EDITION
`
`
`
`
`
` _EEX§
`£5!)
`
`
`
`
`2005
`PHVSICIANS’
`DESK
`REFERENCE
`
`
`
`
`Executive Vice President, PDR: David Duplay
`
`Vice President, Sales and Marketing: Dikran N. Barsamian
`Manager, Editorial Services: Bette LaGow
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`'
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`THOMSON
`Copyright © 2005 and published by Thomson PDR at Montvale, NJ 07645-1742. All rights reserved. None of the content of this publication
`may be reproduced, stored in a retrieval system, resold, redistributed, or transmitted in any form or by any means (electronic, mechanical,
`photocopying, recording, or othen/vise) without the prior written permission of the publisher. Physicians‘ Desk Referencea, PDRB, Pocket
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`Officers of Thomson Healthcare, Inc.: President and Chief Executive Officer: Robert Cullen; Chief financial Officer: Paul Hilger; Chief Technology Officer: Fred Lauber; Executive
`Vice President, Medical Education: Jeff MacDonald; Executive Vice President, Micromedex: Jeff Reihl; Executive Vice President, PDR: David Duplay; Senior Vice President.
`Business Development: Robert Christopher; Senior Vice President, Marketing: Timothy Murray; Vice President, Human Resources: Pamela M. Bilash
`
`ISBN: i~56363-497-X
`
`SUN - lPR2017-01929, Ex. 1033, p. 1 of 29
`SUN - IPR2017-01929, Ex. 1033, p. 1 of 29
`
`

`

`CONTENTS
`
`'
`
`1 S
`
`.
`
`’
`
`Manufacturers’ Index (White Pages)
`
`ection 1
`
`Lists all pharmaceutical manufacturers participating in PHYSICIANS' DESK REFERENCE.
`Includes addresses, phone numbers, and emergency contacts. Shows each manufacturer’s
`products and the page number of those described in PDR.
`
`Brand and Generic III-ame Ind—ex (Pink Pages) 101
`
`_
`Section 2
`Gives the page number of each product by brand and generic name.
`
`
`Product Category Index (Blue Pages) 201 _
`Section 3
`
`Lists all fully described products by prescribing category. An overview of the headings
`appears on pages 201 and 202.
`
`Key to Contolled Substances Categories .................................................................................................. 217
`Gives the definition of each category and the prescribing limitations that apply.
`
`Key to FDA Use-in-Pregnancy Ratings ...................................................................................................... 217
`Provides at—a—glance description of each risk/benefit rating.
`
`U.s. Food and Drug Administration Telephone Directory ............................................................................ 218
`Gives numbers of key reporting programs and information services.
`
`Poison Control Centers ............................................................................................................................ 219
`A national directory arranged alphabetically by state and city.
`
`Vaccine Adverse Event Reporting Form .................................................................................................... 225’
`Includes master copy and instructions for completion.
`
`
`Product Identification Guide (Gray Pages)
`301
`
`Section 4
`
`Presents full-color, actual~size photos of tablets and capsules, plus pictures'of a variety of other
`dosage forms and packages. Arranged alphabetically by manufacturer.
`
`Product Information (White Pages) 401
`
`Section 5
`
`Includes entries for some 3,000 pharmaceuticals. Listings are
`The main section of the book.
`arranged alphabetically by manufacturer.
`
`Diagnostic Product Information
`3437
`
`Section 6
`
`Gives usage guidelines for a variety of diagnostic agents. Arranged alphabetically by manufacturer.
`m___
`
`FDA MedWatch Form ............................................................................................................................. 3441
`Includes master copy and instructions for completion.
`
`SUN - IPR2017-01929, Ex. 1033, p. 2 of 29
`-SUN - IPR2017-01929, EX.1033. p. 2 of 29
`SUN - IPR2017-01929, Ex. 1033, p. 2 of 29
`
`

`

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`;, DESCRIPTION
`Betaseron® (Interferon beta-lb) is a purified, sterile, lyoph-
`ilized protein product produced by recombinant DNA tech-
`niques. Interferon beta-1b is manufactured by bacterial fer-
`‘ mentation of a strain of Escherichia coli that bears a
`genetically engineered plasmid containing the gene for hu-
`man interferon betamu. The native gene was obtained from
`' human fibroblasts and altered in a way that substitutes ser-
`ine for the dystine residue found at position 17. Interferon
`beta»1b has 165 amino acids and an approximate molecular
`weight of 18,500 daltons: It does not include the carbohy-
`'drate side'chains found in the natural material
`The specific activity of Betaseron is apprordméatelyl32 mil-
`lien‘ international units (IU)/mg Interferon beta-lb: Each
`' vial contains 0.3 mg of Interferon beta—lb. The unit mea—
`surement is derived by comparing the antiviral activity of
`the product to the World Health Organization (WHO) refer-
`“ence standard. 'ofrecombinant human interferon beta‘. Man-
`nitol, USP and Albumin (Human). USP [15 mg. each/vial)"
`are added as stabilizers.
