mitoXANTRONE (Monograph)

Brand name: Novantrone
Drug class: Antineoplastic Agents
VA class: AN900
Chemical name: 1,4-dihydroxy-5,8-bis[[2-[2-hydroxyethyl)amino]ethyl]amino]9,10-anthracenedione dihydrochloride
Molecular formula: C₂₂H₂₈N₄O₆• 2HCl
CAS number: 70476-82-3

Medically reviewed by Drugs.com on Nov 15, 2023. Written by ASHP.

Introduction

Antineoplastic agent; a synthetic anthracenedione.

Uses for mitoXANTRONE

Acute Myeloid Leukemia

A component of various chemotherapy regimens for remission induction in acute myeloid (myelogenous, nonlymphocytic) leukemia (AML, ANLL). AML includes acute promyelocytic, monocytic, myelomonocytic, megakaryoblastic, and erythroid leukemias.

Used in combination with other antineoplastic agents in consolidation therapy regimens following induction of complete remission.

Prostate Cancer

Used as an alternative regimen for initial palliative treatment of advanced, symptomatic (i.e., painful) hormone-refractory prostate cancer (in combination with prednisone). Preferred first-line of treatment for hormone-refractory metastatic prostate cancer is docetaxel in combination with prednisone.

Multiple Sclerosis (MS)

Treatment of secondary (chronic) progressive, progressive-relapsing, or worsening relapsing-remitting MS. Used to reduce neurologic disability and/or frequency of relapse.

Has been studied in patients with the following disease patterns: Gradually increasing disability with or without superimposed clinical relapses (secondary progressive and progressive-relapsing subtypes) and clinical relapses resulting in stepwise increases in disability, with substantially abnormal neurologic status between relapses (worsening relapsing-remitting disease).

Not indicated for use in patients with primary progressive MS.

Because of 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 potential benefits greatly outweigh risks. (See Myocardial Toxicity in Boxed Warning and also see Hepatic Impairment under Cautions.)

Non-Hodgkin’s Lymphoma

Used as a component of combination chemotherapy regimens for treatment of low-grade non-Hodgkin’s lymphoma^{† [off-label]}.

Related/similar drugs

methotrexate, estradiol, Premarin, rituximab, cyclophosphamide, Xtandi, Zytiga

mitoXANTRONE Dosage and Administration

General

• Consult specialized references for procedures for proper handling and disposal of antineoplastics.

Acute Myeloid Leukemia

• Appropriate hematologic monitoring required; adjunctive therapies (e.g., anti-infectives, blood and blood products) must be available during the expected period of medullary hypoplasia and severe myelosuppression. Ensure full hematologic recovery before initiating consolidation therapy and monitor closely. (See Hematologic Effects under Cautions.)

Administration

Administer by IV infusion. Do not administer IM or sub-Q. Do not administer by intra-arterial or intrathecal injection. (See Neurotoxicity under Cautions.)

Safety of administration by routes other than IV not established.

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer diluted solution into tubing of a freely running IV solution of 0.9% sodium chloride injection or 5% dextrose injection, preferably via a Butterfly needle or other suitable device inserted into a large vein.

When possible, do not use veins over joints or in extremities with compromised venous or lymphatic drainage.

Avoid extravasation. If signs or symptoms of extravasation occur, immediately stop the infusion and restart in another vein. (See Local Effects under Cautions.) If sub-Q extravasation occurs or is suspected, elevation of the affected extremity and intermittent application of ice to the site may be useful. Because of the progressive nature of extravasation reactions, close observation and surgery consultation recommended.

Handle cautiously (by trained nonpregnant personnel); use protective equipment (e.g., goggles, gloves, protective gowns). Use care to avoid contact of the drug with skin, mucous membranes, and eyes. If skin contact occurs, immediately rinse affected areas with copious amounts of warm water; use standard irrigation techniques immediately in the event of eye involvement.

Dilution

Must be diluted prior to IV infusion.

Dilute dose of mitoxantrone hydrochloride in 0.9% sodium chloride injection or 5% dextrose injection to a final volume of ≥50 mL. Solutions may be further diluted with 5% dextrose injection, 0.9% sodium chloride injection, or 5% dextrose and 0.9% sodium chloride injection.

Diluted solutions contain no preservatives; prepare immediately before use.

Rate of Administration

Administer diluted solution slowly over ≥3 minutes; infusions are typically administered over 15–30 minutes.

In patients with prostate cancer or multiple sclerosis, infuse dose over approximately 5–15 minutes.

Dosage

Available as mitoxantrone hydrochloride; dosage expressed in terms of mitoxantrone.

Adults

Acute Myeloid Leukemia

Induction Therapy

IV

12 mg/m² daily on days 1–3 in combination with cytarabine 100 mg/m² daily (as a continuous IV infusion over 24 hours) on days 1–7.

If antileukemic response to the first induction course is incomplete, a second induction course consisting of 2 days of mitoxantrone (12 mg/m² daily) and 5 days of cytarabine (100 mg/m² daily) may be given.

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

Consolidation Therapy

IV

12 mg/m² daily on days 1 and 2 in combination with cytarabine 100 mg/m² daily (as a continuous IV infusion over 24 hours) on days 1–5. Administer initial consolidation course approximately 6 weeks after the final induction course; administer the second consolidation course generally 4 weeks after the initial course.

Prostate Cancer

IV

12–14 mg/m² once every 21 days; give as an adjunct to corticosteroid therapy (e.g., prednisone 5 mg orally twice daily, hydrocortisone 40 mg orally daily). Some clinicians recommend discontinuance of mitoxantrone (and continuation of corticosteroid therapy alone) in patients who are still responding after a cumulative mitoxantrone dose of 140 mg/m² due to risk of cardiac toxicity.

Multiple Sclerosis

IV

12 mg/m² once every 3 months.

Prescribing Limits

Adults

Multiple Sclerosis

IV

Maximum cumulative lifetime dose: 140 mg/m².

Special Populations

Hepatic Impairment

Decreased clearance; dosage adjustment may be required, however, no specific dosage adjustment recommendations. (See Hepatic Impairment under Cautions.)

Renal Impairment

Dosage reduction not required.

Cautions for mitoXANTRONE

Contraindications

• Known hypersensitivity to mitoxantrone or any ingredient in the formulation.

Warnings/Precautions

Warnings

Hematologic Effects

Risk of myelosuppression, manifested predominantly as neutropenia; may be severe and result in infection.

Frequent monitoring of hematologic parameters required; monitor CBC, including platelet count, prior to each course of therapy and if signs or symptoms of infection occur.

Do not initiate mitoxantrone in patients with preexisting drug-induced myelosuppression unless expected treatment benefit warrants risk.

Except for treatment of AML, use generally not recommended in patients with baseline neutrophil count <1500/mm³.

Cardiotoxicity

Risk of cardiotoxicity during or months to years after therapy. Functional cardiac changes (e.g., decreases in LVEF, irreversible CHF), tachycardia, ECG changes including arrhythmias, and chest pain can occur. Risk of cardiotoxicity increases with increasing cumulative dose. (See Myocardial Toxicity in Boxed Warning.)

Probability of developing CHF is 2.6% at a cumulative dosage of 140 mg/m² in cancer patients; the overall probability of moderate or serious decreases in LVEF was 13% at a cumulative dosage of 140 mg/m².

Preexisting cardiac disease, prior radiotherapy to the mediastinal or pericardial region, and/or previous anthracycline (e.g., doxorubicin, epirubicin) therapy increase risk of mitoxantrone-induced cardiotoxicity; determine benefit-to-risk ratio before initiating therapy in patients previously treated with anthracyclines (e.g., daunorubicin, doxorubicin). Monitor LVEF regularly following initiation of therapy in patients previously treated with an anthracycline or with mediastinal radiotherapy and in those with preexisting cardiovascular disease.

Evaluate cardiac function prior to initiation of therapy. Discontinue therapy in patients with LVEF <50% or a clinically important reduction in LVEF.

Monitor LVEF in patients with multiple sclerosis prior to each dose and if signs/symptoms of CHF develop. (See Myocardial Toxicity in Boxed Warning.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm. Potentially teratogenic based on developmental effects of related agents.

Avoid pregnancy during therapy. If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.

Exclude pregnancy with a negative pregnancy test prior to each dose in women of childbearing potential with multiple sclerosis.

Carcinogenicity

Secondary AML reported in mitoxantrone-treated patients with cancer or multiple sclerosis; risk of refractory AML increases with concomitant use of cytotoxic drugs and/or radiation therapy. (See Secondary Acute Myelogenous Leukemia [AML] in Boxed Warning.)

In clinical trials of breast cancer patients receiving mitoxantrone-containing adjuvant therapy, estimated risk of developing treatment-related leukemia at 4, 5, and 10 years was 2.2, 1.1, and 1.6%, respectively.

In patients with multiple sclerosis receiving mitoxantrone, risk of developing treatment-related leukemia was 0.25% after variable periods of follow up.

Neurotoxicity

Local or regional neuropathy (sometimes irreversible) has been reported following intra-arterial injection. Neurotoxicity (e.g., paralysis with bowel and bladder dysfunction, seizures resulting in coma and severe neurologic sequelae) has been observed following intrathecal injection. Do not administer by intra-arterial or intrathecal injection.

General Precautions

Adequate Patient Evaluation and Monitoring

Administer only under the supervision of qualified clinicians experienced in the use of cytotoxic therapy.

