Glycerol Phenylbutyrate

1 INDICATIONS AND USAGE Glycerol phenylbutyrate oral liquid is indicated for use as a nitrogen-binding agent for chronic management of patients with urea cycle disorders (UCDs) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. Glycerol phenylbutyrate oral liquid must be used with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements). Limitations of Use: Glycerol phenylbutyrate oral liquid is not indicated for the treatment of acute hyperammonemia in patients with UCDs because more rapidly acting interventions are essential to reduce plasma ammonia levels. The safety and efficacy of glycerol phenylbutyrate oral liquid for the treatment of N-acetylglutamate synthase (NAGS) deficiency has not been established. Glycerol phenylbutyrate oral liquid is a nitrogen-binding agent indicated for chronic management of patients with urea cycle disorders (UCDs) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. Glycerol phenylbutyrate oral liquid must be used with dietary protein restriction and, in some cases, dietary supplements. ( 1 ) Limitations of Use: Glycerol phenylbutyrate oral liquid is not indicated for treatment of acute hyperammonemia in patients with UCDs. ( 1 ) Safety and efficacy for treatment of N -acetylglutamate synthase (NAGS) deficiency has not been established. ( 1 )

2 DOSAGE AND ADMINISTRATION Glycerol phenylbutyrate oral liquid should be prescribed by a physician experienced in management of UCDs. For administration and preparation, see full prescribing information. ( 2.1 , 2.6 ) Switching From Sodium Phenylbutyrate Tablets or Powder to Glycerol Phenylbutyrate Oral Liquid: Patients should receive the dosage of glycerol phenylbutyrate that contains the same amount of phenylbutyric acid, see full prescribing information for conversion. ( 2.2 ) Initial Dosage in Phenylbutyrate-Naïve Patients ( 2.3 ): Recommended dosage range is 4.5 to 11.2 mL/m 2 /day (5 to 12.4 g/m 2 /day). For patients with some residual enzyme activity not adequately controlled with dietary restriction, the recommended starting dose is 4.5 mL/m 2 /day. Take into account patient's estimated urea synthetic capacity, dietary protein intake, and diet adherence. Dosage Adjustment and Monitoring: Follow plasma ammonia levels to determine the need for dosage titration. ( 2.4 ) Dosage Modifications in Patients with Hepatic Impairment: Start dosage at lower end of range. ( 2.5 , 8.7 ) 2.1 Important Administration Instructions Glycerol phenylbutyrate oral liquid should be prescribed by a physician experienced in the management of UCDs. Instruct patients to take glycerol phenylbutyrate oral liquid with food or formula and to administer directly into the mouth via oral syringe. Instruct patients to use the glycerol phenylbutyrate oral liquid bottle and oral syringe as follows: Use a new reclosable bottle cap adapter with each new bottle that is opened. Open the glycerol phenylbutyrate oral liquid bottle and twist on the new reclosable bottle cap adapter. Use a new and dry oral syringe to withdraw each prescribed dose of glycerol phenylbutyrate oral liquid. Discard the oral syringe after each dose. Tightly close the tethered tab on the reclosable bottle cap adapter after each use. Do not rinse the reclosable bottle cap adapter. Discard bottle and any remaining contents 28 days after opening. If water or moisture enters the glycerol phenylbutyrate oral liquid bottle, the contents will become cloudy in appearance. If the contents of the bottle appear cloudy at any time, do not use the remaining glycerol phenylbutyrate oral liquid in the bottle and return it to the pharmacy to be discarded. Instruct that glycerol phenylbutyrate oral liquid should be administered just prior to breastfeeding in infants who are breastfeeding. For patients who cannot swallow, see the instructions on administration of glycerol phenylbutyrate oral liquid by nasogastric tube or gastrostomy tube [see Dosage and Administration ( 2.6 )] . For patients who require a volume of less than 1 mL per dose via nasogastric or gastrostomy tube, the delivered dose may be less than anticipated. Closely monitor these patients using ammonia levels [see Dosage and Administration ( 2.6 )] . The recommended dosages for patients switching from sodium phenylbutyrate to glycerol phenylbutyrate oral liquid and patients naïve to phenylbutyric acid are different [see Dosage and Administration ( 2.2 , 2.3 )] . For both subpopulations: Patients 2 years of age and older: Give glycerol phenylbutyrate oral liquid in 3 equally divided dosages, each rounded up to the nearest 0.5 mL. Patients less than 2 years: Give glycerol phenylbutyrate oral liquid in 3 or more equally divided dosages, each rounded up to the nearest 0.1 mL. The maximum total daily dosage is 17.5 mL (19 g). Glycerol phenylbutyrate oral liquid must be used with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements). 2.2 Switching From Sodium Phenylbutyrate to Glycerol Phenylbutyrate Oral Liquid Patients switching from sodium phenylbutyrate to glycerol phenylbutyrate oral liquid should receive the dosage of glycerol phenylbutyrate oral liquid that contains the same amount of phenylbutyric acid. The conversion is as follows: Total …

