Long-acting beta₂-adrenergic agonists, such as salmeterol, may increase the risk of asthma-related death. Data from a large, placebo-controlled US study that compared the safety of salmeterol (SEREVENT Inhalation Aerosol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol (see WARNINGS). Salmeterol is a component of ADVAIR DISKUS. However, the data from this study are not adequate to determine whether concurrent use of inhaled corticosteroids, such as fluticasone propionate, the other component of ADVAIR DISKUS, or other asthma controller therapy modifies the risk of asthma-related death.

Asthma

Adult and Adolescent Patients 12 Years of Age and Older

The incidence of common adverse events in Table 4 is based upon 2 placebo-controlled, 12-week, US clinical studies (Studies 1 and 2). A total of 705 adolescent and adult patients (349 females and 356 males) previously treated with salmeterol or inhaled corticosteroids were treated twice daily with ADVAIR DISKUS (100/50- or 250/50-mcg doses), fluticasone propionate inhalation powder (100- or 250-mcg doses), salmeterol inhalation powder 50 mcg, or placebo.

Table 4. Overall Adverse Events With =3% Incidence in US Controlled Clinical Trials With ADVAIR DISKUS in Patients With Asthma

Table 4 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of 3% or greater in either of the groups receiving ADVAIR DISKUS and were more common than in the placebo group. In considering these data, differences in average duration of exposure should be taken into account. Rare cases of immediate and delayed hypersensitivity reactions, including rash and other rare events of angioedema and bronchospasm, have been reported.

These adverse reactions were mostly mild to moderate in severity.

Other adverse events that occurred in the groups receiving ADVAIR DISKUS in these studies with an incidence of 1% to 3% and that occurred at a greater incidence than with placebo were:

Blood and Lymphatic

Lymphatic signs and symptoms.

Cardiovascular

Palpitations

Drug Interaction, Overdose, and Trauma

Muscle injuries, fractures, wounds and lacerations, contusions and hematomas, burns.

Ear, Nose, and Throat

Rhinorrhea/postnasal drip; ear, nose, and throat infections; ear signs and symptoms; nasal signs and symptoms; nasal sinus disorders; rhinitis; sneezing; nasal irritation; blood in nasal mucosa.

Eye

Keratitis and conjunctivitis, viral eye infections, eye redness.

Gastrointestinal

Dental discomfort and pain, gastrointestinal signs and symptoms, gastrointestinal infections, gastroenteritis, gastrointestinal disorders, oral ulcerations, oral erythema and rashes, constipation, appendicitis, oral discomfort and pain.

Hepatobiliary Tract and Pancreas

Abnormal liver function tests.

Lower Respiratory

Lower respiratory signs and symptoms, pneumonia, lower respiratory infections.

Musculoskeletal

Arthralgia and articular rheumatism; muscle stiffness, tightness, and rigidity; bone and cartilage disorders.

Neurology

Sleep disorders, tremors, hypnagogic effects, compressed nerve syndromes.

Non-Site Specific

Allergies and allergic reactions, congestion, viral infections, pain, chest symptoms, fluid retention, bacterial infections, wheeze and hives, unusual taste.

Skin

Viral skin infections, urticaria, skin flakiness and acquired ichthyosis, disorders of sweat and sebum, sweating.

The incidence of common adverse events reported in Study 3, a 28-week, non-US clinical study of 503 patients previously treated with inhaled corticosteroids who were treated twice daily with ADVAIR DISKUS 500/50, fluticasone propionate inhalation powder 500 mcg and salmeterol inhalation powder 50 mcg used concurrently, or fluticasone propionate inhalation powder 500 mcg was similar to the incidences reported in Table 4.

Pediatric Patients

Pediatric Study

ADVAIR DISKUS 100/50 was well tolerated in clinical trials conducted in children with asthma aged 4 to 11 years. The incidence of common adverse events in Table 5 is based upon a 12-week US study in 203 patients with asthma aged 4 to 11 years (74 females and 129 males) who were receiving inhaled corticosteroids at study entry and were randomized to either ADVAIR DISKUS 100/50 or fluticasone propionate inhalation powder 100 mcg twice daily.

Table 5. Overall Adverse Events With =3% Incidence With ADVAIR DISKUS 100/50 in Patients 4 to 11 Years of Age With Asthma

Table 5 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of 3% or greater in the group receiving ADVAIR DISKUS 100/50.

Chronic Obstructive Pulmonary Disease Associated With Chronic Bronchitis

The incidence of common adverse events in Table 6 is based upon 1 placebo-controlled, 24-week, US clinical trial in patients with COPD associated with chronic bronchitis. A total of 723 adult patients (266 females and 457 males) were treated twice daily with ADVAIR DISKUS 250/50, fluticasone propionate inhalation powder 250 mcg, salmeterol inhalation powder 50 mcg, or placebo.

Table 6. Overall Adverse Events With =3% Incidence With ADVAIR DISKUS 250/50 in Patients With Chronic Obstructive Pulmonary Disease Associated With Chronic Bronchitis

Table 6 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of 3% or greater in the group receiving ADVAIR DISKUS 250/50 and were more common than in the placebo group.

These adverse reactions were mostly mild to moderate in severity.

Other adverse events that occurred in the groups receiving ADVAIR DISKUS 250/50 with an incidence of 1% to 3% and that occurred at a greater incidence than with placebo were:

Cardiovascular

Syncope

Drug Interaction, Overdose, and Trauma

Postoperative complications

Ear, Nose, and Throat

Ear, nose, and throat infections; ear signs and symptoms; laryngitis; nasal congestion/blockage; nasal sinus disorders; pharyngitis/throat infection.

Endocrine and Metabolic

Hypothyroidism

Eye

Dry eyes, eye infections.

