Oxymetazoline in allergic rhinitis: A review of controlled clinical trials
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《中华医药杂志》英文版
Oxymetazoline in allergic rhinitis: A review of controlled clinical trials (pdf)
Correspondence to HansGünther Grigoleit,JohannSebastianBachStr.27 D- 65193 Wiesbaden Germany
Tel:+49 611 520509,Fax:+49 611 5990443,
Email:Dr.Grigoleit@tonline.de
[Abstract] In 12 controlled studies (5 double blind,6 open,1 single blind) 1,499 (807 men,509 women,147 cases no gender recorded) patients were exposed to nasal application of the sympathomimetics oxymetazoline or phenylephrine solution,pseudoephedrine tablets,levocabastine (H1receptor antagonist) or placebo. Patient age ranged from 1~71 years. All patients were diagnosed with allergic rhinitis (hay fever,seasonal or perennial allergy)
The qualitative key variable was “improvement of nasal congestion” (excellent/good; fair/moderate; poor/ no effect) by rating through patients and/ or investigator. Quantitative measurements were done by means of rhinoscopy or rhinomanometry. Variables recorded are: nasal airway area,nasal air flow and nasal air flow resistance
531 patients received nasally oxymetazoline 0.05% and 66,0.025%; 302 patients received placebo,the others phenylephrine or levocabastine nasally or pseudoephedrine orally. Treatment duration ranged from a single dose up to a 3 week treatment period. Dosing frequency was in general 2~3 times daily.
Qualitative data show that with oxymetazoline 0.05% the onset of action can be expected after 3 ~15 minutes with a duration of effect of approximately 4 ~8 hours,which warrants three times daily dosing. At least 75% of patients respond satisfactory (rating “excellent/good”) to treatment with oxymetazoline 0.05%. There was no loss in efficacy over time. No rebound effect was documented. Evidence is provided that oxymetazoline does not act via inhibition of histamine release from the nasal mucosa.
Quantitative results parallel qualitative data and support objectively the decongestive effect of oxymetazoline by documentation of an improved nasal airflow.
A total of 448 adverse events and 43 drop outs were reported. All events were typical,labeled,mild and transient in nature and did not require any intervention.
[Key words] oxymetazoline;nasal application;allergic rhinitis;clinical trials
INTRODUCTION
The nasal mucosa is one of the most commonly infected tissue in adults and children. Apart from infections,allergic disorders affect the nasal mucosa. Whatever the etiology,the inflammatory response of the nasal mucosa involves engorgement of venous sinusoids,with possible complete obstruction of nasal airflow. Significant impairment of daily living activities may result by,e.g. mouth breathing with dry mouth,stuffy nose feeling,headache.
Topical nasal decongestants such as oxymetazoline can provide rapid and prolonged relief. Oxymetazoline HCl is a sympathomimetic imidazoline derivative with predominant alpha 2adrenergic activity. It has alpha 1adrenergic activity at higher concentrations. Both agonist activities result in a vasoconstriction,if applied topically to the nasal mucosa causing decongestion. Benefits are facilitated drainage of the paranasal sinuses and improved quality of life.
The purpose of this paper is to review the clinical efficacy and safety of oxymetazoline in allergic rhinitis on the basis of controlled clinical trials.
MATERIALS AND METHODS
In a document search 12 papers on controlled clinical trials were identified reporting about the nasal use of oxymetazoline HCl exclusively in patients with allergic rhinitis (hay fever,perennial or seasonal allergy). The documents cover the period from 1964 ~1996. The studies were performed in 2 countries (United Kingdom,USA). Table 1 below summarizes in chronological order key features of these trials. Other retrieved papers (see references ) dealing with rhinitis including small subsets of patients with “allergic rhinitis” were not taken into account because deviations from results of the 12 studies reviewed concerning efficacy and safety are not apparent and are covered in relevant regulatory documents (FR FDA,1994[18]; Monographie Oxymetazolin,1994[28]).
