Advair HFA (Fluticasone Propionate / Salmeterol Xinafoate) - Side Effects and Adverse Reactions

ADVERSE REACTIONS

Long-acting beta₂-adrenergic agonists, such as salmeterol, may 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). Salmeterol is a component of ADVAIR HFA. However, the data from this study are not adequate to determine whether concurrent use of inhaled corticosteroids, such as fluticasone propionate, the other component of ADVAIR HFA, or other asthma controller therapy modifies the risk of asthma-related death.

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 45/21 or ADVAIR HFA 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 Inhalation Aerosol in Patients With Asthma

					Salmeterol	Placebo
			Fluticasone		CFC	HFA
			Propionate CFC		Inhalation	Inhalation
Adverse Events	ADVAIR HFA		Inhalation Aerosol		Aerosol	Aerosol
	45/21	115/21	44 mcg	110 mcg	21 mcg
	(n = 187)	(n = 94)	(n = 186)	(n = 91)	(n = 274)	(n = 176)
	%	%	%	%	%	%
Ear, nose, & throat
Upper respiratory	16	24	13	15	17	13
tract infection
Throat irritation	9	7	12	13	9	7
Upper respiratory	4	4	3	7	5	3
inflammation
Hoarseness/dysphonia	3	1	2	0	1	0
Lower respiratory
Viral respiratory	3	5	4	5	3	4
infections
Neurology
Headaches	21	15	24	16	20	11
Dizziness	4	1	1	0	<1	0
Gastrointestinal
Nausea& vomiting	5	3	4	2	2	3
Viral gastrointestinal	4	2	2	0	1	2
infections
Gastrointestinal signs	3	2	2	1	1	1
& symptoms
Non-site specific
Pain	3	1	2	1	2	2
Musculoskeletal
Musculoskeletal pain	5	7	8	2	4	4
Muscle pain	4	1	1	1	3	<1
Drug interaction,
overdose,& trauma
Muscle injuries	3	0	2	1	3	2
Reproduction
Menstruation	5	3	1	0	<1	<1
symptoms
Psychiatry
Intoxication&	3	0	0	0	0	0
hangover
Average duration of	81.3	78.6	79.9	74.6	71.4	56.3
exposure (days)

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 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 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 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, 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, 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 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).