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DAUNORUBICIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) DAUNOrubicin is an anthracycline cytotoxic antibiotic, isolated by a strain of Streptomyces coeruleorubidus. It has antimitotic and cytotoxic activity with antitumor effect.

Specific Substances

    1) Daunomycin
    2) Daunomycin hydrochloride
    3) Daunorubicina
    4) Daunorubicine
    5) Daunorubicinum
    6) Daunorubiciini
    7) DAUNOrubicin citrate
    8) DAUNOrubicin hydrochloride
    9) Rubidomycin hydrochloride
    10) FI-6339
    11) RP-13057
    12) Rubidomicina
    13) Rubidomycin
    14) CAS 20830-81-3 (daunorubicin)
    15) CAS 23541-50-6 (daunorubicin hydrochloride)
    1.2.1) MOLECULAR FORMULA
    1) C27-H29-N-O10-HCL

Available Forms Sources

    A) FORMS
    1) DAUNOrubicin is available in the United States as 20 mg powder for IV solution and 5 mg/mL IV solution (Prod Info daunorubicin HCl intravenous injection, 2012; Prod Info CERUBIDINE(R) intravenous injection, 2008).
    2) DAUNOrubicin citrate liposome is available as 2 mg/mL (50 mg of DAUNOrubicin base) IV solution (Prod Info DaunoXome(R) intravenous injection, 2011).
    B) USES
    1) DAUNOrubicin in combination with other agents is used for remission induction in adult and pediatric patients with acute lymphocytic leukemia and remission induction in adult patients with acute nonlymphocytic leukemia (myelogenous, monocytic, erythroid) (Prod Info daunorubicin HCl intravenous injection, 2012).
    2) DAUNOrubicin citrate liposome is used as a first-line cytotoxic therapy for advanced HIV-associated Kaposi's sarcoma (Prod Info DaunoXome(R) intravenous injection, 2011).

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: DAUNOrubicin in combination with other agents is used for remission induction in adult and pediatric patients with acute lymphocytic leukemia and remission induction in adult patients with acute nonlymphocytic leukemia. DAUNOrubicin citrate liposome is used as a first-line cytotoxic therapy for advanced AIDS-associated Kaposi's sarcoma.
    B) PHARMACOLOGY: DAUNOrubicin hydrochloride is an antimitotic, antitumor and cytotoxic anthracycline antibiotic derived from the strain of Streptomyces coeruleorubidus. It intercalates between base pairs to form complexes with DNA. It maintains the stability of DNA-topoisomerase II complex which prevents topoisomerase II from catalyzing the religation part of the ligation-religation reaction leading to single and double strand DNA breaks. It also blocks polymerase activity, affects regulation of gene expression and produces free radical damage to DNA. Liposomal DAUNOrubicin is a liposomal preparation of DAUNOrubicin formulated to maximize the selectivity of DAUNOrubicin for solid tumors in situ.
    C) TOXICOLOGY: DAUNOrubicin interferes with DNA replication in rapidly dividing cells, such as bone marrow and gastrointestinal epithelium. Cardiac toxicity of DAUNOrubicin may be related to free radical production.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) The acute or subacute cardiotoxicity can develop within 1 to 23 days after the last dose of DAUNOrubicin. Manifestations can include conduction or rhythm disturbances (ie, tachycardia, supraventricular dysrhythmias, heart block) and abnormal ECG findings (nonspecific ST-T changes). A significant decrease in ejection fraction has been documented 24 to 48 hours after drug administration. DAUNOrubicin can also cause cumulative (lifetime), dose-dependent cardiomyopathy as a result of direct endomyocardial tissue damage. It is characterized by irreversible congestive heart failure, the mortality rate ranges from 50% to 80%.
    2) Bone marrow suppression is the acute dose-limiting toxicity. The following adverse effects have also been reported following therapeutic doses of DAUNOrubicin: Nausea, vomiting, diarrhea, stomatitis/mucositis, constipation, abdominal pain, anorexia, fatigue, fever, cough, dyspnea, rhinitis, sinusitis, headache, rigors, acute allergic reactions, back pain, arthralgia, myalgia, diaphoresis, neuropathy, edema, chest pain, malaise, alopecia, dizziness, pruritus, and abnormal vision. Severe local tissue necrosis, cellulitis, thrombophlebitis, or painful induration may develop if extravasation occurs during therapy with DAUNOrubicin.
    F) WITH POISONING/EXPOSURE
    1) Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses.
    2) MILD TO MODERATE TOXICITY: Nausea, vomiting, diarrhea, stomatitis, and myelosuppression may occur following DAUNOrubicin overdose.
    3) SEVERE TOXICITY: Severe myelosuppression (especially granulocytopenia), acute cardiomyopathy (ie, ECG changes, dysrhythmias, hypotension, heart failure), severe mucositis, vomiting, and diarrhea may develop.
    4) INTRATHECAL INJECTION: Severe neurotoxicity ( cerebral atrophy) and death have been reported after unintentional intrathecal administration of DAUNOrubicin.
    0.2.3) VITAL SIGNS
    A) Fever may occur following DAUNOrubicin therapy.
    B) WITH THERAPEUTIC USE
    1) In an open-label, randomized, controlled clinical trial of 227 patients with HIV-related Kaposi's sarcoma, fever was reported in 47% of patients (n=116) receiving DAUNOrubicin citrate liposome 40 mg/m(2) and 54% of patients (n=111) receiving ABV (doxorubicin, bleomycin, and vincristine) (Prod Info DAUNOXOME(R) injection, 2002).
    2) FEVER: A 30-year-old afebrile woman with acute myeloblastic leukemia developed hypotension, fever (42 degrees Celsius), and coma 2 hours after starting an intravenous regimen of DAUNOrubicin 70 mg, vincristine 2 mg, cytarabine 100 mg, and prednisolone 50 mg. The temperature normalized after 2 hours and consciousness returned. It was speculated that the hyperpyrexia was probably due to DAUNOrubicin since repeated use of the other chemotherapy agents did not produce a similar reaction (Ma & Isbister, 1980).
    0.2.20) REPRODUCTIVE
    A) DAUNOrubicin is classified as FDA pregnancy category D. There are no adequate and well-controlled studies with DAUNOrubicin in pregnant women. Both successful pregnancies and adverse fetal outcome have been reported after DAUNOrubicin was used as part of combination chemotherapy. Embryonic, teratogenic, or fetotoxic effects have been observed in animal reproductive studies of DAUNOrubicin.
    0.2.21) CARCINOGENICITY
    A) Secondary leukemias have been reported in patients exposed to topoisomerase II inhibitors in combination with other antineoplastic agents or radiation therapy.

Laboratory Monitoring

    A) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery. Dose-dependent myelosuppression is the most frequent and severe toxicity associated with DAUNOrubicin. It manifests primarily as leukopenia, reaching a nadir towards the end of the second week of therapy and recovering by the end of the third week.
    B) 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.
    C) Monitor vital signs and serial ECGs; institute continuous cardiac monitoring. Evaluate for evidence of cardiomyopathy and congestive heart failure. Echocardiogram or radionucleotide studies may be useful.
    D) Monitor serum electrolytes, renal function, and hepatic enzymes.
    E) Evaluate patients for signs and symptoms of mucositis.

