100 ML pemetrexed 10 MG/ML Injection [Pemrydi Rtu]

INDICATIONS AND USAGE Pemetrexed for injection 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. ( 1.1 ) in combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous (NSCLC) ( 1.1 ) 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. ( 1.1 ) as a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy. ( 1.1 ) Limitations of Use: Pemetrexed for injection is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer. ( 1.1 ) initial treatment, in combination with cisplatin, of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. ( 1.2 ) 1.1 Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Pemetrexed for injection is indicated for: 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, nonsquamous, 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. 1.2 Mesothelioma Pemetrexed for injection is indicated, in combination with cisplatin, for the initial treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. 1.1 Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Pemetrexed for injection is indicated for: 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, nonsquamous, 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.

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. ( 2.1 ) 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. ( 2.1 , 2.2 ) 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. ( 2.4 ) Administer vitamin B 12 , 1 mg intramuscularly, 1 week prior to the first dose of PEMRYDI RTU and every 3 cycles. ( 2.4 ) Administer dexamethasone 4 mg orally, twice daily the day before, the day of, and the day after PEMRYDI RTU administration. ( 2.4 ) 2.1 Recommended Dosage for Non-Squamous NSCLC The recommended dose of PEMRYDI RTU 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 PEMRYDI RTU 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 dose of PEMRYDI RTU 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 dose of PEMRYDI RTU 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 dose of PEMRYDI RTU 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 dose of PEMRYDI RTU 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 PEMRYDI RTU 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 1,000 mcg orally once daily, beginning 7 days before the first dose of PEMRYDI RTU and continuing until 21 days after the last dose of PEMRYDI RTU [see Warnings and Precautions (5.1) ] . Administer vitamin B 12 , 1 mg intramuscularly, 1 week prior to the first dose of PEMRYDI RTU and every 3 cycles thereafter. Subsequent vitamin B 12 injections may be given the same day as treatment with PEMRYDI RTU [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 PEMRYDI RTU administration. 2.5 Dosage Modification of Ibuprofen in Patients with Mild to Moderate Renal Impairment Receiving PEMRYDI RTU 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 PEMRYDI RTU. 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 PEMRYDI RTU if the creatinine clearance is less than 45 mL/min. Delay initiation of the next cycle of PEMRYDI RTU until: recovery of non-hematologic toxicity to Grade 0-2, absolute neutrophil count (ANC) is 1,500 cells/mm 3 or higher, and platelet count is 100,000 cells/mm 3 or higher. Upon recovery, modify the dosage of PEMRYDI RTU 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 Toxicity in Most Recent Treatment Cycle PEMRYDI RTU Dose Modification 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 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 a National Cancer Institute Common Toxicity Criteria for Adverse Events version 2 (NCI CTCAE v2). 2.7 Preparation for Administration PEMRYDI RTU is a hazardous drug. Follow applicable special handling and disposal procedures. 1 Calculate the dose of PEMRYDI RTU and determine the volume of needed PEMRYDI RTU. Each vial contains an excess of PEMRYDI RTU to facilitate delivery of labeled amount. Withdraw the calculated dose of PEMRYDI RTU from the vial(s) and discard the vial(s) with any unused portion. Transfer the calculated dose into an empty intravenous bag. Do NOT further dilute PEMRYDI RTU. Visually inspect for particulate matter and discoloration prior to administration. Discard if particulate matter or discoloration is observed. Immediately administer PEMRYDI RTU undiluted, as an intravenous infusion over 10 minutes using an infusion pump. If not used immediately, store undiluted PEMRYDI RTU solution in infusion bag for no more than 24 hours at controlled room temperature of 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]

