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WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Asthma-Related Death

Long-acting beta2-adrenergic agonists (LABA), such as salmeterol, one of the active ingredients in ADVAIR DISKUS (fluticasone propionate) , increase the risk of asthma-related death. 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. Therefore, when treating patients with asthma, physicians should only prescribe ADVAIR DISKUS (fluticasone propionate) 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 LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g. discontinue ADVAIR DISKUS (fluticasone propionate) ) 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 (fluticasone propionate) for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids.

A large placebo-controlled US study that compared the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol. The Salmeterol Multi-center Asthma Research Trial (SMART) was a randomized, double-blind study that enrolled long-acting beta2-agonist–naive patients with asthma to assess the safety of salmeterol (SEREVENT Inhalation Aerosol) 42 mcg twice daily over 28 weeks compared with placebo when added to usual asthma therapy. A planned interim analysis was conducted when approximately half of the intended number of patients had been enrolled (N = 26,355), which led to premature termination of the study. The results of the interim analysis showed that patients receiving salmeterol were at increased risk for fatal asthma events (see Table 1 and Figure 1). In the total population, a higher rate of asthma-related death occurred in patients treated with salmeterol than those treated with placebo (0.10% vs. 0.02%, relative risk 4.37 [95% CI: 1.25, 15.34]).

Post-hoc subpopulation analyses were performed. In Caucasians, asthma-related death occurred at a higher rate in patients treated with salmeterol than in patients treated with placebo (0.07% vs. 0.01%, relative risk 5.82 [95% CI: 0.70, 48.37]). In African Americans also, asthma-related death occurred at a higher rate in patients treated with salmeterol than those treated with placebo (0.31% vs. 0.04%, relative risk 7.26 [95% CI: 0.89, 58.94]). Although the relative risks of asthma-related death were similar in Caucasians and African Americans, the estimate of excess deaths in patients treated with salmeterol was greater in African Americans because there was a higher overall rate of asthma-related death in African American patients (see Table 1). Given the similar basic mechanisms of action of beta2-agonists, the findings seen in the SMART study are considered a class effect.

Post-hoc analyses in pediatric patients 12 to 18 years of age were also performed. Pediatric patients accounted for approximately 12% of patients in each treatment arm. Respiratory related death or life threatening experience occurred at a similar rate in the salmeterol group 0.12% (2/1653) and the placebo group (0.12%) (2/1622) [relative risk 1.0, 95% CI 0.1-7.2]. All cause hospitalization, however, was increased in the salmeterol group (2%) (35/1653) vs. the placebo group ( < 1%) (16/1622) [relative risk 2.1, 95% CI 1.1-3.7].

The data from the SMART study are not adequate to determine whether concurrent use of inhaled corticosteroids, such as fluticasone propionate, the other active ingredient in ADVAIR DISKUS (fluticasone propionate) , or other long-term asthma-control therapy mitigates the risk of asthma-related death.

Table 1: Asthma-Related Deaths in the 28-Week Salmeterol Multi-center Asthma Research Trial (SMART)

