PDR
`59|
`
`EDITION
`
`2005
`PAYOICIANS
`EOK
`REFERENCE
`
`
`Executive Vice President, PDR: David Duplay
`
`Vice President, Sales and Marketing: Dikran N. Barsamian
`Manager, Editorial Services: Bette LaGow
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`National Account Manager: Marion Reid, RPh
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`THOMSON Copyright © 2005 and published by Thomson PDR at Montvale, NJ 07645-1742. All rights reserved. Noneof the contentof this publication
`ste
`an May be reproduced, stored in a retrieval system, resold, redistributed,or transmitted in any form or by any means(electronic, mechanical,
`photocopying, recording, or otherwise) without the prior written permission of the publisher. Physicians' Desk Reference®, PDR®, Pocket
`PDR
`PDR®, PDR Family Guide to Prescription Drugs®, PDR Family Guide to Women’s Health and Prescription Drugs®, and PDR Family Guide to
`Nutrition and Health® are registered trademarks used herein underlicense. PDR® for Oj
`phthalmic Medicines, PDR® for Nonprescription Drugs and Dietary Supplements, PDR®
`Companion Guide, PDR® Pharmacopoeia, PDR® for Herbal Medicines, PDR? for Nutritional Supplements, PDR® Medical Dictionary, PDR® Nurse's Drug Handbook, PDR®
`Nurse's Dictionary, PDR® Family Guide Encyclopedia of Medical Care, PDR® Family Guide to Natural Medicines and Healing Therapies, PDR® Family Guide to Common
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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: 1-56363-497-X
`
`SUN - IPR2017-01929, Ex. 1033, p. 1 of 29
`SUN - IPR2017-01929, Ex. 1033, p. 1 of 29
`
`

`

`CONTENTS
`
`|
`
`Manufacturers’ Index (white Pages)
`
`!
`
`1 S
`
`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 numberof those described in PDR.
`
`
`
`
`Brand and Generic Name Index (Pink Pages)
`Section 2
`:
`.
`Gives the page numberof each product by brand and generic name.
`
`
`Product Category Index (Blue Pages)
`201
`
`Section 3
`
`101
`
`Lists all fully described products by prescribing category. An overview of the headings
`appears on pages 201 and 202.
`
`Key to Contolled Substances Categories................cccccccccscccccessssessssseeeecesesecacescesirssustaussecanaeeecceceececessecs 217
`Gives the definition of each category and the prescribing limitations that apply.
`Key to FDA Use-in-Pregnancy RatingS .........0........ccccccsccccceesccssunsescecesessessarscesentacusuessutasusnsssesecesccceseccessee. 217
`Provides at-a-glance description of each risk/benefit rating.
`U.S. Food and Drug Administration Telephone Directory......0.....0....cc:ccccccscesseescccesecessesesseseeeeseecceceececcccces 218
`Gives numbers of key reporting programs and information services.
`Poison Control Centers... cece ceeccsseecseecseesessessenssessssssaseacesserseascasesaussausesesstsessssasetersstesscessessees 219
`A nationaldirectory arranged alphabetically by state and city.
`Vaccine Adverse Event Reporting Form ...............ccccccccccsecssessecsccessessaessasesacaecssusecesacesaseseeessessesececececseess 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 picturesof 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.
`eeeceArteBell.)HoneaOhire
`PDA MedWatch Form: vetenl, lscrcnve.hcd.ccclteeesesscsseeclasn tt eke eR te Blneers.--.ccrseee 3441
`Includes master copy and instructions for completion.
`
`SUN - IPR2017-01929, Ex. 1033, p. 2 of 29
`me SUN - IPR2017-01929, Ex. 1033, p. 2 of 29
`SUN - IPR2017-01929, Ex. 1033, p. 2 of 29
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`

`

`Cohsult 2005 PDR® supplements andfuture editions for revisions
`sured in blood fractions from Betaseron-treated patients — Betaseron dose. Biologic response markerlevels peaked be-
` nificantly above baseline six-twelve hours after the first
`
`“ppuct INFORMATION |
`°°
`
`
`meln
`;—Standard symptomatic treatment may be un-
`if overdosageoccurs.If the patient develops a dra-
`jncr’
`ease in blood pressure, 5 to 10 mg of phentola-
`
`mesylate has been shown’to be effective in lowering”
`
`
`ressure for the short time that contro) would be
`4
`It is unknown whether GlucaGen® is dialyzable,
`
`a a
`procedureisunlikely to provide any benefit given
`f-life and nature of the symptoms of overdose.
