DRUGS & SUPPLEMENTS
Active ingredient: Uridine Monophosphate
Uridine Monophosphate uses
1 INDICATIONS AND USAGE
Uridine Monophosphate ® is indicated for the treatment of hereditary orotic aciduria.
Uridine Monophosphate is a pyrimidine analog for Uridine Monophosphate replacement indicated for the treatment of hereditary orotic aciduria. (1)
2 DOSAGE AND ADMINISTRATION
Recommended Dosage :
Preparation and Administration (2.2)
2.1 Recommended Dosage
The recommended starting dosage of oral Uridine Monophosphate is 60 mg/kg once daily. Increase the dosage of Uridine Monophosphate to 120 mg/kg (not to exceed 8 grams) once daily for insufficient efficacy, such as occurrence of one of the following:
The Uridine Monophosphate 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 Uridine Monophosphate contains approximately ¾ teaspoon of Uridine Monophosphate. 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.
Uridine Monophosphate Daily Dose Based on Body Weight (kg)
2.2 Preparation and Administration
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 Uridine Monophosphate packet, discard the unused portion of granules. Do not use any granules left in the open packet.
Administration with Food
Administration in Milk or Infant Formula
Uridine Monophosphate 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 Uridine Monophosphate. After weighing the dose of Uridine Monophosphate:
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)
5 WARNINGS AND PRECAUTIONS
6 ADVERSE REACTIONS
No adverse reactions were reported with Uridine Monophosphate in patients with hereditary orotic aciduria.
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 Uridine Monophosphate 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 Uridine Monophosphate once daily for six weeks. The patients continued to receive Uridine Monophosphate for at least 9 months at dosages of up to 120 mg/kg once daily. No adverse reactions were reported with Uridine Monophosphate.
8 USE IN SPECIFIC POPULATIONS
There are no available data on Uridine Monophosphate use in pregnant women to inform a drug-associated risk. When administered orally to pregnant rats during the period of organogenesis, Uridine Monophosphate triacetate at doses similar to the maximum recommended human dose 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.
In an embryo-fetal development study, Uridine Monophosphate 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.
There are no data on the presence of Uridine Monophosphate 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 Uridine Monophosphate and any potential adverse effects on the breastfed infant from Uridine Monophosphate or from the underlying maternal condition.
8.4 Pediatric Use
The safety and effectiveness of Uridine Monophosphate have been established in pediatric patients. Use of Uridine Monophosphate is supported by a single open-label clinical trial of Uridine Monophosphate triacetate in 4 patients and a retrospective review of the clinical course of 18 patients with hereditary orotic aciduria who were treated with Uridine Monophosphate 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 Monophosphate, however, data are limited.
Uridine Monophosphate (uridine triacetate) oral granules is a pyrimidine analog indicated for Uridine Monophosphate replacement therapy. Uridine Monophosphate 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 Uridine Monophosphate orange-flavored oral granules (95% w/w) contains 2 grams of Uridine Monophosphate 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).
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Uridine Monophosphate triacetate is an acetylated form of Uridine Monophosphate. Following oral administration, Uridine Monophosphate triacetate is deacetylated by nonspecific esterases present throughout the body, yielding Uridine Monophosphate in the circulation.
Figure 1: Uridine Monophosphate Triacetate Conversion to Uridine Monophosphate
Uridine Monophosphate provides Uridine Monophosphate in the systemic circulation of patients with hereditary orotic aciduria who cannot synthesize adequate quantities of Uridine Monophosphate due to a genetic defect in Uridine Monophosphate nucleotide synthesis.
Hereditary orotic aciduria (uridine monophosphate synthase deficiency) is a rare congenital autosomal recessive disorder of pyrimidine metabolism caused by a defect in Uridine Monophosphate monophosphate synthase (UMPS). The UMPS gene encodes Uridine Monophosphate 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.
Uridine Monophosphate delivers Uridine Monophosphate into the circulation, where it can be used by essentially all cells to make Uridine Monophosphate nucleotides, compensating for the genetic deficiency in synthesis in patients with hereditary orotic aciduria. When intracellular Uridine Monophosphate 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.
Uridine Monophosphate delivers 4- to 6-fold more Uridine Monophosphate into the systemic circulation compared to equimolar doses of Uridine Monophosphate itself. Maximum concentrations of Uridine Monophosphate in plasma following oral Uridine Monophosphate 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 Uridine Monophosphate pharmacokinetics in 4 patients. Three of the patients were previously treated with oral Uridine Monophosphate. On Day 0 (baseline), these three patients received their usual daily dose of oral Uridine Monophosphate as a single dose (150 to 200 mg/kg once daily) and on Day 1, initiated oral Uridine Monophosphate treatment (60 mg/kg once daily). A fourth patient was enrolled who was naïve to Uridine Monophosphate replacement therapy. The dose of Uridine Monophosphate was increased on Day 116 to 120 mg/kg once daily in two patients (Patients 3 and 4) and plasma Uridine Monophosphate concentrations were assessed on Day 160 (44 days after the dose increase).
