Summary Basis of Decision for Alrex ®
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:
Alrex®
Loteprednol etabonate, 0.2% w/v, Suspension, Ophthalmic
Bausch and Lomb, Inc.
Submission control no: 117199
Date issued: 2009-04-06
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):
- 02320924
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On December 23, 2008, Health Canada issued a Notice of Compliance to Bausch and Lomb, Inc. for the drug product, Alrex®.
Alrex® contains the medicinal ingredient loteprednol etabonate which is an anti-inflammatory corticosteroid.
Alrex® is indicated for temporary short-term relief of the signs and symptoms of seasonal allergic conjunctivitis. Corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor, arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2.
The market authorization was based on quality, non-clinical, and clinical information submitted. Two Phase III, randomized, double-masked, placebo-controlled, multicentre, parallel group studies assessed the safety and efficacy of Alrex® in the treatment of the signs and symptoms of seasonal allergic conjunctivitis. In both studies, Alrex® had an acceptable safety profile and was more effective than placebo in the reduction of signs and symptoms of seasonal allergic conjunctivitis as demonstrated by statistically significant differences in the primary efficacy parameters, itching and bulbar injection. The treatment effect in favour of Alrex®over placebo started two hours following dosing for the reduction of bulbar injection, and two to three days after for the reduction of itching.
Alrex® (0.2% w/v, loteprednol etabonate) is presented as an ophthalmic suspension. The recommended dose is one drop instilled into the affected eye(s) four times daily for up to 14 days. Dosing guidelines are available in the Product Monograph.
Alrex® is contraindicated for patients that have a suspected or confirmed infection of the eye: viral diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella; untreated ocular infection of the eye; mycobacterial infection of the eye and fungal diseases of ocular structures. Alrex® is also contraindicated for patients who show a hypersensitivity to this drug or any ingredient in the formulation or container, or to other corticosteroids. Alrex® should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Alrex® 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 Alrex® is favourable for temporary short-term relief of the signs and symptoms of seasonal allergic conjunctivitis.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Alrex® is favourable for temporary short-term relief of the signs and symptoms of seasonal allergic conjunctivitis.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Loteprednol etabonate, the medicinal ingredient of Alrex® is a synthetic corticosteroid with anti-inflammatory activity. Corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins which are thought to control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes.
Manufacturing Process and Process Controls
Loteprednol etabonate 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 loteprednol etabonate has been adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within ICH established limits and/or were qualified from batch analysis and therefore, are considered to be acceptable.
Control of Drug Substance
The drug substance specifications and analytical methods used for quality control of loteprednol etabonate are considered acceptable.
Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.
The drug substance packaging is considered acceptable.
Stability
Stability study results based on accelerated, long-term, and stress testing show that loteprednol etabonate is a stable compound when packaged as proposed over the proposed storage period.
3.1.2 Drug Product
Description and Composition
Alrex® is a white to off-white suspension containing 0.2% w/v loteprednol etabonate, a topical anti-inflammatory corticosteroid, for ophthalmic use. The suspension is supplied in a white low density polyethylene (LDPE) plastic bottle with a white controlled drop tip and a pink polypropylene cap in the following sizes:
- 2.5 mL in a 7.5 mL bottle;
- 5 mL in a 7.5 mL bottle;
- 10 mL in a 10 mL bottle.
The non-medicinal ingredients are: benzalkonium chloride, edetate disodium, glycerin, povidone, purified water and tyloxapol. Hydrochloric acid and/or sodium hydroxide may be added to adjust the pH to 5.4-5.5.
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 loteprednol etabonate with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process and formulation 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
Alrex® is tested to verify that its identity, appearance, re-suspendability, pH, osmolality, viscosity, particle size distribution, assay, sterility, and levels of related substances and particulate matter are within acceptance criteria. The test specifications and analytical methods are considered acceptable.
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 long-term and accelerated stability data submitted, the proposed 24-month shelf-life at 15°C - 25°C for Alrex® is considered acceptable when the product is stored upright in LDPE bottles with LDPE tips and polypropylene closures. Stability studies support an in-use period of 28 days when stored upright between 15°C - 25°C after first opening.
The compatibility of the drug product with the container closure system was demonstrated through the stability studies. The container closure system met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
All of the proposed manufacturing sites comply with the requirements of Division 2 of the Food and Drug Regulations. All sites are compliant with Good Manufacturing Practices (GMP).
