AHFS Class:

• Fluoropyrimidine antidote 91:04.32

Generic Name(s):

• Uridine Triacetate

Uridine triacetate, an acetylated prodrug of uridine and a pyrimidine analog, is a direct biochemical antagonist of fluorouracil and a uridine replacement agent.1,3,9,10

Uridine triacetate, formerly called vistonuridine, is commercially available in the US in 2 different oral formulations: Vistogard^® granules, which are used for the treatment of fluorouracil or capecitabine overdosage or toxicity, and Xuriden^® granules, which are used for the treatment of hereditary orotic aciduria.1,3,7,9

Fluorouracil or Capecitabine Overdosage or Toxicity

Uridine triacetate (Vistogard^®) is used for emergency treatment of patients following fluorouracil or capecitabine overdosage regardless of the presence of symptoms.1,6,7,9,10 The drug also is used in patients who exhibit early onset, severe or life-threatening cardiac or CNS toxicity and/or early onset, unusually severe adverse reactions (e.g., GI toxicity, neutropenia) within 96 hours following the end of fluorouracil or capecitabine administration.1,6,10 Uridine triacetate is designated an orphan drug by FDA for use as an antidote in the treatment of fluorouracil or capecitabine poisoning.2 Uridine triacetate is not recommended for the nonemergency treatment of adverse reactions associated with fluorouracil or capecitabine because it may decrease the clinical efficacy of these drugs.1 In addition, the safety and efficacy of uridine triacetate initiated more than 96 hours following the end of fluorouracil or capecitabine administration have not been established.1

Fluorouracil and capecitabine (a prodrug of fluorouracil) are antineoplastic agents that are widely used in the treatment of a variety of malignancies.6,13 Although overdosages of fluorouracil and capecitabine are quite rare, they can result in substantial morbidity and mortality.6 In addition, some patients, such as those with a partial or complete deficiency of the enzyme dihydropyrimidine dehydrogenase (DPYD; a rate-limiting enzyme in the catabolism of fluoropyrimidines), may have impaired elimination of these drugs and experience severe toxicity as a result.6,10,13 For further information concerning fluorouracil and capecitabine toxicity and overdosage, see Capecitabine 10:00 and see also Fluorouracil 10:00.

The current indication for uridine triacetate (Vistogard^®) is based principally on the results of 2 single-arm, open-label studies in 135 patients (median age: 59 years [range: 1-83 years], 56% male, 72% white) with fluorouracil or capecitabine overdosage (87%) or who presented with severe or life-threatening toxicities within 96 hours following the end of fluorouracil or capecitabine administration (13%).1,6,10 The first study was a collection of single-patient investigational new drug applications designed to provide emergency access to uridine triacetate, and the second study was an expanded access protocol designed to provide better efficacy and safety data for the drug.6 Overdosage was defined as administration of fluorouracil at a dose or infusion rate greater than the intended dose or maximum tolerated dose for the patient's intended regimen; 94, 4, or 3% of such patients were overdosed by infusion rate (range: 1.3-720 times the intended infusion rate) alone, dose alone, or both dose and infusion rate, respectively.1,10 Severe or life-threatening toxicities in these patients involved the CNS (e.g., encephalopathy, acute mental status change), cardiovascular system, GI tract (e.g., mucositis), and bone marrow (e.g., neutropenia).1,6,10 Uridine triacetate was administered at a dosage of 10 g orally every 6 hours for 20 doses or at a body surface area-adjusted dosage of 6.2 g/m² per dose for 20 doses for 4 pediatric patients 1-7 years of age.1,10 The primary measure of efficacy was survival at 30 days or until the resumption of chemotherapy if prior to 30 days.1 Of the 135 patients treated with uridine triacetate, overall survival at 30 days was 96%, and 33% of the patients resumed chemotherapy in less than 30 days.1 There were 5 deaths overall; 2 of these patients were treated after 96 hours following the end of fluorouracil administration.1 In patients receiving uridine triacetate for an overdosage of fluorouracil or capecitabine in both studies, survival at 30 days was 97%.1 In patients receiving uridine triacetate for early-onset, severe or life-threatening toxicity, the survival at 30 days was 89%.1 In retrospective case reports that included 25 patients who received only supportive care following fluorouracil overdosages by infusion rate (range: 1.9-64 times the intended infusion rate), the survival rate was 16%.1

