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CLINICAL PHARMACOLOGY Mechanism Of Action Uridine triacetate is an acetylated form of uridine. Following oral administration, uridine triacetate is deacetylated by nonspecific esterases present throughout the body, yielding uridine in the circulation (Figure 1). Figure 1: Uridine Triacetate Conversion to Uridine XURIDEN provides uridine in the systemic circulation of patients with hereditary orotic aciduria who cannot synthesize adequate quantities of uridine due to a genetic defect in uridine nucleotide synthesis. Pharmacodynamics Hereditary orotic aciduria (uridine monophosphate synthase deficiency) is a rare congenital autosomal recessive disorder of pyrimidine metabolism caused by a defect in uridine monophosphate synthase (UMPS). The UMPS gene encodes uridine 5′monophosphate synthase, a bifunctional enzyme that catalyzes the final two steps of the de novo pyrimidine biosynthetic pathway in mammalian cells. The defect in UMP synthase in hereditary orotic aciduria has two primary biochemical consequences. First, the blockade of de novo UMP synthesis results in a systemic deficiency of pyrimidine nucleotides, accounting for most clinical consequences of the disease. Second, orotic acid from the de novo pyrimidine pathway that cannot be converted to UMP is excreted in the urine, accounting for the common name of the disorder, orotic aciduria. Orotic acid crystals in the urine can cause episodes of obstructive uropathy. XURIDEN delivers uridine into the circulation, where it can be used by essentially all cells to make uridine nucleotides, compensating for the genetic deficiency in synthesis in patients with hereditary orotic aciduria. When intracellular uridine nucleotides are restored into the normal range, overproduction of orotic acid is reduced by feedback inhibition, so that urinary excretion of orotic acid is also reduced. Pharmacokinetics Absorption XURIDEN delivers 4- to 6-fold more uridine into the systemic circulation compared to equimolar doses of uridine itself. Maximum concentrations of uridine in plasma following oral XURIDEN are generally achieved within 2 to 3 hours, and the half-life ranges from approximately 2 to 2.5 hours. A study in patients with hereditary orotic aciduria included an assessment of plasma uridine pharmacokinetics in 4 patients. Three of the patients were previously treated with oral uridine. On Day 0 (baseline), these three patients received their usual daily dose of oral uridine as a single dose (150 to 200 mg/kg once daily) and on Day 1, initiated oral XURIDEN treatment (60 mg/kg once daily). A fourth patient was enrolled who was naïve to uridine replacement therapy. The dose of XURIDEN was increased on Day 116 to 120 mg/kg once daily in two patients (Patients 3 and 4) and plasma uridine concentrations were assessed on Day 160 (44 days after the dose increase). Plasma uridine levels in all four patients are depicted in Figure 2. Pharmacokinetic parameters are summarized in Table 3. Mean exposure to plasma uridine as assessed by Cmax and AUC was greater after oral XURIDEN than after oral uridine (approximately 4-fold on an equiweight basis, and 6-fold on an equimolar basis), although individual differences in relative bioavailability were noted. Plasma concentrations of the uridine catabolite uracil were generally below the limit of quantitation in all patients. Table 3: Pharmacokinetic Parameters for Plasma Uridine Pharmacokinetic Parameters (Plasma Uridine) Day 0 (Baseline) (Oral Uridine, 150 to 200 mg/kg once daily) N = 3 a Day 1 (Oral XURIDEN, 60 mg/kg once daily) N = 4 Day 28 (Oral XURIDEN, 60 mg/kg once daily) N = 4 Day 160 (Oral XURIDEN, 120 mg/kg once daily) N = 2b Cmax (ìM) mean ± SD 56.0 ± 16.6 91.3 ± 32.2 88.7 ± 43.2 80.9 ± 20.0 Tmax (hours) median (rangec) 2.0 (1.0, 4.0) 2.0 (1.2, 2.1) 1.3 (1.0, 2.5) 3.0 (2.0, 4.0) t1/2 (hours) mean ± SD 1.6 ± 0.7 1.6 ± 0.6 2.3 ± 1.6 8.2 ± 6.8 AUC(0-8) (μM•hr) mean ± SD 238.0 ± 163.2 311.2 ± 153.3 278.7 ± 148.5 465.6 ± 95.3 a Data shown are from patients previously treated with oral uridine b The dose of XURIDEN was increased on Day 116 to 120 mg/kg per day. Serial plasma samples were taken on Day 160 (44 days after the dose increase) for plasma uridine levels. cTmax range is expressed as the minimum and maximum values obtained Figure 2: Plasma Uridine Following Oral Administration of Uridine (Day 0) or XURIDEN (Days 1, 28 and 160) in Patients with Hereditary Orotic Aciduria Food Effect on Uridine PK A study in healthy adult subjects receiving a slightly different formulation of uridine triacetate granules (6 gram dose) under fed and fasted conditions showed no difference in the overall rate and extent of uridine exposure. Distribution Circulating uridine is taken up into mammalian cells via specific nucleoside transporters, and also crosses the blood brain barrier. Excretion Uridine can be excreted via the kidneys, but is also metabolized by normal pyrimidine catabolic pathways present in most tissues. Drug Interaction Studies In vitro enzyme inhibition data did not reveal meaningful inhibitory effects of uridine triacetate or uridine on CYP3A4, CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1. In vitro enzyme induction data did not reveal an inducing effect of uridine triacetate or uridine on CYP1A2, CYP2B6, or CYP3A4. In vitro data showed that uridine triacetate was a weak substrate for P-glycoprotein. Uridine triacetate inhibited the transport of a known P-glycoprotein substrate, digoxin, with an IC50 of 344 μM. Due to the potential for high local (gut) concentrations of the drug after dosing, the interaction of XURIDEN with orally