CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`202236Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`CIPLA LTD. EXHIBIT 2040 PAGE 1
`
`

`

`SUMMARY REVIEW OF REGULATORY ACTION
`
`Date:
`
`From:
`
`
`
`
`
`May 1, 2012
`
`
`
`
`
`Badrul A. Chowdhury, MD, PhD
`Director, Division of Pulmonary, Allergy, and Rheumatology
`Products, CDER, FDA
`
`Division Director Summary Review
`
`Subject:
`20-2236
`NDA Number:
`Meda Pharmaceuticals, Inc.,
`Applicant Name:
`Date of Submission: April 1, 2011
`PDUFA Goal Date: May 1, 2012 (original goal date was February 1, 2011)
`Proprietary Name: Dymista Nasal Spray
`Established Name:
`azelastine hydrochloride and fluticasone propionate
`Dosage form:
`Nasal Spray
`Strength:
`137 mcg azelastine hydrochloride and 50 mcg of fluticasone
`propionate per actuation in 137 microliters metered volume
`Proposed Indications: Treatment of symptoms of seasonal allergic rhinitis in patients 12
`years of age and older
`Approval
`
`Action:
`
`
`
`Introduction
`1.
`Meda Pharmaceuticals submitted this 505(b)(2) application for use of Dymista (azelastine
`hydrochloride and fluticasone propionate) Nasal Spray for the treatment of symptoms of
`seasonal allergic rhinitis (SAR) in adults and adolescents 12 years of age and older. The
`proposed dose is 1 spray per nostril twice daily, so that the total daily dose is 548 mcg
`azelastine hydrochloride and 200 mcg fluticasone propionate. The application is based
`on clinical efficacy and safety studies. This summary review will provide an overview of
`the application, with a focus on the clinical efficacy and safety studies.
`
`Meda Pharmaceuticals submitted an amendment on December 7, 2011, containing CMC
`information on the pharmaceutical characteristics of the novel single ingredient products
`used as comparators in the pivotal clinical trials, and additional data and methods
`pertaining to the dose performance and microbial safety of the combination drug product.
`As these data and information were critical for the interpretation of the clinical trial
`results and assurance of drug product safety and quality, the amendment was considered
`to be a major amendment, and the review clock was extended by three months.
`
`2. Background
`There are many drugs approved for use in patients with allergic rhinitis (AR) including
`oral and intranasal H1 antihistamines, intranasal corticosteroids, and the oral leukotriene
`receptor antagonist montelukast. Both the active ingredients present in Dymista,
`azelastine hydrochloride and fluticasone propionate, are approved and marketed in the
`United States as nasal spray formulations for the treatment of AR. In addition, there are
`
`Reference ID: 3124414
`
`CIPLA LTD. EXHIBIT 2040 PAGE 2
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`

