-Intact vials (solution): Refrigerate at 2°C to 8°C. Protect from light.
-intact vials (lyophilized powder): room temperature (15°C to 30°C).
-Reconstituted vials: stable for 7 days at room temperature (25°C) and 15 days under refrigeration (5°C). Protect from light.
-Infusions/admixtures: [50-1000 mL D5W or NS] stable for 48 hours – room temperature (25°C). Protect from light.
1. Severe local tissue necrosis will occur if there is extravasation during administration (see DOSAGE AND ADMINISTRATION). Doxorubicin must not be given by the intramuscular or subcutaneous route.
2. Myocardial toxicity manifested in its most severe form by potentially fatal congestive heart failure (CHF) may occur either during therapy or months to years after termination of therapy. The probability of developing impaired myocardial function based on a combined index of signs, symptoms and decline in left ventricular ejection fraction (LVEF) is estimated to be 1 to 2% at a total cumulative dose of 300 mg/m2 of doxorubicin, 3 to 5% at a dose of 400 mg/m2, 5 to 8% at 450 mg/m2 and 6 to 20% at 500 mg/m2. The risk of developing CHF increases rapidly with increasing total cumulative doses of doxorubicin in excess of 400 mg/m2. Risk factors (active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, concomitant use of other cardiotoxic drugs) may increase the risk of cardiac toxicity. Cardiac toxicity with doxorubicin may occur at lower cumulative doses whether or not cardiac risk factors are present. Pediatric patients are at increased risk for developing delayed cardiotoxicity.
3. Secondary acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) has been reported in patients treated with anthracyclines, including doxorubicin (see package insert for ADVERSE REACTIONS). The occurrence of refractory secondary AML or MDS is more common when anthracyclines are given in combination with DNA-damaging anti-neoplastic agents or radiotherapy, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated. [SEE PACKAGE INSERT FOR ADDITIONAL DETAILS]
4. Dosage should be reduced in patients with impaired hepatic function.
5. Severe myelosuppression may occur.
6. Doxorubicin should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents.
The cytotoxic effect of doxorubicin on malignant cells and its toxic effects on various organs are thought to be related to nucleotide base intercalation and cell membrane lipid binding activities of doxorubicin. Intercalation inhibits nucleotide replication and action of DNA and RNA polymerases. The interaction of doxorubicin with topoisomerase II to form DNA-cleavable complexes appears to be an important mechanism of doxorubicin cytocidal activity. Doxorubicin cellular membrane binding may affect a variety of cellular functions. Enzymatic electron reduction of doxorubicin by a variety of oxidases, reductases and dehydrogenases generates highly reactive species including the hydroxyl free radical OH•. Free radical formation has been implicated in doxorubicin cardiotoxicity by means of Cu (II) and Fe (III) reduction at the cellular level. Cells treated with doxorubicin have been shown to manifest the characteristic morphologic changes associated with apoptosis or programmed cell death. Doxorubicin-induced apoptosis may be an integral component of the cellular mechanism of action relating to therapeutic effects, toxicities, or both. Animal studies have shown activity in a spectrum of experimental tumors, immunosuppression, carcinogenic properties in rodents, induction of a variety of toxic effects, including delayed and progressive cardiac toxicity, myelosuppression in all species and atrophy to testes in rats and dogs.
INDICATIONS AND USAGE:
Doxorubicin has been used successfully to produce regression in disseminated neoplastic conditions such as acute lymphoblastic leukemia, acute myeloblastic leukemia, Wilms’ tumor, neuroblastoma, soft tissue and bone sarcomas, breast carcinoma, ovarian carcinoma, transitional cell bladder carcinoma, thyroid carcinoma, gastric carcinoma, Hodgkin’s disease, malignant lymphoma and bronchogenic carcinoma in which the small cell histologic type is the most responsive compared to other cell types. Doxorubicin is also indicated for use as a component of adjuvant therapy in women with evidence of axillary lymph node involvement following resection of primary breast cancer.
CONTRAINDICATIONS: Patients should not be treated with doxorubicin if they have any of the following conditions: baseline neutrophil count <1500 cells/ mm3; severe hepatic impairment; recent myocardial infarction; severe myocardial insufficiency; severe arrhythmias; previous treatment with complete cumulative doses of doxorubicin, daunorubicin, idarubicin, and/or other anthracyclines and anthracenediones; or hypersensitivity to doxorubicin, any of its excipients, or other anthracyclines or anthracenediones.
[SEE PACKAGE INSERT FOR FULL LIST OF WARNINGS]
Doxorubicin should be administered only under the supervision of qualified physicians experienced in the use of cytotoxic therapy. Patients should recover from acute toxicities of prior cytotoxic treatment (such as stomatitis, neutropenia, thrombocytopenia, and generalized infections) before beginning treatment with doxorubicin. Also, initial treatment with doxorubicin should be preceded by a careful baseline assessment of blood counts; serum levels of total bilirubin, AST, and creatinine; and cardiac function as measured by left ventricular ejection function (LVEF). Patients should be carefully monitored during treatment for possible clinical complications due to myelosuppression. Supportive care may be necessary for the treatment of severe neutropenia and severe infectious complications. Monitoring for potential cardiotoxicity is also important, especially with greater cumulative exposure to doxorubicin. Doxorubicin may potentiate the toxicity of other anticancer therapies (see package insert for PRECAUTIONS, Drug Interactions).
