The most common undesirable effect reported in breast/ovarian clinical trials (50 mg/m2
every 4 weeks) was palmar-plantar erythrodysesthesia (PPE). The overall incidence of PPE reported was 44.0 % - 46.1 %. These effects were mostly mild, with severe (Grade III) cases reported in 17 % - 19.5 %. The reported incidence of life-threatening (Grade IV) cases was < 1 %. PPE infrequently resulted in permanent treatment discontinuation (3.7 % - 7.0 %). PPE is characterised by painful, macular reddening skin eruptions. In patients experiencing this event, it is generally seen after two or three cycles of treatment.
Improvement usually occurs in one - two weeks, and in some cases, may take up to 4 weeks or longer for complete resolution. Pyridoxine at a dose of 50 - 150 mg per day and corticosteroids have been used for the prophylaxis and treatment of PPE, however, these therapies have not been evaluated in phase III trials.
Other strategies to prevent and treat PPE, which may be initiated for 4 to 7 days after treatment with Caelyx include 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). PPE appears to be primarily related to the dose schedule and can be reduced by extending the dose interval 1 - 2 weeks (see Dosage & Administration).
However, this reaction can be severe and debilitating in some patients and may require discontinuation of treatment. Stomatitis/mucositis and nausea were also commonly reported in breast/ovarian cancer patient populations, whereas the AIDS-KS Program (20 mg/m2
every 2 weeks), myelosuppression (mostly leukopaenia) was the most common side effect (see AIDS-KS program as follows). PPE was reported in 16 % of multiple myeloma patients treated with Caelyx plus bortezomib combination therapy. Grade 3 PPE was reported in 5 % of patients. No grade 4 PPE was reported. The most frequently reported (treatment-emergent medicine-related) adverse events in combination therapy (Caelyx + bortezomib) were nausea (40 %), diarrhoea (35 %), neutropaenia (33 %), thrombocytopaenia (29 %), vomiting (28 %), fatigue (27 %), and constipation (22 %).
Breast cancer program:
509 patients with advanced breast cancer who had not received prior chemotherapy for metastatic disease were treated with Caelyx (n=254) at a dose of 50 mg/m2
every 4 weeks, or doxorubicin (n=255) at a dose of 60 mg/m2
every 3 weeks, in a phase III clinical trial (I97-328).
The following common adverse events were reported more often with doxorubicin than with Caelyx: nausea (53 % vs. 37 %; Grade III/IV 5 % vs. 3 %),vomiting (31 % vs. 19 %; Grade III/IV 4 % vs. less than 1 %), any alopecia (66 % vs. 20 %), pronounced alopecia (54 % vs. 7 %), and neutropaenia (10 % vs. 4 %; Grade III/IV 8 % vs. 2 %).
Mucositis (23 % vs. 13 %; Grade III/IV 4 % vs. 2 %), and stomatitis (22 % vs. 15 %; Grade III/IV 5 % vs. 2 %) were reported more commonly with Caelyx than with doxorubicin. The average duration of the most common severe (Grade III/IV) events for both groups was 30 days or less. See Table 6 for complete listing of undesirable effects reported in Caelyx-treated patients.
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 5.0 %, 4.0 %, 2.0 %, and 1.0 %, respectively.
The incidence of life threatening (Grade IV) haematologic effects was < 1.0 % and sepsis was reported in 1 % of patients. Growth factor support or transfusion support was necessary in 5.1 % and 5.5 % of patients, respectively (see Dosage & Administration).
Clinically significant laboratory abnormalities (Grades III and IV) in this group was low with elevated total bilirubin, AST and ALT reported in 2.4 %, 1.6 % and < 1 % of patients respectively. 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 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. The proportion of patients experiencing clinically significant laboratory abnormalities was low and comparable numerically to the 254 breast cancer patients receiving Caelyx as first-line therapy, with the exception of leukopenia (20 %). (See Table 6.)
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Ovarian cancer program:
512 patients with ovarian cancer (a subset of 876 solid tumour patients) were treated with Caelyx at a dose of 50 mg/m2
in clinical trials. The most frequently reported treatment related adverse effects included palmar-plantar erythrodysesthesia (PPE) (46.1 %) and stomatitis (38.9 %). These effects were mainly mild, with severe (Grade III) cases reported in 19.5 % and 8.0 % 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).
See Table 7 for undesirable effects reported in Caelyx-treated patients. (See Table 7.)
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Myelosuppression was mostly mild or moderate and manageable.
Leukopenia was the most frequently reported hematologic 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 %, 0.2 %, respectively. Growth factor support was required infrequently (< 5 %) and transfusion support was required in approximately 15 % of patients (see Dosage & Administration).
In a 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 leucopenia was observed infrequently (< 1 %).
Solid tumour patients: in a larger cohort of 929 patients with solid tumours (including breast cancer 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 cancer and ovarian cancer trials.
