Can Mitoxantrone cause febrile neutropenia?

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 < 4000 cells/mm 3 b < 2000 cells/mm 3 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. Clinical adverse events most frequently reported in the mitoxantrone injection 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 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 Menorrhagia a 0 7 M = Mitoxantrone Injection, 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 Injection 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 Injection, 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 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 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 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 [% pts entering induction] Consolidation [% pts entering induction] Event MIT N = 102 DAUN N = 102 MIT N = 55 DAUN N = 49 MIT = Mitoxantrone Injection, DAUN = Daunorubicin. 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

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