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MITOXANTRONE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) MitoXANTRONE, a DNA-reactive agent that intercalates into deoxyribonucleic acid through hydrogen bonding, is a synthetic antineoplastic anthracenedione.

Specific Substances

    1) MitoXANTRONE hydrochloride
    2) Mitozantrone hydrochloride
    3) Novantron
    4) Novantrone
    5) Anthracenedione, 1,4-dihydroxy-5,8-bis((2-((2-hydroxyethyl)amino)ethyl)amino)-, dihydrochoride
    6) Molecular formula: C22-H28-N4-O6.2Cl-H
    7) CAS 65271-80-9

Available Forms Sources

    A) FORMS
    1) MitoXANTRONE is available in the US in a sterile aqueous solution containing mitoXANTRONE hydrochloride at concentrations equivalent to 2 mg mitoXANTRONE per mL in vials. The sizes available are 10 mL/multidose vial (20 mg); 12.5 mL/multidose vial (25 mg); and 15 mL/multidose vial (30 mg) for multidose use (Prod Info NOVANTRONE(R) intravenous injection concentrate, 2012; Prod Info mitoxantrone injection, 2006).
    B) USES
    1) MitoXANTRONE is used in combination with corticosteroids as an initial therapy for patients with chronic pain associated with advanced hormone-refractory prostate cancer (Prod Info NOVANTRONE(R) intravenous injection concentrate, 2012; Prod Info mitoxantrone injection, 2006).
    2) It is also used in combination with other drug therapies as an initial therapy in adults for the treatment of acute nonlymphocytic leukemia (ANLL), which can include myelogenous, promyelocytic, monocytic and erythroid acute leukemia (Prod Info NOVANTRONE(R) intravenous injection concentrate, 2012; Prod Info mitoxantrone injection, 2006).
    3) MitoXANTRONE may also be used as a therapy in patients with chronic (secondary) progressive, progressive relapsing or worsening relapsing-remitting multiple sclerosis for reducing neurologic disability or the reduction of clinical relapse. It is not indicated as a primary therapy for progressive symptoms (Prod Info NOVANTRONE(R) intravenous injection concentrate, 2012).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: MitoXANTRONE is used in combination with corticosteroids as an initial therapy for patients with chronic pain associated with advanced hormone-refractory prostate cancer. It is also used in combination with other drug therapies as an initial therapy in adults for the treatment of acute nonlymphocytic leukemia (ANLL), which can include myelogenous, promyelocytic, monocytic and erythroid acute leukemia. MitoXANTRONE may also be used as a therapy in patients with chronic (secondary) progressive, progressive relapsing or worsening relapsing-remitting multiple sclerosis for reducing neurologic disability or the reduction of clinical relapse.
    B) PHARMACOLOGY: MitoXANTRONE hydrochloride, an antineoplastic drug, is a DNA-reactive agent that intercalates into deoxyribonucleic acid (DNA) causing crosslinks and strand breaks in DNA through hydrogen binding. It also interferes with ribonucleic acid (RNA) and inhibits topoisomerase II, an enzyme responsible for the repairing and uncoiling damaged DNA.
    C) TOXICOLOGY: Interferes with DNA replication in rapidly dividing cells, such as bone marrow and gastrointestinal epithelium. Cardiac toxicity may be related to free radical production.
    D) EPIDEMIOLOGY: Inadvertent iatrogenic overdose is very rare, but has occurred.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Hematologic toxicity is generally the dose-limiting toxicity. Severe myelosuppression will occur when mitoXANTRONE is used at high doses (greater than 14 mg/m(2) x 3 days). The primary dose-limiting toxic effect of mitoXANTRONE is leukopenia which reaches a nadir by day 9 to 13 and returns to normal by day 19 to 21. Other adverse effects include nausea, vomiting, diarrhea, mucositis, elevated liver enzymes, and extravasation injury. Cardiotoxicity including congestive heart failure, tachycardia, dysrhythmias, chest pain and asymptomatic decreases in ejection fraction has also been reported. RARE: Anaphylactoid reactions, interstitial pneumonitis.
    F) WITH POISONING/EXPOSURE
    1) Clinical events in overdose are anticipated to be an extension of adverse effects. Severe myelosuppression may develop after overdose. Based on several inadvertent l overdoses, patients receiving 140 to 180 mg/m(2) as a single bolus injection died as a result of severe leukopenia with infection. Cardiotoxicity, including congestive heart failure and asymptomatic alterations in left ventricle function, has been reported.
    2) Inadvertent intrathecal injection can be neurotoxic, and has resulted in seizures leading to coma, severe neurologic sequelae and paralysis.
    0.2.20) REPRODUCTIVE
    A) MitoXANTRONE is considered a potential human teratogen. It has US FDA Pregnancy Category D rating.

