WASHINGTON, March 11 -- Physicians have heard the complaints.
The plume is much weaker: it doesn't propel medicine into the lungs.
It tastes different. There's no blast of cold air.
It just doesn't work.
The griping has become more common since a ban on chlorofluorocarbons (CFCs) in albuterol metered dose inhalers (MDIs) took effect on Jan. 1.
By that date, 40 million asthma patients in the U.S. were to have switched to inhalers using hydrofluoroalkane (HFA), a propellant that's more environment-friendly.
Some critics of the switchover say primary care physicians may not have been properly prepared to handle the transition.
There certainly are differences between the new HFA inhaler and the old CFC design, but researchers say they're not therapeutic differences. Yes, they say, the plume is weaker. And it lacks that initial cold air blast. But experts insist it works just as well.
Convincing patients that they're still receiving the full benefits of albuterol may be a challenge, since primary care physicians haven't received much information about the transition.
"Everyone knows about the switch from analog to digital television," said Nancy Sander, president of Allergy and Asthma Network Mothers of Asthmatics (AANMA), a patient advocacy group. "But no one knows about the switch from CFC to HFA inhalers."
Sander said physician education could allay some patient fears. A closer follow-up of the transition could help as well, she added, since there's little documentation of problems beyond complaints filed in the FDA's adverse events reporting system.
With a formal follow-up, if more patients are in fact going to the emergency room because the inhalers don't stop asthma attacks, there will be hard epidemiological evidence, she added.
Finding an Alternative
Sanders said federal regulators overlooked a physician education campaign when they decided to ban CFC inhalers.
In the run-up to the switch, the FDA was primarily concerned with finding an alternative propellant to CFC and assuring an adequate supply of the new inhalers. That done, the agency decided in 2005 that the transition deadline would be Dec. 31, 2008.
CFCs in inhalers were among the last ozone-depleting substances banned from consumer products. The chemical has long been purged from more obvious items such as air conditioners, refrigerators, and hairsprays, thanks to national and international regulation during the 1970s and 80s.
The Montreal Protocol -- a global treaty to save the stratosphere's ozone layer by reducing the use of ozone-depleting substances -- was ratified in 1987. But CFCs in inhalers were temporarily exempted by their "essential-use" status because there were no alternatives at the time.
The industry subsequently developed CFC-free devices, which have now been available for more than a decade. But before 2008, the FDA estimated market penetration of HFA inhalers at a mere 5% to 10%.
As recently as May, some 65% of inhalers were HFA-propelled, while 35% used CFCs.
At that point, the HFA market was split among four HFA inhalers, all of which are currently patent-protected: Ventolin by GlaxoSmithKline, ProAir by Teva, Proventil by Schering-Plough, and Xopenex by Sepracor (whose active ingredient is levalbuterol, not albuterol).
The products were declared safe and effective after a host of clinical trials that the FDA relied on in its decision to ban CFC inhalers.
In a 2007 review in the New England Journal of Medicine, Leslie Hendeles, Pharm.D., of the University of Florida, and colleagues reported that patients using the two types of inhalers showed similar bronchodilation and increases in forced expiratory volume.
They also cited postmarketing studies that found no increase in hospitalization rates for respiratory problems with HFA versus CFC albuterol.
"Under rigorous scientific studies, there's not a detectable difference between HFA and CFC in a number of different study designs," Dr. Hendeles said. "So I am absolutely convinced that it's not a difference in the drug product, but in how it's being used."
Patient Concerns
Some patients aren't as confident in those findings.
In 2008, the FDA's Adverse Events Reporting system (AERS) received more than 330 complaints about the new inhalers, although FDA spokesperson Christopher Kelly said not all of them can be classified as adverse events because some patients were only reporting financial problems obtaining the drug.
Kelly said the database recorded a similar number of complaints about the new inhalers in 2007.
Some "good" asthma patients, who say they've always had their condition under control, insist the new inhalers don't work.
Brittany Grayson, 24, who works for a nonprofit agency in Washington, said she was always able to manage her asthma until she had to make the switch.
"With my old inhaler, you could feel the drug drift into your trachea in a cloud," she said. "With this new one, the drug seemed to stop at my teeth."
When she couldn't clear her lungs after a family vacation in smoke-filled Las Vegas, only her nebulizer brought her relief. She says she has also had to cut back on hiking, swimming, working out, and playing the flute.
"I had to cancel a long hike I'd been looking forward to because I wasn't confident that I could go six miles into the mountains and be able to breathe," she said. "I don't like feeling constrained by my asthma."
As a self-described environmentalist, Grayson wonders how much of an impact CFCs from inhalers actually have on the environment.
Estimates of the amount of CFC released by inhalers ranged from 0.1% to 1% of the total, a proportion Sander called "negligible."
