azelastine hcl nasal
HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use azelastine HCl nasal solution (nasal spray), 0.15% safely and effectively. See full prescribing information for azelastine HCl nasal solution (nasal spray), 0.15%.. Azelastine HCl Nasal Solution (Nasal Spray), 0.15%Initial U.S. Approval: 1996INDICATIONS AND USAGEAzelastine HCl nasal solution (nasal spray), 0.15% 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 ADMINISTRATIONFor intranasal use only (2.3).Seasonal allergic rhinitis:• 1 or 2 sprays per nostril twice daily or 2 sprays per nostril once daily in adults and adolescents 12 years of age and older (2.1)Perennial allergic rhinitis:• 2 sprays per nostril twice daily in adults and adolescents 12 years of age and older (2.2)• Prime azelastine HCl nasal solution (nasal spray), 0.15% before initial use and when it has not been used for 3 or more days. (2.3)DOSAGE FORMS AND STRENGTHSAzelastine HCl nasal solution (nasal spray), 0.15%: 205.5 mcg of azelastine hydrochloride in each 0.137 mL spray (3).CONTRAINDICATIONSNone.WARNINGS AND PRECAUTIONS• Somnolence may occur. Avoid engaging in hazardous occupations requiring complete mental alertness such as driving or operating machinery when taking azelastine HCl nasal solution (nasal spray) (5.1)• Avoid concurrent use of alcohol or other central nervous system (CNS) depressants with azelastine HCl nasal solution (nasal spray) because further decreased alertness and impairment of CNS performance may occur (5.1)Side EffectsThe 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 Perrigo at 1-866-634-9120 or www.perrigo.com 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.
FULL PRESCRIBING INFORMATION: CONTENTS*
- 1 AZELASTINE HCL NASAL INDICATIONS AND USAGE
- 2 AZELASTINE HCL NASAL DOSAGE AND ADMINISTRATION
- 3 DOSAGE FORMS AND STRENGTHS
- 4 AZELASTINE HCL NASAL CONTRAINDICATIONS
- 5 WARNINGS AND PRECAUTIONS
- 6 AZELASTINE HCL NASAL ADVERSE REACTIONS
- 7 DRUG INTERACTIONS
- 8 USE IN SPECIFIC POPULATIONS
- 10 OVERDOSAGE
- 11 AZELASTINE HCL NASAL DESCRIPTION
- 12 CLINICAL PHARMACOLOGY
- 13 NONCLINICAL TOXICOLOGY
- 14 CLINICAL STUDIES
- 16 HOW SUPPLIED/STORAGE AND HANDLING
- 17 PATIENT COUNSELING INFORMATION
- PATIENT INFORMATION
- Patient Instructions for Use
- PACKAGE/LABEL PRINCIPAL DISPLAY PANEL - CARTON
- PACKAGE/LABEL PRINCIPAL DISPLAY PANEL - LABEL
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
1.1 Allergic Rhinitis
Azelastine HCl nasal solution (nasal spray), 0.15% is indicated for the relief of the symptoms of seasonal and perennial allergic rhinitis in patients 12 years of age and older.
2 DOSAGE AND ADMINISTRATION
2.1 Seasonal Allergic Rhinitis
The recommended dose of azelastine HCl nasal solution (nasal spray), 0.15% is 1 or 2 sprays per nostril twice daily for seasonal allergic rhinitis. Azelastine HCl nasal solution (nasal spray), 0.15% may also be administered as 2 sprays per nostril once daily.
2.2 Perennial Allergic Rhinitis
The recommended dose of azelastine HCl nasal solution (nasal spray), 0.15% for perennial allergic rhinitis is 2 sprays per nostril twice daily.
