Mitoxantrone

Pregnancy Category: D

Lactation: excreted in breast milk, do not nurse

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Mitoxantrone is part of the drug class:

• Anthracyclines and related substances

Mitoxantrone can cause serious side effects, including:

• decrease in the ability of your bone marrow to make blood cells (myelosuppression). Your doctor may do blood tests during treatment with mitoxantrone to check your blood cell counts. The symptoms of myelosuppression can include:
  • feeling tired
  • increased infections
  • bruising and bleeding easily

• heart problems (congestive heart failure) that may lead to death even in people who have never had heart problems before. Heart failure can happen while you receive mitoxantrone, or months to years after you stop receiving mitoxantrone. Your risk of heart failure increases the more mitoxantrone you receive.
• acute myeloid leukemia (AML). Receiving mitoxantrone increases your risk of AML. AML is a cancer of the blood-forming cells of your bone marrow. Symptoms of AML can include:
  • feeling unusually tired and weak
  • increased infections
  • bruising and bleeding easily
  • fever
  • pain in your bones
  • trouble breathing
  • unexplained weight loss
  • night sweats

• skin problems at your injection site. If mitoxantrone leaks out of your vein, skin problems can happen that may lead to serious skin damage (necrosis). Necrosis may need to be repaired surgically. Tell your doctor right away if you have any of the following problems at your injection site:
  • redness
  • swelling
  • pain
  • burning
  • skin turns a bluish color

Call your doctor or get medical help right away if you have any of these problems during or after treatment with mitoxantrone:

• shortness of breath
• swelling of your ankles or feet
• sudden weight gain
• fast heartbeat or pounding in your chest

Before receiving mitoxantrone for the first time, you should have the following tests done:

• physical examination
• a test to check your heart’s electrical activity (electrocardiogram)
• a test to check your heart’s ability to pump blood

If you receive mitoxantrone to treat Multiple Sclerosis (MS), your doctor should also do the tests above:

• before you receive each mitoxantrone dose
• yearly after you stop receiving mitoxantrone treatment

Multiple Sclerosis

• The recommended dosage of mitoxantrone is 12 mg/m² every 3 months.

Hormone-Refractory Prostate Cancer

• The recommended dosage of mitoxantrone is 12 to 14 mg/m² every 21 days.

Combination Initial Therapy for ANLL in Adults

• For induction, the recommended dosage is 12 mg/m² on Days 1 to 3
• In the event of an incomplete response, a second induction course may be given.
• For consolidation, 12 mg/m² on Days 1 and 2.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.
• This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time this medicine is refilled. If you have any questions about mitoxantrone, please talk with the doctor, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about mitoxantrone. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using mitoxantrone.

Review Date: October 4, 2017

General

Therapy with Mitoxantrone should be accompanied by close and frequent monitoring of hematologic and chemical laboratory parameters, as well as frequent patient observation.

Systemic infections should be treated concomitantly with or just prior to commencing therapy with Mitoxantrone.

Information for Patients

See FDA-approved patient labeling (Medication Guide).

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. 

Laboratory Tests

A complete blood count, including platelets, should be obtained prior to each course of Mitoxantrone and in the event that signs and symptoms of infection develop.  Liver function tests should also be performed prior to each course of therapy.  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.

In leukemia treatment, hyperuricemia may occur as a result of rapid lysis of tumor cells by Mitoxantrone.  Serum uric acid levels should be monitored and hypouricemic therapy instituted prior to the initiation of antileukemic therapy.

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 (see WARNINGS, Pregnancy).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Intravenous treatment of rats and mice, once every 21 days for 24 months, with Mitoxantrone resulted in an increased incidence of fibroma and external auditory canal tumors in rats at a dose of 0.03 mg/kg (0.02 fold the recommended human dose, on a mg/m2 basis), and hepatocellular adenoma in male mice at a dose of 0.1 mg/kg (0.03 fold the recommended human dose, on a mg/m2 basis).  Intravenous treatment of rats, once every 21 days for 12 months with Mitoxantrone resulted in an increased incidence of external auditory canal tumors in rats at a dose of 0.3 mg/kg (0.15 fold the recommended human dose, on a mg/m2 basis).

Mutagenesis

Mitoxantrone was clastogenic in the in vivo rat bone marrow assay.  Mitoxantrone was also clastogenic in two in vitro assays; it induced DNA damage in primary rat hepatocytes and sister chromatid exchanges in Chinese hamster ovary cells.  Mitoxantrone was mutagenic in bacterial and mammalian test systems (Ames/Salmonella and E. coli and L5178Y TK+/-mouse lymphoma).

Drug Interactions

Mitoxantrone and its metabolites are excreted in bile and urine, but it is not known whether the metabolic or excretory pathways are saturable, may be inhibited or induced, or if Mitoxantrone and its metabolites undergo enterohepatic circulation.  To date, post-marketing experience has not revealed any significant drug interactions in patients who have received Mitoxantrone for treatment of cancer.  Information on drug interactions in patients with multiple sclerosis is limited.

