Salmeterol

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 effect

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 )

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 any part of the inhaler in water. 2.4 Dose Counter The Fluticasone Propionate/Salmeterol MDPI has a dose counter: The number 60 is displayed (prior to use). The dose counter will count down each time the mouthpiece is opened and closed [see Patient Counseling Information ( 17 )].

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 cen

7 DRUG INTERACTIONS Fluticasone Propionate/Salmeterol MDPI has been used concomitantly with other drugs, including short‑acting beta 2 ‑agonists, and intranasal corticosteroids, commonly used in patients with asthma without adverse drug reactions [see Clinical Pharmacology ( 12.2 )] . No formal drug interaction trials have been performed with Fluticasone Propionate/Salmeterol MDPI. Avoid strong cytochrome P450 3A4 inhibitors (e.g., ritonavir, ketoconazole): May increase risk of systemic corticosteroid and cardiovascular effects. ( 7.1 ) Monoamine oxidase inhibitors and tricyclic antidepressants: Use with extreme caution. May potentiate effect of salmeterol on vascular system. ( 7.2 ) Beta‑blockers: Use with caution. May block bronchodilatory effects of beta‑agonists and produce severe bronchospasm. ( 7.3 ) Diuretics: Use with caution. Electrocardiographic changes and/or hypokalemia associated with non‑potassium‑sparing diuretics may worsen with concomitant beta‑agonists. ( 7.4 ) 7.1 Inhibitors of Cytochrome P450 3A4 Fluticasone propionate and salmeterol, the individual components of this product, are substrates of CYP3A4. The use of strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with Fluticasone Propionate/Salmeterol MDPI is not recommended because increased systemic corticosteroid and increased cardiovascular adverse effects may occur. Ritonavir : Fluticasone Propionate: A drug interaction trial with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a strong CYP3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations [see Clinical Pharmacology (12.3)] . During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. Ketoconazole : Fluticasone Propionate: Coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in a 1.9‑fold increase in plasma fluticasone propionate exposure and a 45% decrease in plasma cortisol area under the curve (AUC) but had no effect on urinary excretion of cortisol. Salmeterol: In a drug interaction trial in 20 healthy subjects, coadministration of inhaled salmeterol (50 mcg twice daily) and oral ketoconazole (400 mg once daily) for 7 days resulted in greater systemic exposure to salmeterol (AUC increased 16‑fold and C max increased 1.4‑fold). Three (3) subjects were withdrawn due to beta 2 ‑agonist side effects (2 with prolonged QTc and 1 with palpitations and sinus tachycardia). Although there was no statistical effect on the mean QTc, coadministration of salmeterol and ketoconazole was associated with more frequent increases in QTc duration compared with salmeterol and placebo administration [see Clinical Pharmacology ( 12.3 )] . 7.2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants Fluticasone Propionate/Salmeterol MDPI should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of salmeterol, a component of this product, on the vascular system may be potentiated by these agents. 7.3 Beta-Adrenergic Receptor Blocking Agents Beta‑blockers not only block the pulmonary effect of beta‑agonists, such as salmeterol, a component of this product, but may also produce severe bronchospasm in patients with asthma. Therefore, patients with asthma should not normally be treated with beta‑blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta‑adrenergic blocking agents for these patients; cardioselective beta‑blockers could be considered, although they should be administered with caution. 7.4 Non-Potassium-Sparing Diuretics The ECG changes and/or hypokalemia that may result from the administration of non–potassium‑sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta‑agonists, such as salmeterol, a component of this product, especially when the recommended dose of the beta‑agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of Fluticasone Propionate/Salmeterol MDPI with non-potassium‑sparing diuretics.