Mitoxantrone - Novantrone®
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Preparation and Administration Precautions
The dose of mitoxantrone should be diluted to at least 50 mL with either 0.9% Sodium Chloride Injection or 5% Dextrose Injection. Mitoxantrone may be further diluted into Dextrose 5% in Water, Normal Saline or Dextrose 5% with Normal Saline and used immediately.1 DO NOT FREEZE. Usually administered as a short I.V. infusion over 5 to 15 minutes. High doses for bone marrow transplant are usually given
Mitoxantrone should not be mixed in the same infusion as heparin since a precipitate may form. Because specific compatibility data are not available, it is recommended that mitoxantrone not be mixed in the same infusion with other drugs. The diluted solution should be introduced slowly into the tubing as a freely running intravenous infusion of 0.9% Sodium Chloride Injection or 5% Dextrose Injection over a period of not less than 3 minutes. Unused infusion solutions should be discarded immediately in an appropriate fashion. In the case of multidose use, after penetration of the stopper, the remaining portion of the undiluted mitoxantrone injection should be stored not longer than 7 days between 15° to 25°C (59° to 77°F) or 14 days under refrigeration. DO NOT FREEZE. CONTAINS NO PRESERVATIVE.
Store between 15° to 25°C (59° to 77°F). DO NOT FREEZE1.
|Stability / Miscellaneous
Mechanism of Action
Mitoxantrone has been shown in vitro to inhibit B cell, T cell, and macrophage proliferation and impair antigen presentation, as well as the secretion of interferon gamma, TNFα, and IL-2.
In patients administered 15 to 90 mg/m2 of mitoxantrone intravenously, there is a linear relationship between dose and the area under the concentration-time curve (AUC).
Mitoxantrone is 78% bound to plasma proteins in the observed concentration range of 26 to 455 ng/mL. This binding is independent of concentration and is not affected by the presence of phenytoin, doxorubicin, methotrexate, prednisone, prednisolone, heparin, or aspirin.
Metabolism and Elimination
Geriatric -In elderly patients with breast cancer, the systemic mitoxantrone clearance was 21.3 L/hr/m2, compared with 28.3 L/hr/m2 and 16.2 L/hr/m2 for non-elderly patients with nasopharyngeal carcinoma and malignant lymphoma, respectively.
Pediatric - Mitoxantrone pharmacokinetics in the pediatric population are unknown.
Race -The effect of race on mitoxantrone pharmacokinetics is unknown.
Renal Impairment - Mitoxantrone pharmacokinetics in patients with renal impairment are unknown.
Hepatic Impairment - Mitoxantrone clearance is reduced by hepatic impairment. Patients with severe hepatic dysfunction (bilirubin > 3.4 mg/dL) have an AUC more than three times greater than that of patients with normal hepatic function receiving the same dose. Patients with hepatic impairment should be treated with caution and dosage adjustment may be required.
Pharmacokinetic studies of the interaction of mitoxantrone with concomitantly administered medications in humans have not been performed. The pathways leading to the metabolism of mitoxantrone have not been elucidated. To date, post-marketing experience has not revealed any significant drug interactions in patients who have received mitoxantrone for treatment of cancer.
The safety of mitoxantrone injection in patients with hepatic insufficiency is not established (see CLINICAL PHARMACOLOGY).
Safety for use by routes other than intravenous administration has not been established.
Mitoxantrone is not indicated for subcutaneous, intramuscular, or intra-arterial injection. There have been reports of local/regional neuropathy, some irreversible, following intra-arterial injection.
Mitoxantrone must not be given by intrathecal injection. There have been reports of neuropathy and neurotoxicity, both central and peripheral, following intrathecal injection. These reports have included seizures leading to coma and severe neurologic sequelae, and paralysis with bowel and bladder dysfunction.
Topoisomerase II inhibitors, including mitoxantrone, have been associated with the development of acute leukemia and myclodysplasia.
Functional cardiac changes including decreases in left ventricular ejection fraction (LVEF) and irreversible congestive heart failure can occur with mitoxantrone. Cardiac toxicity may be more common in patients with prior treatment with anthracyclines, prior mediastinal radiotherapy, or with preexisting cardiovascular disease. Such patients should have regular cardiac monitoring of LVEF from the initiation of therapy. Cancer patients who received cumulative doses of 140 mg/m2 either alone or in combination with other chemotherapeutic agents had a cumulative 2.6% probability of clinical congestive heart failure. In comparative oncology trials, the overall cumulative probability rate of moderate or severe decreases in LVEF at this dose was 13%.
