- 1. NAME OF THE MEDICINAL PRODUCT
- 2. QUALITATIVE AND QUANTITATIVE COMPOSITION
- 3. PHARMACEUTICAL FORM
- 4. CLINICAL PARTICULARS
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. PHARMACOLOGICAL PROPERTIES
- 6. PHARMACEUTICAL PARTICULARS
- 7. MARKETING AUTHORISATION HOLDER
- 8. MARKETING AUTHORISATION NUMBER(S)
- 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
- 10. DATE OF REVISION OF THE TEXT
1.NAME OF THE MEDICINAL PRODUCT
Ucedane 200 mg dispersible tablets
2.QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 200 mg of carglumic acid.
For the full list of excipients, see section 6.1.
The tablets are white, oval and biconvex with one score line and engraving LL. The tablet can be divided into equal doses.
Ucedane is indicated in treatment of hyperammonaemia due to
4.2Posology and method of administration
Ucedane 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 (see section 4.4).
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 Ucedane.
-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.
Method of administration
This medicine is for oral use ONLY (ingestion or via nasogastric tube using a syringe, if necessary). Based on pharmacokinetic data and clinical experience, it is recommended to divide the total daily
dose into two to four intakes to be given before meals or feedings. The breaking of the tablets in halves allows most of the required posology adjustments. It is not possible to administer Ucedane to patients who require dose adjustments of 50 mg. In such cases, other carglumic acid products which allow for these dose adjustments should be used.
The tablets must be dispersed in a minimum of
- Carbaglu - carglumic acid
Prescription drugs listed. Substance: "Carglumic acid"
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4Special warnings and precautions for use
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.
Protein restriction and arginine supplementation may be indicated in case of low protein tolerance.
4.5Interaction with other medicinal products and other forms of interaction
No specific interaction studies have been performed.
4.6Fertility, 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,
4.7Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed.
Reported adverse reactions are listed below, by system organ class and by frequency. Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10) and uncommon (≥1/1,000 to <1/100) 100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
System Organ Class
Skin and subcutaneous tissue
General disorders and
Administration site conditions
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
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.
- Pheburane - Lucane Pharma
- Granupas (para-aminosalicylic acid lucane) - Lucane Pharma
Prescription drugs listed. Manufacturer: "Lucane Pharma"
Pharmacotherapeutic group: Amino acids and derivatives; ATC code: A16AA05.
Mechanism of action
Carglumic acid is a structural analogue of
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
i) The mitochondrial membrane is more readily permeable for carglumic acid than for N- acetylglutamate
ii) Carglumic acid is more resistant than
Other studies have been conducted in rats under different experimental conditions leading to increased ammonia availability (starvation,
Clinical efficacy and safety
In patients with
instituted before any permanent brain damage, patients exhibited normal growth and psychomotor development.
The pharmacokinetics of carglumic acid has been studied in healthy male volunteers using both radiolabelled and unlabelled product.
After a single oral dose of 100 mg/kg body weight, approximately 30% of carglumic acid is estimated to be absorbed. At that
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
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
The end product of carglumic acid metabolism is carbon dioxide, which is eliminated through the lungs.
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
5.3Preclinical safety data
Safety pharmacology studies have shown that carglumic acid administered orally at doses of 250, 500, 1000 mg/kg had no statistically significant effect on respiration, central nervous system and cardiovascular system.
Carglumic acid 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.
- Carbaglu - A16AA05
Prescription drugs listed. ATC Code: "A16AA05"
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
2000 mg/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.
6.1List of excipients
microcrystalline cellulose, mannitol,
colloidal anhydrous silica, sodium stearyl fumarate, crospovidone type B, copovidone K 28.
6.4Special precautions for storage
6.5Nature and contents of container
Blister (ALU/ALU) packed in cartons.
Pack size of 60 dispersible tablets.
6.6Special precautions for disposal
No special requirements.
7.MARKETING AUTHORISATION HOLDER
172 rue de Charonne
75011 Paris France
8.MARKETING AUTHORISATION NUMBER(S)
9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation:
10.DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.