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  • CLASSES

    Anthracyclines

    BOXED WARNING

    Bone marrow suppression, herpes infection, infection, neutropenia, requires a specialized care setting, requires an experienced clinician, thrombocytopenia, varicella, viral infection

    Severe bone marrow suppression is a relative contraindication to daunorubicin depending upon the etiology of the suppression. Patients with acute leukemia may require treatment with daunorubicin despite severe bone marrow suppression. Daunorubicin should be used cautiously in patients with bone marrow suppression, coagulopathy, or in those who have received previous myelosuppressive therapy such as chemotherapy or radiotherapy. Therefore, treatment with this drug requires an experienced clinician knowledgeable in the use of cancer chemotherapy, and administration of daunorubicin requires a specialized care setting, such as a hospital or treatment facility. Patients with preexisting marrow suppression, including neutropenia and/or thrombocytopenia, should be allowed to recover their counts prior to daunorubicin administration. Patients should be treated for any active infection prior to receiving daunorubicin. Patients with a history of varicella zoster, other herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of the infection when treated with chemotherapy.

    Extravasation, intramuscular administration, subcutaneous administration

    Daunorubicin is considered a vesicant. Extravasation of daunorubicin infusions should be avoided. Patients should be closely monitored for signs and symptoms of extravasation including pain, swelling and decreased blood return. If extravasation occurs, stop the infusion and remove the tubing. Attempt to aspirate the drug prior to removing the needle. Elevate the affected area and treat with ice packs. As this can be a progressive injury, appropriate long-term follow-up is required. Intramuscular administration and subcutaneous administration of daunorubicin is contraindicated due to severe skin and tissue necrosis which may occur.

    Renal failure, renal impairment

    Daunorubicin is eliminated renally. Dosage adjustments are recommended in patients with renal impairment or renal failure to avoid toxicity.

    Cardiac disease, cardiotoxicity, maximum cumulative lifetime dose

    Severe cardiotoxicity including fatal congestive heart failure may occur during daunorubicin therapy or months to years after discontinuing therapy. Cardiotoxicity is dose related and the incidence increases after total cumulative doses exceeding 400 to 550 mg/m2 in adults, 300 mg/m2 in patients greater than 2 years of age, or 10 mg/kg in patients less than 2 years of age. The maximum cumulative lifetime dose of daunorubicin is 550 mg/m2 IV, or 400 mg/m2 IV in patients who have previously received mediastinal radiation. A history of cardiac disease and previous therapy with doxorubicin may increase the risk of daunorubicin-induced cardiotoxicity; perform a risk/benefit analysis prior to starting therapy in these patients. Monitor electrocardiogram and/or systolic ejection fraction prior to each course of daunorubicin therapy.

    DEA CLASS

    Rx

    DESCRIPTION

    Anthracycline chemotherapy agent
    Used in combination with other anticancer drugs in patients with acute leukemias
    Cardiotoxicity and myelosuppression have been reported

    COMMON BRAND NAMES

    Cerubidine

    HOW SUPPLIED

    Cerubidine/Daunorubicin Hydrochloride Intravenous Inj Pwd F/Sol: 20mg
    Daunorubicin Hydrochloride Intravenous Inj Sol: 1mL, 5mg

    DOSAGE & INDICATIONS

    For the treatment of acute nonlymphocytic leukemia including acute myelogenous leukemia (AML).
    As remission induction therapy of acute nonlymphocytic leukemia, in combination with other anticancer agents.
    Intravenous dosage
    Adults less than 60 years

    initial induction therapy, 45 mg/m2 IV daily on days 1, 2, and 3 in combination with cytarabine 100 mg/m2 IV daily for 7 days. Following a bone marrow evaluation, up to 3 courses of induction therapy may be required. For subsequent induction therapy, give daunorubicin 45 mg/m2 IV daily on days 1 and 2 in combination with cytarabine 100 mg/m2 IV daily for 5 days. Higher daunorubicin doses of 60 mg/m2 IV and 90 mg/m2 IV for 3 days (off-label use) in combination with cytarabine have also been evaluated as initial induction therapy in patients with AML in randomized trials.