Laboratory Monitoring

    A) Monitor vital signs.
    B) Obtain an ECG, and institute continuous cardiac monitoring.
    C) Monitor serum electrolytes, renal function and liver enzymes.
    D) Myelosuppression (eg, neutropenia, anemia, and thrombocytopenia) has been reported in patients receiving mitoXANTRONE. The primary dose-limiting toxic effect of mitoXANTRONE is leukopenia which reaches a nadir by day 9 to 13 and returns to normal by day 19 to 21. Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery.
    E) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Treat persistent nausea and vomiting with several antiemetics of different classes. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia, or hemorrhage. Severe nausea and vomiting may respond to a combination of agents from different drug classes.
    C) INTRATHECAL INJECTION
    1) Intrathecal injection has been reported with mitoXANTRONE following inadvertent injection; neuropathy and severe neurotoxicity have occurred. The following recommendations are based on experience with other antineoplastic drugs. Keep the patient upright if possible. Immediately drain at least 20 mL CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free normal saline or lactated ringers). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline or LR through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 to 150 mL/hr for 18 to 24 hours). Fresh frozen plasma (25 mL FFP per liter NS or LR) or albumin 5% have also been used for perfusion; may be useful because of high protein binding. Dexamethasone 4 mg IV every 6 hours to prevent arachnoiditis.
    D) DECONTAMINATION
    1) Prehospital gastrointestinal decontamination is not necessary as mitoXANTRONE is administered intravenously.
    E) AIRWAY MANAGEMENT
    1) Intubate if patient is unable to protect airway or if unstable dysrhythmias develop. Endotracheal intubation and mechanical ventilation may be required in patients with severe allergic reactions, but this is rare.
    F) ANTIDOTE
    1) None.
    G) HYPERSENSITIVITY REACTION
    1) MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    H) MYELOSUPPRESSION
    1) Administer colony stimulating factors following a significant overdose as these patients are at risk for severe neutropenia. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours. Monitor CBC with differential and platelet count daily for evidence of bone marrow suppression until recovery has occurred. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage. Patients with severe neutropenia should be in protective isolation. Transfer to a bone marrow transplant center should be considered.
    I) NEUTROPENIA
    1) Prophylactic therapy with a fluoroquinolone should be considered in high risk patients with expected prolonged (more than 7 days), and profound neutropenia (ANC 100 cells/mm(3) or less).
    J) FEBRILE NEUTROPENIA
    1) If fever (38.3 C) develops during neutropenic phase (ANC 500 cells/mm(3) or less), cultures should be obtained and empiric antibiotics started. HIGH RISK PATIENT (anticipated neutropenia of 7 days or more; unstable; significant comorbidities): IV monotherapy with either piperacillin-tazobactam; a carbapenem (meropenem or imipenem-cilastatin); or an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK PATIENT (anticipated neutropenia of less than 7 days; clinically stable; no comorbidities): oral ciprofloxacin and amoxicillin/clavulanate.
    K) NAUSEA AND VOMITING
    1) Treat severe nausea and vomiting with agents from several different classes. For example: dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol).
    L) STOMATITIS/MUCOSITIS
    1) Treat mild mucositis with bland oral rinses with 0.9% saline, sodium bicarbonate, and water. For moderate cases with pain, consider adding a topical anesthetic (eg, lidocaine, benzocaine, dyclonine, diphenhydramine, or doxepin). Treat moderate to severe mucositis with topical anesthetics and systemic analgesics. Patients with mucositis and moderate xerostomia may receive sialagogues (eg, sugarless candy/mints, pilocarpine/cevimeline, or bethanechol) and topical fluorides to stimulate salivary gland function. Consider prophylactic antiviral and antifungal agents to prevent infections. Topical oral antimicrobial mouthwashes, rinses, pastilles, or lozenges may be used to decrease the risk of infection. Palifermin is indicated to reduce the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. In patients with a mitoXANTRONE overdose, administer palifermin 60 mcg/kg/day IV bolus injection starting 24 hours after the overdose for 3 consecutive days.
    M) EXTRAVASATION INJURY
    1) MitoXANTRONE is a vesicant. If extravasation occurs, stop the infusion. Disconnect the IV tubing, but leave the cannula or needle in place. Attempt to aspirate the extravasated drug from the needle or cannula. If possible, withdraw 3 to 5 mL of blood and/or fluids through the needle/cannula. Elevate the affected area. Apply ice packs for 15 to 20 minutes at least 4 times daily. Do not apply excessive cold to avoid tissue injury. Cold can cause local vasoconstriction and reduces fluid absorption. Treat site with topical dimethyl sulfoxide (DMSO) for a minimum of 7 days and maximum of 14 days; however, if blistering develops, discontinue DMSO and review site. Administer analgesia for severe pain. If pain persists, there is concern for compartment syndrome, or injury is apparent, an early surgical consult should be considered. Close observation of the extravasated area is suggested. If tissue sloughing, necrosis or blistering occurs, treat as a chemical burn (ie, antiseptic dressings, silver sulfadiazine, antibiotics when applicable). Surgical or enzymatic debridement may be required. Risk of infection is increased in chemotherapy patients with reduced neutrophil count following extravasation. Consider culturing any open wounds. Monitor the site for the development of cellulitis, which may require antibiotic therapy.
    N) ENHANCED ELIMINATION
    1) Although there is no information regarding the effectiveness of hemodialysis or hemoperfusion for the removal of mitoXANTRONE from plasma, it is extensively tissue bound and these modalities are not anticipated to be useful.
    O) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no data to support home management.
    2) ADMISSION CRITERIA: Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), cardiac function, and daily monitoring of CBC with differential until bone marrow suppression is resolved.
    3) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with overdose.
    4) TRANSFER CRITERIA: Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    P) PITFALLS
    1) Symptoms of overdose are similar to reported side effects of the medication. Early symptoms of overdose may be delayed or not evident (ie, particularly myelosuppression), so reliable follow-up is imperative. Patients taking these medications may have severe co-morbidities and may be receiving other drugs that may produce synergistic effects (ie, myelosuppression, neurotoxicity, cardiotoxicity).
    Q) PHARMACOKINETICS
    1) Vd: exceeds 1000 L/m(2); protein binding: 78%; excretion: renal: 11%, of the amount found 65% is unchanged; fecal: 25%; elimination half-life: 23 to 215 hours (median approximately 75 hours).
    R) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that cause myelosuppression or cardiotoxicity such as anthracyclines.

