Mitoxantrone Hydrochloride

Pronunciation: (mye-TOX-an-trone HYE-droe-KLOR-ide)
Class: Anthracenedione

Trade Names

Novantrone
- Injection, solution, concentrate 2 mg/mL

Pharmacology

Has a cytocidal effect on proliferating and nonproliferating cultured human cells, suggesting lack of cell-cycle phase specificity.

Pharmacokinetics

Distribution

Distribution to tissues is extensive and is 78% protein bound over a 26 to 455 ng/mL concentration range. Vd exceeds 1,000 L/m ² .

Elimination

Elimination is slow via renal and hepatobiliary systems. Only 11% is recovered in urine within 5 days (65% unchanged, 35% as metabolite); hepatobiliary is more significant, with 25% recovered in feces within 5 days. The elimination half-life is 23 to 215 h (median, approximately 75 h).

Special Populations

Renal Function Impairment

Effects have not been determined.

Hepatic Function Impairment

Ordinarily, do not treat patients with multiple sclerosis (MS) who have hepatic impairment with mitoxantrone. Dosage adjustment may be required for other patients with hepatic impairment. Patients with severe hepatic impairment have an AUC at least 3 times greater than patients with healthy hepatic function.

Elderly

Cl is reduced in elderly patients with breast cancer compared with younger patients with nasopharyngeal carcinoma and malignant lymphoma.

Children

Pharmacokinetics in children are unknown.

Gender

Effects of gender are unknown.

Race

Effects of race are unknown.

Indications and Usage

Initial therapy of adult acute nonlymphocytic leukemia as adjunctive therapy; initial therapy of advanced hormone-refractory prostate cancer (in combination with corticosteroids); secondary (chronic) progressive, progressive relapsing, or worsening relapsing remitting MS.

Unlabeled Uses

Treatment of breast cancer, non-Hodgkin lymphoma, autologous bone marrow transplantation.

Contraindications

None well documented.

Dosage and Administration

Acute Nonlymphocytic Leukemia
Adults

IV

Induction

For induction, give 12 mg/m ² /day on days 1 to 3 as an IV infusion, and give cytarabine 100 mg/m ² for 7 days as a continuous 24-h infusion on days 1 to 7. In the event of incomplete antileukemic response, a second induction course may be given. Give mitoxantrone for 2 days and cytarabine for 5 days using the same daily dosage levels.

Consolidation

For consolidation therapy, give 12 mg/m ² on days 1 and 2 as an IV infusion, and cytarabine 100 mg/m ² for 5 days as a continuous infusion on days 1 to 5. The first course was given approximately 6 wk after the final induction course; the second was generally administered 4 wk after the first.

MS
Adults

IV 12 mg/m ² given as a short (approximately 5 to 15 min) IV infusion every 3 mo. Do not administer to MS patients who have received a cumulative lifetime dose of 140 mg/m ² or more, or those with left ventricular ejection fraction (LVEF) of less than 50% or a clinically important reduction in LVEF.

Prostate Cancer
Adults

IV 12 to 14 mg/m ² given as a short IV infusion every 21 days.

General Advice

For IV use only. Do not administer by IM, intra-arterial, intrathecal, or subcutaneous injection.
Concentrate must be diluted following manufacturer's recommendations before administration.
Administer immediately after dilution.
Do not administer if particulate matter or discoloration is noted.
Administer prescribed dose slowly (over a period of no less than 3 min) into free-flowing IV infusion of sodium chloride 0.9% or dextrose 5% injection.
Do not mix with other medications.
Follow procedures for proper handling and disposal of anticancer drugs. Wear goggles, gloves, and protective gown during preparation and administration.

Storage/Stability

Store unopened vials at 59° to 77°F. Do not freeze. After penetration of multidose vial stopper, the remaining undiluted concentrate can be stored for up to 7 days at 59° to 77°F or refrigerated for up to 14 days at 36° to 46°F. Do not freeze. Discard any unused infusion solution.

