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ASTEPRO
(azelastine hydrochloride) Nasal Spray
ASTEPRO (azelastine hydrochloride) 0.1% nasal spray is an antihistamine (H1 receptor antagonist) formulated as a metered-spray solution for intranasal administration. ASTEPRO (azelastine hydrochloride) 0.15% nasal spray is an antihistamine (H1 receptor antagonist) 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 of 418.37. 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-(2H)-phthalazinone,4-[(4-chlorophenyl) methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-, monohydrochloride. Its molecular formula is C22H24ClN3O•HCl with the following chemical structure:
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ASTEPRO 0.1% contains 0.1% azelastine hydrochloride in an isotonic aqueous solution containing sorbitol, sucralose, hypromellose, sodium citrate, edetate disodium, benzalkonium chloride (125 mcg/mL), and purified water (pH 6.4). After priming [see DOSAGE AND ADMINISTRATION], each metered spray delivers a 0.137 mL mean volume containing 137 mcg of azelastine hydrochloride (equivalent to 125 mcg of azelastine base). The 30-mL (net weight 30 gm of solution) bottle provides 200 metered sprays.
ASTEPRO 0.15% contains 0.15% azelastine hydrochloride in an isotonic aqueous solution containing sorbitol, sucralose, hypromellose, sodium citrate, edetate disodium, benzalkonium chloride (125 mcg/mL), and purified water (pH 6.4). After priming [see DOSAGE AND ADMINISTRATION], each metered spray delivers a 0.137 mL mean volume containing 205.5 mcg of azelastine hydrochloride (equivalent to 187.6 mcg of azelastine base). The 30-mL (net weight 30 gm of solution) bottle provides 200 metered sprays.
ASTEPRO Nasal Spray is indicated for the relief of the symptoms of seasonal allergic rhinitis in patients 2 years of age and older and perennial allergic rhinitis in patients 6 months of age and older.
ASTEPRO 0.1%, 1 spray per nostril twice daily.
ASTEPRO 0.1% or ASTEPRO 0.15%, 1 spray per nostril twice daily.
ASTEPRO 0.1% or ASTEPRO 0.15%, 1 or 2 sprays per nostril twice daily. ASTEPRO 0.15% may also be administered as 2 sprays per nostril once daily.
ASTEPRO 0.1%, 1 spray per nostril twice daily.
ASTEPRO 0.1% or ASTEPRO 0.15%, 1 spray per nostril twice daily.
ASTEPRO 0.15%, 2 sprays per nostril twice daily.
Administer ASTEPRO by the intranasal route only.
Prime ASTEPRO before initial use by releasing 6 sprays or until a fine mist appears. When ASTEPRO has not been used for 3 or more days, reprime with 2 sprays or until a fine mist appears.
Avoid spraying ASTEPRO into the eyes.
ASTEPRO is a nasal spray solution available in two dosage strengths:
ASTEPRO (azelastine hydrochloride) 0.1% nasal spray is supplied as a 30-mL package 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 mL (net weight 30 gm of solution). Each bottle contains 30 mg (1 mg/mL) of azelastine hydrochloride. After priming [see DOSAGE AND ADMINISTRATION], 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.
ASTEPRO (azelastine hydrochloride) 0.15% nasal spray is supplied as a 30-mL package (NDC 0037-0243-30) 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 mL (net weight 30 gm of solution). The 30-mL bottle contains 45 mg (1.5 mg/mL) of azelastine hydrochloride. After priming [see DOSAGE AND ADMINISTRATION], each spray delivers a fine mist containing a mean volume of 0.137 mL solution containing 205.5 mcg of azelastine hydrochloride. The correct amount of medication in each spray cannot be assured before the initial priming and after 200 sprays for the 30-mL bottle have been used, even though the bottle is not completely empty. The bottle should be discarded after 200 sprays have been used.
ASTEPRO should not be used after the expiration date “EXP” printed on the medicine label and carton.
Store upright at controlled room temperature 20° to 25°C (68° to 77°F). Protect from freezing.
Manufactured by: Meda Pharmaceuticals, Somerset, NJ 08873-4120. Revised: 2/2015
Use of ASTEPRO has been associated with somnolence [see WARNINGS AND PRECAUTIONS].
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 observed in practice.
