Friday, January 20, 2012

1960-2012: Evolution of asthma controller meds

Previously I described the history of steroids for the use of asthma, and how inhaled steroids became the preferred method of preventing asthma.  In this post I shall list the asthma controller medicines that have been used since the 1960s.

The following are asthma controller medicines past and present:

1.  Beclomethasone:   First marketed by Allen & Hanbury in 1960 and marketed as Becotide in 1972 overseas with a recommended frequency of two puffs four times daily.  GlaxoSmithKline's version of beclomethasone was Vanceril, and Schering-Plough's version was Beclovent, and both were approved by the FDA for sale in the U.S. in 1982.  Other oversease brand names are Becloforte, and Beconaise.  The initial inhalers were made with the chlorofluorocarbons (CFC) propellant and these have all been since phased out in favor of the HFA verions called Qvar (see below)

2.  Fenoterol:  It was a non-selective long acting beta agonist that asthma patients were allowed to use at home.  It was marketed as Barotek.  It was introduced to the market in New Zealand in 1976.  Shortly thereafter the asthma death rate soared in New Zealand to a rate significantly higher than other nations.  Fenoterol overuse was blamed for the deaths, however, this was never proven.  Some believe that poor education about asthma medicines encouraged some asthmatics to continue using the medicine instead of seeking help.  The New Zealant asthma death rate declined slightly after warnings were incorporated into the package in 1981, yet the death rate in New Zealand continued to be higher than other nations.  The death rate fell 50 percent in 1990.  Despite the warnings, sales of the product remained consistent and actually increased slightly in 1989-90.  (1)  Despite consistent sales, the product was taken off the market in the 1995 due to the scare. The product was also available in Japan and Canada.

Intal Spinhaler
3.  Chromolyn:  The Intal Spinhaler hit the market in the 1960s.  It was and was prescribed as an alternative to inhaled corticosteroids to treat inflammation in asthmatic airways.  It was popular in the 1980s and 90s.  You can read more about the Intal Spinhaler here.  The main problem with the spinhaler was the powder inhaled often precipitates coughing and asthma, plus the patient has to handle each dose.  The FDA approved an MDI (with the CFC propellent) in 1992 which ultimately replaced the spinhaler.  Due to decline in prescriptions of the medicine and the Montreal Protocol's ban on CFC inhalers, the medicine was phased out by December 31, 2010.

Azmacort inhaler
4  Triamcinolome:  It was introduced to the market by in the early 1980s as Azmacort and approved by the FDA in 1984.  It's formula was slightly stronger than beclomethasone and became another inhaled steroid option.  It was the first inhaler to come with its own built in spacer, which assured proper use of the inhaler, and increased compliance.  However, it was bulky and difficult to carry.  Sales started to decline in the late 1990s due to long acting inhaled steroids that required fewer puffs, such as fluticasone  After the declaration by the Montreal Protocol the  medicine was phased out by December 31, 2010.  However, in 2008 the FDA approved an HFA version which continues to be an option to this day. 

Tilade inhaler
5  Nedocromil Sodium:  It was approved by the FDA and introduced to the market in 1993 as an alternative to Tilade  It was an inhaler with the CFC propellant  Since sales of this product declined by the late 1990s due to better asthma controller medicines on the market. After the Montreal Protocol set a timetable to ban the use of the CFC propellant in asthma inhalers, the product was phased out by June 14, 2010.

6.  Flunisolide:  It was approved by the FDA in 1982 introduced to the U.S market as Aerobid.  This turned out to be perfect timing for entry into this market, because in 1989 the National Heart, Lung and Blood Instute's (NHLBI) Asthma Guidelines were created.  The guidelines recommended inhaled steroids as a top line asthma treatment, and sales of inhaled steroids skyrocketed, with Aerobid leading the way. Aerobid was the best selling inhaled steroid during the 1990s mainly because it had a stronger formula than triamcinolome and beclomethasone requiring fewer puffs to achieve the desired dose.

