Index of drugs

In combination with Cisplatin for use in previously untreated chemotherapy patients with inoperable malignant pleural mesothelioma. In combination with Cisplatin, as a first line treatment in patients with locally advanced or metastatic non-small cell lung cancer with histology other than predominantly squamous histology. As a monotherapy, as maintenance treatment in patients with locally advanced or metastatic non-small cell lung cancer, with histology other than the predominantly squamous, in whom progression of disease did not occur immediately after the completion of platinum-based chemotherapy. Monotherapy as a second-line treatment in patients with locally advanced or metastatic non-small cell lung cancer with histology other than predominantly squamous histology.

1 vial contains 100 mg or 500 mg of pemetrexed (as sodium) and respectively 11 mg or 54 mg of sodium.

An anti-cancer drug - a folic acid antagonist. Inhibits thymidyl synthase (TS), dihydrofolate reductase (DHFR) and glycinide ribonucleotide (GARFT) formyltransferase - enzymes using biosynthetic folates.de novo thymidine and purine nucleotides. In the cell, pemetrexed is quickly and efficiently converted into polyglutamates by polyvinylglutamate synthetase. Polyglutamines remain inside the cell and show an even stronger inhibitory effect on TS and GARFT. Polyglutamination occurs in cancer cells and to a lesser extent in the normal tissues of the body. The metabolites formed as a result of polyglutamination are characterized by a prolonged half-life inside the cell, which determines the longer action of the drug in malignant tumor cells. The binding rate of pemetrexed with plasma proteins is approximately 81%. Pemetrexed is metabolised in the liver to a limited extent. The drug is mainly excreted in the urine. Final T_0,5 is 3.5 hours.

Hypersensitivity to pemetrexed or other ingredients. Breastfeeding period. Co-administration of a yellow fever vaccine.

Before each dose of pemetrexed, complete blood counts should be performed, including the white blood cell count (smear) and the number of platelets and blood tests for renal and hepatic function. The condition for starting each cycle of chemotherapy is the following laboratory parameters: absolute neutrophil count (ANC) ≥1500 cells / mm³, platelet count ≥100,000 cells / mm³, creatinine clearance (CCr) ≥45 ml / min, total bilirubin ≤1.5 x upper limit of normal (ULN); alkaline phosphatase, AST, ALT ≤3 x ULN. In patients with liver metastasis, alkaline phosphatase, AST and ALAT values ​​not higher than 5 times those found to be normal are acceptable. Patients with CCr 45-79 ml / min should avoid taking NSAIDs before, on the day of administration and for 2 days after pemetrexed (see interactions). In patients with risk factors for renal dysfunction (ie dehydration, pre-existing hypertension or diabetes) during pemetrexed therapy, there is a risk of severe renal impairment, including acute renal failure. Consider drainage of fluid accumulated in the third space before pemetrexed administration, but this may not be necessary. In patients with risk factors for cardiovascular disease, there is a risk of serious cardiovascular adverse events (including myocardial infarction and cerebrovascular accidents), especially when pemetrexed is used with other cytotoxic agents. In patients undergoing radiotherapy before, during or after pemetrexed, cases of pneumonia following irradiation have been reported; special care should be taken when treating these patients and care should be taken when using other radiosensitisers. In patients who underwent radiation therapy in the previous weeks or years, recurrence of radiation-induced symptoms has been reported. Do not use in patients <18 years.

The medicine can cause serious damage to the fetus. Do not use during pregnancy except if necessary and after careful consideration of the mother's needs and risk to the fetus. Women of childbearing potential must use effective contraception during treatment with pemetrexed. Pemetrexed may damage genetic material. Sexually mature men should not decide to conceive a child during treatment and for 6 months after its completion. It is recommended to use contraceptives or sexual abstinence. Due to the risk of persistent sterility in men caused by pemetrexed, it is recommended that they seek advice from a center specializing in freezing semen before starting treatment. The drug is contraindicated during breastfeeding.

