CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`
`20-114/8006
`
`APPROVAL LETTER
`
`HIGHLY CONFIDENTIAL -
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`PLAINTIFFS'
`TRIAL EXHIBIT
`
`PTX0011
`
`MEDA APTX03502754
`
`PTX0011-00001
`
`CIPLA LTD. EXHIBIT 2019 PAGE 1
`
`

`

`K2.1
`111~m lllllll~lm~~~~~
`
`~1<2. 1<'
`
`. OF 'HEALTH-&. HUMAN SERVICES
`
`)-006
`
`N20114
`lllll~ll~l~l~~~~~~m~~~~~~~~~~
`
`" N20 ll <l "
`
`Wal1ace Laboratories, Division of Carter-Wallace, Inc.
`Half Acre Road
`P.O. Box··toot
`CranbW)', NJ 08512-0181
`
`SEP 15 2000
`
`Attention:
`
`. George R. Hemsworth, Ph.D.
`Director, Regulatory Affairs
`
`Dear Dr. Hemsworth:
`
`Please refer to your supplemental new drug application dated November 10, I 999, received
`November 15, 1999, submitted under section 505(b) of the Federal Food, Drug, and
`Cosmetic Act for Astelin (azela.stine hydrochloride) Nasal Spray.
`
`\\ e acknowledge receipt of your submissions dated February J l. July 13, and August 30,
`2000.
`
`This supplemental new drug application provides for the use of Astelin Nasal Spray for the
`treatment of symptoms of vasomotor rhinitis in adults and children 12 years of age and
`older.
`
`We have completed the review of this supplemental application. as amended, and have
`concluded that adequate information has been presented to demonstrate that the d.ru!! produr.t
`is safe and effective for use as recommended in the agreed upon labeling text and with the
`minor editorial revisions listed below. Accordingly, the supplemental application is
`appro ed effectiVe'On the date of this letter.
`
`Revise the Dosage a...1d Administration secti.on of the package insert as follows.
`
`DOSAGE AND ADl\fiNISTRATION
`Seasonal Allergic Rhinitis
`The recommended dose of A.Steiin® Nasal Spray in adults and children 12 years and
`older with seasonal allergic rhinitis is two sprays per nostril twice daily. The
`recommended dose of Astelin® Nasal Spray in children 5 years to 11 years of age with
`seasonal allergic rhinitis is one spray per nostril twice daily.
`
`Vasomotor Rhinitis
`The recommended dose of Astelin® Nasal Spray in adults and children 12 years and
`oldi!r with vasomotor rhinitis is two sprays per nostril twice daily.
`
`HIGHLY CONFIDENTIAL -
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA APTX03502755
`
`PTX0011-00002
`
`CIPLA LTD. EXHIBIT 2019 PAGE 2
`
`

`

`NDA 20-1 14/S-006
`Pagel
`
`The final printed labeling (FPL) must be identical with the minor agreed upon revisions
`indicated above, to the submitted draft labeling (package insert submitted August 30, 2000).
`These revisions are terms ofthe approval of this application.
`
`Please submit 20 paper copies of the FPL as soon as it is available, in no case more than 30
`days after it is printed. Please individually mount ten of the copies on heavy-weight paper or
`similar material. Alternatively, you may submit the FPL electronically according to the
`guidance for industry titled Providing Regulatory Submissions in Electronic Format - NDAs
`(January 1999). For administrative purposes, this submission should be designated "FPL for
`approved supplement NDA 20-114/S-006." Approval of this submission by FDA is not
`required before the labeling is used.
`
`Be advised that, as of April 1, 1999, all applications for new active ingredfents, new dosage
`forms, ne'Y indications, new routes of administration, and new dosing regimens are required
`to contain an assessment of the safety and effectiveness of the product in pediatric .patients
`unless this requirement is waived or deferred (63 FR 66632). We note that you have not
`fulfilled the requirements of 21 CFR 314.55 (or 601.27) for children below 5 years of age.
`We are deferring submission ofyour pediatric studies until September 14, 2002 . However,
`in the interim, please submit your pediatric drug development plans within 120 days from
`the date of this letter unless you believe a waiver is appropriate. Within approximately 120
`days of receipt of your pediatric drug development plan, we will review your plan and notify
`you of its adequacy.
`
`lfyou believe that this drug qualifies for a waiver of the pediatric study requirement, you
`should submit a request for a waiver with suppo~ing information and documentation in
`accordance with the provisions of21 CFR 314.55 within 60 days from the date of this letter.
`V..1e will notify you within 120 days of receipt of your response whether a waiver is granted.
`If a waiver is not granted, we will ask you to submit your pediatric drug development plans
`within 120 days from the date of denial of the waiver.
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`HIGHLY CONFIDENTIAL -
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX03502756
`
`PTX0011-00003
`
`CIPLA LTD. EXHIBIT 2019 PAGE 3
`
`

`

`NDA 20-114/S-006
`Page 3
`
`Pediatric studies conducted under the terms of section 50?._A of the Federal Food, Drug, and
`Cosmetic Act may result in additional marketing exclusivity for certain products-(pediatric
`exclusivity). You should refei to the Guidance for Industry on Qualifying for Pediatr-ic
`Exclusivity (available on our web site at www .fda.gov/cder/pediatricffor details. If you
`wish to qualify for pediatric exclusivity you should submit-a "Proposed Pediatric Study
`Request" (PPSR) in addition to your plans for pediatric drug development described above.
`We recommend that you-submit a Proposed Pediatric Study Request within 120 days from
`the date of this tetter. [f you are unable to meet this time frame but are interested in pediatric
`exclusi>.ity, please notify the division in writing. FDA genera11y will not accept studies
`submitted to an NDA before issuance of a Written Request as responsive to a Written
`Request. Sponsors should obtrun a Written Request before submitting pediatric studies to an
`NDA. If you do not submit a PPSR or indicate that you are interested in p~diatric
`- exclusivity, we will review your pediatric drug development plan and notify you of its
`adequacy. Please note thatsatisfaction of the requirements in 21 CFR 314.55 alone may not
`qualify you for pediatric exclusivity. FDA does not necessarily ask a sponsor to complete
`the same scope of studies to qualify for pediatric exclusivity as it does to fulfill the
`requirements of the pediatric rule.
`
`_ In addition, please submit three copies of the introductory promotional materials that you
`propose to use for this product. .'~I proposed materials should be submitted in draft or
`mock-up form, not final print. Please submit one copy to this Division and two copies of
`both the promotional materials and the package insert directly to:
`
`Division of Drug Marketing, Advertising, and Communications, HFD-42
`Food and Drug Administration
`5600 Fishers Lane
`RocJ,--ville, Maryland 20857
`
`If a letter communicating important information about this drug product (i.e., a "Dear Health
`Care Practitioaer" letter) is issued to physicians and others responsible for patient care, we
`request that you submit a copy of the letter to this NDA and a copy to the following address:
`
`-
`
`MEDWATCH, HF-2
`FDA
`5600 Fishers Lane
`Rockville, MD 20857
`Please submit one market package of the drug product when it is available.
`
`We remind you that you must comply with the requirements for an approved NDA set forth
`under 21 CFR 314.80 and 314.81 .
`
`HIGHLY CONFIDENTIAL -
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA APTX03502757
`
`PTX0011-00004
`
`CIPLA LTD. EXHIBIT 2019 PAGE 4
`
`

`

`ND A 20-114/S-006
`Page4
`If you have any questions, call Ms. Gretchen Trout, Regulatory Project Manager. at (301)
`827-1058.
`
`Dir ctor
`Di · · n of Pulmonary and Allergy Drug Products
`Office of Drug Evaluation ll
`Center for Drug Evaluation and Research
`
`APPEARS 1H1~ WAY
`OM OR\GlNAL
`
`HIGHLY CONFIDENTIAL -
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA APTX03502758
`
`PTX0011-00005
`
`CIPLA LTD. EXHIBIT 2019 PAGE 5
`
`

`

`-en
`en
`0 a..
`.... -
`Ll.l c:a
`
`U)
`
`ASTELJN•
`(azelastine hydrochloride)
`Nasal Spray, 137 meg
`IN-023SJ-im
`For Intranasal Use Only
`
`DESCRIPTION
`A.stelin• (azelastinc hydrochloride) Nasal Spray,
`is an antihistamine
`137 micrograms
`(meg),
`fonnulatcd as a metered-spray solution for
`Azelastine
`intranasal
`administration.
`hydrochloride occurs as a white, almost odorless.
`It bas a
`crystalline powder with a bitter taste.
`molecular weight of 418.37. It is sparingly soluble
`in water, mel11.31lol. and propylene glycol and
`slightly soluble in ethanol, octanol, and glycerine.
`11 has a melting point of about 225°C and tfie pH
`of a saturated solution is between 5.0 and 5.4. Its
`chemical name is (±)-l-(2H)-pht.halazinone,4-((4-
`chlorophenyl) methyl J-2-{hexahydro-1-methyi-IH(cid:173)
`azepin-4-yl)-, monohydrochloride.
`Its molecular
`fonnula is CnHz~¢!NlO·HCI with the following
`chemical structure:
`
`Astetin• Nasal Spray contains 0.1% aulastine
`hydrochloride in an aqueous solution at pH 6.8 2:
`0.3. It alsO contains benzalkonium chloride (l2S
`meg/mi.). edetate disodiwn, hydroxypropyl methyl
`cellulose, citric acid, dibasic sodium phosphate,
`sodium chloride.. and purified water.
`After priming. each metered spray delive!5 a
`0.137 mL mean volume containing 137 meg of
`azelastine hydrochloride (equivalent to 125 meg of
`az.elastine base). Each bonle can deliver 100
`metered sprays.
`CLffilCALPHARMACOLOGY
`phthala.z:inone
`AzeJastine
`hydrochloride,
`a
`hlstarnine H,-receptor
`derivative,
`exhibits
`tissues. an.imal
`in
`antagonist activity
`isolated
`models. and humans. Astetm• NasaJ Spray is
`racemic mixture with no
`admini~ered as a
`difference in pharmacologic activity noted between
`the enantiomers in in vitro studies. The major
`
`HIGHLY CONFIDENTIAL -
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA APTX03502759
`
`PTX0011-00006
`
`CIPLA LTD. EXHIBIT 2019 PAGE 6
`
`

`

`metabolite, desmethylazelast.ine, also possesses H 1-
`receptor an~~o.list activity.
`
`•
`
`Pharmacokinetics and Metabolism
`systemic
`After
`intranasal administration,
`the
`is
`bioavailabiliry of az.elastine hydrochloride
`Maximum
`plasma
`approximately
`401Y~
`concentrations (Cnwc) are achieved in 2-3 hours.
`Based on intravenoUs and oral administration, the
`elimination half·life,
`steady-state volume of
`distribution, and plasma clearance are 22 hours.
`I.lhlkg,
`and O.S
`respectively.
`14.5 Llkg,
`Approximately 75% of an oral dose of radiolabeJed
`azelastine hydrochloride was excreted in the feces
`less than 10% · as Wlchanged az.elastine.
`with
`Aztlastine
`is oxidatively metabolized
`to
`.the
`principal active met~bolite, desmethylazelastine,
`by tlle cytochrome P450 enzyme system. The
`specific P450
`isofonns
`responsible
`for
`the
`biotransformation of az.elastine have not been
`identified; however, clinical
`interaction studies
`wilh the known CYP3A4 inhibitor erythromycin
`a
`phannacokinetic
`failed
`to
`demonstrate
`interaction. In a multiple-dose, steady-state drug
`lllteraction scudy in normal volunteers, cimetidine
`(400 mg mice daily), a nonspecific P450 inhibitor,
`raised orally administered mean azelastine (4 mg
`twice daily) concentrations by approximately 65%.
`TI1e
`m.1jor
`.active
`metabolite,
`desmetltylazelastine, was not mcasut:1ble (below
`assay
`limits)
`after
`single-dose
`intranasal
`administralion of azelastine hydrochloride. Aft.cr
`intranasal dosing of azelastine hydrochloride to
`steady-state.
`plasma
`concentrations
`of
`fl-om
`desmethylazelastine
`range
`20-50% cf
`azelastine
`concentrations.
`When
`azelastine
`is
`a.dilllnisfered
`hydrochloride
`--
`orally,
`detmetllylazelastine has an elimination half-life of
`S4 houn. Limited data indicate tllllt the metabolite
`profile is similar when az.elastine hydrochloride is
`administered via lhe inuanasai or oral route.
`In vitro studies witJ1 human plasma indicate that
`the plasma protein binding of az.elastine and
`desmeU1ylazelastine are approximately 88% and
`97o/o, respectively.
`administered
`Az.elastine
`hydrochloride
`intranasally at doses above two sprays per nostril
`twice daily for 29 days resulted in greater than
`proportional increases in Cmax and area under the
`curve (AUC) for azelastine.
`Studies in healthy subjects administered oral
`doses of azelastine hydrochloride demonstrated
`linear responses in Cmax and AUC.
`Special Populations
`Following oral administration, phannacokinetic
`parameters were not influenced by age, gender, or
`hepatic impairment
`. Based: on ~gle-dose studies. ~
`clearance <SO mllaun)
`insuffiCJency
`·
`
`HIGHLY CONFIDENTIAL -
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA APTX03502760
`
`PTX0011-00007
`
`CIPLA LTD. EXHIBIT 2019 PAGE 7
`
`

`

`---
`
`KSU~ted. in a 70-7.5o/. higher Cmax and AUC
`compared to normal subjects. Time to maximum
`CXlnc:cnt:ration was \U!Changw.
`Oral az.el.astine has been safely administered to
`over 1400 astlunatic subjects, supporting the s.afety
`of administering Astetin• Nasal Spray to allergic
`rhinitis patients with asthma
`Pbarmacod ynamics
`In a placebo<ontrolled study (95 subjects with
`allergic rhinitis). there was no evidence of an effect
`of Astelin• Nasal Spray (2 sprays per nostril twice
`daily for 56 days) on cardiac repolarizat.ion as
`represented by the corrected QT interval (QTc) of
`the electrocardiogram. At higher oral exposures
`(~4 mg twice daily), a nonclinically significant
`mean change on tl1e QTc (3· 7 millisecond increase)
`was observed.
`the cardiac
`investigating
`Interaction studies
`repolarizalion
`etreclS
`of
`concomitantly
`administered oral az.elastine hydrochloride and
`erythromycin or ketoconazole were conducted.
`Oral eryt.htomycin had no effect on az.elastine
`pharmacokinetics or QTc based on analysis of
`serial electrocardiograms. Ketoconazole interfered
`Vtith the measurement of azelastine plasma levels;
`however, no effects on QTc were observed (see
`PREC~UTJONS. Drug Interactions).
`Clinical Trial!!
`U.S. pL'lcebo-controlled clinical trials of Astetin•
`Nasal Spray included 322 patients with seasonal
`all :rgic rhinitis who received two sprays per nostril
`twice a day for up to 4 weeks. These trials
`included 55 pediatric patients ages 12 to 16 years.
`Asletin• Nasal Spray significantly improved a
`oomplex of symptoms. which included rhinorrhea.
`sneezing. and nasal pruritus.
`In dose-ranging trials, Astelin• Nasal Spray
`administration resulted in a decrease in symptoms,
`which read1ed statistical significan~ from saline
`placebo \vitl1in 3 hours after initial dosing and (cid:173)
`persisted over the 12-hour dosing interval.
`TI1ere were no findings on nasal examination in
`an 8-week. study th~t suggestw any adverse effect
`of azelastine on the nasal mucosa.
`f.t .... :-:-:x-:-: .(i . .,. ... i~~d:re(l~~:.-.··· ~ ~--, .. ?/~~~··:..;:.;$'"'"("'<' <-~I$.:1f~~~
`~~ti~~i,~~7.1~
`l&lfroJr&f~~ms::~'i~~ ~·
`;~16i
`!rlu:ilitk:t&:lr~tto~/';i. r~" · · t~~~ter~
`ffi\'dootai~'~~ui·<iJo't ~~@~;;~~~~1>.;~
`~ine3ts rof:eoshi""'lif~~~-· · : iV!
`"ii1~~ "i~
`v:-.:-~-
`····'«··~;-•·. /.-~:-:-:;-:'!~ ... :~~..("!·~a~ .::~
`·-;~':-:··,;~~~~f}<~~
`~enn•·>Nlsar~ s · ·. · ·· ·.,1Si'" irlC3DtltFitn ''iw&iMai
`~n.~to~:~~t~~~j~~!::~t··
`~ .. 4"-P ... _.,, ....
`
`_grog~~AA;~il~M~it""'""'"~~
`
`·.• .••.
`
`INDICATIONS AND USAGE
`Astelin • Nasal Spray is indicated for the treabnent
`of the symptoms of seasonal allergic rhinitis such
`
`HIGHLY CONFIDENTIAL -
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA APTX03502761
`
`PTX0011-00008
`
`CIPLA LTD. EXHIBIT 2019 PAGE 8
`
`

`

`--
`
`as rbinorrb~ sneezing. and nasai,,,,P~~w.~
`~du~,tM~&J=~~~.,~~~=:r~~~~~~·C:t~\
`~ al~ffitl;:gn.;ffili~Sirtsr-'e~ioO'"aild'':' "/Y"" :!i
`&ir·'in~ittw, tiitaiell 1~ ····fs~~ 1~~
`..:rea..
`... P ........ OJ..
`)A.SL . ,
`~
`..
`CONTRAINDlCATlONS
`Astelin• Nasal Spray is coniTaindicated in patients
`with a known hypersensitivity
`to azelastine
`hydrochloride or any of its components.
`PRECAUTIONS
`Activities Requiring Mental Alertness: In clinical
`trials. the occurrence of somnolence has been
`reported in some patients taking Astetin• Nasal
`Spray~ due caution should therefore be exercised
`when driving a car or operating potentially danger(cid:173)
`ous machinery. Concurrent use of Astelin~ Nasal
`Spray wit11 alcohol or other CNS depressants
`should be avoided beoluse additionaJ reductions in
`impainnent of CNS
`alertness and additional
`performance may occur.
`lnjoFmation fo, Patients: Patients should be
`instructed to use Astelul• Nasal Spray onJy as
`prescribed. For lhe proper use of t11e nasal spray
`and to attain maximum improvement. tile patient
`should read and follow carefully the aC(X)mpanying
`patient instructions. Patients should be instructed
`to prime the delivery system before inilial use and
`after storage for 1 or more dAys (see PATIENT
`INSTRUCTIONS FOR USE). Patients should also
`be instructed to store the bonJe upright at room
`tc::nperllture with \be pwnp tightly closed and out
`ln case of accidental
`of tlle reach of children.
`ingestion by a young child, seek professional
`assistance or contact a poison control center
`inunediately.
`Patients should be advised against the concurrent
`u5e of Astelln., Nasal Spray with other
`antillistamines without co1tSU.Iting a physician.
`Patitnts who are. or may become. pregnant should
`in
`this- product should be used
`be told that
`pregnancy or during lactation onJy if the potential
`benefil justifies the potential risks to the fetus or
`nursing infant Patients should be Jdvised to assess
`t11eir individual responses ro Astelin• Nasal Spflly
`before engaging in any activity requiring mental
`alertness, sucll as driving a car or operating
`machinery. Patients should be advised thai the
`concurrent use of Astelin• Nasal Spray with
`alcohol or other CNS depressants may lead to
`. additional reductions in alertness and impairment
`of CNS perfonnance and should be avoided (see
`Drug Interactions).
`DFug lnteraaions: · Concurrent use of Astelin•
`Nasi! Spray wiU1 alcohol or otlter CNS depressants
`should be avoided beause addilionaJ reductions in
`alenn~ and additional
`impainnent of CNS
`performance may occur.
`increased the
`Cimetidine (400 mg rwicc daily)
`mean Cmax and AUC of orally administ.ettd
`
`-
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA APTX03502762
`
`PTX0011-00009
`
`CIPLA LTD. EXHIBIT 2019 PAGE 9
`
`

`

`·-
`
`az..elastine bydrocb.Joride (4 mg twice daily) by
`approximately 65%.
`Ran.itidine hydrochloride
`(150 mg twice daily) had no-effect on aula.stine
`pharmacokinetics.
`the car_diac
`investigating
`Interaction studies
`effects, as measured by the corrected QT i.rlteNai
`(QTc), of conconutantly-
`.adminislered oral
`azelastine hydrochloride and erythromycin or
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`HIGHLY CONFIDENTIAL -
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA APTX03502763
`
`PTX0011-0001 0
`
`CIPLA LTD. EXHIBIT 2019 PAGE 10
`
`

`

`ASTELJN•
`(azel astine hydrochloride)
`Nasal Spray, 137 meg
`IN-023 SJ .. ;~,..t
`For Intranasal Use Only
`
`~//..C
`
`keloconazole were conducted. Oral erythromycin
`(500 mg three times daily for seven days) bad no
`effeet on az.c:lastine pharmacokinetics or QTc based
`on
`analyses of
`serial
`electrocardiograms.
`Ketoconazole (200 mg twice daily for seven days)
`interfered with &he measurement of a.z.el.astine
`plasma concentrations; however, no effects on QTc
`were observed.
`No significant phannacokinetic interaction was
`observed with lhe coadministration of an oral 4 m~
`dose of azelastine hydrochloride twice daily and
`theophylline 300 mg or 400 mg twice daily.
`Carcinogenesis, Mutagenesis,
`Impairment of
`Fertility: In 2 year carcinogenicity studies in ralS
`and mice...aulastu1e hydrochloride did not show
`evidence of carcinogenicity at oral doses up to 30
`mglkg and 25 mg/k.g. respectively (approximately
`240 and I 00 times t11e ma.ximwn reconunended
`daily intranasal dose in aduJlS and children on a
`mgtm2 basis).
`Az.elastine hydrochloride showed no genotox.ic
`effects in the Ames test. DNA repair test. mouse
`lymphoma
`forward mutation assay, mouse
`micronucleus test. or chromosomal aberration test
`in rat bone marrow.
`Reproduction and fertility studies in ralS showed
`no effects on male or female fertility at oral doses
`. up to 30 mglkg (approximately 240 times the.
`--max:mwn recommended daily intranasal dose in
`aoults on a mg/m2 basis).
`At 68.6 mglkg
`560
`the maximum
`(approximately
`times
`ru:ommended daily intranasal dose in adults on a
`mg/m2 basis), the duration of estrous cycles was
`prolonged and copulatory activity and tile number
`of pregnancies were decreased. 1l1e numbers of
`corpora lutea and implantations were decreased;
`however. pre-implantation loss was not increased.
`Pregnancy Catrgory C: A.z.elast.ine hydrochloride
`h'lS been sh0\\11 to cause developmental toxicity.
`Treabnent of nl.icewillt an oral dose of 68.6 mg./kg
`280
`times
`tbe maximum
`(approximately
`recommended daily intranasal dose in adullS on a
`mg/m2 basis) caused embryo-fetal death.
`
`-
`
`HIGHLY CONFIDENTIAL -
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`
`MEDA APTX03502764
`
`PTX0011-00011
`
`CIPLA LTD. EXHIBIT 2019 PAGE 11
`
`

`

`-
`
`malfonnatioP.': (cleft palate; sbon or absent tail~
`fused. - absent
`delayed
`or branch'!d
`ribs),
`ossification and decreased fetal weight lb.is dose
`also caused maternal toxicity as evidenced by
`decreased body weight Neither fetal nor matemal
`effects occurred at a dose of J - mglkg
`times
`the maximum
`(approximately
`10
`recommendcrl daily intranasal dose in adults on a
`mg/m2 basis).
`In rats, an oral dose of 30 mglkg (approximately
`240
`times
`the maximum recommended daily
`intranasal dose in adults on a mglm1 basis) caused
`malfonnations (oligo-and brachydactylia). delayed
`ossification and skeletal variations, in the absence
`At 68.6 mglkg
`of matema.l
`toxicity.
`560
`(approx.imarely
`times
`the maximum
`recommended daily intranasal dose in adults on a
`mg/m2 basis) azelastine hydrochloride also eaused
`embryo-fetal de3lh and decreased fetal weight;
`the 68.6 mglkg dose caused severe
`however,
`matema1
`toxicity. Neither fetal nor maternal
`effects occurred at a dose of 3 mglkg
`times
`the maximum
`(approximately
`25
`recommended daily intranasal dose in adults on a
`mg/m1 basis).
`_
`In rabbits. oral dGses of 30 mglkg and greater
`500
`times
`the maximum
`(approximately
`recommended daily intranasal dose in adults on a
`mg/m1 basis) caused abortion, delayed ossification
`and decreased fetal weight~ however, these doses
`aJso resulted in severe maternal toxicity. Neither
`fetal nor matem.al effects occurred ala dose of 0.3
`mglkg (approximately 5
`the maximum .
`times
`rec.ommended daily intranasal dose in adults on a
`mg/m2 basis).
`TI1ere eire no- -adequate and well-<X>ntrolled
`clinical studies in pregnant women. Astetin• Nasal
`.. Spray should be used dwing pregnancy only if the
`potential benefit justifies the potential risk to the
`fetus.
`-
`Nursing Motllcn: ll is not known wbelher
`az.ela.stine hydrochloride is excreted in human milk.
`Because many drugs are excn:led in human milk.
`C'lution should be exercised when Astelin• Nasal
`Spray is administered to a nursing woman.
`PediiJiric llse: The safery and effectiveness of
`Astelin• Nasal Spray at a dose of 1 spray per
`nostril t\Yice daily has been established for patients
`5 through I I years of age for the treatment of
`symptoms of seasonal allergic rhinitis. The safety
`of th.is doS<~ge of Astetin• Nasal Spray was
`established in well-<:Ontrolled studies of lhis dose
`in 176 patients 5 to 12 years of age trear.ed for up to
`6 weeks. TI1e efficacy of Astelin• Nasal Spray at
`this dose is based on an extrnpoJation of the finding
`of efficacy in adults. on the likelihood that the
`disease course., pathophysiology and response to
`trearment are substantially similar in children
`compared to adults. and on supportive dala from
`
`HIGHLY CONFIDENTIAL -
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA APTX03502765
`
`PTX0011-00012
`
`CIPLA LTD. EXHIBIT 2019 PAGE 12
`
`

`

`controlled clinkal trials in patients S to 12 years of
`age at the dose of 1 spray per nostril twice daily.
`The safery and effectiveness of Astelin• Nasal
`Spray in patients below tll.e age of S years have DOt
`been established.
`
`.
`
`, .,._ n~·A.r'·' ,. 'c ·· ···'.',~ ,lu
`ADVERSE REACTIONS
`~ --··· ··· ~ - ~ -"-
`Adverse experience infonnation for Astelin Nasal
`Spray is derived from six weU-<:onlrolled, 2-day to
`8·week clinical studies which included 3 91 patients
`who recei cd Astelin Nasal Spray at a dose of 2
`In placet>c;
`sprays per nostril
`twice daily.
`controlled effie3cy
`tl1e
`trials,
`incidence of
`discontinuation due to adverse reactions in patients
`receiving Astelin., Nasal Spray was
`not
`signific:antJy different from vehicle placebo (2.2%
`vs 2.&%, respectively}.
`In these clinical studies, adverse C'tlents that
`occurred statistically significantly more often in
`patients treated witl1 Astetin• Nasal Spray versus
`vehicle placebo included bitter taste (19.7% vs
`0 .6%), somnolence (11.5% vs 5.4%), weigltt
`increase {2.0% vs 0%), and myalgia (1.5% vs 0%).
`1l1e following adverse C'tlents were reported with
`frequencies ~% in clle Astelin• Nasal Spray
`trtaunent group and more frequently tl1an placebo
`in short·lenn (s:2 days) and ll.'ng~erm (2--8 weeks)
`clinical trials.
`
`APPEARS THIS WAY
`ON ORIG\NAl
`
`I
`
`HIGHLY CONFIDENTIAL -
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA APTX03502766
`
`PTX0011-00013
`
`CIPLA LTD. EXHIBIT 2019 PAGE 13
`
`

`

`ADVERSE EVENT
`
`Bitter Taste
`Headache
`Somnolence
`Nasal Burning
`Pharyn~itis
`Dry Mouth
`Paroxysmal
`3neezing
`Nausea
`Rhinitis
`Fatigue
`Dizziness
`E pi st.1.x.i s
`Weight Increase
`
`Aslelin®
`Nasal Spray
`n• 391
`19.7
`14.8
`ll.S
`4.1
`3.8
`2.8
`3.1
`
`-
`
`Vehicle
`Placebo
`n=3S3
`0.6
`12.7
`5.4
`1.7
`2.8
`1.7
`l.l
`
`2.8
`2.3
`2.3
`2.0
`2.0
`2.0
`
`1.1
`1.4
`1.4
`1.4
`1.4
`0.0
`
`A total of 176 patients S to 12 years of age were
`eJ:posed to Astelin• Nasal Spray at a dose of 1
`spray each nostril twice daily in 3 plAcebo(cid:173)
`controlled studies. In these studies, adverse events
`lhat occurred more frequently in patients treated
`"itJl Astelin• Nasal Spray UWl with placebo, and
`th.:ll were not represented in the adult adverse event
`table abOve include rhinitis/cold symptoms (17.0"!.
`\ "S 9.5%), cough (11.4% vs 8.3%), conjunctivitis
`(5. 1% vs 1.8%), and asUuna (4.5% vs 4. 1%).
`TI1e following events were observed infrequently
`(<2% and exceeding placebo incidence) in patients
`who
`received Astelin• Nasal Spray
`(2
`sprays/nostril twice daily) in U.S. clinical trials.
`Cardiovascular:
`flushing.
`hypertension.
`uchycarrlia.
`De.1l13tological: contact dennatitis, eczema, hair
`and follicle infection. furunculosis.
`Digestive: constipation. gastroenteritis, glossitis,
`ulceralive stomatitis, vomiting. increased SGPT,
`aphthous stomatitis.
`Metabolic and Nutritional: increased appetite.
`Musculoskeletal: myalgia,
`temporomandibular
`dislocation.
`Neurological: hyPerkinesia. bypoesthesia.. vertigo.
`PsychologicaJ:
`depersonalization.
`aro::iety.
`depression, nervousness.. sleep disorder, thinking
`abnorrnal
`bronchospasm.
`Respiratory:
`burning. laryngitis.
`Special Senses: conjunctivitis, e:ye abnormality,
`eye pain. watery eyes, taste Joss.
`Urogenitm : albwninuria.. amenorrl\Q, breast pain,
`hematuria, increased urinary frequency.
`Whole Body: allergic reaction. bade pain, bapes
`in
`simplex. viral
`infection, malaise.
`pain
`extremities, abdominal p3in.
`
`coughing.
`
`throat
`
`HIGHLY CONFIDENTIAL -
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA APTX03502767
`
`PTX0011-00014
`
`CIPLA LTD. EXHIBIT 2019 PAGE 14
`
`

`

`---
`
`-
`
`In ron11olled trials involving nasal
`oral
`liic:Jastine· hydrochloride fonnulalions.. !here were
`ilifrequent occurrences of hepatic transaminase
`elevations. TI1e clinical relevance of these repons
`has not been established.
`In addition, t11e following spontaneous adverse
`events ha~e been reported during the rnarlceting of
`Astetin• Nasal Spray and causal relationship with
`the drug _ is unknown: anaphylactoid reaction,
`irritation, chest pain. nasal
`application site
`congestion. confusion. diarrhea, dyspDea. facial
`involuntal)'
`contractions.
`edema,
`muscle
`paresthesia, parosmia, pruritus. rash,
`tolerance,
`vision
`abnormal
`and -
`urinary
`retention,
`xerophthalmia
`
`OVERDOSAGE
`There have been no reponed overdosages with
`Aslelin• Nasal Spray. Acute overdosage by adults
`with this dosage fonn is unlikely to result in
`clinicalJy significant adverse events.. other than
`~ SOilUlolence. since one bottle of Asteun•
`Nasal Sprny contains 17 mg of aulastine
`
`HIGHLY CONFIDENTIAL -
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX03502768
`
`PTX0011-00015
`
`CIPLA LTD. EXHIBIT 2019 PAGE 15
`
`

