Full Prescribing Info
Contents
Pemetrexed disodium trihydrate.
Description
Pemetrexed disodium trihydrate 614.632 mg (equivalent to 500 mg pemetrexed).
Excipients/Inactive Ingredient: Mannitol 500 mg.
Indications/Uses
Pemetrexed is primarily a thymidylate synthase inhibitor like raltitrexed but it also inhibits other folate-dependent enzymes involved in purine synthesis such as dihydrofolate reductase and glycinamide ribonucleotide formyltransferase.
Pemetrexed is indicated for the following treatment: Malignant Plueral Mesothelioma: Pemetrexed in combination with cisplatin is indicated for the treatment of chemotherapy native patients with unresectable malignant pleural mesothelioma.
Non-small cell lung cancer: Pemetrexed 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.
Non-small cell lung cancer: Pemetrexed is indicated 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. First line treatment should be a platinum doublet with gemcitabine, paclitaxel or docetaxel.
Non-small cell lung cancer: Pemetrexed is indicated for the second line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology.
Dosage/Direction for Use
The drug should be used under the guidance of qualified physicians with anticancer drug application experience. The drug can only be used in intravenous infusion, the solution must be prepared in accordance with the instruction of "Preparation of Intravenous Solution".
Malignant Pleural Mesothelioma: The recommended dose of Emetex for injection in combination with cisplatin for the treatment of malignant pleural mesothelioma is 500 mg/m2 on Day 1 of each 21-day cycle, infused intravenously over 10 minutes. According to the recommended dose of 75 mg/m2, cisplatin is administered intravenously over 2 hours beginning approximately 30 minutes after the end of administration of Emetex. Accepting cisplatin for the treatment needs a hydration protocol. See the details in the package insert of "Cisplatin".
Non-Small Cell Lung Cancer: The recommended dose of Emetex is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle.
Premedical regimen: To reduce the incidence and severity of skin reaction, on the day prior to, on the day of, and the day after Emetex; 4 mg dexamethasone should be given orally twice a day.
To reduce toxicity, patients treated with Emetex must take oral folic acid or a multivitamin containing folic acid (350 to 1000 micrograms) on the daily basis. At least five doses of folic acid must be taken during the seven days and for 21 days after the last dose of Emetex. Patients must also receive an intramuscular injection of vitamin B12 (1000 micrograms) in the week preceding the first dose of Emetex and once every three cycles thereafter. Subsequent vitamin B12 injections may be given on the same day as Emetex.
Pharmacokinetics: Pemetrexed has a plasma elimination half-life of 3.5 hours and about 70 to 90% of a dose is eliminated unchanged in the urine within 24 hours.
Administration in renal impairment: A pharmacokinetic study found that pemetrexed clearance decreased with declining renal function. Although systemic exposure increased in these patients, this was not associated with an increase in drug-related dose-limiting toxicities for patients with a GFR of 40 mL/minute or more and receiving vitamin supplementation (folic acid and vitamin B12 supplementation appears to reduce toxicity without altering pemetrexed pharmacokinetics). Patients with a GFR of 80 mL/minute or more tolerated a dose of pemetrexed 600 mg/m2, given intravenously every 3 weeks, whereas patients with a GFR of 40 to 79 mL/minute tolerated 500 mg/m2 every 3 weeks. One patient with a GFR of 19 mL/minute died as a result of treatment-related toxicity and accrual into this group was stopped. As a result, no data were available for patients with a GFR below 40 mL/minute.
Children: Pemetrexed is not recommended for use in children, as safety and efficacy have not been established in children.
Overdosage
There have been few cases of pemetrexed overdose. Reported toxicities included neutropenia, anemia, thrombocytopenia, mucositis, and rash. Anticipated complications of overdose include myelosuppression as manifested by neutropenia, thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea, and mucositis may be observed. If overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician.
In clinical trials, leucovorin was permitted for CTC Grade 4 leukopenia lasting ≥ 3 days, or CTC Grade 4 neutropenia lasting ≥ 3 days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis. The dosage and administration of leucovorin were recommended as following: 100 mg/m2, intravenously once, followed by 50 mg/m2, intravenously every 6 hours for 8 days.
The ability of pemetrexed to be dialyzed is unknown.
Contraindications
Pemetrexed is contraindicated in patients who have been known hypersensitivity to pemetrexed or to any other ingredients in the composition.
Breast-feeding must be discontinued during pemetrexed therapy.
Concomitant yellow fever vaccine.
Special Precautions
Pemetrexed can suppress bone marrow function as manifested by neutropenia, thrombocytopenia and anemia. Myelosuppression is usually the dose-limitation toxicity. Patients should be monitored for myelosuppression during therapy and pemetrexed should not be given to patients until absolute neutrophil count (ANC) returns to ≥1500 cells/mm3 and platelet count returns to 100,000 cells/mm3.
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.
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.
Use In Pregnancy & Lactation
Use in Pregnancy: Pregnancy Category D.
Pemetrexed may cause fetal harm when administered to a pregnant woman.
Embryotoxicity was characterized by increased embryo-fetal deaths and reduced litter sizes. There are no studies of pemetrexed in pregnant women. Patients should be advised to avoid becoming pregnant. If pemetrexed is used during pregnancy, or if the patient becomes pregnant while using pemetrexed, the patient should be apprised of the potential hazard to the fetus.
Use in Lactation: It is not known whether pemetrexed or its metabolites are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from pemetrexed, it is recommended that nursing should be discontinued if the mother is treated with pemetrexed.
Adverse Reactions
Pemetrexed of malignant pleural mesothelioma treated with pemetrexed in combination with cisplatin, the adverse reactions have been observed as below: see Table 1.

