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Drug Details

AMMONAPS 500 mg tablets

• Drug Class Description
  various alimentary tract and metabolism products - ATC code: A16A X03
• Generic Name
  Sodium phenylbutyrate
• Presentation
  Tablet. The tablets are off-white, oval and embossed with “UCY 500”.
• Description
  Each tablet contains 500 mg sodium phenylbutyrate. Each AMMONAPS tablet contains 62 mg of sodium.
• 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.

• Adult Dosage
  

  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.

• Child Dosage
  

  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.

• Contra Indications
  

  − Pregnancy

  − Breast-feeding

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

• Special Precautions
  

  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.

• Interactions
  

  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.

• Adverse Drug Reactions
  

  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.