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Hematologic adverse reactions were infrequently reported and were mostly mild or moderate in severity and manageable. Anemia, neutropenia, leucopenia and thrombocytopenia were infrequently reported at incidences of 5.0%, 4.0%, 2.0% and 1.0%, respectively. Life threatening (Grade 4) hematologic effects were reported at incidences of <1.0%. The need for either growth factor support or transfusion support was minimal (5.1% and 5.5% of patients, respectively) (see Dose and Administration).
Clinically significant laboratory abnormalities (Grade 3 and 4) in this breast cancer group included increases in total bilirubin (2.4%) and AST (1.6%). Increases in ALT were less frequent (<1%). Clinically significant hematologic measurements were infrequent as measured by leukopenia (4.3%), anemia (3.9%), neutropenia (1.6%) and thrombocytopenia (1.2%). Sepsis was reported at an incidence of 1%. No clinically significant increases in serum creatinine were reported.
In 150 patients with advanced breast cancer who had failed a prior first or second line taxane-containing chemotherapy regimen and were subsequently treated with pegylated liposomal doxorubicin at a dose of 50 mg/m2 every 4 weeks in phase III clinical trial (C/I 96-352), the safety profile was consistent with that reported in previous studies using the same dosage regimen (see Table 5). The proportion of patients experiencing clinically significant laboratory abnormalities was low and comparable numerically to the 254 breast cancer patients receiving pegylated liposomal doxorubicin as first-line therapy, with exception of leukopenia (20%). (See Table 5.)
Click on icon to see table/diagram/imageUndesirable effects reported between 1% and 5% in 404 pegylated liposomal doxorubicin-treated breast cancer patients, not previously reported (≥1%) were breast pain, leg cramps, edema, leg edema, peripheral neuropathy, oral pain, ventricular arrhythmia, folliculitis, bone pain, musculo-skeletal pain, thrombocythemia, cold sores (non-herpetic), fungal infection, epistaxis, upper respiratory tract infection, bullous eruption, dermatitis, erythematous rash, nail disorder, scaly skin, lacrimation and blurred vision.
Ovarian Cancer Patients: In clinical trials, safety data are available from 512 ovarian cancer patients (a subset of 876 solid tumor patients) treated with 50 mg/m2 pegylated liposomal doxorubicin.
The most frequently reported therapeutic-related adverse reactions included palmar-plantar erythrodysesthesia (PPE) (46.1%) and stomatitis (38.9%) (see table 6). These reactions were mainly mild. The incidence of severe cases (Grade 3) were 19.5% and 8.0% respectively, and the life-threatening cases (Grade 4) were 0.6% and 0.8% respectively. These reactions infrequently resulted in permanent therapy discontinuation. (<5% and <1% respectively). (See Table 6.)
Click on icon to see table/diagram/imageThe myelosuppression was mostly mild to moderate and treatable. Most frequently reported hematologic adverse reaction was leukopenia, followed by anemia, neutropenia, and thrombocytopenia. Very few happened life-threatening (Grade 4) hematological adverse event, at incidences of; leukopenia (1.6%), anemia (0.4%), neutropenia (2.9%) and thrombocytopenia (0.2%). Less than 5% patients need the growth factor support and less than 15% patients need the blood infusion support. (See Dosage & Administration.)
Other less frequently (1-5%) reported included peripheral edema, mouth moniliasis, vasodilatation, mouth ulceration, pruritus, allergic reaction, dehydration, dyspnea, vesiculobullous rash, chills, infection, weight loss, esophagitis, skin disorder, exfoliative dermatitis, cardiovascular disorder, chest pain, dizziness, maculopapular rash, gastritis, myalgia, back pain, depression, insomnia, dysphagia, increased cough, sweating, nausea and vomiting, malaise, taste perversion, urinary tract infection, conjunctivitis, acne, gingivitis, herpes zoster, hypochromic anemia, anxiety, vaginitis, headache, flatulence, dry mouth, cachexia, neuropathy, hypertension, skin ulcer and dysuria.
In the analysis of the data from 410 ovarian cancer patients, the clinically significant abnormal laboratory values included total bilirubin value elevating (usually in patients with liver metastases) (5%), and serum creatinine clearance levels elevating (5%). Clinically significant measurements, measured by Grade 3 and 4 neutropenia (11.4%), anemia (5.7%) and thrombocytopenia (1.2%) were low. Very few cases (<1%) happened AST elevating. Sepsis related to leukopenia was also not frequently observed. The similar results could be found in solid tumor patients.