`Lyopluliaed Bet’aseron'is a sterile. white to fifi-white‘powder,
`‘ for subcutanedus injection alter reconstitution With the dil-
`uent supplied (Sodium Chloride, 0.54%. Solution).
`1 CLINICAL PHARMACOLOGY
`General
`,
`-—I.nterferons-(IFNs) are a family-of naturally occurring pro-
`- ‘teins; produced by eukaryotic'icells in response to vital in-
`fection and other biologic agents; Three major.groups of in-
`» terferons have been distinguished: alpha, beta, and gamma.
`Interferons alpha and beta comprise the ’Iype I interferons
`'and‘ interferon gamma is arfl‘ype II interferoi'i: Type I inter-
`
`ferons have ionsidl‘erably ov lapping but also distinct bio-
`-—logic activities. The bioacti Vties’of‘ IENs=’are mediated by
`their interactions with speciiié receptois found on the sur-
`' l'faces ofhuman cells. ‘Difi'erences'in bioacti‘vites induced by
`
`“I
`, “likely-reflectdivergencesfin' the signal transduction
`
`p cess induced by IFN-recepto‘r binding.
`’
`g.
`Biologic Activities
`. The mechanism of action of Interferon bola-lb in printing,
`with multiple sclerosis is unknown. Interferon beta-1h re-
`ceptor binding induces the expression of proteins that m3
`responsible for tho plaiutroplc bionclivitiea of Inlorlcron
`bets-1h. A number of thes'o proteins I‘ including rlmptorln',
`pg-niicr'oglpbulirl. MxA protein. and Ila-Ill) have been Inca» .
`
`BERLEX/893
`
`'[JUCT INFORMATION "
`”I
`
`
`”lent/Standard symptomatic treatment may be un-
`n if overdosage occurs. If the patient deVelops a dra—
`increase in blood pressure, 5 to 10 mg of phentola-
`mesylale has been 'shown‘ to be effective in lowering
`'
`l.essure for the short time that control would be
`It is unknown whether GlucaGen® is dialyzable,
`d
`
`.e d1 a procedure isvunlikely to provide any benefit given
`half-life and nature of the symptoms of overdose.
`
`E AND ADMINISTRATION
`‘
`-
`
`Gen® should be reconstituted with 1 ml of Sterilew -A
`
`it: Reconstitution (if supplied) or with 1 mL Sterile Wa-
`for Injection, USE
`'
`h
`.
`'
`. ”m
`r:
`
`.
`‘ng the Syringe, Withdraw all of the Sterile Water for Re-
`
`lsfilution (if supplied) or 1 mL Sterile Water for Injection,
`tinto the GlucaGen® vialiRoll thewial gently '
`and inlec
`
`writer is completely dissolved and no particles re- .
`
`
`in the fluid. The reconstituted fluid should be clear
`.{ngin
`.
`_d o
`{wager—like consistency. The reconstituted GlucaGen® ‘
`
`.95 a concentration of approximately 1 mg/ml Glucagon.
`
`. Elie reconstituted GlucaGen® should be used immediately
`- 5mm- reconstitution. Discard any unused portion.
`.
`-
`lfir the treatment of hypoglycemia: For adults an'd‘for'pe:
`.diatn'c patients weighing 55 lb (25 kg) or‘more, admrnister
`'
`'mg by subcutaneous, intramdsclilar,‘or intravenous miec: ‘
`
`-. m1)" According to‘ the literature, 1A adplt dose (0.5 mg) is
`:mommended for pediatric patients weighin less than
`"55 113125 kg) or younger thanV6-8 years ‘oldf'
`.4,5.e Emeii'
`cy assistance should be sought if the patient fails to re-
`illpond within 15 mlnutes alter subcutaneousor intramdscu-I
`1,”, injection of glucagon. The glucagon mJection may be
`""-ated while waiting for emergency assistance.1 Intrave-
`. us glucose MUST be administered if the patient fails to
`- food to glucagon. When the patienthasresppnded to the
`
`uncut, give oral carbohydrate to restore the liver glyco- .
`and prevent recurrence of hypoglycemia.
