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

`

`
`
`
`
`
`CLINICAL PHARMACOLOGY REVIEW
`
`
`NDA/Supporting document no.
`Submission Date
`Brand Name
`Generic Name
`Reviewer
`Team Leader
`OCP Division
`OND Division
`
`Dosage Regimen
`
`202-236
`04/01/11
`TBD
`Azelastine 0.1% and Fluticasone 0.037%
`Lokesh Jain, Ph.D.
`Suresh Doddapaneni, Ph.D.
`Clinical Pharmacology II
`Division of Pulmonary, Allergy, and Rheumatology
`Products
`Sponsor/Authorized Applicant Meda Pharmaceuticals
`Submission Type; Code
`505(b)(2)
`Formulation; Strength(s)
`Nasal spray
`Indication
`Relief of the symptoms of seasonal allergic rhinitis
`(SAR) in patients 12 years of age and older
`• age 12 years and older: 1 spray per nostril BID
`(total azelastine dose of 548 μg/day and total
`fluticasone dose of 200 mcg/day)
`• not indicated in age group < 12 years
`
`
`Executive Summary ..............................................................................2
`1.
`Recommendation....................................................................................................... 2
`1.1
`Phase IV Commitments ............................................................................................. 2
`1.2
`Summary of Clinical Pharmacology and Biopharmaceutics Findings................. 2
`1.3
`2. Question Based Review ................................................................................3
`2.1
`What are the highlights of the formulations of the drug product? ................................ 3
`General Attributes of the Drug ....................................................................... 4
`2.2
`2.2.2
`What are the proposed dosage and routes of administration? ............................. 5
`2.2.3 What drugs (substances, products) indicated for the same indication are
`approved in the US?.............................................................................................. 5
`General Clinical Pharmacology ..................................................................... 5
`What are the design features of the clinical pharmacology and biopharmaceutics
`studies and the clinical studies used to support dosing or claims?....................... 5
`Are the active moieties in plasma appropriately identified and measured to
`assess pharmacokinetic parameters?................................................................... 7
`Do the DDI studies suggest any potential change in systemic exposures of AZE
`and FLU for MP29-02 vs. monotherapy products (i.e., investigational
`monotherapy comparators and commercial monotherapy products)?.................. 7
`What are the clinical implications of comparable/relatively high exposures as
`discussed under 2.3.3? ......................................................................................... 7
`
`2.3
`2.3.1
`2.3.2
`2.3.3
`
`2.3.4
`
`
`
`Reference ID: 3063275
`
`1
`
`

`

`2.3.5
`
`2.4
`2.4.1
`
`Are there any concerns about impact on hypothalamic-pituitary-adrenal (HPA)
`axis function because of higher fluticasone exposure from MP29-02 compared to
`the commercially available generic FLU products?............................................. 10
`Intrinsic Factors.................................................................................................. 12
`For MP29-02, what dosage regimen adjustments are recommended for each
`group?.................................................................................................................. 12
`2.4.1.1 Renal Impairment ................................................................................................ 12
`2.4.1.2 Hepatic Impairment ............................................................................................. 12
`Analytical Section.............................................................................................. 13
`2.5
`2.5.1
`What bioanalytical methods are used to assess concentrations of the measured
`moieties? ............................................................................................................. 13
`2.5.2
`What are the details of the bioanalytical method and validation parameters for
`fluticasone? ......................................................................................................... 13
`2.5.3 What are the details of the bioanalytical method and validation parameters for
`azelastine? .......................................................................................................... 14
`Detailed Labeling Recommendations ....................................................... 15
`2.6
`Appendix 1 ................................................................................................................................... 20
`Study # X-03065-3282.................................................................................................. 20
`
`Study # X-03065-3283.................................................. Error! Bookmark not defined.2
`
`Appendix 2 - Filing and Review Form ....................................... Error! Bookmark not defined.6
`
`
`1. Executive Summary
`1.1 Recommendation
`The Office of Clinical Pharmacology finds NDA 202236 acceptable.
`1.2 Phase IV Commitments
`None
`1.3 Summary of Clinical Pharmacology and Biopharmaceutics
`Findings
`Meda pharmaceutical, Inc. has submitted NDA #202236 seeking marketing approval for
`a fixed dose combination product containing azelastine hydrochloride (AZE; 0.1% w/w)
`and fluticasone propionate (FLU; 0.0365% w/w), presented as a nasal spray formulation
`MP29-02. If approved it will be the first fixed dose combination nasal spray product to be
`marketed in the USA.
`
`MP29-02 is intended for the relief of symptoms of seasonal allergic rhinitis (SAR) in
`patients 12 years of age and older. The monotherapy components AZE and FLU were
`approved under NDA 20-114 and NDA 20-121, respectively, for symptoms of seasonal
`allergic rhinitis (SAR), vasomotor rhinitis (VMR), and perennial allergic rhinitis (PAR).
`
`In support of this NDA, sponsor conducted five clinical efficacy and safety studies and
`two clinical pharmacology single-dose relative bioavailability studies. The objective of
`clinical pharmacology studies was to assess the relative bioavailability of AZE and FLU
`from MP29-02 against monotherapy products to identify any potential drug-drug
`
`
`
`
`
`Reference ID: 3063275
`
`2
`
`

