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MitoXANtrone

Pronunciation

(mye toe ZAN trone)

Index Terms

  • CL - 232315
  • DHAD
  • DHAQ
  • Dihydroxyanthracenedione
  • Dihydroxyanthracenedione Dihydrochloride
  • Mitoxantrone Dihydrochloride
  • Mitoxantrone HCl
  • Mitoxantrone Hydrochloride
  • Mitozantrone
  • Novantrone

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Concentrate, Intravenous:

Generic: 20 mg/10 mL (10 mL); 25 mg/12.5 mL (12.5 mL); 30 mg/15 mL (15 mL)

Pharmacologic Category

  • Antineoplastic Agent, Anthracenedione
  • Antineoplastic Agent, Topoisomerase II Inhibitor

Pharmacology

Related to the anthracyclines, mitoxantrone intercalates into DNA resulting in cross-links and strand breaks; binds to nucleic acids and inhibits DNA and RNA synthesis by template disordering and steric obstruction; replication is decreased by binding to DNA topoisomerase II and seems to inhibit the incorporation of uridine into RNA and thymidine into DNA; active throughout entire cell cycle (cell-cycle nonspecific)

Absorption

Oral: Poor

Distribution

Vd: 14 L/kg; Vdss: >1,000 L/m2; distributes extensively into pleural fluid, kidney, thyroid, liver, heart, pancreas, spleen, bone marrow, and red blood cells; prolonged retention in tissues

Metabolism

Hepatic; pathway not determined

Excretion

Feces (25%); urine (6% to 11%; 65% as unchanged drug)

Half-Life Elimination

Terminal: 23 to 215 hours (median: ~75 hours); may be prolonged with hepatic impairment

Protein Binding

78%

Special Populations: 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.

Special Populations: Elderly

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

Use: Labeled Indications

Initial treatment of acute nonlymphocytic leukemias (ANLL [includes myelogenous, promyelocytic, monocytic and erythroid leukemias]); treatment of advanced hormone-refractory prostate cancer; secondary progressive or relapsing-remitting multiple sclerosis (MS)

Canadian labeling: Additional uses (not in U.S. labeling): Treatment of metastatic breast cancer, relapsed leukemia (adults), lymphoma, and hepatocellular carcinoma

Use: Unlabeled

Treatment of Hodgkin lymphoma (refractory), non-Hodgkin lymphomas (NHL), acute lymphocytic leukemia (ALL), relapsed acute myeloid leukemia (AML), breast cancer (metastatic), pediatric acute myelogenous leukemia (AML), pediatric acute promyelocytic leukemia (APL); part of a conditioning regimen for autologous hematopoietic stem cell transplantation (HSCT)

Contraindications

Hypersensitivity to mitoxantrone or any component of the formulation

Canadian labeling: Additional contraindications (not in U.S. labeling): Prior hypersensitivity to anthracyclines; prior substantial anthracycline exposure and abnormal cardiac function prior to initiation of mitoxantrone therapy; presence of severe myelosuppression due to prior chemo- and/or radiotherapy; severe hepatic impairment; intrathecal administration

Dosing: Adult

Details concerning dosing in combination regimens should also be consulted.

U.S. labeling:

Acute nonlymphocytic leukemias (ANLL):

Acute myeloid leukemia (AML) induction: 12 mg/m2 once daily for 3 days (in combination with cytarabine); for incomplete response, may repeat (7-10 days later) at 12 mg/m2 once daily for 2 days (in combination with cytarabine) (Arlin, 1990)

AML consolidation (beginning ~6 weeks after initiation of the final induction course): 12 mg/m2 once daily for 2 days (in combination with cytarabine), repeat in 4 weeks (Arlin, 1990)

Multiple sclerosis: 12 mg/m2 every 3 months (maximum lifetime cumulative dose: 140 mg/m2; discontinue use with LVEF <50% or clinically significant reduction in LVEF)

Prostate cancer (advanced, hormone-refractory): 12-14 mg/m2 every 3 weeks (in combination with corticosteroids)

Canadian labeling:

Acute nonlymphocytic leukemias (ANLL):

AML induction: 10-12 mg/m2 once daily for 3 days (in combination with cytarabine); for incomplete response, may repeat at 10-12 mg/m2 once daily for 2 days (in combination with cytarabine)

