Generic Name: fluticasone propionate and salmeterol
Dosage Form: inhalation powder
FULL PRESCRIBING INFORMATION
Long-acting beta2-adrenergic agonists (LABAs), such as salmeterol, one of the active ingredients in Advair Diskus®, increase the risk of asthma-related death. Data from a large placebo-controlled US study that compared the safety of salmeterol (SEREVENT®showed an increase in asthma-related deaths in patients receiving salmeterol (13 deaths out of 13,176 patients treated for 28 weeks on salmeterol versus 3 o Inhalation Aerosol) or placebo added to usual asthma therapy ut of 13,179 patients 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 LABAs. Available data from controlled clinical trials suggest that LABAs increase the risk of asthma-related hospitalization in pediatric and adolescent patients.
Therefore, when treating patients with asthma, physicians should 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 [see Warnings and Precautions (5.1)].
Indications and Usage for Advair Diskus
Treatment of Asthma
Advair Diskus is indicated for the treatment of asthma in patients aged 4 years and older.
Long-acting beta2-adrenergic agonists (LABAs), such as salmeterol, one of the active ingredients in Advair Diskus, increase the risk of asthma-related death. Available data from controlled clinical trials suggest that LABAs increase the risk of asthma-related hospitalization in pediatric and adolescent patients [see Warnings and Precautions (5.1)]. Therefore, when treating patients with asthma, physicians should 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.
Important Limitation of Use: Advair Diskus is NOT indicated for the relief of acute bronchospasm.
Maintenance Treatment of Chronic Obstructive Pulmonary Disease
Advair Diskus 250/50 is indicated for the twice-daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. Advair Diskus 250/50 is also indicated to reduce exacerbations of COPD in patients with a history of exacerbations. Advair Diskus 250/50 twice daily is the only approved dosage for the treatment of COPD because an efficacy advantage of the higher strength Advair Diskus 500/50 over Advair Diskus 250/50 has not been demonstrated.
Important Limitation of Use: Advair Diskus is NOT indicated for the relief of acute bronchospasm.
Advair Diskus Dosage and Administration
Advair Diskus should be administered twice daily every day by the orally inhaled route only. After inhalation, the patient should rinse the mouth with water without swallowing [see Patient Counseling Information (17.4)].
More frequent administration or a higher number of inhalations (more than 1 inhalation twice daily) of the prescribed strength of Advair Diskus is not recommended as some patients are more likely to experience adverse effects with higher doses of salmeterol. Patients using Advair Diskus should not use additional LABAs for any reason. [See Warnings and Precautions (5.3, 5.12).]
Asthma
If asthma symptoms arise in the period between doses, an inhaled, short-acting beta2-agonist should be taken for immediate relief.
Adult and Adolescent Patients Aged 12 Years and Older: For patients aged 12 years and older, the dosage is 1 inhalation twice daily (morning and evening, approximately 12 hours apart).
The recommended starting dosages for Advair Diskus for patients aged 12 years and older are based upon patients’ asthma severity.
The maximum recommended dosage is Advair Diskus 500/50 twice daily.
Improvement in asthma control following inhaled administration of Advair Diskus can occur within 30 minutes of beginning treatment, although maximum benefit may not be achieved for 1 week or longer after starting treatment. Individual patients will experience a variable time to onset and degree of symptom relief.
For patients who do not respond adequately to the starting dosage after 2 weeks of therapy, replacing the current strength of Advair Diskus with a higher strength may provide additional improvement in asthma control.
If a previously effective dosage regimen of Advair Diskus fails to provide adequate improvement in asthma control, the therapeutic regimen should be reevaluated and additional therapeutic options (e.g., replacing the current strength of Advair Diskus with a higher strength, adding additional inhaled corticosteroid, initiating oral corticosteroids) should be considered.
Pediatric Patients Aged 4 to 11 Years: For patients with asthma aged 4 to 11 years who are not controlled on an inhaled corticosteroid, the dosage is 1 inhalation of Advair Diskus 100/50 twice daily (morning and evening, approximately 12 hours apart).
Chronic Obstructive Pulmonary Disease
The recommended dosage for patients with COPD is 1 inhalation of Advair Diskus 250/50 twice daily (morning and evening, approximately 12 hours apart).
If shortness of breath occurs in the period between doses, an inhaled, short-acting beta2-agonist should be taken for immediate relief.
Dosage Forms and Strengths
Disposable purple device with 60 blisters containing a combination of fluticasone propionate (100, 250, or 500 mcg) and salmeterol (50 mcg) as an oral inhalation powder formulation. An institutional pack containing 14 blisters is also available.
Contraindications
The use of Advair Diskus is contraindicated in the following conditions:
- Primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required
- Severe hypersensitivity to milk proteins [see Warnings and Precautions (5.11), Description (11)]
Warnings and Precautions
Asthma-Related Death
LABAs, such as salmeterol, one of the active ingredients in Advair Diskus, 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 LABAs. Available data from controlled clinical trials suggest that LABAs increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma, physicians should 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.