`
`Ie
`cg AND ADMINISTRATION
`
`bP -
`aGen® should be reconstituted with 1 ml of Sterile:Wa--
`
`Ng a Reconstitution (if supplied) or with 1 mL Sterile Wa-
`
`Bee Peppers USE =n
`Me,
`the syringe, withdrawall of the Sterile Water for Re-
`
`‘on
`if supplied) or 1 mL Sterile Waterfor Injection,
`
`”
`nd inject into the GlucaGen® vial-Roll thevial gently -}
`
`:
`powder js completely dissolved and no particles re- «
`]
`i
`« DESCRIPTION
`
`main in the fluid. The reconstituted fluid should be clear
`Betaseron® (Interferon beta-lb) is a purified, sterile, lyoph-
`
`“a erwater-like consistency. The reconstituted GlucaGen® 4
`ilized protein product produced by recombinant DNAtech-
`
`:
`eS 8 concentration of approximately 1 mg/ml Glucagon.
`niques. Interferon beta-1b is manufactured by bacterial fer-
`
`r pe reconstituted GlucaGéen® should be used immediately
`‘mentation of a strain of Escherichia coli that bears a
`her reconstitution. Discard any unused portion...
`>
`- genetically engineered plasmid containing the gene for hu-
`for the treatment of hypoglycemia: For adults andforpe-
`man interferon beta,,,17. The native gene wasobtained from
`-diatric patients weighing 55 Ib (25 kg) ormore, administer
`- human fibroblasts and altered ina way that substitutes ser-
`4
`mg by subcutaneous, intramuscular,or intravenous injec-
`ine for the cystine residue found at position 17. Interferon
` on.
`“ionJ® According to the literature, % adult dose (0.5 mg) is
`beta-1b has 165 amino acids and an approximate molecular
`ecommended for pediatric patients weighing
`less than
`weight of 18,500 daltons: It does not include the carbohy-
`“sg Ib (25 kg) or younger than6-8 years old,?*4°° Emer-
`| ‘drate side’chains found in the natural material.
` pency assistance should be soughtif the patient fails to re-
`The specific activity of Betaseron is approximately32 mil-
`Sond within 15 minutes after subcutaneous or intramuscu-
`lioninternational units (IU)/mg Interferon beta-Ib; Each
`iA injection of glucagon. The glucagon injection may be
`| vial contains 0.3 mg of Interferon beta-Ib. The unit mea-
`“apeated while waiting for emergency assistance.) Intrave-
`surement is derived by comparing the antiviral activity of
`"gous glucose MUST be administered if the patient fails to
`the product to the World Health Organization (WHO)refer-
`respond to glucagon. When the patienthasrespondedto the
`“ence standard ofrecombinant human interferon beta. Man-
`
`“ieatment, give oral carbohydrate to restore the liver glyco-.
`nitol, USP and Albumin (Human), USP (15 ing each/vial).
`are addedasstabilizers.
`and prevent recurrence of hypoglycemia.
`
`Pivctions for Useas a Diagnostic Aid: Reconstituteas in-
`Lyophilized Betaseronis a sterile, white to off-white powder,
`dicated above. Discard any unusedportion. Whenthediag... .
`- for subcutaneousinjection after reconstitution with the dil-
`‘enstic procedure is over, give oral carbohydrateto restore”
`
`uent supplied (Sodium Chloride, 0.54%Solution).
`liver glycogen and prevent occurrence of secondary hy-_
`. CLINICAL PHARMACOLOGY
`yeemia.
`|
`av
`|
`General
`!
