Indications : Rhinitis, seasonal allergic Pregnancy Category C FDA Approved 1996 Oct DRUG CLASS : Antihistamines BRAND NAMES : Alastine (Korea); Allergodil (Germany, France, Russia, Belgium, Denmark, Hungary, Italy, Portugal, Austria, Switzerland, Netherlands); Astelin (US); Azeptin (Korea, Japan); Loxin (Germany); (International brand names outside U.S. in italics) DESCRIPTION : Azelastine HCl nasal spray, 137 micrograms (mug), is an antihistamine formulated as a metered spray solution for intranasal administration. Azelastine HCl 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 C22H24ClN3O·HCl. Astelin nasal spray contains 0.1% azelastine HCl in an aqueous solution at pH 6.8 ± 0.3. It also contains benzalkonium chloride (125 mug/ml), edetate disodium, hydroxypropyl methyl cellulose, citric acid, dibasic sodium phosphate, sodium chloride, and purified water. After priming, each metered spray delivers a 0.137 ml mean volume containing 137 mug of azelastine HCl (equivalent to 125 mug of azelastine base). Each bottle can deliver 100 metered sprays. CLINICAL PHARMACOLOGY : Mechanism of Action Azelastine HCl, a phthalazinone derivative, exhibits histamine Hl receptor antagonist activity in isolated tissues, animal models, and humans. Azelastine 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. Pharmacokinetics and Metabolism After intranasal administration, the systemic bioavailability of azelastine HCl is approximately 40%. Maximum plasma concentrations (Cmax) are achieved in 2-3 hours. Based on intravenous and oral administration, the elimination half-life, steady-state volume of distribution, and plasma clearance are 22 hours, 14.5 L/kg, 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. 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; however, clinical interaction studies with the known CYP3A4 inhibitor erythromycin failed to demonstrate a pharmacokinetic interaction. In a multiple-dose, steady-state drug interaction study in normal volunteers, cimetidine (400 mg twice daily), a non-specific P450 inhibitor, raised orally administered mean azelastine (4 mg twice daily) concentrations by approximately 65%. The major active metabolite, desmethylazelastine, was not measurable (below assay limits) after single-dose intranasal administration of azelastine HCl. After intranasal dosing of azelastine HCl to steady-state, plasma concentrations of desmethylazelastine range from 20-50% of azelastine concentrations. When azelastine HCl is administered orally, desmethylazelastine has an elimination half-life of 54 hours. Limited data indicate that the metabolite profile is similar when azelastine HCl is administered via the intranasal or oral route. In vitro studies with human plasma indicate that the plasma protein binding of azelastine and desmethylazelastine are approximately 88% and 97%, respectively. Azelastine HCl administered intranasally at doses above two sprays per nostril for 29 days resulted in greater than proportional increases in Cmax and area under the curve (AUC) for azelastine. Studies in healthy subjects administered oral doses of azelastine HCl demonstrated linear responses in Cmax and AUC. Special Populations Following oral administration, pharmacokinetic parameters were not influenced by age, gender, or hepatic impairment. Based on oral, single-dose studies, renal insufficiency (creatine clearance <50 ml/min) resulted in a 70-75% higher Cmax and AUC compared to normal subjects. Time to maximum concentration was unchanged. Oral azelastine has been safely administered to over 1400 asthmatic subjects, supporting the safety of administering azelastine HCl nasal spray to allergic rhinitis patients with asthma. Pharmacodynamics In a placebo-controlled study (95 subjects with allergic rhinitis), there was no evidence of an effect of azelastine 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. At higher oral exposures (4 mg twice daily), a non-clinically significant mean change on the QTc (3-7 millisecond increase) was observed. Interaction studies investigating the cardiac repolarization effects of concomitanty administered oral azelastine HCl 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). CLINICAL STUDIES : U.S. placebo-controlled clinical trials of azelastine, included 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. Azelastine significantly improved a complex of symptoms which included rhinorrhea, sneezing, and nasal pruritus. In dose-ranging trials, azelastine administration resulted in a decrease in symptoms which reached statistical significance from saline placebo within 3 hours after initial dosing and persisted over the 12-hour dosing interval. There were no findings on nasal examination in an 8-week study that suggested any adverse effect of azelastine on the nasal mucosa. INDICATIONS AND USAGE : Azelastine is indicated for the treatment of the symptoms of seasonal allergic rhinitis such as rhinorrhea, sneezing, and nasal pruritus in adults and children 12 years and older. CONTRAINDICATIONS : Azelastine is contraindicated in patients with a known hypersensitivity to azelastine HCl or any of its components. WARNINGS : Sympathomimetic amines should be used judiciously and sparingly in patients with hypertension, diabetes mellitus, ischemic heart disease, increased intraocular pressure, hyperthyroidism, renal impairment, or prostatic hypertrophy (see CONTRAINDICATIONS). Sympathomimetic amines may produce central nervous system stimulation with convulsions or cardiovascular collapse with accompanying hypotension. PRECAUTIONS : Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenicity studies in rats and mice with oral azelastine HCl for 24 months at doses up to 30 mg/kg/day and 25 mg/kg/day, respectively (240 and l00 times the maximum recommended human daily intranasal dose on a mg/m2 basis), revealed no evidence of carcinogenicity. 