• ADVAIR DISKUS is contraindicated for primary treatment of status asthmaticus or other acute episodes of asthma or chronic obstructive pulmonary disease (COPD) where intensive measures are required.
• ADVAIR DISKUS is contraindicated in patients with severe hypersensitivity to milk proteins
The following is a summary only; see full prescribing information for complete product information.
The use of ADVAIR DISKUS is contraindicated in the following conditions:
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 Agonists).
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 (ADVAIR DISKUS) with fluticasone propionate inhalation powder [see Clinical Studies], 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 [see Clinical Studies]. 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
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 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 subjects 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 ICS, or initiating systemic corticosteroids. Patients should not use more than 1 inhalation twice daily 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. ADVAIR DISKUS 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 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
ADVAIR DISKUS 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 DISKUS 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 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. Advise the patient to rinse his/her mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.
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 DISKUS 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 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 [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 DISKUS 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 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 significant systemic absorption of ICS in sensitive patients, 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 who are sensitive to these effects. If such effects occur, ADVAIR DISKUS 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 DISKUS 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 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 ADVAIR DISKUS.
Immediate Hypersensitivity Reactions
Immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of ADVAIR DISKUS. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of powder products containing lactose; therefore, patients with severe milk protein allergy should not use ADVAIR DISKUS [see Contraindications].
Cardiovascular and Central Nervous System Effects
Excessive beta-adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia [see Overdosage]. Therefore, ADVAIR DISKUS, 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 ICS. 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, 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. 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 medicine to treat or prevent osteoporosis should be strongly considered.
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.
3-Year Bone Mineral Density Trial
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 subjects with COPD (aged 43 to 87 years) in a 3-year double-blind trial. Of those enrolled, 108 subjects (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 trial regarding BMD decline in subjects treated with ADVAIR DISKUS versus salmeterol due to the inconsistency of treatment differences across gender and between lumbar spine and total hip.
In this trial there were 7 non-traumatic fractures reported in 5 subjects treated with ADVAIR DISKUS and 1 non-traumatic fracture in 1 subject treated with salmeterol. None of the non-traumatic fractures occurred in the vertebrae, hip, or long bones.
3-Year Survival Trial
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 subjects (females and males aged 40 to 80 years) with COPD in the 3-year survival trial. BMD evaluations were conducted at baseline and at 48, 108, and 158 weeks. Conclusions cannot be drawn from this trial because of the large number of dropouts (>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 subjects with COPD in the survival trial (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 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 and COPD following the long-term administration of ICS, 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 subjects with COPD in the 3-year survival trial. Ophthalmic examinations were conducted at baseline and at 48, 108, and 158 weeks. Conclusions about cataracts cannot be drawn from this trial because the high incidence of cataracts at baseline (61% to 71%) resulted in an inadequate number of subjects treated with ADVAIR DISKUS 500/50 who were eligible and available for evaluation of cataracts at the end of the trial (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, a component of ADVAIR DISKUS, 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 DISKUS, 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. 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 DISKUS at recommended doses.
Use of LABA may result in the following:
Systemic and local corticosteroid use may result in the following:
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 Subjects Aged 12 Years and Older
The incidence of adverse reactions associated with ADVAIR DISKUS in Table 2 is based upon two 12-week, placebo-controlled, U.S. clinical trials (Trials 1 and 2). A total of 705 adult and adolescent subjects (349 females and 356 males) previously treated with salmeterol or ICS 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.
The types of adverse reactions and events reported in Trial 3, a 28-week, non-U.S. clinical trial in 503 subjects previously treated with ICS who were treated twice daily with ADVAIR DISKUS 500/50, fluticasone propionate inhalation powder 500 mcg and salmeterol inhalation powder 50 mcg used concurrently, or fluticasone propionate inhalation powder 500 mcg, were similar to those reported in Table 2.
Additional Adverse Reactions
Other adverse reactions not previously listed, whether considered drug-related or not by the investigators, that were reported more frequently by subjects with asthma treated with ADVAIR DISKUS compared with subjects treated with placebo include the following: lymphatic signs and symptoms; muscle injuries; fractures; wounds and lacerations; contusions and hematomas; ear signs and symptoms; nasal signs and symptoms; nasal sinus disorders; keratitis and conjunctivitis; dental discomfort and pain; gastrointestinal signs and symptoms; oral ulcerations; oral discomfort and pain; lower respiratory signs and symptoms; pneumonia; muscle stiffness, tightness, and rigidity; bone and cartilage disorders; sleep disorders; compressed nerve syndromes; viral infections; pain; chest symptoms; fluid retention; bacterial infections; unusual taste; viral skin infections; skin flakiness and acquired ichthyosis; disorders of sweat and sebum.