AML consolidation (beginning ~6 weeks after initiation of the final induction course): 12 mg/m2 once daily for 2 days (in combination with cytarabine), repeat in 4 weeks

Acute leukemias (relapsed): Induction: 12 mg/m2 once daily for 5 consecutive days; may repeat once if needed (at the same dose and duration)

Breast cancer (metastatic), lymphoma: Initial: Single agent: 14 mg/m2 every 21 days; reduce initial dose to ≤12 mg/m2 for myelosuppression due to previous treatment or for poor general health. When used in combination with other agents, reduce initial dose to 10-12 mg/m2.

Hepatocellular cancer: Initial: Single agent: 14 mg/m2 every 21 days; reduce initial dose to ≤12 mg/m2 for myelosuppression due to previous treatment or for poor general health

Adult off-label uses and/or dosing:

AML, refractory:

CLAG-M regimen: 10 mg/m2 once daily for 3 days (in combination with cladribine, cytarabine, and filgrastim), may repeat once if needed (Wierzbowska, 2008)

MEC or EMA regimen: 6 mg/m2 once daily for 6 days (in combination with cytarabine and etoposide) (Amadori, 1991)

Mitoxantrone/Etoposide: 10 mg/m2 once daily for 5 days (in combination with etoposide) (Ho, 1988)

APL consolidation phase (second course): 10 mg/m2 once daily for 5 days (Sanz, 2004)

Hodgkin lymphoma, refractory:

MINE-ESHAP regimen: 10 mg/m2 on day 1 every 28 days for up to 2 cycles (MINE is combination with mesna, ifosfamide, mitoxantrone, and etoposide; MINE alternates with ESHAP for up to 2 cycles of each) (Fernandez, 2010)

VIM-D regimen: 10 mg/m2 on day 1 every 28 days (in combination with etoposide, ifosfamide, mesna, and dexamethasone) (Phillips, 1990)

Non-Hodgkin lymphoma (as part of combination chemotherapy regimens):

CNOP regimen: 10 mg/m2 every 21 days (Bessell, 2003)

FCMR regimen: 8 mg/m2 every 28 days (Forstpointner, 2004)

FMR regimen: 10 mg/m2 every 21 days (Zinzani, 2004)

FND regimen: 10 mg/m2 every 28 days (Tsimberidou, 2002)

MINE-ESHAP regimen: 8 mg/m2 every 21 days for 6 cycles (MINE is combination with mesna, ifosfamide, mitoxantrone, and etoposide; followed by ESHAP) (Rodriguez, 1995)

Stem cell transplantation, autologous: 60 mg/m2 administered 4-5 days prior to autografting (as 3 divided doses over 1 hour each at 1-2 hour intervals on the same day; in combination with other chemotherapeutic agent[s]) (Oyan, 2006; Tarella, 2001)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Details concerning dosing in combination regimens should also be consulted.

Acute nonlymphocytic leukemias: IV:

Acute myeloid leukemia (AML) consolidation phase (second course; off-label use): 10 mg/m2 once daily for 5 days (in combination with cytarabine) (Stevens, 1998)

Acute promyelocytic leukemia (APL) consolidation phase (second course; off-label use): 10 mg/m2 once daily for 5 days (Ortega, 2005; Sanz, 2004)

Dosing: Renal Impairment

No dosage adjustment provided in manufacturer’s labeling (has not been studied).

Hemodialysis: Supplemental dose is not necessary

Peritoneal dialysis: Supplemental dose is not necessary

Elderly: Clearance is decreased in elderly patients; use with caution

Dosing: Hepatic Impairment

U.S. labeling: No dosage adjustment provided in the manufacturer’s labeling; however, clearance is reduced in hepatic dysfunction. Patients with severe hepatic dysfunction (bilirubin >3.4 mg/dL) have an AUC of 3 times greater than patients with normal hepatic function; consider dose adjustments. Note: MS patients with hepatic impairment should not receive mitoxantrone.

Canadian labeling:

Mild-to-moderate impairment: No specific dosage adjustment provided; consider dose adjustments and monitor closely.

Severe impairment: Use is contraindicated.