Multiple Myeloma program:
Of 646 patients with multiple myeloma who have received at least 1 prior therapy, 318 patients were treated with combination therapy of Caelyx 30 mg/m2
as a one hour intravenous infusion administered on day 4 following bortezomib which is administered at 1.3 mg/m2
on days 1, 4, 8, and 11, every three weeks or with bortezomib monotherapy in a phase III clinical trial. See Table 8 for adverse effects reported in ≥ 5 % patients treated with combination therapy of Caelyx plus bortezomib.
Neutropaenia, thrombocytopaenia, and anaemia were the most frequently reported hematologic events reported with both combination therapy of Caelyx plus bortezomib and bortezomib monotherapy. The incidence of grade 3 and 4 neutropaenia was higher in the combination therapy group than in the monotherapy group (28 % vs. 14 %). The incidence of grade 3 and 4 thrombocytopaenia was higher in the combination therapy group than in the monotherapy group (22 % vs. 14 %). The incidence of anaemia was similar in both treatment groups (7 % vs. 5 %).
Stomatitis was reported more frequently in the combination therapy group (16 %) than in the monotherapy group (3 %), and most cases were grade 2 or less in severity. Grade 3 stomatitis was reported in 2 % of patients in the combination therapy group. No grade 4 stomatitis was reported.
Nausea and vomiting were reported more frequently in the combination therapy group (40 % and 28 %) than in the monotherapy group (32 % and 15 %) and were mostly grade 1 and 2 in severity.
Treatment discontinuation of one or both agents due to adverse events was seen in 38 % of patients. Common adverse events which led to treatment discontinuation of bortezomib and Caelyx included PPE, neuralgia, peripheral neuropathy, peripheral sensory neuropathy, thrombocytopaenia, decreased ejection fraction, and fatigue. (See Tabl 8.)
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Clinical studies on AIDS-KS patients treated at 20 mg/m2
with Caelyx show that myelosuppression was the most frequent undesirable effect considered related to Caelyx occurring very commonly (in approximately one-half of the patients).
Leukopaenia is the most frequent undesirable effect experienced with Caelyx in this population; neutropaenia, anaemia and thrombocytopaenia have been observed. These effects may occur early on in treatment. Haematological toxicity may require dose reduction or suspension or delay of therapy. Temporarily suspend Caelyx treatment in patients when the ANC count is < 1,000/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 < 1,000/mm3
in subsequent cycles. The haematological toxicity for ovarian cancer patients is less severe than in the AIDS-KS setting (see Ovarian cancer program as previously mentioned).
Other frequently (> 5%) observed side effects were nausea, asthenia, alopecia, fever, diarrhea, infusion-associated acute reactions, and stomatitis.
Respiratory undesirable effects commonly occurred in clinical studies of Caelyx and may be related to opportunistic infections in the AIDS population. Opportunistic infections (OI's) are observed in KS patients after administration with Caelyx, and are frequently observed in patients with HIV-induced immunodeficiency. The most frequently observed OI's in clinical studies were candidiasis, cytomegalovirus, herpes simplex, Pneumocystis carinii
pneumonia, and Mycobacterium avium
Undesirable effects observed in patients with AIDS-KS according to CIOMS III frequency categories (Very common (≥1/10); Common (≥1/100, <1/10); Uncommon (≥1/1000, <1/100)) were as follows: Infections and infestations:
Common: oral moniliasis.
Blood and lymphatic system disorders:
Very common: neutropaenia, anaemia, leukopaenia.
Metabolism and nutrition disorders:
Nervous system disorders:
Respiratory, thoracic and mediastinal disorders:
Very common: nausea.
Common: diarrhoea, stomatitis, vomiting, mouth ulceration, abdominal pain, glossitis, constipation, nausea and vomiting.
Skin and subcutaneous tissue disorders:
Common: alopecia, rash.
Uncommon: palmar-plantar erythrodysesthesia (PPE).
General disorders and administration site conditions:
Common: asthenia, fever, infusion-associated acute reactions.
Common: weight loss.
Other less frequently (< 5 %) observed undesirable effects included hypersensitivity reactions including anaphylactic reactions. Following marketing, bullous eruption has been reported rarely in this population.
Clinically significant laboratory abnormalities frequently (≥ 5 %) occurred including increases in alkaline phosphatase; AST and bilirubin which were believed to be related to the underlying disease and not Caelyx. Reduction in haemoglobin and platelets were less frequently (< 5 %) reported. Sepsis related to leukopaenia was rarely (< 1 %) observed. Some of these abnormalities may have been related to the underlying HIV infection and not Caelyx.
