Summary Basis of Decision for Efracea ®
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:
Efracea®
Doxycycline, as doxycycline monohydrate, 40 mg, Capsule (modified-release), Oral
Galderma Canada Inc.
Submission control no: 143439
Date issued: 2012-02-28
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):
- 02375885
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Control Number: 143439
Date of Submission:
Date of authorization:
2 Notice of decision
On November 14, 2011, Health Canada issued a Notice of Compliance to Galderma Canada Inc. for the drug product, Efracea.
Efracea contains the medicinal ingredient doxycycline, as doxycycline monohydrate, which belongs to the anti-rosacea class of drugs.
Efracea is indicated for the treatment of only inflammatory lesions (papules and pustules) of rosacea in adult patients. No meaningful effect was demonstrated for generalized erythema (redness) of rosacea. The pathophysiology of the inflammatory lesions of rosacea is, in part, a manifestation of a neutrophil-mediated process. Doxycycline has been shown to inhibit neutrophil activity and several pro-inflammatory reactions.
The market authorization was based on quality, non-clinical, and clinical information submitted. The efficacy and safety of Efracea 40 mg capsules were based on two pivotal multicentre, randomized, double-blind, placebo-controlled Phase III studies in which 269 patients received Efracea 40 mg once daily and 268 patients received placebo for a duration of 16 weeks. Efracea demonstrated a clinically and statistically significant greater reduction in total inflammatory lesion count from baseline to Week 16 compared with placebo treatment (the primary endpoint). The safety profile was similar to tetracycline class antibiotics.
Efracea (40 mg, doxycycline monohydrate) is presented as a modified-release capsule. One Efracea capsule should be taken once daily in the morning, on an empty stomach, preferably at least one hour prior to or two hours after the meal. Dosing guidelines are available in the Product Monograph.
Efracea is contraindicated for patients who are hypersensitive to this drug, to other tetracyclines, or to any ingredient in the formulation or component of the container. Efracea is also contraindicated for women in the second or third trimester of pregnancy, for nursing women, infants, and children up to the age of 8 years, and for patients with myasthenia gravis. Efracea should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Efracea are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Efracea is favourable for the treatment of only inflammatory lesions (papules and pustules) of rosacea in adult patients.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
The medicinal ingredient of Efracea is doxycycline, as doxycycline monohydrate, which has the therapeutic classification, Anti-Rosacea.
Rosacea is a chronic cutaneous disorder primarily of the convexities of the central face (cheeks, chin, nose and central forehead) that is often characterized by remissions and exacerbations. The inflammatory lesions of rosacea are, in part, a manifestation of a neutrophil-mediated process. Doxycycline has been shown to inhibit neutrophil activity and several pro-inflammatory reactions.
Doxycycline monohydrate was submitted as a new chemical entity as it is a new compound and new formulation. The compound doxycycline hyclate 50 mg and 100 mg oral capsules (Vibramycin) (therapeutic classification Antibiotic) obtained market authorization in 1969, and doxycycline hyclate 20 mg immediate-release capsules (Periostat) (therapeutic classification Collagenase Inhibitor for Periodontic Use) received market authorization in 2003.
Manufacturing Process and Process Controls
The drug substance is synthetically derived from oxytetracycline.
The manufacturing process is considered to be adequately controlled within justified limits.
Characterization
The structure of doxycycline monohydrate has been adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory. Appropriate tests control the levels of product- and process-related impurities.
Control of Drug Substance
The drug substance specifications and analytical methods used for quality control of doxycycline monohydrate are considered acceptable.
Validation reports were provided and are considered satisfactory. Data from the batch analyses were reviewed and are within the proposed acceptance criteria.
The proposed packaging components are considered acceptable.
Stability
Based on the long-term, real-time, accelerated stability data submitted, the proposed retest period for the drug substance is supported and considered satisfactory.
3.1.2 Drug Product
Description and Composition
Efracea (doxycycline, as doxycycline monohydrate) 40 mg modified-release capsules are beige, opaque, hard gelatin capsules imprinted with "GLD 40". Each capsule contains two types of beads that together provide a dose of 40 mg of doxycycline (as doxycycline monohydrate). The immediate-release beads contain 30 mg of doxycycline and the delayed-release beads contain 10 mg of doxycycline.
The non-medicinal ingredients in Efracea modified-release capsules are gelatine; hypromellose; methacrylic acid copolymer; opadry beige; sugar spheres; talc; and triethyl citrate.
