Consumer medicine information

Pheburane

Sodium phenylbutyrate

BRAND INFORMATION

Brand name

Pheburane

Active ingredient

Sodium phenylbutyrate

Schedule

What is in this leaflet

This leaflet answers some common questions about Pheburane.

It does not contain all the available information. Some of the information it contains may not apply to you.

It does not take the place of talking to your doctor or pharmacist. All medicines have benefits and risks. In deciding to give you Pheburane, your doctor has weighed the risks of you taking Pheburane against the expected benefits it will have for you.

Always follow the instructions that your doctor and pharmacist give you about Pheburane.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

What is Pheburane used for

Pheburane contains the medicine sodium phenylbutyrate. Pheburane belongs to a group of medicines called nitrogen scavengers.

Nitrogen is a building block of proteins, which are an essential part of the food we eat. Waste nitrogen is converted into ammonia and removed from the body. Liver enzymes are necessary to remove ammonia from the blood stream. In patients with urea cycle disease (UCD), ammonia builds up because the body cannot remove it. Ammonia is especially toxic for the brain and leads, in severe cases, to reduced levels of consciousness and to coma.

Pheburane granules are indicated for the management of hyperammonaemia (elevated bloodammonia) associated with urea cycle disorders. Pheburane should be used with dietary protein restriction and, in some cases, dietary supplements (e.g. essential amino acids, arginine, citrulline, and protein-free calorie supplements).

Pheburane helps the body to eliminate waste nitrogen, reducing the amount of ammonia in your body.

Sodium phenylbutyrate can be used in infants from one month of age and needs to be taken continuously throughout the patient’s lifetime.

Your doctor may have prescribed this medicine for another use. If you want more information, ask your doctor.

Pheburane is only available on a doctor's prescription

Before you take Pheburane

When you must not take it

You should not take Pheburane if:

you are allergic to sodium phenylbutyrate or any of the ingredients listed under 'Product Description' at the end of this leaflet.
you are pregnant
you are breastfeeding
the packaging shows signs of tampering.
the expiry date on the pack has passed. If you use this product after the expiry date has passed, it may not work.

Do not take Pheburane to treat any other complaint unless your doctor says it is safe. Do not give this medicine to anyone else.

Pheburane is recommended for children.

Before you start to take Pheburane

You must tell your doctor if:

you are pregnant or intend to become pregnant. Your doctor will discuss the possible risks and benefits of taking Pheburane during pregnancy.
If you are a woman who could become pregnant, you must use reliable contraception during treatment with Pheburane and should speak with your doctor.
you suffer from congestive heart failure (a type of heart disease where the heart cannot pump enough blood around the body);
have decreased kidney or liver function, since Pheburane is eliminated from the body through the kidney and liver;
are diabetic or have been diagnosed with problems (ie intolerance, malabsorption or enzyme insufficiency) relating to some sugars.
The use of Pheburane during breast feeding has not been investigated. Ask your doctor for advice about breast feeding.
Hypersensitive to the active substance or to any of the excipients

If you have not told your doctor about any of the above, tell him/her before you start taking Pheburane.

While taking Pheburane it is still possible to experience an acute excess of ammonia in the blood. If this happens you may develop symptoms such as feeling sick (nausea), being sick (vomiting), confusion, combativeness, slurred speech, difficulty walking, and even loss of consciousness. This is a medical emergency, and medical assistance should be sought immediately. An infection can cause such a situation; therefore, if you develop a fever you should seek prompt medical assistance.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food store.

Some medicines and Pheburane may interfere with each other. These include:

valproate, topiramate, phenobarbital, or carbamazepine (antiepileptic medicines);
haloperidol (used in certain psychotic disorders);
corticosteroids (medicines that are used to provide relief for inflamed areas of the body);
probenecid (for treatment of hyperuricaemia, high levels of uric acid in the blood, associated with gout);
rifampicin (an antibiotic).

These medicines may change the effect of Pheburane and you may need more frequent blood tests. If you are uncertain if your medicines contain these substances, you should check with your doctor or pharmacist.

Your doctor may need to change the amount of your medicines, or you may need to take different medicines.

If you are unsure about any medicine you are taking youshould check with your doctor or pharmacist. They will have more information on medicines to be careful with or avoid while taking Pheburane.

How to take Pheburane

How to take it

Your doctor will tell you the amount of Pheburane to take each day.

