CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`202236Orig1s000
`
`MEDICAL REVIEW(S)
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`

`

`CLINICAL REVIEW
`
`Application Type NDA
`Application Number(s) 202-236
`Priority or Standard Standard
`
`Submit Date(s) April 1, 2011
`Received Date(s) April 1, 2011
`PDUFA Goal Date February 1, 2012
`Division / Office DPARP/ODE II
`
`Reviewer Name(s)
`Jennifer Rodriguez Pippins, MD, MPH
`Review Completion Date March 27, 2012
`
`Established Name azelastine hydrochloride / fluticasone
`propionate
`(Proposed) Trade Name Dymista
`Therapeutic Class antihistamine/ corticosteroid
`Applicant Meda Pharmaceuticals
`
`Formulation(s) azelastine hydrochloride 0.1%/
`fluticasone propionate 0.037% nasal
`spray
`Dosing Regimen 1 spray per nostril twice daily
`(Total Daily Dose: 548 μg azelastine,
`200 μg fluticasone)
`Indication(s) Seasonal allergic rhinitis
`Intended Population(s) Patients 12 years of age and older
`Template Version: March 6, 2009
`
`Reference ID: 3107643
`
`

`

`Clinical Review
`Jennifer Rodriguez Pippins, MD, MPH
`NDA 202-236
`Dymista (azelastine hydrochloride 0.1% / fluticasone propionate 0.037% nasal spray)
`
`
`Table of Contents
`
`
`
`2
`
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ......................................... 8
`1.1 Recommendation on Regulatory Action ............................................................. 8
`1.2 Risk Benefit Assessment.................................................................................... 9
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies . 10
`1.4 Recommendations for Postmarket Requirements and Commitments .............. 10
`INTRODUCTION AND REGULATORY BACKGROUND ...................................... 10
`2.1 Product Information .......................................................................................... 10
`2.2 Tables of Currently Available Treatments for Proposed Indications ................. 11
`2.3 Availability of Proposed Active Ingredient in the United States ........................ 11
`2.4
`Important Safety Issues With Consideration to Related Drugs......................... 13
`2.5 Summary of Presubmission Regulatory Activity Related to Submission .......... 13
`2.6 Other Relevant Background Information .......................................................... 15
`3 ETHICS AND GOOD CLINICAL PRACTICES....................................................... 15
`3.1 Submission Quality and Integrity ...................................................................... 15
`3.2 Compliance with Good Clinical Practices ......................................................... 16
`3.3 Financial Disclosures........................................................................................ 16
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ......................................................................................................... 16
`4.1 Chemistry Manufacturing and Controls ............................................................ 16
`4.2 Clinical Microbiology......................................................................................... 17
`4.3 Preclinical Pharmacology/Toxicology ............................................................... 17
`4.4 Clinical Pharmacology...................................................................................... 18
`4.4.1 Mechanism of Action.................................................................................. 18
`4.4.2 Pharmacodynamics.................................................................................... 18
`4.4.3 Pharmacokinetics....................................................................................... 18
`5 SOURCES OF CLINICAL DATA............................................................................ 20
`5.1 Tables of Studies/Clinical Trials ....................................................................... 20
`5.2 Review Strategy ............................................................................................... 21
`5.3 Discussion of Individual Studies/Clinical Trials................................................. 22
`6 REVIEW OF EFFICACY......................................................................................... 37
`Efficacy Summary...................................................................................................... 37
`6.1
`Indication .......................................................................................................... 38
`6.1.1 Methods ..................................................................................................... 38
`6.1.2 Demographics............................................................................................ 39
`Subject Disposition................................................................................................. 40
`6.1.4 Analysis of Primary Endpoint(s) ................................................................. 41
`6.1.5 Analysis of Secondary Endpoints(s) .......................................................... 44
`
`Reference ID: 3107643
`
`2
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`

