Carglumic acid tablets for oral suspension is indicated in adult and pediatric patients as:

• Adjunctive therapy to standard of care for the treatment of acute hyperammonemia due to NAGS deficiency.

• Maintenance therapy for the treatment of 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 supervised by a healthcare provider experienced in the treatment of metabolic disorders.

Dosage for Acute Hyperammonemia due to NAGS Deficiency

• The recommended dosage of Carglumic acid tablets for oral suspension in adult and pediatric patients for acute hyperammonemia due to NAGS deficiency is (based on actual body weight) 100 mg/kg to 250 mg/kg orally daily.

• Divide the daily dosage into 2 to 4 doses and round to the nearest 100 mg (i.e., half of a Carglumic acid tablets 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 adult and pediatric patients for chronic hyperammonemia due to NAGS deficiency is (based on actual body weight) 10 mg/kg to 100 mg/kg orally daily.

• Divide the daily dosage into 2 to 4 doses and round to the nearest 100 mg (i.e., half of a Carglumic acid tablets 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 (2.4)].

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.

<div class="scrollingtable"><table class="Noautorules" width="630"> <caption> <span>     </span> </caption> <col width="189"/> <col width="231"/> <col width="210"/> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Moderate Renal Impairment </span> <br/> <span class="Bold"> (eGFR 30-59 mL/min/1.73 m<span class="Sup">2</span>)</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Severe Renal Impairment </span> <br/> <span class="Bold"> (eGFR 15-19 mL/min/1.73 m<span class="Sup">2</span>)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Acute Hyperammonemia due to NAGS Deficiency<br/> </td><td align="left" class="Botrule Rrule" valign="top"> 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)<br/> </td><td align="left" class="Botrule Rrule" valign="top"> 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)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Chronic Hyperammonemia due to NAGS Deficiency<br/> </td><td align="left" class="Botrule Rrule" valign="top"> 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)<br/> </td><td align="left" class="Botrule Rrule" valign="top"> 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)<br/> </td> </tr> </tbody> </table></div>

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" on one side.

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None

{ "type": "p", "children": [], "text": "\nNone" }

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 an 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 treated with carglumic acid tablets for oral suspension.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span> Table 1: Adverse Reactions Reported in ≥ 2 Patients with NAGS deficiency Treated with Carglumic Acid Tablets for Oral Suspension in the Retrospective Case Series </span> </caption> <col width="62%"/> <col width="37%"/> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold"> Adverse Reaction</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Number of Patients (N) (%)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Vomiting<br/> </td><td align="center" class="Botrule Rrule"> 6 (26)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Abdominal pain<br/> </td><td align="center" class="Botrule Rrule"> 4 (17)<br/> </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> Pyrexia<br/> </td><td align="center" class="Rrule"> 4 (17)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> Tonsillitis<br/> </td><td align="center" class="Botrule Rrule Toprule"> 4 (17)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Anemia<br/> </td><td align="center" class="Botrule Rrule"> 3 (13)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Diarrhea<br/> </td><td align="center" class="Botrule Rrule"> 3 (13)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Ear infection<br/> </td><td align="center" class="Botrule Rrule"> 3 (13)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Infections<br/> </td><td align="center" class="Botrule Rrule"> 3 (13)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Nasopharyngitis<br/> </td><td align="center" class="Botrule Rrule"> 3 (13)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Hemoglobin decreased<br/> </td><td align="center" class="Botrule Rrule"> 3 (13)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Headache<br/> </td><td align="center" class="Botrule Rrule"> 3 (13)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Dysgeusia<br/> </td><td align="center" class="Botrule Rrule"> 2 (9)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Asthenia<br/> </td><td align="center" class="Botrule Rrule"> 2 (9)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Hyperhidrosis<br/> </td><td align="center" class="Botrule Rrule"> 2 (9)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Influenza<br/> </td><td align="center" class="Botrule Rrule"> 2 (9)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Pneumonia<br/> </td><td align="center" class="Botrule Rrule"> 2 (9)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Weight decreased<br/> </td><td align="center" class="Botrule Rrule"> 2 (9)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Anorexia<br/> </td><td align="center" class="Botrule Rrule"> 2 (9)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Somnolence<br/> </td><td align="center" class="Botrule Rrule"> 2 (9)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Rash<br/> </td><td align="center" class="Botrule Rrule"> 2 (9)<br/> </td> </tr> </tbody> </table></div>

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.

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.

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).

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.

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 to determine whether they respond differently from younger patients.

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 (2.4)]. 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 the dose.

{ "type": "p", "children": [], "text": "\nOne 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 the 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.

