DOXOrubicin

Pronunciation

(doks oh ROO bi sin)


U.S. Brand Names

Adriamycin PFS®; Adriamycin RDF®; Rubex®



Synonyms

ADR; Adria; Doxorubicin Hydrochloride; Hydroxydaunomycin Hydrochloride; Hydroxyldaunorubicin Hydrochloride; NSC-123127



Generic Available

Yes



Canadian Brand Names

Adriamycin®



Use

Treatment of leukemias, lymphomas, multiple myeloma, osseous and nonosseous sarcomas, mesotheliomas, germ cell tumors of the ovary or testis, and carcinomas of the head and neck, thyroid, lung, breast, stomach, pancreas, liver, ovary, bladder, prostate, uterus, and neuroblastoma



Pregnancy Risk Factor

D



Pregnancy Implications

Advise patients to avoid becoming pregnant (females) and to avoid causing pregnancy (males).



Lactation

Enters breast milk/contraindicated



Contraindications

Hypersensitivity to doxorubicin or any component of the formulation; congestive heart failure or arrhythmias; previous therapy with high cumulative doses of doxorubicin and/or daunorubicin; 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. Administration of live vaccines to immunosuppressed patients may be hazardous.

Total dose should not exceed 550 mg/m2 or 450 mg/m2 in patients with previous or concomitant treatment with daunorubicin, cyclophosphamide, or irradiation of the cardiac region; irreversible myocardial toxicity may occur as total dosage approaches 550 mg/m2. A baseline cardiac evaluation (ECG, LVEF, +/- ECHO) is recommended, especially in patients with risk factors for increased cardiac toxicity and in pediatric patients. Pediatric patients are at increased risk for delayed cardiotoxicity. Reduce dose in patients with impaired hepatic function; severe myelosuppression is also possible. Secondary acute myelogenous leukemia may occur following treatment.

I.V. use only. Doxorubicin is a potent vesicant; if extravasation occurs, severe tissue damage leading to ulceration and necrosis, and pain may occur.

Adverse Reactions

>10%:

Dermatologic: Alopecia, radiation recall

Gastrointestinal: Nausea, vomiting, stomatitis, GI ulceration, anorexia, diarrhea

Genitourinary: Discoloration of urine, mild dysuria, urinary frequency, hematuria, bladder spasms, cystitis following bladder instillation

Hematologic: Myelosuppression, primarily leukopenia (75%); thrombocytopenia and anemia

Onset: 7 days

Nadir: 10-14 days

Recovery: 21-28 days

1% to 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, mediastinal/pericardial radiation therapy, cardiovascular disease, age, and use of cyclophosphamide (or other cardiotoxic agents) all increase the risk.

Recommended maximum cumulative doses:

No risk factors: 550 mg/m2

Concurrent radiation: 450 mg/m2

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

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

Endocrine & metabolic: Hyperuricemia

<1%: Pericarditis, myocarditis, myocardial infection, skin rash, pigmentation of nail beds, nail banding, onycholysis, urticaria, infertility, sterility, elevations of bilirubin and transaminases, hepatitis, systemic hypersensitivity (including urticaria, pruritus, angioedema, dysphagia, and dyspnea)

Overdosage/Toxicology

Symptoms of overdose include myelosuppression, nausea, vomiting, and myocardial toxicity. Treatment of acute overdose consists of treatment of the severely myelosuppressed patient with hospitalization, antibiotics, platelet and granulocyte transfusions, and symptomatic treatment of mucositis.



Drug Interactions

(major) of CYP2D6, 3A4; CYP2B6 (moderate), 2D6 (weak), 3A4 (weak)

SubstrateInhibits

Allopurinol may enhance the antitumor activity of doxorubicin (animal data only).

Cyclophosphamide enhances the cardiac toxicity of doxorubicin by producing additional myocardial cell damage.

Cyclosporine may decrease clearance of parent and metabolite and may induce coma or seizures and enhance hematologic toxicity.

CYP2B6 substrates: Doxorubicin may increase the levels/effects of CYP2B6 substrates. Example substrates include bupropion, promethazine, propofol, selegiline, and sertraline.

CYP2D6 inhibitors: May increase the levels/effects of doxorubicin. Example inhibitors include chlorpromazine, delavirdine, fluoxetine, miconazole, paroxetine, pergolide, quinidine, quinine, ritonavir, and ropinirole.

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of doxorubicin. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 inhibitors: May increase the levels/effects of doxorubicin. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil.

Digoxin: Doxorubicin may decrease plasma levels and effectiveness of digoxin.

Mercaptopurine increases toxicities.

Paclitaxel reduces doxorubicin clearance and increases toxicity if administered prior to doxorubicin.

