various alimentary tract and metabolism products - ATC code: A16A X03

Sodium phenylbutyrate

Each tablet contains 500 mg sodium phenylbutyrate. Each AMMONAPS tablet contains 62 mg of sodium.

Tablet. The tablets are off-white, oval and embossed with “UCY 500”.

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.

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

AMMONAPS granules should be administered orally (to infants and children unable to swallow tablets and to patients with dysphagia) or via gastrostomy or nasogastric tube.

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 neonates, infants and 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 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 should be divided into equal amounts and given with each meal or feeding (e.g. 4-6 times per day in small children). When taken orally, the granules are to be mixed with solid foods (such as mashed potatoes or apple sauce) or liquid foods (such as water, apple juice, orange juice or protein-free infant formulas).

Three dosing spoons are provided which dispense 1.2 g, 3.1 g or 9.0 g of sodium phenylbutyrate. Lightly shake the bottle before dispensing.

The usual total daily dose of sodium phenylbutyrate in clinical experience is 450 - 600mg/kg/day in neonates, infants and children weighing less than 20 kg; 9.9 - 13.0 g/m2/day in children weighing more than 20kg. The total daily dose should be divided into equal amounts and given with each meal or feeding (ie, 4-6 times per day in small children); the granules are to be mixed with food (solid or liquid) . Maximum dose 20g/day. 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.

− Pregnancy

− Breast-feeding

− Hypersensitivity to the active substance or to any of the excipients.

AMMONAPS granules contain 124 mg (5.4 mmol) of sodium per gram of sodium phenylbutyrate, corresponding to 2.5 g (108 mmol) of sodium per 20 g of sodium phenylbutyrate, which is the maximum daily dose. 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.

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.

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.

Swedish Orphan Biovitrum Ltd

(POM)

23 March 2012