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Medically reviewed by Fedorchenko Olga Valeryevna, PharmD. Last updated on 10.04.2022
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Mitoxantron AWD 25 is indicated for reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis (i.e., patients whose neurologic status is significantly abnormal between relapses). Mitoxantron AWD 25 is not indicated in the treatment of patients with primary progressive multiple sclerosis.
The clinical patterns of multiple sclerosis in the studies were characterized as follows: secondary progressive and progressive relapsing disease were characterized by gradual increasing disability with or without superimposed clinical relapses, and worsening relapsing-remitting disease was characterized by clinical relapses resulting in a step-wise worsening of disability.
Mitoxantron AWD 25 in combination with corticosteroids is indicated as initial chemotherapy for the treatment of patients with pain related to advanced hormone-refractory prostate cancer.
Mitoxantron AWD 25 in combination with other approved drug(s) is indicated in the initial therapy of acute nonlymphocytic leukemia (ANLL) in adults. This category includes myelogenous, promyelocytic, monocytic, and erythroid acute leukemias.
(See also WARNINGS)
Multiple Sclerosis
The recommended dosage of Mitoxantron AWD 25 is 12 mg/m² given as a short (approximately 5 to 15 minutes) intravenous infusion every 3 months. Left ventricular ejection fraction (LVEF) should be evaluated by echocardiogram or MUGA prior to administration of the initial dose of Mitoxantron AWD 25 and all subsequent doses. In addition, LVEF evaluations are recommended if signs or symptoms of congestive heart failure develop at any time during treatment with Mitoxantron AWD 25 Mitoxantron AWD 25 should not be administered to multiple sclerosis patients with an LVEF < 50%, with a clinically significant reduction in LVEF, or to those who have received a cumulative lifetime dose of ≥ 140 mg/m². Complete blood counts, including platelets, should be monitored prior to each course of Mitoxantron AWD 25 and in the event that signs or symptoms of infection develop. Mitoxantron AWD 25 generally should not be administered to multiple sclerosis patients with neutrophil counts less than 1500 cells/mm³. Liver function tests should also be monitored prior to each course. Mitoxantron AWD 25 therapy in multiple sclerosis patients with abnormal liver function tests is not recommended because Mitoxantron AWD 25 clearance is reduced by hepatic impairment and no laboratory measurement can predict drug clearance and dose adjustments.
Women with multiple sclerosis who are biologically capable of becoming pregnant, even if they are using birth control, should have a pregnancy test, and the results should be known, before receiving each dose of Mitoxantron AWD 25 (see WARNINGS, Pregnancy).
Hormone-Refractory Prostate Cancer
Based on data from two Phase 3 comparative trials of Mitoxantron AWD 25 plus corticosteroids versus corticosteroids alone, the recommended dosage of Mitoxantron AWD 25 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 Mitoxantron AWD 25 daily on Days 1-3 given as an intravenous infusion, and 100 mg/m² of cytarabine for 7 days given as a continuous 24-hour infusion on Days 1-7.
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. Mitoxantron AWD 25 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 Mitoxantron AWD 25, 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 1-5. 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)
Preparation and Administration Precautions
Mitoxantron AWD 25 CONCENTRATE MUST BE DILUTED PRIOR TO USE.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
The dose of Mitoxantron AWD 25 should be diluted to at least 50 mL with either 0.9% Sodium Chloride Injection (USP) or 5% Dextrose Injection (USP). Mitoxantron AWD 25 may be further diluted into Dextrose 5% in Water, Normal Saline or Dextrose 5% with Normal Saline and used immediately. DO NOT FREEZE.
Mitoxantron AWD 25 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 Mitoxantron AWD 25 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 (USP) or 5% Dextrose Injection (USP) 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 Mitoxantron AWD 25 concentrate should be stored not longer than 7 days between 15°-25°C (59°-77°F) or 14 days under refrigeration. DO NOT FREEZE. CONTAINS NO PRESERVATIVE.
Care in the administration of Mitoxantron AWD 25 will reduce the chance of extravasation. Mitoxantron AWD 25 should be administered into the tubing of a freely running intravenous infusion of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. 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 Mitoxantron AWD 25 with the skin, mucous membranes, or eyes. Mitoxantron AWD 25 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 Mitoxantron AWD 25 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 Mitoxantron AWD 25 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.1-4 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
Mitoxantron AWD 25 is contraindicated in patients who have demonstrated prior hypersensitivity to it.