Hereditary Orotic Aciduria

Uridine triacetate (Xuriden^®) is used for the treatment of hereditary orotic aciduria.3 Uridine triacetate is designated an orphan drug by the FDA for use in this condition.2

Hereditary orotic aciduria (uridine monophosphate synthase deficiency) is a rare congenital autosomal recessive disorder of pyrimidine metabolism; the disorder is usually diagnosed in infants and children and has an estimated birth prevalence of less than 1:1,000,000.3,4,5,12 Hereditary orotic aciduria is caused by a defect in the uridine monophosphate synthase gene, which results in a deficiency of the bifunctional enzyme uridine 5'-monophosphate synthase.3,4,5,12 This enzyme is responsible for catalysis of the final two steps of the de novo pyrimidine biosynthetic pathway in mammalian cells and results in systemic deficiency of pyrimidine nucleotides and excretion of orotic acid in the urine.3,4,5,12 (See Description.) Clinical manifestations of hereditary orotic aciduria include hematologic abnormalities (e.g., megaloblastic anemia, decreased white blood cell and neutrophil counts), urinary tract obstruction due to formation of orotic acid crystals in the urinary tract, failure to thrive, and developmental delays.3,4,5,8,12

The current indication for uridine triacetate (Xuriden^®) is based principally on data from a single-arm, 6-week, open-label study with a 6-month extension phase conducted in 4 patients (age range: 3-19 years, 75% male) with hereditary orotic aciduria that demonstrated improvement or stability in hematologic parameters, urinary orotic acid and orotidine concentrations, and growth.3 All patients received uridine triacetate 60 mg/kg orally once daily for 6 weeks.3 Three of the patients had previously been treated with uridine and were switched to oral uridine triacetate at study entry.3 For these patients, the primary measure of efficacy was stability of the patients' prespecified hematologic parameter during the study period.3 For the treatment-naive (previously untreated) patient, the primary measure of efficacy was improvement of the patient's prespecified hematologic parameter during the study period.3 The prespecified hematologic parameters in the patients were neutrophil count and percentage of neutrophils (1 patient), white blood cell count (1 patient), and mean corpuscular volume (2 patients).3

Uridine triacetate therapy resulted in stability of the hematologic parameters in all 4 patients at both the 6-week and 6-month assessments in this study; the previously untreated patient, however, did not meet the prespecified criteria for improvement of the hematologic parameter.3 All patients with normal urinary orotic acid and orotidine concentrations at baseline maintained such concentrations after 6 weeks of treatment with uridine triacetate.3 During the extension phase of the study in which patients continued to receive uridine triacetate at dosages of 60-120 mg/kg once daily, hematologic parameters and growth (as determined by height and weight percentiles for age) either improved or remained stable and urinary orotic acid and orotidine concentrations remained stable after 6 months of treatment.3 No adverse effects associated with uridine triacetate therapy were reported in this study.3

The efficacy and safety of uridine triacetate therapy in patients with hereditary orotic aciduria are further supported by 19 case reports in the published literature.3 In 18 of these patients, the condition was diagnosed between the ages of 2 months and 12 years and all of these patients were treated with exogenous uridine; the remaining patient, who was diagnosed at 28 years of age, was not treated with exogenous uridine.3 These case reports of patients with hereditary orotic aciduria treated with exogenous sources of uridine demonstrated similar results as uridine triacetate therapy in the pivotal efficacy study.3

General

Uridine triacetate is commercially available in the US as Vistogard^® and Xuriden^®, which have different labeled indications.3 (See Uses.)

Restricted Distribution Program

Uridine triacetate (as Vistogard^®) can only be obtained through a specialty pharmacy.11 For inpatient use, clinicians may contact the specialty pharmacy at 844-293-0007.11 For outpatient use and information on the case management program, clinicians may contact the specialty pharmacy at 844-374-0604.11 Ordering information also is available on the Vistogard^® website ([Web]).11

Uridine triacetate (as Xuriden^®) also can only be obtained through a specialty pharmacy.15 Clinicians may contact the manufacturer at 800-914-0071 for availability and ordering information.15

Administration

Uridine triacetate is administered orally as granules (e.g., Vistogard^®, Xuriden^®) and may be given without regard to meals (see Description).1,3

Opened packets or mixtures of uridine triacetate with food, milk, or infant formula should not be stored.1,3 Packets of the drug are for single use only; any unused portions should be discarded.1,3 Any granules left in an open packet should not be used for subsequent dosing.1,3

Vistogard® Granules

Uridine triacetate (Vistogard^®) treatment should begin as soon as possible following overdosage or early-onset toxicity of fluorouracil or capecitabine and should be given within 96 hours following the end of fluorouracil or capecitabine administration.1

Pediatric doses of uridine triacetate should be weighed using a scale accurate to at least 0.1 g or measured using a graduated teaspoon accurate to one-fourth teaspoonful.1 For patients requiring 10-g doses of uridine triacetate, the contents of a full packet may be administered without weighing or measuring.1

Each Vistogard^® dose should be mixed with 3-4 ounces of soft food (e.g., applesauce, pudding, yogurt) and ingested within 30 minutes.1 The drug may be given without regard to meals.1 The granules should not be chewed.1 Patients should drink at least 120 mL (4 ounces) of water after each dose.1

Nausea and vomiting may occur during Vistogard^® therapy because of capecitabine or fluorouracil toxicity and, less commonly, because of the slightly bitter taste of the uridine triacetate granules.1,7 If a patient vomits within 2 hours after receiving a dose of uridine triacetate, another full dose should be administered as soon as possible after the vomiting episode.1 The next dose should be administered at the regularly scheduled time.1 Use of an antiemetic (e.g., a type 3 serotonin [5-HT₃] receptor antagonist) also may be helpful in such cases.7

If a dose of uridine triacetate is missed, the missed dose should be administered as soon as possible and the next dose should be administered at the regularly scheduled time.1

Nasogastric Tube or Gastrostomy Tube

Uridine triacetate (Vistogard^®) may be administered via nasogastric or gastrostomy tube when necessary (e.g., severe mucositis, coma).1 About 100 mL (approximately 4 fluid ounces) of a food starch-based thickening product in water should be prepared and stirred briskly until the thickener has dissolved.1 The contents of one 10-g packet of Vistogard^® granules should be crushed to a fine powder and then added to about 100 mL (4 ounces) of reconstituted food starch-based thickening product.1 For pediatric patients receiving doses of less than 10 g, the mixture should be prepared in a ratio not exceeding 1 g of uridine triacetate to 10 mL of reconstituted food starch-based thickening product and mixed thoroughly.1

Following administration of the mixture using the nasogastric or gastrostomy tube, the tube should be flushed with water.1

Xuriden® Granules

Doses of uridine triacetate (Xuriden^®) should be weighed using a scale accurate to at least 0.1 g or measured using a graduated teaspoon accurate to the fraction of the dose to be administered.3 For patients requiring doses of uridine triacetate in multiples of 2 g (i.e., three-fourths teaspoonful), the contents of the required number of 2-g packets may be administered without weighing or measuring.3

Doses of uridine triacetate should be administered orally immediately after mixing with 3-4 ounces of applesauce, pudding, or yogurt.3 The granules should not be chewed.3 Administration of each dose should be followed with at least 120 mL (4 ounces) of water.3

Xuriden^® granules may be mixed with 5 mL of milk or infant formula instead of soft foods for patients receiving up to 2 g (three-fourths teaspoonful) of uridine triacetate granules.3 The manufacturer's instructions for preparing such doses using a medicine cup and an oral syringe in the Xuriden^® prescribing information should be consulted.3 Doses that are mixed in milk or infant formula should be administered using an oral syringe placed between the patient's cheek and gum at the back of the mouth.3 A bottle of milk or infant formula may be given after administration of the drug, if desired.3

Dosage

Dosage of uridine triacetate is expressed in terms of the salt.1,3

Fluorouracil or Capecitabine Overdosage or Toxicity

For the emergency treatment of patients following fluorouracil or capecitabine overdosage (regardless of the presence of symptoms) or patients who exhibit early onset, severe or life-threatening cardiac or CNS toxicity and/or early onset, unusually severe adverse reactions (e.g., GI toxicity, neutropenia), the recommended dosage of uridine triacetate (Vistogard^®) in adults is 10 g (one packet) orally every 6 hours for a total of 20 doses for a full course of treatment.1

In pediatric patients with such fluorouracil or capecitabine overdosage or toxicity, the recommended dosage of uridine triacetate is 6.2 g/m² of body surface area (not exceeding 10 g/dose) orally every 6 hours for a total of 20 doses for a full course of treatment.1 (See Table 1.)

Hereditary Orotic Aciduria

The recommended initial dosage of uridine triacetate (Xuriden^®) for the treatment of adult and pediatric patients with hereditary orotic aciduria is 60 mg/kg orally once daily.3 (See Table 2.)

Dosage of uridine triacetate may be increased to 120 mg/kg (not to exceed 8 g) orally once daily for insufficient response.3 (See Table 3.) Signs of insufficient response may include urinary concentrations of orotic acid that are above normal or are increased above the usual or expected range for the patient, worsening of laboratory parameters affected by the condition (e.g., red or white blood cell indices), or worsening of other manifestations of the condition.3

Special Populations

No dosage adjustment is necessary based on age, body size, race, or gender in adults.6

Contraindications

The manufacturer states that there are no known contraindications to the use of uridine triacetate.1,3

Warnings/Precautions

Warnings and Precautions

The manufacturer states that there are no warnings or precautions associated with uridine triacetate therapy.1,3

Specific Populations

Pregnancy

Limited case reports of uridine triacetate (Vistogard^®) use during pregnancy are inadequate to inform a drug-associated risk of birth defects and miscarriage.1 There are no data regarding use of uridine triacetate (Xuriden^®) in pregnant women to inform a drug-associated risk.3

Animal studies have not revealed evidence of teratogenicity or fetal harm at uridine triacetate dosages of about one-half the maximum recommended human dosage of Vistogard^® or 2.7 times the maximum recommended human dosage of Xuriden^® administered to pregnant rats during the period of organogenesis.1,3

Lactation

It is not known whether uridine triacetate is distributed into human milk; effects of the drug on breast-fed infants or milk production also are not known.1,3 The benefits of breast-feeding and the woman's clinical need for uridine triacetate should be considered along with any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.1,3

Pediatric Use

Safety and efficacy of uridine triacetate (Vistogard^®) for emergency treatment following fluorouracil or capecitabine overdosage or early-onset, severe or life-threatening toxicity have been established in pediatric patients.1 Such use is supported by an open-label study that included 6 pediatric patients 1-16 years of age.1 Four of these pediatric patients were 1-7 years of age and received a body surface area-adjusted dosage of the drug.1

Safety and efficacy of uridine triacetate (Xuriden^®) for treatment of hereditary orotic aciduria have been established in a single open-label study in 4 pediatric patients 3 years of age or older and based on case reports of 18 pediatric patients who began uridine triacetate treatment at 2 months to 12 years of age.3

Clinical response and safety of uridine triacetate in adults and pediatric patients are similar; however, data are limited.1,3 (See Uses.)

Geriatric Use

In clinical studies evaluating uridine triacetate (Vistogard^®) for treatment of fluorouracil or capecitabine overdosage or toxicity, 30% of patients were 65 years of age or older and 11% were 75 years of age or older.1 Clinical studies did not include sufficient numbers of patients 65 years of age or older to determine whether they respond differently than younger adults.1

In a population pharmacokinetic analysis, patient age (range: 20-83 years) did not substantially affect uridine pharmacokinetics.1

Common Adverse Effects

The most common adverse effects occurring in more than 2% of patients receiving uridine triacetate (Vistogard^®) for emergency treatment of fluorouracil or capecitabine overdosage or toxicity in clinical trials were vomiting,1 nausea,1 and diarrhea.1

No adverse effects were reported in patients receiving uridine triacetate (Xuriden^®) for the treatment of hereditary orotic aciduria in the principal efficacy study.3

Clinically important drug interactions with uridine triacetate have not been identified to date.1,3

In vitro studies indicate that uridine triacetate and uridine do not have clinically important inhibitory effects on cytochrome P-450 (CYP) isoenzymes 3A4, 1A2, 2C8, 2C9, 2C19, 2D6, or 2E1.1,3 In vitro studies also indicate that uridine triacetate and uridine do not induce CYP isoenzymes 1A2, 2B6, or 3A4.1,3

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Clinically important drug interactions between uridine triacetate and drugs that affect or are metabolized by CYP isoenzymes appear unlikely.1,3,14

Drugs Affecting or Affected by P-glycoprotein Transport System

In vitro studies indicate that uridine triacetate is a weak substrate for P-glycoprotein (P-gp).1,3,6 Uridine triacetate inhibited the transport of digoxin (a P-gp substrate) with an IC₅₀ (concentration that inhibits activity by 50%) of 344 µM.1,3 Potential pharmacokinetic interaction of uridine triacetate with orally administered substrates of P-gp cannot be ruled out due to the potential for locally increased (gut) concentrations of uridine triacetate.1,3

Drugs Affecting GI Absorption

The manufacturer states that the expanded access protocol for uridine triacetate (Vistogard^®) initially contained instructions to avoid drugs that could potentially interfere with the GI absorption of uridine triacetate (e.g., bismuth subsalicylate, cholestyramine, sucralfate).7,15 However, there currently is no evidence that these drugs can slow the absorption of uridine or uridine triacetate.15 In addition, formal drug interaction studies have confirmed the lack of such an interaction.15 Therefore, the instruction to avoid drugs that may interfere with absorption of uridine triacetate was removed from the expanded access protocol and also was not included in the Vistogard^® prescribing information.15

Antineoplastic Agents

The effect of uridine triacetate on the antitumor activity of fluorouracil is not known.6 However, concomitant use of uridine triacetate potentially may result in decreased fluorouracil or capecitabine efficacy.1,6 The manufacturer states that use of uridine triacetate is not recommended for the nonemergency treatment of adverse reactions associated with fluorouracil or capecitabine.1

Description

Uridine triacetate is an acetylated prodrug of uridine and a pyrimidine analog.1,3,9 In fluorouracil or capecitabine overdosage or toxicity, uridine triacetate is a direct biochemical antagonist of fluorouracil.1,9,10 Excess circulating uridine derived from uridine triacetate is converted into uridine triphosphate (UTP), which competes with 5-fluorouridine triphosphate (FUTP; a cytotoxic intermediate metabolite of fluorouracil) for incorporation into RNA, thereby inhibiting cell damage and cell death.1,9

In hereditary orotic aciduria, uridine triacetate provides an exogenous source of uridine for replacement therapy in patients who are unable to synthesize adequate quantities of uridine.3 Uridine can be used for the synthesis of uridine nucleotides by essentially all cells.3 Restoration of intracellular uridine nucleotide concentrations to within the normal range reduces the overproduction of orotic acid by feedback inhibition, thereby also reducing the urinary excretion of orotic acid.3

Following oral administration, uridine triacetate is deacetylated by nonspecific esterases present throughout the body to form uridine.1,3,7 Uridine triacetate has a substantially higher oral bioavailability than uridine, providing fourfold to sixfold more uridine into the systemic circulation than equimolar oral doses of uridine.1,3,7 Uridine triacetate crosses the intestinal mucosa much more readily than uridine,7 and peak plasma concentrations of uridine following single-dose oral administration of uridine triacetate are generally achieved within 2-3 hours.1,3,6 Administration of a slightly different formulation of uridine triacetate granules with food in healthy adults did not affect the overall rate and extent of uridine exposure compared with those observed following administration of the drug in the fasted state.1,3 Uridine crosses the blood-brain barrier.1,3 Circulating uridine is taken up by mammalian cells via specific nucleoside transporters.1,3 Uridine can be excreted by the kidneys or metabolized by normal pyrimidine catabolic pathways present in most tissues.1,3 The elimination half-life of uridine is approximately 2-2.5 hours.1,3,6

Advice to Patients

Importance of providing patients or their caregivers with a copy of the manufacturer's patient information (Vistogard^®) or instructions for use (Xuriden^®).1,3

