Advair Diskus

ADVAIR DISKUS 100/50, ADVAIR DISKUS 250/50, and ADVAIR DISKUS 500/50 are combinations of fluticasone propionate and salmeterol xinafoate.

One active component of ADVAIR DISKUS is fluticasone propionate, a corticosteroid having the chemical name S-(fluoromethyl) 6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3oxoandrosta-1,4-diene-17β-carbothioate, 17-propionate and the following chemical structure:

Fluticasone propionate is a white powder with a molecular weight of 500.6, and the empirical formula is C25H31F3O5S. It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol.

The other active component of ADVAIR DISKUS is salmeterol xinafoate, a beta2-adrenergic bronchodilator. Salmeterol xinafoate is the racemic form of the 1-hydroxy-2-naphthoic acid salt of salmeterol. It has the chemical name 4-hydroxy-α1-[[[6-(4phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol, 1-hydroxy-2naphthalenecarboxylate and the following chemical structure:

Salmeterol xinafoate is a white powder with a molecular weight of 603.8, and the empirical formula is C25H37NO4•C11H8O3. It is freely soluble in methanol; slightly soluble in ethanol, chloroform, and isopropanol; and sparingly soluble in water.

ADVAIR DISKUS is a purple plastic inhaler containing a foil blister strip. Each blister on the strip contains a white powder mix of micronized fluticasone propionate (100, 250, or 500 mcg) and micronized salmeterol xinafoate salt (72.5 mcg, equivalent to 50 mcg of salmeterol base) in 12.5 mg of formulation containing lactose monohydrate (which contains milk proteins). After the inhaler is activated, the powder is dispersed into the airstream created by the patient inhaling through the mouthpiece.

Under standardized in vitro test conditions, ADVAIR DISKUS delivers 93, 233, and 465 mcg of fluticasone propionate and 45 mcg of salmeterol base per blister from ADVAIR DISKUS 100/50, ADVAIR DISKUS 250/50, and ADVAIR DISKUS 500/50, respectively, when tested at a flow rate of 60 L/min for 2 seconds.

In adult subjects with obstructive lung disease and severely compromised lung function (mean FEV1 20% to 30% of predicted), mean peak inspiratory flow (PIF) through the DISKUS® inhaler was 82.4 L/min (range: 46.1 to 115.3 L/min).

Inhalation profiles for adolescent (N = 13, aged 12 to 17 years) and adult (N = 17, aged 18 to 50 years) subjects with asthma inhaling maximally through the DISKUS inhaler show mean PIF of 122.2 L/min (range: 81.6 to 152.1 L/min). Inhalation profiles for pediatric subjects with asthma inhaling maximally through the DISKUS inhaler show a mean PIF of 75.5 L/min (range: 49.0 to 104.8 L/min) for the 4-year-old subject set (N = 20) and 107.3 L/min (range: 82.8 to 125.6 L/min) for the 8-year-old subject set (N = 20).

The actual amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow profile.

• Store Advair Diskus at room temperature.
• Keep Advair Diskus in a dry place away from heat and sunlight.
• Store Advair Diskus in the unopened foil pouch and only open when ready for use.
• Safely throw away Advair Diskus in the trash 1 month after you open the foil pouch or when the counter reads 0, whichever comes first.
• Keep this and all medicines out of reach of children.
• Keep all appointments with your doctor.

WARNING: ASTHMA-RELATED DEATH

Long-acting beta2-adrenergic agonists (LABA), such as salmeterol, one of the active ingredients in ADVAIR DISKUS, increase the risk of asthma-related death. A US trial showed an increase in asthma-related deaths in patients receiving salmeterol (13 deaths out of 13,176 subjects treated for 28 weeks on salmeterol versus 3 out of 13,179 subjects on placebo). Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. 

When treating patients with asthma, only prescribe ADVAIR DISKUS for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue ADVAIR DISKUS) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use ADVAIR DISKUS for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.

You should not use this medicine if you are allergic to fluticasone, salmeterol, or milk proteins.

Fluticasone and salmeterol is not a rescue medicine. It will not work fast enough to treat an asthma or bronchospasm attack.

Salmeterol may increase the risk of death in people with asthma, but the risk in people with COPD is not known.

You should not use this medicine if you are allergic to fluticasone or salmeterol (Serevent), or:

• if you have a severe allergy to milk proteins; or

• if you are having an asthma attack or severe COPD symptoms.

Salmeterol may increase the risk of death in people with asthma, but the risk in people with COPD is not known. Talk with your doctor about your individual risks and benefits of using this medicine.

To make sure this medicine is safe for you, tell your doctor if you have:

• a food or drug allergy;

• heart disease or high blood pressure;

• epilepsy or other seizure disorder;

• any type of infection;

• a weak immune system;

• diabetes;

• glaucoma;

• tuberculosis;

• osteoporosis;

• a thyroid disorder; or

• liver disease.

Long-term use of steroids may lead to bone loss (osteoporosis), especially if you smoke, if you do not exercise, if you do not get enough vitamin D or calcium in your diet, or if you have a family history of osteoporosis.

It is not known whether fluticasone and salmeterol is harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medicine.

It is not known whether this medicine passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Fluticasone can affect growth in children. Talk with your doctor if you think your child is not growing at a normal rate while using this medication.

This medicine is not approved for use by anyone younger than 4 years old.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. Overdose symptoms may include dizziness, vomiting, weakness, chest pain, tremors, feeling nervous, fast or pounding heartbeats, or seizure.

Do not use a second inhaled bronchodilator unless your doctor tells you to. This includes formoterol (Foradil, Perforomist, Symbicort, Dulera), arformoterol (Brovana), indacaterol (Arcapta), olodaterol (Striverdi, Stiolto Respimat), salmeterol (Serevent), or vilanterol (Bree Ellipta, Anoro Ellipta).

Avoid being near people who are sick or have infections. Call your doctor for preventive treatment if you are exposed to chicken pox or measles. These conditions can be serious or even fatal in people who are using steroid medicine.

Fluticasone and salmeterol is a combination of two medicines that are used to help control the symptoms of asthma and improve breathing. It is used when a patient's asthma has not been controlled sufficiently on other asthma medicines, or when a patient's condition is so severe that more than one medicine is needed every day. This medicine will not relieve an asthma attack that has already started.

This medicine is also used to treat air flow blockage and reduce the worsening of chronic obstructive pulmonary disease (COPD). This includes chronic bronchitis and emphysema.

Inhaled fluticasone belongs to the family of medicines known as corticosteroids or steroids (cortisone-like medicines). It works by preventing certain cells in the lungs and breathing passages from releasing substances that cause asthma symptoms.

Inhaled salmeterol is a long-acting bronchodilator. Bronchodilators are medicines that are breathed in through the mouth to open up the bronchial tubes (air passages) in the lungs. It relieves cough, wheezing, shortness of breath, and troubled breathing by increasing the flow of air through the bronchial tubes.

This medicine must be used with a short-acting medicine (eg, albuterol) for an asthma attack or asthma symptoms that need attention right away.

This medicine is available only with your doctor's prescription.

This section provides information on the proper use of a number of products that contain fluticasone and salmeterol. It may not be specific to Advair Diskus. Please read with care.

Inhaled fluticasone and salmeterol is used to prevent asthma attacks and to treat chronic obstructive pulmonary disease (COPD). It is not used to relieve an asthma attack that has already started. For relief of an asthma attack that has already started, you should use another medicine. If you do not have another medicine to use for an attack or if you have any questions about this, check with your doctor.

Inhaled fluticasone and salmeterol is used with a special inhaler that comes with patient directions or a Medication Guide. Read the directions carefully before using this medicine. If you do not understand the directions or you are not sure how to use the Diskus® or inhaler, ask your doctor to show you what to do. Also, ask your doctor to check regularly how you use the Diskus® or inhaler to make sure you are using it properly.

Use this medicine only as directed by your doctor. Do not use more of it and do not use it more often than your doctor ordered. Also, do not stop using this medicine without telling your doctor. To do so may increase the chance of side effects.

In order for this medicine to help prevent asthma attacks, it must be used every day in regularly spaced doses, as ordered by your doctor.

Do not stop using this medicine or other asthma medicines that your doctor has prescribed for you unless you have discussed this with your doctor.

