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Pronunciation:

(daw noe ROO bi sin hye droe KLOR ide)

U.S. Brand Names:

Cerubidine®

Synonyms:

Daunomycin; DNR; NSC-82151; Rubidomycin Hydrochloride

Generic Available:

Yes

Canadian Brand Names:

Cerubidine®

Use:

Treatment of acute lymphocytic (ALL) and nonlymphocytic (ANLL) leukemias

Pregnancy Risk Factor:

Pregnancy Implications:

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; congestive heart failure or arrhythmias; previous therapy with high cumulative doses of daunorubicin and/or doxorubicin; pre-existing bone marrow suppression; pregnancy

Warnings/Precautions:

The U.S. Food and Drug Administration (FDA) currently recommends that procedures for proper handling and disposal of antineoplastic agents be considered. Use with caution in patients who have received radiation therapy or in the presence of hepatobiliary dysfunction. Reduce dosage in patients who are receiving radiation therapy simultaneously. Daunomycin is a potent vesicant; if extravasation occurs, severe tissue damage leading to ulceration and necrosis, and pain may occur.

Total cumulative dose should take into account previous or concomitant treatment with cardiotoxic agents or irradiation of chest.

Irreversible myocardial toxicity may occur as total dosage approaches:

550 mg/m² in adults

400 mg/m² in patients receiving chest radiation

300 mg/m² in children >2 years of age

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. Cumulative dose, radiation therapy, age, and use of cyclophosphamide all increase the risk. Recommended maximum cumulative doses:

No risk factors: 550-600 mg/m²

Concurrent radiation: 450 mg/m²

Regardless of cumulative dose, if the left ventricular ejection fraction is <30% to 40%, the drug is usually not given

Dermatologic: Alopecia, radiation recall

Gastrointestinal: Mild nausea or vomiting, stomatitis

Genitourinary: Discoloration of urine (red)

Hematologic: Myelosuppression, primarily leukopenia; thrombocytopenia and anemia

Onset: 7 days

Nadir: 10-14 days

Recovery: 21-28 days

1% to 10%:

Dermatologic: Skin "flare" at injection site; discoloration of saliva, sweat, or tears

Endocrine & metabolic: Hyperuricemia

Gastrointestinal: GI ulceration, diarrhea

<1%: Systemic hypersensitivity (including urticaria, pruritus, angioedema, dysphagia, dyspnea), pericarditis, myocarditis, MI, skin rash, pigmentation of nail beds, nail banding, onycholysis, infertility, sterility, elevated bilirubin and transaminases, hepatitis

Overdosage/Toxicology:

Symptoms of overdose include myelosuppression, nausea, vomiting, and stomatitis. There are no known antidotes. Treatment is symptomatic and supportive.

Drug Interactions:

Patients may experience impaired immune response to vaccines; possible infection after administration of live vaccines in patients receiving immunosuppressants

Ethanol/Nutrition/Herb Interactions:

Ethanol: Avoid ethanol (due to GI irritation).

Stability:

Store intact vials at room temperature and protect from light. Dilute vials with 4 mL SWFI for a final concentration of 5 mg/mL; 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.

Compatibility:

Incompatible with heparin, sodium bicarbonate, fluorouracil, and dexamethasone.

Stable in D5W, LR, NS, sterile water for injection

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:

ALL combination therapy: Remission induction: 25-45 mg/m² on day 1 every week for 4 cycles or 30-45 mg/m²/day for 3 days

AML combination therapy: Induction: I.V. continuous infusion: 30-60 mg/m²/day on days 1-3 of cycle

Note: In children <2 years or <0.5 m², daunorubicin should be based on weight - mg/kg: 1 mg/kg per protocol with frequency dependent on regimen employed

Cumulative dose should not exceed 300 mg/m²in children >2 years; maximum cumulative doses for younger children are unknown.

Adults:

Range: 30-60 mg/m²/day for 3-5 days, repeat dose in 3-4 weeks

AML: Single agent induction: 60 mg/m²/day for 3 days; repeat every 3-4 weeks

AML: Combination therapy induction: 45 mg/m²/day for 3 days of the first course of induction therapy; subsequent courses: Every day for 2 days

ALL combination therapy: 45 mg/m²/day for 3 days

Cumulative dose should not exceed 400-600 mg/m²

Dosing adjustment in renal impairment:

Clcr<10 mL/minute: Administer 75% of normal dose

Scr >3 mg/dL: Administer 50% of normal dose

Dosing adjustment in hepatic impairment:

Serum bilirubin 1.2-3 mg/dL or AST 60-180 int. units: Reduce dose to 75%

Serum bilirubin 3.1-5 mg/dL or AST >180 int. units: Reduce dose to 50%

Serum bilirubin >5 mg/dL: Omit use

Administration:

Not for I.M. or SubQ administration. Administer IVP over 1-5 minutes into the tubing of a rapidly infusing I.V. solution of D5W or NS; daunorubicin has also been diluted in 100 mL of D5W or NS and infused over 15-30 minutes.

Extravasation management: Apply ice immediately for 30-60 minutes; then alternate off/on every 15 minutes for 1 day. Topical cooling may be achieved using ice packs or cooling pad with circulating ice water. Cooling of site for 24 hours as tolerated by the patient. Elevate and rest extremity 24-48 hours, then resume normal activity as tolerated. Application of cold inhibits vesicant's cytotoxicity. Application of heat or sodium bicarbonate can be harmful and is contraindicated. If pain, erythema, and/or swelling persist beyond 48 hours, refer patient immediately to plastic surgeon for consultation and possible debridement.

Monitoring Parameters:

CBC with differential and platelet count, liver function test, ECG, ventricular ejection fraction, renal function test

Patient Education:

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. 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 hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake, and nutrition (small, frequent meals may help). You will be more susceptible to infection (avoid crowds and exposure to infection and do not have any vaccinations without consulting prescriber). May cause nausea or vomiting (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help); diarrhea (buttermilk, boiled milk, or yogurt may help); 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. Pregnancy/breast-feeding precautions: Do not get pregnant or cause a pregnancy (males) while taking this medication. Consult prescriber for appropriate contraceptive measures. Breast-feeding is not recommended.

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

Oncology: Emetic Potential:

Moderate (30% to 60%)

Oncology: Vesicant:

Yes; see Management of Drug Extravasations.

Dosage Forms:

Injection, powder for reconstitution: 20 mg, 50 mg

Cerubidine®: 20 mg

Injection, solution: 5 mg/mL (4 mL, 10 mL)

International Brand Names:

Cerubidin® (DK, NO, SE); Cerubidine® (BE, CA, CH, CL, CZ); Cérubidine® (FR); Cerubidine® (HK, IL, LU, NL); Cérubidine® (NZ); Cerubidine® (PL, RO, RU); Daunoblastina® (AR, BR, CZ, ES, HK, HR, HU, ID, IT, PT, RO, SG, YU); Daunoblastin® (AT, DE); Daunomicina® (TR); Daunorrubicina® (CL); Daunorubicin® (AU, GB); Daunorubicin HCL® (ID); Daunorubicin hydrochloride® (AU, NZ); DaunoXome® (AT, AU, CH); Daunoxome® (DE); DaunoXome® (DK, ES, FI); Daunoxome® (FR); DaunoXome® (GB, IT, LU); Daunoxome® (NO); DaunoXome® (RU, SE); Maxidauno® (AR); Rubilem® [inj.] (MX)

References

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.

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.

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.

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