Monday, March 21, 2016

1970-2017: Asthma Controller Medicines

For most of history, asthma treatment focused on treating acute (it's happening now) symptoms. The ongoing quest to understand our disease eventually lead to the introduction of new lines of medicines that dealt with the underlying cause of asthma, rather than just the symptoms. These medicines helped shift the focus of asthma treatment away from treating acute symptoms and towards controlling asthma and preventing symptoms. Here is a list of what we would now consider asthma controller medicines. Considering this change in how asthma was treated occurred during my lifetime, I will also include my experience with these medicines.

Barotek
1976: Fenoterol: This medicine was never approved by the FDA, and therefore was never available for sale in the U.S. It was the first non-selective long acting beta agonist (LABA), a long acting bronchodilator, the first such medicine introduced to the market. It was the AMC Pacer of asthma medicines, as it was a noble idea that was ahead of its time.

It was marketed as Barotek, and introduced to the market in New Zealand in 1976.  It was available as 100 mcg. Shortly thereafter the asthma death rate soared in New Zealand to a rate significantly higher than other nations. The Fenoterol inhaler was blamed for the spike, although this was never proven.

Some believed that poor education about asthma medicines encouraged some asthmatics to continue using the medicine instead of seeking help.  The New Zealand 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. The failure of this product would sort of set the floor to how future LABAs would be introduced to the market.

Theo-Dur
1979: Theo-Dur: This is slow release theophylline. It comes in various doses, such as 100, 200 and 300 mg. Theophylline is a white, crystalline powder, so the pills are oval and white.  Researchers still don't understand the exact mechanisms how it works, although they are aware that it helps to relax bronchial smooth muscles to keep airways open long term (it's a bronchodilator). Research also shows that it might have some anti-inflammatory properties as well. Theophylline was available since the 1950's, but the introduction of slow release theophylline made it more applicable for use with asthma. I go into more detail in my post, "My Experience with Theophylline."

Figure 2 -- Intal Spinhaler and Spincap.
Sorry for the poor quality picture.
It was the only one I could find.
I actually saved my spinhaler,
although accidentally tossed it
when I moved in 2004.
1982: Cromolyn (Intal).   This was introduced as an alternative to inhaled corticosteroids to reduce airway inflammation and control asthma.  The active ingredient was disodium cromoglycate. It was a white powder that was delivered by the Intal Spinhaler. The spinhaler was not the first dry powder inhaler (DPI), although it would become the first mass produced DPI.

The Intal Spinhaler was introduced by Fison in 1971. It was a neat little contraption. Once a physician prescribed the medicine, the patient received a box of Intal Spincaps, which were individually wrapped as shown in the picture to the right. Each capsule contained 20 mg of cromolyn. The standard dose was one inhalation four times daily.

Intal Spinhaler
Cromolyn was approved by the FDA and entered the U.S. market in 1982. As my asthma continued to spiral out of control despite the medicines I was currently on at the time, my doctor was eager to prescribe this new medicine for me. I think it came in a yellow and white box.

The spinhaler was taken apart to reveal a holder. The spincap was taken out of it's foil wrap and placed on the holder. The spinhaler was then put back together. The blue part of the inhaler was then cocked up and back down (as shown by the arrows), and this would puncture the capsule. You then exhaled fully, and placed the white mouthpiece into your mouth between your teeth. You inhaled to suck in the powder, and held your breath 3-10 seconds.

To obtain ideal medicine distribution throughout the airways,
you want to inhale at just the perfect speed.
If you inhale too fast, the Spinhaler whistled at you.
If you hear this whistle, inhale slower next time.
Regardless of how fast you inhaled,
the device also made a zzzzzzzzzzzzzzzzzzzzzzzzz
sound as a fan inside spun around as you inhaled.
This is what allowed you to inhale the powder.
A warning on the package said that the dry powder could irritate the back of your throat and trigger the cough reflex. This could incite bronchospasm, thereby causing an asthma attack. I do not ever remember this happening with me, although I could see how it could happen. My doctor warned me about this, and told me to be careful.

