CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`22-203
`
`SUMMARY REVIEW
`
`Exhibit 1078
`IPR2017-00807
`ARGENTUM
`
`000001
`
`

`

`SUMMARY REVIEW OF REGULATORY ACTION
`
`Date:
`
`From:
`
`October 15,2008
`
`Badrul A. Chowdhury, MD, PhD
`Director, Division of Pulmonary and Allergy Products,
`CDER,FDA
`
`Division Director Summary Review
`Subject:
`22-203
`NDA Number:
`MEDA Pharmaceuticals
`Applicant Name:
`Date of Submission: August 15,2008
`PDUFA Goal Date: October 15,2008
`Proprietary Name:
`Astepro Nasal Spray
`Established Name:
`Azelastine hydrochloride
`Dosage form:
`Nasal Spray
`137 mcg in each 0.137 mL spray
`Strength:
`Proposed Indications: Relief of symptoms of seasonal allergic rhinitis in patients 12 years
`of age and older
`Approval
`
`Action:
`
`1.
`Introduction
`MEDA Pharmaceuticals submitted proposed labeling with this application to support
`approval of Astepro (azelastine hydrochloride) Nasal Spray for relief of symptoms of
`seasonal allergic rhinitis (SAR) in patients 12 years of age and older. The proposed dose
`is I or 2 sprays per nostril twice daily. MEDA Pharmaceuticals originally submitted this
`505(b)(l) application on July 30, 2007, for the relief of symptoms ofSAR in patients 5
`years of age and older, and for the relief of symptoms ofvasomotor rhinitis (VMR) in
`patients 12 years of age ana older. A non-approval action letter was issued on May 30,
`2008, citing three deficiencies: (1) Submitted data were not adequate to support the VMR
`indication; (2) Submitted data Were not adequate to support the SAR indication in
`patients 5 to 11 years of age; and (3) The submitted data were not adequate to support the
`-..
`. labeling claim for SAR. MEDA Pharmaceuticals requested a Formal
`Dispute Resolution (FDR) from the Office ofDrug Evaluation II (ODE II) on July 1,
`2008. A FDR meeting was held on July 28, 2008, with representation from ODE II and
`this Division. The ODE II issued a written response on August 7, 2008, stating that the
`SAR indication for ages 12 years and above can be approved, pending labeling
`agreement, while upholding the non-approval of the VMR indication, SAR indication for
`labeling claims for SAR. This resubmission is
`ages 5 to II years, and ..
`consistent with the ODE II position that the application for the SAR indication for ages
`12 years and older can be a Class I submission. This summary review provides an
`overview ofthe application, including materials submitted with the original application,
`and the reasoning behind the original non-approval action. This summary focuses' on the
`efficacy and safety studies.
`
`b(4)
`
`000002
`
`

