Injectable Multiple Sclerosis Medications
`A Patient Survey of Factors Associated with
`Injection-Site Reactions
`
`Thomas M. Stewart, JD, MS, PA-C; Zung Vu Tran, PhD
`
`Although injection-site reactions (ISRs) occur with US Food and Drug Administration–approved
`injectable disease-modifying therapies (DMTs) for multiple sclerosis, there are currently few reports
`of real-world data on ISR management strategies or possible correlations between ISRs and patient
`demographics, disease characteristics, and missed injections. Patient-reported data on the use of
`DMTs, patient demographic and disease characteristics, missed injections, and ISR reduction strate-
`gies were collected via e-mail, a patient registry (www.ms-cam.org), and a Web-based survey. Of the
`1380 respondents, 1201 (87%) indicated that they had used injectable DMTs, of whom 377 (31%)
`had used intramuscular (IM) interferon beta-1a (IFNβ-1a), 172 (14%) had used subcutaneous (SC)
`IFNβ-1a, 183 (15%) had used SC IFNβ-1b, and 469 (39%) had used glatiramer acetate (GA). The
`majority of respondents were older (73% were ≥40 years), female (79%), married or living with a
`partner (72%), white (94%), and nonsmoking (82%). Injection-site reaction incidence, grouped
`according to severity, varied among DMTs, with IM IFNβ-1a causing significantly (P < .001) fewer
`mild, moderate, or severe ISRs than the other therapies. Female sex and younger age were significantly
`(P < .05) associated with more moderate ISRs among users of IM IFNβ-1a, SC IFNβ-1b, and GA.
`Nonwhites reported severe ISRs more often than whites. For all DMTs injection-site massage and
`avoidance of sensitive sites were the most frequently used strategies to minimize ISRs. These data may
`help identify patients with characteristics associated with a higher risk for ISRs, allowing health-care
`professionals to provide anticipatory guidance to patients at risk for decreased adherence or discon-
`tinuation. Int J MS Care. 2012;14:46–53.
`
`Between 1993 and 2002, four injectable disease-
`
`modifying therapies (DMTs) were approved
`by the US Food and Drug Administration
`(FDA) for use in multiple sclerosis (MS) therapy: sub-
`cutaneous interferon beta-1b (SC IFNβ-1b; Betaseron,
`Bayer HealthCare Pharmaceuticals, Wayne, NJ), intra-
`muscular (IM) IFNβ-1a (Avonex, Biogen Idec, Inc,
`Cambridge, MA), SC IFNβ-1a (Rebif, Serono, Inc,
`Rockland, MA), and SC glatiramer acetate (GA; Copax-
`one, Teva Neuroscience, Inc, Kansas City, MO).1-4 A
`fifth injectable DMT (SC IFNβ-1b; Extavia, Novartis
`Pharmaceuticals Corp, East Hanover, NJ) received FDA
`
`From the Rocky Mountain MS Center, Westminster, CO, USA
`(TMS), and the Department of Biostatistics & Informatics, Colorado
`School of Public Health, University of Colorado Anschutz Medi-
`cal Campus, Aurora, CO, USA (ZVT). Correspondence: Thomas
`M. Stewart, JD, MS, PA-C, 8845 Wagner St., Westminster, CO
`80031; e-mail: thomasmstewart@gmail.com.
`
`approval in 2009, after this study was completed.5 Mul-
`tiple clinical trials have shown that treatment with these
`injectable DMTs reduces the frequency of relapses and
`slows disease progression.6-9 Although the MS treatment
`armamentarium is changing with the addition of infused
`and oral therapies that have recently become available or
`will be available soon, injectable DMTs remain critical
`in the treatment of this disease.
