Summary Basis of Decision for Besivance ™
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:
BesivanceTM
Besifloxacin, 0.6% w/v, Suspension, Ophthalmic
Bausch & Lomb Inc.orporated
Submission control no: 123400
Date issued: 2010-04-09
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02336847
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On October 23, 2009, Health Canada issued a Notice of Compliance to Bausch & Lomb Incorporated for the drug product, Besivance™.
Besivance™ contains the medicinal ingredient besifloxacin, an antibacterial agent.
Besivance™ is indicated for the treatment of patients one year of age and older with bacterial conjunctivitis caused by susceptible strains of the following organisms:
Aerobic Gram-Positive
- CDC coryneform group G
- Staphylococcus aureus
- Staphylococcus epidermidis
- Streptococcus mitis
- Streptococcus oralis
- Streptococcus pneumoniae
Aerobic Gram-Negative
- Haemophilus influenzae
Besifloxacin is a fluoroquinolone that has activity against Gram-positive and Gram-negative bacteria. The antibacterial action of besifloxacin is due to the inhibition of both bacterial deoxyribonucleic acid (DNA) gyrase and topoisomerase IV. DNA gyrase is an essential enzyme required for replication, transcription and repair of bacterial DNA. Topoisomerase IV is an essential enzyme required for partitioning of the chromosomal DNA during bacterial cell division.
The market authorization was based on quality, non-clinical, and clinical information submitted. The safety and efficacy were evaluated in two Phase III studies and one Phase II study. All three studies were multicentre, randomized, double-masked, parallel-group studies conducted in patients one year of age and older with bacterial conjunctivitis. Two of the studies were placebo (vehicle) controlled and the other study used an active comparator. Results showed that Besivance™ was more effective than the vehicle, non-inferior to the active comparator, and was generally well-tolerated.
Besivance™ (0.6% w/v, besifloxacin) is presented as a topical ophthalmic suspension. The recommended dosage regimen for Besivance™ in the treatment of patients one year of age and older with bacterial conjunctivitis is to instill one drop in the affected eye(s) 3 times a day for 7 days. Dosing guidelines are available in the Product Monograph.
Besivance™ is contraindicated for patients with known hypersensitivity to this drug, to other quinolones, or to any ingredient in the formulation or component of the container. Detailed conditions for the use of Besivance™ are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Besivance™ is favourable for the indications stated above.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Besivance™ is a topical ophthalmic suspension for the treatment of bacterial conjunctivitis. The medicinal ingredient is besifloxacin, as besifloxacin hydrochloride. The antibacterial action of besifloxacin is achieved through the inhibition of both bacterial DNA gyrase and topoisomerase IV.
Manufacturing Process and Process Controls
Besifloxacin hydrochloride is manufactured via a multi-step synthesis. Each step of the manufacturing process is considered to be controlled within acceptable limits:
- The sponsor has provided information on the quality and controls for all materials used in the manufacture of the drug substance.
- The drug substance specifications are found to be satisfactory. Impurity limits meet International Conference on Harmonisation (ICH) requirements.
- The processing steps have been evaluated and the appropriate ranges for process parameters have been established.
Characterization
The structure of besifloxacin hydrochloride has been adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory.
The sponsor has provided a summary of all potential drug-related impurities. Appropriate tests are adequately controlling the levels of product- and process-related impurities.
Control of Drug Substance
Copies of the analytical methods and, where appropriate, validation reports were provided and are considered satisfactory for all analytical procedures used for release and stability testing of besifloxacin hydrochloride.
Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.
Stability
Based on the long-term, real-time, accelerated, and stress stability data submitted, the proposed retest period and storage conditions for the drug substance were supported and are considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Besivance™ is supplied as a sterile ophthalmic suspension in a white low-density polyethylene bottle with a controlled dropper tip and a tan polypropylene cap. Each 7.5 mL bottle contains 5 mL of the suspension. Tamper evidence is provided with a shrink band around the cap and neck area of the bottle.
