Advair

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Black, tarry stools
• blindness
• blurred vision
• burning, tingling, numbness, or pain in the hands, arms, feet, or legs
• chills
• cough
• decreased vision
• difficulty with breathing or swallowing
• eye pain
• fast heartbeat
• fever
• headache
• hives or welts, skin itching, rash, or redness
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• nausea or vomiting
• noisy breathing
• painful or difficult urination
• sensation of pins and needles
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• stabbing pain in the arms or legs
• swelling of the face, throat, or tongue
• swollen glands
• tearing
• unusual bleeding or bruising

• Abdominal or stomach pain
• backache
• bruising
• darkening of the skin
• decrease in height
• diarrhea
• difficulty with moving
• dizziness
• facial hair growth in females
• fainting
• fast, slow, pounding, or irregular heartbeat or pulse
• flushed, dry skin
• fractures
• fruit-like breath odor
• full or round face, neck, or trunk
• heavy bleeding
• increased hunger
• increased thirst or urination
• irritability
• large, flat, blue, or purplish patches in the skin
• loss of sexual desire or ability
• menstrual irregularities
• mental depression
• muscle pain or stiffness
• muscle wasting
• pain in the back, ribs, arms, or legs
• pain in the joints
• sweating
• troubled breathing
• unexplained weight loss
• unusual tiredness or weakness
• weight gain

Get emergency help immediately if any of the following symptoms of overdose occur:

• Chest pain or tightness
• confusion
• convulsions (seizures)
• decreased urine output
• dry mouth
• faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• general feeling of discomfort or illness
• high blood pressure
• loss of appetite
• mood changes
• nervousness
• numbness or tingling in the hands, feet, or lips
• sudden sweating
• tremors
• trouble with sleeping

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Body aches or pain
• choking
• congestion
• dryness of the throat
• high-pitched noise when breathing
• hoarseness
• runny nose
• sneezing
• trouble with swallowing
• voice changes

• Cough-producing mucus
• flu-like symptoms
• irritation or inflammation of the eye
• muscle pain
• pain or tenderness around the eyes and cheekbones
• sleep disorders
• stuffy nose
• white patches in the mouth or throat or on the tongue

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Inhalation Aerosol. Purple plastic inhaler with a light purple strapcap containing a pressurized metered-dose aerosol canister containing 60 or 120 metered inhalations and fitted with a counter. Each actuation delivers a combination of fluticasone propionate (45, 115, or 230 mcg) and salmeterol (21 mcg) from the mouthpiece.

The use of Advair HFA is contraindicated in the following conditions:

Asthma-Related Death

LABA, such as salmeterol, one of the active ingredients in Advair HFA, increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma, physicians should only prescribe Advair HFA for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Advair HFA) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use Advair HFA for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.

A large placebo-controlled U.S. trial that compared the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol. The Salmeterol Multicenter Asthma Research Trial (SMART) was a randomized double-blind trial that enrolled LABA-naive subjects with asthma to assess the safety of salmeterol 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 subjects had been enrolled (N = 26,355), which led to premature termination of the trial. The results of the interim analysis showed that subjects receiving salmeterol were at increased risk for fatal asthma events (Table 1 and Figure 1). In the total population, a higher rate of asthma-related death occurred in subjects treated with salmeterol than those treated with placebo (0.10% versus 0.02%; relative risk: 4.37 [95% CI: 1.25, 15.34]).

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

Post hoc analyses in pediatric subjects aged 12 to 18 years were also performed. Pediatric subjects accounted for approximately 12% of subjects in each treatment arm. Respiratory-related death or life-threatening experience occurred at a similar rate in the salmeterol group (0.12% [2/1,653]) and the placebo group (0.12% [2/1,622]; relative risk: 1.0 [95% CI: 0.1, 7.2]). All-cause hospitalization, however, was increased in the salmeterol group (2% [35/1,653]) versus the placebo group (less than 1% [16/1,622]; relative risk: 2.1 [95% CI: 1.1, 3.7]).

The data from the SMART trial are not adequate to determine whether concurrent use of inhaled corticosteroids, such as fluticasone propionate, the other active ingredient in Advair HFA, or other long-term asthma control therapy mitigates the risk of asthma-related death.