Efracea is available as 14-capsule blister cards packaged in a carton of 2 cards (28 capsules).
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of doxycycline monohydrate with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.
Manufacturing Process and Process Controls
The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Drug Product
Efracea is tested to verify that its identity, appearance, content uniformity, assay, loss on drying, dissolution, and levels of degradation products and microbiological impurities are within acceptance criteria.
Copies of the analytical methods and, where appropriate, validation reports were provided and are considered satisfactory for all analytical procedures used for release and stability testing of Efracea.
Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Although impurities and degradation products arising from manufacturing and/or storage were reported and characterized, these were found to be within International Conference on Harmonisation (ICH) established limits and therefore, are considered acceptable.
Stability
Based on the real-time, long-term, accelerated stability data submitted, the proposed 24-month shelf-life at 15-30°C for Efracea is considered acceptable.
The compatibility of the drug product with the container closure system was demonstrated through the stability studies. The container closure system met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facilities and equipment that are involved in the production of Efracea are considered suitable for the activities and products manufactured.
3.1.4 Adventitious Agents Safety Evaluation
The excipient, gelatin, in the capsule shell is of animal origin. A letter of attestation confirming that the material is not from a bovine spongiform encephalopathy (BSE), transmissible spongiform encephalopathy (TSE) affected country/area has been provided for this product indicating that it is considered safe for human use.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Efracea has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
The sponsor did not perform new non-clinical studies with doxycycline. Doxycycline, a structural isomer of tetracycline, has been used as an antibiotic in clinical medicine for many years.
3.2.1 Pharmacodynamics
The non-clinical data regarding pharmacologic effects, safety pharmacology, and pharmacodynamic (PD) drug interactions with doxycycline were based on published scientific literature.
The pathophysiology of the inflammatory lesions of rosacea is, in part, a manifestation of a neutrophil-mediated process and doxycycline has been shown to inhibit neutrophil activity and several pro-inflammatory processes in in vitro models. There is no animal model for rosacea.
3.2.2 Pharmacokinetics
Non-clinical pharmacokinetic (PK) studies examining the absorption, distribution, metabolism, and excretion of doxycycline monohydrate were not conducted. The non-clinical pharmacokinetics of doxycycline were derived from the published scientific literature.
3.2.3 Toxicology
The sponsor submitted a series of single-dose toxicity, repeat-dose toxicity, genotoxicity, carcinogenicity, and reproductive and development toxicity studies that were performed in compliance with Good Laboratory Practice regulations. The toxicology studies were conducted with doxycycline hyclate and not with doxycycline monohydrate (the drug substance in Efracea). At this time, this is considered acceptable as the bioequivalence/clinical studies showed similar steady-state plasma levels between the two formulations [that is (i.e.), doxycycline hyclate and doxycycline monohydrate]. The sponsor also submitted several published literature references to help establish the toxic potential of doxycycline.
Single-Dose Toxicity
A single-dose toxicity study conducted in rats demonstrated that the administration of 750 mg/kg doxycycline hyclate was associated with mortality, whereas 500 mg/kg was tolerated. The maximum tolerated dose in rats was 500 mg/kg.
Repeat-Dose Toxicity
The primary organs of toxicity in the repeat-dose toxicity studies conducted with doxycycline hyclate were: the thyroid [for example (e.g.), hyperpigmentation of the thyroid]; the kidneys (e.g., tubular degeneration/regeneration and interstitial oedema in the kidney, increased kidney weights); the stomach (e.g., gastritis, increased mucus production in the stomach); the spleen (e.g., decreased extramedullary haematopoiesis, decreased spleen weight); the adrenal glands (e.g., decreased adrenal weights, increased cortical lipidosis); and the liver (e.g., decreased liver weights).
Genotoxicity
Three genotoxicity studies were conducted with doxycycline hyclate. Under the conditions tested, doxycycline hyclate demonstrated no potential to cause genetic toxicity in an in vitro point mutation study with mammalian cells [Chinese Hamster Ovary (CHO) and hypoxanthine-guanine phosphoribosyltransferase (HGPRT) forward mutation assay] or in an in vivo micronucleus assay conducted in mice. However, data from an in vitro assay with CHO cells for potential to cause chromosomal aberrations suggest that doxycycline hyclate is a weak clastogen.
