Uridine Triacetate

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.

Oral granules: 10 grams of orange-flavored, white-to-off-white, oral granules (95% w/w) in single-dose packets. Oral granules: 10 gram packets ( 3 )

None. None. ( 4 )

None. None. ( 5 )

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%)

8.1 Pregnancy Risk Summary Limited case reports of uridine triacetate use during pregnancy are insufficient to inform a drug-associated risk of birth defects and miscarriage. When administered orally to pregnant rats during the period of organogenesis, uridine triacetate at doses of one-half the maximum recommended human dose (MRHD) of 40 grams per day was not teratogenic and did not produce adverse effects on embryo-fetal development [see Data ] . The background risk of major birth defects and miscarriage for the indicated population are unknown. 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 In an embryo-fetal development study, uridine triacetate was administered orally to pregnant rats during the period of organogenesis at doses up to 2000 mg/kg per day (about one-half the maximum recommended human dose (MRHD) of 40 grams per day on a body surface area basis). There was no evidence of teratogenicity or harm to the fetus and no effect on maternal body weight and overall health.

8.2 Lactation Risk Summary There are no data on the presence of uridine triacetate in human milk, the effect on the breastfed infant or the effect on milk production. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for VISTOGARD and any potential adverse effects on the breastfed infant from VISTOGARD or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of VISTOGARD have been established in pediatric patients. Use of VISTOGARD in pediatric patients is supported by an open-label clinical study of adults (Study 1) and a second open-label clinical study which included 6 pediatric patients ranging in age from 1 to 16 years (Study 2). Four of these pediatric patients were between 1 to 7 years of age and received a body-surface area adjusted dosage of 6.2 grams/m 2 /dose for 20 doses. The clinical response and safety in adult and pediatric patients treated with VISTOGARD were similar; however, clinical data are limited [see Clinical Studies (14) ].

8.5 Geriatric Use Of the 135 patients in clinical studies with VISTOGARD, 30% were 65 and over, including 11% that were 75 and over. Clinical studies of VISTOGARD did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

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.