mitoXANTRONE

INDICATIONS AND USAGE Mitoxantrone injection, USP (concentrate) is indicated for reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis (i.e., patients whose neurologic status is significantly abnormal between relapses). Mitoxantrone injection, USP (concentrate) is not indicated in the treatment of patients with primary progressive multiple sclerosis. The clinical patterns of multiple sclerosis in the studies were characterized as follows: secondary progressive and progressive relapsing disease were characterized by gradual increasing disability with or without superimposed clinical relapses, and worsening relapsing-remitting disease was characterized by clinical relapses resulting in a step-wise worsening of disability. Mitoxantrone injection, USP (concentrate) in combination with corticosteroids is indicated as initial chemotherapy for the treatment of patients with pain related to advanced hormone-refractory prostate cancer. Mitoxantrone injection, USP (concentrate) in combination with other approved drug(s) is indicated in the initial therapy of acute nonlymphocytic leukemia (ANLL) in adults. This category includes myelogenous, promyelocytic, monocytic, and erythroid acute leukemias.

DOSAGE AND ADMINISTRATION (See also WARNINGS .) Multiple Sclerosis The recommended dosage of mitoxantrone injection (concentrate) is 12 mg/m 2 given as a short (approximately 5 to 15 minutes) intravenous infusion every 3 months. Left ventricular ejection fraction (LVEF) should be evaluated by echocardiogram or MUGA prior to administration of the initial dose of mitoxantrone injection (concentrate) and all subsequent doses. In addition, LVEF evaluations are recommended if signs or symptoms of congestive heart failure develop at any time during treatment with mitoxantrone injection (concentrate). Mitoxantrone injection (concentrate) should not be administered to multiple sclerosis patients with an LVEF 140 mg/m 2 . Complete blood counts, including platelets, should be monitored prior to each course of mitoxantrone injection (concentrate) and in the event that signs or symptoms of infection develop. Mitoxantrone injection (concentrate) generally should not be administered to multiple sclerosis patients with neutrophil counts less than 1500 cells/mm 3 . Liver function tests should also be monitored prior to each course. Mitoxantrone injection (concentrate) therapy in multiple sclerosis patients with abnormal liver function tests is not recommended because mitoxantrone injection (concentrate) clearance is reduced by hepatic impairment and no laboratory measurement can predict drug clearance and dose adjustments. 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 mitoxantrone injection (concentrate) (see WARNINGS, Pregnancy ). Hormone-Refractory Prostate Cancer Based on data from two Phase 3 comparative trials of mitoxantrone injection (concentrate) plus corticosteroids versus corticosteroids alone, the recommended dosage of mitoxantrone injection (concentrate) is 12 to 14 mg/m 2 given as a short intravenous infusion every 21 days. Combination Initial Therapy for ANLL in Adults For induction, the recommended dosage is 12 mg/m 2 of mitoxantrone injection (concentrate) daily on Days 1 to 3 given as an intravenous infusion, and 100 mg/m 2 of cytarabine for 7 days given as a continuous 24 hour infusion on Days 1 to 7. Most complete remissions will occur following the initial course of induction therapy. In the event of an incomplete antileukemic response, a second induction course may be given. Mitoxantrone injection (concentrate) should be given for 2 days and cytarabine for 5 days using the same daily dosage levels. If severe or life-threatening nonhematologic toxicity is observed during the first induction course, the second induction course should be withheld until toxicity resolves. Consolidation therapy which was used in two large randomized multicenter trials consisted of mitoxantrone injection (concentrate), 12 mg/m 2 given by intravenous infusion daily on Days 1 and 2 and cytarabine, 100 mg/m 2 for 5 days given as a continuous 24 hour infusion on Days 1 to 5. The first course was given approximately 6 weeks after the final induction course; the second was generally administered 4 weeks after the first. Severe myelosuppression occurred (see CLINICAL PHARMACOLOGY ). Hepatic Impairment For patients with hepatic impairment, there is at present no laboratory measurement that allows for dose adjustment recommendations (see CLINICAL PHARMACOLOGY, Special Populations, Hepatic Impairment ). Preparation and Administration Precautions MITOXANTRONE INJECTION CONCENTRATE MUST BE DILUTED PRIOR TO USE. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. The dose of mitoxantrone injection (concentrate) should be diluted to at least 50 mL with either 0.9% Sodium Chloride Injection (USP) or 5% Dextrose Injection (USP). Mitoxantrone injection (concentrate) may be further diluted into …

CONTRAINDICATIONS Mitoxantrone injection (concentrate) is contraindicated in patients who have demonstrated prior hypersensitivity to it.

ADVERSE REACTIONS Multiple Sclerosis Mitoxantrone injection has been administered to 149 patients with multiple sclerosis in two randomized clinical trials, including 21 patients who received mitoxantrone injection 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/m 2 mitoxantrone injection 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 mitoxantrone injection 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 mitoxantrone injection 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/m 2 group). Of note, alopecia consisted of mild hair thinning. Two of the 127 patients treated with mitoxantrone injection in Study 1 had decreased LVEF to below 50% at some point during the 2 years of treatment. An additional patient receiving 12 mg/m 2 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 Mitoxantrone Injection and That Were Numerically Greater Than in the Placebo Group Study 1 Percent of Patients Preferred Term Placebo (N = 64) 5 mg/m 2 Mitoxantrone Injection (N = 65) 12 mg/m 2 Mitoxantrone Injection (N = 62) Nausea 20 55 76 Alopecia 31 38 61 Menstrual disorder Percentage of female patients. 26 51 61 Amenorrhea 3 28 43 Upper respiratory tract infection 52 51 53 Urinary tract infection 13 29 32 Stomatitis 8 15 19 Arrhythmia 8 6 18 Diarrhea 11 25 16 Urine abnormal 6 5 11 ECG abnormal 3 5 11 Constipation 6 14 10 Back pain 5 6 8 Sinusitis 2 3 6 Headache 5 6 6 The proportion of patients experiencing any infection during Study 1 was 67% for the placebo group, 85% for the 5 mg/m 2 group, and 81% for the 12 mg/m 2 group. However, few of these infections required hospitalization: one placebo patient (tonsillitis), three 5 mg/m 2 patients (enteritis, urinary tract infection, viral infection), and four 12 mg/m 2 patients (tonsillitis, urinary tract infection [two], endometritis). Table 4b summarizes laboratory abnormalities that occurred in ≥ 5% of patients in either mitoxantrone injection dose group, and that were numerically more frequent than in the placebo group. Table 4b: Laboratory Abnormalities Occurring in ≥ 5% of Patients* on Either Dose of Mitoxantrone Injection and That Were More Frequent Than in the Placebo Group Study 1 Percent of Patients Event Placebo (N = 64) 5 mg/m 2 Mitoxantrone Injection (N = 65) 12 mg/m 2 Mitoxantrone Injection (N = 62) Leukopenia a 0 9 19 Gamma-GT increased 3 3 15 SGOT increased 8 9 8 Granulocytopenia b 2 6 6 Anemia 2 9 6 SGPT increased 3 6 5 * Assessed using World Health Organization (WHO) toxicity criteria. a 5% of patients in the mitoxantrone injection group and numerically more frequent than in the control group. Table 5a: Adverse Events of Any Intensity Occurring in > 5% of Patients* in the Mitoxantrone Injection Group and Numerically More Frequent Than in the Control Group Study 2 Percent of Patients Event MP (n = 21) M + MP (n = 21) Amenorrhea a 0 53 Alopecia 0 33 Nausea 0 29 Asthenia 0 24 Pharyngitis/throat infection 5 19 Gastralgia/stomach burn/epigastric pain 5 14 Aphthosis 0 10 Cutaneous mycosis 0 10 Rhinitis 0 10 Menorrhagi …

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, postmarketing experience has not revealed any significant drug interactions in patients who have received mitoxantrone injection for treatment of cancer. Information on drug interactions in patients with multiple sclerosis is limited. Following concurrent administration of mitoxantrone injection with corticosteroids, no evidence of drug interactions has been observed.

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. Mitoxantrone injection 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.

DESCRIPTION Mitoxantrone Injection, USP (concentrate) is a synthetic antineoplastic anthracenedione for intravenous use. The molecular formula is C 22 H 28 N 4 O 6 ∙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 metabisulfite (0.01% w/v), sodium acetate (0.005% w/v), acetic acid (0.046% w/v), and Water for Injection, USP 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: Chemical Structure

OVERDOSAGE There is no known specific antidote for mitoxantrone injection. Accidental overdoses have been reported. Four patients receiving 140 to 180 mg/m 2 as a single bolus injection died as a result of severe leukopenia with infection. Hematologic support and antimicrobial therapy may be required during prolonged periods of severe myelosuppression. Although patients with severe renal failure have not been studied, mitoxantrone injection is extensively tissue bound and it is unlikely that the therapeutic effect or toxicity would be mitigated by peritoneal or hemodialysis.

HOW SUPPLIED Mitoxantrone injection, USP (concentrate) is a sterile aqueous solution containing mitoxantrone hydrochloride, USP at a concentration equivalent to 2 mg mitoxantrone free base per mL supplied in vials for multi-dose use as follows: NDC Mitoxantrone Injection, USP (2 mg per mL) Package Factor 71288- 178 -10 20 mg per 10 mL Multi-Dose Vial 1 vial per carton 71288- 179 -13 25 mg per 12.5 mL Multi-Dose Vial 1 vial per carton Mitoxantrone injection, USP (concentrate) should be stored at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] DO NOT FREEZE. Sterile, Nonpyrogenic, Preservative-free. The container closure is not made with natural rubber latex. Additional Medication Guides are available at http://www.meithealpharma.com or call 1-844-824-8426.