DOXOrubicin (Monograph)

Brand names: Adriamycin, Doxil, Rubex
Drug class: Antineoplastic Agents
VA class: AN200
CAS number: 25316-40-9

Medically reviewed by Drugs.com on Jul 27, 2023. Written by ASHP.

Warning

Severe local tissue necrosis if extravasation occurs.^b Do not administer IM or sub-Q.^b

Possible cardiotoxicity and potentially fatal CHF during or months to years after therapy; risk of developing CHF increases rapidly with increasing total cumulative dosages >450 mg/m².^b Toxicity may occur at lower cumulative dosages whether or not risk factors are present.^b (See Cardiotoxicity under Cautions.)
Probability of developing impaired myocardial function based on combined index of signs, symptoms, and decline in LVEF is estimated to be 1–2, 3–5, 5–8, or 6–20% at total cumulative dosage of 300, 400, 450, or 500 mg/m², respectively.^b
Risk factors (active or dormant cardiovascular disease, doxorubicin exposure at an early or advanced age, prior or concomitant mediastinal/pericardial irradiation, previous therapy with other anthracyclines or anthracenediones, concomitant use of other cardiotoxic agents) may increase risk of cardiotoxicity.^b
Pediatric patients are at increased risk for developing delayed cardiotoxicity.^b
Experience with liposomal doxorubicin at high cumulative dosages is too limited to have established effects on the myocardium; assume myocardial toxicity is similar to that of conventional doxorubicin formulations.^c Administer to patients with history of cardiovascular disease only when benefits outweigh risk.^c

Possible secondary AML in patients treated with anthracyclines, including doxorubicin; occurrence of refractory secondary leukemia is more common when such drugs are given in combination with other DNA-damaging antineoplastics, after extensive exposure to cytotoxic agents, or when anthracycline dosages have been escalated. (See Mutagenicity and Carcinogenicity under Cautions.)^b
Pediatric patients are at risk of developing secondary AML.^b

Infusion-related reactions (e.g., flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness of chest or throat, hypotension) reported in patients receiving liposomal doxorubicin.^c Reactions generally resolve within several hours to a day once infusion terminated; may resolve in some patients with slowing of infusion rate.^c
Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions reported; appropriate therapy and emergency equipment should be available for immediate use.^c
Administer liposomal doxorubicin at initial rate of 1 mg/minute to minimize risk of infusion reactions.^c

Severe myelosuppression may occur.^b ^c (See Hematologic Effects under Cautions.)

Reduce dosage in patients with hepatic impairment.^b ^c (See Special Populations under Dosage and Administration and also see Hepatic Impairment under Cautions.)

Accidental substitution of liposomal doxorubicin for conventional doxorubicin has resulted in severe adverse effects; do not substitute for conventional doxorubicin on a mg-per-mg basis.^c

Administer only under the supervision of qualified clinician experienced in the use of cancer chemotherapeutic agents.^b ^c

Introduction

Antineoplastic agent; anthracycline glycoside antibiotic.^a ^b ^c

Uses for DOXOrubicin

Breast Cancer

Conventional doxorubicin: Treatment (in combination with other antineoplastic agents) of breast cancer.^a ^b

Combination chemotherapy, as adjunct to surgery, increases disease-free (i.e., decreased recurrence) and overall survival in premenopausal and postmenopausal women with node-negative or -positive early (TNM stage I or II) breast cancer.²¹³ ²²¹ ²²² ²²³ ²²⁴ ²²⁵ ²²⁶ ²²⁷ ²²⁸ ²²⁹ ²³⁰ ²³¹ ²³²

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 but 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; differences in toxicity profiles may influence choice of regimen.²²¹ ²²² ²²⁴ ²²⁵ ²²⁷ ²²⁸ ²²⁹ ²³⁰

In stage III (locally advanced) breast cancer, commonly employed effective regimens (with or without hormonal therapy) used sequentially after surgery and radiation therapy for operable disease and after biopsy and radiation therapy for inoperable disease include cyclophosphamide, methotrexate, and fluorouracil; cyclophosphamide, doxorubicin, and fluorouracil; and cyclophosphamide, methotrexate, fluorouracil, and prednisone; combined cyclophosphamide and doxorubicin therapy also has been used.²¹³ ²¹⁵ ²¹⁶ ²¹⁷ ²²¹ These and other regimens have been used in treatment of more advanced (stage IV) and recurrent disease.²¹³ ²¹⁸ ²¹⁹ ²²⁰ ²²¹

AIDS-related Kaposi’s Sarcoma

Conventional doxorubicin: Has been used alone or in combination chemotherapy for the palliative treatment of AIDS-related Kaposi’s sarcoma^{† [off-label]}.²¹³ ²⁷⁶ ²⁷⁷ ²⁷⁸

Liposomal doxorubicin: Palliative treatment of AIDS-related Kaposi’s sarcoma in adults intolerant to combination chemotherapy or whose disease has progressed while receiving such therapy.²⁷³ ²⁷⁵ ²⁷⁹ ²⁸⁰ ²⁸¹ ²⁸² ²⁸³ ²⁸⁴ ²⁸⁵ ²⁸⁶ ²⁸⁷ ²⁸⁸ ²⁸⁹ ³²⁸

Combination chemotherapy that includes conventional doxorubicin (with 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.²¹³ ²⁷⁶ ²⁷⁹ ²⁸⁰ ²⁹⁶

Ovarian Cancer

Conventional doxorubicin: Has been used in treatment (in combination chemotherapy regimens) of ovarian carcinoma, but other agents currently are preferred.²⁰⁰ ²⁰⁶ ²⁰⁸ ²¹³

Liposomal doxorubicin: Palliative treatment of metastatic ovarian carcinoma that is refractory to both paclitaxel- and platinum-based chemotherapy regimens (designated an orphan drug by FDA for this use).²⁰⁶ ²¹³ ²⁷³ ³⁵⁴ ³⁵³

