Glycerol Phenylbutyrate

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 )

Oral liquid: 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 )

RAVICTI 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 )

Neurotoxicity : Phenylacetate (PAA), the active moiety of RAVICTI, may be toxic; reduce dosage for symptoms of neurotoxicity. ( 5.1 ) Pancreatic Insufficiency or Intestinal Malabsorption : Monitor ammonia levels closely. ( 5.2 )

5.1 Neurotoxicity Increased exposure to PAA, the major metabolite of RAVICTI, may be associated with neurotoxicity in patients with UCDs. In a study of adult cancer patients, subjects received sodium phenylacetate administered as a 1-hour infusion twice daily at two dose levels of 125 and 150 mg/kg for a 2-week period. Of 18 subjects enrolled, 7 had a history of primary central nervous system tumor. Signs and symptoms of potential PAA neurotoxicity, which were reversible, were reported at plasma PAA concentrations above 500 micrograms/mL and included somnolence, fatigue, lightheadedness, headache, dysgeusia, hypoacusis, disorientation, impaired memory, and exacerbation of preexisting neuropathy. PAA concentrations were not measured when symptoms resolved. In healthy subjects, after administration of 4 mL and 6 mL RAVICTI 3 times daily (13.2 g/day and 19.8 g/day, respectively) for 3 days, a dose-dependent increase in non-serious nervous system adverse reactions were observed. In subjects who had nervous system adverse reactions, plasma PAA concentrations, which were measured on Day 3 per protocol and not always at onset of symptoms, ranged from 8 to 56 micrograms/mL with 4 mL RAVICTI 3 times daily and from 31 to 242 micrograms/mL with 6 mL RAVICTI 3 times daily. In clinical trials in patients with UCDs who had been on sodium phenylbutyrate prior to administration of RAVICTI, adverse reactions of headache, fatigue, symptoms of peripheral neuropathy, seizures, tremor and/or dizziness were reported. No correlation between plasma PAA concentration and neurologic symptoms was identified but plasma PAA concentrations were generally not consistently measured at the time of neurologic symptom occurrence [see Clinical Pharmacology (12.3) ] . If symptoms of vomiting, nausea, headache, somnolence or confusion are present in the absence of high ammonia or other intercurrent illness which explains these symptoms, consider the potential for PAA neurotoxicity which may need reduction in the RAVICTI dosage [see Dosage and Administration (2.4) ] .

5.2 Pancreatic Insufficiency or Intestinal Malabsorption Exocrine pancreatic enzymes hydrolyze RAVICTI in the small intestine, separating the active moiety, phenylbutyrate, from glycerol. This process allows phenylbutyrate to be absorbed into the circulation. Low or absent pancreatic enzymes or intestinal disease resulting in fat malabsorption may result in reduced or absent digestion of RAVICTI and/or absorption of phenylbutyrate and reduced control of plasma ammonia. Monitor ammonia levels closely in patients with pancreatic insufficiency or intestinal malabsorption.

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

Corticosteroids, valproic acid, or haloperidol : May increase plasma ammonia level; monitor ammonia levels closely. ( 7.1 ) Probenecid : May affect renal excretion of metabolites of RAVICTI, including phenylacetylglutamine (PAGN) and PAA. ( 7.2 ) CYP3A4 Substrates with narrow therapeutic index (e.g., alfentanil, quinidine, cyclosporine) : RAVICTI 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 RAVICTI 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 RAVICTI Probenecid Probenecid may inhibit the renal excretion of metabolites of RAVICTI including PAGN and PAA.

7.3 Potential for RAVICTI to Affect Other Drugs Drugs with Narrow Therapeutic Index That are Substrates of CYP3A4 RAVICTI is a weak inducer of CYP3A4 in humans. Concomitant use of RAVICTI 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 RAVICTI decreased the systemic exposure of midazolam. Monitor for suboptimal effect of midazolam in patients who are being treated with RAVICTI.

Lactation : Breastfeeding is not recommended. ( 8.2 )

8.1 Pregnancy Risk Summary Limited available data with RAVICTI 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 Amgen Inc. at 1-800-77-AMGEN (1-800-772-6436). 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 7 th 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 RAVICTI 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 RAVICTI.

8.4 Pediatric Use Patients 2 Years to 17 Years of Age The safety and effectiveness of RAVICTI 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 RAVICTI, 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 RAVICTI 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 aged 2 months to less than 2 years of age and in 16 patients less than 2 months of age [see Adverse Reactions (6.1) , Clinical Studies (14.3) ] . Juvenile Animal Toxicity Data In a juvenile rat study with daily oral dosing performed on postpartum Day 2 through mating and pregnancy after maturation, terminal body weight was dose-dependently reduced by up to 16% in males and 12% in females at 900 mg/kg/day or higher (3 times the dose of 6.87 mL/m 2 /day in adult patients, based on combined AUCs for PBA and PAA). Learning, memory, and motor activity endpoints were not affected. However, fertility (number of pregnant rats) was decreased by up to 25% at 650 mg/kg/day or higher (2.6 times the dose of 6.87 mL/m 2 /day in adult patients, based on combined AUCs for PBA and PAA).

8.5 Geriatric Use Clinical studies of RAVICTI did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently than 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 The efficacy and safety of RAVICTI in patients with renal impairment are unknown. Monitor ammonia levels closely when starting patients with impaired renal function on RAVICTI.

8.7 Hepatic Impairment No studies were conducted in patients with UCDs and hepatic impairment. Because conversion of PAA to PAGN occurs in the liver, patients with hepatic impairment may have reduced conversion capability and higher plasma PAA and PAA to PAGN ratio [see Clinical Pharmacology (12.3) ] . Therefore, dosage for patients with moderate to severe hepatic impairment should be started at the lower end of the recommended dosing range and should be kept on the lowest dose necessary to control their ammonia levels [see Dosage and Administration (2.5) ] .

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. RAVICTI is a triglyceride containing 3 molecules of PBA. PAA, the major metabolite of PBA, is the active moiety of RAVICTI. 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: RAVICTI Mechanism of Action Figure 1