When you use the Advair® HFA inhaler for the first time, or if you have not used it for 7 days or longer, or if the inhaler has been dropped, it may not deliver the right amount of medicine with the first puff. Therefore, before using the inhaler, prime it by spraying the medicine four times into the air away from the face, and shaking it well for 5 seconds before each spray. Avoid spraying it in your eyes.

Rinsing your mouth with water after each dose may help prevent hoarseness, throat irritation, and infection in the mouth. However, do not swallow the water after rinsing.

To use the Diskus®:

• Open the foil pouch containing the Diskus®.
• To open the Diskus®, push the thumb grip away from you as far as it will go. You will hear a click and feel a snap. When open, the mouthpiece will appear.
• Slide the mouthpiece lever away from you as far as it will go until it clicks. The Diskus® is now ready to use. If you close the Diskus® or push the lever again, you will lose medicine.
• Turn your head away from the Diskus®, and breathe out to the end of a normal breath. Do not breathe into the Diskus®.
• Holding the Diskus® level, put the mouthpiece between your lips and teeth, and close your lips around the mouthpiece. Do not bite down on the mouthpiece. Do not block the mouthpiece with your teeth or tongue.
• Breathe in through your mouth as deeply as you can until you have taken a full deep breath. Do not breathe through your nose.
• Hold your breath and remove the mouthpiece from your mouth. Continue holding your breath as long as you can up to 10 seconds before breathing out slowly. This gives the medicine time to settle in your airways and lungs.
• Turn your head away from the Diskus®, and breathe out slowly to the end of a normal breath. Do not breathe into the Diskus®.
• If your doctor has told you to inhale more than one puff of medicine at each dose, take the second puff following exactly the same steps you used for the first puff.
• When you are finished, close the Diskus®. Place your thumb on the thumb grip, and slide it back toward you as far as it will go. You will hear it click shut.
• Keep the Diskus® dry. Do not wash the mouthpiece, or any other part of the Diskus®. You may use a dry cloth to wipe it clean.
• The Diskus® has a window that shows the number of doses that are left. This tells you when you are getting low on medicine. When the Diskus® has 5 doses left, the numbers from 5 to 0 will show up in red to remind you to refill your prescription.

To use the Advair® HFA inhaler:

• Take the inhaler out of the pouch before you use it for the first time.
• Do not use the inhaler for this medicine with any other medicine.
• Remove the cap and look at the mouthpiece to make sure it is clean.
• Prime the inhaler before use by shaking the inhaler well and then releasing 4 test sprays.
• To inhale this medicine, breathe out fully, trying to get as much air out of the lungs as possible. Put the mouthpiece fully into your mouth and close your lips around it. Do not block the mouthpiece with your teeth or tongue.
• While pressing down firmly and fully on the purple top of the inhaler, breathe in through your mouth as deeply as you can until you have taken a full deep breath.
• Wait for 30 seconds and repeat these steps for the next puff, starting with shaking the inhaler.
• Gargle and rinse your mouth with water after each dose; this will help prevent hoarseness, throat irritation, and infection in the mouth. Do not swallow the water after rinsing.
• Replace the mouthpiece cover after using the medicine.
• The inhaler has a window that shows the number of doses remaining. This tells you when you are getting low on medicine. The doses counting down from 20 to 0 will show up in red to remind you to refill your prescription. Throw away the inhaler when the count is 000. You may not receive the right amount of medicine.

To use the Airduo™ Respiclick®:

• Take the inhaler out of the pouch before you use it for the first time.
• Do not use the inhaler for this medicine with any other medicine.
• This medicine does not require priming. Do not use it with a spacer or volume holding chamber.
• Hold the inhaler upright and open the yellow cap all the way until it clicks. Do not open the yellow cap until you are ready to take a dose of this medicine.
• To inhale this medicine, breathe out fully, trying to get as much air out of the lungs as possible. Put the mouthpiece fully into your mouth and close your lips around it. Do not block the mouthpiece with your teeth or tongue. Do not block the vent above the mouthpiece with your lips or fingers.
• Breathe in through your mouth quickly and deeply as you can until you have taken a full deep breath. Hold your breath for about 10 seconds.
• Close the yellow cap after each inhalation. Rinse your mouth with water without swallowing after each inhalation.
• Keep the inhaler dry and clean at all times. Gently wipe the mouthpiece with a dry cloth or tissue as needed.
• The inhaler has a window that shows the number of doses remaining. This tells you when you are getting low on medicine. The doses counting down from 20 to 0 will show up in red to remind you to refill your prescription. Throw away the inhaler when the dose counter displays 0, 30 days after opening the pouch.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For inhalation dosage form (aerosol liquid):
  • For preventing an asthma attack:
    • Adults and children 12 years of age and older—2 puffs in the morning and another 2 puffs in the evening. The doses should be at least 12 hours apart.
    • Children younger than 12 years of age—Use and dose must be determined by your child's doctor.
• For inhalation dosage form (aerosol powder):
  • Advair® Diskus®:
    • For preventing an asthma attack:
      • Adults and children 4 years of age and older—1 inhalation 2 times per day (morning and evening). The doses should be at least 12 hours apart.
      • Children younger than 4 years of age—Use and dose must be determined by your doctor.
    • For maintenance treatment of COPD:
      • Adults—1 inhalation (250/50) 2 times per day (morning and evening). The doses should be at least 12 hours apart.
      • Children—Use and dose must be determined by your doctor.
  • Airduo™ Respiclick®:
    • For treatment of asthma:
      • Adults and children 12 years of age and older—1 inhalation 2 times per day (morning and evening). The doses should be at least 12 hours apart. Do not use it more than 2 times every 24 hours.
      • Children younger than 12 years of age—Use and dose must be determined by your child's doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

If you miss a dose of Airduo™ Respiclick®, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the canister at room temperature, away from heat and direct light. Do not freeze. Do not keep this medicine inside a car where it could be exposed to extreme heat or cold. Do not poke holes in the canister or throw it into a fire, even if the canister is empty.

Keep the medicine in the foil pouch until you are ready to use it. Store at room temperature, away from heat and direct light. Do not freeze.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

If you will be using this medicine for a long time, it is very important that your doctor check the progress of you or your child at regular visits. This will allow your doctor to see if the medicine is working properly and to check for any unwanted effects.

Tell your doctor if you or your child are also using other medicines for your COPD. Your doctor may want you to stop using the medicine and use it only during a severe COPD attack. Follow your doctor's instructions on how you should take your medicine.

This medicine should not be used if you are having a severe COPD attack, or if symptoms of a COPD attack has already started. Your doctor may prescribe another medicine for you to use in case of an acute COPD attack. If the other medicine does not work as well, tell your doctor right away.

This medicine should only be used as an additional treatment for patients who cannot be treated with other asthma medicines (such as inhaled corticosteroids) or for asthma patients that require two medicines, including salmeterol. Ask your doctor if you have any questions.

Although this medicine decreases the number of asthma episodes, it may increase the chance of a severe asthma attack when they do occur. Be sure to read about these risks in the Medication Guide and talk to your doctor or pharmacist about any questions or concerns that you have.

You should not use this medicine if your asthma attack has already started. Your doctor will prescribe another medicine (eg, a short-acting inhaler) for you to use in case of an acute asthma attack. Make sure you understand how to use the short-acting inhaler. Talk to your doctor if you need instructions.

Talk with your doctor or get medical care right away if:

• Your or your child's symptoms do not improve after using this medicine for 1 week or if they become worse.
• Your short-acting inhaler does not seem to work as well as it used to and you or your child need it more often than normal (eg, you use 1 whole canister of the short-acting inhaler in 8 weeks time, or you need to use 4 or more inhalations of the short-acting inhaler for 2 or more days in a row).
• You or your child have a big decrease in your peak flow when measured as directed by your doctor.

Do not use this medicine to treat wheezing that is getting worse. Call your doctor right away if wheezing worsens while using this medicine.

Do not use any other asthma medicine or medicine for breathing problems without talking to your doctor. This medicine should not be used with other inhalers that contain budesonide and formoterol combination (Symbicort®), formoterol (Foradil® Aerolizer®, Perforomist™), or arformoterol (Brovona™).

This medicine may cause a fungus infection of the mouth or throat (thrush). Tell your doctor right away if you have white patches in the mouth or throat; or pain when eating or swallowing.

Patients with COPD may be more likely to have pneumonia. Call your doctor if you or your child start having increased sputum (spit) production, change in sputum color, fever, chills, increased cough, or an increase in breathing problems.

Do not change your dose or stop using your medicine without first asking your doctor.