`

`2
`
`2. Background
`Azelastine is an antagonist ofthe histamine HI receptor. Antihistamines are used for
`symptomatic treatment ofvarious allergic diseases, such as allergic rhinitis, allergic
`conjunctivitis, and urticaria. MEDA Pharmaceuticals has an ophthalmic formulation of
`azelastine marketed in the United States under the trade name Optivar, and a nasal spray
`formulation of azelastine marketed in the United States under the trade name Astelin.
`Astelin was approved in November 1996 for SAR in patients 12 years of age and older,
`in February 2006 for SAR in patients 5 to 11 years of age, and in September 2000 for
`VMR.
`
`There are many drugs approved for use in patients with allergic rhinitis, including HI
`receptor antagonists, nasal corticosteroids, and the leukotriene receptor antagonist
`montelukast. .The numbers of drugs approved for non-allergic rhinitis are limited.
`Flonase (fluticasone propionate) has a nonallergic rhinitis indication, and Astelin has a
`VMR indication. MEDA Pharmaceuticals originally intended to maintain the VMR
`indication for Astepro.
`
`The major difference between Astepro and Astelin is that the former contains two
`additional excipients, sucralose and sorbitol, which are intended to mask the distinctive
`bitter taste associated with the azelastine drug substance. MEDA Pharmaceuticals wishes
`to market this sweetened formulation of azelastine nasal spray because Astelin' s bitter
`taste that has apparently limited patient acceptance. The bitter taste is from the drug
`substance azelastine hydrochloride.
`
`In the original application, the proposed indications and dosage and administration
`recommendations for various ages of Astepro were identical to Astelin. MEDA
`Pharmaceuticals planned to support approval of Astepro by·demonstrating comparability
`ofAstepro to Astelin, following the principle outlined in the Agency Draft Guidance on
`Allergic Rhinitis. I That approach failed as discussed in section 7c of this review.
`
`3. Chemistry, Manufacturing, and Controls
`The drug substance azelastine hydrochloride is a well known compound that is already
`approved in commercial ophthalmic and nasal spray products as mentioned above.
`Astepro is a 0.1 % w/v solution of azelastine hydrochloride adjusted to a target pH of 6.4.
`The major difference between the currently marketed Astelin and the proposed Astepro is
`that the latter contains two additional excipients, sucralose at - - , w/v and sorbitol at
`f ---fo w/v. These two excipients are added to sweeten the formulation and mask the
`distinctive bitter taste of azelastine. Sucralose is a novel excipient for a nasal spray.
`Sorbitol has been used in other nasal sprays, but at concentrations much lower than the
`concentration in Astepro. The drug substance source, manufacturing, and specifications
`are the same for Astelin and Astepro. Both products deliver 137 mcg azelastine
`hydrochloride per 0.137 mL actuation. The container and pump closure system used in
`Astepro is the same as in Astelin, and the spray characteristics of the two are similar.
`
`I Guidance for Industry. Allergic Rhinitis: Clinical Development Program for Drug Products. Draft
`Guidance. Available at www.fdagov/cder/guidance.
`
`b(4j
`
`000003
`
`

`

`3
`
`The drug product specifications of the two are also similar. All manufacturing and
`testing facilities associated with this application have acceptable EER status. The
`submitted stability data indicate that Astepro can be stored at room temperature with an
`expiry of 24 months.
`.
`
`4. Nonclinical Pharmacology and Toxicology
`A full toxicology assessment was submitted previously and reviewed under NDA 20-144
`for Astelin. To support the two additional excipients, MEDA Pharmaceuticals submitted
`results from a 2-week intranasal toxicology study in dogs and a 6-month intranasal
`toxicology study in rats, comparing the effects ofAstelin and Astepro. The submitted
`studies showed that both formulations have similar toxicity profiles in the nasal mucosa
`and the respiratory system. Both formulations cause slight irritation of the nasal mucosa,
`but the magnitudes of the effects are similar. There are no outstanding nonclinical
`pharmacology and toxicology issues.
`
`5. Clinical Pharmacology and Biopharmaceutics
`The general clinical pharmacology and biopharmaceutic considerations for azelastine
`hydrochloride were addressed in the original NDA for Astelin. The applicant submitted
`results from one clinical pharmacology study (study MP 429) to assess the comparative
`bioavailability between Astelin and Astepro following a single dose. The study was
`conducted in 18 healthy male subjects ages 18 to SO years. The results ofthe study
`showed that there was slightly lower exposure to azelastine and the major active
`metabolite, desmethyazelastine, for Astepro compared to Astelin. The mean azelastine
`Cmax was 200 pglmL and 235 pg/mL for Astepro and Astelin, respectively, and the
`mean azelastine Ave was 4917 pg.hr/mL and 5903 pg.hr/mL for Astepro and Astelin,
`respectively. The numerical differences for desmethyazelastine for the two formulations
`were similar. The lower systemic exposure from Astepro compared to Astelin is
`supportive of systemic safety of Astepro, meaning that the systemic safety profile for
`Astepro is not expected to be worse than Astelin.
`
`6. Clinical Microbiology
`The final product is not sterile, which is acceptable for a nasal spray product. The
`manufacturing process is adequate from a microbiological perspective. The drug product
`contains benzalkonium chloride as an ' -
`
`bl4)
`
`7. Clinical and Statistical- Efficacy
`a. Overview of the clinical program
`The clinical program submitted consists ofthree pivotal studies. The relatively small
`clinical program is acceptable given that Astelin is an approved product and that the
`intent of the clinical program was to establish comparability of Astepro to Astelin. Table
`I summarizes the characteristics of these pivotal clinical studies that form the basis of the
`regulatory decision. The design and conduct of these studies are briefly described below,
`
`000004
`
`

