Summary Basis of Decision for Rosiver
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 Rosiver is located below.
Recent Activity for Rosiver
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 Rosiver
Updated:
The following table describes post-authorization activity for Rosiver, a product which contains the medicinal ingredient ivermectin. 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 02440342 - 1% w/w, ivermectin topical cream
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| Public Advisory | Not applicable | Updated2021-10-19 | Updated public advisory posted (Ivermectin not authorized to prevent or treat COVID-19; may cause serious health problems), containing important information for healthcare professionals about human and veterinary ivermectin. |
| Public Advisory | Not applicable | Posted2021-08-31 | Public advisory posted (Ivermectin not authorized to prevent or treat COVID-19; may cause serious health problems), containing important information for healthcare professionals about human and veterinary ivermectin. |
| NC # 235651 | 2020-01-30 | Issued NOL2020-05-05 | Submission filed as a Level II (90 day) Notifiable Change to update the Product Monograph (PM) with post-market adverse reactions. As a result of the NC, additions were made to the Warnings and Precautions section and Part III: Consumer Information of the PM. The submission was reviewed and considered acceptable, and an NOL was issued. |
| Health product advertising complaint | Not applicable | Date received:2019-09-10 | A health product advertising complaint was received regarding the direct-to-consumer advertising of unauthorized claims of Rosiver. No follow-up was required as material had already been modified/removed/discontinued. |
| NC # 226496 | 2019-04-04 | Issued NOL2019-08-27 | Submission filed as a Level II (90 day) Notifiable Change to update the Product Monograph (PM) with post-market adverse reactions. As a result of the NC, additions were made to the Adverse Reactions section and Part III: Consumer Information of the PM. The submission was reviewed and considered acceptable, and an NOL was issued. |
| Health product advertising complaint | Not applicable | Date received:2018-10-31 | A health product advertising complaint was received regarding the direct-to-consumer advertising of Rosiver. An explanatory letter was sent. |
| Drug product (DIN 02440342) market notification | Not applicable | Date of first sale:2015-05-25 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 172733 | 2014-05-06 | Issued NOC2015-04-22 | Notice of Compliance issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Rosiver
Date SBD issued: 2015-06-04
The following information relates to the new drug submission for Rosiver.
Ivermectin, 1% w/w, cream, topical
Drug Identification Number (DIN):
- 02440342
Galderma Canada Inc.
New Drug Submission Control Number: 172733
On April 22, 2015, Health Canada issued a Notice of Compliance to Galderma Canada Inc. for the drug product Rosiver.
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 Rosiver is favourable for the topical treatment of inflammatory lesions (papules and pustules) of rosacea in adults 18 years of age or older.
1 What was approved?
Rosiver, a topical rosacea therapy, was authorized for the treatment of inflammatory lesions (papules and pustules) of rosacea in adults 18 years of age or older.
In clinical studies, efficacy and safety in the elderly ≥65 were found to be comparable to those in adults less than 65 years of age.
Safety and effectiveness in pediatric patients have not been established.
Rosiver is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. Rosiver was approved for use under the conditions stated in the Rosiver Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Rosiver (ivermectin) Cream, 1%, is presented as a cream for topical application. In addition to the medicinal ingredient, the topical cream contains the following non-medicinal ingredients: carbomer copolymer type B, cetyl alcohol, citric acid monohydrate, dimeticone 20 Cst, disodium edetate, glycerol, isopropyl palmitate, macrogol cetostearyl ether, methyl parahydroxybenzoate, oleyl alcohol, phenoxyethanol, propyl parahydroxybenzoate, propylene glycol, purified water, sodium hydroxide, sorbitan stearate, and stearyl alcohol.
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 Rosiver Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Rosiver approved?
Health Canada considers that the benefit/risk profile of Rosiver is favourable for the topical treatment of inflammatory lesions (papules and pustules) of rosacea in adults 18 years of age or older.
