ADVAIR 250 DISKUS and ADVAIR 500 DISKUS are indicated for:

• the maintenance treatment of COPD, including emphysema and chronic bronchitis, in patients where the use of a combination product is considered appropriate.

  
  

 

ADVAIR DISKUS should not be used as a rescue medication.

Physicians should reassess patients several months after the initiation of ADVAIR DISKUS and if symptomatic improvement has not occurred, ADVAIR DISKUS should be discontinued.

There is no need to adjust the dose in elderly patients.

At present, there is insufficient clinical data to recommend the use of ADVAIR DISKUS in children younger than 4 years of age and the use of ADVAIR inhalation aerosol in children younger than 12 years of age.

• Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see Dosage Forms, Composition and Packaging.

  
  

• Patients with IgE mediated allergic reactions to lactose (which contains milk protein) or milk (ADVAIR DISKUS users only).

  
  

• Patients with cardiac tachyarrhythmias.

  
  

• Patients with untreated fungal, bacterial or tuberculous infections of the respiratory tract.

  
  

• In the primary treatment of status asthmaticus or other acute episodes of asthma, or in patients with moderate to severe bronchiectasis.

  
  

ADVAIR (salmeterol xinafoate/fluticasone propionate) should not be used to treat acute symptoms of asthma. It is crucial to inform patients of this and prescribe rapid onset, short duration inhaled bronchodilator (e.g., salbutamol) to relieve the acute symptoms of asthma. Patients should be clearly instructed to use rapid onset, short duration, inhaled beta₂-agonists only for symptomatic relief if they develop asthma symptoms while taking ADVAIR. When beginning treatment with ADVAIR, patients who have been taking rapid onset, short duration, inhaled beta₂-agonists on a regular basis (e.g., q.i.d) should be instructed to discontinue the regular use of these drugs and use them only for symptomatic relief if they develop acute symptoms of asthma while taking ADVAIR.

Treatment with inhaled corticosteroids should not be stopped abruptly in patients with asthma due to risk of exacerbation. In this case, therapy should be titrated down gradually, under physician supervision. For patients with COPD, cessation of therapy may be associated with symptomatic decompensation and should be supervised by a physician.

Although clinically not significant, a small increase in QTc interval has been reported with therapeutic doses of salmeterol. It is not known if this becomes clinically significant when concomitant medications causing similar effects are prescribed and/or in the presence of heart diseases, hypokalemia, or hypoxia. 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 following excessive use of aerosol preparations containing sympathomimetic amines, the exact cause of which is unknown. Cardiac arrest was reported in several instances.

No clinically significant effect on the cardiovascular system is usually seen after the administration of inhaled salmeterol in recommended doses. Cardiovascular effects such as increased blood pressure and heart rate may occasionally be seen with all sympathomimetic drugs, especially at higher than therapeutic doses. Central nervous system effects (increased excitement) can occur after the use of salmeterol. Occurrence of cardiovascular or central nervous system effects may require discontinuation of the drug.

For this reason, salmeterol—fluticasone propionate, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; in patients with convulsive disorders or thyrotoxicosis; and in patients who are unusually responsive to sympathomimetic amines.

In individual patients any beta₂-adrenergic agonist may have a clinically significant cardiac effect. As has been described with other beta-adrenergic agonist bronchodilators, clinically significant changes in systolic and/or diastolic blood pressure, pulse rate, and electrocardiograms have been seen infrequently in individual patients in controlled clinical studies with salmeterol.

Symptoms of laryngeal spasm, irritation, or swelling, such as stridor and choking, have been reported rarely in patients receiving salmeterol.

Also see Immune, Candidiasis.

Particular care is needed in patients who are transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer. For the transfer of patients being treated with oral corticosteroids, inhaled corticosteroids should first be added to the existing oral steroid therapy which is then gradually withdrawn.

Patients with adrenocortical suppression should be monitored regularly and the oral steroid reduced cautiously. Some patients transferred from other inhaled steroids or oral steroids remain at risk of impaired adrenal reserve for a considerable time after transferring to inhaled fluticasone propionate.