AIDS-KS Patients: Open-label and controlled clinical studies on AIDS-KS patients treated with pegylated liposomal doxorubicin at a dose of 20 mg/m2 show that, the most frequent adverse reaction is bone marrow suppression. About half of the patients have bone marrow suppression.
Within these patients, the most frequent adverse reaction is leukopenia; then neutropenia, anemia and thrombocytopenia have been observed. These reactions may happen in the early stage of the therapy. Dose reduction or suspension or delay of therapy may be required when the hematological toxicities happen. Temporarily suspend Lipo-Dox when the absolute neutrophil count (ANC) is less than 1000/mm3 or/and the platelet count is less than 50,000/mm3. When the ANC <1000/mm3, may add G-CSF (or GM-CSF) in subsequent cycles to support the blood count. The hematological toxicity is milder in breast cancer or ovarian cancer patients than in the AIDS-KS patients with pegylated liposomal doxorubicin treatment. (See Ovarian Cancer Patients as previously mentioned.)
Other frequently (≧5%) adverse reactions include nausea, asthenia, alopecia, fever, diarrhea, infusion-associated acute reactions, and stomatitis.
Respiratory adverse reactions are frequent (≧5%). It may be related to opportunistic infections in the AIDS patients. Opportunistic infections are observed in KS patients with pegylated liposomal doxorubicin treatment, and are frequently seen in patients with HIV-induced immunodeficiency. The most frequent opportunistic infections are candidiasis, cytomegalovirus, herpes simplex, Pneumocystis carinii pneumonia, and Mycobacterium avium complex.
Other less frequent adverse events (<5%) are palmar-plantar erythrodysesthesia, mouth moniliasis, nausea and vomiting, weight loss, rash, mouth ulceration, dyspnea, abdominal pain and hypersensitivity reaction including: anaphylactic reactions, dizziness, vasodilatation, insomnia, glossitis, constipation, paresthesia, retinitis, and confusion.
In pegylated liposomal doxorubicin HCl clinical studies, the frequently (≧5%) significant laboratory abnormalities included alkaline phosphatase increases, AST increases, and bilirubin value increases which are related to the underlying disease and not pegylated liposomal doxorubicin. Reduction in hemoglobin and platelets are less frequently (<5%). Sepsis caused by leukopenia is rarely observed (<1%). These abnormalities may have been related to the underlying HIV infection and not pegylated liposomal doxorubicin.
For Solid Tumor Patients: In a large study containing 929 solid tumor, including breast and ovarian cancer, patients, 50 mg/m2 of Pegylated liposomal doxorubicin/4 weeks was prescribed. The safety properties and the incidence of adverse reactions are similar to the results in the breast and ovarian cancer clinical trial as previously mentioned.
For All Patients: The following reactions, defined with Costart, were occurred within the Pegylated liposomal doxorubicin treatment period among 100 of 928 (10.8%) solid tumor patients: allergic reaction, anaphylactoid reaction, asthma, face edema, hypotension, vasodilatation, urticaria, back pain, chest pain, chills, fever, hypertension, tachycardia, dyspepsia, dizziness, dyspnea, pharyngitis, rash, nausea, pruritus, sweating, injection site reaction and drug interactions. Permanent treatment discontinuation rates were infrequently reported at 2%. A similar incidence of infusion reactions (12.4%) was observed in the pivotal breast cancer trials. The rate of permanent treatment discontinuation was also similar at 1.5%. In the AIDS-KS patients, the infusion related reactions are flushing, shortness of breath, facial edema, headache, chills, back pain, tightness in the chest and throat, and/or hypotension. Those reactions primarily appear during the first treatment and can be expected at the rate of 5-10%.
Usually, temporarily stopping the infusion or reduce infusion rate could resolve these symptom without further therapy. In nearly all patients could resume pegylated liposomal doxorubicin treatment after all symptoms have resolved without recurrence. After the first cycle of pegylated liposomal doxorubicin treatment, the infusion reactions rarely recur.
There was stomatitis reported in patients receiving continuous infusions of conventional doxorubicin HCl and was frequently reported in patients receiving pegylated liposomal doxorubicin. It did not interrupt the treatment and no need to adjust dosage, unless it affects a patient's eating ability. When it occurs, prolong the dose interval by 1 to 2 weeks or reduce dose.
