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.

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 2of 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 2is 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 in Grams	Dose in Graduated Teaspoons
  * 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. † May use 1 entire 10 g packet without weighing or measuring. Do not exceed 10 grams/dose.
  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 †	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:
  1. 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.
  2. Crush the contents of one full 10 gram packet of VISTOGARD granules to a fine powder.
  3. 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 ratio of no greater than 1 gram per 10 mL of reconstituted food starch-based thickening product and mix thoroughly.
  4. After administration of the mixture using the NG tube or G-Tube, flush the tube with water.

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.

8.1 Pregnancy

8.2 Lactation

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.

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.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of uridine triacetate.

Uridine triacetate was not genotoxic in the Ames test, the mouse lymphoma assay and the mouse micronucleus test.

Orally administered uridine triacetate did not affect fertility or general reproductive performance in male and female rats at doses up to 2000 mg/kg per day (about one-half the maximum recommend human dose (MRHD) of 40 grams per day on a body surface area basis).

13.2 Animal Toxicology and/or Pharmacology

In mice given a sub-lethal dose of fluorouracil, the administration of oral uridine triacetate diminished hematological toxicity as a function of increasing dose, but did not completely prevent hematological toxicity. In mice given a lethal dose of fluorouracil, administration of oral uridine triacetate increased survival to 90% when given within 24 hours. Survival diminished with increasing interval between the fluorouracil dose and uridine triacetate treatment demonstrating that earlier administration of uridine triacetate is more beneficial. In similar experiments in mice, uridine triacetate treatment diminished damage to the intestinal mucosa caused by fluorouracil treatment.

Store at USP controlled room temperature, 25°C (77°F); excursions permitted to 15° to 30 °C (59° to 86°F).

Dosing Instructions [see Dosage and Administration (2.1)and (2.2)]

Advise the patient or caregiver:

• The importance of taking all 20 doses, even if they feel well.
• That VISTOGARD can be taken mixed in food (applesauce, pudding or yogurt).
• That the VISTOGARD granules should not be chewed.
• That if the patient vomits within 2 hours of taking a dose of VISTOGARD to take another complete dose as soon as possible after vomiting. Take the next dose at the regularly scheduled time.
• That if the patient misses a dose at the scheduled time, to take that dose of VISTOGARD as soon as possible. Then take the next dose at the regularly scheduled time.