Mitoxantrone Drug Information

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.

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. 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.

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 in the 12 mg/m 2 group). Of note, alopecia consisted of mild hair thinning.

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. 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, 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 There was no difference among treatment groups in the incidence or severity of hemorrhagic events. In Study 2, mitoxantrone injection was administered once a month. Tables 5a and 5b respectively summarize adverse events and laboratory abnormalities occurring in > 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 Table 5b: Laboratory Abnormalities Occurring in > 5% of Patients* in the Mitoxantrone Injection Group and Numerically More Frequent Than in the Control Group Study 2 nd neutropenia were reported in the M + MP group (see Table 5b ). Neutropenia occurred within 3 weeks after mitoxantrone injection administration and was always reversible. Only mild to moderate intensity infections were reported in 9 of 21 patients in the M + MP group and in 3 of 21 patients in the MP group; none of these required hospitalization.

There were no withdrawals from Study 2 for safety reasons. Leukemia Mitoxantrone injection 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 injection + cytarabine was responsible for nausea and vomiting, alopecia, mucositis/stomatitis, and myelosuppression. Table 6 summarizes adverse reactions occurring in patients treated with mitoxantrone injection + cytarabine in comparison with those who received daunorubicin + cytarabine for therapy of ANLL in a large multicenter randomized prospective U.S. trial.

Adverse reactions are presented as major categories and selected examples of clinically significant subcategories. Table 6: Adverse Events Occurring in ANLL Patients Receiving Mitoxantrone Injection or Daunorubicin Induction Consolidation Hormone-Refractory Prostate Cancer Detailed safety information is available for a total of 353 patients with hormone-refractory prostate cancer treated with mitoxantrone injection, including 274 patients who received mitoxantrone injection in combination with corticosteroids. Table 7 summarizes adverse reactions of all grades occurring in ≥ 5% of patients in Trial CCI-NOV22.

Table 8 summarizes adverse events of all grades occurring in ≥ 5% of patients in Trial CALGB 9182. Table 8: Adverse Events of Any Intensity Occurring in ≥ 5 % of Patients Trial CALGB 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 injection, 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/mm 3, Grade 4 neutropenia (ANC <500/mm 3 ) was observed in 54% of patients treated with mitoxantrone injection + low-dose prednisone. Neutropenic fever/infection occurred in 11% and 10% of patients receiving mitoxantrone injection + corticosteroids, respectively, on the two trials. Platelets <50,000/mm 3 were noted in 4% and 3% of patients receiving mitoxantrone injection + corticosteroids on these trials, and there was one patient death on mitoxantrone injection + 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 injection. To report SUSPECTED ADVERSE REACTIONS, contact Meitheal Pharmaceuticals, Inc. at 1-844-824-8426 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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.

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.

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

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.