PHEBURANE Granules Ref.[7695] Active ingredients: Sodium phenylbutyrate

Content of clinically important electrolytes:

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

General considerations:

• Even on therapy, acute hyperammonaemic encephalopathy may occur in a number of patients.
• PHEBURANE is not recommended for the management of acute hyperammonaemia, which is a medical emergency.

Excipients with known effect:

• This medicinal product contains 124 mg sodium per gram, equivalent to 6.2% of the WHO recommended maximum daily intake for sodium. The maximum daily dose of this medicinal product is equivalent to 125% of the WHO recommended maximum daily intake for sodium.
• PHEBURANE is considered high in sodium. This should be particularly taken into account for those on a low salt diet.
• This medicinal product contains 768 mg sucrose per gram. This should be taken into account in patients with diabetes mellitus. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicinal product.

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 medicinal products have to be used.

Women of childbearing potential/Contraception in males and females

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

Pregnancy

There are no or limited amount of data from the use of sodium phenylbutyrate in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3).

Pheburane is contra-indicated during pregnancy (see section 4.3). Women of childbearing potential must use effective contraception during treatment.

Breast-feeding

Available pharmacodynamic/toxicological data in animals have shown excretion of sodium phenylbutyrate/metabolites in milk (see section 5.3). It is unknown whether sodium phenylbutyrate/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Pheburane is contra-indicated during breast-feeding (see section 4.3).

Fertility

There is no evidence available on the effect of sodium phenylbutyrate on fertility

PHEBURANE has negligible influence on the ability to drive and use machines.

Summary of safety profile

In clinical trials with sodium phenylbutyrate, 56% of the patients experienced at least one adverse event and 78% of these adverse events were considered as not related to sodium phenylbutyrate. Adverse reactions mainly involved the reproductive and gastrointestinal system.

Tabulated list of adverse reactions

In the table below all 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, adverse reactions 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 odor

Renal and urinary disorders

Common: renal tubular acidosis

Reproductive system and breast disorders

Very common: amenorrhea, 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

Description of selected adverse reactions

A probable case of toxic reaction to sodium phenylbutyrate (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 the national reporting system listed in Appendix V.

Not applicable.