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`
`EXHIBIT C
`
`EXHIBIT C
`
`

`
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`
`I'I It'll]! .IGl|'I‘S (IF |’R|!lS('?R| Ill NG Il‘il“0Rl\«IA'I‘l0J‘-l
`These
`do not include all the illforrrnttion neelled to use
`ASTELlN“' safely and effectively. See full prescribing inforrmtion for
`ASTELIN.
`
`AS'l‘ICLlN (amelasfirne hydmchloride) nasal spray
`Initial US. Approval: 1996
`
`INDICATIONS AND USAGET
`Astelin Nasal Spray is an 1-1. -receptor antagonist indicated tor the tl'€t1l“lllOllf0f
`the s}-mptcins cfscascnai allergic rhinitis in adults and pediatric patients 5
`years and older and for llie trealmenl uf the S}-1'Ilpl0lTIN ofvastuniitrir fi1iI'IliiSill
`adults and adulescetll patients 12 years and older. (1)
`
`IJOSAGF. AND A Dl\'lIJ\"lS'l'RATlUN
`For intranasal use only (2.3)
`Seasonal allergic rhinitis:
`-:-
`Pediatric patients 5 to 11 years of age: 1 spray per nostril twice daily
`(2.l)
`-_'= Adulls and adolescents 12 years ofage and older: 1 or 2 sprays per
`nostril twice daily (2. 1)
`Vasotnotor rhinitis: 2 sprays per nostril twice daily in adults and
`adolescents I 2 years cfage and older (22)
`Prime Astelin Nasal Spray before initial use and when it has not been
`used for 3 or more days (2.3)
`
`enosarin mm-is AND STRENGTIIS
`Astelin Nasal Spray: 13’! meg nfazelastine hydrocltleride in each 0.137 l]lL
`spray. (3)
`
`FULL PRESCRIBING INFORNIA TION: C?ONTENTS*
`
`l.\I1'Jl(IA'l"I0.\iS AND USAGIE
`DOSAGE AND .-\D_\'Ili\'lS'l‘I{-\ HUN
`2.]
`Seasonal .-'3lIlergIc Rhimtis
`2.2
`Vascrtiotcr Rhinitis
`2.3
`Important .-\t.il'I1IIliSiT'dlit.TI1 i.lI5ll'Ut:1IUIl5
`DOSAGE F(_‘IR'\rIS AND S'I‘RE NGTHS
`t'_.‘0.\l'l‘R.-\I.‘«lDI(..‘A'I IONS
`\’VARN[.NG.‘§ AN!) l’RI*)("Al "l‘l[)NS
`5.1
`Sn.-ntnuleitce in Activities Requiring Mistrial Alertness
`.-\D\’ERSI£ REA(ITI0l\'S
`6.1
`Clinical Trials Experience
`«.2
`lhstrnilrlceting lispcricnee
`DRI it} INTER;-\f'Tl0N$:
`7.]
`Cr.!IlIl'l'li !'\|6l'\'ilLl.‘i Syslettt r}c7pI't3SSilIlI.R
`USE IN SPEC] PIC 1-"(}PI.‘=LA'I'IO_NS
`3. l
`Pl'6gIlal!C_\r'
`3.3
`Nursing _\'lct1iem
`8.4
`Pediatric l is.-:
`
`-.\lei1e. (4)
`
`(J()N'I'RAIJ‘-«|l)lCA'l‘I()NS
`
`\\’.-\R’\lI.\lGS AND PRECAUTIONS
`Scmnolence: Avoid engaging in hazardous‘. occupations requiring
`complete mental aiertuess such as driviiig or operating macltiner}-' when
`taking Astelin Nasal Spray. (5. l)
`Alcohol and other central nervous system (CNS) depressants: Avoid
`concurrent use with Astelin Nasal Spray hecause fitrther decreased
`alertness and impairment of CNS performance may occur. (5.1)
`
`T ADVERSE REACTIONS
`The most common adverse reactions (22% incidence) are: bitter taste.
`headache, somnolencc, d_\-sestltesia, rhinitis. nasal hirming, pharyngitis,
`epislaxis, sinusitis. P$Il'U'X)-Slllfli suecxaing. nausea, drymouth, fatigue.
`dizziness. and weight increase. (6.1)
`
`To report SI f.‘i‘»I’l-‘.(..’I‘|i}l) .=\IWlé}RSI.*'. RIilAtII'I‘l('JNS, contact Mcdn
`Phnniinceuticals Inc. at 1-366-210-5954 or FDA at l-800-FDA-I088 or
`wv|'vr.fd1I.gov.-'nIi:tlw:tttl1.