Treatment Overview

    0.4.4) EYE EXPOSURE
    A) Irrigate eyes with 0.9% saline or water. Perform an eye exam, including slit lamp, if irritation persists.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) Wash exposed skin well with soap and water and remove contaminated clothing.
    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Monitor for signs of congestive heart failure. Administer dexrazoxane to prevent cardiomyopathy. Treat 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. Monitor for signs of congestive heart failure. Dexrazoxane should be used for the prophylaxis of cardiomyopathy and to treat extravasation. Treat patients with heart failure with diuretics, vasodilators, ACE inhibitors, and inotropic agents as indicated. 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 TOXICITY
    1) Inadvertent intrathecal injection has been reported with DAUNOrubicin, resulting in severe neurotoxicity and death. After an overdose, keep the patient upright and immediately drain at least 20 mL of 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 saline). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 to 150 mL/hr for 24 hours). Add fresh frozen plasma (25 mL FFP per liter NS or LR) or 5% albumin to the perfusate to increase elimination as DAUNOrubicin is highly protein bound. Dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis.
    D) DECONTAMINATION
    1) Decontamination is not necessary in most situations as DAUNOrubicin is administered IV. For dermal exposures, cleanse skin with soap and water, and for eye exposures, flush with water.
    E) AIRWAY MANAGEMENT
    1) Intubate if patient is unable to protect airway or if unstable dysrhythmias develop.
    F) ANTIDOTE
    1) There is no antidote, but dexrazoxane should be administered as soon as possible if the dose administered puts the patient at risk for delayed cardiomyopathy, or if extravasation has occurred.
    G) 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.
    H) 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).
    I) 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.
    J) 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).
    K) EXTRAVASATION
    1) Withdraw as much solution as possible from the catheter before it is removed. Administer dexrazoxane 1000 mg/m(2) infused intravenously using a different venous access site over 1 to 2 hours on day 1 (MAX, 2000 mg) within 6 hours of extravasation. Repeat the same dose 24 +/- 3 hours after extravasation on day 2 (MAX, 2000 mg) followed by a 500 mg/m(2) dose 48 +/- 3 hours after extravasation on day 3 (MAX, 1000 mg). Severe injury may require debridement.
    L) DEXRAZOXANE
    1) Dexrazoxane is used to prevent cardiomyopathy at therapeutic doses. There is no published clinical experience after overdose, but it should be administered as soon as possible if the DAUNOrubicin overdose is recognized early. If the DAUNOrubicin overdose is not recognized early, there is probably little benefit to administering dexrazoxane. The usual dose of dexrazoxane to prevent cardiomyopathy is 10 times the doxorubicin dose (ie, 500 mg/m(2) dexrazoxane for a 50 mg/m(2) dose of doxorubicin). Additive myelosuppression generally occurs at dexrazoxane doses above 1000 mg/m(2), so doses larger than this should generally be avoided. For extravasation, the initial dose is 1000 mg/m(2) infused over 1 to 2 hours on day 1 (MAX, 2000 mg) and should be given within 6 hours of extravasation. Repeat the same dose 24 +/- 3 hours after extravasation on day 2 (MAX, 2000 mg) followed by a 500 mg/m(2) dose 48 +/- 3 hours after extravasation on day 3 (MAX, 1000 mg).
    M) 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 (eg, morphine, hydrocodone, oxycodone, fentanyl). 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 DAUNOrubicin overdose, administer palifermin 60 mcg/kg/day IV bolus injection starting 24 hours after the overdose for 3 consecutive days.
    N) ENHANCED ELIMINATION
    1) Dialysis is UNLIKELY to be of benefit due to high protein binding and large volume of distribution. Plasma exchange would be expected to remove significant amounts of liposomal DAUNOrubicin if performed soon after overdose, but there are no clinical reports of use of this technique.
    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 DAUNOrubicin overdose. Consult a cardiologist to manage patients with heart failure. May require surgical consult for extravasation.
    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. Symptoms in patients may be delayed (particularly myelosuppression and cardiomyopathy) so reliable follow up is imperative. Patients taking these medications may have severe co-morbidities and may be receiving other drugs with significant toxicity.
    Q) PHARMACOKINETICS
    1) Protein binding: DAUNOrubicin: 97%. DAUNOrubicin is rapidly and widely distributed in the tissues. The highest concentrations are observed in the spleen, kidneys, liver, lungs, and heart. Vd: DAUNOrubicin: 1006 +/- 622 L; liposomal DAUNOrubicin: 2.9 to 6.4 L; Metabolism: extensively metabolized in the liver and other tissues, mainly by cytoplasmic aldo-keto reductases. Active metabolite: DAUNOrubicinol. Elimination half-life: 45 minutes in the initial phase and 18.5 hours in the terminal phase. Liposomal DAUNOrubicin: 4.4 hours. DAUNOrubicinol: 26.7 hours.
    R) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that cause myelosuppression or cardiotoxicity.

Range Of Toxicity

    A) TOXICITY: Total cumulative doses of greater than 400 to 550 mg/m(2) in adults, 300 mg/m(2) in children greater than 2 years, and 10 mg/kg in children under 2 years of age have resulted in an increase in incidence of myocardial toxicity, including fatal congestive heart failure. Intrathecal injection of 17 mg DAUNOrubicin was fatal in a child.
    B) THERAPEUTIC DOSE: ADULTS: DAUNORUBICIN CITRATE LIPOSOME: 40 mg/m(2) IV over 60 minutes every 2 weeks; DAUNORUBICIN: The usual dose is 30 to 45 mg/m(2)/day for 2 to 3 days in combination with other agents; several courses may be given. CHILDREN : DAUNORUBICIN CITRATE LIPOSOME: The efficacy and safety of liposomal DAUNOrubicin have not been established in children. DAUNORUBICIN (over 2 years of age): The usual dose is 25 mg/m(2) on day 1 of every week in combination with other agents; several courses may be given. DAUNORUBICIN (under 2 years of age or body surface area less than 0.5 m(2)): A dose of 1 mg/kg in combination with other agents is recommended; several courses may be given.

