is used concomitantly with olpruva [ see dosage and administration ( 2.2 ) ].

es of acute hyperammonemia may occur in patients while on olpruva. olpruva is not indicated for the treatment of acute hyperammonemia, which can be a life-threatening medical emergency that requires rapid acting interventions to reduce plasma ammonia levels.

y for 14 days, repeated at 4-week intervals, signs and symptoms of neurotoxicity, which were reversible upon discontinuation, were seen at plasma concentrations ≥ 3.5 mmol/l, and included somnolence, fatigue, and light headedness [ see adverse reactions ( 6 ) ]. olpruva is not approved for intravenous use or for treatment of patients with cancer. if symptoms of vomiting, nausea, headache, somnolence, or confusion are present in the absence of high ammonia levels or other intercurrent illnesses, consider reducing the dose of olpruva [ see dosage and administration ( 2.2 ) ]. phenylacetate caused neurotoxicity when given subcutaneously in rat pups [ see use in specific populations ( 8.4 ) ]. 5.2 hypokalemia renal excretion of phenylacetylglutamine may induce urinary loss of potassium. monitor serum potassium during therapy and initiate appropriate treatment when necessary. 5.3 conditions associated with edema olpruva contains 124 mg (5.4 mmol) of sodium per gram of sodium phenylbutyrate (12.4% w/w) and the mix-aid contains 5 mg of sodium per packet, corresponding to 2.5 g (108 mmol) of sodium in the maximum daily dose of 20 g of olpruva. in order to decide if administration of olpruva is appropriate in patients with diseases that involve edema, such as heart failure, cirrhosis, or nephrosis, calculate the total amount of sodium patients will be exposed to based on their bsas [ see dosage and administration ( 2.1 ) ]. if a patient develops new-onset edema or worsening edema while on treatment, discontinue administration of olpruva and initiate appropriate therapy.

combine olpruva with dietary protein restriction and, in some cases, amino acid supplementation (e.g., essential amino acids, arginine, citrulline, and protein-free calorie supplements). if a dose is missed, take the missed dose as soon as possible on the same day. 2.2 dosage administration and monitoring monitor plasma ammonia levels to determine the need for dosage adjustment. adjust the olpruva dosage to maintain the plasma ammonia level within the normal range for the patient's age, taking into consideration their clinical condition (e.g., nutritional requirements, protein intake, growth parameters, etc.). monitor patients for potential neurotoxicity and obtain measurements of plasma phenylacetate and phenylacetylglutamine levels [ see warnings and precautions ( 5.1 ), adverse reactions ( 6 ) ]. if neurologic symptoms (e.g., vomiting, nausea, headache, somnolence, or confusion) are present in the absence of high ammonia levels or other incurrent illnesses, consider reducing the dose of olpruva. 2.3 dosage adjustment in patients with hepatic impairment for patients with hepatic impairment, start at the lower end of the recommended dosing range and maintain patients on the lowest dose necessary to control plasma ammonia levels [ see use in specific populations ( 8.7 ) ]. 2.4 preparation and administration instructions for oral administration only. do not administer via gastrostomy or nasogastric tubes. pour the entire contents of the mix-aid packet into approximately 4 ounces of water in a cup and stir, forming a suspension. pour the entire contents of the olpruva packet(s) into the suspension and stir. drink the entire suspension within 5 minutes after stirring to minimize dissolution of coating. after 30 minutes, the suspension should be discarded. pour another 4 ounces of water into the cup and drink to make sure that any olpruva remaining in the cup is consumed.

s: renal tubular acidosis skin and subcutaneous tissue disorders: rash laboratory adverse reactions blood and lymphatic system disorders: anemia, leukopenia and leukocytosis, thrombocytopenia, thrombocytosis hepatobiliary disorders: hyperbilirubinemia, increased blood alkaline phosphatase, increased transaminases metabolism and nutrition disorders: acidosis, alkalosis, hyperchloremia, hypophosphatemia, hyperuricemia, hyperphosphatemia, hypernatremia, hypokalemia, hypoalbuminemia, decreased total protein clinical adverse reactions with use of phenylacetate nervous system disorders: neurotoxicity was reported in cancer patients receiving intravenous phenylacetate, the major metabolite of olpruva (olpruva is not approved for intravenous use or for treatment of patients with cancer). signs and symptoms were predominately somnolence, fatigue, and dizziness (lightheadedness); less frequently reported were headache, dysgeusia, hypoacusis, disorientation, memory impairment, and exacerbation of a pre-existing neuropathy. most common adverse reactions (incidence ≥ 3%) are menstrual dysfunction, decreased appetite, body odor and bad taste or taste aversion. ( 6 ) to report suspected adverse reactions, contact acer therapeutics inc. at 1-844-600-2237 or fda at 1-800-fda-1088 or www.fda.gov/medwatch.

is used concomitantly with olpruva [ see dosage and administration ( 2.2 ) ].