`One limitation of injectable DMT use for MS is
`the relatively high rate of treatment discontinuation,
`estimated to range from 24% to 40% over periods of
`2 to 5 years.10-13 Among the patient-provided reasons
`for discontinuing therapy are the side effects of DMTs,
`specifically injection-site reactions (ISRs). In one report,
`the primary reasons for discontinuation among the
`14% of patients who discontinued IFNβ therapy after
`experiencing associated side effects were ISRs (16%),
`flu-like symptoms (23%), depression (21%), and fatigue
`
`International Journal of MS Care
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`

`
`(21%).11 Another study found that among patients
`taking GA, ISRs were the most important side effect
`leading to discontinuation.14 Skin reactions influence
`not only discontinuation rates, but also adherence rates.
`Indeed, approximately 12% of missed injections may
`be related to pain at the injection site or other skin reac-
`tions.14 Not surprisingly, skin reactions are less common
`and appear to be less likely to cause discontinuation in
`users of the IM injectable therapy.1-5,14,15
`Injection-site reactions as a side effect of injectable
`DMTs have important implications for both discon-
`tinuation and adherence. However, few large patient
`surveys have reported effective strategies for managing
`ISRs. Moreover, little is known about the relationships
`between ISRs and patient demographic variables, disease
`characteristics, and the frequency of missed injections.
`
`Methods
`Study Design
`Self-reported patient data on ISR occurrence and
`use of injectable DMTs were collected using e-mail, a
`patient registry (www.ms-cam.org), and a Web-based
`survey instrument. The observational online survey
`collected descriptive information regarding the use of
`injectable DMTs, ISRs, disease characteristics, and how
`respondents with MS addressed the challenges presented
`by DMT-associated ISRs. For the purposes of this study,
`the population of interest was patients with MS who
`were using injectable DMTs. However, given that the
`respondents were from a self-selected registry that may
`not be completely representative of this population of
`interest, any generalizations based on the results should
`take account of this limitation.
`Data Collection
`Data were collected from a registry of patients with
`MS that has been maintained by the Rocky Mountain
`MS Center since June 2000. At the time of the reported
`survey, there were approximately 18,000 individuals
`with self-reported MS in the registry. This registry con-
`tains e-mail addresses and related unique, anonymous
`identifiers in a privately held, protected file. Individual
`patient participants also are given the opportunity to cre-
`ate passwords so that they can log into the server. These
`methods of data collection ensure both patient anonym-
`ity and secure information transfer and have previously
`been described in detail.16
`MS registry participants were recruited through a
`variety of sources, including the Rocky Mountain MS
`
`Factors Associated with Injection-Site Reactions in MS
`
`Center (www.mscenter.org) and National Multiple Scle-
`rosis Society (www.nationalmssociety.org) websites. To
`a lesser extent, patients also learned about this registry
`through in-office clinic visits or by attending programs
`presented by clinicians affiliated with the Rocky Moun-
`tain MS Center. Typically, registrants were referred
`to www.ms-cam.org for MS-specific information per-
`taining to an evidence-based approach to integrative
`medicine. Thus, it is likely that users registered at www.
`ms-cam.org to gain access to such information and to
`participate in survey research. Because the results of
`Rocky Mountain MS Center surveys are made available
`to MS registry participants, the opportunity to learn
`about the experiences of others with MS is an incentive
`for patients to register. All data collected using patient
`self-reports and responses from individual registrants
`remain anonymous.
