Skip to main content

Long-acting beta2-adrenergic agonists may increase the risk of asthma-related death. One of the active ingredients of SYMBICORT (budesonide and formoterol fumarate dihydrate) is formoterol, a long-acting beta2-agonist. Data from a large placebo-controlled US study that compared the safety of another long-acting beta2-adreneergic agonist (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. [see WARNINGS AND PRECAUTIONS].

Systemic and inhaled corticosteroid use may result in the following:

- Candida albicans infection [see WARNINGS AND PRECAUTIONS]
- Pneumonia or lower respiratory tract infections in patients with COPD [see WARNINGS AND PRECAUTIONS]
- Immunosuppression [see WARNINGS AND PRECAUTIONS]
- Hypercorticism and adrenal suppression [see WARNINGS AND PRECAUTIONS]
- Growth effects in pediatric patients [see WARNINGS AND PRECAUTIONS]
- Glaucoma and cataracts [see WARNINGS AND PRECAUTIONS]

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

Clinical Trials Experience in Asthma Patients 12 years and older

The overall safety data in adults and adolescents are based upon 10 active- and placebo-controlled clinical trials in which 3393 patients ages 12 years and older (2052 females and 1341 males) with asthma of varying severity were treated with SYMBICORT (budesonide and formoterol fumarate dihydrate) 80/4.5 or 160/4.5 mcg taken two inhalations once or twice daily for 12 to 52 weeks. In these trials, the patients on SYMBICORT (budesonide and formoterol fumarate dihydrate) had a mean age of 38 years and were predominantly Caucasian (82%).

The incidence of common adverse events in Table 1 below is based upon pooled data from three 12-week, double-blind, placebo-controlled clinical studies in which 401 adult and adolescent patients (148 males and 253 females) age 12 years and older were treated with two inhalations of SYMBICORT (budesonide and formoterol fumarate dihydrate) 80/4.5 or SYMBICORT (budesonide and formoterol fumarate dihydrate) 160/4.5 twice daily. The SYMBICORT (budesonide and formoterol fumarate dihydrate) group was composed of mostly Caucasian (84%) patients with a mean age of 38 years, and a mean percent predicted FEV1 at baseline of 76 and 68 for the 80/4.5 mcg and 160/4.5 mcg treatment groups, respectively. Control arms for comparison included two inhalations of budesonide HFA metered dose inhaler (MDI) 80 or 160 mcg, formoterol dry powder inhaler (DPI) 4.5 mcg, or placebo (MDI and DPI) twice daily. Table 1 includes all adverse events that occurred at an incidence of ≥ 3% in any one SYMBICORT (budesonide and formoterol fumarate dihydrate) group and more commonly than in the placebo group with twice-daily dosing. In considering these data, the increased average duration of patient exposure for SYMBICORT (budesonide and formoterol fumarate dihydrate) patients should be taken into account, as incidences are not adjusted for an imbalance of treatment duration.

Table 1: Adverse reactions occurring at an incidence of ≥ 3% and more commonly than placebo in the SYMBICORT (budesonide and formoterol fumarate dihydrate) groups: pooled data from three 12-week, double-blind, placebo-controlled clinical asthma trials in patients 12 years and older

Treatment* SYMBICORT Budesonide Formoterol Placebo
Adverse Event 80/4.5 mcg
N = 277
%
160/4.5 mcg
N =124
%
80 mcg
N =121
%
160 mcg
N = 109
%
4.5 mcg
N = 237
%
N = 400
%
Nasopharyngitis 10.5 9.7 14.0 11.0 10.1 9.0
Headache 6.5 11.3 11.6 12.8 8.9 6.5
Upper respiratory tract infection 7.6 10.5 8.3 9.2 7.6 7.8
Pharyngolaryngeal pain 6.1 8.9 5.0 7.3 3.0 4.8
Sinusitis 5.8 4.8 5.8 2.8 6.3 4.8
Influenza 3.2 2.4 6.6 0.9 3.0 1.3
Back pain 3.2 1.6 2.5 5.5 2.1 0.8
Nasal congestion 2.5 3.2 2.5 3.7 1.3 1.0
Stomach discomfort 1.1 6.5 2.5 4.6 1.3 1.8
Vomiting 1.4 3.2 0.8 2.8 1.7 1.0
Oral Candidiasis 1.4 3.2 0 0 0 0.8
Average Duration of Exposure (days) 77.7 73.8 77.0 71.4 62.4 55.9
*All treatments were administered as two inhalations twice daily.