  Salmeterol
n (%a)
Placebo
n (%a)
Relative Riskb
(95% Confidence
Interval)
Excess Deaths Expressed per 10,000 Patientsc
(95% Confidence
Interval)
Total Populationd
Salmeterol: N = 13,176 13 (0.10%)   4.37 (1.25, 15.34) 8 (3, 13)
Placebo: N = 13,179   3 (0.02%)    
Caucasian
Salmeterol: N = 9,281 6 (0.07%)   5.82 (0.70, 48.37) 6 (1, 10)
Placebo: N = 9,361   1 (0.01%)    
African American
Salmeterol: N = 2,366 7 (0.31%)   7.26 (0.89, 58.94) 27 (8, 46)
Placebo: N = 2,319   1 (0.04%)    
a Life-table 28-week estimate, adjusted according to the patients' study treatment to account for early withdrawal of patients from the study.
b Relative risk is the ratio of the rate of asthma-related death in the salmeterol group and the rate in the placebo group. The relative risk indicates how many more times likely an asthma­related death occurred in the salmeterol group than in the placebo group in a 28-week treatment period.
c Estimate of the number of additional asthma-related deaths in patients treated with salmeterol in SMART, assuming 10,000 patients received salmeterol for a 28-week treatment period. Estimate calculated as the difference between the salmeterol and placebo groups in the rates of asthma-related death multiplied by 10,000.
d The Total Population includes the following ethnic origins listed on the case report form: Caucasian, African American, Hispanic, Asian, and “Other.” In addition, the Total Population includes those patients whose ethnic origin was not reported. The results for Caucasian and African American subpopulations are shown above. No asthma-related deaths occurred in the Hispanic (salmeterol n = 996, placebo n = 999), Asian (salmeterol n = 173, placebo n = 149), or “Other” (salmeterol n = 230, placebo n =224) subpopulations. One asthma-related death occurred in the placebo group in the subpopulation whose ethnic origin was not reported (salmeterol n = 130, placebo n = 127).

Figure 1: Cumulative Incidence of Asthma-Related Deaths in the 28-Week Salmeterol Multi-center Asthma Research Trial (SMART), by Duration of Treatment

Cumulative Incidence of Asthma-Related Deaths - Illustration

A 16-week clinical study performed in the United Kingdom, the Salmeterol Nationwide Surveillance (SNS) study, showed results similar to the SMART study. In the SNS study, the rate of asthma-related death was numerically, though not statistically significantly, greater in patients with asthma treated with salmeterol (42 mcg twice daily) than those treated with albuterol (180 mcg 4 times daily) added to usual asthma therapy.

The SNS and SMART studies enrolled patients with asthma. No studies have been conducted that were primarily designed to determine whether the rate of death in patients with COPD is increased by long-acting beta2-adrenergic agonists.

Deterioration of Disease and Acute Episodes

ADVAIR DISKUS (fluticasone propionate) should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD. ADVAIR DISKUS (fluticasone propionate) has not been studied in patients with acutely deteriorating asthma or COPD. The initiation of ADVAIR DISKUS (fluticasone propionate) in this setting is not appropriate.

Serious acute respiratory events, including fatalities, have been reported when salmeterol, a component of ADVAIR DISKUS (fluticasone propionate) , has been initiated in patients with significantly worsening or acutely deteriorating asthma. In most cases, these have occurred in patients with severe asthma (e.g., patients with a history of corticosteroid dependence, low pulmonary function, intubation, mechanical ventilation, frequent hospitalizations, previous life-threatening acute asthma exacerbations) and in some patients with acutely deteriorating asthma (e.g., patients with significantly increasing symptoms; increasing need for inhaled, short-acting beta2-agonists; decreasing response to usual medications; increasing need for systemic corticosteroids; recent emergency room visits; deteriorating lung function). However, these events have occurred in a few patients with less severe asthma as well. It was not possible from these reports to determine whether salmeterol contributed to these events.

Increasing use of inhaled, short-acting beta2-agonists is a marker of deteriorating asthma. In this situation, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the possible need for replacing the current strength of ADVAIR DISKUS (fluticasone propionate) with a higher strength, adding additional inhaled corticosteroid, or initiating systemic corticosteroids. Patients should not use more than 1 inhalation twice daily (morning and evening) of ADVAIR DISKUS (fluticasone propionate) .

ADVAIR DISKUS (fluticasone propionate) should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short-acting beta2-agonist, not ADVAIR DISKUS (fluticasone propionate) , should be used to relieve acute symptoms such as shortness of breath. When prescribing ADVAIR DISKUS, the physician must also provide the patient with an inhaled, short-acting beta2-agonist (e.g., albuterol) for treatment of acute symptoms, despite regular twice-daily (morning and evening) use of ADVAIR DISKUS (fluticasone propionate) .

When beginning treatment with ADVAIR DISKUS (fluticasone propionate) , patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs.

