Mitoxantrone Hcl

— THERAPEUTIC CATEGORIES —
  • Leukemias, lymphomas, and other hematologic cancers
  • Multiple sclerosis
  • Prostate and other male cancers
PAGE CONTENTS
  • Jump to Section
  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Mitoxantrone Hcl Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Mitoxantrone (as HCl) 2mg/mL; soln for IV infusion after dilution; preservative-free.

    Pharmacological Class

    Topoisomerase inhibitor.

    How Supplied

    Contact supplier.

    Manufacturer

    Various generic manufacturers

    Mitoxantrone Hcl Indications

    Indications

    Acute nonlymphocytic leukemia (ANLL) in combination with other approved drugs.

    Mitoxantrone Hcl Dosage and Administration

    Prior to Treatment Evaluations

    Laboratory Tests

    • Obtain a complete blood count, including platelets, prior to each course of mitoxantrone and in the event that signs and symptoms of infection develop.

    • Perform liver function tests prior to each course of therapy. 

    • In leukemia treatment, hyperuricemia may occur as a result of rapid lysis of tumor cells by mitoxantrone. Monitor serum uric acid levels and institute hypouricemic therapy prior to the initiation of antileukemic therapy.

    • In multiple sclerosis treatment, evaluate LVEF by echocardiogram or MUGA prior to each dose of mitoxantrone.

    • 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

    Adult

    Give by IV infusion. See full labeling for cytarabine dose. Induction therapy: 12mg/m2 daily on Days 1–3 + cytarabine on days 1–7; if 2nd induction course needed, give for 2 days + cytarabine for 5 days using same daily dosage levels. Consolidation therapy: 12mg/m2 on Days 1–2 + cytarabine on Days 1–5 for 2 courses (1st course given 6 weeks after the final induction course and the 2nd course given 4 weeks after the 1st course).

    Adult

    For induction, the recommended dosage is 12 mg/m2 of mitoxantrone daily on Days 1 to 3 given as an intravenous infusion, and 100 mg/m2 of cytarabine for 7 days given as a continuous 24-hour infusion on Days 1 to 7.

    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 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/m2 given by intravenous infusion daily on Days 1 and 2 and cytarabine, 100 mg/m2 for 5 days given as a continuous 24-hour infusion on Days 1 to 5. The first course was given approximately 6 weeks after the final induction course; the second was generally administered 4 weeks after the first. Severe myelosuppression occurred.

    Children

    Not established.

    Mitoxantrone Hcl Contraindications

    Not Applicable

    Mitoxantrone Hcl Boxed Warnings

    Not Applicable

    Mitoxantrone Hcl Warnings/Precautions

    Warnings/Precautions

    Risk of myelosuppression esp. in high doses (>14mg/m2 daily for 3 days); do not administer if baseline neutrophil count <1500 cell/mm3, except in ANLL. Increased risk of cardiotoxicity with pre-existing cardiovascular disease, prior radiotherapy to mediastinal/pericardial area, or previous anthracycline therapy. Assess cardiac history, physical exam, ECG, and LVEF prior to therapy. Increased risk of secondary acute myeloid leukemia. Hepatic impairment. Monitor CBCs, platelets, liver function tests prior to each course. Monitor for signs of infection. Avoid extravasation. Pregnancy (Cat. D); avoid. Nursing mothers: not recommended.

    Warnings/Precautions

    Severe myelosuppression occur when mitoxantrone is used in high doses (> 14 mg/m2/d × 3 days) such as indicated for the treatment of leukemia. Should 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. Monitor closely during the consolidation therapy phase (if this treatment is used). Mitoxantrone administered at any dose can cause myelosuppression.

    Contains sodium metabisulfite, which 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

    • Do not administer to patients with preexisting myelosuppression as the result of prior drug therapy unless 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.

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

    • Not indicated for subcutaneous, intramuscular, or intra-arterial injection. Do not administer by intrathecal injection. Topoisomerase II inhibitors, including mitoxantrone, have been associated with the development of secondary acute myeloid leukemia and myelosuppression.

    Cardiac Effects

    • Prior to initiation, determine the benefit-to-risk ratio of mitoxantrone therapy because of the possible danger of cardiac effects in patients previously treated with daunorubicin or doxorubicin.

    • Functional cardiac changes including decreases in left ventricular ejection fraction (LVEF) and irreversible congestive heart failure can occur with mitoxantrone. Increased risk of cardiac toxicity in patients with prior treatment with anthracyclines, prior mediastinal radiotherapy, or with preexisting cardiovascular disease. Perform regular cardiac monitoring of LVEF in these patients. 

    Multiple Sclerosis

    • Changes in cardiac function may occur in patients with multiple sclerosis treated with mitoxantrone. Assess MS patients 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. 

    • Do not administer to MS patients with a baseline LVEF below the lower limit of normal. Obtain subsequent LVEF and ECG evaluations if signs or symptoms of congestive heart failure develop and prior to every dose administered to MS patients. Do not administer 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. Obtain yearly quantitative LVEF evaluation in MS patients after stopping mitoxantrone to monitor for late-occurring cardiotoxicity.