The package insert also warned that the product must be used daily as an asthma controller medicine, and not as a rescue medicine.

Overall, I thought the device was simple enough, but with any asthma controller medicine at the time, it needed to be taken four times a day, and good luck getting me to take it four times a day, especially when I was feeling good. I have no memory of taking it to school with me, so you can bet I was not compliant with it on school days.

Obviously, another problem with this medicine is that the patient had to handle each dose. Proper technique also had to be used in order to assure an adequate dose and to prevent the medicine from triggering a cough.

This is a diagram depicting
what it looked like when the
Spinhaler was opened.
You put the capsule
on an opening above
the fan. Then you
put the top on the inhaler on.
You twisted the blue part
to crush the capsule.
Then you put your mouth
over the white mouthpiece,
and you inhaled.
The flow created by you
made the fan go around,
allowing you
to inhale the powder.
You then had to
hold your breath
3-10 seconds, and hope
the powder didn't
make you cough.
An Intal metered dose inhaler (MDI) was approved by the FDA in 1985 and introduced to the market in 1992. This provided a more convenient and safer delivery device. I think I was prescribed the inhaler maybe once, although by this time I was not taking this medicine regularly.

An Intal solution was approved by the FDA in 1994 to be used by the nebulizer route. This would prove useful for the pediatric asthma population. The ampules were initially glass vials that had to be cracked open. This was ultimately changed to plastic ampules with twist-off tops. This made it easier, and probably safer, to prepare Intal nebulzer treatments

One thing that is typical for any asthma controller medicine, is that it be taken every day. As you might imagine, this is hard to do when you are feeling good. Your quest is to be normal, and it's not normal using inhalers every four hours when you're feeling good. So, as my asthma was doing much better by the early 1990s for the most part, I stopped taking Intal even though my doctor didn't approve of this. In retrospect, I think that it would have been a good idea if my doctor would have educated me with every visit the need to take your asthma controller medicines every day exactly as prescribed in order to continue feeling good. This is something the medical community continues to struggle with to this day with modern asthma controller medicines.

Cromolyn was very popular during the 1980s and 90s. The spinhaler was ultimately phased out after the introduction of the Intal MDI. By the time the Montreal Protocol set goals for the phase out of CFC propellants, the Intal inhaler's popularity had fizzled and sales had declined. This was mainly due to the introduction of other controller medicines that are mentioned below.  Rather than going back to the DPI, and rather than making expensive efforts to combine cromolyn with a non-CFC propellent and get it approved by the FDA, Fison sent out notices that the product would be phased out by December 31, 2010. 

Vanceril
1982: Beclomethasone:  This is the first inhaled corticosteroid was introduced to the world in 1960 by Allen and Hanbury, the makers of albuterol (Ventolin). In 1972, it was marketed overseas as Becotide. The recommended frequency was two puffs four times daily. In 1975, GlaxoSmithKlines introduced their version of beclomethasone as Vanceril. In 1982, Schering-Plough introduced their version of beclomethasone as Beclovent. These are all years where these products were approved by the FDA in the U.S. Other overseas brand names are Becloforte, and Beconaise.

Keep in mind that asthma at this time was treated as an acute disease, meaning it was only treated when symptoms were present. Two theories may explain this.  One is that this is how asthma was treated throughout most of history. Two is that fears remained that inhaled corticosteroids would offer the same side effects as systemic corticosteroids. Either one of these theories would explain why my doctor would tell my mom (this is from one of my mom's notes): "Stop Vanceril until he has an attack of asthma. If he does have an attack start Vanceril inhaler & call me." In the meantime, I was prescribed Vanceril "2 inhalations at 8 a.m., 2 p.m. & 8 p.m. to June 28, then just 2 inhalations at 8 a.m. and 8 p.m." Obviously I had seen him due to an asthma exacerbation. Based on my experience as an adult, and considering this note was written during the summer months, I would imagine I was having allergy induced asthma.

Beclovent
During the 1980s results of various studies showed that side effects of inhaled steroids were minimal, and by simply rinsing the mouth after each use side effects became negligible. Results also showed that daily use of inhaled corticosteroids worked to reduce inflammation to prevent and control asthma symptoms. These studies made physicians more likely to prescribe them for daily use as asthma controller medicines.

