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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(daw noe ROO bi sin hye droe KLOR ide)
Generic Available (U.S.)
Yes
Index Terms
U.S. Brand Names
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML)
Pregnancy Risk Factor
D
Pregnancy Considerations
May cause fetal harm when administered to a pregnant woman. Animal studies have shown an increased incidence of fetal abnormalities.
Lactation
Excretion in breast milk unknown/not recommended
Contraindications
Hypersensitivity to daunorubicin or any component of the formulation
Warnings/Precautions
Boxed warnings:
• Bone marrow suppression: See “Concerns related to adverse effects” below.
• Experienced physician: See “Other warnings/precautions” below.
• Hepatic impairment: See “Disease-related concerns” below.
• Myocardial toxicity: See “Concerns related to adverse effects” below.
• Renal impairment: See “Disease-related concerns” below.
• Skin irritation/extravasation: See “Concerns related to adverse effects” below.
Special handling:
• Hazardous agent: Use appropriate precautions for handling and disposal.
Concerns related to adverse effects:
• Bone marrow suppression: [U.S. Boxed Warning]: May cause severe bone marrow suppression.
• Myocardial toxicity: [U.S. Boxed Warning]: May cause cumulative, dose-related myocardial toxicity (concurrent or delayed). Total cumulative dose should take into account previous or concomitant treatment with cardiotoxic agents or irradiation of chest. The incidence of irreversible myocardial toxicity increases as the total cumulative (lifetime) dosages approach: 550 mg/m2 in adults; 400 mg/m2 in adults receiving chest radiation; 300 mg/m2 in children >2 years of age, or 10 mg/kg in children <2 years of age. Although the risk increases with cumulative dose, irreversible cardiotoxicity may occur at any dose level. Patients with pre-existing heart disease, hypertension, concurrent administration of other antineoplastic agents, prior or concurrent chest irradiation, advanced age; and infants and children are at increased risk. Monitor left ventricular (LV) function (baseline and periodic) with ECHO or MUGA scan; monitor ECG.
• Secondary malignancy: Secondary leukemias may occur when used with combination chemotherapy or radiation therapy.
• Skin irritation/extravasation: [U.S. Boxed Warning]: For I.V. administration only. Potent vesicant; if extravasation occurs, severe local tissue damage leading to ulceration and necrosis, and pain may occur.
Disease-related concerns:
• Hepatic impairment: [U.S. Boxed Warning]: Use with caution in patients with hepatic impairment; dosage adjustment recommended.
• Renal impairment: [U.S. Boxed Warning]: Use with caution in patients with renal impairment; dosage adjustment recommended.
Special populations:
• Radiation recipients: Use with caution in patients who have received radiation therapy; reduce dosage in patients who are receiving radiation therapy simultaneously.
Other warnings/precautions:
• Experienced physician: [U.S. Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.
Adverse Reactions
>10%:
Cardiovascular: Transient ECG abnormalities (supraventricular tachycardia, S-T wave changes, atrial or ventricular extrasystoles); generally asymptomatic and self-limiting. CHF, dose related, may be delayed for 7-8 years after treatment.