2.3 Important Administration Instructions
Administer azelastine HCl nasal solution (nasal spray), 0.15% by the intranasal route only. Priming: Prime azelastine HCl nasal solution (nasal spray), 0.15% before initial use by releasing 6 sprays or until a fine mist appears. When azelastine HCl nasal solution (nasal spray), 0.15% has not been used for 3 or more days, reprime with 2 sprays or until a fine mist appears. Avoid spraying azelastine HCl nasal solution (nasal spray), 0.15% into the eyes.
3 DOSAGE FORMS AND STRENGTHS
Azelastine HCl nasal solution (nasal spray), 0.15% is a nasal spray solution. Each spray of azelastine HCl nasal solution (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 azelastine HCl nasal solution (nasal spray), 0.15% [ 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 azelastine HCl nasal solution (nasal spray), 0.15%. Concurrent use of azelastine HCl nasal solution (nasal spray), 0.15% 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 azelastine HCl nasal solution (nasal spray), 0.15% has been associated with somnolence [ see Warnings and Precautions (5.1) ].
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 observed in practice.
Azelastine HCl nasal solution (nasal spray), 0.1%
The safety data described below reflect exposure to azelastine HCl nasal solution (nasal spray), 0.1% in 713 patients 12 years of age and older from 2 clinical trials of 2 weeks to 12 months duration. In a 2-week, double-blind, placebo-controlled, and active-controlled (Azelastine HCl Nasal Solution (Nasal Spray) without sweetener) clinical trial, 285 patients (115 males and 170 females) 12 years of age and older with seasonal allergic rhinitis were treated with azelastine HCl nasal solution (nasal spray), 0.1% one or two sprays per nostril daily. In the 12 month open-label, active-controlled (Azelastine HCl Nasal Solution (Nasal Spray) without sweetener) 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 azelastine HCl nasal solution (nasal spray), 0.1% two sprays per nostril twice daily. The racial and ethnic distribution for the 2 clinical trials was 82% white, 8% black, 6% Hispanic, 3% Asian, and <1% other.
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 allergic rhinitis were treated with one of six treatments: one spray per nostril of either azelastine HCl nasal solution (nasal spray), 0.1%, Azelastine HCl Nasal Solution (Nasal Spray) without sweetener or placebo twice daily; or 2 sprays per nostril of azelastine HCl nasal solution (nasal spray), 0.1%, Azelastine HCl Nasal Solution (Nasal Spray) without sweetener, or placebo twice daily. Overall, adverse reactions were more common in the azelastine HCl nasal solution (nasal spray), 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 azelastine HCl nasal solution (nasal spray), 0.1% in the controlled clinical trial described above.
Long-Term (12 Month) Safety Trial:
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 azelastine HCl nasal solution (nasal spray), 0.1% two sprays per nostril twice daily or Azelastine HCl Nasal Solution (Nasal Spray) without sweetener 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 azelastine HCl nasal solution (nasal spray), 0.1% and 17 patients (4%) treated with Azelastine HCl Nasal Solution (Nasal Spray) without sweetener discontinued from the trial due to adverse events. Azelastine HCl nasal solution (nasal spray), 0.15%
The safety data described below reflect exposure to azelastine HCl nasal solution (nasal spray), 0.15% in 1858 patients (12 years of age and older) with seasonal or perennial allergic rhinitis from 8 clinical trials of 2 weeks to 12 months duration. In 7 double-blind, placebo-controlled clinical trials of 2 to 4 weeks duration, 1544 patients (560 males and 984 females) with seasonal or perennial allergic rhinitis were treated with azelastine HCl nasal solution (nasal spray), 0.15% 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 azelastine HCl nasal solution (nasal spray), 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. The racial distribution for the 8 clinical trials was 80% white, 13% black, 2% Asian, and 5% other.
Adults and Adolescents 12 Years of Age and Older
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 azelastine HCl nasal solution (nasal spray), 0.15% or placebo once or twice daily. Overall, adverse reactions were more common in the azelastine HCl nasal solution (nasal spray), 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 2 contains adverse reactions reported with frequencies greater than or equal to 2% and more frequently than placebo in patients treated with azelastine HCl nasal solution (nasal spray), 0.15% in the seasonal and perennial allergic rhinitis controlled clinical trials.
In the above trials, somnolence was reported in <1% of patients treated with azelastine HCl nasal solution (nasal spray), 0.15% (11 of 1544) or vehicle placebo (1 of 1339).
Long-Term (12 Month) Safety Trial:
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 azelastine HCl nasal solution (nasal spray), 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 azelastine HCl nasal solution (nasal spray), 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 azelastine HCl nasal solution (nasal spray), 0.15% and 17 patients (7%) treated with mometasone nasal spray discontinued from the trial due to adverse events.
6.2 Postmarketing Experience
During the post approval use of azelastine HCL nasal solution (nasal spray), 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 included: abdominal pain, nasal burning, nausea, sweet taste, and throat irritation.
Additionally, the following adverse reactions have been identified during the post approval use of the Azelastine HCl Nasal Solution (Nasal Spray) without sweetener 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, atrial fibrillation, blurred vision, chest pain, confusion, dizziness, dyspnea, facial edema, hypertension, involuntary muscle contractions, nervousness, palpitations, paresthesia, parosmia, paroxysmal sneezing, pruritus, rash, disturbance or loss of sense of smell and/or taste, tachycardia, tolerance, urinary retention, and xerophthalmia.
7 DRUG INTERACTIONS
7.1 Central Nervous System Depressants
Concurrent use of azelastine HCl nasal solution (nasal spray), 0.15% 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 (5.1) ].
7.2 Erythromycin and Ketoconazole
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 ClinicalPharmacology (12.2) and (12.3)].
7.3 Cimetidine
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 (12.3) ].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C: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. Azelastine HCl nasal solution (nasal spray), 0.15% 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 an oral dose approximately 170 times the maximum recommended human daily intranasal dose (MRHDID) in adults on a mg/m2 basis. This dose also caused maternal toxicity as evidenced by decreased body weight. Neither fetal nor maternal effects occurred at a dose that was approximately 7 times the MRHDID.
In rats, azelastine hydrochloride caused malformations (oligo- and brachydactylia), delayed ossification and skeletal variations, in the absence of maternal toxicity, at an oral dose approximately 150 times the MRHDID in adults on a mg/m2 basis. At a dose approximately 340 times the MRHDID, azelastine hydrochloride also caused embryo-fetal death and decreased fetal weight; however, this dose caused severe maternal toxicity. Neither fetal nor maternal effects occurred at a dose approximately 15 times the MRHDID.
In rabbits, azelastine hydrochloride caused abortion, delayed ossification and decreased fetal weight at oral doses approximately 300 times the MRHDID in adults on a mg/m2 basis; however, these doses also resulted in severe maternal toxicity. Neither fetal nor maternal effects occurred at a dose approximately 3 times the MRHDID.
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 azelastine HCl nasal solution (nasal spray), 0.15% is administered to a nursing woman.
8.4 Pediatric Use
Safety and effectiveness of azelastine HCl nasal solution (nasal spray), 0.15% in pediatric patients below the age of 12 years have not been established.
8.5 Geriatric Use
Clinical trials of azelastine HCl nasal solution (nasal spray), 0.15% 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.
10 OVERDOSAGE
There have been no reported overdosages with azelastine HCl nasal solution (nasal spray), 0.15%. 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 azelastine HCl nasal solution (nasal spray), 0.1% contains up to 30 mg of azelastine hydrochloride and one 30-mL bottle of azelastine HCl nasal solution (nasal spray), 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 azelastine HCl nasal solution (nasal spray), 0.15%. Oral ingestion of antihistamines has the potential to cause serious adverse effects in children. Accordingly, azelastine HCl nasal solution (nasal spray), 0.15% should be kept out of the reach of children. Oral doses of 120 mg/kg and greater (approximately 300 times the maximum recommended human daily intranasal dose [MRHDID] in adults and children on a mg/m2 basis) were lethal in mice. Responses seen prior to death were tremor, convulsions, decreased muscle tone, and salivation. In dogs, single oral doses as high as 10 mg/kg (approximately 160 times the MRHDID in adults and children on a mg/m2 basis) were well tolerated, but single oral doses of 20 mg/kg were lethal.