Take Pheburane only as prescribed by your doctor and follow his or her directions carefully. They may differ from the information contained in this leaflet.

The daily dose of Pheburane will be based on your body weight or body surface area and adjusted according to your protein tolerance and diet. You will need regular blood tests to determine the correct daily dose.

Use only the calibrated measuring spoon provided with this medicine to measure out each dose.

For newborns and children who weigh less than 20kg, the usual total daily dose is up to 600 mg/kg.
For children who weigh more than 20 kg, adolescents and adults, the usual total daily dose is up to 13.0 g/m² surface area.

Your total dose per day should not exceed 20 grams.

You should take Pheburane by mouth.

You should take Pheburane with each meal or feeding. In small children this can be 4 to 6 times per day.

A calibrated measuring spoon which dispenses up to 3 g of sodium phenylbutyrate by graduation of 250 mg is provided with themedicine. Only use this measuring spoon to measure out the dose.

To measure the dose:

Lines on the spoon indicate the amount (in grams of sodium phenylbutyrate). Take the correct amount as prescribed by your doctor.
Pour granules directly into the spoon as shown by the picture below.

Tap the spoon once on a table to give a horizontal level of granules and continue filling if necessary.
If you must take more than 3 grams at once, repeat these instructions to obtain the prescribed dose.

DO NOT USE THIS MEASURING SPOON FOR ANY OTHER MEDICINES.

The granules can be directly swallowed with a drink (water, fruit juices, protein-free infant formulas) or sprinkled on to a spoonful of solid foods (mashed potatoes or apple sauce). If you mix them with food, it is important that you take it immediately. This will keep the granules from producing any taste.

Administration by nasogastric tube or gastrostomy tube:
In certain circumstances, your doctor may decide that Pheburane should be administered through nasogastric tube (a tube that goes through the nose to the stomach) or gastrostomy tube (a tube that goes through the abdomen to the stomach). In this case, Pheburane will be prepared into a liquid (50 mg/mL of sodium phenylbutyrate) by hospital or pharmacy staff following specific instructions. Granules should not be taken directly by tube. The exact amount of liquid to measure into the syringe will be determined by your doctor. Do not use the measuring spoon provided with the product to measure the liquid as it is designed to measure the granules only.

The liquid should be stored in a refrigerator between 2 and 8 degree C and used within 7 days. The liquid should be wrapped in aluminum foil to protect it from light.

Take the liquid from the refrigerator and allow to stay at room temperature at least one hours before use.

Shake well before measuring out the prescribed amount of liquid with a syringe.

The liquid must be given with a syringe by fast push directly through the tube. Rinse with water to clear the nasogastric or gastrostomy tube.

Use in children

Sodium phenylbutyrate has not been tested for safety and effectiveness in children under one month of age.

In young infants, from one month of age, the granules can be mixed with a drink (water, fruit juices, protein-free infant formulas) or sprinkled on to a spoonful of solid foods (mashed potatoes or apple sauce). If you mix them with food, it is important that you give it immediately. This will keep the granules from producing any taste.

Use in the elderly

Sodium phenylbutyrate has not been been tested for safety and effectiveness in people over 65 years of age.

Take Pheburane at about the same time each day. Taking your granules at the same time each day will have the best effect. It will alsohelp you to remember when to take it.

You should take Pheburane for as long as your doctor continues to prescribe it. This medicine is intended for long-term use. If you stop taking it the levels of ammonia may increase to the levels before treatment was started, potentially causing damage to your liver.

If you forget to take Pheburane

You should take a dose as soon as possible with your next meal. Make sure that there are at least 3 hours between two doses. Do not take a double dose to make up for a forgotten dose.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

You may experience the following symptoms if you take more Pheburane than you should:

sleepiness,
tiredness
light-headedness

And less frequently:

confusion,
headache,
changes in taste (taste disturbances),
decrease in hearing,
may have an effect on your memory
impaired memory, and
worsening of existing neurological conditions.

In case of drug overdose, contact a health care practitioner, hospital emergency department or regional Poison Control Centre immediately, even if there are no symptoms.

While you are taking Pheburane

Things you must do

Take Pheburane exactly as your doctor has prescribed
Tell your doctor if you become pregnant or plan to become pregnant
Tell your doctor if you decide to breast feed your baby. Your doctor may want to discuss this and change your medicine.
Tell your doctor that you are taking Pheburane if you are about to start on any new medicine.
If you are a woman who could become pregnant, you must use reliable contraception during treatment with Pheburane and should speak with your doctor.

If you become pregnant, your doctor will monitor your pregnancy frequently and discuss with you any risks and benefits of Pheburane treatment.

Keep all your doctor or clinic appointments.

Your doctor will do laboratory tests regularly while you are Pheburane to check levels of ammonia, amino acids and serum proteins.

Your doctor will also provide nutritional advice regarding your diet while you are taking Pheburane. You must follow these instructions carefully.

Do not suddenly stop taking Pheburane without telling your doctor.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Pheburane. Like other medicines Pheburane can cause some side effects. Most are likely to be minor and temporary. However, some may be serious and need medical attention.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor immediately or go to Emergency at your nearest hospital if you notice any of the following:

allergic reaction such as rash, hives, swelling of the face, lips, tongue or throat, difficulty swallowing or breathing
feeling sick (nausea), being sick (vomiting), confusion or drowsiness

These are serious side effects. You may need urgent medical attention.

Tell your doctor if you notice any of the following and they worry you:

changes in menstruation or cessation of a woman’s period
reduced appetite
body odour
changes in taste
low red blood cells
low or high platelets
low or high white blood cells
mood changes
headache
stomach ache
rash
changes in the blood including levels of pH (more or less acidic than normal), proteins, enzymes and electrolytes.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice any other effects.

Do not be alarmed by this list of side effects. Most people do not experience any of them.

After using Pheburane

Storage

Keep your granules in the bottle until it is time to take them.

Once the bottle is opened, the granules must be used within 45 days.

If you take your granules out of the bottle they will not keep well.

Keep Pheburane in a cool, dry place where the temperature stays below 30 degrees C.

Pheburane solution for nasogastric or gastrostomy administration should be stored between 2 and 8 degrees C and used within 7 days.

Protect from light.

Do not store Pheburane or any other medication in the bathroom or near a sink.

Keep Pheburane where young children cannot reach it. A locked cupboard at least one and a half metres above the ground is a good place to store medicines.

Do not use after the expiry date which is stated on the carton and bottle label after “EXP’’. The expiry date refers to the last day of that month.

Disposal

If your doctor tells you to stop taking Pheburane, ask your pharmacist what to do with any granules that are left over.

Product description

What it looks like

Pheburane consists of white to off-white tasteless coated granules. Each gram of granules contains 483 mg/g of sodium phenylbutyrate.

AUST R 273750

Active Ingredient:

Pheburane contains sodium phenylbutyrate 483mg/g

Other Ingredients:

Ethylcellulose
Hypromellose
Macrogel 1500
Maize starch
Povidone
Sucrose

Manufacturer

Pheburane is supplied in Australia by:

Orpharma Pty Ltd
Level 1,
1 Queens Road,
Melbourne VIC 3004

This leaflet was prepared in May, 2017

Published by MIMS December 2017

BRAND INFORMATION

Brand name

Pheburane

Active ingredient

Sodium phenylbutyrate

Schedule

1 Name of Medicine

Sodium phenylbutyrate.

2 Qualitative and Quantitative Composition

Pheburane granules are sugar-coated spheres containing sodium phenylbutyrate.
Each gram of granules contains 483 mg of sodium phenylbutyrate.

Excipient(s) with known effect.

Each gram of sodium phenylbutyrate contains 124 mg (5.4 mmol) of sodium and 768 mg of sucrose. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Granules.
White to off-white granules.

4 Clinical Particulars

4.1 Therapeutic Indications

Pheburane (sodium phenylbutyrate) is indicated for the management of hyperammonaemia associated with urea cycle disorders. Pheburane should be used with dietary protein restriction and, in some cases, dietary supplements (e.g. essential amino acids, arginine, citrulline, and protein-free calorie supplements).

4.2 Dose and Method of Administration

Dosing considerations.

Pheburane treatment should be initiated and supervised by a health professional experienced in the treatment of urea cycle disorders, as part of a multidisciplinary team.
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.

Recommended dose and dosage adjustment.