Dosing: Adjustment for Toxicity

ANLL patients: Severe or life-threatening nonhematologic toxicity: Withhold treatment until toxicity resolves

MS patients:

Neutrophils <1500/mm3: Use is not recommended.

Signs/symptoms of HF: Evaluate for cardiac signs/symptoms and LVEF.

LVEF <50% or baseline LVEF below the lower limit of normal (LLN): Use is not recommended.

Canadian labeling (not in U.S. labeling): Hepatocellular cancer, lymphoma, or breast cancer (metastatic):

WBC nadir >1500/mm3 and platelet nadir >50,000/mm3 and recovery ≤21 days: Repeat previous dose or increase dose by 2 mg/m2 if myelosuppression is inadequate.

WBC nadir >1500/mm3 and platelet nadir >50,000/mm3 and recovery >21 days: Withhold treatment until recovery then resume at previous dose.

WBC nadir <1500/mm3 or platelet nadir <50,000/mm3 (regardless of recovery time): Withhold treatment until recovery then decrease previous dose by 2 mg/m2.

WBC nadir <1000/mm3 or platelet nadir <25,000/mm3 (regardless of recovery time): Withhold treatment until recovery then decrease previous dose by 4 mg/m2.

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs, 2012).

Reconstitution

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). Dilute in at least 50 mL of NS or D5W. May further dilute in D5W, NS or D5NS, use immediately after preparation.

Administration

For IV administration only; do not administer intrathecally, subcutaneously, intramuscularly or intra-arterially. Must be diluted prior to use. Usually administered as a short IV infusion over 5-15 minutes; do not infuse over <3-5 minutes.

High doses for bone marrow transplant (off-label use) are usually given as 3 divided doses over 1 hour each at 1-2 hour intervals on the same day (Oyan, 2006; Tarella, 2001).

Irritant with vesicant-like properties; ensure proper needle or catheter placement prior to and during infusion; avoid extravasation.

Extravasation management: If extravasation occurs, stop infusion immediately and disconnect (leave cannula/needle in place); gently aspirate extravasated solution (do NOT flush the line); remove needle/cannula; elevate extremity. Initiate antidote (dexrazoxane or dimethyl sulfate [DMSO]). Apply dry cold compresses for 20 minutes 4 times daily for 1-2 days (Perez Fidalgo, 2012); withhold cooling beginning 15 minutes before dexrazoxane infusion; continue withholding cooling until 15 minutes after infusion is completed. Topical DMSO should not be administered in combination with dexrazoxane; may lessen dexrazoxane efficacy.

Dexrazoxane: Adults: 1000 mg/m2 (maximum dose: 2000 mg) IV (administer in a large vein remote from site of extravasation) over 1-2 hours days 1 and 2, then 500 mg/m2 (maximum dose: 1000 mg) IV over 1-2 hours day 3; begin within 6 hours of extravasation. Day 2 and day 3 doses should be administered at approximately the same time (± 3 hours) as the dose on day 1 (Mouridsen, 2007; Perez Fidalgo, 2012). Note: Reduce dexrazoxane dose by 50% in patients with moderate to severe renal impairment (CrCl <40 mL/minute).

DMSO: Children and Adults: Apply topically to a region covering twice the affected area every 8 hours for 7 days; begin within 10 minutes of extravasation; do not cover with a dressing (Perez Fidalgo, 2012).

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Compatibility

Stable in D5NS, D5W, NS.

Y-site administration: Incompatible with amphotericin B cholesteryl sulfate complex, aztreonam, cefepime, doxorubicin liposome, pemetrexed, piperacillin/tazobactam, propofol.

Storage

Store intact vials at 15°C to 25°C (59°F to 77°F); do not freeze. Opened vials may be stored at room temperature for 7 days or under refrigeration for up to 14 days. Solutions diluted for administration are stable for 7 days at room temperature or under refrigeration, although the manufacturer recommends immediate use.

