No

Antineoplastic Agent, Anthracycline; Antineoplastic Agent, Antibiotic

Treatment of AIDS-related Kaposi's sarcoma in patients with disease that has progressed on prior combination chemotherapy or in patients who are intolerant to such therapy; treatment of metastatic carcinoma of the ovary in patients with disease that is refractory to both paclitaxel and platinum-based regimens

D

Hypersensitivity to doxorubicin or the components of Doxil®

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. 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.

Information on adverse events is based on the experience reported in 753 patients with AIDS-related Kaposi's sarcoma enrolled in four studies

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.

Irritant chemotherapy

Gastrointestinal: Nausea; emetic potential:

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

>20 mg or <75 mg: Moderate (30% to 60%)

greater than or equal to 75 mg: Moderately high (49%)

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%:

Cardiovascular: Cardiac toxicity (9.7%): Cardiomyopathy, congestive heart failure, arrhythmia, pericardial effusion, tachycardia, facial flushing

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

Endocrine & metabolic: Hyperuricemia

<1%: Allergic reaction, anaphylaxis, fever, chills, urticaria, conjunctivitis

Symptoms of overdose include increases in mucositis, leukopenia, and thrombocytopenia

Treatment of acute overdosage consists of treatment of the severely myelosuppressed patient with hospitalization, antibiotics, platelet and granulocyte transfusions and symptomatic treatment of mucositis

No formal drug interaction studies have been conducted with doxorubicin hydrochloride liposome injection, however, may interact with drugs known to interact with the conventional formulation of doxorubicin hydrochloride

Decreased effect: Doxorubicin may decrease digoxin plasma levels and renal excretion

Increased effect: Allopurinol may enhance the antitumor activity of doxorubicin (animal data only)

Increased toxicity:

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

Mercaptopurine enhances toxicities

Streptozocin greatly enhances leukopenia and thrombocytopenia

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 avoid freezing. Prolonged freezing may adversely affect liposomal drug products, however, short-term freezing (<1 month) does not appear to have a deleterious effect.

Doxil® is doxorubicin hydrochloride encapsulated in long-circulating STEALTH® liposomes. Liposomes are microscopic vesicles composed of a phospholipid bilayer that are capable of encapsulating active drugs. 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.

Distribution: V_d: Steady state volume of distribution is confined mostly to the vascular fluid volume

Protein binding (doxorubicin): 70% bound to plasma proteins

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

Elimination: Mean clearance value of 0.041 L/hour/m²

Refer to individual protocols

AIDS-KS patients: I.V.: 20 mg/m²/dose over 30 minutes once every 3 weeks for as long as patients respond satisfactorily and tolerate treatment

Breast cancer: I.V.: 20-80 mg/m²/dose has been studied in a limited number of phase I/II trials

Ovarian cancer: I.V.: 50 mg/m²/dose repeated every 4 weeks (minimum of 4 courses is recommended)

Solid tumors: I.V.: 50-60 mg/m²/dose repeated every 3-4 weeks has been studied in a limited number of phase I/II trials

Recommended dose modification guidelines:

Palmar-Plantar erythrodysesthesia:

Toxicity Grade 1

Mild erythema, swelling, or desquamation not interfering with daily activities

Redose unless patient has experienced previous Grade 3 or 4 toxicity. If so, delay up to 2 weeks and decrease dose by 25%; return to original dosing interval.

Toxicity Grade 2

Erythema, desquamation, or swelling interfering with, but not precluding, normal physical activities; small blisters or ulcerations <2 cm in diameter

Delay dosing up to 2 weeks or until resolved to Grade 0-1. If after 2 weeks there is no resolution, liposomal doxorubicin should be discontinued.

Toxicity Grade 3

Blistering, ulceration, or swelling interfering with walking or normal daily activities; cannot wear regular clothing

Delay dosing up to 2 weeks or until resolved to Grade 0-1. Decrease dose by 25% and return to original dosing interval; if after 2 weeks there is no resolution, liposomal doxorubicin should be discontinued.

Toxicity Grade 4

Diffuse or local process causing infectious complications, or a bed-ridden state or hospitalization

Delay dosing up to 2 weeks or until resolved to Grade 0-1. Decrease dose by 25% and return to original dosing interval. If after 2 weeks there is no resolution, liposomal doxorubicin should be discontinued.

Stomatitis:

Toxicity Grade 1

Painless ulcers, erythema, or mild soreness

Redose unless patient has experienced previous Grade 3 or 4 toxicity. If so, delay up to 2 weeks and decrease by 25%. Return to original dosing interval.

Toxicity Grade 2

Painful erythema, edema, or ulcers, but can eat

Delay dosing up to 2 weeks or until resolved to Grade 0-1. If after 2 weeks there is no resolution, liposomal doxorubicin should be discontinued.

Toxicity Grade 3

Painful erythema, edema, or ulcers, but cannot eat

Delay dosing up to 2 weeks or until resolved to Grade 0-1. Decrease dose by 25% and return to original dosing interval. If after 2 weeks there is no resolution, liposomal doxorubicin should be discontinued.

Toxicity Grade 4

Requires parenteral or enteral support

Delay dosing up to 2 weeks or until resolved to Grade 0-1. Decrease dose by 25% and return to original dosing interval. If after 2 weeks there is no resolution, liposomal doxorubicin should be discontinued.

Dosing adjustment in hepatic impairment:

Bilirubin 1.2-3 mg/dL or AST 60-180 units/L: Administer 50% of dose

Bilirubin >3 mg/dL: Administer 25% of dose

Dosing adjustment in hematologic toxicity:

Toxicity Grade 1

ANC 1500-1900; platelets 75,000-150,000: Resume treatment with no dose reduction

Toxicity Grade 2

ANC 1000-<1500; platelets 50,000-<75,000: Wait until ANC greater than or equal to 1500 and platelets greater than or equal to 75,000; redose with no dose reduction

Toxicity Grade 3

ANC 500-999; platelets 25,000-<50,000: Wait until ANC greater than or equal to 1500 and platelets greater than or equal to 75,000; redose with no dose reduction

Toxicity Grade 4

ANC <500; platelets <25,000: Wait until ANC greater than or equal to 1500 and platelets greater than or equal to 75,000; redose at 25% dose reduction or continue full dose with cytokine support

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

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. Report fever, chills, unusual bruising or bleeding, signs of infection, abdominal pain or blood in stools, excessive fatigue, yellowing of eyes or skin, darkening in color of urine or pale colored stools, 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: 2 mg/mL (10 mL)

Conley BA, Egorin MJ, Whitacre MY, et al, "Phase I and Pharmacokinetic Trial of Liposome-Encapsulated Doxorubicin," Cancer Chemother Pharmacol, 1993, 33(2):107-12.

Gabizon A, Isacson R, Libson E, et al, "Clinical Studies of Liposome-Encapsulated Doxorubicin," Acta Oncol, 1994, 33(7):779-86.

Gabizon AA, "Liposomal Anthracyclines," Hematol Oncol Clin North Am, 1994, 8(2):431-50.

Harrison M, Tomlinson D, and Stewart S, "Liposomal-Entrapped Doxorubicin: An Active Agent in AIDS-Related Kaposi's Sarcoma," J Clin Oncol, 1995, 13(4):914-20.

Treat J, Greenspan A, Forst D, et al, "Antitumor Activity of Liposome-Encapsulated Doxorubicin in Advanced Breast Cancer: Phase II Study," J Natl Cancer Inst, 1990, 82(21):1706-10.