Mitoxantrone Hydrochloride

Mitoxantrone Hydrochloride

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Questions & Answers

Side Effects & Adverse Reactions

WHEN MitoXANTRONE Injection 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 MitoXANTRONE Injection 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. MitoXANTRONE INJECTION ADMINISTERED AT ANY DOSE CAN CAUSE MYELOSUPPRESSION.

CONTAINS SODIUM METABISULPHITE, A SULPHITE THAT MAY CAUSE ALLERGIC-TYPE REACTIONS INCLUDING ANAPHYLACTIC SYMPTOMS AND LIFE-THREATENING OR LESS SEVERE ASTHMATIC EPISODES IN CERTAIN SUSCEPTIBLE PEOPLE. THE OVERALL PREVALENCE OF SULFITE SENSITIVITY IN THE GENERAL POPULATION IS UNKNOWN AND PROBABLY LOW. SULFITE SENSITIVITY IS SEEN MORE FREQUENTLY IN ASTHMATIC THAN IN NONASTHMATIC PEOPLE.

General

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

The safety of MitoXANTRONE Injection in patients with hepatic insufficiency is not established (see CLINICAL PHARMACOLOGY).

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

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

MitoXANTRONE Injection 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 MitoXANTRONE Injection, have been associated with the development of secondary acute myeloid leukemia 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 MitoXANTRONE Injection 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 MitoXANTRONE Injection. 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 MitoXANTRONE Injection. In one controlled trial (Study 1, see CLINICAL TRIALS, Multiple Sclerosis), two patients (2%) of 127 receiving MitoXANTRONE Injection, 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 MitoXANTRONE Injection therapy. MS patients with a baseline LVEF below the lower limit of normal should not be treated with MitoXANTRONE Injection. 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. MitoXANTRONE Injection 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 MitoXANTRONE Injection to monitor for late-occurring cardiotoxicity.

Leukemia

Acute congestive heart failure may occasionally occur in patients treated with MitoXANTRONE Injection for ANLL. In first-line comparative trials of MitoXANTRONE Injection + 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 MitoXANTRONE Injection. In a randomized comparative trial of MitoXANTRONE Injection plus low-dose prednisone vs low-dose prednisone, 7 of 128 patients (5.5 %) treated with MitoXANTRONE Injection 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 MitoXANTRONE Injection dose administered to patients with cardiac effects ranged from > 48 to 212 mg/m2.

Among 112 patients evaluable for safety on the MitoXANTRONE Injection + 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 MitoXANTRONE Injection doses administered to these patients is not available.

Pregnancy

MitoXANTRONE Injection 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

MitoXANTRONE Injection 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 MitoXANTRONE Injection 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 MitoXANTRONE Injection 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 MitoXANTRONE Injection 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 MitoXANTRONE Injection, 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. MitoXANTRONE Injection 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. Symptoms of acute leukemia may include excessive bruising, bleeding, and recurrent infections.

Legal Issues

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FDA Safety Alerts

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Manufacturer Warnings

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FDA Labeling Changes

There are currently no FDA labeling changes available for this drug.

Uses

MitoXANTRONE Injection is indicated for reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis (i.e., patients whose neurologic status is significantly abnormal between relapses). MitoXANTRONE Injection is not indicated in the treatment of patients with primary progressive multiple sclerosis.

The clinical patterns of multiple sclerosis in the studies were characterized as follows: secondary progressive and progressive relapsing disease were characterized by gradual increasing disability with or without superimposed clinical relapses, and worsening relapsing-remitting disease was characterized by clinical relapses resulting in a step-wise worsening of disability.

MitoXANTRONE Injection in combination with corticosteroids is indicated as initial chemotherapy for the treatment of patients with pain related to advanced hormone-refractory prostate cancer.

MitoXANTRONE Injection in combination with other approved drug(s) is indicated in the initial therapy of acute nonlymphocytic leukemia (ANLL) in adults. This category includes myelogenous, promyelocytic, monocytic, and erythroid acute leukemias.

History

There is currently no drug history available for this drug.

Other Information

MitoXANTRONE Injection USP (Concentrate) is a synthetic antineoplastic anthracenedione for intravenous use. The molecular formula is C22H28N4O6•2HCl and the molecular weight is 517.41. It is supplied as a concentrate that MUST BE DILUTED PRIOR TO INJECTION. The concentrate is a sterile, nonpyrogenic, dark blue aqueous solution containing mitoxantrone hydrochloride equivalent to 2 mg/mL mitoxantrone free base, with sodium chloride (0.80% w/v), sodium acetate (0.005% w/v), Sodium Metabisulphite (0.01% w/v) and acetic acid (0.046% w/v) as inactive ingredients. The solution has a pH of 3.0 to 4.5 and contains 0.14 mEq of sodium per mL. The product does not contain preservatives. The chemical name is 1,4-dihydroxy-5,8-bis[[2-[(2-hydroxyethyl)amino]ethyl]amino]-9,10-anthracenedione dihydrochloride and the structural formula is:

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Mitoxantrone Hydrochloride Manufacturers


  • Pfizer Laboratories Div Pfizer Inc.
    Mitoxantrone Hydrochloride Injection, Solution [Pfizer Laboratories Div Pfizer Inc.]

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