3.1.4 Adventitious Agents Safety Evaluation
Not applicable. 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 Alrex® 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 Pharmacodynamics
Pharmacodynamic data from various animal models of inflammation have shown that loteprednol etabonate is a corticosteroid with lower or similar anti-inflammatory effects than that of the comparator agents evaluated. The studies were intended as proof-of-concept and were not designed to compare potency of loteprednol etabonate verses other anti-inflammatory drugs. Ocular administration of loteprednol etabonate decreased scar formation in corneal wound, and decreased the tensile strength of the resulting scar. The effect of loteprednol etabonate on the wound healing and scarring process was assessed in several in vivo and in vitro studies. Loteprednol etabonate delayed the skin wound healing process with subsequent minimization of scar formation and decreased skin weight. Studies on the potential for intraocular pressure (IOP) elevation in rabbits were of short duration and too low of a dose concentration to definitively conclude no effect on IOP. Results have shown that the metabolites PJ-91 and PJ-90 are devoid of corticosteroid activity.
3.2.2 Pharmacokinetics
Absorption
Pharmacokinetic data from in vivo and in vitro studies indicate that loteprednol etabonate is readily absorbed into ocular tissues, with low systemic exposure following topical ocular administration.
Distribution
In vitro studies demonstrated that loteprednol etabonate is highly protein bound to plasma proteins (95%) and distributes preferentially into the cellular components of blood. The metabolite PJ-91 was also bound to plasma proteins (73%) but less so as compared to loteprednol etabonate.
Ocular administration of radiolabelled loteprednol etabonate in rabbits demonstrated penetration to the ocular tissues. The highest level of loteprednol etabonate was found in the conjunctiva, followed in order by cornea and iris-ciliary body. Low levels were found in the aqueous humor. Loteprednol etabonate and its metabolites were not detectable in the blood.
Metabolism and Excretion
In biological systems, loteprednol etabonate is hydrolyzed to the inactive carboxylic acid PJ-91 which can be metabolized to the inactive PJ-90.
Following ocular administration of radiolabelled loteprednol etabonate in rabbits, loteprednol etabonate was metabolized to a significant degree in the cornea, as evidenced by increased metabolite levels in the cornea versus the active drug.
Intravenous administration data from rats suggest that loteprednol etabonate is extensively metabolized in the blood and is subsequently excreted in bile and urine. Although loteprednol etabonate is rapidly hydrolyzed in rat blood, systemic metabolism in humans likely occurs in the liver.
In vitro testing with rabbit, dog, and human plasma showed no evidence of rapid metabolism in the plasma preparations. In human liver homogenates, loteprednol etabonate was rapidly metabolized. The liver is an important site for the metabolism of loteprednol etabonate, and biliary excretion of the metabolites of loteprednol etabonate is a significant route of elimination.
3.2.3 Toxicology
Single-Dose Toxicity
Loteprednol etabonate has a low order of acute toxicity. The acute oral toxicity studies in rats and mice determined that the maximum tolerated dose (MTD) was 80,000 and 40,000 times the Alrex® clinical dose, respectively.
Repeat-Dose Toxicity
In sub-chronic 28-day toxicity studies in rats (oral administration) and rabbits (ocular administration), laboratory changes and liver hypertrophy suggestive of hepatic toxicity were seen at the higher doses, approximately 100 times the Alrex® clinical dose.
Chronic 6-month studies revealed smaller adrenal glands in rabbits exposed to 12 times the clinical dose of Alrex®. Corresponding microscopic changes (cortical atrophy) were recorded at 18 times the clinical dose of Alrex®.
Overall, ocular toxicity was quite moderate with modest IOP increases noted in the chronic studies. There were no major ocular complications (e.g., severe ocular infections, cataracts, large increases in IOP). Stromal corneal anomalies were noted in the 12-month dog study starting at week 26. The same study in dogs suggested that ocular toxicity was less marked in animals exposed to loteprednol etabonate 0.1% and 0.5% compared to those exposed to dexamethasone 0.1%.
Genotoxicity
Loteprednol etabonate showed no evidence of mutagenic potential in the Ames test, the mouse lymphoma assay, the chromosome aberration test, or in the mouse micronucleus test.
Carcinogenicity
No caricinogenicity studies were included in the drug submission. A waiver was granted based mainly on the very low or clinically insignificant systemic exposure from the ocular topical use of Alrex®. The genotoxicity data revealed no evidence of mutagenic potential.
