Mitoxantrone should be administered under the supervision of a health care provider experienced in the use of cytotoxic chemotherapy agents.
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.
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]).
Multiple sclerosis (MS) patients with a baseline LVEF below the lower limit of normal should not be treated with mitoxantrone.
MS patients should be assessed for cardiac signs and symptoms by history, physical examination, and ECG prior to each dose.
MS patients 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.
MS patients should not receive a cumulative mitoxantrone dose greater than 140 mg/m2.
MS patients should undergo yearly quantitative LVEF evaluation after stopping mitoxantrone to monitor for late-occurring cardiotoxicity.
Mitoxantrone therapy in patients with MS and in patients with cancer increases the risk of developing secondary acute myeloid leukemia.
Note: Mitoxantrone usually should not be administered if baseline neutrophil count <1,500/mm3 (except for in the treatment of acute myeloid leukemia). Administer antihyperuricemic therapy and aggressive hydration as indicated.
Acute lymphoblastic leukemia, relapsed/refractory (off-label use; based on limited data): FLAM regimen: IV: 10 mg/m2 on days 3 and 10 (in combination with fludarabine and cytarabine) (Giebel 2006).
Acute myeloid leukemias, initial therapy:
AML induction: IV: 12 mg/m2 once daily for 3 days (in combination with cytarabine); for incomplete response, may repeat (7 to 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): IV: 12 mg/m2 once daily for 2 days (in combination with cytarabine), repeat in 4 weeks (Arlin 1990).
Acute myeloid leukemia, relapsed/refractory (off-label use):
CLAG-M regimen: IV: 10 mg/m2 once daily for 3 days on days 1, 2, and 3 (in combination with cladribine, cytarabine, and filgrastim), may repeat once if needed (Wierzbowska 2008).
MEC regimen: IV: 6 mg/m2 once daily for 6 days on days 1 to 6 (in combination with cytarabine and etoposide) (Amadori 1991).
Mitoxantrone/Etoposide: IV: 10 mg/m2 once daily for 5 days on days 1 to 5 (in combination with etoposide) (Ho 1988).
Acute promyelocytic leukemia, newly diagnosed (off-label use): Consolidation: IV: 10 mg/m2 once daily for 5 days on days 1 to 5 of consolidation course 2 (in combination with tretinoin all-trans retinoic acid; ATRA) (Sanz 2004).
Hematopoietic stem cell transplantation, autologous (off-label use): Conditioning regimen: IV: 60 mg/m2 administered 4 to 5 days prior to autografting (as 3 divided doses over 1 hour each at 1- to 2-hour intervals on the same day in combination with melphalan) (Oyan 2006; Tarella 2001).
Hodgkin lymphoma (off-label use):
Relapsed or refractory Hodgkin lymphoma: MINE-ESHAP regimen: IV: 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 de Larrea 2010).
Newly diagnosed Hodgkin lymphoma, reduced intensity regimen: Adults ≥66 years of age: VEPEMB regimen: IV: 6 mg/m2 on day 15 every 28 days (in combination with vinblastine, cyclophosphamide, procarbazine, etoposide, and bleomycin) for 3 to 6 cycles (Levis 2004).
Non-Hodgkin lymphomas, relapsed/refractory (off-label use): B-cell lymphomas: R-MINE regimen: IV: 8 mg/m2 on day 1 (in combination with rituximab, mesna, ifosfamide, and etoposide) for up to 3 cycles (Joyce 2003).
Multiple sclerosis, relapsing or secondary progressive (alternative agent): Note: Reserve use for rapidly advancing, refractory multiple sclerosis (MS) (AAN [Rae-Grant 2018]; Olek 2019). In high-risk populations or in countries with high tuberculosis burden, screen for latent infections (eg, hepatitis, tuberculosis) prior to initiating therapy. For patients who screen positive for latent infections, consult infectious disease or other appropriate specialists (eg, liver specialists) regarding treatment options before initiating therapy (AAN [Farez 2019]). Mitoxantrone generally should not be administered to patients with MS with neutrophil counts <1,500 cells/mm3.
IV: 12 mg/m2 every 3 months (maximum lifetime cumulative dose: 140 mg/m2; discontinue with LVEF <50% or clinically significant reduction in LVEF).
