Mesothelioma treatment of specific drugs
Injection pemetrexed disodium Statement
[Drug Name] General: injection pemetrexed disodium trade names: English: ALIMTA Chinese: Thai than English name: Pemetrexed disodium for Injection for the Chinese Phonetic Alphabet: Zhu She Yong Pei Mei Qu Sai Er Na of the main ingredients for chemicals Pemetrexed disodium its chemical name, and structured: a little formula: C20H19N5Na2O6 7H2O molecular weight: 597.49
[Characters] Ben Pinwei white to pale yellow or green yellow solid freeze-drying.
[Pharmaco] pharmacological effects pemetrexed is a structure that contains the core group for the pyrrole pyrimidine anti-folate agents, through the destruction of cells within the normal metabolism of folic acid-dependent process, inhibiting cell replication and thus inhibit tumor生长. In vitro studies have shown that pemetrexed can inhibit thymidylate synthase, dihydrofolate reductase and Gly-nucleotide carbamoyl transferase activity of these enzymes are necessary for folic acid synthesis enzyme involved in Thymidylate and purine nucleotide synthesis of the biological process again, pemetrexed through the delivery of the carrier and folic acid on the cell membrane folate binding protein transport system into the cells. Once pemetrexed into the cells, it leaves at glutamic acid synthase multi-role into the next and more in the form of glutamate. More glutamate remaining in the cells to become thymidylate synthase ammonia and Gan-nucleotide carbamoyl transferase inhibitors. More of glutamic acid present in the tumor cells - the process of concentration-dependent, and in normal Very low concentrations of the organization. Many of glutamic acid metabolite in tumor cells to extend the half-life, which will extend the drug in the tumor cells within the role of the time.
Pre-clinical studies have shown that pemetrexed could mesothelioma cell lines in vitro (MSTO-211H, NCI-H2052) growth. Mesothelioma cell lines MSTO-211H research shows that pemetrexed and cisplatin have synergy.
Pharmacodynamic analysis of the population using the indicators is absolutely neutrophil count; acceptable to the people at this time for single-drug pemetrexed, did not receive folic acid and vitamin B12 supplement treatment. By observing the lowest myeloid hematological toxicity to determine the severity of the occurrence and found the body of their goods with the dose and a negative correlation between. Research also found that patients with baseline inspection cystathionine or high concentrations of homocysteine, its absolute granulocyte count of the decline could be even worse. Folic acid and vitamin B12; can reduce homocysteine cystathionine or both the substrate concentration. After more than pemetrexed treatment cycle, not on the neutrophil accumulation of toxicity.
Pemetrexed body after administration (AUC38.3-316.8μg hr / mL), neutrophil under the lowest point of time is about 8-9.6 days, after the lowest point, the neutrophil count to resume Baseline level of 4.2-7.5 hours of the day.
Toxicology genetic toxicity: in vivo mouse bone marrow micronucleus show determination pemetrexed is broken agent, but the number of in vitro experimental study (Ames determination, CHO cell determination). Mutagenesis did not show.
Reproductive toxicity: pemetrexed in accordance with 0.1mg/kg / day or more doses (equivalent to the amount recommended by the Human 1 / 1666) to give male mice can lead to fertility decline, too little semen and testicular atrophy.
Carcinogenesis: no pemetrexed Walled carcinogenesis.
[Pharmacokinetics] pemetrexed pharmacokinetic evaluation of 426 cases in a variety of tumor types of patients, single-drug treatment, the dose of 0.2-838mg/m2, 10 minutes intravenous administration. Pemetrexed mainly in the form of the original drug from the urinary excretion, drug delivery within 24 hours, 70% -90% of the pemetrexed restored to the original form of the drug from the urine discharge. Pemetrexed overall clearance rate for 91.8mL/min (the elimination of creatinine was 90mL/min), for patients with normal renal function, in vivo half-life of 3.5 hours; as kidney function, the clearance rate will be reduced, but the dose will be增加. With the pemetrexed dose of the increase in area under the curve AUC and maximum plasma concentration (Cmax) will be increased in proportion. Treatment of multi-cycle has not changed pemetrexed pharmacokinetic parameters, pemetrexed showed a steady volume of distribution for 16.1 liters. In vitro studies have shown that pemetrexed plasma protein binding rate is about 81%, and from the kidney function.
