1 INDICATIONS AND USAGE Azelastine hydrochloride and fluticasone propionate nasal spray is indicated for the relief of symptoms of seasonal allergic rhinitis in adult and pediatric patients 6 years of age and older.

Azelastine hydrochloride and fluticasone propionate nasal spray contains an H 1 -receptor antagonist and a corticosteroid, and is indicated for the relief of symptoms of seasonal allergic rhinitis in adult and pediatric patients 6 years of age and older.

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6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Somnolence [see Warnings and Precautions ( 5.1 )] • Local nasal effects, including epistaxis, nasal ulceration, nasal septal perforation, impaired wound healing, and Candida albicans infection [see Warnings and Precautions ( 5.2 )] • Glaucoma and Cataracts [see Warnings and Precautions ( 5.3 )] • Immunosuppression and Risk of Infections [see Warnings and Precautions ( 5.4 )] • Hypercorticism and Adrenal Suppression, including growth reduction [see Warnings and Precautions ( 5.5 and 5.7 ), Use in Specific Populations ( 8.4 )] The most common adverse reactions (≥2% incidence) are: dysgeusia, epistaxis, and headache.

(6.1) To report SUSPECTED ADVERSE REACTIONS, contact Padagis ® at 1-866-634-9120 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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.

Adults and Adolescents 12 Years of Age and Older The safety data described below in adults and adolescents 12 years of age and older reflect exposure to azelastine hydrochloride and fluticasone propionate nasal spray in 853 patients (12 years of age and older; 36% male and 64% female) with seasonal allergic rhinitis in 3 double-blind, placebo-controlled clinical trials of 2-week duration.

The racial distribution for the 3 clinical trials was 80% white, 16% black, 2% Asian, and 1% other.

In the 3 placebo controlled clinical trials of 2-week duration, 3411 patients with seasonal allergic rhinitis were treated with 1 spray per nostril of azelastine hydrochloride and fluticasone propionate nasal spray, azelastine hydrochloride nasal spray, fluticasone propionate nasal spray, or placebo, twice daily.

The azelastine hydrochloride and fluticasone propionate comparators use the same vehicle and device as azelastine hydrochloride and fluticasone propionate nasal spray and are not commercially marketed.

Overall, adverse reactions were 16% in the azelastine hydrochloride and fluticasone propionate nasal spray treatment groups, 15% in the azelastine hydrochloride nasal spray groups, 13% in the fluticasone propionate nasal spray groups, and 12% in the placebo groups.

Overall, 1% of patients in both the azelastine hydrochloride and fluticasone propionate nasal spray and placebo groups discontinued due to adverse reactions.

Table 1 contains adverse reactions reported with frequencies greater than or equal to 2% and more frequently than placebo in patients treated with azelastine hydrochloride and fluticasone propionate nasal spray in the seasonal allergic rhinitis controlled clinical trials.

Table 1.

Adverse Reactions with ≥2% Incidence and More Frequently than Placebo in Placebo-Controlled Trials of 2 Weeks Duration with Azelastine Hydrochloride and Fluticasone Propionate Nasal Spray in Adult and Adolescent Patients with Seasonal Allergic Rhinitis 1 spray per nostril twice daily Azelastine Hydrochloride and Fluticasone Propionate Nasal Spray (N=853)* Azelastine Hydrochloride Nasal Spray † (N=851) Fluticasone Propionate Nasal Spray † (N=846) Vehicle Placebo (N=861) Dysgeusia 30 (4%) 44 (5%) 4 (1%) 2 (<1%) Headache 18 (2%) 20 (2%) 20 (2%) 10 (1%) Epistaxis 16 (2%) 14 (2%) 14 (2%) 15 (2%) *Safety population N=853, intent-to-treat population N=848 † Not commercially marketed In the above trials, somnolence was reported in <1% of patients treated with azelastine hydrochloride and fluticasone propionate nasal spray (6 of 853) or vehicle placebo (1 of 861) [see Warnings and Precautions ( 5.1 )] .

Pediatric Patients 6-11 Years of Age The safety data described below in children 6-11 years of age reflect exposure to azelastine hydrochloride and fluticasone propionate nasal spray in 152 patients (6-11 years of age; 57% male and 43% female) with seasonal allergic rhinitis in one double-blind, placebo-controlled clinical trial of 2-week duration.

The racial distribution for the clinical trial was 69% white, 31% black, 2% Asian and 2% other.

In the placebo-controlled clinical trial of 2-week duration, patients with seasonal allergic rhinitis were treated with 1 spray per nostril of azelastine hydrochloride and fluticasone propionate nasal spray or placebo, twice daily.

Overall, adverse reactions were 16% in the azelastine hydrochloride and fluticasone propionate nasal spray treatment group, and 12% in the placebo group.

Overall, 1% of patients in both the azelastine hydrochloride and fluticasone propionate nasal spray and placebo groups discontinued due to adverse reactions.

Table 2 contains adverse reactions reported with frequencies greater than or equal to 2% and more frequently than placebo in patients treated with azelastine hydrochloride and fluticasone propionate nasal spray in the seasonal allergic rhinitis controlled clinical trial.

Table 2.

Adverse Reactions with ≥2% Incidence and More Frequently than Placebo in Placebo-Controlled Trials of 2 Weeks Duration with Azelastine Hydrochloride and Fluticasone Propionate Nasal Spray in Children 6 to 11 Years of Age with Seasonal Allergic Rhinitis 1 spray per nostril twice daily Azelastine Hydrochloride and Fluticasone Propionate Nasal Spray (N=152)* Vehicle Placebo (N=152) Dysgeusia 6 (4%) 0 (0%) Epistaxis 6 (4%) 4 (3%) *Safety population N=152, intent-to-treat population N=152 In the above trial, somnolence was not reported [see Warnings and Precautions (5.1)] .