{ "type": "p", "children": [], "text": "\nCarglumic 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." }

The chemical name of carglumic acid is N-carbamoyl-L-glutamic acid or (2S)-2-(carbamoylamino) pentanedioic acid. The empirical formula is C6H10N2O5 and the molecular weight is 190.16.

{ "type": "p", "children": [], "text": "The chemical name of carglumic acid is N-carbamoyl-L-glutamic acid or (2S)-2-(carbamoylamino) pentanedioic acid. The empirical formula is C6H10N2O5 and the molecular weight is 190.16." }

The structural formula is:

{ "type": "p", "children": [], "text": "The structural formula is:" }

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.

{ "type": "p", "children": [], "text": "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.

<div class="scrollingtable"><table class="Noautorules" width="626"> <caption> <span> Table 3: Mean (SD) Pharmacokinetic Parameter Values of Carglumic Acid in Healthy Subjects </span> </caption> <col width="177"/> <col width="234"/> <col width="215"/> <tfoot> <tr> <td align="left" colspan="3"> <p class="First Footnote"> <span class="Sup"># </span>Median (range); N/A, not applicable.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> PK parameter<br/> </td><td align="left" class="Botrule Rrule Toprule" valign="top"> IV infusion 8 mg/kg<br/> (N=10)<br/> </td><td align="left" class="Botrule Rrule Toprule" valign="top"> Oral 100 mg/kg<br/> (N=12)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> C<span class="Sub">max</span> (ng/mL)<br/> </td><td align="left" class="Botrule Rrule" valign="top"> 8613 (558)<br/> </td><td align="left" class="Botrule Rrule" valign="top"> 3284 (321)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> T<span class="Sub">max</span> (hr)<span class="Sup">#</span> <br/> </td><td align="left" class="Botrule Rrule" valign="top"> 2 (1-2)<br/> </td><td align="left" class="Botrule Rrule" valign="top"> 3 (2-4)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> AUC (ng*hr/mL)<br/> </td><td align="left" class="Botrule Rrule" valign="top"> 24501 (1613)<br/> </td><td align="left" class="Botrule Rrule" valign="top"> 31426 (2150)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> T<span class="Sub">1/2</span> (hr)<br/> </td><td align="left" class="Botrule Rrule" valign="top"> 31 (3)<br/> </td><td align="left" class="Botrule Rrule" valign="top"> 25 (2)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> CL (L/hr/kg)<br/> </td><td align="left" class="Botrule Rrule" valign="top"> 0.34 (0.02)<br/> </td><td align="left" class="Botrule Rrule" valign="top"> N/A<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Vd (L/kg)<br/> </td><td align="left" class="Botrule Rrule" valign="top"> 15 (1)<br/> </td><td align="left" class="Botrule Rrule" valign="top"> N/A<br/> </td> </tr> </tbody> </table></div>

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 Cmax 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 (0.95, 1.86), 2.0 (1.62, 2.50), and 4.4 (3.11, 6.28) respectively. 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 1.4 (1.09, 1.73), 2.8 (2.27, 3.47), and 6.9 (5.21, 9.24), respectively [see Dosage and Administration (2.4)].

<div class="scrollingtable"><table class="Noautorules" width="689"> <caption> <span> Table 4: Mean (SD) C<span class="Sub">max</span> and AUC<span class="Sub">0-</span><span class="Sub">t</span>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 </span> </caption> <col width="94"/> <col width="119"/> <col width="118"/> <col width="1"/> <col width="119"/> <col width="119"/> <col width="119"/> <tfoot> <tr> <td align="left" colspan="7"> <p class="First Footnote">Treatment groups 1a and 1b represent two separate matched control groups of healthy subjects with normal renal function.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"><span class="Bold"> PK Parameters</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Normal Renal Function<span class="Sup">1a</span>: eGFR ≥90 mL/min/1.73m<span class="Sup">2</span> (N=8)</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" colspan="2"><span class="Bold"> Mild Renal Impairment: eGFR 60-89 mL/min/1.73m<span class="Sup">2</span></span> <br/> <span class="Bold"> (N=8)</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Moderate Renal Impairment: eGFR 30-59 mL/min/1.73m<span class="Sup">2</span> (N=8)</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Normal Renal Function<span class="Sup">1b</span>: eGFR ≥90 mL/min/1.73m<span class="Sup">2</span> (N=8)</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Severe Renal Impairment: eGFR 15-29</span><span class="Bold"> mL/min/1.73m<span class="Sup">2</span></span> <br/> <span class="Bold"> (N=8)</span> <br/> </td> </tr> <tr> <td align="center" class="Botrule"> <br/> </td><td align="center" class="Botrule"><span class="Bold"> 80 mg/kg</span> <br/> </td><td align="center" class="Botrule Rrule" colspan="2"> <br/> </td><td align="center" class="Botrule Rrule" colspan="2"><span class="Bold"> 40 mg/kg</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> C<span class="Sub">max</span> (ng/mL)<br/> </td><td align="center" class="Botrule Rrule"> 2983 (552)<br/> </td><td align="center" class="Botrule Rrule" colspan="2"> 4310 (1937)<br/> </td><td align="center" class="Botrule Rrule"> 6129 (1854)<br/> </td><td align="center" class="Botrule Rrule"> 1890 (901)<br/> </td><td align="center" class="Botrule Rrule"> 8377 (3815)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> AUC<span class="Sub">0-t</span> (ng*hr/mL)<br/> </td><td align="center" class="Botrule Rrule"> 28313 (6204)<br/> </td><td align="center" class="Botrule Rrule" colspan="2"> 39545 (12109)<br/> </td><td align="center" class="Botrule Rrule"> 79766 (19708)<br/> </td><td align="center" class="Botrule Rrule"> 20212 (6186)<br/> </td><td align="center" class="Botrule Rrule"> 143075 (55910)<br/> </td> </tr> </tbody> </table></div>

