4.1. Therapeutic indications

AMMONAPS is indicated as adjunctive therapy in the chronic management of urea cycle disorders, involving deficiencies of carbamylphosphate synthetase, ornithine transcarbamylase or argininosuccinate synthetase.

It is indicated in all patients with neonatal-onset presentation (complete enzyme deficiencies, presenting within the first 28 days of life). It is also indicated in patients with late-onset disease (partial enzyme deficiencies, presenting after the first month of life) who have a history of hyperammonaemic encephalopathy.

4.2. Posology and method of administration

AMMONAPS treatment should be supervised by a physician experienced in the treatment of urea cycle disorders.

The use of AMMONAPS tablets is indicated for adults and children who are able to swallow tablets. AMMONAPS is also available as granules for infants, children who are unable to swallow tablets and for patients with dysphagia.

The daily dose should be individually adjusted according to the patient's protein tolerance and the daily dietary protein intake needed to promote growth and development.

The usual total daily dose of sodium phenylbutyrate in clinical experience is:

• 450 - 600 mg/kg/day in children weighing less than 20 kg

• 9.9 - 13.0 g/m2/day in children weighing more than 20 kg, adolescents and adults.

The safety and efficacy of doses in excess of 20 g/day (40 tablets) have not been established.

Therapeutic monitoring: Plasma levels of ammonia, arginine, essential amino acids (especially branched chain amino acids), carnitine and serum proteins should be maintained within normal limits. Plasma glutamine should be maintained at levels less than 1,000 µmol/l.

Nutritional management: AMMONAPS must be combined with dietary protein restriction and, in some cases, essential amino acid and carnitine supplementation.

Citrulline or arginine supplementation is required for patients diagnosed with neonatal-onset form of carbamyl phosphate synthetase or ornithine transcarbamylase deficiency at a dose of 0.17 g/kg/day or 3.8 g/m2/day.

Arginine supplementation is required for patients diagnosed with deficiency of argininosuccinate synthetase at a dose of 0.4 - 0.7 g/kg/day or 8.8 - 15.4 g/m2/day.

If caloric supplementation is indicated, a protein-free product is recommended.

The total daily dose of AMMONAPS should be divided into equal amounts and given with each meal (e.g. three times per day). The tablets should be taken with a large volume of water.

4.3. Contraindications

- Pregnancy.

- Breast-feeding.

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

4.4. Special warnings and precautions for use

AMMONAPS tablets should not be used in patients with dysphagia due to the potential risk of oesophageal ulceration if tablets are not promptly delivered to the stomach.

This medicinal product contains 62 mg sodium per tablet, equivalent to 3% of the WHO recommended maximum daily intake for sodium.

The maximum recommended daily dose of this product contains 2.5 g sodium which is equivalent to 124% of the WHO recommended maximum daily intake for sodium.

AMMONAPS is considered high in sodium. This should be particularly taken into account for those on a low salt diet.

AMMONAPS should therefore be used with caution in patients with congestive heart failure or severe renal insufficiency, and in clinical conditions where there is sodium retention with oedema.

Since the metabolism and excretion of sodium phenylbutyrate involves the liver and kidneys, AMMONAPS should be used with caution in patients with hepatic or renal insufficiency.

Serum potassium should be monitored during therapy since renal excretion of phenylacetylglutamine may induce a urinary loss of potassium.

Even on therapy, acute hyperammonaemic encephalopathy may occur in a number of patients.

AMMONAPS is not recommended for the management of acute hyperammonaemia, which is a medical emergency.

In children unable to swallow tablets, it is recommended to use AMMONAPS granules instead.

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

Concurrent administration of probenecid may affect renal excretion of the conjugation product of sodium phenylbutyrate.

There have been published reports of hyperammonaemia being induced by haloperidol and by valproate. Corticosteroids may cause the breakdown of body protein and thus increase plasma ammonia levels. More frequent monitoring of plasma ammonia levels is advised when these medications have to be used.

4.6. Fertility, pregnancy and lactation

Pregnancy

The safety of this medicinal product for use in human pregnancy has not been established. Evaluation of experimental animal studies has shown reproductive toxicity, i.e. effects on the development of the embryo or the foetus. Prenatal exposure of rat pups to phenylacetate (the active metabolite of phenylbutyrate) produced lesions in cortical pyramidal cells; dendritic spines were longer and thinner than normal and reduced in number. The significance of these data in pregnant women is not known; therefore the use of AMMONAPS is contra-indicated during pregnancy (see section 4.3).

Effective contraceptive measures must be taken by women of child-bearing potential.

Lactation

When high doses of phenylacetate (190 - 474 mg/kg) were given subcutaneously to rat pups, decreased proliferation and increased loss of neurons were observed, as well as a reduction in CNS myelin. Cerebral synapse maturation was retarded and the number of functioning nerve terminals in the cerebrum was reduced, which resulted in impaired brain growth. It has not been determined if phenylacetate is secreted in human milk and therefore the use of AMMONAPS is contra-indicated during lactation (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

In clinical trials with AMMONAPS, 56 % of the patients experienced at least one adverse event and 78 % of these adverse events were considered as not related to AMMONAPS.

Adverse reactions mainly involved the reproductive and gastrointestinal system.

The adverse reactions are listed below, by system organ class and by frequency. Frequency is 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.

Blood and lymphatic system disorders

Common: Anaemia, thrombocytopenia, leukopenia, leukocytosis, thrombocytosis

Uncommon: Aplastic anaemia, ecchymosis

Metabolism and nutrition disorders

Common: Metabolic acidosis, alkalosis, decreased appetite

Psychiatric disorders

Common: Depression, irritability

Nervous system disorders

Common: Syncope, headache

Cardiac disorders

Common: Oedema

Uncommon: Arrhythmia

Gastrointestinal disorders

Common: Abdominal pain, vomiting, nausea, constipation, dysgeusia

Uncommon: Pancreatitis, peptic ulcer, rectal haemorrhage, gastritis

Skin and subcutaneous tissue disorders

Common: Rash, abnormal skin odour

Renal and urinary disorders

Common: Renal tubular acidosis

Reproductive system and breast disorders

Very common: Amenorrhoea, irregular menstruation

Investigations

Common: Decreased blood potassium, albumin, total protein and phosphate. Increased blood alkaline phosphatase, transaminases, bilirubin, uric acid, chloride, phosphate and sodium. Increased weight.

A probable case of toxic reaction to AMMONAPS (450 mg/kg/d) was reported in an 18-year old anorectic female patient who developed a metabolic encephalopathy associated with lactic acidosis, severe hypokalaemia, pancytopaenia, peripheral neuropathy, and pancreatitis. She recovered following dose reduction except for recurrent pancreatitis episodes that eventually prompted treatment discontinuation.

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:

United Kingdom

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

One case of overdose occurred in a 5-month old infant with an accidental single dose of 10 g (1370 mg/kg). The patient developed diarrhoea, irritability and metabolic acidosis with hypokalaemia. The patient recovered within 48 hours after symptomatic treatment.

These symptoms are consistent with the accumulation of phenylacetate, which showed dose-limiting neurotoxicity when administered intravenously at doses up to 400 mg/kg/day. Manifestations of neurotoxicity were predominantly somnolence, fatigue and light-headedness. Less frequent manifestations were confusion, headache, dysgeusia, hypacusis, disorientation, impaired memory and exacerbation of a pre-existing neuropathy.

In the event of an overdose, discontinue the treatment and institute supportive measures. Haemodialysis or peritoneal dialysis may be beneficial.