Carglumic acid is a medication used in the treatment of a rare genetic disorder called N-acetylglutamate synthase deficiency (NAGS deficiency). This disorder affects the body's ability to produce urea, which is necessary for the removal of ammonia from the body. Carglumic acid works by activating an enzyme called N-acetylglutamate synthase, which helps to regulate the urea cycle and reduce ammonia levels in the body.

NAGS deficiency can lead to high levels of ammonia in the blood, which can be toxic and cause serious health problems. Carglumic acid helps to lower ammonia levels and prevent the buildup of toxic substances in the body. It is usually prescribed as part of a comprehensive treatment plan that may include dietary restrictions and other medications.

Carglumic acid is an orphan drug that helps in converting ammonia into urea in patients with a rare genetic disorder caused by NAGS (N-acetyl glutamate synthase) deficiency. Acute and chronic hyperammonemia caused by a lack of the hepatic enzyme N-acetyl glutamate synthase is treated with it as an additional medication (NAGS).

Carglumic acid Dose in Adults

Carglumic acid for the treatment of Acute hyperammonemia:  

• Take carglumic acid by mouth.
• The dose is typically between 100 to 250 milligrams for each kilogram the person weighs, per day.
• They usually divide this dose into 2 or 4 smaller doses throughout the day.
• Doctors adjust the dose based on how old the person is and how much ammonia is in their blood.
• Doctors often suggest using other treatments alongside carglumic acid to lower ammonia levels.

Carglumic acid for the treatment of Chronic hyperammonemia:  

• Take carglumic acid by mouth.
• The usual dose of carglumic acid is typically less than 100 milligrams for each kilogram the person weighs per day.
• The dose is usually divided into 2 or 4 smaller doses throughout the day.
• Doctors adjust the dose based on the person's age and aim to bring their ammonia levels back to normal.

Carglumic acid Dose in Children

Carglumic acid for the treatment of Acute hyperammonemia:  

When dealing with acute hyperammonemia in infants, children, and adolescents, doctors typically recommend the following dose of carglumic acid:

• Take carglumic acid by mouth.
• The dose usually ranges from 100 to 250 milligrams for each kilogram the child weighs per day.
• This total dose is divided into 2 or 4 smaller doses throughout the day.
• Doctors adjust the dose based on the child's age and aim to bring their ammonia levels back to a normal range.
• Doctors often suggest using other treatments alongside carglumic acid to lower ammonia levels effectively.

Carglumic acid Use in the treatment of Chronic hyperammonemia:  

For chronic hyperammonemia in infants, children, and adolescents, the typical dose of carglumic acid is:

• Take carglumic acid by mouth.
• The usual dose is typically less than 100 milligrams for each kilogram the child weighs per day.
• This dose is divided into 2 or 4 smaller doses throughout the day.
• Doctors adjust the dose based on the child's age and aim to bring their ammonia levels back to a normal range.

This treatment helps manage chronic hyperammonemia by maintaining stable ammonia levels over time.

Pregnancy Risk Factor C

• The Pregnancy Risk Factor C classification for carglumic acid indicates that adverse events have been observed in animal reproduction studies, but there are no adequate and well-controlled studies in pregnant women.
• Despite this lack of data, it's crucial for pregnant women with NAGS deficiency to continue treatment with carglumic acid.
• This is because untreated NAGS deficiency can lead to irreversible fetal neurological damage.
• Therefore, the benefits of treating NAGS deficiency during pregnancy outweigh the potential risks associated with carglumic acid use.

Carglumic acid use during breastfeeding:

• Since it's unclear whether carglumic acid is excreted in breast milk, breastfeeding is not recommended for mothers taking this medication.
• While the exact risks to breastfeeding infants are unknown, it's better to err on the side of caution until more information is available.

Carglumic acid Dose in Renal Disease:

• The manufacturer's labeling for carglumic acid does not include specific dosage adjustments for individuals with renal impairment because it has not been studied in this population.

Carglumic acid Dose in Liver Disease:

• The manufacturer's labeling for carglumic acid does not include specific dosage adjustments for individuals with hepatic impairment because it has not been studied in this population.

