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Novantrone (Mitoxantrone Hydrochloride) - Warnings and Precautions

 
 



BOXED WARNING SECTION

NOVANTRONE® (mitoxantrone for injection concentrate) should be administered under the supervision of a physician experienced in the use of cytotoxic chemotherapy agents.

NOVANTRONE® should be given slowly into a freely flowing intravenous infusion.  It must never be given subcutaneously, intramuscularly, or intra-arterially.  Severe local tissue damage may occur if there is extravasation during administration.  (See ADVERSE REACTIONS, General, Cutaneous and DOSAGE AND ADMINISTRATION, Preparation and Administration Precautions ).

NOT FOR INTRATHECAL USE.  Severe injury with permanent sequelae can result from intrathecal administration.  (See WARNINGS, General)

Except for the treatment of acute nonlymphocytic leukemia, NOVANTRONE® therapy generally should not be given to patients with baseline neutrophil counts of less than 1,500 cells/mm3.  In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving NOVANTRONE®.

Use of NOVANTRONE® has been associated with cardiotoxicity.  Cardiotoxicity can occur at any time during NOVANTRONE® therapy, and the risk increases with cumulative dose. Congestive heart failure (CHF), potentially fatal, may occur either during therapy with NOVANTRONE® or months to years after termination of therapy.  All patients should be carefully assessed for cardiac signs and symptoms by history and physical examination prior to start of NOVANTRONE® therapy. Baseline evaluation of left ventricular ejection fraction (LVEF) by echocardiogram or multi-gated radionuclide angiography (MUGA) should be performed. Multiple sclerosis patients with a baseline LVEF <50% should not be treated with NOVANTRONE®.  LVEF should be reevaluated by echocardiogram or MUGA prior to each dose administered to patients with multiple sclerosis.  Additional doses of NOVANTRONE® should not be administered to multiple sclerosis patients who have experienced either a drop in LVEF to below 50% or a clinically significant reduction in LVEF during NOVANTRONE® therapy.  Patients with multiple sclerosis should not receive a cumulative dose greater than 140 mg/m2.  In cancer patients, the risk of symptomatic congestive heart failure (CHF) was estimated to be 2.6% for patients receiving up to a cumulative dose of 140 mg/m2.  Presence or history of cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or concomitant use of other cardiotoxic drugs may increase the risk of cardiac toxicity.  Cardiac toxicity with NOVANTRONE® may occur whether or not cardiac risk factors are present.  For additional information, see WARNINGS, Cardiac Effects, and DOSAGE AND ADMINISTRATION.

Secondary acute myelogenous leukemia (AML) has been reported in multiple sclerosis and cancer patients treated with mitoxantrone.  In a cohort of mitoxantrone treated MS patients followed for varying periods of time, an elevated leukemia risk of 0.25% (2/802) has been observed.  Postmarketing cases of secondary AML have also been reported.  In 1774 patients with breast cancer who received NOVANTRONE® concomitantly with other cytotoxic agents and radiotherapy, the cumulative risk of developing treatment-related AML, was estimated as 1.1% and 1.6% at 5 and 10 years, respectively (see WARNINGS section).  Secondary acute myelogenous leukemia (AML) has been reported in cancer patients treated with anthracyclines.  NOVANTRONE® is an anthracenedione, a related drug.

The occurrence of refractory secondary leukemia is more common when anthracyclines are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated.

 