WARNINGS
WHEN Mitoxantron AWD 25 IS USED IN HIGH DOSES ( > 14 mg/m²/d x 3 days) SUCH AS INDICATED FOR THE TREATMENT OF LEUKEMIA, SEVERE MYELOSUPPRESSION WILL OCCUR. THEREFORE, IT IS RECOMMENDED THAT Mitoxantron AWD 25 BE ADMINISTERED ONLY BY PHYSICIANS EXPERIENCED IN THE CHEMOTHERAPY OF THIS DISEASE. LABORATORY AND SUPPORTIVE SERVICES MUST BE AVAILABLE FOR HEMATOLOGIC AND CHEMISTRY MONITORING AND ADJUNCTIVE THERAPIES, INCLUDING ANTIBIOTICS. BLOOD AND BLOOD PRODUCTS MUST BE AVAILABLE TO SUPPORT PATIENTS DURING THE EXPECTED PERIOD OF MEDULLARY HYPOPLASIA AND SEVERE MYELOSUPPRESSION. PARTICULAR CARE SHOULD BE GIVEN TO ASSURING FULL HEMATOLOGIC RECOVERY BEFORE UNDERTAKING CONSOLIDATION THERAPY (IF THIS TREATMENT IS USED) AND PATIENTS SHOULD BE MONITORED CLOSELY DURING THIS PHASE. Mitoxantron AWD 25 ADMINISTERED AT ANY DOSE CAN CAUSE MYELOSUPPRESSION.
General
Patients with preexisting myelosuppression as the result of prior drug therapy should not receive Mitoxantron AWD 25 unless it is felt that the possible benefit from such treatment warrants the risk of further medullary suppression.
The safety of Mitoxantron AWD 25 (mitoxantrone for injection concentrate) in patients with hepatic insufficiency is not established (see CLINICAL PHARMACOLOGY).
Safety for use by routes other than intravenous administration has not been established.
Mitoxantron AWD 25 is not indicated for subcutaneous, intramuscular, or intra-arterial injection. There have been reports of local/regional neuropathy, some irreversible, following intra-arterial injection.
Mitoxantron AWD 25 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 Mitoxantron AWD 25, have been associated with the development of secondary acute myeloid leukemia and myelosuppression.
Cardiac Effects
Because of the possible danger of cardiac effects in patients previously treated with daunorubicin or doxorubicin, the benefit-to-risk ratio of Mitoxantron AWD 25 therapy in such patients should be determined before starting therapy.
Functional cardiac changes including decreases in left ventricular ejection fraction (LVEF) and irreversible congestive heart failure can occur with Mitoxantron AWD 25. 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%.
Multiple Sclerosis
Changes in cardiac function may occur in patients with multiple sclerosis treated with Mitoxantron AWD 25. In one controlled trial (Study 1, see Clinical Trials, Multiple Sclerosis), two patients (2%) of 127 receiving Mitoxantron AWD 25, one receiving a 5 mg/m² dose and the other receiving the 12 mg/m² dose, had LVEF values that decreased to below 50%. An additional patient receiving 12 mg/m², who did not have LVEF measured, had a decrease in another echocardiographic measurement of ventricular function (fractional shortening) that led to discontinuation from the trial (see ADVERSE REACTIONS, Multiple Sclerosis). There were no reports of congestive heart failure in either controlled trial.
MS patients should be assessed for cardiac signs and symptoms by history, physical examination, ECG, and quantitative LVEF evaluation using appropriate methodology (ex. Echocardiogram, MUGA, MRI, etc.) prior to the start of Mitoxantron AWD 25 therapy. MS patients with a baseline LVEF below the lower limit of normal should not be treated with Mitoxantron AWD 25. Subsequent LVEF and ECG evaluations are recommended if signs or symptoms of congestive heart failure develop and prior to every dose administered to MS patients. Mitoxantron AWD 25 should not be administered to MS patients who experience a reduction in LVEF to below the lower limit of normal, to those who experience a clinically significant reduction in LVEF, or to those who have received a cumulative lifetime dose of 140 mg/m². MS patients should have yearly quantitative LVEF evaluation after stopping Mitoxantron AWD 25 to monitor for late-occurring cardiotoxicity.
Leukemia
Acute congestive heart failure may occasionally occur in patients treated with Mitoxantron AWD 25 for ANLL. In first-line comparative trials of Mitoxantron AWD 25 + 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 Mitoxantron AWD 25. In a randomized comparative trial of Mitoxantron AWD 25 plus low-dose prednisone vs low-dose prednisone, 7 of 128 patients (5.5 %) treated with Mitoxantron AWD 25 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 Mitoxantron AWD 25 dose administered to patients with cardiac effects ranged from > 48 to 212 mg/m².
Among 112 patients evaluable for safety on the Mitoxantron AWD 25 + 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 Mitoxantron AWD 25 doses administered to these patients is not available.
Pregnancy
Mitoxantron AWD 25 may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant. Mitoxantrone is considered a potential human teratogen because of its mechanism of action and the developmental effects demonstrated by related agents. Treatment of pregnant rats during the organogenesis period of gestation was associated with fetal growth retardation at doses > 0.1 mg/kg/day (0.01 times the recommended human dose on a mg/m² basis). When pregnant rabbits were treated during organogenesis, an increased incidence of premature delivery was observed at doses > 0.1 mg/kg/day (0.01 times the recommended human dose on a mg/m² basis). No teratogenic effects were observed in these studies, but the maximum doses tested were well below the recommended human dose (0.02 and 0.05 times in rats and rabbits, respectively, on a mg/m² basis). There are no adequate and well-controlled studies in pregnant women. Women with multiple sclerosis who are biologically capable of becoming pregnant should have a pregnancy test prior to each dose, and the results should be known prior to administration of the drug. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to the fetus.
Secondary Leukemia
Mitoxantron AWD 25® therapy increases the risk of developing secondary leukemia in patients with cancer and in patients with multiple sclerosis.
In a study of patients with prostate cancer, acute myeloid leukemia occurred in 1% (5/487) of mitoxantrone-treated patients versus no cases in the control group (0/496) not receiving mitoxantrone at 4.7 years followup.
In a prospective, open-label, tolerability and safety monitoring study of Mitoxantron AWD 25® treated MS patients followed for up to five years (median of 2.8 years), leukemia occurred in 0.6% (3/509) of patients. Publications describe leukemia risks of 0.25% to 2.8% in cohorts of patients with MS treated with Mitoxantron AWD 25® and followed for varying periods of time. This leukemia risk exceeds the risk of leukemia in the general population. The most commonly reported types were acute promyelocytic leukemia and acute myelocytic leukemia.
In 1774 patients with breast cancer who received Mitoxantron AWD 25 concomitantly with other cytotoxic agents and radiotherapy, the cumulative risk of developing treatment-related acute myeloid leukemia was estimated as 1.1% and 1.6% at 5 and 10 years, respectively. The second largest report involved 449 patients with breast cancer treated with Mitoxantron AWD 25, usually in combination with radiotherapy and/or other cytotoxic agents. In this study, the cumulative probability of developing secondary leukemia was estimated to be 2.2% at 4 years.
Secondary acute myeloid leukemia has also been reported in cancer patients treated with anthracyclines. Mitoxantron AWD 25 is an anthracenedione, a related drug. The occurrence of 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.
Symptoms of acute leukemia may include excessive bruising, bleeding, and recurrent infections.
PRECAUTIONS
General
Therapy with Mitoxantron AWD 25 should be accompanied by close and frequent monitoring of hematologic and chemical laboratory parameters, as well as frequent patient observation.
Systemic infections should be treated concomitantly with or just prior to commencing therapy with Mitoxantron AWD 25.
Information for Patients
See FDA-approved patient labeling (Medication Guide).
Inform patients of the availability of a Medication Guide and instruct them to read the Medication Guide prior to initiating treatment with Mitoxantron AWD 25 and prior to each infusion. Review the Mitoxantron AWD 25 Medication Guide with every patient prior to initiation of treatment and periodically during treatment. Instruct patients that Mitoxantron AWD 25 should be taken only as prescribed.
Advise patients that Mitoxantron AWD 25 can cause myelosuppression and inform patients of the signs and symptoms of myelosuppression. Advise patients that Mitoxantron AWD 25 can cause congestive heart failure that may lead to death even in people who have never had heart problems before, and inform patients of the signs and symptoms of congestive heart failure. Advise patients receiving Mitoxantron AWD 25 to treat multiple sclerosis that they should receive cardiac monitoring prior to each Mitoxantron AWD 25 dose and yearly after stopping Mitoxantron AWD 25.
Mitoxantron AWD 25 may impart a blue-green color to the urine for 24 hours after administration, and patients should be advised to expect this during therapy. Bluish discoloration of the sclera may also occur.
Laboratory Tests
A complete blood count, including platelets, should be obtained prior to each course of Mitoxantron AWD 25 and in the event that signs and symptoms of infection develop. Liver function tests should also be performed prior to each course of therapy. Mitoxantron AWD 25 therapy in multiple sclerosis patients with abnormal liver function tests is not recommended because Mitoxantron AWD 25 clearance is reduced by hepatic impairment and no laboratory measurement can predict drug clearance and dose adjustments.
