VA Class:AN200

AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• DOXOrubicin Hydrochloride

Doxorubicin is an anthracycline glycoside antineoplastic antibiotic produced by Streptomyces peucetius var. caesius .

Since doxorubicin does not cross the blood-brain barrier or achieve a measurable concentration in CSF, there is a possibility of metastases to the brain and meninges from potentially metastatic tumors.

Breast Cancer

Doxorubicin hydrochloride is used in the treatment of breast cancer.200,213 Use of the drug in combination with other chemotherapeutic agents and/or surgery in the early stage of breast cancer has produced clinically important responses in both quantity and duration. Combination chemotherapy used as an adjunct to surgery has been shown to increase both disease-free (i.e., decreased recurrence) and overall survival in premenopausal and postmenopausal women with node-negative or node-positive early (TNM stage I or II) breast cancer.221,222,223,224,225,226,227,228,229,230,231,232 Although adjuvant combination chemotherapy that includes cyclophosphamide, methotrexate, and fluorouracil has been used most extensively and is considered a regimen of choice for early breast cancer,213,221,222,223,225,227,228,230,231,232 doxorubicin-containing regimens (e.g., combined cyclophosphamide and doxorubicin with or without fluorouracil; combined cyclophosphamide and doxorubicin with or without tamoxifen) appear to be comparably effective and also are considered regimens of choice, but differences in toxicity profiles may influence the choice of regimen.221,222,224,225,227,228,229,230 There is some evidence that the addition of doxorubicin to a regimen of cyclophosphamide, methotrexate, and fluorouracil can improve outcome further in patients with early breast cancer and more than 3 positive axillary lymph nodes,225,231 and that sequential (i.e., administering several courses of doxorubicin first) regimens are more effective than alternating regimens in such patients;225,231 in patients with fewer positive nodes, no additional benefit from doxorubicin has been demonstrated.225,228 The dose intensity of adjuvant combination chemotherapy also appears to be an important factor influencing clinical outcome in patients with early node-positive breast cancer, with response increasing with increasing dose intensity; therefore, arbitrary reductions in dose intensity should be avoided.221,224,232 In stage III (locally advanced) breast cancer, combination chemotherapy (with or without hormonal therapy) is used sequentially following surgery and radiation therapy for operable disease and following biopsy and radiation therapy for inoperable disease; commonly employed effective regimens include cyclophosphamide, methotrexate, and fluorouracil; cyclophosphamide, doxorubicin, and fluorouracil; and cyclophosphamide and doxorubicin.213,215,216,217,221

Patients refractory to cyclophosphamide, vincristine sulfate, dactinomycin, or daunorubicin have responded to doxorubicin hydrochloride; however, apparent cross-resistance between doxorubicin and daunorubicin has been noted in some patients with neuroblastoma. Cross-resistance between doxorubicin and vincristine sulfate or dactinomycin in animals or cell cultures has been reported, but clinical evidence of these cross-resistances in humans is lacking.

AIDS-related Kaposi's Sarcoma

Overview

Doxorubicin hydrochloride as conventional (nonencapsulated) injections has been used alone or in combination chemotherapy for the palliative treatment of AIDS-related Kaposi's sarcoma†, and combination chemotherapy that includes the drug (e.g., doxorubicin, bleomycin, and vincristine) has been a preferred regimen;213,276,277,278,327,328 but many clinicians currently consider a liposomal anthracycline (doxorubicin or daunorubicin) the first-line therapy of choice for advanced AIDS-related Kaposi's sarcoma (see also Uses: AIDS-related Kaposi's Sarcoma in Daunorubicin 10:00).213,276,279,280,296

Although single-agent therapy with conventional (i.e., nonencapsulated) cytotoxic agents generally has been used in the early stage of disease, Kaposi's sarcoma in patients with human immunodeficiency virus (HIV) infection often is rapidly progressive.276,301,302,303,304,305,306,307,322,351 AIDS-related Kaposi's sarcoma often progresses to multifocal, widespread lesions that may involve the skin, oral mucosa, and lymph nodes as well as visceral organs such as the GI tract, lung, liver, and spleen;301,303,304,305,306,308,309,310,311,322,323,351 such lesions often are numerous and may be cosmetically unattractive or disfiguring and accompanied by lymphedema.304,312,313,351 Appropriate evaluation of the effects of drug therapies on survival in patients with Kaposi's sarcoma must include assessment of the effects of such therapies on the development of infection as well as on tumor regression.304,323,351 Although treatment may result in disappearance or reduction in the size of Kaposi's sarcoma skin lesions and thereby alleviate the discomfort associated with chronic edema and ulcerations that often accompany multiple skin lesions on the lower extremities and in symptomatic control of mucosal and visceral lesions, there currently are no data demonstrating unequivocal evidence of improved survival with any therapy.275,276,283,284,327,328,351 Small localized Kaposi's sarcoma lesions may be treated with electrodesiccation and curettage cryotherapy or by surgical excision; the lesions also generally are responsive to local radiation, and excellent palliation often can be achieved.276,351 Localized palatal lesions have been treated effectively with intralesional injections of vinblastine or bleomycin.276,300,323,327,328,351

Alitretinoin gel (Panretin^®, Ligand Pharmaceuticals), a topical retinoid, is used for the treatment of localized cutaneous lesions in patients with AIDS-related Kaposi's sarcoma; responses of cutaneous lesions to topical therapy with alitretinoin have been reported in patients who have received prior systemic and/or topical therapy for Kaposi's sarcoma as well as in those with previously untreated disease.352

Liposomal Agents

Pegylated liposomal doxorubicin is labeled for use273 in the palliative treatment of AIDS-related Kaposi's sarcoma in adults intolerant to combination chemotherapy or whose disease has progressed while receiving such therapy.273,275,279,280,281,282,283,284,286,287,288,289,328 Liposomal daunorubicin citrate is labeled for use as first-line therapy for advanced AIDS-related Kaposi's sarcoma.294 (See Daunorubicin 10:00.) The results of several randomized, multicenter trials indicate that patients receiving a liposomal anthracycline for the treatment of advanced AIDS-related Kaposi's sarcoma experience similar or higher response rates with a more favorable toxic effects profile than those receiving combination therapy with conventional chemotherapeutic agents.276,279,280,296

Administration of doxorubicin hydrochloride encapsulated in PEG-stabilized liposomes (see Chemistry and Stability: Chemistry) allows the drug-containing liposomes to remain circulating in plasma for prolonged periods and reduces extravascular circulation of the drug273,275,283,285,328 while substantially increasing concentrations of the drug in the lesions of Kaposi's sarcoma compared with administration of equivalent doses of conventional (nonencapsulated) doxorubicin hydrochloride injections (see Pharmacokinetics: Distribution).285

In an open-label, single-arm, multicenter study in patients with moderate to severe AIDS-related Kaposi's sarcoma whose disease had progressed on prior combination chemotherapy (consisting of at least 2 cycles of a regimen containing bleomycin, a vinca alkaloid [ vincristine or vinblastine], and/or doxorubicin) or who were intolerant of such therapy, response rates were analyzed according to the investigator assessment of changes in lesions over the entire body or according to changes in indicator lesions; in this study, liposomal doxorubicin was administered IV in doses of 20-mg/m² once every 3 weeks, generally until disease progression or intolerance to doxorubicin therapy occurred.273,275,283 According to investigator assessment of changes, partial response, stable disease, or progressive disease was observed in 27, 29, or 44% of patients, respectively, while duration of partial response or time to partial response was 73 (range: 42-210) days or 43 (range: 15-133) days, respectively.273,275,283 According to indicator lesion assessment, partial response, stable disease, or progressive disease was observed in 48, 26, or 26%, respectively, while duration of partial response or time to partial response was 71 (range: 22-210) days or 22 (range: 15-109) days, respectively.273,275

In a large, randomized trial, patients with AIDS-related Kaposi's sarcoma receiving liposomal doxorubicin (20 mg/m² by IV infusion over 30 minutes) had a higher objective response rate (58.7 versus 23.3%) than those receiving a combination regimen of bleomycin (15 mg/m² by IV infusion over 30 minutes) and vincristine (1.4 mg/m² or a maximum of 2 mg by IV bolus); each regimen was administered every 3 weeks for a maximum of 6 cycles.279 Treatment with liposomal doxorubicin was associated with greater improvement in signs and symptoms of pulmonary Kaposi's sarcoma (e.g., dyspnea, cough, chest pain, effusions) and GI Kaposi's sarcoma (e.g., GI bleeding, early satiety, dysphagia).279 Early termination from the study, withdrawal because of adverse effects, and withdrawal because of progressive disease occurred less frequently in patients receiving liposomal doxorubicin than in those receiving combination chemotherapy with bleomycin and vincristine.279 The incidence of paresthesia, peripheral neuropathy, and constipation was higher in patients receiving bleomycin and vincristine, whereas leukopenia and opportunistic infections (particularly oral candidiasis) occurred more frequently in those receiving liposomal doxorubicin.279 In another large, randomized trial involving 258 patients with advanced AIDS-related Kaposi's sarcoma, a higher rate of objective response (45.9 versus 24.8%) and less toxicity were reported in those receiving liposomal doxorubicin (20 mg/m² IV over 30 minutes) versus the ABV regimen, consisting of conventional doxorubicin (20 mg/m²), bleomycin (10 mg/m²), and vincristine (1 mg); each regimen was administered every 14 days for a maximum of 6 cycles.280 Treatment was discontinued because of adverse effects more frequently among those receiving the ABV regimen (37%) than among those receiving liposomal doxorubicin (11%).280 A higher incidence of nausea and vomiting, alopecia, and peripheral neuropathy was reported in patients receiving the ABV regimen, whereas stomatitis and rash were reported more frequently in patients receiving liposomal doxorubicin.280

Preliminary evidence suggests that the mean survival period in patients with pulmonary AIDS-related Kaposi's sarcoma receiving liposomal doxorubicin may be increased compared with those receiving conventional chemotherapy (bleomycin and/or vincristine).286 Similar response rates, time to treatment failure, and overall survival, with less toxicity, were observed in patients receiving liposomal daunorubicin versus combination chemotherapy with bleomycin, conventional doxorubicin, and vincristine for advanced AIDS-related Kaposi's sarcoma.296 The comparative efficacy of liposomal doxorubicin relative to liposomal daunorubicin has not been established.294,295,296,297

Although treatment may result in the reduction in size or disappearance of specific skin lesions and alleviation of the associated symptoms, no treatment has been shown conclusively to alter the natural history of AIDS-related Kaposi's sarcoma275,276,283,284,304,316,322 and additional study and experience are needed to establish the optimal regimen.275,276,283,284,327,328

Conventional Chemotherapy

Response rates observed with single-agent chemotherapy (e.g., doxorubicin, etoposide, vinblastine, vincristine) appear to be similar to those observed with interferon alfa; however, studies directly comparing the efficacy of doxorubicin alone with that of interferon alfa have not been performed.276,313,327,328 The wide variation in response rates reported in clinical studies generally appear to reflect differences in patient selection and in the heterogeneity of criteria used to evaluate response rather than in drug activity.276 Combined treatment with chemotherapy (e.g., vinblastine314,315,316,317,322 or etoposide)314,316,318,319,322 and interferon alfa generally appears to result in enhanced systemic toxicity without added therapeutic benefits.276,277,314,315,316,317,319,321,322,351

Combination chemotherapy with conventional antineoplastic agents (e.g., conventional doxorubicin, etoposide, vinblastine, vincristine) has been used for advanced disease (e.g., extensive mucocutaneous disease, lymphedema, symptomatic visceral disease).276,277,278,325,351 Evidence from a study in patients with advanced Kaposi's sarcoma indicates that combined therapy with low-dose conventional (nonencapsulated) doxorubicin, bleomycin, and vincristine is more effective than low-dose doxorubicin alone in inducing response and prolonging disease-free survival, although overall survival with either regimen was comparable.277,278,323 In this study, complete and partial tumor remissions as well as disease-free survival were higher in patients receiving combination therapy with low-dose conventional doxorubicin (20 mg/m²), bleomycin (10 units/m²), and vincristine (1.4 mg/m²; up to 2 mg) every 2 weeks than in those receiving low-dose doxorubicin (20 mg/m²) alone every 2 weeks;278 complete and partial remissions occurred in 88 or 48% of patients receiving combination or single-agent chemotherapy, respectively, while a median survival of 9 months was observed with both therapies.278,323

Ovarian Cancer

Liposomal Doxorubicin

Pegylated liposomal doxorubicin is used for the treatment of ovarian cancer that has progressed or recurred following platinum-based chemotherapy.206,213,273

The current indication for use of liposomal doxorubicin in platinum-refractory ovarian cancer is based principally on data from a subset of patients involved in 3 uncontrolled studies and a randomized trial.273,354,358 In these clinical trials, liposomal doxorubicin was administered at an initial dosage of 50 mg/m² IV over 1 hour every 3-4 weeks for 3-6 cycles or more.273,354 Among 145 patients with metastatic ovarian carcinoma refractory to paclitaxel- and platinum-based chemotherapy regimens who received liposomal doxorubicin in 3 open-label, phase II studies, the objective response rate was 13.8% (range: 0-22%), the median time to response was 17.6 weeks, the median duration of response was 39.4 weeks, and the median time to progression was 15.9 weeks.273 In a randomized, open-label trial involving 474 patients with epithelial ovarian cancer (mostly stage III-IV disease) who had received platinum-based chemotherapy, similar median time to progression (4 months), median overall survival (14 months) and response rates (20 versus 17%) were observed in those receiving liposomal doxorubicin or topotecan.273 Hand-foot syndrome (51 versus 1%), stomatitis (41 versus 15%), and rash (28 versus 12%) occurred more frequently in patients receiving liposomal doxorubicin, whereas nausea (63 versus 46%), alopecia (52 versus 19%), and constipation (46 versus 30%) occurred more frequently in those receiving topotecan.273 Severe hematologic toxicity, including neutropenia, anemia, and thrombocytopenia, occurred more frequently in patients receiving topotecan than in those receiving liposomal doxorubicin.273,358 Severe neutropenia (less than 500/mm³) was reported in 4% of patients receiving liposomal doxorubicin compared with 62% of patients receiving topotecan.273

Conventional Doxorubicin

Although conventional doxorubicin is labeled for use in the treatment of ovarian carcinoma200,208 and has been used in combination regimens for the treatment of this cancer, other agents currently are preferred.206,213

Bladder Cancer

Doxorubicin has been used intravesically† for the treatment of residual tumor and/or as adjuvant therapy for prophylaxis of superficial bladder carcinoma†.213,320,332,333,334,335

Complete response rates of about 40-50% have been observed in patients receiving intravesical doxorubicin for the treatment of papillary tumors;333,334,344 complete responses to intravesical doxorubicin also have been reported in a small number of patients with carcinoma in situ.333 No additional benefit has been shown for the use of maintenance therapy with intravesical doxorubicin.333,335,339,345 Treatment with intravesical doxorubicin generally is well tolerated; the most common adverse effect observed is chemical cystitis, usually reversible, in approximately 20-30% of patients.333,344 Systemic toxicity, including hypersensitivity reactions and cardiovascular events, have been reported in patients receiving intravesical doxorubicin for the prophylaxis338 or treatment340 of superficial bladder cancer.

Although evidence from comparative studies is limited, other agents (e.g. mitomycin, epirubicin) that appear to be similar in efficacy but less toxic than doxorubicin generally are preferred for the prophylaxis or treatment of superficial bladder cancer.341,342,343 (See Uses: Bladder Cancer in Mitomycin 10:00 for further discussion of intravesical chemotherapy for superficial bladder cancer.)

Doxorubicin is used in combination regimens with cisplatin, methotrexate, and vinblastine for the treatment of invasive and advanced bladder carcinoma.213,332,336,347,348 (See Uses: Bladder Cancer in Cisplatin 10:00.)

Small Cell Lung Cancer

Doxorubicin is used in combination chemotherapy regimens (e.g., cyclophosphamide, doxorubicin, and vincristine [CAV]; cyclophosphamide, doxorubicin, and etoposide [CAE]) for the treatment of extensive-stage small cell lung cancer†.213,349 Survival outcomes are similar in patients with extensive-stage small cell lung cancer receiving CAV or cisplatin/etoposide.349 Combination chemotherapy regimens have produced response rates of 70-85% and complete response rates of 20-30% in patients with extensive-stage disease; however, comparative efficacy is continually being evaluated.349 Because the current prognosis for small cell lung carcinoma is unsatisfactory regardless of stage and despite considerable diagnostic and therapeutic advances, all patients with this cancer are candidates for inclusion in clinical trials at the time of diagnosis.349

Multiple Myeloma

Induction Therapy Prior to Stem Cell Transplantation

Conventional Doxorubicin

Use of conventional doxorubicin in combination with bortezomib and dexamethasone† (bortezomib-doxorubicin-dexamethasone)10005,10023 as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients† may be considered a reasonable choice (accepted; with possible conditions) based on current evidence from an open-label, randomized phase 3 study (HOVON-65/GMMG-HD4).10034 Factors that should be considered when selecting a combination chemotherapy regimen for use as induction therapy include performance status and preexisting conditions (e.g., peripheral neuropathy).10034

In the HOVON-65/GMMG-HD4 study in 827 patients with newly diagnosed multiple myeloma, patients who received bortezomib-doxorubicin-dexamethasone had prolonged progression-free survival (35 versus 28 months; hazard ratio: 0.75) and higher postinduction (11 versus 5%) and posttransplant (31 versus 15%) complete plus near-complete response rates compared with those who received vincristine-doxorubicin-dexamethasone at a median follow-up of 41 months.10023 Median overall survival had not been reached at a median follow-up of 66 months; however, no significant difference in 5-year overall survival was observed between the groups.10023 Subgroup analyses based on presence of renal insufficiency or high-risk cytogenetic features (i.e., chromosome 13q14 deletion [del(13q14)], t(4;14) translocation, chromosome 17p13 deletion [del(17p13)]) suggested prolonged progression-free and overall survival with bortezomib-doxorubicin-dexamethasone compared with vincristine-doxorubicin-dexamethasone induction therapy in patients with serum creatinine concentrations exceeding 2 mg/dL and in those with del(17p13) chromosomal abnormality, as well as an overall survival benefit for bortezomib-doxorubicin-dexamethasone compared with vincristine-doxorubicin-dexamethasone in patients with del(13q14) chromosomal abnormality.10023

For further information on the use of combination therapy with conventional doxorubicin, bortezomib, and dexamethasone as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients, see Induction Therapy Prior to Stem Cell Transplantation in Newly Diagnosed Multiple Myeloma under Uses: Multiple Myeloma, in Bortezomib 10:00.