Aerobid inhaler
7.  Fluticasone: The Flovent CFC MDI was approved by the FDA and entered the market in 1996.  By 2000 the Flovent Diskus was approved as the DPI version of the medicine.  Soon thereafter the CFC MDI was taken off the market.  The Flovent HFA MDI was approved by the FDA in 2004.  The doses were:  44 mcg, 110 mcg, and 220 mcg.  The medicine is a stronger inhaled steroids than its predicessors and only needed to be taken twice daily.  One puff of the Diskus is equal to 2 puffs of the MDI.

8.  Salmeterol:  It was approved by the FDA in 1994, and became the latest long acting beta adrenergic (LABA) to enter the market.  The medicine attached to beta 2 adrenergic receptor sites in the lungs and continued to release the medicine for up to 12 hours.  All that was needed was two puffs twice a day. The Advair Diskus, a dry powdered inhaler, was approved by the FDA in 1997.  The diskus was green to distinguish it from the brown Flovent Diskus and eventually the Advair purple Diskus).  By 2008 some suspected the medicine was the cause of asthma related deaths and a black box warning was placed on the product.  The NHLBI Asthma Guidelines ultimately recommended the medicine not be used by itself in the treatment of asthma.  If asthma is bad enough that this medicine is needed, the guidelines recommended taking it with an inhaled steroid to control inflammation.  The product is still available as a treatment for other lung diseases such as COPD.

Advair Discus
9.  Advair:  This is a combination drug with both Fluticasone and Salmeterol that was introduced to the market in the 1990s, approved by the FDA in 2000 for ages 12 and up.  The recommended dose is 100/50 (Fluticasone/Salmeterol), 250/50, and 500/50.  It's recommended to start at the lower dose and increase as needed.  The 100/50 dose was approved for children ages 4 and up in 2003.  Some patients, especially younger ones and the very old, may have trouble generating enough flow to actuate the medicine.  For these patients an Advair HFA inhaler was approved by the FDA in 2006 that can be used with a spacer to improve coordination.  Source for above dates is

The medicine was marketed as an asthma controller medicine to prevent bronchospasm and inflammation in asthmatic lungs to prevent asthma.  Because it combined the two medicines and the frequency is one puff twice daily, it greatly improves compliance with asthma medicine (I can personally attest to this).  Sales skyrocketed during the 2000s and it continues to be the top selling asthma controller medicine. Some fear salmeterol is related to asthma deaths and a black box warning was placed on the packaging in 2008.  I wrote about this in more detail here.The patent for Advair expired in the U.S. in 2010 and will expire by 2012 in most European countries.  It's expected that soon generic products will enter the market which would increase competition and lower the cost of the inhalers (currently priced at over $100).

Foradil Inhaler
10.  Formoterol:  Introduced to the market as an alternative to salmeterol.  The Foradil Aerolizer was approved by the FDA in 2001 and the product was marketed in the U.S.  Oxeze, Atock, Atimos and Performist were common names used overseas.  The Foradil Aerolizer was a dry powdered version of the medicine.  The Foradil Centihaler was approved by the FDA in 2006. The NHLBI Asthma Guidelines ultimately recommended the medicine not be used by itself in the treatment of asthma.  If asthma is bad enough that this medicine is needed, the guidelines recommended taking it with an inhaled steroid to control inflammation.   According to the, as of 2007 there were no FDA approved formoterol products on the market in the U.S.  However, it's currently marketed by AstraZeneca in other countries as the Oxis Turbohaler.  The medicine is available, however, in the combination inhaler sold by AstraZeneca known as the Symbicort inhaler (see below).

