Summary Basis of Decision for Jublia

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:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Jublia is located below.

Recent Activity for Jublia

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 Jublia

Updated: 2023-04-24

The following table describes post-authorization activity for Jublia, a product which contains the medicinal ingredient efinaconazole 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 02413388 - 10% w/w efinaconazole, solution, topical administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
SNDS # 252452 2021-05-06 Issued NOC 2021-10-22 Submission filed as a Level I – Supplement for a new “Consumer Aid” insert for Jublia that contains an electronic platform for patients. The submission was reviewed and considered acceptable, and an NOC was issued.
NDS # 234867 2020-01-10 Issued NOC 2020-01-21 Submission filed to transfer ownership of the drug product from Valeant Canada LP to Bausch Health, Canada Inc. An NOC was issued.
SNDS # 232076 2019-09-30 Issued NOC 2019-12-06 Submission filed as a Level I – Supplement to update the labels by adding a positive warning statement with a supporting symbol, and update the PM. The changes were in response to an Advisement Letter issued by Health Canada, dated 2018-02-08, requesting the sponsor update the labels and change the bottle to differentiate from eye-drop bottles. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Dosage and Administration, and Dosage Forms, Composition and Packaging sections of the PM, and corresponding changes were made to Part III: Consumer Information. An NOC was issued.
Health product advertising complaint Not applicable

Date received:

2019-02-23		 A health product advertising complaint was received regarding the direct-to-consumer advertising of Jublia by the Canadian Health & Family, H&F Continuing Education Inc. A Compliance letter was sent to request correction of non-compliance. Material was modified/removed/discontinued.
Health product advertising complaint Not applicable

Date received:

2019-02-23		 A health product advertising complaint was received regarding the direct-to-consumer advertising of Jublia by Dr. Julia Carroll. A Compliance letter was sent to request correction of non-compliance. Material was modified/removed/discontinued.
Health product advertising complaint Not applicable

Date received:

2019-02-23		 A health product advertising complaint was received regarding the direct-to-consumer advertising of Jublia by the Canadian Nail Fungus Resource. A Compliance letter was sent to request correction of non-compliance. Material was modified/removed/discontinued.
Health product advertising complaint Not applicable

Date received:

2019-02-23		 A health product advertising complaint was received regarding the direct-to-consumer advertising of Jublia by Valeant Canada LP.  A Compliance letter was sent to request correction of non-compliance. Material was modified/removed/discontinued.
NC # 204442 2017-04-05 Issued NOL
2017-07-07		 Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update Part III of the PM and the Package Insert to add clarity to the application instructions for patients. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 203924 2017-03-20 Cancellation Letter Received
2017-04-05		 Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update Part III of the PM and the Package Insert to add clarity to the application instructions for patients. The sponsor cancelled the submission before it was reviewed, in order to refile with a revised version of the PM.
SNDS # 197566 2016-08-12 Issued NOC
2016-09-30		 Submission filed as a Level I - Supplement to update the carton label with the statement "new 33% more" to reflect the new package size of 8 mL. No changes were proposed to the PM. A label review was conducted and the submission was considered acceptable. An NOC was issued.
SNDS # 193616 2016-03-24 Issued NOC
2016-05-20		 Submission filed as a Level I - Supplement to introduce a new format containing 8 mL of solution with new inner and outer labels, and to update the labelling artwork to reflect an alternative drug product manufacturing site. No changes were proposed to the PM. A label review was conducted and the submission was considered acceptable. An NOC was issued.
SNDS # 190436 2015-12-14 Issued NOC
2016-02-16		 Submission filed as a Level I - Supplement to introduce a multiple pack container filled with 3 units (trio-pack) of the currently marketed format of efinaconazole. The trio-pack is within the current approved posology and treatment. There were no changes to the Product Monograph (PM). The overall benefits/risks remain favourable. The data were reviewed and considered acceptable, and a Notice of Compliance (NOC) was issued.
SNDS # 181802 2015-02-03 Issued NOC
2015-09-08		 Submission filed as a Level I – Supplement to add an alternate manufacturing site for the production of the efinaconazole drug substance. There were no changes to the drug product as a result. There were no changes to the approved drug substance specifications. The data were reviewed and considered acceptable, and a Notice of Compliance (NOC) was issued.
Drug product (DIN 02413388) market notification Not applicable Date of first sale:
2014-07-21		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 159416 2012-10-19 Issued NOC
2013-10-02		 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Jublia

Date SBD issued: 2013-12-05

The following information relates to the New Drug Submission for Jublia.