`of maximal glucose concentration
`.-Interferons-(IFNs) are a family-of naturally occurring pro-
`avenous: 5 to 20 minutes_
`
`
`muscular: 80 minutes
`==
`|, ‘teins, produced by eukaryoti¢cells in response’to viral in-
`
`1
`utaneous: 30 to 45 minutes
`fection and otherbiologic agents.Three major-groups of in-
`for G! smooth muscle relaxation’ — ne
`-|. terferons have been distinguished:alpha,beta, and gamma,
`wyenous: 0.25 to 2 mg (IU)}--45 seconds.
`:
`Interferons alpha andbeta comprise the Type I interferons
`
`“andinterferon gamma is aType II interferon: TypeI inter-
`umuscular:
`7
`(qed
`rit igi bas
`
`U}—8 to 10 minutes
`i
`ferons have ‘considerably overlapping but’ also ‘distinct bio-
`
`IU}-4to 7minutes
`‘Jogie activities. The bioactivities of IFNs’are mediated by
`
`tion of action—
`their interactions with specifié receptors found on the sur-
`‘|'-faces of humancells, Differencesin bioactivites induced by
`glycemic action-—60 to 90 minutes
`
` IFNs likely.refiect:divergences inthe signal transduction
`fh muscle relaxation—'
`
`
`process induced by IFN-receptor binding,
`oe
`nous:
`hs
`
`BiologicActivities
`$10 0.6 mg. (IL1)—§ to 17. minutes,
`action of Interferon beta-1b in patients
`| The mechanism of
`
`TU)—22 to 26 minutes
`
`with multiple sclerosis is unknown, Interferon beta-1b re-
`
`ubeular:
`oe
`at
`ceptor binding induces the expréssion of proteins that are
`EUU}—12to.27 minutes
`
`responsible for the pleiotropic bioactivities of Interferon
`ae
`IU}—21 to,.42 minutes
`
`beta-1b, A number of these proteins (including neopterin,
`ot
`i
`andstorage
`By-microglobulil, MxA protein, and TL-10) have been mea-
`
`‘The GlucaGen®. package may be
`‘Reconstitution:
`
`up to 24 monthsat controlled room temperature 20?
`and Betaseron-treated healthy volunteers. Immunomodula-
`
`(68° to 77°F) prior to reconstitution, Avoid freezing |
`tory effects of Interferon beta-1b include the enhancement,
`
`protect from light. GlucaGen® should not be used after
`ofsuppressor T cell activity, reduction of pro-inflammatory
`‘expiry date on the vials.
`cytokine production, down-regulation of antigen presenta:
`
`
`
`Bi
`oe
`i
`F
`i
`Reconstitution: Reconstituted GlucaGen® should be
`ibition
`of lymphocytetrafficking into the cen-
`
`
`known if these effects play an
`
`immodiately, Discard any, unused portion. If the solu-
`
`d clinical activity of Betaserar
`
`ay ay, sinof gel formation or particles, it should
`iin
`arded.
`y
`arbre
`
`Pharmacokinetics -
`||
`WSUPPLIED
`i
`'
`
`Because serum concentrations of Intérferon beta-1b are low
`{
`
`;
`heGlucaGen® Diagnnstic Kit includes!
`ctable
`ornot
`following subcutaneous administration of
`
`
`al containing 1 mg(1 TU) GlucaGen® [glucdgon ((DNA
`0.25''mg Ofless of Betaseron, pharmacokinetic information
`
`Hor injettion)
`|”
`yey
`in' patients with MS receiving therecommended dose of
`ial
`containing 1 ml Sterile Water for Reconstitution
`Betaseron is not available. Following single and multiple
`
`55390-004-01
`‘
`:
`daily subcutaneous administrations of 0.5 mg Betaseron to
`healthy volunteers (N=12), serum Interferon beta-1h con-
`:
`SlueaGent 10-plick Includes:
`centrations weregenerally below 100 [U/ml Peak serum
`
`Interferon beta-1b concentrations occurred betweenona: to
`aR containing 1 mg (TU) GlucaGen® [glucagon |
`eight hours, with a mean peak serum interferon concentra-
`A Origin) for injection!
`has
`tion of 40.IU/mL.Bioavailability, based on a total dose of
`
`b 2HS80-004-10
`Hon March 2001
`0.5 mg Betaseron given as'two‘subcutansous injections at
`
`different sites, wasapproximately 50%.
