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

Due to 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 as indications for discontinuation of Caelyx pegylated liposomal therapy. However, a more significant indicator of cardiotoxic effects is reduction of the QRS complex. If this change occurs, more accurate and sensitive assessment of possible anthracycline-induced myocardial injury should be considered, i.e. endomyocardial biopsy. More specific methods for monitoring and evaluating cardiac function compared with ECG are the assessment of left ventricular ejection fraction by echocardiography, or preferably by multigated angiography (MUGA). These tests must be performed routinely before initiation of Caelyx pegylated liposomal therapy and repeated periodically during treatment. Left ventricular function assessment must be considered mandatory before each additional administration of Caelyx pegylated liposomal once the cumulative anthracycline dose exceeds 450 mg/m2. The above monitoring and evaluation procedures used to monitor cardiac performance during anthracycline therapy are applied in the following order: ECG recording, left ventricular ejection fraction assessment, endomyocardial biopsy. If test results indicate possible cardiac damage due to Caelyx pegylated liposomal therapy, the 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 relatively decreased from pre-treatment values and/or the left ventricular ejection fraction is lower than the prognostically relevant value (e.g. < 45%), endomyocardial biopsy may be considered and the benefit of continued therapy must be carefully weighed against the risk of potentially irreversible cardiac damage. Congestive heart failure due to cardiomyopathy may occur suddenly, without prior ECG changes — even several weeks after discontinuation of treatment. 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 also be taken into account when calculating the total dose of doxorubicin hydrochloride. Cardiac toxicity may also occur at cumulative anthracycline doses lower than 450 mg/m2 in patients with prior mediastinal irradiation or in those receiving concurrent cyclophosphamide therapy. The safety profile of the dosing schedule recommended for breast cancer and ovarian cancer (50 mg/m2) 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 their underlying 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 not associated with episodes of neutropenic infection or sepsis. Furthermore, in the controlled clinical study of Caelyx pegylated liposomal versus 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 observed 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 patients with breast or ovarian cancer, the incidence of myelosuppression in patients with AIDS-related KS is a dose-limiting adverse effect (see section 4.8). Due to the potential for bone marrow suppression, blood counts must be monitored regularly during therapy with Caelyx pegylated liposomal, at a minimum 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 observed during treatment with Caelyx pegylated liposomal compared with the bleomycin/vincristine regimen. Patients and physicians must be aware of this higher incidence and take appropriate measures when necessary. Secondary haematological malignancies As with other DNA-damaging cytostatic agents, secondary acute myeloid leukaemia and myelodysplasia have been reported in patients who received doxorubicin combination therapy. 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 treatment or in those exposed to cumulative doses 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 indicative of secondary oral carcinoma. Infusion-related reactions Serious and sometimes life-threatening infusion-related reactions may occur within several minutes of starting the Caelyx pegylated liposomal infusion. These reactions can be characterised as allergic or anaphylactic-like, with symptoms including asthma, flushing, urticarial rash, chest pain, fever, hypertension, tachycardia, pruritus, sweating, shortness of breath, facial oedema, chills, back pain, chest and/or throat tightness and/or hypotension. Convulsions have also been very rarely observed in association with infusion reactions. Temporary interruption 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 the majority of 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 usually 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; however, these therapies have not been evaluated in phase III studies. Other strategies for prevention and treatment of PPE include keeping the hands and feet cool by exposure to cold water (soaking, bathing or swimming), avoiding excessively hot water and not restricting them (no tight socks, gloves or shoes). PPE appears to be primarily related to the dosing schedule and can 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 acute in 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, administration of Caelyx pegylated liposomal must be interrupted and the patient promptly investigated. If ILD is confirmed, Caelyx pegylated liposomal therapy must be discontinued and the patient treated appropriately. Extravasation Although local necrosis following extravasation has been reported very rarely, Caelyx pegylated liposomal is considered 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), stop the infusion immediately and restart in another vein. Application of ice over the extravasation site for approximately 30 minutes may help alleviate the local reaction. Caelyx pegylated liposomal must not be administered by the intramuscular or subcutaneous route. 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 it is essentially 'sodium-free'. Common adverse reactions that required dose adjustment or discontinuation of treatment, see section 4.8.