Novantrone® therapy in patients with MS and in patients with cancer increases the risk of developing secondary acute myeloid leukemia.

For additional information, see WARNINGS and DOSAGE AND ADMINISTRATION.

Novantrone Description
Novantrone® (mitoxantrone hydrochloride) is a synthetic antineoplastic anthracenedione for intravenous use.  The molecular formula is C22H28N4O6•2HCl and the molecular weight is 517.41.  It is supplied as a concentrate that MUST BE DILUTED PRIOR TO INJECTION.  The concentrate is a sterile, nonpyrogenic, dark blue aqueous solution containing mitoxantrone hydrochloride equivalent to 2 mg/mL mitoxantrone free base, with sodium chloride (0.80% w/v), sodium acetate (0.005% w/v), and acetic acid (0.046% w/v) as inactive ingredients.  The solution has a pH of 3.0 to 4.5 and contains 0.14 mEq of sodium per mL.  The product does not contain preservatives.  The chemical name is 1,4-dihydroxy-5,8-bis[[2-[(2-hydroxyethyl) amino]ethyl]amino]-9,10-anthracenedione dihydrochloride and the structural formula is:
Novantrone - Clinical Pharmacology
Mechanism of Action
Mitoxantrone, a DNA-reactive agent that intercalates into deoxyribonucleic acid (DNA) through hydrogen bonding, causes crosslinks and strand breaks.  Mitoxantrone also interferes with ribonucleic acid (RNA) and is a potent inhibitor of topoisomerase II, an enzyme responsible for uncoiling and repairing damaged DNA.  It has a cytocidal effect on both proliferating and nonproliferating cultured human cells, suggesting lack of cell cycle phase specificity.

Novantrone® has been shown in vitro to inhibit B cell, T cell, and macrophage proliferation and impair antigen presentation, as well as the secretion of interferon gamma, TNFα, and IL-2.

Pharmacokinetics
Pharmacokinetics of mitoxantrone in patients following a single intravenous administration of Novantrone® can be characterized by a three-compartment model.  The mean alpha half-life of mitoxantrone is 6 to 12 minutes, the mean beta half-life is 1.1 to 3.1 hours and the mean gamma (terminal or elimination) half-life is 23 to 215 hours (median approximately 75 hours).  Pharmacokinetic studies have not been performed in humans receiving multiple daily dosing.  Distribution to tissues is extensive:  steady-state volume of distribution exceeds 1,000 L/m2.  Tissue concentrations of mitoxantrone appear to exceed those in the blood during the terminal elimination phase.  In the healthy monkey, distribution to brain, spinal cord, eye, and spinal fluid is low.

In patients administered 15-90 mg/m2 of Novantrone intravenously, there is a linear relationship between dose and the area under the concentration-time curve (AUC).

Mitoxantrone is 78% bound to plasma proteins in the observed concentration range of 26-455 ng/mL.  This binding is independent of concentration and is not affected by the presence of phenytoin, doxorubicin, methotrexate, prednisone, prednisolone, heparin, or aspirin.

Metabolism and Elimination

Mitoxantrone is excreted in urine and feces as either unchanged drug or as inactive metabolites.  In human studies, 11% and 25% of the dose were recovered in urine and feces, respectively, as either parent drug or metabolite during the 5-day period following drug administration.  Of the mater