Pediatric Subjects Aged 4 to 11 Years
The safety data for pediatric subjects aged 4 to 11 years is based upon 1 U.S. trial of 12 weeks’ treatment duration. A total of 203 subjects (74 females and 129 males) who were receiving ICS at trial entry were randomized to either ADVAIR DISKUS 100/50 or fluticasone propionate inhalation powder 100 mcg twice daily. Common adverse reactions (≥3% and greater than placebo) seen in the pediatric subjects but not reported in the adult and adolescent clinical trials include: throat irritation and ear, nose, and throat infections.
Laboratory Test Abnormalities
Elevation of hepatic enzymes was reported in ≥1% of subjects in clinical trials. The elevations were transient and did not lead to discontinuation from the trials. In addition, there were no clinically relevant changes noted in glucose or potassium.
In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of any formulation of ADVAIR, fluticasone propionate, and/or salmeterol regardless of indication. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to ADVAIR DISKUS, fluticasone propionate, and/or salmeterol or a combination of these factors.
Arrhythmias (including atrial fibrillation, extrasystoles, supraventricular tachycardia), ventricular tachycardia.
Cushing’s syndrome, Cushingoid features, growth velocity reduction in children/adolescents, hypercorticism.
Abdominal pain, dyspepsia, xerostomia.
Immune System Disorders
Immediate and delayed hypersensitivity reaction (including very rare anaphylactic reaction). Very rare anaphylactic reaction in patients with severe milk protein allergy.
Infections and Infestations
Metabolic and Nutrition Disorders
Hyperglycemia, weight gain.
Musculoskeletal, Connective Tissue, and Bone Disorders
Arthralgia, cramps, myositis, osteoporosis.
Nervous System Disorders
Agitation, aggression, depression. Behavioral changes, including hyperactivity and irritability, have been reported very rarely and primarily in children.
Reproductive System and Breast Disorders
Respiratory, Thoracic, and Mediastinal Disorders
Chest congestion; chest tightness; dyspnea; facial and oropharyngeal edema, immediate bronchospasm; paradoxical bronchospasm; tracheitis; wheezing; reports of upper respiratory symptoms of laryngeal spasm, irritation, or swelling such as stridor or choking.
Skin and Subcutaneous Tissue Disorders
ADVAIR DISKUS has been used concomitantly with other drugs, including short-acting beta2-agonists, methylxanthines, and intranasal corticosteroids, commonly used in patients with asthma or COPD without adverse drug reactions [see Clinical Pharmacology]. No formal drug interaction trials have been performed with ADVAIR DISKUS.
Inhibitors of Cytochrome P450 3A4
Fluticasone propionate and salmeterol, the individual components of ADVAIR DISKUS, are substrates of CYP3A4. The use of strong 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.
Fluticasone Propionate: A drug interaction trial with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a strong CYP3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations [see Clinical Pharmacology]. During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression.
Fluticasone Propionate: Coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma fluticasone propionate exposure and a 45% decrease in plasma cortisol area under the curve (AUC), but had no effect on urinary excretion of cortisol.
Salmeterol: In a drug interaction trial in 20 healthy subjects, coadministration of inhaled salmeterol (50 mcg twice daily) and oral ketoconazole (400 mg once daily) for 7 days resulted in greater systemic exposure to salmeterol (AUC increased 16-fold and Cmax increased 1.4-fold). Three (3) subjects were withdrawn due to beta2-agonist side effects (2 with prolonged QTc and 1 with palpitations and sinus tachycardia). Although there was no statistical effect on the mean QTc, coadministration of salmeterol and ketoconazole was associated with more frequent increases in QTc duration compared with salmeterol and placebo administration.
Monoamine Oxidase Inhibitors and Tricyclic Antidepressants
ADVAIR DISKUS should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of salmeterol, a component of ADVAIR DISKUS, on the vascular system may be potentiated by these agents.
Beta-adrenergic Receptor Blocking Agents
Beta-blockers not only block the pulmonary effect of beta-agonists, such as salmeterol, a component of ADVAIR DISKUS, but may also produce severe bronchospasm in patients with asthma or COPD. Therefore, patients with asthma or COPD should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents for these patients; cardioselective beta-blockers could be considered, although they should be administered with caution.