`
`USE IN SPECIFIC POPULATIONS
`13'regnanc_\_-': Based on animal data. may cause fetal harm (8.1)
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`Revised: 10t2lI'14
`
`Geriatric Lise
`8.3
`{)\-'ERDlJSA(_il£
`Dl*'.S(IR|l"I'IU!‘-l
`(‘L-INICAL PH_i\R3rl_«k(I‘()LOGY
`12.!
`.\’i0L‘-ill:lIll5I]‘l of.-'lcliun
`12.2
`I-’i1£lI‘l1l[lCt)(i}'!'lHlTIiC5
`I23 Phantiac-okiiierics
`iV().N("l.[.NI{‘.—\|_- 'I‘(lX_I(‘.[)L(l(}\'
`I 3.1
`C‘'«!I'L!iI1I_I_gC‘.llt:‘-$ii!>'. }\-liiiagenesis. Impairment nil-'eI1ili1_\_
`(Il..INI(.'AL STUDIES
`l4.l
`Seasena] Allergic Rhinitis
`I-"L2
`\’asomotorl{JtiItitis
`HOW Fil!I’PLIEDi'.‘a‘T()RA(}E AND IIAT‘-IDLING
`PATlEN'I' (_"0I‘=NSF.I.l\iG I.\lF'OR.\[ATl0I\'
`
`I3
`
`I4
`
`16
`I7
`
`*Sections or suhsectiorts omitted from the full prescribing infolimtion
`are not listed.
`
`Reference ID: 364?8?2
`
`APOTEX_AZFL 0059434
`
`

`
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`
`FULL PRESCRIBING INFORMATION
`
`1
`
`INDICATIONS AND USAGE
`
`Astelin Nasal Spray is indicated for the treatment of the symptoms of seasonal allergic rhinitis in
`adults and pediatric patients 5 years and older, and for the treatment of the symptoms of
`vasomotor rhinitis in adults and adolescent patients 12 years and older.
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`2.1
`
`Seasonal Allergic Rhinitis
`
`The recommended dosage of Astelin Nasal Spray in adults and adolescent patients 12 years and
`older with seasonal allergic rhinitis is one or two sprays per nostril twice daily. The
`recommended dosage of Astelin Nasal Spray in pediatric patients 5 years to 11 years of age is
`one spray per nostril twice daily.
`
`2.2
`
`Vasomotor Rhinitis
`
`The recommended dosage of Astelin Nasal Spray in adults and adolescent patients 12 years and
`older with vasomotor rhinitis is two sprays per nostril twice daily.
`
`2.3
`
`Important Administration Instructions
`
`Administer Astelin Nasal Spray by the intranasal route only.
`
`Priming: Prime Astelin Nasal Spray before initial use by releasing 4 sprays or until a fine mist
`appears. When Astelin Nasal Spray has not been used for 3 or more days, reprime with 2 sprays
`or until a fine mist appears. Avoid spraying Astelin Nasal Spray into the eyes.
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`
`Astelin Nasal Spray is a nasal spray solution. Each spray of Astelin Nasal Spray delivers a
`volume of 0.137 mL solution containing 137 mcg of azelastine hydrochloride.
`
`CONTRAINDICATIONS
`
`5
`
`WARNINGS AND PRECAUTIONS
`
`5.1
`
`Somnolence in Activities Requiring Mental Alertness
`
`In clinical trials, the occurrence of somnolence has been reported in some patients taking Astelin
`Nasal Spray [see Adverse Reactions (6.1)]. Patients should be cautioned against engaging in
`hazardous occupations requiring complete mental alertness and motor coordination such as
`
`Reference ID: 3647672
`
`2
`
`APOTEX_AZFL 0059485
`
`

`
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`
`operating machinery or driving a motor vehicle after administration of Astelin Nasal Spray.
`Concurrent use of Astelin Nasal Spray with alcohol or other central nervous system depressants
`should be avoided because additional reductions in alertness and additional impairment of central
`nervous system performance may occur [see Drug Interactions (7.1)].
`
`6
`
`ADVERSE REACTIONS
`
`Use of Astelin Nasal Spray has been associated with somnolence [see Warnings and Precautions
`(5.I)].
`
`6.1
`
`Clinical Trials Experience
`
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of
`another drug and may not reflect rates ob served in practice.
