Caelyx pegylated liposomal is indicated: As monotherapy in patients with metastatic breast cancer where there is increased cardiac risk. For the treatment of advanced ovarian cancer in women in whom first-line platinum-based chemotherapy has failed. In combination with bortezomib for the treatment of progressive multiple myeloma in patients who have received at least one prior th

CAELYX PEGYLATED LIPOSOMAL 2MG/ML Concentrate for solution for infusion: Roztwór do wstrzykiwań 2 mg/ml

Summary of the safety profile The most common adverse reactions (≥ 20%) were neutropenia, nausea, leucopenia, anaemia and fatigue. Serious adverse reactions (grade 3/4 adverse reactions occurring in ≥ 2% of patients) were neutropenia, PPE, leucopenia, lymphopenia, anaemia, thrombocytopenia, stomatitis, fatigue, diarrhoea, vomiting, nausea, pyrexia, dyspnoea and pneumonia. Less fr

Hypersensitivity to the active substance, peanuts or soya, or to any of the excipients listed in section 6.1. Caelyx pegylated liposomal must not be used to treat AIDS-related KS that can be effectively treated with local therapy or systemic alpha-interferon.

CAELYX PEGYLATED LIPOSOMAL 2MG/ML Concentrate for solution for infusion

Q: Warnings?

Due to their different pharmacokinetic profiles and dosing schedules, Caelyx pegylated liposomal should not be used interchangeably with other formulations of doxorubicin hydrochloride. Cardiac toxicity It is recommended that all patients treated with Caelyx pegylated liposomal undergo routine electrocardiographic monitoring. Transient ECG changes such as T-wave flattening, S-T s

Pharmacotherapeutic group: Antineoplastic agents (anthracyclines and related substances), ATC code: L01DB01.‍‍‍‍‍‍‍ Mechanism of action The active substance of Caelyx pegylated liposomal is doxorubicin hydrochloride, a cytotoxic anthracycline antibiotic obtained from Streptomyces peucetius var. caesius. The exact mechanism of the antitumour activity of doxorubicin is not known. It is generally believed, however, that inhibition of DNA and RNA synthesis and protein synthesis is responsible for most of its cytotoxic effects. This is most likely a consequence of the intercalation of the anthracycline between adjacent base pairs of the DNA double helix, which prevents its unwinding required for replication. Clinical efficacy and safety A randomised phase III study comparing Caelyx pegylated liposomal versus doxorubicin in the treatment of metastatic breast cancer was conducted and completed in 509 patients. The protocol-required objective of demonstrating at least equivalent efficacy of Caelyx pegylated liposomal to doxorubicin was achieved — the hazard ratio for progression-free survival was 1.00 (95% confidence interval for the hazard ratio = 0.82–1.22). The therapeutic hazard ratio values for progression-free survival, after standardisation for prognostic variables, were consistent with the values obtained in the overall intention-to-treat population. The primary analysis of cardiotoxic effects demonstrated that the risk of developing cardiac events as a function of cumulative anthracycline dose was significantly lower with Caelyx pegylated liposomal than with doxorubicin (hazard ratio = 3.16, p < 0.001). No cardiac events were observed with Caelyx pegylated liposomal at cumulative doses exceeding 450 mg/m2. A comparative phase III study of Caelyx pegylated liposomal versus topotecan in patients with epithelial ovarian carcinoma after failure of first-line platinum-based chemotherapy was completed in 474 patients. Patients treated with Caelyx pegylated liposomal showed a benefit in overall survival (OS) compared with patients treated with topotecan, as indicated by the hazard ratio (HR) of 1.216 (95% confidence interval: 1.000; 1.478), p = 0.050. Survival rates at 1, 2 and 3 years were 56.3%, 34.7% and 20.2% for Caelyx pegylated liposomal, compared with 54.0%, 23.6% and 13.2% for topotecan. In the subgroup of platinum-sensitive patients, the difference was greater: HR 1.432 (95% confidence interval: 1.066; 1.923), p = 0.017. Survival rates at 1, 2 and 3 years were 74.1%, 51.2% and 28.4% for Caelyx pegylated liposomal, compared with 66.2%, 31.0% and 17.5% for topotecan. Results were similar in patients with platinum-refractory disease: HR 1.069 (95% confidence interval: 0.823; 1.387), p = 0.618. Survival rates at 1, 2 and 3 years were 41.5%, 21.1% and 13.8% for Caelyx pegylated liposomal, compared with 43.2%, 17.2% and 9.5% for topotecan. A randomised, open-label, multicentre phase III clinical trial with parallel groups was conducted comparing the safety and efficacy of combination therapy with Caelyx pegylated liposomal plus bortezomib versus bortezomib monotherapy in 646 patients with multiple myeloma who had received at least one prior therapy and who had not progressed on anthracycline-based treatment. Patients treated with the Caelyx pegylated liposomal plus bortezomib combination showed a significant improvement in the primary endpoint — time to progression (TTP) — compared with patients treated with bortezomib monotherapy, resulting from a risk reduction (RR) of 35% (95% confidence interval: 21–47%), p < 0.0001, based on 407 TTP events. Median TTP was 6.9 months for bortezomib monotherapy versus 8.9 months for Caelyx pegylated liposomal plus bortezomib combination therapy. A protocol-specified interim analysis (based on 249 TTP events) led to early termination of the efficacy evaluation. This interim analysis demonstrated a TTP risk reduction of 45% (95% confidence interval: 29–57%), p < 0.0001. Median time to progression was 6.5 months for bortezomib monotherapy versus 9.3 months for Caelyx pegylated liposomal plus bortezomib combination therapy. These results, although incomplete, were subjected to the protocol-specified final analysis. The final analysis of overall survival conducted at a median follow-up of 8.6 years showed no significant difference in overall survival between the two treatment arms. Median overall survival was 30.8 months (95% confidence interval: 25.2–36.5 months) for bortezomib monotherapy and 33.0 months (95% confidence interval: 28.9–37.1 months) for Caelyx pegylated liposomal plus bortezomib combination therapy.

