ADVAIR DISKUS 100/50, ADVAIR DISKUS 250/50, and ADVAIR DISKUS 500/50 are combinations of fluticasone propionate and salmeterol xinafoate.

One active component of ADVAIR DISKUS 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:

Fluticasone propionate is a white powder with a molecular weight of 500.6, and the empirical formula is C₂₅H₃₁F₃O₅S. It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol. The other active component of ADVAIR DISKUS is salmeterol xinafoate, a beta₂-adrenergic bronchodilator. Salmeterol xinafoate is the racemic form of the 1-hydroxy-2- naphthoic acid salt of salmeterol. The chemical name of salmeterol xinafoate is 4-hydroxy-α¹-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol, 1-hydroxy-2-naphthalenecarboxylate, and it has the following chemical structure:

Salmeterol xinafoate is a white powder with a molecular weight of 603.8, and the empirical formula is C₂₅H₃₇NO_4•C₁₁H₈O₃. It is freely soluble in methanol; slightly soluble in ethanol, chloroform, and isopropanol; and sparingly soluble in water.

ADVAIR DISKUS 100/50, ADVAIR DISKUS 250/50, and ADVAIR DISKUS 500/50 are specially designed plastic devices containing a double-foil blister strip of a powder formulation of fluticasone propionate and salmeterol xinafoate intended for oral inhalation only. Each blister on the double-foil strip within the device contains 100, 250, or 500 mcg of microfine fluticasone propionate and 72.5 mcg of microfine salmeterol xinafoate salt, equivalent to 50 mcg of salmeterol base, in 12.5 mg of formulation containing lactose (which contains milk proteins). Each blister contains 1 complete dose of both medications. After a blister containing medication is opened by activating the device, the medication is dispersed into the airstream created by the patient inhaling through the mouthpiece.

Under standardized in vitro test conditions, ADVAIR DISKUS delivers 93, 233, and 465 mcg of fluticasone propionate and 45 mcg of salmeterol base per blister from ADVAIR DISKUS 100/50, 250/50, and 500/50, respectively, when tested at a flow rate of 60 L/min for 2 seconds. In adult patients with obstructive lung disease and severely compromised lung function (mean FEV₁ 20% to 30% of predicted), mean peak inspiratory flow (PIF) through a DISKUS inhalation device was 82.4 L/min (range, 46.1 to 115.3 L/min).

Inhalation profiles for adolescent (N = 13, aged 12 to 17 years) and adult (N = 17, aged 18 to 50 years) patients with asthma inhaling maximally through the DISKUS® device show mean PIF of 122.2 L/min (range, 81.6 to 152.1 L/min). Inhalation profiles for pediatric patients with asthma inhaling maximally through the DISKUS device show a mean PIF of 75.5 L/min (range, 49.0 to 104.8 L/min) for the 4-year-old patient set (N = 20) and 107.3 L/min (range, 82.8 to 125.6 L/min) for the 8-year-old patient set (N = 20).

The actual amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow profile.

Maintenance Treatment of Asthma

ADVAIR DISKUS is indicated for the long-term, twice-daily, maintenance treatment of asthma in patients 4 years of age and older.

Long-acting beta₂-adrenergic agonists, such as salmeterol, one of the active ingredients in ADVAIR DISKUS, may increase the risk of asthma-related death [see WARNINGS and PRECAUTIONS]. Therefore, when treating patients with asthma, physicians should only prescribe ADVAIR DISKUS for patients not adequately controlled on other asthma-controller medications (e.g., low- to medium-dose inhaled corticosteroids) or whose disease severity clearly warrants initiation of treatment with 2 maintenance therapies.

Important Limitations of Use:

• ADVAIR DISKUS is NOT indicated for the relief of acute bronchospasm.
• ADVAIR DISKUS is not indicated in patients whose asthma can be successfully managed by inhaled corticosteroids along with occasional use of inhaled, short-acting beta₂-agonists.

Maintenance Treatment of Chronic Obstructive Pulmonary Disease

ADVAIR DISKUS 250/50 is indicated for the twice-daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. ADVAIR DISKUS 250/50 is also indicated to reduce exacerbations of COPD in patients with a history of exacerbations. ADVAIR DISKUS 250/50 twice daily is the only approved dosage for the treatment of COPD because an efficacy advantage of the higher strength ADVAIR DISKUS 500/50 over ADVAIR DISKUS 250/50 has not been demonstrated.

Important Limitations of Use: ADVAIR DISKUS is NOT indicated for the relief of acute bronchospasm.

ADVAIR DISKUS should be administered twice daily every day by the orally inhaled route only. After inhalation, the patient should rinse the mouth with water without swallowing [see Patient Counseling Information].

More frequent administration or a higher number of inhalations (more than 1 inhalation twice daily) of the prescribed strength of ADVAIR DISKUS is not recommended as some patients are more likely to experience adverse effects with higher doses of salmeterol. Patients using ADVAIR DISKUS should not use additional long-acting beta₂-agonists for any reason. [See WARNINGS and PRECAUTIONS]

Asthma

If asthma symptoms arise in the period between doses, an inhaled, short-acting beta₂- agonist should be taken for immediate relief.

Adult and Adolescent Patients 12 Years of Age and Older: For patients 12 years of age and older, the dosage is 1 inhalation twice daily (morning and evening, approximately 12 hours apart). The recommended starting dosages for ADVAIR DISKUS for patients 12 years of age and older are based upon patients' asthma severity. For patients not currently on inhaled corticosteroids whose disease severity clearly warrants initiation of treatment with 2 maintenance therapies, or patients inadequately controlled on an inhaled corticosteroid, the recommended starting dosage is ADVAIR DISKUS 100/50 or 250/50 twice daily.

The maximum recommended dosage is ADVAIR DISKUS 500/50 twice daily.

For all patients it is desirable to titrate to the lowest effective strength after adequate asthma stability is achieved.

Improvement in asthma control following inhaled administration of ADVAIR DISKUS can occur within 30 minutes of beginning treatment, although maximum benefit may not be achieved for 1 week or longer after starting treatment. Individual patients will experience a variable time to onset and degree of symptom relief.

For patients who do not respond adequately to the starting dosage after 2 weeks of therapy, replacing the current strength of ADVAIR DISKUS with a higher strength may provide additional improvement in asthma control.

If a previously effective dosage regimen of ADVAIR DISKUS fails to provide adequate improvement in asthma control, the therapeutic regimen should be reevaluated and additional therapeutic options (e.g., replacing the current strength of ADVAIR DISKUS with a higher strength, adding additional inhaled corticosteroid, initiating oral corticosteroids) should be considered.