administered P-gp substrate drugs cannot be ruled out. In vivo data in humans are not available. Clinical Studies The efficacy of XURIDEN was evaluated in an open-label study in 4 patients with hereditary orotic aciduria (3 male, 1 female; age range from 3 to 19 years). Three patients were previously treated with uridine and were switched at study entry to XURIDEN. All patients were administered XURIDEN orally at a daily dosage of 60 mg/kg once daily. The study duration was 6 weeks. The study assessed changes in the patients’ pre-specified hematologic parameters during the 6-week trial period. The pre-specified hematologic parameters were: neutrophil count and percent neutrophils (Patient 1), white blood cell count (Patient 2), and mean corpuscular volume (Patients 3 and 4). For patients switched from oral uridine to oral XURIDEN (Patients 1, 2, and 3), the primary endpoint was stability of the hematologic parameter; for the treatment-naïve patient (Patient 4), the primary endpoint was improvement of the hematologic parameter. Secondary endpoints were urine orotic acid and orotidine levels, and growth (height and weight) for all patients. After six weeks of treatment, Patients 1 and 3 met the pre-specified criteria for stability of the hematologic parameter. When Patient 2 was switched from uridine to XURIDEN treatment, the pre-specified criteria for white blood cell count remained stable; however documentation of a low white blood cell count prior to uridine initiation was not available. Patient 4 did not meet the pre-specified endpoint of improvement of the hematologic parameter. Table 4 summarizes the primary efficacy results. Table 4: Primary Efficacy Results for Study 1 Patient Pre-specified hematologic parameter (Age-specific reference range) Primary Endpoint Baseline (Day 0) Week 6 (Day 42) % Change from Baseline Patient #1 Neutrophil count(1.5 to 8.0 x103/mm3) Stable hematologic value 0.95 0.81 -15% Neutrophil % (26 to 48%) Stable hematologic value 21 23 10% Patient #2 White Blood Cell Count (3.8 to 10.6 x109/L) Stable hematologic value 7.8 7.4 -5% Patient #3 Mean Corpuscular Volume (75 to 91 fL) Stable hematologic value 109.9 108.5 -1% Patient #4 Mean Corpuscular Volume (72 to 90 fL) Stable hematologic value 114.6 113.4 -2% At baseline, three patients had normal urine orotic acid levels and all four patients had normal urine orotidine levels. Three patients who had achieved normal urine orotic acid levels when they were treated with uridine maintained normal levels 6 weeks after transitioning to XURIDEN. All four patients had normal urine orotidine levels at baseline which remained stable after 6 weeks of treatment with XURIDEN. During an extension phase of the trial, patients continued to receive XURIDEN. Dosing during the extension phase ranged from 60 mg/kg to 120 mg/kg once daily. After 6 months of treatment, Patient #1’s neutrophil count and neutrophil percent values normalized; hematologic parameters for the other three patients remained stable. Orotic acid and orotidine levels also remained stable for all four patients. The treatment effect of XURIDEN on growth was assessed in the three pediatric patients (Patients 1, 3, and 4). At baseline, weight and height measurements were at or below the lower limit of normal for age (below 5th percentile for age) for Patients 1 and 4; height and weight measurements were within the normal range for age for Patient 3. After 6 months of treatment, Patients 1 and 3 experienced improved weight growth, as reflected in increases in their weight-for-age percentiles and weight velocity percentiles; Patient 4’s weight growth remained stable (i.e., weight percentile for age and weight velocity percentile for age was unchanged). Height growth remained stable in all three patients (i.e., height percentiles for age and height velocity percentiles for age were unchanged). Case Reports Nineteen (19) case reports of patients with hereditary orotic aciduria have been documented in published literature. Eighteen (18) patients were diagnosed as infants or children between the ages of 2 months and 12 years and were treated with exogenous sources of uridine. One patient, diagnosed at age 28, was not treated with exogenous uridine. All 19 patients presented with significantly elevated levels of urinary orotic acid. Fifteen of 19 had abnormal hematologic parameters at presentation, including 15 with megaloblastic anemia, 8 with leukopenia and at least 2 with neutropenia. Oral administration of exogenous sources of uridine was reported to significantly improve hematologic abnormalities (megaloblastic anemia, leukopenia and neutropenia) within 2 to 3 weeks in almost all documented cases when administered in sufficient amounts. Concentrations of urinary orotic acid were significantly reduced within 1 to 2 weeks of initiating uridine replacement therapy. Some fluctuation in levels of urinary orotic acid were observed, but always at much lower levels than those reported prior to treatment. Improvements in body weight were also documented over time with continued uridine replacement therapy. The effects of exogenous uridine were maintained over months and years, as long as treatment continued at sufficient doses (with appropriate dose increases based on body weight increases). Most hematologic abnormalities and orotic aciduria reappeared within days up to 2 or 3 weeks when administration of uridine was stopped or the dose was reduced. If treatment was interrupted for longer periods, body weight growth receded. If absolute dosages were not adjusted adequately to compensate for body weight gains, signs and symptoms of hereditary orotic aciduria recurred.

