HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information
`needed to use ASTEPRO® Nasal Spray safely and
`effectively. See full prescribing information for
`ASTEPRO Nasal Spray.
`
`ASTEPRO (azelastine hydrochloride) Nasal Spray 0.1%
`
`ASTEPRO (azelastine hydrochloride) Nasal Spray 0.15%
`
`
`Initial U.S. Approval: 1996
`
`----------------INDICATIONS AND USAGE------------------
`ASTEPRO Nasal Spray is an H1 receptor antagonist
`
`indicated for the relief of the symptoms of seasonal and
`perennial allergic rhinitis in patients 12 years of age and
`older. (1.1)
`
`----------------DOSAGE AND ADMINISTRATION---------
`For intranasal use only (2.3).
`
`Seasonal allergic rhinitis:
`
`
`• ASTEPRO Nasal Spray 0.1% and 0.15%: 1 or 2 sprays
`per nostril twice daily in adults and adolescents 12 years of
`age and older (2.1)
`
`• ASTEPRO Nasal Spray 0.15%: 2 sprays per nostril once
`
`daily in adults and adolescents 12 years of age and older (2.1)
`
`Perennial allergic rhinitis:
`
`• ASTEPRO Nasal Spray 0.15%: 2 sprays per nostril
`twice daily in adults and adolescents 12 years of age and
`older (2.2)
`
`
`• Prime ASTEPRO Nasal Spray before initial use and when it
`
`
`
`has not been used for 3 or more days. (2.3)
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1
`
`INDICATIONS AND USAGE
`
`Allergic Rhinitis
`1.1
`
`DOSAGE AND ADMINSTRATION
`
`Seasonal Allergic Rhinitis
`2.1
`
`2.2
`Perennial Allergic Rhinitis
`
`2.3
`Important Administration Instructions
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`
`5.1
`Activities Requiring Mental Alertness
`ADVERSE REACTIONS
`6.1
`Clinical Trials Experience
`6.2
`Postmarketing Experience
`DRUG INTERACTIONS
`
`7.1
`Central Nervous System Depressants
`Erythromycin and Ketoconazole
`7.2
`7.3
`Cimetidine
`USE IN SPECIFIC POPULATIONS
`
`Pregnancy
`8.1
`Nursing Mothers
`8.3
`8.4
`Pediatric Use
`8.5
`Geriatric Use
`
`OVERDOSAGE
`
`
`2
`
`
`3
`
`4
`
`5
`
`
`6
`
`
`7
`
`
`
`
`8
`
`10
`
`----------------DOSAGE FORMS AND STRENGTHS-------
`
`ASTEPRO Nasal Spray 0.1%: 137 mcg of azelastine
`hydrochloride in each 0.137 mL spray (3).
`
`ASTEPRO Nasal Spray 0.15%: 205.5 mcg of azelastine
`hydrochloride in each 0.137 mL spray (3).
`
`---------------CONTRAINDICATIONS------------------------­
`
`None.
`
`-----------------WARNINGS AND PRECAUTIONS----------
`
`• Somnolence may occur. Avoid engaging in hazardous
`
`occupations requiring complete mental alertness such as
`driving or operating machinery when taking ASTEPRO
`Nasal Spray (5.1)
`• Avoid concurrent use of alcohol or other central nervous
`
`
`system (CNS) depressants with ASTEPRO Nasal Spray
`because further decreased alertness and impairment of CNS
`
`performance may occur (5.1)
`
`-----------------ADVERSE REACTIONS-----------------------
`The most common adverse reactions (≥2% incidence) are:
`bitter taste, nasal discomfort, epistaxis, headache, fatigue,
`somnolence and sneezing (6.1)
`
`
`To report SUSPECTED ADVERSE REACTIONS,
`contact MEDA Pharmaceuticals Inc. at 1-800-526-3840 or
`FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`-----------------USE IN SPECIFIC POPULATIONS----------
`• Pregnancy: Based on animal data, may cause fetal harm
`
`
`(8.1)
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`and FDA approved patient labeling.