`

`2
`
`many other intranasal corticosteroids marketed for the treatment of AR in the United
`States. On approval, Dymista will be the first fixed-dose combination nasal spray
`product containing an antihistamine and a corticosteroid for the treatment of SAR.
`
`The development of a fixed-dose combination product containing an intranasal
`corticosteroid and antihistamine raises issues that have not been previously encountered
`in development programs for single-component nasal spray products, including the
`ability of clinical studies to satisfy the requirements of the Combination Rule (21CFR
`300.50), and to demonstrate clinically meaningful efficacy and safety for the fixed-dose
`combination product, given the established safety and efficacy of the single ingredient
`products. Some considerations related to the latter issue are: 1) the identification of an
`appropriate patient population; 2) the loss of dose titration flexibility; 3) the use of two
`components to treat the same symptoms of allergic rhinitis; and 4) the need for
`pharmaceutically comparable single ingredient products that can be used as comparators
`in factorial-design studies.
`
`Early in development (during the review of IND 77,363), given the complexity
`surrounding the development of a fixed-dose combination product containing an
`intranasal corticosteroid and antihistamine for treatment of AR, a Center level Regulatory
`Briefing on this topic was held on April 17, 2009. Based on the feedback received during
`this internal discussion, the following decisions were made: 1) the Division will accept a
`fixed-dose combination product where each single ingredient product present in the
`fixed-dose combination product treats the same symptoms of AR; 2) the evaluation of
`total nasal symptom score as the primary endpoint is acceptable for comparing the
`combination product to the single ingredient products; 3) the contribution of each active
`component in the fixed-dose combination product must be demonstrated through clinical
`studies; 4) there should be no pharmaceutical differences between the fixed-dose
`combination product and the single ingredient products used in pivotal clinical studies; 5)
`the demonstration of a statistically significant difference between the fixed-dose
`combination product and each of its single ingredients is accepted as evidence of a patient
`population requiring concurrent therapy, provided that the effect sizes separating the
`fixed-dose combination product and each of its single ingredients are of reasonable
`magnitude and each single ingredient product also demonstrates superiority to placebo;
`and 6) statistical significance driven by a large sample size with a marginal treatment
`effect is not adequate, and treatment effect size should be defined a priori and comparable
`to the effect size already determined to be acceptable for the single ingredient products.
`
`The Division communicated the above issues and discussed the pathway forward with
`Meda Pharmaceuticals in a teleconference held on April 23, 2009. During the
`teleconference the Division reiterated the need for demonstrating that there were no
`pharmaceutical differences between the combination product and each of the single
`ingredient comparators to be used in pivotal clinical trials. Due to the pharmaceutical
`differences between Dymista and the corresponding commercial single ingredient
`products containing azelastine hydrochloride and fluticasone propionate, Meda
`Pharmaceuticals was advised to develop single ingredient comparator products for the
`clinical development program. Since the single ingredient comparator products would be
`
`Reference ID: 3124414
`
`CIPLA LTD. EXHIBIT 2040 PAGE 3
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`

`

`new products, each would require demonstration of safety and efficacy as compared to
`placebo. Subsequently, Meda Pharmaceuticals developed appropriate single ingredient
`comparator products and conducted an appropriate clinical development program that is
`the subject of this review.
`
`3. Chemistry, Manufacturing, and Controls
`The drug substances azelastine hydrochloride and fluticasone propionate are known
`active ingredients that are already approved in commercial inhalation and nasal spray
`products as mentioned above. Dymista Nasal Spray is a metered dose spray pump unit
`containing a suspension formulation of 0.1% azelastine hydrochloride and 0.03 7%
`fluticasone propionate and compendial excipients. The commercial unit has a fill weight
`of 23 gm and delivers a minimum 120 sprays after priming. The product does not have a
`dose counter. After priming, each metered spray delivers 0.137 mL volume of
`suspension containing 137 mcg of azelastine hydrochloride and 50 mcg of fluticasone
`propionate from the nose piece.
`
`The drug substance azelastine hydrochloride is manufactured by
`and fluticasone propionate is manufactured by
`The drug product is manufactured by Cipla in Goa, India. Each manufacturing and
`testing facility associated with this application has acceptable EER status. The submitted
`stability data support drug product storage at the room temperature and an expiry period
`of 24 months.
`
`(I!) (4)
`D) (4)
`
`Initial review of the CMC data noted deficiencies in the proposed specifications,
`analytical methods, and stability data for the drug product. In addition, it was noted that
`the actuator detached easily from the glass vial during removal of the dust cap. During
`the review cycle Meda Pharmaceuticals adequately addressed all CMC deficiencies and
`proposed new acceptance criteria for spray weight, spray content uniformity, droplet size
`distribution, and the microscopic method for particle size distribution. Manufacturing
`changes were also implemented to seat the actuator more securely on the pump.
`
`Given the issues and complexities of developing a fixed-dose nasal spray combination
`product (discussed in section 2 above), characterization of the single ingredient products
`and their comparison to the fixed-dose combination product for potential pharmaceutical
`interactions was an important part of the CMC review for this application. While
`azelastine hydrochloride and fluticasone propionate are marketed as individual products,
`the formulation of the commercially available products differs from the formulation of
`the proposed fixed-dose combination product. Therefore, Meda Pharmaceuticals
`developed novel azelastine hydrochloride 0.1% nasal spray and fluticasone propionate
`0.037% nasal spray single ingredient products specifically for use in the pivotal clinical
`trials. As mentioned in Section 1 above, complete CMC information for the single
`ingredient comparator products was submitted later in the review cycle, leading to the
`extension of the PDUFA clock. On review of the data for the single ingredient products,
`it was found that there were some minor differences
`(mo
`
`Refe'eme "32 3124414
`
`CIPLA LTD. EXHIBIT 2040 PAGE 4
`
`CIPLA LTD. EXHIBIT 2040 PAGE 4
`
`