Common Side Effects of Carglumic Acid Include:

• Gastrointestinal:
  • Vomiting
  • Abdominal pain
  • Diarrhea
• Central nervous system:
  • Headache
• Miscellaneous:
  • Fever
• Hematologic & oncologic:
  • Anemia
  • Decreased hemoglobin
• Otic:
  • Otic infection
• Infection:
  • Infection
• Respiratory:
  • Tonsillitis
  • Nasopharyngitis

Less Common Side Effects of Carglumic Acid Include:

• Respiratory:
  • Pneumonia
• Dermatologic:
  • Hyperhidrosis
  • Skin rash
• Central nervous system:
  • Drowsiness
• Endocrine & metabolic:
  • Weight loss
• Infection:
  • Influenza
• Gastrointestinal:
  • Anorexia
  • Dysgeusia
• Neuromuscular & skeletal:
  • Weakness

Contraindications to Carglumic Acid include:

• In the manufacturer's labeling for carglumic acid, there are typically no contraindications listed.
• According to Canadian labeling, additional contraindications not found in US labeling include hypersensitivity to carglumic acid or any component of the formulation, as well as breastfeeding.

Warnings and Precautions  

An experienced physician

• If someone is experiencing acute symptomatic hyperammonemia, it's a severe emergency that could be life-threatening.
• When hyperammonemia happens because of N-acetylglutamate synthase (NAGS) deficiency, it's crucial to manage it with the help of experts who know how to handle metabolic disorders.
• Seeking guidance from experienced physicians in managing metabolic disorders is essential for effective treatment and better outcomes in these situations.

Management of nutrition:

• To manage hyperammonemia effectively, it's recommended to restrict intake of complete proteins for 24-48 hours.
• This helps reduce the breakdown of proteins in the body, which can lead to increased ammonia levels.
• Instead, maximizing caloric intake is important to reverse this process and decrease nitrogen turnover.
• By providing sufficient calories, the body can use them for energy without relying on protein breakdown, ultimately helping to lower ammonia levels and manage the condition more effectively.

Monitor:

Plasma Ammonia Levels:

• Keep an eye on the levels of ammonia in the blood.
• Monitor regularly to check if they are within a safe range.

Physical Signs and Symptoms:

• Watch out for signs of hyperammonemia.
• Look for symptoms like:
  • Lethargy (feeling very tired)
  • Ataxia (loss of muscle coordination)
  • Confusion
  • Vomiting
  • Seizures
  • Memory impairment (problems remembering things)

Keeping track of these signs and symptoms helps in early detection and management of hyperammonemia.

How to administer carglumic acid:

• Timing: Administer carglumic acid immediately before meals or feedings.
• Preparation: Disperse the medication in water before giving it. Do not mix it with any other foods or liquids besides water.
• Oral Tablets:
  • Do not crush or swallow the tablets whole.
  • After dispersing in water, give the mixture right away.
  • Note that tablets may not dissolve completely; rinse the container with water and give the rinse immediately.
• Oral Syringe:
  • After dispersing tablets in water, draw the appropriate amount into an oral syringe and give it immediately. Discard any unused mixture.
  • Refill the oral syringe with at least 1 to 2 mL of water after the initial administration, and give it immediately.
• Nasogastric Tube:
  • After dispersing tablets in water, administer the mixture through a nasogastric tube immediately.
  • Note that tablets may not dissolve completely; follow with a flush of additional water to clear the tube.

These instructions ensure proper administration and effectiveness of the medication.

Mechanism of action of Carglumic Acid (carbaglu):

• N-acetylglutamate synthase (NAGS) is an enzyme found in mitochondria, the cell's powerhouses.
• It produces a compound called N-acetylglutamate (NAG).
• NAG plays a vital role as an activator for another important enzyme called carbamoyl phosphate synthetase 1 (CPS 1).
• This enzyme is crucial because it helps convert harmful ammonia into urea, which the body can safely remove.
• However, in patients with NAGS deficiency, the body can't make enough NAG to activate CPS 1 properly.
• This is where carglumic acid comes in.
• It acts as a substitute for NAG, helping to kick-start CPS 1 and keep the urea cycle running smoothly, ultimately reducing ammonia levels in the body.

Distribution:

• Volume of distribution (V) is approximately 2657 liters.
• This indicates how widely the medication spreads throughout the body.

Metabolism:

• Carglumic acid is metabolized by intestinal flora, which are the bacteria in the intestines.
• It's broken down into carbon dioxide, a normal waste product that the body can eliminate.

Half-life elimination:

• The median half-life of elimination is about 5.6 hours, with a range from 4.3 to 9.5 hours.
• Half-life refers to the time it takes for half of the drug to be removed from the bloodstream.

Time to peak:

• It takes a median of about 3 hours for the drug to reach its peak concentration in the bloodstream.

Excretion:

• Carglumic acid is primarily excreted through feces, with up to 60% being eliminated unchanged.
• About 9% is excreted in the urine as unchanged drug.
• Excretion through feces and urine helps remove the drug from the body once it has been metabolized or eliminated.

International Brands of Carglumic acid:

• Cabaglu
• Carbaglu
• Ucedane

Carglumic acid Brands in Pakistan:

No brands available in Pakistan