The dominant clinical symptom of a congested nose,e.g. in allergic rhinitis is nasal breathing impairment and/or the feeling of a stuffy nose. Thus,the key variable focused on in qualitative efficacy assessment is “improvement of nasal congestion”. Ratings were done usually on a 3or 4point rating scale by patient and/or investigator to classify change of symptoms versus baseline (excellent/good; fair/moderate; poor/no). Effects are expressed in percent of patients per rating class.
Quantitative methods employed for efficacy are rhinoscopy (Neidorff,1966[30];Cowen,1966[13]; Selner,et al.1991[32]),nasal air flow resistance by rhinometry (Cohen et al,1969[10]; Connel,et al.1988[13]; Brooks,et al.1993[6];Majchel,et al.1993[26]) nasal airflow (Connel,et al.1987[21]),nasal airway area (Selner,et al.1991[32]) and collection of blown secret (Brooks,et al.1993[6];,Majchel,et al.1993[26]). Nasal secret histamine content was analyzed by Majchel,et al.1993 in order to clarify the mode of action of oxymetazoline.
In 6 studies (Green,1966[19];Neidorff,1966[30];Cowen,1966[14];Cohen,et al.1969[10]; Selner,et al.1991[32];Busse,et al.1996[7]) blood pressure was monitored as a safety measure.
Heart rate was recorded in four studies (Green,1966[19];Cohen,et al.1969[10];Selner,et al.1991[32];Busse,et al.1996[7]) and respiratory rate in three (Green,1966[19];Cohen,et al.1969[10];Busse,et al.1996[7]). In one study (Busse,et al.1996[7] ) pre/post standard laboratory analysis was done. Adverse events were documented as reported.
Table 1 Tabulated Summary of Clinical Trials in Allergic Rhinitis with Oxymetazoline
RESULTS
Five out of the 12 papers deal with data from double blind studies,one is a single blind design and six studies are open,including 2 trials with randomized treatment allocation (see table 1). All patients enrolled were diagnosed as having allergic rhinitis (hay fever,seasonal or perennial rhinitis).
A total of 1,463 patients of all ages were enrolled in 12 studies. Taking into account that in 3 studies (Green,1966[19];Brooks,et al.1993[6]； Majchel,et al.1993[26]) a cross over design was used,36 patients of that total were exposed to 2 treatments,i.e. 1499 patients underwent treatments. The distribution per treatment is listed in the table 2. Treatment time varies from a single dose up to 3 weeks. Daily nasal dosing was in general bid or tid,where applicable (details see table 1).
Table 2 Patient Distribution per Treatment in 12 Studies Reviewed
OXY1= oxymetazoline PHE2=phenylephrine PSE3= pseudoephedrine LEV4=lecovabastine (H1receptor antagonist)
807 of the enrolled patients were males,509 females,for 147 patients no sex was documented. Age range of patients covers 1~71 years.
Table 3 Summary of Efficacy Data of Oxymetazoline HCl in Patients with Allergic Rhinitis
1 Variable: Improvement of nasal congestion 2OXY=oxymetazoline HCl
Data show that with oxymetazoline 0.05% onset of action can be expected after 3~<15 minutes with duration of effect of up to 8 hours,which requires three times daily dosing. At least 75% of patients respond satisfactory to treatment. No or a poor effect is to be expected in 3%~10% of treatments. Treatment failure rate is correspondingly about 10% as a maximum. Subjective improvements are convincingly matched by statistically significant data from quantitative analyses of oxymetazoline effects,e.g. nasal airflow or airway resistance versus placebo or pseudoephedrine,respectively. Qualitative findings thus have a rational basis,which is clearance of nasal airways due to the decongestive effect of oxymetazoline in allergic rhinitis. The therapeutic symptomatic effect of oxymetazoline is obviously mediated by its alphaadrenergic properties rather than by an interference with nasal histamine release as clearly demonstrated by Majchel,et al.1993[26].
