ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
AMMONAPS 500 mg tablets.
2.
Each tablet contains 500 mg sodium phenylbutyrate.
Each AMMONAPS tablet contains 62 mg of sodium.
For a full list of excipients, see section 6.1.
3.
Tablet.
The tablets are off-white, oval and embossed with “UCY 500”.
4.
AMMONAPS 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
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 of
hyperammonaemic encephalopathy.
AMMONAPS treatment should be supervised by a physician experienced in the treatment of urea
cycle 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 and
for patients with dysphagia.
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 children weighing less than 20 kg
9.9 - 13.0 g/m
2
/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 (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:
AMMONAPS must be combined with dietary protein restriction and, in
some cases, essential amino acid and carnitine supplementation.
2
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/m
2
/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/m
2
/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.
AMMONAPS tablets should not be used in patients with dysphagia due to the potential risk of
oesophageal ulceration if tablets are not promptly delivered to the stomach.
Each AMMONAPS tablet contains 62 mg (2.7 mmol) of sodium, corresponding to 2.5 g (108 mmol)
of sodium per 20 g of sodium phenylbutyrate, which is the maximum daily dose. AMMONAPS
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.
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 phenylacetylglutamine
may 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 a
medical 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 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
medications have to be used.
Pregnancy
The safety of this medicinal product for use in human pregnancy has not been established. Evaluation
of experimental animal studies has shown reproductive toxicity, i.e. effects on the development of the
embryo or the foetus. Prenatal exposure of rat pups to phenylacetate (the active metabolite of
3
phenylbutyrate) produced lesions in cortical pyramidal cells; dendritic spines were longer and thinner
than 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.
Lactation
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. It has not been determined if
phenylacetate is secreted in human milk and therefore the use of AMMONAPS is contra-indicated
during 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 and
78 % 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 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, undesirable effects 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 odour
Renal and urinary disorders
Common: Renal tubular acidosis
Reproductive system and breast disorders
4
Very common
:
Amenorrhoea, 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.
A probable case of toxic reaction to AMMONAPS (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.
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-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, hypacusis, disorientation, impaired memory and
exacerbation 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.
5.
5.1 Pharmacodynamic properties
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 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.
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 new-borns 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.
5
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.
AMMONAPS may be required life-long unless orthotopic 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 tablets, measurable plasma levels of phenylbutyrate are detected
15 minutes after dosing. The mean time to peak concentration is 1.35 hour and the mean peak
concentration 218 µg/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.
Metabolism
After a single dose of 5 g of sodium phenylbutyrate, in the form of tablets, measurable plasma levels
of 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 peak
concentration is 48.5 and 68.5 µg/ml, respectively. The elimination half-life was estimated to be 1.2
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.
6
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
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.
6.
6.1 List of excipients
Microcrystalline cellulose
Magnesium stearate
Colloidal anhydrous silica
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
Do not store above 30°C.
6.5 Nature and contents of container
HDPE bottles, with child resistant caps, containing 250 or 500 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Swedish Orphan International AB
Drottninggatan 98
SE-111 60 Stockholm
Sweden
8.
EU/1/99/120/001 (250 tablets)
7
EU/1/99/120/002 (500 tablets)
9.
Date of first authorisation: 08/12/1999
Date of latest renewal: 08/12/2009
10/2009
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA) http://www.emea.europa.eu/.
8
1.
AMMONAPS 940 mg/g granules
2.
Each gram of granules contains 940 mg of sodium phenylbutyrate.
One small spoon of AMMONAPS granules contains 149 mg of sodium.
One medium sized spoon of AMMONAPS granules contains 384 mg of sodium.
One large spoon of AMMONAPS granules contains 1116 mg of sodium.
For a full list of excipients, see section 6.1.
3.
Granules.
The granules are off-white.
4.
AMMONAPS
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
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 of
hyperammonaemic encephalopathy.
AMMONAPS treatment should be supervised by a physician experienced in the treatment of urea
cycle disorders.
AMMONAPS granules should be administered orally (to infants and children unable to swallow
tablets and to patients with dysphagia) or via gastrostomy or nasogastric tube.