DOSAGE AND ADMINISTRATION:
Care in the administration of doxorubicin will reduce the chance of perivenous infiltration (see PACKAGE INSERT FOR FULL LIST OF WARNINGS). It may also decrease the chance of local reactions such as urticaria and erythematous streaking. On intravenous administration of doxorubicin, extravasation may occur with or without an accompanying burning or stinging sensation, even if blood returns well on aspiration of the infusion needle. If any signs or symptoms of extravasation have occurred, the injection or infusion should be immediately terminated and restarted in another vein. If extravasation is suspected, intermittent application of ice to the site for 15 min. q.i.d. x 3 days may be useful. The benefit of local administration of drugs has not been clearly established. Because of the progressive nature of extravasation reactions, close observation and plastic surgery consultation is recommended. Blistering, ulceration and/or persistent pain are indications for wide excision surgery, followed by split-thickness skin grafting. The most commonly used dose schedule when used as a single agent is 60 to 75 mg/m2 as a single intravenous injection administered at 21-day intervals. The lower dosage should be given to patients with inadequate marrow reserves due to old age, or prior therapy, or neoplastic marrow infiltration. Doxorubicin has been used concurrently with other approved chemotherapeutic agents. Evidence is available that in some types of neoplastic disease combination chemotherapy is superior to single agents. The benefits and risks of such therapy continue to be elucidated. When used in combination with other chemotherapy drugs, the most commonly used dosage of doxorubicin is 40 to 60 mg/m2 given as a single intravenous injection every 21 to 28 days.
In a large randomized study (NSABP B-15) of patients with early breast cancer involving axillary lymph nodes (see PACKAGE INSERT – CLINICAL PHARMACOLOGY, Clinical Studies and ADVERSE REACTIONS, Adverse Reactions in Patients with Early Breast Cancer Receiving Doxorubicin-Containing Adjuvant Therapy), the combination dosage regimen of AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2) was administered intravenously on day 1 of each 21-day treatment cycle. Four cycles of treatment were administered.
Patients in the NSABP B-15 study could have dose modifications of AC to 75% of the starting doses for neutropenic fever/infection. When necessary, the next cycle of treatment cycle was delayed until the absolute neutrophil count (ANC) was ≥1000 cells/mm3 and the platelet count was ≥100 000 cells/mm3 and nonhematologic toxicities had resolved.
Doxorubicin dosage must be reduced in case of hyperbilirubinemia as follows:
|Plasma bilirubin concentration (mg/dL)
||Dosage reduction (%)
|1.2 – 3.0
|3.1 – 5.0
Lyophilized powder: Reconstitute with NS, Sterile Water for Injection, or D5W to give a final concentration of 2 mg/mL.
It is recommended that doxorubicin be slowly administered into the tubing of a freely running intravenous infusion of Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP. The tubing should be attached to a Butterfly® needle inserted preferably into a large vein. If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage. The rate of administration is dependent on the size of the vein, and the dosage. However, the dose should be administered in not less than 3 to 5 minutes. Local erythematous streaking along the vein as well as facial flushing may be indicative of too rapid an administration. A burning or stinging sensation may be indicative of perivenous infiltration and the infusion should be immediately terminated and restarted in another vein. Perivenous infiltration may occur painlessly. Doxorubicin should not be mixed with heparin or fluorouracil since it has been reported that these drugs are incompatible to the extent that a precipitate may form. Contact with alkaline solutions should be avoided since this can lead to hydrolysis of doxorubicin. Until specific compatibility data are available, it is not recommended that doxorubicin be mixed with other drugs. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Reconstituted Solution Stability:
After adding the diluent, the vial should be shaken and the contents allowed to dissolve. The reconstituted solution is stable for 7 days at room temperature and under normal room light (100 foot-candles) and 15 days under refrigeration (2° to 8°C). It should be protected from exposure to sunlight. Discard any unused solution from the 10 mg, 20 mg and 50 mg single dose vials. Unused solutions of the multiple dose vial remaining beyond the recommended storage times should be discarded.
Doxorubicin Hydrochloride Injection, USP is a sterile parenteral, isotonic, available in 5 mL (10 mg), 10 mL (20 mg), 25 mL (50 mg), and 37.5 mL (75 mg) single dose vials and a 100 mL (200 mg) multidose vial. Each mL contains doxorubicin HCl and the following inactive ingredients: sodium chloride 0.9% and water for injection q.s. Hydrochloric acid is used to adjust the pH to a target pH of 3.0.
Doxorubicin Hydrochloride for Injection, powder, lyophilized, for solution is available as:
Sterile single use only:
NDC 0013-1086-91 10 mg single dose vial, 10 vial packs
NDC 0013-1096-91 20 mg single dose vial, 10 vial packs
NDC 0013-1106-79 50 mg single dose vial, single packs
Doxorubicin Hydrochloride Injection, USP is available as:
SINGLE DOSE GLASS VIALS: [Solution]
NDC 0013-1136-91 10 mg vial, 2 mg/mL, 5 mL, 10 vial packs
NDC 0013-1146-91 20 mg vial, 2 mg/mL,10 mL, 10 vial packs
NDC 0013-1156-79 50 mg vial, 2 mg/mL, 25 mL, single vial packs
NDC 0013-1176-87 75 mg vial, 2 mg/mL, 37.5 mL, single vial packs
MULTIDOSE VIALS, in Cytosafe™ vial packs:
NDC 0013-1286-83 150 mg, 2 mg/mL, 75 mL
NDC 0013-1266-83 200 mg, 2 mg/mL, 100 mL
Store refrigerated, 2° to 8°C (36° to 46°F). Protect from light. Retain in carton until contents are used. Contains no preservative. Discard unused portion.
1) [PACKAGE INSERT DATA] : Pharmacia and Upjohn Company. DOXORUBICIN HYDROCHLORIDE Package insert. October 2006.
2) IV admixture data: Lexi-Comp OnlineTM , Lexi-Drugs OnlineTM , Hudson, Ohio: Lexi-Comp, Inc.; 2010; June 28, 2010.
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