Summary Basis of Decision for Finacea ®
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:
Finacea®
Azelaic acid, 15%, Gel, Topical
Berlex Canada Inc.
Submission control no: 092975
Date issued: 2006-03-24
Health Products and Food Branch
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Health Canada
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Health Products and Food Branch
Également disponible en français sous le titre : Sommaire des motifs de décision (SMD), FINACEAMD, Acide azélaïque, 15 %, Gel topique, Berlex Canada Inc. , No de contrôle de la présentation 092975
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):
- 02270811
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On September 2, 2005, Health Canada issued a Notice of Compliance to Berlex Canada Inc. for the drug product Finacea. Finacea contains the medicinal ingredient azelaic acid which is an anti-rosacea agent.
Finacea is indicated for the topical treatment of inflammatory papules and pustules, and erythema of mild to moderate rosacea. Rosacea is a chronic disease that affects the skin and sometimes eyes. The disorder is characterized by redness, pimples, and, in advanced stages, thickened skin. Rosacea usually affects the face; other parts of the upper body are only rarely involved. The mechanisms by which azelaic acid interferes with the pathogenic events in rosacea are unknown, but appear to include an anti-inflammatory effect.
The market authorization was based on data from quality control studies (drug substance and drug product), as well as data from pre-clinical and clinical studies. Two identical Phase III multi-centre, double-blind, randomized, placebo-controlled, parallel-group studies were submitted to assess the efficacy and safety of Finacea in 333 patients with mild to moderate forms of papulopustular rosacea. One Phase III active-controlled non-pivotal study was also submitted. Drug-related side effects were limited to cutaneous reactions of mild to moderate intensity and included stinging and tingling, burning, pruritus, and dry skin. Pre-clinical sensitization studies found both cream and gel formulations up to 20% azelaic acid to be well tolerated on the skin. The data submitted demonstrate that Finacea can be administered safely and effectively when used under the conditions stated in the Product Monograph.
Finacea (15% azelaic acid) is presented as a topical gel. A thin layer of Finacea should be applied twice daily to the entire affected area and gently massaged into the skin. The use of occlusive dressings or wrappings should be avoided. The duration of use of Finacea can vary from person to person and depends on the severity of rosacea. Detailed dosing guidelines are available in the Product Monograph.
Finacea is contraindicated in individuals with a history of hypersensitivity to azelaic acid, propylene glycol, or to any other component of the formulation. For a complete listing, see the Dosage Forms, Composition and Packaging section of the Product Monograph. Detailed conditions for the use of Finacea are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Finacea is favourable for the topical treatment of inflammatory papules and pustules and erythema of mild to moderate rosacea.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance ( Medicinal Ingredient )
Manufacturing Process and Process Controls
Azelaic acid 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 ICH requirements.
- The processing steps have been evaluated and the appropriate ranges for process parameters have been established.
Characterisation
Azelaic acid is a white, crystalline powder. The structure of azelaic acid has been adequately explained and the representative spectra have been provided. Physical and chemical properties have been described and found to be satisfactory.
The sponsor has provided a summary of all drug-related impurities. Impurities arising from manufacturing were reported and characterized. These products were found to be within ICH established limits, and therefore considered to be acceptable.
Control of Drug Substance
Validation reports were satisfactorily submitted for all analytical procedures used for in-process and release testing of the drug substance, and to justify the specification of the drug substance.
Data from batch analyses were reviewed and considered to be acceptable according to the specification of the drug substance.
Stability
Based upon the real-time and accelerated stability study data submitted, the proposed shelf-life, storage and shipping conditions for the drug substance were supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Finacea is manufactured in one strength, 15% azelaic acid. The drug product is a hydrogel containing polyacrylate as the main gelling agent. It is available in tubes of 5g, 30g, and 50g. Each tube is made of aluminium, with a membrane closure, an internal epoxide resin coating, a white exterior, and a screw cap made of high-density polyethylene (HDPE).
All excipients found in the drug product are acceptable for use in drugs by the Canadian Food and Drug Regulations. The compatibility of azelaic acid with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Pharmaceutical developmental data, including pH and microbiological attributes, were considered acceptable. Studies which justified the type and proposed concentration of preservative/excipient to be used in the drug product were reviewed and these verified that no potential toxicological or immunological effects can be expected.
Manufacturing Process and Process Controls
The manufacturing process for Finacea includes formulation, mixing, filling, and labelling.
All equipment, operating parameters, in-process tests and detailed instructions are adequately defined in the documentation. The manufacturing process is considered to be adequately controlled within justified limits.
