mitoxantrone 2 MG/ML Injectable Solution

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 < 50%, with a clinically significant reduction in LVEF, or to those who have received a cumulative lifetime dose of > 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 Dextrose 5% in Water, Normal Saline or Dextrose 5% with Normal Saline and used immediately. DO NOT FREEZE. Mitoxantrone injection (concentrate) should not be mixed in the same infusion as heparin since a precipitate may form. Because specific compatibility data are not available, it is recommended that mitoxantrone injection (concentrate) not be mixed in the same infusion with other drugs. The diluted solution should be introduced slowly into the tubing as a freely running intravenous infusion of 0.9% Sodium Chloride Injection (USP) or 5% Dextrose Injection (USP) over a period of not less than 3 minutes. Unused infusion solutions should be discarded immediately in an appropriate fashion. In the case of multidose use, after penetration of the stopper, the remaining portion of the undiluted mitoxantrone injection concentrate should be stored not longer than 7 days between 15° to 25°C (59° to 77°F) or 14 days under refrigeration. DO NOT FREEZE. CONTAINS NO PRESERVATIVE. Care in the administration of mitoxantrone injection (concentrate) will reduce the chance of extravasation. Mitoxantrone injection (concentrate) should be administered into the tubing of a freely running intravenous infusion of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. The tubing should be attached to a Butterfly needle or other suitable device and inserted preferably into a large vein. If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage. Care should be taken to avoid extravasation at the infusion site and to avoid contact of mitoxantrone injection (concentrate) with the skin, mucous membranes, or eyes. MITOXANTRONE INJECTION (CONCENTRATE) SHOULD NOT BE ADMINISTERED SUBCUTANEOUSLY. If any signs or symptoms of extravasation have occurred, including burning, pain, pruritis, erythema, swelling, blue discoloration, or ulceration, the injection or infusion should be immediately terminated and restarted in another vein. During intravenous administration of mitoxantrone injection (concentrate) extravasation may occur with or without an accompanying stinging or burning sensation even if blood returns well on aspiration of the infusion needle. If it is known or suspected that subcutaneous extravasation has occurred, it is recommended that intermittent ice packs be placed over the area of extravasation and that the affected extremity be elevated. Because of the progressive nature of extravasation reactions, the area of injection should be frequently examined and surgery consultation obtained early if there is any sign of a local reaction. Skin accidentally exposed to mitoxantrone injection (concentrate) should be rinsed copiously with warm water and if the eyes are involved, standard irrigation techniques should be used immediately. The use of goggles, gloves, and protective gowns is recommended during preparation and administration of the drug. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. 1-4 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

WARNINGS WHEN MITOXANTRONE INJECTION IS USED IN HIGH DOSES (> 14 mg/m 2 /d × 3 days) SUCH AS INDICATED FOR THE TREATMENT OF LEUKEMIA, SEVERE MYELOSUPPRESSION WILL OCCUR. THEREFORE, IT IS RECOMMENDED THAT MITOXANTRONE INJECTION BE ADMINISTERED ONLY BY PHYSICIANS EXPERIENCED IN THE CHEMOTHERAPY OF THIS DISEASE. LABORATORY AND SUPPORTIVE SERVICES MUST BE AVAILABLE FOR HEMATOLOGIC AND CHEMISTRY MONITORING AND ADJUNCTIVE THERAPIES, INCLUDING ANTIBIOTICS. BLOOD AND BLOOD PRODUCTS MUST BE AVAILABLE TO SUPPORT PATIENTS DURING THE EXPECTED PERIOD OF MEDULLARY HYPOPLASIA AND SEVERE MYELOSUPPRESSION. PARTICULAR CARE SHOULD BE GIVEN TO ASSURING FULL HEMATOLOGIC RECOVERY BEFORE UNDERTAKING CONSOLIDATION THERAPY (IF THIS TREATMENT IS USED) AND PATIENTS SHOULD BE MONITORED CLOSELY DURING THIS PHASE. MITOXANTRONE INJECTION ADMINISTERED AT ANY DOSE CAN CAUSE MYELOSUPPRESSION. General Patients with preexisting myelosuppression as the result of prior drug therapy should not receive mitoxantrone injection unless it is felt that the possible benefit from such treatment warrants the risk of further medullary suppression. The safety of mitoxantrone injection (concentrate) in patients with hepatic insufficiency is not established (see CLINICAL PHARMACOLOGY ). Safety for use by routes other than intravenous administration has not been established. Mitoxantrone injection is not indicated for subcutaneous, intramuscular, or intra-arterial injection. There have been reports of local/regional neuropathy, some irreversible, following intra-arterial injection. Mitoxantrone injection must not be given by intrathecal injection. There have been reports of neuropathy and neurotoxicity, both central and peripheral, following intrathecal injection. These reports have included seizures leading to coma and severe neurologic sequelae, and paralysis with bowel and bladder dysfunction. Topoisomerase II inhibitors, including mitoxantrone injection, have been associated with the development of secondary acute myeloid leukemia and myelosuppression. Cardiac Effects Because of the possible danger of cardiac effects in patients previously treated with daunorubicin or doxorubicin, the benefit-to-risk ratio of mitoxantrone injection therapy in such patients should be determined before starting therapy. Functional cardiac changes including decreases in left ventricular ejection fraction (LVEF) and irreversible congestive heart failure can occur with mitoxantrone injection. Cardiac toxicity may be more common in patients with prior treatment with anthracyclines, prior mediastinal radiotherapy, or with preexisting cardiovascular disease. Such patients should have regular cardiac monitoring of LVEF from the initiation of therapy. Cancer patients who received cumulative doses of 140 mg/m 2 either alone or in combination with other chemotherapeutic agents had a cumulative 2.6% probability of clinical congestive heart failure. In comparative oncology trials, the overall cumulative probability rate of moderate or severe decreases in LVEF at this dose was 13%. Multiple Sclerosis Changes in cardiac function may occur in patients with multiple sclerosis treated with mitoxantrone injection. In one controlled trial (Study 1, see CLINICAL TRIALS, Multiple Sclerosis ), two patients (2%) of 127 receiving mitoxantrone injection, one receiving a 5 mg/m 2 dose and the other receiving the 12 mg/m 2 dose, had LVEF values that decreased to below 50%. An additional patient receiving 12 mg/m 2 , who did not have LVEF measured, had a decrease in another echocardiographic measurement of ventricular function (fractional shortening) that led to discontinuation from the trial (see ADVERSE REACTIONS, Multiple Sclerosis ). There were no reports of congestive heart failure in either controlled trial. MS patients should be assessed for cardiac signs and symptoms by history, physical examination, ECG, and quantitative LVEF evaluation using appropriate methodology (ex. Echocardiogram, MUGA, MRI, etc.) prior to the start of mitoxantrone injection therapy. MS patients with a baseline LVEF below the lower limit of normal should not be treated with mitoxantrone injection. Subsequent LVEF and ECG evaluations are recommended if signs or symptoms of congestive heart failure develop and prior to every dose administered to MS patients. Mitoxantrone injection should not be administered to MS patients who experience a reduction in LVEF to below the lower limit of normal, to those who experience a clinically significant reduction in LVEF, or to those who have received a cumulative lifetime dose of 140 mg/m 2 . MS patients should have yearly quantitative LVEF evaluation after stopping mitoxantrone injection to monitor for late-occurring cardiotoxicity. Leukemia Acute congestive heart failure may occasionally occur in patients treated with mitoxantrone injection for ANLL. In first-line comparative trials of mitoxantrone injection + cytarabine vs. daunorubicin + cytarabine in adult patients with previously untreated ANLL, therapy was associated with congestive heart failure in 6.5% of patients on each arm. A causal relationship between drug therapy and cardiac effects is difficult to establish in this setting since myocardial function is frequently depressed by the anemia, fever and infection, and hemorrhage that often accompany the underlying disease. Hormone-Refractory Prostate Cancer Functional cardiac changes such as decreases in LVEF and congestive heart failure may occur in patients with hormone-refractory prostate cancer treated with mitoxantrone injection. In a randomized comparative trial of mitoxantrone injection plus low-dose prednisone vs. low-dose prednisone, 7 of 128 patients (5.5 %) treated with mitoxantrone injection had a cardiac event defined as any decrease in LVEF below the normal range, congestive heart failure (n = 3), or myocardial ischemia. Two patients had a prior history of cardiac disease. The total mitoxantrone injection dose administered to patients with cardiac effects ranged from > 48 to 212 mg/m 2 . Among 112 patients evaluable for safety on the mitoxantrone injection + hydrocortisone arm of the CALGB trial, 18 patients (19%) had a reduction in cardiac function, 5 patients (5%) had cardiac ischemia, and 2 patients (2%) experienced pulmonary edema. The range of total mitoxantrone injection doses administered to these patients is not available. Pregnancy Mitoxantrone injection may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant. Mitoxantrone is considered a potential human teratogen because of its mechanism of action and the developmental effects demonstrated by related agents. Treatment of pregnant rats during the organogenesis period of gestation was associated with fetal growth retardation at doses ≥ 0.1 mg/kg/day (0.01 times the recommended human dose on a mg/m 2 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/m 2 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/m 2 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 Mitoxantrone injection 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

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

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.