Summary Basis of Decision for Xtoro
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Xtoro is located below.
Recent Activity for Xtoro
SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Post-Authorization Activity Table (PAAT) for Xtoro
Updated:
Le tableau suivant décrit les activités postautorisation menées à l'égard de Xtoro, un produit dont l'ingrédient médicinal est finafloxacin. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
Drug Identification Number (DIN):
- DIN 02452928 - 0,3 % p/v, finafloxacin, suspension, voie otique
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| NDS # 223336 | 2018-12-28 | Issued NOC2019-03-11 | Submission filed to transfer ownership of the product (that is drug sponsor name) from Alcon Canada Inc. to MerLion Pharmaceuticals GmbH, and to update the inner and outer labels and package insert. The information was reviewed and considered acceptable. An NOC was issued. |
| NC # 209695 | 2017-12-19 | Issued NOL2018-02-23 | Submission filed as a Level II (120 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions section of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued. |
| NDS # 172450 | 2014-06-05 | Issued NOC2016-03-11 | Notice of Compliance issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Xtoro
Date SBD issued: 2016-04-13
The following information relates to the new drug submission for Xtoro.
Finafloxacin, 0.3% w/v, suspension, otic
Drug Identification Number (DIN):
- 02452928
Alcon Canada Inc.
New Drug Submission Control Number: 172450
On March 11, 2016, Health Canada issued a Notice of Compliance to Alcon Canada Inc. for the drug product Xtoro.
The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit/risk profile of Xtoro is favourable for the treatment of acute otitis externa caused by susceptible strains of Pseudomonas aeruginosa and Staphylococcus aureus, with or without an otowick, in patients age 1 year and older.
1 What was approved?
Xtoro, an antibacterial agent, was authorized for the treatment of acute otitis externa caused by susceptible strains of Pseudomonas aeruginosa and Staphylococcus aureus, with or without an otowick, in patients age 1 year and older.
No overall differences in safety and effectiveness have been observed between elderly and younger patients.
The safety and efficacy of Xtoro has been studied in pediatric patients 1 year and older (314 patients) in controlled clinical studies. The safety and efficacy of Xtoro in infants below one year of age have not been established.
Xtoro is contraindicated in patients with a history of hypersensitivity to finafloxacin, to other quinolones, or to any of the components in this medication. This product is for otic use only and not approved for ophthalmic use. Xtoro was approved for use under the conditions stated in the Xtoro Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Xtoro (0.3% w/v, finafloxacin) is presented as a suspension. In addition to the medicinal ingredient, finafloxacin, the suspension also contains benzalkonium chloride (preservative), cellulose, hydroxyethyl tyloxapol, magnesium chloride, purified water and sodium chloride. Hydrochloric acid and/or sodium hydroxide may be added to adjust pH.
For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the Xtoro Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Xtoro approved?
Health Canada considers that the benefit/risk profile of Xtoro is favourable for the treatment of acute otitis externa caused by susceptible strains of Pseudomonas aeruginosa and Staphylococcus aureus, with or without an otowick, in patients age 1 year and older.
Acute otitis externa (AOE) is an inflammation of the external auditory canal. This disease, found in all age groups, is often caused by bacterial infection.
Xtoro has been shown to be efficacious in treating patients with AOE caused by susceptible strains of Pseudomonas aeruginosa and Staphylococcus aureus, with or without an otowick, in patients age 1 year and older. The market authorization was based on two pivotal, randomized, multicentre, vehicle-controlled clinical studies. The superiority of Xtoro to vehicle for clinical cure at Day 11 (primary endpoint) was demonstrated in both of the individual studies and in the pooled analysis. The difference in clinical cure rates was 33.6% in favour of the Xtoro group (70.2%) versus (vs.) the vehicle group (36.6%). The non-clinical and clinical studies of Xtoro demonstrated that this new medication has a favourable safety profile, high antibacterial activity at lower pH conditions, and potent activity against pathogens Pseudomonas aeruginosa and Staphylococcus aureusassociated with AOE. No additional risks have been identified with the use of Xtoro compared to the vehicle group, and compared to the known risks of the marketed otic products containing fluoroquinolone.
A Risk Management Plan (RMP) for Xtoro was submitted by Alcon Canada Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.
In June 2015, the sponsor was issued a Notice of Non-Compliance (NON) for Xtoro. The principal issues in the NON were identified in the review of the chemistry and manufacturing information. The sponsor submitted a response to the NON and all of the concerns that led to the NON were satisfactorily addressed.
