Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 05 July 2018

Indication(s)

1 INDICATIONS AND USAGE ALIMTA® is a folate analog metabolic inhibitor indicated: in combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous, non-small cell lung cancer (NSCLC). (1.1) in combination with carboplatin and pembrolizumab for the initial treatment of patients with metastatic, non-squamous NSCLC. This indication is approved under accelerated approval based on tumor response rate and progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. (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: ALIMTA 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) ALIMTA® is indicated: in combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous, non-small cell lung cancer (NSCLC). in combination with carboplatin and pembrolizumab for the initial treatment of patients with metastatic, non-squamous NSCLC. This indication is approved under accelerated approval based on tumor response rate and progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. 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: ALIMTA is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer [see Clinical Studies 14.1]. 1.2 Mesothelioma ALIMTA 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.

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contraindications
4 CONTRAINDICATIONS ALIMTA 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)
Adverse reactions
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 ALIMTA, when administered as a single agent are fatigue, nausea, and anorexia. (6.1) The most common adverse reactions (incidence ≥20%) of ALIMTA when administered with cisplatin are vomiting, neutropenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. (6.1) The most common adverse reactions (incidence ≥30%) of ALIMTA when administered in combination with carboplatin and pembrolizumab are fatigue, nausea, constipation, rash, vomiting, dyspnea, diarrhea, headache, and decreased appetite. To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) 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 ALIMTA, when administered as a single agent, are fatigue, nausea, and anorexia. The most common adverse reactions (incidence ≥20%) of ALIMTA, when administered in combination with cisplatin are vomiting, neutropenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. Non-Squamous NSCLC Initial Treatment in Combination with Cisplatin The safety of ALIMTA 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 ALIMTA 500 mg/m2 intravenously and cisplatin 75 mg/m2 intravenously on Day 1 of each 21-day cycle (n=839) or gemcitabine 1250 mg/m2 intravenously on Days 1 and 8 and cisplatin 75 mg/m2 intravenously on Day 1 of each 21-day cycle (n=830). 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 ALIMTA 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 ethnicities; 36% had an ECOG PS 0. Patients received a median of 5 cycles of ALIMTA. Table 2 provides the frequency and severity of adverse reactions that occurred in ≥5% of 839 patients receiving ALIMTA in combination with cisplatin in Study JMDB. Study JMDB was not designed to demonstrate a statistically significant reduction in adverse reaction rates for ALIMTA, as compared to the control arm, for any specified adverse reaction listed in Table 2. Table 2: Adverse Reactions Occurring in ≥5% of Fully Vitamin-Supplemented Patients Receiving ALIMTA in Combination with Cisplatin Chemotherapy in Study JMDB a NCI CTCAE version 2.0. Adverse Reaction a ALIMTA/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 Constitutional symptoms Fatigue 43 7 45 5 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 Neurology Sensory neuropathy 9 0 12 1 Taste disturbance 8 0 9 0 Dermatology/Skin Alopecia 12 0 21 1 Rash/Desquamation 7 0 8 1 The following additional adverse reactions of ALIMTA 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-ALIMTA Containing Platinum-Based Chemotherapy In Study JMEN, the safety of ALIMTA 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 ALIMTA 500 mg/m2 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 B12. 