mitoxantrone injection, USP ADVERSE REACTIONS

Prescribing Information

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

MEDICATION GUIDE MITOXANTRONE(MITO-XAN-TRONE) INJECTION, USP (CONCENTRATE)

MEDICATION GUIDE MitoXANTRONE (mito-xan-trone) Injection, USP (concentrate)

CONTAINS SODIUM METABISULFITE, A SULFITE THAT MAY CAUSE ALLERGIC-TYPE REACTIONS INCLUDING ANAPHYLACTIC SYMPTOMS AND LIFE-THREATENING OR LESS SEVERE ASTHMATIC EPISODES IN CERTAIN SUSCEPTIBLE PEOPLE. THE OVERALL PREVALENCE OF SULFITE SENSITIVITY IN THE GENERAL POPULATION IS UNKNOWN AND PROBABLY LOW. SULFITE SENSITIVITY IS SEEN MORE FREQUENTLY IN ASTHMATIC THAN IN NONASTHMATIC PEOPLE.

Read this Medication Guide before you start receiving MitoXANTRONE and each time you receive MitoXANTRONE. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment.

What is the most important information I should know about MitoXANTRONE?

MitoXANTRONE can cause serious side effects, including:

•

decrease in the ability of your bone marrow to make blood cells (myelosuppression). Your doctor may do blood tests during treatment with MitoXANTRONE to check your blood cell counts. The symptoms of myelosuppression can include:

o: feeling tired
o: increased infections
o: bruising and bleeding easily

•

heart problems (congestive heart failure) that may lead to death even in people who have never had heart problems before. Heart failure can happen while you receive MitoXANTRONE, or months to years after you stop receiving MitoXANTRONE. Your risk of heart failure increases the more MitoXANTRONE you receive.

Call your doctor or get medical help right away if you have any of these problems during or after treatment with MitoXANTRONE:

o: shortness of breath
o: swelling of your ankles or feet
o: sudden weight gain
o: fast heartbeat or pounding in your chest

Before receiving MitoXANTRONE for the first time, you should have the following tests done:

o: physical examination
o: a test to check your heart's electrical activity (electrocardiogram)
o: a test to check your heart's ability to pump blood

If you receive MitoXANTRONE to treat Multiple Sclerosis (MS), your doctor should also do the tests above:

o: before you receive each MitoXANTRONE dose
o: yearly after you stop receiving MitoXANTRONE treatment

•

acute myeloid leukemia (AML). Receiving MitoXANTRONE increases your risk of AML. AML is a cancer of the blood-forming cells of your bone marrow. Symptoms of AML can include:

o: feeling unusually tired and weak
o: increased infections
o: bruising and bleeding easily
o: fever

o: pain in your bones
o: trouble breathing
o: unexplained weight loss
o: night sweats

•: skin problems at your injection site. If MitoXANTRONE leaks out of your vein, skin problems can happen that may lead to serious skin damage (necrosis). Necrosis may need to be repaired surgically. Tell your doctor right away if you have any of the following problems at your injection site:

o: redness
o: swelling
o: pain

o: burning
o: skin turns a bluish color

What is MitoXANTRONE?

MitoXANTRONE is a prescription medicine used alone or with other medicines to treat people with:

•: secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis (MS)
•: pain related to advanced hormone-refractory prostate cancer
•: acute nonlymphocytic leukemia (ANLL)

MitoXANTRONE is not for people with primary progressive MS. It is not known if MitoXANTRONE is safe and effective in children.

Who should not receive MitoXANTRONE?

Do not receive MitoXANTRONE if you are allergic to MitoXANTRONE or any of the ingredients in MitoXANTRONE. See the end of this Medication Guide for a complete list of ingredients in MitoXANTRONE.

What should I tell my doctor before receiving MitoXANTRONE?

Before you receive MitoXANTRONE, tell your doctor if you have:

•: received MitoXANTRONE in the past
•: heart problems
•: liver problems
•: kidney problems
•: low blood cell counts
•: an infection
•: had radiation treatment in your chest area
•: any other medical conditions
•: are pregnant or plan to become pregnant. MitoXANTRONE may harm your unborn baby. Women who are able to become pregnant should use effective birth control (contraception) while using MitoXANTRONE and should have a pregnancy test, with known results, before receiving each dose of MitoXANTRONE. Talk to your doctor about using effective birth control while you receive MitoXANTRONE.
•: are breastfeeding or plan to breastfeed. MitoXANTRONE can pass into your breast milk and may harm your baby. Talk to your doctor about the best way to feed your baby if you receive MitoXANTRONE. Do not breastfeed while receiving MitoXANTRONE.

Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements.

Using MitoXANTRONE with certain other medicines may cause serious side effects.

Especially tell your doctor if you take or have taken:

•: medicines for cancer treatment called anthracyclines or anthracenediones
•: medicines that may affect your heart

Ask your doctor or pharmacist for a list of these medicines if you are not sure if you take or have taken any of these medicines.

Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How should I receive MitoXANTRONE?

•: MitoXANTRONE is given by slow infusion through a needle placed in a vein (intravenous infusion) in your arm.
•: Your doctor will tell you how often you will receive MitoXANTRONE.
•: If you receive MitoXANTRONE to treat MS, your doctor should check how well your heart is working before each MitoXANTRONE dose. Talk to your doctor if you have not had your heart tests done before your MitoXANTRONE dose.
•: Your doctor will do blood tests during your treatment with MitoXANTRONE to check your blood cell counts.
•: If you are a woman of childbearing age taking MitoXANTRONE to treat MS, your doctor should do a pregnancy test before each MitoXANTRONE dose, even if you are using birth control.
•: If you receive MitoXANTRONE to treat MS, there is a limit to the total amount of MitoXANTRONE you can receive during your lifetime. There is a higher risk of heart failure with increasing total lifetime doses of MitoXANTRONE.

What are the possible side effects of MitoXANTRONE?

MitoXANTRONE may cause serious side effects, including:

•: See "What is the most important information I should know about MitoXANTRONE?" The most common side effects of MitoXANTRONE include:

	o blue-green colored urine for about 24 hours after receiving MitoXANTRONE. This color change is harmless. o bluish coloring of the whites of your eyes for about 24 hours after receiving MitoXANTRONE. This color change is harmless.
	o nausea o constipation o diarrhea o stomach pain o hair loss	o fever and chills due to infections o cough and sore throat due to upper respiratory tract infection o mouth sores due to mouth infection o loss of your menstrual period

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of MitoXANTRONE. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of MitoXANTRONE.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.

This Medication Guide summarizes the most important information about MitoXANTRONE. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about MitoXANTRONE that is written for health professionals.

For more information go to www.pfizer.com or call 1-800-615-0187.

What are the ingredients in MitoXANTRONE?

Active ingredient: MitoXANTRONE hydrochloride

Inactive ingredients: sodium chloride, sodium metabisulfite, sodium acetate, and acetic acid

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Distributed by Hospira Inc., Lake Forest, IL 60045 USA

LAB-1312-2.0

Revised: 7/2025

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