Each mL of Besivance™ contains 6 mg besifloxacin base, derived from 6.63 mg besifloxacin hydrochloride. The non-medicinal ingredients consist of benzalkonium chloride, polycarbophil, mannitol, poloxamer 407, sodium chloride, edetate disodium dihydrate, sodium hydroxide, and water for injection.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of besifloxacin hydrochloride with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process made throughout the pharmaceutical development are considered acceptable upon review.
Manufacturing Process and Process Controls
The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Drug Product
Besivance™ is tested to verify that its identity, appearance, assay, pH, particle size, viscosity, fill volume, sterility, weight, osmolality, impurities, and degradation products are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits, for individual and total degradation products are within acceptable limits.
Validation reports submitted for all analytical procedures used for in-process and release testing of the drug product are considered satisfactory.
Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Stability
Based on the real-time, long-term, accelerated, and stress stability data submitted, the proposed 24-month shelf-life at 15-25°C for Besivance™ is considered acceptable, when protected from light.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facilities and equipment that are involved in the production of Besivance™ are considered suitable for the activities and products manufactured.
3.1.4 Adventitious Agents Safety Evaluation
The excipients used in the drug product formulation are not from animal or human origin.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Besivance™ 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.
3.2 Non-Clinical Basis for Decision
3.2.1 Microbiology
Besifloxacin is a fluoroquinolone that has activity against Gram-positive and Gram-negative bacteria. Besifloxacin appears to be similar to other fluoroquinolones, that is it inhibits bacterial DNA gyrase and topoisomerase IV. The in vitro antibacterial activities of besifloxacin are presented in the Product Monograph. Because Besivance™ is presented as a topical ophthalmic suspension, the sensitivity assays generally conducted for antibiotics were not required.
3.2.2 Pharmacodynamics
Primary pharmacodynamic (PD) studies are not directly applicable to antibacterials. Antibacterial agents differ from other drugs by exerting their pharmacological effects on susceptible bacteria, not animal or human cells. Microbiology studies were conducted to assess the antibacterial activity of besifloxacin. Safety pharmacology studies were conducted to characterize the non-microbiological actions of besifloxacin.
The safety pharmacology studies included in vitro and in vivo studies on the cardiovascular system, with particular attention paid to potential QT-interval prolongation due to the potential risk of cardiac arrhythmias associated with systemic use of some fluoroquinolones in humans. Safety pharmacology studies also evaluated effects on the respiratory system as well as renal function.
Besifloxacin induced a minimal inhibitory effect on hERG (human Ether-à-go-go Related Gene) tail current in stably-transfected HEK-293 (Human Embryonic Kidney 293) cells. The cardiovascular study in animals indicates that the drug has the potential to prolong QT interval when administered systemically. This drug submission is for the topical application of besifloxacin and the systemic exposure to besifloxacin is low. Therefore, QT prolongation is not a concern when besifloxacin is administered topically.
Besifloxacin had no effect on respiratory parameters in conscious rats at doses of 1000 mg/kg administered orally. The creatinine clearance was significantly reduced at 1000 mg/kg dose levels but not at 100 mg/kg dose. The maximum plasma concentration (Cmax) following the oral administration of 100 mg/kg besifloxacin in rats is about 1000-fold higher than the plasma levels seen following topical administration. Therefore, the risk of renal toxicity following topical administration of besifloxacin is negligible.
3.2.3 Pharmacokinetics
Absorption
Pharmacokinetic (PK) studies in rabbits and monkeys indicate that topical ocular administration of 0.6% besifloxacin hydrochloride ophthalmic suspension is associated with rapid absorption and distribution of besifloxacin into the ocular tissues. Repeated topical ocular administration of besifloxacin was associated with low systemic exposure.