The safety data described below reflect exposure to ASTEPRO 0.1% in 975 patients 6 months of age and older from 4 clinical trials of 2 weeks to 12 months duration. In a 2-week, double-blind, placebo-controlled, and active-controlled (Astelin® Nasal Spray; azelastine hydrochloride) clinical trial, 285 patients (115 males and 170 females) 12 years of age and older with seasonal allergic rhinitis were treated with ASTEPRO 0.1% one or two sprays per nostril daily. In the 12 month open-label, active-controlled (Astelin Nasal Spray) clinical trial, 428 patients (207 males and 221 females) 12 years of age and older with perennial allergic rhinitis and/or nonallergic rhinitis were treated with ASTEPRO 0.1% two sprays per nostril twice daily. In a 4-week, double-blind, placebo-controlled clinical trial, 166 patients (101 males and 65 females) ages 6 to 11 years of age with perennial allergic rhinitis, with or without concomitant seasonal allergic rhinitis, were treated with ASTEPRO 0.1% one spray per nostril twice daily. In a 4-week clinical trial, 96 patients (51 males and 45 females) ages 6 months to 5 years of age with seasonal and/or perennial allergic rhinitis were treated with ASTEPRO 0.1% one spray per nostril twice daily. The racial and ethnic distribution for the 4 clinical trials was 80% white, 11% black, 8% Hispanic, 3% Asian, and 2% other.
In the two week clinical trial, 835 patients 12 years of age and older with seasonal allergic rhinitis were treated with one of six treatments: one spray per nostril of either ASTEPRO 0.1%, Astelin Nasal Spray or placebo twice daily; or 2 sprays per nostril of ASTEPRO 0.1%, Astelin Nasal Spray, or placebo twice daily. Overall, adverse reactions were more common in the ASTEPRO 0.1% 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 was similar among the treatment groups.
Table 1 contains adverse reactions reported with frequencies greater than or equal to 2% and more frequently than placebo in patients treated with ASTEPRO 0.1% in the controlled clinical trial described above.
Table 1: Adverse Reactions Reported in ≥ 2% Incidence
in a Placebo-Controlled Trial of 2 Weeks' Duration with ASTEPRO 0.1% in Adult
and Adolescent Patients with Seasonal Allergic Rhinitis
| 1 spray twice daily | 2 sprays twice daily | |||||
| ASTEPRO 0.1% (N=139) |
Astelin Nasal Spray (N=137) |
Vehicle Placebo (N=137) |
ASTEPRO 0.1% (N=146) |
Astelin Nasal Spray (N=137) |
Vehicle Placebo (N=138) |
|
| Bitter Taste | 8 (6%) | 13 (10%) | 2 (2%) | 10 (7%) | 11 (8%) | 3 (2%) |
| Epistaxis | 3 (2%) | 8 (6%) | 3 (2%) | 4 (3%) | 3 (2%) | 0 (0%) |
| Headache | 2 (1%) | 5 (4%) | 1 ( < 1%) | 4 (3%) | 3 (2%) | 1 ( < 1%) |
| Nasal Discomfort | 0 (0%) | 3 (2%) | 1 ( < 1%) | 2 (1%) | 6 (4%) | 0 (0%) |
| Fatigue | 0 (0%) | 1 ( < 1%) | 1 ( < 1%) | 3 (2%) | 3 (2%) | 1 ( < 1%) |
| Somnolence | 2 (1%) | 2 (2%) | 0 (0%) | 3 (2%) | 2 (1%) | 0 (0%) |
In the 12 month, open-label, active-controlled, long-term safety trial, 862 patients 12 years of age and older with perennial allergic and/or nonallergic rhinitis were treated with ASTEPRO 0.1% two sprays per nostril twice daily or Astelin Nasal Spray two sprays per nostril twice daily. The most frequently reported adverse reactions were headache, bitter taste, epistaxis, and nasopharyngitis and were generally similar between treatment groups. Focused nasal examinations were performed and showed that the incidence of nasal mucosal ulceration in each treatment group was approximately 1% at baseline and approximately 1.5% throughout the 12 month treatment period. In each treatment group, 5-7% of patients had mild epistaxis. No patients had reports of nasal septal perforation or severe epistaxis. Twenty-two patients (5%) treated with ASTEPRO 0.1% and 17 patients (4%) treated with Astelin Nasal Spray discontinued from the trial due to adverse events.
In a 4 week clinical trial, 489 patients ages 6 to 11 years with perennial allergic rhinitis, with or without concomitant seasonal allergic rhinitis, were treated with either ASTEPRO 0.1%, ASTEPRO 0.15% or placebo, one spray per nostril twice daily. Overall, adverse events were similar in the ASTEPRO 0.15% group (24%), ASTEPRO 0.1% group (26%) and the placebo group (24%). Overall, less than 1% of the combined ASTEPRO groups discontinued due to adverse events.
Table 2 contains adverse reactions reported with frequencies greater than or equal to 2% and more frequently than placebo in children 6 to 11 years of age treated with ASTEPRO 0.1% or ASTEPRO 0.15% in the controlled trial described above.