Further study is needed to establish role of liposomal doxorubicin in the treatment of advanced epithelial ovarian cancer.³⁵⁴

Bladder Cancer

Conventional doxorubicin: Treatment (in combination regimens with cisplatin, methotrexate, and vinblastine) of invasive and advanced bladder carcinoma.²¹³ ³³² ³³⁶ ³⁴⁷ ³⁴⁸

Has been used intravesically^{† [off-label]} for treatment of residual tumor and/or as adjuvant therapy for prophylaxis of superficial bladder carcinoma^{† [off-label]}.²¹³ ³²⁰ ³³² ³³³ ³³⁴ ³³⁵

Evidence is limited, but other agents (e.g. mitomycin, epirubicin) appear to be similar in efficacy but less toxic than doxorubicin and generally are preferred for prophylaxis or treatment of superficial bladder cancer.³⁴¹ ³⁴² ³⁴³

Small Cell Lung Cancer

Conventional doxorubicin: Treatment (in combination chemotherapy regimens) of extensive-stage small cell lung cancer^{† [off-label]}.²¹³ ³⁴⁹

Multiple Myeloma

Conventional or liposomal doxorubicin: Use with bortezomib and dexamethasone^{† [off-label]}¹⁰⁰²³ ¹⁰⁰²⁴ ¹⁰⁰²⁵ may be considered a reasonable choice (accepted, with possible conditions) as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients^† (see Dosage under Dosage and Administration);¹⁰⁰³⁴ however, in the absence of longer follow-up data, use of a modified bortezomib-liposomal doxorubicin-dexamethasone^† regimen using reduced liposomal doxorubicin and bortezomib dosages¹⁰⁰²⁶ is not fully established because of unclear risk/benefit and/or inadequate experience.¹⁰⁰³⁴ Consider performance status and preexisting conditions (e.g., peripheral neuropathy) when selecting a combination chemotherapy regimen.¹⁰⁰³⁴

Conventional doxorubicin: Used in combination therapy (with vincristine and high-dose dexamethasone) for refractory multiple myeloma^†.²⁰² ²⁰³ ²¹³ ²¹⁴

Other Uses

Conventional doxorubicin: Treatment of solid tumors including thyroid carcinoma, gastric carcinoma, soft-tissue and osteogenic sarcomas, neuroblastoma, and Wilms' tumor; malignant lymphomas of both Hodgkin and non-Hodgkin type; and acute lymphocytic (lymphoblastic) leukemia.²⁰⁰ ²⁰⁸

Conventional doxorubicin: Treatment of carcinoid tumors^†, hepatoblastoma^†, and retinoblastoma^†.^d

Conventional doxorubicin: Treatment of Ewing’s sarcoma^†,²¹³ squamous cell carcinoma of the cervix^†²¹³ and prostate^†,²¹³ and uterine cancer^†.^a

Although conventional doxorubicin is labeled for use in the treatment of AML,²⁰⁰ ²⁰⁸ other agents are preferred.²¹³

DOXOrubicin Dosage and Administration

General

Consult specialized references for procedures for proper handling and disposal of antineoplastics.^b

Optimize results and minimize adverse effects by basing dose on clinical, cardiac, hepatic, renal, and hematologic response, patient tolerance, and other chemotherapy or irradiation being used.^a

Consider pretreatment with or concomitant use of antiemetic therapy for management of nausea and vomiting.²⁷³ ^a ^b

Administration

IV Administration

Administer IV.^b ^c Must not administer IM or sub-Q.^b ^c

Avoid extravasation; extremely irritating to tissues.^a ^b ^c Stinging or burning during IV administration may be a symptom, but extravasation may occur without these symptoms and even when blood returns well during initial aspiration of infusion needle.^a ^b ^c If manifestations of extravasation occur, immediately stop infusion and restart at another site.^a ^b ^c Because of progressive nature of extravasation reactions, frequently examine affected area and consult specialist in plastic surgery.^a ^b ^c Blistering, ulceration, and/or persistent pain are indications for wide excision surgery, followed by split-thickness skin grafting.^b (See Local Effects under Cautions.)

Prepare and handle cautiously to avoid adverse local dermatologic reactions.^a Use of goggles, latex gloves, and protective gowns is recommended during preparation and administration.^a ^b If skin or mucosal contact occurs, immediately wash affected area(s) thoroughly.^a

Conventional Doxorubicin Hydrochloride

Administer commercially available or reconstituted solution slowly into 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.^b

When possible, do not use veins over joints or in extremities with compromised venous or lymphatic drainage.^b

If sub-Q extravasation occurs or is suspected, application of ice to site for 15 minutes 4 times daily for 3 days may be useful.^b Local infiltration with parenteral corticosteroid and irrigation of site with copious amounts of sterile 0.9% sodium chloride solution reported to decrease local reaction;^a benefit of local administration of drugs not clearly established.^b

Liposomal Doxorubicin Hydrochloride

Administer by IV infusion; do not administer by rapid IV injection or as an undiluted solution.²⁷³ Do not use inline filters.²⁷³

If extravasation occurs, application of ice packs over site for about 30 minutes may help alleviate local reaction.²⁷³

Reconstitution of Conventional Doxorubicin Hydrochloride

Withdraw an appropriate volume of air from vial during reconstitution to avoid excessive pressure build-up.^b

Add 5, 10, 25, 50, or 75 mL of 0.9% sodium chloride injection to vial containing 10, 20, 50, 100, or 150 mg of doxorubicin hydrochloride as lyophilized powder, respectively.²⁰⁰ ²⁰⁸ Shake vial and allow contents to dissolve; resultant solution contains 2 mg/mL.^b

