Advair Diskus (fluticasone propionate and salmeterol inhaler) Side Effects, Warnings & Interactions

Advair Diskus and Advair HFA (fluticasone propionate and salmeterol oral inhaler) is a combination of a corticosteroid and a beta2-adrenergic bronchodilator used to treat asthma or chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis.

Common side effects of Advair Diskus include 

• upper respiratory tract infections, 
• headaches, 
• nausea, 
• vomiting, 
• diarrhea, 
• oral thrush, 
• musculoskeletal pain, 
• throat irritation, 
• difficulty speaking, 
• hoarseness, 
• upper respiratory tract inflammation, 
• palpitations, 
• tremors, 
• cough, 
• sinus infection, 
• pneumonia, 
• dizziness, 
• skin reactions, 
• taste changes, and 
• musculoskeletal pain.

Serious side effects of Advair Diskus include 

• pneumonia, 
• bronchospasm, 
• death, 
• serious allergic reactions, 
• adrenal suppression, 
• growth suppression, 
• high blood pressure (hypertension), 
• low blood pressure (hypotension), 
• worsening of asthma, 
• osteoporosis, 
• glaucoma, 
• high blood glucose (hyperglycemia), 
• low potassium, 
• cardiac arrest, and 
• cataracts.

Drugs that may cause harmful interactions when taken with Advair Diskus include 

• monoamine oxidase inhibitors (MOAIs), 
• tricyclic antidepressants, 
• Norvir (ritonavir), 
• Reyataz (atazanavir), 
• Biaxin (clarithromycin), 
• Crixivan (indinavir), 
• Sporanox (itraconazole), 
• ketoconazole, 
• Viracept (nelfinavir), 
• Ketek (telithromycin), and 
• beta-blockers. 

Adequate studies of fluticasone or inhaled salmeterol during pregnancy have not been done. Advair Diskus use during pregnancy should be avoided unless the potential benefit justifies the potential but unknown risk to the fetus. It is not known if fluticasone propionate is secreted in breast milk. 

Other medications in the same class as fluticasone propionate are secreted into breast milk, but it is not known whether the small amounts that may appear in the milk have effects on nursing infants. In rats, salmeterol is excreted in milk. 

Consult your doctor before breastfeeding. 

WARNING

• Use of long acting agents like salmeterol, an active ingredient in Advair, may increase the risk of asthma-related death. Therefore, Advair should only be used in patients whose asthma is uncontrolled by other agents, and who are using long-term asthma-controlling medications such as an inhaled corticosteroid.

Other side effects include:

• Upper respiratory tract infections occur in 20% to 25% of patients using Advair.
• Headaches occur in about 1 in 8 patients who use it.
• Other common adverse events include:
  • Nausea,
  • Vomiting,
  • Diarrhea,
  • Mouth or throat candidiasis
  • Musculoskeletal pain
  • Throat irritation
  • Difficulty speaking (dysphonia)
  • Hoarseness
  • Upper respiratory tract inflammation
  • Palpitations
  • Tremor
  • Cough
  • Sinus infection
  • Pneumonia
  • Dizziness
  • Skin reactions
  • Taste changes
  • Musculoskeletal pain

Use of long acting agents like salmeterol, an active ingredient in Advair, may increase the risk of asthma-related death. Therefore, Advair should only be used in patients whose asthma is uncontrolled by other agents, and who are using long-term asthma-controlling medications such as an inhaled corticosteroid.

Serious adverse events of Advair include:

• Pneumonia
• Bronchospasm
• Death

Serious allergic reactions include:

• Adrenal suppression
• Growth suppression
• High blood pressure
• Low blood pressure
• Worsening of asthma
• Osteoporosis
• Glaucoma
• High blood glucose
• Low potassium
• Cardiac arrest
• Cataracts

LABA, such as salmeterol, one of the active ingredients in Advair Diskus, increase the risk of asthma-related death. Data from a large placebo-controlled U.S. trial that compared the safety of salmeterol or placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol. 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.