`

`«no but the overall dose
`
`performance results are considered to be within the acceptable range (variation of NMT
`(mo) compared to the combination product. Based on the in vitro data, it was concluded
`that there are no significant pharmaceutical differences between the fixed-dose
`combination product and the single-ingredient component products, and no interactions
`between the active ingredients in the fixed—dose combination product, which would
`potentially impact the interpretation of the clinical study results.
`
`4. Nonclinical Pharmacology and Toxicology
`The nonclinical program for Dymista is based upon completed toxicology programs
`conducted for the individual active moieties azelastine hydrochloride and fluticasone
`propionate. These were previously reviewed under the NDAs for these products and
`were found to be acceptable. To support this application, Meda Pharmaceuticals
`conducted 14-day intranasal toxicology studies in rats and dogs and a 3-month intranasal
`toxicology study in rats with azelastine hydrochloride and fluticasone propionate
`administered as a combination product. These toxicology studies did not indicate any
`potential additive or synergistic toxic effects of the combination.
`
`5. Clinical Pharmacology and Biopharmaceutics
`The general clinical pharmacology and biopharmaceutic considerations for azelastine
`hydrochloride and fluticasone propionate were addressed in the original NDAs for these
`products. The clinical pharmacology program for this application included two single-
`dose, relative bioavailability studies in healthy volunteers to assess for potential drug-
`drug interactions and assess systemic exposure. These studies demonstrated that co-
`administration of azelastine hydrochloride and fluticasone propionate does not affect the
`systemic exposure of either. Systemic exposure for azelastine from Dymista is within
`i20% of that associated with the commercially marketed azelastine product, Astelin. The
`systemic exposure for fluticasone propionate from Dymista is 44 to 61% higher than
`exposure from a commercially marketed, generic fluticasone propionate nasal spray
`product at the same nominal dose. However, the systemic exposure of fluticasone
`propionate fiom Dymista is below the systemic exposure from higher doses of
`commercially marketed fluticasone propionate nasal spray (Flonase 200 mcg once daily
`or 400 mcg twice daily), which have been reported to have no effect on adrenal responses
`as is described in the current Flonase package insert. The information regarding relative
`systemic exposures suggests that the higher systemic exposure observed for fluticasone
`propionate from Dymista is not likely to pose new systemic safety concerns. Therefore, a
`separate HPA-axis safety study was not deemed to be necessary for Dymista.
`
`6. Clinical Microbiology
`The final product is not sterile
`which is acceptable for a nasal spray product. Data for the
`(m4) proposed microbial safety controls were reviewed and
`additional controls for the absence ofB. cepacia were requested by the Microbiology
`
`(I!) (0
`
`0)“)
`
`Reference "1 3124414
`
`CIPLA LTD. EXHIBIT 2040 PAGE 5
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`CIPLA LTD. EXHIBIT 2040 PAGE 5
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`

`

`5
`
`review team. The new method and revised microbial controls submitted in the NDA
`amendment dated December 7, 2012, are considered adequate to assure drug product
`safety from the Microbiology perspective.
`
`7. Clinical and Statistical – Efficacy
`a. Overview of the clinical program
`Some characteristics of the studies that form the basis of the review and regulatory
`decision for this application are shown in Table 1. The design and conduct of these
`studies are briefly described below, followed by efficacy findings and conclusions.
`Safety findings are discussed in the following section.
`
`Treatment groups#
`
`N†
`
`Primary efficacy
`variable
`
`Countries
`
`Table 1. Relevant clinical studies
`ID
`Study
`Study
`Patient
`Year
`type
`duration
`Age, yr
`*
`4001
`2008
`
`2 week
`
`Efficacy
`and Safety
`in SAR
`
`Safety in
`PAR and
`VMR
`*Year study subject enrollment ended
`# All treatment administered as 1 spray in each nostril BID except in studies 4001 and 4000 that used commercial
`single ingredient commercial products where Flonase was administered as 2 sprays in each nostril BID
`Note: All doses are from the end of the nose piece of the metered-dose spray pump unit
`† Number randomized
`
`4002
`2008
`
`4004
`2008
`
`4006
`2009
`
`2 week
`
`2 week
`
`2 week
`
`Efficacy
`and Safety
`in SAR
`
`Efficacy
`and Safety
`in SAR
`
`Efficacy
`and Safety
`in SAR
`
`4000
`2009
`
`52 week
`
`12 - 75 Dymista 137/50 mcg BID
`Astelin 137 mcg BID
`Flonase (generic) 50 mcg BID
`Placebo
`12 - 77 Dymista 137/50 mcg BID
`Azelastine 137 mcg BID
`Fluticasone 50 mcg BID
`Placebo
`12 - 77 Dymista 137/50 mcg BID
`Azelastine 137 mcg BID
`Fluticasone 50 mcg BID
`Placebo
`12 - 83 Dymista 137/50 mcg BID
`Azelastine 137 mcg BID
`Fluticasone 50 mcg BID
`Placebo
`12 - 73 Dymista 137/50 mcg BID
`Flonase (generic) 50 mcg BID
`
`Reflective total
`nasal symptom
`score over 2 wks
`
`Reflective total
`nasal symptom
`score over 2 wks
`
`Reflective total
`nasal symptom
`score over 2 wks
`
`Reflective total
`nasal symptom
`score over 2 wks
`
`US
`[Texas]
`
`US
`[Various
`States]
`
`US
`[Various
`States]
`
`US
`[Various
`States]
`
`Safety study
`
`India
`
`153
`153
`153
`151
`207
`208
`207
`210
`195
`194
`189
`201
`451
`449
`450
`451
`405
`207
`
`b. Design and conduct of the studies
`All efficacy and safety studies (4001, 4002, 4004, and 4006) were randomized, double-
`blind, placebo-controlled, and parallel-group in design and conducted in patients 12 years
`of age and older with SAR. For the SAR study 4001, Texas Mountain Cedar was the
`specified allergen. The studies had a 1-week single-blind placebo run-in period followed
`by a double-blind treatment period of 2 weeks with full factorial design using four
`treatment arms that allowed comparison of Dymista with each single ingredient
`comparator product, comparison of each single ingredient product with placebo, and
`comparison of Dymista with placebo (Table 1). The primary efficacy endpoint for all
`studies was the change from baseline in average morning and evening reflective total
`
`Reference ID: 3124414
`
`CIPLA LTD. EXHIBIT 2040 PAGE 6
`
`

`

`6
`
`nasal symptom scores (rTNSS: sum of runny nose, sneezing, itchy nose, and nasal
`congestion; each scored on 0-3 scale) collected daily and averaged over 2 weeks of
`treatment. Some key secondary efficacy variables included: (1) the instantaneous
`recording of the same four symptoms (iTNSS) for all studies, (2) reflective and
`instantaneous total ocular symptom score (rTOSS or iTOSS: sum of ocular itching,
`tearing, and redness; each scored on 0-3 scale), and (3) the Rhinoconjunctivitis Quality of
`Life Questionnaire (RQLQ) for patients 18 years of age and older. Safety assessments
`included recording of adverse events, vital signs, and focused nasal examinations.
`
`Study 4000 was a 52-week dedicated safety study that compared Dymista to
`commercially available generic Flonase. Safety assessments included recording of
`adverse events, vital signs, physical examinations including focused nasal examinations,
`eye examination, ECG, and clinical laboratory measurements. In additional an evaluation
`of the hypothalamic-pituitary-adrenal (HPA) axis by measurement of serum cortisol was
`conducted in a subset of patients at some selected sites.
`
`The design and conduct of efficacy and safety studies were typical of an AR program.
`There were two issues in the clinical program that warrant further comments, as follows.
`
`First, in study 4001 commercially available Astelin and a generic Flonase were used as
`single ingredient comparators. Since there are known pharmaceutical differences
`between Dymista and the single ingredient comparators, the results of this study are not
`adequate to show contribution of each active component in the combination product
`Dymista. Nevertheless, study 4001 provides supportive information. Note that there are
`three other studies (4002, 4004, and 4006) that used appropriate single ingredient
`comparator products that are not pharmaceutically different than Dymista.
`
`Second, in the SAR study 4001, the allergen was specified as Texas Mountain Cedar.
`Mountain Cedar produces intense symptoms and clinical studies conducted in SAR
`patients allergic to this allergen may show a larger treatment effect size compared to
`clinical studies conducted in SAR patients allergic to heterogeneous seasonal allergens.
`Use of a Texas Mountain Cedar-sensitive SAR patient population is acceptable because
`demonstration of efficacy in one allergen-sensitive SAR patient group is expected to
`support efficacy in other allergen sensitive patient groups in SAR since the underlying
`pathophysiology of SAR is similar across allergens. However, the possible inflation of
`treatment effect size is taken in consideration with the other limitations to the relevance
`of study 4001 as stated above.
`
`c. Efficacy findings and conclusions
`The submitted studies support efficacy of Dymista Nasal Spray (azelastine hydrochloride
`137 mcg and fluticasone propionate 50 mcg) at a dose of 1 spray per nostril twice daily
`for daily in adult and adolescent patients with SAR 12 years of age and older who require
`treatment with both azelastine hydrochloride and fluticasone propionate for symptomatic
`relief.
`
`Reference ID: 3124414
`
`CIPLA LTD. EXHIBIT 2040 PAGE 7
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`