Carcinogenicity
In a 2-year carcinogenicity study in rats, increases in benign tumours of the mammary gland (fibroadenoma), uterus (polyp) and thyroid (C-cell adenoma) were noted in females treated with doxycycline hyclate.
Reproductive and Developmental Toxicity
In a fertility and reproductive study, oral administration of doxycycline hyclate adversely affected fertility and reproductive performance in rats, as evidenced by an increased time for mating to occur; reduced sperm motility, velocity, and concentration; abnormal sperm morphology; and increased pre- and post-implantation losses. Doxycycline hyclate induced reproductive toxicity at all doses tested. The lowest dose (50 mg/kg per day) induced a statistically significant reduction in sperm velocity.
No embryo-foetal development studies were conducted with doxycycline. However, doxycycline is known to cross the placenta and literature data indicate that tetracyclines can have toxic effects on the developing foetus.
In a study for effects on prenatal and postnatal development, including maternal function, daily oral administration of 250 and 500 mg/kg/day doxycycline hyclate elicited maternal toxicity and there was also evidence of slight toxicity in the first filial (F1) generation. There was no apparent evidence of maternal toxicity at 100 or 50 mg/kg/day and, apart from a slight increase in the numbers of pups with hair loss at 100 mg/kg/day, there was no apparent evidence of toxicity in the F1 generation at these lower doxycycline hyclate doses.
3.2.4 Summary and Conclusion
The new drug submission for Efracea (doxycycline monohydrate) does not include new non-clinical data regarding pharmacodynamics or pharmacokinetics for doxycycline. This non-clinical data for doxycycline in published scientific literature were considered acceptable for the review. The toxicological studies submitted for doxycycline hyclate are considered adequate at this time to represent the toxicological profile of doxycycline monohydrate.
Appropriate statements are included in the Efracea Product Monograph to convey the risks associated with its use.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
There were no microbiological data directly for Efracea. In vivo microbiological studies using immediate-release doxycycline hyclate (20 mg twice daily) for 6 to 18 months did not reveal any evidence of increased bacterial resistance. Extrapolation of the published in vivo microbiological studies to Efracea (doxycycline monohydrate) was acceptable based upon bioequivalence data which showed similar steady-state plasma levels of doxycycline between the two formulations.
No dose-response studies were conducted with Efracea. Analyses provided were considered acceptable.
Potential interactions with doxycycline are known. No new drug interaction studies were conducted with Efracea. The labelling for Efracea includes the potential drug interactions.
3.3.2 Pharmacokinetics
Clinical studies assessing the distribution, metabolism, and elimination of doxycycline were not conducted with Efracea as this information is documented for other approved doxycycline products. However, absorption of Efracea was studied for bioequivalence to the approved immediate-release formulation doxycycline hyclate (20 mg twice daily), oral bioavailability (fed and fasting); gender effect; and the effect of gastric insufficiency.
Pharmacokinetic (PK) studies showed that Efracea, a once daily oral modified-release formulation of doxycycline monohydrate (40 mg) provided steady-state plasma concentrations of doxycycline at an anti-inflammatory level well below an anti-microbial level. This PK/PD parameter was acceptable for this drug class.
Ingestion of food delayed and reduced the rate and extent of absorption of Efracea, and the bioavailability in the fed versus fasting state was outside accepted criteria. To maximize bioavailability, Efracea should be administered in the fasting state.
A significant effect of gender was observed on the rate and extent of doxycycline absorption with higher maximum plasma concentrations (Cmax) and area under the curve (AUC) values in females compared to males. However, a subgroup analysis by gender in the Phase III clinical studies did not show a gender difference in clinical outcome.
Reduced bioavailability of the drug occurred at a high pH. This has clinical significance for patients with medical conditions which are associated with a high pH of the upper gastrointestinal tract.
3.3.3 Clinical Efficacy
The efficacy of Efracea was evaluated in two multicentre, randomized, double-blind, placebo-controlled Phase III studies (Studies 301 and 302), in which 269 patients received Efracea 40 mg daily and 268 patients received placebo, for a duration of 16 weeks. The study population consisted of adult patients with rosacea, including patients with 10-40 papules or pustules and ≤2 nodules, the presence of telangectasia, and moderate to severe erythema. The study excluded patients with ocular rosacea and those with gastrectomy, gastric bypass surgery, or any surgeries that bypassed or excluded the duodenum or who were otherwise deemed achlorhydric. In Study 302, the treatment period was followed by 4 weeks off therapy to evaluate the persistence of treatment effect.
