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 necessarily mandate discontinuation of Caelyx pegylated liposomal. However, flattening of the QRS complex is a more significant indicator of cardiotoxicity. If this change occurs, more precise and sensitive evaluation of possible anthracycline-induced myocardial injury, namely endomyocardial biopsy, should be considered. More specific techniques for monitoring and assessing cardiac function than ECG include evaluation of left ventricular ejection fraction by echocardiography or, preferably, by multigated radionuclide angiography (MUGA). These assessments should be performed routinely before initiation of Caelyx pegylated liposomal therapy and repeated periodically during treatment. Evaluation of left ventricular function should be considered mandatory before each further administration of Caelyx pegylated liposomal if the cumulative anthracycline dose of 450 mg/m² would be exceeded. The above-mentioned assessment procedures used to monitor cardiac performance during anthracycline therapy are performed in the following sequence: ECG, evaluation of left ventricular ejection fraction, and endomyocardial biopsy. If the results suggest possible cardiac injury due to Caelyx pegylated liposomal therapy, the expected benefit of continued therapy must be carefully weighed against the risk of irreversible cardiac damage. In patients with cardiac disease requiring treatment, Caelyx pegylated liposomal should be administered only when the expected benefit outweighs the risk to the patient. Caelyx pegylated liposomal should be administered with caution in patients with cardiac dysfunction. Whenever cardiomyopathy is suspected—that is, whenever the left ventricular ejection fraction has decreased substantially relative 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 the expected benefit of continued therapy must be carefully weighed against the risk of potential irreversible cardiac damage. Congestive cardiac failure due to cardiomyopathy may occur suddenly, without preceding ECG changes, even several weeks after discontinuation of therapy. Patients previously treated with other anthracyclines must be monitored with caution. The cumulative dose of doxorubicin hydrochloride should also take into account any prior (or concurrent) therapy with cardiotoxic agents, such as other anthracyclines/anthraquinones or, for example, fluorouracil. Cardiotoxicity may also occur at cumulative anthracycline doses below 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 and ovarian cancer (50 mg/m²) is comparable to that of the 20 mg/m² regimen used in patients with AIDS-related KS (see section 4.8). Myelosuppression Many patients treated with Caelyx pegylated liposomal have baseline myelosuppression due to factors such as pre-existing HIV disease, multiple concomitant or prior medications, or bone marrow involvement by tumour. In pivotal clinical studies in patients with ovarian cancer treated at 50 mg/m², myelosuppression was generally mild to moderate, reversible, and was not associated with episodes of neutropenic infection or sepsis. Furthermore, in a controlled clinical study comparing Caelyx pegylated liposomal with topotecan, the incidence of treatment-related sepsis was substantially lower in ovarian cancer patients treated with Caelyx pegylated liposomal than in those treated with topotecan. A similarly low incidence of myelosuppression was observed in a clinical study in which patients with metastatic breast cancer received Caelyx pegylated liposomal as first-line therapy. 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). Because of the potential for bone marrow suppression, complete blood counts should be performed frequently and regularly throughout therapy with Caelyx pegylated liposomal, at minimum prior to administration of 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 than with the bleomycin/vincristine regimen. Patients and physicians should be aware of this increased incidence and take appropriate measures 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. Any patient treated with doxorubicin must therefore be monitored haematologically. Secondary oral neoplasms Very rare cases of secondary oral cancer have been reported in patients receiving Caelyx pegylated liposomal for prolonged periods (more than one year) or with a cumulative dose exceeding 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 oral ulceration or any oral discomfort that may be indicative of secondary oral cancer. Infusion-related reactions Serious and occasionally life-threatening infusion-related reactions, which may be characterised as allergic or anaphylactic-like, may occur within minutes of starting an 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, chest or throat tightness, and/or hypotension. Convulsions have been observed very rarely in association with infusion-related reactions. Temporary interruption of the infusion usually resolves these symptoms without further treatment. Nevertheless, agents to treat such symptoms (such as antihistamines, corticosteroids, adrenaline, and anticonvulsants) and emergency resuscitation equipment must 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 cycle. To minimise the risk of infusion-related 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, reddening skin eruptions. In patients, this event is usually observed after two or three cycles of treatment. Improvement typically occurs within 1 to 2 weeks, and in some cases complete resolution may take 4 weeks or longer. Pyridoxine 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 management of PPE include keeping the hands and feet cool by exposing them to cool water (soaking, bathing, or swimming), avoiding excessive heat or hot water, and avoiding constriction of the hands and feet (no tight-fitting socks, gloves, or shoes). PPE appears to be primarily related to the dosing schedule and may be mitigated by extending the dosing interval by 1 to 2 weeks (see section 4.2). Nevertheless, 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 and has included fatal cases (see section 4.8). If patients develop worsening respiratory symptoms such as dyspnoea, dry cough, and fever, Caelyx pegylated liposomal must be withheld and the patient promptly evaluated. If ILD is confirmed, treatment with Caelyx pegylated liposomal must be 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 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 that the dose is administered in 5% (50 mg/ml) glucose solution for infusion. Excipients This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e. it is essentially "sodium-free". For common adverse reactions requiring dose adjustment or treatment interruption, see section 4.8.