Pemetrexed

When ATH:
L01BA04

Characteristic.

The antitumor agent, antimetaʙolit.

Pemetrexed disodium heptahydrate is white or almost white matter. Molecular weight 597,49.

Pharmacological action.
Antitumor.

Application.

Malignant pleural mesothelioma in combination with platinum drugs. Non-small cell lung cancer (locally advanced or metastatic) as therapy 2 lines.

Contraindications.

Hypersensitivity.

Impaired renal function (Cl creatinine <45 ml / min), giperʙiliruʙinemija (bilirubin level in more than 1,5 times the ULN), increase in liver transaminases over 3 times in the absence of liver metastases or more than 5 times in the presence of liver metastases (insufficient data to evaluate the efficacy and safety of), childhood (efficacy and safety have not been established).

No trials of pemetrexed in pregnant women. In the case of pregnancy or during planned pregnancy must notify the patient of the potential risk to the fetus. Pemetrexed can have adverse effects on the developing fetus when used in pregnant women.

Category actions result in FDA - D. (There is evidence of the risk of adverse effects of drugs on the human fetus, obtained in research or practice, However, the potential benefits, associated with drugs in pregnant, may justify its use, in spite of the possible risk, if the drug is needed in life-threatening situations or severe disease, when safer agents should not be used or are ineffective.)

Shown fetotoxicity and teratogenicity in mice pemetrexed / introduction in doses 0,2 mg / kg (0,6 mg / m²) or 5 mg / kg (15 mg / m²) in the period from the 6th to the 15th day of pregnancy. Pemetrexed caused fetal malformations in the development of (incomplete ossification of talus and skull bones) at 0,2 mg / kg (about 1/833 recommended I / dose for humans based on mg / m²) and cleft palate at 5 mg / kg (about 1/33 recommended I / dose for humans based on mg / m²). Embryotoxicity was characterized by an increase in embriofetalnyh deaths and to reduce the litter.

Unknown, whether it is allocated pemetrexed or its metabolites in breast milk of women. However, since the, that many drugs are excreted into breast milk and may cause serious side effects in children, breastfed, nursing mothers should stop breastfeeding in the treatment of pemetrexed.

Side effects, observed in patients with malignant pleural mesothelioma in the pemetrexed / cisplatin when added to therapy as a preventive measure folic acid and vitamin B₁₂, are presented in Table 1. Causation with taking drugs is not installed. The table below shows adverse effects, who met at least in 5% patients, and also observed less frequently, but it is seen as an important (renal failure, infection). The most common effects were hematologic toxicity, fever, infection, stomatitis / pharyngitis, rash / desquamation.

Side effects, noted in the clinical studies of pemetrexed
Normal 0 21 false false false UK X-NONE X-NONE MicrosoftInternetExplorer4

Normal 0 21 false false false UK X-NONE X-NONE MicrosoftInternetExplorer4

In the table 2 Comparative data are presented adverse events (3 and 4 severity) patients, receiving and not receiving folic acid and cyanocobalamin.

Table 2

Comparative incidence of severe side effects, observed in clinical trials
Normal 0 21 false false false UK X-NONE X-NONE MicrosoftInternetExplorer4

Normal 0 21 false false false UK X-NONE X-NONE MicrosoftInternetExplorer4

Side effects, that the study met more often in patients, Additionally treated with folic acid and vitamin b₁₂, were hypertension (11, 3%), chest pain (8, 6%) and thrombosis/thromboembolism (6, 3%).

Patients older 65 years were more frequent leukopenia, neutropenia, thrombocytopenia. Male patients are more likely (24%), than in women (16%) There was a rash.

Cooperation.

Nefrotoksicnae LS and/or LS, instructions by renal tubular secretion, can reduce the clearance of pemetrexed. The results of the research in vitro show, that pemetrexed does not cause clinically significant inhibition of metabolism of HP, metaboliziruthan involving isoenzymes CYP3A, CYP2D6, CYP2C9, Citohromoma P450 CYP1A2. While ingestion of folic acid or/m introduction zianokobalamina pharmacokinetics of pemetrexed is not changed. Cisplatin does not affect the farmakokinetiku pemetrexed. Pemetrexed will not change the overall clearance of Platinum. Acetylsalicylic acid in low or medium doses (325 mg every 6 no) does not affect the farmakokinetiku pemetrexed. The effect of large doses of acetylsalicylic acid on farmakokinetiku pemetrexed is unknown.

Daily intake of ibuprofen (400 mg 4 once a day) reduces the clearance of pemetrexed approximately 20% (and increases the AUC on 20%) in patients with normal renal function (creatinine clearance ≥ 80 mL/min). The effect of greater doses of ibuprofen on pemetrexed farmakokinetiku unknown. Caution must be exercised while applying ibuprofen and pemetrexed in violation of the kidney mild or moderate (creatinine clearance is 45-79 mL/min). Patients with mild to moderate degree of gravity of the kidney failure should not use NSAIDS with short T_1/2 during 2 days before the use of pemetrexed, the day of application and during 2 days after application. Due to the lack of data on the possible interaction between pemetreksedom and NSAIDS with long T_1/2, All patients, taking NSAIDS, should interrupt treatment NSAIDS at least 5 days before, on the day of admission and during 2 days after the use of pemetrexed. If you want to co-administration of NSAIDs, requires strict control of toxicity, especially against mielosupression and toxicity of the blood.