`RENCES
`After intravenous administrationof Betaseron (0.006 mg to
`i ta Informition for the Health’ Care: Professtinal17”
`
`2.0 mg),similar pharmacokinetic profiles were obtained
`Rockville; Maryland: The United States Pharmato- |
`from healthy volunteers (N=12) and from patients with dis-
`|
`
`2 Convention, Ines 1997; Vol!’ 1) TAVIB1G-1518,
`po
`eases otherithan MS (N=142). In patientsreceiving single
`
`intravenous doses up to 2.0'mg, increases in serum concen-
`Bias al: Use of Glucagon ‘to terminate insulin Felic:
`
`trations sere dose proportional. Mean serumclearance val-
`Cire nD dhahetic children. Nebr Med J 1988;43:56-87."
`
`BoD Mos- Koch -R, Ciitical’ stadiés with glacigou in
`ues rangedfrom 9.4 mi/min#kgi‘io 26.9 wLiainekg"and
`
`hildren,
`V Pediatr 1955;47:161-170),
`i
`were independent of dose. Mean’terminal elimination half-
`
`life values ranged from 8.0 minutesto 4.3 hours and mean
`Dp JCot all Treatment of insulin hypoglycemia in di-
`
`oaiseees Mabetes L045 13:645-648)
`t
`steady-state volume of distribution!values ranged from
`if
`
`> Wrahine L: Hypoplycemin in childhood diabetes |
`0.25 L/kg to 2:88 L/kg! Three-times-a-weekintravenous dos!
`Continued on next page
`PL
`pA petTect of subdiitandouy on intrarhudeullt injection of
`AaLtentaleeEee
`ing-for two weeksresulted in no accumulation of Interferon
`
`pbeta-Ib in sera of patients:'Pharmacokinetic parametersaf-
`iF a dokba:of plucapan. Acta Pedidtr Stand 1988;77:
`ter single and multiple intravenous doses of Betaseron were
`sle
`comparable.”
`4
`1Onti
`; eo AS, iyra JA, and Soltesz G, Hypoglycae-
`
`Following every other day subcutaneous administration of
`Yo
`labitie childrey, in: Frier BM and Fisher BM, eds
`0.25 mg Betaseron in healthy volunteers,biologic response
`
`BgOia and) Diabetes; Edward Arnold, 1993;
`| marker levels (neopterin, §,-micréglobulin, MxA protein,
`
`| and the immunosuppressive cytokine, IL-10) increased sig-
`it Leboratoriest™
`
`bh
`td, OH 44 1
`
`
`: ee.
`
`ie
`See
`tie
`4
`Median Change «46.5%
`peltDO
`j 7
`;
`Hs
`|
`ea
`a a
`
`5) oeom|Cree S88, a Sd 0 hy ap ee
`
`
`Te
`eth eG ORD aa “eh et) aT)
`Percent Changein MMAre
`
`In an evaluation of frequent MRI scans(every six weeks) on
`52 patients at one site, the percent of scans with-new orex-
`panding lesions was 29% in the placebo group and 6%in the
`0.25 mg treatment group (p=1),006),
`‘
`:
`The exact relationship: between MRI findings and) élinical
`status of patients is unknown, Changesin lesion area often
`do not correlate with changes in disability progression. The
`prognostic significance of the MRIfindings in this study has
`not been evaluated:
`
`Information on Berlex products (appearing here) is based
`on the most currant information available at the time
`of publication closing. Further information for these
`and other Berléx products can be obtained from
`Medical & Product Services dt Berlex, Inc. by calling
`
`1-888-BERLEX-4, ;ee
`
`“Berlex, Inc.
`6 WESTBELT
`"WAYNE, NJ 07470.
`www.Berlex.com
`
`_.
`
`.
