Summary Basis of Decision for Vyzulta
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 Vyzulta is located below.
Recent Activity for Vyzulta
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 Vyzulta
Updated:
The following table describes post-authorization activity for Vyzulta, a product which contains the medicinal ingredient latanoprostene bunod. 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 and Applications Guidance.
Drug Identification Number (DIN):
- DIN 02484218 - 0.024% w/v latanoprostene bunod, solution, ophthalmic administration
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| Drug product (DIN 02484218) market notification | Not applicable | Date of first sale:2019-05-17 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 211732 | 2018-01-24 | Issued NOC2018-12-27 | NOC issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Vyzulta
Date SBD issued: 2019-04-08
The following information relates to the new drug submission for Vyzulta.
Latanoprostene bunod
Drug Identification Number (DIN):
- DIN 02484218 - 0.024% w/v, solution, ophthalmic administration
Bausch & Lomb Inc.orporated
New Drug Submission Control Number: 211732
On December 27, 2018, Health Canada issued a Notice of Compliance to Bausch & Lomb Incorporated for the drug product Vyzulta.
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 Vyzulta is favourable for the reduction of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.
1 What was approved?
Vyzulta is classified as a prostaglandin F2α analogue and an intraocular pressure lowering agent. Vyzulta was authorized for the reduction of intraocular pressure in patients with open-angle glaucoma or ocular hypertension.
Pediatric data for children ≤16 years of age were not available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.
Evidence from clinical studies and experience suggest that the safety and effectiveness of Vyzulta are comparable between elderly patients (≥65 years of age) and other adult patients.
Vyzulta is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
Vyzulta was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Vyzulta (latanoprostene bunod, 0.024% w/v solution) is presented as a ophthalmic solution. In addition to the medicinal ingredient, the solution contains benzalkonium chloride, citric acid, ethylenediaminetetraacetic acid (EDTA), glycerin, polysorbate 80, sodium citrate, and water.
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 Vyzulta Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Vyzulta approved?
Health Canada considers that the benefit-risk profile of Vyzulta is favourable for the reduction of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.
Glaucoma is a family of related diseases that is frequently associated with elevated IOP, leading to optic nerve neuropathy and loss of vision. Glaucoma is the second leading cause of blindness worldwide. Primary open-angle glaucoma affects approximately 13.5 million people over the age of 40 worldwide. Although there is currently no cure for glaucoma, evidence from several studies indicate that achieving low levels of IOP can reduce the progression of visual field deterioration in patients with glaucoma. In addition, results show that treating ocular hypertension patients with topical ocular hypotensive medications was effective in delaying or preventing the onset of primary open-angle glaucoma. In Canada, it is estimated that more than 400,000 individuals are affected by this disease.
Vyzulta, a prostaglandin F2α analogue, has been shown to be efficacious in patients with open-angle glaucoma or ocular hypertension. The market authorization was based on two Phase III, randomized, multicentre, double-masked, non-inferiority, pivotal clinical studies (Study 769 and Study 770). In both Phase III studies, non-inferiority of Vyzulta to timolol maleate 0.5% was established for the primary efficacy endpoint of mean IOP in the study eye measured at specified time points: 8 AM, 12 PM, and 4 PM at Week 2, Week 6, and Month 3. In each study, 420 patients were randomized in a 2:1 ratio to receive either Vyzulta or timolol. Both studies had a three-month masked efficacy period. The mean baseline IOP values were comparable between the two treatment groups and both treatment groups demonstrated IOP reductions at each of the nine post-baseline time points in each study. There was an IOP reduction of 7.5 to 9.0 mmHg in the Vyzulta treatment groups compared to 6.5 to 7.9 mmHg in the timolol treatment groups. In these studies, diurnal efficacy of Vyzulta was demonstrated in patients with open-angle glaucoma or ocular hypertension across a range of baseline IOPs. The amount of reduction in IOP was consistent across all relevant subpopulations including age, sex, race/ethnicity, and geographic region. In the pooled results of both Phase III studies, Vyzulta administered once daily led to greater reductions in mean IOP when compared to timolol maleate 0.5% administered twice daily at all evaluation time points (p <0.001 for all time points). A significant greater proportion of patients treated with Vyzulta compared to timolol maleate 0.5% attained a mean IOP ≤18 mmHg at all of the 9 evaluation time points during the first 3 months of treatment (20.2% vs. 11.2%, p = 0.001). In addition, the percentage of patients with IOP reduction ≥25% from baseline at all of the 9 evaluation time points during the first 3 months of treatment (32.9% vs. 19.0%, p = 0.001). Overall, the pivotal and non-pivotal studies provided substantial evidence of efficacy that is consistent with the currently marketed prostaglandin F2α analogues.
