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  • CLASSES

    Anthracenediones
    MS Agents

    BOXED WARNING

    Cardiac disease, cardiotoxicity, heart failure, maximum cumulative lifetime dose, radiation therapy, ventricular dysfunction

    Severe cardiotoxicity including fatal congestive heart failure and severe left ventricular dysfunction may occur during mitoxantrone therapy or months to years after discontinuing therapy. The risk of cardiotoxicity is dose related; the maximum cumulative lifetime dose is 140 mg/m2 IV. Additionally, patients with cardiac disease, a history of prior radiation therapy to the mediastinal/pericardial area, prior therapy with anthracycline or anthracenedione agents, or who are receiving concurrent cardiotoxic agents may also be at increased risk for cardiotoxicity. Perform a cardiac history assessment and physical examination and obtain an electrocardiogram (ECG) and a quantitative evaluation of left ventricular ejection fraction (LVEF) prior to starting mitoxantrone therapy. In patients with multiple sclerosis, obtain an ECG and an LVEF evaluation prior to each mitoxantrone dose; assess LVEF yearly after therapy completion to evaluate for late cardiotoxicity. Do not give the mitoxantrone dose if there is a decrease in LVEF to below the lower limit of normal or a clinically significant reduction in LVEF during therapy.

    New primary malignancy

    Mitoxantrone may cause a new primary malignancy. Patients with either multiple sclerosis or cancer who received mitoxantrone may develop acute myelogenous leukemia (AML). The most commonly reported types were acute promyelocytic leukemia and acute myelocytic leukemia. Secondary AML has been reported in patients with cancer treated with anthracyclines, and mitoxantrone is an anthracenedione, which is a related drug. The occurrence of refractory secondary leukemia is more common when anthracyclines are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated.

    Bone marrow suppression, coagulopathy, fungal infection, herpes infection, neutropenia, requires an experienced clinician, thrombocytopenia, varicella, viral infection

    Myelosuppressive drugs, such as mitoxantrone, can cause an increased incidence of bacterial, viral, and fungal infection, bleeding, and fatigue due to neutropenia, thrombocytopenia, and anemia. Because these adverse effects can be fatal, the patient must be warned to promptly report any signs such as fever, sore throat, or abnormal pain. Severe bone marrow suppression is a relative contraindication to mitoxantrone depending upon the etiology of the suppression. In general, reserve use only for the treatment of acute nonlymphocytic leukemia in patients who have a baseline neutrophil count < 1500/mm3. Mitoxantrone should be used cautiously in patients with bone marrow suppression, coagulopathy, or in those who have received previous myelosuppressive therapy such as chemotherapy or radiotherapy. Therefore, this drug requires an experienced clinician knowledgeable in the use of cancer chemotherapy. Frequent peripheral blood cell count monitoring is recommended for all patients. Patients with preexisting marrow suppression including neutropenia and/or thrombocytopenia should be allowed to recover their counts prior to mitoxantrone administration. Patients with an active infection should be treated prior to receiving mitoxantrone. Patients with a history of varicella zoster, other herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation the infection when treated with chemotherapy.

    Intraarterial administration, intrathecal administration

    Intrathecal administration of mitoxantrone is not recommended. Neuropathy and neurotoxicity including seizures, paralysis, and bowel and bladder dysfunction have been reported after intrathecal injection; severe injury with permanent sequelae can occur. Intraarterial administration of mitoxantrone has been associated with reversible and irreversible local/regional neuropathy and should not be used.

    Extravasation, intramuscular administration, subcutaneous administration

    Mitoxantrone should be given slowly into a freely flowing intravenous infusion. Intramuscular administration and subcutaneous administration of mitoxantrone are not recommended due to the potential for severe local reactions. Take care to avoid extravasation when administering mitoxantrone. Although, mitoxantrone has not been traditionally considered a vesicant, cases of skin necrosis requiring debridement and skin grafting have been reported following extravasation of mitoxantrone into tissues.

    DEA CLASS

    Rx

    DESCRIPTION

    Anthracenedione; structurally similar to the anthracyclines; causes less cardiotoxicity than anthracylines; not a vesicant; used in hematologic malignancies and prostate cancer; also effective in relapsing-remitting and secondary progressive MS.

    COMMON BRAND NAMES

    Novantrone

    HOW SUPPLIED

    Mitoxantrone Hydrochloride/Novantrone Intravenous Inj Sol: 1mL, 2mg

    DOSAGE & INDICATIONS

    For the treatment of acute myelogenous leukemia (AML).
    NOTE: Mitoxantrone has been designated an orphan drug by the FDA for this indication.
    NOTE: If used, consolidation therapy is recommended to be withheld until full hematologic recovery occurs.
    For the treatment of refractory acute myelogenous leukemia in combination with etoposide and cytarabine†.
    Intravenous dosage
    Adults, Adolescents, and Children >= 5 years


    Etoposide 80 mg/m2 IV over 1 hour, then cytarabine 1 g/m2 IV over 6 hours, then 3 hours later, mitoxantrone 6 mg/m2 IV bolus. All should be given daily for 6 days.

    For the treatment of relapsed or refractory acute myelogenous leukemia in combination with cladribine, cytarabine, and filgrastim†.
    Intravenous dosage
    Adults

    10 mg/m2/day IV on days 1 to 3 in combination with cladribine 5 mg/m2/day IV over 2 hours on days 1 to 5, cytarabine 2 g/m2/day IV over 4 hours, starting 2 hours after cladribine, on days 1 to 5, and G-CSF 300 mcg subcutaneously on days 0 to 5 (starting 24 hours prior to chemotherapy) (CLAG-M regimen). Patients who achieved a complete response progressed to consolidation therapy. Patients who achieved a partial response could receive a second course of CLAG-M induction therapy.

    For the treatment of acute myelogenous leukemia in combination with cytarabine.
    Intravenous dosage
    Adults

    For induction, 12 mg/m2/day IV on days 1 to 3 in combination with cytarabine on days 1 to 7. A second induction course of mitoxantrone 12 mg/m2/day IV for 2 days in combination with cytarabine for 5 days may be given for an incomplete antileukemic response once any severe nonhematologic toxicity, if present, is resolved. The first consolidation course is given approximately 6 weeks after the final induction course and consists of mitoxantrone 12 mg/m2/day IV for 2 days with cytarabine for 5 days. The second consolidation therapy course is generally given 4 weeks after the first consolidation course.

    For the palliative treatment of severe pain related to advanced hormone-refractory prostate cancer in combination with corticosteroids.
    NOTE: Mitoxantrone has been designated an orphan drug by the FDA for this indication.
    Intravenous infusion dosage
    Adults

    12 to 14 mg/m2 IV every 21 days in combination with either prednisone or hydrocortisone. In randomized, controlled trials, patients who received mitoxantrone in combination with either hydrocortisone or prednisone had decreased pain intensity and decreased analgesic use. In addition, the prostate specific antigen (PSA) concentration decreased in some patients who received mitoxantrone and corticosteroids. The clinical significance of the decreased PSA is not clear as the changes in PSA did not correlate to palliative response and the studies were not designed to evaluate changes in PSA.

    For the treatment of secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis to reduce neurologic disability and/or frequency of clinical relapses.
    NOTE: Mitoxantrone is not indicated in the treatment of primary progressive multiple sclerosis.
    NOTE: Mitoxantrone has been designated an orphan drug by the FDA for this indication.
    NOTE: Patients with LVEF less than 50%, a clinically significant reduction in LVEF during mitoxantrone therapy, neutrophil count less than 1500/mm3, or a cumulative lifetime dose of 140 mg/m2 should not be treated with mitoxantrone. Further, in July 2008, the FDA issued a MedWatch alerting clinicians to the possibility of decreased LVEF and frank congestive heart failure in patients who had received a cumulative lifetime mitoxantrone dose less than 100 mg/m2. LVEF should be evaluated before initiating treatment with mitoxantrone, prior to administration of each dose, and at yearly intervals after completion of treatment.
    Intravenous infusion dosage
    Adults

    12 mg/m2 IV every 3 months.

    For the treatment of relapsed or refractory acute lymphocytic leukemia (ALL)† in combination with ifosfamide and etoposide.
    Intravenous dosage
    Adults

    8 mg/m2/day IV over 1 hour for 3 days in combination with ifosfamide 1.5 g/m2/day IV over 30 minutes for 5 days and etoposide 100 mg/m2/day IV over 90 minutes for 5 days. All patients received mesna 120 mg/m2 IV administered immediately prior to the first ifosfamide dose and then received mesna 1 g/m2/day as a continuous IV infusion for 6 days. If patients achieved a complete remission, they were eligible to repeat a second cycle of chemotherapy as consolidation treatment.

    For the treatment of malignant pleural effusion†.
    Intrapleural dosage†
    Adults

    30 mg in 100 mL NS instilled in the intrapleural cavity. Thoracostomy tube was then closed for 24 hours, allowing action of the drug. It was opened and the drainage continued until the end of effusion or the manifestation of a side effect. Thoracostomy and tube drainage were also performed prior to instillation of mitoxantrone. Chest radiographs were taken immediately before and after the thoracostomy tube procedure and during the follow-up period.

    For the treatment of previously treated metastatic breast cancer†.
    Intravenous dosage
    Adults

    14 mg/m2 IV on day 1, every 21 days.

    For autologous stem cell transplant preparation† in patients with relapsed/refractory lymphoma, in combination with melphalan.
    Intravenous dosage
    Adults

    Mitoxantrone 60 mg/m2 IV divided in 3 doses (each administered over 1 hour) at 1 hour intervals on day -4, in combination with melphalan 180 mg/m2 IV divided in 2 doses (each administered over 1 hour) at 1 hour intervals on day -1, followed by peripheral blood stem cell infusion on day 0.

    For the treatment of metastatic hepatocellular cancer† in combination with 5-fluorouracil and cisplatin.
    Intravenous dosage
    Adults

    6 mg/m2 IV on day 1 in combination with 5-fluorouracil 450 mg/m2/day continuous IV infusion on days 1 to 5 and cisplatin 80 mg/m2 IV over 2 hours on day 1; in a phase II study, the regimen was repeated every 4 weeks for a maximum of 6 cycles.