3 DOSAGE FORMS AND STRENGTHS Oral liquid: a clear colorless to pale yellow, 1.1 g/mL of glycerol phenylbutyrate (delivers 1.02 g/mL of phenylbutyrate). Oral liquid: 1.1 g/mL. ( 3 )

4 CONTRAINDICATIONS Glycerol phenylbutyrate oral liquid is contraindicated in patients with known hypersensitivity to phenylbutyrate. Signs of hypersensitivity include wheezing, dyspnea, coughing, hypotension, flushing, nausea, and rash. Known hypersensitivity to phenylbutyrate. ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Neurotoxicity [see Warnings and Precautions ( 5.1 )] • Pancreatic insufficiency or Intestinal Malabsorption [see Warnings and Precautions ( 5.2 )] Most common adverse reactions (≥10%) in adults are: diarrhea, flatulence, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 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, 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 clinical practice. Assessment of adverse reactions was based on exposure of 45 adult patients (31 female and 14 male) with UCD subtype deficiencies of ornithine transcarbamylase (OTC, n=40), carbamoyl phosphate synthetase (CPS, n=2), and argininosuccinate synthetase (ASS, n=1) in a randomized, double-blind, active-controlled (glycerol phenylbutyrate vs sodium phenylbutyrate), crossover, 4-week study (Study 1) that enrolled patients 18 years of age and older [see Clinical Studies ( 14.1 )] . One of the 45 patients received only sodium phenylbutyrate prior to withdrawing on day 1 of the study due to an adverse reaction. The most common adverse reactions (occurring in at least 10% of patients) reported during short-term treatment with glycerol phenylbutyrate oral liquid were diarrhea, flatulence, and headache. Table 1 summarizes adverse reactions occurring in 2 or more patients treated with glycerol phenylbutyrate oral liquid or sodium phenylbutyrate (incidence of at least 4% in either treatment arm). Table 1: Adverse Reactions Reported in 2 or More Adult Patients with UCDs (at least 4% in Either Treatment Arm) in Study 1 Number (%) of Patients in Study 1 Sodium Phenylbutyrate (N = 45) Glycerol phenylbutyrate oral liquid (N = 44) Diarrhea 3 (7) 7 (16) Headache 4 (9) 6 (14) Flatulence 1 (2) 6 (14) Abdominal pain 2 (4) 3 (7) Vomiting 2 (4) 3 (7) Decreased appetite 2 (4) 3 (7) Fatigue 1 (2) 3 (7) Dyspepsia 3 (7) 2 (5) Nausea 3 (7) 1 (2) Dizziness 4 (9) 0 Abdominal discomfort 3 (7) 0 Other Adverse Reactions Glycerol phenylbutyrate oral liquid has been evaluated in 77 patients with UCDs (51 adult and 26 pediatric patients ages 2 years to 17 years) in 2 open-label long-term studies, in which 69 patients completed 12 months of treatment with glycerol phenylbutyrate oral liquid (median exposure = 51 weeks). During these studies there were no deaths. Adverse reactions reported in at least 10% of adult patients were nausea, vomiting, diarrhea, decreased appetite, dizziness, headache, and fatigue. Adverse reactions reported in at least 10% of pediatric patients ages 2 years to 17 years were upper abdominal pain, rash, nausea, vomiting, diarrhea, decreased appetite, and headache. Glycerol phenylbutyrate oral liquid has been evaluated in 17 patients with UCDs ages 2 months to less than 2 years in 3 open-label studies. The median exposure was 6 months (range 0.2 to 20 months). Adverse reactions reported in at least 10% of pediatric patients aged 2 months to less than 2 years were neutropenia, vomiting, constipation, diarrhea, pyrexia, hypophagia, cough, nasal congestion, rhinorrhea, rash, and papule. Glycerol phenylbutyrate oral liquid has been evaluated in 16 patients with UCDs less than 2 months of age (age range 0.1 to 2 months, median age 0.5 months) in a single, open-label study. The median exposure was 10 months (range 2 to 20 months). Adverse reactions reported in at least 10% of pediatric patients aged less than 2 months were vomiting, rash, gastroesophageal reflux, increased hepatic enzymes, feeding disorder (decreased appetite, hypophagia), anemia, cough, dehydration, metabolic acidosis, thrombocytosis, thrombocytopenia, neutropenia, lymphocytosis, diarrh …

