FDA Label for Carbaglu

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Carbaglu Product Label

The following document was submitted to the FDA by the labeler of this product Recordati Rare Diseases. The document includes published materials associated whith this product with the essential scientific information about this product as well as other prescribing information. Product labels may durg indications and usage, generic names, contraindications, active ingredients, strength dosage, routes of administration, appearance, warnings, inactive ingredients, etc.

1.1 Acute Hyperammonemia In Patients With Nags Deficiency

CARBAGLU is indicated as an adjunctive therapy in pediatric and adult patients for the treatment of acute hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS). During acute hyperammonemic episodes, concomitant administration of CARBAGLU with other ammonia lowering therapies, such as alternate pathway medications, hemodialysis, and dietary protein restriction, is recommended.

1.2 Chronic Hyperammonemia In Patients With Nags Deficiency

CARBAGLU is indicated as maintenance therapy in pediatric and adult patients for the treatment of chronic hyperammonemia due to deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS). During maintenance therapy, the concomitant use of other ammonia lowering therapies and protein restriction may be needed based on plasma ammonia levels.

2. Dosage And Administration

CARBAGLU treatment should be initiated by a physician experienced in metabolic disorders. Based on clinical experience, the treatment may be started as early as the first day of life.

CARBAGLU tablets are uncoated and should not be swallowed whole or crushed. Disperse CARBAGLU tablets in water immediately before use. For all preparations, use in other foods and liquids has not been studied clinically and is therefore not recommended.

2.1 Recommended Dosage

CARBAGLU should be initiated 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.

Initial Dosage: The recommended initial daily dosage of CARBAGLU in pediatric and adult patients for acute hyperammonemia is 100 mg/kg to 250 mg/kg divided into 2 to 4 doses and rounded to the nearest 100 mg (i.e., half of a CARBAGLU tablet). Concomitant administration of other ammonia lowering therapies is recommended.

Maintenance Dosage: The recommended daily maintenance dosage of CARBAGLU in pediatric and adult patients is 10 mg/kg to 100 mg/kg divided into 2 to 4 doses and rounded to the nearest 100 mg (i.e., half of a CARBAGLU tablet).

Therapeutic Monitoring

Closely monitor plasma ammonia levels. Titrate the CARBAGLU 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.).

2.2 Preparation And Administration

Disperse CARBAGLU tablets in water. Do not swallow whole or crushed.
Mix each 200 mg tablet in a minimum of 2.5 mL of water to yield a concentration of 80 mg/mL.
CARBAGLU tablets do not dissolve completely in water and undissolved particles of the tablet may remain in the mixing container.
Take CARBAGLU immediately before meals or feedings.
The CARBAGLU suspension has a slightly acidic taste.
For all preparations, use in foods or liquids, other than water, has not been studied clinically and is not recommended.

Preparation for Oral Administration in Pediatric and Adult Patients

Add about 2.5 mL of water into a small cup for each CARBAGLU tablet or each ½ CARBAGLU tablet needed for the prescribed dose.
Add the CARBAGLU tablets 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.

Preparation for Nasogastric Tube Administration in Pediatric and Adult Patients

For patients who have a nasogastric tube in place, CARBAGLU should be administered as follows:

Add about 2.5 mL of water into a small cup for each CARBAGLU tablet or each ½ CARBAGLU tablet needed for the prescribed dose.
Add the CARBAGLU tablets 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 nasogastric (NG) tube. Pieces of the tablet may remain in the catheter-tip syringe or NG tube.
Flush immediately with 1 to 2 mL of additional water to clear the NG tube.
Flush the NG tube again, as needed, until no pieces of the tablet are left in the syringe or NG tube.

Preparation for Oral Administration Using an Oral Syringe in Pediatric Patients

For administration via oral syringe, CARBAGLU should be administered as follows:

Add about 2.5 mL of water into a small cup for each CARBAGLU tablet or each ½ CARBAGLU tablet needed for the prescribed dose.
Add the CARBAGLU tablets 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 to 2 mL) and administer immediately.
Flush the oral syringe again, as needed, until no pieces of the tablet are left in the syringe.

3. Dosage Forms And Strengths

CARBAGLU is a white and elongated 200 mg tablet for oral suspension, functionally scored and coded “C” on one side.