Dermatologic: Alopecia (reversible), radiation recall
Gastrointestinal: Mild nausea or vomiting, stomatitis
Genitourinary: Discoloration of urine (red)
Hematologic: Myelosuppression (onset: 7 days; nadir: 10-14 days; recovery: 21-28 days), primarily leukopenia; thrombocytopenia and anemia
1% to 10%:
Dermatologic: Skin “flare” at injection site; discoloration of saliva, sweat, or tears
Endocrine & metabolic: Hyperuricemia
Gastrointestinal: Abdominal pain, GI ulceration, diarrhea
<1%, postmarketing, and/or case reports: Anaphylactoid reaction, arrhythmia, bilirubin increased, cardiomyopathy, hepatitis, infertility; local (cellulitis, pain, thrombophlebitis at injection site); MI, myocarditis, nail banding, neutropenic typhlitis, onycholysis, pericarditis, pigmentation of nailbeds, secondary leukemia, skin rash, sterility, systemic hypersensitivity (including urticaria, pruritus, angioedema, dysphagia, dyspnea); transaminases increased
Metabolism/Transport Effects
Substrate of P-glycoprotein
Drug Interactions
BCG: Immunosuppressants may diminish the therapeutic effect of BCG. Risk X: Avoid combination
Bevacizumab: May enhance the cardiotoxic effect of Antineoplastic Agents (Anthracycline). Risk C: Monitor therapy
Cardiac Glycosides: May diminish the cardiotoxic effect of Antineoplastic Agents (Anthracycline). Antineoplastic Agents (Anthracycline) may decrease the serum concentration of Cardiac Glycosides. The effects of liposomal formulations may be unique from those of the free drug, as liposomal formulation have unique drug disposition and toxicity profiles, and liposomes themselves may alter digoxin absorption/distribution. Risk C: Monitor therapy
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Risk C: Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
P-Glycoprotein Inducers: May decrease the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
P-Glycoprotein Inhibitors: May increase the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Risk X: Avoid combination
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Risk C: Monitor therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Taxane Derivatives: May enhance the adverse/toxic effect of Antineoplastic Agents (Anthracycline). Taxane Derivatives may increase the serum concentration of Antineoplastic Agents (Anthracycline). Taxane Derivatives may also increase the formation of toxic anthracycline metabolites in heart tissue. Risk D: Consider therapy modification
Trastuzumab: May enhance the cardiotoxic effect of Antineoplastic Agents (Anthracycline). Risk D: Consider therapy modification
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Risk X: Avoid combination
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (due to GI irritation).
Storage
Store intact vials of powder for injection at room temperature of 15°C to 30°C (59°F to 86°F); intact vials of solution for injection should be refrigerated at 2°C to 8°C (36°F to 46°F). Protect from light. Reconstituted solution is stable for 4 days at 15°C to 25°C. Further dilution in D5W, LR, or NS is stable at room temperature (25°C) for up to 4 weeks if protected from light.
Reconstitution
Dilute vials of powder for injection with 4 mL SWFI for a final concentration of 5 mg/mL. May further dilute in 100 mL D5W or NS.
Compatibility
Stable in D5W, LR, NS, sterile water for injection. Incompatible with heparin, sodium bicarbonate, fluorouracil, and dexamethasone.
Y-site administration: Compatible: Amifostine, etoposide phosphate, filgrastim, gemcitabine, granisetron, melphalan, methotrexate, ondansetron, sodium bicarbonate, teniposide, thiotepa, vinorelbine. Incompatible: Allopurinol, aztreonam, cefepime, fludarabine, piperacillin/tazobactam.
Compatibility when admixed: Compatible: Cytarabine with etoposide, hydrocortisone sodium succinate. Incompatible: Dexamethasone sodium phosphate, heparin.
Mechanism of Action
Inhibition of DNA and RNA synthesis by intercalation between DNA base pairs and by steric obstruction. Daunomycin intercalates at points of local uncoiling of the double helix. Although the exact mechanism is unclear, it appears that direct binding to DNA (intercalation) and inhibition of DNA repair (topoisomerase II inhibition) result in blockade of DNA and RNA synthesis and fragmentation of DNA.
Pharmacodynamics/Kinetics
Distribution: Many body tissues, particularly the liver, kidneys, lung, spleen, and heart; not into CNS; crosses placenta; Vd: 40 L/kg
Metabolism: Primarily hepatic to daunorubicinol (active), then to inactive aglycones, conjugated sulfates, and glucuronides
Half-life elimination: Distribution: 2 minutes; Elimination: 14-20 hours; Terminal: 18.5 hours; Daunorubicinol plasma half-life: 24-48 hours
Excretion: Feces (40%); urine (∼25% as unchanged drug and metabolites)
Dosage
I.V. (refer to individual protocols):
Children: Note: Cumulative dose should not exceed 300 mg/m2 in children >2 years or 10 mg/kg in children <2 years of age; maximum cumulative doses for younger children are unknown.