`
`yas
`
`ara
`
`tes
`7
`eakat
`
`tie
`Sci
`
`,
`
`-
`
`Direct Inquiriesto:
`1-(888) BERLEX-4
`
`BETASERON®
`[bay-fa-seer-on]
`Interferon beta-1b _
`
`6
`
`(eet
`
`>
`
`é
`
`|
`j
`
`
`
`‘
`
`UN - IPR2017-01929, Ex. 1033, p. 3 of 29
`SUN - IPR2017-01929, Ex. 1033, p. 3 of 29
`
`|
`
`BERLEX/893
`
`1
`
`mst
`
`£ E
`
`
`t _a
`
`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 markerlevels andtheclinicaleffects of In-
`terferon beta-1b in multiple sclerosis is unknown:
`A
`CLINICAL STUDIES
`og
`Thesafety and efficacy of Betaseron have been assessed in
`three multicenter trials. Study 1 evaluated Betaseron in
`relapsing-remitting MS (RRMS)patients and Studies 2 and
`3 assessed Betaseron in secondary progressive MS (SPMS)
`patients,
`9.08)
`uid
`weve’ t
`‘The effectiveness. of Betaseron in. relapsing-remitting MS
`(Study1) was evaluated in a double blind, multiclinic, ran-
`domized, parallel, placebo controlled clinical investigation
`of two years duration. The study enrolled MSpatients, aged
`18 to50, who were ambulatory (EDSSof = 5.5), exhibited a
`relapsing-remitting.clinical course, met Poser’s criteria! for
`clinically, definite and/or. laboratory..supported definite MS
`and hadexperienced at least two exacerbationsover two
`years precedingthetrial without exacerbation inthe pre-
`ceding month. Patients who hadreceived prior immunosup-
`pressant therapy were excluded,
`An. exacerbation was defined as the appearance of a new
`clinicalsign/symptom or the clinical worsening of a previous
`sign/symptom (one that had beenstable for al least 30 days)
`that persisted for a minimum of 24 hours.
`Patients selected for. study were randomized to treatment
`with either placebo (N=123), 0,05 mgof Betaseron (N=125),
`or, 0.25 mgof Betaseron (N=124) self-administered aubcuta-
`neously every other day. Outcome baseon the 272 random,
`ized patients wasevaluated after two years.
`Patients who required more than) three 28-day courses of
`corticosteroids were removed from the study. Minor analge-
`sics (acetaminophen,codeme), antidepressants, and oral ba-
`clofenwere allowedad libitum, but chronic nonsteroidal
`antiinflammatory drug (NSAID)use was not allowed.
`The primary protocol-defined outcome measures were1) fre-
`quency of exacerbationsper patient and. 2) proportion of
`exacerbation free patients. A number of secondary clinical
`and magneticresonance imaging (MRI) measures were also
`employed. All-patients underwentannual T2 MRI imaging
`and a subsetof 52 patients at onesite had MRIs performed
`everysixweeks for assessment of new or expanding lesions.
`The study results are shown in Table 1,
`|
`[See table 1 at. top ofnext page}
`| -Of.the.872 RRMSpatients randomized, 72 (19%) falled to
`complete two fuil years on their assigned treatments.
`Over, the two-year period, there were. 25 MS-related hospi-
`talizations in the 0.25.mg Betaseron-treated group com-
`paredto 48 hospitalizations in the placebo group. In com-
`parison, non-MS hospitalizations were, evenly distributed
`among the groups, with 16 in the 0.25 mg Betaseron group
`and 15:in theplacebo group. The ayerage number, of daysof
`MS-related steroid usé was 41, days in the 0.25 mg
`Betaseron group and 65 days in the placebo, group
`(p=0.004).
`ua
`MRI data weré alsoanalyzed for patients in this study. A
`frequencydistribution of the ‘observed percent changes in
`MRIareaat the endof two years was obtained by grouping
`the percentages in successive intervals of equal width, Fig-
`ute 1 displays a histogram of the proportions of patients,
`which fell inte eachof these intervals. The median percent
`chatigé in MHI arew for the 0.25 mg group was-1.1%, which
`Was significantly ‘smaller than’ the'16.5% observed for the
`placebo group (p=0,0001).
`Distribution ofChange in. MHIArea
`Figure 1
`
`Betenerne 0.25 ing
`he
`,
`Median Change = =1.1%
`|
`ah
`pa
`n
`er
`a
`Placebo
`heb res
`
`

`

`
`
`Primary and Secondary Clinical Outcomes
`
`
`
`
`
`
`
`
`
`
`
`
`--
`
`Betaseron—Cont.