In leukemia treatment, hyperuricemia may occur as a result of rapid lysis of tumor cells by Mitoxantron AWD 25. Serum uric acid levels should be monitored and hypouricemic therapy instituted prior to the initiation of antileukemic therapy.
Women with multiple sclerosis who are biologically capable of becoming pregnant, even if they are using birth control, should have a pregnancy test, and the results should be known, before receiving each dose of Mitoxantron AWD 25 (see WARNINGS, Pregnancy).
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Intravenous treatment of rats and mice, once every 21 days for 24 months, with Mitoxantron AWD 25 resulted in an increased incidence of fibroma and external auditory canal tumors in rats at a dose of 0.03 mg/kg (0.02 fold the recommended human dose, on a mg/m² basis), and hepatocellular adenoma in male mice at a dose of 0.1 mg/kg (0.03 fold the recommended human dose, on a mg/m² basis). Intravenous treatment of rats, once every 21 days for 12 months with Mitoxantron AWD 25 resulted in an increased incidence of external auditory canal tumors in rats at a dose of 0.3 mg/kg (0.15 fold the recommended human dose, on a mg/m² basis).
Mutagenesis
Mitoxantron AWD 25 was clastogenic in the in vivo rat bone marrow assay. Mitoxantron AWD 25 was also clastogenic in two in vitro assays; it induced DNA damage in primary rat hepatocytes and sister chromatid exchanges in Chinese hamster ovary cells. Mitoxantron AWD 25 was mutagenic in bacterial and mammalian test systems (Ames/Salmonella and E. coli and L5178Y TK+/-mouse lymphoma).
Special Populations
Hepatic Impairment
Patients with multiple sclerosis who have hepatic impairment should ordinarily not be treated with Mitoxantron AWD 25. Mitoxantron AWD 25 should be administered with caution to other patients with hepatic impairment. In patients with severe hepatic impairment, the AUC is more than three times greater than the value observed in patients with normal hepatic function.
Pregnancy
Pregnancy Category D (see WARNINGS).
Nursing Mothers
Mitoxantron AWD 25 is excreted in human milk and significant concentrations (18 ng/mL) have been reported for 28 days after the last administration. Because of the potential for serious adverse reactions in infants from Mitoxantron AWD 25, breast feeding should be discontinued before starting treatment.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Multiple Sclerosis: Clinical studies of Mitoxantron AWD 25 did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
Hormone-Refractory Prostate Cancer: One hundred forty-six patients aged 65 and over and 52 younger patients ( < 65 years) have been treated with Mitoxantron AWD 25 in controlled clinical studies. These studies did not include sufficient numbers of younger patients to determine whether they respond differently from older patients. However, greater sensitivity of some older individuals cannot be ruled out.
Acute Nonlymphocytic Leukemia: Although definitive studies with Mitoxantron AWD 25 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.
Multiple Sclerosis
Mitoxantron AWD 25 has been administered to 149 patients with multiple sclerosis in two randomized clinical trials, including 21 patients who received Mitoxantron AWD 25 in combination with corticosteroids.
In Study 1, the proportion of patients who discontinued treatment due to an adverse event was 9.7% (n = 6) in the 12 mg/m² Mitoxantron AWD 25 arm (leukopenia, depression, decreased LV function, bone pain and emesis, renal failure, and one discontinuation to prevent future complications from repeated urinary tract infections) compared to 3.1% (n = 2) in the placebo arm (hepatitis and myocardial infarction). The following clinical adverse experiences were significantly more frequent in the Mitoxantron AWD 25 groups: nausea, alopecia, urinary tract infection, and menstrual disorders, including amenorrhea.
Table 4a summarizes clinical adverse events of all intensities occurring in ≥ 5% of patients in either dose group of Mitoxantron AWD 25 and that were numerically greater on drug than on placebo in Study 1. The majority of these events were of mild to moderate intensity, and nausea was the only adverse event that occurred with severe intensity in more than one patient (three patients [5%] in the 12 mg/m² group). Of note, alopecia consisted of mild hair thinning.
Two of the 127 patients treated with Mitoxantron AWD 25 in Study 1 had decreased LVEF to below 50% at some point during the 2 years of treatment. An additional patient receiving 12 mg/m² did not have LVEF measured, but had another echocardiographic measure of ventricular function (fractional shortening) that led to discontinuation from the study.