Leukemia - Acute congestive heart failure may occasionally occur in patients treated with mitoxantrone for ANLL. In first-line comparative trials of mitoxantrone + cytarabine vs daunorubicin + cytarabine in adult patients with previously untreated ANLL, therapy was associated with congestive heart failure in 6.5% of patients on each arm. A causal relationship between drug therapy and cardiac effects is difficult to establish in this setting since myocardial function is frequently depressed by the anemia, fever and infection, and hemorrhage that often accompany the underlying disease.
Hormone-Refractory Prostate Cancer - Functional cardiac changes such as decreases in LVEF and congestive heart failure may occur in patients with hormone-refractory prostate cancer treated with mitoxantrone. In a randomized comparative trial of mitoxantrone plus low-dose prednisone vs low-dose prednisone, 7 of 128 patients (5.5%) treated with mitoxantrone had a cardiac event defined as any decrease in LVEF below the normal range, congestive heart failure (n = 3), or myocardial ischemia. Two patients had a prior history of cardiac disease. The total mitoxantrone dose administered to patients with cardiac effects ranged from > 48 to 212 mg/m2. Among 112 patients evaluable for safety on the mitoxantrone + hydrocortisone arm of the CALGB trial, 18 patients (19%) had a reduction in cardiac function, 5 patients (5%) had cardiac ischemia, and 2 patients (2%) experienced pulmonary edema. The range of total mitoxantrone doses administered to these patients is not available.
Secondary AML has also been reported in cancer patients treated with anthracyclines. Mitoxantrone is an anthracenedione, a related drug. The occurrence of refractory secondary leukemia is more common when anthracyclines are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated.
Systemic infections should be treated concomitantly with or just prior to commencing therapy with mitoxantrone.
Information for Patients
In leukemia treatment, hyperuricemia may occur as a result of rapid lysis of tumor cells by mitoxantrone. Serum uric acid levels should be monitored and hypouricemic therapy instituted prior to the initiation of antileukemic therapy.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Mutagenesis - Mitoxantrone was clastogenic in the in vivo rat bone marrow assay. Mitoxantrone was also clastogenic in two in vitro assays, it induced DNA damage in primary rat heptocytes and sister chromatid exchanges in Chinese hamster ovary cells. Mitoxantrone was mutagenic in bacterial and mammalian test systems (Ames/Salmonella and E. coli and L5176Y TK+/-mouse lymphoma).
Following concurrent administration of mitoxantrone with corticosteroids, no evidence of drug interactions has been observed.
Teratogenic Effects; Pregnancy Category D
Acute Nonlymphocytic Leukemia - Although definitive studies with mitoxantrone have not been performed in geriatric patients with ANLL, toxicity may be more frequent in the elderly. Elderly patients are more likely to have age-related comorbidities due to disease or disease therapy.
DOSAGE AND ADMINISTRATION
Hormone-Refractory Prostate Cancer: Based on data from two Phase 3 comparative trials of mitoxantrone plus corticosteroids versus corticosteroids alone, the recommended dosage of mitoxantrone is 12 to 14 mg/m2 given as a short intravenous infusion every 21 days.
Combination Initial Therapy for ANLL in Adults: For induction, the recommended dosage is 12 mg/m2 of mitoxantrone daily on Days 1 to 3 given as an intravenous infusion, and 100 mg/m2 of cytarabine for 7 days given as a continuous 24-hour infusion on Days 1 to 7. Most complete remissions will occur following the initial course of induction therapy. In the event of an incomplete antileukemic response, a second induction course may be given. Mitoxantrone should be given for 2 days and cytarabine for 5 days using the same daily dosage levels.
If severe or life-threatening nonhematologic toxicity is observed during the first induction course, the second induction course should be withheld until toxicity resolves.