Distribution
Following a single instillation of radiolabelled besifloxacin ophthalmic suspension in rabbits, radioactivity was detected in all ocular structures of the treated eyes up to 16 hours later. Maximum concentrations were observed in most of the ocular tissues within 0.5-2 hours. The mean maximal amount of radioactivity was found in bulbar and palpebral conjunctivae. For non-ocular tissues, measurable levels of radioactivity were observed in all of the tissues collected, with the highest levels of radioactivity observed in the urinary bladder, ileum, jejunum, duodenum and kidney. The binding of besifloxacin to plasma proteins was less than 50% in rats and humans.
Metabolism
Besifloxacin undergoes minimal metabolism. In rats, following oral administration of radiolabelled besifloxacin, unchanged besifloxacin accounted for the majority of the radioactivity in plasma, urine, and faeces. In plasma, three metabolites were observed, each accounting for <10% of the total radioactivity. In urine, a single metabolite was observed, which accounted for <6% of the total radioactivity in each sample. In faeces, a single metabolite was observed, which accounted for <3% of the total radioactivity in each sample.
Excretion
Following the oral administration of radiolabelled besifloxacin to rats, besifloxacin was eliminated via the faecal and urinary routes with the faecal route predominating. More than 80% of the administered dose was eliminated within 24 hours. Forty-eight hours after the radiolabelled besifloxacin was orally administered, radioactivity was undetectable in most of the tissues, including plasma.
3.2.4 Toxicology
Single-Dose Toxicity
Single-dose toxicity studies were conducted in rats. The plasma concentrations of besifloxacin at which no effect was seen was approximately 15200-fold higher than the highest plasma level (1.3 ng /mL) observed in humans following ocular administration of Besivance™.
Repeat-Dose Toxicity
Repeat-dose oral toxicity studies were performed in rats and dogs. When doses of approximately 400 mg/kg/day besifloxacin were administered to rats for 4 weeks, neither clinical signs of toxicity nor histopathologic changes were observed. At the No Observed Adverse Effect Level (NOAEL) doses, the plasma levels ranged from 2600- to 8200- fold higher than the highest plasma levels observed in humans (1.3 ng/mL) following dosing as per the Product Monograph. Dogs that received 50 mg/kg/day demonstrated salivation and emesis, but no histopathologic changes were observed. The NOAEL was estimated to be 5 mg/kg in the dog and this was associated with a plasma level which was approximately 800-fold higher than the highest plasma levels observed in humans (1.3 ng/mL) following dosing as per the Product Monograph.
Genotoxicity
Besifloxacin was mutagenic in some bacterial strains and clastogenic in Chinese hamster ovary cells. It was also positive in a mouse micronucleus assay in vivo but did not induce unscheduled deoxyribonucleic acid (DNA) synthesis in rat hepatocytes. The positive effects were only seen at drug levels much higher than plasma levels of besifloxacin observed in humans following the recommended dosage regimen. The plasma concentration at the NOAEL for the mouse micronucleus assay was over 3000-fold higher than the highest plasma level observed for humans following the recommended dosage regimen, and over 15000-fold higher in the unscheduled DNA synthesis study in the rat. Due to the short-term use of this product and to the topical application which produced very low systemic exposure, the positive results observed in these studies should not prevent the marketing of this product.
Carcinogenicity
Long-term studies in animals to determine the carcinogenic potential of besifloxacin have not been conducted. Due to the short-term use of this product and to the topical application which produced very low systemic exposure, carcinogenic studies are not required.
Reproductive and Developmental Toxicity
When administered orally, besifloxacin did not reduce fertility in male or female rats at doses up to 500 mg/kg. It was not associated with foetal skeletal or visceral malformations when administered to pregnant rats at doses up to 1000 mg/kg/day, although it did cause maternal toxicity (including mortality) at this high dose. Both embryo-foetal development, as well as peri- and post-natal development studies demonstrated that besifloxacin is foetotoxic. It was associated with increased post-implantation loss, reduced foetal body weights (delayed ossification) and developmental delays in pups born to dams that received 1000 mg/kg/day. The NOAEL was 100 mg/kg/day for reproductive toxicity, and systemic exposure following this dose would be much greater (plasma level in rats was approximately 3900-fold higher than the highest plasma level in humans at 1.3 ng/mL) than the exposure that would occur in humans following the recommended ocular regimen.