`

`1\ydrochloride. OinicaJ srudies in adults with
`single doses of the oral fonnulation of az.elast.in.e
`hydrochloride (up to 16 mg) have not resulted in
`increased incidence of serious adverse_ eytmts.
`General supportive measures should be employed
`if overdosa;e occurs. There is "flO known antidote
`to Astelin Nasal Spray. Oral
`ingestion of
`antiltistamines bas the potential to cause serious
`_ adverse effects in young children. Accordingly,
`As1etin• Nasal Spray should be kept out of the
`reach of children. Oral doses of 120 mglkg and
`greater (approximately 460 times the maximum
`recommended daily inuanasaJ dose in adults and
`children on a mg/m2 basis) were lethal in mice.
`Responses seen prior c 4eath were
`tremor,
`convulsions, decreased muscle tone, and salivation.
`In dogs, single oral doses as high as 10 mglkg
`260
`times
`the maximum
`(approximately
`recommended daily intran.:lsal dose in adults and
`children on a mg/m2 basis) were well tolerated, but
`single oral doses of 20 mg./kg were letlw.
`DOSAGE AND ADMINISTRATION
`l11e recommended dose of Astelin• Nasal Spray in
`ddults and childr~n 12 years and older is two sprays
`per nostril twice daily. ln children 5 years to 11
`years of age, the recorrunended dose of Astelin•
`Nas.'ll Spray is one spray per nostril twice daily.
`Before initial use. tJ1e screw cap on the bottle
`should be replaced with the pump unit and the
`delivery system should be primed with 4 sprays or
`wttil a fine ~st appears. When 3 or more days
`have elapsed since the last use, the pump should be
`reprimed witJ1 2 sprays or Wltil a fme mist appears.
`
`CAUTION: Avoid spraying in the eyes.
`
`Directions for Ust: Illustrated patient instructions
`for proper usc accompany each package of
`Astetm• Nasal Spray.
`
`BOW SUPPLIED
`Astelin• (azelastine hydrochloride) Nasal Spray,
`137 meg, (NDC 0037-0241-10) is supplied as a
`package containing a total of 200 metered sprays in
`two high-<iensity polyethylene (HOPE) bottles
`filled with SC're\Y caps. A sepanlte metered-dose
`spray pump unit and a leaflet of patient instructions
`TI1e sprny pump wlit
`are also provided.
`is
`packaged in a polyethylene wrapper and consists of
`a nasal spray pump fitted will1 a blue safety clip
`and a blue plastic dust cover.
`Eacb Astelin• (az.elastine hydrochloride} Nasal
`Spray, 137 meg. bottle oonta..ins 17 mg (JmglmL)
`of az.elastine hydrochloride to be used with the
`supplied metered~ose spray pump wtil Each
`hnrrle r-1 11 r1t>livl"r tOO ml"tl"ri"Ji c:nrnvc: F~rh c:nrnv
`
`HIGHLY CONFIDENTIAL -
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA APTX03502769
`
`PTX0011-00016
`
`CIPLA LTD. EXHIBIT 2019 PAGE 16
`
`

`

`delivers a mean of 0. 137 mL solution containing
`137 meg of azelastine hydrochloride.
`ATTENTION: The. imprirued expiration date
`applies 10 ll1e product in the bottles with screw -
`caps. After the spray pump is inserted into the first
`botUe of the dispensing package. both bottles of
`product should be discarded after 3 months. not to
`. e.xa:ed the expiration date imprinted on the label.
`Stonge: Store at controlled room temperature 20°·
`25°C (68°-71°F). Protect from freezing.
`
`Manufactured by
`Wallace Laboratories
`Division of Carter-Wallace, Inc.
`Cranbury, NJ 08512-<>181 for
`Wallace Laboratories/ AST A Medica LLC
`02000 WaUace Laboratories/ASTA Medica LLC
`Rev.~
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`-.
`
`HIGHLY CONFIDENTIAL -
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA APTX03502770
`
`PTX0011-00017
`
`CIPLA LTD. EXHIBIT 2019 PAGE 17
`
`