Phenobarbital increases elimination (decreases effect) of doxorubicin.

Phenytoin: Doxorubicin may decrease plasma levels and effectiveness of phenytoin.

Progesterone: High doses of progesterone enhance toxicity (neutropenia and thrombocytopenia).

Streptozocin greatly enhances leukopenia and thrombocytopenia.

Verapamil alters the cellular distribution of doxorubicin and may result in increased cell toxicity by inhibition of the P-glycoprotein pump. Based on mouse studies, cardiotoxicity may be enhanced by verapamil.

Zidovudine: Doxorubicin may decrease the antiviral activity of zidovudine.

Ethanol/Nutrition/Herb Interactions

Herb/Nutraceutical: St John's wort may decrease doxorubicin levels. Avoid black cohosh, dong quai in estrogen-dependent tumors.



Stability

Store intact vials of solution under refrigeration (2°C to 8°C) and protect from light; store intact vials of lyophilized powder at room temperature (15°C to 30°C).

Reconstitute lyophilized powder with NS to a final concentration of 2 mg/mL as follows. Reconstituted solution is stable for 7 days at room temperature (25°C) and 15 days under refrigeration (5°C) when protected from light.

Further dilution in D5W or NS is stable for 48 hours at room temperature (25°C) when protected from light

Unstable in solutions with a pH <3 or >7. Avoid aluminum needles as precipitation or decomposition (darkening of solution) may occur; protect from direct sunlight.

Incompatible with aminophylline, cephalothin, dexamethasone, diazepam, fluorouracil, furosemide, heparin, hydrocortisone, sodium bicarbonate

Y-site compatible with bleomycin, cyclophosphamide, dacarbazine, vinblastine, vincristine

Standard I.V. dilution:

I.V. push: Dose/syringe (concentration: 2 mg/mL)

Syringes are stable for 7 days at room temperature (25°C) and 15 days under refrigeration (5°C) when protected from light

IVPB: Dose/50-100 mL D5W or NS

IVPB solutions are stable for 48 hours at room temperature (25°C) when protected from light

Compatibility

Stable in D5W, LR, NS

Y-site administration: Compatible: Amifostine, aztreonam, bleomycin, chlorpromazine, cimetidine, cisplatin, cladribine, cyclophosphamide, dexamethasone sodium phosphate, diphenhydramine, droperidol, etoposide phosphate, famotidine, filgrastim, fludarabine, fluorouracil, gatifloxacin, gemcitabine, granisetron, hydromorphone, leucovorin, linezolid, lorazepam, melphalan, methotrexate, methylprednisolone sodium succinate, metoclopramide, mitomycin, morphine, ondansetron, paclitaxel, prochlorperazine edisylate, promethazine, ranitidine, sargramostim, sodium bicarbonate, teniposide, thiotepa, topotecan, vinblastine, vincristine, vinorelbine. Incompatible: Allopurinol, amphotericin B cholesteryl sulfate complex, cefepime, ganciclovir, piperacillin/tazobactam, propofol. Variable (consult detailed reference): Furosemide, heparin

Compatibility in syringe: Compatible: Bleomycin, cisplatin, cyclophosphamide, droperidol, leucovorin, methotrexate, metoclopramide, mitomycin, vinblastine, vincristine. Incompatible: Furosemide, heparin. Variable (consult detailed reference): Fluorouracil

Compatibility when admixed: Compatible: Dacarbazine, ondansetron, ondansetron with vincristine, paclitaxel, vinblastine. Incompatible: Aminophylline, diazepam, fluorouracil. Variable (consult detailed reference): Dacarbazine with ondansetron, etoposide with vincristine

Mechanism of Action

Inhibition of DNA and RNA synthesis by intercalation between DNA base pairs by inhibition of topoisomerase II and by steric obstruction. Doxorubicin 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. Doxorubicin is also a powerful iron chelator; the iron-doxorubicin complex can bind DNA and cell membranes and produce free radicals that immediately cleave the DNA and cell membranes.



Pharmacodynamics/Kinetics

Absorption: Oral: Poor (<50%)

Distribution: Vd: 25 L/kg; to many body tissues, particularly liver, spleen, kidney, lung, heart; does not distribute into the CNS; crosses placenta

Protein binding, plasma: 70%

Metabolism: Primarily hepatic to doxorubicinol (active), then to inactive aglycones, conjugated sulfates, and glucuronides

Half-life elimination:

Distribution: 10 minutes

Elimination: Doxorubicin: 1-3 hours; Metabolites: 3-3.5 hours

Terminal: 17-30 hours

Male: 54 hours; Female: 35 hours

Excretion: Feces (~40% to 50% as unchanged drug); urine (~3% to 10% as metabolites, 1% doxorubicinol, <1% adriamycine aglycones, and unchanged drug)