Local Tolerance
Ocular toxicity studies using a 0.6% besifloxacin suspension with a similar formulation to Besivance™ were performed in rabbits (three studies: two of 2-weeks duration and one of 4-weeks duration) and in dogs (one study of 1-month duration). In contrast to the Product Monograph dosage recommendations (3 times per day) the frequency of administration in the animal studies was 4 times per day. The ocular studies demonstrated that besifloxacin in the same vehicle as Besivance™ was generally well-tolerated. Minor signs of ocular irritation [for example (e.g.), redness and conjunctival chemosis] were observed in rabbits but not in dogs. There were no drug-related histopathological findings in the eyes of either species.
The repeated ocular instillation of the vehicle for 1 year in the rabbit induced no signs of ocular (or systemic) toxicity.
Besifloxacin when applied topically to the skin of guinea pigs was not phototoxic and appeared to be devoid of allergenic or irritant potential in the presence and absence of light exposure.
Overall, the ocular tolerance studies demonstrated adequate local tolerance to the 0.6% besifloxacin ophthalmic suspension.
3.2.5 Conclusion
The non-clinical studies for this drug submission are considered suitable. Based on the results of the toxicology studies, Besivance™ appears reasonably safe for the proposed indication of bacterial conjunctivitis for the recommended dosage and duration of administration.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
The in vitro antibacterial profile of besifloxacin was evaluated in multiple studies. To evaluate the PK/PD relationship of the besifloxacin ophthalmic suspension, results from an ocular PK study in humans were used, along with the in vitro MIC90 values (the minimum concentration needed to inhibit 90% of pathogens) for the prevalent bacterial pathogens isolated from patients with bacterial conjunctivitis. The study demonstrated that topical administration of 0.6% besifloxacin ophthalmic suspension resulted in high therapeutic levels of besifloxacin in human tears, which remained above the MIC90 level for at least 24 hours.
The topical ophthalmic use of 0.6% besifloxacin has a low systemic absorption. Therefore, a thorough QT/QTc prolongation study which includes a positive control was not required. Due to low systemic exposure of besifloxacin, QT prolongation in patients is unlikely.
3.3.2 Pharmacokinetics
Absorption
Plasma concentrations of besifloxacin were measured in adult patients with suspected bacterial conjunctivitis who received Besivance™ bilaterally three times a day (16 doses total). Following the first and last dose, variability in plasma concentrations of besifloxacin between patients was large, and the maximum plasma besifloxacin concentration in each patient was <1.3 ng/mL. The mean Cmax of besifloxacin was 0.37 ng/mL on Day 1 and 0.43 ng/mL on Day 6. The systemic exposure to besifloxacin was very low following topical ocular administration. Furthermore, the absorption of besifloxacin into the systemic circulation appears to be similar/comparable in healthy eyes and in eyes with clinical signs of bacterial conjunctivitis.
Distribution
Following a single administration (one drop) of Besivance™, the mean besifloxacin Cmax in tear samples was 610 µg /g and the estimated total systemic exposure (AUC 0-24h) was 1232 µg*h /g. The mean besifloxacin concentration observed in tear samples collected 24 hours after a single administration was 1.6 µg/g. In vitro, besifloxacin was approximately 39-44% bound to proteins in human plasma and was approximately evenly distributed between plasma and the cellular components of human blood. Tissue distribution of besifloxacin was not investigated in humans.
Metabolism
Results from the in vitro and in vivo metabolism studies demonstrated that the overall extent of besifloxacin metabolism was very low.
Excretion
Following repeated topical ocular administration to humans, besifloxacin was eliminated from the systemic circulation with an apparent half-life of 6.8 hours. Excretion of besifloxacin was not studied in humans.
