Kuvan · 4.3 Contraindications · 1

HOS-154368 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile Approximately 35% of the 579 patients aged 4 years and over who received treatment with sapropterin dihydrochloride (5 to 20 mg/kg/day) in the clinical trials for Kuvan experienced adverse reactions. The most commonly reported adverse reactions are headache and rhinorrhoea. In a further clinical trial, approximately 30% of the 27 children aged below 4 years who received treatment with sapropterin dihydrochloride (10 or 20 mg/kg/day) experienced adverse reactions. The most commonly reported adverse reactions are “amino acid level decreased” (hypophenylalaninaemia), vomiting and rhinitis. Tabulated list of adverse reactions In the pivotal clinical trials and in the post-marketing experience for Kuvan, the following adverse reactions have been identified. The following definitions apply to the frequency terminology used hereafter: 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 available data) 8 Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Immune system disorders Not known: Hypersensitivity reactions (including serious allergic reactions) and rash Metabolism and nutrition disorders Common: Hypophenylalaninaemia Nervous system disorders Very common: Headache Respiratory, thoracic and mediastinal disorders Very common: Rhinorrhoea Common: Pharyngolaryngeal pain, nasal congestion, cough Gastrointestinal disorders Common: Diarrhoea, vomiting, abdominal pain, dyspepsia, nausea Not known: Gastritis, oesophagitis Paediatric population Frequency, type and severity of adverse reactions in children were essentially similar to those in adults. 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-154374 · has-adverse-reaction-information · PDF-Seite 21

Summary of the safety profile Approximately 35% of the 579 patients aged 4 years and over who received treatment with sapropterin dihydrochloride (5 to 20 mg/kg/day) in the clinical trials for Kuvan experienced adverse reactions. The most commonly reported adverse reactions are headache and rhinorrhoea. In a further clinical trial, approximately 30% of the 27 children aged below 4 years who received treatment with sapropterin dihydrochloride (10 or 20 mg/kg/day) experienced adverse reactions. The most commonly reported adverse reactions are “amino acid level decreased” (hypophenylalaninaemia), vomiting and rhinitis. 21 Tabulated list of adverse reactions In the pivotal clinical trials and in the post-marketing experience for Kuvan, the following adverse reactions have been identified. The following definitions apply to the frequency terminology used hereafter: 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 available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Immune system disorders Not known: Hypersensitivity reactions (including serious allergic reactions) and rash Metabolism and nutrition disorders Common: Hypophenylalaninaemia Nervous system disorders Very common: Headache Respiratory, thoracic and mediastinal disorders Very common: Rhinorrhoea Common: Pharyngolaryngeal pain, nasal congestion, cough Gastrointestinal disorders Common: Diarrhoea, vomiting, abdominal pain, dyspepsia, nausea Not known: Gastritis, oesophagitis Paediatric population Frequency, type and severity of adverse reactions in children were essentially similar to those in adults. 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-154364 · has-contraindication-information · PDF-Seite 7

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

HOS-154370 · has-contraindication-information · PDF-Seite 20

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

HOS-154369 · has-indication-information · PDF-Seite 15

Kuvan is indicated for the treatment of hyperphenylalaninaemia (HPA) in adults and paediatric patients of all ages with phenylketonuria (PKU) who have been shown to be responsive to such treatment (see section 4.2). Kuvan is also indicated for the treatment of hyperphenylalaninaemia (HPA) in adults and paediatric patients of all ages with tetrahydrobiopterin (BH4) deficiency who have been shown to be responsive to such treatment (see section 4.2).

HOS-154363 · has-indication-information · PDF-Seite 2

Kuvan is indicated for the treatment of hyperphenylalaninaemia (HPA) in adults and paediatric patients of all ages with phenylketonuria (PKU) who have been shown to be responsive to such treatment (see section 4.2). Kuvan is also indicated for the treatment of hyperphenylalaninaemia (HPA) in adults and paediatric patients of all ages with tetrahydrobiopterin (BH4) deficiency who have been shown to be responsive to such treatment (see section 4.2).

HOS-154366 · has-interaction-information · PDF-Seite 7

Although concomitant administration of inhibitors of dihydrofolate reductase (e.g. methotrexate, trimethoprim) has not been studied, such medicinal products may interfere with BH4 metabolism. Caution is recommended when using such medicinal products while taking Kuvan. BH4 is a cofactor for nitric oxide synthetase. Caution is recommended during concomitant use of Kuvan with all medicinal products that cause vasodilation, including those administered topically, by affecting nitric oxide (NO) metabolism or action including classical NO donors (e.g. glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), sodium nitroprusside (SNP), molsidomin), phosphodiesterase type 5 (PDE-5) inhibitors and minoxidil. 7 Caution should be exercised when prescribing Kuvan to patients receiving treatment with levodopa. Cases of convulsion, exacerbation of convulsion, increased excitability and irritability have been observed during co- administration of levodopa and sapropterin in BH4-deficient patients.

HOS-154372 · has-interaction-information · PDF-Seite 21

Although concomitant administration of inhibitors of dihydrofolate reductase (e.g. methotrexate, trimethoprim) has not been studied, such medicinal products may interfere with BH4 metabolism. Caution is recommended when using such medicinal products while taking Kuvan. BH4 is a cofactor for nitric oxide synthetase. Caution is recommended during concomitant use of Kuvan with all medicinal products that cause vasodilation, including those administered topically, by affecting nitric oxide (NO) metabolism or action including classical NO donors (e.g. glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), sodium nitroprusside (SNP), molsidomin), phosphodiesterase type 5 (PDE-5) inhibitors and minoxidil. Caution should be exercised when prescribing Kuvan to patients receiving treatment with levodopa. Cases of convulsion, exacerbation of convulsion, increased excitability and irritability have been observed during co- administration of levodopa and sapropterin in BH4-deficient patients.