Clearance: Male: 113 L/hour; Female: 44 L/hour

Dosage

Refer to individual protocols. I.V.:

Children:

35-75 mg/m2 as a single dose, repeat every 21 days or

20-30 mg/m2 once weekly or

60-90 mg/m2 given as a continuous infusion over 96 hours every 3-4 weeks

Adults: Usual or typical dose: 60-75 mg/m2 as a single dose, repeat every 21 days or other dosage regimens like 20-30 mg/m2/day for 2-3 days, repeat in 4 weeks or 20 mg/m2 once weekly

The lower dose regimen should be given to patients with decreased bone marrow reserve, prior therapy or marrow infiltration with malignant cells

Dosing adjustment in renal impairment:

Mild to moderate renal failure: Adjustment is not required

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

Hemodialysis: Supplemental dose is not necessary

Dosing adjustment in hepatic impairment:

ALT/AST 2-3 times ULN: Administer 75% of dose

ALT/AST >3 times ULN or bilirubin 1.2-3 mg/dL (20-51

mol/L): Administer 50% of dose

Bilirubin 3.1-5 mg/dL (51-85

mol/L): Administer 25% of dose

Bilirubin >5 mg/dL (85

mol/L): Do not administer

Administration

Administer I.V. push over 1-2 minutes or IVPB. Continuous infusions may be administered via central line. Avoid extravasation associated with severe ulceration and soft tissue necrosis. Flush with 5-10 mL of I.V. solution before and after drug administration. Incompatible with heparin. Monitor for local erythematous streaking along vein and/or facial flushing (may indicate rapid infusion rate).

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, cardiac and liver function tests



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 intravenously. Report immediately any swelling, pain, burning, or redness at infusion site. Maintain adequate 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 darker yellow 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 (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. Inform prescriber if you are pregnant. Do not get pregnant while taking this medication or for 1 month following therapy. Consult prescriber for appropriate barrier contraceptives. Do not breast-feed.

Pregnancy/breast-feeding precautions:

Nursing Implications

Facial flushing may indicate too rapid a rate of administration.



Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Stomatitis.



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

Myelosuppression is common; use caution with clozapine and carbamazepine



Oncology: Emetic Potential

20 mg: Moderately low (10% to 30%)

>20 mg or <60 mg: Moderate (30% to 60%)

60 mg: Moderately high (60% to 90%)

Time course for nausea/vomiting: Onset: 1-3 hours; Duration 4-24 hours

Oncology: Vesicant

Yes; see Management of Drug Extravasations.



Dosage Forms

Injection, powder for reconstitution, as hydrochloride: 10 mg, 20 mg, 50 mg [contains lactose]

Adriamycin RDF®: 10 mg, 20 mg, 50 mg, 150 mg [contains lactose; rapid dissolution formula]

Rubex®: 50 mg, 100 mg [contains lactose]

Injection, solution, as hydrochloride [preservative free]: 2 mg/mL (5 mL, 10 mL, 25 mL, 100 mL)

Adriamycin PFS® [preservative free]: 2 mg/mL (5 mL, 10 mL, 25 mL, 37.5 mL, 100 mL)

References

Berg SL, Grisell DL, DeLaney TF, et al, "Principles of Treatment of Pediatric Solid Tumors,"Pediatr Clin North Am, 1991, 38(2):249-67.

Brown JR and Iman SH, "Recent Studies on Doxorubicin and Its Analogues,"Prog Med Chem, 1984, 21:169-236.

Cummings J and Smyth JF, "Pharmacology of Adriamycin: The Message to the Clinician,"Eur J Cancer Clin Oncol, 1988, 24(4):579-82.

Curran CF, "Acute Doxorubicin Overdoses,"Ann Intern Med, 1991, 115(11):913-4.

Curran CF and Luce JK, "Accidental Acute Exposure to Doxorubicin,"Cancer Nurs, 1989, 12(6):329-31.

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.

Gordon KB, Tajuddin A, Guitart J, et al, "Hand-Foot Syndrome Associated With Liposome-Encapsulated Doxorubicin Therapy,"Cancer, 1995, 75(8):2169-73.

Ishii E, Hara T, Ohkubo K, et al, "Treatment of Childhood Acute Lymphoblastic Leukemia With Intermediate Dose Cytosine Arabinoside and Adriamycin,"Med Pediatr Oncol, 1986, 14(2):73-7.

King PD and Perry MC, "Hepatotoxicity of Chemotherapy,"Oncologist, 2001, 6(2):162-76.