The duration of the therapeutic effect extended over the study periods per trial,e.g. 3 weeks in the study by Leitch,1976[25]. Dosing frequency (1 drop/spray per nostril bid~tid) sufficed to obtain satisfactory results as given in table 3. Neither a tachyphylactic nor a rebound effect was observed.
In table 4 the number of adverse events (AE) and drop outs per treatment are summarised.
Table 4 Number of Adverse Events and Drop Outs per Treatment
OXY1=oxymetazoline HCl,PHE2= phenylephrine LEV3=lecovabastine (H1receptor antagonist)
The vast majority of all adverse events and drop outs result from the study by Busse,et al.1996[7] with 1015 patients altogether (416 of a total of 448 AE; 38 of a total of 43 drop outs).All events were mild and transient in nature and did not require any further intervention. Typically,patients complained about watering of eyes,burning and stinging sensation,bad taste,or sneezing. Labeling took place already in relevant documents (FR FDA,1994[18]; Monographie Oxymetazolin,1994[28]). A total of 43 drop outs are identified. Twelve cases were due to an inadequate response. The other cases are related to AEs,but no treatment was needed in any case after discontinuation of study drug. Typical reasons for discontinuation were the same symptoms as those reported for AEs. Between oxymetazoline 0.025% / 0.05% and placebo appears to be a balance in terms of number of AEs and drop outs.
In 6 studies blood pressure was monitored as a safety measure. Heart rate was recorded in 4 and respiratory rate in 3 studies. In one study (Busse,et al.1996[7]; n=1015) pre/post standard laboratory analysis was done. In none of the variables recorded a deviation was observed attributable to study medications.
CONCLUSION
Seven out of 12 studies identified meet the criteria (randomisation,double blind) to provide evidence to describe the clinical efficacy and safety of oxymetazoline. Qualitative data show that with oxymetazoline 0.05% the onset of action can be expected after 3~15 minutes with a duration of effect of up to 8 hours,which warrants three times daily dosing. At least 75% of patients respond satisfactory (rating “excellent/good”) to treatment with oxymetazoline 0.05%. There was no loss in efficacy over time observed in studies up to 3 weeks duration. No rebound effect was documented.
Quantitative results parallel qualitative data and support objectively the decongestive effect of oxymetazoline by documentation of an improved nasal airflow. Findings are statistically significant in favour of oxymetazoline. Qualitative findings thus have a rational basis,which is clearance of nasal airways due to the decongestive effect of oxymetazoline in allergic rhinitis. Evidence is provided that oxymetazoline does not act via inhibition of histamine release from the nasal mucosa.
A total of 448 adverse events and 43 drop outs were reported. All events were typical,labeled,mild and transient in nature and did not require any intervention. No untoward effects on the cardiovascular system were observed.
There is ample and convincing evidence that nasally applied oxymetazoline 0.05% is efficacious and safe in the symptomatic treatment of nasal congestion related to allergic rhinitis. Both qualitative and quantitative findings are in support of that statement. Topical and systemic safety do not present any reason for concern to use oxymetazoline in that indication. This is in line with more than 30 years of experience with the drug and relevant monographs (FR FDA,1994[18]; Monographie Oxymetazolin,1994[28]).
REFERENCES
1. Aikman P. Evaluation of a new oxymetazoline preparation in the treatment of nasal congestion. Practitioner，1975，214: 685-688.
2. Appaix A,Avierinos R. Essais cliniques de lIliadine en O.R.L. (Clinical trial with Iliadine in allergic rhinitis). Sud Medical et chirurgical，1965，2519: 1-11.
3. Bailey BJ. Clinical Evaluation of a topical nasal decongestantoxymetazoline. The Eye,Ear,Nose and Throat Monthly，1969，48: 46-50.
