Summary
Synopsis
Azelastine is an antiallergic agent which demonstrates histamine H1- receptor antagonist activity and also inhibits histamine release from mast cells following antigen and non-antigen stimuli. Azelastine antagonises histamine- and leukotriene-induced bronchospasm in animal studies and reduces airway responsiveness to inhaled antigen or distilled water, and exercise challenge. In comparative studies, orally administered azelastine in doses up to 4 mg/day consistently relieved symptoms in patients with seasonal or perennial rhinitis — comparable to inhaled sodium cromoglycate (cromolyn sodium) 80 mg/day, oral chlorpheniramine (chlorphenamine) and oral terfenadine 120 mg/day. In addition, azelastine administered as an intranasal spray was as effective as oral terfenadine 120 mg/day and intranasal budesonide 0.4 mg/day in alleviating symptoms of rhinitis.
Azelastine is also a potent antiasthmatic agent which produces significant and long lasting bronchodilation in patients with bronchial asthma. The drug is superior to placebo and comparable to oral ketotifen 2 mg/day and sustained release theophylline 700 mg/day when administered as a twice daily oral 4mg dose.
Azelastine is generally well tolerated: the most common adverse effects are altered taste perception and drowsiness. Adverse effects are mild and transient and result in withdrawal of treatment in less than 2% of patients. In a comparative study oral azelastine 2 or 4 mg/day produced no more sedation than terfenadine 120 mg/day.
Thus, barring unexpected findings with wider clinical use, azelastine offers an effective and well tolerated choice of treatment for patients with allergic rhinitis and/or bronchial asthma, which may be particularly beneficial in patients in whom inhaled drug treatment is contraindicated.
Pharmacodynamic Studies
Azelastine has a selective and potent affinity for histamine H1-receptors in vitro and exerts a strong antihistaminic effect in both in vitro and in vivo studies. The drug inhibits histamine release from mast cells induced by antigen and non-antigen stimuli and is at least 5000 times more potent than ketotifen, sodium cromoglycate, theophylline and astemizole in this regard.
In asthmatic patients, single or multiple oral administration of azelastine 4mg inhibits histamine-induced bronchoconstriction and reduces the weal and flare response to intra-dermally injected histamine after only 4 hours. Azelastine weakly antagonises in vitro leukotriene-induced contractile responses and antigen- and non-antigen-induced leukotriene release, but has no effect on leukotriene-mediated bronchoconstriction in asthmatic patients.
Azelastine has negligible anticholinergic activity and inhibits serotonin-induced cutaneous anaphylaxis in rats at high dosages (25 mg/kg). In vitro platelet aggregation, paw oedema, and bronchoconstriction induced by platelet activating factor are inhibited by azelastine.
Azelastine administered as a single oral 4mg dose is a potent bronchodilator causing a marked effect within 1 hour and a maximum effect after 6 hours in patients with asthma or chronic obstructive bronchitis. Bronchoconstriction induced by inhaled allergen, distilled water, or exercise in asthmatic patients is markedly reduced by single oral azelastine doses of 2 to 8mg and the drug appears to inhibit the immediate (within 1 to 2 hours) and delayed (within 2 to 8 hours) bronchoconstrictor response.
The antiallergic properties of azelastine have been demonstrated in several animal models of allergy such as lung anaphylaxis and passive cutaneous anaphylaxis. In atopic patients, skin reactivity to antigen was reduced by up to 39% within 4 hours of an 8mg dose, and inhibition persisted for at least 1 week after withdrawal of treatment.
Although data are limited, azelastine appears to have a negligible effect on psychomotor performance and sedation over a dose range of 2 to 16mg. However, sedation may occur during concomitant alcohol administration.
Pharmacokinetic Studies
The available information on the pharmacokinetics of azelastine in humans is largely based on unpublished data provided by the manufacturer, and additional published clinical studies are required to define more precisely the disposition of the drug. In healthy volunteers a single oral azelastine dose is almost completely (95%) absorbed. Peak plasma concentrations of 3 µg/L occur 4 to 5 hours after a single oral 4mg dose. After multiple azelastine doses (4mg twice daily) a mean peak plasma concentration of 10 µg/L is achieved in 2.3 hours. Absolute bioavailability of azelastine administered as an oral tablet is >80%. In animals azelastine is distributed primarily to peripheral tissues: concentrations are consistently low in the brain. Placental transfer of azelastine has been observed in animal studies. In healthy volunteers azelastine is 78 to 88% bound to plasma proteins. Elimination half-life is 25 hours after a single oral dose and 35.5 hours after multiple oral dosing, due possibly to the accumulation of demethyl-azelastine, a major pharmacologically active metabolite which has an elimination half-life of 42 hours. 75% of a single oral dose is recovered within 120 hours; urinary and fecal recovery is 25% and 50%, respectively.
Therapeutic Use
The efficacy of azelastine has been evaluated in patients with bronchial asthma, allergic rhinitis (seasonal and perennial) and, to a lesser extent, in patients with histaminemediated skin disorders.