Overall, Vyzulta demonstrated a tolerable safety profile with no significant systemic and ocular effects. The safety profile of Vyzulta is similar to other marketed topical prostaglandin F2α analogues. In the pivotal Phase III studies, the most common ocular adverse reactions observed in patients treated with Vyzulta were conjunctival hyperemia (6%), eye irritation (5%), and eye pain (4%), and instillation site pain (2%). Labelling of risks typical for the prostaglandin F2α analogs such as iris and periorbital tissue pigmentation, eyelash changes, and macular edema are included in the Vyzulta Product Monograph.
A Risk Management Plan (RMP) for Vyzulta was submitted by Bausch & Lomb Incorporated 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.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Vyzulta Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
A Look-alike Sound-alike brand name assessment was performed and the proposed name Vyzulta was accepted.
Overall, the therapeutic benefits of Vyzulta therapy seen in the pivotal studies (Study 769 and Study 770) are positive and are considered to outweigh the potential risks. Vyzulta has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling, and adequate monitoring. Appropriate warnings and precautions are in place in the Vyzulta 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 Vyzulta?
Submission Milestones: Vyzulta
| Submission Milestone | Date |
|---|---|
| Submission filed: | 2018-01-24 |
| Screening | |
| Screening Deficiency Notice issued: | 2018-02-07 |
| Response filed: | 2018-02-13 |
| Screening Acceptance Letter issued: | 2018-03-08 |
| Review | |
| Review of Risk Management Plan complete: | 2018-06-15 |
| Biostatistics Evaluation complete: | 2018-06-28 |
| Quality Evaluation complete: | 2018-12-20 |
| Clinical/Medical Evaluation complete: | 2018-12-20 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2018-12-20 |
| Notice of Compliance issued by Director General, Therapeutic Products Directorate: | 2018-12-27 |
The Canadian regulatory decision on the quality, non-clinical and clinical review of Vyzulta was based on a critical assessment of the data package submitted to Health Canada.
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.
- 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, 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
Intraocular pressure is a major modifiable risk factor for glaucoma progression. Reduction of intraocular pressure reduces risk of glaucomatous visual field loss. The medicinal ingredient of Vyzulta, latanoprostene bunod (LBN), is thought to lower intraocular pressure by increasing outflow of aqueous humor through both uveoscleral and trabecular meshwork routes.
The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic (PK) studies.
The systemic exposure of LBN and its metabolites latanoprost acid and butanediol mononitrate were evaluated. There were no quantifiable plasma concentrations of LBN or butanediol mononitrate post ocular administration on Day 1 and Day 28. Latanoprost acid concentrations were quantifiable in the plasma samples of the majority of subjects, especially in the early time point (i.e., 5 minutes post dose). The mean maximal plasma concentrations of latanoprost acid were 59.1 pg/mL and 51.1 pg/mL on Day 1 and Day 28, respectively. The mean maximal plasma concentrations of latanoprost acid did not appear to change over time, suggesting little systemic accumulation of latanoprost acid following repeated once a day (QD) dosing in the study. The mean time of maximal plasma concentration for latanoprost acid was approximately 5 minutes post administration on both Day 1 and Day 28. The elimination of latanoprost acid from human plasma was rapid as the plasma concentration of latanoprost acid dropped below the lower limit of quantification (30.0 pg/mL) in most of the subjects by 15 minutes post ocular administration of LBN in humans. No ocular adverse events were reported and changes in vital signs and laboratory parameters were modest.
In another PK study, the sponsor used the change in percentage of systemic methemoglobin (%MetHb) as a surrogate to assess the systemic nitric oxide exposure indirectly. However, there were no significant changes from baseline in %MetHb for subjects treated with LBN on Day 1 and Day 7. Also, there was no significant change in %MetHb between the vehicle group and the LBN-treated group when directly compared, indicating that the systemic exposure of nitric oxide was likely to be limited and/or minimal following repeated QD dosing of LBN. The data was considered inadequate to support the hypothesis that butanediol mononitrate releases nitric oxide at a sufficient local concentration to relax the trabecular meshwork of the eye.
Overall, the results of the clinical pharmacology studies indicate that daily instillation of LBN is safe for adult populations.