Pediatric Patients 4 to 11 Years of Age: For patients with asthma aged 4 to 11 years who are symptomatic on an inhaled corticosteroid, the dosage is 1 inhalation of ADVAIR DISKUS 100/50 twice daily (morning and evening, approximately 12 hours apart).

Chronic Obstructive Pulmonary Disease

The recommended dosage for patients with COPD is 1 inhalation of ADVAIR DISKUS 250/50 twice daily (morning and evening, approximately 12 hours apart).

If shortness of breath occurs in the period between doses, an inhaled, short-acting beta₂- agonist should be taken for immediate relief.

Dosage Forms And Strengths

Disposable purple device with 60 blisters containing a combination of fluticasone propionate (100, 250, or 500 mcg) and salmeterol (50 mcg) as an oral inhalation powder formulation. An institutional pack containing 28 blisters is also available.

ADVAIR DISKUS 100/50 is supplied as a disposable purple device containing 60 blisters. The DISKUS inhalation device is packaged within a purple, plastic-coated, moisture-protective foil pouch (NDC 0173-0695-00). ADVAIR DISKUS 100/50 is also supplied in an institutional pack of 1 disposable purple device containing 28 blisters. The DISKUS inhalation device is packaged within a purple, plastic-coated, moisture-protective foil pouch (NDC 0173-0695-02). ADVAIR DISKUS 250/50 is supplied as a disposable purple device containing 60 blisters. The DISKUS inhalation device is packaged within a purple, plastic-coated, moisture-protective foil pouch (NDC 0173-0696-00).

ADVAIR DISKUS 250/50 is also supplied in an institutional pack of 1 disposable purple device containing 28 blisters. The DISKUS inhalation device is packaged within a purple, plastic-coated, moisture-protective foil pouch (NDC 0173-0696-02). ADVAIR DISKUS 500/50 is supplied as a disposable purple device containing 60 blisters. The DISKUS inhalation device is packaged within a purple, plastic-coated, moisture-protective foil pouch (NDC 0173-0697-00).

ADVAIR DISKUS 500/50 is also supplied in an institutional pack of 1 disposable purple device containing 28 blisters. The DISKUS inhalation device is packaged within a purple, plastic-coated, moisture-protective foil pouch (NDC 0173-0697-02).

Store at controlled room temperature (see USP), 20° to 25° C (68° to 77° F), in a dry place away from direct heat or sunlight. Keep out of reach of children. The DISKUS inhalation device is not reusable. The device should be discarded 1 month after removal from the moisture-protective foil overwrap pouch or after all blisters have been used (when the dose indicator reads "0"), whichever comes first. Do not attempt to take the device apart.

ADVAIR DISKUS, DISKHALER, DISKUS, FLOVENT, ROTADISK, SEREVENT, and VENTOLIN are registered trademarks of GlaxoSmithKline. NORVIR and KALETRA are registered trademarks of Abbott Laboratories. GlaxoSmithKline, Research Triangle Park, NC 27709. FDA Rev date: 4/30/2008

Long-acting beta₂-adrenergic agonists, such as salmeterol, may 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]. Salmeterol is a component of ADVAIR DISKUS. However, the data from this study are not adequate to determine whether concurrent use of inhaled corticosteroids, such as fluticasone propionate, the other component of ADVAIR DISKUS, or other asthma-controller therapy modifies the risk of asthma-related death.

Systemic and local corticosteroid use may result in the following:

• Candida albicans infection [see WARNINGS and PRECAUTIONS]
• Pneumonia in patients with COPD [see WARNINGS and PRECAUTIONS]
• Immunosuppression [see WARNINGS and PRECAUTIONS]
• Hypercorticism and adrenal suppression [see WARNINGS and PRECAUTIONS]
• Growth effects [see WARNINGS and PRECAUTIONS]
• Glaucoma and cataracts [see WARNINGS and PRECAUTIONS]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trials Experience in Asthma

Adult and Adolescent Patients 12 Years of Age and Older: The incidence of adverse reactions associated with ADVAIR DISKUS in Table 2 is based upon 2 placebo-controlled, 12-week, US clinical studies (Studies 1 and 2). A total of 705 adolescent and adult patients (349 females and 356 males) previously treated with salmeterol or inhaled corticosteroids were treated twice daily with ADVAIR DISKUS (100/50- or 250/50-mcg doses), fluticasone propionate inhalation powder (100- or 250-mcg doses), salmeterol inhalation powder 50 mcg, or placebo. The average duration of exposure was 60 to 79 days in the active treatment groups compared with 42 days in the placebo group.

Table 2. Adverse Reactions With ≥ 3% Incidence With ADVAIR DISKUS in Adult and Adolescent Patients With Asthma

Adverse Event	ADVAIR DISKUS 100/50 (N = 92) %	ADVAIR DISKUS 250/50 (N = 84) %	Fluticasone Propionate 100 mcg (N = 90) %	Fluticasone Propionate 250 mcg (N = 84) %	Salmetero l50 mcg (N = 180) %	Placebo (N = 175) %
Ear, nose, & throat
Upper respiratory tract infection	27	21	29	25	19	14
Pharyngitis	13	10	7	12	8	6
Upper respiratory inflammation	7	6	7	8	8	5
Sinusitis	4	5	6	1	3	4
Hoarseness/dysphonia	5	2	2	4	<1	<1
Oral candidiasis	1	4	2	2	0	0
Lower respiratory
Viral respiratory infections	4	4	4	10	6	3
Bronchitis	2	8	1	2	2	2
Cough	3	6	0	0	3	2
Neurology
Headaches	12	13	14	8	10	7
Gastrointestinal
Nausea & vomiting	4	6	3	4	1	1
Gastrointestinal discomfort & pain	4	1	0	2	1	1
Diarrhea	4	2	2	2	1	1
Viral gastrointestinal infections	3	0	3	1	2	2
Non-site specific Candidiasis unspecified site	3	0	1	4	0	1
Musculoskeletal
Musculoskeletal pain	4	2	1	5	3	3

The types of adverse reactions and events reported in Study 3, a 28-week, non-US clinical study of 503 patients previously treated with inhaled corticosteroids 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 patients with asthma treated with ADVAIR DISKUS compared with patients 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 Patients 4 to 11 Years of Age: The safety data for pediatric patients 4 to 11 years of age is based upon 1 US trial of 12 weeks' treatment duration. A total of 203 patients (74 females and 129 males) who were receiving inhaled corticosteroids at study 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 patients 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 patients in clinical trials. The elevations were transient and did not lead to discontinuation from the studies. In addition, there were no clinically relevant changes noted in glucose or potassium.

