Doxil Side Effects

Please note - some side effects for Doxil may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Doxil - for the Consumer

Doxil

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Doxil:

Constipation; diarrhea; hair loss; indigestion; loss of appetite; nausea; tiredness; weakness; weight changes.

Seek medical attention right away if any of these SEVERE side effects occur when using Doxil:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest or throat; swelling of the mouth, face, lips, or tongue); absence of menstrual cycle or menstrual changes; back pain; black, tarry stools; bluish skin or nails; calf or leg pain, swelling, redness, or tenderness; chest pain; dizziness or light-headedness; fainting; fast, slow, or irregular heartbeat; flushing; headache; loose or bloody stools; pain, redness, burning, stinging, swelling, or open sores at the injection site; rectal bleeding or irritation; redness or discharge of the eyes; redness, pain, swelling, peeling, tingling, or blistering of the palms of the hands and the soles of the feet; severe or persistent nausea; shortness of breath; sudden, unexplained weight gain; swelling of the hands, ankles, or feet; swelling or soreness of the mouth or tongue; symptoms of dehydration (eg, dry mouth or eyes, decreased urination, fast heartbeat, sluggishness, unusual thirst); symptoms of infection (eg, fever, chills, cough, sore throat, burning or painful urination); unusual bruising or bleeding; unusual tiredness or weakness; vomiting.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Doxil Side Effects - for the Professional

Doxil

Overall Adverse Reactions Profile

The following adverse reactions are discussed in more detail in other sections of the labeling.

• Cardiac Toxicity [see Warnings and Precautions (5.1)]
• Infusion reactions [see Warnings and Precautions (5.2)]
• Myelosuppression [see Warnings and Precautions (5.3)]
• Hand-Foot syndrome [see Warnings and Precautions (5.4)]

The most common adverse reactions observed with Doxil are asthenia, fatigue, fever, nausea, stomatitis, vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and neutropenia, thrombocytopenia and anemia.

The most common serious adverse reactions observed with Doxil are described in Section 6.2.

The safety data described below reflect exposure to Doxil in 1310 patients including: 239 patients with ovarian cancer, 753 patients with AIDS-related Kaposi's sarcoma and 318 patients with multiple myeloma [see Adverse Reactions in Clinical Trials (6.2)].

Adverse Reactions in Clinical Trials

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice.

The following tables present adverse reactions from clinical trials of Doxil in ovarian cancer and AIDS-Related Kaposi's sarcoma.

Patients With Ovarian Cancer

The safety data described below are from 239 patients with ovarian cancer treated with Doxil (doxorubicin HCl liposome injection) at 50 mg/m2 once every 4 weeks for a minimum of 4 courses in a randomized, multicenter, open-label study. In this study, patients received Doxil for a median number of 98.0 days (range 1–785 days). The population studied was 27–87 years of age, 91% Caucasian, 6% Black and 3% Hispanic and other.

Table 6 presents the hematologic adverse reactions from the randomized study of Doxil compared to topotecan.

Table 6: Ovarian Cancer Randomized Study Hematology Data Reported in Patients With Ovarian Cancer

	Doxil Patients (n = 239)	Topotecan Patients (n = 235)
Neutropenia
500 – <1000/mm3	19 (7.9%)	33 (14.0%)
<500/mm3	10 (4.2%)	146 (62.1%)
Anemia
6.5 – <8 g/dL	13 (5.4%)	59 (25.1%)
< 6.5 g/dL	1 (0.4%)	10 (4.3%)
Thrombocytopenia
10,000 – <50,000/mm3	3 (1.3%)	40 (17.0%)
<10,000/mm3	0 (0.0%)	40 (17.0%)

Table 7 presents a comparative profile of the non-hematologic adverse reactions from the randomized study of Doxil compared to topotecan.

Table 7: Ovarian Cancer Randomized Study

Non-Hematologic Adverse Reaction 10% or Greater	Doxil (%) treated (n = 239)		Topotecan (%) treated (n =235)
	All grades	Grades 3–4	All grades	Grades 3–4
Body as a Whole
Asthenia	40.2	7.1	51.5	8.1
Fever	21.3	0.8	30.6	5.5
Mucous Membrane Disorder	14.2	3.8	3.4	0
Back Pain	11.7	1.7	10.2	0.9
Infection	11.7	2.1	6.4	0.9
Headache	10.5	0.8	14.9	0
Digestive
Nausea	46.0	5.4	63.0	8.1
Stomatitis	41.4	8.3	15.3	0.4
Vomiting	32.6	7.9	43.8	9.8
Diarrhea	20.9	2.5	34.9	4.2
Anorexia	20.1	2.5	21.7	1.3
Dyspepsia	12.1	0.8	14.0	0
Nervous
Dizziness	4.2	0	10.2	0
Respiratory
Pharyngitis	15.9	0	17.9	0.4
Dyspnea	15.1	4.1	23.4	4.3
Cough increased	9.6	0	11.5	0
Skin and Appendages
Hand-foot syndrome	50.6	23.8	0.9	0
Rash	28.5	4.2	12.3	0.4
Alopecia	19.2	N/A	52.3	N/A

The following additional adverse reactions (not in table) were observed in patients with ovarian cancer with doses administered every four weeks.