The most commonly reported adverse reactions when pemetrexed monotherapy and in combination include: myelosuppression (anemia, neutropenia, leukopenia, thrombocytopenia), gastrointestinal toxicity (anorexia, nausea, vomiting, diarrhea, constipation, pharyngitis, mucositis) and inflammation of the mouth, indigestion), nephrotoxicity (increase in creatinine, reduction of CCr), sensory nerve neuropathy, increased transaminases, fatigue, fatigue, dehydration (especially in combination with cisplatin), alopecia, rash, peeling skin, taste disorders, inflammation conjunctivitis, pruritus, fever. Other side effects include: decreased glomerular filtration rate, renal failure, increased GGT activity, hepatitis, infection, sepsis (sometimes fatal), neutropenic fever, abdominal pain, urticaria, hypersensitivity reactions, erythema multiforme, chest pain, myocardial infarction, arrhythmia, pulmonary embolism, motor neuropathy, edema, increased tearing, dizziness, pancytopenia, colitis (including intestinal and rectal bleeding, sometimes fatal, intestinal perforation, intestinal necrosis and inflammation of the cecum), oesophagitis or radiation oesophagitis, interstitial pneumonitis with respiratory failure (sometimes fatal). The following side effects have been reported during post-marketing experience: uncommon: acute renal failure, radiation pneumonitis (in patients undergoing radiation therapy prior to, during or after pemetrexed administration), peripheral ischemia leading sometimes to limb necrosis; rare: recurrence of radiation effects (in patients undergoing previous radiotherapy), cutaneous bullous diseases (including Stevens-Johnson syndrome and toxic epidermal necrolysis, in some cases fatal), haemolytic anemia, anaphylactic shock.

The preparation may be administered only under the supervision of a doctor qualified in the use of anti-cancer chemotherapy.
Combination therapy with cisplatin: 500 mg / m² pc. as an intravenous infusion over 10 minutes, on the first day of each 21-day cycle. Cisplatin in a dose of 75 mg / m² pc. infusion over 2 h, starting approximately 30 min after completion of pemetrexed infusion on the first day of each 21-day treatment cycle. Patients should be given antiemetics and fluids in an appropriate amount before and / or after cisplatin administration.monotherapy: 500 mg / m² pc. as an intravenous infusion over 10 minutes on the first day of each 21-day treatment cycle.premedication: in order to reduce the incidence and severity of skin reactions, the patient should receive a corticosteroid medicine the day before pemetrexed as well as on the day of administration and on the Next day; the corticosteroid dose should correspond to a dose of 4 mg Dexamethasone given orally 2 times a day.Vitamin supplementation. To reduce toxicity, oral folate or a multivitamin containing this compound (350-1000 μg) should be administered daily. During the 7 days preceding the first dose of pemetrexed, the patient should take at least 5 doses of folic acid. Folic acid should also be given throughout the course of treatment and for 21 days after the last dose of pemetrexed. In the week preceding the first dose of pemetrexed and then every 3 cycles of treatment, patients must also receive intramuscular vitamin B₁₂ (1000 μg). Subsequent injections of vitamin B₁₂ may be given on the day of administration of pemetrexed.Dose modification. The decision on dose modification before the start of the next chemotherapy cycle should be made on the basis of the smallest values ​​of blood count parameters determined during the previous cycle or the highest intensity of toxicity symptoms, in which there were no changes in the blood picture. With ANC <500 / mm³ and platelet count ≥ 50,000 / mm³ 75% of the previous dose should be given, both pemetrexed and cisplatin. With a plate count of <50,000 / mm³ regardless of the lowest number of neutrophils 75% of the previous dose should be given, both pemetrexed and cisplatin. At platelet count <50,000 / mm³ and bleeding regardless of the lowest number of neutrophils should be given 50% of the previous dose, both pemetrexed and cisplatin. If side effects occur ≥3. Grade, other than changes in the blood picture (without neurological toxicity), pemetrexed should be discontinued until the assessed parameters return to pre-treatment or lower values. Re-treatment should be started according to the rules described below. For any Grade 3 or 4 adverse reaction with the exception of mucositis, 75% of the previous dose, both pemetrexed and cisplatin, should be administered. Analogous modification of doses of both drugs should be used for diarrhea requiring hospitalization (regardless of severity) or Grade 3 or 4 diarrhea. Grade 3 or 4 mucositis should be administered 50% of the previous dose of pemetrexed and 100% of the previous dose of cisplatin . In case of neurological toxicity symptoms 0-1. should be given 100% of the previous dose of pemetrexed and cisplatin, and for grade 2 toxicity - 100% of the previous dose of pemetrexed and 50% of the previous dose of cisplatin. If grade 3 or 4 neurological toxicity occurs, treatment should be discontinued. Treatment with pemetrexed should also be discontinued if the patient develops haematological or other grade 3 or 4 toxicities after a dose reduction of 2 times.