1 ---------------------- DOSAGE FORMS AND STRENGTHS --------------------- HIGHLIGHTS OF PRESCRIBING INFORMATION • 100 mg vial for injection (3) These highlights do not include all the information needed to use • 500 mg vial for injection (3) ALIMTA safely and effectively. See full prescribing information for ALIMTA. -------------------------------CONTRAINDICATIONS------------------------------ ALIMTA (pemetrexed disodium) Injection, Powder, Lyophilized, For History of severe hypersensitivity reaction to pemetrexed. (4) Solution for Intravenous Use ------------------------ WARNINGS AND PRECAUTIONS ----------------------- Initial U.S. Approval: 2004 • Premedication regimen: Instruct patients to take folic acid and vitamin B12. Pretreatment with dexamethasone or equivalent reduces --------------------------- RECENT MAJOR CHANGES -------------------------- cutaneous reaction. (5.1) Indications and Usage, Locally Advanced or Metastatic Nonsquamous • Bone marrow suppression: Reduce doses for subsequent cycles based on Non-Small Cell Lung Cancer - Combination with Cisplatin (1.1) 09/2008 hematologic and nonhematologic toxicities. (5.2) Indications and Usage, Locally Advanced or Metastatic Nonsquamous • Renal function: Do not administer when CrCl <45 mL/min. (2.4, 5.3) Non-Small Cell Lung Cancer - Maintenance (1.2) MM/YYYY • NSAIDs with renal insufficiency: Use caution in patients with mild to moderate renal insufficiency (CrCl 45-79 mL/min). (5.4) Indications and Usage, Locally Advanced or Metastatic Nonsquamous • Lab monitoring: Do not begin next cycle unless ANC ≥1500 cells/mm3, Non-Small Cell Lung Cancer - After Prior Chemotherapy (1.3) 09/2008 platelets ≥100,000 cells/mm3, and CrCl ≥45 mL/min. (5.5) Dosage and Administration, Combination Use with Cisplatin (2.1) 09/2008 • Pregnancy: Fetal harm can occur when administered to a pregnant woman. Women should be advised to use effective contraception ----------------------------INDICATIONS AND USAGE --------------------------- measures to prevent pregnancy during treatment with ALIMTA. (5.6) ALIMTA® is a folate analog metabolic inhibitor indicated for: • Locally Advanced or Metastatic Nonsquamous Non-Small Cell Lung -------------------------------ADVERSE REACTIONS ------------------------------ Cancer: The most common adverse reactions (incidence ≥20%) with single-agent use • Initial treatment in combination with cisplatin. (1.1) are fatigue, nausea, and anorexia. Additional common adverse reactions when • Maintenance treatment of patients whose disease has not used in combination with cisplatin include vomiting, neutropenia, leukopenia, progressed after four cycles of platinum-based first-line anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. (6.1) chemotherapy. (1.2) • After prior chemotherapy as a single agent. (1.3) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and • Mesothelioma: in combination with cisplatin. (1.4) Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Limitations of Use: • ALIMTA is not indicated for the treatment of patients with squamous ------------------------------- DRUG INTERACTIONS ------------------------------ cell non-small cell lung cancer. (1.5) • NSAIDs: Use caution with ibuprofen or other NSAIDs. (7.1) • Nephrotoxic drugs: Concomitant use of these drugs and/or substances ----------------------- DOSAGE AND ADMINISTRATION ---------------------- which are tubularly secreted may result in delayed clearance. (7.2) • Combination use in Non-Small Cell Lung Cancer and Mesothelioma: Recommended dose of ALIMTA is 500 mg/m2 i.v. on Day 1 of each See 17 for PATIENT COUNSELING INFORMATION and 21-day cycle in combination with cisplatin 75 mg/m2 i.v. beginning FDA-approved patient labeling Revised: 00/0000 30 minutes after ALIMTA administration. (2.1) • Single-Agent use in Non-Small Cell Lung Cancer: Recommended dose of ALIMTA is 500 mg/m2 i.v. on Day 1 of each 21-day cycle. (2.2) • Dose Reductions: Dose reductions or discontinuation may be needed based on toxicities from the preceding cycle of therapy. (2.4) FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 6.1 Clinical Trials Experience 1.1 Nonsquamous Non-Small Cell Lung Cancer – Combination 6.2 Post-Marketing Experience with Cisplatin 7 DRUG INTERACTIONS 1.2 Nonsquamous Non-Small Cell Lung Cancer –Maintenance 7.1 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) 1.3 Nonsquamous Non-Small Cell Lung Cancer – After Prior 7.2 Nephrotoxic Drugs Chemotherapy 8 USE IN