Excessive Use of ADVAIR DISKUS (fluticasone propionate) and Use With Other Long-Acting Beta2-Agonists

As with other inhaled drugs containing beta2-adrenergic agents, ADVAIR DISKUS (fluticasone propionate) should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medications containing long-acting beta2-agonists, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using ADVAIR

DISKUS should not use an additional long-acting beta2-agonist (e.g., salmeterol, formoterol fumarate, arformoterol tartrate) for any reason, including prevention of exercise-induced bronchospasm (EIB) or the treatment of asthma or COPD.

Local Effects

In clinical studies, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in patients treated with ADVAIR DISKUS (fluticasone propionate) . When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral antifungal) therapy while treatment with ADVAIR DISKUS (fluticasone propionate) continues, but at times therapy with ADVAIR DISKUS (fluticasone propionate) may need to be interrupted. Patients should rinse the mouth after inhalation of ADVAIR DISKUS (fluticasone propionate) .

Pneumonia

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of pneumonia and exacerbations frequently overlap.

Lower respiratory tract infections, including pneumonia, have been reported in patients with COPD following the inhaled administration of corticosteroids, including fluticasone propionate and ADVAIR DISKUS (fluticasone propionate) . In 2 replicate 12-month studies of 1,579 patients with COPD, there was a higher incidence of pneumonia reported in patients receiving ADVAIR DISKUS (fluticasone propionate) 250/50 (7%) than in those receiving salmeterol 50 mcg (3%). The incidence of pneumonia in the patients treated with ADVAIR DISKUS (fluticasone propionate) was higher in patients over 65 years of age (9%) compared with the incidence in patients less than 65 years of age (4%). [See ADVERSE REACTIONS , Use in Specific Populations.]

In a 3-year study of 6,184 patients with COPD, there was a higher incidence of pneumonia reported in patients receiving ADVAIR DISKUS (fluticasone propionate) 500/50 compared with placebo (16% with ADVAIR DISKUS 500/50, 14% with fluticasone propionate 500 mcg, 11% with salmeterol 50 mcg, and 9% with placebo). Similar to what was seen in the 1-year studies with ADVAIR DISKUS (fluticasone propionate) 250/50, the incidence of pneumonia was higher in patients over 65 years of age (18% with ADVAIR DISKUS (fluticasone propionate) 500/50 vs. 10% with placebo) compared with patients less than 65 years of age (14% with ADVAIR DISKUS 500/50 vs. 8% with placebo). [See ADVERSE REACTIONS, Use in Specific Populations.]

Immunosuppression

Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.

Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

Transferring Patients From Systemic Corticosteroid Therapy

Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.

Patients who have been previously maintained on 20 mg or more per day of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although ADVAIR DISKUS may provide control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.

During periods of stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack.

Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to ADVAIR DISKUS (fluticasone propionate) . Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with ADVAIR DISKUS (fluticasone propionate) . Lung function (mean forced expiratory volume in 1 second [FEV1] or morning peak expiratory flow [PEF]), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.

Transfer of patients from systemic corticosteroid therapy to inhaled corticosteroids or ADVAIR DISKUS (fluticasone propionate) may unmask conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions). Some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function.

Hypercorticism and Adrenal Suppression

Fluticasone propionate, a component of ADVAIR DISKUS (fluticasone propionate) , will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since fluticasone propionate is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of ADVAIR DISKUS (fluticasone propionate) in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose. A relationship between plasma levels of fluticasone propionate and inhibitory effects on stimulated cortisol production has been shown after 4 weeks of treatment with fluticasone propionate inhalation aerosol. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing ADVAIR DISKUS (fluticasone propionate) .

Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with ADVAIR DISKUS (fluticasone propionate) should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.

It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients, particularly when fluticasone propionate is administered at higher than recommended doses over prolonged periods of time. If such effects occur, the dosage of ADVAIR DISKUS (fluticasone propionate) should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma symptoms.