Long-Term (12-Month) Safety Trial in Adults and Adolescents 12 Years of Age and Older In the 12-month open-label, active-controlled clinical trial, 404 Asian patients (240 males and 164 females) with perennial allergic rhinitis or vasomotor rhinitis were treated with azelastine hydrochloride and fluticasone propionate nasal spray, 1 spray per nostril twice daily.

In the 12-month, open-label, active-controlled, long-term safety trial in adults and adolescents 12 years of age and older, 404 patients with perennial allergic rhinitis or vasomotor rhinitis were treated with azelastine hydrochloride and fluticasone propionate nasal spray 1 spray per nostril twice daily and 207 patients were treated with fluticasone propionate nasal spray, 2 sprays per nostril once daily.

Overall, adverse reactions were 47% in the azelastine hydrochloride and fluticasone propionate nasal spray treatment group and 44% in the fluticasone propionate nasal spray group.

The most frequently reported adverse reactions (≥ 2%) with azelastine hydrochloride and fluticasone propionate nasal spray were headache, pyrexia, cough, nasal congestion, rhinitis, dysgeusia, viral infection, upper respiratory tract infection, pharyngitis, pain, diarrhea, and epistaxis.

In the azelastine hydrochloride and fluticasone propionate nasal spray treatment group, 7 patients (2%) had mild epistaxis and 1 patient (<1%) had moderate epistaxis.

In the fluticasone propionate nasal spray treatment group 1 patient (<1%) had mild epistaxis.

No patients had reports of severe epistaxis.

Focused nasal examinations were performed and no nasal ulcerations or septal perforations were observed.

Eleven of 404 patients (3%) treated with azelastine hydrochloride and fluticasone propionate nasal spray and 6 of 207 patients (3%) treated with fluticasone propionate nasal spray discontinued from the trial due to adverse reactions.

Long-Term (3-Month) Safety Trial in Pediatric Patients 6-11 Years of Age In the 3-month open label active-controlled clinical trial, 264 patients (60% male, 40% female) (80% white, 19% black, 4% Asian and 2% other) with allergic rhinitis were treated with azelastine hydrochloride and fluticasone propionate nasal spray, 1 spray per nostril twice daily.

In the 3-month, open label, active-controlled, safety trial in pediatric patients 6-11 years of age 264 patients (128 patients ≥6 to <9 years of age, and 136 patients ≥9 to <12 years of age) with allergic rhinitis (based on the Investigator’s assessment) were treated with azelastine hydrochloride and fluticasone propionate nasal spray, 1 spray per nostril twice daily and 89 patients (44 patients ≥6 to <9 years of age, and 45 patients ≥9 to <12 years of age) were treated with fluticasone propionate nasal spray, 1 spray per nostril twice daily.

Overall, adverse reactions were 40% in the azelastine hydrochloride and fluticasone propionate nasal spray treatment group and 36% in the fluticasone propionate nasal spray group.

The most frequently reported adverse reactions (≥2%) with azelastine hydrochloride and fluticasone propionate nasal spray were epistaxis, headache, oropharyngeal pain, vomiting, upper abdominal pain, cough, pyrexia, otitis media, upper respiratory tract infection, diarrhea, nausea, otitis externa, and urticaria.

In the azelastine hydrochloride and fluticasone propionate nasal spray treatment group 23 patients (9%) had mild epistaxis and 3 patients (1%) had moderate epistaxis.

In the fluticasone propionate nasal spray treatment group 8 patients (9%) had mild epistaxis.

No patients had reports of severe epistaxis.

Focused nasal examinations were performed and no ulcerations or septal perforations were observed.

Four of 264 patients (2%) treated with azelastine hydrochloride and fluticasone propionate nasal spray and 3 of 89 (3%) treated with fluticasone propionate nasal spray discontinued from the trial due to adverse reactions.

There were two reports of somnolence, one severe, among children taking azelastine hydrochloride and fluticasone propionate nasal spray [see Warnings and Precautions ( 5.1 )] .

6.2 Postmarketing Experience The following spontaneous adverse reactions have been reported with azelastine hydrochloride and fluticasone propionate nasal spray or one of the components (azelastine and fluticasone).

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.

Cardiac Disorders: atrial fibrillation, increased heart rate, palpitations Eye Disorder: blurred vision, cataracts, conjunctivitis, dryness and irritation, eye swelling, glaucoma, increased intraocular pressure, vision abnormal, xerophthalmia Gastrointestinal Disorders: nausea, vomiting General Disorders and Administration Site Condition: aches and pain, application site irritation, chest pain, edema of face and tongue, fatigue, tolerance Immune System Disorders: anaphylaxis Musculoskeletal and Connective Tissue Disorders: growth suppression [see Use in Specific Populations (8.4)] Nervous System Disorders: disturbance or loss of smell and/ or taste, dizziness, involuntary muscle contractions, paresthesia, parosmia Psychiatric Disorders: anxiety, confusion, nervousness Renal and Urinary Disorders: urinary retention Respiratory, Thoracic and Mediastinal Disorders: bronchospasm, cough, dysphonia, dyspnea, hoarseness, nasal septal perforation, nasal discomfort, nasal dryness, nasal sores, nasal ulcer, sore throat, throat dryness and irritation, voice changes, wheezing Skin and Subcutaneous Tissue Disorder: angioedema, erythema, face swelling, pruritus, rash, urticaria Vascular Disorder: hypertension