Pemetrexed

Pemetrexed is a folate analog metabolic inhibitor that disrupts folate-dependent metabolic processes essential for cell replication. In vitro studies show that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides.

• PEMFEXY™ is a folate analog metabolic inhibitor indicated for: in combination with pembrolizumab and platinum chemotherapy, for the initial treatment of patients with metastatic non-squamous NSCLC, with no EGFR or ALK genomic tumor aberrations. ( 1.1 ) in combination with cisplatin for the initial treatment of patients with locally advanced or metastatic non-squamous, non-small cell lung cancer (NSCLC).ICD-10: C34.90

• PEMFEXY is contraindicated in patients with a history of severe hypersensitivity reaction to pemetrexed [see Adverse Reactions ( 6.1 )] . History of severe hypersensitivity reaction to pemetrexed.contraindicated

The recommended dose of PEMFEXY administered with pembrolizumab and platinum chemotherapy in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m 2 as an intravenous infusion over 10 minutes, administered after pembrolizumab and prior to platinum chemotherapy, on Day 1 of each 21-day cycle. ( 2.1 ) The recommended dosage of PEMFEXY, administered as a single agent or with cisplatin, in patients with creatinine clearance of 45 mL/minute or greater, is 500 mg/m 2 as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. ( 2.1 , 2.2 , 2.3 ) Initiate folic acid 400 mcg to 1000 mcg orally once daily beginning 7 days prior to the first dose of PEMFEXY and continue until 21 days after the last dose. ( 2.4 ) Administer vitamin B 12 1 mg intramuscularly 1 week prior to the first dose of PEMFEXY and every 3 cycles thereafter. ( 2.4 ) Administer dexamethasone 4 mg orally twice daily the day before, the day of, and the day after PEMFEXY administration. ( 2.4 ) 2.1 Recommended Dosage for Non-squamous Non-Small Cell Lung Cancer The recommended dose of PEMFEXY, when administered with pembrolizumab and platinum chemotherapy for the initial treatment of metastatic non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m 2 as an intravenous infusion over 10 minutes administered after pembrolizumab and prior to carboplatin or cisplatin on Day 1 of each 21-day cycle for 4 cycles.

Myelosuppression : Can cause severe bone marrow suppression resulting in cytopenia and an increased risk of infection. Do not administer PEMFEXY when the absolute neutrophil count is less than 1500 cells/mm 3 and platelets are less than 100,000 cells/mm 3 . Initiate supplementation with oral folic acid and intramuscular vitamin B 12 to reduce the severity of hematologic and gastrointestinal toxicity of PEMFEXY. ( 2.4 , 5.1 ) Renal Failure : Can cause severe, and sometimes fatal, renal failure. Do not administer when creatinine clearance is less than 45 mL/min ( 2.3 , 5.2 ) Bullous and Exfoliative Skin Toxicity : Permanently discontinue for severe and life-threatening bullous, blistering or exfoliating skin toxicity. ( 5.3 ) Interstitial Pneumonitis : Withhold for acute onset of new or progressive unexplained pulmonary symptoms. Permanently discontinue if pneumonitis is confirmed. ( 5.4 ) Radiation Recall : Can occur in patients who received radiation weeks to years previously; permanently discontinue for signs of radiation recall. ( 5.5 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.7 , 8.1 , 8.3 ) 5.1 Myelosuppression and Increased Risk of Myelosuppression without Vitamin Supplementation Pemetrexed can cause severe myelosuppression resulting in a requirement for transfusions and which may lead to neutropenic infection. The risk of myelosuppression is increased in patients who do not receive vitamin supplementation.