Non-comparative studies in adult and young patients with bronchial asthma have shown that oral azelastine 4 mg/day consistently improves symptoms and reduces the severity and frequency of asthma attacks and the use of concomitant bronchodilators over treatment periods of 0.5 to 28 months. In comparative studies of up to 12 weeks duration, twice daily administration of oral azelastine 4 mg/day significantly improved peak expiratory flow rate and mean wheeze score compared with placebo, and was at least as effective as oral theophylline 700 mg/day (sustained release formulation) and oral ketotifen 2 mg/day with regard to improving respiratory function and reducing the use of concomitant bronchodilators. The relative efficacy of oral azelastine as an antiasthmatic agent remains to be investigated in longer term studies.
The effectiveness of azelastine administered orally or as an intranasal spray has been studied in patients with seasonal or perennial rhinitis. Oral azelastine 1 to 8 mg/day consistently improved hay fever symptoms and was as effective as chlorpheniramine 4mg given 4 times daily. Over a 6-week period, oral azelastine 4 mg/day or intranasal azelastine 0.56 mg/day was at least as efficacious as oral terfenadine at improving symptoms including rhinorrhoea, stuffy nose, coughing, and lacrimation. Intranasal azelastine 0.56 mg/day and intranasal budesonide 0.4 mg/day have comparable efficacy: after 2 weeks total symptom score improved by 67% in both treatment groups. Improvement was seen after 1 week of treatment with azelastine nasal spray and persisted for up to 6 weeks in another study.
In patients with perennial rhinitis, oral azelastine 2 or 4 mg/day produces good or excellent symptomatic improvement in about 75% of patients after 2 weeks, and in 87 to 96% of patients after treatment lasting up to 6 months. The most pronounced effect was seen during the first 4 weeks of treatment. In comparative studies, oral azelastine 2 or 4 mg/day was significantly superior to placebo and was as effective as inhaled sodium cromoglycate 20mg administered 4 times daily at improving total symptom score in 297 patients. Overall improvement rates after 4 weeks were 63% in patients who received azelastine and 66% in those who received sodium cromoglycate. Intranasally administered azelastine 0.56 mg/day was as effective as oral terfenadine 120 mg/day in 49 patients; total subjective symptom scores improved by 90% and 87%, respectively, while 46% and 37% of azelastine- and terfenadine-treated patients, respectively, showed good or excellent global improvement.
Preliminary data from non-comparative studies indicate that oral azelastine may be efficacious in the treatment of histamine-mediated skin disorders, but these findings require confirmation in controlled studies.
Adverse Effects
The adverse effect profile of azelastine has been compiled from published and unpublished clinical studies and data provided by the manufacturers. The incidence of adverse effects was 7 to 14% in asthmatic patients treated with oral azelastine 4 mg/day and 18 to 25% in patients receiving 8 mg/day. In patients with allergic rhinitis treated with oral azelastine 2 or 4 mg/day adverse effects were reported in 4 to 25% or 19 to 42%, respectively. 12% of patients receiving intranasally administered azelastine 0.56 mg/ day reported adverse effects, the most frequent being burning nose and an altered taste perception. After oral administration, altered taste (2 to 26%) and drowsiness (3 to 18%) were most common. Other adverse effects that affect less than 5% of patients include dry mouth and nose, weight gain, nausea, vomiting, stomach ache, epistaxis, thirst and skin rash.
All adverse effects are generally mild and transient in nature and cause treatment withdrawal in less than 2% of patients.
In 1 study azelastine 2 or 4 mg/day produced no more sedation than terfenadine 120 mg/day, a non-sedating antihistamine. No clinically relevant changes in blood pressure, haematological, hepatic or renal function have been noted during prolonged azelastine treatment.
Dosage and Administration
The recommended daily dose for the prophylaxis and treatment of bronchial asthma is 4mg for adults and 2mg for children aged 6 to 12 years administered orally twice daily. A single 8mg evening dose may be given to patients with nocturnal or early morning symptoms. For the treatment of allergic rhinitis, 1 to 2mg twice daily administered orally is recommended. Recommended dosage requirements for patients with hepatic or renal dysfunction, children aged less than 6 years, and for intranasally administered azelastine are not available.
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Various sections of the manuscript reviewed by: R.H. Champion, Department of Dermatology, Addenbrooke’s Hospital, Cambridge, England; S.T. Holgate, Southampton General Hospital, Southampton, England; F. Horak, Universitäts Dozent, Vienna, Austria; J.P. Kemp, Allergy and Asthma Medical Group and Research Center, San Diego, California, USA; M. Magnussen, Krankenhaus Grosshansdorf, Zentrum für Pneumologie und Thoraxchirurgie, Grosshandsdorf, West Germany; S. Makino, Department of Medicine and Clinical Immunology, Dokkyo University School of Medicine, Tochigi, Japan; H. Ohno, Department of Pediatrics, Kinki University School of Medicine, Osaka, Japan; M. Okuda, Department of Otorhinolaryngology, Nippon Medical School, Tokyo, Japan; N. W, Todd, Division of Otolaryngology, Emory University School of Medicine, Atlanta, Georgia, USA; J.H. Toogood, Allergy Clinic, Victoria Hospital, London, Ontario, Canada.
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McTavish, D., Sorkin, E.M. Azelastine. Drugs 38, 778–800 (1989). https://doi.org/10.2165/00003495-198938050-00005
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DOI: https://doi.org/10.2165/00003495-198938050-00005