After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery or infections, particularly gastroenteritis. Although inhaled fluticasone propionate may provide control of asthmatic symptoms during these episodes, it does not provide the systemic steroid which is necessary for coping with these emergencies. The physician may consider supplying oral steroids for use in times of stress (e.g. worsening asthma attacks, chest infections, and surgery).

During periods of stress or a severe asthmatic attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume systemic steroids immediately and to contact their physician for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic steroids during periods of stress or a severe asthma attack. To assess the risk of adrenal insufficiency in emergency situations, routine tests of adrenal cortical function, including measurement of early morning and evening cortisol levels, should be performed periodically in all patients. An early morning resting cortisol level may be accepted as normal only if it falls at or near the normal mean level.

Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods; these effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, and adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma. It is important therefore, that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control is maintained (see Monitoring and Laboratory Tests).

The long-term effects of fluticasone propionate in human subjects are still unknown. The local effect of the drug on developmental or immunologic processes in the mouth, pharynx, trachea, and lungs is unknown. There is also no information about the possible long-term systemic effects of the agent (see Monitoring and Laboratory Tests).

Long-term use of orally inhaled corticosteroids may affect normal bone metabolism resulting in a loss of bone mineral density. In patients with major risk factors for decreased bone mineral content, such as chronic alcohol use, tobacco use, age, sedentary lifestyle, strong family history of osteoporosis, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants and corticosteroids), ADVAIR may pose an additional risk. Long-term treatment effects of fluticasone propionate on bone mineral density in the COPD population have not been studied.

Doses of the related beta₂-adrenoceptor agonist salbutamol, when administered intravenously, have been reported to aggravate pre-existing diabetes mellitus and ketoacidosis. Administration of beta₂-adrenoceptor agonists may cause a decrease in serum potassium, possibly through intracellular shunting, which has the potential to increase the likelihood of arrhythmias. The effect is usually seen at higher therapeutic doses and the decrease is usually transient, not requiring supplementation. Therefore, salmeterol/fluticasone propionate should be used with caution in patients predisposed to low levels of serum potassium.

The possibility of impaired adrenal response should always be borne in mind in emergency and elective situations likely to produce stress and appropriate corticosteroid treatment must be considered.

Certain individuals can show greater susceptibility to the effects of inhaled corticosteroid than do most patients.

In common with other beta-adrenergic agents, salmeterol can induce reversible metabolic changes (hyperglycemia, hypokalemia). There have been very rare reports of increases in blood glucose levels and this should be considered when prescribing to patients with a history of diabetes mellitus.

There is an enhanced effect of corticosteroids on patients with hypothyroidism.

In rare cases, patients on inhaled fluticasone propionate may present with systemic eosinophilic conditions, with some patients presenting with 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.

There is an enhanced effect of corticosteroids on patients with cirrhosis.

Immediate hypersensitivity reactions may occur after administration of salmeterol, as demonstrated by rare cases of urticaria, angioedema, rash and bronchospasm, and very rare cases of anaphylactic reactions, anaphylactic shock.

Therapeutic dosages of fluticasone propionate frequently cause the appearance of C. albicans (thrush) in the mouth and throat. The development of pharyngeal and laryngeal candidiasis is a cause for concern because the extent of its penetration into the respiratory tract is unknown. Patients may find it helpful to rinse the mouth and gargle with water after using ADVAIR. Symptomatic candidiasis can be treated with topical anti-fungal therapy while continuing to use ADVAIR.

Corticosteroids may mask some signs of infection and new infections may appear. A decreased resistance to localised infection has been observed during corticosteroid therapy. This may require treatment with appropriate therapy or stopping the administration of fluticasone propionate until the infection is eradicated. Patients who are on 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 on corticosteroids. In such children or adults who have not had these diseases, 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 exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with intramuscular pooled immunoglobulin (IG) may be indicated. If chickenpox develops, treatment with antiviral agents may be considered.