`

`interaction (DDI) and formulation issues. Key results from clinical pharmacology studies
`are listed below:
`• Co-administration of FLU and AZE does not affect systemic exposures of each other
`• Systemic exposure of AZE from MP29-02 was within ±20% of the exposure from
`Astelin®, a FDA approved commercially available AZE product
`• Systemic exposure of FLU from MP29-02 is 44-61% higher than the exposure from a
`FDA approved commercially available FLU generic product
`• Higher systemic exposures of FLU from MP29-02 fall in the range of exposures for
`which no significant effect on HPA-axis function has been identified
`Dosing information for intrinsic and extrinsic factors was bridged from that of the
`individual components.
`2. Question Based Review
`2.1 What are the highlights of the formulations of the drug product?
`The formulations used in clinical pharmacology studies were as follows:
`1. investigational AZE-FLU combination product: MP29-02
`2. investigational monotherapy products
`a. a formulation and packaging similar to MP29-02, except the absence of
`AZE (i.e., only FLU in MP29-02 vehicle)
`b. a formulation and packaging similar to MP29-02, except the absence of
`FLU (i.e., only AZE in MP29-02 vehicle)
`3. commercially available monotherapy products
`a. FLU generic product, marketed by Roxane Laboratories
`b. Astelin®, an AZE monotherapy product marketed by Meda
`pharmaceuticals
`
`
`Comparison of the composition of combination vs. monotherapy investigational products
`is shown in Table 1.
`
`The to be marketed combination product is same as the MP29-02 product used in Phase 3
`clinical trials supporting safety and efficacy for this NDA.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3063275
`
`3
`
`

`

`Table 1: Description and composition of NIPZ9-02 and investigational monotherapy
`drug products
`Ingredient
`
`Azelastine Hydrochloride 0.1%
`Nasal Spray
`
`fluticasoue Propionate 0.037010
`Nasal Spray
`
`Azelastine Hydrochloride 0.1%
`and Flnticnsone Pmpionnte
`0.037% Nasal Spray
`
`
`
`
`
`pg"
`spray"
`
`pg.
`spray"
`
`"
`
`pig,
`spray"
`
`mgjg
`
`° 0 WW
`
`Drug Substances:
`
`Azelastine Hydmchloride
`“mm—ll—
`so
`0.365
`0.0365
`«-
`50
`0 365
`0.0365
`Flulicasone Propiouale USP
`
`Excipients:
`Glycerin USP
`Minoan/alanine Cellulme and
`('arboxyuictlwlccllulosc
`Sodium NF
`Polysorbate 80 NF
`Edctatc Disodium USP
`
`0’) (‘1
`
`Bcnzalkomum Chloride NF”
`
`Phenylethyl Alcohol USP
`Purified Wald USP
`
`0”“
`
`4
`W
`
`«W
`
`(b) (4
`
`(w
`
`an) (4)
`
`‘
`
`0 l
`
`2 ,5
`
`(I 01
`
`O .25
`
`0.1
`
`Z .5
`
`0.0]
`
`0.25
`
`
`
`(I!) (4)
`
`2.2 General Attributes of the Drug
`
`2.2.1 What are the proposed mechanism of action and therapeutic
`indications?
`
`
`AZE is a selective histamine Hl-receptor antagonist. Antihistamines are used for
`symptomatic treatment of various allergic diseases. Meda pharmaceuticals markets two
`of the currently approved Azelastine nasal spray products - Astelin® (NDA 20-114) and
`AsteproO (NDA 22—371). 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. The
`approved indications for azelastine and the dosage are as below:
`
`0 Treatment of symptoms of SAR
`— Age 2 12 years: 1-2 sprays per nostril bid (maximum daily dose (MDD) =
`
`548-1096 ug/day)
`— Age 5-12 years: 1 spray per nostril bid GVIDD = 548 pg/day)
`0 Treatment of symptoms of nonallergic VMR
`
`— Age 2 12 years: 2 sprays per nostril bid OVIDD = 1096 ug/day)
`
`FLU is a synthetic glucocorticoid which acts as a glucocorticoid receptor agonist. It is an
`anti-inflammatory agent. The approved indications for fluticasone and the dosage are as
`below:
`
`Reference ID: 3063275
`
`