`
`ll- aliens for Use, as a Diagnostig Aid: ‘ Reconstituteas in-_
`ii. ted above. Discard any unused portion. When the diag-,- ;
`I
`c procedure is over, give oral carbohydrate to restore“
`
`_lver glycogen and prevent occurrence wof secondary hy;
`jlcemia.
`I
`f
`L
`.
`
`of maximal glucose concentration
`avenous: 5 to 20,minutes,
`
`
`
`nuscular: 30 minutes
`.1
`.
`I:
`I sons: 30' to 45 minutes
`
`let G! smooth muscle relaxation}; _
`onous: 0.25 to 2 mg (IU)—-45 seconds.
`muscular:
`.
`.
`'~
`"1 Lu
`
`Ll}—S to 10 minutes
`-
`[Ill—4 to Tl'ininutes
`
`
`'loll of action—
`_lycemic action—60 lo 90 minutes
`
`_' llllust‘la roloxutlou—J
`
`.
`_
`nus:
`.
`
`. 0.5 ing.[IUJ———9 lo 1'! milrutfis,
`
`IU}-—22 lo 25 minutes
`
`useulur.
`_
`.
`
`: “lb—1.2 to 27 minutes
`
`“ll-'3] to 32 minutes
`.
`.
`-
`.lnd_stornga_
`
`scorrslilulion: Tbo (llucuflcnflh putting? may he '
`_
`
`up to 24 months all controlled room tompesrstn'ri': 20}
`
`BESS" to 77°F) prior to remnstitutiou1 Avoid {ranging .
`
`protect from light. GlucuGen® should not be used «her
`.flpiry date on the vials.
`l
`
`Stemmilmion: Reconstitutcd-(llucoficofl should be
`
`
`mmodlutsly. Dismrd any unused portion. If tho solo-
`am” any slm__ol' gel formation or particles. it should
`
`‘
`arded.
`_
`-
`-
`'
`.
`’
`
`.W SUPPLIED .
`
`_
`-. HGlUcaGenCp Diagnostic Kit includes:
`
`'-
`- “whining _1 mull III} Glursfiendil'lglucng'un ”DNA
`
`)for lnjorflo'ril
`'
`'
`,
`.-
`containing 1 ml Stir-rile Water for Reconstitution
`tomorrow;
`'
`'
`
`.
`Glucaflonfll ill-puck includes:
`
`1;le Funlaining 1 mg {I 1U] Gluanun® lclllcnaun .
`dot-lino] for injection!
`I
`'
`I
`. 55390410140
`
`In March 2ou
`
`I _RENCES
`_'
`lg I'lfilrrmr'lin" (or lltl' Hr‘rrltll Corr: Prufhmffunalul'l‘"
`Reck'
`.
`.-
`'1
`.
`---.
`
`WHE' Maryland.
`l‘lio Umlud S'nh‘“ Phnrmnm— .
`El Convention. Inc: lils’l: Vol 1,1filzlfilfi—Il318.
`.‘
`‘
`
`. I.nzsiet a1: Ugo of. Glucag'o‘n'tb terminate insulin reoc'i
`
`
`.
`'Nn n vdiabetic children. Nebr Med J 1953;413:5357.
`'
`‘
`I} Add, I{OClI~R, Clinical nbflliilis wiLlI uiuk'ufimi in
`
`~ildr9n.
`II' Pedidtr- 1955;47:161-170l
`di-
`
`“P 3C: fit 3|! Treatment of insulin hypogh‘rvmifl in
`
`C Camlfl‘l‘fl'. Diabetes l96-l:-'l3:6~l~fi-ti4ll.
`
`ll E‘f‘TEJitll'uuum L: Hypoglycemia: in chilllhnml Iiiulwlw
`_. Hem C
`.Ol lulwulonomm nr intriuuustulllr injrt'l'l‘m “f
`
`_
`P; ‘lUI-‘LIS of l:lllc:ll:llll. Aclu l‘ediul-r Sound 1933177:
`819
`Iron. AS. Eyi'u JA, and Soltesz Ll, [iypoglywm
`
`'-" :1 {liamu children. In: Frier BM and Fisher BM, eds
`
`228”“:qu and Diabetes, ndwm-d ran-mid, 1993;
`
`old Labflmo'rlosm
`
`- rd, OH H lIlIl
`
`UN - IPR2017-01929, EX. 1033, p. 3 of 29
`SUN - IPR2017-01929, Ex. 1033, p. 3 of 29
`
`
`'sured in'bldod fractions from Betasean-treated patients ‘
`
`Betaseron dose. Biologic response marker levels peaked be-
`tween 40 and 124 hours and remained elevated‘above base-
`line throughout the seven-day (168~hour) study. The rela-
`tionship betweenserum Interferon beta-1b levels or induced
`biologic response marker levels and the clinical eflect‘s of In-
`..