4. Barsocchini LM,Hopp ES. Evaluation of oxymetazoline as a nasal decongestant. E. E. N. T. Digest，1968，30: 62-66.
5. Brooks CD，Karl KJ，Francom SF. Effect of vasoconstrictor pre treatment on obstruction,secretion and sneezing after nasal challenge with threshold allergen doses. Rhinology，1993，31:165-8
6. Busse W，Janssens M，Eisen G. A multicenter,double blind,randomized,placebo controlled trial comparing the efficacy and tolerability of levocabastine oxymetazoline nasal spray with levocabastine and oxymetazoline alone in the symptomatic treatment of seasonal allergic rhinitis. Am J Rhinology，1996，10:105-111
7. Cannon NL,Dalgleisch J,Franks H et al. Evaluation of oxymetazoline paediatric in the treatment of nasal congestion. J Matern Child Health，1976，1: 32-33
8. Chatelet J. Etude experimentale et clinique dun nouveau vasoconstricteur de la muqueuse nasale: le chlorhydrate de (butyldimethylhydroxybenzyl)imidazoline (Experimental and clinical study of a new vasoconstrictor of the nasal mucosa: chlorhydrate of (butyldimethylhydroxybenzyl)imidazoline). Imprimerie R. Foulon & Cie，1963，1: 1-73.Paris,Imprimerie R. Foulon & Cie.
9. Cohen BM，Duffy J. Physiologic and clinical estimates of the relief of nasal flow obstruction in allergic rhinitis: effects of a topical decongestant (oxymetazoline). Asthma Res，1969，7:65-72.
10. Connell JT. Effectiveness of topical nasal decongestants. Ann. Allergy 1969; 27: 541-546.
11. Connel JT，Linzmayer MI. Comparison of of nasal airway patency changes after treatment with oxymetazoline and pseudoephedrine. Am J Rhinol,1987,1:87-94.
12. Connel JT，Linzmayer MI. Studies of rebound phenomena and oxymetazoline. J Allergy Clin Immunol,1988,81:179.
13. Cowen ED. Clinical experience with a topical nasal decongestant. Eye,Ear,Nose & Throat Monthly,1966,58:58-61.
14. Cunningham JD. A topical nasal decongestant. Current Therapeutic Research,1965,7: 471-473.
15. Eberhard K. Use of oxymetazoline in general practice. A publication for physicians and surgeons,1965,5(7):73-74.Elias A. Wirkungsbeurteilung des vasokonstriktorisch wirkenden Nasivin (Oxymetazolin) bei Piloten von Duesenflugzeugen (Efficacy of the vasoconstrictor Nasivin (oxymetazoline) in jet pilots. Medizinische Revue Luftwaffe,1970,4: 375-379.
16. FR FDA 08/23/94 F 59 FR 43386 Cold,cough,allergy,bronchodilator,and antiasthmatic drug products for over the counter human use; final monograph for OTC nasal decongestant products. Vol. 59,No. 162,Aug,1994.
17. Green M. Double blind study of nasal decongestion with oxymetazoline and phenylephrine in asthmatic children with rhinitis. Rev Allergy,1966,20:863-868.
18. Haines HL. Oxymetazoline spray in otorhinolaryngology. Curr Ther Res,1966,8:91-93.
19. Harris H. Comparative study of decongestive effectiveness of oxymetazoline hydrochloride in rhinitis. E. E. N. T. Digest,1967,41-43.
20. Kameswaran S. Clinical evaluation of a nasal decongestant Nasivin. The Indian Practitioner,1970,23:453-459.
21. Kuhn A. Evaluation of a new topical nasal decongestant. J Indiana State Med Assoc,1966,59 (11): 1295-1296.
22. Lathrop FD. Nasal decongestion with oxymetazoline HCl. A clinical evaluation with intranasal biopsy studies. AMA Drug Evaluations,1965,114.
23. Leitch GB. A trial of Iliadin in nonspecific allergic rhinitis. Br J Clin Pract,1976,30:37-42.
24. Majchel AM，Baroody F，KageySobotka A et al. Effect of oxymetazoline on the early response to nasal challenge with antigen. J Allergy Clin Immunol,1993,92:767-770.
