Azelastine

INDICATIONS AND USAGE Azelastine hydrochloride nasal solution (nasal spray), 0.1% (137 mcg per spray) 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. Azelastine hydrochloride nasal solution (nasal spray) is an H 1 -receptor antagonist 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. ( 1 )

DOSAGE AND ADMINISTRATION For intranasal use only ( 2.3 ) Seasonal allergic rhinitis: Pediatric patients 5 to 11 years of age: 1 spray per nostril twice daily ( 2.1 ) Adults and adolescents 12 years of age and older: 1 or 2 sprays per nostril twice daily ( 2.1 ) Vasomotor rhinitis: 2 sprays per nostril twice daily in adults and adolescents 12 years of age and older ( 2.2 ) Prime azelastine hydrochloride nasal solution before initial use and when it has not been used for 3 or more days ( 2.3 ) 2.1 Seasonal Allergic Rhinitis The recommended dosage of azelastine hydrochloride nasal solution 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 hydrochloride nasal solution 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 hydrochloride nasal solution 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 hydrochloride nasal solution by the intranasal route only. Priming: Prime azelastine hydrochloride nasal solution before initial use by releasing 4 sprays or until a fine mist appears. When azelastine hydrochloride nasal solution has not been used for 3 or more days, reprime with 2 sprays or until a fine mist appears. Avoid spraying azelastine hydrochloride nasal solution into the eyes.

WARNINGS AND PRECAUTIONS • Somnolence: Avoid engaging in hazardous occupations requiring complete mental alertness such as driving or operating machinery when taking azelastine hydrochloride and fluticasone propionate nasal spray. ( 5.1 ) • Avoid concurrent use of alcohol or other central nervous system (CNS) depressants with azelastine hydrochloride and fluticasone propionate nasal spray because further decreased alertness and impairment of CNS performance may occur. ( 5.1 ) • Epistaxis, nasal ulcerations, nasal septal perforation, impaired wound healing, Candida albicans infection: Monitor patients periodically for signs of adverse effects on the nasal mucosa. Avoid use in patients with recent nasal ulcers, nasal surgery, or nasal trauma. ( 5.2 ) • Glaucoma or posterior subcapsular cataracts: Monitor patients closely with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts. ( 5.3 ) • Potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. More serious or even fatal course of chickenpox or measles in susceptible patients. Use caution in patients with the above because of the potential for worsening of these infections. ( 5.4 ) • Hypercorticism and adrenal suppression with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue azelastine hydrochloride and fluticasone propionate nasal spray slowly. ( 5.5 ) • Potential reduction in growth velocity in children. Monitor growth routinely in pediatric patients receiving azelastine hydrochloride and fluticasone propionate nasal spray. ( 5.7 , 8.4 ) 5.1 Somnolence In clinical trials, the occurrence of somnolence has been reported in some patients (6 of 853 adult and adolescent patients and 2 of 416 children) taking azelastine hydrochloride and fluticasone propionate nasal spray in placebo controlled trials [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 and fluticasone propionate nasal spray. Concurrent use of azelastine hydrochloride and fluticasone propionate 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 Drug Interactions ( 7.1 )]. 5.2 Local Nasal Effects In clinical trials of 2 to 52 weeks’ duration, epistaxis was observed more frequently in patients treated with azelastine hydrochloride and fluticasone propionate nasal spray than those who received placebo [see Adverse Reactions ( 6 )] . Instances of nasal ulceration and nasal septal perforation have been reported in patients following the nasal application of corticosteroids. There were no instances of nasal ulceration or nasal septal perforation observed in clinical trials with azelastine hydrochloride and fluticasone propionate nasal spray. Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal ulcers, nasal surgery, or nasal trauma should avoid use of azelastine hydrochloride and fluticasone propionate nasal spray until healing has occurred. In clinical trials with fluticasone propionate administered nasally, the development of localized infections of the nose and pharynx with Candida albicans has occurred. When such an infection develops, it may require treatment with appropriate local therapy and discontinuation of treatment with azelastine hydrochloride and fluticasone propionate nasal spray. Patients using azelastine hydrochloride and fluticasone propionate nasal spray over several months or longer should be examined periodically for evidence of Candida infection or other signs of adverse effects on the nasal mucosa. 5.3 Glaucoma and Cataracts Nasal and inhaled corticosteroids may result in the development of glaucoma and/or cataracts. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts. Glaucoma and cataract formation were evaluated with intraocular pressure measurements and slit lamp examinations in a controlled 12-month study in 612 adolescent and adult patients aged 12 years and older with perennial allergic or vasomotor rhinitis (VMR). Of the 612 patients enrolled in the study, 405 were randomized to receive azelastine hydrochloride and fluticasone propionate nasal spray (1 spray per nostril twice daily) and 207 were randomized to receive fluticasone propionate nasal spray (2 sprays per nostril once daily). In the azelastine hydrochloride and fluticasone propionate nasal spray group, one patient had increased intraocular pressure at month 6. In addition, three patients had evidence of posterior subcapsular cataract at month 6 and one at month 12 (end of treatment). In the fluticasone propionate group, three patients had evidence of posterior subcapsular cataract at month 12 (end of treatment). 5.4 Immunosuppression and Risk of Infections Persons who are using drugs, such as corticosteroids, that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective Prescribing Information for VZIG and IG) If chickenpox develops, treatment with antiviral agents may be considered. Corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculous infections of the respiratory tract; untreated local or systemic fungal or bacterial infections; systemic viral or parasitic infections; or ocular herpes simplex because of the potential for worsening of these infections. 5.5 Hypercorticism and Adrenal Suppression When nasal steroids are used at higher than recommended dosages or in susceptible individuals at recommended dosages, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, the dosage of azelastine hydrochloride and fluticasone propionate nasal spray should be discontinued slowly, consistent with accepted procedures for discontinuing oral corticosteroid therapy. The concomitant use of nasal corticosteroids with other inhaled corticosteroids could increase the risk of signs or symptoms of hypercorticism and/or suppression of the HPA axis. The replacement of a systemic corticosteroid with a topical corticosteroid can be accompanied by signs of adrenal insufficiency, and in addition some patients may experience symptoms of withdrawal, e.g., joint and/or muscular pain, lassitude, and depression. Patients previously treated for prolonged periods with systemic corticosteroids and transferred to topical corticosteroids should be carefully monitored for acute adrenal insufficiency in response to stress. In those patients who have asthma or other clinical conditions requiring long-term systemic corticosteroid treatment, too rapid a decrease in systemic corticosteroids may cause a severe exacerbation of their symptoms. 5.6 Use of Cytochrome P450 3A4 Inhibitors Ritonavir and other strong cytochrome P450 3A4 (CYP3A4)

