Advair Diskus Side Effects

Please note - some side effects for Advair Diskus may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Advair Diskus - for the Consumer

Advair Diskus Powder

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Advair Diskus Powder:

Diarrhea; dizziness; headache; mild muscle or bone pain; nausea; nervousness; throat irritation; tremor; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur when using Advair Diskus Powder:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); behavior changes; blurred vision or other vision changes; burning, numbness, or tingling; chest pain; choking; fast or irregular heartbeat; overexcitement; seizures; severe muscle weakness, cramps, or spasms; severe or persistent bone pain; severe or persistent dizziness, headache, nervousness, or tremor; signs of infection (eg, fever, chills, cough, persistent sore throat, ear pain, increased mucus production, change in mucus color); swelling or tightness in the throat; symptoms of high blood sugar (eg, increased thirst, urination, or hunger; unusual weakness or drowsiness; confusion); trouble sleeping; unusual tiredness or weakness; vaginal odor or discharge; weight gain; white patches or sores on the tongue or mouth; worsening of asthma or COPD symptoms (eg, increased wheezing, coughing, chest tightness, shortness of breath).

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Advair Diskus Side Effects - for the Professional

Advair Diskus

LABAs, such as salmeterol, one of the active ingredients in Advair Diskus, increase the risk of asthma-related death. Data from a large placebo-controlled US study that compared the safety of salmeterol (SEREVENT Inhalation Aerosol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol [see Warnings and Precautions (5.1)]. 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 [see Warnings and Precautions (5.4)]
• Pneumonia in patients with COPD [see Warnings and Precautions (5.5)]
• Immunosuppression [see Warnings and Precautions (5.6)]
• Hypercorticism and adrenal suppression [see Warnings and Precautions (5.8)]
• Growth effects [see Warnings and Precautions (5.14)]
• Glaucoma and cataracts [see Warnings and Precautions (5.15)]

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

Clinical Trials Experience in Asthma

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

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

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

The types of adverse reactions and events reported in Study 3, a 28-week, non-US clinical study of 503 patients previously treated with inhaled corticosteroids who were treated twice daily with Advair Diskus 500/50, fluticasone propionate inhalation powder 500 mcg and salmeterol inhalation powder 50 mcg used concurrently, or fluticasone propionate inhalation powder 500 mcg, were similar to those reported in Table 2.

Additional Adverse Reactions: Other adverse reactions not previously listed, whether considered drug-related or not by the investigators, that were reported more frequently by patients with asthma treated with Advair Diskus compared with patients treated with placebo include the following: lymphatic signs and symptoms; muscle injuries; fractures; wounds and lacerations; contusions and hematomas; ear signs and symptoms; nasal signs and symptoms; nasal sinus disorders; keratitis and conjunctivitis; dental discomfort and pain; gastrointestinal signs and symptoms; oral ulcerations; oral discomfort and pain; lower respiratory signs and symptoms; pneumonia; muscle stiffness, tightness, and rigidity; bone and cartilage disorders; sleep disorders; compressed nerve syndromes; viral infections; pain; chest symptoms; fluid retention; bacterial infections; unusual taste; viral skin infections; skin flakiness and acquired ichthyosis; disorders of sweat and sebum.

Pediatric Patients Aged 4 to 11 Years: The safety data for pediatric patients aged 4 to 11 years is based upon 1 US trial of 12 weeks’ treatment duration. A total of 203 patients (74 females and 129 males) who were receiving inhaled corticosteroids at study entry were randomized to either Advair Diskus 100/50 or fluticasone propionate inhalation powder 100 mcg twice daily. Common adverse reactions (≥3% and greater than placebo) seen in the pediatric patients but not reported in the adult and adolescent clinical trials include: throat irritation and ear, nose, and throat infections.

Laboratory Test Abnormalities: Elevation of hepatic enzymes was reported in ≥1% of patients in clinical trials. The elevations were transient and did not lead to discontinuation from the studies. In addition, there were no clinically relevant changes noted in glucose or potassium.

Clinical Trials Experience in Chronic Obstructive Pulmonary Disease

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

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

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

In the two 1-year studies, Advair Diskus 250/50 was compared with salmeterol in 1,579 patients (863 males and 716 females). The mean age of the patients was 65, and the majority (94%) was Caucasian. To be enrolled, all of the patients had to have had a COPD exacerbation in the previous 12 months. In this trial, 88% of the patients treated with Advair Diskus and 86% of the patients treated with salmeterol reported an adverse event. The most common events that occurred with a frequency of >5% and more frequently in the patients treated with Advair Diskus were nasopharyngitis, upper respiratory tract infection, nasal congestion, back pain, sinusitis, dizziness, nausea, pneumonia, candidiasis, and dysphonia. Overall, 55 (7%) of the patients treated with Advair Diskus and 25 (3%) of the patients treated with salmeterol developed pneumonia.