CLINICAL PHARMACOLOGY 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. Pharmacokinetics Absorption VISTOGARD delivers 4- to 6-fold more uridine into the systemic circulation compared to equimolar doses of uridine itself. Maximum concentrations of uridine in plasma following oral VISTOGARD are generally achieved within 2 to 3 hours, and the half-life ranges from approximately 2 to 2.5 hours. Studies 1 and 2 included an assessment of plasma uridine in a subgroup of patients who were overdosed with fluorouracil or experiencing early-onset of serious fluorouracil toxicities. Samples were obtained prior to VISTOGARD treatment and at 1 to 4 hours following the first and final doses of VISTOGARD given at 10 g (adults) or 6.2 grams/m2 (pediatric) every 6 hours for up to 20 doses. Plasma uridine concentrations are summarized in Table 3. Table 3 Plasma Uridine Concentrations (μM) in Studies 1 and 2 Study Predose Post First Dose Post Final Dose Study 1* 8 (33) 99 (64) 160 (81) N = 49 N = 49 N = 40 Study 2* 5 (17) 119 (59) 153 (68) N = 27 N = 26 N = 24 *Values shown are mean (standard deviation) for plasma uridine (μM) Food Effect on Uridine PK A study in healthy adult subjects receiving a slightly different formulation of uridine triacetate granules (6 gram dose) under fed and fasted conditions showed no difference in the overall rate and extent of uridine exposure. Distribution Circulating uridine is taken up into mammalian cells via specific nucleoside transporters, and also crosses the blood brain barrier. Excretion Uridine can be excreted via the kidneys, but is also metabolized by normal pyrimidine catabolic pathways present in most tissues. Drug Interaction Studies In vitro enzyme inhibition data did not reveal meaningful inhibitory effects of uridine triacetate or uridine on CYP3A4, CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1. In vitro enzyme induction data did not reveal an inducing effect of uridine triacetate or uridine on CYP1A2, CYP2B6, or CYP3A4. In vitro data showed that uridine triacetate was a weak substrate for P-glycoprotein. Uridine triacetate inhibited the transport of a known P-glycoprotein substrate, digoxin, with an IC50 of 344 μM. Due to the potential for high local (gut) concentrations of the drug after dosing, the interaction of VISTOGARD with orally administered P-gp substrate drugs cannot be ruled out. In vivo data in humans are not available. Specific Populations Sex Pharmacokinetics analyses showed that sex did not have a significant effect on uridine pharmacokinetics. Age Pharmacokinetic analysis showed that within the age range evaluated (20 to 83 years), age did not have a significant effect on uridine pharmacokinetics. Body Size Pharmacokinetic analyses showed no clinically meaningful effect of body surface area on uridine PK in adults. 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. Clinical Studies The efficacy of VISTOGARD was assessed in 135 patients who were treated in two open-label trials, Study 1 (n=60) and Study 2 (n=75). The patients in both studies had either received an overdose of fluorouracil or capecitabine, or presented with severe or life-threatening toxicities within 96 hours following the end of fluorouracil or capecitabine administration. Overdose was defined as administration of fluorouracil at a dose, or infusion rate, greater than the intended dose or maximum tolerated dose for the patient's intended regimen of fluorouracil. 