`
`Seasonal Allergic Rhinitis
`
`Astelin Nasal Spray Two Sprays Per Nosiril Twice Daily
`
`.«-e .<-.-
`e “:9:
`9“ .
`-9 .-.' e-.-.-.2
`-.- he .-
`A
`9
`--.« 9-
`e
`controlled, 2-day to 8-week clinical trials which included 391 patients, 12 years of age and older,
`with seasonal allergic rhinitis who received Astelin Nasal Spray at a dose of 2 sprays per nostril
`twice daily. In placebo-controlled efficacy trials, the incidence of discontinuation due to adverse
`reactions in patients receiving Astelin Nasal Spray and vehicle placebo was 2.2% and 2.8%,
`respectively.
`
`Table 1 contains adverse reactions that were reported with frequencies 22% in the Astelin Nasal
`Spray 2 sprays per nostril twice daily treatment group and more frequently than placebo.
`
`Table 1: Adverse Reactions Reported in 22% Incidence in Placebo-Controlled
`Trials in Patients with Seasonal Allergic Rhinitis [n (%)]
`
`Bittcr Tastc
`
`Headache
`
`Somnolence
`
`Nasal Burning
`
`Pharyngitis
`
`Paroxysmal Sneezing
`
`Dry Mouth
`
`Nausca
`
`Rhinitis
`
`Reference ID: 3647672
`
`Astelin
`
`Nasal Spray
`N = 391
`
`77 (19.7%)
`
`58 (14.8%)
`
`45 (11.5%)
`
`16 (4.1%)
`
`15 (3.8%)
`
`12 (3.1%)
`
`11 (2.8%)
`
`ii (2.8%)
`
`9 (2.3%)
`
`Vehicle
`
`Placebo
`N = 353
`
`2 (0.6%)
`
`45 (12.7%)
`
`19 (5.4%)
`
`6 (1.7%)
`
`10 (2.8%)
`
`4 (1.1%)
`
`6 (1.7%)
`
`4 (1.1%)
`
`5 (1.4%)
`
`APOTEX_AZFL 0059486
`
`

`
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`
`Astelin Nasal Spray One Spray Per Nostril Twice Daily
`
`Adverse experience information for Astelin Nasal Spray at a dose of one spray per nostril twice
`daily is derived from two placebo—controlled 2-week clinical studies which included 276 patients
`12 years of age and older with seasonal allergic rhinitis. The incidence of discontinuation due to
`adverse reactions in patients receiving Astelin Nasal Spray and vehicle placebo was 0.0% and
`0.8%, respectively. Bitter taste was reported in 8.3% of patients compared to none in the placebo
`group. Somnolence was reported in 0.4% of patients compared to none in the placebo group.
`
`A total of 176 patients 5 to 11 years of age were exposed to Astelin Nasal Spray at a dose of 1
`spray each nostril twice daily in 3 placebo—controlled studies. In these studies, adverse reactions
`that occurred more frequently in patients treated with Astelin Nasal Spray than with placebo, and
`that were not represented in the adult adverse reactions table above include rh1n1t1 s/cold
`symptoms (17.0% vs. 9.5%), cough (11.4% vs. 8.3%), conjunctivitis (5.1% vs. 1.8%), and
`asthma (4.5% vs. 4.1%).
`
`Adverse Reactions < 2% in Astelin Nasal Spray One or Two Sprays Per Nostril Twice Daily
`
`The following reactions were observed infrequently (<2% and exceeding placebo incidence) in
`patients who received Astelin Nasal Spray closed at 1 or 2 sprays per nostril twice daily in U.S.
`clinical trials.
`
`Cardiovascular; flushing, hypertension, tachycardia.
`
`Dermatological: contact dermatitis, eczema, hair and follicle infection, furunculosis, skin
`laceration.
`
`1)igeslive: constipation, gastroenteritis, glossitis, ulcerative stomatitis, vomiting, increased
`SGPT, aphthous stomatitis, diarrhea, toothache.
`
`Metabolic (1IldlVZllI‘lllOfl£ll.' increased appetite.
`
`ll/fiisculoskeletals myal gi a, temporomandibular dislocation, rheumatoid arthritis.
`
`Neurological: hyperkinesia, hypoesthesia, verti go.
`
`Psychological: anxiety, depersonalization, depression, nervousness, sleep disorder, thinking
`abnormal.
`
`Respiratory.‘ bronchospasm, coughing, throat burning, laryngitis, bronchitis, dry throat, nocturnal
`dyspnea, nasopharyngitis, nasal congestion, pharyngolaryngeal pain, sinusitis, nasal dryness,
`paranasal sinus hypersecretion, post nasal drip.
