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mitoXANTRONE

Trade Name:

Novantrone® (multiple brands available)

Synonym:

DHAD

dihydroxyanthracenedione dihydrochloride

mitozantrone

Appearance:

Dark blue solution

; may be mixed into larger bags of fluids

Monograph Name:

mitoxantrone

Monograph Body:

Drug Monograph

A - Drug Name

mitoXANTRONE

SYNONYM(S): DHAD; dihydroxyanthracenedione dihydrochloride; mitozantrone

COMMON TRADE NAME(S): Novantrone® (multiple brands available)

B - Mechanism of Action and Pharmacokinetics

Mitoxantrone is an anthracenedione structurally similar to doxorubicin and daunorubicin. The exact mechanism of action is unknown but includes intercalation with DNA to cause inter/intrastrand cross-linking, inhibition of RNA synthesis and DNA topoisomerase II. Mitoxantrone is cell cycle phase-nonspecific.

Absorption

Oral absorption: Poor

Distribution

Widely distributed into tissues.

Cross blood brain barrier?

minimal

PPB

78 %

Metabolism

In liver to polar compounds, pathways not known.

Active metabolites

Inactive metabolites

yes

Elimination

Triphasic. Mainly in bile (25% in feces within 5 days), small amount in urine.

Urine

11 % within 5 days, 65% unchanged.

Half-life

23-215 hours (terminal t½)

C - Indications and Status

Health Canada Approvals:

Acute nonlymphocytic leukemia in adults (in combination), including myelogenous, promyelocytic, monocytic and erythroid acute leukemias
Relapsed leukemia, lymphoma and hepatoma
Metastatic breast cancer

Other Uses:

Hormone refractory prostate cancer (with steroids)

D - Adverse Effects

Emetogenic Potential:

Low

Extravasation Potential: Vesicant

The following table contains adverse effects reported mainly in combination with corticosteroid in prostate cancer.

ORGAN SITE	SIDE EFFECT* (%)	ONSET**
Cardiovascular	Arrhythmia (7%) (transient)	I
	Cardiac ischemia (5%)	E
	Heart failure (2.6%)	D L
	Hypertension (4%)	E
	Hypotension	E
Dermatological	Alopecia (29%)	E
	Nail disorder (11%)	D
	Nail loss	D
Gastrointestinal	Abdominal pain	E
	Anorexia (25%)	E
	Constipation (16%)	E
	Dehydration (rare)	E
	Diarrhea (14%)	E
	Dyspepsia (5%)	E
	GI hemorrhage (rare)	E
	Mucositis (29%)	E
	Nausea (61%)	I
	Vomiting (9%)	I
	Weight changes (17%)	E
General	Edema (30%)	E
	Fatigue (39%)	E
	Fever (6%)	E
Hematological	Myelosuppression (nadir 10 days, recovery 21 days)	E
Hepatobiliary	↑ LFTs (20%)	E
Hypersensitivity	Anaphylaxis (rare)	I
Infection	Infection (10%)	E
Injection site	Phlebitis (10%)	I
	Vein discolouration (blue; rare)	I
Metabolic / Endocrine	Abnormal electrolyte(s) (up to 10%)	E
	Tumor lysis syndrome (rare, in AML)	I
Musculoskeletal	Arthralgia (5%)	E
	Myalgia (5%)	E
Neoplastic	Leukemia (secondary) (1-2%)	L
	MDS (1-2%)	L
Nervous System	Anxiety (5%)	E
	Confusion (rare)	E
	Depression (5%)	E
	Headache (rare)	E
	Paresthesia (rare)	E
	Seizure (rare)	E
	Somnolence (rare)	E
Ophthalmic	Blurred vision (3%)	I E
	Conjunctivitis	I E
Renal	Creatinine increased (13%)	E
	Nephrotoxicity (occasional)	I E
	Proteinuria (6%)	I E
Reproductive and breast disorders	Irregular menstruation (amenorrhea)	D
Respiratory	Cough (5%)	E
	Dyspnea (15%)	E
	Pneumonitis (rare)	E D
Urinary	Urine discoloration (blue-green, for 1-2 days)	I

* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.
Dose-limiting side effects are underlined.

** I = immediate (onset in hours to days) E = early (days to weeks)
D = delayed (weeks to months) L = late (months to years)

Mitoxantrone may be associated with less nausea and vomiting, stomatitis and alopecia than doxorubicin.

Cardiotoxicity may occur with mitoxantrone for months to years after treatment, whether or not cardiac risk factors are present. It is cumulative across members of this class and anthracyclines. The recommended maximum cumulative dose of mitoxantrone is 140 mg/m². At this dose, 13% of patients have moderate to severe decreases in LVEF while 3% of patients may have clinical cardiac failure. The cumulative dose is lower with prior anthracycline therapy, in patients who have received radiation to the mediastinal area or concomitant therapy with other cardiotoxic agents such as cyclophosphamide, in children and in patients with active or dormant cardiovascular disease or multiple sclerosis.