Table 2: Adverse Reactions Reported in ≥ 2%
Incidence in a Placebo-Controlled Trial of 4 Weeks' Duration with ASTEPRO 0.1%
or ASTEPRO 0.15% in Children 6 to 11 Years of Age with Perennial Allergic
Rhinitis
| 1 spray twice daily | |||
| ASTEPRO 0.1% (N=166) |
ASTEPRO 0.15% (N=161) |
Vehicle Placebo (N=162) |
|
| Epistaxis | 8 (5%) | 7 (4%) | 5 (3%) |
| Nasal Discomfort | 1 ( < 1%) | 7 (4%) | 0 (0%) |
| Dysgeusia | 4 (2%) | 6 (4%) | 1 ( < 1%) |
| Upper respiratory infection | 4 (2%) | 4 (3%) | 3 (2%) |
| Sneezing | 3 (2%) | 4 (3%) | 2 (1%) |
In a 4 week clinical trial, 191 patients ages 6 months to 5 years with either seasonal and/or perennial allergic rhinitis were treated with either ASTEPRO 0.1% or ASTEPRO 0.15% one spray per nostril twice daily. The most frequently ( ≥ 2%) reported adverse reactions were pyrexia, cough, epistaxis, sneezing, dysgeusia, rhinalgia, upper respiratory infection, vomiting, otitis media, contact dermatitis, and oropharyngeal pain. Overall, adverse events were slightly higher in the ASTEPRO 0.15% group (28%) compared to ASTEPRO 0.1% group (21%). Focused nasal examinations were performed and showed no incidence of nasal mucosal ulceration at any time point during the study. No patients had reports of nasal septal perforation. Overall, less than 3% of the combined ASTEPRO groups discontinued due to adverse events.
The safety data described below reflect exposure to ASTEPRO 0.15% in 2114 patients (6 months of age and older) with seasonal or perennial allergic rhinitis from 10 clinical trials of 2 weeks to 12 months duration. In 8 double-blind, placebo-controlled clinical trials of 2 to 4 weeks duration, 1703 patients (646 males and 1059 females) with seasonal or perennial allergic rhinitis were treated with ASTEPRO 0.15% one or two sprays per nostril once or twice daily. In the 12 month open-label, active-controlled clinical trial, 466 patients (156 males and 310 females) with perennial allergic rhinitis were treated with ASTEPRO 0.15% two sprays per nostril twice daily. Of these 466 patients, 152 had participated in the 4-week placebo-controlled perennial allergic rhinitis clinical trials. In a 4-week, double-blind, placebo-controlled clinical trial, 161 patients (87 males and 74 females) ages 6 to 11 years of age with perennial allergic rhinitis, with or without concomitant seasonal allergic rhinitis, were treated with ASTEPRO 0.15% one spray per nostril twice daily. In a 4-week clinical trial, 95 patients (59 males and 36 females) ages 6 months to 5 years of age with seasonal and/or perennial allergic rhinitis were treated with ASTEPRO 0.15% one spray per nostril twice daily. The racial distribution for the 10 clinical trials was 79% white, 14% black, 2% Asian, and 5% other.
In the 7 placebo controlled clinical trials of 2 to 4 week duration, 2343 patients with seasonal allergic rhinitis and 540 patients with perennial allergic rhinitis were treated with two sprays per nostril of either ASTEPRO 0.15% or placebo once or twice daily. Overall, adverse reactions were more common in the ASTEPRO 0.15% treatment groups (16-31%) than in the placebo groups (11-24%). Overall, less than 2% of patients discontinued due to adverse reactions and withdrawal due to adverse reactions was similar among the treatment groups.
Table 3 contains adverse reactions reported with frequencies greater than or equal to 2% and more frequently than placebo in patients treated with ASTEPRO 0.15% in the seasonal and perennial allergic rhinitis controlled clinical trials.
Table 3: Adverse Reactions with ≥ 2% Incidence in
Placebo-Controlled Trials of 2 to 4 Weeks' Duration with ASTEPRO 0.15% in Adult
and Adolescent Patients With Seasonal or Perennial Allergic Rhinitis
| 2 sprays twice daily | 2 sprays once daily | |||
| ASTEPRO 0.15% (N=523) |
Vehicle Placebo (N=523) |
ASTEPRO 0.15% (N=1021) |
Vehicle Placebo (N=816) |
|
| Bitter Taste | 31 (6%) | 5 (1%) | 38 (4%) | 2 ( < 1%) |
| Nasal Discomfort | 18 (3%) | 12 (2%) | 37 (4%) | 7 (1%) |
| Epistaxis | 5 (1%) | 7 (1%) | 21 (2%) | 14 (2%) |
| Sneezing | 9 (2%) | 1 ( < 1%) | 14 (1%) | 0 (0%) |
In the above trials, somnolence was reported in < 1% of patients treated with ASTEPRO 0.15% (11 of 1544) or vehicle placebo (1 of 1339).
In the 12 month, open-label, active-controlled, long-term safety trial, 466 patients (12 years of age and older) with perennial allergic rhinitis were treated with ASTEPRO 0.15% two sprays per nostril twice daily and 237 patients were treated with mometasone nasal spray two sprays per nostril once daily. The most frequently reported adverse reactions ( > 5%) with ASTEPRO 0.15% were bitter taste, headache, sinusitis, and epistaxis. Focused nasal examinations were performed and no nasal ulcerations or septal perforations were observed. In each treatment group, approximately 3% of patients had mild epistaxis. No patients had reports of severe epistaxis. Fifty-four patients (12%) treated with ASTEPRO 0.15% and 17 patients (7%) treated with mometasone nasal spray discontinued from the trial due to adverse events.