`Studies 2 and # were multicenter, randomized, double-
`blind,placebocontrolled trials conducted to assess theeffect
`of Betaseronin patients with SPMS. Study 2 was conducted
`in Europe and Study 3 was conductedin North America.
`Bothstudies enrolled patients with clinically definite or lab-
`oratery-supported MS in the secondary progressive phase,
`and who hadevidenceofdisability progreasion (both Study
`2 and8) or two relapses (Study 2 only) within the previous
`two years. Baseline Kurtzke expanded disability status
`scale (EDSS) scores ranged from 3.0 to 6.5.2 Patients in
`Study'2 were randomized ta receive Betaseron 0.25 mg
`(n=360) or placebo (n=358). Patients in Study 3 were ran-
`domized’ to Betaserdn 0.25’ mg (n=317),
`‘Betaseron
`0.16 mg/m” of body surface area (n=314, mean assigned
`dosé 0.30 mg), or placebo (n=308). Test agents were admin-
`istered subcutaneously, every other day for three years. ”
`The primary outcome measure wasprogression of disability,
`defined as a“1.0 point increase in the EDSSscore, or a'0.5
`point increase for patients with baseline EDSS = 6.0. In
`Study 2, time'te progression in-EDSS was longer in the
`Betaseron treatment group (p=0.005), with estimated annu-
`alized ratesof 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 annualized rates of progression ‘of
`12%, 14%, and 12% in’ the ‘Betaseron fixed dose, surface
`area-adjusted dose, and placebo groups,respectively.
`Multiple analyses, including covariate“and subset analyses
`based onsex, age, disease duration, clinical diseaseactivity
`prior to study enrollment, MRI measures at baseline and
`early chaigés in MRIfollowing treatment were evaluated in
`order to'interpret ‘the discordant study results. No demo-
`graphic or-diséase-related factors enabled identification of a
`patiehtsubset 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 ‘relapses ‘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, andpla-
`cebo groups, respectively (p<0.02).
`i
`c
`MRIendpoints in both Study 2 and Study 3 showed lesser
`incréases in T2 MRIlesion area'and decreased number of
`active MRIlesions inpatients in the Betaseron groups. The
`exact’ relatioriship betwéen MRI-findings and the clinical
`status of patients is unknown. Changes in MRIfindings of
`ten do not correlate with changes in disability progression.
`The ‘prognostic ‘significarice of the-MRI findings in these
`studiesig not known:
`*
`”
`:
`’
`Safety and efficacy of treatment with Betaseron beyond
`threé years are not known.
`P
`INDICATIONS ANDUSAGE
`Betaseron (Interferon. beta-1b) -is:indicated for the treat-
`ment of relapsing forms of multiple sclerosis to, reduce-the
`frequencyofclinical exacerbations.
`1
`CONTRAINDICATIONS°
`Betaseron,is, contraindicated in patients with a history of
`hypersensitivity ta natural or recombinant interferon beta,
`Albumin (Human), USP, ,or,any other component, of the
`formulation.”
`"s
`=
`WARNINGS
`Depression and Suicide”
`Betaseron (interferon beta-1b)should be used with caution
`in patients with depression, a condition that is common in
`people with multiple sclerosis. Depressionand suicide have
`been reported to occur with increased frequencyin 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 patient,devel-
`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.
`-
`,
`F
`.
`Injection Site Necrosis
`Injection site necrosis (ISN) has been reported in'5% of pa-
`tients in controlled clinical trials (see ADVERSE REAC-
`TIONS). Typically, injection site necrosis occurs within the
`first four months of therdpy,‘although post-marketing re-
`ports have been received of ISN occurring over one year af-
`ter initiation of therapy. Nécrosis may occur at a single or
`multiple injection, sites. The necrotic lesions are ‘typically
`three cni or less in diameter, butlarger areas have beenre-
`ported. Generally the necrosis has exterided 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 debridement and, infre-
`quently, skin grafting have been required.
`+)
`As with any open lesion,it is important to avoid infection
`and, if it occurs, to treatthe infection. Time to healing was
`yaried depending on the severity of the necrosis at the time
`treatment wasbegun. In most cases healing was associated
`with scarring.
