Novantrone Side Effects

Generic Name: mitoxantrone

Please note - some side effects for Novantrone may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Novantrone - for the Consumer

Novantrone

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Novantrone:

Back pain; blue-green urine; bluish-colored whites of the eyes; constipation; cough; diarrhea; hair loss or thinning; loss of appetite; loss of menstrual period; menstrual changes; mouth pain; nausea; stomach pain or upset; stuffy nose; tiredness; vomiting; weakness.

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); chest pain; dark, pink, or bloody urine; fast or irregular heartbeat; fever, chills, sore throat, or persistent cough; increased, decreased, or painful urination; mental or mood changes (eg, anxiety, depression); mouth sores, inflammation, or severe pain; pain, swelling, or redness at the injection site; severe or persistent tiredness or weakness; shortness of breath; sinus infection; sudden, unexplained weight gain; swelling of hands, legs, or feet; unusual bruising or bleeding; vision changes.

Novantrone Side Effects - for the Professional

Novantrone

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.

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.

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.

Leukopenia and neutropenia were reported in the N +MP group.  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 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.  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.

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.

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.

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.

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. 

Pulmonary -

Interstitial pneumonitis has been reported in cancer patients receiving combination chemotherapy that included Novantrone®.

Side Effects by Body System

Hematologic

Hematologic side effects including leukopenia have been reported. Dose-limiting leukopenia usually occurs within 7 to 14 days, and is the most profound and potentially fatal hematologic side effect. Six percent of patients develop leukocyte counts below 1,000/mm3 and less than 50% have nadir counts below 3,000/mm3. Most patients receiving mitoxantrone for ANLL become neutropenic. Leukocyte nadirs usually occur by day 10 to 14, with recovery by day 21 (rarely day 35). Thrombocytopenia occurs less commonly, but can be severe. Only rarely do platelet counts fall below 100,000/mm3 (1% of patients develop platelet counts less than 25,000/mm3). Erythrocytes do not appear to be significantly effected. Granulocytopenia may result in mild to severe infections, including urinary tract infections (7%), pneumonia (9%), bacteremia/sepsis (34%), and fungal infections (9% to 15%). A case of acute myelogenous leukemia following treatment with mitoxantrone has also been reported.

Myelosuppression associated with mitoxantrone may be cumulative with successive therapy. Its severity appears to be correlated with total dose, patient performance status, treatment history, and the degree of marrow disease involvement.

Early data have shown the ratio of equi-myelosuppressive doses of mitoxantrone to doxorubicin is approximately 1:5.

Autologous bone marrow rescue and recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) have been used to ameliorate mitoxantrone-induced myelosuppression.

Oncologic

Oncologic side effects including secondary myelogenous leukemia have been reported in both cancer patients and multiple sclerosis patients treated with mitoxantrone.

Gastrointestinal

Gastrointestinal side effects are experienced by most patients and have included nausea and vomiting (31% to 72%, severe in 10% to 16%), diarrhea (18% to 47%), abdominal pain (9% to 15%), and mucositis/stomatitis (7% to 29%, severe in 4%).

Appropriate antiemetic therapy usually ameliorates mitoxantrone-induced nausea and vomiting.

Nausea and vomiting associated with mitoxantrone is usually less troublesome than with equivalent doses of doxorubicin or daunorubicin.

Cardiovascular

Cardiovascular side effect have included significantly decreased left ventricular (LV) systolic function and congestive heart failure (CHF). Mitoxantrone-induced CHF may be more common in patients with prior treatment with anthracyclines, prior mediastinal radiotherapy, advanced age, multiple sclerosis, or preexisting cardiovascular disease. The overall cumulative probability rate of moderate or serious decreases in LV ejection fraction and CHF at total doses of 140 mg/m2 averages 13% and 2%, respectively. The risk of CHF increases significantly with total doses of greater than 160 mg/m2 (140 mg/m2 if there is a history of receiving anthracyclines). Other cardiovascular side effects include tachycardia, ECG changes (including arrhythmias, prolonged PR, QT, and QRS intervals, and T-wave inversions). Bradycardia and myocardial infarction have rarely been reported.

Mitoxantrone is less cardiotoxic than similar drugs, the anthracyclines.

In first-line comparative trials of mitoxantrone + cytosine arabinoside versus daunorubicin + cytosine arabinoside in adults with previously untreated acute nonlymphocytic leukemia, the incidence of CHF in each arm was 6.5%. A causal relationship between drug therapy and cardiotoxicity is difficult to establish in this setting since myocardial function is frequently depressed by fever, anemia, infection, and hemorrhage, which often accompany the underlying disease.

Most experts recommend stopping mitoxantrone therapy or at least considering endomyocardial biopsy if the LV ejection fraction (per MUGA scan) is reduced by 20% or more during therapy.

Mitoxantrone is chemically related to the anthracyclines, doxorubicin and daunorubicin, which can form free radicals. Free radicals can directly interact with oxygen, causing peroxidation of the lipid membranes of the heart. Supposedly, mitoxantrone does not form free radicals.

Local

Checking for blue streaking in or around the vein is recommended.

Local infusion site problems have included phlebitis and tissue necrosis following IV extravasation.

Nervous system

Intrathecal administration is contraindicated due to cases of paraplegia in humans and hypoactivity, muscle tremors, and paraparesis in animals associated with this route of administration.

Nervous system side effects have included rare cases of lethargy, fatigue, seizures, and headache. Myelodysplasia has also been reported.

Hypersensitivity

Hypersensitivity reactions including hypotension, urticaria, dyspnea, and/or rashes have been reported occasionally.

Dermatologic

Patients should be warned that this drug may cause a blue-green discoloration of their skin, but should be reminded that this strange discoloration will fade and is reversible.

Dermatologic side effects are often associated with hypersensitivity reactions. In addition, reversible alopecia may present in 25% to 50% of patients (complete in up to 10%). Other, rare dermatologic side effects include onycholysis, photosensitivity, and hyperpigmentation.

Renal

Renal side effects including new or worsened renal insufficiency have rarely been associated with the use of mitoxantrone.

Hepatic

Mild, transient elevations of bilirubin and aspartate and alanine aminotransferase levels have been reported from 4 to 24 days after treatment, returning to baseline or normal a median of 8 days later. In rare cases the abnormalities persisted.

Hepatic side effects including rare cases of elevated hepatic enzymes have been reported.

Other

Other side effects have included urinary and scleral blue-green discoloration and hypomagnesemia and/or hypocalcemia.

Genitourinary

Genitourinary side effects including uroepithelial necrosis and green urine (blue mixed with yellow green) have been associated with intravesicular administration of mitoxantrone for superficial bladder tumors.

Endocrine

The mechanism of mitoxantrone-associated amenorrhea is believed to be direct toxic effects on the ovary, as is seen with other forms of chemotherapy.

Endocrine side effects including amenorrhea have been reported.

Disclaimer: Every effort has been made to ensure that the information provided is accurate, up-to-date, and complete, but no guarantee is made to that effect. In addition, the drug information contained herein may be time sensitive and should not be utilized as a reference resource beyond the date hereof. This information does not endorse drugs, diagnose patients, or recommend therapy. This drug information is a reference resource designed as supplement to, and not a substitute for, the expertise, skill , knowledge, and judgement of healthcare practitioners in patient care. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug of drug combination is safe, effective, or appropriate for any given patient. Drugs.com does not assume any responsibility for any aspect of healthcare administered with the aid of information provided. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse, or pharmacist.