`terferon beta-1b in multiple sclerosis is unknown;
`'
`’
`'
`CLINIQALSTUDIES '.
`‘
`_,
`‘
`’
`The safety and efficacy of Betaseron have been assessed in
`three multice
`er trials. Study 1 evaluated Betasveron in
`1relapsing-remitting MS (RRMS) patients and Studiesl2 and
`5 assessed Betaseron'in secondary progressive MS (SPMS)
`patients.
`5
`.
`.
`.
`‘
`.
`.
`'.
`,
`The efiectiveness. of Betaseron in» relapsing-remitting MS
`(Studyhl) was evaluated in a double blind, multiclinic,,ra.u-
`domized, parallel, placebo controlled clinical investigation
`of two years duration. The study enrolled MS patients, aged
`15 tpu50, who we're ambulatory (EDSS of S 5.5),. exhibited a
`relapsing—remitting-vclinical course, met Poser’s criteria1 for
`clinicallyldefinite andlorlaboratorysupported definite MS
`and had. experienced at least two exacerbations over two
`years preceding the trial without exacerbation in, the pre-
`ceding month. Patients who had received prior immunosup-
`’pressant therapy‘we're excluded.
`An-leiracerbationma‘sdefined as1 the appearance Ufa new
`clinical'sigjn/symptom or the clinical worsening ul'u previous
`sign/symptom (one that had been stable for al. least 30 days)
`that persisted for a minimum of_24 hours.
`Patientsselected for, study were randomized to treatment
`with either placebo (N423), 0,.05‘mg of Betasnruu 1N=l 25),
`or. 0.25 mg of Betaseron (N=124) self-administered subcuta-
`neously eyery other day. Outcome basod on the 372 random-
`ized patients was evaluated after two years.
`Patients _who required more than three Eg-duy courses of
`corticosteroids were removed from the studyuMinor analge»
`sics (acetaminophen._c deine), antidepressants, and oral ba-
`clofen‘ were hallowed adlibitum, .but chronic nonsteroidal
`anti-inflammatory drug (NSAID), use was not allowed.
`The primary protocol~detined outcome measures were 1) fre~
`lquency of exacerbationsper patientgand2) proportion of
`exacerbation free patients. A number of secondary clinical
`and magneticpresonance imaging (MRI) measures were also
`emplpy All-patients underwent annual T2 MRI imaging
`and a subset‘of 52 patients at one site had MRIs performed
`eyer‘ysixuweeks for assessment of new or expanding lesions.
`The study results are shown in Table 1.
`.
`[See table )1, at, top ofnext page}
`‘ Qf theL 12;.R'RMS‘, patients randomized, 72 ililfiil failed to
`complete two full years on their assigned treatments.
`Oventhe twoyearperiod, there were.25 MS-related hospi-
`talizations in the.0.25:mg Betaserpn-treated group com-
`paredto .48 hospitalizations in the placebo group. Incom-
`parison, non:M_S hospitalizations were7evenly distributed
`among the groups, with 16 in the 025 mg Betaseron group
`gnd 15in the'placebo group.,The average number of days.of
`MS—related steroid use was 41_ days in the 0.25 mg
`Betaseron group and 55 days in the placebo 'group
`(p=0.oo4).
`" ’
`MRI 3data weré ‘alsot'analyzed for patients in this study. A
`frequencydistribution of the observed percent changesvin
`MRI area at the end of two years was obtained by grouping
`the percentages in successive intervals of equal width: Fig-
`ure 1 displays a histogram of the proportions of patients,
`which fall into each of these inter-vols. The median percent
`change in Mill urns for the ".25 mgg‘roup was-1.1%. which
`was significimtly smaller Lhari the 16.5% observed for tlie
`plunubu group (p=0.00llll.
`Dism'bufiun a!Change in MRIAm
`Flnurcl
`
`u Ill-Iran!!! IIII
`__ __
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`Pmem Change In Mm Ans
`.
`
`In an evaluation of frequent MRI scans (every six Wankel un
`52 patients at one site, the percent of scans with new or ox-
`panding lesions was 29% in the placebo group and ME. in the
`0.25 mgt‘reatment group (p::ll.ll_06,|.
`-
`'
`The exact relationship'hetween MRI findings and. clinical
`status of patients is unknown Changes in lesion urns often
`do not correlate with changes in disability progression. The
`prognostic significance uftho MRI findings in this study lids
`not been evaluated.
