Inexfal

Uridine:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Use in specific populations
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Instructions for use xuriden® (zur-uh-den)(uridine triacetate)oral granules
• Inexfal (Uridine) reviews

1 INDICATIONS AND USAGE

Inexfal (Uridine) ^® is indicated for the treatment of hereditary orotic aciduria.

Inexfal (Uridine) is a pyrimidine analog for Inexfal (Uridine) replacement indicated for the treatment of hereditary orotic aciduria. (1)

2 DOSAGE AND ADMINISTRATION

Recommended Dosage :

• 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 Inexfal (Uridine) is 60 mg/kg once daily. Increase the dosage of Inexfal (Uridine) 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 Inexfal (Uridine) 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 Inexfal (Uridine) contains approximately ¾ teaspoon of Inexfal (Uridine). 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.

Inexfal (Uridine) Daily Dose Based on Body Weight (kg)

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 Inexfal (Uridine) 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

Inexfal (Uridine) 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 Inexfal (Uridine). After weighing the dose of Inexfal (Uridine):

• 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 Inexfal (Uridine) granules into the syringe barrel and reinsert the syringe plunger. Do not push up on the plunger.
• Gently swirl the syringe to mix the Inexfal (Uridine) 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 Inexfal (Uridine) 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.

3 DOSAGE FORMS AND STRENGTHS

Oral granules: 2 grams of orange-flavored oral granules (95% w/w) in single-use packets

Oral granules: 2 gram packets. (3)

4 CONTRAINDICATIONS

None

None (4)

5 WARNINGS AND PRECAUTIONS

None

None (5)

6 ADVERSE REACTIONS

No adverse reactions were reported with Inexfal in patients with hereditary orotic aciduria (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Wellstat Therapeutics Corporation at (1-800-914-0071) 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 Inexfal (Uridine) 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 Inexfal (Uridine) once daily for six weeks. The patients continued to receive Inexfal (Uridine) for at least 9 months at dosages of up to 120 mg/kg once daily. No adverse reactions were reported with Inexfal (Uridine).

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no available data on Inexfal use in pregnant women to inform a drug-associated risk. When administered orally to pregnant rats during the period of organogenesis, Inexfal (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 .

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, Inexfal (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.

8.2 Lactation

Risk Summary

There are no data on the presence of Inexfal (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 Inexfal (Uridine) and any potential adverse effects on the breastfed infant from Inexfal (Uridine) or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of Inexfal (Uridine) have been established in pediatric patients. Use of Inexfal (Uridine) is supported by a single open-label clinical trial of Inexfal (Uridine) triacetate in 4 patients and a retrospective review of the clinical course of 18 patients with hereditary orotic aciduria who were treated with Inexfal (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 Inexfal (Uridine), however, data are limited.

11 DESCRIPTION

Inexfal (Uridine) (uridine triacetate) oral granules is a pyrimidine analog indicated for Inexfal (Uridine) replacement therapy. Inexfal (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 Inexfal (Uridine) orange-flavored oral granules (95% w/w) contains 2 grams of Inexfal (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).

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Inexfal triacetate is an acetylated form of Inexfal (Uridine). Following oral administration, Inexfal (Uridine) triacetate is deacetylated by nonspecific esterases present throughout the body, yielding Inexfal (Uridine) in the circulation (Figure 1).

Figure 1: Inexfal (Uridine) Triacetate Conversion to Inexfal (Uridine)

Inexfal (Uridine) provides Inexfal (Uridine) in the systemic circulation of patients with hereditary orotic aciduria who cannot synthesize adequate quantities of Inexfal (Uridine) due to a genetic defect in Inexfal (Uridine) nucleotide synthesis.

Figure 1

12.2 Pharmacodynamics

Hereditary orotic aciduria (uridine monophosphate synthase deficiency) is a rare congenital autosomal recessive disorder of pyrimidine metabolism caused by a defect in Inexfal (Uridine) monophosphate synthase (UMPS). The UMPS gene encodes Inexfal (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.

Inexfal (Uridine) delivers Inexfal (Uridine) into the circulation, where it can be used by essentially all cells to make Inexfal (Uridine) nucleotides, compensating for the genetic deficiency in synthesis in patients with hereditary orotic aciduria. When intracellular Inexfal (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

Inexfal (Uridine) delivers 4- to 6-fold more Inexfal (Uridine) into the systemic circulation compared to equimolar doses of Inexfal (Uridine) itself. Maximum concentrations of Inexfal (Uridine) in plasma following oral Inexfal (Uridine) 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 Inexfal (Uridine) pharmacokinetics in 4 patients. Three of the patients were previously treated with oral Inexfal (Uridine). On Day 0 (baseline), these three patients received their usual daily dose of oral Inexfal (Uridine) as a single dose (150 to 200 mg/kg once daily) and on Day 1, initiated oral Inexfal (Uridine) treatment (60 mg/kg once daily). A fourth patient was enrolled who was naïve to Inexfal (Uridine) replacement therapy. The dose of Inexfal (Uridine) was increased on Day 116 to 120 mg/kg once daily in two patients (Patients 3 and 4) and plasma Inexfal (Uridine) concentrations were assessed on Day 160 (44 days after the dose increase).

Plasma Inexfal (Uridine) levels in all four patients are depicted in Figure 2. Pharmacokinetic parameters are summarized in Table 3. Mean exposure to plasma Inexfal (Uridine) as assessed by C_max and AUC was greater after oral Inexfal (Uridine) than after oral Inexfal (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 Inexfal (Uridine) catabolite uracil were generally below the limit of quantitation in all patients.

