Mitoxantrone (Page 6 of 11)

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 Term Placebo (N = 62) 5 mg/m2 Mitoxantrone (N = 64) 12 mg/m2 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/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
Event Placebo (N = 64) 5 mg/m2 Mitoxantrone (N = 65) 12 mg/m2 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/mm3

b. < 1500 cells/mm3

c. < 100,000 cells/mm3

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.

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