Clinical Effects

Summary Of Exposure

    A) USES: DAUNOrubicin in combination with other agents is used for remission induction in adult and pediatric patients with acute lymphocytic leukemia and remission induction in adult patients with acute nonlymphocytic leukemia. DAUNOrubicin citrate liposome is used as a first-line cytotoxic therapy for advanced AIDS-associated Kaposi's sarcoma.
    B) PHARMACOLOGY: DAUNOrubicin hydrochloride is an antimitotic, antitumor and cytotoxic anthracycline antibiotic derived from the strain of Streptomyces coeruleorubidus. It intercalates between base pairs to form complexes with DNA. It maintains the stability of DNA-topoisomerase II complex which prevents topoisomerase II from catalyzing the religation part of the ligation-religation reaction leading to single and double strand DNA breaks. It also blocks polymerase activity, affects regulation of gene expression and produces free radical damage to DNA. Liposomal DAUNOrubicin is a liposomal preparation of DAUNOrubicin formulated to maximize the selectivity of DAUNOrubicin for solid tumors in situ.
    C) TOXICOLOGY: DAUNOrubicin interferes with DNA replication in rapidly dividing cells, such as bone marrow and gastrointestinal epithelium. Cardiac toxicity of DAUNOrubicin may be related to free radical production.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) The acute or subacute cardiotoxicity can develop within 1 to 23 days after the last dose of DAUNOrubicin. Manifestations can include conduction or rhythm disturbances (ie, tachycardia, supraventricular dysrhythmias, heart block) and abnormal ECG findings (nonspecific ST-T changes). A significant decrease in ejection fraction has been documented 24 to 48 hours after drug administration. DAUNOrubicin can also cause cumulative (lifetime), dose-dependent cardiomyopathy as a result of direct endomyocardial tissue damage. It is characterized by irreversible congestive heart failure, the mortality rate ranges from 50% to 80%.
    2) Bone marrow suppression is the acute dose-limiting toxicity. The following adverse effects have also been reported following therapeutic doses of DAUNOrubicin: Nausea, vomiting, diarrhea, stomatitis/mucositis, constipation, abdominal pain, anorexia, fatigue, fever, cough, dyspnea, rhinitis, sinusitis, headache, rigors, acute allergic reactions, back pain, arthralgia, myalgia, diaphoresis, neuropathy, edema, chest pain, malaise, alopecia, dizziness, pruritus, and abnormal vision. Severe local tissue necrosis, cellulitis, thrombophlebitis, or painful induration may develop if extravasation occurs during therapy with DAUNOrubicin.
    F) WITH POISONING/EXPOSURE
    1) Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses.
    2) MILD TO MODERATE TOXICITY: Nausea, vomiting, diarrhea, stomatitis, and myelosuppression may occur following DAUNOrubicin overdose.
    3) SEVERE TOXICITY: Severe myelosuppression (especially granulocytopenia), acute cardiomyopathy (ie, ECG changes, dysrhythmias, hypotension, heart failure), severe mucositis, vomiting, and diarrhea may develop.
    4) INTRATHECAL INJECTION: Severe neurotoxicity ( cerebral atrophy) and death have been reported after unintentional intrathecal administration of DAUNOrubicin.

Vital Signs

    3.3.1) SUMMARY
    A) Fever may occur following DAUNOrubicin therapy.
    B) WITH THERAPEUTIC USE
    1) In an open-label, randomized, controlled clinical trial of 227 patients with HIV-related Kaposi's sarcoma, fever was reported in 47% of patients (n=116) receiving DAUNOrubicin citrate liposome 40 mg/m(2) and 54% of patients (n=111) receiving ABV (doxorubicin, bleomycin, and vincristine) (Prod Info DAUNOXOME(R) injection, 2002).
    2) FEVER: A 30-year-old afebrile woman with acute myeloblastic leukemia developed hypotension, fever (42 degrees Celsius), and coma 2 hours after starting an intravenous regimen of DAUNOrubicin 70 mg, vincristine 2 mg, cytarabine 100 mg, and prednisolone 50 mg. The temperature normalized after 2 hours and consciousness returned. It was speculated that the hyperpyrexia was probably due to DAUNOrubicin since repeated use of the other chemotherapy agents did not produce a similar reaction (Ma & Isbister, 1980).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Conjunctivitis and eye pain have been reported with DAUNOrubicin citrate liposome (Prod Info DAUNOXOME(R) injection, 2002).
    2) In an open-label, randomized, controlled clinical trial of 227 patients with HIV-related Kaposi's sarcoma, abnormal vision was reported in 5% of patients (n=116) receiving DAUNOrubicin citrate liposome 40 mg/m(2) and 3% of patients (n=111) receiving ABV (doxorubicin, bleomycin, and vincristine) (Prod Info DAUNOXOME(R) injection, 2002).
    3.4.4) EARS
    A) WITH THERAPEUTIC USE
    1) Deafness, earache, and tinnitus have been reported with DAUNOrubicin citrate liposome (Prod Info DAUNOXOME(R) injection, 2002).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CARDIOMYOPATHY
    1) WITH THERAPEUTIC USE
    a) Acute or subacute cardiotoxicity can develop within 1 to 23 days after the last dose of DAUNOrubicin. Manifestations can include conduction or rhythm disturbances (ie, tachycardia, supraventricular dysrhythmias, heart block) and abnormal ECG findings (nonspecific ST-T changes). A significant decrease in ejection fraction has been documented 24 to 48 hours after drug administration (Bristow et al, 1978; Wong & Lampkin, 1983; Gilman et al, 1990).
    b) DAUNOrubicin can also cause cumulative (lifetime), dose-dependent cardiomyopathy as a result of direct endomyocardial tissue damage. It is characterized by irreversible congestive heart failure, resistant to digitalis. The mortality rate ranges from 50% to 80% (Gilman et al, 1990; Mortensen et al, 1986; Wong & Lampkin, 1983; Minow et al, 1977).
    c) RISK FACTORS: Infants and children; elderly; pre-existing heart disease; previous therapy with cardiotoxic agents (eg, doxorubicin); total cumulative doses of greater than 400 to 550 mg/m(2) in adults, 300 mg/m(2) in children greater than 2 years, and 10 mg/kg in children under 2 years of age; radiation therapy to the mediastinum (Prod Info CERUBIDINE(R) intravenous injection, 2008). Another source reported that cumulative-dose-related cardiomyopathy with congestive heart failure may occur with chronic therapy at total doses above 300 mg/m(2) (Prod Info DAUNOXOME(R) injection, 2002).
    1) A decrease in systolic ejection fraction and/or a decrease equal to or greater than 30% in limb lead QRS voltage may be associated with a significant risk for DAUNOrubicin cardiotoxicity (Prod Info CERUBIDINE(R) intravenous injection, 2008).
    d) PEDIATRICS
    1) Children (n=120) with acute lymphoblastic leukemia (ALL) treated with cumulative doses of DAUNOrubicin ranging from 90 to 270 mg/m(2) did not have signs or symptoms of heart failure at 6.2 years of follow-up; however, 1 sudden death occurred 8 years after treatment in an otherwise healthy male. Twenty-seven (23%) of all survivors had cardiac abnormalities determined by echocardiography. Increased afterload caused by reduced left ventricular posterior wall thickness occurred in 25 (21%) patients, and reduced contractility occurred in 2 patients (2%). Differences in cardiac adverse effects were not apparent between cumulative doses of 90 mg/m(2), 180 mg/m(2), or 270 mg/m(2) of DAUNOrubicin, which suggests that a completely safe dose of an anthracycline is not available. Disease-free survival was 71%, 61% to 62%, and 57%, for patients receiving cumulative doses of 270 mg/m(2), 180 mg/m(2), and 90 mg/m(2), respectively, of DAUNOrubicin (Sorensen et al, 1997).
    2) In studies, dose-related cardiotoxicity, characterized by impaired left ventricular systolic performance, reduced contractility, congestive heart failure, and death was reported in children after receiving DAUNOrubicin therapy. These conditions were aggravated by thoracic irradiation and appeared months to years after the discontinuation of therapy (Prod Info CERUBIDINE(R) intravenous injection, 2008).
    e) LIPOSOMAL DAUNORUBICIN
    1) Cardiac effects associated with DAUNOrubicin citrate liposome have included hypertension, palpitation, hot flushes, syncope, and tachycardia (Prod Info DAUNOXOME(R) injection, 2002; Gill et al, 1996). Pericardial effusion, pericardial tamponade, ventricular extrasystoles, sinus tachycardia, atrial fibrillation, pulmonary hypertension, myocardial infarction, supraventricular tachycardia, angina pectoris and cardiac arrest have also been reported in patients with Kaposi's sarcoma or other malignancies receiving DAUNOrubicin (Prod Info DAUNOXOME(R) injection, 2002). However, a causal relationship to DAUNOrubicin citrate liposome could not be determined.
    2) In one trial, patients tolerated cumulative doses of more than 1000 mg/m(2) without evidence of cardiotoxicity by repeated measurement of left-ventricular ejection fraction (LVEF) or clinical features of cardiac dysfunction. In this study, reductions in LVEF of 20%, 10%, and 9% were documented in 3 patients; none of these cases were associated with symptoms, and there were no instances of congestive heart failure. The relationship of these changes to DAUNOrubicin citrate liposome was uncertain, especially since 2 patients receiving 720 and 540 mg/m(2) had no significant change in LVEF, even though one had also received previous mediastinal radiation (Gill et al, 1995a).
    B) CHEST PAIN
    1) WITH THERAPEUTIC USE
    a) In an open-label, randomized, controlled clinical trial of 227 patients with HIV-related Kaposi's sarcoma, chest pain was reported in 10% of patients (n=116) receiving DAUNOrubicin citrate liposome 40 mg/m(2) and 7% of patients (n=111) receiving ABV (doxorubicin, bleomycin, and vincristine) (Prod Info DAUNOXOME(R) injection, 2002).
    C) EDEMA
    1) WITH THERAPEUTIC USE
    a) In an open-label, randomized, controlled clinical trial of 227 patients with HIV-related Kaposi's sarcoma, edema was reported in 11% of patients (n=116) receiving DAUNOrubicin citrate liposome 40 mg/m(2) and 9% of patients (n=111) receiving ABV (doxorubicin, bleomycin, and vincristine) (Prod Info DAUNOXOME(R) injection, 2002).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY FINDING
    1) WITH THERAPEUTIC USE
    a) In an open-label, randomized, controlled clinical trial of 227 patients with HIV-related Kaposi's sarcoma, the following respiratory effects were reported in patients (n=116) receiving DAUNOrubicin citrate liposome 40 mg/m(2): cough (28%), dyspnea (26%), rhinitis (12%), and sinusitis (8%) (Prod Info DAUNOXOME(R) injection, 2002).
    b) Other respiratory effects associated with DAUNOrubicin citrate liposome have included hemoptysis, hiccups, pulmonary infiltration, and increased sputum production (Prod Info DAUNOXOME(R) injection, 2002). However, a causal relationship to DAUNOrubicin citrate liposome could not be determined.

