Pemetrexed

1 INDICATIONS AND USAGE Pemetrexed 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 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 Injection is 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. Limitations of Use Pemetrexed Injection is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer [see Clinical Studies ( 14.1 )]. 1.2 Mesothelioma Pemetrexed 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.

2 DOSAGE AND ADMINISTRATION • The recommended dosage of Pemetrexed Injection 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 Pemetrexed Injection, 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 1000 mcg orally, once daily, beginning 7 days prior to the first dose of Pemetrexed Injection and continue until 21 days after the last dose of Pemetrexed Injection. (2.4) • Administer vitamin B 12 , 1 mg intramuscularly, 1 week prior to the first dose of Pemetrexed Injection and every 3 cycles. ( 2.4 ) • Administer dexamethasone 4 mg orally, twice daily the day before, the day of, and the day after Pemetrexed Injection administration. ( 2.4 ) 2.1 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 Pemetrexed Injection and continuing until 21 days after the last dose of Pemetrexed Injection [see Warnings and Precautions ( 5.1 )]. • Administer vitamin B 12 , 1 mg intramuscularly, 1 week prior to the first dose of Pemetrexed Injection and every 3 cycles thereafter. Subsequent vitamin B 12 injections may be given the same day as treatment with Pemetrexed Injection [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 Pemetrexed Injection administration. 2.2 Recommended Dosage and Administration Non-Squamous NSCLC • The recommended dosage of Pemetrexed Injection 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 Pemetrexed Injection 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 Pemetrexed Injection 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 Pemetrexed Injection 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 Pemetrexed Injection 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. Mesothelioma …

3 DOSAGE FORMS AND STRENGTHS Injection: Pemetrexed Injection is a clear, colorless to yellow or green-yellow solution available in sterile single-dose vials as follows: • 100 mg/4 mL (25 mg/mL) • 500 mg/20 mL (25 mg/mL) • 1000 mg/40 mL (25 mg/mL) Injection: 100 mg/4 mL (25 mg/mL), 500 mg/20 mL (25 mg/mL), 1000 mg/40 mL (25 mg/mL) in single-dose vials. ( 3 )

4 CONTRAINDICATIONS Pemetrexed 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 )

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Myelosuppression [see Warnings and Precautions ( 5.1 )] • Renal failure [see Warnings and Precautions ( 5.2 )] • Bullous and exfoliative skin toxicity [see Warning 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 Sandoz Inc. 1-800-525-8747 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 cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. In clinical trials, 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 in combination 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. Non-Squamous NSCLC First-line Treatment of Metastatic Non-squamous NSCLC with Pembrolizumab and Platinum Chemotherapy The safety of pemetrexed, in combination with pembrolizumab and investigator’s choice of platinum (either carboplatin or cisplatin), was investigated in Study KEYNOTE-189, a multicenter, double-blind, randomized (2:1), active-controlled trial in patients with previously untreated, metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations. A total of 607 patients received pemetrexed, pembrolizumab, and platinum every 3 weeks for 4 cycles followed by pemetrexed and pembrolizumab (n=405), or placebo, pemetrexed, and platinum every 3 weeks for 4 cycles followed by placebo and pemetrexed (n=202). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible [see Clinical Studies ( 14.1 )] . The median duration of exposure to pemetrexed was 7.2 months (range: 1 day to 1.7 years). Seventy-two percent of patients received carboplatin. The study population characteristics were: median age of 64 years (range: 34 to 84), 49% age 65 years or older, 59% male, 94% White and 3% Asian, and 18% with history of brain metastases at baseline. Pemetrexed was discontinued for adverse reactions in 23% of patients in the pemetrexed, pembrolizumab, and platinum arm. The most common adverse reactions resulting in discontinuation of pemetrexed in this arm were acute kidney injury (3%) and pneumonitis (2%). Adverse reactions leading to interruption of pemetrexed occurred in 49% of patients in the pemetrexed, pembrolizumab, and platinum arm. The most common adverse reactions or laboratory abnormalities leading to interruption of pemetrexed in this arm (≥2%) were neutropenia (12%), anemia (7%), asthenia (4%), pneumonia ( …

7 DRUG INTERACTIONS OAT3 Inhibitors: Modify the ibuprofen dosage as recommended. Avoid other OAT3 inhibitors. ( 2.5 , 5.6 , 7 ) 7.1 Effects of Other Drugs on Pemetrexed Injection OAT3 Inhibitors Avoid concomitant administration of ibuprofen for 2 days before, the day of, and 2 days following administration of Pemetrexed Injection [see Dosage and Administration ( 2.5 )] . Avoid concomitant administration of other OAT3 inhibitors before and after administration of Pemetrexed Injection, when possible. If concomitant administration cannot be avoided, monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity. Pemetrexed is an OAT3 substrate [see Clinical Pharmacology ( 12.3 )] . Concomitant use with an OAT3 inhibitor increases pemetrexed systemic exposure (AUC) [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of Pemetrexed Injection adverse reactions.

