Neurotoxicity, usually characterized by peripheral neuropathies, has been reported. The neuropathies usually occur after prolonged therapy (4 to 7 months); however, neurologic symptoms have been reported to occur after a single dose. Although symptoms and signs of PLATINOL neuropathy usually develop during treatment, symptoms of neuropathy may begin 3 to 8 weeks after the last dose of PLATINOL. PLATINOL therapy should be discontinued when the symptoms are first observed. The neuropathy, however, may progress further even after stopping treatment. Preliminary evidence suggests peripheral neuropathy may be irreversible in some patients. Elderly patients may be more susceptible to peripheral neuropathy (see PRECAUTIONS: Geriatric Use ). Lhermitte’s sign, dorsal column myelopathy, and autonomic neuropathy have also been reported. Loss of taste, seizures, leukoencephalopathy, and reversible posterior leukoencephalopathy syndrome (RPLS) have also been reported. 10 Reference ID: 3006561 Protocol ADU-CL-02-v8Aduro Biotech, Inc. CRS-207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 116 Muscle cramps, defined as localized, painful, involuntary skeletal muscle contractions of sudden onset and short duration, have been reported and were usually associated in patients receiving a relatively high cumulative dose of PLATINOL and with a relatively advanced symptomatic stage of peripheral neuropathy. Ocular Toxicity Optic neuritis, papilledema, and cerebral blindness have been reported in patients receiving standard recommended doses of PLATINOL. Improvement and/or total recovery usually occurs after discontinuing PLATINOL. Steroids with or without mannitol have been used; however, efficacy has not been established. Blurred vision and altered color perception have been reported after the use of regimens with higher doses of PLATINOL or greater dose frequencies than recommended in the package insert. The altered color perception manifests as a loss of color discrimination, particularly in the blue-yellow axis. The only finding on funduscopic exam is irregular retinal pigmentation of the macular area. Anaphylactic-Like Reactions Anaphylactic-like reactions have been reported in patients previously exposed to PLATINOL. The reactions consist of facial edema, wheezing, tachycardia, and hypotension within a few minutes of drug administration. Reactions may be controlled by intravenous epinephrine with corticosteroids and/or antihistamines as indicated. Patients receiving PLATINOL should be observed carefully for possible anaphylactic-like reactions and supportive equipment and medication should be available to treat such a complication. Hepatotoxicity Transient elevations of liver enzymes, especially SGOT, as well as bilirubin, have been reported to be associated with PLATINOL administration at the recommended doses. Other Events Cardiac abnormalities, hiccups, elevated serum amylase, rash, alopecia, malaise, asthenia, and dehydration have been reported. Local soft tissue toxicity has been reported following extravasation of PLATINOL. Severity of the local tissue toxicity appears to be related to the concentration of the 11 Reference ID: 3006561 Protocol ADU-CL-02-v8Aduro Biotech, Inc. CRS-207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 117 PLATINOL solution. Infusion of solutions with a PLATINOL concentration greater than 0.5 mg/mL may result in tissue cellulitis, fibrosis, necrosis, pain, edema, and erythema. OVERDOSAGE Caution should be exercised to prevent inadvertent overdosage with PLATINOL. Acute overdosage with this drug may result in kidney failure, liver failure, deafness, ocular toxicity (including detachment of the retina), significant myelosuppression, intractable nausea and vomiting and/or neuritis. In addition, death can occur following overdosage. No proven antidotes have been established for PLATINOL overdosage. Hemodialysis, even when initiated four hours after the overdosage, appears to have little effect on removing platinum from the body because of PLATINOL’s rapid and high degree of protein binding. Management of overdosage should include general supportive measures to sustain the patient through any period of toxicity that may occur. DOSAGE AND ADMINISTRATION PLATINOL is administered by slow intravenous infusion. PLATINOL SHOULD NOT BE GIVEN BY RAPID INTRAVENOUS INJECTION. Note: Needles or intravenous sets containing aluminum parts that may come in contact with PLATINOL should not be used for preparation or administration. Aluminum reacts with PLATINOL, causing precipitate formation and a loss of potency. Metastatic Testicular Tumors The usual PLATINOL dose for the treatment of testicular cancer in combination with other approved chemotherapeutic agents is 20 mg/m2 IV daily for 5 days per cycle. Metastatic Ovarian Tumors The usual PLATINOL dose for the treatment of metastatic ovarian tumors in combination with cyclophosphamide is 75 to 100 mg/m2 IV per cycle once every 4 weeks (DAY 1). The dose of cyclophosphamide when used in combination with PLATINOL is 600 mg/m 2 IV once every 4 weeks (DAY 1). 