Hazardous Drugs Classification
NIOSH 2016 List: Group 1
NIOSH (Draft) 2020 List: Table 1
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
For accidental daunorubicin contact with the skin or mucosa, wash the area thoroughly with soap and water.
Administer routine antiemetic prophylaxis prior to treatment.
Administer drug through a central venous line.
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.
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.
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.
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
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
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
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.
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.
Daunorubicin is eliminated renally. Dosage adjustments are recommended in patients with renal impairment or renal failure to avoid toxicity.
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.
Common Brand Names
Anthracycline chemotherapy agent
Used in combination with other anticancer drugs in patients with acute leukemias
Cardiotoxicity and myelosuppression have been reported
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%.
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 immunosuppressants 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.
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.
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.
Cerubidine/Daunorubicin Hydrochloride Intravenous Inj Pwd F/Sol: 20mg
Daunorubicin Hydrochloride Intravenous Inj Sol: 1mL, 5mg
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.
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.
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).
Pregnancy And Lactation
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.