Summary Basis of Decision for Dymista

Clinical Pharmacology

Dymista contains azelastine hydrochloride and fluticasone propionate, which have different modes of action and show synergistic effects in terms of improvement of allergic rhinitis. Fluticasone propionate is a synthetic trifluorinated corticosteroid that possesses a very high affinity for the glucocorticoid receptor and has a potent anti-inflammatory action. Azelastine, a phthalazinone derivative, is classified as a potent long-acting anti-allergic compound with selective H1-antagonist, mast cell stabilizing and anti-inflammatory properties.

As the two medicinal ingredients of Dymista have been marketed worldwide for over 20 years, no new clinical pharmacology studies were conducted. The clinical pharmacodynamic/pharmacokinetic information was primarily a summary of the available published information on the two ingredients, with the exception of two pharmacokinetic interaction studies that were conducted to assess the impact of each ingredient on the absorption of the other. Single dose intranasal administration of Dymista did not result in any clinically significant change in systemic exposure to either ingredient.

Overall, the clinical pharmacological data support the use of Dymista for the specified indication. For further details, please refer to the Dymista Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Dymista (137 mcg azelastine hydrochloride and 50 mcg fluticasone propionate) in patients with seasonal allergic rhinitis (SAR) was evaluated in three pivotal Phase III, 2-week randomized, double-blind, parallel-group, multicentre, placebo-controlled studies (MP4002, MP4004, and MP4006). Patients with moderate to severe nasal symptoms were randomized to one of four treatment groups; one spray per nostril twice daily of Dymista, azelastine hydrochloride nasal spray, fluticasone propionate nasal spray, or vehicle placebo. The azelastine hydrochloride and fluticasone propionate comparators used the same device and vehicle as Dymista nasal spray and are not commercially marketed.

A total of 848 patients (760 adults and 88 adolescents) were treated with Dymista twice per day. The population of the studies was 64% female, 36% male; 80% white, 16% black, 2% Asian, 1% other. Approximately 10% of the patients were 12-18 years of age while only 2% were over 65 years of age.

During the pivotal studies, nasal symptoms of itchy nose, nasal congestion, runny nose, sneezing, and ocular symptoms of itchy eyes, watery eyes, and eye redness were rated twice daily in a diary, using a 4-point scale from 0 (no symptoms) to 3 (severe symptoms). The scores were summed up to a total nasal symptom score (TNSS) and a total ocular symptom score (TOSS), respectively. The primary efficacy endpoint was the change from baseline in the combined (daytime plus nighttime) 12-hour reflective total nasal symptom score (crTNSS: maximum possible score of 24) over the 14-day study period versus (vs.) placebo, azelastine hydrochloride, or fluticasone propionate alone. The key secondary efficacy endpoint in Studies MP4004 and MP4006 was the change from baseline in combined (daytime plus nighttime) 12-hour reflective total ocular symptom score (crTOSS). Other endpoints included measurements for instantaneous TNSS (iTNSS), onset of action, post-nasal drip and quality of life scores [Rhinoconjunctivitis Quality of Life (RQLQ)].

Dymista demonstrated a consistent benefit over placebo in terms of reducing crTNSS. In each pivotal study, Dymista was statistically and clinically significantly superior to placebo and the monotherapy components (azelastine alone and fluticasone alone). For study MP4002, the absolute reductions [least square (LS) mean] in crTNSS from baseline for Dymista, fluticasone propionate, azelastine hydrochloride, and placebo were -5.6, -4.7, -4.2, and -2.9, respectively. For study MP4004, the absolute reductions (LS mean) in crTNSS from baseline for Dymista, fluticasone propionate, azelastine hydrochloride, and placebo were -5.5, -4.6, -4.5, and -3.0, respectively. For study MP4006, the absolute reductions (LS mean) in crTNSS from baseline for Dymista, fluticasone propionate, azelastine hydrochloride, and placebo were -5.5, -4.9, -4.8, and -3.4, respectively.

For the primary efficacy endpoint, crTNSS, the effect of Dymista was statistically significantly greater than that of formulation-matched single ingredient azelastine or fluticasone products. However, when analyzed on a day to day basis, this appears to be driven by a treatment advantage during the first few days of treatment, as the differences between Dymista and fluticasone alone on daily crTNSS generally ceased to be statistically significant after 3-5 days. After this time, there appears little benefit over fluticasone alone, with few instances where the effects of Dymista were statistically significantly better than fluticasone alone.

Compared to placebo, Dymista demonstrated greater improvements in the secondary endpoints: crTOSS, individual nasal and ocular symptoms, RQLQ, and post nasal drip score, in all three pivotal studies.

