Doxil Side Effects
Generic name: doxorubicin liposomal
Note: This document contains side effect information about doxorubicin liposomal. Some of the dosage forms listed on this page may not apply to the brand name Doxil.
Some side effects of Doxil may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.
For the Consumer
Applies to doxorubicin liposomal: intravenous dispersion
Get emergency medical help if you have any of these signs of an allergic reaction while taking doxorubicin liposomal (the active ingredient contained in Doxil) hives; difficult breathing; swelling of your face, lips, tongue, or throat.
Some side effects may occur during the injection. Tell your caregiver right away if you feel dizzy, nauseated, light-headed, sweaty, or have a headache, chest tightness, back pain, trouble breathing, or swelling in your face.
Call your doctor at once if you have:
pain, redness, swelling, blistering, or peeling skin on your hands or feet;
feeling short of breath (even with mild exertion), swelling, rapid weight gain;
fever, chills, body aches, flu symptoms;
white patches or sores inside your mouth or on your lips;
easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin; or
pale skin, feeling light-headed or short of breath, rapid heart rate, trouble concentrating.
Doxorubicin liposomal may cause your urine to turn a reddish-orange color. This side effect by itself is usually not harmful. However, call your doctor if you also have upper stomach pain, clay-colored stools, or jaundice (yellowing of your skin or the whites of your eyes).
Common side effects may include:
loss of appetite, nausea, vomiting;
constipation, diarrhea; or
temporary hair loss.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects.
For Healthcare Professionals
Applies to doxorubicin liposomal: intravenous dispersion, intravenous powder for injection
Myelosuppression, palmar-plantar erythrodysesthesia (hand-foot syndrome), stomatitis, cardiac toxicity, and infusion-related reactions are the major dose-limiting toxicities of doxorubicin liposomal (the active ingredient contained in Doxil)
The side effects listed in this section were for the most part compiled from 4 clinical trials with ovarian cancer patients (n=373) and from 4 trials with AIDS-related Kaposi's sarcoma patients (n=705). Causality was difficult for AIDS patients due to underlying disease and concurrent drug therapy.
Cardiovascular effects have been reported in 9.6% of Kaposi's sarcoma patients; 4.3% were possibly or probably related to doxorubicin liposomal (the active ingredient contained in Doxil) Nine cases of cardiomyopathy and/or congestive heart failure were reported. Seven (1%) severe events included arrhythmia, cardiomyopathy, heart failure, pericardial effusion, and tachycardia. Other cardiac side effects have included chest pain, and hypotension 1 to 5% of patients. Other reported effects have included hypertension, angina pectoris, postural hypotension, palpitations, syncope, shock, bradycardia, phlebitis, cardiomegaly, thrombophlebitis, hemorrhage, palpitation, syncope, bundle branch block, cardiac arrest, thrombosis, and ventricular arrhythmia in less than 1%.
Cardiovascular side effects of conventional doxorubicin 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 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 noninvasive 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.
Limited animal data suggest vitamins A and E, adenosine, coenzyme Q, N-acetylcysteine, and methylene blue may reduce the incidence of doxorubicin-induced cardiotoxicity.
The benefits of doxorubicin must be carefully weighed against the risks in patients with a demonstrable decrease in cardiac function.
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.
Secondary acute myelogenous leukemia has occurred in patients treated with topoisomerase II inhibitors, including anthracyclines.
Hematologic side effects include dose-dependent myelosuppression which may be profound. Anemia is most common, followed by neutropenia, leukopenia and thrombocytopenia.
Hematologic events compiled from ovarian cancer trials have included leukopenia (42.2% <4000/mm3, 8.3% <1000/mm3, 3.3% cytokine support), neutropenia (51.7% <2000/mm3, 8.3% <500/mm3, 0.3% febrile neutropenia), anemia (52.6% <10 g/dL, 25% <8 g/dL, 12.9% RBC transfusions, 2.1% epoetin alpha support), thrombocytopenia (24.2% <150,000/mm3, 1.1% < 25,000/mm3, 1.4% platelet transfusions), hypochromic anemia (<1%), ecchymosis (<1%), and petechiae (<1%).
Side effects compiled from Kaposi's sarcoma trials have included anemia (19.4%), hypochromic anemia (9.8%), thrombocytopenia (9.2%), hemolysis (1% to 5%), increased prothrombin time (1% to 5%), eosinophilia (<1%), petechiae (<1%), and decreased thromboplastin (<1%).
A scalp tourniquet and/or scalp cooling may prevent doxorubicin-induced alopecia. Doxorubicin is often avoided in diseases where the scalp would become a reservoir for disease (i.e., lymphoma or leukemia).
Dermatologic side effects compiled from clinical trials have included palmar-plantar erythrodysesthesia (hand-foot syndrome) (37% all grades, 16.4% Grade 3/4 in ovarian cancer patients), rash (15.2%), alopecia (8.9% to 12.7%), and dry skin (5.5%). Pruritus, skin discoloration, skin disorders, herpes simplex, vesiculobullous rash, maculopapular rash, exfoliative dermatitis, herpes zoster, and sweating were reported in 1% to 5%. Skin ulcers, skin ulcer, skin discoloration, cutaneous moniliasis, erythema multiforme, erythema nodosum, furunculosis, psoriasis, pustular rash, skin necrosis, urticaria, herpes simplex, contact dermatitis, fungal dermatitis, skin nodules, urticaria, and acne were reported in less than 1%.
