NDC 50383-942 Azelastine Hydrochloride

Azelastine Hydrochloride

NDC Product Code 50383-942

NDC 50383-942-30

Package Description: 1 BOTTLE, PUMP in 1 CARTON > 30 mL in 1 BOTTLE, PUMP

NDC Product Information

Azelastine Hydrochloride with NDC 50383-942 is a a human prescription drug product labeled by Hi-tech Pharmacal Co., Inc.. The generic name of Azelastine Hydrochloride is azelastine hydrochloride. The product's dosage form is spray, metered and is administered via nasal form.

Labeler Name: Hi-tech Pharmacal Co., Inc.

Dosage Form: Spray, Metered - A non-pressurized dosage form consisting of valves which allow the dispensing of a specified quantity of spray upon each activation.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Azelastine Hydrochloride Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • AZELASTINE HYDROCHLORIDE 1.5 mg/mL

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • BENZALKONIUM CHLORIDE (UNII: F5UM2KM3W7)
  • EDETATE DISODIUM (UNII: 7FLD91C86K)
  • HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)
  • WATER (UNII: 059QF0KO0R)
  • TRISODIUM CITRATE DIHYDRATE (UNII: B22547B95K)
  • SORBITOL (UNII: 506T60A25R)
  • SUCRALOSE (UNII: 96K6UQ3ZD4)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Nasal - Administration to the nose; administered by way of the nose.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Histamine H1 Receptor Antagonists - [MoA] (Mechanism of Action)
  • Histamine-1 Receptor Antagonist - [EPC] (Established Pharmacologic Class)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Hi-tech Pharmacal Co., Inc.
Labeler Code: 50383
FDA Application Number: ANDA210032 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 08-27-2019 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Azelastine Hydrochloride Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1.1 Allergic Rhinitis

Azelastine hydrochloride nasal spray is indicated for the relief of the symptoms of seasonal allergic rhinitis in patients 6 years of age and older and perennial allergic rhinitis in patients 6 years of age and older.

2.1 Seasonal Allergic Rhinitis

Children 6 to 11 years of age: Azelastine hydrochloride nasal spray, 0.15%, 1 spray per nostril twice daily.Adults and adolescents 12 years of age and older: Azelastine hydrochloride nasal spray, 0.15%, 1 or 2 sprays per nostril twice daily. Azelastine hydrochloride nasal spray 0.15% may also be administered as 2 sprays per nostril once daily.

2.2 Perennial Allergic Rhinitis

Children 6 to 11 years of age: Azelastine hydrochloride nasal spray, 0.15%, 1 spray per nostril twice daily.Adults and adolescents 12 years of age and older: Azelastine hydrochloride nasal spray, 0.15%, 2 sprays per nostril twice daily.

2.3 Important Administration Instructions

Administer azelastine hydrochloride nasal spray by the intranasal route only.Priming: Prime azelastine hydrochloride nasal spray before initial use by releasing 6 sprays or until a fine mist appears. When azelastine hydrochloride nasal spray has not been used for 3 or more days, reprime with 2 sprays or until a fine mist appears.Avoid spraying azelastine hydrochloride nasal spray into the eyes.

3 Dosage Forms And Strengths

Azelastine hydrochloride is a nasal solution:Each spray of azelastine hydrochloride nasal spray, 0.15% delivers a volume of 0.137 mL solution containing 205.5 mcg of azelastine hydrochloride.

4 Contraindications

None.

