Pemetrexed - instructions for use, dose, side effects, contraindications

Pharmacodynamics:Has antitumor effect. Antifolate complex based on the pyrrolopyrimidine nucleus disrupts the folate-dependent metabolic pathways required for cell replication. In vitro inhibits the activity of thymidylate synthetase, dihydrofolate reductase and glycine amidobonucleotide formyltransferase - all folate-dependent enzymes that provide biosynthesis de novo thymidine and purine nucleotides. It is transported inside the cell by the carrier of the reconstituted folate and the membrane folate-binding protein transport system. In the cell, it is converted by folylpolyglutamate synthetase into a polyglutamate form that is retained in the cell and inhibits thymidylate synthetase and glycine aminobonucleotide formyl transferase.Polyglutamination depends on concentration and time and occurs both in tumor cells and, to a lesser extent, in normal tissues. Polyglutamine metabolites have an increased intracellular half-life that prolongs the period of action of pemetrexed in tumor cells. In vitro suppresses the growth of mesothelioma cell lines MSTO-211H and NCI-H2052; Mesothelioma cells MSTO-211H show synergism with cisplatin. The severity of hematological toxicity (by the number of neutrophils) is proportional to the systemic effect of pemetrexed; a more pronounced decrease is noted in patients with elevated concentrations of cystathion or homocysteine (the latter can be reduced by the appointment of folic acid and vitamin B₁₂). The cumulative effect is not fixed.

Pharmacokinetics:Relationship with plasma proteins - 81% (does not depend on the degree of impaired renal function). Half-life is 3.5 hours. The maximum concentration is 8-9.6 days (up to AUC 38.3-316.8 μg / h · ml); returns to the original within 4.2-7.5 days after nadir. Elimination by the kidneys (70-90% unchanged for 24 hours).

Pharmacokinetics does not depend on age. An increase in the activity of transaminases or the concentration of total bilirubin does not affect the pharmacokinetics of pemetrexed,but her research with liver failure was not carried out.

Indications:Malignant pleural mesothelioma in combination with platinum preparations.

Non-small cell lung cancer (locally advanced or metastatic) as 2nd line therapy.

ICD-10

II.C30-C39.C34 Malignant neoplasm of bronchi and lungs

II.C45-C49.C45.0 Mesothelioma of the pleura

Contraindications:Individual intolerance of the drug, renal failure (creatinine clearance less than 45 ml / min), children's age, pregnancy and lactation.

Carefully:Impaired renal function (creatinine clearance less than 45 ml / min), hyperbilirubinemia (bilirubin level more than 1.5 times the upper limit of the norm), an increase in hepatic transaminase activity more than 3 times in the absence of metastases in the liver or more than 5 times in the presence of metastases in the liver (not enough data to assess the effectiveness and safety of use).

Pregnancy and lactation:In case of use during pregnancy or during the period of planned pregnancy, the patient should be warned about the potential risk to the fetus. Pemetrexed can have an adverse effect on fetal development when used in pregnant women. The drug is prohibited for use during breastfeeding. The action category for the fetus by FDA is D.

Dosing and Administration:Intravenously drip (for 10 minutes or more) at a dose of 500 mg / m² on the first day in combination with cisplatin (intravenously drip for 2 hours or more at a dose of 75 mg / m² 30 minutes after the end of pemetrexed injection) every 3 weeks.

Side effects:Blood: anemia, leukopenia, neutropenia, thrombocytopenia, infections with neutropenia III-IV, febrile neutropenia, and other infections with febrile neutropenia.

The cardiovascular system: thrombosis (embolism), supraventricular tachycardia.

Respiratory system: violation of breathing.

Gastrointestinal tract: anorexia, constipation, diarrhea, dysphagia, esophagitis, nausea, vomiting, stomatitis, pharyngitis, singophagia (pain when swallowing), abdominal pain.

Urinary system: renal failure, an increase in the concentration of creatinine in the blood.

Nervous system: depression, peripheral neuropathy (in the form of paresthesias), mood changes.

Leather (more often without premedication with glucocorticoids, premedication with dexamethasone or its analogues reduces the frequency and severity of skin reactions): alopecia, desquamation of the epithelium, skin rashes.

Hypersensitivity: allergic reactions, erythema multiforme.

Reproductive system: when administered intravenously to male mice at a dose of 0.1 mg / kg per day (about 1/1666 the dose recommended for humans) reduces fertility, causes hyperspermia and testicular atrophy.

