CLINICAL PHARMACOLOGY
CLINICAL PHARMACOLOGY
Mechanism of Action
Mitoxantrone, a DNA-reactive agent that intercalates into deoxyribonucleic acid (DNA) through hydrogen bonding, causes crosslinks and strand breaks. Mitoxantrone also interferes with ribonucleic acid (RNA) and is a potent inhibitor of topoisomerase II, an enzyme responsible for uncoiling and repairing damaged DNA. It has a cytocidal effect on both proliferating and nonproliferating cultured human cells, suggesting lack of cell cycle phase specificity.
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, TNFα, and IL-2.
Pharmacokinetics
Pharmacokinetics of mitoxantrone in patients following a single intravenous administration of mitoxantrone can be characterized by a three-compartment model. The mean alpha half-life of mitoxantrone is 6 to 12 minutes, the mean beta half-life is 1.1 to 3.1 hours and the mean gamma (terminal or elimination) half-life is 23 to 215 hours (median approximately 75 hours). Pharmacokinetic studies have not been performed in humans receiving multiple daily dosing. Distribution to tissues is extensive: steady-state volume of distribution exceeds 1,000 L/m2. Tissue concentrations of mitoxantrone appear to exceed those in the blood during the terminal elimination phase. In the healthy monkey, distribution to brain, spinal cord, eye, and spinal fluid is low.
In patients administered 15 to 90 mg/m2 of mitoxantrone intravenously, there is a linear relationship between dose and the area under the concentration-time curve (AUC).
Mitoxantrone is 78% bound to plasma proteins in the observed concentration range of 26 to 455 ng/mL. This binding is independent of concentration and is not affected by the presence of phenytoin, doxorubicin, methotrexate, prednisone, prednisolone, heparin, or aspirin.
Metabolism and Elimination
Mitoxantrone is excreted in urine and feces as either unchanged drug or as inactive metabolites. In human studies, 11% and 25% of the dose were recovered in urine and feces, respectively, as either parent drug or metabolite during the 5-day period following drug administration. Of the material recovered in urine, 65% was unchanged drug. The remaining 35% was composed of monocarboxylic and dicarboxylic acid derivatives and their glucuronide conjugates. The pathways leading to the metabolism of mitoxantrone have not been elucidated.
Special Populations
Geriatric
In elderly patients with breast cancer, the systemic mitoxantrone clearance was 21.3 L/hr/m2, compared with 28.3 L/hr/m2 and 16.2 L/hr/m2 for non-elderly patients with nasopharyngeal carcinoma and malignant lymphoma, respectively.
Hepatic Impairment
Mitoxantrone clearance is reduced by hepatic impairment. Patients with severe hepatic dysfunction (bilirubin > 3.4 mg/dL) have an AUC more than three times greater than that of patients with normal hepatic function receiving the same dose. Patients with multiple sclerosis who have hepatic impairment should ordinarily not be treated with mitoxantrone. Other patients with hepatic impairment should be treated with caution and dosage adjustment may be required.
Drug Interactions
In vitro drug interaction studies have demonstrated that mitoxantrone did not inhibit CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 across a broad concentration range. The results of in vitro induction studies are inconclusive, but suggest that mitoxantrone may be a weak inducer of CYP450 2E1 activity.
Pharmacokinetic studies of the interaction of mitoxantrone with concomitantly administered medications in humans have not been performed. The pathways leading to the metabolism of mitoxantrone have not been elucidated. To date, post-marketing experience has not revealed any significant drug interactions in patients who have received mitoxantrone for treatment of cancer. Information on drug interactions in patients with multiple sclerosis is limited.
MEDICATION GUIDE MITOXANTRONE(MITO-XAN-TRONE) INJECTION, USP (CONCENTRATE)
MEDICATION GUIDE MitoXANTRONE (mito-xan-trone) Injection, USP (concentrate)
CONTAINS SODIUM METABISULFITE, A SULFITE THAT MAY CAUSE ALLERGIC-TYPE REACTIONS INCLUDING ANAPHYLACTIC SYMPTOMS AND LIFE-THREATENING OR LESS SEVERE ASTHMATIC EPISODES IN CERTAIN SUSCEPTIBLE PEOPLE. THE OVERALL PREVALENCE OF SULFITE SENSITIVITY IN THE GENERAL POPULATION IS UNKNOWN AND PROBABLY LOW. SULFITE SENSITIVITY IS SEEN MORE FREQUENTLY IN ASTHMATIC THAN IN NONASTHMATIC PEOPLE.
Read this Medication Guide before you start receiving MitoXANTRONE and each time you receive MitoXANTRONE. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment.
What is the most important information I should know about MitoXANTRONE?
MitoXANTRONE can cause serious side effects, including:
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- decrease in the ability of your bone marrow to make blood cells (myelosuppression). Your doctor may do blood tests during treatment with MitoXANTRONE to check your blood cell counts. The symptoms of myelosuppression can include:
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- feeling tired
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- increased infections
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- bruising and bleeding easily
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- heart problems (congestive heart failure) that may lead to death even in people who have never had heart problems before. Heart failure can happen while you receive MitoXANTRONE, or months to years after you stop receiving MitoXANTRONE. Your risk of heart failure increases the more MitoXANTRONE you receive.
