Summary Basis of Decision for Avamys ™
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:
AvamysTM
Fluticasone furoate, 27.5 µg/actuation, Spray metered dose, Nasal
GlaxoSmithKline Inc.
Submission control no: 107372
Date issued: 2008-01-30
Health Products and Food Branch
Our mission is to help the people of Canada maintain and improve their health.
Health Canada
HPFB's Mandate is to take an integrated approach to managing the health-related risks and benefits of health products and food by:
- minimizing health risk factors to Canadians while maximizing the safety provided by the regulatory system for health products and food; and,
- promoting conditions that enable Canadians to make healthy choices and providing information so that they can make informed decisions about their health.
Health Products and Food Branch
Également disponible en français sous le titre : Sommaire des motifs de décision (SMD), PrAVAMYSMD, Furoate de fluticasone, 27,5 µg/vaporisation, Aérosol-doseur, GlaxoSmithKline Inc., Nº de contrôle de la présentation 107372
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):
- 02298589
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On August 14, 2007, Health Canada issued a Notice of Compliance to GlaxoSmithKline Inc. for the drug product, Avamys™.
Avamys™ contains the medicinal ingredient fluticasone furoate which is a corticosteroid for nasal use.
Avamys™ is indicated for treatment of seasonal allergic rhinitis and its associated symptoms in patients 12 years of age and older. The precise mechanism through which fluticasone furoate affects rhinitis symptoms is not known. Corticosteroids have been shown to have a wide range of actions on multiple cell types and mediators involved in inflammation. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in rhinitis.
The market authorization was based on quality, non-clinical, and clinical information submitted. The efficacy and safety of Avamys™ in patients, 12 years of age and older (n=1527), with seasonal allergic rhinitis were evaluated in four randomized, double-blind, parallel-group, multicentre, placebo-controlled clinical studies. Overall, patients treated with Avamys™ exhibited significantly greater decreases in nasal and ocular symptoms compared to patients treated with placebo.
Avamys™ (27.5 µg/actuation, fluticasone furoate) is presented in a spray metered dose. The recommended dosage is two sprays (27.5 µg of fluticasone furoate per spray) in each nostril once daily (total daily dose, 110 µg). Dosing guidelines are available in the Product Monograph.
Avamys™ is contraindicated in patients with a hypersensitivity to any of its ingredients. Avamys™ 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 Avamys ™ 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 Avamys™ is favourable for treatment of seasonal allergic rhinitis and its associated symptoms in patients 12 years of age and older.
3 Scientific and Regulatory Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Fluticasone furoate, the medicinal ingredient of Avamys™, is a synthetic trifluorinated corticosteroid with potent anti-inflammatory activity. Corticosteroids have been shown to have a wide range of actions on multiple cell types and mediators involved in inflammation. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in rhinitis.
Manufacturing Process and Process Controls
Fluticasone furoate is synthetically derived. The manufacturing process is considered to be adequately controlled within justified limits.
Characterization
Detailed characterization studies were performed to provide assurance that fluticasone furoate consistently exhibits the desired characteristic structure.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within ICH established limits and/or were qualified from toxicological studies and therefore, are considered to be acceptable. These products are within the proposed acceptance criteria in batch analysis of fluticasone furoate.
Control of Drug Substance
The drug substance specifications and analytical methods used for quality control of fluticasone furoate are considered acceptable.
The analytical methods and, where appropriate, validation reports are considered satisfactory for all analytical procedures used for release and stability testing of fluticasone furoate.
Data from batch analyses were reviewed and are within the proposed acceptance criteria.
The drug substance packaging is considered acceptable.
Stability
Based on the long-term and accelerated stability data submitted, the proposed retest period for fluticasone furoate is supported and considered to be satisfactory. The drug is stable under the proposed storage conditions.
3.1.2 Drug Product
Description and Composition
Avamys™ (fluticasone furoate nasal spray) is an unscented, alcohol-free, preserved, aqueous suspension of micronized fluticasone furoate filled into amber glass bottles with metered dose actuators which deliver 27.5 µg of fluticasone furoate per actuation. Avamys™ also contains benzalkonium chloride, glucose anhydrous, disodium edetate, dispersible cellulose, polysorbate 80, and purified water.