Rosacea is a chronic, inflammatory skin condition which occurs in adults. It essentially involves the central region of the face, mainly the forehead, cheeks, chin, and lower part of the nose. Symptoms include redness of the skin (caused by dilated blood vessels), pimples, and in the advanced stages of the disease red bumps which may contain pus or cysts. Women are more commonly affected than men, but disease manifestations are frequently more severe in males than in females.
The cause of rosacea is poorly understood; it is thought to be multifactorial and involve abnormal vascular reactivity, immune system responses, and follicular microorganisms. First-line treatments for managing rosacea that are currently available in Canada include topical metronidazole, topical azelaic acid, and low-dose oral doxycycline.
The mechanism of action of Rosiver in treating inflammatory lesions of rosacea is not established, but may involve anti-inflammatory and/or antimicrobial properties of the medicinal ingredient.
Rosiver has been shown to effectively treat papules and pustules in patients with moderate to severe inflammatory rosacea. The market authorization was based primarily on two randomized, double-blind, vehicle-controlled Phase III studies. The pivotal studies enrolled a total of 1,371 patients and were identical in design. The co-primary efficacy endpoints in both studies were the Success Rate based on the 5-point Investigator Global Assessment (IGA) outcome (percentage of patients "clear" and "almost clear" at Week 12 of the study) and Absolute Change from Baseline in Inflammatory Lesion Counts. In both studies, results demonstrated that Rosiver applied once daily for 12 weeks was more effective than a vehicle cream in terms of IGA Success Rate and Absolute Change in Inflammatory Lesion Counts. Benefits were seen as early as 4 weeks and continued to be observed up to Week 52.
The safety data for Rosiver in the management of moderate to severe inflammatory rosacea demonstrated that Rosiver is safe and well-tolerated for both short- and long-term use in adult patients. In addition, the safety profile of Rosiver remained stable over conditions of long-term use for up to one year, with little evidence of application site irritation. Adverse reactions, reported in ≤1% of patients treated with Rosiver included skin burning sensation, skin irritation, pruritus, and dry skin.
A Risk Management Plan (RMP) was not provided for this New Drug Submission, and is not considered necessary at this time.
A Look-alike Sound-alike brand name assessment was performed and the proposed name has been deemed appropriate and acceptable.
The benefits of Rosiver therapy are considered to outweigh the risks. Rosiver has an acceptable safety profile based on the non-clinical data and clinical studies. Appropriate warnings and precautions are in place in the Rosiver Product Monograph to manage 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 Rosiver?
Submission Milestones: Rosiver
| Submission Milestone | Date |
|---|---|
| Submission filed: | 2014-05-06 |
| Screening | |
| Screening Acceptance Letter issued: | 2014-05-12 |
| Review | |
| Quality Evaluation complete: | 2015-04-21 |
| Clinical Evaluation complete: | 2015-04-21 |
| Labelling Review complete: | 2015-04-21 |
| Notice of Compliance issued by Director General: | 2015-04-22 |
The Canadian regulatory decision on the non-clinical and clinical review of Rosiver was based on a critical assessment of the Canadian data package. The foreign reviews completed by the European Union's centralized procedure European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as an added reference.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
4 What follow-up measures will the company take?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada and have been market notified (that is, the company has told Health Canada the product is being marketed).
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, 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
The clinical pharmacology development program for Rosiver (ivermectin) cream, 1%, included clinical pharmacokinetic studies, pharmacokinetic sampling in clinical efficacy and safety studies, and in vitro studies performed with human biomaterials that were considered pertinent to the clinical pharmacokinetic behaviour. The resulting clinical pharmacological data obtained from these studies support the use of Rosiver for the recommended indication. Approximately 2% of the applied dose of Rosiver was recovered in the skin. There was minimal systemic absorption. Plasma steady state was reached by day 14 (0.7 ng/mL), with no further plasma accumulation of ivermectin after 28 days of once daily topical treatment with Rosiver.
