Oral Adjunct for hyperammonaemia in patients with urea cycle disorders
Adult: Adjunctive therapy in chronic management of urea cycle disorders, involving deficiencies of carbamoyl phosphate synthetase, ornithine transcarbamylase or argininosuccinate synthetase; in patients with neonatal-onset deficiency (complete enzymatic deficiency, presenting within the 1st 28 days of life), or late-onset disease (partial enzymatic deficiency, presenting after the 1st month of life) who have a history of hyperammonaemic encephalopathy: Usual total daily dose: 9.9-13 g/m2 daily; given in equally divided doses and with each meal (e.g. 3-6 times daily). Max: 20 g daily. Daily dosage must be individualised and adjusted according to patient’s protein tolerance and daily dietary protein intake. Therapy must be used in combination with a protein-restricted diet, and essential amino acid or carnitine supplementation if required. Child: Adjunctive therapy in chronic management of urea cycle disorders, involving deficiencies of carbamoyl phosphate synthetase, ornithine transcarbamylase or argininosuccinate synthetase; in patients with neonatal-onset deficiency (complete enzymatic deficiency, presenting within the 1st 28 days of life), or late-onset disease (partial enzymatic deficiency, presenting after the 1st month of life) who have a history of hyperammonaemic encephalopathy: Usual total daily dose: <20 kg: 0.45-0.6 g/kg daily; given in equally divided doses and with each meal/feeding (e.g. 3-6 times daily). Max: 20 g daily; ≥20 kg: Same as adult dose. Daily dosage must be individualised and adjusted according to patient’s protein tolerance and daily dietary protein intake. Therapy must be used in combination with a protein-restricted diet, and essential amino acid or carnitine supplementation if required.
Administration
Should be taken with food.
Contraindications
Management of acute hyperammonaemia. Pregnancy and lactation.
Special Precautions
Patient with CHF, conditions that involve Na retention with oedema, inborn errors of β-oxidation, restricted Na intake, and diabetes mellitus. Patients who require caloric supplementation should receive protein-free caloric supplements. Renal and hepatic impairment. Children.
Adverse Reactions
Significant: Na and fluid retention; signs and symptoms of neurotoxicity (e.g. somnolence, headache, lightheadedness, fatigue, hypoacusis, dysgeusia, disorientation, exacerbation of preexisting neuropathy, impaired memory). Blood and lymphatic system disorders: Thrombocytopenia, anaemia, leucopenia, leucocytosis, thrombocytosis. Cardiac disorders: Syncope. Gastrointestinal disorders: Nausea, vomiting, constipation, abdominal pain. Investigations: Decreased serum total protein, increased serum alkaline phosphatase and liver transaminases, increased weight. Metabolism and nutrition disorders: Metabolic acidosis, alkalosis, hypoalbuminaemia, hyperbilirubinaemia, hyperuricaemia, hyperchloraemia, hypernatraemia, hypophosphataemia, hyperphosphataemia, hypokalaemia, oedema, decreased appetite. Psychiatric disorders: Irritability, depression. Renal and urinary disorders: Renal tubular acidosis. Reproductive system and breast disorders: Irregular menstruation, amenorrhoea. Skin and subcutaneous tissue disorders: Rash, abnormal skin odour. Potentially Fatal: Acute hyperammonaemia or acute hyperammonaemic encephalopathy.
Monitor plasma ammonia levels, serum electrolytes, CBC with differential, serum proteins and plasma amino acid quantitation, urinalysis, hepatic and renal function tests. Monitor nutritional parameters (e.g. weight, height, albumin, head circumference), and for signs and symptoms of hyperammonaemia (e.g. vomiting, confusion, lethargy, ataxia, seizures, memory impairment).
Overdosage
Symptoms: Diarrhoea, irritability, metabolic acidosis, hypokalaemia, and manifestations of neurotoxicity. Management: Supportive and symptomatic treatment. May perform haemodialysis or peritoneal dialysis.
Drug Interactions
Concurrent use with probenecid may affect renal excretion of conjugated products which may increase serum concentrations of phenylacetate and phenylacetylglutamine. Valproates and haloperidol may increase plasma ammonia levels thus diminishing the therapeutic effect of Na phenylbutyrate. Corticosteroids may increase protein catabolism and plasma ammonia concentrations.
Action
Description: Sodium phenylbutyrate, a prodrug, is rapidly converted to phenylacetate which conjugates with glutamine to form phenylacetylglutamine. Phenylacetylglutamine then serves as a substitute for urea in excreting nitrogenous waste from the body via urine. Pharmacokinetics: Absorption: Rapidly absorbed from the gastrointestinal tract. Time to peak plasma concentration: 1-1.35 hours (phenylbutyrate); 3.55-3.74 hours (phenylacetate); approx 3.23 hours (phenylacetylglutamine). Distribution: Volume of distribution: 0.2 L/kg. Metabolism: Rapidly oxidised to phenylacetate followed by conjugation with glutamine via acetylation in the liver and kidney to form phenylacetylglutamine. Excretion: Via urine (80-100% as phenylacetylglutamine). Elimination half-life: Approx 0.8 hours (phenylbutyrate); approx 1.3 hours (phenylacetate); approx 2.4 hours (phenylacetylglutamine).
Chemical Structure
Sodium phenylbutyrate Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 5258, Sodium phenylbutyrate. https://pubchem.ncbi.nlm.nih.gov/compound/Sodium-phenylbutyrate. Accessed Sept. 24, 2021.
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