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

`

`INTEROFFICE MEMO
`
`TO:
`
`
`
`
`
`FROM:
`
`
`
`
`
`NDA 202,236 (DYMISTA; Azelastine Hydrochloride 0.1% and Fluticasone
`Propionate 0.37% Nasal Spray)
`Submissions dated April 1 and July 1, 2011, respectively
`
`Timothy W. Robison, Ph.D., D.A.B.T.
`Pharmacology/Toxicology Team Leader
`Division of Pulmonary, Allergy, and Rheumatology Products
`
`DATE:
`
`December 7, 2011
`
`I concur with the conclusions and recommendations of Dr. Marcie Wood’s Review dated
`September 23, 2011. The review recommended approval of the application from the
`nonclinical perspective.
`
`The applicant has developed a fixed dose combination of azelastine and fluticasone
`propionate administered as a nasal spray for the treatment of allergic rhinitis in children
`and adults 12 years of age and older. This is the first combination product of an anti-
`histamine and corticosteroid.
`
`The nonclinical safety program for the fixed dose combination of azelastine and
`fluticasone propionate administered as a nasal spray is based upon the complete
`toxicology programs conducted with each of the monoproducts. The applicant also
`conducted 14-day intranasal toxicology studies in rats and dogs and a 3-month
`intranasal toxicology study in rats with the combination of azelastine hydrochloride and
`fluticasone propionate to assess for potential additive or synergistic toxic effects of the
`combination. There was no evidence of additive or synergistic toxic effects of the
`combination with particular reference to local toxicity in the nasal cavity and sinuses.
`See Dr. Wood’s review for further details.
`
`Dr. Wood’s Review makes recommendations for changes in the product labeling in Sections
`8.1, 8.3, 10, 12.1, 13.1, and 13.2.
`
`There are no outstanding PharmTox issues.
`
`Reference ID: 3055325
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`TIMOTHY W ROBISON
`12/07/2011
`
`Reference ID: 3055325
`
`

`

`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`Application number:
`Supporting document/s:
`Applicant’s letter date:
`
`CDER stamp date:
`
`NDA 202236
`SDN 1, SDN 4
`SDN 1: April 1, 2011
`SDN 4: July 1, 2011
`SDN 1: April 1, 2011
`SDN 4: July 1, 2011
`Azelastine Hydrochloride 0.1% and Fluticasone
`Propionate 0.37% Nasal Spray
`Seasonal allergic rhinitis
`Meda Pharmaceuticals, Inc.
`Division of Pulmonary, Allergy, and
`Rheumatology Products
`Marcie Wood, Ph.D.
`Reviewer:
`Timothy Robison, Ph.D., DABT
`Supervisor/Team Leader:
`Badrul Chowdhury, M.D., Ph.D.
`Division Director:
`Philantha Bowen
`Project Manager:
`Template Version: September 1, 2010
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 202236 are owned by Meda Pharmaceuticals, Inc. or
`are data for which Meda Pharmaceuticals, Inc. has obtained a written right of reference.
`Any
`information or data necessary
`for approval of NDA 202236
`that Meda
`Pharmaceuticals, Inc. does not own or have a written right to reference constitutes one
`of the following: (1) published literature, or (2) a prior FDA finding of safety or
`effectiveness for a listed drug, as reflected in the drug’s approved labeling. Any data or
`information described or referenced below from reviews or publicly available summaries
`of a previously approved application is for descriptive purposes only and is not relied
`upon for approval of NDA 202236.
`
`Product:
`
`Indication:
`Applicant:
`Review Division:
`
`Reference ID: 3019456
`
`1
`
`

