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## Complete Summary

#### GUIDELINE TITLE

The use of mitoxantrone (Novantrone) for the treatment of multiple
sclerosis: report of the Therapeutics and Technology Assessment
Subcommittee of the American Academy of Neurology.

#### BIBLIOGRAPHIC SOURCE(S)

Goodin DS, Arnason BG, Coyle PK, Frohman EM, Paty DW. The use of
mitoxantrone (Novantrone) for the treatment of multiple sclerosis:
report of the Therapeutics and Technology Assessment Subcommittee of the
American Academy of Neurology. Neurology 2003 Nov 25;61(10):1332-8. \[48
references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14638950)

#### GUIDELINE STATUS

This is the current release of the guideline.

### \*\* REGULATORY ALERT \*\*

#### FDA WARNING/REGULATORY ALERT

**Note from the National Guideline Clearinghouse**: This guideline
references a drug(s) for which important revised regulatory and/or
warning information has been released.

-   [July 29, 2008, Mitoxantrone Hydrochloride (Novantrone, Mitroxone,
    Neotalem, Onkotrone, and
    Pralifan)](http://www.fda.gov/medwatch/safety/2008/safety08.htm#Mitoxantrone):
    The U.S. Food and Drug Administration (FDA) reminded health care
    professionals who treat patients with mitoxantrone about
    recommendations that left ventricular ejection fraction (LVEF) be
    evaluated before initiating treatment and prior to administering
    each dose of mitoxantrone. FDA offered additional recommendations
    for cardiac monitoring to detect late-occurring cardiac toxicity,
    and provided information for patients with multiple sclerosis who
    receive the drug.

### COMPLETE SUMMARY CONTENT

 \*\* REGULATORY ALERT \*\*\
 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

Multiple sclerosis (MS)

#### GUIDELINE CATEGORY

Assessment of Therapeutic Effectiveness\
Management\
Treatment

#### CLINICAL SPECIALTY

Neurology

#### INTENDED USERS

Physicians

#### GUIDELINE OBJECTIVE(S)

To consider both the evidence leading to the recent Food and Drug
Administration (FDA) approval as well as the appropriate clinical role
of mitoxantrone (Novantrone) in the management of patients with multiple
sclerosis

#### TARGET POPULATION

Patients with multiple sclerosis (MS) including secondary progressive MS
(SPMS), progressive-relapsing MS, and worsening relapsing-remitting (RR)
MS.

#### INTERVENTIONS AND PRACTICES CONSIDERED

Mitoxantrone (Novantrone) for treatment of multiple sclerosis

#### MAJOR OUTCOMES CONSIDERED

-   Effect on disease progression

-   Clinical attack rate

-   Magnetic resonance imaging (MRI) outcomes

-   Median time to first relapse

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Hand-searches of Published Literature (Primary Sources)\
Hand-searches of Published Literature (Secondary Sources)\
Searches of Electronic Databases

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

Articles for this review were searched in Medline under the keywords
mitoxantrone and multiple sclerosis (MS). Forty-one articles were
identified by this search. The abstracts of these articles were reviewed
and the original articles were selected for inclusion in the analysis
only if they were either controlled trials or case series using
mitoxantrone in the treatment of MS. Five such articles were identified,
in addition to the phase III trial. In addition, the reference lists of
the articles found in this manner were also reviewed to identify
articles or abstracts not found by the computer search.

#### NUMBER OF SOURCE DOCUMENTS

-   Forty-one articles were identified by the electronic search.

-   The abstracts of these articles were reviewed and the original
    articles were selected for inclusion in the analysis only if they
    were either controlled trials or case series using mitoxantrone in
    the treatment of MS. Five such articles were identified, in addition
    to the phase III trial.

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Weighting According to a Rating Scheme (Scheme Given)

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

**Rating of therapeutic article**

**Class I**: Prospective, randomized, controlled clinical trial (RCT)
with masked outcome assessment, in a representative population. The
following are required:

a.  Primary outcome(s) is/are clearly defined.

b.  Exclusion/inclusion criteria are clearly defined.

c.  Adequate accounting for dropouts and crossovers with numbers
    sufficiently low to have minimal potential for bias.

d.  Relevant baseline characteristics are presented and substantially
    equivalent among treatment groups or there is appropriate
    statistical adjustment for differences.

**Class II**: Prospective matched group cohort study in a representative
population with masked outcome assessment that meets a--d above OR a RCT
in a representative population that lacks one criterion a--d.

**Class III**: All other controlled trials (including well-defined
natural history controls or patients serving as own controls) in a
representative population, where outcome assessment is independent of
patient treatment.