    Leukemia

    • Acute congestive heart failure may occasionally occur in patients treated with mitoxantrone for ANLL. 

    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. 

    Secondary Leukemia

    • Increased risk of developing secondary leukemia in patients with cancer and in patients with multiple sclerosis.

    • Secondary acute myeloid leukemia has also been reported in cancer patients treated with anthracyclines. 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.

    Pregnancy Considerations

    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. 

    Conduct a pregnancy test prior to each dose in women with MS who are biologically capable of becoming pregnant, and the results should be known prior to administration. Inform the patient of the potential risk to the fetus if this drug is used during pregnancy or if the patient becomes pregnant while taking this drug.

    Nursing Mother Considerations

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

    Pediatric Considerations

    Safety and effectiveness in pediatric patients have not been established.

    Geriatric Considerations

    Multiple Sclerosis

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

    Hormone-Refractory Prostate Cancer

    • Clinical studies did not include sufficient numbers of younger patients to determine whether they respond differently from older patients. However, greater sensitivity of some older individuals cannot be ruled out.

    Acute Nonlymphocytic Leukemia

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

    Renal Impairment Considerations

    Mitoxantrone pharmacokinetics in patients with renal impairment are unknown.

    Hepatic Impairment Considerations

    Mitoxantrone clearance is reduced by hepatic impairment. Patients with severe hepatic dysfunction (bilirubin > 3.4 mg/dL) have an AUC more than three times greater than that of patients with normal hepatic function receiving the same dose. Patients with multiple sclerosis who have hepatic impairment should ordinarily not be treated with mitoxantrone. Other patients with hepatic impairment should be treated with caution and dosage adjustment may be required.

    Mitoxantrone Hcl Pharmacokinetics

    Distribution

    Distribution to tissues is extensive: steady-state volume of distribution exceeds 1,000 L/m2. Tissue concentrations of mitoxantrone appear to exceed those in the blood during the terminal elimination phase. In the healthy monkey, distribution to brain, spinal cord, eye, and spinal fluid is low.

    Mitoxantrone is 78% bound to plasma proteins in the observed concentration range of 26 to 455 ng/mL. This binding is independent of concentration and is not affected by the presence of phenytoin, doxorubicin, methotrexate, prednisone, prednisolone, heparin, or aspirin.

    Elimination

    Mitoxantrone is excreted in urine and feces as either unchanged drug or as inactive metabolites. In human studies, 11% and 25% of the dose were recovered in urine and feces, respectively, as either parent drug or metabolite during the 5-day period following drug administration. Of the material recovered in urine, 65% was unchanged drug. The remaining 35% was composed of monocarboxylic and dicarboxylic acid derivatives and their glucuronide conjugates.

    The mean alpha half-life of mitoxantrone is 6 to 12 minutes, the mean beta half-life is 1.1 to 3.1 hours and the mean gamma (terminal or elimination) half-life is 23 to 215 hours (median approximately 75 hours).

    Mitoxantrone Hcl Interactions

    Interactions

    Caution with concomitant cardiotoxic drugs.

    Mitoxantrone Hcl Adverse Reactions

    Adverse Reactions

    Myelosuppression, nausea, vomiting, infection, fever, fatigue, alopecia, dyspnea, hypersensitivity reactions, bluish-green urine, sclera discoloration, hyperuricemia (monitor), menstrual disorders, amenorrhea, interstitial pneumonitis; cardiotoxicity (eg, CHF).

    Mitoxantrone Hcl Clinical Trials

    Clinical Trials

    Acute Nonlymphocytic Leukemia

    In two large randomized multicenter trials, remission induction therapy for acute nonlymphocytic leukemia (ANLL) with mitoxantrone 12 mg/m2 daily for 3 days as a 10-minute IV infusion and cytarabine 100 mg/m2 for 7 days given as a continuous 24-hour infusion was compared with daunorubicin 45 mg/m2 daily by IV infusion for 3 days plus the same dose and schedule of cytarabine used with mitoxantrone. Patients who had an incomplete antileukemic response received a second induction course in which mitoxantrone or daunorubicin was administered for 2 days and cytarabine for 5 days using the same daily dosage schedule. 

    Results showed that treatment with mitoxantrone plus cytarabine (MIT) achieved the following response rates and median survival days compared with daunorubicin plus cytarabine (DAUN), respectively: 

    • US Trial:

      • % Complete response (CR): 63% (n=62/98) vs 53% (n=54/102)

      • Median time to CR (days): 35 vs 42

      • Survival (days): 312 vs 237

    • International Trial:

      • % CR: 50% (n=56/112) vs 51% (n=62/123)

      • Median time to CR (days): 36 vs 42

      • Survival (days): 192 vs 230

    In these studies, 2 consolidation courses were administered to complete responders on each arm. Consolidation therapy consisted of the same drug and daily dosage used for remission induction, but only 5 days of cytarabine and 2 days of mitoxantrone or daunorubicin were given. The first consolidation course was administered 6 weeks after the start of the final induction course if the patient achieved a complete remission. The second consolidation course was generally administered 4 weeks later. Full hematologic recovery was necessary for patients to receive consolidation therapy. 