Incidence 1% to 10%

Cardiovascular: vasodilation, tachycardia, deep thrombophlebitis, hypotension, cardiac arrest.

Digestive: oral moniliasis, mouth ulceration, esophagitis, dysphagia, rectal bleeding, ileus.

Hemic and Lymphatic: ecchymosis.

Metabolic and Nutritional: dehydration, weight loss, hyperbilirubinemia, hypokalemia, hypercalcemia, hyponatremia.

Nervous: somnolence, dizziness, depression.

Respiratory: rhinitis, pneumonia, sinusitis, epistaxis.

Skin and Appendages: pruritus, skin discoloration, vesiculobullous rash, maculopapular rash, exfoliative dermatitis, herpes zoster, dry skin, herpes simplex, fungal dermatitis, furunculosis, acne.

Special Senses: conjunctivitis, taste perversion, dry eyes.

Urinary: urinary tract infection, hematuria, vaginal moniliasis.

Patients With AIDS-Related Kaposi's Sarcoma

The safety data below is based on the experience reported in 753 patients with AIDS-related Kaposi's sarcoma enrolled in four studies. The median age of the population was 38.7 years (range 24–70 years), which was 99% male, 1% female, 88% Caucasian, 6% Hispanic, 4% Black, and 2% Asian/other/unknown. The majority of patients were treated with 20 mg/m2 of Doxil every two to three weeks. The median time on study was 127 days and ranged from 1 to 811 days. The median cumulative dose was 120 mg/m2 and ranged from 3.3 to 798.6 mg/m2. Twenty-six patients (3.0%) received cumulative doses of greater than 450 mg/m2.

Of these 753 patients, 61.2% were considered poor risk for KS tumor burden, 91.5% poor for immune system, and 46.9% for systemic illness; 36.2% were poor risk for all three categories. Patients' median CD4 count was 21.0 cells/mm3, with 50.8% of patients having less than 50 cells/mm3. The mean absolute neutrophil count at study entry was approximately 3,000 cells/mm3.

Patients received a variety of potentially myelotoxic drugs in combination with Doxil. Of the 693 patients with concomitant medication information, 58.7% were on one or more antiretroviral medications; 34.9% patients were on zidovudine (AZT), 20.8% on didanosine (ddI), 16.5% on zalcitabine (ddC), and 9.5% on stavudine (D4T). A total of 85.1% patients were on PCP prophylaxis, most (54.4%) on sulfamethoxazole/trimethoprim. Eighty-five percent of patients were receiving antifungal medications, primarily fluconazole (75.8%). Seventy-two percent of patients were receiving antivirals, 56.3% acyclovir, 29% ganciclovir, and 16% foscarnet. In addition, 47.8% patients received colony-stimulating factors (sargramostim/filgrastim) sometime during their course of treatment.

Adverse reactions led to discontinuation of treatment in 5% of patients with AIDS related Kaposi's sarcoma. Those that did so included bone marrow suppression, cardiac adverse reactions, infusion-related reactions, toxoplasmosis, HFS, pneumonia, cough/dyspnea, fatigue, optic neuritis, progression of a non-KS tumor, allergy to penicillin, and unspecified reasons.

Table 8: Hematology Data Reported in Patients With AIDS-Related Kaposi's Sarcoma

		Patients With Refractory or Intolerant AIDS-Related Kaposi's Sarcoma (n = 74)		Total Patients With AIDS-Related Kaposi's Sarcoma (n = 720)
Neutropenia
	< 1000/mm3	34	(45.9%)	352	(48.9%)
	< 500/mm3	8	(10.8%)	96	(13.3%)
Anemia
	< 10 g/dL	43	(58.1%)	399	(55.4%)
	< 8 g/dL	12	(16.2%)	131	(18.2%)
Thrombocytopenia
	< 150,000/mm3	45	(60.8%)	439	(60.9%)
	< 25,000/mm3	1	(1.4%)	30	(4.2%)

Table 9: Probably and Possibly Drug-Related Non-Hematologic Adverse Reactions Reported in ≥ 5% of Patients With AIDS-Related Kaposi's Sarcoma

Adverse Reactions	Patients With Refractory or Intolerant AIDS-Related Kaposi's Sarcoma (n = 77)		Total Patients With AIDS-Related Kaposi's Sarcoma (n = 705)
Nausea	14	(18.2%)	119	(16.9%)
Asthenia	5	(6.5%)	70	(9.9%)
Fever	6	(7.8%)	64	(9.1%)
Alopecia	7	(9.1%)	63	(8.9%)
Alkaline Phosphatase Increase	1	(1.3%)	55	(7.8%)
Vomiting	6	(7.8%)	55	(7.8%)
Diarrhea	4	(5.2%)	55	(7.8%)
Stomatitis	4	(5.2%)	48	(6.8%)
Oral Moniliasis	1	(1.3%)	39	(5.5%)

The following additional (not in table) adverse reactions were observed in patients with AIDS-related Kaposi's sarcoma.

