Mitoxantrone toxicity

Plasma digoxin levels may decrease when the drug is administered with bleomycin. When bleomycin is used witii cisplatin, there is an increased risk of bleomycin toxicity Pulmonary toxicity may occur when bleomycin is administered with other antineoplastic drugs. Plicamycin, mitomycin, mitoxantrone, and dactino-mycin have an additive bone marrow depressant effect when administered with other antineoplastic drugs. In addition, mitomycin, mitoxantrone, and dactinomycin decrease antibody response to live virus vaccines. Dactinomycin potentiates or reactivates skin or gastrointestinal reactions of radiation therapy There is an increased risk of bleeding when plicamycin is administered witii aspirin, warfarin, heparin, and the NSAIDs. 

Adverse Effects Adverse effects are seen regularly in patients given mitoxantrone (see Table 26-3). Patients often experience bluish discoloration of the sclera and the urine for 24 hours after infusion.46 Transient leukopenia and neutropenia are common with a nadir 10 to 14 days after the infusion. Patients should avoid exposure to infectious individuals during this time.46 Patients taking mitoxantrone should not receive live virus vaccines other vaccines should be held for 4 to 6 weeks after a mitoxantrone dose.46 Amenorrhea, caused by a direct toxic effect on the ovary, may be permanent, an important consideration because the MS population includes women of childbearing potential.27... 

Cardiotoxicity is a serious, rare adverse effect of mitox-antrone. The incidence of congestive heart failure was 0.15% in patients with normal left ventricular ejection fraction and 2.18% in those who had asymptomatic left ventricular ejection fraction of less than 50% at baseline.46 Therefore, mitoxantrone should not be used in patients with baseline cardiomyopathy, even if asymptomatic. The risk of cardiotoxicity is dose-related. The maximum lifetime dose of mitoxantrone is 140 mg/m2, or about 3 years of MS therapy. The use of cyclooxygenase-2 inhibitors should be avoided in patients receiving mitoxantrone because of a potential for worsening cardiac toxicity.46... 

This royal-blue-colored drug is an anthracenedione that inhibits DNA topoisomerase II. The pharmacokinetics of mitoxantrone may best be described by a three-compartment model, with an a half-life of 3 to 10 minutes, a 3 half life of 0.3 to 3 hours, and a median terminal half-life of 12 days. Biliary elimination appears to be the primary route of elimination, with less than 10% of the drug eliminated by the kidney.23 Mitoxantrone has shown clinical activity in the treatment of acute leukemias, breast and prostate cancer, and non-Hodgkin s lymphomas. Myelosuppression, mucositis, nausea and vomiting, and cardiac toxicity are side effects of this drug. The total cumulative dose limit is 160 mg/m2 for patients who have not received prior anthracycline or mediastinal radiation. Patients who have received prior doxorubicin or daunorubicin therapy should not receive a cumulative dose greater than 120 mg/m2 of mitoxantrone. Patients should be counseled that their urine will turn a blue-green color. 

Mitoxantrone-watch cumulative dose—do not exceed 140 mg/M2 possible cardiac toxicity ... 

Myocardial toxicity, manifested in its most severe form by potentially fatal CHF, may occur either during therapy with mitoxantrone or months to years after termination of therapy. Mitoxantrone use has been associated with cardiotoxicity this risk increases with cumulative dose. 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/m. For this reason, monitor patients for evidence of cardiac toxicity and question them about symptoms of heart failure prior to initiation of treatment. Monitor patients with multiple sclerosis (MS) who reach a cumulative dose of 100 mg/m for evidence of cardiac toxicity prior to each subsequent dose. Ordinarily, patients with MS should not receive a cumulative dose greater than 140 mg/m. Active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or concomitant use of other cardiotoxic drugs may increase the risk of cardiac toxicity. Cardiac toxicity with mitoxantrone may occur at lower cumulative doses whether or not cardiac risk factors are present (see Warnings and Administration.and.Dosage). 