    Adults 60 years or older

    initial induction therapy, 30 mg/m2 IV daily on days 1, 2, and 3 in combination with cytarabine 100 mg/m2 IV daily for 7 days. Following a bone marrow evaluation, up to 3 courses of induction therapy may be required. For subsequent induction therapy, give daunorubicin 30 mg/m2 IV daily on days 1 and 2 in combination with cytarabine 100 mg/m2 IV daily for 5 days. Higher daunorubicin doses (initial induction, 45 mg/m2 IV daily on days 1, 2, and 3; subsequent induction, 45 mg/m2 IV daily on days 1 and 2) may be appropriate if optimal supportive care is available. High-dose daunorubicin 90 mg/m2 IV for 3 days (off-label use) in combination with cytarabine has also been evaluated as initial induction therapy in elderly patients aged 60 to 83 years with AML in a randomized, phase 3 trial.

    For the treatment of acute lymphocytic leukemia (ALL).
    As remission induction therapy of ALL, in combination with other anticancer agents.
    Intravenous dosage
    Adults

    45 mg/m2 IV daily on days 1, 2, and 3 in combination with vincristine 2 mg IV on days 1, 8, and 15; prednisone 40 mg/m2 orally daily on days 1 to 22 (then tapered between days 22 to 29); and L-asparaginase 500 international units/kg IV daily for 10 days on days 22 to 32.

    Children 2 years and older and Adolescents

    25 mg/m2 (or 1 mg/kg in patients with a body surface area less than 0.5 m2) IV on day 1 every week in combination with vincristine 1.5 mg/m2 IV on day 1 every week and prednisone 40 mg/m2 orally daily. If a complete remission has not been achieved within 4 courses of therapy and the patient is in a partial remission, an additional 1 or 2 courses may be given.

    Infants and Children less than 2 years

    1 mg/kg IV on day 1 every week in combination with vincristine 1.5 mg/m2 IV on day 1 every week and prednisone 40 mg/m2 orally daily. If a complete remission has not been achieved within 4 courses of therapy and the patient is in a partial remission, an additional 1 or 2 courses may be given.

    MAXIMUM DOSAGE

    Adults

    45 mg/m2 IV, although doses up to 90 mg/m2 IV have been used off-label; maximum cumulative anthracycline dose is 550 mg/m2 (or 400 mg/m2 in patients who have received radiation therapy involving the heart area).

    Geriatric

    45 mg/m2 IV, although doses up to 90 mg/m2 IV have been used off-label; maximum cumulative lifetime anthracycline dose is 550 mg/m2 (or 400 mg/m2 in patients who have received radiation therapy involving the heart area).

    Adolescents

    25 mg/m2 IV weekly; maximum cumulative dose is 300 mg/m2 IV.

    Children

    2 years or older: 25 mg/m2 (or 1 mg/kg in children with a body surface area less than 0.5 m2); maximum cumulative dose is 300 mg/m2 IV.Less than 2 years: 1 mg/kg IV weekly label; maximum cumulative dose is 10 mg/kg.

    Infants

    1 mg/kg IV weekly label; maximum cumulative dose is 10 mg/kg.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Serum bilirubin level of 1.2 to 3 mg/dL: decrease the daunorubicin dose by 25%.Serum bilirubin level greater than 3 mg/dL: decrease the daunorubicin dose by 50%.

    Renal Impairment

    Serum creatinine level greater than 3 mg/dL: decrease the daunorubicin dose by 50%.