Drug Interactions With Strong Cytochrome P450 3A4 Inhibitors

The use of strong CYP 3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with ADVAIR DISKUS (fluticasone propionate) is not recommended because increased systemic corticosteroid and increased cardiovascular adverse effects may occur [see DRUG INTERACTIONS, CLINICAL PHARMACOLOGY].

Paradoxical Bronchospasm and Upper Airway Symptoms

As with other inhaled medications, ADVAIR DISKUS (fluticasone propionate) can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with ADVAIR DISKUS (fluticasone propionate) , it should be treated immediately with an inhaled, short-acting bronchodilator, ADVAIR DISKUS (fluticasone propionate) should be discontinued immediately, and alternative therapy should be instituted. Upper airway symptoms of laryngeal spasm, irritation, or swelling, such as stridor and choking, have been reported in patients receiving fluticasone propionate and salmeterol.

Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions may occur after administration of ADVAIR DISKUS, as demonstrated by cases of urticaria, angioedema, rash, and bronchospasm. There have been reports of anaphylactic reactions in patients with severe milk protein allergy; therefore, patients with severe milk protein allergy should not take ADVAIR DISKUS [see CONTRAINDICATIONS].

Cardiovascular and Central Nervous System Effects

Excessive beta-adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia [see OVERDOSAGE]. Therefore, ADVAIR DISKUS (fluticasone propionate) , like all products containing sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Salmeterol, a component of ADVAIR DISKUS (fluticasone propionate) , can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of salmeterol at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Large doses of inhaled or oral salmeterol (12 to 20 times the recommended dose) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

Reduction in Bone Mineral Density

Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, post-menopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating ADVAIR DISKUS (fluticasone propionate) and periodically thereafter. If significant reductions in BMD are seen and ADVAIR DISKUS (fluticasone propionate) is still considered medically important for that patient's teoporosis should be COPD therapy, use of medication strongly considered.

2-Year Fluticasone Propionate Study

A 2-year study of 160 patients (females aged 18 to 40 years, males 18 to 50) with asthma receiving CFC-propelled fluticasone propionate inhalation aerosol 88 or 440 mcg twice daily demonstrated no statistically significant changes in BMD at any time point (24, 52, 76, and 104 weeks of double-blind treatment) as assessed by dual-energy x-ray absorptiometry at lumbar regions L1 through L4.

3-Year Bone Mineral Density Study

Effects of treatment with ADVAIR DISKUS (fluticasone propionate) 250/50 or salmeterol 50 mcg on BMD at the L1-L4 lumbar spine and total hip were evaluated in 186 patients with COPD (aged 43 to 87 years) in a 3-year double-blind study. Of those enrolled, 108 patients (72 males and 36 females) were followed for the entire 3 years. BMD evaluations were conducted at baseline and at 6-month intervals. Conclusions cannot be drawn from this study regarding BMD decline in patients treated with ADVAIR DISKUS (fluticasone propionate) versus salmeterol due to the inconsistency of treatment differences across gender and between lumbar spine and total hip.

In this study there were 7 non-traumatic fractures reported in 5 patients treated with ADVAIR DISKUS (fluticasone propionate) and 1 non-traumatic fracture in 1 patient treated with salmeterol. None of the non-traumatic fractures occurred in the vertebrae, hip, or long bones.

3-Year Survival Study

Effects of treatment with ADVAIR DISKUS 500/50, fluticasone propionate 500 mcg, salmeterol 50 mcg, or placebo on BMD was evaluated in a subset of 658 patients (females and males aged 40 to 80 years) with COPD in the 3-year survival study. BMD evaluations were conducted at baseline and at 48, 108, and 158 weeks. Conclusions cannot be drawn from this study because of the large number of drop outs ( > 50%) before the end of the follow-up and the maldistribution of covariates among the treatment groups that can affect BMD.

Fracture risk was estimated for the entire population of patients with COPD in the survival study (N = 6,184). The probability of a fracture over 3 years was 6.3% for ADVAIR DISKUS, 5.4% for fluticasone propionate, 5.1% for salmeterol, and 5.1% for placebo.

