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    2020-07-30
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Composition:


active ingredient: pemetrexed;


1 bottle contains pemetrexed 100 mg (in the form of pemetrexed disodium hemipentahydrate);


1 bottle contains pemetrexed 500 mg (in the form of pemetrexed disodium hemipentahydrate);


1 bottle contains pemetrexed 1000 mg (in the form of pemetrexed disodium hemipentahydrate);


excipient: mannitol (E 421).


Dosage form. Lyophilized powder for the preparation of concentrate for infusion solution.


Basic physical and chemical properties: lyophilizate from white to light yellow color.


Pharmacotherapeutic group. Antimetabolites. Structural analogues of folic acid.


ATX code L01B A04.


Pharmacological properties.


Pharmacodynamics.


Pemetrexed is an antitumor antifolate agent of multidirectional action, as a result of which the main folate-dependent metabolic processes necessary for cell replication are disrupted.


In vitro studies have shown that pemetrexed inhibits thymidylate synthetase (TS), dehydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are the main folate-dependent enzymes for de novo thymidine and purine nucleotide biosynthesis. Transport of pemetrexed to the cell occurs due to both the reduced folate transporter and the transport systems of the mebran folate-binding protein. Once in the cell, pemetrexed is rapidly transformed into polyglutamate forms by the enzyme folyl polyglutamate synthetase. Polyglutamate forms accumulate in cells and are even stronger inhibitors of TS and GARFT. Polyglutamation is a time – and concentration-dependent process that occurs in tumor cells and, to a lesser extent, in healthy tissues. Polyglutamate metabolites have a longer intracellular Half-Life, which leads to a longer effect of the drug in malignated cells.


Experiments with the msto-211H mesothelioma cell line demonstrated synergistic effects when combined with pemetrexed and cisplatin.


Pharmacokinetics.


The pharmacokinetic properties of pemetrexed were studied in cancer patients with multiple single tumors after the use of pemetrexed as monotherapy by a 10-minute infusion at a dose of 0.2 to 838 mg/m2. Pemetrexed has a stable volume of distribution equal to 9 l/M2. In vitro studies have shown that approximately 81% of pemetrexed binds to plasma proteins. The degree of renal failure does not affect binding. Pemetrexed is subject to limited hepatic metabolism; 70-90% of the administered dose is mainly excreted unchanged in the urine within 24 hours after administration. In vitro studies have shown that pemetrexed is actively eliminated by OAT3 (an organic anion transporter).


The total plasma clearance of pemetrexed is 91.8 mL/min, and the plasma half – life is 3.5 hours in patients with normal renal function (creatinine clearance is 90 mL/min).


The difference in clearance in patients is moderate and amounts to 19.3 %. The total systemic effect of pemetrexed (AUC) and the maximum plasma concentration increase in proportion to the dose increase. The pharmacokinetics of pemetrexed are constant over multiple treatment cycles.


The pharmacokinetic properties of pemetrexed are not affected by the concomitant use of cisplatin. Oral folic acid supplementation and intramuscular vitamin B12 supplementation do not affect the pharmacokinetics of pemetrexed.


Clinical characteristics.


Indications.


Malignant pleural mesothelioma.


Pemetrexed in combination with cisplatin is indicated for the treatment of patients with malignant inoperable pleural mesothelioma.


Non-small cell lung cancer.


Pemetrexed in combination with cisplatin is indicated for the treatment of patients with locally advanced or metastatic non-small cell non-flat cell lung cancer in the first line of chemotherapy.


Pemetrexed as monotherapy is indicated for the maintenance treatment of patients with locally advanced or metastatic non-small cell non-flat cell lung cancer who have not had disease progression after platinum chemotherapy.


Pemetrexed as monotherapy is indicated for the treatment of patients with locally advanced or metastatic non-small cell non-flat cell lung cancer in the second line of chemotherapy.


Contraindications.


Hypersensitivity to the active substance or to any of the excipients of the drug.


