Composition, structure and packing
Concentrate for solution for infusion in the form of transparent, colorless or slightly yellowish, viscous liquid. 1 ml 1 vial. paclitaxel 6 mg, 30 mg. Excipients: polioksil 35 castor oil (macrogol glitserilgidroksistearat), anhydrous ethanol.
Concentrate for solution for infusion in the form of transparent, colorless or slightly yellowish, viscous liquid. 1 ml 1 vial. paclitaxel 6 mg, 100 mg. Excipients: polioksil 35 Castor Oil (macrogol glitserilgidroksistearat), anhydrous ethanol.
Concentrate for solution for infusion in the form of transparent, colorless or slightly yellowish, viscous liquid. 1 ml 1 vial. paclitaxel 6 mg, 260 mg. Excipients: polioksil 35 castor oil (macrogol glitserilgidroksistearat), anhydrous ethanol.
Clinico-pharmacological group: The antitumor drug.
Pharmacological action
Paclitaxel-LENS is an anticancer drug of natural origin, obtained by semi-synthetic from the plant Taxus Baccata. The mechanism of action associated with the ability to promote the "assembly" of microtubules from tubulin dimer molecules, to stabilize their structure and inhibit the dynamic reorganization of the interphase, which violates the mitotic cell function. It was a dose-dependent suppression of bone marrow hematopoiesis. The experimental data have mutagenic and embryotoxic properties, causes a decrease in reproductive function.
Pharmacokinetics
Absorption
When i / in the introduction of paclitaxel for 3 h at a dose of 135 mg / m Cmax of 2170 ng / ml, AUC - 7952 ng / h / ml. When i / in the introduction of paclitaxel for 24 h at a dose of 135 mg / m Cmax is 195 ng / ml and AUC - 6300 ng / hour / ml, respectively. Cmax and AUC dose-dependent manner: at a 3-hour infusion of increasing the dose to 175 mg/m2 leads to an increase in these parameters by 68% and 89%, respectively, with 24-hour - by 87% and 26%, respectively.
Distribution
Binding to plasma proteins - 88-98%. Average Vd -198-688 l / m 2. Time poluraspredeleniya from the blood into the tissues - 30 min. It is easy to penetrate and adsorb tissues, accumulates mainly in the liver, spleen, pancreas, stomach, intestines, heart and muscles. Repeated infusions not cumulative.
Metabolism
Metabolised in the liver by hydroxylation with the participation of isozymes CYP2D8 (with the formation of metabolite 6-α-gidroksipaklitaksel) and CYP3CA4 (with the formation of metabolites 3-para-gidroksipaklitaksel and 6-α, 3-para-digidroksipaklitaksel).
Withdrawal
Derive mainly from the bile - 90%. T1 / 2 and total clearance are variable and depend on the dose and duration in / in the introduction: 13.1-52.7 h and 12.2-23.8 l/ch/m2, respectively. After i / v infusion (1-24 h) the total removal of the kidneys is 1.3-12.6% of the dose (15-275 mg/m2), which indicates the presence of severe extrarenal clearance. The total clearance - 11-24 l / sq.m.
Statement
combined with cisplatin first-line treatment of patients with common form or residual tumor (> 1 cm) of ovarian cancer after laparotomy;
second-line therapy for metastases of ovarian cancer after standard therapy, which gave no positive result;
breast cancer in the presence of affected lymph nodes after a standard combination therapy (adjuvant therapy);
first-line therapy after relapse of breast cancer within 6 months after the start of adjuvant therapy;
second-line therapy for metastatic breast cancer after standard therapy is ineffective;
combined with cisplatin first-line treatment of patients with non small cell lung cancer of the lungs, which are not planned for surgical treatment and / or radiotherapy;
second-line therapy for Kaposi's sarcoma in patients with AIDS after ineffective therapy liposomal anthracyclines.
Dosage regimen
Paclitaxel-LENS entered into / in to a 3-hour or 24-hour infusion at a dose of 135-175 mg/m2 with an interval between courses of 3 weeks. The recommended dose of the drug Paclitaxel-LENS for the treatment of Kaposi's sarcoma in patients with AIDS is 100 mg/m2 as a 3-hour infusion every 2 weeks. The drug is used as monotherapy or in combination: ovarian cancer and non small cell lung lung cancer with cisplatin, in breast cancer with doxorubicin.