Liposomal Doxorubicin

Use of pegylated liposomal doxorubicin also has been studied in combination with bortezomib and dexamethasone† (bortezomib-liposomal doxorubicin-dexamethasone) as induction therapy for previously untreated multiple myeloma† in 2 open-label, noncomparative phase 2 studies.10004,10024,10025,10026 Based on current evidence,10024,10025 use of liposomal doxorubicin in combination with bortezomib and dexamethasone as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients may be considered a reasonable choice (accepted; with possible conditions);10034 however, in the absence of longer follow-up data, use of a modified bortezomib-liposomal doxorubicin-dexamethasone regimen (i.e., reduced dosages of liposomal doxorubicin and bortezomib)10026 is not fully established because of unclear risk/benefit and/or inadequate experience (see Liposomal Doxorubicin Hydrochloride under Dosage and Administration: Dosage).10034 Factors that should be considered when selecting a combination chemotherapy regimen for induction therapy include performance status and preexisting conditions (e.g., peripheral neuropathy).10034

In the first study in 40 patients with newly diagnosed multiple myeloma, overall response rate and complete plus near-complete response rate were 85 and 38%, respectively, following 6 cycles of induction therapy with bortezomib-liposomal doxorubicin-dexamethasone.10024 Among patients who underwent stem cell transplantation, the complete plus near-complete response rate increased to 57% following transplantation, but the overall response rate did not improve substantially.10024 At a median follow-up of 45.1 months, median progression-free survival had not been reached; however, among patients who underwent stem cell transplantation, actuarial 2- and 4-year progression-free survival rates were 93 and 65%, respectively, and actuarial 2- and 4-year overall survival rates were 97 and 67%, respectively.10025

Because liposomal doxorubicin and bortezomib frequently cause adverse effects, another phase 2 study evaluated a modified bortezomib-liposomal doxorubicin-dexamethasone regimen (i.e., reduced dosages of liposomal doxorubicin and bortezomib) in 35 patients with previously untreated multiple myeloma.10026 Overall and complete response rates were 86 and 20%, respectively.10026 At a median follow-up of 17.7 months, median time to progression, duration of response, and overall survival had not been reached.10026

For further information on the use of combination therapy with liposomal doxorubicin, bortezomib, and dexamethasone as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients, see Induction Therapy Prior to Stem Cell Transplantation in Newly Diagnosed Multiple Myeloma under Uses: Multiple Myeloma, in Bortezomib 10:00.

Refractory Multiple Myeloma

Doxorubicin is used in combination therapy for refractory multiple myeloma†.202,203,213,214 A regimen employing continuous IV infusions of doxorubicin and vincristine and high-dose dexamethasone is used in patients with advanced multiple myeloma refractory to alkylating agents202,213,214 and in patients with relapsing disease.203,214

Other Uses

Doxorubicin hydrochloride is used in the treatment of solid tumors including thyroid cancer, gastric cancer, soft-tissue and osteogenic sarcomas, neuroblastoma, and Wilms' tumor; malignant lymphomas of both Hodgkin and non-Hodgkin type; and acute lymphocytic leukemia.200,208,213

Doxorubicin is used in the treatment of Ewing's sarcoma†,213 squamous cell carcinomas of the cervix†213 and prostate†,213 and uterine cancer†.

Doxorubicin also is used in the treatment of adrenocortical cancer†, carcinoid tumors†, endometrial cancer†, islet cell carcinoma†, chronic lymphocytic leukemia†, liver cancer†, and mesothelioma†.213

Although doxorubicin is labeled for use in the treatment of acute myeloid leukemia,200,208 other agents are preferred.213

Reconstitution and Administration

Doxorubicin hydrochloride conventional and PEG-stabilized liposomal for injection concentrate are administered IV. The drug is extremely irritating to tissues and, therefore, must not be given IM or subcutaneously. (See Cautions: Local Effects.) Care should be taken to avoid extravasation of the drug.

Because doxorubicin may cause adverse local dermatologic reactions, commercially available conventional and liposomal doxorubicin hydrochloride for injection concentrate, the powder for injection, and solutions of the drug must be prepared and handled cautiously and the use of latex gloves is recommended.200,273 If the powder or solutions of the drug contact the skin or mucous membranes, the affected area should be immediately and thoroughly washed with soap and water.200,273 Parenteral doxorubicin hydrochloride solutions should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.200,208,273 However, because PEG-stabilized liposomal doxorubicin hydrochloride occurs as a liposomal dispersion, the for injection concentrate is not clear but rather is translucent and red.273

Conventional Doxorubicin Hydrochloride

The lyophilized drug is reconstituted by adding 5, 10, 25, 50, or 75 mL of 0.9% sodium chloride injection to a vial labeled as containing 10, 20, 50, 100, or 150 mg of doxorubicin hydrochloride, respectively.200,208 The vial should then be shaken and the contents allowed to dissolve. When reconstituted as directed above, the resultant solution contains 2 mg of doxorubicin hydrochloride per mL.200 Diluents containing preservatives should not be used to reconstitute the powder for injection. Alternatively, to avoid the potential risks associated with reconstitution of the powder, the commercially available injection can be used; however, handling of the solution is not without risk.

Solutions of the conventional doxorubicin hydrochloride injection should be administered slowly into the tubing of a freely running IV infusion of 0.9% sodium chloride or 5% dextrose injection, preferably via a Butterfly^® needle inserted into a large vein.200 When possible, veins over joints or in extremities with compromised venous or lymphatic drainage should not be used.200 The rate of the conventional doxorubicin hydrochloride injection depends on the size of the vein and the dose, but the dose should be administered over at least 3-5 minutes.200 Local erythematous streaking along the vein and/or facial flushing may be indicative of too rapid an administration rate.200

Although a stinging or burning sensation may be a symptom of extravasation during IV administration of conventional doxorubicin hydrochloride, extravasation may occur without these symptoms and even when blood returns well during initial aspiration of the infusion needle.200 If any signs or symptoms of extravasation occur, the injection or infusion of conventional doxorubicin hydrochloride should be immediately stopped and restarted at another site.200 When extravasation of the conventional injection occurs or is suspected, intermittent application of ice packs to the site for 15 minutes four times daily for 3 days may be helpful in reducing the local reaction.200 The benefit of local administration of drugs to the extravasation site has not been established.200 Because of the progressive nature of extravasation reactions, the affected area should be examined frequently and consultation with a specialist in plastic surgery should be obtained.200 If blistering, ulceration, and/or persistent pain occurs, wide excision of the affected area followed by split-thickness skin grafting should be considered.200

Liposomal Doxorubicin Hydrochloride

PEG-stabilized liposomal doxorubicin hydrochloride for injection concentrate must be diluted prior to IV infusion. 273 The concentrate should be diluted in 5% dextrose injection only , and no other diluent should be used.273 Doses of PEG-stabilized liposomal doxorubicin hydrochloride for injection concentrate up to 90 mg should be diluted in 250 mL of 5% dextrose injection.273 Doses of PEG-stabilized liposomal doxorubicin hydrochloride for injection concentrate exceeding 90 mg should be diluted in 500 mL of 5% dextrose injection.273 Strict aseptic technique must be observed because the liposomal doxorubicin for injection concentrate does not contain any preservative or bacteriostatic agent.273 Diluents containing preservatives (e.g., benzyl alcohol) should not be used to dilute the liposomal for injection concentrate, and other drugs should not be mixed with the solution.273 Because PEG-stabilized liposomal doxorubicin hydrochloride occurs as a liposomal dispersion of the drug, inline filters should not be used.273 Rapid flushing of the infusion line should be avoided.273

The diluted solution of liposomal doxorubicin hydrochloride should be infused at an initial rate of 1 mg/minute in patients receiving the drug for ovarian cancer or AIDS-related Kaposi's sarcoma to reduce the risk of infusion-related reactions; if no infusion-related reactions occur, the rate of infusion may be increased to complete administration of the infusion over a 1-hour period.273 If infusion reactions manifested as flushing, shortness of breath, facial edema, headache, chills, chest pain, back pain, tightness of the chest or throat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and/or hypotension occur, the rate of infusion should be slowed or the infusion stopped.273 Because rapid infusion may increase the risk of such reactions, the liposomal injection should not be administered by rapid direct injection nor as an undiluted solution.273

Although a stinging or burning sensation may be a symptom of extravasation during IV administration of liposomal doxorubicin hydrochloride, extravasation may occur without these symptoms and even when blood returns well during initial aspiration of the infusion needle.273 If any signs or symptoms of extravasation occur, the injection or infusion of liposomal doxorubicin hydrochloride should be immediately stopped and restarted at another site.273 When extravasation of liposomal doxorubicin hydrochloride occurs, applying ice packs over the site of extravasation for about 30 minutes may help alleviate the local reaction.273

Dosage

To obtain optimum therapeutic results with minimum adverse effects, dosage of doxorubicin hydrochloride must be based on the clinical, cardiac, hepatic, renal, and hematologic response and tolerance of the patient and on other chemotherapy or irradiation being used. Dosage reduction may be necessary in patients who have received extensive prior radiation therapy or in those whose bone marrow has been infiltrated with malignant cells, since severe myelosuppression is likely to occur. Clinicians should consult published protocols for the dosage of doxorubicin hydrochloride and other chemotherapeutic agents and the method and sequence of administration. Dosage of doxorubicin hydrochloride is based indirectly on body weight; if the patient has abnormal fluid retention, the patient's ideal weight is used to calculate body surface area.

Accidental substitution of liposomal doxorubicin for conventional doxorubicin hydrochloride injection has resulted in severe adverse effects.273 Liposomal doxorubicin hydrochloride should not be substituted for conventional doxorubicin hydrochloride, and the drugs are not equivalent on a mg per mg basis.273

The total cumulative dose of doxorubicin hydrochloride should not exceed 550 mg/m² because of the risk of potentially irreversible cardiotoxicity,200,273 but higher cumulative doses may be tolerated when dexrazoxane (Zinecard^®) is used concomitantly as a cardioprotectant.221,233,234,235,236,241,242 (See Cautions: Cardiac Effects.) If previous or concomitant therapy includes the use of other potentially cardiotoxic agents, such as cyclophosphamide, or irradiation of the cardiac region, total doxorubicin hydrochloride dosage should not exceed 400 mg/m².200,273 The total dosage of doxorubicin hydrochloride should include any previous or concomitant therapy with other anthracycline agents or related compounds.200,273

Conventional Doxorubicin Hydrochloride

The usual adult dosage of conventional (nonencapsulated) doxorubicin hydrochloride is 60-75 mg/m², administered as a single dose at 21-day intervals; the lower dose should be considered for patients with poor performance status, inadequate bone marrow reserves secondary to old age, prior therapy, or marrow infiltration with malignant cells.200 Alternatively, a dosage of 20 mg/m² once weekly may be used; this dosage schedule has been reported to produce a lower incidence of congestive heart failure. A dosage of 30 mg/m² daily on 3 successive days every 4 weeks has also been used; this dosage schedule is usually associated with a higher incidence of stomatitis. When used in combination with other chemotherapy, doxorubicin hydrochloride commonly has been used in a dosage of 40-60 mg/m² given as a single IV dose and repeated at 21- to 28-day intervals.200

When doxorubicin hydrochloride has been used in combination with bortezomib and dexamethasone† as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients†, doxorubicin hydrochloride 9 mg/m² per day has been administered IV on days 1-4 along with bortezomib 1.3 mg/m² by IV injection twice weekly for 2 weeks (days 1, 4, 8, and 11) and dexamethasone 40 mg orally on days 1-4, 9-12, and 17-20 of each 28-day cycle for 3 cycles.10023

Liposomal Doxorubicin Hydrochloride

For the treatment of AIDS-related Kaposi's sarcoma, the usual adult dosage of pegylated liposomal doxorubicin hydrochloride is 20 mg/m² once every 3 weeks, administered at an initial rate of 1 mg/minute.273 If no infusion-related adverse effects occur, the rate of infusion may be increased to complete administration of the infusion over a 1-hour period.273 The duration of therapy depends on response and tolerance of the patient.273,279

When used for the treatment of ovarian cancer that has progressed or recurred following platinum-based chemotherapy, the manufacturer recommends a pegylated liposomal doxorubicin hydrochloride dosage of 50 mg/m² IV once every 4 weeks, administered at an initial rate of 1 mg/minute.273 If no infusion-related adverse effects occur, the rate of infusion may be increased to complete administration of the infusion over a 1-hour period.273 In patients without disease progression or intolerable toxicity, the manufacturer recommends a minimum of 4 courses of therapy because the median time to response with liposomal doxorubicin therapy in clinical trials for metastatic ovarian cancer was approximately 4 months.273

When pegylated liposomal doxorubicin hydrochloride has been used in combination with bortezomib and dexamethasone† as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients†, pegylated liposomal doxorubicin hydrochloride 30 mg/m² has been administered IV on day 4 along with bortezomib 1.3 mg/m² by IV injection twice weekly for 2 weeks (days 1, 4, 8, and 11) and dexamethasone 40 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 during cycle 1.10024 During cycles 2-6, the same dosages of pegylated liposomal doxorubicin hydrochloride and bortezomib were administered along with dexamethasone 20 mg orally daily.10024 Treatment cycles were repeated every 3 weeks for a total of 6 cycles.10024

Although a modified regimen using reduced dosages of both pegylated liposomal doxorubicin hydrochloride and bortezomib given in combination with dexamethasone†10026 also has been used as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients†, use of this regimen is not fully established.10034

The management of certain adverse effects (e.g., hand-foot syndrome, hematologic toxicity, stomatitis) in patients receiving liposomal doxorubicin hydrochloride may require reduction in dosage and/or delay of doses.273 The manufacturer recommends the following dosage modifications for liposomal doxorubicin hydrochloride based on drug-induced adverse effects (see Dosage Modification tables).273 Once the dose of liposomal doxorubicin hydrochloride has been reduced because of drug-related toxicity, such as hand-foot syndrome or stomatitis, the dose should not be increased.273 For the management of nausea and vomiting associated with liposomal doxorubicin therapy, pretreatment with or concomitant use of antiemetic therapy should be considered.273

Dosage in Hepatic Impairment

In adults with impairment of hepatic function, conventional or liposomal doxorubicin dosage must be reduced.200,273 Patients with serum bilirubin concentrations of 1.2-3 mg/dL should receive 50% of the usual dose of doxorubicin hydrochloride and those with serum bilirubin concentrations exceeding 3 mg/dL should receive 25% of the usual dose.200,273

Hematologic Effects

Because of the risk of myelosuppression, hematologic status must be monitored carefully in patients receiving conventional or liposomal doxorubicin.200,273

Conventional Doxorubicin

Leukopenia (principally granulocytopenia) is the predominant manifestation of hematologic toxicity, the severity of which depends on the dose of the drug and on the regenerative capacity of the bone marrow.200 Leukocyte counts as low as 1000/mm³ should be anticipated during therapy with appropriate doses of doxorubicin, although severe myelosuppression can occur.200 Thrombocytopenia and anemia may also occur. Deaths from septicemia have been associated with severe leukopenia. Maximum leukopenia, thrombocytopenia, and anemia generally occur during the second week (nadir at 10-14 days) following administration of the drug and generally return to normal by the third week.