SPECIFIC POPULATIONS 1.4 Mesothelioma 8.1 Pregnancy 1.5 Limitations of Use 8.3 Nursing Mothers 2 DOSAGE AND ADMINISTRATION 8.4 Pediatric Use 2.1 Combination Use with Cisplatin 8.5 Geriatric Use 2.2 Single-Agent Use 8.6 Patients with Hepatic Impairment 2.3 Premedication Regimen 8.7 Patients with Renal Impairment 2.4 Laboratory Monitoring and Dose Reduction/Discontinuation 8.8 Gender Recommendations 8.9 Race 2.5 Preparation and Administration Precautions 10 OVERDOSAGE 2.6 Preparation for Intravenous Infusion Administration 11 DESCRIPTION 3 DOSAGE FORMS AND STRENGTHS 12 CLINICAL PHARMACOLOGY 4 CONTRAINDICATIONS 12.1 Mechanism of Action 5 WARNINGS AND PRECAUTIONS 12.2 Pharmacodynamics 5.1 Premedication Regimen 12.3 Pharmacokinetics 5.2 Bone Marrow Suppression 13 NONCLINICAL TOXICOLOGY 5.3 Decreased Renal Function 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.4 Use with Non-Steroidal Anti-Inflammatory Drugs with Mild to Moderate Renal Insufficiency 14 CLINICAL STUDIES 5.5 Required Laboratory Monitoring 14.1 Non-Small Cell Lung Cancer (NSCLC) – Combination with 5.6 Pregnancy Category D Cisplatin 5.7 Third Space Fluid 14.2 Non-Small Cell Lung Cancer – Maintenance 14.3 Non-Small Cell Lung Cancer –After Prior Chemotherapy 6 ADVERSE REACTIONS 14.4 Malignant Pleural Mesothelioma 2 15 REFERENCES 17.1 Need for Folic Acid and Vitamin B12 16 HOW SUPPLIED/STORAGE AND HANDLING 17.2 Low Blood Cell Counts 16.1 How Supplied 17.3 Gastrointestinal Effects 16.2 Storage and Handling 17.4 Concomitant Medications 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed FULL PRESCRIBING INFORMATION 1 1 INDICATIONS AND USAGE 2 1.1 Nonsquamous Non-Small Cell Lung Cancer - Combination with Cisplatin 3 ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or 4 metastatic nonsquamous non-small cell lung cancer. 5 1.2 Nonsquamous Non-Small Cell Lung Cancer - Maintenance 6 ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small 7 cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. 8 1.3 Nonsquamous Non-Small Cell Lung Cancer - After Prior Chemotherapy 9 ALIMTA is indicated as a single-agent for the treatment of patients with locally advanced or metastatic nonsquamous 10 non-small cell lung cancer after prior chemotherapy. 11 1.4 Mesothelioma 12 ALIMTA in combination with cisplatin is indicated for the treatment of patients with malignant pleural mesothelioma whose 13 disease is unresectable or who are otherwise not candidates for curative surgery. 14 1.5 Limitations of Use 15 ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer. [see Clinical Studies 16 (14.1, 14.2, 14.3)] 17 2 DOSAGE AND ADMINISTRATION 18 2.1 Combination Use with Cisplatin 19 Nonsquamous Non-Small Cell Lung Cancer and Malignant Pleural Mesothelioma 20 The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end 22 of ALIMTA administration. Patients should receive appropriate hydration prior to and/or after receiving cisplatin. See cisplatin 23 package insert for more information. 24 2.2 Single-Agent Use 25 Nonsquamous Non-Small Cell Lung Cancer 26 The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 27 21-day cycle. 28 2.3 Premedication Regimen 29 Vitamin Supplementation 30 To reduce toxicity, patients treated with ALIMTA must be instructed to take a low-dose oral folic acid preparation or 31 multivitamin with folic acid on a daily basis. At least 5 daily doses of folic acid must be taken during the 7-day period preceding the 32 first dose of ALIMTA; and dosing should continue during the full course of therapy and for 21 days after the last dose of ALIMTA. 33 Patients must also receive one (1) intramuscular injection of vitamin B12 during the week preceding the first dose of ALIMTA and 34 every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as ALIMTA. In clinical trials, the dose of folic 35 acid studied ranged from 350 to 1000 mcg, and the dose of vitamin B12 was 1000 mcg. The most commonly used dose of oral folic 36 acid in clinical trials was 400 mcg [see Warnings and Precautions (5.1)]. 37 Corticosteroid 38 Skin rash has been reported more frequently in patients not pretreated with a corticosteroid. Pretreatment with dexamethasone 39 (or equivalent) reduces the incidence and severity of cutaneous reaction. In clinical trials, dexamethasone 4 mg was given by mouth 40 twice daily the day before, the day of, and the day after ALIMTA administration [see Warnings and Precautions (5.1)]. 41 2.4 Laboratory Monitoring and Dose Reduction/Discontinuation