Health Canada reviewed the Look-alike Sound-alike Report submitted by the sponsor and accepted the proprietary name for the drug product.
Overall, the therapeutic benefits seen in the pivotal studies are positive and the benefits of Xtoro therapy are considered to outweigh the risks. The approval of Xtoro will add an additional option for physicians and patients for the treatment of AOE. Xtoro has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling. Appropriate warnings and precautions are in place in the Xtoro Product Monograph to address the identified safety concerns.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Xtoro?
A New Drug Submission (NDS) for Xtoro was filed with Health Canada on June 5, 2014. Due to issues identified in the review of the chemistry and manufacturing information, a Notice of Non-Compliance (NON) was issued for Xtoro on June 30, 2015. The principal issue in the NON was the need for adequate validation data. The sponsor submitted a response to the NON and all of the concerns that led to the NON were satisfactorily addressed. A Notice of Compliance was issued on March 11, 2016.
Submission Milestones: Xtoro
| Submission Milestone | Date |
|---|---|
| Submission filed: | 2014-06-05 |
| Screening 1 | |
| Screening Acceptance Letter issued: | 2014-07-29 |
| Review 1 | |
| Quality Evaluation complete: | 2015-06-12 |
| Clinical Evaluation complete: | 2015-05-08 |
| Notice of Non-Compliance (NON) issued by Director General, Therapeutic Products Directorate (quality issues): | 2015-06-30 |
| Response filed: | 2015-09-25 |
| Screening 2 | |
| Screening Acceptance Letter issued: | 2015-10-15 |
| Review 2 | |
| Quality Evaluation complete: | 2016-03-07 |
| Clinical Evaluation complete: | 2016-03-10 |
| Labelling Review complete: | 2016-03-08 |
| Notice of Compliance issued by Director General, Therapeutic Products Directorate: | 2016-03-11 |
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
4 What follow-up measures will the company take?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada and have been market notified (that is, the company has told Health Canada the product is being marketed).
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Part III: Patient Medication Information, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
Clinical Pharmacology
Finafloxacin (the active ingredient in Xtoro) is an antibiotic which has been shown to be active against the bacterial pathogens Pseudomonas aeruginosa and Staphylococcus aureus, in both in vitro and clinical studies.
Systemic exposure to finafloxacin was very low following ototopical administration of Xtoro, and as a result there was insufficient data to determine pharmacokinetic parameters. Also, no human pharmacodynamics studies were conducted as the absorption was very low.
For further details, please refer to the Xtoro Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy of Xtoro (finafloxacin otic suspension, 0.3% w/v) was evaluated in two Phase III, pivotal, multicentre, double-blinded, parallel-group, vehicle-controlled, randomized studies (Study C-10-018 and Study C-10-019). Randomized controlled studies for a topical comparison use the term vehicle rather than placebo as the vehicle in a topical drug product can enhance delivery and efficacy of the active compound. The studies were conducted in patients 6 months of age and older with a clinical diagnosis of acute otitis externa (AOE). The objective of these studies was to demonstrate the superiority of Xtoro (finafloxacin otic suspension) relative to finafloxacin vehicle (referred to as vehicle) based upon clinical cures at test-of-cure (TOC) for the treatment of AOE. Study C-10-018 had 686 patients and Study C-10-019 had 548 patients. Four drops were administered twice daily for 7 days (ototopical administration). The primary efficacy endpoint was the clinical cure rate at Day 11 (TOC). Secondary efficacy endpoints included microbiological success at Day 11 (TOC) and time to cessation of ear pain.
For the primary efficacy endpoint, the percentage of patients at Day 3 with sustained clinical cures was not significantly different between the Xtoro and vehicle groups. However the cure percentage rate was very significant at Day 8 and 11. The superiority of Xtoro to vehicle for clinical cure at Day 11 was demonstrated in both of the individual studies and in the pooled analysis. The clinical cure rates at Day 11 in Study C-10-018 for the Xtoro group and vehicle group were 71.7% and 33.3% respectively, with a difference of 38.4%; and in Study C-10-019; 68.7% and 40.0% respectively, with a difference of 28.7%. In the pooled analysis, the difference in clinical cure rate was 33.6% in favour of the Xtoro group (70.2%) vs. the vehicle group (36.6%).