The clinical pharmacological data support the use of Vyzulta for the specified indication.
For further details, please refer to the Vyzulta Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy of Vyzulta (latanoprostene bunod) was demonstrated in two Phase III randomized, multicentre, double-masked, non-inferiority, pivotal clinical studies (Study 769 and Study 770). Both studies included a 3-month, double-masked efficacy phase followed by an open-label safety extension phase (Study 769, 9 months; Study 770, 3 months).
The primary objective of the two studies was to demonstrate the non-inferiority of Vyzulta to timolol maleate 0.5% with respect to the reduction of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. Combining both studies (the Phase III Pool), the mean (standard deviation) diurnal IOP at baseline was 26.7 (2.43) mmHg in patients randomized to Vyzulta QD and 26.5 (2.35) mmHg in subjects randomized to timolol 0.5% twice a day (BID).
The primary efficacy endpoint was the IOP in the study eye measured at 8 AM, 12 PM, and 4 PM at Week 2, Week 6, and Month 3. Secondary efficacy endpoints included the proportion of patients with IOP ≤18 mmHg and the proportion of patients with IOP reduction ≥25% mmHg (at all 9 time points in the first 3 months). Another secondary endpoint was change in mean diurnal IOP from baseline to Month 3, 6, 9 and 12.
The two Phase III studies (Study 769 and Study 770) were performed in 91 sites. Although the patients were predominantly white, the clinical program assessed the efficacy of Vyzulta in patients across the globe and included Caucasian (white), Black/African-American and Asian subjects. Both studies had a three-month masked efficacy period and therefore safety and efficacy can be generalized across all races. The amount of reduction in IOP was consistent across all relevant subpopulations including age, sex, race/ethnicity, and geographic region. A total of 840 patients were randomized across the two studies (Vyzulta, number of patients [n] = 569; timolol crossover to Vyzulta, n = 271), of which 774 (Vyzulta, n = 523; timolol crossover to Vyzulta, n = 251) completed the efficacy phase, and 738 completed the safety extension phase.
The efficacy results demonstrated that Vyzulta was non-inferior to the active control timolol maleate ophthalmic solution 0.5% in the reduction of IOP. Both Phase III studies demonstrated effective IOP lowering with the use of Vyzulta. Diurnal efficacy of Vyzulta was demonstrated in patients with open-angle glaucoma or ocular hypertension across a range of baseline IOPs. The IOP-lowering effect of Vyzulta QD was up to 7 to 9 mmHg which is considered as clinically significant. The efficacy of Vyzulta, a prostaglandin F2α analogue, is consistent with the currently marketed prostaglandin F2α analogues.
In the Phase III Pool, a significantly greater proportion of Vyzulta-treated patients than timolol-treated patients achieved clinically meaningful endpoints of target IOP (18 mmHg or lower) and at least a 25% reduction from baseline.
Overall, the efficacy data provided in this submission establishes the efficacy of Vyzulta QD in the evening for the treatment of elevated IOP in patients with open-angle glaucoma or ocular hypertension.
Indication
The sponsor filed the New Drug Submission for Vyzulta with the following indication, which Health Canada subsequently approved:
- Vyzulta (latanoprostene bunod ophthalmic solution, 0.024%) is indicated for the reduction of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.
For more information, refer to the Vyzulta Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The clinical safety of Vyzulta was evaluated in three Phase I studies, four Phase II studies and three Phase III studies. The safety database was considered adequate with respect to size, duration of exposure, duration of treatment, patient demographics, and disease characteristics.
The safety profile of Vyzulta is similar to other marketed topical prostaglandin analogues. The most common ocular adverse events (AEs) reported were conjunctival/ocular hyperemia (10%) and eye irritation (5%).
In the two Phase III pivotal studies (Study 769 and Study 770), Vyzulta was evaluated in 811 patients for a duration of 12 months. The most common ocular adverse reactions observed in patients treated with Vyzulta were conjunctival hyperemia (6%), eye irritation (5%), and eye pain (4%), and instillation site pain (2%). Approximately 0.7% of patients discontinued therapy due to ocular adverse reactions including ocular hyperemia, conjunctival irritation, eye irritation, eye pain, conjunctival edema, conjunctivitis, vision blurred, punctate keratitis and foreign body sensation.