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 orally 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.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span> Table 5: Baseline Characteristics of 23 NAGS Deficiency Patients Treated with Carglumic Acid Tablets for Oral Suspension </span> </caption> <col width="59%"/> <col width="24%"/> <col width="16%"/> <tbody class="Headless"> <tr> <td align="right" class="Lrule Rrule Toprule" colspan="3" valign="top"> Patients<br/> N=23<br/> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2"> Sex<br/> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Male<br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> 14 (61%)<br/> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> Female<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 9 (39%)<br/> </td> </tr> <tr> <td align="center" class="Botrule Lrule" rowspan="2"> Age at initiation of carglumic acid tablets for oral suspension therapy (years)<br/> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> Mean (SD)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2 (4)<br/> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> Min to Max<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0 - 13<br/> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" rowspan="3"> Age groups at initiation of carglumic acid tablets for oral suspension therapy<br/> </td><td align="center" class="Botrule Rrule" valign="top"> &lt;30 days<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 9 (39%)<br/> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> &gt;30 days - 11 months<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 9 (39%)<br/> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> ≥1 - 13 years<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5 (22%)<br/> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" rowspan="3"> NAGS gene mutations by DNA testing<br/> </td><td align="center" class="Botrule Rrule" valign="top"> Homozygous<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 14 (61%)<br/> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> Heterozygous<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 4 (17%)<br/> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> Not available<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5 (22%)<br/> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" rowspan="2" valign="top"> Patients current treatment status<br/> </td><td align="center" class="Botrule Rrule" valign="top"> On-going<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 18 (78%)<br/> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> Discontinued<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5 (22%)<br/> </td> </tr> </tbody> </table></div>

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).

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span> Table 6: Plasma Ammonia Levels in NAGS Deficiency Patients at Baseline and After Treatment with Carglumic Acid Tablets for Oral Suspension </span> </caption> <col width="50%"/> <col width="25%"/> <col width="24%"/> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold"> Time point</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Patients </span> <br/> <span class="Bold"> (N = 13)</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Ammonia<span class="Sup">   </span>level</span> <br/> <span class="Bold"> (micromol/L)</span> <br/> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" rowspan="5" valign="top"> <br/> <span class="Bold"> Baseline</span> <br/> (prior to first dose of carglumic acid tablets for oral suspension)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> N<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 13<br/> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> Mean (SD)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 271 (359)<br/> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> Median<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 157<br/> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> Range<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 72-1428<br/> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> Missing Data<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0<br/> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" rowspan="5" valign="top"> <br/> <br/> <span class="Bold"> Day 1</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"> N<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 10<br/> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> Mean (SD)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 181 (358)<br/> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> Median<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 65<br/> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> Range<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 25-1190<br/> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> Missing Data<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3<br/> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" rowspan="5" valign="top"> <br/> <br/> <span class="Bold"> Day 2</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"> N<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 8<br/> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> Mean (SD)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 69 (78)<br/> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> Median<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 44<br/> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> Range<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 11-255<br/> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> Missing Data<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5<br/> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" rowspan="5" valign="top"> <br/> <br/> <span class="Bold"> Day 3</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"> N<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5<br/> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> Mean (SD)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 27 (11)<br/> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> Median<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 25<br/> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> Range<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 12-42<br/> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> Missing Data<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 8<br/> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" rowspan="5" valign="top"><span class="Bold"> Long-term treatment</span> <br/> (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.)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> N<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 13<br/> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> Mean (SD)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 23 (7)<br/> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> Median<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 24<br/> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> Range<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 9-34<br/> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> Missing Data<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0<br/> </td> </tr> </tbody> </table></div>

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

How Supplied

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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.