7 DRUG INTERACTIONS Corticosteroids, valproic acid, or haloperidol : May increase plasma ammonia level; monitor ammonia levels closely. ( 7.1 ) Probenecid : May affect renal excretion of metabolites of glycerol phenylbutyrate oral liquid, including phenylacetylglutamine (PAGN) and PAA. ( 7.2 ) CYP3A4 Substrates with narrow therapeutic index (e.g., alfentanil, quinidine, cyclosporine) : Glycerol phenylbutyrate oral liquid may decrease exposure; monitor for decreased efficacy of the narrow therapeutic index drug. ( 7.3 ) Midazolam : Decreased exposure; monitor for suboptimal effect of midazolam. ( 7.3 ) 7.1 Potential for Other Drugs to Affect Ammonia Corticosteroids Use of corticosteroids may cause the breakdown of body protein and increase plasma ammonia levels. Monitor ammonia levels closely when corticosteroids and glycerol phenylbutyrate oral liquid are used concomitantly. Valproic Acid and Haloperidol Hyperammonemia may be induced by haloperidol and by valproic acid. Monitor ammonia levels closely when use of valproic acid or haloperidol is necessary in patients with UCDs. 7.2 Potential for Other Drugs to Affect Glycerol Phenylbutyrate Oral Liquid Probenecid Probenecid may inhibit the renal excretion of metabolites of glycerol phenylbutyrate oral liquid including PAGN and PAA. 7.3 Potential for Glycerol Phenylbutyrate Oral Liquid to Affect Other Drugs Drugs with narrow therapeutic index that are substrates of CYP3A4 Glycerol phenylbutyrate oral liquid is a weak inducer of CYP3A4 in humans. Concomitant use of glycerol phenylbutyrate oral liquid may decrease the systemic exposure to drugs that are substrates of CYP3A4. Monitor for decreased efficacy of drugs with narrow therapeutic index (e.g., alfentanil, quinidine, cyclosporine) [see Clinical Pharmacology ( 12.3 )] . Midazolam Concomitant use of glycerol phenylbutyrate oral liquid decreased the systemic exposure of midazolam. Monitor for suboptimal effect of midazolam in patients who are being treated with glycerol phenylbutyrate oral liquid.