`

`4
`
`b(4}
`
`followed by efficacy findings and conclusions. Safety findings are discussed in the
`following section.
`
`Table 1. Pivotal clinical studies
`
`ID
`
`MP430
`
`Disease
`StudvtllDe
`SAR
`Efficacy and safety
`Comparability
`
`Study
`duration
`2 weeks
`
`Patient
`Atte,yr
`12-83
`
`MP432
`
`Allergic rhinitis
`Nonallergic rhinitis
`Long term safety
`Comparability
`
`--
`
`Study
`Treatment groups· N
`(ITT) YearN
`2006
`139
`146
`137
`138
`137
`138
`281
`278
`
`A-S I spray BID
`A-S 2 sprays BID
`A 1 spray BID
`A 2 sprays BID
`Pbo 1 spray BID
`Pbo 2 sprays BID
`A-S 2 sprays BID
`A 2 sprays BID
`
`On-
`going
`
`Countries
`
`USA
`
`Australia,
`Europe
`
`-c=: ~~-..,;;;;~
`
`I '
`
`--.
`
`12-82
`
`52 weeks
`(6 month
`Interim)
`
`co
`
`I
`
`-
`I
`I
`I
`* A-S =Astepro Nasal Spray; A = Astelin Nasal Spray; Pbo =Placebo Nasal spray; MF = mometasone
`furoate nasal spray (Nasonex);
`# Year study subject enrollment ended
`
`b. Design and conduct ofthe studies
`
`Study MP 430 was randomized, double-blind, placebo- and active-controlled, parallel(cid:173)
`group in design, conducted in patients 12 years of age and older with SAR. The study
`had a 7-day placebo run-in period followed by a 2-week double-blind treatment period.
`The primary efficacy endpoint was change from baseline in morning plus evening
`reflective total nasal symptom score (rTNSS: sum of runny nose, sneezing, itchy nose,
`and nasal congestion; each scored on 0-3 scale) averaged over 2 weeks of treatment.
`Secondary efficacy variables included the instantaneous recording ofthe same four
`symptoms (iTNSS) and the Rhinoconjunctivits Quality of Life Questionnaire (RQLQ).
`Safety assessments included recording of adverse events, vital signs, physical
`examinations, and clinical laboratory measurements. This study was designed to show
`comparability between Astepro and Astelin and was the subject of a Special Protocol
`Assessment (SPA). In the SPA letter (dated November 4,2005), the Division generally
`agreed with the design of the study.
`
`Study MP 432 was randomized, open-label active-controlled, parallel-group in design,
`conducted in patients 12 years of age and older with perennial allergic rhinitis and non(cid:173)
`allergic rhinitis. The study had a 7-day screening period followed by a 52-week open
`label treatment period. Safety assessments included recording of adverse events, vital
`signs, and physical examination with a focused nasal examination. Efficacy was assessed
`by the Mini RQLQ.
`
`b(4)
`
`000005
`
`

`

`5
`
`b(4)
`
`c. Efficacy findings and conclusions
`The submitted clinical studies, along with the known findings of Astelin; are adequate to
`support the efficacy of Astepro for SAR in patients 12 years of age and older. The
`clinical studies do not support approval ofAstepro forSAR in patients 5 to 11 years of
`age, and also do not support the VMR-indication. MEDA Pharmaceuticals in the original
`application and during the FDR contended that Astepro should have indications and
`dosage and administration recommendations for various ages identical to Astelin.•
`MEDA Pharmaceuticals contention was based on their determination that the submitted
`data demonstrated comparability between Astepro and Astelin, and therefore, all
`indications and dosage and administration recommendations for various ages should be
`carried over from Astelin to Astepro. The Division disagreed that comparability between
`Astepro and Astelin had been demonstrated, and ODEn agreed with the Division at the
`FDR that comparability had n~t been shown. MEDA Pharmaceuticals subsequently
`modified its position and is now only seeking the SAR indication for patients 12 years of
`age and older. The sections below comment on the SAR indication for ages 12 years and
`above, which is the subject ofthe current resubmission, as well as the issues of
`comparability, data needed to support a SAR indication for ages 5 to 11 years; and the
`VMR indication for ages 12 years and older.
`SAR in patients 12 years of age and older, and t-----::-_====--
`
`b(4)
`
`In study MP 430, the 2 spray doses ofAstepro and Astelin were both statistically
`significantly superior to placebo for the primary efficacy endpoint, but the 1 spray dose
`of both products did not statistically significantly separate from placebo (Table 2).
`Secondary efficacy variables generally trended in a similar direction for both products
`and for both doses (data not shown in this review). This single study conducted in
`patients with SAR ages 12 years and above is sufficient to support efficacy in SAR for
`ages 12 years and older. The Agency typically relies on findings from replicate studies as
`substantial evidence of efficacy, but in this specific instance a single study is adequate
`because of previous findings with Astelin, and the fact that both Astelin and Astepro are
`solution formulations with similar container and closure systems and similar in vitro
`characteristics. The dosing recommendation of both 2 sprays and 1 spray can be carried
`over to Astepro. Although the data from this study shows that 1 spray of both
`formulations did not statistically significantly separate from placebo, the efficacy trends
`for both 2 sprays and I spray favored Astepro over Astelin (Table 2). There is no reason
`to believe that Astepro at 1 spray per nostril would not be efficacious in SAR, as previous
`placebo controlled studies have shown a statistically significant difference between
`Astelin at 1 spray per nostril twice daily versus placebo.
`
`000006
`
`

`

`~
`
`Page(s) Withheld
`
`__/_ Trade Secret / Confidential (b4)
`
`_ _ Draft Labeling (b4)
`
`__ Draft Labeling (b5)
`
`_ _ Deliberative Process (b5)
`
`Withheld Track Number: Summary Review-
`
`. I
`
`000007
`
`

`

`7
`
`Comment on Comparability:
`
`The decision to approve the SAR indication for ages 12 years of older is based on the
`reasoning stated above and is not based on demonstration of comparability. For this
`specific decision one does not even need to conclude whether comparability of the two
`products has been demonstrated. Nevertheless, it is worth commenting on comparability
`because MEDA Pharmaceuticals originally concluded that comparability between.
`Astepro and Astelin had been demonstrated through study MP 430. MEDA
`Pharmaceuticals stated that the SAR indication for the full age range and VMR
`indications should be carried over from Astelin to Astepro on the basis of this
`comparability. However, the Division concluded that comparability has not been
`established for reasons stated below.
`
`To support comparability of Astepro and Astelin, MEDA Pharmaceuticals referred to the
`Agency Draft Guidance on Allergic Rhinitis. 2 The Draft Guidance mentions general
`paths for supporting approval of changes in formulation using a comparability approach,
`but the Draft Guidance does not defme how comparability can be established. Also there
`is no precedence of accepting comparability as the basis of approval of a nasal spray
`product. In a meeting with MEDA Pharmaceuticals held on May 3, 2005, the Division
`agreed that a comparability approach based on a single clinical study may support
`approval of Astepro for SAR in patients 5 years of age and older and also for VMR. The
`Agency stated in the meeting that "demonstration of clinical comparability should be
`convincing" and "whether clinical comparability is demonstrated will be a review issue."
`The Draft Guidance on Allergic Rhinitis recommends demonstration of comparability in
`a single study using two doses of each formulation and demonstration of comparability of
`the dose-response curves. Study MP 430 failed to show a dose-response because the 1
`spray dose, which is an approved dose for SAR, did not statistically separate from
`placebo (Table 2). Without demonstration of dose-response, comparability cannot be
`assessed. Therefore, study MP 430 has failed to show comparability between Astepro
`and Astelin.
`
`Another approach to assess comparability oftwo nasal spray products is to use the
`principle outlined in another related Agency Guidance document.3 This guidance is on
`the development of generic nasal spray products. This guidance requires that the tWo
`products be qualitatively and quantitatively the same, meaning that they both contain
`same active and inactive ingredients and the amounts of each be within 5%. Astepro and
`Astelin are qualitatively and quantitatively different because ofthe presence oftwo
`excipients in Astepro that are not present in Astelin; however, because these two are
`solution formulations with the same container and closure system and similar in vitro
`characteristics, one can assume that the differences in excipients will not impact the rate
`and extent of availability ofthe active moiety at the site of action on the nasal mucosa.
`
`2 Guidance for Industry. Allergic Rhinitis: Clinical Development Program for Drug Products. Draft
`Guidance. Available at www.fda.gov/cder/guidance
`3 Guidance for Industry. Bioavailability and bioequivalence studies for nasal aerosol and nasal spray for
`location action. Available at www.fda.gov/cder/guidance
`
`000008
`
`

`

`8
`
`Therefore, the criteria ofbioequivalence described for clinical study in the guidance
`document are not unreasonable to apply here as a test of comparability. The design and
`conduct of study MP 430 are similar to the study recommended in the guidance document
`and allows for such analyses. Our statistical team performed equivalence analysis for
`Astepro and Astelin, which shows that the two products fail the bioequivalence test
`(Table 3). The guidance document recommends testing at the lowest labeled dose to
`optimize sensitivity. In study MP 430 the lowest labeled dose, 1 spray each nostril twice
`daily, did not even statistically separate from placebo and should not be tested.
`Nevertheless, both the 1 spray and the 2 sprays doses were tested and both failed. For the
`2 sprays dose, with which both Astelin and Astepro statistically significantly separated
`from placebo, Astepro tended to be numerically better than Astelin (Table 3).
`
`It appears that adding the two excipients has changed the efficacy of azelastine. The
`efficacy of Astepro may be better than Astelin in treating SAR, but the efficacy of
`Astepro and Astelin is certainly not comparable these criteria.
`
`Table 3. Equivalence analysis for the change from baseline of rTNSS* (study MP 430)
`
`Treatment comparisons
`
`Baseline Mean
`90% CI for the ratio ofmeans
`Astelin and Astepro, 2 sprays
`0.986, 1.466
`Astelin and Astepro, 1 spray
`0.866, 1.324
`* To pass BE equivalence test the 90% CI must fall between 0.8 and 1.25
`
`Baseline Median
`90% CI for the ratio of means
`0.986, 1.464
`0.867, 1.323
`
`SAR in patients 5 to 11 years of age
`
`Astepro could not be approved for SAR for ages of 5 and 11 years'
`-
`_
`_ (Table 1). The primary concern is the lack
`of clinical safety data. In the SPA letter (dated November 4, 2005) the Division stated
`that a "separate clinical safety program to support the safety of the reformulated product"
`will be needed. The applicant has conducted a separate clinical safety study, but the
`study did not include any patients between the ages of 5 and 11 years (Study MP 432,
`Table 1).
`
`MEDA Pharmaceuticals contended in the original application that the submitted clinical
`program should be adequate to - - - - - - - - - - - - - - - - - - - - -
`
`b(4)
`
`000009
`
`

`

`__ Page(s) Withheld
`
`__/_Trade Secret / Confidential (b4)
`
`__ Draft Labeling (b4)
`
`__ Draft Labeling (b5)
`
`__ Deliberative Process (b5)
`
`Withheld Track Number: Summary Review-
`
`.2
`
`000010
`
`

