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DAA Therapies_ What Do The Data Show_ - Projects In Knowledge

VIEWS: 17 PAGES: 27

									Integrating Current and
Emerging MS Therapies
     into Practice



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           Goals of MS
    Disease-Modifying Therapy
   Delay disability progression
   Reduce the frequency of relapses
   Improve MRI measures of disease




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      Modern-Day Goals—Relapse Rate
 Annualized relapse rates (ARRs) in recently completed RRMS trials
with glatiramer acetate (GA), interferon (IFN), and placebo (PBO) arms

                                                               ARR by Treatment Arm
              Study
                                                              GA                 IFN               PBO
              ALLEGRO1                                          –                  –               0.39
              BEYOND2                                        0.34               0.36                  –
              CLARITY3                                          –                  –               0.33
              FORTE4                                         0.33                  –                  –
              FREEDOMS5                                         –                  –               0.40
              REGARD6                                        0.29               0.30                  –
              TEMSO7                                            –                  –               0.54
              TRANSFORMS8                                       –               0.33                  –
1. Comi G, et al. Paper presented at: 63rd AAN; April 9-16, 2011; Honolulu, Hawaii. Abstract P07.194. 2. O'Connor P, et al.
Lancet Neurol. 2009;8:889-897. 3. Giovannoni G, et al. N Engl J Med. 2010;362:416-426. 4. Comi G, et al. Ann Neurol.
2011;69:75-82. 5. Kappos L, et al. N Engl J Med. 2010;362:387-401. 6. Mikol DD, et al. Lancet Neurol. 2008;7:903-914.
7. O’Connor P, et al. Paper presented at: ECTRIMS; October 13­–16, 2010; Gothenburg, Sweden. Abstract 79. 8. Cohen
JA, et al. N Engl J Med. 2010;362:402-415.
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                Modern-Day Goals—Other
      Patients treated with IFN or GA in recent CIS and
                        RRMS studies
Parameter                                                 Study                        GA                   IFN
Relapse-free at 2 years                                BEYOND1                        59%                  58%
Disability progression-free                            BEYOND1                        79%                  73%
at 2 years                                            REGARD2
                                                                                      91%                  88%
                                                      (96 weeks)
Disability progression-free
                                                    CAMMS2233                            –                 59%
at 3 years
Disability progression-free
                                                       BENEFIT4                          –                 75%
5 years after CIS
Reduction in MRI T2
                                                    CAMMS2233                            –                 13%
lesions at 3 years
Abbreviations: CIS, clinically isolated syndrome; GA, glatiramer acetate; IFN, interferon; RRMS, relapsing-remitting MS.
1. O'Connor P, et al. Lancet Neurol. 2009;8:889-897. 2. Mikol DD, et al. Lancet Neurol. 2008;7:903-914. 3. Coles AJ,
et al. N Engl J Med. 2008;359:1786-1801. 4. Kappos L, et al. Lancet Neurol. 2009;8:987-997.
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              Timeline of Approved and
               Emerging MS Therapies
                                                                                                         Alemtuzumab

 IFN β-1b SC                     Natalizumab
                                                                                                          Daclizumab

          IFN β-1a IM                               IFN β-1b SC                                          Ocrelizumab


            Glatiramer acetate
                                                                                             Fumarate (BG12)
                                                                    Fingolimod
                        Mitoxantrone                                                            Laquinimod*


                          IFN β-1a SC                                                          Teriflunomide


   1995           2000         2005             2009           2010           2011       2012
                   Approval Date                                              Estimated Launch Date

                           Approved Therapies                                    Phase III Completed        In Phase III

*In 20-F report filed 2/17/12: Teva will not file an NDA with the FDA for laquinimod for RRMS at this time; development
continues, however.1
Abbreviations: NDA, new drug application; RRMS, relapsing-remitting MS.
1. TEVA Pharmaceutical Industries Ltd. Form 20-F. February 17, 2012. Accessed 3/1/12 at
http://ir.tevapharm.com/phoenix.zhtml?c=73925&p=irol-sec. Graphic courtesy of Dr. Mark J. Tullman.
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                                          What’s New?
                                 Interferon Beta
     BEYOND trial data analysis shows negative impact of
      neutralizing antibodies on MRI measures, but no negative
      impact on clinical measures1
     21-year follow-up from start of phase III enrollment shows
      significant survival benefit vs placebo2
     Meta-analysis finds limited benefits in secondary-
      progressive MS3
     5-year follow-up shows modest beneficial effect on clinical
      variables and brain atrophy in primary-progressive MS4




