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mitoxantrone injection, USP Adverse Reactions

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/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.

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/m2 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 TermPlacebo (N = 64)5 mg/m2
Mitoxantrone (N = 65)
12 mg/m2
Mitoxantrone (N = 62)
*
Percentage of female patients.
Nausea205576
Alopecia313861
Menstrual disorder*265161
Amenorrhea*32843
Upper respiratory tract infection525153
Urinary tract infection132932
Stomatitis81519
Arrhythmia8618
Diarrhea112516
Urine abnormal6511
ECG abnormal3511
Constipation61410
Back pain568
Sinusitis236
Headache566

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).

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
EventPlacebo (N = 64)5 mg/m2
Mitoxantrone (N = 65)
12 mg/m2
Mitoxantrone (N = 62)
*
Assessed using World Health Organization (WHO) toxicity criteria.
< 4000 cells/mm3
< 2000 cells/mm3
Leukopenia0919
Gamma-GT increased3315
SGOT increased898
Granulocytopenia266
Anemia296
SGPT increased365

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
EventMP (N = 21)M + MP (N = 21)
M = mitoxantrone, MP = methylprednisolone
*
Assessed using National Cancer Institute (NCI) common toxicity criteria.
Percentage of female patients.
Amenorrhea053
Alopecia033
Nausea029
Asthenia024
Pharyngitis/throat infection519
Gastralgia/stomach burn/epigastric pain514
Aphthosis010
Cutaneous mycosis010
Rhinitis010
Menorrhagia07
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
EventMP (N = 21)M + MP (N = 21)
M = mitoxantrone, MP = methylprednisolone
*
Assessed using National Cancer Institute (NCI) common toxicity criteria.
< 4000 cells/mm3
< 1500 cells/mm3
§
< 100,000 cells/mm3
WBC low14100
ANC low10100
Lymphocytes low4395
Hemoglobin low4843
Platelets low§033
SGOT high515
SGPT high1015
Glucose high510
Potassium low010

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 acute non-lymphocytic 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.

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
Induction
[% pts entering induction]
Consolidation
[% pts entering induction]
EventMIT
N = 102
DAUN
N = 102
MIT
N = 55
DAUN
N = 49
MIT = mitoxantrone, DAUN = daunorubicin.
Cardiovascular26281124
  CHF5600
  Arrhythmias3344
Bleeding3741206
  GI161222
  Petechiae/ecchymoses79112
Gastrointestinal88855851
  Nausea/vomiting72673131
  Diarrhea4747188
  Abdominal pain15994
  Mucositis/stomatitis2933188
Hepatic1011142
  Jaundice3870
Infections66736043
  UTI7272
  Pneumonia9790
  Sepsis34363118
  Fungal infections151396
Renal failure8602
Fever78712418
Alopecia37402216
Pulmonary43432414
  Cough13992
  Dyspnea182060
CNS30303435
  Seizures4428
  Headache109138
Eye7624
  Conjunctivitis5100

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
EventM + P (n = 80) %P (n = 81) %
M = mitoxantrone, P = prednisone.
No nonhematologic adverse events of Grade 3/4 were seen in > 5% of patients.
Nausea6135
Fatigue3914
Alopecia290
Anorexia256
Constipation1614
Dyspnea115
Nail bed changes110
Edema104
Systemic infection107
Mucositis100
UTI94
Emesis95
Pain89
Fever63
Hemorrhage/bruise61
Anemia53
Cough50
Decreased LVEF50
Anxiety/depression53
Dyspepsia56
Skin infection53
Blurred vision35

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)
Eventn%n%
M = mitoxantrone, H = hydrocortisone
Decreased WBC968744
Abnormal granulocytes/bands887933
Decreased hemoglobin83754239
Abnormal lymphocytes count78722725
Pain45414439
Abnormal platelet count433987
Abnormal alkaline phosphatase41374238
Malaise/fatigue37341614
Hyperglycemia33313230
Edema31301514
Nausea282698
Anorexia24221614
Abnormal BUN24222220
Abnormal transaminase22201614
Alopecia202011
Abnormal cardiac function191800
Infection181744
Weight loss18171312
Dyspnea161598
Diarrhea161444
Fever in absence of infection151476
Weight gain15141615
Abnormal creatinine14131110
Other gastrointestinal13141111
Vomiting121165
Other neurologic111155
Hypocalcemia101055
Hematuria91156
Hyponatremia9933
Sweats9922
Other liver8888
Stomatitis8811
Cardiac dysrhythmia7733
Hypokalemia7744
Neuro/constipation7722
Neuro/motor disorder7733
Neuro/mood disorder6622
Skin disorder6644
Cardiac ischemia5511
Chills5500
Hemorrhage5533
Myalgias/arthralgias5533
Other kidney/bladder5533
Other endocrine5634
Other pulmonary5533
Hypertension4455
Impotence/libido4723
Proteinuria4623
Sterility3523

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.

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