Issues in the pharmacotherapy of asthma

February 2002

Specific topics to be reviewed include newly available drugs, changes in the content of currently available drugs, the withdraw of several products from the commercial market and new guidelines for the treatment of asthma during pregnancy.

New drug products

Two relatively new drug products are now available to clinicians for their patients with asthma – Advair Diskus (GlaxoSmithKline) and Foradil Aerolizer (Novartis); both are dry powder inhalers.

Advair Diskus is unique in that it is a combination product of an inhaled corticosteroid (fluticasone) and a long-acting ß-2 agonist (salmeterol). Advair is a dry powder inhaler and therefore its technique of use (quick and deep inhalation) differs from metered-dose inhalers. It is also important for patients to understand that appropriate use of this dry powder inhaler includes avoidance of moisture (eg, washing the mouthpiece) to prevent clogging.

Advair’s indications include maintenance treatment of asthma for patients 12 and older. Even though Advair contains a ß-2 agonist, salmeterol, a long-acting agent whose onset of action is relatively long (30 minutes), it should not be used for acute symptoms. Patients should also have a short-acting ß-agonist inhaler (eg, albuterol) to use, and it is important that they understand the role and use of each inhaler (ie, for chronic or use as needed).

Available strengths include 100 µg, 250 µg, and 500 µg of fluticasone; each of these strengths also contains 50 µg of salmeterol. Dosing is twice daily, and specific strengths to use may depend upon previous inhaled corticosteroid therapy. Fluticasone and salmeterol as separate agents are appropriate treatment choices for patients with persistent asthma. Their use together is one such treatment option for patients with moderate persistent asthma, according to guidelines from the NIH.

A long-acting bronchodilator may be especially useful for patients with nighttime symptoms. The benefits of inhaled corticosteroids in the treatment of asthma are generally well accepted; however, their potential for serious adverse effects, especially when used in higher doses, is concerning, and often prompts clinicians to use supplemental agents to keep inhaled corticosteroid dosages as low as possible. The benefits of using an inhaled corticosteroid together with a long-acting ß-2 agonist have recently been reported. Studies have shown that adding a long-acting ß-2 agonist to inhaled corticosteroid therapy is more beneficial than increased inhaled corticosteroid doses alone.

Lemanske and colleagues attempted to determine if inhaled corticosteroid therapy could be eliminated after addition of salmeterol in patients with persistent asthma. Patients aged 12-65 years who were previously receiving triamcinolone and who were considered suboptimally controlled were randomized into several groups: triamcinolone plus placebo or traimcinolone plus salmeterol. It was found that in patients receiving triamcinolone and salmeterol together, triamcinolone doses could be reduced by 50% without significant loss of asthma control. Complete elimination of triamcinolone was attempted but was not possible.

This has important implications for the treatment of asthma, by potentially lowering inhaled corticosteroid dosages and their risk of adverse effects. It has been previously shown that ß-agonists and corticosteroids, when used together, may provide several pharmacologic benefits. ß-agonists may effect the glucocorticoid receptor such that its activation is enhanced when corticosteroids are administered therapeutically. As well, corticosteroids may increase ß-2 receptor synthesis in addition to decreasing their desensitization. It is also important to consider that although lowering inhaled corticosteroid dosages may be beneficial in reducing risks of adverse effects, reduced dosages may also lower the beneficial effects corticosteroids can have on the progression of asthma (eg, airway remodeling), which may not be as readily apparent in short-term studies. More studies in this area are needed to define which patients’ inhaled corticosteroid doses can be reduced, and by how much, without affecting disease control, symptoms and progression. Therefore, Advair provides yet another drug product clinicians and patients may choose for asthma control. The combination of two useful drugs together in one product can simplify a patient’s therapy.

Foradil Aerolizer, formoterol fumarate, is another long-acting ß-2 agonist, newly available as a dry powder inhaler. Foradil is approved for use in patients 5 years and older for the maintenance therapy of asthma and for prevention of exercise-induced asthma ( >12 years ). Foradil is comparable to salmeterol by having twice daily dosing and bronchodilatory effects for up to 12 hours; as well, neither should be used for relief of acute symptoms. A difference between Foradil and Serevent (salmeterol, GlaxoSmithKline) that is unlikely to be clinically important is onset of action. Salmeterol’s onset of effect is relatively long (30 minutes) as compared with formoterol (15 minutes); this is less than the onset of short-acting ß-2 agonists, such as albuterol. Thus, the use of formoterol over albuterol (with a duration of effect of several hours) to prevent exercised-induced asthma is unlikely to be greatly beneficial.