Effect on Growth

Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth of pediatric patients receiving ADVAIR DISKUS (fluticasone propionate) routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including ADVAIR DISKUS (fluticasone propionate) , titrate each patient's dose to the lowest dosage that effectively controls his/her symptoms. [See DOSAGE AND ADMINISTRATION, Use in Specific Populations.]

Glaucoma and Cataracts

Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with asthma and COPD following the long-term administration of inhaled corticosteroids, including fluticasone propionate, a component of ADVAIR DISKUS (fluticasone propionate) . Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.

Effects of treatment with ADVAIR DISKUS 500/50, fluticasone propionate 500 mcg, salmeterol 50 mcg, or placebo on development of cataracts or glaucoma was evaluated in a subset of 658 patients with COPD in the 3-year survival study. Ophthalmic examinations were conducted at baseline and at 48, 108, and 158 weeks. Conclusions about cataracts cannot be drawn from this study because the high incidence of cataracts at baseline (61% to 71%) resulted in an inadequate number of patients treated with ADVAIR DISKUS (fluticasone propionate) 500/50 who were eligible and available for evaluation of cataracts at the end of the study (n = 53). The incidence of newly diagnosed glaucoma was 2% with ADVAIR DISKUS (fluticasone propionate) 500/50, 5% with fluticasone propionate, 0% with salmeterol, and 2% with placebo.

Eosinophilic Conditions and Churg-Strauss Syndrome

In rare cases, patients on inhaled fluticasone propionate may present with systemic eosinophilic conditions. Some of these patients have 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. 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.

Coexisting Conditions

ADVAIR DISKUS (fluticasone propionate) , like all medications containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

Hypokalemia and Hyperglycemia

Beta-adrenergic agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects [see CLINICAL PHARMACOLOGY]. The decrease in serum potassium is usually transient, not requiring supplementation. Clinically significant changes in blood glucose and/or serum potassium were seen infrequently during clinical studies with ADVAIR DISKUS (fluticasone propionate) at recommended doses.

Patient Counseling Information

See Medication Guide.

Asthma-Related Death

Patients with asthma should be informed that salmeterol, one of the active ingredients in ADVAIR DISKUS (fluticasone propionate) , increases the risk of asthma-related death and may increase the risk of asthma-related hospitalization in pediatric and adolescent patients. They should also be informed that 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.

Not for Acute Symptoms

ADVAIR DISKUS (fluticasone propionate) is not meant to relieve acute asthma symptoms or exacerbations of COPD and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist such as albuterol. (The physician should provide the patient with such medication and instruct the patient in how it should be used.)

Patients should be instructed to notify their physician immediately if they experience any of the following:

  • Decreasing effectiveness of inhaled, short-acting beta2-agonists
  • Need for more inhalations than usual of inhaled, short-acting beta2-agonists
  • Significant decrease in lung function as outlined by the physician

Patients should not stop therapy with ADVAIR DISKUS (fluticasone propionate) without physician/provider guidance since symptoms may recur after discontinuation.

Do Not Use Additional Long-Acting Beta2-Agonists

When patients are prescribed ADVAIR DISKUS (fluticasone propionate) , other long-acting beta2-agonists for asthma and COPD should not be used.

Risks Associated With Corticosteroid Therapy

Local Effects

Patients should be advised that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing therapy with ADVAIR DISKUS (fluticasone propionate) , but at times therapy with ADVAIR DISKUS (fluticasone propionate) may need to be temporarily interrupted under close medical supervision. Rinsing the mouth after inhalation is advised.

Pneumonia

Patients with COPD have a higher risk of pneumonia and should be instructed to contact their healthcare provider if they develop symptoms of pneumonia.

Immunosuppression

Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physician without delay. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex.

Hypercorticism and Adrenal Suppression

Patients should be advised that ADVAIR DISKUS (fluticasone propionate) may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, patients should be instructed that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids. Patients should taper slowly from systemic corticosteroids if transferring to ADVAIR DISKUS (fluticasone propionate) .