Liposomal Doxorubicin

The principal dose-limiting toxicity of pegylated liposomal doxorubicin in patients with AIDS-related Kaposi's sarcoma has been myelosuppression, commonly manifested by leukopenia and neutropenia; anemia and thrombocytopenia also occur frequently.273,355 Among 720 patients with AIDS-related Kaposi's sarcoma receiving liposomal doxorubicin in clinical trials, neutropenia less than 2000/mm³ was reported in 85% of patients,355 neutropenia less than 1000/mm³ was reported in about 49% of patients, and severe or life-threatening neutropenia (less than 500/mm³) occurred in 13% of patients.273 Leukopenia less than 4000/mm³ was reported in about 91% of patients, and leukopenia less than 1000/mm³ occurred in 11.5% of patients.355 Anemia was reported in 55.4% of patients and was severe or life-threatening in 18.2% of patients.273 Hypochromic anemia was reported in about 10% of patients.273 Thrombocytopenia was reported in 61% of patients and was life-threatening in 4% of patients.273

Patients receiving pegylated liposomal doxorubicin for AIDS-related Kaposi's sarcoma often have baseline myelosuppression secondary to their underlying human immunodeficiency virus (HIV) infection and/or numerous concomitant drug therapy.273 With the recommended dosage schedule, leukopenia associated with liposomal doxorubicin usually is transient, but hematologic toxicity occasionally may be severe enough to require dose reduction or delay or suspension of therapy with the drug.273 Persistent, severe myelosuppression may result in superinfection or hemorrhage.273 In patients with AIDS-related Kaposi's sarcoma receiving liposomal doxorubicin, sepsis273 occurred in 5% of patients and was considered possibly or probably related to the drug in 0.7% of patients.273 Discontinuance of liposomal doxorubicin because of myelosuppression or neutropenia was required in 1.6% of patients with AIDS-related Kaposi's sarcoma.273 The development of neutropenic sepsis rarely has resulted in death.273

Adverse hematologic effects reported in 1-5% of patients receiving pegylated liposomal doxorubicin for AIDS-related Kaposi's sarcoma include hemolysis and increased prothrombin time.273

In patients with relapsed ovarian cancer, myelosuppression associated with pegylated liposomal doxorubicin generally has been moderate and reversible.273 Anemia was the most common adverse hematologic effect in patients with relapsed ovarian cancer, occurring in about 53% of patients receiving liposomal doxorubicin in 3 single-arm clinical trials.273 Neutropenia with an absolute neutrophil count less than 2000/mm³ was reported in 52%,355 and neutropenia with an absolute neutrophil count less than 1000/mm³ was reported in 19%,273 of patients with relapsed ovarian cancer receiving liposomal doxorubicin. Leukopenia (white blood cell count less than 4000/mm³) was reported in 42%, and thrombocytopenia was reported in 24%, of patients with relapsed ovarian cancer receiving liposomal doxorubicin.273 In the randomized trial, anemia occurred in 40%, leukopenia in 37%, neutropenia (absolute neutrophil count less than 1000/mm³) in 35%, and thrombocytopenia in 13%, of patients receiving liposomal doxorubicin for ovarian cancer.273 Granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor was used in 4.6% of patients receiving liposomal doxorubicin for relapsed ovarian cancer to reduce the severity of myelosuppression associated with therapy.273

Cardiac Effects

Types of Cardiotoxicity

Three types of cardiotoxicity may occur in patients receiving an anthracycline (e.g., doxorubicin): an acute transient type; a chronic, subacute type, which is related to cumulative dose and has a later, more indolent onset; and a late-onset type that manifests years after anthracycline therapy and occurs mainly in patients exposed to the drugs as children.244,245,327,350 The use of conventional or liposomal doxorubicin may cause cardiac toxicity.200,273

Acute anthracycline-induced cardiotoxicity usually is uncommon.244,327 It occurs immediately after a single dose or a single course of anthracycline therapy and may involve abnormal ECG findings including ST-T wave changes (e.g., T-wave flattening and ST-segment depression), prolongation of the QT interval, and arrhythmias (e.g., sinus tachycardia; ventricular, supraventricular, and junctional tachycardia).244,327 Conduction disturbances (including atrioventricular [AV] and bundle-branch block) have been reported rarely in acute anthracycline-induced cardiotoxicity (they are more usually associated with late-onset anthracycline-induced cardiotoxicity).244,327 Although acute cardiotoxicity generally is transient, rarely, pericarditis-myocarditis syndrome (e.g., pericardial effusion and/or decreased myocardial contractility) and possible cardiac failure may occur.244,245,324,327

Chronic cardiotoxicity, such as congestive heart failure or cardiomyopathy, usually occurs within 1 year after discontinuance of anthracycline therapy, is more common than acute cardiotoxicity, and is considered clinically the most important anthracycline-associated toxicity.244,350 Chronic cardiotoxicity, such as heart failure, may occur as total cumulative dosage of doxorubicin hydrochloride approaches or exceeds 550 mg/m².200,273,350 Heart failure may occur at a lower total cumulative dosage (i.e., 400 mg/m²) in patients who have received radiotherapy to the mediastinal region or in patients receiving concomitant therapy with other potentially cardiotoxic agents, such as cyclophosphamide.273 Time of onset of chronic cardiotoxicity may vary but usually is manifested within 1 year of anthracycline therapy.244 In one study, onset of congestive heart failure developed 0-231 days after discontinuance of anthracycline therapy.236,244

Chronic cardiotoxicity reflects a progressive injury and loss of cardiac myocytes, with increasing cumulative anthracycline doses resulting in thinning of ventricular walls and decreased systolic performance.327 Initially, there is functional compensation by the remaining myocytes allowing overall cardiac function to appear normal despite histologic damage, which can be demonstrated by endomyocardial biopsy.327 However, as cumulative doses of anthracycline increase, there is a decrease in systolic performance, as measured by a decrease in fractional shortening (FS) and in left-ventricular ejection fraction (LVEF) with eventual progression to symptomatic congestive heart failure, if cardiac reserve is exhausted, and to cardiorespiratory decompensation.327 Symptoms of the described rapidly progressing syndrome may include tachycardia, tachypnea, dilation of the heart, exercise intolerance, pulmonary and venous congestion, poor perfusion, and pleural effusion; these manifestations may respond to cardiac supportive therapy and may be self-limiting, or, alternatively, may be irreversible and unresponsive to therapy and fatal.200,205,225,244,327

Sensitivity to anthracycline-induced cardiotoxicity exhibits interindividual variation,244 with some patients occasionally tolerating cumulative doxorubicin hydrochloride doses exceeding 1 g/m² while other patients exhibit histopathologic changes characteristic of doxorubicin-induced cardiotoxicity, decreases in LVEF, and even congestive heart failure at cumulative doses of less than 300 mg/m².244,246,247,327 Despite such interindividual variation, the risk of developing doxorubicin-induced impairment in myocardial function (based on a combined index of signs, symptoms, and decline in LVEF) increases with increasing cumulative dose, occurring in 1-2% of patients receiving cumulative doses of 300 mg/m² and increasing to 3-5, 5-8, and 6-20% in those receiving cumulative doses of 400, 450, or 500 mg/m² in schedules of rapid IV doses given once every 3 weeks.200 In one retrospective review, congestive heart failure developed in 3, 7, or 21% of patients at cumulative doses of 430, 575, or 728 mg/m², and the slope of the probability curve for developing congestive heart failure increased at around 550 mg/m².200,236 However, in a prospective study in which doxorubicin was administered concomitantly with cyclophosphamide, fluorouracil, and/or vincristine in patients with breast cancer or small cell lung cancer, the risk of congestive heart failure was 1.5, 4.9, 7.7, or 20.5% at cumulative doses of 300, 400, 450, or 500 mg/m².200

Adverse cardiac effects occurred in 9.6% of patients with AIDS-related Kaposi's sarcoma receiving pegylated liposomal doxorubicin in clinical trials and were considered possibly or probably related to the drug in 4.3% of patients.355 Cardiomyopathy and congestive heart failure have been reported in patients receiving liposomal doxorubicin for AIDS-related Kaposi's sarcoma.273 Severe adverse cardiac effects, including arrhythmia, cardiomyopathy, heart failure, pericardial effusion, and tachycardia, were reported in 1% of patients receiving liposomal doxorubicin for AIDS-related Kaposi's sarcoma.355 The manufacturer reports that therapy with liposomal doxorubicin was discontinued because of adverse cardiac events in 3 patients with AIDS-related Kaposi's sarcoma receiving the drug in clinical trials.355

In 250 patients with advanced breast cancer receiving pegylated liposomal doxorubicin hydrochloride at a starting dose of 50 mg/m² every 4 weeks, the incidence of cardiac toxicity was 11% at cumulative doses of 450-500 mg/m² and 500-550 mg/m².273

Factors reported to increase the risk of anthracycline-induced cardiotoxicity (some of which may cause such toxicity at lower cumulative doxorubicin doses) include irradiation to the mediastinal region, concomitant cyclophosphamide, preexisting heart disease (e.g., occult hypertension, subclinical coronary artery disease), extremes in age, liver disease, whole body hyperthermia, and female gender (mainly in children).200,225,236,243,244,246,249,350 In one study in women with early breast cancer receiving cyclophosphamide-based adjuvant chemotherapy following either surgery alone or surgery and mediastinal irradiation, cardiac abnormalities (e.g., ECG changes) developed in about 5% of all (both those who did and did not receive irradiation) patients and about 70% of these cases of cardiac abnormalities occurred in patients receiving irradiation of the left breast; all cases of congestive heart failure (which was fatal in several patients) reported in irradiated patients occurred at cumulative doxorubicin hydrochloride doses that did not exceed 315 mg/m².225 This and other evidence suggest that irradiation of the left breast may be a more important cardiotoxic cofactor than concomitant alkylating chemotherapy.225,243 Anthracycline therapy may potentiate cardiotoxicity caused by high-dose cyclophosphamide therapy used for bone marrow ablation and transplantation.327 It is unclear if lower doses of cyclophosphamide interact with anthracyclines in the development of cardiotoxicity.327 Some evidence also suggests that the risk of cardiotoxicity may be increased in patients receiving calcium-channel blocking agents concomitantly.200 The cardiotoxic risk associated with cumulative doses of doxorubicin also should take into account previous or concomitant therapy with related drugs such as daunorubicin, idarubicin, and mitoxantrone.200

Late-onset anthracycline-induced cardiotoxicity, which may include late-onset ventricular dysfunction, heart failure, conduction disturbances, and arrhythmias (e.g., nonsustained ventricular tachycardia) which may be life-threatening, occurs several years or even decades after discontinuance of anthracycline therapy and it may develop after a prolonged asymptomatic interval.204,205,211,224,244,245,246,247,350 In one study in patients with solid tumors or leukemia, those who were followed for 4 to less than 10 or 10-20 years after discontinuance of anthracycline therapy had an 18 or 38% incidence, respectively, of abnormal FS in echocardiograms.244,246 In another study in children with acute lymphoblastic leukemia who were followed for up to 15 years after discontinuance of anthracycline therapy, increases in myocardial afterload and/or decreases in myocardial contractility were reported in 65% of patients receiving cumulative doses of at least 228 mg/m²;244,252 these cardiac abnormalities appeared to be progressive and were predictive of future cardiac decompensation.244,252 It has been suggested that myocyte damage and ventricular dysfunction progress after the initial myocardial insult and may lead to late-onset cardiac decompensation.244,246,327 Some clinicians state that late-onset cardiotoxicity can be clinically manifest in response to stressful situations (e.g., surgery, pregnancy), exercise (e.g., weight lifting), and acute viral infection.244,246,327 In at least one patient, postpartum-associated congestive heart failure occurred 7 years after discontinuance of doxorubicin therapy.211 Some clinicians suggested that the postpartum effects of anemia, hypertension, and fluid mobilization on subclinical doxorubicin fibrosis resulted in reversible cardiac decompensation.211 The incidence of late-onset cardiotoxicity may be increased with increasing cumulative doses of anthracyclines, high rates of administration, or irradiation to the mediastinal region; young age at the time of anthracycline therapy and female gender may be contributing factors to such cardiotoxicity, but further study is needed.244,246,249

Late-onset anthracycline toxicity can be expected to be observed more frequently with the growing census of long-term survivors (e.g., survivors of childhood cancers) who have received anthracyclines.244,324,327 It also is expected that this cardiotoxicity will be associated with increased morbidity and mortality. Substantial cardiac injury may occur even with low-dose anthracycline therapy.244 Since the observed incidence of severe anthracycline-induced cardiotoxicity appears to increase (especially after irradiation to the mediastinal region) with duration of long-term monitoring, the full extent of late-onset anthracycline toxicity in asymptomatic patients remains to be elucidated since data currently are inadequate regarding cardiotoxicity occurring 15 years or more after discontinuance of anthracycline therapy.244 Long-term follow-up shows that overt cardiac failure occurs in about 4.5-7% of patients receiving anthracycline therapy.244,246,247,252

Assessment of Cardiotoxicity

Clinical manifestations found on physical examination (e.g., shortness of breath, pulmonary rales) and/or changes detected on electrocardiographic monitoring (e.g., sinus tachycardia) are not specific enough to diagnose anthracycline-induced cardiotoxicity.244,350 More sensitive methods are needed to detect early signs of cardiac damage so that the potential benefits from larger than usual dosages of anthracyclines in cancer therapy may be weighed against the possible risks of drug-induced cardiotoxicity.244 Monitoring of the left-ventricular ejection fraction with serial echocardiographic studies is a sensitive, noninvasive method for the detection and follow-up of anthracycline-induced cardiomyopathy.350 Radionuclide angiography also has been used to monitor the ejection fraction, but this procedure exposes the patient to ionizing radiation.350 The combination of exercise stress testing and ejection-fraction studies is a more sensitive indicator for detecting early signs of subclinical cardiomyopathy associated with anthracycline therapy.350 Endomyocardial biopsy (using a semiquantitative histologic scoring system) currently is considered the most sensitive and specific method for diagnosing and determining the degree of anthracycline-induced cardiotoxicity;244,257,258,259,260,269,273 however, this invasive procedure is not routinely used.350 Concerns for safety, especially in children requiring multiple biopsies, and in those with thrombocytopenia, and the lack of experience in obtaining and scoring biopsies have limited the use of endomyocardial biopsy; the correlation between biopsy scores and the long-term effects of anthracycline cardiotoxicity has not been established, and underestimation of cardiac damage may occur.244,251,258,259,269,350 Guidelines for cardiac monitoring of children receiving anthracycline therapy have been published, although their general acceptance remains to be established.244,270,271,272,325 Guidelines also have been published for adults using multigated radionuclide angiography (MUGA scans).326,327

Anthracycline-induced cardiomyopathy usually is associated with characteristic histopathologic changes on endomyocardial (EM) biopsy (e.g., fibrosis, myofibrillar dropout, intracellular vacuolar degeneration) and with decreased LVEF, as determined by multi-gated radionuclide angiography (MUGA scans) and/or echocardiogram (ECHO), relative to baseline values.200,235,241 In adults, a 10% decline in LVEF to below the lower limit of normal, a 20% decline in LVEF at any level, or an absolute LVEF of 45% is indicative of a deterioration in cardiac function.200 Although monitoring the ejection fraction has not been shown to be predictive of impending maximal tolerance of the cumulative doxorubicin dose, the benefits of continued therapy with the drug should be weighed carefully against the risk of irreversible cardiotoxicity whenever test results indicate a deterioration in cardiac function.200

Mechanism of Cardiotoxicity

Several anthracycline-induced effects may contribute to the development of cardiotoxicity.233,234,237,238,239,240 In animals, anthracyclines cause a selective inhibition of cardiac muscle gene expression for α-actin, troponin, myosin light-chain 2, and the M isoform of creatine kinase, which may result in myofibrillar loss associated with anthracycline-induced cardiotoxicity.244,251,261,269 Other potential causes of anthracycline-induced cardiotoxicity include myocyte damage from calcium overload, altered myocardial adrenergic function, release of vasoactive amines, and proinflammatory cytokines.244,264,265,266 Limited data indicate that calcium-channel blocking agents (e.g., prenylamine) or β-adrenergic blocking agents may prevent calcium overload; however, the cardioprotective effects of β-adrenergic blocking agents have not been studied.244 It has been suggested that the principal cause of anthracycline-induced cardiotoxicity is associated with free radical damage to DNA.244,350

Anthracyclines intercalate DNA, chelate metal ions to produce drug-metal complexes, and generate oxygen free radicals via oxidation-reduction reactions.233,234,237,238,239,240 Anthracyclines contain a quinone structure that may undergo reduction via NADPH-dependent reactions to produce a semiquinone free radical that initiates a cascade of oxygen-free radical generation.234,237 It appears that the metabolite, doxorubicinol, may be the moiety responsible for cardiotoxic effects, and the heart may be particularly susceptible to free-radical injury because of relatively low antioxidant concentrations.234 Initial attempts at preventing anthracycline-induced cardiotoxicity by administering antioxidants (e.g., vitamin E) to act as free-radical scavengers were not successful.234,237,238 Limited animal data indicate that probucol (no longer commercially available in the US), an antilipemic agent structurally similar to vitamin E, may prevent anthracycline-induced cardiotoxicity without interfering with the antineoplastic effect of doxorubicin.244 Chelation of metal ions, particularly iron, by the drug results in a doxorubicin-metal complex that catalyzes the generation of reactive oxygen free radicals, and the complex is a powerful oxidant that can initiate lipid peroxidation in the absence of oxygen free radicals.234,239,240 This reaction is not blocked by free-radical scavengers, and probably is the principal mechanism of anthracycline-induced cardiotoxicity.234 As a result, administration of dexrazoxane (ICRF-187), a cyclic derivative of EDTA that is converted intracellularly to a ring-opened chelating agent, can prevent anthracycline-induced cardiotoxicity, at least in part, by chelating free iron and thus preventing the formation of the anthracycline-iron complex and resultant free radical generation.233,234

Management of Cardiotoxicity

Effective management of anthracycline-induced cardiotoxicity requires early diagnosis and intervention by identifying patients with existing risk factors for cardiotoxicity.244,269