For patients with asthma or COPD, consideration should be given to additional corticosteroid therapy and to antibiotics if an exacerbation is associated with an infection.

For COPD patients, it is important that even mild chest infections be treated immediately since these patients may be more susceptible to damaging lung infections than healthy individuals. Patients should be instructed to contact their physician as soon as possible if they suspect an infection.

Physicians should recommend that COPD patients receive an annual influenza vaccination.

For patients at risk, monitoring of ocular effects (cataract and glaucoma) should also be considered in patients receiving maintenance therapy with ADVAIR.

As with other inhalation therapy, paradoxical bronchospasm may occur characterized by an immediate increase in wheezing after dosing. This should be treated immediately with a rapid onset, short duration inhaled bronchodilator (e.g. salbutamol) to relieve acute asthmatic symptoms. ADVAIR should be discontinued immediately, the patient assessed, and if necessary, alternative therapy instituted.

There are no adequate and well-controlled studies with ADVAIR in pregnant women. ADVAIR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In animal studies, some effects on the fetus, typical for a beta-agonist, occurred at exposure levels substantially higher than those that occur with therapeutic use. Extensive use of other beta-agonists has provided no evidence that effects in animals are relevant to human use.

Like other glucocorticoids, fluticasone propionate is teratogenic to rodent species. Adverse effects typical of potent corticosteroids are only seen at high systemic exposure levels; administration by inhalation ensures minimal systemic exposure. The relevance of these findings to humans has not yet been established since well-controlled trials relating to fetal risk in humans are not available. Infants born of mothers who have received substantial doses of glucocorticoids during pregnancy should be carefully observed for hypoadrenalism.

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

Plasma levels of salmeterol after inhaled therapeutic doses are very low (85 to 200 pg/mL) in humans and therefore levels in milk should be correspondingly low. Studies in lactating animals indicate that salmeterol is likely to be secreted in only very small amounts in breast milk.

Glucocorticoids are excreted in human milk. The excretion of fluticasone propionate into human breast milk has not been investigated. When measurable plasma levels were obtained in lactating laboratory rats following subcutaneous administration, there was evidence of fluticasone propionate in the breast milk. However, plasma levels in patients following inhaled fluticasone propionate at recommended doses are likely to be low.

Since there is no experience with use of ADVAIR by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

In adolescents and children, the severity of asthma may vary with age and periodic reassessment should be considered to determine if continued maintenance therapy with ADVAIR is still indicated.

Also see Monitoring and Laboratory Tests.

The safety and efficacy of ADVAIR DISKUS in children younger than 4 years of age have not been established.

The safety and efficacy of ADVAIR inhalation aerosol in children younger than 12 years of age have not been established.

As with other beta₂-agonists, special caution should be observed when using salmeterol in elderly patients who have concomitant cardiovascular disease that could be adversely affected by this class of drug. Based on available data, no adjustment of salmeterol dosage in geriatric patients is warranted.

Monitoring Control of Asthma or COPD: ADVAIR should not be introduced in acutely deteriorating asthma or COPD, which is a potentially life threatening condition. Increasing use of rapid onset, short duration inhaled bronchodilators to control symptoms indicates deterioration of asthma control. Sudden and progressive deterioration in asthma control is potentially life-threatening and the treatment plan should be re-evaluated. Also, where current dosage of ADVAIR has failed to give adequate control of reversible obstructive airways disease the patient should be reviewed by a physician. Before introducing ADVAIR, adequate education should be provided to the patient on how to use the drug and what to do if asthma flares up.

During long-term therapy, HPA axis function and haematological status should be assessed periodically. For patients at risk, monitoring of bone and ocular effects (cataract and glaucoma) should also be considered in patients receiving maintenance therapy with ADVAIR. It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored.

As with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. This should be treated immediately with a rapid onset, short duration inhaled bronchodilator. ADVAIR (salmeterol xinafoate/fluticasone propionate) should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

The type and severity of adverse reactions associated with salmeterol xinafoate and fluticasone propionate may be expected with ADVAIR. There is no incidence of additional adverse events following combined administration of the two compounds.