`This Multiple Sclerosis–Injection Site Reaction (MS-
`ISR) survey was initiated through e-mails sent to the
`subset of registered patients who had expressed interest
`in participating in surveys and also demonstrated an
`ability to complete administered surveys. The method-
`ology and specific content of the MS-ISR survey were
`approved by a local institutional review board. A subset
`of these data was previously presented in a preliminary
`format.17 The MS-ISR survey instrument was designed
`by the authors and carefully reviewed by clinicians sub-
`specializing in MS, although it did not undergo prelimi-
`nary patient testing and evaluation prior to its adminis-
`tration. Patients who received regular medical care and
`who self-identified as having used injectable DMTs were
`asked about a number of other factors that might con-
`tribute to their ISRs, such as injectable medication used
`and time on current medication. Respondents were also
`asked to indicate whether they had tried any of ten pos-
`sible strategies, compiled from multiple sources as well as
`the authors’ own clinical experience, to prevent or relieve
`their ISRs. In addition, respondents were asked about
`their use of autoinjectors. For the purpose of this survey,
`no attempt was made to validate the effectiveness of any
`of these strategies. Disability data were also collected
`using the Patient-Determined Disease Steps model.18,19
`Although ISRs are universally recognized to be an
`issue with the use of injectable DMTs for MS, the
`term currently has no standard definition, nor is there
`any widely accepted method for grading the severity of
`ISRs. In the present survey, respondents were asked to
`rate both the frequency with which they experienced
`
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`

`
`Stewart and Tran
`
`ISRs (rarely, sometimes, or often) and the seriousness
`of these ISRs according to three categories: 1) “mild”—
`usually transient and involving heat, redness, swelling,
`and/or bruising; 2) “moderate”—possibly not transient,
`involving discomfort, and involving itching, pain,
`lumps, dimpling, and/or skin sores; and 3) “severe”—
`including scabs, crusting around wound, infection, and/
`or necrosis. The categories mild, moderate, and severe
`were not mutually exclusive, as respondents could have
`experienced one or more of the three different ISR cat-
`egories. Thus, individual patients may be counted in
`more than one ISR category depending on their indi-
`vidual symptoms.
`Statistical Analyses
`All analyses were performed using SPSS, version 17
`(SPSS, Inc, Chicago, IL). Prior to analyses, data were
`examined for data entry and coding errors. Out-of-range
`and statistical outliers were also checked and, where
`possible, corrected. If data could not be corrected, they
`were treated as missing. Descriptive statistics were gen-
`erated, including medians, means, standard deviations,
`minimums, and maximums; categorical variables were
`expressed as percentages. To assess possible associations
`between two variables, Pearson correlation coefficients
`were calculated for interval data, Spearman rank corre-
`lation coefficients were calculated for ordinal data, and
`point-biserial correlation coefficients were calculated for
`dichotomous variables. An independent-sample t test
`(or its nonparametric counterpart) was used to compare
`means between two groups, and a dependent-sample
`t test (or its nonparametric counterpart) was used to
`compare two means within a group. A one-way analy-
`sis of variance test, with or without repeated measures,
`was used to compare more than two means. Post hoc,
`pairwise multiple comparisons were performed using the
`Bonferroni adjustment. Chi-square analysis was used to
`assess differences in percentages or proportions.20
`
`Results
`Data for the MS-ISR survey were collected in 2007,
`with a total of 1380 eligible patients with MS provid-
`ing responses. However, 179 (13%) respondents did
`not provide information on DMT use, leaving 1201
`responses for analysis. Not all respondents answered all
`questions; thus, the number of patient responses to each
`question is a subset of the total number of 1201 useful
`responses. Patient demographics are reported in Table 1.
`
`Analysis of patient-reported ISRs showed significant
`associations between use of injectable DMTs and reports
`of ISRs, induced discomfort following injection, and
`severe ISRs (Table 2). Intramuscular IFNβ-1a use was
`associated with significantly fewer reported ISRs than
`the other DMTs for all three severity categories, with
`82% of patients receiving IM IFNβ-1a experiencing
`mild side effects (P < .001), 73% experiencing moder-
`ate side effects (P < .001), and 2% experiencing severe
`side effects (P < .001). Also, users of IM IFNβ-1a missed
`fewer injections because of skin reactions than users of
`the other DMTs. In comparison, patients receiving SC
`IFNβ-1a, SC IFNβ-1b, or GA reported a higher inci-
`dence of mild (99%, 94%, and 98%, respectively), mod-
`erate (91%, 78%, and 90%, respectively), and severe
`(7%, 15%, and 9%, respectively) ISRs.
