FDA label 336e77ca-43ff-443e-bd03-d6b99732a079

WARNING Mitoxantrone Injection, USP should be administered under the supervision of a physician experienced in the use of cytotoxic chemotherapy agents. Mitoxantrone should be given slowly into a freely flowing intravenous infusion. It must never be given subcutaneously, intramuscularly, or intra-arterially. Severe local tissue damage may occur it there is extravasation during administration. (See ADVERSE REACTIONS , General, Cutaneous and DOSAGE AND ADMINISTRATION , Preparation and Administration Precautions ) NOT FOR INTRATHECAL USE. Severe injury with permanent sequelae can result from intrathecal administration. (See WARNINGS , General .) Except for the treatment of acute nonlymphocytic leukemia, mitoxantrone therapy generally should not be given to patients with baseline neutrophil counts of less than 1,500 cells/mm 3 . In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving mitoxantrone. Cardiotoxicity: Congestive heart failure (CHF), potentially fatal, may occur either during therapy with mitoxantrone or months to years after termination of therapy. Cardiotoxicity risk increases with cumulative mitoxantrone dose and may occur whether or not cardiac risk factors are present. Presence or history of cardiovascular disease, radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or use of other cardiotoxic drugs may increase this risk. In cancer patients, the risk of symptomatic CHF was estimated to be 2.6% for patients receiving up to a cumulative dose of 140 mg/m2. To mitigate the cardiotoxicity risk with mitoxantrone, prescribers should consider the following: All Patients: • All patients should be assessed for cardiac signs and symptoms by history, physical examination, and ECG prior to start of mitoxantrone therapy. • All patients should have baseline quantitative evaluation of left ventricular ejection fraction (LVEF) using appropriate methodology (ex. Echocardiogram, multi-gated radionuclide angiography (MUGA), MRI, etc.). Multiple Sclerosis Patients: • MS patients with a baseline LVEF below the lower limit of normal should not be treated with mitoxantrone. • MS patients should be assessed for cardiac signs and symptoms by history, physical examination and ECG prior to each dose. • MS patients should undergo quantitative reevaluation of LVEF prior to each dose using the same methodology that was used to assess baseline LVEF. Additional doses of mitoxantrone should not be administered to multiple sclerosis patients who have experienced either a drop in LVEF to below the lower limit of normal or a clinically significant reduction in LVEF during mitoxantrone therapy. • MS patients should not receive a cumulative mitoxantrone dose greater than 140 mg/m2. • MS patients should undergo yearly quantitative LVEF evaluation after stopping mitoxantrone to monitor for late occurring cardiotoxicity. Secondary Leukemia: Mitoxantrone therapy in patients with MS and in patients with cancer increases the risk of developing secondary acute myeloid leukemia. For additional information, see WARNINGS , and DOSAGE AND ADMINISTRATION .

WARNINGS WHEN MITOXANTRONE IS USED IN HIGH DOSES (> 14 mg/m 2 /d x 3 days) SUCH AS INDICATED FOR THE TREATMENT OF LEUKEMIA, SEVERE MYELOSUPPRESSION WILL OCCUR. THEREFORE, IT IS RECOMMENDED THAT MITOXANTRONE 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 ADMINISTERED AT ANY DOSE CAN CAUSE MYELOSUPPRESSION. General Patients with preexisting myelosuppression as the result of prior drug therapy should not receive mitoxantrone unless it is felt that the possible benefit from such treatment warrants the risk of further medullary suppression. The safety of mitoxantrone injection 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 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 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, 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 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. 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. In one controlled trial (Study 1, see CLINICAL TRIALS , Multiple Sclerosis ), two patients (2%) of 127 receiving mitoxantrone, 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/m2, 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 therapy. MS patients with a baseline LVEF below the lower limit of normal should not be treated with mitoxantrone. 