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

a Life-table 28-week estimate, adjusted according to the subjects’ actual lengths of exposure to trial treatment to account for early withdrawal of subjects from the trial.

b Relative risk is the ratio of the rate of asthma-related death in the salmeterol group and the rate in the placebo group. The relative risk indicates how many more times likely an asthma-related death occurred in the salmeterol group than in the placebo group in a 28-week treatment period.

c Estimate of the number of additional asthma-related deaths in subjects treated with salmeterol in SMART, assuming 10,000 subjects received salmeterol for a 28-week treatment period. Estimate calculated as the difference between the salmeterol and placebo groups in the rates of asthma-related death multiplied by 10,000.

d The total population includes the following ethnic origins listed on the case report form: Caucasian, African American, Hispanic, Asian, and “Other.” In addition, the total population includes those subjects 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 Multicenter Asthma Research Trial (SMART), by Duration of Treatment

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

Deterioration of Disease and Acute Episodes

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

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

Increasing use of inhaled, short-acting beta2-agonists is a marker of deteriorating asthma. In this situation, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the possible need for replacing the current strength of Advair HFA with a higher strength, adding additional inhaled corticosteroid, or initiating systemic corticosteroids. Patients should not use more than 2 inhalations twice daily of Advair HFA.

Advair HFA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. Advair HFA has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist.

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

Excessive Use of Advair HFA and Use with Other Long-acting Beta2-agonists

Advair HFA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using Advair HFA should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.

Local Effects of Inhaled Corticosteroids

In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with Advair HFA. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with Advair HFA continues, but at times therapy with Advair HFA may need to be interrupted. Advise the patient to rinse his/her mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.

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 trials in 1,579 subjects with COPD, there was a higher incidence of pneumonia reported in subjects receiving Advair DISKUS 250/50 (7%) than in those receiving salmeterol 50 mcg (3%). The incidence of pneumonia in the subjects treated with Advair DISKUS was higher in subjects older than 65 years (9%) compared with the incidence in subjects younger than 65 years (4%).

In a 3-year trial in 6,184 subjects with COPD, there was a higher incidence of pneumonia reported in subjects receiving Advair DISKUS 500/50 compared with placebo (16% with Advair DISKUS 500/50, 14% with fluticasone propionate 500 mcg, 11% with salmeterol 50 mcg, and 9% with placebo). Similar to what was seen in the 1-year trials with Advair DISKUS 250/50, the incidence of pneumonia was higher in subjects older than 65 years (18% with Advair DISKUS 500/50 versus 10% with placebo) compared with subjects younger than 65 years (14% with Advair DISKUS 500/50 versus 8% with placebo).

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

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

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

Transfer of patients from systemic corticosteroid therapy to Advair HFA may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions).

During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function.

Hypercorticism and Adrenal Suppression

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

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

It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects. If such effects occur, Advair HFA should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and other treatments for management of asthma symptoms should be considered.

Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors

The use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with Advair HFA is not recommended because increased systemic corticosteroid and increased cardiovascular adverse effects may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

Paradoxical Bronchospasm and Upper Airway Symptoms

As with other inhaled medicines, Advair HFA can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with Advair HFA, it should be treated immediately with an inhaled, short-acting bronchodilator; Advair HFA should be discontinued immediately; and alternative therapy should be instituted. Upper airway symptoms of laryngeal spasm, irritation, or swelling, such as stridor and choking, have been reported in patients receiving Advair HFA.

Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of Advair HFA [see Contraindications (4)].

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.

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, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids), should be monitored and treated with established standards of care.

2-Year Fluticasone Propionate Trial

A 2-year trial in 160 subjects (females aged 18 to 40 years, males 18 to 50) with asthma receiving chlorofluorocarbon (CFC)-propelled fluticasone propionate inhalation aerosol 88 or 440 mcg twice daily demonstrated no statistically significant changes in BMD at any time point (24, 52, 76, and 104 weeks of double-blind treatment) as assessed by dual-energy x-ray absorptiometry at lumbar regions L1 through L4.

Effect on Growth

Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth of pediatric patients receiving Advair HFA routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including Advair HFA, titrate each patient’s dosage to the lowest dosage that effectively controls his/her symptoms [see Dosage and Administration (2), Use in Specific Populations (8.4)].

Glaucoma and Cataracts

Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with asthma following the long-term administration of inhaled corticosteroids, including fluticasone propionate, a component of Advair HFA. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.

Eosinophilic Conditions and Churg-Strauss Syndrome

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

Coexisting Conditions

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

Hypokalemia and Hyperglycemia

Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects [see Clinical Pharmacology (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 trials with Advair HFA at recommended doses.

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:

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 HFA 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 C25H37NO4•C11H8O3. It is freely soluble in methanol; slightly soluble in ethanol, chloroform, and isopropanol; and sparingly soluble in water.

Advair HFA is a purple plastic inhaler with a light purple strapcap containing a pressurized metered-dose aerosol canister fitted with a counter. Each canister contains a microcrystalline suspension of micronized fluticasone propionate and micronized salmeterol xinafoate in propellant HFA-134a (1,1,1,2-tetrafluoroethane). It contains no other excipients.

