PDR
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`ISBN; 1-56363-497-X
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`APOTEX - EXHIBIT 1033
`
`

`

`CONTENTS
`
`I
`
`Manufacturers' Index (White Pages)
`Section 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 Name Index (Pink Pages)
`Section 2
`Gives the page number of each product by brand and generic name.
`Product Category Index (Blue Pages)
`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
`Gives the definition of each category and the prescribing limitations that apply.
`Key to FDA Use-in-Pregnancy Ratings
`Provides at-a-giance description of each risk/benefit rating.
`U.S. Food and Drug Administration Telephone Directory
`Gives numbers of key reporting programs and information services.
`Poison Control Centers
`A national directory arranged alphabetically by state and city.
`Vaccine Adverse Event Reporting Form
`Includes master copy and instructions for completion.
`Product Identification Guide (Gray pages)
`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)
`Section 5
`The main section of the book. Includes entries for some 3,000 pharmaceuticals. Listings are
`arranged alphabetically by manufacturer.
`Diagnostic Product Information
`Section 6
`Gives usage guidelines for a variety of diagnostic agents. Arranged alphabetically by manufacturer.
`
`FDA MedWatch Form
`Includes master copy and instructions for completion.
`
`1
`
`101
`
`201
`
`217
`,217
`
`218
`219
`225
`
`301
`
`401
`
`3437
`
`3441
`
`

`

`Betaseron dose. Biologic response marker levels peaked be­
`.^/^-Standard symptomatic treatment may be
`un-
`tween 40 and 124 hours and remained elevated above base­
`7*° j.pp jf overdosage occurs. If the patient develops a dra-
`line throughout the seven-day (168-hour) study. The rela-
`3^7 jncrease in blood pressure, 5 to 10 mg of phentola-
`tionship between serum Interferon beta-lb levels or induced
`Pal1 ^pgyjate has been shown to be effective in lowering'
`biologic response marker levels and the clinical effects of In­
`vl pressure for the short time that control would be
`T jt is unknown whether GlucaGen® is dialyzable,
`terferon beta-lb in multiple sclerosis is unknown;
`ch a procedure is unlikely to provide any benefit given
`CLINICAL STUDIES
`r
`r
`i
`h^nrt balf-Hfe and nature of the symptoms of overdose.
`The safety and efficacy of Betaseron have been assessed in
`iI10,
`1
`Lhfs
`three multicenter trials. Study 1 evaluated Betaseron in
`gAGE AND ADMINISTRATION
`DP
`relapsing-remitting MS (RRMS) patients and Studies 2 and
`aGen® should be reconstituted with 1 ml of Sterile Wa- -
`Glue
`I 3 assessed Betaseron in secondary progressive MS (SPMS)
`. ggconstitution (if supplied) or with 1 mL Sterile Wa-
`trf for
`patients.
`,,rforInj«tioI1'USR
`The effectiveness, of Betaseron in relapsing-remitting MS
`jjjg syringe, withdraw all of the Sterile Water for Re-
`p .
`(Study 1) was evaluated in a double blind, multiclinic,
`titution (if supplied) or 1 mL Sterile Water for Injection,
`ran-
`domized, parallel, placebo controlled clinical investigation
`and inject into the GlucaGen® vialrRoll the vial gently
`of two years duration. The study enrolled MS patients, aged
`nFsjrRTPTTnM
`... D0Wder is completely dissolved and no particles re-
`UJ^KIKIIUIN
`lg tp SO, who were ambulatory (EDSS of ^ 5.5), exhibited
`•
`in the fluid. The reconstituted fluid should be clear
`relapsing-remitting clinical course, met Poser's criteria1 for
`tor-like consistency. The reconstituted GlucaGen® Betaseron® (Interferon beta-lb) is a purified, sterile, lyoph-
`clinically definite and/or laboratory supported definite MS
`iljzed protein product produced by recombinant DNA tech-
`a concentration of approximately 1 rng/ml Glucagon.
`|in
`anci had experienced at least two exacerbations over two
`reconstituted GlucaGen® should be used immediately
`niques. Interferon beta-lb is manufactured by bacterial fer-
`jjT
`mentation of a strain of Escherichia coli that bears a
`years preceding the trial without exacerbation in the pre-
`fTr reconstitution. Discard any unused portion.
`r C the irectment of hypoglycemia: For adults and for pe-
`ceding month. Patients who had received prior immunosup-
`genetically engineered plasmid containing the gene for hu-
`pressant therapy were excluded.
`^ric patients weighing 55 lb (25 kg) or more, administer
`111311 interferon betas<rl7. The native gene was obtained from
`/me by subcutaneous, intramuscular, or intravenous injec-
`human fibroblasts and altered in a way that substitutes ser- ^ exacerbation was defined as the appearance of a new
`n 1,6 According to the literature, x/z adult dose (0.5 mg) is
`ine for
`cystine residue found at position 17. Interferon
`clinical sign/symptom or the clinical worsening of a previous
`•rnmraended for pediatric patients weighing less than
`beta-lb has 165 amino acids and an approximate molecular
`sign/symptom (one that had been stable for at least 30 days)
`tf lb (25 kg) or younger than 6-8 years old.2, ,4,5,e Emef- weight of 18,500 daltons. It does not include the carbohy-
`that persisted for a minimum of 24 hours.
`drate side chains found in the natural material.
`' v assistance should be sought if the patient fails to re-
`Patients selected for study were randomized to treatment
`^
`J within 15 minutes after subcutaneous or intramuscu-
`The specific activity of Betaseron is approximately 32 mil- with either placebo (N=I23)) 0.05 mg of Betaseron < N-125),
`[!- injection of glucagon. The glucagon injection may be
`international units (IU)/mg Interferon beta-lb. Each
`or 0.25 mg of Betaseron (N= 124) self-adminiHU-ml suhcuta-
`ated whije waiting for emergency assistance.1 Intrave-
`vial contains 0.3 mg of Interferon beta-lb. 'Hie unit mea-
`i neously every other day. Outcome based on the 372 random
`glucose MUST be administered if the patient fails to
`surement is derived by comparing the antiviral activity of
`; izecj patients was evaluated after two years.
`n
`iffDond to glucagon. When the patient has responded to the
`the product to the World Health Organization (WHO) refer-
`I patients who required more than three 28-day courses of
`LTa'.mcnt, give oral carbohydrate to restore the liver glyco-,
`e^ce standard of recombinant human inteiferon beta. Man-
`corticosteroids were removed from the study. Minor analge-
`pn And prevent recurrence of hypoglycemia,
`nitol, USP and Albumin (Human), USP '15 mg each/vial)
`sics (acetaminophen, codeme), antidepressants, and oral ba-
`Duvdions for Use as a Diagnostic Aid: Reconstitute as in-
`are added as stabilizers.
`clofen were allowed ad libitum, but chronic nonsteroidal
`dkated above. Discard any unused portion. When the diag-
`Lyophilized Betaseron is a sterile, white to off-white "powder,
`anti-inflammatory drug (NSA1D) use was not allowed,
`frftic procedure is over, give oral carbohydrate to restore
`for subcutaneous injection after reconstitution with the dil-
`The primary protocol-defined outcome measures were 1) fre-
`llie liver glycogen and prevent occurrence of secondary by-
`uent supplied (Sodium Chloride, 0.54% Solution).
`quency of exacerbations per patient and 2) proportion of
`poglycemia.
`CLINICAL PHARMACOLOGY
`exacerbation free patients. A number of secondaiy clinical
`of maximal glucose concentration
`General
`magnetic resonance imaging (MRI) measures were also
`nrie
`Intravenous: 5 to 20 minutes
`Interferons (IFNs) are a family of naturally occurring pro-
`i employed. All patients underwent annual T2 MRI imaging
`~ n"
`Inlroinuscular: 30 minutes
`teins, produced by eukaryotic cells in response to viral in-
`,a subset of 52 patients at one site had MRIs performed
`Sabcutimeous: 30 to 45 minutes
`fection and other biologic agents. Three major groups of in-
`every six weeks for assessment of new or expanding lesions.
`Jim# for Gl smooth muscle relaxation1
`terferons have been distinguished: alpha, beta, and gamma.
`'^le study results are shown in Table 1.
`vttrovonous: 0.25 to 2 mg (IU)—45 seconds.
`Interferons alpha and beta comprise the TVpe I interferons
`(^ee table 1 at top of next page]
`Istrwnuscular:
`and interferon gamma is a Type II interferon. Type I inter-
`Of the 372 RRMS patients randomized, 72 i PJ' . i failed to
`Inf (IU)-—8 to 10 minutes
`ferons have considerably overlapping but also distinct bio-
`complete two full years on their assigned treatments.
`IIU>—1 to 7 minutes
`logic activities. The bioactivities of IFNs are mediated by
`0vf-r the two-year period, there were 25 MS-related hospi-
`llon of action—
`their interactions with specific receptors found on the sur-
`talizations in the 0.25 mg Betaserpn-treated group com-
`Dursti
`mjcemic action—60 to 90 minutes
`faces of human cells. Differences in bioactivites induced by
`pared to 48 hospitalizations in the placebo group. In com-
`•Hjprr
`to»th muscle relaifltion—1
`IFNs likely reflect divergences in the signal transduction
`I parison, non-MS hospitalizations were evenly distributed
`I
`g-
`ufl-
`I process induced by IFN-receptor binding.
`among the Er0UPs» with ™ 111 the 0.25 mg Betaseron group
`Ik 0 fi'rm? (IU)—9 to 17 minutes
`Biologic Activities
`.
`and 15 in the plac^o group. The average number of days of
`l^niTy—^2 to 25 minutes
`: The mechanism of action of Interferon beta-lb in patieni's MS-related steroid use was 41 days in the 0.25 mg
`fcframnHfulHr "
`'
`multiple sclerosis is unknown. Interferon beta-lb re- Betaseron group and 55 days ,jn the placebo group
`I
`n J; "to
`iml irV iV+rt 97 rmniitoo
`ceptor binding induces the expression of proteins that are •
`(p=0-004).
`.
`.
`.
`•
`;
`responsible for the pleiotropic bioactivities of Interferon MRI data were also analyzed for patients m tins study. A
`V
`miI1U 'S
`beta-lb. A number of these proteinf. .including neopterin. frequency
`distribution of the observed percent changes in
`sUbillty iind storage
`p2-microglobulin. MxA protein, and IL-10) have been mea- MRI area at the end of tw0 years was obtained by grouping
`Mm Hemtshtutm: The GlucaGen® package may be -red in bjdod fractions froin Betas^ron-ireated patients
`the percentages in successive intervals of equal width. Fig-
`IM up to 24 months at controlled room temperature 20, ^ Betaseron.lreated healthy volunteers. Immunomodula-
`Ure 1 displays a histogram of the proportions of patients,
`C (68° to 770t) pnor to reconstitution. Avoid freezing
`,
`tory ofrfictfi of Interferon betJt-lb include die enhancement
`which fell into each of the*e intervals. The median percent
`M Protect from light. GIucsGen® should not be used after
`of sUppressor T ce\] a&hrifo reduction of pro-inflummatorv
`chan^ in MRI
`ni« ^rnuP w,lfi
`for
`0
`which
`wjury date on the vials.
`^
`,
`: cytokine pi^bduction, down-regulation of iintigen preHenta-
`was significantly hmaller thiin Uiu 16.5% observed f.ir the
`Wr HrronsUtution: Reconstituted GlucaGen® should be ^ ^ yjubitipn of lymphocyte trafficking into the cen-
`P,ucebo F0UP (P=0.0001).
`Ww immediately. Discard any unused portion. If Uie solu-
`traj nervoUs system. It is not known if these effects play an
`on aiiows any sign of gel formation or particles, it shoujp
`important role in the observed clinical activity of Betaseron
`lwdl,,carded-
`iA multiple sclerosis' CMS).
`BOW SUPPLIED
`Pharmacokinetics
`fflucaGon® DingnoMic Kit indudos:
`I ***»*,
`conpentrations of I„terf™n teta-lb are low
`
`t
`
`1 r(1 n;> ^ 'rDNA
`
`. . .
