Vistogard

Keep all appointments with your doctor.

Do not let anyone else take your medication.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

Uridine triacetate works by slowing down cell damage caused by certain cancer medicines (capecitabine or fluorouracil).

Uridine triacetate is used to treat an overdose of capecitabine or fluorouracil.

Uridine triacetate is also used in an emergency to treat life-threatening side effects caused by capecitabine or fluorouracil. This includes effects on the heart, nervous system, stomach, intestines, or blood cells.

This medicine may be given before overdose symptoms appear. However, treatment with uridine triacetate must begin within 96 hours after you last received capecitabine or fluorouracil.

Uridine triacetate may also be used for purposes not listed in this medication guide.

Follow all directions on your medicine label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use.

Before you use uridine triacetate, tell your doctor about all your medical conditions or allergies, and all the medicines you are using. In some cases, you may not be able to use this medicine, or you may need a dose adjustment or special precautions.

It is not known whether uridine triacetate will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether uridine triacetate passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

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).

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

Tell your doctor if you are pregnant or plan to become pregnant.

There have been no studies done in humans with Vistogard. In animal studies, pregnant animals were given Vistogard and the babies did not show any medical problems related to this medication. It is not known if Vistogard will harm your unborn baby. Talk to your doctor about the risks and benefits associated with taking Vistogard while pregnant.

This medication guide provides information about the Vistogard brand of uridine triacetate. Xuriden is another brand of uridine triacetate that is not covered in this medication guide.

Uridine triacetate works by slowing down cell damage caused by certain cancer medicines (capecitabine or fluorouracil).

Uridine triacetate is used to treat an overdose of capecitabine or fluorouracil.

Uridine triacetate is also used in an emergency to treat life-threatening side effects caused by capecitabine or fluorouracil. This includes effects on the heart, nervous system, stomach, intestines, or blood cells.

This medicine may be given before overdose symptoms appear. However, treatment with uridine triacetate must begin within 96 hours after you last received capecitabine or fluorouracil.

Uridine triacetate may also be used for purposes not listed in this medication guide.

Before you use uridine triacetate, tell your doctor about all your medical conditions or allergies, and all the medicines you are using. In some cases, you may not be able to use this medicine, or you may need a dose adjustment or special precautions.

It is not known whether uridine triacetate will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether uridine triacetate passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

This section provides information on the proper use of a number of products that contain uridine triacetate. It may not be specific to Vistogard. Please read with care.

Take this medicine only as directed by your doctor to benefit your condition as much as possible. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

This medicine should come with a patient instruction leaflet. Read and follow these instructions carefully. Ask your doctor if you have any questions.

Take Xuriden™ with food. You may take Vistogard® without regard to meals.

It is important to take all doses of Vistogard®, even if you feel well.

To prepare:

• Measure the dose by using either a scale accurate to at least 0.1 gram, or a graduated teaspoon, accurate to the fraction of the dose to be given.
• Throw away any unused granules left in the packet.

To mix Xuriden™ or Vistogard® with food:

• Mix the measured amount of granules in 3 to 4 ounces of applesauce, pudding, or yogurt in a small, clean container.
• Swallow the mixture immediately and do not chew the granules. Do not save any of the mixture to use later.
• Drink at least 4 ounces of water.

You may also mix Xuriden™ with milk or infant formula:

• Pour 5 mL of milk or infant formula into a medicine cup.
• Use an oral syringe to draw up the 5 mL of milk or infant formula.
• Cap the tip of the syringe, remove the plunger, and pour the measured amount of granules into the syringe.
• Gently swirl the syringe to mix the granules with the liquid.
• 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 or infant formula.
• Gently swirl to rinse any remaining granules and flush it to the patient's mouth.
• This may be followed by a bottle of milk or infant formula, if desired.

If you are taking Vistogard® through a nasogastric tube or gastrostomy tube:

• Mix 100 mL of food starch-based thickening product in water and stir until the thickener has dissolved.
• Crush the contents of 1 full 10 gram packet of granules into a fine powder.
• Add the crushed Vistogard® granules to 100 mL of the thickener mixture. For children receiving less than 10 grams, prepare the mixture at a ratio of no greater than 1 gram per 10 mL of the mixture.
• Take this medicine through a nasogastric tube or gastrostomy tube.
• Flush the tube with water.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (oral granules):
  • For treatment of hereditary orotic aciduria:
    • Adults and children—Dose is based on body weight and must be determined by your doctor. The starting dose is 60 milligrams (mg) per kilogram (kg) of body weight (1 to 3 packets) once a day. Your doctor may increase your dose as needed. However, the dose is usually not more than 120 mg per kg of body weight (2 to 4 packets) once a day.
  • For emergency treatment of patients who have an overdose of fluorouracil or capecitabine:
    • Adults—10 grams (1 packet) every 6 hours for 20 doses.
    • Children—Dose is based on body size and must be determined by your doctor. The starting dose is 6.2 grams per square meter (m[2]) of body size (not to exceed 10 grams per dose) every 6 hours for 20 doses.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

If you vomit within 2 hours of taking a dose of Vistogard®, take another dose immediately. Then, take your next dose at your regularly scheduled time.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

It is important that your doctor check your progress at regular visits. This is to make sure that this medicine is working properly and to check for unwanted effects.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about Vistogard (uridine triacetate (vistogard)), please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Vistogard. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Vistogard.

Review Date: October 4, 2017

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.

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 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 Based on Body Surface Area (m2)

  Patient Body Surface Area (m2)	Table 1 Vistogard 6.2 grams/m2/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.

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.

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.

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 body-surface 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 (14)].

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.

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 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).

Vistogard (uridine triacetate) works by slowing down cell damage caused by certain cancer medicines (capecitabine or fluorouracil).

Vistogard is used to treat an overdose of capecitabine or fluorouracil.

Vistogard is also used in an emergency to treat life-threatening side effects caused by capecitabine or fluorouracil. This includes effects on the heart, nervous system, stomach, intestines, or blood cells.

This medicine may be given before overdose symptoms appear. However, treatment with Vistogard must begin within 96 hours after you last received capecitabine or fluorouracil.

Other drugs may interact with uridine triacetate, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Applies to uridine: oral granule

Along with its needed effects, uridine (the active ingredient contained in Vistogard) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking uridine:

• Rash or itching skin

Some side effects of uridine may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Vomiting

• Diarrhea
• Nausea