Clinical Trials Experience in Chronic Obstructive Pulmonary Disease

Short-Term (6 Months to 1 Year) Trials: The short-term safety data are based on exposure to ADVAIR DISKUS 250/50 twice daily in one 6-month and two 1-year clinical trials. In the 6-month trial, a total of 723 adult patients (266 females and 457 males) were treated twice daily with ADVAIR DISKUS 250/50, fluticasone propionate inhalation powder 250 mcg, salmeterol inhalation powder, or placebo. The mean age of the patients was 64, and the majority (93%) was Caucasian. In this trial, 70% of the patients treated with ADVAIR DISKUS reported an adverse reaction compared with 64% on placebo. The average duration of exposure to ADVAIR DISKUS 250/50 was 141.3 days compared with 131.6 days for placebo. The incidence of adverse reactions in the 6-month study is shown in Table 3.

Table 3. Overall Adverse Reactions With ≥ 3% Incidence With ADVAIR DISKUS 250/50 in Patients With Chronic Obstructive Pulmonary Disease Associated With Chronic Bronchitis

Adverse Event	ADVAIR DISKUS 250/50 (N = 178) %	Fluticasone Propionate 250 mcg (N = 183) %	Salmeterol 50 mcg (N = 177) %	Placebo (N = 185) %
Ear, nose, & throat
Candidiasis mouth/throat	10	6	3	1
Throat irritation	8	5	4	7
Hoarseness/dysphonia	5	3	<1	0
Sinusitis	3	8	5	3
Lower respiratory
Viral respiratory infections	6	4	3	3
Neurology
Headaches	16	11	10	12
Dizziness	4	<1	3	2
Non-site specific
Fever	4	3	0	3
Malaise & fatigue	3	2	2	3
Musculoskeletal
Musculoskeletal pain	9	8	12	9
Muscle cramps & spasms	3	3	1	1

In the two 1-year studies, ADVAIR DISKUS 250/50 was compared with salmeterol in 1,579 patients (863 males and 716 females). The mean age of the patients was 65, and the majority (94%) was Caucasian. To be enrolled, all of the patients had to have had a COPD exacerbation in the previous 12 months. In this trial, 88% of the patients treated with ADVAIR DISKUS and 86% of the patients treated with salmeterol reported an adverse event. The most common events that occurred with a frequency of > 5% and more frequently in the patients treated with ADVAIR DISKUS were nasopharyngitis, upper respiratory tract infection, nasal congestion, back pain, sinusitis, dizziness, nausea, pneumonia, candidiasis, and dysphonia. Overall, 55 (7%) of the patients treated with ADVAIR DISKUS and 25 (3%) of the patients treated with salmeterol developed pneumonia. The incidence of pneumonia was higher in patients over 65 years of age, 9% in the patients treated with ADVAIR DISKUS compared with 4% in the patients treated with ADVAIR DISKUS less than 65 years of age. In the patients treated with salmeterol, the incidence of pneumonia was the same (3%) in both age-groups. [See WARNINGS and PRECAUTIONS, Use in Specific Populations]

Long-Term (3-Year) Trial: The safety of ADVAIR DISKUS 500/50 was evaluated in a randomized, double-blind, placebo-controlled, multicenter, international, 3-year study in 6,184 adult patients with COPD (4,684 males and 1,500 females). The mean age of the patients was 65, and the majority (82%) was Caucasian. The distribution of adverse events was similar to that seen in the 1-year trials with ADVAIR DISKUS 250/50. In addition, pneumonia was reported in a significantly increased number of patients treated with ADVAIR DISKUS 500/50 and fluticasone propionate 500 mcg (16% and 14%, respectively) compared with patients treated with salmeterol 50 mcg or placebo (11% and 9%, respectively). When adjusted for time on treatment, the rates of pneumonia were 84 and 88 events per 1,000 treatment-years in the groups treated with fluticasone propionate 500 mcg and with ADVAIR DISKUS 500/50, respectively, compared with 52 events per 1,000 treatment-years in the salmeterol and placebo groups. 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 vs. 10% with placebo) compared with patients less than 65 years of age (14% with ADVAIR DISKUS 500/50 vs. 8% with placebo). [See WARNINGS and PRECAUTIONS, Use in Specific Populations]

Additional Adverse Reactions: Other adverse reactions not previously listed, whether considered drug-related or not by the investigators, that were reported more frequently by patients with COPD treated with ADVAIR DISKUS compared with patients treated with placebo include the following: syncope; ear, nose, and throat infections; ear signs and symptoms; laryngitis; nasal congestion/blockage; nasal sinus disorders; pharyngitis/throat infection; hypothyroidism; dry eyes; eye infections; gastrointestinal signs and symptoms; oral lesions; abnormal liver function tests; bacterial infections; edema and swelling; viral infections. Laboratory Abnormalities: There were no clinically relevant changes in these trials. Specifically, no increased reporting of neutrophilia or changes in glucose or potassium was noted.

Postmarketing Experience

In addition to adverse events reported from clinical trials, the following events have been identified during worldwide use of any formulation of ADVAIR, fluticasone propionate, and/or salmeterol regardless of indication. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. 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.

Cardiac Disorders: Arrhythmias (including atrial fibrillation, extrasystoles, supraventricular tachycardia), ventricular tachycardia.

Endocrine Disorders: Cushing syndrome, Cushingoid features, growth velocity reduction in children/adolescents, hypercorticism.

Eye Disorders: Glaucoma.

Gastrointestinal Disorders: 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.

Metabolic and Nutrition Disorders: Hyperglycemia, weight gain.

Musculoskeletal, Connective Tissue, and Bone Disorders: Arthralgia, cramps, myositis, osteoporosis.

Nervous System Disorders: Paresthesia, restlessness.

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

Reproductive System and Breast Disorders: Dysmenorrhea.

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: Ecchymoses, photodermatitis.

Vascular Disorders: Pallor.

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. No formal drug interaction studies have been performed with ADVAIR DISKUS.

Inhibitors of Cytochrome P450 3A4

Fluticasone propionate and salmeterol, the individual components of ADVAIR DISKUS, are substrates of CYP 3A4. The use of strong CYP 3A4 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.

Ritonavir: Fluticasone Propionate: A drug interaction study with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a strong CYP 3A4 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 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 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 produce severe bronchospasm in patients with reversible obstructive airways disease. Therefore, patients with asthma and 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.

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, 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 beta-agonists with nonpotassium-sparing diuretics.

Included as part of the PRECAUTIONS section.

Risk of Asthma-Related Death With Long-Acting beta₂-Adrenergic Agonists

Long-acting beta₂-adrenergic agonists, such as salmeterol, one of the active ingredients in ADVAIR DISKUS, may increase the risk of asthma-related death. Therefore, when treating patients with asthma, physicians should only prescribe ADVAIR DISKUS for patients not adequately controlled on other asthma-controller medications (e.g., low- to medium-dose inhaled corticosteroids) or whose disease severity clearly warrants initiation of treatment with 2 maintenance therapies.

A large placebo-controlled US study that compared the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol. The Salmeterol Multi-center Asthma Research Trial (SMART) was a randomized, double-blind study that enrolled long-acting beta₂-agonist-naive patients with asthma to assess the safety of salmeterol (SEREVENT Inhalation Aerosol) 42 mcg twice daily over 28 weeks compared with placebo when added to usual asthma therapy. A planned interim analysis was conducted when approximately half of the intended number of patients had been enrolled (N = 26,355), which led to premature termination of the study. The results of the interim analysis showed that patients receiving salmeterol were at increased risk for fatal asthma events (see Table 1 and Figure 1). In the total population, a higher rate of asthma-related death occurred in patients treated with salmeterol than those treated with placebo (0.10% vs. 0.02%, relative risk 4.37 [95% CI: 1.25, 15.34]).

Post-hoc subpopulation analyses were performed. In Caucasians, asthma-related death occurred at a higher rate in patients treated with salmeterol than in patients treated with placebo (0.07% vs. 0.01%, relative risk 5.82 [95% CI: 0.70, 48.37]). In African Americans also, asthma-related death occurred at a higher rate in patients treated with salmeterol than those treated with placebo (0.31% vs. 0.04%, relative risk 7.26 [95% CI: 0.89, 58.94]). Although the relative risks of asthma-related death were similar in Caucasians and African Americans, the estimate of excess deaths in patients treated with salmeterol was greater in African Americans because there was a higher overall rate of asthma-related death in African American patients (see Table 1). Given the similar basic mechanisms of action of beta₂-agonists, it is possible that the findings seen in the SMART study represent a class effect.

The data from the SMART study are not adequate to determine whether concurrent use of inhaled corticosteroids, such as fluticasone propionate, the other active ingredient in ADVAIR DISKUS, or other asthma-controller therapy modifies the risk of asthma-related death.

Table 1. Asthma-Related Deaths in the 28-Week Salmeterol Multi-center Asthma Research Trial (SMART)

	Salmeterol n (%*)	Placebo n (%*)	Relative Risk† (95% Confidence Interval)	Excess Deaths Expressed per 10,000 Patients‡ (95% Confidence Interval)
Total Population§
Salmeterol: N = 13,176	13 (0.10%)		4.37 (1.25, 15.34)	8 (3, 13)
Placebo: N = 13,179		3 (0.02%)
Caucasian
Salmeterol: N = 9,281	6 (0.07%)		5.82 (0.70, 48.37)	6 (1, 10)
Placebo: N = 9,361		1 (0.01%)
African American
Salmeterol: N = 2,366	7 (0.31%)		7.26 (0.89, 58.94)	27 (8, 46)
Placebo: N = 2,319		1 (0.04%)
*Life-table 28-week estimate, adjusted according to the patients' actual lengths of exposure to study treatment to account for early withdrawal of patients from the study. †Relative risk is the ratio of the rate of asthma-related death in the salmeterol group and the rate in the placebo group. The relative risk indicates how many more times likely an asthma-related death occurred in the salmeterol group than in the placebo group in a 28-week treatment period. ‡Estimate of the number of additional asthma-related deaths in patients treated with salmeterol in SMART, assuming 10,000 patients received salmeterol for a 28-week treatment period. Estimate calculated as the difference between the salmeterol and placebo groups in the rates of asthma-related death multiplied by 10,000. §The Total Population includes the following ethnic origins listed on the case report form: Caucasian, African American, Hispanic, Asian, and "Other." In addition, the Total Population includes those patients whose ethnic origin was not reported. The results for Caucasian and African American subpopulations are shown above. No asthma-related deaths occurred in the Hispanic (salmeterol n = 996, placebo n = 999), Asian (salmeterol n = 173, placebo n = 149), or "Other" (salmeterol n = 230, placebo n = 224) subpopulations. One asthma-related death occurred in the placebo group in the subpopulation whose ethnic origin was not reported (salmeterol n = 130, placebo n = 127).

Figure 1. Cumulative Incidence of Asthma-Related Deaths in the 28-Week Salmeterol Multi-center Asthma Research Trial (SMART), by Duration of Treatment

A 16-week clinical study performed in the United Kingdom, the Salmeterol Nationwide Surveillance (SNS) study, showed results similar to the SMART study. In the SNS study, the rate of asthma-related death was numerically, though not statistically significantly, greater in patients with asthma treated with salmeterol (42 mcg twice daily) than those treated with albuterol (180 mcg 4 times daily) added to usual asthma therapy.

The SNS and SMART studies enrolled patients with asthma. No studies have been conducted that were primarily designed to determine whether the rate of death in patients with COPD is increased by long-acting beta₂-adrenergic agonists.

Deterioration of Disease and Acute Episodes

ADVAIR DISKUS should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD. ADVAIR DISKUS has not been studied in patients with acutely deteriorating asthma or COPD. The initiation of ADVAIR DISKUS in this setting is not appropriate.

Serious acute respiratory events, including fatalities, have been reported when salmeterol, a component of ADVAIR DISKUS, has been initiated in patients with significantly worsening or acutely deteriorating asthma. In most cases, these have occurred in patients with severe asthma (e.g., patients with a history of corticosteroid dependence, low pulmonary function, intubation, mechanical ventilation, frequent hospitalizations, previous life-threatening acute asthma exacerbations) and in some patients with acutely deteriorating asthma (e.g., patients with significantly increasing symptoms; increasing need for inhaled, short-acting beta₂-agonists; decreasing response to usual medications; increasing need for systemic corticosteroids; recent emergency room visits; deteriorating lung function). However, these events have occurred in a few patients with less severe asthma as well. It was not possible from these reports to determine whether salmeterol contributed to these events.

Increasing use of inhaled, short-acting beta₂-agonists is a marker of deteriorating asthma. In this situation, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the possible need for replacing the current strength of ADVAIR DISKUS with a higher strength, adding additional inhaled corticosteroid, or initiating systemic corticosteroids. Patients should not use more than 1 inhalation twice daily (morning and evening) of ADVAIR DISKUS.

