Regulatory Decision Summary for Levodexa

The New Drug Submission (NDS) was originally filed to seek market authorization for Levodexa (dexamethasone and levofloxacin) ophthalmic solution for the prevention and treatment of inflammation and prevention of infection associated with cataract surgery in adults. Clinical evidence to support the proposed indication was based on one phase III non-inferiority (NI), active comparator, pivotal clinical trial conducted in 2018 and one supportive pharmacokinetic study conducted in 2018. Non-clinical evidence to support safety and efficacy consisted of 5 studies and numerous literature references, as well as references to a Canadian approved levofloxacin product (ACT Levofloxacin tablets) and a Canadian approved dexamethasone product (Maxidex dexamethasone ophthalmic ointment, USP).

Health Canada considers the benefit-harm-uncertainty (BHU) profile of Levodexa (dexamethasone and levofloxacin) ophthalmic solution for the prevention and treatment of inflammation, and the prevention of infection, associated with cataract surgery in adults, acceptable based on the review of all submitted data.

Clinical evidence to support the proposed indication was based on one phase III, non-inferiority (NI), active comparator, pivotal clinical trial and one supportive pharmacokinetic study.

The clinical safety and efficacy of Levodexa was investigated in a single international, multicentre, phase III, randomized, blinded-assessor, parallel-group pivotal study evaluating the NI of the test treatment (7 days Levodexa + 7 days Maxidex 0.1% dexamethasone eye drops following cataract surgery) versus standard treatment (14 days Tobradex 0.3% tobramycin/0.1% dexamethasone following cataract surgery). A NI margin of 10% was set. The primary endpoint, proportion of patients without signs of anterior chamber inflammation, and other endpoints were appropriate for the study. Overall adherence to treatment was high. A difference of 0.28% (95% CI [-2.75%; 3.31%]) was observed between the proportions of patients without signs of anterior chamber inflammation in the test and reference arms. In general, all treatment arms demonstrated acceptable safety profiles.

The supportive pharmacokinetic study, iPERME, evaluated the penetration of levofloxacin and dexamethasone sodium phosphate into the aqueous humour (AH) after topical ocular administration in combination compared with single active ingredients. The iPERME study adequately demonstrated no differences in the AH concentration of levofloxacin and no clinically relevant differences in the AH concentration of dexamethasone between the combination and single ingredient arms.

The clinical safety and efficacy assessment could not be completed during the initial review due to several deficiencies, including insufficient clinical and statistical justification for the selection of the 10% NI margin in the pivotal study, inadequate evidence for the stated claim of negligible systemic absorption of levofloxacin following ocular absorption, and an incomplete risk assessment concerning the potential for nitrosamine impurity contaminants. A Notice of Deficiency (NOD) was issued in September 2022 due to the above deficiencies. In the Response to NOD (R/NOD), the Sponsor addressed all deficiencies by providing adequate rationales and well-supported evidence.

The non-clinical data to support safety and efficacy complies with relevant regulatory requirements, supports the proposed indication, and demonstrates an acceptable safety profile.

Regarding post-market safety, the risks associated with the active ingredients, dexamethasone and levofloxacin, are well known and communicated in the Canadian Product Monograph (PM) for Levodexa. A risk of retinal detachment with the use of systemic fluoroquinolones was noted during review. Levodexa is administered by the ophthalmic route and it would likely not achieve the same systemic exposure as compared to oral administration of levofloxacin. However, the site of the administration for Levodexa is on the eye, and the patients using the product may experience symptoms (e.g. blurry vision) similar to retinal detachment as they are recovering from cataract surgery. One patient experienced retinal detachment that was not considered treatment related in the treatment arm of the pivotal trial. Retinal detachment is listed as a less common clinical trial adverse reaction in the approved PM for Levodexa .

Overall, the anticipated benefits of Levodexa (dexamethasone and levofloxacin) ophthalmic solution are expected to outweigh its risks under the conditions of use recommended in the Levodexa PM at this time.

For further details about Levodexa, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.