Drug Interactions

Cyclosporine

Therapeutic and toxic effects of mitoxantrone may be increased by cyclosporine. Close clinical and laboratory monitoring are indicated.

CYP-450 system

The results of in vitro induction studies are inconclusive, but suggest that mitoxantrone is a weak inducer of CYP2E1.

Digoxin

Digoxin plasma concentrations may be reduced, decreasing the pharmacologic effects. Monitor digoxin concentrations and the patient for signs of clinical deterioration (eg, CHF). Adjust the digoxin dose as needed.

Hydantoins (eg, phenytoin)

Plasma concentrations and therapeutic effectiveness of hydantoins may be reduced by mitoxantrone, increasing the risk of seizures. Monitor plasma hydantoin concentrations and seizure frequency when starting or stopping mitoxantrone. Adjust the hydantoin dose as needed.

Live vaccines

The risk of live vaccine–induced adverse reactions may be increased by coadministration of mitoxantrone. If possible, the use of live vaccines in patients receiving mitoxantrone should be deferred.

Palifermin

Coadministration of palifermin and mitoxantrone within the same 24-h time period may increase the severity and duration of mitoxantrone-induced oral mucositis. Palifermin should not be administered within 24 h before, during, or 24 h after administration of mitoxantrone.

Trastuzumab

The risk of trastuzumab-induced cardiac dysfunction may be increased by coadministration of mitoxantrone. Closely monitor for signs of cardiac dysfunction.

Adverse Reactions

Cardiovascular

Abnormal cardiac function, arrhythmia (18%); abnormal ECG (11%); cardiac ischemia, CHF, decreased LVEF (5%); hypertension (4%).

CNS

Fatigue (39%); malaise (34%); asthenia (24%); headache (13%); other neurologic problems (11%); neuro/motor disorder (7%); neuro/mood disorder (6%); anxiety/depression (5%); seizures (4%).

Dermatologic

Alopecia (61%); petechiae/ecchymoses (11%); cutaneous mycosis (10%); sweats (9%); skin disorder (6%); skin infection (5%).

EENT

Pharyngitis/throat infection (19%); rhinitis (10%); sinusitis (6%); conjunctivitis (5%); blurred vision (3%).

GI

Nausea (76%); nausea/vomiting (72%); diarrhea (47%); mucositis/stomatitis (29%); anorexia (25%); weight loss (17%); constipation, GI bleed (16%); abdominal pain (15%); gastralgia/stomach burn/epigastric pain, other GI problems, weight gain (14%); vomiting (11%); emesis (9%); dyspepsia (5%).

Genitourinary

Menstrual disorder (61%); amenorrhea (53%); UTI (32%); abnormal BUN (22%); abnormal creatinine (13%); abnormal urine, hematuria (11%); renal failure (8%); impotence/libido, menorrhagia (7%); proteinuria (6%); other kidney/bladder problems, sterility (5%).

Hematologic

Decreased ANC, decreased WBC (100%); decreased lymphocytes (95%); abnormal granulocytes/bands (79%); decreased Hgb (75%); decreased platelets (39%); leukopenia (19%); anemia (9%); granulocytopenia (6%); hemorrhage (5%).

Hepatic

Abnormal transaminase (20%); increased ALT, increased AST, increased gamma-glutamyltransferase (15%); other liver problems (8%); jaundice (7%).

Hypersensitivity

Allergic reactions; anaphylaxis/anaphylactoid reactions (rare).

Local

Extravasation, phlebitis.

Metabolic

Abnormal alkaline phosphatase (37%); hyperglycemia (31%); edema (30%); glucose increased, hypocalcemia, potassium decreased (10%); hyponatremia (9%); hypokalemia (7%); other endocrine problems (6%).

Respiratory

Upper respiratory tract infection (53%); dyspnea (18%); cough (13%); pneumonia (9%); other pulmonary problems (5%); interstitial pneumonitis.

Miscellaneous

Fever (78%); infections (66%); pain (41%); bleeding (37%); sepsis (34%) fungal infections (15%); fever in the absence of infection (14%); nailbed changes (11%); aphthosis, systemic infection (10%); back pain (8%); hemorrhage/bruise (6%); chills, myalgias/arthralgias (5%); secondary acute myelogenous leukemia (AML) (postmarketing).