`

`11
`
`b(4)
`
`8. Safety
`a. Safety database
`The safety assessment ofAstepro was based on the studies MP 430 and MP 432 (Table
`1). A total of 564 patients 12 years of age and older were exposed to Astepro in these
`two studies 2 weeks and 6 months in duration. The overall safety database was adequate.
`
`b. Safety findings and conclusion
`The submitted data support the safety of Astepro in patients 12 years of age and older.
`As mentioned above the application does not support safety for ages 5 to 11 years. There
`were no deaths in the clinical program. Serious adverse events were few and did not
`suggest a new safety signal. The majority ofthe adverse events were mild and generally
`similar between Astepro and Astelin. Common adverse events that occurred more in
`drug-treated groups compared to placebo in the 2-week study were bitter taste, epistaxis,
`headache, nasal discomfort, fatigue, and somnolence. In the long-term safety study,
`reporting of adverse events was similar. Nasal mucosal ulcerations and epistaxis were
`seen in both active treatment arms with similar frequency.
`
`Addition ofthe two sweetening agents did not seem to mask the bitter taste of azelastine.
`In the 2 week study, bitter taste was the most common adverse event reported for"both
`formulations, with a frequency of 7% and 6% with Astepro 2 sprays per nostril twice
`daily and 1 spray per nostril once daily, respectively, and 8% and 10% with Astelin 2
`prays per nostril twice daily and 1 spray per nostril once daily, respectively. This is not
`surprising because bitter taste receptors are in the back ofthe tongue whereas sweet taste
`receptors are mostly at the tip ofthe tongue. A nasal spray formulation drips to the back
`ofthe tongue and does not reach the tip of the tongue in any substantial amount.
`
`(12 years of age and older) with vasomotor rhinitis (VMR). Available at:
`http://Gtr.gsk.co.uk/Summary/FluticasoneJuroate/studylist.asp
`II Product label for Flonase (fluticasone propionate) Nasal Spray, 50 mcg
`12 Product labels for Proventil HFA Inhalation Aerosol, Ventolin HFA Inhalation Aerosol, and ProAir HFA
`Inhalation Aerosol.
`
`000011
`
`

`

`12
`
`c. REMSlRiskMAP
`REMS and RiskMAP were not deemed necessary for Astepro. Other oral or nasal
`antihistamines or any spray products for allergic rhinitis do not have REMSor RiskMAP.
`
`9. Advisory Committee Meeting
`An advisory committee was not convened for this application. Azelastine is not a new
`molecular entity. Antihistamines, including nasal antihistamines, are a well studied drug
`class, and efficacy and safety of this class of drug, including azelastine, are well
`understood. There were no issues that warrant discussion at an advisory committee
`meeting.
`
`10. Pediatric
`This NDA does not trigger PREA because there is no new active ingredient, no new
`indication, no new dosage form, no new dosing regimen, or no new route of
`administration. The applicant has a reasonable pediatric development plan for azelastine
`nasal spray. During approval of the Astelin supplement (NDA 20-114, February 17,
`2006) for 1 spray per nostril twice daily dosing for SAR, studies in children 2 years of
`age and older were deferred, and studies below 2 years of age were waived. The Division
`. has taken the position that SAR does not occur in children below 2 years of age.
`Although the lower age cut-off is somewhat arbitrary, there is literature to support the
`lower age bound (J Allergy Clin Immunol2000; 106:832). The deferred pediatric studies
`will adequately address all pediatric drug development for azelastine nasal spray down to
`.
`the age of2 years.
`
`11. Other Relevant Regulatory Issues
`a. DSI Audits
`No DSI audit was requested for this application because azelastine nasal spray is a well
`studied product, and the two clinical studies conducted with Astepro were fairly routine
`standard studies. During review ofthe submission no irregularities were found that
`would raise concerns' regarding data integrity. No ethical issues were present. All studies
`were performed in accordance with acceptable ethical standards.
`b. Financial Disclosure
`The applicant submitted acceptable financial disclosure statements. There were 3
`investigators with significant equity interest in MEDA Pharmaceuticals or its
`predecessor. The number of subjects that these investigators enrolled was not large
`enough to alter the outcome of any study. Furthermore, the multi-center nature ofthe
`studies makes it unlikely that equity interests could have influenced or biased the results
`ofthese studies.
`c. Others
`There are no outstanding issues with consult reviews received from pDMAC.
`
`000012
`
`