⚠️ Warnings

Due to their different pharmacokinetic profiles and dosing schedules, Caelyx pegylated liposomal should not be used interchangeably with other formulations of doxorubicin hydrochloride. Cardiac toxicity It is recommended that all patients treated with Caelyx pegylated liposomal undergo routine electrocardiographic monitoring.‍‍‍‍‍‍‍ Transient ECG changes such as T-wave flattening, S-T segment depression and benign arrhythmias need not necessarily be considered indications for discontinuation of Caelyx pegylated liposomal therapy. However, a more significant indicator of cardiotoxic effects is QRS complex flattening. If this change occurs, more precise and sensitive evaluation of potential anthracycline-induced myocardial damage, i.e. endomyocardial biopsy, should be considered. More specific methods for monitoring and evaluating cardiac function than ECG include assessment of left ventricular ejection fraction by echocardiography or, preferably, by multigated angiography (MUGA). These examinations must be performed routinely before initiation of Caelyx pegylated liposomal therapy and repeated regularly during treatment. Left ventricular function assessment should be considered mandatory before each additional administration of Caelyx pegylated liposomal whenever a cumulative anthracycline dose of 450 mg/m2 would be exceeded. The above examination and evaluation procedures used for monitoring cardiac performance during anthracycline therapy are performed in the following order: ECG, left ventricular ejection fraction assessment, endomyocardial biopsy. If test results indicate possible cardiac damage due to treatment with Caelyx pegylated liposomal, the expected benefit of continued therapy must be carefully weighed against the risk of irreversible cardiac damage. Patients with cardiac disease requiring treatment should receive Caelyx pegylated liposomal only when the expected benefit outweighs the risks to the patient. Caution should be exercised when administering Caelyx pegylated liposomal to patients with cardiac dysfunction. Whenever cardiomyopathy is suspected, i.e. whenever left ventricular ejection fraction has declined relative to pre-treatment values and/or is lower than a prognostically relevant value (e.g. < 45%), endomyocardial biopsy may be considered and it must be carefully assessed whether the expected benefit of continued therapy outweighs the risk of potentially irreversible cardiac damage. Congestive heart failure due to cardiomyopathy may occur suddenly without prior ECG changes — even several weeks after treatment discontinuation. Patients who have been treated with other anthracyclines must be monitored with caution. Any prior (or concurrent) therapy with cardiotoxic medicinal products, such as other anthracyclines/anthraquinones or e.g. fluorouracil, must be taken into account when calculating the total doxorubicin hydrochloride dose. Cardiac toxicity may also occur at cumulative anthracycline doses below 450 mg/m2 in patients with prior mediastinal irradiation or those concomitantly receiving cyclophosphamide therapy. The safety profile of the dosing regimen recommended for breast cancer and ovarian cancer (50 mg/m2) in patients with cardiac disease is similar to that of the 20 mg/m2 dose in AIDS-KS patients (see section 4.8). Myelosuppression Many patients treated with Caelyx pegylated liposomal have baseline myelosuppression due to factors such as prior HIV disease or treatment with numerous concomitant or prior medications, or tumours involving the bone marrow. In pivotal clinical studies in patients with ovarian cancer treated at a dose of 50 mg/m2, myelosuppression was generally mild to moderate, reversible and was not associated with episodes of neutropenic infection or sepsis. Additionally, in the controlled clinical study of Caelyx pegylated liposomal compared with topotecan, the incidence of treatment-related sepsis was substantially lower in patients with ovarian cancer treated with Caelyx pegylated liposomal compared with the topotecan group. Similarly low incidence of myelosuppression was seen in the clinical study in which patients with metastatic breast cancer were treated with Caelyx pegylated liposomal as first-line therapy. In contrast to the experience in breast cancer or ovarian cancer patients, myelosuppression is a dose-limiting adverse reaction in patients with AIDS-related KS (see section 4.8). Due to the potential for bone marrow suppression, blood counts must be monitored regularly during Caelyx pegylated liposomal therapy, at least before each dose of Caelyx pegylated liposomal. Persistent severe myelosuppression may result in superinfection or haemorrhage. In controlled clinical studies in patients with AIDS-related KS, a higher incidence