`

`
`
`Clinical Review
`Jennifer Rodriguez Pippins, MD, MPH
`NDA 202-236
`Dymista (azelastine hydrochloride 0.1% / fluticasone propionate 0.037% nasal spray)
`
`
`6.1.6 Other Endpoints ......................................................................................... 49
`6.1.7 Subpopulations .......................................................................................... 50
`6.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations .... 52
`6.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects................. 52
`6.1.10 Additional Efficacy Issues/Analyses........................................................... 53
`7 REVIEW OF SAFETY............................................................................................. 54
`Safety Summary ........................................................................................................ 54
`7.1 Methods............................................................................................................ 56
`7.1.1 Studies/Clinical Trials Used to Evaluate Safety ......................................... 56
`7.1.2 Categorization of Adverse Events.............................................................. 65
`7.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare
`Incidence.................................................................................................... 66
`7.2 Adequacy of Safety Assessments .................................................................... 67
`7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of
`Target Populations..................................................................................... 67
`7.2.2 Explorations for Dose Response................................................................ 70
`7.2.3 Special Animal and/or In Vitro Testing ....................................................... 71
`7.2.4 Routine Clinical Testing ............................................................................. 71
`7.2.5 Metabolic, Clearance, and Interaction Workup .......................................... 71
`7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class .. 71
`7.3 Major Safety Results ........................................................................................ 71
`7.3.1 Deaths........................................................................................................ 71
`7.3.2 Nonfatal Serious Adverse Events .............................................................. 72
`7.3.3 Dropouts and/or Discontinuations .............................................................. 73
`7.3.4 Significant Adverse Events ........................................................................ 75
`7.3.5 Submission Specific Primary Safety Concerns .......................................... 76
`7.4 Supportive Safety Results ................................................................................ 80
`7.4.1 Common Adverse Events .......................................................................... 80
`7.4.2 Laboratory Findings ................................................................................... 83
`7.4.3 Vital Signs .................................................................................................. 85
`7.4.4 Electrocardiograms (ECGs) ....................................................................... 87
`7.4.5 Special Safety Studies/Clinical Trials......................................................... 87
`7.4.6
`Immunogenicity.......................................................................................... 90
`7.5 Other Safety Explorations................................................................................. 90
`7.5.1 Dose Dependency for Adverse Events ...................................................... 90
`7.5.2 Time Dependency for Adverse Events....................................................... 90
`7.5.3 Drug-Demographic Interactions ................................................................. 90
`7.5.4 Drug-Disease Interactions.......................................................................... 91
`7.5.5 Drug-Drug Interactions............................................................................... 92
`7.6 Additional Safety Evaluations ........................................................................... 92
`7.6.1 Human Carcinogenicity.............................................................................. 92
`7.6.2 Human Reproduction and Pregnancy Data................................................ 93
`7.6.3 Pediatrics and Assessment of Effects on Growth ...................................... 93
`
`Reference ID: 3107643
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`

`

`Clinical Review
`Jennifer Rodriguez Pippins, MD, MPH
`NDA 202-236
`Dymista (azelastine hydrochloride 0.1% / fluticasone propionate 0.037% nasal spray)
`
`
`7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound...................... 95
`7.7 Additional Submissions / Safety Issues............................................................ 95
`8 POSTMARKET EXPERIENCE............................................................................... 96
`
`
`
`9 APPENDICES ........................................................................................................ 97
`9.1 Literature Review/References .......................................................................... 97
`9.2 Labeling Recommendations ............................................................................. 97
`9.3 Advisory Committee Meeting............................................................................ 99
`
`
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`Reference ID: 3107643
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`4
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`

