Kuvan

/ Medison

This formulation is provided as 100 mg tablets. The calculated daily dose based on body weight should be rounded to the nearest multiple of 100. For instance, a calculated dose of 401 to 450 mg should be rounded down to 400 mg corresponding to 4 tablets. A calculated dose of 451 mg to 499 mg should be rounded up to 500 mg corresponding to 5 tablets.
PKU: The starting dose in adult and paediatric patients with PKU is 10 mg/kg body weight once daily. The dose is adjusted, usually between 5 and 20 mg/kg/day, to achieve and maintain adequate blood phenylalanine levels as defined by the physician.
BH4 deficiency: The starting dose in adult and paediatric patients with BH4 deficiency is 2 to 5 mg/kg body weight once daily. Doses may be adjusted up to 20 mg/kg/day. It may be necessary to divide the total daily dose into 2 or 3 administrations, distributed over the day, to optimise the therapeutic effect.
Paediatric population: The safety and efficacy in children under 4 years of age has not been established. Currently available data are described in section 5.1, but no recommendation on posology can be made.
Elderly patients: Safety and efficacy in patients above 65 years of age have not been established. Caution must be exercised when prescribing to elderly patients. Patients with renal or hepatic impairment Safety and efficacy in patients with renal or hepatic insufficiency have not been established. Caution must be exercised when prescribing to such patients.
Determination of Response It is of primary importance to initiate the treatment as early as possible to avoid the appearance of non-reversible clinical manifestations of neurological disorders in paediatric patients and cognitive deficits and psychiatric disorders in adults due to sustained elevations of blood phenylalanine. Response to treatment is determined by a decrease in blood phenylalanine following treatment with this drug. Blood phenylalanine levels should be checked before initiating treatment and after 1 week of treatment with this drug at the recommended starting dose. If an unsatisfactory reduction in blood phenylalanine levels is observed, then the dose of the drug can be increased weekly to a maximum of 20 mg/kg/day, with continued weekly monitoring of blood phenylalanine levels over a one month period. The dietary phenylalanine intake should be maintained at a constant level during this period. A satisfactory response is defined as a ≥30 percent reduction in blood phenylalanine levels or attainment of the therapeutic blood phenylalanine goals defined for an individual patient by the treating physician. Patients who fail to achieve this level of response within the described one month test period should be considered non-responsive and should not receive treatment with this formulation. Once responsiveness to the drug has been established, the dose may be adjusted within the range of 5 to 20 mg/kg/day according to response to therapy. It is recommended that blood phenylalanine and tyrosine levels be tested one or two weeks after each dose adjustment and monitored frequently thereafter under the direction of the treating physician. Patients treated with this drug 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).

Treatment of hyperphenylalaninemia (HPA) in adult and pediatric patients of 4 years of age and over with phenylketonuria (PKU) who have been shown to be responsive to such treatment. Treatment of hyperphenylalaninemia (HPA) in adult and pediatric patients with tetrahydrobiopterin (BH4) deficiency who have been shown to be responsive to such treatment.

Hypersensitivity to the active substance or to any of the excipients.

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. In clinical studies of patients with BH4 deficiency treated with a preparation of sapropterin, convulsions and exacerbation of convulsions was observed. This was not observed in the clinical trials of Kuvan in patients with PKU.
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.
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.
Pediatric patients: Treatment has not been specifically studied in patients under 4 years of age. Elderly patients: Safety and efficacy in patients above 65 years of age have not been established. Caution must therefore be exercised when prescribing to this group.Renal or hepatic insufficiency: Safety and efficacy have not been established. Caution must therefore be exercised when prescribing to sucpatient.
Pregnancy and lactation: No clinical data on exposed pregnancies are available. Maternal blood phenylalanine levels must 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 fetus. Physician-supervised restriction of dietary phenylalanine intake prior to and throughout pregnancy is the first choice of treatment in this patient group. Treatment 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. Should not be used during breast-feeding.

Headache ,rhinorrhoea, hypophenylalaninaemia, pharyngolaryngeal pain, nasal congestion, cough, diarrhoea, vomiting, abdominal pain.
See prescribing information for full details.

No interaction studies have been performed. Although concomitant administration of inhibitors of dihydrofolate reductase (e.g. methotrexate, trimethoprim) has not been studied, such medicdbinal products may interfere with BH4 metabolism. Caution is recommended when using such agents during therapy. BH4 is a cofactor for nitric oxide synthetase. Caution is recommended during concomitant use 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 to patients receiving treatment with levodopa, as it may cause increased excitability and irritability.

Pregnancy: No clinical data on exposed pregnancies are available.
Lactation: It is not known whether Sapropterin or its metabolites are excreted in human breast milk.
See prescribing information for full details.

Headache and dizziness have been reported after the administration of sapropterin dihydrochloride above the recommended maximum dose of 20 mg/kg/day. Treatment of overdose should be directed to symptoms.