Carglumic acid (Tablets) Instructions for Use

ATC Code

A16AA05 (Carglumic acid)

Active Substance

Carglumic acid

Clinical-Pharmacological Group

Hypoammonemic drug

Pharmacotherapeutic Group

Other drugs for the treatment of gastrointestinal diseases and metabolic disorders; amino acids and their derivatives; ademetionine

Pharmacological Action

Carglumic acid is a structural analog of N-acetylglutamate (NAG), which is a natural activator of carbamoyl phosphate synthetase (CPS), the first enzyme in the urea cycle.

Carglumic acid increases the activity of hepatic CPS. Despite the lower ability of CPS to bind to carglumic acid compared to NAG, it has been established that during ammonium intoxication, the protective effect and increase in CPS activity of carglumic acid are significantly more pronounced compared to NAG. These noted data may be explained by the following observations: firstly, by the fact that the permeability of carglumic acid through the mitochondrial membrane is higher than that of NAG, and secondly, by the fact that Carglumic acid is more resistant to hydrolysis by aminoacylase contained in the cytosol.

Carglumic acid reduces the concentration of ammonia in the blood and increases the concentration of urea in the blood plasma and its content in the urine. A significant increase in the content of CPS activators in the liver was observed.

In patients with NAG synthase deficiency, the use of carglumic acid promotes rapid normalization of plasma ammonia concentration, usually within 24 hours. When treatment of such patients is started before the development of permanent brain damage, psychomotor development and growth of patients normalize. In patients with acidemia developing due to impaired excretion of organic acids (in newborns and children over 1 month of age), treatment with carglumic acid is accompanied by a rapid decrease in blood ammonia concentration, reducing the risk of neurological complications.

Pharmacokinetics

After a single oral dose of 100 mg/kg, approximately 30% of carglumic acid is absorbed. The mean C_max of carglumic acid in blood plasma is 2.6 µg/ml (range 1.8-4.8 µg/ml) and is achieved in 3 hours (range 2-4 hours). The concentration of carglumic acid in blood plasma was determined in patients of all age groups, including newborns and adolescents, after administration in a wide range of doses (7-122 mg/kg/day). The range of concentrations in newborns corresponded to that in healthy adult volunteers. Regardless of the daily dose, within 15 hours the concentration of carglumic acid slowly decreased to values of about 100 ng/ml.
The expected V_d in the human body is about 2657 L. Diffusion into erythrocytes is not observed. Binding to plasma proteins was not determined. Part of the administered dose of carglumic acid undergoes metabolism. It is assumed that the bacterial flora of the intestine may, depending on its activity, participate in initiating the process of carglumic acid breakdown, with the formation of metabolites at its different stages. One of the metabolites is glutamic acid, which is excreted through the gastrointestinal tract. C_max of metabolites are determined in blood plasma after 36-48 hours. The final product of carglumic acid metabolism is carbon dioxide, which is excreted by the lungs.
After a single dose of carglumic acid of 100 mg/kg, about 9% of the administered dose of the active substance is excreted unchanged by the kidneys and about 60% by the intestines. Metabolites are excreted over a long period of time (T_1/2 – about 100 hours).

Indications

Hyperammonemia due to primary N-acetylglutamate synthase deficiency; isovaleric acidemia, methylmalonic acidemia, propionic acidemia.

ICD codes

Dosage Regimen

Administer orally. The tablets are dispersible; disperse in a minimum of 5-10 mL of water immediately prior to administration.

The initial daily dose for acute hyperammonemia is 100 mg/kg to 250 mg/kg. Divide the total daily dose into two to four separate administrations.

For maintenance therapy, titrate the dose individually to achieve and maintain normal plasma ammonia concentrations. The typical maintenance dose range is 10 mg/kg to 100 mg/kg daily.

Take doses shortly before meals or feedings. Administer each dose at the beginning of a meal to synchronize with protein intake.

Adjust the dosage based on regular monitoring of plasma ammonia levels and clinical response. Consider dose adjustments during periods of metabolic stress, intercurrent illness, or rapid growth.

Do not exceed the maximum recommended daily dose. For patients requiring a dose exceeding 2 grams daily, administer in three or four divided doses.

Adverse Reactions

Skin and subcutaneous tissue disorders common – hyperhidrosis; frequency unknown – skin rash.

Cardiovascular system disorders uncommon – bradycardia.

Digestive system disorders uncommon – diarrhea, vomiting, increased activity of hepatic transaminases.

General disorders uncommon – pyrexia.

Contraindications

Hypersensitivity to carglumic acid; breastfeeding period.

With caution

Elderly patients (> 65 years), pregnancy.

Use in Pregnancy and Lactation

There are no clinical data on the use of carglumic acid in pregnant women. Minimal embryotoxic effects were identified in animal studies. The use of carglumic acid during pregnancy is possible only in case of extreme necessity. Therapy with carglumic acid should be carried out under special supervision.

Carglumic acid penetrates into the milk of lactating rats. There are no data on the penetration of carglumic acid into human breast milk. The use of carglumic acid during breastfeeding is contraindicated.

Use in Hepatic Impairment

Due to the very limited safety data for carglumic acid, liver function should be monitored.

Use in Renal Impairment

Due to the very limited safety data for carglumic acid, kidney function should be monitored.

Geriatric Use

Use with caution in elderly patients over 65 years of age.

Special Precautions

It is necessary to regularly determine the concentration of ammonia and amino acids in the blood plasma, preventing deviations from normal values.

Due to the very limited safety data for carglumic acid, it is necessary to monitor the function of the liver, kidneys, heart, including assessment of hematological parameters.

In case of protein absorption disorders, protein intake may need to be restricted, as well as additional administration of agents containing arginine.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.