Though EMD Serono's Novantrone (mitoxantrone) injection is the only drug approved by the US Food and Drug Administration (FDA) for the treatment of secondary progressive multiple sclerosis (SPMS), progressive-relapsing multiple sclerosis (PRMS), or worsening relapsing-remitting multiple sclerosis (RRMS), its use is associated with significant risks.
Though EMD Serono’s Novantrone (mitoxantrone) injection is the only drug approved by the US Food and Drug Administration (FDA) for the treatment of secondary progressive multiple sclerosis (SPMS), progressive-relapsing multiple sclerosis (PRMS), or worsening relapsing-remitting multiple sclerosis (RRMS), its use is associated with significant risks, warnings, and side effects that include cardiotoxicity, treatment-related leukemia, and amenorrhea.
To better evaluate the drug’s long-term safety profile and the factors contributing to its risks in those three forms of the chronic neurological disorder, Victor M. Rivera from the Baylor College of Medicine in Houston, TX; researchers from Cornerstone Health Care in Advance, NC, and the University at Buffalo-State University of New York in Buffalo, NY; and two EMD Serono employees recently completed a five-year phase IV Registry to Evaluate Novantrone Effects in Worsening Multiple Sclerosis (RENEW) study and published the results in the July 11, 2013, edition of BMC Neurology.
For their clinical trial, the authors infused a mean cumulative intravenous dose of 69.8 mg/m2 of mitoxantrone — a synthetic anthracenedione agent that inhibits the proliferation of T cells, B cells, and macrophages — in 395 patients diagnosed with SPMS, 33 patients with PRMS, and 81 patients with worsening RRMS across 46 multiple sclerosis (MS) treatment centers in the United States; however, only 33.8 percent of the cohort completed the RENEW study. In response to an FDA request, the researchers also conducted post-hoc analyses in all patients to assess the potential factors contributing to cardiotoxicity.
According to the authors, the main study results were “consistent with previous reports (that) mitoxantrone therapy in MS patients is associated with significant side effects,” as 31 patients experienced left ventricular ejection fraction reduction under 50 percent either during the treatment phase or during the annual follow-up phase; 10 patients experienced signs and symptoms of congestive heart failure; three patients were diagnosed with therapy-related leukemia; and 32 female patients with regular menses at baseline developed persistent amenorrhea after receiving a mean cumulative dose of 52.1 mg/m2.
Additionally, the results of the post-hoc analyses clearly showed that “cumulative mitoxantrone dose is the primary risk factor associated with cardiotoxicity, (as) mean cumulative dose was higher in patients with cardiac events (93.9 mg/m2) than in those without cardiac events (63.7 mg/m2).”
“Use of mitoxantrone in worsening RRMS, transitional forms, and in patients no longer responding to first-line therapies should be cautiously considered,” the researchers concluded. “Prescribing physicians should stay on-label, use the lowest possible cumulative dose that achieves the desired clinical effect, and vigilantly monitor patients for clinical, cardiac, and neoplastic complications before every dose of mitoxantrone and annually following treatment.”