Mitoxantrone Hydrochloride

Trade Names:
Novantrone
- Injection 2 mg/mL

Pharmacology

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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

Effects have not been determined.

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.

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

Effects of gender are unknown.

Effects of race are unknown.

Indications and Usage

Initial therapy of adult acute nonlymphocytic leukemia (ANLL) 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

Standard considerations.

Dosage and Administration

IV 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. 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.

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.

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

General Advice

• 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 period of no less than 3 min) into free-flowing IV infusion.
• 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

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

Mitoxantrone may decrease oral absorption of quinolone antibiotics.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Arrhythmia, cardiac function (18%); abnormal ECG (11%); cardiac ischemia, CHF, decreased LVEF (5%); hypertension (4%); chest pain, ECG changes, tachycardia.

CNS

Malaise/fatigue (39%); asthenia (24%); headache (13%); other neurologic (11%); neuro/motor (7%); neuro/mood (6%); anxiety/depression (5%); seizures (4%)

Dermatologic

Alopecia (61%); cutaneous mycosis (10%); sweats (9%); skin (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, weight gain (14%); vomiting (11%); emesis (9%); dyspepsia (5%).

Genitourinary

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

Hematologic

Decreased ANC, decreased WBC (100%); decreased lymphocytes (95%); granulocytes/bands (79%); Hgb low (75%); decreased Hgb (43%); decreased platelets (39%); leukopenia (19%); anemia (9%); granulocytopenia (6%); hemorrhage (5%).

Hypersensitivity

Allergic reactions; anaphylaxis/anaphylactoid reactions (rare).

Local

Extravasation, phlebitis.

Metabolic

Alkaline phosphatase (37%); hyperglycemia (31%); edema (30%); transaminase (20%); increased ALT, increased AST, increased gamma-glutamyltransferase (15%); glucose increased, hypocalcemia, potassium decreased (10%); hyponatremia (9%); other liver (8%).

Respiratory

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

Miscellaneous

Fever (78%); infections (66%); pain (41%); bleeding (37%); sepsis (34%) fungal infections (15%); fever in the absence of infection (14%); nail bed changes, petechiae/ecchymoses (11%); aphthosis, systemic infection (10%); back pain, renal failure (8%); jaundice (7%); hemorrhage/bruise, other endocrine (6%); chills, myalgias/arthralgias (5%); secondary acute myelogenous leukemia (AML) (postmarketing).

Precautions

Pregnancy

Category D .

Lactation

Excreted.

Children

Safety and efficacy not established.

Elderly

Toxicity may be more frequent in elderly patients.

Hypersensitivity

Hypotension, urticaria, dyspnea, and rashes 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 commencing 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.

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