CARBAGLU 200mg dispersible tablets medication leaflet

Carbaglu 200 mg dispersible tablets

Each tablet contains 200 mg of carglumic acid.

For a full list of excipients, see section 6.1

Dispersible tablet

The tablets are white and elongated with three score marks and engraved on one side.

The tablet can be divided into equal doses.

Carbaglu is indicated in treatment of

* hyperammonaemia due to N-acetylglutamate synthase primary deficiency.

* hyperammonaemia due to isovaleric acidaemia.

* hyperammonaemia due to methylmalonic acidaemia.

* hyperammonaemia due to propionic acidaemia.

Carbaglu treatment should be initiated under the supervision of a physician experienced in thetreatment of metabolic disorders.

* For N-acetylglutamate synthase deficiency:

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 (seesection 4.4).

In the long term, it may not be necessary to increase the dose according to body weight as long asadequate 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 termtreatment. As examples

- In a comatose child, start with a dose of 100 to 250 mg/kg/day and measure ammonia plasmaconcentration at least before each administration; it should normalise within a few hours afterstarting Carbaglu.

- In a patient with moderate hyperammonaemia, administer a test dose of 100 to 200 mg/kg/dayfor 3 days with a constant protein intake and perform repeated determinations of ammoniaplasma concentration (before and 1 hour after a meal); adjust the dose in order to maintainnormal ammonia plasma levels.

* For isovaleric acidaemia, methylmalonic acidaemia and propionic acidaemia:

The treatment should start upon hyperammonaemia in organic acidaemia patients. The initial dailydose should be 100 mg/kg, up to 250 mg/kg if necessary.

It should then be individually adjusted in order to maintain normal ammonia plasma levels (seesection 4.4).

Caution is advised when administering Carbaglu to patients with impaired renal function.

Dosage adjustment is required according to GFR.

* Patients with moderate renal impairment (GFR 30-59 mL/min)o the recommended initial dose is 50 mg/kg/day to 125 mg/kg/day for patientspresenting an hyperammonemia due to NAGS deficiency or organic acidaemia,o In the long term use the daily dose will be in the range of 5 mg/kg/day to 50mg/kg/day and should be adjusted individually in order to maintain normal ammoniaplasma levels

* Patients with severe renal impairment (GFR ≤ 29 mL/min)o the recommended initial dose is 15 mg/kg/day to 40 mg/kg/day for patients presentingan hyperammonaemia due to NAGS deficiency or organic acidaemia,o In the long term use the daily dose will be in the range of 2 mg/kg/day to 20mg/kg/day and should be adjusted individually in order to maintain normal ammoniaplasma levels

The safety and effectiveness of Carbaglu for the treatment of pediatric patients (birth to 17 years ofage) with acute or chronic hyperammonemia due to NAGS deficiency and acute hyperammonemiadue to IVA, PA or MMA have been established, and based on these data, posology adjustments inneonates are not deemed necessary.

This medicine 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 dailydose into two to four doses to be given before meals or feedings. The breaking of the tablets in halvesallows most of the required posology adjustments. Occasionally, the use of quarter tablets may also beuseful 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 oradministered by fast push through a syringe via a nasogastric tube.

The suspension has a slightly acidic taste.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 .

Breast-feeding during the use of carglumic acid is contraindicated (see sections 4.6 and 5.3).

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.

Use in patients with renal impairment

The dose of Carbaglu must be reduced in patients with renal impairment (see section 4.2)

No specific interaction studies have been performed.

For carglumic acid no clinical data on exposed pregnancies are available.

Animal studies have revealed minimal developmental toxicity (see section 5.3). Caution should beexercised when prescribing to pregnant women.

Although it is not known whether carglumic acid is secreted into human milk, it has been shown to bepresent in the milk of lactating rats (see section 5.3). Therefore, breast-feeding during the use ofcarglumic acid is contraindicated (see section 4.3).

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 aredefined as: very common (≥ 1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare(≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), not known (cannot be estimated from the availabledata).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

- Undesirable effects in N-acetylglutamate synthase deficiency

Investigations Uncommon: increased transaminases

Skin and subcutaneous tissue Common: increased sweatingdisorders Not known: rash

- Undesirable effects in organic acidaemia

Cardiac disorders Uncommon: bradycardia

Gastrointestinal disorders Uncommon: diarrhoea, vomiting

General disorders and Uncommon: pyrexia

Administration site conditions

Skin and subcutaneous tissue Not known: rashdisorders

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted 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 andrestlessness. These symptoms resolved once the dose was reduced.

Pharmacotherapeutic group: Amino acids and derivatives; ATC code: A16AA05

Carglumic acid is a structural analogue of N-acetylglutamate, which is the naturally occurringactivator 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 alower 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 muchmore effective than N-acetylglutamate in protecting against ammonia intoxication in rats. This couldbe explained by the following observations:i) The mitochondrial membrane is more readily permeable for carglumic acid than for N-acetylglutamateii) Carglumic acid is more resistant than N-acetylglutamate to hydrolysis by aminoacylase present inthe cytosol.

Other studies have been conducted in rats under different experimental conditions leading toincreased ammonia availability (starvation, protein-free or high-protein diet). Carglumic acid wasshown to decrease blood ammonia levels and increase urea levels in blood and urine, whereas theliver content of carbamoyl phosphate synthetase activators was significantly increased.

