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  • Pemetrexed Teva
    / Abic


    Active Ingredient
    Pemetrexed 100, 500, 1000 mg

    Status in Israel
    RX

    Presentation and Status in Health Basket

    Presentation Basket Yarpa Pharmasoft

    Vial

    1 X 100 mg

    partial basket chart 52424

    Vial

    1 X 500 mg

    partial basket chart 52425

    Vial

    1 X 1000 mg

    partial basket chart 52426

    Dosage

    Pemetrexed must only be administered under the supervision of a physician qualified in the use of anti-cancer chemotherapy.
    Pemetrexed in combination with cisplatin: The recommended dose of Pemetrexed is 500 mg/m2 of body surface area (BSA) administered as an intravenous infusion over 10 minutes on the first day of each 21- day cycle. The recommended dose of cisplatin is 75 mg/m2 BSA infused over two hours approximately 30 minutes after completion of the pemetrexed infusion on the first day of each 21-day cycle. Patients must receive adequate anti-emetic treatment and appropriate hydration prior to and/or after receiving cisplatin.
    Pemetrexed as single agent: In patients treated for non-small cell lung cancer after prior chemotherapy, the recommended dose of Pemetrexed is 500 mg/m2 BSA administered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle.
    Pre-medication Regimen: To reduce the incidence and severity of skin reactions, a corticosteroid should be given the day prior to, on the day of, and the day after pemetrexed administration. The corticosteroid should be equivalent to 4 mg of dexamethasone administered orally twice a day. To reduce toxicity, patients treated with pemetrexed must also receive vitamin supplementation. Patients must take oral folic acid or a multivitamin containing folic acid (350 to 1,000 micrograms) on a daily basis. At least five doses of folic acid must be taken during the seven days preceding the first dose of pemetrexed, and dosing must continue during the full course of therapy and for 21 days after the last dose of pemetrexed. Patients must also receive an intramuscular injection of vitamin B12 (1,000 micrograms) in the week preceding the first dose of pemetrexed and once every three cycles thereafter. Subsequent vitamin B12 injections may be given on the same day as pemetrexed.
    Monitoring: Patients receiving pemetrexed should be monitored before each dose with a complete blood count, including a differential white cell count (WCC) and platelet count. Prior to each chemotherapy administration, blood chemistry tests should be collected to evaluate renal and hepatic function. Before the start of any cycle of chemotherapy, patients are required to have the following: absolute neutrophil count (ANC) should be ≥ 1,500 cells/mm3 and platelets should be ≥ 100,000 cells/mm3. Creatinine clearance should be ≥ 45 ml/min. The total bilirubin should be ≤ 1.5-times upper limit of normal. Alkaline phosphatase (AP), aspartate aminotransferase (AST or SGOT), and alanine aminotransferase (ALT or SGPT) should be ≤ 3-times upper limit of normal. Alkaline phosphatase, AST, and ALT ≤ 5-times upper limit of normal is acceptable if liver has tumour involvement.
    Dose Adjustments: Dose adjustments at the start of a subsequent cycle should be based on nadir haematologic counts or maximum non-haematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, patients should be re-treated.
    See prescribing information for full details.
    Elderly: In clinical studies, there has been no indication that patients 65 years of age or older are at increased risk of adverse events compared to patients younger than 65 years old. No dose reductions other than those recommended for all patients are necessary.
    Paediatric population: There is no relevant use of Pemetrexed in the paediatric population in malignant pleural mesothelioma and non-small cell lung cancer.
    Patients with renal impairment: (standard Cockcroft and Gault formula or glomerular filtration rate measured Tc99m DPTA serum clearance method): Pemetrexed is primarily eliminated unchanged by renal excretion. In clinical studies, patients with creatinine clearance of ≥ 45 ml/min required no dose adjustments other than those recommended for all patients. There are insufficient data on the use of pemetrexed in patients with creatinine clearance below 45 ml/min; therefore, the use of pemetrexed is not recommended.
    Patients with hepatic impairment: No relationships between AST (SGOT), ALT (SGPT), or total bilirubin and pemetrexed pharmacokinetics were identified. However, patients with hepatic impairment, such as bilirubin > 1.5-times the upper limit of normal and/or aminotransferase > 3.0-times the upper limit of normal (hepatic metastases absent) or > 5.0-times the upper limit of normal (hepatic metastases present), have not been specifically studied.
    Method of administration: For precautions to be taken before handling or administering Pemetrexed. Pemetrexed should be administered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle.
    See prescribing information for full details.