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 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 ALIMTA 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 ethnicities; 39% had an ECOG PS 0. Patients received a median of 5 cycles of ALIMTA and a relative dose intensity of ALIMTA of 96%. Approximately half the patients (48%) completed at least six, 21-day cycles and 23% completed ten or more 21-day cycles of ALIMTA. Table 3 provides the frequency and severity of adverse reactions reported in ≥5% of the 438 ALIMTA-treated patients in Study JMEN. Table 3: Adverse Reactions Occurring in ≥5% of Patients Receiving ALIMTA in Study JMEN a NCI CTCAE version 3.0. Adverse Reaction a ALIMTA (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 Infection 5 2 2 0 Neurology Sensory neuropathy 9 1 4 0 Dermatology/Skin Rash/desquamation 10 0 3 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 ALIMTA arm compared to the placebo arm. The following additional adverse reactions were observed in patients who received ALIMTA. Incidence 1% to<5% Dermatology/Skin — alopecia, pruritus/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 ALIMTA Plus Platinum Chemotherapy The safety of ALIMTA 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 ALIMTA in combination with cisplatin as first-line therapy for NSCLC. Patients were randomized to receive ALIMTA 500 mg/m2 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 B12 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 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 ALIMTA 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 ALIMTA and placebo arms. Dose reductions for adverse reactions occurred in 3.3% of patients in the ALIMTA arm and 0.6% in the placebo arm. Dose delays for adverse reactions occurred in 22% of patients in the ALIMTA arm and 16% in the placebo arm. Table 4 provides the frequency and severity of adverse reactions reported in ≥5% of the 333 ALIMTA-treated patients in PARAMOUNT. Table 4: Adverse Reactions Occurring in ≥5% of Patients Receiving ALIMTA in PARAMOUNT a NCI CTCAE version 3.0. Adverse Reaction a ALIMTA (N=333) Placebo (N=167) All Grades (%) Grade 3-4 (%) All Grades (%) Grades 3-4 (%) All adverse reactions 53 17 34 4.8 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 0.6 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 ALIMTA arm compared to the placebo arm. The following additional Grade 3 or 4 adverse reactions were observed more frequently in the ALIMTA 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 ALIMTA 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 ALIMTA 500 mg/m2 intravenously or docetaxel 75 mg/m2 intravenously on Day 1 of each 21-day cycle. All patients on the ALIMTA arm received folic acid and vitamin B12 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 less than 45 mL/min. Patients unable to discontinue 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 ALIMTA 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 ethnicities; 19% had an ECOG PS 0. Table 5 provides the frequency and severity of adverse reactions reported in ≥5% of the 265 ALIMTA-treated patients in Study JMEI. Study JMEI is not designed to demonstrate a statistically significant reduction in adverse reaction rates for ALIMTA, as compared to the control arm, for any specified adverse reaction listed in the Table 5 below. Table 5: Adverse Reactions Occurring in ≥5% of Fully Supplemented Patients Receiving ALIMTA in Study JMEI a NCI CTCAE version 2.0. Adverse Reaction a ALIMTA (N=265) Docetaxel (N=276) All Grades (%) Grades 3-4 (%) All Grade (%) Grades 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 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 Constitutional symptoms Fatigue 34 5 36 5 Fever 8 0 8 0 Dermatology/Skin Rash/desquamation 14 0 6 0 Pruritus 7 0 2 0 Alopecia 6 1 38 2 The following additional adverse reactions were observed in patients assigned to receive ALIMTA. 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 First-line Treatment of Non-squamous NSCLC, with Carboplatin and Pembrolizumab The safety of ALIMTA administered with carboplatin and pembrolizumab was investigated in a randomized (1:1) open-label cohort in Study KEYNOTE-021. Patients with previously untreated, metastatic non-squamous NSCLC received ALIMTA with carboplatin and pembrolizumab (n=59) or ALIMTA with carboplatin alone (n=62). 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 number of cycles of ALIMTA was 11 (range, 1-24). The study population characteristics were: median age of 64 years (range: 37 to 80), 48% age 65 years or older, 39% Male, 87% White and 8% Asian, 97% with metastatic disease, and 12% with brain metastases. ALIMTA was discontinued for adverse reactions in 9% of patients. The most common adverse reaction resulting in discontinuation of ALIMTA (≥2%) was acute kidney injury (3.4%). Adverse reactions leading to interruption of ALIMTA occurred in 36% of patients; the most common (≥2%) were fatigue (9%), neutrophil count decreased (9%), anemia (7%), dyspnea (3.4%), and pneumonitis (3.4%). Table 6 summarizes the adverse reactions that occurred in at least 20% of patients in KEYNOTE-021. KEYNOTE-021 was not designed to demonstrate a statistically significant difference in adverse reactions between study