Special Populations and Conditions
The pharmacokinetics of besifloxacin have not been studied specifically in special populations (e.g., paediatrics, geriatrics, gender, race, genetic polymorphism) or certain conditions (e.g., hepatic insufficiency, renal insufficiency).
Drug Interactions
No specific interaction studies have been performed. Due to the low systemic exposure of besifloxacin following topical administration, Besivance™ is not expected to elicit any systemic PK drug interactions.
3.3.3 Clinical Efficacy
The safety and efficacy of Besivance™ were primarily evaluated in two Phase III studies (Studies 433 and 434) and one Phase II study (Study 373). All three studies were multicentre, randomized, double-masked, parallel-group studies conducted in patients one year of age and older with bacterial conjunctivitis. Two of the studies (Studies 373 and 433) were vehicle-controlled and the other study (Study 434) used an active comparator (moxifloxacin hydrochloride ophthalmic solution 0.5%). Studies 373 and 433 were superiority studies evaluating the clinical and microbial efficacy of Besivance™ compared to its vehicle in the treatment of bacterial conjunctivitis. Study 434 was a non-inferiority study evaluating the clinical and microbial efficacy of Besivance™ compared to moxifloxacin in the treatment of bacterial conjunctivitis. The comparator used in the study is approved in Canada for the same indication as Besivance™. A total of 2377 patients were enrolled in the three studies; 1187 were treated with Besivance™, 614 were treated with the vehicle, and 576 were treated with the active comparator. All patients were treated with the assigned drug three times daily (TID) for five days.
The primary efficacy parameters were clinical resolution and microbiological eradication in the modified Intent-to-Treat (mITT) population at Visit 2. The mITT population included patients who were randomized to treatment and received at least one drop of study medication, and who had baseline cultures in at least one eye indicating bacteria levels at or above threshold for any accepted ocular species. Clinical resolution was defined as the absence of ocular discharge and bulbar conjunctival injection. Microbial eradication was defined as the absence of all accepted ocular bacterial species that were present at or above threshold at baseline.
In the three studies, the efficacy of Besivance™ was greater than its vehicle alone and comparable to the moxifloxacin ophthalmic solution on Days 4 to 6 (Days 3 to 5 in Study 373) in patients with conjunctivitis and positive conjunctival bacterial cultures. A higher clinical resolution rate was observed with Besivance™ compared to vehicle in Studies 433 and 373. In Study 433, the clinical resolution rate was 45.5% for the Besivance™ group versus 33% for the vehicle group; and in Study 373, the clinical resolution rate was 33.3% for the Besivance™ group compared to 17.2% for the vehicle group. Differences in clinical resolution between Besivance™ and moxifloxacin ophthalmic solution were not statistically significant. Microbiological outcomes demonstrated a statistically higher eradication rate for causative pathogens of 91.4% for the Besivance™ group versus 59.7% for the vehicle group in one study, and 90% for the Besivance™ group versus 46.6% for the vehicle group in another study (Studies 433 and 373, respectively). Microbiological outcomes demonstrated a comparable eradication rate for causative pathogens of 94.5% for the Besivance™ group versus 89.9% for the moxifloxacin group. Note that microbiologic eradication does not always correlate with clinical outcome in anti-infective trials.
Based on the review of the data, the following pathogens were considered to have been studied in sufficient quantity and have shown adequate eradication success rates to be included in the labelling:
- Aerobic, Gram-Positive: CDC coryneform group G, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus mitis, Streptococcus oralis, Streptococcus pneumoniae
- Aerobic, Gram-Negative: Haemophilus influenzae.
The safety and effectiveness of Besivance™ in infants below one year of age have not been established. The efficacy of Besivance™ in treating bacterial conjunctivitis in paediatric patients one year or older has been demonstratedin controlled clinical trials.
3.3.4 Clinical Safety
The safety data was combined from the three safety and efficacy studies described in 3.3.3 Clinical Efficacy. A total of 2377 patients were enrolled in the three safety and efficacy trials: 1187 were treated with Besivance™, 614 were treated with the vehicle, and 576 were treated with the active comparator. Besivance™ was administered three-times a day for five days. The population treated with Besivance™ was between 1 and 98 years old with clinical signs and symptoms of bacterial conjunctivitis.