Figure 2 Plasma Inexfal (Uridine) Following Oral Administration of Inexfal (Uridine) (Day 0) or Inexfal (Uridine) (Days 1, 28 and 160) in Patients with Hereditary Orotic Aciduria

Figure 2

Food Effect on Inexfal (Uridine) PK: A study in healthy adult subjects receiving a slightly different formulation of Inexfal (Uridine) triacetate granules (6 gram dose) under fed and fasted conditions showed no difference in the overall rate and extent of Inexfal (Uridine) exposure.

Distribution

Circulating Inexfal (Uridine) is taken up into mammalian cells via specific nucleoside transporters, and also crosses the blood brain barrier.

Excretion

Inexfal (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 Inexfal (Uridine) triacetate or Inexfal (Uridine) on CYP3A4, CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1. In vitro enzyme induction data did not reveal an inducing effect of Inexfal (Uridine) triacetate or Inexfal (Uridine) on CYP1A2, CYP2B6, or CYP3A4.

In vitro data showed that Inexfal (Uridine) triacetate was a weak substrate for P-glycoprotein. Inexfal (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 Inexfal (Uridine) with orally administered P-gp substrate drugs cannot be ruled out.

In vivo data in humans are not available.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Inexfal (Uridine) triacetate.

Inexfal (Uridine) triacetate was not genotoxic in the Ames test, the mouse lymphoma assay and the mouse micronucleus test.

Orally administered Inexfal (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).

14 CLINICAL STUDIES

The efficacy of Inexfal (Uridine) 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 Inexfal (Uridine) and were switched at study entry to Inexfal (Uridine). All patients were administered Inexfal (Uridine) 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 Inexfal (Uridine) to oral Inexfal (Uridine) (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 Inexfal (Uridine) to Inexfal (Uridine) treatment, the pre-specified criteria for white blood cell count remained stable; however documentation of a low white blood cell count prior to Inexfal (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 Inexfal (Uridine) maintained normal levels 6 weeks after transitioning to Inexfal (Uridine). All four patients had normal urine orotidine levels at baseline which remained stable after 6 weeks of treatment with Inexfal (Uridine).

During an extension phase of the trial, patients continued to receive Inexfal (Uridine). 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 Inexfal (Uridine) 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 Inexfal (Uridine). One patient, diagnosed at age 28, was not treated with exogenous Inexfal (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 Inexfal (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 Inexfal (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 Inexfal (Uridine) replacement therapy.

The effects of exogenous Inexfal (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 Inexfal (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.

16 HOW SUPPLIED/STORAGE AND HANDLING

Inexfal (Uridine) orange-flavored oral granules (95% w/w) are available in single-use packets (NDC 69468-152-02) containing 2 grams of Inexfal (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).

17 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 Inexfal (Uridine) can be taken mixed in food (applesauce, pudding or yogurt) or mixed in milk or infant formula.
• That the Inexfal (Uridine) granules should not be chewed.

Manufactured and distributed by:

Wellstat Therapeutics Corporation

Rockville, MD 20850

Inexfal (Uridine) ^® is a registered trademark of Wellstat Therapeutics Corporation. The Wellstat logo is a registered trademark of Wellstat Therapeutics Corporation.

Instructions for Use

Inexfal ^® (ZUR-uh-den)

(uridine triacetate)

oral granules

Read this Instructions for Use before you prepare Inexfal (Uridine) 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 Inexfal (Uridine) the right way.

Important Information

• Take Inexfal (Uridine) exactly as your healthcare provider tells you to.
• Your healthcare provider will prescribe the dose of Inexfal (Uridine) depending on your body weight. Your healthcare provider will tell you the right dose to take.
• Your healthcare provider will show you how to measure the prescribed dose. The prescribed dose of Inexfal (Uridine) 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.
• Inexfal (Uridine) may be taken by mixing Inexfal (Uridine) with 3 to 4 ounces of applesauce, pudding or yogurt or may be mixed with milk or infant formula.
• Inexfal (Uridine) 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 Inexfal (Uridine) oral granules.

For each dose of Inexfal (Uridine) given in applesauce, pudding or yogurt, you will need the following :

• paper towels
• Inexfal (Uridine) 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

For each dose of Inexfal (Uridine) given in milk or formula to children receiving up to ¾ teaspoon (2 grams of Inexfal (Uridine)), you will need the following :

• paper towels
• Inexfal (Uridine) 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)

How should I store Inexfal (Uridine)?

• Store Inexfal (Uridine) at room temperature between 59° F to 86°F (15° to 30°C).
• Keep Inexfal (Uridine) and all medicines out of the reach of children.

General information about the safe and effective use of Inexfal (Uridine)

This Instructions for Use leaflet summarizes the most important information about Inexfal (Uridine). If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Inexfal (Uridine) that is written for healthcare professionals.

For more information, go to www. XURIDEN.com.

What are the ingredients in Inexfal (Uridine)?

Active ingredient: Inexfal (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.

Manufactured and distributed by

Wellstat Therapeutics Corporation,

Rockville, MD 20850 USA

Inexfal (Uridine)^® is a registered trademark of Wellstat Therapeutics Corporation.

© Wellstat Therapeutics Corporation. All rights reserved.

Issued: 9/2015

Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure

PRINCIPAL DISPLAY PANEL - 2 g Packet Carton

NDC 69468-152-30

Rx Only

Inexfal (Uridine)^® 2 g

(uridine triacetate)

Oral Granules

Carton contains 30 x 2 gram packets

Wellstat Therapeutics

CORPORATION

PRINCIPAL DISPLAY PANEL - 2 g Packet Carton