11  Budesonide:  The inhaled steroid solution of Pulmicort was introduced to the market in the early 1980s as the only inhaled steroid available as a solution for home use.  Studies showed it was the safest and best corticosteroid solution.  It was mainly prescribed for kids, however it's recommended for any asthmatics who requires inhaled steroids and has trouble coordinationg an inhaler. From what I can tell it has the same potency as Flovent.  A Pulmicort Turbohaler hit the market in the late 1980s as the first corticosteroid as a dry powder inhaler.  In 1997 the Pulmicort Turbohaler  was approved by the FDA as the first DPI inhaled corticosteroid.  The inhaler never caught on and was later discontinued.  In 2000 Pulmicort Respules became the first corticosteroid nebulizer solution to be approved by the FDA.  However, due better inhaled steroids and the Monteral Protocol, the Pulmicort Turbohaler was phased out by June 30, 2011.  The Pulmicort Respules continue to be marketed as an inhaled corticosteroid option for children and adults with poor coordination skills with their corticosteroid MDIs.

Symbicort inhaler
12.  Symbicort:   Marketed by AstraZeneca and approved by the FDA in 2006. 
It basically works the same as Advair except the LABA (formoterol) is faster acting and appears to have a stronger cardiac effect.  The steroid in this inhaler is mometasone furoate (see below).  It's availabe as either a metered dose inhaler or dry powder inhaler via the Turbohaler.  Note:  Some countries have adopted the Symbicort Smart program whereby you can use your Symbicort as a rescue inhaler.  I wrote about this here

13.  Beclomethasone:  I'm mentioning this again because the older CFC versions of this inhaler were taken off the market and replaced by an HFA inhaler which has been rebranded as QVAR.  It was approved by the FDA in 2000.  The medicine is the same, yet some studies show the smaller particle size allows the medicine to penetrate deeper into the lungs as compared with other inhaled corticosteroids presently on the market.

Symbicort Twisthaler
14.  Mometasone furoate:  It's the latest long acting inhaled corticosteroid to enter the market.  It was approved by the FDA in 2008.  It's a once a day medicine, or twice a day if need be, that was introduced to the market as Azmanex.  It's a dry powder inhaler taken via the Azmanex Twisthaler.  I have never tried this medicne, although I had to teach myself how to use the inhaler so I could teach how to use it to patients. 

15.  Dulera:  It was approved by the FDA in June of 2010.  It hit the market as an alternative to Advair and Symbicort.  It containes Mometasone and Furosimide.  Other than that it works similar to Advair and Symbicort.  Whether one of these works better than the other is a matter of personal choice and physician preference.  I trialed this medicine once and it make my heart beat like a jackhammer and I went back on Advair. 

Singulair pills
16.  Montelukast sodium:  This product was introduced to the market in 1998 as Singulair.  It was the first leukotriene receptor antagonist.  What it does it it blocks the affects of leukotrienes and prevents them from causing inflammation and bronchospasm.  Leukotrienes are released from mast cells during the allergic response along with histamine.  While histamine causes inflammation of the respiratory tract, leukotrienes do this, but they mostly cause bronchospasm.  So Singulair was marketed as a product to help allergic asthmatics.  With insurance these pills cost about $1.00 each, or $30 for a month supply (as of this writing in January 2012). I took this medicine the past three years, but with my doctor's permission I just quit becasue I haven't noticed any results.  My doctor said he's recommending all his asthma patients quit taking it. 

17:  Zafirlucast:  This was another leukotriene receptor agonist admitted to the market as Accolate to compete with Singulair.   It was approved by the FDA in 1999.

18.  Zileuton:  This was another leukotriene receptor agonist marketed as Ziflo.  It was introduced to the market in 2007 and was discontinued in 2008 (you can read the discontinuation letter here).  It failed to take off becaue the other options only had to be taken once daily, while this one had to be taken four times daily. 

19.  Omalizumab:  This is the first medicine on the market to block the effects of IgE, an antibody that is responsible for the allergic response.  The medicine is marketed as Xolair and consists of a series of injections.  It costs $10,000 to $30,000 for an annual prescription, and for this reason it's only recommended for severe, persistent asthma (hardluck asthma) non responsive to other asthma remedies.  It was approved by the FDA in 2003.

Further reading:

  1. Beasley, Richard, Sankei Nishima, Neil Pearce, Julian Crane, "Fenoterol and Asthma Mortality," The Lancet, August 8, 1998, volume 352, Issue 9126, page 486

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