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 - 13.0 g/m
2
/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.
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:
AMMONAPS must be combined with dietary protein restriction and, in
some cases, essential amino acid and carnitine supplementation.
9
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/m
2
/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/m
2
/day.
If caloric supplementation is indicated, a protein-free product is recommended.
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). When taken orally, the granules are to be mixed with solid foods
(such as mashed potatoes or apple sauce) or liquid foods (such as water, apple juice, orange juice or
protein-free infant formulas).
Three dosing spoons are provided which dispense 1.2 g, 3.1 g or 9.0 g of sodium phenylbutyrate.
Lightly shake the bottle before dispensing.
Pregnancy.
Breast-feeding.
Hypersensitivity to the active substance or to any of the excipients.
AMMONAPS granules contain 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. AMMONAPS 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.
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 phenylacetylglutamine
may 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 a
medical emergency.
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
medications have to be used.
Pregnancy
The safety of this medicinal product for use in human pregnancy has not been established. Evaluation
of experimental animal studies has shown reproductive toxicity, i.e. effects on the development of the
10
embryo or the foetus. 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. 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.
Lactation
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. It has not been determined if
phenylacetate is secreted in human milk and therefore the use of AMMONAPS is contra-indicated
during 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 and
78 % 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 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, undesirable effects 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 odour
Renal and urinary disorders
Common: Renal tubular acidosis
11
Reproductive system and breast disorders
Very common
:
Amenorrhoea, 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.
A probable case of toxic reaction to AMMONAPS (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.
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-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, hypacusis, disorientation, impaired memory and
exacerbation 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.
5.
5.1 Pharmacodynamic properties
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 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.
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 new-borns 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.
12
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.
AMMONAPS may be required life-long unless orthotopic 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 are detected
15 minutes after dosing. The mean time to peak concentration is 1 hour and the mean peak
concentration 195 µg/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.
Metabolism
After a single dose of 5 g of sodium phenylbutyrate, in the form of granules, measurable plasma levels
of phenylacetate and phenylacetylglutamine are detected 30 and 60 minutes respectively after dosing.
The mean time to peak concentration is 3.55 and 3.23 hours, respectively, and the mean peak
concentration is 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 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.
13
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
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.
6.
6.1 List of excipients
Calcium stearate
Colloidal anhydrous silica
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
During the shelf life the patient may store the finished product for a single period of 3 months at a
temperature not above 25°C, after which the product must be discarded.
6.4 Special precautions for storage
Store in a refrigerator (2C – 8C).
6.5 Nature and contents of container
HDPE bottles, with child resistant caps, containing 266 g or 532 g of granules.
Three measuring spoons of different measures are provided.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
It is recommended that a heaped measuring spoon is removed from the container and a flat surface,
e.g. the blade of a knife, is drawn across the top of the measure. This will give the following doses:
small measure 1.2 g, medium measure 3.1 g and large measure 9.0 g of sodium phenylbutyrate.
Where a patient requires administration by tube, it is possible to re-constitute AMMONAPS in water
prior to use (solubility for sodium phenylbutyrate is up to 5 g in 10 ml water). Please note that the re-
constituted granules will normally produce a milky white suspension.
14
Where AMMONAPS granules need to be added to food, liquid or water, it is important that it is taken
immediately after mixing.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Swedish Orphan International AB
Drottninggatan 98
SE-111 60 Stockholm
Sweden
8.
EU/1/99/120/003 (266 g granules)
EU/1/99/120/004 (532 g granules)
9.
Date of first authorisation: 08/12/1999
Date of latest renewal: 08/12/2009
10/2009
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA) http://www.emea.europa.eu/.
15
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING
AUTHORISATION
16
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Bioglan AB, Borrgatan 31, SE-211 24
Malmö, Sweden
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
17
ANNEX III
LABELLING AND PACKAGE LEAFLET
18
A. LABELLING
19
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
OUTER CARTON AND BOTTLE LABEL FOR TABLETS
1.
AMMONAPS 500 mg tablets
sodium phenylbutyrate
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 500 mg of sodium phenylbutyrate.
3.
