Pemetrexed Disodium for Injection

Pemetrexed is an antifolate preparation with a core pyrrolopyrimidine group in its structure. It inhibits cell replication and thus tumor growth by destroying the normal metabolic process of intracellular folate dependence. In vitro studies have shown that pemetrexed can inhibit the activity of thymidylate synthase, dihydrofolate reductase and glycinamide nucleotide formyltransferase, which are enzymes necessary for the synthesis of folate and participate in the bioresynthesis of thymine nucleotides and purine nucleotides. Pemetrexed enters the cell through the carrier carrying folic acid and the folate binding protein transport system on the cell membrane. Once pemetrexed enters the cell, it is converted into polyglutamate under the action of folylpolyglutamate synthetase. Polyglutamate remains in the cell and becomes an inhibitor of thymidylate synthase and glycinamide nucleotide formyltransferase. Polyglutamate is a time-concentration dependent process in tumor cells, while the concentration in normal tissues is very low. The half-life of polyglutamate metabolites in tumor cells is prolonged, thereby prolonging the action time of the drug in tumor cells. Preclinical studies have shown that pemetrexed can inhibit the growth of mesothelioma cell lines (MSTO-211H, NCI-H2052) in vitro. Studies on the mesothelioma cell line MSTO-211H have shown that pemetrexed combined with cisplatin has a synergistic effect.

The main ingredient of this product is pemetrexed disodium. Molecular formula: C20H19N5Na2O6bull;7H2O Molecular weight: 597.49.

This product is a white to light yellow or greenish yellow freeze-dried solid.

This product is used in combination with cisplatin to treat inoperable malignant pleural mesothelioma.

This product should be used under the guidance of a qualified physician with experience in the application of anti-tumor chemotherapy. This product can only be used for intravenous infusion, and the preparation of its solution must be carried out in accordance with the instructions for intravenous infusion preparation. Malignant pleural mesothelioma: The recommended dose of this product combined with cisplatin for the treatment of malignant pleural mesothelioma is 500 mg/m2 of this product infused over 10 minutes every 21 days, and the recommended dose of cisplatin is 75 mg/m2 infused over 2 hours. Cisplatin infusion should be given 30 minutes after the end of this product administration. A hydration plan is required for cisplatin treatment. For details, please refer to the cisplatin instructions. Pre-medication: Corticosteroids-Patients who have not taken corticosteroids in advance have a higher incidence of rash when using this product. Pre-medication with dexamethasone (or similar drugs) can reduce the incidence and severity of skin reactions. Dosage: Dexamethasone 4 mg orally twice a day, 1 day before, on the day of administration, and 1 day after administration of this product for 3 consecutive days. Vitamin Supplementation - In order to reduce toxic reactions, this product must be used simultaneously with low-dose folic acid or other multivitamin preparations containing folic acid.

The following table lists the statistical results of the frequency and severity of adverse reactions greater than 5% in 168 patients with malignant pleural mesothelioma who were randomized to receive pemetrexed and cisplatin combination therapy and 163 patients with malignant pleural mesothelioma who received cisplatin alone in clinical studies. In both trial groups, patients who had not previously received chemotherapy were supplemented with adequate folic acid and vitamin B12. System Organ Frequency Events Pemetrexed/Cisplatin Cisplatin (N=168) (N=163) All % 3-4 degree % All % 3-4 degree % Blood and lymphatic system abnormalities Very common Neutrophils 56.0 23.2 13.5 3.1 White blood cells 53.0 14.9 16.60.6 Hemoglobin 26.24.2 10.40.0 Platelets 23.25.4 8.60.0 Eye abnormalities Common Conjunctivitis 5.40.0 0.60.0 Gastrointestinal abnormalities Very common Nausea 82.1 11.9 76.75.5 Vomiting 56.5 10.7 49.74.3 Stomatitis/pharyngitis 23.23.0 6.10.0 Anorexia 20.21.2 14.10.6 Diarrhea 16.7 3.6 8.0 0.0 Constipation 11.9 0.6 7.4 0.6 Common Indigestion 5.4 0.6 0.6 0.0 General abnormalities Very common Fatigue 47.6 10.1 4 2.3 9.2 Metabolism Nutrition abnormalities Common Dehydration 6.5 4.2 0.6 0.6 Nervous system abnormalities Very common Nervous/sensory 10.1 0.0 9.8 0.6 Common Taste disturbance 7.7 0.0 6.10.6 Renal abnormalities Very common Decreased creatinine clearance 10.7 0.6 9.8 1.2 Renal/urinary system disorders 16.7 0.6 18.4 2.5 Skin and subcutaneous tissue abnormalities Very common Rash 16.1 0.6 4.9 0.0 Hair loss 11.3 0.0 5.5 0.0 * For the classification of adverse reactions, please refer to NCICTC version 2.0. Very common refers to ge; 10%; Common refers to 5% and 10%. (The incidence of all adverse reactions listed in this table has been reduced by 5% to exclude the possibility that the investigators may be subjectively related to pemetrexed and cisplatin.) Clinically relevant toxic reactions with an incidence between 1% and 5% (including 5%) in patients randomized to pemetrexed and cisplatin included: increased AST, ALT and GGT, infection, fever, neutropenic fever, renal failure, chest pain and urticaria; clinically relevant toxic reactions with an incidence of 1% included arrhythmia and motor neuron disease. The following table lists the statistical results of the frequency and severity of adverse reactions greater than 5% in 265 patients randomized to pemetrexed monotherapy and folic acid and vitamin B12 supplementation and 276 patients receiving docetaxel monotherapy in clinical studies. In both trial groups, they were diagnosed with locally advanced or metastatic non-small cell lung cancer. They had received previous chemotherapy. System Organ Frequency Events Pemetrexed/Cisplatin Cisplatin N=265 N=276 All % 3-4 degree % All % 3-4 degree % Blood and lymphatic system abnormalities Very common Hemoglobin 19.24.222.14.3 Leukocytes 12.14.234.127.2 Neutrophils/Granulocytes 10.95.345.340.2 Common Platelets 8.31.91.10.4 Gastrointestinal abnormalities Very common Nausea 30.92.616.71.8 Anorexia 21.91.923.92.5 Vomiting 16.21.512.01.1 Stomatitis/Pharyngitis 14.71.117.4 1.1 Diarrhea 12.80.424.32.5 Common Constipation 5.70.04.00.0 General Abnormality Very Common Fatigue 34.05.335.95.4 Common Fever 8.30.07.60.0 Hepatobiliary Abnormality Common SGPT (ALT) 7.91.91.40.0 SGOT (AST) 6.81.10.70.0 Skin and Subcutaneous Tissue Abnormality Very Common Rash/Desquamation 14.00.06.20.0 Common Itch 6.80.41.80.0 Hair Loss 6.40.437.72.2 bull; Adverse reaction grading refers to NCICTC 2.0 version. Very common refers to ge; 10%; Common refers to 5% and 10%. (The incidence of all adverse reactions listed in this table is reduced by 5% to exclude the possibility that the researchers subjectively believe that it may be related to pemetrexed). Clinically relevant toxicities occurring in 1% and 5% of patients randomized to pemetrexed included: neuropathy, motor neuron disease, abdominal pain, increased creatinine, febrile neutropenia, infection without neutropenia, allergic reaction/anaphylaxis, and erythema multiforme; clinically relevant toxicities occurring in 1% or 1% of patients randomized to pemetrexed included supraventricular arrhythmia. The incidence of grade 3 and 4 laboratory toxicities in the three integrated phase 2 studies of pemetrexed alone (n = 164) was similar to that in the phase 3 studies of pemetrexed alone listed above, except for the incidence of neutropenia (12.8% and 5.3%, respectively) and elevated alanine aminotransferase (15.2% and 1.9%, respectively), which was primarily due to differences in the study population, as the phase 2 studies included patients with breast cancer who had liver metastases and/or abnormal baseline liver function tests, some of whom had not been previously treated with chemotherapy and some of whom had been heavily treated with chemotherapy.