1. Goodin DS, et al. Mult Scler. 2012;18:181-195. 2. Goodin D, et al. Paper presented at ECTRIMS/ACTRIMS 2011;
October 19–20, 2011; Amsterdam, Netherlands. Abstract P940. 3. La Mantia L, et al. Cochrane Database Syst Rev.
2012;1:CD005181. 4. Tur C, et al. Arch Neurol. 2011;68:1421-1427.                                              6
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                                         What’s New?
                          Glatiramer Acetate
     Long-term follow-up of patients with mean MS duration of 22
      years receiving continuous glatiramer acetate for up to 15 years
      shows long-term efficacy and safety1
       –      Reduced relapse rates, decreased disability progression,
              decreased transition to secondary-progressive MS
       –      No long-term safety issues
     5-year brain MRI study showed less progression of brain
      atrophy with glatiramer vs interferon2
     Preliminary analysis of Coptimize study shows significant
      reduction in annualized relapse rate after switching to
      glatiramer acetate3
     Induces in vivo expansion of immunosuppressive CD4+ T-cells4
1. Ford C, et al. Mult Scler. 2010;16:342-350. 2. Khan O, et al. J Neurol Sci. 2012;312:7-12.
3. Ziemssen T, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract P510.
4. Ryzhkova A, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract P799.      7
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                                         What’s New?
                                      Fingolimod
    TRANSFORMS subgroup analysis: brain volume reduction with
     fingolimod not accounted for by inflammatory lesion activity or new
     disease activity during 1st year of treatment1
    Data from safety study extension shows sustained low level of disease
     activity over 5 years2
    July 2011, fingolimod label expanded to include reduction in MRI
     gadolinium-enhancing lesions3
    December 2011, FDA announced safety evaluation of a patient who died
     within 24 hours of taking first dose; exact cause of death has not been
     established4
    January 2012, Novartis announced a total of 31 deaths worldwide are
     being investigated: 11 "deaths of potential interest" plus 20 other deaths
     in 30,000+ patients treated since 20035
1. Barkhof F, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract P907. 2. Montalbán
S, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract P978. 3. FDA letter. July 20,
2011. Accessed 3/5/12 at: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/022527s002ltr.pdf.
4. FDA. Safety announcement. December 20, 2011. Accessed 3/6/12 at:
http://www.fda.gov/Drugs/DrugSafety/ucm284240.htm. 5. Novartis webcast, January 25, 2012. Accessed 3/8/12 at:
http://www.novartis.com/investors/                                                                                  8
event-calendar/index.shtml#2012-01-25_full-year-results.            Electronic Image Safe (Remove for final output)
                                         What’s New?
                                     Natalizumab
     Long-term outcomes from AFFIRM in patients free of disease
      activity after 2 years presented at ECTRIMS1
     Patients treated with natalizumab had higher magnetization
      transfer ratio volume in normal-appearing brain tissue
      compared with patients treated with IFN or healthy controls
      at years 1 and 22
     FDA approves STRATIFY JCV antibody ELISA test3
     Pathologic and radiologic characteristics of immune
      reconstitution inflammatory syndrome described4




1. Rudick R, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract P513. 2. Zivadinov
R, et al. Mult Scler. 2011 Dec 22. [Epub ahead of print]. 3. FDA. News release. 1/20/12. Accessed 3/20/12 at:
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm288471.htm. 4. Metz I, et al. Acta Neuropathol.
2012;123:235-245.                                                                                                  9
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                                           What’s New?
                                     Mitoxantrone
     Mitoxantrone found to exert cytotoxic and immunomodulatory
      effects on central nervous system (CNS) microglia, major CNS
      antigen-presenting cells that play a key role in MS pathogenesis1
     5-year prospective safety study from French cohort
      (N = 802) reported2
       –      0.1% acute congestive heart failure
       –      4.9% asymptomatic left ventricular ejection fraction
              reduction under 50%
       –      0.25% therapy-related leukemia
       –      17.3% persistent age-dependent amenorrhea in women
              treated before age 45 years



1. Li JM, et al. Immunopharmacol Immunotoxicol. 2012;34:36-41. 2. Le Page E, et al. Mult Scler. 2011;17:867-875.10
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            Fumarate (BG-12)–DEFINE,
                    Phase III
     BG-12 240 mg BID and TID vs placebo for 2 years
      (N = 1234 RRMS)
     All primary and secondary endpoints met
     Compared with placebo, BG-12 BID and TID
       –      Reduced the relapse rate by 49% and 50%, respectively
              (P <.0001)
       –      Reduced annualized relapse rate by 53% and 48%,
              respectively (P <.001)
       –      Reduced 12-week disability progression by 38%
              (P <.01) and 34%, respectively (P <.05)