Table 4a : Adverse Events of Any Intensity Occurring in ≥ 5% of Patients on Any Dose of Mitoxantron AWD 25 and That Were Numerically Greater Than in the Placebo Group Study 1
| Preferred Term | Percent of Patients | ||
| Placebo (N = 64) | 5 mg/m² Mitoxantron AWD 25 (N = 65) | 12 mg/m² Mitoxantron AWD 25 (N = 62) | |
| Nausea | 20 | 55 | 76 |
| Alopecia | 31 | 38 | 61 |
| Menstrual disorder * | 26 | 51 | 61 |
| Amenorrhea * | 3 | 28 | 43 |
| Upper respiratory tract infection | 52 | 51 | 53 |
| Urinary tract infection | 13 | 29 | 32 |
| Stomatitis | 8 | 15 | 19 |
| Arrhythmia | 8 | 6 | 18 |
| Diarrhea | 11 | 25 | 16 |
| Urine abnormal | 6 | 5 | 11 |
| ECG abnormal | 3 | 5 | 11 |
| Constipation | 6 | 14 | 10 |
| Back pain | 5 | 6 | 8 |
| Sinusitis | 2 | 3 | 6 |
| Headache | 5 | 6 | 6 |
| * Percentage of female patients. |
The proportion of patients experiencing any infection during Study 1 was 67% for the placebo group, 85% for the 5 mg/m² group, and 81% for the 12 mg/m² group. However, few of these infections required hospitalization: one placebo patient (tonsillitis), three 5 mg/m² patients (enteritis, urinary tract infection, viral infection), and four 12 mg/m² patients (tonsillitis, urinary tract infection [two], endometritis).
Table 4b summarizes laboratory abnormalities that occurred in ≥ 5% of patients in either Mitoxantron AWD 25 dose group, and that were numerically more frequent than in the placebo group.
Table 4b : Laboratory Abnormalities Occurring in ≥ 5% of Patients* on Either Dose of Mitoxantron AWD 25 and That Were More Frequent Than in the Placebo Group Study 1
| Event | Percent of Patients | ||
| Placebo (N = 64) | 5 mg/m² Mitoxantron AWD 25 (N = 65) | 12 mg/m² Mitoxantron AWD 25 (N = 62) | |
| Leukopenia a | 0 | 9 | 19 |
| Gamma-GT increased | 3 | 3 | 15 |
| SGOT increased | 8 | 9 | 8 |
| Granulocytopenia b | 2 | 6 | 6 |
| Anemia | 2 | 9 | 6 |
| SGPT increased | 3 | 6 | 5 |
| *Assessed using World Health Organization (WHO) toxicity criteria. < 4000 cells/mm³ < 2000 cells/mm³ |
There was no difference among treatment groups in the incidence or severity of hemorrhagic events.
In Study 2, Mitoxantron AWD 25 was administered once a month. Clinical adverse events most frequently reported in the Mitoxantron AWD 25 group included amenorrhea (53% of female patients), alopecia (33% of patients), nausea (29% of patients), and asthenia (24% of patients). Tables 5a and 5b respectively summarize adverse events and laboratory abnormalities occurring in > 5% of patients in the Mitoxantron AWD 25 group and numerically more frequent than in the control group.
Table 5a : Adverse Events of Any Intensity Occurring in > 5% of Patients* in the Mitoxantron AWD 25 Group and Numerically More Frequent Than in the Control Group Study 2
| Event | Percent of Patients | |
| MP (n = 21) | N + MP (n = 21) | |
| Amenorrhea a | 0 | 53 |
| Alopecia | 0 | 33 |
| Nausea | 0 | 29 |
| Asthenia | 0 | 24 |
| Pharyngitis/throat infection | 5 | 19 |
| Gastralgia/stomach burn/epigastric pain | 5 | 14 |
| Aphthosis | 0 | 10 |
| Cutaneous mycosis | 0 | 10 |
| Rhinitis | 0 | 10 |
| Menorrhagia a | 0 | 7 |
| N = Mitoxantron AWD 25, MP = methylprednisolone *Assessed using National Cancer Institute (NCI) common toxicity criteria. a Percentage of female patients. |
Table 5b : Laboratory Abnormalities Occurring in > 5% of Patients* in the Mitoxantron AWD 25 Group and Numerically More Frequent Than in the Control Group Study 2
| Event | Percent of Patients | |
| MP (n = 21) | N + MP (n = 21) | |
| WBC low a | 14 | 100 |
| ANC low b | 10 | 100 |
| Lymphocytes low | 43 | 95 |
| Hemoglobin low | 48 | 43 |
| Platelets low c | 0 | 33 |
| SGOT high | 5 | 15 |
| SGPT high | 10 | 15 |
| Glucose high | 5 | 10 |
| Potassium low | 0 | 10 |
| N = Mitoxantron AWD 25, MP = methylprednisolone. *Assessed using National Cancer Institute (NCI) common toxicity criteria. a < 4000 cells/mm3 b < 1500 cells/mm3 c < 100,000 cells/mm3 |
Leukopenia and neutropenia were reported in the N +MP group (see Table 5b).
