Xuriden

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Xuriden, there are no specific foods that you must exclude from your diet when receiving this medication.

Uridine triacetate is used to treat hereditary orotic aciduria. Hereditary orotic aciduria is a rare metabolic disease that is caused by uridine deficiency. Uridine triacetate is a pyrimidine analog that works by replacing the uridine that cannot be normally produced in patients with hereditary orotic aciduria.

Uridine triacetate is also used as an emergency treatment for patients who had an overdose of the cancer medicines fluorouracil or capecitabine, or who develop certain severe or life-threatening side effects within 4 days of receiving these cancer medicines.

This medicine is available only with your doctor's prescription.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of uridine triacetate in children.

Geriatric

Although appropriate studies on the relationship of age to the effects of Vistogard® have not been performed in the geriatric population, geriatric-specific problems are not expected to limit the usefulness of Vistogard® in the elderly.

No information is available on the relationship of age to the effects of Xuriden™ in geriatric patients.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

• It is used to treat a rare metabolism health problem called orotic aciduria.

• If you have an allergy to Xuriden (uridine triacetate (xuriden)) or any part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.

This medicine may interact with other drugs or health problems.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Xuriden with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Your doctor will tell you how to take Xuriden. Be sure you know how much to take, how often to take this medicine, and how to store this drug. If your doctor does not tell you how to use Xuriden or if you are not sure how to use it, talk with your doctor.
• Throw away any part of the packet not used after use.
• Mix granules with 3 to 4 ounces (90 to 120 mL) of applesauce, pudding, or yogurt.
• Do not chew this medicine.
• Drink at least 4 ounces (120 mL) of water.
• Keep taking Xuriden as you have been told by your doctor or other health care provider, even if you feel well.
• Some doses of this medicine may be mixed with milk or infant formula. If you are mixing Xuriden with milk or infant formula, follow what the doctor has told you or read the package insert.
• Swallow the mixture right away. Do not store for use at a later time.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

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)

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

1. Place 3 to 4 ounces of applesauce, pudding or yogurt in a small clean container.
2. Mix the measured amount of granules in the applesauce, pudding or yogurt
3. Swallow applesauce/pudding/yogurt immediately. Do not chew the granules. Do not save the applesauce/pudding/yogurt for later use.
4. 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:

1. Pour 5 mL of milk or infant formula into a 30 mL medicine cup.
2. Insert the tip of the oral syringe into the medicine cup and draw up 5 mL of milk/infant formula into the syringe.
3. 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.
4. Place the cap over the tip of the syringe. Then invert the syringe so the syringe tip is pointing down, and remove the plunger.
5. Pour the measured amount of Xuriden granules into the syringe barrel and reinsert the syringe plunger. Do not push up on the plunger.
6. Gently swirl the syringe to mix the Xuriden granules with the liquid.
7. 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.
8. 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.
9. Refill the syringe with another 5 mL of milk/infant formula.
10. Gently swirl the syringe to rinse any remaining Xuriden granules from the syringe barrel.
11. 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.
12. Follow with a bottle of milk or infant formula, if desired.

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 (14)]

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.

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.