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NeurAlert: New FDA Advisory for Management of Mitoxantrone Therapy in Patients with MS

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The risk of serious cardiotoxicity associated with the immunosuppressant mitoxantrone prompted the FDA to issue a regulatory alert in 2005 recommending cardiac left ventricular ejection fraction (LVEF) monitoring before administering each dose of the drug. Now, the accumulation of more safety data has impelled the FDA to issue an updated alert recommending long-term annual LVEF monitoring following completion of mitoxantrone treatment to detect late-occurring cardiotoxicity. Below, Neura has reprinted the relevant parts of the updated FDA alert (dated July 29, 2008) on cardiac management of patients with multiple sclerosis (MS) receiving mitoxantrone.

Visit www.fda.gov/cder/drug/InfoSheets/HCP/mitroxantroneHCP.htm for the complete alert.

FDA ALERT [7/29/2008]: FDA is informing healthcare professionals about additional recommendations for cardiac monitoring and reminding of the importance of monitoring cardiac function in patients with MS who are treated with mitoxantrone.

In March 2005, the labeling for mitoxantrone was changed to recommend that LVEF be evaluated before initiating treatment and prior to administering each dose of mitoxantrone to patients with MS. These changes were established in response to post-marketing reports and case reports in the medical literature that described decreases in LVEF or frank congestive heart failure in patients with MS who had received cumulative doses of mitoxantrone that were lower than 100 mg/m².

Since that time, FDA has received information from a post-marketing safety study that demonstrated there is poor adherence to these recommendations in clinical practice. FDA is working with the manufacturers to educate healthcare providers to adhere to cardiac monitoring recommendations for patients with MS.

In addition to adherence to the recommendations made in 2005, FDA and the manufacturers of mitoxantrone are now advising that all patients with MS who have finished treatment with mitoxantrone receive yearly quantitative LVEF evaluation to detect late-occurring cardiac toxicity.

This information reflects FDA�s current analysis of available data concerning this drug. FDA intends to update this document when additional information or analyses become available.

To report any unexpected adverse reactions or serious events associated with the use of this drug, please contact the FDA MedWatch program and complete a form online at: www.fda.gov/medwatch/report.htm, or report by fax to 1-800-FDA-0178, by mail using the postage-paid FDA form 3500 available at: www.fda.gov/MedWatch/getforms.htm or by telephone to 1-800-FDA-1088

Considerations: Congestive heart failure (CHF), potentially fatal, may occur either during therapy with mitoxantrone or months to years after termination of therapy. The risk of cardiotoxicity increases with increasing cumulative doses and may occur whether or not risk factors for cardiac disease are present. To mitigate this risk, prescribers should consider the following:

Assess signs and symptoms of cardiac disease by history, physical examination, and ECG prior to initiating therapy with mitoxantrone and before each succeeding dose.
Perform a baseline quantitative evaluation of LVEF using an appropriate methodology (eg, echocardiogram, multigated radionuclide angiography, MRI).
Patients with baseline LVEF below lower limit of normal should not be treated with mitoxantrone.
Patients should undergo a quantitative reevaluation of LVEF prior to each dose using the same methodology for each assessment. Additional doses of mitoxantrone should not be administered to patients who have experienced either a drop in LVEF to below the lower limit of normal or a clinically significant reduction in LVEF during mitoxantrone therapy.
Patients should not receive a cumulative mitoxantrone dose greater than 140 mg/m².
Patients should undergo yearly quantitative LVEF evaluation (by the same methods used during treatment) after stopping mitoxantrone to monitor for late-occurring cardiotoxicity.

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