Avamys™ is presented in three pack sizes with fill weights designed to deliver 30, 60, or 120 doses for topical administration to the nasal mucosa by means of a metering, atomizing, spray pump.
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 fluticasone furoate 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, including development of the nasal spray container closure system, are considered acceptable. Studies which justified the type and proposed concentration of excipients to be used in the drug product were also reviewed and are considered to be acceptable.
Manufacturing Process and Process Controls
The manufacturing process for Avamys™ has been described in detail. Sufficient information has been provided for each step of the process that includes numerical ranges for processing parameters, process controls, and equipment. The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Drug Product
Avamys™ is tested to verify that the identity, appearance, content, weight of contents, levels of degradation products, microbiological impurities, pH, delivered dose, and droplet size distribution are within acceptance criteria. The test specifications are considered acceptable to control the drug product.
The analytical methods and, where appropriate, validation reports are considered satisfactory for all analytical procedures used for release and stability testing of Avamys™.
Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Stability
Based on the long-term and accelerated stability data submitted, the proposed shelf-life of 24-months is considered acceptable when the product is stored between 4°C and 30°C. As per the approved label, the product should be stored in an upright position with the cap in place, and should not be refrigerated or frozen.
The compatibility of the drug product with the container closure system was demonstrated through stability studies. The quality and safety of the nasal spray container closure system has also been demonstrated.
3.1.3 Facilities and Equipment
The design, operations and controls of the facility and equipment that are involved in the production 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.
All sites are rated Good Manufacturing Practices (GMP) compliant for the associated manufacturing activities.
3.1.4 Adventitious Agents Safety Evaluation
Not applicable. There are no excipients of human or animal origin.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Avamys™ 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.
3.1 Quality Basis for Decision
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
A number of in vitro and in vivo studies were submitted as a part of the non-clinical evaluation. In the in vitro studies, fluticasone furoate was shown to be a potent human glucocorticoid receptor (GR) agonist, which dissociated very slowly from the receptor. Fluticasone furoate also exhibited a high affinity and a potent agonistic activity for the progesterone receptor, behaved as a low intrinsic efficacy agonist towards the mineralcorticoid receptor, showed some affinity but displayed no agonistic activity for the androgen receptor, and exhibited no affinity for the estrogen receptors.
Fluticasone furoate was demonstrated to have a potent anti-inflammatory activity using in vivo models of inflammation. In the rat ovalbumin induced lung eosinophilia model, a model designed to mimic allergen induced lung eosinophilia, fluticasone furoate inhibited the antigen induced eosinophil accumulation in the lungs of sensitized rats. In a delayed type hypersensitivity model of ear inflammation in mice and rats, fluticasone furoate inhibited skin inflammation. Compared with fluticasone propionate, fluticasone furoate demonstrated a lower tendency to cause thymus involution in rats, a documented index of the systemic side effects of glucocorticoids.
Fluticasone furoate was administered to animals in a number of studies designed to assess its effects upon vital functions and to detect any potential adverse pharmacodynamic effects. The safety pharmacology studies revealed no potential effects of fluticasone furoate on the cardiovascular, respiratory, and central nervous systems.
3.2.2 Pharmacokinetics
Absorption
Oral bioavailability of fluticasone furoate was very low, limited by extensive first-pass metabolism in all species. In the inhaled repeat-dose studies in mice, rats, and dogs, systemic exposure to fluticasone furoate increased in approximate proportion with the dose, with no differences between the sexes and no evidence of accumulation. In the repeat-dose studies in dogs where fluticasone furoate was administered intranasally, there was no accumulation at 400 µg/animal/day for 1 month; however, systemic exposure was found to increase slightly over the course of the 6-month intranasal toxicity study.
Distribution
Following intravenous administration, fluticasone furoate had a large steady state volume of distribution in rats, rabbits, and dogs, indicating extensive distribution into tissues.
In vitro plasma protein binding of fluticasone furoate was high (98.5 to 99.9%) in samples from mice, rats, rabbits, dogs and humans.