When you select and the doses in each individual case should be guided by the data of literature. In order to prevent severe hypersensitivity reactions, all patients should be premedication with GCS, antihistamines, and histamine blockers of H2-receptors.
For example, 20 mg dexamethasone (or equivalent) into approximately 12 and 6 h before injection of the drug Paclitaxel-LENS 50 mg diphenhydramine (or its equivalent) in /, and 300 mg cimetidine or 50 mg of ranitidine in / 30-60 min before injection of the drug Paclitaxel-LENS. The introduction of the drug Paclitaxel-LENS should not be repeated for as long as content of neutrophils did not make, at least, 1500/mkl of blood and platelets at least 100 000/mkl of blood.
Patients who, after the introduction of Paclitaxel-LENS have severe neutropenia (neutrophil content of <500/mm3 within 7 days or longer periods of time) or a severe form of peripheral neuropathy in subsequent treatment courses, dose Paclitaxel-LENS should be reduced by 20%.
The solution preparation is prepared immediately prior to the introduction, breeding concentrate 0.9% sodium chloride solution or 5% dextrose or 5% dextrose in 0.9% sodium chloride injection or 5% dextrose in Ringer's solution to a final concentration of 0.3 to 1.2 mg / ml. Reconstituted solutions may opalestsirovat because of the presence in the dosage form the basis of the carrier, and after filtration solution opalescence persists.
When cooking, storage and administration of the drug Paclitaxel-LENS must use equipment that does not contain parts of PVC. Paclitaxel-LENS should enter through the system with built-in membrane filter (pore size less than 0.22 microns).
Side effect
The frequency and severity of side effects are dose-dependent nature. On the part of the hemopoietic system: neutropenia, thrombocytopenia, anemia. The suppression of bone marrow function, mainly granulocytic germ, was the major toxicity, dose-limiting drug. The maximum reduction of neutrophils is usually observed at 8-11 days, normalization occurs at 22 days.
Since the cardiovascular system: the reduction or increase (rarely) blood pressure, bradycardia, tachycardia, AV-block, ECG changes, thrombosis, thrombophlebitis.
On the part of the respiratory system: pneumonia, pulmonary fibrosis, pulmonary embolism, radiation pneumonitis in patients simultaneously undergoing radiotherapy.
From the CNS and peripheral nervous system: paresthesia; rarely - seizures types of grand mal, visual disturbances, ataxia, encephalopathy, autonomic neuropathy, manifested paralytic ileus and orthostatic arterial hypotension.
On the part of the digestive system: nausea, vomiting, diarrhea, mucositis, anorexia, constipation, increased activity of hepatic transaminases (usually ACT), alkaline phosphatase, bilirubin in the blood serum, isolated cases - an acute intestinal obstruction, intestinal perforation, mesenteric artery thrombosis, ischemic colitis. Cases of development gepatonekroza and hepatic encephalopathy.
The part of the musculoskeletal system: arthralgia, myalgia. Local reactions: pain, swelling, erythema, induration and pigmentation of the skin at the injection site; extravasations may cause inflammation and necrosis of the subcutaneous tissue.
Dermatological reactions: alopecia; rarely - violation pigmentation or discoloration of the nail bed. Allergic reactions: in the early hours - hypersensitivity reactions, manifested bronchospasm, decreased blood pressure, pain behind the sternum, a rush of blood to the face, skin rash, generalized urticaria, angioedema, isolated cases - chills, back pain. Other: asthenia, general malaise.
Contraindications
original content of neutrophils <1500/mkl in patients with solid tumors,
original or registered in the course of treatment the content of neutrophils <1000/mkl with Kaposi's sarcoma in patients with AIDS;
Pregnancy
breastfeeding;
increased sensitivity to drugs, dosage form which includes polioksietilirovannogo castor oil.
With care use in patients with thrombocytopenia (<100 000/mkl), hepatic failure, acute infectious diseases (including herpes zoster, chickenpox, herpes), a severe course of coronary heart disease, myocardial infarction (history), arrhythmia.
Pregnancy and lactation
Paclitaxel-LENS contraindicated during pregnancy and during breastfeeding. Patients during treatment with paclitaxel-LENS, and, at least within 3 months after therapy should use reliable methods of contraception.
Application for violations of liver function
With care use in patients with hepatic insufficiency.
Cautions
Application of Paclitaxel-LENS must be carried out under the supervision of a physician who has experience working with antitumor chemotherapeutic agents. In order to prevent severe hypersensitivity reactions, all patients should be premedication with steroids, antihistamines and H2 blockers histaminic receptors.