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Carglumic acid tablets for oral suspension is supplied in a high-density polyethylene bottle with a child resistant polypropylene cap and desiccant unit. Each bottle contains either 5 or 60 tablets.

{ "type": "p", "children": [], "text": "Carglumic acid tablets for oral suspension is supplied in a high-density polyethylene bottle with a child resistant polypropylene cap and desiccant unit. Each bottle contains either 5 or 60 tablets." }

Bottle of 5 tablets: NDC 68475-006-01

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Bottle of 60 tablets: NDC 68475-006-02

{ "type": "p", "children": [], "text": "Bottle of 60 tablets: NDC 68475-006-02" }

Storage

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Store at 20° to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].

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After first opening of the bottle:

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{ "type": "ul", "children": [ "Store at room temperature between 15°C and 30°C (59°F and 86°F). Do not refrigerate.", "Keep the bottle tightly closed between openings in order to protect from moisture.", "Write the date of opening on the bottle.", "Do not use carglumic acid tablets for oral suspension after the expiration date stated on the bottle.", "Discard bottle one month after first opening." ], "text": "" }

Advise the patient to read the FDA-approved patient labeling (Instructions for Use).

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Advise the patient or caregiver on the following:

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Preparation and Administration [see Dosage and Administration (2.5)]

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{ "type": "ul", "children": [ "Disperse carglumic acid tablets for oral suspension in water. Do not swallow whole or crushed.", "Take carglumic acid tablets for oral suspension immediately before meals or feedings.", "Carglumic acid tablets for oral suspension dispersed in water can be administered orally or via a nasogastric tube or gastrostomy tube, as described in the Instructions for Use ." ], "text": "" }

Storage [see How Supplied/Storage and Handling (16)]

{ "type": "p", "children": [], "text": "\nStorage [see How Supplied/Storage and Handling (16)]\n" }

{ "type": "ul", "children": [ "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 bottle: Do not refrigerate. Store at room temperature between 15° to 30°C (59° to 86°F). Keep the bottle tightly closed in order to protect from moisture. Write the date of opening on the bottle.", "Discard bottle one month after first opening. Do not use carglumic acid tablets for oral suspension after the expiration date stated on the bottle." ], "text": "" }

Manufactured for:

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Navinta LLC

{ "type": "p", "children": [], "text": "\nNavinta LLC\n" }

1499 lower Ferry Road, Ewing,

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NJ 08618

{ "type": "p", "children": [], "text": "NJ 08618" }

Revised: 03/2024

{ "type": "p", "children": [], "text": "Revised: 03/2024" }

31230622 R1

{ "type": "p", "children": [], "text": "31230622 R1" }

INSTRUCTIONS FOR USE

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Carglumic Acid Tablets for Oral Suspension

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Important information:

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{ "type": "ul", "children": [ "\nCarglumic acid tablet for oral suspension must be mixed in water before taking. Carglumic acid tablets for oral suspension should not be mixed in any other food or liquid.", "\nDo not swallow carglumic acid tablets for oral suspension whole.", "\nDo not crush carglumic acid tablets for oral suspension.", "Take carglumic acid tablets for oral suspension right before meals or feedings.", "The carglumic acid tablet for oral suspension and water mixture has a slightly sour taste." ], "text": "" }

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.

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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. 

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Taking carglumic acid tablets for oral suspension by mouth using a cup:

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Children and Adults

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Taking carglumic acid tablets for oral suspension by mouth using an oral syringe:

{ "type": "p", "children": [], "text": "\nTaking carglumic acid tablets for oral suspension by mouth using an oral syringe:\n" }

Children

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{ "type": "", "children": [], "text": "" }

Giving carglumic acid tablets for oral suspension through a nasogastric (NG) tube or gastrostomy tube (G-tube):

{ "type": "p", "children": [], "text": "\nGiving carglumic acid tablets for oral suspension through a nasogastric (NG) tube or gastrostomy tube (G-tube):\n" }

Children and Adults

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{ "type": "", "children": [], "text": "" }

How should I store carglumic acid tablets for oral suspension?