Stomatitis is dose-limiting with the 5-day schedule and with the high doses used for bone marrow transplantation (e.g. high grade mucositis in nearly 70% of BMT patients in one study). It usually occurs within 1 week of therapy.

Signs and symptoms (e.g. hyperuricemia, hyperkalemia, hypocalcemia, acute renal failure, elevated LDH, high fever) consistent with tumour lysis syndrome have been reported to occur within 1 to 2 hours after first infusion. Patients at risk (high tumour burden) should be closely monitored and prophylaxis considered.

E - Dosing

Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Guidelines for dosing also include consideration of white blood cell count. Dosage may be reduced and/or delayed in patients with bone marrow depression due to cytotoxic/radiation therapy. Except for the treatment of acute nonlymphocytic leukemia, mitoxantrone should not be given to patients with baseline neutrophil counts of less than 1.5 x 10⁹/L.

Adults:

Solid tumours:

q3w: 12-14 mg/m² IV
Decrease by 2-4 mg/m² for combination therapy, prior therapy, or poor performance status

Leukemia:

Single agent: 12 mg/m²/day IV x 5 days
With cytarabine: 10 – 12 mg/m² x 3 days. If a second course is indicated: 10-12 mg/m² x 2 days

Maximum lifetime dose:

140 mg/m² (no prior anthracycline, normal cardiac function; lower in children and patients with multiple sclerosis).
Careful cardiac monitoring is important as cardiotoxicity may occasionally occur at lower cumulative doses. If tumour responding when lifetime dose reached, obtain cardiac consultation before continuing treatment.

Dosage with Toxicity:

Dosage in myelosuppression:

Modify according to protocol by which patient is being treated; if no guidelines available refer to Appendix 6 "Dosage Modification Hematologic and Non-Hematologic Toxicities".

Suggested modifications are:

WBC and Platelet Nadir (x 10⁹/L)			Time to Recovery	Subsequent Dose
WBC		Platelets
> 1.5	AND	> 50	≤ 21 days	No change. May increase by 2mg/m² if inadequate myelosuppression
> 1.5	AND	> 50	> 21 days	Hold until recovery. Do not increase dose
1 to 1.499	OR	25 to 49		Reduce dose by 2mg/m²
< 1	OR	< 25		Reduce dose by 4mg/m²

Dosage with Hepatic Impairment:

Hepatic Impairment	Dose
Mild-Moderate	↓ 50%
Bilirubin > 2-3 x ULN	Hold
Severe	Hold

Dosage with Renal Impairment:

No adjustment required

Dosage in the elderly:

May have an increased risk of toxicity

Children:

Safety and efficacy not established

F - Administration Guidelines

Doses may be mixed in 50-100mL minibag (Normal Saline or 5% Dextrose); Infuse through sidearm of free flowing IV over 10-30 minutes.
Slow push through sidearm of free-flowing IV, not less than 3 to 5 minutes.
Mitoxantrone should not be mixed in the same infusion with heparin since a precipitate may form.
Do not admix with other drugs.
If any signs or symptoms of extravasation occur, the injection or infusion should be immediately terminated and restarted in another vein. Any known or suspected extravasation should be managed promptly.
Store at room temperature.

G - Special Precautions

Other:

Mitoxantrone is contraindicated in patients with known hypersensitivity to mitoxantrone, its excipients or other anthracyclines. Mitoxantrone should not be used for intrathecal, subcutaneous, intramuscular or intra-arterial administration. Vaccination with live vaccines is contraindicated. It is also contraindicated in patients with severe hepatic impairment, in patients who have not recovered from severe myelosuppression due to prior cytotoxic or radiation treatment, and in patients with abnormal cardiac function who have received prior substantial anthracycline exposure. Mitoxantrone should be used with caution in patients with poor performance status.

Cardiotoxicity is cumulative across members of the anthracycline (daunorubicin, doxorubicin, epirubicin, idarubicin) and anthracenedione (mitoxantrone) classes of drugs. Patients who have received these drugs are at increased risk of toxicity and should be carefully monitored. The safe cumulative dose is lower in patients who have received radiation to the mediastinal area or concomitant therapy with other cardiotoxic agents such as cyclophosphamide.

Mitoxantrone is mutagenic, clastogenic, carcinogenic and fetotoxic and should not be used in pregnancy. Adequate contraception should be used by both sexes, during mitoxantrone treatment and for at least 6 months after the last dose. Its effects on fertility have not been established. Breast feeding is not recommended due to secretion into breast milk.

