Salmeterol

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 )

12.1 Mechanism of Action This product contains both fluticasone propionate and salmeterol. The mechanisms of action described below for the individual components apply to this combination product. These drugs represent 2 different classes of medications (a synthetic corticosteroid and a LABA) that have different effects on clinical, physiologic, and inflammatory indices. Fluticasone Propionate : Fluticasone propionate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. Fluticasone propionate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is 18 times that of dexamethasone, almost twice that of beclomethasone-17-monopropionate (BMP), the active metabolite of beclomethasone dipropionate, and over 3 times that of budesonide. Data from the McKenzie vasoconstrictor assay in humans are consistent with these results. The clinical significance of these findings is unknown. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation. These anti-inflammatory actions of corticosteroids contribute to their efficacy in the treatment of asthma. Salmeterol : Salmeterol is a selective LABA. In vitro studies show salmeterol to be at least 50 times more selective for beta 2 ‑adrenoceptors than albuterol. Although beta 2 ‑adrenoceptors are the predominant adrenergic receptors in bronchial smooth muscle and beta 1 ‑adrenoceptors are the predominant receptors in the heart, there are also beta 2 ‑adrenoceptors in the human heart comprising 10% to 50% of the total beta‑adrenoceptors. The precise function of these receptors has not been established, but their presence raises the possibility that even selective beta 2 ‑agonists may have cardiac effects. The pharmacologic effects of beta 2 ‑adrenoceptor agonist drugs, including salmeterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3′,5′-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells. In vitro tests show that salmeterol is a potent and long‑lasting inhibitor of the release of mast cell mediators, such as histamine, leukotrienes, and prostaglandin D 2 , from human lung. Salmeterol inhibits histamine‑induced plasma protein extravasation and inhibits platelet‑activating factor‑induced eosinophil accumulation in the lungs of guinea pigs when administered by the inhaled route. In humans, single doses of salmeterol administered via inhalation aerosol attenuate allergen‑induced bronchial hyperresponsiv

2 DOSAGE AND ADMINISTRATION For oral inhalation only. ( 2.1 ) Starting dosage is based on prior asthma therapy and disease severity. ( 2.2 ) 1 inhalation of Fluticasone Propionate/Salmeterol 55 mcg/14 mcg, 113 mcg/14 mcg, or 232 mcg/14 mcg twice daily. ( 2.2 ) Do not use with a spacer or volume holding chamber. ( 2.2 ) 2.1 Administration Instructions Fluticasone Propionate/Salmeterol MDPI is for oral inhalation and does not require priming. Do not use Fluticasone Propionate/Salmeterol MDPI with a spacer or volume holding chamber. Do not use more than two times every 24 hours. More frequent administration or a greater number of daily inhalations (more than one inhalation twice daily) is not recommended as some patients are more likely to experience adverse reactions with higher salmeterol dosages. Avoid the concomitant use of other long acting beta 2 -adrenergic agonist (LABAs) [see Warnings and Precautions ( 5.3 , 5.11 )]. If asthma symptoms arise in the period between doses, an inhaled, short-acting beta 2 -agonist should be taken for immediate relief. 2.2 Recommended Dosage Administer 1 inhalation of Fluticasone Propionate/Salmeterol MDPI twice daily by oral inhalation (approximately 12 hours apart at the same time every day). Rinse the mouth with water without swallowing after each inhalation. Dosage Selection The recommended starting dosage for Fluticasone Propionate/Salmeterol MDPI is based on asthma severity and current inhaled corticosteroid use and strength. Patients not taking inhaled corticosteroids (ICS) (with less severe asthma): 1 inhalation of 55 mcg/14 mcg Fluticasone Propionate/Salmeterol MDPI dose strength (55 mcg of fluticasone propionate and 14 mcg of salmeterol), twice daily by oral inhalation. Patients with greater asthma severity, use the higher dose strengths: 1 inhalation of 113 mcg/14 mcg Fluticasone Propionate/Salmeterol MDPI (113 mcg of fluticasone propionate and 14 mcg of salmeterol) twice daily; or 1 inhalation of 232 mcg/14 mcg Fluticasone Propionate/Salmeterol MDPI (232 mcg of fluticasone propionate and 14 mcg of salmeterol) twice daily Patients switching to Fluticasone Propionate/Salmeterol MDPI from another inhaled corticosteroid or combination product: 1 inhalation of low (55 mcg/14 mcg), medium (113 mcg/14 mcg) or high (232 mcg/14 mcg) Fluticasone Propionate/Salmeterol MDPI twice daily by oral inhalation based on the strength of the previous inhaled corticosteroid product, or the strength of the inhaled corticosteroid from a combination product, and disease severity. The maximum recommended dosage of Fluticasone Propionate/Salmeterol MDPI is 232 mcg/14 mcg twice daily. General Dosing Information Improvement in asthma control following Fluticasone Propionate/Salmeterol MDPI administration can occur within 15 minutes of beginning treatment; although maximum benefit may not be achieved for 1 week or longer after starting treatment. Individual patients will experience a variable time to onset and degree of symptom relief. For patients who do not respond adequately to the starting dose of Fluticasone Propionate/Salmeterol MDPI after 2 weeks of therapy, consider increasing the strength (replace with higher strength) to possibly provide additional improvement in asthma control. If a previously effective dosage regimen fails to provide adequate improvement in asthma control, re-evaluate the therapeutic regimen, including patient compliance and inhaler technique, and consider additional therapeutic options (e.g., increasing the dose of Fluticasone Propionate/Salmeterol MDPI with a higher strength, adding additional controller therapies). After asthma stability has been achieved, it is desirable to titrate to the lowest effective dosage to reduce the risk of adverse reactions. 2.3 Storing and Cleaning the Inhaler Keep the inhaler in a cool dry place. Routine maintenance is not required. If the mouthpiece needs cleaning, gently wipe the mouthpiece with a dry cloth or tissue as needed. Never wash or put

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 rep

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-relat

4 CONTRAINDICATIONS Fluticasone Propionate/Salmeterol MDPI is contraindicated in: the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required [see Warnings and Precautions ( 5.2 )] . patients with known severe hypersensitivity to milk proteins or who have demonstrated hypersensitivity to fluticasone propionate or any of the excipients [see Warnings and Precautions ( 5.10 ) and Description ( 11 )] . Primary treatment of status asthmaticus or acute episodes of asthma requiring intensive measures. ( 4 ) Severe hypersensitivity to milk proteins or any ingredients of Fluticasone Propionate/Salmeterol MDPI. ( 4 )

10 OVERDOSAGE This product contains both fluticasone propionate and salmeterol; therefore, the risks associated with overdosage for the individual components described below apply to Fluticasone Propionate/Salmeterol MDPI. Treatment of overdosage consists of discontinuation of Fluticasone Propionate/Salmeterol MDPI together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta‑receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. Cardiac monitoring is recommended in cases of overdosage. Fluticasone propionate Chronic overdosage of fluticasone propionate may result in signs/symptoms of hypercorticism [see Warnings and Precautions ( 5.7 )] . Salmeterol The expected signs and symptoms with overdosage of salmeterol are those of excessive beta‑adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms of beta‑adrenergic stimulation (e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, hypokalemia, metabolic acidosis). Overdosage with salmeterol can lead to clinically significant prolongation of the QTc interval, which can produce ventricular arrhythmias. As with all inhaled sympathomimetic medicines, cardiac arrest and even death may be associated with an overdose of salmeterol.