5.1 Activities Requiring Mental Alertness

In clinical trials, the occurrence of somnolence has been reported in some patients taking azelastine hydrochloride [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 hydrochloride. Concurrent use of azelastine hydrochloride 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 hydrochloride 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 Hydrochloride Nasal Spray, 0.15%The safety data described below reflect exposure to azelastine hydrochloride nasal spray, 0.15% in 2114 patients (6 months of age and older) with season 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 azelastine hydrochloride 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 azelastine hydrochloride 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 azelastine hydrochloride 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 azelastine hydrochloride 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.Adults and Adolescents 12 Years of Age and OlderIn 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 hydrochloride 0.15% or placebo once or twice daily. Overall, adverse reactions were more common in the azelastine hydrochloride 0.15% treatment groups (16 to 31%) than in the placebo groups (11 to 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 azelastine hydrochloride 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 Azelastine Hydrochloride 0.15% in Adult and Adolescent Patients With Seasonal orPerennial Allergic Rhinitis2 Sprays Twice Daily2 Sprays Once DailyAzelastine Hydrochloride 0.15%(N=523)Vehicle Placebo(N=523)Azelastine Hydrochloride 0.15%(N=1021)Vehicle Placebo(N=816)Bitter Taste31 (6%)5 (1%)38 (4%)2 (<1%)Nasal Discomfort18 (3%)12 (2%)37 (4%)7 (1%)Epistaxis5 (1%)7 (1%)21 (2%)14 (2%)Sneezing9 (2%)1 (<1%)14 (1%)0 (0%)In the above trials, somnolence was reported in <1% of patients treated with azelastine hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride 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.

7.1 Central Nervous System Depressants

Concurrent use of azelastine hydrochloride 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 (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 Clinical Pharmacology (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)].

8.1 Pregnancy

Risk Summary Limited data from postmarketing experience over decades of use with azelastine hydrochloride in pregnant women have not identified any drug associated risks of miscarriage, birth defects, or other adverse maternal or fetal outcomes. In animal reproduction studies, there was no evidence of fetal harm at oral doses approximately 4 times the clinical daily dose. Oral administration of azelastine hydrochloride to pregnant mice, rats, and rabbits, during the period of organogenesis, produced developmental toxicity that included structural abnormalities, decreased embryo-fetal survival, and decreased fetal body weights at doses 180 times and higher than the maximum recommended human daily intranasal dose (MRHDID) of 1.644 mg. However, the relevance of these findings in animals to pregnant women was considered questionable based upon the high animal to human dose multiple.The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.DataAnimal DataIn an embryo-fetal development study in mice dosed during the period of organogenesis, azelastine hydrochloride caused embryo-fetal death, structural abnormalities (cleft palate; short or absent tail; fused, absent or branched ribs), delayed ossification, and decreased fetal weight at approximately 200 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 maternal body weight. Neither fetal nor maternal effects occurred in mice at approximately 9 times the MRHDID in adults (on a mg/m2 basis at a maternal oral dose of 3 mg/kg/day).In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 7 to 17, azelastine hydrochloride caused structural abnormalities (oligo-and brachydactylia), delayed ossification, and skeletal variations, in the absence of maternal toxicity, at approximately 180 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 410 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 10 times the MRHDID (on a mg/m2 basis at a maternal oral dose of 2 mg/kg/day).In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6 to 18, azelastine hydrochloride caused abortion, delayed ossification and decreased fetal weight and severe maternal toxicity at approximately 360 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 4 times the MRHDID (on a mg/m2 basis at a maternal oral dose of 0.3 mg/kg/day).In a prenatal and postnatal development study in pregnant rats dosed from late in the gestation period and through the lactation period from gestation day 17 through lactation day 21, azelastine hydrochloride produced no adverse developmental effects on pups at maternal doses up to approximately 180 times the MRHDID (on mg/m2 basis at a maternal dose of 30 mg/kg/day).

8.2 Lactation

Risk SummaryThere are no data on the presence of azelastine hydrochloride in human milk, the effects on the breastfed infant, or the effects on milk production following use of azelastine hydrochloride. Because many drugs are excreted in human milk, caution should be exercised when azelastine hydrochloride is administered to a nursing woman.The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for azelastine hydrochloride and any potential adverse effects on the breastfed infant from azelastine hydrochloride or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of azelastine hydrochloride 0.15% have been established for seasonal allergic rhinitis in pediatric patients 6 to 17 years of age and perennial allergic rhinitis in pediatric patients 6 to 17 years of age [see Clinical Studies (14)]. The safety and effectiveness of azelastine hydrochloride 0.15% in pediatric patients below 6 years of age have not been established.

