Summary Basis of Decision for Ozanex

Clinical Pharmacology

Ozanex (ozenoxacin) is a topical antibiotic intended for the management of impetigo, a superficial, gram-positive bacterial skin infection. Ozenoxacin is a non-fluorinated quinolone that shows negligible systemic absorption.

In Phase I studies, following topical applications of ozenoxacin 1% w/w cream twice daily for 5 days, high concentrations of ozenoxacin were found in the stratum corneum and epidermis; however, systemic absorption of ozenoxacin was negligible. Levels of ozenoxacin were generally below the limit of quantitation 0.5 ng/mL.

Pharmacokinetic parameters were not investigated because of the negligible systemic absorption.

No photoallergic reactions, photoirritation, dermal sensitization issues, or evidence of irritation were reported in the Phase I studies. The dermal tolerability studies are considered acceptable.

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

Clinical Efficacy

The clinical efficacy of Ozanex (ozenoxacin) was demonstrated in two multicentre, randomized, placebo-controlled pivotal Phase III studies (Study P-110880-01 and Study P-110881-01). A total of 362 adult and pediatric patients ≥2 months of age with impetigo received Ozanex. In Study P-110880-01, a third group received retapamulin 1% ointment. Enrolled patients could have an affected area of no more than 100 cm² in total surface area, or not exceeding 2% of body surface area in patients less than 12 years of age. The mean area studied was 15.1 cm² in patients more than 12 years of age and 0.09% of body surface area in patients less than 12 years.

Ozanex or placebo (or retapamulin 1% ointment in Study P-110880-01) was applied to the affected area twice daily for 5 days. The study duration was approximately 2 weeks, including 5 days of treatment with a follow-up 5-7 days later. Clinical and microbiological evaluations were performed at Day 3-4 on-therapy (Visit 2), end of therapy (Visit 3, Day 6-7) and 5-7 days after the last application (Visit 4, Day 10-13).

The primary efficacy endpoint in both studies was clinical response (success or failure) at the end of therapy in the intent-to-treat clinical (ITTC) population. Secondary efficacy endpoints included microbiological response (success or failure) at all post-baseline visits (ITTB population) and overall therapeutic response (combined clinical and microbiological response, ITTB population) at the end of therapy.

In both Phase III studies, the clinical success rate at the end of therapy was higher in the Ozanex group than in the placebo group; Study P-110880-01 (34.8% vs. 19.2% [ITTC], respectively); and Study P-110881-01 (55.2% vs. 39.2% [ITTC], respectively). In Study P-110880-01, the clinical success rate for the active/internal control, retapamulin, was 37.7% (ITTC).

Microbiological success was defined as the absence of the original pathogen(s) (Visit 1, baseline) from the culture of specimen from the baseline affected area.

In Study P-110880-01, the microbiological response success rates (ITTB population) at Visit 2 for the Ozanex and placebo groups were 70.8% and 38.2%, respectively; and at Visit 3: 79.2% and 56.6%, respectively. The microbiological success for the active control (retapamulin) at Visit 3 was 81.7%.

In Study P-110881-01, the microbiological response success rates (ITTB population) at Visit 2 for the Ozanex and placebo groups were 87.2% and 70.4%, respectively; and at Visit 3: 93.5% and 81.3%, respectively.

Health Canada recognizes that the definition of clinical success (the primary efficacy endpoint) for the two pivotal studies was stricter than that used in previous impetigo studies (patients with clinical improvement could previously be considered a clinical success). The definition of clinical success at end of therapy (Day 5) in the two pivotal studies was as follows: Skin Infection Rating Scale (SIRS) score of 0 for exudate/pus, crusting, tissue warmth and pain, and no more than 1 for erythema/inflammation, tissue edema and itching respectively, and no additional antimicrobial therapy necessary. For this reason, clinical success rates were relatively low compared to the published data on impetigo treatments. However, in pivotal Study 110880-01, where retapamulin was used for internal study validation, clinical success rates were very similar for Ozanex and for retapamulin (34.8% and 37.7%, respectively); providing a secondary comparison. There was also a significant placebo effect seen in both pivotal studies. This was possibly related to the presence of benzoic acid, a non-medicinal ingredient present in both the Ozanex drug product and the placebo vehicle cream.

In both pivotal studies, the most commonly found pathogens were Staphylococcus aureus and Streptococcus pyogenes. Limited in vivo clinical study data indicate that Ozanex is effective against MRSA (9/10 MRSA eradicated; clinical cure plus improvement 100%).

Impetigo primarily affects the pediatric population; clinical study data included 289 patients aged 2 months to 18 years, including 31 patients aged 2 months to <2 years. There was limited data for impetigo infections affecting >50 cm² body surface area (BSA) (>1% BSA in children <12 years). Ozanex was not studied in impetigo infections affecting >100 cm² (>2% BSA in children <12 years). Limited data also exists for bullous impetigo. Bullous impetigo is related to an infection with Staphylococcus aureus and to a toxin produced by the pathogen. The appropriate choice of treatment in this situation is considered a clinical treatment issue, to be assessed by the treating physician. The Dosage and Administration section of the Ozanex Product Monograph states that "Patients not showing a clinical response within 3 days should be re-evaluated and alternative therapy should be considered."

Overall, based on the data provided, Ozanex is efficacious for use in the treatment of impetigo in patients two months of age and older. Total skin surface area involved should be limited to 100 cm² (2% BSA in children <12 years age; equivalent to two palm surface areas of the child). The recommended indication is the same as the proposed indication submitted with the drug submission.

For more information, refer to the Ozanex Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

Ozanex (ozenoxacin) was evaluated for safety in 458 patients with superficial skin infections, including 289 pediatric patients of whom 31 were aged 2 months to <2 years. The safety profile of Ozanex was assessed in two randomized, controlled, Phase III clinical studies (Study P-110880-01 and Study P-110881-01, described in the Clinical Efficacy section). These studies included 362 adult and pediatric patients ≥2 months of age, who used at least one dose of Ozanex. Ozenoxacin had negligible systemic absorption (generally below the level of quantitation of 0.5 ng/ml). There were no safety concerns in the pediatric or the adult populations. There were no deaths or serious adverse events. No adverse drug reactions were reported at a frequency of ≥1%.

Ozenoxacin is a non-fluorinated quinolone antibiotic. The lack of a fluoride substituent at the 6-position clearly differentiates ozenoxacin from fluoroquinolone antibacterials. The fluoroquinolone products present various safety concerns, probably caused by the presence of fluoride substituents at the 6-position in the quinolone structure, which may allow for increased systemic exposure to the quinolone moiety with attendant adverse drug reactions.

Overall, Ozanex has an excellent clinical safety profile and a very large safety margin for toxic effects (non-clinical [topical application] and clinical). The most commonly reported adverse events were cutaneous manifestations such as erythema, and application site erythema, pruritus and irritation, all at a frequency of <1%.

For more information, refer to the Ozanex Product Monograph, approved by Health Canada and available through the Drug Product Database.