Metabolism
In vitro studies and in vivo studies in rats and dogs have shown that fluticasone furoate was extensively metabolized. The cytochrome P450 isozyme 3A4 was shown to be specifically involved in the biotransformation of fluticasone furoate. Fluticasone furoate was predominantly metabolized in the presence of hepatocytes from all species.
Excretion
In rats, dogs and humans, following intravenous, oral, or subcutaneous administration, the principal route of elimination of fluticasone furoate was via biliary excretion into the gastro-intestinal tract and subsequent elimination via the feces. There was negligible renal excretion of the parental compound. Following intravenous or oral administration, the majority of the dose was excreted within 24 hours in rats and 48 hours in dogs. Following subcutaneous administration, approximately 50% of the dose was retained at the site of administration.
Drug Interactions
Systemic interactions between fluticasone furoate or its metabolite and other drugs co-administered at therapeutic doses are unlikely due to the pharmacokinetic profile of fluticasone furoate and its low plasma levels following intranasal administration.
3.2.3 Toxicology
Single-Dose Toxicity
Acute oral and inhalation toxicity studies in rats and mice indicate that the potential for toxicity following accidental overdosage of Avamys™ is low, especially since each bottle contains only approximately 3 mg of fluticasone furoate and the systemic bioavailability is ≤ 1%.
Repeat-Dose Toxicity
Repeated administration of fluticasone furoate to mice, rats, and dogs resulted in findings typically associated with systemic exposure to glucocorticoids and commonly reported for other marketed intranasal steroids. These effects included lymphocytopaenia, reduced cellularity of lymphoid tissues and bone marrow, reduced plasma cortisol, adrenocortical atrophy, increased hepatic glycogen, and infection secondary to immunosuppression. Clinical studies showed that repeated intranasal doses of up to 800 µg/day were well tolerated, with generally non-quantifiable levels of fluticasone furoate in plasma. Therefore, the effects seen in animals due to high systemic exposure to fluticasone furoate are not considered to be clinically relevant to the intranasal use of the final product.
Mutagenicity and Genotoxicity
Fluticasone furoate did not cause gene mutations in the Ames test for bacterial mutagenicity or chromosomal damage in the mouse lymphoma in vitro assay. There was also no evidence of genotoxicity in the in vivo mouse micronucleus tests.
Carcinogenicity
The carcinogenicity studies indicate the absence of tumorogenic potential for inhaled fluticasone furoate.
Reproductive and Developmental Toxicity
Findings in the reproductive toxicity studies were typical of those seen following systemic exposure to potent corticosteroids. In view of the low systemic exposure to fluticasone furoate in patients, fetal exposure and therefore potential for reproductive toxicity is expected to be very low. Nevertheless, Avamys™ should be used in pregnancy only if the benefits to the mother outweigh the potential risks to the fetus.
3.2.4 Summary and Conclusion
Primary pharmacodynamic studies have shown that fluticasone furoate is a potent and effective glucocorticoid with a sustained and selective mechanism of action. Safety pharmacology studies revealed no potential effects of fluticasone furoate on the cardiovascular, respiratory, and central nervous systems. A series of non-clinical pharmacokinetic studies showed that systemic interactions between fluticasone furoate and other drugs co-administered at therapeutic doses are unlikely.
The potential for toxicity following accidental over dosage of Avamys™ is low. The results from the non-clinical studies indicate that it is unlikely that Avamys™ would result in significant toxic side effects when administered intranasally in patients with allergic rhinitis.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
In a human pharmacodynamic study, a determination of efficacy was carried out in 55 white/Caucasian patients. An 8-day course of 200 µg of fluticasone furoate significantly reduced symptoms of allergic rhinitis elicited by an allergen challenge commencing one hour after dosing, compared with placebo. The positive effect was sustained over 24 hours suggesting that fluticasone furoate should be efficacious as a once-daily medication in patients with allergic rhinitis.
A placebo-controlled clinical study was carried out in 382 patients with seasonal allergic rhinitis, of which 80% were African American, to determine the onset of action of fluticasone furoate using an allergen challenge chamber (ACC). Patients with a confirmed diagnosis of ragweed allergy were exposed to controlled pollen concentration in an ACC and then treated with a single dose of either fluticasone furoate 110 µg aqueous nasal spray or vehicle placebo nasal spray following which the instantaneous total nasal symptom score (iTNSS) was determined hourly for 12 hours. A statistically significant difference versus placebo was not shown during the entire 12-hour study duration; therefore no efficacy was demonstrated with fluticasone furoate by which an onset of action could be determined based on the results of this study.