    For the US trial, median granulocyte nadirs for patients receiving mitoxantrone + cytarabine for consolidation courses 1 and 2 were 10/mm3 for both courses, and for those patients receiving daunorubicin + cytarabine nadirs were 170/mm3 and 260/mm3, respectively. Median platelet nadirs for patients who received mitoxantrone + cytarabine for consolidation courses 1 and 2 were 17,000/mm3 and 14,000/mm3, respectively, and were 33,000/mm3 and 22,000/mm3 in courses 1 and 2 for those patients who received daunorubicin + cytarabine. The benefit of consolidation therapy in ANLL patients who achieve a complete remission remains controversial. However, in the only well-controlled prospective, randomized multicenter trials with mitoxantrone in ANLL, consolidation therapy was given to all patients who achieved a complete remission. During consolidation in the U.S. study, two myelosuppression-related deaths occurred in the mitoxantrone arm and one on the daunorubicin arm. However, in the international study there were eight deaths on the mitoxantrone arm during consolidation which were related to the myelosuppression and none on the daunorubicin arm where less myelosuppression occurred.

    Mitoxantrone Hcl Note

    Notes

    Formerly known under the brand name Novantrone.

    Mitoxantrone Hcl Patient Counseling

    Patient Counseling

    Inform patients of the availability of a Medication Guide and instruct them to read the Medication Guide prior to initiating treatment with Mitoxantrone and prior to each infusion. Review the Mitoxantrone Medication Guide with every patient prior to initiation of treatment and periodically during treatment. Instruct patients that Mitoxantrone should be taken only as prescribed.

    Advise patients that Mitoxantrone can cause myelosuppression and inform patients of the signs and symptoms of myelosuppression. 

    Advise patients that Mitoxantrone can cause congestive heart failure that may lead to death even in people who have never had heart problems before, and inform patients of the signs and symptoms of congestive heart failure. 

    Advise patients receiving Mitoxantrone to treat multiple sclerosis that they should receive cardiac monitoring prior to each Mitoxantrone dose and yearly after stopping Mitoxantrone.

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

    Mitoxantrone Hcl Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Mitoxantrone (as HCl) 2mg/mL; soln for IV infusion after dilution; preservative-free.

    Pharmacological Class

    Topoisomerase inhibitor.

    How Supplied

    Contact supplier.

    Manufacturer

    Various generic manufacturers

    Mitoxantrone Hcl Indications

    Indications

    Reduction of neurologic disability and/or frequency of clinical relapses in secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis (MS). Not indicated for the treatment of primary progressive MS.

    Mitoxantrone Hcl Dosage and Administration

    Prior to Treatment Evaluations

    Laboratory Tests

    • Obtain a complete blood count, including platelets, prior to each course of mitoxantrone and in the event that signs and symptoms of infection develop.

    • Perform liver function tests prior to each course of therapy. 

    • In leukemia treatment, hyperuricemia may occur as a result of rapid lysis of tumor cells by mitoxantrone. Monitor serum uric acid levels and institute hypouricemic therapy prior to the initiation of antileukemic therapy.

    • In multiple sclerosis treatment, evaluate LVEF by echocardiogram or MUGA prior to each dose of mitoxantrone.

    • 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

    Adult

    Give as a short (approx. 5–15mins) IV infusion. 12mg/m2 every 3 months. Do not administer to those with an LVEF <50%, or a clinically significant reduction in LVEF, or who have received a cumulative lifetime dose of ≥140mg/m2.

    Adult

    Multiple Sclerosis

    • The recommended dosage of mitoxantrone is 12 mg/m2 given as a short (approx. 5 to 15 minutes) IV infusion every 3 months. 

    • Do not administer if LVEF <50%, with a clinically significant reduction in LVEF, or to those who have received a cumulative lifetime dose of ≥140 mg/m2. 

    • Do not administer if neutrophil counts <1500 cells/mm3. Mitoxantrone therapy in multiple sclerosis patients with abnormal liver function tests is not recommended because mitoxantrone clearance is reduced by hepatic impairment and no laboratory measurement can predict drug clearance and dose adjustments.

    Children

    Not established.

    Mitoxantrone Hcl Contraindications

    Not Applicable

    Mitoxantrone Hcl Boxed Warnings

    Not Applicable

    Mitoxantrone Hcl Warnings/Precautions

    Warnings/Precautions

    Risk of myelosuppression esp. in high doses (>14mg/m2 daily for 3 days); do not administer if baseline neutrophil count <1500 cell/mm3, except in ANLL. Increased risk of cardiotoxicity with pre-existing cardiovascular disease, prior radiotherapy to mediastinal/pericardial area, or previous anthracycline therapy. Assess cardiac history, physical exam, ECG, and LVEF prior to therapy, and undergo yearly LVEF evaluation after stopping. Increased risk of secondary acute myeloid leukemia. Hepatic impairment: not recommended. Monitor CBCs, platelets, liver function tests prior to each course. Monitor for signs of infection. Avoid extravasation. Perform pregnancy test prior to each dose in women who are capable of becoming pregnant. Pregnancy (Cat. D); avoid. Nursing mothers: not recommended.