`

`Clinical Review
`Jennifer Rodriguez Pippins, MD, MPH
`NDA 202-236
`Dymista (azelastine hydrochloride 0.1% / fluticasone propionate 0.037% nasal spray)
`
`
`Table of Tables
`
`
`
`Table 1. FDA-Approved Nasal Sprays for Seasonal Allergic Rhinitis............................ 11
`Table 2. Point Estimates and 90%-Confidence Intervals for Pharmacokinetic Ratios... 19
`Table 3. Clinical development program for MP29-02 .................................................... 20
`Table 4. 2-week Phase 3 Efficacy and Safety Trials ..................................................... 22
`Table 5. Prohibited medications and washout periods, Trials MP-4001, MP-4002, MP-
`4004, and MP-4006 ....................................................................................... 28
`Table 6. Schedule of Trial Procedures, Trials MP-4001, MP-4002, MP-4004, and MP-
`4006............................................................................................................... 30
`Table 7. Demographics and Baseline Characteristics for the pooled ITT population,
`Trials MP-4002, MP-4004, and MP-4006....................................................... 39
`Table 8. Subject Disposition: Trials MP-4002, MP-4004, and MP-4006........................ 41
`Table 9. rTNSS (AM and PM Combined), Change from Baseline over the 14-Day
`Treatment Period, ITT Population, Analysis using Imputed Scores ............... 42
`Table 10. rTNSS, Results Based on Imputed Scores vs. Raw Scores.......................... 43
`Table 11. iTNSS (AM and PM Combined), Change from Baseline over the 14-Day
`Treatment Period, ITT Population, Analysis using Imputed Scores ............... 44
`Table 12. iTNSS, Results Based on Imputed Scores vs. Raw Scores .......................... 45
`Table 13. rTOSS (AM and PM Combined), Change from Baseline over the 14-Day
`Treatment Period, ITT Population, Analysis using Imputated Scores ............ 46
`Table 14. rTOSS, Results based on Imputed Scores vs. Raw Scores.......................... 47
`Table 15. Change from Baseline to Day 14 in RQLQ Overall Score, ITT Population, Age
`18 or older...................................................................................................... 48
`Table 16. Change from Baseline in 4-Hour iTNSS, ITT Population: Trials MP-4002, MP-
`4004, MP-4006 .............................................................................................. 49
`Table 17. rTNSS (AM and PM Combined), Change from Baseline over the 14-Day
`Treatment Period, Pooled ITT Population by Age: Trials MP-4001, MP-4002,
`MP-4004, and MP-4006................................................................................. 51
`Table 18. rTNSS (AM and PM Combined), Change from Baseline over the 14-Day
`Treatment Period, Pooled ITT Population by Gender: Trials MP-4001, MP-
`4002, MP-4004, and MP-4006....................................................................... 51
`Table 19. rTNSS (AM and PM Combined), Change from Baseline over the 14-Day
`Treatment Period, Pooled ITT Population by Race: Trials MP-4001, MP-4002,
`MP-4004, and MP-4006................................................................................. 51
`Table 20. rTNSS (AM and PM Combined), Change from Baseline over the 14-Day
`Treatment Period, Pooled ITT Population by Ethnicity: Trials MP-4001, MP-
`4002, MP-4004, and MP-4006....................................................................... 52
`Table 21. rTNSS (AM and PM Combined), Change from Baseline over the 14-Day
`Treatment Period, ITT Population, Analysis using Imputed Scores, Trial MP-
`4001............................................................................................................... 53
`Table 22. Focused Nasal Examination, Components and Grading............................... 57
`Table 23. Prohibited medications and washout periods, Trial MP-4000........................ 61
`Table 24. Schedule of Trial Procedures, Trial MP-4000................................................ 62
`
`Reference ID: 3107643
`
`5
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`

