Pemfexy Drug Information

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. 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.

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%), thrombocytopenia (4%), increased blood creatinine (3%), diarrhea (3%), and fatigue (3%). Table 2 summarizes the adverse reactions that occurred in ≥20% of patients treated with pemetrexed, pembrolizumab, and platinum. Table 2: Adverse Reactions Occurring in ≥20% of Patients in KEYNOTE-189 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.

Adverse Reaction Pemetrexed Pembrolizumab Platinum Chemotherapy n=405 Placebo Pemetrexed Platinum Chemotherapy n=202 All Grades a (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Gastrointestinal Disorders Nausea 56 3.5 52

Constipation 35 1.0 32 0.5 Diarrhea 31 5 21 3.0 Vomiting 24

3.7 23

General Disorders and

Administration Site Conditions Fatigue b 56 12 58 6 Pyrexia 20 0.2 15 0 Metabolism and Nutrition Disorders Decreased appetite 28 1.5 30

Skin and Subcutaneous Tissue Disorders Rash c 25 2.0 17 2.5 Respiratory

Thoracic and Mediastinal Disorders Cough 21 0 28 0 Dyspnea 21 3.7 26 5 Table 3 summarizes the laboratory abnormalities that worsened from baseline in at least 20% of patients treated with pemetrexed, pembrolizumab, and platinum. Table 3: Laboratory Abnormalities Worsened from Baseline in ≥20% of Patients in KEYNOTE-189 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/pembrolizumab/platinum chemotherapy (range: 381 to 401 patients) and placebo/pemetrexed/platinum chemotherapy (range: 184 to 197 patients). b.

Graded per NCI CTCAE version 4.03. Pemetrexed Pembrolizumab Platinum Chemotherapy Placebo Pemetrexed Platinum Chemotherapy Laboratory Test a All Grades (%) b Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Chemistry Hyperglycemia 63 9 60 7 Increased ALT 47 3.8 42

Increased

AST 47 2.8 40

Hypoalbuminemia 39 2.8 39 1.1 Increased creatinine 37 4.2 25 1.0 Hyponatremia

32 7 23 6 Hypophosphatemia 30 10 28 14 Increased alkaline phosphatase 26 1.8 29

Hypocalcemia 24 2.8 17 0.5 Hyperkalemia 24 2.8 19 3.1 Hypokalemia 21

5 20 5 Hematology Anemia 85 17 81 18 Lymphopenia 64 22 64 25 Neutropenia 48 20 41 19 Thrombocytopenia 30 12 29 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. Patients received either pemetrexed 500 mg/m 2 intravenously in combination with cisplatin 75 mg/m 2 intravenously on Day 1 of each 21-day cycle (n=839) or gemcitabine 1250 mg/m 2 intravenously on Days 1 and 8 in combination with cisplatin 75 mg/m 2 intravenously on Day 1 of each 21-day cycle (n=830). 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. Median age was 61 years (range 26-83 years); 70% of patients were men; 78% were White, 16% were Asian, 2.9% were Hispanic or Latino, 2.1% were Black or African American, and < 1% were other races; 36% had an ECOG PS 0. 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 4. Table 4: Adverse Reactions Occurring in ≥ 5% of Fully Vitamin-Supplemented Patients Receiving Pemetrexed in Combination with Cisplatin in Study JMDB a NCI CTCAE version 2.0. Adverse Reaction a Pemetrexed/Cisplatin (N=839) Gemcitabine/Cisplatin (N=830) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) All Adverse Reactions 90 37 91 53 Laboratory Hematologic Anemia 33 6 46 10 Neutropenia 29 15 38 27 Thrombocytopenia 10 4 27 13 Renal Elevated creatinine 10 1 7 1 Clinical Gastrointestinal Nausea 56 7 53 4 Vomiting 40 6 36 6 Anorexia 27 2 24 1 Constipation 21 1 20 0 Stomatitis/Pharyngitis 14 1 12 0 Diarrhea 12 1 13 2 Dyspepsia/Heartburn 5 0 6 0 Constitutional Symptoms Fatigue 43 7 45 5 Dermatology/Skin Alopecia 12 0 21 1 Rash/Desquamation 7 0 8 1 Neurology Sensory neuropathy 9 0 12 1 Taste disturbance 8 0 9 0 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.