11 DESCRIPTION
Azelastine HCl nasal solution (nasal spray), 0.15%, 205.5 micrograms (mcg), 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 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:
Azelastine HCl nasal solution (nasal spray), 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 (2.3) ], 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.
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. Azelastine HCl nasal solution (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, desmethylazelastine, also possesses H1 -receptor antagonist activity.
12.2 Pharmacodynamics
Cardiac Effects:
In a placebo-controlled trial (95 patients with allergic rhinitis), there was no evidence of an effect of azelastine HCl nasal solution (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 (7.2) ].
12.3 Pharmacokinetics
Absorption: After intranasal administration of 2 sprays per nostril (548 mcg total dose) of azelastine HCl nasal solution (nasal spray), 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 azelastine HCl nasal solution (nasal spray), 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.
Distribution: 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.
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 a single-dose, intranasal administration of azelastine HCl nasal solution (nasal spray), 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 azelastine HCl nasal solution (nasal spray), 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.
Elimination: Following intranasal administration of azelastine HCl nasal solution (nasal spray), 0.1%, the elimination half-life of azelastine is 22 hours while that of desmethylazelastine is 52 hours. Following intranasal administration of azelastine HCl nasal solution (nasal spray), 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. 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 healthy subjects. Time to maximum concentration was unchanged.
Age: Following oral administration, pharmacokinetic parameters were not influenced by age.
Gender: Following oral administration, pharmacokinetic parameters were not influenced by gender.
Race: The effect of race has not been evaluated.
Drug-Drug Interactions:
Erythromycin: 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 (7.2) ].
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%. 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 (7.3) ].
Theophylline: 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.
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.
13.2 Animal Toxicology and/or Pharmacology
Reproductive Toxicology Studies
Azelastine hydrochloride has been shown to cause developmental toxicity. Treatment of mice with an oral dose of 68.6 mg/kg (approximately 170 times the maximum recommended human daily intranasal dose [MRHDID] on a mg/m2 basis) caused embryo-fetal death, malformations (cleft palate; short or absent tail; fused, absent or branched ribs), delayed ossification, and decreased fetal weight. This dose also caused 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 basis).
In rats, an oral dose of 30 mg/kg (approximately 150 times the MRHDID on a mg/m2 basis) caused malformations (oligo-and brachydactylia), delayed ossification and 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 death and decreased fetal weight; however, the 68.6 mg/kg dose caused severe maternal toxicity. Neither fetal nor maternal effects occurred at a dose of 3 mg/kg (approximately 15 times the MRHDID on a mg/m2 basis).
In rabbits, oral doses of 30 mg/kg and greater (approximately 300 times the MRHDID on a mg/m2 basis) caused abortion, delayed ossification and decreased fetal weight; however, these doses also resulted in severe maternal toxicity. Neither fetal nor maternal effects occurred at a dose of 0.3 mg/kg (approximately 3 times the MRHDID on a mg/m2 basis).
14 CLINICAL STUDIES
14.1 Seasonal Allergic Rhinitis
Azelastine HCl nasal solution (nasal spray), 0.1%
The efficacy and safety of azelastine HCl nasal solution (nasal spray), 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 azelastine HCl nasal solution (nasal spray), 0.1%, Azelastine HCl Nasal Solution (Nasal Spray) without sweetener or vehicle placebo twice daily; or 2 sprays per nostril of azelastine HCl nasal solution (nasal spray), 0.1%, Azelastine HCl Nasal Solution (Nasal Spray) without sweetener 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, azelastine HCl nasal solution (nasal spray), 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 3 (Trial 1).
