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

Due to the 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 be mandatorily considered as indications for discontinuation of Caelyx pegylated liposomal therapy. However, a more significant indicator of cardiotoxic effects is flattening of the QRS complex. If this change occurs, more precise and sensitive evaluation of possible anthracycline-induced myocardial damage should be considered, i.e. endomyocardial biopsy. More specific methods for monitoring and evaluating cardiac function than ECG include evaluation of left ventricular ejection fraction by echocardiography, or preferably by Multigated Acquisition (MUGA) scan. These investigations must be performed routinely before starting Caelyx pegylated liposomal therapy and repeated regularly during treatment. Left ventricular function assessment should be considered mandatory before each additional dose of Caelyx pegylated liposomal once the cumulative anthracycline dose exceeds 450 mg/m2. The above-mentioned assessment and evaluation procedures used for monitoring cardiac performance during anthracycline therapy are performed in the following order: ECG recording, left ventricular ejection fraction assessment, endomyocardial biopsy. If the test results suggest possible cardiac damage due to Caelyx pegylated liposomal therapy, the expected benefit of continued therapy must be carefully weighed against the risk of irreversible cardiac damage. Patients with cardiac disease requiring therapy should only receive Caelyx pegylated liposomal 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 the left ventricular ejection fraction declines relative to pre-treatment values and/or the left ventricular ejection fraction is lower than a prognostically relevant value (e.g. < 45%), endomyocardial biopsy may be considered and a careful assessment must be made of whether the expected benefit of continued therapy outweighs the risk of potentially irreversible cardiac damage. Congestive heart failure caused by cardiomyopathy may occur suddenly, without prior ECG changes appearing — even several weeks after treatment has ended. 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 doxorubicin hydrochloride dose. Cardiac toxicity may also occur at cumulative anthracycline doses lower than 450 mg/m2 in patients with prior mediastinal irradiation or in those receiving concomitant cyclophosphamide therapy. The safety profile of the dosing schedule recommended for breast and ovarian carcinoma (50 mg/m2) is similar to that of the 20 mg/m2 dose in patients with AIDS-KS (see section 4.8). Myelosuppression Many patients treated with Caelyx pegylated liposomal have baseline myelosuppression due to such factors as their pre-existing HIV disease, treatment with many concomitant medications or prior medications, or tumours involving the bone marrow. In pivotal clinical trials in patients with ovarian carcinoma treated at a dose of 50 mg/m2, myelosuppression was mostly mild to moderate, reversible, and was not associated with episodes of neutropenic infection or sepsis. Furthermore, in a controlled clinical trial with Caelyx pegylated liposomal versus topotecan, the incidence of treatment-related sepsis was substantially lower in patients with ovarian carcinoma treated with Caelyx pegylated liposomal compared with the topotecan-treated group. A similarly low incidence of myelosuppression was observed in a clinical trial in which patients with metastatic breast carcinoma were treated with Caelyx pegylated liposomal as first-line therapy. In contrast to the experience in patients with breast or ovarian carcinoma, the incidence of myelosuppression in patients with AIDS-related KS is a dose-limiting adverse reaction (see section 4.8). Because of the potential for bone marrow suppression, blood counts must be monitored regularly and frequently 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 trials in patients with AIDS-related KS, a higher incidence of opportunistic infections was observed with Caelyx pegylated liposomal treatment compared with the bleomycin/vincristine dosing regimen. Patients and physicians must be aware of this higher incidence and take appropriate measures when needed. 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, any 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 in those exposed to a cumulative dose exceeding 720 mg/m2. Secondary oral carcinoma cases 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 that may be indicative of secondary oral carcinoma. Infusion-related reactions Serious and sometimes life-threatening infusion-related reactions, characterised as allergic or anaphylactic-like reactions, may occur within minutes of starting a Caelyx pegylated liposomal infusion, with symptoms including asthma, flushing, urticaria, chest pain, pyrexia, hypertension, tachycardia, pruritus, sweating, shortness of breath, facial oedema, chills, back pain, tightness of the chest or throat, and/or hypotension. Very rarely, convulsions have also been observed in association with infusion reactions. Temporarily stopping 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 immediately available. In most patients, treatment may be continued after resolution of all symptoms without recurrence. Infusion-related reactions only 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 per day and corticosteroids have been used for prophylaxis and treatment of PPE; however, these therapies have not been evaluated in phase III studies. Additional strategies for PPE prevention and treatment 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 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 present acutely, has been observed in patients receiving pegylated liposomal doxorubicin, including fatal cases (see section 4.8). If respiratory symptoms such as dyspnoea, dry cough, and fever worsen in patients, administration of Caelyx pegylated liposomal must be interrupted and the patient must be promptly evaluated. If ILD is confirmed, treatment with Caelyx pegylated liposomal 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 suggest that administration of doxorubicin hydrochloride in a liposomal formulation reduces the potential for extravasation injury. If any signs or symptoms of extravasation occur (e.g. stinging, erythema), the infusion should be stopped immediately and restarted 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 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, meaning it is essentially "sodium-free". For common adverse reactions requiring dose modification or treatment interruption, see section 4.8.