This product is contraindicated in patients with a history of severe allergic reaction to pemetrexed or other ingredients of the drug.

Chemotherapy drugs - Cisplatin does not change the pharmacokinetics of pemetrexed, and pemetrexed has no effect on the pharmacokinetics of all platinum drugs. Vitamins - Simultaneous administration of oral folic acid and intramuscular vitamin B12 does not change the pharmacokinetics of pemetrexed. Cytochrome P450 enzymes on drug metabolism - In vitro liver microglobulin prediction studies showed that pemetrexed did not lead to a decrease in the clearance of drugs metabolized by CYP3A enzymes, CYP2D6 enzymes, CYP2C9 enzymes, and CYP1A2 enzymes. No studies have been conducted to observe the effect of pemetrexed on cytochrome P450 isoenzymes. Because, if the recommended dosing schedule (once every 21 days) is followed, this product has no significant induction effect on any enzyme. Aspirin - Low to moderate doses of aspirin (325 mg every 6 hours) did not affect the pharmacokinetics of pemetrexed, and the effect of high doses of aspirin on the pharmacokinetics of pemetrexed is currently unclear. Ibuprofen - In patients with normal renal function, ibuprofen at a daily dose of 400 mg, 4 times / day, can reduce the clearance of pemetrexed by 20% (AUC increased by 20%). The effect of higher doses of ibuprofen on the pharmacokinetics of pemetrexed is currently unknown. This product is mainly excreted from the body in the urinary tract in the form of the original drug through glomerular filtration and tubular excretion. Concomitant administration of drugs that are harmful to the kidneys will delay the clearance of this product, and concomitant administration of other drugs that increase the burden on the renal tubules (such as probenecid) may also delay the clearance of this product. For patients with normal renal function (patients with creatinine clearance ≥ 80ml/min), this product can be used simultaneously with ibuprofen (400mg, 4 times / day), but for patients with mild to moderate renal insufficiency (creatinine clearance between 45 and 79ml/min), this product should be used with caution with ibuprofen. Patients with mild to moderate renal insufficiency should not use short-half-life NSAIDs 2 days before, on, and 2 days after treatment with this product. The potential interaction between long-half-life NSAIDs and this product is still uncertain. However, NSAID treatment should also be interrupted 5 days before, on, and 2 days after treatment with this product. If NSAIDs must be used, toxic reactions must be closely monitored, especially bone marrow suppression, renal and gastrointestinal toxicity.

This product should be stored at room temperature. The solution of this product prepared according to the above method does not contain antibacterial preservatives. From the perspective of microorganisms, it should be used immediately and not partially discarded. If it is not used up at one time, the prepared solution of this product can be placed in a refrigerator (2-8°C) or stored at room temperature (15-30°C). It does not need to be protected from light. Its physical and chemical properties remain stable within 24 hours. This product is not photosensitizing.

0.5g (based on C20H21N5O6)

Sinopharm A-Think Pharmaceutical Co., Ltd.

• Founded in:

  1997-12-10

• Address:

  No. 111, Yixin Road, Shuangyang Economic Development Zone, Changchun

• Tax NO.:

  912201012440638092

• Registered Funds:

  100 million yuan

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