In the case of severe hypersensitivity reactions infusion of the drug Paclitaxel-LENS should immediately stop and start symptomatic treatment, and re-enter the drug should not be. During the drug treatment should be regularly monitored peripheral blood picture, blood pressure, pulse rate and the number of breaths (especially for 1 hour infusion), ECG monitoring (and before treatment).
In cases of violations of the AV-conduction, after repeated administration is necessary to conduct continuous cardiac monitoring. If Paclitaxel-LENS used in combination with cisplatin, the first should enter Paclitaxel-LENS. Polioksietilirovannogo castor oil, which is part of the drug Paclitaxel-LENS, may cause the extraction DEGP [di-(2-hexyl) phthalate] from plasticized PVC containers, and the degree of washout DEGP increases with increasing concentration of the solution over time.
Therefore, when preparing, storing and administration of the drug Paclitaxel-LENS must use equipment that does not contain parts of PVC. Paclitaxel-LENS is a cytotoxic agent, with the work that needs to be careful, use gloves and avoid its contact with skin or mucous membranes, which in such cases should be rinsed thoroughly with soap and water, or (eye) with plenty of water.
Use in pediatrics
Safety and efficacy of the drug Paclitaxel-LENS children has not been established.
Effects on ability to drive vehicles and management mechanisms
During treatment Paclitaxel-LENS should refrain from the study of potentially hazardous activities that require high concentration and speed of psychomotor reactions.
Overdose
Symptoms: aplasia of the bone marrow, peripheral neuropathy, mucositis. Treatment: symptomatic. Antidote to paclitaxel is unknown.
Drug Interactions
Cisplatin decreases the total clearance of paclitaxel by 20% (with more pronounced myelosuppression observed when paclitaxel is introduced after cisplatin). The simultaneous use of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect the relationship with paclitaxel plasma proteins. Inhibitors of microsomal oxidation (including ketoconazole, cimetidine, verapamil, diazepam, quinidine, cyclosporine) inhibit the metabolism of paclitaxel.
Terms and Conditions of storage
List B. The drug should be stored out of reach of children, protected from light at temperatures below 25 ° C. Shelf life - 2 years.
Concentrate for solution for infusion in the form of transparent, colorless or slightly yellowish, viscous liquid. 1 ml 1 vial. paclitaxel 6 mg, 30 mg. Excipients: polioksil 35 castor oil (macrogol glitserilgidroksistearat), anhydrous ethanol.
Concentrate for solution for infusion in the form of transparent, colorless or slightly yellowish, viscous liquid. 1 ml 1 vial. paclitaxel 6 mg, 100 mg. Excipients: polioksil 35 Castor Oil (macrogol glitserilgidroksistearat), anhydrous ethanol.
Concentrate for solution for infusion in the form of transparent, colorless or slightly yellowish, viscous liquid. 1 ml 1 vial. paclitaxel 6 mg, 260 mg. Excipients: polioksil 35 castor oil (macrogol glitserilgidroksistearat), anhydrous ethanol.
Clinico-pharmacological group: The antitumor drug.
Pharmacological action
Paclitaxel-LENS is an anticancer drug of natural origin, obtained by semi-synthetic from the plant Taxus Baccata. The mechanism of action associated with the ability to promote the "assembly" of microtubules from tubulin dimer molecules, to stabilize their structure and inhibit the dynamic reorganization of the interphase, which violates the mitotic cell function. It was a dose-dependent suppression of bone marrow hematopoiesis. The experimental data have mutagenic and embryotoxic properties, causes a decrease in reproductive function.
Pharmacokinetics
Absorption
When i / in the introduction of paclitaxel for 3 h at a dose of 135 mg / m Cmax of 2170 ng / ml, AUC - 7952 ng / h / ml. When i / in the introduction of paclitaxel for 24 h at a dose of 135 mg / m Cmax is 195 ng / ml and AUC - 6300 ng / hour / ml, respectively. Cmax and AUC dose-dependent manner: at a 3-hour infusion of increasing the dose to 175 mg/m2 leads to an increase in these parameters by 68% and 89%, respectively, with 24-hour - by 87% and 26%, respectively.
Distribution
Binding to plasma proteins - 88-98%. Average Vd -198-688 l / m 2. Time poluraspredeleniya from the blood into the tissues - 30 min. It is easy to penetrate and adsorb tissues, accumulates mainly in the liver, spleen, pancreas, stomach, intestines, heart and muscles. Repeated infusions not cumulative.