The initial inhalers were made with the chlorofluorocarbons (CFC) propellant. The Montreal Protocol, first approved in 1987, called for the gradual phase out of CFC propellants. Initially the FDA exempted medicines. However, pharmaceutical companies eventually gave up the fight, and the FDA set dates for the gradual phase out of inhalers with CFC propellants.

The CFC propellent was replaced with the new hydrofluoroalkane (HFA) propellant, and beclomethasone was rebranded as QVAR. This was approved by the FDA in 2000. It is a brown inhaler.

The initial beclomethasone products were available as brown inhalers. This was part of the coding system where rescue inhalers were blue and controller medicines brown. However, once generic products were on the market, this color coding system was sometimes violated. One example was the introduction of Vanceril as a pink inhaler. This was probably done to distinguish the generic product from the brand products.

 Flunisolide:
It was approved by the FDA in 1982 
and introduced to the U.S market as Aerobid.
1982: Flunisolide (Aerobid) This turned out to be perfect timing for entry into this market, because in 1989 the National Heart, Lung and Blood Instute's (NHLBIAsthma Guidelines were created.  These 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, meaning fewer puffs were needed to achieve the desired effect.

Aerobic was gradually phased out and discontinued by December, 2010. It was another victim to the what I would like to call "controversial" Montreal Protocol. It succeeded in taking away so many nice asthmatic inhalers away from asthmatics.

Azmacort inhaler4  
1984: Triamcinolome:  It was introduced to the market 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 daily puffs, such as fluticasone (Flovent). 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
1993:  Nedocromil Sodium:  It was approved by the FDA and introduced to the market as Tilade in 1993 as an alternative to Intal  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, the product was phased out by the timetable set forth after the Montreal Protocol.

The product was discontinued by June 14, 2010.

Serevent Inhaler. 
1994: Salmeterol:  It was approved by the FDA in 1994 as a long acting beta adrenergic (LABA) under the brand name Serevent.  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 inhaler was green to distinguish it from the brown steroid inhalers and the blue rescue inhalers. It was also a shorter inhaler, which also helped to distinguish is from the other inhalers. This was useful, I thought, because, when you reach for your inhalers in the dark, you know that the shorter one should not be used as a rescue inhaler.

Serevent Diskus
Regardless, the NHLBI Asthma Guidelines ultimately recommended the medicine not be used by itself in the treatment of asthma.  The theory was that if a LABA was needed to control asthma, the asthmatic should also be on an inhaled corticosteroid to control underlying airway inflammation. This ultimately created a market for LABA/ inhaled corticosteroid inhalers. Salmeterol continues to be a viable option for COPD, but is only marketed for COPD. At present, it is available only as the Serevent Diskus, which was the same design as the Flovent Diskuss pictured below, only green.

A DPI version of salmeterol using the Serevent Discus was approved by the FDA in 1997. By 2008 some suspected the medicine was the cause of asthma related deaths and a black box warning was placed on the product. No evidence was ever found that it was the medicine, and some suspected that it was simply that some patients over-relied on this medicine as opposed to seeking help for asthma attacks.

1996:  Fluticasone: A brown 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.

Flovent Inhaler and Flovent Diskus
Initially it was thought that the DPI version of Flovent would be sufficient, although studies using QVAR showed that metered dose inhalers resulted in greater distribution of the medicine, particularly into deeper airways. This resulted in the quest to create another Flovent MDI.

A Flovent HFA MDI was approved by the FDA in 2004.  The doses were:  44 mcg, 110 mcg, and 220 mcg.

Flovent is generally considered to be a stronger inhaled steroid than its predecessors. It requires only 2 puffs twice a day, and this was nice because it greatly improved compliance. I switched to this medicine in 1998, and it was nice because it replaced 4 puffs 4 times every day of Azmacort.  One puff of the DPI Flovent was equal to 2 puffs of the MDI Flovent. This was a nice incentive to using the Discus.

Singulair
1998: 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.

1999:  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.