Your doctor may want you to carry a medical identification (ID) card stating that you or your child are using this medicine. The card will say that you may need additional medicine during an emergency, a severe asthma attack or other illness, or unusual stress.

Using too much of this medicine or using it for a long time may cause may increase your risk of having adrenal gland problems. Talk to your doctor if you or your child have more than one of these symptoms while you are using this medicine: darkening of the skin, diarrhea, dizziness, fainting, loss of appetite, mental depression, nausea, skin rash, unusual tiredness or weakness, or vomiting.

This medicine may cause paradoxical bronchospasm, which means your breathing or wheezing will get worse. Paradoxical bronchospasm may be life-threatening. Check with your doctor right away if you or your child are having a cough, difficulty with breathing, shortness of breath, or wheezing after using this medicine.

If you or your child develop a skin rash, hives, or any allergic reaction (including anaphylaxis) to this medicine, check with your doctor as soon as possible.

Check with your doctor right away if you or your child have chest pain, a fast heartbeat, nervousness, shaking of the hands or feet, noisy breathing, a feeling of choking, or tightness or irritation of the throat while using this medicine.

This medicine may affect blood sugar and potassium levels. If you have heart disease or are diabetic and notice a change in the results of your blood or urine sugar or potassium tests, check with your doctor.

Check with your doctor right away if blurred vision, difficulty in reading, or any other change in vision occurs during or after treatment. Your doctor may want you or your child to have your eyes checked by an ophthalmologist (eye doctor).

This medicine may decrease bone mineral density when used for a long time. A low bone mineral density can cause weak bones or osteoporosis. If you have any questions about this, ask your doctor.

This medicine may cause children to grow more slowly than usual. Talk to your child's doctor if you have any concerns.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

• It is used to treat asthma.
• Some brands are used to treat COPD (chronic obstructive pulmonary disease).
• It may be given to you for other reasons. Talk with the doctor.
• This medicine is not to be used to treat intense flare-ups of shortness of breath. Use a rescue inhaler. Talk with the doctor.

Mechanism of Action

Advair Diskus

Advair Diskus contains both fluticasone propionate and salmeterol. The mechanisms of action described below for the individual components apply to Advair Diskus. These drugs represent 2 different classes of medications (a synthetic corticosteroid and a LABA) that have different effects on clinical, physiologic, and inflammatory indices.

Fluticasone Propionate

Fluticasone propionate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. Fluticasone propionate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is 18 times that of dexamethasone, almost twice that of beclomethasone-17-monopropionate (BMP), the active metabolite of beclomethasone dipropionate, and over 3 times that of budesonide. Data from the McKenzie vasoconstrictor assay in man are consistent with these results. The clinical significance of these findings is unknown.

Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma.

Inflammation is also a component in the pathogenesis of COPD. In contrast to asthma, however, the predominant inflammatory cells in COPD include neutrophils, CD8+ T-lymphocytes, and macrophages. The effects of corticosteroids in the treatment of COPD are not well defined and inhaled corticosteroids and fluticasone propionate when used apart from Advair Diskus are not indicated for the treatment of COPD.

Salmeterol Xinafoate

Salmeterol is a selective LABA. In vitro studies show salmeterol to be at least 50 times more selective for beta2-adrenoceptors than albuterol. Although beta2-adrenoceptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-adrenoceptors are the predominant receptors in the heart, there are also beta2-adrenoceptors in the human heart comprising 10% to 50% of the total beta-adrenoceptors. The precise function of these receptors has not been established, but their presence raises the possibility that even selective beta2-agonists may have cardiac effects.

The pharmacologic effects of beta2-adrenoceptor agonist drugs, including salmeterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3′,5′-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

In vitro tests show that salmeterol is a potent and long-lasting inhibitor of the release of mast cell mediators, such as histamine, leukotrienes, and prostaglandin D2, from human lung. Salmeterol inhibits histamine-induced plasma protein extravasation and inhibits platelet-activating factor-induced eosinophil accumulation in the lungs of guinea pigs when administered by the inhaled route. In humans, single doses of salmeterol administered via inhalation aerosol attenuate allergen-induced bronchial hyper-responsiveness.

Pharmacodynamics

Advair Diskus

Healthy Subjects: Cardiovascular Effects: Since systemic pharmacodynamic effects of salmeterol are not normally seen at the therapeutic dose, higher doses were used to produce measurable effects. Four (4) trials were conducted with healthy adult subjects: (1) a single-dose crossover trial using 2 inhalations of Advair Diskus 500/50, fluticasone propionate powder 500 mcg and salmeterol powder 50 mcg given concurrently, or fluticasone propionate powder 500 mcg given alone, (2) a cumulative dose trial using 50 to 400 mcg of salmeterol powder given alone or as Advair Diskus 500/50, (3) a repeat-dose trial for 11 days using 2 inhalations twice daily of Advair Diskus 250/50, fluticasone propionate powder 250 mcg, or salmeterol powder 50 mcg, and (4) a single-dose trial using 5 inhalations of Advair Diskus 100/50, fluticasone propionate powder 100 mcg alone, or placebo. In these trials no significant differences were observed in the pharmacodynamic effects of salmeterol (pulse rate, blood pressure, QTc interval, potassium, and glucose) whether the salmeterol was given as Advair Diskus, concurrently with fluticasone propionate from separate inhalers, or as salmeterol alone. The systemic pharmacodynamic effects of salmeterol were not altered by the presence of fluticasone propionate in Advair Diskus. The potential effect of salmeterol on the effects of fluticasone propionate on the HPA axis was also evaluated in these trials.

Hypothalamic-Pituitary-Adrenal Axis Effects: No significant differences across treatments were observed in 24-hour urinary cortisol excretion and, where measured, 24-hour plasma cortisol AUC. The systemic pharmacodynamic effects of fluticasone propionate were not altered by the presence of salmeterol in Advair Diskus in healthy subjects.

Subjects with Asthma: Adult and Adolescent Subjects: Cardiovascular Effects: In clinical trials with Advair Diskus in adult and adolescent subjects aged 12 years and older with asthma, no significant differences were observed in the systemic pharmacodynamic effects of salmeterol (pulse rate, blood pressure, QTc interval, potassium, and glucose) whether the salmeterol was given alone or as Advair Diskus. In 72 adult and adolescent subjects with asthma given either Advair Diskus 100/50 or Advair Diskus 250/50, continuous 24-hour electrocardiographic monitoring was performed after the first dose and after 12 weeks of therapy, and no clinically significant dysrhythmias were noted.

Hypothalamic-Pituitary-Adrenal Axis Effects: In a 28-week trial in adult and adolescent subjects with asthma, Advair Diskus 500/50 twice daily was compared with the concurrent use of salmeterol powder 50 mcg plus fluticasone propionate powder 500 mcg from separate inhalers or fluticasone propionate powder 500 mcg alone. No significant differences across treatments were observed in serum cortisol AUC after 12 weeks of dosing or in 24-hour urinary cortisol excretion after 12 and 28 weeks.

In a 12-week trial in adult and adolescent subjects with asthma, Advair Diskus 250/50 twice daily was compared with fluticasone propionate powder 250 mcg alone, salmeterol powder 50 mcg alone, and placebo. For most subjects, the ability to increase cortisol production in response to stress, as assessed by 30-minute cosyntropin stimulation, remained intact with Advair Diskus. One subject (3%) who received Advair Diskus 250/50 had an abnormal response (peak serum cortisol less than 18 mcg/dL) after dosing, compared with 2 subjects (6%) who received placebo, 2 subjects (6%) who received fluticasone propionate 250 mcg, and no subjects who received salmeterol.

In a repeat-dose, 3-way crossover trial, 1 inhalation twice daily of Advair Diskus 100/50, FLOVENT® DISKUS® 100 mcg (fluticasone propionate inhalation powder, 100 mcg), or placebo was administered to 20 adult and adolescent subjects with asthma. After 28 days of treatment, geometric mean serum cortisol AUC over 12 hours showed no significant difference between Advair Diskus and FLOVENT DISKUS or between either active treatment and placebo.

Pediatric Subjects: Hypothalamic-Pituitary-Adrenal Axis Effects: In a 12-week trial in subjects with asthma aged 4 to 11 years who were receiving inhaled corticosteroids at trial entry, Advair Diskus 100/50 twice daily was compared with fluticasone propionate inhalation powder 100 mcg administered twice daily via the DISKUS. The values for 24-hour urinary cortisol excretion at trial entry and after 12 weeks of treatment were similar within each treatment group. After 12 weeks, 24-hour urinary cortisol excretion was also similar between the 2 groups.

