Pemfexy

2 DOSAGE AND ADMINISTRATION 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. Following completion of platinum-based therapy, treatment with PEMFEXY with or without pembrolizumab is administered until disease progression or unacceptable toxicity. Please refer to the full prescribing information for pembrolizumab and for carboplatin or cisplatin. The recommended dosage of PEMFEXY, when administered with cisplatin for initial treatment of locally advanced or 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 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 dosage of PEMFEXY for maintenance treatment of 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 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 dosage of PEMFEXY for treatment of recurrent 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 on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity. 2.2 Recommended Dosage for Mesothelioma The recommended dosage of PEMFEXY, when administered with cisplatin, 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 on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity. 2.3 Renal Impairment PEMFEXY dosing recommendations are provided for patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater [see Dosage and Administration ( 2.1 , 2.2 )] . There is no recommended dose for patients whose creatinine clearance is less than 45 mL/min [see Use in Specific Populations ( 8.6 )] . 2.4 Premedication and Concomitant Medications to Mitigate Toxicity Vitamin Supplementation Initiate folic acid 400 mcg to 1000 mcg orally once daily, beginning 7 days before the first dose of PEMFEXY and continuing until 21 days after the last dose [see Warnings and Precautions ( 5.1 )] . Administer vitamin B 12 1 mg intramuscularly 1 week prior to the first dose of PEMFEXY and every 3 cycles thereafter. Subsequent vitamin B 12 injections may be given the same day as treatment with PEMFEXY [see Warnings and Precautions ( 5.1 )] . Do not substitute oral vitamin B 12 for intramuscular vitamin B 12 . Corticosteroids Administer dexamethasone 4 mg orally twice daily for three consecutive days, beginning the day before each PEMFEXY administration. 2.5 Dosage Modification of Ibuprofen in Patients with Mild to Moderate Renal Impairment Receiving PEMFEXY In patients with creatinine clearances between 45 mL/min and 79 mL/min, modify administration of ibuprofen as follows [see Warnings and Precautions ( 5.6 ), Drug Interactions ( 7 ) and Clinical Pharmacology ( 12.3 )] . Avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of PEMFEXY. Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided. 2.6 Dosage Modifications for Adverse Reactions Obtain complete blood count on Days 1, 8, and 15 of each cycle. Assess creatinine clearance prior to each cycle. Do not administer PEMFEXY if the creatinine clearance is less than 45 mL/min. Delay initiation of the next cycle of PEMFEXY until: Recovery of non-hematologic toxicity to Grade 0-2, Absolute neutrophil count (ANC) is 1500 cells/mm 3 or higher, and Platelet count is 100,000 cells/mm 3 or higher. Upon recovery, modify the dosage of PEMFEXY in the next cycle as specified in Table 1 . For dosing modifications for cisplatin, carboplatin, or pembrolizumab, refer to their prescribing information. Table 1: Recommended Dosage Modifications for Adverse Reactions a a National Cancer Institute Common Toxicity Criteria for Adverse Events version 2 (NCI CTCAE v2) Toxicity in Most Recent Treatment Cycle PEMFEXY Dosage Modifications for Next Cycle Myelosuppressive toxicity [see Warnings and Precautions ( 5.1 )] ANC less than 500/mm 3 and platelets greater than or equal to 50,000/mm 3 OR Platelet count less than 50,000/mm 3 without bleeding. 75% of previous dose Platelet count less than 50,000/mm 3 with bleeding 50% of previous dose Recurrent Grade 3 or 4 myelosuppression after 2 dose reductions Permanently discontinue. Non-hematologic toxicity Any Grade 3 or 4 toxicities EXCEPT mucositis or neurologic toxicity OR Diarrhea requiring hospitalization 75% of previous dose Grade 3 or 4 mucositis 50% of previous dose Renal toxicity [see Warnings and Precautions ( 5.2 )] Withhold until creatinine clearance is 45 mL/min or greater. Grade 3 or 4 neurologic toxicity Permanently discontinue. Recurrent Grade 3 or 4 non-hematologic toxicity after 2 dose reductions Permanently discontinue. Severe and life-threatening skin toxicity [see Warnings and Precautions ( 5.3 )] Permanently discontinue. Interstitial pneumonitis [see Warnings and Precautions ( 5.4 )] Permanently discontinue. 2.7 Preparation and Administration PEMFEXY is a hazardous drug. Follow applicable special handling and disposal procedures. 1 Calculate the dose of PEMFEXY and determine the number of vials needed. Withdraw the calculated dose of PEMFEXY from the vial(s). Store unused portion in vial refrigerated at 2°C to 8°C (36°F to 46°F) for up to 28 days. Each vial contains 500 mg pemetrexed per 20 mL (25 mg/mL). The vial contains an excess of pemetrexed to facilitate delivery of labeled amount. Dilute PEMFEXY with 5% Dextrose in Water, USP or Normal Saline to achieve a total volume of 100 mL for intravenous infusion. Do not use other diluents, such as Lactated Ringer’s Injection, USP or Ringer’s Injection, USP. Visually inspect for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard if particulate matter or discoloration is observed. Administer PEMFEXY as an intravenous infusion over 10 minutes. Store diluted PEMFEXY refrigerated at 2°C to 8°C (36 °F to 46°F) for no more than 48 hours. PEMFEXY diluted with 5% Dextrose in Water, USP can also be stored at ambient room temperature and room light for no more than 48 hours. When prepared as directed, infusion solutions of PEMFEXY contain no antimicrobial preservatives. Discard after 48 hours. PEMFEXY is compatible with polyolefin infusion bags with polyvinyl chloride (PVC) ports.

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1 INDICATIONS AND USAGE 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.