Doxorubicin

Owing to differing 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 receiving Caelyx pegylated liposomal undergo routine electrocardiographic monitoring. Transient ECG changes such as T-wave flattening, S-T segment depression and benign arrhythmias do not mandatorily warrant discontinuation of Caelyx pegylated liposomal therapy. However, flattening of the QRS complex is a more significant indicator of cardiotoxic effects. If this change is observed, more definitive and sensitive evaluation of possible anthracycline-induced myocardial injury, i.e. endomyocardial biopsy, should be considered. More specific methods for monitoring and evaluating cardiac function compared with ECG include assessment of left ventricular ejection fraction by echocardiography or, preferably, by multigated radionuclide angiography (MUGA). These evaluations must be performed routinely before initiation of Caelyx pegylated liposomal therapy and repeated periodically during treatment. Assessment of left ventricular function must be considered mandatory before each further administration of Caelyx pegylated liposomal once a cumulative anthracycline dose of 450 mg/m² has been exceeded. The investigations and assessments described above for monitoring cardiac performance during anthracycline therapy are performed in the following order: ECG recording, assessment of left ventricular ejection fraction, endomyocardial biopsy. If the results of these investigations suggest possible cardiac injury related to Caelyx pegylated liposomal therapy, the anticipated benefit of continued treatment must be carefully weighed against the risk of irreversible cardiac damage. In patients with cardiac disease requiring therapy, Caelyx pegylated liposomal should be administered only when the anticipated benefit outweighs the risk to the patient. Caelyx pegylated liposomal should be administered with caution in patients with impaired cardiac function. Whenever cardiomyopathy is suspected — that is, whenever the left ventricular ejection fraction has decreased relatively to pre-treatment values and/or the left ventricular ejection fraction is below a prognostically relevant value (e.g. < 45%) — endomyocardial biopsy may be considered and a careful assessment must be made of whether the anticipated benefit of continued therapy outweighs the risk of potentially irreversible cardiac damage. Congestive heart failure due to cardiomyopathy may occur suddenly without preceding ECG changes, and may also occur several weeks after discontinuation of therapy. Patients who have previously received other anthracyclines must be monitored with caution. Any prior (or concurrent) therapy with cardiotoxic medicinal products, such as other anthracyclines/anthraquinones or, for example, 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 concomitant cyclophosphamide therapy. The safety profile of the dosing schedule recommended for breast and ovarian cancer (50 mg/m²) is similar to that of the 20 mg/m² dose in patients with AIDS-related KS (see section 4.8). Myelosuppression Many patients treated with Caelyx pegylated liposomal have baseline myelosuppression as a result of factors such as their underlying HIV disease, multiple concomitant or previous medicinal products, or tumours involving the bone marrow. In pivotal clinical studies in patients with ovarian cancer treated at 50 mg/m², myelosuppression was generally mild to moderate, reversible, and not associated with episodes of neutropenic infection or sepsis. In addition, in a controlled clinical study of Caelyx pegylated liposomal versus topotecan, the incidence of treatment-related sepsis was substantially lower in ovarian cancer patients treated with Caelyx pegylated liposomal than in patients treated with topotecan. A similarly low incidence of myelosuppression was observed in a clinical study in which patients with metastatic breast cancer were treated with first-line Caelyx pegylated liposomal. In contrast to the experience in patients with breast or ovarian cancer, myelosuppression is the dose-limiting adverse reaction in patients with AIDS-related KS (see section 4.8). Owing to the potential for bone marrow suppression, complete blood counts must be monitored frequently and regularly during therapy with Caelyx pegylated liposomal, at minimum before each subsequent dose. 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 with Caelyx pegylated liposomal compared with the bleomycin/vincristine regimen. Patients and physicians must be aware of this higher incidence and take appropriate action as required. Secondary haematological malignancies As with other DNA-damaging cytotoxic agents, secondary acute myeloid leukaemia and myelodysplasia have been reported in patients receiving combination therapy with doxorubicin. Every patient treated with doxorubicin must therefore undergo haematological monitoring. Secondary oral neoplasms Very rare cases of secondary oral cancer have been reported in patients receiving long-term (more than one year) treatment with Caelyx pegylated liposomal or in patients exposed to cumulative doses greater than 720 mg/m². Cases of secondary oral cancer have been 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 cancer. Infusion-related reactions Serious and occasionally life-threatening infusion-related reactions, characterised as similar to allergic or anaphylactic reactions, may occur within minutes of starting the infusion of Caelyx pegylated liposomal. Symptoms include 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, convulsions have also been observed in association with infusion reactions. Temporary interruption of the infusion usually resolves these symptoms without further treatment. Nevertheless, agents to treat these symptoms (such as antihistamines, corticosteroids, adrenaline and anticonvulsants), as well as emergency equipment, should be available for immediate use. In most patients, treatment can be resumed after all symptoms have resolved, 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 erythrodysesthesia (PPE) syndrome PPE is characterised by painful, macular, reddening 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 4 weeks or longer. Pyridoxine at a dose of 50 to 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 studies. Additional strategies for the prevention and treatment of PPE include keeping the hands and feet cool by exposure to cool water (soaking, bathing or swimming), avoiding excessively hot water, and avoiding constriction (no tight socks, gloves or shoes). PPE appears to be related primarily to the dosing schedule and may be reduced 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 discontinuation of treatment (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 and has included fatal cases (see section 4.8). If patients experience 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, treatment with Caelyx pegylated liposomal must be permanently discontinued and the patient managed 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 as 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 discontinued immediately and restarted in a different vein. Application of ice over the extravasation site for approximately 30 minutes may help to relieve 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 that the dose is administered in 5% (50 mg/mL) glucose solution for infusion. Excipients This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially "sodium-free". For common adverse reactions requiring dose modification or treatment discontinuation, see section 4.8.