Breast-feeding period.


Concomitant use of the yellow fever vaccine.


Children's age.


Special security measures.


As with other potentially toxic antitumor agents, great attention should be paid to safety measures when preparing and using pemetrexed solution for infusions. It is recommended to use gloves. If pemetrexed solution gets on the skin, wash the skin immediately with soap and water. If the pemetrexed solution gets on the mucous membrane, rinse with water. Pemetrexed does not cause blisters. There is no specific antidote to eliminate hemorrhages resulting from the use of pemetrexed. Several cases of hemorrhage caused by pemetrexed have been reported, which were not classified as serious by the researchers. Hemorrhages should be treated according to local standards.


Interactions with other drugs and other types of interactions.


Pemetrexed is mainly excreted unchanged by the kidneys by tubular secretion or, less often, glomerular filtration. Concomitant use of nephrotoxic drugs (for example, aminoglycosides, loop diuretics, platinum preparations, cyclosporine) may lead to a decrease in the clearance of pemetrexed. Such combinations should be used with caution. If necessary, creatinine clearance should be carefully monitored.


Concomitant use of substances that are also eliminated by tubular secretion (probenecid, penicillin) can potentially lead to a decrease in the clearance of pemetrexed. These medications should be combined with pemetrexed with caution. If necessary, creatinine clearance should be carefully monitored.


In patients with normal renal function (creatinine clearance ≥ 80 mL/min), high doses of nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen (>1600 mg/day) and aspirin (≥ 1.3 g/day), may reduce the excretion of pemetrexed and, thus, increase the frequency of adverse reactions. Therefore, caution should be exercised when prescribing high doses of nonsteroidal anti-inflammatory drugs together with pemetrexed to patients with normal renal function (creatinine clearance ≥ 80 mL/min).


In patients with mild to moderate renal insufficiency (creatinine clearance 45-79 mL/min), concomitant use of pemetrexed with nonsteroidal anti-inflammatory drugs (for example, ibuprofen or aspirin) in high doses should be avoided for 2 days before the use of pemetrexed, on the day of its use and for 2 days after.


In the absence of data on potential interactions with nonsteroidal anti-inflammatory drugs that have a long half-life, such as Piroxicam or rofecoxib, concomitant use of these drugs in patients with mild to moderate renal insufficiency should be discontinued 5 days before the use of pemetrexed, on the day of its use and for 2 days after. If concomitant use of NSAIDS is necessary, the patient's condition should be carefully monitored for toxicity phenomena, especially myelosuppression and gastrointestinal toxicity.


Pemetrexed undergoes little metabolism in the liver. The results of in vitro studies with human liver microsomes suggest that pemetrexed does not clinically significantly inhibit the clearance of drugs that are metabolized by CYP3A, CYP2D6, CYP2C9 and CYP1A2.


Interactions inherent in all cytotoxins.


Due to the increased risk of thrombosis, cancer patients often use anticoagulant therapy. High individual variability of coagulation status during the course of the disease and the likelihood of interaction between oral anticoagulants and antitumor chemotherapy drugs require an increase in the frequency of INR control (international normalized ratio), if a decision was made to use oral anticoagulants in such patients.


Concomitant use is contraindicated: yellow fever vaccine-due to the risk of developing a fatal generalized vaccine disease.


Co-administration is not recommended: live attenuated vaccines (except for the yellow fever vaccine, co-administration with which is contraindicated due to the risk of systemic, possibly fatal disease. The risk increases if the patient already has immunosuppression due to an existing disease. In this case, an inactivated vaccine should be used, if any (polio).


Application features.


Pemetrexed may inhibit bone marrow function, which manifests itself in the form of neutropenia, thrombocytopenia, anemia (or pancytopenia); myelosuppression is usually a dose-limiting toxicity. Myelosuppression in patients should be monitored throughout treatment. Pemetrexed should not be used in patients until the absolute neutrophil count (IFN) returns to ≥ 1.5×109/L and platelet count returns to ≥ 100×109/L. Dose reduction in subsequent cycles is based on the following indicators obtained from previous treatment: the minimum IFN value, platelet count, and the strongest possible manifestations of non-hematological toxicity.