Children <2 years or BSA <0.5 m2: ALL combination therapy: 1 mg/kg/dose per protocol, with frequency dependent on regimen employed
Children ≥2 years and BSA ≥0.5 m2:
ALL combination therapy: Remission induction: 25 mg/m2 on day 1 every week for up to 4-6 cycles
AML combination therapy: Induction: I.V. continuous infusion: 30-60 mg/m2/day on days 1-3 of cycle
Adults: Note: Cumulative dose should not exceed 550 mg/m2 in adults without risk factors for cardiotoxicity and should not exceed 400 mg/m2 in adults receiving chest irradiation.
Range: 30-60 mg/m2/day for 3 days, repeat dose in 3-4 weeks
ALL combination therapy: 45 mg/m2/day for 3 days
AML combination therapy:
Adults <60 years: Induction: 45 mg/m2/day for 3 days of the first course of induction therapy; subsequent courses: 45 mg/m2/day for 2 days
Adults ≥60 years: Induction: 30 mg/m2/day for 3 days of the first course of induction therapy; subsequent courses: 30 mg/m2/day for 2 days
Dosing adjustment in renal impairment:
The FDA-approved labeling recommends the following adjustment: Scr >3 mg/dL: Administer 50% of normal dose
The following guidelines have been used by some clinicians (Aronoff, 2007):
Children:
Clcr <30 mL/minute: Administer 50% of dose
Hemodialysis/continuous ambulatory peritoneal dialysis (CAPD): Administer 50% of dose
Adults: No adjustment recommended
Dosing adjustment in hepatic impairment:
The FDA-approved labeling recommends the following adjustments:
Serum bilirubin 1.2-3 mg/dL: Administer 75% of dose
Serum bilirubin >3 mg/dL: Administer 50% of dose
The following guidelines have been used by some clinicians (Floyd, 2006):
Serum bilirubin 1.2-3 mg/dL: Administer 75% of dose
Serum bilirubin 3.1-5 mg/dL: Administer 50% of dose
Serum bilirubin >5 mg/dL: Avoid use
Dosage: Combination Regimens
Leukemia, acute lymphocytic:
DVP
Larson Regimen (ALL)
Linker Protocol (ALL)
PVDA
Leukemia, acute myeloid:
5 + 2
7 + 3 + 7
7 + 3 (Daunorubicin)
Leukemia, acute promyelocytic:
Tretinoin-Daunorubicin (APL)
Tretinoin-Daunorubicin-Cytarabine (APL)
Administration: I.V.
Vesicant. Never administer I.M. or SubQ. Administer as slow I.V. push over 1-5 minutes into the tubing of a rapidly infusing I.V. solution of D5W or NS or dilute in 100 mL of D5W or NS and infuse over 15-30 minutes.
Administration: I.V. Detail
Avoid extravasation, can cause severe tissue damage. Flush with 5-10 mL of I.V. solution before and after drug administration.
pH: 4.5-6.5
Monitoring Parameters
CBC with differential and platelet count, liver function test, ECG, left ventricular ejection function (echocardiography [ECHO] or multigated radionuclide angiography [MUGA] scan), renal function test
Patient Education
This medication can only be administered I.V. Report immediately any swelling, pain, burning, or redness at infusion site. Avoid alcohol. It is important to maintain adequate nutrition and hydration, unless instructed to restrict fluid intake. You will be more susceptible to infection. May cause nausea or vomiting, diarrhea, loss of hair (reversible), or red-pink urine (normal). Report immediately chest pain, swelling of extremities, respiratory difficulty, palpitations, or rapid heartbeat. Report unresolved nausea, vomiting, or diarrhea; alterations in urinary pattern (increased or decreased); opportunistic infection (eg, fever, chills, unusual bruising or bleeding fatigue, purulent vaginal discharge, unhealed mouth sores); abdominal pain or blood in stools; excessive fatigue; or yellowing of eyes or skin.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Stomatitis and discoloration of saliva.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
None reported
Mental Health: Effects on Psychiatric Treatment
May produce myelosuppression; use caution with clozapine and carbamazepine
Nursing: Physical Assessment/Monitoring
Use with caution in presence of pre-existing bone marrow suppression, impaired hepatic or renal function, or cardiac disease. Infusion site must be closely monitored; extravasation can cause severe cellulitis or tissue necrosis. Monitor for tachycardia, cough, dyspnea, and gastrointestinal upset prior to each infusion and throughout therapy.