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. Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses of up to 30 mg/kg/day (240 times the maximum recommended human daily intranasal dose on a mg/m2 basis). At 68.6 mg/kg/day (550 times the maximum recommended human daily intranasal dose 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 the implantation ratio was not affected. Pregnancy Category C Azelastine HCl has been shown to be embryotoxic fetotoxic, and teratogenic (external and skeletal abnormalities) in mice at an oral dose of 68.6 mg/kg/day (280 times the maximum recommended human daily intranasal dose on a mg/m2 basis). At an oral dose of 30 mg/kg/day (240 times the maximum recommended human daily intranasal dose on a mg/m2 basis), delayed ossification (undeveloped metacarpus), and the incidence of 14th rib were increased in rats. At 68.6 mg/kg/day (550 times the maximum recommended human daily intranasal dose on a mg/m2 basis) azelastine HCl caused abortion and fetotoxic effects in rats. The relevance to humans of these skeletal findings noted at only high drug exposure levels is unknown. There are no adequate and well-controlled clinical studies in pregnant women. Azelastine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether azelastine HCl is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when azelastine is administered to a nursing woman. Pediatric Use Safety and efficacy of azelastine in pediatric patients below the age of 12 years have not been established. Geriatric Use U.S. placebo-controlled clinical trials included 11 patients above the age of 60 years who were treated with azelastine. While this number is very small and no substantial conclusions can be drawn, the adverse events in this group were similar to patients under age 60 years. Activities Requiring Mental Alertness In clinical trials, the occurrence of somnolence has been reported in some patients taking azelastine nasal spray: due caution should therefore be exercised when driving a car or operating potentially dangerous machinery. Concurrent use of azelastine nasal spray with alcohol or other CNS depressants should be avoided because additional reductions in alertness and additional impairment of CNS performance may occur. Information for the Patient Patients should be instructed to use azelastine only as prescribed. For the proper use of the nasal spray and to attain maximum improvement, the patient should read and follow carefully the accompanying patient instructions. Patients should be instructed to prime the delivery system before initial use and after storage for 3 or more days (see PATIENT INSTRUCTIONS FOR USE). Patients should also be instructed to store the bottle upright at room temperature with the pump tightly closed and away from children. Patients should be advised against the concurrent use of azelastine with other antihistamines without consulting a physician. Patients who are, or may become, pregnant should be told that this product should be used in pregnancy or during lactation only if the potential benefit justifies the potential risks to the fetus or nursing infant. Patients should be advised to assess their individual responses to azelastine before engaging in any activity requiring mental alertness, such as driving a car or operating machinery. Patients should be advised that the concurrent use of azelastine with alcohol or other CNS depressants may lead to additional reductions in alertness and impairment of CNS performance and should be avoided (see DRUG INTERACTIONS). DRUG INTERACTIONS : Concurrent use of azelastine with alcohol or other CNS depressants should be avoided because additional reductions in alertness and additional impairment of CNS performance may occur. Cimetidine (400 mg twice daily) increased the mean Cmax and AUC of orally administered azelastine HCl (4 mg twice daily) by approximately 65%. Ranitidine HCl (150 mg twice daily) had no effect on azelastine pharmacokinetics. Interaction studies investigating the cardiac effects, as measured by the corrected QT interval (QTc), of concomitantly administered oral azelastine HCl and erythromycin or ketoconazole were conducted. Oral erythromycin (500 mg three times daily for seven days) had no effect on azelastine pharmacokinetics or QTc based on analyses of serial electrocardiograms. Ketoconazole (200 mg twice daily for 7 days) interfered with the measurement of azelastine plasma concentrations; however, no effects on QTc were observed. No significant pharmacokinetic interaction was observed with the coadministration of an oral 4-mg dose of azelastine HCl twice daily and theophylline 300 mg or 400 mg twice daily. ADVERSE REACTIONS : Adverse experience information for azelastine is derived from six well-controlled, 2-day to 8-week clinical studies which included 391 