Prostate cancer, advanced, hormone-refractory: IV: 12 mg/m2 once every 3 weeks (in combination with prednisone or prednisolone) for up to 10 cycles (Tannock 2004) or 12 to 14 mg/m2 once every 3 weeks (in combination with prednisone) until disease progression or unacceptable toxicity, up to a maximum cumulative mitoxantrone dose of 144 mg/m2 (Petrylak 2004).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
There are no dosage adjustments 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. Patients with multiple sclerosis with hepatic impairment should not receive mitoxantrone.
(For additional information see "Mitoxantrone: Pediatric drug information")
Note: Dosing regimens may vary by dose, cycles, and combination therapy; refer to individual protocols.
Acute lymphocytic leukemia (ALL), relapsed: Limited data available: Children and Adolescents: Induction: 10 mg/m2/dose once daily on days 1 and 2 (in combination with dexamethasone, vincristine, pegaspargase, and intrathecal methotrexate), with follow-up therapy (allogeneic stem cell transplant or continued chemotherapy) determined by risk stratification (Parker 2010)
Acute myeloid leukemia (AML): Limited data available:
Gamis 2014: Infants, Children, and Adolescents: Note: Some aspects of protocol dosing presented in previous reports (Cooper 2012)
Intensification Course 2:
BSA <0.6 m2: IV: 0.4 mg/kg once daily for 4 days on Days 3 to 6 of a 28-day cycle (in combination with cytarabine)
BSA ≥0.6 m2: IV: 12 mg/m2 once daily for 4 days on Days 3 to 6 of a 28-day cycle (in combination with cytarabine)
Perel 2002: LAME 89/91 regimen: Infants, Children, and Adolescents:
Remission Induction:
<1 year: IV: 8 mg/m2 once daily for 5 days (in combination with cytarabine); if persistent disease, additional course of 8 mg/m2 for 2 days (in combination with cytarabine) was administered
≥1 year: IV: 12 mg/m2 once daily for 5 days (in combination with cytarabine); if persistent disease, additional course of 12 mg/m2 for 2 days (in combination with cytarabine) was administered
Gibson 2011: MAE and MidAC regimens:
Induction Course 1 (MAE 3+10+5) or Course 2 (MAE 3+8+5):
Infants: IV: 9 mg/m2 once daily on Days 1, 3, and 5 (in combination with cytarabine and etoposide)
Children and Adolescents <17 years: IV: 12 mg/m2 once daily on Days 1, 3, and 5 (in combination with cytarabine and etoposide)
Consolidation Course 4/5 (MidAC):
Infants: IV: 7.5 mg/m2 once daily on Days 1 to 5 (in combination with cytarabine)
Children and Adolescents <17 years: IV: 10 mg/m2 once daily on Days 1 to 5 (in combination with cytarabine)
Acute promyelocytic leukemia (APL): Limited data available: Consolidation Course 2: Children ≥2 years and Adolescents: IV: 10 mg/m2 once daily for 5 days of a 28-day cycle (combined with tretinoin [ATRA]) (Ortega 2005; Sanz 2004)
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Dosing adjustment for toxicity: The presented dosing adjustments are based on experience in adult patients; specific recommendations for pediatric patients are limited. Refer to specific protocol for management in pediatric patients if available.
Adult:
Oncology uses: Severe or life-threatening nonhematologic toxicity: Withhold treatment until toxicity resolves
Multiple sclerosis:
Neutrophils <1,500/mm3: Use is not recommended
Signs/symptoms of HF: Evaluate for cardiac signs/symptoms and monitor LVEF
LVEF <50% or baseline LVEF below the lower limit of normal (LLN): Use is not recommended
There are no pediatric specific recommendations; refer to individual protocols; based on experience in adults, supplemental doses are not necessary with hemodialysis or peritoneal dialysis.
There are no pediatric specific recommendations; refer to individual protocols. Based on experience in adults, 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.
Refer to adult dosing.
ASCO Guidelines for appropriate chemotherapy dosing in adults with cancer with a BMI ≥30 kg/m2 (excludes HSCT dosing): 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 patients with a BMI <30 kg/m2; if a dose reduction is utilized due to toxicity, may consider resumption of full weight-based dosing with subsequent cycles, if cause of toxicity (eg, hepatic or renal impairment) is clearly established and fully resolved (ASCO [Griggs 2021]).