LIST OF EXCIPIENTS
Contains sodium, see package leaflet for further information.
4.
250 tablets
500 tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30C.
20
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Swedish Orphan International AB
Drottninggatan 98
SE-111 60 Stockholm
Sweden
EU/1/99/120/001 250 tablets
EU/1/99/120/002 500 tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Ammonaps 500 mg
[outer packaging only]
21
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
OUTER CARTON AND BOTTLE LABEL FOR GRANULES
1.
AMMONAPS 940 mg/g granules.
sodium phenylbutyrate
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
1 g of granules contains 940 mg of sodium phenylbutyrate
3.
LIST OF EXCIPIENTS
Contains sodium, see package leaflet for further information.
4.
266 g granules
532 g granules
Three measuring spoons of different measures are provided.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
22
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
[the below is for immediate packaging only]
AMMONAPS granules can be stored for a single period of 3 months at a temperature not above 25°C,
after which the product must be discarded.
Date removed from refrigerator: _______________
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Swedish Orphan International AB
Drottninggatan 98
SE-111 60 Stockholm
Sweden
EU/1/99/120/003 266 g granules
EU/1/99/120/004 532 g granules
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
[Justification for not including Braille accepted]
23
B. PACKAGE LEAFLET
24
PACKAGE LEAFLET: INFORMATION FOR THE USER
AMMONAPS 500 mg tablets
Sodium phenylbutyrate
Read all of this leaflet carefully before you start taking this medicine.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What AMMONAPS is and what it is used for
2.
Before you take AMMONAPS
3.
How to take AMMONAPS
4.
Possible side effects
5.
How to store AMMONAPS
6.
Further information
1.
WHAT AMMONAPS IS AND WHAT IT IS USED FOR
AMMONAPS is prescribed to patients with urea cycle disorders. Patients with these rare disorders
have a deficiency of certain liver enzymes and are therefore unable to eliminate nitrogen waste.
Nitrogen is a building block of proteins, because of this, there is a build up of nitrogen in the body
after eating protein. Nitrogen waste, in the form of ammonia, is especially toxic for the brain and
leads, in severe cases, to reduced levels of consciousness and to coma.
AMMONAPS helps the body to eliminate nitrogen waste, reducing the amount of ammonia in your
body.
2.
BEFORE YOU TAKE AMMONAPS
Do not take AMMONAPS if you:
-
are breast-feeding.
-
are allergic (hypersensitive) to sodium phenylbutyrate or any of the other ingredients of
AMMONAPS.
Take special care with AMMONAPS
-
if you have difficulty swallowing. AMMONAPS tablets can get stuck in the oesophagus and
cause ulcers. If you have difficulty swallowing it is recommended to use AMMONAPS
granules instead.
-
if you suffer from heart failure, a decrease in your kidney function or other diseases, where the
retention of the sodium salt contained in this medicine, may make your condition worse.
-
if you have decreased kidney or liver function, since AMMONAPS is eliminated from the body
through the kidney and liver.
-
when given to small children, since they may not be able to swallow the tablets and may choke.
It is recommended to use AMMONAPS granules instead.
AMMONAPS must be combined with a diet reduced in proteins designed especially for you by the
doctor and the dietician. You must follow this diet carefully.
25
-
Keep this leaflet. You may need to read it again.
-
are pregnant.
AMMONAPS does not completely prevent the occurrence of an acute excess of ammonia in the blood
and is not appropriate for treating such a condition, which is a medical emergency.
If you require laboratory tests, it is important to remind your doctor that you are taking AMMONAPS,
since sodium phenylbutyrate may influence certain laboratory test results.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
It is especially important to tell your doctor if you are taking medicines containing:
-
valproic acid (an antiepileptic drug),
-
haloperidol (used in certain psychotic disorders),
-
corticosteroids (cortisone-like medicines that are used to provide relief for inflamed areas of the
body),
-
probenecid (for treatment of hyperuricemia associated with gout).
These medicines may change the effect of AMMONAPS and you will need more frequent blood
controls. If you are uncertain if your medicines contain these substances, you should check with your
doctor or pharmacist.