Plasma Uridine Monophosphate levels in all four patients are depicted in Figure 2. Pharmacokinetic parameters are summarized in Table 3. Mean exposure to plasma Uridine Monophosphate as assessed by Cmax and AUC was greater after oral Uridine Monophosphate than after oral Uridine Monophosphate (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 Uridine Monophosphate catabolite uracil were generally below the limit of quantitation in all patients.
Figure 2 Plasma Uridine Monophosphate Following Oral Administration of Uridine Monophosphate (Day 0) or Uridine Monophosphate (Days 1, 28 and 160) in Patients with Hereditary Orotic Aciduria
Food Effect on Uridine Monophosphate PK: A study in healthy adult subjects receiving a slightly different formulation of Uridine Monophosphate triacetate granules (6 gram dose) under fed and fasted conditions showed no difference in the overall rate and extent of Uridine Monophosphate exposure.
Circulating Uridine Monophosphate is taken up into mammalian cells via specific nucleoside transporters, and also crosses the blood brain barrier.
Uridine Monophosphate 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 Uridine Monophosphate triacetate or Uridine Monophosphate on CYP3A4, CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1. In vitro enzyme induction data did not reveal an inducing effect of Uridine Monophosphate triacetate or Uridine Monophosphate on CYP1A2, CYP2B6, or CYP3A4.
In vitro data showed that Uridine Monophosphate triacetate was a weak substrate for P-glycoprotein. Uridine Monophosphate 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 Uridine Monophosphate 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 Uridine Monophosphate triacetate.
Uridine Monophosphate triacetate was not genotoxic in the Ames test, the mouse lymphoma assay and the mouse micronucleus test.
Orally administered Uridine Monophosphate 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 Uridine Monophosphate 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 Monophosphate and were switched at study entry to Uridine Monophosphate. All patients were administered Uridine Monophosphate 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 Monophosphate to oral Uridine Monophosphate (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 Monophosphate to Uridine Monophosphate treatment, the pre-specified criteria for white blood cell count remained stable; however documentation of a low white blood cell count prior to Uridine Monophosphate 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 Monophosphate maintained normal levels 6 weeks after transitioning to Uridine Monophosphate. All four patients had normal urine orotidine levels at baseline which remained stable after 6 weeks of treatment with Uridine Monophosphate.
During an extension phase of the trial, patients continued to receive Uridine Monophosphate. 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 Uridine Monophosphate 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).
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 Monophosphate. One patient, diagnosed at age 28, was not treated with exogenous Uridine Monophosphate.
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 Monophosphate 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 Monophosphate 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 Monophosphate replacement therapy.
The effects of exogenous Uridine Monophosphate 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 Monophosphate 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
Uridine Monophosphate orange-flavored oral granules (95% w/w) are available in single-use packets (NDC 69468-152-02) containing 2 grams of Uridine Monophosphate 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)
Advise the patient or caregiver:
Manufactured and distributed by:
Wellstat Therapeutics Corporation
Rockville, MD 20850
Uridine Monophosphate ® is a registered trademark of Wellstat Therapeutics Corporation. The Wellstat logo is a registered trademark of Wellstat Therapeutics Corporation.
Instructions for Use
Read this Instructions for Use before you prepare Uridine Monophosphate 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 Uridine Monophosphate the right way.
For each dose of Uridine Monophosphate given in applesauce, pudding or yogurt, you will need the following :
For each dose of Uridine Monophosphate given in milk or formula to children receiving up to ¾ teaspoon (2 grams of Uridine Monophosphate), you will need the following :
How should I store Uridine Monophosphate?
General information about the safe and effective use of Uridine Monophosphate
This Instructions for Use leaflet summarizes the most important information about Uridine Monophosphate. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Uridine Monophosphate that is written for healthcare professionals.
For more information, go to www. XURIDEN.com.
What are the ingredients in Uridine Monophosphate?
Active ingredient: Uridine Monophosphate 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
Uridine Monophosphate® is a registered trademark of Wellstat Therapeutics Corporation.
© Wellstat Therapeutics Corporation. All rights reserved.
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PRINCIPAL DISPLAY PANEL - 2 g Packet Carton
Uridine Monophosphate® 2 g
Carton contains 30 x 2 gram packets
PRINCIPAL DISPLAY PANEL - 2 g Packet Carton
Uridine Monophosphate available forms, composition, doses:
Indications and Usages:
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Frequently asked QuestionsCan i drive or operate heavy machine after consuming Uridine Monophosphate?
Depending on the reaction of the Uridine Monophosphate after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Uridine Monophosphate not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.Is Uridine Monophosphate addictive or habit forming?
Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
ReviewsDrugs.com conducted a study on Uridine Monophosphate, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Uridine Monophosphate consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.
The information was verified by Dr. Arunabha Ray, MD Pharmacology