Do not use diluents containing preservatives.^b

To avoid potential risks associated with reconstitution of the powder, commercially available injection can be used; however, handling of solution is not without risk.^a

Dilution of Liposomal Doxorubicin Hydrochloride

Dilute appropriate dose (maximum 90 mg) in 250 mL of 5% dextrose injection; observe strict aseptic technique since formulation does not contain any preservative or bacteriostatic agent.²⁷³

Do not use diluents containing preservatives.²⁷³

Rate of Administration of Conventional Doxorubicin Hydrochloride

Rate of injection depends on size of vein and dose, but do not administer faster than over 3–5 minutes; local erythematous streaking along vein and/or facial flushing may indicate that administration rate is too rapid.^a ^b

Rate of Administration of Liposomal Doxorubicin Hydrochloride

In patients receiving the drug for AIDS-related Kaposi's sarcoma, administer diluted solution by IV infusion over 30 minutes.²⁷³

In patients receiving the drug for ovarian cancer, administer diluted solution by IV infusion at initial rate of 1 mg/minute; if no infusion-related reactions occur, may increase rate to complete administration of infusion over 1 hour.²⁷³

If infusion reactions (flushing, shortness of breath, facial edema, headache, chills, back pain, tightness of chest or throat, and/or hypotension) occur, slow rate or stop infusion.²⁷³

Dosage

Available as conventional (nonencapsulated) doxorubicin hydrochloride and PEG-stabilized liposomal doxorubicin hydrochloride; dosage expressed in terms of the salt.^b ^c

Do not substitute liposomal doxorubicin hydrochloride for conventional doxorubicin hydrochloride; the drugs are not equivalent on a mg-per-mg basis.²⁷³ Accidental substitution may result in severe adverse effects.²⁷³

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.^a ^b

Dosage is based indirectly on body weight; if patient has abnormal fluid retention, use ideal body weight to calculate body surface area.^a

Pediatric Patients

Conventional Doxorubicin Hydrochloride

IV

Consult published protocols for dosages in combination regimens and methods and sequence of administration.^a

Adults

Conventional Doxorubicin Hydrochloride

IV

Usual dosage when used as a single agent is 60–75 mg/m², given as a single dose at 21-day intervals; consider the lower dose for patients with poor performance status, inadequate bone marrow reserves secondary to old age, prior therapy, or marrow infiltration with malignant cells.^a ^b

Alternatively, may use 20 mg/m² once weekly (this dosage schedule reported to produce a lower incidence of CHF).^a

30 mg/m² daily on 3 successive days every 4 weeks also has been used (this dosage schedule usually associated with higher incidence of stomatitis).^a

In combination with other chemotherapy, dosage of 40–60 mg/m², given as a single dose and repeated at 21- to 28-day intervals, is commonly used.²⁰⁰ ^b

In combination with bortezomib and dexamethasone^† as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients^†, 9 mg/m² per day 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

Consult published protocols for dosages in combination regimens and methods and sequence of administration.^a

Liposomal Doxorubicin Hydrochloride

AIDS-related Kaposi's Sarcoma

20 mg/m² by IV infusion once every 3 weeks.²⁷³ ²⁷⁹

Duration of therapy depends on patient response and tolerance.²⁷³ ²⁷⁹

Ovarian Cancer

50 mg/m² by IV infusion every 4 weeks.²⁷³

In patients without disease progression or intolerable toxicity, minimum of 4 courses is recommended (since median time to response in clinical trials for metastatic ovarian cancer was approximately 4 months).²⁷³

Multiple Myeloma

In combination with bortezomib and dexamethasone^† as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients^†, 30 mg/m² administered 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, liposomal doxorubicin hydrochloride and bortezomib (same dosages as in cycle 1) administered with dexamethasone 20 mg orally daily.¹⁰⁰²⁴ Treatment cycles repeated every 3 weeks for a total of 6 cycles.¹⁰⁰²⁴

Dosage Modification for Toxicity

Management of certain adverse effects may require dosage reduction and/or delay of doses.²⁷³ Manufacturer recommends the following dosage modifications based on drug-induced adverse effects.²⁷³ For further information on reduced dosage of Doxil (liposomal doxorubicin hydrochloride) based on drug-induced adverse effects, consult the manufacturer at (415) 617-3078.

Table 1. Dosage Modification of Liposomal Doxorubicin Hydrochloride for Palmar-Plantar Erythrodysesthesia
Toxicity Grade	Symptoms	Dose Modification
0	No symptoms	None
1	Mild erythema, swelling, or desquamation not interfering with daily activities	Redose unless patient has experienced previous grade 3 or 4 skin toxicity, in which case delay dose up to 2 weeks and decrease dose by 25%; then return to original dose interval
2	Erythema, desquamation, or swelling interfering with, but not precluding, normal physical activities; small blisters or ulcerations <2 cm in diameter	Delay dosing up to 2 weeks or until toxicity has resolved to grade 0–1; if no resolution after 2 weeks, discontinue liposomal doxorubicin
3	Blistering, ulceration, or swelling interfering with walking or normal daily activities; cannot wear regular clothing	Delay dosing up to 2 weeks or until toxicity resolved to grade 0–1, then decrease dose by 25% and return to original dose interval; if no resolution after 2 weeks, discontinue liposomal doxorubicin
4	Diffuse or local process causing infectious complications, or a bedridden state or hospitalization	Delay dosing up to 2 weeks or until toxicity resolved to grade 0–1, then decrease dose by 25% and return to original dose interval; if no resolution after 2 weeks, discontinue liposomal doxorubicin

Table 2. Dosage Modification of Liposomal Doxorubicin Hydrochloride for Hematologic Toxicity
Toxicity Grade	ANC (per mm³)	Platelets (per mm³)	Dose Modification
1	1500–1900	75,000–150,000	None
2	1000–1499	50,000–74,999	Wait until ANC ≥1500 and platelets ≥75,000, then redose with no dose reduction
3	500–999	25,000–49,999	Wait until ANC ≥1500 and platelets ≥75,000, then redose with no dose reduction
4	<500	<25,000	Wait until ANC ≥1500 and platelets ≥75,000, then decrease dose by 25% or continue full dose with cytokine support