The incidence of pneumonia was higher in patients over 65 years of age, 9% in the patients treated with Advair Diskus compared with 4% in the patients treated with Advair Diskus less than 65 years of age. In the patients treated with salmeterol, the incidence of pneumonia was the same (3%) in both age-groups. [See Warnings and Precautions (5.5), Use in Specific Populations (8.5).]

Long-Term (3-Year) Trial: The safety of Advair Diskus 500/50 was evaluated in a randomized, double-blind, placebo-controlled, multicenter, international, 3-year study in 6,184 adult patients with COPD (4,684 males and 1,500 females). The mean age of the patients was 65, and the majority (82%) was Caucasian. The distribution of adverse events was similar to that seen in the 1-year trials with Advair Diskus 250/50. In addition, pneumonia was reported in a significantly increased number of patients treated with Advair Diskus 500/50 and fluticasone propionate 500 mcg (16% and 14%, respectively) compared with patients treated with salmeterol 50 mcg or placebo (11% and 9%, respectively). When adjusted for time on treatment, the rates of pneumonia were 84 and 88 events per 1,000 treatment-years in the groups treated with fluticasone propionate 500 mcg and with Advair Diskus 500/50, respectively, compared with 52 events per 1,000 treatment-years in the salmeterol and placebo groups. Similar to what was seen in the 1-year studies with Advair Diskus 250/50, the incidence of pneumonia was higher in patients over 65 years of age (18% with Advair Diskus 500/50 versus 10% with placebo) compared with patients less than 65 years of age (14% with Advair Diskus 500/50 versus 8% with placebo). [See Warnings and Precautions (5.5), Use in Specific Populations (8.5).]

Additional Adverse Reactions: Other adverse reactions not previously listed, whether considered drug-related or not by the investigators, that were reported more frequently by patients with COPD treated with Advair Diskus compared with patients treated with placebo include the following: syncope; ear, nose, and throat infections; ear signs and symptoms; laryngitis; nasal congestion/blockage; nasal sinus disorders; pharyngitis/throat infection; hypothyroidism; dry eyes; eye infections; gastrointestinal signs and symptoms; oral lesions; abnormal liver function tests; bacterial infections; edema and swelling; viral infections.

Laboratory Abnormalities: There were no clinically relevant changes in these trials. Specifically, no increased reporting of neutrophilia or changes in glucose or potassium was noted.

Postmarketing Experience

In addition to adverse events reported from clinical trials, the following events have been identified during worldwide use of any formulation of ADVAIR, fluticasone propionate, and/or salmeterol regardless of indication. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to Advair Diskus, fluticasone propionate, and/or salmeterol or a combination of these factors.

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

Endocrine Disorders: Cushing’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.

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.

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Side Effects by Body System - for Healthcare Professionals

Endocrine

Endocrine side effects of fluticasone have rarely included symptoms of hypothalamic-pituitary-adrenal (HPA) axis suppression. These effects were more likely when higher potency corticosteroids were used in large doses. The use of a large-volume spacer has helped minimize HPA suppression when fluticasone was inhaled orally.

Due to extensive first-pass metabolism of fluticasone to an inactive carboxylic acid, significant systemic effects are not expected from any amount of the drug that may be ingested via inhalation of normally recommended dosages.

Gastrointestinal

Gastrointestinal side effects of fluticasone have included nausea, vomiting, and diarrhea. Oropharyngeal candidiasis and candida-like lesions have also been reported. Gastrointestinal intolerance to salmeterol has occurred resulting in nausea and diarrhea.

Hypersensitivity

Cases of serious eosinophilic conditions also have been reported with other inhaled corticosteroids in this clinical setting.

Hypersensitivity side effects of fluticasone have included rare cases of immediate and delayed reactions including rash, angioedema and bronchospasm. Hypersensitivity side effects have also included postmarketing reports of a systemic eosinophilic condition. Clinical features of this condition have included a vasculitis consistent with Churg-Strauss syndrome, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy. These events have usually been associated with a reduction and/or discontinuation of oral corticosteroid therapy following introduction of fluticasone. Hypersensitivity reactions to salmeterol have presented as rash or urticaria.

Immunologic

Immunologic side effects of fluticasone may have included infections resulting from immune suppression associated with inhaled corticosteroids. No conclusive evidence is available to support an increase in tuberculosis or viral infections in patients receiving inhaled fluticasone.