Range Of Toxicity

    A) TOXICITY: Limited data. ADULTS: Cases of leukopenia and infection leading to death have been reported with inadvertent overdoses ranging from 140 to 180 mg/m(2). Doses of 100 to 180 mg/m(2) have caused severe myelosuppression and left ventricular dysfunction in patients who survived. CHILDREN: A 9-year-old girl with AML developed severe myelosuppression after inadvertently receiving a 10-fold overdose bolus injection of 98 mg (100 mg/m(2)) of mitoXANTRONE instead of 9.8 mg. She recovered following supportive care.
    B) THERAPEUTIC DOSE: Recommended dosage is 12 mg/m(2) usually given as a short infusion (5 to 15 minutes) every 3 months.

Clinical Effects

Summary Of Exposure

    A) USES: MitoXANTRONE is used in combination with corticosteroids as an initial therapy for patients with chronic pain associated with advanced hormone-refractory prostate cancer. It is also used in combination with other drug therapies as an initial therapy in adults for the treatment of acute nonlymphocytic leukemia (ANLL), which can include myelogenous, promyelocytic, monocytic and erythroid acute leukemia. MitoXANTRONE may also be used as a therapy in patients with chronic (secondary) progressive, progressive relapsing or worsening relapsing-remitting multiple sclerosis for reducing neurologic disability or the reduction of clinical relapse.
    B) PHARMACOLOGY: MitoXANTRONE hydrochloride, an antineoplastic drug, is a DNA-reactive agent that intercalates into deoxyribonucleic acid (DNA) causing crosslinks and strand breaks in DNA through hydrogen binding. It also interferes with ribonucleic acid (RNA) and inhibits topoisomerase II, an enzyme responsible for the repairing and uncoiling damaged DNA.
    C) TOXICOLOGY: Interferes with DNA replication in rapidly dividing cells, such as bone marrow and gastrointestinal epithelium. Cardiac toxicity may be related to free radical production.
    D) EPIDEMIOLOGY: Inadvertent iatrogenic overdose is very rare, but has occurred.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Hematologic toxicity is generally the dose-limiting toxicity. Severe myelosuppression will occur when mitoXANTRONE is used at high doses (greater than 14 mg/m(2) x 3 days). The primary dose-limiting toxic effect of mitoXANTRONE is leukopenia which reaches a nadir by day 9 to 13 and returns to normal by day 19 to 21. Other adverse effects include nausea, vomiting, diarrhea, mucositis, elevated liver enzymes, and extravasation injury. Cardiotoxicity including congestive heart failure, tachycardia, dysrhythmias, chest pain and asymptomatic decreases in ejection fraction has also been reported. RARE: Anaphylactoid reactions, interstitial pneumonitis.
    F) WITH POISONING/EXPOSURE
    1) Clinical events in overdose are anticipated to be an extension of adverse effects. Severe myelosuppression may develop after overdose. Based on several inadvertent l overdoses, patients receiving 140 to 180 mg/m(2) as a single bolus injection died as a result of severe leukopenia with infection. Cardiotoxicity, including congestive heart failure and asymptomatic alterations in left ventricle function, has been reported.
    2) Inadvertent intrathecal injection can be neurotoxic, and has resulted in seizures leading to coma, severe neurologic sequelae and paralysis.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) After intravenous administration, the sclera may take on a bluish discoloration (Prod Info NOVANTRONE(R) intravenous injection concentrate, 2012).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CONGESTIVE HEART FAILURE
    1) WITH THERAPEUTIC USE
    a) MitoXANTRONE has been associated with cardiotoxicity and the risk increases with cumulative dose. Congestive heart failure (CHF) may develop during the course of therapy or months to years following the course of treatment. Its estimated that the probability of developing CHF is 2.6% with a cumulative dose of 140 mg/m(2) in cancer patients (Prod Info NOVANTRONE(R) intravenous injection concentrate, 2012).
    b) Among 801 patients receiving at least one course of mitoXANTRONE in 14 Phase II Southwest Oncology Group protocols, 12 developed congestive heart failure (1.5%), with an additional 12 patients exhibiting decreased ejection fraction (1.5%); myocardial infarction occurred in 2 patients (0.25%) (Clark et al, 1984). Patients experiencing cardiotoxic effects were comparable to those with no cardiotoxicity with respect to age, sex, prior mediastinal irradiation, and percentage of patients who had received prior doxorubicin. Cardiotoxicity was cumulative with increasing doses of the drug and the probability of developing CHF exceeded 10% with cumulative doses exceeding 120 milligrams/square meter (mg/m(2)) (Clark et al, 1984).
    c) Congestive heart failure was reported in 4 of 31 high risk patients during or after treatment with mitoXANTRONE for breast cancer. All patients had received prior doxorubicin therapy (Schell et al, 1982).
    d) Despite an increased risk of cardiotoxicity in patients with a history of cardiac illness, patients with no history of disease can also develop toxicity (Prod Info NOVANTRONE(R) IV injection, 2010).
    e) In a cohort study of 820 patients with relapsing-remitting or progressive relapsing multiple sclerosis, 52 patients were treated with mitoXANTRONE. Of those patients, 3 developed delayed CHF at 24, 39 and 80 months, respectively. MitoXANTRONE was administered at a dose of 12 mg/m(2) once a month for 3 months and then at 3-month intervals to reach a cumulative dose of 144 mg/m(2). Although all patients initially recovered, one patient had recurring severe symptoms despite clinical management (Goffette et al, 2005).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Three patients were inadvertently administered 100 mg/m(2) (2 patients) and 183 mg/m(2) (1 patient) of mitoXANTRONE as a single injection, and one patient, with a history of previous daunomycin therapy, developed CHF approximately 4 months after exposure. The other patients were not observed for late cardiac symptoms because they died due to tumor progression (Siegert et al, 1989).
    B) LEFT VENTRICULAR CARDIAC DYSFUNCTION
    1) WITH THERAPEUTIC USE
    a) Cardiotoxicity including tachycardia, ECG changes including dysrhythmias, chest pain and asymptomatic decreases in ejection fraction in some patients have been associated with mitoXANTRONE therapy (Prod Info NOVANTRONE(R) intravenous injection concentrate, 2012).