`

`
`For the relief of symptoms of SAR, PAR, and nonallergic rhinitis in patients 4
`years of age and older
`• Adults: 2-sprays per nostril qd (200 μg/day) or 1-spray per nostril bid (200
`μg/day)
`• Adolescents and Children: starting dose 1-spray per nostril qd (100 μg/day)
`with maximum daily dose up to 200 μg/day
`
`
`Purported rational for combination
`Due to different primary mechanisms of action, the combination product of azelastine
`and fluticasone was hypothesized to have a potential for greater efficacy than with each
`agent alone.
`
`2.2.2 What are the proposed dosage and routes of administration?
`MP29-02 is to be administered intra-nasally at the proposed dose of 1 spray per nostril
`BID in patients’ age 12 years and older (total azelastine dose of 548 μg/day and total
`fluticasone dose of 200 mcg/day). At this stage, sponsor is not seeking an indication for
`age group <12 years.
`
`2.2.3 What drugs (substances, products) indicated for the same indication
`are approved in the US?
`There are no approved fixed dose combination nasal spray products. If approved, MP29-
`02 will be the first product in this category.
`
`The US approved products for monotherapy components are listed below.
`
`
` Table 2: The US approved products for AZE and FLU
`
`Product
`AZE (metered nasal spray)
`Astelin®
`Astepro®
`Generic Azelastine
`FLU (metered nasal spray)
`Flonase®
`Generic Fluticasone
`Generic Fluticasone
`Generic Fluticasone
`
`Sponsor
`
`
`Meda Pharmaceuticals
`Meda Pharmaceuticals
`Apotex Inc.
`
`Glaxosmithkline
`Apotex Inc.
`Hi Tech Pharma
`Roxane
`
`2.3 General Clinical Pharmacology
`
`2.3.1 What are the design features of the clinical pharmacology and
`biopharmaceutics studies and the clinical studies used to support
`dosing or claims?
`The clinical pharmacology program for this NDA consisted of the following studies:
`• Phase 1 (healthy volunteers) single dose PK drug-drug interaction study
`
`
`
`Reference ID: 3063275
`
`5
`
`

`

`1. For fluticasone (study # X-030605-3282)
`2. For azelastine (study # X-030605-3283)
`
`
`These studies were planned to assess the relative systemic exposures of AZE and FLU
`from combination product MP29-02 vs. monotherapy comparators (investigational FLU
`and AZE monotherapy comparators and commercial monotherapy products).
`
`The clinical program consisted of five safety and efficacy studies, which are outlined in
`Table 3. Efficacy results for the primary endpoint, rTNSS (reflective combined AM+PM
`Total Nasal Symptom Score), from the key double-blind trials as summarized by the
`sponsor showing a significant difference for MP29-02 and each component drug
`compared to placebo are depicted in Figure 1. For final assessment of efficacy and safety
`findings of MP29-02 from these studies, please refer to the clinical review by Dr. Jennifer
`R Pippins.
`
`Table 3. Summary of Phase 3 safety and efficacy studies
`Study # Duration Objective
`MP-4000
`1-year
`Randomized, open-label, active-controlled study of efficacy and safety
`comparing two treatments: (A) MP29-02 and (B) Generic fluticasone
`propionate nasal spray
`MP-4001 2-week Randomized, double-blind, placebo and active-controlled trial of efficacy
`and safety comparing four treatments: (A) MP29-02, (B) Astelin® nasal
`spray, (C) Generic fluticasone propionate nasal spray, and (D) placebo
`MP-4002 2-week Randomized, double-blind, placebo and active-controlled trial of efficacy
`and safety comparing four treatments: (A) MP29-02, (B) only AZE in
`MP29-02 vehicle, (C) only FLU in MP29-02 vehicle, and (D) placebo
`MP-4004 2-week Randomized, double-blind, placebo and active-controlled trial of efficacy
`and safety comparing four treatments: (A) MP29-02, (B) only AZE in
`MP29-02 vehicle, (C) only FLU in MP29-02 vehicle, and (D) placebo
`MP-4006 2-week Randomized, double-blind, placebo and active-controlled trial of efficacy
`and safety comparing four treatments: (A) MP29-02, (B) only AZE in
`MP29-02 vehicle, (C) only FLU in MP29-02 vehicle, and (D) placebo
`
`
`
`
`
`
`
`Reference ID: 3063275
`
`6
`
`

