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

1 ) limitations of use pheburane is not indicated for the treatment of acute hyperammonemia. ( 1 )

ion or sucrase-isomaltase insufficiency. ( 5.4 ) 5.1 neurotoxicity of phenylacetate increased exposure to phenylacetate, the major metabolite of pheburane, may be associated with neurotoxicity in patients with ucds. in a study of adult cancer patients receiving intravenous phenylacetate, 250-300 mg/kg/day 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 ) ] . pheburane 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 pheburane [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 pheburane contains 124 mg (5.4 mmol) of sodium per gram of sodium phenylbutyrate, corresponding to 2.5 g (108 mmol) of sodium in the maximum daily dose of 20 g of sodium phenylbutyrate. in order to decide if administration of pheburane 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 weight or body surface area (bsa) [see dosage and administration ( 2.1 )] . if a patient develops new-onset edema or worsening edema while on treatment, discontinue administration of pheburane and initiate appropriate therapy. 5.4 diabetes mellitus, hereditary fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency pheburane contains 768 mg of sucrose per gram of sodium phenylbutyrate, corresponding to 15.4 g of sucrose in the maximum daily dose of 20 g of sodium phenylbutyrate. this should be considered in patients with diabetes mellitus. avoid use of pheburane in patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency.

g/day of sodium phenylbutyrate orally. divide the calculated total daily dose into three to six doses. administer as three to six divided doses and take with food. patients weighing greater than or equal to 20 kg: 9.9 – 13 g/m 2 /day of sodium phenylbutyrate orally. divide the calculated total daily dose into three to six doses. administer as three to six divided doses and take with food. the maximum dosage is 20 grams per day. combine pheburane with dietary protein restriction and, in some cases, amino acid supplementation (e.g., essential amino acids, arginine, citrulline, and protein-free calorie supplements). measure the dose using only the calibrated spoon provided in the packaging. this calibrated dosing spoon directly measures pheburane oral pellets as sodium phenylbutyrate [see dosage and administration ( 2.4 ) ] . if a dose is missed, take the missed dose as soon as possible. there should be at least 3 hours between two doses and doses should not be doubled to make up for the missed dose. 2.2 dosage adjustment and monitoring monitor plasma ammonia levels to determine the need for dosage adjustment. adjust the pheburane 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 intercurrent illnesses, consider reducing the dose of pheburane. 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 administration instructions for oral administration only. administration via gastrostomy or nasogastric tubes has not been evaluated. schedule pheburane dosages at the same time as food consumption (meal or snack). use the calibrated dosing spoon to measure pheburane oral pellets. the dosing spoon is directly calibrated in grams of sodium phenylbutyrate. swallow the coated oral pellets with a drink (e.g., water, fruit juices, protein-free infant formulas) or sprinkle onto spoonful of apple sauce or carrot puree. do not chew pheburane oral pellets directly or mix into liquids. swallow immediately to minimize dissolution of coating. administration of pheburane oral pellets with other foods has not been studied and is not recommended. additionally, administration with soft food is only recommended in patients old enough to consume soft foods.

on renal and urinary disorders : 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, hyperchloraemia, hypophosphataemia, 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 pheburane (pheburane 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 medunik usa, inc. at 1-844-884-5520 or fda at 1-800-fda-1088 or www.fda.gov/medwatch .

enecid is used concomitantly with pheburane [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 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 pheburane and any potential adverse effects on the breastfed infant from pheburane or from the underlying maternal condition. 8.4 pediatric use the safety and effectiveness of pheburane have been established as adjunctive therapy to the standard of care, which includes dietary management, in the chronic management of pediatric patients with urea cycle disorders (ucds), involving deficiencies of carbamylphosphate synthetase (cps), ornithine transcarbamylase (otc) or argininosuccinic acid synthetase (as). pheburane 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 pheburane 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 )] . neurotoxicity has been observed in juvenile animals with phenylacetate exposure [see warnings and precautions ( 5.1 )] . juvenile animal toxicity data when given subcutaneously to rat pups, 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 pheburane 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 pheburane were conducted in subjects with renal impairment. monitor plasma ammonia levels when starting patients with impaired renal function on pheburane [see clinical pharmacology ( 12 )] . 8.7 hepatic impairment no studies with pheburane 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 ( 12.3 ), 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 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.