Precautions

Warnings

Administration

Administer mitoxantrone under the supervision of a health care provider experienced in the use of cytotoxic chemotherapy. Administer slowly into a free-flowing IV infusion.

Cardiotoxicity

Cardiotoxicity, including fatal CHF, may occur during or for months to years after stopping mitoxantrone therapy. The risk increases with cumulative dose. Cardiotoxicity may occur whether or not cardiac risk factors are present. However, presence or history of CV disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with anthracyclines or anthracenediones, or concurrent use of other cardiotoxic agents may increase the risk of cardiac toxicity. Assess all patients for cardiac signs and symptoms by history, physical examination, ECG, and LVEF prior to start of therapy.

Extravasation risk

Local irritation or phlebitis may occur. Refer to institution-specific protocol.

Intrathecal

Not for intrathecal use.

Leukemia

Secondary AML has been reported in MS and cancer patients treated with agents related to mitoxantrone.

Neutropenia

Except for the treatment of acute nonlymphocytic leukemia, do not administer to patients with baseline neutrophil counts less than 1,500 cells/mm ³ .

Monitor

Perform baseline evaluation of LVEF by echocardiogram or multigated radionuclide angiography (MUGA). Do not treat MS patients with mitoxantrone when their baseline LVEF is less than 50%. Reevaluate LVEF by echocardiogram or MUGA prior to administration of each dose to patients with MS. Observe patient frequently and obtain a CBC, including platelets, and perform LFTs prior to each course of therapy. Perform frequent peripheral blood cell counts. MS patients should undergo annual quantitative LVEF evaluation after stopping treatment to monitor for late-occurring cardiotoxicity. Monitor serum uric acid levels and start hypouricemic therapy prior to the initiation of antileukemic therapy. Assess MS patients for cardiac signs and symptoms by history, physical exam, and ECG prior to each dose. Women with MS who are capable of becoming pregnant, even if they are using birth control, should have a pregnancy test and the results should be obtained before receiving each dose of mitoxantrone.

Pregnancy

Category D .

Lactation

Excreted.

Children

Safety and efficacy not established.

Elderly

Toxicity may be more frequent in elderly patients.

Hypersensitivity

Dyspnea, hypotension, rashes, and urticaria have been reported. Anaphylaxis/anaphylactoid reactions have been reported rarely.

Hepatic Function

Ordinarily, do not use mitoxantrone to treat patients with MS who have hepatic impairment. A dosage adjustment may be required for other patients with hepatic impairment.

Administration

For IV use only. Never give subcutaneous, IM, intrathecal, or intra-arterial injection.

Cardiac

Functional cardiac changes, including irreversible CHF and decreased LVEF, can occur.

Hyperuricemia

May occur in patients with leukemia. Ensure that hypouricemic therapy is initiated before starting treatment.

Infections

Treat systemic infections concomitantly with or just prior to starting mitoxantrone therapy.

Myelosuppression

Mitoxantrone administered at any dose can cause myelosuppression. Do not administer mitoxantrone to patients with preexisting myelosuppression caused by prior drug therapy.

Secondary AML

Has been reported.

Overdosage

Symptoms

Death as a result of severe leukopenia with infection.

Patient Information

Advise patient to read patient information leaflet before starting therapy and prior to each treatment.
Advise patient, family, or caregiver that medication will be prepared and administered by a health care provider in a medical setting.
Review dose and dosing schedule, depending on condition being treated.
Advise patient, family, or caregiver that urine may have a blue-green color for 24 h after administration and bluish discoloration of the sclera may occur.
Instruct patient to immediately report any of the following to health care provider: bleeding or unusual bruising; cough or difficulty breathing on exertion; fever, sore throat, or other signs of infection; infusion-site reaction or pain; sores in or around the mouth; swelling of legs or feet.
Advise women of childbearing potential to use effective contraception during therapy.