Mitoxantrone is active against breast carcinomas, leukemias, and lymphomas. Its antitumor efficacy in patients with breast cancer is slightly lower than that of doxorubicin. Its major toxicity is myelosuppression mucositis and diarrhea also may occur. Mitoxantrone produces less nausea, alopecia, and cardiac toxicity than does doxorubicin. 

Al-Ahmad, A., Ktimmerer, K. and Schon, G. (1997) Biodegradation and toxicity of the antineoplastics mitoxantron hydrochloride and treosulfane in the Closed Bottle Test (OECD 301 D). Bull. Environ. Contam. Toxicol., 58 (5), 704—711. 

Mitoxantrone (mitozantrone) (Figure 3.57) is a synthetic analogue of the anthracyclinones in which the non-aromatic ring and the aminosugar have both been replaced with aminoalkyl side-chains. This agent has reduced toxicity compared with doxorubicin, and is effective in the treatment of solid tumours and leukaemias. 

Mitoxantrone 10-12 mg/m2 IV every 3-4 weeks Nausea Bone marrow depression, occasional cardiac toxicity, mild alopecia... 

MITOXANTRONE CICLOSPORIN - high doses (leading to levels of cidosporin from 3000 to 5000ng/mL) t mitoxantrone levels no t toxicity has been reported 1 clearance (>40%) and t terminal half-life (>50%) due to inhibition of P-gp in normal tissues 1 dose of mitoxantrone of 40% has been recommended in paediatric patients. Advisable to monitor mitoxantrone levels... 

Hypokinetic heart wall motion abnormalities and early signs of chronic cardiomyopathy have been identified as a significant toxic effect of mitoxantrone in patients who received cumulative doses of 32-174 mg (31). Electrocardiographic T wave inversion and cardiac complications have been described from intensive therapy with mitoxantrone 40 mg/m over 5 days and cyclophosphamide 1550 mg/m for 4 days, given before bone marrow transplantation for metastatic breast cancer. All the patients had had previous exposure to doxorubicin in cumulative doses that did not exceed 442 mg/m (19). 

Bmsamolino E, Bertini M, Guidi S, Vitolo U, Inverardi D, Merante S, Colombo A, Resegotti L, Bemasconi C, Ferrini PR, et al. CHOP versus CNOP (N = mitoxantrone) in non-Hodgkin s lymphoma an interim report comparing efficacy and toxicity. Haematologica 1988 73(3) 217-22. 

The anthracyclines and related compounds, such as mitoxantrone and amsacrine (9), also exert their cytotoxic effects via inhibition of topoisomerase II. However, they differ from the camptothecins and podophyllotoxins in respect to DNA intercalation and have a different pattern of cardiac toxicity. 

The mode of action of mitoxantronc involves intercalation and inhibition of topoisomcrasc 11. In contrast to doxorubicin. it docs not undergo redox cycling to form oxygen free radicals, because iLs redox potential is outside the reductive capability of mammalian reductases. Mitoxantrone is approved for remission-induction therapy in acute nonlympho-cytic leukemia, where it typically is used with cytarabine. It also is active against other leukemias, breast cancer, and ovarian cancer. The dose-limiting toxic effect is myelosup-... 

The major toxicities of these four groups are bone marrow depression, nausea and vomiting, mucositis, and diarrhea. Daunorubicin, doxorubicin, epirubicin, idarubicin, and to a lesser extent, mitoxantrone, cause cardiac toxicity. Mitomycin and bleomycin cause... 

Cardiomyopathy is the most common chemotherapy-associated cardiac toxicity. Myocardial ischemia, pericarditis, arrhythmias, miscellaneous electrocardiogram (ECG) changes, and angina occur much less frequently. The anthracyclines (da-unorubicin, doxorubicin, epirubicin, and idarubicin) have the highest consistent risk for cardiomyopathy, which is cumulative dose related. There is evidence that high-dose cyclophosphamide, mitoxantrone, and fluorouracil also pose an increased risk of cardiac damage. The concurrent use of traztuzu-mab with an anthracycline and cyclophosphamide is associated with a risk of cardiac dysfunction, but the consequences of sequential use are not yet known. 

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