Control of Drug Product
Finacea is tested to verify its identity, appearance, pH, micropenetration, particle size, content uniformity, and the presence of degradation products and microbiological impurities. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits, for individual and total degradation products are within acceptable limits.
The validation process is considered to be complete. Validation reports were submitted for in-process and release testing of the drug product, and no anomalies were present. The results for all of the batches were within the proposed specification limits.
Stability
Stability data show that aluminium tubes with HDPE screw caps are acceptable container/closure systems for the finished product.
Based upon real-time and accelerated stability study data submitted, the proposed 24 month shelf-life at 15-30oC for the drug product is considered to be acceptable.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facilities and the equipment are considered suitable for the activities and products manufactured. All of the proposed manufacturing sites comply with the requirements of Division 2 of the Food and Drug Regulations.
3.1.4 Adventitious Agents Safety Evaluation
N/A
3.1.5 Summary and Conclusion
The Chemistry and Manufacturing information submitted for Finacea has demonstrated that the drug substance and drug product can be consistently manufactured to meet the specifications agreed upon. Proper development and validation studies were conducted, and adequate controls are in place for the commercial process.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
Azelaic acid was evaluated for its antimicrobial effects in aerobic and anaerobic bacteria, yeasts and fungi. Studies were also conducted in rabbits to assess the in vivo comedolytic effect of azelaic acid and in hamsters to evaluate the impact of azelaic acid on the sebaceous gland and lipid metabolism. Pharmacodynamic effects seen included:
- bacteristatic and bactericidal activities against a number of aerobic and anaerobic organisms including Propionibacterium acnes and Staphylococcus aureus
- significant reduction of follicular epithelial hyperplasia after daily application of 20% solution or cream for 11 days
- a transient increase in plasma lactate concentration with a corresponding decrease in the amount of free fatty acid concentration after a single intravenous (IV) dose
- slightly delayed glucose tolerance after 6 consecutive days of IV dosing, but no effects on liver function, plasma concentrations of lactate, pyruvate and glucose, and serum concentrations of urea and creatinine
- sporadic mydriasis (prolonged dilation of the pupil) and slightly reduced locomotor activity after single IV administration
No changes on tissue lipid profiles, total serum cholesterol, triglycerides, fatty acids of the sebaceous glad, or weight of the flank organ were seen after 4 months of daily applications. No treatment-related effects were observed after 11 consecutive days of treatment with a 20% solution of the first β-oxidation metabolite of azelaic acid.
3.2.2 Pharmacokinetics
Oral and IV pharmacokinetic studies were conducted in rats, rabbits, dogs, and monkeys to determine the absorption and systemic bioavailability of azelaic acid. Results showed that azelaic acid was almost completely absorbed and rapidly distributed in the body. Radioactivity appeared primarily in the kidney, and to a lesser extent in the liver. Trace amounts appeared to cross the blood/brain barrier, however no radioactive material was detected in the fetus of pregnant animals except in trace amounts at very high doses. No preferential accumulation of azelaic acid occurred in melanocytes of pigmented animals. Excretion occurred rapidly (within 24 hours) via the urine, with a slower elimination through respiration and only trace amounts recovered in the feces.
Percutaneous studies with mouse skin, rats, and dogs were also conducted. In vitro, the gel formulation was found to be capable of delivering a higher dose of the drug substance on the surface of the skin as compared to a 20% azelaic acid cream formulation. However, the gel formulation had a lower perfusion rate indicating a lower potential of systemic burden. In vivo studies showed low levels of absorption for both cream and gel formulations which increased with increasing dosage for the cream, but decreased with increasing dosage for the gel. The average daily percutaneous flux was 2-4 times greater with the 20% cream than the 15% gel.
3.2.3 Toxicology
Acute Studies
Acute studies with azelaic acid were conducted in mice, rats, and dogs. Single oral doses of microcrystalline suspensions vs. intraperitoneal (IP) administration in mice revealed a lower minimum lethal dose for IP administration. Minimum lethal oral doses occurred at very high concentrations of azelaic acid. Single IP administration of microcrystalline suspensions of azelaic acid vs. sodium azelainate in rats indicated that sodium azelainate was much less toxic than the microcrystalline suspension. The main clinical signs in both rodent species were apathy, disturbances in gait, prone position (conscious), eyelid closure, extended abdomen, ruffled fur, accelerated respiration, unconsciousness, and tremors. In dogs, oral dosing by capsule resulted in emesis (vomiting) at doses
250 mg/kg and higher and, therefore, the minimum lethal dose could not be determined.