`
`
`Revised mm/yy
`
`
`
`11
`12
`
`13
`
`
`
`
`14
`
`
`16
`17
`
`
`
`
`
`
`
`
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2
`Pharmacodynamics
`12.3
`Pharmacokinetics
`NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis,
`Impairment of Fertility
`
`
`
`13.2 Animal Toxicology and/or
`Pharmacology
`CLINICAL STUDIES
`
`14.1
`Seasonal Allergic Rhinitis
`14.2
`Perennial Allergic Rhinitis
`HOW SUPPLIED/STORAGE AND HANDLING
`PATIENT COUNSELING INFORMATION
`
`
`
`17.1 Activities Requiring Mental Alertness
`
`
`Concurrent Use of Alcohol and Other
`17.2
`
`Central Nervous System Depressants
`
`Common Adverse Reactions
`17.3
`
`Priming
`17.4
`
`17.5 Keep Spray Out of Eyes
`17.6 Keep Out of Children’s Reach
`
`
`
`* Sections or subsections omitted from the full prescribing
`information are not listed
`
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`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`26
`27
`28
`29
`30
`31
`32
`33
`34
`35
`36
`37
`38
`39
`40
`41
`42
`43
`44
`45
`46
`
`
`
`FULL PRESCRIBING INFORMATION
`
`1
`INDICATIONS AND USAGE
`1.1 Allergic Rhinitis
`
`
`ASTEPRO Nasal Spray 0.1% and 0.15% is indicated for the relief of the symptoms
`of seasonal and perennial allergic rhinitis in patients 12 years of age and older.
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`2.1 Seasonal Allergic Rhinitis
`
` The recommended dose of ASTEPRO Nasal Spray 0.1% and 0.15% is 1 or 2 sprays
`
`per nostril twice daily for seasonal allergic rhinitis. ASTEPRO Nasal Spray 0.15% may
`
`also be administered as 2 sprays per nostril once daily.
`2.2 Perennial Allergic Rhinitis
`
` The recommended dose of ASTEPRO Nasal Spray 0.15% for perennial allergic
`rhinitis is 2 sprays per nostril twice daily.
`
`
`2.3 Important Administration Instructions
`
`Administer ASTEPRO Nasal Spray by the intranasal route only.
`
`
`Priming: Prime ASTEPRO Nasal Spray before initial use by releasing 6 sprays or
`
`until a fine mist appears. When ASTEPRO Nasal Spray has not been used for 3 or more
`days, reprime with 2 sprays or until a fine mist appears. Avoid spraying ASTEPRO Nasal
`Spray into the eyes.
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`ASTEPRO Nasal Spray is a nasal spray solution. Each spray of ASTEPRO Nasal
`
`Spray 0.1% delivers a volume of 0.137 mL solution containing 137 mcg of azelastine
`
`hydrochloride. Each spray of ASTEPRO Nasal Spray 0.15% delivers a volume of 0.137
`mL solution containing 205.5 mcg of azelastine hydrochloride.
`
`
`4
`
`CONTRAINDICATIONS
`None.
`
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Activities Requiring Mental Alertness
`In clinical trials, the occurrence of somnolence has been reported in some patients
`
`taking ASTEPRO 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 operating machinery or driving a motor vehicle after
`administration of ASTEPRO Nasal Spray. Concurrent use of ASTEPRO 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)].
`
`
`ADVERSE REACTIONS
`6
`Use of ASTEPRO Nasal Spray has been associated with somnolence [see Warnings
`
`and Precautions (5.1)].
`
`6.1 Clinical Trials Experience
`
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`47 Because clinical trials are conducted under widely varying conditions, adverse reaction
`48
`rates observed in clinical trials of a drug cannot be directly compared to rates in the
`49
`clinical trials of another drug and may not reflect rates observed in practice.
`50
`
`ASTEPRO Nasal Spray 0.1%
`51
`
`The safety data described below reflect exposure to ASTEPRO Nasal Spray 0.1% in
`52
`
`713 patients 12 years of age and older from 2 clinical trials of 2 weeks to 12 months
`53
`duration. In a 2 week, double-blind, placebo-controlled, and active controlled (Astelin®
`54
`
`55 Nasal Spray; azelastine hydrochloride) clinical trial, 285 patients (115 males and 170
`56
`females) 12 years of age and older with seasonal allergic rhinitis were treated with
`57 ASTEPRO Nasal Spray 0.1% one or two sprays per nostril daily. In the 12 month open­
`58
`label, active controlled (Astelin Nasal Spray) clinical trial, 428 patients (207 males and
`59
`221 females) 12 years of age and older with perennial allergic rhinitis and/or nonallergic
`60
`rhinitis were treated with ASTEPRO Nasal Spray 0.1% two sprays per nostril twice daily.
`61
`The racial and ethnic distribution for the 2 clinical trials was 82% white, 8% black, 6%
`
`62 Hispanic, 3% Asian, and <1% other.
