LABORATORY TESTS SECTION.

Laboratory Tests: Plasma levels of ammonia, arginine, branched-chain amino acids, and serum proteins should be maintained within normal limits, and plasma glutamine should be maintained at levels less than 1,000 mcmol/L. Serum drug levels of phenylbutyrate and its metabolites, phenylacetate and phenylacetylglutamine, should be monitored periodically.

NURSING MOTHERS SECTION.

Nursing Mothers:. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when sodium phenylbutyrate is administered to nursing woman.

OVERDOSAGE SECTION.

OVERDOSAGE Overdoses of sodium phenylbutyrate exceeding ten-fold the maximum recommended dosage may produce emesis, CNS depression, metabolic acidosis with or without respiratory alkalosis, hypernatremia, hypokalemia, and hypophosphatemia. Symptoms of overdose overlap with those of acute hyperammonemia. If overdose occurs, discontinue sodium phenylbutyrate, monitor plasma phenylacetate and ammonia levels closely, and institute appropriate emergency management, which may include hemodialysis, continuous veno-venous hemofiltration (CVVH), or extracorporeal membrane oxygenation (ECMO).

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL . bottlelabel.

PEDIATRIC USE SECTION.

Pediatric Use: The use of tablets for neonates, infants and children to the weight of 20 kg is not recommended (see Dosage and Administration).

ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS The assessment of clinical adverse events came from 206 patients treated with sodium phenylbutyrate. Adverse events (both clinical and laboratory) were not collected systematically in these patients, but were obtained from patient visit reports by the 65 co-investigators. Causality of adverse effects is sometimes difficult to determine in this patient population because they may result from either the underlying disease, the patients restricted diet, intercurrent illness, or sodium phenylbutyrate. Furthermore, the rates may be underestimated because they were reported primarily by parent or guardian and not the patient.Clinical Adverse EventsIn female patients, the most common clinical adverse event reported was amenorrhea/menstrual dysfunction (irregular menstrual cycles), which occurred in 23% of the menstruating patients.Decreased appetite occurred in 4% of all patients. Body odor (probably caused by the metabolite, phenylacetate) and bad taste or taste aversion 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 acidosisPsychiatric: depression Skin: rashMiscellaneous: headache, syncope, and weight gainNeurotoxicity 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 pre-existing neuropathy. These adverse events were mainly mild in severity. The acute onset and reversibility when the phenylacetate infusion was discontinued suggest 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity, mutagenicity, and fertility studies of sodium phenylbutyrate have not been conducted.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY Sodium phenylbutyrate is pro-drug and is rapidly metabolized to phenylacetate. Phenylacetate is metabolically active compound that conjugates with glutamine via acetylation to form phenylacetylglutamine. Phenylacetylglutamine then is excreted by the kidneys. On molar basis, it is comparable to urea (each containing two moles of nitrogen). Therefore, phenylacetylglutamine provides an alternate vehicle for waste nitrogen excretion.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS Sodium phenylbutyrate tablets should not be used to manage acute hyperammonemia, which is medical emergency.

DESCRIPTION SECTION.

DESCRIPTION. Sodium Phenylbutyrate Tablets, USP for oral administration contain sodium phenylbutyrate, USP. Sodium phenylbutyrate is white to yellowish-white powder which is freely soluble in water and has strong salty taste. Sodium phenylbutyrate also is freely soluble in methanol, sparingly soluble in ethanol and practically insoluble in methylene chloride, acetone and diethyl ether. It is known chemically as 4-phenylbutyric acid, sodium salt with molecular weight of 186.18 g/mol and the molecular formula C10H11O2Na.Chemical Structure:Each tablet of sodium phenylbutyrate tablets, USP contains 500 mg of sodium phenylbutyrate, USP and the inactive ingredients calcium stearate, colloidal silicon dioxide, magnesium stearate and microcrystalline cellulose. FDA approved dissolution specifications differs from the USP.. structure.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION For oral use only.The use of sodium phenylbutyrate tablets is indicated for children weighing more than 20 kg and for adults.The usual total daily dose of sodium phenylbutyrate tablets for patients with urea cycle disorders is 450 to 600 mg/kg/day in patients weighing less than 20 kg, or 9.9 to 13.0 g/m2/day in larger patients. The tablets is to be taken in equally divided amounts with each meal or feeding (i.e., three to six times per day).The safety or efficacy of doses in excess of 20 grams (40 tablets) per day has not been established.

GENERAL PRECAUTIONS SECTION.