For further details, please refer to the Rosiver Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The sponsor conducted 15 clinical studies as part of its clinical development program. Of these, the efficacy of Rosiver for the treatment of rosacea in patients 18 years or older was evaluated primarily in two Phase III studies, namely RD.06.SRE.18170 and RD.06.SRE.18171 (herein referred to as Study 18170 and Study 18171, respectively). Both studies were randomized, vehicle-controlled studies and enrolled a total of 1,371 patients. In addition, both studies were identical in design, whereby patients 18 years and older were treated once daily with either Rosiver 1% cream or a vehicle cream.
Patients who were eligible for enrolment in either study were required to have moderate to severe rosacea based on the 5-point Investigator Global Assessment (IGA) scale at the Baseline visit. The IGA is a 5-grade global clinical assessment of rosacea that ranges from '0' = 'clear' to '4' = 'severe' which closely reflects the dermatologist's evaluation of disease severity in the clinical setting. The definitions for the IGA scale scoring and grades are as follows:
| Grade | Score | Clinical Description |
|---|---|---|
| Clear | 0 | No inflammatory lesions present, no erythema |
| Almost Clear | 1 | Very few small papules/pustules, very mild erythema present |
| Mild | 2 | Few small papules/pustules, mild erythema |
| Moderate | 3 | Several small or large papules/pustules, moderate erythema |
| Severe | 4 | Numerous small and/or large papules/pustules, severe erythema |
Eligible patients were required to have 15 to 70 inflammatory lesions on the face, (and no more than two nodules) to participate in either study.
Using the 5-point Investigator Global Assessment (IGA) scale, 79% of subjects were scored as moderate (IGA = 3) and 21% scored as severe (IGA = 4) at Baseline.
In both studies, the study design was divided into three phases, an initial 12-week, double-blind, randomized, vehicle-controlled parallel group phase (Part A), followed by an active-controlled, 40-week extension period (Part B), and then a 4-week treatment-free follow-up (Part C).
Part A used a 2:1 randomization ratio to maximize the exposure to Rosiver treatment.
In Part B, patients treated with Rosiver 1% cream once daily during the 12-week Part A phase continued with this treatment. Patients treated with the vehicle cream once daily during Part A were switched to a topical treatment regimen of azelaic acid 15% gel twice daily. The re-assignment of vehicle-treated patients to azelaic acid 15% gel twice daily was done to ensure the retention of patients in the study, thereby permitting long-term safety follow-up.
In both Phase III studies, the two co-primary endpoints were Success Rate and Change in Inflammatory Lesion Counts from Baseline. Success Rate was defined as the percentage of patients achieving an IGA score of 0 ("clear") or 1 ("almost clear").
The results from both Phase III clinical studies demonstrated that Rosiver applied once daily for 12 weeks was statistically more effective than the vehicle cream by satisfying both co-primary endpoints (Success Rate and Absolute Change in Inflammatory Lesion Counts).
In Study 18170, 173 out of 451 patients (38.4%) randomized to Rosiver achieved an IGA score of 0 ("clear") or 1 ("almost clear") compared to 27 out of 232 patients (11.6%) randomized to the vehicle treatment. The Mean Absolute Change in Inflammatory Lesion Count from Baseline to Week 12 was -20.5 (-64.9%) for patients in the Rosiver arm of the study compared to -12.0 (-41.6%) for patients treated with vehicle (p<0.001).
Similar results were also noted in Study 18171 where 184 out of 459 patients (40.1%) randomized to Rosiver achieved an IGA score of 0 ("clear") or 1 ("almost clear") compared to 43 out of 229 patients (18.8%) randomized to the vehicle treatment. The Mean Absolute Change in Inflammatory Lesion Count from Baseline to Week 12 was -22.2 (-65.7%) compared to -13.4 (-43.4%) for patients treated with vehicle (p<0.001).