Call your doctor or get medical help right away if you have any of these problems during or after treatment with MitoXANTRONE:- o
- shortness of breath
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- swelling of your ankles or feet
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- sudden weight gain
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- fast heartbeat or pounding in your chest
- Before receiving MitoXANTRONE for the first time, you should have the following tests done:
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- physical examination
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- a test to check your heart's electrical activity (electrocardiogram)
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- a test to check your heart's ability to pump blood
- If you receive MitoXANTRONE to treat Multiple Sclerosis (MS), your doctor should also do the tests above:
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- before you receive each MitoXANTRONE dose
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- yearly after you stop receiving MitoXANTRONE treatment
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- acute myeloid leukemia (AML). Receiving MitoXANTRONE increases your risk of AML. AML is a cancer of the blood-forming cells of your bone marrow. Symptoms of AML can include:
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- skin problems at your injection site. If MitoXANTRONE leaks out of your vein, skin problems can happen that may lead to serious skin damage (necrosis). Necrosis may need to be repaired surgically. Tell your doctor right away if you have any of the following problems at your injection site:
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What is MitoXANTRONE?
MitoXANTRONE is a prescription medicine used alone or with other medicines to treat people with:
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- secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis (MS)
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- pain related to advanced hormone-refractory prostate cancer
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- acute nonlymphocytic leukemia (ANLL)
MitoXANTRONE is not for people with primary progressive MS. It is not known if MitoXANTRONE is safe and effective in children.
Who should not receive MitoXANTRONE?
Do not receive MitoXANTRONE if you are allergic to MitoXANTRONE or any of the ingredients in MitoXANTRONE. See the end of this Medication Guide for a complete list of ingredients in MitoXANTRONE.
What should I tell my doctor before receiving MitoXANTRONE?
Before you receive MitoXANTRONE, tell your doctor if you have:
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- received MitoXANTRONE in the past
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- heart problems
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- liver problems
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- kidney problems
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- low blood cell counts
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- an infection
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- had radiation treatment in your chest area
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- any other medical conditions
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- are pregnant or plan to become pregnant. MitoXANTRONE may harm your unborn baby. Women who are able to become pregnant should use effective birth control (contraception) while using MitoXANTRONE and should have a pregnancy test, with known results, before receiving each dose of MitoXANTRONE. Talk to your doctor about using effective birth control while you receive MitoXANTRONE.
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- are breastfeeding or plan to breastfeed. MitoXANTRONE can pass into your breast milk and may harm your baby. Talk to your doctor about the best way to feed your baby if you receive MitoXANTRONE. Do not breastfeed while receiving MitoXANTRONE.
Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements.
Using MitoXANTRONE with certain other medicines may cause serious side effects.
Especially tell your doctor if you take or have taken:
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- medicines for cancer treatment called anthracyclines or anthracenediones
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- medicines that may affect your heart
Ask your doctor or pharmacist for a list of these medicines if you are not sure if you take or have taken any of these medicines.
Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.
How should I receive MitoXANTRONE?
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- MitoXANTRONE is given by slow infusion through a needle placed in a vein (intravenous infusion) in your arm.
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- Your doctor will tell you how often you will receive MitoXANTRONE.
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- If you receive MitoXANTRONE to treat MS, your doctor should check how well your heart is working before each MitoXANTRONE dose. Talk to your doctor if you have not had your heart tests done before your MitoXANTRONE dose.
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- Your doctor will do blood tests during your treatment with MitoXANTRONE to check your blood cell counts.
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- If you are a woman of childbearing age taking MitoXANTRONE to treat MS, your doctor should do a pregnancy test before each MitoXANTRONE dose, even if you are using birth control.
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- If you receive MitoXANTRONE to treat MS, there is a limit to the total amount of MitoXANTRONE you can receive during your lifetime. There is a higher risk of heart failure with increasing total lifetime doses of MitoXANTRONE.
What are the possible side effects of MitoXANTRONE?
MitoXANTRONE may cause serious side effects, including:
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- See "What is the most important information I should know about MitoXANTRONE?" The most common side effects of MitoXANTRONE include:
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Tell your doctor if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of MitoXANTRONE. For more information, ask your doctor or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of MitoXANTRONE.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
This Medication Guide summarizes the most important information about MitoXANTRONE. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about MitoXANTRONE that is written for health professionals.
For more information go to www.pfizer.com or call 1-800-615-0187.
What are the ingredients in MitoXANTRONE?
Active ingredient: MitoXANTRONE hydrochloride
Inactive ingredients: sodium chloride, sodium metabisulfite, sodium acetate, and acetic acid
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Distributed by Hospira Inc., Lake Forest, IL 60045 USA
LAB-1312-2.0
Revised: 7/2025
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