General: Sodium phenylbutyrate tablets should not be administered to patients with known hypersensitivity to sodium phenylbutyrate or any component of this preparation.There have been published reports of hyperammonemia being induced by haloperidol and by valproic acid.Neurotoxicity of phenylacetate in animals:When given subcutaneously to rat pups, 190 to 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. Prenatal exposure of rat pups to phenylacetate produced lesions in layer of the cortical pyramidal cells; dendritic spines were longer and thinner than normal and reduced in number.

HOW SUPPLIED SECTION.

HOW SUPPLIED Sodium Phenylbutyrate Tablets, USP are available in 300 cc bottles which contain 250 sodium phenylbutyrate tablets, USP (NDC 68462-853-20). The bottles are equipped with child-resistant caps. Each tablet is off-white, oval shaped, and debossed with G853 on one side and plain on the other side. Each tablet contains 500 mg of sodium phenylbutyrate, USP. Store at 20oC to 25oC (68oF to 77oF); excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature]. AFTER OPENING, KEEP BOTTLE TIGHTLY CLOSED. Preserve in tight containers.All trademarks are the property of their respective owners.Manufactured by:Glenmark Pharmaceuticals LimitedPithampur, Madhya Pradesh 454775, India Manufactured for:Glenmark Pharmaceuticals Inc., USA Mahwah, NJ 07430Questions (888) 721-7115www.glenmarkpharma-us.comAugust 2022. logo.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE Sodium phenylbutyrate tablets are indicated as adjunctive therapy in the chronic management of patients with urea cycle disorders involving deficiencies of carbamylphosphate synthetase (CPS), ornithine transcarbamylase (OTC), or argininosuccinic acid synthetase (AS). It is indicated in all patients with neonatal-onset deficiency (complete enzymatic deficiency, presenting within the first 28 days of life). It is also indicated in patients with late-onset disease (partial enzymatic deficiency, presenting after the first month of life) who have history of hyperammonemic encephalopathy. It is important that the diagnosis be made early and treatment initiated immediately to improve survival. Any episode of acute hyperammonemia should be treated as life-threatening emergency.Sodium phenylbutyrate tablets must be combined with dietary protein restriction and, in some cases, essential amino acid supplementation (see Nutritional Supplementation subsection of the DOSAGE 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 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 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 IQs in the average to low average/borderline mentally retarded range. Reversal of preexisting 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 lifelong unless orthotopic liver transplantation is elected.(See CLINICAL PHARMACOLOGY, Pharmacodynamics subsection for the biochemical effects of sodium phenylbutyrate tablets).

INFORMATION FOR PATIENTS SECTION.

Information for Patients: The full text of the separate insert of information for patients is reprinted at the end of the labeling.

PHARMACOKINETICS SECTION.

PHARMACOKINETICS General:Pharmacokinetic studies have not been conducted in the primary patient population (neonates, infants, and children), but pharmacokinetic data were obtained from normal adult subjects.Absorption:Peak plasma levels of phenylbutyrate occur within hour after single dose of grams of sodium phenylbutyrate tablet with Cmax of 218 mcg/mL under fasting conditions. The effect of food on phenylbutyrates absorption is unknown.Disposition:The overall disposition of sodium phenylbutyrate and its metabolites has not been characterized fully. However, the drug is known to be metabolized to phenylacetate and subsequently to phenylacetylglutamine. Following oral administration of 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 Cmax (mcg/mL), Tmax (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 decreased 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 Cmax), 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.

PRECAUTIONS SECTION.

PRECAUTIONS General: Sodium phenylbutyrate tablets should not be administered to patients with known hypersensitivity to sodium phenylbutyrate or any component of this preparation.There have been published reports of hyperammonemia being induced by haloperidol and by valproic acid.Neurotoxicity of phenylacetate in animals:When given subcutaneously to rat pups, 190 to 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. Prenatal exposure of rat pups to phenylacetate produced lesions in layer of the cortical pyramidal cells; dendritic spines were longer and thinner than normal and reduced in number.. Information for Patients: The full text of the separate insert of information for patients is reprinted at the end of the labeling.. Laboratory Tests: Plasma levels of ammonia, arginine, branched-chain amino acids, and serum proteins should be maintained within normal limits, and plasma glutamine should be maintained at levels less than 1,000 mcmol/L. Serum drug levels of phenylbutyrate and its metabolites, phenylacetate and phenylacetylglutamine, should be monitored periodically.. Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity, mutagenicity, and fertility studies of sodium phenylbutyrate have not been conducted.. Pregnancy:. Animal reproduction studies have not been conducted with sodium phenylbutyrate. It is also not known whether sodium phenylbutyrate can cause fetal harm when administered to pregnant woman or can affect reproduction capacity.Sodium phenylbutyrate should be given to pregnant woman only if clearly needed.. Nursing Mothers:. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when sodium phenylbutyrate is administered to nursing woman.. Pediatric Use: The use of tablets for neonates, infants and children to the weight of 20 kg is not recommended (see Dosage and Administration).