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/m2 /dose for 20 doses for four patients between 1 and 7 years of age. The major efficacy outcome was survival at 30 days or until the resumption of chemotherapy if prior to 30 days. In Study 1 and Study 2 combined, the median age of the patients was 59 years (range: 1 to 83), 56% were male, 72% were white, 9% were Black/African American, 6% were Hispanic, 4% were Asian, and 95% had a cancer diagnosis. Of the 135 patients, 117 were treated with VISTOGARD following an overdose of fluorouracil (n=112) or capecitabine (n=5), and 18 were treated after exhibiting severe or lifethreatening fluorouracil toxicities within 96 hours following the end of fluorouracil administration. The severe or life-threatening toxicities involved the central nervous system (such as encephalopathy, acute mental status change), cardiovascular system, gastrointestinal system (such as mucositis), and bone marrow. A total of six pediatric patients were administered VISTOGARD. Four patients initiated VISTOGARD more than 96 hours following the end of fluorouracil or capecitabine administration. Of the 112 patients overdosed with fluorouracil, 105 (94%) were overdosed by infusion rate only (range 1.3 to 720 times the planned infusion rate), four (4%) were overdosed by dose only, and three (3%) were overdosed by both dose and rate. The survival results are shown in Table 4. Of the 135 patients who were treated with VISTOGARD in Studies 1 and 2 there were five deaths due to fluorouracil or capecitabine toxicity (4%). Of the five patients who died, two were treated after 96 hours following the end of fluorouracil administration. In the patients treated with VISTOGARD for an overdose of fluorouracil or capecitabine in Studies 1 and 2 combined (n=117), survival at 30 days was 97% (n=114). In the patients receiving VISTOGARD for early-onset severe or life-threatening toxicity in Studies 1 and 2 combined (n=18), the survival at 30 days was 89% (n=16). In these studies 33% of patients (n=45) resumed chemotherapy in less than 30 days. Based on retrospective historical case reports of 25 patients who were overdosed with fluorouracil and received supportive care only, all were overdosed by rate with a range 1.9 to 64 times the planned infusion rate, and 84% died. Table 4 Combined Efficacy: All Patients in Study 1 and Study 2 Overdose Early-Onset Overall Total Enrolled 117 18 135 Survival* 114 (97%) 16 (89%) 130 (96%) Death 3 (3%) 2 (11%) 5 (4%) *Survival includes patients who survived at 30 days or patients who resumed chemotherapy prior to 30 days.

Find Lowest Prices on XURIDEN® (uridine triacetate) Oral Granules DESCRIPTION XURIDEN (uridine triacetate) oral granules is a pyrimidine analog indicated for uridine replacement therapy. Uridine triacetate has the chemical designation (2',3',5'-tri-O-acetyl-ß-D-ribofuranosyl)-2,4(1H,3H)-pyrimidinedione. The molecular weight is 370.3 and it has an empirical formula of C15H18N2O9. The structural formula is: Each single-use 2 gram packet of XURIDEN orange-flavored oral granules (95% w/w) contains 2 grams of uridine triacetate and the following inactive ingredients: ethylcellulose (0.062 grams), Opadry Clear [proprietary dispersion of hydroxypropylmethylcellulose and Macrogol] (0.015 grams), and natural orange juice flavor (0.026 grams).

Find Lowest Prices on VISTOGARD® (uridine triacetate) Oral Granules DESCRIPTION VISTOGARD oral granules contain the active ingredient uridine triacetate which is a pyrimidine analog. The chemical name for uridine triacetate is (2',3',5'-tri-O-acetyl-β-D-ribofuranosyl)- 2,4(1H,3H)-pyrimidinedione. The molecular weight is 370.3 grams/m2ole and it has an empirical formula of C15H18N2O9. The structural formula is: Each single-dose 10 gram packet of VISTOGARD orange-flavored oral granules (95% w/w) contains 10 grams of uridine triacetate and the following inactive ingredients: ethylcellulose (0.309 grams), Opadry® Clear [proprietary dispersion of hydroxypropylmethylcellulose and Macrogol] (0.077 grams), and natural orange juice flavor (0.131 grams).