**Class IV**: Evidence from uncontrolled studies, case series, case
reports, or expert opinion.

#### METHODS USED TO ANALYZE THE EVIDENCE

Systematic Review

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

Not stated

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Other

#### DESCRIPTION OF METHODS USED TO FORMULATE THE RECOMMENDATIONS

When formulating the recommendations the guideline developers considered
the *magnitude* of the effect (benefit or harm of therapy, accuracy of
tests, yield of studies) and the relative *value* of various outcomes.
Under most circumstances, there is a direct link between the level of
evidence used to formulate conclusions and the strength of the
recommendation. This linkage is illustrated in Appendix 9 of the 2004
AAN Guideline Process Manual (see Companion Documents field). Thus, an
\"established as\" (two class I) conclusion supports a \"should be
done\" (level A) recommendation; a \"probably effective\" (two class II)
conclusion supports a \"should be considered\" (level B) recommendation;
a \"possibly effective\" (two class III) conclusion supports a \"may be
considered\" recommendation. In those circumstances where the evidence
indicates that the intervention is not effective or useful, wording was
modified. For example, if multiple adequately powered class I studies
demonstrated that an intervention is not effective, the recommendation
read, \"should not be done.\"

There are important exceptions to the rule of having a direct linkage
between the level of evidence and the strength of recommendations. Some
situations where it may be necessary to break this linkage are listed
below:

-   A statistically significant but marginally important benefit of the
    intervention is observed

-   The intervention is exorbitantly costly

-   Superior and established alternative interventions are available

-   There are competing outcomes (both beneficial and harmful) that
    cannot be reconciled

Under such circumstances the guideline developers may have downgraded
the level of the recommendation.

Edlund W, Gronseth G, So Y, Franklin G. Clinical practice guideline
process manual. St. Paul (MN): American Academy of Neurology (AAN);
2004. 49 p.

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

**Rating of Recommendations**

**A** = Established as effective, ineffective, or harmful for the given
condition in the specified population.

**B** = Probably effective, ineffective, or harmful for the given
condition in the specified population.

**C** = Possibly effective, ineffective, or harmful for the given
condition in the specified population.

**U** = Data inadequate or conflicting; given current knowledge,
treatment is unproven.

**Translation of Evidence to Recommendations**

**Level A** rating requires at least one convincing class I study or at
least two consistent, convincing class II studies.

**Level B** rating requires at least one convincing class II study or at
least three consistent class III studies.

**Level C** rating requires at least two convincing and consistent class
III studies.

#### COST ANALYSIS

A formal cost analysis was not performed and published cost analyses
were not reviewed.

#### METHOD OF GUIDELINE VALIDATION

External Peer Review\
Internal Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

The reviewer of early drafts of the manuscript is acknowledged in the
original guideline document.

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

Definitions of the strength of the recommendations (A, B, C, U) and
classification of the evidence (Class I through Class IV) are provided
at the end of the \"Major Recommendations\" field.

**Practice Recommendations**

1.  On the basis of evidence from a single Class I study and a few Class
    II or III studies, it appears that mitoxantrone may have a
    beneficial effect on disease progression in patients with multiple
    sclerosis (MS) whose clinical condition is deteriorating (**Type B
    recommendation**). In general, however, this agent is of limited use
    and of potentially great toxicity. Therefore, it should be reserved
    for patients with rapidly advancing disease who have failed other
    therapies.

2.  On the basis of several consistent Class II and III studies,
    mitoxantrone probably reduces the clinical attack rate and reduces
    attack-related magnetic resonance imaging (MRI) outcomes in patients
    with relapsing MS (**Type B recommendation**). The potential
    toxicity of mitoxantrone, however, considerably limits its use in
    patients with relapsing forms of MS.

3.  Because of the potential toxicity of mitoxantrone, it should be
    administered under the supervision of a physician experienced in the
    use of cytotoxic chemotherapeutic agents (**Type A
    Recommendation**). In addition, patients being treated with
    mitoxantrone should be monitored routinely for cardiac, liver, and
    kidney function abnormalities (**Type A Recommendation**).

**[Definitions]{.underline}**:

**Rating of Recommendations**

**A** = Established as effective, ineffective, or harmful for the given
condition in the specified population.

**B** = Probably effective, ineffective, or harmful for the given
condition in the specified population.

**C** = Possibly effective, ineffective, or harmful for the given
condition in the specified population.

**U** = Data inadequate or conflicting; given current knowledge,
treatment is unproven.

**Translation of Evidence to Recommendations**

**Level A** rating requires at least one convincing class I study or at
least two consistent, convincing class II studies.

**Level B** rating requires at least one convincing class II study or at
least three consistent class III studies.

**Level C** rating requires at least two convincing and consistent class
III studies.

**Rating of therapeutic article**

**Class I**: Prospective, randomized, controlled clinical trial (RCT)
with masked outcome assessment, in a representative population. The
following are required:

a.  Primary outcome(s) is/are clearly defined.

b.  Exclusion/inclusion criteria are clearly defined.

c.  Adequate accounting for dropouts and crossovers with numbers
    sufficiently low to have minimal potential for bias.

d.  Relevant baseline characteristics are presented and substantially
    equivalent among treatment groups or there is appropriate
    statistical adjustment for differences.

**Class II**: Prospective matched group cohort study in a representative
population with masked outcome assessment that meets a--d above OR a RCT
in a representative population that lacks one criterion a--d.

**Class III**: All other controlled trials (including well-defined
natural history controls or patients serving as own controls) in a
representative population, where outcome assessment is independent of
patient treatment.

