Mitoxantrone treatment of multiple sclerosis: Safety considerations
Robert G.Pratt, PharmD, FDA, Center for Drug Evaluation and Research, 5600 Fishers Lane, HFD-430 Rockville, MD 20857prattr@cder.fda.gov
Gerard A. Boehm, MD, MPH, Cindy M. Kortepeter, PharmD, Judith A. Racoosin, MD, MPH
Submitted June 07, 2005
Evaluation of cardiac safety data in multiple sclerosis (MS) patients
treated with mitoxantrone (Novantrone) has led the Food and Drug
Administration (FDA) and Serono, Inc. (the manufacturer of Novantrone) to
issue updated product labeling recommendations for cardiac monitoring.
In
a recent review paper outlining the safety issues to consider when using
mitoxantrone to treat patients with worsening MS, Cohen and Mikol [1]
discuss mitoxantrone-induced cardiotoxicity and recommendations for
cardiac monitoring; these authors advocate more frequent measurement of
left ventricular ejection fraction (LVEF). We agree that more frequent
monitoring is in the best interest of patient safety and bring to your
attention revised cardiac monitoring recommendations that have just been
added to the mitoxantrone labeling.
The revised mitoxantrone labeling states that for MS patients, LVEF
should be evaluated by echocardiogram or multiple gated radionuclide
angiography (MUGA) prior to administration of the initial dose and prior
to each subsequent dose of mitoxantrone, as well as whenever the patient
develops signs or symptoms of heart failure.
The updated cardiac monitoring recommendations are based on a review
of postmarketing reports submitted to the FDA's Adverse Event Reporting
System and an interim analysis of data from the RENEW postmarketing study
being conducted by Serono, Inc. These analyses identified MS patients who
experienced decreases in LVEF with and without clinically symptomatic
congestive heart failure and occurring at cumulative doses of less than
100 mg/m2. In some patients, decreases in LVEF of at least 10% from
baseline (a clinically important reduction) were observed with cumulative
doses below 36 mg/m2. Furthermore, Avasarala et al [2] described five
patients with MS who received a minimum cumulative dose of 37.5 mg/m2 of
mitoxantrone and experienced a "significant decline in LVEF from
baseline". Because these patients did not receive LVEF monitoring prior
to each dose, the decreases in LVEF reported for a particular cumulative
dose could have been present at a lower cumulative dose and gone
undetected.
Mitoxantrone is known to have cardiotoxic effects which can be life
threatening in severe cases. Available data suggest that patients can
experience declines in LVEF at cumulative doses below the previously
recommended cumulative dose threshold for monitoring. The updated cardiac
monitoring recommendation will allow for earlier detection of decreases in
LVEF in mitoxantrone treated MS patients and allow for discontinuation of
mitoxantrone in affected patients.
Evaluation of cardiac safety data in multiple sclerosis (MS) patients treated with mitoxantrone (Novantrone) has led the Food and Drug Administration (FDA) and Serono, Inc. (the manufacturer of Novantrone) to issue updated product labeling recommendations for cardiac monitoring.
In a recent review paper outlining the safety issues to consider when using mitoxantrone to treat patients with worsening MS, Cohen and Mikol [1] discuss mitoxantrone-induced cardiotoxicity and recommendations for cardiac monitoring; these authors advocate more frequent measurement of left ventricular ejection fraction (LVEF). We agree that more frequent monitoring is in the best interest of patient safety and bring to your attention revised cardiac monitoring recommendations that have just been added to the mitoxantrone labeling.
The revised mitoxantrone labeling states that for MS patients, LVEF should be evaluated by echocardiogram or multiple gated radionuclide angiography (MUGA) prior to administration of the initial dose and prior to each subsequent dose of mitoxantrone, as well as whenever the patient develops signs or symptoms of heart failure.
The updated cardiac monitoring recommendations are based on a review of postmarketing reports submitted to the FDA's Adverse Event Reporting System and an interim analysis of data from the RENEW postmarketing study being conducted by Serono, Inc. These analyses identified MS patients who experienced decreases in LVEF with and without clinically symptomatic congestive heart failure and occurring at cumulative doses of less than 100 mg/m2. In some patients, decreases in LVEF of at least 10% from baseline (a clinically important reduction) were observed with cumulative doses below 36 mg/m2. Furthermore, Avasarala et al [2] described five patients with MS who received a minimum cumulative dose of 37.5 mg/m2 of mitoxantrone and experienced a "significant decline in LVEF from baseline". Because these patients did not receive LVEF monitoring prior to each dose, the decreases in LVEF reported for a particular cumulative dose could have been present at a lower cumulative dose and gone undetected.
Mitoxantrone is known to have cardiotoxic effects which can be life threatening in severe cases. Available data suggest that patients can experience declines in LVEF at cumulative doses below the previously recommended cumulative dose threshold for monitoring. The updated cardiac monitoring recommendation will allow for earlier detection of decreases in LVEF in mitoxantrone treated MS patients and allow for discontinuation of mitoxantrone in affected patients.
References
1. Cohen BA, Mikol DD. Mitoxantrone treatment of multiple sclerosis. Safety considerations. Neurology 2004;63(Suppl 6):S28-S32.
2. Avasarala JR, Cross AH, Clifford DB, et al. Rapid onset mitoxantrone-induced cardiotoxicity in secondary progressive multiple sclerosis. Multiple Sclerosis 2003;9:59-62.
The authors have no competing interests to declare.