Carbaglu approved for N-acetylglutamate synthase (NAGS) deficiency

The FDA has approved Carbaglu (carglumic acid tablets, from Orphan Europe) for the treatment of the genetic disorder N-acetylglutamate synthase (NAGS) deficiency, which causes hyperammonemia. This approval was based on study results in 23 patients that demonstrated that Carbaglu reduced blood ammonia levels within 24 hours and normalized ammonia levels within three days. The majority of patients in the study appeared to maintain normal plasma ammonia levels with long-term Carbaglu treatment.

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1.    NAME OF THE MEDICINAL PRODUCT
Carbaglu 200 mg dispersible tablets

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 200 mg of carglumic acid.

3.    PHARMACEUTICAL FORM
Dispersible tablet
The tablets are white and elongated with three score marks.
The tablet can be divided into equal halves.
4.    CLINICAL PARTICULARS
4.1   Therapeutic indications
Treatment of hyperammonaemia due to N-acetylglutamate synthase deficiency.
4.2   Posology and method of administration
Carbaglu treatment should be initiated under the supervision of a physician experienced in the
treatment of metabolic disorders.
Based on clinical experience, the treatment may be started as early as the first day of life.
The initial daily dose should be 100 mg/kg, up to 250 mg/kg 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 mg/kg to 100 mg/kg.
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 to 250 mg/kg/day and measure ammonia plasma
concentration at least before each administration; it should normalise within a few hours after
starting Carbaglu.

-      In a patient with moderate hyperammonaemia, administer a test dose of 100 to 200 mg/kg/day
for 3 days with a constant protein intake and perform repeated determinations of ammonia
plasma concentration (before and 1 hour after a meal); adjust the dose in order to maintain
normal ammonia plasma levels.
Based on pharmacokinetic data and clinical experience, it is recommended to divide the total daily
dose into two to four 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 prescribed by the physician.

The tablets must be dispersed in a minimum of 5-10 ml of water and ingested immediately or
administered by fast push through a syringe via a nasogastric tube.

The suspension has a slightly acidic taste.

4.3   Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Breast-feeding during the use of carglumic acid is contraindicated (see sections 4.6 and 5.3).
4.4   Special warnings and precautions for use
Therapeutic monitoring
Plasma levels of ammonia and amino acids should be maintained within normal limits.
As very few data on the safety of carglumic acid are available, systematic surveillance of liver, renal,
cardiac functions and haematological parameters is recommended.
Nutritional management
Protein restriction and arginine supplementation may be indicated in case of low protein tolerance.
4.5   Interaction with other medicinal products and other forms of interaction
No specific interaction studies have been performed.
4.6   Pregnancy and lactation
For carglumic acid no clinical data on exposed pregnancies are available.
Animal studies have revealed minimal developmental toxicity (see section 5.3). Caution should be
exercised when prescribing to pregnant women. 
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 (see section 5.3). Therefore, breast-feeding during the use of
carglumic acid is contraindicated. (see section 4.3).
4.7   Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed.
4.8   Undesirable effects

Clinical experience has been collected in about 170 patient-years.

4.9   Overdose
In one patient treated with carglumic acid, where the dose was increased up to 750 mg/kg/day,
symptoms of intoxication occurred which can be characterised as a sympathomimetic reaction:
tachycardia, profuse sweating, increased bronchial secretion, increased body temperature and
restlessness. These symptoms resolved once the dose was reduced.

5.    PHARMACOLOGICAL PROPERTIES
5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Amino acids and derivatives; ATC code: A16AA05
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:
i) The mitochondrial membrane is more readily permeable for carglumic acid than for N-
acetylglutamate
ii) Carglumic acid is more resistant than N-acetylglutamate to hydrolysis by aminoacylase present in
the cytosol.
Other studies have been conducted in rats under different experimental conditions leading to
increased ammonia availability (starvation, protein-free or high-protein diet). Carglumic acid was
shown to decrease blood ammonia levels and increase urea levels in blood and urine, whereas the
liver content of carbamoyl phosphate synthetase activators was significantly increased.
In patients with N-acetylglutamate synthase deficiency, carglumic acid was shown to induce a rapid
normalisation of plasma ammonia levels, usually within 24 hours. When the treatment was instituted
before any permanent brain damage, patients exhibited normal growth and psychomotor development.
5.2   Pharmacokinetic properties
The pharmacokinetics of carglumic acid has been studied in healthy male volunteers using both
radiolabelled and unlabelled product.

Absorption
After a single oral dose of 100 mg/kg body weight, approximately 30% of carglumic acid is estimated
to be absorbed. At that dose-level, in 12 volunteers given Carbaglu tablets, plasma concentration
peaked at 2.6 µg/ml (median; range 1.8-4.8) after 3 hours (median; range 2-4).

Distribution
The plasma elimination curve of carglumic acid is biphasic with a rapid phase over the first 12 hours
after administration followed by a slow phase (terminal half life up to 28 hours).
Diffusion into erythrocytes is non existent. Protein binding has not been determined.

Metabolism
A proportion of carglumic acid is metabolised. It is suggested that depending on its activity, the
intestinal bacterial flora may contribute to the initiation of the degradation process, thus leading to a
variable extent of metabolism of the molecule. One metabolite that has been identified in the faeces is
glutamic acid. Metabolites are detectable in plasma with a peak at 36-48 hours and a very slow
decline (half-life around 100 hours).
The end product of carglumic acid metabolism is carbon dioxide, which is eliminated through the
lungs.

Elimination
After a single oral dose of 100 mg/kg body weight, 9% of the dose is excreted unchanged in the urine
and up to 60% in the faeces.
Plasma levels of carglumic acid were measured in patients of all age categories, from newborn infants
to adolescents, treated with various daily doses (7 – 122 mg/kg/day). Their range was consistent with
those measured in healthy adults, even in newborn infants. Whatever the daily dose, they were slowly
declining over 15 hours to levels around 100 ng/ml.
5.3   Preclinical safety data
Safety pharmacology studies have shown that Carbaglu administered orally at doses of 250, 500,
1000 mg/kg had no statistically significant effect on respiration, central nervous system and
cardiovascular system.
Carbaglu showed no significant mutagenic activity in a battery of genotoxicity tests performed in
vitro (Ames test, human lymphocyte metaphase analysis) and in vivo (micronucleus test in rat).
Single doses of carglumic acid up to 2800 mg/kg orally and 239 mg/kg intravenously did not induce
any mortality or abnormal clinical signs in adult rats. In newborn rats receiving daily carglumic acid
by oral gavage for 18 days as well as in young rats receiving daily carglumic acid for 26 weeks, the
No Observed Effect Level (NOEL) was established at 500 mg/kg/day and the No Observed Adverse
Effect Level (NOAEL) was established at 1000 mg/kg/day.
No adverse effects have been observed on male or female fertility. In rats and rabbits no evidence has
been seen of embryotoxicity, foetotoxicity or teratogenicity up to maternotoxic doses leading to fifty
times exposure as compared to humans in rats and seven times in rabbits. Carglumic acid is secreted
in the milk of lactating rats and although developmental parameters were unaffected, there were some
effects on body weight / body weight gain of pups breast-fed by dams treated with 500 mg/kg/day and
a higher mortality of pups from dams treated with 2000/kg/day, a dose that caused maternotoxicity.
The maternal systemic exposures after 500 and 2000 mg/kg/day were twenty five times and seventy
times the expected human exposure.
No carcinogenicity study has been conducted with carglumic acid.

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