`

`7
`
`Formal dose ranging studies with Dymista were not conducted. Dose selection for each
`component of azelastine hydrochloride and fluticasone propionate was based on the
`approved doses of each of these products and supported by the submitted efficacy and
`safety data (Table 1). This is acceptable because a combination product such as Dymista
`is a product of convenience for patients who require treatment with both azelastine
`hydrochloride and fluticasone propionate.
`
`In studies 4001, 4002, 4004, and 4006, Dymista demonstrated statistically significant
`differences from each single ingredient comparator product in the primary efficacy
`endpoint of rTNSS and also for iTNSS (Table 2). The only borderline result was the
`comparison of Dymista to fluticasone propionate for rTNSS in study 4004 (p=0.06), but
`in the same study the results were statistically significant for iTNSS. Study 4001 is
`considered supportive for reasons stated above (use of commercially available Astelin
`and a generic Flonase as single ingredient comparators). The other three studies
`considered pivotal (4002, 4004, and 4006) used appropriate single ingredient comparator
`products. The two single ingredient products specifically formulated for comparing to
`Dymista demonstrated statistically significant differences from placebo in studies 4002,
`4004, and 4006 (raw data shown in Table 2, p<0.001). The data overall provide evidence
`of the contribution of each active component in the combination product Dymista, and
`also show a clinically meaningful efficacy advantage for the combination product
`Dymista over the single ingredient products that were also efficacious in SAR. The
`magnitude of the treatment differences between Dymista and each active single
`ingredient comparator product were reasonable and comparable to the differences
`observed for nasal antihistamines and nasal corticosteroids in other clinical programs for
`SAR. Statistical significance for the differences between Dymista and the single
`ingredient comparator products were achieved in all studies. All studies, except 4006,
`had sample sizes comparable to those used in the clinical studies that supported approval
`of these single ingredient products. The sample size used in study 4006 was substantially
`larger, but this study provides point estimates for the treatment differences with more
`precision than the smaller studies. The smaller studies 4002 and 4004 provide necessary
`and adequate evidence of efficacy, and study 4006 provides additional confirmatory
`evidence.
`
`Table 2. Change from baseline in nasal symptoms scores rTNSS and iTNSS *
`Treatments †
`Difference from Dymista
`n
`Baseline
`Change from
`LS mean
`95% CI
`P value
`LS mean
`baseline
`
`iTNSS
`
`SAR Study 4001
`rTNSS
`Dymista 137/50 mcg
`Astelin 137 mcg
`Flonase 50 mcg
`Placebo
`Dymista 137/50 mcg
`Astelin 137 mcg
`Flonase 50 mcg
`Placebo
`SAR Study 4002
`rTNSS
`Dymista 137/50 mcg
`Azelastine 137 mcg
`
`153
`152
`151
`150
`153
`152
`151
`150
`
`207
`208
`
`18.6
`17.9
`18.1
`18.5
`17.1
`16.5
`16.8
`17.5
`
`18.3
`18.3
`
`-5.4
`-3.4
`-4.0
`-2.3
`-4.5
`-3.0
`-3.6
`-1.7
`
`-5.6
`-4.3
`
`-2.1
`-1.4
`-3.1
`
`-1.5
`-0.9
`-2.8
`
`-1.4
`
`(-3.0, -1.2)
`(-2.4, -0.5)
`(-4.0, -2.2)
`
`(-2.4, -0.6)
`(-1.8, -0.1)
`(-3.7, -1.9)
`
`<0.001
`0.003
`<0.001
`
`0.002
`0.066
`<0.001
`
`(-2.2, -0.5)
`
`0.002
`
`Reference ID: 3124414
`
`CIPLA LTD. EXHIBIT 2040 PAGE 8
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`

