Pemetrexed Disodium Drug Information

Recommended Dosage for Non-Squamous NSCLC •

The recommended dose of pemetrexed for 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, pemetrexed for injection may be administered as maintenance therapy, alone or with pembrolizumab, until disease progression or unacceptable toxicity. Pembrolizumab should be administered prior to pemetrexed for injection when given on the same day.

Please refer to the full prescribing information for pembrolizumab and for carboplatin.

Renal Impairment • Pemetrexed for injection dosing recommendations are provided for patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater. There is no recommended dose for patients whose creatinine clearance is less than 45 mL/min.

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 for injection and continuing until 21 days after the last dose of pemetrexed for injection. •Administer vitamin B 12, 1 mg intramuscularly, 1 week prior to the first dose of pemetrexed for injection and every 3 cycles thereafter. Subsequent vitamin B 12 injections may be given the same day as treatment with pemetrexed for injection. 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 for injection administration.

Dosage Modification of Ibuprofen in Patients with Mild to Moderate Renal Impairment Receiving Pemetrexed for Injection In patients with creatinine clearances between 45 mL/min and 79 mL/min, modify administration of ibuprofen as follows: • Avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of pemetrexed for injection. • Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided.

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 pemetrexed for injection if the creatinine clearance is less than 45 mL/min.

Upon recovery, modify the dosage of pemetrexed for injection in the next cycle as specified in Table 1. For dosing modifications for cisplatin, refer to the prescribing information for cisplatin. Table 1: Recommended Dosage Modifications for Adverse Reactions a Severe and life-threatening Skin Toxicity Permanently discontinue Interstitial Pneumonitis Permanently discontinue a National Cancer Institute Common Toxicity Criteria for Adverse Events version 2 (NCI CTCAE v2).

Preparation for Administration • Pemetrexed for injection is a hazardous drug. Follow applicable special handling and disposal procedures. 1 • Calculate the dose of pemetrexed for injection and determine the number of vials needed. • Reconstitute pemetrexed for injection to achieve a concentration of 25 mg/mL as follows: - Reconstitute each 100-mg vial with 4.2 mL of 0.9% Sodium Chloride Injection, USP (preservative-free) - Reconstitute each 500-mg vial with 20 mL of 0.9% Sodium Chloride Injection, USP (preservative-free) - Reconstitute each 1 g vial with 40 mL of 0.9% Sodium Chloride Injection, USP (preservative-free) - Do not use calcium-containing solutions for reconstitution. • Gently swirl each vial until the powder is completely dissolved. The resulting solution is clear and ranges in color from colorless to yellow or green-yellow.

Discard vial after 24 hours. • Inspect reconstituted product visually for particulate matter and discoloration prior to further dilution. If particulate matter is observed, discard vial. • Withdraw the calculated dose of pemetrexed for injection from the vial(s) and discard vial with any unused portion. • Further dilute pemetrexed for injection with 0.9% Sodium Chloride Injection (preservative-free) to achieve a total volume of 100 mL for intravenous infusion. • Store diluted, reconstituted product under refrigerated conditions 2 to 8°C (36 to 46°F) or 20° to 25°C (68° to 77°F) for no more than 24 hours from the time of reconstitution. Discard after 24 hours.

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

The most common adverse reactions (incidence ≥20%) of pemetrexed for injection, 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 for injection, 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 for injection, pembrolizumab, and platinum every 3 weeks for 4 cycles followed by pemetrexed for injection and pembrolizumab (n=405), or placebo, pemetrexed for injection, and platinum every 3 weeks for 4 cycles followed by placebo and pemetrexed for injection (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. The median duration of exposure to pemetrexed for injection was 7.2 months (range: 1 day to 1.7 years). Seventy-two percent of patients received carboplatin.

Pemetrexed for injection was discontinued for adverse reactions in 23% of patients in the pemetrexed for injection, pembrolizumab, and platinum arm. The most common adverse reactions resulting in discontinuation of pemetrexed for injection in this arm were acute kidney injury (3%) and pneumonitis (2%). Adverse reactions leading to interruption of pemetrexed for injection occurred in 49% of patients in the pemetrexed for injection, pembrolizumab, and platinum arm.

Table 2 summarizes the adverse reactions that occurred in ≥20% of patients treated with pemetrexed for injection, pembrolizumab, and platinum Table 2: 5 a Graded per NCI CTCAE version 4.03. b Includes asthenia and fatigue. c Includes genital rash, rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular. Table 3 summarizes the laboratory abnormalities that worsened from baseline in at least 20% of patients treated with pemetrexed for injection, pembrolizumab, and platinum. Table 3: Laboratory Abnormalities Worsened from Baseline in ≥ 8 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: pemetrexed for injection /pembrolizumab/platinum chemotherapy (range: 381 to 401 patients) and placebo/pemetrexed for injection /platinum chemotherapy (range: 184 to 197 patients). b Graded per NCI CTCAE version 4.03.