Although she cares about the environment, Grayson said she's concerned not only about herself, but about other patients whose asthma isn't as mild as hers.
Her physician told her to use a spacer with the HFA inhaler, and to take three puffs instead of her regular two to get the same amount of albuterol into her lungs that she got from the old CFC inhaler.
What to Tell Patients
That's fairly consistent with the instructions other physicians are giving their patients. Most have noticed three key differences in inhaler use: priming, cleaning, and inhalation technique.
"[The HFA inhalers] are much less user-friendly than previous CFC inhalers," said Bradley Chipps, M.D., a pulmonologist in Sacramento, Calif., and fellow of the American Academy of Allergy, Asthma, and Immunology (AAAAI).
He said HFA inhalers must be primed and actuated more frequently than their predecessors, and each of the four inhalers has different directions for priming and storing.
"My message to patients is to read the package insert and follow the instructions for your specific inhaler," Dr. Chipps said.
Cleaning the inhaler is also more important with HFA models, because they are more likely to become clogged.
Hendeles said patients need to rinse an HFA inhaler with warm water once a week and let it air dry.
Also, some physicians say the change in spray should prompt some patients to check their inhalation techniques.
The less forceful HFA-propelled spray doesn't prevent medication from reaching the lungs, Hendeles said, although it may require a slower inhale.
Dr. Chipps said he tells patients to take three or four puffs from the HFA inhaler, instead of the two they took with CFC-propelled devices.
In addition to a weaker spray, patients also complain about a strange taste. Hendeles said that's a result of differences in other inactive ingredients, especially excipients, which help aerosolize the drug.
In fact, each inhaler has a different formula. Ventolin has no extra inactive ingredients. ProAir has ethanol and Proventil has ethanol and oleic acid. Xopenex has dehydrated alcohol and oleic acid.
Sander says many of the complaints her organization receives concern the brands that have alcohol, which is a known airway irritant.
In addition to changes in priming, cleaning, and breathing technique, patients have to pay significantly more for the new inhalers, which are still on patent. Whereas CFC inhalers cost $5 to $25 apiece, HFA inhalers range from $30 to $60.
The FDA says the drugs will remain on patent until about 2012, when generics will become available. Sander said several drug companies offer assistance programs or coupons to patients who cannot afford the devices.
Some Skeptical
The new procedures appear to be well known among allergists and immunologists, but less so among practitioners of internal medicine.
Asriani Chiu, M.D., of the Medical College of Wisconsin, who is also an AAAAI fellow, said her organization kept her well informed of the transition. But her husband, an internist, wasn't as familiar with it.
"He felt that he was not well educated on how to address patients' concerns [about the new inhalers]," Dr. Chiu said. "In fact, I remember forwarding him information from our organization."
Michael Light, M.D., a pulmonologist at the University of Miami, said he, too, had to look up information on the transition after several patients complained about the new inhalers.
But Dr. Light and some colleagues say better education programs may not necessarily aid the transition: he's skeptical about the new devices themselves.
"I feel the patient knows what's working and what's not," he said.
If a patient feels an HFA inhaler works, he tells them to continue with it. In other cases, he still prescribes MaxAir, the lone CFC-propelled inhaler still on the market. The device benefited from a loophole because it contains pirbuterol, not albuterol.
Arthur Abramson, president of the National Campaign to Save CFC Asthma Inhalers, is similarly skeptical.
"I would be amazed if it turns out that only 1% of the patient population has serious problems with HFA MDIs that they never had with CFC MDIs," Abramson said. "But even a 1% adverse reaction rate would mean that potentially hundreds of thousands of patients are being harmed due to HFA MDIs in the U.S. alone."
On the other end of the spectrum, Sander says if HFA inhalers don't work for patients, it may indicate their asthma was worse than they thought.
"It is highly likely that these are patients whose asthma was not well controlled for years," she said. "They tend to go through one or more inhalers per month."
Dr. Chiu said the transition may be a "blessing in disguise" by forcing patients and physicians "to focus more on the treatment of the underlying inflammation, thus using more preventative inhalers like inhaled corticosteroids."
Sanders noted that inhaled corticosteroids have similarly migrated to HFA propellants, but with no complaints.
To quell patient fears, some critics want a large-scale epidemiological study to assess risk. That's why Sander said her organization has requested that a major federal agency -- possibly the CDC, the National Institutes of Health, or the Centers for Medicare and Medicaid Services -- perform a prospective study of HFA inhalers after the transition.
"Have we seen an explosion of emergency room visits due to asthma since Jan. 1?" Sander asked. "No one knows, because nobody's looking."
Most physicians agree that such information could not be detrimental, only helpful.
"It's either going to allay concerns," Dr. Chipps said, "or strike a chord for more studies."