8.5 Geriatric Use

Clinical trials of azelastine hydrochloride 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 hydrochloride nasal spray. 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 hydrochloride 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 hydrochloride. Oral ingestion of antihistamines has the potential to cause serious adverse effects in children. Accordingly, azelastine hydrochloride nasal spray should be kept out of the reach of children.

11 Description

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 C22H24 ClN3 O•HCl with the following chemical structure:Azelastine Hydrochloride 0.15% Nasal Spray 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.

12.1 Mechanism Of Action

Azelastine hydrochloride, a phthalazinone derivative, exhibits histamine H1-receptor antagonist activity in isolated tissues, animal models, and humans. Azelastine hydrochloride 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 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 (7.2)].

12.3 Pharmacokinetics

Absorption:After intranasal administration of 2 sprays per nostril (822 mcg total dose) of azelastine hydrochloride 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 hydrochloride 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 to 50% of azelastine concentrations.Elimination:Following intranasal administration of azelastine hydrochloride 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 to 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 co-administration of an oral 4 mg dose of azelastine hydrochloride twice daily and theophylline 300 mg or 400 mg twice daily.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Two-year carcinogenicity studies in Crl:CD(SD)BR rats and NMRI mice were conducted to assess the carcinogenic potential of azelastine hydrochloride. No evidence of tumorigenicity was observed in rats at doses up to 30 mg/kg day (approximately 180 and 160 times the MRHDID for adults and children, respectively, on a mg/m2 basis). No evidence for tumorigenicity was observed in mice at doses up to 25 mg/kg (approximately 75 and 65 times the MRHDID for adults and children, respectively, 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.There were no effects on male or female fertility and reproductive performance in male and female rats at oral doses up to 30 mg/kg (approximately 180 times the MRHDID in adults on a mg/m2 basis). At 68.6 mg/kg (approximately 410 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, preimplantation loss was not increased.

14.1 Seasonal Allergic Rhinitis

Azelastine Hydrochloride 0.15% Nasal SprayThe efficacy and safety of azelastine hydrochloride 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 hydrochloride nasal spray, 0.15% dosed at 2 sprays twice daily. The first trial (Trial 2) compared the efficacy of azelastine hydrochloride 0.15% and Astelin (azelastine hydrochloride) Nasal Spray to vehicle placebo. The other trial (Trial 3) compared the efficacy of azelastine hydrochloride 0.15% to vehicle placebo. In these two trials, azelastine hydrochloride 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 azelastine hydrochloride, 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, azelastine hydrochloride 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 azelastine hydrochloride 0.15% are shown in Table 5. In Trials 5 and 6, azelastine hydrochloride 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 RhinitisTreatment(sprays pernostril)nBaselineLS MeanChangefromBaselineDifference From PlaceboLS Mean 95% CI P valueTrial 2Two sprays twice dailyAzelastine Hydrochloride 0.15%Astelin Nasal SprayVehicle Placebo15315315318.217.918.1-4.3-3.9-3.0-1.2-0.9-2.1, -0.3-1.8, 0.10.010.07Trial 3Two sprays twice dailyAzelastine Hydrochloride 0.15%Vehicle Placebo17717717.717.7-5.1-2.1-3.0-3.9, -2.1<0.001Trial 4Two sprays once dailyAzelastine Hydrochloride 0.15%Vehicle Placebo23824217.417.4-3.4-2.4-1.0-1.7, -0.30.008Trial 5Two sprays once dailyAzelastine Hydrochloride 0.15%Vehicle Placebo26626618.518.0-3.3-1.9-1.4-2.1, -0.8<0.001Trial 6Two sprays once dailyAzelastine Hydrochloride 0.15%Vehicle Placebo25125418.518.8-3.4-2.0-1.4-2.1, -0.7<0.001*Sum of AM and PM rTNSS for each day (Maximum score=24) and averaged over the 14 day treatment periodTable 5. Mean Change from Baseline AM Instantaneous TNSS over 2 Weeks* in Adults and Children ≥ 12 years with Seasonal Allergic RhinitisTreatment(sprays per nostril once daily)nBaselineLS MeanChangefromBaselineDifference From PlaceboLS 95% CI P valueMeanTrial 4Two sprays once dailyAzelastine Hydrochloride 0.15%Vehicle Placebo2382428.18.3-1.3-1.1-0.2-0.6, 0.10.15Trial 5Two sprays once dailyAzelastine Hydrochloride 0.15%Vehicle Placebo2662668.78.3-1.4-0.7-0.7-1.0, -0.4<0.001Trial 6Two sprays once dailyAzelastine Hydrochloride 0.15%Vehicle Placebo2512548.98.9-1.4-0.8-0.6-0.9, -0.3<0.001*AM iTNSS for each day (Maximum score=12) and averaged over the 14 day treatment periodAzelastine hydrochloride 0.15% at a dose of 1 spray twice daily was not studied. The azelastine hydrochloride 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 azelastine hydrochloride 0.15% to Astelin Nasal Spray (Table 4).The efficacy and safety of azelastine hydrochloride 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).

