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adverse reactions
ADVERSE REACTIONS DaunoXome contains daunorubicin, encapsulated within a liposome. Conventional daunorubicin has acute myelosuppression as its dose limiting side effect, with the greatest effect on the granulocytic series. In addition, daunorubicin causes alopecia, and nausea and vomiting in a significant number of patients treated. Extravasation of conventional daunorubicin can cause severe local tissue necrosis. Chronic therapy at total doses above 300 mg/m 2 causes a cumulative-dose-related cardiomyopathy with congestive heart failure. Administered as DaunoXome, daunorubicin has substantially altered pharmacokinetics and some differences in toxicity. The most important acute toxicity of DaunoXome remains myelosuppression, principally of the granulocytic series, with much less marked effects on the platelets and erythroid series. In an open-label, randomized, controlled clinical trial conducted in 13 centers in the U.S.A. and Canada in advanced HIV-related Kaposi's sarcoma, two treatment regimens were compared as first line cytotoxic therapy: DaunoXome and ABV (doxorubicin (Adriamycin ® ), bleomycin, and vincristine). All drugs were administered intravenously every 2 weeks. The safety data presented below include all reported or observed adverse experiences, including those not considered to be drug related. Patients with advanced HIV-associated Kaposi's sarcoma are seriously ill due to their underlying infection and are receiving several concomitant medications including potentially toxic antiviral and antiretroviral agents. The contribution of the study drugs to the adverse experience profile is therefore difficult to establish. Table III summarizes the important safety data. TABLE III SUMMARY OF IMPORTANT SAFETY DATA DaunoXome (N = 116) % of patients ABV (N = 111) % of patients Neutropenia (< 1000 cells/mm 3 ) 36% 35% Neutropenia (< 500 cells/mm 3 ) 15% 5% Opportunistic Infections/Illnesses,% of patients 40% 27% Median time to first Opportunistic Infections/Illnesses 214 days 412 days p = 0.21 Number of cases with absolute reduction in ejection fraction of 20 – 25% The denominator is uncertain since there were several instances of missing repeat cardiac evaluations. 3 1 Number of cases removed from therapy due to cardiac causes 2 0 Alopecia All grades % of patients 8% 36% p < 0.001 Neuropathy All grades % of patients 13% 41% A triad of back pain, flushing and chest tightness was reported in 13.8% of the patients (16/116) treated with DaunoXome in the Phase III clinical trial and in 2.7% of treatment cycles (27/994). Most of the episodes were mild to moderate in severity (12% of patients and 2.5% of treatment cycles). Mild alopecia was reported in 6% of patients treated with DaunoXome and moderate alopecia in 2% of patients. Mild nausea was reported in 35% of DaunoXome patients, moderate nausea in 16% of patients and severe nausea in 3% of patients. For patients treated with DaunoXome, mild vomiting was reported in 10%, moderate in 10%, and severe in 3% of patients. Although grade 3 – 4 injection site inflammation was reported in 2 patients treated with DaunoXome, no instances of local tissue necrosis were observed with extravasation. Table IV is a listing of all the mild-moderate and severe adverse events reported on both treatment arms in Protocol 103-09 in ≥ 5% of DaunoXome patients. TABLE IV ADVERSE EXPERIENCES: PROTOCOL 103-09 DaunoXome (N = 116) ABV (N = 111) Mild Moderate Severe Mild Moderate Severe Nausea 51% 3% 45% 5% Fatigue 43% 6% 44% 7% Fever 42% 5% 49% 5% Diarrhea 34% 4% 29% 6% Cough 26% 2% 19% 0% Dyspnea 23% 3% 17% 3% Headache 22% 3% 23% 2% Allergic Reactions 21% 3% 19% 2% Abdominal Pain 20% 3% 23% 4% Anorexia 21% 2% 26% 2% Vomiting 20% 3% 26% 2% Rigors 19% 0% 23% 0% Back Pain 16% 0% 8% 0% Increased Sweating 12% 2% 12% 0% Neuropathy 12% 1% 38% 3% Rhinitis 12% 0% 6% 0% Edema 9% 2% 8% 1% Chest Pain 9% 1% 7% 0% Depression 7% 3% 6% 0% Malaise 9% 1% 11% 1% Stomatitis 9% 1% 8% 0% Alopecia 8% 0% 36% 0% Dizziness 8% 0% 9% 0% Sinusitis 8% 0% 5% 1% Arthralgia 7% 0% 6% 0% Constipation 7% 0% 18% 0% Myalgia 7% 0% 12% 0% Pruritus 7% 0% 14% 0% Insomnia 6% 0% 14% 0% Influenza-like symptoms 5% 0% 5% 0% Tenesmus 4% 1% 1% 0% Abnormal vision 3% 2% 3% 0% The following adverse events were reported in ≤ 5% of patients treated with DaunoXome, tabulated by body system. Body As A Whole: Injection site inflammation Cardiovascular: Hot flushes, hypertension, palpitation, syncope, tachycardia. In other follow-up clinical trials of DaunoXome (daunorubicin citrate liposome injection) use in treatment of Kaposi's sarcoma or other malignancies, the following serious cardiac events were reported: Pericardial effusion, pericardial tamponade, ventricular extrasystoles, cardiac arrest, sinus tachycardia, atrial fibrillation, pulmonary hypertension, myocardial infarction, supraventricular tachycardia, angina pectoris (see WARNINGS section). Digestive: Increased appetite, dysphagia, GI hemorrhage, gastritis, gingival bleeding, hemorrhoids, hepatomegaly, melena, dry mouth, tooth caries Hemic and Lymphatic: Lymphadenopathy, splenomegaly Metabolic and Nutritional: Dehydration, thirst Nervous: Amnesia, anxiety, ataxia, confusion, convulsions, emotional lability, abnormal gait, hallucination, hyperkinesia, hypertonia, meningitis, somnolence, abnormal thinking, tremor Respiratory: Hemoptysis, hiccups, pulmonary infiltration, increased sputum Skin: Folliculitis, seborrhea, dry skin Special Senses: Conjunctivitis, deafness, earache, eye pain, taste perversion, tinnitus Urogenital: Dysuria, nocturia, polyuria