`
`63
`64
` Adults and Adolescents 12 Years of Age and Older
`
`
`
`In the two week clinical trial, 835 patients 12 years of age and older with seasonal
`
`65
`
` allergic rhinitis were treated with one of six treatments: one spray per nostril of either
`66
`67 ASTEPRO Nasal Spray 0.1%, Astelin Nasal Spray or placebo twice daily; or 2 sprays per
`68
`nostril of ASTEPRO Nasal Spray 0.1%, Astelin Nasal Spray, or placebo twice daily.
`69 Overall, adverse reactions were more common in the ASTEPRO Nasal Spray 0.1%
`70
`treatment groups (21-28%) than in the placebo groups (16-20%). Overall, less than 1% of
`patients discontinued due to adverse reactions and withdrawal due to adverse reactions
`71
`72 was similar among the treatment groups.
`
`73
`Table 1 contains adverse reactions reported with frequencies greater than or equal
`to 2% and more frequently than placebo in patients treated with ASTEPRO Nasal Spray
`74
`75
`0.1% in the controlled clinical trial described above.
`
`76
`
`Vehicle
`Placebo
`
`(N=137)
`
`2 (2%)
`3 (2%)
`
`1 (<1%)
`
`1 (<1%)
`1 (<1%)
`
`0 (0%)
`
`
`2 sprays twice daily
`
`
` ASTEPRO
`Astelin
`Nasal Spray
`Nasal Spray
`
` 0.1%
`(N=137)
`
`(N=146)
`10 (7%)
`11 (8%)
`4 (3%)
`3 (2%)
`
`
`4 (3%)
`3 (2%)
`
`
`2 (1%)
`6 (4%)
`3 (2%)
`3 (2%)
`
`
`3 (2%)
`2 (1%)
`
`
`
`
`
`Vehicle
`Placebo
`
`(N=138)
`
`3 (2%)
`0 (0%)
`
`1 (<1%)
`
`0 (0%)
`1 (<1%)
`
`0 (0%)
`
`
`
`
` ASTEPRO
`
`Nasal Spray
` 0.1%
`
`(N=139)
`8 (6%)
`3 (2%)
`
`2 (1%)
`
`0 (0%)
`0 (0%)
`
`2 (1%)
`
`
`
`
`
` Table 1. Adverse Reactions Reported in ≥2% Incidence in a Placebo-Controlled Trial of 2 Weeks
`
` Duration with ASTEPRO Nasal Spray 0.1% in Adult and Adolescent Patients with Seasonal Allergic
`
`
`
`Rhinitis
`1 spray twice daily
`
`Astelin
`Nasal Spray
`
`(N=137)
`13 (10%)
`8 (6%)
`
`5 (4%)
`
`3 (2%)
`1 (<1%)
`
`2 (2%)
`
`
`Bitter Taste
`Epistaxis
`Headache
`Nasal Discomfort
`Fatigue
`Somnolence
`
`77
`
`Long-Term (12 Month) Safety Trial:
`
`78
`
`In the 12 month, open-label, active-controlled, long-term safety trial, 862 patients 12
`79
`years of age and older with perennial allergic and/or nonallergic rhinitis were treated with
`80
`81 ASTEPRO Nasal Spray 0.1% two sprays per nostril twice daily or Astelin Nasal Spray two
`82
`sprays per nostril twice daily. The most frequently reported adverse reactions were
`
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`headache, bitter taste, epistaxis, and nasopharyngitis and were generally similar between
`83
`treatment groups. Focused nasal examinations were performed and showed that the
`84
`incidence of nasal mucosal ulceration in each treatment group was approximately 1% at
`85
`baseline and approximately 1.5% throughout the 12 month treatment period. In each
`86
`treatment group, 5-7% of patients had mild epistaxis. No patients had reports of nasal
`87
`septal perforation or severe epistaxis. Twenty-two patients (5%) treated with ASTEPRO
`88
`89 Nasal Spray 0.1% and 17 patients (4%) treated with Astelin Nasal Spray discontinued from
`
`90
`the trial due to adverse events.
