VA Class:AN900

AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• mitoXANTRONE Hydrochloride

Chemical Name:

• 1,4-dihydroxy-5,8-bis[[2-[2-hydroxyethyl)amino]ethyl]amino]9,10-anthracenedione dihydrochloride

Molecular Formula:

• C₂₂H₂₈N₄O₆•2HCl

Mitoxantrone hydrochloride, a synthetic anthracenedione, is an antineoplastic agent.1,2,3,4,26

Acute Myeloid Leukemia

Mitoxantrone is used as a component of various chemotherapeutic regimens for remission induction in acute myeloid (myelogenous, nonlymphocytic) leukemia (AML, ANLL) in adults.1,2,3,7,8,9,10,11,24 AML includes acute promyelocytic, monocytic, myelomonocytic, megakaryoblastic, and erythroid leukemias.1,23 Induction regimens are used to rapidly reduce the tumor burden in order to achieve complete remission, which generally is defined as less than 5% leukemic blast cells in the bone marrow and normalization of peripheral blood counts (including hemoglobin concentration, hematocrit, granulocyte count, and platelet count), and absence of any evidence of extramedullary disease.7,23 Optimal postremission therapy has not been established, but current approaches include consolidation chemotherapy with cytarabine-based regimens similar to standard induction regimens, consolidation chemotherapy with high-dose cytarabine-based regimens (for younger adults), high-dose chemotherapy or chemoradiotherapy with autologous bone marrow rescue, or high-dose marrow-ablative therapy with allogeneic bone marrow rescue.23,24 There is no evidence of benefit from prolonged administration of chemotherapy in the treatment of AML, and most current treatment regimens in the US no longer employ maintenance therapy.23

Although cytarabine and an anthracycline (usually daunorubicin) have been principal components of induction regimens, various regimens (e.g., cytarabine combined with mitoxantrone, daunorubicin, or idarubicin) have been used in combination therapy and comparative efficacy is continually being evaluated.1,2,7,8,9,10,11,23,24 The results of randomized trials comparing combined mitoxantrone and cytarabine therapy with combined daunorubicin and cytarabine therapy have shown the 2 regimens to have similar efficacy and toxicity as induction therapy in patients with previously untreated AML.1,2,3,7,8,9,10,11,23 Mitoxantrone also has been used in combination with etoposide or etoposide plus cytarabine for initial induction therapy in patients with AML.2,23 In addition, mitoxantrone has been used alone or in combination with etoposide and/or cytarabine in patients with refractory or relapsed AML, and incomplete cross-resistance between mitoxantrone and daunorubicin has been demonstrated in some trials.2,23

In 2 large randomized multicenter trials (the US Trial and the International Trial), remission induction therapy for AML with mitoxantrone 12 mg/m² daily for 3 days (administered IV over 10 minutes) and cytarabine 100 mg/m² for 7 days (administered as a continuous 24-hour IV infusion) was compared with daunorubicin 45 mg/m² daily (administered by IV infusion) for 3 days plus the same dose and schedule of cytarabine used with mitoxantrone.1,8,10 Patients who had an incomplete antileukemic response received a second induction course in which mitoxantrone or daunorubicin was given for 2 days and cytarabine for 5 days using the same daily dosage schedule.1,8,10 In the US Trial, complete response rate (63 versus 53%) and median survival (312 versus 237 days) were similar in patients receiving mitoxantrone/cytarabine or daunorubicin/cytarabine, respectively.1 Among patients experiencing complete response, the percentage of patients who entered remission following one course of induction therapy was higher for those receiving mitoxantrone and cytarabine than for those receiving daunorubicin and cytarabine.8 In the International Trial, response rates (50 versus 51%) and median survival (192 versus 230 days) were similar for patients receiving mitoxantrone/cytarabine or daunorubicin/cytarabine, respectively.1

In these studies, two consolidation courses were administered to complete responders in both groups.1,8,10 Consolidation therapy consisted of the same drug and daily dosage used for remission induction, but with only 5 days of cytarabine and 2 days of mitoxantrone or daunorubicin.1,8,10 The first consolidation course was administered 6 weeks after the start of the final induction course if the patient achieved a complete remission, and the second consolidation course generally was administered 4 weeks later.1,8 The benefit of consolidation therapy in patients with AML who achieve a complete remission is not firmly established; however, in the only well-controlled prospective, randomized multicenter trials with mitoxantrone in AML, consolidation therapy was given to all patients who achieved a complete remission.1,8,10

The degree of myelosuppression was greater for patients receiving mitoxantrone and cytarabine than for those receiving daunorubicin and cytarabine.1 Full hematologic recovery was required for patients to receive consolidation therapy.1 In the US Trial, the median granulocyte nadirs for consolidation courses 1 and 2 were 10/mm³ (for both courses) for patients receiving mitoxantrone and cytarabine and 170/mm³ and 260/mm³ for patients receiving daunorubicin and cytarabine.1 The median platelet nadirs for consolidation courses 1 and 2 were 17,000/mm³ and 14,000/mm³ for patients receiving mitoxantrone and cytarabine and 33,000/mm³ and 22,000/mm³ for patients receiving daunorubicin and cytarabine.1 Two deaths from myelosuppression occurred in the mitoxantrone group and one occurred in the daunorubicin group.1 In the International Trial, 8 deaths related to myelosuppression occurred in the mitoxantrone group during consolidation therapy and none occurred in the daunorubicin group; this difference was attributed to greater myelosuppression in the mitoxantrone group and lack of proper supportive care.1,10

The incidence and severity of toxicity were similar in patients receiving either mitoxantrone/cytarabine or daunorubicin/cytarabine for AML.8,10 The most common adverse effects in patients receiving mitoxantrone and cytarabine as induction therapy for AML were fever (78%), nausea and vomiting (72%), infections (66%), diarrhea (47%), and pulmonary events (43%).1

Prostate Cancer

Docetaxel used in combination with prednisone is a preferred first-line treatment for androgen-independent (hormone-refractory) metastatic prostate cancer.22 Mitoxantrone and prednisone is used as an alternative regimen for advanced hormone-refractory prostate cancer.22,24 In a multicenter, randomized trial, median survival was prolonged (18.9 versus 16.5 months) in patients receiving docetaxel (once-every-3-weeks regimen) and prednisone compared with those receiving mitoxantrone and prednisone.33

Mitoxantrone in combination with a corticosteroid is an alternative regimen used as initial chemotherapy for the palliative treatment of advanced, symptomatic (i.e., painful) hormone-refractory prostate cancer.1,12,13,14,24,26 Randomized studies have shown that the addition of mitoxantrone to corticosteroid therapy results in a greater proportion of patients achieving a palliative response (i.e., pain reduction) and a longer duration of such response compared with corticosteroid treatment alone.1,12,13,14,22,26 Although statistically significant differences between the regimens were not demonstrated,14,22 improvement in some quality-of-life measures, including indicators related to pain, physical activity or function, constipation, and mood, favored combination therapy.13,14

Combination therapy with mitoxantrone and low-dose prednisone was compared with low-dose prednisone alone in a randomized, multicenter trial.1,14,22 Patients included in the trial had metastatic or locally advanced prostate cancer that had progressed on standard hormonal therapy, serum testosterone concentrations consistent with castration, and at least mild pain at study entry.1,14 Patients were randomized to receive low-dose prednisone (5 mg orally twice daily) alone or combination therapy with low-dose prednisone and mitoxantrone (12 mg/m² by short IV infusion every 3 weeks).1,14 Patients randomized to receive prednisone alone were crossed over to the combination therapy arm if their disease progressed or if no improvement was seen after at least 6 weeks of prednisone treatment.1,14