    ADMINISTRATION

    CAUTION: Observe and exercise appropriate precautions for handling, preparing, and administering cytotoxic drugs. For accidental daunorubicin contact with the skin or mucosa, wash the area thoroughly with soap and water.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Daunorubicin is available as a sterile, single-dose 5 mg/mL solution vial.
    Do NOT administer intramuscularly or subcutaneously.
    Monitor the IV infusion site for signs or symptoms of extravasation.
    Dilution:
    Add the calculated dose (volume) of daunorubicin to a syringe containing 10 to 15 mL of 0.9% Sodium Chloride injection.
    Storage: Store at room temperature (20 to 25 degrees C; 68 to 77 degrees F) for up to 24 hours protected from light; discard unused vial portion.
    Intravenous Injection:
    Inject daunorubicin into the tubing or sidearm of a rapidly flowing IV infusion of 0.9% Sodium Chloride injection or 5% Dextrose injection.
    Do not mix with other drugs including heparin.

    STORAGE

    Generic:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in carton until contents are used
    Cerubidine:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Anthracycline hypersensitivity

    Daunorubicin is contraindicated in patients with known daunorubicin hypersensitivity; it is prudent to use with caution in patients with documented allergic reaction to other anthracycline medications (i.e., anthracycline hypersensitivity).

    Bone marrow suppression, herpes infection, infection, neutropenia, requires a specialized care setting, requires an experienced clinician, thrombocytopenia, varicella, viral infection

    Severe bone marrow suppression is a relative contraindication to daunorubicin depending upon the etiology of the suppression. Patients with acute leukemia may require treatment with daunorubicin despite severe bone marrow suppression. Daunorubicin should be used cautiously in patients with bone marrow suppression, coagulopathy, or in those who have received previous myelosuppressive therapy such as chemotherapy or radiotherapy. Therefore, treatment with this drug requires an experienced clinician knowledgeable in the use of cancer chemotherapy, and administration of daunorubicin requires a specialized care setting, such as a hospital or treatment facility. Patients with preexisting marrow suppression, including neutropenia and/or thrombocytopenia, should be allowed to recover their counts prior to daunorubicin administration. Patients should be treated for any active infection prior to receiving daunorubicin. Patients with a history of varicella zoster, other herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of the infection when treated with chemotherapy.

    Radiation therapy

    Patients who have had previous radiation therapy may experience radiation recall reactions during daunorubicin therapy. Daunorubicin is a radiation sensitizer and should be used with caution in patients receiving concurrent radiation therapy.

    Dental disease, dental work

    Myelosuppressive effects of daunorubicin can increase the risk of infection or bleeding; therefore, dental work should be delayed until blood counts have returned to normal. Patients, especially those with dental disease, should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks.

    Extravasation, intramuscular administration, subcutaneous administration

    Daunorubicin is considered a vesicant. Extravasation of daunorubicin infusions should be avoided. Patients should be closely monitored for signs and symptoms of extravasation including pain, swelling and decreased blood return. If extravasation occurs, stop the infusion and remove the tubing. Attempt to aspirate the drug prior to removing the needle. Elevate the affected area and treat with ice packs. As this can be a progressive injury, appropriate long-term follow-up is required. Intramuscular administration and subcutaneous administration of daunorubicin is contraindicated due to severe skin and tissue necrosis which may occur.

    Intramuscular injections

    Intramuscular injections should not be administered to patients with platelet counts < 50,000/mm3 who are receiving daunorubicin. IM injections may cause bleeding, bruising, or hematomas due to daunorubicin-induced thrombocytopenia.

    Hepatic disease, jaundice

    Patients with hepatic disease and/or jaundice should receive daunorubicin cautiously. The dose should be adjusted for elevations in the total bilirubin because daunorubicin is significantly cleared through the biliary tree.

    Renal failure, renal impairment

    Daunorubicin is eliminated renally. Dosage adjustments are recommended in patients with renal impairment or renal failure to avoid toxicity.

    Hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, tumor lysis syndrome (TLS)

    Hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, and decreased urine output may be indicative of daunorubicin-induced tumor lysis syndrome (TLS). Appropriate measures (e.g. aggressive hydration and allopurinol) must be taken to prevent severe electrolyte imbalances and renal toxicity during and following chemotherapy administration in patients with large chemosensitive tumors.

