"The U.S. Food and Drug Administration today approved Tecfidera (dimethyl fumarate) capsules to treat adults with relapsing forms of multiple sclerosis (MS).
MS is a chronic, inflammatory, autoimmune disease of the central nervous system"...
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.
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 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 acute myeloid leukemia and myelosuppression.
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%.
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.
MS patients should be assessed for cardiac signs and symptoms by history, physical examination, ECG, and quantitative LVEF evaluation using appropriate methodology (ex. Echocardiogram, MUGA, MRI, etc.) prior to the start of NOVANTRONE therapy. MS patients with a baseline LVEF below the lower limit of normal should not be treated with NOVANTRONE. Subsequent LVEF and ECG evaluations are recommended if signs or symptoms of congestive heart failure develop and prior to every dose administered to MS patients. NOVANTRONE should not be administered to MS patients who experience a reduction in LVEF to below the lower limit of normal, to those who experience a clinically significant reduction in LVEF, or to those who have received a cumulative lifetime dose of 140 mg/m². MS patients should have yearly quantitative LVEF evaluation after stopping NOVANTRONE to monitor for late-occurring cardiotoxicity.
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.
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.
NOVANTRONE® therapy increases the risk of developing secondary leukemia in patients with cancer and in patients with multiple sclerosis.
In a study of patients with prostate cancer, acute myeloid leukemia occurred in 1% (5/487) of mitoxantrone-treated patients versus no cases in the control group (0/496) not receiving mitoxantrone at 4.7 years followup.
In a prospective, open-label, tolerability and safety monitoring study of NOVANTRONE® treated MS patients followed for up to five years (median of 2.8 years), leukemia occurred in 0.6% (3/509) of patients. Publications describe leukemia risks of 0.25% to 2.8% in cohorts of patients with MS treated with NOVANTRONE® and followed for varying periods of time. This leukemia risk exceeds the risk of leukemia in the general population. The most commonly reported types were acute promyelocytic leukemia and acute myelocytic leukemia.
In 1774 patients with breast cancer who received NOVANTRONE concomitantly with other cytotoxic agents and radiotherapy, the cumulative risk of developing treatment-related acute myeloid leukemia 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 acute myeloid leukemia has also been reported in cancer patients treated with anthracyclines. NOVANTRONE is an anthracenedione, a related drug. The occurrence of 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.
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
See FDA-approved patient labeling (Medication Guide).
Inform patients of the availability of a Medication Guide and instruct them to read the Medication Guide prior to initiating treatment with Novantrone and prior to each infusion. Review the Novantrone Medication Guide with every patient prior to initiation of treatment and periodically during treatment. Instruct patients that Novantrone should be taken only as prescribed.
Advise patients that Novantrone can cause myelosuppression and inform patients of the signs and symptoms of myelosuppression. Advise patients that Novantrone can cause congestive heart failure that may lead to death even in people who have never had heart problems before, and inform patients of the signs and symptoms of congestive heart failure. Advise patients receiving Novantrone to treat multiple sclerosis that they should receive cardiac monitoring prior to each Novantrone dose and yearly after stopping Novantrone.
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.
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
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).
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).
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 Category D (see WARNINGS).
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, breast feeding should be discontinued before starting treatment.
Safety and effectiveness in pediatric patients have not been established.
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.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 4/19/2012
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