For many of the secondary endpoints, the results of Dymista were not statistically significantly better than fluticasone alone. However, despite the lack of consistent statistically significant benefits, the results obtained with Dymista were consistently numerically superior to fluticasone alone for all endpoints assessed. Comparisons against azelastine alone were considered of less relevance as there are currently no azelastine monotherapy products on the Canadian market.

During the original filing of this New Drug Submission (NDS), the proposed indication by the sponsor was the following: Dymista is indicated for the symptomatic treatment of moderate to severe seasonal allergic rhinitis and rhinoconjunctivitis in adults and adolescents aged 12 years and older.

The indication which has been approved by Health Canada is as follows: Dymista is indicated for symptomatic treatment of moderate to severe seasonal allergic rhinitis (SAR) and associated ocular symptoms in adults and adolescents aged 12 years and older for whom monotherapy with either antihistamines or intranasal corticosteroids is not considered sufficient.

Rhinoconjunctivitis was removed from the indication as it is considered to include perennial allergic rhinitis. A claim for perennial allergic rhinitis was not made in this submission and would require separate clinical studies to support the safety and efficacy for this indication. Also, a qualifying statement was added to the indication to limit use to patients for whom monotherapy is not considered sufficient. This is consistent with current treatment guidelines and general principles for a step wise approach to treatment wherein combination therapy is initiated only when single ingredient products are not effective.

Overall, the submitted clinical studies demonstrated that Dymista was effective in reducing both nasal and ocular symptom scores associated with SAR, as well as in improving individual nasal and ocular symptoms, RQLQ, and reducing post-nasal drip scores to a greater extent than placebo.

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

Clinical Safety

The clinical safety of Dymista was evaluated in three 2-week pivotal studies (described in the Clinical Efficacy section) and one non-pivotal 2-week, randomized, double-blind placebo-controlled study. A total of 1,006 patients (97 adolescents and 909 adults) with Seasonal Allergic Rhinitis (SAR) were treated with Dymista twice per day per nostril. Long-term safety was evaluated in a 12-month, open-label, active-controlled study in which 404 patients (28 adolescents and 376 adults) with perennial allergic rhinitis or vasomotor rhinitis were treated with Dymista (1 spray per nostril twice daily) and 207 patients were treated with fluticasone propionate nasal spray (2 sprays per nostril once daily).

In the four 2-week SAR studies, the percentage of patients with any treatment-emergent adverse event was low in all treatment groups and the majority of these events were mild in nature. Only three patients [2 patients (0.2%) treated with Dymista, 1 patient (0.1%) treated with placebo] had serious adverse events; none of these events were considered to be related to the study drug. No deaths were reported in these studies. The most common treatment-emergent adverse events reported for Dymista were (in decreasing order of magnitude): dysgeusia (4.1%), epistaxis (2.2%) and headache (2.2%). Oropharyngeal pain, mucosal erosion, nasal discomfort, somnolence, upper respiratory tract infection, nausea and cough were also reported in 0.5 to 0.9% of the pooled study population.

The 12-month safety study demonstrated that prolonged use does not significantly alter the safety profile of Dymista. The nature and severity of adverse events seen in this study were similar to those reported in the 2-week SAR studies, albeit with somewhat higher incidences, which is not unexpected given the longer duration of treatment. The severity of adverse events was generally mild or moderate.

All the studies demonstrated that the safety profile for Dymista was similar to that seen with either fluticasone or azelastine monotherapy treatment.

Since Dymista was approved for use by the United States Food and Drug Administration (FDA) in September 2012, a total of 42 medically confirmed post-market case reports were registered, comprising of a total of 68 adverse events. Of these 68, 3 events were considered as serious, including nasal septum perforation (2 cases) and convulsion (1 case) although the latter was deemed non-valid as insufficient information was provided. The 65 non-serious adverse events were reflective of the adverse event profiles seen in the clinical studies, with the most frequently reported being epistaxis, headache, nasal dryness and burning sensation.

A Risk Management Plan (RMP) was reviewed by Health Canada. The Dymista Product Monograph was revised to include various post-market findings, the risk of infection/immune suppression in the Warnings and Precautions section, and concern regarding the lack of clinical trial experience in patients with cardiac-related diseases.  Health Canada intends to screen the updated RMP approximately 1 year after issuance of the Notice of Compliance and to screen Periodic Benefit-Risk Evaluation Reports (PBRERs) for the first three years of marketing with particular attention given to cardiac-related adverse events as well as the identified and potential risks outlined in the RMP. Additionally, the Product Monograph was revised to include sections under Warning and Precautions regarding the potential for slowed wound healing and somnolence that may be associated with Dymista treatment. All of the listed Warnings and Precautions are consistent with those for currently marketed intranasal corticosteroid or antihistamine nasal spray preparations.

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