Breast Cancer Patients:
About 254 patients with advanced breast cancer who had not received prior chemotherapy for metastatic disease were treated with Caelyx at a dose of 50 mg/m2
every 4 weeks in a phase III clinical trial (197-328). The most frequently reported treatment-related adverse effects included PPE (48%) and nausea (37%) (see Table 7). These effects were mostly mild and reversible, with severe (grade III) cases reported in 17% and 3%, respectively, and no reported incidences of life-threatening (grade IV) cases for either PPE or nausea. Infrequently, these effects resulted in permanent treatment discontinuation (7% and 0%, respectively). Pronounced alopecia (or total hair loss) was seen in only 7% of Caelyx-treated patients as compared with 54% of patients treated with doxorubicin.
Hematologic adverse effects were infrequently reported, and were mostly mild or moderate in severity and manageable. Anemia, neutropenia, leukopenia and thrombocytopenia were infrequently reported at incidences of 5%, 4%, 2% and 1%, respectively. Life-threatening (grade IV) hematologic effects were reported at incidences of <1%. 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 (grades III and IV) 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 1st- or 2nd-line taxane-containing chemotherapy regimen and were subsequently treated with Caelyx at a dose of 50 mg/m2
every 4 weeks in a phase III clinical trial (C/I96-352), the safety profile was consistent with that reported for Caelyx in previous studies using the same dosage regimen (see Table 8). The proportion of patients experiencing clinically significant laboratory abnormalities was low and comparable numerically to the 254 breast cancer patients receiving Caelyx as 1st-line therapy, with the exception of leukopenia (20%).
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Adverse Reactions reported between 1% and 5% in 404 Caelyx-treated breast cancer patients, not previously reported in Caelyx clinical trials (≥1%) were breast pain, leg cramps, edema, leg edema, peripheral neuropathy, oral pain, ventricular arrhythmia, folliculitis, bone pain, musculoskeletal pain, thrombocythemia, cold sores (nonherpetic), fungal infection, epistaxis, upper respiratory tract infection, bullous eruption, dermatitis, erythematous rash, nail disorder, scaly skin, lacrimation and blurred vision.
Ovarian Cancer Patients:
About 512 patients with ovarian cancer (a subset of 876 solid tumor patients) were treated with Caelyx at a dose of 50 mg/m2
in clinical trials. The most frequently reported treatment-related adverse effects included PPE (46.1%) and stomatitis (38.9%) (see Table 9). These effects were mainly mild, with severe (grade III) cases reported in 19.5% and 8%, respectively, and life-threatening (grade IV) cases reported in 0.6% and 0.8%, respectively. These resulted infrequently in permanent treatment discontinuation (<5% and <1%, respectively).
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Myelosuppression was mostly mild or moderate and manageable. Leukopenia was the most frequently reported hematological adverse effect, followed by anemia, neutropenia and thrombocytopenia. Life-threatening (grade IV) hematologic effects were reported at incidences of 1.6%, 0.4%, 2.9% and 0.2%, respectively. Growth factor support was required infrequently (<5%) and transfusion support was required in approximately 15% of patients (see Dosage & Administration).
Other less frequently (1-5%) reported adverse reactions included peripheral edema, oral moniliasis, vasodilation, 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, hypertonia, skin ulcer and dysuria.
In the subset of 410 patients with ovarian cancer, clinically significant laboratory abnormalities occurring in clinical trials with Caelyx included increases in total bilirubin (usually in patients with liver metastases) (5%) and serum creatinine levels (5%). Clinically significant measurements, measured by grades III and IV neutropenia (11.4%), anemia (5.7%) and thrombocytopenia (1.2%) were low. Increases in AST were less frequently (<1%) reported. Sepsis related to leukopenia was observed infrequently (<1%).
Solid Tumor Patients:
In a larger cohort of 929 patients with solid tumors (including breast and ovarian cancer) predominantly treated at a dose of 50 mg/m2
every 4 weeks, the safety profile and incidence of adverse effects are comparable to those of the patients treated in the pivotal breast and ovarian cancer trials.
Open-label and controlled clinical studies on AIDS-KS patients treated with Caelyx at a dose of 20 mg/m2
show that myelosuppression was the most frequent side effect considered related to Caelyx, occurring in approximately ½ of the patients.
Leukopenia is the most frequent adverse reaction experienced with Caelyx in this population; neutropenia, anemia and thrombocytopenia have been observed. These effects may occur early on in treatment. Hematological toxicity may require dose reduction, or suspension or delay of therapy. Temporarily suspend Caelyx treatment in patients when the ANC count is <1000/mm3
and/or the platelet count is <50,000/mm3
. G-CSF (or GM-CSF) may be given as concomitant therapy to support the blood count when the ANC count is <1000/mm3
in subsequent cycles. The hematological toxicity for breast or ovarian cancer patients is less severe than in the AIDS-KS setting (see Ovarian Cancer Patients in the previous texts).
Other frequently (≥5%) observed side effects were nausea, asthenia, alopecia, fever, diarrhea, infusion-associated acute reactions and stomatitis.
Respiratory side effects frequently (≥5%) occurred in clinical studies of Caelyx and may be related to opportunistic infections in the AIDS population. Opportunistic infections (OIs) are observed in AIDS-KS patients after administration with Caelyx and are frequently observed in patients with HIV-induced immunodeficiency. The most frequently observed OIs in clinical studies were candidiasis, cytomegalovirus, herpes simplex, Pneumocystis carinii
pneumonia and Mycobacterium avium
Other less frequently (<5%) observed side effects included PPE, oral moniliasis, nausea and vomiting, weight loss, rash, mouth ulceration, dyspnea, abdominal pain, hypersensitivity reactions including anaphylactic reactions, vasodilatation, dizziness, anorexia, glossitis, constipation, paresthesia, retinitis and confusion.