8 USE IN SPECIFIC POPULATIONS Lactation : Breastfeeding is not recommended. ( 8.2 ) 8.1 Pregnancy Risk Summary Limited available data with glycerol phenylbutyrate oral liquid use in pregnant women are insufficient to inform a drug-associated risk of major birth defects and miscarriage. In an animal reproduction study, administration of oral glycerol phenylbutyrate to pregnant rabbits during organogenesis at doses up to 2.7– times the dose of 6.87 mL/m 2 /day in adult patients resulted in maternal toxicity, but had no effects on embryo-fetal development. In addition, there were no adverse developmental effects with administration of oral glycerol phenylbutyrate to pregnant rats during organogenesis at 1.9 times the dose of 6.87 mL/m 2 /day in adult patients; however, maternal toxicity, reduced fetal weights, and variations in skeletal development were observed in pregnant rats administered oral glycerol phenylbutyrate during organogenesis at doses greater than or equal to 5.7 times the dose of 6.87 mL/m 2 /day in adult patients [see Data] . Report pregnancies to Teva at 1-888-838-2872. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. 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. Data Animal Data Oral administration of glycerol phenylbutyrate during the period of organogenesis up to 350 mg/kg/day in rabbits produced maternal toxicity, but no effects on embryo-fetal development. The dose of 350 mg/kg/day in rabbits is approximately 2.7 times the dose of 6.87 mL/m 2 /day in adult patients, based on combined area under the plasma concentration-time curve [AUCs] for PBA and PAA. In rats, at an oral dose of 300 mg/kg/day of glycerol phenylbutyrate (1.9 times the dose of 6.87 mL/m 2 /day in adult patients, based on combined AUCs for PBA and PAA) during the period of organogenesis, no effects on embryo-fetal development were observed. Doses of 650 mg/kg/day or greater produced maternal toxicity and adverse effects on embryo-fetal development including reduced fetal weights and cervical ribs at the 7th cervical vertebra. The dose of 650 mg/kg/day in rats is approximately 5.7 times the dose of 6.87 mL/m 2 /day in adult patients, based on combined AUCs for PBA and PAA. No developmental abnormalities, effects on growth, or effects on learning and memory were observed through maturation of offspring following oral administration in pregnant rats with up to 900 mg/kg/day of glycerol phenylbutyrate (8.5 times the dose of 6.87 mL/m 2 /day in adult patients, based on combined AUCs for PBA and PAA) during organogenesis and lactation. 8.2 Lactation Risk Summary There are no data on the presence of glycerol phenylbutyrate oral liquid in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions, including neurotoxicity and tumorigenicity in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with glycerol phenylbutyrate oral liquid. 8.4 Pediatric Use Patients 2 Years to 17 Years of Age The safety and effectiveness of glycerol phenylbutyrate oral liquid in patients 2 years to less than 18 years of age have been established in 3 clinical studies: 2 open-label, fixed-sequence, switchover clinical studies from sodium phenylbutyrate to glycerol phenylbutyrate oral liquid, and 1 long-term, open label safety study [see Adverse Reactions ( 6.1 ), Clinical Studies ( 14.2 )] . Patients Less Than 2 Years of Age The safety and effectiveness of glycerol phenylbutyrate oral liquid in patients with UCDs less than 2 years of age have been established in 3 open-label studies. Pharmacokinetics and pharmacodynamics (plasma ammonia), and safety were studied in 17 patients ag …

12.1 Mechanism of Action UCDs are inherited deficiencies of enzymes or transporters necessary for the synthesis of urea from ammonia (NH 3 , NH 4 + ). Absence of these enzymes or transporters results in the accumulation of toxic levels of ammonia in the blood and brain of affected patients. Glycerol phenylbutyrate oral liquid is a triglyceride containing 3 molecules of PBA. PAA, the major metabolite of PBA, is the active moiety of glycerol phenylbutyrate oral liquid. PAA conjugates with glutamine (which contains 2 molecules of nitrogen) via acetylation in the liver and kidneys to form PAGN, which is excreted by the kidneys (Figure 1). On a molar basis, PAGN, like urea, contains 2 moles of nitrogen and provides an alternate vehicle for waste nitrogen excretion. Figure 1: Glycerol Phenylbutyrate Oral Liquid Mechanism of Action fig. 1

11 DESCRIPTION Glycerol phenylbutyrate is a clear, colorless to pale yellow oral liquid. It is insoluble in water and most organic solvents, and it is soluble in dimethylsulfoxide (DMSO) and greater than 65% acetonitrile. Glycerol phenylbutyrate is a nitrogen-binding agent. It is a triglyceride containing 3 molecules of PBA linked to a glycerol backbone, the chemical name of which is benzenebutanoic acid, 1', 1''–(1,2,3-propanetriyl) ester with a molecular weight of 530.67. It has a molecular formula of C 33 H 38 O 6 . The structural formula is: Glycerol phenylbutyrate

10 OVERDOSAGE While there is no experience with overdosage in human clinical trials, PAA, a toxic metabolite of glycerol phenylbutyrate oral liquid, can accumulate in patients who receive an overdose [see Warnings and Precautions ( 5.1 )] . If over-exposure occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage.

16 HOW SUPPLIED/STORAGE AND HANDLING Glycerol Phenylbutyrate Oral Liquid 1.1 g/mL is supplied in multi-use, 25 mL glass bottles. The bottles are supplied in the following configurations: • NDC 31722-605-31: Single 25 mL bottle per carton • NDC 31722-605-32: Four 25 mL bottles per carton Store at 20° to 25°C (68° to 77°F), with excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Discard bottle 28 days after opening.