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LABAs, such as salmeterol, one of the active ingredients in ADVAIR HFA, 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 HFA 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 HFA) 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 HFA 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 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% 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 3). 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 HFA, 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)
|Relative Riskb (95% Confidence Interval)||Excess Deaths Expressed per 10,000 Patientsc (95% Confidence Interval)|
n = 13,176
|13 (0.10%)||4.37 (1.25, 15.34)|
n = 13,179
|3 (0.02%)||8 (3, 13)|
n = 9,281
|6 (0.07%)||5.82 (0.70, 48.37)|
n = 9,361
|1 (0.01%)||6 (1, 10)|
n = 2,366
|7 (0.31%)||7.26 (0.89, 58.94)|
n = 2,319
|1 (0.04%)||27 (8, 46)|
|a 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.
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
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.
Deterioration of Disease and Acute Episodes
ADVAIR HFA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma. ADVAIR HFA has not been studied in patients with acutely deteriorating asthma. The initiation of ADVAIR HFA in this setting is not appropriate.
Serious acute respiratory events, including fatalities, have been reported 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, 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 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.
ADVAIR HFA 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 HFA, should be used to relieve acute symptoms such as 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 acute symptoms, 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.
Excessive Use of ADVAIR HFA and Use With Other Long-Acting Beta2- Agonists
As with other inhaled drugs containing beta2-adrenergic agents, ADVAIR HFA 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 HFA 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.
In clinical studies, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in patients treated with ADVAIR HFA. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral antifungal) therapy while treatment with ADVAIR HFA continues, but at times therapy with ADVAIR HFA may need to be interrupted. Patients should rinse the mouth after inhalation of ADVAIR HFA.
Lower respiratory tract infections, including pneumonia, have been reported in patients with chronic obstructive pulmonary disease (COPD) following the inhaled administration of corticosteroids, including fluticasone propionate and ADVAIR DISKUS (flu®ticasone propionate and salmeterol inhalation powder). In 2 replicate 1-year 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).
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 HFA may provide control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiologic 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 HFA. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with ADVAIR HFA. 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 HFA 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 HFA, 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 HFA 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 HFA.
Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with ADVAIR HFA 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 HFA 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 HFA 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 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. 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
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 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. 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.
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.
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 HFA routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including ADVAIR HFA, titrate each patient's dose to the lowest dosage that effectively controls his/her symptoms [see Use In Specific Populations].
Glaucoma and Cataracts
Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with asthma following the long-term administration of inhaled corticosteroids, including fluticasone propionate, a component of ADVAIR HFA. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.
Eosinophilic Conditions and Churg-Strauss Syndrome
In rare cases, patients on inhaled fluticasone propionate, a component of ADVAIR HFA, 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.
ADVAIR HFA, 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 HFA at recommended doses.
Patient Counseling Information
See FDA-approved patient labeling (Medication Guide).
Patients should be informed that salmeterol, one of the active ingredients in ADVAIR HFA, 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 LABAs.
Not for Acute Symptoms
ADVAIR HFA is not meant to relieve acute asthma symptoms, 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 healthcare provider should provide the patient with such medication and instruct the patient in how it should be used.
Patients should be instructed to seek medical attention 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 HFA without physician/provider guidance since symptoms may recur after discontinuation.
Do Not Use Additional Long-Acting Beta2-Agonists
When patients are prescribed ADVAIR HFA, other LABAs for asthma 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 HFA, but at times therapy with ADVAIR HFA 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 they are exposed to consult their physicians 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 HFA 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 HFA.
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 inhaledcorticosteroids, including 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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Fluticasone propionate demonstrated no tumorigenic potential in mice at oral doses up to 1,000 mcg/kg (approximately 5 times the MRHD on a mcg/m² basis) for 78 weeks or in rats at inhalation doses up to 57 mcg/kg (less than the MRHD on a mcg/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 mcg/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 10 times the MRHD 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 ovarian cysts. No tumors were seen at 0.2 mg/kg (approximately 2 times the MRHD for adults 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 80 times the MRHD on a mg/m² basis). No tumors were seen at 0.21 mg/kg (approximately 25 times the MRHD 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 230 times the MRHD on a mg/m² basis).
Use In Specific Populations
Teratogenic Effects - Pregnancy Category C
There are no adequate and well-controlled studies with ADVAIR HFA in pregnant women. The combination of fluticasone propionate and salmeterol was teratogenic in mice and 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 HFA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Combination of Fluticasone Propionate and Salmeterol: In the mouse reproduction assay, fluticasone propionate by the subcutaneous route at a dose approximately equivalent to the maximum recommended human daily inhalation dose (MRHD) (on a mcg/m² basis at a maternal dose of 150 mcg/kg) combined with oral salmeterol at a dose approximately 580 times the MRHD (on a mg/m² basis at a maternal dose of 10 mg/kg) 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 1/5 the MRHD (on a mcg/m² basis at a maternal dose of 40 mcg/kg) and oral doses of salmeterol up to approximately 80 times the MRHD (on a mg/m basis at a maternal dose of 1.4 mg/kg). In rats, combining fluticasone propionate subcutaneously at a dose equivalent to the MRHD (on a mcg/m² basis at a maternal dose of 100 mcg/kg) and an oral dose of salmeterol at approximately 1,200 times the MRHD (on a mg/m² basis at a maternal dose of 10 mg/kg) 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 mcg/m² basis at a maternal dose of 30 mcg/kg) and an oral dose of salmeterol at approximately 120 times the MRHD (on a mg/m² basis at a maternal dose of 1 mg/kg).