    Warnings/Precautions

    Severe myelosuppression occur when mitoxantrone is used in high doses (> 14 mg/m2/d × 3 days) such as indicated for the treatment of leukemia. Should 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. Monitor closely during the consolidation therapy phase (if this treatment is used). Mitoxantrone administered at any dose can cause myelosuppression.

    Contains sodium metabisulfite, which 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

    • Do not administer to patients with preexisting myelosuppression as the result of prior drug therapy unless 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.

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

    • Not indicated for subcutaneous, intramuscular, or intra-arterial injection. Do not administer by intrathecal injection. Topoisomerase II inhibitors, including mitoxantrone, have been associated with the development of secondary acute myeloid leukemia and myelosuppression.

    Cardiac Effects

    • Prior to initiation, determine the benefit-to-risk ratio of mitoxantrone therapy because of the possible danger of cardiac effects in patients previously treated with daunorubicin or doxorubicin.

    • Functional cardiac changes including decreases in left ventricular ejection fraction (LVEF) and irreversible congestive heart failure can occur with mitoxantrone. Increased risk of cardiac toxicity in patients with prior treatment with anthracyclines, prior mediastinal radiotherapy, or with preexisting cardiovascular disease. Perform regular cardiac monitoring of LVEF in these patients. 

    Multiple Sclerosis

    • Changes in cardiac function may occur in patients with multiple sclerosis treated with mitoxantrone. Assess MS patients 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. 

    • Do not administer to MS patients with a baseline LVEF below the lower limit of normal. Obtain subsequent LVEF and ECG evaluations if signs or symptoms of congestive heart failure develop and prior to every dose administered to MS patients. Do not administer 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. Obtain yearly quantitative LVEF evaluation in MS patients after stopping mitoxantrone to monitor for late-occurring cardiotoxicity.

    Leukemia

    • Acute congestive heart failure may occasionally occur in patients treated with mitoxantrone for ANLL. 

    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. 

    Secondary Leukemia

    • Increased risk of developing secondary leukemia in patients with cancer and in patients with multiple sclerosis.

    • Secondary acute myeloid leukemia has also been reported in cancer patients treated with anthracyclines. 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.

    Pregnancy Considerations

    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. 

    Conduct a pregnancy test prior to each dose in women with MS who are biologically capable of becoming pregnant, and the results should be known prior to administration. Inform the patient of the potential risk to the fetus if this drug is used during pregnancy or if the patient becomes pregnant while taking this drug.

    Nursing Mother Considerations

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

    Pediatric Considerations

    Safety and effectiveness in pediatric patients have not been established.

    Geriatric Considerations

    Multiple Sclerosis

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

    Hormone-Refractory Prostate Cancer

    • Clinical studies did not include sufficient numbers of younger patients to determine whether they respond differently from older patients. However, greater sensitivity of some older individuals cannot be ruled out.

    Acute Nonlymphocytic Leukemia

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

    Renal Impairment Considerations

    Mitoxantrone pharmacokinetics in patients with renal impairment are unknown.

    Hepatic Impairment Considerations

    Mitoxantrone clearance is reduced by hepatic impairment. Patients with severe hepatic dysfunction (bilirubin > 3.4 mg/dL) have an AUC more than three times greater than that of patients with normal hepatic function receiving the same dose. Patients with multiple sclerosis who have hepatic impairment should ordinarily not be treated with mitoxantrone. Other patients with hepatic impairment should be treated with caution and dosage adjustment may be required.

    Mitoxantrone Hcl Pharmacokinetics

    Distribution

    Distribution to tissues is extensive: steady-state volume of distribution exceeds 1,000 L/m2. Tissue concentrations of mitoxantrone appear to exceed those in the blood during the terminal elimination phase. In the healthy monkey, distribution to brain, spinal cord, eye, and spinal fluid is low.

    Mitoxantrone is 78% bound to plasma proteins in the observed concentration range of 26 to 455 ng/mL. This binding is independent of concentration and is not affected by the presence of phenytoin, doxorubicin, methotrexate, prednisone, prednisolone, heparin, or aspirin.

    Elimination

    Mitoxantrone is excreted in urine and feces as either unchanged drug or as inactive metabolites. In human studies, 11% and 25% of the dose were recovered in urine and feces, respectively, as either parent drug or metabolite during the 5-day period following drug administration. Of the material recovered in urine, 65% was unchanged drug. The remaining 35% was composed of monocarboxylic and dicarboxylic acid derivatives and their glucuronide conjugates.