The efficacy of azelastine HCl nasal solution (nasal spray), 0.1% one spray per nostril twice daily for seasonal allergic rhinitis is supported by two, 2-week, placebo-controlled clinical trials with Azelastine HCl Nasal Solution (Nasal Spray) without sweetener in 413 patients with seasonal allergic rhinitis. In these trials, efficacy was assessed using the TNSS (described above). Azelastine HCl Nasal Solution (Nasal Spray) without sweetener demonstrated a greater decrease from baseline in the summed AM and PM rTNSS compared with placebo and the difference was statistically significant.
Azelastine HCl nasal solution (nasal spray), 0.15%
The efficacy and safety of azelastine HCl nasal solution (nasal spray), 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 azelastine HCl nasal solution (nasal spray), 0.15% dosed at 2 sprays twice daily. The first trial (Trial 2) compared the efficacy of azelastine HCl nasal solution (nasal spray), 0.15% and Azelastine HCl Nasal Solution (Nasal Spray) without sweetener to vehicle placebo. The other trial (Trial 3) compared the efficacy of azelastine HCl nasal solution (nasal spray), 0.15% and azelastine HCl nasal solution (nasal spray), 0.1% to vehicle placebo. In these two trials, azelastine HCl nasal solution (nasal spray), 0.15% demonstrated greater decreases in rTNSS than placebo and the differences were statistically significant (Table 3).
Three 2-week seasonal allergic rhinitis trials evaluated the efficacy of azelastine HCl nasal solution (nasal spray), 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 3). Trial 5 and Trial 6 were conducted in patients with Texas mountain cedar allergy. In Trial 5 and Trial 6, azelastine HCl nasal solution (nasal spray), 0.15% demonstrated a greater decrease in rTNSS than placebo and the differences were statistically significant (Trials 5 and 6; Table 3). Instantaneous TNSS results for the once daily dosing regimen of azelastine HCl nasal solution (nasal spray), 0.15% are shown in Table 4. In Trials 5 and 6, azelastine HCl nasal solution (nasal spray), 0.15% demonstrated a greater decrease in iTNSS than placebo and the differences were statistically significant.
Azelastine HCl nasal solution (nasal spray), 0.15% at a dose of 1 spray twice daily was not studied. The azelastine HCl nasal solution (nasal spray), 0.15% 1 spray twice daily dosing regimen is supported by previous findings of efficacy for Azelastine HCl Nasal Solution (Nasal Spray) without sweetener and a favorable comparison of azelastine HCl nasal solution (nasal spray), 0.15% to Azelastine HCl Nasal Solution (Nasal Spray) without sweetener and azelastine HCl nasal solution (nasal spray), 0.1% (Table 3).
14.2 Perennial Allergic Rhinitis
Azelastine HCl nasal solution (nasal spray), 0.15%
The efficacy and safety of azelastine HCl nasal solution (nasal spray), 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 azelastine HCl nasal solution (nasal spray), 0.15%, azelastine HCl nasal solution (nasal spray), 0.1%, and vehicle placebo dosed at 2 sprays per nostril twice daily. In this trial, azelastine HCl nasal solution (nasal spray), 0.15% demonstrated a greater decrease in rTNSS than placebo and the difference was statistically significant (Table 5).
16 HOW SUPPLIED/STORAGE AND HANDLING
Azelastine HCl nasal solution (nasal spray), 0.15% is supplied as a 30 mL package (NDC 45802-026-83) 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 violet safety clip and a violet 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 andAdministration (2.3) ], 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. Azelastine HCl nasal solution (nasal spray), 0.15% should not be used after the expiration date “EXP” printed on the medicine label and carton.
Storage:
Store upright at controlled room temperature 20° - 25°C (68° - 77°F). Protect from freezing.