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) In a clinical trial, mild-to-moderate fatigue occurred in 59% of patients (n=39) receiving DAUNOrubicin citrate liposome in doses of up to 60 mg/m(2) every 2 weeks (Gill et al, 1995a).
    b) In an open-label, randomized, controlled clinical trial of 227 patients with HIV-related Kaposi's sarcoma, the following CNS effects were reported in patients (n=116) receiving DAUNOrubicin citrate liposome 40 mg/m(2): fatigue (49%), headache (25%), rigors (19%), neuropathy (13%), malaise (10%), dizziness (8%), and insomnia (6%) (Prod Info DAUNOXOME(R) injection, 2002).
    c) Central nervous system effects associated with DAUNOrubicin citrate liposome have included amnesia, anxiety, ataxia, confusion, convulsions, emotional lability, abnormal gait, hallucinations, hyperkinesia, meningitis, somnolence, hypertonia, and tremor (Prod Info DAUNOXOME(R) injection, 2002). However, a causal relationship to DAUNOrubicin citrate liposome could not be determined.
    2) WITH POISONING/EXPOSURE
    a) Fatigue may occur following DAUNOrubicin overdose (Prod Info DAUNOXOME(R) injection, 2002).
    B) CEREBRAL ATROPHY
    1) WITH POISONING/EXPOSURE
    a) INTRATHECAL ADMINISTRATION/CASE REPORT (PEDIATRIC): A 3.5-year-old child with acute lymphoblastic leukemia inadvertently received 17 mg (25 mg/m(2)) of DAUNOrubicin intrathecally instead of the intended route of IV. The error was recognized 1 hour later, and CSF barbotage was initiated along with intrathecal hydrocortisone. A subarachnoid lumbar catheter was placed and 450 mL of CSF was drained over 36 hours. Despite these measures, only 33% of the dose was recovered. The patient's clinical status deteriorated, and CT scans over 6 weeks demonstrated increasing cerebral atrophy. By 9 weeks, an EEG showed no neuronal activity. Ventilator support was removed and the patient subsequently expired. It is thought that the intrathecal DAUNOrubicin was responsible for the nervous system destruction (Mortensen et al, 1992).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting are common with DAUNOrubicin therapy and usually subside in 24 to 48 hours (Prod Info CERUBIDINE(R) intravenous injection, 2008; Gill et al, 1995a; Presant et al, 1993; Prod Info DAUNOXOME(R) injection, 2002).
    b) In an open-label, randomized, controlled clinical trial of 227 patients with HIV-related Kaposi's sarcoma, nausea was reported in 54% of patients (n=116) receiving DAUNOrubicin citrate liposome 40 mg/m(2) and 50% of patients (n=111) receiving ABV (doxorubicin, bleomycin, and vincristine). In the same study, vomiting was reported in 23% of patients (n=116) receiving DAUNOrubicin citrate liposome 40 mg/m(2) and 28% of patients (n=111) receiving ABV (doxorubicin, bleomycin, and vincristine) (Prod Info DAUNOXOME(R) injection, 2002).
    2) WITH POISONING/EXPOSURE
    a) Nausea and vomiting may occur following DAUNOrubicin overdose (Prod Info DAUNOXOME(R) injection, 2002).
    B) STOMATITIS
    1) WITH THERAPEUTIC USE
    a) Mucositis can develop 3 to 7 days after a course of treatment with DAUNOrubicin. The onset is characterized by a burning, painful sensation in the oral mucosa, followed 1 to 3 days later by ulcer formation that heals in 1 to 2 weeks. Mucosal ulcers can increase the risk of systemic infection, especially in neutropenic patients (Prod Info CERUBIDINE(R) intravenous injection, 2008; Wong & Lampkin, 1983).
    b) In an open-label, randomized, controlled clinical trial of 227 patients with HIV-related Kaposi's sarcoma, stomatitis was reported in 10% of patients (n=116) receiving DAUNOrubicin citrate liposome 40 mg/m(2) and 8% of patients (n=111) receiving ABV (doxorubicin, bleomycin, and vincristine) (Prod Info DAUNOXOME(R) injection, 2002).
    C) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea has been reported in patients receiving DAUNOrubicin (Prod Info CERUBIDINE(R) intravenous injection, 2008).
    b) In an open-label, randomized, controlled clinical trial of 227 patients with HIV-related Kaposi's sarcoma, diarrhea was reported in 38% of patients (n=116) receiving DAUNOrubicin citrate liposome 40 mg/m(2) and 35% of patients (n=111) receiving ABV (doxorubicin, bleomycin, and vincristine) (Prod Info DAUNOXOME(R) injection, 2002).
    D) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain has been reported in patients receiving DAUNOrubicin (Prod Info CERUBIDINE(R) intravenous injection, 2008).
    b) In an open-label, randomized, controlled clinical trial of 227 patients with HIV-related Kaposi's sarcoma, abdominal pain was reported in 23% of patients (n=116) receiving DAUNOrubicin citrate liposome 40 mg/m(2) and 27% of patients (n=111) receiving ABV (doxorubicin, bleomycin, and vincristine) (Prod Info DAUNOXOME(R) injection, 2002).
    E) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) In an open-label, randomized, controlled clinical trial of 227 patients with HIV-related Kaposi's sarcoma, anorexia was reported in 23% of patients (n=116) receiving DAUNOrubicin citrate liposome 40 mg/m(2) and 28% of patients (n=111) receiving ABV (doxorubicin, bleomycin, and vincristine) (Prod Info DAUNOXOME(R) injection, 2002).
    F) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) In an open-label, randomized, controlled clinical trial of 227 patients with HIV-related Kaposi's sarcoma, constipation was reported in 7% of patients (n=116) receiving DAUNOrubicin citrate liposome 40 mg/m(2) and 18% of patients (n=111) receiving ABV (doxorubicin, bleomycin, and vincristine) (Prod Info DAUNOXOME(R) injection, 2002).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Mild, reversible increases in aspartate aminotransferase (AST; SGOT) concentrations developed in 17 of 24 patients receiving DAUNOrubicin citrate liposome; however, since these patients were receiving multiple drugs for HIV infection, a causal relationship to DAUNOrubicin citrate liposome could not be determined (Presant et al, 1993).
    b) In another study, mild-to-moderate elevations in liver enzymes occurred in 10 patients and in 4% of cycles (13 of 289) (Gill et al, 1995a).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) DYSURIA
    1) WITH THERAPEUTIC USE
    a) Dysuria, nocturia, and polyuria have been reported with DAUNOrubicin citrate liposome (Prod Info DAUNOXOME(R) injection, 2002). However, a causal relationship to DAUNOrubicin citrate liposome could not be determined.