    The mean alpha half-life of mitoxantrone is 6 to 12 minutes, the mean beta half-life is 1.1 to 3.1 hours and the mean gamma (terminal or elimination) half-life is 23 to 215 hours (median approximately 75 hours).

    Mitoxantrone Hcl Interactions

    Interactions

    Caution with concomitant cardiotoxic drugs.

    Mitoxantrone Hcl Adverse Reactions

    Adverse Reactions

    Myelosuppression, nausea, vomiting, infection, fever, fatigue, alopecia, dyspnea, hypersensitivity reactions, bluish-green urine, sclera discoloration, hyperuricemia (monitor), menstrual disorders, amenorrhea, interstitial pneumonitis; cardiotoxicity (eg, CHF).

    Mitoxantrone Hcl Clinical Trials

    Clinical Trials

    Multiple Sclerosis (Study 1)

    • Study 1 is a randomized, controlled study conducted in 188 patients with secondary progressive or progressive relapsing multiple sclerosis who had experienced a mean deterioration in EDSS (Kurtzke Expanded Disability Status Scale) of about 1.6 points over the 18 months prior to enrollment. Patients were randomized to receive placebo, 5 mg/m2 mitoxantrone, or 12 mg/m2 mitoxantrone administered IV every 3 months for 2 years. High-dose methylprednisolone was administered to treat relapses. 

    • A multivariate analysis of five clinical variables (EDSS, Ambulation Index [AI], number of relapses requiring treatment with steroids, months to first relapse needing treatment with steroids, and Standard Neurological Status [SNS]) was used to determine primary efficacy.

    • At month 24, results showed that treatment with mitoxantrone 12 mg/m2 met the primary efficacy multivariate analysis vs placebo (P <.0001). Moreover, treatment with mitoxantrone 5 mg/m2 and 12 mg/m2 achieved the following results at month 24 from baseline vs placebo, respectively: 

      • EDSS change (mean): -0.23 and -0.13 vs 0.23 (P =.0194)

      • Ambulation Index change (mean): 0.41 and 0.30 vs 0.77 (P =.0306)

      • Mean number of relapses per patient requiring corticosteroid treatment (adjusted for discontinuation): 0.73 and 0.40 vs 1.20 (P =.0002)

      • Months to first relapse requiring corticosteroid treatment (median [1st quartile]): Not reached (NR) [6.9] and NR [20.4] vs 14.2 [6.7] (P =.0004)

      • Standard Neurological Status change (mean): -0.38 and -1.07 vs 0.77 (P =.0269)

      • MRI (Number of patients with new Gd-enhancing lesions): 11% (n=4/37) and 0% (n=0/31) vs 16% (n=5/32) (P =.022)

      • MRI (Change in number of T2-weighted lesions, mean [n]): 0.68 (34) and 0.29 (28) vs 1.94 (32) (P =.027)

    Multiple Sclerosis (Study 2)

    • A second randomized, controlled study (Study 2) evaluated mitoxantrone in combination with methylprednisolone (MP) and was conducted in patients with secondary progressive or worsening relapsing-remitting multiple sclerosis who had residual neurological deficit between relapses. All patients had experienced at least two relapses with sequelae or neurological deterioration within the previous 12 months. The average deterioration in EDSS was 2.2 points during the previous 12 months. 

    • During the screening period, patients were treated with two monthly doses of 1 g of IV MP and underwent monthly MRI scans. Only patients who developed at least one new Gd-enhancing MRI lesion during the 2-month screening period were eligible for randomization. A total of 42 evaluable patients received monthly treatments of 1 g of IV MP alone (n = 21) or ~12 mg/m2 of IV mitoxantrone plus 1 g of IV MP (n = 21) (MIT + MP) for 6 months. Patients were evaluated monthly, and study outcome was determined after 6 months. 

    • The primary measure of effectiveness in this study was a comparison of the proportion of patients in each treatment group who developed no new Gd-enhancing MRI lesions at 6 months; these MRIs were assessed by a blinded panel. Additional outcomes were measured, including EDSS and number of relapses, but all clinical measures in this trial were assessed by an unblinded treating physician. 

    • At month 6, results showed that 90% (n=19/21) of patients treated with MIT+ MP met the primary endpoint with no new Gd-enhancing lesions on MRI compared with 31% (n=5/21) of those treated with MP alone (P =.001). Moreover, treatment with MIT + MP achieved the following secondary endpoints at month 6 vs MP alone, respectively: 

      • EDSS change: -1.1 vs -0.1 (P =.013)

      • Annualized relapse rate (mean per patient): 0.7 vs 3.0 (P =.003)

      • Patients (%) without relapses: 14 (67%) vs 7 (33%) (P =.031)

    Mitoxantrone Hcl Note

    Not Applicable

    Mitoxantrone Hcl Patient Counseling

    Patient Counseling

    Inform patients of the availability of a Medication Guide and instruct them to read the Medication Guide prior to initiating treatment with Mitoxantrone and prior to each infusion. Review the Mitoxantrone Medication Guide with every patient prior to initiation of treatment and periodically during treatment. Instruct patients that Mitoxantrone should be taken only as prescribed.

