Regulatory Decision Summary for RAVICTI

The safety and efficacy of Ravicti were demonstrated in four (two adult and two pediatric) short-term (1-2 weeks) switch-over studies enrolling 85 patients who switched from sodium phenylbutyrate (NaPBA) to Ravicti and three long-term (12 months) studies enrolling 100 patients with urea cycle disorders. The long-term studies consisted of a Phase III study in adult and pediatric patients, as well as safety extensions of both pediatric short-term studies.

The Phase III study achieved its primary efficacy endpoint, non-inferiority of Ravicti to NaPBA in controlling blood ammonia levels in patients with urea cycle disorders. Efficacy results of the Phase III study were supported by the short-term studies.

There were insufficient clinical data to establish safety and efficacy in children between 2 months and 2 years of age. In the pediatric population, only 7 patients aged 2 months to 2 years were studied. Higher phenylacetate levels were noted in this age group and it was determined that Ravicti was not sufficiently studied to recommend use in this patient population. However, based on the mechanism of action of Ravicti, the orphan status of Ravicti, and on several cases where Ravicti was used in children between 2 months and 2 years of age, Ravicti was not contraindicated in this age group.

Since children under 2 months of age may have immature pancreatic function that could impair Ravicti hydrolysis, a contraindication for the use of Ravicti in this age group was added.

The safety assessment determined that most adverse events (AEs) reported were mild or moderate in intensity. Treatment-Related AEs reported in ≥5% of patients in UCD studies included diarrhea, nausea, vomiting, dyspepsia, flatulence, decreased appetite, headache and skin odour abnormalities.

Non-UCD patients with hepatic impairment had a greater number and more severe AEs and in this patient population, one potentially drug-related death was reported. There were insufficient data in patients >65 years of age, in pregnant women, and in patients with pancreatic or renal insufficiency. Use in these patients may involve a greater risk.

An electrocardiogram assessment study demonstrated a dose- and concentration-dependent increase in heart rate over the therapeutic dose range as well as QTcF interval shortening at a level which is not known to have pro-arrhythmic consequences. Use of Ravicti in patients with conditions that can be worsened by an increase in heart rate is a potential risk.

The risks and uncertainties associated with Ravicti use are mitigated through adequate labelling and by the Risk Management Plan, which includes a patient registry.

The benefit-risk profile for the use of Ravicti as per the recommended indication was considered favorable and a Notice of Compliance was issued by Health Canada.

For more information on Health Canadas decision, please view the Summary Basis of Decision.