8 USE IN SPECIFIC POPULATIONS 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 Injection 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 Special Populations ( 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 . At doses, based on BSA, greater than or equal to 0.0012 times the 500 mg/m 2 human dose, pemetrexed administration resulted in dose-dependent increases in developmental delays (incomplete ossification of talus and skull bone; and decreased fetal weight). 8.2 Lactation Risk Summary There is no information regarding the presence of pemetrexed or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed infants from Pemetrexed Injection, advise women not to breastfeed during treatment with Pemetrexed Injection and for one week after the last dose. 8.3 Females and Males of Reproductive Potential Based on animal data pemetrexed can cause malformations and developmental delays when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )]. Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to initiating Pemetrexed Injection [see Use in Specific Populations ( 8.1 )]. Contraception Females Because of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment with Pemetrexed Injection and for 6 months after the last dose. Males Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with Pemetrexed Injection and for 3 months after the last dose [see Nonclinical Toxicology ( 13.1 )] . Infertility Males Pemetrexed may impair fertility in males of reproductive potential. It is not known whether these effects on fertility are reversible [see Nonclinical Toxicology ( 13.1 )] . 8.4 Pediatric Use The safety and effectiveness of pemetrexed in pediatric patients have not been established. The safety and pharmacokinetics of pemetrexed were evaluated in two clinical studies conducted in pediatric patients with recurrent solid tumors (NCT00070473, N=32 and NCT00520936, N=72). Patients in both studies received concomitant vitamin B 12 and folic acid supplementation and dexamethasone. No tumor responses were observed. No new safety signals were observed. Single-dose pharmacokinetics of pemetrexed were evaluated in 22 patients aged 4 to 18 years enrolled in NCT00070473 were within range of values in adults. 8.5 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 to 4 anemia, fatigue, thrombocytopenia, hypertension, and neutropenia were higher in patients 65 years of age and older as compared to younger pat …

12.1 Mechanism of Action 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.

11 DESCRIPTION Pemetrexed Injection is a folate analog metabolic inhibitor. The drug substance, pemetrexed disodium, has the chemical name N-[[4-[2-(2-Amino-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]phenyl] carbonyl] -L-glutamic acid disodium, 2.5H 2 O with a molecular formula of C 20 H 19 N 5 Na 2 O 6 2.5 H 2 O and a molecular weight of 516.41 The structural formula is as follows: Pemetrexed Injection is supplied as a sterile clear colorless to yellow or green-yellow solution for intravenous infusion available in single-dose vials. Each mL contains 25 mg pemetrexed (30.2 mg pemetrexed disodium 2.5 hydrate), 0.5 mg sodium thiosulfate pentahydrate, 50 mg propylene glycol, water for injection. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH. Pemetrexed Injection requires dilution prior to intravenous infusion. Pemetrexed Injection should be diluted in 0.9% sodium chloride injection (preservative-free) to achieve a total volume of 100 mL for intravenous infusion. chemical-structure

10 OVERDOSAGE 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.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Pemetrexed Injection is supplied as a sterile single-dose vial containing clear colorless to yellow or green-yellow solution in a clear glass vial with a grey rubber closure, aluminum cap, and light blue flip-off cap Strength/Fill volume NDC number Pack style 100 mg/4 mL NDC 0781-3518-76 Carton containing one (1) single-dose vial 500 mg/20 mL NDC 0781-3519-90 Carton containing one (1) single-dose vial 1,000 mg/40 mL NDC 0781-3520-91 Carton containing one (1) single-dose vial Storage and Handling Store solution at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light. Keep the vial in the carton box until the time of use. Pemetrexed Injection is a hazardous drug. Follow applicable special handling and disposal procedures [see References ( 15 )]. 1