Subjects with Chronic Obstructive Pulmonary Disease: Cardiovascular Effects: In clinical trials with Advair Diskus in subjects with COPD, no significant differences were seen in pulse rate, blood pressure, potassium, and glucose between Advair Diskus, the individual components of Advair Diskus, and placebo. In a trial of Advair Diskus 250/50, 8 subjects (2 [1.1%] in the group given Advair Diskus 250/50, 1 [0.5%] in the fluticasone propionate 250-mcg group, 3 [1.7%] in the salmeterol group, and 2 [1.1%] in the placebo group) had QTc intervals greater than 470 msec at least 1 time during the treatment period. Five (5) of these 8 subjects had a prolonged QTc interval at baseline.

In a 24-week trial, 130 subjects with COPD received continuous 24-hour electrocardiographic monitoring prior to the first dose and after 4 weeks of twice-daily treatment with either Advair Diskus 500/50, fluticasone propionate powder 500 mcg, salmeterol powder 50 mcg, or placebo. No significant differences in ventricular or supraventricular arrhythmias and heart rate were observed among the groups treated with Advair Diskus 500/50, the individual components, or placebo. One (1) subject in the fluticasone propionate group experienced atrial flutter/atrial fibrillation, and 1 subject in the group given Advair Diskus 500/50 experienced heart block. There were 3 cases of nonsustained ventricular tachycardia (1 each in the placebo, salmeterol, and fluticasone propionate 500-mcg treatment groups).

In 24-week clinical trials in subjects with COPD, the incidence of clinically significant ECG abnormalities (myocardial ischemia, ventricular hypertrophy, clinically significant conduction abnormalities, clinically significant arrhythmias) was lower for subjects who received salmeterol (1%, 9 of 688 subjects who received either salmeterol 50 mcg or Advair Diskus) compared with placebo (3%, 10 of 370 subjects).

No significant differences with salmeterol 50 mcg alone or in combination with fluticasone propionate as Advair Diskus 500/50 were observed on pulse rate and systolic and diastolic blood pressure in a subset of subjects with COPD who underwent 12-hour serial vital sign measurements after the first dose (n = 183) and after 12 weeks of therapy (n = 149). Median changes from baseline in pulse rate and systolic and diastolic blood pressure were similar to those seen with placebo.

Hypothalamic-Pituitary-Adrenal Axis Effects: Short-cosyntropin stimulation testing was performed both at Day 1 and Endpoint in 101 subjects with COPD receiving twice-daily Advair Diskus 250/50, fluticasone propionate powder 250 mcg, salmeterol powder 50 mcg, or placebo. For most subjects, the ability to increase cortisol production in response to stress, as assessed by short cosyntropin stimulation, remained intact with Advair Diskus 250/50. One (1) subject (3%) who received Advair Diskus 250/50 had an abnormal stimulated cortisol response (peak cortisol less than 14.5 mcg/dL assessed by high-performance liquid chromatography) after dosing, compared with 2 subjects (9%) who received fluticasone propionate 250 mcg, 2 subjects (7%) who received salmeterol 50 mcg, and 1 subject (4%) who received placebo following 24 weeks of treatment or early discontinuation from trial.

After 36 weeks of dosing, serum cortisol concentrations in a subset of subjects with COPD (n = 83) were 22% lower in subjects receiving Advair Diskus 500/50 and 21% lower in subjects receiving fluticasone propionate 500 mcg than in subjects receiving placebo.

Other Fluticasone Propionate Products

Subjects with Asthma: Hypothalamic-Pituitary-Adrenal Axis Effects: In clinical trials with fluticasone propionate inhalation powder using dosages up to and including 250 mcg twice daily, occasional abnormal short cosyntropin tests (peak serum cortisol less than 18 mcg/dL assessed by radioimmunoassay) were noted both in subjects receiving fluticasone propionate and in subjects receiving placebo. The incidence of abnormal tests at 500 mcg twice daily was greater than placebo. In a 2-year trial carried out with the DISKHALER® inhalation device in 64 subjects with mild, persistent asthma (mean FEV1 91% of predicted) randomized to fluticasone propionate 500 mcg twice daily or placebo, no subject receiving fluticasone propionate had an abnormal response to 6-hour cosyntropin infusion (peak serum cortisol less than 18 mcg/dL). With a peak cortisol threshold of less than 35 mcg/dL, 1 subject receiving fluticasone propionate (4%) had an abnormal response at 1 year; repeat testing at 18 months and 2 years was normal. Another subject receiving fluticasone propionate (5%) had an abnormal response at 2 years. No subject on placebo had an abnormal response at 1 or 2 years.

Subjects with Chronic Obstructive Pulmonary Disease: Hypothalamic-Pituitary-Adrenal Axis Effects: After 4 weeks of dosing, the steady-state fluticasone propionate pharmacokinetics and serum cortisol levels were described in a subset of subjects with COPD (n = 86) randomized to twice-daily fluticasone propionate inhalation powder via the DISKUS 500 mcg, fluticasone propionate inhalation powder 250 mcg, or placebo. Serial serum cortisol concentrations were measured across a 12-hour dosing interval. Serum cortisol concentrations following 250- and 500-mcg twice-daily dosing were 10% and 21% lower than placebo, respectively, indicating a dose-dependent increase in systemic exposure to fluticasone propionate.

Other Salmeterol Xinafoate Products

Subjects with Asthma: Cardiovascular Effects: Inhaled salmeterol, like other beta-adrenergic agonist drugs, can produce dose-related cardiovascular effects and effects on blood glucose and/or serum potassium [see Warnings and Precautions (5.12, 5.18)]. The cardiovascular effects (heart rate, blood pressure) associated with salmeterol inhalation aerosol occur with similar frequency, and are of similar type and severity, as those noted following albuterol administration.

The effects of rising inhaled doses of salmeterol and standard inhaled doses of albuterol were studied in volunteers and in subjects with asthma. Salmeterol doses up to 84 mcg administered as inhalation aerosol resulted in heart rate increases of 3 to 16 beats/min, about the same as albuterol dosed at 180 mcg by inhalation aerosol (4 to 10 beats/min). Adult and adolescent subjects receiving 50-mcg doses of salmeterol inhalation powder (N = 60) underwent continuous electrocardiographic monitoring during two 12-hour periods after the first dose and after 1 month of therapy, and no clinically significant dysrhythmias were noted.

Concomitant Use of Advair Diskus with Other Respiratory Medications

Short-acting Beta2-agonists: In clinical trials in subjects with asthma, the mean daily need for albuterol by 166 adult and adolescent subjects aged 12 years and older using Advair Diskus was approximately 1.3 inhalations/day and ranged from 0 to 9 inhalations/day. Five percent (5%) of subjects using Advair Diskus in these trials averaged 6 or more inhalations per day over the course of the 12-week trials. No increase in frequency of cardiovascular adverse events was observed among subjects who averaged 6 or more inhalations per day.

In a clinical trial in subjects with COPD, the mean daily need for albuterol for subjects using Advair Diskus 250/50 was 4.1 inhalations/day. Twenty-six percent (26%) of subjects using Advair Diskus 250/50 averaged 6 or more inhalations of albuterol per day over the course of the 24-week trial. No increase in frequency of cardiovascular adverse reactions was observed among subjects who averaged 6 or more inhalations per day.

Methylxanthines: The concurrent use of intravenously or orally administered methylxanthines (e.g., aminophylline, theophylline) by adult and adolescent subjects aged 12 years and older receiving Advair Diskus has not been completely evaluated. In clinical trials in subjects with asthma, 39 subjects receiving Advair Diskus 100/50, Advair Diskus 250/50, or Advair Diskus 500/50 twice daily concurrently with a theophylline product had adverse event rates similar to those in 304 subjects receiving Advair Diskus without theophylline. Similar results were observed in subjects receiving salmeterol 50 mcg plus fluticasone propionate 500 mcg twice daily concurrently with a theophylline product (n = 39) or without theophylline (n = 132).

In a clinical trial in subjects with COPD, 17 subjects receiving Advair Diskus 250/50 twice daily concurrently with a theophylline product had adverse event rates similar to those in 161 subjects receiving Advair Diskus without theophylline. Based on the available data, the concomitant administration of methylxanthines with Advair Diskus did not alter the observed adverse event profile.