`91
`
`ASTEPRO Nasal Spray 0.15%
`
`92
`The safety data described below reflect exposure to ASTEPRO Nasal Spray 0.15%
`93
`
`in 1858 patients (12 years of age and older) with seasonal or perennial allergic rhinitis
`94
`95
`from 8 clinical trials of 2 weeks to 12 months duration. In 7 double-blind, placebo­
`96
`controlled clinical trials of 2 to 4 weeks duration, 1544 patients (560 males and 984
`97
`females) with seasonal or perennial allergic rhinitis were treated with ASTEPRO Nasal
`98
`Spray 0.15% two sprays per nostril once or twice daily. In the 12 month open-label,
`99
`active-controlled clinical trial, 466 patients (156 males and 310 females) with perennial
`100
`allergic rhinitis were treated with ASTEPRO Nasal Spray 0.15% two sprays per nostril
`101
`twice daily. Of these 466 patients, 152 had participated in the 4-week placebo-controlled
`102
`perennial allergic rhinitis clinical trials. The racial distribution for the 8 clinical trials
`
`103 was 80% white, 13% black, 2% Asian, and 5% other.
`
`104
`Adults and Adolescents 12 Years of Age and Older
`105
`
`
`
`In the 7 placebo controlled clinical trials of 2 to 4 week duration, 2343 patients with
`106
`
`seasonal allergic rhinitis and 540 patients with perennial allergic rhinitis were treated
`107
`108 with two sprays per nostril of either ASTEPRO Nasal Spray 0.15% or placebo once or
`109
`twice daily. Overall, adverse reactions were more common in the ASTEPRO Nasal Spray
`110
`0.15% treatment groups (16-31%) than in the placebo groups (11-24%). Overall, less
`111
`than 2% of patients discontinued due to adverse reactions and withdrawal due to adverse
`112
`reactions was similar among the treatment groups.
`113
`Table 2 contains adverse reactions reported with frequencies greater than or equal to
`
`2% and more frequently than placebo in patients treated with ASTEPRO Nasal Spray
`114
`115
`0.15% in the seasonal and perennial allergic rhinitis controlled clinical trials.
`116
`
`
` Table 2. Adverse Reactions with ≥2% Incidence in Placebo-Controlled Trials of 2 to 4 Weeks’
`
`
`
`
` Duration with ASTEPRO Nasal Spray 0.15% in Adult and Adolescent Patients With Seasonal or
`Perennial Allergic Rhinitis
`2 sprays twice daily
`
`Vehicle Placebo
`
` ASTEPRO
` Nasal Spray 0 15%.
`
`
`
`
`(N=523)
`(N=523)
`31 (6%)
`5 (1%)
`18 (3%)
`12 (2%)
`
`
` 5 (1%)
`7 (1%)
`
`
`9 (2%)
`1 (<1%)
`
`Bitter Taste
`Nasal Discomfort
`
`Epistaxis
`Sneezing
`
`117
`In the above trials, somnolence was reported in <1% of patients treated with ASTEPRO
`118
`119 Nasal Spray 0.15% (11 of 1544) or vehicle placebo (1 of 1339).
`
`120
`
`
`
`2 sprays once daily
`
`
` ASTEPRO
`Vehicle Placebo
`
` Nasal Spray 0. 5%1
`
`
`
`
`(N=1021)
`(N=816)
`38 (4%)
`2 (<1%)
`37 (4%)
`7 (1%)
`
`
`21 (2%)
`14 (2%)
`
`
`14 (1%)
`0 (0%)
`
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` Long-Term (12 Month) Safety Trial:
`
`
`121
`In the 12 month, open-label, active-controlled, long-term safety trial, 466 patients (12
`
`122
`years of age and older) with perennial allergic rhinitis were treated with ASTEPRO Nasal
`123
`Spray 0.15% two sprays per nostril twice daily and 237 patients were treated with
`124
`125 mometasone nasal spray two sprays per nostril once daily. The most frequently reported
`126
`adverse reactions (>5%) with ASTEPRO Nasal Spray 0.15% were bitter taste, headache,
`127
`sinusitis, and epistaxis. Focused nasal examinations were performed and no nasal
`128
`ulcerations or septal perforations were observed. In each treatment group, approximately
`129
`3% of patients had mild epistaxis. No patients had reports of severe epistaxis. Fifty-four
`130
`patients (12%) treated with ASTEPRO Nasal Spray 0.15% and 17 patients (7%) treated
`131 with mometasone nasal spray discontinued from the trial due to adverse events.