Special crowd pemetrexed special populations research pharmacokinetics in patients with a total of 400 cases in a single research group.
One of the elderly - the age group of 26-80 years old, pemetrexed Pharmacokinetics no significant change.
Children - not included in clinical studies in patients with children.
Gender - male and female patients compared with patients pemetrexed Pharmacokinetics non.
A Caucasian ethnic origin and patients of African descent, pemetrexed pharmacokinetics similar. Japan has been on trial in patients with pharmacokinetic study, although there was no Japanese patients and patients in the West between the pharmacokinetic parameters of the statistical norm in the control of the report, but still shows that both doses of the absolute value is similar to the basic , But no significant clinical differences.
Liver dysfunction - aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT) and total bilirubin increase does not affect the pemetrexed pharmacokinetics. However, no liver damage in patients with pharmacokinetics. (See [Notes] under the "patients with liver dysfunction").
Renal failure - a total of 127 cases of renal failure patients were pemetrexed pharmacokinetics. If the merger at the same time there are cisplatin treatment, with reduced kidney function, pemetrexed plasma clearance rate, and the whole body exposure dose. Will pemetrexed total body exposure (AUC) and creatinine clearance rate of 100mL/min comparison, when the creatinine clearance rate was 45, 50 and 80mL/min, total body exposure (AUC) increased by 65% to 54% And 13%. (See [the amount of usage] and [attention] under the "warning" section)
[Indication] of the goods and cisplatin for the treatment of surgery can not be malignant pleural mesothelioma.
[The amount of usage] of the goods should have anti-tumor chemotherapy application of the experience under the guidance of qualified doctors to use. This product can only be used for intravenous drip, the solution must be prepared in accordance with the "intravenous drip ready" for that.
Malignant pleural mesothelioma: This product combined with cisplatin for the treatment of malignant pleural mesothelioma the recommended dose for infusion of 500mg/m2 every 21 days of the goods more than 10 minutes, the recommended dose of cisplatin 75mg/m2 drip for more than 2 Hours, this should be the end of the goods delivery 30 minutes later to give cisplatin infusion. Cisplatin treatment must accept the program of hydration. Cisplatin can be found in the specific statement.
Pre-service drugs: corticosteroids - did not pre-service corticosteroids in patients with the drug, using this product should be a higher incidence of skin rash. Pre-service dexamethasone (or similar drugs) can reduce the incidence of skin reaction and its severity. Delivery: 4mg oral dexamethasone 2 times a day, 1 day before the goods delivery, delivery and administration of the day after 1 day even served 3 days. Vitamin A supplement in order to reduce the toxicity of this treatment must be at the same time taking low-dose folic acid and other vitamins containing folic acid compound preparations. Take time: for the first time to give the treatment at least 7 days before the start of the next day, taking 5 doses of folic acid has been taken as a whole cycle of treatment, 1 in the final of the goods 21 days after the delivery service can be stopped. Patients also for the first time in the delivery of the goods within 7 days before the intramuscular injection of vitamin B12 once every 3 months after the first injection cycle, after the administration of vitamin B12 with this drug products in the same day. Dose folic acid :350-1000μg, common dose is 400μg: Vitamin B12 dose 1000μg. (See [Notes] under the "warning").
Laboratory monitoring of the recommended dose adjustment deduction: monitoring - all prepared to accept this treatment of patients with drug use before completion of the platelet count, including the examination of blood cells, after the administration of the need to monitor blood cells and the lowest point in recovery, clinical research At the beginning of the period of a week, 8 days and the first 15 days of inspections of the above-mentioned projects. Patients must neutrophils ≥ 1500/mm3, platelets ≥ 100000cells/mm3, creatinine clearance ≥ 45mL/min, this treatment can begin. Week period required for the treatment of liver function and kidney function in biological and chemical examination.