Neutropenia occurred within 3 weeks after Mitoxantron AWD 25 administration and was always reversible. Only mild to moderate intensity infections were reported in 9 of 21 patients in the N +MP group and in 3 of 21 patients in the MP group; none of these required hospitalization. There was no difference among treatment groups in the incidence or severity of hemorrhagic events. There were no withdrawals from Study 2 for safety reasons.
Leukemia
Mitoxantron AWD 25 has been studied in approximately 600 patients with acute nonlymphocytic leukemia (ANLL). Table 6 represents the adverse reaction experience in the large U.S. comparative study of mitoxantrone + cytarabine vs daunorubicin + cytarabine. Experience in the large international study was similar. A much wider experience in a variety of other tumor types revealed no additional important reactions other than cardiomyopathy (see WARNINGS). It should be appreciated that the listed adverse reaction categories include overlapping clinical symptoms related to the same condition, e.g., dyspnea, cough and pneumonia. In addition, the listed adverse reactions cannot all necessarily be attributed to chemotherapy as it is often impossible to distinguish effects of the drug and effects of the underlying disease. It is clear, however, that the combination of Mitoxantron AWD 25 + cytarabine was responsible for nausea and vomiting, alopecia, mucositis/stomatitis, and myelosuppression.
Table 6 summarizes adverse reactions occurring in patients treated with Mitoxantron AWD 25 + cytarabine in comparison with those who received daunorubicin + cytarabine for therapy of ANLL in a large multicenter randomized prospective U.S. trial.
Adverse reactions are presented as major categories and selected examples of clinically significant subcategories.
Table 6 : Adverse Events Occurring in ANLL Patients Receiving Mitoxantron AWD 25 or Daunorubicin
| Event | Induction [% pts entering induction] | Consolidation [% pts entering induction] | ||
| NOV N = 102 | DAUN N = 102 | NOV N = 55 | DAUN N = 49 | |
| Cardiovascular | 26 | 28 | 11 | 24 |
| CHF | 5 | 6 | 0 | 0 |
| Arrhythmias | 3 | 3 | 4 | 4 |
| Bleeding | 37 | 41 | 20 | 6 |
| GI | 16 | 12 | 2 | 2 |
| Petechiae/ecchymoses | 7 | 9 | 11 | 2 |
| Gastrointestinal | 88 | 85 | 58 | 51 |
| Nausea/vomiting | 72 | 67 | 31 | 31 |
| Diarrhea | 47 | 47 | 18 | 8 |
| Abdominal pain | 15 | 9 | 9 | 4 |
| Mucositis/stomatitis | 29 | 33 | 18 | 8 |
| Hepatic | 10 | 11 | 14 | 2 |
| Jaundice | 3 | 8 | 7 | 0 |
| Infections | 66 | 73 | 60 | 43 |
| UTI | 7 | 2 | 7 | 2 |
| Pneumonia | 9 | 7 | 9 | 0 |
| Sepsis | 34 | 36 | 31 | 18 |
| Fungal infections | 15 | 13 | 9 | 6 |
| Renal failure | 8 | 6 | 0 | 2 |
| Fever | 78 | 71 | 24 | 18 |
| Alopecia | 37 | 40 | 22 | 16 |
| Pulmonary | 43 | 43 | 24 | 14 |
| Cough | 13 | 9 | 9 | 2 |
| Dyspnea | 18 | 20 | 6 | 0 |
| CNS | 30 | 30 | 34 | 35 |
| Seizures | 4 | 4 | 2 | 8 |
| Headache | 10 | 9 | 13 | 8 |
| Eye | 7 | 6 | 2 | 4 |
| Conjunctivitis | 5 | 1 | 0 | 0 |
| NOV = Mitoxantron AWD 25, DAUN = daunorubicin. |
Hormone-Refractory Prostate Cancer
Detailed safety information is available for a total of 353 patients with hormone-refractory prostate cancer treated with Mitoxantron AWD 25, including 274 patients who received Mitoxantron AWD 25 in combination with corticosteroids.