Long-term safety - asthma clinical trials in patients 12 years and older

Long-term safety studies in adolescent and adult patients 12 years of age and older, treated for up to 1 year at doses up to 1280/36 mcg/day (640/18 mcg twice daily), revealed neither clinically important changes in the incidence nor new types of adverse events emerging after longer periods of treatment. Similarly, no significant or unexpected patterns of abnormalities were observed for up to 1 year in safety measures including chemistry, hematology, ECG, Holter monitor, and HPA-axis assessments.

Clinical Trials Experience in Chronic Obstructive Pulmonary Disease

The incidence of common adverse events in Table 2 below is based upon pooled data from two double-blind, placebo-controlled clinical studies (6 and 12 months in duration) in which 771 adult COPD patients (496 males and 275 females) 40 years of age and older were treated with SYMBICORT (budesonide and formoterol fumarate dihydrate) 160/4.5, two inhalations twice daily. Of these patients 651 were treated for 6 months and 366 were treated for 12 months. The SYMBICORT (budesonide and formoterol fumarate dihydrate) group was composed of mostly Caucasian (93%) patients with a mean age of 63 years, and a mean percent predicted FEV1 at baseline of 33%. Control arms for comparison included two inhalations of budesonide HFA (MDI) 160 mcg, formoterol (DPI) 4.5 mcg or placebo (MDI and DPI) twice daily. Table 2 includes all adverse events that occurred at an incidence of ≥ 3% in the SYMBICORT (budesonide and formoterol fumarate dihydrate) group and more commonly than in the placebo group. In considering these data, the increased average duration of patient exposure to SYMBICORT (budesonide and formoterol fumarate dihydrate) should be taken into account, as incidences are not adjusted for an imbalance of treatment duration.

Table 2: Adverse reactions occurring at an incidence of ≥ 3% and more commonly than placebo in the SYMBICORT (budesonide and formoterol fumarate dihydrate) group: pooled data from two double-blind, placebo-controlled clinical COPD trials

Treatment* SYMBICORT Budesonide Formoterol Placebo
Adverse Event 160/4.5 mcg
N = 771
%
160 mcg
N = 275
%
4.5 mcg
N = 779
%
N = 781
%
Nasopharyngitis 7.3 3.3 5.8 4.9
Oral candidiasis 6.0 4.4 1.2 1.8
Bronchitis 5.4 4.7 4.5 3.5
Sinusitis 3.5 1.5 3.1 1.8
Upper respiratory tract infection viral 3.5 1.8 3.6 2.7
Average Duration of Exposure (days) 255.2 157.1 240.3 223.7
* All treatments were administered as two inhalations twice daily.

Lung infections other than pneumonia (mostly bronchitis) occurred in a greater percentage of subjects treated with SYMBICORT (budesonide and formoterol fumarate dihydrate) 160/4.5 compared with placebo (7.9% vs. 5.1%, respectively). There were no clinically important or unexpected patterns of abnormalities observed for up to 1 year in chemistry, haematology, ECG, ECG (Holter) monitoring, HPA-axis, bone mineral density and ophthalmology assessments.

Postmarketing Experience

The following adverse reactions have been reported during post-approval use of SYMBICORT (budesonide and formoterol fumarate dihydrate) . 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. Some of these adverse reactions may also have been observed in clinical studies with SYMBICORT (budesonide and formoterol fumarate dihydrate) .

Cardiac disorders: angina pectoris, tachycardia, atrial and ventricular tachyarrhythmias, atrial fibrillation, extrasystoles, palpitations

Endocrine disorders: hypercorticism, growth velocity reduction in pediatric patients

Eye disorders: cataract, glaucoma, increased intraocular pressure

Gastrointestinal disorders: oropharyngeal candidiasis, nausea

Immune system disorders: immediate and delayed hypersensitivity reactions, such as anaphylactic reaction, angioedema, bronchospasm, urticaria, exanthema, dermatitis, pruritus

Metabolic and nutrition disorders: hyperglycemia, hypokalemia

Musculoskeletal, connective tissue, and bone disorders: muscle cramps

Nervous system disorders: tremor, dizziness

Psychiatric disorders: behavior disturbances, sleep disturbances, nervousness, agitation, depression, restlessness

Respiratory, thoracic, and mediastinal disorders: dysphonia, cough, throat irritation

Skin and subcutaneous tissue disorders: skin bruising

Vascular disorders: hypotension, hypertension