nasogastric tube or gastrostomy tube, see full prescribing information. 2.1 recommended dosage for acute or chronic hyperammonemia due to nags deficiency treatment initiation initiate carglumic acid tablets for oral suspension treatment as soon as the diagnosis of nags deficiency is suspected, which may be as soon as at birth, and managed by a physician and medical team experienced in metabolic disorders. dosage for acute hyperammonemia due to nags deficiency the recommended daily dosage of carglumic acid tablets for oral suspension in pediatric and adult patients for acute hyperammonemia due to nags deficiency is 100 mg/kg to 250 mg/kg. divide the daily dosage into 2 to 4 doses and round to the nearest 100 mg (i.e., half of a carglumic acid tablet for oral suspension). during acute hyperammonemic episodes, administer carglumic acid tablets for oral suspension with other ammonia lowering therapies, such as alternate pathway medications, hemodialysis, and protein restriction. dosage for chronic hyperammonemia due to nags deficiency the recommended daily dosage of carglumic acid tablets for oral suspension in pediatric and adult patients for chronic hyperammonemia due to nags deficiency is 10 mg/kg to 100 mg/kg. divide the daily dosage into 2 to 4 doses and round to the nearest 100 mg (i.e., half of a carglumic acid tablet for oral suspension). during maintenance therapy, the concomitant use of other ammonia lowering therapies and protein restriction may be needed based on plasma ammonia levels. therapeutic monitoring closely monitor plasma ammonia levels. titrate the carglumic acid tablets for oral suspension dosage to maintain the plasma ammonia level within the normal range for the patient’s age, taking into consideration their clinical condition (e.g., nutritional requirements, protein intake, growth parameters, etc.). adjust the recommended dosage in patients with moderate or severe renal impairment [see dosage and administration (2.3)] . 2.3 dosage adjustment in patients with renal impairment no dosage adjustment is warranted in patients with mild renal impairment (egfr 60-89 ml/min/1.73 m 2 ). the recommended dosage of carglumic acid tablets for oral suspension in patients with moderate or severe renal impairment is shown below. moderate renal impairment (egfr 30-59 ml/min/1.73 m 2 ) severe renal impairment (egfr ≤ 29 ml/min/1.73 m 2 ) acute hyperammonemia due to nags deficiency 50 mg/kg/day to 125 mg/kg/day divided into 2 to 4 doses and rounded to the nearest 50 mg (i.e., one-quarter of a carglumic acid tablet for oral suspension) 15 mg/kg/day to 60 mg/kg/day divided into 2 to 4 doses and rounded to the nearest 50 mg (i.e., one-quarter of a carglumic acid tablet for oral suspension) chronic hyperammonemia due to nags deficiency 5 mg/kg/day to 50 mg/kg/day divided into 2 to 4 doses and rounded to the nearest 50 mg (i.e., one-quarter of a carglumic acid tablet for oral suspension) 2 mg/kg/day to 25 mg/kg/day divided into 2 to 4 doses and rounded to the nearest 50 mg (i.e., one-quarter of a carglumic acid tablet for oral suspension) 2.4 preparation and administration overview disperse carglumic acid tablets for oral suspension in water. do not swallow whole or crushed. carglumic acid tablets for oral suspension do not dissolve completely in water, and undissolved particles of the tablet may remain in the mixing container. take carglumic acid tablets for oral suspension immediately before meals or feedings. the carglumic acid tablet suspension has a slightly acidic taste. for all preparations, use in foods or liquids other than water has not been studied and is not recommended. oral administration for oral administration, administer carglumic acid tablets for oral suspension as follows: add a minimum of 2.5 ml of water into a small cup for each carglumic acid tablet for oral suspension or each ½ or ¼ carglumic acid tablet for oral suspension needed for the prescribed dose. add the carglumic acid tablets for oral suspension to the water in the cup. carefully stir the tablet and water mixture. swallow the mixture immediately. pieces of the tablet may remain in the cup. rinse the cup with additional water and swallow the mixture immediately. repeat as needed until no pieces of the tablet are left in the cup. use of an oral syringe for oral administration for administration via an oral syringe, administer carglumic acid tablets for oral suspension as follows: add a minimum of 2.5 ml of water into a small cup for each carglumic acid tablet for oral suspension or each ½ or ¼ carglumic acid tablet for oral suspension needed for the prescribed dose. add the carglumic acid tablets for oral suspension to the water in the cup. carefully stir the tablet and water mixture. draw up the mixture in an oral syringe and administer immediately. pieces of the tablet may remain in the oral syringe. refill the oral syringe with a minimum volume of water (1 ml to 2 ml) and administer immediately. flush the oral syringe again, as needed, until no pieces of the tablet are left in the syringe. use of nasogastric tube (ng tube) or gastrostomy tube (g-tube) for feeding tube administration for patients who have a ng tube or g-tube in place, administer carglumic acid tablets for oral suspension as follows: add a minimum of 2.5 ml of water into a small cup for each carglumic acid tablet for oral suspension or each ½ or ¼ carglumic acid tablet for oral suspension needed for the prescribed dose. add the carglumic acid tablets for oral suspension to the water in the cup. carefully stir the tablet and water mixture. draw up the mixture into a catheter-tip syringe. administer the mixture immediately through the ng tube or g-tube. pieces of the tablet may remain in the catheter-tip syringe or the feeding tube. flush immediately with 1 to 2 ml of additional water to clear the ng tube or g-tube. flush the ng tube or g-tube again, as needed, until no pieces of the tablet are left in the syringe or the feeding tube.