`132
`
`6.2 Postmarketing Experience
`
`133
` The following adverse reactions have been identified during the post approval use
`134
`135
`of the Astelin brand of azelastine hydrochloride 0.1% nasal spray (total daily dose 0.55
`136 mg to 1.1 mg). Because these reactions are reported voluntarily from a population of
`137
`uncertain size, it is not always possible to reliably estimate their frequency or establish a
`138
`causal relationship to drug exposure. Adverse reactions reported include the following:
`139
`anaphylactoid reaction, application site irritation, atrial fibrillation, blurred vision, chest
`140
`pain, confusion, dizziness, dyspnea, facial edema, hypertension, involuntary muscle
`141
`contractions, nervousness, palpitations, paresthesia, parosmia, paroxysmal sneezing,
`142
`pruritus, rash, disturbance or loss of sense of smell and/or taste, tachycardia, tolerance,
`143
`urinary retention, and xerophthalmia.
`
`144
`DRUG INTERACTIONS
`7
`145
`7.1 Central Nervous System Depressants
`146
`
`147
`Concurrent use of ASTEPRO Nasal Spray with alcohol or other central nervous
`system depressants should be avoided because reductions in alertness and impairment of
`148
`central nervous system performance may occur [see Warnings and Precautions (5.1)].
`
`149
`7.2 Erythromycin and Ketoconazole
`150
`
`151
`Interaction studies investigating the cardiac effects, as measured by the corrected
`152 QT interval (QTc), of concomitantly administered oral azelastine hydrochloride and
`153
`erythromycin or ketoconazole were conducted. Oral erythromycin (500 mg three times
`154
`daily for 7 days) had no effect on azelastine pharmacokinetics or QTc based on analyses
`155
`of serial electrocardiograms. Ketoconazole (200 mg twice daily for 7 days) interfered
`156 with the measurement of azelastine plasma concentrations on the analytic HPLC;
`however, no effects on QTc were observed [see Clinical Pharmacology (12.2) and
`157
`(12.3)].
`158
`7.3 Cimetidine
`159
`160
`Cimetidine (400 mg twice daily) increased the mean Cmax and AUC of orally
`
`administered azelastine hydrochloride (4 mg twice daily) by approximately 65%
`161
`[see Clinical Pharmacology (12.3)].
`
`162
`
`163
`8
`USE IN SPECIFIC POPULATIONS
`
`164
`
`8.1 Pregnancy
`165
`
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` Pregnancy Category C: There are no adequate and well-controlled clinical trials in
`
`
`166
`167
`pregnant women. Azelastine hydrochloride has been shown to cause developmental
`168
`toxicity in mice, rats, and rabbits. ASTEPRO Nasal Spray should be used during
`169
`pregnancy only if the potential benefit justifies the potential risk to the fetus.
`
` Teratogenic Effects: In mice, azelastine hydrochloride caused embryo-fetal death,
`170
`
`171 malformations (cleft palate; short or absent tail; fused, absent or branched ribs), delayed
`172
`ossification, and decreased fetal weight at an oral dose approximately 170 times the
`173 maximum recommended human daily intranasal dose (MRHDID) in adults on a mg/m2
`174
`basis. This dose also caused maternal toxicity as evidenced by decreased body weight.
`175 Neither fetal nor maternal effects occurred at a dose that was approximately 7 times the
`176 MRHDID.
`
`177
`In rats, azelastine hydrochloride caused malformations (oligo- and brachydactylia),
`delayed ossification and skeletal variations, in the absence of maternal toxicity, at an oral
`178
`dose approximately 150 times the MRHDID in adults on a mg/m2 basis. At a dose
`179
`180
`approximately 340 times the MRHDID, azelastine hydrochloride also caused embryo­
`181
`fetal death and decreased fetal weight; however, this dose caused severe maternal
`182
`toxicity. Neither fetal nor maternal effects occurred at a dose approximately 15 times the
`183 MRHDID.
`
`184
`In rabbits, azelastine hydrochloride caused abortion, delayed ossification and
`decreased fetal weight at oral doses approximately 300 times the MRHDID in adults on a
`185
`186 mg/m2 basis; however, these doses also resulted in severe maternal toxicity. Neither fetal
`187
`nor maternal effects occurred at a dose approximately 3 times the MRHDID.
`8.3 Nursing Mothers
`
`188
`
`189
`It is not known whether azelastine hydrochloride is excreted in human milk.
`190 Because many drugs are excreted in human milk, caution should be exercised when
`191 ASTEPRO Nasal Spray is administered to a nursing woman.
`8.4 Pediatric Use
`192
`
`193
` Safety and effectiveness of ASTEPRO Nasal Spray in pediatric patients below the
`age of 12 years have not been established.