New products with hydrofluoroalkane

Several newly formulated products for the treatment of asthma have recently become available. The active drug in these metered-dose, orally inhaled products is not new, but the propellant is – hydrofluoroalkane (HFA). This has replaced chlorofluorocarbon (CFC), which has been linked to depletion of the planet’s ozone layer. Several products are now available with hydrofluoroalkane: Qvar (beclomethasone, 3M Pharmaceuticals), Ventolin HFA (albuterol, GlaxoSmithKline), and Proventil HFA (albuterol, Schering). More drug products with HFA in place of CFC are expected to be released over the next few years. This is due to requirements that all products (drug and nondrug) with CFC be reformulated to phase out use of CFCs. These requirements stem from the Montreal Protocol on Substances that Deplete the Ozone Layer adopted in 1987. Medicinal devices, such as metered-dose inhalers (MDIs), containing CFCs will not be removed from the commercial market until CFC-free products are available. Patients should be informed of this, as it is possible that lay publications may imply a shortage of current MDIs for asthma treatment.

Propellants such as CFC and HFA propel the active drug in MDIs to the lung. CFCs have been linked to depletion of Earth’s ozone layer, which can cause an increase in ultraviolet radiation reaching Earth’s surface, and a subsequent increase in the risk of skin cancer, cataracts and other health problems. CFCs are released into the environment, albeit in small amounts, by an individual patient. Comprised of fluorine, chlorine and carbon, CFCs are resistant to degradation and when released into the environment (ie, when MDIs are actuated) they eventually (over several years) rise to the ozone layer, approximately 10-20 miles into the atmosphere. CFC compounds can remain in the atmosphere for 100 years while eventually being degraded by the sun’s radiation. Once degraded, chlorine is released; one chlorine atom can destroy more than 100,000 ozone molecules. One study has estimated that a 1% decrease in the ozone concentration may increase the risk of nonmelanoma skin cancer by 2%. The Montreal Protocol states CFC production should cease by 2005-2006, although the FDA has not yet determined exactly when all CFC–containing drug products should be phased-out.

Qvar is a MDI formulated with HFA. Use of HFA results in delivery of beclomethasone in smaller particle sizes, which allows use of smaller doses for equal clinical effect. When transitioning patients to Qvar, the manufacturer recommends initiating doses at one-half of the prior CFC-containing beclomethasone product dose. Qvar is available as 40 µg and 80 µg dosage strengths. Ventolin HFA and Proventil HFA dosages remain the same as CFC-containing products. When transitioning to non-CFC products, it is important that clinicians discuss the change with their patients, as non-CFC products may appear different (eg, forcefulness of spray, taste), or care of the new product may differ. The product’s package insert should be followed.

Treatment of asthma in pregnancy

New treatment guidelines for the treatment of asthma in a pregnant patient have been published. While the NIH asthma guidelines also include information about asthma therapy during pregnancy, information on newly available drugs is included in these recent guidelines. Most drugs used for asthma therapy are relatively safe when taken in pregnancy. Certainly, consideration of the risk-benefit ratio (ie, risk of drug therapy vs. risk of uncontrolled asthma vs. benefit of controlled asthma) of drug use during pregnancy should be discussed with pregnant patients. Inhaled ß-agonists are relatively safe to use, as are inhaled corticosteroids. Drugs that may potentially result in adverse fetal outcomes include Zyflo (zileuton, Abbott) and pseudoephedrine (for concomitant allergic disorders).

Zyflo, a leukotriene modifying agent, has been linked to adverse fetal outcomes in animal models. Pseudoephedrine has been recently linked to new data indicating a possible relationship between its use and development of gastroschisis. It is also possible that use of other systemic decongestants may result in similar outcomes.

Lastly, clinicians should be aware that several theophylline-containing products have recently been withdrawn from the commercial market by manufacturers. New agents and products introduced into the market in recent years have caused theophylline products to be used less, thus reducing profits for manufacturers. Theolair-SR, Theo-Dur, Uni-Dur, Slo-Bid and Slo-Phylline, are no longer produced. T-Phyl, Theolair, and Uniphyl will continue to be manufactured, as will several generic formulations. If switching a patient to a new theophylline product, it is wise to verify attainment of therapeutic blood levels, as differences in product bioavailability may be possible.

For more information:

• Lemanske RF. Inhaled corticosteroid reduction and elimination in patients with persistent asthma receiving salmeterol, a randomized controlled trial. JAMA. 2001;285:2594-2603.
• FDA Web site: www.fda.gov/cder/mdi/default.htm.
• Dombrowski MP. The use of newer asthma and allergy medications during pregnancy. Ann Allergy Immunol. 2000;84:475-480.