12 Reference ID: 3006561 Protocol ADU-CL-02-v8Aduro Biotech, Inc. CRS-207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 118 For directions for the administration of cyclophosphamide, refer to the cyclophosphamide package insert. In combination therapy, PLATINOL and cyclophosphamide are administered sequentially. As a single agent, PLATINOL should be administered at a dose of 100 mg/m2 IV per cycle once every 4 weeks. Advanced Bladder Cancer PLATINOL should be administered as a single agent at a dose of 50 to 70 mg/m2 IV per cycle once every 3 to 4 weeks depending on the extent of prior exposure to radiation therapy and/or prior chemotherapy. For heavily pretreated patients an initial dose of 50 mg/m2 per cycle repeated every 4 weeks is recommended. All Patients Pretreatment hydration with 1 to 2 liters of fluid infused for 8 to 12 hours prior to a PLATINOL dose is recommended. The drug is then diluted in 2 liters of 5% Dextrose in 1/2 or 1/3 normal saline containing 37.5 g of mannitol, and infused over a 6- to 8-hour period. If diluted solution is not to be used within 6 hours, protect solution from light. Adequate hydration and urinary output must be maintained during the following 24 hours. A repeat course of PLATINOL should not be given until the serum creatinine is below 1.5 mg/100 mL, and/or the BUN is below 25 mg/100 mL. A repeat course should not be given until circulating blood elements are at an acceptable level (platelets t100,000/mm 3, WBC t4000/mm3). Subsequent doses of PLATINOL should not be given until an audiometric analysis indicates that auditory acuity is within normal limits. PREPARATION OF INTRAVENOUS SOLUTIONS Preparation Precautions Caution should be exercised in handling the powder and preparing the solution of cisplatin. Procedures for proper handling and disposal of anticancer drugs should be utilized. Several guidelines on this subject have been published.1-4 To minimize the risk 13 Reference ID: 3006561 Protocol ADU-CL-02-v8Aduro Biotech, Inc. CRS-207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 119 of dermal exposure, always wear impervious gloves when handling vials and IV sets containing PLATINOL for injection. Skin reactions associated with accidental exposure to cisplatin may occur. The use of gloves is recommended. If PLATINOL powder or PLATINOL solution contacts the skin or mucosa, immediately and thoroughly wash the skin with soap and water and flush the mucosa with water. More information is available in the references listed below. Instructions for Preparation The 50 mg vials should be reconstituted with 50 mL of Sterile Water for Injection, USP. Each mL of the resulting solution will contain 1 mg of PLATINOL. Reconstitution as recommended results in a clear, colorless to slight yellow solution. The reconstituted solution should be used intravenously only and should be administered by IV infusion over a 6- to 8-hour period (see DOSAGE AND ADMINISTRATION ). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. NOTE TO PHARMACIST: Exercise caution to prevent inadvertent PLATINOL overdosage. Please call prescriber if dose is greater than 100 mg/m2 per cycle. Aluminum and flip-off seal of vial have been imprinted with the following statement: CALL DR. IF DOSE>100 MG/M2/CYCLE. STABILITY Unopened vials of dry powder are stable for the lot life indicated on the package when stored at room temperature (25q C, 77q F). The reconstituted solution is stable for 20 hours at room temperature (25 q C, 77q F). Solution removed from the amber vial should be protected from light if it is not to be used within six hours. Important Note: Once reconstituted, the solution should be kept at room temperature (25q C, 77q F). If the reconstituted solution is refrigerated a precipitate will form. 14 Reference ID: 3006561 Protocol ADU-CL-02-v8Aduro Biotech, Inc. CRS-207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 120 HOW SUPPLIED PLATINOL® (cisplatin for injection, USP) NDC 0015-3072-20—Each amber vial contains 50 mg of cisplatin REFERENCES 1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings.