Get your patient on Azelastine Hydrochloride - Azelastine spray, Metered (Azelastine)

The recommended dosage of azelastine HCl nasal spray, 0.1% 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 HCl nasal spray, 0.1% in pediatric patients 5 years to 11 years of age is one spray per nostril twice daily.

The recommended dosage of azelastine HCl nasal spray, 0.1% in adults and adolescent patients 12 years and older with vasomotor rhinitis is two sprays per nostril twice daily.

Administer azelastine HCl nasal spray, 0.1% by the intranasal route only.

Priming: Prime azelastine HCl nasal spray, 0.1% before initial use by releasing 4 sprays or until a fine mist appears. When azelastine HCl nasal spray, 0.1% has not been used for 3 or more days, reprime with 2 sprays or until a fine mist appears. Avoid spraying azelastine HCl nasal spray, 0.1% into the eyes.

In clinical trials, the occurrence of somnolence has been reported in some patients taking azelastine HCl nasal spray, 0.1% [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 HCl nasal spray, 0.1%. Concurrent use of azelastine HCl nasal spray, 0.1% 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) ] .

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.

Seasonal Allergic Rhinitis

Azelastine HCl nasal spray, 0.1% Two Sprays Per Nostril Twice Daily

Adverse experience information for azelastine HCl nasal spray, 0.1% is derived from six placebo- and active-controlled, 2-day to 8-week clinical trials which included 391 patients, 12 years of age and older, with seasonal allergic rhinitis who received azelastine HCl nasal spray, 0.1% at a dose of 2 sprays per nostril twice daily. In placebo-controlled efficacy trials, the incidence of discontinuation due to adverse reactions in patients receiving azelastine HCl nasal spray, 0.1% and vehicle placebo was 2.2% and 2.8%, respectively.

Table 1 contains adverse reactions that were reported with frequencies ≥2% in the azelastine HCl nasal spray, 0.1% 2 sprays per nostril twice daily treatment group and more frequently than placebo.

Table 1: Adverse Reactions Reported in ≥2% Incidence in Placebo-Controlled Trials in Patients with Seasonal Allergic Rhinitis [n (%)]

Azelastine HCl Nasal Spray, 0.1% One Spray Per Nostril Twice Daily

Adverse experience information for azelastine HCl nasal spray, 0.1% at a dose of one spray per nostril twice daily is derived from two placebo-controlled 2-week clinical studies which included 276 patients 12 years of age and older with seasonal allergic rhinitis. The incidence of discontinuation due to adverse reactions in patients receiving azelastine HCl nasal spray, 0.1% and vehicle placebo was 0.0% and 0.8%, respectively. Bitter taste was reported in 8.3% of patients compared to none in the placebo group. Somnolence was reported in 0.4% of patients compared to none in the placebo group.

A total of 176 patients 5 to 11 years of age were exposed to azelastine HCl nasal spray, 0.1% at a dose of 1 spray each nostril twice daily in 3 placebo-controlled studies. In these studies, adverse reactions that occurred more frequently in patients treated with azelastine HCl nasal spray, 0.1% than with placebo, and that were not represented in the adult adverse reactions table above include rhinitis/cold symptoms (17.0% vs. 9.5%), cough (11.4% vs. 8.3%), conjunctivitis (5.1% vs. 1.8%), and asthma (4.5% vs. 4.1%).

Adverse Reactions <2% in azelastine HCl nasal spray, 0.1% One or Two Sprays Per Nostril Twice Daily

The following reactions were observed infrequently (<2% and exceeding placebo incidence) in patients who received azelastine HCl nasal spray, 0.1% dosed at 1 or 2 sprays per nostril twice daily in U.S. clinical trials.

Cardiovascular: flushing, hypertension, tachycardia.

Dermatological: contact dermatitis, eczema, hair and follicle infection, furunculosis, skin laceration.

Digestive: constipation, gastroenteritis, glossitis, ulcerative stomatitis, vomiting, increased SGPT, aphthous stomatitis, diarrhea, toothache.

Metabolic and Nutritional: increased appetite.

Musculoskeletal: myalgia, temporomandibular dislocation, rheumatoid arthritis.

Neurological: hyperkinesia, hypoesthesia, vertigo.

Psychological: anxiety, depersonalization, depression, nervousness, sleep disorder, thinking abnormal.

Respiratory: bronchospasm, coughing, throat burning, laryngitis, bronchitis, dry throat, nocturnal dyspnea, nasopharyngitis, nasal congestion, pharyngolaryngeal pain, sinusitis, nasal dryness, paranasal sinus hypersecretion, post nasal drip.

Special Senses: conjunctivitis, eye abnormality, eye pain, watery eyes, taste loss.