`

`NDA # 202236
`
`
`
`Reviewer: Marcie Wood, Ph.D.
`
`TABLE OF CONTENTS
`
`EXECUTIVE SUMMARY ......................................................................................... 4
`1.1
`INTRODUCTION.................................................................................................... 4
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 4
`1.3
`RECOMMENDATIONS............................................................................................ 5
`2 DRUG INFORMATION .......................................................................................... 11
`2.1
`DRUG............................................................................................................... 11
`2.2
`RELEVANT INDS, NDAS, BLAS AND DMFS......................................................... 12
`2.3
`DRUG FORMULATION ......................................................................................... 13
`2.4
`COMMENTS ON NOVEL EXCIPIENTS..................................................................... 13
`2.5
`COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ....................................... 13
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN .................................... 13
`2.7
`REGULATORY BACKGROUND .............................................................................. 13
`STUDIES SUBMITTED.......................................................................................... 14
`3.1
`STUDIES REVIEWED........................................................................................... 14
`3.2
`STUDIES NOT REVIEWED ................................................................................... 14
`3.3
`PREVIOUS REVIEWS REFERENCED...................................................................... 14
`PHARMACOLOGY................................................................................................ 14
`PRIMARY PHARMACOLOGY................................................................................. 14
`4.1
`4.2
`SECONDARY PHARMACOLOGY............................................................................ 14
`SAFETY PHARMACOLOGY................................................................................... 14
`4.3
`PHARMACOKINETICS/ADME/TOXICOKINETICS .............................................. 14
`5.1
`PK/ADME........................................................................................................ 14
`5.2
`TOXICOKINETICS ............................................................................................... 15
`6 GENERAL TOXICOLOGY..................................................................................... 15
`6.1
`SINGLE-DOSE TOXICITY..................................................................................... 15
`6.2
`REPEAT-DOSE TOXICITY.................................................................................... 15
`7 GENETIC TOXICOLOGY ...................................................................................... 15
`
` 1
`
`3
`
`4
`
`5
`
`8 CARCINOGENICITY ............................................................................................. 15
`
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY ................................ 15
`
`SPECIAL TOXICOLOGY STUDIES................................................................... 15
`
`INTEGRATED SUMMARY AND SAFETY EVALUATION................................. 15
`
`APPENDIX/ATTACHMENTS............................................................................. 36
`
`10
`
`11
`
`12
`
`
`Reference ID: 3019456
`
`2
`
`

`

`NDA # 202236
`
`
`
`Reviewer: Marcie Wood, Ph.D.
`
`Table of Tables
`
`Table 1: Safety margins for proposed clinical doses of azelastine and fluticasone ....... 20
`Table 2: Azelastine hydrochloride animal to human exposure ratios based on mg/m2
`comparisons.................................................................................................................. 34
`Table 3: Fluticasone propionate human exposure ratios based on mg/m2 comparisons
`...................................................................................................................................... 35
`
`
`Reference ID: 3019456
`
`3
`
`

`

`NDA # 202236
`
`
`
`Reviewer: Marcie Wood, Ph.D.
`
`1
`
`Executive Summary
`
`Introduction
`1.1
`The applicant has developed a fixed dose combination of azelastine and fluticasone
`propionate administered as a nasal spray for the treatment of allergic rhinitis in children
`and adults 12 years of age and older.
`1.2 Brief Discussion of Nonclinical Findings
`The nonclinical safety program for the fixed dose combination of azelastine and
`fluticasone propionate administered as a nasal spray is based upon the complete
`toxicology programs conducted for both individual active drugs. The nonclinical
`programs for the individual active drugs include single dose toxicology, subchronic
`toxicology, chronic toxicology, reproductive toxicology, genotoxicity, and carcinogenicity
`studies. The applicant conducted 14-day intranasal toxicology studies in rats and dogs
`and 3-month intranasal toxicology study in rats with the combination of azelastine
`hydrochloride and fluticasone propionate to assess for potential additive or synergistic
`toxic effects of the combination.
`
`In 14-day toxicology studies, the NOAEL for both the rat and the dog was the only
`combination dose tested, 0.1% azelastine and 0.0365% fluticasone propionate (0.4
`mL/day = 0.4 mg azelastine/day and 0.146 mg fluticasone/day). There was no
`difference between species sensitivity to the drug combination in the 14-day studies, but
`the reviewer notes that the sponsor did not evaluate a range of doses of azelastine and
`fluticasone in the dog to identify dose limiting toxicity and/or target organs of toxicity. TK
`parameters were not evaluated in the 14-day rat and dog studies.
`
`In a 3-month intranasal toxicity study in rats, the toxicity of azelastine/fluticasone
`combination nasal spray was compared with the Astelin (azelastine) and fluticasone
`propionate marketed monoproducts. Only one dose of the azelastine/fluticasone
`combination (0.1% azelastine and 0.0365% fluticasone propionate; 0.4 mL/day = 0.4 mg
`azelastine/day and 0.146 mg fluticasone/day) was tested, and control (0.9% sodium
`chloride) and placebo (vehicle) groups were also included. Azelastine systemic
`exposure in the combination azelastine/fluticasone treatment group was lower than the
`Astelin group for males and females on Days 1 and 91. Fluticasone propionate was not
`detected in the plasma of the combination treatment group or the fluticasone propionate
`monoproduct group. Body weight was decreased in males and females in the
`azelastine/fluticasone (-7 and -9% for males and females, respectively) and fluticasone
`propionate (-6 and -15% for males and females, respectively) groups on Day 91 versus
`controls. Body weight gain was also decreased in males and females in the
`azelastine/fluticasone (-10 and -17% for males and females, respectively) and
`fluticasone propionate (-9 and -29% for males and females, respectively) groups (Days
`1-91) versus controls. Mast cells were increased in the mesenteric lymph nodes in the
`azelastine/fluticasone (9/10 males and 10/10 females) and fluticasone propionate (7/10
`males and 8/10 females) groups versus controls. This increase was attributed to effects
`of fluticasone propionate. Mast cells were also increased in the mandibular lymph nodes
`
`Reference ID: 3019456
`
`4
`
`