The effects on adrenal function were investigated in two controlled clinical trials. No significant systemic effects on serum cortisol concentrations were observed with doses up to 800 µg administered once daily for seven days. No significant differences were seen in 24-hour urinary cortisol excretion between placebo groups and the groups treated with fluticasone furoate.
3.3.2 Pharmacokinetics
Absorption
Following the nasal application of fluticasone furoate to healthy volunteers at the clinical dose of 110 µg/day, the plasma levels were below the quantification limit of 10 pg/mL. At supra-therapeutic dosages of 880 µg given intranasally at 8-hour intervals for 10 doses or 2640 µg/day, the absolute nasal bioavailability was 0.5%. The oral bioavailability of a solution given at a dose of 2000 µg was 1.26%.
Distribution
Following intravenous dosing, fluticasone furoate was extensively distributed. The average volume of distribution at steady state was 608 L which is greater than the total body water for a 70 kg man (42 L).
Metabolism
Fluticasone furoate is primarily metabolized by hepatic metabolism via the cytrochrome P450 isozyme CYP3A4. The primary metabolite of fluticasone furoate was shown to be a pharmacologically inactive carboxylic acid metabolite. In vivo studies have revealed no evidence of cleavage of the furoate moiety to form fluticasone.
Following intravenous dosing, fluticasone furoate was rapidly cleared. The average clearance was 57.4 L/h which was similar to liver plasma flow (49 L/h).
Excretion
Elimination following oral and intravenous administration was predominantly via the feces suggesting biliary excretion. Urinary excretion was a minor route of elimination accounting for approximately 1% and 2% of administered dose following oral and intravenous dosing, respectively.
Interaction Studies
Since fluticasone furoate is primarily metabolized by CYP3A4, the potential for increased exposure to fluticasone furoate when co-administered with a CYP3A4 inhibitor was investigated on the basis of cortisol suppression. The results of that study suggest evidence of increased systemic exposure on co-administration of fluticasone furoate 110 µg given once daily with ketoconazole (200 mg) compared with placebo because fluticasone furoate was quantifiable in 6 out of 20 subjects with the administration of ketoconazole compared with only 1 out of 20 subjects after placebo. Results showed no effect on serum cortisol levels. It should be noted that the dose of 200 mg ketoconazole used in this study is only half of the maximum daily dose of 400 mg, so the potential for further interaction of fluticasone furoate with ketoconazole remains. A warning concerning the potential for increased fluticasone furoate plasma concentration resulting in markedly reduced serum cortisol concentration when Avamys™ is co-administrated with potent CYP3A4 inhibitors such as ritonavir and ketoconazole, is included in the Product Monograph.
3.3.3 Clinical Efficacy
Four pivotal studies (FFR20001, FFR30003, FFR103184, FFR104861) were submitted to support the efficacy of Avamys™ (fluticasone furoate nasal spray) 110 µg once daily in the treatment of patients with seasonal allergic rhinitis (12 years of age and older). All of the studies were randomized, double-blind, placebo-controlled, parallel-group, multicentre studies. A total of 1527 patients were enrolled; 571 received Avamys™. Together, these studies evaluated a broad spectrum of seasonal allergens (i.e. trees, grasses and weeds) known to trigger seasonal allergic rhinitis (SAR).
Studies FFR30003, FFR103184, and FFR104861 were Phase III studies. Study FFR2001 was a Phase IIb dose-ranging study that compared the safety and efficacy of once-daily doses of fluticasone furoate nasal spray 55 µg, 110 µg, 220 µg, and 440 µg with placebo for 14 days in patients with SAR. The once-daily dose of 110 µg was selected as the dose that provided the optimal risk-benefit ratio for further study in the Phase III allergic rhinitis clinical programme.
The primary efficacy endpoint in the pivotal studies was based on the daily assessment of nasal symptoms (rhinorrhea, nasal congestion, nasal itching, and sneezing) using the reflective total nasal symptom score (rTNSS). The key secondary efficacy endpoints in all pivotal studies were the morning (AM) pre-dose instantaneous total nasal symptom score (iTNSS) and overall evaluation of response to therapy (evaluated on a 7-point categorical scale). The three Phase III pivotal studies also had an additional key secondary efficacy endpoint, reflective total ocular symptom score (rTOSS). Other secondary endpoints were AM rTNSS, PM rTNSS, individual nasal symptoms (rhinorrhea, nasal congestion, nasal itching and sneezing), and instantaneous total ocular symptom scores (iTOSS). The Intent-to-Treat (ITT) population was defined as all randomized subjects who receive at least one dose of study drug. The ITT population was used for all efficacy, safety, and health outcomes analyses.
The results from the four pivotal studies showed that patients treated with Avamys™ exhibited statistically significant reductions from baseline for the primary endpoint (daily rTNSS) compared to patients treated with placebo. In addition, treatment with Avamys™ was also shown to be clinically relevant compared to placebo for the primary efficacy endpoint in three of the four pivotal studies.
In adult and adolescent patients, the improvement of nasal symptoms in the Phase III studies with Avamys™ compared with placebo persisted for a full 24 hours, as evaluated by mean AM pre-dose iTNSS.
The three Phase III studies confirmed the efficacy on ocular symptoms demonstrated in the Phase IIb study. Across all three studies, Avamys™ exhibited statistically significant decreases in rTOSS that were greater than those of placebo-treated patients. These findings were generally supported by the mean change from baseline in AM pre-dose iTOSS, AM and PM rTOSS, and by individual ocular symptom scores, where Avamys™ showed significantly greater improvements compared with placebo for most endpoints.
For overall evaluation of response to therapy in adult and adolescent subjects, the treatment difference between Avamys™ and placebo was statistically significant in the integrated analysis of the four pivotal studies. More patients who were treated with Avamys™ reported being moderately to significantly improved compared with those treated with placebo: 52% and 30%, respectively.
Onset of action was investigated in the four pivotal studies. In two studies, the onset of action was observed at 8 hours after initial administration (FFR20001 and FFR104861) as evaluated by mean AM pre-dose iTNSS. In a third study (FFR103814), a significant improvement in nasal symptoms occurred within the first day (12 to 24 hours) following initial administration. In the fourth study (FFR30003), a significant difference in mean AM pre-dose iTNSS compared with placebo was observed at 24 hours, but was not consistently maintained until Day 6.
3.3.4 Clinical Safety
Four pivotal studies (FFR20001, FFR30003, FFR103184, FFR104861) and eight non-pivotal clinical studies were submitted to support the safety of Avamys™ (fluticasone furoate nasal spray) in the treatment of seasonal allergic rhinitis in adults and adolescents (12 years of age and older). The total number of patients randomized to Avamys™ was 1990 of which 571 patients received Avamys™ (110 µg once daily administered as two sprays in each nostril) in the pivotal trials. Of these patients, 198 adolescent patients (ages 12 to <18 years of age) were treated for a mean exposure period of 172 days.
The majority of studies in this program were two to twelve weeks in treatment duration, and thus approximately 80% of the patient exposures were 12 weeks or less. In the safety database of fluticasone furoate, 547 (27%) of the patients exposed to fluticasone furoate 110 µg were exposed to treatment for a period ≥ 3 months, 501 (25%) were exposed for a period of ≥ 6 months, 473 (24%) were exposed for a period of ≥ 9 months, and 400 (20%) of the patients treated with fluticasone furoate were exposed for ≥ 12 months. Overall, the numbers of subjects exposed to fluticasone furoate met the International Conference on Harmonization (ICH) Guidance E1 for extent of population exposure to assess clinical safety.
In six adult and adolescent studies, adverse events were reported with approximately the same frequency by patients treated with Avamys™ ( fluticasone furoate nasal spray) 110 µg and those treated with placebo. Headache was the most commonly reported adverse event in both the Avamys™ group and in placebo group, occurring at incidences of 9% and 7%, respectively. Epistaxis was the next most commonly reported adverse event, occurring at an incidence of 6% and 4%, respectively, in the Avamys™ group and placebo group.