`;• „
`Kl,co"!it,tut!on
`
`r
`
`I „ .
`S i " V "1' " "1, " 1
`:
`m, St"rllc w
`• >390-004-01
`
`'
`
`i n p a l i e n l s w i t h M S . r e c e i v i n g t l i c r e c o m m e n d e d d o s e o f
`Betaseron is not available. Following single nnd roultiple
`daily subcutaneous administrations of 0.5 mg Betaseron to
`healthy volunteers ^=12), serum Interferon bi-ta-lb con-
`centrations were generally below 100 lU/mL. Peak serum
`.ca^n®1
`Interferon beta-lb concentrations occurred between one to |
`V'a- ct,nln'n'11^ 1
`eight hours, with a mean peak serum interferon concentra-
`origin) for injection!
`1
`tion of 40 lU/mL. Bioavailability, based on a total doMj of
`|(DC 55390-004-10
`.
`1 0.5 mg Betaseron given as two'subcutaneous injections at
`Wltlwj March 2001
`! dl^erent sites, was approximately 509c.
`REFERENCES
`, ,-ih 1 After intravenous administration of Betaseron (0.006 mg to
`1 j i r , . . r r
`.
`2.0 mg),-similar pharmacokinetic profiles were obtained
`tW p '\ ' r 'unf[n,n
`!' m il "T
`,r
`'mi i ^ i "i^t A
`. 7
`healthy volunteers (N=12) and from patients with dis-
`r1aarmnCOi from
`' pcial r V
`1. 1A:1516-1J18.
`2. r.I.L
`r'"v,,ntl0}1'Irir".
`| eases 0therJthan MS!(N=142). In patients receiving single
`^ j. ^ ^ucaSon to terminate raBulin nac-
`tij.
`intravenous doses up to 2.0 mg, increases in serum concen-
`>c^j'dreri; Nebr Med J 19f!8;43:5f> -51,
`3. C; S ^ ^
`trations were dose proportional. Mean serum clearance val:
`cun'tal
`Ailli fciucaj,uu in
`ues ranged from 9.4 mIVmin*kg^ lu 25.9
`and
`^ g,. rpn- " Pediair-1955;47:161-17(>
`were independent of dose. Mean terminal elimination half-
`JC' " r n,: Treatm,,rit ,'f insulin hypoglycemia in di-
`iife vaiues ranged from 8.0 minutes to 4.3 hours and mean
`g .16 lc canllHirK. Diabetes lOtT'l: 18:645
`i steady-state volume of distribution^ values ranged froni
`i,^ 1,Vrunn*' 1' Hypoglycemia in childhood diabetes
`0.25 IVkg to 2.88 lAg; Three-times-a-week intravenous dos-
`di'lf
`^ ^'1,'K,u'Anc'Jl,K or Intnuniwtulur inject inn of
`ingfor two weeks resulted in no accumulation of Interferon
`glucagon. Acta Pediatr Scnnd 1988;77:
`j beta-lb in sera of patients. Pharmacokinetic parameters af-
`ter single and multiple intravenous doses of Betaseron were
`. ^ 'f'-'t'n AS, Eyro JA, and Soitesz G, Hypoglycae | comparable.
`.O.Y
`J." ln diabetic children, fn: Frier BM and Fisher BM, eds
`Following every other day subcutaneous administration of
`^ypoglycactliin and Diabetes. Kdward Arnold, 1993;
`0.25 mg Betaseron in healthy volunteers,'biologic response
`li^
`•
`marker levels (neopterin, po-Juicroglobulin; MxA protein,
`^LBbavtorieS"
`j and the immunosuppressive cytokine, 11.-10) increased sig-
`2
`rd> 0H 4414G
`I nificantly above baseline six-twelve h6urs after1 the first
`
`tiV.
`
`includes
`IU) GlucaGen® (glucagon
`
`-
`
`0
`
`r
`:
`
`'
`[•
`
`fe
`
`,
`
`pUCT INFORMATION
`MO
`
`BERLEX/893
`
`Berlex, Inc.