ADVAIR DISKUS should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short-acting beta₂-agonist, not ADVAIR DISKUS, should be used to relieve acute symptoms such as shortness of breath. When prescribing ADVAIR DISKUS, the physician must also provide the patient with an inhaled, short-acting beta₂-agonist (e.g., albuterol) for treatment of acute symptoms, despite regular twice-daily (morning and evening) use of ADVAIR DISKUS.

When beginning treatment with ADVAIR DISKUS, patients who have been taking oral or inhaled, short-acting beta₂-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs.

Excessive Use of ADVAIR DISKUS and Use With Other Long-Acting beta₂-Agonists

As with other inhaled drugs containing beta₂-adrenergic agents, ADVAIR DISKUS should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medications containing long-acting beta₂-agonists, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using ADVAIR DISKUS should not use an additional long-acting beta₂-agonist (e.g., salmeterol, formoterol fumarate, arformoterol tartrate) for any reason, including prevention of exercise-induced bronchospasm (EIB) or the maintenance treatment of asthma or COPD.

Local Effects

In clinical studies, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in patients treated with ADVAIR DISKUS. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral antifungal) therapy while treatment with ADVAIR DISKUS continues, but at times therapy with ADVAIR DISKUS may need to be interrupted. Patients should rinse the mouth after inhalation of ADVAIR DISKUS.

Pneumonia

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of pneumonia and exacerbations frequently overlap.

Lower respiratory tract infections, including pneumonia, have been reported in patients with COPD following the inhaled administration of corticosteroids, including fluticasone propionate and ADVAIR DISKUS. In 2 replicate 12-month studies of 1,579 patients with COPD, there was a higher incidence of pneumonia reported in patients receiving ADVAIR DISKUS 250/50 (7%) than in those receiving salmeterol 50 mcg (3%). The incidence of pneumonia in the patients treated with ADVAIR DISKUS was higher in patients over 65 years of age (9%) compared with the incidence in patients less than 65 years of age (4%). [See ADVERSE REACTIONS, Use in Specific Populations]

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 vs. 10% with placebo) compared with patients less than 65 years of age (14% with ADVAIR DISKUS 500/50 vs. 8% with placebo). [See ADVERSE REACTIONS, Use in Specific Populations]

Immunosuppression

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

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

Transferring Patients From Systemic Corticosteroid Therapy

Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.

Patients who have been previously maintained on 20 mg or more per day of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although ADVAIR DISKUS may provide control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.

During periods of stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack.

Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to ADVAIR DISKUS. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with ADVAIR DISKUS. Lung function (mean forced expiratory volume in 1 second [FEV₁] or morning peak expiratory flow [PEF]), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.

Transfer of patients from systemic corticosteroid therapy to inhaled corticosteroids or ADVAIR DISKUS may unmask conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions). Some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function.

Hypercorticism and Adrenal Suppression

Fluticasone propionate, a component of ADVAIR DISKUS, will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since fluticasone propionate is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of ADVAIR DISKUS in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose. A relationship between plasma levels of fluticasone propionate and inhibitory effects on stimulated cortisol production has been shown after 4 weeks of treatment with fluticasone propionate inhalation aerosol. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing ADVAIR DISKUS.

Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with ADVAIR DISKUS should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.

It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients, particularly when fluticasone propionate is administered at higher than recommended doses over prolonged periods of time. If such effects occur, the dosage of ADVAIR DISKUS should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma symptoms.

Drug Interactions With Strong Cytochrome P450 3A4 Inhibitors

The use of strong CYP 3A4 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 medications, ADVAIR DISKUS can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with ADVAIR DISKUS, it should be treated immediately with an inhaled, short-acting bronchodilator, ADVAIR DISKUS should be discontinued immediately, and alternative therapy should be instituted. Upper airway symptoms of laryngeal spasm, irritation, or swelling, such as stridor and choking, have been reported in patients receiving fluticasone propionate and salmeterol.

Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions may occur after administration of ADVAIR DISKUS, as demonstrated by cases of urticaria, angioedema, rash, and bronchospasm. There have been reports of anaphylactic reactions in patients with severe milk protein allergy; therefore, patients with severe milk protein allergy should not take ADVAIR DISKUS [see CONTRAINDICATIONS].

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 ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Large doses of inhaled or oral salmeterol (12 to 20 times the recommended dose) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

Reduction in Bone Mineral Density

Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, post-menopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating ADVAIR DISKUS and periodically thereafter. If significant reductions in BMD are seen and ADVAIR DISKUS is still considered medically important for that patient's COPD therapy, use of medication to treat or prevent osteoporosis should be strongly considered.

A 2-year study of 160 patients (females 18 to 40 years of age, 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.

Effects of treatment with ADVAIR DISKUS 500/50, fluticasone propionate 500 mcg, salmeterol 50 mcg, or placebo on BMD was evaluated in a subset of 658 patients (females and males 40 to 80 years of age) with COPD in the 3-year survival study. BMD evaluations were conducted at baseline and at 48, 108, and 158 weeks. Conclusions cannot be drawn from this study because of the large number of drop outs ( > 50%) before the end of the follow-up and the maldistribution of covariates among the treatment groups that can affect BMD.

Fracture risk was estimated for the entire population of patients with COPD in the survival study (N = 6,184). The probability of a fracture over 3 years was 6.3% for ADVAIR DISKUS, 5.4% for fluticasone propionate, 5.1% for salmeterol, and 5.1% for placebo.

Effect on Growth

Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth of pediatric patients receiving ADVAIR DISKUS routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including ADVAIR DISKUS, titrate each patient's dose to the lowest dosage that effectively controls his/her symptoms. [See DOSAGE AND ADMINISTRATION, 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 inhaled corticosteroids, including fluticasone propionate, a component of ADVAIR DISKUS. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.

Effects of treatment with ADVAIR DISKUS 500/50, fluticasone propionate 500 mcg, salmeterol 50 mcg, or placebo on development of cataracts or glaucoma was evaluated in a subset of 658 patients with COPD in the 3-year survival study. Ophthalmic examinations were conducted at baseline and at 48, 108, and 158 weeks. Conclusions about cataracts cannot be drawn from this study because the high incidence of cataracts at baseline (61% to 71%) resulted in an inadequate number of patients treated with ADVAIR DISKUS 500/50 who were eligible and available for evaluation of cataracts at the end of the study (n = 53). The incidence of newly diagnosed glaucoma was 2% with ADVAIR DISKUS 500/50, 5% with fluticasone propionate, 0% with salmeterol, and 2% with placebo.

