ADVAIR HFA

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.

5.2 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.

5.3 Excessive Use of ADVAIR HFA and Use With Other Long-Acting Beta-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.

5.4 Local Effects

In clinical studies, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in patients treated with ADVAIR 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.

5.5 Pneumonia

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^® (fluticasone 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).

5.6 Immunosuppression

Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.

Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

5.7 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.

5.8 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.

5.9 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 (7.1), Clinical Pharmacology (12.3)].

5.10 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.

5.11 Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions may occur after administration of ADVAIR HFA, as demonstrated by cases of urticaria, angioedema, rash, and bronchospasm [see Adverse Reactions (6.2)].

5.12 Cardiovascular and Central Nervous System Effects

Excessive beta-adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia [see Overdosage (10)]. Therefore, ADVAIR 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.

5.13 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.

5.14 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 (8.4)].

5.15 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.

5.16 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.

5.17 Coexisting Conditions

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.

5.18 Hypokalemia and Hyperglycemia

Beta-adrenergic agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects [see Clinical Pharmacology (12.2)]. The decrease in serum potassium is usually transient, not requiring supplementation. Clinically significant changes in blood glucose and/or serum potassium were seen infrequently during clinical studies with ADVAIR HFA at recommended doses.

6 ADVERSE REACTIONS

LABAs, such as salmeterol, one of the active ingredients in ADVAIR HFA, increase the risk of asthma-related death. Data from a large placebo-controlled US study that compared the safety of salmeterol (SEREVENT Inhalation Aerosol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol [see Warnings and Precautions (5.1)]. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABAs. Available data from controlled clinical trials suggest that LABAs increase the risk of asthma-related hospitalization in pediatric and adolescent patients.

Systemic and local corticosteroid use may result in the following:

• •Candida albicans infection [see Warnings and Precautions (5.4)]
• •Pneumonia in patients with COPD [see Warnings and Precautions (5.5)]
• •Immunosuppression [see Warnings and Precautions (5.6)]
• •Hypercorticism and adrenal suppression [see Warnings and Precautions (5.8)]
• •Growth effects [see Warnings and Precautions (5.14)]
• •Glaucoma and cataracts [see Warnings and Precautions (5.15)]

6.1 Clinical Trials Experience

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.

Adult and Adolescent Patients Aged 12 Years and Older: The incidence of adverse reactions associated with ADVAIR HFA in Table 2 is based upon 2 placebo-controlled 12-week US clinical studies (Studies 1 and 3) and 1 active-controlled 12-week US clinical study (Study 2). A total of 1,008 adult and adolescent patients with asthma (556 females and 452 males) previously treated with albuterol alone, salmeterol, or inhaled corticosteroids were treated twice daily with 2 inhalations of ADVAIR HFA 45/21 or ADVAIR HFA 115/21, fluticasone propionate chlorofluorocarbon (CFC) inhalation aerosol (44- or 110-mcg doses), salmeterol CFC inhalation aerosol 21 mcg, or placebo HFA inhalation aerosol. The average duration of exposure was 71 to 81 days in the active treatment groups compared with 51 days in the placebo group.

The incidence of common adverse reactions reported in Study 4, a 12-week non-US clinical study of 509 patients previously treated with inhaled corticosteroids who were treated twice daily with 2 inhalations of ADVAIR HFA 230/21, fluticasone propionate CFC inhalation aerosol 220 mcg, or 1 inhalation of ADVAIR DISKUS 500/50 was similar to the incidences reported in Table 2.

Additional Adverse Reactions: Other adverse reactions not previously listed, whether considered drug-related or not by the investigators, that occurred in the groups receiving ADVAIR HFA with an incidence of 1% to 3% and that occurred at a greater incidence than with placebo include the following: tachycardia, arrhythmias, myocardial infarction, postoperative complications, wounds and lacerations, soft tissue injuries, ear signs and symptoms, rhinorrhea/postnasal drip, epistaxis, nasal congestion/blockage, laryngitis, unspecified oropharyngeal plaques, dryness of nose, weight gain, allergic eye disorders, eye edema and swelling, gastrointestinal discomfort and pain, dental discomfort and pain, candidiasis mouth/throat, hyposalivation, gastrointestinal infections, disorders of hard tissue of teeth, abdominal discomfort and pain, oral abnormalities, arthralgia and articular rheumatism, muscle cramps and spasms, musculoskeletal inflammation, bone and skeletal pain, muscle injuries, sleep disorders, migraines, allergies and allergic reactions, viral infections, bacterial infections, candidiasis unspecified site, congestion, inflammation, bacterial reproductive infections, lower respiratory signs and symptoms, lower respiratory infections, lower respiratory hemorrhage, eczema, dermatitis and dermatosis, urinary infections.

Laboratory Test Abnormalities: In Study 3, there were more reports of hyperglycemia among adults and adolescents receiving ADVAIR HFA, but this was not seen in Studies 1 and 2.

6.2 Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing 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, fluticasone propionate, and/or salmeterol or a combination of these factors.

Cardiovascular: Arrhythmias (including atrial fibrillation, extrasystoles, supraventricular tachycardia), hypertension, ventricular tachycardia.

Ear, Nose, and Throat: Aphonia, earache, facial and oropharyngeal edema, paranasal sinus pain, rhinitis, throat soreness, tonsillitis.

Endocrine and Metabolic: Cushing’s syndrome, Cushingoid features, growth velocity reduction in children/adolescents, hypercorticism, osteoporosis.

Eye: Cataracts, glaucoma.

Gastrointestinal: Dyspepsia, xerostomia.

Hepatobiliary Tract and Pancreas: Abnormal liver function tests.

Immune System: Immediate and delayed hypersensitivity reactions, including rash and rare events of angioedema, bronchospasm, and anaphylaxis.

Infections and Infestations: Esophageal candidiasis.

Musculoskeletal: Back pain, myositis.

Neurology: Paresthesia, restlessness.

Non-Site Specific: Fever, pallor.

Psychiatry: Agitation, aggression, anxiety, depression. Behavioral changes, including hyperactivity and irritability, have been reported very rarely and primarily in children.

Respiratory: Asthma; asthma exacerbation; chest congestion; chest tightness; cough; dyspnea; immediate bronchospasm; influenza; paradoxical bronchospasm; tracheitis; wheezing; pneumonia; reports of upper respiratory symptoms of laryngeal spasm, irritation, or swelling such as stridor or choking.

Skin: Contact dermatitis, contusions, ecchymoses, photodermatitis, pruritus.

Urogenital: Dysmenorrhea, irregular menstrual cycle, pelvic inflammatory disease, vaginal candidiasis, vaginitis, vulvovaginitis.

7 DRUG INTERACTIONS

ADVAIR HFA has been used concomitantly with other drugs, including short-acting beta₂-agonists, methylxanthines, and intranasal corticosteroids, commonly used in patients with asthma, without adverse drug reactions [see Clinical Pharmacology (12.2)]. No formal drug interaction studies have been performed with ADVAIR HFA.

7.1 Inhibitors of Cytochrome P450 3A4

Fluticasone propionate and salmeterol, the individual components of ADVAIR HFA, are substrates of CYP3A4. The use of strong 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.

Ritonavir: Fluticasone Propionate: A drug interaction study 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 (12.3)]. 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.

Ketoconazole: Fluticasone Propionate: Coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in increased plasma fluticasone propionate exposure and reduced plasma cortisol area under the curve (AUC), but had no effect on urinary excretion of cortisol.

Salmeterol: In a drug interaction study 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 C_max 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.

7.2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants

ADVAIR HFA 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 HFA, on the vascular system may be potentiated by these agents.

7.3 Beta-Adrenergic Receptor Blocking Agents

Beta-blockers not only block the pulmonary effect of beta-agonists, such as salmeterol, a component of ADVAIR HFA, but may produce severe bronchospasm in patients with reversible obstructive airways disease. Therefore, patients with asthma 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.

7.4 Diuretics

The ECG changes and/or hypokalemia that may result from the administration of nonpotassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists such as salmeterol, a component of ADVAIR HFA, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical relevance of these effects is not known, caution is advised in the coadministration of ADVAIR HFA with nonpotassium-sparing diuretics.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

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/m² 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 (12.3)].

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.

8.2 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.

8.3 Nursing Mothers

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.

8.4 Pediatric Use

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 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 (6.1)].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 (12.2, 12.3)].

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 (5.14)]. 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 – 3^rd percentile = 3.8 cm/year, 50^th percentile = 5.4 cm/year, and 97^th percentile = 7.0 cm/year; girls – 3^rd percentile = 4.2 cm/year, 50^th percentile = 5.7 cm/year, and 97^th 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.

8.5 Geriatric Use

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.

8.6 Hepatic Impairment

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.

8.7 Renal Impairment

Formal pharmacokinetic studies using ADVAIR HFA have not been conducted in patients with renal impairment.

10 OVERDOSAGE

Fluticasone Propionate: Chronic overdosage with fluticasone propionate may result in signs/symptoms of hypercorticism [see Warnings and Precautions (5.7)]. 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 patients were well tolerated. Adverse reactions were of mild or moderate severity, and incidences were similar in active and placebo treatment groups.

Salmeterol: 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 following: 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, and insomnia. Overdosage with salmeterol can lead to clinically significant prolongation of the QTc interval, which can produce ventricular arrhythmias. Other signs of overdosage may include hypokalemia and hyperglycemia.

As with all sympathomimetic medications, cardiac arrest and even death may be associated with abuse of salmeterol.

Treatment consists of discontinuation of salmeterol together with appropriate symptomatic therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of salmeterol. Cardiac monitoring is recommended in cases of overdosage.

11 DESCRIPTION

ADVAIR HFA 45/21 Inhalation Aerosol, ADVAIR HFA 115/21 Inhalation Aerosol, and ADVAIR HFA 230/21 Inhalation Aerosol are combinations of fluticasone propionate and salmeterol xinafoate.

One active component of ADVAIR HFA is fluticasone propionate, a corticosteroid having the chemical name S-(fluoromethyl) 6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, 17-propionate and the following chemical structure: