Ozone Aid May Be Life Threatening to Low Income Asthmatics

WASHINGTON, DC, June 14, 2004 (ENS) - Two alternatives to inhalers that deplete the ozone layer are now on the U.S. market, so the U.S. Food and Drug Administration is seeking public comment on a proposal to withdraw essential use status under the Montreal Protocol for the ozone depleting inhalers now in common use. Both alternative products are safe and effective, but the higher price of ozone friendly inhalers may keep as many as a million canisters each year from reaching patients, the agency predicts.

Metered dose inhalers are small, pressurized aerosol devices that deliver a measured dose of a drug from a canister into the mouth for inhalation into the lungs. The drug most often used is known as albuterol in the United States, or salbutamol elsewhere in the world.

Chlorofluorocarbons (CFCs) have been the propellants in metered dose inhalers used by people with asthma, emphysema and chronic bronchitis to prevent and ease spasms. But CFCs damage the stratospheric ozone, which shields the Earth from the Sun's harmful ultraviolet rays.

Albuterol metered-dose inhalers have been using trichlorofluoromethane (CFC-11) and dichlorodifluoromethane (CFC-12) as propellants.

Both of the alternative products use the hydrofluoroalkane HFA-134a as a propellant, replacing the CFCs. HFA-134a, an inert gas, does not affect stratospheric ozone, the agency says.

Because albuterol is fast acting, albuterol metered dose inhalers are used as rescue inhalers for treatment of bronchospasm during acute episodes, lifesaving for some patients at certain times.


Today's inhalers deliver an essential medication with a propellant that depletes the ozone layer. Researchers are working on alternative inhalers. (Photo courtesy VCU)
So the FDA says that although there are "compelling reasons" to phase out the use of these products, public comments will help in weighing the potential public health impacts of a phaseout.

The alternatives are Proventil HFA, an albuterol sulfate metered dose inhaler which was introduced into the U.S. market in 1996, and Ventolin HFA, an albuterol sulfate inhaler, which went on the market in February 2002.

Under the Montreal Protocol on Substances that Deplete the Ozone Layer and the U.S. Clean Air Act, production and import of CFCs have been banned for all commercial purposes in the United States since January 1996.

The only exceptions are products that are considered medically essential with no suitable alternatives. Albuterol CFC metered-dose inhalers for asthma and other chronic respiratory diseases have been considered exceptions from the ban.

But under the Montreal Protocol and the Clean Air Act, the United States is expected to phase out these products when suitable alternatives are available, and a resolution passed each year by the governments that are parties to the protocol urges the early phaseout of inhalers using CFCs as propellant.

Fran Du Melle, executive vice president of the American Lung Association, submitted a citizen petition to the FDA on behalf of the U.S. Stakeholders Group on MDI Transition in January 2003. The petition requested that the agency initiate rulemaking to remove the essential-use designation for albuterol metered-dose inhalers.

The Lung Association expressed concern that the parties to the Montreal Protocol could refuse to allocate CFCs for use in albuterol CFC inhalers, adversely affecting a smooth transition that ensured adequate supplies of both albuterol CFC and the albuterol HFA inhalers.

Another concern expressed in the petition was the possibility that supplies of pharmaceutical grade CFCs could be interrupted by actions of other countries.

The Food and Drug Administration said, "We concluded that the petition, though informative, did not provide the level of evidence needed for us to initiate rulemaking. This proposed rule is being issued on our own initiative in accordance with the Clean Air Act and the Montreal Protocol."

Commenters included inhaler manufacturer GlaxoSmithKline (GSK), Honeywell Chemicals (Honeywell), National Economic Research Associates, Inc., patient advocacy groups, a drug industry association, and a law firm.


Ventolin inhaler and medication (Photo credit unknown)
Determining whether the albuterol HFA inhalers would perform as well as the albuterol CFC inhalers have performed was straightforward for most criteria, the agency said. The same substance is being delivered in the same way - inhalation. The devices are similar, and the albuterol HFA inhalers only a little more time consuming to maintain.

In the seven years Proventil HFA has been on the market and the two years Ventolin HFA has been sold, the agency says it has received no reports of unexpected adverse events, or any unanticipated problems with the safety, effectiveness, tolerability, and patient acceptance, when the products are properly used.

The most difficult criterion to apply, said the agency, is whether supplies and production capacity for the albuterol HFA inhalers will be sufficient to meet patient needs once the old albuterol CFC inhalers are phased out.

Industry is reluctant to establish new manufacturing facilities to ensure adequate supplies and production of albuterol HFA inhalers without assurance that albuterol CFC inhalers will be phased out, the agency explained.

At the same time, the agency said it cannot eliminate the essential use of CFCs for albuterol inhalers until adequate supplies and production of alternative products is assured.

Inhaler manufacturer GlaxoSmithKline told the agency they could have capacity to produce adequate supplies of Ventolin HFA within 12 to 18 months of the start of their production scale-up, which the agency presumes would start when the final rule eliminating the essential use of ozone depleting substances is published.

But GlaxoSmithKline did not describe the circumstances that were presumed for their 12 to 18 month projection, nor did the company explain what they meant by “adequate supplies and production capacity.”

The manufacturer of Proventil HFA, the 3M Company, has not submitted any comments on the Stakeholders’ petition and the Food and Drug Administration says it has no information about their plans regarding future supplies and production capacity.


Proventil inhalers deliver the medication without destroying the stratospheric ozone layer. (Photo credit unknown)
The agency has "tentatively concluded" that capacity to produce adequate supplies of albuterol inhalers propelled by hydrofluoroalkane HFA-134a could be in place no sooner than 12 months after date of publication in the Federal Register of the final rule.

Price is an issue, however. Current retail prices of Proventil HFA and Ventolin HFA are in excess of $20 more than the prices of generic albuterol CFC inhalers.

Even a minor price change "could amount to as many as a million" inhaler canisters not purchased each year, the FDA says. Private and public health insurance should ease some of the anticipated adverse impacts of price increases, the agency said, though differences in co-payments between generics and branded products may make the CFC-free inhalers more expensive for even insured patients.

GlaxoSmithKline has offered to provide two million free HFA canisters a year, once the essential use waiver is lifted and the CFC-free inhaler rule goes into effect. Still, the agency says it needs more information to determine how access to inhalers for low-income, uninsured patients might be affected by higher prices after the essential use waivers for CFC inhalers run out.

Low income communities are likely to have a high proportion of asthmatics as industrial facilities that emit air pollutants that may trigger asthma are often sited near such communities. Residents in low income housing may also be at greater risk of asthma triggers such as dust mites, cockroaches, rodents, moisture and mold.

Prices will come down once low cost generic copies of Proventil HFA and Ventolin HFA are available, which could be in either 2010 or 2015, depending on which patents control the availability of generic alternatives.

The agency is considering extending the date when the essential use waiver is phased out to match the dates when low cost generic HFA inhalers are available, but there is a catch.

"Such an outcome," the agency explains, "rests on the assumption that the United States can continue to successfully petition the Parties to the Montreal Protocol to grant the United States an essential use exemption for CFCs for use in albuterol metered dose inhalers for a time period up to 2010 or 2015."

The United States has received approval for an essential use exemption for 2005, and a request for an exemption for 2006 is pending for consideration by the Parties to the Montreal Protocol in November 2004.

"The Parties will not approve U.S. essential use exemption requests indefinitely," the FDA warned.

A 60 day public comment period on the proposal to remove the essential use designation for CFC propelled inhalers is now open. It ends August 10. "We welcome the submission of additional information on the production and supply of alternative products," the agency said, "and the time it may take to put in place any additional production capacity that may be needed to meet projected U.S. needs."

View the proposed rule online at: http://www.fda.gov/OHRMS/DOCKETS/98fr/03p-0029-npr0001.pdf