17 PATIENT COUNSELING INFORMATION
[See FDA-Approved Patient Labeling]
Patients should be instructed to use azelastine HCl nasal solution (nasal spray) only as prescribed. For the proper use of the nasal spray and to attain maximum improvement, the patient should read and follow carefully the accompanying FDA-Approved Patient Labeling.
17.1 Activities Requiring Mental Alertness
Somnolence has been reported in some patients taking azelastine HCl nasal solution (nasal spray). Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness and motor coordination such as driving or operating machinery after administration of azelastine HCl nasal solution (nasal spray) [ see Warnings and Precautions (5.1) ].
17.2 Concurrent Use of Alcohol and other Central Nervous System Depressants
Concurrent use of azelastine HCl nasal solution (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 Warnings andPrecautions (5.1) ].
17.3 Common Side Effects
Patients should be informed that the treatment with azelastine HCl nasal solution (nasal spray) may lead to adverse reactions, which include bitter taste, nasal discomfort, epistaxis, headache, fatigue, somnolence, and sneezing [ see Adverse Reactions (6.1) ].
17.4 Priming
Patients should be instructed to prime the pump before initial use and when azelastine HCl nasal solution (nasal spray) has not been used for 3 or more days [ see Dosage and Administration (2.3) ].
17.5 Keep Spray Out of Eyes
Patients should be instructed to avoid spraying azelastine HCl nasal solution (nasal spray) into their eyes.
17.6 Keep Out of Children’s Reach
Patients should be instructed to keep azelastine HCl nasal solution (nasal spray) out of the reach of children. If a child accidentally ingests azelastine HCl nasal solution (nasal spray), seek medical help or call a poison control center immediately.
Made in Israel
Manufactured by Perrigo
Yeruham 80500, Israel
Rev 07/12
9H400RCJ1
PATIENT INFORMATION
Azelastine HCl nasal solution (nasal spray), 0.15%
Important: For use in your nose only
Read this information carefully before you start using azelastine HCl nasal solution (nasal spray) and each time you get a refill. There may be new information. This leaflet does not take the place of talking to your healthcare provider about your medical condition or your treatment.
What is azelastine HCl nasal solution (nasal spray)?
• Azelastine HCl nasal solution (nasal spray) is a prescription medicine used to relieve symptoms of seasonal allergies in people age 12 and older.
• Azelastine HCl nasal solution (nasal spray) is also used to relieve symptoms of year-round allergies in people age 12 and older.
• Azelastine HCl nasal solution (nasal spray) contains an antihistamine that may help reduce the nasal symptoms of rhinitis (inflammation of the lining of the nose): stuffy nose, runny nose, itching and sneezing.
It is not known if azelastine HCl nasal solution (nasal spray) works and is safe or effective in children younger than age 12.
What should I tell my healthcare provider before using azelastine HCl nasal solution (nasal spray)?
Before using azelastine HCl nasal solution (nasal spray) tell your healthcare provider about all your medical conditions, including if you are:
• allergic to any of the ingredients in azelastine HCl nasal solution (nasal spray). See the end of this leaflet for a complete list of ingredients in azelastine HCl nasal solution (nasal spray).
• pregnant, think you may be pregnant, or planning to become pregnant. It is not known if azelastine HCl nasal solution (nasal spray) will harm your unborn baby.
• breastfeeding. It is not known if azelastine HCl nasal solution (nasal spray) passes into your breast milk.
Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal products. Azelastine HCl nasal solution (nasal spray) and other medicines may affect each other, causing side effects.
Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider when you get a new medicine.
How should I use azelastine HCl nasal solution (nasal spray)?
• Azelastine HCl nasal solution (nasal spray) is to be sprayed in your nose only.
Do not spray it into your eyes or mouth.
• Use azelastine HCl nasal solution (nasal spray) exactly as your healthcare provider tells you. Do not use more than your healthcare provider tells you.