arms for any specified reaction listed in Table 6. Table 6: Adverse Reactions Occurring in ≥20% of Patients in KEYNOTE-021 a Graded per NCI CTCAE v4.0. b Includes rash, rash generalized, rash macular, rash maculo-papular, and rash pruritic. ALIMTA Carboplatin Pembrolizumab n=59 ALIMTA Carboplatin n=62 Adverse Reaction All Grades a Toxicity (%) Grade 3-4 a Toxicity (%) All Grades a Toxicity (%) Grades 3-4 a Toxicity (%) General Disorders and Administration Site Conditions Fatigue 71 3.4 50 0 Peripheral Edema 22 0 18 0 Gastrointestinal Disorders Nausea 68 1.7 56 0 Constipation 51 0 37 1.6 Vomiting 39 1.7 27 0 Diarrhea 37 1.7 23 1.6 Skin and Subcutaneous Tissue Disorders Rashb 42 1.7 21 1.6 Pruritus 24 0 4.8 0 Alopecia 20 0 3.2 0 Respiratory, Thoracic and Mediastinal Disorders Dyspnea 39 3.4 21 0 Cough 24 0 18 0 Metabolism and Nutrition Disorders Decreased Appetite 31 0 23 0 Nervous System Disorders Headache 31 0 16 1.6 Dizziness 24 0 16 0 Dysgeusia 20 0 11 0 Psychiatric Disorders Insomnia 24 0 15 0 Infections and Infestations Upper respiratory tract infection 20 0 3.2 0 Musculoskeletal and Connective Tissue Disorders Arthralgia 15 0 24 1.6 Table 7: Laboratory Abnormalities Worsened from Baseline in ≥20% of Patients in KEYNOTE-021 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: ALIMTA carboplatin pembrolizumab (range: 56 to 58 patients) and ALIMTA carboplatin (range: 55 to 61 patients). b Graded per NCI CTCAE v 4.0. ALIMTA Carboplatin Pembrolizumab ALIMTA Carboplatin Laboratory Test a All Grades b Toxicity (%) Grade 3-4 b Toxicity (%) All Grades b Toxicity (%) Grades 3-4 b Toxicity (%) Chemistry Hyperglycemia 74 9 61 5 Lymphocytes decreased 53 23 60 28 Aspartate aminotransferase increased 51 3.5 46 1.7 Hypertriglyceridemia 50 0 43 0 Alanine aminotransferase increased 40 3.5 32 1.7 Creatinine increased 34 3.4 19 1.7 Hyponatremia 33 5 35 3.5 Hypoalbuminemia 32 0 31 0 Hypocalcemia 30 5 19 1.7 Hypokalemia 29 5 22 1.7 Hypophosphatemia 29 5 24 11 Alkaline phosphatase increased 28 0 9 0 Hematology Hemoglobin decreased 83 17 84 19 Neutrophils decreased 47 14 43 8 Platelets decreased 24 9 36 10 Mesothelioma The safety of ALIMTA 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 ALIMTA 500 mg/m2 intravenously in combination with cisplatin 75 mg/m2 intravenously on Day 1 of each 21-day cycle or cisplatin 75 mg/m2 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 ALIMTA in combination with cisplatin and 222 patients who received at least one dose of cisplatin alone. Among 226 patients who received ALIMTA in combination with cisplatin, 74% (n=168) received full supplementation with folic acid and vitamin B12 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 less than 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 ALIMTA in 168 patients that were fully supplemented with folic acid and vitamin B12. 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 ethnicities; 54% had KPS of 90-100. The median number of treatment cycles administered was 6 in the ALIMTA/cisplatin fully supplemented group and 2 in the ALIMTA/cisplatin never supplemented group. Patients receiving ALIMTA in the fully supplemented group had a relative dose intensity of 93% of the protocol-specified ALIMTA 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 ALIMTA-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 ALIMTA, as compared to the control arm, for any specified adverse reaction listed in the table below. Table 8: Adverse Reactions Occurring in ≥5% of Fully Supplemented Subgroup of Patients Receiving ALIMTA/Cisplatin in Study JMCHa a In Study JMCH, 226 patients received at least one dose of ALIMTA 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 ALIMTA in combination with cisplatin (168 patients) or cisplatin alone (163 patients) who received full supplementation with folic acid and vitamin B12 during study therapy. b NCI CTCAE version 2.0. Adverse Reaction b ALIMTA/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 Elevated creatinine 11 1 10 1 Decreased creatinine clearance 16 1 18 2 Clinical Eye Disorder Conjunctivitis 5 0 1 0 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 Metabolism and Nutrition Dehydration 7 4 1 1 Neurology Sensory neuropathy 10 0 10 1 Taste disturbance 8 0 6 0 Dermatology/Skin Rash 16 1 5 0 Alopecia 11 0 6 0 The following additional adverse reactions were observed in patients receiving ALIMTA 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 ALIMTA-treated patients who did not receive vitamin supplementation (never supplemented) as compared with those who received vitamin supplementation with daily folic acid and vitamin B12 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 ALIMTA in Combination with Cisplatin with or without Full Vitamin Supplementation in Study JMCHa a NCI CTCAE version 2.0. Grade 3-4 Adverse Reactions Fully Supplemented Patients N=168 (%) Never Supplemented Patients N=32 (%) Neutropenia 23 38 Thrombocytopenia 5 9 Vomiting 11 31 Febrile neutropenia 1 9 Infection with Grade 3/4 neutropenia 0 6 Diarrhea 4 9 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: <1% 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ALIMTA. 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