H - Interactions

AGENT	EFFECT	MECHANISM	MANAGEMENT
Cardiotoxic drugs (i.e., cyclophosphamide, trastuzumab, other anthracyclines)	↑ cardiotoxicity	Additive	Caution if prior treatment with these agents
Live vaccines	↑ risk of severe infection	Immunocompromised status	Avoid

I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

Monitor Type	Monitor Frequency
CBC	Baseline and regular
Serum uric acid levels (hematologic malignancies)	Baseline and regular
Cardiac function tests (Echo, RNA and/or MUGA scans) especially patients with risk factors, or close to the lifetime threshold	Baseline and regular
Liver function tests (especially If poor Performance Status)	Baseline and regular
Clinical assessment for symptoms of CHF, bleeding, infection, local toxicity.	At each visit

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

K - References

Cancer Drug Manual (the Manual), 1994, British Columbia Cancer Agency (BCCA)

McEvoy GK, editor. AHFS Drug Information 2009. Bethesda: American Society of Health-System Pharmacists, p. 1179-84.

Mitoxantrone: e-Cancer Chemotherapy Manual.

Prescribing Information: Novantrone® (mitoxantrone). OSI Pharmaceuticals, September 2009.

Product Monograph: Mitoxantrone Injection. Pharmaceutical Partners of Canada Inc., January 15, 2008.

October 2017 edited indications

L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.

CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.

Info Sheet Name:

mitoxantrone (patient)

Info Sheet Introduction:

For treating breast cancer that has spread to other parts of the body, blood cancers such as leukemias an lymphomas, liver cancer and prostate cancer.

Info Sheet Date: Tuesday, May 22, 2018 Info Sheet body:

Medication Information Sheet

mitoXANTRONE (my-toe-ZAN-trone)

This document provides general information about your medication. It does not replace the advice of your health care professional. Always discuss your therapy with your health care professional and refer to the package insert for more details.

Other Name: Generic brand(s) available, Novantrone®

Appearance:

Dark blue solution

; may be mixed into larger bags of fluids

What is this medication for?

For treating breast cancer that has spread to other parts of the body, blood cancers such as leukemias an lymphomas, liver cancer and prostate cancer.

What should I do before I have this medication?

Tell your doctor if you have/had significant medical condition(s), especially if you have / had heart disease, or any allergies.
MitoXANTrone may harm the unborn baby.
Let your doctor know if you are breastfeeding, pregnant or plan to become pregnant
People who have cancer or leukemia are at a higher risk of developing other cancers/leukemias (usually some years later). Some cancer medications may increase these risks, especially if used for a prolonged period of time. You should discuss any concerns about this drug with your doctor.

How will this medication affect sex, pregnancy and breastfeeding?

Do not use mitoXANTrone if you are pregnant. If there is ANY chance that you or your partner may become pregnant, you and your partner together must:►Use 2 effective forms of birth control at the same time while on mitoXANTrone. Do not take birth control pills if you have breast cancer. Keep using birth control until 6 months after the last dose (general recommendation). Discuss with your healthcare team.
Tell your doctor right away if you or your partner becomes pregnant.
Do not breastfeed while on mitoXANTtrone treatment. Breastfeeding should be discontinued prior to mitoXANTrone treatment.

Effects on Fertility: Unknown

How is this medication given?

This drug is given by injection into a vein.

What else do I need to know while on this medication?

This medication can interact with other medications and can result in the treatment not working as well or cause severe side effects.
Make sure your health care team knows about all your medications (prescription, over-the-counter, herbals and supplements). Check with your health care team before starting or stopping any of them.

Your urine may turn blue-green for 1-2 days after receiving mitoxantrone.

What are the side effects of this medication?

The following side effects are common or severe. You may not have all of the side effects. Other side effects may occur. If you have any unusual or bothersome symptoms, discuss with your doctor.

Side effects and what to do	When to contact doctor?
More Common Side Effects

Liver problems
(yellow skin or eyes, dark urine)

Get emergency medical help right away

Hair thinning or loss

Use a gentle soft brush; care should be taken with hair sprays, bleaches, dyes and perms.
Your hair usually grows back after your treatment ends, but the texture or colour may change.

Diarrhea

May occur days to weeks after the drug is given / after treatment starts
Drink plenty of clear fluids. Limit hot, spicy, fried foods, foods/drinks with caffeine, orange or prune juice.
Try a low-fiber BRAT diet (Bananas, white Rice, Apple sauce, Toast made with white bread).
Take anti-diarrhea drug(s) if given to you by your doctor.
Also see Diarrhea pamphlet.*

Contact your health care team if no improvement or if severe

Tiredness

Rest often; take naps if needed. Move slowly when getting up.
Eat well-balanced meals and drink plenty of fluids. Light exercise may help.
Do not drive a motor vehicle or operate machinery when feeling tired.

