Mitoxantrone – Uses, Dosage, Side Effects, Interaction

Indications

  • For the treatment of secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis
  • Mitoxantrone is an antineoplastic antibiotic that is used in the treatment of acute leukemia, lymphoma, and prostate and breast cancer, but also for late-stage, severe multiple sclerosis.
  • Mitoxantrone (NOVANTRONE) is supplied for iv infusion. To induce remission in acute nonlymphocytic leukemia in adults, the drug is given in a daily dose … for 3 days as a component of a regimen that also includes cytosine arabinoside. Mitoxantrone also is used in advanced hormone-resistant prostate cancer. In 2000, mitoxantrone was approved by the FDA for the treatment of late-stage secondary progressive multiple sclerosis.
  • To reduce neurologic disability and/or the frequency of clinical relapses in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis (i.e., patients whose neurologic status is significantly abnormal between relapses)
  • The combination of mitoxantrone and prednisone is approved as a second-line treatment for metastatic hormone-refractory prostate cancer. Until recently this combination was the first line of treatment; however, a combination of docetaxel and prednisone improves survival rates and lengthens the disease-free period.[rx]
  • Mitoxantrone is also used to treat multiple sclerosis (MS), most notably the subset of the disease known as secondary-progressive MS. In the absence of a cure, mitoxantrone is effective in slowing the progression of secondary-progressive MS and extending the time between relapses in both relapsing-remitting MS and progressive-relapsing MS.[rx]
  • Acute Lymphoblastic Leukemia (ALL)
  • Acute Myeloid Leukemia
  • Acute Promyelocytic Leukemia
  • Hodgkin’s Lymphoma
  • Metastatic Breast Cancer
  • Non-Hodgkin’s Lymphoma (NHL)
  • Progressive Relapsing Multiple Sclerosis
  • Relapsed Leukemia
  • Relapsed Lymphomas
  • Relapsing-Remitting Multiple Sclerosis (RRMS)
  • Secondary Progressive Multiple Sclerosis (SPMS)
  • Hormone refractory, advanced Prostate cancer
  • Relapsed Hepatocellular carcinoma

Use in Cancer

Mitoxantrone hydrochloride is approved to be used with other drugs to treat:

Mitoxantrone hydrochloride is also being studied in the treatment of other types of cancer.

Contraindications

  • a bacterial infection.
  • an infection due to a fungus.
  • a bad infection.
  • decreased function of bone marrow.
  • anemia.
  • decreased blood platelets.
  • low levels of white blood cells.
  • low levels of a type of white blood cell called neutrophils.

Dosage

 Strengths: 2 mg/mL

Acute Nonlymphocytic Leukemia

  • INDUCTION THERAPY: 12 mg/m2 IV daily on days 1 to 3 (in combination with cytarabine at 100 mg/m2 given as a continuous 24-hour IV infusion on days 1 to 7)
  • SECOND INDUCTION THERAPY (if needed in the event of an incomplete antileukemic response to the first induction): 12 mg/m2 IV daily on days 1 and 2 (in combination with cytarabine given as a continuous 24-hour IV infusion on days 1 to 5)
  • CONSOLIDATION THERAPY: 12 mg/m2 given IV daily on days 1 and 2 (in combination with cytarabine given as a continuous 24-hour IV infusion on days 1 to 5). The first course is given approximately 6 weeks after the final induction course and the second is generally administered 4 weeks after the first.
  • The IV infusion should be given over 5 to 15 minutes.
  • Most complete remissions from ANLL occur during initial induction therapy. In the event of an incomplete antileukemic response, a second induction course may be administered.
  • Second inductions should be withheld until severe or life-threatening nonhematologic toxicity associated with the first induction dose is cleared.
  • For the initial therapy of acute nonlymphocytic leukemia (ANLL) in adults (includes myelogenous, promyelocytic, monocytic, and erythroid acute leukemias) in combination with other approved drug(s)

Multiple Sclerosis

  • 12 mg/m2 given as a short (approximately 5 to 15 minute) IV infusion every 3 months
  • The IV infusion should be given over 5 to 15 minutes.
  • Evaluation of left ventricular ejection fraction (LVEF) by echocardiogram or multiple gated acquisition (MUGA) scan is recommended prior to all doses.
  • LVEF evaluations are recommended if signs of congestive heart failure develop.
  • This drug should not be administered to MS patients who have received a cumulative lifetime dose of 140 mg/m2 or more, or those with either an LVEF less than 50% or a clinically significant reduction in LVEF.
  • Complete blood counts, including platelets, should be monitored prior to each dose and if signs of infection develop.
  • This drug should not be administered to MS patients with neutrophil counts less than 1500 cells/mm3.
  • Liver function tests should also be monitored prior to each dose. Use of this drug in MS abnormal liver function tests is not recommended.
  • Women who are capable of becoming pregnant (even if they are using birth control) should have a pregnancy test before each dose.

