SAPROPTERIN DIHYDROCHLORIDE

Treatment with sapropterin dihydrochloride must be initiated and supervised by a physician experienced in the treatment of PKU and BH4 deficiency. Active management of dietary phenylalanine and overall protein intake while taking this medicinal product is required to ensure adequate control of blood phenylalanine levels and nutritional balance.

1). Posology PKU The starting dose of sapropterin dihydrochloride 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 of sapropterin dihydrochloride in adult and paediatric patients with BH4 deficiency is 2 to 5 mg/kg body weight total daily dose. Doses may be adjusted up to a total of 20 mg/kg per day. For patients above 20 kg body weight, the calculated daily dose based on body weight should be rounded to the nearest multiple of 100 mg.

Dose adjustment Treatment with sapropterin may decrease blood phenylalanine levels below the desired therapeutic level. Adjustment of the sapropterin dihydrochloride dose or modification of dietary phenylalanine intake may be required to achieve and maintain blood phenylalanine levels within the desired therapeutic range.

Blood phenylalanine and tyrosine levels should be tested, particularly in the paediatric population, one to two weeks after each dose adjustment and monitored frequently thereafter, under the direction of the treating physician. If inadequate control of blood phenylalanine levels is observed during treatment with sapropterin dihydrochloride, the patient’s adherence to the prescribed treatment, and diet, should be reviewed before considering an adjustment of the dose of sapropterin.

Discontinuation of treatment should be done only under the supervision of a physician. More frequent monitoring may be required, as blood phenylalanine levels may increase. Dietary modification may be necessary to maintain blood phenylalanine levels within the desired therapeutic range.

Determination of response It is of primary importance to initiate 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.

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 sapropterin 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 sapropterin, 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.

Dietary intake Patients treated with sapropterin dihydrochloride 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 sapropterin dihydrochloride 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 sapropterin dihydrochloride to patients receiving treatment with levodopa. 5). Discontinuation of treatment Rebound, as defined by an increase in blood phenylalanine levels above pre- treatment levels, may occur upon cessation of treatment.

7 mg) potassium per sachet. To be taken into consideration by patients with reduced kidney function or patients on a controlled potassium diet.

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