Initial Treatment in Combination with Cisplatin The safety of pemetrexed for injection was evaluated in Study JMDB, a randomized (1:1), open-label, multicenter trial conducted in chemotherapy-naive patients with locally advanced or metastatic NSCLC. All patients were fully supplemented with folic acid and vitamin B12. Study JMDB excluded patients with an Eastern Cooperative Oncology Group Performance Status (ECOG PS of 2 or greater), uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min.

Patients unable to stop using aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin B12 or corticosteroids were also excluded from the study. The data described below reflect exposure to pemetrexed for injection plus cisplatin in 839 patients in Study JMDB. Patients received a median of 5 cycles of pemetrexed.

Table 4 provides the frequency and severity of adverse reactions that occurred in ≥5% of 839 patients receiving pemetrexed for injection in combination with cisplatin in Study JMDB. Study JMDB was not designed to demonstrate a statistically significant reduction in adverse reaction rates for pemetrexed for injection, as compared to the control arm, for any specified adverse reaction listed in Table 4. The following additional adverse reactions of pemetrexed were observed.

Incidence 1% to <5% Body as a Whole — febrile neutropenia, infection, pyrexia General Disorders — dehydration Metabolism and Nutrition — increased AST, increased ALT Renal — creatinine clearance decrease, renal failure Eye Disorder — conjunctivitis Incidence < 1% Cardiovascular — arrhythmia General Disorders — chest pain Metabolism and Nutrition — increased GGT Neurology — motor neuropathy Maintenance Treatment Following First-line Non-Pemetrexed for injection Containing Platinum-Based Chemotherapy In Study JMEN, the safety of pemetrexed for injection was evaluated in a randomized (2:1), placebo-controlled, multicenter trial conducted in patients with non-progressive locally advanced or metastatic NSCLC following four cycles of a first-line, platinum-based chemotherapy regimen. Patients received either pemetrexed for injection 500 mg/m 2 or matching placebo intravenously every 21 days until disease progression or unacceptable toxicity. Patients in both study arms were fully supplemented with folic acid and vitamin B 12.

The data described below reflect exposure to pemetrexed for injection in 438 patients in Study JMEN. Approximately half the patients (48%) completed at least six, 21-day cycles and 23% completed ten or more 21-day cycles of pemetrexed for injection. Table 5 provides the frequency and severity of adverse reactions reported in ≥5% of the 438 pemetrexed for injection -treated patients in Study JMEN.

Table 5: Adverse Reactions Occurring in ≥5% of Patients Receiving Pemetrexed for injection in Study JMEN. The following additional adverse reactions were observed in patients who received pemetrexed. Incidence 1% to <5% Dermatology/Skin — alopecia, pruritis/itching Gastrointestinal — constipation General Disorders — edema, fever Hematologic — thrombocytopenia Eye Disorder — ocular surface disease (including conjunctivitis), increased lacrimation Incidence < 1% Cardiovascular — supraventricular arrhythmia Dermatology/Skin — erythema multiforme General Disorders — febrile neutropenia, allergic reaction/hypersensitivity Neurology — motor neuropathy Renal — renal failure Maintenance Treatment Following First-line pemetrexed Plus Platinum Chemotherapy The safety of pemetrexedwas evaluated in PARAMOUNT, a randomized (2:1), placebo-controlled study conducted in patients with non-squamous NSCLC with non-progressive (stable or responding disease) locally advanced or metastatic NSCLC following four cycles of pemetrexedin combination with cisplatin as first-line therapy for NSCLC.

The data described below reflect exposure to pemetrexed in 333 patients in PARAMOUNT. The median number of maintenance cycles was 4 for pemetrexed and placebo arms. Dose reductions for adverse reactions occurred in 3.3% of patients in the pemetrexed arm and 0.6% in the placebo arm.

Dose delays for adverse reactions occurred in 22% of patients in the pemetrexed arm and 16% in the placebo arm. Table 6 provides the frequency and severity of adverse reactions reported in ≥5% of the 333 pemetrexed-treated patients in PARAMOUNT. The following additional Grade 3 or 4 adverse reactions were observed more frequently in the pemetrexed arm.