Lower overall toxicity and reduced hematological and non-hematological toxicity of Grade III-IV, such as neutropenia, Febrile neutropenia, and infection with Grade III‒IV neutropenia, were observed if folic acid and vitamin B12 were previously used. 


Skin reactions were observed in patients who did not receive corticosteroids. Previous treatment with dexamethasone (or equivalent) may reduce the number of cases and severity of skin reactions.

Clinical experience with the use of the drug in patients with creatinine clearance below 45 mL/min is limited, so such patients should not use pemetrexed.


Patients with mild to moderate renal insufficiency are advised to avoid taking nonsteroidal anti-inflammatory drugs, such as ibuprofen and acetylsalicylic acid (> 1.3 g/day) for 2 days before the use of pemetrexed, on the day of its use, and for 2 days thereafter.


Patients with mild to moderate renal insufficiency who are prescribed pemetrexed therapy, therapy with nonsteroidal anti-inflammatory drugs with a long Half-Life should be discontinued 5 days before treatment, on the day of its use and within 2 days after administration of pemetrexed.


Serious renal disorders, including acute renal failure, have been observed both with pemetrexed monotherapy and when used in combination with other chemotherapeutic agents. Most patients who experienced such disorders had a risk factor for kidney disorders, including dehydration, hypertension, or diabetes. Cases of nephrogenic diabetes insipidus and renal tubular necrosis have also been reported in post-marketing studies using pemetrexed alone or together with other chemotherapeutic agents. Most of these phenomena disappear after discontinuation of pemetrexed. Acute tubular necrosis, decreased renal function, and symptoms of nephrogenic diabetes insipidus (such as hypernatremia) should be monitored regularly in patients.


The effect of oral fluids such as pleural effusion and ascites on pemetrexed has not been fully established. In a Phase 2 study of pemetrexed involving 31 patients with single tumors with stable fluid levels in the serous cavities, there was no difference in the dose-normalized plasma concentration or clearance of pemetrexed compared to patients who had no fluid in the serous cavities. Therefore, drainage should be considered before prescribing pemetrexed to patients with a significant volume of oral fluid.


Severe dehydration associated with gastrointestinal toxicity of pemetrexed in combination with cisplatin was observed. Therefore, patients should receive adequate antiemetic therapy and appropriate hydration before and / or after treatment.


Serious cardiovascular cases, including myocardial infarction, and cerebrovascular disorders have been infrequently observed in clinical trials of pemetrexed, usually when a combination of pemetrexed with other cytotoxic agents is prescribed. Most of the patients who reported such cases had cardiovascular risk factors.


Most cancer patients have an immunosuppressive status, so the combined use of weakened vaccines is not recommended.


Pemetrexed can cause genetic disorders. Sexually mature men are not recommended to plan Parenthood during treatment with pemetrexed and for 6 months after therapy. It is recommended to use contraception or refrain from sexual contact. Given the property of pemetrexed to cause irreversible infertility, men are advised to take measures to store sperm before starting treatment.


Women of reproductive age should use effective contraceptives during treatment with pemetrexed.


Cases of "radiation memory" have been reported in patients treated in previous weeks or years.


The drug contains approximately 108 mg of sodium per bottle, which should be considered if the patient is on a controlled sodium diet.


Use during pregnancy or lactation.


Contraception in men and women.


Women who may become pregnant should take effective contraception measures during treatment with pemetrexed. Pemetrexed can cause genetic disorders. Sexually mature men are not recommended to plan paternity during treatment with pemetrexed and for 6 months after therapy. It is recommended to take contraceptive measures or refrain from sexual contact.


Pregnancy.


