AXTLE

RECENT MAJOR CHANGES Indications and Usage ( 1.1 ) 10/2025 Dosage and Administration ( 2 ) 10/2025

1 INDICATIONS AND USAGE AXTLE 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: AXTLE 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) AXTLE 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: AXTLE is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer [see Clinical Studies (14.1) ] . ● 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 ) 1.2 Mesothelioma AXTLE 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 dose of AXTLE 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 AXTLE, 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 AXTLE and continue until 21 days after the last dose of AXTLE. ( 2.4 ) Administer vitamin B 12 , 1 mg intramuscularly, 1 week prior to the first dose of AXTLE and every 3 cycles. ( 2.4 ) Administer dexamethasone 4 mg orally, twice daily the day before, the day of, and the day after AXTLE administration. ( 2.4 ) 2.1 Recommended Dosage for Non-Squamous NSCLC The recommended dose of AXTLE 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 AXTLE 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 AXTLE 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 AXTLE 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 AXTLE 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 AXTLE 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 AXTLE 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 AXTLE and continuing until 21 days after the last dose of AXTLE [see Warnings and Precautions (5.1) ] . Administer vitamin B 12, 1 mg intramuscularly, 1 week prior to …

3 DOSAGE FORMS AND STRENGTHS For injection: 100 mg or 500 mg pemetrexed equivalent to 118.3 mg or 591.5 mg pemetrexed dipotassium as a sterile preservative free white to light-yellow or green-yellow lyophilized powder in single-dose vials for reconstitution. For Injection: 100 mg or 500 mg pemetrexed equivalent to 118.3 mg or 591.5 mg pemetrexed dipotassium as lyophilized powder in single-dose vial ( 3 )

4 CONTRAINDICATIONS AXTLE 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 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 Avyxa Pharma, LLC at 1-888-520-0954 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 (4%), thrombocy …

7 DRUG INTERACTIONS Effects of Ibuprofen on Pemetrexed Ibuprofen increases exposure (AUC) of pemetrexed [see Clinical Pharmacology (12.3) ] . 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 AXTLE [see Dosage and Administration (2.5) ] . Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided. Ibuprofen increased risk of pemetrexed 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. ( 2.5 , 5.6 , 7 )

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, AXTLE 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 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, advise women not to breastfeed during treatment with AXTLE 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 AXTLE [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 AXTLE 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 AXTLE and for 3 months after the last dose [see Nonclinical Toxicology (13.1) ] . Infertility Males AXTLE 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 AXTLE 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. Adverse reactions observed in pediatric patients were similar to those observed in adults. Single-dose pharmacokinetics of pemetrexed were evaluated in 22 patients age 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 3-4 anemia, fatigue, thrombocytopenia, hypertension, and neutropenia were higher in patients 65 years of age and older as compared to younger patients: in at least one of five randomized clinical …

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 is a folate analog metabolic inhibitor. The drug substance is pemetrexed dipotassium heptahydrate, has the chemical name L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, dipotassium salt, heptahydrate. It is a white to off-white powder having blue or green tinge with a molecular formula of C 20 H 19 K 2 N 5 O 6 .7 H 2 O and a molecular weight of 629.49. Pemetrexed dipotassium is freely soluble in water. The reported pKaS are 3.6 and 4.5. The structural formula of pemetrexed dipotassium heptahydrate is as follows: AXTLE is supplied as a sterile white to light-yellow or green-yellow lyophilized powder or cake for intravenous infusion available in single-dose vials. Each 100-mg or 500-mg vial of AXTLE contains 100 mg pemetrexed equivalent to 118.3 mg pemetrexed dipotassium and 106 mg mannitol or 500 mg pemetrexed equivalent to 591.5 mg pemetrexed dipotassium and 500 mg mannitol, respectively. Hydrochloric acid may have been added to adjust the pH. Image

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 AXTLE TM , is a sterile preservative free white-to-light yellow or green-yellow lyophilized powder supplied in single-dose vials for reconstitution for intravenous infusion. NDC 83831-131-01: 100 mg single-dose vial containing pemetrexed equivalent to 118.3 mg pemetrexed dipotassium with aluminum flip-off seals with grey color button individually packaged in a carton. NDC 83831-132-01: 500 mg single-dose vial containing pemetrexed equivalent to 591.5 mg pemetrexed dipotassium with aluminum flip-off seals with red color button individually packaged in a carton. Storage and Handling Store at controlled room temperature, 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. AXTLE is a hazardous drug. Follow applicable special handling and disposal procedures. 1