The usual total daily dose of sodium phenylbutyrate is:
up to 600 mg/kg/day in neonates, infants and children weighing less than 20 kg;
up to 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.
The recommended dose is expressed in terms of milligrams (mg) or grams (g) of sodium phenylbutyrate, rather than the weight of the granules.
A calibrated dosing spoon is provided which dispenses Pheburane granules equivalent to amounts up to 3 g of sodium phenylbutyrate in graduations of 250 mg.
Use only the dosing spoon provided with the medicine to measure out the dose. Do not use any other measuring device to measure out the dose.
The total daily dose of Pheburane should be divided into equal amounts and given with each meal or feeding (e.g. 4-6 times per day in small children). The granules can be directly swallowed with a drink (water, fruit juices, protein-free infant formulas) or sprinkled on to a spoonful of solid food (mashed potatoes or apple sauce); in this case, it is important that the Pheburane and food is taken immediately in order to preserve the taste-masking. In case of mixture of the granules with solid foods or liquid it is important that it is taken immediately after mixing. Any unused medicinal product or waste material should be disposed of.

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 the 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 calorific supplementation is indicated, a protein-free product is recommended.

Therapeutic monitoring.

Pheburane dosage should be adjusted according to the results of monitoring of plasma levels of ammonia, glutamine, serum protein and amino acids, and, where indicated, levels of phenylbutyrate and its metabolites).
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 micromol/L.

Administration.

Pheburane should be administered orally. For patients unable to take the product orally, Pheburane may be administered by nasogastric or gastrostomy tube, as described below.

Administration by nasogastric or gastrostomy tube.

Pheburane granules should not be administered by tube. A solution of Pheburane (50 mg/mL of sodium phenylbutyrate) must be prepared by hospital or pharmacy personnel for administration through a nasogastric or gastrostomy tube according to the instructions below:
1. Weigh 51.75 g of Pheburane granules using a balance. One gram of Pheburane granules contains 0.483 g of sodium phenylbutyrate so 51.75 g of Pheburane granules is equivalent to 25 g of sodium phenylbutyrate.
2. Fill a 500 mL volumetric flask with about 400 mL of purified water; add a stir bar and start mixing on a magnetic stirrer.
3. Slowly pour Pheburane through a funnel into the volumetric flask; maintain constant vigorous stirring for 60 minutes.
4. Remove the stir bar and make up to the 500 mL mark with purified water; stopper the flask and invert once to mix.
5. Filter the solution through a stainless steel sieve (250 micrometer) and store in a sealed glass bottle. Protect from light with aluminum foil. Store in a refrigerator between 2°C to 8°C. Take the glass bottle from the refrigerator at least one (1) hour before use and shake vigorously prior to administration.

Note.

The prepared solution provides 50 mg/mL of sodium phenylbutyrate and not the equivalent of 50 mg of Pheburane granules.
The appropriate volume of solution must be measured and administered with the use of a syringe directly through the nasogastric or gastrostomy tube and rinsed with water to clear the nasogastric or gastrostomy tube.
The solution of Pheburane should be used within 7 days when stored between 2°C to 8°C and protected from light.

Missed dose.

In the event a dose is missed, the dose should be taken as soon as possible, with the next meal. There should be at least 3 hours between two doses. The dose should not be doubled to make up for the missed doses.

4.3 Contraindications

Hypersensitivity to sodium phenylbutyrate or to any ingredient in the formulation.
Pregnancy.
Breastfeeding.

4.4 Special Warnings and Precautions for Use

General.

Pheburane should have therapy initiated and ongoing treatment supervised by a medical practitioner with expertise in the management of urea cycle disorders, as part of an individualised multidisciplinary approach.

Hyperammonia.

Episodes of acute hyperammonemic encephalopathy may occur in patients even when they are on Pheburane therapy.
Pheburane is not recommended for the management of acute hyperammonemia, which is a life-threatening medical emergency that requires more rapidly acting interventions to reduce plasma ammonia levels.

Sodium content.

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 (the maximum daily dose). Pheburane should be used with extreme caution, if at all, in patients with congestive heart failure or severe renal insufficiency, and with care in patients on a controlled sodium diet or in clinical conditions where there is sodium retention with edema.

Serum potassium levels.

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

Sucrose content.

Pheburane contains 768 mg of sucrose for each gram of sodium phenylbutyrate, corresponding to 15.4 g of sucrose in the maximum daily dose of 20 g of sodium phenylbutyrate. This should be considered in patients with diabetes mellitus. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take Pheburane.

Neurologic.

