Glycerol Phenylbutyrate

1 INDICATIONS AND USAGE RAVICTI 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. RAVICTI 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: RAVICTI 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 RAVICTI for the treatment of N- acetylglutamate synthase (NAGS) deficiency has not been established. RAVICTI 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. RAVICTI must be used with dietary protein restriction and, in some cases, dietary supplements. ( 1 ) Limitations of Use : RAVICTI 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 RAVICTI 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 RAVICTI : Patients should receive the dosage of RAVICTI 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 RAVICTI should be prescribed by a physician experienced in the management of UCDs. Instruct patients to take RAVICTI with food or formula and to administer directly into the mouth via oral syringe. Instruct patients to use the RAVICTI bottle and oral syringe as follows: Use a new reclosable bottle cap adapter with each new bottle that is opened. Open the RAVICTI bottle and twist on the new reclosable bottle cap adapter. Use a new and dry oral syringe to withdraw each prescribed dose of RAVICTI. 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 RAVICTI bottle, the contents will become cloudy in appearance. If the contents of the bottle appear cloudy at any time, do not use the remaining RAVICTI in the bottle and return it to the pharmacy to be discarded. Instruct that RAVICTI should be administered just prior to breastfeeding in infants who are breastfeeding. For patients who cannot swallow, see the instructions on administration of RAVICTI 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 RAVICTI 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 RAVICTI in 3 equally divided dosages, each rounded up to the nearest 0.5 mL Patients less than 2 years: Give RAVICTI 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). RAVICTI 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 RAVICTI Patients switching from sodium phenylbutyrate to RAVICTI should receive the dosage of RAVICTI that contains the same amount of phenylbutyric acid. The conversion is as follows: Total daily dosage of RAVICTI (mL) = total daily dosage of sodium phenylbutyrate tablets (g) × 0.86 Total daily dosage of RAVICTI (mL) = total daily dosage of sodium phenylbutyrate powder (g) × 0.81 2.3 Initial Dosage in Phenylbutyrate-Naïve Patients The recommended dosage range, based upon body surface area, in patients naïve to phenylbutyrate (PBA) 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 who are not adequately controlled with protein restriction, the recommended starting dosage is 4.5 mL/m 2 /day. In determining the starting dosage of RAVICTI in treatment-naïve patients, consider the patient's residual urea synthetic capacity, dietary protein requirements, and diet adherence. Dietary protein is approximately 16% nitrogen by weight. Given that approximately 47% of dietary nitrogen is excreted as waste and approximately 70% of an administered PBA dose will be converted to urinary phenylacetylglutamine (U-PAGN), an initial estimated RAVICTI dose for a 24-hour period is 0.6 mL RAVICTI per gram of dietary protein ingested per 24-hour period. The total daily dosage should not exceed 17.5 mL. 2.4 Dosage Adjustment and Monitoring During treatment with RAVICTI, patients should be followed clinically and with plasma ammonia levels to determine the need for dosage titration. Closely monitor plasma ammonia levels during treatment with RAVICTI and when changing the dosage of RAVICTI. The methods used for measuring plasma ammonia levels vary among individual laboratories and values obtained using different assay methods may not be interchangeable. Normal ranges and therapeutic target levels for plasma ammonia depend upon the assay method used by the individual laboratory. During treatment with RAVICTI, refer to the assay-specific normal ranges and to the therapeutic target ranges for plasma ammonia. Normal Plasma Ammonia In patients treated with RAVICTI who experience neurologic symptoms (e.g., nausea, vomiting, headache, somnolence or confusion) in the absence of high plasma ammonia or other intercurrent illness to explain these symptoms, consider reducing the RAVICTI dosage and clinically monitor patients for potential neurotoxicity from high phenylacetate (PAA) concentrations. If available, obtain measurements of plasma PAA concentrations and plasma phenylacetylglutamine (PAGN) to calculate the ratio of plasma PAA to PAGN which may help to guide RAVICTI dosing. The PAA to PAGN ratio has generally been less than 1 in patients with UCDs who did not have significant plasma PAA accumulation. In general, a high PAA to PAGN ratio may indicate a slower or less efficient conjugation reaction to form PAGN, which may lead to increases in PAA without further conversion to PAGN [see Warnings and Precautions (5.1) , Clinical Pharmacology (12.3) ] . Elevated Plasma Ammonia In patients 6 years and older, when plasma ammonia is elevated, increase the RAVICTI dosage to maintain fasting plasma ammonia to less than half the upper limit of normal (ULN). In infants and pediatric patients below 6 years of age, if obtaining fasting ammonia is problematic due to frequent feedings, adjust the RAVICTI dosage to keep the first ammonia of the morning below the ULN for age. If available, the ratio of PAA to PAGN in the same plasma sample may provide additional information to assist in dosage adjustment decisions [see Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ] . Dietary Protein Intake If available, urinary phenylacetylglutamine (U-PAGN) measurements may be used to help guide RAVICTI dosage adjustment. Each gram of U-PAGN excreted over 24 hours covers waste nitrogen generated from 1.4 grams of dietary protein. If U-PAGN excretion is insufficient to cover daily dietary protein intake and the fasting ammonia is greater than half the ULN, the RAVICTI dosage should be increased. The amount of dosage adjustment should factor in the amount of dietary protein that has not been covered, as indicated by the 24-hour U-PAGN output, and the estimated RAVICTI dose needed per gram of dietary protein ingested and the maximum total daily dosage (i.e., 17.5 mL). Consider a patient's use of concomitant medications, such as probenecid, when making dosage adjustment decisions based on U-PAGN. Probenecid may result in a decrease of the urinary excretion of PAGN [see Drug Interactions (7.2) ] . 2.5 Dosage Modifications in Patients with Hepatic Impairment For patients with moderate to severe hepatic impairment, the recommended starting dosage is at the lower end of the recommended dosing range (4.5 mL/m 2 /day) and the dosage should be kept at the lowest necessary to control the patient's plasma ammonia [see Use in Specific Populations (8.7) ] . 2.6 Preparation for Nasogastric Tube or Gastrostomy Tube Administration It is recommended that all patients who can swallow take RAVICTI orally, even those with nasogastric and/or gastrostomy tubes. For patients who cannot swallow, a nasogastric tube or gastrostomy tube may be used to administer RAVICTI as follows: Utilize a new dry oral syringe to withdraw each prescribed dosage of RAVICTI from the bottle. Place the tip of the syringe into the nasogastric/gastrostomy tube. Utilizing the plunger of the syringe, administer RAVICTI into the tube. Use a separate syringe to flush the nasogastric/gastrostomy tube. Flush once with 10 mL of water or formula and allow the flush to drain. If needed, flush a second time with an additional 10 mL of water or formula to clear the tube. For patients who require a volume of less than 1 mL per dose via nasogastric or gastrostomy tube, the delivered dosage may be less than anticipated due to adherence of RAVICTI to the plastic tubing. Therefore, these patients should be closely monitored using ammonia levels following initiation of RAVICTI dosing or dosage adjustments.

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 Amgen Inc. at 1-800-77-AMGEN (1-800-772-6436) 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 (RAVICTI 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 RAVICTI were diarrhea, flatulence, and headache. Table 1 summarizes adverse reactions occurring in 2 or more patients treated with RAVICTI 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) RAVICTI (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 RAVICTI 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 RAVICTI (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. RAVICTI 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. RAVICTI 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, diarrhea, flatulence, constipation, pyrexia, lethargy, and irritability/agitation. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of RAVICTI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Abnormal body odor, including from skin, hair and urine Retching and gagging Dysgeusia or burning sensation in mouth

