Specialty Formalary
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It is used in the treatment of certain types of cancer, mostly metastatic breast cancer, acute myeloid leukemia, and non-Hodgkin's lymphoma. It was also shown to improve the survival of children suffering from first relapse of acute lymphoblastic leukaemia. The combination of mitoxantrone and prednisone is approved as a second-line treatment for metastatic hormone-refractory prostate cancer. This combination has been the first line of treatment, until recently, when combination of docetaxel and prednisone has been shown to improve survival and disease-free period. Mitoxantrone is also used to treat multiple sclerosis (MS), most notably the subset known as secondary progressive MS. Mitoxantrone will not cure multiple sclerosis, but is effective in slowing the progression of secondary progressive MS and extending the time between relapses in relapsing-remitting MS and progressive relapsing MS.
Adverse Effects: 
Multiple Sclerosis MITOXANTRONE has been administered to 149 patients with multiple sclerosis in two randomized clinical trials, including 21 patients who received MITOXANTRONE 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/m² MITOXANTRONE 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 groups: nausea, alopecia, urinary tract infection, and menstrual disorders, including amenorrhea. Two of the 127 patients treated with MITOXANTRONE in Study 1 had decreased LVEF to below 50% at some point during the 2 years of treatment. An additional patient receiving 12 mg/m² did not have LVEF measured, but had another echocardiographic measure of ventricular function (fractional shortening) that led to discontinuation from the study. The proportion of patients experiencing any infection during Study 1 was 67% for the placebo group, 85% for the 5 mg/m² group, and 81% for the 12 mg/m² group. However, few of these infections required hospitalization: one placebo patient (tonsillitis), three 5 mg/m² patients (enteritis, urinary tract infection, viral infection), and four 12 mg/m² patients (tonsillitis, urinary tract infection [two], endometritis). In Study 2, MITOXANTRONE was administered once a month. Clinical adverse events most frequently reported in the MITOXANTRONE group included amenorrhea (53% of female patients), alopecia (33% of patients), nausea (29% of patients), and asthenia (24% of patients). Tables 5a and 5b respectively summarize adverse events and laboratory abnormalities occurring in > 5% of patients in the MITOXANTRONE group and numerically more frequent than in the control group. Neutropenia occurred within 3 weeks after MITOXANTRONE administration and was always reversible. Only mild to moderate intensity infections were reported in 9 of 21 patients in the N +MP group and in 3 of 21 patients in the MP group; none of these required hospitalization. There was no difference among treatment groups in the incidence or severity of hemorrhagic events. There were no withdrawals from Study 2 for safety reasons. Leukemia MITOXANTRONE has been studied in approximately 600 patients with acute nonlymphocytic leukemia (ANLL). Table 6 represents the adverse reaction experience in the large U.S. comparative study of mitoxantrone + cytarabine vs daunorubicin + cytarabine. Experience in the large international study was similar. A much wider experience in a variety of other tumor types revealed no additional important reactions other than cardiomyopathy (see WARNINGS). It should be appreciated that the listed adverse reaction categories include overlapping clinical symptoms related to the same condition, e.g., dyspnea, cough and pneumonia. In addition, the listed adverse reactions cannot all necessarily be attributed to chemotherapy as it is often impossible to distinguish effects of the drug and effects of the underlying disease. It is clear, however, that the combination of MITOXANTRONE + cytarabine was responsible for nausea and vomiting, alopecia, mucositis/stomatitis, and myelosuppression. Adverse reactions are presented as major categories and selected examples of clinically significant subcategories. Detailed safety information is available for a total of 353 patients with hormone-refractory prostate cancer treated with MITOXANTRONE, including 274 patients who received MITOXANTRONE in combination with corticosteroids. General Allergic Reaction Hypotension, urticaria, dyspnea, and rashes have been reported occasionally. Anaphylaxis/anaphylactoid reactions have been reported rarely. Cutaneous Extravasation at the infusion site has been reported, which may result in erythema, swelling, pain, burning, and/or blue discoloration of the skin. Extravasation can result in tissue necrosis with resultant need for debridement and skin grafting. Phlebitis has also been reported at the site of the infusion. Hematologic Topoisomerase II inhibitors, including