Fluticasone Propionate Nasal Spray: In adult and adolescent subjects aged 12 years and older taking Advair Diskus in clinical trials, no difference in the profile of adverse events or HPA axis effects was noted between subjects who were taking FLONASE® (fluticasone propionate) Nasal Spray, 50 mcg concurrently (n = 46) and those who were not (n = 130).

Pharmacokinetics

Absorption

Fluticasone Propionate: Healthy Subjects: Fluticasone propionate acts locally in the lung; therefore, plasma levels do not predict therapeutic effect. Trials using oral dosing of labeled and unlabeled drug have demonstrated that the oral systemic bioavailability of fluticasone propionate is negligible (less than 1%), primarily due to incomplete absorption and presystemic metabolism in the gut and liver. In contrast, the majority of the fluticasone propionate delivered to the lung is systemically absorbed.

Following administration of Advair Diskus to healthy adult subjects, peak plasma concentrations of fluticasone propionate were achieved in 1 to 2 hours. In a single-dose crossover trial, a higher-than-recommended dose of Advair Diskus was administered to 14 healthy adult subjects. Two (2) inhalations of the following treatments were administered: Advair Diskus 500/50, fluticasone propionate powder 500 mcg and salmeterol powder 50 mcg given concurrently, and fluticasone propionate powder 500 mcg alone. Mean peak plasma concentrations of fluticasone propionate averaged 107, 94, and 120 pg/mL, respectively, indicating no significant changes in systemic exposures of fluticasone propionate.

In 15 healthy subjects, systemic exposure to fluticasone propionate from 4 inhalations of ADVAIR® HFA 230/21 (fluticasone propionate 230 mcg and salmeterol 21 mcg) Inhalation Aerosol (920/84 mcg) and 2 inhalations of Advair Diskus 500/50 (1,000/100 mcg) was similar between the 2 inhalers (i.e., 799 versus 832 pg•h/mL, respectively), but approximately half the systemic exposure from 4 inhalations of fluticasone propionate CFC inhalation aerosol 220 mcg (880 mcg, AUC = 1,543 pg•h/mL). Similar results were observed for peak fluticasone propionate plasma concentrations (186 and 182 pg/mL from ADVAIR HFA and Advair Diskus, respectively, and 307 pg/mL from the fluticasone propionate CFC inhalation aerosol). Absolute bioavailability of fluticasone propionate was 5.3% and 5.5% following administration of ADVAIR HFA and Advair Diskus, respectively.

Subjects with Asthma and COPD: Peak steady-state fluticasone propionate plasma concentrations in adult subjects with asthma (N = 11) ranged from undetectable to 266 pg/mL after a 500-mcg twice-daily dose of fluticasone propionate inhalation powder using the DISKUS inhaler. The mean fluticasone propionate plasma concentration was 110 pg/mL.

Full pharmacokinetic profiles were obtained from 9 female and 16 male subjects with asthma given fluticasone propionate inhalation powder 500 mcg twice daily using the DISKUS inhaler and from 14 female and 43 male subjects with COPD given 250 or 500 mcg twice daily. No overall differences in fluticasone propionate pharmacokinetics were observed.

Peak steady-state fluticasone propionate plasma concentrations in subjects with COPD averaged 53 pg/mL (range: 19.3 to 159.3 pg/mL) after treatment with 250 mcg twice daily (n = 30) and 84 pg/mL (range: 24.3 to 197.1 pg/mL) after treatment with 500 mcg twice daily (n = 27) via the fluticasone propionate DISKUS inhaler. In another trial in subjects with COPD, peak steady-state fluticasone propionate plasma concentrations averaged 115 pg/mL (range: 52.6 to 366.0 pg/mL) after treatment with 500 mcg twice daily via the fluticasone propionate DISKUS inhaler (n = 15) and 105 pg/mL (range: 22.5 to 299.0 pg/mL) via Advair Diskus (n = 24).

Salmeterol Xinafoate: Healthy Subjects: Salmeterol xinafoate, an ionic salt, dissociates in solution so that the salmeterol and 1-hydroxy-2-naphthoic acid (xinafoate) moieties are absorbed, distributed, metabolized, and eliminated independently. Salmeterol acts locally in the lung; therefore, plasma levels do not predict therapeutic effect.

Following administration of Advair Diskus to healthy adult subjects, peak plasma concentrations of salmeterol were achieved in about 5 minutes.

In 15 healthy subjects receiving ADVAIR HFA 230/21 Inhalation Aerosol (920/84 mcg) and Advair Diskus 500/50 (1,000/100 mcg), systemic exposure to salmeterol was higher (317 versus 169 pg•h/mL) and peak salmeterol concentrations were lower (196 versus 223 pg/mL) following ADVAIR HFA compared with Advair Diskus, although pharmacodynamic results were comparable.

Subjects with Asthma: Because of the small therapeutic dose, systemic levels of salmeterol are low or undetectable after inhalation of recommended dosages (50 mcg of salmeterol inhalation powder twice daily). Following chronic administration of an inhaled dose of 50 mcg of salmeterol inhalation powder twice daily, salmeterol was detected in plasma within 5 to 45 minutes in 7 subjects with asthma; plasma concentrations were very low, with mean peak concentrations of 167 pg/mL at 20 minutes and no accumulation with repeated doses.

Distribution

Fluticasone Propionate: Following intravenous administration, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The volume of distribution averaged 4.2 L/kg.

The percentage of fluticasone propionate bound to human plasma proteins averages 99%. Fluticasone propionate is weakly and reversibly bound to erythrocytes and is not significantly bound to human transcortin.

Salmeterol: The percentage of salmeterol bound to human plasma proteins averages 96% in vitro over the concentration range of 8 to 7,722 ng of salmeterol base per milliliter, much higher concentrations than those achieved following therapeutic doses of salmeterol.

Metabolism

Fluticasone Propionate: The total clearance of fluticasone propionate is high (average, 1,093 mL/min), with renal clearance accounting for less than 0.02% of the total. The only circulating metabolite detected in man is the 17β-carboxylic acid derivative of fluticasone propionate, which is formed through the CYP3A4 pathway. This metabolite had less affinity (approximately 1/2,000) than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man.

Salmeterol: Salmeterol base is extensively metabolized by hydroxylation, with subsequent elimination predominantly in the feces. No significant amount of unchanged salmeterol base was detected in either urine or feces.

An in vitro study using human liver microsomes showed that salmeterol is extensively metabolized to α-hydroxysalmeterol (aliphatic oxidation) by CYP3A4. Ketoconazole, a strong inhibitor of CYP3A4, essentially completely inhibited the formation of α-hydroxysalmeterol in vitro.

Elimination

Fluticasone Propionate: Following intravenous dosing, fluticasone propionate showed polyexponential kinetics and had a terminal elimination half-life of approximately 7.8 hours. Less than 5% of a radiolabeled oral dose was excreted in the urine as metabolites, with the remainder excreted in the feces as parent drug and metabolites. Terminal half-life estimates of fluticasone propionate for ADVAIR HFA, Advair Diskus, and fluticasone propionate CFC inhalation aerosol were similar and averaged 5.6 hours.

Salmeterol: In 2 healthy adult subjects who received 1 mg of radiolabeled salmeterol (as salmeterol xinafoate) orally, approximately 25% and 60% of the radiolabeled salmeterol was eliminated in urine and feces, respectively, over a period of 7 days. The terminal elimination half-life was about 5.5 hours (1 volunteer only).

The xinafoate moiety has no apparent pharmacologic activity. The xinafoate moiety is highly protein bound (greater than 99%) and has a long elimination half-life of 11 days. No terminal half-life estimates were calculated for salmeterol following administration of Advair Diskus.

Special Populations

A population pharmacokinetic analysis was performed for fluticasone propionate and salmeterol utilizing data from 9 controlled clinical trials that included 350 subjects with asthma aged 4 to 77 years who received treatment with Advair Diskus, the combination of HFA-propelled fluticasone propionate and salmeterol inhalation aerosol (ADVAIR HFA), fluticasone propionate inhalation powder (FLOVENT DISKUS), HFA-propelled fluticasone propionate inhalation aerosol (FLOVENT® HFA), or chlorofluorocarbon (CFC)-propelled fluticasone propionate inhalation aerosol. The population pharmacokinetic analyses for fluticasone propionate and salmeterol showed no clinically relevant effects of age, gender, race, body weight, body mass index, or percent of predicted FEV1 on apparent clearance and apparent volume of distribution.

