URIDINE TRIACETATE: 110 Adverse Event Reports & Safety Profile

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/mole and it has an empirical formula of C 15 H 18 N 2 O 9 . 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).

Chemical

Structure

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.

AND ADMINISTRATION Recommended Dosage ( 2.1 ): The starting dosage is 60 mg/kg once daily; the dose may be increased to120 mg/kg (not to exceed 8 grams) once daily for insufficient efficacy. See the full prescribing information for 60 mg/kg and 120 mg/kg weight-based dosing tables. Preparation and Administration ( 2.2 ) 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. Administer the dose with food (applesauce, pudding or yogurt) or in milk or infant formula. See full prescribing information for preparation and administration instructions.

2.1 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.

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.

None. None. ( 4 )

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%)

AND PRECAUTIONS None. None. ( 5 )