MITOXANTRONE HCL
Chemistry - Mitoxantrone HCl is a synthetic anthracenedione antineoplastic.
Highest concentrations of the drug are found in the liver, heart, thyroid and red blood cells. Inhumans, it is approximately 78% bound to plasma proteins. Mitoxantrone is metabolized in theliver, but the majority of the drug is excreted unchanged in the urine. Half life of the drug inhumans averages about 5 days as a result of the drug being taken up, bound by, and then slowlyreleased by tissues.
Mitoxantrone affected fetal birth weights in rats. In a rabbit study no teratogenic effects werenoted, but there was an increased incidence of premature deliveries. Use during pregnancy onlywhen the benefits outweigh the risks involved. While it is unknown whether mitoxantrone entersmilk, it is recommended to use milk replacer for nursing puppies.
Unlike doxorubicin, cardiotoxicity has not yet been reported in dogs and only rarely occurs inhumans. Other adverse effects less frequently or rarely noted in humans and potentially possible indogs, include conjunctivitis, jaundice, renal failure, seizures, allergic reactions, thrombocytopenia, irritation or phlebitis at injection site. Tissue necrosis associated with extravasation has only beenreported in a few human cases.
Live virus vaccines should be used with caution, if at all during therapy.
Cardiotoxicity risks may be enhanced in patients who have previously received doxorubicin, daunorubicin or radiation therapy to the mediastinum.
Laboratory Considerations - Mitoxantrone may raise serum uric acid levels. Drugs such asallopurinol may be required to control hyperuricemia. Liver function tests may become abnormal, indicating hepatotoxicity.
Storage, Stability, Compatibility
Mitoxantrone HCl should be stored at room temperature; donot freeze. Do not mix or use the same IV line with heparin infusions (precipitate may form). Atpresent, it is not recommended to mix with other IV drugs.Pharmacology - MITOXANTRONE HCL
By intercalation between base pairs and also a nonintercalative electrostatic interaction, mitoxantrone binds to DNA and inhibits both DNA and RNA synthesis. Mitoxantrone isnot cell-cycle phase specific, but appears to be most active during the S phase.Uses, Indications
Mitoxantrone may be useful in the treatment of several neoplastic diseases indogs, including lymphosarcoma (Note: preliminary studies have been disappointing with usingmitoxantrone in the treatment of lymphoma when compared to other drug regimens), renal adenocarcinoma, fibroid sarcoma, thyroid or transitional cell carcinomas and hemangiopericytoma.Pharmacokinetics - MITOXANTRONE HCL
Mitoxantrone is rapidly and extensively distributed after intravenous infusion.Highest concentrations of the drug are found in the liver, heart, thyroid and red blood cells. Inhumans, it is approximately 78% bound to plasma proteins. Mitoxantrone is metabolized in theliver, but the majority of the drug is excreted unchanged in the urine. Half life of the drug inhumans averages about 5 days as a result of the drug being taken up, bound by, and then slowlyreleased by tissues.
Contraindications, Precautions, Reproductive Safety
Mitoxantrone is relatively contraindicated (weigh risk vs. benefit) in patients with myelosuppression, concurrent infection, impairedcardiac function or those who have received prior cytotoxic drug or radiation exposure. It should beused with caution in patients with sensitivity to mitoxantrone, hyperuricemia or hyperuricuria, orimpaired hepatic function.Mitoxantrone affected fetal birth weights in rats. In a rabbit study no teratogenic effects werenoted, but there was an increased incidence of premature deliveries. Use during pregnancy onlywhen the benefits outweigh the risks involved. While it is unknown whether mitoxantrone entersmilk, it is recommended to use milk replacer for nursing puppies.
Adverse Effects, Warnings
In dogs, effects include dose-dependent GI distress (vomiting, anorexia, diarrhea) and infection secondary to bone marrow depression. White cel nadirs generallyoccur on day 10. Some evidence exists that by giving recombinant granulocyte-colony stimulatingfactor bone marrow depression severity and duration may be reduced.Unlike doxorubicin, cardiotoxicity has not yet been reported in dogs and only rarely occurs inhumans. Other adverse effects less frequently or rarely noted in humans and potentially possible indogs, include conjunctivitis, jaundice, renal failure, seizures, allergic reactions, thrombocytopenia, irritation or phlebitis at injection site. Tissue necrosis associated with extravasation has only beenreported in a few human cases.
Overdosage, Acute Toxicity
Because of the potential serious toxicity associated with this agent, dosage determinations must be made carefully.Drug Interactions
Use extreme caution when used concurrently with other drugs that are alsomyelosuppressive, including many of the other antineoplastics and other bone marrow depressant drugs (e.g., chloramphenicol, flucytosine, amphotericin B, or colchicine). Bonemarrow depression may be additive. In humans, enhanced bone marrow depression has occurredwhen used concomitantly with trimethoprim/sulfa. Use with other immunosuppressant drugs(e.g., azathioprine, cyclophosphamide, corticosteroids) may increase the risk of infection.Live virus vaccines should be used with caution, if at all during therapy.
Cardiotoxicity risks may be enhanced in patients who have previously received doxorubicin, daunorubicin or radiation therapy to the mediastinum.
Laboratory Considerations - Mitoxantrone may raise serum uric acid levels. Drugs such asallopurinol may be required to control hyperuricemia. Liver function tests may become abnormal, indicating hepatotoxicity.