`For IM IFNβ-1a, SC IFNβ-1b, and GA, female sex
`and younger age were significantly associated with mod-
`erate ISRs, including perceptions of discomfort. Female
`users of IM IFNβ-1a and GA reported more transient
`ISRs than did male users (Table 3). Also, nonwhite
`patients receiving IM IFNβ-1a, SC IFNβ-1a, and GA
`reported more severe reactions than whites. Smoking,
`therapy duration, and disability level were not signifi-
`cantly associated with any category (transient, discom-
`fort-causing, or serious) of skin reactions.
`The specific strategies used to manage ISRs were
`similar among users of each of the four injectable
`DMTs, with a group of six management strategies
`constituting the top five strategies for all four injectable
`DMTs (Table 4). The top two management strategies,
`injection-site massage and avoidance of sensitive injec-
`tion sites, were identical across all four injectable DMTs.
`In addition, of the 55% of all respondents who used SC
`autoinjectors, 24% reported that autoinjectors amelio-
`rated their ISRs.
`
`Discussion
`Multiple studies and clinical experience have demon-
`strated that ISRs are a common side effect of injectable
`DMTs.21-23 It is also clear from the present data set and
`multiple other reported studies that less severe ISRs are
`reported with IM IFNβ-1a than with the other inject-
`able DMTs for MS.14,24,25 Our findings on the frequency
`of ISRs (Table 2) generally conform with what has
`previously been reported and underscore the deleteri-
`ous effect that ISRs have on treatment continuation and
`adherence.9,25,26 These data highlight the need for con-
`
`International Journal of MS Care
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`MYLAN PHARMS. INC. EXHIBIT 1092 PAGE 3
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`

`
`Table 1. Demographics for 1201 respondents using one of the four FDA-approved injectable DMTs
`
`Factors Associated with Injection-Site Reactions in MS
`
`Number
`
`Percentage
`
`22
`74
`
`31
`
`31
`14
`15
`39
`
`26
`74
`
`83
`17
`
`34
`66
`
`37
`63
`
`49
`
`6
`
`19
`81
`
`89
`
`2
`
`16
`84
`
`11
`<1
`
`261
`892
`31
`17
`
`377
`172
`183
`469
`
`99
`278
`
`143
`29
`
`63
`120
`
`175
`294
`
`12b
`295
`
`32
`138
`
`13
`160
`
`73
`384
`
`123
`8
`
`93
`
`4
`29
`17
`Range
`3–52
`3–56
`
`107
`387
`339
`191
`Mean (SD)
`15.0 (9.2)
`10.6 (6.5)
`
`Variable
`MS provider
` MS center or MS clinic
` Neurologist’s office
` Primary-care physician
` Other
`Injectable DMT
` IM IFNβ-1a
` SC IFNβ-1a
` SC IFNβ-1b
` GA
`Time on current DMT, y
` IM IFNβ-1a
` <2
` ≥2
` SC IFNβ-1a
` <2
` ≥2
` SC IFNβ-1b
` <2
` ≥2
` GA
` <2
` ≥2
`Did ISRs cause missed injections?
` IM IFNβ-1a
` Yes
` No
` SC IFNβ-1a
` Yes
` No
` SC IFNβ-1b
` Yes
` No
` GA
` Yes
` No
`Provider of injectable DMT
`instruction
` Neurologist
` Physician (not neurologist)
` Nurse
` Office
` Home health care
` Pharmaceutical
` MS specialist
`
`Years since symptom onset
`Years since MS diagnosis
`
`Number
`
`Percentage
`
`27
`73
`
`21
`79
`
`15
`72
`11
`2
`
`94
`6
`
`18
`82
`
`<1
`25
`17
`32
`25
`
`34
`21
`13
`24
`
`1 1 1 5
`
`59
`41
`
`17
`35
`13
`15
`
`7 6 5 2
`
`322
`878
`
`250
`946
`
`178
`862
`133
`23
`
`1122
`75
`
`217
`974
`
`5
`295
`206
`384
`294
`
`404
`256
`156
`289
`11
`10
`17
`58
`
`707
`482
`
`204
`416
`161
`175
`84
`69
`61
`29
`
`Variable
`Age, y
` <40
` ≥40
`Gender
` Male
` Female
`Marital status
` Single
` Married/living with partner
` Divorced
` Widowed
`Race
` White
` Nonwhite
`Smoking status
` Yes
` No
`Education level
` Less than high school
` High school
` Associate degree
` Bachelor degree
` Graduate degree
`Regional residence
` Eastern US
` Midwestern US
` Southern US
` Western US
` Eastern Canada
` Central Canada
` Western Canada
` Other
`Employment status
` Yes
` No
`Disease stepa
` No disability
` Mild disability
` Moderate disability
` Early cane
` Late cane
` Bilateral support
` Wheelchair-bound
` Unclassifiable
`
`Abbreviations: DMT, disease-modifying therapy; FDA, US Food and Drug Administration; GA, glatiramer acetate; IFNβ-1a, interferon beta-1a;
`IFNβ-1b, interferon beta-1b; IM, intramuscular; ISR, injection-site reaction; MS, multiple sclerosis; SC, subcutaneous; SD, standard deviation.
