Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: BioMarin International Limited, Shanbally, Ringaskiddy, County Cork, Ireland
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
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).
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.
Consultation with a physician is recommended during illness as blood phenylalanine levels may increase.
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).
Rebound, as defined by an increase in blood phenylalanine levels above pre-treatment levels, may occur upon cessation of treatment.
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.
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.
There are limited amount of data from the use of Kuvan in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.
Available disease-associated maternal and/or embryofoetal risk data from the Maternal Phenylketonuria Collaborative Study on a moderate amount of pregnancies and live births (between 300-1,000) in PKU-affected women demonstrated that uncontrolled phenylalanine levels above 600 μmol/l are associated with a very high incidence of neurological, cardiac, facial dysmorphism, and growth anomalies.
Maternal blood phenylalanine levels must therefore be strictly controlled before and during pregnancy. If maternal phenylalanine levels are not strictly controlled before and during pregnancy, this could be harmful to the mother and the foetus. 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 to pregnant women.
It is not known whether sapropterin or its metabolites are excreted in human breast milk. Kuvan should not be used during breast-feeding.
In preclinical studies, no effects of sapropterin on male and female fertility were observed.
Kuvan has no or negligible influence on the ability to drive and use machines.
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.
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.
Not known: Hypersensitivity reactions (including serious allergic reactions) and rash
Common: Hypophenylalaninaemia
Very common: Headache
Very common: Rhinorrhoea
Common: Pharyngolaryngeal pain, nasal congestion, cough
Common: Diarrhoea, vomiting, abdominal pain, dyspepsia, nausea
Not known: Gastritis, oesophagitis
Frequency, type and severity of adverse reactions in children were essentially similar to those in adults.
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.
Not applicable.
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