Subchronic Studies
No direct compound-related signs of toxicity were observed after repeated oral administration of a microcrystalline suspension of azelaic acid to rats at 1500 mg/kg for 4 weeks or after doses of 100 mg/kg and 1000 mg/kg/day for 6 months. Administration of 250 mg/kg/day for 4 weeks to monkeys also did not result in any compound-related toxicity. Clinical effects included decreased serum fatty acids, apathy, decreased food intake and body weight, unconsciousness, and tremors. Necropsy also revealed overdistension of the stomach, hemorrhage of glandular gastric mucosa, obstructive atelectasis of the lungs, and aspiration pneumonia. All results were independent of gender. It should also be noted that concentrations used in these studies are very high compared with the azelaic acid concentration used in the marketed product.
Reproductive and Developmental Studies
Daily intragastric administration of microcrystalline suspensions of azelaic acid during spermatogenesis and mating did not affect the fertility and reproductive performance of the female and male rats, respectively. No effects were seen in F1 offspring. Oral dosing did not result in teratogenic effects in rats, rabbits, or monkeys up to 500 mg/kg/day, however embryolethal effects were observed at 2500 mg/kg/day in rats, 150 mg/kg/day in rabbits, and 500 mg/kg/day in monkeys. Dose levels which produced parental toxicity had a slight effect on the postnatal development of the F1 generation. The viability index was also slightly reduced in the F1 generation and a slight retardation of the ossification process was observed in the F2 generation.
Gentoxicity Studies
In vitro mutagenic studies, carried out in bacterial cells and in somatic mammalian cells, revealed that azelaic acid was not a gene mutagen in the presence or absence of an extrinsic metabolizing system. In vitro clastogenic and chromosome aberration studies, performed with human lymphocytes, and the in vivo mouse model, using the dominant lethal assay or micronucleus assay, revealed no effects by azelaic acid in the presence or absence of an extrinsic metabolizing system.
Local Tolerance Studies
Azelaic acid was not found to be a contact sensitizer in a maximization test conducted in guinea pigs. Dermal tolerance studies produced slight incompatibility reactions and ocular tolerance studies revealed moderate to severe ocular irritation and pain reactions.
3.2.4 Summary and Conclusion
Pharmacological tests with azelaic acid revealed that it did not have negative impacts on intermediary metabolism, liver, kidney, cardiovascular, and smooth muscle functions, or on the central nervous system. The results provided evidence, in part, that the therapeutic effect of azelaic acid in rosacea was likely due to the bacteriostatic properties of the active ingredient. Azelaic acid was found to have a concentration- and time-dependent anti-proliferative effect on murine and human keratinocytes in vitro and influenced differentiation of human keratinocytes in vivo but did not inhibit sebaceous gland activity.
The pharmacokinetic and biotransformation studies with azelaic acid produced similar results in all laboratory animals and in human studies. Topical application of the gel showed that azelaic acid could penetrate into all layers of the skin, however most of the active substance remained on the surface of the skin. Both azelaic acid and its metabolites have been shown to be rapidly excreted in the urine of all animals tested.
Toxicological studies with azelaic acid showed very low levels of toxicity after single intragastric administrations of either the pure substance or 20% azelaic acid cream to rats and mice. Systemic tolerance studies revealed no relevant signs of toxicity after repeated intragastric administration. Fertility of parental animals, as well as the fertility and reproductive performance of the F1 generation were also not affected. No teratogenic effects were seen and mutagenicity and genotoxicity studies were negative. Azelaic acid caused moderate to severe irritation when applied into the eyes of rabbits and monkeys and it is recommended to avoid contact with the eyes when applying the 15% azelaic acid gel. Topical applications of 20% azelaic acid cream did not increase the skin sensitivity of the guinea pig or result in comedogenic developments in the rabbit. All non-medicated ingredients were generally regarded as safe.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
Five Phase I pharmacodynamic studies were performed to determine the safety and tolerability of the topical application of azelaic acid in normal healthy volunteers.
The 21-day cumulative irritancy and scarification tests consistently showed mild irritations associated with the 15% azelaic acid gel as well as moderate levels of irritation associated with prolonged vehicle use. Adverse events (AEs) were of cutaneous origin, primarily sensory skin symptoms such as burning, stinging, tingling, and itching, were observed in 18.9% of patients, and were of mild to moderate intensity. Similar adverse effects were also seen in the repeat insult patch test and at the same frequency. No serious adverse events or deaths were observed and there was no evidence of sensitization potential in healthy skin. Neither 15% azelaic acid nor its vehicle elicited photosensitization or photoallergenic reactions in any of the healthy volunteers and no phototoxic reactions were observed. Azelaic acid gel does not appear to absorb UV light.
