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Mitoxantrone
Overview
What is Mitoxantrone?
Mitoxantrone Injection, USP (concentrate) is a synthetic antineoplastic anthracenedione for intravenous use. The molecular formula is CHNO∙2HCl and the molecular weight is 517.41. It is supplied as a concentrate that MUST BE DILUTED PRIOR TO INJECTION. The concentrate is a sterile, nonpyrogenic, dark blue aqueous solution containing mitoxantrone hydrochloride equivalent to 2 mg/mL mitoxantrone free base, with sodium chloride (0.80% w/v), sodium metabisulfite (0.01% w/v), sodium acetate (0.005% w/v), acetic acid (0.046% w/v), and Water for Injection, USP as inactive ingredients. The solution has a pH of 3.0 to 4.5 and contains 0.14 mEq of sodium per mL. The product does not contain preservatives. The chemical name is 1, 4-dihydroxy-5, 8-bis[[2-[(2-hydroxyethyl) amino]ethyl]amino]-9,10- anthracenedione dihydrochloride and the structural formula is:
What does Mitoxantrone look like?
What are the available doses of Mitoxantrone?
Sorry No records found.
What should I talk to my health care provider before I take Mitoxantrone?
Sorry No records found
How should I use Mitoxantrone?
Mitoxantrone 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). Mitoxantrone 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.
Mitoxantrone in combination with corticosteroids is indicated as initial chemotherapy for the treatment of patients with pain related to advanced hormone-refractory prostate cancer.
Mitoxantrone 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.
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What interacts with Mitoxantrone?
Mitoxantrone is contraindicated in patients who have demonstrated prior hypersensitivity to it.
What are the warnings of Mitoxantrone?
Research
WHEN MITOXANTRONE IS USED IN HIGH DOSES (> 14 mg/m/d × 3 days) SUCH AS INDICATED FOR THE TREATMENT OF LEUKEMIA, SEVERE MYELOSUPPRESSION WILL OCCUR. THEREFORE, IT IS RECOMMENDED THAT MITOXANTRONE 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. MITOXANTRONE ADMINISTERED AT ANY DOSE CAN CAUSE MYELOSUPPRESSION.
CONTAINS SODIUM METABISULFITE, A SULFITE THAT MAY CAUSE ALLERGIC-TYPE REACTIONS INCLUDING ANAPHYLACTIC SYMPTOMS AND LIFE-THREATENING OR LESS SEVERE ASTHMATIC EPISODES IN CERTAIN SUSCEPTIBLE PEOPLE. THE OVERALL PREVALENCE OF SULFITE SENSITIVITY IN THE GENERAL POPULATION IS UNKNOWN AND PROBABLY LOW. SULFITE SENSITIVITY IS SEEN MORE FREQUENTLY IN ASTHMATIC THAN IN NONASTHMATIC PEOPLE.
General
Patients with preexisting myelosuppression as the result of prior drug therapy should not receive mitoxantrone unless it is felt that the possible benefit from such treatment warrants the risk of further medullary suppression.
The safety of Mitoxantrone Injection, USP (concentrate) in patients with hepatic insufficiency is not established (see ).
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 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 mitoxantrone 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 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/m 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
Array
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
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Pregnancy
Mitoxantrone 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/m 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/m 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/m 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
Mitoxantrone 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 mitoxantrone 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 risk of 0.25% to 2.8% in cohorts of patients with MS treated with mitoxantrone 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 mitoxantrone 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 mitoxantrone, 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. Mitoxantrone 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.
What are the precautions of Mitoxantrone?
General
Therapy with mitoxantrone 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 mitoxantrone.
Information for Patients
See .
Inform patients of the availability of a Medication Guide and instruct them to read the Medication Guide prior to initiating treatment with MitoXANTRONE and prior to each infusion. Review the MitoXANTRONE Medication Guide with every patient prior to initiation of treatment and periodically during treatment. Instruct patients that MitoXANTRONE should be taken only as prescribed.