`
`ie
`
`|
`
`SUN - 1PR2017-01929, Ex. 1033, p. 4 of 29
`SUN - IPR2017-01929, Ex. 1033, p. 4 of 29
`
`lesion area at-endpoint: »:
`7
`ND. Notdone, #3 se >
`+ 14 exacerbation freepatients (0 from placebo, six from 0.05 mg,and eight from 0.25 mg)dropped outofthe studyt ify }
`completing six months-of therapy. These patients are, excluded from this analysis.
`i
`e
`Tt Sequelae and Functional Neurologic Status, both required by protocol, were not analyzed individuallybut-areinl ised
`, as a function of the EDSS....
`,-
`sk EDSSscores range from,1-10, with higher scores reflecting greater disability.
`.ty.en.07
`Lott
`“tt Scripps neurologic rating scores,range from 0-100, with smaller scoresreflecting greater disability:
`
`Female patients should be cautioned about the abort
`Some patients have experienced healing of necrotic skin le-
`potential of Betaseron (see PRECAUTIONS,Prag
`sions while Betaseron therapy continued; others have not.
`wits
`Teratogenic Effects).
`re
`'
`Whetherto discontinue therapy followinga single site ofhe-
`Instruction on Self-injection Technique and Procedures —
`cfdsig 18 depéndent on the extent of necrosis, For patients
`
`Patients should be instructed inthe tide of aseptic techniue
`whocontinue therapy with Betnseran afterinjection’site ne-
`when administering Betaseron."Appropriata instruction ft
`erosishas occurred, Betaseron should not be administered
`
`intothé affected area until it is fully healed. If multiple
`reconstitution of Betaseron andself-injection shouldbe pre
`vided, including careful teview of the Betaseron Medicatit
`lesions occur, therapy should be discontinued until healing
`
`occurs,
`\
`Guide, The first ‘injection should be'performed unde!
`Patient understanding and use of aseptic self-injection tech-
`supervision of an appropriately qualified health
`
`professional. «
`A
`:
`niques and procedures should be periodically reevaluated,
`particularlyif injection site necrosis has occurred.
`;
`;
`Patients should be cautioned against the re-use of
`
`Anaphylaxis
`,
`;
`;
`,
`or syringes and instructed in safe disposal procedures
`#
`puncture resistant container for disposal of-yaed needles
`Anaphylaxis has been reported as a rare complicationof
`Betaseron use. Otherallergi¢ reactions have included dys-
`it
`arid‘syringes should be supplied to the patient hlong y
`instructions for safe disposal of full containers.”
`pnea, bronchospasm, tongue edema, skin rash and urticaria
`(see ADVERSE REACTIONS).
`.
`,
`Patients should be advised of the importance of rotating |
`Albumin (Human), USP
`:
`areasofinjection with each dose,to minimize the Iikelinood
`
`This product containg albumin, a derivative ofhuman blood.
`of severe injection sitereactions,.including necrosis arloca|
`Based on effective donor screening and product manufactur-
`ized infection, (seePicking an Injection Site section. of the
`|
`ing processes,it carries an extremely remote risk for trans-
`Medication Guide). ; 4 en
`a" a
`Laboratory Tests oe
`;
`ae
`mission ofviral diseases, A theoretical risk for transmission:
`of Creutafeldt-Jaleob disease (CJD) alsois considered @x-
`In addition to those laboratory tests normally requll ¥s |
`tremely remote. No cases of transmission of viral diseases
`monitoring patients with multiple sclerosis, completebl
`hy
`oy CAD have ever been identified for albumin.
`:
`anddifferential white bloodcell counts,platelet counts ana
`PRECAUTIONS.
`blood chemistries;includingliver function tests,are rea
`
`Information for Patients
`mendedat regular intervals (one,three, andbix months)!