4. Contraindications

None

5.1 Hyperammonemia

Any episode of acute symptomatic hyperammonemia should be treated as a life-threatening emergency. Treatment of severe hyperammonemia may require dialysis, preferably hemodialysis and/or hemofiltration, to reduce plasma ammonia concentration. Untreated hyperammonemia can result in brain damage and death, and prompt use of all therapies necessary to reduce plasma ammonia level is essential.

Since hyperammonemia in NAGS deficiency is the result of imbalance between ammonia detoxification capacity and protein catabolism, complete protein restriction during an acute hyperammonemic episode is recommended for no longer than 12 to 36 hours while maximizing caloric supplementation to reverse catabolism. Protein should be reintroduced as early as possible, following improvement of metabolic and clinical abnormalities in this setting. During long-term management, dietary protein restriction should be instituted to maintain blood ammonia level within an acceptable range for age.

Ongoing monitoring of plasma ammonia level, neurological status, growth parameters, protein intake/nutritional status (both during acute hyperammonemic episodes and long-term), and relevant laboratory tests in patients receiving CARBAGLU should be part of evaluating the clinical response to treatment.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Table 1 summarizes adverse reactions occurring in 2 or more patients treated with CARBAGLU in the retrospective case series (≥ 9%).

Table 1: Adverse Reactions Reported in ≥ 2 Patients in the Retrospective Case Series Treated with CARBAGLU
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	2 (9)
Dysguesia	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)

8.1 Pregnancy

Pregnancy Category C

There are no adequate and well controlled studies or available human data with CARBAGLU in pregnant women. Decreased survival and growth occurred in offspring born to animals that received carglumic acid at a dose approximately 38 times the maximum reported human maintenance dose. Because untreated N-acetylglutamate synthase (NAGS) deficiency results in irreversible neurologic damage and death, women with NAGS must remain on treatment throughout pregnancy.

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).

In a peri- and post-natal developmental study, female rats received oral carglumic acid from organogenesis through lactation at doses of 500 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).

8.3 Nursing Mothers

It is not known whether CARBAGLU is excreted in human milk. Carglumic acid is excreted in rat milk, and an increase in mortality and impairment of body weight gain occurred in neonatal rats nursed by mothers receiving carglumic acid. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from CARBAGLU, breast-feeding is not recommended. Treatment is continuous and life-long for NAGS deficiency patients.

8.4 Pediatric Use

The efficacy of CARBAGLU for the treatment of hyperammonemia in patients with NAGS deficiency from birth to adulthood was evaluated in a retrospective review of the clinical course of 23 NAGS deficiency patients who all began CARBAGLU treatment during infancy or childhood. There are no apparent differences in clinical response between adults and pediatric NAGS deficiency patients treated with CARBAGLU, however, data are limited.

8.5 Geriatric Use

CARBAGLU has not been studied in the geriatric population. Therefore, the safety and effectiveness in geriatric patients have not been established.

10. Overdosage

One patient treated with 650 mg/kg/day of carglumic acid developed symptoms characterized as a monosodium glutamate intoxication-like syndrome: tachycardia, profuse sweating, increased bronchial secretion, increased body temperature and restlessness. These symptoms resolved upon reduction of dose.

Repeated oral dosing of carglumic acid at 2000 mg/kg/day was lethal to most neonatal rats within 2-3 days of treatment. The plasma concentrations that produced lethality were not measured. In adult rats, a single oral administration of carglumic acid was not lethal at doses up to 2800 mg/kg (approximately 20 times the maximum starting dose based on C _max).

11. Description

CARBAGLU 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 boiling water, slightly soluble in cold water, practically insoluble in organic solvents.

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:

Carbaglu structure - 1

Molecular Formula: C ₆H ₁₀N ₂O ₅

The inactive ingredients of CARBAGLU are croscarmellose sodium, hypromellose, microcrystalline cellulose, silica colloidal anhydrous, sodium lauryl sulfate, sodium stearyl fumarate.

12.1 Mechanism Of Action

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 in patients with NAGS deficiency, thereby removing the block in the urea cycle and facilitating ammonia detoxification and urea production.

12.2 Pharmacodynamics

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.

12.3 Pharmacokinetics

The pharmacokinetics of carglumic acid have been studied in healthy male subjects using both radiolabeled and non-radiolabeled carglumic acid.

Absorption

The median Tmax of CARBAGLU was 3 hours (range: 2 to 4 hours). Absolute bioavailability has not been determined.