The observations made during the five Phase I trials supported the conclusion that 15% azelaic acid gel is safe for human use.
3.3.2 Pharmacokinetics
Human pharmacokinetics studies with azelaic acid revealed that the substance was quickly absorbed from the intestine and made available to the body. In the circulation, the Cmax and AUC were found to increase linearly up to 3.5 g dose following oral administration. Azelaic acid was rapidly eliminated in the urine; the plasma half-life was found to be around 45 minutes. The total body clearance estimated from intravenous data was 182 mL/min. The renal clearance of azelaic acid ranged from 140 mL/min to 300 mL/min after intravenous and oral administration, respectively, suggesting the presence of active tubular secretion. While there was evidence of systemic β-oxidation of azelaic acid to dicarboxylic acid metabolites, the bulk of azelaic acid was excreted unchanged in the urine. Azelaic acid was only moderately bound (43%) to plasma proteins and distributed primarily to the extracellular water.
The active substance was capable of penetrating into the stratum corneum and other viable skin layers, however the extent of penetration ranged between 3 to 5% of an applied single dose during the first 24 hrs. The initial rate of skin penetration was more pronounced in damaged skin than intact skin. The bulk of the active ingredient was recovered on the surface of the skin and its concentration decreased as a function of time (after 48 hrs, 48% was recovered on the surface of the skin). Only trace quantities were recovered across the skin (eg. 1-2% after 48 hrs) while approximately 10% was recovered in epidermis and dermis after 24 hours. The depth of skin penetration was greater in living skin.
Percutaneous absorption studies conducted in healthy volunteers with 20% azelaic acid cream revealed that approximately 4% of the active ingredient was absorbed through the skin. Although the plasma Cmax for Azelaic acid were 2 and 2.5 times the baseline concentration after single and multiple applications, respectively, the relative magnitude between the Cmax values post-dosing and the baseline concentration were similar to the values reported in the control group.
The daily urinary excretions of Azelaic acid in acne patients, treated with the 20% azelaic acid cream or 15% azelaic acid gel for 8 weeks were similar and within the range observed from individuals under normal dietary intakes (4 to 28 mg).
Following treatment with 15% azelaic acid gel for at least 8 weeks, the plasma azelaic acid concentration in rosacea patients ranged from 42 to 63.1 ng/mL. These values were within the range reported for healthy volunteers (52 ng/mL) and acne patients (83.8 ng/mL) on a regular diet, and in volunteers (136 ng/mL) and acne patients (89.6 ng/mL) treated with azelaic acid 20% cream. These results indicated that topical treatment with the 15% azelaic acid gel did not increase the normal systemic burden of azelaic acid beyond that derived from endogenous and dietary sources.
3.3.3 Clinical Efficacy
The efficacy of 15% azelaic acid gel in the treatment of moderate papulopustular rosacea was assessed in two identical pivotal studies. Additional supporting information was also provided in the form of a comparative non-pivotal study where the proposed formulation was compared to an already authorized Canadian medication. A total of 915 male and female patients were enrolled in the three studies.
In the pivotal studies, the twice-daily application of Finacea for 12 weeks resulted in significant improvements of mild to moderate papulopustular rosacea. Significant positive effects were reported against the primary characteristics of rosacea such as lesions and erythema which included nominal change in inflammatory lesion counts from baseline and response rate based on the 7-point IGA static scoring system. Patients treated with azelaic acid had a 58% decrease in lesion count which was an increase of 18% over those treated solely with the vehicle. The medication effects appeared to be stronger when the baseline number of lesions was high. Severity of erythema was also assessed, and treatment resulted in significant shifts in the absolute number or percentage of patients with high severity ratings (moderate to severe) to patients displaying lower severity ratings (mild to none). The beneficial treatment effect observed with medication was much higher than that of the vehicle, but it should be noted that approximately 50% of the patient population remained unchanged. Telangiectasia, evaluated by the same rating criteria as erythema, revealed only slight shifts in the number or percentage of patients from the high intensity rating category (moderate) to the lower rating categories (mild to none) after treatment with azelaic acid. Telangiectasia rating changes from baseline showed no significance between treatment with azelaic acid or vehicle.