`
`Continued on next page
`u .
`_________—_.
`
`Information on Berlcx products [appearing hero! ls based
`on the most current information available at rho limo
`‘ol publication closing. Further lnlormotlon {or these
`and other Barlow: products can be obtained I'rom
`Medical 8e Producl Services at Burl”. luc. by calling
`1-83’3-BERLEX-4.
`'
`_—_____—_.——-
`
`Cmmrll 2 ll 0 F: FDR” supplements and luturo editions for revisions
`
`.
`
`“ Berlex, Inc.
`6 WEST BELT
`' WAYNE,‘ NJ 07470
`vvww.Berlex.com
`
`_.
`
`.
`
`Direct lnquiries'to:
`1-(888) BERLEX-4
`
`,BETASERON®
`.
`[bay-ta-seér-bn]
`Interferon beta-1b
`
`_and Betaseron-treated healthy voluutoorfi. Immunomodula-
`tor-y effects of Interferon betug‘lh include the enhancement
`bf‘suppressqor T c'cll activity, reduction of pm-inflnmruuthry
`cytokine production;'downireg'ulation of antigen premola-
`
`.
`.-l
`
`l;
`.
`.
`-
`'
`'
`'
`'
`of lymphocytertrafficking into the new
`
`
`known if those cfi‘ucls plnynn
`rl clinical activity of Bola-aurora
`
`1 Pharmacokinetics -
`
`Because serum concentrations oilnlli’wrfcron beta-1h om low
`
`, ‘ab
`'o'rj‘no't
`following subcutaneous administrutioo of
`0.‘2 ’me or less (if Betaseron. phuroincoI-rinotic iolhrroation
`in‘poiienla with MS receiving Lhorccom‘mended dose or
`be soron is (not, available. Following single and rouitipl:l
`daily subcutmieouaI'éidriiiniutraiiriria of 0.5 mg Botanic-ran to
`healthy voluntcrzra‘lN-slzl. E'urulu Interferon buts-1b Enli-
`centrations Were‘gbnefally below 100 lUlmL'. I‘cuk scrum
`Interferon beta-1b concentrations occurred between one to
`eight hours, With a mean peak serum interferon concentra-
`tion of* 40.1U/mLI' Bioavailabilityg-b'ased on a total door of
`0.5 mg Betaseron given as‘two'subcutaneous injections at
`different sites, was approximately 50%.
`Alter intravenous administration‘rof Betaseron (0.006 mg to
`.-2.0 ni‘g),gsimilar 'phai‘macokinetic profiles were obtained
`
`from healthy volunteers (N=12) and from patients with dis-
`eases 'otherrthari MS (N=142). In‘p'atientsreceiving single
`intravenous doses up to 2.0'mg, increases in serum concen-
`trations ivere dose‘proportional. Mean serum clearance vall
`ues ranged from 9.4 mIJinin-kgi‘l to 28.9 iuUmimkg" and
`Were independent of dose. Mean'terminaleliminatio'n half-
`life values ranged from 8.0 minutes to 4.3 hours and mean
`steadyestate volume of distribution'rvalues' ranged from
`' 0.25 L/kg to 2588 L/kgi Three-times-a—week‘intravenou's dost
`ing-for two weeks resulted in no accumulation of Interferon
`beta—1b in sera of patients:‘Pharmacokinetic parameters af-
`ter single and multiple intravenous doses of Betaserén were
`cbnrparable.’
`‘
`.0”.
`Following every other day subcutaneous administration of
`0.25 mg Betaseron in healthy volunteei‘s,"biologic response
`I marker levels (neopterin,. Bfmicroglobulin; MXA protein,
`f and the immunosuppressive cytokin'e, lL-lO) increased Sig.-
`nificautly above baseline six-twelve hours after the fii‘st
`
`ll
`
`
`
`

`

`894/.BERLEX
`
`
`Piimary and Secondaryglinical Outcomes
`
`-
`.
`TABLE _1_
`_
`. >"T\\.In Year RRMS Study Results
`
`,
`
`-
`
`.
`
`_
`
`.-
`
`
`
`.
`‘
`“
`Statistical Comparison-3'
`'
`‘
`'
`Efficacy Parameters
`Treatment Groups
`p-valuo
`
`Placebo
`0.05 mg .
`'
`0.25 mg
`Placebo Fl
`0.06 mg
`_
`l
`_
`vs
`vs
`(N=123)
`(N=125)'
`.
`, (N=124l
`0.05 mg
`0.25 mg
`1.31
`1.14
`'”
`0.90
`0.005
`0.113
`.1675: l
`l 318%
`2535:
`0,609
`0.25Il_|
`,L .