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 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 to monitor for late-occurring cardiotoxicity. Leukemia - Acute congestive heart failure may occasionally occur in patients treated with mitoxantrone for ANLL. In first-line comparative trials of mitoxantrone + 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. In a randomized comparative trial of mitoxantrone plus low-dose prednisone vs low-dose prednisone, 7 of 128 patients (5.5%) treated with mitoxantrone 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 dose administered to patients with cardiac effects ranged from > 48 to 212 mg/m 2 . Among 112 patients evaluable for safety on the mitoxantrone + 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 doses administered to these patients is not available. Pregnancy Mitoxantrone 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 it the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to the fetus. Secondary Leukemia Mitoxantrone 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 1% (5/487) of mitoxantrone-treated patients versus no cases in the control group (0/496) not receiving mitoxantrone at 4.7 years followup. In a prospective, open-label, tolerability and safety monitoring study of mitoxantrone treated MS patients followed for up to five years (median of 2.8 years), leukemia occurred in 0.6% (3/509) of patients. Publications describe leukemia risks of 0.25% to 2.8% in cohorts of patients with MS treated with mitoxantrone and followed for varying periods of time. This leukemia risk exceeds the risk of leukemia in the general population. The most commonly reported types were acute promyelocytic leukemia and acute myelocytic leukemia. In 1774 patients with breast cancer who received mitoxantrone concomitantly with other cytotoxic agents and radiotherapy, the cumulative risk of developing treatment-related acute myeloid leukemia was estimated as 1.1% and 1.6% at 5 and 10 years, respectively. The second largest report involved 449 patients with breast cancer treated with mitoxantrone, usually in combination with radiotherapy and/or other cytotoxic agents. In this study, the cumulative probability of developing secondary leukemia was estimated to be 2.2% at 4 years. Secondary acute myeloid leukemia has also been reported in cancer patients treated with anthracyclines. Mitoxantrone is an anthracenedione, a related drug. The occurrence of secondary leukemia is more common when anthracyclines are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated. Symptoms of acute leukemia may include excessive bruising, bleeding, and recurrent infections.

ADVERSE REACTIONS 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/m 2 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. Table 4a summarizes clinical adverse events of all intensities occurring in ≥ 5% of patients in either dose group of mitoxantrone 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 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. Table 4a: Adverse Events of Any Intensity Occurring in ≥ 5% of Patients on Any Dose of Mitoxantrone and That Were Numerically Greater Than in the Placebo Group. Study 1 Percent of Patients Preferred Term Placebo (N = 62) 5 mg/m 2 Mitoxantrone (N = 64) 12 mg/m 2 Mitoxantrone (N = 65) Nausea 20 55 76 Alopecia 31 38 61 Menstrual disorder * 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 * Percentage of female patients. 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 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 and That Were More Frequent Than in the Placebo Group. Study 1 Percent of Patients Event Placebo (N = 64) 5 mg/m 2 Mitoxantrone (N = 65) 12 mg/m 2 Mitoxantrone (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 Heath Organization (WHO) toxicity criteria. a. < 4000 cells/mm3 b. < 2000 cells/mm3 There was no difference among treatment groups in the incidence or severity of hemorrhagic events. 