MITOXANTRONE, in combination with other antineoplastic agents or alone, have been associated with the development of acute leukemia (see WARNINGS). Leukemia Myelosuppression is rapid in onset and is consistent with the requirement to produce significant marrow hypoplasia in order to achieve a response in acute leukemia. The incidences of infection and bleeding seen in the U.S. trial are consistent with those reported for other standard induction regimens. Hormone-Refractory Prostate Cancer In a randomized study where dose escalation was required for neutrophil counts greater than 1000/mm³, Grade 4 neutropenia (ANC < 500 /mm³) was observed in 54% of patients treated with MITOXANTRONE + low-dose prednisone. In a separate randomized trial where patients were treated with 14 mg/m², Grade 4 neutropenia in 23% of patients treated with MITOXANTRONE + hydrocortisone was observed. Neutropenic fever/infection occurred in 11% and 10% of patients receiving MITOXANTRONE + corticosteroids, respectively, on the two trials. Platelets < 50,000/mm³ were noted in 4% and 3% of patients receiving MITOXANTRONE + corticosteroids on these trials, and there was one patient death on MITOXANTRONE + hydrocortisone due to intracranial hemorrhage after a fall. Gastrointestinal Nausea and vomiting occurred acutely in most patients and may have contributed to reports of dehydration, but were generally mild to moderate and could be controlled through the use of antiemetics. Stomatitis/mucositis occurred within 1 week of therapy. Cardiovascular Congestive heart failure, tachycardia, EKG changes including arrhythmias, chest pain, and asymptomatic decreases in left ventricular ejection fraction have occurred. (See WARNINGS) Pulmonary Interstitial pneumonitis has been reported in cancer patients receiving combination chemotherapy that included MITOXANTRONE.
MITOXANTRONE is contraindicated in patients who have demonstrated prior hypersensitivity to it.
Special Precaution: 
General Therapy with MITOXANTRONE 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 MITOXANTRONE. Information for Patients Inform patients of the availability of a Medication Guide and instruct them to read the Medication Guide prior to initiating treatment with MITOXANTRONE and prior to each infusion. Review the MITOXANTRONE Medication Guide with every patient prior to initiation of treatment and periodically during treatment. Instruct patients that MITOXANTRONE should be taken only as prescribed. Advise patients that MITOXANTRONE can cause myelosuppression and inform patients of the signs and symptoms of myelosuppression. Advise patients that MITOXANTRONE can cause congestive heart failure that may lead to death even in people who have never had heart problems before, and inform patients of the signs and symptoms of congestive heart failure. Advise patients receiving MITOXANTRONE to treat multiple sclerosis that they should receive cardiac monitoring prior to each MITOXANTRONE dose and yearly after stopping MITOXANTRONE. MITOXANTRONE 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 discoloration of the sclera may also occur. Laboratory Tests A complete blood count, including platelets, should be obtained prior to each course of MITOXANTRONE and in the event that signs and symptoms of infection develop. Liver function tests should also be performed prior to each course of therapy. MITOXANTRONE therapy in multiple sclerosis patients with abnormal liver function tests is not recommended because MITOXANTRONE clearance is reduced by hepatic impairment and no laboratory measurement can predict drug clearance and dose adjustments. In leukemia treatment, hyperuricemia may occur as a result of rapid lysis of tumor cells by MITOXANTRONE. Serum uric acid levels should be monitored and hypouricemic therapy instituted prior to the initiation of antileukemic therapy. 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. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Intravenous treatment of rats and mice, once every 21 days for 24 months, with MITOXANTRONE resulted in an increased incidence of fibroma and external auditory canal tumors in rats at a dose of 0.03 mg/kg (0.02 fold the recommended human dose, on a mg/m² basis), and hepatocellular adenoma in male mice at a dose of 0.1 mg/kg (0.03 fold the recommended human dose, on a mg/m² basis). Intravenous treatment of rats, once every 21 days for 12 months with MITOXANTRONE resulted in an increased incidence of external auditory canal tumors in rats at a dose of 0.3 mg/kg (0.15 fold the recommended human dose, on a mg/m² basis). Mutagenesis MITOXANTRONE was clastogenic in the in vivo rat bone marrow assay. MITOXANTRONE was also clastogenic in two in vitro assays; it induced DNA damage in primary rat hepatocytes and sister chromatid exchanges in Chinese hamster ovary cells. MITOXANTRONE was mutagenic in bacterial and