Efinaconazole, 10% w/w, solution, topical

Drug Identification Number (DIN):

  • 02413388

Valeant Canada LP

New Drug Submission Control Number: 159416

On October 2, 2013, Health Canada issued a Notice of Compliance to Valeant Canada LP for the drug product, Jublia.

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 Jublia is favourable for the topical treatment of mild to moderate onychomycosis (tinea unguium) of toenails without lunula involvement due to Trichophyton rubrum and Trichophyton mentagrophytes in immunocompetent adult patients.

1 What was approved?

 

Jublia a triazole antifungal agent, was authorized for the topical treatment of mild to moderate onychomycosis (tinea unguium) of toenails without lunula involvement due to Trichophyton rubrum and Trichophyton mentagrophytes in immunocompetent adult patients.

Jublia is contraindicated in patients with a known hypersensitivity to efinaconazole or to any of the excipients of Jublia or component of the container. Jublia was approved for use under the conditions stated in the Jublia Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Jublia (10% w/w efinaconazole) is presented as a solution for topical use. In addition to the medicinal ingredient, the solution also contains the following non-medicinal ingredients: alcohol, butylated hydroxytoluene, C12-15 alkyl lactate, citric acid, cyclomethicone, diisopropyl adipate, disodium edetate, and purified 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 Jublia Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Jublia approved?

 

Health Canada considers that the benefit/risk profile of Jublia is favourable for the topical treatment of mild to moderate onychomycosis (tinea unguium) of toenails without lunula involvement due to Trichophyton rubrum and Trichophyton mentagrophytes in immunocompetent adult patients.

Of the total number of subjects in clinical studies for Jublia, 8.3% were 65 years of age and over while none were 75 years of age and over. No overall differences in safety and effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. The safety and effectiveness of Jublia in pediatric patients under the age of 18 has not been established.

Onychomycosis is a chronic and recurring fungal infection of the fingernails and toenails that accounts for about half of all nail disorders; it is the most common nail disorder in adults. Onychomycosis of the toenail can result in permanent toenail deformity and has a significant impact on quality of life due to concerns with the appearance of the toenails and interference with wearing shoes, walking, and participating in various sports activities.

Currently available treatment of onychomycosis includes both systemic and topical medications.

Jublia demonstrated statistical superiority over Vehicle in the topical treatment of mild to moderate onychomycosis of toenails in immunocompetent adult patients. In addition, a benefit of Jublia is the simple overall nail management program which includes daily drug application and regular nail clipping by the patient. No debridement or comprehensive nail management program is required. The formulation characteristics allow for access to diseased areas including accessible toenail bed regions based on in vitro findings, although this was not definitively demonstrated in the clinical setting. Efficacy rates of topical treatment for onychomycosis are generally lower than that of currently available systemic medications and the treatment course is longer (6 to 12 months).

The safety profile of Jublia when applied topically to the toenails demonstrated that treatment-related events were predominantly application site reactions (non-serious) of mild to moderate severity. This safety profile differs from that of systemic antifungal agents used to treat onychomycosis which have a potential to be hepatotoxic and a potential to have drug-drug interactions with concomitant medication. Topical treatment reduces the likelihood of systemic side-effects and the requirement for laboratory monitoring.

Overall, the therapeutic benefits of Jublia therapy currently outweigh the potential risks.

Long-term efficacy and safety for longer than 48 weeks have not been established.

Health Canada reviewed the Look-alike Sound-alike Report submitted by the sponsor and accepted the proprietary name for the drug product.

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 Jublia?

 

Submission Milestones: Jublia

Submission Milestone Date
Submission filed: 2012-10-19
Screening  
Screening Acceptance Letter issued: 2012-12-06
Review  
Quality Evaluation complete: 2013-09-23
Clinical Evaluation complete: 2013-10-01
Labelling Review complete: 2013-09-24
Notice of Compliance issued by Director General: 2013-10-02

 

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.

 

5 What post-authorization activity has taken place for Jublia?

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.