25. Miller J. Oxymetazoline in allergic rhinitis. Clin Medicine，1964，71:1561-426.
26. Monographie Oxymetazolin. Bundesanzeiger (Code of Federal Regulations Germany) Nr，1994，138(26)：509-513.
27. Neffson A-H. A topical nasal decongestant for children. The Eye,Ear,Nose and Throat Monthly,1968,47:121-123.
27. Neidorff AH. Clinical note:double blind comparison of the duration of effect of oxymetazoline and phenylephrine in children. Ann Allergy,1966,24:250-251.
28. Sells L. Nasal decongestion by topical medication. Coll Paprs,1965,5: 517.
29. Selner JC，Koepke JW，Staudenmayer H，et al. Assessment of nasal patency by rhinoscopic measurement of cross sectional nasal airway area: correlation with subjective nasal symptoms. Ann Allergy,1991,66:43-47.
30. Stride R. Nasal Decongestant Therapy. The British Journal of Clinical Practice,1967,21(11): 541-548.
31. Teichmann B,Tschaikin M. Anwendung von Nasivin sanft 0.01% Dosiertropfen für Saeuglinge (Rhinas 1/99) (Use of Nasivin sanft 0.01% metered drops in infants). P?diatrische Nachrichten,2000.
32. Ten Eyck T. Nasal decongestants in otorhinolaryngology. Western Medicine,1966,158-159.
33. Thulin A,Walter B. Vergleichende DoppelBlindstudie zwischen Neseril,einem neuen Nasentropfenpr?parat und Ephedrin (Double blind trial comparing Neseril,a new nasal drop drug versus ephedrine). Saertryck ur Svenska Laekartidningen,1964,61:3204-3213.
34. Voss HE,Coleman M. Doubleblind analysis of oxymetazoline in acute and chronic infectious or allergic rhinitis. Clin Med,1973,80:11-14.
35. Weimann M-I,Heights H. A topical nasal decongestant for children. J Med Soc New Jersey,1976,64: 260-261.
(Editor Emilian)(HansGünther Grigoleit)
Correspondence to HansGünther Grigoleit,JohannSebastianBachStr.27 D- 65193 Wiesbaden Germany
Tel:+49 611 520509,Fax:+49 611 5990443,
Email:Dr.Grigoleit@tonline.de
[Abstract] In 12 controlled studies (5 double blind,6 open,1 single blind) 1,499 (807 men,509 women,147 cases no gender recorded) patients were exposed to nasal application of the sympathomimetics oxymetazoline or phenylephrine solution,pseudoephedrine tablets,levocabastine (H1receptor antagonist) or placebo. Patient age ranged from 1~71 years. All patients were diagnosed with allergic rhinitis (hay fever,seasonal or perennial allergy)
The qualitative key variable was “improvement of nasal congestion” (excellent/good; fair/moderate; poor/ no effect) by rating through patients and/ or investigator. Quantitative measurements were done by means of rhinoscopy or rhinomanometry. Variables recorded are: nasal airway area,nasal air flow and nasal air flow resistance
531 patients received nasally oxymetazoline 0.05% and 66,0.025%; 302 patients received placebo,the others phenylephrine or levocabastine nasally or pseudoephedrine orally. Treatment duration ranged from a single dose up to a 3 week treatment period. Dosing frequency was in general 2~3 times daily.
Qualitative data show that with oxymetazoline 0.05% the onset of action can be expected after 3 ~15 minutes with a duration of effect of approximately 4 ~8 hours,which warrants three times daily dosing. At least 75% of patients respond satisfactory (rating “excellent/good”) to treatment with oxymetazoline 0.05%. There was no loss in efficacy over time. No rebound effect was documented. Evidence is provided that oxymetazoline does not act via inhibition of histamine release from the nasal mucosa.
Quantitative results parallel qualitative data and support objectively the decongestive effect of oxymetazoline by documentation of an improved nasal airflow.
