Carglumic acid

Registered South African indications:

• Hyperammonaemia

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Breastfeeding

Cautions

• Pregnancy
• Renal impairment
• Hepatic impairment
• Elderly
• Low protein tolerance
• Low salt diet
  (See Additional Prescribing Points)

Forms avail. in SA and covered in this monograph: dsp

Dosages below include:

• International manufacturer recommendations
• South African manufacturer recommendations

International manufacturer recommendations

Hyperammonaemia
- Due to N-acetylglutamate synthase primary deficiency

• Oral (dsp): Initial: 100mg/kg, dly: Titrate up to 250mg/kg, dly, if necessary

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It should then be adjusted individually in order to maintain normal ammonia plasma levels

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In the long term, it may not be necessary to increase the dose according to body weight as long as adequate metabolic control is achieved; daily doses range from 10-100mg/kg

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Treatment should be initiated under the supervision of a physician experienced in the treatment of metabolic disorders

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For examples of carglumic acid responsiveness test in different patient profiles, see Additional Prescribing Points

For administration directions, see Additional Prescribing Points

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South African manufacturer recommendations

Hyperammonaemia
- Due to N-acetylglutamate synthase primary deficiency

• Oral (dsp): Initial: 100mg/kg, dly: Titrate up to 250mg/kg, dly, if necessary

---

It should then be adjusted individually in order to maintain normal ammonia plasma levels

---

In the long term, it may not be necessary to increase the dose according to body weight as long as adequate metabolic control is achieved; daily doses range from 10-100mg/kg

---

Treatment should be initiated under the supervision of a physician experienced in the treatment of metabolic disorders

---

For examples of carglumic acid responsiveness test in different patient profiles, see Additional Prescribing Points

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- Due to isovaleric acidaemia
- Due to methylmalonic acidaemia
- Due to propionic acidaemia

• Oral (dsp): Initial: 100mg/kg, dly: Titrate up to 250mg/kg, dly, if necessary

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The treatment should start upon hyperammonaemia in organic acidaemia patients

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It should then be individually adjusted in order to maintain normal ammonia plasma levels

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For administration directions, see Additional Prescribing Points

Paed. forms avail. in SA and covered in this monograph: dsp

Paed. dosages below include:

• International manufacturer recommendations
• South African manufacturer recommendations

International manufacturer recommendations

Hyperammonaemia
- Due to N-acetylglutamate synthase primary deficiency

• See adult dosage

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Based on clinical experience, the treatment may be started as early as the first day of life

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South African manufacturer recommendations

Hyperammonaemia
- Due to N-acetylglutamate synthase primary deficiency

• See adult dosage

---

Based on clinical experience, the treatment may be started as early as the first day of life

---

- Due to isovaleric acidaemia
- Due to methylmalonic acidaemia
- Due to propionic acidaemia

• No information available

Pregnancy

• Caution
• For carglumic acid no clinical data on exposed pregnancies are available
• Animal studies have revealed minimal developmental toxicity. Caution should be exercised when prescribing to pregnant women

Breastfeeding

• Contraindicated
• Although it is not known whether carglumic acid is secreted into human milk, it has been shown to be present in the milk of lactating rats. Therefore, breastfeeding during the use of carglumic acid is contraindicated

Fertility

• No human data on the effect of carglumic acid on fertility are available. In rats, no adverse effects have been observed on male or female fertility with carglumic acid treatment

Renal Impairment

• Caution; no information available

Hepatic Impairment

• Caution; no information available

Elderly

• Caution; no information available

Porphyria Information

• Not porphyrinogenic (NP)

Hepatobiliary Disorders

• Increased transaminases

Skin and Subcutaneous Tissue Disorders

• Increased sweating
• Rash

None known

• Ammonia plasma levels
• Amino acid plasma levels
• Renal function
• Hepatic function
• Cardiac function
• Haematologic parameters

Additional observations

• Physical signs/symptoms of hyperammonemia
  - Lethargy
  - Ataxia
  - Confusion
  - Vomiting
  - Seizures
  - Memory impairment

Carglumic acid responsiveness test

It is recommended to test individual responsiveness to carglumic acid before initiating any long term treatment. As examples:

• In a comatose child
  Start with a dose of 100-250mg/kg/day and measure ammonia plasma concentration at least before each administration; it should normalise within a few hours after starting carglumic acid 200mg dispersible tablets
• In a patient with moderate hyperammonaemia
  Administer a test dose of 100-200mg/kg/day for 3 days with a constant protein intake and perform repeated determinations of ammonia plasma concentration (before and 1hr after a meal)
  Adjust the dose in order to maintain normal ammonia plasma levels

Administration directions

• Carglumic acid is for oral use ONLY (ingestion or via a nasogastric tube using a syringe, if necessary)
• Based on pharmacokinetic data and clinical experience, it is recommended to divide the total daily dose into 2-4 doses to be given before meals or feedings
• The breaking of the tablets in halves allows most of the required posology adjustments. Occasionally, the use of quarter tablets may also be useful to adjust the posology
• The tablets must be dispersed in a minimum of 5-10ml of water and ingested immediately or administered by fast push through a syringe via a nasogastric tube

Nutritional management

• Protein restriction and arginine supplementation may be indicated in case of low protein tolerance
• This medicinal product contains up to 3mg sodium per dose, equivalent to 0.15% of the WHO recommended maximum daily intake for sodium
• The maximum daily dose of this product is equivalent to 20% of the WHO recommended maximum daily intake for sodium
• Carglumic acid dispersible tablets are considered high in sodium. This should be particularly taken into account for those on a low salt diet

Carglumic acid is a structural analogue of N-acetylglutamate, which is the naturally occurring activator of carbamoyl phosphate synthetase, the first enzyme of the urea cycle. Carglumic acid has been shown in vitro to activate liver carbamoyl phosphate synthetase. Despite a lower affinity of carbamoyl phosphate synthetase for carglumic acid than for N-acetylglutamate, carglumic acid has been shown in vivo to stimulate carbamoyl phosphate synthetase and to be much more effective than N-acetylglutamate in protecting against ammonia intoxication in rats. This could be explained by the following observations; Firstly, the mitochondrial membrane is more readily permeable for carglumic acid than for N-acetylglutamate, and secondly, carglumic acid is more resistant than N-acetylglutamate to hydrolysis by aminoacylase present in the cytosol.

Tablet Dispersible 200mg

• Carbaglu ( Equity Pharmaceuticals) originator