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Given the difference in pharmacokinetic profiles and dosing schedules, Lipo-Dox should not be used interchangeably with other formulations of doxorubicin hydrochloride.
Cardiac Toxicity: All patients treating with Lipo-Dox should routinely undergo ECG monitoring. When T-wave flattening, S-T segment depression and arrhythmia occur, therapy discontinuance immediately is not necessary. However, reduction of the QRS complex is considered more indicative of cardiac toxicity. Endomyocardial biopsy should be considered to define for anthracycline induced myocardial injury. (see Adverse Reactions).
Besides ECG, there are many specific methods for monitoring cardiac functions, such as a measurement of LVEF by cardiac echo or preferably by Multigated Angiography (MUGA). These methods should be applied routinely before or during the Lipo-Dox treatment.
The evaluation of left ventricular function is considered to be mandatory before each addition administration of pegylated liposomal doxorubicin which exceeds a lifetime cumulative anthracycline dose of 400 mg/m2 in patients without prior anthracycline exposure. For patients who have received prior adjuvant anthracyclines (epirubicin or doxorubicin), LVEF assessments should be performed before each additional administration of pegylated liposomal doxorubicin that exceeds a lifetime, doxorubicin-equivalent, cumulative anthracycline dose of 450 mg/m2 and each time when the accumulated dosage increment of pegylated liposomal doxorubicin is 100mg/m2, the patients must receive the evaluation of LVEF.
The evaluation tests and monitoring of cardiac performance during anthracycline therapy should be employed in the following order: ECG monitoring, measurement of left ventricular ejection fraction, endomyocardial biopsy. If the test result indicates possible cardiac injury associated with pegylated liposomal doxorubicin therapy, the benefit of continuance of therapy or not must be carefully evaluated.
In patients with cardiovascular disease requiring treatment, administer pegylated liposomal doxorubicin only when the benefit outweighs the risk to the patient.
Caution should be exercised in patients with impaired cardiac function who receive pegylated liposomal doxorubicin.
If the test results indicate possible cardiac injury, such as the left ventricular ejection fraction lower than pre-treatment baseline and/or LVEF is lower than a prognostically relevant values, endomyocardial biopsy might be considered. The benefit of continuance of therapy must be carefully weighed against the risk of developing irreversible myocardial injury.
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 should be observed in patients who have received other anthracyclines. The total dose of doxorubicin HCl should be taken into account any previous (or concomitant) therapy with cardiotoxic compounds such as other anthracyclines/anthraquinones or 5-fluorouracil. The cardiac toxicity also may occur at cumulative anthracycline doses lower than 450 mg/m2 in patients with prior mediastinal irradiation or in those with concurrent cyclophosphamide therapy.
The cardiac safety profile for dosing schedule recommended for both breast and ovarian cancer (50 mg/m2/every 4 weeks) is similar to the 20mg/m2/every 2 weeks profile in AIDS-KS patients. (See Adverse Reactions).
Myelosuppression: Many patients treated with pegylated liposomal doxorubicin have baseline myelosuppression due to such factors as their pre-existing HIV disease or concomitant or previous medications, or tumors involving bone marrow.
In contrast to the experience in breast cancer and ovarian cancer patients, the myelosuppression appears to be the dose-limiting adverse event in AIDS-KS patients. Because of the potential for bone marrow suppression, periodic blood counts must be performed during the course of pegylated liposomal doxorubicin, and at least before each dose of pegylated liposomal doxorubicin.
Persistent severe myelosuppression, may result in recurrent infection or hemorrhage.
Due to the different pharmacokinetic properties and dosing schedules, Lipo-Dox should not be interchanged with other doxorubicin HCl formulations. Combination chemotherapy with pegylated liposomal doxorubicin has been studied in solid tumor populations. Pegylated liposomal doxorubicin has been safely co-administered with standard doses of chemotherapeutic agents that are frequently used in the treatment of advanced breast cancer or ovarian cancer; however the efficacy of such combination regimens has not been established.
Diabetic Patients: Each vial of Lipo-Dox contains sucrose and is administered in Dextrose 5% in Water for intravenous infusion, so precaution should be exercised.
Infusion-associated Adverse Reactions: Severe and sometimes life-threatening infusion reactions which are characterized by allergic-like or anaphylactoid-like reactions, with symptoms including asthma, flushing, urticaria, chest pain, fever, hypertension, tachycardia, pruritus, sweating, shortness of breath, facial edema, chills, back pain, tightness in the chest and throat and/or hypotension may occur within minutes of starting the infusion of pegylated liposomal doxorubicin. Temporarily stopping the infusion usually resolved these symptoms without further therapy. However, medications to treat these symptoms (e.g., antihistamines, corticosteroids, and adrenaline), as well as emergency equipment should be available for immediate use. In most patients can be resumed after all symptoms have resolved, without recurrence. Infusion reactions rarely recur after the first treatment cycle. The initial rate of infusion should be not over 1mg/min to help minimize the risk of infusion reactions. (See Adverse Reactions).
Effects on ability to drive or use machines: Pegylated lipoosmal doxorubicin does not affect on patient's driving, but occur dizziness and somnolence on few people. Driving and machine operations should be avoided in patients who suffer from these effects.
Use in pregnancy and lactation: Pegylated liposomal doxorubicin is embryotoxic in rats and embryotoxic and abortifacient in rabbits. Teratogenicity cannot be excluded. There is no experience in pregnant women with pegylated liposomal doxorubicin, therefore administration to pregnant women is not recommended. Avoid pregnancy in women of childbearing potential and their male partner within 6 months after discontinuation of Lipo-Dox therapy.
It is not known whether Lipo-Dox is excreted in human milk and because of the potential for severe adverse reactions in nursing infants, mothers should discontinue nursing. Medical experts recommend that HIV-infected women should not nurse infants under any circumstances in order to avoid transmission of HIV.
