Azelastine Hydrochloride and Fluticasone Propionate: Package Insert and Label Information

AZELASTINE HYDROCHLORIDE AND FLUTICASONE PROPIONATE- azelastine hydrochloride and fluticasone propionate spray, metered
Mylan Pharmaceuticals Inc.

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.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended dosage of azelastine hydrochloride and fluticasone propionate nasal spray is 1 spray (137 mcg of azelastine hydrochloride and 50 mcg of fluticasone propionate) in each nostril twice daily.

2.2 Important Administration Instructions

Administer azelastine hydrochloride and fluticasone propionate nasal spray by the nasal route only.
Shake the bottle gently before each use.
Avoid spraying azelastine hydrochloride and fluticasone propionate nasal spray into the eyes. If sprayed in the eyes, flush eyes with water for at least 10 minutes.

Priming

Prime azelastine hydrochloride and fluticasone propionate nasal spray before initial use by releasing 6 sprays or until a fine mist appears.

Repriming (as needed)

When azelastine hydrochloride and fluticasone propionate nasal spray has not been used for 14 or more days, reprime with 1 spray or until a fine mist appears.

3 DOSAGE FORMS AND STRENGTHS

Nasal Spray: 137 mcg of azelastine hydrochloride and 50 mcg of fluticasone propionate per spray.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

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) inhibitors can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations [see Drug Interactions (7.2) and 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 azelastine hydrochloride and fluticasone propionate nasal spray and ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.

Use caution with the coadministration of azelastine hydrochloride and fluticasone propionate nasal spray and other potent CYP3A4 inhibitors, such as ketoconazole [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].

5.7 Effect on Growth

Corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth routinely of pediatric patients receiving azelastine hydrochloride and fluticasone propionate nasal spray [see Use in Specific Populations (8.4)].

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 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)]

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
*
Safety population N = 853, intent-to-treat population N = 848
Not commercially marketed

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%)

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
*
Safety population N = 152, intent-to-treat population N = 152

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%)

In the above trial, somnolence was not reported [see Warnings and Precautions (5.1) ].

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