Reduction in Bone Mineral Density

Patients who are at an increased risk for decreased BMD should be advised that the use of corticosteroids may pose an additional risk.

Reduced Growth Velocity

Patients should be informed that orally inhaled corticosteroids, including fluticasone propionate, a component of ADVAIR DISKUS (fluticasone propionate) , may cause a reduction in growth velocity when administered to pediatric patients. Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route.

Ocular Effects

Long-term use of inhaled corticosteroids may increase the risk of some eye problems (cataracts or glaucoma); regular eye examinations should be considered.

Risks Associated With Beta-Agonist Therapy

Patients should be informed of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Fluticasone Propionate

Fluticasone propionate demonstrated no tumorigenic potential in mice at oral doses up to 1,000 mcg/kg (approximately 4 and 10 times the MRHD for adults and children, respectively, on a mg/m² basis) for 78 weeks or in rats at inhalation doses up to 57 mcg/kg (less than and approximately equivalent to the MRHD for adults and children, respectively, on a mg/m² basis) for 104 weeks.

Fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells in vitro . No significant clastogenic effect was seen in cultured human peripheral lymphocytes in vitro or in the in vivo mouse micronucleus test.

No evidence of impairment of fertility was observed in reproductive studies conducted in rats at subcutaneous doses up to 50 mcg/kg (less than the MRHD on a mg/m² basis). Prostate weight was significantly reduced.

Salmeterol

In an 18-month carcinogenicity study in CD-mice, salmeterol at oral doses of 1.4 mg/kg and above (approximately 20 times the MRHD for adults and children based on comparison of the plasma AUCs) caused a dose-related increase in the incidence of smooth muscle hyperplasia, cystic glandular hyperplasia, leiomyomas of the uterus, and cysts in the ovaries. No tumors were seen at 0.2 mg/kg (approximately 3 times the MRHD for adults and children based on comparison of the AUCs).

In a 24-month oral and inhalation carcinogenicity study in Sprague Dawley rats, salmeterol caused a dose-related increase in the incidence of mesovarian leiomyomas and ovarian cysts at doses of 0.68 mg/kg and above (approximately 55 and 25 times the MRHD for adults and children, respectively, on a mg/m² basis). No tumors were seen at 0.21 mg/kg (approximately 15 and 8 times the MRHD for adults and children, respectively, on a mg/m² basis). These findings in rodents are similar to those reported previously for other beta-adrenergic agonist drugs. The relevance of these findings to human use is unknown.

Salmeterol produced no detectable or reproducible increases in microbial and mammalian gene mutation in vitro . No clastogenic activity occurred in vitro in human lymphocytes or in vivo in a rat micronucleus test. No effects on fertility were identified in rats treated with salmeterol at oral doses up to 2 mg/kg (approximately 160 times the MRHD for adults on a mg/m² basis).

Use In Specific Populations

Pregnancy

Teratogenic Effects

Pregnancy Category C. There are no adequate and well-controlled studies with ADVAIR DISKUS (fluticasone propionate) in pregnant women. ADVAIR DISKUS (fluticasone propionate) was teratogenic in mice and not in rats, although it lowered fetal weight in rats. Fluticasone propionate alone was teratogenic in mice, rats, and rabbits, and salmeterol alone was teratogenic in rabbits and not in rats. From the reproduction toxicity studies in mice and rats, no evidence of enhanced toxicity was seen using combinations of fluticasone propionate and salmeterol when compared with toxicity data from the components administered separately.