A total of 448 adverse events and 43 drop outs were reported. All events were typical,labeled,mild and transient in nature and did not require any intervention.
[Key words] oxymetazoline;nasal application;allergic rhinitis;clinical trials
INTRODUCTION
The nasal mucosa is one of the most commonly infected tissue in adults and children. Apart from infections,allergic disorders affect the nasal mucosa. Whatever the etiology,the inflammatory response of the nasal mucosa involves engorgement of venous sinusoids,with possible complete obstruction of nasal airflow. Significant impairment of daily living activities may result by,e.g. mouth breathing with dry mouth,stuffy nose feeling,headache.
Topical nasal decongestants such as oxymetazoline can provide rapid and prolonged relief. Oxymetazoline HCl is a sympathomimetic imidazoline derivative with predominant alpha 2adrenergic activity. It has alpha 1adrenergic activity at higher concentrations. Both agonist activities result in a vasoconstriction,if applied topically to the nasal mucosa causing decongestion. Benefits are facilitated drainage of the paranasal sinuses and improved quality of life.
The purpose of this paper is to review the clinical efficacy and safety of oxymetazoline in allergic rhinitis on the basis of controlled clinical trials.
MATERIALS AND METHODS
In a document search 12 papers on controlled clinical trials were identified reporting about the nasal use of oxymetazoline HCl exclusively in patients with allergic rhinitis (hay fever,perennial or seasonal allergy). The documents cover the period from 1964 ~1996. The studies were performed in 2 countries (United Kingdom,USA). Table 1 below summarizes in chronological order key features of these trials. Other retrieved papers (see references ) dealing with rhinitis including small subsets of patients with “allergic rhinitis” were not taken into account because deviations from results of the 12 studies reviewed concerning efficacy and safety are not apparent and are covered in relevant regulatory documents (FR FDA,1994[18]; Monographie Oxymetazolin,1994[28]).
The dominant clinical symptom of a congested nose,e.g. in allergic rhinitis is nasal breathing impairment and/or the feeling of a stuffy nose. Thus,the key variable focused on in qualitative efficacy assessment is “improvement of nasal congestion”. Ratings were done usually on a 3or 4point rating scale by patient and/or investigator to classify change of symptoms versus baseline (excellent/good; fair/moderate; poor/no). Effects are expressed in percent of patients per rating class.
Quantitative methods employed for efficacy are rhinoscopy (Neidorff,1966[30];Cowen,1966[13]; Selner,et al.1991[32]),nasal air flow resistance by rhinometry (Cohen et al,1969[10]; Connel,et al.1988[13]; Brooks,et al.1993[6];Majchel,et al.1993[26]) nasal airflow (Connel,et al.1987[21]),nasal airway area (Selner,et al.1991[32]) and collection of blown secret (Brooks,et al.1993[6];,Majchel,et al.1993[26]). Nasal secret histamine content was analyzed by Majchel,et al.1993 in order to clarify the mode of action of oxymetazoline.
In 6 studies (Green,1966[19];Neidorff,1966[30];Cowen,1966[14];Cohen,et al.1969[10]; Selner,et al.1991[32];Busse,et al.1996[7]) blood pressure was monitored as a safety measure.
Heart rate was recorded in four studies (Green,1966[19];Cohen,et al.1969[10];Selner,et al.1991[32];Busse,et al.1996[7]) and respiratory rate in three (Green,1966[19];Cohen,et al.1969[10];Busse,et al.1996[7]). In one study (Busse,et al.1996[7] ) pre/post standard laboratory analysis was done. Adverse events were documented as reported.
Table 1 Tabulated Summary of Clinical Trials in Allergic Rhinitis with Oxymetazoline
RESULTS
Five out of the 12 papers deal with data from double blind studies,one is a single blind design and six studies are open,including 2 trials with randomized treatment allocation (see table 1). All patients enrolled were diagnosed as having allergic rhinitis (hay fever,seasonal or perennial rhinitis).