Gold R, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract 95.              11
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    Laquinimod–ALLEGRO, Phase III

    Laquinimod 0.6 mg/d vs placebo for 24 months
     (N = 1106 RRMS)
    Achieved primary end point showing annualized relapse rate
     significantly reduced by 23% (P = .002)
    Achieved secondary endpoints
       –     Expanded Disability Status Scale progression of disability
             significantly reduced by 36% (P = .01)
       –     Mean cumulative number Gad-enhancing lesions
             significantly reduced by 37% (P <.001)
       –     Mean cumulative number new or enlarging T2 lesions
             significantly reduced by 30% (P <.001)


Comi G, et al. N Engl J Med. 2012;366:1000-1009.                                              12
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       Laquinimod–BRAVO, Phase III
    Laquinimod 0.6 mg/d vs placebo vs IFN β-1a for 24 months
     (N = 1331 RRMS)
    Compared with placebo, laquinimod
       Did not statistically reduce unadjusted annualized relapse
          rate (ARR) (P = .075)
      – Reduced adjusted ARR by 22% (P = .026)
      – Reduced disability progression by 33.5% (P = .044)
      – Reduced brain atrophy by 27.5% (P <.0001)
    Compared with placebo, interferon β-1a
      – Significantly reduced ARR by 29% (P = .002)
      – Did not significantly reduce disability progression or brain
          atrophy


Vollmer TL, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract 148.         13
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    Teriflunomide–Phase III TEMSO Data

    Teriflunomide 7 mg/d or 14 mg/d vs placebo for 2 years
     (N = 1088 RRMS)
    Achieved primary endpoint showing ARR significantly reduced
     by 31.2% at 7 mg and by 31.5% at 14 mg (P <.001 for both)
    Achieved key secondary endpoint showing 12-week disability
     progression significantly reduced by 24%
     (P = .08) at 7 mg and by 30% (P = .03) for 14 mg
    Was superior for a range of MRI endpoints
       –      Significantly reduced total lesion volume by 39.4% at 7 mg
              and by 67.4% at 14 mg (P = .03)
       –      Significantly reduced number of Gad-enhancing lesions by
              57% at 7 mg and by 80% at 14 mg (P <.001)


O'Connor P, et al. N Engl J Med. 2011;365:1293-1303.                                              14
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               Alemtuzumab–CAMMS223
                     Phase II Trial
     Alemtuzumab 12 mg or 24 mg vs IFN β-1a for 3 years
      (N = 334 early RRMS)1
     Achieved primary endpoints (both doses combined)1
        –      Significantly reduced relapse rate by 74% (P <.001)
        –      Significantly reduced risk of sustained disability by 71%
               (P <.001)
     Achieved secondary MRI endpoints (both doses combined)1
        –      Significantly reduced lesion burden (P = .005)
        –      Significantly reduced reduction in brain volume (P = .05)
     Treatment effect durable through 5 years2
1. Coles, AJ. N Engl J Med. 2008;359:1786-1801. 2. Twyman C, et al. 63rd AAN; April 9-16, 2011;
Honolulu, Hawaii. Abstract PD6.003.
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              Alemtuzumab–CARE-MS I
                   Phase III Trial
     Alemtuzumab vs IFN β-1a for 2 years (N = 581 treatment-naive RRMS)1
     Compared with IFN β-1a, alemtuzumab (primary endpoints)1,2
       –      Significantly reduced ARR by 54% (P <.0001)
       –      Did not significantly reduce sustained accumulation of disability
              (11% vs 8%; P = .22)
     Other outcomes1,2
       –      Percentage relapse-free: 78% alemtuzumab, 59% IFN (P <.0001)
       –      Percentage with new/enlarging T2 lesions: 49% alemtuzumab, 58% IFN
              (P = .035)
       –      Mean change in Expanded Disability Status Scale disability score: 0.14 for both
              alemtuzumab and IFN
       –      Percentage with new T1 hypointense lesions: 24% alemtuzumab, 31% IFN
              (P = .05)
       –      Brain atrophy: -0.87% alemtuzumab, -1.49% IFN (P <.0001)
     Safety1,2
       –      0.8% immune thrombocytopenia, 18% thyroiditis
1. Coles A, et al. Paper presented at: ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands.
Abstract 151. 2. Gever J. MedPage Today. October 22, 2011. Accessed 3/12/12 at:
http://www.medpagetoday.com/MeetingCoverage/ECTRIMS/29173.                                                   16
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                    Daclizumab–CHOICE and
                        SELECT Phase II
 •     CHOICE phase II trial1
         —     3 arms: 2 doses of daclizumab and placebo added to IFN (N = 230 RRMS)
         —     No significant difference in relapse rate
         —     Decrease in new MRI lesions with higher dose vs IFN alone
         —     5% serious infections with daclizumab, all resolved with standard therapy