The major metabolite of sodium phenylbutyrate, phenylacetate, is associated with neurotoxicity. In a study of cancer patients administered phenylacetate intravenously, signs and symptoms of neurotoxicity were seen at plasma concentrations ≥ 3.5 mmol/L, including somnolence, fatigue, light headedness, headache, dysgeusia, hypoacusis, disorientation, impaired memory, and exacerbation of pre-existing neuropathy. The adverse events were reversible upon discontinuation.
Serum drug levels of phenylbutyrate and its metabolites, phenylacetate and phenylglutamine, may be monitored periodically. In particular, plasma phenylacetate levels may be useful to guide dosing of Pheburane if symptoms of vomiting, nausea, headache, somnolence, confusion, or sleepiness are present in the absence of high ammonia or intercurrent illness.

Patient monitoring.

Plasma levels of ammonia, arginine, essential amino acids (especially branched chain amino acids), carnitine and serum proteins should be maintained within normal limits. A fasting plasma ammonia level of less than half the age-adjusted upper limit of normal (ULN) has been used as a therapeutic target, and plasma glutamine should be maintained at levels less than 1,000 micromol/L. Urinalysis, blood chemistry profiles, and hematologic tests should be monitored routinely.

Use in hepatic impairment.

Since sodium phenylbutyrate is metabolized in the liver and kidneys, Pheburane should be used with caution in patients with hepatic insufficiency.

Use in renal impairment.

Sodium phenylbutyrate is metabolized in the liver and kidneys to phenylacetylglutamine, which is primarily excreted by the kidneys. Pheburane should therefore be used with caution in patients with renal insufficiency (CrCl or eGFR < 60 mL/min).

Effects on ability to drive and use machines.

No studies on the effects on the ability to drive and use machines have been performed.

Use in the elderly.

Pheburane has not been studied in the geriatric population.

Paediatric use.

Pheburane is recommended for infants (> 1 month of age), children and adolescents based on the available clinical data.

Effects on laboratory tests.

Interactions with laboratory tests have not been established.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Drug-drug interactions.

No formal clinical drug-drug interaction studies have been performed with Pheburane. The drugs listed in Table 1 are based on potential pharmacologic interactions which may affect plasma ammonia levels; the potential interaction with probenecid is through pharmacokinetic interactions with sodium phenylbutyrate rather than a direct effect on the underlying metabolic disease.

More frequent monitoring of plasma ammonia levels is advised if the above-mentioned medicinal products must be used.

Drug-food interactions.

Interactions with food have not been established.

Drug-herb interactions.

Interactions with herbal products have not been established.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Dedicated fertility studies have not been conducted with sodium phenylbutyrate. A related substance, glycerol phenylbutyrate, had no effect on fertility or reproductive function in male and female rats dosed orally at up to 900 mg/kg/day (combined systemic exposure for phenylbutyrate and the active metabolite phenylacetate approximately 8 times that anticipated clinically with Pheburane). At doses of 1200 mg/kg/day, maternal toxicity was observed and the number of nonviable embryos was increased.
Amenorrhea/menstrual dysfunction was common in menstruating women administered sodium phenylbutyrate.
(Category B3 )
The safety of this medicinal product for use in human pregnancy has not been established.
Exposure of rats to the active metabolite phenylacetic acid during pregnancy or early postnatal life was associated with reduced fetal brain weight, impaired performance in learning and memory tasks and neuroanatomical deficits. Reproductive toxicity studies have been conducted with glycerol phenylbutyrate, which is closely related to sodium phenylbutyrate. Oral administration of glycerol phenylbutyrate to rabbits at doses up to 350 mg/kg/day during the period of organogenesis had no effect on embryofetal development (combined systemic exposure for phenylbutyrate and the active metabolite phenylacetate approximately 2 times that anticipated clinically). In rats, no effects on embryofetal development were observed at oral doses of 300 mg/kg/day (combined systemic exposure for phenylbutyrate and phenylacetate approximately 4 times that anticipated clinically with Pheburane). Doses ≥ 650 mg/kg/day produced maternal toxicity and adverse effects on embryofetal development, including reduced fetal weights, skeletal variations and delayed ossification, and a wide range of non-specific malformations. No developmental abnormalities, effects on growth, or effects on learning and memory were observed in rats through day 92 postpartum following oral administration of glycerol phenylbutyrate to pregnant rats at up to 900 mg/kg/day (combined systemic exposure for phenylbutyrate and the active metabolite phenylacetate approximately 8 times that anticipated clinically with Pheburane).
The significance of these data in pregnant women is not known; therefore the use of Pheburane is contra-indicated during pregnancy. Effective contraceptive measures must be taken by women of child-bearing potential.
It is not known if phenylacetate is secreted in human milk, therefore the use of Pheburane is contraindicated during breastfeeding (see Section 4.3 Contraindications).