`
`Special Senses: conjunctivitis, eye abnormality, eye pain, watery eyes, taste loss.
`
`Urogenital: albuminuria, amenorrhea, breast pain, hematuria, increased urinary frequency.
`
`Reference ID: 3647672
`
`APOTEX_AZFL 0059487
`
`

`
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`
`Whole Body: allergic reaction, back pain, herpes simplex, viral infection, malaise, pain in
`extremities, abdominal pain, pyrexia.
`
`Vasomotor Rhinitis
`
`Adverse experience information for Astelin Nasal Spray is derived from two placebo-controlled
`clinical studies which included 216 patients 12 years and older with vasomotor rhinitis who
`received Astelin Nasal Spray at a dose of 2 sprays per nostril twice daily for up to 28 days. The
`incidence of discontinuation due to adverse reactions in patients receiving Astelin Nasal Spray
`and vehicle placebo was 2.8% and 2.9%, respectively.
`
`The following adverse reactions were reported with frequencies 2 2% in the Astelin Nasal Spray
`treatment group and more frequently than placebo.
`
`Table 2: Adverse Reactions Reported in 22% Incidence in Placebo-Controlled
`Trials in Patients with Vasomotor Rhinitis [n (%)]
`
`Astelin
`
`Nasal Spray
`N?2‘lo
`
`Bitter Taste
`Headache
`Dysesthesia
`Riiiiiiiis
`Epistaxis
`Sinusitis
`
`5 (2.4%)
`16 (7.6%)
`7 (3.3%)
`5 (24%)
`5 (2.4%)
`4 (1.9%)
`
`Reactions observed infrequently (<2% and exceeding placebo incidence) in patients who
`received Astelin Nasal Spray (2 sprays/nostril twice daily) in U.S. clinical trials in vasomotor
`rhinitis were similar to those observed in U.S. clinical trials in seasonal allergic rhinitis.
`
`In controlled trials involving nasal and oral azelastine hydrochloride formulations, there were
`infrequent occurrences of hepatic transaminase elevations.
`
`6.2
`
`Postmarketing Experience
`
`During the post approval use of Astelin Nasal Spray, the following adverse reactions have been
`identified. Because these reactions are reported voluntarily from a population of uncertain size, it
`is not always possible to reliably estimate their frequency or establish a causal relationship to
`drug exposure. Adverse reactions reported include: anaphylaxis, application site irritation, atrial
`fibrillation, chest pain, confusion, dyspnea, facial edema, involuntary muscle contractions, nasal
`sores, palpitations, paresthesia, parosmia, pruritus, rash, disturbance or loss of sense of smell
`and/or taste, tolerance, urinary retention, vision abnormal and xerophthalmia.
`
`Reference ID: 3647672
`
`APOTEX_AZFL 0059488
`
`

`
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`
`7
`
`7.]
`
`DRUG INTERACTIONS
`
`Central Nervous System Depressants
`
`Concurrent use of Astelin Nasal Spray with alcohol or other central nervous system depressants
`should be avoided because reductions in alertness and irnpairrnent of central nervous system
`performance may occur [see Warnings and Precautions (5. 1)].
`
`8
`
`USE IN SPECIFIC POPULATION S
`
`8.1
`
`Pregnancy
`
`Pregnancy Category C: There are no adequate and well-controlled clinical studies in pregnant
`women. Azelastine hydrochloride has been shown to cause developmental toxicity in mice, rats,
`and rabbits. Astelin Nasal Spray should be used during pregnancy only if the potential benefit
`justifies the potential risk to the fetus.
`
`Teratogenic Effects: In mice, azelastine hydrochloride caused embryo-fetal death, malformations
`(cleft palate; short or absent tail; fused, absent or branched ribs), delayed ossification, and
`decreased fetal weight at approximately 170 times the maximum recommended human daily
`intranasal dose (MRHDID) in adults (on a mg/m2 basis at a maternal oral dose of 68.6 mg/kg/day
`which also caused maternal toxicity as evidenced by decreased body weight). Neither fetal nor
`maternal effects occurred in mice at approximately 7 times the MRHDID in adults (on a m g/m2
`basis at a maternal oral dose of 3 mg/kg/day).
`
`In rats, azelastine hydrochloride caused malformations (oligo- and brachydactylia), delayed
`ossification and skeletal variations, in the absence of maternal toxicity, at approximately l50
`times the MRHDID in adults (on a mg/m2 basis at a maternal oral dose of3O mg/kg/day).