    For the treatment of chronic lymphocytic leukemia (CLL)†, in combination with cladribine and cyclophosphamide.
    Intravenous dosage
    Adults

    10 mg/m2 IV on day 1 in combination with cyclophosphamide 650 mg/m2 IV on day 1 and cladribine 0.12 mg/kg/day IV over 2 hours on days 1 to 3 repeated every 28 days for up to 6 cycles (median, 3 cycles) has been evaluated in a randomized, phase III trial.

    For the treatment of non-Hodgkin's lymphoma (NHL)†.
    For the treatment of relapsed or refractory NHL in combination with rituximab, ifosfamide, and etoposide†.
    Intravenous dosage
    Adults

    8 mg/m2 IV on day 1 in combination with ifosfamide 2g/m2/day IV on days 1 to 3, etoposide 100 mg/m2/day IV on days 1 to 3, and rituximab 375 mg/m2 IV on the day prior to each chemotherapy cycle and on day 7 of cycle 3 prior to stem cell collection. The regimen was repeated for 3 cycles.

    For the treatment of intermediate or high-grade NHL in combination with cyclophosphamide, vincristine, and prednisone†.
    Intravenous dosage
    Adults

    10 mg/m2 IV on day 1 in combination with cyclophosphamide 600 mg/m2 IV on day 1, vincristine 1 mg IV on day 1, and prednisolone 20 mg PO daily on days 1 to 5, repeated every 21 days for up to 6 cycles.

    For the treatment of previously untreated follicular NHL in combination with fludarabine and rituximab†.
    Intravenous dosage
    Adults

    10 mg/m2 IV on day 1 in combination with fludarabine 25 mg/m2 IV daily on days 1, 2, and 3 and rituximab 375 mg/m2 IV on day 1 repeated every 21 days for 6 cycles followed by 2 additional rituximab 375 mg/m2 IV doses given at 21-day intervals has been evaluated in patients with previously untreated follicular lymphoma in a randomized, phase III trial.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    The maximum cumulative lifetime dose of mitoxantrone is 140 mg/m2 IV.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; however, mitoxantrone clearance is reduced in patients with hepatic impairment (see Pharmacokinetics). Multiple sclerosis patients with hepatic impairment, in general, should not receive mitoxantrone. Mitoxantrone should be used cautiously and potentially in lower doses in other patients with hepatic impairment; however, specific adjustment guidelines are not available from the manufacturer.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

     
    CAUTION: Observe and exercise appropriate precautions for handling, preparing, and administering cytotoxic drugs. Goggles, gloves, and protective gowns are recommended during mitoxantrone preparation and administration. Rinse accidentally exposed skin with warm water.

    Injectable Administration

    Evaluation of left ventricular ejection fraction (LVEF) is recommended at baseline and in patients with evidence of heart failure. Mitoxantrone therapy should not be given to patients with multiple sclerosis and a LVEF < 50% or neutrophil counts < 1500/mm3 (see Contraindications).
    Women with multiple sclerosis who are able to have children should have a negative pregnancy test confirmed prior to treatment and before each mitoxantrone dose.
    Patients with multiple sclerosis should be provided with the Patient Package Insert with each dose of mitoxantrone.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Mitoxantrone is administered by IV infusion. Avoid any contact with skin. Use Luer Lok fittings to prevent accidental leakage of mitoxantrone during administration. If spills occur, clean up with a solution containing 5.5 parts calcium hypochlorite in 13 parts water.
    If evidence of extravasation occurs during administration, the infusion should be stopped and completed via another vein, preferably in another limb.
    Intravenous injection:
    Dilute to at least 50 ml with NS or D5W. Discard unused portion immediately.
    Do not mix mitoxantrone in the same infusion as heparin because a precipitate may form. Due to an absence of compatibility data, do not mix mitoxantrone with other drugs.
    Inject desired dose of the diluted injection slowly over at least 3 minutes into a free-flowing IV infusion of NS or D5W.
    Although mitoxantrone is not a vesicant, care should be taken to avoid extravasation because the drug may be irritating to extravascular tissue. Use of a large vein and avoidance of veins over joints or in extremities with compromised venous or lymphatic drainage is preferable.

    Other Administration Route(s)

    Intraperitoneal Administration†
    NOTE: Mitoxantrone is not approved by the FDA for intraperitoneal administration.
    One method of intraperitoneal (IP) administration of mitoxantrone includes infusing 500 ml Ringer's solution IP over 30 minutes, followed by mitoxantrone diluted in 500 ml Ringer's solution and infused IP over 30 minutes, and then 1000 ml Ringer's solution infused IP over 60 minutes. Other methods include mitoxantrone diluted in 2 liters of 0.9% Sodium Chloride (NS) and given as an intraperitoneal infusion.
    Intrapleural Administration†
    NOTE: Mitoxantrone is not approved by the FDA for intrapleural administration.
    Dilute to at least 50 ml with NS or D5W. Discard unused portion immediately. Further dilution of a dose can be made with 50—100 ml of NS. The solution is sometimes warmed to body temperature before administration.
    Administer via a 16—20 char chest tube. Retain solution for about 48 hours.
    To maximize contact between the drug and the pleura the patient can be rotated into different positions for the first 2 hours after administration, followed by continuous mobilization.
    Intraarterial Administration†
    NOTE: Mitoxantrone is not approved by the FDA for intraarterial administration.
    Dilute to 1000 ml NS. Discard unused portion immediately.
    Administered via hepatic artery catheters placed at the time of laparotomy or by the percutaneous Seldinger technique.

