AMMONAPS 500mg tablets medication leaflet

AMMONAPS 500 mg tablets.

Each tablet contains 500 mg sodium phenylbutyrate.

Each tablet contains 2.7 mmol (62 mg) of sodium.

For the full list of excipients, see section 6.1.

Tablet.

The tablets are off-white, oval and embossed with “UCY 500”.

AMMONAPS is indicated as adjunctive therapy in the chronic management of urea cycle disorders,involving deficiencies of carbamylphosphate synthetase, ornithine transcarbamylase orargininosuccinate 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 ofhyperammonaemic encephalopathy.

AMMONAPS treatment should be supervised by a physician experienced in the treatment of ureacycle disorders.

The use of AMMONAPS tablets is indicated for adults and children who are able to swallow tablets.

AMMONAPS is also available as granules for infants, children who are unable to swallow tablets andfor patients with dysphagia.

The daily dose should be individually adjusted according to the patient’s protein tolerance and thedaily 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 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 (40 tablets) have not been established.

Therapeutic monitoring: Plasma levels of ammonia, arginine, essential amino acids (especiallybranched 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, insome cases, essential amino acid and carnitine supplementation.

Citrulline or arginine supplementation is required for patients diagnosed with neonatal-onset form ofcarbamyl phosphate synthetase or ornithine transcarbamylase deficiency at a dose of 0.17 g/kg/day or3.8 g/m2/day.

Arginine supplementation is required for patients diagnosed with deficiency of argininosuccinatesynthetase 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 of AMMONAPS should be divided into equal amounts and given with each meal(e.g. three times per day). The tablets should be taken with a large volume of water.

− Pregnancy.− Breast-feeding.− Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

AMMONAPS tablets should not be used in patients with dysphagia due to the potential risk ofoesophageal ulceration if tablets are not promptly delivered to the stomach.

This medicinal product contains 62 mg sodium per tablet, equivalent to 3% of the WHO recommendedmaximum daily intake for sodium.

The maximum recommended daily dose of this product contains 2.5 g sodium which is equivalent to124% of the WHO recommended maximum daily intake for sodium.

AMMONAPS is considered high in sodium. This should be particularly taken into account for thoseon a low salt diet.

AMMONAPS should therefore be used with caution in patients with congestive heart failure or severerenal 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 phenylacetylglutaminemay 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 amedical emergency.

In children unable to swallow tablets, it is recommended to use AMMONAPS granules instead.

Concurrent administration of probenecid may affect renal excretion of the conjugation product ofsodium phenylbutyrate.

There have been published reports of hyperammonaemia being induced by haloperidol and byvalproate. Corticosteroids may cause the breakdown of body protein and thus increase plasmaammonia levels. More frequent monitoring of plasma ammonia levels is advised when thesemedications have to be used.

The safety of this medicinal product for use in human pregnancy has not been established. Evaluationof experimental animal studies has shown reproductive toxicity, i.e. effects on the development of theembryo or the foetus. Prenatal exposure of rat pups to phenylacetate (the active metabolite ofphenylbutyrate) produced lesions in cortical pyramidal cells; dendritic spines were longer and thinnerthan normal and reduced in number. The significance of these data in pregnant women is not known;therefore the use of AMMONAPS is contra-indicated during pregnancy (see section 4.3).

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

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 CNSmyelin. Cerebral synapse maturation was retarded and the number of functioning nerve terminals inthe cerebrum was reduced, which resulted in impaired brain growth. It has not been determined ifphenylacetate is secreted in human milk and therefore the use of AMMONAPS is contra-indicatedduring lactation (see section 4.3).

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

In clinical trials with AMMONAPS, 56 % of the patients experienced at least one adverse event and78 % 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 definedas 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 availabledata). Within each frequency grouping, undesirable effects are presented in order of decreasingseriousness.

Common: Anaemia, thrombocytopenia, leukopenia, leukocytosis, thrombocytosis

Uncommon: Aplastic anaemia, ecchymosis

Common: Metabolic acidosis, alkalosis, decreased appetite

Common: Depression, irritability

Common: Syncope, headache

Common: Oedema

Uncommon: Arrhythmia

Common: Abdominal pain, vomiting, nausea, constipation, dysgeusia

Uncommon: Pancreatitis, peptic ulcer, rectal haemorrhage, gastritis

Common: Rash, abnormal skin odour

Common: Renal tubular acidosis

Very common: Amenorrhoea, irregular menstruation

Common: Decreased blood potassium, albumin, total protein and phosphate. Increased blood alkalinephosphatase, 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 oldanorectic female patient who developed a metabolic encephalopathy associated with lactic acidosis,severe hypokalaemia, pancytopaenia, peripheral neuropathy, and pancreatitis. She recovered followingdose reduction except for recurrent pancreatitis episodes that eventually prompted treatmentdiscontinuation.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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 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-limitingneurotoxicity when administered intravenously at doses up to 400 mg/kg/day. Manifestations ofneurotoxicity were predominantly somnolence, fatigue and light-headedness. Less frequentmanifestations were confusion, headache, dysgeusia, hypacusis, disorientation, impaired memory andexacerbation of a pre-existing neuropathy.

In the event of an overdose, discontinue the treatment and institute supportive measures.