    Indications

    Malignant pleural mesothelioma: in combination with cisplatin is indicated for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curatible surgery. Non-small cell lung cancer: Pemetrexed in combination with cisplatin is indicated for the first line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology. Pemetrexed is indicated as monotherapy for the maintenance treatment of locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology in patients whose disease has not progressed immediately following platinum-based chemotherapy. Pemetrexed is indicated as monotherapy for the second line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology.


    Contra-Indications

    Hypersensitivity to the active substance or to any of the excipients. Breast-feeding. Concomitant yellow fever vaccine.


    Special Precautions

    Pemetrexed can suppress bone marrow function as manifested by neutropenia, thrombocytopenia, and anaemia (or pancytopenia). Myelosuppression is usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during therapy and pemetrexed should not be given to patients until absolute neutrophil count (ANC) returns to ≥ 1,500 cells/mm3 and platelet count returns to ≥ 100,000 cells/mm3. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum non-haematologic toxicity seen from the previous cycle.
    Less toxicity and reduction in Grade 3/4 haematologic and non-haematologic toxicities, such as neutropenia, febrile neutropenia, and infection with Grade 3/4 neutropenia, were reported when pre-treatment with folic acid and vitamin B12 was administered. Therefore, all patients treated with pemetrexed must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce treatment-related toxicity. Skin reactions have been reported in patients not pre-treated with a corticosteroid. Pretreatment with dexamethasone (or equivalent) can reduce the incidence and severity of skin reactions. An insufficient number of patients has been studied with creatinine clearance of below 45 ml/min. Therefore, the use of pemetrexed in patients with creatinine clearance of < 45 ml/min is not recommended. Patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 ml/min) should avoid taking non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, and aspirin (> 1.3 g daily) for 2 days before, on the day of, and 2 days following pemetrexed administration.
    In patients with mild to moderate renal insufficiency eligible for pemetrexed therapy, NSAIDs with long elimination half-lives should be interrupted for at least 5 days prior to, on the day of, and at least 2 days following pemetrexed administration. Serious renal events, including acute renal failure, have been reported with pemetrexed alone or in association with other chemotherapeutic agents. Many of the patients in whom these occurred had underlying risk factors for the development of renal events, including dehydration or pre-existing hypertension or diabetes.
    The effect of third-space fluid, such as pleural effusion or ascites, on pemetrexed is not fully defined. A Phase 2 study of pemetrexed in 31 solid tumour patients with stable third-space fluid demonstrated no difference in pemetrexed dose normalised plasma concentrations or clearance compared to patients without third-space fluid collections. Thus, drainage of third-space fluid collection prior to pemetrexed treatment should be considered, but may not be necessary. Due to the gastrointestinal toxicity of pemetrexed given in combination with cisplatin, severe dehydration has been observed. Therefore, patients should receive adequate antiemetic treatment and appropriate hydration prior to and/or after receiving treatment.
    Serious cardiovascular events, including myocardial infarction and cerebrovascular events, have been uncommonly reported during clinical studies with pemetrexed, usually when given in combination with another cytotoxic agent. Most of the patients in whom these events have been observed had pre-existing cardiovascular risk factors. Immunodepressed status is common in cancer patients. As a result, concomitant use of live attenuated vaccines is not recommended. Pemetrexed can have genetically damaging effects. Sexually mature males are advised not to father a child during the treatment and up to 6 months thereafter. Contraceptive measures or abstinence are recommended. Owing to the possibility of pemetrexed treatment causing irreversible infertility, men are advised to seek counselling on sperm storage before starting treatment. Women of childbearing potential must use effective contraception during treatment with pemetrexed.
    Cases of radiation pneumonitis have been reported in patients treated with radiation either prior, during, or subsequent to their pemetrexed therapy. Particular attention should be paid to these patients, and caution exercised with use of other radiosensitising agents. Cases of radiation recall have been reported in patients who received radiotherapy weeks or years previously.


    Side Effects

    The most commonly reported undesirable effects related to pemetrexed, whether used as monotherapy or in combination, are bone marrow suppression manifested as anaemia, neutropenia, leucopenia, thrombocytopenia; and gastrointestinal toxicities, manifested as anorexia, nausea, vomiting, diarrhoea, constipation, pharyngitis, mucositis, and stomatitis.
    Other undesirable effects include renal toxicities, increased aminotransferases, alopecia, fatigue, dehydration, rash, infection/sepsis and neuropathy. Rarely seen events include Stevens-Johnson syndrome and Toxic epidermal necrolysis.
    See prescribing information for full details.


