2010/06/15

Daunorubicin liposomal

International name:
Liposomal Daunorubicin (Daunorubicin liposomal)

Group Affiliation:
Antitumor agents, antibiotic

Description of the active substance (INN):
Daunorubicin liposomal

Dosage form:
Concentrate for solution for infusion

Mode of action:
The antitumor antibiotic anthracyclines, produced by Streptomyces coeruleorubidis, with cytostatic effect. It acts on the S-phase of mitosis. Blocks matrix function of DNA, disrupting the synthesis of nucleic acids and protein. It is believed that the mechanism of action is based on the anthracycline intercalation between adjacent base pairs of the double helix of DNA, which prevents its deploying for subsequent replication. Antitumor activity is also realized through the interaction with membranes and the formation of free radicals of semiquinone type. Characterized by high antimitotic activity and high (in contrast to neliposomalnogo daunorubicin) selectivity of action. It is believed that the mechanism for delivery daunorubicin in solid tumors is associated with increased permeability of the vascular network of the tumor for some of the particles, similar in size to the vesicles liposomal daunorubicin. Inside the vesicles tumor drug penetrate into the tumor cell, after which the cleavage of liposomes with release into the cell-free daunorubicin. In addition, free daunorubicin in the measured concentrations present in plasma, which could further enhance the antitumor effect. The study of the therapeutic action showed a higher efficiency effects on solid tumors of liposomal daunorubicin in front of the ordinary.

Indications:
Kaposi's sarcoma against a background of HIV infection (in ineffectiveness of local therapy or systemic therapy with interferon alpha).

Contraindications:
Hypersensitivity (including to other anthracyclines or antratsendionam), severe depression of bone marrow function (leukopenia - the number of counts below 4 thousand / ml, granulocytopenia - less 750/mkl, thrombocytopenia - platelet count less than 120 thousand / ml) , decompensated chronic heart failure, end stage disease, cachexia, severe hepatic and / or renal failure, peptic ulcer and 12 duodenal ulcer (in acute), acute infectious diseases of viral, fungal or bacterial origin (including chicken pox, zoster). C care. The simultaneous use of lipid drugs for parenteral nutrition, depression of bone marrow hematopoiesis (including on a background of concomitant radiotherapy or chemotherapy, bone marrow infiltration by tumor cells), hyperuricemia (gout especially manifested or urate nefrourolitiazom), pregnancy, lactation, childhood and old age (safety and efficacy not established).

Side effects:
From the side of hematopoiesis: suppression of bone marrow hematopoiesis (anemia, leukopenia, granulocytopenia, thrombocytopenia). On the part of the SSA: increased blood pressure (nesimptomaticheskoe), syncope; potentially feasible (at high doses - more than 300 mg / sqm) development of CH (arrhythmia, tachycardia, shortness of breath, swelling of the ankles). On the part of the digestive system: dry mouth, tooth pain, dysphagia, nausea, vomiting, diarrhea, tenesmus, abdominal pain, ulceration of the mucous membrane of the gastrointestinal (ulcerative stomatitis and esophagitis, etc.) . the nervous system: headache, drowsiness or insomnia, tremor. On the part of the urinary system: dysuria, nocturia, or polyuria. On the part of the sense organs: eye pain, conjunctivitis, tinnitus. Allergic reactions: skin rash, itching; infusion reaction - back pain, a feeling of compression in the chest (there in the first 5-10 min infusion, and are at lower speeds infusion or its termination). Local reactions: at the injection site - phlebitis, painful inflammation (cellulitis), with exposure to skin - necrosis of surrounding tissues. Other: alopecia, hyperuricemia, opportunistic infections, lihoradka.Peredozirovka. Symptoms: mucositis, neutropenia, thrombocytopenia. Treatment: symptomatic, the appointment of colony stimulating factor (filgrastim).

Dosage and administration:
Only in / for at least 30-60 minutes, the recommended starting dose - 40 mg / m 1 time in 2 weeks. Dose picked individually to obtain a positive effect and continue throughout the life of effectiveness. Before the introduction of the solution is diluted with 5% dextrose to a concentration of 0.2-1 mg / ml. The finished solution should be used no later than 6 h after preparation. Patients with impaired renal function reduce the dose - when the concentration of serum creatinine above 0.3 mg / dL is recommended to use half the usual dose. If the liver function and concentration of bilirubin in the blood serum of 20.5 -51.3 mmol / l should use 3 / 4 normal doses at a concentration of bilirubin above 51.3 mmol / L - half the normal dose.