After priming, each actuation of the inhaler delivers 50, 125, or 250 mcg of fluticasone propionate and 25 mcg of salmeterol in 75 mg of suspension from the valve. Each actuation delivers 45, 115, or 230 mcg of fluticasone propionate and 21 mcg of salmeterol from the actuator. Twenty-one micrograms (21 mcg) of salmeterol base is equivalent to 30.45 mcg of salmeterol xinafoate. The actual amount of drug delivered to the lung will depend on patient factors, such as the coordination between the actuation of the inhaler and inspiration through the delivery system.

Prime Advair HFA before using for the first time by releasing 4 sprays into the air away from the face, shaking well for 5 seconds before each spray. In cases where the inhaler has not been used for more than 4 weeks or when it has been dropped, prime the inhaler again by releasing 2 sprays into the air away from the face, shaking well for 5 seconds before each spray.

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 5 times the MRHDID on a mg/m2 basis) for 78 weeks or in rats at inhalation doses up to 57 mcg/kg (less than the MRHDID on a mg/m2 basis) for 104 weeks.

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

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

Salmeterol

In an 18-month carcinogenicity study in CD-mice, salmeterol at oral doses of 1.4 mg/kg and above (approximately 10 times the MRHDID based on comparison of the plasma AUCs) caused a dose-related increase in the incidence of smooth muscle hyperplasia, cystic glandular hyperplasia, leiomyomas of the uterus, and ovarian cysts. No tumors were seen at 0.2 mg/kg (approximately 2 times the MRHDID for adults based on comparison of the AUCs).

In a 24-month oral and inhalation carcinogenicity study in Sprague Dawley rats, salmeterol caused a dose-related increase in the incidence of mesovarian leiomyomas and ovarian cysts at doses of 0.68 mg/kg and above (approximately 80 times the MRHDID on a mg/m2 basis). No tumors were seen at 0.21 mg/kg (approximately 25 times the MRHDID on a mg/m2 basis). These findings in rodents are similar to those reported previously for other beta-adrenergic agonist drugs. The relevance of these findings to human use is unknown.

Salmeterol produced no detectable or reproducible increases in microbial and mammalian gene mutation in vitro. No clastogenic activity occurred in vitro in human lymphocytes or in vivo in a rat micronucleus test. No effects on fertility were identified in rats treated with salmeterol at oral doses up to 2 mg/kg (approximately 230 times the MRHDID on a mg/m2 basis).

Animal Toxicology and/or Pharmacology

Preclinical

Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. The clinical relevance of these findings is unknown.

Propellant HFA-134a

In animals and humans, propellant HFA-134a was found to be rapidly absorbed and rapidly eliminated, with an elimination half-life of 3 to 27 minutes in animals and 5 to 7 minutes in humans. Time to maximum plasma concentration (Tmax) and mean residence time are both extremely short, leading to a transient appearance of HFA-134a in the blood with no evidence of accumulation.

Propellant HFA-134a is devoid of pharmacological activity except at very high doses in animals (i.e., 380 to 1,300 times the maximum human exposure based on comparisons of area under the plasma concentration versus time curve [AUC] values), primarily producing ataxia, tremors, dyspnea, or salivation. These events are similar to effects produced by the structurally related CFCs, which have been used extensively in metered-dose inhalers. In drug interaction studies in male and female dogs, there was a slight increase in the salmeterol-related effect on heart rate (a known effect of beta2-agonists) when given in combination with high doses of fluticasone propionate. This effect was not observed in clinical trials.

You should not use Advair if you are allergic to fluticasone, salmeterol, or milk proteins.

Advair is not a rescue medicine. It will not work fast enough to treat an asthma or bronchospasm attack.

Salmeterol may increase the risk of death in people with asthma, but the risk in people with COPD is not known. Use only the prescribed dose of Advair, and do not use it for longer than your doctor recommends. Follow all patient instructions for safe use. Talk with your doctor about your individual risks and benefits of using Advair.

Usual Adult Dose of Advair for Chronic Obstructive Pulmonary Disease - Maintenance:

Fluticasone 250 mcg-salmeterol 50 mcg (1 inhalation) orally twice a day, approximately 12 hours apart

Comments:
-If shortness of breath occurs in the period between doses, use an inhaled, short-acting beta2-agonist for immediate relief.
-Fluticasone 250 mcg-salmeterol 50 mcg is the only approved dosage for the treatment of COPD; higher doses are not recommended, as advantage of the higher strength has not been demonstrated.

