|Drug Name:||ADVAIR HFA|
In studies where geriatric patients (65 years of age or older, see PRECAUTIONS: Geriatric Use) have been treated with ADVAIR HFA, efficacy and safety did not differ from that in younger patients.Based on available data for ADVAIR HFA and its active components, no dosage adjustment is recommended.
ADVAIR HFA is indicated for the long-term, twice-daily maintenance treatment of asthma in patients 12 years of age and older.Long-acting beta2-adrenergic agonists, such as salmeterol, one of the active ingredients in ADVAIR HFA, may increase the risk of asthma-related death (see WARNINGS).
Therefore, when treating patients with asthma, physicians should only prescribe ADVAIR HFA for patients not adequately controlled on other asthma-controller medications (e.g., low- to medium-dose inhaled corticosteroids) or whose disease severity clearly warrants initiation of treatment with 2 maintenance therapies.ADVAIR HFA is not indicated in patients whose asthma can be successfully managed by inhaled corticosteroids along with occasional use of inhaled, short-acting beta2-agonists.ADVAIR HFA is NOT indicated for the relief of acute bronchospasm.
Long-acting beta2-adrenergic agonists, such as salmeterol, one of the active ingredients in ADVAIR HFA, may increase the risk of asthma-related death.
Therefore, when treating patients with asthma, physicians should only prescribe ADVAIR HFA for patients not adequately controlled on other asthma-controller medications (e.g., low- to medium-dose inhaled corticosteroids) or whose disease severity clearly warrants initiation of treatment with 2 maintenance therapies. 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 3 and Figure 5).
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 3).
Given the similar basic mechanisms of action of beta2-agonists, it is possible that the findings seen in the SMART study represent a class effect.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 HFA, or other asthma-controller therapy modifies the risk of asthma-related death.
Table 3: Asthma-Related Deaths in the 28-Week Salmeterol Multi-center Asthma Research Trial (SMART) Salmeteroln (%*)Placebon (%*)Relative Risk†(95% Confidence Interval)Excess Deaths Expressed per 10,000 Patients‡(95% Confidence Interval) Total Population§ Salmeterol: N = 13,17613 (0.10%)4.37 (1.25, 15.34)8 (3, 13) Placebo: N = 13,1793 (0.02%) Caucasian Salmeterol: N = 9,2816 (0.07%)5.82 (0.70, 48.37)6 (1, 10) Placebo: N = 9,3611 (0.01%) African American Salmeterol: N = 2,3667 (0.31%)7.26 (0.89, 58.94)27 (8, 46) Placebo: N = 2,3191 (0.04%) *Life-table 28-week estimate, adjusted according to the patients’ actual lengths of exposure to study treatment to account for early withdrawal of patients from the study.†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 asthma-related death occurred in the salmeterol group than in the placebo group in a 28-week treatment period.‡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.§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 5.
Cumulative Incidence of Asthma-Related Deaths in the 28-Week Salmeterol Multi-center Asthma Research Trial (SMART), by Duration of Treatment 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 following additional WARNINGS about ADVAIR HFA should be noted.1.
ADVAIR HFA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma.
Serious acute respiratory events, including fatalities, have been reported both in the United States and worldwide when salmeterol, a component of ADVAIR HFA, 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, or previous life-threatening acute asthma exacerbations) and/or in some patients in whom asthma has been acutely deteriorating (e.g., unresponsive to usual medications; increasing need for inhaled, short-acting beta2-agonists; increasing need for systemic corticosteroids; significant increase in symptoms; recent emergency room visits; sudden or progressive deterioration in pulmonary function).
However, they 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.2.
ADVAIR HFA should not be used to treat acute symptoms.
An inhaled, short-acting beta2-agonist, not ADVAIR HFA, should be used to relieve acute symptoms of shortness of breath.
When prescribing ADVAIR HFA, the physician must also provide the patient with an inhaled, short-acting beta2-agonist (e.g., albuterol) for treatment of shortness of breath that occurs acutely, despite regular twice-daily (morning and evening) use of ADVAIR HFA.When beginning treatment with ADVAIR HFA, 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.
For patients taking ADVAIR HFA, inhaled, short-acting beta2-agonists should only be used for symptomatic relief of acute symptoms of shortness of breath (see PRECAUTIONS: Information for Patients).3.
