P&T News: October 1997

Salmeterol Use in Asthma: Facts and Controversies

Charles S. Dayton, R.Ph.
Peer Review Status: Internally peer reviewed by D. Michael Shasby, M.D.

The recently revised Expert Panel 2, Guidelines for the Diagnosis and Management of Asthma published by the National Institutes of Health, National Heart, Lung, and Blood Institute' has served as a reminder that questions remain regarding the appropriate use of long-acting, B2-agonist therapy in the treatment of asthma. Resolution of questions regarding risk for special populations has yet to be addressed. Reports of sudden severe attacks of asthma following the use of salmeterol has raised concerns that perhaps the drug is not equally tolerated in all patient populations. Patient education and appropriate use of other asthma medications with salmeterol are questions also addressed by the revised asthma guidelines. The focus of this article will be salmeterol. Currently, salmeterol is the only long-acting ,B2 agonist marketed in the U.S.

Three areas of discussion are presented here, including: 1) tolerance (tachyphylaxis) to the bronchoprotective effects of salmeterol; 2) the interaction of salmeterol with inhaled anti-inflammatory agents; and 3) the treatment of nocturnal asthma symptoms with salmeterol. A summary of recommendations on the use of salmeterol in asthma as stated in the National Asthma Education Guidelines is also presented.'

Tolerance (Tachyphylaxis) - New Studies
The physiology of the B receptor in humans is very complex. An extensive review of the mechanisms of B 2- receptor activity was recently published in the American Journal of Respiratory and Critical Care Medicine.2 Tachyphylaxis is defined as the short-term desensitization of the cell surface receptors, while tolerance refers to desensitization after repeated applications of an agonist. So called "down-regulation" of the B receptor occurs after long-term exposure to a beta-agonist agent and may result in reduced mRNA production. This reduced production in turn may result in a reduction in B 2-receptor density.

The clinical applicability of this information remains uncertain. Several studies have recently been published that attempt to answer questions of safety and clinical relevance of these data. A summary of these studies follows.

It is well understood from earlier studies' that tolerance to the bronchoprotective effects of salmeterol develop after sustained use; however, the forced expiratory volume in the first second (FEV1) generally remains unchanged. The conclusion of these studies is that no clinically significant decrease in effect of the drug is seen. Additionally, these studies were done without the use of an anti-inflammatory agent given concurrently with salmeterol.

Recently, additional studies have been performed in which long-acting, B 2-agonist agents were used in combination with inhaled steroid products. The first study, published in the European Respiratory Journal,3 evaluated 14 stable adult asthmatics, eight of whom did not use concomitant inhaled glucocorticoid preparations, and six who did. Unfortunately, there was not a breakdown of the data separating those subjects on steroids and those who were not. The study showed a significant difference in the provocative concentration of methacholine required to produce a 20% fall in FEV' (referred to as PC20) after four days of treatment which was attributed to the twice daily administration of salmeterol. However, there were no significant differences in mean baseline FEV1 between treatments. Once again, this study showed heightened bronchial hyperreactivity with no change in pulmonary function parameters. The authors conclude that the need for continued surveillance of the safety of regularly-used long-acting B 2-agonist in "more troublesome asthma" should be continued.

Two other recently published studies involved subjects who received orally inhaled glucocorticoid preparations in conjunction with salmeterol. The investigators asked two different but specific questions:

1) Could the use of one dose per day of salmeterol prevent the development of tolerance as measured by FEV1 pre- and post-exercise testing in adolescents receiving regular glucocorticoid inhalers? and,

2) Could the addition of salmeterol reduce the need for inhaled glucocorticoid use, decrease exacerbations of asthma, and decrease use of oral steroids?

In the first study,4 14 subjects were given salmeterol or placebo once daily for 28 days in a crossover design fashion. By the end of the 28 days, there was no significant difference in the maximum percent fall in FEV1 before and after exercise testing between salmeterol and placebo at the late afternoon testing time. Early on, salmeterol once daily protected against a fall in FEV' in the late afternoon exercise test, but at the end of the study, no such effect was seen. The authors concluded that once-daily administration of salmeterol to protect against exercise-induced asthma was not in the best interest of this patient population. Once-daily administration of salmeterol in this study did not protect against tolerance to the drug, and it was not effective for day-long protection.

In the second study,5 87 subjects were started on twice-daily salmeterol inhalation or placebo for six months each and crossed over. Inhaled steroid doses were adjusted according to established study guidelines. In the study population, subjects were able to reduce their requirements for inhaled glucocorticoid and showed improvement in lung function and symptom control. The authors concluded that, in their opinion, a long-acting, B 2-agonist agent should be added earlier in the treatment of asthma, which may allow a subsequent reduction in the inhaled steroid dose without having a detrimental effect in patients following an appropriate asthma management plan.

In summary, recent studies have shown that, while the bronchoprotective effects of long-acting B 2-agonist agents are lessened over time, the changes in pulmonary functions are minimal. Additionally, once-daily dosing for exercise- induced asthma may not be appropriate, and the addition of salmeterol to an asthma regimen earlier in the course of therapy may have the potential to reduce doses of inhaled steroid preparations. Caution should be exercised in utilizing long-acting B 2-agonist therapy in "problem asthmatics."

The Interaction Between Salmeterol and Glucocorticoids
Another confounding factor in the administration of long-acting B 2-agonist agents is their interaction with glucocorticoids. In a recent review on B-adrenergic receptors,2 a mechanism is presented which implies that high doses of, B 2-agonist agents may interfere with the anti-inflammatory response to glucocorticoids. It is possible that high concentrations of beta-agonist agents may activate transcription factors which can bind to the activated glucocorticoid receptor, resulting in inhibition of the effect of glucocorticoids on the cell. The significance of this in clinical practice is debated.

Additionally, due to their powerful anti-inflammatory potency, inhaled steroids were proposed to possibly blunt the tolerance and tachyphylaxis seen with early studies of the long-acting B 2-agonist agents. Two studies appeared in the pulmonary literature in 1996 that addressed this possibility.6,7 Both studies used bronchial provocation testing with methacholine as a measure of development of tolerance. A study by Yates et al6 confirmed the observations from earlier studies that improvements in lung function occur despite decreases in the bronchial protective effects when using salmeterol. The authors went on to demonstrate that this paradox occurs during the concurrent administration of an inhaled steroid. Their conclusions were that inhaled glucocorticoids do not protect against the tolerance to the bronchial protective effects of concurrently administered, B 2-agonist agents. Kalra et al1 demonstrated these same effects, comparing groups with and without the addition of inhaled steroid agents.

It should be emphasized, that while recent studies show that inhaled steroids do not protect against the tolerance to the bronchial protective effects of long-acting B 2-agonist therapy, the concomitant use of inhaled steroids with a long-acting B 2-agonist agent is the current standard of care for the control of asthma. Controlling inflammation with inhaled steroids seems to be key to the effectiveness and safety of long-acting B 2-agonist agents.1

Table 1. LONG-ACTING INHALED
B 2 AGONISTS: PLACE IN ASTHMA THERAPY

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From: Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma'

Salmeterol in Nocturnal Asthma
In moderate to severe asthma, the phenomenon of nocturnal increases in airway obstruction and bronchial hyperresponsiveness has been documented.1 Due to the long duration of action of salmeterol, it has been postulated that administering the agent to asthmatics may have the effect of blunting the symptoms of nocturnal asthma. Several studies,8-10 incorporating small numbers of subjects, have been conducted in an attempt to confirm this hypothesis.

A study by Selby et al8 looked at the question of using salmeterol in place of oral theophylline for nocturnal asthma. Only 15 of the 23 enrolled patients were able to successfully complete the study. The study showed that there are no major differences between inhaled salmeterol and sustained-release theophylline when measuring symptoms, side effects, pulmonary function tests, or subjective sleep quality. One might argue that the potential for side effects and toxicity may be greater with oral theophylline products. Additionally, theophylline requires serum level sampling which may add to the cost of therapy. The authors concluded that salmeterol works for nocturnal asthma symptoms, but probably no better than sustained-release theophylline.

A second study done by Weersink et al9 evaluated the effects of six weeks of treatment with salmeterol alone, a glucocorticoid (fluticasone) inhaler alone, or salmeterol in conjunction with a glucocorticoid inhaler in nocturnal asthma in 50 subjects. In this study, an equal effect on the circadian variation in pulmonary function tests was shown with each agent alone, and with the two agents in combination. In general, salmeterol, fluticasone, and the combination of the two provided comparable therapeutic effects. However, fluticasone alone and the combination of salmeterol and fluticasone provided equal protection against bronchial hyperreactivity, while salmeterol alone did not. The current guidelines for the treatment of asthma suggest using a combination of B 2 agonist and glucocorticoid therapy in all asthmatics except those with mild, intermittent asthma. This combination treatment helps protect patients from a possible decrease in bronchial hyperreactivity, which may be clinically significant.

In the final study in this series, Kraft et al10 evaluated 10 patients with asthma in a double-blind, randomized, placebo-controlled, crossover study. Salmeterol and placebo were each used for six weeks in each patient with a one- week interval between drugs. This study demonstrated that while nocturnal awakenings were decreased during the administration of salmeterol, objective findings of overnight pulmonary function tests were not changed.

In summary, these studies show that either a high-potency glucocorticoid inhaler alone or a combination of salmeterol and a steroid inhaler may be a better choice than salmeterol alone for symptoms of nocturnal asthma. Even though nighttime awakenings may be decreased, other parameters of lung function and bronchial hyperreactivity may remain unchanged or worsened with salmeterol alone. Additionally, for all cases of persistent asthma, the current National Asthma Education guidelines' suggest the use of the combination of a long-acting B 2- agonist agent and an inhaled glucocorticoid.

Table 2. SALMETEROL IN ASTHMA: SAFETY CONSIDERATIONS

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Product Information: Serevent (Salmeterol xinafoate) Inhalation Aerosol, GlaxoWellcome, September 1996.11

Conclusions and Recommendations
Controversy continues to surround the use of salmeterol, but three points need to be made. First, most studies show sustained clinical efficacy while continuing to use salmeterol for extended periods of time. Concerns centering on test results which measure bronchial hyperreactivity (i.e., methacholine challenge testing) still need further exploration. There seems little doubt that salmeterol increases the sensitivity of the airways to bronchial provocation when given for extended time periods. However, it has also been shown in several studies that clinical deterioration or decrease in asthma control, usually measured by pulmonary function testing, rarely occurs. It is suggested that patients at particular risk for the reported adverse effects of salmeterol be given special consideration. Those patients who may be at increased risk for bronchospasm and those with a past history of unexplained paradoxical bronchospastic episodes while on short-acting B -agonist agents should be carefully evaluated prior to initiation of therapy with salmeterol.

Secondly, the use of salmeterol in nocturnal asthma seems reasonable when used in conjunction with a glucocorticoid inhaler. If a combination of these agents is prescribed, there seems little need for the addition of theophylline to the regimen. Also, exercise-induced asthma responds well to treatment with salmeterol with effects lasting up to 10 to 12 hours. Lastly, according to the National Asthma Education guidelines,1 salmeterol should not be used alone in the treatment of asthma without prescribing a regularly scheduled inhaled glucocorticoid medication.

Salmeterol appears to be a safe and efficacious drug when used according to the data presented here. Tables 1 and 2 present some salient features from the National Asthma Education guidelines,1 as well as from the manufacturer of salmeterol to help ensure its appropriate place in the management of asthma. Proper patient education by health care professionals at every clinic visit is vital to the success of any asthma medication regimen.

References

1. Clinical Practice Guidelines: Expert Panel Report 2, Guidelines for the Diagnosis and Management of Asthma. National Institutes of Health: National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program. Bethesda, MD NIH Publication No. 97-4051. April 1997.
2. Am J Respir Crit Care Med l995; 152:838-60.
3. Eur Respir J 1997;10:330-6.
4. Pediatrics 1997; 89:655-9.
5. BMJ 1997; 314: 1441-6.
6. Am J Respir Crit Care Med 1996; 154:1603-7.
7. Chest 1996; 109:953-6.
8. Am J Respir Crit Care Med l 997; 155:104-8.
9. Am J Respir Crit Care Med 1997; 155:1241-6.
10. Chest 1997; 111:1249-54.
11. Product Information: Serevent (Salmeterol xinafoate) Inhalation Aerosol, Glaxo Wellcome, September 1996.

PHARMACY AND THERAPEUTICS SUBCOMMITTEE ACTIONS

DRUGS ADDED TO STOCK

BECLOMETHASONE DIPROPIONATE Oral Inhaler: 84 mcg per inhalation Beclomethasone dipropionate 84 mcg per inhalation (Vanceril[R] Double Strength - Schering) oral inhaler is indicated for twice-daily dosing for the maintenance treatment of asthma.

IPRATROPIUM PLUS ALBUTEROL Oral Inhaler: 18 mcg plus 90 mcg Ipratropium plus albuterol (Combivent[R] - BI) oral inhaler is indicated for use in patients with chronic obstructive pulmonary disease who continue to have bronchospasm and require a second bronchodilator.

OLOPATADINE Ophthalmic Solution: 0.1% Olopatadine (Patanol[R]. - Alcon) is an H1-receptor antagonist and mast cell stabilizer that is indicated for the temporary prevention of allergic conjunctivitis.

ADDITIONAL ACTIONS

ENOXAPARIN (LOVENOX[R]) A 40 mg per 0.4 ml syringe has been added to stock.

TROGLITAZONE (REZULIN[R]) A 300 mg tablet has been added to stock. NOTE: The prescribing of troglitazone is restricted to Endocrinology.

DRUGS DELETED FROM STOCK

BECLOMETHASONE 42 MCG PER INHALATION (VANCERIL[R]/BECLOVENT[R]) ORAL INHALER This product is being replaced with beclomethasone 84 mcg per inhalation (Vanceril[R] Double Strength) oral inhaler.

FLUTICASONE 44 MCC PER INHALATION (FLOVENT[R]) ORAL INHALER Deleted due to low use. Flunisolide, triamcinolone, and beclomethasone double strength oral inhalers are available.

PROGESTERONE 25 MG SUPPOSITORIES Discontinued due to low use; 50 mg and 200 mg suppositories are available.

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