Doxorubicin, an anthracycline antibiotic, damages DNA by intercalation into DNA, metal ion chelation, or by generation of free radicals. Doxorubicin has also been shown to inhibit DNA topoisomerase II which is critical to DNA function. Cytotoxic activity is cell cycle phase non-specific.
Extensively distributed into tissues.
|Cross blood brain barrier?||no|
|PPB||50 - 85 %|
Liver (major site) and other tissues. Clearance is reduced, with elevated levels of doxorubicin and its metabolites, in patients with hepatic dysfunction especially if bilirubin elevated.
|Active metabolites||Doxorubicinol (major metabolite)|
Elimination primarily via liver and biliary system. Predominantly in bile, 40-50% in feces within 7 days (50% unchanged).
Clearance is reduced in obese patients (e.g. >130% of ideal body weight).
|Urine||4-5% over 5 days.|
|Half-life||(terminal) 20-48 hours|
- Acute lymphocytic leukemia
- Acute myeloblastic leukemia
- Bladder cancer (intravenous and intravesical)
- Breast cancer
- Gastric cancer
- Head and neck cancer, squamous cell
- Hodgkin lymphoma
- Lung cancer (small cell and non-small cell)
- Non-Hodgkin lymphoma
- Osteogenic sarcoma
- Gynecologic cancer/sarcoma
- Sarcoma, soft tissue
- Testicular cancer
- Thyroid cancer
- Wilms’ tumour
- Adrenocortical cancer
- Neuroendocrine tumour
- Hepatocellular cancer
- Renal cell cancer
- Multiple myeloma
- Unknown primary tumour
- Small cell carcinomas
- Ewing sarcoma
High (≥ 60 mg/m2)
Extravasation Potential: Vesicant
Incidences below are based on various sources. Incidences reported from the doxorubicin treatment arm (70 mg/m2) in a phase III metastatic breast cancer study with anthracycline-naïve and mitoxantrone-naïve patients are marked with an asterisk (*).
|ORGAN SITE||SIDE EFFECT* (%)||ONSET**|
|Cardiovascular||Arrhythmia (<3%) (acute)||I E|
|Cardiotoxicity (<10%) * (symptomatic)||E D L|
|ECG changes (20-30%)||I E|
|Myocarditis (also pericarditis; rare)||E D|
|Venous thromboembolism (rare)||E|
|Dermatological||Alopecia (97%) * (complete in most patients)||E|
|Radiation recall reaction (rare)||I E|
|Rash (<10%) (may be severe)||E|
|Skin hyperpigmentation (also mucosa, nails; rare)||D|
|Gastrointestinal||Anorexia (30%) *||I E|
|Diarrhea (21%) * (may be severe with cytarabine)||I E|
|Mucositis (62%) * (10% severe)||E|
|Nausea, vomiting (75%) * (26% severe)||I E|
|Hematological||Myelosuppression ± infection, bleeding (86%) * (severe)||E|
|Hepatobiliary||↑ LFTs (rare; may be severe)||E|
|Infusion related reaction (doxorubicin flare - histamine release; skin rash, fever, chills)||I E|
|Injection site||Phlebitis (15%) * (chemical)||I|
|Metabolic / Endocrine||Hyperuricemia (during periods of active cell lysis)||I|
|Neoplastic||Leukemia (secondary) (3%)||L|
|Watering eyes (rare)||E|
|Urinary||Cystitis (chemical, with bladder instillation)||I E|
|Urine discoloration (red, for 1-2 days)||I|
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.
** I = immediate (onset in hours to days) E = early (days to weeks)
D = delayed (weeks to months) L = late (months to years)
The most common side effects for DOXOrubicin include alopecia, myelosuppression ± infection, bleeding, nausea/vomiting, mucositis, anorexia, diarrhea, phlebitis, and ECG changes.
Myelosuppression is the most common dose-limiting toxicity; severe and fatal infections may occur.