    b) A decrease in left ventricle ejection fraction (LVEF) has been associated with mitoXANTRONE therapy. Baseline assessment of cardiac function and evaluation of LVEF by echocardiogram and multi-gated radionuclide angiography (MUGA) are recommended for all patients treated with mitoXANTRONE (Prod Info NOVANTRONE(R) intravenous injection concentrate, 2012).
    c) In a meta-analysis of multiple sclerosis patients treated with mitoXANTRONE, limited cardiotoxicity was reported in clinical trials. In a pivotal clinical trial, 2 patients developed a decrease in LVEF to less than 50% of baseline after receiving 12 mg/m(2) of mitoXANTRONE. Its suggested that long-term use may compromise left ventricular function and cumulative dose should not exceed 140 mg/m(2) or 2 to 3 years of therapy (Fox, 2006).
    d) In a study of 78 patients receiving mitoXANTRONE for advanced malignancy, of 9 patients receiving more than 100 mg/m(2), one patient developed increasing cardiac diameter following 144 mg/m(2) requiring withdrawal of mitoXANTRONE and 34 patients had a decrease in ejection fraction after cumulative doses of 144 to 256 mg/m(2) (Stuart-Harris et al, 1984).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 9-year-old girl with acute myelogenous leukemia started induction therapy, and received an inadvertent 10-fold overdose bolus injection of 98 mg (100 mg/m(2)) mitoXANTRONE instead of 9.8 mg. A total dose of 110 mg/m(2) was given over 2 days. The patient developed sinus tachycardia, likely related to fever, but no cardiac dysrhythmias or CHF. Sequential echocardiograms revealed a reversible decrease of the shortening fraction of the left ventricle. The effect was not associated with any clinical symptoms and no treatment was required (Hachimi-Idrissi et al, 1993).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) INTERSTITIAL PNEUMONIA
    1) WITH THERAPEUTIC USE
    a) Interstitial pneumonitis has occurred rarely in patients administered combination chemotherapy that included mitoXANTRONE (Prod Info NOVANTRONE(R) intravenous injection concentrate, 2012).
    b) Two cases of Interstitial pneumonitis occurring during treatment with intravenous mitoXANTRONE and oral chlorambucil and prednisone (MCP) are reported. In the first, a 70-year-old male experienced rapidly increasing shortness of breath on exertion, fever and a dry cough 2 weeks after the second cycle of chemotherapy administered for non-Hodgkin's lymphoma. Chest radiographs and computed tomography (CT) scans demonstrated diffuse interstitial shadowing bilaterally. A transbronchial biopsy revealed an organizing pneumonia with an interstitial chronic inflammatory cell infiltrate, but no evidence of infection or lymphoma. Clinical resolution was observed within 1 month of discontinuing chemotherapy and reinstituting prednisone 40 mg daily. Subsequent rechallenge with chlorambucil was not associated with recurrence of pulmonary symptoms. In the second case, a 56-year-old female with non-Hodgkin's lymphoma complained of shortness of breath and fever following the fourth and fifth cycles of chemotherapy. After the sixth cycle, she presented with fever, a dry cough, and anorexia. CT of the chest showed bilateral alveolar infiltrates. An open lung biopsy confirmed the presence of an organizing pneumonia with a chronic inflammatory cell infiltrate. No evidence for infection or lymphoma was observed. Her condition resolved over a 5-month period following discontinuation of chemotherapy (Tomlinson et al, 1999).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) CASE REPORTS
    1) A 39-year-old male with resistant leukemia and central nervous system involvement developed paraplegia following the administration of intrathecal mitoXANTRONE. It was administered at 2 mg weekly. The patient experienced local pain after the second injection and the third dose was reduced to 1 mg. Local pain recurred, which required the use of analgesics. Severe pain in the lower extremities occurred 3 to 4 days later and paraplegia with absent leg reflexes developed over 2 weeks. No sensory loss or alteration in bladder or bowel function occurred. Four months later, the patient remained paraplegic (Lakhani et al, 1986).
    2) Paraplegia developed following the intrathecal administration of mitoXANTRONE in a 46-year-old man diagnosed with lymphoblastic lymphoma. Due to the progression of the lymphoma and development of side effects to previous therapy, intrathecal mitoXANTRONE 1 mg twice a week was administered. The patient subsequently received 10 more intrathecal injections of mitoXANTRONE at which time an Ommaya reservoir was implanted. The patient received mitoXANTRONE 2 mg twice a week for 4 weeks via the reservoir. The lymphoma was resistant to systemic chemotherapy and the patient died approximately 4 months after initiating intrathecal mitoXANTRONE. One month prior to death, paraplegia developed. It was unknown if the paraplegia was related to the intrathecal administration of mitoXANTRONE, previous therapy or local relapse (La Porte et al, 1985).
    2) WITH POISONING/EXPOSURE
    a) Intrathecal injection of mitoXANTRONE can result in seizures leading to coma, severe neurologic sequelae, and paralysis (Prod Info NOVANTRONE(R) intravenous injection concentrate, 2012).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting occurs in most patients treated with mitoXANTRONE (Prod Info NOVANTRONE(R) intravenous injection concentrate, 2012; Bonnem et al, 1982; Stuart-Harris & Smith, 1982; Anderson et al, 1982; Bedikian et al, 1983; Smith, 1983a).
    B) DIARRHEAL DISORDER
    1) WITH THERAPEUTIC USE
    a) Diarrhea occurs in 4% to 16% of patients treated with mitoXANTRONE (Prod Info NOVANTRONE(R) intravenous injection concentrate, 2012; Bedikian et al, 1983; Smith, 1983a).
    C) INFLAMMATORY DISEASE OF MUCOUS MEMBRANE
    1) WITH THERAPEUTIC USE
    a) Mucositis occurs fairly frequently during treatment with mitoXANTRONE (Prod Info NOVANTRONE(R) intravenous injection concentrate, 2012). In 2 reports, 26% to 54% of patients experienced mucositis (Estey et al, 1983; Bedikian et al, 1983), while other studies report an incidence of only 4% (Smith, 1983a). STOMATITIS and mucositis occur within 1 week of therapy (Prod Info NOVANTRONE(R) injection, 2005).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INJURY OF LIVER
    1) WITH THERAPEUTIC USE
    a) Liver enzyme abnormalities were reported in 31% of patients with acute leukemia who received mitoXANTRONE (Estey et al, 1983), however, other studies have not reported elevations in liver enzymes and no cases of hepatotoxicity have been reported.