Increasing use of inhaled, short-acting beta2-agonists is a marker of deteriorating asthma.
The physician and patient should be alert to such changes.
The patient’s condition may deteriorate acutely over a period of hours or chronically over several days or longer.
If the patient’s inhaled, short-acting beta2-agonist becomes less effective, the patient needs more inhalations than usual, or the patient develops a significant decrease in lung function, this may be a marker of destabilization of the disease.
In this setting, 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 HFA with a higher strength, adding additional inhaled corticosteroid, or initiating systemic corticosteroids.
Patients should not use more than 2 inhalations twice daily (morning and evening) of ADVAIR HFA.4.
ADVAIR HFA should not be used for 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 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 inhaled corticosteroids may provide control of asthma symptoms during these episodes, in recommended doses they supply less than normal physiologic amounts of glucocorticoid (cortisol) systemically and do 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.5.
ADVAIR HFA should not be used in conjunction with an inhaled, long-acting beta2-agonist.
Patients who are receiving ADVAIR HFA twice daily should not use additional salmeterol or other long-acting beta2-agonists (e.g., formoterol) for prevention of exercise-induced bronchospasm (EIB) or the maintenance treatment of asthma.
Additional benefit would not be gained from using supplemental salmeterol or formoterol for prevention of EIB since ADVAIR HFA already contains an inhaled, long-acting beta2-agonist.
The recommended dosage should not be exceeded.
ADVAIR HFA should not be used more often or at higher doses than recommended.
Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.
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.7.
As with other inhaled asthma medications, ADVAIR HFA can produce paradoxical bronchospasm, which may be life threatening.
If paradoxical bronchospasm occurs following dosing with ADVAIR HFA, it should be treated immediately with an inhaled, short-acting bronchodilator; ADVAIR HFA should be discontinued immediately; and alternative therapy should be instituted.8.
Immediate hypersensitivity reactions.
Immediate hypersensitivity reactions may occur after administration of ADVAIR HFA, as demonstrated by cases of urticaria, angioedema, rash, and bronchospasm.9.
Upper airway symptoms.
Symptoms of laryngeal spasm, irritation, or swelling, such as stridor and choking, have been reported in patients receiving fluticasone propionate and salmeterol, components of ADVAIR HFA.10.
ADVAIR HFA, 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 HFA, 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 electrocardiogram (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.11.
Discontinuation of systemic corticosteroids.
Transfer of patients from systemic corticosteroid therapy to ADVAIR HFA may unmask conditions previously suppressed by the systemic corticosteroid therapy, e.g., rhinitis, conjunctivitis, eczema, arthritis, and eosinophilic conditions.12.
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 exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated.
If 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.13.
Pneumonia: 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.
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 250/50 (7%) than in those receiving salmeterol 50 mcg (3%).
The incidence of pneumonia in the patients treated with ADVAIR DISKUS was higher in patients over 65 years of age (9%) compared with the incidence in patients less than 65 years of age (4%).In a 3-year study of 6,184 patients with COPD, there was a higher incidence of pneumonia reported in patients receiving ADVAIR DISKUS 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 250/50, the incidence of pneumonia was higher in patients over 65 years of age (18% with ADVAIR DISKUS 500/50 versus 10% with placebo) compared with patients less than 65 years of age (14% with ADVAIR DISKUS 500/50 versus 8% with placebo.14.
Potential drug interactions with CYP 3A4 inhibitors.
Both fluticasone propionate and salmeterol are substrates of CYP 3A4.Fluticasone Propionate: A drug interaction study in healthy subjects has shown that ritonavir (a strong cytochrome P450 3A4 inhibitor) can significantly increase systemic fluticasone propionate exposure (AUC), resulting in significantly reduced serum cortisol concentrations (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Fluticasone Propionate: Drug Interactions and PRECAUTIONS: Drug Interactions: Inhibitors of Cytochrome P450).
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.Salmeterol: Because of the potential for drug interactions and the potential for increased risk of cardiovascular adverse events, the concomitant use of ADVAIR HFA with strong CYP 3A4 inhibitors (e.g., ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) is not recommended (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Salmeterol Xinafoate: Drug Interactions).