`194
`8.5 Geriatric Use
`195
`
`196
`Clinical trials of ASTEPRO Nasal Spray did not include sufficient numbers of
`
`patients 65 years of age and older to determine whether they respond differently from
`197
`198
`younger patients. Other reported clinical experience has not identified differences in
`199
`responses between the elderly and younger patients. In general, dose selection for an
`200
`elderly patient should be cautious, usually starting at the low end of the dosing range,
`201
`reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of
`202
`concomitant disease or other drug therapy.
`
`203
`10 OVERDOSAGE
`204
`
`205
`There have been no reported overdosages with ASTEPRO Nasal Spray. Acute
`
`overdosage by adults with this dosage form is unlikely to result in clinically significant
`206
`adverse events, other than increased somnolence, since one 30-mL bottle of ASTEPRO
`207
`208 Nasal Spray 0.1% contains up to 30 mg of azelastine hydrochloride and one 30-mL bottle
`209 ASTEPRO Nasal Spray 0.15% contains up to 45 mg of azelastine hydrochloride. Clinical
`210
`trials in adults with single doses of the oral formulation of azelastine hydrochloride (up to
`211
`16 mg) have not resulted in increased incidence of serious adverse events. General
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`supportive measures should be employed if overdosage occurs. There is no known
`212
`
` antidote to ASTEPRO Nasal Spray. Oral ingestion of antihistamines has the potential to
`213
`cause serious adverse effects in children. Accordingly, ASTEPRO Nasal Spray should be
`214
`kept out of the reach of children. Oral doses of 120 mg/kg and greater (approximately
`215
`300 times the maximum recommended human daily intranasal dose [MRHDID] in adults
`216
`and children on a mg/m2 basis) were lethal in mice. Responses seen prior to death were
`217
`tremor, convulsions, decreased muscle tone, and salivation. In dogs, single oral doses as
`218
`high as 10 mg/kg (approximately 160 times the MRHDID in adults and children on a
`219
`220 mg/m2 basis) were well tolerated, but single oral doses of 20 mg/kg were lethal.
`221
`
`11 DESCRIPTION
`222
`223
`ASTEPRO (azelastine hydrochloride) Nasal Spray 0.1%, 137 micrograms (mcg), is
`
`an antihistamine formulated as a metered-spray solution for intranasal administration.
`224
`225 ASTEPRO (azelastine hydrochloride) Nasal Spray 0.15%, 205.5 micrograms (mcg), is
`226
`formulated as a metered-spray solution for intranasal administration.
`227
`
`Azelastine hydrochloride occurs as a white, almost odorless, crystalline powder
`228
`
`229 with a bitter taste. It has a molecular weight of 418.37. It is sparingly soluble in water,
`230 methanol, and propylene glycol and slightly soluble in ethanol, octanol, and glycerine. It
`231
`has a melting point of about 225°C and the pH of a saturated solution is between 5.0 and
`232
`5.4. Its chemical name is (±)-1-(2H)-phthalazinone,4-[(4-chlorophenyl) methyl]-2­
`233
`(hexahydro-1-methyl-1H-azepin-4-yl)-, monohydrochloride. Its molecular formula is
`234 C22H24ClN3O·HCl with the following chemical structure:
`
`
`235
`
`
`ASTEPRO Nasal Spray 0.1% contains 0.1% azelastine hydrochloride in an isotonic
`236
`
`aqueous solution containing sorbitol, sucralose, hypromellose, sodium citrate, edetate
`237
`disodium, benzalkonium chloride (125 mcg/mL), and purified water (pH 6.4).
`238
`After priming [see Dosage and Administration (2.3)], each metered spray delivers a
`239
`
`0.137 mL mean volume containing 137 mcg of azelastine hydrochloride (equivalent to
`240
`125 mcg of azelastine base). The 30-mL (net weight 30 gm of solution) bottle provides
`241
`200 metered sprays.
`242
`
`ASTEPRO Nasal Spray 0.15% contains 0.15% azelastine hydrochloride in an
`243
`isotonic aqueous solution containing sorbitol, sucralose, hypromellose, sodium citrate,
`244
`edetate disodium, benzalkonium chloride (125 mcg/mL), and purified water (pH 6.4).
`245
`After priming [see Dosage and Administration (2.3)], each metered spray delivers a
`
`246
`0.137 mL mean volume containing 205.5 mcg of azelastine hydrochloride (equivalent to
`247
`187.6 mcg of azelastine base). The 17 mL (net weight 17 gm of solution) bottle provides
`248
`106 metered sprays and the 30 mL (net weight 30 gm of solution) bottle provides 200
`249
`250 metered sprays.