nd 15% to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk pregnancy is a time of increased metabolic demand which increases the risk for hyperammonemic episodes when metabolic demands are not met. hyperammonemic episodes in pregnancy are associated with impaired cognition in the mother and an increased risk of maternal and fetal death. data animal data in rats, intrauterine exposure to phenylacetate produced lesions in the neonatal brain in layer 5 of the cortical pyramidal cells; dendritic spines were longer and thinner than normal and reduced in number. 8.2 lactation risk summary there are no data on the presence of sodium phenylbutyrate and its metabolite in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for olpruva and any potential adverse effects on the breastfed infant from olpruva or from the underlying maternal condition. 8.4 pediatric use the safety and effectiveness of olpruva have been established as adjunctive therapy to the standard of care, which includes dietary management, in the chronic management of pediatric patients weighing 20 kg or greater and with a body surface area 1.2 m 2 or greater, with urea cycle disorders (ucds) involving deficiencies of carbamylphosphate synthetase (cps), ornithine transcarbamylase (otc), or argininosuccinic acid synthetase (as). olpruva is not indicated for the treatment of acute hyperammonemia which can be a life-threatening medical emergency that requires rapid acting interventions to reduce plasma ammonia levels. the sodium content of olpruva has the potential to cause new-onset edema or worsening edema from salt and water retention, particularly in patients with underlying predisposing conditions [ see warnings and precautions ( 5.3 ) ]. olpruva is not approved in pediatric patients weighing less than 20 kg or in pediatric patients weighing 20 kg or greater with a bsa of less than 1.2 m 2 . neurotoxicity has been observed in juvenile animals with phenylacetate exposure [ see warnings and precautions ( 5.1 ) ]. juvenile animal toxicity data when given subcutaneously to neonatal rats, 190-474 mg/kg phenylacetate caused decreased proliferation and increased loss of neurons, and it reduced cns myelin. cerebral synapse maturation was retarded, and the number of functioning nerve terminals in the cerebrum was reduced, which resulted in impaired brain growth. 8.5 geriatric use clinical studies of olpruva did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. other reported clinical experience has not identified differences in responses between the elderly and younger patients. in general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. 8.6 renal impairment no studies with olpruva were conducted in subjects with renal impairment. monitor plasma ammonia levels when starting patients with impaired renal function on olpruva [ see clinical pharmacology ( 12 ) ]. 8.7 hepatic impairment no studies with olpruva were conducted in subjects with hepatic impairment. start at the lower end of the recommended dosing range and maintain patients with hepatic impairment on the lowest dose necessary to control plasma ammonia levels [ see clinical pharmacology ( 12 ) , dosage and administration ( 2.3 ) ].

linical considerations disease-associated maternal and/or embryo/fetal risk pregnancy is a time of increased metabolic demand which increases the risk for hyperammonemic episodes when metabolic demands are not met. hyperammonemic episodes in pregnancy are associated with impaired cognition in the mother and an increased risk of maternal and fetal death. data animal data in rats, intrauterine exposure to phenylacetate produced lesions in the neonatal brain in layer 5 of the cortical pyramidal cells; dendritic spines were longer and thinner than normal and reduced in number.

ith a bsa of less than 1.2 m 2 . neurotoxicity has been observed in juvenile animals with phenylacetate exposure [ see warnings and precautions ( 5.1 ) ]. juvenile animal toxicity data when given subcutaneously to neonatal rats, 190-474 mg/kg phenylacetate caused decreased proliferation and increased loss of neurons, and it reduced cns myelin. cerebral synapse maturation was retarded, and the number of functioning nerve terminals in the cerebrum was reduced, which resulted in impaired brain growth.

in table 1. table 1 c max and auc of phenylbutyrate and phenylacetate following a single oral dose administration of olpruva (5 g) in healthy subjects under fasted conditions pk parameters phenylbutyrate results (mean ± sd) phenylacetate results (mean ± sd) c max (μg/ml) 229 ± 48 39 ± 14 auc inf (hr•μg/ml) 510 ± 129 183 ± 76 effect of food compared to those under fasted conditions, phenylbutyrate c max was decreased by 50% and auc inf decreased by 39% when olpruva was administered with a high-fat meal (total 980 calories with 55% fat). for the metabolite phenylacetate, c max decreased by 32% and auc inf decreased by 29% with a high-fat meal compared to fasted conditions. distribution the apparent volume of distribution of phenylbutyrate was 7.2 l under fasted conditions. elimination the mean half-life of phenylbutyrate was 0.5 hours under fasted conditions. the mean half-life of phenylacetate was 1.2 hours under fasted conditions. metabolism following oral administration, sodium phenylbutyrate is metabolized by β-oxidation into phenylacetate which is converted to its coenzyme a ester, phenylacetyl-coenzyme a and further conjugated with glutamine to form phenylacetylglutamine. phenylacetylglutamine is excreted by the kidneys. the major sites for metabolism of sodium phenylbutyrate are the liver and kidneys. phenylacetate is also hydrolyzed by esterases in liver and blood. excretion approximately 80-100% of sodium phenylbutyrate is excreted by the kidneys within 24 hours as phenylacetylglutamine. for each gram of sodium phenylbutyrate administered, it is estimated that between 0.12-0.15 grams of phenylacetylglutamine nitrogen are produced. specific populations patients with renal impairment or hepatic impairment olpruva has not been studied in patients with renal impairment or in patients with hepatic impairment. drug interaction studies in vitro or clinical studies with olpruva for determination of potential drug-drug interaction have not been conducted.