    Cardiac disease, cardiotoxicity, maximum cumulative lifetime dose

    Severe cardiotoxicity including fatal congestive heart failure may occur during daunorubicin therapy or months to years after discontinuing therapy. Cardiotoxicity is dose related and the incidence increases after total cumulative doses exceeding 400 to 550 mg/m2 in adults, 300 mg/m2 in patients greater than 2 years of age, or 10 mg/kg in patients less than 2 years of age. The maximum cumulative lifetime dose of daunorubicin is 550 mg/m2 IV, or 400 mg/m2 IV in patients who have previously received mediastinal radiation. A history of cardiac disease and previous therapy with doxorubicin may increase the risk of daunorubicin-induced cardiotoxicity; perform a risk/benefit analysis prior to starting therapy in these patients. Monitor electrocardiogram and/or systolic ejection fraction prior to each course of daunorubicin therapy.

    Females

    Females may have an increased risk of anthracycline-induced cardiotoxicity. Female patients had a significantly greater reduction in cardiac contractility compared with male patients based on echocardiogram evaluations in a study in 120 children and adults who had been treated with bolus doses of doxorubicin (cumulative doses of 244—550 mg/m2) in childhood.

    Children, infants

    The risk of anthracycline-induced cardiotoxicity appears to be increased in infants, children, and adolescents and may occur at lower cumulative doses. Cardiotoxicity is dose dependent and may be worse in patients who received thoracic irradiation. Impaired left ventricular systolic performance, reduced contractility, congestive heart failure, and death have been reported in pediatric patients who received anthracycline therapy, including daunorubicin. Children treated with anthracyclines may develop late cardiotoxicity. Due to the risk of long-term cardiotoxicity, it has been recommended that patients treated with anthracyclines should undergo screening with electrocardiograms and echocardiograms every 2 years and 24-hour continuous electrocardiograms and radionuclide angiograms every 5 years.

    Infertility

    Infertility may occur in male patients who receive daunorubicin, based on information from animal studies.

    Pregnancy

    Daunorubicin is classified as FDA pregnancy risk category D. It may cause fetal harm if administered during pregnancy, based on animal studies. Females of reproductive potential should avoid pregnancy during daunorubicin therapy. If a woman takes daunorubicin during pregnancy or becomes pregnant during therapy, she should be advised of the potential risks to the fetus. Fetal toxicity has been reported in animal studies at daunorubicin doses that were below the recommended human dose (based on mg/kg in rabbits or body surface area in rats).

    Breast-feeding

    It is unknown whether daunorubicin is excreted in breast-milk. Due to the potential for severe toxicity in the nursing infant, it is recommended women discontinue breast-feeding during daunorubicin therapy.

    ADVERSE REACTIONS

    Severe

    heart failure / Delayed / 0-10.0
    myocarditis / Delayed / 0-1.0
    pericarditis / Delayed / 0-1.0
    anaphylactoid reactions / Rapid / 0-1.0
    pancytopenia / Delayed / 10.0
    AV block / Early / Incidence not known
    cardiomyopathy / Delayed / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    cardiotoxicity / Delayed / Incidence not known
    tissue necrosis / Early / Incidence not known
    tumor lysis syndrome (TLS) / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known

    Moderate

    contact dermatitis / Delayed / 0-1.0
    anemia / Delayed / 10.0
    neutropenia / Delayed / 10.0
    leukopenia / Delayed / 10.0
    thrombocytopenia / Delayed / 10.0
    bleeding / Early / Incidence not known
    bone marrow suppression / Delayed / Incidence not known
    superinfection / Delayed / Incidence not known
    QT prolongation / Rapid / Incidence not known
    ST-T wave changes / Rapid / Incidence not known
    bundle-branch block / Early / Incidence not known
    premature ventricular contractions (PVCs) / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    supraventricular tachycardia (SVT) / Early / Incidence not known
    oral ulceration / Delayed / Incidence not known
    phlebitis / Rapid / Incidence not known
    hyperuricemia / Delayed / Incidence not known