 •     SELECT phase IIb trial2
         —     Daclizumab monotherapy 150 mg vs 300 mg vs placebo (N = 600 RRMS)
         —     Compared with placebo, daclizumab
                           Significantly reduced ARR
                           Significantly reduced proportion of patients who relapsed
                           Reduced new or enlarging Gad+ lesions between weeks 8 and 24

         —     Adverse effects included increase in serious infections (2%)

1. Wynn D, et al. Lancet Neurol. 2010;9:381-390. 2. Giovannoni G, et al. ECTRIMS/ACTRIMS 2011; October 19–20,
2011; Amsterdam, Netherlands. Abstract 149.                                                                  17
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             Ocrelizumab–Phase II Data
    Ocrelizumab (OCR) 600 mg and 2000 mg vs IFN β-1a vs placebo
     (N = 220 RRMS)1
    At week 24, Gad-enhancing lesions reduced by 89% and 96%
     with OCR 600 mg and 2000 mg, respectively, compared with
     placebo1
    At week 24, ARR reduced by 80% and 73% with OCR 600 mg and
     2000 mg1, respectively, compared with placebo
    Adverse effects1
       –      Serious infection rates were similar across groups
       –      41-year-old woman treated with ocrelizumab 2000 mg died
              at week 14 of systemic inflammatory response syndrome
    Deaths in rheumatoid arthritis and systemic lupus
     erythematosus trials suspends development in those settings2

1. Kappos L, et al. Lancet. 2011;378:1779-1787. 2. Reid, K. Reuters. March 8, 2010. Accessed 3/12/12
at: http://www.reuters.com/article/2010/03/08/roche-idUSLDE62705720100308.                                     18
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                          Risk Stratification by Baseline
                                     Brain MRI
                                          20-Year Clinical Status
                          100                                             100
   % Conversion to CDMS




                                         82    85                                               EDSS >3
                                                     81
                           80                                              80
                                                                                                EDSS ≥6
                                                                                                                 65




                                                             % Patients
                           60                                              60
                                                                                                       50
                                                                                                                      45
                           40                                              40                36             35
                                                                                   26
                                   21                                                             18
                           20                                              20
                                                                                         6
                            0                                               0
                                   0    1–3   4–9   ≥10                              0        1–3       4–9       ≥10
                                Number of T2 Brain Lesions                        Number of T2 Brain Lesions
                                       at Baseline                                       at Baseline
Abbreviations: CDMS, clinically definite MS; EDSS, Expanded Disability Status Scale.
Fisniku LK et al. Brain. 2008;131:808-817. Graphics courtesy of Dr. Mark J. Tullman.                                       19
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       Factors in Selecting a
    Disease-Modifying Therapy
   Efficacy
   Safety/tolerance
   Convenience
   Patient preference
   Cost
   Escalation vs induction
   Window of opportunity
   Risk mitigation

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    Risk Mitigation–Estimated Incidence of PML in
    Natalizumab-Treated Patients by Risk Factors
                            Anti-JCV antibody status1,2

      Negative                                                                  Positive

                                                             Prior immunosuppressive use
                                                                 No                                       Yes

                                 Natalizumab
                                                           No Prior IS Use                 Prior IS Use
  ≤0.10/1000                      Exposure
95% CI: 0–0.593
                                     1–24 mo                     <1/1000                        2/1000

                                    25–48 mo                      4/1000                      11/1000
Abbreviations: JCV, JC virus; IS, immunosuppressant; PML, progressive multifocal leukoencephalopathy.
1. Tysabri. [package insert]. South San Francisco, CA: Biogen Idec Inc; 2012. 2. FDA Drug Safety
Communication. January 20, 2012. Accessed 2/23/12 at http://www.fda.gov/Drugs/DrugSafety/ucm288186.htm.
3. Bloomgren G, ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract P995.
Graphics courtesy of Dr. Mark J. Tullman.                                                                    21
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                 Monitoring for
      Interferon-β–Specific Safety Issues
    Monitoring                                                     Monitoring
    Category                                                        Activity
                              • Complete blood count, with differential and platelets1-4
    Routine labs
                              • Blood chemistries with liver function tests1-4

