Although Phase II clinical trials, combined with conventional chemotherapy agents have been conducted n patients with gynecological malignancies, there is no formal drug interaction studies. Caution should be exercised in the concomitant use of drugs known to interact with conventional doxorubicin HCl. Like other doxorubicin HCl preparations, pegylated liposomal doxorubicin may induce the toxicity of other anti-cancer drugs.
Pegylated liposomal doxorubicin HCl has been administered to 230 patients with solid tumors (including ovarian cancer or breast cancer) as part of combination therapy regimen (combined with either cyclophosphamide, taxanes or vinorelbine), In AIDS-KS patients, it has been reported that conventional doxorubicin HCl exacerbates the cyclophosphamide-induced hemorrhage cystitis and enhances the hepatotoxicity of 6-mercaptopurine. With caution when use with other anti-cancer drugs, especially those may induce bone marrow suppression.
Breast Cancer Patients: 254 patients with advanced breast cancer who had not received prior chemotherapy for metastatic disease were treated with pegylated liposomal doxorubicin at a dose of 50 mg/m2 every 4 weeks in a Phase III clinical trial (I 97-328). The most frequently reported treatment related adverse reactions included palmar-plantar erythrodysesthesia (PPE) (48.0%) and nausea (37.0%) (see Table 5). These effects were mostly mild and reversible, with severe (Grade 3) cases reported in 17.0% and 3.0% respectively, and no reported incidences of life-threatening (Grade 4) cases for either PPE or nausea. Infrequently, these effects resulted in permanent treatment discontinuation (7.0% and 0% respectively). Pronounced alopecia (or total hair loss) was seen in only 7.0% of pegylated liposomal doxorubicin-treated patients compared with 54.0% of patients treated with conventional doxorubicin.
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 Dosage & 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 leucopenia (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.)
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The incidence of adverse reactions have been reported between 1% and 5% in 404 pegylated liposomal doxorubicin-treated breast cancer patients and the adverse reactions which had been reported previously (≥1%) were breast pain, leg cramps, 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 incidences 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.)
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The myelosuppression was mostly mild to moderate and treatable. Most frequently reported hematologic adverse reaction was leucopenia, followed by anemia, neutropenia, and thrombocytopenia. Life-threatening (Grade 4) hematological adverse events occurred at incidences of leucopenia (1.6%), anemia (0.4%), neutropenia (2.9%) and thrombocytopenia (0.2%). Less than 5% of the patients need the growth factor support and less than 15% of the patients need the blood infusion support. (See Dosage & Administration.)
Other less frequently (1-5%) reported adverse events 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 data analysis of the data from 410 ovarian cancer patients, the clinically significant abnormal laboratory result included total bilirubin elevating (usually in patients with liver metastases) (5%), and serum creatinine clearance elevating (5%). Clinically significant measurements, measured by Grade 3 and 4 neutropenia (11.4%), anemia (5.7%) and thrombocytopenia (1.2%) were low. AST elevating occurred in very few cases (<1%). Leukopenia-related sepsis was also observed frequently. The similar results could be found in solid tumor patients.
For Solid Tumor Patients: In a large study containing 929 patients with solid tumor, inducing breast and ovarian cancer, 50 mg/m2 of pegylated liposomal doxorubicin every 4 weeks was prescribed. The safely properties and the incidence of adverse reactions are similar to the results in the breast and ovarian cancer clinical trial described previously.
AIDS-KS Patients: In open-labeled and active controlled clinical studies, it was shown that the most frequent adverse reaction in AIDS-KS patients treated with pegylated liposomal doxorubicin at a dose of 20 mg/m2 was bone marrow suppression. It happened on half of these patients.
Within these patients, the most frequent adverse reaction was leukopenia, then neutropenia, anemia, and thrombocytopenia were observed. These reactions might happen in the early stage of the therapy. Dose reduction, suspension or delay of therapy might be required when the hematological toxicities happened. 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) might be added in subsequent cycles to keep the blood cell count. The hematological toxicity is minor in breast cancer or ovarian cancer patients than in AIDS-KS patients with pegylated liposomal doxorubicin treatment. (See Ovarian Cancer Patients previously.)
Other frequently (%) 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 leucopenia is rarely observed (1%). These abnormalities may have been related the underlying HIV infection and not pegylated liposomal doxorubicin.
For All Patients: The following reactions, defined with Costart 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 and were reported about 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 appeared during the first treatment and can be expected at the rate of 5-10%.
Usually, temporarily stopping the infusion or reducing infusion rate could resolve these symptoms 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 recurred.
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. Otherwise, prolong the dose interval by 1 or 2 weeks or reduce the dosage.
Palmar-Plantar erythrodysesthesia (PPE), characterized by painful, macular reddening skin eruptions, is generally seen after 2 or 3 cycles of treatment. No matter whether treater with corticosteroid or not, it usually disappears within 1-2 weeks. Pyridoxine at a dose of 50-150 mg per day has 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. Avoid to contact heat or hot water and keep hands and feet unrestricted (no socks, gloves or shoes that are tight fitting). This reaction is related to dose regimen. Prolonging dose interval 1 to 2 weeks or reducing dose could improve it. If the reaction was severe or patients feel very then the treatment may be required to be discontinued.
Treatment of conventional doxorubicin HCl at cumulative doses of lifetime was above 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 do not show anthracycline-induced cardiomyopathy. The recommended dosage of pegylated liposomal doxorubicin for AIDS-KS patients is 20 mg/m2 every 2 to 3 weeks. Cumulative doses (>400 mg/m2) which may cause cardiotoxicity, a main concern in AIDS-KS patients, will require more than 20 courses within 40 to 60 weeks.
In addition, endomyocardial biopsies were performed in 8 solid tumor patients with cumulative anthracycline doses of 509-1680 mg/m2. These range of Billingham cardiotoxicity scores were grades 0-1.5. These grading scores are consistent with no or minor cardiac toxicity.
In the pivotal Phase III trial (pegylated liposomal doxorubicin 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-treated patients developed signs and symptoms of CHF.
The recurrence of skin reaction due to prior radiotherapy is very rarely seen in pegylated liposomal doxorubicin HCl administration.