Included as part of the "PRECAUTIONS" Section
Serious Asthma-Related Events – Hospitalizations, Intubations, Death
Use of LABA as monotherapy (without ICS) for asthma is associated with an increased risk of asthma-related death [see Salmeterol Multicenter Asthma Research Trial (SMART)]. Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients. These findings are considered a class effect of LABA monotherapy. When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone
(see Serious Asthma-Related Events with Inhaled Corticosteroid/Long-acting Beta2-adrenergic
Serious Asthma-Related Events With Inhaled Corticosteroid/Long-Acting Beta2-Adrenergic Agonists
Four (4) large, 26-week, randomized, double-blind, active-controlled clinical safety trials were conducted to evaluate the risk of serious asthma-related events when LABA were used in fixed-dose combination with ICS compared with ICS alone in subjects with asthma. Three (3) trials included adult and adolescent subjects aged 12 years and older: 1 trial compared fluticasone propionate/salmeterol inhalation powder with fluticasone propionate inhalation powder, 1 trial compared mometasone furoate/formoterol with mometasone furoate, and 1 trial compared budesonide/formoterol with budesonide. The fourth trial included pediatric subjects aged 4 to 11 years and compared fluticasone propionate/salmeterol inhalation powder with fluticasone propionate inhalation powder. The primary safety endpoint for all 4 trials was serious asthma-related events (hospitalizations, intubations, death). A blinded adjudication committee determined whether events were asthma related.
The 3 adult and adolescent trials were designed to rule out a risk margin of 2.0, and the pediatric trial was designed to rule out a risk margin of 2.7. Each individual trial met its pre-specified objective and demonstrated non-inferiority of ICS/LABA to ICS alone. A meta-analysis of the 3 adult and adolescent trials did not show a significant increase in risk of a serious asthma-related event with ICS/LABA fixed-dose combination compared with ICS alone (Table 1). These trials were not designed to rule out all risk for serious asthma-related events with ICS/LABA compared with ICS.
Table 1. Meta-analysis of Serious Asthma-Related Events in Subjects with Asthma Aged 12 Years and Older
(n = 17,537)a
(n = 17,552)a
|ICS/LABA vs. ICS Hazard Ratio
|Serious asthma-related eventc
| Asthma-related death
| Asthma-related intubation
| Asthma-related hospitalization
ICS = Inhaled Corticosteroid; LABA = Long-acting Beta2-adrenergic Agonist.
a Randomized subjects who had taken at least 1 dose of study drug. Planned treatment used for analysis.
b Estimated using a Cox proportional hazards model for time to first event with baseline hazards stratified by each of the 3 trials.
c Number of subjects with event that occurred within 6 months after the first use of study drug or 7 days after the last date of study drug, whichever date was later. Subjects can have one or more events, but only the first event was counted for analysis. A single, blinded, independent
adjudication committee determined whether events were asthma related.
The pediatric safety trial included 6,208 pediatric subjects aged 4 to 11 years who received ICS/LABA (fluticasone propionate/salmeterol inhalation powder) or ICS (fluticasone propionate inhalation powder). In this trial, 27/3,107 (0.9%) subjects randomized to ICS/LABA and 21/3,101 (0.7%) subjects randomized to ICS experienced a serious asthma-related event. There were no asthma-related deaths or intubations. ICS/LABA did not show a significantly increased risk of a serious asthma-related event compared with ICS based on the pre-specified risk margin (2.7), with an estimated hazard ratio of time to first event of 1.29 (95% CI: 0.73, 2.27).
Salmeterol Multicenter Asthma Research Trial (SMART)
A 28-week, placebo-controlled, U.S. trial that compared the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol versus 3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). Use of background ICS was not required in SMART. The increased risk of asthma-related death is considered a class effect of LABA monotherapy.
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 subjects 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 ICS, or initiating systemic corticosteroids. Patients should not use more than 2 inhalations twice daily 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. ADVAIR HFA has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist.
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
ADVAIR HFA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, 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 another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.
Local Effects Of Inhaled Corticosteroids
In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects 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. Advise the patient to rinse his/her mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.
