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Novantrone Side Effects, and Drug Interactions - Mitoxantrone

Novantrone Side Effects, and Drug Interactions - Mitoxantrone

SIDE EFFECTS

Multiple Sclerosis

NOVANTRONE^® has been administered to 149 patients with multiple sclerosis in two randomized clinical trials, including 21 patients who received NOVANTRONE^® 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 NOVANTRONE^® 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 NOVANTRONE^® groups: nausea, alopecia, urinary tract infection, and menstrual disorders, including amenorrhea.

Table 4a summarizes clinical adverse events of all intensities occurring in ³ 5% of patients in either dose group of NOVANTRONE^® 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 NOVANTRONE^® 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 ³ 5% of Patients on Any Dose of NOVANTRONE® and That Were Numerically Greater Than in the Placebo Group Study 1
Preferred Term	Percent of Patients
	Placebo (N = 64)	5 mg/m2 NOVANTRONE® (N = 65)	12 mg/m2 NOVANTRONE® (N = 62)
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 ³ 5% of patients in either NOVANTRONE^® dose group, and that were numerically more frequent than in the placebo group.

Table 4b: Laboratory Abnormalities Occurring in ³ 5% of Patients* on Either Dose of NOVANTRONE® and That Were More Frequent Than in the Placebo Group Study 1
Event	Percent of Patients
	Placebo (N = 64)	5 mg/m2 NOVANTRONE® (N = 65)	12 mg/m2 NOVANTRONE® (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, NOVANTRONE^® was administered once a month. Clinical adverse events most frequently reported in the NOVANTRONE^® 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 NOVANTRONE^® group and numerically more frequent than in the control group.

Table 5a: Adverse Events of Any Intensity Occurring in > 5% of Patients* in the NOVANTRONE® Group and Numerically More Frequent Than in the Control Group Study 2
Event	Percent of Patients
	MP (n = 21)	N + 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
N = NOVANTRONE®, 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 NOVANTRONE® Group and Numerically More Frequent Than in the Control Group Study 2
Event	Percent of Patients
	MP (n = 21)	N + 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
N = NOVANTRONE®, 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 N +MP group (see Table 5b). Neutropenia occurred within 3 weeks after NOVANTRONE^® administration and was always reversible. Only mild to moderate intensity infections were reported in 9 of 21 patients in the N +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

NOVANTRONE^® has been studied in approximately 600 patients with 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 NOVANTRONE^® + cytarabine was responsible for nausea and vomiting, alopecia, mucositis/stomatitis, and myelosuppression.

Table 6 summarizes adverse reactions occurring in patients treated with NOVANTRONE^® + 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 NOVANTRONE® or Daunorubicin
Event	Induction		Consolidation
	[% pts entering induction]		[% pts entering induction]
	NOV N= 102	DAUN N= 102	NOV N= 55	DAUN N= 49
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
NOV = NOVANTRONE®, DAUN = daunorubicin.

Hormone-Refractory Prostate Cancer

Detailed safety information is available for a total of 353 patients with hormone-refractory prostate cancer treated with NOVANTRONE^®, including 274 patients who received NOVANTRONE^® in combination with corticosteroids

Table 7 summarizes adverse reactions of all grades occurring in ³ 5% of patients in Trial CCI-NOV22.

Table 7: Adverse Events of Any Intensity Occurring in ³ 5% of Patients Trial CCI-NOV22
Event	N + P (n = 80) %	P (n = 81) %
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
N = NOVANTRONE®, P = prednisone.
No nonhematologic adverse events of Grade 3/4 were seen in > 5% of patients.

Table 8 summarizes adverse events of all grades occurring in ³ 5% of patients in Trial CALGB 9182.

Table 8: Adverse Events of Any Intensity Occurring in ³ 5 % of Patients. Trial CALGB 9182
Event	N + H (n = 112) n	%	H (n = 113) n	%
Decreased WBC	96	87	4	4
Granulocytes/bands	88	79	3	3
Decreased hemoglobin	83	75	42	39
Lymphocytes	78	72	27	25
Pain	45	41	44	39
Platelets	43	39	8	7
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
BUN	24	22	22	20
Transaminase	22	20	16	14
Alopecia	20	20	1	1
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
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	7	7	3	3
Neuro/mood	6	6	2	2
Skin	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
N= NOVANTRONE®, H= hydrocortisone

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 NOVANTRONE^®, in combination with other antineoplastic agents, 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 NOVANTRONE^® + 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 NOVANTRONE^® + hydrocortisone was observed. Neutropenic fever/infection occurred in 11% and 10% of patients receiving NOVANTRONE^® + corticosteroids, respectively, on the two trials. Platelets < 50,000/mm³ were noted in 4% and 3% of patients receiving NOVANTRONE^® + corticosteroids on these trials, and there was one patient death on NOVANTRONE^® + 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 NOVANTRONE^®.

DRUG INTERACTIONS

Mitoxantrone and its metabolites are excreted in bile and urine, but it is not known whether the metabolic or excretory pathways are saturable, may be inhibited or induced, or if mitoxantrone and its metabolites undergo enterohepatic circulation. To date, post-marketing experience has not revealed any significant drug interactions in patients who have received NOVANTRONE^® for treatment of cancer. Information on drug interactions in patients with multiple sclerosis is limited.

Following concurrent administration of NOVANTRONE^® with corticosteroids, no evidence of drug interactions has been observed.

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