• Read the Patient Instructions for Use at the end of this leaflet for detailed instructions about how to use azelastine HCl nasal solution (nasal spray).
• Before you use azelastine HCl nasal solution (nasal spray) for the first time, you will need to prime the bottle. See priming instructions at the end of this leaflet in the detailed Patient Instructions for Use.
• Do not use azelastine HCl nasal solution (nasal spray) unless you see a fine mist after you do the priming sprays.
• Throw away your azelastine HCl nasal solution (nasal spray) bottle after using 200 sprays. Even though the bottle may not be completely empty, you may not get the correct dose of medicine.
• If a child accidentally swallows azelastine HCl nasal solution (nasal spray), get medical help or call a poison control center right away.
What should I avoid while using azelastine HCl nasal solution
(nasal spray)?
Azelastine HCl nasal solution (nasal spray) can cause sleepiness:
• Do not drive a car, operate machinery or do dangerous activities after you use azelastine HCl nasal solution (nasal spray).
• Avoid drinking alcohol or taking other medicines that may cause you to feel sleepy while using azelastine HCl nasal solution (nasal spray).
What are the possible side effects of azelastine HCl nasal solution
(nasal spray)?
Side effects of azelastine HCl nasal solution (nasal spray) include:
• unusual taste (bitter or sweet)
• nose pain or discomfort
• nosebleeds
• headache
• fatigue
• sleepiness
• sneezing
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 azelastine HCl nasal solution (nasal spray). 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 azelastine HCl nasal solution (nasal spray)?
• Keep azelastine HCl nasal solution (nasal spray) upright at 68° to 77°F (20° to 25°C).
• Do not freeze azelastine HCl nasal solution (nasal spray).
• Do not use azelastine HCl nasal solution (nasal spray) after the expiration date “EXP” on the medicine label and box.
Keep azelastine HCl nasal solution (nasal spray) and all medicines out of reach of children.
General information about azelastine HCl nasal solution (nasal spray). Medicines are sometimes prescribed for conditions other than those mentionedin patient information leaflets. Do not use azelastine HCl nasal solution (nasalspray) for a condition for which it was not prescribed. Do not give azelastine HCl nasal solution (nasal spray) to other people, even if they have the samesymptoms that you have. It may harm them.
This patient information leaflet summarizes the most important information about azelastine HCl nasal solution (nasal spray). If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about azelastine HCl nasal solution (nasal spray) that is written for health professionals.
What are the ingredients in azelastine HCl nasal solution (nasal spray)?
Active ingredient: azelastine hydrochloride
Inactive ingredients: sorbitol, sucralose, hypromellose, sodium citrate, edetate disodium, benzalkonium chloride, and purified water.
Made in Israel
Manufactured by Perrigo
Yeruham 80500, Israel
Rev. 07/12
Patient Instructions for Use
For use in your nose only
It is important that you read and follow these Patient Instructions for Use carefully to be sure you use azelastine HCl nasal solution (nasal spray) the right way.
For the correct dose of medicine:
Made in Israel
Manufactured by Perrigo
Yeruham 80500, Israel
Rev. 07/12
PACKAGE/LABEL PRINCIPAL DISPLAY PANEL - CARTON
Azelastine HCl Nasal Solution (Nasal Spray), 0.15%
205.5 mcg per spray
FOR INTRANASAL USE ONLY
DO NOT SPRAY IN EYES
PACKAGE/LABEL PRINCIPAL DISPLAY PANEL - LABEL
Azelastine HCl Nasal Solution (Nasal Spray), 0.15%
205.5 mcg per spray
200 Metered Sprays
FOR INTRANASAL USE ONLY
DO NOT SPRAY IN EYES
Each spray delivers 0.137 mL (205.5 mcg azelastine hydrochloride).
azelastine hcl nasalAzelastine HCl SPRAY
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