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) MYELOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) Dose-dependent myelosuppression is the most frequent and severe toxicity associated with DAUNOrubicin (Prod Info CERUBIDINE(R) intravenous injection, 2008; Prod Info DAUNOXOME(R) injection, 2002). It manifests primarily as leukopenia, reaching a nadir towards the end of the second week of therapy and recovering by the end of the third week (Wong & Lampkin, 1983).
    b) In clinical trials, neutropenia, anemia, and thrombocytopenia have occurred, but have generally not been severe except in patients receiving doses greater than 40 mg/m(2) every 14 days (Gill et al, 1995a; Guaglianone et al, 1994a).
    c) In an open-label, randomized, controlled clinical trial of 227 patients with HIV-related Kaposi's sarcoma, neutropenia (less than 1000 cells/mm(3)) was reported in 36% of patients (n=116) receiving DAUNOrubicin citrate liposome 40 mg/m(2) and 35% of patients (n=111) receiving ABV (doxorubicin, bleomycin, and vincristine). In the same trial, neutropenia (less than 500 cells/mm(3)) was reported in 15% of patients (n=116) receiving DAUNOrubicin citrate liposome 40 mg/m(2) and 5% of patients (n=111) receiving ABV (doxorubicin, bleomycin, and vincristine) (Prod Info DAUNOXOME(R) injection, 2002).
    2) WITH POISONING/EXPOSURE
    a) Myelosuppression (especially granulocytopenia) may occur following DAUNOrubicin overdose (Prod Info DAUNOXOME(R) injection, 2002).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) SKIN FINDING
    1) WITH THERAPEUTIC USE
    a) Folliculitis, seborrhea, and dry skin have been reported with DAUNOrubicin citrate liposome (Prod Info DAUNOXOME(R) injection, 2002). Rash, contact dermatitis, and urticaria may rarely occur in patients receiving DAUNOrubicin (Prod Info CERUBIDINE(R) intravenous injection, 2008).
    b) In an open-label, randomized, controlled clinical trial of 227 patients with HIV-related Kaposi's sarcoma, pruritus was reported in 7% of patients (n=116) receiving DAUNOrubicin citrate liposome 40 mg/m(2) and 14% of patients (n=111) receiving ABV (doxorubicin, bleomycin, and vincristine) (Prod Info DAUNOXOME(R) injection, 2002).
    B) SKIN NECROSIS
    1) WITH THERAPEUTIC USE
    a) EXTRAVASATION
    1) Severe local tissue necrosis, severe cellulitis, thrombophlebitis, or painful induration may develop if extravasation occurs during therapy with DAUNOrubicin (Prod Info CERUBIDINE(R) intravenous injection, 2008). Typically, the extravasated area will become erythematous and painful within 24 hours. Over the subsequent weeks, deep ulceration and local tissue necrosis can develop (DeVita et al, 1989).
    2) CASE REPORT: Digital necrosis involving the skin and subcutaneous tissues occurred in a 50-year-old woman following DAUNOrubicin infusion, immediately distal to an arteriovenous fistula of the wrist (Dragon & Braine, 1979).
    C) HAND-FOOT SYNDROME IN SICKLE CELL ANEMIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORTS: Two patients developed palmar-plantar erythrodysesthesia syndrome (Hand-foot syndrome) after treatment with liposomal DAUNOrubicin (Hui & Cortes, 2000).
    1) The first patient was a 54-year-old woman with relapsed acute myelogenous leukemia who received chemotherapy with liposomal DAUNOrubicin 125 mg/m(2) infused over 2 hours daily for 3 days plus cytarabine 1 g/m(2)/day. Previous induction chemotherapy contained cyclophosphamide, cytarabine, and topotecan with no report of cutaneous toxicities. Edema, desquamation, and tenderness were reported on both palms within 5 days of initiating liposomal DAUNOrubicin therapy. Triamcinolone cream was applied as needed and symptoms resolved within 3 weeks. Three more courses of chemotherapy containing liposomal DAUNOrubicin (dosed reduced secondary to prolonged myelosuppression) were subsequently given with no reports of palmar-plantar erythrodysesthesia.
    2) The second patient was a 64-year-old patient diagnosed with acute myelogenous leukemia (AML) 2 years after achieving remission for a diagnosis of chronic lymphocytic leukemia. AML induction therapy consisted of liposomal DAUNOrubicin 100 mg/m(2) infused over 6 hours daily for 3 days and cytarabine 1 g/m(2)/day as a continuous infusion for 3 days. The patient was also receiving imipenem-cilastatin, valacyclovir, and fluconazole. On day 4 of chemotherapy, the patient developed a rash on his body as well as redness and soreness confined to his palms and soles. Within a few days of changing the imipenem-cilastatin to cefepime and administering steroids the redness and soreness resolved .
    D) HYPERPIGMENTATION OF SKIN
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Extensive hyperpigmentation occurred in a 47-year-old man with acute myelocytic leukemia after DAUNOrubicin therapy. Chemotherapy was initiated with DAUNOrubicin 75 mg IV on days 1, 2, and 3 and cytarabine 160 mg/day by continuous IV infusion for 7 days. A second course was administered 17 days after chemotherapy was initially begun. One month after first receiving these drugs, the patient's skin over the face, neck, arms, and upper part of the chest and back darkened and looked erythematous. The hyperpigmentation disappeared within 6 to 8 weeks after chemotherapy was completed. Following the use of DAUNOrubicin again, the hyperpigmentation returned within 2 weeks and covered the same areas of the body (Kelly et al, 1984).
    E) NAIL FINDING
    1) WITH THERAPEUTIC USE
    a) Hyperpigmentation of the nail beds and skin may occur (Dorr & Fritz, 1980).
    F) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) Reversible alopecia has been reported in 4% to 8% of patients receiving DAUNOrubicin (Prod Info CERUBIDINE(R) intravenous injection, 2008; Prod Info DAUNOXOME(R) injection, 2002; Gill et al, 1996; Gill et al, 1995a; Presant et al, 1993).
    G) EXCESSIVE SWEATING
    1) WITH THERAPEUTIC USE
    a) In an open-label, randomized, controlled clinical trial of 227 patients with HIV-related Kaposi's sarcoma, increased sweating was reported in 14% of patients (n=116) receiving DAUNOrubicin citrate liposome 40 mg/m(2) and 12% of patients (n=111) receiving ABV (doxorubicin, bleomycin, and vincristine) (Prod Info DAUNOXOME(R) injection, 2002).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) BACKACHE
    1) WITH THERAPEUTIC USE
    a) In an open-label, randomized, controlled clinical trial of 227 patients with HIV-related Kaposi's sarcoma, back pain was reported in 16% of patients (n=116) receiving DAUNOrubicin citrate liposome 40 mg/m(2) and 8% of patients (n=111) receiving ABV (doxorubicin, bleomycin, and vincristine).(Prod Info DAUNOXOME(R) injection, 2002).
    B) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) In an open-label, randomized, controlled clinical trial of 227 patients with HIV-related Kaposi's sarcoma, arthralgia was reported in 7% of patients (n=116) receiving DAUNOrubicin citrate liposome 40 mg/m(2) and 6% of patients (n=111) receiving ABV (doxorubicin, bleomycin, and vincristine).(Prod Info DAUNOXOME(R) injection, 2002).
    C) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) In an open-label, randomized, controlled clinical trial of 227 patients with HIV-related Kaposi's sarcoma, myalgia was reported in 7% of patients (n=116) receiving DAUNOrubicin citrate liposome 40 mg/m(2) and 12% of patients (n=111) receiving ABV (doxorubicin, bleomycin, and vincristine).(Prod Info DAUNOXOME(R) injection, 2002).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERURICEMIA
    1) WITH THERAPEUTIC USE
    a) Hyperuricemia may occur in patients receiving DAUNOrubicin(Prod Info CERUBIDINE(R) intravenous injection, 2008).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) Acute allergic reactions, including anaphylactoid reaction (rarely) have been reported in patients receiving DAUNOrubicin (Prod Info CERUBIDINE(R) intravenous injection, 2008; Prod Info DAUNOXOME(R) injection, 2002).
    b) In an open-label, randomized, controlled clinical trial of 227 patients with HIV-related Kaposi's sarcoma, acute allergic reactions were reported in 24% of patients (n=116) receiving DAUNOrubicin citrate liposome 40 mg/m(2) and 21% of patients (n=111) receiving ABV (doxorubicin, bleomycin, and vincristine) (Prod Info DAUNOXOME(R) injection, 2002).