The following clinically significant adverse reactions are described elsewhere in the labeling: Myelosuppression [see Warnings and Precautions ( 5.1 )] Renal failure [see Warnings and Precautions ( 5.2 )] Bullous and exfoliative skin toxicity [see Warnings and Precautions ( 5.3 )] Interstitial pneumonitis [see Warnings and Precautions ( 5.4 )] Radiation recall [see Warnings and Precautions ( 5.5 )] The most common adverse reactions (incidence ≥ 20%) of pemetrexed, when administered as a single agent are fatigue, nausea, and anorexia. ( 6.1 ) The most common adverse reactions (incidence ≥ 20%) of pemetrexed when administered with cisplatin are vomiting, neutropenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. ( 6.1 ) The most common adverse reactions (incidence ≥20%) of pemetrexed when administered in combination with pembrolizumab and platinum chemotherapy are fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, and pyrexia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eagle Pharmaceuticals, Inc. at 1-855-318-2170 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in clinical trials of drugs cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Lactation : Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, pemetrexed can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . There are no available data on pemetrexed use in pregnant women. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and malformations at doses lower than the recommended human dose of 500 mg/m 2 ( see Data ). Advise pregnant women of the potential risk to a fetus [see use in Specific Population ( 8.3 )] . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Pemetrexed was teratogenic in mice. Daily dosing of pemetrexed by intravenous injection to pregnant mice during the period of organogenesis increased the incidence of fetal malformations (cleft palate; protruding tongue; enlarged or misshaped kidney; and fused lumbar vertebra) at doses (based on BSA) 0.03 times the human dose of 500 mg/m 2 .

Metabolism

Absorption The pharmacokinetics of pemetrexed administered as a single-agent in doses ranging from 0.2 mg/m 2 to 838 mg/m 2 infused over a 10-minute period have been evaluated in 426 patients with a variety of solid tumors. Pemetrexed total systemic exposure (AUC) and maximum plasma concentration (C max ) increased proportionally with increase of dose.

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.

• Feb 4, 2004NDANDA021462Lilly
• Feb 8, 2020NDANDA209472Eagle Pharms
• Aug 21, 2020NDANDA208419Actavis
• May 25, 2022ANDAANDA090384Fresenius Kabi Usa
• May 26, 2022NDANDA214657Sandoz
• Jun 22, 2022NDANDA214218Hospira
• May 22, 2023NDANDA215179Shilpa
• Jun 28, 2024NDANDA210661Avyxa Holdings

1. 1Malignant Neoplasm Progression3,0428.3%
2. 2Off Label Use2,2676.2%
3. 3Anaemia2,0735.6%
4. 4Nausea1,8765.1%
5. 5Diarrhoea1,7834.9%
6. 6Pancytopenia1,7014.6%
7. 7Neutropenia1,6894.6%
8. 8Death1,6734.6%
9. 9Thrombocytopenia1,5904.3%
10. 10Fatigue1,4223.9%
11. 11Vomiting1,3953.8%
12. 12Disease Progression1,3703.7%
13. 13Dyspnoea1,3033.5%
14. 14Acute Kidney Injury1,2553.4%
15. 15Pyrexia1,2513.4%

Recent PubMed references pinned to Pemetrexed as a MeSH major topic. Citations link to pubmed.ncbi.nlm.nih.gov.