In this trial, a primary palliative response was defined as a 2-point decrease in pain intensity in a 6-point pain scale associated with stable analgesic use and lasting a minimum of 6 weeks, and a secondary palliative response was defined as a 50% or greater decrease in analgesic use associated with stable pain intensity and lasting a minimum of 6 weeks.1,14 Higher primary and overall (primary and secondary) palliative response rates were achieved in patients who received combination therapy compared with those who received prednisone alone (29 and 38% versus 12 and 21%, respectively).1,14 In addition, median duration of primary and overall palliative responses were longer in patients who received combination therapy (7.6 and 5.6 months versus 2.1 and 1.9 months, respectively).1 Time to progression, defined as a 1-point increase in pain intensity, a greater than 25% increase in analgesic use, radiographic evidence of disease progression, or requirement for radiotherapy, was shorter in patients who received prednisone alone (2.3 months) than in those who received combination therapy (4.4 months).1 Median survival time did not differ significantly in the 2 groups.1 Among patients randomized to receive prednisone alone and subsequently crossed over to receive combination therapy, 19% achieved a palliative response with combined mitoxantrone and prednisone treatment.1

Retrospective analysis showed that a decrease in serum prostate specific antigen (PSA) concentration (decrease of at least 50% for 2 consecutive follow-up assessments after baseline) was observed in 33% of patients receiving mitoxantrone and prednisone compared with 9% of patients receiving prednisone alone.1 Some patients were not evaluable for response, and there was an imbalance in the number of evaluable patients per treatment group.1 In addition, the clinical importance of a decline in serum PSA concentration following chemotherapy is uncertain, and PSA reduction did not necessarily correlate with palliative response, the primary efficacy endpoint in this study.1 Because of these limitations, the importance of these findings is not certain.1

Nausea (61 versus 35%), fatigue (39 versus 14%), alopecia (29 versus 0%), and anorexia (25 versus 6%) occurred more frequently in patients receiving mitoxantrone than in those receiving prednisone alone for advanced hormone-refractory prostate cancer.1

A phase 3 trial comparing mitoxantrone and hydrocortisone to hydrocortisone alone in patients with hormone-refractory prostate cancer also was conducted (CALGB 9182).1,34 Patients in this trial received hydrocortisone orally at a dosage of 40 mg daily with or without mitoxantrone 14 mg/m² IV every 21 days.1,34 No difference in survival was observed between the treatment groups.1,34 Using National Prostate Cancer Project (NPCP) criteria for response, 8.4% of patients in the combination therapy group and 1.6% of patients in the hydrocortisone group achieved partial responses (by intent-to-treat analysis).1 A trend toward longer median time to progression was observed for the combination therapy group compared with the hydrocortisone monotherapy group (7.3 versus 4.1 months).1 Beneficial effects also were observed with the addition of mitoxantrone to hydrocortisone treatment in the best percent change from baseline in mean analgesic use (-17% versus +17%) and the best percent change from baseline in mean pain intensity (-14% versus +8%).1

In addition to myelosuppression, particularly leukopenia (87 versus 4%) and anemia (75 versus 39%), fatigue or malaise (34 versus 14%), edema (30 versus 14%), nausea (26 versus 8%), alopecia (20 versus 1%), and decreased cardiac function (18 versus 0%) occurred more frequently in patients receiving mitoxantrone and hydrocortisone than in those receiving hydrocortisone alone for advanced hormone-refractory prostate cancer.1

Multiple Sclerosis

Mitoxantrone is used to reduce neurologic disability and/or the frequency of clinical relapses in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis (MS; i.e., patients with substantially abnormal neurologic status between relapses).1,27 In clinical studies, secondary progressive and progressive relapsing disease was characterized by gradually increasing disability with or without superimposed clinical relapses, and worsening relapsing-remitting disease was characterized by clinical relapses resulting in stepwise worsening of disability.1 Mitoxantrone is used as an immunosuppressant in the treatment of MS.27 The drug is not indicated for use in the treatment of primary progressive MS.1 Because of the high incidence of severe toxicity (e.g., cardiomyopathy, ovarian failure, male infertility, chromosomal aberrations, promyelocytic leukemia), the American Academy of Neurology (AAN) states that mitoxantrone should not be used in patients with MS unless the potential therapeutic benefits greatly outweigh the risks.76

The current indication for the use of mitoxantrone in secondary progressive MS is based on the results of 2 randomized multicenter clinical trials.1,28,29 In a placebo-controlled randomized study, 188 evaluable patients with secondary progressive MS or progressive relapsing MS (also known as worsening relapsing-remitting MS) received mitoxantrone (at a treatment dose level of 12 mg/m² or an exploratory dose level of 5 mg/m²) IV every 3 months for 2 years or placebo.1,28 Placebo solution was mixed with methylene blue to match the color of the mitoxantrone solution.28 Patients who experienced relapses received high-dose methylprednisolone.1,28 The primary endpoint for the study was a multivariate analysis of 5 clinical variables: the Kurtz Expanded Disability Status Scale (EDSS), a scale of neurologic disability; ambulation index (AI), a scale of progressive ambulatory impairment; number of relapses requiring corticosteroid therapy; number of months to first relapse requiring corticosteroid therapy; and Standard Neurological Status (SNS), a measure of neurologic impairment and disability.1,28 A subset of patients underwent magnetic resonance imagery (MRI) at baseline, month 12, and month 24.1,28 Neurologic assessments and MRI reviews were conducted by clinicians who were blinded to the study drug and clinical outcome.1,28 Diagnosis and decisions to treat relapses were made by treating physicians who were not blinded.1,28 Patients were evaluated every 3 months and clinical outcome was determined at 24 months.1

At 24 months, multivariate analysis showed that overall primary efficacy was superior in patients receiving mitoxantrone 12 mg/m² IV every 3 months compared with those receiving placebo.1,28 Preplanned univariate analysis of the individual variables showed that the strongest treatment effects for mitoxantrone were reduction in the number of treated relapses and increased time to first treated relapse.28 However, the strength of this evidence is limited by the lack of blinding of the clinicians who diagnosed and treated these clinical attacks.27 These clinical findings were supported by secondary outcome measures in the MRI reviews for the subset of study patients undergoing MRI scans, which showed that the number of patients with new gadolinium-enhanced lesions and the mean change in the number of T2-weighted lesions were reduced in patients receiving mitoxantrone (12 mg/m²) compared with those receiving placebo.1,30

Nausea, alopecia, urinary tract infection, and menstrual disorders, including amenorrhea, occurred more frequently in patients receiving mitoxantrone than in those receiving placebo.1 Most of these adverse effects were mild to moderate in severity.1,28 Cardiac toxicity occurred in 3 patients receiving mitoxantrone: left ventricular ejection fraction (LVEF) decreased below 50% in 2 patients, one receiving the 5-mg/m² dose and the other receiving the 12-mg/m² dose; a patient receiving mitoxantrone 12 mg/m² was withdrawn from the study after fractional shortening was observed during echocardiographic measurement of LVEF.1 More patients receiving mitoxantrone 12 mg/m² discontinued treatment because of an adverse effect than those receiving placebo (about 10 versus 3%).1

In a second randomized controlled study, 42 patients with secondary progressive MS or worsening relapsing-remitting MS received mitoxantrone and methylprednisolone (mitoxantrone at a dose of approximately 12 mg/m² IV and methylprednisolone 1 g IV) or methylprednisolone alone (same dose as in combination regimen) monthly for 6 months.1,29 Patients who experienced relapses were allowed additional courses of methylprednisolone (1 g daily IV for 3 days).29 All patients had experienced at least 2 relapses with sequelae or neurologic deterioration within the preceding 12 months.1 The deterioration in neurologic status (using the EDSS) during the preceding 12 months averaged 2.2 points.1 During the screening period for the study, patients received 2 monthly doses of methylprednisolone 1 g IV and underwent a baseline and 2 monthly MRI scans.1,29 Only patients who developed at least one gadolinium-enhanced lesion on MRI scan during the 2-month screening period were eligible for enrollment in the study.1,29 The primary endpoint for the study was the proportion of patients who did not develop any new Gd-enhancing lesions at 6 months based on MRI reviews by a blinded panel.1,29 Secondary endpoints, including measurement of neurologic disability using the EDSS and number of clinical relapses, were assessed by an unblinded physician.1,29