The comparative non-pivotal study was randomized, double-blind, multi-centre, parallel-group, and assessed 251 patients with stage two papulopustular rosacea. Finacea was found to be superior to the comparator medicine (metronidazole 0.75% gel) on each of the primary endpoints (reduction in the number of inflammatory lesion counts from baseline, percent change in inflammatory lesions from baseline, and IGA assessment of rosacea) when analyzed at the end of the study period. The studies also demonstrated that the higher the lesion count was at baseline, the greater the effect of medication. The reduction of inflammatory lesion counts occurred throughout the study, with Finacea producing faster and more effective changes than the comparator. Analysis of rosacea by the IGA scoring system showed a more significant decrease from the more to less severe scoring categories than the comparator. The overall improvement rating by the more traditional form of efficacy analysis was also found to be statistically significant and more patients were reported to be in the "complete remission" and "excellent improvement" categories than the comparator (48% vs 35%). Finacea was also more efficacious in reducing the severity of erythema. Both forms of treatment however, showed no appreciable effect on telangiectasia, suggesting that the treatments had no effect on the vascular alterations of rosacea.
Gender, age, race, and duration of treatment did not have significant effects on the outcome of treatment in any study, however the subgroups were too small to make any definitive conclusions.
3.3.4 Clinical Safety
The safety data from the pivotal clinical studies found both the vehicle and 15% azelaic acid to be safe for the treatment of papulopustular rosacea. Treatment-related AEs were of cutaneous origin and included burning, paresthesia (stinging and tingling), pruritus (itching), dry skin, and to a lesser extent, rash. These adverse events occurred in more than 10% of patients. Systemic AEs occurred at a much lower frequency but were not concentrated in a single body system. Headaches also occurred in 6.1% of patients treated with 15% azelaic acid. The majority of adverse effects seen were of mild to moderate intensity; adverse effects of severe intensity occurred in only 6% of patients. At the end of the study period, investigators and patients evaluated the tolerability of the medication and patients also evaluated the acceptance of cosmetics. In both clinical studies the overall rating of improvement by both patients and investigators was found to be significantly in favour of the medication over the vehicle. The overall cosmetic acceptance by the patients was found to be "very good" in both treatment groups and no statistically significant difference was observed.
Treatment in the non-pivotal studies also showed azelaic acid to be safe for the treatment of papulopustular rosacea. The emerging AEs were predominantly of cutaneous origin and were of mild to moderate intensity. The most common symptoms were burning sensation of the skin, pruritus, and paresthesia. Patients' assessment of local tolerability found the comparator to be more favourable than Finacea and was statistically significant, however cosmetic acceptance was considered favourable in both groups and showed no evaluation or significant differences between treatments.
The systemic effects of azelaic acid were investigated in two separate clinical studies with patients displaying moderate forms of acne and treated with 20% azelaic acid cream for periods of 5 and 12 months. The long term administration of the 20% cream gave clinical chemistry results, for the most part, within the normal range of the study parameters. Only a small percentage of patients (5.6%) were considered to have had clinically significant variations. None of the patients discontinued the studies as a result of the laboratory testing variations. Overall, no substance-related effects of pathological significance were observed. One case of persistent dermal allergy was observed however, as well as one case of transient photoallergic reaction. Thus, although rare, one cannot totally exclude possible dermal or photoallergic reactions associated with the medication.
Post-market experience with both 15% azelaic acid gel and 20% azelaic acid cream products indicated no serious adverse drug reaction (ADR) reports and that azelaic acid present in topical products were generally safe for use. The observed cutaneous adverse events were of mild intensity, in-line with the observations of the pivotal and non-pivotal clinical trials.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
The efficacy results reported with azelaic acid for treatment of papulopustular rosacea, along with the good safety and local tolerability, and absence of systemic safety concerns, provide substantial support for Finacea. The benefits of Finacea outweigh the minimal risks associated with the use of this drug. This conclusion is also supported by post-marketing ADR reports which show that the history of the 20% azelaic acid cream (marketed internationally since 1990, but not in Canada) appears to be free from serious adverse events.
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 Finacea is favourable in the treatment of inflammatory lesions in patients with mild to moderate papulopustular facial rosacea. 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: Finacea®
| Submission Milestone | Date |
|---|---|
| Submission filed | 2004-07-26 |
| Screening 1 | |
| Screening Deficiency Notice issued | 2004-09-03 |
| Response received | 2004-09-21 |
| Screening Acceptance Letter issued | 2004-11-09 |
| Review 1 | |
| Biopharmaceutics Evaluation complete | |
| Clinical Evaluation complete | 2005-07-27 |
| Quality Evaluation complete | 2005-08-05 |
| Labelling Evaluation complete | 2005-08-31 |
| NOC issued by Director General | 2005-09-01 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| FINACEA | 02270811 | LEO PHARMA INC | AZELAIC ACID 15 % / W/W |