Uridine Triacetate

1 INDICATIONS AND USAGE VISTOGARD ® is indicated for the emergency treatment of adult and pediatric patients: following a fluorouracil or capecitabine overdose regardless of the presence of symptoms, or who exhibit early-onset, severe or life-threatening toxicity affecting the cardiac or central nervous system, and/or early-onset, unusually severe adverse reactions (e.g., gastrointestinal toxicity and/or neutropenia) within 96 hours following the end of fluorouracil or capecitabine administration. VISTOGARD ® is a pyrimidine analog indicated for the emergency treatment of adult and pediatric patients: following a fluorouracil or capecitabine overdose regardless of the presence of symptoms, or who exhibit early-onset, severe or life-threatening toxicity affecting the cardiac or central nervous system, and/or early-onset, unusually severe adverse reactions (e.g., gastrointestinal toxicity and/or neutropenia) within 96 hours following the end of fluorouracil or capecitabine administration. ( 1 ) Limitations of use: VISTOGARD is not recommended for the non-emergent treatment of adverse reactions associated with fluorouracil or capecitabine because it may diminish the efficacy of these drugs. ( 1 ) The safety and efficacy of VISTOGARD initiated more than 96 hours following the end of fluorouracil or capecitabine administration have not been established. ( 1 ) Limitations of Use VISTOGARD is not recommended for the non-emergent treatment of adverse reactions associated with fluorouracil or capecitabine because it may diminish the efficacy of these drugs. The safety and efficacy of VISTOGARD initiated more than 96 hours following the end of fluorouracil or capecitabine administration have not been established.

12.1 Mechanism of Action Uridine triacetate is an acetylated pro-drug of uridine. Following oral administration, uridine triacetate is deacetylated by nonspecific esterases present throughout the body, yielding uridine in the circulation. Uridine competitively inhibits cell damage and cell death caused by fluorouracil. Fluorouracil is a cytotoxic antimetabolite that interferes with nucleic acid metabolism in normal and cancer cells. Cells anabolize fluorouracil to the cytotoxic intermediates 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). FdUMP inhibits thymidylate synthase, blocking thymidine synthesis. Thymidine is required for DNA replication and repair. Uridine is not found in DNA. The second source of fluorouracil cytotoxicity is the incorporation of its metabolite, FUTP, into RNA. This incorporation of FUTP into RNA is proportional to systemic fluorouracil exposure. Excess circulating uridine derived from VISTOGARD is converted into uridine triphosphate (UTP), which competes with FUTP for incorporation into RNA.

