Pemetrexed

Pemetrexed is used for: Non-small cell lung cancer, Malignant pleural mesothelioma

Intravenous Malignant Pleural Mesothelioma Indicated for mesothelioma in combination with cisplatin in patients whose disease is unresectable or are not candidates for curative surgery Combination use with cisplatin: 500 mg/m² IV over 10 minutes on Day 1 of each 21-day cycle; administer cisplatin (75 mg/m² IV over 2 hr) 30 minutes after end of premetrexed infusion Nonsquamous Non-Small Cell Lung Carcinoma Indications Initial treatment: In combination with cisplatin for initial treatment with locally advanced or metastatic nonsquamous NSCLC Maintenance: Locally advanced or metastatic nonsquamous NSCLC in patients whose disease has not progressed after 4 cycles of platinum-based first-line chemotherapy After prior chemotherapy: As a single agent of locally advanced or metastatic nonsquamous NSCLC after prior chemotherapy Single-agent use: 500 mg/m² IV infusion over 10 minutes on Day 1 of each 21-day cycle Combination use with cisplatin: 500 mg/m² IV over 10 minutes on Day 1 of each 21-day cycle; administer cisplatin (75 mg/m² IV over 2 hr) 30 minutes after end of premetrexed infusion Premedication Regimen Folic acid: 400-1000 mcg PO qDay beginning 7 days before first pemetrexed dose; continue during the full course of therapy and for 21 days after the last dose Vitamin B12: 1 mg IM beginning 1 week before first pemetrexed dose and repeat every 3 cycles thereafter; subsequent doses may be administered on the same day as pemetrexed Do not substitute PO B12 for IM (see Cautions) Dexamethasone: 4 mg PO BID on the day before, day of, and day after pemetrexed administration treatment to help prevent skin rash Dosage Modifications If nadir ANC <500/mm³ & nadir platelets >50,000/mm³ Adjust to 75% of previous dose (both drugs) If nadir platelets <50,000/mm³ regardless of nadir ANC Adjust to 50% of previous dose (both drugs) Any Grade 3 or 4 toxicities except mucositis Adjust to 75% of previous dose (both drugs) Any diarrhea requiring hospitalization Adjust to 75% of previous dose (both drugs) Grade 3 or 4 mucositis Adjust pemetrexed to 50% of previous dose CTC Grade 2 Adjust Cisplatin to 50% of previous dose

Safety and efficacy not established

Renal impairment: CrCl (ml/min) Dosage Recommendation <45 Usage is not recommended.

IV Preparation Aseptically reconstitute with 20 mL of 0.9% NaCl (preservative free) to give a 25 mg/mL solution Gently swirl until completely dissolved; resulting solution is clear and ranges in color from colorless to yellow/green-yellow without adversely affecting quality Aseptically dilute required dose to 100 mL with 0.9% NaCl (preservative free) IV Administration Infuse over 10 min

Hypersensitivity.

Monitor CBC, platelet counts, and CrCl for nadir and recovery before each cycle. Periodic hepatic monitoring Premedication with folate and vitamin B12 are recommended as prophylaxis against haematological and GI toxicity during treatment. Pre-treatment with a corticosteroid also reduces the incidence and severity of skin reactions. Caution when used in renal or hepatic impairment. Not recommended for use in pregnancy. Lactation: not safe

Pregnancy Based on findings from animal studies and its mechanism of action, therapy can cause fetal harm when administered to a pregnant woman; there are no available data in pregnant women; in animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during organogenesis was teratogenic, resulting in developmental delays and malformations at doses lower than recommended human dose of 500 mg/m²; advise pregnant women of the potential risk to a fetus Contraception Therapy can cause fetal harm when administered to a pregnant woman; because of potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment for at least 6 months after final dose Advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 months after final dose Infertility Therapy may impair fertility in males of reproductive potential; it is not known whether these effects on fertility are reversible Lactation There is no information regarding presence of drug or its metabolites in human milk, effects on breastfed infant, or on milk production; because of potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment and for 1 week after last dose

High doses of NSAIDs and aspirin may reduce the elimination of pemetrexed; avoid usage 2 days (5 days for longer-acting NSAIDs) before, during and 2 days after treatment with pemetrexed in patients with impaired renal function. Additive GI side effects when used with SSRIs, acetylcholinesterase inhibitors, aripiprazole or ziprasidone. Additive sedation when used with psychotropics. Concurrent use with nephrotoxic drugs (e.g. aminoglycosides, loop diuretics, platinum compounds and ciclosporin) may decrease pemetrexed clearance, thus increasing the risk of toxicity. Clearance may be reduced when used with drugs that are cleared by tubular secretion e.g. probenecid and penicillin.

Side effects of Pemetrexed : >10% Nausea (84%), Fatigue (80%), Pulmonary dyspnea (66%), Neutropenia (58%), Vomiting (58%), Leukopenia (55%), Constipation (44%), Chest pain (40%), Anorexia (35%), Anemia (33%), Pharyngitis (28%), Stomatitis (28%), Thrombocytopenia (27%), Diarrhea without colostomy (26%), Rash/desquamation (22%), Fever (17%), Neuropathy/sensory (17%), Creatinine elevation (16%), Mood alteration/depression (14%), Infection without neutropenia (11%) 1-10% Dehydration, thrombosis/embolism (7%), Dysphagia/esophagitis/odynophagia (6%), Infection with Grade 3 or Grade 4 neutropenia (6%), Neutropenia-other (3%), Allergic reaction/hypersensitivity (2%), Renal failure (2%), Febrile neutropenia (1%) <1% Esophagitis, Arrhythmia, Motor neuropathy, Febrile neutropenia, Erythema multiforme Potentially Fatal: Acute renal failure.

Pemetrexed is a thymidylate synthase inhibitor. It works by inhibiting thymidylate synthase, dihydrofolate reductase, glycinamide ribonucleotide formyltransferase and aminoimidazole carboxamide ribonucleotide formyltransferase, the enzymes involved in folate metabolism and DNA synthesis, thus inhibiting purine and thymidine nucleotide and protein synthesis.