`

`NDA # 202236
`
`
`
`Reviewer: Marcie Wood, Ph.D.
`
`of males and females in the azelastine/fluticasone group only versus control, vehicle,
`and monoproduct groups. The toxicological significance of this finding is uncertain.
`
`The NOAEL was determined to be the only dose tested, 0.1% azelastine and 0.0365%
`fluticasone propionate (0.4 mL/day = 0.4 mg azelastine/day and 0.146 mg
`fluticasone/day).
`Increased mast cells
`in
`the mandibular
`lymph node
`in
`the
`azelastine/fluticasone combination group versus control and monoproduct groups are of
`uncertain toxicological relevance as they were also found at high background levels in
`the tracheobronchial lymph nodes of control males.
`1.3 Recommendations
`
`1.3.1 Approvability
`From a PharmTox perspective, the application is recommended for approval.
`1.3.2 Additional Non Clinical Recommendations
`None
`1.3.3 Labeling
`
`Reference ID: 3019456
`
`5
`
`(b) (4)
`
`5 Pages of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately
`following this page.
`
`

`

`NDA # 202236
`
`
`
`Reviewer: Marcie Wood, Ph.D.
`
`2
`
`Drug Information
`
`2.1 Drug
`CAS Registry Number (Optional): N/A
`
`Generic Name: Azelastine Hydrochloride 0.1% and Fluticasone Propionate 0.37%
`Nasal Spray
`
`Code Name: MP29-02
`
`Chemical Name
`
`
`Azelastine Hydrochloride: (±)-1-(2H)-phthalazinone,4-[(4-chlorophenyl)methyl]-2-
`(hexahydro-1-methyl-1H-azepin-4-yl)-,monohydrochloride
`
`Fluticasone Propionate: S-(fluoromethyl) 6(cid:302),9-difluoro-11(cid:533)-17-dihydroxy-16(cid:302)-
`methyl-3-oxoandrosta-1,4-diene-17(cid:533)-carbothioate, 17-propionate
`
`
`Molecular Formula/Molecular Weight
`
`
`Azelastine Hydrochloride: C22H24ClN3O•HCl / 418.37
`
`Fluticasone Propionate: C25H31F3O5S / 500.6
`
`
`Structure or Biochemical Description
`
`
`Azelastine Hydrochloride:
`
`
`Reference ID: 3019456
`
`11
`
`(b) (4)
`
`