2 DOSAGE AND ADMINISTRATION Recommended Dosage Adults : 10 grams (1 packet) orally every 6 hours for 20 doses, without regard to meals. ( 2.1 ) Pediatric : 6.2 grams/m 2 of body surface area (not to exceed 10 grams per dose) orally every 6 hours for 20 doses, without regard to meals. See the full prescribing information for body surface area-based dosing. ( 2.1 ) Preparation and Administration Pediatric : Measure the dose using either a scale accurate to at least 0.1 gram, or a graduated teaspoon accurate to ¼ teaspoon. ( 2.1 ) Mix each VISTOGARD dose with 3 to 4 ounces of soft foods such as applesauce, pudding or yogurt and ingest within 30 minutes of mixing. Do not chew the VISTOGARD granules. Drink at least 4 ounces of water. ( 2.2 ) If a patient vomits within 2 hours of taking a dose of VISTOGARD, initiate another complete dose as soon as possible after the vomiting episode. Administer the next dose at the regularly scheduled time. ( 2.2 ) If a patient misses a dose at the scheduled time, administer that dose of VISTOGARD as soon as possible. Administer the next dose at the regularly scheduled time. ( 2.2 ) Administer VISTOGARD via a nasogastric tube (NG tube) or gastrostomy tube (G-Tube) when necessary (e.g., severe mucositis or coma). ( 2.2 ) 2.1 Recommended Dosage Adults: 10 grams (1 packet) orally every 6 hours for 20 doses, without regard to meals. Pediatric: 6.2 grams/m 2 of body surface area (not to exceed 10 grams per dose) orally every 6 hours for 20 doses, without regard to meals. The VISTOGARD dose to be administered at 6.2 grams/m 2 is presented in Table 1. Measure the dose using either a scale accurate to at least 0.1 gram, or a graduated teaspoon accurate to ¼ teaspoon. Discard any unused portion of granules. Do not use granules left in the open packet for subsequent dosing. Table 1 VISTOGARD Pediatric Dose Based on Body Surface Area (m 2 ) Patient Body Surface Area (m 2 ) Table 1 VISTOGARD 6.2 grams/m 2 /dose Dose by body surface area category in this table was rounded to achieve the approximate dose. Each dose is administered every 6 hours for 20 doses. Dose in Grams Dose in Graduated Teaspoons 0.34 to 0.44 2.1 to 2.7 1 0.45 to 0.55 2.8 to 3.4 1 ¼ 0.56 to 0.66 3.5 to 4.1 1 ½ 0.67 to 0.77 4.2 to 4.8 1 ¾ 0.78 to 0.88 4.9 to 5.4 2 0.89 to 0.99 5.5 to 6.1 2 ¼ 1.00 to 1.10 6.2 to 6.8 2 ½ 1.11 to 1.21 6.9 to 7.5 2 ¾ 1.22 to 1.32 7.6 to 8.1 3 1.33 to 1.43 8.2 to 8.8 3 ¼ 1.44 and above May use 1 entire 10 g packet without weighing or measuring. Do not exceed 10 grams/dose. 10.0 1 full packet Administer VISTOGARD as soon as possible after an overdose or early-onset toxicity within 96 hours following the end of fluorouracil or capecitabine administration. Administer full course of VISTOGARD (20 doses) as directed. 2.2 Preparation and Administration Mix each VISTOGARD dose with 3 to 4 ounces of soft foods such as applesauce, pudding or yogurt and ingest within 30 minutes. Do not chew the VISTOGARD granules. Drink at least 4 ounces of water. If a patient vomits within 2 hours of taking a dose of VISTOGARD, initiate another complete dose as soon as possible after the vomiting episode. Administer the next dose at the regularly scheduled time. If a patient misses a dose at the scheduled time, administer that dose of VISTOGARD as soon as possible. Administer the next dose at the regularly scheduled time. Administer VISTOGARD via a nasogastric tube (NG tube) or gastrostomy tube (G-Tube) when necessary (eg, severe mucositis or coma). Follow the instructions below for each dose administration: Prepare approximately 4 fluid ounces (about 100 mL) of a food starch-based thickening product in water and stir briskly until the thickener has dissolved. Crush the contents of one full 10 gram packet of VISTOGARD granules to a fine powder. Add the crushed VISTOGARD granules to 4 ounces (about 100 mL) of the reconstituted food starch-based thickening product. For pediatric patients receiving less than 10 grams, prepare the mixture at a

6 ADVERSE REACTIONS Adverse reactions occurring in >2% of patients receiving VISTOGARD included vomiting, nausea, and diarrhea. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact BTG International Inc at (1-877-377-3784) 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 and using a wide range of doses, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of VISTOGARD was assessed in 135 patients (median age 59 years, 56% male) treated in 2 single-arm, open-label, multi-center trials. VISTOGARD was administered at 10 grams orally every 6 hours for 20 doses or at a body surface area adjusted dosage of 6.2 grams/m 2 /dose for 20 doses in four patients between 1 and 7 years of age. The median duration of exposure was 4.8 days, with a median of 20 doses (range 1 to 23). VISTOGARD was discontinued for adverse reactions in two (1.4%) patients. Serious adverse reactions and Grade ≥3 adverse reactions were seen in one patient receiving VISTOGARD (Grade 3 nausea and vomiting). Table 2 summarizes the adverse reactions that occurred in greater than 2% of patients in Studies 1 and 2 combined. Table 2 Adverse Reactions in > 2% of Patients Receiving VISTOGARD in Studies 1 and 2 Adverse Reaction N=135 Patients Vomiting 13 (10%) Nausea 7 (5%) Diarrhea 4 (3%)

5 WARNINGS AND PRECAUTIONS None. None. ( 5 )

4 CONTRAINDICATIONS None. None. ( 4 )