Doxorubicin Side Effects
Not all side effects for doxorubicin may be reported. You should always consult a doctor or healthcare professional for medical advice. Side effects can be reported to the FDA here.
For the Consumer
Applies to doxorubicin: intravenous powder for solution, intravenous solution
Along with its needed effects, doxorubicin may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor or nurse immediately if any of the following side effects occur while taking doxorubicin:Less common
- Cough or hoarseness accompanied by fever or chills
- darkening or redness of the skin (if you recently had radiation treatment)
- fast or irregular heartbeat
- fever or chills
- joint pain
- lower back or side pain accompanied by fever or chills
- pain at the injection site
- painful or difficult urination accompanied by fever or chills
- red streaks along the injected vein
- shortness of breath
- stomach pain
- swelling of the feet and lower legs
- Black, tarry stools
- blood in the urine
- pinpoint red spots on the skin
- unusual bleeding or bruising
Some side effects of doxorubicin may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:More common
- Hair loss, thinning of hair
- nausea and vomiting
- sores in the mouth and on the lips
- Darkening of the soles, palms, or nails
After you stop using this medicine, it may still produce some side effects that need attention. During this period of time, check with your doctor immediately if you notice the following side effects:
- Fast or irregular heartbeat
- shortness of breath
- swelling of the feet and lower legs
For Healthcare Professionals
Applies to doxorubicin: compounding powder, intravenous powder for injection, intravenous solution
The risk of heart failure is significantly increased after total doses of 550 mg/m2 (350 to 400 mg/m2 if there is history of prior radiation therapy which included the heart or the area around it or use of other potentially cardiotoxic agents, such as cyclophosphamide). Doxorubicin-induced heart failure can present one month to one year or more after termination of therapy. It is increasingly common to note LATE cardiomyopathy, especially in patients who received doxorubicin as a child or adolescent. Prevention has focused on cumulative dose limitation, earlier diagnosis (radionuclide angiocardiography or echocardiography), alterations in the schedule of administration (substitution of prolonged, continuous IV infusion for bolus injection), the development of less cardiotoxic anthracyclines, and use of cardioprotectors (dexrazoxane).
Treatment of doxorubicin-induced heart failure consists of traditional therapy with rest, digitalis, diuretics, and/or angiotensin converting enzyme (ACE) inhibitors as indicated.
While there has not been a reliable marker to predict which patients will develop doxorubicin-induced heart failure, serial non-invasive testing of LV function (radionuclide angiocardiography is usually more accurate than echocardiography) is strongly recommended (ECG has limited value). Recent data suggest plasma endothelin-1 and/or atrial natriuretic peptide levels may be useful for predicting the risk of cardiotoxicity associated with this drug. Endomyocardial biopsy permits a definitive evaluation of risk, but is invasive, expensive, and potentially risky. Male sex, older age, higher dose of doxorubicin, radiotherapy, and being overweight have all reported as risk factors for the development of cardiomyopathy.
Limited animal data suggest vitamins A and E, adenosine, coenzyme Q, N-acetylcysteine, and methylene blue may reduce the incidence of doxorubicin-induced cardiotoxicity. Other animal data has suggested that suitable antagonists of calcium-dependent pore formation such as cyclosporine A or tacrolimus may improve heart tolerance to doxorubicin.
The benefits of doxorubicin must be carefully weighed against the risks in patients with a demonstrable decrease in cardiac function.
Cardiovascular side effects have included congestive heart failure due to the development of left ventricular (LV) systolic dysfunction in 1% to 2% of patients. Retrospective data have shown that the incidence of clinical heart failure in patients with preexisting LV systolic dysfunction (ejection fraction [LVEF] < 50%), who experienced a decline of 10% or more in absolute LVEF, and who received at least 450 mg/m2 cumulative dose, is approximately 16%. (Data have shown right ventricular septal wall motion may also be affected and that LV diastolic dysfunction may precede the development of doxorubicin-induced LV systolic dysfunction.)
Early effects of anthracyclines also include extremely rare cases of pericarditis-myocarditis (which can affect patients with no prior history of cardiac disease and which carries a high mortality rate of about 20%), left ventricular dysfunction (which may lead to clinically significant heart failure in patients with limited cardiac reserve), and arrhythmias, the most common of which is sinus tachycardia. Although rhythm disturbances are common after acute administration they are rarely of clinical importance. Isolated cases of symptomatic supraventricular tachycardia, heart block, and ventricular arrhythmias (some sudden and fatal) have also been reported.
The leukocyte count usually reaches a nadir at 10 to 14 days after treatment.
Severe and/or persistent myelosuppression may result in superinfection and/or hemorrhage. GCSF has been used clinically to avoid dose reductions or interruptions in dose schedules.
A single case of acute hemolytic anemia has been reported after the administration of doxorubicin to a patient with glucose-6-phosphate dehydrogenase (G6PD) deficiency. This drug generates reactive oxygen compounds and methemoglobin in normal human red blood cells (RBCs) in vitro. In RBCs deficient in G6PD doxorubicin probably poses a potent oxidant stress. Thus patients with G6PD might be susceptible to hemolysis after receiving doxorubicin.