In 1993, the American Academy of Allergy and Immunology (AAAI) requested that the FDA review its decision regarding the labeled risks of the use of inhaled corticosteroids during severe viral infections. The AAAI's request was based on the lack of data linking inhaled corticosteroids to increases in complications of viral infections.

Local

Local side effects associated with inhaled fluticasone have included dysphonia, sore throat, bronchitis, chest congestion, nasal congestion, nasal discharge, and eye irritation.

Asthma treatment with high doses of inhaled fluticasone powder apparently led to a serious case of laryngeal aspergillosis in a 75-year-old-man. The patient had been using fluticasone 1 mg twice daily via Diskhaler for about 3 years. The patient experienced progressive hoarseness which led to complete aphonia. Aspergillosis fumigatus was cultured from the vocal cords. Amphotericin B lozenges were used to treat the infection. After 14 weeks the patient's voice was still gruff but intelligible. It is recommended that tests for fungal infection be performed in patients on fluticasone therapy who become hoarse, particularly if taking high doses.

Musculoskeletal

Musculoskeletal side effects of fluticasone have included joint pain and muscle soreness. Long-term use of inhaled corticosteroids has been associated with a reduction in bone density. This effect may have been dose related and has been reported with high dosages of orally inhaled beclomethasone and budesonide (>=800 mcg/day for >=1 year). Reduced levels of total body calcium have also been demonstrated in patients receiving lower dosages. The musculoskeletal effects of salmeterol are mediated by beta-2 receptors and have been manifested as tremors, especially at higher doses. Tolerance can lead to the tremorogenic effects. Severe muscle cramping is rarely reported.

Nervous system

One patient has reported episodes of vertigo lasting 36 hours each following inhalation of salmeterol. These episodes occurred several months apart during separate attempts to reinstitute therapy.

Nervous system side effects of fluticasone have included headache, dizziness, giddiness, fatigue, and insomnia. The nervous system has been adversely affected by salmeterol resulting in headache, restlessness, anxiety, nervousness, irritability, and insomnia.

Ocular

Ocular side effects of fluticasone have included occasional reports of posterior capsular cataracts. In addition, one epidemiologic study suggested that prolonged use of high-dose inhaled corticosteroids (>= 1500 mcg of fluticasone) may have been associated with increased risk of ocular hypertension and open-angle glaucoma.

Cardiovascular

Changes in heart rate of approximately 8 to 16 beats per minute may be produced by 0.2 mg of salmeterol given by MDI. At an inhaled dose of 0.4 mg, two subjects have experienced nonspecific T-wave changes, and one subject experienced QT prolongation. Higher doses of salmeterol should be used with caution in patients with cardiac disease, arrhythmias, or hypertension. All of these effects are dose-related and lower doses may be tolerated.

Cardiovascular side effects of salmeterol have included palpitations and peripheral vasodilation, commonly resulting in reflex tachycardia. Blood pressure has been increased and decreased. Higher doses have rarely aggravated angina, myocardial ischemia, or caused atrial or ventricular arrhythmias.

General

Salmeterol has been generally well-tolerated and adverse effects seen were consistent with its pharmacological action. In general, the severity of these adverse effects were dependent on dose. Tolerance to the adverse effects of salmeterol has occurred.

Metabolic

Following a 400-mcg dose of salmeterol via MDI, a decrease in plasma potassium concentrations of 0.45 mEq/L has been reported. Salmeterol may stimulate sodium-potassium ATPase resulting in an intracellular shift of potassium.

Metabolic side effects associated with salmeterol have included hypokalemia, and less commonly hyperglycemia.

Respiratory

Respiratory side effects of salmeterol have occasionally included cough and paradoxical bronchospasm. Additional side effects reported have included upper respiratory tract infections, viral respiratory infections, bronchitis, and pneumonia.

Less commonly respiratory side effects have included chest congestion, chest tightness, dyspnea, immediate bronchospasm, influenza, tracheitis, wheezing, and reports of upper respiratory symptoms of laryngeal spasm, irritation, or swelling such as stridor or choking. Lower respiratory tract infections, including pneumonia, have been reported following the inhaled administration of corticosteroids. There was a higher incidence of pneumonia among patients receiving fluticasone-salmeterol (7%) than among those receiving salmeterol (4%) in a clinical study.

Other

Other side effects have concerned the development of tachyphylaxis to the bronchodilating and bronchoprotective effects of beta-agonists. Although conflicting data exist, the development of complete tolerance has not been reported.

Psychiatric

Psychiatric side effects have included post marketing reports of agitation, aggression, depression. Behavioral changes, including hyperactivity and irritability, have been reported very rarely and primarily in children.

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