Palmar-Plantar erythrodysesthesia (PPE), characterized by painful, macular reddening skin eruptions, is generally seen after 2 or 3 cycles of treatment. No matter whether treated with corticosteroid or not, it usually disappears in 1-2 weeks. Pyridoxine at a dose of 50-150 mg per day had been used for the prophylaxis and treatment of PPE. Other strategies to prevent and treat PPE may be initiated 4-7 days after pegylated liposomal doxorubicin treatment. Immerse hands and feet in cold water (soaks, baths or swimming) to keep them cool. Avoiding to contact heat or hot water and keeping hands and feet unrestricted (no socks, gloves or shoes that are tight fitting). This reaction is related to dose and schedule. Prolonging dose interval 1 to 2 weeks or reducing dose could improve it. The reaction can be severe and debilitating in some patients and may require discontinuation of treatment.
Treatment of conventional doxorubicin HCl, at cumulative lifetime doses >450 mg/m2 or at lower doses for patients with cardiac risk factors, may increase the incidence of congestive heart failure. However, in 10 AIDS-KS patients receiving pegylated liposomal doxorubicin treatment and cumulative doses exceeding 460 mg/m2, Endomyocardial biopsies on 9 patients did not show anthracycline-induced cardiomyopathy. The recommended dose of pegylated liposomal doxorubicin for AIDS-KS patients is 20 mg/m2 every 2 to 3 weeks. Therefore, to cumulative doses at which cardiotoxicity would become a concern for these patients (>400 mg/m2) would required more than 20 courses over 40 to 60 weeks.
In addition, endomyocardial biopsies were performed in 8 solid tumor patients with cumulative anthracycline doses of 509 mg/m2-1680 mg/m2. The range of Billingham cardiotoxicity scores was grades 0-1.5. These grading scores are consistent with no or mild cardiac toxicity.
In the pivotal phase III trial versus conventional doxorubicin, 10/254 patients randomized to receive pegylated liposomal doxorubicin (at a dose of 50 mg/m2/every 4 weeks) versus 48/255 patients randomized to receive conventional doxorubicin met the protocol-defined criteria for cardiac toxicity during treatment and/or follow-up. Cardiac toxicity was defined as a decrease of 20 points or greater from baseline if the resting LVEF remained in the normal range or a decrease of 10 points or greater if the LVEF became abnormal (less than the lower limit for normal). Patients were also assessed for signs and symptoms of congestive heart failure (CHF). None of the 10 pegylated liposomal doxorubicin patients developed CHF. In contract, 10 of 48 conventional doxorubicin patients developed signs and symptoms of CHF.
The incidence of clinically significant cardiac injure was very low in the solid tumor patients (including breast and ovarian cancers) receiving dosage of 50 mg/m2 at every cycle with lifetime cumulative anthracycline doses up to 1532 mg/m2. Within 929 patients treated with 50 mg/m2 of pegylated liposomal doxorubicin every cycle, 418 patients received the baseline measurement of left ventricular ejection fraction (LVEF) and at least once follow-up measurement by MUGA scan as evaluation method. 88 out of these 418 patients had a cumulative anthracycline dosage exceeding 400 mg/m2. Under the conventional doxorubicin HCl formulation therapy, such high dosage is enough to increase risk of cardiac toxicity. Only 13 of these 88 patients (15%) occurred at least once clinically significant change in their LVEF, defined as an LVEF value less than 45% or a decrease of at least 20 points from baseline. Only one patient with cumulative dosage of 944 mg/m2 discontinued the clinical study due to clinical symptoms of congestive heart failure. Although local tissue necrosis following extravasation of pegylated liposomal doxorubicin has been reported very rarely, but an irritant should be considered. Animal studies indicate that the liposomal doxorubicin HCl could reduce the potential for extravasation injury. If any symptoms of extravasation occur (e.g., stinging, erythema), the infusion should be immediately terminated and restarted in another vein. The application of ice over the site of extravasation for approximately 30 minutes may be helpful in alleviating the local reaction. Pegylated liposomal doxorubicin must not be given by the intramuscular or subcutaneous route.
The recall of skin reaction due to prior radiotherapy is very rarely seen in pegylated liposomal doxorubicin HCl administration.
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