Caelyx Adverse Reactions

Summary of the safety profile: The most frequent adverse reactions (≥ 20%) were neutropaenia, nausea, leukopaenia, anaemia, and fatigue.
Severe adverse reactions (Grade 3/4 adverse reactions occurring in ≥ 2% of patients) were neutropaenia, PPE, leukopaenia, lymphopaenia, anaemia, thrombocytopaenia, stomatitis, fatigue, diarrhoea, vomiting, nausea, pyrexia, dyspnoea, and pneumonia. Less frequently reported severe adverse reactions included Pneumocystis jirovecii pneumonia, abdominal pain, cytomegalovirus infection including cytomegalovirus chorioretinitis, asthenia, cardiac arrest, cardiac failure, cardiac failure congestive, pulmonary embolism, thrombophlebitis, venous thrombosis, anaphylactic reaction, anaphylactoid reaction, toxic epidermal necrolysis, and Stevens-Johnson syndrome.
Tabulated list of adverse reactions: Table 6 summarises the adverse drug reactions that occurred in patients receiving Caelyx pegylated liposomal in 4,231 patients for the treatment of breast cancer, ovarian cancer, multiple myeloma, and AIDS-related KS. Post-marketing adverse reactions are also included, as indicated by ^"b". Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (frequency cannot be estimated from the available data). Within each frequency grouping, where relevant, adverse reactions are presented in order of decreasing seriousness. (See Tables 6a and 6b.)

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Description of selected adverse reactions: Palmar plantar erythrodysaesthesia: The most common undesirable effect reported in breast/ovarian clinical trials was palmar-plantar erythrodysesthesia (PPE). The overall incidence of PPE reported was 41.3% and 51.1% in the ovarian and breast clinical trials, respectively. These effects were mostly mild, with severe (grade 3) cases reported in 16.3% and 19.6% of patients. The reported incidence of life-threatening (grade 4) cases was < 1%. PPE infrequently resulted in permanent treatment discontinuation (1.9% and 10.8%). PPE was reported in 16% of multiple myeloma patients treated with Caelyx pegylated liposomal plus bortezomib combination therapy. Grade 3 PPE was reported in 5% of patients. No grade 4 PPE was reported. The rate of PPE was substantially lower in the AIDS-KS population (1.3% all grade, 0.4% grade 3 PPE, no grade 4 PPE). See Precautions.
Opportunistic infections: Respiratory undesirable effects commonly occurred in clinical studies of Caelyx pegylated liposomal and may be related to opportunistic infections (OI's) in the AIDS population. Opportunistic infections are observed in KS patients after administration with Caelyx pegylated liposomal, 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 jirovecii pneumonia, and Mycobacterium avium complex.
Cardiac toxicity: 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 pegylated liposomal greater than 460 mg/m² indicate no evidence of anthracycline-induced cardiomyopathy. The recommended dose of Caelyx pegylated liposomal 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 pegylated liposomal 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%) randomised subjects (10 treated with Caelyx pegylated liposomal 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). None of the 10 Caelyx pegylated liposomal 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 418 patients treated with Caelyx pegylated liposomal 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.
Radiation recall phenomenon: Recall of skin reaction due to prior radiotherapy has occurred uncommonly with Caelyx pegylated liposomal administration.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.