Regulatory Decision Summary for Vlexio

The safety and efficacy of Cardene Injection (nicardipine hydrochloride, 2.5 mg/mL) solution were reviewed and approved in 1994 (New Drug Submission (NDS), control number 23912), but Cardene Injection has never been marketed in Canada. The proposed Vlexio (nicardipine hydrochloride, 0.1 mg/mL) is a ready-to-use premixed solution in either 4.8% dextrose or 0.86% saline. A waiver to conduct comparative bioavailability studies for the proposed Vlexio and Cardene Injection was granted, given that the dosage regimen and aqueous solution compositions are the same. The proposed indication for Vlexio is also aligned with the indication approved for Cardene Injection.

The clinical efficacy and safety for the proposed indication and clinical use of Vlexio were based on the results of two previously reviewed clinical trials provided in the NDS for Cardene Injection. In the first study including postoperative hypertensive patients, nicardipine hydrochloride (HCl) showed a 94% (67/71) therapeutic response [defined as ≥ 15% reduction from baseline systolic blood pressure (SBP) or diastolic blood pressure (DBP)] vs. a 12% (6/50) therapeutic response in the placebo group. In the second study including severe hypertensive patients with or without end-organ damage, treatment with nicardipine resulted in a 95% (69/73) clinically meaningful response (defined as SBP ≤ 160 mmHg, DBP ≤ 95 mmHg or DBP decrease ≥ 25 mmHg from baseline) vs. 0% in the placebo group. The most frequent adverse events reported in the clinical trials were headache, nausea/vomiting, hypotension, vasodilatation and tachycardia.

The sponsor has also been referencing Cardene Injection to support their proposed impurity limits for Vlexio. However, tighter limits are now applicable due to an existing United States Pharmacopeia (USP) monograph for this product. As such, the proposed limits were not considered qualified for the intended use. The sponsor did not agree with the tighter impurity limits and therefore, a Notice of Non-compliance (NON) was issued on May 16, 2019.

In the response to the NON, the sponsor maintained the proposed limits with no additional justification and therefore, a Notice of Non-compliance Withdrawal (NON-W) Letter was issued, pursuant to section C.08.004 of the Food and Drug Regulations.