The government has ordered that a boxed warning be added to the labeling of the multiple sclerosis medication, Novantrone (mitoxantrone/Serono). The warning includes additional information about the potential risk of heart damage and a form of leukemia known as secondary acute myelogenous leukemia (AML) for those taking the medication.
Novantrone was approved in 2000 as a treatment to reduce neurological disability and/or the frequency of relapses in people with secondary/progressive, progressive-relapsing, and worsening relapsing-remitting multiple sclerosis.1 Heart problems can result in people who use the medication, but according to its manufacturer, Serono, and other medical experts, that risk at recommended doses is small.2,3
Precautionary Steps
Still, Serono says doctors typically conduct heart tests before prescribing Novantrone, and take repeat tests before each dose is given. Because of this potential risk, the drug's original prescribing information indicated that only those with normal heart function should receive a prescription and that a maximum cumulative dose of 140 mg/m2 (about 8 to 12 doses over 2 to 3 years) should be prescribed. The labeling also required that patients be carefully assessed prior to starting treatment with Novantrone, including an evaluation of left ventricular ejection fraction, or LVEF. That test measures the ability of the left ventricle in the heart to contract, and tells doctors how much blood is being pumped out by the heart with each beat.4 A low ejection fraction is an indicator of cardiac dysfunction. Those with an ejection fraction below 50% are not candidates for Novantrone, according to the labeling.
The original labeling also included information about the possible risk of secondary acute myeloid leukemia (AML). Though no cases of the disease occurred in clinical trials of the drug, AML was known to occur in breast cancer patients who had been treated with significantly higher doses of Novantrone.5
Since the medication's approval, post-marking reports of adverse effects have indicated that impaired heart function can occur at any time, even early on in treatment, and the risk increases with each dose. Congestive heart failure risk was also reported, though Serono has stressed that these risks are very low when normal doses are used.
New Precautions
Nonetheless, the FDA has ordered additional warnings to Novantrone's prescribing information:
• Prior to starting treatment, patients should be carefully evaluated via examination and medical history for signs and symptoms of heart disease.
• An initial evaluation of LVEF should be performed.
• A person whose LVEF is lower than 50% should not be given Novantrone.
• LVEF should be re-tested prior to each dose of the medication.
• Any person whose LVEF changes significantly or drops below 50% should not be given Novantrone.
• Known factors that may increase the risk of a person's cardiac dysfunction using Novantrone include a current or prior history of heart disease, using other medications simultaneously with Novantrone that can damage the heart, and previous therapy with certain kinds of chemotherapies.
Post-marketing data have also been released on the risk of secondary AML relative to Novantrone use. In one group of MS patients treated with the medication, 2 of 802 patients developed AML. This represents a risk of about one-quarter of 1% (0.25%). The risk of leukemia following treatment with the medication is increased for patients who have been treated with other types of chemotherapies known as anthracyclines (ann-thruh-SYE-kleens).
Meanwhile, further patient follow-up studies are being conducted involving the use of the medication. The Registry to Evaluate Novantrone Effects in Worsening MS (RENEW) was established four years ago to follow a group of more than 500 people with MS using Novantrone. The observational analysis is set to last a total of five years.
1. Food and Drug Administration. FDA's Report on New Health Care Products Approved in 2000. Available at: http://www.fda.gov/bbs/topics/answers/2001/ANS01066.html. Accessed May 16, 2005.
2. Serono. Novantrone Patient Information. Available at: http://www.novantrone.com/patients_info.jsp. Accessed May 16, 2005.
3. Scott LJ, Figgitt DP. Mitoxantrone: a review of its use in multiple sclerosis. CNS Drugs 2004;18(6):379-96.
4. The Merck Manual. Heart Failure. Available at: http://www.merck.com/mmhe/sec03/ch025/ch025a.html?qt=left%20venticular%20ejection%20fraction&alt=sh. Accessed May 16, 2005.
5. Kroger N, Damon L, Zander AR et al. Secondary acute leukemia following mitoxantrone-based high-dose chemotherapy for primary breast cancer patients. Bone Marrow Transplant 2003 Dec;32(12):1153-7.
John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include overseeing health news coverage for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications.
