doxorubicin hydrochloride
Adriamycin PFS, Adriamycin RDF, Rubex

Available forms
Available by prescription only
Injection (preservative-free): 2 mg/ml (10 mg, 20 mg, 50 mg, 75 mg, and 200 mg)
Powder for injection: 10-mg, 20-mg, 50-mg, 100-mg, 150-mg vials

Indications and dosages
Dosage and indications may vary. Check current literature for recommended protocol or for information on liposomal doxorubicin.
 Bladder, breast, lung, ovarian, stomach, and thyroid cancers; Hodgkin’s disease; acute lymphoblastic and myeloblastic leukemia; Wilms’ tumor; neuroblastoma; lymphoma; sarcoma. Adults: 60 to 75 mg/m² I.V. as a single dose q 21 days; or 25 to 30 mg/m² I.V. as a single daily dose on days 1 to 3 of 4-week cycle. Or, 20 mg/m² I.V. once weekly. Maximum cumulative dosage is 550 mg/m² (450 mg/m² in patients who have received chest irradiation).
≡ Dosage adjustment. If serum bilirubin level is 1.2 to 3 mg/dl, decrease dose by 50%. If serum bilirubin level is 3.1 to 5 mg/dl, decrease dose by 75%.

Pharmacodynamics
Antineoplastic action: Doxorubicin exerts its cytotoxic activity by intercalating between DNA base pairs and uncoiling the DNA helix. The result is inhibition of DNA synthesis and DNA-dependent RNA synthesis. Doxorubicin also inhibits protein synthesis and causes apoptosis, which contributes to its therapeutic and toxic effects.

Pharmacokinetics
Absorption: Administered I.V.
Distribution: Distributed widely into body tissues, with the highest levels found in the liver, heart, and kidneys. It doesn’t cross the blood-brain barrier. It’s about 75% protein-bound, especially to albumin. The free fraction of drug is related to patient’s hematocrit; the lower the hematocrit, the higher the free drug concentration.
Metabolism: Extensively metabolized by hepatic microsomal enzymes to several metabolites, one of which possesses cytotoxic activity.
Excretion: Excreted primarily in bile. A minute amount is eliminated in urine. The plasma elimination of doxorubicin is described as biphasic with a half-life of about 15 to 30 minutes in the initial phase and 16 1/2 hours in the terminal phase.

Contraindications and precautions
Contraindicated in patients hypersensitive to conventional or liposomal doxorubicin. Also contraindicated in patients with marked myelosuppression induced by previous treatment with other antitumor drugs or by radiotherapy and in those who have received lifetime cumulative dosage of 550 mg/m² of anthracycline antibiotics.

Interactions
Drug-drug. Actinomycin-D: May cause "recall pneumonitis" in patients receiving radiation therapy. Monitor patient closely.
Aminophylline, cephalosporins, dexamethasone phosphate, fluorouracil, heparin sodium, hydrocortisone, sodium phosphate: Causes a precipitate when mixed with doxorubicin. Administer through separate I.V. lines.
Cyclophosphamide, daunorubicin: Potentiates cardiotoxicity of doxorubicin through additive effects on the heart. Avoid use together.
Cyclophosphamide: May worsen induced hemorrhagic cystitis. Monitor patient closely.
Cyclosporine: May decrease doxorubicin metabolism, increasing risk for toxicity. Monitor patient for toxicity.
Digoxin: May decrease digoxin levels. Monitor serum digoxin levels closely.
Mercaptopurine: Causes hepatotoxicity. Don’t use together.
Paclitaxel: Decreases doxorubicin clearance resulting in increased risk of neutropenia and stomatitis. Monitor patient for signs of toxicity.
Phenobarbital: May increase doxorubicin elimination. Monitor patient for effects.
Phenytoin: Decreases phenytoin levels. Monitor serum phenytoin levels.
Progesterone: May increase risk of neutropenia and thrombocytopenia. Monitor serum levels.
Radiation: May increase risk of radiation-induced toxicities. Use together cautiously.
Streptozocin: Increases plasma half-life of doxorubicin, increasing activity of doxorubicin. Dosage may need adjustment.
Verapamil: Increases doxorubicin levels. Monitor patient for signs of toxicity.
Drug-herb. Green tea: May enhance antitumor activity of doxorubicin. Monitor patient closely.