    b) HEPATIC DYSFUNCTION with mitoXANTRONE is estimated to occur at an incidence of 0.6% (Smith, 1983a).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) DISCOLORED URINE
    1) WITH THERAPEUTIC USE
    a) MitoXANTRONE may cause the urine to change to a blue-green color for 24 hours after administration (Prod Info NOVANTRONE(R) intravenous injection concentrate, 2012).
    B) AMENORRHEA
    1) WITH THERAPEUTIC USE
    a) Menstrual disorders and amenorrhea occurred in 51% to 61% and 28% to 43% of women with multiple sclerosis receiving mitoXANTRONE, respectively (Prod Info NOVANTRONE(R) intravenous injection concentrate, 2012).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Hematologic toxicity is generally the dose-limiting toxicity. Severe myelosuppression will occur when mitoXANTRONE is used at high dose (greater than 14 mg/m(2) x 3 days) (Prod Info NOVANTRONE(R) intravenous injection concentrate, 2012).
    b) The primary dose-limiting toxic effect of mitoXANTRONE is leukopenia (Prod Info NOVANTRONE(R) intravenous injection concentrate, 2012), which reaches a nadir by day 9 to 13 and returns to normal by day 19 to 21 (Coltman et al, 1983; Anderson et al, 1983; Von Hoff et al, 1980).
    c) Leukopenia was the major toxic effect of mitoXANTRONE therapy in 87 courses of treatment for 54 patients with small cell carcinoma of the lung who were given 12 mg/m(2) every 3 weeks intravenously. The median total white blood cell count was 2,000 (range 400 to 13,700) with a mean granulocyte count of 1,100. Twelve patients had a granulocyte count of less than 1,000 and 6 of the 12 had a granulocyte count of less than 500, with the median day of granulocyte nadir at day 12 and full recovery by day 21. No drug-related deaths were reported. Thrombocytopenia was not observed at the doses administered (Von Hoff et al, 1983).
    2) WITH POISONING/EXPOSURE
    a) Based on several accidental overdoses, patients receiving 140 to 180 mg/m(2) of mitoXANTRONE as a single bolus injection died as a result of severe leukopenia with infection (Prod Info NOVANTRONE(R) intravenous injection concentrate, 2012).
    b) CASE REPORT: A 9-year old girl with acute myelogenous leukemia started induction therapy, and received an inadvertent 10-fold overdose bolus injection of 98 mg (100 mg/m(2)) mitoXANTRONE instead of 9.8 mg. A total dose of 110 mg/m(2) was given over 2 days. By day 7, the patient developed severe cytopenia (nadir neutrophil count 0). Similar decreases in WBC and platelets occurred. The patient became febrile on day 28 and was treated empirically with antibiotics. The patient recovered and reached complete remission (Hachimi-Idrissi et al, 1993).
    B) FEBRILE NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) In 2 randomized studies in patients with advanced hormone-refractory prostate cancer, neutropenic fever/infection was reported in 11% and 10% of patients who received mitoXANTRONE in combination with corticosteroids (Prod Info NOVANTRONE(R) intravenous injection concentrate, 2012).
    C) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thrombocytopenia can also develop, but the incidence is much less than that of leukopenia (Prod Info NOVANTRONE(R) intravenous injection concentrate, 2012; Anderson et al, 1983; Wynert et al, 1982).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 9-year-old girl with acute myelogenous leukemia started induction therapy, and received an inadvertent 10-fold overdose bolus injection of 98 mg (100 mg/m(2)) of mitoXANTRONE instead of 9.8 mg. A total dose of 110 mg/m(2) was given over 2 days. By day 7, the patient developed severe cytopenia. Similar decreases in WBC and platelets occurred. The patient required repeat platelet transfusions to maintain a platelet count above 20,000/mm(3). The patient recovered and reached complete remission (Hachimi-Idrissi et al, 1993).
    D) ACUTE MYELOID LEUKEMIA, DISEASE
    1) WITH THERAPEUTIC USE
    a) Secondary acute myelogenous leukemia (AML) has been reported in both cancer and multiple sclerosis patients treated with mitoXANTRONE (Prod Info NOVANTRONE(R) intravenous injection concentrate, 2012).
    b) In patients with breast cancer who received mitoXANTRONE in combination with other cytotoxic agents and radiotherapy (n=1774), the cumulative risk of developing treatment-related acute myelogenous leukemia (AML) was estimated as 1.1% at 5 years, and 1.6% at 10 years. The cumulative probability of developing secondary leukemia was estimated to be 2.2% at 4 years in another study of similar patients (n=449) (Prod Info NOVANTRONE(R) intravenous injection concentrate, 2012).
    c) An increased risk of leukemia (0.25% [2/802]) was observed over various time periods in a cohort of multiple sclerosis patients treated with mitoXANTRONE. Secondary acute myelogenous leukemia has also been reported during postmarketing use of the drug (Prod Info NOVANTRONE(R) intravenous injection concentrate, 2012).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DERMATOLOGICAL FINDING
    1) WITH THERAPEUTIC USE
    a) Mild PHLEBITIS and a blue discoloration of the veins have been observed during treatment with mitoXANTRONE (Anderson et al, 1982; Anderson et al, 1983).
    b) Erythematous maculopapular eruptions have rarely occurred with mitoXANTRONE treatment, and resolve promptly upon discontinuation of the drug (Taylor et al, 1986; Bedikian et al, 1983; Anderson et al, 1982).
    c) Severe pruritus and skin desquamation caused by progressive dryness (asteatosis) from mitoXANTRONE therapy developed in 4 of 18 patients (Dharmasena et al, 1985).
    B) EXTRAVASATION INJURY
    1) WITH THERAPEUTIC USE
    a) Extravasation of mitoXANTRONE has occurred, producing tissue necrosis which can result in the need for debridement and skin grafting (Prod Info NOVANTRONE(R) intravenous injection concentrate, 2012; Ketelbey, 1989; Khoury, 1986; Man, 1986).
    C) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) Alopecia has occurred during treatment with mitoXANTRONE, however, this effect does not appear to be common (Bedikian et al, 1983; Coltman et al, 1983). In combining the results of several studies, severe alopecia occurred in only 0.4% of patients. A mild degree of hair loss was also reported for 11% of patients (Smith, 1983a).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    1) There have been occasional reports of allergic reactions characterized by hypotension, urticaria, dyspnea, and rashes. There have been rare reports of anaphylaxis/anaphylactoid reactions (Prod Info NOVANTRONE(R) intravenous injection concentrate, 2012).