Eosinophilic Conditions and Churg-Strauss Syndrome

In rare cases, patients on inhaled fluticasone propionate may present with systemic eosinophilic conditions. Some of these patients have clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of fluticasone propionate. Cases of serious eosinophilic conditions have also been reported with other inhaled corticosteroids in this clinical setting. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between fluticasone propionate and these underlying conditions has not been established.

Coexisting Conditions

ADVAIR DISKUS, like all medications containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta₂-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

Hypokalemia and Hyperglycemia

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

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Fluticasone Propionate: Fluticasone propionate demonstrated no tumorigenic potential in mice at oral doses up to 1,000 mcg/kg (approximately 4 and 10 times the MRHD for adults and children, respectively, on a mg/m² basis) for 78 weeks or in rats at inhalation doses up to 57 mcg/kg (less than and approximately equivalent to the MRHD for adults and children, respectively, on a mg/m² basis) for 104 weeks.

Fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells in vitro. No significant clastogenic effect was seen in cultured human peripheral lymphocytes in vitro or in the in vivo mouse micronucleus test.

No evidence of impairment of fertility was observed in reproductive studies conducted in rats at subcutaneous doses up to 50 mcg/kg (less than the MRHD on a mg/m² basis). Prostate weight was significantly reduced.

Salmeterol: In an 18-month carcinogenicity study in CD-mice, salmeterol at oral doses of 1.4 mg/kg and above (approximately 20 times the MRHD for adults and children based on comparison of the plasma AUCs) caused a dose-related increase in the incidence of smooth muscle hyperplasia, cystic glandular hyperplasia, leiomyomas of the uterus, and cysts in the ovaries. No tumors were seen at 0.2 mg/kg (approximately 3 times the MRHD for adults and children based on comparison of the AUCs).

In a 24-month oral and inhalation carcinogenicity study in Sprague Dawley rats, salmeterol caused a dose-related increase in the incidence of mesovarian leiomyomas and ovarian cysts at doses of 0.68 mg/kg and above (approximately 55 and 25 times the MRHD for adults and children, respectively, on a mg/m² basis). No tumors were seen at 0.21 mg/kg (approximately 15 and 8 times the MRHD for adults and children, respectively, on a mg/m² basis). These findings in rodents are similar to those reported previously for other beta-adrenergic agonist drugs. The relevance of these findings to human use is unknown.

Salmeterol produced no detectable or reproducible increases in microbial and mammalian gene mutation in vitro. No clastogenic activity occurred in vitro in human lymphocytes or in vivo in a rat micronucleus test. No effects on fertility were identified in rats treated with salmeterol at oral doses up to 2 mg/kg (approximately 160 times the MRHD for adults on a mg/m² basis).

Use In Specific Populations

Pregnancy

Teratogenic Effects: Pregnancy Category C. There are no adequate and well-controlled studies with ADVAIR DISKUS in pregnant women. ADVAIR DISKUS was teratogenic in mice and not in rats, although it lowered fetal weight in 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 DISKUS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

ADVAIR DISKUS: In the mouse reproduction assay, fluticasone propionate by the subcutaneous route at a dose approximately 3/5 the maximum recommended human daily inhalation dose (MRHD) on a mg/m² basis combined with oral salmeterol at a dose approximately 410 times the MRHD on a mg/m² basis 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 1/6 the MRHD on a mg/m² basis and oral doses of salmeterol up to approximately 55 times the MRHD on a mg/m² basis. In rats, combining fluticasone propionate subcutaneously at a dose equivalent to the MRHD on a mg/m² basis and an oral dose of salmeterol at approximately 810 times the MRHD on a mg/m² basis 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 mg/m² basis and an oral dose of salmeterol at approximately 80 times the MRHD on a mg/m² basis.

Fluticasone Propionate: Subcutaneous studies in the mouse at a dose less than the MRHD on a mg/m² basis and in the rat at a dose equivalent to the MRHD on a mg/m² basis revealed fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification.

In the rabbit, fetal weight reduction and cleft palate were observed at a subcutaneous dose less than the MRHD on a mg/m² basis. However, no teratogenic effects were reported at oral doses up to approximately 5 times the MRHD on a mg/m² basis. No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration [see CLINICAL PHARMACOLOGY].

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 160 times the MRHD on a mg/m² basis. In Dutch rabbits administered oral doses approximately 50 times the MRHD based on comparison of the AUCs, 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 20 times the MRHD based on comparison of the AUCs.

New Zealand White rabbits were less sensitive since only delayed ossification of the frontal bones was seen at an oral dose approximately 1,600 times the MRHD on a mg/m² basis. Extensive use of other beta-agonists has provided no evidence that these class effects in animals are relevant to their use in humans.

Labor and Delivery

There are no well-controlled human studies that have investigated effects of ADVAIR DISKUS on preterm labor or labor at term. Because of the potential for beta-agonist interference with uterine contractility, use of ADVAIR DISKUS during labor should be restricted to those patients in whom the benefits clearly outweigh the risks.

Nursing Mothers

Plasma levels of salmeterol, a component of ADVAIR DISKUS, after inhaled therapeutic doses are very low. In rats, salmeterol xinafoate is excreted in the milk. There are no data from controlled trials on the use of salmeterol by nursing mothers. It is not known whether fluticasone propionate, a component of ADVAIR DISKUS, 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 DISKUS by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue ADVAIR DISKUS, taking into account the importance of ADVAIR DISKUS to the mother.

Caution should be exercised when ADVAIR DISKUS is administered to a nursing woman.

Pediatric Use

Use of ADVAIR DISKUS 100/50 in patients 4 to 11 years of age is supported by extrapolation of efficacy data from older patients and by safety and efficacy data from a study of ADVAIR DISKUS 100/50 in children with asthma aged 4 to 11 years [see ADVERSE REACTIONS, Clinical Studies]. The safety and effectiveness of ADVAIR DISKUS in children with asthma less than 4 years of age have not been established.

Inhaled corticosteroids, 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 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 8.5 years of age, the mean age of children in this study, the range for expected growth velocity is: boys - 3rd percentile = 3.8 cm/year, 50th percentile = 5.4 cm/year, and 97th percentile = 7.0 cm/year; girls - 3rd percentile = 4.2 cm/year, 50th percentile = 5.7 cm/year, and 97th percentile = 7.3 cm/year. The clinical relevance of these growth data is not certain.