Click on icon to see table/diagram/image

Patients of non-small cell lung cancer treated with single-agent pemetrexed supplemented with folic acid and vitamin B12, as second-line therapy, the adverse reactions have been observed as below: see Table 2.

Click on icon to see table/diagram/image
Drug Interactions
High dose of NSAIDs and aspirin may decrease pemetrexed elimination. In patients with mild to moderate renal impairment (creatinine clearance 45 to 79 mL/minute) high dose of NSAIDs and aspirin should be avoided from 2 days before until 2 days after pemetrexed use, and NSAIDs that have longer half-lives, such as piroxicam, should be avoided from 5 days before until 2 days after pemetrexed use.
Analgesics:
Enteric-coated aspirin 325 mg given orally every 6 hours for a total of 9 doses before pemetrexed did not affect the pharmacokinetic profile of pemetrexed in an interaction study; it should consider no dose adjustment necessary when moderate doses of aspirin were given with pemetrexed. However, this result could not be extrapolated to high-dose aspirin regimens, as the interaction might be dependent on salicylate concentrations. In contrast ibuprofen 400 mg by mouth every 6 hours for a total of 9 doses before pemetrexed significantly reduced systemic pemetrexed clearance. Despite an increase in pemetrexed exposure, no increase in toxicity was seen. Dose adjustments were not considered necessary in patient with normal renal function (defined as creatinine clearance of 80 mL/minute or greater). However, in patients with pre-existing reduced pemetrexed clearance due to renal impairment, giving ibuprofen may result in further increases in pemetrexed exposure; caution should be considered when using these 2 drugs together in patients with a creatinine clearance of less than 80 mL/minute.
Caution For Usage
Preparation for Intravenous Infusion Administration: Reconstitution and dilution process should be sterile operation.
Calculate the dose of Emetex and the number of vials needed. Each vial contains 500 mg of Emetex.
Dissolve 500 mg vials with 20 ml of 0.9% Sodium Chloride Injection (preservative free) to get a solution containing 25 mg/ml Emetex. Gently swirl each vial until the powder is completely dissolved. The reconstituted solution is clear and ranges in color from colorless to yellow or green-yellow. The pH of the reconstituted Emetex solution is between 6.6 and 7.8.
Further dilution is required.
The Emetex solution should be inspected visually for particulate matter and discoloration before administration. If particulate matter or discoloration is observed, do not administer.
Diluted reconstituted Emetex solution with 0.9% Sodium Chloride Injection (preservative free) to 100 ml and administered as an intravenous infusion over 10 minutes.
Chemical and physical stability of reconstituted and infusion solutions of Emetex were demonstrated for up to 24 hours following initial reconstitution, when stored at refrigerated or room temperature (15-30°C) and lighting. When prepared as directed, reconstitution and infusion solution of Emetex contain no antimicrobial preservatives. Discard any unused portion.
Reconstitution and further dilution prior to intravenous infusion is only recommended with 0.9% Sodium Chloride Injection (preservative free).
Incompatibility: Reconstitution and further dilution prior to intravenous infusion is only recommended with 0.9% Sodium Chloride Injection. Emetex is physically incompatible with diluents containing calcium, including Lactated Ringer's Injection, USP and Ringer's Injection, USP and therefore these should not be used. Coadministration of Emetex with other drugs and diluents has not been studied, and therefore is not recommended.
A study found Emetex disodium 20 mg/mL to be physically incompatible with 24 drugs resulting in precipitation or colour change during simulated Y-site administration. These drugs include amphotericin B, some cephalosporin and cephamycin antibacterials, chlorpromazine hydrochloride, ciprofloxacin, dobutamine hydrochloride, doxorubicin hydrochloride, doxycycline hyclate, droperidol, gemcitabine hydrochloride, gentamicin sulfate, irinotecan hydrochloride, metronidazole, minocycline hydrochloride, mitoxantrone hydrochloride, nalbuphine hydrochloride, ondansetron hydrochloride, prochlorperazine edisilate, tobramycin sulfate, and topotecan hydrochloride.
Storage
Store below 30°C. Preserve in tightly closed containers, stored in a dry place, protected from light.
ATC Classification
L01BA04 - pemetrexed ; Belongs to the class of antimetabolites, folic acid analogues. Used in the treatment of cancer.
Presentation/Packing
Infusion (vial) 100 mg x 1's. 500 mg x 1's.
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