The efficacy data for Efracea demonstrated a clinically and statistically significant greater reduction in total inflammatory lesion count from baseline to Week 16 (the primary endpoint) compared with placebo treatment. In Study 301, the mean change was -11.8 in the Efracea group versus -5.9 in the placebo group [probability (p) <0.001)]. In Study 302, the results showed -9.5 in the Efracea group versus -4.3 in the placebo group (p <0.001). In both studies, a significantly greater proportion of patients treated with Efracea achieved a clear or near clear response in the Investigator Global Assessment (IGA) at Week 16 compared to those who received placebo. In the individual studies, the proportion of treatment responders (clear or near clear) was 30.7% in the Efracea group versus 19.4% in the placebo group (p = 0.036) in Study 301, and 14.8% in the Efracea group versus 6.3% in the placebo group (p = 0.012) in Study 302. In the combined analysis, 33.5% of the patients in the Efracea group had a 2-point or greater improvement in the IGA score at Week 16, compared to 20.5% of patients in the placebo group. The Clinician's Erythema Assessment (CEA) score change was not clinically meaningful for the reduction of erythema of rosacea. The results for CEA from baseline to Week 16 were inconsistent, being statistically significant in Study 301 (p = 0.017) and in the combined studies (p = 0.024) but not in Study 302 (p = 0.428). The reductions in total inflammatory lesion counts were comparable to the reductions found with topical products approved for rosacea.
The treatment benefit of Efracea was maintained post-treatment but was reduced. In the 4-week follow-up period in Study 302 (off treatment), there was a significant increase in total inflammatory lesion counts only within the Efracea group from Week 16 (mean 8.3) to Week 20 (mean 10.3) (p = 0.008). The difference at Week 20 between the Efracea group and the placebo group (mean 15.3) was 5 lesions, compared to a difference of 5.2 lesions at Week 16.
In summary, the Efracea efficacy data for the primary endpoint of change in total inflammatory lesions in adults with rosacea were adequate for approval. These results were adequately supported by secondary endpoint improvements of treatment response (assessed by a dichotomized static IGA) and improvements in the IGA score. However, Efracea has limited efficacy for the treatment of rosacea overall, as lesions are only one feature of the disease. The reported efficacy of Efracea is modest for an oral medication. Efracea is not recommended for use in patients with significant ocular involvement or in patients deemed achlorhydric, as these patients were not included in the studies.
3.3.4 Clinical Safety
The clinical safety evaluation of Efracea was based on two pivotal Phase III studies (Studies 301 and 302) in adult patients with rosacea (see section 3.3.3 Clinical Efficacy), and four pharmacokinetic studies in healthy adults. Six hundred and thirty one patients were enrolled in the completed Phase II and III studies. Of these, 362 patients were exposed to Efracea. The majority of exposure to Efracea was in the pivotal Phase III studies.
The safety evaluation in the two pivotal Phase III studies involved 537 patients; 269 patients in the Efracea group with a mean exposure of 102 days; and 268 patients in the placebo group with a mean exposure of 107 days; with a study duration of 16 weeks (plus follow-up off treatment for 4 weeks in Study 302).
In the combined pivotal studies, adverse events (AEs) were reported for 55% and 46% of the patients in the Efracea and placebo groups, respectively. The most frequently reported AEs in the Efracea group were nasopharyngitis (5%); headache (5%); upper respiratory tract infection (3%); and hypertension (3%). AEs with >2% difference in frequency between Efracea and placebo were diarrhea; hypertension; and sinusitis. Most AEs were mild to moderate in severity. No deaths were reported. All serious adverse events (SAEs) were related to disease or medical conditions unrelated to rosacea, and were considered not to be related to the study medication by the investigator. Discontinuations due to AEs were 7.4% for the patients treated with Efracea and 4.5% for the placebo patients, with the most frequently reported AEs being gastrointestinal disorders in both treatment groups.
The frequency of adverse reactions (ADRs) assessed by the investigator as possibly or probably related to study medication in the Efracea group was 20.8% versus (vs.) 14.2% in the placebo group, and the most common adverse reactions for Efracea were in the gastrointestinal System Organ Class (SOC), consistent with tetracycline class antibiotics. The following common ADRs (≥1%), by preferred term, were reported in the Efracea group: diarrhea (4.1%); headache (2.2%); upper abdominal pain (1.9%); nausea (1.9%); fungal infection (1.9%); increased levels of aspartate aminotransferase (1.5%); and stomach discomfort (1.1%). Most ADRS were mild to moderate in severity. There were no treatment-related serious adverse reactions. The most frequent adverse reaction leading to discontinuation was diarrhea (0.7%).