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 LABA-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% versus 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% versus 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% versus 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 aged 12 to 18 years 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% [2/1,653]) and the placebo group (0.12% [2/1,622]; relative risk: 1.0 [95% CI: 0.1, 7.2]). All-cause hospitalization, however, was increased in the salmeterol group (2% [35/1,653]) versus the placebo group (<1% [16/1,622]; 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, or other long-term asthma control therapy mitigates the risk of asthma-related death.
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%) | |||
| aLife-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. | ||||
| bRelative 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. | ||||
| cEstimate 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. | ||||
| dThe 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
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 LABAs.
Deterioration of Disease and Acute Episodes
Advair Diskus should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD. Advair Diskus has not been studied in patients with acutely deteriorating asthma or COPD. The initiation of Advair Diskus in this setting is not appropriate.
Serious acute respiratory events, including fatalities, have been reported when salmeterol, a component of Advair Diskus, 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 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.
Advair Diskus 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, 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.
When beginning treatment with Advair Diskus, 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 and Use With Other Long-Acting Beta2-Agonists
As with other inhaled drugs containing beta2-adrenergic agents, Advair Diskus should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medications containing LABAs, 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 LABA (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. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral antifungal) therapy while treatment with Advair Diskus continues, but at times therapy with Advair Diskus may need to be interrupted. Patients should rinse the mouth after inhalation of Advair Diskus.
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. 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%). [See Adverse Reactions (6.2), Use in Specific Populations (8.5).]
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). [See Adverse Reactions (6.2), Use in Specific Populations (8.5).]
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. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with Advair Diskus. 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 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, 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 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.
Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with Advair Diskus 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 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 cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with Advair Diskus is not recommended because increased systemic corticosteroid and increased cardiovascular adverse effects may occur [see Drug interactions (7.1), Clinical Pharmacology (12.3)].
Paradoxical Bronchospasm and Upper Airway Symptoms
As with other inhaled medications, Advair Diskus can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with Advair Diskus, it should be treated immediately with an inhaled, short-acting bronchodilator; Advair Diskus 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 (4)].
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 (10)]. Therefore, Advair Diskus, 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, 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. 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 and periodically thereafter. If significant reductions in BMD are seen and Advair Diskus is still considered medically important for that patient’s COPD therapy, use of medication to treat or prevent osteoporosis should be 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 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 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 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 routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including Advair Diskus, titrate each patient’s dose to the lowest dosage that effectively controls his/her symptoms. [See Dosage and Administration (2.1), Use in Specific Populations (8.4).]
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. 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 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 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, 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 (12.2)]. 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 at recommended doses.
Adverse Reactions
LABAs, such as salmeterol, one of the active ingredients in Advair Diskus, 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 and Precautions (5.1)]. 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.
Systemic and local corticosteroid use may result in the following:
- Candida albicans infection [see Warnings and Precautions (5.4)]
- Pneumonia in patients with COPD [see Warnings and Precautions (5.5)]
- Immunosuppression [see Warnings and Precautions (5.6)]
- Hypercorticism and adrenal suppression [see Warnings and Precautions (5.8)]
- Growth effects [see Warnings and Precautions (5.14)]
- Glaucoma and cataracts [see Warnings and Precautions (5.15)]
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Clinical Trials Experience in Asthma
Adult and Adolescent Patients Aged 12 Years and Older: The incidence of adverse reactions associated with Advair Diskus in Table 2 is based upon 2 placebo-controlled, 12-week, US clinical studies (Studies 1 and 2). A total of 705 adult and adolescent 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. The average duration of exposure was 60 to 79 days in the active treatment groups compared with 42 days in the placebo group.
| Adverse Event | ADVAIR DISKUS 100/50 (N = 92) % | ADVAIR DISKUS 250/50 (N = 84) % | Fluticasone Propionate 100 mcg (N = 90) % | Fluticasone Propionate 250 mcg (N = 84) % | Salmeterol 50 mcg (N = 180) % | Placebo (N = 175) % |
| Ear, nose, & throat | ||||||
Upper respiratory tract infection | 27 | 21 | 29 | 25 | 19 | 14 |
| Pharyngitis | 13 | 10 | 7 | 12 | 8 | 6 |
Upper respiratory inflammation | 7 | 6 | 7 | 8 | 8 | 5 |
| Sinusitis | 4 | 5 | 6 | 1 | 3 | 4 |
| Hoarseness/dysphonia | 5 | 2 | 2 | 4 | <1 | <1 |
| Oral candidiasis | 1 | 4 | 2 | 2 | 0 | 0 |
| Lower respiratory | ||||||
| Viral respiratory infections | 4 | 4 | 4 | 10 | 6 | 3 |
| Bronchiti |
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