The pharmacological side effects of beta₂-agonist treatment, such as tremor, subjective palpitations and headache, have been reported, but tend to be transient and reduce with regular therapy.

Cardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia and extrasystoles) may occur in some patients.

There have been reports of arthralgia and hypersensitivity reactions, including rash, urticaria, bronchospasm, edema, angioedema, anaphylactic reaction and anaphylactic shock.

There have been reports of oropharyngeal irritations as well as rare reports of muscle cramps.

Symptoms of laryngeal spasm, irritation, or swelling, such as stridor and choking, have been reported rarely in patients receiving salmeterol.

Clinically significant changes in blood glucose and/or serum potassium were seen rarely during clinical studies with long-term administration of salmeterol at recommended doses.

In general, inhaled corticosteroid therapy may be associated with dose dependent increases in the incidence of ocular complications, reduced bone density, suppression of HPA axis responsiveness to stress, and inhibition of growth velocity in children. Such events have been reported rarely in clinical trials with fluticasone propionate.

Possible systemic effects include Cushing's syndrome, Cushingoid features and adrenal suppression.

Glaucoma may be exacerbated by inhaled corticosteroid treatment. In patients with established glaucoma who require long-term inhaled corticosteroid treatment, it is prudent to measure intraocular pressure before commencing the inhaled corticosteroid and to monitor it subsequently. In patients without established glaucoma, but with a potential for developing intraocular hypertension (e.g. the elderly), intraocular pressure should be monitored at appropriate intervals.

In elderly patients treated with inhaled corticosteroids, the prevalence of posterior subcapsular and nuclear cataracts is probably low but increases in relation to the daily and cumulative lifetime dose. Cofactors such as smoking, ultraviolet B exposure, or diabetes may increase the risk. Children may be less susceptible.

A reduction of growth velocity in children or teenagers may occur as a result of inadequate control of chronic diseases such as asthma or from use of corticosteroids for treatment. Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route and weigh the benefits of corticosteroid therapy and asthma control against the possibility of growth suppression if any child's or adolescent's growth appears slowed.

Osteoporosis and fracture are the major complications of long-term treatment with parenteral or oral steroids. Inhaled corticosteroid therapy is also associated with dose-dependent bone loss although the degree of risk is very much less than with oral steroid. This risk may be offset by estrogen replacement in post-menopausal women, and by titrating the daily dose of inhaled steroid to the minimum required to maintain optimal control of respiratory symptoms. It is not yet known whether the peak bone density achieved during youth is adversely affected if substantial amounts of inhaled corticosteroid are administered prior to 30 years of age.

Failure to achieve maximal bone density during youth could increase the risk of osteoporotic fracture when those individuals reach 60 years of age and older.

Hoarseness and candidiasis (thrush) of the mouth and throat can occur in some patients receiving inhaled fluticasone propionate. These may be relieved by rinsing the mouth and gargling with water after use of ADVAIR. Symptomatic candidiasis can be treated with topical anti-fungal therapy while still continuing with ADVAIR (see Drug Interactions).

There have been uncommon reports of cutaneous hypersensitivity reactions. There have also been rare reports of hypersensitivity reactions manifesting as angioedema (mainly facial and oropharyngeal edema), respiratory symptoms (dyspnea and/or bronchospasm) and very rarely, anaphylactic reactions.

There have been very rare reports of anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability (predominantly in children and adolescents).

In rare cases, patients on inhaled fluticasone propionate may present with systemic eosinophilic conditions, with some patients presenting with 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.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

There have been very rare reports of anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability (predominantly in children and adolescents).

In clinical trials involving 1824 adult and adolescent patients, the most commonly reported adverse events with the combination salmeterol xinafoate/fluticasone propionate DISKUS were: hoarseness/dysphonia, throat irritation, headache, candidiasis of mouth and throat and palpitations as detailed in Table 1.