See summary under ASTEPRO 0.1%
During the post approval use of ASTEPRO 0.1% and ASTEPRO 0.15%, 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: abdominal pain, atrial fibrillation, blurred vision, chest pain, confusion, disturbance or loss of sense of smell and/or taste, dizziness, dyspnea, facial swelling, hypertension, involuntary muscle contractions, nasal burning, nausea, nervousness, palpitations, paresthesia, parosmia, pruritus, rash, sneezing, insomnia, sweet taste, tachycardia, and throat irritation.
Additionally, the following adverse reactions have been identified during the post approval use of the Astelin brand of azelastine hydrochloride 0.1% nasal spray (total daily dose 0.55 mg to 1.1 mg). 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 the following: anaphylactoid reaction, application site irritation, facial edema, paroxysmal sneezing, tolerance, urinary retention, and xerophthalmia.
Concurrent use of ASTEPRO Nasal Spray with alcohol or other central nervous system depressants should be avoided because reductions in alertness and impairment of central nervous system performance may occur [see WARNINGS AND PRECAUTIONS].
Interaction studies investigating the cardiac effects, as measured by the corrected QT interval (QTc), of concomitantly administered oral azelastine hydrochloride and erythromycin or ketoconazole were conducted. Oral erythromycin (500 mg three times daily for 7 days) had no effect on azelastine pharmacokinetics or QTc based on analyses of serial electrocardiograms. Ketoconazole (200 mg twice daily for 7 days) interfered with the measurement of azelastine plasma concentrations on the analytic HPLC; however, no effects on QTc were observed [see CLINICAL PHARMACOLOGY].
Cimetidine (400 mg twice daily) increased the mean Cmax and AUC of orally administered azelastine hydrochloride (4 mg twice daily) by approximately 65% [see CLINICAL PHARMACOLOGY].
Included as part of the PRECAUTIONS section.
In clinical trials, the occurrence of somnolence has been reported in some patients taking ASTEPRO [see ADVERSE REACTIONS]. 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. Concurrent use of ASTEPRO 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].
See FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use).
Somnolence has been reported in some patients taking ASTEPRO. Caution patients against engaging in hazardous occupations requiring complete mental alertness and motor coordination such as driving or operating machinery after administration of ASTEPRO [see WARNINGS AND PRECAUTIONS].
Avoid concurrent use of ASTEPRO with alcohol or other central nervous system depressants because additional reductions in alertness and additional impairment of central nervous system performance may occur [see WARNINGS AND PRECAUTIONS].
Inform patients that the treatment with ASTEPRO may lead to adverse reactions, most common of which include pyrexia, dysgeusia, nasal discomfort, epistaxis, headache, sneezing, fatigue, somnolence, upper respiratory infection, cough, rhinalgia, vomiting, otitis media, contact dermatitis, and oropharyngeal pain. [see ADVERSE REACTIONS].
Instruct patients to prime the pump before initial use and when ASTEPRO has not been used for 3 or more days [see DOSAGE AND ADMINISTRATION].
Instruct patients to avoid spraying ASTEPRO into their eyes.
Instruct patients to keep ASTEPRO out of the reach of children. If a child accidentally ingests ASTEPRO, seek medical help or call a poison control center immediately.
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.
There are no adequate and well-controlled clinical trials in pregnant women. Azelastine hydrochloride has been shown to cause developmental toxicity in mice, rats, and rabbits. ASTEPRO Nasal Spray should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
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 mg/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 150 times the MRHDID in adults (on a mg/m² basis at a maternal oral dose of 30 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 MRHDID (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).
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 ASTEPRO is administered to a nursing woman.
The safety and effectiveness of ASTEPRO have been established for seasonal allergic rhinitis in pediatric patients 2 to 17 years of age and perennial allergic rhinitis in pediatric patients 6 months of age to 17 years of age [see Clinical Studies]. The safety and effectiveness of ASTEPRO in pediatric patients below 6 months of age have not been established.
Clinical trials of ASTEPRO did not include sufficient numbers of patients 65 years of age and older 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. In 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.
There have been no reported overdosages with ASTEPRO. Acute overdosage by adults with this dosage form is unlikely to result in clinically significant adverse events, other than increased somnolence, since one 30-mL bottle of ASTEPRO 0.1% contains up to 30 mg of azelastine hydrochloride and one 30-mL bottle of ASTEPRO 0.15% contains up to 45 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 events. General supportive measures should be employed if overdosage occurs. There is no known antidote to ASTEPRO. Oral ingestion of antihistamines has the potential to cause serious adverse effects in children. Accordingly, ASTEPRO should be kept out of the reach of children.