Incidence 1% to 5%

Body as a Whole: headache, back pain, infection, allergic reaction, chills.

Cardiovascular: chest pain, hypotension, tachycardia.

Cutaneous: herpes simplex, rash, itching.

Digestive: mouth ulceration, anorexia, dysphagia.

Metabolic and Nutritional: SGPT increase, weight loss, hyperbilirubinemia.

Other: dyspnea, pneumonia, dizziness, somnolence.

Incidence Less Than 1%

Body As A Whole: sepsis, moniliasis, cryptococcosis.

Cardiovascular: thrombophlebitis, cardiomyopathy, palpitation, bundle branch block, congestive heart failure, heart arrest, thrombosis, ventricular arrhythmia.

Digestive: hepatitis.

Metabolic and Nutritional Disorders: dehydration

Respiratory: cough increase, pharyngitis.

Skin and Appendages: maculopapular rash, herpes zoster.

Special Senses: taste perversion, conjunctivitis.

Patients With Multiple Myeloma

The safety data below are from 318 patients treated with Doxil (30 mg/m2 as a 1-hr i.v. infusion) administered on day 4 following bortezomib (1.3 mg/m2 i.v. bolus on days 1, 4 , 8 and 11) every three weeks, in a randomized, open-label, multicenter study. In this study, patients in the Doxil + bortezomib combination group were treated for a median number of 138 days (range 21–410 days). The population was 28–85 years of age, 58% male, 42% female, 90% Caucasian, 6% Black, and 4% Asian and other. Table 10 lists adverse reactions reported in 10% or more of patients treated with Doxil in combination with bortezomib for multiple myeloma.

Table 10. Frequency of treatment emergent adverse reactions reported in ≥10% patients treated for multiple myeloma with Doxil in combination with bortezomib, by Severity, Body System, and MedDRA Terminology.

Adverse Reaction	Doxil + bortezomib (n=318)			Bortezomib (n=318)
	Any (%)	Grade 3	Grade 4	Any (%)	Grade 3	Grade 4
* Peripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathy peripheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS. † Rash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, exfoliative rash, and rash generalized.
Blood and lymphatic system disorders
Neutropenia	36	22	10	22	11	5
Thrombocytopenia	33	11	13	28	9	8
Anemia	25	7	2	21	8	2
General disorders and administration site conditions
Fatigue	36	6	1	28	3	0
Pyrexia	31	1	0	22	1	0
Asthenia	22	6	0	18	4	0
Gastrointestinal disorders
Nausea	48	3	0	40	1	0
Diarrhea	46	7	0	39	5	0
Vomiting	32	4	0	22	1	0
Constipation	31	1	0	31	1	0
Mucositis/Stomatitis	20	2	0	5	<1	0
Abdominal pain	11	1	0	8	1	0
Infections and infestations
Herpes zoster	11	2	0	9	2	0
Herpes simplex	10	0	0	6	1	0
Investigations
Weight decreased	12	0	0	4	0	0
Metabolism and Nutritional disorders
Anorexia	19	2	0	14	<1	0
Nervous system disorders
Peripheral Neuropathy*	42	7	<1	45	10	1
Neuralgia	17	3	0	20	4	1
Paresthesia/dysesthesia	13	<1	0	10	0	0
Respiratory, thoracic and mediastinal disorders
Cough	18	0	0	12	0	0
Skin and subcutaneous tissue disorders
Rash†	22	1	0	18	1	0
Hand-foot syndrome	19	6	0	<1	0	0

Post Marketing Experience

The following additional adverse reactions have been identified during post approval use of Doxil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Musculoskeletal and Connective Tissue Disorders: rare cases of muscle spasms.

Respiratory, Thoracic and Mediastinal Disorders: rare cases of pulmonary embolism (in some cases fatal).

Hematologic disorders: Secondary acute myelogenous leukemia with and without fatal outcome has been reported in patients whose treatment included Doxil.

Skin and subcutaneous tissue disorders: rare cases of erythema multiforme, Stevens- Johnson syndrome and toxic epidermal necrolysis have been reported.

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Side Effects by Body System - for Healthcare Professionals

General

Myelosuppression, palmar-plantar erythrodysesthesia (hand-foot syndrome), stomatitis, cardiac toxicity, and infusion-related reactions are the major dose-limiting toxicities of doxorubicin liposomal.

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

Cardiovascular effects have been reported in 9.6% of Kaposi's sarcoma patients; 4.3% were possibly or probably related to doxorubicin liposomal. 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.

Hematologic

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%).

Dermatologic

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

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

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. Other side effects have included unspecified allergic reactions (1% to 5%) and anaphylactoid reaction (<1%).

Renal

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.

Other

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

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

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

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

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

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

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

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

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%.

Other

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.

Other

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

Local side effects have included injection site pain, injection site hemorrhage, and inflammation in less than 1% of patients.

Endocrine

Endocrine side effects have included diabetes mellitus in less than 1%.

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