Dexrazoxane has been shown to prevent or reduce the incidence and severity of anthracycline-induced cardiotoxicity,221,233,234,235,241,244 although some,233,234,242,244 but not all,233,234,235,241 evidence suggests that the drug also may interfere with the antineoplastic efficacy of certain chemotherapeutic regimens (e.g., when initiated concurrently with cyclophosphamide, doxorubicin, and fluorouracil therapy). This potentially detrimental effect was not observed when dexrazoxane therapy was withheld until several initial courses of chemotherapy could be administered, and results from most clinical studies have failed to demonstrate interference by dexrazoxane with the antineoplastic efficacy of chemotherapeutic regimens.233,234 Therefore, the manufacturer of dexrazoxane currently recommends that cardioprotectant therapy with the drug not be initiated at the time doxorubicin-containing chemotherapy is initiated but instead be delayed until patients have received a cumulative doxorubicin dose of 300 mg/m².233 Although patients receiving dexrazoxane generally can tolerate higher cumulative doses of doxorubicin before experiencing cardiotoxicity, the cardioprotectant will not eliminate the risk of cardiotoxicity in patients who have already received cumulative doxorubicin hydrochloride doses of 300 mg/m².233,244 Therefore, cardiac function should be monitored carefully even when dexrazoxane is used.233 Use of dexrazoxane is associated with severe myelosuppression, which is potentiated by doxorubicin, and the long-term effect of the drug on the prevention of doxorubicin-induced cardiotoxicity is not known.350

In one study in women receiving doxorubicin with cyclophosphamide and fluorouracil for advanced breast cancer, patients receiving concomitant cardioprotection with dexrazoxane tolerated higher cumulative doxorubicin hydrochloride doses (median: 500 mg/m²) than those who did not receive the cardioprotectant (median: 441 mg/m²), and one-third of cardioprotected patients were able to tolerate cumulative doxorubicin doses of at least 700 mg/m² (about 40% of whom received cumulative doses of 1 g/m² or more) whereas only 4% of unprotected patients could tolerate such doses.235 There also was some evidence that dexrazoxane may reduce the risk of doxorubicin-induced cardiotoxicity in patients with other contributing risk factors (e.g., mediastinal irradiation).235

Doxorubicin-induced cardiotoxicity also has reportedly been reduced by administration of low doses of doxorubicin at weekly intervals or by administration of the drug by prolonged, continuous IV infusion (e.g., over 48-96 hours) via a central venous catheter; the comparative efficacy of these dosage schedules in various cancers and the long-term effects on the development of anthracycline-induced cardiotoxicity have not been established.350

Management of doxorubicin-induced congestive heart failure should include cardiac glycosides, inotropic agents (e.g., dobutamine), diuretics, after-load reduction (e.g., with vasodilators), angiotensin-converting enzyme (ACE) inhibitors, restricted sodium intake, and bed rest.200,244,246,247,268β-Blocking agents (β₁-selective adrenergic blocking agents) also have been used in conjunction with other treatment for anthracycline-induced congestive heart failure.350 Early treatment of subclinical anthracycline-induced systolic dysfunction, possibly with an ACE inhibitor, may reduce mortality rates in these patients.244 Although such interventions may provide symptomatic relief and improvement in the functional status of the patient,200,244 myocardial toxicity can be poorly responsive and irreversible;200,225,244,264,268 prognosis for patients with anthracycline-induced cardiomyopathic failure is poor.350 (See Cautions: Precautions and Contraindications.) Heart transplantation may be a consideration for some patients with cardiac decompensation.236,242,292,293

Other Cardiovascular Effects

Adverse cardiovascular effects reported in 1-5% of patients receiving pegylated liposomal doxorubicin for AIDS-related Kaposi's sarcoma include chest pain, hypotension, and tachycardia.273

Adverse cardiovascular effects reported in 1-10% of patients receiving pegylated liposomal doxorubicin for ovarian cancer include vasodilation, tachycardia, deep thrombophlebitis, hypotension, pallor, and cardiac arrest.273

GI Effects

Conventional Doxorubicin

Stomatitis and esophagitis (mucositis) may occur in patients receiving doxorubicin, especially when the drug is administered daily on several successive days.200 Stomatitis usually begins as a burning sensation accompanied by erythema of the oral mucosa, which in 2-3 days may progress to ulceration, particularly in the sublingual and lateral tongue margins and on the palate. Ulceration is sometimes severe enough to result in difficulty in swallowing, but seldom requires cessation of therapy. Stomatitis is maximal during the second week of therapy and lasts an additional 3-7 days. GI toxicity (evidenced frequently by nausea and vomiting and occasionally by anorexia and diarrhea) may occur, usually on the day of drug administration.200 Nausea and vomiting can be severe but may be alleviated by antiemetic therapy.200

Ulceration and necrosis of the colon, particularly the cecum, leading to bleeding or severe and possibly fatal infection, have occurred in patients with acute myelogenous leukemia who received combined doxorubicin and cytarabine therapy.200

Liposomal Doxorubicin

Among patients receiving pegylated liposomal doxorubicin for AIDS-related Kaposi's sarcoma in randomized trials, nausea occurred in 17%, vomiting in 8%, diarrhea in 8%, and stomatitis in 7%, of patients.273 Oral moniliasis was reported in 5.5% of these patients.273 Adverse GI effects reported in 1-5% of patients receiving liposomal doxorubicin for AIDS-related Kaposi's sarcoma include mouth ulceration, glossitis, constipation, aphthous stomatitis, anorexia, dysphagia, and abdominal pain.273

Among patients receiving pegylated liposomal doxorubicin for ovarian cancer in the randomized trial, nausea occurred in 46%, stomatitis in 41%, and vomiting in 33%, of patients.273 Abdominal pain occurred in 33.5% of these patients.273 Constipation was reported in 30%, and diarrhea and anorexia each were reported in about 20% of these patients.273 Dyspepsia occurred in 12%, and intestinal obstruction in 11%, of patients receiving liposomal doxorubicin for ovarian cancer in the randomized trial.273 Adverse GI effects reported in 1-10% of patients receiving liposomal doxorubicin for ovarian cancer include oral moniliasis, mouth ulceration, dry mouth, gingivitis, esophagitis, dysphagia, flatulence, rectal bleeding, ileus, enlarged abdomen, and ascites.273

Dermatologic Effects

Conventional Doxorubicin

Complete alopecia almost always accompanies doxorubicin therapy, and patients should be advised of this effect.200 Regrowth of hair usually begins 2-3 months after doxorubicin is discontinued. The degree of doxorubicin-induced alopecia has been reduced by use of scalp hypothermia before and for 30 minutes after administration of the drug. Hyperpigmentation of nailbeds, pigmented banding of fingernails, and phalangeal and other dermal creases may occur in patients receiving doxorubicin.200 One clinician reported that pigment changes appeared 6 or more weeks following initiation of doxorubicin administration. Onycholysis, plantar callus formation, and epidermolysis also have been reported in patients receiving the drug.

Like dactinomycin, doxorubicin has reactivated latent effects of previous irradiation in some patients, producing erythema with vesiculation, nonpitting edema, severe pain, and moist desquamation in sites which were previously subjected to radiation therapy and which had subsequently returned to normal appearance. The reaction occurred from 4-7 days after each doxorubicin hydrochloride dose was administered and lasted an average of 7 days thereafter.

Liposomal Doxorubicin

Palmar-plantar erythrodysesthesia (PPE), or hand-foot syndrome, characterized by swelling, pain, erythema, and occasionally desquamation of the hands and feet, has been reported in patients receiving pegylated liposomal doxorubicin for ovarian cancer or AIDS-related Kaposi's sarcoma.273 In patients receiving liposomal doxorubicin for ovarian cancer in the randomized trial, hand-foot syndrome occurred in 51% of patients and was severe (grade 3 or 4) in 24% of patients; 4.2% of patients discontinued therapy with the drug because of hand-foot syndrome or other dermatologic toxicity.273 In patients receiving liposomal doxorubicin 20 mg/m² every 2 weeks for AIDS-related Kaposi's sarcoma, 3.4% developed palmar-plantar skin eruptions,273,330 and 0.9% of patients discontinued therapy with the drug because of such effects.273

Hand-foot syndrome generally developed after 2 or 3 cycles (i.e., 6 or more weeks) of therapy but occasionally occurred sooner.273 Although the reaction generally is mild and resolves within 1-2 weeks so that prolonged delay of therapy usually is not necessary, dose modification may be necessary (see Dosage Modification for Hand-Foot Syndrome table in Dosage section), and discontinuance of liposomal doxorubicin therapy may be required in some patients because of severe and debilitating effects.273

Among patients receiving pegylated liposomal doxorubicin for AIDS-related Kaposi's sarcoma in randomized trials, alopecia was reported in about 9% of patients.273 Adverse dermatologic effects reported in 1-5% of patients receiving liposomal doxorubicin for AIDS-related Kaposi's sarcoma include herpes simplex, rash, and itching.273

Among patients receiving pegylated liposomal doxorubicin for ovarian cancer in the randomized trial, rash occurred in 28.5%, and alopecia in 19%, of patients.273 Adverse dermatologic effects reported in 1-10% of patients receiving liposomal doxorubicin for ovarian cancer include pruritus, skin discoloration, vesiculobullous rash, maculopapular rash, exfoliative dermatitis, herpes zoster, sweating, dry skin, herpes simplex, fungal dermatitis, furunculosis, and acne.273

Infusion-related Effects

Acute infusion-related reactions in patients receiving pegylated liposomal doxorubicin were characterized by one or more of the following manifestations: flushing, shortness of breath, facial edema, headache, chills, chest pain, back pain, tightness of the chest and throat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension.273 Allergic or anaphylactoid-like reactions, sometimes life-threatening or fatal, also have been reported.273

Acute infusion-related reactions occurred in 7% of patients with ovarian cancer receiving pegylated liposomal doxorubicin in the randomized trial; 2 patients (0.8%) discontinued therapy because of infusion-related reactions.273 Discontinuance of therapy with liposomal doxorubicin because of infusion-related reactions was required in 1.7% of patients receiving drug for solid tumors and in 0.9% of patients receiving the drug for AIDS-related Kaposi's sarcoma.273

Infusion-related reactions typically occur during the first infusion and usually resolve over the course of several hours to a day once the infusion is stopped.273 Occasionally, the reactions may resolve simply by slowing the rate of infusion.273 The manufacturer recommends an initial infusion rate of 1 mg/minute to minimize the risk of infusion-related reactions in patients receiving liposomal doxorubicin.273 Medications and emergency equipment for the treatment of allergic or anaphylactoid-like reactions should be available for immediate use in patients receiving liposomal doxorubicin.273 Similar reactions have not been reported with conventional doxorubicin and therefore have been attributed to the liposomes or one of their surface components.273

Local Effects

Conventional Doxorubicin

Extravasation of conventional doxorubicin produces severe local tissue necrosis, as well as possible cellulitis, vesication, thrombophlebitis, lymphangitis, or painful induration and may result in limitation of mobility of the adjacent joints. Erythematous streaking along the vein proximal to the site of injection has been reported.200 Phlebosclerosis may also occur, especially when conventional doxorubicin is administered into small vein or repeatedly into a single vein.200

Liposomal Doxorubicin

Although animal evidence suggests that lesions associated with extravasation of pegylated liposomal doxorubicin may be minor and reversible relative to more severe and irreversible lesions associated with conventional doxorubicin, liposomal doxorubicin also should be considered an irritant, and the usual precautions to avoid extravasation of the drug should be followed.273 For information on the management of extravasation of conventional or liposomal doxorubicin, see Dosage and Administration: Reconstitution and Administration.

Sensitivity Reactions

Conventional Doxorubicin

Fever, chills, and urticaria have been reported occasionally in patients receiving conventional doxorubicin.200 Anaphylaxis may occur, and a case of apparent cross-sensitivity to lincomycin has been reported.200

Liposomal Doxorubicin

Allergic or anaphylactoid-like reactions, sometimes life-threatening or fatal, have been reported in patients receiving liposomal doxorubicin.273 Among patients receiving pegylated liposomal doxorubicin for AIDS-related Kaposi's sarcoma, allergic reactions were reported in 1-5% of patients.273

Respiratory Effects

Pulmonary embolism, sometimes fatal, has occurred rarely in patients receiving pegylated liposomal doxorubicin.273

Dyspnea and pneumonia were each reported in 1-5% of patients receiving pegylated liposomal doxorubicin for AIDS-related Kaposi's sarcoma.273

Pharyngitis occurred in 16%, dyspnea in 15%, and increased cough in about 10%, of patients receiving pegylated liposomal doxorubicin for ovarian cancer in the randomized trial.273 Adverse respiratory effects reported in 1-10% of patients receiving liposomal doxorubicin for ovarian cancer include rhinitis, pneumonia, pleural effusion, sinusitis, apnea, and epistaxis.273

Nervous System Effects

Conventional Doxorubicin

Peripheral neurotoxicity, manifested as local-regional sensory and/or motor disturbances, has been reported in patients receiving conventional doxorubicin by intra-arterial administration; in most cases, patients also were receiving cisplatin.200 Seizures and coma have been reported in patients receiving doxorubicin in combination with cisplatin or vincristine.200 Seizures also have been reported in a patient receiving doxorubicin at 2-3 times the recommended dosage in combination with high-dose cyclophosphamide.208

Liposomal Doxorubicin

Adverse neurologic effects reported in 1-5% of patients receiving pegylated liposomal doxorubicin for AIDS-related Kaposi's sarcoma include headache, dizziness, and somnolence.273

Among patients receiving pegylated liposomal doxorubicin for ovarian cancer in the randomized trial, paresthesia and headache each occurred in about 10%, and dizziness occurred in 4%, of patients.273 Adverse neurologic effects reported in 1-10% of patients receiving liposomal doxorubicin for ovarian cancer include somnolence, dizziness, depression, insomnia, anxiety, confusion, neuropathy, hypertonia, agitation, neuralgia, peripheral neuritis, and vertigo.273

Metabolic and Electrolyte Effects

Conventional Doxorubicin

As a result of extensive purine catabolism accompanying rapid cellular destruction, hyperuricemia may occur in patients receiving conventional doxorubicin, and serum uric acid concentrations should be monitored. Hyperuricemia and its potential adverse effects may be minimized or prevented by adequate hydration, alkalinization of the urine, and/or administration of allopurinol.

Liposomal Doxorubicin

Adverse metabolic and electrolyte effects reported in 1-5% of patients receiving pegylated liposomal doxorubicin for AIDS-related Kaposi's sarcoma include weight loss, hypocalcemia, and hyperglycemia.273

Adverse metabolic and electrolyte effects reported in 1-10% of patients receiving pegylated liposomal doxorubicin for ovarian cancer include dehydration, weight loss, hypokalemia, hypercalcemia, edema, cachexia, hyperglycemia, and hyponatremia.273

Genitourinary Effects

Albuminuria was reported in 1-5% of patients receiving pegylated liposomal doxorubicin for AIDS-related Kaposi's sarcoma.273

Adverse genitourinary effects reported in 1-10% of patients receiving pegylated liposomal doxorubicin for ovarian cancer include urinary tract infection, dysuria, leukorrhea, urinary frequency, cystitis, hematuria, urinary incontinence, urinary urgency, vaginal moniliasis, vaginal bleeding, and pelvic pain.273

Musculoskeletal Effects

Adverse musculoskeletal effects reported in 1-10% of patients receiving pegylated liposomal doxorubicin for ovarian cancer include myalgia, arthralgia, and pathological fracture.273 Muscle spasms have been reported rarely in patients receiving liposomal doxorubicin.273

Ocular Effects

Conventional Doxorubicin

Conjunctivitis and lacrimation occur rarely in patients receiving doxorubicin.200

Liposomal Doxorubicin

Retinitis was reported in 1-5% of patients receiving pegylated liposomal doxorubicin for AIDS-related Kaposi's sarcoma.273

Adverse ocular effects reported in 1-10% of patients receiving pegylated liposomal doxorubicin for ovarian cancer include conjunctivitis and dry eyes.273

Hepatic Effects

Among patients receiving pegylated liposomal doxorubicin for AIDS-related Kaposi's sarcoma in randomized trials, increased serum concentrations of alkaline phosphatase occurred in 8% of patients.273 Other adverse hepatic effects reported in 1-5% of patients receiving liposomal doxorubicin for AIDS-related Kaposi's sarcoma include increased serum concentrations of ALT (SGPT) and hyperbilirubinemia.273

Among patients receiving pegylated liposomal doxorubicin for ovarian cancer, hyperbilirubinemia was reported in 1-10% of patients.273

Other Adverse Effects

Conventional Doxorubicin

Other reported adverse effects of doxorubicin include facial flushes (especially when doxorubicin is injected rapidly) and rarely conjunctivitis and lacrimation.200

Acute “recall” pneumonitis, occurring at variable times after local radiation therapy, has been reported in children receiving concomitant doxorubicin and dactinomycin.200 Prepubertal growth failure and gonadal impairment, usually reversible, have occurred in children receiving doxorubicin-containing regimens.200

Liposomal Doxorubicin

Among patients receiving pegylated liposomal doxorubicin for AIDS-related Kaposi's sarcoma in randomized trials, asthenia occurred in 10%, and fever occurred in 9%, of patients.273 Other adverse effects reported in 1-5% of patients receiving liposomal doxorubicin for AIDS-related Kaposi's sarcoma include back pain, infection, chills, and emotional lability.273

Among patients receiving pegylated liposomal doxorubicin for ovarian cancer in the randomized trial, asthenia occurred in 40%, fever in 21%, pain in 21%, mucous membrane disorder in 14%, back pain in 12%, infection in 12%, and peripheral edema in 11%, of patients.273 Other adverse effects reported in 1-10% of patients receiving liposomal doxorubicin for ovarian cancer include ecchymosis, taste perversion, and ear pain.273

Precautions and Contraindications

The usual precautions and contraindications of doxorubicin apply to both the conventional and liposomal formulations.