Recommended dose adjustment method based on a previous cycle low blood cell count and the most serious non-hematologic toxicity dose adjustment. If the 21-day cycle in patients yet to recover from the adverse effects, treatment should be delayed. Patients waiting for the restoration, in accordance with Table 1, Table 2, Table 3 of the requirements for treatment.
Table 1: hematology caused by toxic chemicals present (monotherapy or combination) and cisplatin dose adjustments neutrophil lowest <500/mm3 n = "168)" n = "163 ) "> 5% and the" 10%. (This table lists all the adverse reaction rates were reduced to 5% of the subjective rule out the possibility that researchers may be related to pemetrexed and cisplatin-related). n = "265" n = "276"> 5% and the "10%. (This table lists all the adverse reaction rates were reduced to 5% of the subjective rule out the possibility that researchers might be related to pemetrexed). n = "164) in 3 and 4 degrees laboratory toxicity and the incidence of the above listed pemetrexed administration of a separate clinical study of 3 similar, in addition to neutropenia incidence of (respectively For 12.8 percent and 5.3 percent) and alanine aminotransferase increase in the incidence (of 1.9% and 15.2%), mainly caused by the different groups of subjects, as in Phase 2 studies included those with liver metastasis and / Or baseline abnormal liver function abnormalities in patients with breast cancer, some of these patients prior to chemotherapy has not been too many times already, and some chemotherapy. "> 1.5 times the upper limit of normal in patients with non-clinical research into the products: the patients with liver metastasis, Transaminase> 3.0 times the upper limit of normal, non-clinical research into the products; there are patients with liver metastasis, if transaminase in the 3.0 and 5.0 times the upper limit of normal, clinical research into the products. Liver dysfunction in patients with the dose adjustment see table 2. (See [pharmacokinetics] under the "special groups").
The patients with renal insufficiency of the goods, primarily by renal excretion. And compared to patients with normal renal function. Renal failure in patients with the overall clearance rate decreased, AUC increased. With moderate renal failure patients, cisplatin combination products with the security has not yet been determined (see [pharmacokinetics] under the "special groups").
Drug interactions with the laboratory has not yet been determined. There is no research to prove whether or not to serve patients using this product to drive and operate the machines have an impact, however, proved that Ben Pinke can lead to fatigue, if there is such a scenario, the patient should be informed of careless driving and operating machinery.
【Pregnant women and breast-feeding women use pregnancy】: pregnant women to receive this treatment may be harmful to the fetus. Pregnancy 6 days -15 days of the mice, the vein to 0.2mg/kg (0.6mg/m2) or 5mg/kg (15 mg/m2) pemetrexed, fetal toxicity and teratogenicity. 0.2mg/kg dose given to mice (about recommended human dose of 1 / 833) pemetrexed can cause fetal malformation (talus and the first skull of incomplete ossification), 5mg/kg can cause cleft palate (equivalent to Recommended human dose of 1 / 33). Embryo toxicity mainly in the fetal mortality rate increase at the same time embryo growth retardation. Pregnancy does not have information on women's access to treatment in this study, as recommended in patients with contraception. If during pregnancy the use of the goods so that patients using this product during pregnancy should be informed of the fetus may be potentially dangerous. Breast-feeding: or its metabolites in the secretion of milk from whether or not yet determined. But Ben Pinke to suck the breast of the baby has serious potential harm to accept this treatment should stop breast-feeding mothers.
【Use of children】 for children of drug safety and efficacy has not yet been determined.
【Elderly patients with drug】 of all patients in accordance with the dose adjustment methods, no special program (see [pharmacokinetics] in a special part of the population).
