Mitoxantrone Hydrochloride

Antineoplastic agent; a synthetic anthracenedione.1 2 3 4 26

Acute Myeloid Leukemia

A component of various chemotherapy regimens for remission induction in acute myeloid (myelogenous, nonlymphocytic) leukemia (AML, ANLL).1 2 3 7 8 9 10 11 24 AML includes acute promyelocytic, monocytic, myelomonocytic, megakaryoblastic, and erythroid leukemias.1 23

Used in combination with other antineoplastic agents in consolidation therapy regimens following induction of complete remission.1 8 10

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).1 12 13 14 22 24 26 Preferred first-line of treatment for hormone-refractory metastatic prostate cancer is docetaxel in combination with prednisone.22

Multiple Sclerosis (MS)

Treatment of secondary (chronic) progressive, progressive-relapsing, or worsening relapsing-remitting MS.1 Used to reduce neurologic disability and/or frequency of relapse.1

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).1

Not recommended for use in patients with primary progressive MS.1

Should not be used for treatment of MS in patients with baseline LVEF <50% (see Myocardial Toxicity in Boxed Warning).1 Generally not recommended for use in those with hepatic impairment (see Hepatic Impairment under Cautions) or in those with neutrophil count <1500/mm3.1

Non-Hodgkin’s Lymphoma

Used as a component of combination chemotherapy regimens for treatment of low-grade non-Hodgkin’s lymphoma†.24

General

• Consult specialized references for procedures for proper handling and disposal of antineoplastics.1

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.1 23 Ensure full hematologic recovery before initiating consolidation therapy and monitor closely.1 23 (See Hematologic Effects under Cautions.)

Administration

Administer by IV infusion.1 Do not administer IM or sub-Q.1 Do not administer by intra-arterial or intrathecal injection.1 (See Neurotoxicity under Cautions.)

Safety of administration by routes other than IV not established.1

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.1

When possible, do not use veins over joints or in extremities with compromised venous or lymphatic drainage.1

Avoid extravasation.1 If signs or symptoms of extravasation occur, immediately stop the infusion and restart in another vein.1 (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.1 Because of the progressive nature of extravasation reactions, close observation and surgery consultation recommended.1

Handle cautiously (by trained nonpregnant personnel); use protective equipment (e.g., goggles, gloves, protective gowns).1 Use care to avoid contact of the drug with skin, mucous membranes, and eyes.1 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.1

Must be diluted prior to IV infusion.1 2 3

Dilute dose of mitoxantrone hydrochloride in 0.9% sodium chloride injection or 5% dextrose injection to a final volume of ≥50 mL.1 3 Solutions may be further diluted with 5% dextrose injection, 0.9% sodium chloride injection, or 5% dextrose and 0.9% sodium chloride injection.1

Diluted solutions contain no preservatives; prepare immediately before use.1

Administer diluted solution slowly over ≥3 minutes;1 2 3 infusions are typically administered over 15–30 minutes.3 15

In patients with prostate cancer or multiple sclerosis, infuse dose over approximately 5–15 minutes.1

Dosage

Available as mitoxantrone hydrochloride; dosage expressed in terms of mitoxantrone.1

Adults

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 1–7.1 8 10 11

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.1 8 10 11

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

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 1–5.1 8 10 Administer initial consolidation course approximately 6 weeks after the final induction course; administer the second consolidation course generally 4 weeks after the initial course.1 8

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).1 14 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.14

12 mg/m2 once every 3 months.1

Prescribing Limits

Adults

Maximum cumulative lifetime dose: 140 mg/m2.1

Special Populations

Hepatic Impairment

Decreased clearance; dosage adjustment may be required, however, no specific dosage adjustment recommendations.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Dosage reduction not required.15 16

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

No formal pharmacokinetic drug interaction studies to date.1 Clinically important drug interactions not reported; information on interactions in patients with multiple sclerosis is limited.1

Specific Drugs

Distribution

Extent

Extensively distributed into tissues.1 Distributed into milk.1 Low concentrations attained in brain, spinal cord, eye, and CSF in monkeys.1

Plasma Protein Binding

78%.1

Special Populations

Increased tissue penetration and protein binding in patients with abnormalities of the third space (e.g., edema, ascites, pleural effusion).3

Elimination

Metabolism

Metabolic pathways not elucidated.1

Elimination Route

Eliminated in feces (25%) by the hepatobiliary system1 and to a lesser extent in urine (approximately 10%)1 2 16 17 as unchanged drug or inactive metabolites.1

Half-life

Triphasic; terminal half-life is approximately 23–215 hours (median: approximately 75 hours).1

Special Populations

Severe hepatic impairment (serum total bilirubin concentration >3.4 mg/dL) decreases clearance.1 15 Decreased clearance may occur in patients with abnormalities of the third space (e.g., edema, ascites, pleural effusion).3