The following Structured Product Label (SPL) was submitted to the FDA by Burel Pharmaceuticals, Llc for the product Carglumic Acid (NDC 35573-459). This document serves as the official prescribing information, containing essential scientific data and clinical materials required for healthcare providers and patients.
This specific version of the label includes detailed information regarding 1.1 acute and chronic hyperammonemia due to n-acetylglutamate synthase (nags) deficiency, 2.1 recommended dosage for acute or chronic hyperammonemia due to nags deficiency, 2.3 dosage adjustment in patients with renal impairment, 2.4 preparation and administration, oral administration, use of an oral syringe for oral administration, use of nasogastric tube (ng tube) or gastrostomy tube (g-tube) for feeding tube administration, 3 dosage forms and strengths, and other regulatory disclosures. Use the navigation below to review specific sections of the FDA submission.
Carglumic acid tablets for oral suspension is indicated in pediatric and adult patients as:
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
Dosage for Chronic Hyperammonemia due to NAGS Deficiency
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)].
No dosage adjustment is warranted in patients with mild renal impairment (eGFR 60-89 mL/min/1.73 m2). 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 m2) | Severe Renal Impairment (eGFR ≤29 mL/min/1.73 m2) | |
| 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 tablets 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 tablets 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 tablets 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 tablets for oral suspension) |
Overview
For oral administration, administer Carglumic acid tablets for oral suspension as follows:
For administration via an oral syringe, administer Carglumic acid tablets for oral suspension as follows:
For patients who have a NG Tube or G-Tube in place, administer carglumic acid tablets for oral suspension as follows:
Carglumic acid tablets for oral suspension 200 mg are white to off-white elongated tablets, functionally scored with 3 lines for splitting into 4 equal portions, and engraved 'N's on one side.
None
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 practice.
Acute and Chronic Hyperammonemia due to NAGS Deficiency
In a retrospective case series of 23 NAGS deficiency patients treated with Carglumic acid tablets for oral suspension, 17 of the 23 patients reported any adverse reaction. The most common adverse reactions (occurring in ≥ 13% of patients) were vomiting, abdominal pain, 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%).
| 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) |
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
Although rare case reports of carglumic acid tablets for oral suspension use in pregnant women are insufficient to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes, untreated NAGS deficiency can result in irreversible neurologic damage and death in pregnant women [see Clinical Considerations].
In an animal reproduction study, decreased survival and growth occurred in offspring born to rats that received carglumic acid at a dose approximately 38 times the maximum reported human maintenance dose.
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, miscarriage, 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.
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.
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 to 14 days post-partum) periods. Maternal complications related to hyperammonemic crisis can include neurological impairment, coma and in some cases death.
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).
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.
Clinical studies of Carglumic acid tablets for oral suspension did not include patients 65 years of age and older.
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.
One patient treated with 650 mg/kg/day of Carglumic acid tablets for oral suspension developed symptoms resembling monosodium glutamate intoxication-like syndrome and characterized by tachycardia, profuse sweating, increased bronchial secretion, increased body temperature, and restlessness. These symptoms resolved upon reduction of dose.
Carglumic acid tablets for oral suspension contain 200 mg of carglumic acid. Carglumic acid, the active substance, is a carbamoyl phosphate synthetase 1 (CPS 1) activator and is soluble in dimethyl formamide and sparingly soluble in water.
Chemically, carglumic acid is N-carbamoyl-L-glutamic acid or (2S)-2-(carbamoylamino) pentanedioic acid, with a molecular weight of 190.16.
The structural formula is:
Image (5d8ac14d Dd85 4d80 9e3d 07a52e1f72ab 195 1)
Molecular Formula: C6H10N2O5
The inactive ingredients of carglumic acid tablets for oral suspension are croscarmellose sodium, microcrystalline cellulose, sodium lauryl sulfate, colloidal silicon dioxide and sodium stearyl fumarate.
Carglumic acid is a synthetic structural analogue of N-acetylglutamate (NAG) which is produced from glutamate and acetyl-CoA in a reaction catalyzed by N-acetylglutamate synthase (NAGS), a mitochondrial liver enzyme. NAG acts as an essential allosteric activator of carbamoyl phosphate synthetase 1 (CPS 1), a mitochondrial liver enzyme which catalyzes the first reaction of the urea cycle. The urea cycle, whose role is the disposition of ammonia, includes a series of biochemical reactions in the liver resulting in the conversion of ammonia into urea, which is then excreted through the urine. Carglumic acid acts as a CPS1 activator, improves or restores the function of the urea cycle, and facilitates ammonia detoxification and urea production.
In a retrospective review of the clinical course in 23 patients with NAGS deficiency, carglumic acid reduced plasma ammonia levels within 24 hours when administered with and without 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).
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.
# Median (range); N/A, not applicable | ||
| PK parameter | IV infusion 8 mg/kg (N=10) | Oral 100 mg/kg (N=12) |
| Cmax (ng/mL) | 8613 (558) | 3284 (321) |
| Tmax (hr)# | 2 (1-2) | 3 (2-4) |
| AUC (ng*hr/mL) | 24501 (1613) | 31426 (2150) |
| T1/2 (hr) | 31 (3) | 25 (2) |
| CL (L/hr/kg) | 0.34 (0.02) | N/A |
| Vd (L/kg) | 15 (1) | N/A |
Following an oral administration of Carglumic acid tablets for oral suspension 100 mg/kg in healthy subjects, the absolute bioavailability was approximately 10%.
Carglumic acid is not bound to plasma proteins.
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.