AML: Severe or life-threatening nonhematologic toxicity: Withhold treatment until toxicity resolves.
MS:
Neutrophils <1,500/mm3: Use is not recommended.
Signs/symptoms of HF: Evaluate for cardiac signs/symptoms and monitor LVEF.
LVEF <50% or baseline LVEF below the lower limit of normal (LLN): Use is not recommended.
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)
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Concentrate, Intravenous:
Generic: 2 mg/mL (10 mL)
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019297s035mg.pdf, must be dispensed with this medication.
IV: 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 to 15 minutes; do not infuse over less than 3 to 5 minutes.
Mitoxantrone was infused over 20 to 30 minutes in some (off-label) regimens; refer to protocol for infusion details. High doses for bone marrow transplant (off-label use) are usually given as 3 divided doses over 1 hour each at 1-to 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 to 2 days (ESMO/EONS [Pérez 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: 1,000 mg/m2 (maximum dose: 2,000 mg) IV (administer in a large vein remote from site of extravasation) over 1 to 2 hours days 1 and 2, then 500 mg/m2 (maximum dose: 1,000 mg) IV over 1 to 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 (ESMO/EONS [Pérez Fidalgo 2012]; Mouridsen 2007). Note: Reduce dexrazoxane dose by 50% in patients with moderate to severe renal impairment (CrCl <40 mL/minute).
DMSO: 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 (ESMO/EONS [Pérez Fidalgo 2012]).
Parenteral: For IV administration only; do not administer by SubQ, IM, intrathecal, or intra-arterial injection. Must be diluted prior to use; may administer by IV bolus over 5 to 15 minutes or IV intermittent infusion over 15 to 60 minutes; refer to protocol for infusion details.
Irritant with vesicant-like properties; ensure proper needle or catheter placement prior to and during infusion; avoid extravasation. 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 (dimethyl sulfate [DMSO] or dexrazoxane [Adults]) (see Management of Drug Extravasations for more details). Apply dry cold compresses for 20 minutes 4 times daily for 1 to 2 days (ESMO/EONS [Pérez 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.
Hazardous agent (NIOSH 2016 [group 1]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Acute myeloid leukemias: Initial treatment (in combination with other agents) of acute nonlymphocytic leukemia (ANLL [includes myelogenous, promyelocytic, monocytic and erythroid leukemias]).
Multiple sclerosis, relapsing or secondary progressive: Treatment of secondary (chronic) progressive, progressive relapsing, or worsening or relapsing-remitting multiple sclerosis (RRMS) to reduce neurologic disability and/or the frequency of clinical relapse.
Limitation of use: Mitoxantrone is not indicated for the treatment of primary progressive MS. Reserve use for rapidly-advancing, refractory multiple sclerosis (AAN [Rae-Grant 2018]; Olek 2019).
Prostate cancer: Treatment of advanced hormone-refractory prostate cancer (in combination with corticosteroids).
Acute lymphoblastic leukemia, relapsed/refractory; Acute myeloid leukemia, relapsed/refractory; Acute promyelocytic leukemia, newly diagnosed; Hematopoietic stem cell transplantation, autologous (conditioning regimen); Hodgkin lymphoma; Non-Hodgkin lymphomas, relapsed/refractory
MitoXANTRONE may be confused with methotrexate, mitoMYcin, mitotane, MTX Patch, Mutamycin
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. 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%, postmarketing, and/or case reports: 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
Hypersensitivity to mitoxantrone or any component of the formulation
Canadian labeling: Additional contraindications (not in the US labeling): Prior hypersensitivity to anthracyclines; prior substantial anthracycline exposure (if 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
Concerns related to adverse effects:
• Bone marrow suppression: Mitoxantrone may lead to severe myelosuppression (at any dose). Unless the expected benefit outweighs the risk, mitoxantrone is generally not recommended in patients with preexisting myelosuppression due to prior chemotherapy.
• Extravasation: Mitoxantrone is an irritant with vesicant-like properties. 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.
• Hypersensitivity: May contain sodium metabisulfite, which is associated with allergic-type reactions (including anaphylactic symptoms and potentially severe asthmatic episodes). The risk for hypersensitivity is higher in patients with asthma.