`

`
`Figure 1. Treatment differences for change from baseline in rTNSS, AM and PM
`combined (ITT population) – least square means and 95% confidence
`intervals for pairwise differences from placebo
`
`
`
`
`
`2.3.2 Are the active moieties in plasma appropriately identified and
`measured to assess pharmacokinetic parameters?
`The moieties measured in these studies were AZE and FLU. Please see section 2.5 for
`further details.
`
`2.3.3 Do the DDI studies suggest any potential change in systemic
`exposures of AZE and FLU for MP29-02 vs. monotherapy products
`(i.e., investigational monotherapy comparators and commercial
`monotherapy products)?
`The systemic exposure of AZE from MP29-02 was equivalent to the exposure from only
`AZE formulated in MP29-02 vehicle and commercial Astelin® product (see Table 4).
`The systemic exposure of FLU from MP29-02 was equivalent to the exposure from only
`FLU formulated in MP29-02 vehicle. However, fluticasone exposure from MP29-02 was
`44-61% higher than the exposure from commercial generic product of fluticasone (see
`Table 4).
`
`2.3.4 What are the clinical implications of comparable/relatively high
`exposures as discussed under 2.3.3?
`With respect to FLU
`(a) comparable exposure of FLU in MP29-02 versus FLU formulated in MP29-02
`vehicle, indicates to no effect of azelastine co-administration on FLU systemic
`
`
`
`Reference ID: 3063275
`
`7
`
`

`

`exposure (i.e., no drug-drug interaction)
`(b) almost 60% higher Cmax and 44-61% higher AUC of FLU in MP29-02 versus
`FLU in generic nasal spray, indicates that systemic safety profile of MP29-02
`with respect to FLU might be different from that of commercially available FLU
`generic nasal spray product (see 2.3.5 for further discussion).
`
`
`With respect to AZE
`(a) comparable exposure of AZE in MP29-02 versus AZE formulated in MP29-02
`vehicle, indicates no effect of FLU co-administration on AZE systemic exposure
`(i.e., no drug-drug interaction)
`(b) comparable exposure of AZE in MP29-02 versus AZE in Astelin®, indicates that
`systemic safety profile of MP29-02 with respect to AZE will be comparable to
`that of Astelin® nasal spray.
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3063275
`
`8
`
`

`

`GM ratio (90% CI)
`AUC0-t
`PE(CI)*
`
`0.94 (0.84-1.05)
`1.61 (1.37-1.89)
`
`
`0.99 (0.91-1.07)
`1.06 (0.96-1.16)
`
`Table 4: Comparison of single-dose PK parameters for different formulations of FLU (FLU) and AZE (AZE)
`
`
`Cmax
`
`PE(CI)*
`N
`N
`
`X-03065-3282
`
`
`
` MP29-02 vs. FLU in MP29-02 vehicle 19/19 0.91 (0.83-1.00) 19/19
` MP29-02 vs. FLU generic
`19/19 1.57 (1.32-1.87) 19/19
`
`
`
`
`X-03065-3283
`
`
`
` MP29-02 vs. AZE in MP29-02 vehicle
`26/26 1.03 (0.92-1.14) 26/26
` MP29-02 vs. Astelin
`26/26 1.07 (0.93-1.24) 26/26
`*PE(CI): point estimate (90% confidence interval)
`
`
`
`
`
`
`
`
`
`
`
`AUC0-∞
`PE(CI)*
`N
`
`
`16/19 1.01 (0.85-1.20)
`16/18 1.44 (1.15-1.80)
`
`
`
`
`26/26 0.98 (0.90-1.07)
`26/26 1.05 (0.96-1.16)
`
`
`
`Reference ID: 3063275
`
`9
`
`