14.2 Perennial Allergic Rhinitis

Azelastine Hydrochloride 0.15% Nasal SprayThe efficacy and safety of azelastine hydrochloride 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 hydrochloride 0.15%, and vehicle placebo dosed at 2 sprays per nostril twice daily. In this trial, azelastine hydrochloride 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 RhinitisTreatment (sprays pernostril twice daily)nBaselineLS MeanChangefromBaselineDifference From PlaceboLS 95% CI P valueMeanTwo sprays twice dailyAzelastine Hydrochloride 0.15%Vehicle Placebo19219215.814.7-4.0-3.1-0.9-1.7, -0.10.03*Sum of AM and PM rTNSS for each day (Maximum score=24) and averaged over the 28 day treatment periodThe efficacy and safety of azelastine hydrochloride 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 RhinitisTreatment (sprays per nostril twice daily)nBaselineLS MeanChange fromBaselineDifference From PlaceboLS 95% CI P valueMeanOne spray twice dailyAzelastine Hydrochloride 0.15%Vehicle Placebo15916116.616.1-3.5-1.0-1.7, -0.30.005*Sum of AM and PM rTNSS for each day (Maximum score=24) and averaged over the 28 day treatment periodThe efficacy of azelastine hydrochloride nasal spray, 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).

16 How Supplied/Storage And Handling

Azelastine Hydrochloride 0.15% Nasal Spray is supplied as a 30-mL package (NDC 50383-942-30) 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 white safety clip and a clear 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 (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 Hydrochloride Nasal Spray should not be used after the expiration date “EXP” printed on the medicine label and carton.StorageStore upright at controlled room temperature 20° to 25°C (68° to 77°F). Protect from freezing.