`
`i
`
`l
`
`.
`
`Primary End Points
`Annual exacerbation rate
`Proportion ofexacerbation-
`free patients?
`
`Exacerbation
`frequency
`per patient
`'
`
`'
`
`.
`Secondary Endpoints‘i‘r
`
`or
`1
`2
`3
`4
`25
`
`. Median number of months:
`to first on-studyexacerbatiou
`
`\
`
`l
`
`i
`._ .
`
`.
`
`‘
`
`1
`
`.
`
`'
`
`_l
`
`20 _
`32 ‘
`20
`15
`15
`21
`,
`
`, 22
`31
`28
`15
`7
`16
`_1_—
`
`"
`
`'
`
`.
`
`20
`(in
`IT
`H .
`H
`El
`
`.
`
`0.151
`
`0,017
`
`J—
`
`5
`
`I
`
`6
`
`_
`
`9
`
`0.299
`
`0.09?
`
`-
`
`Rate ofmoderate
`0.47
`11.29
`0.23
`0.020
`0.257
`' aim
`or severe exacerbations per year
`_
`_
`_"_
`
`‘ Mean number ofmoderate
`' {Wt '-
`l
`_
`I16.1.
`33.2
`19.5
`0.225
`0.06s].
`oi- swore exacerbation)
`'
`. "m '
`-
`
`days per patient
`-
`‘
`Mean change In EDSS
`0.2].
`0.21
`.
`l'
`007
`0.955
`0.108
`scorei at endpoint
`. IMMean- change in Scnpp‘s'
`scorn: at endpoint
`Median duration in days
`per exacerbation,
`
`I
`
`43.53
`
`,
`
`I,
`
`36
`
`'
`
`.0. o
`'
`33
`
`'
`
`; i'
`
`lesion area atendpoint .
`
`-
`
`-
`
`»
`
`..'
`
`I
`
`.I
`
`‘
`
`35.5
`
`l
`
`f)" 0.66
`
`' 0.541
`
`l
`
`0.051 '
`
`,7
`. g
`‘
`
`Betaseron—Cont.
`Studies 2 and :3 Were multicenter, randomized, double
`blind, placebo controlled trials conducted to assess the effect
`of Betaseron in patients with SPMS. Study 2 was conducted
`in Europe and Study 3 was conducted. in North America.
`Both studies enrolled patients with clinically definite or Inh—
`oratory-supported MS in the secondary [iriii'rrémaii'e phase,
`and who had, evidence of disability progression {both Study
`2 and 3) or two relapses (Study 2 only] within the previous
`two years. Baseline Kurtzke expanded disability status
`scale (EDSS) scores ranged from .1." to [$5.2 Patients in
`Study‘2_w_ere randomized to recoivofietaseron 0.25 mg
`(nl=’360) dr placebo fn=358). Patients in Study 3 were ran-
`domized ' to Betaseron 0.25 mg (n=317), Betaseron
`016 mg'lm2 of‘body surface area (n=314, mean assigned
`dose 030 mg), or placebo (n=308). Test agents were odmim
`istered subcutaneously, every other day for three years. '
`The primary outcome measure was progression of disability,
`defined as a‘1.0 point increase in the EDSS score, or a! 0.5
`point increase for patients with baseline EDSS 2 6.0. In
`Study 2, time to progression ln'EDSS was longer in the
`Betaseron treatment group (p=0.005), with estimated annu»
`alized rates of progression of 16% and 19% in the Betaseron
`and placebo groups, respectively. In Study 3, the rates of
`progression'did not differ significantly between treatment
`groups, with estimated-aimualize‘d rates of progression 'of
`12%, 14%, and 12% in'the’Betaseron fixed dose, surface
`area—adjusted dose, and placebo groups, respectively
`Multiple analyses, including covariat'e'and subset analyses
`based on sex, age, disease duration, clinical disease activity
`prior to study enrollment, MRI measures at baseline and
`early changes in MRI following treatment were evaluated in
`order to interpret-the discordant study results. No demo-
`graphic ordiseaseirelated factors enabled identification of a
`patient subset where Betaseron treatment was predictably
`associated with delayed progression of disability.
`In Studies 2 and 3, like Study '1, a statistically significant
`decrease in the incidence of ‘relap's'es associated with
`Betaseron treatment was-demonstrated. In Study 2, the
`mean annual relapse rates were 0.42 'and‘0.63 in the
`Betaseron and placebo groups, respectively (p<0.001). In
`Study 3, the mean annual relapse rates were 0.16, 0:20; and
`0.28, for the fixed dose, surface area-adjusted dose, 'and pla-
`cebo groups, respectively (p<0.02).