• Efficacy and toxicity of maintenance therapy with PD-1/PD-L1 inhibitors plus pemetrexed vs . immunotherapy alone for stage III/IV non-squamous non-small cell lung cancer: A real-world study.
  Chinese medical journal · 2026 · Huang Z, Mei S, Liu J, et al.
  PMID 42036883DOI 10.1097/CM9.0000000000004083
• Pseudocellulitis in a patient with non-small cell lung cancer on carboplatin, pemetrexed and pembrolizumab.
  BMJ case reports · 2026 · Beadman T, Chan MM
  PMID 42031384DOI 10.1136/bcr-2025-269581
• [Huangqi Guizhi Wuwu Decoction in the Treatment of Pemetrexed 
Intrathecal Chemotherapy-induced Neurotoxicity in NSCLC Patients 
with Leptomeningeal Metastases: A Randomized Controlled Trial].
  Zhongguo fei ai za zhi = Chinese journal of lung cancer · 2026 · Li H, Chen X, Xie Y, et al.
  PMID 41975647DOI 10.3779/j.issn.1009-3419.2026.102.02
• Cost comparison of osimertinib plus platinum-pemetrexed versus amivantamab plus lazertinib for the first-line treatment of patients with locally advanced or metastatic epidermal growth factor receptor-mutated non-small cell lung cancer.
  Journal of medical economics · 2026 · Lopes GL, Freeman H, Procter E, et al.
  PMID 41973054DOI 10.1080/13696998.2025.2609507
• Spectroscopic and Thermodynamic Exploration of Folic Acid's Modulatory Impact on the Bimolecular Interactions of Hemoglobin with Pemetrexed.
  Molecular pharmaceutics · 2026 · Nakka S, Prabha R, Chahar D, et al.
  PMID 41958042DOI 10.1021/acs.molpharmaceut.6c00128
• Safety and efficacy of intrathecal pemetrexed and bevacizumab in non-small cell lung cancer (NSCLC) patients with leptomeningeal metastases (LM): protocol for a single-arm, prospective, phase Ia trial.
  BMJ open · 2026 · Kuang Y, Teng J, Wang W, et al.
  PMID 41877338DOI 10.1136/bmjopen-2026-116187
• [Efficacy and Safety of High-dose Furmonertinib plus Intrathecal Pemetrexed 
for EGFR-mutant Non-small Cell Lung Cancer with Leptomeningeal Metastasis].
  Zhongguo fei ai za zhi = Chinese journal of lung cancer · 2025 · Chen X, He M, Chen C, et al.
  PMID 41777061DOI 10.3779/j.issn.1009-3419.2025.101.24
• Concurrent Pemetrexed With EGFR-TKI Slows the Accumulation of De Novo Mutations During In Vitro Exposure.
  Anticancer research · 2026 · Haque EF, Tanino R, Okimoto T, et al.
  PMID 41760274DOI 10.21873/anticanres.18032

The 10 most recently updated of 1,508 ClinicalTrials.gov registrations naming Pemetrexed as an intervention. Registration is not evidence of efficacy or safety — reference crosswalk only.