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 Cmax and AUC0-t of carglumic acid are summarized in Table 4. The geometric mean ratio (90% CI) of AUC0-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)].
Treatment groups 1a and 1b represent two separate matched control groups of healthy subjects with normal renal function. | |||||
| PK Parameters | Normal Renal Function1a: eGFR ≥90 mL/min/1.73m2 (N=8) | Mild Renal Impairment: eGFR 60-89 mL/min/1.73m2 (N=8) | Moderate Renal Impairment: eGFR 30-59 mL/min/1.73m2 (N=8) | Normal Renal Function1b: eGFR ≥90 mL/min/1.73m2 (N=8) | Severe Renal Impairment: eGFR ≤29 mL/min/1.73m2 (N=8) |
| 80 mg/kg | 40 mg/kg | ||||
| Cmax (ng/mL) | 2983 (552) | 4310 (1937) | 6129 (1854) | 1890 (901) | 8377 (3815) |
| AUC0-t (ng*hr/mL) | 28313 (6204) | 39545 (12109) | 79766 (19708) | 20212 (6186) | 143075 (55910) |
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 carcinogenic potential of carglumic acid was assessed in a 2-year carcinogenicity study in rats. Carglumic acid was not tumorigenic at oral doses up to 1000 mg/kg/day (approximately 34 times the maximum reported human maintenance dose [100 mg/kg/day] based on AUC).
Carglumic acid was negative in the Ames test, chromosomal aberration assay in human lymphocytes, and the in vivo micronucleus assay in rats.
There were no effects on fertility or reproductive performance in female rats at oral doses up to 2000 mg/kg/day (approximately 38 times the maximum reported human maintenance dose [100 mg/kg/day] based on AUC). In a separate study, mating and fertility were unaffected in male rats at oral doses up to 1000 mg/kg/day (approximately 34 times the maximum reported human maintenance dose [100 mg/kg/day] based on AUC).
The efficacy of carglumic acid tablets for oral suspension in the treatment of acute and chronic hyperammonemia due to NAGS deficiency was evaluated in a retrospective case series of 23 NAGS deficiency patients treated with Carglumic acid tablets for oral suspension over a median duration of 7.9 years (range 0.6 to 20.8 years). For acute treatment, patients received Carglumic acid tablets for oral suspension at 100 mg/kg/day to 250 mg/kg/day primarily administered in 2 to 4 divided doses. For maintenance treatment, the dosage was reduced over time based on plasma ammonia level and clinical responses.
The baseline characteristics of the patient population are shown in Table 5.
| Patients N=23 | ||
| Sex | Male | 14 (61%) |
| Female | 9 (39%) | |
| Age at initiation of carglumic acid tablets for oral suspension therapy (years) | Mean (SD) | 2 (4) |
| Min to 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 6 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).
| Time point | 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 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
Image (5d8ac14d Dd85 4d80 9e3d 07a52e1f72ab 220 1)
How Supplied
Carglumic acid tablets for oral suspension 200 mg are white to off-white elongated tablets, functionally scored with 3 lines for splitting into 4 equal portions, and engraved 'N's on one side.
Carglumic acid tablets for oral suspension are available in 60 tablets in a high density polyethylene bottle with child resistant polypropylene cap and desiccant unit.
NDC 35573-459-60 Bottles of 60 tablets
Storage
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].
After first opening of the container:
Advise the patient to read the FDA-approved patient labeling (Instructions for Use).
Instruct the patient on the following:
Preparation and Administration [see Dosage and Administration (2.3)]
Storage [see How Supplied/Storage and Handling (16)]
Manufactured for:
Burel Pharmaceuticals, LLC
Mason, OH 45040 USA
Revised: 09/2022
31230922 R0
INSTRUCTIONS FOR USE
Carglumic Acid Tablets for Oral Suspension
Important information:
You may need to ask your healthcare provider or pharmacist for a medicine cup to measure the correct amount of water you will need to prepare the dose of carglumic acid tablets for oral suspension.
The Carglumic acid tablets for oral suspension has 3 lines used for splitting the tablet into 4 equal parts in order to get the prescribed dose. Ask your healthcare provider if you have any questions about how to split the tablet the right way or have any questions about the prescribed dose.
Taking carglumic acid tablets for oral suspension by mouth using a cup:
Children and Adults
Taking carglumic acid tablets for oral suspension by mouth using an oral syringe:
Children
Giving carglumic acid tablets for oral suspension through a nasogastric (NG) tube or gastrostomy tube (G-tube):
Children and Adults
How should I store carglumic acid tablets for oral suspension?
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Manufactured for:
Burel Pharmaceuticals, LLC
Mason, OH 45040 USA
Revised: 09/2022
31230922 R0
Bottle label - 60 Tablets in Bottle
NDC 35573-459-60
Carglumic Acid
Tablets for Oral
Suspension
200 mg
Store at 20° to 25°C (68°F to 77°F);
excursions permitted between 15°C
and 30°C (59°F and 86°F) [See USP
Controlled Room Temperature].
60 Tablets
Rx only
1 (5d8ac14d Dd85 4d80 9e3d 07a52e1f72ab 01)
Carton label - 60 Tablets in Bottle
NDC 35573-459-60
Carglumic Acid
Tablets for Oral
Suspension
200 mg
Disperse Carglumic Acid Tablets in water.
Do not swallow whole or crushed.
Discard one month after first opening.
Date of first opening:
60 Tablets
Rx only
2 (5d8ac14d Dd85 4d80 9e3d 07a52e1f72ab 02)
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