All patients: 100 out of 929 patients (10.8 %) with solid tumours 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 oedema, hypotension, vasodilatation, urticaria, back pain, chest pain, chills, fever, hypertension, tachycardia, dyspepsia, nausea, dizziness, dyspnoea, pharyngitis, rash, pruritus, sweating, injection site reaction and medicinal product interaction. Permanent treatment discontinuation was infrequently reported at 2 %. A similar incidence of infusion reactions (12.4 %) and treatment discontinuation (1.5 %) was observed in the breast cancer program. In patients with multiple myeloma receiving Caelyx plus bortezomib, infusion-associated reactions have been reported at a rate of 3 %. In patients with AIDS-KS, infusion-associated reactions, were characterised by flushing, shortness of breath, facial oedema, headache, chills, back pain, tightness in the chest and throat and/or hypotension and can be expected at the rate of 5 % to 10 %. Very rarely, convulsions have been observed in relation to infusion reactions. In all patients, infusion associated reactions occurred primarily during the first 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 first treatment cycle with Caelyx (see Dosage & Administration).
Myelosuppression associated with anaemia, thrombocytopaenia, leukopaenia, and rarely febrile neutropaenia, has been reported in Caelyx-treated patients.
Stomatitis has been reported in patients receiving continuous infusions of conventional doxorubicin hydrochloride 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 (see Dosage & Administration).
Palmar-plantar erythrodysesthesia is characterized by painful, macular reddening skin eruptions. In patients experiencing this event, it is generally seen after two or three cycles of treatment. In most patients it clears in one or two weeks, with or without treatment with corticosteroids. 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, which may be initiated 4 to 7 days after treatment with Caelyx include keeping hands and feet cool, 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 by 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 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 nine of ten AIDS-KS patients receiving cumulative doses of Caelyx greater than 460 mg/m2
indicate no evidence of anthracycline-induced cardiomyopathy. The recommended dose of Caelyx for AIDS-KS patients is 20 mg/m2
every two-to-three weeks. The cumulative dose at which cardiotoxicity would become a concern for these AIDS-KS patients (> 400 mg/m2
) would require more than 20 courses of Caelyx therapy over 40 to 60 weeks.
In addition, endomyocardial biopsies were performed in 8 solid tumour patients with cumulative anthracycline doses of 509 mg/m2
- 1,680 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, 58/509 (11.4 %) randomized subjects (10 treated with Caelyx at a dose of 50 mg/m2
/every 4 weeks versus 48 treated with doxorubicin 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). The risk of developing a cardiac event as a function of cumulative anthracycline dose was significantly lower with Caelyx than with doxorubicin (HR [doxorubicin/ Caelyx]=3.16, p<0.001). Patients were also assessed for signs and symptoms of congestive heart failure (CHF). None of the 10 Caelyx subjects who had cardiac toxicity by LVEF criteria developed signs and symptoms of CHF. In contrast, 10 of 48 doxorubicin subjects who had cardiac toxicity by LVEF criteria also developed signs and symptoms of CHF.
In patients with solid tumours, 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 1,532 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 left ventricular ejection fraction (LVEF) and at least one follow-up measurement were conducted in 418 patients and assessed by MUGA scan. Of the 418 patients treated with Caelyx 50 mg/m2
/cycle, and having a baseline measurement of left ventricular ejection fraction (LVEF) and at least one follow-up measurement assessed by MUGA scan, 88 patients had a cumulative anthracycline dose of > 400 mg/m2
, an exposure level associated with an increased risk of cardiovascular toxicity with conventional doxorubicin.
Only 13 of these 88 patients (15 %) had at least one clinically significant change in their LVEF, defined as an LVEF value less than 45 % or a decrease of at least 20 points from baseline. Furthermore, only 1 patient (cumulative anthracycline dose of 944 mg/m2
), discontinued study treatment because of clinical symptoms of congestive heart failure.
As with other DNA-damaging antineoplastic agents, secondary acute myeloid leukemias and myelodysplasias have been reported in patients having received combined treatment with doxorubicin. Therefore, any patient treated with doxorubicin should be kept under haematological supervision.
Although local necrosis following extravasation has been reported very rarely, Caelyx is considered to be an irritant.
Animal studies indicate that administration of doxorubicin hydrochloride as a liposomal formulation reduces the potential for extravasation injury. If any signs or symptoms of extravasation occur (e.g., stinging, erythema) terminate the infusion immediately and restart in another vein. The application of ice over the site of extravasation for approximately 30 minutes may be helpful in alleviating the local reaction. Caelyx must not be given by the intramuscular or subcutaneous route.
Recall of skin reaction due to prior radiotherapy has rarely occurred with Caelyx administration.
Following the marketing of Caelyx, serious skin conditions including erythema multiforme, Stevens Johnson syndrome and toxic epidermal necrolysis have been reported very rarely.
In patients treated with Caelyx, cases of venous thromboembolism, including thrombophlebitis, venous thrombosis and pulmonary embolism have been seen uncommonly. However, because patients with cancer are at increased risk for thromboembolic disease, a causal relationship cannot be determined.
Very rare cases of secondary oral cancer have been reported in patients with long term (more than one year) exposure to Caelyx or those receiving a cumulative Caelyx dose greater than 720 mg/m2