At 6 months, the percentage of patients without new Gd-enhancing lesions on MRI scan was greater in those receiving mitoxantrone and methylprednisolone (90%) than in those receiving methylprednisolone alone (31%).1,29 Clinical measures were more favorable in patients receiving mitoxantrone and methylprednisolone compared with those receiving methylprednisolone alone.1,29 Five patients, all receiving methylprednisolone only, withdrew from the study because of worsening condition.1,29

Amenorrhea, alopecia, nausea, and asthenia were the most frequent events occurring in patients receiving mitoxantrone and methylprednisolone; these adverse effects did not occur in patients receiving methylprednisolone alone.1 No cardiotoxicity was detected on monthly ECG or the baseline and end-of-study echocardiographic studies.29

Limited data from small studies suggest that mitoxantrone reduces the clinical attack rate in patients with relapsing-remitting multiple sclerosis.31,32

Because of the limits to blinding in these clinical trials and the use of objective measures such as MRI scans as a proxy for clinical efficacy, additional follow-up and confirmatory trials are necessary to establish the role of mitoxantrone in the treatment of secondary progressive MS.27,29

Non-Hodgkin's Lymphoma

Mitoxantrone is used as a component of combination chemotherapy regimens for the treatment of low-grade non-Hodgkin's lymphoma†.24

Reconstitution and Administration

Mitoxantrone hydrochloride is administered by IV infusion.1 The manufacturer states that safety of administration of mitoxantrone hydrochloride by routes other than IV has not been established.1 Mitoxantrone should not be administered by subcutaneous, intramuscular, intra-arterial, or intrathecal injection.1 Local or regional neuropathy, in some cases irreversible, has been reported following intra-arterial injection of mitoxantrone.1 Severe injury with permanent damage can result from intrathecal administration of mitoxantrone.1 Manifestations of central and peripheral neurotoxicity, including seizures leading to coma and severe neurologic sequelae and paralysis with bowel and bladder dysfunction, have been observed following intrathecal injection of the drug.1

Mitoxantrone hydrochloride for injection concentrate must be diluted prior to IV infusion .1,2,3 The dose of mitoxantrone hydrochloride should be diluted to at least 50 mL with either 0.9% sodium chloride injection or 5% dextrose injection.1,3 These solutions may then be further diluted with 5% dextrose injection, 0.9% sodium chloride injection, or 5% dextrose and 0.9% sodium chloride injection and used immediately.1 The manufacturer states that mitoxantrone hydrochloride for injection concentrate and diluted solutions of the drug should not be frozen.1

Diluted mitoxantrone hydrochloride solutions should be introduced slowly into a freely running IV infusion solution of 0.9% sodium chloride or 5% dextrose over a period of at least 3 minutes,1,2,3 with infusions typically being administered over 15-30 minutes.3,15

Care should be taken to avoid extravasation at the infusion site and to avoid contact of the drug with skin, mucous membranes, and the eyes.1 To reduce the possibility of extravasation, diluted mitoxantrone solution should be administered into the tubing of a freely running IV infusion of 0.9% sodium chloride or 5% dextrose injection.1 Tubing for the IV infusion should be attached to a butterfly needle or other suitable device that preferably is inserted into a large vein.1 If possible, veins over joints or veins in extremities with compromised venous or lymphatic drainage should be avoided as infusion sites.1 Mitoxantrone should not be administered subcutaneously.1

If any manifestations of extravasation occur, such as burning, pain, pruritus, erythema, swelling, blue discoloration, or ulceration, the mitoxantrone infusion should be terminated immediately and reinitiated in a different vein.1 Extravasation during mitoxantrone infusion may occur with or without an accompanying stinging or burning sensation even if blood returns well upon aspiration of the infusion needle.1 If extravasation of the drug into subcutaneous tissue is known or suspected, ice packs should be placed over the affected area intermittently and the affected extremity should be elevated.1 Because extravasation reactions may be progressive, the injection area should be examined frequently.1 If any signs of local reaction develop, early surgical consultation is advised.1

Caution should be exercised in handling and preparing solutions of mitoxantrone hydrochloride.1 Because skin reactions may occur with accidental exposure to the drug, the manufacturer recommends the use of goggles, gloves, and protective gowns during preparation and administration of mitoxantrone hydrochloride.1 Skin accidentally exposed to the drug should be rinsed thoroughly with copious amounts of warm water, and standard irrigation techniques should be used immediately in the event of eye involvement.1

Mitoxantrone hydrochloride solutions should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.1 Mitoxantrone hydrochloride should not be mixed in the same infusion as heparin because of the possibility of precipitate formation.1 Because specific compatibility data are not available, the manufacturer also recommends that mitoxantrone hydrochloride not be mixed in the same infusion with any other drugs.1

According to the manufacturer, mitoxantrone hydrochloride solutions are compatible with filters; during the manufacturing process, a solution of the drug is passed through a 0.22-µm filter without loss of potency.15

Dosage

Dosage of mitoxantrone hydrochloride is expressed in terms of the base.1

Prior to each course of mitoxantrone therapy, a complete blood cell count, including platelets, and liver function tests should be performed.1

Acute Myeloid Leukemia

Rapid lysis of tumor cells by mitoxantrone may cause hyperuricemia.1 Prior to the initiation of mitoxantrone therapy for leukemia, preventive (hypouricemic) therapy should be initiated and serum uric acid concentrations should be monitored during therapy.1

For remission induction therapy in patients with acute myeloid (myelogenous, nonlymphocytic) leukemia (AML, ANLL), the recommended dosage of mitoxantrone is 12 mg/m² daily given on days 1-3 (administered by IV infusion) in combination with cytarabine 100 mg/m² daily (as a continuous IV infusion over 24 hours) given on days 1-7.1,8,10,11 A second induction course, consisting of 2 days of mitoxantrone and 5 days of cytarabine in the same daily dosage levels, may be given in the event of an incomplete antileukemic response.1,8,10,11

If severe or life-threatening nonhematologic toxicity is observed during the initial induction course, the second induction course should be withheld until toxicity resolves.1

Consolidation therapy, which was used in 2 large randomized multicenter trials, consisted of mitoxantrone 12 mg/m² daily (by IV infusion) given on days 1 and 2 and cytarabine 100 mg/m² daily (as a continuous IV infusion over 24 hours) given on days 1-5.1,8,10 The initial consolidation course was given approximately 6 weeks after the final induction course, and the second consolidation course generally was administered 4 weeks after the initial course.1,8

Prostate Cancer

For the treatment of advanced hormone-refractory prostate cancer, the recommended mitoxantrone dosage is 12-14 mg/m² given as a short IV infusion once every 21 days; mitoxantrone is given as an adjunct to corticosteroid therapy (e.g., oral prednisone 5 mg twice daily, oral hydrocortisone 40 mg daily).1,14 Because of the risk of cardiac toxicity, some clinicians have recommended discontinuance of mitoxantrone (and continuation of corticosteroid therapy alone) in patients who are still responding after a cumulative mitoxantrone dose of 140 mg/m² has been administered.14

Multiple Sclerosis

Prior to administration of the initial dose and all subsequent doses of mitoxantrone, cardiac status should be assessed by history, physical examination, and ECG and left ventricular ejection fraction (LVEF) should be evaluated by echocardiogram, multigated radionuclide angiography (MUGA), or magnetic resonance imagery (MRI).1,40 Complete blood cell counts, including platelets, should be performed prior to each course of mitoxantrone therapy.1

For the reduction of neurologic disability and/or the frequency of clinical relapses in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis, the recommended dosage of mitoxantrone is 12 mg/m² administered as a short IV infusion (approximately 5-15 minutes) every 3 months.1

A cumulative dose of up to 140 mg/m² may be used for the treatment of multiple sclerosis.1 At the recommended dosage, this cumulative dose is reached after about 8-12 doses administered over 2-3 years.1

Dosage Modification for Toxicity and Contraindications for Continued Therapy

Hematologic Toxicity

For patients who develop manifestations of infection, a complete blood cell count, including platelets, should be obtained.1

