Special Warning : אזהרת שימוש

4.4 Special warnings and precautions for use
Given the difference in pharmacokinetic profiles and dosing schedules, Lipodox Liposomal should not be used interchangeably with other non-liposomal formulations of doxorubicin hydrochloride.

Cardiac toxicity:
It is recommended that all patients receiving Lipodox Liposomal routinely undergo frequent ECG monitoring.
Transient ECG changes such as T-wave flattening, S-T segment depression and benign arrhythmias are not considered mandatory indications for the suspension of Lipodox Liposomal therapy. However, reduction of the QRS complex is considered more indicative of cardiac toxicity. If this change occurs, the most definitive test for anthracycline myocardial injury, i.e., endomyocardial biopsy, must be considered.
More specific methods for the evaluation and monitoring of cardiac functions as compared to ECG are a measurement of left ventricular ejection fraction by echocardiography or preferably by Multigated Angiography (MUGA). These methods must be applied routinely before the initiation of Lipodox Liposomal therapy and repeated periodically during treatment. The evaluation of left ventricular function is considered to be mandatory before each additional administration of Lipodox Liposomal that exceeds a lifetime cumulative anthracycline dose of 450 mg/m 2.
The evaluation tests and methods mentioned above concerning the monitoring of cardiac performance during anthracycline therapy are to be employed in the following order: ECG monitoring, measurement of left ventricular ejection fraction, endomyocardial biopsy. If a test result indicates possible cardiac injury associated with Lipodox Liposomal therapy, the benefit of continued therapy must be carefully weighed against the risk of myocardial injury.
In patients with cardiac disease requiring treatment, administer Lipodox Liposomal only when the benefit outweighs the risk to the patient.

Exercise caution in patients with impaired cardiac function who receive Lipodox Liposomal.
Whenever cardiomyopathy is suspected, i.e., the left ventricular ejection fraction has substantially decreased relative to pre-treatment values and/or left ventricular ejection fraction is lower than a prognostically relevant value (e.g. < 45%), endomyocardial biopsy may be considered and the benefit of continued therapy must be carefully evaluated against the risk of developing irreversible cardiac damage.
Congestive heart failure due to cardiomyopathy may occur suddenly, without prior ECG changes and may also be encountered several weeks after discontinuation of therapy.
Caution must be observed in patients who have received other anthracyclines. The total dose of doxorubicin hydrochloride must also take into account any previous (or concomitant) therapy with cardiotoxic compounds such as other anthracyclines/anthraquinones or e.g. 5-fluorouracil. Cardiac toxicity also may occur at cumulative anthracycline doses lower than 450 mg/m 2 in patients with prior mediastinal irradiation or in those receiving concurrent cyclophosphamide therapy.
The cardiac safety profile for the dosing schedule recommended for both breast and ovarian cancer (50 mg/m 2) is similar to the 20 mg/m2 profile in patients with AIDS-KS (see section 4.8).

Myelosuppression:
Many patients treated with Lipodox Liposomal have baseline myelosuppression due to such factors as their pre- existing HIV disease or numerous concomitants or previous medications, or tumours involving bone marrow. In the pivotal trial in patients with ovarian cancer treated at a dose of 50 mg/m 2, myelosuppression was generally mild to moderate, reversible, and was not associated with episodes of neutropaenic infection or sepsis. Moreover, in a controlled clinical trial of Lipodox Liposomal vs. topotecan, the incidence of treatment related sepsis was substantially less in the Lipodox Liposomal-treated ovarian cancer patients as compared to the topotecan treatment group. A similar low incidence of myelosuppression was seen in patients with metastatic breast cancer receiving Lipodox Liposomal in a first-line clinical trial. In contrast to the experience in patients with breast cancer or ovarian cancer, myelosuppression appears to be the dose- limiting adverse event in patients with AIDS-KS (see section 4.8). Because of the potential for bone marrow suppression, periodic blood counts must be performed frequently during the course of Lipodox Liposomal therapy, and at a minimum, prior to each dose of Lipodox Liposomal.
Persistent severe myelosuppression, may result in superinfection or haemorrhage.
In controlled clinical studies in patients with AIDS-KS against a bleomycin/vincristine regimen, opportunistic infections were apparently more frequent during treatment with Lipodox Liposomal. Patients and doctors must be aware of this higher incidence and take action as appropriate.

