ceiving Novantrone, one receiving a 5 mg/m2 dose and the other receiving the 12 mg/m2 dose, had LVEF values that decreased to below 50%. An additional patient receiving 12 mg/m2, who did not have LVEF measured, had a decrease in another echocardiographic measurement of ventricular function (fractional shortening) that led to discontinuation from the trial (see ADVERSE REACTIONS, Multiple Sclerosis). There were no reports of congestive heart failure in either controlled trial.
MS patients should be assessed for cardiac signs and symptoms by history, physical examination, ECG, and quantitative LVEF eva luation using appropriate methodology (ex. Echocardiogram, MUGA, MRI, etc.) prior to the start of Novantrone therapy. MS patients with a baseline LVEF below the lower limit of normal should not be treated with Novantrone. Subsequent LVEF and ECG eva luations are recommended if signs or symptoms of congestive heart failure develop and prior to every dose administered to MS patients. Novantrone should not be administered to MS patients who experience a reduction in LVEF to below the lower limit of normal, to those who experience a clinically significant reduction in LVEF, or to those who have received a cumulative lifetime dose of 140 mg/m2. MS patients should have yearly quantitative LVEF eva luation after stopping Novantrone to monitor for late-occurring cardiotoxicity.
Leukemia
Acute congestive heart failure may occasionally occur in patients treated with Novantrone for ANLL. In first-line comparative trials of Novantrone + cytarabine vs daunorubicin + cytarabine in adult patients with previously untreated ANLL, therapy was associated with congestive heart failure in 6.5% of patients on each arm. A causal relationship between drug therapy and cardiac effects is difficult to establish in this setting since myocardial function is frequently depressed by the anemia, fever and infection, and hemorrhage that often accompany the underlying disease.
Hormone-Refractory Prostate Cancer
Functional cardiac changes such as decreases in LVEF and congestive heart failure may occur in patients with hormone-refractory prostate cancer treated with Novantrone. In a randomized comparative trial of Novantrone plus low-dose prednisone vs low-dose prednisone, 7 of 128 patients (5.5 %) treated with Novantrone had a cardiac event defined as any decrease in LVEF below the normal range, congestive heart failure (n = 3), or myocardial ischemia. Two patients had a prior history of cardiac disease. The total Novantrone dose administered to patients with cardiac effects ranged from > 48 to 212 mg/m2.
Among 112 patients eva luable for safety on the Novantrone + hydrocortisone arm of the CALGB trial, 18 patients (19%) had a reduction in cardiac function, 5 patients (5%) had cardiac ischemia, and 2 patients (2%) experienced pulmonary edema. The range of total Novantrone doses administered to these patients is not available.
Pregnancy
Novantrone may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant. Mitoxantrone is considered a potential human teratogen because of its mechanism of action and the developmental effects demonstrated by related agents. Treatment of pregnant rats during the organogenesis period of gestation was associated with fetal growth retardation at