INDICATIONS XURIDEN® is indicated for the treatment of hereditary orotic aciduria. DOSAGE AND ADMINISTRATION Recommended Dosage The recommended starting dosage of oral XURIDEN is 60 mg/kg once daily. Increase the dosage of XURIDEN to 120 mg/kg (not to exceed 8 grams) once daily for insufficient efficacy, such as occurrence of one of the following: Levels of orotic acid in urine remain above normal or increase above the usual or expected range for the patient Laboratory values (e.g., red blood cell or white blood cell indices) affected by hereditary orotic aciduria show evidence of worsening Worsening of other signs or symptoms of the disease The XURIDEN dose to be administered at the 60 mg/kg and 120 mg/kg dose levels by body-weight is presented in Tables 1 and 2. A 2 gram packet of XURIDEN contains approximately ¾ teaspoon of XURIDEN. Therefore, in the tables below for patients requiring doses in multiples of 2 grams (¾ teaspoon) an entire packet(s) may be administered without weighing or measuring. Patient Weight Table 1: XURIDEN 60 mg/kg§ Dose Level Kilograms Dose to be Administered Using a Scale (grams) Dose in Teaspoons up to 5 0.4 1/8 6-10 0.4 to 0.6 ¼ 11-15 0.7 to 0.9 16-20 1 to 1.2 21-25 1.3 to 1.5 26-30 1.6 to 1.8 ¾ * 31-35 1.9 to 2.1* 36-40 2.2 to 2.4 1 41-45 2.5 to 2.7 46-50 2.8 to 3 51-55 3.1 to 3.3 1 ¼ 56-60 3.4 to 3.6 61-65 3.7 to 3.9** 1 ½ ** 66-70 4 to 4.2** 71-75 4.3 to 4.5 Above 75 6*** 2 *** § total daily dose by weight category in the tables was rounded to achieve the approximate dose level * may use 1 entire 2 gram packet without weighing or measuring ** may use 2 entire 2 gram packets without weighing or measuring *** may use 3 entire 2 gram packets without weighing or measuring Patient Weight Table 2: XURIDEN 120 mg/kg§ Dose Level Kilograms Dose to be Administered Using a Scale (grams) Dose in Teaspoons up to 5 0.8 ¼ 6-10 0.8 to 1.2 ½ 11-15 1.4 to 1.8 ¾ 16-20 2 to 2.4 1 21-25 2.6 to 3 26-30 3.2 to 3.6 1 ¼ 31-35 3.8 to 4.2** 1 ½ ** 36-40 4.4 to 4.8 1 ¾ 41-45 5 to 5.4 2*** 46-50 5.6 to 6 51-55 6.2 to 6.6 2 ¼ 56-60 6.8 to 7.2 2 ½ 61-65 7.4 to 7.8 66-70 8**** 2 ¾ **** 71-75 8**** Above 75 8**** § total daily dose by weight category in the tables was rounded to achieve the approximate dose level ** may use 2 entire 2 gram packets without weighing or measuring *** may use 3 entire 2 gram packets without weighing or measuring **** may use 4 entire 2 gram packets without weighing or measuring Preparation And Administration Preparation Measure the dose using either a scale accurate to at least 0.1 gram, or a graduated teaspoon, accurate to the fraction of the dose to be administered. Once the measured dose has been removed from the XURIDEN packet, discard the unused portion of granules. Do not use any granules left in the open packet. Administration With Food Place 3 to 4 ounces of applesauce, pudding or yogurt in a small clean container. Mix the measured amount of granules in the applesauce, pudding or yogurt Swallow applesauce/pudding/yogurt immediately. Do not chew the granules. Do not save the applesauce/pudding/yogurt for later use. Drink at least 4 ounces of water. Administration In Milk Or Infant Formula XURIDEN can be mixed with milk or infant formula instead of the soft foods described above for patients receiving up to 3/4 teaspoon (2 grams) of XURIDEN. After weighing the dose of XURIDEN: Pour 5 mL of milk or infant formula into a 30 mL medicine cup. Insert the tip of the oral syringe into the medicine cup and draw up 5 mL of milk/infant formula into the syringe. Hold the syringe with the tip pointing upward. Pull down on the plunger until the plunger reaches 10 mL. This will add air to the syringe. Place the cap over the tip of the syringe. Then invert the syringe so the syringe tip is pointing down, and remove the plunger. Pour the measured amount of XURIDEN granules into the syringe barrel and reinsert the syringe plunger. Do not push up on the plunger. Gently swirl the syringe to mix the XURIDEN granules with the liquid. Turn the syringe so the syringe tip is pointing up. Then remove the syringe cap and push up on the plunger until the plunger reaches the 5 mL mark. This will remove air from the syringe. Place the tip of the syringe in the patient’s mouth between the cheek and gum at the back of the mouth. Gently push the plunger all the way down. Refill the syringe with another 5 mL of milk/infant formula. Gently swirl the syringe to rinse any remaining XURIDEN granules from the syringe barrel. Place the tip of the syringe in the patient’s mouth between the cheek and gum at the back of the mouth. Gently push the plunger all the way down. Follow with a bottle of milk or infant formula, if desired. HOW SUPPLIED Dosage Forms And Strengths Oral granules: 2 grams of orange-flavored oral granules (95% w/w) in single-use packets Storage And Handling XURIDEN orange-flavored oral granules (95% w/w) are available in single-use packets (NDC 69468-152-02) containing 2 grams of uridine triacetate in cartons of 30 packets each (NDC 69468-152-30). Store at controlled room temperature, 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). Manufactured by:Wellstat Therapeutics Corporation, Rockville, MD 20850 USA. Revised: February 2017

