and administration section.) previously, neonatal-onset disease was almost universally fatal within the first year of life, even when treated with peritoneal dialysis and essential amino acids or their nitrogen-free analogs. however, with hemodialysis, use of alternative waste nitrogen excretion pathways (sodium phenylbutyrate, sodium benzoate, and sodium phenylacetate), dietary protein restriction, and, in some cases, essential amino acid supplementation, the survival rate in newborns diagnosed after birth but within the first month of life is almost 80%. most deaths have occurred during an episode of acute hyperammonemic encephalopathy. patients with neonatal-onset disease have a high incidence of mental retardation. those who had iq tests administered had an incidence of mental retardation as follows: ornithine transcarbamylase deficiency, 100% (14/14 patients tested); argininosuccinic acid synthetase deficiency, 88% (15/17 patients tested); and carbamylphosphate synthetase deficiency, 57% (4/7 patients tested). retardation was severe in the majority of the retarded patients. in patients diagnosed during gestation and treated prior to any episode of hyperammonemic encephalopathy, survival is 100%, but even in these patients, most subsequently demonstrate cognitive impairment or other neurologic deficits. in late-onset deficiency patients, including females heterozygous for ornithine transcarbamylase deficiency, who recover from hyperammonemic encephalopathy and are then treated chronically with sodium phenylbutyrate tablets and dietary protein restriction, the survival rate is 98%. the two deaths in this group of patients occurred during episodes of hyperammonemic encephalopathy. however, compliance with the therapeutic regimen has not been adequately documented to allow evaluation of the potential for sodium phenylbutyrate tablets and dietary protein restriction to prevent mental deterioration and recurrence of hyperammonemic encephalopathy if carefully adhered to. the majority of these patients tested (30/46 or 65%) have iq's in the average to low average/borderline mentally retarded range. reversal of pre-existing neurologic impairment is not likely to occur with treatment and neurologic deterioration may continue in some patients. even on therapy, acute hyperammonemic encephalopathy recurred in the majority of patients for whom the drug is indicated. sodium phenylbutyrate tablets may be required life-long unless orthotopic liver transplantation is elected. (see clinical pharmacology , pharmacodynamics subsection for the biochemical effects of sodium phenylbutyrate tablets).

of sciences, 1989. the allocation of dietary nitrogen into natural protein and essential amino acids is a function of age, residual urea-cycle enzyme activity, and the dose of sodium phenylbutyrate. at the recommended dose of sodium phenylbutyrate, it is suggested that infants with neonatal-onset cps and otc deficiencies initially receive a daily dietary protein intake limited to approximately 1.6 g/kg/day for the first 4 months of life. if tolerated, the daily protein intake may be increased to 1.9 g/kg/day during this period. protein tolerance will decrease as the growth rate decreases, requiring a reduction in dietary nitrogen intake. from 4 months to 1 year of age, it is recommended that the infant receive at least 1.4 g/kg/day, but 1.7 g/kg/day is advisable. from 1 to 3 years of age, the protein intake should not be less than 1.2 g/kg/day; 1.4 g/kg/day is advisable during this period. for neonatal-onset patients with carbamylphosphate synthetase deficiency or ornithine transcarbamylase deficiency who are at least 6 months of age, it is recommended that the daily protein intake be equally divided between natural protein and supplemental essential amino acids. patients with argininosuccinic acid synthetase deficiency and those with late-onset disease (partial deficiencies, including females heterozygous for ornithine transcarbamylase), initially may receive a diet containing the age-determined minimal daily natural protein allowance. the protein intake may be increased as tolerated and determined by plasma glutamine and other amino acid levels. however, many patients with partial deficiencies avoid dietary protein. citrulline supplementation is required and recommended for patients diagnosed with neonatal-onset deficiency of carbamylphosphate synthetase or ornithine transcarbamylase; citrulline daily intake is recommended at 0.17 g/kg/day or 3.8 g/m 2 /day. the free-base form of arginine may be used instead of citrulline in patients with milder forms of carbamylphosphate synthetase and ornithine transcarbamylase deficiency (daily intake is recommended at 0.17 g/kg/day or 3.8 g/m 2 /day). arginine supplementation is needed for patients diagnosed with deficiency of argininosuccinic acid synthetase; arginine (free base) daily intake is recommended at 0.4 to 0.7 g/kg/day or 8.8 to 15.4 g/m 2 /day. if caloric supplementation is indicated, a protein-free product is recommended. caloric intake should be based upon the "recommended dietary allowances", 10th ed., food and nutrition board, national research council, national academy of sciences, 1989.