12.3 Pharmacokinetics Absorption RAVICTI is a pro-drug of PBA. Upon oral ingestion, PBA is released from the glycerol backbone in the gastrointestinal tract by lipases. PBA derived from RAVICTI is further converted by β-oxidation to PAA. In healthy, fasting adult subjects receiving a single oral dose of 2.9 mL/m 2 of RAVICTI, peak plasma levels of PBA, PAA, and PAGN occurred at 2 hours, 4 hours, and 4 hours, respectively. Upon single-dose administration of RAVICTI, plasma concentrations of PBA were quantifiable in 15 of 22 participants at the first sample time postdose (0.25 hours). Mean maximum concentration (C max ) for PBA, PAA, and PAGN was 37.0 micrograms/mL, 14.9 micrograms/mL, and 30.2 micrograms/mL, respectively. In healthy subjects, intact glycerol phenylbutyrate was detected in plasma. While the study was inconclusive, the incomplete hydrolysis of glycerol phenylbutyrate cannot be ruled out. In healthy subjects, the systemic exposure to PAA, PBA, and PAGN increased in a dose-dependent manner. Following 4 mL of RAVICTI 3 times a day for 3 days, the mean C max and AUC were 66 micrograms/mL and 930 micrograms∙h/mL for PBA and 28 micrograms/mL and 942 micrograms∙h/mL for PAA, respectively. In the same study, following 6 mL of RAVICTI three times a day for 3 days, mean C max and AUC were 100 micrograms/mL and 1400 micrograms∙h/mL for PBA and 65 µg/mL and 2064 micrograms∙h/mL for PAA, respectively. In adult patients with UCDs receiving multiple doses of RAVICTI, maximum plasma concentrations at steady state (C max,ss ) of PBA, PAA, and PAGN occurred at 8 hours, 12 hours, and 10 hours, respectively, after the first dose in the day. Intact glycerol phenylbutyrate was not detectable in plasma in patients with UCDs. In clinical studies of RAVICTI in patients with UCDs, the peak observed PAA concentrations by age group are shown in Table 2. Table 2: Peak PAA Concentrations in Patients with UCDs Treated with RAVICTI in Clinical Trials Age Range RAVICTI Dose Mean Peak PAA Concentration micrograms/mL (SD) Median Peak PAA Concentration (Range) Less than 2 months (n = 16) 3.1 to 12.7 mL/m 2 /day (3.4 to 14 g/m 2 /day) 257 (162) 205 (96 to 707) 2 months to less than 2 years (n = 17) 3.3 to 12.3 mL/m 2 /day (3.7 to 13.5 g/m 2 /day) 142 (299) 35 (1 to 1215) 2 years to 17 years (n = 53) 1.4 to 13.7 mL/m 2 /day (1.5 to 15.1 g/m 2 /day) 70 (79) 50 (1 to 410) Adults (n = 43) 0.6 to 14 mL/m 2 /day (0.7 to 15.4 g/m 2 /day) 39 (40) 25 (1.6 to 178) Distribution In vitro , the extent of plasma protein binding for 14 C-labeled metabolites was 81% to 98% for PBA (over 1 to 250 micrograms/mL), and 37% to 66% for PAA (over 5 to 500 micrograms/mL). The protein binding for PAGN was 7% to 12% and no concentration effects were noted. Elimination Metabolism Upon oral administration, pancreatic lipases hydrolyze RAVICTI (i.e., glycerol phenylbutyrate), and release PBA. PBA undergoes β-oxidation to PAA, which is conjugated with glutamine in the liver and in the kidney through the enzyme phenylacetyl-CoA: L-glutamine-N-acetyltransferase to form PAGN. PAGN is subsequently eliminated in the urine. Saturation of conjugation of PAA and glutamine to form PAGN was suggested by increases in the ratio of plasma PAA to PAGN with increasing dose and with increasing severity of hepatic impairment. In healthy subjects, after administration of 4 mL, 6 mL, and 9 mL 3 times daily for 3 days, the ratio of mean AUC 0-23h of PAA to PAGN was 1, 1.25, and 1.6, respectively. In a separate study, in patients with hepatic impairment (Child-Pugh B and C), the ratios of mean C max values for PAA to PAGN among all patients dosed with 6 mL and 9 mL twice daily were 3 and 3.7. In in vitro studies, the specific activity of lipases for glycerol phenylbutyrate was in the following decreasing order: pancreatic triglyceride lipase, carboxyl ester lipase, and pancreatic lipase-related protein 2. Further, glycerol phenylbutyrate was hydrolyzed in vitro by esterases in human plasma. In these in vitro studies, a complete disappearance of glycerol phenylbutyrate did not produce molar equivalent PBA, suggesting the formation of mono- or bis-ester metabolites. However, the formation of mono- or bis-esters was not studied in humans. Excretion The mean (SD) percentage of administered PBA excreted as PAGN was approximately 69% (17) in adults and 66% (24) in pediatric patients with UCDs at steady state. PAA and PBA represented minor urinary metabolites, each accounting for less than 1% of the administered dose of PBA. Specific Populations Age: Pediatric Population Population pharmacokinetic