Distribution

The apparent volume of distribution was 2657 L (range: 1616-5797). Protein binding has not been determined.

Elimination

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

Median value for the terminal half-life was 5.6 hours (range 4.3 to 9.5 hours), the apparent total clearance was 5.7 L/min (range 3.0 to 9.7 L/min), the renal clearance was 290 mL/min (range 204 to 445 mL/min), and the 24-hour urinary excretion was 4.5% of the dose (range 3.5 to 7.5%). Following administration of a single radiolabeled oral dose of 100 mg/kg of body weight, 9% of the dose was excreted unchanged in the urine and up to 60% of the dose was excreted unchanged in the feces.

Drug Interaction Studies

No drug interaction studies have been performed. Based on in vitro studies, CARBAGLU 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.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

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).

14.1 Responses Of Patients With Nags Deficiency To Acute And Chronic Treatment

The efficacy of CARBAGLU in the treatment of hyperammonemia due to NAGS deficiency was evaluated in a retrospective review of the clinical course of 23 NAGS deficiency patients who received CARBAGLU treatment for a median of 7.9 years (range 0.6 to 20.8 years). Treatment with CARBAGLU was divided in two regimens. For acute treatment, patients received a total daily dose of 100 to 250 mg/kg per day primarily administered in 2 to 4 divided doses for the first few days of treatment. For maintenance treatment, the dosage was reduced over time based upon biochemical and clinical responses.

The demographics characteristics of the patient population are shown in Table 2.

Table 2: Baseline Characteristics of the 23 NAGS deficiency patients
		Patients N=23
Gender	Male	14 (61%)
Gender	Female	9 (39%)
Age at initiation of CARBAGLU therapy (years)	Mean (SD)	2 (4)
Age at initiation of CARBAGLU therapy (years)	Min-Max	0-13
Age groups at initiation of CARBAGLU 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%)
Patients current treatment status	Discontinued	5 (22%)

The clinical observations in the 23 patient case series were retrospective, unblinded and uncontrolled and preclude any meaningful formal statistical analyses of the data. However, short-term efficacy was evaluated using mean and median change in plasma ammonia levels from baseline to days 1 to 3. Persistence of efficacy was evaluated using long-term mean and median change in plasma ammonia level. Table 3 summarizes the plasma ammonia levels at baseline, days 1 to 3 post-CARBAGLU treatment, and long-term CARBAGLU treatment for 13 evaluable patients. Of the 23 NAGS deficiency patients who received treatment with CARBAGLU, a subset of 13 patients who had both well documented plasma ammonia levels prior to CARBAGLU treatment and after long-term treatment with CARBAGLU were selected for analysis.

All 13 patients had abnormal ammonia levels at baseline. The overall mean baseline plasma ammonia level was 271 micromol/L. By day 3, normal plasma ammonia levels were attained in patients for whom data were available. Long-term efficacy was measured using the last reported plasma ammonia level for each of the 13 patients analyzed (median length of treatment was 6 years; range 1 to 16 years). The mean and median ammonia levels were 23 micromol/L and 24 micromol/L, respectively, after a mean treatment duration of 8 years.

Table 3: Plasma ammonia levels at baseline and after treatment with CARBAGLU
13/23 patients with complete short-term and long-term plasma ammonia documentation *Mean ammonia normal range: 5 to 50 micromol/L
Timepoint	Statistics (N = 13*)	Ammonia** (micromol/L)
Baseline (prior to first treatment with CARBAGLU)	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 Mean: 8 years Median: 6 years 1 to 16 years (last available value on CARBAGLU 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 CARBAGLU in 13 evaluable patients with NAGS deficiency is illustrated in Figure 1.

Figure 1: Ammonia response for 13 evaluable NAGS deficiency patients at baseline and after treatment with CARBAGLU

ammonia response chart - 2

16. How Supplied/Storage And Handling

How Supplied

CARBAGLU is a white and elongated 200 mg tablet for oral suspension, functionally scored and coded “C” on one side.

CARBAGLU is available in 5 or 60 tablets in a high density polyethylene bottle with child resistant polypropylene cap and desiccant unit.

NDC 52276-312-05 Bottles of 5 tablets

NDC 52276-312-60 Bottles of 60 tablets

Storage

Store in the original unopened container at 2 – 8 °C (36 – 46 °F).