`6 WEST BELT
`WAYNE. NJ 07470
`.Berlex.com www
`
`
`Direct Inquiries to;
`i /ooo, RITRT PY A
`
`.
`
`_.
`
`BETASERON®
`Ihay-ta-seer-on]
`Interferon beta-lb
`
`I
`
`I
`
`H
`
`)
`
`• !
`
`\1
`
`•. 5
`
`.
`
`<
`
`I
`1
`
`Distribution of Change in MRI Area
`Figure 1
`
`^ B«Utttie0»nn
`
`f.1' :1 .. . .'
`
`Mtdtwi
`
`III
`I
`
`I."
`
`1
`
`Fraa
`t#
`
`-4S
`-«
`<-40 . »
`
`-ro
`
`• •
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`fJO
`10P
`iC
`too <1M. «.!W
`
`t»a«
`
`e M m M
`•
`<?0
`•.40
`.,M
`. fn
`Pccent Cftiijc In MP Vr*
`In an evaluation of frequent MRI scans (every hix weeks) on
`52 patients at one site, the percent of scana with new or ex­
`panding lesions was 29% in the placebo group and 69r in the
`0.25 mg treatment group (p=»0.006),
`The exact relationship between MRI findings nnd clinical
`status of patients is unknown Changes in lesion area often
`do not correlate with changes in disability progression. The
`•
`l "'.-MRI findings in thh
`prognostic signifi- -
`not been evaluated.
`
`Continued on next page
`
`Information on Berlex products (appearing here) Is based
`on the most current information available at the time
`of publication closing. Further Information for these
`and other Berlex products can be obtained from
`Medical & Product Services at Berlex, Inc. by catling
`1-888-BERLEX-4,
`
`Cotttult 200b PDR' supplements and futim- editions tor revision*-.
`
`Ji
`
`

`

`894/.BERLEX
`
`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 lab­
`oratory-supported MS in the secondary progressive phoso,
`and who had evidence of disability profcreflfcipn (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 3.0 to 6.5.2 Patients in
`Study"2 were randomized to receive Betaseron 0.25 mg
`(n=360) or placebo (n=358). Patients in Study 3 were ran-
`domized
`to Betaaoi'on 0.25 mg (n=317), Betaseron
`0.16 mg/m2 of body surface area (n=314, mean assigned
`dose 0.30 ihg), or placebo (n=308). Tfest agents wero admin­
`istered sub'cutaiieously, eveiy other day for three years,
`The primaiy 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 s 6.0. In
`Study 2, time to progression in-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 covariate'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-
`grapKic or-disease-related 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 "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'CO.OOl). 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).
`J
`1
`MRI endpoints in both Study 2 and Study 3 showed lesser
`increases in T2 MRI lesion area and decreased number of
`active MRI lesions in patients 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 prognostic signiflcariee of tho- MRI findings
`in these
`studies is' not known.
`Safety and 'efficacy of treatmehf with Betaseron beyond
`three years are not known.
`INDICATIONS AND tlSAGE
`Betaseron (Interferon, beta^lb) is .indicated for the treat­
`ment of relapsing forms of multiple sclerosis to, reduce the
`frequency of clinical exacerbations.
`CONTRAINDICATIONS
`Betaseron, ist,contraindicated in patients with a history of
`hypersensitivity to natural or recombinant interferon beta,
`Albumin (Human); USP, or.any other component of the
`formulation."
`WARNINGS
`Depression and Suicide "
`Betaseron (Interferon beta-lb)_should 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 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 B.etaseron treated groups compared to one sui­
`cide arid four suicide attempts among the 789 patients in
`the placebo groups.
`Injection Site Necrosis
`Injection site necrosis (ISN) has been reported in 5% of pa-
`tients in coritrolled 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 in diameter, 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 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 treat the infection. Time to healing was
`varied depending on the severity of the necrpsis at the time
`treatment was begun. In most cases healing was associated
`with scarring.
`
`TABLE ,1.
