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Novantrone

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Novantrone

Side Effects
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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 ≥ 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 ≥ 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 ≥ 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 ≥ 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 Health Organization (WHO) toxicity criteria.
< 4000 cells/mm³
< 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 acute nonlymphocytic 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 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 [% pts entering induction] Consolidation [% 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 ≥ 5% of patients in Trial CCI-NOV22.

Table 7 : Adverse Events of Any Intensity Occurring in ≥ 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 ≥ 5% of patients in Trial CALGB 9182.

Table 8 : Adverse Events of Any Intensity Occurring in ≥ 5 % of Patients Trial CALGB 9182

Event N + H
(n = 112)
H
(n = 113)
n % n %
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
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 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 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.

Read the Novantrone (mitoxantrone for injection concentrate) Side Effects Center for a complete guide to possible side effects

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.

Read the Novantrone Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 4/19/2012
This monograph has been modified to include the generic and brand name in many instances.

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