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{ "type": "ul", "children": [ "\nBefore opening, store carglumic acid tablets for oral suspension at controlled room temperature between 68°F to 77°F (20°C to 25°C) in the bottle it comes in.", "\nAfter opening, store carglumic acid tablets for oral suspension at room temperature between 59°F to 86°F (15°C to 30°C). Do not store carglumic acid tablets for oral suspension in a refrigerator after opening.\nKeep carglumic acid tablets for oral suspension in a tightly closed bottle to protect the tablets from moisture.\nWrite the date the carglumic acid tablet for oral suspension bottle is opened on the bottle label. Throw away any unused tablets one month after opening the bottle.\n\n", "Do not use carglumic acid tablets for oral suspension after the expiration date on the bottle.", "\nKeep carglumic acid tablets for oral suspension and all medicines out of the reach of children.\n" ], "text": "" }

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

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Manufactured for:

{ "type": "p", "children": [], "text": "\nManufactured for:\n" }

Navinta LLC

{ "type": "p", "children": [], "text": "\nNavinta LLC\n" }

1499 lower Ferry Road, Ewing,

{ "type": "p", "children": [], "text": "1499 lower Ferry Road, Ewing, " }

NJ 08618

{ "type": "p", "children": [], "text": "NJ 08618" }

Revised: 03/2024

{ "type": "p", "children": [], "text": "Revised: 03/2024" }

31230622 R1

{ "type": "p", "children": [], "text": "31230622 R1" }

Bottle label - 5 Tablets in Bottle

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NDC 68475-006-01

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Carglumic Acid

{ "type": "p", "children": [], "text": "Carglumic Acid" }

Tablets for Oral

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Suspension

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200 mg

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Store at 20° to 25°C (68°F to 77°F);

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excursions permitted between 15°C

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and 30°C (59°F and 86°F)

{ "type": "p", "children": [], "text": "and 30°C (59°F and 86°F) " }

[See USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "[See USP Controlled Room Temperature]." }

5 Tablets

{ "type": "p", "children": [], "text": "5 Tablets" }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

Navinta LLC

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Carton label - 5 Tablets in Bottle

{ "type": "p", "children": [], "text": "\nCarton label - 5 Tablets in Bottle\n" }

NDC 68475-006-01

{ "type": "p", "children": [], "text": "NDC 68475-006-01" }

Carglumic Acid

{ "type": "p", "children": [], "text": "Carglumic Acid" }

Tablets for Oral

{ "type": "p", "children": [], "text": "Tablets for Oral" }

Suspension

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200 mg

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Disperse Carglumic Acid Tablets in water.

{ "type": "p", "children": [], "text": "Disperse Carglumic Acid Tablets in water." }

Do not swallow whole or crushed.

{ "type": "p", "children": [], "text": "Do not swallow whole or crushed." }

5 Tablets

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Rx only

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Navinta LLC

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Bottle label - 60 Tablets in Bottle

{ "type": "p", "children": [], "text": "\nBottle label - 60 Tablets in Bottle\n" }

NDC 68475-006-02

{ "type": "p", "children": [], "text": "NDC 68475-006-02" }

Carglumic Acid

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Tablets for Oral

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Suspension

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200 mg

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Store at 20° to 25°C (68°F to 77°F);

{ "type": "p", "children": [], "text": "Store at 20° to 25°C (68°F to 77°F); " }

excursions permitted between 15°C

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and 30°C (59°F and 86°F).

{ "type": "p", "children": [], "text": "and 30°C (59°F and 86°F). " }

[See USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "[See USP Controlled Room Temperature]." }

60 Tablets

{ "type": "p", "children": [], "text": "60 Tablets" }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

Navinta LLC

{ "type": "p", "children": [], "text": "Navinta LLC" }

Carton label - 60 Tablets in Bottle

{ "type": "p", "children": [], "text": "\nCarton label - 60 Tablets in Bottle\n" }

NDC 68475-006-02

{ "type": "p", "children": [], "text": "NDC 68475-006-02" }

Carglumic Acid

{ "type": "p", "children": [], "text": "Carglumic Acid" }

Tablets for Oral

{ "type": "p", "children": [], "text": "Tablets for Oral" }

Suspension

{ "type": "p", "children": [], "text": "Suspension" }

200 mg

{ "type": "p", "children": [], "text": "200 mg" }

Disperse Carglumic Acid Tablets in water.

{ "type": "p", "children": [], "text": "Disperse Carglumic Acid Tablets in water." }

Do not swallow whole or crushed.

{ "type": "p", "children": [], "text": "Do not swallow whole or crushed." }

60 Tablets

{ "type": "p", "children": [], "text": "60 Tablets" }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

Navinta LLC

{ "type": "p", "children": [], "text": "Navinta LLC" }