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mitoXANTRONE
mitoXANTRONE
SYNONYM(S): DHAD; dihydroxyanthracenedione dihydrochloride; mitozantrone
COMMON TRADE NAME(S): Novantrone® (multiple brands available)
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.
Widely distributed into tissues.
| Cross blood brain barrier? | minimal |
| PPB | 78 % |
In liver to polar compounds, pathways not known.
| Active metabolites | no |
| Inactive metabolites | yes |
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) |
- 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)
Emetogenic Potential:
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.
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.
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 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 |
|
Hepatic Impairment |
Dose |
|
Mild-Moderate |
↓ 50% |
|
Bilirubin > 2-3 x ULN |
Hold |
|
Severe |
Hold |
No adjustment required
May have an increased risk of toxicity
Safety and efficacy not established
- 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.
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.
| 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 |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| 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
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
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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