Table 7 summarizes adverse reactions of all grades occurring in ≥ 5% of patients in Trial CCI-NOV22.
Table 7 : Adverse Events of Any Intensity Occurring in ≥ 5% of Patients Trial CCI-NOV22
| Event | N + P (n = 80) % | P (n = 81) % |
| Nausea | 61 | 35 |
| Fatigue | 39 | 14 |
| Alopecia | 29 | 0 |
| Anorexia | 25 | 6 |
| Constipation | 16 | 14 |
| Dyspnea | 11 | 5 |
| Nail bed changes | 11 | 0 |
| Edema | 10 | 4 |
| Systemic infection | 10 | 7 |
| Mucositis | 10 | 0 |
| UTI | 9 | 4 |
| Emesis | 9 | 5 |
| Pain | 8 | 9 |
| Fever | 6 | 3 |
| Hemorrhage/bruise | 6 | 1 |
| Anemia | 5 | 3 |
| Cough | 5 | 0 |
| Decreased LVEF | 5 | 0 |
| Anxiety/depression | 5 | 3 |
| Dyspepsia | 5 | 6 |
| Skin infection | 5 | 3 |
| Blurred vision | 3 | 5 |
| N = Mitoxantron AWD 25, P = prednisone. |
No nonhematologic adverse events of Grade 3/4 were seen in > 5% of patients.
Table 8 summarizes adverse events of all grades occurring in ≥ 5% of patients in Trial CALGB 9182.
Table 8 : Adverse Events of Any Intensity Occurring in ≥ 5 % of Patients Trial CALGB 9182
| Event | N + H (n = 112) | H (n = 113) | ||
| n | % | n | % | |
| Decreased WBC | 96 | 87 | 4 | 4 |
| Abnormal granulocytes/bands | 88 | 79 | 3 | 3 |
| Decreased hemoglobin | 83 | 75 | 42 | 39 |
| Abnormal lymphocytes count | 78 | 72 | 27 | 25 |
| Pain | 45 | 41 | 44 | 39 |
| Abnormal platelet count | 43 | 39 | 8 | 7 |
| Abnormal alkaline phosphatase | 41 | 37 | 42 | 38 |
| Malaise/fatigue | 37 | 34 | 16 | 14 |
| Hyperglycemia | 33 | 31 | 32 | 30 |
| Edema | 31 | 30 | 15 | 14 |
| Nausea | 28 | 26 | 9 | 8 |
| Anorexia | 24 | 22 | 16 | 14 |
| Abnormal BUN | 24 | 22 | 22 | 20 |
| Abnormal Transaminase | 22 | 20 | 16 | 14 |
| Alopecia | 20 | 20 | 1 | 1 |
| Abnormal Cardiac function | 19 | 18 | 0 | 0 |
| Infection | 18 | 17 | 4 | 4 |
| Weight loss | 18 | 17 | 13 | 12 |
| Dyspnea | 16 | 15 | 9 | 8 |
| Diarrhea | 16 | 14 | 4 | 4 |
| Fever in absence of infection | 15 | 14 | 7 | 6 |
| Weight gain | 15 | 14 | 16 | 15 |
| Abnormal creatinine | 14 | 13 | 11 | 10 |
| Other gastrointestinal | 13 | 14 | 11 | 11 |
| Vomiting | 12 | 11 | 6 | 5 |
| Other neurologic | 11 | 11 | 5 | 5 |
| Hypocalcemia | 10 | 10 | 5 | 5 |
| Hematuria | 9 | 11 | 5 | 6 |
| Hyponatremia | 9 | 9 | 3 | 3 |
| Sweats | 9 | 9 | 2 | 2 |
| Other liver | 8 | 8 | 8 | 8 |
| Stomatitis | 8 | 8 | 1 | 1 |
| Cardiac dysrhythmia | 7 | 7 | 3 | 3 |
| Hypokalemia | 7 | 7 | 4 | 4 |
| Neuro/constipation | 7 | 7 | 2 | 2 |
| Neuro/motor disorder | 7 | 7 | 3 | 3 |
| Neuro/mood disorder | 6 | 6 | 2 | 2 |
| Skin disorder | 6 | 6 | 4 | 4 |
| Cardiac ischemia | 5 | 5 | 1 | 1 |
| Chills | 5 | 5 | 0 | 0 |
| Hemorrhage | 5 | 5 | 3 | 3 |
| Myalgias/arthralgias | 5 | 5 | 3 | 3 |
| Other kidney/bladder | 5 | 5 | 3 | 3 |
| Other endocrine | 5 | 6 | 3 | 4 |
| Other pulmonary | 5 | 5 | 3 | 3 |
| Hypertension | 4 | 4 | 5 | 5 |
| Impotence/libido | 4 | 7 | 2 | 3 |
| Proteinuria | 4 | 6 | 2 | 3 |
| Sterility | 3 | 5 | 2 | 3 |
| N= Mitoxantron AWD 25, H= hydrocortisone |
General
Allergic Reaction
Hypotension, urticaria, dyspnea, and rashes have been reported occasionally. Anaphylaxis/anaphylactoid reactions have been reported rarely.
Cutaneous
Extravasation at the infusion site has been reported, which may result in erythema, swelling, pain, burning, and/or blue discoloration of the skin. Extravasation can result in tissue necrosis with resultant need for debridement and skin grafting. Phlebitis has also been reported at the site of the infusion.
Hematologic
Topoisomerase II inhibitors, including Mitoxantron AWD 25, in combination with other antineoplastic agents or alone, have been associated with the development of acute leukemia (see WARNINGS).
Leukemia
Myelosuppression is rapid in onset and is consistent with the requirement to produce significant marrow hypoplasia in order to achieve a response in acute leukemia. The incidences of infection and bleeding seen in the U.S. trial are consistent with those reported for other standard induction regimens.
Hormone-Refractory Prostate Cancer
In a randomized study where dose escalation was required for neutrophil counts greater than 1000/mm³, Grade 4 neutropenia (ANC < 500 /mm³) was observed in 54% of patients treated with Mitoxantron AWD 25 + low-dose prednisone. In a separate randomized trial where patients were treated with 14 mg/m², Grade 4 neutropenia in 23% of patients treated with Mitoxantron AWD 25 + hydrocortisone was observed. Neutropenic fever/infection occurred in 11% and 10% of patients receiving Mitoxantron AWD 25 + corticosteroids, respectively, on the two trials. Platelets < 50,000/mm³ were noted in 4% and 3% of patients receiving Mitoxantron AWD 25 + corticosteroids on these trials, and there was one patient death on Mitoxantron AWD 25 + hydrocortisone due to intracranial hemorrhage after a fall.
Gastrointestinal
Nausea and vomiting occurred acutely in most patients and may have contributed to reports of dehydration, but were generally mild to moderate and could be controlled through the use of antiemetics. Stomatitis/mucositis occurred within 1 week of therapy.
Cardiovascular
Congestive heart failure, tachycardia, EKG changes including arrhythmias, chest pain, and asymptomatic decreases in left ventricular ejection fraction have occurred. (See WARNINGS)
Pulmonary
Interstitial pneumonitis has been reported in cancer patients receiving combination chemotherapy that included Mitoxantron AWD 25.
There is no known specific antidote for Mitoxantron AWD 25. Accidental overdoses have been reported. Four patients receiving 140-180 mg/m² as a single bolus injection died as a result of severe leukopenia with infection. Hematologic support and antimicrobial therapy may be required during prolonged periods of severe myelosuppression.
Although patients with severe renal failure have not been studied, Mitoxantron AWD 25 is extensively tissue bound and it is unlikely that the therapeutic effect or toxicity would be mitigated by peritoneal or hemodialysis.
Pharmacokinetics of mitoxantrone in patients following a single intravenous administration of Mitoxantron AWD 25® can be characterized by a three-compartment model. The mean alpha half-life of mitoxantrone is 6 to 12 minutes, the mean beta half-life is 1.1 to 3.1 hours and the mean gamma (terminal or elimination) half-life is 23 to 215 hours (median approximately 75 hours). Pharmacokinetic studies have not been performed in humans receiving multiple daily dosing. Distribution to tissues is extensive: steady-state volume of distribution exceeds 1,000 L/m². Tissue concentrations of mitoxantrone appear to exceed those in the blood during the terminal elimination phase. In the healthy monkey, distribution to brain, spinal cord, eye, and spinal fluid is low.
In patients administered 15-90 mg/m² of Mitoxantron AWD 25 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 26455 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
Mitoxantrone is excreted in urine and feces as either unchanged drug or as inactive metabolites. In human studies, 11% and 25% of the dose were recovered in urine and feces, respectively, as either parent drug or metabolite during the 5-day period following drug administration. Of the material recovered in urine, 65% was unchanged drug. The remaining 35% was composed of monocarboxylic and dicarboxylic acid derivatives and their glucuronide conjugates. The pathways leading to the metabolism of Mitoxantron AWD 25 have not been elucidated.