`
`251
`12 CLINCIAL PHARMACOLOGY
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`12.1 Mechanism of Action
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`Azelastine hydrochloride, a phthalazinone derivative, exhibits histamine H1 ­
`254
`receptor antagonist activity in isolated tissues, animal models, and humans. ASTEPRO
`255
`256 Nasal Spray is administered as a racemic mixture with no difference in pharmacologic
`activity noted between the enantiomers in in vitro studies. The major metabolite,
`
`257
`desmethylazelastine, also possesses H1 -receptor antagonist activity.
`258
`
`12.2 Pharmacodynamics
`259
`
`260
`Cardiac Effects:
`261
`In a placebo-controlled trial (95 patients with allergic rhinitis), there was no evidence
`
`of an effect of azelastine hydrochloride nasal spray (2 sprays per nostril twice daily for 56
`262
`263
`days) on cardiac repolarization as represented by the corrected QT interval (QTc) of the
`264
`electrocardiogram. Following multiple dose oral administration of azelastine 4 mg or 8 mg
`265
`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
`266
`
`administered oral azelastine hydrochloride and erythromycin or ketoconazole were
`267
`
`conducted. Oral erythromycin had no effect on azelastine pharmacokinetics or QTc based
`268
`269
`on analysis of serial electrocardiograms. Ketoconazole interfered with the measurement
`of azelastine plasma levels; however, no effects on QTc were observed [see Drug
`270
`Interactions (7.2)].
`271
`
`
`12.3 Pharmacokinetics
`272
`Absorption: After intranasal administration of 2 sprays per nostril (548 mcg total
`273
`
`dose) of ASTEPRO Nasal Spray 0.1%, the mean azelastine peak plasma concentration
`274
`275
`(Cmax) is 200 pg/mL, the mean extent of systemic exposure (AUC) is 5122 pg•hr/mL and
`the median time to reach Cmax (tmax) is 3 hours. After intranasal administration of 2 sprays
`276
`277
`per nostril (822 mcg total dose) of ASTEPRO Nasal Spray 0.15%, the mean azelastine
`278
`peak plasma concentration (Cmax) is 409 pg/mL, the mean extent of systemic exposure
`(AUC) is 9312 pg•hr/mL and the median time to reach Cmax (tmax) is 4 hours. The systemic
`279
`280
`bioavailability of azelastine hydrochloride is approximately 40% after intranasal
`281
`administration.
`
`Distribution: Based on intravenous and oral administration, the steady-state volume
`282
`of distribution of azelastine is 14.5 L/kg. In vitro studies with human plasma indicate that
`283
`284
`the plasma protein binding of azelastine and its metabolite, desmethylazelastine, are
`285
`approximately 88% and 97%, respectively.
`
`Metabolism: Azelastine is oxidatively metabolized to the principal active
`
`286
`
`287 metabolite, desmethylazelastine, by the cytochrome P450 enzyme system. The specific
`288
`P450 isoforms responsible for the biotransformation of azelastine have not been
`289
`identified. After a single-dose, intranasal administration of ASTEPRO Nasal Spray 0.1%
`290
`(548 mcg total dose), the mean desmethylazelastine Cmax is 23 pg/mL, the AUC is 2131
`pg•hr/mL and the median tmax is 24 hours. After a single-dose, intranasal administration
`291
`292
`of ASTEPRO Nasal Spray 0.15% (822 mcg total dose), the mean desmethylazelastine
`293 Cmax is 38 pg/mL, the AUC is 3824 pg•hr/mL and the median tmax is 24 hours. After
`294
`intranasal dosing of azelastine to steady-state, plasma concentrations of
`295
`desmethylazelastine range from 20-50% of azelastine concentrations.
`Elimination: Following intranasal administration of ASTEPRO Nasal Spray 0.1%,
`296
`
`the elimination half-life of azelastine is 22 hours while that of desmethylazelastine is 52
`297
`298
`hours. Following intranasal administration of ASTEPRO Nasal Spray 0.15%, the
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`elimination half-life of azelastine is 25 hours while that of desmethylazelastine is 57
`
`300
`hours. Approximately 75% of an oral dose of radiolabeled azelastine hydrochloride was
`301
`excreted in the feces with less than 10% as unchanged azelastine.
`Special Populations:
`302
`Hepatic Impairment: Following oral administration, pharmacokinetic parameters
`303
`
`304 were not influenced by hepatic impairment.
`Renal Impairment: Based on oral, single-dose studies, renal insufficiency
`305
`306
`(creatinine clearance <50 mL/min) resulted in a 70-75% higher Cmax and AUC compared
`307
`to healthy subjects. Time to maximum concentration was unchanged.
