Regulatory Decision Summary for Dymista

Dymista has previously been established in adolescents and adults as providing seasonal allergic rhinitis (SAR) symptom relief superior to that of monotherapy with its constituent drugs, fluticasone propionate or azelastine hydrochloride. In a 2-week randomized double-blind, placebo-controlled clinical study in children aged 6-11 years with SAR, symptom relief in children treated with Dymista was numericallysuperior compared to placebo. However, a statistically significant benefit was not shown with Dymista in treating nasal or ocular symptoms. The mean difference of -0.8 Total Nasal Symptom Score (TNSS) points between Dymista and placebo did exceed the minimal clinically important difference established in adults, which has been estimated at between 0.23-0.59 TNSS points on the 12-point scale. Efficacy can also be inferred in children 6-11 years of age based on extrapolation from efficacy data in adolescents and adults and based on the demonstrated symptom relief produced by the monocomponents in children.

Both fluticasone propionate and azelastine are considered effective therapies for treating Allergic Rhinitis (AR) in children. Fluticasone propionate is currently approved for use in persons aged 4 and up in Canada for the treatment of SAR and perennial AR. Azelastine hydrochloride is not approved as a monotherapy in Canada, though it is approved for use in children and adults in Europe, the United States , Australia and many other countries. Studies provided by the sponsor in the current submission were generally supportive of the efficacy and safety of azelastine monotherapy in treating AR in children ≥ 6 years of age. In addition to the demonstrated efficacies of the monocomponents, secondary efficacy endpoints were supportive of a treatment benefit with Dymista used in children. This included numerically superior, but statistically insignificant, changes from baseline in instantaneous TNSS and reflective Total Ocular Symptom Score. Dymista also provided a statistically significant benefit compared to placebo for overall AR symptom improvements based on a paediatric rhinoconjunctivitis quality of life questionnaire in 6-11 year-old children. In consideration of this data along with data generated from monotherapies in younger children, and data generated in adolescents and adults with the fixed-dose combination, there is reasonable support for the efficacy of Dymista in the paediatric population 6-11 years of age.

Difficulty in demonstrating a statistically significant benefit in 6-11 year-old children may be due to a reduced treatment benefit in children, a high placebo effect, and/or the inappropriateness of the testing methods. A reduced treatment benefit for AR drugs in children in general is indicated by the smaller treatment effect size consistently observed in paediatric clinical trials. The generally high placebo effect seen with AR medication use, which may contribute to an apparent reduced treatment effect, was particularly prominent with the caregiver/parent reflective Total Nasal Symptom Score (rTNSS) assessments in the sponsors submitted paediatric studies. The use of rTNSS as the primary efficacy endpoint reflects the fact that assessments of TNSS are the only generally accepted clinical endpoint to demonstrate AR drug efficacy for regulatory approval. TNSS was the primary endpoint used in clinical trials that assessed the efficacy of Dymista in adolescents and adults, as well as fluticasone propionate and azelastine monotherapies in children. However, rTNSS has not been validated for use in children. The sponsors post hoc analysis indicated that the use of this assessment tool in children who are incapable of self-assessing symptoms is inappropriate. Thus, TNSS is of limited utility in accurately assessing treatment effect in young children incapable of self-assessing.

The safety of Dymista in children aged 6-11 years was established in the 2-week study discussed above and in a separate 3-month safety study. Adverse effects were consistent with what has been observed in studies using adolescents and adults. The most common treatment-related adverse events were nosebleeds, headaches, and altered sense of taste. No serious side effects were reported that were attributable to the use of the drug.

Given the clinically meaningful SAR symptom relief in children aged 6-11 years treated with Dymista, and the acceptable safety profile of this combination drug, the overall potential benefits outweigh the potential harms for an expanded paediatric indication.

Onset of action information was added to the Clinical Trials section of the Dymista Product Monograph (PM) based on the results of a randomized, active and placebo-controlled, double-blinded three-way crossover pollen chamber study. This made use of a newly developed electronic scoring system that enabled the demonstration of a rapid onset of action; 5 minutes for nasal symptom relief and 10 minutes for ocular symptom relief. Results from a responder analysis, which the sponsor was requested to include in the updated PM, indicated a median time to reach 50% nasal symptom reduction of 30 minutes with Dymista, consistent with the onset of action time determined from the pivotal clinical studies conducted for the initial approval of Dymista. The newly added data was consistent with prior knowledge regarding the rapid onset of action with antihistamine nasal sprays, in general.

In summary the benefit-risk-uncertainty assessment of Dymista was favourable for the recommended indication.