Table 3. Dosage Modification of Liposomal Doxorubicin Hydrochloride for Stomatitis
Toxicity Grade	Symptoms	Dose Modification
1	Painless ulcers, erythema, or mild soreness	Redose unless patient has experienced previous grade 3 or 4 toxicity, in which case delay up to 2 weeks and decrease dose by 25%, returning to original dose interval
2	Painful erythema, edema, or ulcers, but can eat	Delay dosing up to 2 weeks or until resolved to grade 0–1; if no improvement after 2 weeks, discontinue liposomal doxorubicin
3	Painful erythema, edema, or ulcers, and cannot eat	Delay dosing up to 2 weeks or until resolved to grade 0–1, then decrease dose by 25% and return to original dose interval; if no improvement after 2 weeks, discontinue liposomal doxorubicin
4	Requires parenteral or enteral support	Delay dosing up to 2 weeks or until resolved to grade 0–1, then decrease dose by 25% and return to original dose interval; if no improvement after 2 weeks, discontinue liposomal doxorubicin

Prescribing Limits

Adults

IV

Risk of developing CHF increases rapidly with increasing total cumulative dosages >450 mg/m².^b

Previously recommended that total cumulative dose of doxorubicin hydrochloride not exceed 550 mg/m² because of risk of potentially irreversible cardiotoxicity, but higher cumulative doses may be tolerated, particularly when dexrazoxane (Zinecard) is used concomitantly as a cardioprotectant.²²¹ ²³³ ²³⁴ ²³⁵ ²³⁶ ²⁴¹ ²⁴²

It has been suggested that total cumulative dose not exceed 400 mg/m² if previous or concomitant therapy includes use of related tetracyclic compounds (e.g., daunorubicin), cyclophosphamide, or irradiation of cardiac region; some evidence suggests that higher cumulative doses may be tolerated if cardioprotection with dexrazoxane is employed.^a

Special Populations

Hepatic Impairment

Conventional or Liposomal Doxorubicin Hydrochloride

In patients with serum bilirubin concentrations of 1.2–3 mg/dL, administer 50% of usual dose; in those with serum bilirubin concentrations ≥3 mg/dL, administer 25% of usual dose.²⁷³ ^b ^c

Cautions for DOXOrubicin

Contraindications

Usual precautions and contraindications of doxorubicin apply to both conventional and PEG-stabilized liposomal formulations.^a

Marked myelosuppression induced by previous treatment with other antineoplastic agents or radiation therapy.^b
Previous treatment with complete cumulative dosages of doxorubicin, daunorubicin, idarubicin, and/or other anthracyclines and anthracenes.^b

Known hypersensitivity to conventional doxorubicin preparations or any ingredient in the liposomal formulation.²⁷³
Nursing women.²⁷³

Warnings/Precautions

Warnings

Cardiotoxicity

Irreversible myocardial toxicity, including life-threatening or fatal CHF, may occur during therapy or months to years after termination of therapy.^b Risk of developing CHF increases rapidly with increasing total cumulative dosages ≥450 mg/m².^b

Probability of developing impaired myocardial function based on combined index of signs, symptoms, and decline in LVEF is estimated to be 1–2, 3–5, 5–8, or 6–20% at a total cumulative dosage of 300, 400, 450, or 500 mg/m², respectively, in schedules of rapid IV doses given once every 3 weeks.²⁰⁰ ^b

Active or dormant cardiovascular disease, doxorubicin exposure at an early or advanced age, prior or concomitant mediastinal/pericardial irradiation, previous therapy with other anthracyclines or anthracenediones, or concomitant use of other cardiotoxic agents may increase risk of cardiotoxicity; toxicity may occur at lower cumulative dosages whether or not these risk factors are present.^b

Total dosage administered to patient should take into account previous or concomitant therapy with related agents (e.g., daunorubicin, idarubicin, mitoxantrone).^b

Pediatric patients are at increased risk for developing delayed cardiotoxicity; doxorubicin-induced cardiomyopathy impairs myocardial growth as pediatric patients mature, leading to possible development of CHF during early adulthood.^b

Early recognition of drug-induced cardiac failure appears essential for successful treatment with digoxin, diuretics, afterload reducers (e.g., ACE inhibitors), sodium restriction, and rest.^a ^b Such interventions may relieve symptoms and improve functional status.^b

Perform cardiac evaluation (with ECG, LVEF, and/or echocardiogram [ECHO]) prior to initiation and subsequently prior to each dose or course of therapy after a total cumulative dosage of 400 mg/m²; ²⁰⁰ such evaluation is particularly important in patients with preexisting risk factors for cardiotoxicity.²⁰⁰

Continue periodic monitoring of cardiac function with evaluation of ejection fraction throughout the patient’s lifetime, since cardiotoxicity may develop long after discontinuance of therapy.³⁵⁰

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

Acute life-threatening arrhythmias reported during or within a few hours after administration.^b

Hematologic Effects

High incidence of bone marrow suppression, manifested predominantly as leukopenia (principally granulocytopenia); severity depends on dose of drug and on regenerative capacity of bone marrow.^a ^b Anticipate leukocyte counts as low as 1000/mm³, although severe myelosuppression can occur.²⁰⁰ Thrombocytopenia and anemia may also occur.^a Maximum leukopenia, thrombocytopenia, and anemia generally occur during second week (nadir at 10–14 days) after administration and generally return to normal by third week.^a ^b

Dosage reduction or temporary suspension or discontinuance of therapy may be required.^a Persistent, severe myelosuppression may result in superinfection or hemorrhage.²⁷³ Deaths from septicemia have been associated with severe leukopenia.^a