Systemic and local corticosteroid use may result in the following:

• Candida albicans infection
• Pneumonia in patients with COPD
• Immunosuppression
• Hypercorticism and adrenal suppression
• Reduction in bone mineral density
• Growth effects
• Glaucoma and cataracts

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 Subjects Aged 12 Years And Older

The incidence of adverse reactions associated with ADVAIR DISKUS in Table 2 is based upon two 12-week, placebo-controlled, U.S. clinical trials (Trials 1 and 2). A total of 705 adult and adolescent subjects (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 Advair Diskus with ≥ 3% Incidence and More Common than Placebo in Adult and Adolescent Subjects with Asthma

The types of adverse reactions and events reported in Trial 3, a 28-week non-U.S. clinical trial in 503 subjects 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 subjects with asthma treated with Advair Diskus compared with subjects 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 Subjects Aged 4 To 11 Years

The safety data for pediatric subjects aged 4 to 11 years is based upon 1 U.S. trial of 12 weeks' treatment duration. A total of 203 subjects (74 females and 129 males) who were receiving inhaled corticosteroids at trial entry were randomized to either Advair Diskus 100/50 or fluticasone propionate inhalation powder 100 mcg twice daily. Common adverse reactions (greater than or equal to 3% and greater than placebo) seen in the pediatric subjects 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 greater than or equal to 1% of subjects in clinical trials. The elevations were transient and did not lead to discontinuation from the trials. 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 subjects (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 subjects was 64, and the majority (93%) was Caucasian. In this trial, 70% of the subjects 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 trial is shown in Table 3.

Table 3: Overall Adverse Reactions with Advair Diskus 250/50 with ≥ 3% Incidence in Subjects with Chronic Obstructive Pulmonary Disease Associated with Chronic Bronchitis

In the two 1-year trials, Advair Diskus 250/50 was compared with salmeterol in 1,579 subjects (863 males and 716 females). The mean age of the subjects was 65 years, and the majority (94%) was Caucasian. To be enrolled, all of the subjects had to have had a COPD exacerbation in the previous 12 months. In this trial, 88% of the subjects treated with Advair Diskus and 86% of the subjects treated with salmeterol reported an adverse event. The most common events that occurred with a frequency of greater than 5% and more frequently in the subjects 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 subjects treated with Advair Diskus and 25 (3%) of the subjects treated with salmeterol developed pneumonia.

The incidence of pneumonia was higher in subjects older than 65 years, 9% in the subjects treated with ADVAIR DISKUS compared with 4% in the subjects treated with Advair Diskus younger than 65 years. In the subjects treated with salmeterol, the incidence of pneumonia was the same (3%) in both age-groups.

Long-Term (3 Years) Trial

The safety of Advair Diskus 500/50 was evaluated in a randomized, double-blind, placebo-controlled, multicenter, international, 3-year trial in 6,184 adult subjects with COPD (4,684 males and 1,500 females). The mean age of the subjects was 65 years, 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 subjects treated with Advair Diskus 500/50 and fluticasone propionate 500 mcg (16% and 14%, respectively) compared with subjects 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 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)

Additional Adverse Reactions

Other adverse reactions not previously listed, whether considered drug-related or not by the investigators, that were reported more frequently by subjects with COPD treated with Advair Diskus compared with subjects 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 reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of any formulation of ADVAIR, fluticasone propionate, and/or salmeterol regardless of indication. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to Advair 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's 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.

Infections And Infestations

Esophageal candidiasis.

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 beta₂agonists, methylxanthines, and intranasal corticosteroids, commonly used in patients with asthma or COPD without adverse drug reactions. No formal drug interaction trials have been performed with Advair Diskus.

Inhibitors Of Cytochrome P450 3A4

Fluticasone propionate and salmeterol, the individual components of Advair Diskus, are substrates of CYP3A4. The use of strong CYP3A4 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 trial with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a strong CYP3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations. During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression.

Ketoconazole

Fluticasone Propionate: Coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma fluticasone propionate exposure and a 45% decrease in plasma cortisol area under the curve (AUC), but had no effect on urinary excretion of cortisol.

Salmeterol: In a drug interaction trial 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 also produce severe bronchospasm in patients with asthma or COPD. Therefore, patients with asthma or 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.

Non–Potassium-Sparing Diuretics

The ECG changes and/or hypokalemia that may result from the administration of non–potassiumsparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, such as salmeterol, a component of Advair Diskus, 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 Advair Diskus with non–potassium-sparing diuretics.