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Adverse Effects (Undesirable Effects)

Adverse event overview.

The adverse events reported in the following section were derived from the published literature and the known safety profile of phenylbutyrate.
The most common clinical adverse event reported was amenorrhea/ menstrual dysfunction (irregular menstrual cycles), which occurred in 23% of menstruating female patients. Decreased appetite occurred in 4% of patients. Body odour (probably caused by the metabolite, phenylacetate) and bad taste or taste aversion were each reported in 3% of patients.

Clinical trial adverse events.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Clinical adverse events were assessed in 183 urea cycle disorder patients treated with sodium phenylbutyrate in a published report of a long term Phase 3 clinical trial. Adverse events (clinical and laboratory) were not collected systematically, but were obtained from patient visit reports by the co-investigators. Assessment of causality of adverse events was challenging in this population since the events may have resulted from either the underlying disease, the patient's restricted diet, intercurrent illness, or sodium phenylbutyrate. Furthermore, the rates may be under-estimated because they were reported primarily by a parent or guardian and not the patient.
All adverse events are listed in Table 2 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 events are presented in order of decreasing seriousness.

Post-marketing adverse events.

The following adverse events have been reported during post-marketing surveillance: hyperammonaemia, ammonia increased, loss of consciousness, vomiting, urinary incontinence; abnormal faeces, choking, medication residue present and septic shock.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
In the event of an overdose, treatment with Pheburane should be discontinued and supportive measures instituted. Hemodialysis or peritoneal dialysis may be beneficial.
One case of overdose occurred in a 5-month old infant with an accidental single dose of 10 g (1370 mg/kg). The patient developed diarrhea, 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.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

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

Mechanism of action.

Sodium phenylbutyrate is an ammonia scavenger. 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.
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.

Clinical trials.

The efficacy of sodium phenylbutyrate in the treatment of urea cycle disorders was evaluated using the published clinical literature in this rare indication. In an open label, single arm, multicentre Phase 3 study of patients with deficiencies of carbamyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC) or argininosuccinate synthetase (ASS). Efficacy results were evaluable for 183 patients enrolled across the United States and Canada over a period of more than 10 years. Efficacy criteria included survival, incidence of hyperammonemic episodes, cognitive development, growth, and plasma ammonia and glutamine levels.
Amongst late-onset deficiency patients, including females heterozygous for ornithine transcarbamylase deficiency, those who recovered from an episode of hyperammonemic encephalopathy and were then treated chronically with sodium phenylbutyrate and dietary protein restriction, the survival rate was 98%. The two deaths in this group of patients occurred during episodes of hyperammonaemic encephalopathy. However, compliance with the prescribed therapeutic regimen was not well documented, precluding evaluation of the potential for sodium phenylbutyrate and dietary protein restriction to prevent mental deterioration and recurrence of hyperammonaemic encephalopathy with optimal adherence. The majority of patients tested (30/46 or 65%) had IQ's in the average to low average/ borderline mentally impaired range. Their cognitive performance remained relatively stable during phenylbutyrate therapy. Reversal of pre-existing neurologic impairment is considered unlikely to occur with treatment, and neurologic deterioration may continue in some patients, although cognitive performance remained relatively stable during phenylbutyrate therapy.
Even on therapy, acute hyperammonaemic encephalopathy recurred in the majority of patients for whom the drug was indicated.
Additional published studies (Lee et al., 2010, Diaz et al., 2011, Lichter-Konecki et al., 2011 and Smith et al., 2013) investigated a total of 85 patients (26 paediatric and 59 adult patients) with urea cycle disorders (UCDs). This total patient population included the following enzyme deficiency subtypes: OTC (n = 64); ASS (n = 8); CPS (n = 2); argininosuccinate lyase (ASL) (n = 9); arginase (ARG) (n = 1) or hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (HHH) (n = 1).
In the short-term cross-over phases of these studies, sodium phenylbutyrate was used as the control arm to investigate non-inferiority of glycerol phenylbutyrate versus sodium phenylbutyrate. These studies provide further evidence of the clinical efficacy of sodium phenylbutyrate in UCD in terms of the clinical outcomes monitored in these studies.
Two meta-analyses of paediatric studies (Berry et al., 2014) or short-term paediatric and adult studies (Diaz et al., 2013) provide further confirmation of the efficacy of sodium phenylbutyrate in UCD.

