoaomel damage to animal eo
`macic celle and human bone marrow cells the clinical sig
`romaine uncertain Non-Hodgkins lymphoma and
`nificance
`low
`other tumore have been reported in patients receiving
`there have been instencoe
`dose oral roothotroxeto However
`lymphoma arising during treatment with low
`of malignant
`dose oral methotrexate which have
`regreaaed
`completely
`following withdrawal of methotrexate without requiring ac
`tive anti-lymphoma treatment Benefits should be weighed
`cieka before using methotroxate alone
`against the potential
`or in combination with other drugs especially in pediatric
`patients or young adults Methofrexate causes embryotoxic
`in humane It has also been
`ity abortion and fetal defecte
`reported to cause impairment of fertility oligoepermia and
`menstrual dysfunction in humane during and for
`abort
`of therapy
`period after cessation
`Pregnancy
`ertbrltie Methotrexats
`Peoriesie and rheumatoid
`See CONTRAINDICAXIONS
`
`ie in
`
`patients
`
`Pregnancy Category
`Nursing Mothers
`See CONTRAINDICATIONS
`Pudlstrlo Use
`in pediatric patients have not been
`Safety and effectiveness
`established other than in cancer chemotherapy
`Organ System Toxicity
`If vomiting diarrhea or stematitis occur
`Oustroinrestüsol
`should be
`In dehydration methotrsxsts
`which may result
`discontinued until recovery occurs Metbotrexats eboold be
`used with extreme caution in the presence of peptic ulcer
`disease or ulcerative colitis
`can suppress hematspeissis
`Herrsototogic Methotrexats
`and cause anemia leukopenia and/or
`thrombocytopenia In
`patients with malignancy and preexisting hematopoistic
`impairment the drug should be used with csutton if at all
`trials in rheumatoid arthritis n128
`In controlled clinical
`leukoponia WBC 3000/mm3 was
`sean In
`patients
`thrombocytopenis platelets 100000/mm3 in
`and psncytopenis in
`patients
`In psoriasis and rheumatoid arthritis mothofrexats should
`be stopped immediately if there is
`significant drop in blood
`counts In the treetmeot of neoplestic diseases methotrex
`the potsntial benefit war
`ate should be continued only if
`rants the risk of severe myeloeuppression Patients with
`and fever should be evaluated
`profirund grenulocytopenis
`and usually require psronteral bread-spec
`immediately
`truni antibiotic therapy
`Hepotic Methotrexats has the potential
`for acuts elevat
`ed trsnssminsses and chronic fibrosis and cirrhosis hop
`stotoxicity Chronic toxicity is potentially fatal it generally
`has occurred
`sitar prolonged use generally two years or
`mare and after
`total dose of at least 1.5 grams In studies
`in psoriatic patients hepstotoxicity appeared
`func
`to be
`tion of tetel cumulative dose and appeared
`to be enhanced
`by alcoholism obesity diabetes and advanced age An accu
`rate has not been determined the rats of pro
`rate incidence
`of lesions is not known Special
`grsseian and reversibility
`caution is indicated in the presence of preexieting liver dam
`age or impaired hopstic function
`function tests including serum albumin
`In panriasis liver
`should be performed periodically prior to dosing but are of
`ten nannsl
`in the face of developing fibrosis or cirrhosis
`Those lesions may be detectable
`only by biopsy The usual
`rocummendetion is in obtain
`prothompy
`liver biopsy at
`or shortly after initiation of therapy 24 months 21 etetsl
`after each sdditional
`cumulative dose of 1.5 grams and
`1.0 to 1.5 grams.1 Moderate fibrosis or any cirrhosis nor
`mally leads to discontinuetion of the drug- mild fibrosis our
`repeat biopsy in months Milder histo
`mally suggests
`logic findings such es fetty change
`and low grade portal in
`common pretherspy Although
`flammation are relatively
`these mild changes are usually note reason
`to avoid or dis
`the drug should be used
`continue methotrexate therapy
`with caution
`In rbeumateid arthritis sge at first use of methotrexste and
`duration of therapy have been reported as risk factors for
`hepatotoxicity other risk factors similar to those observed
`in psorissis may be .presont in rheumatoid arthritis but
`have not been confirmed in date Persistent abnormalities
`function tests may precede
`appearance
`in liver
`of fibrosis or
`cirrhosis in this population There is
`combined
`reported
`in 217 rheumatoid arthritis patients with liver
`experience
`
`and during treatment after
`biopsies both before
`tive dose of at least 1.5 gland in 714 patients with
`are 64 7% cases of fibrosis
`only during treatment There
`and 0.l%l case of cirrhosis Of the 64 cases of fibrosis 60
`were deemed mild The reticulin stain is more aenaitive
`for
`early flbreais and its usa mey increase
`these
`unknown whether even longer use will
`increase
`these risks
`Liver function tests should be performed at baseline and at
`4S week
`intervals in patients receiving methetrssats for
`rheumatoid arthritis Pretreatment
`should be
`liver
`
`cumula
`
`biopsy
`
`figures It
`
`is
`
`alcohol
`
`function
`
`biopsy
`performed for patients with
`history of excessive
`consumption persistently abnormal baseline
`liver
`infection During
`or
`test values or chronic hepatitis
`therapy liver biopsy should be performed if
`there are per
`de
`liver
`function test sbnnrmslities
`or there is
`aistent
`cressa in serum albumin below the normal range in the set
`ting of well controlled rheumatoid arthritis
`liver biopsy show mild changes
`IRoenigk
`If
`the results of
`II ills msthotrexats may be continued
`snd the
`grades
`listed above
`patient mnnitored as per recommendations
`Methotrexats
`should be discontinued in any patient who
`displays persistontiy abnormal
`functisn tests and re
`liver
`fuses liver biopsy or in any patient whose liver biopsy thaws
`moderate in severe changes Reenigk grade 11Th or IV
`Jnfecrisn nr Immuno/ogic Stotet- Methotrexate should be
`used with extreme caution in the presence nf active
`infec
`tion and is usually contraindicated in patients with overt or
`laboratory evidence of immunodeficiency sysdromse Immu
`nization may be ineffective when given during methotrexsts
`therapy Immunization with live virus vaccines
`is generAlly
`not recommended There have been reports of disseminated
`veccinis infections after smallpox immunization in patients
`receiving methotrexats
`therapy Rypogammaglohulinemis
`has been reported rarely
`fatal opportunistic infections especially Plsau
`Potentially
`mocystis corinii pneumonia may occur with methotreiate
`therapy When
`patient presents with pulmonary symp
`conch
`toms the possibility of Pteumocystis
`pneumonia
`should be considered
`There have been reports of leukoencephslopa
`Neurologic
`thy following intravenous administration of methotrexate to
`patients who
`have had craniospinal
`irrsdiation Serious
`eenretetcity froquentiy manifested as generelired or local
`reported with unexpectedly incroesed
`seizures has been
`frequency among pediatric patients with acute lymphoblas
`leukemia who were frosted wtih intermediate-dose in
`tic
`gmAt5 Symptomatic patients
`travsnous methotrexste
`were commonly noted to have leukoencsphslepathy and/or
`calcifications on diagnostic imaging stud
`microanginpsthic
`ies Chronic leukoencephalopathy has also been repotted in
`doses of high-dose metbo
`patients who
`psceived
`repeated
`trexate with leucovorin rescue even without cranial
`irradi
`ation Discontinuation of methotrexate does not always re
`sult in complete
`
`recovery
`transient acute neurolegic syndrome has been observed in
`patients treated with high dosage regimens Manifestations
`of this stroke-like encephalopethy may include confusion
`is un
`seizures and coma The exact
`hemiparesis
`cause
`known
`
`the central ner
`use of methotrsxate
`After
`the intrathecal
`vous system toxicity which may occur
`con be clseeifled as
`follows acute chemical arachnniditis msnifested by such
`back pain eucbal
`and fe
`symptoms as headache
`rigidity
`ver sub-acute myslopathy
`characterized by perapsresis/
`paraplegia associated with involvement with one or more
`leukoencophalopathy
`manifested
`spinal nerve roots chronic
`semnolence stasis dementia sei
`by confusion irritsbllity
`zures and coma This condition can be progressive and avon
`fetal
`
`dry non
`Pulmenery symptoms eepecially
`Pistmonnry
`productive cough or
`pneumonitis occurring
`nonspecific
`during methotrexsts therapy may be indicative of
`poten
`tially dangerous lesion and
`of treat
`require interruption
`ment and careful
`investigation Although clinically vsrisble
`the typical patient with methotrexnte induced
`lung disesse
`presents with fever cough dyspnea hypoxemia and an in
`to be excluded This
`filtrate on chest X-ray infection needs
`lesion csn occur at all dosages
`Rend High doses of methotrexste used in the treatment
`of osteossrcoma may cause renal damage
`leading to acute
`renal failure
`
`Lilly Ex. 2020
`Sandoz v. Lilly IPR2016-00318
`
`

`
`1400/IMMUNEX
`
`CORPORATION
`
`Methotrexate SodiurnCont
`
`less common reactions included decraasad hemato
`Other
`crit headache upper
`anorexia at
`respiratory
`infection
`thralgias chest pain coughing dysuria eye discomfort em
`infection sweating tinnitua and vaginal dis
`istaxis fever
`
`studies
`
`charge
`Adverse ReactIons In Psorisals
`There are no recent placeho-controlled
`trials in patients
`with psoriasit There are two literature reports Roenigk
`1969 and Nylon 1978 describing large series na204
`248
`of psoriasis patients treated with methotrexate
`Dosages
`ranged up to 25 mg per week and treatment was adminis
`teted for up to thur years With the exception of alopecia
`and burning of akin lesiona each 3% to
`photosensitivit
`10%