Secondary haematological malignancies
As with other DNA-damaging antineoplastic agents, secondary acute myeloid leukemias and myelodysplasias have been reported in patients having received combined treatment with doxorubicin. Therefore, any patient treated with doxorubicin should be kept under haematological supervision.

Secondary oral neoplasms
Very rare cases of secondary oral cancer have been reported in patients with long-term (more than one year) exposure to Lipodox Liposomal or those receiving a cumulative Lipodox Liposomal dose greater than 720 mg/m2. Cases of secondary oral cancer were diagnosed both, during treatment with Lipodox Liposomal, and up to 6 years after the last dose. Patients should be examined at regular intervals for the presence of oral ulceration or any oral discomfort that may be indicative of secondary oral cancer.

Infusion-associated reactions:
Serious and sometimes life-threatening infusion reactions, which are characterised by allergic-like or anaphylactoid-like reactions, 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 and throat and/or hypotension may occur within minutes of starting the infusion of Lipodox Liposomal.
Very rarely, convulsions also have been observed in relation to infusion reactions. Temporarily stopping the infusion usually resolves these symptoms without further therapy. However, medications to treat these symptoms (e.g., 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 reactions rarely recur after the first treatment cycle. To minimise the risk of infusion reactions, the initial dose should be administered at a rate no greater than 1 mg/minute (see section 4.2).

Palmar plantar erythrodysaesthesia syndrome (PPE)
PPE is characterised by painful, macular reddening skin eruptions. In patients experiencing this event, it is generally seen after two or three cycles of treatment. Improvement usually occurs in 1-2 weeks, and in some cases, may take up to 4 weeks or longer for complete resolution. Pyridoxine at a dose of 50-150 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 trials. Other strategies to prevent and treat PPE include keeping hands and feet cool, by exposing them to cool water (soaks, baths, or swimming), avoiding excessive heat/hot water and keeping them unrestricted (no socks, gloves, or shoes that are tight fitting). PPE appears to be primarily related to the dose schedule and can be reduced by extending the dose interval 1- 2 weeks (see section 4.2). However, this reaction can 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 have an acute onset, has been observed in patients receiving pegylated liposomal doxorubicin, including fatal cases (see section 4.8). If patients experience worsening of respiratory symptoms such as dyspnoea, dry cough, and fever, Lipodox Liposomal should be interrupted and the patient should be promptly investigated. If ILD is confirmed, Lipodox Liposomal should be discontinued and the patient treated appropriately.

Extravasation
Although local necrosis following extravasation has been reported very rarely, Lipodox Liposomal is considered to be 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) terminate the infusion immediately and restart in another vein. The application of ice over the site of extravasation for approximately 30 minutes may be helpful in alleviating the local reaction. Lipodox liposomal must not be given by the intramuscular or subcutaneous route.

Diabetic patients:
Please note that each vial of Lipodox Liposomal contains sucrose and the dose is administered in 5 % (50 mg/ml) glucose solution for infusion.

Excipients
This medicine contains less than 1 mmol sodium (23 mg) per dose and is essentially ‘sodium-free’.
For common adverse events which required dose modification or discontinuation see section 4.8.

Effects on Driving

4.7 Effects on ability to drive and use machines
Lipodox Liposomal has no or negligible influence on the ability to drive and use machines. However, in clinical studies to date, dizziness and somnolence were associated infrequently (< 5 %) with the administration of Lipodox Liposomal. Patients who suffer from these effects must avoid driving and operating machinery.