Brovana: First Nebulized Long-Acting Beta2-Agonist for COPD

Arformoterol tartrate inhalation solution (Brovana; Sepracor) is the first inhaled long-acting beta₂-adrenergic agonist to be approved for use with a nebulizer for the treatment of patients with chronic obstructive pulmonary disease (COPD). The other currently available beta₂-agonists indicated for the treatment of COPD—including salmeterol (Serevent Diskus) and formoterol (Foradil Aerolizer)—are administered as dry-powder inhalers, and the only bronchodilators available so far in a nebulized form are short-acting agents.

The National Institutes of Health estimates that more than 12 million Americans have been diagnosed with COPD, but about 24 million adults who smoke have evidence of impaired lung function.

Arformoterol tartrate—a single isomer form of formoterol—was approved by the FDA in October 2006 and is expected to become available in the next few months. Unlike formoterol, it was not studied for asthma therapy.

Nicola A. Hanania, MD, FCCP, director of the Asthma Clinical Research Center at Baylor College of Medicine in Houston, Tex, is a principal investigator of the arformoterol pivotal studies. Dr Hanania emphasizes that in clinical trials, the efficacy of arformoterol was very similar to that of salmeterol, but the new medication has some distinct advantages.

One of the advantages arformoterol has over salmeterol and formoterol is that it is the first long-acting beta₂-agonist to be delivered in a nebulized formulation, instead of by dry-powder devices.

“Many patients with COPD like their inhalers, but others don’t like dry-powder devices, and they prefer a nebulizer ….We now have smaller devices that deliver drugs in a shorter period of time. And a nebulized long-acting agent is a new thing that many COPD patients would prefer,” he explains. Dr Hanania hopes that this appeal will translate into better patient compliance, which is an issue “with any chronic disease.”

Another advantage of arformoterol is its rapid onset of action. Arformoterol “has immediate onset of action, within a minute or two, just like a rescue medication, although it is not approved to be used as a rescue medication. But the action delivers for 12 hours, and it is a twice-a-day medication,” he says.

Mechanism of Action

Beta₂-agonists work by attaching to the beta-receptors on bronchial smooth-muscle cells, Dr Hanania explains. Once this attachment occurs—which happens quickly with arformoterol and formoterol and more slowly with salmeterol—and the receptor is activated, it causes relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, particularly from mast cells.

“Smooth-muscle cells in the airways are not the only cells that have these receptors,” Dr Hanania points out. “These beta-receptors are present in other cells, like inflammatory cells, and there are suggestions from animal studies that beta₂-agonists, including arformoterol, may have several nonbronchodilatory effects that may enhance their effect in the treatment of COPD; however, these effects need to be further evaluated in human studies.”

For now, the most important effect of long-acting beta₂-agonists is significantly improved bronchodilation, he says.

Evidence from Clinical Trials

Arformoterol was evaluated in 2 identical 12-week, double-blind, placebo- and active-controlled, randomized, multicenter, parallel-group, US trials that included a total of 1456 adult patients with COPD (age, 34-89 years). Inclusion criteria were previous clinical diagnosis of COPD; >15 pack-year smoking history; spirometry testing showing forced expiratory volume in 1 second (FEV₁) ≤65% of predicted and >0.70 L; and an FEV₁/forced vital capacity ratio ≤70%.

Each trial compared arformoterol 15 or 25 μg twice daily, and 50 μg once daily with placebo and also included salmeterol, 42 μg twice daily, as an active comparator.

Results of both studies showed that arformoterol offered significantly greater postdose bronchodilation compared with placebo (Table). The 15-μg twice-daily dosage significantly improved bronchodilation in the 12 hours after dosing throughout the 12 weeks of the studies relative to placebo.

The 25-μg twice-daily and 50-μg once-daily dosages of arformoterol offered no additional benefits over the twice-daily 15-μg dose, and they were associated with dose-related side effects.

The median time to the onset of clinically significant bronchodilation was 6.7 minutes in patients treated with 15 μg of arformoterol compared with 30 to 48 minutes with salmeterol.

Prescribing Arformoterol

Arformoterol is indicated for the long-term maintenance of bronchoconstriction in adults with COPD, including chronic bronchitis and emphysema.

The recommended dose is 15 μg twice daily, once in the morning and once in the evening, administered with a standard jet nebulizer attached to an air compressor. The total daily dose should not exceed 30 μg.

Because larger doses used in clinical trials did not improve patient outcomes but did result in an increase in side effects, patients should be told not to take more than the prescribed daily dose (up to 30 μg/day).

This agent is available as 15 μg arformoterol in a 2-mL sterile solution packaged in individually wrapped vials, to be used with the nebulizer.

When prescribing arformoterol, patients should also be prescribed a short-acting inhaled beta₂-adrenergic agonist for the relief of acute respiratory symptoms. The new nebulizer should not be prescribed as monotherapy.

Who Is a Good Candidate?

Dr Hanania advises that arformoterol therapy should be considered in patients with moderate-to-severe COPD who have daily symptoms. Patients with very mild COPD who have intermittent symptoms may be able to control their disease with short-acting agents that can be used on an as-needed basis.

“When…patients with moderate-to-severe COPD have symptoms that occur every day, that’s when the use of a long-acting bronchodilator like arformoterol plays a major role,” he says.

It should not be prescribed in patients with asthma, because it has not been tested in this population. It should also not be used as a rescue medication, because it is not approved as such in this country, and patients should be made aware of this when prescribing this agent, Dr Hanania stresses.

Side Effects, Precautions

The packaging for arformoterol includes a black box warning about the risk of asthma-related deaths with long-acting beta₂-agonists, such as arformoterol. Contraindications and other precautions include:

• Do not use as rescue therapy

• Do not use in patients with acutely deteriorating COPD

• Do not use in children

• Do not coadminister with other long-acting beta₂-agonists

• When beginning treatment, instruct patients to discontinue regular use (>4 times per day) of short-acting beta₂-agonists and to use them only for the symptomatic relief of acute respiratory symptoms

• Use with caution in patients with cardiovascular disease

• Because arformoterol has a pregnancy category C, it should only be used during pregnancy when the benefits to the mother justify the potential risks to the fetus.

In clinical trials, the side-effect profile of arformoterol was similar to that of salmeterol at the approved dose of 15 μg twice a day, Dr Hanania says. At higher doses, there may be a dose-dependent adverse effect. “There is also some evidence of some loss of efficacy that can happen shortly after using this drug, but this effect usually plateaus…with prolonged therapy, and so there is no need for patients to increase their dose with time,” he adds. “But it does occur with this drug, just like it occurs with most other beta₂-agonists, but it is not of major clinical significance.”

Clinical Therapeutics

The most common side effects (reported by ≥5% of patients) in two 12-week trials that compared arformoterol (15 μg twice daily) with placebo, respectively, included pain (8% vs 5%), chest pain (7% vs 6%), back pain 6% vs 2%), diarrhea (6% vs 4%), and sinusitis (5% vs 4%). Leg cramps, dyspnea, and rash were each reported by 4% of patients using arformoterol. The first article describing these studies will be published in an upcoming issue of .

Drug Interactions

A number of drugs may interact with arformoterol, including other adrenergic agents, aminophylline, theophylline (eg, Bronkodyl, Elixophyllin), steroids, diuretics (including potassium-sparing diuretics), monoamine oxidase inhibitors, tricyclic antidepressants, drugs known to prolong the QT_c interval, and beta-blockers.