Pregnancy and breast-feeding
Do not use AMMONAPS if you are pregnant, because this medicine can harm your unborn baby. If
you are a woman who could get pregnant, you must use reliable contraception, during treatment with
AMMONAPS.
Do not use AMMONAPS if you are breast-feeding, because this medicine can pass into the breast-
milk and harm your baby.
Driving and using machines
No studies on the effects on the ability to drive and use machines have been performed.
Important information about some of the ingredients of AMMONAPS
Each AMMONAPS tablet contains 62 mg of sodium. To be taken into consideration by patients on a
sodium controlled diet.
3.
HOW TO TAKE AMMONAPS
Always take AMMONAPS exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
Dosage
The daily dose of AMMONAPS will be calculated from your protein tolerance
,
diet and body weight
or body surface. You will need regular blood tests to determine the correct daily dose. Your doctor
will tell you how many tablets you should take.
Method of administration
You should take AMMONAPS by mouth in equally divided doses with each meal (for example three
times per day).You should take AMMONAPS with a large volume of water.
AMMONAPS must be taken with a special diet reduced in protein.
AMMONAPS tablets should not be given to children who are not able to swallow tablets. It is
recommended that AMMONAPS granules are used instead.
You will need to have treatment and to follow a diet throughout your life, unless you have a successful
liver transplantation.
26
If you take more AMMONAPS than you should
Patients who have taken very high doses of AMMONAPS experienced:
-
sleepiness, tiredness, light-headedness and less frequently confusion,
-
headache,
-
changes in taste (taste disturbances),
-
decrease in hearing,
-
disorientation,
-
impaired memory,
-
worsening of existing neurological conditions.
If you experience any of these symptoms, you should immediately contact your doctor or the nearest
hospital emergency department for supportive treatment.
If you forget to take AMMONAPS
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 have any further questions on the use of this medicine, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, AMMONAPS can cause side effects, although not everybody gets them.
The frequency of possible side effects is listed below.
Very common: Affects more than 1 user in 10
Common:
Affects 1 to 10 users in 100
Uncommon:
Affects 1 to 10 users in 1,000
Rare:
Affects 1 to 10 users in 10,000
Very rare:
Affects less than 1 user in 10,000
Not known:
Frequency cannot be estimated from the available data
Very common side effects
: irregular menstrual periods and cessation of menstrual periods.
If you are sexually active and your period stops altogether, do not assume that this is caused by
AMMONAPS. If this occurs, please discuss it with your doctor, because the absence of your period
may be caused by pregnancy (see Pregnancy and breast-feeding section above).
Common side effects
: changes in number of blood cells (red cells, white cells and platelets), reduced
appetite, depression, irritability, headache, fainting, fluid retention (swelling), changes in taste (taste
disturbances),pain in the abdomen, vomiting, nausea, constipation, skin odour, rash, abnormal kidney
function, weight gain, altered laboratory test values.
Uncommon side effects
: deficiency in red blood cells due to bone marrow depression, bruising, altered
heart rhythm, rectal bleeding, stomach irritation, stomach ulcer, inflammation of the pancreas.
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
If persistent vomiting occurs, you should contact your doctor immediately.
5.
HOW TO STORE AMMONAPS
Keep out of the reach and sight of children.
27
Do not use AMMONAPS after the expiry date which is stated on the carton and the bottle label after
“EXP”. The expiry date refers to the last day of that month.
Do not store above 30C.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What AMMONAPS contains
The active substance is:
-
sodium phenylbutyrate.
Each tablet of AMMONAPS contains 500 mg of sodium phenylbutyrate.
The other ingredients are:
-
microcrystalline cellulose, magnesium stearate and colloidal anhydrous silica.
What AMMONAPS looks like and contents of the pack
AMMONAPS tablets are off-white, oval and embossed with “UCY 500”.
The tablets are packaged in plastic bottles with child-resistant caps. Each bottle contains 250 or
500 tablets.
Marketing Authorisation Holder
Swedish Orphan International AB
Drottninggatan 98
SE-111 60 Stockholm
Sweden
Manufacturer
Bioglan AB
PO Box 50310
SE-202 13 Malmö
Sweden
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu/.