For the secondary efficacy endpoints, microbiological success at Day 11 (TOC) and time to cessation of ear pain, the Xtoro group also showed superiority to the vehicle group. Microbiological success at Day 11 (TOC) was defined as the absence of all pre-therapy bacteria in the specimen. In the pooled analysis, the difference in microbiological success was 54.1% in favour of the Xtoro group (66.4%) vs. vehicle group (12.3%). The eradication rates for the primary pathogens, Staphylococcus aureus (number [N] = 56), and Pseudomonas aeruginosa (N = 167), were 89.3% and 89.2%, respectively. For the other bacteria found in the clinical samples, it was difficult to determine if they were the cause of the infections as they were either normal skin flora or co-existed at the infection site with the primary pathogens. In the pooled analysis, the median time to cessation of ear pain for the Xtoro group was 3.5 days compared to 7.0 days for the vehicle group.
In summary, Xtoro, a fourth-generation fluoroquinolone, is an effective antibiotic, which not only eradicates pathogens but also provides resolution of signs and symptoms associated with AOE. The pivotal studies demonstrated the effectiveness of Xtoro in the treatment of AOE caused by susceptible strains of Pseudomonas aeruginosa and Staphylococcus aureus, with or without an otowick, in patients age 1 year and older.
For more information, refer to the Xtoro Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The clinical safety of Xtoro (finafloxacin otic suspension, 0.3% w/v) was primarily evaluated in the two Phase III studies described in the Clinical Efficacy section. The majority of common adverse events reported in the Xtoro group were local otic side effects which were also reported in the vehicle group. The overall incidences were similar; both groups had less than 1% of patients for adverse drug reactions (ADRs) reported. No unique common adverse events for Xtoro were observed. Based upon a review of the common adverse events, Xtoro was well-tolerated and no clinically meaningful differences were observed between the Xtoro group and the vehicle group. No serious adverse reactions were reported. The most frequently reported adverse reactions occurring at an incidence of 0.5% of those exposed to Xtoro included ear pruritus and dizziness.
A review of adverse events by age category, gender, and race revealed no clinically relevant differences between subgroups. The conclusions based upon a review of adverse events in the subgroups were consistent with those drawn from the review of the overall safety population.
The infant group (6 months to 2 years of age) had no adverse events reported. One of the youngest treated with Xtoro was an 11-month old patient. This patient along with two other patients (ages 12 months and 16 months) had no ADR reported. Since the medication demonstrated efficacy and no safety issues were identified in this group of patients, even though the number of treated patients were only three, approval for patients ages 1 year and older was recommended; however, safety will be needed to be further monitored in this age group during post-market surveillance.
In summary, based upon a review of adverse events, Xtoro was well-tolerated when dosed twice daily for up to 8 days in the safety population, with an overall safety profile comparable with that of its vehicle. The types of ADRs associated with Xtoro were consistent with those of marketed fluoroquinolone products for the treatment of AOE.
For more information, refer to the Xtoro Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
Finafloxacin, the medicinal ingredient of Xtoro, belongs to fluoroquinolone class of antibacterials involved in the inhibition of bacterial type II topoisomerase, deoxyribonucleic acid (DNA) gyrase and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair and recombination. In vitro and clinical studies have demonstrated finafloxacin to be active against the bacterial pathogens, Staphylococcus aureus and Pseudomonas aeruginosa, associated with AOE. Studies showed that the optimal antibacterial activity was achieved at a low pH (range of 5.8 to 6.2). In contrast, ciprofloxacin and levofloxacin had reduced activity at a lower pH compared to neutral conditions. The finding that finafloxacin is most potent in a low pH environment suggests that finafloxacin would have an advantage over other fluoroquinolones as a therapy for infection, as acute infection sites are often associated with a low pH.
Finafloxacin was found to be potentially mutagenic, teratogenic, and toxic to cartilage and hepatocytes after systemic administration. Since the topical otic administration resulted in minimal absorption, the systemic toxicities observed in animal studies are not expected in humans for treatment of external ear infection.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Xtoro Product Monograph. In view of the intended use of Xtoro, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Xtoro Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
The drug submission for Xtoro previously received a Notice of Non-Compliance (NON) as validation data for various test methods were lacking. In response to the NON, the sponsor provided adequate information and sufficient evidence to address all of the issues identified in the NON, and the drug submission was again accepted into review.
The Chemistry and Manufacturing information submitted for Xtoro has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf-life of 2 years is acceptable when the product is stored between 2° to 25°C.
All sites involved in production are compliant with Good Manufacturing Practices.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.
The excipients used in the drug product formulation are not of animal or human origin.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| XTORO | 02452928 | MERLION PHARMACEUTICALS GMBH | FINAFLOXACIN 0.3 % / W/V |