Gastrointestinal

Constipation, gastrointestinal signs and symptoms, oral lesions.

Hepatobiliary Tract and Pancreas Abnormal liver function tests.

Lower Respiratory

Breathing disorders, lower respiratory signs and symptoms.

Non-Site Specific

Bacterial infections, candidiasis unspecified site, edema and swelling, nonspecific conditions, viral infections.

Psychiatry

Situational disorders.

Observed During Clinical Practice

In addition to adverse events reported from clinical trials, the following events have been identified during worldwide use of any formulation of ADVAIR, fluticasone propionate, and/or salmeterol regardless of indication. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to ADVAIR DISKUS, fluticasone propionate, and/or salmeterol or a combination of these factors.

In extensive US and worldwide postmarketing experience with salmeterol, a component of ADVAIR DISKUS, serious exacerbations of asthma, including some that have been fatal, have been reported. In most cases, these have occurred in patients with severe asthma and/or in some patients in whom asthma has been acutely deteriorating (see WARNINGS), but they have also occurred in a few patients with less severe asthma. It was not possible from these reports to determine whether salmeterol contributed to these events.

Cardiovascular

Arrhythmias (including atrial fibrillation, extrasystoles, supraventricular tachycardia), ventricular tachycardia.

Ear, Nose, and Throat

Aphonia, earache, facial and oropharyngeal edema, paranasal sinus pain, throat soreness.

Endocrine and Metabolic

Cushing syndrome, Cushingoid features, growth velocity reduction in children/adolescents, hypercorticism, hyperglycemia, weight gain, osteoporosis.

Eye

Cataracts, glaucoma.

Gastrointestinal

Abdominal pain, dyspepsia, xerostomia.

Musculoskeletal

Back pain, cramps, muscle spasm, myositis.

Neurology

Paresthesia, restlessness.

Non-Site Specific

Immediate and delayed hypersensitivity reaction (including very rare anaphylactic reaction), pallor. Very rare anaphylactic reaction in patients with severe milk protein allergy.

Psychiatry

Agitation, aggression, depression.

Respiratory

Chest congestion; chest tightness; dyspnea; immediate bronchospasm; influenza; paradoxical bronchospasm; tracheitis; wheezing; reports of upper respiratory symptoms of laryngeal spasm, irritation, or swelling such as stridor or choking.

Skin

Contact dermatitis, contusions, ecchymoses, photodermatitis.

Urogenital

Dysmenorrhea, irregular menstrual cycle, pelvic inflammatory disease, vaginal candidiasis, vaginitis, vulvovaginitis.

Eosinophilic Conditions

In rare cases, patients on inhaled fluticasone propionate, a component of ADVAIR DISKUS, may present with systemic eosinophilic conditions, with some patients presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of fluticasone propionate. Cases of serious eosinophilic conditions have also been reported with other inhaled corticosteroids in this clinical setting. While ADVAIR DISKUS should not be used for transferring patients from systemic corticosteroid therapy, physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between fluticasone propionate and these underlying conditions has not been established (see PRECAUTIONS: General: Eosinophilic Conditions ).

ADVAIR DISKUS has been used concomitantly with other drugs, including short-acting beta₂-agonists, methylxanthines, and intranasal corticosteroids, commonly used in patients with asthma or COPD, without adverse drug reactions. No formal drug interaction studies have been performed with ADVAIR DISKUS.

Short-Acting beta₂-Agonists

In clinical trials with patients with asthma, the mean daily need for albuterol by 166 adult and adolescent patients 12 years of age and older using ADVAIR DISKUS was approximately 1.3 inhalations/day, and ranged from 0 to 9 inhalations/day. Five percent (5%) of patients 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 reactions was observed among patients who averaged 6 or more inhalations per day.

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

Methylxanthines

The concurrent use of intravenously or orally administered methylxanthines (e.g., aminophylline, theophylline) by adult and adolescent patients 12 years of age and older receiving ADVAIR DISKUS has not been completely evaluated. In clinical trials with patients with asthma, 39 patients receiving ADVAIR DISKUS 100/50, 250/50, or 500/50 twice daily concurrently with a theophylline product had adverse event rates similar to those in 304 patients receiving ADVAIR DISKUS without theophylline. Similar results were observed in patients 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 COPD clinical trial, 17 patients receiving ADVAIR DISKUS 250/50 twice daily concurrently with a theophylline product had adverse event rates similar to those in 161 patients 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 patients 12 years of age and older taking ADVAIR DISKUS in clinical trials, no difference in the profile of adverse events or HPA axis effects was noted between patients taking FLONASE® (fluticasone propionate) Nasal Spray, 50 mcg concurrently (n = 46) and those who were not (n = 130).

Monoamine Oxidase Inhibitors and Tricyclic Antidepressants

ADVAIR DISKUS should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of salmeterol, a component of ADVAIR DISKUS, on the vascular system may be potentiated by these agents.

Beta-Adrenergic Receptor Blocking Agents

Beta-blockers not only block the pulmonary effect of beta-agonists, such as salmeterol, a component of ADVAIR DISKUS, but may produce severe bronchospasm in patients with asthma. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with asthma. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.

Diuretics

The ECG changes and/or hypokalemia that may result from the administration of nonpotassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with nonpotassium-sparing diuretics.

Inhibitors of Cytochrome P450

Fluticasone propionate and salmeterol are substrates of cytochrome P450 3A4. A drug interaction study with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Fluticasone Propionate: Drug Interactions). During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression. Therefore, coadministration of fluticasone propionate and ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.

In a placebo-controlled, crossover study 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. Caution should be exercised when ADVAIR DISKUS is coadministered with ketoconazole and other known potent cytochrome P450 3A4 inhibitors.

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