Mitoxantrone should not be administered to patients with multiple sclerosis who have neutrophil counts less than 1500/mm³.1

Cardiotoxicity

During treatment for multiple sclerosis, cardiac status should be assessed by history, physical examination, and ECG and LVEF should be evaluated by echocardiogram, MUGA, or MRI prior to each dose of mitoxantrone.1,40 LVEF also should be evaluated if manifestations of congestive heart failure occur at any time during mitoxantrone therapy.1 The drug should be discontinued in patients with LVEF below the lower limit of normal or a clinically important reduction in LVEF.1,40

Hepatotoxicity

Liver function tests should be performed prior to each dose of mitoxantrone.1 Mitoxantrone therapy for multiple sclerosis should be discontinued in patients with abnormal results of liver function tests.1

Other Toxicity

For patients who develop severe or life-threatening nonhematologic toxicity during the initial induction course of mitoxantrone and cytarabine for AML, the second induction course should be withheld until toxicity resolves.1

Dosage in Renal and Hepatic Impairment

The effect of renal and/or hepatic impairment on the disposition of mitoxantrone has not been fully determined.1

Renal excretion of mitoxantrone is limited, accounting for only up to approximately 10% of the total clearance of the drug.1,2,16,17 Therefore, reduction of mitoxantrone dosage in patients with impaired renal function does not appear to be necessary.15,16

Mitoxantrone appears to be eliminated principally by the hepatobiliary system, and the manufacturer states that the safety of the drug in patients with hepatic insufficiency is not established.1 The clearance of mitoxantrone is reduced in patients with severe hepatic impairment (i.e., serum total bilirubin concentration exceeding 3.4 mg/dL).1,15 Decreased clearance of mitoxantrone also may occur in patients with abnormalities of the third space (e.g., edema, ascites, pleural effusion) because of the extensive tissue penetration and protein-binding of the drug.3 Patients with cancer who have hepatic impairment should be treated with caution, and reduction of mitoxantrone dosage may be required.1 Patients with multiple sclerosis who have hepatic impairment generally should not be treated with mitoxantrone.1

Unless otherwise noted, incidence rates for adverse effects of mitoxantrone reported here are based on 102 patients receiving mitoxantrone and cytarabine as induction therapy for acute myeloid leukemia (AML) in the US trial, 80 patients receiving mitoxantrone and prednisone and 112 patients receiving mitoxantrone and hydrocortisone for advanced hormone-refractory prostate cancer in 2 randomized trials, 127 patients receiving mitoxantrone for secondary progressive or progressive relapsing multiple sclerosis in a placebo-controlled randomized trial (62 patients receiving mitoxantrone 12 mg/m² and 65 patients receiving mitoxantrone 5 mg/m²), and 21 patients receiving mitoxantrone (approximately 12 mg/m²) and methylprednisolone for secondary progressive or worsening relapsing-remitting multiple sclerosis in a randomized trial.1

GI Effects

Nausea and vomiting, generally mild to moderate, occur in most patients receiving mitoxantrone and typically can be managed with antiemetic agents.1 Nausea and vomiting may contribute to reports of dehydration in patients receiving mitoxantrone.1 Stomatitis or mucositis occurs within 1 week of therapy.1

Among patients receiving mitoxantrone and cytarabine as induction therapy for AML, adverse GI effects were reported in 88% of patients.1 These adverse GI effects included nausea or vomiting in 72%, diarrhea in 47%, mucositis/stomatitis in 29%, and abdominal pain in 15% of patients.1 GI bleeding occurred in 16% of patients receiving mitoxantrone and cytarabine as induction therapy for AML.1

Among patients receiving mitoxantrone and prednisone for advanced hormone-refractory prostate cancer, nausea occurred in 61%, anorexia in 25%, constipation in 16%, mucositis in 10%, emesis in 9%, and dyspepsia in 5% of patients.1 Among patients receiving mitoxantrone and hydrocortisone for advanced hormone-refractory prostate cancer, nausea was reported in 26%, anorexia in 22%, diarrhea in 14%, other adverse GI effects in 14%, vomiting in 11%, and stomatitis in 8% of patients.1

Among patients receiving mitoxantrone 12 mg/m² for multiple sclerosis, nausea occurred in 76%, stomatitis in 19%, diarrhea in 16%, and constipation in 10% of patients.1 Severe nausea was reported in 3 patients (5%) receiving mitoxantrone 12 mg/m² for multiple sclerosis.1 Among patients receiving mitoxantrone and methylprednisolone for multiple sclerosis, nausea was reported in 29%; gastralgia, stomach burn, or epigastric pain in 14%; and aphthosis in 10% of patients.1

Hematologic Effects and Infectious Complications

Rapid onset of myelosuppression is the desired effect of mitoxantrone in the treatment of acute leukemia.1 The incidence rates of adverse effects associated with myelosuppression, such as infection and bleeding, in patients receiving mitoxantrone are similar to those reported for other standard induction regimens for acute leukemia.1 Among patients receiving mitoxantrone and cytarabine as induction therapy for AML, fever was reported in 78% and infections were reported in 66% of patients.1 The types of infections that occurred included sepsis (34%), fungal infection (15%), pneumonia (9%), and urinary tract infection (7%).1 Bleeding occurred in 37% of these patients, including GI bleeding in 16% and petechiae/ecchymoses in 7%.1

A high rate of grade 4 neutropenia (54%) was reported in patients receiving mitoxantrone and low-dose prednisone for advanced hormone-refractory prostate cancer in a randomized trial that required dose escalation of mitoxantrone for patients with neutrophil counts exceeding 1000/mm³.1 Among patients receiving mitoxantrone and prednisone for advanced hormone-refractory prostate cancer, systemic infection was reported in 10%, urinary tract infection in 9%, and skin infection in 5% of patients.1 Hemorrhage or bruise was reported in 6%, fever in 6%, and anemia in 5% of these patients.1 Among patients receiving mitoxantrone and hydrocortisone for advanced hormone-refractory prostate cancer, most patients experienced myelosuppression, including leukopenia in 87%, decreased granulocytes/bands in 79%, decreased hemoglobin in 75%, lymphopenia in 72%, and thrombocytopenia in 39%.1 Grade 4 neutropenia occurred in 23% of these patients.1 Infection was reported in 17%, fever in the absence of infection in 14%, and hemorrhage in 5% of these patients.1 Similar rates of neutropenic fever/infection (11 or 10%) and severe thrombocytopenia (4 or 3%) occurred in patients receiving mitoxantrone with corticosteroid therapy (prednisone or hydrocortisone, respectively) in the 2 randomized trials.1

Among patients receiving mitoxantrone 12 mg/m² for multiple sclerosis, leukopenia (less than 4000/mm³) occurred in 19% and granulocytopenia (less than 2000/mm³) and anemia each occurred in 6% of patients.1 Among patients receiving mitoxantrone and methylprednisolone for multiple sclerosis, all patients experienced leukopenia (less than 4000/mm³) and neutropenia (less than 1500/mm³).1 Neutropenia, which was reversible, occurred within 3 weeks of mitoxantrone administration.1 Lymphopenia occurred in 95%, anemia in 43%, and thrombocytopenia (less than 100,000/mm³) in 33% of patients in this group.1 There was no difference in the incidence or severity of hemorrhagic events between the treatment groups in either of these randomized trials.1

Among patients receiving mitoxantrone 12 mg/m² for multiple sclerosis, infection occurred in 81% of patients.1 Upper respiratory tract infection occurred in 53% of patients and urinary tract infection in 32% of patients in this group.1 Four of these patients had infections that required hospitalization, including tonsillitis, urinary tract infection (2 cases), and endometritis.1 Among patients receiving mitoxantrone and methylprednisolone for multiple sclerosis, infections occurred in 43% of patients.1 These infections were mild to moderate in intensity and no hospitalizations were required.1