Changes in iris pigmentation, eyelid pigmentation, and eyelash growth were identified as adverse events of special interest in the Vyzulta clinical development program. This was assessed by evaluating AEs that occurred with the preferred terms of blepharal pigmentation, iris color change, eyelash thickening, growth of eyelashes, hyperpigmentation of eyelid, and iris hyperpigmentation including the evaluation of lids and iris color conducted during slit lamp examinations.
The proportion of patients with non-ocular treatment-emergent adverse events (TEAEs) was similar across all treatment groups. The only non-ocular TEAE that occurred in ≥2% of patients in any treatment group was nasopharyngitis.
There were two treatment-emergent deaths, unrelated to the study drug, during the Vyzulta clinical development program. Both patients had significant histories of cardiovascular disease prior to the initiation of the studies and both patients died of myocardial ischemia (one after exiting the study).
There were no notable differences between the treatment groups across all study visits for results of clinical laboratory evaluations, vital signs, best-corrected visual acuity, slit lamp examinations, ophthalmoscopy, and cup disc ratio.
Vyzulta was not studied in the pediatric population and pregnant and nursing women.
Overall, the safety data contained in this submission establishes the safety and tolerability of Vyzulta QD in the evening for the treatment of elevated IOP in patients with open-angle glaucoma or ocular hypertension.
Appropriate warnings and precautions are in place in the approved Vyzulta Product Monograph to address the identified safety concerns.
For more information, refer to the Vyzulta Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
The non-clinical pharmacology and toxicology studies support the use of latanoprostene bunod (LBN), the medicinal ingredient of Vyzulta, for the specified indication.
The sponsor claimed that LBN is hydrolyzed by esterases to two active moieties: a prostaglandin F2α (FP) receptor agonist, latanoprost acid; and butanediol mononitrate (BDMN). It was stated that BDMN is then further hydrolyzed to the active signalling molecule nitric oxide (NO) and 1, 4-butanediol; and NO has an additional intra-ocular pressure (IOP) lowering effect over the IOP lowering effect of several approved FP receptor agonists.
After review of the non-clinical pharmacology, it was determined that the proposed hypothesis that LBN released NO resulting in increased outflow facility to improve the IOP lowering effect over latanoprost was not demonstrated. The pharmacokinetic studies failed to demonstrate that LBN is metabolized to free BDMN which releases NO (active signaling molecule) at sufficient local concentrations to relax the trabecular meshwork of the eye, thereby further lowering IOP.
The sponsor conducted adequate toxicology studies with LBN. No signs of systemic toxicity were noted, and no target organs for toxicity were identified in either rabbits, non-human primates (NHP), or rats. In all of these studies, treatments with LBN, regardless of the study duration or route of administration, were well-tolerated providing large margins of safety relative to the maximum recommended human dose.
Based on the fast metabolism of LBN, the rapid clearance of its metabolites and the relatively large margins of safety in studies conducted in NHP by the intended route of dosing in humans, it can be concluded that LBN does not pose a significant risk in humans under the recommended clinical use.
Carcinogenicity studies conducted in mice and rats showed that LBN does not pose a mutagenic or carcinogenic risk under its proposed use.
In the embryofetal development studies, LBN was found to induce fetotoxicity, and external and skeletal malformations in rats. Taking into account that LBN was found to be fetotoxic, abortifacient, and teratogenic, and that no well-controlled non-clinical studies were conducted on blood-placenta, and lacteal transfer of LBN and/or studies on animal neonates and juveniles, it is recommended that LBN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Additionally, the active metabolites of LBN may pass into breast milk and LBN should therefore be used with caution in nursing women. The developmental and health benefits of breastfeeding should be considered, along with the mother's clinical need for LBN, and any potential adverse effects on the breastfed infant from LBN.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Vyzulta Product Monograph. In view of the intended use of Vyzulta, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Vyzulta Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
The Chemistry and Manufacturing information submitted for Vyzulta 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 36 months for the 5 mL fill format is acceptable when the unopened bottle is stored at refrigerated conditions (2ºC to 8ºC). Once the bottle is opened it may be stored at 2º to 25ºC for 8 weeks. During shipment, bottles may be maintained at temperatures up to 40°C for a period not exceeding 14 days.
Proposed limits of drug-related impurities are considered adequately qualified (i.e. within International Council for Harmonisation limits and/or qualified from toxicological studies).
All sites involved in production are compliant with Good Manufacturing Practices.
All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.
None of the excipients used in the formulation of Vyzulta is of human or animal origin.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| VYZULTA | 02484218 | BAUSCH & LOMB INC | LATANOPROSTENE BUNOD 0.024 % / W/V |