inistered with a high-fat meal (total 980 calories with 55% fat). for the metabolite phenylacetate, c max decreased by 32% and auc inf decreased by 29% with a high-fat meal compared to fasted conditions. distribution the apparent volume of distribution of phenylbutyrate was 7.2 l under fasted conditions. elimination the mean half-life of phenylbutyrate was 0.5 hours under fasted conditions. the mean half-life of phenylacetate was 1.2 hours under fasted conditions. metabolism following oral administration, sodium phenylbutyrate is metabolized by β-oxidation into phenylacetate which is converted to its coenzyme a ester, phenylacetyl-coenzyme a and further conjugated with glutamine to form phenylacetylglutamine. phenylacetylglutamine is excreted by the kidneys. the major sites for metabolism of sodium phenylbutyrate are the liver and kidneys. phenylacetate is also hydrolyzed by esterases in liver and blood. excretion approximately 80-100% of sodium phenylbutyrate is excreted by the kidneys within 24 hours as phenylacetylglutamine. for each gram of sodium phenylbutyrate administered, it is estimated that between 0.12-0.15 grams of phenylacetylglutamine nitrogen are produced. specific populations patients with renal impairment or hepatic impairment olpruva has not been studied in patients with renal impairment or in patients with hepatic impairment. drug interaction studies in vitro or clinical studies with olpruva for determination of potential drug-drug interaction have not been conducted.

to 77°f); excursions permitted between 15°c and 30°c (59°f and 86°f) [see usp controlled room temperature].

on, ma 02458 for more information call acer therapeutics inc. at 1-844-600-2237. © 2022 acer therapeutics inc. all rights reserved. 65003012 acer therapeutics logo

eater with a bsa of less than 1.2 m 2 . before taking olpruva, tell your or your child's healthcare provider about all of your medical conditions, including if you: have heart problems have kidney or liver problems are pregnant or plan to become pregnant. it is not known if olpruva will harm your unborn baby. are breastfeeding or plan to breastfeed. it is not known if olpruva passes into breastmilk. talk to your healthcare provider about the best way to feed your baby during treatment with olpruva. tell your healthcare provider about all the medicines you or your child take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. certain medicines may increase the level of ammonia in your blood or cause serious side effects when taken during treatment with olpruva. especially tell your healthcare provider if you or your child take: corticosteroids valproic acid haloperidol probenecid know the medicines you take. keep a list of them to show your or your child's healthcare provider and pharmacist when you get a new medicine. how should i or my child take olpruva? read the detailed instructions for use that comes with olpruva for information about the right way to prepare and take a dose of olpruva. take olpruva exactly as prescribed by your healthcare provider. your healthcare provider may change your dose if needed. do not change your dose unless your healthcare provider tells you to. your healthcare provider will prescribe olpruva based on your or your child's weight. take your olpruva dose with food. if you miss a dose of olpruva, take it as soon as possible that same day. do not give or take olpruva through a gastrostomy or nasogastric tube. if you take too much olpruva, call your healthcare provider or go to the nearest hospital emergency room right away. what are the possible side effects of olpruva? olpruva can cause serious side effects, including: nervous system problems (neurotoxicity). call your healthcare provider right away if you or your child get any of the following symptoms during treatment with olpruva: sleepiness tiredness lightheadedness vomiting nausea headache confusion low potassium levels in your blood (hypokalemia). your healthcare provider will monitor your blood potassium levels during treatment with olpruva and treat if needed. conditions related to swelling (edema). olpruva contains salt (sodium), which can cause swelling from salt and water retention. your healthcare provider will decide if olpruva is right for you if you have certain medical conditions that cause edema, such as heart failure, liver problems or kidney problems. the most common side effects of olpruva include: absent or irregular menstrual periods decreased appetite body odor bad taste or avoiding foods that you ate prior to getting sick (taste aversion) your healthcare provider may do certain blood tests to check you or your child for side effects during treatment with olpruva. these are not all of the possible side effects of olpruva. call your doctor for medical advice about side effects. you may report side effects to fda at 1-800-fda-1088. how should i store olpruva? store olpruva at room temperature between 68°f and 77°f (20°c and 25°c). keep olpruva and all medicines out of the reach of children. general information about the safe and effective use of olpruva. medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. do not use olpruva for a condition for which it was not prescribed. do not give olpruva to other people, even if they have the same symptoms that you have. it may harm them. you can ask your pharmacist or healthcare provider for information about olpruva that is written for health professionals. what are the ingredients in olpruva? active ingredient : sodium phenylbutyrate inactive ingredients : amino methacrylate copolymer, hypromellose, microcrystalline cellulose, polyethylene glycol 6000, silicon dioxide, and talc. manufactured for: acer therapeutics inc. 300 washington st. newton, ma 02458 for more information, go to www.olpruva.com or call acer therapeutics inc. at 1-844-600-2237. © 2022 acer therapeutics inc. all rights reserved. acer therapeutics logo