`

`b(4)
`
`b(4)
`
`13
`
`12. Labeling
`a. Proprietary Name
`-
`With the original NDA, MEDA Pharmaceuticals proposed the trade name
`this product. DMEDP reviewed that trade name and found it unacceptable. MEDA
`_, during
`Pharmaceticals submitted two additional trade names, / -
`and /
`the original NDA review. Both ofthese names were not acceptable to DMEDP. The
`. problem with these trade names is that the root name for the product is the same, and the
`suffix contains an abbreviation that does not convey any specific meaning. Subsequently
`the applicant submitted two other trade names, Astepro and -_ , also during the
`original NDA review. With this resubmission, MEDA Pharmaceuticals submitted the
`trade name Astepro. DMEDP finds this name acceptable. The name was also found to
`be acceptable to DDMAC from a promotional perspective.
`
`for
`
`b. Physician Labeling
`With the original NDA, MEDA Pharmaceuticals submitted a label in the Physician's
`Labeling Rule format that generally contains information consistent with other products
`of this class. The label was reviewed by various disciplines of this Division, and by
`DDMAC, and DMEDP, during the original NDA review. Various changes to different
`sections of the label were recommended to reflect the data accurately and truthfully and
`better communicate the findings to health care providers. During the original NDA
`review, MEDA Pharmaceuticals agreed to remove the VMR indication, and the SAR
`indication for ages 5 to 11 years, but at the same time attempted to request a FDR with
`the Office ofNew Drugs. The FDR was not accepted because there was no regulatory
`action to dispute. The Division and MEDA Pharmaceuticals were unable to come to a
`.claim for SAR. Therefore, there
`clear agreement about the removal of the'
`was no agreed upon label at the time ofthe previous action. With the resubmission,
`MEDA Pharmaceuticals submitted a label with only the SAR indication for ages 12 years
`. J claim for SAR. The label was again
`and older, and has removed the I
`'"'"""'Sitt
`reviewed by various disciplines ofthis Division. The Division and MEDA
`Pharmaceuticals have agreed to the final version ofthe label.
`
`c. Carton and Immediate Container Labels
`These were reviewed by various disciplines ofthis Division, DDMAC, and DMEP, and
`the last version was found to be acceptable.
`
`d. Patient Labeling and Medication Guide
`The patient instructions for use was reviewed by various disciplines ofthis Division, and
`DSRCS, and found to be acceptable.
`
`13. Action and Risk Benefit Assessment
`a. Regulatory Action
`The applicant has submitted adequate data to support approval ofAstepro for the relief of
`symptoms ofSAR in patients 12 years of age and older. The action on this application
`.
`will be Approval.
`
`000013
`
`

`

`14
`
`b. Risk Benefit Assessment
`The overall risk and benefit assessment ofAstepro supports its approval for relief of
`symptoms of SAR in patients 12 years of age and older without any specific restrictions.
`The submitted clinical study showed efficacy in SAR patients ages 12 years and older,
`and the safety profile was acceptable for this age group. The major safety findings of
`clinical concern were somnolence, fatigue, epistaxis, and nasal mucosal ulcerations.
`Sedation manifesting as somnolence and fatigue is common with some antihistamines,
`and was also seen with Astelin Nasal Spray.. Local nasal mucosal irritation manifesting
`as epistaxis and ulceration is common with nasal spray formulation, and was also seen
`with Astelin.
`
`c. Post-marketing Risk Management Activities
`There are no specific safety concerns and no specific risk management activities are
`warranted.
`
`d. Post-marketing Study Commitments
`There will be no post-marketing study commitments.
`
`000014
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the el~ctronic signature.
`
`/s/
`
`Badrul Chowdhury
`10/15/2008 12:43:46 PM
`MEDICAL OFFICER
`
`000015
`
`