17 Patient Counseling Information

  • See FDA-approved patient labeling (Patient Information and Instructions for Use).Activities Requiring Mental AlertnessSomnolence has been reported in some patients taking azelastine hydrochloride nasal spray. Caution patients against engaging in hazardous occupations requiring complete mental alertness and motor coordination such as driving or operating machinery after administration of azelastine hydrochloride nasal spray [see Warnings and Precautions (5.1)].Concurrent Use of Alcohol and other Central Nervous System DepressantsAvoid concurrent use of azelastine hydrochloride nasal spray 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 (5.1)].Common Adverse ReactionsInform patients that the treatment with azelastine hydrochloride nasal spray 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 (6.1)].PrimingInstruct patients to prime the pump before initial use and when azelastine hydrochloride nasal spray has not been used for 3 or more days [see Dosage and Administration (2.3)].Keep Spray Out of EyesInstruct patients to avoid spraying azelastine hydrochloride nasal spray into their eyes.Keep Out of Children’s ReachInstruct patients to keep azelastine hydrochloride nasal spray out of the reach of children. If a child accidentally ingests azelastine hydrochloride nasal spray, seek medical help or call a poison control center immediately.Manufactured by:Hi-Tech Pharmacal Co., Inc.Amityville, NY 11701Rev.942:00 08/19PATIENT INFORMATIONAzelastine Hydrochloride Nasal Spray, 0.15%(a zel’ as teen)Important: For use in your nose only.What is Azelastine Hydrochloride Nasal Spray? •Azelastine Hydrochloride Nasal Spray is a prescription medicine used to treat symptoms of seasonal allergic rhinitis in patients 6 years of age and older and year-round allergic rhinitis in people age 6 years and older. •Azelastine Hydrochloride Nasal Spray may help to reduce your nasal symptoms including stuffy nose, runny nose, itching and sneezing.It is not known if Azelastine Hydrochloride Nasal Spray is safe and effective in children under 6 years of age.What should I tell my healthcare provider before using Azelastine Hydrochloride Nasal Spray?Before using Azelastine Hydrochloride Nasal Spray, tell your healthcare provider if you are: •allergic to any of the ingredients in Azelastine Hydrochloride Nasal Spray. See the end of this leaflet for a complete list of ingredients in Azelastine Hydrochloride Nasal Spray. •pregnant, or plan to become pregnant. •breastfeeding, or plan to breastfeed. It is not known if Azelastine Hydrochloride passes into your breast milk. You and your healthcare provider should decide if you will use Azelastine Hydrochloride Nasal Spray if you plan to breastfeed.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Azelastine Hydrochloride Nasal Spray and other medicines may affect each other, causing side effects.How should I use Azelastine Hydrochloride Nasal Spray? •Read the Instructions for Use at the end of this leaflet for information about the right way to use AzelastineHydrochloride Nasal Spray. •An adult should help a young child use Azelastine Hydrochloride Nasal Spray. •Spray Azelastine Hydrochloride Nasal Spray in your nose only. Do not spray it into your eyes or mouth. •Use Azelastine Hydrochloride Nasal Spray exactly as your healthcare provider tells you to use it. • Do not use more than your healthcare provider tells you. •Throw away your Azelastine Hydrochloride Nasal Spray, 0.15% bottle after using 200 sprays. Even though the bottle may not be completely empty, you may not get the correct dose of medicine. •If you use too much or a child accidentally swallows Azelastine Hydrochloride, call your healthcare provider or go to the nearest hospital emergency room right away.What should I avoid while using Azelastine Hydrochloride Nasal Spray?Azelastine Hydrochloride Nasal Spray can cause sleepiness: •Do not drive, operate machinery, or do other dangerous activities until you know how Azelastine Hydrochloride Nasal Spray affects you. •Do not drink alcohol or take other medicines that may cause you to feel sleepy while using Azelastine Hydrochloride Nasal Spray. It may make your sleepiness worse.What are the possible side effects of Azelastine Hydrochloride Nasal Spray?The most common side effects of Azelastine Hydrochloride Nasal Spray include: •fever •unusual taste •nose pain or discomfort •nosebleeds •headache •sneezing •fatigue • sleepiness •upper respiratory tract infections •cough •vomiting •middle ear infection •skin rash •sore throatTell 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 Hydrochloride 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 Hydrochloride Nasal Spray? •Keep Azelastine Hydrochloride Nasal Spray upright at 68°F to 77°F (20°C