There are no data on the use of pemetrexed in pregnant women, but like other antimetabolites, pemetrexed can cause serious birth defects when used during pregnancy. Animal studies have revealed reproductive toxicity. Do not use pemetrexed during pregnancy, except in cases of urgent need – after a thorough assessment of the benefit to the pregnant woman and the risk to the fetus.


Breast-feeding.


It is not known whether pemetrexed passes into breast milk. The occurrence of adverse reactions in infants who are breastfed is not excluded. Therefore, breast-feeding should be discontinued for the duration of treatment with pemetrexed.


Fertility.


Given the property of pemetrexed to cause irreversible infertility, men are advised to take measures to store sperm before starting treatment.


Ability to influence the reaction rate when driving vehicles or other mechanisms.


No studies have been conducted on the effect of the drug on the reaction rate when driving vehicles or other mechanisms. However, pemetrexed has been reported to cause fatigue, so patients should be careful when driving a car or other mechanisms.


Dosage and administration.


The drug should be used under the supervision of a qualified doctor with experience in treatment with antitumor drugs.


Use in combination with cisplatin.


The recommended dose of pemetrexed Vista is 500 mg/m2 of body surface area (PPT) as an intravenous infusion administered for 10 minutes on the first day of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 of PPT as an infusion administered for 2 hours, approximately 30 minutes after the end of the pemetrexed infusion on the first day of each 21-day cycle. The patient should receive adequate antiemetic therapy. Proper hydration of the patient should be performed before or/and after cisplatin administration.


Use as monotherapy.


For the treatment of non-small cell lung cancer (NDRL) after previous chemotherapy, the recommended dose of pemetrexed-Vista is 500 mg/m2ppt as an intravenous infusion administered for 10 minutes on the first day of each 21-day cycle.


Premedication mode


In order to reduce the frequency and severity of skin reactions, corticosteroids should be used the day before the appointment of pemetrexed, on the day of its appointment and on the day after its administration. The corticosteroid dose should be equivalent to 4 mg of dexamethasone orally twice a day.


To reduce toxicity, patients treated with pemetrexed should be prescribed folic acid preparations or multivitamins containing folic acid (350-1000 mcg) daily. During the seven-day period before the first dose of pemetrexed, at least 5 daily doses of folic acid should be taken, folic acid should be continued throughout the entire course of therapy and for 21 days after the last dose of pemetrexed. Patients should also take vitamin B12 intramuscularly 1 time a day for a week before the first dose of pemetrexed and 1 time every 3 cycles thereafter. Subsequent vitamin B12 injections can be given on the day of pemetrexed administration.

Overdose.


Symptoms. The following symptoms have been reported: neutropenia, anemia, thrombocytopenia, mucositis, sensory polyneuropathy, and rash. Suspected complications of overdose include bone marrow suppression, which manifests as neutropenia, thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea and/or mucositis are possible.


Treatment. If an overdose is suspected, it is necessary to monitor the patient's condition, conduct appropriate blood tests, and prescribe symptomatic therapy if necessary. The use of calcium folinate folic acid should be considered.


Adverse reactions.


Adverse reactions with pemetrexed, both in monotherapy and in combination, which were most often reported: bone marrow suppression, manifested in the form of anemia, neutropenia, leukopenia and thrombocytopenia, as well as gastrointestinal toxicity, manifested as anorexia, nausea, vomiting, diarrhea, constipation, pharyngitis, mucositis and stomatitis. Other adverse reactions include renal toxicity, increased aminotransferase levels, alopecia, weakness, dehydration, rash, infection/sepsis, and neuropathy. Stevens–Johnson syndrome and Toxic Epidermal Necrolysis have rarely been reported.


The following table shows the frequency and severity of side effects observed in > 5% of 168 mesothelioma patients randomly selected for cisplatin therapy with pemetrexed and 163 mesothelioma patients randomly selected for cisplatin monotherapy. In both treatment groups, patients received folic acid and vitamin B12 in full.

Tags: Pemetrexed