`aNo disability—functionally normal with no limitations on activity or lifestyle; mild disability—mild signs or symptoms; moderate disability—
`main feature is a visibly abnormal gait; early cane—uses a cane or other form of unilateral support for greater distances, but can walk at least
`25 feet without it; late cane—unable to walk 25 feet without a cane or other form of unilateral support; bilateral support—requires bilateral
`support to walk 25 feet; wheelchair-bound—essentially confined to wheelchair.
`bP < .001
`
`International Journal of MS Care
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`

`
`Stewart and Tran
`
`Table 2. Perceived injection-site reaction
`severity with different DMTs
`Perceived injection-site reaction severity
`
`DMT
`
`IM IFNβ-1a
`
`SC IFNβ-1a
`
`SC IFNβ-1b
`
`GA
`
`Mild
`
`82%
`(306/374)a
`
`99%
`(169/171)
`
`94%
`(170/181)
`
`98%
`(456/465)
`
`Moderate
`
`73%
`(266/366)a
`
`91%
`(153/168)
`
`78%
`(135/174)
`
`90%
`(409/455)
`
`Severe
`
`2%
`(9/364)a
`
`7%
`(11/169)
`
`15%
`(25/170)
`
`9%
`(40/449)
`
`tinued study of these side effects and their causes and
`for continued patient education to alleviate symptoms,
`maintain compliance, and positively affect long-term
`MS outcomes.
`Regarding associations among demographic char-
`acteristics and ISRs, the present results elaborate on
`previous findings reported by other investigators by
`identifying new associations and challenging a few previ-
`ously proposed associations. In accordance with other
`studies,15,27,28 the present data suggest that females report
`more moderate ISRs than do males. However, this spe-
`cific finding was not apparent with SC IFNβ-1a, possi-
`bly as the result of a ceiling effect, with a high frequency
`of moderate side effects being reported by almost all
`users of that drug. This study also revealed two demo-
`graphic associations that, to our knowledge, have not
`been previously reported. First, younger patients (<40
`years of age) had more frequent complaints of discom-
`fort with injections. Again, this specific association was
`not apparent with patients receiving SC IFNβ-1a, possi-
`Table 3. Perceived transient, discomfort-causing, or serious injection-site reactions by select
`demographic variables
`
`Abbreviations: DMT, disease-modifying therapy; GA, glatiramer
`acetate; IFNβ-1a, interferon beta-1a; IFNβ-1b, interferon beta-1b;
`IM, intramuscular; SC, subcutaneous.
`Note: Responses were from patients reporting ever having experi-
`enced an ISR while on an injectable DMT. Individual patients may
`be counted in more than one ISR category depending on their indi-
`vidual symptoms.
`aSignificantly different from other DMTs, P < .001.
