Carbaglu

Name: Carbaglu

What happens if I miss a dose?

Take the missed dose as soon as you remember, but only if you are getting ready to eat a meal. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

If you skip a meal, do not take your dose of carglumic acid. Wait until your next meal.

Introduction

Ammonia detoxicant; a synthetic structural analog of N-acetylglutamate (NAG), a physiologic activator of the urea cycle.1 3 4

Carbaglu Dosage and Administration

General

  • Initiate therapy as soon as the diagnosis of hyperammonemia due to NAGS deficiency is suspected.3 4 5

  • During acute hyperammonemic episodes, concomitant use of other therapies to lower plasma ammonia concentrations is recommended.1 3 4 5 8 9 (See Hyperammonemia under Uses.)

Restricted Distribution

  • Must be obtained from Accredo Health Group; not available in US from other distributors or at community pharmacies.11 12

  • Distributed to hospital pharmacies via Accredo wholesale distribution services.12

  • Contact Accredo at 888-454-8860 or for additional information or to enroll patients.11 12

Administration

Oral Administration

Administer orally in 2–4 divided doses daily immediately before meals or feedings.1

Administer as aqueous dispersion; tablets should not be swallowed whole or crushed.1 10 Do not disperse tablets in food or mix with liquids other than water.1 10

Dispersion for Adult Use

Place each 200-mg tablet in a cup containing ≥2.5 mL of water.1 10 Stir or shake gently until tablet is dispersed (tablet will not completely dissolve).1 10

Administer immediately; to ensure full dose is administered, resuspend any residue in the cup with additional volumes of water and swallow immediately.1 10

Dispersion for Pediatric Use

Place each 200-mg tablet in a cup containing 2.5 mL of water to prepare a suspension containing 80 mg/mL.1 10 Stir or shake gently until tablet is dispersed (tablet will not completely dissolve).1 10

Using oral syringe, withdraw appropriate dose and administer immediately; to ensure full dose is administered, refill the oral syringe with 1–2 mL of water and administer immediately.1 10 Discard any unused portion of dispersion.1 10

NG Tube

May administer aqueous dispersion through NG tube.1 10

Dosage

Pediatric Patients

Hyperammonemia Acute Hyperammonemia Oral

100–250 mg/kg daily given in 2–4 divided doses.1 Adjust dosage based on symptoms and plasma ammonia concentrations.1

Chronic Hyperammonemia Oral

Based on limited data, maintenance dosage usually <100 mg/kg daily; give in 2–4 divided doses.1 Adjust dosage to maintain a target normal (age-adjusted) plasma ammonia concentration.1 3

Adults

Hyperammonemia Acute Hyperammonemia Oral

100–250 mg/kg daily.1 Round total daily dosage to nearest 100 mg (i.e., half-tablet dosage strength) and administer in 2–4 divided doses.1 12 Adjust dosage based on symptoms and plasma ammonia concentrations.1

Chronic Hyperammonemia Oral

Based on limited data, maintenance dosage usually <100 mg/kg daily.1 Round total daily dosage to nearest 100 mg (i.e., half-tablet dosage strength) and administer in 2–4 divided doses.1 12 Adjust dosage to maintain a target normal plasma ammonia concentration.1 3

Special Populations

No special population dosage recommendations at this time.1

Cautions for Carbaglu

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Emergency Treatment of Hyperammonemia

Risk of rapid brain damage or death if acute symptomatic hyperammonemia is left uncontrolled; treat as a life-threatening emergency.1 3 4 5 8 9 Prompt use of all necessary therapies to reduce serum ammonia concentrations (e.g., dialysis [preferably hemodialysis]) is essential.1 3 4 5 8 9 Caloric supplementation recommended to reverse catabolism and reduce protein turnover; complete restriction of dietary protein recommended for 24–48 hours.1 4 5 8 9 (See Hyperammonemia under Uses.)

Manage hyperammonemia due to inborn errors of metabolism in coordination with medical personnel familiar with such conditions; usually requires health-care facilities able to provide multidisciplinary treatment (e.g., hemodialysis, nutritional management, medical support).1 4 5 8 9

Laboratory Monitoring

Closely monitor plasma ammonia concentrations, neurologic status, laboratory tests, and clinical response during treatment.1

Nutritional Management

Protein restriction and hypercaloric intake recommended to block ammonia-generating catabolic pathways during acute hyperammonemic episodes.1 4 5 8 9 Dietary protein intake may be increased when plasma ammonia concentrations normalize, with goal of unrestricted protein intake.1 3 4

Specific Populations

Pregnancy

Category C.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Use not recommended because of potential risk to nursing infants.1 3

Pediatric Use

Efficacy evaluated in neonates, infants, and children.1 No substantial differences in response relative to adults; however, data limited.1

Geriatric Use

Safety and efficacy not established.1

Common Adverse Effects

Infections (e.g., tonsilitis, ear infection, nasopharyngitis), vomiting, abdominal pain, diarrhea, fever, anemia, headache.1

Uses For Carbaglu

Carglumic acid is used together with diet and other medicines to treat and prevent hyperammonemia (too much ammonia in the blood) when it is caused by the lack of a liver enzyme called N-acetylglutamate synthase (NAGS).

Ammonia is formed in the body when we digest protein. A person without the NAGS enzyme can not process ammonia properly, and too much ammonia will collect in the blood. This will cause serious unwanted effects. Carglumic acid acts by replacing the NAGS enzyme and helps reduce the amount of ammonia in the blood.

This medicine is available only with your doctor's prescription.

