(7.1)• Nephrotoxic drugs: Concomitant use of these drugs and/or substances which are tubularly secreted may result in delayed clearance. (7.2) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling Revised: 12/2011 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Nonsquamous Non-Small Cell Lung Cancer – Combination with Cisplatin 1.2 Nonsquamous Non-Small Cell Lung Cancer – Maintenance 1.3 Nonsquamous Non-Small Cell Lung Cancer – After Prior Chemotherapy 1.4 Mesothelioma 1.5 Limitations of Use 2 DOSAGE AND ADMINISTRATION 2.1 Combination Use with Cisplatin 2.2 Single-Agent Use 2.3 Premedication Regimen 2.4 Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations 2.5 Preparation and Administration Precautions2.6 Preparation for Intravenous Infusion Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS 5.1 Premedication Regimen 5.2 Bone Marrow Suppression5.3 Decreased Renal Function 5.4 Use with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) with Mild to Moderate Renal Insufficiency 5.5 Required Laboratory Monitoring5.6 Pregnancy Category D 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS7.1 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)7.2 Nephrotoxic Drugs 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use8.5 Geriatric Use 8.6 Patients with Hepatic Impairment 8.7 Patients with Renal Impairment8.8 Gender 8.9 Race 10 OVERDOSAGE 11 DESCRIPTION12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Non-Small Cell Lung Cancer (NSCLC) – Combination with Cisplatin 14.2 Non-Small Cell Lung Cancer – Maintenance 14.3 Non-Small Cell Lung Cancer – After Prior Chemotherapy 14.4 Malignant Pleural Mesothelioma 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage and HandlingProtocol ADU-CL-02-v8Aduro Biotech, Inc. CRS-207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 85 2 17 PATIENT COUNSELING INFORMATION 17.1 Need for Folic Acid and Vitamin B 12 17.2 Low Blood Cell Counts17.3 Gastrointestinal Effects 17.4 Concomitant Medications *Sections or subsections omitted from the full prescribing information are not listed FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Nonsquamous Non-Small Cell Lung Cancer - Combination with Cisplatin ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. 1.2 Nonsquamous Non-Small Cell Lung Cancer - Maintenance ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. 1.3 Nonsquamous Non-Small Cell Lung Cancer - After Prior Chemotherapy ALIMTA is indicated as a single-agent for the treatment of patients with locally advanced or metastatic nonsquamous non- small cell lung cancer after prior chemotherapy.1.4 Mesothelioma ALIMTA in combination with cisplatin is indicated for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery.1.5 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, 14.2, 14.3)] 2 DOSAGE AND ADMINISTRATION 2.1 Combination Use with Cisplatin Nonsquamous Non-Small Cell Lung Cancer and Malignant Pleural Mesothelioma The recommended dose of ALIMTA is 500 mg/m2administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2infused over 2 hours beginning approximately 30 minutes after the end of ALIMTA administration. Patients should receive appropriate hydration prior to and/or after receiving cisplatin. See cisplati n package insert for more information. 2.2 Single-Agent Use Nonsquamous Non-Small Cell Lung Cancer The recommended dose of ALIMTA is 500 mg/m2administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. 2.3 Premedication Regimen Vitamin Supplementation To reduce toxicity, patients treated with ALIMTA must be instructed to take a low-dose oral folic acid preparation or 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 first dose of ALIMTA; and dosing should continue during the full course of therapy and for 21 days after the last dose of ALIMTA. Patients must also receive one (1) intramuscular injection of vitamin B 12during the week preceding the first dose of ALIMTA and every 3 cycles thereafter. Subsequent vitamin B 12injections may be given the same day as ALIMTA. In clinical trials, the dose of folic acid studied ranged from 350 to 1000 mcg, and the dose of vitamin B 12was 1000 mcg. The most commonly used dose of oral folic acid in clinical trials was 400 mcg [see Warnings and Precautions (5.1)] . Corticosteroid Skin rash has been reported more frequently in patients not pretreated with a corticosteroid. Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction. In clinical trials, dexamethasone 4 mg was given by mo uth twice daily the day before, the day of, and the day after ALIMTA administration [see Warnings and Precautions (5.1)] . 2.4 Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations Monitoring Complete blood cell counts, including platelet counts, should be performed on all patients receiving ALIMTA. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle . Patients should not begin a new cycle of treatment unless the ANC is ൒1500 cells/mm3, the platelet count is ൒100,000 cells/mm3, and creatinine clearance is ൒45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function [see Warnings and Precautions (5.5)] . Dose Reduction Recommendations Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, pat ients should be retreated using the guidelines in Tables 1-3, which are suitable for using ALIMTA as a single-agent or in combination with cisplatin.Protocol ADU-CL-02-v8Aduro Biotech, Inc. CRS-207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 86 3 Table 1: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Hematologic Toxicities Nadir ANC <500/mm3and nadir platelets ൒50,000/mm3. 75% of previous dose (pemetrexed and cisplatin). Nadir platelets <50,000/mm3without bleeding regardless of nadir ANC. 75% of previous dose ( pemetrexed and cisplatin). Nadir platelets <50,000/mm3with bleedinga, regardless of nadir ANC. 50% of previous dose (pemetrexed and cisplatin). aThese criteria meet the CTC version 2.0 (NCI 1998) definition of ൒CTC Grade 2 bleeding. If patients develop nonhematologic toxicities (excluding neurotoxicity) ൒Grade 3, treatment should be withheld until resolution to less than or equal to the patient’s pre-therapy value. Treatment should be resumed according to guidelines in Tab le 2. Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Nonhematologic Toxicitiesa,b Dose of ALIMTA (mg/m2)Dose of Cisplatin (mg/m2) Any Grade 3 or 4 toxicities except mucositis 75% of previous dose 75% of previous dose Any diarrhea requiring hospitalization (irrespective of Grade) or Grade 3 or 4 diarrhea75% of previous dose 75% of previous dose Grade 3 or 4 mucositis 50% of previous dose 100% of previous dose aNCI Common Toxicity Criteria (CTC). bExcluding neurotoxicity (see Table 3). In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced. Table 3: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Neurotoxicity Dose of ALIMTA (mg/m2)Dose of Cisplatin (mg/m2) CTC Grade 0-1 100% of previous dose 100% of previous dose 2 100% of previous dose 50% of previous dose Discontinuation Recommendation ALIMTA therapy should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed. Renally Impaired Patients In clinical studies, patients with creatinine clearance ൒45 mL/min required no dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to ma ke dosage recommendations for this group of patients [see Clinical Pharmacology (12.3)] . Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min using the standard Cockcroft and Gault formula (below) or GFR measured by Tc99m-DPTA serum clearance method: Males:[140 - Age in years] × Actual Body Weight (kg)= mL/min72 × Serum Creatinine (mg/dL) Females: Estimated creatinine clearance for males × 0.85 Caution should be exercised when administering ALIMTA concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min [see Drug Interactions (7.1)] . 2.5 Preparation and Administration Precautions As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions of ALIMTA. The use of gloves is recommended. If a solution of ALIMTA contacts the skin, wash the skin immediately and thoroughly with soap and water. If ALIMTA contacts the mucous membranes, flush thoroughly with water. Several published guidelines for handling and disposal of anticancer agents are available [see References (15)] . ALIMTA is not a vesicant. There is no specific antidote for extravasation of ALIMTA. To date, there have been few reported cases of ALIMTA extravasation, which were not assessed as serious by the investigator. ALIMTA extravasation should be managed with local standard practice for extravasation as with other non-vesicants. 2.6 Preparation for Intravenous Infusion Administration 1. Use aseptic technique during the reconstitution and further dilution of ALIMTA for intravenous infusion administration. 2. Calculate the dose of ALIMTA and determine the number of vials needed. Vials contain either 100 mg or 500 mg of ALIMTA. The vials contain an excess of ALIMTA to facilitate delivery of label amount. 3. Reconstitute each 100-mg vial with 4.2 ml of 0.9% Sodium Chloride Injection (preservative free). Reconstitute each 500-mg vial with 20 mL of 0.9% Sodium Chloride Injection (preservative free). Reconstitution of either size vial gives aProtocol ADU-CL-02-v8Aduro Biotech, Inc. CRS-207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 87 4 solution containing 25 mg/mL ALIMTA. 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 without adversely affecting product quality. The pH of the reconstituted ALIMTA solution is between 6.6 and 7.8. FURTHER DILUTION IS REQUIRED.