FDA ALERT [7/29/2008]: FDA is informing health care professionals about additional recommendations for cardiac monitoring and reminding of the importance of monitoring cardiac function in patients with multiple sclerosis (MS) who are treated with mitoxantrone.
In March 2005, the labeling for mitoxantrone was changed to recommend that left ventricular ejection fraction (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 multiple sclerosis (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 either online, by regular mail or by fax, using the contact information at the bottom of this page.
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:
For all patients:
- Assess signs and symptoms of cardiac disease by history and physical examination and ECG prior to initiating therapy with mitoxantrone.
- Perform a baseline quantitative evaluation of left ventricular ejection fraction (LVEF) using an appropriate methodology [e.g., echocardiogram, multi-gated radionuclide angiography (MUGA), MRI].
For patients with multiple sclerosis:
- Patients with a baseline LVEF below the lower limit of normal should not be treated with mitoxantrone.
- Patients should be assessed for cardiac signs and symptoms by history, physical examination and ECG prior to each dose.
- 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 after stopping mitoxantrone to monitor for late-occurring cardiotoxicity, using the same methodology that was used for assessments that were done during treatment.
For patients with cancer:
- The possible danger of cardiac effects in patients previously treated with daunorubicin or doxorubicin should be considered when weighing the benefits and risks of mitoxantrone for such patients prior to starting therapy.
- Presence or history of cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or concomitant use of other cardiotoxic drugs may increase the risk of cardiac toxicity. Patients with these risk factors should have regular monitoring of LVEF after the initiation of therapy.
Information for Patients with Multiple Sclerosis who are Receiving Mitoxantrone:
There is a risk that mitoxantrone can seriously injure your heart. The risk increases as the total amount of mitoxantrone you receive over your lifetime increases, but it can happen at any time during or after your treatment has ended. To reduce the risk of this injury, your heart function will be checked and the total amount of mitoxantrone that you receive over time will be limited. It is important that you understand this risk and talk with your healthcare provider if you have any questions. You should be aware of the following:
- Before you receive your first dose of mitoxantrone your healthcare provider will test your heart function to make sure that your heart is working properly.
- Your heart function will also be tested before each of the following doses of mitoxantrone and for some time after you have completed all of your treatments.
- You should keep track of how much mitoxantrone you receive at each treatment. Ask your doctor about the dose of mitoxantrone (how much) you will receive each time you come in for a treatment. You should not receive more than 140 mg/m2 of mitoxantrone during your lifetime.
Cardiotoxicity is a safety issue of concern for all patients treated with mitoxantrone. Since the product was first approved for use in 1996 in patients with advanced hormone-refractory prostate cancer and acute nonlymphocytic leukemia in adults, the product labeling has recommended that left ventricular ejection fraction (LVEF) be assessed by echocardiogram or multi-gated radionuclide angiography (MUGA) prior to initiating treatment. It was also recommended that patients believed to be at greater risk of cardiotoxicity (those previously treated with anthracyclines, those who received mediastinal radiotherapy, or those with preexisting cardiovascular disease) have regular LVEF monitoring for the duration of treatment.
In October 2000, the indication for use of mitoxantrone was expanded to include the treatment of patients with secondary (chronic) progressive, progressive relapsing or worsening relapsing-remitting multiple sclerosis (MS). In an effort to mitigate the cardiotoxic effects, the labeling at the time of FDA approval for the indication was amended to include recommendations to limit the cumulative lifetime dose to 140mg/m2 and to monitor LVEF prior to each dose in patients with MS who had reached a cumulative dose of <100mg/m2. FDA also required that the manufacturer conduct post-marketing safety studies in patients with MS that would provide additional information about cardiotoxicity and would assess compliance with monitoring recommendations.
Subsequently, one of the post-marketing studies and reports in the medical literature indicated that decreases in LVEF and frank congestive heart failure were occurring in some patients with MS who had received cumulative doses lower than 100mg/m2. As a result, in March 2005, the labeling for mitoxantrone was changed to recommend that LVEF be evaluated prior to initiating treatment and before administering each subsequent dose to patients with MS. A “Dear Healthcare Professional” letter announcing and describing the labeling change was issued and posted on FDA’s MedWatch site in April 2005.
The post-marketing safety study assessing compliance with the cardiac monitoring recommendations showed that quantitative LVEF monitoring is not being performed in a majority of patients with MS treated with mitoxantrone. This study used insurance claims data and medical record review to examine cardiac monitoring patterns in clinical practice. In this study it was noted that four patients developed congestive heart failure 4-17 months after completing therapy with mitoxantrone.
Given the potential severity of cardiotoxicity and evidence suggesting poor adherence to the recommendations for monitoring cardiac function, FDA is reminding healthcare professionals of the importance of cardiac monitoring in patients with MS who are treated with mitoxantrone. The FDA is currently working with the manufacturers of mitoxantrone to educate healthcare providers to adhere to cardiac monitoring recommendations for patients with MS.