Contraindicated in patients with marked preexisting myelosuppression.^a ^b

Careful hematologic monitoring required; perform leukocyte, erythrocyte, and platelet counts prior to and at frequent intervals during therapy.^a ^b If profound drop in blood cell count occurs, closely observe patient and initiate anti-infective therapy if signs of infection appear; suspension of therapy may be necessary.^a

Platelet and leukocyte transfusions have proved beneficial in patients with severe bone marrow depression; may also consider use of hematopoietic agents (colony-stimulating factors).^a

Principal dose-limiting toxicity in patients with AIDS-related Kaposi’s sarcoma receiving liposomal doxorubicin is myelosuppression, commonly manifested as leukopenia and neutropenia; anemia and thrombocytopenia also occur frequently.²⁷³ Occasionally may require dose reduction or delay or suspension of therapy.²⁷³ Neutropenic sepsis rarely has resulted in death.²⁷³

In patients with ovarian cancer, myelosuppression associated with liposomal doxorubicin generally is moderate and reversible.²⁷³ Anemia²⁷³ occurred most commonly;²⁷³ neutropenia,²⁷³ leukopenia,²⁷³ and thrombocytopenia²⁷³ also occurred.²⁷³

Toxicity Potentiation with Concomitant Therapy

May potentiate toxicity of other antineoplastic agents.^b

Concomitant or previous administration with cyclophosphamide, irradiation of the cardiac region, daunorubicin, idarubicin, or mitoxantrone may potentiate cardiotoxic effects of doxorubicin; reduce maximum cumulative doxorubicin dosage.^a

Combined therapy with other myelosuppressive agents may increase severity of hematologic toxicity.^a

Exacerbation of cyclophosphamide-induced hemorrhagic cystitis and enhancement of hepatotoxicity of mercaptopurine reported.^b ^c

Doxorubicin reportedly increases radiation-induced toxicity to myocardium, mucosae, skin, and liver.^b ^c Pediatric patients receiving concomitant doxorubicin and dactinomycin have manifested acute “recall” pneumonitis at variable times after local radiation therapy.^b

Latent effects of previous irradiation reactivated in some patients, producing erythema with vesiculation, nonpitting edema, severe pain, and moist desquamation in sites previously subjected to radiation therapy which had subsequently returned to normal appearance; occurs from 4–7 days after each doxorubicin dose is administered and lasts an average of 7 days thereafter.^a

Necrotizing colitis manifested by typhilitis (cecal inflammation), bloody stools, and severe and sometimes fatal infections, have been associated with combination of doxorubicin (given IV push daily for 3 days) and cytarabine (given by continuous IV infusion daily for ≥7 days).^b

Seizures and/or coma have occurred in patients receiving doxorubicin and vincristine concomitantly.²⁰⁰ Seizures also reported in a patient receiving doxorubicin at 2–3 times the approved dosage in combination with high-dose cyclophosphamide.²⁰⁸

Palmar-Plantar Erythrodysesthesia (PPE)

PPE, characterized by swelling, pain, erythema, and occasionally desquamation of hands and feet, reported in patients receiving liposomal doxorubicin; generally developed after 2 or 3 cycles (i.e., ≥6 weeks) of therapy, but occasionally occurred sooner.²⁷³

PPE generally is mild and resolves within 1–2 weeks; prolonged delay of therapy usually is not needed, but dose modification may be necessary (see Table 1: Dosage Modification for Palmar-Plantar Erythrodysesthesia under Dosage and Administration); discontinuance may be required in some patients because of severe and debilitating effects.²⁷³

Local Effects

Extravasation produces severe local tissue necrosis; cellulitis, vesication, thrombophlebitis, lymphangitis, or painful induration possible.^a ^b May result in limitation of mobility of adjacent joints.^a

Erythematous streaking along vein proximal to injection site reported.^a Phlebosclerosis may occur, especially when drug is administered into small vein or repeatedly into a single vein.^a

Animal evidence suggests that lesions associated with extravasation of liposomal doxorubicin may be minor and reversible compared with the more severe and irreversible lesions associated with conventional doxorubicin; however, consider liposomal doxorubicin an irritant and follow usual precautions to avoid extravasation.²⁷³ (See IV Administration under Dosage and Administration.)

Infusion-related Effects

Acute infusion-related reactions (flushing, shortness of breath, facial edema, headache, chills, back pain, tightness of the chest and throat, and/or hypotension) reported in patients receiving liposomal doxorubicin; attributed to liposomes or one of their surface components.²⁷³ ³³⁰ Similar reactions not reported with conventional doxorubicin.²⁷³

Reactions typically occur during first infusion and usually resolve over several hours to a day once infusion is stopped; occasionally may resolve simply by slowing infusion rate.²⁷³ Minimize risk by infusing at initial rate of 1 mg/minute.²⁷³

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm;²⁷³ embryotoxic, teratogenic, and abortifacient in animals.^b Avoid pregnancy during therapy.^b If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.^b

Sensitivity Reactions

Hypersensitivity Reactions

Fever,²⁰⁰ chills,²⁰⁰ and urticaria²⁰⁰ reported occasionally; anaphylaxis²⁰⁰ may occur. Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions reported with liposomal doxorubicin; appropriate therapy and emergency equipment should be available for immediate use.^c

General Precautions

Usual precautions of doxorubicin apply to conventional and PEG-stabilized liposomal formulations.^a

Adequate Patient Evaluation and Monitoring

Therapeutic response is not likely to occur without some evidence of toxicity (e.g., effects on bone marrow, GI and oral mucosa, hair follicles).^a Consider possible synergism of therapeutic response and toxicity with other antineoplastic agents used in concomitant chemotherapy.^a (See Toxicity Potentiation with Concomitant Therapy under Cautions.)