`."Two Year RRMS Study Results
`Primary and Secondary Clinical Outcomes
`
`Efficacy Parameters
`
`Treatment Groups
`
`Primary End Points
`
`(N=i23) 1
`
`(N=i25)
`
`(N=124)
`
`Placebo
`
`0.05 mg
`
`0.25 mg
`
`Annual exacerbation rate
`
`1.31
`
`1.14
`
`P
`
`S«i
`ti
`
`T
`b
`
`PHYSICIANS'. DESK REFEREMc&)
`
`Statistical Comparisonj
`p-valuo
`
`Placebo
`V8
`0.05 nig
`
`0.005
`
`0.609
`
`0.05 rag
`V8
`0.25 mg
`
`0.113
`
`0.288
`
`P&fo
`VI
`0.25^
`
`0.0001
`
`0.094
`
`0.151
`
`0.077
`
`0.001
`
`0.299
`
`0.097
`
`0.020
`
`0.257
`
`0.229
`
`0.064
`
`0.010
`
`0.001
`
`0.001
`
`0.90
`
`25%
`
`29
`39
`17
`14
`9
`8
`
`9
`
`0.23
`
`19.5
`
`•
`
`'•
`
`20
`32
`20
`15
`15
`21
`
`5
`
`0.47
`
`44.1
`
`22
`31
`28
`15
`7
`16
`
`6
`
`0.29
`
`33.2
`
`Proportion of exacerbation-
`free patientst
`
`Exacerbation
`frequency
`per patient
`
`0t
`1
`2
`3
`4
`2:5
`
`Secondary Endpointsft
`
`Median number of monthfi
`to first on-study .exacerbation
`
`Rate of moderate
`or severe exacerbations per year
`
`Mean number of moderate
`or severe oxacerbalion
`days per patient
`
`Mean change in EDSS
`scoret at endpoint
`
`Mean change in Scripps
`scorett at endpoint
`
`Median duration in days
`per exacerbation
`
`%• change in mean MRI
`lesion area at endpoint .
`
`0.21
`
`0.21
`
`-0.07
`
`0.995
`
`0.108
`
`0.144
`
`/
`
`•0.53
`
`-0.50
`
`36
`
`33
`
`0.66
`
`35.5
`
`0.641
`
`0.051
`
`NT)
`
`ND
`
`0.12$
`
`ND
`
`21.4%
`
`9.8%
`
`-0.9%
`
`0.015
`
`0.019
`
`0.0001
`
`1
`
`•
`
`f
`
`I
`^
`ND Not done
`t 14 exacerbatibn free patients (0 from placebo, six from 0.05 mg, and eight from 0.25 mg) dropped out of the study befcn _
`completing six months of therapy. These patients are, excluded from this analysis.
`tt Sequelae and Functional Neurologic Status, both required by protocol, were not analyzed individually but are induiJ •
`;• as a function of the EDSS.:,
`"
`'
`-
`J
`t EDSS scores range fromJ.-10, with higher scores reflecting greater disability.
`.-j r..
`. ; .
`tt Scripps neurologic rating scores,range from 0-100, with smaller scores reflecting greater disability
`Some patients have experienced healing of necrotic skin le-
`Female patients should be cautioned about the abortifadeal
`sions while Betaseron therapy continued; others have not.
`potential of Betaseron (see PRECAUTIONS, Pregnane^'
`Whether'to discontinue therapy following a single site of ne- Teratogenic Effects),
`cfpsis is dependent on the extent of necroais. For patients
`Instruction on Self-injection Technique and Procedures
`who continue therapy with Betaseron after injection site ne­
`Patients should be instructed in the use of aseptic techflHT*
`crosis has occurred, Betasofgn should not bo administered
`when administering Betaseron.'Appfopriato instruction fw
`into the affected area until it is fully healed. If multiple
`reconstitution of Betaseron and self-injection should be pro-
`lesions occur, therapy should be discontinued until healing
`yide'd, including careful review of the Betaseron MedicaUa
`occurs.
`Guide. The first
`injection should be'performed under th«
`Patient understanding and ^se of aseptic self-ii\joction tech­
`supervision of an appropriately qualified health curt
`niques arid procedures should be periodically reevaluated,
`professional. -•'£
`particularly if injection site necrosis has occurred.