`
`Variable
`Sex
` Male
` Female
`
`Age, y
` <40
` ≥40
`
`Smoking
` Yes
` No
`
`Disability
` 0 or 1
` ≥2
`
`Therapy
`duration, y
` <2
` ≥2
`
`Race
` White
` Non white
`
`Transient
`
`IM IFNβ-1a
`Discomfort
`
`Serious
`
`Transient
`
`SC IFNβ1a
`Discomfort
`
`Serious
`
`61% (49/80)
`87% (255/292)a
`
`62% (49/79)
`76% (216/285)b
`
`3% (2/79)
`2% (7/283)
`
`100% (34/34)
`99% (134/136)
`
`91% (29/32)
`91% (123/135)
`
`13% (4/32)
`5% (7/131)
`
`88% (84/95)
`22% (68/305)
`
`98% (84/86)
`67% (181/269)a
`
`3% (3/89)
`3% (8/240)
`
`100% (61/61)
`98% (108/110)
`
`95% (58/61)
`89% (95/107)
`
`7% (4/61)
`7% (7/103)
`
`83% (57/69)
`82% (247/302)
`
`71% (49/69)
`73% (215/294)
`
`4% (3/69)
`2% (6/292)
`
`100% (23/23)
`99% (144/146)
`
`96% (22/23)
`90% (129/143)
`
`9% (2/23)
`6% (9/139)
`
`77% (56/73)
`83% (241/289)
`
`75% (54/72)
`72% (203/282)
`
`4% (3/71)
`2% (6/281)
`
`14% (3/22)
`14% (20/145)
`
`80% (20/25)
`77% (112/146)
`
`14% (3/22)
`14% (20/145)
`
`80% (78/98)
`83% (228/276)
`
`69% (66/95)
`74% (200/271)
`
`4% (4/94)
`2% (5/270)
`
`99% (141/143)
`100% (28/28)
`
`91% (130/143)
`92% (23/25)
`
`7% (10/139)
`4% (1/25)
`
`83% (285/344)
`70% (19/27)
`
`71% (240/336)
`85% (23/27)
`
`2% (6/334)
`11% (3/27)c
`
`99% (154/156)
`100% (15/15)
`
`92% (140/153)
`87% (13/15)
`
`4% (6/149)
`33% (5/15)a
`
`Abbreviations: GA, glatiramer acetate; IFNβ-1a, interferon beta-1a; IFNβ-1b, interferon beta-1b; IM, intramuscular; SC, subcutaneous.
`Note: Responses were from patients reporting ever having experienced an injection-site reaction while on an injectable disease-modifying
`therapy. Individual patients may be counted in more than one injection-site reaction category depending on their individual symptoms.
`aP < .001.
`bP < .05.
`cP < .01.
`
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`

`
`bly because of the higher proportion of patients describ-
`ing moderate side effects. Second, for every DMT other
`than SC IFNβ-1b, nonwhites described more severe
`ISRs than did whites. (Subcutaneous IFNβ-1b may
`simply be an anomaly because of the small numbers of
`nonwhite patients receiving this DMT.)
`No other significant associations were detected
`between other recorded demographic variables (tobacco
`smoking, disability level, or duration of therapy) and
`perceived ISR severity. Although at least one commen-
`tary29 has anecdotally suggested that cigarette smoking
`concurrent with injectable DMT use may increase ISR
`severity, neither the present study nor another unpub-
`lished analysis30 has confirmed such an association.
`However, the latter analysis did identify an association
`between “ever having smoked” and a perceived higher
`severity of skin reactions to SC DMTs.30 Interestingly,
`that same analysis also identified an association between
`increased body-mass index (BMI) and more severe ISRs
`in response to SC DMTs. Although the present study
`
`Factors Associated with Injection-Site Reactions in MS
`
`did not assess BMI, findings on this topic are equivocal,
`with at least one other report suggesting that BMI might
`be inversely related to ISR severity.15
`It has been suggested that ISRs may become less
`severe with greater time on therapy.27 This statement
`is not supported by the present results, which are con-
`sistent with reported results from a 4-year study of SC
`IFNβ-1a in which the percentage of people reporting
`ISRs did not change over the 4-year study period.31
`Recently, Treadaway et al.14 reported that 12% of
`patients with MS receiving a DMT were nonadherent
`(having missed more than one injection in the previ-
`ous 4 weeks) because of concerns about ISRs and pain.