Rosiver was more effective than vehicle cream on the co-primary efficacy endpoints starting from 4 weeks of treatment in both studies.
Confirmative Study
The efficacy of Rosiver was also evaluated in a randomized, investigator-blinded, active-controlled clinical confirmative study, namely RD.06.SRE.40173. In this study, a total of 962 patients, aged 18 years and older, were treated for 16 weeks with either Rosiver 1% cream once daily or metronidazole 7.5 mg/g cream twice daily.
In order to be eligible to participate in this study, patients were required to have moderate to severe rosacea on the 5-point IGA scale at the Baseline visit. Of those enrolled, 83% of patients were scored as moderate (IGA = 3) and 17% were scored as severe (IGA = 4) at Baseline.
The results of the study demonstrated that Rosiver was statistically significantly more effective than metronidazole 7.5 mg/g cream for the primary efficacy endpoint (Mean Percent Change in Inflammatory Lesion Counts) with a reduction of 83% and 74% from Baseline after 16 weeks of treatment for the Rosiver and metronidazole groups respectively.
For more information, refer to the Rosiver Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
A total of 15 clinical studies were performed as part of the clinical development program for Rosiver 1% cream: 10 of the 15 studies were conducted in patients with rosacea and 5 studies were conducted in healthy subjects. During clinical studies, a total of 3,999 patients were exposed to Rosiver: 3,546 patients with rosacea and 453 healthy subjects.
Pooled safety data from the two Phase III pivotal studies previously described in the Clinical Efficacy section, revealed that 589 treatment emergent adverse events (TEAEs) were reported in 350 of the 910 patients (38.5% of patients) treated with Rosiver in Part A of the studies, versus 38.0% for vehicle cream. Of the 589 TEAEs reported for Rosiver, 41 TEAEs in 31 patients (3.4% of patients) were considered by the clinical investigator to be related to the study drug (versus 7.2% of patients for vehicle cream). Nine related TEAEs in seven patients (0.8%) led to study discontinuation (versus 1.7% in the vehicle control group).
The most common related TEAEs reported in patients receiving Rosiver in the pivotal clinical studies were: skin burning sensation (9 patients, 1.0%), skin irritation (8 patients, 0.9%), pruritus (7 patients, 0.8%), and dry skin (5 patients, 0.5%).
Across the entire clinical development program there were 2 cases of suspected sensitization considered related to Rosiver (0.1%) and one case of moderate sunburn reaction (0.04%) also considered related to Rosiver.
No serious adverse events related to Rosiver were reported in any of the studies; no deaths were reported in any of the clinical studies.
Over the course of the clinical program, routine blood chemistry and hematology assessments, in addition to thorough investigations of neutrophil cell counts were performed. Values of neutrophil cell counts <1.5 g/L, whether considered clinically significant or not, were reported. Results from this assessment showed that the incidence of low neutrophil cell counts was comparable across all treatment groups, without any indication of a trend towards a higher incidence in Rosiver-treated patients.
For more information regarding clinical safety, refer to the Rosiver Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
The results of non-clinical program are considered adequate to support treatment with Rosiver 1% Cream once daily (QD) in humans for chronic use. Label statements in the Rosiver Product Monograph address the potential for delayed sensitization and photoallergenicity and the lack of information regarding mechanism of action and potential local interactions. In view of the intended use of Rosiver, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Rosiver 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 Rosiver 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 is acceptable, when the cream is maintained in its original container and stored between 15 to 30°C.
Proposed limits of drug-related impurities are considered adequately qualified [that is (i.e.) within International Conference on Harmonisation (ICH) limits and/or qualified from toxicological studies].
Both sites involved in production of Rosiver 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 manufacture of Rosiver are of human or animal origin.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| ROSIVER | 02440342 | GALDERMA CANADA INC. | IVERMECTIN 1 % / W/W |