INDICATIONS 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. 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. DOSAGE AND ADMINISTRATION Recommended Dosage Adults: 10 grams (1 packet) orally every 6 hours for 20 doses, without regard to meals. Pediatric: 6.2 grams/m2 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 Sections or subsections omitted from the full prescribing information are not listed. grams/m2 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 Bas ed on Body Surface Area (m2) Patient Body Surface Area (m2 ) Table 1 VISTOGARD 6.2 grams/m2dose* Dose in Grams Dose in Graduated Teas poons 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† *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. 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. 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 ratio of no greater than 1 gram per 10 mL of reconstituted food starch-based thickening product and mix thoroughly. After administration of the mixture using the NG tube or G-Tube, flush the tube with water. HOW SUPPLIED Dosage Forms And Strengths Oral granules: 10 grams of orange-flavored, white-to-off-white, oral granules (95% w/w) in singledose packets. Storage And Handling VISTOGARD orange-flavored oral granules (95% w/w) are available in single-dose packets containing 10 grams of uridine triacetate. NDC Number Package Configuration 69468-151-20 Course of therapy package: 1 carton containing 20 single-dose packets of VISTOGARD 69468-151-04 24-Hour Pack: 1 carton containing 4 single-dose packets of VISTOGARD Store at USP controlled room temperature, 25°C (77°F); excursions permitted to 15° to 30 °C (59° to 86°F). Manufactured by: Wellstat Therapeutics Corporation, Rockville, MD 20850. Revised: Feb 2017

PATIENT INFORMATION Instructions for Use XURIDEN® (ZUR-uh-den) (uridine triacetate) Oral Granules Read this Instructions for Use before you prepare XURIDEN for the first time, each time you get a refill, and as needed. There may be new information. This information does not take the place of talking to your healthcare provider about your or your child’s medical condition or treatment. Ask your healthcare provider if you have any questions about how to mix or give a dose of XURIDEN the right way. Important Information Take XURIDEN exactly as your healthcare provider tells you to. Your healthcare provider will prescribe the dose of XURIDEN depending on your body weight. Your healthcare provider will tell you the right dose to take. Your healthcare provider w ill show you how to measure the prescribed dose. The prescribed dose of XURIDEN can be measured using a scale or an adjustable measuring spoon. Your healthcare provider may change your dose if needed. Do not change the dose without first talking with your healthcare provider. XURIDEN may be taken by mixing XURIDEN with 3 to 4 ounces of applesauce, pudding or yogurt or may be mixed with milk or infant formula. XURIDEN mixed with applesauce, pudding or yogurt should be eaten right away. Do not save the mixed applesauce, pudding or yogurt for later use. Do not chew the XURIDEN oral granules. For each dose of XURIDEN given in applesauce, pudding or yogurt, you will need the following (See Figure A): paper towels XURIDEN packet or packets containing the medicine needed for the prescribed dose 1 scale or 1 adjustable measuring spoon small spoon for stirring 1 small clean container (such as a small cup or bowl) 3 to 4 ounces of applesauce, pudding or yogurt 4 ounces of drinking water Figure A Step 1: Choose a clean flat work surface. Place a clean paper towel on the work surface. Then place the other supplies on the paper towel. Step 2: Wash and dry your hands. Step 3: Place 3 to 4 ounces of soft food such as applesauce, pudding, or yogurt in the small clean cup or bowl. Step 4: Select the number of XURIDEN packets needed for the prescribed dose. Step 5: Measure the dose: If you are using a scale: Open the packet or packets and measure out the amount needed for the prescribed dose on the scale. Follow the instructions that came with the scale for correct and accurate use. If you are using an adjustable measuring spoon: Open the packet or packets and use the adjustable measuring spoon to measure out the amount needed for the prescribed dose as shown. Throw away any unused XURIDEN in the trash. Do not use any XURIDEN left in