`

`2.3.5 Are there any concerns about impact on hypothalamic-pituitary-
`adrenal (HPA) axis function because of higher fluticasone exposure
`from MP29-02 compared to the commercially available generic FLU
`products?
`No dedicated HPA axis effect study was conducted by the sponsor despite the higher
`systemic exposure for fluticasone component from MP29-02 compared to the marketed
`generic fluticasone product.
`
`Sponsor stated that inspite of higher FLU exposure, MP29-02 is not likely to pose any
`additional safety concerns with respect to HPA axis function compared to the
`commercially available FLU products because of the following reasons:
`
`
`(a) Effect on HPA axis was compared between MP29-02 and FLU generic nasal
`spray product by measuring the serum cortisol levels in trial MP4000. One fasting
`AM serum sample was drawn each at baseline, month 6, and month 12. There was
`no significant change in cortisol levels after 6-months or 12-months treatment
`with MP29-02 compared to baseline as shown in Table 5.
`
`
`The current FDA guidance1 on clinical development of allergic rhinitis drug products
`recommends “assessment of adrenal function using either timed urinary free cortisol level
`measurements (i.e., 12-hour or 24-hour), or 24-hour plasma cortisol AUC levels
`pretreatment and after at least 6 weeks post-treatment with study medication”. Guidance
`also recommends including a placebo and an active control (e.g., oral prednisone) in
`these studies.
`
`Sponsor’s evaluation of adrenal function in trial MP4000, as stated above, falls short of
`the standards recommended by the FDA. Therefore, no effect on serum cortisol based on
`only one AM serum sample by itself would offer limited assurance about effect of MP29-
`02 on HPA-axis function.
`
`(b) A higher dose of FLU (either 200 μg once-daily or 400 μg twice-daily) from a
`FDA approved FLU product, Flonase® nasal spray, was reported to have no
`effect on the adrenal response to a 6-hour consyntropin stimulation test.
`
`To refer to the effect of Flonase® on HPA-axis information, sponsor cited the Flonase®
`prescribing information. The study mentioned in prescribing information to discuss the
`effect on HPA-axis function was published in J Allergy Clin Immunol (1998)2, which can
`be referred for further information. In this study HPA-axis function was evaluated by
`measuring the (a) plasma cortisol response to a short cosyntropin stimulation test and (b)
`
`1 Allergic Rhinitis: Clinical Development Programs for Drug Products. Guidance for Industry by FDA.
`Draft April 2000.
`http://www fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071293.
`pdf
`2 Vargas R, Dockhorn RJ, Findlay SR, Korenblat PE, Field EA, Kral KM. Effect of FLU aqueous nasal spray versus
`oral prednisone on the hypothalamic-pituitary-adrenal axis. J Allergy Clin Immunol 1998 Aug; 102(2): 191-7
`
`
`
`
`Reference ID: 3063275
`
`10
`
`

`

`24-hour urinary excretion of free cortisol (unstimulated). In addition to FLU, this study
`also had active prednisone control arms (7.5 mg QD and 15 mg QD) and a placebo arm.
`Results from this study demonstrated that 24-hour urine cortisol levels were comparable
`between placebo and subjects receiving a total FLU daily dose of up to 800 μg for 4
`weeks, suggesting that effect of FLU on adrenal axis function in tested doses may not be
`different from that of placebo.
`
`
`(c) Recommended starting doses (i.e., 88-440 μg bid) for another FDA approved
`FLU product, Flovent® HFA, had equal or relatively high systemic FLU exposure
`than that for MP29-02 (see Table 6). Inspite of relatively high systemic exposure
`of FLU, no significant effect on HPA axis has been reported for Flovent® HFA.
`The label for Flovent® HFA states that (i) there was no discernable effect of
`Flovent 88 μg bid on the HPA axis compared to placebo in age group 1 to <4
`years, (ii) geometric mean ratio of serum cortisol over 12 hours (AUC0-12) was
`0.95 for Flovent HFA 88 μg bid vs. placebo after 4-weeks treatment of children
`with reactive airways disease in age group 6 to <12 months, reassuring lack of
`effect on HPA axis, (iii) in patients with asthma receiving Flovent HFA at 44,110,
`220 μg bid dose for at least 4 weeks, differences in serum cortisol AUC0-12hr and
`24-hour urinary excretion of cortisol compared to placebo were not related to dose
`and generally not significant, and (iv) 24 hour urinary excretion of cortisol was
`not affected after 4 weeks of treatment with Flovent HFA 88 μg bid compared to
`2 weeks of treatment with placebo [geometric mean ratio (90% CI): 0.987 (0.796-
`1.223)].
`
`
`Table 3: Summary of HPA axis test results (fasting serum cortisol) screening to on-
`treatment visits, safety population
`
`
`
`
`
`
`
`
`
`Reference ID: 3063275
`
`
`
`11
`
`