Doxorubicin hydrochloride is a toxic drug with a low therapeutic index. A therapeutic response is not likely to occur without some evidence of toxicity. The major toxic effects of the drug are on the normal, rapidly proliferating tissues, particularly those of the bone marrow, GI and oral mucosa, and hair follicles. Patients receiving doxorubicin should be under constant supervision by clinicians experienced in cancer chemotherapy and should be hospitalized during the initial phase of treatment. If feasible, subsequent therapy and patient evaluation may be performed on an outpatient basis. Determinations of hepatic, hematopoietic, and cardiac function should be performed prior to and at regular intervals during doxorubicin therapy. Possible synergism of therapeutic response and toxicity with other antineoplastic agents used in concomitant chemotherapy should be considered.

Medications and emergency equipment for the treatment of allergic or anaphylactoid-like reactions should be available for immediate use in patients receiving liposomal doxorubicin.273

Myelosuppression

Leukocyte, erythrocyte, and platelet counts should be performed prior to and at frequent intervals during doxorubicin therapy. Hematopoietic toxicity may require dosage reduction or suspension of the drug until blood cell counts return to normal or may be severe enough to require discontinuance of therapy. If a profound drop in blood cell count occurs, the patient should be closely observed and anti-infective therapy initiated if there are signs of infection; suspension of doxorubicin therapy may be necessary during this period. Platelet and leukocyte transfusions have proved beneficial in patients with severe bone marrow depression; use of hematopoietic agents (colony-stimulating factors) also can be considered. Doxorubicin is contraindicated in patients with preexisting myelosuppression.

Cardiotoxicity

Early recognition of drug-induced cardiac failure appears essential for successful treatment with cardiac glycosides, diuretics, sodium intake restriction, and rest. Cardiac evaluation employing ECGs and determination of left-ventricular ejection fraction with echocardiogram (ECHO) should be performed prior to initiation of doxorubicin therapy and subsequently prior to each dose or course of therapy after a total cumulative dosage of 400 mg/m² has been given.200 Such evaluation is particularly important in patients with preexisting risk factors for cardiotoxicity (e.g., those with heart disease or who received mediastinal irradiation or cyclophosphamide).200 Although T-wave flattening, ST depression, and arrhythmias may occur and last up to 2 weeks after a dose or course of doxorubicin, these effects currently are not considered indications for suspension of doxorubicin therapy.

Doxorubicin-induced cardiomyopathy has been reported to be associated with persistent reduction in QRS voltage, prolongation of the systolic time interval, and reduction of the ejection fraction (as determined by echocardiography or radionuclide angiography), but none of these tests has been shown to consistently identify those patients who are approaching their maximally tolerated cumulative dose of doxorubicin. If these or other test results indicate changes in cardiac function associated with doxorubicin, the benefit of continued therapy must be carefully weighed against the risk of irreversible cardiac damage. Fatal cardiotoxicity can occur without antecedent ECG alterations.244,327

Administration of low doses of doxorubicin at weekly intervals or administration of the drug by continuous IV infusion (e.g., over 48-96 hours) reportedly has reduced anthracycline-associated cardiotoxicity.244,350 Consideration also can be given to cardioprotectant therapy with dexrazoxane, which can reduce substantially but not eliminate fully, the risk of doxorubicin-induced cardiotoxicity.221,233,234,235,241,242 Because anthracycline-induced cardiotoxicity may develop long after discontinuance of therapy with the drug, periodic monitoring of cardiac function with evaluation of ejection fraction should be continued throughout the patient's lifetime.350

Patients with a history of cardiovascular disease should receive doxorubicin only when the potential benefit outweighs the risk.273 Doxorubicin is contraindicated in patients with impaired cardiac function and in patients who have been treated previously with complete cumulative doses of doxorubicin, daunorubicin, and/or epirubicin. In patients who have received anthracyclines previously, addition of further anthracycline therapy can be contemplated only after careful assessment of the cardiac status of the patient with noninvasive and/or invasive procedures.327 However, it also should be considered that functional impairment can be masked by compensatory hypertrophy and patients with previous abnormal test results should still be considered at risk.327 The potential benefit of additional anthracycline therapy must be weighed carefully against the possible risks of cardiotoxicity associated with such therapy.244,327

Hepatic Impairment

Prolonged and elevated plasma concentrations of doxorubicin and its metabolites in patients with impaired hepatic function have resulted in increased toxicity. Prior to each dose of doxorubicin, it is recommended that liver function tests be performed, including serum AST (SGOT), ALT (SGPT), alkaline phosphatase, and bilirubin concentrations.200 Dosage of doxorubicin hydrochloride should be reduced in patients with impaired hepatic function.

Advice to Patients

Conventional doxorubicin often imparts a red color to the urine for 1-2 days after administration, and patients should be advised to expect this effect during therapy.200

Patients receiving pegylated liposomal doxorubicin should be informed to notify the clinician if they experience signs or symptoms of any of the expected adverse effects of the drug, including hand-foot syndrome (tingling or burning, redness, flaking, bothersome swelling, small blisters, or small sores on the palms of the hands or soles of the feet), stomatitis (painful redness, swelling, or sores in the mouth), fever of 100.5°F or higher, nausea, vomiting, tiredness, weakness, rash, or mild hair loss.273 Patients should be informed that urine or other body fluids may appear reddish-orange in color during therapy with liposomal doxorubicin; this is a nontoxic reaction and the color will dissipate as the drug is eliminated from the body.273

Other Precautions and Contraindications

Clearance of doxorubicin is reduced in obese women (actual body weight exceeding 130% of ideal body weight).200

In addition to the usual precautions and contraindications associated with doxorubicin therapy, use of liposomal doxorubicin hydrochloride is contraindicated in patients who are hypersensitive to conventional doxorubicin preparations or to any component in the liposomal formulation.273

Pediatric Precautions

Cardiotoxicity

Doxorubicin-induced cardiomyopathy impairs myocardial growth as children mature.200 Therefore, pediatric patients appear to be at particular risk for developing delayed cardiac toxicity with the drug, with possible subsequent development of congestive heart failure during early adulthood.200

Results of studies to date are inconclusive concerning the relative risk of children for developing acute or chronic anthracycline-induced cardiotoxicity.327 Children are at increased risk for developing late-onset anthracycline toxicity since such cardiotoxicity is expected to increase with the growing census of long-term survivors (e.g., survivors of childhood cancers).244,327 Children who have received doxorubicin therapy develop subclinical cardiac dysfunction including abnormal fractional shortening (FS) in 23% of patients246 and abnormal afterload and/or contractility in 65% of patients.252 Overt congestive heart failure has been reported in about 5% of patients during long-term follow-up with a median length of follow-up of 9 years;246 5-10% develop overt congestive heart failure during long-term follow-up.200 This late cardiotoxicity may be dose related, and the rate of detection increases with increased duration of follow-up.200 Therefore, periodic long-term follow-up is recommended for children treated with doxorubicin.200 In children, deterioration in cardiac function during or after therapy with the drug is indicated by a decrease in fractional shortening (FS) that declines by an absolute value of 10 or more percentile units or to less than 29%, and by a decrease in left-ventricular ejection fraction (LVEF) of 10 percentile units or an LVEF less than 55%.200 Although monitoring the ejection fraction has not been shown to be predictive of impending maximal tolerance of the cumulative doxorubicin dose, the benefits of continued therapy with the drug should be weighed carefully against the risk of irreversible cardiotoxicity whenever test results indicate a deterioration in cardiac function.200

Other Precautions

Doxorubicin, when administered as a component of intensive chemotherapy regimens in children, may contribute to prepubertal growth failure.200 Gonadal impairment, which usually is reversible, also may occur.200

The use of doxorubicin or other topoisomerase II inhibitors in children is associated with increased risk of acute myelogenous leukemia and other secondary malignancies.200

Caregivers of children receiving doxorubicin should be advised to take precautions (e.g., wearing latex gloves) to prevent contact with the patient's urine and other body fluids for at least 5 days after administration of doxorubicin.200,208

The manufacturer states that safety and efficacy of pegylated liposomal doxorubicin hydrochloride in children have not been established.273

Geriatric Precautions

Safety and efficacy of liposomal doxorubicin in geriatric patients have not been specifically studied to date.273 In single-arm studies of pegylated liposomal doxorubicin for ovarian cancer, 29% of patients were 60-69 years of age, and 23% were 70 years of age or older.273 In the randomized trial of pegylated liposomal doxorubicin for ovarian cancer, 35% of patients were 65 years of age or older.273 No overall differences in efficacy or safety were observed between geriatric and younger patients.273

Mutagenicity and Carcinogenicity

Doxorubicin has been shown to be mutagenic and carcinogenic in experimental models. Secondary acute myeloid (myelogenous) leukemia, sometimes fatal, has been reported in adults and children receiving topoisomerase II inhibitors, including rare cases in patients receiving liposomal doxorubicin.200,273 The extent of increased risk of developing secondary malignancies associated with the use of doxorubicin has not been fully established.200 There was no evidence of mutagenic potential when Stealth^® liposomes (see Chemistry and Stability: Chemistry) that were devoid of doxorubicin hydrochloride were tested in vitro in the Ames, mouse lymphoma, and chromosomal aberration assays or in vivo in the mammalian micronucleus assay.273

Pregnancy, Fertility, and Lactation

Pregnancy

Doxorubicin can cause fetal toxicity when administered to pregnant women, but potential benefits from use of the drug may be acceptable in certain conditions despite the possible risks to the fetus.200,273,356,357 The drug is embryotoxic and teratogenic in rats and embryotoxic and abortifacient in rabbits,200,273 and trace amounts of drug have been found in mouse fetuses and in one aborted human fetus following administration of conventional (nonencapsulated) doxorubicin.327 Liposomal doxorubicin is embryotoxic at doses of 1 mg/kg daily (about one-eighth the 50 mg/m² human dose on a mg/m² basis) in rats and is embryotoxic and abortifacient at doses of 0.5 mg/kg daily (about one-eighth the 50 mg/m² human dose on a mg/m² basis) in rabbits.273 Embryotoxicity consisted of increased embryo-fetal deaths and reduced live litter sizes.273

There are no adequate and well-controlled studies to date using conventional or liposomal doxorubicin in pregnant women.200,273 Doxorubicin should be used during pregnancy only in life-threatening situations or for disease for which safer drugs cannot be used or are ineffective.356 When conventional or liposomal doxorubicin is used during pregnancy, or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus.200,273 If a patient becomes pregnant during the first few months following liposomal doxorubicin therapy, the prolonged elimination half-life of the drug must be taken into account.273 Women of childbearing potential should be advised to avoid becoming pregnant during doxorubicin therapy.200,273

Fertility

Information on whether conventional or liposomal doxorubicin affects fertility has not been evaluated adequately.200,273 Liposomal doxorubicin hydrochloride has been associated with mild to moderate ovarian and testicular atrophy in mice after a single 36-mg/kg dose (about 2 times the 50-mg/m² human dose on a mg/m² basis), decreased testicular weight and hypospermia in rats after repeated dosages of 0.25 mg/kg or more daily (about one-thirtieth of the 50-mg/m² human dosage on a mg/m² basis), and diffuse degeneration of the seminiferous tubules and marked decreases in spermatogenesis in dogs after repeated dosages of 1 mg/kg daily (about one-half the 50-mg/m² human dosage on a mg/m² basis).273

Lactation

Conventional (nonencapsulated) doxorubicin is distributed into milk.201 It is not known whether liposomal doxorubicin is distributed into milk.273 Because of the potential for serious adverse reactions to doxorubicin in nursing infants, nursing should be discontinued during doxorubicin therapy.200,273 Liposomal doxorubicin is contraindicated in nursing women.273

Formal drug interaction studies employing liposomal doxorubicin have not been performed to date; therefore, pending further accumulation of data, drugs known to interact with conventional (nonencapsulated) doxorubicin should be considered to also interact with the liposomal formulation.273 In addition, although most patients who have received liposomal doxorubicin to date were receiving antiviral therapy concomitantly, the potential for interactions with these drugs has not been evaluated.273

Antineoplastic Agents

Doxorubicin has been used in combination with other antineoplastic agents.200 Although combination chemotherapy has been shown to be more effective than single-agent therapy in some types of neoplasms, the benefits and risks of such therapy have not been fully elucidated.200

Compared with administration of doxorubicin followed by paclitaxel, initial administration of paclitaxel (by IV infusion over 24 hours) followed by doxorubicin (administered over 48 hours) was shown to result in a decrease in doxorubicin clearance and an increase in the severity of neutropenia and stomatitis.200

Doxorubicin may potentiate the toxicity of other antineoplastic therapies and vice versa. Doxorubicin reportedly has exacerbated cyclophosphamide-induced hemorrhagic cystitis and enhanced mercaptopurine-induced hepatotoxicity. Concomitant or previous administration with cyclophosphamide, irradiation of the cardiac region, daunorubicin, idarubicin, or mitoxantrone may potentiate the cardiotoxic effects of doxorubicin, and the maximum cumulative dose of doxorubicin should be reduced. (See Dosage and Administration: Dosage.) Combined therapy with other myelosuppressive agents may increase the severity of hematologic toxicity. Acute “recall” pneumonitis,200 occurring at variable times after local radiation therapy, has been reported in children receiving concomitant doxorubicin and dactinomycin.200 Seizures and/or coma have occurred in patients receiving doxorubicin and vincristine concomitantly.200 Seizures also have been reported in a patient receiving doxorubicin at 2-3 times the recommended dosage in combination with high-dose cyclophosphamide.208

Cyclosporine

The use of cyclosporine in combination with doxorubicin may result in an increase in the area under the plasma concentration-time curve for both doxorubicin and doxorubicinol, possibly due to a decrease in doxorubicin clearance and a decrease in the metabolism of doxorubicinol.200 Evidence suggests that concomitant use of cyclosporine may result in more severe and prolonged hematologic toxicity associated with doxorubicin.200 In addition, seizures and/or coma have occurred in patients receiving doxorubicin and cyclosporine concomitantly.200

Other Drugs

Some evidence suggests that doxorubicin-induced cardiotoxicity may be potentiated by concomitant use of calcium-channel blocking agents.200

Exacerbation of doxorubicin-induced neutropenia and thrombocytopenia has been reported in patients with advanced malignancies receiving high doses of progesterone (up to 10 g IV over 24 hours) concomitantly with doxorubicin (60 mg/m² by IV bolus).200

Phenobarbital has increased the elimination of doxorubicin, doxorubicin has decreased serum phenytoin concentrations, and streptozocin may inhibit hepatic metabolism of doxorubicin.200

Acute Toxicity

Overdosage with doxorubicin exacerbates known adverse effects of the drug, including mucositis, leukopenia, and thrombocytopenia.200,273

Management of acute doxorubicin overdosage consists of hospitalization of the severely myelosuppressed patient, anti-infective therapy, platelet and granulocyte transfusions, and symptomatic treatment of mucositis.200,273 The use of hematopoietic growth factor (granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor) to reduce the severity of myelosuppression may be considered.200

Pharmacology

Doxorubicin hydrochloride is an antineoplastic antibiotic with pharmacologic actions similar to those of daunorubicin. Although the drug has anti-infective properties, its cytotoxicity precludes its use as an anti-infective agent. The precise and/or principal mechanism(s) of the antineoplastic action of doxorubicin is not fully understood. It appears that the cytotoxic effect of the drug results from a complex system of multiple modes of action related to free radical formation secondary to metabolic activation of the doxorubicin by electron reduction, intercalation of the drug into DNA, induction of DNA breaks and chromosomal aberrations, and alterations in cell membranes induced by the drug.233,234,237,238,239,240,244,299 Evidence from in vitro studies in cells treated with doxorubicin suggests that apoptosis (programmed cell death) also may be involved in the drug's mechanism of action.200 These and other mechanisms (chelation of metal ions to produce drug-metal complexes) also may contribute to the cardiotoxic effects of the drug.233,234,237,238,239,240,244,299 (See Cautions: Cardiac Effects.)

Doxorubicin undergoes enzymatic 1- and 2-electron reduction to the corresponding semiquinone and dihydroquinone.299 7-Deoxyaglycones are formed enzymatically by 1-electron reduction, and the resulting semiquinone free radical reacts with oxygen to produce the hydroxyl radical in a cascade of reactions; this radical may lead to cell death by reacting with DNA, RNA, cell membranes, and proteins.233,237,244,299 The dihydroquinone that results from 2-electron reduction of doxorubicin also can be formed by the reaction of 2 semiquinones.299 In the presence of oxygen, dihydroquinone reacts to form hydrogen peroxide, and in its absence, loses its sugar and gives rise to the quinone methide, a monofunctional alkylating agent with low affinity for DNA.299 The contribution of dihydroquinone and the quinone methide to the cytotoxicity of doxorubicin is unclear.299 Experimental evidence indicates that doxorubicin forms a complex with DNA by intercalation between base pairs, causing inhibition of DNA synthesis and DNA-dependent RNA synthesis by the resulting template disordering and steric obstruction. Doxorubicin also inhibits protein synthesis. Doxorubicin is active throughout the cell cycle including the interphase.