Clinically significant laboratory abnormalities frequently (≥5%) occurred in clinical studies with Caelyx. These included increases in alkaline phosphatase and increases in AST and bilirubin which are believed to be related to the underlying disease and not Caelyx. Reduction in hemoglobin and platelets were less frequently (<5%) reported. Sepsis related to leukopenia was rarely (<1%) observed. Some of these abnormalities may have been related to the underlying HIV-infection and not Caelyx.
100 out of 929 patients (10.8%) with solid tumors were described as having an infusion-associated reaction during treatment with Caelyx as defined by the following COSTART terms:
Allergic reaction, anaphylactoid reaction, asthma, face edema, hypotension, vasodilation, urticaria, back pain, chest pains, chills, fever, hypertension, tachycardia, dyspepsia, nausea, dizziness, dyspnea, pharyngitis, rash, pruritus, sweating, injection site reaction and drug interaction. 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 patients with AIDS-KS, infusion-associated reactions were characterised by flushing, shortness of breath, facial edema, headache, chills, back pain, tightness in the chest and throat, and/or hypotension and can be expected at the rate of 5-10%. Very rarely, convulsions have been observed in relation to infusion reactions. In all patients, infusion-associated reactions occurred primarily during the 1st infusion. Temporarily stopping the infusion usually resolves these symptoms without further therapy. In nearly all patients, Caelyx treatment can be resumed after all symptoms have resolved without recurrence. Infusion reactions rarely recur after the 1st treatment cycle with Caelyx.
Stomatitis has been reported in patients receiving continuous infusions of conventional doxorubicin HCl and was frequently reported in patients receiving Caelyx. It did not interfere with patients completing therapy and no dosage adjustments are generally required, unless stomatitis is affecting a patient's ability to eat. In this case, the dose interval may be extended by 1-2 weeks or the dose reduced.
Palmar-plantar erythrodysesthesia (PPE) is characterised by painful, macular reddening skin eruptions. In patients experiencing this event, it is generally seen after 2 or 3 cycles of treatment. In most patients, it clears in 1 or 2 weeks, with or without treatment with corticosteroids. Pyridoxine at a dose of 50-150 mg/day has been used for the prophylaxis and treatment of PPE. Other strategies to prevent and treat PPE, which may be initiated 4-7 days after treatment with Caelyx includes keeping hands and feet cool by exposing them to cool water (soaks, baths or swimming), avoiding excessive heat/hot water, and keeping them unrestricted (no socks, gloves or shoes that are tight fitting). It appears to be dose- and schedule-related and can be reduced by extending the dose interval of 1-2 weeks or reducing the dose. This reaction can be severe and debilitating in some patients, however, and may require discontinuation of treatment.
An increased incidence of congestive heart failure (CHF) is associated with doxorubicin therapy at cumulative lifetime doses >450 mg/m2
or at lower doses for patients with cardiac risk factors. Endomyocardial biopsies on 9 of 10 AIDS-KS patients receiving cumulative doses of Caelyx >460 mg/m2
indicate no evidence of anthracycline-induced cardiomyopathy. The recommended dose of Caelyx for AIDS-KS patients is 20 mg/m2
every 2-3 weeks. The cumulative dose at which cardiotoxicity would become a concern for these AIDS-KS patients (>400 mg/m2
) would require >20 courses of Caelyx therapy over 40-60 weeks.
In addition, endomyocardial biopsies were performed in 8 solid tumor patients with cumulative anthracycline doses of 509-1680 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 doxorubicin, 10/254 patients randomized to receive Caelyx (treated at a dose of 50 mg/m2
every 4 weeks) versus 48/255 patients randomized to receive doxorubicin (treated at a dose of 60 mg/m2
every 3 weeks) 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 CHF. None of the 10 Caelyx patients who had cardiac toxicity by LVEF criteria developed signs and symptoms of CHF. In contrast, 10 of 48 doxorubicin patients who had cardiac toxicity by LVEF criteria also developed signs and symptoms of CHF.
In patients with solid tumors, including a subset of patients with breast and ovarian cancers, treated at a dose of 50 mg/m2
/cycle with lifetime cumulative anthracycline doses up to 1532 mg/m2
, the incidence of clinically significant cardiac dysfunction was low. Of the 929 patients treated with Caelyx 50 mg/m2
/cycle, baseline measurement of LVEF and at least 1 follow-up measurement were conducted in 418 patients and assessed by MUGA scan. Of these 418 patients, 88 patients had a cumulative anthracycline dose of >400 mg/m2
, an exposure level associated with an increased risk of cardiovascular toxicity with the conventional formulation of doxorubicin. Only 13 of these 88 patients (15%) had at least 1 clinically significant change in their LVEF, defined as an LVEF value <45% or a decrease of at least 20 points from baseline. Furthermore, only 1 patient (who received a cumulative dose of 944 mg/m2
), discontinued study treatment because of clinical symptoms of CHF.
Although local necrosis following extravasation has been reported very rarely, Caelyx should be considered an irritant. Animal studies indicate that administration of doxorubicin HCl as a liposomal formulation reduces the potential for extravasation injury. If any signs or symptoms of extravasation occur (eg, 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 min may be helpful in alleviating the local reaction. Caelyx must not be given by the IM or SC route.
Recall of skin reaction due to prior radiotherapy has rarely occurred with Caelyx administration.