Cardiovascular Effects

Mitoxantrone can cause cardiotoxicity.1 Functional cardiac changes, including asymptomatic decreases in left-ventricular ejection fraction (LVEF) and irreversible congestive heart failure, can occur in patients receiving mitoxantrone.1,2,3,18,19,20,26 Tachycardia, ECG changes including arrhythmias, and chest pain also have occurred in patients receiving mitoxantrone.1 Cardiotoxicity may occur regardless of the presence of cardiac risk factors.1 Cardiotoxicity can occur at any time during or after therapy with mitoxantrone.1 Potentially fatal congestive heart failure can occur during mitoxantrone therapy or months to years following termination of mitoxantrone therapy.1

Among patients receiving mitoxantrone and cytarabine as induction therapy for AML, adverse cardiovascular effects occurred in 26% of patients.1 These adverse cardiovascular effects included congestive heart failure in 5% and arrhythmias in 3% of patients.1

The risk of mitoxantrone-induced cardiotoxicity increases with increasing cumulative dose.2,18,26 In clinical trials involving cancer patients who received mitoxantrone either alone or in combination with other antineoplastic agents, the cumulative probability of developing clinical evidence of congestive heart failure was 2.6% for patients who had received cumulative doses of 140 mg/m², and the overall cumulative probability of moderate or serious decreases in LVEF at a cumulative dose of 140 mg/m² was 13% in comparative trials.1,2

Among patients receiving either mitoxantrone and cytarabine or daunorubicin and cytarabine as first-line therapy for AML in a randomized trial, congestive heart failure occurred in 6.5% of patients in each group.1 In addition to the effects of drug therapy, manifestations of the underlying disease, such as anemia, fever and infection, and hemorrhage, may contribute to the depression of myocardial function in patients with AML.1 Among 128 patients receiving mitoxantrone and prednisone for advanced hormone-refractory prostate cancer in a randomized trial, 7 patients (5.5%) experienced a cardiac event, including decrease in LVEF below the normal range, congestive heart failure (3 patients), or myocardial ischemia.1 Two of the 7 patients had a history of cardiac disease.1 The cumulative dose of mitoxantrone administered to these patients ranged from more than 48 mg/m² to 212 mg/m².1 Among 112 evaluable patients receiving mitoxantrone and hydrocortisone for advanced hormone-refractory prostate cancer in a randomized trial, 18% had a reduction in cardiac function, 7% had cardiac dysrhythmia, 5% had cardiac ischemia, 4% had hypertension, and 2% had pulmonary edema.1 Among patients receiving mitoxantrone for multiple sclerosis in 2 randomized trials, decreases in LVEF were reported in 3 patients in one trial; there were no reports of congestive heart failure in either trial.1

Other adverse cardiovascular effects reported in patients receiving mitoxantrone include arrhythmia in 18% and abnormal ECG in 11% of patients receiving mitoxantrone 12 mg/m² for multiple sclerosis and edema in 10% of patients receiving mitoxantrone and prednisone for advanced hormone-refractory prostate cancer.1

Respiratory Effects

Among patients receiving mitoxantrone and cytarabine as induction therapy for AML, adverse respiratory effects were reported in 43% of patients.1 These adverse respiratory effects included dyspnea in 18% and cough in 13% of patients.1 Interstitial pneumonitis has been reported in patients receiving mitoxantrone in combination chemotherapy for cancer.1

Among patients receiving mitoxantrone and prednisone for advanced hormone-refractory prostate cancer, dyspnea occurred in 11% and cough occurred in 5% of patients.1 Among patients receiving mitoxantrone and hydrocortisone for advanced hormone-refractory prostate cancer, dyspnea was reported in 15% of patients and other adverse pulmonary effects were reported in 5% of patients.1

Among patients receiving mitoxantrone 12 mg/m² for multiple sclerosis, upper respiratory tract infection occurred in 53% and sinusitis in 6% of patients.1 Among patients receiving mitoxantrone and methylprednisolone for multiple sclerosis, pharyngitis or throat infection was reported in 19% and rhinitis in 10% of patients.1

Dermatologic Effects

Among patients receiving mitoxantrone and cytarabine as induction therapy for AML, alopecia occurred in 37% of patients.1

Among patients receiving mitoxantrone and prednisone for advanced hormone-refractory prostate cancer, alopecia occurred in 29%, nail bed changes in 11%, and skin infection in 5% of patients.1 Among patients receiving mitoxantrone and hydrocortisone for advanced hormone-refractory prostate cancer, alopecia was reported in 20%, sweats in 9%, and skin disorder in 6% of patients.1

Among patients receiving mitoxantrone 12 mg/m² for multiple sclerosis, alopecia (consisting of mild hair thinning) occurred in 61% of patients.1 Among patients receiving mitoxantrone and methylprednisolone for multiple sclerosis, alopecia was reported in 33% and cutaneous mycosis in 10% of patients.1

Nervous System Effects

Among patients receiving mitoxantrone and cytarabine as induction therapy for AML, adverse CNS effects were reported in 30% of patients.1 These adverse nervous system effects included headache in 10% and seizures in 4% of patients.1

Among patients receiving mitoxantrone and prednisone for advanced hormone-refractory prostate cancer, fatigue was reported in 39% and anxiety or depression was reported in 5% of patients.1 Among patients receiving mitoxantrone and hydrocortisone for advanced hormone-refractory prostate cancer, malaise or fatigue occurred in 34%, other adverse neurologic effects in 11%, neurologically based constipation in 7%, adverse motor effects in 7%, and mood alteration in 6% of patients.1

Among patients receiving mitoxantrone 12 mg/m² for multiple sclerosis, headache occurred in 6% of patients.1 Among patients receiving mitoxantrone and methylprednisolone for multiple sclerosis, asthenia was reported in 24% of patients.1

Sensitivity Reactions

Anaphylaxis or anaphylactoid reactions have been reported rarely in patients receiving mitoxantrone.1 Hypotension, urticaria, dyspnea, or rashes associated with allergic reactions have occurred occasionally in patients receiving mitoxantrone.1

Hepatic Effects

Among patients receiving mitoxantrone and cytarabine as induction therapy for AML, adverse hepatic effects were reported in 10% of patients, including jaundice in 3%.1

Among patients receiving mitoxantrone and hydrocortisone for advanced hormone-refractory prostate cancer, increased serum alkaline phosphatase concentrations were reported in 37%, increased serum transaminase concentrations in 20%, and other adverse hepatic effects in 8% of patients.1

Among patients receiving mitoxantrone 12 mg/m² for multiple sclerosis, increased serum concentrations of GGT (15%), AST (8%), and ALT (5%) were reported.1 Among patients receiving mitoxantrone and methylprednisolone for multiple sclerosis, increased serum AST and ALT concentrations each occurred in 15% of patients.1

Renal and Electrolyte Effects

Among patients receiving mitoxantrone and cytarabine as induction therapy for AML, renal failure occurred in 8% of patients.1

Among patients receiving mitoxantrone and hydrocortisone for advanced hormone-refractory prostate cancer, elevated BUN occurred in 22%, elevated serum creatinine concentration in 13%, and proteinuria in 6% of patients.1 Electrolyte disturbances reported in these patients included hypocalcemia in 10%, hyponatremia in 9%, and hypokalemia in 7%.1

Among patients receiving mitoxantrone and methylprednisolone for multiple sclerosis, hypokalemia was reported in 10% of patients.1

Genitourinary Effects

Among patients receiving mitoxantrone and hydrocortisone for advanced hormone-refractory prostate cancer, hematuria occurred in 11% and other adverse kidney or bladder effects occurred in 5% of patients.1 Impotence or decreased libido was reported in 7% and sterility was reported in 5% of this group of patients.1

Among patients receiving mitoxantrone 12 mg/m² for multiple sclerosis, 61% of female patients experienced menstrual disorder and 43% had amenorrhea.1 Urinary tract infection was reported in 32% of patients and abnormal urine in 11% of all patients in this group.1 Among patients receiving mitoxantrone and methylprednisolone for multiple sclerosis, 53% of female patients experienced amenorrhea and 7% had menorrhagia.1