Age: When the population pharmacokinetic analysis for fluticasone propionate was divided into subgroups based on fluticasone propionate strength, formulation, and age (adolescents/adults and children), there were some differences in fluticasone propionate exposure. Higher fluticasone propionate exposure from Advair Diskus 100/50 compared with FLOVENT DISKUS 100 mcg was observed in adolescents and adults (ratio 1.52 [90% CI: 1.08, 2.13]). However, in clinical trials of up to 12 weeks’ duration comparing Advair Diskus 100/50 and FLOVENT DISKUS 100 mcg in adolescents and adults, no differences in systemic effects of corticosteroid treatment (e.g., HPA axis effects) were observed. Similar fluticasone propionate exposure was observed from Advair Diskus 500/50 and FLOVENT DISKUS 500 mcg (ratio 0.83 [90% CI: 0.65, 1.07]) in adolescents and adults.

Steady-state systemic exposure to salmeterol when delivered as Advair Diskus 100/50, Advair Diskus 250/50, or ADVAIR HFA 115/21 (fluticasone propionate 115 mcg and salmeterol 21 mcg) Inhalation Aerosol was evaluated in 127 subjects aged 4 to 57 years. The geometric mean AUC was 325 pg•h/mL (90% CI: 309, 341) in adolescents and adults.

The population pharmacokinetic analysis included 160 subjects with asthma aged 4 to 11 years who received Advair Diskus 100/50 or FLOVENT DISKUS 100 mcg. Higher fluticasone propionate exposure (AUC) was observed in children from Advair Diskus 100/50 compared with FLOVENT DISKUS 100 mcg (ratio 1.20 [90% CI: 1.06, 1.37]). Higher fluticasone propionate exposure (AUC) from Advair Diskus 100/50 was observed in children compared with adolescents and adults (ratio 1.63 [90% CI: 1.35, 1.96]). However, in clinical trials of up to 12 weeks’ duration comparing Advair Diskus 100/50 and FLOVENT DISKUS 100 mcg in both adolescents and adults and in children, no differences in systemic effects of corticosteroid treatment (e.g., HPA axis effects) were observed.

Exposure to salmeterol was higher in children compared with adolescents and adults who received Advair Diskus 100/50 (ratio 1.23 [90% CI: 1.10, 1.38]). However, in clinical trials of up to 12 weeks’ duration with Advair Diskus 100/50 in both adolescents and adults and in children, no differences in systemic effects of beta2-agonist treatment (e.g., cardiovascular effects, tremor) were observed.

Gender: The population pharmacokinetic analysis involved 202 males and 148 females with asthma who received fluticasone propionate alone or in combination with salmeterol and showed no gender differences for fluticasone propionate pharmacokinetics.

The population pharmacokinetic analysis involved 76 males and 51 females with asthma who received salmeterol in combination with fluticasone propionate and showed no gender differences for salmeterol pharmacokinetics.

Hepatic and Renal Impairment: Formal pharmacokinetic studies using Advair Diskus have not been conducted in patients with hepatic or renal impairment. However, since both fluticasone propionate and salmeterol are predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of fluticasone propionate and salmeterol in plasma. Therefore, patients with hepatic disease should be closely monitored.

Drug Interactions

In the repeat- and single-dose trials, there was no evidence of significant drug interaction in systemic exposure between fluticasone propionate and salmeterol when given alone or in combination via the DISKUS. The population pharmacokinetic analysis from 9 controlled clinical trials in 350 subjects with asthma showed no significant effects on fluticasone propionate or salmeterol pharmacokinetics following co-administration with beta2-agonists, corticosteroids, antihistamines, or theophyllines.

Inhibitors of Cytochrome P450 3A4: Ritonavir: Fluticasone Propionate: Fluticasone propionate is a substrate of CYP3A4. Coadministration of fluticasone propionate and the strong CYP3A4 inhibitor ritonavir is not recommended based upon a multiple-dose, crossover drug interaction trial in 18 healthy subjects. Fluticasone propionate aqueous nasal spray (200 mcg once daily) was coadministered for 7 days with ritonavir (100 mg twice daily). Plasma fluticasone propionate concentrations following fluticasone propionate aqueous nasal spray alone were undetectable (less than 10 pg/mL) in most subjects, and when concentrations were detectable peak levels (Cmax) averaged 11.9 pg/mL (range: 10.8 to 14.1 pg/mL) and AUC(0-τ) averaged 8.43 pg•h/mL (range: 4.2 to 18.8 pg•h/mL). Fluticasone propionate Cmax and AUC(0-τ) increased to 318 pg/mL (range: 110 to 648 pg/mL) and 3,102.6 pg•h/mL (range: 1,207.1 to 5,662.0 pg•h/mL), respectively, after coadministration of ritonavir with fluticasone propionate aqueous nasal spray. This significant increase in plasma fluticasone propionate exposure resulted in a significant decrease (86%) in serum cortisol AUC.

Ketoconazole: Fluticasone Propionate: In a placebo-controlled, crossover trial in 8 healthy adult volunteers, coadministration of a single dose of orally inhaled fluticasone propionate (1,000 mcg) with multiple doses of ketoconazole (200 mg) to steady state resulted in increased plasma fluticasone propionate exposure, a reduction in plasma cortisol AUC, and no effect on urinary excretion of cortisol.

Salmeterol: In a placebo-controlled, crossover drug interaction trial in 20 healthy male and female subjects, coadministration of salmeterol (50 mcg twice daily) and the strong CYP3A4 inhibitor ketoconazole (400 mg once daily) for 7 days resulted in a significant increase in plasma salmeterol exposure as determined by a 16-fold increase in AUC (ratio with and without ketoconazole 15.76 [90% CI: 10.66, 23.31]) mainly due to increased bioavailability of the swallowed portion of the dose. Peak plasma salmeterol concentrations were increased by 1.4-fold (90% CI: 1.23, 1.68). Three (3) out of 20 subjects (15%) were withdrawn from salmeterol and ketoconazole coadministration due to beta-agonist–mediated systemic effects (2 with QTc prolongation and 1 with palpitations and sinus tachycardia). Coadministration of salmeterol and ketoconazole did not result in a clinically significant effect on mean heart rate, mean blood potassium, or mean blood glucose. Although there was no statistical effect on the mean QTc, coadministration of salmeterol and ketoconazole was associated with more frequent increases in QTc duration compared with salmeterol and placebo administration.

Erythromycin: Fluticasone Propionate: In a multiple-dose drug interaction trial, coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone propionate pharmacokinetics.

Salmeterol: In a repeat-dose trial in 13 healthy subjects, concomitant administration of erythromycin (a moderate CYP3A4 inhibitor) and salmeterol inhalation aerosol resulted in a 40% increase in salmeterol Cmax at steady state (ratio with and without erythromycin 1.4 [90% CI: 0.96, 2.03], P = 0.12), a 3.6-beat/min increase in heart rate ([95% CI: 0.19, 7.03], P less than 0.04), a 5.8-msec increase in QTc interval ([95% CI: -6.14, 17.77], P = 0.34), and no change in plasma potassium.

Asthma

Adult and Adolescent Subjects Aged 12 Years and Older

In clinical trials comparing Advair Diskus with its individual components, improvements in most efficacy endpoints were greater with Advair Diskus than with the use of either fluticasone propionate or salmeterol alone. In addition, clinical trials showed similar results between Advair Diskus and the concurrent use of fluticasone propionate plus salmeterol at corresponding doses from separate inhalers.

Trials Comparing Advair Diskus with Fluticasone Propionate Alone or Salmeterol Alone: Three (3) double-blind, parallel-group clinical trials were conducted with Advair Diskus in 1,208 adult and adolescent subjects (aged 12 years and older, baseline FEV1 63% to 72% of predicted normal) with asthma that was not optimally controlled on their current therapy. All treatments were inhalation powders given as 1 inhalation from the DISKUS inhaler twice daily, and other maintenance therapies were discontinued.

Trial 1: Clinical Trial with Advair Diskus 100/50: This placebo-controlled, 12-week, U.S. trial compared Advair Diskus 100/50 with its individual components, fluticasone propionate 100 mcg and salmeterol 50 mcg. The trial was stratified according to baseline asthma maintenance therapy; subjects were using either inhaled corticosteroids (n = 250) (daily doses of beclomethasone dipropionate 252 to 420 mcg; flunisolide 1,000 mcg; fluticasone propionate inhalation aerosol 176 mcg; or triamcinolone acetonide 600 to 1,000 mcg) or salmeterol (n = 106). Baseline FEV1 measurements were similar across treatments: Advair Diskus 100/50, 2.17 L; fluticasone propionate 100 mcg, 2.11 L; salmeterol, 2.13 L; and placebo, 2.15 L.