Historical data.

Historically, urea cycle disorders with a neonatal-onset were almost universally fatal within the first year after birth, despite treatment with peritoneal dialysis and essential amino acids, or their nitrogen-free analogs. However, with hemodialysis, 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 was almost 80%. Most deaths occurred during an episode of acute hyperammonemic encephalopathy. Patients with neonatal-onset disease had a high incidence of mental impairment. Those who had IQ tests administered had an incidence of mental impairment as follows: ornithine transcarbamylase deficiency, 100% (14/14 patients tested); argininosuccinic acid synthetase deficiency, 88% (15/17 patients tested); and carbamylphosphate synthetase deficiency, 57% (4/7 patients tested). Impairment was severe in the majority of the patients.
In patients diagnosed during gestation and treated prior to any episode of hyperammonemic encephalopathy, survival was 100%, but even in these patients, most subsequently demonstrated cognitive impairment or other neurologic deficits.
Pheburane may be required life-long unless orthotropic liver transplantation is elected.

5.2 Pharmacokinetic Properties

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. After a single oral dose of 5 g of sodium phenylbutyrate, in the form of granules, measurable plasma levels of phenylbutyrate were detected 15 minutes after dosing. The mean time to peak concentration was 1 hour and the mean peak concentration 195 microgram/mL. The elimination half-life was estimated to be 0.8 hours.
The effect of food on absorption is unknown.

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 microgram/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 C_max 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.

5.3 Preclinical Safety Data

Genotoxicity.

Sodium phenylbutyrate was not genotoxic in the Ames test, in an in vitro chromosomal aberration assay in human lymphocytes or in an in vivo micronucleus assay in rats. Sodium phenylbutyrate metabolites phenylacetate (PAA) and phenylacetylglutamine (PAGN) were not genotoxic in the Ames test or in vitro chromosome aberration assay in Chinese hamster ovary cells.

Carcinogenicity.

Carcinogenicity studies have not been conducted with sodium phenylbutyrate. In a rat study, the related substance, glycerol phenylbutyrate caused a statistically significant increase in the incidence of pancreatic acinar cell adenoma, carcinoma, and combined adenoma or carcinoma at a dose of 650 mg/kg/day in males (4 times the anticipated exposure in adult patients, based on combined AUCs for PBA and phenylacetate (PAA) and 900 mg/kg/day in females (9 times the anticipated exposure in adult patients, based on combined AUCs for PBA and PAA). The incidence of the following tumors was also increased in female rats at a dose of 900 mg/kg/day: thyroid follicular cell adenoma, carcinoma and combined adenoma or carcinoma, adrenal cortical combined adenoma or carcinoma, uterine endometrial stromal polyp, and combined polyp or sarcoma. Glycerol phenylbutyrate was not tumourigenic in a 26-week transgenic mouse study.

6 Pharmaceutical Particulars

6.1 List of Excipients

Ethylcellulose, hypromellose, macrogol 1500, maize starch, povidone, Suglets sugar spheres 250/355 micrometres (ARPING 12751).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this product.

6.3 Shelf Life

Pheburane granules.

Store below 30°C. Protect from light.
Shelf life: 3 years. After the first opening, Pheburane should be used within 45 days.

Pheburane solution for nasogastric or gastrostomy administration.

Store between 2°C to 8°C. Protect from light.
After preparation, Pheburane solution (50 mg/mL of sodium phenylbutyrate) should be used within 7 days.

6.4 Special Precautions for Storage

Store below 30°C. Protect from light.

6.5 Nature and Contents of Container

HDPE bottle, child-resistant closure with desiccant, containing 174 g of granules. Each carton contains one bottle.
A calibrated measuring spoon is provided.

6.6 Special Precautions for Disposal

In case of mixture of the granules with solid foods or liquid it is important that it is taken immediately after mixing.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Sodium 4-phenylbutanoate.
Molecular Formula: C₁₀H₁₁NaO₂.
Molecular weight: 186.2.

Chemical structure.

CAS number.

104206-65-7.
The active substance is a white or yellowish-white powder and freely soluble in water and in methanol, practically insoluble in methylene chloride. Its pKa is 4.76 and log P is 2.42.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

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Pheburane

Sodium phenylbutyrate

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