Regulatory Decision Summary for Kuvan

The proposed powder formulation in sachets and the current marketed Kuvan tablet can both be used to deliver an identical dose of the active pharmaceutical ingredient sapropterin dihydrochloride. Dosing of Kuvan is based upon body weight. The sponsor has indicated that Kuvan powder 100 mg and 500 mg for oral solution is designed to improve the taste, flavour and appearance of sapropterin dihydrochloride and is expected to improve convenience to the patient as the tablets must be crushed and then dissolved prior to ingestion.

The sponsor initially requested a Biopharmaceutics Classification System (BCS)-based biowaiver for the proposed product based on its relationship to the currently marketed tablet product. However, according to Health Canadas Guidance document Biopharmaceutics Classification System Based Biowaiver (2014), a product is eligible for a BCS-based biowaiver providing, among other things, that the drug product is a dosage form that is the same as the reference product. Given that, as stated in the Product Monograph (PM), the Kuvan 100 mg tablet can be dissolved and administered as a solution, as can the proposed powder product, and that both products will be in solution at the time of administration, the sponsor has instead requested a biowaiver based on comparative in vitro dissolution data of the powder and tablets formulations.

Although there are qualitative differences between the formulations for the Kuvan tablet and the proposed powder, sufficient information has been provided to conclude that the excipient differences should not affect the bioavailability of sapropterin dihydrochloride from the powder in comparison to the tablet. Further, sapropterin dihydrochloride is considered to have uncomplicated pharmacokinetic characteristics and the sponsor has demonstrated that the same drug substance from both the tablet or powder product will be in solution at the time of administration to the patient, based on the proposed administration instructions in the currently approved PM and in the draft PM for the powder product. Taken together, it was concluded that a waiver from the requirement to conduct a comparative bioavailability study with the proposed product can be accepted based on the principles discussed in the Health Canada Guidance for Industry Pharmaceutical Quality of Aqueous Solutions (2015).

From the biopharmaceutical and quality perspective, Kuvan Powder for oral solution 100 mg and 500 mg single sachets are considered acceptable. The PM and labelling components are also found to be satisfactory.