What are some things I need to know or do while I take Carbaglu?

  • Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
  • Have blood work checked as you have been told by the doctor. Talk with the doctor.
  • Follow the diet plan that your doctor told you about.
  • Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using Carbaglu while you are pregnant.

What are some other side effects of Carbaglu?

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

  • Headache.
  • Loose stools (diarrhea).
  • Belly pain.
  • Upset stomach or throwing up.
  • Change in taste.
  • Nose or throat irritation.
  • Feeling tired or weak.
  • Weight loss.
  • Not hungry.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Contraindications

None

Carbaglu - Clinical Pharmacology

Mechanism of Action

Carglumic acid is a synthetic structural analogue of N-acetylglutamate (NAG), which is an essential allosteric activator of Carbamoyl Phosphate Synthetase 1 (CPS 1) in liver mitochondria. CPS 1 is the first enzyme of the urea cycle, which converts ammonia into urea. NAG is the product of N-acetylglutamate synthase (NAGS), a mitochondrial enzyme. Carglumic acid acts as a replacement for NAG in NAGS deficiency patients by activating CPS 1.

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.

Pharmacokinetics

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

Absorption

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

Distribution

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

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.

Elimination

Median values for the terminal half-life was 5.6 hours (range 4.3-9.5), the apparent total clearance was 5.7 L/min (range 3.0-9.7), the renal clearance was 290 mL/min (range 204-445), and the 24-hour urinary excretion was 4.5% of the dose (range 3.5-7.5). 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.

How Supplied/Storage and Handling

How Supplied

Carbaglu® is a white and elongated tablet, scored and coded "C" on one side.

Each tablet contains 200 mg of carglumic acid. Carbaglu® is available in 5 or 60 tablets in a polypropylene bottle with polyethylene cap and desiccant unit.

NDC 52276-312-05 Bottle of 5 tablets

NDC 52276-312-60 Bottle of 60 tablets

Storage

Before opening, store refrigerated at 2-8 °C (36-46 °F).
After first opening of the container:

  • Do not refrigerate, do not store above 30 °C (86 °F).
  • Keep the container tightly closed 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.

Patient Counseling Information

Physicians should inform patients and caregivers about the following instructions for safe use of Carbaglu®:

  • Carbaglu® tablets should not be swallowed whole or crushed. Each tablet should be dispersed in a minimum of 2.5 mL of water. Carbaglu® tablets do not dissolve completely in water and undissolved particles of the tablet may remain in the mixing container. The mixing container should be rinsed with additional volumes of water and the contents swallowed immediately.
  • Before opening, store in a refrigerator 2-8 °C (36-46 °F).
  • Keep the container tightly closed in order to protect from moisture.
  • After first opening of the container: do not refrigerate, do not store above 30 °C (86 °F).
  • 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.

Physicians should also advise patients and caregivers that:

  • When plasma ammonia levels have normalized, dietary protein intake can usually be increased with the goal of unrestricted protein intake.
  • Human milk-feeding is not recommended.
  • The most common adverse reactions are vomiting, abdominal pain, pyrexia, tonsilitis, anemia, ear infection, diarrhea, nasopharyngitis, and headache.


Supplied by:

Orphan Europe SARL

Paris, France

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.

Licensed to:

Recordati Rare Diseases, Inc.

Lebanon, NJ 08833

Carbaglu® is a registered Trademark of RRD

For Healthcare Professionals

Applies to carglumic acid: oral tablet dispersible

Hematologic

Hematologic side effects have included anemia (13%) and decreased hemoglobin (13%).[Ref]

General

General side effects have included ear infection (13%).[Ref]

Gastrointestinal

Gastrointestinal side effects have included abdominal pain (17%), diarrhea (13%), vomiting (26%), and dysgeusia (9%).[Ref]

Musculoskeletal

Musculoskeletal side effects have included asthenia (9%).[Ref]

Metabolic

Metabolic side effects have included hyperhidrosis (9%), pyrexia (17%), anorexia (9%), and decreased weight (9%).[Ref]

Nervous system

Nervous system side effects have included headache (13%) and somnolence (9%).[Ref]

Immunologic

Immunologic side effects have included infection (13%), influenza (9%), nasopharyngitis (13%), pneumonia (9%), and tonsillitis (17%).[Ref]

Dermatologic

Dermatologic side effects have included rash (9%).[Ref]

Some side effects of Carbaglu may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Carglumic acid Pregnancy Warnings

In embryofetal developmental toxicity studies, pregnant rats and rabbits received oral carglumic acid during organogenesis at doses up to 1.3 times the maximum recommended human starting dose based on body surface area (mg/m2). Actual doses were 500 and 2000 mg/kg/day (rats) and 250 and 1000 mg/kg/day (rabbits). The high doses resulted in maternal toxicity in both rats and rabbits. No effects on embryofetal development were observed in either species. In a perinatal and postnatal developmental study, female rats received oral carglumic acid from organogenesis through day 21 postpartum at doses up to 1.3 times the maximum recommended starting human dose based on body surface area (mg/m2). Actual doses were 500 and 2000 mg/kg/day. A reduction in offspring survival was seen at the high dose and a reduction in offspring growth was seen at both doses.

Carglumic acid has been assigned to pregnancy category C by the FDA. Decreased survival and growth occurred in offspring born to animals that received carglumic acid at doses similar to the maximum recommended starting human dose during pregnancy and lactation. Because untreated N-acetylglutamate synthase (NAGS) deficiency results in irreversible neurologic damage and death, women with NAGS must remain on carglumic acid therapy throughout pregnancy.

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