fluticasone propionate and salmeterol
Generic: FLUTICASONE PROPIONATE AND SALMETEROL
Basic Information
Manufacturer
Preferred Pharmaceuticals Inc.
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
RESPIRATORY (INHALATION)
FDA Set ID
0dea4818-e9d6-42f2-a702-90419fff2695
Indications & Usage
1 INDICATIONS AND USAGE Fluticasone propionate and salmeterol inhalation powder is a combination product containing a corticosteroid and a long-acting beta 2 -adrenergic agonist (LABA) indicated for: • Twice-daily treatment of asthma in patients aged 4 years and older.
( 1.1 ) • Maintenance treatment of airflow obstruction and reducing exacerbations in patients with chronic obstructive pulmonary disease (COPD).
( 1.2 ) Important Limitation of Use: Not indicated for relief of acute bronchospasm.
( 1.1 , 1.2 ) 1.1 Treatment of Asthma Fluticasone propionate and salmeterol inhalation powder is indicated for the twice-daily treatment of asthma in patients aged 4 years and older.
Fluticasone propionate and salmeterol inhalation powder should be used for patients not adequately controlled on a long-term asthma control medication such as an inhaled corticosteroid (ICS) or whose disease warrants initiation of treatment with both an ICS and long-acting beta 2 -adrenergic agonist (LABA).
Important Limitation of Use Fluticasone propionate and salmeterol inhalation powder is NOT indicated for the relief of acute bronchospasm.
1.2 Maintenance Treatment of Chronic Obstructive Pulmonary Disease Fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg is indicated for the twice-daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.
Fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg is also indicated to reduce exacerbations of COPD in patients with a history of exacerbations.
Fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg twice daily is the only approved dosage for the treatment of COPD because an efficacy advantage of the higher strength fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg over fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg has not been demonstrated.
Important Limitation of Use Fluticasone propionate and salmeterol inhalation powder is NOT indicated for the relief of acute bronchospasm.
( 1.1 ) • Maintenance treatment of airflow obstruction and reducing exacerbations in patients with chronic obstructive pulmonary disease (COPD).
( 1.2 ) Important Limitation of Use: Not indicated for relief of acute bronchospasm.
( 1.1 , 1.2 ) 1.1 Treatment of Asthma Fluticasone propionate and salmeterol inhalation powder is indicated for the twice-daily treatment of asthma in patients aged 4 years and older.
Fluticasone propionate and salmeterol inhalation powder should be used for patients not adequately controlled on a long-term asthma control medication such as an inhaled corticosteroid (ICS) or whose disease warrants initiation of treatment with both an ICS and long-acting beta 2 -adrenergic agonist (LABA).
Important Limitation of Use Fluticasone propionate and salmeterol inhalation powder is NOT indicated for the relief of acute bronchospasm.
1.2 Maintenance Treatment of Chronic Obstructive Pulmonary Disease Fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg is indicated for the twice-daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.
Fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg is also indicated to reduce exacerbations of COPD in patients with a history of exacerbations.
Fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg twice daily is the only approved dosage for the treatment of COPD because an efficacy advantage of the higher strength fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg over fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg has not been demonstrated.
Important Limitation of Use Fluticasone propionate and salmeterol inhalation powder is NOT indicated for the relief of acute bronchospasm.
Adverse Reactions
6 ADVERSE REACTIONS Use of LABA may result in the following: • Serious asthma-related events – hospitalizations, intubations, death [see Warnings and Precautions ( 5.1 )] • Cardiovascular and central nervous system effects [see Warnings and Precautions ( 5.12 )] 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 )] • Reduction in bone mineral density [see Warnings and Precautions ( 5.13 )] • 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.
Most common adverse reactions (incidence greater than or equal to 3%) include: • Asthma: Upper respiratory tract infection or inflammation, pharyngitis, dysphonia, oral candidiasis, bronchitis, cough, headaches, nausea and vomiting.
( 6.1 ) • COPD: Pneumonia, oral candidiasis, throat irritation, dysphonia, viral respiratory infections, headaches, musculoskeletal pain.
( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc.
at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical Trials Experience in Asthma Adult and Adolescent Subjects Aged 12 Years and Older The incidence of adverse reactions associated with fluticasone propionate and salmeterol inhalation powder 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 ICS were treated twice daily with fluticasone propionate and salmeterol inhalation powder (100 mcg/50 mcg or 250 mcg/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 1: Adverse Reactions with Fluticasone Propionate and Salmeterol Inhalation Powder with ≥3% Incidence and More Common than Placebo in Adult and Adolescent Subjects with Asthma Adverse Event Fluticasone Propionate and Salmeterol Inhalation Powder 100 mcg/50 mcg (n = 92) % Fluticasone Propionate and Salmeterol Inhalation Powder 250 mcg/50 mcg (n = 84) % Fluticasone Propionate 100 mcg (n = 90) % Fluticasone Propionate 250 mcg (n = 84) % Salmeterol 50 mcg (n = 180) % Placebo (n = 175) % Ear, Nose, and 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 and Vomiting 4 6 3 4 1 1 Gastrointestinal Discomfort and 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 Trial 3, a 28-week, non-U.S.
clinical trial in 503 subjects previously treated with ICS who were treated twice daily with fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg, 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 fluticasone propionate and salmeterol inhalation powder 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 ICS at trial entry were randomized to either fluticasone propionate and salmeterol inhalation powder 100 mcg/50 mcg or fluticasone propionate inhalation powder 100 mcg twice daily.
Common adverse reactions (≥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 ≥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.
6.2 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 fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg 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 fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg, 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 fluticasone propionate and salmeterol inhalation powder reported an adverse reaction compared with 64% on placebo.
The average duration of exposure to fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg 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 2: Overall Adverse Reactions with Fluticasone Propionate and Salmeterol Inhalation Powder 250 mcg/50 mcg with ≥3% Incidence in Subjects with Chronic Obstructive Pulmonary Disease Associated with Chronic Bronchitis Adverse Event Fluticasone Propionate and Salmeterol Inhalation Powder 250 mcg/50 mcg (n = 178) % Fluticasone Propionate 250 mcg (n = 183) % Salmeterol 50 mcg (n = 177) % Placebo (n = 185) % Ear, Nose, and Throat Candidiasis - Mouth/Throat Throat Irritation Hoarseness/Dysphonia Sinusitis 10 8 5 3 6 5 3 8 3 4 <1 5 1 7 0 3 Lower Respiratory Viral Respiratory Infections 6 4 3 3 Neurology Headaches Dizziness 16 4 11 <1 10 3 12 2 Non-site Specific Fever Malaise and Fatigue 4 3 3 2 0 2 3 3 Musculoskeletal Musculoskeletal Pain Muscle Cramps and Spasms 9 3 8 3 12 1 9 1 In the two 1-year trials, fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg 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 fluticasone propionate and salmeterol inhalation powder and 86% of the subjects treated with salmeterol reported an adverse event.
The most common events that occurred with a frequency of >5% and more frequently in the subjects treated with fluticasone propionate and salmeterol inhalation powder 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 fluticasone propionate and salmeterol inhalation powder 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 fluticasone propionate and salmeterol inhalation powder compared with 4% in the subjects treated with fluticasone propionate and salmeterol inhalation powder younger than 65 years.
In the subjects 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 Years) Trial The safety of fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg 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 fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg.
In addition, pneumonia was reported in a significantly increased number of subjects treated with fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg 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 fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg, 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 fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg, the incidence of pneumonia was higher in subjects older than 65 years (18% with fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg versus 10% with placebo) compared with subjects younger than 65 years (14% with fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg 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 subjects with COPD treated with fluticasone propionate and salmeterol inhalation powder 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.
6.3 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 fluticasone propionate and salmeterol, 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 fluticasone propionate and salmeterol inhalation powder, 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.
Most common adverse reactions (incidence greater than or equal to 3%) include: • Asthma: Upper respiratory tract infection or inflammation, pharyngitis, dysphonia, oral candidiasis, bronchitis, cough, headaches, nausea and vomiting.
( 6.1 ) • COPD: Pneumonia, oral candidiasis, throat irritation, dysphonia, viral respiratory infections, headaches, musculoskeletal pain.
( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc.
at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical Trials Experience in Asthma Adult and Adolescent Subjects Aged 12 Years and Older The incidence of adverse reactions associated with fluticasone propionate and salmeterol inhalation powder 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 ICS were treated twice daily with fluticasone propionate and salmeterol inhalation powder (100 mcg/50 mcg or 250 mcg/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 1: Adverse Reactions with Fluticasone Propionate and Salmeterol Inhalation Powder with ≥3% Incidence and More Common than Placebo in Adult and Adolescent Subjects with Asthma Adverse Event Fluticasone Propionate and Salmeterol Inhalation Powder 100 mcg/50 mcg (n = 92) % Fluticasone Propionate and Salmeterol Inhalation Powder 250 mcg/50 mcg (n = 84) % Fluticasone Propionate 100 mcg (n = 90) % Fluticasone Propionate 250 mcg (n = 84) % Salmeterol 50 mcg (n = 180) % Placebo (n = 175) % Ear, Nose, and 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 and Vomiting 4 6 3 4 1 1 Gastrointestinal Discomfort and 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 Trial 3, a 28-week, non-U.S.
clinical trial in 503 subjects previously treated with ICS who were treated twice daily with fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg, 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 fluticasone propionate and salmeterol inhalation powder 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 ICS at trial entry were randomized to either fluticasone propionate and salmeterol inhalation powder 100 mcg/50 mcg or fluticasone propionate inhalation powder 100 mcg twice daily.
Common adverse reactions (≥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 ≥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.
6.2 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 fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg 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 fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg, 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 fluticasone propionate and salmeterol inhalation powder reported an adverse reaction compared with 64% on placebo.
The average duration of exposure to fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg 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 2: Overall Adverse Reactions with Fluticasone Propionate and Salmeterol Inhalation Powder 250 mcg/50 mcg with ≥3% Incidence in Subjects with Chronic Obstructive Pulmonary Disease Associated with Chronic Bronchitis Adverse Event Fluticasone Propionate and Salmeterol Inhalation Powder 250 mcg/50 mcg (n = 178) % Fluticasone Propionate 250 mcg (n = 183) % Salmeterol 50 mcg (n = 177) % Placebo (n = 185) % Ear, Nose, and Throat Candidiasis - Mouth/Throat Throat Irritation Hoarseness/Dysphonia Sinusitis 10 8 5 3 6 5 3 8 3 4 <1 5 1 7 0 3 Lower Respiratory Viral Respiratory Infections 6 4 3 3 Neurology Headaches Dizziness 16 4 11 <1 10 3 12 2 Non-site Specific Fever Malaise and Fatigue 4 3 3 2 0 2 3 3 Musculoskeletal Musculoskeletal Pain Muscle Cramps and Spasms 9 3 8 3 12 1 9 1 In the two 1-year trials, fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg 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 fluticasone propionate and salmeterol inhalation powder and 86% of the subjects treated with salmeterol reported an adverse event.
The most common events that occurred with a frequency of >5% and more frequently in the subjects treated with fluticasone propionate and salmeterol inhalation powder 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 fluticasone propionate and salmeterol inhalation powder 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 fluticasone propionate and salmeterol inhalation powder compared with 4% in the subjects treated with fluticasone propionate and salmeterol inhalation powder younger than 65 years.
In the subjects 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 Years) Trial The safety of fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg 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 fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg.
In addition, pneumonia was reported in a significantly increased number of subjects treated with fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg 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 fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg, 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 fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg, the incidence of pneumonia was higher in subjects older than 65 years (18% with fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg versus 10% with placebo) compared with subjects younger than 65 years (14% with fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg 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 subjects with COPD treated with fluticasone propionate and salmeterol inhalation powder 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.
6.3 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 fluticasone propionate and salmeterol, 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 fluticasone propionate and salmeterol inhalation powder, 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.