the open packet. Step 6: Sprinkle the XURIDEN onto the soft food. Step 7: Use the small spoon to mix the medicine and the applesauce, pudding, or yogurt together. Step 8: Use the small spoon to give or take the soft food and XURIDEN mixture. XURIDEN mixed with soft food should be eaten right away without chewing. To avoid a bitter taste from the medicine, do not chew the granules. Make sure all of the mixture is swallowed. Do not save the food for later use. Step 9: Drink at least 4 ounces of water. Step 10: Wash the supplies needed to give the dose as your healthcare provider has told you. Throw away the paper towel and clean the work surface. Wash your hands. For each dose of XURIDEN given in milk or formula to children receiving up to ¾ teaspoon (2 grams of XURIDEN), you will need the following (See Figure B): paper towels XURIDEN packet or packets containing the medicine needed for your prescribed dose 1 oral dosing syringe (10mL) with a cap 1 scale or 1 adjustable measuring spoon milk or infant formula (10mL) 1 medicine cup (30mL) Figure B Step 1: Choose a clean flat work surface. Place a clean paper towel on the work surface. Then place the other supplies on the paper towel. If using infant formula, prepare the formula according to the directions on the infant formula package. Step 2: Wash and dry your hands. Step 3: Open one XURIDEN packet. Step 4: Measure the dose: If you are using a scale: Open the packet and measure out the amount needed for the prescribed dose on the scale. Follow the instructions that came with the scale for correct and accurate use. If you are using an adjustable measuring spoon: Open the packet and use the adjustable measuring spoon to measure out the amount needed for the prescribed dose as shown. Throw away any unused XURIDEN in the trash. Do not use any XURIDEN left in the open packet. Step 5: Pour 5 mL of either milk or infant formula into the 30mL medicine cup. Step 6: Place the syringe tip into the medicine cup. Pull up on the plunger until all the liquid is removed from the cup and the plunger reaches the 5 mL line on the syringe. Step 7: Hold the syringe with the tip pointing upward. Pull down on the plunger until the plunger reaches the 10 mL line on the syringe. This will add air to the syringe. Step 8: Place the syringe cap over the tip of the syringe. Now hold the syringe so the tip is pointing down and remove the plunger. Step 9: Pour the measured amount of XURIDEN granules into the syringe barrel, and put the plunger back in. Do not push further on the plunger. Step 10: Gently swirl the syringe to mix the XURIDEN with the liquid. Step 11: Turn the syringe so the syringe tip is pointing up, then remove the syringe cap, and push up on the plunger until the plunger reaches the 5mL line on the syringe. This will remove the air from the syringe. Step 12: Give the mixture to the child right away to avoid a bitter taste from the medicine. Place the tip of the syringe in your child’s mouth between the cheek and the gum at the back of the mouth. Gently push the plunger all the way down. Step 13: Pour another 5 mL of milk or formula into the medicine cup. Step 14: Refill the syringe by placing the syringe tip into the medicine cup. Pull up on the plunger until all the liquid is removed from the cup and the plunger reaches the 5 mL line on the syringe. Step 15: Gently swirl the syringe to make sure any medicine remaining in the syringe is mixed with the liquid. Step 16: Give the liquid to the child right away. Place the tip of the syringe in your child’s mouth between the cheek and the gum at the back of the mouth. Gently push the plunger all the way down. Step 17: Give your child a bottle of milk or formula after giving the XURIDEN dose if you wish to. Step 18: Remove the plunger from the barrel of the dosing syringe and wash the syringe and mixing cup, with warm water and dish soap. Rinse with water and air dry. Wash the supplies needed to measure your dose as your healthcare provider has told you. Throw away the paper towel and clean the work surface. Wash your hands. How should I store XURIDEN? Store XURIDEN at room temperature between 59° F to 86°F (15° to 30°C). Keep XURIDEN and all medicines out of the reach of children. General information about the safe and effective use of XURIDEN This Instructions for Use leaflet summarizes the most important information about XURIDEN. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about XURIDEN that is written for healthcare professionals. For more information, go to www.XURIDEN.com. What are the ingredients in XURIDEN? Active ingredient: uridine triacetate Inactive ingredients: ethylcellulose, hydroxypropylmethylcellulose, Macrogol, natural orange juice flavor This Instructions for Use has been approved by the U.S. Food and Drug Administration.

