Daunoxome Side Effects
Please note - some side effects for Daunoxome may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).
Side Effects of Daunoxome - for the Consumer
DaunoXome
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 DaunoXome:
Seek medical attention right away if any of these SEVERE side effects occur when using DaunoXome:Diarrhea; hair loss; loss of appetite; mouth pain; nausea; sore throat; stomach pain; tiredness; weakness.
TopSevere allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); back pain; black, tarry stools; blood in the stools; chest pain; chills; cough or sore throat; excessive bleeding; fever; flushing; irregular heartbeat; pain, redness, or swelling at the injection site; shortness of breath; sores on the mouth or lips; unusual bruising or bleeding.
Daunoxome Side Effects - for the Professional
DaunoXome
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/m2 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.
| SUMMARY OF IMPORTANT SAFETY DATA | ||
|---|---|---|
| DaunoXome (N = 116) % of patients |
ABV (N = 111) % of patients |
|
| Neutropenia (< 1000 cells/mm3) | 36% | 35% |
| Neutropenia (< 500 cells/mm3) | 15% | 5% |
| Opportunistic Infections/Illnesses,% of patients | 40% | 27% |
| Median time to first Opportunistic Infections/Illnesses | 214 days | 412 days* |
| Number of cases with absolute reduction in ejection fraction of 20 – 25%† | 3 | 1 |
| Number of cases removed from therapy due to cardiac causes† | 2 | 0 |
| Alopecia All grades % of patients |
8% | 36%‡ |
| 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.
| 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.
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
TopSide Effects by Body System
General
In general the two main dose-limiting toxicities are myelosuppression and cumulative cardiotoxicity. Acute febrile drug reactions have occurred in up to 50% of patients (probably represent reactions to histamine release), but are not generally observed with steroid and other premedications. The main metabolite, daunorubicinol, has only approximately 1/10th the toxicity of the parent compound.
Hematologic
Hematologic toxicity can be expected after therapeutic doses and is a dose-limiting toxicity of daunorubicin. Daunorubicin is a potent bone marrow suppressant, and can cause significant reductions in all bone marrow cell lines for one to two weeks after therapy. Persistent, severe myelosuppression may result in superinfection, hemorrhage, and/or death.
In a study with HIV-related Kaposi's sarcoma patients (n=116), neutropenia of 1000 cells/mm3 or less was reported in 36% of patients and neutropenia of less than 500 cells/mm3 was reported in 15%. Causality was difficult to establish due to concurrent medications and disease complications.
Cardiovascular
In one patient with Kaposi's sarcoma, congestive heart failure has been reported at a cumulative dose of 340 mg/m2. In eight Kaposi's sarcoma patients, left ventricular ejection fraction (LVEF) decreases have been reported at cumulative doses ranging from 200 mg/m2 to 2100 mg/m2 (median dose of 320 mg/m2) of daunorubicin liposomal. Congestive heart failure has been reported at a cumulative dose as low as 200 mg/m2 in clinical studies in malignancies other than Kaposi's sarcoma and treated with greater than the recommend dose of 40 mg/m2 of daunorubicin liposomal.
Patients who have received prior therapy with anthracyclines (doxorubicin >300 mg/m2 or equivalent), have preexisting cardiac disease, or have received previous radiotherapy encompassing the heart may be more susceptible to cardiac adverse events. It is recommended that monitoring of LVEF occur prior to therapy and every 160 mg/m2 for these patients.
Cardiovascular toxicity has included congestive heart failure, pericardial effusion, pericardial tamponade, ventricular extrasystoles, cardiac arrest, sinus tachycardia, atrial fibrillation, pulmonary hypertension, myocardial infarction, supraventricular tachycardia, angina pectoris, hot flushes, hypertension, palpitation, syncope, and tachycardia in 5% or fewer patients (n=116). Additionally, edema (9% mild/moderate, 2% severe) and chest pain (9% mild/moderate, 1% severe) have been reported.