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. Table 5a: Adverse Events of Any Intensity Occurring in > 5% of Patients* in the Mitoxantrone 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 17 Menorrhagia a 0 7 M = mitoxantrone, MP = methylprednisolone * Assessed using National Cancer Institute (NCI) common toxicity criteria. a. Percentage of female patients. Table 5b: Laboratory Abnormalities Occurring in > 5% of Patients* in the Mitoxantrone Group and Numerically More Frequent Than in the Control Group. Study 2 Percent of Patients Event MP (n = 21) M + MP(n = 21) WBC low a 14 100 ANC low b 10 100 Lymphocytes low 43 95 Hemoglobin low 48 43 Platelets low c 0 33 SGOT high 5 15 SGPT high 10 15 Glucose high 5 10 Potassium low 0 10 M = mitoxantrone, MP = methylprednisolone. * Assessed using National Cancer Institute (NCI) common toxicity criteria. a. < 4000 cells/mm 3 b. < 1500 cells/mm 3 c. < 100,000 cells/mm 3 Leukopenia and neutropenia were reported in the M +MP group (see Table 5b). 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 M +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 ANLL. Table 2 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. Table 6 summarizes adverse reactions occurring in patients treated with mitoxantrone + 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 or Daunorubicin MITO = mitoxantrone, DAUN = daunorubicin Event Introduction (%pts entering induction) Consolidation (%pts entering induction) MITO N=102 DAUN N=102 MITO N=55 DAUN N=49 Cardiovascular 26 28 11 24 CHF 5 6 0 0 Arrhythmias 3 3 4 4 Bleeding 37 41 20 6 GI 16 12 2 2 Petechiae/ecchymoses 7 9 11 2 Gastrointestinal 88 85 58 51 Nausea/vomiting 72 67 31 31 Diarrhea 47 47 18 8 Abdominal pain 15 9 9 4 Mucositis/stomatitis 29 33 18 8 Hepatic 10 11 14 2 Jaundice 3 8 7 0 Infections 66 73 60 43 UTI 7 2 7 2 Pneumonia 9 7 9 0 Sepsis 34 36 31 18 Fungal infections 15 13 9 6 Renal failure 8 6 0 2 Fever 78 71 24 18 Alopecia 37 40 22 16 Pulmonary 43 43 24 14 Cough 13 9 9 2 Dyspnea 18 20 6 0 CNS 30 30 34 35 Seizures 4 4 2 8 Headache 10 9 13 8 Eye 7 6 2 4 Conjunctivitis 5 1 0 0 Hormone-Refractory Prostate Cancer 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. Table 7 summarizes adverse reactions of all grades occurring in ≥ 5% of patients in Trial CCI-NOV22. Table 7: Adverse Events of Any Intensity Occurring in ≥ 5% of Patients Trial CCI-NOV22 M = mitoxantrone, P = prednisolone No nonhematologic adverse events of Grade 3/4 were seen in > 5% of patients. Event M + P (n=80) % P (n=81) % Event M + P (n=80) % P (n=81) % Nausea 61 35 Emesis 9 5 Fatigue 39 14 Pain 8 9 Alopecia 29 0 Fever 6 3 Anorexia 25 6 Hemorrhage/bruise 6 1 Constipation 16 14 Anemia 5 3 Dyspnea 11 5 Cough 5 0 Nail bed changes 11 0 Decreased LVEF 5 0 Edema 10 4 Anxiety/depression 5 3 Systemic infection 10 7 Dyspepsia 5 6 Mucositis 10 0 Skin infection 5 3 UTI 9 4 Blurred vision 3 5 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 9182 M = mitoxantrone, H= hydrocortisone Event M + H (n=112) H (n=113) n % n % Decreased WBC 96 87 4 4 Abnormal Granulocytes/bands 88 79 3 3 Decreased hemoglobin 83 75 42 39 Abnormal lymphocytes count 78 72 27 25 Pain 45 41 44 39 Abnormal Platelet Count 43 39 8 7 Abnormal alkaline phosphatase 41 37 42 38 Malaise/fatigue 37 34 16 14 Hyperglycemia 33 31 32 30 Edema 31 30 15 14 Nausea 28 26 9 8 Anorexia 24 22 16 14 Abnormal BUN 24 22 22 20 Abnormal Transaminase 22 20 16 14 Alopecia 20 20 1 1 Abnormal Cardiac function 19 18 0 0 Infection 18 17 4 4 Weight loss 18 17 13 12 Dyspnea 16 15 9 8 Diarrhea 16 14 4 4 Fever in absence of infection 15 14 7 6 Weight gain 15 14 16 15 Abnormal Creatinine 14 13 11 10 Other gastrointestinal 13 14 11 11 Vomiting 12 11 6 5 Other neurologic 11 11 5 5 Hypocalcemia 10 10 5 5 Hematuria 9 11 5 6 Hyponatremia 9 9 3 3 Sweats 9 9 2 2 Other liver 8 8 8 8 Stomatitis 8 8 1 1 Cardiac dysrhythmia 7 7 3 3 Hypokalemia 7 7 4 4 Neuro/constipation 7 7 2 2 Neuro/motor disorder 7 7 3 3 Neuro/mood disorder 6 6 2 2 Skin disorder 6 6 4 4 Cardiac ischemia 5 5 1 1 Chills 5 5 0 0 Hemorrhage 5 5 3 3 Myalgias/arthralgias 5 5 3 3 Other kidney/bladder 5 5 3 3 Other endocrine 5 6 3 4 Other pulmonary 5 5 3 3 Hypertension 4 4 5 5 Impotence/libido 4 7 2 3 Proteinuria 4 6 2 3 Sterility 3 5 2 3 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/mm 3 , Grade 4 neutropenia (ANC < 500 /mm 3 ) was observed in 54% of patients treated with mitoxantrone + low-dose prednisone. In a separate randomized trial where patients were treated with 14 mg/m 2 , 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/mm 3 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.

<table ID="_Refid_3116357e-fc13-45db-a9ea-4a7b2fb81"> <caption>Table 4a: Adverse Events of Any Intensity Occurring in &#x2265; 5% of Patients on Any Dose of Mitoxantrone and That Were Numerically Greater Than in the Placebo Group. Study 1</caption> <col width="25%"/> <col width="25%"/> <col width="25%"/> <col width="25%"/> <tbody> <tr> <td styleCode="Rrule Botrule Toprule "/> <td align="center" colspan="3" styleCode="Botrule Toprule "> <paragraph> <content styleCode="bold">Percent of Patients</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph> <content styleCode="bold">Preferred Term</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph> <content styleCode="bold">Placebo (N = 62) </content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph> <content styleCode="bold"> 5 mg/m²Mitoxantrone (N = 64)</content> </paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph> <content styleCode="bold">12 mg/m²Mitoxantrone (N = 65)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph>Nausea</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>20</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>55</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>76</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph>Alopecia</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>31</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>38</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>61</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph>Menstrual disorder *</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>26</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>51</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>61</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph>Amenorrhea *</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>28</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>43</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph>Upper respiratory tract infection</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>52</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>51</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>53</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph>Urinary tract infection</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>13</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>29</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>32</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph>Stomatitis</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>15</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>19</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph>Arrhythmia</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>6</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>18</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph>Diarrhea</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>11</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>25</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>16</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph>Urine abnormal </paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>6</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>5</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>11</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph>ECG abnormal</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>5</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>11</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph>Constipation</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>6</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>14</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>10</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph>Back pain</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>6</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>8</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph>Sinusitis</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>3</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>6</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph>Headache</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>6</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>6</paragraph> </td> </tr> </tbody> </table>

<table ID="_Refid_ff86b02e-d8cc-4bb1-b3d3-3328aa493"> <caption>Table 4b: Laboratory Abnormalities Occurring in &#x2265; 5% of Patients* on Either Dose of Mitoxantrone and That Were More Frequent Than in the Placebo Group. Study 1</caption> <col width="25%"/> <col width="25%"/> <col width="25%"/> <col width="25%"/> <tbody> <tr> <td styleCode="Rrule Botrule Toprule "/> <td colspan="3" styleCode="Botrule Toprule "> <paragraph> <content styleCode="bold">Percent of Patients</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph> <content styleCode="bold">Event</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph> <content styleCode="bold">Placebo (N = 64)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph> <content styleCode="bold">5 mg/m² Mitoxantrone (N = 65)</content> </paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph> <content styleCode="bold">12 mg/m²Mitoxantrone (N = 62)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph>Leukopenia ^a </paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>9</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>19</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph>Gamma-GT increased</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>3</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>15</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph>SGOT increased</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>9</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>8</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph>Granulocytopenia ^b </paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>6</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>6</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph>Anemia</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>9</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>6</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph>SGPT increased</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>6</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>5</paragraph> </td> </tr> </tbody> </table>

<table ID="_Refid_a0759801-f180-4b66-a8a0-9fc8350e2"> <caption>Table 5a: Adverse Events of Any Intensity Occurring in &gt; 5% of Patients* in the Mitoxantrone Group and Numerically More Frequent Than in the Control Group. Study 2</caption> <col width="33%"/> <col width="33%"/> <col width="33%"/> <tbody> <tr> <td styleCode="Rrule Botrule Toprule "/> <td align="center" colspan="2" styleCode="Botrule Toprule "> <paragraph> <content styleCode="bold">Percent of Patients</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph> <content styleCode="bold">Event</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph> <content styleCode="bold">MP (n = 21)</content> </paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph> <content styleCode="bold">M + MP (n = 21)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph>Amenorrhea ^a </paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>53</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph>Alopecia</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>33</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph>Nausea</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>29</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph>Asthenia</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>24</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph>Pharyngitis/throat infection</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>5</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>19</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph>Gastralgia/stomach burn/epigastric pain</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>5</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>14</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph>Aphthosis</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>10</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph>Cutaneous mycosis</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>10</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph>Rhinitis</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>17</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule "> <paragraph>Menorrhagia a</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>7</paragraph> </td> </tr> </tbody> </table>