Pheburane Oral Solution 350 mg Oral solution

PHEBURANE 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 disease (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.

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

Posology

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 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 of sodium phenylbutyrate 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

PHEBURANE 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.

Special populations

Renal and hepatic impairment

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

Paediatric population

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

• 450 - 600 mg/kg/day in neonates, infants and children weighing less than 20 kg.

• 9.9 - 13 g/m²/day in children weighing more than 20 kg.

Method of administration

PHEBURANE oral solution is for oral use.

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).

A dosing syringe with a press in bottle adapter (PIBA) is provided for accurate measurement of the prescribed dose of the oral solution. The PIBA allows to connect the dosing syringe to the bottle and to dose PHEBURANE oral solution.

Only the dosing syringe provided with PHEBURANE oral solution should be used to measure a dose of PHEBURANE oral solution. No other devices/spoons/syringes should be used to administer PHEBURANE oral solution.

The syringe is graduated in grams of sodium phenylbutyrate (from 0.5 g to 3 g of sodium phenylbutyrate.

PHEBURANE oral solution can also be administered by nasogastric or gastrostomy tubes.

Instructions for oral administration and administration via nasogastric or gastrostomy tube are provided in section 6.6.

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

• Pregnancy.

• Breast-feeding.

Content of clinically important electrolytes

• Each gram of PHEBURANE oral solution (2.86 mL of PHEBURANE oral solution) contains 124 mg (5.4 mmol) of sodium. The maximum daily dose of sodium phenylbutyrate is 20 g (57.14 mL of PHEBURANE oral solution), this would bring an associated amount of: 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 oral solution is not recommended for the management of acute hyperammonaemia, which is a medical emergency.

Excipients with known effect

PHEBURANE 350 mg/mL oral solution

• This medicinal product contains 124 mg (5.4 mmol) sodium per g dose of sodium phenylbutyrate, equivalent to 6.2% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

The maximum daily dose of this medicinal product contains 2.5 g sodium , equivalent to 125% of the WHO recommended maximum daily intake of 2 g of sodium for an adult. PHEBURANE oral solution is considered high in sodium. This should be particularly taken into account for those on a low salt diet.

• This medicinal product contains 5.7 mg aspartame per g dose of sodium phenylbutyrate. Aspartame is a source of phenylalanine. It may be harmful for persons who have phenylketonuria (PKU), a rare genetic disorder in which phenylalanine builds up because the body cannot remove it properly. Neither non-clinical nor clinical data are available to assess aspartame (E951) use in infants below 12 weeks of age.

Blackcurrant flavour topping

The blackcurrant flavour topping contains 26.55 mg propylene glycol per drop.

If your baby is less than 4 weeks old, talk to your doctor or pharmacist before giving them this medicine, in particular if the baby is given other medicines that contain propylene glycol or alcohol.

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.

Description of selected adverse reactions

A probable case of toxic reaction to sodium phenylbutyrate (450 mg/kg/day) 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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

One case of overdose occurred in a 5-month old infant with an accidental single dose of 10 g (1,370 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, hypoacusis, disorientation, impaired memory and exacerbation of a pre- existing neuropathy.

In the event of an overdose, the treatment should be discontinued and supportive measures be instituted. Haemodialysis or peritoneal dialysis may be beneficial.

Pharmacotherapeutic group: Other alimentary tract and metabolism products, various alimentary tract and metabolism products, ATC code: A16AX03.

Mechanism of action and pharmacodynamic effects

Sodium phenylbutyrate is a pro-drug and is rapidly metabolised to phenylacetate. Phenylacetate is a metabolically active compound that conjugates with glutamine via acetylation to form phenylacetylglutamine which is then excreted by the kidneys. On a molar basis, phenylacetylglutamine is comparable to urea (each containing 2 moles of nitrogen) and therefore provides an alternate vehicle for waste nitrogen excretion.

Clinical efficacy and safety

Based on studies of phenylacetylglutamine excretion in patients with urea cycle disorders it is possible to estimate that, for each gram of sodium phenylbutyrate administered, between 0.12 and 0.15 g of phenylacetylglutamine nitrogen are produced. As a consequence, sodium phenylbutyrate reduces elevated plasma ammonia and glutamine levels in patients with urea cycle disorders. It is important that the diagnosis is made early and treatment is initiated immediately to improve the survival and the clinical outcome.