Reproductive

    3.20.1) SUMMARY
    A) DAUNOrubicin is classified as FDA pregnancy category D. There are no adequate and well-controlled studies with DAUNOrubicin in pregnant women. Both successful pregnancies and adverse fetal outcome have been reported after DAUNOrubicin was used as part of combination chemotherapy. Embryonic, teratogenic, or fetotoxic effects have been observed in animal reproductive studies of DAUNOrubicin.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) CHEMOTHERAPY AGENTS
    a) The teratogenic potential of chemotherapeutic agents is difficult to assess because of the relatively small number of reports, variation in dosages, routes of administration, timing of administration with respect to gestational age, and the variety of combinations of drugs administered. Although fetal exposure to chemotherapy throughout all trimesters of pregnancy has been reported to not induce abnormalities, there is no assurance that deleterious fetal effects will not occur. Exposure during the first trimester is still considered by the majority of practitioners as the most critical for abnormal fetal development (Glantz, 1994).
    B) ANIMAL STUDIES
    1) Animal studies have indicated that DAUNOrubicin causes fetal abnormalities, including parieto-occipital cranioschisis, umbilical hernias, and rachischisis in rabbits at doses of 0.05 mg/kg/day (approximately 1/100th of the maximum human dose based on body surface area). DAUNOrubicin administered to rats at a dose of 4 mg/kg/day (approximately 1/2 the human dose based on body surface area) caused an increase in esophageal, cardiovascular, and urogenital abnormalities, and rib fusions (Prod Info CERUBIDINE(R) intravenous injection, 2008).
    2) LIPOSOMAL DAUNORUBICIN: In animal studies, fetal malformations (anophthalmia, microphthalmia, incomplete ossification) were observed in rats administered liposomal DAUNOrubicin 0.3 mg/kg/day (approximately 1/20th the recommended human dose on a mg/m(2) basis) on gestation days 6 through 15 (Prod Info DAUNOXOME(R) injection, 2002).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) DAUNOrubicin is classified as FDA pregnancy category D (Prod Info CERUBIDINE(R) intravenous injection, 2008).
    B) CHROMOSOMAL ABNORMALITIES
    1) CASE REPORT: In one case report, DAUNOrubicin was used with other cytotoxic drugs to treat acute lymphoblastic leukemia in a 34-year-old woman during the 22nd week of pregnancy. A healthy infant was born after 18 weeks of chemotherapy. The infant had a normal karyotype, but with several gaps and a ring chromosome. Chromosome abnormalities may increase the risk of cancer and genetic damage in the next generation (Schleuning & Clemm, 1987).
    C) COMBINATION THERAPY
    1) There are numerous case reports of DAUNOrubicin used during pregnancy in combination with other chemotherapeutic agents. Most resulted in no congenital malformations in the infants (Colbert et al, 1980; Alegre et al, 1982; Gililland & Weinstein, 1983).
    2) CASE SERIES: A total of 160 patients who received anthracyclines during pregnancy for leukemia or solid tumors were analyzed. Most patients received either doxorubicin (n=99; 62%) or DAUNOrubicin (n=50; 31%) during the study period, along with other chemotherapeutic agents: antimetabolites (37%) alkylating agents (20%), mitotic spindle poisons (20%) or others in 90% of patients. The median duration of treatment with doxorubicin and DAUNOrubicin were 12 and 5 weeks, respectively. The duration of exposure was not associated with the occurrence of severe fetal toxicity, but the risk of severe fetal toxicity increased 30-fold when the dose per cycle of doxorubicin exceeded 70 mg/m(2) per cycle (p=0.037). Fetal outcome was normal in 123 cases, with fetal death reported in 15 cases (6 cases were directly associated with maternal death). During the study, five malformations developed and were all associated with combination regimens (ie, antimetabolites or alkylating agents along with either DAUNOrubicin (3 cases) or doxorubicin (2 cases). The effects were variable and affected any organ. Spontaneous abortion was reported in 4 cases with 2 cases occurring in the first trimester. Drug therapy during the second and third trimester was associated with anthracycline-induced toxicities (eg, cardiac toxicity). Nine cases of prematurity occurred after exposure during the second trimester, with respiratory distress (73%), ventricular hemorrhage (18%), and enterocolitis (9%) reported the most frequently (Germann et al, 2004).
    D) ANIMAL STUDIES
    1) Animal studies have indicated that DAUNOrubicin causes abortions in rabbits at doses of 0.05 mg/kg/day (approximately 1/100th of the maximum human dose based on body surface area). Low birth weight and decreased growth rate were observed in mice (Prod Info CERUBIDINE(R) intravenous injection, 2008).
    2) LIPOSOMAL DAUNORUBICIN: In animal studies, severe maternal toxicity and embryolethality were observed in rats administered liposomal DAUNOrubicin 2 mg/kg/day (approximately one-third the recommended human dose on a mg/m(2) basis) on gestation days 6 through 15 . Embryotoxicity (increased embryo-fetal deaths, reduced numbers of litters, and reduced litter sizes) was observed in rats administered liposomal DAUNOrubicin 0.3 mg/kg/day (approximately 1/20th the recommended human dose on a mg/m(2) basis) on gestation days 6 through 15 (Prod Info DAUNOXOME(R) injection, 2002).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) CHEMOTHERAPY AGENTS
    a) The effects on the nursing infant from exposure to DAUNOrubicin in milk are unknown. Until more data are available, nursing should be discontinued during chemotherapy (Prod Info CERUBIDINE(R) intravenous injection, 2008).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Testicular atrophy was noted in male dogs administered IV DAUNOrubicin at a daily dose of 0.25 mg/kg. Histological examination confirmed total aplasia of the spermatocyte series in the seminiferous tubules with complete aspermatogenesis (Prod Info CERUBIDINE(R) intravenous injection, 2008).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) Secondary leukemias have been reported in patients exposed to topoisomerase II inhibitors in combination with other antineoplastic agents or radiation therapy.
    3.21.3) HUMAN STUDIES
    A) SECONDARY LEUKEMIAS
    1) Secondary leukemias have been reported in patients exposed to topoisomerase II inhibitors in combination with other antineoplastic agents or radiation therapy (Prod Info CERUBIDINE(R) intravenous injection, 2008).
    3.21.4) ANIMAL STUDIES
    A) DAUNORUBICIN
    1) MICE AND RATS: DAUNOrubicin caused fibrosarcomas at the injection site when administered subQ to mice. Rats administered a single dose of IV DAUNOrubicin (1.6 times the recommended human dose) developed mammary adenocarcinomas at 1 year. Male rats administered DAUNOrubicin three times weekly for 6 months (1/70th the human dose based on body surface area) developed peritoneal sarcomas after 18 months of observation (Prod Info CERUBIDINE(R) intravenous injection, 2008).
    B) LACK OF EFFECT
    1) MICE: There were no carcinogenic effects observed in mice administered intraperitoneal DAUNOrubicin 3 times weekly after 18 months (Prod Info CERUBIDINE(R) intravenous injection, 2008).

