Serono sent to healthcare professionals a supplement information concerning the risks of cardiotoxicity associated with Novantrone ( Mitoxantrone for injection concentrate ) treatment for multiple sclerosis ( MS ) and also provides supplemental information regarding secondary acute myelogenous leukemia ( AML ) reported in multiple sclerosis patients treated with Novantrone
Reports received through post-marketing surveillance, have shown that diminished cardiac function may occur early on in the treatment with Novantrone.

Therefore, the Product Labeling for Novantrone was updated in March 2005 to state that cardiac monitoring of MS patients should be performed at baseline and prior to administration of every dose of Novantrone.

Novantrone is indicated for reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary ( chronic ) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis ( i.e., patients whose neurologic status is significantly abnormal between relapses ). Novantrone is not indicated in the treatment of patients with primary progressive multiple sclerosis.

Use of Novantrone has been associated with cardiotoxicity.
Cardiotoxicity can occur at any time during Novantrone therapy, and the risk increases with cumulative dose. Congestive heart failure ( CHF ), potentially fatal, may occur either during therapy with Novantrone or months to years after termination of therapy. All patients should be carefully assessed for cardiac signs and symptoms by history and physical examination prior to start of Novantrone therapy.
Baseline evaluation of left ventricular ejection fraction ( LVEF ) by echocardiogram or multi-gated radionuclide angiography ( MUGA ) should be performed.
Multiple sclerosis patients with a baseline LVEF <50% should not be treated with Novantrone.
LVEF should be reevaluated by echocardiogram or MUGA prior to each dose administered to patients with multiple sclerosis.

Additional doses of Novantrone should not be administered to multiple sclerosis patients who have experienced either a drop in LVEF to below 50% or a clinically significant reduction in LVEF during Novantrone therapy. Patients with multiple sclerosis should not receive a cumulative dose greater than 140mg/m2.

In cancer patients, the risk of symptomatic congestive heart failure ( CHF ) was estimated to be 2.6% for patients receiving up to a cumulative dose of 140mg/m2.

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. Cardiac toxicity with Novantrone may occur whether or not cardiac risk factors are present.

Secondary acute myelogenous leukemia ( AML ) has been reported in multiple sclerosis and cancer patients treated with Mitoxantrone. In a cohort of Mitoxantrone treated MS patients followed for varying periods of time, an elevated leukemia risk of 0.25% ( 2/802 ) has been observed. postmarketing cases of secondary AML have also been reported.
In 1774 patients with breast cancer who received Novantrone concomitantly with other cytotoxic agents and radiotherapy, the cumulative risk of developing treatment-related AML, was estimated as 1.1% and 1.6% at 5 and 10 years, respectively.
Secondary acute myelogeneous leukemia ( AML ) has been reported in cancer patients treated with anthracyclines.
Novantrone is an anthracenedione, a related drug.
The occurrence of refractory secondary leukemia is more common when anthracyclines are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated.

Cases of secondary AML in multiple sclerosis patients treated with Novantrone have been reported in peer-reviewed literature, through the collection of spontaneous reports, and in a prospective observational study.
Because the number of multiple sclerosis patients exposed to Novantrone in post-marketing is unknown and because spontaneous reporting of adverse events can be subject to under-reporting, it is not possible to determine incidence—or relative risk to an MS patient—of developing secondary AML.

Effects in Worsening MS ( RENEW ) is an ongoing 5-year, post-marketing, observational study involving a cohort of 505 patients with worsening relapsing-remitting, secondary progressive, or progressive-relapsing MS.
Since initiation of patient enrollment in April 2001, there has been one case of secondary AML reported, involving a 52-year-old female with secondary progressive multiple sclerosis.
She had received a cumulative total of 72 mg/m2 of Novantrone, in six infusions given from August 2001 to December 2002, when she was noted to be neutropenic, at which time her treatment with Novantrone was stopped.
In May 2004, she was noted to have peripheral blasts and bone marrow biopsy confirmed AML.
This patient had no other known risk factors for leukemia and no concomitant potentially cytotoxic drugs were listed.
Her AML was considered probably related to Novantrone.
Since treatment with Idarubicin and Ara-C, she has been in remission.
Based on this case, the incidence rate in this study is increased as compared to a non-exposed matched population.
Because of the risk of secondary AML, strict adherence to existing blood cell count monitoring recommendations for patients being treated with Novantrone for MS should be followed with complete blood counts, including platelets, prior to each course of Novantrone and in the event that signs or symptoms of infection develop.

Novantrone generally should not be administered to MS patients with neutrophil counts less than 1500 cells/mm3.
Also, regular blood cell counts should be monitored after discontinuation of Novantrone therapy.

Source: FDA, 2005


XagenaMedicine2005