You are using an outdated browser. We suggest you update your browser for a better experience. Click here for update.
Close this notification.
Skip to main content Skip to search

COVID-19: Get the latest updates or take a self-assessment.

Chemotherapy and other systemic treatment regimens may change due to COVID-19. Find out more at Systemic Treatment Regimens During COVID-19.

A - Drug Name

DOXOrubicin

COMMON TRADE NAME(S):   Adriamycin®

 
B - Mechanism of Action and Pharmacokinetics

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.



Distribution

Extensively distributed into tissues.

Cross blood brain barrier? no
PPB 50 - 85 %
Metabolism

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)
Inactive metabolites yes
Elimination

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
 
C - Indications and Status
Health Canada Approvals:

  • 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)
  • Neuroblastoma
  • Non-Hodgkin lymphoma
  • Osteogenic sarcoma
  • Gynecologic cancer/sarcoma
  • Sarcoma, soft tissue
  • Testicular cancer
  • Thyroid cancer
  • Wilms’ tumour


Other Uses:

  • Adrenocortical cancer
  • Neuroendocrine tumour
  • Hepatocellular cancer
  • Renal cell cancer
  • Multiple myeloma
  • Thymoma
  • Unknown primary tumour
  • Small cell carcinomas
  • Ewing sarcoma
 
D - Adverse Effects

Emetogenic Potential:  

Moderate (< 60 mg/m2)
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
Hand-foot syndrome E
Photosensitivity I  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
Hypersensitivity Hypersensitivity (rare) I
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
Ophthalmic Conjunctivitis (rare) E
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.

 
E - Dosing

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.)



Adults:

Intravenous:                        

  • 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

Intravesical:     

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:*

 

3-weekly regimen

Weekly regimen

Cardiac risk factors

400 mg/m2

550 mg/m2

No cardiac risk factor

550 mg/m2

700 mg/m2

*includes all anthracyclines and anthracenediones


Dosage with Toxicity:

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
Doxorubicin Dose
for Next Cycle
Febrile Neutropenia / Thrombocytopenic bleeding / ANC grade 4 ≥ 7 days
  1 dose level*
Cardiotoxicity**
Discontinue
Grade 3 related organ
1 dose level*
Grade 4 related organ
Discontinue

*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:

Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.

 

Grade Management Re-challenge
1 or 2
  • Stop or slow the infusion rate.
  • Manage the symptoms.
  • Consider pre-medications and administering at a slower infusion rate.
3 or 4
  • Stop treatment.
  • Aggressively manage symptoms.
  • Re-challenge is discouraged, especially if vital symptoms have been affected.
  • Consider desensitization if therapy is necessary.  


Dosage with Hepatic Impairment:

Doxorubicin is contraindicated in patients with severe hepatic impairment, and doses should be modified for mild-moderate impairment.

Bilirubin (µmol/L)

 

 

AST/ALT

 

% Usual Dose

1-2x ULN

 

 

50%

2-4x ULN

and/or

5-10 x ULN

25%

>4xULN

and/or

> 10 x ULN

OMIT



Dosage with Renal Impairment:

No adjustment required



Dosage in the elderly:

Use with caution.



Children:

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.



 
F - Administration Guidelines

  • 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.
 



 
G - Special Precautions
Contraindications:

  • 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

Other Warnings/Precautions:

  •  Avoid the use of live vaccines; use may result in serious infections in immunocompromised patients


Other Drug Properties:

  • Carcinogenicity: Yes

Pregnancy and Lactation:
  • Embryotoxicity: Yes
    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: Yes
    Breastfeeding is not recommended.
  • Fertility effects: Yes
    May be partially reversible.
 
H - Interactions

AGENT EFFECT MECHANISM MANAGEMENT
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
mercaptopurine ↑ hepatotoxicity Uncertain monitor
quinolones ↓ antimicrobial effects of quinolones ↓ Quinolones absorption monitor, may need to modify dose of quinolones
cytarabine typhlitis Uncertain Treat appropriately
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
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

Monitor Type Monitor Frequency

CBC

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



 
K - References

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.

 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.

CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.