ADVAIR DISKUS (fluticasone propionate) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

ADVAIR DISKUS (fluticasone propionate) : In the mouse reproduction assay, fluticasone propionate by the subcutaneous route at a dose approximately 3/5 the maximum recommended human daily inhalation dose (MRHD) on a mg/m² basis combined with oral salmeterol at a dose approximately 410 times the MRHD on a mg/m² basis produced cleft palate, fetal death, increased implantation loss, and delayed ossification. These observations are characteristic of glucocorticoids. No developmental toxicity was observed at combination doses of fluticasone propionate subcutaneously up to approximately 1/6 the MRHD on a mg/m² basis and oral doses of salmeterol up to approximately 55 times the MRHD on a mg/m² basis. In rats, combining fluticasone propionate subcutaneously at a dose equivalent to the MRHD on a mg/m² basis and an oral dose of salmeterol at approximately 810 times the MRHD on a mg/m² basis produced decreased fetal weight, umbilical hernia, delayed ossification, and changes in the occipital bone. No such effects were seen when combining fluticasone propionate subcutaneously at a dose less than the MRHD on a mg/m² basis and an oral dose of salmeterol at approximately 80 times the MRHD on a mg/m² basis.

Fluticasone Propionate:Subcutaneous studies in the mouse at a dose less than the MRHD on a mg/m² basis and in the rat at a dose equivalent to the MRHD on a mg/m² basis revealed fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification.

In the rabbit, fetal weight reduction and cleft palate were observed at a subcutaneous dose less than the MRHD on a mg/m² basis. However, no teratogenic effects were reported at oral doses up to approximately 5 times the MRHD on a mg/m² basis. No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration [see CLINICAL PHARMACOLOGY].

Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiologic, doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. In addition, because there is a natural increase in corticosteroid production during pregnancy, most women will require a lower exogenous corticosteroid dose and many will not need corticosteroid treatment during pregnancy.

Salmeterol: No teratogenic effects occurred in rats at oral doses approximately 160 times the MRHD on a mg/m² basis. In Dutch rabbits administered oral doses approximately 50 times the MRHD based on comparison of the AUCs, salmeterol exhibited fetal toxic effects characteristically resulting from beta-adrenoceptor stimulation. These included precocious eyelid openings, cleft palate, sternebral fusion, limb and paw flexures, and delayed ossification of the frontal cranial bones. No such effects occurred at an oral dose approximately 20 times the MRHD based on comparison of the AUCs.

New Zealand White rabbits were less sensitive since only delayed ossification of the frontal bones was seen at an oral dose approximately 1,600 times the MRHD on a mg/m² basis. Extensive use of other beta-agonists has provided no evidence that these class effects in animals are relevant to their use in humans.

Labor and Delivery

There are no well-controlled human studies that have investigated effects of ADVAIR DISKUS (fluticasone propionate) on preterm labor or labor at term. Because of the potential for beta-agonist interference with uterine contractility, use of ADVAIR DISKUS (fluticasone propionate) during labor should be restricted to those patients in whom the benefits clearly outweigh the risks.

Nursing Mothers

Plasma levels of salmeterol, a component of ADVAIR DISKUS (fluticasone propionate) , after inhaled therapeutic doses are very low. In rats, salmeterol xinafoate is excreted in the milk. There are no data from controlled trials on the use of salmeterol by nursing mothers. It is not known whether fluticasone propionate, a component of ADVAIR DISKUS (fluticasone propionate) , is excreted in human breast milk. However, other corticosteroids have been detected in human milk. Subcutaneous administration to lactating rats of tritiated fluticasone propionate resulted in measurable radioactivity in milk.

Since there are no data from controlled trials on the use of ADVAIR DISKUS (fluticasone propionate) by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue ADVAIR DISKUS (fluticasone propionate) , taking into account the importance of ADVAIR DISKUS to the mother.

Caution should be exercised when ADVAIR DISKUS (fluticasone propionate) is administered to a nursing woman.

Pediatric Use

Use of ADVAIR DISKUS 100/50 (fluticasone propionate) in patients aged 4 to 11 years is supported by extrapolation of efficacy data from older patients and by safety and efficacy data from a study of ADVAIR DISKUS 100/50 (fluticasone propionate) in children with asthma aged 4 to 11 years [see ADVERSE REACTIONS, Clinical Studies]. The safety and effectiveness of ADVAIR DISKUS (fluticasone propionate) in children with asthma less than 4 years of age have not been established.