    STORAGE

    Novantrone:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Do not freeze
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store upright

    CONTRAINDICATIONS / PRECAUTIONS

    Cardiac disease, cardiotoxicity, heart failure, maximum cumulative lifetime dose, radiation therapy, ventricular dysfunction

    Severe cardiotoxicity including fatal congestive heart failure and severe left ventricular dysfunction may occur during mitoxantrone therapy or months to years after discontinuing therapy. The risk of cardiotoxicity is dose related; the maximum cumulative lifetime dose is 140 mg/m2 IV. Additionally, patients with cardiac disease, a history of prior radiation therapy to the mediastinal/pericardial area, prior therapy with anthracycline or anthracenedione agents, or who are receiving concurrent cardiotoxic agents may also be at increased risk for cardiotoxicity. Perform a cardiac history assessment and physical examination and obtain an electrocardiogram (ECG) and a quantitative evaluation of left ventricular ejection fraction (LVEF) prior to starting mitoxantrone therapy. In patients with multiple sclerosis, obtain an ECG and an LVEF evaluation prior to each mitoxantrone dose; assess LVEF yearly after therapy completion to evaluate for late cardiotoxicity. Do not give the mitoxantrone dose if there is a decrease in LVEF to below the lower limit of normal or a clinically significant reduction in LVEF during therapy.

    New primary malignancy

    Mitoxantrone may cause a new primary malignancy. Patients with either multiple sclerosis or cancer who received mitoxantrone may develop acute myelogenous leukemia (AML). The most commonly reported types were acute promyelocytic leukemia and acute myelocytic leukemia. Secondary AML has been reported in patients with cancer treated with anthracyclines, and mitoxantrone is an anthracenedione, which is a related drug. The occurrence of refractory secondary leukemia is more common when anthracyclines are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated.

    Bone marrow suppression, coagulopathy, fungal infection, herpes infection, neutropenia, requires an experienced clinician, thrombocytopenia, varicella, viral infection

    Myelosuppressive drugs, such as mitoxantrone, can cause an increased incidence of bacterial, viral, and fungal infection, bleeding, and fatigue due to neutropenia, thrombocytopenia, and anemia. Because these adverse effects can be fatal, the patient must be warned to promptly report any signs such as fever, sore throat, or abnormal pain. Severe bone marrow suppression is a relative contraindication to mitoxantrone depending upon the etiology of the suppression. In general, reserve use only for the treatment of acute nonlymphocytic leukemia in patients who have a baseline neutrophil count < 1500/mm3. Mitoxantrone should be used cautiously in patients with bone marrow suppression, coagulopathy, or in those who have received previous myelosuppressive therapy such as chemotherapy or radiotherapy. Therefore, this drug requires an experienced clinician knowledgeable in the use of cancer chemotherapy. Frequent peripheral blood cell count monitoring is recommended for all patients. Patients with preexisting marrow suppression including neutropenia and/or thrombocytopenia should be allowed to recover their counts prior to mitoxantrone administration. Patients with an active infection should be treated prior to receiving mitoxantrone. Patients with a history of varicella zoster, other herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation the infection when treated with chemotherapy.

    Dental disease, dental work

    Myelosuppressive effects of mitoxantrone can increase the risk of infection or bleeding; therefore, dental work should be delayed until blood counts have returned to normal. Patients, especially those with dental disease, should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks.

    Intraarterial administration, intrathecal administration

    Intrathecal administration of mitoxantrone is not recommended. Neuropathy and neurotoxicity including seizures, paralysis, and bowel and bladder dysfunction have been reported after intrathecal injection; severe injury with permanent sequelae can occur. Intraarterial administration of mitoxantrone has been associated with reversible and irreversible local/regional neuropathy and should not be used.

    Intramuscular injections

    Intramuscular injections should not be administered to patients receiving mitoxantrone with platelet counts < 50,000/mm3. IM injections may cause bleeding, bruising, or hematomas when administered to patients with mitoxantrone-induced thrombocytopenia.

    Extravasation, intramuscular administration, subcutaneous administration

    Mitoxantrone should be given slowly into a freely flowing intravenous infusion. Intramuscular administration and subcutaneous administration of mitoxantrone are not recommended due to the potential for severe local reactions. Take care to avoid extravasation when administering mitoxantrone. Although, mitoxantrone has not been traditionally considered a vesicant, cases of skin necrosis requiring debridement and skin grafting have been reported following extravasation of mitoxantrone into tissues.

    Hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, tumor lysis syndrome (TLS)

    Hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, and decreased urine output may be indicative of mitoxantrone-induced tumor lysis syndrome (TLS). Appropriate measures (e.g. aggressive hydration and allopurinol) must be taken to prevent severe electrolyte imbalances and renal toxicity during and following chemotherapy administration in patients with large chemosensitive tumors.

    Hepatic disease, jaundice

    The safety of mitoxantrone use in patients with hepatic insufficiency has not been established. Patients with multiple sclerosis and hepatic impairment, in general, should not receive mitoxantrone. Mitoxantrone should be used with caution in other patients with hepatic disease, especially in patients with jaundice or hyperbilirubinemia. Mitoxantrone is eliminated hepatically, and clearance may be decreased with hepatic dysfunction. Dosage adjustments may be necessary (see Dosage).

    Pregnancy

    Mitoxantrone should not be administered during pregnancy because of the possibility of teratogenic effects (FDA pregnancy risk category D). There are no adequate and well-controlled trials in pregnant women. Females who may become pregnant should use appropriate contraception. Women with multiple sclerosis who are of childbearing potential should have a pregnancy test prior to each dose of mitoxantrone, and the results should be known prior to administering the drug. If mitoxantrone is used during pregnancy or a woman becomes pregnant while taking this drug, the patient should be apprised of the potential risk to the fetus.

    Breast-feeding

    Mitoxantrone is excreted in breast milk and significant concentrations (18 ng/ml) have been reported for up to 28 days after the last dose. Breast-feeding should be discontinued before beginning mitoxantrone therapy because of the possibility of severe adverse reactions to the infant.

    Accidental exposure, ocular exposure

    Caution is recommended during the preparation, handling, and administration of mitoxantrone solution to avoid accidental exposure. Following cutaneous and ocular exposure, eyes and skin should be thoroughly rinsed. The use of protective gowns, gloves, and goggles during preparation and administration is recommended.

    Vaccination

    Vaccination during chemotherapy or radiation therapy, such as with mitoxantrone, should be avoided because the antibody response is suboptimal. When chemotherapy is being planned, vaccination should precede the initiation of chemotherapy by >= 2 weeks. The administration of live vaccines to immunocompromised patients should be avoided. Those undergoing chemotherapy should not be exposed to others who have recently received the oral poliovirus vaccine (OPV). Measles-mumps-rubella (MMR) vaccination is not contraindicated for the close contacts, including health care professionals, of immunocompromised patients. Passive immunoprophylaxis with immune globulins may be indicated for immunocompromised persons instead of, or in addition to, vaccination. When exposed to a vaccine-preventable disease such as measles, severely immunocompromised children should be considered susceptible regardless of their vaccination history.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 23.0-54.0
    GI bleeding / Delayed / 2.0-16.0
    renal failure (unspecified) / Delayed / 0-8.0
    heart failure / Delayed / 2.3-5.0
    seizures / Delayed / 2.0-4.0
    new primary malignancy / Delayed / 0.3-2.8
    pulmonary edema / Early / 2.0-2.0
    anaphylactoid reactions / Rapid / 0-1.0
    intracranial bleeding / Delayed / 0-1.0
    pancytopenia / Delayed / Incidence not known
    cardiomyopathy / Delayed / Incidence not known
    tissue necrosis / Early / Incidence not known
    tumor lysis syndrome (TLS) / Delayed / Incidence not known

    Moderate

    anemia / Delayed / 5.0-75.0
    lymphopenia / Delayed / 72.0-72.0
    thrombocytopenia / Delayed / 3.0-39.0
    bleeding / Early / 5.0-37.0
    hyperglycemia / Delayed / 31.0-31.0
    edema / Delayed / 10.0-30.0
    stomatitis / Delayed / 8.0-29.0
    elevated hepatic enzymes / Delayed / 5.0-20.0
    leukopenia / Delayed / 0-19.0
    dyspnea / Early / 5.0-18.0
    constipation / Delayed / 10.0-16.0
    hematuria / Delayed / 11.0-11.0
    hypocalcemia / Delayed / 10.0-10.0
    hyponatremia / Delayed / 9.0-9.0
    jaundice / Delayed / 3.0-7.0
    impotence (erectile dysfunction) / Delayed / 7.0-7.0
    hypokalemia / Delayed / 7.0-7.0
    proteinuria / Delayed / 6.0-6.0
    conjunctivitis / Delayed / 0-5.0
    infertility / Delayed / 5.0-5.0
    depression / Delayed / 5.0-5.0
    bone marrow suppression / Delayed / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    dehydration / Delayed / Incidence not known
    skin ulcer / Delayed / Incidence not known
    phlebitis / Rapid / Incidence not known
    erythema / Early / Incidence not known
    hyperuricemia / Delayed / Incidence not known
    pneumonitis / Delayed / Incidence not known

    Mild

    infection / Delayed / 5.0-81.0
    fever / Early / 6.0-78.0
    nausea / Early / 26.0-76.0
    vomiting / Early / 9.0-72.0
    alopecia / Delayed / 20.0-61.0
    diarrhea / Early / 14.0-47.0
    amenorrhea / Delayed / 43.0-43.0
    fatigue / Early / 34.0-39.0
    malaise / Early / 34.0-34.0
    anorexia / Delayed / 22.0-25.0
    weight loss / Delayed / 17.0-17.0
    abdominal pain / Early / 9.0-15.0
    cough / Delayed / 9.0-13.0
    headache / Early / 6.0-13.0
    ecchymosis / Delayed / 7.0-11.0
    petechiae / Delayed / 7.0-11.0
    onycholysis / Delayed / 11.0-11.0
    hyperhidrosis / Delayed / 9.0-9.0
    back pain / Delayed / 8.0-8.0
    libido decrease / Delayed / 7.0-7.0
    sinusitis / Delayed / 6.0-6.0
    myalgia / Early / 5.0-5.0
    arthralgia / Delayed / 5.0-5.0
    chills / Rapid / 5.0-5.0
    anxiety / Delayed / 5.0-5.0
    skin discoloration / Delayed / Incidence not known
    injection site reaction / Rapid / Incidence not known
    rash / Early / Incidence not known
    urine discoloration / Early / Incidence not known
    urticaria / Rapid / Incidence not known

    DRUG INTERACTIONS

    Acalabrutinib: (Moderate) Coadministration of acalabrutinib and mitoxantrone may increase mitoxantrone exposure and increase the risk of mitoxantrone toxicity. Acalabrutinib is a substrate and inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Mitoxantrone is a BCRP subtrate.
    Alemtuzumab: (Major) Concomitant use of mitoxantrone with alemtuzumab may increase the risk of immunosuppression. Avoid the use of these drugs together.
    Alpha interferons: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Amlodipine; Celecoxib: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Azelastine; Fluticasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Beclomethasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Betamethasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Budesonide: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Budesonide; Formoterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Budesonide; Glycopyrrolate; Formoterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Bupivacaine; Meloxicam: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Celecoxib: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Ciclesonide: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Ciprofloxacin: (Major) Chemotherapy including mitoxantrone has been shown to decrease oral absorption of ciprofloxacin, presumably by altering the intestinal mucosa. In 6 cancer patients receiving chemotherapy and after 13 days of chemotherapy, there were decreases in mean maximum serum concentration, in mean time to reach maximum concentration, and in the area under the concentration curve of ciprofloxacin. Concomitant use of mitoxantrone with other quinolones may decrease GI absorption of the quinolone and possibly decrease the antimicrobial effect of the quinolone. The effects of mitoxantrone on the pharmacokinetics of intravenous ciprofloxacin are unclear at this time.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Corticosteroids: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Cortisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Cyclosporine: (Major) Concurrent use of mitoxantrone with other agents which cause bone marrow or immune suppression such as other immunosuppressives may result in additive effects. In addition, high doses of cyclosporine (starting at 16 mg/kg/day IV) may increase exposure to anthracyclines in cancer patients. Cyclosporine is a substrate and inhibitor of P-glycoprotein, an energy-dependent drug efflux pump encoded for by the multidrug resistance gene-1 (MDR1). Overexpression of this protein has been described as a mechanism of resistance to naturally-occurring (non-synthetic) chemotherapy agents. Cyclosporine can block MDR1-mediated resistance when given at much higher doses than those used in transplantation and may also enhance the efficacy of mitoxantrone by inhibiting this protein. Valspodar is a cyclosporine analog with less renal and immunosuppressive effects than cyclosporine while retaining effects on MDR. The addition of cyclosporine or valspodar to mitoxantrone therapy may increase the intracellular concentrations of mitoxantrone leading to increased efficacy and side effects.
    Cytarabine, ARA-C: (Minor) There is a synergistic cytotoxic effect seen during the concomittant administration of mixotrantrone and high-dose cytarabine, ARA-C. In studies of leukemic blast cells from patients treated with this combination, there was enhanced accumulation of araCTP, the active form of cytarabine, in these cells.
    Daclatasvir: (Moderate) Systemic exposure of mitoxantrone, a substrate of the drug transporter breast cancer resistance protein (BCRP), may be increased when administered concurrently with daclatasvir, a BCRP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of mitoxantrone; monitor patients for potential adverse effects.
    Deflazacort: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Dexamethasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Diclofenac: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diclofenac; Misoprostol: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diflunisal: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Diphenhydramine; Ibuprofen: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diphenhydramine; Naproxen: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to drugs that alter immune system activity like antineoplastic drugs. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Elbasvir; Grazoprevir: (Moderate) Administering mitoxantrone with elbasvir; grazoprevir may result in elevated mitoxantrone plasma concentrations. Mitoxantrone is a substrate for the breast cancer resistance protein (BCRP); both elbasvir and grazoprevir are BCRP inhibitors.
    Eltrombopag: (Moderate) Use caution and monitor for adverse reactions if eltrombopag and mitoxantrone are coadministered. Eltrombopag is an inhibitor of Breast Cancer Resistance Protein (BCRP). Drugs that are substrates for this transporter, such as mitoxantrone, may exhibit an increase in systemic exposure if coadministered with eltrombopag.
    Etodolac: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Famotidine; Ibuprofen: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
    Fenoprofen: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Fludrocortisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Flunisolide: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Flurbiprofen: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Fluticasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Fluticasone; Salmeterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Fluticasone; Umeclidinium; Vilanterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Fluticasone; Vilanterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Formoterol; Mometasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Fostamatinib: (Moderate) Monitor for mitoxantrone toxicities that may require mitoxantrone dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a BCRP substrate may increase the concentration of the BCRP substrate. The active metabolite of fostamatinib, R406, is a BCRP inhibitor; mitoxantrone is a substrate for BCRP. Coadministration of fostamatinib with another BCRP substrate increased the BCRP substrate AUC by 95% and Cmax by 88%.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and mitoxantrone as coadministration may increase serum concentrations of mitoxantrone and increase the risk of adverse effects. Mitoxantrone is a substrate of breast cancer resistance protein (BCRP); glecaprevir is an inhibitor of BCRP. (Moderate) Caution is advised with the coadministration of pibrentasvir and mitoxantrone as coadministration may increase serum concentrations of mitoxantrone and increase the risk of adverse effects. Mitoxantrone is a substrate of breast cancer resistance protein (BCRP); pibrentasvir is an inhibitor of BCRP.
    Hydrocodone; Ibuprofen: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Hydrocortisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Ibuprofen: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ibuprofen; Oxycodone: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ibuprofen; Pseudoephedrine: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Indomethacin: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Interferon Alfa-2a: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-2b; Ribavirin: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfacon-1: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-n3: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Itraconazole: (Moderate) Systemic exposure of mitoxantrone, a substrate of the drug transporter breast cancer resistance protein (BCRP), may be increased when administered concurrently with itraconazole, a BCRP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of mitoxantrone; monitor patients for potential adverse effects.
    Ketoprofen: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ketorolac: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Lansoprazole; Naproxen: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Leflunomide: (Moderate) Closely monitor for mitoxantrone-induced side effects such as hepatotoxicity or hematologic toxicity when these drugs are used together. In some patients, a dosage reduction of mitoxantrone may be required. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Teriflunomide is an inhibitor of the Breast Cancer Resistance Protein (BCRP). Use of teriflunomide with mitoxantrone, a substrate of BCRP, may increase mitoxantrone plasma concentrations.
    Live Vaccines: (Contraindicated) Do not administer live vaccines to mitoxantrone recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving mitoxantrone. At least 2 weeks before initiation of mitoxantrone therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Mitoxantrone recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
    Meclofenamate Sodium: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Mefenamic Acid: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Meloxicam: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Methylprednisolone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Mometasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Nabumetone: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Naproxen: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Naproxen; Esomeprazole: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Naproxen; Pseudoephedrine: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Natalizumab: (Major) Natalizumab should not be used in combination with mitoxantrone because of the potential for increased risk of progressive multifocal leukoencephalopathy and other serious infections. Ordinarily, multiple sclerosis patients receiving chronic immunomodulatory therapy should not be treated with natalizumab.
    Nonsteroidal antiinflammatory drugs: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ocrelizumab: (Moderate) Ocrelizumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis. Concomitant use of ocrelizumab with any of these therapies may increase the risk of immunosuppression. Use caution when switching patients from long-acting therapies with immune effects such as mitoxantrone. The median elimination half-life of mitoxantrone is 75 hours (range 23 to 215 hours).
    Ofatumumab: (Moderate) Concomitant use of ofatumumab with mitoxantrone may increase the risk of immunosuppression. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as mitoxantrone. Consider the duration and mechanism of action of drugs with immunosuppressive effects when switching therapies for multiple sclerosis patients. The median elimination half-life of mitoxantrone is 75 hours (range 23 to 215 hours).
    Osimertinib: (Moderate) Monitor for an increase in mitoxantrone-related adverse reactions if coadministration with osimertinib is necessary. Mitoxantrone is a BCRP substrate and osimertinib is a BCRP inhibitor.
    Oxaprozin: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ozanimod: (Moderate) Concomitant use of ozanimod with mitoxantrone may increase the risk of immunosuppression. Ozanimod has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis. Use caution when switching patients from long-acting therapies with immune effects such as mitoxantrone. The median elimination half-life of mitoxantrone is 75 hours (range 23 to 215 hours).
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Pegfilgrastim: (Major) Pegfilgrastim induces the proliferation of neutrophil-progenitor cells, and because antineoplastic agents exert toxic effects against rapidly growing cells, pegfilgrastim should not be given 14 days before or for 24 hours after cytotoxic chemotherapy.
    Peginterferon Alfa-2a: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Peginterferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Piroxicam: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Prednisolone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Prednisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Rofecoxib: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ropeginterferon alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Safinamide: (Moderate) Safinamide at the 100 mg dose and its major metabolite may inhibit intestinal breast cancer resistance protein (BCRP), which could increase plasma concentrations of BCRP substrates such as mitoxantrone. Monitor patients for increased pharmacologic or adverse effects of BCRP substrates during concurrent use of safinamide, particularly the 100 mg dose.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Simeprevir: (Moderate) Use mitoxantrone and simeprevir together with caution; increased systemic exposure of mitoxantrone may occur resulting in increased mitoxantrone adverse effects. If these drugs are taken together, monitor patients for signs of mitoxantrone adverse effects. Mitoxantrone is a substrate of the breast cancer resistance protein (BCRP) drug transporter and simeprevir may inhibit BCRP.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid concurrent administration of voxilaprevir with mitoxantrone. Taking these medications together may increase the plasma concentrations of mitoxantrone. Mitoxantrone is a substrate for the drug transporter Breast Cancer Resistance Protein (BCRP). Voxilaprevir is a BCRP inhibitor.
    Sulindac: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Sumatriptan; Naproxen: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Teriflunomide: (Moderate) Concurrent use of teriflunomide, an inhibitor of the breast cancer resistance protein (BCRP), with mitoxantrone, a substrate of BCRP, may increase exposure to mitoxantrone. Consider reducing the dosage of mitoxantrone as necessary and clinically appropriate, and monitor patients closely. Additive hepatotoxicity or hematologic toxicity may occur. The potential for additive effects should also be considered when such medications would be prescribed after teriflunomide administration has ceased, if the patient has not received the teriflunomide elimination procedure.
    Tolmetin: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Triamcinolone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Valdecoxib: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.