Genotoxicity

    A) DAUNOrubicin was mutagenic or clastogenic in the following tests: in vitro Ames assay, V79 hamster cell assay, in vitro CCRFCEM human lymphoblasts, and in the in vivo SCE assay in mouse bone marrow test (Prod Info CERUBIDINE(R) intravenous injection, 2008).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery. Dose-dependent myelosuppression is the most frequent and severe toxicity associated with DAUNOrubicin. It manifests primarily as leukopenia, reaching a nadir towards the end of the second week of therapy and recovering by the end of the third week.
    B) 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.
    C) Monitor vital signs and serial ECGs; institute continuous cardiac monitoring. Evaluate for evidence of cardiomyopathy and congestive heart failure. Echocardiogram or radionucleotide studies may be useful.
    D) Monitor serum electrolytes, renal function, and hepatic enzymes.
    E) Evaluate patients for signs and symptoms of mucositis.
    4.1.2) SERUM/BLOOD
    A) HEMATOLOGIC
    1) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery. Dose-dependent myelosuppression is the most frequent and severe toxicity associated with DAUNOrubicin (Prod Info CERUBIDINE(R) intravenous injection, 2008; Prod Info DAUNOXOME(R) injection, 2002). It manifests primarily as leukopenia, reaching a nadir towards the end of the second week of therapy and recovering by the end of the third week (Prod Info Cerubidine(R), 1999; Gilman et al, 1990; Wong & Lampkin, 1983).
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) ENDOMYOCARDIAL BIOPSY: Other than endomyocardial biopsy, noninvasive methods of assessment of cardiac function that accurately monitor for DAUNOrubicin cardiotoxicity are lacking. A decrease in systolic ejection fraction and/or a decrease equal to or greater than 30% in limb lead QRS voltage may be associated with a significant risk for DAUNOrubicin cardiotoxicity and are currently suggested as possible monitoring parameters before each course of DAUNOrubicin (Prod Info CERUBIDINE(R) intravenous injection, 2008).

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 DAUNOrubicin overdose. Consult a cardiologist to manage patients with heart failure. May require surgical consult for extravasation.
    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 serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery. Dose-dependent myelosuppression is the most frequent and severe toxicity associated with DAUNOrubicin. It manifests primarily as leukopenia, reaching a nadir towards the end of the second week of therapy and recovering by the end of the third week.
    B) 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.
    C) Monitor vital signs and serial ECGs; institute continuous cardiac monitoring. Evaluate for evidence of cardiomyopathy and congestive heart failure. Echocardiogram or radionucleotide studies may be useful.
    D) Monitor serum electrolytes, renal function, and hepatic enzymes.
    E) Evaluate patients for signs and symptoms of mucositis.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Decontamination is not necessary in most situations as DAUNOrubicin is administered IV. For dermal exposures, clean skin with soap and water, and for eye exposures, flush with water.
    6.5.3) TREATMENT
    A) GENERAL TREATMENT
    1) Treatment should include recommendations listed in the PARENTERAL EXPOSURE section when appropriate.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Dialysis is UNLIKELY to be of benefit due to high protein binding and large volume of distribution.
    B) PLASMA EXCHANGE
    1) Plasma exchange would be expected to remove significant amounts of liposomal DAUNOrubicin if performed soon after overdose, but there are no clinical reports of use of this technique.

Range Of Toxicity

Summary

    A) TOXICITY: Total cumulative doses of greater than 400 to 550 mg/m(2) in adults, 300 mg/m(2) in children greater than 2 years, and 10 mg/kg in children under 2 years of age have resulted in an increase in incidence of myocardial toxicity, including fatal congestive heart failure. Intrathecal injection of 17 mg DAUNOrubicin was fatal in a child.
    B) THERAPEUTIC DOSE: ADULTS: DAUNORUBICIN CITRATE LIPOSOME: 40 mg/m(2) IV over 60 minutes every 2 weeks; DAUNORUBICIN: The usual dose is 30 to 45 mg/m(2)/day for 2 to 3 days in combination with other agents; several courses may be given. CHILDREN : DAUNORUBICIN CITRATE LIPOSOME: The efficacy and safety of liposomal DAUNOrubicin have not been established in children. DAUNORUBICIN (over 2 years of age): The usual dose is 25 mg/m(2) on day 1 of every week in combination with other agents; several courses may be given. DAUNORUBICIN (under 2 years of age or body surface area less than 0.5 m(2)): A dose of 1 mg/kg in combination with other agents is recommended; several courses may be given.