Advair Discus
2000: Advair:  This is a combination drug with both the inhaled corticosteroid fluticasone and LABA salmeterol. It was introduced to the market in the 1990s, and approved by the FDA in 2000 for ages 12 and up.  The recommended dose is 100/50, fluticasone/ salmeterol. Other doses are 250/50 and 500/50. The recommendation is to begin with the lower dose, and if ideal asthma control is not obtained to increase to the higher doses. The 500/50 dose is generally reserved for severe asthmatics or for COPD.

In 2003, the 100/50 dose was approved for children ages 4 and up.  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 FDA.gov.

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 improved compliance.  Sales skyrocketed during the 2000s and it continues to be the top selling asthma controller medicine.

A couple of problems with this inhaler have been noted, although no study has ever offered any hard core evidence. One, salmeterol has been linked with asthma related deaths, and this was explained above. Two, fluticasone has been linked with increased risk of pneumonia, especially in COPD patients. However, COPD patients have an increased risk of developing pneumonia anyway. So these fears often come with abject criticism.

Despite the criticism of the fears, a black box warning was placed on the packaging in 2008.

The patent for Advair expired in 2010, and the patent on the Discus expired in 2012. Due to difficulty and cost of creating an inhaler device, no present generic versions of this medicine have entered the market.

Pulmicort
Respules
2000: Budesonide:  It was first intro
Pulmicort
Turbohaler
duced during the 1980's, and was involved in extensive testing. Studies determined it was the safest and most effective steroid in solution form. In 2000, Pulmicort Respules were approved for use by the FDA. This was a solution to be inhaled with a nebulizer.

Budesonide Respules proved useful for the pediatric population, especially those children not old enough to coordinate inhaled corticosteroid inhalers. It also proved ideal for the elderly who lacked coordination with inhalers. It was typically marketed for the pediatric population, and physicians were allowed to prescribe to patients they deemed would benefit from it. It's also ideal for severe COPD patients who cannot generate enough flow to actuate inhalers, particularly the Advair inhaler, of which requires a specific flow to get an adequate dosage.

Pulmicort Flexhaler
The Pulmicort Turbohaler was introduced in the late 1980's as the first corticosteroid DPI.  In 1997, it was approved by the FDA.  The inhaler never caught on, mainly because physicians were used to prescribing other inhaled corticosteroids.

In 2016, the Pulmicort Flexhaler was approved by the FDA and entered the market. It remains a viable option for those who require an inhaled corticosteroid. It's available in the 180mcg dose and the 90 mcg dose.
Foradil Inhaler
2000:  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 FDA.com, 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).

2003: 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.
Symbicort inhaler
Symbicort Twisthaler

2006:  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.

2005: Mometasone Furoate:  It's the latest long acting inhaled corticosteroid to enter the market.  It was approved by the FDA in 2005.  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.

In 2015, the Azmanex HFA inhaler was introduced to the market. This inhaler is the same color as Dulera below, with the exception of the pink cap. So, I can see how the this could pose some confusion for patients.

Dulera Inhaler
2010: 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.

2007: 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 because the other options only had to be taken once daily, while this one had to be taken four times daily.

Breo Elipta
2013: Breo It's another combination inhaler approved by the FDA in 2013. It contains the inhaled steroid LABA vilanterol (25 mcg) and the inhaled corticosteroid fluticasone (100 mcg)  It was the first once a day medicine of it's kind. In the testing phase it was referred to as Super Advair, as it was meant to be the replacement for Advair once the patent expired. The 25/100 inhaler was approved for COPD. A few years later, a 25/100 inhaler was approved for asthma.

Further reading:
References:
  1. Beasley, Richard, Sankei Nishima, Neil Pearce, Julian Crane, "Fenoterol and Asthma Mortality," The Lancet, August 8, 1998, volume 352, Issue 9126, page 486
  2. Schleimer, Robert P, Paul M. O'Byrne, Stanley J. Szefler, Ralph Brattsand, editors, "Inhaled Steroids in Asthma: Optimizing Effects in the Airways," 2002, New York, Marcel Dekker Inc. 

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