For Vistogard^® or Xuriden^® doses less than the entire contents of a packet, importance of weighing or measuring the prescribed dose using appropriate equipment (e.g., a scale accurate to at least 0.1 g, a graduated teaspoon accurate to one-fourth teaspoonful or the fraction of the dose to be administered).1,3

Uridine triacetate granules should not be chewed.1,3 Vistogard^® and Xuriden^® granules may be mixed with food (e.g., applesauce, pudding, yogurt).1,3 Xuriden^® also may be mixed in milk or infant formula.3 Any unused portion of uridine triacetate granules remaining in the single-use packets after measuring out the appropriate dose should be discarded.1,3

Importance of patients completing the full course of treatment (i.e., 20 doses) of Vistogard^® even if they feel well.1 If a patient vomits within 2 hours after receiving a dose of Vistogard^®, another full dose should be administered as a replacement as soon as possible after the vomiting episode; the next dose should be administered at the regularly scheduled time.1 If a dose of Vistogard^® is missed, the missed dose should be administered as soon as possible and the next dose should be administered at the regularly scheduled time.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1,3

Importance of advising women receiving uridine triacetate to inform clinicians if they are or plan to become pregnant or plan to breast-feed.1,3

Importance of informing patients of other important precautionary information.1,3 (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Wellstat Therapeutics Corporation. Vistogard^® (uridine triacetate) oral granules prescribing information. Gaithersburg, MD; 2015 Dec.

2. Food and Drug Administration. Search Orphan Drug Designations and Approvals. Silver Spring, MD. From FDA website. Accessed 2016 Jul 18. [Web]

3. Wellstat Therapeutics Corporation. Xuriden^® (uridine triacetate) oral granules prescribing information. Gaithersburg, MD; 2015 Sep.

4. Nyhan WL. Disorders of purine and pyrimidine metabolism. Mol Genet Metab . 2005 Sep-Oct; 86:25-33.

5. . In brief: Uridine triacetate (Xuriden) for hereditary orotic aciduria. Med Lett Drugs Ther . 2016; 58:e49.

6. Ison G, Beaver JA, McGuinn WD et al. FDA Approval: Uridine Triacetate for the Treatment of Patients Following Fluorouracil or Capecitabine Overdose or Exhibiting Early-Onset Severe Toxicities Following Administration of These Drugs. Clin Cancer Res . 2016; 22:4545-9. [PubMed 27401247]

7. McEvilly M, Popelas C, Tremmel B. Use of uridine triacetate for the management of fluorouracil overdose. Am J Health Syst Pharm . 2011; 68:1806-9. [PubMed 21930638]

8. O'Malley PA. Vistogard (Uridine Triacetate): The First and Only Drug Approved for the Treatment of 5-Fluorouracil or Capecitabine Overdose: Implications for the Clinical Nurse Specialist. Clin Nurse Spec . 2016 May-Jun; 30:145-7.

9. von Borstel R, O'Neil J, Bamat M. Vistonuridine: an orally administered, life-saving antidote for 5-fluorouracil (5FU) overdose. J Clin Oncol . 2009; 27: Abstract 9616 (presented at the 2009 ASCO annual meeting).

10. Bamat MK, Tremmel R, von Borstel R et al. Clinical experience with uridine triacetate for 5-FU overexposure: an update. J Clin Oncol . 2013; 31: Abstract e20592 (presented at the 2013 ASCO annual meeting).

11. Wellstat Therapeutics Corporation. Vistogard^® (uridine triacetate) oral granules: ordering information. 2016 May. Accessed 2016 Sep 29. [Web]

12. Food and Drug Administration. FDA news release: FDA approves new orphan drug to treat rare autosomal recessive disorder. Silver Spring, MD. From FDA website. Accessed 2016 Sep 29. [Web]

13. Saif MW, Diasio RB. Benefit of uridine triacetate (Vistogard) in rescuing severe 5-fluorouracil toxicity in patients with dihydropyrimidine dehydrogenase (DPYD) deficiency. Cancer Chemother Pharmacol . 2016; 78:151-6. [PubMed 27278667]

14. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 208169Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. [Web]

15. Wellstat Therapeutics, Cincinnati, OH: Personal communication.