Contact your health care team if no improvement or if severe

Mouth sores

Maintain good mouth hygiene. Regular teethbrushing with a soft toothbrush or Toothette®, and regular use of mouthwashes, especially after meals and at bedtime. Use alcohol-free mouthwashes.
Instead, try a homemade mouthwash:
Mix 1 teaspoonful of baking soda and 1 teaspoonful of salt in 4 cups (1L) of water.
Avoid hot, spicy, acidic, hard or crunchy foods.
Check with your doctor or nurse as soon as you notice sores in mouth/lips or pain with swallowing. Your doctor may prescribe a prescription mouthwash to relieve mouth sores and prevent infection.
Also see Mouth Care pamphlet.*

Contact your health care team as soon as possible

Unusual bleeding or bruising

You may have black stools, cough up blood, blood in your urine, purple or red dots on your skin or bleeding that will not stop.

Fever, chills, infection

You have a fever if your temperature taken in your mouth (oral temperature) is:

38.3°C (100.9°F) or higher at any time OR
38.0°C (100.4°F) or higher for at least one hour.

While you are getting chemotherapy treatments:

Keep a digital thermometer at home and take your temperature if you feel hot or unwell (for example, chills).
Avoid taking medications that treat a fever before you take your temperature (for example, Tylenol®, acetaminophen, Advil® or ibuprofen) as they may hide a fever.
Do not eat or drink anything hot or cold right before taking your temperature.
Wash your hands often.
Check with your doctor before getting any vaccines, surgeries or visiting your dentist.

If you have a fever, talk to your health care team or go to the closest emergency room.
See our Neutropenia (Low white blood cell count) pamphlet for more information.

Get emergency medical help right away

Nausea and vomiting

May occur in hours to days after the dose is given/ after treatment starts.
Drink clear fluids and avoid large meals. Get fresh air and rest.
Limit spicy, fried foods or foods with a strong smell.
Take anti-nausea drug(s) exactly as directed by your doctor. It is easier to prevent nausea than to treat it.
Contact your doctor if nausea lasts more than 1 day or if any vomiting occurs.
Also see Nausea & Vomiting pamphlet.*

Contact your health care team if no improvement or if severe

Pain, burning, redness, or swelling on skin where drug was injected

Let your healthcare team know right away when this happens, since this drug can harm or irritate tissues if it leaks from the vein during injection.

Get emergency medical help right away

Side effects and what to do	When to contact doctor?
Less Common Side Effects, but may be Severe

Allergic reaction
(fever, severe rash, itchiness, swollen face, lip or tongue, chest or throat tightness)

May occur during or shortly after the drug is given.

Get emergency medical help right away

Heart problems
(irregular heartbeat, chest pain, fainting, swelling, shortness of breath)

Get emergency medical help right away

Lung problems
(increased cough, breathing problems, chest pain, coughing blood)

Get emergency medical help right away

Loss of consciousness, seizures, confusion

Get emergency medical help right away

Rapid killing of cancer cells when you start treatment may lead to build up of cell waste products

If mild, this may cause gout, with joint pains, but if severe, may cause fevers, kidney failure, confusion and be life-threatening.
You MUST take the preventive medicines given by your doctor AND
Drink plenty of fluids (6-8 glasses per day) and void (urinate) frequently.

Get emergency medical help right away

For more links on how to manage your symptoms go to www.cancercareontario.ca/symptoms.

The information set out in the medication information sheets, regimen information sheets, and symptom management information (for patients) contained in the Drug Formulary (the "Formulary") is intended to be used by health professionals and patients for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or side effects of a certain drug, nor should it be used to indicate that use of a particular drug is safe, appropriate or effective for a given condition.

A patient should always consult a healthcare provider if he/she has any questions regarding the information set out in the Formulary. The information in the Formulary is not intended to act as or replace medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

Info Sheet (English):

mitoxantrone patient.pdf Info Sheet (French):

mitoxantrone pour le patient.pdf Monograph:

mitoxantrone.pdf Phonetic Spelling:

my-toe-ZAN-trone

Cancer Type: Genitourinary Prostate Hematologic Leukemia - Chronic Lymphocytic (CLL) Lymphoma - Non-Hodgkin's High Grade Lymphoma - Non-Hodgkin's Intermediate Grade Lymphoma - Non-Hodgkin's Low Grade Type of Content: Drug Monograph Status: Null Info Sheet Status: Null Global Date: Tuesday, August 9, 2016 Universal Date: 2018-05-22 00:00:00 AddThis: Title URL: mitoXANTRONE Drug Display Status: Active Revision Summary:

edited indications