Reproductive and Developmental Toxicity
As expected from a corticosteroid, there was substantial toxicity on the reproductive function of the dams and on the embryo-fetal development (including teratogenicity). Malformations such as meningocele, cleft palate, incomplete digestive tract, vascular malformations, and growth retardation were related to loteprednol etabonate. Toxicity was suggested at relatively low doses (approx. 10 times the Alrex® clinical dose).
Local Tolerance
There was no evidence that loteprednol etabonate 0.5% cream was able to induce significant delayed contact hypersensitivity. No significant ocular irritation was detected in the eye irritation studies.
3.2.4 Conclusion
The non-clinical pharmacology and toxicology data submitted by the sponsor was adequate to cover all areas relevant to the indication and the therapeutic class of Alrex®. Overall, the nature and severity of the toxic effects were those expected from a corticosteroid.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
The pharmacodynamic data consisted of conjunctival provocation tests (acute allergic conjunctivitis model) which showed that loteprednol etabonate was able to reduce allergic symptoms but the results were inconsistent, and did not allow the precise characterization of the effect of loteprednol etabonate (duration of effect, clear dose response). Nonetheless, the data showed that the effect was most marked after 14 days of treatment, and allowed the sponsor to select the 0.2% concentration for use in the pivotal clinical trials for its best risk/benefit profile.
3.3.2 Pharmacokinetics
In humans, the potential for systemic exposure of loteprednol etabonate following ocular administration is considered minimal.
The clinical pharmacology data showed that loteprednol etabonate and its metabolites were undetectable in the blood and that cortisol levels were not significantly reduced during ocular treatment with loteprednol etabonate 0.5% for 42 days. This suggests that the systemic absorption and impact of loteprednol etabonate administered by ocular route is of no or little clinical significance.
3.3.3 Clinical Efficacy
Two Phase III, multicentre, randomized, double-masked, placebo-controlled studies (LE-143 and LE-144) assessed the efficacy of Alrex® (loteprednol etabonate 0.2% ophthalmic suspension) administered four times daily (q.i.d). The design and conduct of the studies were acceptable, and there were no concerns related to statistical analysis. The studies enrolled 268 allergic patients with moderate to severe signs/symptoms of seasonal allergic conjunctivitis (SAC). Among the enrolled patients, 133 were exposed to Alrex® for 42 days, while the primary efficacy endpoint was assessed on Day 14. Both studies were large and adequately powered, and the selected study samples reflect the target population. The clinical efficacy outcome measures were adequate and adhered to the relevant guidelines.
The primary efficacy variables were bulbar conjunctival injection (BCI) and ocular itching (overall mean change from baseline over the first two weeks), as well as the cure rate. The secondary efficacy outcome was the Investigator's Global Assessment which was based on the evaluation of the control of signs/symptoms as per the ophthalmic examination findings and patient diary entries from all previous visits. The supportive efficacy variables measures included, tearing, discharge, chemosis, erythema, conjunctival injection, discomfort, foreign body sensation, burning/stinging sensation, and photophobia.
The treatment effect started two hours following dosing for the reduction of BCI, and two to three days after dosing for the reduction of itching. The reductions of BCI and itching, in the Alrex® groups were statistically significant. In study LE-143, the treatment effect in favour of Alrex (i.e., the difference between Alrex® and placebo in score change) over two weeks was -0.54 and -0.62 for BCI and itching, respectively. In study LE-144, these results were -0.52 and -0.40, respectively. The differences in reduction of score were modest, but were clinically significant when interpreted in the context of the cure. For example, in one of the pivotal studies at the end of week 2, the cure rate of bulbar injection in the Alrex® group was 3.4 times higher than that found in control patients (31% versus 9%); while the cure rate of itching was 1.4 times higher in the Alrex® group (54% versus 38%). The cure rates provide a better and clear-cut criterion for interpreting clinical significance. Also, all patients in the studies had at least moderate BCI (Grade-2 on a 4-step scale, from 0 to 3), and severe itching (Grade-4 on a 5-step scale, from 0 to 5). As a result, a cure would be equivalent to a 100% reduction in signs, with a 2 to 3 point decrease in itching and a 4-point decrease in BCI. The cure rates were noticeably higher in the Alrex® group compared to the placebo group. This is clinically significant, and is probably of significance for the patient at the individual level.
Secondary outcome parameters supported the primary results. Possible confounding was generally accounted for, and subgroup analyses were thoroughly performed and did not detect any clinically relevant interaction. Both pivotal studies confirmed the efficacy of Alrex 0.2% in treating the signs and symptoms of SAC.