In the pivotal Phase III studies, with regard to AEs of particular interest for drugs in the tetracycline class, gastrointestinal AEs had a higher frequency in the Efracea group than in the placebo group (13% versus 9%). Photosensitivity was not reported, sunburn was reported for Efracea (2) and placebo (1); and rash was reported for Efracea (2) and placebo (2). Health Canada requested precautionary labelling regarding the risk of hypersensitivity reactions.
Clinical laboratory values that were considered clinically significant by the investigator and reported as ADRs for Efracea included: abnormal liver function tests (alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase); and increased uric acid. An increase in blood urea nitrogen (a recognized anabolic effect with tetracyclines) was not reported.
Non-pivotal studies with Efracea 40 mg capsules once daily did not indicate any additional safety concerns or changes in the labelling. No SAEs were reported in the pharmacokinetic studies.
No drug interaction studies were conducted with Efracea but potential interactions relevant to the use of higher antimicrobial doses of doxycycline are known.
No pregnancies were reported during the clinical studies. Post-market experience and data are limited.
No cases of overdose were reported during the clinical studies. Post-market experience data are limited.
No specific studies have been conducted to evaluate the effects of Efracea on a patient's ability to drive or operate machinery. Dizziness, as a reported ADR, has been reported in clinical trials (fasting state), and in the literature.
The risk for emergence of resistance in the intestinal and upper respiratory microflora associated with long-term use of Efracea is a potential safety issue. Data for
immediate-release doxycycline hyclate (20 mg twice daily) used for 6 to 18 months demonstrated no detectable effect on bacterial flora samples from the oral cavity, skin, intestinal tract, and vagina. Extrapolation of the published in vivo microbiological studies to Efracea was acceptable based upon PK data. Development of bacterial resistance cannot be excluded for Efracea. This continues to be studied in a Phase IV study conducted to examine the effects of Efracea on oropharyngeal and intestinal microflora, in compliance with the European Risk Management Plan.
Overall, the safety profile of Efracea is similar to that reported with the use of other doxycycline products. The labelling was modified to inform the prescriber/user of the adverse drug reactions reported with Efracea as well as adverse drug reactions and drug interactions observed in those patients receiving tetracyclines/doxycycline at higher antimicrobial doses.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Efracea (doxycycline, as doxycycline monohydrate) modified-release capsule, 40 mg offers a treatment option for adult patients with rosacea. Efracea may cover an unmet medical need for patients who cannot use approved topical treatments for rosacea. The demonstrated benefit of Efracea was limited to a reduction of total inflammatory lesions of rosacea (papules and pustules) in adult patients with facial rosacea. To date, studies have shown that it does not induce bacterial resistance. There is extensive clinical experience with doxycycline as doxycycline hyclate. This active ingredient has been marketed in higher antimicrobial doses for over 40 years and in similar daily doses for periodontic use since 2003.
The Efracea safety profile showed an increase in gastrointestinal adverse reactions, similar to tetracycline class antibiotics. The known risks of doxycycline apply to Efracea. To date, development of bacterial resistance has not been detected.
Overall, the benefit/risk assessment is acceptable. Risk management through Schedule F (requiring the drug to be sold only on prescription); product labeling; and regular assessments of spontaneous adverse event reporting through Periodic Safety Update Reports is sufficient.
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 Efracea is favourable in the treatment of only inflammatory lesions (papules and pustules) of rosacea in adult patients. No meaningful effect was demonstrated for generalized erythema (redness) of 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: Efracea®
| Submission Milestone | Date |
|---|---|
| Submission filed: | 2010-12-02 |
| Screening | |
| Screening Acceptance Letter issued: | 2011-01-24 |
| Review | |
| Biopharmaceutics Evaluation complete: | 2011-10-24 |
| Quality Evaluation complete: | 2011-11-03 |
| Clinical Evaluation complete: | 2011-11-08 |
| Labelling Review complete: | 2011-11-04 |
| Notice of Compliance issued by Director General: | 2011-11-14 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| APPRILON | 02375885 | GALDERMA CANADA INC | DOXYCYCLINE (DOXYCYCLINE MONOHYDRATE) 40 MG |