`Azelastine hydrochloride caused embryo-fetal death and decreased fetal weight and severe
`maternal toxicity at approximately 340 times the MRHDID (on a mg/m2 basis at a maternal oral
`dose of 68.6 mg/kg/day). Neither fetal nor maternal effects occurred at approximately 15 times
`the MRI-IDID (on a mg/m2 basis at a maternal oral dose of 2 mg/kg/day).
`
`In rabbits, azelastine hydrochloride caused abortion, delayed ossification and decreased fetal
`weight and severe maternal toxicity at approximately 300 times the MRHDID in adults (on a
`mg/m2 basis at a maternal oral dose of 30 mg/kg/day). Neither fetal nor maternal effects occurred
`at approximately 3 times the MRHDID (on a mg/m2 basis at a maternal oral dose of 0.3
`mg/kg/day).
`
`8.3
`
`Nursing Mothers
`
`It is not known whether azelastine hydrochloride is excreted in human milk. Because many drugs
`are excreted in human milk, caution should be exercised when Astelin Nasal Spray is
`administered to a nursing woman.
`
`8.4
`
`Pediatric Use
`
`The safety and effectiveness of Astelin Nasal Spray for the treatment of symptoms of seasonal
`allergic rhinitis have been established for patients 5 years and older [see Adverse Reactions (6.1)
`
`6
`
`Reference ID: 3647672
`
`APOTEX_AZFL 0059489
`
`

`
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`
`and Ct'in£caa' Studies’ (14. 1)]. The safety and effectiveness of Astelin Nasal Spray for the
`treatment of vasomotor rhinitis have been established for patients 12 years and older [see
`Aa‘ver.se Reactions (6. I) and Cfirrical .S'tudie5 (1'4.2)]. The safety and effectiveness of Astelin
`Nasal Spray in pediatric patients below the age of 5 years with seasonal allergic rhinitis and in
`pediatric patients below the age of 12 years with vasomotor rhinitis have not been established.
`
`8.5
`
`Geriatric Use
`
`Clinical trials of Astelin Nasal Spray did not include sufficient numbers of patients aged 65 and
`over to determine whether they respond differently from younger patients. Other reported
`clinical experience has not identified differences in responses between the elderly and younger
`patients. 1n general, dose selection for an elderly patient should be cautious, usually starting at
`the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
`cardiac function, and of concomitant disease or other drug therapy.
`
`10
`
`OVERDOSAGE
`
`There have been no reported overdosages with Astelin Nasal Spray. Acute overdosage by adults
`with this dosage form is unlikely to result in clinically significant adverse reactions, other than
`increased somnolence, since one bottle of Astelin Nasal Spray contains 30 mg of azelastine
`hydrochloride. Clinical trials in adults with single doses of the oral formulation of azelastine
`hydrochloride (up to 16 mg) have not resulted in increased incidence of serious adverse
`reactions. General supportive measures should be employed if overdosage occurs. There is no
`known antidote to Astelin Nasal Spray. Oral ingestion of antihistamines has the potential to
`cause serious adverse effects in young children. Accordingly, Astelin Nasal Spray should be kept
`out of the reach of children.
`
`11
`
`DESCRIPTION
`
`Astelin (azelastine hydrochloride) Nasal Spray, 137 micrograms (meg), is an antihistamine
`formulated as a metered-spray solution for intranasal administration. Azelastine hydrochloride
`occurs as a white, almost odorless, crystalline powder with a bitter taste. It has a molecular
`weight of4l8,37. It is sparingly soluble in water, methanol, and propylene glycol and slightly
`soluble in ethanol, octanol, and glycerine. It has a melting point of about 225°C and the pH of a
`saturated solution is between 5.0 and 5.4. Its chemical name is (:|:)-1-(ZH)-phthalazinone,4-[(4-
`chlorophenyl) methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-, monohydrochloride. Its
`molecular formula is C 23H24ClN30'HCl with the following chemical structure:
`
`X
`
`BHQGI
`'9 N —{;H -HCI
`
`Id
`
`Reference ID: 3647672
`
`APOTEX_AZFL 0059490
`
`

`
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`
`Astelin Nasal Spray contains 0.1% azelastine hydrochloride in an aqueous solution at pH 6.8 :
`0.3. It also contains benzalkonium chloride (125 mcg/mL), edetate disodium, hypromellose,
`citric acid, dibasic sodium phosphate, sodium chloride, and purified water.
`
`After priming [see Dosage and Adzmnisfrafion (2.3)], each metered spray delivers a 0.137 mL
`mean volume containing 137 mcg of azelastine hydrochloride (equivalent to 125 mcg of
`azelastine base). The bottle can deliver 200 metered sprays.
`
`12
`
`CLINICAL PHARMACOLOGY
`
`12.1
`
`Mechanism of Action
`
`Azelastine hydrochloride, a phthalazinone derivative, exhibits histamine H1-receptor antagonist
`activity in isolated tissues, animal models, and humans. Astelin Nasal Spray is administered as a
`racemic mixture with no difference in pharmacologic activity noted between the enantiomers in
`in vizro studies. The major metabolite, desmethylazelastine, also possesses H1-receptor
`antagonist activity.
`
`12.2
`
`Pharmacodynamics
`
`Cardiac Electrophvsiolog_v:
`
`In a placebo-controlled 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
`repolarization as represented by the corrected QT interval (QTc) of the electrocardiogram.
`Following multiple dose oral administration of azelastine 4 mg or 8 mg twice daily, the mean
`change in QTc was 7.2 msec and 3.6 msec, respectively.
`
`Interaction studies investigating the cardiac repolarization effects of concomitantly administered
`oral azelastine hydrochloride and erythromycin or ketoconazole were conducted. These drugs
`had no effect on QTc based on analysis of serial electrocardiograms. At a dose approximately 8
`times the maximum recommended dose, azelastine hydrochloride does not prolong the QTc
`interval to any clinically relevant extent.
`
`12.3
`
`Pharmacokinetics
`
`Absorption: After intranasal administration, the systemic bioavailability of azelastine
`hydrochloride is approximately 40%. Maximum plasma concentrations (Cmax) are achieved in 2-
`3 hours.
`
`Azelastine hydrochloride administered 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.
`
`Distribution: Based on intravenous and oral administration, the steady-state volume of
`distribution is 14.5 L/kg. In vitro studies with human plasma indicate that the plasma protein
`binding of azelastine and its metabolite, desmethylazelastine, are approximately 88% and 97%,
`respectively.
`
`Reference ID: 3647672
`
`APOTEX_AZFL 0059491
`
`

`
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`Metabolism: Azelastine is oxidatively metabolized to the principal active metabolite,
`desmethylazelastine, by the cytochrome P450 enzyme system. The specific P450 isoforms
`responsible for the biotransformation of azelastine have not been identified. After intranasal
`dosing of azelastine hydrochloride to steady-state, plasma concentrations of desmethylazelastine
`range from 20-50% of azelastine concentrations. Limited data indicate that the metabolite profile
`is similar when azelastine hydrochloride is administered via the intranasal or oral route.
`
`Elimination: Based on intravenous and oral administration, the elimination half-life and plasma
`clearance are 22 hours and 0.5 L/h/kg, respectively. Approximately 75% of an oral dose of
`radiolabeled azelastine hydrochloride was excreted in the feces with less than 10% as unchanged
`azelastine.
`
`Special Populations:
`
`Hepatic Impairment: Following oral administration, pharmacokinetic parameters were not
`influenced by hepatic impairment.
`
`Renal Impairment: Based on oral, single-dose studies, renal insufficiency (creatinine
`clearance <50 mL/min) resulted in a 70-75% higher Cmax and AUC compared to normal subjects.
`Time to maximum concentration was unchanged.
`
`Gender.‘ Following oral administration, pharmacokinetic parameters were not influenced by
`gender.
`
`Race: The effect of race has not been evaluated.
`
`Drug-Drug Interactions:
`
`Erythromycinx No significant pharmacokinetic interaction was ob served with the co-
`administration of orally administered azelastine (4 mg twice daily) with erythromycin (500 mg
`three times daily for 7 days). In this study, co-administration of orally administered azelastine
`with erythromycin resulted in Cmax of 5.36 :: 2.6 ng/mL and AUC of 49.7 :: 24 ng-h/mL for
`azelastine, whereas, administration of azelastine alone resulted in Cmax. of 5.57 :: 2.7 ng/mL and
`AUC of 48.4 :: 24 ng-h/mL for azelastine.
`
`Cimetidine and Ranitidine: In a multiple-dose, steady-state drug interaction trial in healthy
`subjects, cimetidine (400 mg twice daily) increased orally administered mean azelastine (4 mg
`twice daily) concentrations by approximately 65%. No pharmacokinetic interaction was
`observed with co-administration of orally administered azelastine (4 mg twice daily) with
`ranitidine hydrochloride (150 mg twice daily). Oral co-administration of azelastine with
`ranitidine resulted in Cmax of 8.89 ::3.28 ng/mL and AUC of 88.22 :: 40.43 ng-h/mL for
`azelastine, whereas, azelastine when administered alone resulted in Cmax of 7.83 :: 4.06 ng/mL
`and AUC of 80.09 :: 43.55 ng-h/mL for azelastine.
`
`Theophyllinez I\o significant pharmacokinetic interaction was observed with the co-
`administration of an oral 4 mg dose of azelastine hydrochloride twice daily and theophylline 300
`mg or 400 mg twice daily.
`
`Reference ID: 3647672
`
`APOTEX_AZFL 0059492
`
`

`
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`13
`
`NONCLINICAL TOXICOLOGY
`
`13.1
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`In 2-year carcinogenicity studies in rats and mice, azelastine hydrochloride did not show
`evidence of carcinogenicity at oral doses up to 30 mg/kg and 25 mg/kg, respectively. These
`doses were approximately 150 and 60 times the maximum recommended human daily intranasal
`dose [MRHDID] on a mg/m2 basis.
`
`Azelastine hydrochloride showed no genotoxic 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 rats showed no effects on male or female fertility at oral
`doses up to 30 mg/kg (approximately 150 times the MRHDID in adults on a mg/m2 basis). At
`68.6 mg/kg (approximately 340 times the MRHDID on a mg/m2 basis), the duration of estrous
`cycles was prolonged and copulatory activity and the number of pregnancies were decreased.
`The numbers of corpora lutea and implantations were decreased; however, pre—implantation loss
`was not increased.
`
`14
`
`CLINICAL STUDIES
`
`14.1
`
`Seasonal Allergic Rhinitis
`
`Two Sprays Per Nostril Twice Daily
`
`The efficacy and safety of Astelin Nasal Spray were evaluated in three placebo-controlled
`clinical trials of Astelin Nasal Spray including 322 patients with seasonal allergic 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. Assessment of efficacy was based on the 12-hour reflective Total
`Symptom Complex (TSC) and Major Symptom Complex (MSC). The MSC was calculated as
`the average of individual symptoms of nose blows, sneezes, runny nose/sniffles, itchy nose, and
`watery eyes as assessed by patients on a 0-5 categorical scale. Astelin Nasal Spray two sprays
`per nostril twice daily demonstrated a greater decrease in the MSC than placebo (Table 3).
`
`Reference ID: 3647672
`
`APOTEX_AZFL 0059493
`
`

`
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`Mean Change from Baseline in Reflective MSC* in Adults and Adolescents
`212 Years with Seasonal Allergic Rhinitis Treated with Astelin Nasal Spray
`Two Sprays Per Nostril Twice Daily Versus Placebo
`
`Treatment
`
`N
`
`Baseline
`LS Mean
`
`Change from
`Baseline
`
`Treatment
`Difference
`
`P-value
`
`Trial 1: 12 Hour AM and PM Reflective MSC
`
`6
`Astelin Nasal Spray
`60
`‘ Placebo Nasal Spray
`Trial 2: 12 Hour AM and PM Reflective MSC
`
`3
`
`(SD)
`
`(SD)
`
`11.48 (4.13)
`10.84 (4.53)
`
`-3.05 (3.51)
`-1.07 (3.52)
`
`Astelin Nasal Spray
`
`.
`
`12.50 (4.5)
`
`-4.10 (3.46)
`
`Placebo Nasal Spray
`
`12.18 (4.64)
`
`-2.07 (4.01)
`
`Trial 3: 12 Hour AM and PM Reflective MSC
`
`I AstelinNasal Spray
`Placebo Nasal Spray
`
`66
`66
`
`12.04 (4.03)
`11.66 (3.96)
`
`—3.31(3.74)
`-1.96 (3.57)
`
`1.35
`
`* Major Symptom Comlex (MSC): Average of individual symptoms of nose blows, sneezes, runny nose/sniffles,
`itchy nose, and watery eyes as assessed by patients on a 0-5 categorical scale.
`
`In dose-ranging trials, administration of Astelin Nasal Spray two sprays per nostril twice daily
`resulted in a statistically significant decrease in symptoms compared to saline placebo within 3
`hours after initial dosing and persisted over the 12-hour dosing interval.