Ocular Effects

Among patients receiving mitoxantrone and cytarabine as induction therapy for AML, adverse ocular effects were reported in 7% of patients, including conjunctivitis in 5%.1

Among patients receiving mitoxantrone and prednisone for advanced hormone-refractory prostate cancer, blurred vision occurred in 3% of patients.1

Metabolic Effects

Hyperuricemia may result from rapid lysis of tumor cells in patients receiving mitoxantrone for leukemia.1

Among patients receiving mitoxantrone and hydrocortisone for advanced hormone-refractory prostate cancer, hyperglycemia occurred in 31%, weight loss in 17%, and weight gain in 14% of patients.1 Other adverse endocrine effects were reported in 6% of these patients.1

Among patients receiving mitoxantrone and methylprednisolone for multiple sclerosis, hyperglycemia was reported in 10% of patients.1

Musculoskeletal Effects

Myalgias or arthralgias were reported in 5% of patients receiving mitoxantrone and hydrocortisone for advanced hormone-refractory prostate cancer.1

Among patients receiving mitoxantrone 12 mg/m² for multiple sclerosis, 8% of patients experienced back pain.1

Local Effects

Extravasation during administration of mitoxantrone can cause severe tissue damage, such as tissue necrosis requiring debridement and skin grafting.1 Extravasation at the infusion site has resulted in erythema, swelling, pain, burning, and/or blue discoloration of the skin.1 Phlebitis also has been reported at the site of mitoxantrone infusion.1

Other Adverse Effects

Among patients receiving mitoxantrone and prednisone for advanced hormone-refractory prostate cancer, pain occurred in 8% of patients.1 Among patients receiving mitoxantrone and hydrocortisone for advanced hormone-refractory prostate cancer, pain was reported in 41%, and chills were reported in 5% of patients.1

Precautions and Contraindications

Mitoxantrone should be used under the supervision of a qualified clinician experienced in the use of this agent.1,27

Frequent monitoring of hematologic and chemical parameters as well as close observation is advised for patients receiving mitoxantrone.1 Systemic infections should be treated prior to initiation of therapy or concomitantly during mitoxantrone therapy.1

Myelosuppression

Mitoxantrone should not be administered to patients with preexisting medullary suppression secondary to prior drug therapy unless it is believed that the possible benefit from such treatment warrants the risk of further myelosuppression.1 Except when used in the treatment of AML, mitoxantrone generally should not be given to patients with baseline neutrophil counts less than 1500/mm³.1

Because mitoxantrone causes myelosuppression, particularly neutropenia, which may be severe and result in infection, peripheral blood cell counts should be performed frequently in all patients receiving mitoxantrone.1

Mitoxantrone, at any dose, can cause hematologic toxicity, but the use of high-dose mitoxantrone for the treatment of leukemia causes severe myelosuppression.1 Laboratory and supportive services must be available for hematologic and chemistry monitoring of these patients as well as adjunctive therapies, including anti-infectives; blood and blood products must be available to support these patients during the expected period of medullary hypoplasia and severe myelosuppression.1,23 Particular care should be given to ensure full hematologic recovery before initiating consolidation therapy (if this treatment is used), and patients should be monitored closely during this phase.1,23

Cardiotoxicity

Because mitoxantrone can cause cardiotoxicity, all patients should be carefully assessed by history, physical examination, and ECG before initiation of therapy with the drug.1,40 Cardiac examination should include baseline evaluation of left ventricular ejection fraction (LVEF) by echocardiogram, multigated radionuclide angiography (MUGA), or MRI.1,40

Patients with multiple sclerosis who have a baseline LVEF below the lower limit of normal should not receive mitoxantrone therapy.1,40 During treatment for multiple sclerosis, patients should be carefully assessed by history, physical examination, and ECG and LVEF should be evaluated by echocardiogram, MUGA, or MRI prior to each dose of mitoxantrone using the same method for each evaluation.1,40 Mitoxantrone therapy for multiple sclerosis should be discontinued in patients with LVEF below the lower limit of normal or a clinically important reduction in LVEF.1,40 After completion or discontinuance of mitoxantrone therapy for multiple sclerosis, patients should be monitored for late cardiotoxicity with annual evaluation of LVEF with the same method that was used during treatment.40

Among patients receiving mitoxantrone for the treatment of cancer, the risk of cardiotoxicity may be increased by the presence or history of cardiovascular disease, prior or concomitant radiotherapy to the mediastinal or pericardial region, previous therapy with other anthracycline or anthracenedione agents, or concomitant use of other cardiotoxic drugs.1 Such patients should undergo regular monitoring of LVEF upon initiation of and during mitoxantrone therapy.1 Because of the increased risk of cardiac toxicity in patients previously treated with anthracyclines (e.g., daunorubicin or doxorubicin), the benefit-to-risk ratio of mitoxantrone in such patients should be determined before initiating therapy.1,2,3,18,19,20 (See Cautions: Cardiac Effects, in Doxorubicin 10:00.)

Secondary Acute Myeloid Leukemia

Secondary acute myeloid leukemia (AML) has been reported in patients receiving mitoxantrone for cancer or multiple sclerosis.1 (Also see Cautions: Mutagenicity and Carcinogenicity.) The risk of secondary AML is increased when anthracyclines are administered in combination with DNA-damaging antineoplastic agents, when patients have disease that has been heavily pretreated with cytotoxic drugs, and when doses of anthracyclines have been escalated.1

Information for Patients

Patients should be told to expect a blue-green color of the urine for 24 hours following administration of mitoxantrone.1 Bluish discoloration of the sclera also may occur.1

Patients should be advised to contact the clinician if they experience any signs or symptoms of infection, such as fever, chills, sore throat, cough, pain with urination, or frequent urination.1 Patients should be advised to contact the clinician if they experience any unusual bleeding or bruising.1

For patients receiving mitoxantrone for multiple sclerosis, the clinician should discuss and provide a copy of the manufacturer's patient information shortly before each treatment.1 Women with multiple sclerosis who are capable of becoming pregnant should receive a pregnancy test prior to each dose of mitoxantrone even if they are using an effective method of contraception, and the results of the test should be known before the drug is administered.1 (See Pregnancy under Cautions: Pregnancy, Fertility, and Lactation.)

Other Precautions and Contraindications

The use of mitoxantrone is contraindicated in patients who have demonstrated hypersensitivity to the drug.1

Pediatric Precautions

Safety and efficacy of mitoxantrone in children younger than 12 years of age have not been established.1,25

Geriatric Precautions

Clinical studies of mitoxantrone for multiple sclerosis or hormone-refractory prostate cancer did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.1 Safety and efficacy of mitoxantrone for AML in geriatric patients have not been studied specifically to date.1 Although other clinical experience has not revealed age-related differences in response or tolerance to mitoxantrone, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.1 The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.1 Toxicity associated with mitoxantrone may occur more frequently in geriatric patients.1

Mutagenicity and Carcinogenicity

Mitoxantrone is mutagenic and carcinogenic.1 Mitoxantrone has exhibited mutagenic activity in bacterial and mammalian test systems.1 In vivo tests (rat bone marrow assay) and in vitro tests (DNA damage in primary rat hepatocytes and sister chromatid exchange in Chinese hamster ovary cells) demonstrate that mitoxantrone is clastogenic.1

Secondary acute myeloid leukemia (AML) has been reported in patients receiving mitoxantrone for cancer or multiple sclerosis.1 Among 1774 patients receiving mitoxantrone concomitantly with other cytotoxic agents and radiotherapy for breast cancer, the estimated cumulative risk of developing treatment-related AML was 1.1% at 5 years and 1.6% at 10 years following treatment.1 Among 449 patients receiving mitoxantrone for breast cancer, usually with radiotherapy and/or other cytotoxic agents, the estimated cumulative risk of developing treatment-related AML was 2.2% at 4 years following treatment.1 Secondary AML also has been reported in patients receiving anthracyclines, and mitoxantrone, an anthracenedione, is structurally similar to anthracyclines.1 In a cohort of patients receiving mitoxantrone for multiple sclerosis who were followed for varying periods of time, an increased risk of leukemia (0.25%) has been observed.1 Cases of secondary AML also have been reported in postmarketing studies of mitoxantrone for multiple sclerosis.1

An increased incidence of fibroma and external auditory canal tumors was observed in rats receiving mitoxantrone 0.03 mg/kg IV (0.02-fold the recommended human dose on a mg/m² basis) once every 21 days for 24 months.1 Another study in which rats received mitoxantrone 0.3 mg/kg IV (0.15-fold the recommended human dose on a mg/m² basis) once every 21 days for 12 months also showed an increased incidence of external auditory canal tumors.1 An increased incidence of hepatocellular adenoma was observed in male mice receiving mitoxantrone 0.1 mg/kg IV (0.03-fold the recommended human dose on a mg/m² basis) once every 21 days for 24 months.1

Pregnancy, Fertility, and Lactation

Pregnancy

Mitoxantrone can cause fetal toxicity when administered to pregnant women, but potential benefits may be acceptable in certain conditions despite the possible risks to the fetus.1,35,36

Mitoxantrone is considered a potential human teratogen because of its mechanism of action and the adverse developmental effects observed with similar agents.1 Fetal growth retardation was observed in reproduction studies of rats receiving mitoxantrone doses of 0.1 mg/kg daily (0.01 times the recommended human dose on a mg/m² basis) or greater during the organogenesis period of gestation.1 An increased incidence of premature delivery was observed in reproduction studies of rabbits receiving mitoxantrone doses of 0.1 mg/kg daily (0.01 times the recommended human dose on a mg/m² basis) or greater during the organogenesis period of gestation.1 No teratogenic effects were observed in these animal studies, but the maximum doses administered were well below the recommended human dose for mitoxantrone.1

There are no adequate and well-controlled studies to date using mitoxantrone in pregnant women.1 Women with multiple sclerosis who are capable of becoming pregnant should receive a pregnancy test prior to each dose of mitoxantrone and the results of the test should be known before the drug is administered.1 Mitoxantrone should be used during pregnancy only in life-threatening situations or for severe disease for which safer drugs cannot be used or are ineffective.35 When mitoxantrone is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.1 Women of childbearing potential should be advised to avoid becoming pregnant during therapy with mitoxantrone.1

Fertility

Sperm counts decreased substantially in men receiving mitoxantrone in combination with other antineoplastic agents for Hodgkin's disease, but these changes were reversible, typically within several months.37 Mitoxantrone may have detrimental effects on spermatocytes and oocytes in patients receiving the drug for multiple sclerosis; further study is needed to establish the effect of mitoxantrone on fertility in these patients.38

Lactation

Mitoxantrone is distributed into milk.1 Because of the potential for serious adverse reactions from mitoxantrone in nursing infants, breast feeding should be discontinued before initiation of therapy with the drug.1

Formal drug interaction studies have not been performed to date.1 There have been no reports of marked drug interactions in patients receiving mitoxantrone for cancer.1 Limited information is available on drug interactions in patients receiving mitoxantrone for multiple sclerosis.1

Acute Toxicity

Limited information is available on the acute toxicity of mitoxantrone, but accidental overdoses of the drug have been reported.1 Four patients who received mitoxantrone 140-180 mg/m² as a single bolus injection died from severe leukopenia with infection.1 Treatment of toxicity may require hematologic support and anti-infective therapy during prolonged periods of severe myelosuppression.1 There is no known specific antidote for overdosage with mitoxantrone.1

Pharmacology

Antineoplastic Effect

Mitoxantrone is a DNA-reactive agent.1 Despite the presence of the planar polycyclic aromatic ring structure, DNA intercalation has been shown not to correlate with the in vivo cytotoxic activity of mitoxantrone.2 Instead, mitoxantrone is believed to exert its cytotoxic effect by interfering with the function of topoisomerase II, thereby preventing religation of DNA strand breaks.2,5,26 Topoisomerase enzymes catalyze the formation of single-strand or double-strand DNA breaks, facilitate passage of DNA strands through these breaks, and promote religation of the DNA strands via a covalently linked enzyme-DNA intermediate (the cleavable complex).2,6 This cleavable complex is involved in a reaction that alters the topology of DNA by introducing a temporary double-strand break in the sequence through which an intact helix can pass.2,4 Mitoxantrone is believed to stabilize the cleavable complex, preventing the rejoining of DNA strands.2,6 Other effects of mitoxantrone that may contribute to its cytotoxic activity include the aggregation and compaction of DNA via electrostatic cross-linking, generation of free radicals (which may cause breaks in DNA strands), inhibition of protein kinase C activity, and induction of apoptosis in leukemic cells.2,26

Mitoxantrone exerts a cytocidal effect on both proliferating and nonproliferating cultured human cells, suggesting a lack of cell-cycle phase specificity.1 Mitoxantrone produces concentration-proportional and time-proportional delays in cell-cycle progression and, although not considered cell-cycle specific, the drug is most cytotoxic to cells in late S phase.3

Tumor resistance to mitoxantrone may occur as a result of increased P-glycoprotein expression, alteration of the levels or activity of topoisomerase II, enhanced DNA repair mechanisms, or a combination of these and other mechanisms.2,3,26 Incomplete cross-resistance with anthracyclines has been demonstrated in vitro, and although partial cross-resistance to mitoxantrone and various anthracyclines is common in resistant cell lines in vitro, patients who fail to respond to anthracycline therapy have been reported to respond to mitoxantrone in some cases.2,3,7

Additive or synergistic effects in inducing cellular DNA damage have been demonstrated in vitro with combined exposure of cells to mitoxantrone and other antineoplastic agents, including cytarabine, amsacrine, cisplatin, doxorubicin, and etoposide.2 In addition, sequential exposure of cells to mitoxantrone and cytarabine has been shown to result in enhanced cytotoxic effects.2

Immunologic Effects

In vitro studies show that mitoxantrone inhibits the proliferation of B cells, T cells, and macrophages.1 Mitoxantrone also impairs antigen presentation and interferes with the secretion of interferon gamma, tumor necrosis factor-α, and interleukin-2.1

Pharmacokinetics

The pharmacokinetics of mitoxantrone have not been studied in patients receiving multiple daily doses of the drug.1

Absorption

Following IV doses of 15-90 mg/m², mitoxantrone exhibits a linear relationship between dose and area under the concentration-time curve (AUC).1

Distribution

Mitoxantrone is widely distributed into tissues.1 At steady state, the volume of distribution exceeds 1000 L/m².1 During the terminal phase of elimination, greater concentrations of mitoxantrone are found in tissue than in blood.1

At plasma concentrations of 26-455 ng/mL, 78% of the drug is bound to plasma proteins.1 Protein binding of the drug is independent of plasma concentration and is unaffected by the presence of aspirin, doxorubicin, heparin, phenytoin, prednisone, prednisolone, or methotrexate.1

In healthy monkeys, the concentrations of mitoxantrone detected in the brain, spinal cord, eye, and CSF are low.1

Mitoxantrone is distributed into milk.1 Substantial concentrations of mitoxantrone (18 ng/mL) were detected in milk at 28 days following administration of the last dose of the drug.1,39

Elimination

Following a single IV dose, the pharmacokinetic disposition of mitoxantrone may be represented by a 3-compartment model.1 The half-life of mitoxantrone averages 6-12 minutes in the initial (t_½α) phase, about 1-3 hours in the second phase (t_½β), and 23-215 hours (median: approximately 75 hours) in the terminal phase (t_½γ).1

The precise metabolic pathway of mitoxantrone has not been determined.1 Mitoxantrone is excreted in urine and feces as unchanged drug or inactive metabolites.1 During the 5-day period following administration of the drug, 25% of the dose was recovered in feces in the form of unchanged drug or metabolite; 11% of the dose was recovered in urine, mostly as unchanged drug (65%) with the remainder (35%) being monocarboxylic and dicarboxylic acid derivatives and their glucuronide conjugates.1