Inhaled corticosteroids, including fluticasone propionate, a component of ADVAIR DISKUS, may cause a reduction in growth velocity in children and adolescents [see WARNINGS AND PRECAUTIONS]. The growth of pediatric patients receiving orally inhaled corticosteroids, including ADVAIR DISKUS (fluticasone propionate) , should be monitored.

A 52-week placebo-controlled study to assess the potential growth effects of fluticasone propionate inhalation powder (FLOVENT® ROTADISK® ) at 50 and 100 mcg twice daily was conducted in the US in 325 prepubescent children (244 males and 81 females) aged 4 to 11 years. The mean growth velocities at 52 weeks observed in the intent-to-treat population were 6.32 cm/year in the placebo group (N = 76), 6.07 cm/year in the 50-mcg group (N = 98), and 5.66 cm/year in the 100-mcg group (N = 89). An imbalance in the proportion of children entering puberty between groups and a higher dropout rate in the placebo group due to poorly controlled asthma may be confounding factors in interpreting these data. A separate subset analysis of children who remained prepubertal during the study revealed growth rates at 52 weeks of 6.10 cm/year in the placebo group (n = 57), 5.91 cm/year in the 50-mcg group (n = 74), and 5.67 cm/year in the 100-mcg group (n = 79). In children aged 8.5 years, the mean age of children in this study, the range for expected growth velocity is: boys – 3rd percentile = 3.8 cm/year, 50th percentile = 5.4 cm/year, and 97th percentile = 7.0 cm/year; girls – 3rd percentile = 4.2 cm/year, 50th percentile = 5.7 cm/year, and 97th percentile = 7.3 cm/year. The clinical relevance of these growth data is not certain.

If a child or adolescent on any corticosteroid appears to have growth suppression, the possibility that he/she is particularly sensitive to this effect of corticosteroids should be considered. The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained. To minimize the systemic effects of orally inhaled corticosteroids, including ADVAIR DISKUS (fluticasone propionate) , each patient should be titrated to the lowest strength that effectively controls his/her asthma [see DOSAGE AND ADMINISTRATION].

Geriatric Use

Clinical studies of ADVAIR DISKUS (fluticasone propionate) for asthma did not include sufficient numbers of patients aged 65 years and older to determine whether older patients with asthma respond differently than younger patients.

Of the total number of patients in clinical studies receiving ADVAIR DISKUS (fluticasone propionate) for COPD, 1,621 were aged 65 years or older and 379 were aged 75 years or older. Patients with COPD aged 65 years and older had a higher incidence of serious adverse events compared with patients less than 65 years of age. Although the distribution of adverse events was similar in the 2 age-groups, patients over 65 years of age experienced more severe events. In two 1-year studies, the excess risk of pneumonia that was seen in patients treated with ADVAIR DISKUS (fluticasone propionate) compared with those treated with salmeterol was greater in patients over 65 years of age than in patients less than 65 years of age [see ADVERSE REACTIONS]. As with other products containing beta2-agonists, special caution should be observed when using ADVAIR DISKUS (fluticasone propionate) in geriatric patients who have concomitant cardiovascular disease that could be adversely affected by beta2-agonists. Based on available data for ADVAIR DISKUS (fluticasone propionate) or its active components, no adjustment of dosage of ADVAIR DISKUS (fluticasone propionate) in geriatric patients is warranted.

No relationship between fluticasone propionate systemic exposure and age was observed in 57 patients with COPD (aged 40 to 82 years) given 250 or 500 mcg twice daily.

Hepatic Impairment

Formal pharmacokinetic studies using ADVAIR DISKUS (fluticasone propionate) have not been conducted in patients with hepatic 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.

Renal Impairment

Formal pharmacokinetic studies using ADVAIR DISKUS (fluticasone propionate) have not been conducted in patients with renal impairment.

Last reviewed on RxList: 1/24/2011
This monograph has been modified to include the generic and brand name in many instances.

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