`

`Table 4: FLU peak exposure (Cmax) and total exposure (AUC) following an approved
`Flovent HFA inhalation dose compared with the MP29-02 dose administered in study X-
`03065-3282
`
`
`Flovent HFA†
`Steady-state
`440 μg BID
`220 μg BID
`88 μg BID
`Bronchodilators alone Inhaled corticosteroids Oral corticosteroids
`76.2**
`297.5**
`600.9**
`25.2
`60.8
`103.1
`
`MP29-02
`
`Single-dose
`
`200 μg QD
`
`
`GM
`88.3*
`AUC
`9.6
`Cmax
`*AUC0-∞ after single-dose
`** AUC0-12 at steady-state
`†Data for Flovent HFA are taken from drugs@fda website (Summary Basis of Approval,
`Clinical Pharmacology and Biopharmaceutics Review, Table 1, Page 4)
`Note: AUC0-∞,sd and AUC0-t,ss are different PK metrics and can not be directly compared,
`but under the assumption of linear PK, the AUC0-∞,sd after 200 μg single-dose
`administration of MP29-02 will be comparable to that of AUC0-12,ss after 100 μg BID
`administration of MP29-02. Therefore, AUC0-∞,sd for MP29-02 can be compared with
`AUC0-12,ss for Flovent HFA.
`
`The true effect of higher exposure of FLU in MP29-02 vs. commercial Flonase® on HPA-
`axis function remains unknown in the absence of a dedicated study conducted with
`MP29-02. However, available supportive information indirectly derived from data
`acquired with other approved fluticasone products seems to indicate that systemic levels
`of fluticasone from MP29-02 may not be high enough to cause a significant effect on
`HPA-axis function.
`
`
`2.4
`
`Intrinsic Factors
`
`2.4.1 For MP29-02, what dosage regimen adjustments are recommended
`for each group?
`
`2.4.1.1 Renal Impairment
`Dosing information for MP29-02 in patients with renal impairment was bridged from that
`of the individual component drugs.
`
`2.4.1.2 Hepatic Impairment
`Dosing information for MP29-02 in patients with hepatic impairment was bridged from
`that of the individual component drugs.
`
`
`
`Reference ID: 3063275
`
`12
`
`

`

`
`
`2.5 Analytical Section
`
`2.5.1 What bioanalytical methods are used to assess concentrations of the
`measured moieties?
`Table 7 lists the molecules measured and validation report no. for studies submitted this
`NDA.
`
`
`Table 7: Analytical methods for DDI studies
`Study #
`Moiety
`Matrix Method description
`measured
`FLU
`
`X-03065-
`3282
`X-03065-
`3283
`
`AZE
`
`Serum HPLC-MS/MS
`method
`Plasma HPLC-MS/MS
`method
`
`Validation report #
`
`VAL-47610
`
`Azelastine /
`100006051
`
`2.5.2 What are the details of the bioanalytical method and validation
`parameters for fluticasone?
`Bioanalytical method for fluticasone is detailed in Table 8 below. Based on reported
`validation parameters, this method is adequate for quantitation of fluticasone.
`
`Table 8: Description of bioanalytical method for fluticasone
`Parameter
`Description
`Analyte name (matrix)
`Fluticasone (serum)
`Take 1 mL of matrix sample, to that add 25 μL of internal
`Method description
`standard working solution and 5 mL of DIPE. Shake
`tubes vigorously using a DVX-2500 multitube vortexer
`for 5 min for extraction. Centrifuge at 4000 rpm for 2
`minutes. Store at -70˚C for about 10 minutes and decant
`the organic phase into centrifuge vials. Evaporate the
`organic phase and add 50 μL of 50% methanol to
`residual. Vortex and transfer approximately 45 μL
`volume to auto-sampler vials.
`API 5000 mass spectrometer
`0.250 pg/mL
`0.250 pg/mL -50.0 pg/mL
`
`Instrument
`Limit of quantitation (LOQ)
`Standard curve concentration
`range
`Regression model & weighting
`factor
`QC concentration QC Low
` QC Medium
` QC High
`Accuracy
`Precision Interbatch
` Intrabatch
`
`Quadratic (y=ax2 + bx + c), 1/conc.
`
`0.700 pg/mL
`25.0 pg/mL
`37.5 pg/mL
`93.7 – 103.6 %
`4.76-14.68%
`Not reported
`
`
`
`Reference ID: 3063275
`
`13
`
`