Advise patients that MitoXANTRONE can cause myelosuppression and inform patients of the signs and symptoms of myelosuppression. Advise patients that MitoXANTRONE 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 MitoXANTRONE to treat multiple sclerosis that they should receive cardiac monitoring prior to each MitoXANTRONE dose and yearly after stopping MitoXANTRONE.
MitoXANTRONE 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 mitoxantrone and in the event that signs and symptoms of infection develop. Liver function tests should also be performed prior to each course of therapy. Mitoxantrone therapy in multiple sclerosis patients with abnormal liver function tests is not recommended because mitoxantrone 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 mitoxantrone. 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 mitoxantrone (see ).
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Intravenous treatment of rats and mice, once every 21 days for 24 months, with mitoxantrone 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/m 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/m basis). Intravenous treatment of rats, once every 21 days for 12 months with mitoxantrone 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/m basis).
Mutagenesis
Mitoxantrone was clastogenic in the rat bone marrow assay. Mitoxantrone was also clastogenic in two assays; it induced DNA damage in primary rat hepatocytes and sister chromatid exchanges in Chinese hamster ovary cells. Mitoxantrone was mutagenic in bacterial and mammalian test systems (Ames/Salmonella and and L5178Y TK+/-mouse lymphoma).
Drug Interactions
Mitoxantrone and its metabolites are excreted in bile and urine, but it is not known whether the metabolic or excretory pathways are saturable, may be inhibited or induced, or if mitoxantrone and its metabolites undergo enterohepatic circulation. To date, post-marketing experience has not revealed any significant drug interactions in patients who have received mitoxantrone for treatment of cancer. Information on drug interactions in patients with multiple sclerosis is limited.
Following concurrent administration of mitoxantrone with corticosteroids, no evidence of drug interactions has been observed.
Special Populations
Patients with multiple sclerosis who have hepatic impairment should ordinarily not be treated with mitoxantrone. Mitoxantrone 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
(see ).
Nursing Mothers
Mitoxantrone 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 mitoxantrone, 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 mitoxantrone 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 mitoxantrone 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 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.
What are the side effects of Mitoxantrone?
Multiple Sclerosis
Mitoxantrone has been administered to 149 patients with multiple sclerosis in two randomized clinical trials, including 21 patients who received mitoxantrone 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/m mitoxantrone 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 mitoxantrone 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 mitoxantrone 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/m group). Of note, alopecia consisted of mild hair thinning.
Two of the 127 patients treated with mitoxantrone in Study 1 had decreased LVEF to below 50% at some point during the 2 years of treatment. An additional patient receiving 12 mg/m did not have LVEF measured, but had another echocardiographic measure of ventricular function (fractional shortening) that led to discontinuation from the study.
The proportion of patients experiencing any infection during Study 1 was 67% for the placebo group, 85% for the 5 mg/m group, and 81% for the 12 mg/m group. However, few of these infections required hospitalization: one placebo patient (tonsillitis), three 5 mg/m patients (enteritis, urinary tract infection, viral infection), and four 12 mg/m patients (tonsillitis, urinary tract infection [two], endometritis).
Table 4b summarizes laboratory abnormalities that occurred in ≥ 5% of patients in either mitoxantrone dose group, and that were numerically more frequent than in the placebo group.
There was no difference among treatment groups in the incidence or severity of hemorrhagic events.
In Study 2, mitoxantrone was administered once a month. Clinical adverse events most frequently reported in the mitoxantrone 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 mitoxantrone group and numerically more frequent than in the control group.
Leukopenia and neutropenia were reported in the M + MP group (see ).