modeling and dosing simulations suggest body surface area to be the most significant covariate explaining the variability of PAA clearance. PAA clearance was 10.9 L/h, 16.4 L/h, and 24.4 L/h, respectively, for patients ages 3 to 5, 6 to 11, and 12 to 17 years with UCDs. In pediatric patients with UCDs (n = 14) ages 2 months to less than 2 years, PAA clearance was 6.8 L/h. In pediatric patients with UCDs (n = 16) ages less than 2 months, PAA clearance was 3.8 L/h. The mean peak ratio of PAA to PAGN in UCD patients aged birth to less than 2 months was higher (mean: 1.6; range: 0.1 to 7.1) than that of UCD patients aged 2 months to less than 2 years (mean: 0.5; range: 0.1 to 1.2). Sex In healthy adult subjects, a gender effect was found for all metabolites, with women generally having higher plasma concentrations of all metabolites than men at a given dose level. In healthy female subjects, mean C max for PAA was 51 and 120% higher than in male volunteers after administration of 4 mL and 6 mL 3 times daily for 3 days, respectively. The dose normalized mean AUC 0-23h for PAA was 108% higher in females than in males. Renal Impairment The pharmacokinetics of RAVICTI in patients with impaired renal function, including those with end-stage renal disease (ESRD) or those on hemodialysis, have not been studied [see Use in Specific Populations (8.6) ] . Hepatic Impairment The effects of hepatic impairment on the pharmacokinetics of RAVICTI were studied in patients with mild, moderate and severe hepatic impairment of (Child-Pugh class A, B, and C, respectively) receiving 100 mg/kg of RAVICTI twice daily for 7 days. Plasma glycerol phenylbutyrate was not measured in patients with hepatic impairment. After multiple doses of RAVICTI in patients with hepatic impairment of Child-Pugh A, B, and C, geometric mean AUC t of PBA was 42%, 84%, and 50% higher, respectively, while geometric mean AUC t of PAA was 22%, 53%, and 94% higher, respectively, than in healthy subjects. In patients with hepatic impairment of Child-Pugh A, B, and C, geometric mean AUC t of PAGN was 42%, 27%, and 22% lower, respectively, than that in healthy subjects. The proportion of PBA excreted as PAGN in the urine in Child-Pugh A, B, and C was 80%, 58%, and 85%, respectively, and, in healthy volunteers, was 67%. In another study in patients with moderate and severe hepatic impairment (Child-Pugh B and C), mean C max of PAA was 144 micrograms/mL (range: 14 to 358 micrograms/mL) after daily dosing of 6 mL of RAVICTI twice daily, while mean C max of PAA was 292 micrograms/mL (range: 57 to 655 micrograms/mL) after daily dosing of 9 mL of RAVICTI twice daily. The ratio of mean C max values for PAA to PAGN among all patients dosed with 6 mL and 9 mL twice daily were 3 and 3.7, respectively. After multiple doses, a PAA concentration greater than 200 micrograms/mL was associated with a ratio of plasma PAA to PAGN concentrations higher than 2.5 [see Dosage and Administration (2.5) ] . Drug Interaction Studies In vitro PBA or PAA did not induce CYP1A2, suggesting that in vivo drug interactions via induction of CYP1A2 is unlikely. In in vitro studies, PBA at a concentration of 800 micrograms/mL caused greater than 60% reversible inhibition of cytochrome P450 isoenzymes CYP2C9, CYP2D6, and CYP3A4/5 (testosterone 6β-hydroxylase activity). The in vitro study suggested that in vivo drug interactions with substrates of CYP2D6 cannot be ruled out. The inhibition of CYP isoenzymes 1A2, 2C8, 2C19, and 2D6 by PAA at the concentration of 2.8 mg/mL was observed in vitro . Clinical implication of these results is unknown. Effects of RAVICTI on Other Drugs Midazolam In healthy subjects, when oral midazolam was administered after multiple doses of RAVICTI (4 mL three times a day for 3 days) under fed conditions, the mean C max and AUC for midazolam were 25% and 32% lower, respectively, compared to administration of midazolam alone. In addition, the mean C max and AUC for 1-hydroxy midazolam were 28% and 58% higher, respectively, compared to administration of midazolam alone [see Drug Interactions (7.3) ] . Celecoxib Concomitant administration of RAVICTI did not significantly affect the pharmacokinetics of celecoxib, a substrate of CYP2C9. When 200 mg of celecoxib was orally administered with RAVICTI after multiple doses of RAVICTI (4 mL three times a day for 6 days) under fed conditions (a standard breakfast was consumed 5 minutes after celecoxib administration), the mean C max and AUC for celecoxib were 13% and 8% lower than after administration of celecoxib alone.