`
`One Spray Per Nostril Twice Daily
`
`The efficacy and safety of Astelin Nasal Spray were evaluated in two placebo-controlled clinical
`trials of Astelin Nasal Spray including 275 patients with seasonal allergic rhinitis who received
`one spray per nostril twice a day for up to 2 weeks. Assessment of efficacy was based on the 12-
`hour reflective Total Nasal Symptom Score [rTNSS]. rTNSS is calculated as the sum of the
`patients scoring of four individual nasal symptoms (runny nose, sneezing, itchy nose, and nasal
`congestion) as assessed by patients on a 0-3 categorical scale. The primary efficacy endpoint was
`the change from Baseline to Day 14 in rTNSS. The mean change from baseline in rTNSS was
`greater in patients receiving Astelin Nasal Spray one spray per nostril twice daily than those
`receiving placebo (Table 4).
`
`Reference ID: 3647672
`
`APOTEX_AZFL 0059494
`
`

`
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`Table 4:
`
`Mean Change from Baseline in Reflective TNSS* in Adults and Adolescents
`212 years with Seasonal Allergic Rhinitis Treated with Astelin Nasal Spray
`One Spray Per Nostril Twice Daily Versus Placebo
`
`Treatment
`
`Baseline
`LS Mean
`
`Change from
`Baseline
`
`Treatment
`Difference
`
`P—value
`
`Trial 4: 12 Hour AM and PM Reflective TNSS
`
`(SD)
`
`(SD)
`
`138
`Astelin Nasal Spray
`1
`‘ Placebo Nasal Spray
`Trial 5: 12 Hour AM and PM Reflective TNSS
`
`41
`
`16.34 (4.22)
`17.21 (4.32)
`
`-2.69 (4.79)
`-1.31 (4.29)
`
`Astclin Nasal Spray
`
`.
`
`16.62 (4.20)
`
`-3.68 (4.16)
`
`Placebo Nasal Spray
`
`16.84 (4.77)
`
`-2.50 (4.01)
`
`* Total Nasal Symploni Score (TNSS): Average of individual symptoms of runny nose, sneezing, itchy nose, and
`nasal congestion as assessed by patients on a 0-3 categorical scale.
`
`Two-week studies comparing the efficacy (and safety) of Astelin Nasal Spray two sprays per
`nostril twice daily versus one spray per nostril twice daily were not conducted.
`
`14.2
`
`Vasomotor Rhinitis
`
`The efficacy and safety of Astelin Nasal Spray were evaluated in two placebo-controlled clinical
`trials of Astelin Nasal Spray including 216 patients with vasomotor rhinitis who received two
`sprays per nostril twice a day for up to 4 weeks. These patients had vasomotor rhinitis for at least
`one year, negative skin tests to indoor and outdoor aeroallergens, negative nasal smears for
`eosinophils, and negative sinus X-rays. Astelin Nasal Spray demonstrated a significantly greater
`decrease in a symptom complex comprised of rhinorrhea, post nasal drip, nasal congestion, and
`sneezing compared to placebo.
`
`16
`
`HOW SUPPLIED/STORAGE AND HANDLING
`
`Astelin (azelastine hydrochloride) Nasal Spray, 137 mcg is supplied as a 30-mL package (NDC
`0037-0241-30) delivering 200 metered sprays in a high-density polyethylene (HDPE) bottle
`fitted with a metered-dose spray pump unit. The spray pump unit consists of a nasal spray pump
`fitted with a blue safety clip and a blue plastic dust cover. The net content of the bottle is 30 1nL
`(net weight 30 gm of solution). Each bottle contains 30 mg (1 mg/mL) of azelastine
`hydrochloride. After priming [see Dosage and Administration (2.3)], each spray delivers a fine
`mist containing a mean volume of 0.137 mL solution containing 137 mcg of azelastine
`hydrochloride. The correct amount of medication in each spray cannot be assured before the
`initial priming and after 200 sprays have been used, even though the bottle is not completely
`empty. The bottle should be discarded after 200 sprays have been used. Astelin Nasal Spray
`should not be used after the expiration date “EXP” printed on the medicine label and carton.
`
`Storage:
`
`Reference ID: 3647672
`
`APOTEX_AZFL 0059495
`
`

`
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`
`Store at controlled room temperature 20° to 25°C (68° to 77°F). Protect from freezing.
`
`17
`
`PATIENT COUNSELING INFORMATION
`
`See FDA-approved patient labeling (Patient Information and Instructions for Use).
`
`Activities Reguiring Mental Alertness
`
`Somnolence has been reported in some patients taking Astelin Nasal Spray. Caution patients
`against engaging in hazardous occupations requiring complete mental alertness and motor
`coordination such