WARNINGS SECTION

WHEN NOVANTRONE® IS USED IN HIGH DOSES (> 14 mg/m2/d x 3 days) SUCH AS INDICATED FOR THE TREATMENT OF LEUKEMIA, SEVERE MYELOSUPPRESSION WILL OCCUR.  THEREFORE, IT IS RECOMMENDED THAT NOVANTRONE® BE ADMINISTERED ONLY BY PHYSICIANS EXPERIENCED IN THE CHEMOTHERAPY OF THIS DISEASE.  LABORATORY AND SUPPORTIVE SERVICES MUST BE AVAILABLE FOR HEMATOLOGIC AND CHEMISTRY MONITORING AND ADJUNCTIVE THERAPIES, INCLUDING ANTIBIOTICS.  BLOOD AND BLOOD PRODUCTS MUST BE AVAILABLE TO SUPPORT PATIENTS DURING THE EXPECTED PERIOD OF MEDULLARY HYPOPLASIA AND SEVERE MYELOSUPPRESSION.  PARTICULAR CARE SHOULD BE GIVEN TO ASSURING FULL HEMATOLOGIC RECOVERY BEFORE UNDERTAKING CONSOLIDATION THERAPY (IF THIS TREATMENT IS USED) AND PATIENTS SHOULD BE MONITORED CLOSELY DURING THIS PHASE.  NOVANTRONE® ADMINISTERED AT ANY DOSE CAN CAUSE MYELOSUPPRESSION.

General:

Patients with preexisting myelosuppression as the result of prior drug therapy should not receive NOVANTRONE® unless it is felt that the possible benefit from such treatment warrants the risk of further medullary suppression.

The safety of NOVANTRONE® (mitoxantrone for injection concentrate) in patients with hepatic insufficiency is not established (see CLINICAL PHARMACOLOGY).

Safety for use by routes other than intravenous administration has not been established.

NOVANTRONE® is not indicated for subcutaneous, intramuscular, or intra-arterial injection.  There have been reports of local/regional neuropathy, some irreversible, following intra-arterial injection.

NOVANTRONE® must not be given by intrathecal injection.  There have been reports of neuropathy and neurotoxicity, both central and peripheral, following intrathecal injection.  These reports have included seizures leading to coma and severe neurologic sequelae, and paralysis with bowel and bladder dysfunction.

Topoisomerase II inhibitors, including NOVANTRONE®, have been associated with the development of secondary AML and myelosuppression.

Cardiac Effects:

Because of the possible danger of cardiac effects in patients previously treated with daunorubicin or doxorubicin, the benefit-to-risk ratio of NOVANTRONE® therapy in such patients should be determined before starting therapy.

Functional cardiac changes including decreases in left ventricular ejection fraction (LVEF) and irreversible congestive heart failure can occur with NOVANTRONE®.  Cardiac toxicity may be more common in patients with prior treatment with anthracyclines, prior mediastinal radiotherapy, or with preexisting cardiovascular disease.  Such patients should have regular cardiac monitoring of LVEF from the initiation of therapy.  Cancer patients who received cumulative doses of 140 mg/m2 either alone or in combination with other chemotherapeutic agents had a cumulative 2.6% probability of clinical congestive heart failure.  In comparative oncology trials, the overall cumulative probability rate of moderate or severe decreases in LVEF at this dose was 13%.

Multiple Sclerosis:

Changes in cardiac function may occur in patients with multiple sclerosis treated with NOVANTRONE®.  In one controlled trial (Study 1, see CLINICAL TRIALS, Multiple Sclerosis), two patients (2%) of 127 receiving NOVANTRONE®, one receiving a 5 mg/m2 dose and the other receiving the 12 mg/m2 dose, had LVEF values that decreased to below 50%.  An additional patient receiving 12 mg/m2, who did not have LVEF measured, had a decrease in another echocardiographic measurement of ventricular function (fractional shortening) that led to discontinuation from the trial (see ADVERSE REACTIONS, Multiple Sclerosis).  There were no reports of congestive heart failure in either controlled trial.

LVEF should be evaluated by echocardiogram or MUGA prior to administration of the initial dose of NOVANTRONE®.  Multiple sclerosis patients with a baseline LVEF of <50% should not be treated with NOVANTRONE®.  Subsequent LVEF evaluations are recommended if signs or symptoms of congestive heart failure develop, and prior to all doses administered to multiple sclerosis patients. NOVANTRONE® should not be administered to multiple sclerosis patients with an LVEF <50%, with a clinically significant reduction in LVEF, or to those who have received a cumulative lifetime dose of > 140 mg/m2.

