Special Populations

Gender

The effect of gender on mitoxantrone pharmacokinetics is unknown.

Geriatric

In elderly patients with breast cancer, the systemic mitoxantrone clearance was 21.3 L/hr/m2, compared with 28.3 L/hr/m2 and 16.2 L/hr/m2 for non-elderly patients with nasopharyngeal carcinoma and malignant lymphoma, respectively.

Pediatric

Mitoxantrone pharmacokinetics in the pediatric population are unknown.

Race

The effect of race on mitoxantrone pharmacokinetics is unknown.

Renal Impairment

Mitoxantrone pharmacokinetics in patients with renal impairment are unknown.

Hepatic Impairment

Mitoxantrone clearance is reduced by hepatic impairment.  Patients with severe hepatic dysfunction (bilirubin > 3.4 mg/dL) have an AUC more than three times greater than that of patients with normal hepatic function receiving the same dose.  Patients with multiple sclerosis who have hepatic impairment should ordinarily not be treated with Novantrone.  Other patients with hepatic impairment should be treated with caution and dosage adjustment may be required.

Drug Interactions: In vitro drug interaction studies have demonstrated that mitoxantrone did not inhibit CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 across a broad concentration range.  The results of in vitro induction studies are inconclusive, but suggest that mitoxantrone may be a weak inducer of CYP450 2E1 activity.

Pharmacokinetic studies of the interaction of Novantrone with concomitantly administered medications in humans have not been performed.  The pathways leading to the metabolism of Novantrone have not been elucidated.  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.

Clinical Trials
Multiple Sclerosis

The safety and efficacy of Novantrone in multiple sclerosis were assessed in two randomized, multicenter clinical studies.

One randomized, controlled study (Study 1) was conducted in patients with secondary progressive or progressive relapsing multiple sclerosis.  Patients in this study demonstrated significant neurological disability based on the Kurtzke Expanded Disability Status Scale (EDSS).  The EDSS is an ordinal scale with 0.5 point increments ranging from 0.0 to 10.0 (increasing score indicates worsening) and based largely on ambulatory impairment in its middle range (EDSS 4.5 to 7.5 points).  Patients in this study had experienced a mean deterioration in EDSS of about 1.6 points over the 18 months prior to enrollment.

Patients were randomized to receive placebo, 5 mg/m2 Novantrone, or 12 mg/m2 Novantrone administered IV every 3 months for 2 years.  High-dose methylprednisolone was administered to treat relapses.  The intent-to-treat analysis cohort consisted of 188 patients; 149 completed the 2-year study.  Patients were eva luated every 3 months, and clinical outcome was determined after 24 months.  In addition, a subset of patients was a