Pemetrexed disodium hemipentahydrate

1. INDICATIONS AND USAGE PEMRYDI RTU ® is a folate analog metabolic inhibitor indicated: in combination with pembrolizumab and platinum chemotherapy, for the initial treatment of patients with metastatic non-squamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations. in combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous NSCLC. as a single agent for the 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 for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy.

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, and glycinamide ribonucleotide formyltransferase (GARFT), which are folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is taken into cells by membrane carriers such as the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT.

2. DOSAGE AND ADMINISTRATION The recommended dose of PEMRYDI RTU 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. The recommended dose of PEMRYDI RTU, 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. Initiate folic acid 400 mcg to 1,000 mcg orally, once daily, beginning 7 days prior to the first dose of PEMRYDI RTU and continue until 21 days after the last dose of PEMRYDI RTU.

4. CONTRAINDICATIONS PEMRYDI RTU is contraindicated in patients with a history of severe hypersensitivity reaction to pemetrexed. History of severe hypersensitivity reaction to pemetrexed.

5. WARNINGS AND PRECAUTIONS Myelosuppression: Can cause severe bone marrow suppression resulting in cytopenia and an increased risk of infection. Do not administer PEMRYDI RTU when the absolute neutrophil count is less than 1,500 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 PEMRYDI RTU. Renal Failure: Can cause severe, and sometimes fatal, renal failure. Do not administer when creatinine clearance is less than 45 mL/min. Bullous and Exfoliative Skin Toxicity: Permanently discontinue for severe and life-threatening bullous, blistering or exfoliating skin toxicity. Interstitial Pneumonitis: Withhold for acute onset of new or progressive unexplained pulmonary symptoms. Permanently discontinue if pneumonitis is confirmed.

6. ADVERSE REACTIONS 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 The most common adverse reactions (incidence ≥ 20%) of pemetrexed, when administered as a single agent are fatigue, nausea, and anorexia. The most common adverse reactions (incidence ≥ 20%) of pemetrexed when administered with cisplatin are vomiting, neutropenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. 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.

7. DRUG INTERACTIONS Effects of Ibuprofen on Pemetrexed Ibuprofen increases exposure (AUC) of pemetrexed. In patients with creatinine clearance between 45 mL/min and 79 mL/min: Avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of PEMRYDI RTU. Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided. Ibuprofen increased risk of PEMRYDI RTU toxicity in patients with mild to moderate renal impairment. Modify the ibuprofen dosage as recommended for patients with a creatinine clearance between 45 mL/min and 79 mL/min.

Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F).