`

`Treatments †
`
`n
`
`207
`209
`207
`208
`207
`209
`
`193
`193
`188
`199
`193
`194
`188
`199
`
`Baseline
`LS mean
`18.2
`18.6
`17.2
`16.8
`16.8
`17.3
`
`Change from
`baseline
`-4.7
`-2.9
`-5.2
`-3.9
`-4.5
`-2.7
`
`18.3
`18.5
`18.6
`18.2
`17.2
`17.3
`17.2
`16.8
`
`-5.5
`-4.5
`-4.7
`-3.1
`-5.2
`-4.1
`-4.4
`-2.6
`
`8
`
`Difference from Dymista
`LS mean
`95% CI
`P value
`-1.0
`(-1.8, -0.2)
`0.022
`-2.7
`(-3.5, -1.9)
`<0.001
`
`-1.3
`-0.7
`-2.6
`
`-1.0
`-0.9
`-2.4
`
`-1.1
`-0.8
`-2.6
`
`-0.8
`-0.6
`-2.2
`
`(-2.1, -0.5)
`(-1.5, 0.2)
`(-3.4, -1.8)
`
`(-1.9, -0.1)
`(-1.8, 0.0)
`(-3.2, -1.6)
`
`(-1.9, -0.2)
`(-1.7, 0.1)
`(-3.4, -1.8)
`
`0.002
`0.116
`<0.001
`
`0.030
`0.060
`<0.001
`
`0.020
`0.084
`<0.001
`
`(-1.3, -0.2)
`(-1.2, -0.1)
`(-2.7, -1.6)
`
`0.012
`0.030
`<0.001
`
`Fluticasone 50 mcg
`Placebo
`Dymista 137/50 mcg
`Azelastine 137 mcg
`Fluticasone 50 mcg
`Placebo
`SAR Study 4004
`rTNSS
`Dymista 137/50 mcg
`Azelastine 137 mcg
`Fluticasone 50 mcg
`Placebo
`Dymista 137/50 mcg
`Azelastine 137 mcg
`Fluticasone 50 mcg
`Placebo
`SAR Study 4006
`rTNSS
`-5.6
`19.3
`448
`Dymista 137/50 mcg
`-4.8
`19.5
`443
`Azelastine 137 mcg
`-4.9
`19.4
`450
`Fluticasone 50 mcg
`-3.4
`19.4
`448
`Placebo
`-5.0
`17.9
`448
`Dymista 137/50 mcg
`-4.3
`18.0
`445
`Azelastine 137 mcg
`0.019
`(-1.3, -0.1)
`-0.7
`-4.7
`17.8
`450
`Fluticasone 50 mcg
`0.345
`(-0.9, 0.3)
`-0.3
`-3.1
`17.9
`448
`Placebo
`<0.001
`(-2.5, -1.4)
`-1.9
`* Subject-rated rated AM and PM reflective or instantaneous total nasal symptom scores (rTNSS or iTNSS) (maximum
`score = 24) averaged over the 2-week treatment period. Analyses used raw scores.
`† Treatment administered as 1 spray in each nostril BID except in study 4001 that used commercial single ingredient
`commercial products where Flonase was administered as 2 sprays in each nostril BID
`Note: All doses are from the end of the nose piece of the metered-dose spray pump unit
`
`iTNSS
`
`iTNSS
`
`iTNSS
`
`Reference ID: 3124414
`
`(b) (4)
`
`CIPLA LTD. EXHIBIT 2040 PAGE 9
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`