Of the cell types tested in vitro, cardiac cells are the most sensitive to the effects of doxorubicin, followed by sarcoma and melanoma cells, normal muscle fibroblasts, and normal skin fibroblasts. Normal, rapidly proliferating tissues such as those of bone marrow, GI and oral mucosa, and hair follicles are also affected to varying degrees. Doxorubicin hydrochloride also has immunosuppressive activity.

Pharmacokinetics

Nonencapsulated (conventional) doxorubicin hydrochloride exhibits linear pharmacokinetics;299 PEG-stabilized liposomal doxorubicin hydrochloride also exhibits dose-proportional, linear pharmacokinetics over a dosage range of 10-20 mg/m².273,283,285 The pharmacokinetics of liposomally encapsulated doxorubicin at a dose of 50 mg/m² have been reported to be nonlinear.273 At a dose of 50 mg/m², a longer elimination half-life and lower clearance compared to those observed with a 20 mg/m² dose are expected, with greater-than-proportional increases in area under the plasma concentration-time curve.273 Encapsulation of doxorubicin hydrochloride in PEG-stabilized (Stealth^®) liposomes substantially alters the pharmacokinetics of the drug relative to conventional IV formulations (i.e., nonencapsulated drug), with resultant decreased distribution into the peripheral compartment, increased distribution into Kaposi's lesions, and decreased plasma clearance.273,283,285 The pharmacokinetics of the drug encapsulated in PEG-stabilized liposomes have not been evaluated separately by gender, ethnic group, or hepatic or renal impairment.273 In the Pharmacokinetics section, liposomal doxorubicin hydrochloride was administered as the drug encapsulated in PEG-stabilized liposomes.

Absorption

Nonencapsulated doxorubicin hydrochloride is not stable in gastric acid, and animal studies indicate that the drug undergoes little, if any, absorption from the GI tract. The drug is extremely irritating to tissues and, therefore, must be administered IV. Following IV infusion of a single 10- or 20-mg/m² dose of liposomal doxorubicin hydrochloride in patients with AIDS-related Kaposi's sarcoma, average peak plasma doxorubicin (mostly bound to liposomes) concentrations are 4.33 or 10.1 mcg/mL, respectively, following a 15-minute infusion285 and 4.12 or 8.34 mcg/mL, respectively, following a 30-minute infusion.273,283 Following IV infusion over 15 minutes of a 40-mg/m² dose of liposomal doxorubicin hydrochloride in adults with AIDS-related Kaposi's, peak plasma concentrations averaged 20.1 mcg/mL.285

Distribution

Doxorubicin administered as a conventional injection is widely distributed in the plasma and in tissues. As early as 30 seconds after IV administration, doxorubicin is present in the liver, lungs, heart, and kidneys. Doxorubicin is absorbed by cells and binds to cellular components, particularly to nucleic acids. The volume of distribution of doxorubicin hydrochloride administered IV as a conventional injection is about 700-1100 L/m².273,283,285 Nonencapsulated doxorubicin is approximately 50-85% bound to plasma proteins;273,283,299 the protein binding of liposomally encapsulated drug has not been determined.273,283

Encapsulation in PEG-stabilized liposomes substantially slows the rate of distribution of doxorubicin into the extravascular space.273,283,285 As a result, the liposomally encapsulated drug does not distribute into plasma and tissues as widely as doxorubicin hydrochloride administered as the conventional injection; doxorubicin hydrochloride encapsulated in liposomes distributes mainly in intravascular fluid,273,283,285 whereas nonencapsulated drug distributes widely into extravascular fluids and tissues.273,283,285,299 Animal studies indicate that liposomally encapsulated doxorubicin hydrochloride distributes from blood vessels into tumors, and once distributed into the tissue compartment, the drug is released; the exact mechanism of drug release from liposomal encapsulation is not known.273 The steady-state volume of distribution of doxorubicin following IV administration of a single 10-40-mg/m² dose of the drug as a PEG-stabilized liposomal for injection concentrate in patients with AIDS-related Kaposi's sarcoma ranges from 2.2-4.4 L/m².273,283,285

Doxorubicin hydrochloride administered IV as the liposomally encapsulated drug distributes into Kaposi's sarcoma lesions to a greater extent than into healthy skin.273,283 Following IV administration of a single 20-mg/m² dose of liposomal doxorubicin hydrochloride, doxorubicin concentrations in Kaposi's sarcoma lesions were 19 (range: 3-53)-fold higher than those observed in healthy skin;273 however, blood concentrations in the lesions or in healthy skin were not considered.273 In addition, distribution of doxorubicin into Kaposi's sarcoma lesions following IV administration of liposomally encapsulated drug was 5.2-11.4 times greater than that following IV administration of comparable doses of a conventional (nonencapsulated) injection.285 The mechanism by which liposomal encapsulation enhances doxorubicin distribution into Kaposi's sarcoma lesions has not been elucidated fully, but similar PEG-stabilized liposomes containing colloidal gold as a marker have been shown to enter Kaposi's sarcoma-like lesions in animals.285 Extravasation of the liposomes also may occur by passage of the particles through endothelial cell gaps present in Kaposi's sarcoma.285 Once within the lesions, the drug presumably is released locally as the liposomes degrade and become permeable in situ .285

Doxorubicin does not cross the blood-brain barrier or achieve a measurable concentration in the CSF.

Trace amounts of doxorubicin have been found in fetal mice whose mothers received the drug during pregnancy, and there are limited data to indicate that nonencapsulated doxorubicin crosses the human placenta. Nonencapsulated doxorubicin is distributed into milk, achieving concentrations that often exceed those in plasma; doxorubicinol (the major metabolite) also distributes into milk.200,201

Elimination

Plasma concentrations of nonencapsulated doxorubicin and its metabolites decline in a biphasic or triphasic manner. In the first phase of the triphasic model, nonencapsulated doxorubicin is rapidly metabolized, presumably by a first-pass effect through the liver. It appears that most of this metabolism is completed before the entire dose is administered. In the triphasic model, nonencapsulated doxorubicin and its metabolites are rapidly distributed into the extravascular compartment with a plasma half-life of approximately 0.2-0.6 hours for doxorubicin and 3.3 hours for its metabolites. This is followed by relatively prolonged plasma concentrations of doxorubicin and its metabolites, probably resulting from tissue binding. During the second phase, the plasma half-life of nonencapsulated doxorubicin is 16.7 hours and that of its metabolites is 31.7 hours. In the biphasic model, the initial distribution t_½ has been reported to average about 5-10 minutes, and the terminal elimination t_½ has been reported to average about 30 hours.285,299

In patients with impaired hepatic function, particularly those who are hyperbilirubinemic, clearance of doxorubicin is reduced and plasma concentrations of both the drug and its metabolites are elevated; doxorubicin dosage must be reduced in patients with hepatic impairment.200 (See: Dosage and Administration: Dosage in Hepatic Impairment.)

Plasma clearance of nonencapsulated doxorubicin (when administered as a conventional injection) ranges from 8-20 mL/minute per kilogram (or 324-809 mL/minute per m²).200 Systemic clearance of doxorubicin is reduced in obese women (actual body weight exceeding 130% of ideal body weight).200 Clearance of doxorubicin was reduced without any change in volume of distribution in obese patients compared with patients with an actual body weight less than 115% of ideal body weight.200 Limited evidence suggests that the pharmacokinetics of nonencapsulated doxorubicin is influenced by gender.200 In a clinical study involving 6 men and 21 women with no history of prior anthracycline treatment, doxorubicin clearance was higher in men than in women (1883 versus 750 mL/min, respectively).200 However, the terminal elimination half-life of the drug was longer in men than in women (54 versus 35 hours, respectively).200

The pharmacokinetics of nonencapsulated doxorubicin also appears to be influenced by age.200 In a pharmacokinetic study in 60 children and adolescents (aged 2 months to 20 years) receiving 10-75 mg/m² nonencapsulated doxorubicin, a mean clearance of 1443 mL/min per m² was reported.200 Further analysis indicated that doxorubicin clearance in 52 children older than 2 years of age (1540 mL/minute per m²) was increased compared with clearance reported for adults.200 In contrast, clearance of the drug in children younger than 2 years of age (813 mL/minute per m²) was decreased compared with that in older children and approached the range of clearance values reported for adults.200

Plasma concentrations of liposomally encapsulated doxorubicin hydrochloride appear to decline in a biphasic manner.273,285,331 Following IV administration of a single 10- to 40-mg/m² dose of doxorubicin hydrochloride as a liposomal injection in patients with AIDS-related Kaposi's sarcoma, the initial plasma half-life (t_½α) of doxorubicin averaged 3.76-5.2 hours while the terminal elimination half-life (t_½β) averaged 39.1-55 hours.273,283,285

Plasma clearance of doxorubicin encapsulated in PEG-stabilized liposomes appears to be substantially slower than that of nonencapsulated doxorubicin.273,285 In adults with AIDS-related Kaposi's sarcoma, plasma clearance of PEG-stabilized liposomal doxorubicin hydrochloride following a single IV dose of 10-40 mg/m² averaged 0.57-1.8 mL/minute per m².273,285 This reduction in plasma clearance with liposomal doxorubicin results in a substantial increase in the area under the plasma concentration-time curve (AUC) compared with that of nonencapsulated drug.273,285

Nonencapsulated doxorubicin is metabolized by NADPH-dependent aldoketoreductases to the hydrophilic 13-hydroxyl metabolite doxorubicinol, which exhibits antineoplastic activity and is the major metabolite; these reductases are present in most if not all cells, but particularly in erythrocytes, liver, and kidney.299 Although not clearly established, doxorubicinol also appears to be the moiety responsible for the cardiotoxic effects of the drug.234,327 Undetectable or low plasma concentrations (i.e., 0.8-26.2 ng/mL) of doxorubicinol have been reported following IV administration of a single 10- to 50-mg/m² dose of doxorubicin hydrochloride as a PEG-stabilized liposomal injection;273,285 it remains to be established whether such liposomally encapsulated anthracyclines are less cardiotoxic than conventional (nonencapsulated) drug,244,273,298 and the usual precautions for unencapsulated drug currently also should be observed for the liposomal preparation.273 (See Cautions: Cardiac Effects.) Substantially reduced or absent plasma concentrations of the usual major metabolite of doxorubicin observed with the PEG-stabilized liposomal injection suggests that either the drug is not released appreciably from the liposomes as they circulate or that some doxorubicin may be released but that the rate of doxorubicinol elimination greatly exceeds the release rate; doxorubicin hydrochloride encapsulated in liposomes that have not been PEG-stabilized is metabolized to doxorubicinol.285

Other metabolites, which are therapeutically inactive, include the poorly water-soluble aglycones, doxorubicinone (adriamycinone) and 7-deoxydoxorubicinone (17-deoxyadriamycinone), and conjugates.299 The aglycones are formed in microsomes by NADPH-dependent, cytochrome reductase-mediated cleavage of the amino sugar moiety.299 The enzymatic reduction of doxorubicin to 7-deoxyaglycones is important to the cytotoxic effect of the drug since it results in hydroxyl radicals that cause extensive cell damage and death.299 (See Pharmacology.) With nonencapsulated doxorubicin, more than 20% of the total drug in plasma is present as metabolites as soon as 5 minutes after a dose, 70% in 30 minutes, 75% in 4 hours, and 90% in 24 hours.

Nonencapsulated doxorubicin and its metabolites are excreted predominantly in bile; about 10-20% of a single dose is excreted in feces in 24 hours, and 40-50% of a dose is excreted in bile or feces within 7 days. About 50% of the drug in bile is unchanged drug, 23% is doxorubicinol, and the remainder is other metabolites including aglycones and conjugates. About 4-5% (range: 0.7-23%) of the administered dose is excreted in urine after 5 days, principally as unchanged doxorubicin. It appears that very little further urinary excretion of the drug occurs after 5 days. Although only small urinary concentrations of the drug usually are achieved, doxorubicin often imparts a red color to the urine for the first hours to days after administration, and patients should be advised to expect this effect during therapy.200

Chemistry and Stability

Chemistry

Doxorubicin is an anthracycline glycoside antibiotic produced by Streptomyces peucetius var. caesius. The drug is structurally related to daunorubicin and epirubicin. Doxorubicin differs structurally from daunorubicin in that doxorubicin contains a hydroxyacetyl group instead of an acetyl group in the 8-position. Epirubicin is the 4'-epimer of doxorubicin.

Doxorubicin is commercially available as the hydrochloride salt. Commercially available doxorubicin hydrochloride powder for injection occurs as a sterile, lyophilized, crystalline, red-orange or red powder; the powder for injection also may contain lactose and methylparaben to enhance dissolution.200,208 Doxorubicin hydrochloride is freely soluble in water, slightly soluble in 0.9% sodium chloride solution, and very slightly soluble in alcohol. When doxorubicin hydrochloride powder for injection is reconstituted with 0.9% sodium chloride injection, the pH of the resulting solution is 3.8-6.5.

Doxorubicin hydrochloride also is commercially available as a sterile, isotonic, aqueous solution of the drug.200,207 Hydrochloric acid is added during manufacture of the injection to adjust the pH to approximately 3 (range: 2.5-3.5);200,207 the injection also contains 0.9% sodium chloride.200

As an injection, doxorubicin hydrochloride also is available in a liposomal formulation.273,275,283,284,285,328 In the liposomal doxorubicin hydrochloride for injection concentrate, an aqueous core of doxorubicin hydrochloride is encapsulated in Stealth^®liposomes; approximately 90% of the drug present in the commercially available liposomal doxorubicin hydrochloride is encapsulated.273,275,283,328 Liposomes are microscopic vesicles composed of a phospholipid bilayer that is capable of encapsulating drugs; the lipid bilayer separates the internal aqueous core, which for doxorubicin hydrochloride liposomal for injection concentrate contains the drug, from the external environment.273,283 Stealth^® liposomes, which contain hydrogenated soy phosphatidylcholine (HSPC) and cholesterol in the phospholipid bilayer, are formulated with methoxypolyethylene glycol (MPEG, a hydrophilic polymer) combined with distearoyl- sn -glycerophosphoethanolamine (DSPE) on their surface (combined as MPEG-DSPE).273,283,328 Formulating the liposomes with surface-bound MPEG has been referred to as “pegylation,” and the resulting polymer coating protects the liposomes from opsonization by plasma proteins and subsequent detection as a foreign protein by the mononuclear phagocyte system (MPS) and rapid clearance from circulation (e.g., by fixed macrophages in the liver and spleen); as a result, the blood circulation time of the liposomes is prolonged.273,283 The Stealth^® liposomes also have been referred to as PEG-stabilized;283,285 the MPEG groups extend 5 nm from the liposome surface creating a protective wall that inhibits interaction between the lipid bilayer membrane and plasma components.283 It has been suggested that liposomes can penetrate the altered and often compromised vasculature of tumors because of their small size (about 100 nm) and persistence in the blood circulation.273 Doxorubicin hydrochloride liposomal for injection concentrate is a sterile, translucent red liposomal dispersion.273 Hydrochloric acid and/or sodium hydroxide is added during manufacture of the for injection concentrate to adjust the pH to approximately 6.5.273 Doxorubicin hydrochloride liposomal for injection concentrate also contains sucrose for isotonicity, histidine as a buffer, and ammonium sulfate.273 During manufacturing, inclusion of sucrose in the external phase and ammonium sulfate in the internal phase creates the chemical gradient needed for promoting diffusion of doxorubicin hydrochloride from the external phase into the aqueous core of the liposomes.283

Stability

Commercially available doxorubicin hydrochloride lyophilized powder for injection should be stored in a dry place protected from sunlight. When stored at 15-30°C, Adriamycin RDF^® or Rubex^® has an expiration date of 3 or 2 years, respectively, following the date of manufacture. Doxorubicin hydrochloride conventional (nonencapsulated) injection should be protected from light and refrigerated at 2-8°C;200 when stored under these conditions, the injection is stable for 18 months.

Solutions of doxorubicin hydrochloride should be protected from exposure to sunlight.200,208 When reconstituted as directed, solutions prepared from the single-dose or multiple-dose vial of the powder for injection can be stored for up to 7 days at room temperature and under normal room light (100 foot-candles) or for up to 15 days when refrigerated at 2-8°C; unused portions should be discarded after these storage periods. 200,208 Doxorubicin hydrochloride is unstable in solutions with a pH less than 3 or greater than 7. Acids split the glycosidic bond in doxorubicin, yielding a red-colored, water insoluble aglycone (doxorubicinone, also known as adriamycinone) and a water soluble, reducing amino sugar (daunosamine). Doxorubicin hydrochloride solution is chemically incompatible with heparin sodium injection, and a precipitate may form if the solutions are mixed. Doxorubicin hydrochloride solution also is reportedly incompatible with fluorouracil, and a precipitate may form if the solutions are mixed. The manufacturers recommend that doxorubicin hydrochloride solutions or doxorubicin liposomal dispersion generally not be mixed with other drugs; specialized references should be consulted for specific compatibility information.