`

`
`
`Clinical Review
`Jennifer Rodriguez Pippins, MD, MPH
`NDA 202-236
`Dymista (azelastine hydrochloride 0.1% / fluticasone propionate 0.037% nasal spray)
`
`Table 25. Duration of Exposure and Compliance, Safety Population: Trials MP-4002,
`MP-4004, MP-4006........................................................................................ 67
`Table 26. Duration of Exposure and Compliance, Safety Population: Trial MP-4000 ... 68
`Table 27. Surrogate markers for compliance, ITT Population: MP-4000....................... 68
`Table 28. Demographics and Baseline Characteristics for the Safety population, Trial
`MP-4000 ........................................................................................................ 69
`Table 29. SAEs for the Safety Population, Trials MP-4002, MP-4004, and MP-4006 ... 72
`Table 30. SAEs for the Safety Population, Trials MP-4000........................................... 72
`Table 31. Adverse Events Leading to Discontinuation of Treatment, Safety Population,
`Trials MP-4002, MP-4004, and MP-4006....................................................... 73
`Table 32. Adverse Events Leading to Discontinuation of Treatment, Safety Population,
`Trial MP-4000 ................................................................................................ 74
`Table 33. Results of Nasal Examinations at Day 14/ET, Safety Population: Trials MP-
`4002, MP-4004, MP-4006.............................................................................. 76
`Table 34. Results of Nasal Examinations, Safety Population: Trial MP-4000 ............... 78
`Table 35. Results of Ophthalmic Examinations, Safety Population: Trial MP-4000 ...... 80
`Table 36. TEAEs with an Incidence ≥ 0.5% in MP29-02 Treatment Group, by
`Decreasing Order of Frequency, Safety Population: Trials MP-4002, MP-4004,
`MP-4006 ........................................................................................................ 81
`Table 37. TEAEs with an Incidence ≥ 2.0% in MP29-02 Treatment Groups, by
`Decreasing Order of Frequency, Safety Population: Trial MP-4000 .............. 82
`Table 38. TEAEs Reported for X-03065-3282 and X-03065-3283 ................................ 83
`Table 39. Shifts in Hematology Laboratory Parameters, Safety Population: Trial MP-
`4000............................................................................................................... 84
`Table 40. Shifts in Chemistry Laboratory Parameters, Safety Population: Trial MP-4000
`....................................................................................................................... 84
`Table 41. Baseline and Changes in Vital Signs, Safety Population: Trials MP-4001, MP-
`4002, MP-4004, MP-4006.............................................................................. 85
`Table 42. Baseline and Changes in Vital Signs, Safety Population: Trial MP-4000 ...... 86
`Table 43. Fasting Serum Cortisol, Safety Population: Trial MP-4000 (HPA-Axis
`Substudy)....................................................................................................... 88
`Table 44. Percent Change in Fasting Serum Cortisol, Safety Population: Trial MP-4000
`(HPA-Axis Substudy) ..................................................................................... 88
`Table 45. Shifts in Serum Cortisol, Safety Population: Trial MP-4000 (HPA-Axis
`Substudy)....................................................................................................... 89
`Table 46. Frequency of AEs by Demographic Characteristics, Safety Population: Trials
`MP-4001, MP-4002, MP-4004, MP-4006....................................................... 90
`Table 47. Overview of AEs by Disease Subgroup, Safety Population: Trial MP-4000 .. 92
`Table 48. Table of rTNSS and iTNSS Results Proposed for Inclusion in the Product
`Label .............................................................................................................. 99
`
`
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`Reference ID: 3107643
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`6
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`

`

`Clinical Review
`Jennifer Rodriguez Pippins, MD, MPH
`NDA 202-236
`Dymista (azelastine hydrochloride 0.1% / fluticasone propionate 0.037% nasal spray)
`
`
`Table of Figures
`
`
`
`Figure 1. General Trial Design: Trials MP-4001, MP-4002, MP-4004, MP-4006........... 23
`Figure 2. General Trial Design: Trial MP-4000.............................................................. 58
`
`
`Reference ID: 3107643
`
`7
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`