Predefined withdrawal criteria for lack of efficacy, an indicator of worsening asthma, were utilized for this placebo-controlled trial. Worsening asthma was defined as a clinically important decrease in FEV1 or PEF, increase in use of VENTOLIN® (albuterol, USP) Inhalation Aerosol, increase in night awakenings due to asthma, emergency intervention or hospitalization due to asthma, or requirement for asthma medication not allowed by the protocol. As shown in Table 4, statistically significantly fewer subjects receiving Advair Diskus 100/50 were withdrawn due to worsening asthma compared with fluticasone propionate, salmeterol, and placebo.

Table 4. Percent of Subjects Withdrawn due to Worsening Asthma in Subjects Previously Treated with Either Inhaled Corticosteroids or Salmeterol (Trial 1)

The FEV1 results are displayed in Figure 2. Because this trial used predetermined criteria for worsening asthma, which caused more subjects in the placebo group to be withdrawn, FEV1 results at Endpoint (last available FEV1 result) are also provided. Subjects receiving Advair Diskus 100/50 had significantly greater improvements in FEV1 (0.51 L, 25%) compared with fluticasone propionate 100 mcg (0.28 L, 15%), salmeterol (0.11 L, 5%), and placebo (0.01 L, 1%). These improvements in FEV1 with Advair Diskus were achieved regardless of baseline asthma maintenance therapy (inhaled corticosteroids or salmeterol).

Figure 2. Mean Percent Change from Baseline in FEV1 in Subjects with Asthma Previously Treated with Either Inhaled Corticosteroids or Salmeterol (Trial 1)

The effect of Advair Diskus 100/50 on morning and evening PEF endpoints is shown in Table 5.

Table 5. Peak Expiratory Flow Results for Subjects with Asthma Previously Treated with Either Inhaled Corticosteroids or Salmeterol (Trial 1)

aChange from baseline = change from baseline at Endpoint (last available data).

The subjective impact of asthma on subjects’ perception of health was evaluated through use of an instrument called the Asthma Quality of Life Questionnaire (AQLQ) (based on a 7-point scale where 1 = maximum impairment and 7 = none). Subjects receiving Advair Diskus 100/50 had clinically meaningful improvements in overall asthma-specific quality of life as defined by a difference between groups of greater than or equal to 0.5 points in change from baseline AQLQ scores (difference in AQLQ score of 1.25 compared with placebo).

Trial 2: Clinical Trial with Advair Diskus 250/50: This placebo-controlled, 12-week, U.S. trial compared Advair Diskus 250/50 with its individual components, fluticasone propionate 250 mcg and salmeterol 50 mcg, in 349 subjects with asthma using inhaled corticosteroids (daily doses of beclomethasone dipropionate 462 to 672 mcg; flunisolide 1,250 to 2,000 mcg; fluticasone propionate inhalation aerosol 440 mcg; or triamcinolone acetonide 1,100 to 1,600 mcg). Baseline FEV1 measurements were similar across treatments: Advair Diskus 250/50, 2.23 L; fluticasone propionate 250 mcg, 2.12 L; salmeterol, 2.20 L; and placebo, 2.19 L.

Efficacy results in this trial were similar to those observed in Trial 1. Subjects receiving Advair Diskus 250/50 had significantly greater improvements in FEV1 (0.48 L, 23%) compared with fluticasone propionate 250 mcg (0.25 L, 13%), salmeterol (0.05 L, 4%), and placebo (decrease of 0.11 L, decrease of 5%). Statistically significantly fewer subjects receiving Advair Diskus 250/50 were withdrawn from this trial for worsening asthma (4%) compared with fluticasone propionate (22%), salmeterol (38%), and placebo (62%). In addition, Advair Diskus 250/50 was superior to fluticasone propionate, salmeterol, and placebo for improvements in morning and evening PEF. Subjects receiving Advair Diskus 250/50 also had clinically meaningful improvements in overall asthma-specific quality of life as described in Trial 1 (difference in AQLQ score of 1.29 compared with placebo).

Trial 3: Clinical Trial with Advair Diskus 500/50: This 28-week, non-U.S. trial compared Advair Diskus 500/50 with fluticasone propionate 500 mcg alone and concurrent therapy (salmeterol 50 mcg plus fluticasone propionate 500 mcg administered from separate inhalers) twice daily in 503 subjects with asthma using inhaled corticosteroids (daily doses of beclomethasone dipropionate 1,260 to 1,680 mcg; budesonide 1,500 to 2,000 mcg; flunisolide 1,500 to 2,000 mcg; or fluticasone propionate inhalation aerosol 660 to 880 mcg [750 to 1,000 mcg inhalation powder]). The primary efficacy parameter, morning PEF, was collected daily for the first 12 weeks of the trial. The primary purpose of weeks 13 to 28 was to collect safety data.

Baseline PEF measurements were similar across treatments: Advair Diskus 500/50, 359 L/min; fluticasone propionate 500 mcg, 351 L/min; and concurrent therapy, 345 L/min. Morning PEF improved significantly with Advair Diskus 500/50 compared with fluticasone propionate 500 mcg over the 12-week treatment period. Improvements in morning PEF observed with Advair Diskus 500/50 were similar to improvements observed with concurrent therapy.

Onset of Action and Progression of Improvement in Asthma Control: The onset of action and progression of improvement in asthma control were evaluated in the 2 placebo-controlled U.S. trials. Following the first dose, the median time to onset of clinically significant bronchodilatation (greater than or equal to 15% improvement in FEV1) in most subjects was seen within 30 to 60 minutes. Maximum improvement in FEV1 generally occurred within 3 hours, and clinically significant improvement was maintained for 12 hours (Figure 3). Following the initial dose, predose FEV1 relative to Day 1 baseline improved markedly over the first week of treatment and continued to improve over the 12 weeks of treatment in both trials. No diminution in the 12-hour bronchodilator effect was observed with either Advair Diskus 100/50 (Figures 3 and 4) or Advair Diskus 250/50 as assessed by FEV1 following 12 weeks of therapy.

Figure 3. Percent Change in Serial 12-Hour FEV1 in Subjects with Asthma Previously Using Either Inhaled Corticosteroids or Salmeterol (Trial 1)

First Treatment Day

Figure 4. Percent Change in Serial 12-Hour FEV1 in Subjects with Asthma Previously Using Either Inhaled Corticosteroids or Salmeterol (Trial 1)

Last Treatment Day (Week 12)

Reduction in asthma symptoms and use of rescue VENTOLIN Inhalation Aerosol and improvement in morning and evening PEF also occurred within the first day of treatment with Advair Diskus, and continued to improve over the 12 weeks of therapy in both trials.

Pediatric Subjects

In a 12-week U.S. trial, Advair Diskus 100/50 twice daily was compared with fluticasone propionate inhalation powder 100 mcg twice daily in 203 children with asthma aged 4 to 11 years. At trial entry, the children were symptomatic on low doses of inhaled corticosteroids (beclomethasone dipropionate 252 to 336 mcg/day; budesonide 200 to 400 mcg/day; flunisolide 1,000 mcg/day; triamcinolone acetonide 600 to 1,000 mcg/day; or fluticasone propionate 88 to 250 mcg/day). The primary objective of this trial was to determine the safety of Advair Diskus 100/50 compared with fluticasone propionate inhalation powder 100 mcg in this age-group; however, the trial also included secondary efficacy measures of pulmonary function. Morning predose FEV1 was obtained at baseline and Endpoint (last available FEV1 result) in children aged 6 to 11 years. In subjects receiving Advair Diskus 100/50, FEV1 increased from 1.70 L at baseline (n = 79) to 1.88 L at Endpoint (n = 69) compared with an increase from 1.65 L at baseline (n = 83) to 1.77 L at Endpoint (n = 75) in subjects receiving fluticasone propionate 100 mcg.

The findings of this trial, along with extrapolation of efficacy data from subjects aged 12 years and older, support the overall conclusion that Advair Diskus 100/50 is efficacious in the treatment of asthma in subjects aged 4 to 11 years.