`Using a similar definition of adherence, the results of
`the present study were similar, with 11% of patients
`reporting having missed one or more injections because
`of ISRs. There were also significant differences between
`DMT groups in the percentage of patients report-
`ing having missed one or more injections because of
`ISRs, with IM IFNβ-1a having the fewest (4%) and
`
`Transient
`
`SC IFNβ-1b
`Discomfort
`
`Serious
`
`Transient
`
`GA
`Discomfort
`
`Serious
`
`15% (6/40)
`15% (19/130)
`
`61% (25/41)
`83% (110/133)c
`
`15% (6/40)
`15% (19/130)
`
`93% (86/92)
`99% (368/371)a
`
`83% (73/88)
`92% (334/365)b
`
`7% (6/85)
`9% (33/362)
`
`10% (5/48)
`16% (20/122)
`
`88% (45/51)
`73% (90/123)b
`
`10% (5/48)
`16% (20/122)
`
`100% (110/110)
`97% (346/355)
`
`97% (106/109)
`88% (303/346)c
`
`11% (12/109)
`8% (28/340)
`
`14% (5/36)
`15% (20/131)
`
`83% (30/36)
`77% (104/135)
`
`14% (5/36)
`15% (20/131)
`
`96% (82/85)
`98% (372/378)
`
`89% (74/83)
`90% (333/370)
`
`10% (8/82)
`9% (32/365)
`
`14% (3/22)
`14% (20/145)
`
`80% (20/25)
`77% (112/146)
`
`14% (3/22)
`14% (20/145)
`
`100% (77/77)
`98% (367/376)
`
`93% (70/75)
`89% (327/368)
`
`4% (3/75)
`10% (37/363)
`
`10% (6/58)
`17% (19/112)
`
`76% (45/59)
`78% (90/115)
`
`10% (6/58)
`17% (19/112)
`
`98% (171/174)
`98% (285/291)
`
`91% (155/170)
`89% (254/285)
`
`8% (13/168)
`10% (27/281)
`
`15% (25/164)
`0% (0/6)
`
`79% (132/168)
`50% (3/6)
`
`15% (25/164)
`0% (0/6)
`
`98% (431/439)
`96% (24/25)
`
`90% (385/430)
`96% (23/24)
`
`8% (35/424)
`21% (5/24)b
`
`International Journal of MS Care
`51
`
`MYLAN PHARMS. INC. EXHIBIT 1092 PAGE 6
`
`

`
`Stewart and Tran
`
`Table 4. Most frequently used strategies to minimize injection-site reactions
`Strategy
`IM IFNβ-1a
`SC IFNβ-1a
`SC IFNβ-1b
`Site massage
`28% (107/377)
`65% (111/172)
`60% (110/183)
`Avoidance of some sites
`27% (100/377)
`63% (108/172)
`51% (93/183)
`Ice before injection
`15% (57/377)
`39% (67/172)
`17% (32/183)
`Ice after injection
`7% (27/377)
`38% (65/172)
`19% (34/183)
`Diphenhydramine
`3% (11/377)
` (Benadryl) tablets
`Topical hydrocortisone cream
`
`14% (25/183)
`
`9% (15/172)
`
`GA
`27% (128/469)
`42% (197/469)
`23% (110/469)
`34% (160/469)
`
`10% (47/469)
`
`Abbreviations: GA, glatiramer acetate; IFNβ-1a, interferon beta-1a; IFNβ-1b, interferon beta-1b; IM, intramuscular; SC, subcutaneous.
`
`SC IFNβ-1a having the most (19%) missed injection
`reports (P < .001) (Table 1).