0–474 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.

ea under the plasma concentration-time curve (auc) of phenylbutyrate ranged from 272 (78) to 283 (68) h*μg/ml. effect of food compared to fasted condition, auc of phenylbutyrate decreased by 40-45% and c max of phenylbutyrate decreased by 55%, when pheburane was administered with a high-fat, high-calorie meal (total 800 to 1000 calories with approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively). when pheburane was administered with a normal-fat, normal-calorie, low-protein meal (total 600 to 700 calories with approximately 60, 200, and 400 calories from protein, fat, and carbohydrate, respectively), auc of phenylbutyrate decreased by 56-63% and cmax decreased by 43-45% compared to fasted condition. elimination the mean half-life of phenylbutyrate ranged from 0.5 to 0.8 hour. 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 hydrolysed 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 pheburane has not been studied in patients with renal impairment or in patients with hepatic impairment. drug interaction studies in vitro or clinical studies with pheburane for determination of potential drug-drug interaction have not been conducted.

rie, low-protein meal (total 600 to 700 calories with approximately 60, 200, and 400 calories from protein, fat, and carbohydrate, respectively), auc of phenylbutyrate decreased by 56-63% and cmax decreased by 43-45% compared to fasted condition. elimination the mean half-life of phenylbutyrate ranged from 0.5 to 0.8 hour. 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 hydrolysed 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 pheburane has not been studied in patients with renal impairment or in patients with hepatic impairment. drug interaction studies in vitro or clinical studies with pheburane for determination of potential drug-drug interaction have not been conducted.

two doses and doses should not be doubled to make up for the missed dose [see dosage and administration ( 2.1 )] . storage and handling advise the patient or caregiver to discard any remaining pheburane 45 days after first opening of the bottle. distributed by: medunik usa, inc. 919 conestoga road bryn mawr, pa 19010 pheburane ® is a registered trademark of lucane pharma medunik logo

ncy. are pregnant or plan to become pregnant. it is not known if pheburane will harm your unborn baby. are breastfeeding or plan to breastfeed. it is not known if pheburane passes into your breastmilk. talk to your healthcare provider about the best way to feed your baby during treatment with pheburane. 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 pheburane. 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 take pheburane? read the detailed instructions for use that comes with pheburane for information about the right way to prepare and take a dose of pheburane. take pheburane 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 pheburane based on your or your child’s weight. schedule your pheburane dose at the same time you eat a meal or snack. use the calibrated dosing spoon to measure pheburane oral pellets. pheburane oral pellets should be taken with a drink such as water, fruit juices or protein-free infant formulas, or soft food, such as apple sauce or carrot puree. it is not recommended to use other foods to take your dose of pheburane oral pellets. do not chew pheburane oral pellets directly or mix pheburane oral pellets into liquids. if you miss a dose of pheburane, take it as soon as possible. each dose of pheburane should be taken at least 3 hours apart. if you have missed a dose within 3 hours of the next dose, take only one dose the next time it is scheduled. do not give or take pheburane through a gastrotomy or nasogastric tube. if you take too much pheburane, call your healthcare provider or poison help line at 1-800-222-1222, or go to the nearest hospital emergency room right away. what are the possible side effects of pheburane? pheburane can cause serious side effects, including: nervous system problems (neurotoxicity). call your healthcare provider right away if get any of the following symptoms during treatment with pheburane: 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 pheburane and treat if needed. conditions related to swelling (edema). pheburane contains salt (sodium), which can cause swelling from salt and water retention. your healthcare provider will decide if pheburane is right for you if you have certain medical conditions that can cause swelling, such as heart failure, liver problems or kidney problems. the most common side effects of pheburane 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 pheburane. these are not all of the possible side effects of pheburane. 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 pheburane? store pheburane at room temperature between 68°f and 77°f (20°c and 25°c). pheburane comes in a child-resistant bottle. the bottle cap contains a desiccant to help keep pheburane dry. throw away (discard) any remaining pheburane 45 days after first opening of the bottle. keep pheburane and all medicines out of the reach of children. general information about the safe and effective use of pheburane. medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. do not use pheburane for a condition for which it was not prescribed. do not give pheburane to other people, even if they have the same symptoms that you have. it may harm them. you can ask your healthcare provider or pharmacist for information about pheburane that is written for health professionals. what are the ingredients in pheburane? active ingredient: sodium phenylbutyrate inactive ingredients: ethylcellulose, hypromellose, polyethylene glycol 1500, povidone k25, and sugar spheres. distributed by: medunik usa, inc., 919 conestoga road, bryn mawr, pa, 19010 for more information, go to www.medunikusa.com this patient information has been approved by the u.s. food and drug administration. issued: june 2022