**Class IV**: Evidence from uncontrolled studies, case series, case
reports, or expert opinion.

#### CLINICAL ALGORITHM(S)

None provided

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

The type of supporting evidence is identified and graded for each
recommendation (see \"Major Recommendations\").

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

There is evidence from several Class II and III studies that
mitoxantrone reduces clinical attack rate and attack-related magnetic
resonance imaging (MRI) outcome measures in patients with relapsing
forms of multiple sclerosis (MS).

#### POTENTIAL HARMS

-   Adverse effects of mitoxantrone

-   Use of this agent in relapsing MS will have to take into account its
    potential toxicity. Patients treated with mitoxantrone are at
    increased risk for cardiac toxicity as manifested by cardiomyopathy,
    reduced left ventricular ejection fraction, and irreversible
    congestive heart failure.

-   Because of concerns about such potential cardiac toxicity, a
    cumulative dose of mitoxantrone more than 140 mg/m^2^ is not
    recommended for treatment of MS, although doses of up to 96 mg/m^2^
    seem to be safe.

-   Other potential side effects include amenorrhea, which in some cases
    can be permanent, and a risk of late malignancy.

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

-   Because of the modest clinical benefits on disease progression
    reported in the pivotal phase III mitoxantrone trial, this result
    should be replicated in another (and hopefully much larger) clinical
    trial before mitoxantrone can be recommended widely for the
    treatment of patients with multiple sclerosis (MS).

-   This statement is provided as an educational service of the American
    Academy of Neurology (AAN). It is based on an assessment of current
    scientific and clinical information. It is not intended to include
    all possible proper methods of care for a particular neurologic
    problem or all legitimate criteria for choosing to use a specific
    procedure. Neither is it intended to exclude any reasonable
    alternative methodologies. The AAN recognizes that specific care
    decisions are the prerogative of the patient and the physician
    caring for the patient, based on all of the circumstances involved.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

An implementation strategy was not provided.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Living with Illness

#### IOM DOMAIN

Effectiveness

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Goodin DS, Arnason BG, Coyle PK, Frohman EM, Paty DW. The use of
mitoxantrone (Novantrone) for the treatment of multiple sclerosis:
report of the Therapeutics and Technology Assessment Subcommittee of the
American Academy of Neurology. Neurology 2003 Nov 25;61(10):1332-8. \[48
references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14638950)

#### ADAPTATION

Not applicable: The guideline was not adapted from another source.

#### DATE RELEASED

2003 Nov 25

#### GUIDELINE DEVELOPER(S)

American Academy of Neurology - Medical Specialty Society

#### SOURCE(S) OF FUNDING

American Academy of Neurology (AAN)

#### GUIDELINE COMMITTEE

Therapeutics and Technology Assessment Subcommittee of the American
Academy of Neurology

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

*American Academy of Neurology (AAN) Therapeutics and Technology
Assessment Subcommittee Members*: Douglas S. Goodin, MD (*Chair*); Yuen
T. So (*Vice-chair*); Carmel Armon, MD, MHS; Richard M. Dubinsky, MD;
Mark Hallett, MD; David Hammond, MD; Cynthia L. Harden, MD; Chung Y.
Hsu, MD, PhD; Andres M. Kanner, MD; David S. Lefkowitz, MD; Janis
Miyasaki, MD; Michael A. Sloan, MD; James C. Stevens, MD

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

Not stated

#### GUIDELINE STATUS

This is the current release of the guideline.

#### GUIDELINE AVAILABILITY

Electronic copies: A list of American Academy of Neurology (AAN)
guidelines, along with a link to a Portable Document Format (PDF) file
for this guideline, is available at the [AAN Web
site](http://aan.com/go/practice/guidelines).

Print copies: Available from the AAN Member Services Center, (800)
879-1960, or from AAN, 1080 Montreal Avenue, St. Paul, MN 55116.

#### AVAILABILITY OF COMPANION DOCUMENTS

The following are available:

-   AAN guideline development process \[online\]. St. Paul (MN):
    American Academy of Neurology (AAN). Available from the [AAN Web
    site](http://aan.com/go/practice/guidelines/development).

-   Edlund W, Gronseth G, So Y, Franklin G. Clinical practice guideline
    process manual. St. Paul (MN): American Academy of Neurology
    (AAN); 2004. 49 p. Electronic copies available in Portable Document
    Format (PDF) from the [AAN Web
    site](http://aan.com/globals/axon/assets/2535.pdf).

#### PATIENT RESOURCES

None available

#### NGC STATUS

This NGC summary was completed by ECRI on August 17, 2004. The
information was verified by the guideline developer on September 9,
2004. This summary was updated by ECRI on May 27, 2005, following the
U.S. Food and Drug Administration (FDA) advisory on Novantrone
(mitoxantrone for injection concentrate). This summary was updated by
ECRI Institute on August 11, 2008 following the U.S. Food and Drug
Administration advisory on mitoxantrone hydrochloride.

#### COPYRIGHT STATEMENT

This NGC summary is based on the original guideline, which is
copyrighted by the American Academy of Neurology.

### DISCLAIMER

#### NGC DISCLAIMER

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© 1998-2008 National Guideline Clearinghouse

Date Modified: 11/3/2008