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Dosing and administration
2 DOSAGE AND ADMINISTRATION The recommended dose of ALIMTA, administered as a single agent or with cisplatin or with carboplatin and pembrolizumab, in patients with creatinine clearance of 45 mL/minute or greater, is 500 mg/m2 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 ALIMTA and continue until 21 days after the last dose of ALIMTA. (2.4) Administer vitamin B12, 1 mg intramuscularly, 1 week prior to the first dose of ALIMTA and every 3 cycles. (2.4) Administer dexamethasone 4 mg orally, twice daily the day before, the day of, and the day after ALIMTA administration. (2.4) 2.1 Recommended Dosage for Non-Squamous NSCLC The recommended dose of ALIMTA when administered with cisplatin for initial treatment of NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m2 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 ALIMTA for maintenance treatment of NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m2 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 ALIMTA for treatment of recurrent NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m2 as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity. The recommended dose of ALIMTA when administered with carboplatin and pembrolizumab for the initial treatment of NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m2 administered as an intravenous infusion over 10 minutes prior to carboplatin on Day 1 of each 21-day cycle for 4 cycles. Following completion of platinum-based therapy, ALIMTA may be administered as maintenance therapy, alone or with pembrolizumab, until disease progression or unacceptable toxicity. Pembrolizumab should be administered prior to ALIMTA when given on the same day. Please refer to the full prescribing information for pembrolizumab and for carboplatin. 2.2 Recommended Dosage for Mesothelioma The recommended dose of ALIMTA when administered with cisplatin in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m2 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 ALIMTA 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 ALIMTA and continuing until 21 days after the last dose of ALIMTA [see Warnings and Precautions (5.1)]. Administer vitamin B12, 1 mg intramuscularly, 1 week prior to the first dose of ALIMTA and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with ALIMTA [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 ALIMTA administration. 2.5 Dosage Modification of Ibuprofen in Patients with Mild to Moderate Renal Impairment Receiving ALIMTA In patients with creatinine clearances between 45 mL/min and 79 mL/min, modify administration of ibuprofen as follows [see Warnings and Precautions (5.6), Drug Interactions (7) and Clinical Pharmacology (12.3)]: Avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of ALIMTA. Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided. 2.6 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 ALIMTA if the creatinine clearance is less than 45 mL/min. Delay initiation of the next cycle of ALIMTA until: recovery of non-hematologic toxicity to Grade 0-2, absolute neutrophil count (ANC) is 1500 cells/mm3 or higher, and platelet count is 100,000 cells/mm3 or higher. Upon recovery, modify the dosage of ALIMTA 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 Reactionsa a National Cancer Institute Common Toxicity Criteria for Adverse Events version 2 (NCI CTCAE v2). Toxicity in Most Recent Treatment Cycle ALIMTA Dose Modification for Next Cycle Myelosuppressive toxicity [see Warnings and Precautions (5.1)] ANC less than 500/mm3 and platelets greater than or equal to 50,000/mm3 OR Platelet count less than 50,000/mm3 without bleeding. 