    Mild

    nail discoloration / Delayed / 0-1.0
    rash / Early / 0-1.0
    urticaria / Rapid / 0-1.0
    fever / Early / 0-1.0
    chills / Rapid / 0-1.0
    alopecia / Delayed / 10.0
    urine discoloration / Early / 10.0
    infection / Delayed / Incidence not known
    vomiting / Early / Incidence not known
    diarrhea / Early / Incidence not known
    abdominal pain / Early / Incidence not known
    nausea / Early / Incidence not known
    injection site reaction / Rapid / Incidence not known

    DRUG INTERACTIONS

    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Cyclophosphamide: (Moderate) Monitor for signs and symptoms of cardiac dysfunction if coadministration of cyclophosphamide with anthracyclines is necessary as there is an additive or potentially synergistic increase in the risk of cardiomyopathy.
    Cyclosporine: (Major) Concurrent use of daunorubicin with other agents which cause bone marrow or immune suppression such as other immunosuppressives may result in additive effects. In addition, high doses of cyclosporine (starting at 16 mg/kg/day IV) may increase exposure to anthracyclines (e.g. daunorubicin) in cancer patients. Cyclosporine is a substrate and inhibitor of P-glycoprotein, an energy-dependent drug efflux pump encoded for by the multidrug resistance gene-1 (MDR1). Overexpression of this protein has been described as a mechanism of resistance to naturally-occurring (non-synthetic) chemotherapy agents. Cyclosporine can block MDR1-mediated resistance when given at much higher doses than those used in transplantation and may also enhance the efficacy of daunorubicin by inhibiting this protein. Valspodar is a cyclosporine analog with less renal and immunosuppressive effects than cyclosporine while retaining effects on MDR. The addition of cyclosporine or valspodar to daunorubicin therapy may result in increases in AUC for both daunorubicin and daunorubincinol possibly due to a decrease in clearance of parent drug, a decrease in metabolism of daunorubincinol, or an increase in intracellular daunorubicin concentrations.
    Daclizumab: (Minor) Concurrent use of daunorubicin with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Elbasvir; Grazoprevir: (Moderate) Administering daunorubicin with elbasvir; grazoprevir may result in elevated daunorubicin plasma concentrations. Daunorubicin is a substrate for the breast cancer resistance protein (BCRP); both elbasvir and grazoprevir are BCRP inhibitors.
    Gadobenate Dimeglumine: (Moderate) Gadobenate dimeglumine is a substrate for the canalicular multi-specific organic anion transporter (MOAT). Use with other MOAT substrates, such as anthracyclines, may result in prolonged systemic exposure of the coadministered drug. Caution is advised if these drugs are used together.
    Margetuximab: (Major) Avoid administration of anthracyclines during margetuximab therapy and for up to 4 months after the last dose of margetuximab due to the risk of increased cardiac dysfunction. If concomitant use is unavoidable, closely monitor cardiac function. This interaction has not been studied with margetuximab; however, clinical data from other HER2-directed antibodies warrants consideration.
    Mycophenolate: (Major) Concurrent use of daunorubicin with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pertuzumab; Trastuzumab; Hyaluronidase: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Sirolimus: (Minor) Concurrent use of daunorubicin with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Trastuzumab: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
    Trastuzumab; Hyaluronidase: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.

    PREGNANCY AND LACTATION

    Pregnancy

    Daunorubicin is classified as FDA pregnancy risk category D. It may cause fetal harm if administered during pregnancy, based on animal studies. Females of reproductive potential should avoid pregnancy during daunorubicin therapy. If a woman takes daunorubicin during pregnancy or becomes pregnant during therapy, she should be advised of the potential risks to the fetus. Fetal toxicity has been reported in animal studies at daunorubicin doses that were below the recommended human dose (based on mg/kg in rabbits or body surface area in rats).

