Fluticasone/Salmeterol

Advair Diskus is a combination medication used in the treatment of asthma and COPD (chronic obstructive pulmonary disease). Advair consists of an inhaled steroid, fluticasone, and an inhaled long-acting medicine that dilates bronchi, salmeterol. Together, these medicines relieve the symptoms of coughing, wheezing, and shortness of breath better than either fluticasone or salmeterol taken separately. The medication is available in the form of a rotadisk, from which the medication can be inhaled in much the same way as an inhaler. Advair is produced and sold by GlaxoSmithKline.

Fluticasone; Source: Wikimedia Commons

Salmeterol; Source: Wikimedia Commons

Other Names

• The generic name of Advair is fluticasone/salmeterol.

This drug marketed is marketed in other countries under the following names:

• Seretide (EU)
• Viani (Germany)
• Adoair (Japan)
• ForAir (India)

Description

The Advair diskus contains two medications -- fluticasone propionate, an inhaled corticosteroid, and salmeterol, which is a beta-agonist.

Uses

Advair is used for COPD and chronic bronchitis in adults. Advair is also used in both adults and children for asthma that cannot be controlled with either short-acting bronchodilators alone (i.e. albuterol) or with inhaled steroids (i.e. Flovent) alone, and has been categorized by the NHLBI (National Heart, Lung and Blood Institute) as moderate persistent asthma or severe persistent asthma.

The Advair Diskus is approved for children four years of age and older. Testing of the medication has been done on children as young as four years of age, but not younger. The assumption is that it takes a child at least four years of age to operate the diskus. However, if a younger child is particularly intelligent and can operate the diskus, then the medication may be used in these children. The use of Advair under four years of age is best done under the supervision of a pediatric pulmonologist, and only in cases where other drugs cannot control the asthma. Although Advair is not indicated for use under four years of age, the component drugs have been used extensively in children under this age. In cases where Advair is needed in younger children, the parent can administer the medication as well.

For all approved uses of Advair for children and adults, the recommended dose is one puff twice a day, .

How Fluticasone/Salmeterol is Taken

Advair is available as a dry powder inhaler, which is administered through a rotadisk, called Diskus in the U.S. These purple disk-shaped containers are about 3.5 inches in diameter. The diskus has a lever which advances the medication through the disk, much like a camera film is advanced, exposing the medication that is ready to be inhaled. Each rotadisk has about 60 doses. One puff of Advair is equivalent to two puffs of Serevent (by inhaler) and two puffs of the corresponding strength of Flovent.

Three dosage strengths are available: 100μg fluticasone propionate/50μg salmeterol, 250μg fluticasone propionate/50μg salmeterol, and 500μg fluticasone propionate/50μg salmeterol. The 250μg/50μg dose is used for COPD and chronic bronchitis in adults. The 500μg/50μg strength of Advair has recently been disapproved by the FDA for its use in COPD and chronic bronchitis. Advair is used in all three strengths in adults and children for asthma that is not controlled with either short-acting bronchodilators alone (i.e. albuterol) or with inhaled steroids (i.e. Flovent) alone.

Advair is also available as a metered-dose inhaler (MDI), marketed as Advair HFA.

How It Works

Fluticasone propionate

Fluticasone propionate is an inhaled corticosteroid medicine. Inhaled corticosteroids (a form of steroid) help to decrease inflammation in the lungs that leads to asthma symptoms. Inhaled corticosteroids have also recently been shown to help repair lung tissue that has already been damaged by asthma. Inhaled corticosteroids have a small short-term benefit in controlling asthma symptoms (over a few hours) and a long-term benefit in controlling asthma symptoms (over one to three days). The main benefit is in the long-term control of symptoms. Inhaled steroids in general do not immediately help control asthma symptoms during a sudden asthma attack.

Salmeterol

Salmeterol is a beta-agonist medicine. Beta-agonists act on the receptors of lung bronchial tissue (beta-2 receptors) to relax the muscles surrounding the bronchi and bronchioles (airway passages into the lungs). This opens up the bronchial passageways and allows more air to reach the lungs. Beta-agonists are also called bronchodilators because they dilate the bronchioles. Beta-agonists also trigger receptors on the heart (beta-1 receptors), which speeds up the heart. The beta-agonists used for asthma are designed to work selectively on the beta-2 receptors of the lungs, and not on the beta-1 receptors on the heart. For this reason, these medications are called selective beta-2-agonists, which means that they open up the bronchioles in the lung but do not significantly affect the heart rate. However, even selective beta-agonists have a small effect on the receptors of the heart as well as on the blood vessels. So these medications can have side effects which include speeding up the heart rate and constricting the blood vessels (which can increase blood pressure).