3.3.4 Clinical Safety
The clinical safety of Alrex® (loteprednol etabonate 0.2%) was assessed from the two pivotal studies (LE-143 and LE-144, described in 3.3.3 Clinical Efficacy) along with 17 other clinical studies. Together, this data provided adequate information for the safety and risk assessment of Alrex®. In the nineteen studies ranging from 1-42 days in length, 1,209 patients received various concentrations of loteprednol etabonate in topical ocular drops. There were approximately 900 participants with various eye conditions who were exposed to loteprednol etabonate ≥0.2% for 14-42 days. In the two pivotal studies, 133 patients with SAC were exposed to loteprednol etabonate 0.2%.
Safety results from the studies with a 42-day follow-up showed no particular safety issues, as most adverse events were mild and not serious. The most frequent non-ocular event reported related to therapy was headache (1.2%, 15/1215). None of the ocular events reported were unexpected for an ocular corticosteroid. The most frequent ocular event related to therapy was increased IOP: 6% (77/1215) in patients that received loteprednol etabonate, compared to 3% (25/806) for those that received placebo.
In each pivotal study, there were more patients with IOP increases of 6 to 9 mmHg in the Alrex® group compared to the placebo group. In pivotal study LE-143, among the patients with IOP increases of 6 to 9 mmHg, four patients reached an IOP value of 22 to 23 mmHg, and one patient reached 29 mmHg and was discontinued. All five patients were treated with Alrex®. In both pivotal studies, no drug-related visual acuity impairment, incidence of cataract formation, or incidence of viral or fungal infection were reported. Very few patients (2 treated with Alrex® and 3 treated with placebo) were discontinued for adverse reactions directly related to treatment.
The post-marketing safety data showed nothing unexpected regarding the safety of Alrex® during eight years of use in an estimated 9 million patients. The number of significant adverse reactions was extremely low (four cases), and none of the adverse events were unexpected for this therapeutic class. These adverse reactions were IOP elevation with glaucoma, corneal perforation/anomalies, and one case of mild cataract development. The sponsor did not report any safety issues or any actions by foreign regulatory agencies.
In summary, the data from the clinical studies (especially the pivotal studies) do not suggest any particular safety issue. The safety profile is clearly favourable considering Alrex® is an ocular corticosteroid.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Alrex® (loteprednol etabonate 0.2%) was shown to be efficacious in the reduction of the symptoms and signs of SAC (itching and BCI). The results were robust and reproducible as was demonstrated in two adequately designed and conducted multicentre, randomized, parallel, double-masked, placebo controlled studies. The primary outcome measures were significantly better in patients treated with Alrex® as compared to placebo. The cure rates, the patient diary entries, and the Investigator's Global Assessment also supported the primary efficacy findings, and the clinical relevance of the effect of Alrex®.
Possible complications of ocular corticosteroids include secondary ocular infections, IOP elevation (and its consequences), cataracts, and delayed wound healing. The safety results from the two pivotal studies showed no particular safety issues, as most adverse events were mild and not serious, and none of the ocular events were unexpected. There were very few patients who discontinued due to adverse reactions. There were virtually no cases of large increases in IOP (≥10 mmHg) or decreases in visual acuity, and no cases of cataract development were reported. The data did show, however, that moderate increases in IOP of 6 to 9 mmHg occurred more often in patients treated with Alrex® compared to those treated with placebo.
Overall, the data submitted in this submission by the sponsor supports a favourable benefit/risk profile for Alrex® for the indication of temporary short-term relief of the signs and symptoms of seasonal allergic conjunctivitis.
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 Alrex® is favourable for temporary short-term relief of the signs and symptoms of seasonal allergic conjunctivitis. The 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.
4 Submission Milestones
Submission Milestones: Alrex®
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2007-05-23 |
| Submission filed: | 2007-10-03 |
| Screening | |
| Screening Deficiency Notice issued: | 2007-11-19 |
| Response filed: | 2008-01-04 |
| Screening Acceptance Letter issued: | 2008-02-08 |
| Review | |
| Quality Evaluation complete: | 2008-12-15 |
| Clinical Evaluation complete: | 2008-12-04 |
| Labelling Review complete: | 2008-12-18 |
| NOC issued by Director General: | 2008-12-23 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| ALREX | 02320924 | BAUSCH & LOMB INC | LOTEPREDNOL ETABONATE 0.2 % / W/V |