`

`Clinical Review
`Jennifer Rodriguez Pippins, MD, MPH
`NDA 202-236
`Dymista (azelastine hydrochloride 0.1% / fluticasone propionate 0.037% nasal spray)
`
`
`
`
`1 Recommendations/Risk Benefit Assessment
`
`
`1.1 Recommendation on Regulatory Action
`
`The clinical recommendation for this application is New Drug Application (NDA) is
`Approval. The Application contains adequate evidence of efficacy to support the
`indication, “the relief of the symptoms of seasonal allergic rhinitis in patients 12 years of
`age and older who require treatment with both azelastine hydrochloride and fluticasone
`propionate for symptomatic relief,” and provides an acceptable safety profile for the
`proposed product.
`
`Meda Pharmaceuticals has submitted a 505(b)(2) application for a fixed-dose
`combination nasal spray of 0.1% azelastine hydrochloride, a H1-receptor antagonist,
`and 0.037% fluticasone propionate, a corticosteroid. The proposed tradename is
`Dymista® (code name: MP29-02). Each actuation of the product contains 137 μg of
`azelastine hydrochloride and 50 μg of fluticasone propionate. The proposed dosing
`regimen is one spray per nostril twice daily, for a total daily dose of 548 μg of azelastine
`hydrochloride and 200 μg of fluticasone propionate. Both azelastine hydrochloride and
`fluticasone propionate are available in the United States as active ingredients in multiple
`products including Astelin (azelastine hydrochloride 0.1% unsweetened), which
`received initial U.S. approval on November 1, 1996, and Flonase (fluticasone
`propionate), which received initial U.S. approval on October 19, 1994. In addition to
`relying on the Agency’s prior findings of efficacy and safety for the reference products,
`the Applicant completed an extensive clinical development program for MP29-02, which
`includes four 2-week phase 3 efficacy and safety clinical trials (MP-4001, MP-4002, MP-
`4004, and MP-4006) and a year-long safety trial (MP-4000). In addition, two
`pharmacokinetic (PK) trials were conducted (X-03065-3282 and X-03065-3283).
`
`Evidence of efficacy comes primarily from Trials MP-4002, MP-4004, and MP-4006,
`which were randomized, double-blind, placebo- and active-controlled, with a 2-week
`treatment period. These trials employed a factorial design, evaluating the proposed
`product, MP29-02, along with placebo, as well as two investigational monotherapy
`comparators, azelastine hydrochloride and fluticasone propionate, each formulated
`(separately) in the MP29-02 vehicle. This factorial design allows for the evaluation of
`the contribution of each component to the efficacy of the novel combination product. In
`each of the three pivotal 2-week efficacy and safety trials, results for the analysis of the
`primary endpoint, the change from baseline in the reflective Total Nasal Symptom Score
`(rTNSS) AM and PM combined over the 14-Day treatment period, were statistically
`significant for the comparisons between MP29-02 and placebo, as well as the
`comparisons of MP29-02 to each of the monotherapy comparators. These results
`provide replicate evidence of efficacy for the proposed combination product; the factorial
`
`Reference ID: 3107643
`
`8
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`

`

`Clinical Review
`
`Jennifer Rodriguez Pippins, MD, MPH
`NDA 202-236
`
`Dymista (azelastine hydrochloride 0.1% I fluticasone propionate 0.037% nasal spray)
`
`design also provides replicate evidence of the contribution of each component. Results
`for the secondary endpoints were generally supportive of the primary analysis. Based
`on these results, the clinical review concludes that the Application provides sufficient
`evidence to support the seasonal allergic rhinitis indication. The Application does not,
`however, provide adequate support for a claim
`W"
`‘0: \4)
`being sought by the Applicant.
`
`The safety of MP29-02 is primarily supported by the results of the three 2-week efficacy
`and safety trials (MP-4002, MP-4004, and MP-4006) and the year-long safety trial (MP-
`4000). There were no deaths in the clinical development program, and the rate of
`serious adverse events and adverse events leading to the discontinuation of treatment
`were low. There were no occurrences of nasal septal perforation, and only one
`instance of nasal ulceration which was reported for a patient receiving placebo. The
`incidence of epistaxis associated with MP29-02 was 1—2%, which is comparable to that
`reported in the Astelin product label, and lower than that reported for Flonase. Other
`common adverse events associated with MP29-02 in clinical trials were: dysgesuia,
`headache, pyrexia, cough, nasal congestion, rhinitis, viral infection, upper respiratory
`tract infection, pharyngitis, pain, and diarrhea. The rate of somnolence was low.
`Ophthalmic examinations did not reveal any signals for either glaucoma or posterior
`subcapsular cataract formation, and results from an HPA-Axis substudy indicate that the
`effect of MP29—02 is comparable to that of commercially available generic fluticasone
`propionate.
`
`In summary, the clinical recommendation is Approval, based on the assessment that the
`Application has provided adequate evidence to support efficacy of MP29-02 in the
`treatment of the symptoms of SAR for adults and adolescents 12 years of age and older
`who require treatment with both azelastine hydrochloride and fluticasone propionate,
`and has also demonstrated an acceptable safety profile.
`It is notable that MP29—02, if
`approved, would be the first combination intranasal product for the treatment of allergic
`rhinitis.
`
`1.2 Risk Benefit Assessment
`
`The clinical review's risk-benefit assessment is favorable for the proposed product. This
`is based on the overall results for the primary endpoint from the 2-week efficacy and
`safety trials, which were both statistically significant and of reasonable magnitude. The
`clinical development program therefore provides sufficient evidence of the likelihood
`that patients requiring treatment with both azelastine hydrochloride and fluticasone
`propionate will benefit from the combination treatment offered by MP29-02. This,
`
`Reference ID: 31 07643
`
`