`

`SUMMARY REVIEW OF REGULATORY ACTION
`
`Date:
`
`From:
`
`May 30, 2008
`
`BadrulA. Chowdhury, MD, PhD
`Director, Division of Pulmonary and Allergy Products,
`CDER,FDA
`
`Division Director Summary Review
`Subject:
`22-203
`NDA Number:
`MEDA Pharmaceuticals
`Applicant Name:
`Date of Submission:
`July 20, 2007
`PDUFA Goal Date: May 30, 2008
`Proprietary Name:
`- Nasal Spray
`Established Name:
`Azelastine hydrochloride
`Dosage form:
`Nasal Spray
`Strength:
`137 mcg in each OJ37 mL spray
`Proposed Indications: Treatment of symptoms of seasonal allergic rhinitis and vasomotor
`rhinitis
`Not Approval
`
`Action:
`
`b(4)
`
`1.
`Introduction
`MEDA Pharmaceuticals submitted this SOS(b)(1) application for use of a sweetened nasal
`spray formulation of azelastine hydrochloride (called
`.
`in this review) for the·
`treatment of symptoms of seasonal allergic rhinitis (SAR) in patients 5 years of age and
`older and for treatment of symptoms of vasomotor rhinitis (VMR) in patients 12 years of
`age and older. The proposed dose is 1 or 2 sprays per nostril twice daily for SAR in
`patients 12 years of age and older, 1 spray per' nostril twice daily for SAR in patients 5 to
`11 years of age, and 2 sprays per nostril tWice daily for VMR in patients 12 years of age
`and older. The applicant wishes to market this sweetened formulation of azelastine nasal
`spray because the currently marketed formulation, Astelin Nasal Spray, has a high
`frequency of reports of a distinctive bitter taste that has apparently limited patient
`acceptance. The bitter taste is from the drug substance azelastine hydrochloride. The
`application is based on clinical efficacy and safety studies. This summary review will
`provide an overview of the application, with a focus on clinical efficacy and safety
`studies.
`
`b(4)
`
`2. Background
`Azelastine is an antagonist of the histamine HI receptor. Antihistamines are used for
`symptomatic treatment of various allergic diseases, such as allergic rhinitis, allergic
`conjunctivitis, and urticaria. The applicant has an ophthalmic formulation of azelastine
`marketed in the United States under the trade name Optivar, and a nasal spray
`formulation of azelastine marketed in the United States under the trade name Astelin.
`Astelin was approved in November 1996 for SAR, and in September 2000 for VMR.
`
`000016
`
`

`

`2
`
`The indications and dosage and administration recommendations for various ages of
`Astelin are identical to those proposed for / ~ in the current application.
`
`There are many drugs approved for lise in patients with allergic rhinitis, most of them
`belonging to classes of HI receptor antagonists, nasal corticosteroids, and the leukQtriene
`receptor antagonist montelukast. The numbers of drugs approved for non-allergic rhinitis
`are limited. Flonase (fluticasone propionate) Nasal Spray has a label indication of
`nonallergic rhinitis, and Astelin(azelastine hydrochloride) has a label indication ofVMR.
`No other drug has a specific VMR indication.
`
`b(4)
`
`-' using a comparability approach
`The applicant proposed development of
`"'''''",0,,
`referring to the Agency Draft Guidance on Allergic Rhinitis. 1 This Draft Guidance
`mentions general paths for supporting approval of changes in formulation using a
`comparability approach. The guidance does not define how comparability can be
`established, and also there is no prior precedence of accepting comparability as the basis
`of approval for a nasal spray product. In a meeting with the applicant held on May 3, .
`2005, the Division agreed that a comparability approach based on a single clinical study
`may support approval of - - for SAR in patients 5 years of age and older and also
`for VMR. The Agency stated in the meeting that "demonstration of clinical
`comparability should be convincing" and "whether clinical comparability is demonstrated
`will be a review issue." The single clinical study was the subject of a Special Protocol
`Assessment (SPA). On review of the SPA the Division agreed to the general concept of
`In the SPA letter (dated November 4, 2005) theAgency stated that a
`the study design.
`"separate clinical safety program to support the safety of the reformulated product" will
`be needed. These points are relevant to the action of the application. The applicant'