Yes

Antineoplastic Agent, Antibiotic

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, Wilms' tumor, breast, stomach, pancreas, liver, ovary, bladder, prostate, and uterus, neuroblastoma

D

Hypersensitivity to doxorubicin or any component, severe congestive heart failure, cardiomyopathy, pre-existing myelosuppression, patients with impaired cardiac function, patients who received previous treatment with complete cumulative doses of doxorubicin, idarubicin, and/or daunorubicin

The U.S. Food and Drug Administration (FDA) currently recommends that procedures for proper handling and disposal of antineoplastic agents be considered. Total dose should not exceed 550 mg/m² or 400 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 (EKG, LVEF, +/- ECHO) is recommended, especially in patients with risk factors for increased cardiac toxicity. I.V. use only, severe local tissue necrosis will result if extravasation occurs; reduce dose in patients with impaired hepatic function; severe myelosuppression is also possible.

>10%:

Dermatologic: Alopecia

Extravasation: Doxorubicin is one of the most notorious vesicants. Infiltration can cause severe inflammation, tissue necrosis, and ulceration. If the drug is infiltrated, consult institutional policy, apply ice to the area, and elevate the limb. Can have ongoing tissue destruction secondary to propagation of free radicals; may require debridement.

Vesicant chemotherapy

Gastrointestinal: Acute nausea and vomiting may be seen in 21% to 55% of patients; mucositis, ulceration, and necrosis of the colon, anorexia, and diarrhea, stomatitis, esophagitis

Emetic potential:

less than or equal to 20 mg: Moderately low (10% to 30%)

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

greater than or equal to 60 mg: Moderately high (60% to 90%)

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

Genitourinary: Discoloration of urine (red)

Hematologic: Myelosuppressive: 60% to 80% of patients will have leukopenia; dose-limiting toxicity

WBC: Moderate

Platelets: Moderate

Onset (days): 7

Nadir (days): 10-14

Recovery (days): 21-28

1% to 10%:

Cardiac toxicity: Dose-limiting and related to cumulative dose; usually a maximum total lifetime dose of 450-550 mg/m² is administered; although, it has been demonstrated that if given by continuous infusion in breast cancer patients, higher doses may be tolerated. Patients may present with acute toxicity (arrhythmias, heart block, pericarditis-myocarditis) which may be fatal. More commonly, chronic toxicity is seen, in which patients present with signs of congestive heart failure. Treatment includes aggressive management of CHF with digoxin, diuretics and peripheral vasodilators. Several methods of monitoring cardiac toxicity have been utilized, including myocardial biopsy (expensive and hazardous procedure).

Cardiovascular: Facial flushing

Dermatologic: Hyperpigmentation of nail beds, erythematous streaking along the vein if administered too rapidly

Endocrine & metabolic: Hyperuricemia

<1%: Fever, chills, urticaria, conjunctivitis, allergic reaction, anaphylaxis; radiation recall noticed in patients who have had prior irradiation; reactions include redness, warmth, erythema, and dermatitis in the radiation port. Can progress to severe desquamation and ulceration. Occurs 5-7 days after doxorubicin administration; local therapy with topical corticosteroids and cooling have given the best relief.

Symptoms of overdose include myelosuppression, nausea, vomiting, myocardial toxicity

CYP3A3/4 enzyme substrate; CYP2D6 enzyme inhibitor

Doxorubicin may decrease digoxin plasma levels and renal excretion

Phenobarbital increases elimination of doxorubicin

Phenytoin levels decreased by doxorubicin

Increased toxicity:

Cyclosporine may induce coma or seizures. The addition of cyclosporine to doxorubicin may result in increases in AUC for both doxorubicin and doxorubicinol possibly due to a decrease in clearance of parent drug and a decrease in metabolism of the doxorubicinol. Literature reports suggest that adding cyclosporine to doxorubicin results in more profound and prolonged hematologic toxicity than doxorubicin alone.

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

Mercaptopurine increases toxicities

Paclitaxel: Two published studies report that initial administration of paclitaxel infused over 24 hours followed by doxorubicin administered over 48 hours resulted in a significant decrease in doxorubicin clearance with more profound neutropenic and stomatitis episodes than the reverse sequence administration

Progesterone: Enhanced doxorubicin-induced neutropenia and thrombocytopenia were observed with progesterone given intravenously to patients with advanced malignancies at high doses concomitantly with a fixed doxorubicin dose (60 mg/m²) via bolus.

Streptozocin greatly enhances leukopenia and thrombocytopenia by inhibiting doxorubicin metabolism

Verapamil alters the cellular distribution of doxorubicin; may result in increased cell toxicity by inhibition of the P-glycoprotein pump

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). Gensia formulation of generic doxorubicin is stable for up to 30 days at room temperature.