Leukemia:

Acute congestive heart failure may occasionally occur in patients treated with NOVANTRONE® for ANLL.  In first-line comparative trials of NOVANTRONE® + cytarabine vs daunorubicin + cytarabine in adult patients with previously untreated ANLL, therapy was associated with congestive heart failure in 6.5% of patients on each arm.  A causal relationship between drug therapy and cardiac effects is difficult to establish in this setting since myocardial function is frequently depressed by the anemia, fever and infection, and hemorrhage that often accompany the underlying disease.

Hormone-Refractory Prostate Cancer:

Functional cardiac changes such as decreases in LVEF and congestive heart failure may occur in patients with hormone-refractory prostate cancer treated with NOVANTRONE®.  In a randomized comparative trial of NOVANTRONE® plus low-dose prednisone vs low-dose prednisone, 7 of 128 patients (5.5 %) treated with NOVANTRONE® had a cardiac event defined as any decrease in LVEF below the normal range, congestive heart failure (n = 3), or myocardial ischemia.  Two patients had a prior history of cardiac disease.  The total NOVANTRONE® dose administered to patients with cardiac effects ranged from > 48 to 212 mg/m2.

Among 112 patients evaluable for safety on the NOVANTRONE® + hydrocortisone arm of the CALGB trial, 18 patients (19%) had a reduction in cardiac function, 5 patients (5%) had cardiac ischemia, and 2 patients (2%) experienced pulmonary edema.  The range of total NOVANTRONE® doses administered to these patients is not available.

Pregnancy:

NOVANTRONE® may cause fetal harm when administered to a pregnant woman.  Women of childbearing potential should be advised to avoid becoming pregnant.  Mitoxantrone is considered a potential human teratogen because of its mechanism of action and the developmental effects demonstrated by related agents.  Treatment of pregnant rats during the organogenesis period of gestation was associated with fetal growth retardation at doses > 0.1 mg/kg/day (0.01 times the recommended human dose on a mg/m2 basis).  When pregnant rabbits were treated during organogenesis, an increased incidence of premature delivery was observed at doses > 0.1 mg/kg/day (0.01 times the recommended human dose on a mg/m2 basis).  No teratogenic effects were observed in these studies, but the maximum doses tested were well below the recommended human dose (0.02 and 0.05 times in rats and rabbits, respectively, on a mg/m2 basis).  There are no adequate and well-controlled studies in pregnant women.  Women with multiple sclerosis who are biologically capable of becoming pregnant should have a pregnancy test prior to each dose, and the results should be known prior to administration of the drug.  If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to the fetus.

Secondary Leukemia:

Secondary acute myelogenous leukemia (AML) has been reported in multiple sclerosis and cancer patients treated with mitoxantrone.  In a cohort of mitoxantrone treated MS patients followed for varying periods of time, an elevated leukemia risk of 0.25% (2/802) has been observed.  Postmarketing cases of secondary AML have also been reported.  In 1774 patients with breast cancer who received NOVANTRONE® concomitantly with other cytotoxic agents and radiotherapy, the cumulative risk of developing treatment-related AML was estimated as 1.1% and 1.6% at 5 and 10 years, respectively.  The second largest report involved 449 patients with breast cancer treated with NOVANTRONE®, usually in combination with radiotherapy and/or other cytotoxic agents.  In this study, the cumulative probability of developing secondary leukemia was estimated to be 2.2% at 4 years.

Secondary AML has also been reported in cancer patients treated with anthracyclines.  NOVANTRONE® is an anthracenedione, a related drug.  The occurrence of refractory secondary leukemia is more common when anthracyclines are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated.

PRECAUTIONS SECTION

GENERAL PRECAUTIONS SECTION

Therapy with NOVANTRONE® should be accompanied by close and frequent monitoring of hematologic and chemical laboratory parameters, as well as frequent patient observation.

Systemic infections should be treated concomitantly with or just prior to commencing therapy with NOVANTRONE®.