PATIENT INFORMATION VISTOGARD (VIS-toe-gard) (uridine triacetate) Oral Granules What is VISTOGARD? VISTOGARD is a prescription medicine that contains uridine, a substance that is normally found in your body. VISTOGARD is used for emergency treatment of adults and children: After an overdose of fluorouracil or capecitabine with or without symptoms, or who have early signs of severe or life-threatening side effects that affect the heart, or early signs of severe or life threatening neurologic (central nervous system) problems, or certain unusually severe side effects within 4 days (96 hours) after receiving treatment with fluorouracil or capecitabine VISTOGARD should only be used for the emergency treatment of side effects of fluorouracil or capecitabine, because it may decrease the effectiveness of these medicines. It is not known if VISTOGARD is safe and effective if started more than 4 days (96 hours) after the end of a dose of fluorouracil or capecitabine. Before taking VISTOGARD, tell your healthcare provider about all your medical conditions , including if you: are pregnant or plan to become pregnant. It is not known if VISTOGARD will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if VISTOGARD passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take VISTOGARD. Tell your healthcare provider about all the medicines you take, including prescription and over-thecounter medicines, vitamins, and herbal supplements. How should I take VISTOGARD? Take VISTOGARD exactly as prescribed by your healthcare provider. It is important that you take all 20 doses of VISTOGARD even if you feel well. VISTOGARD comes in single-dose packets that contain 10 grams of orange-flavored granules. If your healthcare provider decides that you can give VISTOGARD to your child at home, it is important that you follow your healthcare provider's instructions. Your healthcare provider will prescribe VISTOGARD to your child based on your child's weight. The usual adult dose of VISTOGARD is 1 packet taken by mouth every 6 hours for a total of 20 doses. If you vomit within 2 hours of taking a dose of VISTOGARD, take another full dose as soon as possible. Then take your next VISTOGARD dose at your next regularly scheduled time. If you miss a dose of VISTOGARD at the scheduled time, take the missed dose as soon as possible. Then take the next dose at the regularly scheduled time. Preparing and taking a dose of VISTOGARD: Mix each packet of VISTOGARD granules with 3 to 4 ounces of soft food such as applesauce, pudding or yogurt in a small container. Take all of the VISTOGARD granules mixed with food within 30 minutes of mixing. Do not chew the VISTOGARD granules. Drink at least 4 ounces of water to make sure that you swallow all of the medicine. What are the possible side effects of VISTOGARD? Common side effects of VISTOGARD include: vomiting, nausea, and diarrhea. These are not all the possible side effects of VISTOGARD. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800- FDA-1088. How should I store VISTOGARD? Store VISTOGARD at room temperature between 68°F to 77°F (20°C to 25°C) Keep VISTOGARD and all medicines out of the reach of children. General information about the safe and effective use of VISTOGARD. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use VISTOGARD for a condition for which it was not prescribed. Do not give VISTOGARD to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about VISTOGARD that is written for health professionals. What are the ingredients of VISTOGARD? Active Ingredient: uridine triacetate Inactive Ingredients : ethylcellulose, Opadry Clear [proprietary dispersion of hydroxypropylmethylcellulose and Macrogol], and natural orange juice flavor.

OVERDOSE No information provided. CONTRAINDICATIONS None

OVERDOSE No Information Provided CONTRAINDICATIONS None.

SIDE EFFECTS 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 XURIDEN was assessed in 4 patients with hereditary orotic aciduria ranging in age from 3 to 19 years (3 male, 1 female) who received 60 mg/kg of XURIDEN once daily for six weeks. The patients continued to receive XURIDEN for at least 9 months at dosages of up to 120 mg/kg once daily. No adverse reactions were reported with XURIDEN. DRUG INTERACTIONS No Information Provided

SIDE EFFECTS 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/m2 /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%) DRUG INTERACTIONS No Information Provided

WARNINGS Included as part of the "PRECAUTIONS" Section PRECAUTIONS None Nonclinical Toxicology 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 2.7 times the maximum recommend human dose (MRHD) of 120 mg/kg per day on a body surface area basis). Patient Counseling Information Advise the patient or caregiver to read the FDA-approved patient labeling (Instructions for Use) Administration Advise the patient or caregiver: To measure the prescribed dose using either a scale accurate to at least 0.1 gram, or a graduated teaspoon, accurate to the fraction of the dose to be administered. To discard the unused portion of granules in a packet after measuring out the dose. That XURIDEN can be taken mixed in food (applesauce, pudding or yogurt) or mixed in milk or infant formula. That the XURIDEN granules should not be chewed. Use In Specific Populations Pregnancy Risk Summary There are no available data on XURIDEN use in pregnant women to inform a drug-associated risk. When administered orally to pregnant rats during the period of organogenesis, uridine triacetate at doses similar to the maximum recommended human dose (MRHD) of 120 mg/kg 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 2.7 times the maximum recommend human dose (MRHD) of 120 mg/kg 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. 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 XURIDEN and any potential adverse effects on the breastfed infant from XURIDEN or from the underlying maternal condition. Pediatric Use The safety and effectiveness of XURIDEN have been established in pediatric patients. Use of XURIDEN is supported by a single open-label clinical trial of uridine triacetate in 4 patients and a retrospective review of the clinical course of 18 patients with hereditary orotic aciduria who were treated with uridine beginning at ages 2 months to 12 years. There are no apparent differences in clinical response between adults and pediatric patients with hereditary orotic aciduria treated with uridine, however, data are limited. [see Clinical Studies]

WARNINGS Included as part of the "PRECAUTIONS" Section PRECAUTIONS None. Patient Counseling Information Advise the patient or caregiver to read the FDA-approved patient labeling (PATIENT INFORMATION) Dosing Instructions [see DOSAGE AND ADMINISTRATION] 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. Nonclinical Toxicology 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). Use In Specific Populations Pregnancy Risk Summary Limited case reports of uridine triacetate use during pregnancy are insufficient to inform a drugassociated 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. 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. 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 bodysurface area adjusted dosage of 6.2 grams/m2 /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]. 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.