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.
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). 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 ). , 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.
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 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 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 7:
Adverse Events of Any Intensity Occurring in ≥ 5% of Patients Trial CCI-NOV22 Event M + P (n = 80) % P (n = 81) % M = Mitoxantrone Injection, P = Prednisone. Nausea 61 35 Fatigue 39 14 Alopecia 29 0 Anorexia 25 6 Constipation 16 14 Dyspnea 11 5 Nail bed changes 11 0 Edema 10 4 Systemic infection 10 7 Mucositis 10 0 UTI 9 4 Emesis 9 5 Pain 8 9 Fever 6 3 Hemorrhage/bruise 6 1 Anemia 5 3 Cough 5 0 Decreased LVEF 5 0 Anxiety/depression 5 3 Dyspepsia 5 6 Skin infection 5 3 Blurred vision 3 5 No nonhematologic adverse events of Grade 3/4 were seen in > 5% of patients.
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 + H (n = 112) H (n = 113) Event n % n % M= Mitoxantrone Injection, H= Hydrocortisone 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 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. 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.
In a separate randomized trial where patients were treated with 14 mg/m 2 , Grade 4 neutropenia in 23% of patients treated with mitoxantrone injection + hydrocortisone was observed. 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.
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