`Patients should be cautioned against the re-use of ntfedlei
`Anaphylaxis
`or syringes and instructed in safe disposal procedures A
`Ariaphylaxia has been reported as a rare complication of
`puncture resistant container for disposal of used needles
`Betaseron use. Other allergic reactions have included dys­
`arid .iyringes should be supplied to the patient along
`pnea, bronchospasm, tongue edema, skin rash and urticaria
`instructions for safe disposal of full containers.
`(see ADVERSE REACTIONS).
`Patients should be advised of the importance of rotating
`Albumin (Human), USP
`of injection with each dose; to minimize the jikeiihixo
`areas
`This product contains albumin, a derivative of human blood.
`of severe injection site reactions,including necrosis or local­
`Based on effective donor screening and product manufactur­
`ized infection^ (see Picking an Injection Site section oftW
`ing processes, it carries an extremely remote risk for trans­
`Medication Guide),
`j
`mission of viral diseases. A theoretical risk for transmiiifiion
`Laboratory Tests
`of Creutzfeldt-jakob disease (CJD) also is considerod ex­
`In addition to those laboratory tests normally required for
`tremely remote. No cases of transmission of viral diseases
`monitoring patients with multiple sclerosis, complete bio0®
`or CJt) have ever been identified for albumin.
`and differential white blood cell counts, platelet counts and |
`PRECAUTIONS
`blood chemistries; including liver function tests' are recoflj-
`Information for Patients
`mended at regular intervals (one, three, and six months) IO'"
`All patients should be instructed to carefully read the supr
`lowing introduction of Betaseron therapy, and then period­
`plied Betaseron Medication Guide. Patients should be cau­
`ically thereafter in the absence of clinical Hympt0"1*
`tioned not to change the dose or schedule of administration
`Thyroid function tests are recommended every six monl"1
`without medical consultation.
`in patients .with a,history of thyroid dysfunction or as clio-
`Patients should be made aware that serious adverse reac-
`iqally indicated. Patients with niyelosuppression nift)'
`tions during the use of Betaseron have been reported," iri!-
`quire more intensive monitoring of complete blwo^ cc
`eluding depression and suicidal ideation, injection site ne-
`counts, with differential and platelet counts.
`crosis, and anaphylaxis (see WARNINGS). Patients should
`Drug Interactions
`be advised of the symptoms of depression or suicidal idea-
`No. formal drug interaction studies have been eolidy
`tion and be told to repoifthem immediately .to their physi-
`B
`• i
`with Betaseron. In the placebo controlled studies in
`cian. Patients should also be advised of the symptoins of al-
`ticosteroids or ACTH were administered for treatment OT ^ I
`lergic reactions and anaphylaxis.
`I
`lapses for periods of up to 28 days in patients (N=^^rS
`Patients- should be advised to promptly report any break in
`ceiving Betaseron.
`^
`.
`the skin, which may be associated with blue-black discolor-
`<
`I i
`Carcinogenesis, Mutagenesis, and Impairment of
`ation, swelling, or drainage of fluid from
`the injection site,
`I
`Carcinogenesis: Interferon beta-lb has not been
`prior to continuing their Betaseron therapy. •
`its carcinogenic potential in animals.
`Patients should be informed that.flu-like symptoms are
`common following initiation of therapy with Betaseron. In Mutagenesis: Betaseron was not mutagenic when
`the controlled clinical, trials, antipyretics and analgesics
`for genotoxicity in the Ames bacterial test in the presence
`were permitted for 'relief of these symptoms. In addition,
`absence of metabolic activation. Interferon beta-lb vvas ^
`gradual dose titration during initiation of Betaseron treat- mutagenic to human peripheral blood lymphocytes in w
`ment may reduce flu-like symptoms (see DOSAGE AND
`in the presence or absence of metabolic inactit3"
`Betaseron treatment of mouse BALBc-3T3. cells did AC1
`ADMINISTRATION).
`
`1
`
`.
`
`

`

`PRODUCT INFORMATION
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