mammalian test systems (Ames/Salmonella and E. coli and L5178Y TK+/-mouse lymphoma). Special Populations Hepatic Impairment Patients with multiple sclerosis who have hepatic impairment should ordinarily not be treated with MITOXANTRONE. MITOXANTRONE should be administered with caution to other patients with hepatic impairment. In patients with severe hepatic impairment, the AUC is more than three times greater than the value observed in patients with normal hepatic function. Pregnancy Pregnancy Category D Nursing Mothers MITOXANTRONE is excreted in human milk and significant concentrations (18 ng/mL) have been reported for 28 days after the last administration. Because of the potential for serious adverse reactions in infants from MITOXANTRONE, breast feeding should be discontinued before starting treatment. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Multiple Sclerosis: Clinical studies of MITOXANTRONE did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Hormone-Refractory Prostate Cancer: One hundred forty-six patients aged 65 and over and 52 younger patients ( < 65 years) have been treated with MITOXANTRONE in controlled clinical studies. These studies did not include sufficient numbers of younger patients to determine whether they respond differently from older patients. However, greater sensitivity of some older individuals cannot be ruled out. Acute Nonlymphocytic Leukemia: Although definitive studies with MITOXANTRONE have not been performed in geriatric patients with ANLL, toxicity may be more frequent in the elderly. Elderly patients are more likely to have age-related comorbidities due to disease or disease therapy.
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, post-marketing experience has not revealed any significant drug interactions in patients who have received MITOXANTRONE for treatment of cancer. Information on drug interactions in patients with multiple sclerosis is limited. Following concurrent administration of MITOXANTRONE with corticosteroids, no evidence of drug interactions has been observed.
Multiple Sclerosis The recommended dosage of MITOXANTRONE is 12 mg/m² 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 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 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/m². Complete blood counts, including platelets, should be monitored prior to each course of MITOXANTRONE and in the event that signs or symptoms of infection develop. MITOXANTRONE generally should not be administered to multiple sclerosis patients with neutrophil counts less than 1500 cells/mm³. Liver function tests should also be monitored prior to each course. MITOXANTRONE therapy in multiple sclerosis patients with abnormal liver function tests is not recommended because MITOXANTRONE 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. Hormone-Refractory Prostate Cancer Based on data from two Phase 3 comparative trials of MITOXANTRONE plus corticosteroids versus corticosteroids alone, the recommended dosage of MITOXANTRONE is 12 to 14 mg/m² given as a short intravenous infusion every 21 days. Combination Initial Therapy for ANLL in Adults For induction, the recommended dosage is 12 mg/m² of MITOXANTRONE daily on Days 1-3 given as an intravenous infusion, and 100 mg/m² of cytarabine for 7 days given as a continuous 24-hour infusion on Days 1-7. 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 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, 12 mg/m² given by intravenous infusion daily on Days 1 and 2 and cytarabine, 100 mg/m² for 5 days given as a continuous 24-hour infusion on Days 1-5. 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. Hepatic Impairment For patients with hepatic impairment, there is at present no laboratory measurement that allows for dose adjustment recommendations. Preparation and Administration Precautions MITOXANTRONE 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 should be diluted to at least 50 mL with either 0.9% Sodium Chloride Injection (USP) or 5% Dextrose Injection (USP). MITOXANTRONE may be further diluted into Dextrose 5% in Water, Normal Saline or Dextrose 5% with Normal Saline and used immediately. DO NOT FREEZE. MITOXANTRONE 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 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 concentrate should be stored not longer than 7 days between 15°-25°C (59°-77°F) or 14 days under refrigeration. DO NOT FREEZE. CONTAINS NO PRESERVATIVE. Care in the administration of MITOXANTRONE will reduce the chance of extravasation. MITOXANTRONE 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 with the skin, mucous membranes, or eyes. MITOXANTRONE 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 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 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.

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