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Statement

Indian Pediatrics 2000;37: 752-754

Use of ‘Fixed’ Combination Preparations of Inhaled Short Acting b-2 Agonists and Inhaled Corticosteroids


Correspondence to: Dr. Arun Gupta, Secretary, Society for Asthma Care and Research, G 303, Rashmi Apartments, Harsh Vihar, Pitampura, Delhi 110 034, India.

E-mail: [email protected]

Society for Asthma Care and Research

This position statement is the result of a review of currently available scientific and objective data on the subject by the expert group (Annexure 1). The position statement was finalized by correspondence and no formal meeting of expert group was held.

Introduction

Over the past ten years there has been paradigm shift in the understanding of the pathophysiology of asthma, from that of a disease marked by acute exacerbations to a disease characterized by chronic inflammation. Comprehensive pharmacological therapy for long-term management of asthma aims to reverse and prevent the airway inflammation and to manage acute exacerbations of asthma. Therefore, asthma drugs are divided in two broad categories: () Quick relief drugs (bronchodilators); and (ii ) Long-term controller drugs (anti-inflammatories).

In a review of 94 studies(1), all reports recommended short acting inhaled beta-2 agonists as the first line treatment of acute exacerbations of asthma and inhaled cortico-steroids as the drug of choice when regular long-term therapy is needed. The current global guidelines recommend that short acting beta-2 agonists serves as a useful indicator of the severity of asthma and helps to decide the need for additional long-term controller medica-tion(2,3). Contrary to the recommendations, inhaled short acting beta-2 agonists still seem to be the most popularly used drug, combination drugs were only the second most popular regimen among young asthmatics(4). The use of fixed combinatins was found to be three times the use of preventers (3.7 million usage days vs 1.35 million usage days unpublished Society for Asthma Care and Research data). Regular use of short-acting beta-2 agonists or their combinations with inhaled steroids in asthma patients becomes a matter of serious concern.

Such a use could be potentially harmful to the patient as it may be associated with increased morbidity and mortality due to asthma because of poor asthma control and because of the delay in seeking medical advice during acute episodes(5). The partial control that these agents provide prevents a correct assessment of the degree of severity and risks involved. Disadvantages also include increased bronchial hyper-reactivity(6). In a double blind cross over study on stable asthma patients, morning and evening PEF rose a little more with the combination than with Budesonide alone, but there was no evidence of a difference in bronchial reactivity (AMP PD20) between the two treatment regimens over 2 weeks(7). There is little information available on relative benefits of such a combination and the individual constituents inhalers. In a double-blind crossover study on 68 adult patients with mild to moderate asthma, combination treatment did provide a significant improve-ment in morning and evening PEF as well as patient compliance over short acting beta-2 agonists or budesonide given alone during a period of four weeks(8). The limitation of the study was its duration, being only four weeks during which it is difficult to evaluate anti-inflammatory effects of inhaled steroids and the compliance.

Practical Disadvantages of Using "Fixed" Combination

Possible disadvantages of using ‘fixed’ combinations include:

1. Difficulties in classifying asthma severity– Since the frequency of use of beta-2 agonists serves as an indicator of the severity of asthma and the need for addi-tional anti-inflammatory therapy, combina-tion therapy may interfere with the classification of asthma severity leading to () difficulties in stepping up and stepping down therapy; and (ii ) difficulties in the monitoring of asthma on a long-term basis.

2. Unnecessary overuse of these two drugs in stepwise management of asthma.

3. Poor control of nocturnal symptoms.

4. Potential of increased morbidity and mortality due to asthma.

Recommendations

Concerned over the adverse effects of the regular use of short-acting beta-2 agonists and their combination with inhaled steroids, considering that the use of such combinations is not consistent with the recommendations for long-term control of asthma, and recognizing that these are overused, the expert group feels that such a combination is unethical and irrational and therefore recommends:

1. That short-acting beta-2 agonists be used as per the global recommendations.

2. To the appropriate drug authorities and the State to take measures to ensure stricter control over the production and availability of such combinations.

3. That professionals be informed about the recent advances in management of asthma particularly pharmacotherapy: Overuse of short acting beta-2 agonists (more than 3-4 times during 24-hour period or one canister of 200 meter dose of salbutamol in a month) should serve as alarm to the doctor to review the medication plans of the patient. A slow withdrawal (in patients who are already on such combinations) of short-acting beta-2 drugs to the level recommended, or the usage of long acting beta-2 agonists instead of short acting ones be attempted.

4. To the manufacturers of these combina-tions to consider not to advocate the use of such combination to all categories of doctors and finally avoid marketing of such combinations.

Competing interests: None stated.

Funding: None.

References

1. Svedmyr N, Lofdahi CG. The use of beta-2 adrenoceptor agonists in the treatment of bronchial asthma. Pharmacol Toxicol 1996; 78: 3-11.

2. Expert Panel Report 2: Clinical Practice Guidelines. Guidelines for the Diagnosis and Management of Asthma. National Institute of Health, NHLBI, April 1997.

3. British Thoracic Society. Guidelines for Asthma Treatment. Thorax 1997; 52: S1-S20.

4. Gaist D, Hallas J, Hansen NC, Gram LF. Are young adults with asthma treated sufficiently with inhaled steroids? A population based study of prescription data from 1991 and 1994. British J Clin Pharm 1996; 41: 285-289.

5. Sears MR, Taylor DR, Print CG. Regular inhaled beta agonist treatment in bronchial asthma. Lancet 1990: 336: 1391-1396.

6. Cockroft DW, McParland CP, Britto SA, Swystun VA, Rutherford BC. Regular inhaled salbutamol and airway responsiveness to allergen. Lancet 1993; 342: 833-837.

7. Wilding PJ, Clark MM, Oborne J, Bennett JA, Tattersfield AE. Effect of regular terbutaline on the airway response to inhaled budesonide. Thorax 1996; 51: 989-992.

8. Barnes PJ, O’ Connor BJ. Use of a fixed combination beta-2 agonist and steroid dry powder inhaler in asthma. Am J Respir Crit Care Med 1995; 151: 1053-1057.

Annexure 1: Members of Expert Committee*

Lata Kumar (Chandigarh), A.A, Mahasur (Mumbai), P.S. Shankar (Mumbai), Swati Y. Bhave (Mumbai), A.K. Prasad (Delhi), N.B. Kumta (Mumbai), Ajit Vigg, (Hyderabad), A.B. Singh (Delhi), U.P.S. Sidhu (Ludhiana), K.P. Kushwaha (Gorakhpur), Avdhesh Bansal (New Delhi), Harbans Bansal (Patiala), Meenu Singh (Chandigarh), K. Chugh (New Delhi), Raj K. Mani (New Delhi), Rita Gupta (Delhi), Arun Gupta (Delhi).

* These are the members of the expert group who concurred with the finalized statement, two experts felt that there was no need for publication of such a statement since clear guidelines are available (their names do not appear in the list). Some experts did not respond; their names also do not appear in the list.

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