Azelastine Hydrochloride: Package Insert and Label Information

AZELASTINE HYDROCHLORIDE- azelastine hydrochloride spray, metered
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1 INDICATIONS AND USAGE

Azelastine hydrochloride (HCl) nasal spray, 0.1% is indicated for the treatment of the symptoms of seasonal allergic rhinitis in adults and pediatric patients 5 years and older, and for the treatment of the symptoms of vasomotor rhinitis in adults and adolescent patients 12 years and older.

2 DOSAGE AND ADMINISTRATION

2.1 Seasonal Allergic Rhinitis

The recommended dosage of azelastine HCl nasal spray, 0.1% in adults and adolescent patients 12 years and older with seasonal allergic rhinitis is one or two sprays per nostril twice daily. The recommended dosage of azelastine HCl nasal spray, 0.1% in pediatric patients 5 years to 11 years of age is one spray per nostril twice daily.

2.2 Vasomotor Rhinitis

The recommended dosage of azelastine HCl nasal spray, 0.1% in adults and adolescent patients 12 years and older with vasomotor rhinitis is two sprays per nostril twice daily.

2.3 Important Administration Instructions

Administer azelastine HCl nasal spray, 0.1% by the intranasal route only.

Priming: Prime azelastine HCl nasal spray, 0.1% before initial use by releasing 4 sprays or until a fine mist appears. When azelastine HCl nasal spray, 0.1% has not been used for 3 or more days, reprime with 2 sprays or until a fine mist appears. Avoid spraying azelastine HCl nasal spray, 0.1% into the eyes.

3 DOSAGE FORMS AND STRENGTHS

Azelastine HCl nasal spray, 0.1% is a nasal spray solution. Each spray of azelastine HCl nasal spray, 0.1% delivers a volume of 0.137 mL solution containing 137 mcg of azelastine HCl, USP.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Somnolence in Activities Requiring Mental Alertness

In clinical trials, the occurrence of somnolence has been reported in some patients taking azelastine HCl nasal spray, 0.1% [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 spray, 0.1%. Concurrent use of azelastine HCl nasal spray, 0.1% 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 spray, 0.1% 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.

Seasonal Allergic Rhinitis

Azelastine HCl nasal spray, 0.1% Two Sprays Per Nostril Twice Daily

Adverse experience information for azelastine HCl nasal spray, 0.1% is derived from six placebo- and active-controlled, 2-day to 8-week clinical trials which included 391 patients, 12 years of age and older, with seasonal allergic rhinitis who received azelastine HCl nasal spray, 0.1% at a dose of 2 sprays per nostril twice daily. In placebo-controlled efficacy trials, the incidence of discontinuation due to adverse reactions in patients receiving azelastine HCl nasal spray, 0.1% and vehicle placebo was 2.2% and 2.8%, respectively.

Table 1 contains adverse reactions that were reported with frequencies ≥2% in the azelastine HCl nasal spray, 0.1% 2 sprays per nostril twice daily treatment group and more frequently than placebo.

Table 1: Adverse Reactions Reported in ≥2% Incidence in Placebo-Controlled Trials in Patients with Seasonal Allergic Rhinitis [n (%)]

Azelastine HCl Nasal Spray, 0.1% N = 391

Vehicle Placebo N = 353

Bitter Taste

77 (19.7%)

2 (0.6%)

Headache

58 (14.8%)

45 (12.7%)

Somnolence

45 (11.5%)

19 (5.4%)

Nasal Burning

16 (4.1%)

6 (1.7%)

Pharyngitis

15 (3.8%)

10 (2.8%)

Paroxysmal Sneezing

12 (3.1%)

4 (1.1%)

Dry Mouth

11 (2.8%)

6 (1.7%)

Nausea

11 (2.8%)

4 (1.1%)

Rhinitis

9 (2.3%)

5 (1.4%)

Fatigue

9 (2.3%)

5 (1.4%)

Dizziness

8 (2.0%)

5 (1.4%)

Epistaxis

8 (2.0%)

5 (1.4%)

Weight Increase

8 (2.0%)

0 (0.0%)

Azelastine HCl Nasal Spray, 0.1% One Spray Per Nostril Twice Daily

Adverse experience information for azelastine HCl nasal spray, 0.1% at a dose of one spray per nostril twice daily is derived from two placebo-controlled 2-week clinical studies which included 276 patients 12 years of age and older with seasonal allergic rhinitis. The incidence of discontinuation due to adverse reactions in patients receiving azelastine HCl nasal spray, 0.1% and vehicle placebo was 0.0% and 0.8%, respectively. Bitter taste was reported in 8.3% of patients compared to none in the placebo group. Somnolence was reported in 0.4% of patients compared to none in the placebo group.

A total of 176 patients 5 to 11 years of age were exposed to azelastine HCl nasal spray, 0.1% at a dose of 1 spray each nostril twice daily in 3 placebo-controlled studies. In these studies, adverse reactions that occurred more frequently in patients treated with azelastine HCl nasal spray, 0.1% than with placebo, and that were not represented in the adult adverse reactions table above include rhinitis/cold symptoms (17.0% vs. 9.5%), cough (11.4% vs. 8.3%), conjunctivitis (5.1% vs. 1.8%), and asthma (4.5% vs. 4.1%).