CONTRAINDICATIONS Azelastine hydrochloride and fluticasone propionate nasal spray is contraindicated in patients with hypersensitivity to azelastine hydrochloride, fluticasone propionate, or to any other ingredients of azelastine hydrochloride and fluticasone propionate nasal spray. Reactions have included anaphylaxis [see Adverse Reactions ( 6.2 )] . Hypersensitivity to azelastine hydrochloride, fluticasone propionate, or to any ingredients of azelastine hydrochloride and fluticasone propionate nasal spray. Reactions have included anaphylaxis. ( 4 )

DRUG INTERACTIONS No formal drug interaction studies have been performed with azelastine hydrochloride and fluticasone propionate nasal spray. The drug interactions of the combination are expected to reflect those of the individual components. • Potent inhibitors of cytochrome P450 (CYP) 3A4: May increase blood levels of fluticasone propionate. • Ritonavir: Coadministration is not recommended. ( 5.6 , 7.2 ) • Other potent CYP3A4 inhibitors, such as ketoconazole: use caution with coadministration. ( 5.6 , 7.2 ) 7.1 Central Nervous System Depressants Concurrent use of azelastine hydrochloride and fluticasone propionate nasal spray with alcohol or other central nervous system depressants should be avoided because somnolence and impairment of central nervous system performance may occur [see Warnings and Precautions ( 5.1 )] . 7.2 Cytochrome P450 3A4 Ritonavir (a strong CYP3A4 inhibitor) significantly increased plasma fluticasone propionate exposure following administration of fluticasone propionate aqueous nasal spray, resulting in significantly reduced serum cortisol concentrations [see Clinical Pharmacology ( 12.3 )] . During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression. Therefore, coadministration of fluticasone propionate and ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. Ketoconazole (also a strong CYP3A4 inhibitor), administered in multiple 200 mg doses to steady-state, increased plasma exposure of fluticasone propionate, reduced plasma cortisol AUC, but had no effect on urinary excretion of cortisol, following administration of a single 1000 mcg dose of fluticasone propionate by oral inhalation route. Caution should be exercised when azelastine hydrochloride and fluticasone propionate nasal spray is coadministered with ketoconazole and other known strong CYP3A4 inhibitors.

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 fo 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 Perrigo 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

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 hydrochloride 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 Electrophysiology In a placebo-controlled study (95 subjects 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. These drugs had no effect on QTc based on analysis of serial electrocardiograms. At a dose approximately 8 times the maximum recommended dose, azelastine hydrochloride does not prolong the QTc interval to any clinically relevant extent. 12.3 Pharmacokinetics Absorption After intranasal administration, the systemic bioavailability of azelastine hydrochloride is approximately 40%. Maximum plasma concentrations (C max ) are achieved in 2­-3 hours. Azelastine hydrochloride administered intranasally at doses above two sprays per nostril twice daily for 29 days resulted in greater than proportional increases in C max and area under the curve (AUC) for azelastine. Distribution Based on intravenous and oral administration, the steady-state volume of distribution 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 intranasal dosing of azelastine hydrochloride to steady-state, plasma concentrations of desmethylazelastine range from 20 to 50% of azelastine concentrations. Limited data indicate that the metabolite profile is similar when azelastine hydrochloride is administered via the intranasal or oral route. Elimination Based on intravenous and oral administration, the elimination half-life and plasma clearance are 22 hours and 0.5 L/h/kg, respectively. 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 C max and AUC compared to normal 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 No significant pharmacokinetic interaction was observed with the co­-administration of orally administered azelastine (4 mg twice daily) with erythromycin (500 mg three times daily for 7 days). In this study, co-administration of orally administered azelastine with erythromycin resulted in C max 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 C max of 5.57 ± 2.7 ng/mL and AUC of 48.4 ± 24 ng•h/mL for azelastine. 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%. No pharmacokinetic interaction was observed with co-administration of orally administered azelastine (4 mg twice daily) with ranitidine hydrochloride (150 mg twice daily). Oral co-administration of azelastine with ranitidine resulted in C max of 8.89 ±3.28 ng/mL and AUC of 88.22 ± 40.43 ng•h/mL for azelastine, whereas, azelastine when administered alone resulted in C max of 7.83 ± 4.06 ng/mL and AUC of 80.09 ± 43.55 ng•h/mL for azelastine. 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.