PREGNANCY SECTION.

Pregnancy:. Animal reproduction studies have not been conducted with sodium phenylbutyrate. It is also not known whether sodium phenylbutyrate can cause fetal harm when administered to pregnant woman or can affect reproduction capacity.Sodium phenylbutyrate should be given to pregnant woman only if clearly needed.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT PACKAGE INSERT: Sodium Phenylbutyrate (SOE-dee-um fen-il-BUE-ti-rate) Tablets, USPWhat is the most important information should know about sodium phenylbutyrate tabletsSodium phenylbutyrate tablets are prescribed along with changes in diet for long-term treatment of urea cycle disorders. Sodium phenylbutyrate tablets can only be obtained with prescription from your doctor.Sodium phenylbutyrate tablets must be taken exactly as the doctor prescribes; do not increase or decrease the dose of this medication without the doctors approval.What are urea cycle disordersUrea cycle disorders include group of diseases, each having specific liver enzyme deficiency. Because they are inherited, other family members may be affected. These disorders vary in severity and may be first detected at various ages, from newborn infants to adults. They lead to increased amounts of ammonia in the blood, which may cause disturbed brain function and severe brain damage. Typical signs of the disease 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 medical emergency. An infection can cause the condition to go out of control. Therefore, if fever develops, the doctor should be seen immediately. patient or carrier of these disorders should wear Medic Alert tag stating the diagnosis. In the event that the patient has 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 particular patients 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 are sodium phenylbutyrate tabletsSodium phenylbutyrate tablets is 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 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 lifelong therapy or as temporary measure until liver transplantation is performed.What diet should or my child followIn addition to taking sodium phenylbutyrate tablets, it is equally important that prescribed diet be followed. Because there is great variability in the severity of urea cycle disorders, each patients diet should be custom designed by physician and nutritionist. Because the diet is so important, it is recommended that the prescribed diet be discussed with nutritionist who is familiar with urea cycle disorders.Who should not take sodium phenylbutyrate tabletsSodium phenylbutyrate tablets are prescribed only for patients with urea cycle disorders. It is not to be used for any other reason. Keep the medication in safe place where children cannot reach it.What other medical conditions may also be present that could increase the risk of taking sodium phenylbutyrate tabletsHeart 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 or my child take sodium phenylbutyrate tabletsThe dose of sodium phenylbutyrate tablets prescribed for adults and children is based upon the patients weight or size. It is very important that the full amount prescribed for any 24-hour period be taken. If 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 or my child avoid or be cautious of taking while on sodium phenylbutyrate tabletsPatients with urea cycle disorders usually should not take Depakene(R) (valproic acid), drug sometimes prescribed for seizure disorders, or Haldol(R) (haloperidol), 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 drugProbenecid, 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 tabletsThe 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, 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 side effects. You may report side effects to FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.How should sodium phenylbutyrate tablets be storedSodium phenylbutyrate tablets should be stored in tightly closed bottle at room temperature.This leaflet provides 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 doctors instructions. For more complete information, consult your physician, or call at (888) 721-7115 or write Glenmark Pharmaceuticals Inc., USA, Mahwah, NJ 07430.All trademarks are the property of their respective owners.Manufactured by:Glenmark Pharmaceuticals LimitedPithampur, Madhya Pradesh 454775, India Manufactured for:Glenmark Pharmaceuticals Inc., USA Mahwah, NJ 07430Questions (888) 721-7115www.glenmarkpharma-us.comAugust 2022. glenmarklogo.

WARNINGS SECTION.

WARNINGS Each sodium phenylbutyrate tablet contains 62 mg of sodium (9.2% w/w) (corresponding to 124 mg of sodium per gram of sodium phenylbutyrate [12.4% w/w]). Sodium phenylbutyrate should be used with great care, if at all, in patients with congestive heart failure or severe renal insufficiency, and in clinical states in which there is sodium retention with edema.Because sodium phenylbutyrate is metabolized in the liver and kidney, and phenylacetylglutamine is primarily excreted by the kidney, use caution when administering the drug to patients with hepatic or renal insufficiency or inborn errors of beta oxidation. Probenecid is known to inhibit the renal transport of many organic compounds, including hippuric acid, and may affect renal excretion of the conjugated product of sodium phenylbutyrate as well as its metabolite.Use of corticosteroids may cause the breakdown of body protein and increase plasma ammonia levels.