In late-onset deficiency patients, including females heterozygous for ornithine transcarbamylase deficiency, who recovered from hyperammonaemic encephalopathy and were then treated chronically with dietary protein restriction and sodium phenylbutyrate, the survival rate was 98%. The majority of the patients who were tested had an IQ in the average to low average/borderline mentally retarded range.

Their cognitive performance remained relatively stable during phenylbutyrate therapy. Reversal of pre-existing neurologic impairment is not likely to occur with treatment, and neurologic deterioration may continue in some patients.

PHEBURANE oral solution may be required life-long unless orthotropic liver transplantation is elected.

Paediatric population

Previously, neonatal-onset presentation of urea cycle disorders was almost universally fatal within the first year of life, even when treated with peritoneal dialysis and essential amino acids or their nitrogen-free analogues. With haemodialysis, use of alternative waste nitrogen excretion pathways (sodium phenylbutyrate, sodium benzoate and sodium phenylacetate), dietary protein restriction, and, in some cases, essential amino acid supplementation, the survival rate in newborns diagnosed after birth (but within the first month of life) increased to almost 80% with most deaths occurring during an episode of acute hyperammonaemic encephalopathy. Patients with neonatal-onset disease had a high incidence of mental retardation.

In patients diagnosed during gestation and treated prior to any episode of hyperammonaemic encephalopathy, survival was 100%, but even in these patients, many subsequently demonstrated cognitive impairment or other neurologic deficits.

Phenylbutyrate is known to be oxidised to phenylacetate which is enzymatically conjugated with glutamine to form phenylacetylglutamine in the liver and kidney. Phenylacetate is also hydrolysed by esterases in liver and blood.

Plasma and urine concentrations of phenylbutyrate and its metabolites have been obtained from fasting normal adults who received a single dose of 5 g of sodium phenylbutyrate and from patients with urea cycle disorders, haemoglobinopathies and cirrhosis receiving single and repeated oral doses up to 20 g/day (uncontrolled studies). The disposition of phenylbutyrate and its metabolites has also been studied in cancer patients following intravenous infusion of sodium phenylbutyrate (up to 2 g/m²) or phenylacetate.

Absorption

Phenylbutyrate is rapidly absorbed under fasting conditions. Under fed conditions in the single-dose, open, pharmacokinetic study (CPA 537-21), after a single oral dose of 5 g of sodium phenylbutyrate, in the form of oral solution, measurable plasma levels of phenylbutyrate were detected 10 minutes after dosing. The mean time to peak concentration was 0.5 hour and the mean peak concentration 150.44 μg/ml. The elimination half-life was estimated to be 0.63 hours.

Distribution

The volume of distribution of phenylbutyrate is 0.2 l/kg.

Biotransformation

After a single dose of 5 g of sodium phenylbutyrate, in the form of granules, measurable plasma levels of phenylacetate and phenylacetylglutamine were detected 30 and 60 minutes respectively after dosing. The mean time to peak concentration was 3.55 and 3.23 hours, respectively, and the mean peak concentration was 45.3 and 62.8 μg/ml, respectively. The elimination half-life was estimated to be 1.3 and 2.4 hours, respectively.

Studies with high intravenous doses of phenylacetate showed non-linear pharmacokinetics characterised by saturable metabolism to phenylacetylglutamine. Repeated dosing with phenylacetate showed evidence of an induction of clearance.

In the majority of patients with urea cycle disorders or haemoglobinopathies receiving various doses of phenylbutyrate (300–650 mg/kg/day up to 20 g/day) no plasma level of phenylacetate could be detected after overnight fasting. In patients with impaired hepatic function the conversion of phenylacetate to phenylacetylglutamine may be relatively slower. Three cirrhotic patients (out of 6) who received repeated oral administration of sodium phenylbutyrate (20 g/day in three doses) showed sustained plasma levels of phenylacetate on the third day that were five times higher than those achieved after the first dose.