WARNINGS AND PRECAUTIONS • Myelosuppression: Can cause severe bone marrow suppression resulting in cytopenia and an increased risk of infection. Do not administer pemetrexed for injection 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 pemetrexed for injection ( 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 forinjection 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. In Study JMCH, incidences of Grade 3 to 4 neutropenia (38% versus 23%), thrombocytopenia (9% versus 5%), febrile neutropenia (9% versus 0.6%), and neutropenic infection (6% versus 0) were higher in patients who received pemetrexed plus cisplatin without vitamin supplementation as compared to patients who were fully supplemented with folic acid and vitamin B 12 prior to and throughout pemetrexed plus cisplatin treatment. Initiate supplementation with oral folic acid and intramuscular vitamin B 12 prior to the first dose of pemetrexed; continue vitamin supplementation during treatment and for 21 days after the last dose of pemetrexed to reduce the severity of hematologic and gastrointestinal toxicity of pemetrexed for injection [see Dosage and Administration ( 2.4 ) ]. Obtain a complete blood count at the beginning of each cycle. Do not administer pemetrexed for injection until the ANC is at least 1500 cells/mm 3 and platelet count is at least 100,000 cells/mm 3 . Permanently reduce pemetrexed for injection in patients with an ANC of less than 500 cells/mm 3 or platelet count of less than 50,000 cells/mm 3 in previous cycles [see Dosage and Administration ( 2.6 ) ]. In Studies JMDB and JMCH, among patients who received vitamin supplementation, incidence of Grade 3 to 4 neutropenia was 15% and 23%, the incidence of Grade 3 to 4 anemia was 6% and 4%, and incidence of Grade 3 to 4 thrombocytopenia was 4% and 5%, respectively. In Study JMCH, 18% of patients in the pemetrexed for injection arm required red blood cell transfusions compared to 7% of patients in the cisplatin arm [see Adverse Reactions ( 6.1 ) ]. In Studies JMEN, PARAMOUNT, and JMEI, where all patients received vitamin supplementation, incidence of Grade 3 to 4 neutropenia ranged from 3% to 5%, and incidence of Grade 3 to 4 anemia ranged from 3% to 5%. 5.2 Renal Failure Pemetrexed for injection can cause severe, and sometimes fatal, renal toxicity. The incidences of renal failure in clinical studies in which patients received pemetrexed with cisplatin were: 2.1% in Study JMDB and 2.2% in Study JMCH. The incidence of renal failure in clinical studies in which patients received pemetrexed for injection as a single agent ranged from 0.4% to 0.6% (Studies JMEN, PARAMOUNT, and JMEI [see Adverse Reactions ( 6.1 ) ]. Determine creatinine clearance before each dose and periodically monitor renal function during treatment with pemetrexed for injection. Withhold pemetrexed for injection in patients with a creatinine clearance of less than 45 mL/minute [see Dosage and Administration ( 2.3 ) ]. 5.3 Bullous and Exfoliative Skin Toxicity Serious and sometimes fatal, bullous, blistering and exfoliative skin toxicity, including cases suggestive of Stevens-Johnson Syndrome/Toxic epidermal necrolysis can occur with pemetrexed for injection. Permanently discontinue pemetrexed for severe and life-threatening bullous, blistering or exfoliating skin toxicity. 5.4 Interstitial Pneumonitis Serious interstitial pneumonitis, including fatal cases, can occur with pemetrexed for injection treatment. Withhold pemetrexed for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, or fever pending diagnostic evaluation. If pneumonitis is confirmed, permanently discontinue pemetrexed. 5.5 Radiation Recall Radiation recall can occur with pemetrexed for injection in patients who have received radiation weeks to years previously. Monitor patients for inflammation or blistering in areas of previous radiation treatment. Permanently discontinue pemetrexed for injection for signs of radiation recall. 5.6 Increased Risk of Toxicity with Ibuprofen in Patients with Renal Impairment Exposure to pemetrexed is increased in patients with mild to moderate renal impairment who take concomitant ibuprofen, increasing the risks of adverse reactions of pemetrexed. In patients with creatinine clearances 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 pemetrexed. If concomitant ibuprofen use cannot be avoided, monitor patients more frequently for pemetrexed adverse reactions, including myelosuppression, renal, and gastrointestinal toxicity [see Dosage and Administration ( 2.5 ), Drug Interactions ( 7 ), and Clinical Pharmacology ( 12.3 ) ]. 5.7 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, pemetrexed can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and increased malformations at doses lower than the recommended human dose of 500 mg/m 2 . Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with pemetrexed and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with pemetrexed and for 3 months after the last dose [see Use in Specific Populations ( 8.1 , 8.3 ) and Clinical Pharmacology ( 12.1 ) ]. 5.7 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, pemetrexed can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and increased malformations at doses lower than the recommended human dose of 500 mg/m 2 . Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with pemetrexed and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with pemetrexed and for 3 months after the last dose [see Use in Specific Populations ( 8.1 , 8.3 ) and Clinical Pharmacology ( 12.1 ) ].

CONTRAINDICATIONS Pemetrexed for Injection 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. ( 4 )

Mechanism of Action Pemetrexed for injection, is a folate analog metabolic inhibitor that exerts its action by 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. Polyglutamation is a time- and concentration-dependent process that occurs in tumor cells and, is thought to occur to a lesser extent, in normal tissues. Polyglutamated metabolites are thought to have an increased intracellular half-life resulting in prolonged drug action in malignant cells.