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ARTICLES: Bruce A. Cohen and Daniel D. Mikol Mitoxantrone treatment of multiple sclerosis: Safety considerations Neurology 2004; 63: S28-32S [Abstract] [Full text]

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Reply to Pratt et al

Bruce A. Cohen M.D., Daniel D. Mikol, M.D. Ph.D   (7 June 2005)

Mitoxantrone treatment of multiple sclerosis: Safety considerations

Robert G. Pratt, PharmD, Gerard A. Boehm, MD, MPH, Cindy M. Kortepeter, PharmD, Judith A. Racoosin, MD, MPH   (7 June 2005)

Reply to Pratt et al 7 June 2005
Bruce A. Cohen M.D., Davee Dept of Neurology, Feinberg School of Medicine, Northwestern University 710 North Lake Shore Drive, Abbott Hall 1121, Chicago Illinois 60611, Daniel D. Mikol, M.D. Ph.D Send Correspondence to journal: Re: Reply to Pratt et al bac106{at}northwestern.edu Bruce A. Cohen M.D., et al.	We appreciate the comments of Pratt et al regarding our comments on the need for more frequent monitoring of cardiac function when treating MS patients with mitoxantrone. [1] The recent recommendations by Serono and the FDA now make our suggested intervals obsolete. Current data has indicated a low risk for both symptomatic heart failure and asymptomatic but significant reductions in cardiac ejection fraction. [2] Nonetheless, Avasarala et al described five patients with early significant decline in ejection fraction while undergoing mitoxantrone therapy for MS. [3] We concur with the decision by Serono and the FDA to amend the product labeling for mitoxantrone to incorporate earlier and more frequent cardiac monitoring. Prompt recognition of significant asymptomatic reduction in ejection fraction should further reduce the low incidence of symptomatic cardiac failure with this agent in doses used for MS. References 1. Cohen BA, Mikol DD. Mitoxantrone treatment of multiple sclerosis:safety consideraions. Neurology 2004;63(suppl 6):S28-S32 2. Ghalie RG, Edan G, Laurent M, et al. Cardiac adverse effects associated with mitoxantrone (Novantrone)therapy in patients with MS. Neurology 2002;59:909-913. 3. Avasarala JR, Cross AH, Clifford DB, et al. Rapid onset mitoxantrone- induced cardiotoxicity in secondary progressive multiple sclerosis. Mult Scler 2003;9:59-62.
Mitoxantrone treatment of multiple sclerosis: Safety considerations 7 June 2005
Robert G. Pratt, PharmD, FDA, Center for Drug Evaluation and Research 5600 Fishers Lane, HFD-430 Rockville, MD 20857, Gerard A. Boehm, MD, MPH, Cindy M. Kortepeter, PharmD, Judith A. Racoosin, MD, MPH Send Correspondence to journal: Re: Mitoxantrone treatment of multiple sclerosis: Safety considerations prattr{at}cder.fda.gov Robert G. Pratt, PharmD, et al.	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.