None.
Azelastine hydrochloride, a phthalazinone derivative, exhibits histamine H1-receptor antagonist activity in isolated tissues, animal models, and humans. ASTEPRO is administered as a racemic mixture with no difference in pharmacologic activity noted between the enantiomers in in vitro studies. The major metabolite, desmethylazelastine, also possesses H1-receptor antagonist activity.
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 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. Oral erythromycin had no effect on azelastine pharmacokinetics or QTc based on analysis of serial electrocardiograms. Ketoconazole interfered with the measurement of azelastine plasma levels; however, no effects on QTc were observed [see DRUG INTERACTIONS].
After intranasal administration of 2 sprays per nostril (548 mcg total dose) of ASTEPRO 0.1%, the mean azelastine peak plasma concentration (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 per nostril (822 mcg total dose) of ASTEPRO 0.15%, the mean azelastine 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 bioavailability of azelastine hydrochloride is approximately 40% after intranasal administration.
Based on intravenous and oral administration, the steady-state volume of distribution of azelastine 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.
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 a single-dose, intranasal administration of ASTEPRO 0.1% (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 of ASTEPRO 0.15% (822 mcg total dose), the mean desmethylazelastine Cmax is 38 pg/mL, the AUC is 3824 pg•hr/mL and the median tmax is 24 hours. After intranasal dosing of azelastine to steady-state, plasma concentrations of desmethylazelastine range from 20-50% of azelastine concentrations.
Following intranasal administration of ASTEPRO 0.1%, the elimination half-life of azelastine is 22 hours while that of desmethylazelastine is 52 hours. Following intranasal administration of ASTEPRO 0.15%, the elimination half-life of azelastine is 25 hours while that of desmethylazelastine is 57 hours. Approximately 75% of an oral dose of radiolabeled azelastine hydrochloride was excreted in the feces with less than 10% as unchanged azelastine.
Following oral administration, pharmacokinetic parameters were not influenced by hepatic 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 healthy subjects. Time to maximum concentration was unchanged.
Following oral administration, pharmacokinetic parameters were not influenced by age.
Following oral administration, pharmacokinetic parameters were not influenced by gender.
The effect of race has not been evaluated.
Co-administration of orally administered azelastine (4 mg twice daily) with erythromycin (500 mg three times daily for 7 days) 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 [see DRUG INTERACTIONS].
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%. Co-administration of 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 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].
No significant pharmacokinetic interaction was observed with the coadministration of an oral 4 mg dose of azelastine hydrochloride twice daily and theophylline 300 mg or 400 mg twice daily.
The efficacy and safety of ASTEPRO 0.1% was evaluated in a 2-week, randomized, multicenter, double-blind, placebo-controlled clinical trial including 834 adult and adolescent patients 12 years of age and older with symptoms of seasonal allergic rhinitis. The population was 12 to 83 years of age (60% female, 40% male; 69% white, 16% black, 12% Hispanic, 2% Asian, 1% other).
Patients were randomized to one of six treatment groups: 1 spray per nostril of either ASTEPRO 0.1%, Astelin (azelastine hydrochloride) Nasal Spray or vehicle placebo twice daily; or 2 sprays per nostril of ASTEPRO 0.1%, Astelin or vehicle placebo twice daily.
Assessment of efficacy was based on the 12-hour reflective total nasal symptom score (rTNSS) assessed daily in the morning and evening, in addition to the instantaneous total nasal symptom score (iTNSS) and other supportive secondary efficacy variables. TNSS is calculated as the sum of the patients' scoring of the four individual nasal symptoms (rhinorrhea, nasal congestion, sneezing, and nasal itching) on a 0 to 3 categorical severity scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe). The rTNSS required patients to record symptom severity over the previous 12 hours. For the primary efficacy endpoint, the mean change from baseline rTNSS, morning (AM) and evening (PM) rTNSS scores were summed for each day (maximum score of 24) and then averaged over the 2 weeks. The iTNSS, recorded immediately prior to the next dose, were assessed as an indication of whether the effect was maintained over the dosing interval.
In this trial, ASTEPRO 0.1% two sprays twice a day demonstrated a greater decrease in rTNSS and iTNSS than placebo and the difference was statistically significant. The trial results are presented in Table 4 (Trial 1).
The efficacy of ASTEPRO 0.1% one spray per nostril twice daily for seasonal allergic rhinitis is supported by two, 2-week, placebo-controlled clinical trials with Astelin (azelastine hydrochloride) Nasal Spray in 413 patients with seasonal allergic rhinitis. In these trials, efficacy was assessed using the TNSS (described above). Astelin demonstrated a greater decrease from baseline in the summed AM and PM rTNSS compared with placebo and the difference was statistically significant.