Cautions:
Treatment should be conducted in a specialized department specialist with experience in anti-tumor chemotherapy. Should be used only freshly prepared solution of the drug. Before and during treatment is necessary to monitor patterns of peripheral blood of renal function, liver, CAS (echocardiography, EKG). The treatment of anthracycline In most patients there may be alopecia, which is less pronounced in the treatment of liposomal daunorubicin and disappears after 5 weeks or more after completion of therapy. Particular attention should be paid to patients receiving combination chemotherapy with other anticancer drugs that have a dampening effect on bone marrow function . should exercise caution when using in conjunction with lipid preparations for parenteral nutrition, and together with other liposomal products. When in / introduction should take precautions to avoid extravasation of the drug, and avoid contact with eyes. It must be borne in mind that the use of the drug may cause heritable genetic changes. Male patients should be carefully observe measures of contraception during therapy and for 6 months after treatment. Women should avoid pregnancy during treatment. Application neliposomalnogo daunorubicin may lead to the Commission and the CHF. Such side effects have been observed in clinical use of liposomal daunorubicin. Nevertheless, it should consider the possibility of cardiotoxic actions, so all patients receiving the drug should be subjected to during the entire course of treatment is often the ECG examination. Transient ECG changes, such as flattening of the T wave, reduction of ST segment and clinically insignificant arrhythmias, are not indications to stop therapy. Reduction of QRS voltage is a more specific manifestation of the cardiotoxic actions. When this change should consider the possibility of conducting specific tests to most accurately detect myocardial damage induced by anthracyclines, - a biopsy of the endocardium. Compared with the ECG a more specific method for the evaluation and monitoring of cardiac function is the measurement of left ventricular ejection fraction. These methods should be used in patients with increased risk for the Commission before the start of therapy (including those with a history of disease CAS) and periodically during treatment, especially in cases where the cumulative dose exceeds 800 mg / sqm. If signs of CMS (the decline of left ventricular ejection fraction compared with that before the start of therapy and / or value of the indicator of clinically meaningful reduced - less than 45%) should be endocardial biopsy. It is necessary to carefully assess the ratio of potential benefits from further therapy and the risk of irreversible damage to the heart muscle. CHF as a result of the Commission may develop suddenly, without previously observed changes in ECG, and can occur several weeks after cessation of therapy. When calculating the total dose should be considered as dose cardiotoxicity of drugs (including other anthracyclines, antratsendionov, 5-fluorouracil and etc.) derived or received by the patient. During the period of treatment is not recommended immunization with viral vaccines, should also avoid contact with bacterial infections and contact sports classes, which are likely to hemorrhage and trauma (especially in patients with depression of bone marrow hemopoiesis).

Interaction:
Side effects in the interaction with antiretroviral drugs were observed. Pharmaceutical incompatible with heparin and dexamethasone phosphate (daunorubicin precipitate formed), highly alkaline solutions (pH over 8, because of the instability of the glycosidic linkage daunorubicin), 0.9% solution of NaCl (aggregation of liposomes), impurities contained bacteriostatic agents - benzyl alcohol or other substance detergentopodobnye (can cause rupture of the membrane bilayer of liposomes, leading to a premature leak of the active ingredient). The solvent can be used only 5% dextrose. Compatible with vincristine, cyclophosphamide, 6-mercaptopurine, prednisolone, L -asparaginase, methotrexate. Hepatotoxic drugs (including methotrexate) increase the risk of liver problems. Ap. anticancer drugs enhance the therapeutic effect and severity of bone marrow suppression. cyclophosphamide, radiation therapy, other anticancer drugs, medications Li + increase the cardiotoxicity. arthrifuge reduces the effect of allopurinol, colchicine, sulfinpirazon blockers and tubular secretion (may require adjustment of doses of drugs arthrifuge; to eliminate hyperuricemia, arising during the treatment of liposomal daunorubicin, allopurinol is preferred because urikozuricheskie arthrifuge drugs increase the risk of nephropathy). With the introduction of live virus vaccines available vaccine virus replication and increased adverse effects of inactivated vaccines - decrease production of antiviral antibodies.