ain, pyrexia, tonsillitis, anemia, diarrhea, ear infection, infections, nasopharyngitis, hemoglobin decreased, and headache. table 1 summarizes adverse reactions occurring in 2 or more patients with nags deficiency treated with carglumic acid tablets for oral suspension in the retrospective case series (≥ 9%). table 1: adverse reactions reported in ≥ 2 patients with nags deficiency treated with carglumic acid tablets for oral suspension in the retrospective case series adverse reaction number of patients (n) (%) vomiting 6 (26) abdominal pain 4 (17) pyrexia 4 (17) tonsillitis 4 (17) anemia 3 (13) diarrhea 3 (13) ear infection 3 (13) infections 3 (13) nasopharyngitis 3 (13) hemoglobin decreased 3 (13) headache 3 (13) dysgeusia 2 (9) asthenia 2 (9) hyperhidrosis 2 (9) influenza 2 (9) pneumonia 2 (9) weight decreased 2 (9) anorexia 2 (9) somnolence 2 (9) rash 2 (9) 6.2 postmarketing experience the following adverse reactions have been identified during postapproval use of carglumic acid tablets for oral suspension. because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure. psychiatric disorders : mania skin and subcutaneous tissue disorders : pruritus, rash including rash erythematous, rash maculopapular, rash pustular

linical considerations disease-associated maternal and/or embryo/fetal risk pregnant women with urea cycle disorders may experience an increase in catabolic stress which can trigger a hyperammonemic crisis both in the intrapartum and in the post-partum (3-14 days post-partum) periods. maternal complications related to hyperammonemic crisis can include neurological impairment, coma and in some cases death. data animal data no effects on embryo-fetal development were observed in pregnant rats treated with up to 2000 mg/kg/day (approximately 38 times the maximum reported human maintenance dose [100 mg/kg/day] based on auc [area under the plasma concentration-time curve]) from two weeks prior to mating through organogenesis or in pregnant rabbits treated with up to 1000 mg/kg/day (approximately 6 times the maximum reported human maintenance dose [100 mg/kg/day] based on auc) during organogenesis. in a pre-and post-natal developmental study, female rats received oral carglumic acid from organogenesis through lactation at doses of 500 mg/kg/day and 2000 mg/kg/day. decreased growth of offspring was observed at 500 mg/kg/day and higher (approximately 38 times the maximum reported human maintenance dose [100 mg/kg/day] based on auc), and reduction in offspring survival during lactation was observed at 2000 mg/kg/day (approximately 38 times the maximum reported human maintenance dose [100 mg/kg/day] based on auc). no effects on physical and sexual development, learning and memory, or reproductive performance were observed through maturation of the surviving offspring at maternal doses up to 2000 mg/kg/day. the high dose (2000 mg/kg/day) produced maternal toxicity (impaired weight gain and approximately 10% mortality). 8.2 lactation risk summary it is not known whether carglumic acid is present in human milk. there are no available data on the effects of carglumic acid on the breastfed infant or the effects on milk production. carglumic acid is present in milk from treated rats. when a drug is present in animal milk, it is likely that the drug will be present in human milk. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for carglumic acid tablets for oral suspension and any potential adverse effects on the breastfed child from carglumic acid tablets for oral suspension or from the underlying maternal condition. 8.4 pediatric use the safety and effectiveness of carglumic acid tablets for oral suspension for the treatment of pediatric patients (birth to 17 years of age) with acute or chronic hyperammonemia due to nags deficiency have been established, and the information on these uses are discussed throughout the labeling. there are insufficient data to determine if there is a difference in clinical or biochemical responses between adult and pediatric patients treated with carglumic acid tablets for oral suspension. 8.5 geriatric use clinical studies of carglumic acid tablets for oral suspension did not include patients 65 years of age and older. 8.6 renal impairment plasma concentrations of carglumic acid increased in patients with renal impairment [see clinical pharmacology (12.3)] . reduce the carglumic acid tablets for oral suspension dosage in patients with moderate or severe renal impairment [see dosage and administration (2.3)] . the pharmacokinetics of carglumic acid have not been evaluated in patients with end stage renal disease.