Metabolism
Metabolised in the liver by hydroxylation with the participation of isozymes CYP2D8 (with the formation of metabolite 6-α-gidroksipaklitaksel) and CYP3CA4 (with the formation of metabolites 3-para-gidroksipaklitaksel and 6-α, 3-para-digidroksipaklitaksel).
Withdrawal
Derive mainly from the bile - 90%. T1 / 2 and total clearance are variable and depend on the dose and duration in / in the introduction: 13.1-52.7 h and 12.2-23.8 l/ch/m2, respectively. After i / v infusion (1-24 h) the total removal of the kidneys is 1.3-12.6% of the dose (15-275 mg/m2), which indicates the presence of severe extrarenal clearance. The total clearance - 11-24 l / sq.m.
Statement
combined with cisplatin first-line treatment of patients with common form or residual tumor (> 1 cm) of ovarian cancer after laparotomy;
second-line therapy for metastases of ovarian cancer after standard therapy, which gave no positive result;
breast cancer in the presence of affected lymph nodes after a standard combination therapy (adjuvant therapy);
first-line therapy after relapse of breast cancer within 6 months after the start of adjuvant therapy;
second-line therapy for metastatic breast cancer after standard therapy is ineffective;
combined with cisplatin first-line treatment of patients with non small cell lung cancer of the lungs, which are not planned for surgical treatment and / or radiotherapy;
second-line therapy for Kaposi's sarcoma in patients with AIDS after ineffective therapy liposomal anthracyclines.
Dosage regimen
Paclitaxel-LENS entered into / in to a 3-hour or 24-hour infusion at a dose of 135-175 mg/m2 with an interval between courses of 3 weeks. The recommended dose of the drug Paclitaxel-LENS for the treatment of Kaposi's sarcoma in patients with AIDS is 100 mg/m2 as a 3-hour infusion every 2 weeks. The drug is used as monotherapy or in combination: ovarian cancer and non small cell lung lung cancer with cisplatin, in breast cancer with doxorubicin.
When you select and the doses in each individual case should be guided by the data of literature. In order to prevent severe hypersensitivity reactions, all patients should be premedication with GCS, antihistamines, and histamine blockers of H2-receptors.
For example, 20 mg dexamethasone (or equivalent) into approximately 12 and 6 h before injection of the drug Paclitaxel-LENS 50 mg diphenhydramine (or its equivalent) in /, and 300 mg cimetidine or 50 mg of ranitidine in / 30-60 min before injection of the drug Paclitaxel-LENS. The introduction of the drug Paclitaxel-LENS should not be repeated for as long as content of neutrophils did not make, at least, 1500/mkl of blood and platelets at least 100 000/mkl of blood.
Patients who, after the introduction of Paclitaxel-LENS have severe neutropenia (neutrophil content of <500/mm3 within 7 days or longer periods of time) or a severe form of peripheral neuropathy in subsequent treatment courses, dose Paclitaxel-LENS should be reduced by 20%.
The solution preparation is prepared immediately prior to the introduction, breeding concentrate 0.9% sodium chloride solution or 5% dextrose or 5% dextrose in 0.9% sodium chloride injection or 5% dextrose in Ringer's solution to a final concentration of 0.3 to 1.2 mg / ml. Reconstituted solutions may opalestsirovat because of the presence in the dosage form the basis of the carrier, and after filtration solution opalescence persists.
When cooking, storage and administration of the drug Paclitaxel-LENS must use equipment that does not contain parts of PVC. Paclitaxel-LENS should enter through the system with built-in membrane filter (pore size less than 0.22 microns).
Side effect
The frequency and severity of side effects are dose-dependent nature. On the part of the hemopoietic system: neutropenia, thrombocytopenia, anemia. The suppression of bone marrow function, mainly granulocytic germ, was the major toxicity, dose-limiting drug. The maximum reduction of neutrophils is usually observed at 8-11 days, normalization occurs at 22 days.
Since the cardiovascular system: the reduction or increase (rarely) blood pressure, bradycardia, tachycardia, AV-block, ECG changes, thrombosis, thrombophlebitis.
On the part of the respiratory system: pneumonia, pulmonary fibrosis, pulmonary embolism, radiation pneumonitis in patients simultaneously undergoing radiotherapy.