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. In 2 replicate 1-year trials in 1,579 subjects with COPD, there was a higher incidence of pneumonia reported in subjects receiving ADVAIR DISKUS 250/50 (7%) than in those receiving salmeterol 50 mcg (3%). The incidence of pneumonia in the subjects treated with ADVAIR DISKUS was higher in subjects older than 65 years (9%) compared with the incidence in subjects younger than 65 years (4%).
In a 3-year trial in 6,184 subjects with COPD, there was a higher incidence of pneumonia reported in subjects 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 trials with ADVAIR DISKUS 250/50, the incidence of pneumonia was higher in subjects older than 65 years (18% with ADVAIR DISKUS 500/50 versus 10% with placebo) compared with subjects younger than 65 years (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.
ICS should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; 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 ICS because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available ICS. 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 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 control 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 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 [AM PEF]), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition, 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 ADVAIR HFA may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions).
During withdrawal from oral corticosteroids, 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 significant systemic absorption of ICS in sensitive patients, 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 who are sensitive to these effects. If such effects occur, ADVAIR HFA should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and other treatments for management of asthma symptoms should be considered.
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 medicines, 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 ADVAIR HFA.
Immediate Hypersensitivity Reactions
Immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of ADVAIR HFA [see CONTRAINDICATIONS].
Cardiovascular And Central Nervous System Effects
Excessive beta-adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia [see OVERDOSE]. 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 ICS. The clinical significance of small changes in BMD with regard to longterm
consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal 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 Trial
A 2-year trial in 160 subjects (females aged 18 to 40 years, males 18 to 50) with asthma receiving chlorofluorocarbon (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 dosage to the lowest dosage that effectively controls his/her symptoms [see DOSAGE AND ADMINISTRATION, Use In Specific Populations].
Glaucoma And Cataracts
Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with asthma following the long-term administration of ICS, 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 ICS 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 medicines 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. Large 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 medicines 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 trials with ADVAIR HFA at recommended doses.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use).
Serious Asthma-Related Events
Inform patients with asthma that LABA when used alone increases the risk of asthma-related hospitalization or asthma-related death. Available data show that when ICS and LABA are used together, such as with ADVAIR HFA, there is not a significant increase in the risk of these events.
Not For Acute Symptoms
Inform patients that ADVAIR HFA is not meant to relieve acute asthma symptoms and extra doses should not be used for that purpose. Advise patients to treat acute asthma symptoms with an inhaled, short-acting beta2-agonist such as albuterol. Provide patients with such medication and instruct them in how it should be used.
Instruct patients 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
Tell patients they 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
Instruct patients not to use other LABA for asthma.
Inform patients that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, treat it 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. Advise patients to rinse the mouth with water without swallowing after inhalation to help reduce the risk of thrush.
Patients with COPD have a higher risk of pneumonia; instruct them to contact their healthcare providers if they develop symptoms of pneumonia.
Warn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to chickenpox or measles and, if exposed, to consult their physicians without delay. Inform patients of potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.
Hypercorticism And Adrenal Suppression
Advise patients that ADVAIR HFA may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, inform patients 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.
Immediate Hypersensitivity Reactions
Advise patients that immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of ADVAIR HFA. Patients should discontinue ADVAIR HFA if such reactions occur.
Reduction In Bone Mineral Density
Advise patients who are at an increased risk for decreased BMD that the use of corticosteroids may pose an additional risk.
Reduced Growth Velocity
Inform patients that orally inhaled corticosteroids, 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.
Inform patients that long-term use of ICS may increase the risk of some eye problems (cataracts or glaucoma); consider regular eye examinations.
Risks Associated With Beta-Agonist Therapy
Inform patients 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 MRHDID on a mg/m2 basis) for 78 weeks or in rats at inhalation doses up to 57 mcg/kg (less than the MRHDID on a mg/m2 basis) for 104 weeks.
Fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells in vitro. No significant clastogenic effect was seen in cultured human peripheral lymphocytes in vitro or in the in vivo mouse micronucleus test.
