Regulatory Decision Summary for Vitrakvi

This Supplement to a New Drug Submission (SNDS) for Vitrakvi was filed to seek approval for a change in the composition of the oral solution dosage form. This change fulfills a commitment made to the European Medicine Agency (EMA) and other Health Authorities to replace the initially developed ORA-SWEET-based Larotrectinib solution 2 % for oral use formulation with an optimized pediatric formulation. The new formulation does not change the medicinal ingredient.

Vitrakvi is a Neurotrophic Tyrosine Receptor Kinase (NTRK) gene fusion inhibitor approved for the treatment of adult and pediatric patients with solid tumours that have a Neurotrophic Tyrosine Receptor Kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity and have no satisfactory treatment options.

This drug product is manufactured by dissolving the active pharmaceutical ingredient (API) in water to create a solution. The solution is not sterilized. The formulation and manufacturing process used for the bio-waiver lot have been found to be representative of those proposed for the commercial lots. A request for a waiver to perform comparative in vivo bioequivalence studies was provided for the product. The differences in viscosity and buffering capacity are not considered ‘essentially the same’, however, the Sponsor has provided scientific rationales to explain the differences. As such, the Quality requirements of Health Canada’s Pharmaceutical Quality of Aqueous Solutions guidance document have been met. A Notice of Compliance is recommended from Quality perspective.

The sponsor has requested a waiver from the requirement to conduct a comparative bioavailability study comparing the proposed formulation to the currently marketed formulation of Vitrakvi (larotrectinib as larotrectinib sulfate) 20 mg/mL oral solution (Bayer Inc.), based on the criteria described in the Health Canada guidance document Pharmaceutical Quality of Aqueous Solutions (2005). Despite the qualitative and quantitative differences in non-medicinal ingredients between the proposed versus currently marketed formulations, the Division of Biopharmaceutics Evaluation 2 (DBE2) concludes that the differences between the two formulations are not expected to impact the bioavailability of larotrectinib. As such, the requirements for a biowaiver as per the above noted guidance document have been satisfied by the proposed product with respect to safety and efficacy. DBE2 recommended that a biowaiver be granted for this product, provided the Pharmaceutical Drugs Quality Division (PDQD) concludes the comparative physicochemical data are acceptable.

A clinical consultation was requested due to the presence sodium benzoate in the new formulation and the increased risk of jaundice in newborn babies. Because Vitrakvi has a pediatric indication, Health Canada recommended the inclusion of a warning regarding the presence of sodium benzoate in Vitrakvi oral solution, which the sponsor agreed.

The labelling elements, including the Patient Medication Information and the mock-up package insert, were reviewed and found acceptable and all issues were appropriately addressed by the sponsor.

Overall, the benefit-risk profile of Vitrakvi remains favorable when used under the approved conditions of use.

For more details on Vitrakvi, please consult the Product Monograph, approved by Health Canada and available in the Drug Product Database.