`'
`‘
`MRI endpoints in both Study 2 and Study 3 showed lesser
`increases in T2 MRI'lesion area and decreased number of
`active 'MRIleSions inpatients in the Betaseron groups. The
`exact' relationship between MRI-findings and the clinical
`status of patients is unknown. Changes in MRI findings ‘of-
`ten do not correlate 'with changes in disability progression.
`The prognosticsi'gniflcorica of tho-MRI findings in these
`studies is not known.
`'
`i
`_
`'
`Safety and “efficacy of treatment'with Betaseron beyond
`three years 'are not know“.
`'
`INDICATIONS AND' USAGE
`Betaseron (Interferon_beta.~1b) -is.indicated for the treat—
`ment of relapsing forms of multiple sclerosis to, reduce the
`frequency _of clinical exacerbations.
`-
`.
`CONTRAINDICATIONS ;
`Betaseron, is, contraindicated in patients with n historyr of
`hypersensitivity to natural or rcoofnbioont_intorfsrnn bum,
`Albumin (HPmflnli,U,SP..flT.fl-PY other component of the
`formulation: ’
`'
`”
`WARNINGS
`Depression and Suicide"
`Betaseron (Interferon beta-lblshould be used with caution
`in patients with depression, a condition that is common in
`people with multiple sclerosis.‘ Depression'and suicide have
`been reported to occur with increased frequency in patients
`receiving interferon compounds, including Betaseron. Pa-
`tients treated with Betaseron should'be advised to report
`immediately any symptoms of depression and/or suicidal
`ideation to their prescribing physicians. If a patientdevel-
`ops depression, cessation of Betaseron therapy should be
`considered.
`,
`In the three randomized controlled studies there were three
`suicides and eight suicide attempts among the 1240 pa-
`tients in, the Betaseron treated groups compared to one sui—
`cide and four suicide attempts'among the 789 patients in
`the placebo groups.
`-
`-
`’
`‘
`Iniection Site Necrosis
`Injectionsite necrosis (ISN) has been reported in 5% of pa—
`tients in'co'ntrolled clinical trials (see ADVERSE REAC-
`TIONS). Typically, injection site necrosis occurs within the
`first four months of therapy‘although post-marketing re—
`ports have been received of ISN occurring over one year af-
`ter initiation of therapy. Necrosis may occur at a single or
`multiple injection, sites. .The necrotic lesions are 'typically
`three cm or less indiameter, but'larger areas have been re-
`ported. Generally the necrosis has extended only to subcu-
`taneous fat. However, there are also reports of necrosis ex-
`tending .to and including fascia overlying muscle. In some
`lesions where biopsy results are available, vasculitis has
`been “reported, For some lesions debridementand, infre-
`quently, skin gr'afting‘have been required.
`,
`,
`'
`As with any open lesion, it is important tok'avoid infection
`and, if it occurs, to treatthe infection. Time to healing. was
`varied depending on the severity 'of the necrosis at the time
`treatment Was begun. In most cases healing Was associated
`with scarring.
`
`SUN - lPFI2017-01929, Ex. 1033, p. 4 of 29
`SUN - IPR2017-01929, Ex. 1033, p. 4 of 29
`
`
`
`
`
`
`
`
`
`
` ‘
`
`
`%ichange in meanMRI.
`I
`i
`21.4% --
`9.8%
`new:
`.
`0.015
`0.019
`
`ND
`
`ND
`I
`
`'
`
`C
`J
`ND Not done
`'I‘ 14 exacerbation free-patients (0 from placebo, six from 0.05 mg, and eight from 0.25 mg)rd.ropped outofthe study I
`f
`completing six months:of therapy. These patients are, excluded from this analysis.
`-
`'
`l:‘
`_TT Sequelae and Functional Neurologic Status, both required by protocol, were not analyzed individually but are in! ---.'|
`‘ as a function of the EDSS;
`-
`It EDSS scores range from 1-16, with higher scores reflecting greater disability.
`.
`a; g
`, A
`'ztt .Scripps neurologic rating scores, range from 0-100, with smaller scores reflecting greater disability.
`2,. -
`
`Female patients should be cautioned about the nbi'li't
`Some patients have experienbed healing of necrotic skin le-
`potential of BetaseronIsee PRECAUTIONS, P -
`:
`sions while Betaseron therapy continued; others have not.
`'.‘
`Teratogenic Effects).