INFORMATION FOR PATIENTS SECTION

NOVANTRONE® may impart a blue-green color to the urine for 24 hours after administration, and patients should be advised to expect this during therapy.  Bluish discoloration of the sclera may also occur.  Patients should be advised of the signs and symptoms of myelosuppression.

Patients with multiple sclerosis should be provided with the Patient Package Insert at the time that the decision is made to treat with NOVANTRONE® and prior to and in close temporal proximity to each treatment.  In addition, the physician should discuss the issues addressed in the Patient Package Insert with the patient.

LABORATORY TESTS SECTION

A complete blood count, including platelets, should be obtained prior to each course of NOVANTRONE® and in the event that signs and symptoms of infection develop.  Liver function tests should also be performed prior to each course of therapy.  NOVANTRONE® therapy in multiple sclerosis patients with abnormal liver function tests is not recommended because NOVANTRONE® clearance is reduced by hepatic impairment and no laboratory measurement can predict drug clearance and dose adjustments.

In leukemia treatment, hyperuricemia may occur as a result of rapid lysis of tumor cells by NOVANTRONE®.  Serum uric acid levels should be monitored and hypouricemic therapy instituted prior to the initiation of antileukemic therapy.

Women with multiple sclerosis who are biologically capable of becoming pregnant, even if they are using birth control, should have a pregnancy test, and the results should be known, before receiving each dose of NOVANTRONE® (see WARNINGS, Pregnancy).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION

Carcinogenesis -

Intravenous treatment of rats and mice, once every 21 days for 24 months, with NOVANTRONE® resulted in an increased incidence of fibroma and external auditory canal tumors in rats at a dose of 0.03 mg/kg (0.02 fold the recommended human dose, on a mg/m2 basis), and hepatocellular adenoma in male mice at a dose of 0.1 mg/kg (0.03 fold the recommended human dose, on a mg/m2 basis).  Intravenous treatment of rats, once every 21 days for 12 months with NOVANTRONE® resulted in an increased incidence of external auditory canal tumors in rats at a dose of 0.3 mg/kg (0.15 fold the recommended human dose, on a mg/m2 basis).

Mutagenesis -

NOVANTRONE® was clastogenic in the in vivo rat bone marrow assay.  NOVANTRONE® was also clastogenic in two in vitro assays; it induced DNA damage in primary rat hepatocytes and sister chromatid exchanges in Chinese hamster ovary cells.  NOVANTRONE® was mutagenic in bacterial and mammalian test systems (Ames/Salmonella and E. coli and L5178Y TK+/-mouse lymphoma).

DRUG INTERACTIONS SECTION

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.

Special Populations:

Hepatic Impairment

Patients with multiple sclerosis who have hepatic impairment should ordinarily not be treated with NOVANTRONE®.  NOVANTRONE® should be administered with caution to other patients with hepatic impairment.  In patients with severe hepatic impairment, the AUC is more than three times greater than the value observed in patients with normal hepatic function.

PREGNANCY SECTION

Pregnancy Category D (see WARNINGS).

NURSING MOTHERS SECTION

NOVANTRONE® is excreted in human milk and significant concentrations (18 ng/mL) have been reported for 28 days after the last administration.  Because of the potential for serious adverse reactions in infants from NOVANTRONE®, breastfeeding should be discontinued before starting treatment.

PEDIATRIC USE SECTION

Safety and effectiveness in pediatric patients have not been established.

GERIATRIC USE SECTION

Multiple Sclerosis: Clinical studies of NOVANTRONE® did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.  Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Hormone-Refractory Prostate Cancer: One hundred forty-six patients aged 65 and over and 52 younger patients (<65 years) have been treated with NOVANTRONE® in controlled clinical studies.  These studies did not include sufficient numbers of younger patients to determine whether they respond differently from older patients.  However, greater sensitivity of some older individuals cannot be ruled out.

Acute Nonlymphocytic Leukemia: Although definitive studies with NOVANTRONE® have not been performed in geriatric patients with ANLL, toxicity may be more frequent in the elderly.  Elderly patients are more likely to have age-related comorbidities due to disease or disease therapy.

Page last updated: 2008-01-30

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