The efficacy of ASTEPRO 0.1% and ASTEPRO 0.15% in children 6 months to 5 years of age with allergic rhinitis was explored in a 4 week, randomized, open-label safety trial in 191 patients. While the primary objective was to determine the safety of ASTEPRO in this age group, the study included an exploratory efficacy assessment of daily overall allergy symptom scores. Efficacy in children 6 months to 5 years of age was supported by a numerical decrease in the overall allergy symptom score in both treatment groups. There was no statistically significant difference between the two treatment groups.
The efficacy and safety of ASTEPRO 0.15% in seasonal allergic rhinitis was evaluated in five randomized, multicenter, double-blind, placebo-controlled clinical trials in 2499 adult and adolescent patients 12 years and older with symptoms of seasonal allergic rhinitis (Trials 2, 3, 4, 5, and 6). The population of the trials was 12 to 83 years of age (64% female, 36% male; 81% white, 12% black, < 2% Asian, 5% other; 23% Hispanic, 77% non-Hispanic). Assessment of efficacy was based on the rTNSS, iTNSS as described above, and other supportive secondary efficacy variables. The primary efficacy endpoint was the mean change from baseline in rTNSS over 2 weeks.
Two 2-week seasonal allergic rhinitis trials evaluated the efficacy of ASTEPRO Nasal Spray 0.15% dosed at 2 sprays twice daily. The first trial (Trial 2) compared the efficacy of ASTEPRO 0.15% and Astelin (azelastine hydrochloride) Nasal Spray to vehicle placebo. The other trial (Trial 3) compared the efficacy of ASTEPRO 0.15% and ASTEPRO 0.1% to vehicle placebo. In these two trials, ASTEPRO 0.15% demonstrated greater decreases in rTNSS than placebo and the differences were statistically significant (Table 4).
Three 2-week seasonal allergic rhinitis trials evaluated the efficacy of ASTEPRO 0.15% dosed at 2 sprays once daily compared to the vehicle placebo. Trial 4 demonstrated a greater decrease in rTNSS than placebo and the difference was statistically significant (Table 4). Trial 5 and Trial 6 were conducted in patients with Texas mountain cedar allergy. In Trial 5 and Trial 6, ASTEPRO 0.15% demonstrated a greater decrease in rTNSS than placebo and the differences were statistically significant (Trials 5 and 6; Table 4). Instantaneous TNSS results for the once daily dosing regimen of ASTEPRO 0.15% are shown in Table 5. In Trials 5 and 6, ASTEPRO 0.15% demonstrated a greater decrease in iTNSS than placebo and the differences were statistically significant.
Table 4: Mean Change from Baseline in Reflective TNSS
over 2 Weeks* in Adults and Children ≥ 12 years with Seasonal Allergic
Rhinitis
| Treatment (sprays per nostril) | n | Baseline LS Mean | Change from Baseline | Difference From Placebo | |||
| LS Mean | 95% CI | P value | |||||
| Trial 1 | |||||||
| Two sprays twice daily | ASTEPRO 0.1% | 146 | 18.0 | -5.0 | -2.2 | .2 -1. < N -3. | < 0.001 |
| Astelin Nasal Spray | 137 | 18.2 | -4.2 | -1.4 | -2.4,-0.4 | 0.01 | |
| Vehicle Placebo | 138 | 18.2 | -2.8 | ||||
| One spray twice daily | ASTEPRO 0.1% | 139 | 18.2 | -4.2 | -0.7 | -1.7, 0.3 | 0.18 |
| Astelin Nasal Spray | 137 | 18.1 | -4.0 | -0.4 | -1.5, 0.6 | 0.41 | |
| Vehicle Placebo | 137 | 18.0 | -3.5 | ||||
| Trial 2 | |||||||
| Two sprays twice daily | ASTEPRO 0.15% | 153 | 18.2 | -4.3 | -1.2 | .3 -0. -2. | 0.01 |
| Astelin Nasal Spray | 153 | 17.9 | -3.9 | -0.9 | -1.8, 0.1 | 0.07 | |
| Vehicle Placebo | 153 | 18.1 | -3.0 | ||||
| Trial 3 | |||||||
| Two sprays twice daily | ASTEPRO 0.15% | 177 | 17.7 | -5.1 | -3.0 | .1 -2. G) -3. | < 0.001 |
| ASTEPRO 0.1% | 169 | 18.2 | -4.2 | -2.1 | .2 -1. 0, -3. | < 0.001 | |
| Vehicle Placebo | 177 | 17.7 | -2.1 | ||||
| Trial 4 | |||||||
| Two sprays once daily | ASTEPRO 0.15% | 238 | 17.4 | -3.4 | -1.0 | .3 -0. rC 1. | 0.008 |
| Vehicle Placebo | 242 | 17.4 | -2.4 | ||||
| Trial 5 | |||||||