Patients in both study arms were fully supplemented with folic acid and vitamin B 12. Study JMEN excluded patients with an ECOG PS of 2 or greater, uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function or a calculated creatinine clearance < 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 in 438 patients in Study JMEN. Median age was 61 years (range 26-83 years), 73% of patients were men; 65% were White, 31% were Asian, 2.9% were Hispanic or Latino, and < 2% were other races; 39% had an ECOG PS 0. Patients received a median of 5 cycles of pemetrexed and a relative dose intensity of pemetrexed of 96%. Approximately half the patients (48%) completed at least six 21-day cycles and 23% completed ten or more 21-day cycles of pemetrexed.

Table 5 provides the frequency and severity of adverse reactions reported in ≥ 5% of the 438 pemetrexed-treated patients in Study JMEN. Table 5: Adverse Reactions Occurring in ≥ 5% Fully Supplemented Patients Receiving Pemetrexed in Study JMEI a NCI CTCAE version 3.0. Adverse Reaction a Pemetrexed (N=438) Placebo (N=218) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) All adverse reactions 66 16 37 4 Laboratory Hematologic Anemia 15 3 6 1 Neutropenia 6 3 0 0 Hepatic Increased ALT 10 0 4 0 Increased AST 8 0 4 0 Clinical Constitutional Symptoms Fatigue 25 5 11 1 Gastrointestinal Nausea 19 1 6 1 Anorexia 19 2 5 0 Vomiting 9 0 1 0 Mucositis/Stomatitis 7 1 2 0 Diarrhea 5 1 3 0 Dermatology/Skin Rash/Desquamation 10 0 3 0 Neurology Sensory neuropathy 9 1 4 0 Infection 5 2 2 0 The requirement for transfusions (9.5% versus 3.2%), primarily red blood cell transfusions, and for erythropoiesis stimulating agents (5.9% versus 1.8%) were higher in the pemetrexed arm compared to the placebo arm. 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. PARAMOUNT excluded patients with an ECOG PS of 2 or greater, uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance < 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 in 333 patients in PARAMOUNT. Median age was 61 years (range 32 to 83 years); 58% of patients were men; 94% were White, 4.8% were Asian, and < 1% were Black or African American; 36% had an ECOG PS 0. 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. Table 6: Adverse Reactions Occurring in ≥ 5% of Patients Receiving Pemetrexed in PARAMOUNT a NCI CTCAE version 3.0. Adverse Reaction a Pemetrexed (N=333) Cisplatin (N=167) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) All Adverse Reactions 53 17 34

Laboratory Hematologic Anemia 15 4.8 4.8 0.6 Neutropenia 9 3.9 0.6 0

Clinical Constitutional Symptoms Fatigue 18 4.5 11

Gastrointestinal Nausea 12 0.3 2.4 0 Vomiting 6 0 1.8 0 Mucositis/Stomatitis

5 0.3 2.4 0 General Disorders Edema 5 0 3.6 0 The requirement for red blood cell (13% versus 4.8%) and platelet (1.5% versus 0.6%) transfusions, erythropoiesis stimulating agents (12% versus 7%), and granulocyte colony stimulating factors (6% versus 0%) were higher in the pemetrexed arm compared to 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.

Patients received pemetrexed 500 mg/m 2 intravenously or docetaxel 75 mg/m 2 intravenously on Day 1 of each 21-day cycle. All patients on the pemetrexed arm received folic acid and vitamin B 12 supplementation. Study JMEI excluded patients with an ECOG PS of 3 or greater, uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance < 45 mL/min.

Patients unable to discontinue 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 in 265 patients in Study JMEI. Median age was 58 years (range 22 to 87 years); 73% of patients were men; 70% were White, 24% were Asian, 2.6% were Black or African American, 1.8% were Hispanic or Latino, and < 2% were other races; 19% had an ECOG PS 0. Table 7 provides the frequency and severity of adverse reactions reported in ≥ 5% of the 265 pemetrexed-treated 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 Table 7 below. Table 7: Adverse Reactions Occurring in ≥ 5% Fully Supplemented Patients Receiving Pemetrexed in Study JMEI a NCI CTCAE version 2.0. Adverse Reaction a Pemetrexed (N=265) Docetaxel (N=276) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Laboratory Hematologic Anemia 19 4 22 4 Neutropenia 11 5 45 40 Thrombocytopenia 8 2 1 0 Hepatic Increased ALT 8 2 1 0 Increased AST 7 1 1 0 Clinical Constitutional Symptoms Fatigue 34 5 36 5 Fever 8 0 8 0 Gastrointestinal Nausea 31 3 17 2 Anorexia 22 2 24 3 Vomiting 16 2 12 1 Stomatitis/Pharyngitis 15 1 17 1 Diarrhea 13 0 24 3 Constipation 6 0 4 0 Dermatology/Skin Rash/Desquamation 14 0 6 0 Pruritis 7 0 2 0 Alopecia 6 1 38 2 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 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. Patients received pemetrexed 500 mg/m 2 intravenously in combination with cisplatin 75 mg/m 2 intravenously on Day 1 of each 21-day cycle or cisplatin 75 mg/m 2 intravenously on Day 1 of each 21-day cycle administered until disease progression or unacceptable toxicity. 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. Among 226 patients who received pemetrexed in combination with cisplatin, 74% (n=168) received full supplementation with folic acid and vitamin B 12 during study therapy, 14% (n=32) were never supplemented, and 12% (n=26) were partially supplemented.