Administer only under constant supervision of qualified clinician experienced in cancer chemotherapy.^a ^b Hospitalize patient during initial phase of treatment; if feasible, perform subsequent therapy and patient evaluation on outpatient basis.^a ^b

Evaluate hepatic, hematopoietic, and cardiac function prior to and at regular intervals during therapy.^b

Tumor Lysis Syndrome

Tumor lysis syndrome and hyperuricemia may result from extensive purine catabolism accompanying rapid cellular destruction; monitor serum uric acid concentration.^a ^b Minimize or prevent by adequate hydration, alkalinization of the urine, and/or administration of allopurinol.^b

Mutagenicity and Carcinogenicity

Mutagenic and carcinogenic in experimental models.^b

Treatment-related AML reported in patients receiving doxorubicin-containing adjuvant chemotherapy regimens.^b Risk of developing secondary AML and other neoplasms is increased in pediatric patients receiving doxorubicin or other topoisomerase II inhibitors; extent of increased risk with doxorubicin not fully established.^b

In clinical trials of breast cancer patients receiving doxorubicin-containing regimens, estimated risk of developing treatment-related leukemia at 10 years was 2.5 or 0.5% in patients receiving radiation therapy plus chemotherapy or chemotherapy alone, respectively.^b

No evidence of mutagenic potential observed in tests with Stealth liposomes devoid of doxorubicin hydrochloride.²⁷³

Specific Populations

Pregnancy

Category D.^b ^c (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Conventional doxorubicin and its major metabolite (doxorubicinol) are distributed into milk;²⁰⁰ ²⁰¹ not known whether liposomal doxorubicin is distributed into milk.^b ²⁷³ Discontinue nursing because of potential risk to nursing infants.^b ²⁷³

Pediatric Use

Increased risk of developing delayed cardiotoxicity;²⁰⁰ periodic long-term follow-up cardiac evaluations recommended.²⁰⁰ (See Cardiotoxicity under Cautions.)

May contribute to prepubertal growth failure when administered as a component of intensive chemotherapy regimens;²⁰⁰ gonadal impairment (usually reversible) may occur.²⁰⁰

Safety and efficacy of liposomal doxorubicin not established in children.²⁷³

Geriatric Use

No substantial differences relative to younger adults observed during clinical trials with liposomal doxorubicin, but increased sensitivity cannot be ruled out; insufficient data for a comparative evaluation of efficacy according to age.²⁷³

Hepatic Impairment

Possible increased toxicity if given at usual recommended dosages; reduction of conventional doxorubicin dosage is recommended.^b ²⁷³ (See Hepatic Impairment under Dosage and Administration.) Perform liver function tests (e.g., AST, ALT, alkaline phosphatase, bilirubin) prior to individual dosing.^b ²⁷³

Limited experience with liposomal doxorubicin in patients with hepatic impairment; reduce dosage based on experience with conventional doxorubicin.²⁷³

Common Adverse Effects

Conventional doxorubicin: Alopecia, nausea, vomiting, mucositis, myelosuppression.^b

Liposomal doxorubicin: Myelosuppression (neutropenia, anemia, thrombocytopenia), palmer-plantar erythrodysesthesia, stomatitis, nausea, asthenia, vomiting, rash, alopecia, constipation, anorexia, mucous membrane disorder, diarrhea, abdominal pain, paresthesia, pain, fever, pharyngitis, dry skin, headache.^c

Drug Interactions

No formal drug interaction studies conducted with liposomal doxorubicin to date; pending further accumulation of data, consider drugs known to interact with conventional doxorubicin to also interact with the liposomal formulation.²⁷³ ^c

Specific Drugs

Drug	Interaction
Antineoplastic agents	Possible potentiation of toxicities associated with doxorubicin and/or other antineoplastic agents^b (see Toxicity Potentiation with Concomitant Therapy under Cautions)
Antiviral agents	Most patients receiving liposomal doxorubicin to date received antiviral therapy concomitantly, but potential for interaction not evaluated²⁷³ ^c
Calcium-channel blocking agents (e.g., verapamil)	Possible increased risk of doxorubicin-induced cardiotoxicity²⁰⁰ ^b
Cyclosporine	Possible increased AUCs of doxorubicin and doxorubicinol, possibly due to decreased doxorubicin clearance and decreased metabolism of doxorubicinol²⁰⁰ Potential for more severe and prolonged hematologic toxicity²⁰⁰ Seizures and/or coma reported²⁰⁰
Paclitaxel	Administration sequence of paclitaxel followed by doxorubicin resulted in substantially decreased doxorubicin clearance, with more profound neutropenia and stomatitis, than did the reverse sequence of administration^b
Phenobarbital	Increased elimination of doxorubicin²⁰⁰
Phenytoin	Decreased serum phenytoin concentrations²⁰⁰
Progesterone	Enhanced doxorubicin-induced neutropenia and thrombocytopenia reported²⁰⁰
Streptozocin	Possible inhibition of doxorubicin metabolism²⁰⁰
Vaccines, live	Potentially hazardous in immunosuppressed patients, including those undergoing cytotoxic chemotherapy^b

DOXOrubicin Pharmacokinetics

Encapsulation in PEG-stabilized (Stealth) liposomes substantially alters pharmacokinetics relative to conventional IV formulations, with resultant decreased distribution into peripheral compartment, increased distribution into Kaposi's lesions, and decreased plasma clearance.²⁷³ ²⁸³ ²⁸⁵

Absorption

Bioavailability

Nonencapsulated doxorubicin hydrochloride is not stable in gastric acid; appears to undergo little, if any, absorption from GI tract.^a Must administer IV.^a