| Two sprays once daily | ASTEPRO 0.15% | 266 | 18.5 | -3.3 | -1.4 | .8 -0. -2. | < 0.001 |
| Vehicle Placebo | 266 | 18.0 | -1.9 | ||||
| Trial 6 | |||||||
| Two sprays once daily | ASTEPRO 0.15% | 251 | 18.5 | -3.4 | -1.4 | -2.1, -0.7 | < 0.001 |
| Vehicle Placebo | 254 | 18.8 | -2.0 | ||||
| *Sum of AM and PM rTNSS for each day (Maximum score=24) and averaged over the 14 day treatment period | |||||||
Table 5: Mean Change from
Baseline AM Instantaneous TNSS over 2 Weeks* in Adults and Children ≥ 12 years with Seasonal Allergic Rhinitis
| Treatment (sprays per nostril once daily) | n | Baseline LS Mean | Change from Baseline | Difference From Placebo | |||
| LS Mean | 95% CI | P value | |||||
| Trial 4 | |||||||
| Two sprays once daily | ASTEPRO 0.15% | 238 | 8.1 | -1.3 | -0.2 | -0.6, 0.1 | 0.15 |
| Vehicle Placebo | 242 | 8.3 | -1.1 | ||||
| Trial 5 | |||||||
| Two sprays once daily | ASTEPRO 0.15% | 266 | 8.7 | -1.4 | -0.7 | .4 -0. O. 1. | < 0.001 |
| Vehicle Placebo | 266 | 8.3 | -0.7 | ||||
| Trial 6 | |||||||
| Two sprays once daily | ASTEPRO 0.15% | 251 | 8.9 | -1.4 | -0.6 | .3 -0. -0. | < 0.001 |
| Vehicle Placebo | 254 | 8.9 | -0.8 | ||||
| *AM iTNSS for each day (Maximum score=12) and averaged over the 14 day treatment period | |||||||
ASTEPRO 0.15% at a dose of 1 spray twice daily was not studied. The ASTEPRO 0.15% 1 spray twice daily dosing regimen is supported by previous findings of efficacy for Astelin (azelastine hydrochloride) Nasal Spray and a favorable comparison of ASTEPRO 0.15% to Astelin Nasal Spray and ASTEPRO 0.1% (Table 4).
The efficacy and safety of ASTEPRO 0.1% and 0.15% in children 6 to 11 years of age with seasonal allergic rhinitis was evaluated in a clinical study that enrolled pediatric patients with perennial allergic rhinitis, with or without concomitant seasonal allergic rhinitis (described below in Section 14.2).
The efficacy and safety of ASTEPRO 0.15% in perennial allergic rhinitis was evaluated in one randomized, multicenter, double-blind, placebo-controlled clinical trial in 578 adult and adolescent patients 12 years and older with symptoms of perennial allergic rhinitis. The population of the trial was 12 to 84 years of age (68% female, 32% male; 85% white, 11% black, 1% Asian, 3% other; 17% Hispanic, 83% non-Hispanic).
Assessment of efficacy was based on the 12-hour reflective total nasal symptom score (rTNSS) assessed daily in the morning and evening, the instantaneous total nasal symptom score (iTNSS), and other supportive secondary efficacy variables. The primary efficacy endpoint was the mean change from baseline rTNSS over 4 weeks. The one 4-week perennial allergic rhinitis trial evaluated the efficacy of ASTEPRO 0.15%, ASTEPRO 0.1%, and vehicle placebo dosed at 2 sprays per nostril twice daily. In this trial, ASTEPRO 0.15% demonstrated a greater decrease in rTNSS than placebo and the difference was statistically significant (Table 6).
Table 6: Mean Change from Baseline in Reflective TNSS
over 4 Weeks* in Adults and Children ≥ 12 years with Perennial
Allergic Rhinitis
| Treatment (sprays per nostril twice daily) | n | Baseline LS Mean | Change from Baseline | Difference From Placebo | |||
| LS Mean | 95% CI | P value | |||||
| Two sprays twice daily | ASTEPRO 0.15% | 192 | 15.8 | -4.0 | -0.9 | -1.7, -0.1 | 0.03 |
| ASTEPRO 0.1% | 194 | 15.5 | -3.8 | -0.7 | -1.5, 0.1 | 0.08 | |
| Vehicle Placebo | 192 | 14.7 | -3.1 | ||||
| *Sum of AM and PM rTNSS for each day (Maximum score=24) and averaged over the 28 day treatment period | |||||||
The efficacy and safety of ASTEPRO 0.1% and ASTEPRO 0.15% in pediatric patients 6 to 11 years of age with perennial allergic rhinitis, with or without concomitant seasonal allergic rhinitis, was evaluated in a randomized, double-blind, placebo-controlled clinical trial in 486 patients. All patients received one spray per nostril twice daily. The study population was 58% males and 42% females; 78% white, 13% black, 3% Asian, and 6% other.