Closely observe patient and evaluate hematopoietic, hepatic, and cardiac function prior to and at regular intervals during therapy. (See Warnings under Cautions.)

Treat systemic infections prior to beginning therapy or concomitantly with therapy.

Pregnancy test recommended prior to each dose in women of childbearing potential with multiple sclerosis. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Tumor Lysis Syndrome

Hyperuricemia may result from rapid lysis of tumor cells; monitor serum uric acid concentration. Administer hypouricemic therapy (e.g., allopurinol) prior to initiating therapy for leukemia.

Local Effects

Extravasation may result in tissue necrosis; debridement and skin graft may be required. Erythema, swelling, pain, or blue discoloration has been reported following extravasation. Phlebitis has been reported at injection site.

Specific Populations

Pregnancy

Category D. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Distributed into milk. Discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.

Possibility exists of greater sensitivity to the drug and more frequent toxicity in some geriatric individuals.

Hepatic Impairment

Safety not established; use with caution in patients with cancer. Use not recommended in patients with MS who have hepatic impairment (i.e., abnormal liver function test results).

Decreased clearance reported in patients with severe hepatic impairment (i.e., serum total bilirubin concentration >3.4 mg/dL). Manufacturer states that drug clearance and required dosage adjustments cannot be predicted from liver function test results; therefore, no specific dosage adjustment recommendations for patients with hepatic impairment.

Renal Impairment

Not studied in patients with renal impairment.

Common Adverse Effects

Nausea, diarrhea, anorexia, alopecia, menstrual disorders, amenorrhea, myelosuppression, infection, fever, stomatitis, asthenia, fatigue, edema, dyspnea.

Does not inhibit CYP isoenzymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, or 3A4 in vitro; may be a weak inducer of CYP2E1.

No formal pharmacokinetic drug interaction studies to date. Clinically important drug interactions not reported; information on interactions in patients with multiple sclerosis is limited.

Specific Drugs

mitoXANTRONE Pharmacokinetics

Distribution

Extent

Extensively distributed into tissues. Distributed into milk. Low concentrations attained in brain, spinal cord, eye, and CSF in monkeys.

Plasma Protein Binding

78%.

Special Populations

Increased tissue penetration and protein binding in patients with abnormalities of the third space (e.g., edema, ascites, pleural effusion).

Elimination

Metabolism

Metabolic pathways not elucidated.

Elimination Route

Eliminated in feces (25%) by the hepatobiliary system and to a lesser extent in urine (approximately 10%) as unchanged drug or inactive metabolites.

Half-life

Triphasic; terminal half-life is approximately 23–215 hours (median: approximately 75 hours).

Special Populations

Severe hepatic impairment (serum total bilirubin concentration >3.4 mg/dL) decreases clearance. Decreased clearance may occur in patients with abnormalities of the third space (e.g., edema, ascites, pleural effusion).

Stability

Storage

Parenteral

Injection Concentrate

15–25°C. Do not freeze.

Undiluted concentrate may be stored for 7 days at 15–25°C or 14 days under refrigeration after puncture of the vial stopper.

Compatibility

Parenteral

Compatible with filters; during the manufacturing process, drug solution is passed through a 0.22-µm filter without loss of potency.

Solution CompatibilityHID

Drug Compatibility

Do not mix in the same infusion as heparin; precipitation may occur.

Actions

• A DNA-reactive agent that interferes with the function of topoisomerase II, thereby preventing religation of DNA strand breaks.

• Cytotoxic activity also may result from 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.

• Exerts a cytocidal effect on both proliferating and nonproliferating cultured human cells.

• Produces concentration- and time-proportional delays in cell-cycle progression. Not considered cell-cycle specific; however, mitoxantrone is most cytotoxic to cells in late S phase.

• Possible additive or synergistic effects with other antineoplastic agents (e.g., cytarabine, amsacrine, cisplatin, doxorubicin, etoposide).

• Tumor resistance 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.

• Incomplete cross-resistance with anthracyclines has been demonstrated in vitro.

• Inhibits B-cell, T-cell, and macrophage proliferation; impairs antigen presentation; and inhibits secretion of cytokines (interferon gamma, tumor necrosis factor, interleukin-2) in vitro.

Advice to Patients

• Importance of providing patients who have multiple sclerosis with a copy of the manufacturer’s patient information prior to initiation of therapy and before each dose of the drug.

• Importance of recognizing and reporting adverse effects of mitoxantrone, including myelosuppressive effects (and related precautions), CHF symptoms, and injection site pain.

• Risk of irreversible myocardial toxicity and secondary leukemia.

• Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy and advise pregnant women of risk to the fetus.

• Importance of patients informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.

• Possible blue-green appearance of urine for 24 hours after administration; the white part of the eyes also may appear blue.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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