Gastrointestinal side effects compiled from ovarian cancer trials have included stomatitis (37.4% all grades, 7.7% Grade 3/4), nausea (37.7% all grades, 4.2% Grade 3/4), vomiting (21.6%), constipation (12.7%), anorexia (11.9%), diarrhea (10%), and abdominal pain (8%). Dyspepsia, oral moniliasis, mouth ulceration, esophagitis, and dysphagia were reported in 1% to 5% of patients. Gingivitis, eructation, increased salivation, melena, gastrointestinal hemorrhage, proctitis, jaundice, ileus, periodontal abscess, flatulence, aphthous stomatitis, gastritis, glossitis, and gum hemorrhage were reported in less than 1%.
Side effects were compiled from Kaposi's sarcoma trials have included nausea (16.9%), vomiting (7.8%), diarrhea (6.8%), stomatitis (6.8%), and oral moniliasis (5.5%). Mouth ulceration, glossitis, constipation, aphthous stomatitis, anorexia, dysphagia, and abdominal pain were reported in 1% to 5%. Dyspepsia, gastritis, gingivitis, ulcerative proctitis, colitis, esophageal ulcer, esophagitis, gastrointestinal hemorrhage, oral leukoplakia, pancreatitis, ulcerative stomatitis, increased appetite, sclerosing cholangitis, tenesmus, and fecal impaction were reported in less than 1%.
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.
Hypersensitivity side effects have included acute infusion-associated reactions (flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and/or hypotension) in 5% to 10% of patients treated with doxorubicin liposomal (the active ingredient contained in Doxil) Other side effects have included unspecified allergic reactions (1% to 5%) and anaphylactoid reaction (<1%).
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. Albuminuria has been reported in 1% to 5% of Kaposi's sarcoma patients. Creatinine elevations, abnormal kidney function, hydronephrosis, hematuria, glycosuria, increased BUN, and kidney failure have been reported in less than 1%.
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.
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 conjunctivitis (less than 1% to 5%), retinitis (1% to 5%), amblyopia (<1%), blepharitis (<1%), abnormal vision (<1%), blindness (<1%), conjunctivitis (<1%), eye pain (<1%), optic neuritis (<1%), visual field defect (<1%).
Genitourinary side effects compiled from ovarian cancer trials have included urinary tract infection, leukorrhea, cystitis, nocturia, breast pain, mastitis, oliguria, vaginitis, vaginal hemorrhage, and vaginal moniliasis in less than 1%. Side effects compiled from Kaposi's sarcoma trials have included balanitis, cystitis, dysuria, and genital edema in less than 1%.
Musculoskeletal side effects have included myalgia in 1% to 5% of patients, and arthralgia, bone pain, myositis, and myasthenia in less than 1%.
Nervous system side effects have included asthenia (9.9% of Kaposi's sarcoma patients), paresthesia (7.2% of ovarian cancer patients), pain (6.9% of ovarian cancer patients), and headache (5.3%). Dizziness, emotional lability, somnolence, depression, insomnia, and anxiety were reported in 1% to 5%. Peripheral neuritis, incoordination, abnormal thinking, paresthesia, confusion, neuropathy, convulsion, hypotonia, hypertonia, acute brain syndrome, nervousness, migraine, vertigo, hypokinesia, hyperesthesia, hypesthesia, hemiplegia, neuropathy, and ataxia were reported in less than 1%.
Respiratory side effects have included pharyngitis (5.5% of ovarian cancer patients). Dyspnea, increased cough, and rhinitis were reported in 1% to 5%. Pleural effusion, asthma, hiccup, pneumothorax, bronchitis, hyperventilation, laryngitis, pneumothorax, sinusitis, voice alteration, epistaxis, and pneumonia were reported in less than 1%.
Metabolic side effects have included increased alkaline phosphatase (7.8% of Kaposi's sarcoma patients). Peripheral edema, generalized edema, dehydration, hypercalcemia, hypocalcemia, hyperglycemia, hypoglycemia, hyperkalemia, hypokalemia, hypermagnesemia, hypomagnesemia, hypernatremia, hyponatremia, weight gain, weight loss, and cachexia have been reported in less than 1% to 5%. Increased lactic dehydrogenase, dehydration, hyperlipidemia, hypolipidemia, hyperuricemia, hypophosphatemia, hypoproteinemia, ketosis, and hypochloremia have been reported in less than 1%.
Hepatic side effects compiled from clinical trials have included SGPT increase (1% to 5%) and hyperbilirubinemia (1% to 5%). SGOT elevations, cholestatic jaundice, hepatic failure, hepatitis, hepatosplenomegaly, and jaundice have been reported in less than 1%.
Side effects affecting the special senses have included taste perversion (less than 1 to 5%), parosmia (<1%), taste loss (<1%), otitis media (<1%), tinnitus (<1%) and loss of the sense of taste.
Side effects compiled from ovarian cancer trials have included mucous membrane disorder (11.6%) and fever (5.5%). Chills, infection, chest pain, back pain, enlarged abdomen, and malaise were reported in 1 to 5%. Cellulitis, ascites, flu syndrome, neck pain, moniliasis, facial edema, chills and fever, pelvic pain, and substernal chest pain were reported in less than 1%.
Side effects compiled from Kaposi's sarcoma trials have included back pain, infection, and chills in 1% to 5%. Facial edema, cellulitis, sepsis, abscess, radiation injury, flu syndrome, moniliasis, hypothermia, cryptococcosis, and ascites have been reported in less than 1%.
Local side effects have included injection site pain, injection site hemorrhage, and inflammation in less than 1% of patients.
Endocrine side effects have included diabetes mellitus in less than 1%.
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