Neutropenia occurred within 3 weeks after mitoxantrone administration and was always reversible. Only mild to moderate intensity infections were reported in 9 of 21 patients in the M + 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.
| Percent of Patients | |||
|---|---|---|---|
| Preferred Term | Placebo (N = 64) | 5 mg/m Mitoxantrone (N = 65) | 12 mg/m Mitoxantrone (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 |
| Percent of Patients | |||
| Event | Placebo (N = 64) | 5 mg/m Mitoxantrone (N = 65) | 12 mg/m Mitoxantrone (N = 62) |
| Leukopenia | 0 | 9 | 19 |
| Gamma-GT increased | 3 | 3 | 15 |
| SGOT increased | 8 | 9 | 8 |
| Granulocytopenia | 2 | 6 | 6 |
| Anemia | 2 | 9 | 6 |
| SGPT increased | 3 | 6 | 5 |
| M = mitoxantrone, MP = methylprednisolone | |||
| Percent of Patients | |||
| Event | MP (N = 21) | M + MP (N = 21) | |
| Amenorrhea | 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 | 0 | 7 | |
| M = mitoxantrone, MP = methylprednisolone | |||
| Percent of Patients | |||
| Event | MP (N = 21) | M + MP (N = 21) | |
| WBC low | 14 | 100 | |
| ANC low | 10 | 100 | |
| Lymphocytes low | 43 | 95 | |
| Hemoglobin low | 48 | 43 | |
| Platelets low | 0 | 33 | |
| SGOT high | 5 | 15 | |
| SGPT high | 10 | 15 | |
| Glucose high | 5 | 10 | |
| Potassium low | 0 | 10 |
Leukemia
Mitoxantrone has been studied in approximately 600 patients with acute non-lymphocytic 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 ). 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 mitoxantrone + cytarabine was responsible for nausea and vomiting, alopecia, mucositis/stomatitis, and myelosuppression.
Table 6 summarizes adverse reactions occurring in patients treated with mitoxantrone + 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.
| Induction | Consolidation | |||
|---|---|---|---|---|
| Event | ||||
| 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 |
Hormone-Refractory Prostate Cancer
Detailed safety information is available for a total of 353 patients with hormone-refractory prostate cancer treated with mitoxantrone, including 274 patients who received mitoxantrone in combination with corticosteroids.
Table 7 summarizes adverse reactions of all grades occurring in ≥5% of patients in Trial CCI-NOV22.
Table 8 summarizes adverse events of all grades occurring in ≥ 5% of patients in Trial CALGB 9182.
| M = mitoxantrone, P = prednisone.No nonhematologic adverse events of Grade 3/4 were seen in > 5% of patients. | Event | M + 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 | ||
| M = mitoxantrone, H = hydrocortisone | ||||
| M + H (n = 112) | H (n = 113) | |||
| Event | 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 |
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 mitoxantrone, in combination with other antineoplastic agents or alone, have been associated with the development of acute leukemia (see ).
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/mm, Grade 4 neutropenia (ANC < 500/mm) was observed in 54% of patients treated with mitoxantrone + low-dose prednisone. In a separate randomized trial where patients were treated with 14 mg/m, Grade 4 neutropenia in 23% of patients treated with mitoxantrone + hydrocortisone was observed. Neutropenic fever/infection occurred in 11% and 10% of patients receiving mitoxantrone + corticosteroids, respectively, on the two trials. Platelets < 50,000/mm were noted in 4% and 3% of patients receiving mitoxantrone + corticosteroids on these trials, and there was one patient death on mitoxantrone + 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 )
Pulmonary
Interstitial pneumonitis has been reported in cancer patients receiving combination chemotherapy that included mitoxantrone.
What should I look out for while using Mitoxantrone?
Mitoxantrone is contraindicated in patients who have demonstrated prior hypersensitivity to it.
WHEN MITOXANTRONE IS USED IN HIGH DOSES (> 14 mg/m/d × 3 days) SUCH AS INDICATED FOR THE TREATMENT OF LEUKEMIA, SEVERE MYELOSUPPRESSION WILL OCCUR. THEREFORE, IT IS RECOMMENDED THAT MITOXANTRONE 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. MITOXANTRONE ADMINISTERED AT ANY DOSE CAN CAUSE MYELOSUPPRESSION.
CONTAINS SODIUM METABISULFITE, A SULFITE THAT MAY CAUSE ALLERGIC-TYPE REACTIONS INCLUDING ANAPHYLACTIC SYMPTOMS AND LIFE-THREATENING OR LESS SEVERE ASTHMATIC EPISODES IN CERTAIN SUSCEPTIBLE PEOPLE. THE OVERALL PREVALENCE OF SULFITE SENSITIVITY IN THE GENERAL POPULATION IS UNKNOWN AND PROBABLY LOW. SULFITE SENSITIVITY IS SEEN MORE FREQUENTLY IN ASTHMATIC THAN IN NONASTHMATIC PEOPLE.