In patients with N-acetylglutamate synthase deficiency, carglumic acid was shown to induce a rapidnormalisation of plasma ammonia levels, usually within 24 hours. When the treatment was institutedbefore any permanent brain damage, patients exhibited normal growth and psychomotor development.

In patients with organic acidaemia (neonates and non-neonates), the treatment with carglumic acidinduced a quick decrease of ammonia plasma levels, reducing the risk of neurological complications.

The pharmacokinetics of carglumic acid has been studied in healthy male volunteers using bothradiolabelled and unlabelled product.

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

The plasma elimination curve of carglumic acid is biphasic with a rapid phase over the first 12 hoursafter 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.

A proportion of carglumic acid is metabolised. It is suggested that depending on its activity, theintestinal bacterial flora may contribute to the initiation of the degradation process, thus leading to avariable extent of metabolism of the molecule. One metabolite that has been identified in the faeces isglutamic acid. Metabolites are detectable in plasma with a peak at 36-48 hours and a very slowdecline (half-life around 100 hours).

The end product of carglumic acid metabolism is carbon dioxide, which is eliminated through thelungs.

After a single oral dose of 100 mg/kg body weight, 9% of the dose is excreted unchanged in the urineand up to 60% in the faeces.

Plasma levels of carglumic acid were measured in patients of all age categories, from newborn infantsto adolescents, treated with various daily doses (7 - 122 mg/kg/day). Their range was consistent withthose measured in healthy adults, even in newborn infants. Whatever the daily dose, they were slowlydeclining over 15 hours to levels around 100 ng/ml.

Patients with Renal Impairment

The pharmacokinetics of carglumic acid in subjects with renal impairment were compared withsubjects with normal renal function following oral administration of a single dose of Carbaglu 40mg/kg or 80 mg/kg. The Cmax and AUC0-T of carglumic acid are summarized in the table below. Thegeometric mean ratio (90% CI) of AUC0-T in subjects with mild, moderate, and severe renalimpairment relative to those in their matched control subjects with normal renal function wereapproximately 1.8 (1.34, 2.47), 2.8 (2.17, 3.65), and 6.9 (4.79, 9.96), respectively. Renal clearance(CLr) decreased by 0.79-, 0.53-, and 0.15-fold in mild, moderate and severe renal impaired subjects,respectively, when compared to subjects with normal renal function. It is considered that the PKchanges of carglumic acid accompanied with impaired renal function are clinically relevant, anddosage adjustment on the dose would be warranted in moderate and severe renal impaired subjects[see Posology and method of administration (4.2)].

Mean (± SD) Cmax and AUC0-T of Carglumic Acid Following Single Oral Dose Administration of

Carbaglu 80 mg/kg or 40 mg/kg in Subjects with Renal Impairmentand Matched Control

Subjects with Normal Renal Function

Normal Mild Moderate Normal Severe

PK Function (1a) Impairment Impairment Function (1b) Impairmentparameters N=8 N=7 N=6 N=8 N=680 mg/kg 40 mg/kg

Cmax 2982.9 5056.1 (2074.7) 6018.8 1890.4 8841.8(ng/mL) (552.1) (2041.0) (900.6) (4307.3)

AUC0-T 28312.7 53559.3 80543.3 20212.0 144924.6(ng*h/mL) (6204.1) (20267.2) (22587.6) (6185.7) (65576.0)

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 andcardiovascular system.

Carbaglu showed no significant mutagenic activity in a battery of genotoxicity tests performed invitro (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 induceany mortality or abnormal clinical signs in adult rats. In newborn rats receiving daily carglumic acidby 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 hasbeen seen of embryotoxicity, foetotoxicity or teratogenicity up to maternotoxic doses leading to fiftytimes exposure as compared to humans in rats and seven times in rabbits. Carglumic acid is secretedin the milk of lactating rats and although developmental parameters were unaffected, there were someeffects on body weight/body weight gain of pups breast-fed by dams treated with 500 mg/kg/day anda higher mortality of pups from dams treated with 2000 mg/kg/day, a dose that causedmaternotoxicity. The maternal systemic exposures after 500 and 2000 mg/kg/day were twenty fivetimes and seventy times the expected human exposure.

No carcinogenicity study has been conducted with carglumic acid.

Microcrystalline cellulosesodium laurilsulfatehypromellosecroscarmellose sodiumsilica colloidal anhydroussodium stearyl fumarate

Not applicable

36 months

After first opening of the tablet container: 3 months

Store in a refrigerator (2°C - 8°C)

After first opening of the tablet container:

Do not refrigerate.

Do not store above 30°C.

Keep the container tightly closed in order to protect from moisture.

5-, 15- or 60- high density polyethylene tablet containers closed by a child resistant polypropylene capwith a desiccant unit.

Not all pack sizes may be marketed.

No special requirements

Recordati Rare Diseases

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EU/1/02/246/001 (15 dispersible tablets)

EU/1/02/246/002 (60 dispersible tablets)

EU/1/02/246/003 (5 dispersible tablets)

Date of first authorisation: 24 January 2003

Date of renewal: 20 May 2008

Detailed information on this medicinal product is available on the website of the European Medicines

Agency (EMA) http://www.ema.europa.eu.