    Advise patients that Mitoxantrone can cause myelosuppression and inform patients of the signs and symptoms of myelosuppression. 

    Advise patients that Mitoxantrone can cause congestive heart failure that may lead to death even in people who have never had heart problems before, and inform patients of the signs and symptoms of congestive heart failure. 

    Advise patients receiving Mitoxantrone to treat multiple sclerosis that they should receive cardiac monitoring prior to each Mitoxantrone dose and yearly after stopping Mitoxantrone.

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

    Mitoxantrone Hcl Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Mitoxantrone (as HCl) 2mg/mL; soln for IV infusion after dilution; preservative-free.

    Pharmacological Class

    Topoisomerase inhibitor.

    How Supplied

    Contact supplier.

    Manufacturer

    Various generic manufacturers

    Mitoxantrone Hcl Indications

    Indications

    Treatment of pain in advanced hormone-refractory prostrate cancer in combination with corticosteroids.

    Mitoxantrone Hcl Dosage and Administration

    Prior to Treatment Evaluations

    Laboratory Tests

    • Obtain a complete blood count, including platelets, prior to each course of mitoxantrone and in the event that signs and symptoms of infection develop.

    • Perform liver function tests prior to each course of therapy. 

    • In leukemia treatment, hyperuricemia may occur as a result of rapid lysis of tumor cells by mitoxantrone. Monitor serum uric acid levels and institute hypouricemic therapy prior to the initiation of antileukemic therapy.

    • In multiple sclerosis treatment, evaluate LVEF by echocardiogram or MUGA prior to each dose of mitoxantrone.

    • 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

    Adult

    Give as a short IV infusion. 12–14mg/m2 every 21 days.

    Adult

    Multiple Sclerosis

    • The recommended dosage of mitoxantrone is 12 mg/m2 given as a short (approx. 5 to 15 minutes) IV infusion every 3 months. 

    • Do not administer if LVEF <50%, with a clinically significant reduction in LVEF, or to those who have received a cumulative lifetime dose of ≥140 mg/m2. 

    • Do not administer if neutrophil counts <1500 cells/mm3. Mitoxantrone therapy in multiple sclerosis patients with abnormal liver function tests is not recommended because mitoxantrone clearance is reduced by hepatic impairment and no laboratory measurement can predict drug clearance and dose adjustments.

    Children

    Not established.

    Mitoxantrone Hcl Contraindications

    Not Applicable

    Mitoxantrone Hcl Boxed Warnings

    Not Applicable

    Mitoxantrone Hcl Warnings/Precautions

    Warnings/Precautions

    Risk of myelosuppression esp. in high doses (>14mg/m2 daily for 3 days); do not administer if baseline neutrophil count <1500 cell/mm3, except in ANLL. Increased risk of cardiotoxicity with pre-existing cardiovascular disease, prior radiotherapy to mediastinal/pericardial area, or previous anthracycline therapy. Assess cardiac history, physical exam, ECG, and LVEF prior to therapy. Increased risk of secondary acute myeloid leukemia. Hepatic impairment. Monitor CBCs, platelets, liver function tests prior to each course. Monitor for signs of infection. Avoid extravasation. Pregnancy (Cat. D); avoid. Nursing mothers: not recommended.

    Warnings/Precautions

    Severe myelosuppression occur when mitoxantrone is used in high doses (> 14 mg/m2/d × 3 days) such as indicated for the treatment of leukemia. Should 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. Monitor closely during the consolidation therapy phase (if this treatment is used). Mitoxantrone administered at any dose can cause myelosuppression.

    Contains sodium metabisulfite, which 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

    • Do not administer to patients with preexisting myelosuppression as the result of prior drug therapy unless 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.

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

    • Not indicated for subcutaneous, intramuscular, or intra-arterial injection. Do not administer by intrathecal injection. Topoisomerase II inhibitors, including mitoxantrone, have been associated with the development of secondary acute myeloid leukemia and myelosuppression.

    Cardiac Effects

    • Prior to initiation, determine the benefit-to-risk ratio of mitoxantrone therapy because of the possible danger of cardiac effects in patients previously treated with daunorubicin or doxorubicin.

    • Functional cardiac changes including decreases in left ventricular ejection fraction (LVEF) and irreversible congestive heart failure can occur with mitoxantrone. Increased risk of cardiac toxicity in patients with prior treatment with anthracyclines, prior mediastinal radiotherapy, or with preexisting cardiovascular disease. Perform regular cardiac monitoring of LVEF in these patients. 

    Multiple Sclerosis

    • Changes in cardiac function may occur in patients with multiple sclerosis treated with mitoxantrone. Assess MS patients 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. 

