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.

Pemetrexed is indicated for:

• Initial treatment of patients with locally advanced or metastatic, non-squamous, non-small cell lung cancer (NSCLC) in combination with cisplatin.
• Maintenance treatment of patients with locally advanced or metastatic, non-squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy, as a single agent.
• Treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy, as a single agent.

Recommended Dosage And Schedule For Non-Squamous NSCLC:

• The recommended dose of Pemetrexed in combination with cisplatin for initial treatment of NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m² as an intravenous infusion over 10 minutes administered prior to cisplatin on Day 1 of each 21-day cycle for up to six cycles in the absence of disease progression or unacceptable toxicity.
• The recommended dose of Pemetrexed for maintenance treatment of NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m² as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity after four cycles of platinum-based first-line chemotherapy.
• The recommended dose of Pemetrexed for treatment of recurrent NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m² as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity.

Recommended Dosage And Schedule For Mesothelioma: The recommended dose of Pemetrexed, administered in combination with cisplatin, in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m² as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity.

Pemetrexed is contraindicated in patients with a history of severe hypersensitivity reaction to pemetrexed

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Myelosuppression
• Renal failure
• Bullous and exfoliative skin toxicity 
• Interstitial pneumonitis
• Radiation recall

Overdose Effects

No drugs are approved for the treatment of Pemetrexed overdose. Based on animal studies, administration of leucovorin may mitigate the toxicities of Pemetrexed overdosage. It is not known whether pemetrexed is dialyzable.

Monitor CBC. 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 and lactation.

Use in Special Populations

Renal Impairment: Pemetrexed dosing recommendations are provided for patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater. There is no recommended dose for patients whose creatinine clearance is less than 45 mL/min

Pediatric Use: The safety and effectiveness of Pemetrexed in pediatric patients have not been established. 

Geriatric Use: Of the 3,946 patients enrolled in clinical studies of Pemetrexed, 34% were 65 and over and 4% were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. The incidences of Grade 3-4 anemia, fatigue, thrombocytopenia, hypertension, and neutropenia were higher in patients 65 years of age and older as compared to younger patients: in at least one of five randomized clinical trials.

Pregnancy & Lactation

Pregnancy Category D. There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Lactation: Advise women not to breastfeed during treatment with Pemetrexed and for 1 week after the final dose