4.1. Therapeutic indications

Carbaglu is indicated in treatment of

• hyperammonaemia due to N-acetylglutamate synthase primary deficiency.

• hyperammonaemia due to isovaleric acidaemia.

• hyperammonaemia due to methymalonic acidaemia.

• hyperammonaemia due to propionic acidaemia.

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.

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.

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 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.

• 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.

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

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

Method of administration:

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 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 listed in section 6.1.

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.

Use in patients with renal impairment

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

4.5. Interaction with other medicinal products and other forms of interaction

No specific interaction studies have been performed.

4.6. Fertility, pregnancy and lactation

Pregnancy

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.

Breast-feeding

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

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 (≥1/1000 to <1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), 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 professionals are asked to report any suspected adverse reactions via the national reporting system Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.