Following concurrent administration of Mitoxantrone with corticosteroids, no evidence of drug interactions has been observed.

Special Populations

Hepatic Impairment

Patients with multiple sclerosis who have hepatic impairment should ordinarily not be treated with Mitoxantrone.  Mitoxantrone should be administered with caution to other patients with hepatic impairment.  In patients with severe hepatic impairment, the AUC is more than three times greater than the value observed in patients with normal hepatic function.

Pregnancy

Pregnancy Category D

(see WARNINGS).

Nursing Mothers

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, breastfeeding should be discontinued before starting treatment.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

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

One hundred forty-six patients aged 65 and over and 52 younger patients (<65 years) have been treated with Mitoxantrone in controlled clinical studies.  These 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.

Mitoxantrone Injection, USP (concentrate) is a sterile aqueous solution containing Mitoxantrone hydrochloride at a concentration equivalent to 2 mg Mitoxantrone free base per mL supplied in vials for multidose use as follows:

The above products are packaged individually.

STORE AT: 20º to 25ºC (68° to 77°F) [see USP Controlled Room Temperature].  Keep from freezing.

The container closure is not made with natural rubber latex.

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 and malignant lymphoma.

Includes events reported with any indication; incidence varies based on treatment, dose, and/or concomitant medications.

>10%:

Cardiovascular: Edema (10% to 30%), cardiac disease (≤18%), cardiac arrhythmia (3% to 18%), ECG changes (≤11%)

Central nervous system: Pain (8% to 41%), fatigue (≤39%), headache (6% to 13%)

Dermatologic: Alopecia (20% to 61%), nail bed changes (≤11%)

Endocrine & metabolic: Menstrual disease (26% to 61%), amenorrhea (28% to 53%), hyperglycemia (10% to 31%), weight gain (≤17%), weight loss (≤17%), increased gamma-glutamyl transferase (3% to 15%)

Gastrointestinal: Nausea (26% to 76%), vomiting (6% to 72%), diarrhea (14% to 47%), mucositis (10% to 29%; onset: ≤1 week), stomatitis (8% to 29%; onset: ≤1 week), anorexia (22% to 25%), constipation (10% to 16%), gastrointestinal hemorrhage (2% to 16%), abdominal pain (9% to 15%), dyspepsia (5% to 14%)

Genitourinary: Urinary tract infection (7% to 32%), hematuria (≤11%), urine abnormality (5% to 11%)

Hematologic & oncologic: Neutropenia (79% to 100%; onset: ≤3 weeks; grade 4: 23% to 54%), leukopenia (9% to 100%), lymphocytopenia (72% to 95%), anemia (≤75%), decreased hemoglobin (≤75%), thrombocytopenia (33% to 39%; grades 3/4: 3% to 4%), bruise (≤11%), febrile neutropenia (≤11%), petechia (≤11%)

Hepatic: Increased serum alkaline phosphatase (≤37%), increased serum transaminases (5% to 20%)

Infection: Infection (4% to 60%), sepsis (≤34%), fungal infection (9% to 15%)

Neuromuscular & skeletal: Weakness (≤24%)

Renal: Increased blood urea nitrogen (≤22%), increased serum creatinine (≤13%)

Respiratory: Upper respiratory tract infection (7% to 53%), pharyngitis (≤19%), dyspnea (6% to 18%), cough (5% to 13%)

Miscellaneous: Fever (6% to 78%)

1% to 10%:

Cardiovascular: Cardiac failure (≤5%), ischemia (≤5%), decreased left ventricular ejection fraction (≤5%), hypertension (≤4%)

Central nervous system: Chills (≤5%), anxiety (5%), depression (5%), seizure (2% to 4%)

Dermatologic: Diaphoresis (≤9%), skin infection (≤5%)

Endocrine & metabolic: Hypocalcemia (10%), hypokalemia (7% to 10%), hyponatremia (9%), hypermenorrhea (7%)

Gastrointestinal: Aphthous stomatitis (≤10%)

Genitourinary: Impotence (≤7%), proteinuria (≤6%), sterility (≤5%)

Hematologic & oncologic: Granulocytopenia (6%), hemorrhage (5% to 6%), acute leukemia (≤3%; secondary; includes AML, APL)

Hepatic: Jaundice (3% to 7%)

Infection: Fungal infection (cutaneous: ≤10%)

Neuromuscular & skeletal: Back pain (6% to 8%), arthralgia (≤5%), myalgia (≤5%)

Ophthalmic: Conjunctivitis (≤5%), blurred vision (≤3%)

Renal: Renal failure (≤8%)

Respiratory: Rhinitis (10%), pneumonia (≤9%), sinusitis (≤6%)

<1% (Limited to important or life-threatening): Anaphylactoid reaction, anaphylaxis, chest pain, dehydration, hypersensitivity reaction, interstitial pneumonitis (with combination chemotherapy), hyperuricemia, hypotension, ocular discoloration (blue discoloration of sclera), phlebitis (at infusion site), skin rash, tachycardia, urine discoloration (blue-green), urticaria

Mitoxantrone should be administered under the supervision of a health care provider experienced in the use of cytotoxic chemotherapy agents.