28
PACKAGE LEAFLET: INFORMATION FOR THE USER
AMMONAPS 940 mg/g granules
Sodium phenylbutyrate
Read all of this leaflet carefully before you start taking this medicine.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What AMMONAPS is and what it is used for
2.
Before you take AMMONAPS
4.
Possible side effects
5.
How to store AMMONAPS
6.
Further information
1.
WHAT AMMONAPS IS AND WHAT IT IS USED FOR
AMMONAPS is prescribed to patients with urea cycle disorders. Patients with these rare disorders
have a deficiency of certain liver enzymes and are therefore unable to eliminate nitrogen waste.
Nitrogen is a building block of proteins, because of this there is a build up of nitrogen in the body after
eating protein. Nitrogen waste, in the form of ammonia, is especially toxic for the brain and leads, in
severe cases, to reduced levels of consciousness and to coma.
AMMONAPS helps the body to eliminate nitrogen waste, reducing the amount of ammonia in your
body.
2.
BEFORE YOU TAKE AMMONAPS
Do not take AMMONAPS if you:
-
are breast-feeding.
-
are allergic (hypersensitive) to sodium phenylbutyrate or any of the other ingredients of
AMMONAPS.
Take special care with AMMONAPS
-
if you suffer from heart failure, a decrease in your kidney function or other diseases where the
retention of the sodium salt contained in this medicine may make your condition worse.
-
if you have decreased kidney or liver function, since AMMONAPS is eliminated from the body
through the kidney and liver.
AMMONAPS must be combined with a diet reduced in proteins, designed especially for you by the
doctor and the dietician. You must follow this diet carefully.
AMMONAPS does not completely prevent the occurrence of an acute excess of ammonia in the blood
and is not appropriate for treating such a condition, which is a medical emergency.
If you require laboratory tests, it is important to remind your doctor that you are taking
AMMONAPS, since sodium phenylbutyrate may influence certain laboratory test results.
29
-
Keep this leaflet. You may need to read it again.
3.
How to take AMMONAPS
-
are pregnant.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
It is especially important to tell your doctor if you are taking medicines containing:
-
valproic acid (an antiepileptic drug),
-
haloperidol (used in certain psychotic disorders),
-
corticosteroids (cortisone-like medicines that are used to provide relief for inflamed areas of the
body),
-
probenecid (for treatment of hyperuricemia associated with gout)
These medicines may change the effect of AMMONAPS and you will need more frequent blood
controls. If you are uncertain if your medicines contain these substances, you should check with your
doctor or pharmacist.
Pregnancy and breast-feeding
Do not use AMMONAPS if you are pregnant, because this medicine can harm your unborn baby. If
you are a woman who could get pregnant, you must use reliable contraception, during treatment with
AMMONAPS.
Do not use AMMONAPS if you are breast-feeding, because this medicine can pass into the breast-
milk and harm your baby.
Driving and using machines
No studies on the effects on the ability to drive and use machines have been performed.
Important information about some of the ingredients of AMMONAPS
One small white spoon of AMMONAPS granules contains 149 mg of sodium.
One medium sized yellow spoon of AMMONAPS granules contains 384 mg of sodium.
One large blue spoon of AMMONAPS granules contains 1116 mg of sodium.
To be taken into consideration by patients on a sodium controlled diet.
3.
HOW TO TAKE AMMONAPS
Always take AMMONAPS exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
Dosage
The daily dose of AMMONAPS will be calculated from your protein tolerance, diet and body weight
or body surface. You will need regular blood tests to determine the correct daily dose. Your doctor
will tell you the amount of granules you should take.
Method of administration
You should take AMMONAPS in equally divided doses by mouth, through a gastrostomy (tube that
goes through the abdomen to the stomach) or through a nasogastric tube (tube that goes through the
nose to the stomach).
AMMONAPS must be taken with a special diet reduced in protein.
You should take AMMONAPS with each meal or feeding. In small children this can be 4 to 6 times
per day.
To measure the dose:
Shake the bottle lightly before opening
30
Use the correct spoon to dispense the following amount of Ammonaps: 1.2 g = small white
spoon, 3.1 g = medium sized yellow spoon and 9.0 g = large blue spoon
Take a heaped spoonful of granules out of the bottle
Pass a flat surface, e.g. the back of a knife blade, over the top of the spoon to remove the excess
of granules
The granules left in the spoon are one spoonful
Take the correct number of spoonfuls granules from the bottle
When taken by mouth
Mix the measured dose with solid foods (such as mashed potatoes or apple sauce) or liquid foods
(such as water, apple juice, orange juice or protein-free infant formulas) and take it immediately after
mixing.
Patients with a gastrostomy or nasogastric tube
Mix the granules with water until there are no dry granules left (stirring the solution helps to dissolve
the granules). When the granules are dissolved in water you get a milky white liquid. Take the solution
immediately after mixing.
You will need to have treatment and to follow a diet throughout your life, unless you have a successful
liver transplantation.
If you take more AMMONAPS than you should
Patients who have taken very high doses of AMMONAPS experienced:
-
sleepiness, tiredness, light-headedness and less frequently confusion,
-
headache,
-
changes in taste (taste disturbances),
-
decrease in hearing,
-
disorientation,
-
impaired memory,
-
worsening of existing neurological conditions.
If you experience any of these symptoms, you should immediately contact your doctor or the nearest
hospital emergency department for supportive treatment.
If you forget to take AMMONAPS
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 have any further questions on the use of this medicine, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, AMMONAPS can cause side effects, although not everybody gets them.
The frequency of possible side effects is listed below.
Very common: Affects more than 1 user in 10
Common:
Affects 1 to 10 users in 100
Uncommon:
Affects 1 to 10 users in 1,000
Rare:
Affects 1 to 10 users in 10,000
Very rare:
Affects less than 1 user in 10,000
Not known:
Frequency cannot be estimated from the available data
Very common side effects: irregular menstrual periods and cessation of menstrual periods.
31
If you are sexually active and your period stops altogether, do not assume that this is caused by
AMMONAPS. If this occurs, please discuss it with your doctor, because the absence of your period
may be caused by pregnancy (see Pregnancy and breast-feeding section above).
Common side effects
: changes in number of blood cells (red cells, white cells and platelets), reduced
appetite, depression, irritability, headache, fainting, fluid retention (swelling), changes in taste (taste
disturbances),pain in the abdomen, vomiting, nausea, constipation, skin odour, rash, abnormal kidney
function, weight gain, altered laboratory test values.
Uncommon side effects
: deficiency in red blood cells due to bone marrow depression, bruising, altered
heart rhythm, rectal bleeding, stomach irritation, stomach ulcer, inflammation of the pancreas.
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
If persistent vomiting occurs, you should contact your doctor immediately.
5.
HOW TO STORE AMMONAPS
Keep out of the reach and sight of children.
Do not use AMMONAPS after the expiry date which is stated on the carton and the bottle label after
“EXP”. The expiry date refers to the last day of that month.
Store in a refrigerator (2°C – 8°C).
AMMONAPS granules can be removed from the refrigerator for one single period of maximum
3 months and stored at a temperature not above 25°C. After this time the product must be discarded.
Do not forget to mark the date on the bottle, when removed from the refrigerator.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What AMMONAPS contains
The active substance is:
-
sodium phenylbutyrate.
One gram of AMMONAPS granules contains 940 mg of sodium phenylbutyrate.
The other ingredients are:
-
calcium stearate and colloidal anhydrous silica.
What AMMONAPS looks like and contents of the pack
AMMONAPS granules are off-white.
The granules are packaged in plastic bottles with child-resistant caps. Each bottle contains 266 g or
532 g of granules. Three spoons (one small white spoon, one medium sized yellow spoon and one
large blue spoon) are included to measure your daily dose.
Marketing Authorisation Holder
Swedish Orphan International AB
Drottninggatan 98
SE-111 60 Stockholm
Sweden
32
Manufacturer
Bioglan AB
PO Box 50310
SE-202 13 Malmö
Sweden
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu/.
33
Source: European Medicines Agency
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