to 25°C). •Do not freeze Azelastine Hydrochloride Nasal Spray. •Do not use Azelastine Hydrochloride Nasal Spray after the expiration date “EXP” on the medicine label and box.Keep Azelastine Hydrochloride Nasal Spray and all medicines out of reach of children.General information about the safe and effective use of Azelastine Hydrochloride Nasal Spray.Medicines are sometimes prescribed for conditions other than those listed in a Patient Information leaflet. Do not use Azelastine Hydrochloride Nasal Spray for a condition for which it was not prescribed. Do not give Azelastine Hydrochloride Nasal Spray 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 Azelastine Hydrochloride 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 Hydrochloride Nasal Spray that is written for health professionals.For more information, call 1-800-262-9010.What are the ingredients in Azelastine Hydrochloride Nasal Spray?Active ingredient: azelastine hydrochlorideInactive ingredients: sorbitol, sucralose, hypromellose, sodium citrate, edetate disodium, benzalkonium chloride, and purified water.Manufactured by:Hi-Tech Pharmacal Co., Inc.Amityville, NY 11701Rev.942:00 08/19Instructions for UseAzelastine Hydrochloride Nasal Spray, 0.15%(a zel’ as teen)Important: For use in your nose only.For the correct dose of medicine: •Keep your head tilted downward when spraying into your nostril. •Change nostrils each time you use the spray. •Breathe gently and do not tip your head back after using the spray. This will keep the medicine from running down into your throat. You may get a bitter taste in your mouth.Figure A identifies the parts of your Azelastine Hydrochloride Nasal Spray pumpBefore you use Azelastine Hydrochloride Nasal Spray for the first time, you will need to prime the bottle.For use in young children: An adult should help a young child use Azelastine Hydrochloride Nasal Spray. (See “Using your Azelastine Hydrochloride Nasal Spray” Steps 1 through 8).Priming your Azelastine Hydrochloride Nasal SprayRemove the clear dust cover over the tip of the bottle and the white safety clip just under the “shoulders” of the bottle (SeeFigure B). •Hold the bottle upright with 2 fingers on the shoulders of the spray pump unit and put your thumb on the bottom of the bottle. Press upward with your thumb and release for the pumping action. Repeat this until you see a fine mist (See Figure C). •To get a fine mist you must pump the spray fast and use firm pressure against the bottom of the bottle. If you see a stream of liquid, the pump is not working correctly and you may have nasal discomfort. •This should happen in 6 sprays or less.Now your pump is primed and ready to use. •Do not use Azelastine Hydrochloride Nasal Spray unless you see a fine mist after you do the priming sprays. If you do not see a fine mist, clean the tip of the spray nozzle. See the “Cleaning the Spray Tip of your Azelastine Hydrochloride Nasal Spray” section below. •If you do not use Azelastine Hydrochloride Nasal Spray for 3 or more days, you will need to prime the pump with 2 sprays or until you see a fine mist.Using your Azelastine Hydrochloride Nasal SprayFor use in young children: An adult should help a young child use Azelastine Hydrochloride Nasal Spray (See Steps 1through 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).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).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 Azelastine Hydrochloride Nasal Spray. This will help to keep the medicine from going into your throat.Step 8. When you finish using your Azelastine Hydrochloride Nasal Spray, 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 Azelastine Hydrochloride Nasal Spray •If the spray tip opening is clogged, do not use a pin or pointed object to unclog the tip. Unscrew the spray pump unit from the bottle by turning it to the left (counter-clockwise) (See Figure F). •Soak only the spray pump unit in warm water. Squirt the spray unit several times while holding it under water. Use the pumping action to clear the opening in the tip (See Figure G). •Let the spray pump unit air dry. Make sure it is dry before you put it back onto the bottle. •Put the spray pump unit back into the open bottle and tighten it by turning clockwise (to the right). •To keep the medicine from leaking out, use firm pressure when you put the pump back onto the bottle. •After cleaning, follow the instructions for priming.This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration.Manufactured by:Hi-Tech Pharmacal Co., Inc.Amityville, NY 11701Rev.942:00 08/19

Package/Label Display Panel

AKORNNDC 50383-942-30Azelastine Hydrochloride Nasal Spray, 0.15%205.5 mcg per SprayFOR INTRANASAL USE ONLYDO NOT SPRAY IN EYESRx only 30 mL

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