Lauvin R, Miglianico L, and Hellegouarc'h R, "Skin Cancer Occurring 10 Years After the Extravasation of Doxorubicin,"N Engl J Med, 1995, 332(11):754.

Legha SS, Benjamin RS, Mackay B, et al, "Reduction of Doxorubicin Cardiotoxicity by Prolonged Continuous Intravenous Infusion,"Ann Intern Med, 1982, 96(2):133-9.

Namer M, "Anthracyclines in the Adjuvant Treatment of Breast Cancer,"Drugs, 1993, 45(Suppl 2):4-9.

Seifert CF, Nesser ME, and Thompson DF, "Dexrazoxane in the Prevention of Doxorubicin-Induced Cardiotoxicity,"Ann Pharmacother, 1994, 28(9):1063-72.

Speth PA, van Hoesel QG, and Haanen C, "Clinical Pharmacokinetics of Doxorubicin,"Clin Pharmacokinet, 1988, 15(1):15-31.

Speyer JL, Green MD, Kramer E, et al, "Protective Effect of the Bispiperazinedione ICRF-187 Against Doxorubicin-Induced Cardiac Toxicity in Women With Advanced Breast Cancer,"N Engl J Med, 1988, 319(12):745-52.

Zimmerman S, Adkins D, Graham M, et al, "Irreversible, Severe, Congestive Cardiomyopathy Occurring in Association With Interferon Alpha Therapy,"Cancer Biother, 1994, 9(4):291-9.

International Brand Names

Adriacin® (JP); Adriamycin® (AU, CA, DK, FI, HK, NO, NZ, SE, SG); Adriblastina® (AR, BE, CZ, HR, HU, IT, LU, MX, NL, PT, RO, SI, TR); Adriblastina CS® (CO); Adriblastina PFS® (IL, PL); Adriblastina RD® (BG, BR, MX, PL, TH); Adriblastina RTU® (BE, CL); Adriblastin® (AT, CH, DE, IL, RU); Adriblastine® (FR); Adrimedac® (DE); Adrim® (IN, TH); Asta Medica Doxorrubicina® (BR); Biorubina® (PL); Caelyx® (AR, AT, AU, BD, BE, CH, CR, CZ, DE, DK, DO, EC, ES, FI, FR, GB, GT, HN, HU, IT, MX, NO, NZ, PA, PL, PT, RO, SE, SG, SI, SV, TH); Carcinocin® (ID); Cloridrato de Doxorrubicina® (BR); Colhidrol® (AR); Cytosafe Doxorubicin HCL® (ID); DBL Doxorubicin® (TH); Dicladox® (AR); Doxil® (IL); Doxina® (BR); DOXO-cell® (DE); Doxocris® (AR); Doxolem® (AT, CZ, MX, PL, RO, RU, TH); Doxorrubicina® (BR, CL); Doxorrubicina Delta Farma® (AR); Doxorubicina Asofarma® (AR); Doxorubicina Faulding® (AR); Doxorubicina Ferrer Farma® (ES); Doxorubicina Filaxis® (AR); Doxorubicina Funk® (ES); Doxorubicina Gador® (AR); Doxorubicina Tedec® (ES); Doxorubicin® (AU, CZ, GB, ID, NO, NZ, SG); Doxorubicin Austropharm® (AT); Doxorubicin Bigmar® (CH); Doxorubicin Ebewe® (AT, CH, CZ, DK, HU, ID, PL, RO, RU, SI, TH, YU); Doxorubicine Faulding® (BE); Doxorubicin HCl Pharmacia® (SG); Doxorubicin Hexal® (DE); Doxorubicin Hydrochloride® (AU, ID, NZ, RU, SG); Doxorubicin Meiji® (IN); Doxorubicin NC® (DE); Doxorubicin Nycomed® [inj.] (FI, SE); Doxorubicin Pharmachemie® (TH); Doxorubicin Pharmacia & Upjohn® (AT); Doxorubicin Pharmalink® (SE); Doxorubicin Pliva® (SI); Doxorubicin Rapid® (GB); Doxorubicin-Teva® (HU, IL, RO); Doxorubin® (BE, GB, NZ, SI); Doxotec® (MX); Doxtie® (AR); Farmiblastina® (ES); Faulding-Doxorrubicina® (BR); Flavicina® (AR); K.U. Doxorubicin HCl® (SG); Myocet® (AT, DE, ES, FR, GB, IT); Nagun® (AR); Onkodox® (DE); Pallagicin® (HU, ID); Quimotus® (AR); Ranxas® (AR); Rastocin® (CZ, HR, PL, RU); Ribodoxo® (DE); Roxorin® (AR); Rubex® (BR); Sindroxocin® (RO)



Review Date: 1969-12-31 Reviewed By: Keywords: ,
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