Reproductive

    3.20.1) SUMMARY
    A) MitoXANTRONE is considered a potential human teratogen. It has US FDA Pregnancy Category D rating.
    3.20.2) TERATOGENICITY
    A) GENERAL
    1) MitoXANTRONE is considered a potential human teratogen. Women of childbearing potential should avoid becoming pregnant, and pregnancy should be ruled out prior to each dose of mitoXANTRONE (Prod Info NOVANTRONE(R) injection, 2005).
    2) In general, antineoplastic agents given during the first trimester may increase the risk of congenital malformations; when given during the second or third trimesters, they may increase the risk of growth retardation (Glantz, 1994; Doll et al, 1988). Depending on the nature of the malignancy, disease progression, and gestational stage, chemotherapy may be deferred to allow fetal maturation; in some cases, earlier-than-term delivery may be an acceptable compromise between maternal and fetal risk (Cunningham et al, 1993; Doll et al, 1988).
    3.20.3) EFFECTS IN PREGNANCY
    A) GENERAL
    1) Pregnancy Category D (Prod Info NOVANTRONE(R) injection, 2005)
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) GENERAL
    1) MitoXANTRONE is excreted in human breast milk in clinically significant concentrations (18 ng/mL) (Prod Info NOVANTRONE(R) injection, 2005). Due to concern for potentially serious adverse reactions in nursing infants, breastfeeding should be discontinued prior to initiating mitoXANTRONE therapy (Dillon et al, 1997).