`Several general techniques for mitigating ISRs are
`recommended to patients with MS who are receiving
`a DMT. Some techniques—such as use of an autoin-
`jector,32 EMLA (eutectic mixture of local anesthetics)
`cream,33 massage,34,35 and a cooling pack36—are support-
`ed by at least small studies. However, evidence in the
`literature on use of other techniques (eg, nonsteroidal
`anti-inflammatory agents37 or oral antihistamines38) is
`either nonsupportive or conflicting. The package inserts
`for SC IFNβ-1b, SC IFNβ-1a, and GA also recommend
`injection-site rotation and avoiding reinjection of sites
`where the skin is red, sore, or damaged.1,3,4 The most
`frequently reported ISR management techniques in the
`current study included injection-site massage, site rota-
`tion, and the use of cooling techniques and autoinjec-
`tors. All other ISR management methods were employed
`
`PracticePoints
`• Injection-site reactions (ISRs) are common among
`users of FDA-approved injectable disease-modify-
`ing therapies (DMTs) for MS.
`• Users of the intramuscular agent report fewer
`ISRs than do users of the subcutaneously (SC)
`injected therapies.
`• Patients who use the SC therapies, are under 40
`years of age, are female, or are members of a
`racial minority appear to be more likely to expe-
`rience bothersome ISRs.
`• Our findings reaffirm the importance of MS
`patient education on injectable DMT use and
`ISRs, and also suggest strategies for anticipating
`which patients are more likely to experience and
`to report ISRs.
`
`by fewer than 5% of respondents. Widespread use of
`common clinical injection-site management techniques
`suggests that patients with MS may generally be receiv-
`ing instructions on injection techniques and managing
`ISRs from their prescribers or clinical trainers.
`One limitation of this study is that all data were col-
`lected by patient self-report, with responses provided
`by a self-selected group, as noted previously. A sub-
`stantial proportion of this self-selected group consisted
`of well-educated, nonsmoking, married white females
`over 40 years of age, which should be considered when
`interpreting the results of the study. Having sought out
`additional Web-based sources of information on MS,
`this patient cohort may have a more detailed under-
`standing of their disease, what to expect when using
`injectable DMTs, and ISR prevention and management
`techniques than the typical person with MS. However,
`because the current findings are generally consistent with
`previous reports, we believe that these results accurately
`represent the general experiences of patients with MS
`in the real world. In addition, since the time that this
`survey was conducted, the formulation for SC IFNβ-1a
`has changed, and the new formulation seems to produce
`fewer ISRs than the previous formulation, although this
`difference may depend on the delivery device used.39,40
`The present findings reaffirm the importance of
`patient education on injectable DMT use and ISRs, and
`also suggest strategies for anticipating which patients
`may experience more severe ISRs. All patients should
`receive instruction on strategies for reducing ISR inci-
`dence and severity, including education regarding ways
`to manage side effects, such as site rotation and site mas-
`sage. Similarly, all patients should be educated about
`possible severe injection reactions, such as infection and
`necrosis. Especially when providing anticipatory guid-
`ance to patients using SC DMTs and to patients who
`
`International Journal of MS Care
`52
`
`MYLAN PHARMS. INC. EXHIBIT 1092 PAGE 7
`
`

`
`are female, under the age of 40, and/or nonwhite, it
`may be important to note that ISRs may be a barrier to
`adherence. o
`
`Acknowledgments: The authors thank the many people with MS
`who took time to respond to our survey. They also gratefully acknowl-
`edge the support of the staff at the Rocky Mountain MS Center in col-
`lecting the data used for this study; the support of Allen Bowling, MD,
`PhD, Heidi Maloni, PhD, ANP-BC, Margaret O’Leary, RN, MSN,
`MSCN, and Patricia Kennedy, RN, CNP, MSCN, in developing
`and reviewing the survey instrument used for this study; and editorial
`support from Infusion Communications, which was funded by Biogen
`Idec, Inc.
`
`Financial Disclosures: Mr. Stewart has received speaking hono-
`raria from several companies that manufacture and distribute the
`injectable MS therapies that are the subject of this study, including
`Biogen Idec, Inc, and Teva Pharmaceuticals.
`
`Funding/Support: This study was supported by Biogen Idec, Inc,
`through a grant to the Rocky Mountain MS Center.
`
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