on were each reported in 3% of patients. other adverse events reported in 2% or fewer patients were: gastrointestinal : abdominal pain, gastritis, nausea and vomiting; constipation, rectal bleeding, peptic ulcer disease, and pancreatitis each occurred in one patient. hematologic : aplastic anemia and ecchymoses each occurred in one patient. cardiovascular : arrhythmia and edema each occurred in one patient. renal : renal tubular acidosis psychiatric : depression skin : rash miscellaneous : headache, syncope, and weight gain neurotoxicity was reported in cancer patients receiving intravenous phenylacetate, 250 to 300 mg/kg/day for 14 days, repeated at 4-week intervals. manifestations were predominately somnolence, fatigue, and lightheadedness; with less frequent headache, dysgeusia, hypoacusis, disorientation, impaired memory, and exacerbation of a pre-existing neuropathy. these adverse events were mainly mild in severity. the acute onset and reversibility when the phenylacetate infusion was discontinued suggest a drug effect. laboratory adverse events in patients with urea cycle disorders, the frequency of laboratory adverse events by body system were: metabolic : acidosis (14%), alkalosis and hyperchloremia (each 7%), hypophosphatemia (6%), hyperuricemia and hyperphosphatemia (each 2%), and hypernatremia and hypokalemia (each 1%). nutritional : hypoalbuminemia (11%) and decreased total protein (3%). hepatic : increased alkaline phosphatase (6%), increased liver transaminases (4%), and hyperbilirubinemia (1%). hematologic : anemia (9%), leukopenia and leukocytosis (each 4%), thrombocytopenia (3%), and thrombocytosis (1%). the clinician is advised to routinely perform urinalysis, blood chemistry profiles, and hematologic tests.

has not been characterized fully. however, the drug is known to be metabolized to phenylacetate and subsequently to phenylacetylglutamine. following oral administration of 5 grams (tablets), measurable plasma levels of phenylbutyrate and phenylacetate were detected 15 and 30 minutes after dosing, respectively, and phenylacetylglutamine was detected shortly thereafter. the pharmacokinetic parameters for phenylbutyrate for c max (mcg/ml), t max (hours), and elimination half-life (hours) were 218, 1.35, and 0.77, respectively, and for phenylacetate were 48.5, 3.74, and 1.15, respectively. the major sites for metabolism of sodium phenylbutyrate are the liver and kidney. excretion: a majority of the administered compound (approximately 80 to 100%) was excreted by the kidneys within 24 hours as the conjugation product, phenylacetylglutamine. for each gram of sodium phenylbutyrate administered, it is estimated that between 0.12 to 0.15 grams of phenylacetylglutamine nitrogen are produced. pharmacodynamics: in patients with urea cycle disorders, sodium phenylbutyrate decreases elevated plasma ammonia glutamine levels. it increases waste nitrogen excretion in the form of phenylacetylglutamine. special populations gender: significant gender differences were found in the pharmacokinetics of phenylbutyrate and phenylacetate, but not for phenylacetylglutamine. the pharmacokinetic parameters (auc and c max ), for both plasma phenylbutyrate and phenylacetate were about 30 to 50 percent greater in females than in males. hepatic insufficiency: in patients who did not have urea cycle disorders but had impaired hepatic function, the metabolism and excretion of sodium phenylbutyrate were not affected. however, this information was obtained from unvalidated, uncontrolled case studies.