• KEYMAKER-U01 Substudy 01J: A Study of Pembrolizumab Plus MK-1084 in Participants With Non-Small Cell Lung Cancer (NSCLC) With Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) G12C Mutations (MK-3475-01J/KEYMAKER-U01J)
  Recruiting · Phase 2 · Interventional · 130 enrolled · Merck Sharp & Dohme LLC
  NCT07252739updated 2026-06-12
• Testing the Addition of a Type of Drug Called Immunotherapy to the Usual Chemotherapy Treatment for Non-small Cell Lung Cancer, an ALCHEMIST Treatment Trial (Chemo-IO [ACCIO])
  Recruiting · Phase 3 · Interventional · 1,210 enrolled · National Cancer Institute (NCI)
  NCT04267848updated 2026-06-12
• Toripalimab Combined With Platinum-based Chemotherapy With or Without H1 Receptor Antagonist in the Perioperative Treatment of Resectable Non-small Cell Lung Cancer
  Not yet recruiting · Phase 2 · Interventional · 120 enrolled · Tianjin Medical University Cancer Institute and Hospital
  NCT07358689updated 2026-06-12
• Pemetrexed Response in Relation to Tumor Alterations of Gene Status for the Treatment of Patients With Metastatic Urothelial Bladder Cancer and Other Solid Tumors
  Recruiting · Phase 2 · Interventional · 64 enrolled · Northwestern University
  NCT06630416updated 2026-06-12
• A Clinical Study of Calderasib (MK-1084) and Other Treatments for Participants With Non-Small Cell Lung Cancer (MK-1084-007/KANDLELIT-007)
  Recruiting · Phase 3 · Interventional · 675 enrolled · Merck Sharp & Dohme LLC
  NCT07190248updated 2026-06-12
• Study to Evaluate Adverse Events and Efficacy of Intravenous (IV) Telisotuzumab Adizutecan in Combination With a PD-1 Immune Checkpoint Inhibitor in Adult Participants With Advanced or Metastatic Non-Squamous NSCLC With No Prior Treatment for Advanced Disease, and No Actionable Genomic Alterations
  Recruiting · Phase 1 · Phase 2 · Interventional · 252 enrolled · AbbVie
  NCT06772623updated 2026-06-12
• Beamion 44: A Study to Test How Well Zongertinib is Tolerated by People With Advanced Non-small Cell Lung Cancer With HER2 Mutations When Given in Combination With Chemotherapy With or Without Pembrolizumab
  Recruiting · Phase 2 · Interventional · 60 enrolled · Boehringer Ingelheim
  NCT07486817updated 2026-06-12
• Neoadjuvant Inhaled Azacytidine With Platinum-Based Chemotherapy and Durvalumab (MEDI4736) - a Combined Epigenetic-Immunotherapy (AZA-AEGEAN) Regimen for Operable Early-Stage Non-Small Cell Lung Cancer (NSCLC)
  Recruiting · Phase 1 · Phase 2 · Interventional · 60 enrolled · National Cancer Institute (NCI)
  NCT06694454updated 2026-06-12
• A Study of BL-B01D1 in Combination With Osimertinib as Perioperative Therapy in Patients With EGFR-mutated Resectable Non-small Cell Lung Cancer(PANKU-Lung09)
  Not yet recruiting · Phase 2 · Phase 3 · Interventional · 90 enrolled · Sichuan Baili Pharmaceutical Co., Ltd.
  NCT07642024updated 2026-06-11
• Testing the Addition of an Anti-Cancer Drug, TRC102, to the Usual Chemotherapy Treatment (Pemetrexed, Cisplatin or Carboplatin) During Radiation Therapy for Stage III Non-Squamous Non-Small Cell Lung Cancer
  Recruiting · Phase 2 · Interventional · 42 enrolled · National Cancer Institute (NCI)
  NCT05198830updated 2026-06-11

Frequently asked questions

How does Pemetrexed work?

Pemetrexed is a folate analog metabolic inhibitor that disrupts folate-dependent metabolic processes essential for cell replication. In vitro studies show that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides.

What is Pemetrexed used for?

According to FDA labeling, Pemetrexed carries indications including: PEMFEXY™ is a folate analog metabolic inhibitor indicated for: in combination with pembrolizumab and platinum chemotherapy, for the initial treatment of patients with metastatic non-squamous NSCLC, with no EGFR or ALK genomic tumor aberrations. ( 1.1 ) in combination with cisplatin for the initial treatment of patients with locally advanced or metastatic non-squamous, non-small cell lung cancer (NSCLC).. This is a reference summary of labeled uses, not medical advice or a treatment recommendation.

What class of drug is Pemetrexed?

Pemetrexed is classified as Folic acid analogues, Folate Analog Metabolic Inhibitor, Dihydrofolate Reductase Inhibitors, Folic Acid Metabolism Inhibitors, Protein Synthesis Inhibitors, Thymidylate Synthetase Inhibitors, Decreased DNA Integrity, Decreased Protein Synthesis.

What are the brand names for Pemetrexed?

Pemetrexed is marketed under brand names including Alimta, Axtle, Pemfexy, Pemrydi Rtu.

What are the contraindications for Pemetrexed?

Pemetrexed labeling lists contraindications including: PEMFEXY is contraindicated in patients with a history of severe hypersensitivity reaction to pemetrexed [see Adverse Reactions ( 6.1 )] . History of severe hypersensitivity reaction to pemetrexed.. Always consult the full prescribing information and a clinician.