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

The safety of Mitoxantrone Injection, USP (concentrate) in patients with hepatic insufficiency is not established (see

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

Mitoxantrone 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 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, 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 mitoxantrone 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.  Cardiac toxicity may be more common in patients with prior treatment with anthracyclines, prior mediastinal radiotherapy, or with pre-existing 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/m

Changes in cardiac function may occur in patients with multiple sclerosis treated with mitoxantrone. In one controlled trial (Study 1, see

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 therapy. MS patients with a baseline LVEF below the lower limit of normal should not be treated with mitoxantrone. 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 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/m

Acute congestive heart failure may occasionally occur in patients treated with mitoxantrone for ANLL.  In first-line comparative trials of mitoxantrone + 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.

Functional cardiac changes such as decreases in LVEF and congestive heart failure may occur in patients with hormone-refractory prostate cancer treated with mitoxantrone.  In a randomized comparative trial of mitoxantrone plus low-dose prednisone vs. low-dose prednisone, 7 of 128 patients (5.5 %) treated with mitoxantrone 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 dose administered to patients with cardiac effects ranged from > 48 to 212 mg/m

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

Mitoxantrone 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/m

Mitoxantrone 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 follow-up.

In a prospective, open-label, tolerability and safety monitoring study of mitoxantrone 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 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 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, 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 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.

The recommended dosage of Mitoxantrone Injection, USP is 12 mg/m

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 Mitoxantrone Injection, USP (see

Based on data from two Phase 3 comparative trials of mitoxantrone injection plus corticosteroids versus corticosteroids alone, the recommended dosage of mitoxantrone is 12 to 14 mg/m

For induction, the recommended dosage is 12 mg/m

Most complete remissions will occur following the initial course of induction therapy.  In the event of an incomplete antileukemic response, a second induction course may be given.  Mitoxantrone Injection should be given for 2 days and cytarabine for 5 days using the same daily dosage levels.

If severe or life-threatening nonhematologic toxicity is observed during the first induction course, the second induction course should be withheld until toxicity resolves.

Consolidation therapy which was used in two large randomized multicenter trials consisted of mitoxantrone, 12 mg/m

For patients with hepatic impairment, there is at present no laboratory measurement that allows for dose adjustment recommendations (see

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

The dose of mitoxantrone should be diluted to at least 50 mL with either 0.9% Sodium Chloride Injection (USP) or 5% Dextrose Injection (USP).  Mitoxantrone Injection, USP (concentrate) may be further diluted into Dextrose 5% in Water, Normal Saline or Dextrose 5% with Normal Saline and used immediately.  DO NOT FREEZE.

Mitoxantrone should not be mixed in the same infusion as heparin since a precipitate may form.  Because specific compatibility data are not available, it is recommended that mitoxantrone not be mixed in the same infusion with other drugs.  The diluted solution should be introduced slowly into the tubing as a freely running intravenous infusion of 0.9% Sodium Chloride Injection (USP) or 5% Dextrose Injection (USP) over a period of not less than 3 minutes.  Unused infusion solutions should be discarded immediately in an appropriate fashion.  In the case of multidose use, after penetration of the stopper, the remaining portion of the undiluted Mitoxantrone Injection, USP (concentrate) should be stored not longer than 7 days between 15° to 25°C (59° to 77°F) or 14 days under refrigeration.  DO NOT FREEZE.  CONTAINS NO PRESERVATIVE.

Care in the administration of mitoxantrone will reduce the chance of extravasation.  Mitoxantrone should be administered into the tubing of a freely running intravenous infusion of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.  The tubing should be attached to a Butterfly needle or other suitable device and inserted preferably into a large vein.  If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage.  Care should be taken to avoid extravasation at the infusion site and to avoid contact of mitoxantrone with the skin, mucous membranes, or eyes.  MITOXANTRONE SHOULD NOT BE ADMINISTERED SUBCUTANEOUSLY.  If any signs or symptoms of extravasation have occurred, including burning, pain, pruritus, erythema, swelling, blue discoloration, or ulceration, the injection or infusion should be immediately terminated and restarted in another vein.  During intravenous administration of mitoxantrone extravasation may occur with or without an accompanying stinging or burning sensation even if blood returns well on aspiration of the infusion needle.  If it is known or suspected that subcutaneous extravasation has occurred, it is recommended that intermittent ice packs be placed over the area of extravasation and that the affected extremity be elevated.  Because of the progressive nature of extravasation reactions, the area of injection should be frequently examined and surgery consultation obtained early if there is any sign of a local reaction.

Skin accidentally exposed to mitoxantrone should be rinsed copiously with warm water and if the eyes are involved, standard irrigation techniques should be used immediately.  The use of goggles, gloves, and protective gowns is recommended during preparation and administration of the drug.

Procedures for proper handling and disposal of anticancer drugs should be considered.  Several guidelines on this subject have been published.