`

`Selectivity
`
`Average recovery of drug (%)
`Matrix factor
`Freeze-thaw stability in matrix
`Short-term stability in injection
`solution
`Long-term stability
`
`
`
`Assessed with six samples from different individuals
`at LLOQ level
`56.4%
`1.06/1.08
`Established up to 3 cycles
`Established up to 30 hours
`
`Not reported (current report states that it will be
`reported in an amendment to validation report)
`
`2.5.3 What are the details of the bioanalytical method and validation
`parameters for azelastine?
`The method used for quantitation of azelastine was validated for both azelastine and its
`metabolite desmethyl-azelastine. However, Table 9, below, describes the validation
`parameters for only azelastine. Based on reported validation parameters, this method is
`adequate for quantitation of azelastine.
`
`Table 9: Description of bioanalytical method for azelastine
`Parameter
`Description
`Analyte name (matrix)
`Azelastine and Desmethyl-azelastine (Plasma)
`To 500 μL plasma sample, add 10 μL internal standard.
`Method description
`To this add 500 μL ammonium acetate solution of pH 9
`and 2 mL ethyl acetate. Shake, centrifuge for 5 min at
`3500 g, store at -80˚C for a short while and decant into
`new vials. To this add 150 μL water + 0.1% formic acid.
`Centrifuge for 5 min at 3500 g, and separate the organic
`ethyl acetate layer. Store samples for 5 min at approx.
`60˚C in vacuum centrifuge, transfer 100 μL in new vials
`of which 40 μL is injected into HPLC system.
`API 4000 MS 2, Agilent 1200 Series HPLC system
`0.5 pg/mL
`2 pg/mL
`2 pg/mL -1000 pg/mL
`
`Instrument
`Limit of detection (LOD)
`Limit of quantitation (LOQ)
`Standard curve concentration
`range
`Regression model & weighting
`factor
`QC concentration LLOQ
` QC Low
` QC Medium
` QC High
` QC Dilution
`Accuracy Inter-assay
` Intra-assay
` Dilution
`Precision Inter-batch
`
`Linear, 1/conc2
`
`2 pg/mL
`6 pg/mL
`300 pg/mL
`750 pg/mL
`3000 pg/mL (10x dilution)
`2.54% – 6.29 %
`1.63% - 9.30%
`8.10%
`2.51-6.29%
`
`
`
`Reference ID: 3063275
`
`14
`
`

`

`IntIa-batch
`
`1.06% -3.09%
`
`Assessed by using six difl'erent human plasma
`s n les
`
`Avera e recove of dru_ %
`
`74.04%
`
`Freeze-thaw stabili
`
`inmatrix
`
`Autos. u uler stabili
`
`Short-term stabili
`
`16 hours I a rox. 10°C
`
`
`
`Stock solution stabili
`
`At least for 9 weeks at 4°C
`
`Long-term stability
`
`Not reported (report states that it will be reported in
`an amendment
`
`2.6 Detailed Labeling Recommendations
`
`Following are the labeling comments for the sponsor.
`0
`Stakeout—text- should be removed from labeling and
`to labeling.
`
`5.
`
`WARNINGS AND PRECAUTIONS
`
`should be added
`
`
`
`
`DRUG INTERACTIONS
`
`7.
`
` Reference ID: 3063275
`
`

`

`(b) (4)
`
`Appendix 1
`
`Title: Single dose pharmacokinetics of intranasal fluticasone delivered by a fixed
`combination with azelastine OVIP29-02) in comparison to two different fluticasone nasal
`sprays.
`
`Objectives:
`Primary
`To assess the effect of AZE on the relative bioavailability of FLU when administered as
`fixed AZE-FLU combination product (Test) compared to a similar formulation without
`containing AZE (i.e. FLU alone in the MP29—02 vehicle; Reference).
`
`Secondary
`0 To compare the relative bioavailability of FLU when administered either as fixed
`AZE-FLU combination product (Test) or as marketed FLU product, FLU Nasal
`Spray, Roxane Laboratories (comparator)
`
`0 To compare the effects of AZE on other pharmacokinetic parameters of FLU
`0 To assess adverse events
`
`Study design: Single-centre, randomized, open—label, three-period, six-sequence, cross-
`over trial (William’s design) in healthy subjects
`
`Number of subjects: 30 subjects were to be randomized with at least 12 female subjects
`
`Treatments and dose:
`
`Treatment
`
`Dose
`
`Total dose
`
`Test M2902)
`(=US formulation as used in pivotal trials)
`Reference G"LU in MP29-02 vehicle)
`(=combination product formulation without
`any AZE; US FLU mono formulation as used
`in pivotal studies)
`Comparator (FLU nasal spray, Roxane
`Laboratories) 1=US marketed product!
`
`2 sprays per nostril
`
`2 sprays per nostril
`
`548 Hg AZE plus
`200 ”g FLU
`200 Hg FLU
`
`2 sprays per nostril
`
`200 Hg FLU
`
`Results:
`
`Study subjects
`
`Reference ID: 3063275
`
`20
`
`

`

`A total of 69 subjects were screened; of which 30 subjects were randomized and exposed
`to at least one dose of study medication. 11 subjects were excluded from per-protocol
`(PP) population because of perceived protocol deviations with possible relevance to PK
`analyses. Two randomized/exposed subjects discontinued the study prematurely. Seven
`subjects were excluded from PP population, because of complete but slow (with low
`force) application of nasal spray, e.g., sprays (partly) applied hesitantly or weakly, spray
`insufficient. Two subjects were excluded because of incomplete or additional doses (one
`subject applied nasal spray with slow and low force with an additional spray which led to
`incorrect dosage and the other subject did not press down spray pump completely). Impact of
`exclusion of these subjects on study results was evaluated by sensitivity analysis; however,
`data from one subject with incorrect dosage administration was not included.
`
`All randomized/exposed subjects were included in the safety analysis set. 19 subjects
`(63.3% of the randomized/exposed subjects) were included in the PP population; a total
`of n=26 subjects were included in the sensitivity analysis.
`
`Pharmacokinetic analysis
`The serum concentration – time curves for the test, reference, and comparator treatments
`are shown in Figure 1. These profiles are largely comparable for test and reference, but
`the profile for comparator differs from that of both test and reference. The PK parameters
`from these treatment arms are summarized in Table 10. Geometric mean ratio and 90%
`CI for comparison of PK between these treatments are shown in Table 11.
`
`90% CI for comparison of PK parameters between test and reference were between 80%-
`125%. While for comparison of test and comparator, both point estimate and 90% CI
`were outside the 80%-125% range. The mean systemic exposure (AUC0-24 and Cmax) for
`test were 52-57% higher than that of comparator.
`
`
`
`
`Figure 1: Time course of mean FLU concentrations (pg/mL) by treatment on log-
`linear scale (PP analysis)
`
`
`
`Reference ID: 3063275
`
`21
`
`

`

`Table 10: PK parameters for test, reference, and comparator products in study X-
`03065—3282
`
`Parameter
`
`AUCo.24 [pgoh/mL]
`AUCoM [pgoh/mL]
`AUCMm [pgoh/mL]
`Cmax
`mL
`
`Test
`Geometric
`mean
`
`61 .921
`88.301
`61.921
`9.600
`
`N
`
`19
`16
`19
`19
`
`N
`
`19
`19
`19
`19
`
`Reference
`Geometric
`mean
`
`N
`
`Conlparator
`Geometric
`mean
`
`65.690
`87.782
`65.690
`10.518
`
`19
`18
`19
`19
`
`40.035
`59.163
`37.906
`6.061
`
`Table 11: Geometric mean ratio (point estimate and 90% CI) for comparison of test,
`referencez and comparator in study X-03065-3282
`