    PREGNANCY AND LACTATION

    Pregnancy

    Mitoxantrone should not be administered during pregnancy because of the possibility of teratogenic effects (FDA pregnancy risk category D). There are no adequate and well-controlled trials in pregnant women. Females who may become pregnant should use appropriate contraception. Women with multiple sclerosis who are of childbearing potential should have a pregnancy test prior to each dose of mitoxantrone, and the results should be known prior to administering the drug. If mitoxantrone is used during pregnancy or a woman becomes pregnant while taking this drug, the patient should be apprised of the potential risk to the fetus.

    Mitoxantrone is excreted in breast milk and significant concentrations (18 ng/ml) have been reported for up to 28 days after the last dose. Breast-feeding should be discontinued before beginning mitoxantrone therapy because of the possibility of severe adverse reactions to the infant.

    MECHANISM OF ACTION

    Mechanism of Action: Mitoxantrone inhibits DNA and RNA synthesis. It binds to DNA by intercalation between base pairs, preferable G-C base pairs. Mitoxantrone also forms electrostatic cross-links within DNA to stabilize the intercalation and forms lace-like intertwining of DNA strands. Mitoxantrone inhibits topoisomerase II, an enzyme known to be important for the repair of damaged DNA. The interaction with topoisomerase II leads to single and double strand DNA breaks. Mitoxantrone also binds to the intracellular cytoskeleton protein cytokeratin 8, which may impair cell division. Unlike other anthracyclines, mitoxantrone does not form oxygen free radicals. Mitoxantrone is not a substrate for reductases, does not undergo redox cycling and may inhibit microsomal oxidative-reductive drug metabolism. Very little lipid peroxidation occurs in cardiac tissues and this is most likely the reason for the decreased cardiac effects of mitoxantrone as compared to other anthracyclines. Mitoxantrone is not cell phase specific, but appears to be most active in the late G-2 phase. It has a cytocidal effect on both nonproliferating and proliferating cultured human cells; however, rapidly proliferating cells are more sensitive to mitoxantrone. Mitoxantrone has been shown in vitro to inhibit B-cell, T-cell and macrophage proliferation and impair antigen presentation, as well as the secretion of interferon gamma, tumor necrosis factor-alpha, and interleukin-2. Resistance to mitoxantrone is due to amplification of the multiple drug resistance gene (mdr) increasing the expression of P170-glycoprotein; however, this may not be the only mechanism of decreased mitoxantrone intracellular accumulation.

    PHARMACOKINETICS

    Mitoxantrone is administered as an intravenous infusion. Mitoxantrone concentrations are highest in the liver, bone marrow, heart, lung, kidney, blood components, pancreas, spleen, and thyroid. Mitoxantrone is 78% bound to plasma proteins. No drug interactions with other highly protein bound drugs have been recognized. A three compartment model best describes the elimination profile of mitoxantrone. The initial alpha half-life is 2—15 minutes reflecting mitoxantrone distribution into blood components. The beta half-life ranges from 17 minutes to 3 hours due to redistribution of mitoxantrone back into the blood and into other tissues. The median terminal half-life of mitoxantrone is 75 hours (range 23—215 hours) reflecting slow release from tissues. Renal, hepatic, and metabolic clearance of mitoxantrone is low suggesting the major route of elimination from the plasma is by tissue uptake and binding. Mitoxantrone is then gradually released from these tissues. Mitoxantrone is metabolized to 2 inactive metabolites. The parent drug may also be conjugated with glutathione or glucuronide. Less than 10% of the total mitoxantrone dose is detected in the urine. Elimination of drug in the urine is pharmacokinetically insignificant but is clinically important since it will change the urine to a bluish-green color. Approximately 25% of a dose is eliminated via the hepatobiliary system after 5 days.

    Intravenous Route

    After intravenous infusion, mitoxantrone is rapidly and extensively distributed to tissue.