【Chemotherapy drug interactions 】- cisplatin does not change pemetrexed pharmacokinetics, pemetrexed are all platinum drugs had no effect on pharmacokinetics. Vitamins - folic acid and at the same time to give oral vitamin B12 injection does not change pemetrexed pharmacokinetics. Cytochrome P450 enzymes of drug metabolism - in vitro liver MG forecast results show that pemetrexed has not led to the adoption of CYP3A enzyme, CYP2D6 enzyme, CYP2C9 enzyme CYP1A2 enzyme and metabolism of the drug reduced the rate of removal. Chapei study did not view the United States side of the music of cytochrome P450 isozymes. Because, according to the schedule recommended by the administration (1 every 21 days), any of the goods-induced no significant role. Aspirin - to give low-to medium-dose (6 hours per 325mg) of aspirin did not affect the pemetrexed pharmacokinetics of high doses of aspirin on the pemetrexed power-generation drugs It was not immediately clear impact on learning. Ibuprofen - in patients with normal renal function, the daily dose of ibuprofen 400mg, 4 times / day, could pemetrexed clearance rate of 20% (AUC, an increase of 20%). The higher dose of ibuprofen pemetrexed pharmacokinetics impact is still unclear. This product mainly through the glomerular filtration and tubular excretion of the role of the original forms of drugs from the urinary tract eliminated from the body. At the same time give to the kidneys against the drug will be delayed clearance of the goods at the same time given the increase in the burden of renal tubular other drugs (such as probenecid) may also delay the removal of the goods. For normal renal function (creatinine clearance rate of patients with ≥ 80ml/min) patients, and to Ben Pinke drug ibuprofen at the same time (400mg, 4 times / day), but there is light to moderate renal insufficiency (creatinine clearance Between 45 to 79ml/min) patients, the goods and the use of ibuprofen at the same time to be careful. There are light to moderate renal failure patients using this product should be in the 2 days before treatment, drug treatment and the day after 2 days, do not use the short half-life of non-steroidal anti-inflammatory drugs. Long half-life of non-steroidal anti-inflammatory drugs with the potential interaction of chemicals, not yet identified. However, using this product should be 5 days before treatment, drug treatment and the day after 2 days, but also interrupted non-steroidal anti-inflammatory drug treatment. If the application must be non-steroidal anti-inflammatory drugs must be closely monitored toxicity, particularly bone marrow suppression, gastrointestinal and renal toxicity.
【Drug overdose】 just a few of the items drug overdose. The major adverse reaction to neutropenia, anemia, thrombocytopenia, mucositis and skin rash. The drug can be expected to have a major overdose of complications of bone marrow suppression, for the performance of neutropenia, thrombocytopenia, and anemia. In addition, it may be accompanied or not accompanied by fever infections, diarrhea and mucositis. In the event of a drug overdose, doctors should be immediately taken under the guidance of the appropriate measures. Clinical studies, if there is more than 4 degrees 3 days or 3 days leukopenia more than 4 degrees neutropenia, folinic acid can be used, if there is 4 degrees or 3 degrees thrombocytopenia thrombocytopenia or bleeding associated 3 / 4 degree of mucositis, should the use of leucovorin. Folinic acid and the recommended dose is: intravenous drug delivery, 1st dose of 100mg/m2, after 50mg/m2, every 6 hours 1, MS 8 days. Dialysis through the lifting of the goods over the role has not yet been determined.
【Specifications】 0.5 g / bottle
【 Key Storage】 This product should be preserved at room temperature. In accordance with the above-mentioned methods of preparation of this solution products, non-anti-bacterial preservatives, micro-organisms from the point of view should be used immediately, do not throw away part. If you do not run out of time, with good products in this solution can be placed in refrigerator (2-8 ℃) or at room temperature preservation (15-30 ℃), no dark, and its physical and chemical properties within 24 hours remained stable. This product is not photosensitive.
【Packaging】 Glass bottle packaging equipment, a bottle box
【Validity】 valid for 24 months
【Drug Registration No.】 H20050441
【manufacturers】 Lilly France SAS Address: rue du Colonel Lilly, 67640 Fegersheim, France