Regulatory Decision Summary for Kuvan
Review decision
The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.
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What was the purpose of this submission?
This Supplemental New Drug Submission was filed to extend the pediatric indication to include children aged 1 month to 4 years, add safety information, add population pharmacokinetic information regarding children aged 4 to 6 years, and revise the Product Monograph based on new in vitro drug interaction studies and updates to the Core Safety Data Sheet.
Why was the decision issued?
Two 6-month, open-label, Phase 3b trials - Spark and PKU-015 - were supportive of the efficacy of Kuvan, administered in doses of 10mg/kg/day to 20mg/kg/day, in reducing blood phenylalanine (Phe) and increasing dietary Phe tolerance in children with Kuvan-responsive phenylketonuria (PKU), aged one month to <4 years.
No new safety signals were identified in the studied pediatric age group compared to older children and adults evaluated in previous clinical trials, except low blood Phe levels, particularly in children <1 year of age, and small mean decreases in platelets.
Results of the in vitro drug interaction study indicated the potential for Kuvan to inhibit P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) in the gut at therapeutic doses, which could lead to increased systemic exposure of drugs that are substrates for these enzymes. The submitted in vitro drug metabolism studies demonstrated that drugs that are substrates of cytochrome P450 (CYP) 1A2, 2B6, or 3A4/5 enzymes can be safely co-administered with Kuvan. The effects of genetic polymorphism, renal and hepatic impairment on the pharmacokinetics of Kuvan are unknown.
Based on the review, labelling has been revised to warn of the risk of low blood Phe, particularly in infants <1 year of age, include clinical trial findings of decreases in platelets and recommend caution if Kuvan is co-administered with drugs that are substrates of P-gp and BCRP.
A Risk Management Plan and Periodic Benefit Risk Evaluation Report were reviewed by the Marketed Health Products Directorate.
The benefit-harm-uncertainty assessment of Kuvan for the pediatric extension is favourable.
Decision issued
Approved; issued Notice of Compliance in accordance with the Food and Drug Regulations