If a child or adolescent on any corticosteroid appears to have growth suppression, the possibility that he/she is particularly sensitive to this effect of corticosteroids should be considered. The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained. To minimize the systemic effects of orally inhaled corticosteroids, including ADVAIR DISKUS, each patient should be titrated to the lowest strength that effectively controls his/her asthma [see DOSAGE AND ADMINISTRATION].

Geriatric Use

Clinical studies of ADVAIR DISKUS for asthma did not include sufficient numbers of patients aged 65 years and older to determine whether older patients with asthma respond differently than younger patients.

Of the total number of patients in clinical studies receiving ADVAIR DISKUS for COPD, 1,621 were 65 years of age or older and 379 were 75 years of age or older. Patients with COPD 65 years of age and older had a higher incidence of serious adverse events compared with patients less than 65 years of age. Although the distribution of adverse events was similar in the 2 age-groups, patients over 65 years of age experienced more severe events. In two 1-year studies, the excess risk of pneumonia that was seen in patients treated with ADVAIR DISKUS compared with those treated with salmeterol was greater in patients over 65 years of age than in patients less than 65 years of age [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 patients with COPD (aged 40 to 82 years) given 250 or 500 mcg twice daily.

Hepatic Impairment

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.

Renal Impairment

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.

No deaths occurred in rats given an inhaled single-dose combination of salmeterol 3.6 mg/kg (approximately 290 and 140 times the MRHD for adults and children, respectively, on a mg/m² basis) and 1.9 mg/kg of fluticasone propionate (approximately 15 and 35 times the MRHD for adults and children, respectively, on a mg/m² basis).

Fluticasone Propionate: Chronic overdosage with 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 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.

No deaths were seen in mice given an oral dose of 1,000 mg/kg (4,100 and 9,600 times the MRHD dose for adults and children, respectively, on a mg/m² basis). No deaths were seen in rats given an oral dose of 1,000 mg/kg (8,100 and 19,200 times the MRHD for adults and children, respectively, on a mg/m² basis).

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.

No deaths were seen in rats given salmeterol at an inhalation dose of 2.9 mg/kg (approximately 240 and 110 times the MRHD for adults and children, respectively, on a mg/m² basis) and in dogs at an inhalation dose of 0.7 mg/kg (approximately 190 and 90 times the MRHD for adults and children, respectively, on a mg/m² basis). By the oral route, no deaths occurred in mice at 150 mg/kg (approximately 6,100 and 2,900 times the MRHD for adults and children, respectively, on a mg/m² basis) and in rats at 1,000 mg/kg (approximately 81,000 and 38,000 times the MRHD for adults and children, respectively, on a mg/m² basis).

The use of ADVAIR DISKUS is contraindicated in the following conditions:

Primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required. Severe hypersensitivity to milk proteins [see WARNINGS and PRECAUTIONS, DESCRIPTION].

Mechanism of Action

ADVAIR DISKUS: Since ADVAIR DISKUS contains both fluticasone propionate and salmeterol, the mechanisms of action described below for the individual components apply to ADVAIR DISKUS. These drugs represent 2 classes of medications (a synthetic corticosteroid and a selective, long-acting beta-adrenergic receptor agonist) that have different effects on clinical and physiological indices.

Fluticasone Propionate: Fluticasone propionate is a synthetic trifluorinated corticosteroid with potent anti-inflammatory activity. In vitro assays using human lung cytosol preparations have established fluticasone propionate as a human glucocorticoid receptor agonist with an affinity 18 times greater than dexamethasone, almost twice that of beclomethasone-17-monopropionate (BMP), the active metabolite of beclomethasone dipropionate, and over 3 times that of budesonide. Data from the McKenzie vasoconstrictor assay in man are consistent with these results.

Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to inhibit multiple cell types (e.g., mast cells, eosinophils, basophils, lymphocytes, macrophages, neutrophils) and mediator production or secretion (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in the asthmatic response. These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma.

Inflammation is also a component in the pathogenesis of COPD. In contrast to asthma, however, the predominant inflammatory cells in COPD include neutrophils, CD8+ T-lymphocytes, and macrophages. The effects of corticosteroids in the treatment of COPD are not well defined and inhaled corticosteroids and fluticasone propionate when used apart from ADVAIR DISKUS are not indicated for the treatment of COPD.

Salmeterol Xinafoate: Salmeterol is a selective, long-acting beta₂-adrenergic agonist. In vitro studies show salmeterol to be at least 50 times more selective for beta₂-adrenoceptors than albuterol. Although beta₂-adrenoceptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-adrenoceptors are the predominant receptors in the heart, there are also beta₂-adrenoceptors in the human heart comprising 10% to 50% of the total beta-adrenoceptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta₂-agonists may have cardiac effects.

The pharmacologic effects of beta₂-adrenoceptor agonist drugs, including salmeterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3',5' -adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

In vitro tests show that salmeterol is a potent and long-lasting inhibitor of the release of mast cell mediators, such as histamine, leukotrienes, and prostaglandin D₂, from human lung.

Salmeterol inhibits histamine-induced plasma protein extravasation and inhibits platelet-activating factor-induced eosinophil accumulation in the lungs of guinea pigs when administered by the inhaled route. In humans, single doses of salmeterol administered via inhalation aerosol attenuate allergen-induced bronchial hyper-responsiveness.

Pharmacodynamics

ADVAIR DISKUS: Healthy Subjects: Cardiovascular Effects: Since systemic pharmacodynamic effects of salmeterol are not normally seen at the therapeutic dose, higher doses were used to produce measurable effects. Four (4) studies were conducted in healthy adult subjects: (1) a single-dose crossover study using 2 inhalations of ADVAIR DISKUS 500/50, fluticasone propionate powder 500 mcg and salmeterol powder 50 mcg given concurrently, or fluticasone propionate powder 500 mcg given alone, (2) a cumulative dose study using 50 to 400 mcg of salmeterol powder given alone or as ADVAIR DISKUS 500/50, (3) a repeat-dose study for 11 days using 2 inhalations twice daily of ADVAIR DISKUS 250/50, fluticasone propionate powder 250 mcg, or salmeterol powder 50 mcg, and (4) a single-dose study using 5 inhalations of ADVAIR DISKUS 100/50, fluticasone propionate powder 100 mcg alone, or placebo. In these studies no significant differences were observed in the pharmacodynamic effects of salmeterol (pulse rate, blood pressure, QTc interval, potassium, and glucose) whether the salmeterol was given as ADVAIR DISKUS, concurrently with fluticasone propionate from separate inhalers, or as salmeterol alone. The systemic pharmacodynamic effects of salmeterol were not altered by the presence of fluticasone propionate in ADVAIR DISKUS. The potential effect of salmeterol on the effects of fluticasone propionate on the HPA axis was also evaluated in these studies.