`

`NDA # 202236
`
`Reviewer: Marcie Wood, Ph.D.
`
`E I
`
`\‘N
`
`CH2@CI
`:N
`o CN—CHg-HCI
`
`Fluticasone Propionate:
`
`0
`
`F
`
`\|
`
`CH3 “$30
`'
`
`CH]
`
`o
`
`Pharmacologic Class
`
`Azelastine Hydrochloride: H1-receptor antagonist
`
`Fluticasone Propionate: Glucocorticoid agonist
`
`2-2
`
`Relevant lNDs, NDAs, BLAs and DMFs
`
`Inc., Azelastine Hydrochloride 0.1% and
`IND 77,363 (Meda Pharmaceuticals,
`Fluticasone Propionate 0.37% Nasal Spray)
`NDA 20-114 (Meda Pharmaceuticals,
`Inc., Astelin (Azelastine Hydrochloride) Nasal
`Spray)
`NDA 20-121 (GlaxoSmithKline, Flonase (Fluticasone Propionate) Nasal Spray)
`DMFs
`
`0’) (4)
`
`(b) (4)
`
`multidose nasal spray pump
`
`DMF
`
`actuator and cap)
`“m Type 1 amber glass bottles
`
`m"
`
`Reference ID: 301 9456
`
`1 2
`
`

`

`NDA # 202236
`
`Reviewer: Marcie Wood, Ph.D.
`
`2.3
`
`Drug Formulation
`
`The drug product contains azelastine hydrochloride and fluticasone propionate in a
`suspension with the following excipients.
`
`
`
`
`
`
`
`mam—WM
`_—
`_—-_—-m-mm-
`
`
`——-_-i-—mmz$-
`
`Exci . ients
`“W
`GI cerin USP
`
`
`Microcrystalline Cellulose and
`
`Carboxymethylcellulose Sodium
`
`NF
`(0)14)
`Pol sorbate 80 NF
`
`Edetate Disodium USP
`
`Benzalkonium Chloride NF
`
`Phen leth I Alcohol USP
`
`
`Purified Water USP
`
`
`
`WI “I
`
`0.1
`2.5
`
`0.01
`0.25
`
`2.4 Comments on Novel Excipients
`
`There are no novel excipients.
`
`2.5 Comments on Impurities/Degradants of Concern
`
`Impurities and/or degradants will be addressed under a separate Chemistry
`Consultation.
`
`2.6
`
`Proposed Clinical Population and Dosing Regimen
`
`The proposed indication for MP29-02 is for the relief of the symptoms of seasonal
`allergic rhinitis in patients 12 years of age and older. The recommended dose is one
`spray per nostril twice daily (137 pg of azelastine hydrochloride and 50 pg fluticasone
`propionate per spray) for a total daily dose of 548 pg of azelastine hydrochloride and
`200 pg of fluticasone propionate.
`
`2.7
`
`Regulatory Background
`
`in the
`ingredients, azelastine and fluticasone propionate,
`The two active principal
`proposed fixed dose combination product, are approved monoproducts. Astelin was
`approved on November 1, 1996 and Flonase was approved on October 19, 1994 in the
`US under NDA 20—114 and NDA 20—121, respectively. The recommended dose of
`Astelin is one or two 137 pg sprays per nostril twice daily for adults and children 2 12
`years of age (Astelin approved label, April 2007), and the recommended dose of
`Flonase is either two 50 pg sprays in each nostril once daily or one 50 pg spray in each
`nostril twice daily (starting dose in pediatric patients 4 years of age and older; Flonase
`approved label, March 2004).
`
`Reference ID: 301 9456
`
`1 3
`
`

`

`NDA # 202236
`
`
`
`Reviewer: Marcie Wood, Ph.D.
`
`3
`
`Studies Submitted
`
`Report Number
`
`Review Location
`
`3.1 Studies Reviewed
`Studies reviewed under IND 77,363 for the combination of azelastine hydrochloride and
`fluticasone propionate include the following:
`
`Study
`Toxicology
`A 14-day intranasal toxicity study with 0.1% azelastine
`and 0.0365% fluticasone in Sprague-Dawley rats
`A 14-day intranasal toxicity study with 0.1% azelastine
`and 0.0365% fluticasone in Beagle dogs
`A 90-day intranasal toxicity study with azelastine and
`fluticasone in Sprague-Dawley rats
`3.2 Studies Not Reviewed
`None
`3.3 Previous Reviews Referenced
`Pharmacology and Toxicology Review of IND 77,363 dated May 3, 2007
`Pharmacology and Toxicology Review of IND 77,363 dated July 2, 2008
`Pharmacology and Toxicology Review of IND 77,363 dated August 10, 2010
`Pharmacology and Toxicology Review of IND 77,363 dated August 8, 2011
`Pharmacology and Toxicology Review of NDA 20-114 (Astelin)
`Pharmacology and Toxicology Review of NDA 20-121 (Flonase)
`4
`Pharmacology
`
`0437RM57.006
`
`IND 77,363
`
`0437DM57.007
`
`IND 77,363
`
`0470RM57.001
`
`IND 77,363
`
`4.1 Primary Pharmacology
`See NDA 20-114 and NDA 20-121 for studies conducted with azelastine hydrochloride
`and fluticasone propionate, respectively.
`4.2 Secondary Pharmacology
`See NDA 20-114 and NDA 20-121 for studies conducted with azelastine hydrochloride
`and fluticasone propionate, respectively.
`4.3 Safety Pharmacology
`See NDA 20-114 and NDA 20-121 for studies conducted with azelastine hydrochloride
`and fluticasone propionate, respectively.
`5
`Pharmacokinetics/ADME/Toxicokinetics
`
`5.1 PK/ADME
`See NDA 20-114 and NDA 20-121 for ADME studies conducted with azelastine
`hydrochloride and fluticasone propionate, respectively.
`
`Reference ID: 3019456
`
`14
`
`

`

`NDA # 202236
`
`
`
`Reviewer: Marcie Wood, Ph.D.
`
`5.2 Toxicokinetics
`See NDA 20-114 and NDA 20-121 for TK studies conducted with azelastine
`hydrochloride and fluticasone propionate, respectively.
`
`Toxicokinetic parameters of MP29-02 were assessed in a 3-month toxicology study in
`rats under IND 77,363.
`6
`General Toxicology
`
`6.1 Single-Dose Toxicity
`See NDA 20-114 and NDA 20-121 for studies conducted with azelastine hydrochloride
`and fluticasone propionate, respectively.
`6.2 Repeat-Dose Toxicity
`See NDA 20-114 and NDA 20-121 for studies conducted with azelastine hydrochloride
`and fluticasone propionate, respectively.
`
`See the attached reviews of 14-day intranasal toxicology studies in rats and dogs and 3-
`month
`intranasal
`toxicology study
`in rats with
`the combination of azelastine
`hydrochloride and fluticasone propionate under IND 77,363.
`7
`Genetic Toxicology
`See NDA 20-114 and NDA 20-121 for studies conducted with azelastine hydrochloride
`and fluticasone propionate, respectively.
`8
`Carcinogenicity
`See NDA 20-114 and NDA 20-121 for studies conducted with azelastine hydrochloride
`and fluticasone propionate, respectively.
`9
`Reproductive and Developmental Toxicology
`See NDA 20-114 and NDA 20-121 for studies conducted with azelastine hydrochloride
`and fluticasone propionate, respectively.
`10
`Special Toxicology Studies
`See NDA 20-114 and NDA 20-121 for studies conducted with azelastine hydrochloride
`and fluticasone propionate, respectively.
`11
`Integrated Summary and Safety Evaluation
`The sponsor has developed an azelastine hydrochloride + fluticasone propionate
`(MP29-02) combination nasal spray for the relief of the symptoms of seasonal allergic
`rhinitis in patients 12 years of age and older. The recommended dose is one spray per
`nostril twice daily (137 (cid:541)g of azelastine hydrochloride and 50 (cid:541)g fluticasone propionate
`per spray) for a total daily dose of 548 (cid:541)g of azelastine hydrochloride and 200 (cid:541)g of
`fluticasone propionate.
`
`
`Reference ID: 3019456
`
`15
`
`

`

`NDA # 202236
`
`
`
`Reviewer: Marcie Wood, Ph.D.
`
`The nonclinical safety program for MP29-02 is based upon the complete nonclinical
`safety programs conducted for both individual active drugs (NDA 20-114 for azelastine
`hydrochloride and NDA 20-121 for fluticasone propionate) as well as bridging toxicology
`studies with the combination up to 3 months in duration. The nonclinical programs for
`the
`individual active drugs, azelastine and
`fluticasone propionate,
`included
`pharmacology, safety pharmacology, toxicology, genotoxicity, carcinogenicity, and
`reproductive toxicology studies. The applicant conducted 14-day intranasal toxicology
`studies in rats and dogs and 3-month intranasal toxicology study in rats with the
`combination of azelastine hydrochloride and fluticasone propionate to assess for
`potential additive or synergistic toxic effects of the combination.
`
`Pharmacology:
`
`Azelastine hydrochloride: Azelastine hydrochloride, a phthalazinone derivative, exhibits
`histamine H1-receptor antagonist activity in isolated tissues, animal models, and
`humans. The major metabolite, desmethylazelastine, also possesses H1-receptor
`antagonist activity.
`
`Fluticasone propionate: Fluticasone propionate is a synthetic trifluorinated corticosteroid
`with anti-inflammatory activity. In vitro dose response studies on a cloned human
`glucocorticoid receptor system involving binding and gene expression afforded 50%
`responses at 1.25, and 0.17 nM concentrations, respectively. Fluticasone propionate
`was 3-fold to 5-fold more potent that dexamethasone in these assays. Data from the
`McKenzie vasoconstrictor assay in man also support its potent glucocorticoid activity.
`
`The precise mechanism through which fluticasone propionate affects allergic rhinitis
`symptoms is not known. Corticosteroids have been shown to have a wide range of
`effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages,
`and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and
`cytokines) involved in inflammation.
`
`Safety Pharmacology:
`
`Azelastine hydrochloride: The effects of azelastine hydrochloride on the cardiovascular,
`behavioral, autonomic, and neurologic systems were evaluated in mice, rats, cats, and
`dogs.
`
`Azelastine hydrochloride administered at high oral doses in mice and rats produced little
`or no apparent CNS changes except depressed motor activity in mice at doses >20
`mg/kg. However, the administration of high doses (10-30 mg/kg SC) to dogs and 3-6
`mg/kg IV to cynomolgus monkeys produced CNS stimulation and even convulsions at
`10 mg/kg IV in monkeys.
`
`In general, azelastine hydrochloride in therapeutic dose ranges usually effective against
`allergic responses was devoid of any effects on the cardiovascular and respiratory
`systems of anesthetized rats, dogs and cats.
`
`Reference ID: 3019456
`
`16
`
`

`

`NDA # 202236
`
`
`
`Reviewer: Marcie Wood, Ph.D.
`
`
`Intravenous administration of azelastine hydrochloride to rats, dogs and cats did not
`affect systemic blood pressure or heart rate. However, higher doses (5-10 mg/kg,
`depending on species tested) resulted in increase or decrease in blood pressure and in
`heart rate.
`
`In dogs, 1 mg/kg IV exerted long-lasting reduction of ST segment elevation. Orally, ECG
`changes, prolonged Q-T intervals at 20 mg/kg and prolonged QRS and QT intervals
`were observed at >40 mg/kg in one toxicity study. In addition, localized myocardial
`degeneration in the heart and adipose cell infiltration in the interstitial tissue of the
`myocardium have been noted at 40 and 60 mg/kg, respectively, suggesting an effect of
`azelastine administration on the heart at very high doses.
`
`
`Azelastine hydrochloride caused a dose-dependent increase in tracheobronchial
`secretion in the mouse with an ED50 of 0.52 mg/kg, p.o. and enhanced mucolytic
`activity in the tracheobronchial lumen of rats (ED50 =0.33 mg/kg). It was found to
`decrease mucus rigidity in beagle dogs at a dose equivalent to 3 mg/kg and decreased
`antigen-elevated viscoelasticity of tracheal mucus in the dogs.
`
`
`Oral administration of azelastine hydrochloride at 1 to 50 mg/kg did not influence gastric
`motility and emptying in mice, but in rats, 1 to 10 mg/kg produced a slight acceleration
`of gastric emptying and retardation at 50 mg/kg. It exerted little or no effect on intestinal
`motility or pancreatic, biliary and salivary secretions in rats.
`
`Fluticasone propionate: Safety pharmacology endpoints were addressed in fluticasone
`propionate studies conducted in mice, rats, cats, dogs, and monkeys. Following oral
`and SC doses, no behavioral modifications were observed in rodents. In anesthetized
`cats, an increased in tracheal inflation pressure and vomiting was observed following an
`acute dose of fluticasone. No changes in heart rates were observed following a 5 mg/kg
`dose of fluticasone propionate by the oral or SC routes of administration. In cynomolgus
`monkeys, fluticasone propionate did not cause arrhythmias or alterations in blood
`pressure.
`
`ADME:
`
`Azelastine hydrochloride: The absorption of azelastine hydrochloride is very rapid in
`animals evidenced by short Tmax of 1-2 hours compared to human Tmax of 4-6 hours
`following a single dose. Plasma concentrations for both animals and humans show
`general dose proportionality up to 30 mg/kg in rats, 60 mg/kg in mice and 2-16 mg in
`humans.
`
`In both laboratory animals and humans, azelastine hydrochloride is widely distributed to
`body tissues with a preferential uptake by the lung observed in two species studied, rat
`and guinea pig. In the dog, the volume of distribution of azelastine after intravenous
`dosing was approximately 20 times the body weight. There is clear evidence for a
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`Reviewer: Marcie Wood, Ph.D.
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`placental transfer, very low levels of transfer to the brain in rodents and a high first pass
`effect in animals and humans.
`
`
`Azelastine hydrochloride is metabolized to various metabolites (eight possible metabolic
`pathways), desmethylazelastine being the major metabolite of importance. Qualitatively,
`the metabolic fate of azelastine hydrochloride is similar in the mouse, rat, guinea pig,
`dog and human. However, there are quantitative inter-species differences in the major
`metabolites which may be partly responsible for different toxicity between rats and dogs.
`Azelastine hydrochloride is not an enzyme inducer when tested for antipyrine half-life.
`The degree of protein binding of total radioactivity was found to be 53-57% in rats. In
`human, the degree of protein binding was 88% for azelastine and 97% for desmethyl-
`azelastine.
`
`
`The major route of elimination in the animals and humans was biliary excretion. In the
`rat, approximately 50% and 80% of the [14C] azelastine hydrochloride doses following
`oral and intravenous administration, respectively, were eliminated in the bile. A
`significant portion (19%) of the biliary radioactivity was recirculated. In humans, 25 and
`50% of the radioactivity was recovered in urine and feces, respectively after five days of
`oral administration (4 mg) and 25 and 75% after ten days. There were no signs of tissue
`accumulation with repeated dosing. The terminal half-lives for elimination of azelastine
`and its metabolite in rodents was 4-8 hours compared to 15-25 hours in dogs and 20-50
`hours in human. This long half-life of the metabolite which is active pharmacologically
`explains the long duration of action in azelastine hydrochloride.
`
`Fluticasone propionate: Animal PK studies showed that fluticasone propionate is
`absorbed after higher oral doses, and rapid first pass metabolism affects oral
`bioavailability. Following SC dosing, PK profiles indicate a depot-like effect with a slow
`release into systemic circulation. Systemic fluticasone was also measurable after a
`single intranasal dose of 10 (cid:541)g/kg to rats. In vitro plasma protein binding ranged from
