Pemfexy Drug Information

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.

Renal Impairment

PEMFEXY 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 PEMFEXY and continuing until 21 days after the last dose. Subsequent vitamin B 12 injections may be given the same day as treatment with PEMFEXY. 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.

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. 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.

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.

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. Severe and life-threatening skin toxicity Permanently discontinue.

Interstitial pneumonitis Permanently discontinue.

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.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in clinical trials of drugs cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in 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 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 Non-Small Cell Lung Cancer (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. 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 was 7.2 months (range: 1 day to 1.7 years). Seventy-two percent of patients received carboplatin. 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. Table 2 summarizes the adverse reactions that occurred in ≥20% of patients treated with pemetrexed, pembrolizumab, and platinum. 5 Table 3 summarizes the laboratory abnormalities that worsened from baseline in at least 20% of patients treated with pemetrexed, pembrolizumab, and platinum. 8 Initial Treatment in Combination with Cisplatin The safety of pemetrexed 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 B 12. 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 B 12 or corticosteroids were also excluded from the study.

The data described below reflect exposure to pemetrexed 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 in combination with cisplatin in Study JMDB.

Study JMDB was 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 Table 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 — 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 Containing Platinum-Based Chemotherapy The safety of pemetrexed was evaluated in Study JMEN, 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 500 mg/m 2 or matching placebo intravenously every 21 days until disease progression or unacceptable toxicity.

The data described below reflect exposure to pemetrexed 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. 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 pemetrexed was 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 pemetrexed in combination with cisplatin as first-line therapy for NSCLC. Patients were randomized to receive pemetrexed 500 mg/m 2 or matching placebo intravenously on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity. Patients in both study arms received folic acid and vitamin B 12 supplementation.

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. 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 < 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 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 arm received folic acid and vitamin B 12 supplementation. The data described below reflect exposure to pemetrexed in 265 patients in Study JMEI. Table 7 provides the frequency and severity of adverse reactions reported in ≥ 5% of the 265 pemetrexed-treated patients in Study JMEI.

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 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 < 45 mL/min.

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 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-treated patients who were fully vitamin supplemented in Study JMCH. The following additional adverse reactions were observed in patients receiving pemetrexed plus cisplatin.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of pemetrexed. 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. 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 Respiratory — interstitial pneumonitis Skin — Serious and fatal bullous skin conditions, Stevens-Johnson syndrome, and toxic epidermal necrolysis

Effect of Other Drugs on Pemetrexed Ibuprofen

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

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. 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. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 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).

Pediatric Use The safety and effectiveness of PEMFEXY 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 B12 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.

PEMFEXY 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 overdose. Based on animal studies, administration of leucovorin may mitigate the toxicities of pemetrexed overdosage. It is not known whether pemetrexed is dialyzable.