`
`All patients should be instructed to carefully read the sup-
`lowingintroduction of Betaseron therapy,and then peries
`ically thereafter in the absence of clinical aymptome
`plied Betaseron Medication: Guide. Patients should be cau-
`tioned not to change the dose or schedule of administration
`Thyroid function tests are recommended every six,onl
`
`without medical consultation:
`fi
`in patients with-ahistory of thyroid dysfunction oF 2° clit:
`
`Patients should beimade aware that serious adverse reac:
`ically indicated. Patients with myelosuppression meycall
`tions during the use of Betaseron have been reported; int
`quire more intensive, monitoring of complete. bloo®\®™
`cluding depression:and suicidal ideation, injection site ne-
`counts, with differential and platelet counts.
`ee
`
`crosis, and anaphylaxis (see WARNINGS). Patients should
`Drug Interactions
`i
`t
`Wha:
`No, formal drug interaction studies have been conduct
`be advised of the symptoms of depression-of suicidal idea-
`
`tion and betold io report them immediately.to their physi-
`with Betaseron.In the placebo controlled studiesin M5,
`cian, Patients should also be:advised of the symptomsof al-
`ticosteroids or AGTH were administered for treatment ae |
`lergic reactions ‘and anaphylaxis.
`~
`J
`5
`it
`lapses for periods of up to 28 days in patients (N=b64) fe
`Patients: should be advised to promptly report any break in
`ceiving Betaseron.,
`ettucerstl wT
`as
`ae
`
`the skin, which may be associated with blue-black discolor-
`Carcinogenesis, Mutagenesis, and Impairment ofFertil!
`ation, swelling, or drainage of fluid from the injection site,
`Carcinogenesis:
`Interferon beta-1b has not been:
`He
`prior to continuing their Betaseron. therapy.
`«
`its carcinogenic potential in animals.
`~~
`Patients should be informed that. flu-like symptoms are
`Mutagenesis: Betaseron was not mutagenic when # aye
`common following initiation of therapy with Betaseron. In
`for genotoxicity in the Ames bacterialtest in the presen i
`the. controlled. clinical. trials, antipyretics and analgesics
`absence of metabolic activation. Interferon beta-1b W3°"
`were permitted forrelief of these symptoms. In addition,
`mutagenic to human peripheral blood lymphocytes inva
`gradual dose titration during initiation of Betaseron treat-
`in the presence or absence of metabolic amactil et
`ment may reduceflu-like symptoms (see DOSAGE AND
`ADMINISTRATION).
`~~
`Betaseron treatment of mouse BALBc-3T3. cells aidnot
`
`
`
`41 9eehangeinmeanMBI* © 21.4% 15|)9.8% 0.9% °|0.016¢\% ! 0,019
`
`894/BERLEX
`
`
`=
`TABLE 1,
`E
`"Twa Year RRMS Study Results
`
`t
`
`al
`‘<
`
`A
`:
`=
`Statistical Comparisong” 7]
`Efficacy Parameters
`Treatment Groupe
`p-value
`
`0.05 mg ‘}.
`Placebo } 0.05. mg.
`Placebo
`0.25 mg
`sate ale
`|
`va
`ve
`(N=123)
`(N=125) | (N=124)
`0.08 mg
`0.28 me
`
`Primary End Points
`
`
`
`
`
`Annual exacerbation rate 1.3leU0| | 114 iige.0,90 0.005 0.113
`
`
`Proportionofexacerbation-
`| 16%)|18%
`25%
`0.609 7
`0.288
`|
`
`free patientst
`Exacerbation
`frequency
`per pationt
`{
`
`a
`
`3
`
`nate
`
`|
`
`0.53
`
`al
`
`hve
`
`i
`
`:
`
`0.151
`
`0,077
`
`“0.641
`
`0.081
`
`*
`Aral
`29
`| 22
`20
`ot
`ag
`31
`oo
`1
`17
`28
`20
`2
`14.
`16
`16
`3
`9
`7
`16
`4
`=5
`lian!
`16
`8 era
`1
`ie
`
`Secondary Endpoints}t
`” Median numberof months
`5
`6
`9
`0.299
`0,097
`to first on-study exacerbation
`i
`;
`
`Rate of moderate
`0.47
`10.29
`0.23
`|.
`0.020
`0.257
`|. Soon
`orsevereexacerbationsperyear
`a
`
`Mean number of moderate
`‘O0 ra
`p Att
`33.2
`19.5
`0.229
`0.064
`:
`or severe