Oncology: Emetic Potential
Moderate (30% to 90%)
Oncology: Vesicant
Vesicant; see Management of Drug Extravasations.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, powder for reconstitution [strength expressed as base]: 20 mg
Cerubidine®: 20 mg [contains mannitol]
Injection, solution [strength expressed as base, preservative free]: 5 mg/mL (4 mL, 10 mL)
References
Aronoff GR, Bennett WM, Berns JS, et al, Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children, 5th Ed. Philadelphia, PA: American College of Physicians, 2007, 98.
Aubel-Sadron G and Londos-Gagliardi D, "Daunorubicin and Doxorubicin, Anthracycline Antibiotics, a Physicochemical and Biological Review," Biochimie, 1984, 66(5):333-52.
Bassan R, Lerede T, Rambaldi A, et al, “Role of Anthracyclines in the Treatment of Adult Acute Lymphoblastic Leukemia,” Acta Haematol, 1996, 95(3-4):188-92.
Crom WR, Glynn-Barnhart AM, Rodman JH, et al, “Pharmacokinetics of Anticancer Drugs in Children,” Clin Pharmacokinet, 1987, 12(3):168-213.
Cuttner J, Mick R, Budman DR, et al, “Phase III Trial of Brief Intensive Treatment of Adult Acute Lymphocytic Leukemia Comparing Daunorubicin and Mitoxantrone: A CALGB Study,” Leukemia, 1991, 5(5):425-31.
Davis HL and Davis TE, “Daunorubicin and Adriamycin in Cancer Treatment: An Analysis of Their Roles and Limitations,” Cancer Treat Rep, 1979, 63(5):809-15.
Floyd J, Mirza I, Sachs B, et al, “Hepatotoxicity of Chemotherapy,” Semin Oncol, 2006, 33(1):50-67.
Floyd JD, Nguyen DT, Lobins RL, et al, “Cardiotoxicity of Cancer Therapy,” J Clin Oncol, 2005, 23(30):7685-96.
Keefe DL, “Anthracycline-Induced Cardiomyopathy,” Semin Oncol, 2001, 28(4 Suppl 12):2-7.
Maral RJ and Jouanne M, "Toxicology of Daunorubicin in Animals and Man," Cancer Treat Rep, 1981, 65 Suppl 4:9-18.
Masaoka T, Ogawa M, Yamada K, et al, “A Phase II Comparative Study of Idarubicin Plus Cytarabine Versus Daunorubicin Plus Cytarabine in Adult Acute Myeloid Leukemia,” Semin Hematol, 1996, 33(4 Suppl 3):12-7.
Morgan C, Tillett T, Braybrooke J, et al, “Management of Uncommon Chemotherapy-Induced Emergencies,” Lancet Oncol, 2011 [epub ahead of print].
Riggs CE Jr., "Clinical Pharmacology of Daunorubicin in Patients With Acute Leukemia," Semin Oncol, 1984, 11(4 Suppl 3):2-11.
Speth PA, Minderman H, and Haanen C, "Idarubicin v Daunorubicin: Preclinical and Clinical Pharmacokinetic Studies," Semin Oncol, 1989, 16(1 Suppl 2):2-9.
Weick JK, Kopecky KJ, Appelbaum FR, et al, “A Randomized Investigation of High-Dose Versus Standard-Dose Cytosine Arabinoside With Daunorubicin in Patients With Previously Untreated Acute Myeloid Leukemia: A Southwest Oncology Group Study,” Blood, 1996, 88(8):2841-51.
Weiss RB and Bruno S, "Daunorubicin Treatment of Adult Solid Tumors," Cancer Treat Rep, 1981, 65 Suppl 4:25-8.
International Brand Names
Lexi-Comp.com
Last full review/revision May 2011
Content last modified May 2011
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