Azelastine Hcl Nasal (Page 3 of 6)

11 DESCRIPTION

Azelastine HCl nasal spray, 0.15% is an antihistamine (H1 receptor antagonist) formulated as a metered-spray solution for intranasal administration.

Azelastine hydrochloride, USP occurs as a white, almost odorless, crystalline powder with a bitter taste. It has a molecular weight of 418.37. It is sparingly soluble in water, methanol, and propylene glycol and slightly soluble in ethanol, octanol, and glycerine. It has a melting point of about 225°C and the pH of a saturated solution is between 5.0 and 5.4. Its chemical name is (±)-1-(2H)-phthalazinone,4-[(4-chlorophenyl) methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-, monohydrochloride.

Its molecular formula is C22 H24 ClN3 O•HCl with the following chemical structure:

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Azelastine HCl nasal spray, 0.15% contains 0.15% azelastine hydrochloride, USP in an isotonic aqueous solution containing sorbitol, sucralose, hypromellose, sodium citrate, edetate disodium, benzalkonium chloride (125 mcg/mL), and purified water (pH 6.4).

After priming [see Dosage and Administration (2.3) ], each metered spray delivers a 0.137 mL mean volume containing 205.5 mcg of azelastine hydrochloride, USP (equivalent to 187.6 mcg of azelastine base). The 30-mL (net weight 30 gm of solution) bottle provides 200 metered sprays.

12 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 HCl nasal spray, 0.15% 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 Effects:

In a placebo-controlled trial (95 patients 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. Oral erythromycin had no effect on azelastine pharmacokinetics or QTc based on analysis of serial electrocardiograms. Ketoconazole interfered with the measurement of azelastine plasma levels; however, no effects on QTc were observed [see Drug Interactions (7.2) ].

12.3 Pharmacokinetics

Absorption:

After intranasal administration of 2 sprays per nostril (822 mcg total dose) of azelastine HCl nasal spray, 0.15%, the mean azelastine peak plasma concentration (Cmax ) is 409 pg/mL, the mean extent of systemic exposure (AUC) is 9312 pg•hr/mL and the median time to reach Cmax (tmax ) is 4 hours. The systemic bioavailability of azelastine hydrochloride is approximately 40% after intranasal administration.

Distribution:

Based on intravenous and oral administration, the steady-state volume of distribution of azelastine 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 a single-dose, intranasal administration of azelastine HCl nasal spray, 0.15% (822 mcg total dose), the mean desmethylazelastine Cmax is 38 pg/mL, the AUC is 3824 pg•hr/mL and the median tmax is 24 hours. After intranasal dosing of azelastine to steady-state, plasma concentrations of desmethylazelastine range from 20-50% of azelastine concentrations.

Elimination:

Following intranasal administration of azelastine HCl nasal spray, 0.15%, the elimination half-life of azelastine is 25 hours while that of desmethylazelastine is 57 hours. 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 70-75% higher Cmax and AUC compared to healthy 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: Co-administration of orally administered azelastine (4 mg twice daily) with erythromycin (500 mg three times daily for 7 days) resulted in Cmax 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 Cmax of 5.57 ± 2.7 ng/mL and AUC of 48.4 ± 24 ng•h/mL for azelastine [see Drug Interactions (7.2) ].

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%. Co-administration of orally administered azelastine (4 mg twice daily) with ranitidine hydrochloride (150 mg twice daily) resulted in Cmax of 8.89 ±3.28 ng/mL and AUC of 88.22 ± 40.43 ng•h/mL for azelastine, whereas, administration of azelastine alone resulted in Cmax of 7.83 ± 4.06 ng/mL and AUC of 80.09 ± 43.55 ng•h/mL for azelastine [see Drug Interactions (7.3) ].

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.

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 180 and 160 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 75 and 65 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 180 times the MRHDID in adults on a mg/m2 basis). At 68.6 mg/kg (approximately 410 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

Azelastine HCl nasal spray, 0.15%

The efficacy and safety of azelastine HCl nasal spray, 0.15% in seasonal allergic rhinitis was evaluated in five randomized, multicenter, double-blind, placebo-controlled clinical trials in 2499 adult and adolescent patients 12 years and older with symptoms of seasonal allergic rhinitis (Trials 2, 3, 4, 5, and 6). The population of the trials was 12 to 83 years of age (64% female, 36% male; 81% white, 12% black, <2% Asian, 5% other; 23% Hispanic, 77% non-Hispanic). Assessment of efficacy was based on the rTNSS, iTNSS as described above, and other supportive secondary efficacy variables. The primary efficacy endpoint was the mean change from baseline in rTNSS over 2 weeks.

