doses ≥ 0.1 mg/kg/day (0.01 times the recommended human dose on a mg/m2 basis). When pregnant rabbits were treated during organogenesis, an increased incidence of premature delivery was observed at doses ≥ 0.1 mg/kg/day (0.01 times the recommended human dose on a mg/m2 basis). No teratogenic effects were observed in these studies, but the maximum doses tested were well below the recommended human dose (0.02 and 0.05 times in rats and rabbits, respectively, on a mg/m2 basis). There are no adequate and well-controlled studies in pregnant women. Women with multiple sclerosis who are biologically capable of becoming pregnant should have a pregnancy test prior to each dose, and the results should be known prior to administration of the drug. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to the fetus.
Secondary Leukemia
Novantrone® therapy increases the risk of developing secondary leukemia in patients with cancer and in patients with multiple sclerosis.
In a study of patients with prostate cancer, acute myeloid leukemia occurred in 1% (5/487) of mitoxantrone-treated patients versus no cases in the control group (0/496) not receiving mitoxantrone at 4.7 years followup.
In a prospective, open-label, tolerability and safety monitoring study of Novantrone® treated MS patients followed for up to five years (median of 2.8 years), leukemia occurred in 0.6% (3/509) of patients. Publications describe leukemia risks of 0.25% to 2.8% in cohorts of patients with MS treated with Novantrone® and followed for varying periods of time. This leukemia risk exceeds the risk of leukemia in the general population. The most commonly reported types were acute promyelocytic leukemia and acute myelocytic leukemia.
In 1774 patients with breast cancer who received Novantrone concomitantly with other cytotoxic agents and radiotherapy, the cumulative risk of developing treatment-related acute myeloid leukemia was estimated as 1.1% and 1.6% at 5 and 10 years, respectively. The second largest report involved 449 patients with breast cancer treated with Novantrone, usually in combination with radiotherapy and/or other cytotoxic agents. In this study, the cumulative probability of developing secondary leukemia was estimated to be 2.2% at 4 years.
Secondary acute myeloid leukemia has also been reported in cancer patients treated with anthracyclines. Novantrone is an anthracenedione, a related drug. The occurrence of 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.
Symptoms of acute leukemia may include excessive bruising, bleeding, and recurrent infections.
Precautions
General
Therapy with Novantrone should be accompanied by close and frequent monitoring of hematologic and chemical laboratory parameters, as well as frequent patient observation.
Systemic infections should be treated concomitantly with or just prior to commencing therapy with Novantrone.
Information for Patients
Novantrone may impart a blue-green color to the urine for 24 hours after administration, and patients should be advised to expect this during therapy. Bluish discolorati