In the one-year long-term safety study, adult and adolescent patients were randomized for treatment with Avamys™ 110 µg or placebo nasal spray, in a 3 to 1 ratio (605 patients for Avamys™ and 201 patients for placebo). Epistaxis was more commonly reported in the Avamys™ group compared to the placebo group, with incidences of 20% and 8%, respectively. Epistaxis led to withdrawal of 15 patients (2%) receiving Avamys™ and none receiving placebo. Presence of small/large turbinate or septum ulcers for all visits was similar between the Avamys™ group (0 -6%) and the placebo group (0-4%). Nasopharyngitis occurred at similar incidences in both treatment groups (26% and 25% for the Avamys™ and placebo groups, respectively). Nasopharyngitis was deemed unrelated to the study drug for all patients except for four in the Avamys™ group and two in the placebo group.
Findings from the ophthalmic examinations demonstrated that 12 patients (2%) treated with Avamys™ had an isolated increase in intraocular pressure (in at least one eye) compared to none in the placebo group. Events in all patients were considered to be related to study treatment. In ophthalmic examinations, seven subjects (1%) treated with Avamys™ were identified as having cataracts during the study that were not present at baseline. Increased intraocular pressure and cataracts are highlighted under the Warnings and Precautions section of the Avamys™ Product Monograph.
During the clinical studies, evidence of localized infections of the nose with Candida albicans was seen on nasal exams in 7 of 2,745 patients treated with Avamys™ and was reported as an adverse event in 3 patients.
Five clinical studies examined the effects of fluticasone furoate on Hypothalamic Pituitary Adrenal (HPA) axis function as assessed by 24-hour serum cortisol profiles and 24-hour urine cortisol excretion. Avamys™ was not associated with HPA axis suppression in adults and adolescents.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Avamys™ 110 µg once daily has been shown to be effective in the treatment of seasonal allergic rhinitis in patients 12 years of age and older. Avamys™ was statistically significant and clinically meaningful in the primary efficacy endpoint of reflective total nasal symptoms score (rTNSS). Furthermore, Avamys™ demonstrated significant improvements in ocular symptoms. The onset of action was shown at 8 hours in two of the four adult and adolescent seasonal allergic rhinitis studies, and at 12 to 24 hours in one of the other studies.
The safety data from the pivotal and non-pivotal studies are in general as expected for this therapeutic class and do not reveal signals of any new concerns. The incidence of epistaxis was higher in the long-term study as compared to the short-term studies in adults and adolescents. Across the clinical studies, there was a low incidence of serious adverse events and adverse events leading to withdrawal. No deaths were reported in any of the studies. The HPA axis suppression was not observed at the proposed dose of 110 µg once daily. The ophthalmic examinations indicated a higher rate of increased intraocular pressure and cataracts which is captured in the Warnings and Precautions section of the Product Monograph.
Avamys™ (fluticasone furoate nasal spray) is cleared by extensive first-pass metabolism mediated by the cytochrome P450 isozyme CYP3A4. A warning concerning the potential for increased fluticasone furoate plasma concentration resulting in markedly reduced serum cortisol concentration when Avamys™ is co-administrated with potent CYP3A4 inhibitors such as ritonavir and ketoconazole is included in the Product Monograph.
In conclusion, the benefits of Avamys™ outweigh the risks. Based on results from the pivotal clinical studies, Avamys™ 110 µg is recommended for treatment of seasonal allergic rhinitis in adults and adolescents 12 years of age and older.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Avamys™ is favourable in the treatment of seasonal allergic rhinitis and its associated symptoms in patients 12 years of age and older. 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: AvamysTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2006-05-17 |
| Submission filed | 2006-07-24 |
| Screening | |
| Screening Deficiency Notice issued | 2006-09-08 |
| Response filed | 2006-09-12 |
| Screening Acceptance Letter issued | 2006-10-20 |
| Review | |
| Quality Evaluation complete | 2007-08-10 |
| Clinical Evaluation complete | 2007-08-10 |
| Labelling Review complete | 2007-08-10 |
| NOC issued by Director General | 2007-08-14 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| AVAMYS | 02298589 | GLAXOSMITHKLINE INC | FLUTICASONE FUROATE 27.5 MCG / ACT |