Table 1: ADVAIR DISKUS

Number (and percentage) of Patients with Drug-related Adverse Events (incidence ≥1%^a) (Safety Population)

Adverse Events	Salmeterol Xinafoate/ Fluticasone Propionate Combination Product	Salmeterol Xinafoate and Fluticasone Propionate Concurrent Therapy	Fluticasone Propionate Alone	Salmeterol Xinafoate Alone	Placebo
Number of Patients	644	486	339	180	175
Any Event	110 (17%)	81 (17%)	50 (15%)	9 (5%)	5 (3%)
Hoarseness/ Dysphonia	15 (2%)	11 (2%)	8 (2%)	1 (<1%)	0
Throat Irritation	14 (2%)	10 (2%)	8 (2%)	1 (<1%)	1 (<1%)
Candidiasis of Mouth and Throat	15 (2%)	9 (2%)	5 (1%)	0	0
Headaches	16 (2%)	11 (2%)	3 (<1%)	0	0
Asthmab	9 (1%)	11 (2%)	3 (<1%)	0	0
Palpitations	7 (1%)	4 (<1%)	2 (<1%)	1 (<1%)	0
Cough	6 (<1%)	2 (<1%)	5 (1%)	1 (<1%)	0
Breathing Disorders	6 (<1%)	2 (<1%)	4 (1%)	0	0
Candidiasis- Unspecified Site	6 (<1%)	3 (<1%)	4 (1%)	0	2 (1%)
Upper Respiratory Tract Infection	5 (<1%)	5 (1%)	2 (<1%)	0	0

^a. In any integrated treatment group.
^b. Asthma was not recorded as an adverse event in those studies which included treatment with salmeterol xinafoate alone or placebo (unless it was a serious adverse event).

In the ADVAIR DISKUS group, there was no apparent relationship to fluticasone propionate dose for drug-related adverse events (15% with 50/100 µg, 19% with 50/250 µg and 17% with 50/500 µg).

In clinical trials, the most commonly reported adverse events with the combination salmeterol xinafoate/fluticasone propionate inhalation aerosol were: hoarseness/dysphonia, throat irritation and headache. All other adverse events with a reasonable possibility of being related to study drug were reported in ≤1% of subjects. See Table 2.

Table 2: ADVAIR Inhalation Aerosol

Number (and percentage) of Patients with Drug-related Adverse Events (Incidence ≥1%^a) (Safety Population)

Adverse Events	Salmeterol Xinafoate/ Fluticasone Propionate MDI Combination Product	Fluticasone Propionate Alone	Salmeterol Xinafoate Alone	Placebo
Number of Patients	622	614	274	176
Any Event	67 (11%)	71 (11%)	29 (11%)	9 (5%)
Hoarseness/Dysphonia	13 (2%)	7 (1%)	3 (2%)	0 (0%)
Throat Irritation	13 (2%)	14 (2%)	10 (4%)	3 (2%)
Candidiasis of Mouth and Throat	8 (1%)	8 (1%)	0 (0%)	1 (<1%)
Headaches	11 (2%)	11 (2%)	5 (2%)	3 (2%)
Cough	3 (<1%)	3 (<1%)	6 (2%)	1 (<1%)
Hyposalivation	6 (1%)	2 (<1%)	1 (<1%)	0 (0%)

^a. In any integrated treatment group.

Legend:

The incidence of drug-related adverse events for the MDI combination product groups was similar to the individual components.

A total of 257 pediatric patients participated in the clinical development programme and received either the combination 50 µg salmeterol xinafoate/100 µg fluticasone propionate DISKUS or concurrent therapy (with salmeterol and fluticasone propionate administered via separate inhalers). Only one drug-related adverse event, candidiasis, was reported with an incidence of 2% or more in the ADVAIR group. The combination product was generally well tolerated and the safety profile was comparable to that observed in the concurrent therapy group.

There have been very rare reports of anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability (predominantly in children and adolescents).

