Prescription Drug Information: AZELASTINE HYDROCHLORIDE (Page 3 of 4)

13 NONCLINICAL TOXICOLOGY

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 270 and 240 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 110 and 100 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 270 times the MRHDID in adults on a mg/m2 basis). At 68.6 mg/kg (approximately 610 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.

14 CLINICAL STUDIES

14.1 Seasonal Allergic Rhinitis

Two Sprays Per Nostril Twice Daily

The efficacy and safety of Azelastine Hydrochloride Nasal Spray were evaluated in three placebo-controlled clinical trials of Azelastine Hydrochloride Nasal Spray including 322 patients with seasonal allergic rhinitis who received two sprays per nostril twice a day for up to 4 weeks. These trials included 55 pediatric patients ages 12 to 16 years. Assessment of efficacy was based on the 12-hour reflective Total Symptom Complex (TSC) and Major Symptom Complex (MSC). The MSC was calculated as the average of individual symptoms of nose blows, sneezes, runny nose/sniffles, itchy nose, and watery eyes as assessed by patients on a 0-5 categorical scale. Azelastine Hydrochloride Nasal Spray two sprays per nostril twice daily demonstrated a greater decrease in the MSC than placebo (Table 3).

Table 3: Mean Change from Baseline in Reflective MSC * in Adults and Adolescents ≥12 Years with Seasonal Allergic Rhinitis Treated with Azelastine Hydrochloride Nasal Spray Two Sprays Per Nostril Twice Daily Versus Placebo
Treatment N Baseline LS Mean
(SD)
Change from Baseline
(SD)
Treatment Difference P-value
*
Major Symptom Complex (MSC): Average of individual symptoms of nose blows, sneezes, runny nose/sniffles, itchy nose, and watery eyes as assessed by patients on a 0-5 categorical scale.
Trial 1: 12 Hour AM and PM Reflective MSC
Azelastine Hydrochloride Nasal Spray 63 11.48 (4.13) -3.05 (3.51) 1.98 <0.01
Placebo Nasal Spray 60 10.84 (4.53) -1.07 (3.52)
Trial 2: 12 Hour AM and PM Reflective MSC
Azelastine Hydrochloride Nasal Spray 63 12.50 (4.5) -4.10 (3.46) 2.03 <0.01
Placebo Nasal Spray 63 12.18 (4.64) -2.07 (4.01)
Trial 3: 12 Hour AM and PM Reflective MSC
Azelastine Hydrochloride Nasal Spray 66 12.04 (4.03) -3.31 (3.74) 1.35 0.04
Placebo Nasal Spray 66 11.66 (3.96) -1.96 (3.57)

In dose-ranging trials, administration of Azelastine Hydrochloride Nasal Spray two sprays per nostril twice daily resulted in a statistically significant decrease in symptoms compared to saline placebo within 3 hours after initial dosing and persisted over the 12-hour dosing interval.

One Spray Per Nostril Twice Daily

The efficacy and safety of Azelastine Hydrochloride Nasal Spray were evaluated in two placebo-controlled clinical trials of Azelastine Hydrochloride Nasal Spray including 275 patients with seasonal allergic rhinitis who received one spray per nostril twice a day for up to 2 weeks. Assessment of efficacy was based on the 12-hour reflective Total Nasal Symptom Score [rTNSS]. rTNSS is calculated as the sum of the patients scoring of four individual nasal symptoms (runny nose, sneezing, itchy nose, and nasal congestion) as assessed by patients on a 0-3 categorical scale. The primary efficacy endpoint was the change from Baseline to Day 14 in rTNSS. The mean change from baseline in rTNSS was greater in patients receiving Azelastine Hydrochloride Nasal Spray one spray per nostril twice daily than those receiving placebo (Table 4).

Table 4: Mean Change from Baseline in Reflective TNSS * in Adults and Adolescents ≥12 years with Seasonal Allergic Rhinitis Treated with Azelastine Hydrochloride Nasal Spray One Spray Per Nostril Twice Daily Versus Placebo
Treatment N Baseline LS Mean
(SD)
Change from Baseline
(SD)
Treatment Difference P-value
*
Total Nasal Symptom Score (TNSS): Average of individual symptoms of runny nose, sneezing, itchy nose, and nasal congestion as assessed by patients on a 0-3 categorical scale.
Trial 4: 12 Hour AM and PM Reflective TNSS
Azelastine Hydrochloride Nasal Spray 138 16.34 (4.22) -2.69 (4.79) 1.38 0.01
Placebo Nasal Spray 141 17.21 (4.32) -1.31 (4.29)
Trial 5: 12 Hour AM and PM Reflective TNSS
Azelastine Hydrochloride Nasal Spray 137 16.62 (4.20) -3.68 (4.16) 1.18 0.02
Placebo Nasal Spray 136 16.84 (4.77) -2.50 (4.01)

Two-week studies comparing the efficacy (and safety) of Azelastine Hydrochloride Nasal Spray two sprays per nostril twice daily versus one spray per nostril twice daily were not conducted.

14.2 Vasomotor Rhinitis

The efficacy and safety of Azelastine Hydrochloride Nasal Spray were evaluated in two placebo-controlled clinical trials of Azelastine Hydrochloride Nasal Spray including 216 patients with vasomotor rhinitis who received two sprays per nostril twice a day for up to 4 weeks. These patients had vasomotor rhinitis for at least one year, negative skin tests to indoor and outdoor aeroallergens, negative nasal smears for eosinophils, and negative sinus X-rays. Azelastine Hydrochloride Nasal Spray demonstrated a significantly greater decrease in a symptom complex comprised of rhinorrhea, post nasal drip, nasal congestion, and sneezing compared to placebo.

16 HOW SUPPLIED/STORAGE AND HANDLING

NDC: 63629-2057-1: 30 mL Nasal Spray 0.1% in a BOTTLE, SPRAY

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Patient Information and Instructions for Use).

Activities Requiring Mental Alertness

Somnolence 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 Depressants

Instruct patients to avoid 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 Reactions

Inform patients that the treatment with Azelastine Hydrochloride Nasal Spray may lead to adverse reactions, which include bitter taste, headache, somnolence, dysesthesia, rhinitis, nasal burning, pharyngitis, epistaxis, sinusitis, paroxysmal sneezing, nausea, dry mouth, fatigue, dizziness, and weight increase [see Adverse Reactions (6.1) ].

Priming

Instruct 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 Eyes

Instruct patients to avoid spraying Azelastine Hydrochloride Nasal Spray into their eyes.

Keep Out of Children’s Reach

Instruct 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.

Distributed by:
Breckenridge Pharmaceutical, Inc.
Berlin, CT 06037

Manufactured by:
Woodfield Pharmaceutical, LLC
Houston, TX 77099

Revised: 08/2019

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