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mitoXANTRONE

( my-toe-ZAN-trone )
Other Name(s): Novantrone® (multiple brands available)
Appearance: Dark blue solution ; may be mixed into larger bags of fluids
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 no
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

> 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.