e are decreased mental awareness, vomiting, combativeness, slurred speech, unstable gait, and unconsciousness. the diagnosis of urea cycle disorders requires special laboratory tests. these typical signs of the disease may recur after the diagnosis is made if the condition is not under control. if they do, the doctor should be notified immediately because this is a medical emergency. an infection can cause the condition to go out of control. therefore, if a fever develops, the doctor should be seen immediately. a patient or carrier of these disorders should wear a medic alert tag stating the diagnosis. in the event that the patient has a sudden, rapid accumulation of ammonia in the blood, and, therefore, in the brain, leading to unconsciousness, the doctor will be alerted to treat the disease properly. periodically, depending upon the severity of a particular patient's urea cycle disorder, it will be necessary to perform blood tests. these include plasma ammonia, plasma amino acid levels, and other more routine blood tests to evaluate nutritional status. what is sodium phenylbutyrate tablets? sodium phenylbutyrate tablets is a drug that helps to prevent ammonia from accumulating in the blood. sodium phenylbutyrate tablets aids the body in eliminating substances that produce ammonia. however, despite drug treatment, blood ammonia levels may become elevated periodically and there may be episodes of altered brain function in association with these ammonia elevations. patients who have disease onset as newborns have a high incidence of mental retardation. medical attention should be obtained as soon as signs appear (see above under "what are urea cycle disorders?"). sodium phenylbutyrate tablets may be used as life-long therapy or as a temporary measure until liver transplantation is performed. what diet should i or my child follow? in addition to taking sodium phenylbutyrate tablets, it is equally important that a prescribed diet be followed. because there is great variability in the severity of urea cycle disorders, each patient's diet should be custom designed by a physician and a nutritionist. because the diet is so important, it is recommended that the prescribed diet be discussed with a nutritionist who is familiar with urea cycle disorders. who should not take sodium phenylbutyrate tablets? sodium phenylbutyrate tablets is prescribed only for patients with urea cycle disorders. it is not to be used for any other reason. keep the medication in a safe place where children cannot reach it. what other medical conditions may also be present that could increase the risk of taking sodium phenylbutyrate tablets? heart failure or decreased kidney function may lead to retention of the sodium content of sodium phenylbutyrate tablets with potentially serious consequences such as worsening heart failure, high blood pressure, and swelling. if these medical conditions are present, the doctor will determine if your child should take sodium phenylbutyrate tablets. how should i or my child take sodium phenylbutyrate tablets? the dose of sodium phenylbutyrate tablets prescribed for adults and children is based upon the patient's weight or size. it is very important that the full amount prescribed for any 24-hour period be taken. if a dose is missed it should be administered as soon as possible that same day. the total daily dose should be administered in equally divided amounts with meals. what medications should i or my child avoid or be cautious of taking while on sodium phenylbutyrate tablets? patients with urea cycle disorders usually should not take depakene ® (valproic acid), a drug sometimes prescribed for seizure disorders, or haldol ® (haloperidol), a drug used to treat certain types of psychiatric or neurologic disorders. both of these drugs have been reported to increase blood ammonia levels. steroids may break down body protein, thereby increasing blood ammonia levels. the doctor should be consulted before administering medications containing steroids. what medications may affect the way the body breaks down the drug? probenecid, a medication used to treat gout, may affect the way the kidneys excrete sodium phenylbutyrate tablets (consult the doctor for details). what are the most common side effects of sodium phenylbutyrate tablets? the most common side effect reported in premenopausal women taking sodium phenylbutyrate tablets was absent or irregular menstrual periods. decreased appetite was reported in 4% of all people treated. body odor and bad taste were each reported in 3% of all patients treated. a breakdown product of sodium phenylbutyrate tablets has been associated mainly with sleepiness and light-headedness. because these symptoms may also be due to the urea cycle going out of control, a doctor should see the patient immediately if these symptoms occur, so the cause can be determined. blood tests should be performed periodically for adverse effects and for levels of medication and its breakdown products. call your doctor for medical advice about the side effects. you may report side effects to fda at 1-800-fda-1088 how should sodium phenylbutyrate tablets be stored? sodium phenylbutyrate tablets should be stored in a tightly closed bottle at room temperature. this leaflet provides a brief summary of the information available on sodium phenylbutyrate tablets . the information here is incomplete and is not designed to take the place of your doctor's instructions. for more complete information, consult your physician or call or write par pharmaceutical companies, inc. one ram ridge road, chestnut ridge, new york 10977. call toll free 1-800-828-9393. distributed by: par pharmaceutical companies, inc. chestnut ridge, ny 10977 u.s.a. manufactured by: par formulations private limited, 9/215, pudupakkam, kelambakkam – 603 103 made in india mfg. lic. no.: tn00002121 os170-01-74-01 issued: 06/2017