Salmeterol is unlike other beta-agonist medications because it is a long-acting beta-agonist. The effect of short-acting beta-agonists lasts about four hours, while the effect of salmeterol lasts about 12-24 hours. The purpose of short-acting beta-agonists, such as albuterol, is to provide immediate relief or short-term relief of symptoms of asthma, For this reason, albuterol is helpful during an asthma attack. Salmeterol acts on a long-term basis. This medication is used so that a person always has baseline bronchodilator activity throughout the day and night. This helps air enter the lungs more easily.

Benefits

Advair is effective for asthma that is poorly controlled on other medications. It is more effective than either inhaled steroids or long-acing beta-agonists (salmeterol) used alone.

The following graph, taken from the National Institute of Health, shows the relative advantage of using Advair.

Image:Advair graph.jpg

In addition to the obvious advantage of being more effective in treating asthma, the combination of both drugs used together has the convenience of not having to take two separate drugs. In the past, when these drugs were used separately, a few people would take the salmeterol because of the immediate feeling of relief while neglecting or forgetting to take the fluticasone (or other inhaled steroid). Over time, as the underlying cause of the asthma, the inflammation, was not being treated, the asthma worsened. Then these people needed to use the salmeterol with increasing frequency. In some cases, the asthma finally worsened to the point where it was fatal in some cases. The combination of the two medications decrease the likelihood of the above scenario occuring because they treat the immediate symptoms while also treating the underlying problem (the inflammation). However, it has not been proven that this combination drug has actually reduced the number of deaths caused by worsening asthma symptoms when salmeterol is used alone. (See below under side effects of salmeterol).

Side Effects

Side effects are generally rare, and can be due to the inhaled steroid component (fluticasone) or the long-acting beta-agonist component (salmeterol) of the medication.

Thrush

Inhaled steroids can have the relatively common side effect of causing thrush, a white growth on the tongue, caused by the fungus Candida albicans. This condition is also called oral candidiasis. This is the most common side effect of Advair.

The thrush is caused by particles of the inhaled steroid that land on the tongue, suppressing the local immune response on the tongue itself. This makes it more difficult for the affected area to fight infection, especially fungi in this case.

Thrush is common in infants but is generally worrisome when found in adults, as it is usually caused by an immune deficiency, such as AIDS or leukemia, or having an abnormally low calcium levels. However, if the thrush resolves by simply stopping the medication for a few days, then it is attributable to use of this medication and not to an immune deficiency.

The thrush caused by inhaled steroids can be prevented for the most part by gargling or rinsing the mouth each time after using Advair.

The thrush may be treated with liquid Nystatin, an antifungal medication, applied on the tongue. The thrush may resolves on its own even without treatment if the individual simply stops using the medication for a few days, or starts rinsing the mouth out after each use. However, before stopping any medication like Advair, it is always important to discuss troublesome symptoms with a doctor.

Growth delay

There has been concern that inhaled steroids used in children can cause growth delay or short stature, in much the same way as oral steroids, especially when used chronically in the treatment of asthma. Extensive long-term studies in children who received inhaled steroids have shown a temporary growth delay during the childhood years, but the final height of the children was the same as children who were not taking the inhaled steroids. The knowledge that the growth delay will be minimal and will have only a short-term effect can be assuring to parents and children. It is also important to note that asthma that is not controlled by sufficient medications can itself cause some growth delay.

The study may not be applicable to high doses of inhaled steroids, or in particular to individuals who are unusually sensitive to the inhaled steroid in asthma. If a decrease in a child's rate of growth is noticed, the decision to change or continue the medication is usually done on a case-by-case basis.

However, the National Institutes of Health (NIH) has issued the following statement: "The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown. The potential for “catch-up” growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied." --National Institute of Health

Immune suppression

Immune suppression has not been shown to occur in children taking inhaled steroids. It is generally believed that inhaled steroids enter the lungs only and do not enter the bloodstream in significant quantities. However, high-dose inhaled steroids, such as Advair 500/50, can result in small levels of steroids in the blood. So far, it is unknown whether this causes any significant side effects associated with steroids. Children on inhaled steroids are not considered immunosupressed and may still receive live-virus vaccines, such as the varicella vaccine and the MMR vaccine.