75% of previous dose Platelet count less than 50,000/mm3 with bleeding 50% of previous dose Recurrent Grade 3 or 4 myelosuppression after 2 dose reductions Discontinue Non-hematologic toxicity Any Grade 3 or 4 toxicities EXCEPT mucositis or neurologic toxicity OR Diarrhea requiring hospitalization 75% of previous dose Grade 3 or 4 mucositis 50% of previous dose Renal toxicity [see Warnings and Precautions (5.2)] Withhold until creatinine clearance is 45 mL/min or greater Grade 3 or 4 neurologic toxicity Permanently discontinue Recurrent Grade 3 or 4 non-hematologic toxicity after 2 dose reductions Permanently discontinue Severe and life-threatening Skin Toxicity [see Warnings and Precautions (5.3)] Permanently discontinue Interstitial Pneumonitis [see Warnings and Precautions (5.4)] Permanently discontinue 2.7 Preparation for Administration ALIMTA is a cytotoxic drug. Follow applicable special handling and disposal procedures.1 Calculate the dose of ALIMTA and determine the number of vials needed. Reconstitute ALIMTA 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) 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. FURTHER DILUTION IS REQUIRED prior to administration. Store reconstituted, preservative-free product under refrigerated conditions [2-8°C (36-46°F)] for no longer than 24 hours from the time of reconstitution. 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 ALIMTA from the vial(s) and discard vial with any unused portion. Further dilute ALIMTA 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 [2-8°C (36-46°F)] for no more than 24 hours from the time of reconstitution. Discard after 24 hours.
Use in special populations
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, ALIMTA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on ALIMTA 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/m2 [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/m2. At doses, based on BSA, greater than or equal to 0.0012 times the 500 mg/m2 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 ALIMTA, advise women not to breastfeed during treatment with ALIMTA and for one week after last dose. 8.3 Females and Males of Reproductive Potential Contraception Females ALIMTA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Because of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment with ALIMTA for at least 6 months after the final dose of ALIMTA. Males Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with ALIMTA and for 3 months after the final dose [see Nonclinical Toxicology (13.1)]. Infertility Males ALIMTA 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 ALIMTA in pediatric patients have not been established. The safety and pharmacokinetics of ALIMTA were evaluated in two clinical studies conducted in pediatric patients with recurrent solid tumors. ALIMTA was administered at doses ranging from 400 to 2480 mg/m2 intravenously over 10 minutes on Day 1 of a 21-day cycle to 32 pediatric patients with recurrent solid tumors in a dose-finding study. The maximum tolerated dose (MTD) was determined to be 1910 mg/m2 (60 mg/kg for patients <12 months old). ALIMTA was administered at the MTD every 21 days in an activity-estimating study enrolling 72 patients with relapsed or refractory osteosarcoma, Ewing sarcoma/peripheral primitive neural ectodermal tumor (PNET), rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/supratentorial PNET, or non-brainstem high grade glioma. 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 ALIMTA administered at doses ranging from 400 to 2480 mg/m2 were evaluated in 22 patients (13 males and 9 females) age 4 to 18 years (average age 12 years). Pemetrexed exposure (AUC and Cmax) appeared to increase proportionally with dose. Average clearance (2.30 L/h/m2) and half-life (2.3 hours) were similar in pediatric patients compared to adults. 8.5 Geriatric Use Of the 3,946 patients enrolled in clinical studies of ALIMTA, 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 trials [see Adverse Reactions (6.1) and Clinical Studies (14.1, 14.2)]. 8.6 Patients with Renal Impairment ALIMTA is primarily excreted by the kidneys. Decreased renal function results in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function [Warnings and Precautions (5.2, 5.6) and Clinical Pharmacology (12.3)]. No dose is recommended for patients with creatinine clearance less than 45 mL/min [see Dosage and Administration (2.3)].

Interactions

7 DRUG INTERACTIONS Ibuprofen increased risk of ALIMTA 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) 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 ALIMTA [see Dosage and Administration (2.5)]. Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided.

More information

Category Value
Authorisation number NDA021462
Agency product number 9T47E4OM16
Orphan designation No
Product NDC 0002-7623,0002-7640
Date Last Revised 15-06-2018
Type HUMAN PRESCRIPTION DRUG
RXCUI 1728079
Storage and handling Storage and Handling Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. ALIMTA is a cytotoxic drug. Follow applicable special handling and disposal procedures [see References (15)].
Marketing authorisation holder Eli Lilly and Company