• Infections: When using for the treatment of multiple sclerosis in high-risk populations or in countries with high tuberculosis burden, screen for latent infections (eg, hepatitis, tuberculosis) prior to initiating therapy. For patients who screen positive for latent infections, consult infectious disease or other specialists (eg, liver specialists) regarding treatment options before initiating therapy (AAN [Farez 2019]).
• Myocardial toxicity: May cause myocardial toxicity and potentially fatal heart failure (HF); risk increases with cumulative dosing. Cardiotoxicity 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 or current cardiovascular disease, concomitant use of cardiotoxic drugs, and mediastinal/pericardial irradiation, although may also occur in patients without risk factors. Mitoxantrone is not recommended for use in patients with MS when 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 patients with MS prior to each dose. Patients with MS should not receive a cumulative dose of >140 mg/m2. Do not administer mitoxantrone if LVEF falls below LLN or if a significant decrease in LVEF is observed during treatment. Patients with MS should undergo annual LVEF evaluation following discontinuation of therapy to monitor for delayed cardiotoxicity. Evaluate potential risk versus benefit in patients who have previously received anthracycline therapy. If signs/symptoms of heart failure develop, evaluate LVEF and ECG.
• Secondary malignancy: Treatment with mitoxantrone increases the risk of developing secondary acute myeloid 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/or with combination chemotherapy.
• Tumor lysis syndrome: Rapid lysis of tumor cells may lead to hyperuricemia and tumor lysis syndrome.
Disease-related concerns:
• Hepatic impairment: Clearance is reduced in patients with hepatic impairment; use with caution. Not for treatment of multiple sclerosis in patients with concurrent hepatic impairment.
Other warnings/precautions:
• Appropriate administration: For IV administration only; 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.
• Immunizations: Avoid live-attenuated vaccines in patients who currently receive or have recently discontinued mitoxantrone for multiple sclerosis; consider using live-attenuated vaccines only if risk of infection is high and killed vaccines are unavailable (AAN [Farez 2019]).
Substrate of BCRP/ABCG2, P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Baricitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
BCG Products: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination
Brincidofovir: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination
Cladribine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy
Coccidioides immitis Skin Test: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing cytotoxic chemotherapy several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification
COVID-19 Vaccine (Adenovirus Vector): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector). Management: In the US, after receipt of the single dose COVID-19 adenovirus vector vaccine (Janssen), administer an additional 2nd dose using an mRNA COVID-19 vaccine, at least 28 days after the primary vaccine dose, in patients taking immunosuppressive therapies. Risk D: Consider therapy modification
COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy
COVID-19 Vaccine (mRNA): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA). Management: Consider administration of a 3rd dose of COVID-19 vaccine, at least 28 days after completion of the primary 2-dose series, in patients 5 years of age and older taking immunosuppressive therapies. Risk D: Consider therapy modification
COVID-19 Vaccine (Subunit): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). Risk C: Monitor therapy
CycloSPORINE (Systemic): May increase the serum concentration of MitoXANTRONE. Risk C: Monitor therapy
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification
Dengue Tetravalent Vaccine (Live): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination
Denosumab: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and cytotoxic chemotherapy. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modification
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination
Echinacea: May diminish the therapeutic effect of Immunosuppressants (Cytotoxic Chemotherapy). Management: Consider avoiding echinacea in patients receiving therapeutic immunosuppressants, such cytotoxic chemotherapy. If combined, monitor for reduced efficacy of cytotoxic chemotherapy. Risk D: Consider therapy modification
Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination
Inebilizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy
Influenza Virus Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating chemotherapy if possible. If vaccination occurs less than 2 weeks prior to or during chemotherapy, revaccinate at least 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification
Leflunomide: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents, such as cytotoxic chemotherapy. Risk D: Consider therapy modification
Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modification
Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination
Ocrelizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy
Ofatumumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy
Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Risk D: Consider therapy modification
Pidotimod: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy
Pimecrolimus: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Pneumococcal Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy
Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination
Polymethylmethacrylate: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Rabies Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If post-exposure rabies vaccination is required during immunosuppressant therapy, administer a 5th dose of vaccine and check for rabies antibodies. Risk D: Consider therapy modification
Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification
Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination
Ruxolitinib (Topical): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination
Sipuleucel-T: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants, such as cytotoxic chemotherapy, prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification
Sphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk C: Monitor therapy
Tacrolimus (Topical): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination
Talimogene Laherparepvec: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination
Tertomotide: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination
Tofacitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Tofacitinib. Risk X: Avoid combination
Typhoid Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination
Upadacitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination
Vaccines (Inactivated): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Vaccines (Inactivated). Management: Give inactivated vaccines at least 2 weeks prior to initiation of chemotherapy when possible. Patients vaccinated less than 14 days before initiating or during chemotherapy should be revaccinated at least 3 months after therapy is complete. Risk D: Consider therapy modification
Vaccines (Live): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Vaccines (Live) may diminish the therapeutic effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Yellow Fever Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination
Pregnancy status should be evaluated prior to treatment in patients who can become pregnant. Mitoxantrone is associated with amenorrhea, ovarian failure, and male infertility (AAN [Rae-Grant 2018]).