In clinical trials involving 2054 adults, the most commonly reported adverse events with ADVAIR DISKUS after 24 weeks were: upper respiratory tract infection, throat irritation, headache and musculoskeletal pain as detailed in Table 3. These adverse reactions were mostly mild to moderate in severity.

Table 3 includes all events (whether considered drug-related or non drug-related by the investigator) that occurred at a rate of 3% or greater in either of the groups receiving ADVAIR DISKUS and were more common than in the placebo group.

Table 3: ADVAIR DISKUS

Overall Adverse Experiences with ≥3% Incidence in Controlled Clinical Trials with ADVAIR DISKUS in Patients with COPD

After 52 weeks of treatment with ADVAIR DISKUS (50/500 µg), fluticasone propionate 500 µg, salmeterol 50 µg and placebo in 1465 patients with COPD, the most commonly reported drug related adverse event was candidiasis of the mouth and throat (ADVAIR DISKUS 50/500 µg, 6%; fluticasone propionate 500 µg, 6%; salmeterol 50 µg, 1%; placebo, 1%).

arrhythmias, hypertension, palpitations.

contusions, fractures, hematomas, lacerations and wounds.

ear/nose/throat infections, ear/nose/throat signs and symptoms, ear signs and symptoms, epistaxis, laryngitis, nasal sinus disorders, pharyngitis/throat infections, rhinorrhea/post nasal drip, sputum abnormalities.

diabetes mellitus, hypothyroidism.

constipation, dental discomfort and pain, diverticulosis, dyspeptic symptoms, gastrointestinal infections, gum signs and symptoms, hyposalivation, oral discomfort and pain; oral lesions, regurgitation and reflux.

abnormal liver function tests.

bacterial infections, candidiasis unspecified site, viral infections.

anxiety, situational disorders, sleep disorders, syncope, tremors, vertigo.

bone and skeletal pain, edema and swelling, non-site specific pain, non-specific condition, soft tissue injuries.

dry eyes, eye infections, lacrimal disorders, ocular pressure disorders, visual disturbances.

postoperative complications.

breathing disorders, bronchitis, lower respiratory hemorrhage, lower respiratory signs and symptoms, pneumonia.

fungal skin infections and skin infections.

There have been uncommon reports of cutaneous hypersensitivity reactions. There have also been rare reports of hypersensitivity reactions manifesting as angioedema (mainly facial and oropharyngeal edema), respiratory symptoms (dyspnea and/or bronchospasm) and very rarely, anaphylactic reactions, anaphylactic shock.

There have been very rare reports of anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability (predominantly in children and adolescents). Very rarely, hyperglycemia and hypertension have been reported.

Use ADVAIR (salmeterol xinafoate/fluticasone propionate) with caution in patients receiving other medications causing hypokalemia and/or increased QTc interval (diuretics, high dose steroids, anti-arrhythmics, astemizole, terfenadine) since cardiac and vascular effects may be potentiated.

Under normal circumstances, low plasma concentrations of fluticasone propionate are achieved after inhaled dosing, due to extensive first pass metabolism and high systemic clearance mediated by cytochrome P450 3A4 in the gut and liver. Hence, clinically significant drug interactions involving fluticasone propionate are unlikely.

A drug interaction study of intranasal fluticasone propionate in healthy subjects has shown that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can greatly increase fluticasone propionate plasma concentrations, resulting in markedly reduced serum cortisol concentrations. During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving intranasal or inhaled fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression. Therefore, concomitant use of fluticasone propionate and ritonavir should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side-effects.

This study has shown that other inhibitors of cytochrome P450 3A4 produce negligible (erythromycin) and minor (ketoconazole) increases in systemic exposure to fluticasone propionate without notable reductions in serum cortisol concentrations. However, there have been a few case reports during world-wide post-market use of adrenal cortisol suppression associated with concomitant use of azole anti-fungals and inhaled fluticasone propionate. Therefore, care is advised when co-administering potent cytochrome P450 3A4 inhibitors (e.g. ketoconazole) as there is potential for increased systemic exposure to fluticasone propionate.