Carcinogenicity (mutagenicity): studies of the carcinogenicity of pemetrexed were not conducted.

Others: increased transaminase activity in the blood, arthralgia, myalgia, infections not caused by neutropenia, chest pain, dehydration, peripheral edema, fatigue, fever.

Overdose:When an overdose is observed neutropenia, anemia, thrombocytopenia, mucositis, skin rashes. It is possible to develop febrile neutropenia, diarrhea, infection.

Treatment: the need for symptomatic therapy is determined by the attending physician. It is recommended to administer calcium folinate (intravenously at a dose of 100 mg / m² once, then 50 mg / m² every 6 hours for 8 days).Possible use of thymidine. The effectiveness of hemodialysis is unknown.

Interaction:Acetylsalicylic acid does not affect the pharmacokinetics of pemetrexed when administered at low and moderate doses (325 mg every 6 hours). The effect of high doses of acetylsalicylic acid on the pharmacokinetics of pemetrexed has not been studied.

Ibuprofen 400 mg 4 times a day with normal kidney function reduces clearance of pemetrexed by 20% and increases AUC by 20%; possible a parallel application with normal kidney function (creatinine clearance more than 80 ml / min). In case of unexplained or moderate renal failure (creatinine clearance 45-79 ml / min) should be combined with caution. The effect of high doses of ibuprofen on the pharmacokinetics of pemetrexed has not been studied.

Nephrotoxic agents [aldesleukin, aminoglycosides (for parenteral or topical application to the damaged mucosa), amphotericin B (for parenteral administration), paracetamol (in high doses), paracetamol in combination with acetylsalicylic acid or other salicylates (with prolonged high-dosage therapy), acyclovir (for parenteral administration), bacitracin (for parenteral administration), vancomycin (for parenteral administration), deferoxamine (with prolonged use), ifosfamide, capreomycin, carmustine, methotrexate (in high doses), methoxyflurane, sodium calcium edetate (in high doses), neomycin (ingestion), non-steroidal anti-inflammatory drugs, oxaliplatinum, gold preparations, lithium preparations, pamidronic acid, penicillamine, pentamidine, polymyxins (for parenteral use), radiocontrast iodine-containing water-soluble drugs (for intravascular administration), rifampicin, means for cholecystography taken internally, streptozocin, a combination of sulfamethoxazole and trimethoprim, sulfonamides (for systemic administration), tacrolimus, tetracyclines (with the exception of doxycycline and minocycline), tretinoin, phenacetin, sodium foscarnet, ciprofloxacin, cisplatin, cyclosporin] - pemetrexed mainly excreted by the kidneys through glomerular filtration and tubular secretion; when used concomitantly with nephrotoxic agents, its clearance may be slowed.

It is necessary to abolish non-steroidal anti-inflammatory drugs with a short half-life in patients with unexplained or moderate renal insufficiency 2 days before the administration of pemetrexed and prescribe them again no earlier than 2 days after its administration. The interaction of non-steroidal anti-inflammatory drugs with a long half-life and pemetrexed has not been studied. It is recommended to cancel them 5 days before the introduction of pemetrexed and resume treatment no earlier than 2 days after its application. If parallel therapy is necessary, careful monitoring of side effects, especially myelosuppression, nephro- and gastrointestinal toxicity, is carried out.

Pharmacokinetics of pemetrexed does not change with simultaneous ingestion of folic acid, intramuscular injection of cyanocobalamin, and also with the introduction of cisplatin. Pemetrexed does not change the overall clearance of platinum preparations.

Drugs excreted via tubular secretion can slow the clearance of pemetrexed in parallel use.

In vitro pemetrexed minimally interacts with drugs metabolized by cytochrome P450 (3A, 2D6, 2C9, 1A2).

Chemically incompatible with solvents containing Ca2 +, including solutions with Ringer and Ringer lactate.

Do not mix with solutions of other medicines.

Special instructions:During the treatment, it is necessary to monitor the peripheral blood counts, including platelets (before each injection, during the nadir period, on the 8th to 15th day of each cycle and until the toxicity regresses), the biochemical parameters of the liver and kidney function (in all patients for 8-15- th day of each cycle and prior to recourse to toxicity), signs of myelosuppression, nephro- and gastrointestinal toxicity (with concurrent use with non-steroidal anti-inflammatory drugs).

Instructions

Pemetrexed (Pemetrexedum)