A total of 1,463 patients of all ages were enrolled in 12 studies. Taking into account that in 3 studies (Green,1966[19];Brooks,et al.1993[6]； Majchel,et al.1993[26]) a cross over design was used,36 patients of that total were exposed to 2 treatments,i.e. 1499 patients underwent treatments. The distribution per treatment is listed in the table 2. Treatment time varies from a single dose up to 3 weeks. Daily nasal dosing was in general bid or tid,where applicable (details see table 1).
Table 2 Patient Distribution per Treatment in 12 Studies Reviewed
OXY1= oxymetazoline PHE2=phenylephrine PSE3= pseudoephedrine LEV4=lecovabastine (H1receptor antagonist)
807 of the enrolled patients were males,509 females,for 147 patients no sex was documented. Age range of patients covers 1~71 years.
Table 3 Summary of Efficacy Data of Oxymetazoline HCl in Patients with Allergic Rhinitis
1 Variable: Improvement of nasal congestion 2OXY=oxymetazoline HCl
Data show that with oxymetazoline 0.05% onset of action can be expected after 3~<15 minutes with duration of effect of up to 8 hours,which requires three times daily dosing. At least 75% of patients respond satisfactory to treatment. No or a poor effect is to be expected in 3%~10% of treatments. Treatment failure rate is correspondingly about 10% as a maximum. Subjective improvements are convincingly matched by statistically significant data from quantitative analyses of oxymetazoline effects,e.g. nasal airflow or airway resistance versus placebo or pseudoephedrine,respectively. Qualitative findings thus have a rational basis,which is clearance of nasal airways due to the decongestive effect of oxymetazoline in allergic rhinitis. The therapeutic symptomatic effect of oxymetazoline is obviously mediated by its alphaadrenergic properties rather than by an interference with nasal histamine release as clearly demonstrated by Majchel,et al.1993[26].
The duration of the therapeutic effect extended over the study periods per trial,e.g. 3 weeks in the study by Leitch,1976[25]. Dosing frequency (1 drop/spray per nostril bid~tid) sufficed to obtain satisfactory results as given in table 3. Neither a tachyphylactic nor a rebound effect was observed.
In table 4 the number of adverse events (AE) and drop outs per treatment are summarised.
Table 4 Number of Adverse Events and Drop Outs per Treatment
OXY1=oxymetazoline HCl,PHE2= phenylephrine LEV3=lecovabastine (H1receptor antagonist)
The vast majority of all adverse events and drop outs result from the study by Busse,et al.1996[7] with 1015 patients altogether (416 of a total of 448 AE; 38 of a total of 43 drop outs).All events were mild and transient in nature and did not require any further intervention. Typically,patients complained about watering of eyes,burning and stinging sensation,bad taste,or sneezing. Labeling took place already in relevant documents (FR FDA,1994[18]; Monographie Oxymetazolin,1994[28]). A total of 43 drop outs are identified. Twelve cases were due to an inadequate response. The other cases are related to AEs,but no treatment was needed in any case after discontinuation of study drug. Typical reasons for discontinuation were the same symptoms as those reported for AEs. Between oxymetazoline 0.025% / 0.05% and placebo appears to be a balance in terms of number of AEs and drop outs.
In 6 studies blood pressure was monitored as a safety measure. Heart rate was recorded in 4 and respiratory rate in 3 studies. In one study (Busse,et al.1996[7]; n=1015) pre/post standard laboratory analysis was done. In none of the variables recorded a deviation was observed attributable to study medications.
CONCLUSION
Seven out of 12 studies identified meet the criteria (randomisation,double blind) to provide evidence to describe the clinical efficacy and safety of oxymetazoline. Qualitative data show that with oxymetazoline 0.05% the onset of action can be expected after 3~15 minutes with a duration of effect of up to 8 hours,which warrants three times daily dosing. At least 75% of patients respond satisfactory (rating “excellent/good”) to treatment with oxymetazoline 0.05%. There was no loss in efficacy over time observed in studies up to 3 weeks duration. No rebound effect was documented.