From the CNS and peripheral nervous system: paresthesia; rarely - seizures types of grand mal, visual disturbances, ataxia, encephalopathy, autonomic neuropathy, manifested paralytic ileus and orthostatic arterial hypotension.
On the part of the digestive system: nausea, vomiting, diarrhea, mucositis, anorexia, constipation, increased activity of hepatic transaminases (usually ACT), alkaline phosphatase, bilirubin in the blood serum, isolated cases - an acute intestinal obstruction, intestinal perforation, mesenteric artery thrombosis, ischemic colitis. Cases of development gepatonekroza and hepatic encephalopathy.
The part of the musculoskeletal system: arthralgia, myalgia. Local reactions: pain, swelling, erythema, induration and pigmentation of the skin at the injection site; extravasations may cause inflammation and necrosis of the subcutaneous tissue.
Dermatological reactions: alopecia; rarely - violation pigmentation or discoloration of the nail bed. Allergic reactions: in the early hours - hypersensitivity reactions, manifested bronchospasm, decreased blood pressure, pain behind the sternum, a rush of blood to the face, skin rash, generalized urticaria, angioedema, isolated cases - chills, back pain. Other: asthenia, general malaise.
Contraindications
original content of neutrophils <1500/mkl in patients with solid tumors,
original or registered in the course of treatment the content of neutrophils <1000/mkl with Kaposi's sarcoma in patients with AIDS;
Pregnancy
breastfeeding;
increased sensitivity to drugs, dosage form which includes polioksietilirovannogo castor oil.
With care use in patients with thrombocytopenia (<100 000/mkl), hepatic failure, acute infectious diseases (including herpes zoster, chickenpox, herpes), a severe course of coronary heart disease, myocardial infarction (history), arrhythmia.
Pregnancy and lactation
Paclitaxel-LENS contraindicated during pregnancy and during breastfeeding. Patients during treatment with paclitaxel-LENS, and, at least within 3 months after therapy should use reliable methods of contraception.
Application for violations of liver function
With care use in patients with hepatic insufficiency.
Cautions
Application of Paclitaxel-LENS must be carried out under the supervision of a physician who has experience working with antitumor chemotherapeutic agents. In order to prevent severe hypersensitivity reactions, all patients should be premedication with steroids, antihistamines and H2 blockers histaminic receptors.
In the case of severe hypersensitivity reactions infusion of the drug Paclitaxel-LENS should immediately stop and start symptomatic treatment, and re-enter the drug should not be. During the drug treatment should be regularly monitored peripheral blood picture, blood pressure, pulse rate and the number of breaths (especially for 1 hour infusion), ECG monitoring (and before treatment).
In cases of violations of the AV-conduction, after repeated administration is necessary to conduct continuous cardiac monitoring. If Paclitaxel-LENS used in combination with cisplatin, the first should enter Paclitaxel-LENS. Polioksietilirovannogo castor oil, which is part of the drug Paclitaxel-LENS, may cause the extraction DEGP [di-(2-hexyl) phthalate] from plasticized PVC containers, and the degree of washout DEGP increases with increasing concentration of the solution over time.
Therefore, when preparing, storing and administration of the drug Paclitaxel-LENS must use equipment that does not contain parts of PVC. Paclitaxel-LENS is a cytotoxic agent, with the work that needs to be careful, use gloves and avoid its contact with skin or mucous membranes, which in such cases should be rinsed thoroughly with soap and water, or (eye) with plenty of water.
Use in pediatrics
Safety and efficacy of the drug Paclitaxel-LENS children has not been established.
Effects on ability to drive vehicles and management mechanisms
During treatment Paclitaxel-LENS should refrain from the study of potentially hazardous activities that require high concentration and speed of psychomotor reactions.
Overdose
Symptoms: aplasia of the bone marrow, peripheral neuropathy, mucositis. Treatment: symptomatic. Antidote to paclitaxel is unknown.
Drug Interactions
Cisplatin decreases the total clearance of paclitaxel by 20% (with more pronounced myelosuppression observed when paclitaxel is introduced after cisplatin). The simultaneous use of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect the relationship with paclitaxel plasma proteins. Inhibitors of microsomal oxidation (including ketoconazole, cimetidine, verapamil, diazepam, quinidine, cyclosporine) inhibit the metabolism of paclitaxel.
Terms and Conditions of storage
List B. The drug should be stored out of reach of children, protected from light at temperatures below 25 ° C. Shelf life - 2 years.
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