Patients with multiple sclerosis should be provided with the Patient Package Insert at the time that the decision is made to treat with Novantrone and prior to and in close temporal proximity to each treatment.  In addition, the physician should discuss the issues addressed in the Patient Package Insert with the patient.

Laboratory Tests
A complete blood count, including platelets, should be obtained prior to each course of Novantrone and in the event that signs and symptoms of infection develop.  Liver function tests should also be performed prior to each course of therapy.  Novantrone therapy in multiple sclerosis patients with abnormal liver function tests is not recommended because Novantrone clearance is reduced by hepatic impairment and no laboratory measurement can predict drug clearance and dose adjustments.

In leukemia treatment, hyperuricemia may occur as a result of rapid lysis of tumor cells by Novantrone.  Serum uric acid levels should be monitored and hypouricemic therapy instituted prior to the initiation of antileukemic therapy.

Women with multiple sclerosis who are biologically capable of becoming pregnant, even if they are using birth control, should have a pregnancy test, and the results should be known, before receiving each dose of Novantrone (see WARNINGS, Pregnancy).

Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis

Intravenous treatment of rats and mice, once every 21 days for 24 months, with Novantrone resulted in an increased incidence of fibroma and external auditory canal tumors in rats at a dose of 0.03 mg/kg (0.02 fold the recommended human dose, on a mg/m2 basis), and hepatocellular adenoma in male mice at a dose of 0.1 mg/kg (0.03 fold the recommended human dose, on a mg/m2 basis).  Intravenous treatment of rats, once every 21 days for 12 months with Novantrone resulted in an increased incidence of external auditory canal tumors in rats at a dose of 0.3 mg/kg (0.15 fold the recommended human dose, on a mg/m2 basis).

Mutagenesis

Novantrone was clastogenic in the in vivo rat bone marrow assay.  Novantrone was also clastogenic in two in vitro assays; it induced DNA damage in primary rat hepatocytes and sister chromatid exchanges in Chinese hamster ovary cells.  Novantrone was mutagenic in bacterial and mammalian test systems (Ames/Salmonella and E. coli and L5178Y TK+/-mouse lymphoma).

Drug Interactions
Mitoxantrone and its metabolites are excreted in bile and urine, but it is not known whether the metabolic or excretory pathways are saturable, may be inhibited or induced, or if mitoxantrone and its metabolites undergo enterohepatic circulation.  To date, post-marketing experience has not revealed any significant drug interactions in patients who have received Novantrone for treatment of cancer.  Information on drug interactions in patients with multiple sclerosis is limited.

Following concurrent administration of Novantrone with corticosteroids, no evidence of drug interactions has been observed.

Special Populations

Hepatic Impairment

Patients with multiple sclerosis who have hepatic impairment should ordinarily not be treated with Novantrone.  Novantrone should be administered with caution to other patients with hepatic impairment.  In patients with severe h