HOS-154373 · has-pregnancy-information · PDF-Seite 21

Pregnancy There is a limited amount of data from the use of sapropterin in pregnant women, including data from the Kuvan registries KAMPER and PKUDOS. The data are too limited to conclude on malformative or foeto- neonatal toxicity. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). Uncontrolled maternal phenylalanine levels are associated with a high incidence of intellectual impairment, microcephaly, cardiac anomalies, growth restriction and facial dysmorphism in the offspring. Maternal blood phenylalanine levels must therefore be strictly controlled before and during pregnancy. . Physician-supervised restriction of dietary phenylalanine intake prior to and throughout pregnancy is the first choice of treatment in this patient group. The use of Kuvan should be considered only if strict dietary management does not adequately reduce blood phenylalanine levels. Caution must be exercised when prescribing sapropterin to pregnant women. Breast-feeding It is not known whether sapropterin or its metabolites are excreted in human breast milk. Kuvan should not be used during breast-feeding. Fertility In preclinical studies, no effects of sapropterin on male and female fertility were observed.

HOS-154367 · has-pregnancy-information · PDF-Seite 8

Pregnancy There is a limited amount of data from the use of sapropterin in pregnant women, including data from the Kuvan registries KAMPER and PKUDOS. The data are too limited to conclude on malformative or foeto- neonatal toxicity. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). Uncontrolled maternal phenylalanine levels are associated with a high incidence of intellectual impairment, microcephaly, cardiac anomalies, growth restriction and facial dysmorphism in the offspring. Maternal blood phenylalanine levels must therefore be strictly controlled before and during pregnancy. Physician-supervised restriction of dietary phenylalanine intake prior to and throughout pregnancy is the first choice of treatment in this patient group. The use of Kuvan should be considered only if strict dietary management does not adequately reduce blood phenylalanine levels. Caution must be exercised when prescribing sapropterin to pregnant women. Breast-feeding It is not known whether sapropterin or its metabolites are excreted in human breast milk. Kuvan should not be used during breast-feeding. Fertility In preclinical studies, no effects of sapropterin on male and female fertility were observed.

HOS-154365 · has-warning-information · PDF-Seite 7

Dietary intake Patients treated with Kuvan must continue a restricted phenylalanine diet and undergo regular clinical assessment (such as monitoring of blood phenylalanine and tyrosine levels, nutrient intake, and psycho- motor development). Low blood phenylalanine and tyrosine levels Sustained or recurrent dysfunction in the phenylalanine-tyrosine-dihydroxy-L-phenylalanine (DOPA) metabolic pathway can result in deficient body protein and neurotransmitter synthesis. Prolonged exposure to low blood phenylalanine and tyrosine levels during infancy has been associated with impaired neurodevelopmental outcome. Active management of dietary phenylalanine and overall protein intake while taking Kuvan is required to ensure adequate control of blood phenylalanine and tyrosine levels and nutritional balance. Health disturbances Consultation with a physician is recommended during illness as blood phenylalanine levels may increase. Convulsions disorders Caution should be exercised when prescribing Kuvan to patients receiving treatment with levodopa. Cases of convulsion, exacerbation of convulsion, increased excitability and irritability have been observed during co- administration of levodopa and sapropterin in BH4-deficient patients (see section 4.5). Discontinuation of treatment Rebound, as defined by an increase in blood phenylalanine levels above pre-treatment levels, may occur upon cessation of treatment. Sodium content This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

HOS-154371 · has-warning-information · PDF-Seite 20

Dietary intake Patients treated with Kuvan must continue a restricted phenylalanine diet and undergo regular clinical assessment (such as monitoring of blood phenylalanine and tyrosine levels, nutrient intake, and psycho- motor development). Low blood phenylalanine and tyrosine levels Sustained or recurrent dysfunction in the phenylalanine-tyrosine-dihydroxy-L-phenylalanine (DOPA) metabolic pathway can result in deficient body protein and neurotransmitter synthesis. Prolonged exposure to low blood phenylalanine and tyrosine levels during infancy has been associated with impaired neurodevelopmental outcome. Active management of dietary phenylalanine and overall protein intake while taking Kuvan is required to ensure adequate control of blood phenylalanine and tyrosine levels and nutritional balance. Health disturbances Consultation with a physician is recommended during illness as blood phenylalanine levels may increase. Convulsions disorders Caution should be exercised when prescribing Kuvan to patients receiving treatment with levodopa. Cases of convulsion, exacerbation of convulsion, increased excitability and irritability have been observed during co- administration of levodopa and sapropterin in BH4-deficient patients (see section 4.5). Discontinuation of treatment Rebound, as defined by an increase in blood phenylalanine levels above pre-treatment levels, may occur upon cessation of treatment. Potassium content Kuvan 100 mg powder for oral solution This medicinal product contains 0.3 mmol (12.6 mg) potassium per sachet. To be taken into consideration by patients with reduced kidney function or patients on a controlled potassium diet. Kuvan 500 mg powder for oral solution This medicinal product contains 1.6 mmol (62.7 mg) potassium per sachet. To be taken into consideration by patients with reduced kidney function or patients on a controlled potassium diet. 20