Dermatologic
Dermatologic side effects have included reversible alopecia (6% mild, 2% moderate) and pruritus (7% mild/moderate). Urticaria , folliculitis, dry skin, seborrhea have been reported in 5% or fewer patients (n=116). Chemical thrombophlebitis and local necrosis have occurred in cases of extravasation.
Cases of palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome) have been reported in 2 patients receiving high dose daunorubicin liposomal therapy (100 to 125 mg/m2 daily for 3 days) in combination with cytarabine, and in one patient receiving recommended doses (40 mg/m2).
Gastrointestinal
Gastrointestinal side effects have included nausea (35% mild, 16% moderate, 3% severe), diarrhea (34% mild/moderate, 4% severe), abdominal pain (20% mild/moderate, 3% severe), vomiting (10% mild, 10% moderate, 3% severe), anorexia (21% mild/moderate, 2% severe), stomatitis (9% mild/moderate, 1% severe), constipation (7% mild/moderate), and tenesmus (4% mild/moderate, 1% severe). Increase appetite, dysphagia, GI hemorrhage, gastritis, gingival bleeding, hemorrhoids, hepatomegaly, melena, dry mouth, and tooth caries have been reported in 5% or fewer patients (n=116).
Local
Local side effects have included thrombophlebitis and necrosis following extravasation, and injection site inflammation (<=5%).
Hepatic
Hepatic serum transaminase and bilirubin concentration elevations have been transiently observed.
Renal
Renal side effects have rarely included new or worsened renal insufficiency, probably associated with hyperuricemia and/or dehydration.
Other
Back pain, flushing, and chest tightness (generally occurring during the first five minutes of therapy) have been reported in 13.8% of patients treated in Phase III clinical trials and in 2.7% of treatment cycles.
One case report describes chest and back pain in a patient receiving a 6-hour infusion of high dose daunorubicin liposomal (125 mg/m2).
Immunologic
Immunologic side effects have included reports of opportunistic infections in 40% of patients with HIV-related Kaposi's sarcoma (n=116). The median time to the first opportunistic illness was 214 days. Causality was difficult to determine due to disease complications and multiple concurrent medications.
Nervous system
Nervous system side effects have included fatigue (43% mild/moderate, 6% severe), headache (22% mild/moderate, 3% severe), neuropathy (12% mild/moderate, 1% severe), and dizziness (8% mild/moderate), depression (7% mild/moderate, 3% severe) insomnia (6% mild/moderate). Amnesia, anxiety, ataxia, confusion, convulsions, emotional lability, abnormal gait, hallucination, hyperkinesia, hypertonia, meningitis, somnolence, abnormal thinking, tremor, taste perversion, deafness, earache, and tinnitus have been reported in 5% or fewer patients (n=116).
Metabolic
Metabolic side effects have included dehydration and thirst in 5% or fewer patients (n=116).
Respiratory
Respiratory side effects have included dyspnea (23% mild/moderate, 3% severe), cough (26% mild/moderate, 2% severe), rhinitis (12% mild/moderate), and sinusitis (8% mild/moderate). Hemoptysis, hiccups, pulmonary infiltration, and increased sputum have been reported in 5% or fewer patients (n=116).
Ocular
Ocular side effects have included abnormal vision (3% mild./moderate, 2% severe), conjunctivitis (<=5%), and eye pain (<=5%).
Genitourinary
Genitourinary side effects have included dysuria, nocturia and polyuria in 5% or fewer patients (n=116).
Endocrine
Endocrine side effects have included increased sweating (12% mild/moderate, 2% severe).
Other
Other side effects have included malaise (9% mild/moderate, 1% severe), influenza-like symptoms (5% mild/moderate), lymphadenopathy (<=5%), and splenomegaly (<=5%) (n=116).
Musculoskeletal
Musculoskeletal side effects have included rigors (19% mild/moderate), back pain (16% mild/moderate), arthralgia (7% mild/moderate), and myalgia (7% mild/moderate).
Hypersensitivity
Hypersensitivity reactions have been reported (21% mild/moderate, 3% severe) (n=116).
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