Overdose.

There are very few cases of overdose of pemetrexed. Symptoms: bone marrow depression (neutropenia, thrombocytopenia and anemia), the accession of secondary infections, diarrhea, mucositis, skin rash.

Treatment: symptomatic, incl. immediate application of the calcium folinata (Lejkovorina).

Dosing and Administration.

B / drop, during 10 m.

Malignant mesothelioma of the pleura (combined treatment with cisplatin): the recommended dose of pemetrexed is 500 mg / m² in the 1 St day of each 21-day cycle; cisplatin is 75 mg / m² as a 2-hour on/in infusions amid hydration through 30 min after the introduction of pemetrexed in the 1 St day of each 21-day cycle.

In non-small cell lung cancer (monotherapy): the recommended dose is 500 mg / m² in the 1 St day of each 21-day cycle.

Dose adjustment before repeated courses should be based on the lowest threshold of hematological indicators or maximum negematologičeskoj toxicity during the previous cycle of treatment. Treatment can be delayed in order to restore. As patients need to continue treatment scheme (in monotherapy or in combination with cisplatin): When neutrophils <500 cells / mm³ and the minimum content of platelets ≥ 50000/mm³ introduced 75% from the previous dose (both HP); If the number of platelets <50000 cells / mm³ regardless of the minimum content of neutrophils is prescribed 50% from the previous dose (both HP). With the development of hematological toxicity (excluding neurotoxicity) more 3-rd degree (except for the increase in liver transaminaz 3-rd degree) introduction of pemetrexed must defer to the recovery indicators, the level prior to the start of treatment. Further therapy continue to scheme: any grade 3 toxicity (except for the increase in liver transaminaz 3-rd degree) or 4-th degree except for inflammation of mucous membranes — 75% from the previous dose (both HP); diarrhea, requiring hospitalization (regardless of) or diarrhea 3-rd or 4-th degree — 75% from the previous dose (both HP); inflammation of the mucous membrane of the 3-rd or 4-th degree — 50% from the previous dose for pemetrexed and 100% from the previous dose for cisplatin. In the case of neurotoxicity correction doses of pemetrexed and cisplatin on diagram: 0-1-I degree of toxicity is 100% from the previous dose (both HP); 2-I degree of toxicity is 100% from the previous dose for pemetrexed and 50% from the previous dose for cisplatin. Treatment hereof, If the neurotoxicity of 3-rd or 4-th degree, as well as hematological and negematologičeskaâ toxicity of 3-rd or 4-th degree after two doses of cuts (except for the increase in liver transaminaz 3-rd degree) and immediately cancelled when there is neurotoxicity of 3-rd or 4-th degree.

Precautions.

Pemetrexed must be under the supervision of a qualified physician, with experience of therapy HP.

Premedication regimen

The need for folate intake and zianokobalamina. To reduce the toxicity of pemetrexed patient should receive drugs folic acid and vitamin b₁₂ as a preventive measure to reduce treatment-related hematological and gastrointestinal toxicity. Drugs folic acid or multivitamins, containing a daily dose of folic acid (350-1000 mcg, average 400 g), You must take at least 5 days before the first introduction of pemetrexed. Intake of folic acid should continue during the entire cycle of treatment and within 21 days after the last administration of pemetrexed. You also need to enter once zianokobalamin dose 1000 ug / m during 7 days before the first introduction of pemetrexed and every 3 cycle after treatment. The subsequent introduction of radio in the same dose can be held on the day of the introduction of pemetrexed. In clinical studies, it was reported that, that the advance admission of folic acid and vitamin b₁₂ There was less toxicity in General, hematological toxicity reduction 3/4 degree and negematologičeskoj toxicity, incl. neutropenia, febrile neutropenia and neutropenic infection 3/4 degrees.

Corticosteroids. Patients, treated pemetreksedom and did not impose preliminary corticosteroids, more often there was a skin rash. In clinical trials show, that the appointment of dexamethasone (or equivalent) oral dose 4 mg 2 times per day 1 day prior to the start of treatment pemetreksedom, on the day of the introduction and subsequent day after introduction of pemetrexed decreases the frequency and severity of skin reactions.

Impaired renal function. In patients with impaired renal function creatinine clearance at ≥ 45 mL/min correction mode is not required. When creatinine clearance <45 mL/min is not recommended due to the lack of data on the use of pemetrexed in this group of patients.

One patient with severe renal insufficiency (creatinine clearance 19 ml / min), who did not receive folic acid and cyanocobalamin, died due to a drug-caused toxicity following the introduction of pemetrexed.

Bone marrow suppression. Pemetrexed may call oppression of the bone marrow, manifested by neutropenia, thrombocytopenia and anemia (cm. Side effects). Myelosuppression is usually the dose. Lower doses with repeated courses should take into account the reduction in the absolute number of neutrophils, When calculating the number of platelets and the analysis of maximum negematologičeskoj toxicity in the previous cycle (cm. "Dosage and administration").

Laboratory monitoring. Before the use of the drug in the absolute number of neutrophils must be ≥ 1500 cells/mm³, platelets — ≥ 100000 cells/mm³. Before each introduction of pemetrexed must conduct an overall analysis of blood leukocyte formula and the number of platelets.

To evaluate renal and hepatic function should be periodically carried out biochemical analysis of blood.