Drug Interactions

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

CycloSPORINE (Systemic): May increase the serum concentration of MitoXANtrone. Management: Consider mitoxantrone dose reduction, as clinically appropriate, when used with cyclosporine. Use this combination with caution and monitor closely for toxic effects of mitoxantrone. Consider therapy modification

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Adverse Reactions

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

>10%:

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

Central nervous system: Fever (6% to 78%), pain (8% to 41%), fatigue (≤39%), headache (6% to 13%)

Dermatologic: Alopecia (20% to 61%), nail bed changes (≤11%), petechiae/bruising (6% to 11%)

Endocrine & metabolic: Menstrual disorder (26% to 61%), amenorrhea (28% to 53%), hyperglycemia (10% to 31%)

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%), weight gain/loss (13% to 17%), constipation (10% to 16%), GI bleeding (2% to 16%), abdominal pain (9% to 15%), dyspepsia (5% to 14%)

Genitourinary: Urinary tract infection (7% to 32%), abnormal urine (5% to 11%)

Hematologic: Neutropenia (79% to 100%; onset: ≤3 weeks; grade 4: 23% to 54%), leukopenia (9% to 100%), lymphopenia (72% to 95%), anemia/hemoglobin decreased (5% to 75%) thrombocytopenia (33% to 39%; grades 3/4: 3% to 4%), neutropenic fever (≤11%)

Hepatic: Alkaline phosphatase increased (≤37%), transaminases increased (5% to 20%), GGT increased (3% to 15%)

Neuromuscular & skeletal: Weakness (≤24%)

Renal: BUN increased (≤22%), creatinine increased (≤13%), hematuria (≤11%)

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

Miscellaneous: Infection (4% to 60%), sepsis (ANLL 31% to 34%), fungal infection (9% to 15%)

1% to 10%:

Cardiovascular: CHF (≤5%), ischemia (≤5%), LVEF decreased (≤5%), hypertension (≤4%)

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

Dermatologic: Cutaneous mycosis (≤10%), skin infection (≤5%)

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

Gastrointestinal: Aphthosis (≤10%)

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

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

Hepatic: Jaundice (3% to 7%)

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

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

Renal: Renal failure (≤8%), proteinuria (≤6%)

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

Miscellaneous: Systemic infection (≤10%), diaphoresis (≤9%)

<1% (Limited to important or life-threatening): Allergic reaction, anaphylactoid reactions, anaphylaxis, chest pain, dehydration; extravasation at injection site (may result in burning, erythema, pain, skin discoloration, swelling, or tissue necrosis); interstitial pneumonitis (with combination chemotherapy), hyperuricemia, hypotension, phlebitis at the infusion site, rash, sclera discoloration (blue), tachycardia, urine discoloration (blue-green), urticaria

ALERT: U.S. Boxed Warning

Experienced physician:

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

Bone marrow suppression:

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.

Cardiotoxicity:

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.

Secondary leukemia:

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

Appropriate administration:

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.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Treatment may lead to severe myelosuppression; unless the expected benefit outweighs the risk, use is generally not recommended in patients with pre-existing myelosuppression from prior chemotherapy. [U.S. Boxed Warning]: Usually should not be administered if baseline neutrophil count <1500 cells/mm3 (except for in the treatment of ANLL). Monitor blood counts and monitor for infection due to neutropenia.

• Extravasation: Irritant with vesicant-like properties. [U.S. Boxed Warning]: For IV administration only, into a free-flowing IV; may cause severe local tissue damage if extravasation occurs. Extravasation resulting in burning, erythema, pain, swelling and skin discoloration (blue) has been reported; may result in tissue necrosis and require debridement for skin graft. Ensure proper needle or catheter placement prior to and during infusion. Avoid extravasation.

• Hyperuricemia: Rapid lysis of tumor cells may lead to hyperuricemia.

• Myocardial toxicity: [U.S. Boxed Warning]: May cause myocardial toxicity and potentially-fatal heart failure (HF); risk increases with cumulative dosing. Effects may occur during therapy or may be delayed (months or years after completion of therapy). Predisposing factors for mitoxantrone-induced cardiotoxicity include prior anthracycline or anthracenedione therapy, prior cardiovascular disease, concomitant use of cardiotoxic drugs, and mediastinal/pericardial irradiation, although may also occur in patients without risk factors. Prior to therapy initiation, evaluate all patients for cardiac-related signs/symptoms, including history, physical exam, and ECG; and evaluate baseline left ventricular ejection fraction (LVEF) with echocardiogram or multigated radionuclide angiography (MUGA) or MRI. Not recommended for use in MS patients when LVEF <50%, or baseline LVEF below the lower limit of normal (LLN). Evaluate for cardiac signs/symptoms (by history, physical exam, and ECG) and evaluate LVEF (using same method as baseline LVEF) in MS patients prior to each dose and if signs/symptoms of HF develop. Use in MS should be limited to a cumulative dose of ≤140 mg/m2, and discontinued if LVEF falls below LLN or a significant decrease in LVEF is observed; decreases in LVEF and HF have been observed in patients with MS who have received cumulative doses <100 mg/m2. Patients with MS should undergo annual LVEF evaluation following discontinuation of therapy to monitor for delayed cardiotoxicity.