    • Do not administer to MS patients with a baseline LVEF below the lower limit of normal. Obtain subsequent LVEF and ECG evaluations if signs or symptoms of congestive heart failure develop and prior to every dose administered to MS patients. Do not administer 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. Obtain yearly quantitative LVEF evaluation in MS patients after stopping mitoxantrone to monitor for late-occurring cardiotoxicity.

    Leukemia

    • Acute congestive heart failure may occasionally occur in patients treated with mitoxantrone for ANLL. 

    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. 

    Secondary Leukemia

    • Increased risk of developing secondary leukemia in patients with cancer and in patients with multiple sclerosis.

    • Secondary acute myeloid leukemia has also been reported in cancer patients treated with anthracyclines. 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.

    Pregnancy Considerations

    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. 

    Conduct a pregnancy test prior to each dose in women with MS who are biologically capable of becoming pregnant, and the results should be known prior to administration. Inform the patient of the potential risk to the fetus if this drug is used during pregnancy or if the patient becomes pregnant while taking this drug.

    Nursing Mother Considerations

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

    Pediatric Considerations

    Safety and effectiveness in pediatric patients have not been established.

    Geriatric Considerations

    Multiple Sclerosis

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

    Hormone-Refractory Prostate Cancer

    • Clinical studies did not include sufficient numbers of younger patients to determine whether they respond differently from older patients. However, greater sensitivity of some older individuals cannot be ruled out.

    Acute Nonlymphocytic Leukemia

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

    Renal Impairment Considerations

    Mitoxantrone pharmacokinetics in patients with renal impairment are unknown.

    Hepatic Impairment Considerations

    Mitoxantrone clearance is reduced by hepatic impairment. Patients with severe hepatic dysfunction (bilirubin > 3.4 mg/dL) have an AUC more than three times greater than that of patients with normal hepatic function receiving the same dose. Patients with multiple sclerosis who have hepatic impairment should ordinarily not be treated with mitoxantrone. Other patients with hepatic impairment should be treated with caution and dosage adjustment may be required.

    Mitoxantrone Hcl Pharmacokinetics

    Distribution

    Distribution to tissues is extensive: steady-state volume of distribution exceeds 1,000 L/m2. Tissue concentrations of mitoxantrone appear to exceed those in the blood during the terminal elimination phase. In the healthy monkey, distribution to brain, spinal cord, eye, and spinal fluid is low.

    Mitoxantrone is 78% bound to plasma proteins in the observed concentration range of 26 to 455 ng/mL. This binding is independent of concentration and is not affected by the presence of phenytoin, doxorubicin, methotrexate, prednisone, prednisolone, heparin, or aspirin.

    Elimination

    Mitoxantrone is excreted in urine and feces as either unchanged drug or as inactive metabolites. In human studies, 11% and 25% of the dose were recovered in urine and feces, respectively, as either parent drug or metabolite during the 5-day period following drug administration. Of the material recovered in urine, 65% was unchanged drug. The remaining 35% was composed of monocarboxylic and dicarboxylic acid derivatives and their glucuronide conjugates.

    The mean alpha half-life of mitoxantrone is 6 to 12 minutes, the mean beta half-life is 1.1 to 3.1 hours and the mean gamma (terminal or elimination) half-life is 23 to 215 hours (median approximately 75 hours).

    Mitoxantrone Hcl Interactions

    Interactions

    Caution with concomitant cardiotoxic drugs.

    Mitoxantrone Hcl Adverse Reactions

    Adverse Reactions

    Myelosuppression, nausea, vomiting, infection, fever, fatigue, alopecia, dyspnea, hypersensitivity reactions, bluish-green urine, sclera discoloration, hyperuricemia (monitor), menstrual disorders, amenorrhea, interstitial pneumonitis; cardiotoxicity (eg, CHF).

    Mitoxantrone Hcl Clinical Trials

    Clinical Trials

    Advanced Hormone-Refractory Prostate Cancer

    Phase 2 Trial

    • A multicenter trial of mitoxantrone and low-dose prednisone (M + P) was conducted in 27 symptomatic patients with hormone-refractory prostate cancer. Using NPCP (National Prostate Cancer Project) criteria for disease response, there was 1 partial responder and 12 patients with stable disease. However, 9 patients or 33% achieved a palliative response defined on the basis of reduction in analgesic use or pain intensity.

    • These findings led to the initiation of a randomized multicenter trial (CCI-NOV22) comparing the effectiveness of (M + P) to low-dose prednisone alone (P) in 161 patients with metastatic or locally advanced disease that had progressed on standard hormonal therapy, a castrate serum testosterone level, and at least mild pain at study entry. Patients received either mitoxantrone 12 mg/m2 by short IV infusion every 3 weeks (n=80) or prednisone 5 mg twice a day (n=81). Patients randomized to the prednisone arm were crossed over to the M + P arm if they progressed or if they were not improved after a minimum of 6 weeks of therapy with prednisone alone.

    • Results showed that 29% of patients treated with M + P achieved a primary palliative response (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) compared with 12% of patients treated with P alone (P =.011). Two responders left the study after meeting primary response criterion for two consecutive cycles. For the purposes of this analysis, these two patients were assigned a response duration of zero days. 