Assessment of efficacy was based on the 12-hour reflective total nasal symptom score (rTNSS) assessed daily in the morning and evening. The primary efficacy endpoint was the mean change from baseline rTNSS over 4 weeks (Table 7). Both active treatments demonstrated statistically significant decreases in rTNSS compared to placebo. There was no statistically significant difference between the two active-treatment groups. There was also no difference in treatment effect between patients with perennial allergic rhinitis only compared to those with perennial allergic rhinitis and concomitant seasonal allergic rhinitis.
Table 7: Mean Change from
Baseline in Reflective TNSS over 4 Weeks* in Children 6 to 11 years with
Perennial Allergic Rhinitis
| Treatment (sprays per nostril twice daily) | n | Baseline LS Mean | Change from Baseline | Difference From Placebo | |||
| LS Mean | 95% CI | P value | |||||
| One spray twice daily | ASTEPRO 0.15% | 159 | 16.6 | -3.5 | -1.0 | -1.7, -0.3 | 0.005 |
| ASTEPRO 0.1% | 166 | 16.4 | -3.4 | -0.9 | .2 -0. 1. | 0.015 | |
| Vehicle Placebo | 161 | 16.1 | -2.5 | ||||
| *Sum of AM and PM rTNSS for each day (Maximum score=24) and averaged over the 28 day treatment period | |||||||
The efficacy of ASTEPRO 0.1% and ASTEPRO 0.15% in children 6 months to 5 years of age with allergic rhinitis was explored in a clinical study (described above in Section 14.1).
ASTEPRO
[AS-ta-PRO]
(azelastine hydrochloride) Nasal Spray 0.1% Nasal Spray 0.15%
Important: For use in your nose only.
What is ASTEPRO Nasal Spray?
It is not known if ASTEPRO is safe and effective in children under 6 months of age.
What should I tell my healthcare provider before using ASTEPRO?
Before using ASTEPRO, tell your healthcare provider if you are:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. ASTEPRO and other medicines may affect each other, causing side effects.
How should I use ASTEPRO?
What should I avoid while using ASTEPRO?
ASTEPRO can cause sleepiness:
What are the possible side effects of ASTEPRO?
The most common side effects of ASTEPRO include:
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
These are not all of the possible side effects of ASTEPRO. For more information, ask your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store ASTEPRO?
Keep ASTEPRO and all medicines out of reach of children.
General information about the safe and effective use of ASTEPRO.
Medicines are sometimes prescribed for conditions other than those listed in a Patient Information leaflet. Do not use ASTEPRO for a condition for which it was not prescribed. Do not give ASTEPRO to other people, even if they have the same symptoms that you have. It may harm them.
This Patient Information leaflet summarizes the most important information about ASTEPRO. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about ASTEPRO that is written for health professionals.
For more information, go to www.ASTEPRO.com or call 1-800-598-4856.
What are the ingredients in ASTEPRO?
Active ingredient: azelastine hydrochloride
Inactive ingredients: sorbitol, sucralose, hypromellose, sodium citrate, edetate disodium, benzalkonium chloride, and purified water.
Instructions for Use
ASTEPRO
[AS-ta-PRO] (azelastine hydrochloride) Nasal Spray 0.1% Nasal Spray 0.15%
Important: For use in your nose only.
For the correct dose of medicine:
Figure A identifies the parts of your ASTEPRO Nasal Spray pump
Figure A
 |
Before you use ASTEPRO for the first time, you will need to prime the bottle.
For use in young children: An adult should help a young child use ASTEPRO. (See “Using your ASTEPRO” Steps 1 through 8).
Priming your ASTEPRO
Remove the blue dust cover over the tip of the bottle and the blue safety clip just under the “shoulders” of the bottle (See Figure B).
Figure B
 |
Now your pump is primed and ready to use.
Figure C
 |
Using your ASTEPRO
For use in young children: An adult should help a young child use ASTEPRO. (See Steps 1 through 8).
Step 1. Blow your nose to clear your nostrils.
Step 2. Keep your head tilted downward toward your toes.
Step 3. Place the spray tip about ¼ inch to ½ inch into 1 nostril. Hold bottle upright and aim the spray tip toward the back of your nose (See Figure D).
Figure D
 |
Step 4. Close your other nostril with a finger. Press the pump 1 time and sniff gently at the same time, keeping your head tilted forward and down (See Figure E).
Figure E
 |
Step 5. Repeat Step 3 and Step 4 in your other nostril.
Step 6. If your healthcare provider tells you to use 2 sprays in each nostril, repeat Steps 2 through 4 above for the second spray in each nostril.
Step 7. Breathe in gently, and do not tilt your head back after using ASTEPRO. This will help to keep the medicine from going into your throat.
Step 8. When you finish using your ASTEPRO, wipe the spray tip with a clean tissue or cloth. Put the safety clip and dust cover back on the bottle.
Cleaning the Spray Tip of your ASTEPRO
Figure F
 |
Figure G
 |
This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration.