Quantitative results parallel qualitative data and support objectively the decongestive effect of oxymetazoline by documentation of an improved nasal airflow. Findings are statistically significant in favour of oxymetazoline. Qualitative findings thus have a rational basis,which is clearance of nasal airways due to the decongestive effect of oxymetazoline in allergic rhinitis. Evidence is provided that oxymetazoline does not act via inhibition of histamine release from the nasal mucosa.
A total of 448 adverse events and 43 drop outs were reported. All events were typical,labeled,mild and transient in nature and did not require any intervention. No untoward effects on the cardiovascular system were observed.
There is ample and convincing evidence that nasally applied oxymetazoline 0.05% is efficacious and safe in the symptomatic treatment of nasal congestion related to allergic rhinitis. Both qualitative and quantitative findings are in support of that statement. Topical and systemic safety do not present any reason for concern to use oxymetazoline in that indication. This is in line with more than 30 years of experience with the drug and relevant monographs (FR FDA,1994[18]; Monographie Oxymetazolin,1994[28]).
REFERENCES
1. Aikman P. Evaluation of a new oxymetazoline preparation in the treatment of nasal congestion. Practitioner，1975，214: 685-688.
2. Appaix A,Avierinos R. Essais cliniques de lIliadine en O.R.L. (Clinical trial with Iliadine in allergic rhinitis). Sud Medical et chirurgical，1965，2519: 1-11.
3. Bailey BJ. Clinical Evaluation of a topical nasal decongestantoxymetazoline. The Eye,Ear,Nose and Throat Monthly，1969，48: 46-50.
4. Barsocchini LM,Hopp ES. Evaluation of oxymetazoline as a nasal decongestant. E. E. N. T. Digest，1968，30: 62-66.
5. Brooks CD，Karl KJ，Francom SF. Effect of vasoconstrictor pre treatment on obstruction,secretion and sneezing after nasal challenge with threshold allergen doses. Rhinology，1993，31:165-8
6. Busse W，Janssens M，Eisen G. A multicenter,double blind,randomized,placebo controlled trial comparing the efficacy and tolerability of levocabastine oxymetazoline nasal spray with levocabastine and oxymetazoline alone in the symptomatic treatment of seasonal allergic rhinitis. Am J Rhinology，1996，10:105-111
7. Cannon NL,Dalgleisch J,Franks H et al. Evaluation of oxymetazoline paediatric in the treatment of nasal congestion. J Matern Child Health，1976，1: 32-33
8. Chatelet J. Etude experimentale et clinique dun nouveau vasoconstricteur de la muqueuse nasale: le chlorhydrate de (butyldimethylhydroxybenzyl)imidazoline (Experimental and clinical study of a new vasoconstrictor of the nasal mucosa: chlorhydrate of (butyldimethylhydroxybenzyl)imidazoline). Imprimerie R. Foulon & Cie，1963，1: 1-73.Paris,Imprimerie R. Foulon & Cie.
9. Cohen BM，Duffy J. Physiologic and clinical estimates of the relief of nasal flow obstruction in allergic rhinitis: effects of a topical decongestant (oxymetazoline). Asthma Res，1969，7:65-72.
10. Connell JT. Effectiveness of topical nasal decongestants. Ann. Allergy 1969; 27: 541-546.
11. Connel JT，Linzmayer MI. Comparison of of nasal airway patency changes after treatment with oxymetazoline and pseudoephedrine. Am J Rhinol,1987,1:87-94.
12. Connel JT，Linzmayer MI. Studies of rebound phenomena and oxymetazoline. J Allergy Clin Immunol,1988,81:179.
13. Cowen ED. Clinical experience with a topical nasal decongestant. Eye,Ear,Nose & Throat Monthly,1966,58:58-61.
14. Cunningham JD. A topical nasal decongestant. Current Therapeutic Research,1965,7: 471-473.
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(Editor Emilian)(HansGünther Grigoleit)