Incidence 1% to 5% Blood/Bone Marrow — thrombocytopenia General Disorders — febrile neutropenia Incidence Less than 1% Cardiovascular — ventricular tachycardia, syncope General Disorders — pain Gastrointestinal — gastrointestinal obstruction Neurologic — depression Renal — renal failure Vascular — pulmonary embolism Treatment of Recurrent Disease After Prior Chemotherapy The safety of pemetrexed for injection was evaluated in Study JMEI, a randomized (1:1), open-label, active-controlled trial conducted in patients who had progressed following platinum-based chemotherapy. All patients on the pemetrexed for injection arm received folic acid and vitamin B 12 supplementation. Patients unable to discontinue aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin B 12 orcorticosteroids were also excluded from the study.

The data described below reflect exposure to pemetrexed for injection in 265 patients in Study JMEI. Study JMEI is not designed to demonstrate a statistically significant reduction in adverse reaction rates for pemetrexed, as compared to the control arm, for any specified adverse reaction listed in the Table7 below. Table 7: Adverse Reactions Occurring in ≥5% of Fully Supplemented Patients Receiving Pemetrexed forInjection in Study JMEI.

The following additional adverse reactions were observed in patients assigned to receive pemetrexed. Incidence 1% to <5% Body as a Whole — abdominal pain, allergic reaction/hypersensitivity, febrile neutropenia, infection Dermatology/Skin — erythema multiforme Neurology — motor neuropathy, sensory neuropathy Incidence <1% Cardiovascular — supraventricular arrhythmias Renal — renal failure Mesothelioma The safety of pemetrexed for injection was evaluated in Study JMCH, a randomized (1:1), single-blind study conducted in patients with MPM who had received no prior chemotherapy for MPM. Safety was assessed in 226 patients who received at least one dose of pemetrexed in combination with cisplatin and 222 patients who received at least one dose of cisplatin alone.

Study JMCH excluded patients with Karnofsky Performance Scale (KPS) of less than 70, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. The data described below reflect exposure to pemetrexed for injection in 168 patients that were fully supplemented with folic acid and vitamin B 12. The median number of treatment cycles administered was 6 in the pemetrexed /cisplatin fully supplemented group and 2 in the pemetrexed/cisplatin never supplemented group.

Patients receiving pemetrexed for injection in the fully supplemented group had a relative dose intensity of 93% of the protocol-specified pemetrexed dose intensity. The most common adverse reaction resulting in dose delay was neutropenia. Table 8 provides the frequency and severity of adverse reactions ≥5% in the subgroup of pemetrexed for injection-treated patients who were fully vitamin supplemented in Study JMCH.

Table 8 provides the ADRs for subgroup of patients treated with pemetrexed for injection in combination with cisplatin (168 patients) or cisplatin alone (163 patients) who received full supplementation with folic acid and vitamin B 12 during study therapy. b NCI CTCAE version 2.0. Table 9: Exploratory Subgroup Analysis of Selected Grade 3/4 Adverse Reactions Occurring in Patients Receiving Pemetrexed for Injection in Combination with Cisplatin with or without Full Vitamin Supplementation in Study JMCH a. Additional Experience Across Clinical Trials Sepsis, with or without neutropenia, including fatal cases: 1% Severe esophagitis, resulting in hospitalization: <1%

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of pemetrexed for injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions have occurred with pemetrexed for injection when used as a single-agent and in combination therapies.

Blood and Lymphatic System — immune-mediated hemolytic anemia Gastrointestinal — colitis, pancreatitis General Disorders and Administration Site Conditions — edema Injury, poisoning, and procedural complications — Radiation recall has been reported in patients who have previously received radiotherapy. Respiratory — interstitial pneumonitis Skin — Bullous conditions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Some cases were fatal.

Effects of Ibuprofen on Pemetrexed Ibuprofen increases exposure (AUC) of pemetrexed. Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided. Ibuprofen increased risk of pemetrexed for injection 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.

Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, pemetrexed for injection can cause fetal harm when administered to a pregnant woman. There are no available data on pemetrexed for 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.

Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Data Animal DataPemetrexed 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).

Pediatric Use The safety and effectiveness of pemetrexed for injection in pediatric patients have not been established. The safety and pharmacokinetics of pemetrexed for injection 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 for injection were evaluated in 22 patients age 4 to 18 years enrolled in NCT00070473 were within range of values in adults.

Pemetrexed for injection is contraindicated in patients with a history of severe hypersensitivity reaction to pemetrexed. History of severe hypersensitivity reaction to pemetrexed.

No drugs are approved for the treatment of pemetrexed for injection overdose. Based on animal studies, administration of leucovorin may mitigate the toxicities of pemetrexed overdosage. It is not known whether pemetrexed is dialyzable.