`81-95% and was similar across species. In an oral and IV distribution study, fluticasone
`was absorbed within 0.5 hrs and distributed mainly to the GI tract. The major metabolic
`pathway involves hydrolysis of the fluticasone at the 17 position to yield a carboxyl
`derivative that is excreted in feces and urine of mice, rats, and humans. This metabolite
`does not have pharmacologic activity at the glucocorticoid receptor.
`
`Following SC administration in rats, high levels of radioactivity were found in fetal lung,
`liver, and placenta at 1 to 6 hrs after a single maternal dose on GD 18. Radiolabeled
`fluticasone was also detected in the milk of lactating female rats within 2 hrs after a
`single dose.
`
`Toxicology: Oral toxicity studies up to 12-months in rats and dogs and intranasal
`toxicity studies up to 6-months in rats and dogs have been conducted with azelastine
`hydrochloride. Systemic toxicity studies (oral, SC) up to 6-months in rats and dogs and
`inhalation (nose-only) toxicity studies up to 78-weeks in rats and 12-months in dogs
`have been conducted with fluticasone propionate.
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`Reference ID: 3019456
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`Reviewer: Marcie Wood, Ph.D.
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`Azelastine hydrochloride: In subacute and chronic oral studies in the rat (up to 12-
`months duration), most of the changes in hematology (elevated serum ALP, SGOT and
`SGPT), urinary parameters (increased urine volume and potassium), liver and kidney
`weight increases, and hepatocellular changes (cytoplasmic vacuolation) occurred at oral
`doses (cid:149) 30 mg/kg/day. The target organs of toxicity were liver and kidney, and drug-
`induced changes appeared to be reversible. However, increased kidney weight was not
`accompanied by changes in kidney function parameters or histopathology, and liver
`findings may be considered an adaptive response. In neonatal rats, slight toxicity
`(comparable to that seen in adult rats) was observed at oral doses of 30 mg/kg
`azelastine hydrochloride and no effects were observed at oral doses (cid:148) 5 mg/kg.
`
`In dogs, aggression and convulsions were observed at oral doses of azelastine
`hydrochloride of 10 mg/kg/day and death occurred at 20 mg/kg/day. Emesis and
`salivation were noted at 3 mg/kg/day. Hepatic changes were not observed in dogs at (cid:148)
`10 mg/kg following a 12-month treatment duration.
`
`Two six-month studies were conducted with the intranasal formulation in rats (0.2, 0.4,
`and 0.8 mg/day) and dogs (0.84, 1.68, and 3.36 mg/day). Except for a marginal
`decrease in body weight gain observed in dogs at highest dose level, there were no
`clinical findings indicative of systemic toxicity of azelastine hydrochloride and no signs
`of irritation to the epithelium lining of the nasal cavity in either species. The intranasal
`administration of azelastine hydrochloride up to 0.8 mg/day to rats and 3.36 mg/day to
`dogs appeared to be safe in these studies.
`
`
`Fluticasone propionate: Fluticasone propionate was shown to be a potent glucocorticoid
`receptor agonist, and the toxicity profile was consistent with other glucocorticoid
`agonists. Toxicology studies conducted for fluticasone propionate demonstrated activity
`against testosterone and progesterone receptors and suggest that fluticasone may
`cause changes in primary and secondary sexual characteristics in males and females if
`administered during puberty. Rats administered fluticasone propionate by inhalation had
`an increase in the absence of corpora lutea and an increase in white striae in the tunica
`of the testes. Other target organs included the heart (perivascular inflammation in mice,
`coronary arteritis in dogs), stomach, lungs (septal thickening), and eyes (keratitis, retinal
`folding, retinal detachment in rats).
`
`Azelastine + fluticasone propionate: Toxicology studies (up to 14-days duration in rats
`and dogs and 3-months in rats) have been conducted with azelastine/fluticasone
`(MP29-02) nasal spray under IND 77,363. In 14-day studies, the NOAEL for both the rat
`and the dog was the only combination dose tested, 0.1% azelastine and 0.0365%
`fluticasone propionate (0.4 mL/day = 0.4 mg azelastine/day and 0.146 mg
`fluticasone/day). There was no difference between species sensitivity to the drug
`combination in the 14-day studies, but the reviewer notes that the sponsor did not
`evaluate a range of doses of azelastine and fluticasone in the dog to identify dose
`limiting toxicity and/or target organs of toxicity. The intranasal safety margin for the
`sponsor’s proposed clinical dose of 0.548 mg azelastine and 0.200 mg fluticasone was
`0.6 (calculated using nasal surface areas of 221 cm2 and 180 cm2 for the dog and
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`Reference ID: 3019456
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`NDA # 202236
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`Reviewer: Marcie Wood, Ph.D.
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`human, respectively). TK parameters were not evaluated in the 14-day rat and