`

`9
`
`Meda Pharmaceuticals included the RQLQ in the studies to support a labeling claim. The
`RQLQ is a 28-item disease specific (allergic rhinitis) quality of life instrument with seven
`domains (activity limitations, sleep problems, non-nose/eye symptoms, practical
`problems, nasal symptoms, eye symptoms, and emotional function). Patients treated with
`Dymista demonstrated statistically significant improvements in RQLQ compared to
`placebo, but not compared to the single ingredient products (Table 4). The treatment
`group differences for Dymista compared to placebo in each of the studies crossed 0.5,
`which is considered to be the MID (minimum important difference). The results
`comparing Dymista to placebo will be described in the product label. This will be
`consistent with similar labeling language that has been permitted for inhaled combination
`products for the treatment of patients with asthma.
`
`Table 4. Change from baseline in RQLQ over 2 weeks (ITT population, excluding patients with
`missing baseline value) *
`Treatments †
`
`Baseline
`LS mean
`
`Change from
`baseline
`
`Difference from Dymista
`LS mean
`95% CI
`P value
`
`n
`
`SAR Study 4002
`RQLQ Dymista 137/50 mcg
`Azelastine 137 mcg
`Fluticasone 50 mcg
`Placebo
`SAR Study 4004
`RQLQ Dymista 137/50 mcg
`Azelastine 137 mcg
`Fluticasone 50 mcg
`Placebo
`SAR Study 4006
`RQLQ Dymista 137/50 mcg
`-1.6
`3.9
`381
`0.043
`(-0.3, 0.0)
`-0.2
`-1.4
`3.9
`394
`Azelastine 137 mcg
`0.629
`(-0.2, 0.1)
`-0.0
`-1.6
`3.9
`384
`Fluticasone 50 mcg
`<0.001
`(-0.7, -0.4)
`-0.6
`-1.0
`3.9
`393
`Placebo
`* Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) (28 items in 7 domains (activities, sleep, non-
`nose/eye symptoms, practical problems, nasal symptoms, eye symptoms, and emotional) evaluated on a 7-
`
`-0.3
`-0.0
`-0.8
`
`-0.3
`-0.2
`-0.7
`
`(-0.5, 0.0)
`(-0.4, 0.2)
`(-1.1, -0.6)
`
`(-0.5, 0.0)
`(-0.5, 0.1)
`(-1.0, -0.5)
`
`0.029
`0.907
`<0.001
`
`0.031
`0.123
`<0.001
`
`176
`174
`184
`169
`
`176
`172
`169
`171
`
`3.9
`3.8
`3.8
`3.9
`
`3.8
`3.8
`3.8
`3.9
`
`-1.6
`-1.4
`-1.6
`-0.9
`
`-1.7
`-1.4
`-1.5
`-1.0
`
`Reference ID: 3124414
`
`(b) (4)
`
`CIPLA LTD. EXHIBIT 2040 PAGE 10
`
`