Chronic Obstructive Pulmonary Disease

The efficacy of Advair Diskus 250/50 and Advair Diskus 500/50 in the treatment of subjects with COPD was evaluated in 6 randomized, double-blind, parallel-group clinical trials in adult subjects aged 40 years and older. These trials were primarily designed to evaluate the efficacy of Advair Diskus on lung function (3 trials), exacerbations (2 trials), and survival (1 trial).

Lung Function

Two of the 3 clinical trials primarily designed to evaluate the efficacy of Advair Diskus on lung function were conducted in 1,414 subjects with COPD associated with chronic bronchitis. In these 2 trials, all the subjects had a history of cough productive of sputum that was not attributable to another disease process on most days for at least 3 months of the year for at least 2 years. The trials were randomized, double-blind, parallel-group, 24-week treatment duration. One trial evaluated the efficacy of Advair Diskus 250/50 compared with its components fluticasone propionate 250 mcg and salmeterol 50 mcg and with placebo, and the other trial evaluated the efficacy of Advair Diskus 500/50 compared with its components fluticasone propionate 500 mcg and salmeterol 50 mcg and with placebo. Trial treatments were inhalation powders given as 1 inhalation from the DISKUS inhaler twice daily. Maintenance COPD therapies were discontinued, with the exception of theophylline. The subjects had a mean pre-bronchodilator FEV1 of 41% and 20% reversibility at trial entry. Percent reversibility was calculated as 100 times (FEV1 post-albuterol minus FEV1 pre-albuterol)/FEV1 pre-albuterol.

Improvements in lung function (as defined by predose and postdose FEV1) were significantly greater with Advair Diskus than with fluticasone propionate, salmeterol, or placebo. The improvement in lung function with Advair Diskus 500/50 was similar to the improvement seen with Advair Diskus 250/50.

Figures 5 and 6 display predose and 2-hour postdose, respectively, FEV1 results for the trial with Advair Diskus 250/50. To account for subject withdrawals during the trial, FEV1 at Endpoint (last evaluable FEV1) was evaluated. Subjects receiving Advair Diskus 250/50 had significantly greater improvements in predose FEV1 at Endpoint (165 mL, 17%) compared with salmeterol 50 mcg (91 mL, 9%) and placebo (1 mL, 1%), demonstrating the contribution of fluticasone propionate to the improvement in lung function with Advair Diskus (Figure 5). Subjects receiving Advair Diskus 250/50 had significantly greater improvements in postdose FEV1 at Endpoint (281 mL, 27%) compared with fluticasone propionate 250 mcg (147 mL, 14%) and placebo (58 mL, 6%), demonstrating the contribution of salmeterol to the improvement in lung function with Advair Diskus (Figure 6).

Figure 5. Predose FEV1: Mean Percent Change from Baseline in Subjects with Chronic Obstructive Pulmonary Disease

Figure 6. Two-Hour Postdose FEV1: Mean Percent Changes from Baseline over Time in Subjects with Chronic Obstructive Pulmonary Disease

The third trial was a 1-year trial that evaluated Advair Diskus 500/50, fluticasone propionate 500 mcg, salmeterol 50 mcg, and placebo in 1,465 subjects. The subjects had an established history of COPD and exacerbations, a pre-bronchodilator FEV1 less than 70% of predicted at trial entry, and 8.3% reversibility. The primary endpoint was the comparison of pre-bronchodilator FEV1 in the groups receiving Advair Diskus 500/50 or placebo. Subjects treated with Advair Diskus 500/50 had greater improvements in FEV1 (113 mL, 10%) compared with fluticasone propionate 500 mcg (7 mL, 2%), salmeterol (15 mL, 2%), and placebo (-60 mL, -3%).

Exacerbations

Two trials were primarily designed to evaluate the effect of Advair Diskus 250/50 on exacerbations. In these 2 trials, exacerbations were defined as worsening of 2 or more major symptoms (dyspnea, sputum volume, and sputum purulence) or worsening of any 1 major symptom together with any 1 of the following minor symptoms: sore throat, colds (nasal discharge and/or nasal congestion), fever without other cause, and increased cough or wheeze for at least 2 consecutive days. COPD exacerbations were considered of moderate severity if treatment with systemic corticosteroids and/or antibiotics was required and were considered severe if hospitalization was required.

Exacerbations were also evaluated as a secondary outcome in the 1- and 3-year trials with Advair Diskus 500/50. There was not a symptomatic definition of exacerbation in these 2 trials. Exacerbations were defined in terms of severity requiring treatment with antibiotics and/or systemic corticosteroids (moderately severe) or requiring hospitalization (severe).

The 2 exacerbation trials with Advair Diskus 250/50 were identical trials designed to evaluate the effect of Advair Diskus 250/50 and salmeterol 50 mcg, each given twice daily, on exacerbations of COPD over a 12-month period. A total of 1,579 subjects had an established history of COPD (but no other significant respiratory disorders). Subjects had a pre-bronchodilator FEV1 of 33% of predicted, a mean reversibility of 23% at baseline, and a history of greater than or equal to 1 COPD exacerbation in the previous year that was moderate or severe. All subjects were treated with Advair Diskus 250/50 twice daily during a 4-week run-in period prior to being assigned trial treatment with twice-daily Advair Diskus 250/50 or salmeterol 50 mcg. In both trials, treatment with Advair Diskus 250/50 resulted in a significantly lower annual rate of moderate/severe COPD exacerbations compared with salmeterol (30.5% reduction [95% CI: 17.0, 41.8], P less than 0.001) in the first trial and (30.4% reduction [95% CI: 16.9, 41.7], P less than 0.001) in the second trial. Subjects treated with Advair Diskus 250/50 also had a significantly lower annual rate of exacerbations requiring treatment with oral corticosteroids compared with subjects treated with salmeterol (39.7% reduction [95% CI: 22.8, 52.9], P less than 0.001) in the first trial and (34.3% reduction [95% CI: 18.6, 47.0], P less than 0.001) in the second trial. Secondary endpoints including pulmonary function and symptom scores improved more in subjects treated with Advair Diskus 250/50 than with salmeterol 50 mcg in both trials.

Exacerbations were evaluated in the 1- and the 3-year trials with Advair Diskus 500/50 as 1 of the secondary efficacy endpoints. In the 1-year trial, the group receiving Advair Diskus 500/50 had a significantly lower rate of moderate and severe exacerbations compared with placebo (25.4% reduction compared with placebo [95% CI: 13.5, 35.7]) but not when compared with its components (7.5% reduction compared with fluticasone propionate [95% CI: -7.3, 20.3] and 7% reduction compared with salmeterol [95% CI: -8.0, 19.9]). In the 3-year trial, the group receiving Advair Diskus 500/50 had a significantly lower rate of moderate and severe exacerbations compared with each of the other treatment groups (25.1% reduction compared with placebo [95% CI: 18.6, 31.1], 9.0% reduction compared with fluticasone propionate [95% CI: 1.2, 16.2], and 12.2% reduction compared with salmeterol [95% CI: 4.6, 19.2]).

There were no trials conducted to directly compare the efficacy of Advair Diskus 250/50 with Advair Diskus 500/50 on exacerbations. Across trials, the reduction in exacerbations seen with Advair Diskus 500/50 was not greater than the reduction in exacerbations seen with Advair Diskus 250/50.

Survival

A 3-year multicenter, international trial evaluated the efficacy of Advair Diskus 500/50 compared with fluticasone propionate 500 mcg, salmeterol 50 mcg, and placebo on survival in 6,112 subjects with COPD. During the trial subjects were permitted usual COPD therapy with the exception of other inhaled corticosteroids and long-acting bronchodilators. The subjects were aged 40 to 80 years with an established history of COPD, a pre-bronchodilator FEV1 less than 60% of predicted at trial entry, and less than 10% of predicted reversibility. Each subject who withdrew from double-blind treatment for any reason was followed for the full 3-year trial period to determine survival status. The primary efficacy endpoint was all-cause mortality. Survival with Advair Diskus 500/50 was not significantly improved compared with placebo or the individual components (all-cause mortality rate 12.6% Advair Diskus versus 15.2% placebo). The rates for all-cause mortality were 13.5% and 16.0% in the groups treated with salmeterol 50 mcg and fluticasone propionate 500 mcg, respectively. Secondary outcomes, including pulmonary function (post-bronchodilator FEV1), improved with Advair Diskus 500/50, salmeterol 50 mcg, and fluticasone propionate 500 mcg compared with placebo.