Adverse reactions
CNS: fever, peripheral neuropathy, dizziness, depression, anxiety, confusion, paresthesia, asthenia.
CV: cardiac depression, seen in such ECG changes as sinus tachycardia, T-wave flattening, ST-segment depression, voltage reduction; arrhythmias; acute left ventricular failure; irreversible cardiomyopathy.
EENT: conjunctivitis.
GI: nausea, vomiting, diarrhea,stomatitis, esophagitis, anorexia, necrotizing colitis, constipation.
GU: red urine.
Hematologic: leukopenia during days 10 to 15 with recovery by day 21,THROMBOCYTOPENIA,MYELOSUPPRESSION, anemia, NEUTROPENIA.
Metabolic: hyperuricemia.
Skin: urticaria, facial flushing, rash, severe cellulitis or tissue sloughing (with extravasation), alopecia.
Other: chills, anaphylaxis, sepsis.

Effects on lab test results
• May increase bilirubin and glucose levels. May decrease calcium levels.
• May increase PT. May decrease hemoglobin and WBC, neutrophil, and platelet counts.

Overdose and treatment
Signs and symptoms of overdose include myelosuppression, nausea, vomiting, mucositis, and irreversible myocardial toxicity.
 Treatment is usually supportive and includes transfusion of blood components, antiemetics, antibiotics for infections that may develop, symptomatic treatment of mucositis, and cardiac glycoside preparations.

Special considerations
 ALERT Reddish color is similar to that of daunorubicin. Don’t confuse the two drugs.
• If signs of heart failure occur, stop drug and reevaluate patient.
• The alternative dosage schedule (once-weekly dosing) has been found to cause a lower risk of cardiomyopathy.
• To reconstitute, add 5 ml normal saline injection, USP, to the 10-mg vial, 10 ml to the 20-mg vial, and 25 ml to the 50-mg vial, to yield a concentration of 2 mg/ml.
• Drug may be further diluted with normal saline solution or D₅W and administered by I.V. infusion.
• Reconstituted solution is stable at room temperature for 7 days and 15 days if under refrigeration.
• Drug may be administered by I.V. push injection over 5 to 10 minutes into the tubing of a freely flowing I.V. infusion.
• If cumulative dose exceeds 550 mg/m² body surface area, cardiac adverse reactions, which begin 2 weeks to 6 months after stopping drug, develop in 30% of patients. With high doses of doxorubicin, consider concomitant dosing with the cardioprotective agent dexrazoxane.
• The occurrence of streaking along a vein or facial flushing indicates that drug is being administered too rapidly.
• Applying a scalp tourniquet or ice may decrease alopecia. However, don’t use these if treating leukemias or other neoplasms in which stem cells may be present in scalp.
• Discontinue drug or slow infusion if tachycardia develops. Drug is a vesicant; treat extravasation with topical application of dimethyl sulfoxide and ice packs. Discontinue drug and change injection site.
Breast-feeding patients
• Doxorubicin appears in breast milk. Because of the risk of serious adverse reactions, mutagenicity, and carcinogenicity in the infant, breast-feeding isn’t recommended.
Pediatric patients
• Children younger than age 2 have a higher risk of drug-induced cardiotoxicity.
Geriatric patients
• Patients older than age 70 have an increased risk of drug-induced cardiotoxicity. Use cautiously in elderly patients with low bone marrow reserve to prevent serious hematologic toxicity.

Patient education
• Encourage adequate fluid intake to increase urine output and facilitate excretion of uric acid.
• Advise patient to avoid exposure to people with infections.
• Warn patient that alopecia will occur. Explain that hair growth should resume 2 to 5 months after drug is stopped.
• Advise patient that urine will appear red for 1 to 2 days after the dose and doesn’t indicate bleeding. The urine may stain clothes.
• Instruct patient not to receive immunizations during therapy and for several weeks after. Other members of the patient’s household should also not receive immunizations during the same period.
• Tell patient to call if unusual bruising or bleeding or signs of infection occur.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use