Anthracycline-induced cardiotoxicity may manifest either as an initial acute effect with transient sinus tachycardia and/or ECG abnormalities, or a later cumulative, dose-dependent cardiomyopathy. The acute electrocardiographic changes are usually reversible, unrelated to total dose and do not predict subsequent development of delayed cardiotoxicity.
The more serious cardiotoxicity is a dose-dependent cardiomyopathy. The onset of cardiomyopathy may be delayed, occurring 2-3 months or up to years after therapy. The incidence of drug-induced congestive heart failure at cumulative doses of 300 mg/m2 is 1-2% in contrast to 20% incidence with cumulative dose >550 mg/m2. The usual maximum cumulative dose of doxorubicin is 550 mg/m2 (q21d cycles); however, certain patients (prior mediastinal radiation, prior anthracyclines or trastuzumab, older age, active or dormant cardiovascular disease, including hypertension) are at higher risk and may develop cardiotoxicity at lower cumulative doses of doxorubicin. These patients should receive cumulative doses of doxorubicin <400mg/m2. In adults with risk factors, cardiac function monitoring (echocardiogram or MUGA scan) should be performed before treatment and periodically throughout treatment. All patients who have received total cumulative doses of 450 mg/m2 and in whom further therapy with doxorubicin is indicated should undergo cardiac assessment before continuing treatment. The risk of cardiotoxicity may be lower with weekly regimens; total cumulative doses should not exceed 700mg/m2 even with weekly regimens. Dexrazoxane may be used as a cardioprotectant in patients with advanced or metastatic cancer who are at risk of developing cardiotoxicity when receiving chemotherapy containing doxorubicin.
Children less than 15 years of age are more likely to develop CHF from cumulative doses greater than 550 mg/m2 than those patients aged 15 to 40 years.
Patients at risk of tumour lysis syndrome should have adequate prophylaxis and be monitored closely.
Erythematous streaking (a histamine release phenomena) along the vein proximal to the site of injection has been reported and usually subsides within 30 minutes. The injection may be continued, more slowly in the same site or may be changed to another site. Diphenhydramine 25 mg or hydrocortisone 100 mg, by slow IV push over 5 minutes into the IV line may hasten clearing of the reaction.
The tissue necrosis that occurs with extravasation may happen days to weeks after the treatment. Patients must be observed for delayed reactions and prior injection sites carefully inspected. Local protocols should be followed regarding management; dexrazoxane has been studied in the treatment of anthracycline extravasation (Mouridsen et al).
Doxorubicin has the potential to enhance radiation injury to tissues. The skin is the site most commonly affected, resulting in erythema followed by dry desquamation. Skin reactions generally occur only if the drug is given within 7 days of the radiation. Rarely, reactions after 30 days have been noted. Skin involvement, while unpleasant, is not as debilitating as in the case for internal organs. Enhancement of radiation injury to the esophagus and gastrointestinal tract is the most severe when the drug and the radiation are given concomitantly. Recurrent injury to a previously irradiated site may occur weeks to months following radiation.
Refer to protocol by which patient is being treated.
May need to consider lower starting doses or longer intervals between cycles for heavily pretreated patients, children, elderly, obese patients (e.g. > 130% of ideal body weight), or patients with bone marrow depression due to cytotoxic/radiation therapy, or tumour infiltration.
Patients should recover from toxicity before retreatment (i.e. stomatitis, neutropenia, thrombocytopenia, etc.)
- q1w: 10-20 mg/m2 bolus
- q3w: 60-75 mg/m2 bolus (40-60mg/m2 when used in combination)\
- q4w: 20-30 mg/m2/day bolus for 3 consecutive days
q1w: 50-80 mg via bladder instillation (in 50-100mL), retained 1-2 hours, weekly x 4 then monthly. Voided urine should be inactivated with hypochlorite solution.
Maximum lifetime dose:*
Cardiac risk factors
No cardiac risk factor
*includes all anthracyclines and anthracenediones
Modify according to protocol by which patient is being treated.
Suggested dose levels: 75, 60, 50, 40 mg/m2.
Worst Toxicity / Counts in Prior Cycle
for Next Cycle
Febrile Neutropenia / Thrombocytopenic bleeding / ANC grade 4 ≥ 7 days
↓ 1 dose level*
Grade 3 related organ
↓ 1 dose level*
Grade 4 related organ
*Do not start new cycle until organ toxicity ≤ grade 2, platelets ≥ 100 x 109/L and ANC ≥ 1.5 x 109/L
**including any signs and symptoms of heart failure, greater than 10% decline in LVEF to below the lower limit of normal, a greater than 20% decline in LVEF from any level, or LVEF ≤ 45%.
Management of Infusion-related reactions with Anthracyclines:
|1 or 2||
|3 or 4||
Doxorubicin is contraindicated in patients with severe hepatic impairment, and doses should be modified for mild-moderate impairment.
% Usual Dose
5-10 x ULN
> 10 x ULN
No adjustment required
Use with caution.
At higher risk of secondary leukemia. Children and adolescents are at an increased risk of developing delayed cardiotoxicity (up to 15 years after treatment). Females may have a higher risk than males. Increased monitoring is required.
- Slow push through sidearm of free flowing IV (5% Dextrose, Normal Saline). Depending on the dose volume and vein condition, administer the dose between 3 to 10 minutes to minimize thrombosis risk or extravasation.
- Do not admix with other drugs unless data are available; precipitates with fluorouracil and heparin.
- Avoid contact with alkaline solutions as this can lead to hydrolysis of doxorubicin.
- Slow down injection rate if erythematous streaking or facial flushing occurs.
- If any signs or symptoms of extravasation occur, the injection or infusion should be immediately terminated and restarted in another vein. Any known or suspected extravasation should be managed promptly as per local guidelines and should include application of ice to the affected area.
- Store vials under refrigeration (2 to 8ºC) and protect from light.
Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.
- Patients who have a hypersensitivity to this drug or any of its components, other anthracyclines or anthracenediones (i.e. epirubicin, daunorubicin, mitoxantrone or mitomycin C)
- Persistent myelosuppression induced by chemotherapy or radiation
- Severe hepatic impairment
- Severe myocardial insufficiency, arrhythmias or history of cardiac disease or recent myocardial infarction
- Previous treatment with maximum cumulative doses of doxorubicin, other anthracyclines or anthracenediones
- Avoid intravesicular use in patients with hematuria, urinary tract infections or bladder inflammation
- Avoid the use of live vaccines; use may result in serious infections in immunocompromised patients
Other Drug Properties:
Doxorubicin is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose (general recommendation).
Excretion into breast milk:
Breastfeeding is not recommended.
May be partially reversible.
