Carbaglu

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

Posology: • 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. 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 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.

3 • For isovaleric acidaemia, methylmalonic acidaemia and propionic acidaemia: The treatment should start upon hyperammonaemia in organic acidaemia patients. The initial daily dose should be 100 mg/kg, up to 250 mg/kg if necessary. 4).

Renal impairment:

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 patients presenting 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 50 mg/kg/day and should be adjusted individually in order to maintain normal ammonia plasma 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 presenting an 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 20 mg/kg/day and should be adjusted individually in order to maintain normal ammonia plasma levels Paediatric population The safety and effectiveness of Carbaglu for the treatment of pediatric patients (birth to 17 years of age) with acute or chronic hyperammonemia due to NAGS deficiency and acute hyperammonemia due to IVA, PA or MMA have been established, and based on these data, posology adjustments in neonates are not deemed necessary.

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), 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 available data).

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 disorders Common: increased sweating Not known: rash - Undesirable effects in organic acidaemia Cardiac disorders Uncommon: bradycardia Gastrointestinal disorders Uncommon: diarrhoea, vomiting General disorders and Administration site conditions Uncommon: pyrexia Skin and subcutaneous tissue disorders Not known: rash 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 5 professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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. 2)

1 . 3).