Fluticasone Propionate: Subcutaneous studies in mice at a dose less than the MRHD (on a mcg/m² basis at a maternal dose of 45 mcg/kg) and in rats at a dose equivalent to the MRHD (on a mcg/m² basis at a maternal dose of 100 mcg/kg) revealed fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification. No teratogenicity was seen in rats at inhalation doses approximately equivalent to the MRHD (on a mcg/m² basis at maternal doses up to 68.7 mg/kg).
In rabbits, fetal weight reduction and cleft palate were observed at a subcutaneous dose less than the MRHD (on a mcg/m² basis at a maternal dose of 4 mcg/kg). However, no teratogenic effects were reported at oral doses up to approximately 6 times the MRHD (on a mcg/m² basis at maternal doses up to 300 mcg/kg). No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration [see CLINICAL PHARMACOLOGY].
Fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats and oral administration to rabbits.
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 230 times the MRHD (on a mg/m² basis at maternal doses up to 2 mg/kg). In Dutch rabbits administered oral doses approximately 25 times the MRHD (on an AUC basis at maternal doses of 1 mg/kg and higher), 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 10 times the MRHD (on an AUC basis at a maternal dose of 0.6 mg/kg).
New Zealand White rabbits were less sensitive since only delayed ossification of the frontal cranial bones was seen at an oral dose approximately 2,300 times the MRHD (on a mg/m² basis at a maternal dose of 10 mg/kg). Extensive use of other beta-agonists has provided no evidence that these class effects in animals are relevant to their use in humans. Salmeterol xinafoate crossed the placenta following oral administration to mice and rats.
Labor and Delivery
There are no well-controlled human studies that have investigated effects of ADVAIR HFA on preterm labor or labor at term. Because of the potential for beta-agonist interference with uterine contractility, use of ADVAIR HFA during labor should be restricted to those patients in whom the benefits clearly outweigh the risks.
Plasma levels of salmeterol, a component of ADVAIR HFA, 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 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 HFA by nursing mothers, caution should be exercised when ADVAIR HFA is administered to a nursing woman.
Thirty-eight (38) patients aged 12 to 17 years were treated with ADVAIR HFA in US pivotal clinical trials. Patients in this age-group demonstrated efficacy results similar to those observed in patients aged 18 years and older. There were no obvious differences in the type or frequency of adverse events reported in this age-group compared with patients aged 18 years and older.
In a 12-week study, the safety of ADVAIR HFA 45/21 given as 2 inhalations twice daily was compared with that of fluticasone propionate 44 mcg HFA (FLOVENT® HFA) 2 inhalations twice daily in 350 subjects aged 4 to 11 years with persistent asthma currently being treated with inhaled corticosteroids. No new safety concerns were observed in children aged 5 to 11 years treated for 12 weeks with ADVAIR HFA 45/21 compared with adults and adolescents aged 12 years and older. Common adverse reactions ( > 3%) seen in children aged 5 to 11 years treated with ADVAIR HFA 45/21 but not reported in the adult and adolescent clinical trials of ADVAIR HFA include: pyrexia, cough, pharyngolaryngeal pain, rhinitis, and sinusitis [see ADVERSE REACTIONS].This study was not designed to assess the effect of salmeterol, a component of ADVAIR HFA, on asthma hospitalizations and death in patients aged 4 to 11 years.
The pharmacokinetics and pharmacodynamic effect on serum cortisol of 21 days of treatment with ADVAIR HFA 45/21 (2 inhalations twice daily with or without a spacer) or ADVAIR DISKUS 100/50 (1 inhalation twice daily) was evaluated in a study of 31 children aged 4 to 11 years with mild asthma. Systemic exposure to salmeterol xinafoate was similar for ADVAIR HFA, ADVAIR HFA delivered with a spacer, and ADVAIR DISKUS while the systemic exposure to fluticasone propionate was lower with ADVAIR HFA compared with that of ADVAIR HFA delivered with a spacer or ADVAIR DISKUS. There were reductions in serum cortisol from baseline in all treatment groups (14%, 22%, and 13% for ADVAIR HFA, ADVAIR HFA delivered with a spacer, and ADVAIR DISKUS, respectively) [see CLINICAL PHARMACOLOGY].
The safety and effectiveness of ADVAIR HFA in children less than 12 years have not been established.
Effects on Growth: Inhaled corticosteroids, including fluticasone propionate, a component of ADVAIR HFA, 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 HFA, 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 HFA, each patient should be titrated to the lowest strength that effectively controls his/her asthma.
Clinical studies of ADVAIR HFA did not include sufficient numbers of patients aged 65 years and older to determine whether older patients respond differently than younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. In addition, as with other products containing beta2-agonists, special caution should be observed when using ADVAIR HFA in geriatric patients who have concomitant cardiovascular disease that could be adversely affected by beta2-agonists.
Formal pharmacokinetic studies using ADVAIR HFA 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.
Formal pharmacokinetic studies using ADVAIR HFA have not been conducted in patients with renal impairment.
Last reviewed on RxList: 1/10/2013
This monograph has been modified to include the generic and brand name in many instances.
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