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. Patients unable to stop using aspirin or other non-steroidal anti-inflammatory drugs were also excluded from the study. The data described below reflect exposure to pemetrexed in 168 patients that were fully supplemented with folic acid and vitamin B 12. Median age was 60 years (range 19 to 85 years); 82% were men; 92% were White, 5% were Hispanic or Latino, 3.0% were Asian, and < 1% were other races; 54% had KPS of 90-100. 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. Study JMCH 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 the table below.

Table 8: Adverse Reactions Occurring in ≥ 5% Fully Supplemented Subgroup Patients Receiving Pemetrexed/Cisplatin in Study JMCH a a In Study JMCH, 226 patients received at least one dose of pemetrexed in combination with cisplatin and 222 patients received at least one dose of cisplatin. Table 8 provides the ADRs for subgroup of patients treated with pemetrexed 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

Adverse Reaction b Pemetrexed/Cisplatin (N=168) Cisplatin (N=163) All Grades (%) Grade 3-4

(%) All Grades (%) Grade 3-4 (%) Laboratory Hematologic Neutropenia 56 23 13 3 Anemia 26 4 10 0 Thrombocytopenia 23 5 9 0 Renal Decreased creatinine clearance 16 1 18 2 Elevated creatinine 11 1 10 1 Clinical Gastrointestinal Nausea 82 12 77 6 Vomiting 57 11 50 4 Stomatitis/Pharyngitis 23 3 6 0 Anorexia 20 1 14 1 Diarrhea 17 4 8 0 Constipation 12 1 7 1 Dyspepsia 5 1 1 0 Constitutional Symptoms Fatigue 48 10 42 9 Dermatology/Skin Rash 16 1 5 0 Alopecia 11 0 6 0 Neurology Sensory neuropathy 10 0 10 1 Taste disturbance 8 0 6 0 Metabolism and Nutrition Dehydration 7 4 1 1 Eye Disorder Conjunctivitis 5 0 1 0 The following additional adverse reactions were observed in patients receiving pemetrexed plus cisplatin. Incidence 1% to < 5% Body as a Whole — febrile neutropenia, infection, pyrexia Dermatology/Skin — urticaria General Disorders — chest pain Metabolism and Nutrition — increased AST, increased ALT, increased GGT Renal — renal failure Incidence < 1% Cardiovascular — arrhythmia Neurology — motor neuropathy Exploratory Subgroup Analyses based on Vitamin Supplementation Table 9 provides the results of exploratory analyses of the frequency and severity of NCI CTCAE Grade 3 or 4 adverse reactions reported in more pemetrexed-treated patients who did not receive vitamin supplementation (never supplemented) as compared with those who received vitamin supplementation with daily folic acid and vitamin B 12 from the time of enrollment in Study JMCH (fully-supplemented). Table 9: Exploratory Subgroup Analysis of Selected Grade 3-4 Adverse Reactions Occurring in Patients Receiving Pemetrexed in Combination with Cisplatin with or without Full Vitamin Supplementation in Study JMCH a a NCI CTCAE version

Grade 3-4 Adverse Reaction Fully Supplemented Patients (N=168) Never Supplemented Patients (N=32)

Neutropenia 23 38 Vomiting 11 31 Thrombocytopenia 5 9 Diarrhea 4 9 Febrile neutropenia 1 9 Infection with Grade 3-4 neutropenia 0 6 The following adverse reactions occurred more frequently in patients who were fully vitamin supplemented than in patients who were never supplemented: hypertension (11% versus 3%) chest pain (8% versus 6%) thrombosis/embolism (6% versus 3%) Additional Experience Across Clinical Trials Sepsis, with or without neutropenia, including fatal cases: 1% Severe esophagitis, resulting in hospitalization: less than 1%

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 . 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 PEMFEXY . 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 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).

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.

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.