Except for the treatment of acute nonlymphocytic leukemia, mitoxantrone therapy generally should not be given to patients with baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression (primarily neutropenia, which may be severe and result in infection), it is recommended that frequent peripheral blood cell counts be performed on all patients receiving mitoxantrone.

Congestive heart failure (CHF), potentially fatal, may occur during therapy with mitoxantrone or months to years after termination of therapy. Cardiotoxicity risk increases with cumulative mitoxantrone dose and may occur whether or not cardiac risk factors are present. Presence or history of cardiovascular disease, radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or use of other cardiotoxic drugs may increase this risk. In patients with cancer, the risk of symptomatic CHF was estimated to be 2.6% for patients receiving up to a cumulative dose of 140 mg/m2. To mitigate the cardiotoxicity risk with mitoxantrone, consider the following:

All patients should be assessed for cardiac signs and symptoms by history, physical examination, and electrocardiogram (ECG) prior to start of mitoxantrone therapy.

All patients should have baseline quantitative evaluation of left ventricular ejection fraction (LVEF) using appropriate methodology (eg, echocardiogram, multigated radionuclide angiogram [MUGA], magnetic resonance imaging [MRI]).

Patients with multiple sclerosis (MS) with a baseline LVEF below the lower limit of normal should not be treated with mitoxantrone.

Patients with MS should be assessed for cardiac signs and symptoms by history, physical examination, and ECG prior to each dose.

Patients with MS should undergo quantitative reevaluation of LVEF prior to each dose using the same methodology that was used to assess baseline LVEF. Additional doses of mitoxantrone should not be administered to MS patients who have experienced a drop in LVEF to below the lower limit of normal or a clinically significant reduction in LVEF during mitoxantrone therapy.

Patients with MS should not receive a cumulative mitoxantrone dose higher than 140 mg/m2.

Patients with MS should undergo yearly quantitative LVEF evaluation after stopping mitoxantrone to monitor for late-occurring cardiotoxicity.

Mitoxantrone therapy in MS patients and in patients with cancer increases the risk of developing secondary acute myeloid leukemia (AML).

Mitoxantrone should be given slowly into a freely flowing intravenous (IV) infusion. It must never be given subcutaneously, intramuscularly (IM), or intra-arterially. Severe local tissue damage may occur if there is extravasation during administration. Not for intrathecal use. Severe injury with permanent sequelae can result from intrathecal administration.

12 mg/m2 given as a short (approximately 5 to 15 minute) IV infusion every 3 months

Comments:
-The IV infusion should be given over 5 to 15 minutes.
-Evaluation of left ventricular ejection fraction (LVEF) by echocardiogram or multiple gated acquisition (MUGA) scan is recommended prior to all doses.
-LVEF evaluations are recommended if signs of congestive heart failure develop.
-This drug should not be administered to MS patients who have received a cumulative lifetime dose of 140 mg/m2 or more, or those with either an LVEF less than 50% or a clinically significant reduction in LVEF.
-Complete blood counts, including platelets, should be monitored prior to each dose and if signs of infection develop.
-This drug should not be administered to MS patients with neutrophil counts less than 1500 cells/mm3.
-Liver function tests should also be monitored prior to each dose. Use of this drug in MS abnormal liver function tests is not recommended.
-Women who are capable of becoming pregnant (even if they are using birth control) should have a pregnancy test before each dose.

Use: To reduce neurologic disability and/or the frequency of clinical relapses in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis (i.e., patients whose neurologic status is significantly abnormal between relapses)

Data not available

UK: Use is contraindicated. AU and US: Use should be avoided. Excreted into human milk: Yes Comments: -This drug is excreted in human milk and significant concentrations have been reported for up to 28 days after the last administration. -Most sources consider breastfeeding to be contraindicated during maternal antineoplastic drug therapy. It might be possible to breastfeed safely during intermittent therapy with an appropriate period of breastfeeding abstinence, but the duration of abstinence is not clear. -The effects in the nursing infant are unknown.

LactMed Record Number

185

Last Revision Date

20170411

Disclaimer

Information presented in this database is not meant as a substitute for professional judgment. You should consult your healthcare provider for breastfeeding advice related to your particular situation. The U.S. government does not warrant or assume any liability or responsibility for the accuracy or completeness of the information on this Site.