Reconstitute lyophilized powder with SWI or 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.

10 mg vial = 5 mL

20 mg vial = 10 mL

50 mg vial = 25 mL

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 and bacteriostatic diluents as precipitation occurs; decomposing drug turns purple; 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)

Maximum syringe size for IVP is a 30 mL syringe and syringe should be less than or equal to 75% full

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

Doxorubicin works through inhibition of topoisomerase-II at the point of DNA cleavage. A second mechanism of action is the production of free radicals (the hydroxy radical OH) by doxorubicin, which in turn can destroy DNA and cancerous cells. Doxorubicin is also a very powerful iron chelator, equal to deferoxamine. The iron-doxorubicin complex can bind DNA and cell membranes rapidly and produce free radicals that immediately cleave the DNA and cell membranes. Inhibits DNA and RNA synthesis by intercalating between DNA base pairs and by steric obstruction; active throughout entire cell cycle.

Absorption: Oral: Poor, <50%

Distribution: V_d: 25 L/kg; rapidly distributed into the liver, spleen, kidney, lung and heart, also distributes into breast milk

Protein binding: 70% bound to plasma proteins

Metabolism: In both the liver and in plasma to both active and inactive metabolites

Half-life, triphasic: Primary: 30 minutes; Secondary: 3-3.5 hours for metabolites; Terminal: 17-30 hours for doxorubicin and its metabolites

Elimination: Triphasic; 80% eventually excreted in bile and feces; clearance has been shown to be significantly reduced in obese women with weight >130% of IBW

Refer to individual protocols

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: 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

Currently the maximum cumulative dose is 550 mg/m² or 450 mg/m² in patients who have received RT to the mediastinal areas; a baseline MUGA should be performed prior to initiating treatment. If the LVEF is <30% to 40%, therapy should not be instituted; LVEF should be monitored during therapy.

Doxorubicin has also been administered intraperitoneal (phase I in refractory ovarian cancer patients) and intra-arterially.

Dosing adjustment in renal impairment: Adjustments not required in mild to moderate renal failure

Cl_cr <10 mL/minute: Reduce dose to 75% of normal dose in severe renal failure

Hemodialysis: Supplemental dose is not necessary

Dosing adjustment in hepatic impairment:

Bilirubin 1.2-3 mg/dL: Administer 50% of dose

Bilirubin 3.1-5 mg/dL: Administer 25% of dose

Bilirubin >5 mg/dL: Avoid use

CBC with differential and platelet count, echocardiogram, liver function tests

None reported

Myelosuppression is common; use caution with clozapine and carbamazepine

No information available to require special precautions

No effects or complications reported

This medication can only be administered I.V. During therapy, do not use alcohol, aspirin-containing products, and OTC medications without consulting prescriber. It is important to maintain adequate nutrition and hydration (2-3 L/day of fluids unless instructed to restrict fluid intake) during therapy; frequent small meals may help. You may experience nausea or vomiting (frequent small meals, frequent mouth care, sucking lozenges, or chewing gum may help). You may experience loss of hair (reversible); you will be more susceptible to infection (avoid crowds and exposure to infection as much as possible). Urine may turn red-brown (normal). Yogurt or buttermilk may help reduce diarrhea (if unresolved, contact prescriber for medication relief). Frequent mouth care and use of a soft toothbrush or cotton swabs may reduce mouth sores. May discolor urine (red/pink). Report fever, chills, unusual bruising or bleeding, signs of infection, abdominal pain or blood in stools, excessive fatigue, yellowing of eyes or skin, swelling of extremities, difficulty breathing, or unresolved diarrhea. Pregnancy/breast-feeding precautions: Do not get pregnant or cause a pregnancy (males) while taking this medication; use appropriate barrier contraceptive measures for at least 1 month following therapy. Do not breast-feed.

Local erythematous streaking along the vein and/or facial flushing may indicate too rapid a rate of administration

Extravasation management:

Apply ice immediately for 30-60 minutes; then alternate off/on every 15 minutes for one 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

Injection, as hydrochloride:

Aqueous, with NS: 2 mg/mL (5 mL, 10 mL, 25 mL)

Preservative free: 2 mg/mL (5 mL, 10 mL, 25 mL, 100 mL)

Powder for injection, as hydrochloride, lyophilized: 10 mg, 20 mg, 50 mg, 100 mg

Powder for injection, as hydrochloride, lyophilized, rapid dissolution formula: 10 mg, 20 mg, 50 mg, 150 mg

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