mitoxantrone injection, USP Adverse Reactions

Prescribing Information

Health Professional Information

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 Term	Placebo (N = 64)	5 mg/m2 Mitoxantrone (N = 65)	12 mg/m2 Mitoxantrone (N = 62)
* Percentage of female patients.
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

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)
* Assessed using World Health Organization (WHO) toxicity criteria. † < 4000 cells/mm3 ‡ < 2000 cells/mm3
Leukopenia†	0	9	19
Gamma-GT increased	3	3	15
SGOT increased	8	9	8
Granulocytopenia‡	2	6	6
Anemia	2	9	6
SGPT increased	3	6	5

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)
M = mitoxantrone, MP = methylprednisolone
* Assessed using National Cancer Institute (NCI) common toxicity criteria. † Percentage of female patients.
Amenorrhea†	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†	0	7

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)
M = mitoxantrone, MP = methylprednisolone
* Assessed using National Cancer Institute (NCI) common toxicity criteria. † < 4000 cells/mm3 ‡ < 1500 cells/mm3 § < 100,000 cells/mm3
WBC low†	14	100
ANC low‡	10	100
Lymphocytes low	43	95
Hemoglobin low	48	43
Platelets low§	0	33
SGOT high	5	15
SGPT high	10	15
Glucose high	5	10
Potassium low	0	10

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]
Event	MIT N = 102	DAUN N = 102	MIT N = 55	DAUN N = 49
MIT = mitoxantrone, 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, 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
Event	M + P (n = 80) %	P (n = 81) %
M = mitoxantrone, P = prednisone. No nonhematologic adverse events of Grade 3/4 were seen in > 5% of patients.
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

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, 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, 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.

Medication Guide

Download Consumer Medicine Information

Health Professional Information

Additional Resources

Chat online with Pfizer Medical Information regarding your inquiry on a Pfizer medicine or vaccine.

Speak with a Pfizer Medical Information Professional regarding your Pfizer medicine or vaccine inquiry.

Available 9AM-5PM ET Monday to Friday; excluding holidays.

Submit a medical question for a Pfizer medicine or a vaccine.

The submission will be reviewed during our standard business hours.

To report an adverse event related to a Pfizer product and you are not part of a clinical trial* for this medication, click the link below to submit your information:
Pfizer Safety Reporting Site

*If you are involved in a clinical trial for either product, adverse events should be reported to your coordinating study site.

If you cannot use the above website to report an adverse event related to a Pfizer medication, please call (800) 438-1985.

You may also contact the U.S. Food and Drug Administration (FDA) directly to report adverse events or product quality concerns either online at www.fda.gov/medwatch or by calling (800) 332-1088.