In general, disease-modifying therapies for multiple sclerosis (MS) are stopped prior to a planned pregnancy except in patients at high risk of MS activity (AAN [Rae-Grant 2018]). Consider use of agents other than mitoxantrone for patients at high risk of disease reactivation who are planning to become pregnant. Delaying pregnancy is recommended for patients with persistent high disease activity; when disease-modifying therapy is needed in these patients, other agents are preferred (ECTRIMS/EAN [Montalban 2018]).
Based on the mechanism of action and adverse events observed in animal reproduction studies, mitoxantrone may cause fetal harm if administered during pregnancy. Information related to pregnancy outcomes following use of mitoxantrone during pregnancy is limited (Amato 2015; Frau 2018; Houtchens 2013; NTP 2013).
In general, disease-modifying therapies for multiple sclerosis (MS) are not initiated during pregnancy, except in patients at high risk of MS activity (AAN [Rae-Grant 2018]). When disease-modifying therapy is needed in these patients, other agents are preferred (ECTRIMS/EAN [Montalban 2018]).
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 (ESMO [Peccatori 2013]).
Mitoxantrone is present in breast milk.
Mitoxantrone concentrations in breast milk were evaluated in a female following treatment for acute promyelocytic leukemia. The patient was administered mitoxantrone 6 mg/m2 for 3 days as part of consolidation therapy. Therapy was initiated during pregnancy; breast milk was sampled after the third dose of the third consolidation treatment postpartum. The highest milk concentrations (120 ng/mL) occurred following mitoxantrone administration; significant concentrations (18 ng/mL) were still observed 28 days after the last dose (Azuno 1995). Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer recommends that breastfeeding be discontinued before starting mitoxantrone treatment.
CBC with differential (frequently when used to treat cancer; prior to each dose when treating multiple sclerosis [MS]), serum uric acid (for leukemia treatment), LFTs. Evaluate pregnancy status (prior to treatment in patients who can become pregnant; prior to each dose in patients with MS). Monitor for infections due to neutropenia, and for signs/symptoms of tumor lysis syndrome or secondary malignancies. For the treatment of MS, latent infection screening (eg, hepatitis, tuberculosis) in high-risk populations or in countries with high tuberculosis burden (at baseline). 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.
Oncology uses: The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Mitoxantrone is an anthracenedione, which is 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 may inhibit the incorporation of uridine into RNA and thymidine into DNA; mitoxantrone is active throughout entire cell cycle (cell-cycle nonspecific).
Distribution: Vdss: >1,000 L/m2. Mitoxantrone distributes extensively into kidney, liver, heart, lung, and bone marrow, but does not cross the blood brain barrier (Perry 2012).
Protein binding: 78%
Metabolism: Hepatic
Half-life elimination: Terminal: 23 to 215 hours (median: ~75 hours)
Excretion: Feces (25%); urine (11%; 65% as unchanged drug)
Hepatic function impairment: Clearance is reduced in patients with hepatic impairment. The AUC is at least 3 times greater in patients with severe hepatic impairment (bilirubin >3.4 mg/dL) compared to patients with normal hepatic function.
Concentrate (mitoXANTRONE HCl Intravenous)
20 mg/10 mL (per mL): $20.40 - $48.92
25 mg/12.5 mL (per mL): $20.71 - $54.07
30 mg/15 mL (per mL): $20.71 - $51.00
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