    Special tests             • Thyroid tests, as indicated1-4

                              • Monitor for depression, suicidal ideation, and/or
                                psychosis1-4
                              • Monitor for cardiac symptoms in patients with pre-existing
    Other
                                cardiac disease1,2
                              • Monitor for seizures in patients with pre-existing seizure
                                disorders1-3,4

                   See prescribing information for complete details.
1. Avonex [PI]. Cambridge, MA: Biogen Idec Inc.; 2012. 2. Betaseron [PI]. Montville, NJ: Bayer HealthCare
Pharmaceuticals Inc.; 2010. 3. Extavia [PI]. East Hanover, NJ: Novartis Pharmaceutical Corporation; 2009. 4. Rebif [PI].
Rockland, MA: EMD Serono, Inc.; 2011.                                                                             22
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      Monitoring for Glatiramer Acetate-
           Specific Safety Issues

    Monitoring                                                   Monitoring
    Category                                                      Activity

    Routine labs             • No routine monitoring for safety required

    Special tests                                                    ––

                             • No known safety issue with immediate
    Other                      postinjection hypersensitivity reactions
                               (tolerability issue)
                 See prescribing information for complete details.


Copaxone [PI]. Kansas City, MO: Teva Neuroscience, Inc.; 2009.                                                23
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 Monitoring for Fingolimod-Specific Safety Issues
  Monitoring                                                            Monitoring
  Category                                                               Activity
                              •    Complete blood count with differential and platelets, baseline and
                                   periodic1
                                     — Lymphocyte subsets (optional)2
  Routine labs                •    Liver function tests, baseline and as indicated1
                              •    IgG antivaricella zoster antibody test, baseline1
                              •    Hepatitis panel screen, baseline and as indicated1,2
                              •    HIV (especially if there are risk factors)2
                              •    Baseline ECG and after first 6 hours to check for bradycardia; serial
                                   ECG monitoring during 6 hours may be useful2,3; EMA recommends
                                   continuous ECG monitoring during the 6 hours4
  Special tests               •    Chest X-ray2
                              •    Pulmonary function tests, as indicated1
                              •    Ophthalmologic exam, baseline and periodic1
                              •    Monitor blood pressure
  Other1                      •    Monitor for infection
                    See prescribing information for complete details.
Abbreviations: ECG, electrocardiogram; EMEA, European Medicines Agency; HIV, human immunodeficiency virus.
1. Gilenya [PI]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2011. 2. Robert P. Lisak, MD. Written communication.
3/6/12. 3. FDA. Safety announcement. December 20, 2011. Accessed 3/6/12 at:
http://www.fda.gov/Drugs/DrugSafety/ucm284240.htm. 4. EMA. Press release. January 12, 2012. Accessed 3/15/12 at:
http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2012/01/WC500120703.pdf.                            24
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   Monitoring for Natalizumab-Specific
              Safety Issues
   Monitoring                                          Monitoring
   Category                                             Activity
                             • Complete blood count, with differential and
   Routine labs                platelets
                             • Liver function tests

   Special tests             • JC virus antibody testing

                             • Monitor for symptoms of hypersensitivity
                               (ie, hives, urticaria)
                             • Monitor for infection
   Other
                             • Monitor for symptoms of progressive multifocal
                               leukoencephalopathy (PML); if question of PML,
                               additional action and testing required
                See prescribing information for complete details.
Tysabri [PI]. Cambridge, MA: Biogen Idec Inc.; 2012.                                                25
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  Monitoring for Mitoxantrone-Specific
             Safety Issues
    Monitoring                                                    Monitoring
    Category                                                       Activity
                              • Complete blood count with differential and platelets
    Routine labs                prior to each infusion
                              • Liver function tests prior to each infusion
                              • Baseline ECG and quantitative LVEF evaluation
                                (eg, MUGA scan); repeat before each infusion plus
    Special tests               yearly after discontinuation
                              • Pregnancy test prior to each infusion for women
                                biologically capable of becoming pregnant
                        • Monitor for infection
    Other
                        • Nausea and vomiting (can become safety issue)
                  See prescribing information for complete details.
Abbreviations: ECG, electrocardiogram; LVEF, left ventricular ejection fraction; MUGA, multiple gate acquisition scan.
Mitoxantrone [PI]. Irvine, CA: Teva Parenteral Medicines, Inc.; 2011.
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   Making Switching Decisions

                   Decide whether to switch
  Monitoring
  outcomes         Decide when to switch


Agent-specific
   factors
                   Decide how to switch
Patient-specific
    factors
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