Therapeutic Dose

    7.2.1) ADULT
    A) DAUNORUBICIN CITRATE LIPOSOME: 40 mg/m(2) IV over 60 minutes every 2 weeks safety (Prod Info DaunoXome(R) intravenous injection, 2011)
    B) DAUNORUBICIN
    1) ACUTE NONLYMPHOCYTIC LEUKEMIA: In combination with other agents, 30 to 45 mg/m(2) on days 1, 2, and 3 days of the first course and on days 1 and 2 on subsequent courses (Prod Info daunorubicin HCl intravenous injection, 2012)
    2) ADULT ACUTE LYMPHOCYTIC LEUKEMIA: In combination with other agents, 45 mg/m(2) on days 1, 2, and 3 (Prod Info daunorubicin HCl intravenous injection, 2012)
    7.2.2) PEDIATRIC
    A) DAUNORUBICIN CITRATE LIPOSOME: Safety and efficacy in the pediatric or adolescent population have not been established (Prod Info DaunoXome(R) intravenous injection, 2011).
    B) DAUNORUBICIN (over 2 years of age): In combination with other agents, 25 mg/m(2) on day 1 of every week; several courses may be given (Prod Info daunorubicin HCl intravenous injection, 2012)
    C) DAUNORUBICIN (under 2 years of age or body surface area less than 0.5 m(2)): In combination with other agents, 1 mg/kg; several courses may be given(Prod Info daunorubicin HCl intravenous injection, 2012)

Minimum Lethal Exposure

    A) Total cumulative doses of greater than 400 to 550 mg/m(2) in adults, 300 mg/m(2) in children greater than 2 years, and 10 mg/kg in children under 2 years of age have resulted in an increase in incidence of myocardial toxicity, including fatal congestive heart failure (Prod Info CERUBIDINE(R) intravenous injection, 2008).
    B) INTRATHECAL - A 3.5-year-old child with acute lymphoblastic leukemia inadvertently received 17 mg (25 mg/m(2)) of DAUNOrubicin intrathecally instead of the intended route of IV. The error was acknowledged 1 hour later, and CSF barbotage was initiated along with intrathecal hydrocortisone. Despite these measures and allowing the CSF to drain for 36 hours, only 33% of the dose was recovered. The patient's clinical status deteriorated, and CT scans over 6 weeks demonstrated increasing cerebral atrophy. By 9 weeks, an EEG showed no neuronal activity. Ventilator support was removed and the patient subsequently expired. It is thought that the intrathecal DAUNOrubicin was responsible for the nervous system destruction (Mortensen et al, 1992).

Maximum Tolerated Exposure

    A) In one trial, patients tolerated cumulative doses of more than 1000 mg/m(2) without evidence of cardiotoxicity by repeated measurement of left-ventricular ejection fraction (LVEF) or clinical features of cardiac dysfunction. In this study, reductions in LVEF of 20%, 10%, and 9% were documented in 3 patients; none of these cases were associated with symptoms, and there were no instances of congestive heart failure. The relationship of these changes to DAUNOrubicin citrate liposome was uncertain, especially since 2 patients receiving 720 and 540 mg/m(2) had no significant change in LVEF, even though one had also received previous mediastinal radiation (Gill et al, 1995a).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAPERITONEAL)MOUSE:
    1) 2500 mcg/kg (RTECS, 2006)
    B) LD50- (ORAL)MOUSE:
    1) 205 mg/kg (RTECS, 2006)
    C) LD50- (INTRAPERITONEAL)RAT:
    1) 20 mg/kg (RTECS, 2006)
    D) LD50- (ORAL)RAT:
    1) 336 mg/kg (RTECS, 2006)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) DAUNOrubicin hydrochloride, an antimitotic, antitumor and cytotoxic anthracycline antibiotic derived from the strain of Streptomyces coeruleorubidus, intercalates between base pairs to form complexes with DNA. It maintains the stability of DNA-topoisomerase II complex which prevents topoisomerase II from catalyzing the religation part of the ligation-religation reaction leading to single and double strand DNA breaks. It also blocks polymerase activity, affects regulation of gene expression and produces free radical damage to DNA (Prod Info daunorubicin HCl intravenous injection, 2012).
    B) LIPOSOMAL DAUNORUBICIN: Liposomal DAUNOrubicin is a liposomal preparation of DAUNOrubicin formulated to increase the selectivity of DAUNOrubicin for solid tumors in situ (Prod Info DaunoXome(R) intravenous injection, 2011; Forssen et al, 1992; Forssen & Ross, 1994).

Toxicologic Mechanism

    A) Anthracyclines interfere with DNA replication in rapidly dividing cells, such as bone marrow and gastrointestinal epithelium. Cardiac toxicity of doxorubicin may be related to free radical production. Doxorubicin accumulates in cardiac tissue. Cardiac toxicity may be an oxidative mechanism. Cardiac tissue is not adequately equipped to handle the quantity of free radical produced (Olson et al, 1981).

Physicochemical

Physical Characteristics

    A) DAUNOrubicin hydrochloride is a hygroscopic, crystalline, reddish, lyophilized powder that is soluble in water (Prod Info CERUBIDINE(R) intravenous injection, 2008).

Ph

    A) 4.5 to 6.5 (5 mg/mL solution) (Prod Info CERUBIDINE(R) intravenous injection, 2008)

Molecular Weight

    A) 563.99 (Prod Info CERUBIDINE(R) intravenous injection, 2008)

References

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    55) Product Information: ADRIAMYCIN intravenous injection, DOXOrubicin HCl intravenous injection. Bedford Laboratories, Bedford, OH, 2006.
    56) Product Information: CERUBIDINE(R) intravenous injection, daunorubicin HCl intravenous injection. Bedford Laboratories, Bedford, OH, 2008.
    57) Product Information: COMPAZINE(R) tablets, injection, suppositories, syrup, prochlorperazine tablets, injection, suppositories, syrup. GlaxoSmithKline, Research Triangle Park, NC, 2004.
    58) Product Information: Cerubidine(R), daunorubicin. Ben Venue Laboratories, Bedford, OH, USA, 1999.
    59) Product Information: Compazine(R), prochlorperazine maleate spansule. GlaxoSmithKline, Research Triangle Park, NC, 2002.
    60) Product Information: DAUNOXOME(R) injection, daunorubicin citrate liposome injection. Gilead Sciences, San Dimas, CA, 2002.
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    63) Product Information: LEUKINE(R) subcutaneous, IV injection, sargramostim subcutaneous, IV injection. Bayer Healthcare, Seattle, WA, 2008.
    64) Product Information: NEUPOGEN(R) IV, subcutaneous injection, filgrastim IV, subcutaneous injection. Amgen Manufacturing, Thousand Oaks, CA, 2010.
    65) Product Information: Totect(TM) intravenous injection, dexrazoxane intravenous injection. TopoTarget USA Inc., Rockaway, NJ, 2009.
    66) Product Information: ZINECARD(R) IV injection, dexrazoxane hcl iv injection. Pharmacia & Upjohn Company, New York, NY, 2004.
    67) Product Information: Zinecard (R), dexrazoxane for injection. Pharmacia & Upjohn Company, New York, NY, 2005.
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