of opportunistic infections was noted with Caelyx pegylated liposomal compared with the bleomycin/vincristine regimen. Both patients and physicians must be aware of this higher incidence and take appropriate measures as necessary. Secondary haematological malignancies As with other DNA-damaging cytotoxic agents, secondary acute myeloid leukaemia and myelodysplasia have been reported in patients who received combination therapy with doxorubicin. Therefore, every patient treated with doxorubicin must be monitored haematologically. Secondary oral neoplasms Very rare cases of secondary oral carcinoma have been reported in patients receiving long-term (more than one year) Caelyx pegylated liposomal or those who had been exposed to a cumulative dose exceeding 720 mg/m2. Cases of secondary oral carcinoma were diagnosed both during treatment with Caelyx pegylated liposomal and up to 6 years after the last dose. Patients should be monitored at regular intervals for the presence of oral ulceration or oral discomfort, which may be a sign of secondary oral carcinoma. Infusion-related reactions Serious and sometimes life-threatening infusion-related reactions, which may be characterised as allergic or anaphylactic-like reactions, may occur within a few minutes of starting the Caelyx pegylated liposomal infusion, with symptoms including asthma, flushing, urticarial rash, chest pain, fever, hypertension, tachycardia, pruritus, sweating, shortness of breath, facial oedema, chills, back pain, tightness in the chest or throat, and/or hypotension. Very rarely, seizures have also been observed in association with infusion reactions. Temporary discontinuation of the infusion usually resolves these symptoms without further treatment. However, medications to treat these symptoms (such as antihistamines, corticosteroids, adrenaline and anticonvulsants) and emergency equipment must be available for immediate use. In most patients, treatment may be continued after resolution of all symptoms without recurrence. Infusion-related reactions rarely recur after the first treatment cycle. To minimise the risk of infusion reactions, the initial dose should be administered at a rate of ≤ 1 mg/min (see section 4.2). Palmar-plantar erythrodysaesthesia syndrome (PPE) PPE is characterised by painful, macular, reddened skin eruptions. In patients, this event is generally observed after two or three treatment cycles. Improvement usually occurs within 1 to 2 weeks, and in some cases complete resolution may take up to 4 weeks or longer. Pyridoxine at a dose of 50 to 150 mg daily and corticosteroids have been used for the prophylaxis and treatment of PPE, but these therapies have not been evaluated in phase III studies. Other strategies for PPE prevention and treatment include keeping the hands and feet cool by exposing them to cold water (soaking, bathing or swimming), avoiding excessively hot water and avoiding restricting them (no tight socks, gloves or shoes). PPE appears to be primarily related to the dosing schedule and may be limited by extending the dosing interval by 1 to 2 weeks (see section 4.2). However, this reaction may be severe and debilitating in some patients and may require treatment discontinuation (see section 4.8). Interstitial lung disease (ILD) Interstitial lung disease (ILD), which may be of acute onset, has been observed in patients receiving pegylated liposomal doxorubicin, including fatal cases (see section 4.8). If patients develop worsening respiratory symptoms such as dyspnoea, dry cough and fever, Caelyx pegylated liposomal must be discontinued and the patient promptly investigated. If ILD is confirmed, Caelyx pegylated liposomal treatment must be discontinued and the patient appropriately treated. Extravasation Although local necrosis following extravasation has been reported very rarely, Caelyx pegylated liposomal is considered an irritant. Animal studies suggest 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), stop the infusion immediately and restart in another vein. Application of ice over the site of extravasation for approximately 30 minutes may help to alleviate the local reaction. Caelyx pegylated liposomal must not be administered intramuscularly or subcutaneously. Patients with diabetes It should be noted that each vial of Caelyx pegylated liposomal contains sucrose and the dose is administered in 5% (50 mg/ml) glucose solution for infusion. Excipients This medicinal product contains less than 1 mmol (23 mg) sodium per dose, that is to say essentially "sodium-free". Common adverse reactions requiring dose modification or treatment discontinuation, see section 4.8.

CAELYX PEGYLATED LIPOSOMAL 2MG/ML Concentrate for solution for infusion

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