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Long-acting beta₂-adrenergic agonists, such as salmeterol one of the active ingredients in ADVAIR HFA (fluticasone propionate and salmeterol) , 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). Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long­term 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.

The incidence of common adverse events in Table 4 is based upon 2 placebo-controlled, 12-week, US clinical studies (Studies 1 and 3) and 1 active-controlled, 12-week, US clinical study (Study 2). A total of 1,008 adolescent and adult patients with asthma (556 females and 452 males) previously treated with albuterol alone, salmeterol, or inhaled corticosteroids were treated twice daily with 2 inhalations of ADVAIR HFA (fluticasone propionate and salmeterol) 45/21 or ADVAIR HFA (fluticasone propionate and salmeterol) 115/21, fluticasone propionate CFC inhalation aerosol (44- or 110-mcg doses), salmeterol CFC inhalation aerosol 21 mcg, or placebo HFA inhalation aerosol.

Table 4: Overall Adverse Events With ≥ 3% Incidence in US Controlled Clinical Trials With ADVAIR HFA (fluticasone propionate and salmeterol) Inhalation Aerosol in Patients With Asthma

Table 4 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of 3% or greater in any of the groups receiving ADVAIR HFA (fluticasone propionate and salmeterol) and were more common than in the placebo group. In considering these data, differences in average duration of exposure should be taken into account. These adverse reactions were mostly mild to moderate in severity.

Other adverse events that occurred in the groups receiving ADVAIR HFA (fluticasone propionate and salmeterol) in these studies with an incidence of 1% to 3% and that occurred at a greater incidence than with placebo were:

Cardiovascular: Tachycardia, arrhythmias, myocardial infarction.

Drug Interaction, Overdose, and Trauma: Postoperative complications, wounds and lacerations, soft tissue injuries, poisoning and toxicity, pressure-induced disorder.

Ear, Nose, and Throat: Ear, nose, and throat infection; ear signs and symptoms; rhinorrhea/postnasal drip; epistaxis; nasal congestion/blockage; laryngitis; unspecified oropharyngeal plaques; dryness of nose.

Endocrine and Metabolic: Weight gain.

Eye: Allergic eye disorders, eye edema and swelling.

Gastrointestinal: Gastrointestinal discomfort and pain, dental discomfort and pain, candidiasis mouth/throat, hyposalivation, gastrointestinal infections, disorders of hard tissue of teeth, hemorrhoids, gastrointestinal gaseous symptoms, abdominal discomfort and pain, constipation, oral abnormalities.

Musculoskeletal: Arthralgia and articular rheumatism, muscle cramps and spasms, musculoskeletal inflammation, bone and skeletal pain.

Neurology: Sleep disorders, migraines.

Non-Site Specific: Allergies and allergic reactions, viral infections, bacterial infections, candidiasis unspecified site, congestion, inflammation.

Reproduction: Bacterial reproductive infections.

Respiratory: Lower respiratory signs and symptoms, lower respiratory infections, lower respiratory hemorrhage.

Skin: Eczema, dermatitis and dermatosis.

Urology: Urinary infections.

Rare cases of immediate and delayed hypersensitivity reactions, including rash and other rare events of angioedema and bronchospasm, have been reported.

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

Observed During Clinical Practice

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, fluticasone propionate, and/or salmeterol or a combination of these factors.

In extensive US and worldwide postmarketing experience with salmeterol, a component of ADVAIR HFA (fluticasone propionate and salmeterol) , serious exacerbations of asthma, including some that have been fatal, have been reported. In most cases, these have occurred in patients with severe asthma and/or in some patients in whom asthma has been acutely deteriorating (see WARNINGS), but they have also occurred in a few patients with less severe asthma. It was not possible from these reports to determine whether salmeterol contributed to these events.

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

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

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

Eye: Cataracts, glaucoma.

Gastrointestinal: Dyspepsia, xerostomia.

Hepatobiliary Tract and Pancreas: Abnormal liver function tests.

Musculoskeletal: Back pain, myositis.

Neurology: Paresthesia, restlessness.

Non-Site Specific: Fever, immediate and delayed hypersensitivity reaction, pallor.

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

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

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

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

Eosinophilic Conditions: In rare cases, patients on inhaled fluticasone propionate, a component of ADVAIR HFA (fluticasone propionate and salmeterol) , 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. While ADVAIR HFA (fluticasone propionate and salmeterol) should not be used for transferring patients from systemic corticosteroid therapy, 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 (see PRECAUTIONS: General: Eosinophilic Conditions).

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

Short-Acting Beta₂-Agonists

In three 12-week US clinical trials, the mean daily need for additional beta₂-agonist use in 277 patients receiving ADVAIR HFA (fluticasone propionate and salmeterol) was approximately 1.2 inhalations/day and ranged from 0 to 9 inhalations/day. Two percent (2%) of patients receiving ADVAIR HFA (fluticasone propionate and salmeterol) in these trials averaged 6 or more inhalations per day over the course of the 12-week trials. No increase in frequency of cardiovascular events was observed among patients who averaged 6 or more inhalations per day.

Methylxanthines

The concurrent use of intravenously or orally administered methylxanthines (e.g., aminophylline, theophylline) by patients receiving ADVAIR HFA (fluticasone propionate and salmeterol) has not been completely evaluated. In five 12-week clinical trials (3 US and 2 non-US), 45 patients receiving ADVAIR HFA (fluticasone propionate and salmeterol) 45/21, 115/21, or 230/21 twice daily concurrently with a theophylline product had adverse event rates similar to those in 577 patients receiving ADVAIR HFA (fluticasone propionate and salmeterol) without theophylline.

Fluticasone Propionate Nasal Spray

In patients receiving ADVAIR HFA (fluticasone propionate and salmeterol) in three 12-week US clinical trials, no difference in the profile of adverse events or HPA axis effects was noted between patients receiving FLONASE® (fluticasone propionate) Nasal Spray, 50 mcg concurrently (n = 89) and those who were not (n = 192).

Monoamine Oxidase Inhibitors and Tricyclic Antidepressants

ADVAIR HFA (fluticasone propionate and salmeterol) should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of salmeterol, a component of ADVAIR HFA (fluticasone propionate and salmeterol) , 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 HFA (fluticasone propionate and salmeterol) , but may produce severe bronchospasm in patients with asthma. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with asthma. In this setting, 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 significance of these effects is not known, caution is advised in the coadministration of beta-agonists with nonpotassium-sparing diuretics.

Inhibitors of Cytochrome P450

Fluticasone propionate and salmeterol are substrates of cytochrome P450 3A4.

Fluticasone propionate

A drug interaction study with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a strong cytochrome P450 3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Fluticasone Propionate: Drug Interactions). During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression. Therefore, coadministration of fluticasone propionate and ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.

In a placebo-controlled, crossover study in 8 healthy adult volunteers, coadministration of a single dose of orally inhaled fluticasone propionate (1,000 mcg) with multiple doses of ketoconazole (200 mg) to steady state resulted in increased systemic fluticasone propionate exposure, a reduction in plasma cortisol AUC, and 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. Due to the potential increased risk of cardiovascular adverse events, the concomitant use of salmeterol with strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) is not recommended (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Salmeterol Xinafoate: Drug Interactions).

Last reviewed on RxList: 7/23/2010
This monograph has been modified to include the generic and brand name in many instances.