`

`Clinical Review
`
`Jennifer Rodriguez Pippins, MD, MPH
`NDA 202-236
`
`Dymista (azelastine hydrochloride 0.1% I fluticasone propionate 0.037% nasal spray)
`
`coupled with a relatively benign adverse event profile as described above, supports a
`favorable risk-benefit assessment for MP29—02.
`
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies
`
`No postmarket Risk Evaluation and Mitigation Strategies (REMS) are recommended at
`this time.
`
`1.4 Recommendations for Postmarket Requirements and Commitments
`
`A pediatric program for ages 4-11 years will be required under the Pediatric Research
`Equity Act (PREA); see Section 7.6.3.
`
`2 Introduction and Regulatory Background
`
`2.1 Product Information
`
`The proposed product, Dymista Nasal Spray (code name: MP29—02), is a fixed-dose
`combination nasal spray of 0.1% azelastine hydrochloride, a H1-receptor antagonist,
`and 0.037% fluticasone propionate, a corticosteroid. Each actuation of MP29—02
`contains 137 pg of azelastine hydrochloride and 50 pg of fiuticasone propionate. The
`proposed product will be supplied in a glass bottle fitted with a metered-dose spray
`pump unit, consisting of a nasal spray pump and a plastic dust cap. Each bottle
`contains 23 mg (1 mg/g) of azelastine hydrochloride and 8.5 mg (0.37 mg/g) of
`fluticasone propionate as active ingredients. The 23 g trade package is designed to
`deliver 120 metered sprays.
`
`The proposed indication is
`
`“M"
`” The proposed dosing regimen is one spray per
`nostril twice daily, for a total daily dose of 548 pg of azelastine hydrochloride and 200
`pg of fluticasone propionate.
`
`1 As discussed in Section 6.1 , the clinical review recommends a modification of the indication to: “the
`relief of the symptoms of seasonal allergic rhinitis in patients 12 years of age and older who require
`treatment with both azelastine hydrochloride and fluticasone propionate for symptomatic relief.”
`
`Reference ID: 31 07643
`
`1 0
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`

`

`Clinical Review
`
`Jennifer Rodriguez Pippins, MD, MPH
`NDA 202-236
`
`Dymista (azelastine hydrochloride 0.1% I fluticasone propionate 0.037% nasal spray)
`
`2.2 Tables of Currently Available Treatments for Proposed Indications
`
`Both of the active ingredients comprising the proposed fixed-dose combination product,
`azelastine hydrochloride and fluticasone propionate, are FDA-approved treatments for
`allergic rhinitis (see Section 2.3).
`In addition, there are numerous other nasal sprays
`available for the treatment of allergic rhinitis, as summarized in Table 1.
`
`Table 1. FDA-Approved Nasal Sprays for Seasonal Allergic Rhinitis
`
`Azelastine hydrochloride
`
`Oloatadine
`
`H1-rece . tor anta . onists
`Astelin and generic
`Asteo ro
`
`2 12 ears
`
`———
`Corticosteroids
`
`Beclomethasone
`
`—Em_-_
`
`—IIEE_-_
`
`2.3 Availability of Proposed Active Ingredient in the United States
`
`Both azelastine hydrochloride and fluticasone propionate are available in the United
`States as active ingredients in multiple products.
`
`Azelastine hydrochloride 0.1% (unsweetened) is available both as a branded product
`(Astelin) and generic. Astelin received initial U.S. approval on November 1, 1996.
`Azelastine hydrochloride 0.1% (unsweetened) is indicated for seasonal allergic rhinitis
`in adults and children 5 years of age and older, and for vasomotor rhinitis in adults and
`adolescents 12 years of age and older.
`
`Dosage and administration for Astelin are as follows:
`0 Adults and adolescents (12 years of age and older):
`0 SAR: 1-2 sprays (137 mcglspray) in each nostril BID (MDD=1096 mcg)
`o VMR: 2 sprays (137 mcglspray) in each nostril BID (TDD=1096 mcg)
`
`0 Children (5-11 years)
`
`0 SAR: 1 spray (137 mcglspray) in each nostril BID (TDD=548 mcg)
`
`Reference ID: 31 07643
`
`1 1
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`