The PAAT for Jublia is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

 

6 What other information is available about drugs?

 

Up to date information on drug products can be found at the following links:

 

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

 

Clinical Pharmacology

Efinaconazole is a triazole antifungal agent. Efinaconazole inhibits fungal lanosterol 14α-demethylase involved in ergosterol biosynthesis. The accumulation of 14α-methyl sterols and subsequent loss of ergosterol in the fungi cell wall may be responsible for the fungistatic and fungicidal activity of efinaconazole. Efinaconazole is shown in vitro to be substantially absorbed to keratin but keratin binding is weak. Efinaconazole's low keratin affinity is expected to result in increased availability of free drug to the nail infection site.

A number of well-designed clinical pharmacology studies were submitted to demonstrate the properties of efinaconazole topical solution. A decrease in ergosterol in fungi cell membranes upon incubation with efinaconazole was demonstrated in in vitro. Efinaconazole was adequately shown to be active against the isolates of microorganisms Trichophyton mentagrophytes and Trichophyton rubrum, both in vitro and in clinical studies for the treatment of toenail infections.

Pharmacokinetic studies indicated low systemic exposure to efinaconazole and the major metabolite H3 after maximal use, repeated topical application of Jublia 10% topical solution to healthy and diseased toenails (severe onychomycosis). Efinaconazole steady state mean plasma Cmax on Day 28 was 0.67 ng/mL and Cmax range was 0.1-1.5 ng/mL. There is in vitro evidence that efinaconazole permeates the nail plate after repeated topical application though clinical relevance in unknown. There is in vitro evidence that efinaconazole binds to keratin but keratin binding is weak. Efinaconazole's low keratin affinity is expected to result in increased availability of free drug to the nail infection site. Efinaconazole in vitro binding to human plasma proteins is high but because of low systemic levels, efinaconazole plasma protein binding is not expected to be clinically relevant.

No case of contact sensitization was reported in the clinical pharmacology studies.

A thorough QT study was not conducted, although an electrocardiography (ECG) data were collected during phase III studies. There is little potential to delay cardiac repolarization based on the low systemic drug exposure resulting from topical nail application, and non-clinical evaluations.

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

Clinical Efficacy

The evidence for efficacy and safety of Jublia (IDP-108) are supported principally by results from two pivotal Phase III clinical studies (DPSI-IDP-108-P3-01 and DPSI-IDP-108-P3-02). Both studies shared identical objectives, inclusion/exclusion criteria, study design, and analysis endpoints.

A total number of 870 subjects were enrolled in the DPSI-IDP-108-P3-01 study of which 618 patients received Jublia and 202 received the Vehicle. A total number of 785 subjects were enrolled in the DPSI-IDP-108-P3-02 study of which 580 received Jublia and 201 received the Vehicle.

Enrolled patients were immunocompetent adults with onychomycosis, defined as patients with 20% to 50% clinical involvement of the area of the target great toenail, without dermatophytomas or lunula (matrix) involvement. One application daily of Jublia or Vehicle was applied topically to the affected toenail(s) for a duration of 48 weeks.

The primary efficacy endpoint was Complete Cure rate at Week 52 (the four-week post-treatment follow-up visit). A Complete Cure was defined as 0% clinical involvement of the target toenail (toenail was totally clear) in addition to a negative potassium hydroxide (KOH) examination and a negative fungal culture of the target toenail sample.

The primary efficacy results, complete cure at week 52 (4-weeks after completion of therapy), were Jublia 18.8% and Vehicle 3.5% for the DPSI-IDP-108-P3-01 study and Jublia 15.2% and Vehicle 5.5% for DPSI-IDP-108-P3-02 study.

In these studies, the primary endpoint data demonstrated the statistical superiority of Jublia over Vehicle for the treatment of mild to moderate onychomycosis. Long-term outcomes were not assessed within these studies.

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

Clinical Safety

The clinical safety of Jublia was evaluated in the pivotal studies described in the Clinical Efficacy section.

The safety profile of Jublia when applied topically to the toenails demonstrated that treatment-related events were predominantly application site reactions (non-serious). 