-associated maternal and/or embryo/fetal risk pregnant women with urea cycle disorders may experience an increase in catabolic stress which can trigger a hyperammonemic crisis both in the intrapartum and in the post-partum (3-14 days post-partum) periods. maternal complications related to hyperammonemic crisis can include neurological impairment, coma and in some cases death. data animal data no effects on embryo-fetal development were observed in pregnant rats treated with up to 2000 mg/kg/day (approximately 38 times the maximum reported human maintenance dose [100 mg/kg/day] based on auc [area under the plasma concentration-time curve]) from two weeks prior to mating through organogenesis or in pregnant rabbits treated with up to 1000 mg/kg/day (approximately 6 times the maximum reported human maintenance dose [100 mg/kg/day] based on auc) during organogenesis. in a pre-and post-natal developmental study, female rats received oral carglumic acid from organogenesis through lactation at doses of 500 mg/kg/day and 2000 mg/kg/day. decreased growth of offspring was observed at 500 mg/kg/day and higher (approximately 38 times the maximum reported human maintenance dose [100 mg/kg/day] based on auc), and reduction in offspring survival during lactation was observed at 2000 mg/kg/day (approximately 38 times the maximum reported human maintenance dose [100 mg/kg/day] based on auc). no effects on physical and sexual development, learning and memory, or reproductive performance were observed through maturation of the surviving offspring at maternal doses up to 2000 mg/kg/day. the high dose (2000 mg/kg/day) produced maternal toxicity (impaired weight gain and approximately 10% mortality).

thout concomitant ammonia lowering therapies. no dose-response relationship has been identified. cardiac electrophysiology the effect of carglumic acid was evaluated in a phase 1, randomized study in 76 healthy volunteers. the study suggests a lack of clinically relevant qt prolongation effect at the highest therapeutic dose level (250 mg/kg/day). 12.3 pharmacokinetics the pharmacokinetics of carglumic acid in healthy subjects following an intravenous (iv) infusion over 2 hours at 8 mg/kg or an oral administration at 100 mg/kg are summarized in table 3. table 3 : mean (sd) pharmacokinetic parameter values of carglumic acid in healthy subjects pk parameter iv infusion 8mg/kg (n=10) oral 100 mg/kg (n=12) c max (ng/ml) 8613 (558) 3284 (321) t max (hr) # 2 (1-2) 3 (2-4) auc (ng*hr/ml) 24501 (1613) 31426 (2150) t 1/2 (hr) 31 (3) 25 (2) cl (l/hr/kg) 0.34 (0.02) n/a v d (l/kg) 15 (1) n/a # median (range); n/a, not applicable absorption following an oral administration of carglumic acid tablets for oral suspension 100 mg/kg in healthy subjects, the absolute bioavailability was approximately 10%. distribution carglumic acid is not bound to plasma proteins. elimination carglumic acid is predominantly excreted by the kidneys as unchanged product. metabolism a proportion of carglumic acid may be metabolized by the intestinal bacterial flora. the likely end product of carglumic acid metabolism is carbon dioxide, eliminated through the lungs. excretion following an oral administration of radiolabeled carglumic acid tablets for oral suspension at 100 mg/kg, 9% of the dose is excreted unchanged in the urine and up to 60% of the dose is recovered unchanged in the feces. specific populations patients with renal impairment the pharmacokinetics of carglumic acid in subjects with renal impairment were compared with healthy subjects with normal renal function following oral administration of a single dose of carglumic