`

`n
`
`Treatments †
`
`Change from
`Baseline
`Difference from Dymista
`LS mean
`95% CI
`P value
`baseline
`LS mean
`point scale where 0=no impairment and 6=maximum impairment), which was administered to patients 18
`years of age and older. An overall RQLQ score is calculated from the mean of all items in the instrument.
`† Treatment administered as 1 spray in each nostril BID
`Note: All doses are from the end of the nose piece of the metered-dose spray pump unit
`
`10
`
`To support an onset of action claim, Meda Pharmaceuticals did not conduct dedicated
`studies such as an “allergen chamber” study or “day-in-the-park” study that provides
`pharmacodynamic onset of action. Instead, onset of action for Dymista was assessed by
`frequent recording of iTNSS in the SAR studies after the first dose. For regulatory
`purposes, onset of action is defined as the first time point, replicated in two studies,
`where the difference between the active treatment and placebo in the efficacy measure is
`statistically significant and the difference persists consistently after that time point. It is
`also expected that the difference would be clinically meaningful. The pivotal SAR
`studies provide a more clinically meaningful assessment of onset of action than
`pharmacodynamic “allergen chamber” and “day-in-the-park” type studies would. The
`data submitted support an onset of action of 30 minutes for Dymista.
`
`8. Safety
`a. Safety database
`The safety assessment of Dymista is primarily based on studies listed in Table 1, as well
`as the known safety profiles of the commercially marketed single ingredient nasal spray
`products containing azelastine hydrochloride and fluticasone propionate. The overall
`safety database for Dymista was adequate.
`
`Two separate pooling of 2-week studies were done for assessment of safety. One pooling
`included studies 4001, 4002, 4004, and 4006, and the second pooling excluded study
`4001 (Table 1). In the product label, data from pooled studies 4002, 4004, and 4006 are
`reported. Results of study 4001 are excluded because this study included single
`ingredient comparators different from the other three studies. Including all studies in
`product label would necessitate listing multiple single ingredient product comparators
`that would increase complexity, but would not provide additional useful information.
`
`b. Safety findings and conclusion
`The submitted data support the safety of Dymista Nasal Aerosol in patients 12 years of
`age and older. There were no deaths in the clinical program. Serious adverse events
`were few, did not appear to be related to Dymista, and did not suggest a new safety
`signal. The discontinuations due to adverse events also did not suggest a new safety
`signal for Dymista. Common adverse events in Dymista treated patients were dysgeusia,
`headache, and epistaxis. These are typical adverse events seen in SAR studies using nasal
`spray products containing antihistamines or corticosteroids.
`
`Focused nasal examinations were conducted in all clinical studies because local nasal
`toxicities such as nasal septal perforation, nasal mucosal ulceration, and epistaxis are
`
`Reference ID: 3124414
`
`CIPLA LTD. EXHIBIT 2040 PAGE 11
`
`

`

`11
`
`safety concerns of interest for nasal spray products. In the clinical program for Dymista
`there were no septal perforations seen. There was one report of nasal ulceration in a
`patient on placebo treatment. There were few cases of epistaxis, but they were generally
`mild in severity. Overall, these findings do not raise any safety concerns for Dymista.
`
`Ophthalmologic examination was done in the Dymista clinical studies. Events of
`interest, such as increased intraocular pressure and cataracts, were rare and similar across
`treatment arms.
`
`HPA axis effect was not formally assessed for Dymista in a dedicated study. The totality
`of the information provided by Meda Pharmaceuticals does not suggest a clinically
`relevant HPA-axis effect for Dymista. As mentioned previously, while systemic
`exposure for fluticasone propionate from Dymista is slightly higher than that for
`commercial Flonase at the same nominal dose, it falls within the range of systemic
`exposure observed for approved doses of Flonase that have been previously shown not to
`impact the HPA-axis. In addition, Meda Pharmaceuticals included serum cortisol
`measurements in a subset of patients in the long-term safety study 4000. Results for
`Dymista and Flonase were similar in the study and did not indicate clinically significant
`changes.
`
`A linear growth study with Dymista is not necessary because a growth study has been
`conducted with another product containing fluticasone propionate. Comparative systemic
`exposure data for fluticasone propionate from Dymista compared to other products do not
`raise specific concerns about growth suppression with Dymista, however, the package
`insert includes class labeling describing the association between intranasal corticosteroids
`and the reduction of growth velocity.
`
`c. REMS/RiskMAP
`There are no substantial safety concerns that would require a REMS or RiskMAP. Other
`nasal spray products containing single ingredient azelastine hydrochloride or fluticasone
`propionate also do not have a REMS or RiskMAP.
`
`9. Advisory Committee Meeting
`An advisory committee was not convened for this application. Both azelastine
`hydrochloride and fluticasone propionate are not new molecular entities. Nasal spray
`products containing both these active moieties are well studied for AR, and the efficacy
`and safety of these single entity products for AR are well known. The efficacy and safety
`findings seen in the clinical program for Dymista were obvious. There were no issues
`that warrant discussion at an advisory committee meeting. A CDER regulatory briefing
`addressing issues relevant to the development of a fixed-dose combination product
`containing an intranasal corticosteroid and antihistamine for treatment of AR was held on
`April 17, 2009 as discussed in Section 2 above.
`
`Reference ID: 3124414
`
`CIPLA LTD. EXHIBIT 2040 PAGE 12
`
`

`

`10. Pediatric
`
`12
`
`(m4)
`
`As is the case for patients 12 years of
`age and older, Dymista may be appropriate for younger patients who would require
`treatment with both azelastine hydrochloride and fluticasone propionate. Furthermore,
`single ingredient A