After first opening of the container:

Do not refrigerate, store at room temperature between 15 – 30°C (59 – 86°F).
Keep the container tightly closed between openings in order to protect from moisture.
Write the date of opening on the tablet container.
Do not use after the expiration date stated on the tablet container.
Discard one month after first opening.

17. Patient Counseling Information

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

Preparation and Administration

Disperse CARBAGLU tablets in water. Do not swallow whole or crushed.
Take CARBABLU immediately before meals or feedings.
CARBAGLU tablets dispersed in water can be administered orally or via a nasogastric tube, as described in the Instructions for Use.

Storage

Store UNOPENED container in a refrigerator at 2 to 8 °C (36 to 46 °F).
fter first opening of the container: do not refrigerate, store at room temperature between 15 to 30°C (59 to 86°F). Keep the container tightly closed in order to protect from moisture. Write the date of opening on the tablet container. Discard one month after first opening. Do not use after the expiration date stated on the tablet container.

Lactation

Advise women not to breast-feed during treatment with CARBAGLU [see Use in Specific Populations ( 8.3)] .

Supplied by:

Orphan Europe SARL
Puteaux, France

Licensed to and Distributed by:

Recordati Rare Diseases Inc.
Lebanon, NJ 08833

For drug or ordering information please call Accredo Health Group Inc., Customer Service at 1-888-454-8860.

Carbaglu ^® is a licensed trademark of Recordati Rare Diseases Inc.

This product label may have been updated. For the most recent prescribing information, please visit www.recordatirarediseases.com or www.carbaglu.net.

Instructions For Use

CARBAGLU (CAR-buh-gloo)

(carglumic acid)

tablet for oral suspension

Important information:

CARBAGLU tablet for oral suspension (CARBAGLU tablet) must be mixed in water before taking. CARBAGLU tablets should not be mixed in any other food or liquid.
Do not swallow CARBAGLU tablets whole.
Do not crush CARBAGLU tablets.
Take CARBAGLU right before meals or feedings.
The CARBAGLU tablet and water mixture has a slightly sour taste.

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 your dose of CARBAGLU.

Taking CARBAGLU tablets by mouth using a cup:

Children and Adults

Add about 2.5 mL of water into a small cup for each CARBAGLU tablet, or each ½ CARBAGLU tablet, needed for the prescribed dose. For example, if the prescribed dose is 2 CARBAGLU tablets, add about 5 mL of water into the cup. If the prescribed dose is 2½ CARBAGLU tablets, add about 7.5 mL of water into the cup. Ask your healthcare provider if you are not sure of how much water you should use for the prescribed dose of CARBAGLU.
Place the prescribed number of CARBAGLU tablets into the water in the cup.
Carefully stir the CARBAGLU tablet and water mixture in the cup to avoid spilling the mixture. CARBAGLU tablets do not dissolve completely in water.
Swallow the CARBAGLU tablet and water mixture right away.
Pieces of the tablet may remain in the cup. Add more water to the cup to rinse the cup and swallow the mixture right away.
Repeat step 5 until there are no pieces of the tablet left in the cup.

Taking CARBAGLU tablets by mouth using an oral syringe:
Children

Add about 2.5 mL of water into a small cup for each CARBAGLU tablet, or each ½ CARBAGLU tablet, needed for the prescribed dose. For example, if the prescribed dose is 2 CARBAGLU tablets, add about 5 mL of water into the cup. If the prescribed dose is 2½ CARBAGLU tablets, add about 7.5 mL of water into the cup. Ask your healthcare provider if you are not sure of how much water you should use for the prescribed dose of CARBAGLU.
Place the prescribed number of CARBAGLU tablets into the water in the cup.
Carefully stir the CARBAGLU tablet and water mixture in the cup to avoid spilling the mixture. CARBAGLU tablets do not dissolve completely in water.
Draw up all of the CARBAGLU tablet and water mixture in the cup into an oral syringe.
Give your child the CARBAGLU tablet and water mixture right away by placing the tip of the oral syringe along the inner cheek of their mouth, on either the right or left side. Slowly push all the way down on the plunger to give the medicine.
Pieces of the tablet may remain in the oral syringe. Refill the oral syringe with at least 1 mL to 2 mL of water, and give your child the mixture right away.
Repeat step 6 until there are no pieces of the tablet left in the oral syringe.

Giving CARBAGLU tablets through a nasogastric (NG) tube: