Ammonaps · 4.4 Special warnings and precautions for use · 2

HOS-083784 · has-adverse-reaction-information · PDF-Seite 4

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 4 Common: Rash, abnormal skin odour Renal and urinary disorders Common: Renal tubular acidosis 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. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

HOS-083790 · has-adverse-reaction-information · PDF-Seite 11

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 11 Common: Rash, abnormal skin odour Renal and urinary disorders Common: Renal tubular acidosis 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. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

HOS-083780 · has-contraindication-information · PDF-Seite 3

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

HOS-083786 · has-contraindication-information · PDF-Seite 10

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

HOS-083779 · has-indication-information · PDF-Seite 2

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.

HOS-083785 · has-indication-information · PDF-Seite 9

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.

HOS-083782 · has-interaction-information · PDF-Seite 3

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. 3

HOS-083788 · has-interaction-information · PDF-Seite 10

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. 10

HOS-083789 · has-pregnancy-information · PDF-Seite 11

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 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).

HOS-083783 · has-pregnancy-information · PDF-Seite 4

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 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).

HOS-083787 · has-warning-information · PDF-Seite 10

This medicinal products contain 124 mg (5.4 mmol) sodium per gram of sodium phenylbutyrate, equivalent to 6% of the WHO recommended maximum daily intake for sodium. The maximum recommended daily dose of this product contains 2.5 g sodium which is equivalent to 124% of the WHO recommended maximum daily intake for sodium. AMMONAPS is considered high in sodium. This should be particularly taken into account for those on a low salt diet. 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.

HOS-083781 · has-warning-information · PDF-Seite 3

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. This medicinal product contains 62 mg sodium per tablet, equivalent to 3% of the WHO recommended maximum daily intake for sodium. The maximum recommended daily dose of this product contains 2.5 g sodium which is equivalent to 124% of the WHO recommended maximum daily intake for sodium. AMMONAPS is considered high in sodium. This should be particularly taken into account for those on a low salt diet. 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.