Urogenital: albuminuria, amenorrhea, breast pain, hematuria, increased urinary frequency.

Whole Body: allergic reaction, back pain, herpes simplex, viral infection, malaise, pain in extremities, abdominal pain, pyrexia.

Vasomotor Rhinitis

Adverse experience information for azelastine HCl nasal spray, 0.1% is derived from two placebo-controlled clinical studies which included 216 patients 12 years and older with vasomotor rhinitis who received azelastine HCl nasal spray, 0.1% at a dose of 2 sprays per nostril twice daily for up to 28 days. The incidence of discontinuation due to adverse reactions in patients receiving azelastine HCl nasal spray, 0.1% and vehicle placebo was 2.8% and 2.9%, respectively.

The following adverse reactions were reported with frequencies ≥ 2% in the azelastine HCl nasal spray, 0.1% treatment group and more frequently than placebo.

Table 2: Adverse Reactions Reported in ≥2% Incidence in Placebo-Controlled Trials in Patients with Vasomotor Rhinitis [n (%)]

Reactions observed infrequently (<2% and exceeding placebo incidence) in patients who received azelastine HCl nasal spray, 0.1% (2 sprays/nostril twice daily) in U.S. clinical trials in vasomotor rhinitis were similar to those observed in U.S. clinical trials in seasonal allergic rhinitis.

In controlled trials involving nasal and oral azelastine HCl formulations, there were infrequent occurrences of hepatic transaminase elevations.

During the post approval use of azelastine HCl nasal spray, 0.1%, the following adverse reactions have been identified. 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. Adverse reactions reported include: anaphylaxis, application site irritation, atrial fibrillation, chest pain, confusion, dyspnea, facial edema, involuntary muscle contractions, nasal sores, palpitations, paresthesia, parosmia, pruritus, rash, disturbance or loss of sense of smell and/or taste, tolerance, urinary retention, vision abnormal and xerophthalmia.

Concurrent use of azelastine HCl nasal spray, 0.1% with alcohol or other central nervous system depressants should be avoided because reductions in alertness and impairment of central nervous system performance may occur [see Warnings and Precautions (5.1) ] .

Azelastine HCl, a phthalazinone derivative, exhibits histamine H ₁ -receptor antagonist activity in isolated tissues, animal models, and humans. Azelastine HCl nasal spray, 0.1% 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 H ₁ -receptor antagonist activity.

Cardiac Electrophysiology:

In a placebo-controlled study (95 subjects with allergic rhinitis), there was no evidence of an effect of azelastine HCl nasal spray, 0.1% (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 HCl 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 HCl does not prolong the QTc interval to any clinically relevant extent.

Absorption: After intranasal administration, the systemic bioavailability of azelastine HCl is approximately 40%. Maximum plasma concentrations (C _max ) are achieved in 2 to 3 hours.

Azelastine HCl 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 HCl 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 HCl 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 HCl 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 HCl twice daily and theophylline 300 mg or 400 mg twice daily.

Two-year carcinogenicity studies in Crl:CD(SD)BR rats and NMRI mice were conducted to assess the carcinogenic potential of azelastine HCl. No evidence of tumorigenicity was observed in rats at doses up to 30 mg/kg (approximately 270 and 240 times the MRHDID for adults and children, respectively, on a mg/m ² 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/m ² basis).

Azelastine HCl 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/m ² basis). At 68.6 mg/kg (approximately 610 times the MRHDID on a mg/m ² 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.

Two Sprays Per Nostril Twice Daily

The efficacy and safety of azelastine HCl nasal spray, 0.1% were evaluated in three placebo-controlled clinical trials of azelastine HCl nasal spray, 0.1% 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 to 5 categorical scale. Azelastine HCl nasal spray, 0.1% 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 HCl Nasal Spray, 0.1% Two Sprays Per Nostril Twice Daily Versus Placebo

In dose-ranging trials, administration of azelastine HCl nasal spray, 0.1% 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 HCl nasal spray, 0.1% were evaluated in two placebo-controlled clinical trials of azelastine HCl nasal spray, 0.1% 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 to 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 HCl nasal spray, 0.1% 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 HCl Nasal Spray, 0.1% One Spray Per Nostril Twice Daily Versus Placebo

Two-week studies comparing the efficacy (and safety) of azelastine HCl nasal spray, 0.1% two sprays per nostril twice daily versus one spray per nostril twice daily were not conducted.

The efficacy and safety of azelastine HCl nasal spray, 0.1% were evaluated in two placebo-controlled clinical trials of azelastine HCl nasal spray, 0.1% 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 HCl nasal spray, 0.1% demonstrated a significantly greater decrease in a symptom complex comprised of rhinorrhea, post nasal drip, nasal congestion, and sneezing compared to placebo.