    Drug interactions

    Pemetrexed is mainly eliminated unchanged renally by tubular secretion and to a lesser extent by glomerular filtration. Concomitant administration of nephrotoxic drugs (e.g., aminoglycoside, loop diuretics, platinum compounds, cyclosporin) could potentially result in delayed clearance of pemetrexed. This combination should be used with caution. If necessary, creatinine clearance should be closely monitored. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid, penicillin) could potentially result in delayed clearance of pemetrexed. Caution should be made when these drugs are combined with pemetrexed. If necessary, creatinine clearance should be closely monitored. In patients with normal renal function (creatinine clearance ≥ 80 ml/min), high doses of non-steroidal anti-inflammatory drugs (NSAIDs, such as ibuprofen > 1600 mg/day) and aspirin at higher doses (≥ 1.3 g daily) may decrease pemetrexed elimination and, consequently, increase the occurrence of pemetrexed adverse events. Therefore, caution should be made when administering higher doses of NSAIDs or aspirin, concurrently with pemetrexed to patients with normal function (creatinine clearance ≥ 80 ml/min). In patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 ml/min), the concomitant administration of pemetrexed with NSAIDs (e.g., ibuprofen) or aspirin at higher doses should be avoided for 2 days before, on the day of, and 2 days following pemetrexed administration. In the absence of data regarding potential interaction with NSAIDs having longer halflives such as piroxicam or rofecoxib, the concomitant administration with pemetrexed in patients with mild to moderate renal insufficiency should be interrupted for at least 5 days prior to, on the day of, and at least 2 days following pemetrexed administration. If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression and gastrointestinal toxicity. Pemetrexed undergoes limited hepatic metabolism. Results from in vitro studies with human liver microsomes indicated that pemetrexed would not be predicted to cause clinically significant inhibition of the metabolic clearance of drugs metabolised by CYP3A, CYP2D6, CYP2C9, and CYP1A2.
    Interactions Common to all Cytotoxics: Due to the increased thrombotic risk in patients with cancer, the use of anticoagulation treatment is frequent. The high intra-individual variability of the coagulation status during diseases and the possibility of interaction between oral anticoagulants and anticancer chemotherapy require increased frequency of INR (International Normalised Ratio) monitoring, if it is decided to treat the patient with oral anticoagulants.
    Concomitant Use Contraindicated: Yellow fever vaccine: Risk of fatal generalised vaccinale disease.
    Concomitant Use Not Recommended: Live attenuated vaccines (except yellow fever, for which concomitant use is contraindicated): Risk of systemic, possibly fatal, disease. The risk is increased in subjects who are already immunosuppressed by their underlying disease. Use an inactivated vaccine where it exists (poliomyelitis).


    Pregnancy and Lactation

    Pregnancy: There are no data from the use of pemetrexed in pregnant women; but pemetrexed, like other anti-metabolites, is suspected to cause serious birth defects when administered during pregnancy. Animal studies have shown reproductive toxicity. Pemetrexed should not be used during pregnancy unless clearly necessary, after a careful consideration of the needs of the mother and the risk for the foetus.
    Lactation: It is not known whether pemetrexed is excreted in human milk, and adverse reactions on the suckling child cannot be excluded. Breast-feeding must be discontinued during pemetrexed therapy.


    Overdose

    Reported symptoms of overdose include neutropenia, anaemia, thrombocytopenia, mucositis, sensory polyneuropathy, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anaemia. In addition, infection with or without fever, diarrhoea, and/or mucositis may be seen. In the event of suspected overdose, patients should be monitored with blood counts and should receive supportive therapy as necessary. The use of calcium folinate/ folinic acid in the management of pemetrexed overdose should be considered.


    Important notes

    Incompatibilities: Pemetrexed is physically incompatible with diluents containing calcium, including lactated Ringer’s injection and Ringer’s injection. In the absence of other compatibility studies this medicinal product must not be mixed with other medicinal products.
    Sodium content: 100 mg: This medicinal product contains less than 1 mmol sodium (approximately 11 mg) per vial. To be taken into consideration by patients on a controlled sodium diet.
    500 mg: This medicinal product contains approximately 2.3 mmol sodium (approximately 54 mg) per vial. To be taken into consideration by patients on a controlled sodium diet.
    1000 mg: This medicinal product contains approximately 4.7 mmol sodium (approximately 109 mg) per vial. To be taken into consideration by patients on a controlled sodium diet.
    Store below 25°C.


    Manufacturer
    Teva Pharmaceutical Industries Ltd, Israel
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