KUVAN

What it is

KUVAN contains sapropterin dihydrochloride, with each soluble tablet containing 100 mg of sapropterin dihydrochloride (equivalent to 77 mg of sapropterin). The product is also available as powder for oral solution in 100 mg and 500 mg sachets. Sapropterin dihydrochloride is a synthetic version of the naturally occurring 6R-BH4, which is a cofactor of the hydroxylases for phenylalanine, tyrosine and tryptophan.

Approved indications

— Treatment of hyperphenylalaninemia (HPA) in sapropterin-responsive adult and paediatric patients with phenylketonuria (PKU). — Treatment of hyperphenylalaninemia (HPA) in sapropterin-responsive adult and paediatric patients with tetrahydrobiopterin (BH4) deficiency.

Dosing overview

Treatment with KUVAN must be initiated and supervised by a physician experienced in the treatment of PKU and BH4 deficiency. KUVAN should be administered with a meal to increase absorption. For patients with PKU, KUVAN should be administered as a single daily dose, and at the same time each day, preferably in the morning. For patients with BH4 deficiency, divide the total daily dose into 2 or 3 administrations, distributed over the day. Response to KUVAN cannot be accurately pre-determined by laboratory testing alone and can only be determined by a therapeutic trial of KUVAN, assessed by a decrease in blood phenylalanine following treatment, with a satisfactory response 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 whose blood phenylalanine does not decrease from baseline after 1 month of administration at 20 mg/kg per day are non-responders and should not be treated with KUVAN.

Key safety warnings

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. Prolonged elevations in blood phenylalanine levels in patients with PKU and BH4 deficiency can result in severe neurologic damage, including severe mental retardation, microcephaly, delayed speech, seizures, and behavioural abnormalities, which may occur even if patients are taking KUVAN but not adequately controlling their blood phenylalanine levels within the recommended target range. Prolonged exposure to low blood phenylalanine and tyrosine levels during infancy has been associated with impaired neurodevelopmental outcome. Caution is advised when KUVAN is used in patients with predisposition to convulsions, as events of convulsion and exacerbation of convulsion have been reported in such patients. KUVAN should be used with caution in patients receiving concomitant levodopa, as combined treatment may cause increased excitability and irritability, and events of convulsion and exacerbation of convulsion have been observed during co-administration of levodopa and sapropterin dihydrochloride in BH4-deficient patients. Gastritis and oesophagitis were reported as serious adverse reactions, and patients should be monitored for signs and symptoms of these conditions.

Contraindications

KUVAN is contraindicated in patients with hypersensitivity to sapropterin or to any of the excipients.

PBS listing

In November 2018, PBAC recommended KUVAN for the treatment of hyperphenylalaninemia (HPA) caused by phenylketonuria (PKU) with Section 85 Authority Required listing and age restriction for initiation. In July 2019, PBAC recommended listing of 100 mg and 500 mg powder for oral solution for treatment of hyperphenylalaninaemia (HPA) due to BH4 deficiency and HPA due to PKU, with a change in authority level from Authority Required (Written) to Authority Required (Telephone). In December 2020, PBAC recommended Authority Required listing of sapropterin in combination with a phenylalanine-restricted diet for the treatment of maternal phenylketonuria (MPKU).

Regulatory history

KUVAN received approval on 2010-10-21 for the treatment of hyperphenylalaninaemia (HPA) in sapropterin-responsive adult and paediatric patients with phenylketonuria (PKU) or tetrahydrobiopterin (BH4) deficiency. ARTG registration for KUVAN sapropterin dihydrochloride 100 mg soluble tablet was first listed on 2010-10-28. ARTG registrations for KUVAN sapropterin dihydrochloride 100 mg and 500 mg oral powder sachets were first listed on 2018-12-13. In November 2018, PBAC recommended KUVAN for treatment of hyperphenylalaninemia caused by phenylketonuria. In July 2019, PBAC recommended listing of the powder formulations for treatment of hyperphenylalaninaemia due to both BH4 deficiency and PKU. In December 2020, PBAC recommended Authority Required listing for maternal phenylketonuria.