In normal volunteers gender differences were found in the pharmacokinetic parameters of phenylbutyrate and phenylacetate (AUC and Cmax about 30–50% greater in females), but not phenylacetylglutamine. This may be due to the lipophilicity of sodium phenylbutyrate and consequent differences in volume of distribution.

Excretion

Approximately 80–100% of the medicinal product is excreted by the kidneys within 24 hours as the conjugated product, phenylacetylglutamine.

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 (see section 4.6).

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. (see section 4.6).

Sodium phenylbutyrate was negative in 2 mutagenicity tests, i.e. the Ames test and the micronucleus test. Results indicate that sodium phenylbutyrate did not induce any mutagenic effects in the Ames test with or without metabolic activation.

Micronucleus test results indicate that sodium phenylbutyrate was considered not to have produced any clastogenic effect in rats treated at toxic or non-toxic dose levels (examined 24 and 48 hours after a single oral administration of 878 to 2800 mg/kg).

Carcinogenicity and fertility studies have not been conducted with sodium phenylbutyrate.

Oral solution

Purified water

Aspartame (E951)

Sucralose

Glycerol

Hydroxyethylcellulose

Flavour toppings

Blackcurrant flavour topping

Blackcurrant and mint flavouring, contains propylene glycol (E1520).

Lemon-mint flavour topping

Lemon and mint flavouring.

Not applicable.

Oral solution

Unopened bottle: 3 years

After first opening: 4 weeks

This medicinal product does not require any special storage conditions.

Amber glass bottle containing 100 mL closed with a plastic child-resistant cap.

Each pack contains:

- One amber glass bottle containing 100 mL PHEBURANE oral solution,

- One amber glass bottle containing 3 mL of lemon-mint flavour topping.

- One amber glass bottle containing 3 mL of blackcurrant flavour topping.

- One dosing syringe ranging from 0.5 g to 3 g with 0.25 increments with attached bottle adapter (PIBA).The graduation of the dosing syringe reflects the grams of sodium phenylbutyrate.

The oral solution of PHEBURANE is ready-to use.

Administration for oral use

1. The bottle of PHEBURANE oral solution should be opened by pushing down on the cap and twisting it to the left;

2. The CE marked dosing syringe is attached to the bottle adapter;

3. The bottle adapter should be placed/pushed into the neck of the open bottle while the syringe is in it;

4. The bottle should be inverted;

5. The required dose of PHEBURANE (see section 4.2) should be taken from the bottle (equivalent to the number of grams sodium phenylbutyrate as prescribed and according to the amount to be given with the respective meal) with the use of the dosing syringe;

6. The dosing syringe with PHEBURANE should be detached from the bottle adapter and the quantity of PHEBURANE oral solution should then be poured from the dosing syringe into a glass with minimum 20 ml of water;

7. PHEBURANE oral solution tastes neutral. In order to improve the taste, one drop of the preferred flavour topping can be added to the content of the glass of water; swirled gently, and then consumed (If one drop of flavour topping would not provide the taste intensity, patient could use 2 drops);

8. The bottle with PHEBURANE oral solution should be closed, without removing the bottle adapter inserted in the neck of the bottle.

Preparation for nasogastric tube or gastrostomy tube administration

PHEBURANE oral solution can be administered with tubes of a diameter of 2 mm (7-8 French) and larger.

In patients who have to receive sodium phenylbutyrate, permanently or at certain times during daytime (e.g. at night) via a nasogastric tube or gastrostomy tube/button, these routes may be used to administer PHEBURANE oral solution following the instructions below:

1. Steps 1 to 5 of the administration for oral use above should be followed;

2. The oral solution of PHEBURANE is ready-to use and no dilution is needed;

3. When used via nasogastic/gastrostomy tube the flavour topping should not be added;

4. The tip of the syringe filled with the medicinal product should be inserted onto the tip of the nasogastric/gastrostomy tube;

5. The plunger of the dosing syringe to administer the dose of PHEBURANE oral solution into the nasogastric/gastrostomy tube should be used;

6. The tube should be flushed once with the adequate volume of lukewarm water and allowed to drain after the administration. For adults, 20 ml of lukewarm water should be used. For children weighing less than 20 kg and neonates use 3 mL of water.

Disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.