`Age: Following oral administration, pharmacokinetic parameters were not
`308
`
`influenced by age.
`309
`Gender: Following oral administration, pharmacokinetic parameters were not
`310
`
`influenced by gender.
`311
`Race: The effect of race has not been evaluated.
`312
`
`313 Drug-Drug Interactions:
`
`Erythromycin: Co-administration of orally administered azelastine (4 mg twice
`314
`
`
`daily) with erythromycin (500 mg three times daily for 7 days) resulted in Cmax of 5.36 ±
`315
`2.6 ng/mL and AUC of 49.7 ± 24 ng•h/mL for azelastine, whereas, administration of
`316
`azelastine alone resulted in Cmax of 5.57 ± 2.7 ng/mL and AUC of 48.4 ± 24 ng•h/mL for
`317
`azelastine [see Drug Interactions (7.2)].
`
`318
`Cimetidine and Ranitidine: In a multiple-dose, steady-state drug interaction trial
`
`319
`in healthy subjects, cimetidine (400 mg twice daily) increased orally administered mean
`320
`321
`azelastine (4 mg twice daily) concentrations by approximately 65%. Co-administration of
`322
`orally administered azelastine (4 mg twice daily) with ranitidine hydrochloride (150 mg
`twice daily) resulted in Cmax of 8.89 ±3.28 ng/mL and AUC of 88.22 ± 40.43 ng•h/mL for
`323
`324
`azelastine, whereas, administration of azelastine alone resulted in Cmax of 7.83 ± 4.06
`ng/mL and AUC of 80.09 ± 43.55 ng•h/mL for azelastine [see Drug Interactions (7.3)].
`
`325
`Theophylline: No significant pharmacokinetic interaction was observed with the
`
`326
`co-administration of an oral 4 mg dose of azelastine hydrochloride twice daily and
`327
`328
`theophylline 300 mg or 400 mg twice daily.
`
`329
`
`13 NONCLINICAL TOXICOLOGY
`330
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`331
`
`332
`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,
`333
`
`334
`respectively. These doses were approximately 150 and 60 times the maximum
`recommended human daily intranasal dose [MRHDID] on a mg/m2 basis.
`335
`
`336
`Azelastine hydrochloride showed no genotoxic effects in the Ames test, DNA repair
`test, mouse lymphoma forward mutation assay, mouse micronucleus test, or
`337
`338
`chromosomal aberration test in rat bone marrow.
`
`339
`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
`340
`a mg/m2 basis). At 68.6 mg/kg (approximately 340 times the MRHDID on a mg/m2
`341
`342
`basis), the duration of estrous cycles was prolonged and copulatory activity and the
`343
`number of pregnancies were decreased. The numbers of corpora lutea and implantations
`344 were decreased; however, pre-implantation loss was not increased.
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` 13.2 Animal Toxicology and/or Pharmacology
`
`345
`Reproductive Toxicology Studies
`346
`
`Azelastine hydrochloride has been shown to cause developmental toxicity.
`347
`Treatment of mice with an oral dose of 68.6 mg/kg (approximately 170 times the
`348
`349 maximum recommended human daily intranasal dose [MRHDID] on a mg/m2 basis)
`350
`caused embryo-fetal death, malformations (cleft palate; short or absent tail; fused, absent
`351
`or branched ribs), delayed ossification, and decreased fetal weight. This dose also caused
`352 maternal toxicity as evidenced by decreased body weight. Neither fetal nor maternal
`effects occurred at a dose of 3 mg/kg (approximately 7 times the MRHDID on a mg/m2
`353
`354
`basis).
`
`355
`In rats, an oral dose of 30 mg/kg (approximately 150 times the MRHDID on a
`356 mg/m2 basis) caused malformations (oligo-and brachydactylia), delayed ossification and
`357
`skeletal variations, in the absence of maternal toxicity. At 68.6 mg/kg (approximately 340
`times the MRHDID on a mg/m2 basis) azelastine hydrochloride also caused embryo-fetal
`358
`359
`death and decreased fetal weight; however, the 68.6 mg/kg dose caused severe maternal
`360
`toxicity. Neither fetal nor maternal effects occurred at a dose of 3 mg/kg (approximately
`15 times the MRHDID on a mg/m2 basis).
`361
`
`362
`In rabbits, oral doses of 30 mg/kg and greater (approximately 300 times the
`363 MRHDID on a mg/m