patients who received azelastine at a dose of 2 sprays per nostril twice daily. In placebo-controlled efticacy trials, the incidence of discontinuation due to adverse reactions in patients receiving azelastine was not significantly different from vehicle placebo (2.2% vs 2.8%, respectively). In these clinical studies, adverse events that occurred statistically significantly more often in patients treated wth azelastine versus vehicle placebo included bitter taste (19.7% vs 0.6%), somnolence (11.5% vs 5.4%), weight increase (2.0% vs 0%), and myalgia (1.5% vs 0%). The adverse events listed in TABLE 1 were reported with frequencies 2% in the azelastine treatment group and more frequently than placebo in short-term (2 days) and long-term (2-8 weeks) clinical trials. TABLE 1 Adverse Event Azelastine HCl Nasal Spray (n=391) Vehicle Placebo (n=353) Bitter Taste* 19.7 0.6 Headache 14.8 12.7 Somnolence* 11.5 5.4 Nasal Burning 4.1 1.7 Pharyngitis 3.8 2.8 Dry Mouth 2.8 1.7 Paroxysmal Sneezing 3.1 1.1 Nausea 2.8 1.1 Rhinitis 2.3 1.4 Fatigue 2.3 1.4 Dizziness 2.0 1.4 Epistaxis 2.0 1.4 Weight Increase* 2.0 0.0 * P<0.05, Fisher’s Exact Test (two-tailed) The following events were observed infrequently (<2% and exceeding placebo incidence) in patients who received azelastine (2 sprays/nostril twice daily) in U. S. clinical trials: Cardiovascular : Flushing, hypertension, tachycardia. Dermatologica l: Contact dermatitis, eczema, hair and follicle infecton, furunculosis. Digestive : Constipation, gastroenteritis, glossitis, ulcerative stomatitis, vomiting, increased SGPT, aphthous stomatitis. Metabolic and Nutritional: Increased appetite. Musculoskeleta l: Myalgia, temporomandibular dislocation. Neurological : Hyperkinesia, hypoesthesia, vertigo. Psychologica : Anxiety, depersonalization, depression, nervousness, sleep disorder, thinking abnormal. Respiratory : Bronchospasm, coughing, throat burning, laryngitis. 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. In controlled trials involving nasal and oral azelastine HCl formulations, there were infrequent occurrences of hepatic transaminase elevations. The clinical relevance of these reports has not been established. OVERDOSAGE : There have been no reported overdosages with azelastine. Acute overdosage with this dosage form is unlikely to result in clinically significant adverse events, other than increased somnolence, since one bottle of azelastine contains 17 mg of azelastine HCl. Clinical studies with single doses of the oral formulation of azelastine HCl (up to 16 mg) have not resulted in increased incidence of serious adverse events. General supportive measures should be employed if overdosage occurs. Oral doses greater than 120 mg/kg (480 times the maximum recommended human daily intranasal dose on a mg/m2 basis) produced a significant mortality in mice. Responses seen prior to mortality were tremor, convulsions, decreased muscle tone, and salivation. Single doses as high as 10 mg/kg (270 times the maximum recommended human daily intranasal dose on a mg/m2 basis) were well tolerated in dogs, but single doses of 20 mg/kg were lethal. DOSAGE AND ADMINISTRATION : The recommended dose of azelastine in adults and children 12 years and older is two sprays per nostril twice daily. Before initial use, the child-resistant screw cap on the bottle should be replaced with the pump unit and the delivery system should be primed with 4 sprays or until a fine mist appears. When 3 or more days have elapsed since the last use, the pump should be reprimed with 2 sprays or until a fine mist appears. Warning : Avoid spraying in the eyes. Directions for Use : Illustrated patient instructions for proper use accompany each package of azelastine. PATIENT INFORMATION: Azelastine is used for the treatment of symptoms of seasonal allergic rhinitis. Use with caution in pregnancy and lactation. May cause drowsiness; use caurion while driving or operating hazardous machinery. Inform your physician if you are taking any other medications, including over-the-counter products. Avoid alcohol and other CNS depressants while taking azelastine. May cause bitter taste, drowsiness, weight gain, and muscle pain. Patient package insert is available with product. HOW SUPPLIED : Astelin nasal spray, 137 mug is supplied as a package containing a total of 200 metered sprays in two high-density polyethylene (HDPE) bottles fitted with child-resistant screw caps. A separate metered-dose spray pump unit and a leaflet of patient instructions are also provided. The spray pump unit is packaged in a polyethylene wrapper and consists of a nasal spray pump fitted with a blue safety clip and a blue plastic dust cover. Each Astelin nasal spray, 137 mug, bottle contains 17 mg (1 mg/ml) of azelastine HCl to be used with the supplied metered-dose spray pump unit. Each bottle can deliver 100 metered sprays. Each spray delivers a mean of 0.137 ml solution containing 137 mug of azelastine HCl. Attention : The imprinted expiration date applies to the product in the bottles with child-resistant screw caps. After the spray pump is inserted into the first bottle of the dispensing package, both bottles of product should be discarded after 6 months, not to exceed the expiration date imprinted on the label. Storage : Store at controlled room temperature 20-25°C (68-77°F). Protect from freezing.