The safety data did not identify any major safety concerns related to the topical ophthalmic use of Besivance™ in the five-day, three times a day treatment of patients one year of age and older with bacterial conjunctivitis.
No serious adverse reactions related to Besivance™ were reported. Overall, 75/1187 (6.3%) of the patients treated with Besivance™ had a treatment-emergent non-ocular adverse event (AE). Similarly, 139/1187 (11.7%) of the study eyes treated with Besivance™ had a treatment-emergent ocular AE. Of the patients who were treated with Besivance™, 15/1187 (1.3%) of the patients discontinued treatment due to an AE.
The most frequently reported treatment-emergent AEs in the study eye were blurred vision (2.1%), eye pain (1.9%), eye irritation (1.4%), conjunctivitis (1.2%), eye pruritus (1.1%), and bacterial conjunctivitis (0.6%). The most frequently reported non-ocular AE was headache (1.8%).
The most frequently reported treatment-related ocular AEs (possibly, probably or definitely related) in the study eye were blurred vision (1.9%), eye irritation (1.3%), and eye pain (1.2%).
Given the minimal systemic absorption, adverse systemic effects and/or drug interactions are unlikely to occur under the recommended conditions of use.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
The active ingredient in Besivance™, besifloxacin hydrochloride, is a novel fluoroquinolone antibiotic and is a new chemical entity developed for ophthalmic use. There are no other formulations (intravenous or oral) for this antibiotic that are currently available on the Canadian market. Besivance™ is a topical ophthalmic suspension for the treatment of bacterial conjunctivitis.
The review of efficacy data resulted in the acceptance of the following organisms for the indication: Aerobic, Gram-Positive: CDC coryneform group G, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus mitis, Streptococcus oralis, Streptococcus pneumoniae, and Aerobic, Gram-Negative: Haemophilus influenzae. Besivance™ demonstrated both clinical resolution as well as microbiological eradication in patients one year of age and older with bacterial conjunctivitis caused by susceptible organisms. Based on the current clinical practice guidelines as well as the previously approved dosing regimen for similar products, the dosing regimen was changed to 7 days to ensure efficacy.
Besivance™ appears to have a low propensity for development of resistance. In vitro resistance to besifloxacin develops via multiple-step mutations, and generally occurs at a low frequency. Given that there is potential for the development of resistance to other currently available therapies and that alternate therapies should be available for treatment, Besivance™ has shown benefit.
The non-clinical safety studies did not reveal any specific risks associated with the use of Besivance™. There is minimal systemic absorption and therefore systemic exposure is minimal. The clinical studies revealed that the frequency and the intensity of the adverse drug reactions were low. The Product Monograph adequately describes the safe use of the product.
Overall, the benefit/risk profile of Besivance™ is favourable. Besivance™ provides both adult and paediatric (≥1 year of age) patients with a convenient and effective alternative topical ophthalmic treatment for bacterial conjunctivitis caused by the following organisms: CDC coryneform group G, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus mitis, Streptococcus oralis, Streptococcus pneumoniae, and Haemophilus influenzae.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Besivance™ is favourable for the indication stated above. The New Drug Submission (NDS) complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance (NOC) pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: BesivanceTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2007-09-27 |
| Submission filed: | 2008-11-03 |
| Screening | |
| Screening Acceptance Letter issued: | 2008-12-29 |
| Review | |
| Quality Evaluation complete: | 2009-10-21 |
| Clinical Evaluation complete: | 2009-10-23 |
| Labelling Review complete: | 2009-10-23 |
| Notice of Compliance issued by Director General: | 2009-10-23 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| BESIVANCE | 02336847 | BAUSCH & LOMB INC | BESIFLOXACIN (BESIFLOXACIN HYDROCHLORIDE) 0.6 % / W/V |