The ECG changes and/or hypokalemia that may result from the administration of non–potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, such as salmeterol, a component of ADVAIR DISKUS, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of ADVAIR DISKUS with non–potassium-sparing diuretics.
There are no randomized clinical studies of ADVAIR DISKUS or individual monoproducts, fluticasone propionate and salmeterol xinafoate, in pregnant women. There are clinical considerations with the use of ADVAIR DISKUS in pregnant women (see Clinical Considerations). In animals, teratogenicity characteristic of corticosteroids, decreased fetal body weight and/or skeletal variations, in rats, mice, and rabbits were observed with subcutaneously administered maternal toxic doses of fluticasone propionate less than the maximum recommended human daily inhaled dose (MRHDID) on a mcg/m2 basis (see Data). However, fluticasone propionate administered via inhalation to rats decreased fetal body weight, but did not induce teratogenicity at a maternal toxic dose less than the MRHDID on a mcg/m2 basis (see Data). Experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. Oral administration of salmeterol to pregnant rabbits caused teratogenicity characteristic of beta-adrenoceptor stimulation at maternal doses approximately 50 times the MRHDID on an AUC basis. These adverse effects generally occurred at large multiples of the MRHDID when salmeterol was administered by the oral route to achieve high systemic exposures. No such effects occurred at an oral salmeterol dose approximately 20 times the MRHDID (see Data).
The estimated risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Disease-Associated Maternal and/or Embryofetal Risk: In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal adverse outcomes such as pre-eclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control.
Human Data: Fluticasone Propionate: Following inhaled administration, fluticasone propionate was detected in the neonatal cord blood after delivery.
Animal Data: Fluticasone Propionate and Salmeterol: In an embryofetal development study with pregnant rats that received the combination of subcutaneous administration of fluticasone propionate and oral administration of salmeterol at doses of 0/1,000; 30/0; 10/100; 30/1,000; and 100/10,000 mcg/kg/day (as fluticasone propionate/salmeterol) during the period of organogenesis, findings were generally consistent with the individual monoproducts and there was no exacerbation of expected fetal effects. Omphalocele, increased embryofetal deaths, decreased body weight, and skeletal variations were observed in rat fetuses in the presence of maternal toxicity when combining fluticasone propionate at a dose approximately equivalent to the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 100 mcg/kg/day) and salmeterol at a dose approximately 970 times the MRHDID (on a mcg/m2 basis at a maternal oral dose of 10,000 mcg/kg/day). The rat no observed adverse effect level (NOAEL) was observed when combining fluticasone propionate at a dose approximately 0.3 times the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 30 mcg/kg/day) and salmeterol at a dose approximately 100 times the MRHDID (on a mcg/m2 basis at a maternal oral dose of 1,000 mcg/kg/day).
In an embryofetal development study with pregnant mice that received the combination of following subcutaneous administration of fluticasone propionate and oral administration of salmeterol at doses of 0/1,400; 40/0; 10/200; 40/1,400; or 150/10,000 mcg/kg/day (as fluticasone propionate/salmeterol) during the period of organogenesis, findings were generally consistent with the individual monoproducts and there was no exacerbation of expected fetal effects. Cleft palate, fetal death, increased implantation loss, and delayed ossification were observed in mouse fetuses when combining fluticasone propionate at a dose approximately 0.7 times the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 150 mcg/kg/day) and salmeterol at a dose approximately 490 times the MRHDID (on a mcg/m2 basis at a maternal oral dose of 10,000 mcg/kg/day). No developmental toxicity was observed at combination doses of fluticasone propionate up to approximately 0.2 times the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 40 mcg/kg) and doses of salmeterol up to approximately 70 times the MRHDID (on a mcg/m2 basis at a maternal oral dose of 1,400 mcg/kg).
Fluticasone Propionate: In embryofetal development studies with pregnant rats and mice dosed by the subcutaneous route throughout the period of organogenesis, fluticasone propionate was teratogenic in both species. Omphalocele, decreased body weight, and skeletal variations were observed in rat fetuses, in the presence of maternal toxicity, at a dose approximately equivalent to the MRHDID (on a mcg/m2 basis with a maternal subcutaneous dose of 100 mcg/kg/day). The rat NOAEL was observed at approximately 0.3 times the MRHDID (on a mcg/m2 basis with a maternal subcutaneous dose of 30 mcg/kg/day). Cleft palate and fetal skeletal variations were observed in mouse fetuses at a dose approximately 0.2 times the MRHDID (on a mcg/m2 basis with a maternal subcutaneous dose of 45 mcg/kg/day). The mouse NOAEL was observed with a dose approximately 0.07 times the MRHDID (on a mcg/m2 basis with a maternal subcutaneous dose of 15 mcg/kg/day).
In an embryofetal development study with pregnant rats dosed by the inhalation route throughout the period of organogenesis, fluticasone propionate produced decreased fetal body weights and skeletal variations, in the presence of maternal toxicity, at a dose approximately 0.25 times the MRHDID (on a mcg/m2 basis with a maternal inhalation dose of 25.7 mcg/kg/day); however, there was no evidence of teratogenicity. The NOAEL was observed with a dose approximately 0.05 times the MRHDID (on a mcg/m2 basis with a maternal inhalation dose of 5.5 mcg/kg/day).
In an embryofetal development study in pregnant rabbits that were dosed by the subcutaneous route throughout organogenesis, fluticasone propionate produced reductions of fetal body weights, in the presence of maternal toxicity, at doses approximately 0.012 times the MRHDID and higher (on a mcg/m2 basis with a maternal subcutaneous dose of 0.57 mcg/kg/day). Teratogenicity was evident based upon a finding of cleft palate for 1 fetus at a dose approximately 0.08 times the MRHDID (on a mcg/m2 basis with a maternal subcutaneous dose of 4 mcg/kg/day). The NOAEL was observed in rabbit fetuses with a dose approximately 0.002 times the MRHDID (on a mcg/m2 basis with a maternal subcutaneous dose of 0.08 mcg/kg/day).
Fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats and oral administration to rabbits.
In a pre- and post-natal development study in pregnant rats dosed by the subcutaneous route from late gestation through delivery and lactation (Gestation Day 17 to Postpartum Day 22), fluticasone propionate was not associated with decreases in pup body weight, and had no effects on developmental landmarks, learning, memory, reflexes, or fertility at doses up to 0.5 times the MRHDID (on a mcg/m2 basis with maternal subcutaneous doses up to 50 mcg/kg/day).
Salmeterol: In 3 embryofetal development studies, pregnant rabbits received oral administration of salmeterol at doses ranging from 100 to 10,000 mcg/kg/day during the period of organogenesis. In pregnant Dutch rabbits administered salmeterol doses approximately 50 times the MRHDID (on an AUC basis at maternal oral doses of 1,000 mcg/kg/day and higher), fetal toxic effects were observed 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 20 times the MRHDID (on an AUC basis at a maternal oral dose of 600 mcg/kg/day). New Zealand White rabbits were less sensitive since only delayed ossification of the frontal cranial bones was seen at a salmeterol dose approximately 2,000 times the MRHDID (on a mcg/m2 basis at a maternal oral dose of 10,000 mcg/kg/day).
In 2 embryofetal development studies, pregnant rats received salmeterol by oral administration at doses ranging from 100 to 10,000 mcg/kg/day during the period of organogenesis. Salmeterol produced no maternal toxicity or embryofetal effects at doses up to 973 times the MRHDID (on a mcg/m2 basis at maternal oral doses up to 10,000 mcg/kg/day).
In a peri- and post-natal development study in pregnant rats dosed by the oral route from late gestation through delivery and lactation, salmeterol at a dose 973 times the MRHDID (on a mcg/m2 basis with a maternal oral dose of 10,000 mcg/kg/day) was fetotoxic and decreased the fertility of survivors.
Salmeterol xinafoate crossed the placenta following oral administration to mice and rats.
There are no available data on the presence of fluticasone propionate or salmeterol in human milk, the effects on the breastfed child, or the effects on milk production. Other corticosteroids have been detected in human milk. However, fluticasone propionate and salmeterol concentrations in plasma after inhaled therapeutic doses are low and therefore concentrations in human breast milk are likely to be correspondingly low [see Clinical Pharmacology]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ADVAIR DISKUS and any potential adverse effects on the breastfed child from ADVAIR DISKUS or from the underlying maternal condition.
Animal Data: Subcutaneous administration of tritiated fluticasone propionate at a dose in lactating rats approximately 0.08 times the MRHDID for adults (on a mcg/m2 basis) resulted in measurable levels in milk. Oral administration of salmeterol at a dose in lactating rats approximately 973 times the MRHDID for adults (on a mcg/m2 basis) resulted in measurable levels in milk.
Use of ADVAIR DISKUS 100/50 in patients aged 4 to 11 years is supported by extrapolation of efficacy data from older subjects and by safety and efficacy data from a trial of ADVAIR DISKUS 100/50 in children with asthma aged 4 to 11 years [see Adverse Reactions, Clinical Pharmacology, Clinical Studies]. The safety and effectiveness of ADVAIR DISKUS in children with asthma younger than 4 years have not been established.
ICS, including fluticasone propionate, a component of ADVAIR DISKUS, may cause a reduction in growth velocity in children and adolescents [see Warnings and Precautions]. The growth of pediatric patients receiving orally inhaled corticosteroids, including ADVAIR DISKUS, 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 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 trial 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 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 DISKUS, each patient should be titrated to the lowest strength that effectively controls his/her asthma [see Dosage and Administration].
Clinical trials of ADVAIR DISKUS for asthma did not include sufficient numbers of subjects aged 65 years and older to determine whether older subjects with asthma respond differently than younger subjects.
Of the total number of subjects in clinical trials receiving ADVAIR DISKUS for COPD, 1,621 were aged 65 years and older and 379 were aged 75 years and older. Subjects with COPD aged 65 years and older had a higher incidence of serious adverse events compared with subjects younger than 65 years. Although the distribution of adverse events was similar in the 2 age groups, subjects older than 65 years experienced more severe events. In two 1-year trials, the excess risk of pneumonia that was seen in subjects treated with ADVAIR DISKUS compared with those treated with salmeterol was greater in subjects older than 65 years than in subjects younger than 65 years [see Adverse Reactions]. As with other products containing beta2-agonists, special caution should be observed when using ADVAIR DISKUS in geriatric patients who have concomitant cardiovascular disease that could be adversely affected by beta2-agonists. Based on available data for ADVAIR DISKUS or its active components, no adjustment of dosage of ADVAIR DISKUS in geriatric patients is warranted.
No relationship between fluticasone propionate systemic exposure and age was observed in 57 subjects with COPD (aged 40 to 82 years) given 250 or 500 mcg twice daily.
Formal pharmacokinetic studies using ADVAIR DISKUS 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 DISKUS have not been conducted in patients with renal impairment.
No human overdosage data has been reported for ADVAIR DISKUS.
ADVAIR DISKUS contains both fluticasone propionate and salmeterol; therefore, the risks associated with overdosage for the individual components described below apply to ADVAIR DISKUS. Treatment of overdosage consists of discontinuation of ADVAIR DISKUS together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. Cardiac monitoring is recommended in cases of overdosage.
Chronic overdosage of fluticasone propionate may result in signs/symptoms of hypercorticism [see Warnings and Precautions]. Inhalation by healthy volunteers of a single dose of 4,000 mcg of fluticasone propionate inhalation powder or single doses of 1,760 or 3,520 mcg of fluticasone propionate CFC inhalation aerosol was well tolerated. Fluticasone propionate given by inhalation aerosol at dosages of 1,320 mcg twice daily for 7 to 15 days to healthy human volunteers was also well tolerated. Repeat oral doses up to 80 mg daily for 10 days in healthy volunteers and repeat oral doses up to 20 mg daily for 42 days in subjects were well tolerated. Adverse reactions were of mild or moderate severity, and incidences were similar in active and placebo treatment groups.
The expected signs and symptoms with overdosage of salmeterol are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms of beta-adrenergic stimulation (e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, hypokalemia, metabolic acidosis). Overdosage with salmeterol can lead to clinically significant prolongation of the QTc interval, which can produce ventricular arrhythmias.
As with all inhaled sympathomimetic medicines, cardiac arrest and even death may be associated with an overdose of salmeterol.
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 DISKUS, there is not a significant increase in the risk of these events.
Not for Acute Symptoms
Inform patients that ADVAIR DISKUS is not meant to relieve acute asthma symptoms or exacerbations of COPD and extra doses should not be used for that purpose. Advise patients to treat acute 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 DISKUS 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 and COPD.
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 DISKUS, but at times therapy with ADVAIR DISKUS 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.
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 DISKUS 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 DISKUS.
Immediate Hypersensitivity Reactions
Advise patients that immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of ADVAIR DISKUS. Patients should discontinue ADVAIR DISKUS if such reactions occur. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of powder products containing lactose; therefore, patients with severe milk protein allergy should not take ADVAIR DISKUS.
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.