Pregnancy
Pregnancy Category D (see WARNINGS).

Nursing Mothers
Novantrone is excreted in human milk and significant concentrations (18 ng/mL) have been reported for 28 days after the last administration.  Because of the potential for serious adverse reactions in infants from Novantrone, breast feeding should be discontinued before starting treatment.

Pediatric Use:
Safety and effectiveness in pediatric patients have not been established.

Geriatric Use:
Multiple Sclerosis: Clinical studies of Novantrone did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.  Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Hormone-Refractory Prostate Cancer: One hundred forty-six patients aged 65 and over and 52 younger patients (<65 years) have been treated with Novantrone in controlled clinical studies.  These studies did not include sufficient numbers of younger patients to determine whether they respond differently from older patients.  However, greater sensitivity of some older individuals cannot be ruled out.

Acute Nonlymphocytic Leukemia: Although definitive studies with Novantrone have not been performed in geriatric patients with ANLL, toxicity may be more frequent in the elderly.  Elderly patients are more likely to have age-related comorbidities due to disease or disease therapy.

Adverse Reactions
Multiple Sclerosis

Novantrone has been administered to 149 patients with multiple sclerosis in two randomized clinical trials, including 21 patients who received Novantrone in combination with corticosteroids.

In Study 1, the proportion of patients who discontinued treatment due to an adverse event was 9.7% (n = 6) in the 12 mg/m2 Novantrone arm (leukopenia, depression, decreased LV function, bone pain and emesis, renal failure, and one discontinuation to prevent future complications from repeated urinary tract infections) compared to 3.1% (n = 2) in the placebo arm (hepatitis and myocardial infarction).  The following clinical adverse experiences were significantly more frequent in the Novantrone groups:  nausea, alopecia, urinary tract infection, and menstrual disorders, including amenorrhea.

Table 4a summarizes clinical adverse events of all intensities occurring in ≥ 5% of patients in either dose group of Novantrone and that were numerically greater on drug than on placebo in Study 1.  The majority of these events were of mild to moderate intensity, and nausea was the only adverse event that occurred with severe intensity in more than one patient (three patients [5%] in the 12 mg/m2 group).  Of note, alopecia consisted of mild hair thinning.

Two of the 127 patients treated with Novantrone in Study 1 had decreased LVEF to below 50% at some point during the 2 years of treatment.  An additional patient receiving 12 mg/m2 did not have LVEF measured, but had another echocardiographic measure of ventricular function (fractional shortening) that led to discontinuation from the study.

Table 4a Adverse Events of Any Intensity Occurring in ≥ 5% of Patients on Any Dose of Novantrone and That Were Numerically Greater Than in the Placebo Group Study 1