Carcinogenicity

    3.21.3) HUMAN STUDIES
    A) SECONDARY LEUKEMIA
    1) Secondary acute myelogenous leukemia (AML) has been reported in both cancer and multiple sclerosis patients treated with mitoXANTRONE (Prod Info Novantrone(R) injection concentrate, 2005).
    2) In patients with breast cancer who received mitoXANTRONE in combination with other cytotoxic agents and radiotherapy (n=1774), the cumulative risk of developing treatment-related acute myelogenous leukemia (AML) was estimated as 1.1% at 5 years, and 1.6% at 10 years. The cumulative probability of developing secondary leukemia was estimated to be 2.2% at 4 years in another study of similar patients (n=449) (Prod Info Novantrone(R) injection concentrate, 2005).
    3) An increased risk of leukemia (0.25% [2/802]) was observed over various time periods in a cohort of multiple sclerosis patients treated with mitoXANTRONE. Secondary acute myelogenous leukemia has also been reported during postmarketing use of the drug (Prod Info Novantrone(R) injection concentrate, 2005).
    3.21.4) ANIMAL STUDIES
    A) CANAL TUMORS
    1) In rats treated with intravenous mitoXANTRONE once daily for 21 days over 24 months an increased incidence of fibroma and external auditory canal tumors were observed at doses of 0.03 mg/kg. Doses of 0.3 mg/kg once daily for 21 days for 12 months produced an increased incidence of external auditory canal tumors (Prod Info NOVANTRONE(R) injection, 2005).
    B) HEPATOCELLULAR ADENOMA
    1) In mice studies, mitoXANTRONE at doses of 0.1 mg/kg once daily for 21 days for 24 months resulted in an increased incidence of hepatocellular adenoma (Prod Info NOVANTRONE(R) injection, 2005).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs.
    B) Obtain an ECG, and institute continuous cardiac monitoring.
    C) Monitor serum electrolytes, renal function and liver enzymes.
    D) Myelosuppression (eg, neutropenia, anemia, and thrombocytopenia) has been reported in patients receiving mitoXANTRONE. The primary dose-limiting toxic effect of mitoXANTRONE is leukopenia which reaches a nadir by day 9 to 13 and returns to normal by day 19 to 21. Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery.
    E) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    4.1.2) SERUM/BLOOD
    A) Myelosuppression (eg, neutropenia, anemia, and thrombocytopenia) has been reported in patients receiving mitoXANTRONE. The primary dose-limiting toxic effect of mitoXANTRONE is leukopenia which reaches a nadir by day 9 to 13 and returns to normal by day 19 to 21. Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery (Prod Info NOVANTRONE(R) IV injection, 2010; Coltman et al, 1983; Anderson et al, 1983; Von Hoff et al, 1980).
    B) Monitor serum electrolytes, renal function and liver enzymes.
    C) Serum uric acid levels should be obtained in patients with suspected tumor lysis syndrome.
    4.1.4) OTHER
    A) OTHER
    1) Obtain a baseline ECG and repeat as indicated following a significant exposure; cardiac monitoring as necessary.
    2) Monitor for symptoms of congestive heart failure following a significant exposure. Reductions in left ventricular ejection fraction (LVEF) have also occurred in both therapeutic use and limited cases of inadvertent exposure.

Radiographic Studies

    A) A baseline echocardiogram or multi-gated radionuclide angiography (MUGA) should be obtained in any patient with evidence of cardiotoxicity or following a significant exposure. Repeat as indicated to evaluate LVEF.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), cardiac function, and daily monitoring of CBC with differential until bone marrow suppression is resolved.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no data to support home management.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with overdose.
    6.3.2.4) PATIENT TRANSFER/PARENTERAL
    A) Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.

Monitoring

    A) Monitor vital signs.
    B) Obtain an ECG, and institute continuous cardiac monitoring.
    C) Monitor serum electrolytes, renal function and liver enzymes.
    D) Myelosuppression (eg, neutropenia, anemia, and thrombocytopenia) has been reported in patients receiving mitoXANTRONE. The primary dose-limiting toxic effect of mitoXANTRONE is leukopenia which reaches a nadir by day 9 to 13 and returns to normal by day 19 to 21. Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery.
    E) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is not necessary as mitoXANTRONE is administered intravenously.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Refer to parenteral treatment sections for more information.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Although there is no information regarding the effectiveness of hemodialysis or hemoperfusion for the removal of mitoXANTRONE from plasma, it is extensively tissue bound and these modalities are not anticipated to be useful (Prod Info NOVANTRONE(R) injection, 2005).

Range Of Toxicity

Summary

    A) TOXICITY: Limited data. ADULTS: Cases of leukopenia and infection leading to death have been reported with inadvertent overdoses ranging from 140 to 180 mg/m(2). Doses of 100 to 180 mg/m(2) have caused severe myelosuppression and left ventricular dysfunction in patients who survived. CHILDREN: A 9-year-old girl with AML developed severe myelosuppression after inadvertently receiving a 10-fold overdose bolus injection of 98 mg (100 mg/m(2)) of mitoXANTRONE instead of 9.8 mg. She recovered following supportive care.
    B) THERAPEUTIC DOSE: Recommended dosage is 12 mg/m(2) usually given as a short infusion (5 to 15 minutes) every 3 months.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) MitoXANTRONE is ONLY indicated for intravenous use, and is not intended for subcutaneous, intramuscular, intra-arterial or intrathecal routes. Reports of local and/or regional neuropathy, irreversible in some cases, have been associated with intra-arterial injection. Intrathecal injection has also resulted in neuropathy and neurotoxicity including severe seizures, coma, and paralysis with bowel and bladder dysfunction (Prod Info NOVANTRONE(R) intravenous injection concentrate, 2012).
    B) ACUTE MYELOID LEUKEMIA, COMBINATION THERAPY
    1) INDUCTION: The recommended induction dose is 12 mg/m(2)/day IV on days 1 to 3 in combination with cytarabine 100 mg/m(2)/day as continuous IV 24-hr infusion on days 1 to 7; if leukemia persists, a second induction course of 12 mg/m(2)/day IV for 2 days in combination with cytarabine 100 mg/m(2) daily as continuous IV 24-hr infusion on days 1 to 5 may be given; in patients who develop severe or life-threatening nonhematologic toxicity, do not give a second induction course until toxicity resolves (Prod Info NOVANTRONE(R) intravenous injection concentrate, 2012).
    2) CONSOLIDATION: The recommended consolidation dose is 12 mg/m(2)/day IV on days 1 and 2 in combination with cytarabine 100 mg/m(2)/day as continuous 24-hr IV infusion on days 1 to 5; the first course is usually started 6 weeks after final induction therapy, with the second course given 4 weeks after the first (Prod Info NOVANTRONE(R) intravenous injection concentrate, 2012).
    C) HORMONE-REFRACTORY PROSTATE CANCER, COMBINATION THERAPY
    1) The recommended dose is 12 to 14 mg/m(2) given as a short IV infusion every 21 days, in combination with corticosteroids (Prod Info NOVANTRONE(R) intravenous injection concentrate, 2012).
    D) MULTIPLE SCLEROSIS
    1) The recommended dose is 12 mg/m(2) given as a short (approximately 5 to 15 minutes) IV infusion every 3 months; should not be administered to patients who have received a cumulative dose of 140 mg/m(2) or greater(Prod Info NOVANTRONE(R) intravenous injection concentrate, 2012).
    7.2.2) PEDIATRIC
    A) PEDIATRIC
    1) The safety and efficacy of mitoXANTRONE administration in pediatric patients have not been established (Prod Info NOVANTRONE(R) intravenous injection concentrate, 2012). However, it has been used in children in some studies.
    2) MitoXANTRONE in combination with etoposide has been administered to children (ages 18 months to 14 years) who had refractory or relapsed acute nonlymphocytic leukemia. MitoXANTRONE 10 mg/m(2) as a one-hour infusion followed by etoposide (100 mg/m(2)) was given for 3 days (first 5 patients) or 5 days (12 patients). Ten patients achieved complete remission (less than 5% blast cells in bone marrow examination) and 4 patients achieved partial remission (5 to 25% blast cells in bone marrow examination); 3 patients failed to respond. Remission rates were similar between the children with refractory or relapsed disease. Duration of remission was short despite repeat regimens (5 children) or bone marrow transplantation (5 children) in those who had initial complete remission (Pourtsidis et al, 1997).

Minimum Lethal Exposure

    A) Cases of leukopenia and infection leading to death have been reported with inadvertent overdoses ranging from 140 to 180 mg/m(2) (Prod Info NOVANTRONE(R) intravenous injection concentrate, 2012).

Maximum Tolerated Exposure

    A) Three adults developed nausea and vomiting along with reversible neutropenia and thrombocytopenia following inadvertent mitoXANTRONE overdoses of 100 mg/m(2) (n=2) and 180 mg/m(2) (n=1) as single bolus injections. One patient developed cardiac toxicity 4 months after exposure, the other 2 patients were not evaluated due to tumor progression leading to death (Siegert et al, 1989).
    B) CASE REPORT: A 9-year old girl with acute myelogenous leukemia started induction therapy, and received an inadvertent 10-fold overdose bolus injection of 98 mg (100 mg/m(2)) of mitoXANTRONE instead of 9.8 mg. A total dose of 110 mg/m(2) was given over 2 days. The patient developed severe myelosuppression and required platelet transfusions and empiric antibiotic therapy, but recovered (Hachimi-Idrissi et al, 1993).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) MitoXANTRONE (dihydroxyanthracenedione) is an anthracenedione derivative which was developed in an effort to produce a doxorubicin analog with less cardiotoxicity (Smith, 1983; Johnson et al, 1979; Murdock et al, 1979; Wallace et al, 1979; Zee-Cheng & Cheng, 1978). It is a DNA-reactive agent that intercalates into DNA through hydrogen bonding, causing crosslinks and strand breaks. MitoXANTRONE can also interfere with ribonucleic acid (RNA) and is a potent inhibitor of topoisomerase II, an enzyme that can uncoil and repair damaged DNA. It does not appear to have cell cycle specificity, based on a cytocidal effect on both proliferating and nonproliferating cultured human cells (Prod Info NOVANTRONE(R) injection, 2005).

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