Distribution

Extent

Conventional doxorubicin: Widely distributed into plasma and tissues; absorbed by cells and binds to cellular components, particularly to nucleic acids.^a Does not cross blood-brain barrier or achieve measurable concentration in CSF.^a Nonencapsulated drug and its major metabolite (doxorubicinol) distribute into milk.²⁰⁰ ²⁰¹

Liposomal doxorubicin: Encapsulation in PEG-stabilized liposomes slows rate of distribution into extravascular space;²⁷³ ²⁸³ ²⁸⁵ distributes mainly into intravascular fluid.²⁷³ ²⁸³ ²⁸⁵ Exact mechanism of drug release from liposomal encapsulation is not known.²⁷³

Distribution into Kaposi's sarcoma lesions after IV administration as liposomal doxorubicin was 5.2–11.4 times greater than that after comparable IV doses of conventional doxorubicin.²⁸⁵ Liposomal doxorubicin distributes into Kaposi's sarcoma lesions to greater extent than into healthy skin.²⁷³ ²⁸³

Plasma Protein Binding

Conventional doxorubicin: Approximately 50–85%.²⁷³ ²⁸³ ²⁹⁹

Liposomal doxorubicin: Not determined.²⁷³ ²⁸³ ^c

Elimination

Metabolism

Conventional doxorubicin: Metabolized by NADPH-dependent aldoketoreductases to 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 With conventional doxorubicin, >20% of total drug in plasma is present as metabolites as soon as 5 minutes after dose, 70% in 30 minutes, 75% in 4 hours, and 90% in 24 hours.^a

Liposomal doxorubicin: Undetectable or low plasma concentrations of doxorubicinol reported after single-dose IV administration;²⁷³ ²⁸⁵ suggests that drug is not released appreciably from circulating liposomes or that some doxorubicin may be released but 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

Elimination Route

Conventional doxorubicin: Excreted predominantly in bile as unchanged drug and metabolites; about 4–5% (range: 0.7–23%) of administered dose excreted in urine after 5 days, principally as unchanged drug.^a

Half-life

Conventional doxorubicin: Nonencapsulated drug and metabolites decline in a biphasic or triphasic manner.^a In triphasic model, half-life during second phase is 16.7 hours; 31.7 hours for metabolites.^a In biphasic model, terminal half-life averages about 30 hours.²⁸⁵ ²⁹⁹

Liposomal doxorubicin: Biphasic; ²⁷³ ²⁸⁵ ³³¹ terminal half-life averages 39–55 hours.²⁷³ ²⁸³ ²⁸⁵

Special Populations

In patients with hepatic impairment, clearance is reduced and plasma concentrations of doxorubicin and its metabolites are elevated.²⁰⁰

In obese women (actual body weight >130% of ideal body weight), systemic clearance of nonencapsulated doxorubicin is reduced.²⁰⁰ Clearance is reduced without any changes in volume of distribution in obese patients compared with patients with an actual body weight <115% of ideal body weight.²⁰⁰

Limited evidence suggests that clearance of nonencapsulated doxorubicin is higher in men than in women; however, terminal elimination half-life was longer in men than women.²⁰⁰

In children >2 years of age, clearance of nonencapsulated doxorubicin was increased compared with that in adults; clearance in children <2 years of age was decreased compared with that in older children and approached range reported for adults.²⁰⁰

Stability

Storage

Parenteral

Injection (Conventional Doxorubicin Hydrochloride)

2–8°C; protect from light.²⁰⁰ ^b

Powder for Injection (Conventional Doxorubicin Hydrochloride)

15–30°C; protect from light.^b

Protect reconstituted solution from exposure to sunlight; use within 7 days (if stored at 15–30°C under normal room light) or 15 days (if stored at 2–8°C).²⁰⁰ ²⁰⁸ ^b

Injection Concentrate (Liposomal Doxorubicin Hydrochloride)

2–8°C; avoid freezing (prolonged freezing may adversely affect stability of liposomal drugs; however, freezing for <1 month does not appear to affect stability of liposomal doxorubicin hydrochloride).²⁷³ ²⁸³

Following dilution as directed, store at 2–8°C and use within 24 hours.²⁷³ ²⁸³

Compatibility

Parenteral

Conventional Doxorubicin Hydrochloride

Manufacturers state that doxorubicin hydrochloride should not be mixed with heparin or fluorouracil (precipitation reported) and do not recommend mixing with other drugs until specific compatibility data are available.^b

Solution Compatibility (for Conventional Doxorubicin Hydrochloride)HID

Compatible
Dextrose 3.3% in sodium chloride 0.3%
Dextrose 5% in water
Normosol R, pH 7.4
Ringer’s injection, lactated
Sodium chloride 0.9%

Drug Compatibility

Admixture Compatibility (for Conventional Doxorubicin Hydrochloride)HID
Compatible
Etoposide phosphate with vincristine sulfate
Ondansetron HCl
Ondansetron HCl with vincristine sulfate
Paclitaxel
Vincristine sulfate
Incompatible
Aminophylline
Diazepam
Fluorouracil
Variable
Dacarbazine with ondansetron HCl
Etoposide with vincristine sulfate
Vinblastine sulfate

Y-site Compatibility (for Conventional Doxorubicin Hydrochloride)HID
Compatible
Amifostine
Aztreonam
Bleomycin sulfate
Chlorpromazine HCl
Cimetidine HCl
Cisplatin
Cladribine
Cyclophosphamide
Dexamethasone sodium phosphate
Diphenhydramine HCl
Droperidol
Etoposide phosphate
Famotidine
Filgrastim
Fludarabine phosphate
Fluorouracil
Gemcitabine HCl
Granisetron HCl
Hydromorphone HCl
Leucovorin calcium
Linezolid
Lorazepam
Melphalan HCl
Methotrexate sodium
Methylprednisolone sodium succinate
Metoclopramide HCl
Mitomycin
Morphine sulfate
Ondansetron HCl
Oxaliplatin
Paclitaxel
Prochlorperazine edisylate
Promethazine HCl
Ranitidine HCl
Sargramostim
Sodium bicarbonate
Teniposide
Thiotepa
Topotecan HCl
Vinblastine sulfate
Vincristine sulfate
Vinorelbine tartrate
Incompatible
Allopurinol sodium
Amphotericin B cholesteryl sulfate complex
Cefepime HCl
Ganciclovir sodium
Gallium nitrate
Lansoprazole
Pemetrexed disodium
Piperacillin sodium–tazobactam sodium
Propofol
Variable
Furosemide
Heparin sodium

Liposomal Doxorubicin Hydrochloride

Manufacturer recommends that liposomal doxorubicin not be mixed with other drugs, diluents other than 5% dextrose injection, or used with any bacteriostatic agent (e.g., benzyl alcohol).^c

Drug Compatibility

Y-site Compatibility (for Liposomal Doxorubicin Hydrochloride)HID
Compatible
Acyclovir sodium
Allopurinol sodium
Aminophylline
Ampicillin sodium
Aztreonam
Bleomycin sulfate
Butorphanol tartrate
Calcium gluconate
Carboplatin
Cefazolin sodium
Cefepime HCl
Cefoxitin sodium
Ceftizoxime sodium
Ceftriaxone sodium
Chlorpromazine HCl
Cimetidine HCl
Ciprofloxacin
Cisplatin
Clindamycin phosphate
Co-trimoxazole
Cyclophosphamide
Cytarabine
Dacarbazine
Dexamethasone sodium phosphate
Diphenhydramine HCl
Dobutamine HCl
Dopamine HCl
Droperidol
Enalaprilat
Etoposide
Famotidine
Fluconazole
Fluorouracil
Furosemide
Ganciclovir sodium
Gentamicin sulfate
Granisetron HCl
Haloperidol lactate
Heparin sodium
Hydrocortisone sodium succinate
Hydromorphone HCl
Ifosfamide
Leucovorin calcium
Lorazepam
Magnesium sulfate
Mesna
Methotrexate sodium
Methylprednisolone sodium succinate
Metronidazole
Ondansetron HCl
Potassium chloride
Prochlorperazine edisylate
Ranitidine HCl
Ticarcillin disodium–clavulanate potassium
Tobramycin sulfate
Vancomycin HCl
Vinblastine sulfate
Vincristine sulfate
Vinorelbine tartrate
Zidovudine
Incompatible
Amphotericin B
Amphotericin B cholesteryl sulfate complex
Buprenorphine HCl
Ceftazidime
Docetaxel
Hydroxyzine HCl
Mannitol
Meperidine HCl
Metoclopramide HCl
Mitoxantrone HCl
Morphine sulfate
Ofloxacin
Paclitaxel
Piperacillin sodium–tazobactam sodium
Promethazine HCl
Sodium bicarbonate

Actions

Mechanism(s) of antineoplastic action not fully understood but appear to involve free radical formation secondary to metabolic activation by electron reduction, intercalation 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 apoptosis (programmed cell death) also may be involved.²⁰⁰ These and other mechanisms (chelation of metal ions to produce drug-metal complexes) may contribute to cardiotoxic effects.²³³ ²³⁴ ²³⁷ ²³⁸ ²³⁹ ²⁴⁰ ²⁴⁴ ²⁹⁹
Cytotoxicity precludes use as anti-infective agent.^a

Advice to Patients

Importance of recognizing and reporting adverse effects, including GI, dermatologic, and myelosuppressive effects (and related precautions), infectious complications, CHF symptoms, and injection site pain.^b ^c
Risk of myocardial toxicity and leukemia.^b ^c
Importance of informing caregivers of children receiving doxorubicin to take precautions (e.g., wearing latex gloves) to prevent contact with the patient’s urine and other body fluids for ≥5 days after administration.²⁰⁰ ²⁰⁸
Advise patients to expect transient red coloration of urine after administration.^b
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.^b ^c
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy.^b ^c
Importance of informing patients of other important precautionary information.^b ^c (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

DOXOrubicin Hydrochloride
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for IV use only	10 mg*	Adriamycin (preservative-free)	Bedford
			Adriamycin RDF (with methylparaben)	Pfizer
			DOXOrubicin Hydrochloride for Injection	Baxter
		20 mg*	Adriamycin (preservative-free)	Bedford
			Adriamycin RDF (with methylparaben)	Pfizer
			DOXOrubicin Hydrochloride for Injection	Bedford
		50 mg*	Adriamycin (preservative-free)	Bedford
			Adriamycin RDF (with methylparaben)	Pfizer
			DOXOrubicin Hydrochloride for Injection	Baxter
			Rubex	Bristol-Myers Squibb
		100 mg	Rubex	Bristol-Myers Squibb
		150 mg	Adriamycin RDF (with methylparaben)	Pfizer
	Injection, for IV use only	2 mg/mL (10, 20, 50, 75, 150, and 200 mg)*	Adriamycin (preservative-free)	Bedford
			Adriamycin PFS (preservative-free; available in Cytosafe and glass vials)	Pfizer
			DOXOrubicin Hydrochloride Injection (preservative-free; available in polymer vials)	Abraxis

DOXOrubicin Hydrochloride Liposomal
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection concentrate, for IV infusion only	2 mg/mL (20 and 50 mg)	Doxil	Centocor Ortho Biotech

† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.

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Mutagenicity and Carcinogenicity

Specific Populations

Pregnancy

Lactation

Pediatric Use

Geriatric Use

Hepatic Impairment

Common Adverse Effects

Drug Interactions

Specific Drugs

DOXOrubicin Pharmacokinetics

Absorption

Bioavailability

Distribution

Extent

Plasma Protein Binding

Elimination

Metabolism

Elimination Route

Half-life

Special Populations

Stability

Storage

Parenteral