Prostate Cancer

  • 12 to 14 mg/m2 given as a short IV infusion every 21 days (in combination with corticosteroids)
  • The IV infusion should be given over 5 to 15 minutes.

US BOXED WARNINGS:

  • This drug should be administered under the supervision of a physician experienced in the use of cytotoxic chemotherapy agents.
  • This drug should be given slowly into a freely flowing IV infusion. It should never be given subcutaneously, 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, this drug 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 this drug.
  • Cardiotoxicity: Congestive heart failure (CHF), potentially fatal, may occur either during therapy or months to years after termination of therapy. The risk increases with cumulative 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 anthracene diones, or use of other cardiotoxic drugs may increase this risk. In cancer patients, 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, prescribers should consider the following:
  • ALL PATIENTS: All patients should be assessed for cardiac signs and symptoms by history, physical examination, and ECG prior to starting therapy. All patients should have baseline quantitative evaluation of left ventricular ejection fraction (LVEF) using appropriate methodology (e.g., echocardiogram, multi-gated radionuclide angiography (MUGA), MRI).
  • MULTIPLE SCLEROSIS PATIENTS: MS patients with a baseline LVEF below the lower limit of normal should not be treated with this drug. 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 multiple sclerosis patients who have experienced either a drop in LVEF to below the lower limit of normal or a clinically significant reduction in LVEF during 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 therapy to monitor for late-occurring cardiotoxicity.
  • SECONDARY LEUKEMIA: Therapy in patients with MS and in patients with cancer increases the risk of developing secondary acute myeloid leukemia.

Patient advice:

  • Patients should be informed of the availability of a Medication Guide and instructed to read it prior to initiating treatment and prior to each infusion.
  • Patients should be advised that this drug can cause myelosuppression and be informed of signs of myelosuppression.
  • Patients should be advised that this drug can cause congestive heart failure that may lead to death, even in people who have never had heart problems before.
  • Patients with MS should be advised that they should receive cardiac monitoring prior to each dose and yearly after stopping therapy.
  • Patients should be advised that this drug may impart a blue-green color to the urine and/or sclera for 24 hours after administration.

Side Effects

The Most Common

  • nausea
  • vomiting
  • diarrhea
  • constipation
  • heartburn
  • loss of appetite
  • sores on the mouth and tongue
  • runny or stuffed nose
  • thinning or loss of hair
  • changes in the area around or under fingernails and toenails
  • missed or irregular menstrual periods
  • extreme tiredness
  • weakness
  • headache
  • back pain
  • unusual bleeding or bruising
  • small red or purple dots on the skin
  • hives
  • itching
  • rash
  • difficulty swallowing
  • shortness of breath
  • fainting
  • dizziness
  • pale skin
  • yellowing of the skin or eyes
  • seizures
  • redness, pain, swelling, burning, or blue discoloration at the site where the injection was given

More common

  • Black, tarry stools
  • bladder pain
  • bloody or cloudy urine
  • cough or shortness of breath
  • difficult, burning, or painful urination
  • dizziness
  • fainting
  • fast, slow, or irregular heartbeat
  • frequent urge to urinate
  • lower back or side pain
  • pale skin
  • stomach pain
  • swelling or inflammation of the mouth
  • troubled breathing with exertion
  • ulcers, sores, or white spots in the mouth
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • Absent, missed, or irregular menstrual periods
  • back pain
  • body aches or pains
  • congestion
  • constipation
  • diarrhea
  • dryness or soreness of the throat
  • hair loss
  • headache
  • longer or heavier menstrual periods
  • nausea or vomiting
  • oral bleeding
  • pain or tenderness around the eyes and cheekbones
  • runny nose
  • sneezing
  • stopping of menstrual bleeding
  • stuffy nose
  • tender, swollen glands in the neck
  • thinning of the hair

Rare

  • Blood in the urine or stools
  • decrease in urination
  • fever or chills
  • pinpoint red spots on the skin
  • seizures
  • sore, red eyes
  • swelling of the feet and lower legs
  • yellow eyes or skin
  • Blue skin at the place of injection
  • pain or redness at the place of injection
  • skin rash

Drug Interactions

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Pregnancy and Lactation

AU TGA pregnancy category: D
US FDA pregnancy category: D

Pregnancy

This drug can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women with who are capable of becoming pregnant, even if they are using birth control, should have a pregnancy test, before receiving each dose of this drug. Women of childbearing potential should be advised to avoid becoming pregnant. During therapy and for at least 6 months after termination of therapy, effective contraception should be practiced by patients of reproductive age, of either sex

Lactation

Most sources consider breastfeeding to be contraindicated during maternal antineoplastic drug therapy, such as mitoxantrone. It might be possible to breastfeed safely during intermittent therapy with an appropriate period of breastfeeding abstinence, but the duration of abstinence is not clear. In one patient, mitoxantrone was still detectable in milk 28 days after a dose of 6 mg per square meter. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breast milk. Women who receive chemotherapy during pregnancy are more likely to have difficulty nursing their infant.

One mother received 3 daily doses of 6 mg/sq. m. of mitoxantrone intravenously along with 5 daily doses of etoposide 80 mg/sq. m. and cytarabine 170 mg/sq. m. intravenously. She resumed breastfeeding her infant 3 weeks after the third dose of mitoxantrone at a time when mitoxantrone was still detectable in milk. The infant had no apparent abnormalities at 16 months of age.

One mother received 3 daily doses of 6 mg/sq. m. of mitoxantrone intravenously along with 5 daily doses of etoposide 80 mg/sq. m. and cytarabine 170 mg/sq. m. intravenously. She resumed breastfeeding her infant 3 weeks after the third dose of mitoxantrone at a time when mitoxantrone was still detectable in milk. The infant had no apparent abnormalities at 16 months of age.

Why is this medication prescribed?

Mitoxantrone injection is used to adults with various forms of multiple sclerosis (MS; a disease in which the nerves do not function properly and people may experience weakness, numbness, loss of muscle coordination, and problems with vision, speech, and bladder control) including the following:

  • relapsing-remitting forms (course of disease where symptoms flare up from time to time), or
  • progressive relapsing (course of disease with occasional relapses), or
  • secondary progressive forms (course of disease where relapses occur more often).

Mitoxantrone injection is also used together with steroid medications to relieve pain in people with advanced prostate cancer who did not respond to other medications. Mitoxantrone injection is also used with other medications to treat certain types of leukemia. Mitoxantrone injection is in a class of medications called anthracene diones. Mitoxantrone treats MS by stopping certain cells of the immune system from reaching the brain and spinal cord and causing damage. Mitoxantrone treats cancer by stopping the growth and spread of cancer cells.

How should this medicine be used?

Mitoxantrone injection comes as a liquid to be given intravenously (into a vein) by a doctor or nurse in a hospital or clinic. When mitoxantrone injection is used to treat MS, it is usually given once every 3 months for about 2 to 3 years (for a total of 8 to 12 doses). When mitoxantrone injection is used to treat prostate cancer, it is usually given once every 21 days. When mitoxantrone injection is used to treat leukemia, you will continue to receive this medication based on your condition and how you respond to the treatment.

If you are using mitoxantrone injection for MS, you should know that it controls MS but does not cure it. Continue to receive treatments even if you feel well. Talk to your doctor if you no longer want to receive treatment with mitoxantrone injection.

If you are using mitoxantrone injection for MS, ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient.

Other uses for this medicine

Mitoxantrone injection is also sometimes used to treat non-Hodgkin’s lymphoma (NHL; cancer that begins in a type of white blood cell that normally fights infection). Talk to your doctor about the risks of using this medication for your condition.

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

What special precautions should I follow?

Before using mitoxantrone injection,

  • tell your doctor and pharmacist if you are allergic to mitoxantrone injection, any other medications, sulfites, or any of the other ingredients in mitoxantrone injection. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention the medications listed in the IMPORTANT WARNING section. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor if you have or have ever had any blood-clotting problems, anemia (decreased amount of red blood cells in the blood), or liver disease.
  • tell your doctor if you are pregnant or plan to become pregnant. You should not become pregnant while you are using mitoxantrone injection. Talk to your doctor about effective birth control methods that you can use during your treatment. If you become pregnant while using mitoxantrone injection, call your doctor immediately. Mitoxantrone injection may harm the fetus. If you are using mitoxantrone injection to treat MS, even if you are using birth control, your doctor should give you a pregnancy test before each treatment. You must have a negative pregnancy test before the start of each treatment.
  • tell your doctor if you are breastfeeding. Do not breastfeed while you are using mitoxantrone injection.
  • if you are having surgery, including dental surgery, tell the doctor or dentist that you are using mitoxantrone injection.
  • you should know that mitoxantrone injection is dark blue in color and may cause the white parts of your eyes to have a slight blue color for a few days after you receive each dose. It may also change the color of your urine to a blue-green color for about 24 hours after you receive a dose.

References