Uses: Maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema; to reduce exacerbations of COPD in patients with a history of exacerbations

Usual Adult Dose of Advair for Asthma - Maintenance:

Inhalation Powder:
-1 inhalation of fluticasone 100 mcg-salmeterol 50 mcg, fluticasone 250 mcg-salmeterol 50 mcg, or fluticasone 500 mcg-salmeterol 50 mcg orally twice a day
-Maximum dose: Fluticasone 500 mcg-salmeterol 50 mcg orally twice a day

Inhalation Aerosol:
-2 inhalations of fluticasone 45 mcg-salmeterol 21 mcg, fluticasone 115 mcg-salmeterol 21 mcg, or fluticasone 230 mcg-salmeterol 21 mcg orally twice a day
-Maximum dose: Fluticasone 230 mcg-salmeterol 31 mcg orally twice a day

Comments:
-Inhalations should be administered approximately 12 hours apart.
-Initial dose should be based on the patient's asthma severity.
-If shortness of breath occurs in the period between doses, use an inhaled, short-acting beta2-agonist for immediate relief.
-Improvement in asthma control occurs within 30 minutes of beginning treatment; maximum benefit can take 1 week or longer.
-The inhalation dose can be increased if response does not improve after 2 weeks of therapy.
-If previously effective dose fails to improve asthma control, reevaluate treatment and consider additional therapies (e.g., adding additional inhaled or oral corticosteroid).

Uses: Treatment of asthma in patients not adequately controlled on a long term asthma control medication such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA

Usual Pediatric Dose of Advair for Asthma - Maintenance:

Inhalation Powder:
Less than 4 years: Not recommended.

4 years to 11 years:
-Fluticasone 100 mcg-salmeterol 50 mcg (1 inhalation) orally twice a day

12 years or older:
-1 inhalation of fluticasone 100 mcg-salmeterol 50 mcg, fluticasone 250 mcg-salmeterol 50 mcg, or fluticasone 500 mcg-salmeterol 50 mcg orally twice a day
-Maximum dose: Fluticasone 500 mcg-salmeterol 50 mcg orally twice a day

Inhalation Aerosol:
Less than 12 years: Use is not approved.

12 years and older:
-2 inhalations of fluticasone 45 mcg-salmeterol 21 mcg, fluticasone 115 mcg-salmeterol 21 mcg, or fluticasone 230 mcg-salmeterol 21 mcg orally twice a day

Comments:
-Inhalations should be administered approximately 12 hours apart.
-Initial dose should be based on the patient's asthma severity.
-If shortness of breath occurs in the period between doses, use an inhaled, short-acting beta2-agonist for immediate relief.
-Improvement in asthma control occurs within 30 minutes of beginning treatment; maximum benefit can take 1 week or longer.
-The dose can be increased if response does not improve after 2 weeks of therapy.
-If previously effective dose fails to improve asthma control, reevaluate treatment and consider additional therapies (e.g., adding additional inhaled or oral corticosteroid).

Uses: Treatment of asthma in patients not adequately controlled on a long term asthma control medication such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA

Do not use a second inhaled bronchodilator unless your doctor tells you to. This includes formoterol (Foradil, Perforomist, Symbicort, Dulera), arformoterol (Brovana), indacaterol (Arcapta), olodaterol (Striverdi, Stiolto Respimat), salmeterol (Serevent), or vilanterol (Bree Ellipta, Anoro Ellipta).

Avoid being near people who are sick or have infections. Call your doctor for preventive treatment if you are exposed to chicken pox or measles. These conditions can be serious or even fatal in people who are using steroid medicine.

Corticosteroids and beta2-agonists have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. In mouse reproduction assays, fluticasone propionate by the subcutaneous route at a dose approximately 3/5 the maximum recommended human daily inhalation dose (MRHDID) combined with oral salmeterol at a dose approximately 410 times the MRHDID 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 MRHDID and doses of salmeterol up to approximately 55 times the MRHDID. In rats, combining fluticasone propionate subcutaneously at a dose equivalent to the MRHDID and a dose of salmeterol at approximately 810 times the MRHDID produced decreased fetal weight, umbilical hernia, delayed ossification, and changes in the occipital bone. These effects were not seen when combining fluticasone propionate subcutaneously at a dose less than the MRHDID and an oral dose of salmeterol at approximately 80 times the MRHDID. There are no controlled data in human pregnancy. AU TGA pregnancy category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans. US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

This drug should not be used during pregnancy unless the benefit outweighs the risk to the fetus. AU TGA pregnancy category: B3 US FDA pregnancy category: C Comments: Patients should contact their physician if pregnancy occurs while taking this drug. If needed, the lowest effective dose of this drug should be used.