r 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. xuriden daily dose based on body weight (kg) patient weight table 1: xuriden 60 mg/kg total daily dose by weight category in the tables was rounded to achieve the approximate dose level dose level kilograms dose to be administered using a scale (grams) dose in teaspoons up to 5 0.4 ⅛ 6-10 0.4 to 0.6 ¼ 11-15 0.7 to 0.9 ½ 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 may use 1 entire 2 gram packet without weighing or measuring 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 may use 2 entire 2 gram packets without weighing or measuring 1 ½ 66-70 4 to 4.2 71-75 4.3 to 4.5 above 75 6 may use 3 entire 2 gram packets without weighing or measuring 2 patient weight table 2: xuriden 120 mg/kg total daily dose by weight category in the tables was rounded to achieve the approximate dose level 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 may use 2 entire 2 gram packets without weighing or measuring 1 ½ 36-40 4.4 to 4.8 1 ¾ 41-45 5 to 5.4 2 may use 3 entire 2 gram packets without weighing or measuring 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 may use 4 entire 2 gram packets without weighing or measuring 71-75 8 above 75 8 2.2 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.

s). 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 xuriden and any potential adverse effects on the breastfed infant from xuriden or from the underlying maternal condition. 8.4 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 (14) ] . 8.5 geriatric use clinical trials of xuriden did not include patients 65 years of age and older.

eratogenicity or harm to the fetus and no effect on maternal body weight and overall health.

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. 12.3 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 c max 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 data shown are from patients previously treated with oral uridine 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 = 2 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. c max (µm) mean ± sd 56.0 ± 16.6 91.3 ± 32.2 88.7 ± 43.2 80.9 ± 20.0 t max (hours) median (range t max range is expressed as the minimum and maximum values obtained ) 2.0 (1.0, 4.0) 2.0 (1.2, 2.1) 1.3 (1.0, 2.5) 3.0 (2.0, 4.0) t ½ (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 figure 2 plasma uridine following oral administration of uridine (day 0) or xuriden (days 1, 28 and 160) in patients with hereditary orotic aciduria figure 2 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.

asma 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 c max 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 data shown are from patients previously treated with oral uridine 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 = 2 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. c max (µm) mean ± sd 56.0 ± 16.6 91.3 ± 32.2 88.7 ± 43.2 80.9 ± 20.0 t max (hours) median (range t max range is expressed as the minimum and maximum values obtained ) 2.0 (1.0, 4.0) 2.0 (1.2, 2.1) 1.3 (1.0, 2.5) 3.0 (2.0, 4.0) t ½ (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 figure 2 plasma uridine following oral administration of uridine (day 0) or xuriden (days 1, 28 and 160) in patients with hereditary orotic aciduria figure 2 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.

tologic 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. table 4 summarizes the changes in the patients' pre-specified hematologic parameters at week 6 and 24 months compared to baseline. after 6 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 parameter of 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. by 24 months of treatment with xuriden, the pre-specified hematologic parameter for patient 1 worsened, but the assessment was confounded by cohen syndrome with associated neutropenia, which was diagnosed after the patient completed the study. the pre-specified hematologic parameters for patients 2, 3, and 4 remained essentially unchanged. table 4: pre-specified hematologic parameters at baseline, 6 weeks and 24 months in xuriden-treated patients with hereditary orotic aciduria patient pre-specified hematologic parameter (age-specific reference range) baseline (day 0) 6 weeks (% change from baseline) 24 months (% change from baseline) patient 1 neutrophil count (1.5 to 8.0 x10 3 /mm 3 ) 0.95 0.81 (-15%) 0.61 (-36%) neutrophil % (26 to 48%) 21 23 (10%) 13 (-38%) patient 2 white blood cell count (3.8 to 10.6 x10 9 /l) 7.8 7.4 (-5%) 8.6 (10%) patient 3 mean corpuscular volume (75 to 91 fl) 109.9 108.5 (-1%) 108.8 (-1%) patient 4 mean corpuscular volume (72 to 90 fl) 114.6 113.4 (-1%) 112.9 (-1.5%) at baseline, patients 1, 2, and 3, previously treated with uridine, had normal urine orotic acid levels, and those remained stable after 6 weeks of treatment with xuriden. all four patients had normal urine orotidine levels at baseline which remained stable after 6 weeks of treatment with xuriden. after 24 months of treatment, urine orotic acid and orotidine levels remained stable in 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 were at or below the lower limit of normal for age for all three patients. after 24 months of treatment, each patient's growth parameters remained essentially 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.