No evidence of impairment of fertility was observed in rats at subcutaneous doses up to 50 mcg/kg (less than the MRHDID on a mg/m2 basis). Prostate weight was significantly reduced.
In an 18-month carcnogenicity study in CD-mice, salmeterol at oral doses of 1.4 mg/kg and above (approximately 10 times the MRHDID 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 MRHDID 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 MRHDID on a mg/m2 basis). No tumors were seen at 0.21 mg/kg (approximately 25 times the MRHDID 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 MRHDID on a mg/m2 basis).
Use In Specific Populations
Pregnancy Category C. There are no adequate and well-controlled trials with ADVAIR HFA in pregnant women. Corticosteroids and beta2-agonists have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Because animal reproduction studies are not always predictive of human response, ADVAIR HFA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women should be advised to contact their physicians if they become pregnant while taking ADVAIR HFA.
Fluticasone Propionate and Salmeterol:
In the mouse reproduction assay, fluticasone propionate at a dose approximately equivalent to the maximum recommended human daily inhalation dose (MRHDID) (on a mcg/m2 basis at a maternal subcutaneous dose of 150 mcg/kg) combined with salmeterol at a dose approximately 580 times the MRHDID (on a mg/m2 basis at a maternal oral 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 up to approximately 1/5 the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 40 mcg/kg) and doses of salmeterol up to approximately 80 times the MRHDID (on a mg/m2 basis at a maternal oral dose of 1.4 mg/kg).
In rats, combining fluticasone propionate at a dose equivalent to the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 100 mcg/kg) and a dose of salmeterol at approximately 1,200 times the MRHDID (on a mg/m2 basis at a maternal oral 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 at a dose less than the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 30 mcg/kg) and a dose of
salmeterol at approximately 120 times the MRHDID (on a mg/m2 basis at a maternal oral dose of 1 mg/kg).
Mice and rats at fluticasone propionate doses less than or equivalent to the MRHDID (on a mcg/m2 basis at maternal subcutaneous doses of 45 and 100 mcg/kg, respectively) showed 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 doses approximately equivalent to the MRHDID (on a mcg/m2 basis at maternal inhaled doses up to 68.7 mcg/kg).
In rabbits, fetal weight reduction and cleft palate were observed at a fluticasone propionate dose less than the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 4 mcg/kg). However, no teratogenic effects were reported at fluticasone propionate doses up to approximately 6 times the MRHDID (on a mcg/m2 basis at maternal oral 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.
No teratogenic effects occurred in rats at salmeterol doses approximately 230 times the MRHDID (on a mg/m2 basis at maternal oral doses up to 2 mg/kg). In pregnant Dutch rabbits administered salmeterol doses approximately 25 times the MRHDID (on an AUC basis at maternal oral 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 a salmeterol dose approximately 10 times the MRHDID (on an AUC basis at a maternal oral 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 a salmeterol dose approximately 2,300 times the MRHDID (on a mg/m2 basis at a maternal oral dose of 10 mg/kg). Salmeterol xinafoate crossed the placenta following oral administration to mice and rats.
Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored.
Labor And Delivery
There are no well-controlled human trials 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, a component of ADVAIR HFA, 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) subjects aged 12 to 17 years were treated with ADVAIR HFA in U.S. pivotal clinical trials. Subjects in this age group demonstrated efficacy results similar to those observed in subjects 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 subjects aged 18 years and older.
In a 12-week trial, 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 ICS. No new safety concerns were observed in children aged 4 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 4 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 trial was not designed to assess the effect of salmeterol, a component of ADVAIR HFA, on asthma hospitalizations and death in subjects 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 trial 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 younger than 12 years have not been established.
Effects On Growth
ICS, 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 trial to assess the potential growth effects of fluticasone propionate inhalation powder (FLOVENT ROTADISK) at 50 and 100 mcg twice daily was conducted in the U.S. 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
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 trial revealed growth rates at 52 weeks of
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 trial, 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 [see DOSAGE AND ADMINISTRATION].
Clinical trials of ADVAIR HFA did not include sufficient numbers of subjects aged 65 years and older to determine whether older subjects respond differently than younger subjects. 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.