The following sections updated:
4.2 Special warnings and precautions for use
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.
There are limited data regarding the long-term use of Kuvan.
Caution is advised when sapropterin is used in patients with predisposition to convulsions. Events of convulsion and exacerbation of convulsion have been reported in such patients.
Sapropterin should be used with caution in patients who are receiving concomitant levodopa, as combined treatment with sapropterin may cause increased excitability and irritability.
Special populations
Kuvan has not been specifically studied in paediatric patients under 4 years of age (see section 5.1).
Safety and efficacy of Kuvan in patients above 65 years of age have not been established. Caution must be exercised when prescribing to elderly patients.
Safety and efficacy of Kuvan in patients with renal or hepatic insufficiency have not been established.
4.3 Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed.
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 agents while taking Kuvan.
BH4 is a cofactor for nitric oxide synthetase. Caution is recommended during concomitant use of Kuvan with all agents 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. Events of convulsion, exacerbation of convulsion, increased excitability and irritability have been observed during co-administration of levodopa and sapropterin in BH4-deficient patients.
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