Fluticasone Propionate and 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 )

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 …

3 DOSAGE FORMS AND STRENGTHS Inhalation powder: an inhalation-driven, multidose, dry powder inhaler (MDPI) for oral inhalation that meters 55 mcg, 113 mcg, or 232 mcg of fluticasone propionate with 14 mcg of salmeterol from the device reservoir and delivers 49 mcg, 100 mcg, or 202 mcg of fluticasone propionate with 12.75 mcg of salmeterol, respectively, from the mouthpiece per actuation. The Fluticasone Propionate/Salmeterol MDPI is a white inhaler with a yellow cap, and is provided in a sealed foil pouch with desiccant [see How Supplied/Storage and Handling ( 16 )] . Inhalation powder: 55 mcg/14 mcg, 113 mcg/14 mcg, or 232 mcg/14 mcg of fluticasone propionate/salmeterol in each actuation ( 3 ).

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 )

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 …

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 c …

8 USE IN SPECIFIC POPULATIONS Hepatic impairment: Monitor for systemic corticosteroid effects. ( 8.6 ) 8.1 Pregnancy Risk Summary There are no randomized clinical studies of fluticasone propionate/salmeterol MDPI or individual monoproducts, fluticasone propionate and salmeterol, in pregnant women. There are clinical considerations with the use of Fluticasone Propionate/Salmeterol MDPI in pregnant women [see Clinical Considerations] . Animal reproduction studies are available with the combination of fluticasone propionate and salmeterol as well as individual components. In animals, teratogenicity characteristic of corticosteroids, decreased fetal body weight and/or skeletal variations, in rats, mice, and rabbits were observed with subcutaneously administered maternal toxic doses of fluticasone propionate less than the maximum recommended human daily inhaled dose (MRHDID) on a mcg/m 2 basis [see Data] . However, fluticasone propionate administered via inhalation to rats decreased fetal body weight, but did not induce teratogenicity at a maternal toxic dose less than the MRHDID on a mcg/m 2 basis [see Data] . Experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. Oral administration of salmeterol to pregnant rabbits caused teratogenicity characteristic of beta-adrenoceptor stimulation at maternal doses approximately 700 times the MRHDID on a mcg/m 2 basis. These adverse effects generally occurred at large multiples of the MRHDID when salmeterol was administered by the oral route to achieve high systemic exposures. No such effects occurred at an oral salmeterol dose approximately 420 times the MRHDID [see Data] . The estimated risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease‐Associated Maternal and/or Embryo/Fetal Risk In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal adverse outcomes such as preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control. Data Animal Data Fluticasone Propionate and Salmeterol: In an embryo/fetal development study with pregnant rats that received the combination of subcutaneous administration of fluticasone propionate and oral administration of salmeterol at doses of 0/1000, 30/0, 10/100, 30/1000, and 100/10,000 mcg/kg/day (as fluticasone propionate/salmeterol) during the period of organogenesis, findings were generally consistent with the individual monoproducts and there was no exacerbation of expected fetal effects. Omphalocele, increased embryo/fetal deaths, decreased body weight, and skeletal variations were observed in rat fetuses, in the presence of maternal toxicity, when combining fluticasone propionate at a dose approximately 2 times the MRHDID (on a mcg/m 2 basis at a maternal subcutaneous dose of 100 mcg/kg/day) and a dose of salmeterol at approximately 3500 times the MRHDID (on a mcg/m 2 basis at a maternal oral dose of 10,000 mcg/kg/day). The rat no observed adverse effect level (NOAEL) was observed when combining fluticasone propionate at a dose 0.6 times the MRHDID (on a mcg/m 2 basis at a maternal subcutaneous dose of 30 mcg/kg/day) and a dose of salmeterol at approximately 350 times the MRHDID (on a mcg/m 2 basis at a maternal oral dose of 1000 mcg/kg/day). In an embryo/fetal development study with pregnant mice that received the combination of subcutaneous administration of fluticasone propionate and oral administration of salmeterol at doses of 0/1400, 40/0, 10/200, 40/1400, or 150/10,000 mcg/kg/day (as fluticasone propionate/salmeterol) during the per …

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 hyperresponsiveness.

11 DESCRIPTION Fluticasone Propionate/Salmeterol MDPI 55 mcg/14 mcg, 113 mcg/14 mcg and 232 mcg/14 mcg are combinations of fluticasone propionate and salmeterol. Fluticasone Propionate One active component of this product is fluticasone propionate, a corticosteroid having the chemical name S -(fluoromethyl) 6α,9-difluoro-11ß,17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17ß-carbothioate, 17-propionate, and the following chemical structure: Fluticasone propionate is a white powder with a molecular weight of 500.6, and the empirical formula is C 25 H 31 F 3 O 5 S. It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol. Salmeterol Xinafoate The other active component of this product is salmeterol xinafoate, a beta 2 –adrenergic bronchodilator. Salmeterol xinafoate is the racemic form of the 1‐hydroxy‐2‐naphthoic acid salt of salmeterol. It has the chemical name 4-hydroxy-α -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol, 1-hydroxy-2-naphthalenecarboxylate and the following chemical structure: Salmeterol xinafoate is a white powder with a molecular weight of 603.8, and the empirical formula is C 25 H 37 NO 4 •C 11 H 8 O 3 . It is freely soluble in methanol; slightly soluble in ethanol, chloroform, and isopropanol; and sparingly soluble in water. Fluticasone Propionate/Salmeterol MDPI Fluticasone Propionate/Salmeterol MDPI is a multidose dry powder inhaler (MDPI) for oral inhalation only. It contains fluticasone propionate, salmeterol xinafoate, and lactose monohydrate (which may contain milk proteins). The opening of the mouthpiece cover meters 5.5 mg of the formulation from the device reservoir, which contains 55 mcg, 113 mcg, or 232 mcg of fluticasone propionate, and 14 mcg of salmeterol base (equivalent to 20.3 mcg of salmeterol xinafoate). Patient inhalation through the mouthpiece causes the deagglomeration and aerosolization of the drug particles as the formulation moves through the cyclone component of the device. This is followed by dispersion into the airstream. Under standardized in vitro test conditions, the Fluticasone Propionate/Salmeterol MDPI delivers 49 mcg, 100 mcg, or 202 mcg of fluticasone propionate and 12.75 mcg of salmeterol base (equivalent to 18.5 mcg of salmeterol xinafoate), with lactose from the mouthpiece when tested at a flow rate of 85 L/min for 1.4 seconds. The amount of drug delivered to the lung will depend on patient factors such as inspiratory flow profiles. In adult subjects (N=50, aged 18 to 45 years) with asthma, mean peak inspiratory flow (PIF) through the Fluticasone Propionate/Salmeterol MDPI was 108.28 L/min (range: 70.37 to 129.24 L/min). In adolescent subjects (N=50, aged 12 to 17 years) with asthma, mean peak inspiratory flow (PIF) through the Fluticasone Propionate/Salmeterol MDPI was 106.72 L/min (range: 73.64 to 125.51 L/min). FP chem structure Salmeterol chem structure

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.

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 113 mcg/14 mcg (medium) 63629-8809-1 Each Fluticasone Propionate/Salmeterol MDPI has a dose counter attached to the actuator. Patients should never try to alter the numbers for the dose counter. Discard the inhaler when the counter displays 0, 30 days after opening the foil pouch or after the expiration date on the product, whichever comes first. The labeled amount of medication in each actuation cannot be assured after the counter displays 0, even though the inhaler is not completely empty and will continue to operate [see Patient Counseling Information (17)]. 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