The effects of age, gender, or race on the pharmacokinetics of mitoxantrone have not been established.1 The effects of renal impairment on the pharmacokinetics of mitoxantrone have not been established.1 Plasma clearance of mitoxantrone is reduced in patients with hepatic impairment.1 The AUC in patients with severe hepatic dysfunction (serum bilirubin concentration exceeding 3.4 mg/dL) was more than 3 times greater than the AUC in patients with normal hepatic function who received the same dose of mitoxantrone.1

Chemistry and Stability

Chemistry

Mitoxantrone hydrochloride, a synthetic anthracenedione, is an antineoplastic agent.1,2,3,4,26 Mitoxantrone is derived from the anthraquinone dye ametantrone and is structurally similar to the anthracyclines doxorubicin and daunorubicin.2,3 Anthracenediones share the planar polycyclic aromatic ring structure (which enables interaction with DNA) of anthracyclines but lack the amino sugar moiety and tetracyclic A ring normally present in anthracyclines.2 In place of the amino sugar moiety, mitoxantrone contains two identical aminoalkyl side chains.4

Commercially available mitoxantrone for injection concentrate is a sterile, nonpyrogenic, dark blue aqueous solution that has a pH of 3-4.5 and contains 0.14 mEq of sodium per mL.1 The commercially available injection contains mitoxantrone hydrochloride equivalent to 2 mg of mitoxantrone free base per mL and is free of preservatives.1

Stability

Mitoxantrone hydrochloride for injection concentrate should be stored at 15-25°C; the drug should not be frozen.1 According to the manufacturer, after penetration of the container, undiluted mitoxantrone hydrochloride for injection concentrate may be stored no longer than 7 days at a room temperature of 15-25°C or 14 days under refrigeration, but should not be frozen.1 Unused portions of diluted mitoxantrone solution should be discarded immediately in an appropriate manner.1

Mitoxantrone hydrochloride should not be mixed in the same infusion as heparin because of the possibility of precipitate formation.1 Because specific compatibility data are not available, the manufacturer also recommends that mitoxantrone hydrochloride not be mixed in the same infusion with any other drugs.1

Additional Information

For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

1. EMD Serono. Novantrone^® (mitoxantrone) for injection concentrate prescribing information. Rockland, MA; 2007 May.

2. Dunn CJ, Goa KL. Mitoxantrone: a review of its pharmacological properties and use in acute nonlymphoblastic leukaemia. Drugs Aging . 1996; 9:122-47. [PubMed 8820798]

3. Faulds D, Balfour JA, Chrisp P et al. Mitoxantrone: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in the chemotherapy of cancer. Drugs . 1991; 41:400-49. [PubMed 1711446]

4. Chabner BA, Myers CE. Antitumor antibiotics. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 4th ed. Philadelphia, PA: J. B. Lippincott; 1993:374-84.

5. Capranico G, Zunino F. DNA topoisomerase-trapping antitumour drugs. Eur J Cancer . 1992; 28A:2055-60. [PubMed 1329885]

6. Morrow CS, Cowan KH. Mechanisms of antineoplastic drug resistance. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 4th ed. Philadelphia, PA: J. B. Lippincott; 1993:340-8.

7. McCauley DL. Treatment of adult acute leukemia. Clin Pharm . 1992; 11:767-96. [PubMed 1521402]

8. Arlin Z, Case DC Jr, Moore J et al. Randomized multicenter trial of cytosine arabinoside with mitoxantrone or daunorubicin in previously untreated adult patients with acute nonlymphocytic leukemia (ANLL). Leukemia . 1990; 4:177-83. [PubMed 2179638]

9. Feldman EJ. Acute myelogenous leukemia in the older patient. Semin Oncol . 1995; 22(Suppl 1):21-4. [PubMed 7532322]

10. Pavlovsky S, Gonzalez Llaven J, Garcia Martinez MA et al. A randomized study of mitoxantrone plus cytarabine versus daunomycin versus cytarabine in the treatment of previously untreated adult patients with acute nonlymphocytic leukemia. Ann Hematol . 1994; 69:11-5. [PubMed 8061102]

11. Wahlin A, Hornsten P, Hedenus M et al. Mitoxantrone and cytarabine versus daunorubicin and cytarabine in previously untreated patients with acute myeloid leukemia. Cancer Chemother Pharmacol . 1991; 28:480-3. [PubMed 1934252]

12. Immunex Corporation. Mitoxantrone for injection concentrate: clinical use in hormone-resistant prostate cancer. Seattle, WA: 1996.

13. Vogelzang NJ. One hundred thirteen men with hormone-refractory prostate cancer died today. J Clin Oncol . 1996; 14:1753-5. [PubMed 8656242]

14. Tannock IF, Osoba D, Stockler MR et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol . 1996; 14:1756-64. [PubMed 8656243]

15. Immunex Corporation. Mitoxantrone for injection concentrate: technical monograph. Seattle, WA: 1994.

16. Birchall LA, Bailey NP, Blackledge GRP. An overview of mitozantrone. Br J Clin Pract . 1991; 45:208-11. [PubMed 1805919]

17. Schleyer E, Kamischke A, Kaufmann CC et al. New aspects on the pharmacokinetics of mitoxantrone and its two major metabolites. Leukemia . 1994; 8:435-40. [PubMed 8127148]

18. Crossley RJ. Clinical safety and tolerance of mitoxantrone. Semin Oncol . 1984; 11(Suppl 1):54-8. [PubMed 6385266]

19. Mather FJ, Simon RM, Clark GM et al. Cardiotoxicity in patients treated with mitoxantrone: Southwest Oncology Group phase II studies. Cancer Treat Rep . 1987; 71:609-13. [PubMed 3581099]

20. Posner LE, Dukart G, Goldberg J et al. Mitoxantrone: an overview of safety and toxicity. Invest New Drugs . 1985; 3:123-32. [PubMed 3894276]

21. Prostate Cancer Trialists' Collaborative Groups. Maximum androgen blockade in advanced prostate cancer: an overview of 22 randomized trials with 3283 deaths in 5710 patients. Lancet . 1995; 346:265-9. [PubMed 7630245]

22. Prostate cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2008 Mar 5.

23. Adult acute myeloid leukemia. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2008 Mar 3.

24. Anon. Drugs of choice for cancer. Treat Guidel Med Lett . 2003; 1:41-52.

25. Immunex Corporation, Seattle, WA: Personal communication.

26. Wiseman LR, Spencer CM. Mitoxantrone: a review of its pharmacology and clinical efficacy in the management of hormone-resistant advanced prostate cancer. Drug Aging . 1997; 10:473-85.

27. Goodin DS, Arnason BG, Coyle PK et al. The use of mitoxantrone (Novantrone) for the treatment of multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology . 2003; 61:1332-8. [PubMed 14638950]

28. Hartung HP, Gonsette R, König N et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet . 2002; 360:2018-25. [PubMed 12504397]

29. Edan G, Miller D, Clanet M et al. Therapeutic effect of mitoxantrone combined with methylprednisolone in multiple sclerosis: a randomised multicentre study of active disease using MRI and clinical criteria. J Neurol Neurosurg Psychiatry . 1997; 62:112-8. [PubMedCentral][PubMed 9048709]

30. Krapf H, Morrissey SP, Zenker O et al. Effect of mitoxantrone on MRI in progressive MS: results of the MIMS trial. Neurology . 2005; 65:690-5. [PubMed 16157900]

31. Bastianello S, Pozzilli C, D'Andrea F et al. A controlled trial of mitoxantrone in multiple sclerosis: serial MRI evaluation at one year. Can J Neurol Sci . 1994; 21:266-70. [PubMed 8000984]

32. Millefiorini E, Gasperini C, Pozzilli C et al. Randomized placebo-controlled trial of mitoxantrone in relapsing-remitting multiple sclerosis: 24-month clinical and MRI outcome. J Neurol . 1997; 244:153-9. [PubMed 9050955]

33. Tannock IF, de Wit R, Berry WR et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med . 2004; 351:1502-12. [PubMed 15470213]

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