Commercially available doxorubicin hydrochloride liposomal for injection concentrate should be refrigerated at 2-8°C and protected from freezing.273,283 The manufacturer states that prolonged freezing may adversely affect stability of liposomal doxorubicin hydrochloride; however, short-term freezing (less than 1 month) does not appear to affect stability of liposomal doxorubicin hydrochloride.273,283 During shipping, vials of doxorubicin hydrochloride for injection concentrate are packaged with a gel refrigerant (“blue ice”) to maintain a temperature of 2-8°C.283 When diluted as directed with 5% dextrose injection, solutions of liposomal doxorubicin hydrochloride are stable for 24 hours when refrigerated at 2-8°C.273,283

Additional Information

For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

Only references cited for selected revisions after 1984 are available electronically.

200. Pharmacia & Upjohn. Adriamycin RDF^® (doxorubicin hydrochloride) for injection, Adriamycin PFS^® (doxorubicin hydrochloride) injection prescribing information. Kalamazoo, MI; 2002 Jun.

201. Egan PC, Costanza ME, Dodion P et al. Doxorubicin and cisplatin excretion into human milk. Cancer Treat Rep . 1985; 69:1387-9. [PubMed 4075315]

202. Barlogie B, Smith L, Alexanian R. Effective treatment of advanced multiple myeloma refractory to alkylating agents. N Engl J Med . 1984; 310:1353-6. [PubMed 6546971]

203. Alexanian R, Barlogie B, Dixon D. High-dose glucocorticoid treatment of resistant myeloma. Ann Intern Med . 1986; 105:8-11. [PubMed 3717812]

204. Gottlieb SL, Edmiston WA Jr, Haywood LJ. Late, late doxorubicin cardiotoxicity. Chest . 1980; 78:880-2. [PubMed 7449470]

205. Freter CE, Lee TC, Billingham ME et al. Doxorubicin cardiac toxicity manifesting seven years after treatment: case report and review. Am J Med . 1986; 80:483-5. [PubMed 3513562]

206. Ovarian epithelial cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2006 May 4.

207. Food and Drug Administration. Antibiotic drugs: doxorubicin hydrochloride injection (Docket No. 88N-0232). Fed Regist . 1988; 53:37291-3.

208. Bristol-Myers Squibb. Rubex^® (doxorubicin hydrochloride for injection, USP) prescribing information. Princeton, NJ; 2001 Mar.

209. Bambarola FA (Bristol-Myers Oncology, Evansville, IN): Personal Communication; 1989 Sep 5.

210. Ench J (Adria Laboratories, Columbus, OH): Personal Communication; 1989 Dec 28.

211. Davis LE, Brown CEL. Peripartum heart failure in a patient treated previously with doxorubicin. Obstet Gynecol . 1988; 71:506-8. [PubMed 3162299]

212. Committee on Drugs, American Academy of Pediatrics. Transfer of drugs and other chemicals into human milk. Pediatrics . 1989; 84:924-36. [PubMed 2677964]

213. Anon. Drugs of choice for cancer. Treat Guidel Med Lett . 2003; 1:41-52. [PubMed 15529105]

214. Alexanian R, Dimopoulos M. The treatment of multiple myeloma. N Engl J Med . 1994; 330:484-9. [PubMed 8289856]

215. Buzdar AU, Kau SW, Smith TL et al. Ten-year results of FAC adjuvant chemotherapy trial in breast cancer. Am J Clin Oncol . 1989; 12:123-8. [PubMed 2705401]

216. Buzdar AU, Smith TL, Powell KC et al. Effect of timing of initiation of adjuvant chemotherapy on disease-free survival in breast cancer. Breast Cancer Res Treat . 1982; 2:163-9. [PubMed 6897369]

217. Jones SE, Salman SE, Allen H et al. Adjuvant treatment of node-positive breast cancer with adriamycin-cyclophosphamide with or without radiation: interim results of an ongoing clinical trial. Recent Results Cancer Res . 1982; 80:162-9. [PubMed 7036279]

218. Hortobagyi GN, Frye D, Buzdar AU et al. Decreased cardiac toxicity of doxorubicin administered by continuous intravenous infusion in combination chemotherapy for metastatic breast carcinoma. Cancer . 1989; 63:37-45. [PubMed 2910423]

219. Smalley RV, Lefante J, Bartolucci A et al. A comparison of cyclophosphamide, adriamycin, and 5-fluorouracil (CAF) and cyclophosphamide, methotrexate, 5-fluorouracil, vincristine and prednisone (CMFVP) in patients with advanced breast cancer: a Southwestern Cancer Study Group project. Breast Cancer Res Treat . 1983; 3:209-20. [PubMed 6688538]

220. Tranum BL, McDonald B, Thigpen T et al. Adriamycin combinations in advanced breast cancer: a Southwest Oncology Group study. Cancer . 1982; 49:835-9. [PubMed 7037152]

221. Breast cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 1995 Dec 12.

222. Early Breast Cancer Trialists' Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomized trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet . 1992; 339:1-15,71-85. [PubMed 1345950]

223. Bonadonna G, Valagussa P, Moliterni A et al. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med . 1995; 332:901-6. [PubMed 7877646]

224. Wood WC, Budman DR, Korzun AH et al. Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med . 1994; 330:1253-9. [PubMed 8080512]

225. Bonadonna G, Zambetti M, Valagussa P. Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes: ten-year results. JAMA . 1995; 273:542-7. [PubMed 7837388]

226. Fisher B, Redmond C, Dimitrov NV et al. A randomized clinical trial evaluating sequential methotrexate and fluorouracil in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med . 1989; 320:473-8. [PubMed 2644531]

227. Fisher B, Brown AM, Dimitrov NV et al. Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol . 1990; 8:1483-96. [PubMed 2202791]

228. Moliterni A, Bonadonna G, Valagussa P et al. Cyclophosphamide, methotrexate, and fluorouracil with and without doxorubicin in the adjuvant treatment of resectable breast cancer with one to three positive nodes. J Clin Oncol . 1991; 9:1124-30. [PubMed 2045854]

229. Fisher B, Redmond C, Wickerman DL et al. Doxorubicin-containing regimens for the treatment of stage II breast cancer: the National Surgical Adjuvant Breast and Bowel Project experience. J Clin Oncol . 1989; 7:572-82. [PubMed 2651576]

230. National Institutes of Health Office of Medical Applications of Research. Consensus conference: treatment of early-stage breast cancer. JAMA . 1991; 265:391-5. [PubMed 1984541]

231. Buzzoni R, Bonadonna G, Valagussa P et al. Adjuvant chemotherapy with doxorubicin plus cyclophosphamide, methotrexate, and fluorouracil in the treatment of resectable breast cancer with more than three positive axillary nodes. J Clin Oncol . 1991; 9:2134-40. [PubMed 1960555]

232. Goldhirsch A, Gelber RD, Price KN et al. Effect of systemic adjuvant treatment on first sites of breast cancer relapse. Lancet . 1994; 343:377-81. [PubMed 7905550]

233. Zinecard^® (dexrazoxane) for injection prescribing information. Dublin, OH; 1995 May 22.

234. Lewis C. A review of the use of chemoprotectants in cancer chemotherapy. Drug Safety . 1994; 11:153-162. [PubMed 7811398]

235. Speyer JL, Green MD, Zeleniuch-Jacquotte A et al. ICRF-187 permits longer treatment with doxorubicin in women with breast cancer. J Clin Oncol . 1992; 10:117-27. [PubMed 1727913]

236. Von Hoff DD, Layard MW, Basa P et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med . 1979; 91:710-7. [PubMed 496103]

237. Legha S, Wang YM, Mackay B et al. Clinical and pharmacological investigation of the effects of alpha-tocopherol on adriamycin cardiotoxicity. Ann NY Acad Sci . 1982; 393:411-8. [PubMed 6959564]

238. Myers CE, Bonow R, Palmeri S et al. A randomized controlled trial assessing the prevention of doxorubicin cardiomyopathy by N -acetylcysteine. Semin Oncol . 1983; 10(Suppl 1):53-5. [PubMed 6340204]

239. Myers CE, Gianna L, Zweier J et al. Role of iron in adriamycin biochemistry. Fed Proc . 1986; 45:2792-7. [PubMed 3533644]

240. Sugioka KA, Nakano M. Mechanisms of phospholipid peroxidations induced by ferric iron-ADP adriamycin co-ordination complex. Biochem Biophys Acta . 1982; 713:333-43. [PubMed 6295497]

241. Speyer JL, Green MD, Kramer E et al. Protective effects of the bispiperazinedione ICRF-187 against doxorubicin-induced cardiac toxicity in women with advanced breast cancer. N Engl J Med . 1988; 319:745-52. [PubMed 3137469]

242. ten Bokkel-Huinink WW, Schreuder JE, Dubbleman R et al. ICRF-187 protects against doxorubicin induced cardiomyopathy. Ann Oncol . 1992; 1(Suppl 3):A221.

243. Valagussa P, Zarobetti M, Biasi S et al. Cardiac effects following adjuvant chemotherapy and breast irradiation in operable breast cancer. Ann Oncol . 1994; 5:803-808. [PubMed 7848882]

244. Shan K, Lincoff AM, Young JB et al. Anthracycline-induced cardiotoxicity. Ann Intern Med . 1996; 125:47-58. [PubMed 8644988]

245. Steinherz LJ, Yahalom J. Cardiac complications of cancer therapy. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 4th ed. Philadelphia, PA: J. B. Lippincott; 1993:2370-85.

246. Steinherz LJ, Steinherz PG, Tan CTC et al. Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA . 1991; 266:1672-7. [PubMed 1886191]

247. Steinherz LJ, Steinherz PG, Tan C. Cardiac failure and dysrhythmias 6-19 years after anthracycline therapy: a series of 15 patients. Med Pediatr Oncol . 1995; 24:352-61. [PubMed 7715541]

248. Lipshultz SE, Lipsitz SR, Mone SM et al. Female sex and higher drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Engl J Med . 1995; 332:1738-43. [PubMed 7760889]

249. Silber JH, Jakacki RI, Larsen RL et al. Increased risk of cardiac dysfunction after anthracyclines in girls. Med Pediatr Oncol . 1993; 21:477-9. [PubMed 8341214]

250. Doroshow JH. Doxorubicin-induced cardiac toxicity. N Engl J Med . 1991; 324:843-5. [PubMed 1997858]

251. Ferrans VJ. Overview of cardiac pathology in relation to anthracycline cardiotoxicity. Cancer Treat Rep . 1978; 62:955-61. [PubMed 352510]

252. Lipshultz SE, Colan SD, Gelber RD et al. Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med . 1991; 324:808-15. [PubMed 1997853]

253. Alexander J, Dainiak N, Berger HJ et al. Serial assessment of doxorubicin cardiotoxicity with quantitative radionuclide angiocardiography. N Engl J Med . 1979; 300:278-83. [PubMed 759880]

254. Bristow MR, Mason JW, Billingham ME et al. Dose-effect and structure-function relationships in doxorubicin cardiomyopathy. Am Heart J . 1981; 102:709-18. [PubMed 7282516]

255. Bielack SS, Erttmann R, Winkler K et al. Doxorubicin: effect of different schedules on toxicity and anti-tumor efficacy. Eur J Cancer Clin Oncol . 1989; 25:873-82. [PubMed 2661240]

256. Bristow MR, Mason JW, Billingham ME et al. Doxorubicin cardiomyopathy: evaluation by phonocardiography, endomyocardial biopsy, and cardiac catheterization. Ann Intern Med . 1978; 88:168-75. [PubMed 626445]

257. Legha SS, Benjamin RS, Mackay B et al. Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med . 1982; 96:133-9. [PubMed 7059060]

258. Valdes Olmos RA, ten Bokkel Huinink WW, ten Hoeve RFA et al. Assessment of anthracycline-related myocardial adrenergic derangement by [¹²³I]metaiodobenzylguanidine scintigraphy. Eur J Cancer . 1995; 31A:26-31. [PubMed 7695974]

259. Pegelow CH, Popper RW, de Wit SA et al. Endomyocardial biopsy to monitor anthracycline therapy in children. J Clin Oncol . 1984; 2:443-6. [PubMed 6587017]

260. Mason JW, Bristow MR, Billingham ME et al. Invasive and noninvasive methods of assessing adriamycin cardiotoxic effects in man: superiority of histopathologic assessment using endomyocardial biopsy. Cancer Treat Rep . 1978; 62:857-64. [PubMed 667859]

261. Ito H, Miller SC, Billingham ME et al. Doxorubicin selectively inhibits muscle gene expression in cardiac muscle cells in vivo and in vitro . Proc Natl Acad Sci USA . 1990; 87:4275-9. [PubMedCentral][PubMed 2349236]

262. Hitchcock-Bryan S, Gelber R, Cassady JR et al. The impact of induction anthracycline on long-term failure-free survival in childhood acute lymphoblastic leukemia. Med Pediatr Oncol . 1986; 14:211-5. [PubMed 3462467]

263. Waagstein F, Bristow MR, Swedberg K et al for the Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Lancet . 1993; 342:1441-6. [PubMed 7902479]

264. Mann DL, Young JB. Basic mechanisms in congestive heart failure: recognizing the role of proinflammatory cytokines. Chest . 1994; 105:897-904. [PubMed 8131560]

265. Matsumori A, Yamada T, Suzuki H et al. Increased circulating cytokines in patients with myocarditis and cardiomyopathy. Br Heart J . 1994; 72:561-6. [PubMedCentral][PubMed 7857740]

266. Kusuoka H, Futaki S, Koretsune Y et al. Alterations of intracellular calcium homeostasis and myocardial energetics in acute adriamycin-induced heart failure. J Cardiovasc Pharmacol . 1991; 18:437-4. [PubMed 17,20844]

267. Booser DJ, Hortobagyi GN. Anthracycline antibiotics in cancer therapy: focus on drug resistance. Drugs . 1994; 47:223-58. [PubMed 7512899]

268. Gaasch WH. Diagnosis and treatment of heart failure based on left ventricular systolic or diastolic dysfunction. JAMA . 1994; 271:1276-80. [PubMed 8151903]

269. Billingham ME, Bristow MR, Glatstein E et al. Adriamycin cardiotoxicity: endomyocardial biopsy evidence of enhancement by irradiation. Am J Surg Pathol . 1977; 1:17-23. [PubMed 602969]

270. Lipshultz SE, Sanders SP, Goorin AM et al. Monitoring for anthracycline cardiotoxicity. Pediatrics . 1994; 93:433-7. [PubMed 7818624]

271. Barber G. The anthracycline cardiotoxicity debate. Pediatrics . 1994; 94:778-82. [PubMed 7936922]

272. Steinherz LJ, Graham T, Hurwitz R et al. Guidelines for monitoring of anthracycline cardiomyopathy: a rebuttal. Pediatrics . 1994; 94:782-4. [PubMed 7936926]

273. Tibotec Therapeutics. Doxil^® (doxorubicin HCl liposome injection) prescribing information. Raritan, NJ; 2006 May.

274. James VE (Sequus Pharmaceuticals, Menlo Park, CA): Personal communication; 1995 Dec 5.

275. Northfelt DW. Efficacy of Doxil^® (doxorubicin HCl liposome injection) in the treatment of refractory AIDS-related Kaposi's sarcoma. In: Doxil Clinical Series. Vol. 1, No. 3. Menlo Park, CA: Sequus Pharmaceuticals, Inc; 1996:1-8.

276. Kaposi's sarcoma. From: CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 May.

277. Northfelt DW. Treatment of Kaposi's sarcoma: current guidelines and future perspectives. Drugs . 1994; 48:569-82. [PubMed 7528130]

278. Gill PS, Rarick M, McCutchan JA et al. Systemic treatment of AIDS-related Kaposi's sarcoma: results of a randomized trial. Am J Med . 1991; 90:427-33. [PubMed 1707230]

279. Stewart S, Jablonowski H, Goebel FD et al. Randomized comparative trial of pegylated liposomal doxorubicin versus bleomycin and vincristine in the treatment of AIDS-related Kaposi's sarcoma. J Clin Oncol . 1998; 16:683-91. [PubMed 9469358]

280. Northfelt DW, Dezube BJ, Thommes JA et al. Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine in the treatment of AIDS-related Kaposi's sarcoma: results of a randomized phase III clinical trial. J Clin Oncol . 1998; 16:2445-51. [PubMed 9667262]

281. Bogner JR, Kronawitter U, Rolinski B et al. Liposomal doxorubicin in the treatment of advanced AIDS-related Kaposi sarcoma. J Acquir Immune Defic Syndr . 1994; 7:463-8. [PubMed 8158540]

282. Esser S, Bleil M, Reimann G et al. Long term treatment with liposomal doxorubicin in patients with AIDS-related Kaposi's sarcoma. In: XI International Conference on AIDS, 1996. Vancouver, BC; 1996 Jul 7-12. Abstract No. Th.A.4077.

283. Coleman R. Treatment of refractory AIDS-related Kaposi's sarcoma with Doxil^®(doxorubicin HCl liposome injection): a pharmacy perspective. In: Doxil Clinical Series. Vol. 1, No. 4. Menlo Park, CA: Sequus Pharmaceuticals, Inc; 1996:1-12.

284. Dezube BJ. Safety assessment: Doxil^® (doxorubicin HCl liposome injection) in refractory AIDS-related Kaposi's sarcoma. In: Doxil Clinical Series. Vol. 1, No. 2. Menlo Park, CA: Sequus Pharmaceuticals, Inc; 1996:1-8.