Two 2-week seasonal allergic rhinitis trials evaluated the efficacy of azelastine HCl nasal spray, 0.15% dosed at 2 sprays twice daily. The first trial (Trial 2) compared the efficacy of azelastine HCl nasal spray, 0.15% and azelastine HCl nasal spray without sweetener to vehicle placebo. The other trial (Trial 3) compared the efficacy of azelastine HCl nasal spray, 0.15% and azelastine HCl nasal spray, 0.1% to vehicle placebo. In these two trials, azelastine HCl nasal spray, 0.15% demonstrated greater decreases in rTNSS than placebo and the differences were statistically significant (Table 4).

Three 2-week seasonal allergic rhinitis trials evaluated the efficacy of azelastine HCl nasal spray, 0.15% dosed at 2 sprays once daily compared to the vehicle placebo. Trial 4 demonstrated a greater decrease in rTNSS than placebo and the difference was statistically significant (Table 4). Trial 5 and Trial 6 were conducted in patients with Texas mountain cedar allergy. In Trial 5 and Trial 6, azelastine HCl nasal spray, 0.15% demonstrated a greater decrease in rTNSS than placebo and the differences were statistically significant (Trials 5 and 6; Table 4). Instantaneous TNSS results for the once daily dosing regimen of azelastine HCl nasal spray, 0.15% are shown in Table 5. In Trials 5 and 6, azelastine HCl nasal spray, 0.15% demonstrated a greater decrease in iTNSS than placebo and the differences were statistically significant.

Table 4. Mean Change from Baseline in Reflective TNSS over 2 Weeks*

in Adults and Children12 years with Seasonal Allergic Rhinitis

Treatment

(sprays per nostril)

n

Baseline

LS

Mean

Change

from

Baseline

Difference From Placebo

LS

Mean

95% CI

P

value

Trial 2

Two sprays twice daily

Azelastine HCl nasal spray, 0.15%

153

18.2

-4.3

-1.2

-2.1, -0.3

0.01

Azelastine HCl nasal spray without sweetener

153

17.9

-3.9

-0.9

-1.8, 0.1

0.07

Vehicle Placebo

153

18.1

-3.0

Trial 3

Two sprays twice daily

Azelastine HCl nasal spray, 0.15%

177

17.7

-5.1

-3.0

-3.9, -2.1

<0.001

Azelastine HCl nasal spray, 0.1%

169

18.2

-4.2

-2.1

-3.0, -1.2

<0.001

Vehicle Placebo

177

17.7

-2.1

Trial 4

Two sprays once daily

Azelastine HCl nasal spray, 0.15%

238

17.4

-3.4

-1.0

-1.7, -0.3

0.008

Vehicle Placebo

242

17.4

-2.4

Trial 5

Two sprays once daily

Azelastine HCl nasal spray, 0.15%

266

18.5

-3.3

-1.4

-2.1, -0.8

<0.001

Vehicle Placebo

266

18.0

-1.9

Trial 6

Two sprays once daily

Azelastine HCl nasal spray, 0.15%

251

18.5

-3.4

-1.4

-2.1, -0.7

<0.001

Vehicle Placebo

254

18.8

-2.0

*Sum of AM and PM rTNSS for each day (Maximum score=24) and averaged over the 14 day treatment period

Table 5. Mean Change from Baseline AM Instantaneous TNSS over 2 Weeks*

in Adults and Children12 years with Seasonal Allergic Rhinitis

Treatment

(sprays per nostril once daily)

n

Baseline

LS

Mean

Change

from

Baseline

Difference From Placebo

LS

Mean

95% CI

P

value

Trial 4

Two sprays once daily

Azelastine HCl nasal spray, 0.15%

238

8.1

-1.3

-0.2

-0.6, 0.1

0.15

Vehicle Placebo

242

8.3

-1.1

Trial 5

Two sprays once daily

Azelastine HCl nasal spray, 0.15%

266

8.7

-1.4

-0.7

-1.0, -0.4

<0.001

Vehicle Placebo

266

8.3

-0.7

Trial 6

Two sprays once daily

Azelastine HCl nasal spray, 0.15%

251

8.9

-1.4

-0.6

-0.9, -0.3

<0.001

Vehicle Placebo

254

8.9

-0.8

*AM iTNSS for each day (Maximum score=12) and averaged over the 14 day treatment period

Azelastine HCl nasal spray, 0.15% at a dose of 1 spray twice daily was not studied. The azelastine HCl nasal spray, 0.15% 1 spray twice daily dosing regimen is supported by previous findings of efficacy for azelastine HCl nasal spray without sweetener and a favorable comparison of azelastine HCl nasal spray, 0.15% to azelastine HCl nasal spray without sweetener and azelastine HCl nasal spray, 0.1% (Table 4).

The efficacy and safety of azelastine HCl nasal spray, 0.15% in children 6 to 11 years of age with seasonal allergic rhinitis was evaluated in a clinical study that enrolled pediatric patients with perennial allergic rhinitis, with or without concomitant seasonal allergic rhinitis (described below in Section 14.2).

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