`,
`. "
`'
`Whether‘tb discontinue therapy following a single site ofne-
`Instruction on Self-iniectioh Technigue and Ptoéé'dtll‘fl '-
`ciers‘is‘ dependant on theoflont'offricerosis. For patients
`
`Patients should be instructed in‘the uso'ol‘ aseptic lecithin;
`whocpntinue therapy with Betaseron ufler'injoction'site ne'-
`when administering Betaseron'.‘Appropi-iatd tsunami - ‘
`cro'sis’has occurred. Betaseron should not be administered
`
`into‘the alfected area until it is fully healed. If‘ multiple
`reconstitution of Betaseron and self-injection Bho'tlld'lfi'fifl‘
`yided, infiluding‘ careful review of the Betaseron Media'at'
`lesionsloccur, therapy should be discontinued until healing
`
`occurs.
`7
`‘
`‘
`'
`Guide The first'injection should be'perfornied undo
`supervision of an appropriately qualified health
`Patient understanmng and usoofnsoptic self-infliction tech-
`professional. »‘
`’1
`'
`'
`'
`niques and procedures should be periodically reapiihiated,
`
`particular-mi! injection alto necrosis has occurred.
`'
`‘
`Patients should be cautioned against the re-use of
`
`Anaph'ylaxis
`_
`_
`'
`.
`or syrin‘ge's‘and instructed in safe dispoSal pmc'o'dfll‘é!
`:'
`Anaphylain's hnslheeh reported as a rare complication of
`puncture resistant container for disposal ofmaimed“,
`
`Betaseron use. Other nlleriric reactirlna._hnvo included din;-
`and.'syi~inges should be supplied to the patient almlflfiu-
`instructions for safe disposal of full containers.
`'
`pnea, bronchospasm, tongue édomo, skin rush and urticaria
`(see ADVERSE REACTIONS}.
`_'
`’
`Patients should be advised of the importance of rotating I
`Albumin (Human), USP
`.
`areas of injection with each dose;
`’
`'
`'mize the “1‘59“th
`This product contains albumin, n derivntire nfhuman blood.
`
`of severe '
`j2cvtion site reactions,.inclu
`g necrosis ELI“ ,-
`Based on effective don'nr screening and product manufactur-
`'ized infection: (see’iPicking an Iniéctioh Site mucofif
`-
`,
`‘,..'.
`ing processes, it carries on extremely remote rial; for trans-7
`Medication Guide).
`,
`.
`'
`.,
`'
`. '
`'
`
`mission nfiviral diseases. A theoretical risk for transmission
`.
`.
`V
`Laboratory’Tests"
`‘
`. fit! I
`-
`of Qreutzfeldtglnkob dish-ass (cm: _ulmi'
`in considered u'x-
`In addition to those laboratory tests normally requl'fiIoS |
`tremely remote. No case's of transmission ul'virol dismmus
`monitoring patients with multiple sclerosis, complete-Ill.“
`i
`or CJD have ever been idonflfiEdloi' albhmin.
`'
`
`anddififerential white blood cell counts, platelet count? ’51“; '.
`PRECAUTIONS .
`blood chemistries,’ including liver function tests’,_ar% Few}?
`Information for” Patients
`
`mended at regular intervals (one, three, and'six months);U ‘
`All patients should be instructed to carefully read the sup.-
`lowing introduction of Betaseron therapy, and then p9“ .:
`-
`plied Betaseron Medication Guide. Patients should be cau—
`ically thereafter in the absence of clinical symptqm";
`tioned not to change the dose or schedule of administration
`Thyroid function tests are recommended every ail-m0“,
`
`without medical consultation.
`"
`in patients ,with‘alustory of thyroid dysfunction or _615 9i"?
`Patients, should be made aware that serious adverse reac#
`
`ically indicated. Patients with _myelosuppression 159633-313
`tions during the use of Betaseron have been reported; lif-
`quire more intensive monitoring of complete hl‘fi-
`I
`"
`cluding depression and suicidal ideation, injection site ne-
`
`counts, with diflerential and platelet counts.
`i
`:
`crosis, and anaphylaxis (see WARNINGS). Patients should
`Drug Interactions
`.
`'
`_I’ >1
`be advised of the symptoms of depression-or suicidal idea-
`No,formal drUg interaction studies have been Cullillfmd'
`
`tion and be told to report them immediately.to their physL
`with Betaseron. In the placebo controlled studies in Nb:-
`cian. Patients should also be‘advised of the symptoms of al-
`ticosteroids or ACTH were administered for treatn‘u‘flIt Qt“: -
`lergic reactions and anaphylaxis.
`'
`.'
`v
`‘z
`‘
`lapses for periods of