285. Northfelt DW, Martin FJ, Working P et al. Doxorubicin encapsulated in liposomes containing surface-bound polyethylene glycol: pharmacokinetics, tumor localization, and safety in patients with AIDS-related Kaposi's sarcoma. J Clin Pharmacol . 1996; 36:55-63. [PubMed 8932544]

286. Gruenaug M, Bogner JR, Loch O et al. Liposomal doxorubicin in pulmonary Kaposi's sarcoma: improved survival as compared to patients without liposomal doxorubicin. In: XI International Conference on AIDS, 1996: Abstracts-on-disk^®. Vancouver, BC; 1996 Jul 7-12. Abstract No. Tu.B.2221.

287. Harrison M, Tomlinson D, Stewart S. Liposomal-entrapped doxorubicin: an active agent in AIDS-related Kaposi's sarcoma. J Clin Oncol . 1995; 13:914-20. [PubMed 7707119]

288. Moran TA. Treatment of refractory AIDS-related Kaposi's sarcoma with Doxil^®(doxorubicin HCl liposome injection): a nursing perspective. In: Doxil Clinical Series. Vol. 1, No. 5. Menlo Park, CA: Sequus Pharmaceuticals, Inc; 1996:1-8.

289. Laubenstein LJ, Krigel RL, Odajnyk CM et al. Treatment of epidemic Kaposi's sarcoma with etoposide or a combination of doxorubicin, bleomycin, and vinblastine. J Clin Oncol . 1984; 2:1115-20. [PubMed 6208343]

290. Fischl MA, Krown SE, O'Boyle KP et al and the AIDS Clinical Trials Group. Weekly doxorubicin in the treatment of patients with AIDS-related Kaposi's sarcoma. J Acquir Immune Defic Syndr . 1993; 6:259-64. [PubMed 8450401]

291. Gill PS, Rarick MU, Espina B et al. Advanced acquired immune deficiency syndrome-related Kaposi's sarcoma: results of pilot studies using combination chemotherapy. Cancer . 1990; 65:1074-8. [PubMed 1689209]

292. Armitage JM, Kormos RL, Griffith BP et al. Heart transplantation in patients with malignant disease. J Heart Transplant . 1990; 9:627-30. [PubMed 2277299]

293. Dorent R, Pavie A, Nataf P et al. Heart transplantation is a valid therapeutic option for anthracycline cardiomyopathy. Transplant Proc . 1995; 27:1683. [PubMed 7725449]

294. NeXstar Pharmaceuticals, Inc. DaunoXome^® (daunorubicin citrate liposome injection) prescribing information. San Dimas, CA; 1999 Apr.

295. Presant CA, Scolaro M, Kennedy P et al. Liposomal daunorubicin treatment of HIV-associated Kaposi's sarcoma. Lancet . 1993; 341:1242-3. [PubMed 8098393]

296. Gill PS, Wernz J, Scadden DT et al. Randomized phase III trial of liposomal daunorubicin versus doxorubicin, bleomycin, and vincristine in AIDS-related Kaposi's sarcoma. J Clin Oncol . 1996; 14:2353-64. [PubMed 8708728]

297. Schurmann D, Dormann A, Grunewald T et al. Successful treatment of AIDS-related pulmonary Kaposi's sarcoma with liposomal daunorubicin. Eur Respir J . 1994; 7:824-5. [PubMed 8005268]

298. Berry G, Billingham M, Alderman E et al. Reduced cardiotoxicity of Doxil (pegylated liposomal doxorubicin) in AIDS Kaposi's sarcoma patients compared to a matched control group of cancer patients given doxorubicin. Proc ASCO . 1996; 15:Abstract No.

299. Speth PAJ, van Hoesel QGCM, Haanen C. Clinical pharmacokinetics of doxorubicin. Clin Pharmacokinet . 1988; 15:15-31. [PubMed 3042244]

300. Epstein JB, Lozada-Nur F, McLeod WA et al. Oral Kaposi's sarcoma in acquired immunodeficiency syndrome: review of management and report of the efficacy of intralesional vinblastine. Cancer . 1989; 64:2424-30. [PubMed 2819653]

301. De Wit R, Schattenkerk JKME, Boucher CAB et al. Clinical and virological effects of high-dose recombinant interferon-α in disseminated AIDS-related Kaposi's sarcoma. Lancet . 1988; 2:1214-7. [PubMed 2903953]

302. Groopman JE, Gottlieb MS, Goodman J et al. Recombinant alpha-2 interferon therapy for Kaposi's sarcoma associated with the acquired immunodeficiency syndrome. Ann Intern Med . 1984; 100:671-6. [PubMed 6712031]

303. Mayer-da-Silva A, Stadler R, Imcke E et al. Disseminated Kaposi's sarcoma in AIDS: histogenesis-related populations and influence of long-term treatment with rIFN-αA. J Invest Dermatol . 1987; 89:618-24. [PubMed 3680987]

304. Groopman JE. Biology and therapy of epidemic Kaposi's sarcoma. Cancer . 1987; 59:633-7. [PubMed 10822462]

305. Volberding PA, Mitsuyasu R. Recombinant interferon alpha in the treatment of acquired immune deficiency syndrome—related Kaposi's sarcoma. Semin Oncol . 1985;12:2-6. [PubMed 3909416]

306. Mitsuyasu RT, Taylor JMG, Glaspy J et al. Heterogeneity of epidemic Kaposi's sarcoma: implications for therapy. Cancer . 1986; 57:1657-61. [PubMed 3081246]

307. Safai B. Pathophysiology and epidemiology of epidemic Kaposi's sarcoma. Semin Oncol . 1987; 14(Suppl 3):7-12. [PubMed 3299718]

308. Gelmann EP, Preble OT, Steis R et al. Human lymphoblastoid interferon treatment of Kaposi's sarcoma in the acquired immune deficiency syndrome: clinical response and prognostic parameters. Am J Med . 1985; 78:737-41. [PubMed 3838854]

309. Kovacs JA, Deyton L, Davey R et al. Combined zidovudine and interferon-α therapy in patients with Kaposi sarcoma and the acquired immunodeficiency syndrome (AIDS). Ann Intern Med . 1989; 111:280-7. [PubMed 2757312]

310. Krown SE, Real FX, Vadhan-Raj S et al. Kaposi's sarcoma and the acquired immune deficiency syndrome: treatment with recombinant interferon alpha and analysis of prognostic factors. Cancer . 1986; 57:1662-5. [PubMed 3081247]

311. Krown SE, Gold JWM, Niedzwiecki D et al. Interferon-α with zidovudine: safety, tolerance, and clinical and virologic effects in patients with Kaposi sarcoma associated with the acquired immunodeficiency syndrome (AIDS). Ann Intern Med . 1990; 112:812-21. [PubMed 1971504]

312. Anon. Treatment of AIDS-related Kaposi's sarcoma. Am J Hosp Pharm . 1989;46:1211. (IDIS 255633)

313. Reviewers' comments (personal observations) on interferon alfa 10:00.

314. Groopman JE, Scadden DT. Interferon therapy for Kaposi sarcoma associated with the acquired immunodeficiency syndrome (AIDS). Ann Intern Med . 1989; 110:335-7. [PubMed 2644884]

315. Rios A, Mansell P, Newell G et al. The use of lymphoblastoid interferon HuIFN alpha(Ly) and vinblastine in the treatment of acquired immunodeficiency syndrome (AIDS) related Kaposi's sarcoma (KS). Proc Am Soc Clin Oncol . 1985; 4:6.

316. Abrams DI, Volberding PA. Alpha interferon therapy of AIDS-associated Kaposi's sarcoma. Semin Oncol . 1986; XIII(Suppl 2):43-7.

317. Krown SE, Gold JW, Real FX et al. Interferon alpha-2A +/- vinblastine (VLB) in AIDS-associated Kaposi's sarcoma (KS/AIDS): therapeutic activity, toxicity and effects on HTLV-III/LAV viremia. J Interferon Res . 1986; 6(Suppl 1):3.

318. Krigel RL, Slywotzky CM, Lonberg M et al. Treatment of epidemic Kaposi's sarcoma with a combination of interferon-alfa 2_b and etoposide. J Biol Response Mod . 1988; 7:359-64. [PubMed 3049944]

319. Lonberg M, Odajnyk C, Krigel R et al. Sequential and simultaneous alpha 2 interferon (IFN) and VP16 in epidemic Kaposi's sarcoma (EKS). Proc Am Soc Clin Oncol . 1985; 4:2.

320. Kurth K, Tunn U, Ay R et al. Adjuvant chemotherapy for superficial transitional cell bladder carcinoma: long-term results of a European Organization for Research and Treatment of Cancer randomized trial comparing doxorubicin, ethoglucid and transurethral resection alone. J Urol . 1997; 158:378-84. [PubMed 9224307]

321. Fischl M, Lucas S, Gorowski E et al. Interferon alpha-N1 wellferon (WFN) in Kaposi's sarcoma: single agent or combination with vinblastine (VLB). J Interferon Res . 1986;6(Suppl 1):4.

322. Krown SE. The role of interferon in the therapy of epidemic Kaposi's sarcoma. Semin Oncol . 1987; 14(Suppl 3):27-33. [PubMed 2440110]

323. Karp JE, Groopman JE, Broder S. Cancer in AIDS. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 4th ed. Philadelphia: JB Lippincott Company; 1993:2093-2110.

324. Bu'Lock FA, Mott MG, Oakhill A et al. Early identification of anthracycline cardiomyopathy: possibilities and implications. Arch Dis Child . 1996; 75:41622.

325. Steinherz LJ, Graham T, Hurwitz R et al. Guidelines for cardiac monitoring of children during and after anthracycline therapy: report of the Cardiology Committee of the Childrens Cancer Study Group. Pediatrics . 1992; 89:942-9. [PubMed 1579408]

326. Schwartz RG, McKenzie WB, Alexander J et al. Congestive heart failure and left ventricular dysfunction complicating doxorubicin therapy: seven-year experience using serial radionuclide angiocardiography. Am J Med . 1987; 82:1109-18. [PubMed 3605130]

327. Reviewers' comments (personal observations).

328. Sequus Pharmaceuticals, Inc, Menlo Park, CA: Personal communication.

329. Pharmacia & Upjohn, Kalamazoo, MI: Personal communication.

330. Uziely B, Jeffers S, Isacson R et al. Liposomal doxorubicin: antitumor activity and unique toxicities during two complementary phase I studies. J Clin Oncol . 1995; 13:1777-85. [PubMed 7602367]

331. Gabizon A, Catane R, Uziely B et al. Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes. Cancer Res . 1994; 54:987-92. [PubMed 8313389]

332. Bladder cancer. From: CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Oct.

333. Witjes JA. Current recommendations for the management of bladder cancer: drug therapy. Drugs . 1997; 53:404-14. [PubMed 9074842]

334. Bouffioux C, van der Meijden A, Kurth KH et al. Objective response of superficial bladder tumors to intravesical treatment (including review of response of marker lesions). Prog Clin Biol Res . 1992; 378:29-42. [PubMed 1301584]

335. Akaza H, Isaka S, Koiso K et al. Comparative analysis of short-term and long-term prophylactic chemotherapy of superficial bladder cancer. Cancer Chemother Pharmacol . 1987; 20(Suppl):S91-6.

336. Scher HI, Shipley WU, Herr HW. Cancer of the bladder. In: DeVita VT Jr, Hellman S, Rosenberg SA eds. Cancer: principles and practice of oncology. 5th ed. Philadelphia: Lippincott-Raven Publishers; 1997:1300-22.

337. Lamm DL, Griffith JG. Intravesical therapy: does it affect the natural history of superficial bladder cancer? Semin Urol . 1992; 10:39-44.

338. Crawford ED, McKenzie D, Mansson W et al. Adverse reactions to the intravesical administration of doxorubicin hydrochloride: report of 6 cases. J Urol . 1986; 136:668-9. [PubMed 3735544]

339. Lamm DL. Long-term results of intravesical therapy for superficial bladder cancer. Urol Clin North Am . 1992; 19:573-80. [PubMed 1636241]

340. Kurth KH, Schroder FH, Tunn U et al. Adjuvant chemotherapy of superficial transitional cell bladder carcinoma: preliminary results of a European Organization for Research on Treatment of Cancer randomized trial comparing doxorubicin hydrochloride, ethoglucid and transurethral resection alone. J Urol . 1984; 132:258-62. [PubMed 6376827]

341. Reviewers' comments (personal observations) on bladder cancer.

342. Smith JA Jr, Labasky RF, Cockett ATK et al. Bladder cancer clinical guidelines panel summary report on the management of nonmuscle invasive bladder cancer (stages Ta, T1 and TIS). The American Urological Association. J Urol . 1999; 162:1697-701. [PubMed 10524909]

343. Ali-el-Dein B, el-Baz M, Aly ANM et al. Intravesical epirubicin versus doxorubicin for superficial bladder tumors (stages pTa and pT1): a randomized prospective study. J Urol . 1997; 158:68-74. [PubMed 9186325]

344. Raghaven D, Huben R. Management of bladder cancer. Curr Prob Cancer . 1995; 19:1-64.

345. Bouffioux C, Kurth KH, Bono A et al. Intravesical adjuvant chemotherapy for superficial transitional cell bladder carcinoma: results of 2 European Organization for Research and Treatment of Cancer randomized trials with mitomycin C and doxorubicin comparing early versus delayed instillations and short-term versus long-term treatment. J Urol . 1995; 153:934-41. [PubMed 7853578]

346. Kurth KH. Diagnosis and treatment of superficial transitional cell carcinoma of the bladder: facts and perspectives. Eur Urol . 1997; 31(Suppl 1):10-9. [PubMed 9076481]

347. Roth BJ. Chemotherapy for advanced bladder cancer. Semin Oncol . 1996; 23:633-44. [PubMed 8893874]

348. Vogelzang NJ, Moormeier JA, Awan AM et al. Methotrexate, vinblastine, doxorubicin and cisplatin followed by radiotherapy or surgery for muscle invasive bladder cancer: the University of Chicago experience. J Urol . 1993; 149:753-7. [PubMed 8455237]

349. Small cell lung cancer. From: CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Oct.

350. Singal PK, Iliskovic N. Doxorubicin-induced cardiomyopathy. N Engl J Med . 1998; 339:900-5. [PubMed 9744975]

351. Miles SA, Mitsuyasu RI, Aboulafia DM. AIDS-related malignancies. In: DeVita VT Jr, Hellman S, Rosenberg SA eds. Cancer: principles and practice of oncology. 5th ed. Philadelphia: Lippincott-Raven Publishers; 1997:2445-67.

352. Ligand Pharmaceuticals, Inc. Panretin^® (alitretinoin) gel prescribing information. San Diego, CA; 1999 Jan.

353. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD; [October 22, 1999]. From FDA web site. [Web]

354. Muggia FM, Hainsworth JD, Jeffers S et al. Phase II study of liposomal doxorubicin in refractory ovarian cancer: antitumor activity and toxicity modification by liposomal encapsulation. J Clin Oncol . 1997; 15:987-93. [PubMed 9060537]

355. Alza Pharmaceuticals, Inc. Doxil^® (doxorubicin HCl liposome injection) prescribing information. Mountain View, CA; 2000 Jul.

356. Food and Drug Administration. Labeling and prescription drug advertising; content and format for labeling for human prescription drugs. 21 CFR Parts 201 and 202. Final Rule. [Docket No. 75N-0066] Fed Regist . 1979; 44:37434-67.

357. Department of Health and Human Services, Food and Drug Administration. Subpart B—Labeling requirements for prescription drugs and/or insulin. (21 CFR Ch. 1 (4-1-87 Ed.)). 1987:18-24.

358. Gordon AN, Fleagle JT, Guthrie D et al. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol . 2001; 19:3312-22. [PubMed 11454878]

10004. Palumbo A, Avonto I, Patriarca F et al. Bortezomib, pegylated-lyposomal-doxorubicin and dexamethasone followed by melphalan 100 mg/m² in elderly new diagnosed patients: an interim analysis. Blood. 2007; 110: Abstract 448 (presented at the 49th annual ASH meeting. Atlanta, GA: 2007 Dec 10).

10005. Popat R, Oakervee H, Hallam S et al. Bortezomib, doxorubicin, and dexamethasone (PAD) front line treatment of multiple myeloma: updated results after long term follow up. Br J Haematol. 2008; 141: 512-16. [PubMed 18371113]

10023. Sonneveld P, Schmidt-Wolf IG, van der Holt B et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol . 2012; 30:2946-55. [PubMed 22802322]

10024. Jakubowiak AJ, Kendall T, Al-Zoubi A et al. Phase II trial of combination therapy with bortezomib, pegylated liposomal doxorubicin, and dexamethasone in patients with newly diagnosed myeloma. J Clin Oncol . 2009; 27:5015-22. [PubMed 19738129]

10025. Dytfeld D, Griffith KA, Friedman J et al. Superior overall survival of patients with myeloma achieving very good partial response or better to initial treatment with bortezomib, pegylated liposomal doxorubicin, and dexamethasone, predicted after two cycles by a free light chain- and M-protein-based model: extended follow-up of a phase II trial. Leuk Lymphoma . 2011; 52:1271-80. [PubMed 21699382]

10026. Berenson JR, Yellin O, Chen CS et al. A modified regimen of pegylated liposomal doxorubicin, bortezomib and dexamethasone (DVD) is effective and well tolerated for previously untreated multiple myeloma patients. Br J Haematol . 2011; 155:580-7. [PubMed 21950583]

10034. AHFS final determination of medical acceptance: Off-label use of bortezomib in combination with doxorubicin and dexamethasone as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients. Published 17 May 2018.