    It is unknown whether daunorubicin is excreted in breast-milk. Due to the potential for severe toxicity in the nursing infant, it is recommended women discontinue breast-feeding during daunorubicin therapy.

    MECHANISM OF ACTION

    Daunorubicin cytotoxicity occurs via mechanisms similar to other anthracyclines. Daunorubicin complexes with DNA by intercalating between DNA base pairs, causing the helix to change shape. This simple act of changing the conformation of DNA can interfere with strand elongation by inhibiting DNA polymerase and can inhibit protein synthesis due to affects on RNA polymerase. Daunorubicin also affects topoisomerase II, an enzyme responsible for DNA strand breaks during transcription. Daunorubicin stabilizes the initial DNA-enzyme complex leading to double-strand DNA breaks. Daunorubicin also undergoes reduction to form oxygen free radical intermediates. In the presence of oxygen and metal catalysts such as Fe2+, daunorubicin undergoes reduction to the semiquone radical. In the presence of oxygen, the semiqunone radical can form a superperoxide that in the presence of hydrogen peroxide forms hydroxyl radicals. Daunorubicin-derived radicals can induce membrane lipid peroxidation, DNA strand scission, and direct oxidation of purine or pyrimidine bases, thiols and amines. Daunorubicin cytotoxicity is cell cycle nonspecific, but the majority occurs in the S-phase.
     
    Resistance to daunorubicin may occur through several mechanisms. One of the most important mechanisms of resistance is multidrug resistance (MDR) which is mediated through an overexpression of a P170-glycoprotein. This membrane protein functions as an energy-dependent drug efflux pump in resistance cells. Several compounds including cyclosporine, cyclosporine analogs and verapamil may block this protein and can reverse resistance. Other mechanisms of resistance include changes in topoisomerase II and glutathione activity.
     
    Daunorubicin-induced free radical formation also contributes to its cardiotoxicity. Once daunorubicin enters cardiac cells, it is reduced to an anthracycline free radical that is rapidly oxidized with oxygen to form the original drug and superoxide anions. Normally, these superoxide radicals are converted back to oxygen via glutathione peroxidase (GP); however, the heart is essentially devoid of this enzyme. Consequently, H2O2 is forced to react with ferrous ions (Fe2+) to form the highly toxic superhydroxide free radical that causes severe lipid peroxidation leading to extensive mitochondrial destruction. Both cardiac and malignant cells are rich in mitochondria. Additionally, these free radicals crosslink sulfhydryl groups of calcium-release channels and inhibit Ca-ATPase which leads to extensive depletion of sarcoplasmic reticulum (SR) calcium stores and prevention of restoration of calcium stores in the SR, respectively.
     
    Daunorubicin also has antibacterial and immunosuppressive effects.

    PHARMACOKINETICS

    Daunorubicin is administered intravenously. It is rapidly distributed throughout the body tissues, concentrating in the liver, lymph nodes, muscle, kidney, and heart; it also binds to cellular components (e.g., nucleic acids). Daunorubicin does not appear to cross the blood-brain barrier; however, it crosses the placental barrier. Following daunorubicin administration, the initial half-life is 45 minutes and the terminal half-life is 18.5 hours. Daunorubicin is extensively metabolized in the liver via demethylation and conjugation and in other tissues via cytoplasmic aldo-keto reductases. The active metabolite, daunorubicinol, has a half-life of 26.7 hours. Daunorubicinol accounts for 40% and 60% of the total drug in plasma at 30 minutes and 4 hours, respectively. Daunorubicin elimination occurs via biliary (40%) and urinary (25%) excretion.
    Affected cytochrome P450 isoenzymes and drug transporters: P-gp
    Daunorubicin is a substrate for the multi-drug resistance protein, P-glycoprotein (P-gp).