Steroid side effects

Generally, side effects associated with steroids, such as weight gain, humped back, moon facies, acne, excessive hair growth, immune suppression, depression, and psychosis, have not been associated with inhaled steroid use.

Beta-agonist side effects (fight or flight response)

Salmeterol is a selective beta-agonist, acting primarily on the receptors of the lungs. However, there is also a small effect on other organs in the body that generally promote a fight or flight response, also known as an adrenergic response. Symptoms of a fight or flight response include:

• Increased heart rate (tachycardia)
• Palpitations
• Agitation
• Anxiety, nervousness
• Hyperactivity
• Anger
• Insomnia (unable to sleep), particularly when taken at night
• Increased blood pressure (hypertension)
• Nausea, vomiting
• Headaches
• Abdominal cramps
• Loss of appetite

Risks

Complications

Anaphylaxis

In very rare cases, Advair may cause anaphylaxis, a severe life-threatening allergic reaction. This occurs primarily in people with severe milk protein allergy.

Sudden death

The risk of sudden death has been attributed to the salmeterol component in Advair. Salmeterol has historically been associated with rare cases of sudden death. It was believed that the combination drug of Advair would negate this effect, but recent studies show that Advair also has an associated risk of sudden death.

Salmeterol may provide some partial relief during an asthma attack but is not nearly as helpful as short-acting medications, such as albuterol. Because salmeterol can have a deceptively helpful effect on improving asthma symptoms in the short-term, people have been known to use it repeatedly during asthma attacks, which builds up the level of medication in the blood and can have an opposite effect of increasing irritation and reactivity in the lungs, which causes worsening asthma. Prolonged use of salmeterol to control an ongoing asthma attack can lead to a person avoiding getting appropriate treatment. In the meantime, asthma symptoms may continue to worsen and may eventually lead to death. Salmeterol has also been known to cause sudden death, possibly for a similar reason (using salmeterol instead of the appropriate medication albuterol).

In November, 2005, the FDA alerted the public to findings showing that salmeterol could lead to worsening symptoms of asthma and, in some cases, death.

In a recent study, Salmeterol: a Multi-center Asthma Research Trial (SMART), it was shown that salmeterol may increase the risk of death due to asthma. This additional risk does not appear to be reduced when the salmeterol is given in a combination drug with an inhaled steroid, such as in Advair. This seems to occur because salmeterol promotes bronchial inflammation and sensitivity in an unpredictable way and without warning.

The concern for increased risk of death in the use of Advair certainly calls for precaution. It is important to note that, in general, the risk of death is higher from poorly asthma than from use of these medications. In many cases, Advair is the only medication that can control the asthma.

Drug interactions

Drugs that are CYP3A4 inhibitors, of which ketoconazole is the most common example, can interfere with the metabolism of fluticasone and can result in high levels of the drug and lead to suppression of the adrenal gland. Adrenal suppression can lead to diarrhea, loss of blood pressure (hypotension), and (in rare cases) death, if blood pressure is very low, and stays very low, for a prolonged period of time, or if a viral infection or other stress has occurred in the body during this time.

Drugs that interact with Advair include:

• Ritonavir
• Ketoconazole=== Precautions ===

• Advair Diskus does not relieve sudden breathing problems. A short-acting bronchodilator medicine, such as albuterol is used to treat sudden breathing problems.
• Advair should not be stopped abruptly.
• Advair should not be used more often than prescribed, repeatedly, for worsening astma symptoms.
• Asthma should not be used with certain drugs that inhibit CYP3A4, specifically ritonavir and ketoconazole.
• Advair may rarely cause a severe allergic reaction, particularly in individuals with severe milk protein allergy.
• Advair is Pregnancy Category C--uncertain risk. No human and animal studies have been done to assure safety in pregnancy.

References

External Links

GSK receives decision from FDA on Advair 500/50 for COPD

An article reviewing the following study: Salpeter S, Buckley N, Ormiston T, Salpeter E (2006). "Meta-analysis: effect of long-acting beta-agonists on severe asthma exacerbations and asthma-related deaths.". Ann Intern Med 144 (12): 904-12 Abstract

Detailed drug information of Advair from the NIH