HPA Axis Effects: No significant differences across treatments were observed in 24-hour urinary cortisol excretion and, where measured, 24-hour plasma cortisol AUC. The systemic pharmacodynamic effects of fluticasone propionate were not altered by the presence of salmeterol in ADVAIR DISKUS in healthy subjects.

Asthma: Adults and Adolescent Patients: Cardiovascular Effects: In clinical studies with ADVAIR DISKUS in adult and adolescent patients 12 years of age and older with asthma, no significant differences were observed in the systemic pharmacodynamic effects of salmeterol (pulse rate, blood pressure, QTc interval, potassium, and glucose) whether the salmeterol was given alone or as ADVAIR DISKUS. In 72 adolescent and adult patients with asthma given either ADVAIR DISKUS 100/50 or ADVAIR DISKUS 250/50, continuous 24-hour electrocardiographic monitoring was performed after the first dose and after 12 weeks of therapy, and no clinically significant dysrhythmias were noted.

HPA Axis Effects: In a 28-week study in adolescent and adult patients with asthma, ADVAIR DISKUS 500/50 twice daily was compared with the concurrent use of salmeterol powder 50 mcg plus fluticasone propionate powder 500 mcg from separate inhalers or fluticasone propionate powder 500 mcg alone. No significant differences across treatments were observed in serum cortisol AUC after 12 weeks of dosing or in 24-hour urinary cortisol excretion after 12 and 28 weeks.

In a 12-week study in adolescent and adult patients with asthma, ADVAIR DISKUS 250/50 twice daily was compared with fluticasone propionate powder 250 mcg alone, salmeterol powder 50 mcg alone, and placebo. For most patients, the ability to increase cortisol production in response to stress, as assessed by 30-minute cosyntropin stimulation, remained intact with ADVAIR DISKUS. One patient (3%) who received ADVAIR DISKUS 250/50 had an abnormal response (peak serum cortisol < 18 mcg/dL) after dosing, compared with 2 patients (6%) who received placebo, 2 patients (6%) who received fluticasone propionate 250 mcg, and no patients who received salmeterol.

In a repeat-dose, 3-way crossover study, 1 inhalation twice daily of ADVAIR DISKUS 100/50, FLOVENT® DISKUS® 100 mcg (fluticasone propionate inhalation powder, 100 mcg), or placebo was administered to 20 adolescent and adult patients with asthma. After 28 days of treatment, geometric mean serum cortisol AUC over 12 hours showed no significant difference between ADVAIR DISKUS and FLOVENT DISKUS or between either active treatment and placebo.

Pediatric Patients: HPA Axis Effects: In a 12-week study in patients with asthma aged 4 to 11 years who were receiving inhaled corticosteroids at study entry, ADVAIR DISKUS 100/50 twice daily was compared with fluticasone propionate inhalation powder 100 mcg administered twice daily via the DISKUS. The values for 24-hour urinary cortisol excretion at study entry and after 12 weeks of treatment were similar within each treatment group. After 12 weeks, 24-hour urinary cortisol excretion was also similar between the 2 groups.

Chronic Obstructive Pulmonary Disease: Cardiovascular Effects: In clinical studies with ADVAIR DISKUS in patients with COPD, no significant differences were seen in pulse rate, blood pressure, potassium, and glucose between ADVAIR DISKUS, the individual components of ADVAIR DISKUS, and placebo. In a study of ADVAIR DISKUS 250/50, 8 patients (2 [1.1%] in the group given ADVAIR DISKUS 250/50, 1 [0.5%] in the fluticasone propionate 250-mcg group, 3 [1.7%] in the salmeterol group, and 2 [1.1%] in the placebo group) had QTc intervals > 470 msec at least 1 time during the treatment period. Five (5) of these 8 patients had a prolonged QTc interval at baseline.

In a 24-week study, 130 patients with COPD received continuous 24-hour electrocardiographic monitoring prior to the first dose and after 4 weeks of twice-daily treatment with either ADVAIR DISKUS 500/50, fluticasone propionate powder 500 mcg, salmeterol powder 50 mcg, or placebo. No significant differences in ventricular or supraventricular arrhythmias and heart rate were observed among the groups treated with ADVAIR DISKUS 500/50, the individual components, or placebo. One (1) subject in the fluticasone propionate group experienced atrial flutter/atrial fibrillation, and 1 subject in the group given ADVAIR DISKUS 500/50 experienced heart block. There were 3 cases of nonsustained ventricular tachycardia (1 each in the placebo, salmeterol, and fluticasone propionate 500-mcg treatment groups).

In 24-week clinical studies in patients with COPD, the incidence of clinically significant electrocardiogram (ECG) abnormalities (myocardial ischemia, ventricular hypertrophy, clinically significant conduction abnormalities, clinically significant arrhythmias) was lower for patients who received salmeterol (1%, 9 of 688 patients who received either salmeterol 50 mcg or ADVAIR DISKUS) compared with placebo (3%, 10 of 370 patients).

No significant differences with salmeterol 50 mcg alone or in combination with fluticasone propionate as ADVAIR DISKUS 500/50 were observed on pulse rate and systolic and diastolic blood pressure in a subset of patients with COPD who underwent 12-hour serial vital sign measurements after the first dose (N = 183) and after 12 weeks of therapy (N = 149). Median changes from baseline in pulse rate and systolic and diastolic blood pressure were similar to those seen with placebo.

HPA Axis Effects: Short-cosyntropin stimulation testing was performed both at Day 1 and Endpoint in 101 patients with COPD receiving twice-daily ADVAIR DISKUS 250/50, fluticasone propionate powder 250 mcg, salmeterol powder 50 mcg, or placebo. For most patients, the ability to increase cortisol production in response to stress, as assessed by short cosyntropin stimulation, remained intact with ADVAIR DISKUS 250/50. One (1) patient (3%) who received ADVAIR DISKUS 250/50 had an abnormal stimulated cortisol response (peak cortisol < 14.5 mcg/dL assessed by high-performance liquid chromatography) after dosing, compared with 2 patients (9%) who received fluticasone propionate 250 mcg, 2 patients (7%) who received salmeterol 50 mcg, and 1 patient (4%) who received placebo following 24 weeks of treatment or early discontinuation from study.

After 36 weeks of dosing, serum cortisol concentrations in a subset of patients with COPD (n = 83) were 22% lower in patients receiving ADVAIR