In the phase III studies, 1,189 patients were exposed to Jublia applied topically to toenails once a day; 1,124 (94.5%) patients were exposed for 24 weeks and 757 (63.7%) patients were exposed for 48 weeks. The overall number of patients who reported treatment-emergent adverse events (AE) assessed by the Investigator to be at least possibly related to study medication was 6.1% versus (vs.) 3.5% for Jublia and Vehicle group respectively. The most common treatment-emergent AEs for Jublia, assessed by the Investigator as at least possibly related to treatment, included application site dermatitis 2.0% and application site vesicles 1.4%. None of the reported serious AEs (including two fatalities) were determined by the Investigator to be treatment related. Discontinuations occurred in 2.7% (32/1189) of the Jublia group and 0.2% (1/401) of the Vehicle group, and the most common adverse reaction associated with discontinuation was application site dermatitis in 1.1%. 

No major safety concerns were identified and overall, the drug is well tolerated. 

Overall, based on the results obtained from the clinical program, Jublia is effective, generally safe, and well-tolerated when applied once daily for up to 48 weeks in the treatment of mild to moderate onychomycosis of the toenail. 

Long term efficacy and safety have not been established.

Appropriate warnings and precautions are in place in the approved Jublia Product Monograph to address the safe use of the product.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

The effect of efinaconazole on core physiological systems (cardiovascular, respiratory and central nervous system) as well as gastrointestinal and urinary function have been investigated in animals and isolated cells and tissues. These results suggest that efinaconazole has limited potential for any adverse pharmacological effects. Only high parenteral doses or concentrations produced test article effects on these functions. The systemic exposure to efinaconazole with topical nail administration in clinical use is low as compared to the levels achieved in the parenteral animal, ex vivo, and in vitro studies. Therefore the results suggest that efinaconazole has no potential for adverse pharmacological effects with topical nail administration.

The non-clinical pharmacokinetics of efinaconazole was characterized in rats and dogs and included dermal, oral, subcutaneous and intravenous routes of administration. The systemic absorption of efinaconazole following dermal application is low. Efinaconazole is extensively metabolized. It is oxidatively metabolized, cleaved and conjugated to glucuronic acid. Efinaconazole was a potent competitive inhibitor of cytochrome P450 (CYP) 2C8, CYP2C9, CYP2C19 and CYP3A4. Topical efinaconazole administration for onychomycosis therapy has very low systemic exposure and therefore, potential for drug interactions due to CYP inhibition is not a concern.

Repeat-dose dermal toxicity has been performed in mini-pigs and mice. Efinaconazole was well-tolerated. The no observed adverse effect level (NOAEL) was established in mini-pigs by 30% strength which had an exposure of 208-folds for efinaconazole as compared to human exposure levels. Efinaconazole was not mutagenic or clastogenic in a standard battery of genotoxicity tests including an in vitro test for gene mutation in bacteria, an in vitro test with cytogenetic evaluation for chromosomal damage in mammalian cells [ lung fibroblast cells of Chinese hamsters (CHL/IU cells)] and an in vivo test for chromosomal damage in rodent hematopoetic cells (mouse micronucleus).

All genotoxicity studies have employed appropriate positive controls to validate the study models. In the micronucleus assay the highest dose of efinaconazole used was 500 mg/kg which gave systemic exposure which was 8,000-folds higher as compared to human exposure. The final to-be-marketed formulation of efinaconazole was not carcinogenic in mice with a lifetime of dermal exposure.

Efinaconazole was tested for developmental toxicity in pregnant rats and rabbits via subcutaneous administration. At maternally toxic doses, efinaconazole was embryofetal and neonatal lethal in rats but not teratogenic at ≥89 times the area under the curve (AUC) at the clinical maximal use dose. The rat pre/postnatal NOAEL was 22-times the AUC in onychomycosis patients.

In conclusion, the non-clinical studies of efinaconazole characterized its safety in different animal species with dermal, oral, subcutaneous and intravenous routes of administration. The choice of the animal models and route of administration are appropriate. There was no deficiency in methodologies that weaken the validity of the studies.

For more information, refer to the Jublia 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 Jublia 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 24 months when the efinaconazole solution is stored between 15oC and 30oC is acceptable.

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.

The excipients are not of animal origin, therefore there is no potential for bovine spongiform encephalopathy (BSE) / transmissible encephalopathy (TSE) impacts.

 

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