|barbiturates||↓ therapeutic effects of doxorubicin||↑ clearance of doxorubicin||monitor if barbiturates initiated or discontinued|
|cyclophosphamide||exacerbation of cyclophosphamide-induced hemorrhagic cystitis||unknown||Caution|
|cyclophosphamide||cardiotoxicity||Additive||Caution; refer to regimen by which patient is treated|
|digoxin||↓ digoxin levels; interaction may occur several days after treatment||decreased digoxin absorption||monitor digoxin levels and patient|
|quinolones||↓ antimicrobial effects of quinolones||↓ Quinolones absorption||monitor, may need to modify dose of quinolones|
|streptozocin||↑ toxicity of doxorubicin||liver damage by streptozocin decreases metabolism of doxorubicin||Caution|
|zidovudine||↓ effect of zidovudine||doxorubicin decreases intracellular activation||Avoid|
|stavudine||↓ effect of stavudine||Inhibits stavudine phosphorylation/metabolism||Avoid|
|trastuzumab||↑ cardiotoxicity||Additive||Avoid anthracycline-based therapy for up to 28 weeks after stopping trastuzumab|
|bevacizumab||↑ cardiotoxicity effect of anthracyclines||Unknown||Avoid|
|paclitaxel followed by doxorubicin||↑ neutropenia and stomatitis||↓ doxorubicin clearance||use paclitaxel after doxorubicin|
|dactinomycin||↑ radiation recall pneumonitis||Additive effects||Caution|
|phenytoin||↓ phenytoin levels||Unknown||Caution, check levels|
|cyclosporine||↑ doxorubicin plasma level up to 55%, hematologic and neuro toxicity reported||↓ doxorubicin clearance/ metabolism||Caution; avoid if possible|
|calcium channel blockers (e.g. verapamil)||↑ cardiotoxicity||Additive||Avoid|
|high dose progesterone (e.g. up to 10 g over 24 h)||↑ hematologic toxicity||Unknown||Caution|
|sorafenib||↑ doxorubicin toxicity||↑ doxorubicin exposure (up to 47%)||Caution; combination not indicated|
|p-glycoprotein inhibitors (i.e. quinidine, verapamil, cyclosporine)||↑ doxorubicin toxicity||↑ doxorubicin exposure (up to 2x)||Caution; monitor|
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
|Monitor Type||Monitor Frequency|
|Baseline and before each dose|
Liver function tests
|Baseline and before each cycle|
Cardiac function tests (Echo, RNA and/or MUGA scans) for all patients with cardiac risk factors (including prior trastuzumab or patients at or above threshold dose levels)
|Baseline and as clinically indicated|
Clinical toxicity assessment for infection, bleeding, stomatitis, nausea, vomiting, injection site reactions, cardiac effects, dermatologic effects, hyperuricemia
|At each visit|
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
Cancer Drug Manual (the Manual), 1994, British Columbia Cancer Agency (BCCA).
Chan S, Friedrichs K, Noel D, et al. Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol 1999;17(8):2341-54.
Lexi-comp: Doxorubicin drug monograph.
McEvoy GK, editor. AHFS Drug Information 2009. Bethesda: American Society of Health-System Pharmacists, p. 1046-55.
Mouridsen HT, Langer SW, Buter J, et al. Treatment of anthracycline extravasation with Savene® (dexrazoxane): results from two prospective clinical multicentre studies. Annals of Oncology 2007; 18: 546–50.
Norris B, Pritchard KI, James K, et al. Phase III comparative study of vinorelbine combined with doxorubicin versus doxorubicin alone in disseminated metastatic/recurrent breast cancer: National Cancer Institute of Canada Clinical Trials Group Study MA8. J Clin Oncol 2000;18(12):2385-94.
Pai VB, Nahata MC. Cardiotoxicity of chemotherapeutic agents: incidence, treatment and prevention. Drug Saf 2000;22(4):263-302.
Paridaens R, Biganzoli L, Bruning P, et al. Paclitaxel versus doxorubicin as first-line single-agent chemotherapy for metastatic breast cancer: a European Organization for Research and Treatment of Cancer Randomized Study with cross-over. J Clin Oncol 2000;18(4):724-33.
Prescribing information: Adriamycin. Bedford Laboratories (US), April 2012.
Product Monograph: Doxorubicin. Pfizer Canada, June 5, 2019.
Sledge GW, Neuberg D, Bernardo P, et al. Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol 2003;21(4):588-92.
Summary of Product Characteristics: Doxorubicin. Accord Healthcare Ltd. (UK), May 2016.
van Wijk FH, Aapro MS, Bolis G, et al. Doxorubicin versus doxorubicin and cisplatin in endometrial carcinoma: definitive results of a randomised study (55872) by the EORTC Gynaecological Cancer Group. Ann Oncol 2003;14(3):441-8.
Volkova M, Russell R 3rd. Anthracycline cardiotoxicity: prevalence, pathogenesis and treatment. Curr Cardiol Rev 2011;7(4):214-20.
September 2019 Updated infusion reaction information in Dosing section.
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