    • Additionally, 38% of patients treated with M + P achieved an overall palliative response (defined as primary plus secondary responses; secondary response was defined as a 50% or greater decrease in analgesic use, associated with stable pain intensity, and lasting a minimum of 6 weeks) compared with 21% of patients treated with P alone (P =.025).

    • The median duration of primary palliative response for patients randomized to M + P was 7.6 months compared with 2.1 months for patients randomized to P alone (P =.0009). The median duration of overall palliative response for patients randomized to M + P was 5.6 months compared with 1.9 months for patients randomized to P alone (P =.0004).

    • Time to progression was defined as a 1-point increase in pain intensity, or a > 25% increase in analgesic use, or evidence of disease progression on radiographic studies, or requirement for radiotherapy. The median time to progression for all patients randomized to M + P was 4.4 months compared with 2.3 months for all patients randomized to P alone (P =.0001). Median time to death was 11.3 months for all patients on the M + P arm compared with 10.8 months for all patients on P alone (P =.2324).

    • 48 patients on the P arm crossed over to receive M + P. Of these, thirty patients had progressed on P, while 18 had stable disease on P. The median cycle of crossover was 5 cycles (range of 2 to 16 cycles). Time trends for pain intensity prior to crossover were significantly worse for patients who crossed over than for those who remained on P alone (P =.012). Nine patients (19%) demonstrated a palliative response on M + P after crossover. The median time to death for patients who crossed over to M + P was 12.7 months.

    • In the CCI-NOV22 trial, 33% of all patients randomized to the M + P arm had a PSA fall of 50% or greater for 2 consecutive follow-up assessments after baseline compared with 9% of all patients randomized to the P arm. These findings should be interpreted with caution since PSA responses were not defined prospectively. A number of patients were inevaluable for response, and there was an imbalance between treatment arms in the numbers of evaluable patients. In addition, PSA reduction did not correlate precisely with palliative response, the primary efficacy endpoint of this study. Also, among 42 evaluable patients on this arm who did not have this reduction in PSA, 8 nonetheless had a primary palliative response.

    Phase 3 Comparative Trial

    • Investigators at Cancer and Leukemia Group B (CALGB) conducted a phase 3 comparative trial of mitoxantrone plus hydrocortisone (M + H) vs hydrocortisone alone (H) in patients with hormone-refractory prostate cancer (CALGB 9182). Eligible patients were required to have metastatic disease that had progressed despite at least one hormonal therapy. Patients received mitoxantrone 14 mg/m2 intravenously every 21 days and hydrocortisone was administered orally at a daily dose of 40 mg. A total of 242 patients were randomly assigned to receive M + H (n=119) or H (n=123). There were no differences in survival between the two arms, with a median of 11.1 months in the M + H arm and 12 months in the H arm (P = 0.3298).

    • Using NPCP criteria for response, partial responses were achieved in 10 patients (8.4%) randomized to the M + H arm compared with 2 patients (1.6%) randomized to the H arm (P = 0.018). The median time to progression, defined by NPCP criteria, for patients randomized to the M + H arm was 7.3 months compared to 4.1 months for patients randomized to H alone (P =.0654).

    • Approximately 60% of patients on each arm required analgesics at baseline. Analgesic use was measured in this study using a 5-point scale. The best percent change from baseline in mean analgesic use was -17% for 61 patients with available data on the M + H arm, compared with +17% for 61 patients on H alone (P = 0.014). A time trend analysis for analgesic use in individual patients also showed a trend favoring the M + H arm over H alone but was not statistically significant.

    • Pain intensity was measured using the Symptom Distress Scale (SDS) Pain Item 2 (a 5-point scale). The best percent change from baseline in mean pain intensity was -14% for 37 patients with available data on the M + H arm, compared with +8% for 38 patients on H alone (P =.057). A time trend analysis for pain intensity in individual patients showed no difference between treatment arms.

    Mitoxantrone Hcl Note

    Notes

    Formerly known under the brand name Novantrone.

    Mitoxantrone Hcl Patient Counseling

    Patient Counseling

    Inform patients of the availability of a Medication Guide and instruct them to read the Medication Guide prior to initiating treatment with Mitoxantrone and prior to each infusion. Review the Mitoxantrone Medication Guide with every patient prior to initiation of treatment and periodically during treatment. Instruct patients that Mitoxantrone should be taken only as prescribed.

    Advise patients that Mitoxantrone can cause myelosuppression and inform patients of the signs and symptoms of myelosuppression. 

    Advise patients that Mitoxantrone can cause congestive heart failure that may lead to death even in people who have never had heart problems before, and inform patients of the signs and symptoms of congestive heart failure. 

    Advise patients receiving Mitoxantrone to treat multiple sclerosis that they should receive cardiac monitoring prior to each Mitoxantrone dose and yearly after stopping Mitoxantrone.

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

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