• Secondary malignancy: [U.S. Boxed Warning]: Treatment with mitoxantrone increases the risk of developing secondary acute myelogenous leukemia (AML) in patients with cancer and in patients with MS; acute promyelocytic leukemia (APL) has also been observed. Symptoms of acute leukemia include excessive bruising, bleeding and recurrent infections. The risk for secondary leukemia is increased in patients who are heavily pretreated, with higher doses, and with combination chemotherapy.

Disease-related concerns:

• Hepatic impairment: Clearance is reduced in patients with hepatic impairment; use with caution; dosage adjustment recommended. Not for treatment of multiple sclerosis in patients with concurrent hepatic impairment. Canadian labeling contraindicates use in severe impairment.

• Multiple sclerosis: Not for treatment of primary progressive multiple sclerosis.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Other warnings/precautions:

• Appropriate administration: [U.S. Boxed Warning]: For IV administration only, into a free-flowing IV; do not administer subcutaneously, intramuscularly, or intra-arterially. Do not administer intrathecally; may cause serious and permanent neurologic damage.

• Blue-green coloration: May cause urine, saliva, tears, and sweat to turn blue-green for 24 hours postinfusion; whites of eyes may have blue-green tinge.

• Experienced physician: [U.S. Boxed Warning]: Should be administered under the supervision of a physician experienced in cancer chemotherapy agents.

Monitoring Parameters

CBC with differential, serum uric acid (for leukemia treatment), liver function tests; for the treatment of multiple sclerosis, obtain pregnancy test; monitor injection site for extravasation

Cardiac monitoring: Prior to initiation, evaluate all patients for cardiac-related signs/symptoms, including history, physical exam, and ECG; evaluate baseline and periodic left ventricular ejection fraction (LVEF) with echocardiogram or multigated radionuclide angiography (MUGA) or MRI. In patients with MS, evaluate for cardiac signs/symptoms (by history, physical exam, and ECG) and evaluate LVEF (using same method as baseline LVEF) prior to each dose and if signs/symptoms of HF develop. Patients with MS should undergo annual LVEF evaluation following discontinuation of therapy to monitor for delayed cardiotoxicity.

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Based on the mechanism of action, mitoxantrone may cause fetal harm if administered during pregnancy. Use of effective contraception during therapy is recommended. Information related to pregnancy outcomes following maternal use of mitoxantrone in pregnancy is limited (Amato 2015; Houtchens 2013; NTP 2013).

Infertility and amenorrhea have been reported in women with MS using mitoxantrone (Amato 2015; Houtchens 2013). Women with multiple sclerosis who are of reproductive potential should have a pregnancy test prior to each dose. Women who wish to become pregnant should discontinue therapy at least 2 to 3 months prior to conception (Houtchens 2013).

The European Society for Medical Oncology has published guidelines for diagnosis, treatment, and follow-up of cancer during pregnancy. The guidelines recommend referral to a facility with expertise in cancer during pregnancy and encourage a multidisciplinary team (obstetrician, neonatologist, oncology team). In general, if chemotherapy is indicated, it should be avoided in the first trimester, there should be a 3-week time period between the last chemotherapy dose and anticipated delivery, and chemotherapy should not be administered beyond week 33 of gestation (Peccatori 2013).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience blue or green urine, abdominal pain, diarrhea, constipation, lack of appetite, headache, mouth sores, lip irritation, hair loss, back pain, or amenorrhea. Have patient report immediately to prescriber signs of heart problems (cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out), signs of infection, severe dizziness, passing out, severe nausea, vomiting, excessive weight loss, bruising, bleeding, loss of strength and energy, bone pain, night sweats, skin discoloration, or severe injection site pain or irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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