Haemodialysis or peritoneal dialysis may be beneficial.

Pharmacotherapeutic group: various alimentary tract and metabolism products, ATC code: A16A X03.

Sodium phenylbutyrate is a pro-drug and is rapidly metabolised to phenylacetate. Phenylacetate is ametabolically active compound that conjugates with glutamine via acetylation to formphenylacetylglutamine which is then excreted by the kidneys. On a molar basis,phenylacetylglutamine is comparable to urea (each containing 2 moles of nitrogen) and thereforeprovides an alternate vehicle for waste nitrogen excretion. Based on studies of phenylacetylglutamineexcretion in patients with urea cycle disorders it is possible to estimate that, for each gram of sodiumphenylbutyrate administered, between 0.12 and 0.15 g of phenylacetylglutamine nitrogen areproduced. As a consequence, sodium phenylbutyrate reduces elevated plasma ammonia and glutaminelevels in patients with urea cycle disorders. It is important that the diagnosis is made early andtreatment is initiated immediately to improve the survival and the clinical outcome.

Previously, neonatal-onset presentation of urea cycle disorders was almost universally fatal within thefirst 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 (sodiumphenylbutyrate, sodium benzoate and sodium phenylacetate), dietary protein restriction, and, in somecases, essential amino acid supplementation, the survival rate in new-borns diagnosed after birth (butwithin the first month of life) increased to almost 80 % with most deaths occurring during an episodeof acute hyperammonaemic encephalopathy. Patients with neonatal-onset disease had a high incidenceof mental retardation.

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

In late-onset deficiency patients, including females heterozygous for ornithine transcarbamylasedeficiency, who recovered from hyperammonaemic encephalopathy and were then treated chronicallywith dietary protein restriction and sodium phenylbutyrate, the survival rate was 98 %. The majority ofthe patients who were tested had an IQ in the average to low average/borderline mentally retardedrange. Their cognitive performance remained relatively stable during phenylbutyrate therapy.

Reversal of pre-existing neurologic impairment is not likely to occur with treatment, and neurologicdeterioration may continue in some patients.

AMMONAPS may be required life-long unless orthotopic liver transplantation is elected.

Phenylbutyrate is known to be oxidised to phenylacetate which is enzymatically conjugated withglutamine to form phenylacetylglutamine in the liver and kidney. Phenylacetate is also hydrolysed byesterases in liver and blood.

Plasma and urine concentrations of phenylbutyrate and its metabolites have been obtained from fastingnormal adults who received a single dose of 5 g of sodium phenylbutyrate and from patients with ureacycle disorders, haemoglobinopathies and cirrhosis receiving single and repeated oral doses up to20 g/day (uncontrolled studies). The disposition of phenylbutyrate and its metabolites has also beenstudied in cancer patients following intravenous infusion of sodium phenylbutyrate (up to 2 g/m²) orphenylacetate.

Phenylbutyrate is rapidly absorbed under fasting conditions. After a single oral dose of 5 g of sodiumphenylbutyrate, in the form of tablets, measurable plasma levels of phenylbutyrate are detected15 minutes after dosing. The mean time to peak concentration is 1.35 hour and the mean peakconcentration 218 µg/ml. The elimination half-life was estimated to be 0.8 hours.

The effect of food on absorption is unknown.

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

After a single dose of 5 g of sodium phenylbutyrate, in the form of tablets, measurable plasma levelsof phenylacetate and phenylacetylglutamine are detected 30 and 60 minutes respectively after dosing.

The mean time to peak concentration is 3.74 and 3.43 hours, respectively, and the mean peakconcentration is 48.5 and 68.5 µg/ml, respectively. The elimination half-life was estimated to be 1.2and 2.4 hours, respectively.

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

In the majority of patients with urea cycle disorders or haemoglobinopathies receiving various dosesof phenylbutyrate (300 - 650 mg/kg/day up to 20 g/day) no plasma level of phenylacetate could bedetected after overnight fasting. In patients with impaired hepatic function the conversion ofphenylacetate 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) showedsustained plasma levels of phenylacetate on the third day that were five times higher than thoseachieved after the first dose.

In normal volunteers gender differences were found in the pharmacokinetic parameters ofphenylbutyrate and phenylacetate (AUC and Cmax about 30 - 50 % greater in females), but notphenylacetylglutamine. This may be due to the lipophilicity of sodium phenylbutyrate and consequentdifferences in volume of distribution.

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

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

Micronucleus test results indicate that sodium phenylbutyrate was considered not to have producedany clastogenic effect in rats treated at toxic or non-toxic dose levels (examined 24 and 48 hours aftera single oral administration of 878 to 2800 mg/kg). Carcinogenicity and fertility studies have not beenconducted with sodium phenylbutyrate.

Microcrystalline cellulose

Magnesium stearate

Colloidal anhydrous silica

Not applicable.

2 years.

Do not store above 30°C.

HDPE bottles, with child resistant caps, containing 250 or 500 tablets.

Not all pack sizes may be marketed.

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

Immedica Pharma AB

SE-113 63 Stockholm

Sweden

EU/1/99/120/001 (250 tablets)

EU/1/99/120/002 (500 tablets)

Date of first authorisation: 08/12/1999

Date of latest renewal: 08/12/2009

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu/.