`

`
`
`Clinical Review
`Jennifer Rodriguez Pippins, MD, MPH
`NDA 202-236
`Dymista (azelastine hydrochloride 0.1% / fluticasone propionate 0.037% nasal spray)
`
`Azelastine hydrochloride is also available as 0.1% and 0.15% sweetened formulations
`under the tradename Astepro. Both the 0.1% and 0.15% sweetened formulations are
`indicated for seasonal allergic rhinitis in adults and adolescents 12 years of age and
`older; the 0.15% sweetened formulation is also indicated for perennial allergic rhinitis in
`adults and adolescents 12 years of age and older.
`
`Dosage and administration for Astepro are as follows:
`• Adults and adolescents (12 years of age and older):
`o SAR:
`(cid:131) 0.1%: 1-2 sprays (137 mcg/spray) in each nostril BID (MDD=1096
`mcg)
`(cid:131) 0.15%:
`• 1-2 sprays (205.5 mcg/spray) in each nostril BID
`(MDD=1644 mcg) – OR –
`• 2 sprays in each nostril QD (TDD=822)
`
`o PAR:
`(cid:131) 0.15%: 2 sprays in each nostril BID (TDD=1644 mcg)
`
`
`Fluticasone propionate is available both as a branded product (Flonase) and as multiple
`generic products. Flonase received initial U.S. approval on October 19, 1994.
`Fluticasone propionate nasal spray is indicated for seasonal allergic rhinitis, perennial
`allergic rhinitis, and nonallergic rhinitis in adults and pediatric patients 4 years of age
`and older.
`
`Dosage and administration for fluticasone propionate nasal spray are as follows:
`• Adults
`o 2 sprays (50 mcg/spray) in each nostril QD (TDD=200 mcg)
`o May be divided into 100 mcg BID
`o May be able to reduce to 1 spray (50 mcg/each) in each nostril QD
`(TDD=100 mcg) for maintenance therapy
`o May be able to use 200 mcg QD prn
`• Adolescents and Children (4 years of age and older)
`o 1 spray (50 mcg/spray) in each nostril QD (TDD=100 mcg)
`o May increase to 2 sprays (50 mcg/spray) in each nostril QD (TDD=200
`mcg)
`o Once control achieved, should decrease to 1 spray (50 mcg/spray) in each
`nostril QD (TDD=100 mcg)
`
`
`
`
`
`
`Reference ID: 3107643
`
`12
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`

`

`Clinical Review
`Jennifer Rodriguez Pippins, MD, MPH
`NDA 202-236
`Dymista (azelastine hydrochloride 0.1% / fluticasone propionate 0.037% nasal spray)
`
`2.4
`
`Important Safety Issues With Consideration to Related Drugs
`
`
`
`Antihistamines
`Antihistamines are known to be associated with somnolence. This is true for Astelin,
`which carries a Precautions statement in its product label. There is also a history of an
`association between Terfenadine, an early second-generation antihistamine, and QT
`interval prolongation as well as cardiac arrhythmias, which led to the removal of
`Terfenadine from the market. The Astelin product label states that a study evaluating
`the impact of Astelin on cardiac repolarization did not demonstrate an effect on
`corrected QT interval (QTc).
`
`Corticosteroids
`Corticosteroids are known to be associated with a number of important systemic and
`local safety issues. Systemic adverse events include: immunosuppression, HPA Axis
`effects, and reduction in growth velocity. Local adverse events include: epistaxis, nasal
`ulceration, and nasal septal perforation. This class of drugs is also known to carry an
`association with the development of cataracts and glaucoma. These events are all
`described in the Flonase product label.
`
`
`
`2.5 Summary of Presubmission Regulatory Activity Related to Submission
`
`The following timeline summarizes the presubmission regulatory activity related to the
`clinical development program for the proposed product and this NDA submission.
`
`
`•
`
`IND 77,363 submitted by MedPointe Pharmaceuticals on April 2, 2007
`o
`IND allowed to proceed
`o Comments provided on May 21, 2007 included:
`(cid:131) Reminder that the pro