acid tablets for oral suspension 40 mg/kg or 80 mg/kg. the c max and auc 0-t of carglumic acid are summarized in table 4. the geometric mean ratio (90% ci) of auc 0-t in subjects with mild, moderate, and severe renal impairment relative to those in their matched control subjects with normal renal function were approximately 1.3 (1.01, 1.68), 2.0 (1.65, 2.54), and 4.6 (3.36, 6.34) respectively [see dosage and administration (2.3)] . table 4: mean (sd) c max and auc 0- t of carglumic acid following single oral dose administration of carglumic acid tablets for oral suspension 80 mg/kg or 40 mg/kg in subjects with renal impairment and matched healthy control subjects with normal renal function pk parameters normal renal function 1a : egfr ≥ 90 ml/min/1.73m 2 (n=8) mild renal impairment: egfr 60-89 ml/min/1.73m 2 (n=8) moderate renal impairment: egfr 30-59 ml/min/1.73m 2 (n=8) normal renal function 1b : egfr ≥ 90 ml/min/1.73m 2 (n=8) severe renal impairment: egfr ≤ 29 ml/min/1.73m 2 (n=8) 80 mg/kg 40 mg/kg c max (ng/ml) 2983 (552) 4310 (1937) 6129 (1854) 1890 (901) 8377 (3815) auc 0-t (ng*hr/ml) 28313 (6204) 39545 (12109) 79766 (19708) 20212 (6186) 143075 (55910) treatment groups 1a and 1b represent two separate matched control groups of healthy subjects with normal renal function. drug interaction studies based on in vitro studies, carglumic acid is not an inducer of cyp1a1/2, cyp2b6, cyp2c, and cyp3a4/5 enzymes, and not an inhibitor of cyp1a2, cyp2a6, cyp2b6, cyp2c8, cyp2c9, cyp2c19, cyp2d6, cyp2e1, and cyp3a4/5 enzymes. based on in vitro studies, carglumic acid is a substrate of the human oat1 transporter. carglumic acid is not a substrate of mdr1, bcrp, mate1, mate2-k, oat1, oat3, oatp1b1, oatp1b3, oct1, and oct2. carglumic acid is not an inhibitor of human bsep, bcrp, mdr1, mate1, mate2-k, oat1, oat3, oatp1b1, oatp1b3, oct1, and oct2 transporters.

. the likely end product of carglumic acid metabolism is carbon dioxide, eliminated through the lungs. excretion following an oral administration of radiolabeled carglumic acid tablets for oral suspension at 100 mg/kg, 9% of the dose is excreted unchanged in the urine and up to 60% of the dose is recovered unchanged in the feces. specific populations patients with renal impairment the pharmacokinetics of carglumic acid in subjects with renal impairment were compared with healthy subjects with normal renal function following oral administration of a single dose of carglumic acid tablets for oral suspension 40 mg/kg or 80 mg/kg. the c max and auc 0-t of carglumic acid are summarized in table 4. the geometric mean ratio (90% ci) of auc 0-t in subjects with mild, moderate, and severe renal impairment relative to those in their matched control subjects with normal renal function were approximately 1.3 (1.01, 1.68), 2.0 (1.65, 2.54), and 4.6 (3.36, 6.34) respectively [see dosage and administration (2.3)] . table 4: mean (sd) c max and auc 0- t of carglumic acid following single oral dose administration of carglumic acid tablets for oral suspension 80 mg/kg or 40 mg/kg in subjects with renal impairment and matched healthy control subjects with normal renal function pk parameters normal renal function 1a : egfr ≥ 90 ml/min/1.73m 2 (n=8) mild renal impairment: egfr 60-89 ml/min/1.73m 2 (n=8) moderate renal impairment: egfr 30-59 ml/min/1.73m 2 (n=8) normal renal function 1b : egfr ≥ 90 ml/min/1.73m 2 (n=8) severe renal impairment: egfr ≤ 29 ml/min/1.73m 2 (n=8) 80 mg/kg 40 mg/kg c max (ng/ml) 2983 (552) 4310 (1937) 6129 (1854) 1890 (901) 8377 (3815) auc 0-t (ng*hr/ml) 28313 (6204) 39545 (12109) 79766 (19708) 20212 (6186) 143075 (55910) treatment groups 1a and 1b represent two separate matched control groups of healthy subjects with normal renal function. drug interaction studies based on in vitro studies, carglumic acid is not an inducer of cyp1a1/2, cyp2b6, cyp2c, and cyp3a4/5 enzymes, and not an inhibitor of cyp1a2, cyp2a6, cyp2b6, cyp2c8, cyp2c9, cyp2c19, cyp2d6, cyp2e1, and cyp3a4/5 enzymes. based on in vitro studies, carglumic acid is a substrate of the human oat1 transporter. carglumic acid is not a substrate of mdr1, bcrp, mate1, mate2-k, oat1, oat3, oatp1b1, oatp1b3, oct1, and oct2. carglumic acid is not an inhibitor of human bsep, bcrp, mdr1, mate1, mate2-k, oat1, oat3, oatp1b1, oatp1b3, oct1, and oct2 transporters.

rapy (years) mean (sd) 2 (4) min-max 0-13 age groups at initiation of carglumic acid tablets for oral suspension therapy <30 days 9 (39%) >30 days - 11 months 9 (39%) ≥1 - 13 years 5 (22%) nags gene mutations by dna testing homozygous 14 (61%) heterozygous 4 (17%) not available 5 (22%) patients current treatment status on-going 18 (78%) discontinued 5 (22%) the clinical and biochemical data in the 23-patient case series were retrospectively collected, unblinded, and uncontrolled and preclude formal statistical testing. short-term efficacy was evaluated using mean and median change in plasma ammonia levels from baseline to days 1 to 3. persistence of the effect was evaluated using long-term mean and median change in plasma ammonia level. of the 23 nags deficiency patients in the case series, 13 patients had documented plasma ammonia levels prior to carglumic acid tablets for oral suspension treatment and after long-term treatment with carglumic acid tablets for oral suspension and were evaluable. table 5 summarizes the plasma ammonia levels at baseline, days 1 to 3 post- carglumic acid tablets for oral suspension treatment, and long-term carglumic acid tablets for oral suspension treatment (mean 8 years) in the 13 evaluable patients. all 13 patients had increased plasma ammonia levels at baseline (mean 271 micromol/l; normal range: 5 to 50 micromol/l). by day 3 and with long-term treatment, normal plasma ammonia levels were attained (table 6). table 6: plasma ammonia levels in nags deficiency patients at baseline and after treatment with carglumic acid tablets for oral suspension timepoint patients (n = 13) ammonia level (micromol/l) baseline (prior to first dose of carglumic acid tablets for oral suspension) n 13 mean (sd) 271 (359) median 157 range 72-1428 missing data 0 day 1 n 10 mean (sd) 181 (358) median 65 range 25-1190 missing data 3 day 2 n 8 mean (sd) 69 (78) median 44 range 11-255 missing data 5 day 3 n 5 mean (sd) 27 (11) median 25 range 12-42 missing data 8 long-term treatment (mean duration 8 years; median duration 6 years; range 1-16 years based on last available value while on carglumic acid tablets for oral suspension treatment) n 13 mean (sd) 23 (7) median 24 range 9-34 missing data 0 the mean plasma ammonia level at baseline and the decline that is observed after treatment with carglumic acid tablets for oral suspension in 13 evaluable patients with nags deficiency is illustrated in figure 1. figure 1: mean plasma ammonia in 13 evaluable nags deficiency patients at baseline and after treatment with carglumic acid tablets for oral suspension figure-1

om first opening. do not use after the expiration date stated on the tablet container. all trademarks are the property of their respective owners. manufactured by: novitium pharma llc 70 lake drive, east windsor new jersey 08520 distributed by: eton pharmaceuticals, inc. deer park, il 60010 usa issued: 03/2022 lb4191-03