What might happen if I take too much Mitoxantrone?
There is no known specific antidote for mitoxantrone. Accidental overdoses have been reported. Four patients receiving 140 to 180 mg/m 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, mitoxantrone is extensively tissue bound and it is unlikely that the therapeutic effect or toxicity would be mitigated by peritoneal or hemodialysis.
How should I store and handle Mitoxantrone?
Unopened vials of Gemzar are stable until the expiration date indicated on the package when stored at controlled room temperature 20° to 25°C (68° to 77°F) and that allows for excursions between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature] . Mitoxantrone Injection, USP (concentrate) is a sterile aqueous solution containing mitoxantrone hydrochloride at a concentration equivalent to 2 mg mitoxantrone free base per mL supplied in vials for multidose use as follows:NDC 61703-343-18 – 20 mg/10 mL multidose vialNDC 61703-343-65 – 25 mg/12.5 mL multidose vialNDC 61703-343-66 – 30 mg/15 mL multidose vialMitoxantrone Injection, USP (concentrate) is a sterile aqueous solution containing mitoxantrone hydrochloride at a concentration equivalent to 2 mg mitoxantrone free base per mL supplied in vials for multidose use as follows:NDC 61703-343-18 – 20 mg/10 mL multidose vialNDC 61703-343-65 – 25 mg/12.5 mL multidose vialNDC 61703-343-66 – 30 mg/15 mL multidose vial
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
Mitoxantrone, a DNA-reactive agent that intercalates into deoxyribonucleic acid (DNA) through hydrogen bonding, causes crosslinks and strand breaks. Mitoxantrone also interferes with ribonucleic acid (RNA) and is a potent inhibitor of topoisomerase II, an enzyme responsible for uncoiling and repairing damaged DNA. It has a cytocidal effect on both proliferating and nonproliferating cultured human cells, suggesting lack of cell cycle phase specificity.
Mitoxantrone has been shown 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.
Non-Clinical Toxicology
Mitoxantrone is contraindicated in patients who have demonstrated prior hypersensitivity to it.WHEN MITOXANTRONE IS USED IN HIGH DOSES (> 14 mg/m/d × 3 days) SUCH AS INDICATED FOR THE TREATMENT OF LEUKEMIA, SEVERE MYELOSUPPRESSION WILL OCCUR. THEREFORE, IT IS RECOMMENDED THAT MITOXANTRONE 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. MITOXANTRONE ADMINISTERED AT ANY DOSE CAN CAUSE MYELOSUPPRESSION.
CONTAINS SODIUM METABISULFITE, A SULFITE THAT MAY CAUSE ALLERGIC-TYPE REACTIONS INCLUDING ANAPHYLACTIC SYMPTOMS AND LIFE-THREATENING OR LESS SEVERE ASTHMATIC EPISODES IN CERTAIN SUSCEPTIBLE PEOPLE. THE OVERALL PREVALENCE OF SULFITE SENSITIVITY IN THE GENERAL POPULATION IS UNKNOWN AND PROBABLY LOW. SULFITE SENSITIVITY IS SEEN MORE FREQUENTLY IN ASTHMATIC THAN IN NONASTHMATIC PEOPLE.
Mitoxantrone and its metabolites are excreted in bile and urine, but it is not known whether the metabolic or excretory pathways are saturable, may be inhibited or induced, or if mitoxantrone and its metabolites undergo enterohepatic circulation. To date, post-marketing experience has not revealed any significant drug interactions in patients who have received mitoxantrone for treatment of cancer. Information on drug interactions in patients with multiple sclerosis is limited.
Following concurrent administration of mitoxantrone with corticosteroids, no evidence of drug interactions has been observed.
Therapy with mitoxantrone 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 mitoxantrone.
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).