Adverse Reactions <2% in azelastine HCl nasal spray, 0.1% One or Two Sprays Per Nostril Twice Daily

The following reactions were observed infrequently (<2% and exceeding placebo incidence) in patients who received azelastine HCl nasal spray, 0.1% dosed at 1 or 2 sprays per nostril twice daily in U.S. clinical trials.

Cardiovascular: flushing, hypertension, tachycardia.

Dermatological: contact dermatitis, eczema, hair and follicle infection, furunculosis, skin laceration.

Digestive: constipation, gastroenteritis, glossitis, ulcerative stomatitis, vomiting, increased SGPT, aphthous stomatitis, diarrhea, toothache.

Metabolic and Nutritional: increased appetite.

Musculoskeletal: myalgia, temporomandibular dislocation, rheumatoid arthritis.

Neurological: hyperkinesia, hypoesthesia, vertigo.

Psychological: anxiety, depersonalization, depression, nervousness, sleep disorder, thinking abnormal.

Respiratory: bronchospasm, coughing, throat burning, laryngitis, bronchitis, dry throat, nocturnal dyspnea, nasopharyngitis, nasal congestion, pharyngolaryngeal pain, sinusitis, nasal dryness, paranasal sinus hypersecretion, post nasal drip.

Special Senses: conjunctivitis, eye abnormality, eye pain, watery eyes, taste loss.

Urogenital: albuminuria, amenorrhea, breast pain, hematuria, increased urinary frequency.

Whole Body: allergic reaction, back pain, herpes simplex, viral infection, malaise, pain in extremities, abdominal pain, pyrexia.

Vasomotor Rhinitis

Adverse experience information for azelastine HCl nasal spray, 0.1% is derived from two placebo-controlled clinical studies which included 216 patients 12 years and older with vasomotor rhinitis who received azelastine HCl nasal spray, 0.1% at a dose of 2 sprays per nostril twice daily for up to 28 days. The incidence of discontinuation due to adverse reactions in patients receiving azelastine HCl nasal spray, 0.1% and vehicle placebo was 2.8% and 2.9%, respectively.

The following adverse reactions were reported with frequencies ≥ 2% in the azelastine HCl nasal spray, 0.1% treatment group and more frequently than placebo.

Table 2: Adverse Reactions Reported in ≥2% Incidence in Placebo-Controlled Trials in Patients with Vasomotor Rhinitis [n (%)]

Azelastine HCl Nasal Spray, 0.1% N = 216

Vehicle Placebo N = 210

Bitter Taste

42 (19.4%)

5 (2.4%)

Headache

17 (7.9%)

16 (7.6%)

Dysesthesia

17 (7.9%)

7 (3.3%)

Rhinitis

12 (5.6%)

5 (2.4%)

Epistaxis

7 (3.2%)

5 (2.4%)

Sinusitis

7 (3.2%)

4 (1.9%)

Somnolence

7 (3.2%)

2 (1.0%)

Reactions observed infrequently (<2% and exceeding placebo incidence) in patients who received azelastine HCl nasal spray, 0.1% (2 sprays/nostril twice daily) in U.S. clinical trials in vasomotor rhinitis were similar to those observed in U.S. clinical trials in seasonal allergic rhinitis.

In controlled trials involving nasal and oral azelastine HCl formulations, there were infrequent occurrences of hepatic transaminase elevations.

6.2 Postmarketing Experience

During the post approval use of azelastine HCl nasal spray, 0.1%, the following adverse reactions have been identified. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported include: anaphylaxis, application site irritation, atrial fibrillation, chest pain, confusion, dyspnea, facial edema, involuntary muscle contractions, nasal sores, palpitations, paresthesia, parosmia, pruritus, rash, disturbance or loss of sense of smell and/or taste, tolerance, urinary retention, vision abnormal and xerophthalmia.

7 DRUG INTERACTIONS

7.1 Central Nervous System Depressants

Concurrent use of azelastine HCl nasal spray, 0.1% 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)] .

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Limited data from post-marketing experience over decades of use with azelastine HCl nasal spray, 0.1% 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 5 times the clinical daily dose. Oral administration of azelastine HCl 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 270 times and higher than the maximum recommended human daily intranasal dose (MRHDID) of 1.096 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.

Data

Animal Data

In an embryo-fetal development study in mice dosed during the period of organogenesis, azelastine HCl 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 300 times the maximum recommended human daily intranasal dose (MRHDID) in adults (on a mg/m 2 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 15 times the MRHDID in adults (on a mg/m 2 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 HCl caused structural abnormalities (oligo-and brachydactylia), delayed ossification, and skeletal variations, in the absence of maternal toxicity, at approximately 270 times the MRHDID in adults (on a mg/m 2 basis at a maternal oral dose of 30 mg/kg/day). Azelastine HCl caused embryo-fetal death and decreased fetal weight and severe maternal toxicity at approximately 610 times the MRHDID (on a mg/m 2 basis at a maternal oral dose of 68.6 mg/kg/day). Neither fetal nor maternal effects occurred at approximately 20 times the MRHDID (on a mg/m 2 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 HCl caused abortion, delayed ossification and decreased fetal weight and severe maternal toxicity at approximately 530 times the MRHDID in adults (on a mg/m 2 basis at a maternal oral dose of 30 mg/kg/day). Neither fetal nor maternal effects occurred at approximately 5 times the MRHDID (on a mg/m 2 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 HCl produced no adverse developmental effects on pups at maternal doses up to approximately 270 times the MRHDID (on mg/m 2 basis at a maternal dose of 30 mg/kg/day).

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