Consolidation therapy which was used in two large randomized multicenter trials consisted of mitoxantrone, 12 mg/m2 given by intravenous infusion daily on Days 1 and 2 and cytarabine, 100 mg/m2 for 5 days given as a continuous 24-hour infusion on Days 1 to 5. The first course was given approximately 6 weeks after the final induction course, the second was generally administered 4 weeks after the first. Severe myelosuppression occurred. (See CLINICAL PHARMACOLOGY.)
Hepatic Impairment: For patients with hepatic impairment, there is at present no laboratory measurement that allows for dose adjustment recommendations. (See CLINICAL PHARMACOLOGY, Special Populations, Hepatic Impairment.)
The dose of mitoxantrone should be diluted to at least 50 mL with either 0.9% Sodium Chloride Injection or 5% Dextrose Injection. Mitoxantrone may be further diluted into Dextrose 5% in Water, Normal Saline or Dextrose 5% with Normal Saline and used immediately. DO NOT FREEZE.
Mitoxantrone should not be mixed in the same infusion as heparin since a precipitate may form. Because specific compatibility data are not available, it is recommended that mitoxantrone not be mixed in the same infusion with other drugs. The diluted solution should be introduced lowly into the tubing as a freely running intravenous infusion of 0.9% Sodium Chloride Injection or 5% Dextrose Injection over a period of not less than 3 minutes. Unused infusion solutions should be discarded immediately in an appropriate fashion. In the case of multidose use, after penetration of the stopper, the remaining portion of the undiluted mitoxantrone injection should be stored not longer than 7 days between 15° to 25°C (59° to 77°F) or 14 days under refrigeration. DO NOT FREEZE. CONTAINS NO PRESERVATIVE.
Care in the administration of mitoxantrone will reduce the chance of extravasation. Mitoxantrone should be administered into the tubing of a freely running intravenous infusion of sodium chloride injection (0.9%) or 5% dextrose injection. The tubing should be attached to a Butterfly needle or other suitable device and inserted preferably into a large vein. If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage. Care should be taken to avoid extravasation at the infusion site and to avoid contact of mitoxantrone with the skin, mucous membranes or eyes. MITOXANTRONE SHOULD NOT BE ADMINISTERED SUBCUTANEOUSLY. If any signs or symptoms of extravasation have occurred, including burning, pain, pruritis, erythema, swelling, blue discoloration, or ulceration, the injection or infusion should be immediately terminated and restarted in another vein. During intravenous administration of mitoxantrone extravasation may occur with or without an accompanying stinging or burning sensation even if blood returns well on aspiration of the infusion needle. If it is known or suspected that subcutaneous extravasation has occurred, it is recommended that intermittent ice packs be placed over the area of extravasation and that the affected extremity be elevated. Because of the progressive nature of extravasation reactions, the area of injection should be frequently examined and surgery consultation obtained early if there is any sign of a local reaction.
Skin accidentally exposed to mitoxantrone should be rinsed copiously with warm water and if the eyes are involved, standard irrigation techniques should be used immediately. The use of goggles, gloves, and protective gowns is recommended during preparation and administration of the drug.
Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
NDC 55390-083-01; 10 mL/multidose vial (20 mg); individually-boxed
Store between 15° to 25°C (59° to 77°F). DO NOT FREEZE.
1) [PACKAGE INSERT DATA] : mitoxantrone (Mitoxantrone hydrochloride) injection, solution. [Bedford Laboratories] Bedford, OH 44146 Bedford, OH 44146. January 2006.
2) Solimando, Dominic A. Drug Information Handbook for Oncology: A Complete Guide to Combination Chemotherapy Regimens, 8th ed. Hudson, OH: Lexi-Comp, Inc.; 2010.
Procedures for proper handling and disposal: Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publication No. 83-2621. For sale by the Superintendent of Documents, US Government Printing Office, Washington, DC 20402. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA 1985;253:1590. National Study Commission on Cytotoxic Exposure - Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, Sc D, Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115. Clinical Oncological Society of Australia: Guidelines and recommendations for safe handling of antineoplastic agents. Med J Australia 1983; 1:426. Jones RB, et al. Safe handling of chemotherapeutic agents: A report from the Mount Sinai Medical Center. CA Cancer J Clin 1983; 33:258. American Society of Hospital Pharmacists technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm 1990; 47:1033. Controlling occupational exposure to hazardous drugs. Am J Health-System Pharm 1996; 53:1669.