Salmeterol
Beta-2 adrenergic agonist (bronchodilator)
What it is used for
1 INDICATIONS AND USAGE Fluticasone Propionate/Salmeterol Multidose Dry Powder Inhaler (FS MDPI) is indicated for the treatment of asthma in adult and pediatric patients aged 12 years and older. Fluticasone Propionate/Salmeterol MDPI should be used for patients not adequately controlled on a long term asthma control medication such as an inhaled corticosteroid or whose disease warrants initiation of treatment with both an inhaled corticosteroid and long acting beta 2 -adrenergic agonist (LABA). Limitations of Use : Fluticasone Propionate/Salmeterol MDPI is not indicated for the relief of acute bronchospasm. Fluticasone Propionate/Salmeterol Multi-Dose Dry Powder Inhaler (MDPI) is a combination of fluticasone propionate, a corticosteroid, and salmeterol, a long-acting beta 2 -adrenergic agonist (LABA), indicated for treatment of asthma in adult and pediatric patients aged 12 years and older. Fluticasone Propionate/Salmeterol inhalation powder should be used for patients not adequately controlled on a long term asthma control medication such as an inhaled corticosteroid or whose disease warrants initiation of treatment with both an inhaled corticosteroid and long acting beta 2 -adrenergic agonist (LABA). ( 1 ) Limitations of Use : Not indicated for the relief of acute bronchospasm. ( 1 )
Warnings
5 WARNINGS AND PRECAUTIONS LABA monotherapy increases the risk of serious asthma-related events. ( 5.1 ) Deterioration of asthma and acute episodes: Do not use for relief of acute symptoms. Patients require immediate re-evaluation during rapidly deteriorating asthma. ( 5.2 ) Do not use in combination with an additional medicine containing LABA because of risk of overdose. ( 5.3 ) Localized infections: Candida albicans infection of the mouth and pharynx may occur. Monitor patients periodically. Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk. ( 5.4 ) Immunosuppression: Potential worsening of existing tuberculosis, fungal, bacterial, viral, parasitic infection, or ocular herpes simplex. Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. ( 5.5 ) Transferring patients from systemic corticosteroids: Risk of impaired adrenal function when transferring from systemic corticosteroids. Taper patients slowly from systemic corticosteroids if transferring to Fluticasone Propionate/Salmeterol. ( 5.6 ) Hypercorticism and adrenal suppression: May occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue Fluticasone Propionate/Salmeterol slowly. ( 5.7 ) Paradoxical bronchospasm: Discontinue Fluticasone Propionate/Salmeterol and institute alternative therapy if paradoxical bronchospasm occurs. ( 5.9 ) Use with caution in patients with cardiovascular or central nervous system disorders because of beta adrenergic stimulation. ( 5.11 ) Decreases in bone mineral density: Monitor patients with major risk factors for decreased bone mineral content. ( 5.12 ) Monitor growth of pediatric patients. ( 5.13 ) Close monitoring for glaucoma and cataracts is warranted. ( 5.14 ) Be alert to eosinophilic conditions, hypokalemia, and hyperglycemia. ( 5.15 , 5.17 ) Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. ( 5.16 ) 5.1 Serious Asthma-Related Events – Hospitalizations, Intubations, Death Use of LABA as monotherapy [without inhaled corticosteroids (ICS)] for asthma is associated with an increased risk of asthma-related death [see Salmeterol Multicenter Asthma Research Trial (SMART)] . Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients. These findings are considered a class effect of LABA monotherapy. When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone [see Serious Asthma-Related Events with Inhaled Corticosteroid/Long-acting Beta 2 -adrenergic Agonists] . Serious Asthma-Related Events with Inhaled Corticosteroid/Long-acting Beta 2 -adrenergic Agonists Four large, 26-week, randomized, blinded, active-controlled clinical safety trials were conducted to evaluate the risk of serious asthma-related events when LABA were used in fixed-dose combination with ICS compared with ICS alone in subjects with asthma. Three (3) trials included adult and adolescent subjects aged 12 years and older: 1 trial compared budesonide/formoterol to budesonide, 1 trial compared fluticasone propionate/salmeterol inhalation powder to fluticasone propionate inhalation powder, and 1 trial compared mometasone furoate/formoterol to mometasone furoate. The fourth trial included pediatric subjects aged 4 to 11 years and compared fluticasone propionate/salmeterol inhalation powder to fluticasone propionate inhalation powder. The primary safety endpoint for all 4 trials was serious asthma-related events (hospitalizations, intubations, death). A blinded adjudication committee determined whether events were asthma-related. The 3 adult and adolescent trials were designed to rule out a risk margin of 2.0, and the pediatric trial was designed to rule out a risk margin of 2.7. Each individual trial met its pre-specified objective and demonstrated non-inferiority of ICS/LABA to ICS alone. A meta-analysis of the 3 adult and adolescent trials did not show a significant increase in risk of a serious asthma-related event with ICS/LABA fixed-dose combination compared with ICS alone (Table 1). These trials were not designed to rule out all risk for serious asthma-related events with ICS/LABA compared with ICS. Table 1. Meta-analysis of Serious Asthma-Related Events in Subjects with Asthma Aged 12 Years and Older ICS/LABA (n =17,537) a ICS (n = 17,552) a ICS/LABA vs. ICS Hazard Ratio (95% CI) b Serious asthma-related event c 116 105 1.10 (0.85, 1.44) Asthma-related death 2 0 Asthma-related intubation (endotracheal) 1 2 Asthma-related hospitalization (≥24-hour stay) 115 105 ICS = Inhaled Corticosteroid; LABA = Long-acting Beta 2 -adrenergic Agonist. a Randomized subjects who had taken at least 1 dose of study drug. Planned treatment used for analysis. b Estimated using a Cox proportional hazards model for time to first event with baseline hazards stratified by each of the 3 trials. c Number of subjects with events that occurred within 6 months after the first use of study drug or 7 days after the last date of study drug, whichever date was later. Subjects can have one or more events, but only the first event was counted for analysis. A single, blinded, independent adjudication committee determined whether events were asthma related. The pediatric safety trial included 6,208 pediatric patients aged 4 to 11 years who received ICS/LABA (fluticasone propionate/salmeterol inhalation powder) or ICS (fluticasone propionate inhalation powder). In this trial 27/3,107 (0.9%) of patients treated with ICS/LABA and 21/3,101 (0.7%) of patients treated with ICS experienced a serious asthma‑related event. There were no asthma-related deaths or intubations. ICS/LABA did not show a significantly increased risk of a serious asthma-related event compared to ICS based on the prespecified risk margin (2.7), with an estimated hazard ratio of time to first event of 1.29 (95% CI: 0.73, 2.27). Salmeterol Multicenter Asthma Research Trial (SMART) A 28-week, placebo-controlled, U.S. trial that compared the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol versus 3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). Use of background ICS was not required in SMART. The increased risk of asthma‑related death is considered a class effect of LABA monotherapy. 5.2 Deterioration of Disease and Acute Episodes Fluticasone Propionate/Salmeterol MDPI should not be initiated in patients during rapidly deteriorating or potentially life‑threatening episodes of asthma. Fluticasone Propionate/Salmeterol MDPI has not been studied in subjects with acutely deteriorating asthma. The initiation of Fluticasone Propionate/Salmeterol MDPI in this setting is not appropriate. Serious acute respiratory events, including fatalities, have been reported when salmeterol, a component of this product, has been initiated in patients with significantly worsening or acutely deteriorating asthma. In most cases, these have occurred in patients with severe asthma (e.g., patients with a history of corticosteroid dependence, low pulmonary function, intubation, mechanical ventilation, frequent hospitalizations, previous life‑threatening acute asthma exacerbations) and in some patients with acutely deteriorating asthma (e.g., patients with significantly increasing symptoms; increasing need for inhaled, short‑acting beta 2 ‑agonists; decreasing response to usual medications; increasing need for systemic corticosteroids; recent emergency room visits; deteriorating lung function). However, these events have occurred in a few patients with less severe asthma as well. It was not possible from these reports to determine whether salmeterol contributed to these events. Increasing use of inhaled, short‑acting beta 2 ‑agonists is a marker of deteriorating asthma. In this situation, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the possible need for replacing the current strength of Fluticasone Propionate/Salmeterol MDPI with a higher strength, adding additional inhaled corticosteroid, or initiating systemic corticosteroids. Patients should not use more than 1 inhalation twice daily of Fluticasone Propionate/Salmeterol MDPI. Fluticasone Propionate/Salmeterol MDPI should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short‑acting beta 2 ‑agonist, not Fluticasone Propionate/Salmeterol MDPI, should be used to relieve acute symptoms such as shortness of breath. When prescribing Fluticasone Propionate/Salmeterol MDPI, the healthcare provider should also prescribe an inhaled, short‑acting beta 2 -agonist (e.g., albuterol) for treatment of acute symptoms, despite regular twice‑daily use of Fluticasone Propionate/Salmeterol MDPI. When beginning treatment with Fluticasone Propionate/Salmeterol MDPI, patients who have been taking oral or inhaled, short‑acting beta 2 ‑agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs. 5.3 Avoid Excessive Use of Fluticasone Propionate/Salmeterol and Avoid Use with Other Long-Acting Beta 2 -Agonists Fluticasone Propionate/Salmeterol MDPI should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using Fluticasone Propionate/Salmeterol MDPI should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason. 5.4 Oropharyngeal Candidiasis In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with Fluticasone Propionate/Salmeterol MDPI. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with Fluticasone Propionate/Salmeterol MDPI continues, but at times therapy with Fluticasone Propionate/Salmeterol MDPI may need to be interrupted. Advise the patient to rinse his/her mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis. 5.5 Immunosuppression and Risk of Infections Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible adolescents or adults using corticosteroids. In such patients who have not had these diseases or who have not been properly immunized, particular care should be taken to avoid exposure. How the dose, route and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella-zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment
Possible side effects
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Serious asthma-related events – hospitalizations, intubations, death [see Warnings and Precautions ( 5.1 )] Oropharyngeal candidiasis [see Warnings and Precautions ( 5.4 )] Immunosuppression and risk of infections [see Warnings and Precautions ( 5.5 )] Hypercorticism and adrenal suppression [see Warnings and Precautions ( 5.7 )] Cardiovascular and central nervous system effects [see Warnings and Precautions ( 5.11 )] Reduction in bone mineral density [see Warnings and Precautions ( 5.12 )] Growth effects in pediatrics [see Warnings and Precautions ( 5.13 )] Glaucoma and cataracts [see Warnings and Precautions ( 5.14 )] Most common adverse reactions (greater than or equal to 3%): nasopharyngitis, oral candidiasis, headache, cough and back pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals at 1-888-483-8279 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience in Asthma 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. In two placebo-controlled, 12-week, clinical studies (Trials 1 and 2) [see Clinical Studies ( 14 )] , a total of 1,364 adolescent and adult patients with persistent symptomatic asthma despite ICS or ICS/LABA therapy were treated twice daily with either placebo; fluticasone propionate MDPI 55 mcg, 113 mcg, 232 mcg; or fluticasone propionate/salmeterol MDPI 55 mcg/14 mcg, 113 mcg/14 mcg, 232 mcg/14 mcg. Sixty percent of patients were female and 80% of patients were white. The average duration of exposure was 82 to 84 days in the fluticasone propionate MDPI and fluticasone propionate/salmeterol MDPI treatment groups compared with 75 days in the placebo group. Table 2 displays the incidence of most common adverse reactions in pooled Trials 1 and 2. Table 2: Adverse Reactions with ≥3% Incidence with Fluticasone Propionate/Salmeterol MDPI, and More Common than Placebo in Subjects with Asthma (Trials 1 and 2) Adverse Reaction Fluticasone Propionate MDPI 55 mcg(n=129)% Fluticasone Propionate MDPI 113 mcg(n=274)% Fluticasone Propionate MDPI 232 mcg(n=146)% Fluticasone Propionate /Salmeterol MDPI 55 mcg/14 mcg(n=128)% Fluticasone Propionate /Salmeterol MDPI 113 mcg/14 mcg(n=269)% Fluticasone Propionate /Salmeterol MDPI232 mcg/14 mcg (n=145)% Placebo(n=273)% Nasopharyngitis 5.4 5.8 4.8 8.6 4.8 6.9 4.4 Oral candidiasis* 3.1 2.9 4.8 1.6 2.2 3.4 0.7 Headache 1.6 7.3 4.8 5.5 4.8 2.8 4.4 Cough 1.6 1.8 3.4 2.3 3.7 0.7 2.6 Back pain 0 1.5 1.4 3.1 0.7 0 1.8 *Oral candidiasis includes oropharyngeal candidiasis, oral fungal infection, and oropharyngitis fungal Other adverse reactions not previously listed (and occurring in <3% of patients and in three or more patients on Fluticasone Propionate/Salmeterol MDPI) that were reported more frequently by patients with asthma treated with Fluticasone Propionate/Salmeterol MDPI compared with patients treated with placebo include the following: Sinusitis, oropharyngeal pain, pharyngitis, dizziness, influenza, rhinitis allergic, respiratory tract infection, rhinitis, nasal congestion, abdominal pain upper, myalgia, pain in extremity, dyspepsia, laceration, dermatitis contact, and palpitations. Long Term Safety Study: This was a 26-week, open labeled study of 674 patients previously treated with ICS who were treated twice daily with fluticasone propionate MDPI 113 mcg or 232 mcg; fluticasone propionate/salmeterol MDPI 113 mcg/14 mcg or 232 mcg/14 mcg; fluticasone propionate inhalation aerosol 110 mcg or 220 mcg; fluticasone propionate and salmeterol inhalation powder (250 mcg/50 mcg), or fluticasone propionate and salmeterol inhalation powder (500 mcg/50 mcg). The types of adverse reactions were similar to those reported above in placebo controlled studies. 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during post approval use of 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/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, blurred vision and central serous chorioretinopathy. 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.
Storage
16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Fluticasone Propionate/Salmeterol MDPI inhalation powder: a multidose, dry-powder inhaler (MDPI) each inhaler is white, has a yellow cap and is packaged individually in a foil pouch with a dessicant, each pouch is packed in a carton each inhaler contains 0.45 grams of the formulation and provides 60 actuations STRENGTH NDC CODE Fluticasone Propionate/Salmeterol 55 mcg/14 mcg (low) 63629-8811-1 Storage and Handling Store at room temperature (between 15ºC and 25ºC; 59ºF and 77ºF) in a dry place; excursions permitted from 59º F to 86º F (15ºC to 30ºC). Avoid exposure to extreme heat, cold, or humidity. Store Fluticasone Propionate/Salmeterol MDPI inside the unopened moisture‑protective foil pouch until initial use. Discard the product 30 days after opening the foil pouch or when the counter reads 0, whichever comes first. The inhaler is not reusable. Do not attempt to take the inhaler apart. Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504
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