Hematologic side effects have been reported in 60% to 80% of patients and they may be profound (depending entirely on dose). While myelosuppression can affect all cell lines, leukopenia is most common, appearing in 60% to 75% of all treated patients. Absolute white blood cell counts of less than 1,000/mm3 are not uncommon after recommended therapeutic doses.
A scalp tourniquet and/or scalp cooling may prevent doxorubicin-induced alopecia.
Dermatologic side effects have included reversible alopecia (scalp, pubis, and/or axilla). Less commonly, hyperpigmentation of nailbeds and dermal creases and oncholysis (nail loss) have been reported.
Nausea and vomiting are preventable with appropriate antiemetic therapy.
Stomatitis or other ulcerations typically occur 2 to 10 days after administration and, if severe, can be complicated by bleeding or local infection. Severe cases of colonic ulceration can be fatal.
Gastrointestinal side effects have included acute nausea and vomiting in 20% to 85% of patients. Stomatitis has been reported in up to 80% of patients, and is dose and schedule-related. Ulceration of the esophagus and the colon (particularly the cecum) have also been reported. Anorexia and diarrhea have been reported in approximately 15% of patients. Rare cases of tongue hyperpigmentation have also been associated with the use of doxorubicin.
Local side effects have included IV site problems such as phlebosclerosis (especially when a single vein and/or a small vein is used) and extravasation tissue necrosis.
Extravasation may occur with or without accompanying stinging or burning even if there is good blood return on aspiration of the infusion needle. If there are signs or symptoms of extravasation, the injection or infusion should be immediately terminated. If further therapy is necessary, an injection or infusion may be restarted in another vein and the affected area should be immediately treated. Many treatments have been proposed to slow or heal doxorubicin extravasation ulcers. The standard of care is ice packs for 24 hours for acute extravasation injury; some advocate topical application of 10% to 99% dimethyl sulfoxide (DMSO) with ice packs. However, because of the inconsistent results associated with some of these therapies and the progressive nature of extravasation reactions, plastic surgery consultation is generally recommended.
Hypersensitivity reactions have occasionally been reported, and may include fever, chills, urticaria, angioneurotic edema or anaphylaxis.
Local IV site "flares" can be confused with extravasation, but are probably due to allergy to this drug. Flare reactions were reported in 3% to 18% of patients, but are now rare since the vehicle in which doxorubicin is carried has changed. Antiemetic therapy, antihistamines, and/or corticosteroids can decrease the risk of flares.
Flare reactions may be differentiated from extravasation. Flare reactions are characterized by erythema, appear proximally along the affected vein, and typically resolve within 45 minutes. Pain, burning and adverse sequelae are infrequent or absent. Extravasation, on the other hand, appears at the injection site and resolves slowly over days to weeks. As opposed to flare reactions, pain, burning, and edema are common, and adverse sequelae are variable and may be serious.
Allergic reactions have also been reported after the intravesical administration of doxorubicin.
Renal insufficiency has been associated with doxorubicin-induced hyperuricemia (secondary to cell lysis). Adequate hydration, diuresis, and allopurinol can be preventative.
Animal data suggest that doxorubicin may cause glomerular basement membrane injury via production of reactive oxygen species. Administration of some antioxidants, however, have failed to reduce the urinary excretion of lysozyme and N-acetyl-glucosaminidase (markers of tubule injury) in treated animals.
Renal side effects have included rare cases of new or worsened renal insufficiency. A single case of rapidly progressive glomerulonephritis without evidence of a secondary cause or immunologic mechanism has been reported.
Radiation pneumonitis or esophagitis may be more likely with the combination of doxorubicin and XRT than with XRT alone. Prior XRT to the heart/mediastinum also increases the risk of doxorubicin-induced cardiomyopathy.
Endomyocardial biopsy data have demonstrated that the cellular morphological changes in patients who received doxorubicin and who were previously treated with cardiac or mediastinal XRT are markedly different and more severe than in treated patients without a history of cardiac or mediastinal XRT. Prior cardiac or mediastinal XRT appears to portend a higher risk of doxorubicin-induced cardiomyopathy.
Other side effects of doxorubicin have included the predisposition of patients who have previously received radiation therapy (XRT) to demonstrate the so-called "recall" phenomenon.
Oncologic side effects including secondary leukemia have been associated with prior exposure to doxorubicin. A single case of skin cancer that developed at the site of doxorubicin extravasation 10 years prior has also been reported.
Ocular side effects have included rare cases of conjunctivitis, periorbital edema, lacrimation, blepharospasm, keratitis, and decreased visual acuity.
Genitourinary side effects including rare cases of bladder contracture have been reported.
Musculoskeletal side effects have been extremely rare. In one case, administration of doxorubicin was associated with a clinically significant flare of ankylosing spondylitis.
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